Pyrrole derivates for treating cytokine mediated diseases

专利摘要:
Compounds of formula (I) have excellent activity against the production of inflammatory cytokines, wherein A is a pyrrole ring; R 1 is an optionally substituted aryl or heteroaryl group; R 2 is an optionally substituted nitrogen-containing heteroaryl group; And R 3 is formula (IIa), (IIb) or (IIc) wherein m is 1 or 2, one of D and E is nitrogen, and the other is> C (R 5 ) — (wherein R 5 is hydrogen Is a substituent group α or a substituent group β), B is a nitrogen-containing 4- to 7-membered heterocyclic ring, R 4 is 1 to 3 substituents from the substituent group α, the substituent group β and the substituent group γ ; Provided that R 1 and R 3 are bonded to two atoms of the pyrrole ring adjacent to the atom of the pyrrole ring to which R 2 is bonded; Substituent groups α are hydroxyl, nitro, cyano, halogen, alkoxy, halogeno alkoxy, alkylthio and halogeno alkylthio groups, and the formulas NR a R b wherein R a and R b are hydrogen, alkyl, al Kenyl, alkynyl, aralkyl and alkylsulfonyl, or R a and R b together with the nitrogen atom to which they are attached form a heterocyclyl group; Substituent group β consists of optionally substituted alkyl, alkenyl and alkynyl groups, and aralkyl and cycloalkyl groups; Substituent group γ consists of oxo, hydroxyimino, alkoxyimino, alkylene, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, optionally substituted aryl, optionally substituted aryloxy, alkylidedenyl and aralkylidedenyl groups] .
公开号:KR20030076619A
申请号:KR10-2003-7009619
申请日:2002-01-22
公开日:2003-09-26
发明作者:도미오 기무라；노부유끼 오까와；아끼라 나까오；다까요시 나가사끼；다까노리 야마자끼
申请人:상꾜 가부시키가이샤；
IPC主号:

专利说明:

Pyrrole derivatives for the treatment of cytokine mediated diseases {PYRROLE DERIVATES FOR TREATING CYTOKINE MEDIATED DISEASES}
[2] Nonsteroidal anti-inflammatory drugs (NSAIDs), as their main pharmaceutical action, have antipyretic, soothing, and anti-inflammatory actions based on their ability to inhibit prostaglandin (PG) biosynthesis through inhibition of cyclooxygenase action. It has been widely used for the prevention and treatment of various inflammatory diseases and for pain relief. Other classes of compounds commonly used in the treatment of rheumatoid arthritis include disease-adapted antirheumatic drugs (DMARDs), examples of which include methotrexate and sulfasalazine. This is a broad class of drugs in which the compounds do not have a common mechanism of action. For the treatment of chronic rheumatism, NSAIDs are used against disease and DMARDs are used against etiology. There are many problems associated with this class of drugs. Existing NSAIDs can induce undesirable side effects including gastrointestinal disorders such as gastric ulcer and kidney disorders, causing difficulties for any patients who have to take these drugs for long periods of time. DMARDs can also induce undesirable side effects, including nausea and diarrhea, and they still do not seem to show a stable and long lasting effect.
[3] Recently, a class of active ingredients, commonly called cytokines, produced in the body by immune cells has been discovered. One group of cytokines is known as inflammatory cytokines, which include interleukin (IL) -1, IL-6 and IL-8 and tumor necrosis factor (TNF). Inflammatory cytokines have been demonstrated to play an important role in numerous biological processes. These include acting as inflammatory mediators through stimulation of arachidonic acid metabolic pathways resulting in PG production, white blood cell migration, acute phase protein production, and activation of osteoclasts.
[4] Inflammatory cytokines are thought to be associated with many diseases including inflammatory diseases and induction of bone resorption. Due to their mechanism of action different from existing drugs such as those described above, compounds that can inhibit the production of inflammatory cytokines include improved new generations of antipyretic, analgesic and anti-inflammatory drugs, and autoimmune diseases such as chronic rheumatism, It is expected to provide a medicament for the treatment of bone diseases such as osteoporosis and many other diseases believed to be involved in the inflammatory cytokines described above.
[5] Compounds which are said to exhibit an inhibitory action on the production of inflammatory cytokines include various heteroaryl compounds (see, eg, WO 96/21452, WO 97/5877, WO 97/23479 and WO 00/31063). . Examples of compounds of this type include:
[6]
[7] There is still a need for compounds with improved action, pharmacokinetics and safety, and that is what is referred to by the present invention. Compounds having bicyclic amino groups characteristic of the compounds of the present invention are neither disclosed nor proposed in the prior art.
[8] Summary of the Invention
[9] It is therefore an object of the present invention to inhibit the production of inflammatory cytokines, resulting in antipyretic, analgesic, antiviral and anti-inflammatory effects, involving autoimmune such as chronic rheumatism, bone diseases such as osteoporosis and inflammatory cytokines mentioned above To provide a series of novel pyrrole derivatives with novel bicyclic amino substituents that have utility in the treatment and prevention of many other diseases.
[10] Other objects and advantages of the invention will become apparent as the invention is described.
[11] Compounds of the invention are compounds of formula I and pharmaceutically acceptable salts, esters or other derivatives thereof:
[12]
[13] Wherein A represents a pyrrole ring;
[14] R ¹ is an aryl group defined below which may be optionally substituted with one or more substituents selected from substituent group α and substituent group β defined below, and
[15] A heteroaryl group defined below which may be optionally substituted with one or more substituents selected from the substituent group α defined below and the substituent group β defined below;
[16] R ² represents a heteroaryl group defined below having one or more ring nitrogen atoms, said heteroaryl group optionally substituted with one or more substituents selected from the substituent group α and the substituent group β defined below;
[17] R ³ represents a group of formula (IIa), (IIb) or (IIc) shown below:
[18]
[19]
[20]
[21] [Wherein m represents 1 or 2,
[22] One of D and E represents a nitrogen atom, and the other is selected from the group consisting of the formula> C (R ⁵ )-(wherein R ⁵ is a hydrogen atom, a substituent group α defined below and a substituent group β defined below ) Group,
[23] B is a 4- to 7-membered heterocyclic ring having at least one ring nitrogen atom (the heterocyclic ring may be saturated or unsaturated, an aryl group as defined below, a heteroaryl group as defined below, cyclo as defined below) Alkyl groups and heterocyclyl groups defined below), optionally fused with a group selected from:
[24] R ⁴ represents 1 to 3 substituents independently selected from the group consisting of a substituent group α defined below, a substituent group β defined below and a substituent group γ defined below, or
[25] When B is a heterocyclic ring fused to an aryl group, heteroaryl group, cycloalkyl group or heterocyclyl group, R ⁴ may be a hydrogen atom;
[26] Provided that the substituents R ¹ and R ³ are bonded to two atoms of the pyrrole ring adjacent to an atom of the pyrrole ring to which the substituent R ² is bonded;
[27] Substituent group α is a hydroxyl group, a nitro group, a cyano group, a halogen atom, a lower alkoxy group defined below, a halogeno lower alkoxy group defined below, a lower alkylthio group defined below, a halogeno lower alkylthio group defined below And groups of formula -NR ^a R ^{b wherein} R ^a and R ^b are the same or different from each other, and each a hydrogen atom, a lower alkyl group defined below, a lower alkenyl group defined below, a lower alkynyl group defined below, Independently selected from the group consisting of a lower aralkyl group defined and a lower alkylsulfonyl group defined below, or R ^a and R ^b together with the nitrogen atom to which they are attached form a heterocyclyl group;
[28] Substituent group β is a lower alkyl group defined below which may be optionally substituted with one or more substituents selected from substituent group α as defined above, and a lower alkenyl group defined below which may be optionally substituted with one or more substituents selected from substituent group α as defined above. A lower alkynyl group as defined below, an aralkyl group as defined below, and a cycloalkyl group as defined below, which may be optionally substituted with one or more substituents selected from the substituent group α as defined above;
[29] Substituent group γ is an oxo group, a hydroxyimino group, a lower alkoxyimino group defined below, a lower alkylene group defined below, a lower alkylenedioxy group defined below, a lower alkylsulfinyl group defined below, a lower alkylsulfo defined below One or more substituents selected from the following defined aryl groups, the above defined substituent groups α and the above defined substituent groups β, which may be optionally substituted with one or more substituents selected from the group including the defined substituent groups α and the above defined substituent groups β It consists of an aryloxy group, lower alkylidenyl group and aralkylidedenyl group defined below which may be optionally substituted.
[30] The present invention also provides a pharmaceutical composition comprising a carrier or diluent therefor, together with an effective amount of a pharmaceutically active compound, wherein the pharmaceutically active compound is a compound of formula I or a pharmaceutically acceptable Salts, esters or other derivatives.
[31] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof for use as a medicament.
[32] The invention also provides the use of one or more compounds of formula (I) or pharmaceutically acceptable salts, esters or other derivatives thereof in the manufacture of a medicament that inhibits the production of inflammatory cytokines in mammals, which may be human.
[33] The invention also provides the use of one or more compounds of formula (I) or pharmaceutically acceptable salts, esters or other derivatives thereof in the manufacture of a medicament that inhibits bone resorption in a mammal, which may be human.
[34] The present invention also provides the use of one or more compounds of formula (I) or pharmaceutically acceptable salts, esters or other derivatives thereof for the manufacture of a medicament for the treatment or prevention of inflammatory diseases in a mammal, which may be human.
[35] The invention also provides the use of one or more compounds of formula (I) or pharmaceutically acceptable salts, esters or other derivatives thereof for the manufacture of a medicament for the treatment or prevention of viral diseases in a mammal, which may be human.
[36] The present invention also provides the use of one or more compounds of formula (I) or pharmaceutically acceptable salts, esters or other derivatives thereof for the manufacture of a medicament for reducing pain or fever in a mammal, which may be human.
[37] The invention also provides the use of one or more compounds of formula (I) or pharmaceutically acceptable salts, esters or other derivatives thereof for the manufacture of a medicament for the treatment or prevention of chronic rheumatoid arthritis in a mammal, which may be human.
[38] The invention also provides the use of at least one compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof for the manufacture of a medicament for the treatment or prevention of osteoarthritis in a mammal, which may be human.
[39] The invention also provides the use of at least one compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof for the manufacture of a medicament for the treatment or prevention of cancer in a mammal, which may be human.
[40] The invention also provides the use of at least one compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof for the manufacture of a medicament for the treatment or prevention of hepatitis in a mammal, which may be human.
[41] The invention also relates to an allergic disease, sepsis, psoriasis, asthma, degenerative arthritis, Crohn's disease in a mammal, which may be human, of one or more compounds of formula (I) or pharmaceutically acceptable salts, esters or other derivatives thereof disease), systemic lupus erythematosus, osteoporosis, ulcerative colitis, diabetes, nephritis, ischemic heart disease, Alzheimer's disease, and atherosclerosis.
[42] The invention also provides a method for inhibiting the production of inflammatory cytokines in a mammal comprising administering to a mammal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, ester or other derivative thereof.
[43] The present invention also includes administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof to a mammal, which may be a human, who is undergoing bone absorption, wherein Provide a method.
[44] The invention also includes administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof to a mammal, which may be human, suffering from an inflammatory disease, of an inflammatory disease in said mammal. Provide a method of treatment or prevention.
[45] The present invention also includes administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof to a mammal, which may be a human, suffering from a viral disease, which is viral Provide a method for treating or preventing a disease.
[46] The invention also includes administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof to a mammal, which may be human, suffering from pain or fever, or Provides a way to alleviate fever.
[47] The present invention also includes administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, ester, or other derivative thereof to a mammal, which may be a human, suffering from chronic rheumatoid arthritis. Provided are methods of treating or preventing rheumatoid arthritis.
[48] The invention also provides for the treatment of osteoarthritis in a mammal, comprising administering to a mammal, which may be human, suffering from osteoarthritis, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof Provide preventive measures.
[49] The present invention also provides a method of treating cancer in a mammal, comprising administering to a mammal, which may be a human suffering from cancer, an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, ester or other derivative thereof Provide preventive measures.
[50] The invention also provides for the treatment of hepatitis in a mammal comprising administering to a mammal, which may be human, suffering from hepatitis, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof Provide preventive measures.
[51] The invention also includes administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof to a mammal, which may be a human, suffering from the following disease: A method of treating or preventing a disease selected from the group consisting of sepsis, psoriasis, asthma, degenerative arthritis, Crohn's disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, diabetes, nephritis, ischemic heart disease, Alzheimer's disease, and arteriosclerosis to provide.
[1] The present invention provides a series of heteroaryl substitutions with excellent inhibitory activity against the production of inflammatory cytokines such as interleukin (IL) -1, IL-6 and IL-8 and tumor necrosis factor (TNF), in particular IL-1β and TNFα. To pyrrole derivatives. As a result, the compounds of the present invention have antipyretic, analgesic, antiviral and anti-inflammatory effects, and autoimmune diseases such as chronic rheumatism, bone diseases such as osteoporosis, and many other diseases in which inflammatory cytokines described above are involved. It is useful for prevention and treatment. The present invention also provides methods and compositions using these novel compounds, and the use of these compounds and methods for their preparation.
[52] The condition that the substituents R ¹ and R ³ must be bonded to two atoms of the pyrrole ring adjacent to the atom of the pyrrole ring to which the substituent R ² is bonded among the compounds of the formula (I) is a compound of formula (I) -5 is selected from compounds:
[53]
[54]
[55]
[56]
[57]
[58] Wherein R ¹ , R ² and R ³ are as defined above.
[59] In the above formula (I), R ⁴ groups in the groups of the formulas (IIa), (IIb) and (IIc) are independently selected from the group consisting of the substituent group α defined below, the substituent group β defined below, and the substituent group γ defined below Substituents, or if B is a heterocyclic ring fused with an aryl group, heteroaryl group, cycloalkyl group or heterocyclyl group, then R ⁴ may be a hydrogen atom. " This means that it encompasses the following options: (i) 1, 2 or 3 substituents selected from substituent group α, substituent group β and substituent group γ on any bicyclic ring system of Formula IIa, Formula IIb and Formula IIc A compound of formula I in which is present; And (ii) the heterocyclic group B is fused with an aryl group, heteroaryl group, cycloalkyl group or heterocyclyl group, and the substituent group α, the substituent group β at any position on the ring system of the formulas (IIa), (IIb) and (IIc) And a compound of formula (I) in which 0, R ⁴ represents hydrogen, 1, 2 or 3 substituents selected from substituent group γ are present.
[60] R ¹ represents an aryl group which may be optionally substituted with one or more substituents selected from the group consisting of the above-described substituent group α and the above-described substituent group β, or the substituent group γ is the substituent group α and the substituents defined above. When an aryl group is optionally substituted with one or more substituents selected from the group consisting of group β, the aryl group is an aromatic hydrocarbon group having 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms in at least one ring, And phenyl, naphthyl, phenanthryl and anthracenyl groups. Among these, phenyl and naphthyl groups are preferable, and most preferably, they are phenyl groups.
[61] The aryl groups as defined and exemplified above may be fused to cycloalkyl groups having 3 to 10 carbon atoms. Examples of such fused ring groups include 5-indanyl groups.
[62] When R ¹ or substituent group γ represents an aryl group substituted with at least one substituent selected from the group consisting of the substituent group α as defined above and the substituent group β as defined above, preferably the substituent group α as defined above and the substituents defined above An aryl group substituted with 1 to 4 substituents selected from the group consisting of group β, and more preferably aryl substituted with 1 to 3 substituents selected from the group consisting of the above-described substituent group α and the above-described substituent group β. It is. Examples of such substituted aryl groups include 4-fluorophenyl, 3-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3,4 , 5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl, 3-trifluoromethoxyphenyl and 3-trifluoromethylphenyl.
[63] When R ¹ represents a heteroaryl group substituted with one or more substituents selected from the group consisting of the above-described substituent group α and the above-described substituent group β, the heteroaryl group is 1 selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom 5- to 7-membered aromatic heterocyclic groups containing 3 to 3 heteroatoms. Examples of such heteroaryl groups are furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyri Diazinyl, pyrimidyl and pyrazinyl groups. Preference is given to 5- or 6-membered aromatic heterocyclic groups containing one or two heteroatoms selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms, examples of which are furyl, thienyl, pyrrolyl, pyrazolyl, Dazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl and pyrazinyl groups. Of these, furyl, thienyl, pyridyl and pyrimidyl groups are particularly preferred.
[64] The heteroaryl groups defined and exemplified above may be fused to other cyclic groups selected from the group consisting of aryl groups and cycloalkyl groups having from 3 to 10 carbon atoms as defined above. Examples of such fused heteroaryl groups include indolyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl, quinazolyl, tetrahydroquinolyl and tetrahydroisoquinolyl groups.
[65] When R ¹ represents a heteroaryl group substituted with at least one substituent selected from the group consisting of a substituent group α and a substituent group β, the heteroaryl group is preferably one to three selected from the group consisting of a substituent group α and a substituent group β It is a heteroaryl group substituted by a substituent, More preferably, it is a heteroaryl group substituted by 1 or 2 substituents selected from the group which consists of a substituent group (alpha) and a substituent group (beta). Examples of such substituted heteroaryl groups include 5-fluoro-2-furyl, 4-chloro-2-thienyl, 5-difluoromethoxy-3-furyl, 5-trifluoromethyl-3-thienyl and 5-fluoro-2-oxazolyl group.
[66] When R ² is a heteroaryl group having one or more ring nitrogen atoms, the heteroaryl group is a group optionally substituted with one or more substituents selected from the group consisting of the above-described substituent group α and the above-described substituent group β, wherein the heteroaryl A group is a 5- to 7-membered aromatic heterocyclic group containing one or more nitrogen atoms and optionally containing further 1 or 2 hetero atoms selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms. Examples of such groups are pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidyl and pyra It includes a genyl group. Of these, a 5- or 6-membered aromatic heterocyclic group containing one nitrogen atom and optionally containing a further one heteroatom selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom is preferred, examples of which Pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl and pyrazinyl groups. More preferred are 5- or 6-membered aromatic heterocyclic groups containing 1 or 2 nitrogen atoms, such as imidazolyl, pyridyl, pyridazinyl, pyrimidyl and pyrazinyl groups, with pyridyl and pyrimidyl groups Particularly preferred.
[67] When R ² represents a heteroaryl group having at least one ring nitrogen atom, 4-pyridyl and 4-pyrimidyl groups are most preferred.
[68] When R ² represents a heteroaryl group having at least one ring nitrogen atom, the heteroaryl group is a group optionally substituted with at least one substituent selected from the group consisting of a substituent group α and a substituent group β, and the heteroaryl group is preferably a substituent A group substituted with 1 to 3 substituents selected from the group consisting of group α and a substituent group β, and more preferably a heteroaryl group substituted with 1 or 2 substituents selected from the group consisting of a substituent group α and a substituent group β And even more preferably a heteroaryl group substituted with one substituent selected from the group consisting of a substituent group α and a substituent group β, particularly preferably it is a substituent selected from the substituent group α and the substituent group β 4-pyridyl or 4-pyrimidyl group substituted in the 2-position. Most preferably, the heteroaryl group is represented by the formula -NR ^a R ^b wherein R ^a and R ^b are the same or different, and each independently a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aralkyl group or A lower alkylsulfonyl group, or R ^a and R ^b together with the nitrogen atom to which they are attached form a substituent or a formula -NR ^a R ^b wherein R ^a and R ^b are the same as above; 4-pyridyl or 4-pyrimidyl group substituted at the 2-position with a lower alkyl group substituted with a substituent. Preferred examples of such groups are 2-amino-4-pyridyl, 2-amino-4-pyrimidyl, 2-methylamino-4-pyridyl, 2-methylamino-4-pyrimidyl, 2-methoxy-4 -Pyridyl, 2-methoxy-4-pyrimidyl, 2-benzylamino-4-pyridyl, 2-benzylamino-4-pyrimidyl, 2- (α-methylbenzylamino) -4-pyridyl and 2 -(α-methylbenzylamino) -4-pyrimidyl.
[69] Ring B is defined as "a 4- to 7-membered heterocyclic ring having at least one ring nitrogen atom", which is a D group, an E group, and a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom,> SO and> A 4- to 7-membered heterocyclic ring consisting of 2 to 5 atoms or groups selected from SO ₂ , said heterocyclic ring containing one or more ring nitrogen atoms. It will be understood that when ring B contains only one ring nitrogen atom, it is this nitrogen atom rk D group or E group. The 4- to 7-membered heterocyclic ring of ring B may be a saturated heterocyclic ring or an unsaturated heterocyclic ring. Preferably, ring B contains one nitrogen atom, and further optionally may contain one ring hetero atom or a ring group selected from nitrogen atom, oxygen atom, sulfur atom,> SO and> SO ₂ . Or a 6-membered heterocyclic ring; More preferably it is pyrrolidone, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, oxazolidine, thiazolidine, piperidine, tetrahydropyridine, dihydropyridine, piperazine , Morpholine or thiomorpholine; More preferably it is pyrrolidone, pyrroline or imidazoline; And most preferably it is pyrrolidone or pyrroline.
[70] The heterocyclic ring B as defined and exemplified above may be optionally fused with an aryl group, heteroaryl group, cycloalkyl group or heterocyclyl group, wherein the aryl, heteroaryl and heterocyclyl groups are the substituent groups α and And optionally substituted with one or more substituents selected from the substituent group β as defined above. The aryl group is as defined and exemplified above for substituent R ¹ and substituent group γ. The heteroaryl group is as defined and exemplified above for the substituent R ¹ . The cycloalkyl group is a cycloalkyl group having 3 to 7 carbon atoms, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl group, of which cycloalkyl group having 3 to 6 carbon atoms is preferable. . The heterocyclyl group is a 4- to 7-membered heterocyclyl group having 1 to 3 ring sulfur atoms, oxygen atoms and / or nitrogen atoms, and preferably 1 or selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms. 4- to 7-membered heterocyclyl group having two heteroatoms. Of these, preferred are 5- or 6-membered heterocyclyl groups which contain one ring nitrogen atom and may optionally contain one oxygen atom, sulfur atom or nitrogen atom, examples of such groups being Azeti Diyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyridyl, dihydropyridyl, Piperazinyl, morpholinyl, thiomorpholinyl and homopiperidinyl.
[71] Examples of such fused ring systems for ring B include tetrahydroquinoline, octahydroquinoline, decahydroquinoline, tetrahydroisoquinoline, octahydroisoquinoline, decahydroisoquinoline, indolin, octahydroindole, isoindolin and octa Hydroisoindoles.
[72] The lower alkyl moiety of the lower alkyl group which may optionally be substituted with one or more substituents selected from lower alkyl group and substituent group α in the definition of R ^a , R ^b and substituent group β has 1 to 6 carbon atoms. Linear or branched alkyl groups. Examples of the lower alkyl group include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1, 2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl groups. Alkyl groups having 1 to 4 carbon atoms are preferred, methyl, ethyl, propyl, isopropyl and butyl groups are more preferred, and methyl, ethyl and propyl groups are most preferred.
[73] Lower alkenyl moieties of lower alkenyl groups which may be optionally substituted with lower alkenyl groups in the definition of R ^a , R ^b and substituent group β and one or more substituents selected from substituent group α in the definition of substituent group β are from 2 to 6 carbons Linear or branched alkenyl groups having an atom. Examples of the lower alkenyl group include vinyl, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl- 2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl- 3-butenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl , 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl groups. Alkenyl groups having 2 to 4 carbon atoms are preferred, alkenyl groups having 2 or 3 carbon atoms are most preferred.
[74] Lower alkynyl moieties of lower alkynyl groups which may be optionally substituted with lower alkynyl groups in the definition of R ^a , R ^b and substituent group β and one or more substituents selected from substituent group α in the definition of substituent group β are from 2 to 6 carbons Linear or branched alkynyl groups having an atom. Examples of the lower alkynyl group include ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butyn Neyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentynyl, 1- Methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4 -Hexynyl and 5-hexynyl groups. Alkynyl groups having 2 to 4 carbon atoms are preferred, and alkynyl groups having 2 or 3 carbon atoms are most preferred.
[75] The aralkyl group in the definition of R ^a , R ^b and substituent group β is as defined above substituted with one or more aryl groups which may be optionally substituted with one to three substituents selected from substituent group α and the substituent group β as defined above. Same lower alkyl group. Examples of such groups are benzyl, indenylmethyl, phenanthrylmethyl, anthrylmethyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthryl Methyl, piperonyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2 -Naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4 -Naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4- Naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2-naphthyl Hexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl and 6-naphthylhexyl. Among them, benzyl, phenanthrylmethyl, anthrylmethyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, 9-anthrylmethyl, piperonyl, 1-phenethyl, 2- Phenyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl and 4-phenylbutyl are preferred.
[76] As indicated above, the aryl portion of the aralkyl group may be optionally substituted with 1 to 3 substituents selected from substituent group α and substituent group β as defined above. Examples of such substituted aralkyl groups include aralkyl groups substituted with halogen atoms, and include, for example: 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3- Chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3,5-difluorobenzyl, 2,5-difluorophenethyl, 2,6-di Fluorobenzyl, 2,4-difluorophenethyl, 3,5-dibromobenzyl, 2,5-dibromophenethyl, 2,6-dichlorobenzyl, 2,4-dichlorophenethyl, 2,3 , 6-trifluorobenzyl, 2,3,4-trifluorophenethyl, 3,4,5-trifluorobenzyl, 2,5,6-trifluorophenethyl, 2,4,6-tri Fluorobenzyl, 2,3,6-tribromophenethyl, 2,3,4-tribromobenzyl, 3,4,5-tribromophenethyl, 2,5,6-trichlorobenzyl, 2,4 , 6-trichlorophenethyl, 1-fluoro-2-naphthylmethyl, 2-fluoro-1-naphthylethyl, 3-fluoro-1-naphthylmethyl, 1-chloro-2-naphthylethyl , 2-claw Rho-1-naphthylmethyl, 3-bromo-1-naphthylethyl, 3,8-difluoro-1-naphthylmethyl, 2,3-difluoro-1-naphthylethyl, 4,8 -Difluoro-1-naphthylmethyl, 5,6-difluoro-1-naphthylethyl, 3,8-dichloro-1-naphthylmethyl, 2,3-dichloro-1-naphthylethyl, 4 , 8-dibromo-1-naphthylmethyl, 5,6-dibromo-1-naphthylethyl, 2,3,6-trifluoro-1-naphthylmethyl, 2,3,4-tri Fluoro-1-naphthylethyl, 3,4,5-trifluoro-1-naphthylmethyl, 4,5,6-tri-fluoro-1-naphthylethyl, 2,4,8-trifluoro Rho-1-naphthylmethyl, bis (2-fluorophenyl) methyl, 3-fluorophenylphenylmethyl, bis (4-fluorophenyl) methyl, 4-fluorophenylphenylmethyl, bis (2-chlorophenyl ) Methyl, bis (3-chlorophenyl) methyl, bis (4-chlorophenyl) methyl, 4-chlorophenylphenylmethyl, 2-bromophenylphenylmethyl, 3-bromophenylphenylmethyl, bis (4-bromo Phenyl) methyl, bis (3,5-difluorophenyl) methyl, bis (2,5-diple Orophenyl) methyl, bis (2,6-difluorophenyl) methyl, 2,4-difluorophenylphenylmethyl, bis (3,5-dibromophenyl) methyl, 2,5-dibromophenyl Phenylmethyl, 2,6-dichlorophenylphenylmethyl, bis (2,4-dichlorophenyl) methyl and bis (2,3,6-trifluorophenyl) methyl; Aralkyl groups substituted with halogeno lower alkyl groups, such as 2-trifluoromethylbenzyl, 3-trifluoromethylphenethyl, 4-trifluoromethylbenzyl, 2-trichloromethylphenethyl, 3-dichloromethylbenzyl , 4-trichloromethylphenethyl, 2-tribromomethylbenzyl, 3-dibromomethylphenethyl, 4-dibromomethylbenzyl, 3,5-bistrifluoromethylphenethyl, 2,5- Bistrifluoromethylbenzyl, 2,6-bistrifluoromethylphenethyl, 2,4-bistrifluoromethylbenzyl, 3,5-bistribromomethylphenethyl, 2,5-bisdibromomethyl Benzyl, 2,6-bisdichloromethylmethylphenethyl, 2,4-bisdichloromethylbenzyl, 2,3,6-tristrifluoromethylphenethyl, 2,3,4-tristrifluoromethylbenzyl, 3 , 4,5-tristrifluoromethylphenethyl, 2,5,6-tristrifluoromethylbenzyl, 2,4,6-tristrifluoromethylphenethyl, 2,3,6-tristribromo Methylbenzyl, 2,3,4-trisdi Bromomethylphenethyl, 3,4,5-tristribromomethylbenzyl, 2,5,6-trisdichloromethylmethylphenethyl, 2,4,6-trisdichloromethylbenzyl, 1-trifluoromethyl- 2-naphthylethyl, 2-trifluoromethyl-1-naphthylmethyl, 3-trifluoromethyl-1-naphthylethyl, 1-trichloromethyl-2-naphthylmethyl, 2-dichloromethyl-1 Naphthylethyl, 3-tribromomethyl-1-naphthylmethyl, 3,8-bistrifluoromethyl-1-naphthylethyl, 3,8-bistrifluoromethyl-1-naphthylethyl, 2,3-bistrifluoromethyl-1-naphthylmethyl, 4,8-bistrifluoromethyl-1-naphthylethyl, 5,6-bistrifluoromethyl-1-naphthylmethyl, 3, 8-Bistrichloromethyl-1-naphthylethyl, 2,3-bisdichloromethyl-1-naphthylmethyl, 4,8-bisdibromomethyl-1-naphthylethyl, 5,6-bistribromo Methyl-1-naphthylmethyl, 2,3,6-tristrifluoromethyl-1-naphthylethyl, 2,3,4-tristrifluoromethyl-1-naph Tylmethyl, 3,4,5-tristrifluoromethyl-1-naphthylethyl, 4,5,6-tristrifluoromethyl-1-naphthylmethyl, 2,4,8-tristrifluoromethyl -1-naphthylmethyl, bis (4-trifluoromethylphenyl) methyl, 4-trifluoromethylphenylphenylmethyl, bis (2-trichloromethylphenyl) methyl, bis (3-trichloromethylphenyl) methyl, bis (4 -Trichloromethylphenyl) methyl, 2-tribromomethylphenylphenylmethyl, 3-tribromomethylphenylphenylmethyl, bis (4-tribromomethylphenyl) methyl, bis (3,5-bistrifluoromethylphenyl) methyl, Bis (2,5-bistrifluoromethylphenyl) methyl, bis (2,6-bistrifluoromethylphenyl) methyl, 2,4-bistrifluoromethylphenylphenylmethyl, bis (3,5-bistribromomethylphenyl ) Methyl, 2,5-bistribromomethylphenylphenylmethyl, 2,6-bistrichloromethylphenylphenylmethyl, bis (2,4-bistrichloromethylphenyl) methyl and bis (2,3,6-tri Trifluoromethylphenyl) methyl; Aralkyl groups substituted with lower alkyl groups, such as 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methylphenethyl, 4-methylphenethyl, 2-ethylbenzyl, 3-propylphenethyl, 4- Ethylbenzyl, 2-butylphenethyl, 3-pentylbenzyl, 4-pentylphenethyl, 3,5-dimethylbenzyl, 2,5-dimethylphenethyl, 2,6-dimethylbenzyl, 2,4-dimethylphenethyl, 3,5-dibutylbenzyl, 2,5-dipentylphenethyl, 2,6-dipropylbenzyl, 2,4-dipropylphenethyl, 2,3,6-trimethylbenzyl, 2,3,4-trimethylphen Netyl, 3,4,5-trimethylbenzyl, 2,4,6-trimethylbenzyl, 2,5,6-trimethylphenethyl, 2,3,6-tributylphenethyl, 2,3,4-tripentylbenzyl , 3,4,5-tributylphenethyl, 2,5,6-tripropylbenzyl, 2,4,6-tripropylphenethyl, 1-methyl-2-naphthylmethyl, 2-methyl-1-naph Methylethyl, 3-methyl-1-naphthylmethyl, 1-ethyl-2-naphthylethyl, 2-propyl-1-naphthylmethyl, 3-butyl-1-naphthylethyl, 3,8-dimethyl-1 -Naphthylmethyl, 2,3-dimethyl-1-naphthylethyl, 4,8-dimethyl-1-naphthylmethyl, 5,6-dimeth -1-naphthylethyl, 3,8-diethyl-1-naphthylmethyl, 2,3-dipropyl-1-naphthylmethyl, 4,8-dipentyl-1-naphthylethyl, 5,6- Dibutyl-1-naphthylmethyl, 2,3,6-trimethyl-1-naphthylmethyl, 2,3,4-trimethyl-1-naphthylethyl, 3,4,5-trimethyl-1-naphthylmethyl , 4,5,6-trimethyl-1-naphthylmethyl, 2,4,8-trimethyl-1-naphthylmethyl, bis (2-methylphenyl) methyl, 3-methylphenylphenylmethyl, bis (4-methylphenyl) methyl , 4-methylphenylphenylmethyl, bis (2-ethylphenyl) methyl, bis (3-ethylphenyl) methyl, bis (4-ethylphenyl) methyl, 2-propylphenylphenylmethyl, 3-propylphenylphenylmethyl, bis ( 4-propylphenyl) methyl, bis (3,5-dimethylphenyl) methyl, bis (2,5-dimethylphenyl) methyl, bis (2,6-dimethylphenyl) methyl, 2,4-dimethylphenylphenylmethyl, bis (3,5-dipropylphenyl) methyl, 2,5-dipropylphenylphenylmethyl, 2,6-diethylphenylphenylmethyl, bis (2,4-diethylphenyl) methyl and bis (2,3,6 -Trimethylphenyl) methyl; Aralkyl groups substituted with lower alkoxy groups such as 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3-methoxyphenethyl, 2-ethoxyphenethyl, 3-propoxybenzyl, 4- Ethoxyphenethyl, 2-butoxybenzyl, 3-pentoxyphenethyl, 4-pentoxybenzyl, 3,5-dimethoxyphenethyl, 2,5-dimethoxybenzyl, 2,6-dimethoxyphenethyl, 2,4-dimethoxybenzyl, 3,5-dibutoxyphenethyl, 2,5-dipentoxybenzyl, 2,6-dipropoxyphenethyl, 2,4-dipropoxybenzyl, 2,3,6- Trimethoxyphenethyl, 2,3,4-trimethoxybenzyl, 3,4,5-trimethoxyphenethyl, 2,5,6-trimethoxybenzyl, 2,4,6-trimethoxyphen Netyl, 2,3,6-tributoxybenzyl, 2,3,4-tripentoxyphenethyl, 3,4,5-tributoxybenzyl, 2,5,6-tripropoxyphenethyl, 2, 4,6-tripropoxybenzyl, 1-methoxy-2-naphthylmethyl, 2-methoxy-1-naphthylmethyl, 3-methoxy-1-naphthylethyl, 1-ethoxy-2-naph Methylmethyl, 2-propoxy-1-naphthylmethyl, 3-butoxy-1-naphthylethyl, 3,8-dimethoxy-1-naph Methylmethyl, 2,3-dimethoxy-1-naphthylmethyl, 4,8-dimethoxy-1-naphthylethyl, 5,6-dimethoxy-1-naphthylmethyl, 3,8-diethoxy-1 -Naphthylmethyl, 2,3-dipropoxy-1-naphthylethyl, 4,8-dipentoxy-1-naphthylmethyl, 5,6-dibutoxy-1-naphthylmethyl, 2,3,6 -Trimethoxy-1-naphthylethyl, 2,3,4-trimethoxy-1-naphthylmethyl, 3,4,5-trimethoxy-1-naphthylmethyl, 4,5,6-tri Methoxy-1-naphthylethyl, 2,4,8-trimethoxy-1-naphthylmethyl, bis (2-methoxyphenyl) methyl, 3-methoxyphenylphenylmethyl, bis (4-methoxyphenyl ) Methyl, 4-methoxyphenylphenylmethyl, bis (2-ethoxyphenyl) methyl, bis (3-ethoxyphenyl) methyl, bis (4-ethoxyphenyl) methyl, 2-propoxyphenylphenylmethyl, 3 Propoxyphenylphenylmethyl, bis (4-propoxyphenyl) methyl, bis (3,5-dimethoxyphenyl) methyl, bis (2,5-dimethoxyphenyl) methyl, bis (2,6-dimethoxyphenyl ) Methyl, 2,4-dimethoxyphenylphenylmethyl, bis (3,5-dipropoxyphenyl) methyl, 2,5-di Propoxyphenylphenylmethyl, 2,6-diethoxyphenylphenylmethyl, bis (2,4-diethoxyphenyl) methyl and bis (2,3,6-trimethoxyphenyl) methyl; Aralkyl groups substituted with amino groups, such as 2-aminophenethyl, 3-aminobenzyl, 4-aminophenethyl, 3,5-diaminobenzyl, 2,5-diaminophenethyl, 2,6-diaminobenzyl , 2,4-diaminophenethyl, 2,3,6-triaminobenzyl, 2,3,4-triaminophenethyl, 3,4,5-triaminobenzyl, 2,5,6-triaminophen Netyl, 2,4,6-triaminobenzyl, 1-amino-2-naphthylmethyl, 2-amino-1-naphthylethyl, 3-amino-1-naphthylmethyl, 3,8-diamino-1 -Naphthylmethyl, 2,3-diamino-1-naphthylethyl, 4,8-diamino-1-naphthylmethyl, 5,6-diamino-1-naphthylmethyl, 2,3,6- Triamino-1-naphthylethyl, 2,3,4-triamino-1-naphthylmethyl, 3,4,5-triamino-1-naphthylmethyl, 4,5,6-triamino-1- Naphthylethyl, 2,4,8-triamino-1-naphthylmethyl, bis (2-aminophenyl) methyl, 3-aminophenylphenylmethyl, bis (4-aminophenyl) methyl, 4-aminophenylphenylmethyl , Bis (3,5-diaminophenyl) methyl, bis (2,5-diamino Phenyl) methyl, bis (2,6-diaminophenyl) methyl, 2,4-diaminophenylphenylmethyl and bis (2,3,6-triaminophenyl) methyl; Aralkyl groups substituted with nitro groups such as 2-nitrophenethyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-nitrophenethyl, 3,5-dinitrobenzyl, 2,5-dinitrophenethyl, 2, 6-dinitrobenzyl, 2,4-dinitrophenethyl, 2,3,6-trinitrobenzyl, 2,3,4-trinitrophenethyl, 3,4,5-trinitrobenzyl, 2,5,6-trinitro Phenethyl, 2,4,6-trinitrobenzyl, 1-nitro-2-naphthylmethyl, 2-nitro-1-naphthylethyl, 3-nitro-1-naphthylmethyl, 3,8-dinitro-1 -Naphthylmethyl, 2,3-dinitro-1-naphthylethyl, 4,8-dinitro-1-naphthylmethyl, 5,6-dinitro-1-naphthylmethyl, 2,3,6- Trinitro-1-naphthylethyl, 2,3,4-trinitro-1-naphthylmethyl, 3,4,5-trinitro-1-naphthylmethyl, 4,5,6-trinitro-1-naphthylethyl, 2,4,8-trinitro-1-naphthylmethyl, bis (2-nitrophenyl) methyl, 3-nitrophenylphenylmethyl, bis (4-nitrophenyl) methyl, 4-nitrophenylphenylmethyl, bis (3, 5-dinitrophenyl) methyl, b (2,5-dinitrophenyl) methyl, bis (2,6-dinitrophenyl) methyl, 2,4-dinitrophenyl-phenyl methyl and bis (2,3,6-trinitrotoluene) methyl; And aralkyl groups substituted with cyano groups, such as 2-cyanophenethyl, 3-cyanobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, 4-cyanophenethyl, 3,5-dicyano Benzyl, 2,5-dicyanophenethyl, 2,6-dicyanobenzyl, 2,4-dicyanophenethyl, 2,3,6-tricyanobenzyl, 2,3,4-tricyanophenethyl, 3, 4,5-tricyanobenzyl, 2,5,6-tricyanophenethyl, 2,4,6-tricyanobenzyl, 1-cyano-2-naphthylmethyl, 3-cyano-1-naphthylmethyl, 3,8-dicyano-1-naphthylmethyl, 2,3-dicyano-1-naphthylethyl, 4,8-dicyano-1-naphthylmethyl, 5,6-dicyano-1-naphthylmethyl Methyl, 2,3,6-tricyano-1-naphthylethyl, 2,3,4-tricyano-1-naphthylmethyl, 3,4,5-tricyano-1-naphthylmethyl, 4,5 , 6-tricyano-1-naphthylethyl, 2,4,8-tricyano-1-naphthylmethyl, bis (2-cyanophenyl) methyl, 3-cyanophenylphenylmethyl, bis (4-sia Nophenyl) methyl, 4-cyanophenylphenylmethyl, bis (3,5-dicyanophenyl) meth , Bis (2,5-dicyano-phenyl) methyl, bis (2,6-dicyano-phenyl) methyl, 2,4-dicyano-phenyl-phenyl-methyl and bis (2,3,6 Tricia furnace) methyl.
[77] Of these, an unsubstituted aralkyl group and an aralkyl group substituted with one or more substituents selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group are preferable, and an unsubstituted aralkyl group and a halogen atom and a lower alkyl group selected from the group Most preferred are aralkyl groups substituted with one or more substituents.
[78] When R ^a , R ^b or the substituent γ represent a lower alkylsulfonyl group, this is a group in which the lower alkyl group as defined and exemplified above is bonded to a sulfonyl group (—SO ₂ —). Lower alkylsulfonyl groups are preferably straight or branched alkylsulfonyl groups having 1 to 4 carbon atoms, more preferably methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or butylsulfonyl groups, And most preferably methylsulfonyl, ethylsulfonyl or propylsulfonyl groups.
[79] When R ^a , R ^b represent a heterocyclyl group together with the nitrogen atom to which they are attached, the heterocyclyl group contains one nitrogen atom and further one hetero selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom 4- to 7-membered heterocyclyl group optionally containing an atom. Such heterocyclyl groups are 1-azetidinyl, 1-pyrrolidinyl, 1-pyrrolinyl, 1-imidazolidinyl, 1-imidazolinyl, 1-pyrazolidinyl, 1-pyrazolinyl, 3 Oxazolidinyl, 3-thiazolidinyl, 1-piperidinyl, tetrahydropyridin-1-yl, dihydropyridin-1-yl, 1-piperazinyl, 4-morpholinyl, 4-thiomorpholi Nyl, 1-homopiperidinyl, 8-azabicyclo [3.2.1] octan-8-yl, 8-azabicyclo [3.2.1] octen-8-yl, 9-azabicyclo [3.3.1] nonan- 9-yl and 9-azabicyclo [3.3.1] nonen-9-yl.
[80] When the substituents R ^a , R ^b together with the nitrogen atom to which they are attached form a heterocyclyl group as defined and exemplified above, the heterocyclyl group is selected from the group consisting of the aryl group defined above and the heteroaryl group defined above. Can be fused with a clicker. Such fused heterocyclyl groups include tetrahydroquinolin-1-yl and tetrahydroisoquinolin-2-yl.
[81] Halogen atoms in the definition of substituent group α include fluorine, chlorine, bromine and iodine atoms, of which fluorine and chlorine atoms are preferred.
[82] When the substituent in the definition of substituent group α is a lower alkoxy group, it is a group in which an oxygen atom is bonded to a lower alkyl group as defined and exemplified above. The alkoxy group is preferably a straight or branched alkoxy group having 1 to 4 carbon atoms, more preferably a methoxy, ethoxy, propoxy, isopropoxy or butoxy group, particularly preferably methoxy, Oxy or propoxy group.
[83] When the substituent in the definition of substituent group α is a halogeno lower alkoxy group, it is a lower alkoxy group as defined above substituted with one or more halogen atoms as exemplified above. It is preferably a halogeno lower alkoxy group having 1 to 4 carbon atoms, more preferably selected from the group consisting of difluoromethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy groups. . Most preferred are difluoromethoxy groups.
[84] When the substituent in the definition of substituent group α is a lower alkylthio group, it is a group in which a sulfur atom is bonded to a lower alkyl group as defined and exemplified above. Lower alkylthio groups are preferably straight-chain or branched alkylthio groups having 1 to 4 carbon atoms, more preferably methylthio, ethylthio, propylthio, isopropylthio or butylthio groups, particularly preferably Methylthio, ethylthio, or propylthio groups.
[85] When the substituent in the definition of substituent group α is a halogeno lower alkylthio group, it is a group in which a lower alkylthio group as defined above is substituted with one or more halogen atoms as exemplified above. The halogeno lower alkylthio group preferably has 1 to 4 carbon atoms, more preferably selected from the group consisting of difluoromethylthio, trifluoromethylthio and 2,2,2-trifluoroethylthio groups do.
[86] When the substituent in the definition of substituent group β represents a cycloalkyl group, the cycloalkyl group is a cycloalkyl group having 3 to 7 carbon atoms, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl group, among which Preference is given to cycloalkyl groups having 3 to 6 carbon atoms, in particular cyclopentyl and cyclohexyl groups.
[87] When the substituent in the definition of substituent group γ represents a lower alkoxyimino group, it is a group in which the hydrogen atom of the hydroxyimino group is substituted by a lower alkyl group as defined and exemplified above. It is preferably an alkoxyimino group having 1 to 4 carbon atoms, more preferably a methoxyimino, ethoxyimino or propoxyimino group.
[88] When the substituent in the definition of substituent group γ represents a lower alkylene group, it is a straight or branched chain alkylene group having 2 to 6 carbon atoms, examples of which are ethylene, trimethylene, propylene, tetramethylene, 1-methyltri Methylene, 2-methyltrimethylene, 1,1-dimethylethylene, pentamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,2-dimethyltrimethylene and hexamethylene groups. It is preferably a straight or branched alkylene group having 2 to 4 carbon atoms, more preferably it is an ethylene, trimethylene, propylene or tetramethylene group. It will be appreciated that the lower alkylene group forms a spiro group together with the atoms of the group of formula (IIa), (IIb) or (IIc).
[89] When the substituent in the definition of substituent group γ represents a lower alkylenedioxy group, it is a straight or branched chain alkylene group having 1 to 6 carbon atoms, for example methylene, ethylene, trimethylene, propylene, tetramethylene, 1-methyl The alkylene moiety being trimethylene, 2-methyltrimethylene, 1,1-dimethylethylene, pentamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,2-dimethyltrimethylene and hexamethylene Group substituted with two oxy groups. Preferably, the alkylenedioxy group is a straight or branched chain alkylenedioxy group having 1 to 4 carbon atoms, more preferably it is methylenedioxy, ethylenedioxy, trimethylenedioxy, propylenedioxy or tetra Methylenedioxy group. It will be understood that the lower alkylenedioxy forms a spiro group together with the atoms of the group of formula IIa, formula IIb or formula IIc to which two oxy groups are attached.
[90] When the substituent in the definition of substituent group γ represents a lower alkylsulfinyl group, this is the group in which the lower alkyl group as defined and exemplified above is bonded to the sulfinyl group (—SO—). Lower alkylsulfinyl groups are preferably linear or branched alkylsulfinyl groups having 1 to 4 carbon atoms, more preferably methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, isopropylsulfinyl group or butylsulfinyl group And most preferably methylsulfinyl group, ethylsulfinyl group or propylsulfinyl group.
[91] When the substituent in the definition of substituent group γ represents a lower alkylidedenyl group, it is a straight or branched alkylidedenyl group having 1 to 6 carbon atoms, examples of which are methylidedenyl, ethylidedenyl, propylidenyl, 1 -Methylethylidedenyl, butylidedenyl and 1-methylpropylideneyl groups. Lower alkylideneyl groups are preferably straight-chain or branched alkylideneyl groups having 1 to 4 carbon atoms, most preferably it is a methylidenyl, ethylidedenyl or propylidenyl group.
[92] When a substituent in the definition of substituent group γ represents an aralkylidedenyl group, it is a straight or branched alkylidedenyl group as defined and exemplified above substituted with one or more aryl groups as defined and exemplified above. Examples of these lower aralkylidedenyl groups include benzylideneyl, phenylethylidedenyl, phenylpropylidedenyl and naphthylmethylidedenyl groups. The aralkylidedenyl group is a straight or branched alkylidedenyl group having 1 to 4 carbon atoms, preferably substituted with a phenyl group or a naphthyl group, most preferably a benzylideneyl or phenylethylidedenyl group.
[93] When the substituent γ represents an aryloxy group optionally substituted with one or more substituents selected from the group consisting of the above-described substituent group α and the above-described substituent group β, the aryloxy group is oxygen attached to an aryl group as defined and exemplified above. Atoms, examples of which include phenoxy, naphthyloxy, phenanthryloxy and anthracenyloxy groups. Of these, phenoxy and naphthyloxy groups are preferable, and most preferably phenoxy group.
[94] Preferred groups of substituents of the substituent group α include a halogen atom, a lower alkoxy group as defined above, a halogeno lower alkoxy group as defined above and one of the formulas -NR ^a R ^{b wherein} R ^a and R ^b Substituent group α ¹ consisting of a hydrogen atom or a lower alkyl group as defined above, the other being a hydrogen atom, a lower alkyl group as defined above or an aralkyl group as defined above.
[95] Preferred groups of the substituents of the substituent group β are lower alkyl groups as defined above, halogeno lower alkyl groups as defined above, hydroxyl lower alkyl groups, nitro lower alkyl groups, amino lower alkyl groups, lower alkylamino lower alkyl groups, di (lower alkyl) Substituent group (beta) ¹ which consists of an amino lower alkyl group and an aralkylamino lower alkyl group.
[96] When the substituent in the definition of substituent group β ¹ represents a halogeno lower alkyl group, it is a group in which a lower alkyl group as defined and exemplified above is substituted with one or more halogen atoms as exemplified above. It is preferably a straight or branched halogenoalkyl group having 1 to 4 carbon atoms; More preferably it is trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoro An ethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl or 2,2-dibromoethyl group; More preferably it is a trifluoromethyl, trichloromethyl, difluoromethyl or fluoromethyl group; And most preferably it is a trifluoromethyl group.
[97] When the substituent in the definition of substituent group β ¹ represents a hydroxy lower alkyl group, it is a group in which a lower alkyl group as defined and exemplified above is substituted with one or more hydroxy groups. It is preferably a hydroxyalkyl group having 1 to 4 carbon atoms, most preferably it is a hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl group.
[98] When the substituent in the definition of substituent group β ¹ represents a nitro lower alkyl group, it is a group in which a lower alkyl group as defined and exemplified above is substituted with one or more nitro groups. It is preferably a nitroalkyl group having 1 to 4 carbon atoms, most preferably it is a nitromethyl, 2-nitroethyl or 3-nitropropyl group.
[99] When the substituent in the definition of substituent group β ^{1 represents} an amino lower alkyl group, a lower alkylamino lower alkyl group, a di (lower alkyl) amino lower alkyl group or an aralkylamino lower alkyl group, this means that a lower alkyl group as defined and exemplified above is represented by the formula- NR ^a R ^b (wherein one of R ^a and R ^b represents a hydrogen atom or a lower alkyl group as defined above and the other a hydrogen atom, a lower alkyl group as defined above or an aralkyl group as defined above Is a group substituted with a group of). Of these, substituents in which the alkyl moiety substituted with —NR ^a R ^b group have 1 to 4 carbon atoms are preferred. Aminomethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethyl, 2- (methylamino) ethyl, 3- (methylamino) propyl, ethylaminomethyl, 2- (ethylamino) ethyl, 3- (ethylamino ) Propyl, dimethylaminomethyl, 2- (dimethylamino) ethyl, 3- (dimethylamino) propyl, diethylaminomethyl, 2- (diethylamino) ethyl, 3- (diethylamino) propyl, benzylaminomethyl, More preferred are 2- (benzylamino) -ethyl and 3- (benzylamino) propyl groups.
[100] The present invention encompasses esters and other derivatives of the compounds of formula (I). These esters and other derivatives are formulas in which the functional groups (e.g., hydroxyl, amino, imino or sulfonamide groups) of the compounds of formula I are modified by adding protecting groups using conventional techniques known in the art. I compounds (see, eg, "Protective Groups in Organic Synthesis", Second Edition, Theodora W. Greene and Peter GM Wuts, 1991, John Wiley & Sons, Inc.).
[101] The nature of such protecting groups is not particularly limited, provided that esters or other derivatives are for therapeutic purposes, provided that they are pharmaceutically acceptable, i.e. by metabolic processes (eg hydrolysis) upon administration of the compound to the body of a living mammal. The protecting group must be removed to provide the compound of formula (I) or a salt thereof. In other words, pharmaceutically acceptable esters or other derivatives are prodrugs of formula I of the present invention. However, if the ester or other derivative of the compound of formula (I) of the present invention is for non-treatment purposes (eg, as a manufacturing intermediate of other compounds), the requirement that the ester or other derivative is pharmaceutically acceptable does not apply. .
[102] Whether esters or other derivatives of the compounds of formula I of the invention are pharmaceutically acceptable or not can be readily determined. The compound to be observed is administered intravenously to experimental animals such as rats or mice, and then the body fluids of the animals are studied. If a compound of formula (I) or a pharmaceutically acceptable salt thereof can be detected in the body fluid, the compound to be observed is determined to be a pharmaceutically acceptable ester or other derivative.
[103] Compounds of formula (I) of the invention may be converted to esters, examples of which include compounds of formula (I) in which hydroxyl groups present therein are esterified. The ester moiety can be a general protecting group when the esterified compound is used as an intermediate or a protecting group that can be removed by in vivo metabolic processes (eg hydrolysis) if the esterified compound is pharmaceutically acceptable.
[104] The general protecting groups mentioned above are protecting groups which can be removed by chemical processes such as hydrolysis, hydrocracking, electrolysis or photolysis. Preferred examples of such general protecting groups used to synthesize compounds of formula I wherein the hydroxyl residues therein have been modified include:
[105] (i) aliphatic acyl groups, examples of which include:
[106] Alkylcarbonyl groups having 1 to 25 carbon atoms, examples of which include formyl, acetyl, propionyl, butyryl, isobutyryl, fentanolyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, Decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl , Hexadecanoyl, 1-methylpentadecanoyl, 14-methyl-pentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl Including nonadecanoyl, eicosanoyl and hencosanoyl groups,
[107] Halogenated alkylcarbonyl groups having 1 to 25 carbons, the alkyl moiety of which is substituted by one or more halogen atoms, examples of which include chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl groups,
[108] Lower alkoxyalkylcarbonyl groups containing alkylcarbonyl groups having 1 to 25 carbon atoms substituted by at least one lower alkoxy group as defined above, examples of the lower alkoxyalkylcarbonyl groups include methoxyacetyl groups, and
[109] Unsaturated alkylcarbonyl groups having 1 to 25 carbon atoms, examples of which include acryloyl, propionyl, methacryloyl, crotonoyl, isocrotonoyl and (E) -2-methyl-2-butenoyl groups and;
[110] Of these, alkylcarbonyl groups having 1 to 6 carbon atoms are preferable;
[111] (ii) aromatic acyl groups, examples of which include:
[112] Arylcarbonyl groups containing a carbonyl group substituted with an aryl group as defined above, examples of which include benzoyl, α-naphthoyl and β-naphthoyl groups,
[113] Halogenated arylcarbonyl groups containing arylcarbonyl groups as defined above substituted with one or more halogen atoms, examples of which include 2-bromobenzoyl, 4-chlorobenzoyl and 2,4,6-trifluorobenzoyl groups,
[114] Lower alkylated arylcarbonyl groups containing an arylcarbonyl group as defined above substituted with one or more lower alkyl groups as defined above, examples of which include 2,4,6-trimethyl-benzoyl and 4-toluyl groups,
[115] Lower alkoxylated arylcarbonyl groups containing an arylcarbonyl group as defined above substituted with one or more lower alkoxy groups as defined above, examples of which include 4-anisoyl groups,
[116] Arylcarbonyl oxide groups containing arylcarbonyl groups as defined above substituted with one or more nitro groups, examples of which include 4-nitrobenzoyl and 2-nitrobenzoyl groups,
[117] Lower alkoxycarbonylated arylcarbonyl groups containing an arylcarbonyl group as defined above substituted with a lower alkoxy group as defined above and substituted with a carbonyl group itself, examples of which include 2- (methoxycarbonyl) benzoyl groups , And
[118] Arylated arylcarbonyl groups containing an arylcarbonyl group as defined above substituted with one or more aryl groups as defined above, examples of which include 4-phenylbenzoyl groups;
[119] (iii) alkoxycarbonyl groups, examples of which include:
[120] Lower alkoxycarbonyl groups containing a carbonyl group substituted with a lower alkoxy group as defined above, examples of which are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t- Butoxycarbonyl and isobutoxycarbonyl groups; And
[121] Lower alkoxycarbonyl groups as defined above substituted with one or more substituents selected from the group consisting of halogen atoms and tri (lower alkyl) silyl groups, wherein the lower alkyl groups are as defined above, examples of which include 2,2, 2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl group;
[122] (iv) a tetrahydropyranyl or tetrahydrothiopyranyl group which may be optionally substituted with one or more substituents selected from lower alkyl groups, halogen atoms as defined above and lower alkoxy groups as defined above, examples of which are tetrahydropyran -2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl and 4-methoxytetrahydrothiopyran-4-yl groups It includes;
[123] (v) a tetrahydrofuranyl or tetrahydrothiofuranyl group which may be optionally substituted with one or more substituents selected from lower alkyl groups as defined above, halogen atoms and lower alkoxy groups as defined above, examples of which are tetrahydrofuran 2-yl and tetrahydrothiofuran-2-yl groups;
[124] (vi) silyl groups, examples of which include:
[125] Tri (lower alkyl) silyl groups, wherein the lower alkyl groups are as defined above, examples of which are trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyl- Di-t-butylsilyl and triisopropylsilyl groups,
[126] Tri (lower alkyl) silyl groups in which at least one of the lower alkyl groups is substituted with one or two aryl groups as defined above, examples of which are diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiiso Propylsilyl group;
[127] (vii) alkoxymethyl groups, examples of which include:
[128] Lower alkoxymethyl groups containing methyl groups substituted with lower alkoxy groups as defined above, examples of which include methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, Containing butoxymethyl and t-butoxymethyl groups,
[129] Lower alkoxylated lower alkoxymethyl groups containing lower alkoxymethyl groups as defined above substituted by lower alkoxy groups as defined above, examples of which include 2-methoxyethoxymethyl groups,
[130] Lower halogeno alkoxymethyl groups containing lower alkoxymethyl groups as defined above wherein the alkoxy moiety is substituted with one or more halogen atoms, examples being 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) A methyl group;
[131] (viii) substituted ethyl groups, examples of which include:
[132] Lower alkoxylated ethyl groups containing an ethyl group substituted with a lower alkoxy group as defined above, examples of which include 1-ethoxyethyl and 1- (isopropoxy) ethyl groups,
[133] Halogenated ethyl groups such as 2,2,2-trichloroethyl group;
[134] (ix) aralkyl groups as defined above, examples of which include:
[135] Lower alkyl groups as defined above substituted with one to three aryl groups as defined above, examples being benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldi Phenylmethyl and 9-anthrylmethyl groups, and
[136] 1 to 3 aryl groups as defined above wherein the aryl moiety is substituted with one or more substituents selected from the group consisting of lower alkyl groups as defined above, lower alkoxy groups as defined above, nitro groups, halogen atoms and cyano groups Substituted lower alkyl groups as defined above, examples of which are 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl , 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl groups;
[137] (x) an "alkenyloxycarbonyl group" containing a carbonyl group substituted with an alkenyloxy group having 2 to 6 carbon atoms, examples of which include vinyloxycarbonyl and allyloxycarbonyl groups; And
[138] (xi) an aralkyloxycarbonyl group containing a carbonyl group substituted with an aralkyloxy group (oxygen atom substituted with an aralkyl group as defined above), wherein the aryl portion thereof is a lower alkoxy group and a nitro group as defined above Optionally substituted with one or two substituents selected from examples of which are benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl group.
[139] Protecting groups that can be removed by metabolic processes (eg, hydrolysis) in vivo are removed by metabolic processes (eg, hydrolysis) upon in vivo administration of a living mammal to provide a compound of formula (I) or a salt thereof will be. Preferred examples of such protecting groups include:
[140] (i) 1- (acyloxy) lower alkyl groups, examples of which include:
[141] 1- (aliphatic acyloxy) lower alkyl groups containing lower alkyl groups as defined above, substituted with alkylcarbonyloxy groups having 1 to 6 carbon atoms, examples of which are formyloxymethyl, acetoxymethyl, propionyl Oxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propy Carbonyl-oxy-pentyl, 1-butyryl-oxy-pentyl, and include 1-pivaloyloxymethyl-pentyl and 1-pivaloyloxymethyl-hexyl group,
[142] 1- (cycloalkylcarbonyloxy) lower alkyl group containing a lower alkyl group as defined above substituted with a cycloalkylcarbonyloxy group substituted with a cycloalkyl group as defined above, examples being cyclopentylcar Carbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclo Pentylcarbonyloxybutyl and 1-cyclohexylcarbonyloxybutyl groups, and
[143] A 1- (aromatic acyloxy) lower alkyl group containing a lower alkyl group as defined above substituted with an arylcarbonyloxy group containing an oxygen atom substituted with an arylcarbonyl group, examples of which include a benzoyloxymethyl group;
[144] (ii) substituted carbonyloxyalkyl groups, examples of which include:
[145] A lower alkoxy group, as defined above, or a cycloalkyl group, as defined above, substituted with a lower alkoxycarbonyloxy group containing a carbonyloxy group substituted with a lower alkoxy group or a cycloalkoxy group as defined above (lower alkoxy Carbonyloxy) alkyl groups, examples of which are methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxy Methyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (isopart Cycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, 1- (pentyloxycarbonyloxy) ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbon Carbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) propyl, 1- (cyclohexyloxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbon Nyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl , 1- (propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (pentyl Oxycarbonyloxy) propyl, 1- (hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) Butyl, 1- (iso Propoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy) pentyl, 1- (ethoxycarbonyloxy) Pentyl, 1- (methoxycarbonyloxy) hexyl and 1- (ethoxycarbonyloxy) hexyl groups, and oxodioxolenylmethyl groups, which include one or more lower alkyl groups as defined above, as defined above A methyl group substituted with an oxodioxolenyl group which may itself be optionally substituted with a group selected from the group consisting of a lower alkyl group as defined above and an aryl group as defined above, which may be optionally substituted with the same lower alkoxy group or a halogen atom And examples thereof include (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxolene-4- Il] methyl, [5- (4-methoxyphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3 -D Solen-4-yl] methyl, [5- (4-chlorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, (2-oxo-1,3-dioxolen-4-yl ) -Methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5 -Propyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl) methyl and (5-butyl-2- Oxo-1,3-dioxolen-4-yl) methyl group;
[146] (iii) a phthalidinyl group containing a phthalidyl group which may be optionally substituted with a substituent selected from the group consisting of a lower alkyl group as defined above and a lower alkoxy group as defined above, examples being phthalidyl, dimethyl A thalidil and a dimethoxyphthalidinyl group;
[147] (iv) aliphatic acyl groups such as those defined and exemplified above with respect to general protecting groups for hydroxyl groups;
[148] (v) aromatic acyl groups such as those defined and exemplified above with respect to general protecting groups for hydroxyl groups;
[149] (vi) half-ester salt residues of succinic acid;
[150] (vii) phosphate ester salt residues;
[151] (viii) ester forming residues of amino acids;
[152] (ix) carbamoyl groups which may be optionally substituted with one or two lower alkyl groups as defined above; And
[153] (x) a 1- (acyloxy) alkoxycarbonyl group containing a lower alkoxycarbonyl group as defined above, wherein the lower alkoxy moiety is substituted with an aliphatic acyloxy group as defined above or an aromatic acyloxy group as defined above, Examples include pivaloyloxymethyloxycarbonyl groups.
[154] Among the above protecting groups that can be removed by in vivo metabolic processes (eg, hydrolysis) used to synthesize modified compounds of formula (I), a substituted carbonyloxyalkyl group is preferred.
[155] When the compounds of the formula (I) of the present invention have amino groups, imino groups and / or sulfonamide groups, the compounds may be converted to derivatives other than the esters described above and the pharmaceutically acceptable salts described below. "Other derivatives" of compounds of formula I include such derivatives. Examples of such derivatives include amide derivatives wherein the aliphatic acyl groups defined and exemplified above or the aromatic acyl groups defined and exemplified above are bonded to the nitrogen atoms of the amino, imino and / or sulfonamide groups present in the compounds of formula (I). Include. If the derivative is a pharmaceutically acceptable derivative of the compound of formula (I), it is degraded by metabolic processes (eg hydrolysis) upon administration of the compound to the body of a living mammal to give the compound of formula (I) or a salt thereof You should be able to.
[156] When the compound of formula (I) or a pharmaceutically acceptable ester or other derivative thereof of the present invention has a basic group such as an amino group, the compound may be converted into a salt by reaction with an acid, and the compound of formula (I) of the present invention or If the pharmaceutically acceptable ester or other derivative has an acidic group such as a sulfonamide group, the compound may be converted to a salt by reaction with a base. Compounds of the present invention encompass such salts. If the salts are used for therapeutic use, they must be pharmaceutically acceptable.
[157] Preferred examples of salts formed with basic groups present in compounds of formula I of the present invention are; Inorganic acid salts such as hydrohalogenated acid salts (eg, hydrochloride, hydrobromide and hydroiodide), nitrates, perchlorates, sulfates and phosphates; Lower alkansulfonates whose lower alkyl moieties are as defined above (eg methanesulfonate, trifluoromethanesulfonate and ethanesulfonate), arylsulfonates whose aryl moieties are as defined above (eg, Benzenesulfonate or p-toluenesulfonate), organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate and maleate; And amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate and aspartate.
[158] Preferred examples of salts formed with acidic groups present in the compounds of formula (I) of the invention include metal salts, such as alkali metal salts (eg sodium salts, potassium salts and lithium salts), alkaline earth metal salts (eg calcium salts and magnesium salts) , Aluminum salts and iron salts; Amine salts such as inorganic amine salts (eg ammonium salts) and organic amine salts (eg t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt , N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts and tris (hydroxymethyl) aminomethane salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate and aspartate It includes.
[159] The compounds of formula I of the present invention sometimes take up water upon exposure to the atmosphere or upon recrystallization to absorb water or form hydrates, which are also within the scope of the present invention. In addition, the compounds of the present invention may take any other solvent to form solvates, which also form part of the present invention.
[160] The compounds of formula (I) of the present invention may sometimes exist in the form of geometric isomers (cis and trans isomers, or E and Z isomers), and may exist in the form of optical isomers if they contain one or more asymmetric centers. In the compounds of the present invention, each of the isomers and a mixture of the isomers is described by one formula, i. Accordingly, the present invention encompasses all mixtures of any ratio thereof, including individual isomers and racemic mixtures.
[161] Preferred classes of compounds of the invention are compounds of formula I and pharmaceutically acceptable salts, esters and other derivatives thereof, wherein:
[162] (A) R ¹ is an aryl group which may be optionally substituted with one or more substituents selected from the substituent group α and the substituent group β as defined above;
[163] (B) R ¹ is a phenyl or naphthyl group, said group may be optionally substituted with one or more substituents selected from the substituent group α and the substituent group β as defined above;
[164] (C) R ¹ is a phenyl group which may be optionally substituted with one or more substituents selected from substituent group α ^{1 as} defined above and substituent β ^{1 as} defined above;
[165] (D) R ¹ is a phenyl group which may be optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a halogeno lower alkyl group as defined above and a halogeno lower alkoxy group as defined above;
[166] (E) R ¹ is phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4 -A substituent selected from the group consisting of -fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl group;
[167] (F) R ² is a 5- or 6-membered aromatic heterocyclic group having 1 or 2 nitrogen atoms, said group optionally substituted with one or more substituents selected from the above defined substituent group α and the above defined substituent group β Become;
[168] (G) R ² is a pyridyl or pyrimidinyl group, optionally substituted with one or more substituents selected from the group consisting of the substituent group α and the substituent group β as defined above;
[169] (H) R ² is a 4-pyridyl or 4-pyrimidinyl group, said group optionally substituted with one or more substituents selected from the group consisting of the above-described substituent group α and the above-described substituent group β;
[170] (I) R ² is a 4-pyridyl or 4-pyrimidinyl group, said group being optionally substituted at its 2-position with a substituent selected from the group consisting of the above defined substituent group α and the above defined substituent group β;
[171] (J) R ² is a 4-pyridyl or 4-pyrimidinyl group, said group optionally substituted at its 2-position with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α-methylbenzylamino groups Substituted;
[172] (K) B has one ring nitrogen atom, optionally a further one ring hetero atom or a 5- or 6-membered hetero atom having a ring atom selected from a nitrogen atom, an oxygen atom, a sulfur atom,> SO and> SO ₂ A cyclic ring (the ring may be saturated or unsaturated, and may be optionally fused with an aryl group as defined above, a heteroaryl group as defined above, a cycloalkyl group as defined above or a heterocyclyl group as defined above);
[173] (L) B is a 5- or 6-membered heterocyclic ring consisting of a D group, an E group and 3 or 4 carbon atoms (the ring may be saturated or unsaturated, an aryl group as defined above, hetero as defined above Optionally fused with an aryl group, a cycloalkyl group as defined above or a heterocyclyl group as defined above);
[174] (M) B is a pyrrolidinyl ring or a pyrrolinyl ring;
[175] (N) R ³ is formula IIa or formula IIb;
[176] (O) R ³ is of formula IIa;
[177] (P) m is 1;
[178] (Q) R ⁴ is 1 or 2 substituents independently selected from the group consisting of the above-described substituent group α, the above-described substituent group β and the substituent group γ ¹ , wherein the substituent group γ ¹ is an oxo group, hydroxy Imino groups, lower alkoxyimino groups as defined above, lower alkylene groups as defined above, lower alkylenedioxy groups as defined above, lower alkylsulfinyl groups as defined above, lower alkyl as defined above A sulfonyl group and an aryl group as defined above which may be optionally substituted with one or more substituents selected from the above defined substituent group α and the above defined substituent group β;
[179] (R) R ⁴ is a hydroxyl group, a halogen atom, a lower alkoxy group as defined above, a lower alkylthio group as defined above, a halogeno lower alkoxy group as defined above, a lower alkyl group as defined above, a halogeno lower alkyl group as defined above, oxo The above defined aryl group, the above defined lower alkylenedioxy group, the above defined lower alkylene group and the above defined lower group optionally substituted with one or more substituents selected from the group above defined substituent group α and the above defined substituent group β. A substituent selected from the group consisting of alkylsulfonyl groups;
[180] (S) R ⁴ is a hydroxyl group, a fluorine atom, a chlorine atom, a methoxy group, an ethoxy group, a propoxy group, a methyl group, an ethyl group, a propyl group and at least one substituent selected from the above-described substituent group α and the above-described substituent group β A substituent selected from the group consisting of phenyl groups which may be optionally substituted;
[181] (T) R ⁴ is a substituent selected from the group consisting of methoxy group, methyl group, ethyl group, propyl group and phenyl group;
[182] (U) R ⁴ is the aryloxy group defined above, the alkyridene group defined above and the aralkylidene defined above, which may be optionally substituted with one or more substituents selected from the substituent group α and the substituent group β A substituent selected from the group consisting of groups;
[183] (V) R ⁴ is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups;
[184] (W) D is a group of the formula> C (R ⁵ )-wherein R ⁵ is selected from the group consisting of a hydrogen atom, the above defined substituent group α and the above defined substituent group β, and E is nitrogen An atom;
[185] (X) The compound of formula I is represented by formula I-1 or I-3 shown below:
[186] [Formula I-1]
[187]
[188] [Formula I-3]
[189] .
[190] (Y) The compound of formula I represents the formula
[191] [Formula I-1]
[192] .
[193] (A) to (E); (F) to (J) above; (K) to (M); (N) and (O) above; (P) above; (Q) to (V) above; (W) above; And compounds of formula (I) containing any combination of factors freely selected from the eight groups consisting of (X) and (Y) above.
[194] More preferred compounds of the present invention are compounds of formula I and their pharmaceutically acceptable salts, esters and other derivatives, wherein:
[195] (i) R ¹ is as defined in (A) above, R ² is as defined in (F) above, R ³ is as defined in (N) above, and m is the above (P ) And D and E are as defined in (W) above and R ⁴ is as defined in (Q) above;
[196] (ii) R ¹ is as defined in (B) above, R ² is as defined in (G) above, R ³ is as defined in (N) above, and m is the above (P) As defined in, D and E are as defined in (W) above, and R ⁴ is as defined in (R) above;
[197] (iii) R ¹ is as defined in (C) above, R ² is as defined in (H) above, R ³ is as defined in (N) above, wherein m is (P) As defined in, D and E are as defined in (W) above and R ⁴ is as defined in (R) above;
[198] (iv) R ¹ is as defined in (D) above, R ² is as defined in (I) above, R ³ is as defined in (O) above, where m is (P) As defined in, D and E are as defined in (W) above, and R ⁴ is as defined in (S) above;
[199] (v) R ¹ is as defined in (E) above, R ² is as defined in (J) above, R ³ is as defined in (O) above, and m is the above (P) As defined in, D and E are as defined in (W) above, and R ⁴ is as defined in (T) above;
[200] (vi) R ¹ is as defined in (A) above, R ² is as defined in (F) above, R ³ is as defined in (N) above, and m is the above (P) As defined in, D and E are as defined in (W) above, and R ⁴ is as defined in (U) above;
[201] (vii) R ¹ is as defined in (B) above, R ² is as defined in (G) above, R ³ is as defined in (N) above, and m is the above (P) As defined in, D and E are as defined in (W) above, and R ⁴ is as defined in (U) above;
[202] (viii) R ¹ is as defined in (C) above, R ² is as defined in (H) above, R ³ is as defined in (N) above, and m is the above (P) As defined in, D and E are as defined in (W) above, and R ⁴ is as defined in (U) above;
[203] (ix) R ¹ is as defined in (D) above, R ² is as defined in (I) above, R ³ is as defined in (O) above, and m is the above (P) As defined in, D and E are as defined in (W) above, and R ⁴ is as defined in (V) above;
[204] (x) R ¹ is as defined in (E) above, R ² is as defined in (J) above, R ³ is as defined in (O) above, where m is (P) As defined in, D and E are as defined in (W) above, and R ⁴ is as defined in (V) above;
[205] (xi) any of the compounds (i) to (x) above, wherein the compound of formula I is a compound of formula I-1 or formula I-3 as defined in (X) above; And
[206] (xii) The compound of any of (i) to (x), wherein the compound of formula (I) is a compound of formula (I-1) as defined in (Y) above.
[207] Among the above, preferred compounds of the present invention are compounds of formula I, pharmaceutically acceptable salts, esters and other derivatives thereof selected from the group of the following compounds:
[208] 2- (3-fluorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[209] 2- (3-fluorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[210] 2- (3-fluorophenyl) -4- [2-hydroxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[211] 2- (3-fluorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[212] 4- [2-Fluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (3-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[213] 2- (4-fluorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[214] 2- (4-fluorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[215] 2- (4-fluorophenyl) -4- [2-hydroxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[216] 2- (4-fluorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[217] 4- [2,2-ethylenedioxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine-4- 1) -1 H -pyrrole,
[218] 2- (4-fluorophenyl) -4- [2-oxo-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[219] 4- [2-Fluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[220] 4- [2-Chloro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[221] 4- [2,2-difluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine-4- 1) -1 H -pyrrole,
[222] 2- (3-chlorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[223] 2- (3-chlorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[224] 2- (3-chlorophenyl) -4- [2-hydroxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[225] 2- (3-chlorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[226] 2- (3-chlorophenyl) -4- [2-fluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[227] 4- [2-Chloro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (3-chlorophenyl) -3- (pyridin-4-yl) -1 H Pyrrole,
[228] 4- [2-Methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[229] 4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[230] 4- [2-hydroxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl) -1 H -pyrrole,
[231] 4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl) -1 H -pyrrole,
[232] 4- [2-fluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl) -1 H -pyrrole,
[233] 4- [2-Chloro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[234] 4- [2,8-dimethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[235] 2- (4-fluorophenyl) -4- [2-hydroxy-8-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine-4 -Yl) -1 H -pyrrole,
[236] 2- (4-fluorophenyl) -4- [2-methoxy-8-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine-4 -Yl) -1 H -pyrrole,
[237] 4- [2-fluoro-8-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine-4 -Yl) -1 H -pyrrole,
[238] 4- [2-Chloro-8-methyl-1, 2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine-4- 1) -1 H -pyrrole,
[239] 2- (4-fluorophenyl) -4- [2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[240] 2- (4-fluorophenyl) -4- [2-hydroxy-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[241] 2- (4-fluorophenyl) -4- [2-methoxy-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[242] 4- [2-Chloro-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[243] 4- [2,2-difluoro-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine-4- 1) -1 H -pyrrole,
[244] 4- [cyclopropanespiro-6 '-(1', 2 ', 3', 5 ', 6', 8a'-hexahydroindolizin) -7'-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[245] 2- (4-fluorophenyl) -4- [2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[246] 4- [2,2-dimethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[247] 2- (4-fluorophenyl) -4- [2-methylthio-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[248] 4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[249] 4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (3-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[250] 2- (3-chlorophenyl) -4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[251] 4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[252] 2- (4-chlorophenyl) -4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[253] 4- [2-butylthio-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[254] 4- [2-ethylthio-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[255] 4- [2-ethylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[256] 2- (4-fluorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[257] 2- (3-fluorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[258] 2- (3-chlorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[259] 4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[260] 2- (4-chlorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[261] 4- [2-ethoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[262] 4- [Cyclopentanespiro-2 '-(1', 2 ', 3', 5 ', 6', 8a'-hexahydroindolizin) -7'-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[263] 4- [2-benzylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[264] 2- (4-fluorophenyl) -4- [2-propylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[265] 4- [5,5-dimethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[266] 4- [2-ethyl-3,5,6,8a-tetrahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[267] 2- (4-fluorophenyl) -4- [2-propyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[268] 2- (4-fluorophenyl) -4- [2-phenyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[269] 2- (4-chlorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[270] 2- (4-chlorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole, and
[271] 2- (4-chlorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -Pyrrole.
[272] Among the above, more preferred compounds of the present invention are compounds of formula (I) selected from the group of compounds and pharmaceutically acceptable salts, esters and other derivatives thereof:
[273] 2- (3-fluorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[274] 2- (3-fluorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[275] 2- (3-fluorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[276] 2- (4-fluorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[277] 2- (4-fluorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[278] 2- (4-fluorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[279] 2- (3-chlorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[280] 2- (3-chlorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[281] 2- (3-chlorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[282] 4- [2-Methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[283] 4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[284] 4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl) -1 H -pyrrole,
[285] 2- (4-fluorophenyl) -4- [2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[286] 2- (4-fluorophenyl) -4- [2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[287] 4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[288] 4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (3-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[289] 2- (3-chlorophenyl) -4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[290] 4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[291] 2- (4-fluorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[292] 2- (3-fluorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[293] 2- (3-chlorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[294] 4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[295] 4- [2-ethyl-3,5,6,8a-tetrahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[296] 2- (4-fluorophenyl) -4- [2-propyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole, And
[297] 2- (4-fluorophenyl) -4- [2-phenyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole.
[298] Among the above, the most preferred compounds of the present invention are the compounds of formula I selected from compounds of the following group, and pharmaceutically acceptable salts, esters and other derivatives thereof:
[299] 2- (4-fluorophenyl) -4-[(2R, 8aS) -2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine- 4-yl) -1 H -pyrrole,
[300] 2- (4-fluorophenyl) -4-[(8aS) -2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine-4- 1) -1 H -pyrrole,
[301] 2- (4-fluorophenyl) -4-[(8aS) -2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine-4 -Yl) -1 H -pyrrole,
[302] 2- (4-fluorophenyl) -4-[(8aS) -2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[303] 4-[(2S, 8aS) -2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl) -2- (4-fluorophenyl) -3- (pyridine- 4-yl) -1 H -pyrrole, and
[304] 2- (4-fluorophenyl) -4-[(2S, 8aS) -2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine- 4-yl) -1 H -pyrrole.
[305] Specific examples of the compounds of formula I of the present invention include the following compounds of the following Tables 1-6.
[306] TABLE 1
[307]
[308]
[309]
[310]
[311]
[312]
[313]
[314]
[315]
[316]
[317]
[318]
[319]
[320]
[321]
[322]
[323]
[324]
[325]
[326]
[327]
[328]
[329]
[330]
[331]
[332]
[333]
[334]
[335]
[336]
[337]
[338]
[339]
[340]
[341]
[342] TABLE 2
[343]
[344]
[345]
[346]
[347]
[348]
[349]
[350]
[351]
[352]
[353] TABLE 3
[354]
[355]
[356]
[357] TABLE 4
[358]
[359]
[360]
[361]
[362] TABLE 5
[363]
[364]
[365] TABLE 6
[366]
[367]
[368]
[369] In the table, the following abbreviations were used.
[370] Bn represents benzyl,
[371] Bu represents butyl,
[372] Et represents ethyl,
[373] Me represents methyl,
[374] Ph represents phenyl,
[375] Phet stands for phenethyl,
[376] Pr represents a profile,
[377] Pym represents pyrimidyl,
[378] Pyr represents pyridyl,
[379] > CH ₂ represents methylidedenyl,
[380] > CHMe represents ethylideneyl,
[381] > CHEt stands for propylidedenyl,
[382] > C (Me) ₂ represents isopropylidedenyl,
[383] > CHPr represents butylidedenyl, and
[384] > CHPh represents benzylideneyl.
[385] In Tables 1 to 6 above, examples of preferred compounds include compounds of the following compound number:
[386] 1-5 to 1-7, 1-10, 1-14 to 1-23, 1-26, 1-27, 1-37 to 1-40, 1-42 to 1-44, 1-149 to 1- 151, 1-154, 1-158 to 1-167, 1-170, 1-171, 1-181 to 1-184, 1-186 to 1-188, 1-197 to 1-199, 1-202, 1-206 to 1-215, 1-218, 1-219, 1-229 to 1-232, 1-234 to 1-236, 1-245 to 1-247, 1-250, 1-254 to 1- 263, 1-266, 1-267, 1-277 to 1-280, 1-282 to 1-284, 1-293 to 1-296, 1-298, 1-301 to 1-311, 1-314, 1-315, 1-324 to 1-328, 1-330 to 1-332, 1-341 to 1-343, 1-346, 1-350 to 1-359, 1-362, 1-363, 1- 373 to 1-376, 1-378 to 1-380, 1-389 to 1-391, 1-394, 1-398 to 1-407, 1-410, 1-411, 1-421 to 1-424, 1-426 to 1-428, 1-433 to 1-439, 1-442, 1-446 to 1-455, 1-458, 1-459, 1-469 to 1-472, 1-474 to 1- 476, 1-485 to 1-487, 1-490, 1-494 to 1-503, 1-506, 1-507, 1-517 to 1-520, 1-522 to 1-524, 1-533 to 1-535, 1-538, 1-542 to 1-551, 1-554, 1-555, 1-565 to 1-568, 1-570 to 1-572, 1-5 81 to 1-583, 1-586, 1-590 to 1-599, 1-602, 1-603, 1-613 to 1-616, 1-618 to 1-620, 1-629 to 1-631, 1-634, 1-638 to 1-647, 1-650, 1-651, 1-661 to 1-664, 1-666 to 1-668, 1-677 to 1-679, 1-682, 1- 686 to 1-695, 1-698, 1-699, 1-709 to 1-712, 1-714 to 1-716, 1-725 to 1-727, 1-730, 1-734 to 1-743, 1-746, 1-747, 1-757 to 1-760, 1-762 to 1-764, 1-946 to 1-987, 1-989 to 1-998, 1-1005 to 1-1008, 1- 1010, 1-1014 to 1-1023, 1-1026, 1-1027, 1-1037 to 1-1040, 1-1042 to 1-1044, 1-1049 to 1-1056, 1-1058 to 1-1067, 1-1070 to 1-1081,
[387] 2-5 to 2-7, 2-10, 2-14 to 2-23, 2-26, 2-27, 2-37 to 2-40, 2-49 to 2-51, 2-54, 2- 58 to 2-67, 2-70, 2-71, 2-81 to 2-84, 2-93 to 2-95, 2-98, 2-102 to 2-111, 2-114, 2-115, 2-125 to 2-128, 2-137 to 2-139, 2-142, 2-146 to 2-155, 2-158, 2-159, 2-169 to 2-172, 2-181 to 2- 183, 2-186, 2-190 to 2-199, 2-202, 2-203, 2-213 to 2-216, 2-225 to 2-227, 2-230, 2-234 to 2-243, 2-246, 2-247, 2-257 to 2-260, 2-265 to 2-276,
[388] 3-1 to 3-4, 3-6, 3-17 to 3-21, 3-23 to 3-25,
[389] 4-5 to 4-7, 4-10, 4-14 to 4-23, 4-26, 4-27, 4-50 to 4-55, 4-57 to 4-66,
[390] 5-1, 5-3, 5-5 to 5-8,
[391] 6-1 to 6-3 and 6-6.
[392] Examples of more preferred compounds include compounds of the following compound number:
[393] 1-5, 1-6, 1-10, 1-14 to 1-16, 1-18 to 1-23, 1-26, 1-27, 1-37, 1-38, 1-40, 1- 42, 1-43, 1-149 to 1-151, 1-154, 1-158 to 1-160, 1-162 to 1-167, 1-170, 1-171, 1-181, 1-182, 1-184, 1-186, 1-187, 1-197, 1-198, 1-202, 1-206 to 1-208, 1-210 to 1-215, 1-218, 1-219, 1- 229, 1-230, 1-232, 1-234, 1-235, 1-245, 1-246, 1-250, 1-254 to 1-256, 1-258 to 1-263, 1-266, 1-267,1-277, 1-278, 1-280, 1-282, 1-283, 1-293 to 1-295, 1-298, 1-301 to 1-304, 1-306 to 1- 311, 1-314, 1-315, 1-324 to 1-326, 1-328, 1-330, 1-331, 1-341, 1-342, 1-346, 1-350 to 1-352, 1-354 to 1-359, 1-362, 1-363, 1-373, 1-374, 1-376, 1-378, 1-379, 1-389, 1-390, 1-394, 1- 398 to 1-400, 1-402 to 1-407, 1-410, 1-411, 1-421, 1-422, 1-424, 1-426, 1-427, 1-437 to 1-439, 1-442, 1-446 to 1-448, 1-450 to 1-455, 1-458, 1-459, 1-469, 1-470, 1-472, 1-474, 1-475, 1- 485, 1-486, 1-490, 1-494 to 1-496, 1-498 to 1-503, 1-506, 1-507, 1-517, 1-518, 1-520, 1-522, 1-523, 1-5 33, 1-534, 1-538, 1-542 to 1-544, 1-546 to 1-551, 1-554, 1-555, 1-565, 1-566, 1-568, 1-570, 1-571, 1-581 to 1-583, 1-586, 1-590 to 1-592, 1-594 to 1-599, 1-602, 1-603, 1-613, 1-614, 1- 616, 1-618, 1-619, 1-629, 1-630, 1-634, 1-638 to 1-640, 1-642 to 1-647, 1-650, 1-651, 1-661, 1-662, 1-664, 1-666, 1-667, 1-677, 1-678, 1-682, 1-686 to 1-688, 1-690 to 1-695, 1-698, 1- 699, 1-709, 1-710, 1-712, 1-714, 1-715, 1-725, 1-726, 1-730, 1-734 to 1-736, 1-738 to 1-743, 1-746, 1-747, 1-757, 1-758, 1-760, 1-762, 1-763, 1-946 to 1-987, 1-989 to 1-998, 1-1005 to 1- 1008, 1-1010, 1-1014 to 1-1023, 1-1051 to 1-1056, 1-1058 to 1-1067, 1-1070 to 1-1075,
[394] 2-93, 2-94, 2-98, 2-102 to 2-104, 2-106 to 2-111, 2-114, 2-115, 2-125, 2-126, 2-128, 2- 137, 2-138, 2-142, 2-146, 2-147, 2-150 to 2-155, 2-158, 2-159, 2-169, 2-170, 2-172, 2-181, 2-182, 2-186, 2-190 to 2-192, 2-194 to 2-199, 2-202, 2-203, 2-213, 2-214, 2-216, 2-265 to 2- 276,
[395] 3-1 to 3-4, 3-6, 3-17, 3-18, 3-20, 3-23, 3-24,
[396] 4-5, 4-10, 4-14 to 4-16, 4-20 to 4-23, 4-26, 4-27,
[397] 5-1, 5-3, and 5-5 to 5-8.
[398] Examples of preferred compounds include compounds of the following compound numbers: 1-5, 1-10, 1-14, 1-15, 1-20 to 1-23, 1-26, 1-37, 1-40, 1-42, 1-149 to 1-151, 1-154, 1-158, 1-159, 1-164 to 1-167, 1-170, 1-181, 1-184, 1-186, 1- 197, 1-202, 1-206, 1-207, 1-212 to 1-215, 1-218, 1-229, 1-232, 1-234, 1-245, 1-250, 1-254, 1-255, 1-260 to 1-263, 1-266, 1-277, 1-280, 1-282, 1-293 to 1-295, 1-298, 1-301 to 1-304, 1- 308 to 1-311, 1-314, 1-324, 1-325, 1-328, 1-330, 1-341, 1-346, 1-350, 1-351, 1-356 to 1-359, 1-362, 1-373, 1-376, 1-378, 1-389, 1-394, 1-398, 1-399, 1-404 to 1-407, 1-410, 1-421, 1- 424, 1-426, 1-437 to 1-439, 1-442, 1-446, 1-447, 1-452 to 1-455, 1-458, 1-469, 1-472, 1-474, 1-485, 1-490, 1-494, 1-495, 1-500 to 1-503, 1-506, 1-517, 1-520, 1-522, 1-533, 1-538, 1- 542, 1-543, 1-548 to 1-551, 1-554, 1-565, 1-568, 1-570, 1-581 to 1-583, 1-586, 1-590, 1-591, 1-596 to 1-599, 1-602, 1-613, 1-616, 1-618, 1-629, 1-634, 1 -638, 1-639, 1-644 to 1-647, 1-650, 1-661, 1-664, 1-666, 1-677, 1-682, 1-686, 1-687, 1-692 To 1-695, 1-698, 1-709, 1-712, 1-714, 1-725, 1-730, 1-734, 1-735, 1-740 to 1-743, 1-746, 1 -757, 1-760, 1-946, 1-949, 1-952 to 1-961, 1-964, 1-967, 1-970 to 1-979,1-982 to 1-987, 1-991 To 1-996, 1-998, 1-1005 to 1-1008, 1-1010, 1-1014 to 1-1016, 1-1051 to 1-1056, 1-1070 to 1-1075,
[399] 2-93, 2-98, 2-102, 2-103, 2-108 to 2-111, 2-114, 2-125, 2-128, 2-137, 2-142, 2-146, 2- 147, 2-152 to 2-155, 2-158, 2-169, 2-172, 2-181, 2-186, 2-190, 2-191, 2-196 to 2-199, 2-202, 2-213, 2-216,
[400] 3-1 to 3-4, 3-6, 3-17, 3-20, 3-23,
[401] 4-14, 4-15, 4-22, 4-23, and 4-26.
[402] Examples of particularly preferred compounds include the following compounds:
[403] 2- (3-fluorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[404] 2- (3-fluorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[405] 2- (3-fluorophenyl) -4- [2-hydroxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[406] 2- (3-fluorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[407] 4- [2-Fluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (3-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[408] 2- (4-fluorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[409] 2- (4-fluorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[410] 2- (4-fluorophenyl) -4- [2-hydroxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[411] 2- (4-fluorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[412] 4- [2,2-ethylenedioxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine-4- 1) -1 H -pyrrole,
[413] 2- (4-fluorophenyl) -4- [2-oxo-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[414] 4- [2-Fluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[415] 4- [2-Chloro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[416] 4- [2,2-difluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine-4- 1) -1 H -pyrrole,
[417] 2- (3-chlorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[418] 2- (3-chlorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[419] 2- (3-chlorophenyl) -4- [2-hydroxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[420] 2- (3-chlorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[421] 2- (3-chlorophenyl) -4- [2-fluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[422] 4- [2-Chloro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (3-chlorophenyl) -3- (pyridin-4-yl) -1 H Pyrrole,
[423] 4- [2-Methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[424] 4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[425] 4- [2-hydroxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl) -1 H -pyrrole,
[426] 4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl) -1 H -pyrrole,
[427] 4- [2-fluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl) -1 H -pyrrole,
[428] 4- [2-Chloro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[429] 4- [2,8-dimethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[430] 2- (4-fluorophenyl) -4- [2-hydroxy-8-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine-4 -Yl) -1 H -pyrrole,
[431] 2- (4-fluorophenyl) -4- [2-methoxy-8-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine-4 -Yl) -1 H -pyrrole,
[432] 4- [2-fluoro-8-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine-4 -Yl) -1 H -pyrrole,
[433] 4- [2-Chloro-8-methyl-1, 2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine-4- 1) -1 H -pyrrole,
[434] 2- (4-fluorophenyl) -4- [2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[435] 2- (4-fluorophenyl) -4- [2-hydroxy-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[436] 2- (4-fluorophenyl) -4- [2-methoxy-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[437] 4- [2-Chloro-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[438] 4- [2,2-difluoro-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine-4- 1) -1 H -pyrrole,
[439] 4- [cyclopropanespiro-6 '-(1', 2 ', 3', 5 ', 6', 8a'-hexahydroindolizin) -7'-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[440] 2- (4-fluorophenyl) -4- [2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[441] 4- [2,2-dimethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[442] 2- (4-fluorophenyl) -4- [2-methylthio-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[443] 4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[444] 4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (3-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[445] 2- (3-chlorophenyl) -4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[446] 4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[447] 2- (4-chlorophenyl) -4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[448] 4- [2-butylthio-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[449] 4- [2-ethylthio-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[450] 4- [2-ethylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[451] 2- (4-fluorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[452] 2- (3-fluorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[453] 2- (3-chlorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[454] 4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[455] 2- (4-chlorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[456] 4- [2-ethoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[457] 4- [Cyclopentanespiro-2 '-(1', 2 ', 3', 5 ', 6', 8a'-hexahydroindolizin) -7'-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[458] 4- [2-benzylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl)- 1 H -pyrrole,
[459] 2- (4-fluorophenyl) -4- [2-propylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[460] 4- [5,5-dimethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[461] 4- [2-ethyl-3,5,6,8a-tetrahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[462] 2- (4-fluorophenyl) -4- [2-propyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[463] 2- (4-fluorophenyl) -4- [2-phenyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[464] 2- (4-chlorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[465] 2- (4-chlorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole, and
[466] 2- (4-chlorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -Pyrrole.
[467] Examples of particularly preferred compounds include the following compounds:
[468] 2- (3-fluorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[469] 2- (3-fluorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[470] 2- (3-fluorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[471] 2- (4-fluorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[472] 2- (4-fluorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[473] 2- (4-fluorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[474] 2- (3-chlorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[475] 2- (3-chlorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[476] 2- (3-chlorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[477] 4- [2-Methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[478] 4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[479] 4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl) -1 H -pyrrole,
[480] 2- (4-fluorophenyl) -4- [2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[481] 2- (4-fluorophenyl) -4- [2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
[482] 4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[483] 4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (3-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[484] 2- (3-chlorophenyl) -4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[485] 4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[486] 2- (4-fluorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[487] 2- (3-fluorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[488] 2- (3-chlorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
[489] 4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
[490] 4- [2-ethyl-3,5,6,8a-tetrahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
[491] 2- (4-fluorophenyl) -4- [2-propyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole, And
[492] 2- (4-fluorophenyl) -4- [2-phenyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole.
[493] Examples of the most preferred compounds include the following compounds:
[494] 2- (4-fluorophenyl) -4-[(2R, 8aS) -2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine- 4-yl) -1 H -pyrrole,
[495] 2- (4-fluorophenyl) -4-[(8aS) -2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine-4- 1) -1 H -pyrrole,
[496] 2- (4-fluorophenyl) -4-[(8aS) -2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine-4 -Yl) -1 H -pyrrole,
[497] 2- (4-fluorophenyl) -4-[(8aS) -2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
[498] 4-[(2S, 8aS) -2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl) -2- (4-fluorophenyl) -3- (pyridine- 4-yl) -1 H -pyrrole, and
[499] 2- (4-fluorophenyl) -4-[(2S, 8aS) -2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine- 4-yl) -1 H -pyrrole.
[500] The compounds of Tables 1 to 6 are of formula I-1. Combinations of substituents (R ¹ , R ² and R ³ ) exemplified for I-1 may also be applied to formulas (I-2), (I-3), (I-4) and (I-5), mentioned above as preferred compounds Preference is also given to compounds represented by the formulas (I-2), (I-3), (I-4) and (I-5) corresponding to the above compounds.
[501] The compounds of the formula (I) of the present invention can be prepared by the methods mentioned below.
[502] Method A
[503] Method A is a method of preparing a compound of formula I represented by formula I-1:
[504]
[505] In the above formula, R ¹ , R ² and R ³ are as defined above.
[506] Step A1
[507] In this step, a pyrrolidine compound of formula 3a is prepared by reacting an aminonitrile compound of formula 1a with an α, β-unsaturated aldehyde compound of formula 2a. This type of reaction is well known in the field of organic chemical synthesis and can be carried out using well known techniques, for example according to the method disclosed in EP 0799823, the contents of which are incorporated herein by reference.
[508] More specifically, this step is carried out in the presence of a base. There is no particular limitation on the nature of the base used, and any base commonly used in this type of reaction may equally be used here. Examples of such bases include: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; Alkali metal amides such as lithium amide, sodium amide, potassium amide and lithium bis (trimethylsilyl) amide; And alkali metal alkoxides, such as lithium ethoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide. Of these, lithium amide is preferred.
[509] The reaction is carried out generally and preferably in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that the reaction or the reagent involved is free of side effects and can dissolve the reagent to some extent. Examples of suitable solvents include: aliphatic hydrocarbons such as hexane and heptane; Aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; And alcohols such as methanol, ethanol, propanol, isopropanol and butanol. Of these, ether is preferred.
[510] The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. Preferred reaction temperatures will depend on the nature of the solvent and factors such as the starting material or the reagent used. In general, however, it has been found to be convenient to carry out the reaction at -78 ° C to 100 ° C, more preferably at -78 ° C to room temperature. The time required for the reaction can also vary widely and depends on many factors, especially the reaction temperature and the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions indicated above, a period of 10 minutes to 30 hours, more preferably 1 hour to 20 hours will generally be sufficient.
[511] Step A2
[512] In this step, the preferred pyrrole derivatives of the formula (I-1) of the present invention are prepared by removing water and hydrogen cyanide from the compound of the formula (3a) prepared in step A1. These reactions are well known in the field of organic chemical synthesis and can be carried out according to well known techniques, for example the methods described in detail in EP 0799823.
[513] More specifically, the residue obtained by distilling off the solvent from the product of step A1 is heated or, after completion of step A1, the residue is extracted with water and preferably at a temperature of 100 ° C. or higher in the presence or absence of solvent. Washing and distilling off the solvent can achieve this by heating the material. The reaction proceeds sufficiently in the absence of solvent, but when a solvent is used, the solvent is preferably inert and has a higher boiling point. Examples of suitable solvents include: toluene, xylene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, diglyme and diphenyl ether.
[514] Method B, Method C, Method D, and Method E
[515] Method B, Method C, Method D and Method E are used to prepare compounds of Formulas I-2, I-3, I-4 and I-5 using the procedures summarized in the following Schemes B-E, respectively do.
[516]
[517] In the above formula, R ¹ , R ² and R ³ are as defined above.
[518] The reaction schemes B1, C1, D1 and E1 are carried out in a similar manner to step A1 and steps B2, C2, D2 and E2 are performed similarly to step A2.
[519] Method F
[520] In this process, compounds of formula (I-1) [I-1a, I-1b, and I-1c] of the present invention are prepared as shown in Scheme F.
[521]
[522] In the above formula, B, D, E, R ¹ , R ² , R ⁴ and m have the same meaning as defined above,
[523] R ⁶ represents a hydrogen atom, a lower alkyl group as defined above, or an aralkyl group as defined above,
[524] Each R ⁷ is the same or different and each represents a hydrogen atom, a lower alkyl group as defined above, an aryl group as defined above or an aralkyl group as defined above.
[525] Step F1
[526] In this step, a pyrrole carboxylic acid derivative of formula (6) is prepared by reacting an α, β-unsaturated compound of formula (4) with an isonitrile compound of formula (5). This type of reaction is well known in the field of organic chemical synthesis and is well known in the art, for example R. Di. Santo et al., Synthetic Communications, 25 (6), pp. 795-802 (1995), the contents of which are incorporated herein by reference.
[527] Step F2
[528] In this step, the disubstituted pyrrole compound (7) is first R ⁶ is pyrrole-carboxylic acid indicate a lower alkyl group or an aralkyl group of the ester (6), by removing the protective group R ⁶ pyrrole-carboxylic acid compound (6) Wherein R ⁶ represents a hydrogen atom, followed by a decarboxylation reaction on the compound. This type of decarboxylation reaction is well known in the field of organic chemical synthesis and employs well known techniques, for example using heating under acidic, basic or neutral conditions. Yoshida et al., Yakugaku Zasshi, 93 (5), 584-598 (1973), the contents of which are incorporated herein by reference; For example, it may be carried out using a solvent and an acid or a base under the conditions described below. When R ⁶ is a lower alkyl or aralkyl group, TW Greene et al .: Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. Deprotection reactions can be carried out using well known techniques according to the methods described in.
[529] The decarboxylation reaction is generally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that there is no side effect in the reaction or the reagents involved and the reagent can be dissolved to some extent. Examples of suitable solvents include water and mixtures of water and organic solvents, examples of organic solvents include aliphatic hydrocarbons such as pentane, hexane and heptane; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; Alcohols such as methanol, ethanol, propanol, isopropanol, butanol, s-butanol, isobutanol and t-butanol; Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide; Nitriles such as acetonitrile; And esters such as methyl acetate and ethyl acetate, of which water, alcohol or mixtures thereof are preferred.
[530] The acid used in the decarboxylation reaction is not particularly limited, provided that it is conventionally used as an acid in a hydrolysis reaction, and examples thereof include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; Carboxylic acids such as formic acid, acetic acid, propionic acid and trifluoroacetic acid; And sulfonic acids such as methanesulfonic acid and ethanesulfonic acid, of which hydrochloric acid, sulfuric acid or acetic acid are preferred.
[531] The base used in the decarboxylation reaction is not particularly limited, provided that it is conventionally used as a base in the hydrolysis reaction, and examples thereof include alkali metal hydrides such as sodium hydride and lithium hydride; Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as sodium carbonate and potassium carbonate; And amines such as triethylamine, tributylamine, pyridine, picoline and 1,8-diazabicyclo [5.4.0] undec-7-ene, of which sodium hydroxide or potassium hydroxide is preferred.
[532] The reaction can be carried out over a wide range of temperatures, and the exact reaction temperature is not critical to this reaction. Preferred reaction temperatures will depend on the nature of the solvent and factors such as the starting materials or reagents used. In general, however, it has been found to be convenient to carry out the reaction at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. The time required for the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 48 hours, preferably 30 minutes to 12 hours is generally sufficient.
[533] Steps F3 through F5
[534] In step F3, the silylated compound (8) is prepared by silylating nitrogen at the 1-position of the disubstituted pyrrole compound (7) obtained according to the method of step F2.
[535] In step F4, the silylated compound (8) obtained according to the method of step F3 is converted to the brominated pyrrole compound (9) using a brominating agent (eg N-bromosuccinimide), and in step F5, so The compound (9) obtained and isolated is first lithiated and then reacted with the heterocyclyl ketone (10) to give the hydroxyheterocyclyl compound (11).
[536] The reaction of steps F3, F4 and F5 is a technique commonly known in the field of organic chemical synthesis, such as Brian L. Bray et al., J. Org. Chem., 55 , 6317-6318 (1990), the contents of which are incorporated herein by reference.
[537] Step F6
[538] In this step, the unsaturated heterocyclyl compound (12) is prepared by dehydrating the hydroxyheterocyclyl compound (11) obtained in step F5. Dehydration reactions are well known in the art of organic chemical synthesis and can be carried out using well known techniques. For example, it may be carried out in the presence of an acid catalyst such as sulfuric acid, a solid catalyst such as alumina or a halogenating agent such as thionyl chloride [these reactions are for example G.H. Coleman & H.F. Johnstone, Org. Synth., I. 183 (1941); R. L. Sawyer & D. W. Andrus, Org. Synth., III. 276 (1955); And J. S. Lamos et al., Tetrahedron Lett., 599 (1971), the contents of which are incorporated herein by reference]. Alternatively, the dehydration reaction in this step is carried out by the reaction of hydroxyheterocyclyl compound (11) with trialkylsilanes such as triethylsilane, tripropylsilane or tributylsilane and trifluoroacetic acid [ See, eg, Francis A. Carey & Henry S. Tremper, J. Am. Chem. Soc., 91, 2967-2972 (1969), the contents of which are incorporated herein by reference].
[539] Step F7
[540] In this step, the preferred compound of the formula (I-1a) of the present invention is prepared by removing the protecting group (silyl group) from the pyrrole nitrogen of the unsaturated heterocyclyl compound (12) prepared in step F6. This type of desilylation reaction is well known in the field of organic chemical synthesis, and well known techniques such as Brian, L. Bray et al., J. Org. Chem., 55 , 6317-6318 (1990) can be performed using a desilylation reagent such as tetrabutylammonium fluoride (TBAF), the contents of which are incorporated herein by reference.
[541] Step F8
[542] In this step, the unsaturated heterocyclyl compound (13) is prepared by dehydrating the hydroxyheterocyclyl compound (11) obtained in step F5. This dehydration reaction is carried out in a similar manner to that described in step F6 above.
[543] Step F9
[544] In this step, the preferred compound of the formula (I-1b) of the present invention is prepared by removing the protecting group (silyl group) from the pyrrole nitrogen of the unsaturated heterocyclyl compound (13) prepared in step F8. This step can be carried out in a similar manner as described in step F7 above.
[545] Step F10
[546] In this step, hydroxyheterocyclyl compound (15) is prepared by first lithiating compound (9) prepared in step F4 and then reacting it with heterocyclyl ketone (14). This step can be carried out in a similar manner as described in step F5 above.
[547] Step F11
[548] In this step, the unsaturated heterocyclyl compound (16) is prepared by carrying out the dehydration reaction of the hydroxyheterocyclyl compound (15) obtained in step (10). This carbolysis reaction is carried out in the same manner as described in step F6 above.
[549] Step F12
[550] In this step, preferred compounds of the formula (I-1c) of the present invention are prepared by removing the protecting group (silyl group) from the pyrrole nitrogen of the unsaturated heterocyclyl compound (16) prepared in step F11. This step can be carried out in a similar manner as described in step F7 above.
[551] Method G
[552] In general, the compounds of formula (I) of the present invention can be prepared by introducing R ³ groups into pyrrole compounds already substituted on the pyrrole ring with R ¹ and R ² groups. Compounds of formula (I-1) can be prepared according to Method G, for example as shown in Scheme G below.
[553]
[554] In the above formula, R ¹ , R ² , R ³ and R ⁷ are as defined above and L represents a leaving group.
[555] Leaving group L is a group that can be detached as a nucleophilic moiety. Examples include halogen atoms such as fluorine, chlorine, bromine and iodine, trihalogenomethyloxy groups such as trichloromethoxy, lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy groups, lower halogeno Alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy groups, and arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy Contains groups. Of these, halogen atoms are preferred, and bromine atoms are particularly preferred.
[556] Step G1
[557] In this step, the compound of formula 18 is first lithiated the bromopyrrole compound of formula 9 (prepared as described in step F4 above), and then the lithiated intermediate is prepared in a similar manner to step F5. Prepared by reaction with Substitution reactions of this type of lithiated pyrrole intermediates are well known in the field of organic chemical synthesis and can be carried out according to well known techniques, for example the methods detailed in WO 99/01449, the content of which is herein Is reflected as a reference.
[558] Step G2
[559] In this step, the compound of formula I-1 of the present invention is prepared by removing the protecting group (silyl group) of the compound of formula 18 obtained in step G1 according to a procedure similar to that described in step F7 above.
[560] Method H
[561] In this process, R ² is a heteroaryl group having at least one ring nitrogen atom, and a compound of formula (Ia) of the present invention substituted with ^a group of formula NR ^a R ^b can be prepared as shown in Scheme H below.
[562]
[563] In the above formula, the cyclic groups A, R ¹ , R ³ , R ^a and R ^b are defined above, R ^{2 ′} is a heteroaryl group having at least one ring nitrogen atom, L ′ represents a leaving group, − R ^{2 ′} -L ′ represents a heteroaryl group having at least one ring nitrogen atom (as illustrated and defined above for substituent R ² ), which represents a leaving group (eg, 2-methanesulfonyl-pyrimidine-4- 1, 2-methanesulfonylpyridin-4-yl, etc.).
[564] Leaving group L 'is a group similar to the leaving group exemplified and defined above in the definition of L, or a lower alkylsulfonyl group as exemplified and defined above, for example methanesulfonyl, ethanesulfonyl, propanesulfonyl or butanesulfo Or an arylsulfonyl group, such as a benzenesulfonyl, p-toluenesulfonyl or p-nitrobenzenesulfonyl group. The L 'group is preferably a lower alkylsulfonyl group, more preferably a methanesulfonyl group.
[565] Step H1
[566] In this step, preferred compounds of formula (Ia) of the present invention are prepared by reacting a compound of formula (19) with an amine compound of formula (20), replacing the leaving group with ^a group of formula -NR ^a R ^b . This reaction is generally carried out in a solvent in the presence or absence of a base.
[567] The reaction is carried out generally and preferably in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that the reaction and associated reagents are free of side effects and that the reagent can be dissolved to some extent or more. Examples of suitable solvents include: alcohols such as methanol, ethanol and isopropanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; Aprotic polar solvents such as dimethylformamide, dimethylacetamide and dimethyl sulfoxide; Nitriles such as acetonitrile; Esters such as methyl acetate and ethyl acetate; Aromatic hydrocarbons such as benzene, toluene and xylene; And aliphatic hydrocarbons such as pentane, hexane and heptane, alcohols of which are preferred, with methanol and ethanol being more preferred.
[568] The base used in this step is not particularly limited as long as it is effective for this reaction, examples of which include: alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide; Alkali metal hydrides such as sodium hydride and lithium hydride; Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as sodium carbonate and potassium carbonate; And amines such as triethylamine, tributylamine, pyridine, picoline and 1,8-diazabicyclo [5.4.0] undec-7-ene, of which amines are preferred, triethylamine, pyridine and 1 , 8-diazabicyclo [5.4.0] undec-7-ene is more preferred.
[569] The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. Preferred reaction temperatures will depend on the nature of the solvent, starting materials and other factors such as the reagents used. In general, however, it is convenient to carry out the reaction at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. In addition, the time required for the reaction may vary widely depending on many factors, especially the reaction temperature, the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 48 hours, preferably 30 minutes to 12 hours is generally sufficient.
[570] Almost all of the starting materials used in the above methods A to H, i.e. compounds (1a), (1b), (1c), (1d), (1e), (2a), (2b), (2c), (2d ), (2e), (4), (5), (10), (14), (17) and (20) are well known compounds, or they are known methods (eg, described in WO97 / 5877 And compounds (19) can be prepared from known compounds by carrying out the reaction in a manner similar to that described in each of methods A to E above.
[571] Alternatively, starting compounds of formula (10) as defined above can be prepared by the methods I to M described below.
[572] Method I
[573] This is a process for the preparation of compounds of formulas 26 and 27, which is a compound of formula 10 wherein D represents a group of formula> CR ^4a -wherein R ^4a is as defined below and E represents a nitrogen atom This method is carried out as represented by Scheme I below.
[574]
[575] Wherein R, B, L and m are as defined above, and groups each of R ^4a is the same or different, general formula R ⁴ (provided that at least one group of R ^4a, such as a hydrogen atom or the above definitions, R ⁴ R ⁸ and R ⁹ are the same or different and each represents a lower alkyl group as defined above or an aralkyl group as defined above.
[576] Step I1
[577] In this step, the cyclic amine diester compound of formula 23 is prepared by condensation of the cyclic amino acid ester compound of formula 22 with the carboxylic acid ester compound of formula 21 having a leaving group (L).
[578] This reaction is generally carried out in a solvent in the presence or absence of a base.
[579] The reaction is carried out generally and preferably in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that the reaction and associated reagents are free of side effects and that the reagent can be dissolved to some extent or more. Examples of suitable solvents include: alcohols such as methanol, ethanol, propanol and isopropanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; Aprotic polar solvents such as dimethylformamide, dimethylacetamide and dimethyl sulfoxide; Nitriles such as acetonitrile; Esters such as methyl acetate and ethyl acetate; Aromatic hydrocarbons such as benzene, toluene and xylene; And aliphatic hydrocarbons such as pentane, hexane and heptane, of which alcohols, ethers, aprotic solvents and esters are preferred.
[580] The base used in this step is not particularly limited as long as it is effective for this reaction, examples of which include: alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide; Alkali metal hydrides such as sodium hydride and lithium hydride; Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as sodium carbonate and potassium carbonate; And amines such as triethylamine, tributylamine, pyridine, picoline and 1,8-diazabicyclo [5.4.0] undec-7-ene, among which sodium carbonate, potassium carbonate, triethyl Preferred are amines, pyridine and 1,8-diazabicyclo [5.4.0] undec-7-ene.
[581] The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. Preferred reaction temperatures will depend on the nature of the solvent, the starting material or other factors such as the reagent used. In general, however, it is convenient to carry out the reaction at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. In addition, the time required for the reaction may vary widely depending on many factors, especially the reaction temperature, the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 48 hours, preferably 30 minutes to 12 hours is generally sufficient.
[582] Steps I2 to I4
[583] In step I2, the cyclic amine diester compound of formula 23 prepared in step I1 is converted to a keto ester compound of formula 24 and / or a keto ester compound of formula 25 using a Dieckmann reaction. In steps I3 and I4, the product of formula 24 thus obtained and / or product of formula 25 is then subsequently hydrolyzed and decarboxylated to give preferred cyclic aminoketone compounds of formula 26 and / or preferred cyclic amino The ketone compound (27) is prepared.
[584] The reaction of steps I2 to I4 is described in J.R. Harrison et al., J. Chem, Soc., Perkin Trans. 1, 1999, 3623-3631, the contents of which are incorporated herein by reference. For example, steps I3 and I4 can be performed as follows.
[585] The reaction of steps I3 and I4 is generally carried out in a single step in the presence or absence of a solvent in the presence or absence of an acid or base.
[586] The reaction is carried out generally and preferably in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that the reaction and associated reagents are free of side effects and that the reagent can be dissolved to some extent or more. Examples of suitable solvents include: water, or water and organic solvents, examples of which include: aliphatic hydrocarbons such as pentane, hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, s- Butanol, isobutanol and t-butanol; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide; nitriles such as acetonitrile; and esters such as methyl Acetate and ethyl acetate), of which a mixture of water, water and alcohol and a mixture of water and ether are preferred.
[587] The acid used in the reaction is not particularly limited as long as it is generally used as an acid in a hydrolysis reaction, and examples thereof include: inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; Carboxylic acids such as formic acid, acetic acid, propionic acid or trifluoric acid; And sulfuric acid, such as methanesulfonic acid or ethanesulfonic acid. The two-step reaction is accelerated by the addition of an acid, of which inorganic acids and carboxylic acids are preferred, and hydrochloric acid, sulfuric acid, formic acid and acetic acid are more preferred.
[588] The base used in this step is not particularly limited as long as it is effective for this reaction, examples of which include: alkali metal hydrides such as sodium hydride and lithium hydride; Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as sodium carbonate and potassium carbonate; And amines such as triethylamine, tributylamine, pyridine, picoline and 1,8-diazabicyclo [5.4.0] undec-7-ene, of which alkali metal hydroxides are preferred, sodium hydroxide and Potassium hydroxide is more preferred.
[589] The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. Preferred reaction temperatures will depend on the nature of the solvent, starting materials and other factors such as the reagents used. In general, however, it is convenient to carry out the reaction at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. In addition, the time required for the reaction may vary widely depending on many factors, especially the reaction temperature, the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 48 hours, preferably 30 minutes to 12 hours is generally sufficient.
[590] Method J
[591] This is a process for the preparation of compounds of formula 32, wherein E represents a nitrogen atom, D represents a group> CH-, R ^4a is as defined above and W is a compound of formula 10 as defined below This method is carried out as shown in the following formula (J).
[592]
[593] Wherein R ^4a is as defined above,
[594] R ¹⁰ and R ¹¹ are the same or different and each represents a lower alkyl group as defined above or an aralkyl group as defined above,
[595] R ¹² and R ¹³ are the same or different and each represents a lower alkyl group as defined above or R ¹² and R ¹³ together form a lower alkylene group as defined above,
[596] W represents a lower alkylene group as described above substituted with one to three R ⁴ groups as defined above, said alkylene group being selected from the group consisting of nitrogen atom, oxygen atom, sulfur atom,> SO group and> SO ² group Any 1 or 2 atoms or groups selected are inserted,
[597] The cyclic group containing W shown in the formulas (31) and (32) is a group corresponding to the cyclic group B as defined above, which is unsubstituted or substituted with 1 to 3 R ⁴ groups.
[598] Steps J1 and J2 are both well known in the field of organic chemical synthesis and can be performed using any combination of such known methods, for example O. Pollet et al., Heterocycles, 43, 1391 (1996) or Anet et al., Austral. J. Scient. Res., <A> 3, 635-640 (1950), which may be carried out in a similar manner, the contents of which are incorporated herein by reference.
[599] Method K
[600] This is a process for the preparation of compounds of formula 37, wherein D represents a group of formula> CR ^4a -wherein R ^4a is as defined above, and E is a compound of formula 10 representing a nitrogen atom, Is carried out as shown in Scheme K below.
[601]
[602] In the above formula, B and R ^4a are as defined above,
[603] R ¹⁴ represents an amino protecting group,
[604] Hal represents a halogen atom (preferably a chlorine atom, bromine atom or iodine atom),
[605] Y is a halogenocarbonyl group (e.g., -CO-Cl, -CO-Br or -CO-I), N- (lower alkoxy) -N- (lower alkyl) carbamoyl group, wherein the lower alkoxy and lower Alkyl moieties are as defined above (examples of such groups are N-methoxy-N-methylcarbanoyl, N-ethoxy-N-methoxycarbamoyl and N-ethyl-N-methoxycarbamoyl groups Or cyano group.
[606] The amino protecting group in the definition of R ¹⁴ may be any protecting group for amino groups commonly used in organic synthesis, examples of which include TWGreene et al .: Protective Groups in Organic Synthesis, John Willey & Sons, Inc. There is. Specific examples of suitable amino protecting groups include aliphatic acyl groups as defined and exemplified above, aromatic acyl groups as defined and exemplified above, silyl groups as defined and exemplified above, aralkyl groups as defined and exemplified above, Alkoxycarbonyl groups as defined and exemplified, alkenyloxycarbonyl groups as defined and exemplified above and aralkyloxycarbonyl groups as defined and exemplified above, among which alkoxycarbonyl groups are preferred, and t-butoxycarbonyl groups are more preferred Do.
[607] Step K1
[608] In this step, an α, β-unsaturated ketone derivative of Formula 35 is prepared by reacting a cyclic amino acid derivative of Formula 33 with a Grignard reagent of an olefin compound of Formula 34. This type of reaction is well known for the preparation of ketones from carboxylic acid derivatives and Grignard reagents, and any such known reaction can be used in the field of organic synthesis; For example, H.R. Snyder et al., Org. Synth., III 798 (1955); J. Cason et al., J. Org. Chem., 26, 1768 (1961); G.H. Posner et al., J. Am. Chem. Soc., 94, 5106 (1972); And in G. H. Posner, Org. React., 19, 1 (1972), which may be performed using the procedures described in detail, the contents of which are incorporated by reference in their entirety.
[609] Step K2 and K3
[610] In step K2, the nitrogen protecting group (R ¹⁴ ) is removed from the α, β-unsaturated ketone derivative of formula 35 prepared in step K1 to provide a deprotecting intermediate of formula 36, which is then cyclicized in step K3 to give a preferred There is provided a cyclic aminoketone compound of formula 37. In step K2, the deprotection reaction used may be any conventionally used in organic synthesis (examples are described in TWGreene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc.). Preferably, the deprotection reaction is carried out under neutral or acidic conditions. After the deprotection reaction, the isolated compound of formula 36, which is not isolated, is immediately cyclized to give the preferred aminoketone compound of formula 37. The deprotection reaction is more preferably carried out under acidic conditions, and the aminoketone compound of formula 37 is prepared without further reaction by neutralizing the reaction mixture.
[611] Method L
[612] This is a process for the preparation of formula (40), which is a compound of formula (10) in which D represents a group> CR ^4a -wherein R ^4a is as defined above and E represents a nitrogen atom, Is performed as shown in
[613]
[614] In the above formula, B, R ^4a , R ¹⁴ and m are as defined above, L ″ is a leaving group as defined for the leaving group L, a lower alkylsulfonyl group as defined above, as defined above The same arylsulfonyl group or halogeno lower alkyl moiety represents a halogeno lower alkylsulfonyl group as defined above (examples of such groups include trifluoromethanesulfonyl and pentafluoroethanesulfonyl groups).
[615] Step L1 and L2
[616] Steps L1 and L2 first remove the amino protecting group (R ¹⁴ ) from the ketone compound (38) having the leaving group L ″ to provide a deprotected intermediate of formula 39, and then cyclically to the intermediate to Producing an aminoketone compound, these steps can be carried out in a manner similar to the reactions described in steps K2 and K3 above.
[617] Starting compounds of the formula 38 used as starting materials in this process can be known compounds or can be prepared from known compounds using known methods [eg, S.W. Goldstein et al., J. Org. Chem., 57, 1179-1190 (1992); And in B. Achille et al., J. Comb. Chem., 2, 337-340 (2000), the contents of which are incorporated herein by reference].
[618] Method M
[619] This method is a method for preparing a compound of formula 47, which is a compound of formula 10 wherein D represents a group> CR ^4a -wherein R ^4a is as defined above, and E represents a nitrogen atom. Is carried out as shown in Scheme M below.
[620]
[621] In the above formula, R ^4a , R ⁶ , R ¹⁴ and B are as defined above,
[622] R ¹⁵ and R ¹⁶ are the same or different and each represents a hydrogen atom, a lower alkyl group as defined above or an aralkyl group as defined above, or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached Or forms a 6-membered heterocyclic ring, which comprises one ring nitrogen atom and may optionally comprise one further heteroatom selected from oxygen, sulfur and nitrogen atoms (examples of such groups include Lalidinyl, piperidyl, piperazinyl, morpholinyl and thiomorpholinyl groups).
[623] Step M1 and M2
[624] In these steps, the ketoractam compound of formula 43 is prepared by first removing the amino protecting group (R ¹⁴ ) from the α-ketosan compound of formula 41 to provide a deprotected intermediate of formula 42, and then cyclically slicing the intermediate. do. These steps are carried out in a similar manner as described in steps K2 and K3 above.
[625] Step M3
[626] In this step, the cyclic enaminolactam compound of formula 45 is prepared by reacting the ketorlactam compound of formula 43 prepared in step M2 with a secondary amine compound of formula 44. Any technique commonly used in the field of organic chemical synthesis for the preparation of enamine derivatives can be used. For example, this step is described below or by G. Stork et al., J. Am, Chem. Soc., 85.207 (1963), the contents of which are incorporated herein by reference.
[627] The reaction is generally carried out in a solvent in the presence or absence of an acid.
[628] The reaction is carried out generally and preferably in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that the reaction and associated reagents are free of side effects and that the reagent can be dissolved to some extent or more. Examples of suitable solvents include: aliphatic hydrocarbons such as pentane, hexane and heptane; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; Alcohols such as methanol, ethanol, propanol, isopropanol, butanol, s-butanol, isobutanol and t-butanol; Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide; Nitriles such as acetonitrile; Preferred are esters, such as methyl acetate and ethyl acetate, of which ether.
[629] The acid used in the reaction is not particularly limited as long as it is generally used in such a reaction, and examples thereof include: inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, perchloric acid and phosphoric acid; And organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid and trifluoromethane, among which sulfuric acid, hydrochloric acid and p-toluenesulfonic acid are more preferred.
[630] The reaction of this stage can be effectively carried out by removing the water produced during the reaction using a molecular sieve or water separator (for example Dean Stark Water Separator, available from Aldrich).
[631] The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. Preferred reaction temperatures will depend on the nature of the solvent, the starting material or other factors such as the reagent used. In general, however, it is convenient to carry out the reaction at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. In addition, the time required for the reaction can vary widely depending on many factors, especially the reaction temperature and the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 48 hours, preferably 30 minutes to 12 hours is generally sufficient.
[632] Step M4
[633] In this step, the cyclic enamine compound of formula 46 is produced by reducing the cyclic enaminolactam compound of formula 45 prepared in step M3. Any technique commonly used in the field of organic chemical synthesis can be used to carry out the reduction reaction. For example, the reduction is described in S. Cortes et al., J. Org. Chem., 48, 2246 (1983); Y. Tsuda et al., Synthesis, 652 (1977); H. C. Brown et al., J. Am. Chem. Soc., 86, 3566 (1964) and R. J. Sandberg et al., J. Org. Chem., 46, 3730 (1981), the contents of which are incorporated herein by reference.
[634] This reaction is generally carried out in a solvent in the presence of a reducing agent.
[635] Examples of reducing agents used are hydride reagents such as alkali metal borohydrides such as sodium borohydride and lithium borohydride, and aluminum hydrides such as lithium aluminum hydride and lithium triethoxyalumino hydride ; Lewis acid examples include combinations of aluminum chloride, tin tetrachloride or titanium tetrachloride with hydrides as defined above; And boron compounds such as diborane, of which lithium aluminum hydride is preferred.
[636] In the reduction reactions, nonpolar solvents can be used, preferred examples of which include: aliphatic hydrocarbons such as pentane, hexane and heptane; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; And ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane. Of these, ether is preferred.
[637] The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. Preferred reaction temperatures will depend on the nature of the solvent, starting materials and other factors such as the reagents used. In general, however, it is convenient to carry out the reaction at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. In addition, the time required for the reaction may vary widely depending on many factors, especially the reaction temperature, the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 48 hours, preferably 30 minutes to 12 hours is generally sufficient.
[638] Step M5
[639] In this step, the preferred cyclic aminoketone compound of formula 47 is obtained by hydrolyzing the cyclic enamine compound of formula 46 prepared in step M4 above. This reaction is carried out by contacting the cyclic enamine compound of formula 46 with water, with or without the addition of an acid or base, in the presence or absence of a solvent.
[640] The reaction is carried out generally and preferably in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that the reaction and associated reagents are free of side effects and that the reagent can be dissolved to some extent or more. Examples of suitable solvents include water or water and organic solvents, examples of which include: aliphatic hydrocarbons such as pentane, hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane Chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, s-butanol, isobutanol and t -Butanol; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide; nitriles such as acetonitrile; and esters such as methyl acetate and ethyl acetate) Mixtures are preferred, of which water, a mixture of water and alcohol and a mixture of water and ether are preferred.
[641] The acid used is not particularly limited as long as it is generally used as an acid in a hydrolysis reaction, and examples thereof include: inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; Carboxylic acids such as formic acid, acetic acid, propionic acid or trifluoric acid; And sulfuric acid, such as methanesulfonic acid or ethanesulfonic acid, of which hydrochloric acid, sulfuric acid and acetic acid are preferred. The hydrolysis reaction is accelerated by acid addition.
[642] The base used is not particularly limited as long as it is generally used as a base in a hydrolysis reaction, examples of which include: alkali metal hydrides such as sodium hydride and lithium hydride; Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as sodium carbonate and potassium carbonate; And amines such as triethylamine, tributylamine, pyridine, picoline and 1,8-diazabicyclo [5.4.0] undec-7-ene, of which sodium hydroxide and potassium hydroxide are preferred.
[643] The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. Preferred reaction temperatures will depend on the nature of the solvent, the starting material or other factors such as the reagent used. In general, however, it is convenient to carry out the reaction at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. In addition, the time required for the reaction may vary widely depending on many factors, especially the reaction temperature, the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 48 hours, preferably 30 minutes to 12 hours is generally sufficient.
[644] Method M
[645] Compounds of formula 45 which are intermediates in the preparation of the cyclic aminoketone compounds of formula 47 in method M can also be prepared by method N according to Scheme N below.
[646]
[647] In the above formula, B, R ^4a , R ⁸ , R ⁹ , R ¹⁵ and R ¹⁶ are as defined above, and R ¹⁷ represents a hydrogen atom or a carboxyl protecting group.
[648] The carboxyl protecting group in the definition of R ¹⁷ may be any such protecting group commonly used in organic chemistry; Preferably, it is a lower alkyl group as defined above or an aralkyl group as defined above.
[649] Step N1
[650] In this step, the aminodiester compound of formula 50 is produced by the reaction of a cyclic amino acid ester compound of formula 48 with a malonic acid derivative of formula 49 or a reactive derivative thereof. Any technique commonly used in the field of organic chemical synthesis for the amidation reaction can be used, and this step can be carried out, for example, in the manner described in the following methods (a), (b) and (c).
[651] (a) When R ¹⁷ is a hydrogen atom, the reaction is carried out in a solvent in the presence or absence of a base and in the presence of a condensing agent.
[652] There is no particular limitation on the nature of the solvent used, provided that the reaction and associated reagents are free of side effects and that the reagent can be dissolved to some extent or more. Examples of solvents used include the following: aliphatic hydrocarbons such as pentane, hexane and heptane; Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; Alcohols such as methanol, ethanol, propanol, isopropanol, butanol, s-butanol, isobutanol and t-butanol; Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide; Nitriles such as acetonitrile; Esters such as methyl acetate and ethyl acetate; water; Or mixtures of these solvents described above, of which halogenated hydrocarbons, ethers and esters are preferred, with dichloromethane, tetrahydrofuran and ethyl acetate being more preferred.
[653] Any suitable condensing agent conventionally used in such reactions can be used, for example dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N, N'-carbonyldi Imidazole and the like.
[654] The base used in this step is not particularly limited as long as it is generally used as a base in such a reaction, examples of which include: alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide ; Alkali metal hydrides such as sodium hydride and lithium hydride; Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as sodium carbonate and potassium carbonate; And amines such as triethylamine, tributylamine, pyridine, picoline and 1,8-diazabicyclo [5.4.0] undec-7-ene, of which amines are preferred, triethylamine, pyridine and 1 , 8-diazabicyclo [5.4.0] undec-7-ene is more preferred.
[655] The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. Preferred reaction temperatures will depend on the nature of the solvent, starting materials and other factors such as the reagents used. In general, however, it is convenient to carry out the reaction at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. In addition, the time required for the reaction may vary widely depending on many factors, especially the reaction temperature, the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 48 hours, preferably 30 minutes to 12 hours is generally sufficient.
[656] Alternatively, when R ¹⁷ is a hydrogen atom, the reaction of step N1 may also convert the compound of formula 49 to its reactive derivative and then carry out the procedure described by method (c) below.
[657] (b) when R ¹⁷ is a carboxyl protecting group (preferably a lower alkyl group as defined above or an aralkyl group as defined above), the reaction is carried out by heating in the presence or absence of a solvent.
[658] When the reaction is carried out in a solvent, the same solvent as described in the method (a) can be used. The reaction temperature is between 30 ° C and 100 ° C, preferably in the range of ± 5 ° C of the boiling point of the solvent used. Most preferably, the reaction is carried out by heating the reaction mixture at reflux.
[659] If no solvent is used in this reaction, preferred compounds are prepared by heating a mixture of the compounds of formula 48 and formula 49. The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. Preferred reaction temperatures will depend on factors such as the nature of the starting material used. In general, however, it is convenient to carry out the reaction at a temperature of 30 ° C to 150 ° C, preferably at 50 ° C to 120 ° C. In addition, the time required for the reaction can vary widely depending on many factors, in particular the reaction temperature, and the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 48 hours, preferably 30 minutes to 12 hours is generally sufficient.
[660] (c) When reactive derivatives of the compounds of formula 49 are used, the reactive derivatives may be acid halides, mixed acid anhydrides, activated esters, active amides and the like, and the reaction is carried out in a solvent in the presence and absence of a base and the presence of a condensing agent. do.
[661] Acid halides of compounds of formula 49 are prepared by the reaction of compounds of formula 49 wherein R ¹⁷ is a hydrogen atom and a halogenating agent (eg, thionyl chloride, oxalyl chloride, etc.); Mixed acid anhydrides are prepared by the reaction of a compound of formula 49, wherein R ¹⁷ is a hydrogen atom, with an acid halide (eg, methyl chlorocarbonate, ethyl chlorocarbonate, etc.); Activated esters include, for example, compounds containing a compound of formula 49 (wherein R ¹⁷ is a hydrogen atom) and a hydroxyl group in the presence of a condensing agent as described in method (a) above (e.g., N- Hydroxysuccinimide, N-hydroxyphthalimide, etc.); Active amides (eg, Weinreb amides) are compounds of formula 49 in which R ¹⁷ is a hydrogen atom and N- (lower alkoxy) -N- in the presence of a condensing agent as described in method (a) above. It is prepared by the reaction of (lower alkyl) hydroxylamine (eg, N-methoxy-N-methylhydroxylamine, etc.). Each of these reactions described may be carried out under reaction conditions generally used in the field of organic chemical synthesis for such reactions.
[662] With regard to the solvent, condensing agents and bases, solvents, condensing agents and bases described in the above process (a) can be used.
[663] The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. Preferred reaction temperatures will depend on the nature of the solvent, starting materials and other factors such as the reagents used. In general, however, it is convenient to carry out the reaction at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. In addition, the time required for the reaction can vary widely depending on many factors, especially the reaction temperature and the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 48 hours, preferably 30 minutes to 12 hours is generally sufficient.
[664] Step N2 and N3
[665] In steps N2 and N3, the ketoractam compound of formula 52 is first subjected to a Dieckman reaction in the amido diester compound of formula 50 produced in step N1 to give a ketoractam ester compound (51), which is then obtained Prepared by carrying out hydrolysis and decarboxylation reaction on the product. These steps can be carried out in a similar manner as described in steps I2 and I3 above.
[666] Step N4
[667] In this step, the desired cyclic enaminolactam compound of formula 45 is prepared by the reaction of the ketorlactam compound of formula 52 obtained in step N3 with the secondary amine compound of formula 44, wherein the reaction is as described in step M3 It is done in a similar way.
[668] Method O
[669] Compounds of formula 51, which are intermediates in method N described above, can also be synthesized by method O according to Scheme O below.
[670]
[671] Wherein B, R ^4a , R ⁹ and R ¹⁷ are as defined above.
[672] Step O1
[673] In this step, the amido monoester compound of formula 54 is prepared by the reaction of a cyclic amino acid compound of formula 53 with a malonic acid derivative of formula 49 or a reactive derivative thereof. This step is carried out in a manner similar to that described in the methods (a), (b) and (c) of step N1 above.
[674] Step O2
[675] In this step, the desired ketoractam ester compound of formula 51 is prepared by intramolecular condensation of the active methylene group and carboxyl group of the amido monoester compound of formula 54 prepared in step O1 above. In this step, the compound of formula 54 can be used after being converted into its underivatized form or first to its reactive derivative.
[676] (a) When the compound of formula 54 is used in its non-derivatized form, the reaction is carried out in a solvent with or without a condensing agent and a base.
[677] There is no particular limitation on the nature of the solvent used, provided that the reaction and associated reagents are free of side effects and that the reagent can be dissolved to some extent or more. Examples of solvents used include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; Alcohols such as methanol, ethanol, propanol, isopropanol, butanol, s-butanol, isobutanol and t-butanol; Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide; Nitriles such as acetonitrile; And esters such as methyl acetate and ethyl acetate; water; Or mixtures of these solvents as described above, of which halogenated hydrocarbons, ethers and esters are preferred, and dichloromethane, tetra hydrofuran and ethyl acetate are more preferred.
[678] Any suitable condensing agent conventionally used in such reactions can be used, for example dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N, N'-carbonyldi Imidazole and the like.
[679] The base used is not particularly limited as long as it is generally used as a base in this reaction, examples of which include: alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide; Alkali metal hydrides such as sodium hydride and lithium hydride; Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali metal carbonates such as sodium carbonate and potassium carbonate; And amines such as triethylamine, tributylamine, pyridine, picoline and 1,8-diazabicyclo [5.4.0] undec-7-ene, of which amines are preferred, triethylamine, pyridine and 1 , 8-diazabicyclo [5.4.0] undec-7-ene is more preferred.
[680] The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. Preferred reaction temperatures will depend on the nature of the solvent and other factors such as starting materials or reagents used. In general, however, it is convenient to carry out the reaction at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. In addition, the time required for the reaction can vary widely depending on many factors, especially the reaction temperature and the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 48 hours, preferably 30 minutes to 12 hours is generally sufficient.
[681] (b) When compound (54) is first converted to a reactive derivative and then used, examples of the reactive derivative include acid halides, mixed acid anhydrides, activated esters, active amides, and the like.
[682] Acid halides are prepared by the reaction of a compound of formula 54 with a halogenating agent (eg, thionyl chloride, oxalyl chloride, etc.); Mixed acid anhydrides are prepared by the reaction of a compound of formula 54 with an acid halide (eg, methyl chlorocarbonate, ethyl chlorocarbonate, etc.); Activated esters include, for example, compounds containing a compound of formula 54 and a hydroxyl group in the presence of a condensing agent described in method (a) (e.g., N-hydroxysuccinimide, N-hydroxyphthal Mead etc.); Active amides (e.g., Weinreb amides) are compounds of formula 54 and N- (lower alkoxy) -N- (lower alkyl) hydroxylamines (e.g. , N-methoxy-N-methylhydroxylamine, etc.). Each of these reactions described may be carried out under reaction conditions generally used in the field of organic chemical synthesis for such reactions.
[683] Cyclation of such reactive derivatives is generally used in the presence or absence of a base.
[684] With regard to the solvent, condensing agents and bases, solvents, condensing agents and bases described in the above method (a) can be used.
[685] The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. Preferred reaction temperatures will depend on the nature of the solvent and other factors such as starting materials and reagents used. In general, however, it is convenient to carry out the reaction at a temperature of -20 ° C to 150 ° C, preferably 0 ° C to 100 ° C. In addition, the time required for the reaction can vary widely depending on many factors, especially the reaction temperature and the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions outlined above, a period of 10 minutes to 48 hours, preferably 30 minutes to 12 hours is generally sufficient.
[686] Substituent R ³ , which is one of the components of the compound of formula I, may be substituted with various substituents (R ⁴ ). Substituent R ⁴ may be converted to other substituents falling within the scope of the definition of R ⁴ at each stage described above. The substituent R ⁴ may be converted, for example, as illustrated below using conventional organic synthesis methods.
[687]
[688] Wherein R ^a , R ^b and Hal have the same meanings as defined above,
[689] R ¹⁸ represents an aryl group which may be optionally substituted with one or more substituents selected from lower alkyl groups as defined above, halogenated lower alkyl as defined above or substituents α and substituents β as defined above,
[690] R ¹⁹ groups are the same or different and each represents a lower alkyl group as defined above or a halogenated lower alkyl group as defined above, or two R ¹⁹ groups can form together a lower alkylene group as defined above.
[691] R ²⁰ represents lower alkyl as defined above,
[692] R ²¹ represents a hydrogen atom or a lower alkyl group as defined above,
[693] R ²² is a lower alkyl group which may be optionally substituted with one or more substituents selected from substituent α, a lower alkenyl group which may be optionally substituted with one or more substituents selected from substituent α, and a lower group that may be optionally substituted with one or more substituents selected from substituent α An alkynyl group, an aralkyl group or a cycloalkyl group as defined above in the definition of substituent β, or an aryl group which may be optionally substituted with one or more substituents selected from substituent α and substituent β as defined above.
[694] In addition, when R ⁴ is a halogen atom, a hydroxyl group, a cyano group or a lower alkylsulfonyl group, R ⁴ forms a double bond, followed by reduction of the double bond using conventional methods such as those shown below to yield hydrogen. Can be converted to an atom.
[695]
[696] In the above formula, R ^4a has the same meaning as defined above, and R ^4b represents a halogen atom, a hydroxyl group, a cyano group or a lower alkylsulfonyl group.
[697] When R ⁴ represents a lower alkylidene group or an aralkylidedenyl group, such compounds can be prepared from the corresponding oxo derivatives as shown below. The alkylidenyl or aralkylidedenyl compound can then be converted to the corresponding alkyl or aralkyl group by reduction of the double bond.
[698]
[699] In the above formula, R ²³ and R ²⁴ are the same or different and each represents a hydrogen atom, a lower alkyl group as defined above, an aryl group as defined above or an aralkyl group as defined above.
[700] After completing each of the reactions described in the steps of Methods A to O above, the preferred compounds can be isolated from the reaction mixture in a conventional manner. For example, if necessary, neutralize the reaction mixture, remove any insoluble material by filtration, add organic solvents that do not mix with each other, such as water and ethyl acetate, wash with water, etc., The organic layer containing the desired compound is separated and dried over anhydrous magnesium sulfate or the like and then distilled off the solvent.
[701] If desired, the preferred compounds thus obtained can be isolated and purified using conventional methods, such as recrystallization or reprecipitation, or by chromatography. Examples of chromatography include adsorption column chromatography using a carrier such as silica gel, alumina or magnesium-silica gel type Florisil, chromatography using a synthetic adsorbent, such as a carrier such as Sephadex LH-20 ( Pharmacia products), fractional column chromatography using Amberlite XAD-11 from Rohm & Hass or Diaion HP-20 from Mitsubishi Chemical, ion exchange chromatography using silica gel or alkylated silica gel and normal phase-reverse column column chromatography Chromatography (high performance liquid chromatography). If desired, two or more of these techniques can be used in combination to isolate and isolate the desired compound.
[702] The pyrrole derivatives of the present invention exhibit excellent inhibitory activity against the production of inflammatory cytokines. As a result, they are effective as medicaments, especially as agents for the prophylaxis or treatment of diseases mediated by inflammatory cytokines. Examples of such prophylactic agents include analgesics, anti-inflammatory and virucidal agents, and chronic rheumatoid arthritis, osteoarthritis, allergic diseases, asthma, sepsis, psoriasis, osteoporosis, autoimmune diseases (eg systemic lupus erythematosus, ulcerative colitis and Crohn's disease) Agents for the prevention or treatment of diabetes, nephritis, hepatitis, cancer, ischemic heart disease, Alzheimer's disease and atherosclerosis. Among them, the compounds of the present invention are particularly useful as agents for the prevention and treatment of analgesics and anti-inflammatory drugs and chronic rheumatism, osteoarthritis, allergic diseases, sepsis, psoriasis, osteoporosis, ulcerative colitis, diabetes, hepatitis and arteriosclerosis.
[703] The compounds of formula (I), pharmaceutically acceptable salts, esters and other derivatives thereof according to the invention can be administered by a number of different routes. Examples of these routes of administration include oral administration in the form of tablets, capsules, granules, powders or syrups and parenteral administration in the form of injections or suppositories. Such formulations may be prepared in a known manner using additives such as excipients, lubricants, binders, disintegrants, stabilizers, corrective agents and diluents.
[704] Examples of suitable excipients include: organic excipients, examples of which include sugar derivatives such as lactose, sucrose, dextrose, mannitol and sorbitol, corn starch, potato starch, α-starch, dextrin and carboxymethyl starch Starch derivatives, crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose and sodium intercrossed carboxymethyl cellulose, cellulose derivatives such as gum arabic, dextran and pullulan It includes; And inorganic excipients, examples of which are soft silicic anhydride, silicate derivatives such as synthetic aluminum silicate and magnesium aluminomethysilicate, phosphates such as calcium phosphate, carbonates such as calcium carbonate, and alcohols such as calcium sulfate Contains the pate.
[705] Examples of suitable lubricants include: metal salts of stearic acid, such as calcium stearate and magnesium stearate; Talc; Colloidal silica; Waxes such as bee gum and sperm; Boric acid; Adipic acid; Sulfates such as sodium sulfate; Glycols; Fumaric acid; Sodium benzoate; DL-leucine; Sodium salts of aliphatic acids; Lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; Silicic acid derivatives such as silicic anhydride and silicic acid hydrate; And starch derivatives exemplified above as examples of suitable excipients.
[706] Examples of suitable binders are polyvinylpyrrolidone, Macrogol And compounds similar to those exemplified above as suitable excipients.
[707] Examples of suitable disintegrants include compounds similar to those exemplified above as suitable excipients and chemically modified starch or cellulose derivatives such as sodium croscarmellose, sodium carboxymethyl starch and crosslinked polyvinylpyrrolidone.
[708] Examples of suitable stabilizers include paraoxybenzoate esters such as methylparaben and propylparaben; Alcohols such as chlorobutanol, benzyl alcohol and phenylether alcohol; Benzalkonium chloride; Phenol derivatives such as phenol and cresol; Thimerosal; Dihydroacetic acid; And sorbic acid. Examples of suitable corrective agents include sweeteners, acidifiers and flavorings commonly used for this purpose.
[709] The dosage of the compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to the invention will vary depending on various factors including the condition of the person to be treated, the age of the patient and the route of administration. In oral administration, adults are administered an amount of 0.1 mg per day (preferably 0.5 mg) as a lower limit and 2000 mg per day (preferably 500 mg) as an upper limit. Depending on the condition of the patient it can be administered in one to several times. When administered intravenously, adults are dosed with an amount of 0.01 mg per day (preferably 0.05 mg) as a lower limit and 200 mg (preferably 50 mg) per day as an upper limit. Depending on the condition of the patient it can be administered in one to several times.
[710] The following examples, preparations, formulations and test examples are intended to further illustrate the invention and do not limit the scope of the invention in any way.
[711] Example 1
[712] 2- (4-fluorophenyl) -4-[(2R, 8aS) -methoxy-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridine-4 -Day) -1 H-Pyrrole (compound number: 4-15)
[713]
[714] 1 (i) 4-ethoxycarbonyl-2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H-Pyrrole
[715] 36 ml (54.7 mmol) of 1.53N butyllithium solution in hexane was added to 240 ml of tetrahydrofuran. Then, a solution of 15.90 g (54.7 mmol) of α- (p-toluenesulfonyl) -4-fluorobenzyl isocyanide in 120 ml of tetrahydrofuran was added to the solution obtained at −45 ° C., and then The mixture obtained at temperature was stirred for 10 minutes. At the end of this time, 25.00 g (273 mmol) of 95% lithium bromide are added and the resulting mixture is stirred for 30 minutes, then 8.73 g (49.2 mmol) of ethyl 3- (4- in 120 ml of tetrahydrofuran Pyridyl) acrylate solution was added. The resulting mixture was stirred at the same temperature for 1 hour, then the cold bath was removed and the mixture was stirred at room temperature for an additional 1 hour. At the end of this time, 500 ml of water were added and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure to give a solid. The solid was washed with diethyl ether to give 13.61 g (yield: 89%) of the title compound as a pale yellow powder.
[716] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[717] 8.84 (1H, broad singlet);
[718] 8.51 (2H, doublet, J = 7 Hz);
[719] 7.58 (1H, doublet, J = 3 Hz);
[720] 7.21 (2H, doublet, J = 6 Hz);
[721] 7.11 (2H, doublet of doublets, J = 9 Hz, 5 Hz);
[722] 6.97 (2H, triplet, J = 9 Hz);
[723] 4.18 (2H, quartet, J = 7 Hz);
[724] 1.20 (3H, triplet, J = 7 Hz).
[725] 1 (ii) 2- (4-fluorophenyl) -4- (pyridin-4-yl) -1 H-Pyrrole
[726] 15.00 g (48.3 mmol) of 4-ethoxycarbonyl-2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole [as described in Example 1 (i) above Obtained] was dissolved in a mixture of 90 ml of acetic acid, 30 ml of sulfuric acid and 60 ml of water, and the obtained solution was stirred at 100 ° C. for 16 hours. After cooling to room temperature, the reaction mixture was made basic by the addition of 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic extract thus obtained was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure to yield 11.40 g (yield: 99%) of the title compound as a pale red powder.
[727] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[728] 9.78 (1H, broad singlet);
[729] 8.42 (2H, doublet, J = 7 Hz);
[730] 7.37 (2H, doublet of doublets, J = 9 Hz, 5 Hz);
[731] 7.22 (2H, doublet, J = 6 Hz);
[732] 7.06 (2H, triplets, J = 9 Hz);
[733] 6.90 (1H, triplet, J = 3 Hz);
[734] 6.47 (1H, triplets, J = 3 Hz).
[735] 1 (iii) 2- (4-fluorophenyl) -3- (pyridin-4-yl) -1-triisopropylsilyl-1 H-Pyrrole
[736] 11.30 g (47.4 mmol) of 2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole [obtained as described in Example 1 (ii) above] is 300 ml of Dissolved in tetrahydrofuran. Thereafter, 31 ml (47.4 mmol) of 1.57N butyllithium solution in hexane was added to the solution obtained at -78 ° C. After the reaction mixture was stirred for 10 minutes, 13.4 ml (49.8 mmol) of triisopropylsilyl triflate were added at the same temperature. The resulting mixture was stirred at rt for 30 min. At the end of this time, 200 ml of water and 300 ml of saturated aqueous sodium bicarbonate solution were added and the mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure to yield 18.70 g (quantitative yield) of the title compound as red-purple oil.
[737] ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ ppm:
[738] 8.25 (2H, doublet, J = 6 Hz);
[739] 7.39 (2H, doublet of doublets, J = 9 Hz, 6 Hz);
[740] 7.28 (2H, triplets, J = 9 Hz);
[741] 7.00 (1H, doublet, J = 3 Hz);
[742] 6.91 (2H, doublet, J = 7 Hz);
[743] 6.71 (1H, doublet, J = 3 Hz);
[744] 1.15-1.05 (3H, multiplet);
[745] 0.98 (18H, doublet, J = 8 Hz).
[746] 1 (iv) 4-bromo-2- (4-fluorophenyl) -3- (pyridin-4-yl) -1-triisopropylsilyl-1 H-Pyrrole
[747] 18.70 g (47.4 mmol) of 2- (4-fluorophenyl) -3- (pyridin-4-yl) -1-triisopropylsilyl-1 H -pyrrole [as described in Example 1 (iii) above Obtained] was dissolved in 300 ml of tetrahydrofuran. 8.61 g (47.4 mmol) of N-bromosuccinimide suspension in 100 ml of tetrahydrofuran was added slowly to the mixture obtained at -78 ° C. Thereafter, the obtained mixture was stirred at −78 ° C. for 6 hours, followed by an additional 1 hour at room temperature, and then 400 ml of hexane was added and any insoluble matter was filtered off. The filtrate was concentrated by evaporation under reduced pressure. The obtained residue was purified by chromatography on silica gel column using a mixture of hexane and ethyl acetate (volume ratio 2: 1) as eluent to yield 9.57 g (yield: 43%) of the title compound as a pale yellow prism.
[748] ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ ppm:
[749] 8.36 (2H, doublet, J = 6 Hz);
[750] 7.34 (2H, doublet of doublets, J = 9 Hz, 6 Hz);
[751] 7.18 (2H, triplets, J = 9 Hz);
[752] 7.12 (1H, singlet);
[753] 7.04 (2H, doublet, J = 6 Hz);
[754] 1.16-1.08 (3H, multiplet);
[755] 0.99 (18H, doublet, J = 8 Hz).
[756] 1 (v) 2- (4-fluorophenyl) -4-[(2R, 8aS) -2-methoxy-1,2,3,5,8,8a-hexahydroindolizin-7-yl]- 3- (pyridin-4-yl) -1 H-Pyrrole
[757] 3.00 g (6.34 mmol) of 4-bromo-2- (4-fluorophenyl) -3- (pyridin-4-yl) -1-triisopropylsilyl-1 H -pyrrole [Example 1 (iv above) Obtained as described above) in 60 ml of tetrahydrofuran. Then, a solution of 4.36 ml (6.97 mmol) of 1.6M butyllithium in hexane was added to the solution obtained at -78 ° C. After stirring the reaction mixture at −78 ° C. for 10 min, 1.29 g (7.60 mmol) of (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydro Indolizin-7-one (prepared according to Preparation Example 1 below) was added at room temperature. The resulting mixture was stirred at −78 ° C. for 2 hours and then at room temperature for 1 hour. At the end of this time, a saturated aqueous solution of sodium bicarbonate was added and then the reaction mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure.
[758] The obtained residue was dissolved in 40 ml of dichloroethane and 1.95 ml (25.3 mmol) of trifluoroacetic acid was added to the obtained solution, and then the reaction mixture was heated to reflux for 1 hour. After cooling to room temperature, the reaction mixture was concentrated by evaporation under reduced pressure. The obtained residue was dissolved in 30 ml of tetrahydrofuran and 25.3 ml (25.3 mmol) of 1 M tetrabutylammonium fluoride solution in tetrahydrofuran was added to the resulting solution, and the mixture was then stirred at room temperature for 10 minutes. Stirred. At the end of this time water was added and the resulting mixture was acidified with 1N hydrochloric acid and then extracted with ethyl acetate. The aqueous layer was made basic by the addition of sodium carbonate and then extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. Purification by chromatography on silica gel column using a mixture of ethyl acetate, methanol and isopropylamine (volume ratio 100: 10: 1) as eluent to give 545 mg (yield: 22%) of the title compound as a light brown powder (Rf value). = 0.45).
[759] Melting Point: 203-205 ° C (Decomposition)
[760] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[761] 11.38 (1H, broad singlet);
[762] 8.44 (2H, doublet, J = 6 Hz);
[763] 7.20-7.06 (6H, multiplet);
[764] 6.90 (1H, doublet, J = 3 Hz);
[765] 5.27-5.22 (1H, multiplet);
[766] 3.92-3.85 (1H, multiplet);
[767] 3.40 (1H, doublet of doublets, J = 9 Hz, 7 Hz);
[768] 3.29-3.19 (1H, multiplet);
[769] 3.16 (3H, singlet);
[770] 2.71-2.62 (1H, multiplet);
[771] 2.37-2.20 (2H, multiplet);
[772] 2.04-1.90 (2H, multiplet);
[773] 1.88-1.80 (1H, multiplet);
[774] 1.51-1.41 (1H, multiplet).
[775] Example 2
[776] 2- (4-fluorophenyl) -4-[(2R, 8aS) -2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine -4- day) -1 H-Pyrrole (compound number: 1-303)
[777]
[778] Silicagel column chromatography carried out in Example 1 (v) above gave 300 mg (yield: 12%) of the title compound (Rf value 0.40) as light brown powder.
[779] Melting Point: 198-200 ℃ (Decomposition)
[780] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[781] 11.39 (1H, broad singlet);
[782] 8.44 (2H, doublet, J = 6 Hz);
[783] 7.21-7.05 (6H, multiplet);
[784] 6.92 (1H, doublet, J = 3 Hz);
[785] 5.16-5.11 (1H, multiplet);
[786] 3.92-3.84 (1H, multiplet);
[787] 3.39-3.25 (1H, multiplet);
[788] 3.23-3.11 (1H, multiplet);
[789] 3.15 (H, singlet);
[790] 3.05 (1H, doublets of doublets, J = 10 Hz, 6 Hz);
[791] 2.86-2.77 (1H, multiplet);
[792] 2.64-2.54 (1H, multiplet);
[793] 2.30-2.19 (1H, multiplet);
[794] 2.10-2.00 (1H, multiplet);
[795] 1.76-1.67 (1H, multiplet);
[796] 1.48-1.38 (1H, multiplet).
[797] Example 3
[798] 2- (4-fluorophenyl) -4-[(2R, 8aS) -2-hydroxy-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridine -4- day) -1 H-Pyrrole (compound number: 4-14)
[799]
[800] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (2R, 8aS) -2- (t-butyldimethylsilyloxy) -1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (described in Preparation Example 2 below) Reaction and silica gel column chromatography (volume mixing ratio of ethyl acetate, methanol and isopropylamine as a eluent, respectively, 100: 10: 2.5) were carried out using 587 mg (yield: 25%) as light brown powder. The title compound (Rf value = 0.25) was obtained.
[801] Melting Point: 208-21O ℃ (Decomposition)
[802] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[803] 11.37 (1H, broad singlet);
[804] 8.44 (2H, doublet, J = 6 Hz);
[805] 7.20-7.06 (6H, multiplet);
[806] 6.90 (1H, doublet, J = 3 Hz);
[807] 5.26-5.22 (1H, multiplet);
[808] 4.72 (1H, doublet, J = 4 Hz);
[809] 4.25-4.16 (1H, multiplet);
[810] 3.38-3.27 (1H, multiplet);
[811] 3.25-3.17 (1H, multiplet);
[812] 2.72-2.63 (1H, multiplet);
[813] 2.45-2.35 (1H, multiplet);
[814] 2.26-2.18 (1H, multiplet);
[815] 1.98-1.87 (2H, multiplet);
[816] 1.71-1.64 (1H, multiplet);
[817] 1.57-1.46 (1H, multiplet).
[818] Example 4
[819] 2- (4-fluorophenyl) -4-[(2R, 8aS) -2-hydroxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine -4- day) -1 H-Pyrrole (compound number: 1-302)
[820]
[821] Silicagel column chromatography carried out in Example 3 above gave 213 mg (yield: 9%) of the title compound (Rf = 0.20) as a light brown powder.
[822] Melting Point: 209-211 ℃ (Decomposition)
[823] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[824] 11.38 (1H, broad singlet);
[825] 8.44 (2H, doublet, J = 5 Hz);
[826] 7.20-7.05 (6H, multiplet);
[827] 6.90 (1H, doublet, J = 3 Hz);
[828] 5.16-5.12 (1H, multiplet);
[829] 4.63 (1H, doublet, J = 5 Hz);
[830] 4.25-4.16 (1H, multiplet);
[831] 3.30-3.20 (1H, multiplet);
[832] 3.00 (1H, doublets of doublets, J = 10 Hz, 6 Hz);
[833] 2.84-2.74 (1H, multiplet);
[834] 2.63-2.53 (1H, multiplet);
[835] 2.40 (1H, doublets of doublets, J = 10 Hz, 4 Hz);
[836] 2.27-2.16 (1H, multiplet);
[837] 2.08-1.98 (1H, multiplet);
[838] 1.62-1.52 (1H, multiplet);
[839] 1.52-1.42 (1H. Multiplet).
[840] Example 5
[841] 4-[(2S, 8aS) -2-chloro-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine- 4-day) -1 H-Pyrrole (compound number: 4-23)
[842]
[843] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (2R, 8aS) -2-chloro-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation Example 3 below) was used Reaction and silica gel column chromatography (volume mixing ratio of ethyl acetate, methanol and isopropylamine as eluent 40: 1: 1 respectively) to give 520 mg (yield: 21%) of the title compound (Rf value = 0.45) was obtained.
[844] Melting Point: 195-197 ℃ (Decomposition)
[845] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[846] 8.46 (2H, doublet, J = 6 Hz);
[847] 8.38 (1H, broad singlet);
[848] 7.16 (2H, doublet, J = 6 Hz);
[849] 7.13 (2H, doublet of doublets, J = 9 Hz, 5 Hz);
[850] 6.97 (2H, triplet, J = 9 Hz);
[851] 6.83 (1H, doublet, J = 3 Hz);
[852] 5.54-5.53 (1H, multiplet);
[853] 4.42-4.36 (1H, multiplet);
[854] 3.54 (1H, doublets of doublets, J = 16 Hz, 5 Hz);
[855] 3.39 (1H, doublet, J = 11 Hz);
[856] 2.79 (1H, doublet, J = 16 Hz);
[857] 2.68-2.60 (2H, multiplet);
[858] 2.30-2.16 (H, multiplet);
[859] 1.85-1.76 (1H, multiplet).
[860] Example 6
[861] 4-[(2S, 8aS) -2-chloro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine- 4-day) -1 H-Pyrrole (compound number: 1-311)
[862]
[863] Silicagel column chromatography carried out in Example 5 gave 400 mg (yield: 16%) of the title compound (Rf = 0.35) as a light brown powder.
[864] Melting Point: 177-180 ℃ (Decomposition)
[865] ¹ H-NMR spectrum (400 MHz, CDCl ₆ ) δ ppm:
[866] 8.49 (2H, doublet, J = 5 Hz);
[867] 8.37 (1H, broad singlet);
[868] 7.17 (2H, doublet, J = 5 Hz);
[869] 7.13 (2H, doublet of doublets, J = 8 Hz, 5 Hz);
[870] 6.98 (2H, triplets, J = 8 Hz);
[871] 6.84 (1H, doublet, J = 3 Hz);
[872] 5.40 (1H, singlet);
[873] 4.38-4.32 (1H, multiplet);
[874] 3.53-3.45 (1H, multiplet);
[875] 3.23 (1H, doublet of doublets, J = 11Hz, 7 Hz);
[876] 3.13-3.06 (2H, multiplet);
[877] 2.90-2.82 (1H, multiplet);
[878] 2.59 (1H, double triplets, J = 14 Hz, 8 Hz);
[879] 2.43-2.31 (1H, multiplet);
[880] 2.13-2.02 (1H, multiplet);
[881] 1.79-1.69 (1H, multiplet).
[882] Example 7
[883] 4-[(8aS) -2,2-difluoro-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- ( Pyridin-4-yl) -1 H-Pyrrole (compound number: 4-26)
[884]
[885] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead (8aS) -2,2-difluoro-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation Example 4 below) Reaction and silica gel column chromatography (volume mixing ratio 49: 1 of dichloromethane and methanol as eluent, respectively) were carried out to give 358 mg (yield: 28%) of the title compound (Rf value = 0.35) as a light brown powder. It was.
[886] Melting Point: 201-203 ° C (Decomposition)
[887] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[888] 11.42 (1 H, broad singlet);
[889] 8.45 (2H, doublet, J = 6 Hz);
[890] 7.21-7.02 (6H, multiplet);
[891] 6.93 (1H, doublet, J = 3 Hz);
[892] 5.27-5.22 (1H, multiplet);
[893] 3.48-3.37 (1H, multiplet);
[894] 3.33-3.22 (1H, multiplet);
[895] 2.77-2.68 (1H, multiplet);
[896] 2.59-2.36 (3H, multiplet);
[897] 2.34-2.26 (1H, multiplet);
[898] 2.16-2.06 (1H, multiplet);
[899] 1.96-1.78 (1H, multiplet).
[900] Example 8
[901] 4-[(8aS) -2,2-difluoro-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- ( Pyridin-4-yl) -1 H-Pyrrole (compound number: 1-314)
[902]
[903] Silicagel column chromatography carried out in Example 7 above gave 290 mg (yield: 23%) of the title compound (Rf = 0.30) as a light brown powder.
[904] Melting Point: 202-204 ° C (Decomposition)
[905] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[906] 11.44 (1H, broad singlet);
[907] 8.43 (2H, doublet, J = 6 Hz);
[908] 7.21-7.07 (6H, multiplet);
[909] 6.96 (1H, doublet, J = 3 Hz);
[910] 5.15-5.11 (1H, multiplet);
[911] 3.46-3.39 (1H, multiplet);
[912] 3.26-3.15 (1H, multiplet);
[913] 2.98-2.85 (2H, multiplet);
[914] 2.71-2.62 (1H, multiplet);
[915] 2.39-2.25 (2H, multiplet);
[916] 2.12-2.04 (1H, multiplet);
[917] 1.83-1.67 (1H, multiplet).
[918] Example 9
[919] (±) -2- (4-fluorophenyl) -3- (pyridin-4-yl) -4- (6,9,9a, 10-tetrahydropyrido [1,2-a] indole-8- Day) -1 H-Pyrrole (compound number: 5-8)
[920]
[921] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead reaction using (±) -6,7,8,9,9a, 10-hexahydropyrido [1,2-a] indole-8-one (prepared as described in Preparation Example 5 below) And silica gel column chromatography (volume mixing ratio of ethyl acetate and hexane each as 1: 1 as an eluent) gave 70 mg (yield: 5%) of the title compound (Rf value = 0.40) as a pale yellow powder.
[922] Melting Point: 214-216 ° C (Decomposition)
[923] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[924] 8.48 (2H, doublet, J = 6 Hz);
[925] 8.29 (1H, broad singlet);
[926] 7.18 (2H, doublet, J = 6 Hz);
[927] 7.14 (2H, doublet of doublets, J = 9 Hz, 5 Hz);
[928] 7.11-7.06 (2H, multiplet);
[929] 6.98 (2H, triplets, J = 9 Hz);
[930] 6.87 (1H, doublet, J = 3 Hz);
[931] 6.69 (1H, triplet, J = 8 Hz);
[932] 6.46 (1H. Doublet, J = 8 Hz);
[933] 5.62-5.60 (1H, multiplet);
[934] 4.00-3.90 (1H, multiplet);
[935] 3.47-3.34 (2H, multiplet);
[936] 3.03 (1H, doublets of doublets, J = 15 Hz, 8 Hz);
[937] 2.61 (1H, doublets of doublets, J = 1 5 Hz, 12 Hz);
[938] 2.51-2.33 (2H, multplet).
[939] Example 10
[940] (±) -2- (4-fluorophenyl) -3- (pyridin-4-yl) -4- (6,7,9a, 10-tetrahydropyrido [1,2-a] indole-8- Day) -1 H-Pyrrole (compound number: 5-1)
[941]
[942] Silicagel column chromatography carried out in Example 9 above gave 230 mg (yield: 15%) of the title compound (Rf = 0.20) as a pale yellow powder.
[943] Melting Point: 205-207 ° C (Decomposition)
[944] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[945] 8.32 (2H, doublet, J = 6 Hz);
[946] 8.27 (1H, broad singlet);
[947] 7.15-7.05 (4H, multiplet);
[948] 6.95 (2H, triplets, J = 9 Hz);
[949] 6.88 (2H, doublet, J = 6 Hz);
[950] 6.77-6.72 (2H, multiplet);
[951] 6.60 (1H, doublet, J = 8 Hz);
[952] 5.26 (1H, singlet);
[953] 4.35-4.26 (1H, multiplet);
[954] 3.77 (1H, doublet of doublets, J = 14 Hz, 6 Hz);
[955] 3.35-3.27 (1H, multiplet);
[956] 3.13 (1H, doublet of doublets, J = 1 5 Hz, 1 0 Hz);
[957] 2.55 (1H, doublet, J = 15 Hz);
[958] 2.50-2.39 (1H, multiplet);
[959] 1.91-1.82 (1H, multiplet).
[960] Example 11
[961] 2- (4-fluorophenyl) -4-[(2R, 8aS) -2-phenyl-1,2.3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridine-4- Day) -1 H-Pyrrole (compound number: 4-10)
[962]
[963] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (2R, 8aS) -2-phenyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation Example 6 below) was used Reaction and silica gel column chromatography (volume mixing ratio of ethyl acetate, methanol and isopropylamine as eluent 100: 10: 1 respectively) to give 399 mg (yield: 19%) of the title compound (Rf value = 0.45) was obtained.
[964] Melting Point: 191-193 ℃ (Decomposition)
[965] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[966] 11.39 (1H, broad singlet);
[967] 8.46 (2H, doublet, J = 5 Hz);
[968] 7.38-7.06 (1H, multiplet);
[969] 6.94 (1H, doublet, J = 2 Hz);
[970] 5.36-5.29 (1H, multiplet);
[971] 3.42-3.27 (2H, multiplet);
[972] 3.07-2.98 (1H, multiplet);
[973] 2.75-2.63 (1H, multiplet);
[974] 2.62-2.50 (1H, multiplet);
[975] 2.46-2.22 (3H, multiplet);
[976] 2.16-2.05 (1H, multiplet);
[977] 1.40-1.29 (1H, multiplet).
[978] Example 12
[979] 2- (4-fluorophenyl) -4-[(2R, 8aS) -2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine- 4-day) -1 H-Pyrrole (compound number: 1-298)
[980]
[981] Silicagel column chromatography carried out in Example 11 above gave 369 mg (yield: 17%) of the title compound (Rf = 0.30) as a white powder.
[982] Melting Point: 208-21O ℃ (Decomposition)
[983] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[984] 11.40 (1H, broad singlet);
[985] 8.35 (2H, doublet, J = 6 Hz);
[986] 7.38-7.07 (1 H, multiplet);
[987] 6.95 (1H, doublet, J = 3 Hz);
[988] 5.25-5.20 (1H, multiplet);
[989] 3.49-3.40 (1H, multiplet);
[990] 3.33-3.21 (1H, multiplet);
[991] 3.04-2.90 (2H, multiplet);
[992] 2.83-2.69 (2H, multiplet);
[993] 2.39-2.26 (2H, multiplet);
[994] 2.04-1.95 (1H, multiplet);
[995] 1.32-1.22 (1H, multiplet).
[996] Example 13
[997] 4-[(8aS) -2,2-ethylenedioxy-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- ( Pyridin-4-yl) -1 H-Pyrrole (compound number: 4-20)
[998]
[999] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead (8aS) -2,2-ethylenedioxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation 7 below) Reaction and silica gel column chromatography (volume mixing ratio of ethyl acetate, methanol and isopropylamine as eluent 100: 10: 0.5 respectively) were carried out to give 694 mg (yield: 30%) of the title compound (Rf as a white powder). Value = 0.55).
[1000] Melting Point: 230-232 ℃ (Decomposition)
[1001] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1002] 11.39 (1H, broad singlet);
[1003] 8.44 (2H, doublet, J = 6 Hz);
[1004] 7.21-7.06 (6H, multiplet);
[1005] 6.91 (1H, doublet, J = 2 Hz);
[1006] 5.27-5.21 (1H, multiplet);
[1007] 3.91-3.71 (4H, multiplet);
[1008] 3.27-3.18 (1H, multiplet);
[1009] 3.12 (1H, doublet, J = 10 Hz);
[1010] 2.68-2.58 (1H, multiplet);
[1011] 2.37-2.16 (3H, multiplet);
[1012] 2.11-1.97 (2H, multiplet);
[1013] 1.55 (1H, doublets of doublets, J = 13 Hz, 10 Hz).
[1014] Example 14
[1015] 4-[(8aS) -2,2-ethyledoxyoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-4fluorophenyl) -3- (Pyridin-4-yl) -1 H-Pyrrole (compound number: 1-308)
[1016]
[1017] Silicagel column chromatography carried out in Example 13 above gave 409 mg (yield: 8%) of the title compound (Rf = 0.40) as light brown powder.
[1018] Melting Point: 196-198 ℃ (Decomposition)
[1019] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1020] 11.40 (1H, broad singlet);
[1021] 8.43 (2H, doublet, J = 6 Hz);
[1022] 7.21-7.05 (6H, multiplet);
[1023] 6.93 (1H, doublet, J = 3 Hz);
[1024] 5.19-5.14 (1H, multiplet);
[1025] 3.89-3.72 (4H, multiplet);
[1026] 3.23-3.14 (1H, multiplet);
[1027] 2.96-2.85 (2H, multiplet);
[1028] 2.62-2.48 (2H, multiplet);
[1029] 2.34-2.21 (1H, multiplet);
[1030] 2.12-2.01 (1H, multiplet);
[1031] 1.93 (1H, doublet of doublets, J = 13 Hz, 7 Hz);
[1032] 1.51 (1H, doublet of doublets, J = 13 Hz, 9 Hz).
[1033] Example 15
[1034] 2- (4-fluorophenyl) -4-[(8aS) -2-methyl-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridine-4- Day) -1 H-Pyrrole (compound number: 4-5)
[1035]
[1036] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead using (8aS) -2-methyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation Example 8 below) And silica gel column chromatography (volume mixing ratio of ethyl acetate, methanol and isopropylamine, respectively, as a eluent: 10: 1: 1) to give 253 mg (yield: 9%) of the title compound (Rf value = 0.65) as a light brown powder. Obtained.
[1037] Melting Point: 190-193 ℃ (Decomposition)
[1038] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1039] 8.46 (2H, doublet, J = 6 Hz);
[1040] 8.32 (1H, broad singlet);
[1041] 7.17 (2H, doublet, J = 6 Hz);
[1042] 7.13 (2H, doublet of doublets, J = 9 Hz, 5 Hz);
[1043] 6.97 (2H, triplet, J = 9 Hz);
[1044] 6.82 (1H, doublet, J = 3 Hz);
[1045] 5.53-5.51 (1H, multiplet);
[1046] 3.49-3.43 (1H, multiplet);
[1047] 2.83 (1H, doublets of doublets, J = 9 Hz, 3 Hz);
[1048] 2.82-2.73 (1H, multiplet);
[1049] 2.41 (1H, triplet, J = 9 Hz);
[1050] 2.30-2.05 (5H, multiplet);
[1051] 1.09 (3H, doublet, J = 7 Hz);
[1052] 1.06-0.98 (1H, multiplet).
[1053] Example 16
[1054] 2- (4-fluorophenyl) -4-[(8aS) -2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine-4- Day) -1 H-Pyrrole (compound number: 1-293)
[1055]
[1056] Silicagel column chromatography carried out in Example 15 above gave 280 mg (yield: 10%) of the title compound (Rf = 0.40) as light brown powder.
[1057] Melting Point: 181-185 ℃ (Decomposition)
[1058] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1059] 8.47 (2H, doublet, J = 6 Hz);
[1060] 8.30 (1H, broad singlet);
[1061] 7.16 (2H, doublet, J = 6 Hz);
[1062] 7.13 (2H, doublet of doublets, J = 9 Hz, 5 Hz);
[1063] 6.97 (2H, triplet, J = 9 Hz);
[1064] 6.82 (1H, doublet, J = 3 Hz);
[1065] 5.41 (0.2H, singlet);
[1066] 5.39 (0.8H, singlet);
[1067] 3.53-3.43 (0.8H, multiplet);
[1068] 3.41-3.22 (0.2H, multiplet);
[1069] 3.11-3.05 (0.2H, multiplet);
[1070] 3.04-2.90 (1H, multiplet);
[1071] 2.89-2.77 (1.6H, multiplet);
[1072] 2.73-2.64 (0.2H, multiplet);
[1073] 2.48 (0.8H, triplet, J = 9 Hz);
[1074] 2.41-2.07 (3.2H, multiplet);
[1075] 2.04-1.93 (1H, multiplet);
[1076] 1.06 (2.4H, doublet, J = 7 Hz);
[1077] 1.02 (0.6H, doublet, J = 7 Hz);
[1078] 0.99-0.93 (1H, multiplet).
[1079] Example 17
[1080] 2- (4-fluorophenyl) -4-[(8aS) -8-methyl-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridine-4- Day) -1 H-Pyrrole (compound number: 4-41)
[1081]
[1082] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead using (8aS) -8-methyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation 9 below) And silica gel column chromatography (volume mixing ratio 10: 0.5: 0.5 of ethyl acetate, methanol and isopropylamine as eluent, respectively) to give 57 mg (yield: 5%) of the title compound (Rf value = 0.45) as an orange powder. Obtained.
[1083] Melting Point: 205-207 ° C (Decomposition)
[1084] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[1085] 8.46 (2H, doublet, J = 8 Hz);
[1086] 8.29-8.18 (1H, broad singlet);
[1087] 7.18-7.13 (4H. Multiplet);
[1088] 6.97 (2H, triplet, J = 9 Hz);
[1089] 6.73 (1H, doublet, J = 3 Hz);
[1090] 5.62-5.55 (1H, multiplet);
[1091] 3.58-3.50 (1H, multiplet);
[1092] 3.24-3.17 (1H, multiplet);
[1093] 2.77-2.68 (1H, multiplet);
[1094] 2.23-2.08 (2H, multiplet);
[1095] 2.04-1.95 (1H, multiplet);
[1096] 1.90-1.78 (2H, multiplet);
[1097] 1.77-1.68 (1H, multiplet);
[1098] 1.43-1.33 (1H, multiplet);
[1099] 0.76 (3H, doublet, J = 7 Hz).
[1100] Example 18
[1101] 2- (4-fluorophenyl) -4-[(8aS) -8-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine-4- Day) -1 H-Pyrrole (compound number: 1-330)
[1102]
[1103] Silicagel column chromatography carried out in Example 17 above gave 708 mg (yield: 17%) of the title compound (Rf = 0.30) as pale pink powder.
[1104] Melting Point: 233-234 ℃
[1105] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[1106] 8.43 (2H, doublet, J = 8 Hz);
[1107] 8.36-8.25 (1H, broad singlet);
[1108] 7.22 (2H, doublet of doublets, J = 9 Hz, 5 Hz);
[1109] 7.08 (2H, doublet, J = 8 Hz);
[1110] 7.00 (2H, triplets, J = 9 Hz);
[1111] 6.70 (1H, doublet, J = 3 Hz);
[1112] 3.07-3.01 (1H, multiplet);
[1113] 2.97-2.92 (1H, multiplet);
[1114] 2.91-2.84 (1H, multiplet);
[1115] 2.70-2.62 (1H, multiplet);
[1116] 2.57-2.49 (1H, multiplet);
[1117] 2.34-2.24 (1H, multiplet);
[1118] 2.12-2.03 (1H, multiplet);
[1119] 2.02-1.94 (1H, multiplet);
[1120] 1.92-1.84 (1H, multiplet);
[1121] 1.81-1.70 (1H, multiplet).
[1122] 1.55-1.45 (1H, multiplet);
[1123] 1.46 (3H, singlet).
[1124] Example 19
[1125] 4- [cyclopropanespiro-6 '-[(8a'S) -1', 2 ', 3', 5 ', 6', 8a'-hexahydroindolizin] -7'-yl] -2- (4- Fluorophenyl) -3- (pyridin-4-yl) -1 H-Pyrrole (compound number: 1-952)
[1126]
[1127] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead cyclopropanespiro-6 '-[(8a'S) -1', 2 ', 3', 5 ', 6', 7 ', 8', 8a'-octahydroindoligin] -7'-one Reaction and silica gel column chromatography (produced as described in Preparation 16) and subjected to silica gel column chromatography (volume mixing ratio of ethyl acetate, methanol and isopropylamine as eluent 100: 10: 1 respectively) to 170 mg (as light brown powder) Yield: 11%) of the title compound (Rf = 0.24).
[1128] Melting Point: 189-191 ℃ (Decomposition)
[1129] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1130] 11.35 (1H, broad singlet);
[1131] 8.39 (2H, doublet, J = 6 Hz);
[1132] 7.23 (2H, doublet of doublets, J = 9 Hz, 6 Hz);
[1133] 7.14 (2H, triplets, J = 9 Hz);
[1134] 7.09 (2H, doublet, J = 6 Hz);
[1135] 6.69 (1H, doublet, J = 2 Hz);
[1136] 5.33-5.30 (1H, multiplet);
[1137] 3.50-3.42 (1H, multiplet);
[1138] 2.98-2.85 (2H, multiplet);
[1139] 2.65-2.57 (1H, multiplet);
[1140] 2.39 (1H, doublet, J = 13 Hz);
[1141] 1.91-1.80 (1H, multiplet);
[1142] 1.76-1.53 (2H, multiplet);
[1143] 1.31-1.20 (1H, multiplet);
[1144] 0.56-0.42 (3H, multiplet);
[1145] 0.22-0.15 (1H, multiplet).
[1146] Example 20
[1147] 2- (4-fluorophenyl) -4-[(2S, 8aS) -2-methoxy-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridine -4- day) -1 H-Pyrrole (compound number: 4-15)
[1148]
[1149] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (2S, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation Example 10 below) Reaction and silica gel column chromatography (volume mixing ratio of ethyl acetate, methanol and isopropylamine as eluent 100: 10: 1 respectively) were carried out to give 228 mg (yield: 6%) of the title compound (Rf value as a white powder). = 0.50).
[1150] Melting Point: 212-213 ° C (Decomposition)
[1151] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[1152] 8.46 (2H, doublet, J = 6 Hz);
[1153] 8.38-8.27 (1H, broad singlet);
[1154] 7.16 (2H, doublet, J = 6 Hz);
[1155] 7.12 (2H, doublet of doublets, J = 9 Hz, 5 Hz);
[1156] 6.97 (2H, triplet, J = 9 Hz);
[1157] 6.81 (1H, doublet, J = 3 Hz);
[1158] 5.52-5.47 (1H, multiplet);
[1159] 3.91-3.84 (1H, multiplet);
[1160] 3.54-3.47 (1H, multiplet);
[1161] 3.30-3.24 (1H, multiplet);
[1162] 3.27 (3H, singlet);
[1163] 2.78-2.69 (1H, multiplet);
[1164] 2.35 (1H, quinine, J = 7 Hz);
[1165] 2.27-2.10 (4H, multiplet);
[1166] 1.48-1.39 (1H, multiplet).
[1167] Example 21
[1168] 2- (4-fluorophenyl) -4-[(2S, 8aS) -2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl) -3- (pyridine -4- day) -1 H-Pyrrole (compound number: 1-303)
[1169]
[1170] Silicagel column chromatography carried out in Example 20, above, yielded 184 mg (yield: 5%) of the title compound (Rf = 0.30) as light brown powder.
[1171] Melting Point: 219-220 ℃ (Decomposition)
[1172] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[1173] 8.47 (2H, doublet, J = 6 Hz);
[1174] 8.41-8.30 (1H, broad singlet);
[1175] 7.17 (2H, doublet, J = 6 Hz);
[1176] 7.12 (2H, doublet of doublets, J = 9 Hz, 5 Hz);
[1177] 6.97 (2H, triplet, J = 9 Hz);
[1178] 6.82 (1H, doublet, J = 3 Hz);
[1179] 5.45-5.41 (1H, multiplet);
[1180] 4.01-3.93 (1H, multiplet);
[1181] 3.30 (3H, singlet);
[1182] 3.28-3.17 (1H, broad singlet);
[1183] 3.10-3.03 (1H, multiplet);
[1184] 2.95 (1H, doublet of doublets, J = 10 Hz, 4 Hz);
[1185] 2.87-2.78 (1H, multiplet);
[1186] 2.75-2.65 (1H, multiplet);
[1187] 2.45-2.35 (1H, multiplet);
[1188] 2.30-2.21 (1H, multiplet);
[1189] 2.17-2.07 (1H, multiplet);
[1190] 1.51-1.41 (1H, multiplet).
[1191] Example 22
[1192] 2- (4-fluorophenyl) -4-[(8aS) -2-methylidene-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridine-4 -Day) -1 H-Pyrrole (compound number: 4-50)
[1193]
[1194] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead using (8aS) -2-methylidene-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation 11 below) Reaction and silica gel column chromatography (volume mixing ratio of ethyl acetate, methanol and isopropylamine as eluents, respectively, 10: 1: 1) were carried out to give 184 mg (yield: 10%) of the title compound (Rf = 0.50) was obtained.
[1195] Melting Point: 212-214 ° C (Decomposition)
[1196] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1197] 8.47 (2H, doublet, J = 6 Hz);
[1198] 8.29 (1H, broad singlet);
[1199] 7.17 (2H, doublet, J = 6 Hz);
[1200] 7.13 (2H, doublet of doublets, J = 9 Hz, 5 Hz);
[1201] 6.97 (2H, triplet, J = 9 Hz);
[1202] 6.83 (1H, doublet, J = 3 Hz);
[1203] 5.52-5.48 (1H, multiplet);
[1204] 4.92 (1H, broad singlet);
[1205] 4.89 (1H, broad singlet);
[1206] 3.79 (1H, doublet, J = 13 Hz);
[1207] 3.54-3.43 (1H, multiplet);
[1208] 2.92-2.80 (2H, multiplet);
[1209] 2.59 (1H, doublets of doublets, J = 16 Hz, 6 Hz);
[1210] 2.50-2.38 (1H, multiplet);
[1211] 2.33-2.25 (1H, multiplet);
[1212] 2.24-2.10 (2H, multiplet).
[1213] Example 23
[1214] 2- (4-fluorophenyl) -4-[(8aS) -2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine-4 -Day) -1 H-Pyrrole (compound number: 1-982)
[1215]
[1216] Silicagel column chromatography carried out in Example 22 above gave 195 mg (yield: 11%) of the title compound (Rf = 0.30) as a white powder.
[1217] Melting Point: 217-218 ℃ (Decomposition)
[1218] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1219] 8.46 (2H, doublet, 3 = 6 Hz);
[1220] 8.29 (1H, broad singlet);
[1221] 7.20-7.09 (4H, multiplet);
[1222] 6.97 (2H, triplet, J = 9 Hz);
[1223] 6.83 (1H, doublet, J = 3 Hz);
[1224] 5.42 (1H, doublet, J = 2 Hz);
[1225] 4.953 (1H, broad singlet);
[1226] 4.949 (1H, broad singlet);
[1227] 3.50-3.32 (3H, multiplet);
[1228] 2.99-2.93 (1H, multiplet);
[1229] 2.80-2.72 (1H, multiplet);
[1230] 2.56 (1H, doublets of doublets, J = 16 Hz, 7 Hz);
[1231] 2.42-2.31 (1H, multiplet);
[1232] 2.22-2.10 (2H, multiplet).
[1233] Example 24
[1234] (±) -4- (2,2-diphenyl) -1,2,3,5,8,8a-hexahydroindolizin-7-yl) -2- (4-fluorophenyl) -3- ( Pyridin-4-yl) -1 H-Pyrrole (compound number: 4-56)
[1235]
[1236] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead of (±) -2,2-diphenyl-1,2,3,5,6,7,8,8a-octahydroindolin-7-one [J. Med. Prepared as described in Chem, 31, 9, 1708-1712 (1998) and subjected to silica gel column chromatography (volume mixing ratio 39: 1 of methylene chloride and methanol as eluent, respectively) as a light brown powder. 363 mg (Yield 11%) of the title compound (Rf value = 0.50) were obtained.
[1237] Melting Point: 224-227 ° C (Decomposition)
[1238] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1239] 11.39 (1H, broad singlet);
[1240] 8.44 (2H, doublet, J = 5 Hz);
[1241] 7.33-7.07 (16H, multiplet);
[1242] 6.93 (1H, doublet, J = 3 Hz);
[1243] 5.34-5.29 (1H, multiplet);
[1244] 3.85 (1H, doublet, J = 9 Hz);
[1245] 3.42-3.32 (1H, multiplet);
[1246] 2.86 (1H, doublet of doublets, J = 13 Hz, 7 Hz);
[1247] 2.75-2.65 (2H, multiplet);
[1248] 2.49-2.39 (1H, multiplet);
[1249] 2.33-2.24 (1H, multiplet);
[1250] 2.16-2.03 (2H, multiplet).
[1251] Example 25
[1252] (±) -4- (2,2-diphenyl-1,2,3,5,6,8a-hexahydroindolizin-7yl) -1- (4-fluorophenyl) -3- (pyridine- 4-day) -1 H-Pyrrole (compound number: 1-988)
[1253]
[1254] Silicagel column chromatography carried out in Example 24 above yielded 0.50 g (yield: 15%) of the title compound (Rf = 0.30) as light brown powder.
[1255] Melting Point: 241-244 ° C (Decomposition)
[1256] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1257] 11.38 (1H, broad singlet);
[1258] 8.21 (2H, doublet, J = 6 Hz);
[1259] 7.36-7.28 (4H, multiplet);
[1260] 7.25-7.08 (10H, multiplet);
[1261] 7.02 (2H, doublet, J = 6 Hz);
[1262] 6.91 (1H, doublet, J = 3 Hz);
[1263] 5.24-5.21 (1H, multiplet);
[1264] 3.62-3.55 (1H, multiplet);
[1265] 3.53-3.47 (1H, multiplet);
[1266] 3.17 (1H, doublet, J = 6 Hz);
[1267] 2.94-2.75 (3H, multiplet);
[1268] 2.35-2.24 (1H, multiplet);
[1269] 1.97-1.87 (1H, multiplet);
[1270] 1.75 (1H, doublet of doublets, 13 Hz, 8 Hz).
[1271] Example 26
[1272] 4-[(8aS) -2,2-Dimethyl-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine- 4-day) -1 H-Pyrrole (compound number: 4-13)
[1273]
[1274] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead (8aS) -2,2-dimethyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation 17 below) was used Reaction and silica gel column chromatography (volume mixing ratio of ethyl acetate, methanol and isopropylamine as eluent 100: 10: 1 respectively) to give 0.85 g (yield: 32%) of the title compound (Rf value = 0.50) was obtained.
[1275] Melting Point: 193-196 ℃ (Decomposition)
[1276] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1277] 11.37 (1H, broad singlet);
[1278] 8.44 (2H, doublet, J = 6 Hz);
[1279] 7.19-7.07 (6H, multiplet);
[1280] 6.90 (1H, doublet, J = 3 Hz);
[1281] 5.27-5.22 (1H, multiplet);
[1282] 3.27-3.18 (1H, multiplet);
[1283] 2.78 (1H, doublet, J = 9 Hz);
[1284] 2.64-2.54 (1H, multiplet);
[1285] 2.33-2.15 (2H, multiplet);
[1286] 2.06-1.94 (1H, multiplet);
[1287] 1.93-1.85 (1H, multiplet);
[1288] 1.67 (1H, doublets of doublets, J = 12 Hz, 7 Hz);
[1289] 1.21-1.12 (1H, multiplet);
[1290] 1.07 (3H, singlet);
[1291] 1.02 (3H, singlet).
[1292] Example 27
[1293] 4-[(8aS) -2,2-dimethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine- 4-day) -1 H-Pyrrole (compound number: 1-301)
[1294]
[1295] Silicagel column chromatography carried out in Example 26 above gave 0.47 g (yield: 18%) of the title compound (Rf = 0.25) as a brown powder.
[1296] Melting Point: 190-193 ℃ (Decomposition)
[1297] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1298] 11.38 (1H, broad singlet);
[1299] 8.43 (2H, doublet, J = 6 Hz);
[1300] 7.20-7.08 (6H, multiplet);
[1301] 6.91 (1H, doublet, J = 3 Hz);
[1302] 5.15-5.11 (1H, multiplet);
[1303] 3.28-3.19 (1H, multiplet);
[1304] 2.95-2.86 (1H, multiplet);
[1305] 2.66-2.55 (2H, multiplet);
[1306] 2.36-2.21 (2H, multiplet);
[1307] 2.00-1.92 (1H, multiplet);
[1308] 1.56 (1H, doublets of doublets, J = 12 Hz, 7 Hz);
[1309] 1.10-0.98 (1H, multiplet);
[1310] 1.05 (3H, singlet);
[1311] 1.02 (3H, singlet).
[1312] Example 28
[1313] 2- (4-fluorophenyl) -4 [(2S, 8aS) -2-methylthio-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridine- 4-day) -1 H-Pyrrole (Compound No. 4-63)
[1314]
[1315] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (2S, 8aS) -2-methylthio-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation Example 12 below) 1.51 g (yield: 17%) of the title compound by reaction and silica gel column chromatography (using a mixture of ethyl acetate, methanol and isopropylamine in each volume ratio of 100: 1: 1 as an eluent) using (Rf value = 0.25) was obtained as a light brown powder.
[1316] Melting Point: 212-213 ℃ (decomposition)
[1317] ¹ H-NMR spectrum (400 MHz, CD ₃ OD) δ ppm:
[1318] 8.35 (2H, doublet of doublets, J = 5 Hz, 1 Hz);
[1319] 7.24 (2H, doublet of doublets, J = 5 Hz, 1 Hz);
[1320] 7.20-7.15 (2H, multiplet);
[1321] 7.03-6.98 (2H, multiplet);
[1322] 6.85 (1H, singlet);
[1323] 5.38 (1H, triplet, J = 2 Hz);
[1324] 3.43-3.37 (1H, multiplet);
[1325] 3.31-3.24 (1H, multiplet);
[1326] 3.15 (1H, doublet of doublets, J = 10 Hz, 3 Hz);
[1327] 2.82-2.77 (1H, multiplet);
[1328] 2.63 (1H, doublets of doublets, J = 10 Hz, 9 Hz);
[1329] 2.49-2.30 (3H, multiplet);
[1330] 2.27-2.13 (1H, multiplet);
[1331] 2.10 (3H, singlet);
[1332] 1.37-1.29 (1H, multiplet).
[1333] Example 29
[1334] 2- (4-fluorophenyl) -4 [(2S, 8aS) -2-methylthio-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine- 4-day) -1 H-Pyrrole (Compound No. 1-995)
[1335]
[1336] Silica gel column chromatography carried out in Example 28 above also gave 1.03 g (yield: 12%) of the title compound (Rf value: 0.10) as a light brown powder.
[1337] Melting Point: 198-200 ℃ (Decomposition)
[1338] ¹ H-NMR spectrum (400 MHz, CD ₃ OD) δ ppm:
[1339] 8.38 (2H, doublet of doublets, J = 4 Hz, 1 Hz);
[1340] 7.24 (2H, doublet of doublets, J = 4 Hz, 1 Hz);
[1341] 7.20-7.15 (2H, multiplet);
[1342] 7.03-6.97 (2H, multiplet);
[1343] 6.86 (1H, singlet);
[1344] 5.28 (1H, doublet, J = 2 Hz);
[1345] 3.53-3.48 (1H, multiplet);
[1346] 3.25 (1H, quinine, J = 8 Hz);
[1347] 3.14 (1H, doublet of doublets, J = 10 Hz, 8 Hz);
[1348] 3.08-3.03 (1H, multiplet);
[1349] 2.87-2.78 (2H, multiplet);
[1350] 2.40 (1H, doublet of doublets, J = 13 Hz, 8 Hz, 3 Hz);
[1351] 2.36-2.30 (1H, multiplet);
[1352] 2.17-2.16 (1H, multiplet);
[1353] 2.14 (3H, singlet);
[1354] 1.36 (1H, doublet of doublets, J = 13 Hz, 8 Hz, 3 Hz).
[1355] Example 30
[1356] 2- (4-fluorophenyl) -4 [(8aS) -2-methyl-3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H-Pyrrole (Compound No. 6-1)
[1357]
[1358] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, reaction and silica using (8aS) -2-methyl-3,5,6,7,8,8a-hexahydroindolizin-7-one (prepared as described in Preparation Example 19 below) By gel column chromatography (using a mixture of 10: 1: 1 by volume of ethyl acetate, methanol and isopropylamine as eluent), 130 mg (yield: 3%) of the title compound (Rf value = 0.50) were obtained. Obtained as a pale brown powder.
[1359] Melting Point: 183-185 ℃ (Decomposition)
[1360] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1361] 8.48 (2H, doublet, J = 6 Hz);
[1362] 8.37 (1H, broad singlet);
[1363] 7.20-7.09 (4H, multiplet);
[1364] 6.97 (2H, triplet, J = 9 Hz);
[1365] 6.83 (1H, doublet, J = 3 Hz);
[1366] 5.58-5.50 (1H, multiplet);
[1367] 5.38-5.32 (1H, multiplet);
[1368] 3.71-3.32 (4H, multiplet);
[1369] 3.30-3.20 (1H, multiplet);
[1370] 2.50-2.28 (2H, multiplet);
[1371] 1.79 (3H, multiplet).
[1372] Example 31
[1373] 2- (4-fluorophenyl) -4 [(8aS) -2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H-Pyrrole (Compound No. 3-1)
[1374]
[1375] Silica gel column chromatography carried out in Example 30 above also gave 190 mg (yield: 5%) of the title compound (Rf value: 0.30) as a light brown powder.
[1376] Melting Point: 181-183 ℃ (Decomposition)
[1377] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1378] 8.45 (2H, doublet, J = 6 Hz);
[1379] 8.37 (1H, broad singlet);
[1380] 7.20-7.09 (4H, multiplet);
[1381] 6.97 (2H, triplet, J = 9 Hz);
[1382] 6.81 (1H, doublet, J = 3 Hz);
[1383] 5.44 (1H, broad singlet);
[1384] 5.24 (1H, broad singlet);
[1385] 4.42-4.38 (1H, multiplet);
[1386] 3.60-3.44 (2H, multiplet);
[1387] 3.04-2.92 (2H, multiplet);
[1388] 2.40-2.28 (1H, multiplet);
[1389] 1.97-1.85 (1H, multiplet);
[1390] 1.75 (3H, singlet).
[1391] Example 32
[1392] 4-[(2S, 8aS) -2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine- 4-day) -1 H-Pyrrole (Compound No. 1-294)
[1393]
[1394] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (2S, 8aS) -2-ethyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation Example 27 below) 1.12 g (yield: 21%) of the title compound (by using a reaction and silica gel column chromatography (using a mixture of ethyl acetate, methanol and isopropylamine in each volume ratio of 100: 10: 5 as the eluent) by using Rf value = 0.50) was obtained as a light brown powder.
[1395] Melting Point: 203-205 ℃ (Decomposition)
[1396] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1397] 11.39-11.38 (1H, broad singlet);
[1398] 8.43 (2H, doublet, J = 6 Hz);
[1399] 7.19-7.16 (2H, multiplet);
[1400] 7.15-7.10 (4H, multiplet);
[1401] 6.91 (1H, doublet, J = 3 Hz);
[1402] 5.13-5.12 (1H, broad singlet);
[1403] 3.32-3.26 (2H, multiplet);
[1404] 2.94-2.90 (1H, multiplet);
[1405] 2.70-2.64 (2H, multiplet);
[1406] 2.50-2.41 (1H, multiplet);
[1407] 2.31-2.25 (1H, multiplet);
[1408] 2.02-1.88 (3H, multiplet);
[1409] 1.38-1.28 (2H, multiplet);
[1410] 0.85 (3H, triplet, J = 7 Hz).
[1411] Example 33
[1412] 4-[(2S, 8aS) -2-butylthio-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine -4- day) -1 H-Pyrrole (Compound No. 4-66)
[1413]
[1414] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (2S, 8aS) -2-butylthio-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation 14 below) 426 mg (yield: 8%) of the title compound by reaction and silica gel column chromatography (using a mixture of 100: 1: 1 each by volume of ethyl acetate, methanol and isopropylamine as eluent) using (Rf value = 0.25) was obtained as a pale pink powder.
[1415] Melting Point: 189-190 ° C (decomposition)
[1416] ¹ H-NMR spectrum (400 MHz, CD ₃ OD) δ ppm:
[1417] 8.35 (2H, doublet of doublets, J = 5 Hz, 2 Hz);
[1418] 7.24 (2H, doublet of doublets, J = 5 Hz, 2 Hz);
[1419] 7.15 (2H, doublet of doublets, J = 5 Hz, 3 Hz);
[1420] 7.03-6.97 (2H, multiplet);
[1421] 6.85 (1H, singlet);
[1422] 5.37 (1H, triplet, J = 2 Hz);
[1423] 3.42-3.33 (2H, multiplet);
[1424] 3.13 (1H, doublet of doublets, J = 10 Hz, 3 Hz);
[1425] 2.83-2.77 (1H, multiplet);
[1426] 2.66 (1H, triplet, J = 10 Hz);
[1427] 2.56 (2H, triplet, J = 7 Hz);
[1428] 2.53-2.30 (3H, multiplet);
[1429] 2.21-2.13 (1H, multiplet);
[1430] 1.57 (2H, quinine, J = 8 Hz);
[1431] 1.42 (2H, hexagonal line, J = 7 Hz);
[1432] 1.36-1.29 (1H, multiplet);
[1433] 0.92 (3H, triplet, J = 7 Hz).
[1434] Example 34
[1435] 4-[(2S, 8aS) -2-butylthio-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine -4- day) -1 H-Pyrrole (Compound No. 1-998)
[1436]
[1437] Silica gel column chromatography carried out in Example 33 above also gave 612 mg (yield: 13%) of the title compound (Rf value: 0.10) as a light brown powder.
[1438] Melting Point: 199-200 ℃ (decomposition)
[1439] ¹ H-NMR spectrum (400 MHz, CD ₃ OD) δ ppm:
[1440] 8.37 (2H, doublet of doublets, J = 5 Hz, 2 Hz);
[1441] 7.23 (2H, doublet of doublets, J = 5 Hz, 2 Hz);
[1442] 7.17 (2H, doublet of doublets, J = 6 Hz, 3 Hz);
[1443] 7.03-6.97 (2H, multiplet);
[1444] 6.86 (1H, singlet);
[1445] 5.26 (1H, doublet, J = 1 Hz);
[1446] 3.53-3.49 (1H, multiplet);
[1447] 3.14 (1H, doublet of doublets, J = 10 Hz, 8 Hz);
[1448] 3.08-3.03 (1H, multiplet);
[1449] 2.88-2.76 (2H, multiplet);
[1450] 2.59 (2H, triplet, J = 7 Hz);
[1451] 2.44-2.29 (2H, multiplet);
[1452] 2.16-2.11 (1H, multiplet);
[1453] 1.59 (2H, triplets of triplets, J = 16 Hz, 7 Hz);
[1454] 1.44 (2H, hexagonal line, J = 7 Hz);
[1455] 1.35 (2H, triplets of triplets, J = 13 Hz, 8 Hz);
[1456] 1.24 (3H, triplet, J = 7 Hz).
[1457] Example 35
[1458] 4-[(2S, 8aS) -2-ethylthio-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine -4- day) -1 H-Pyrrole (Compound No. 4-64)
[1459]
[1460] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (2S, 8aS) -2-ethylthio-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation Example 13 below) 672 mg (yield: 24%) of the title compound by using the reaction and silica gel column chromatography (using a mixture of 100: 1: 1 each by volume of ethyl acetate, methanol and isopropylamine as eluent) (Rf value = 0.25) was obtained as a light brown powder.
[1461] Melting Point: 205-207 ℃ (Decomposition)
[1462] ¹ H-NMR spectrum (400 MHz, CD ₃ OD) δ ppm:
[1463] 8.35 (2H, doublet of doublets, J = 4 Hz, 1 Hz);
[1464] 7.23 (2H, doublet of doublets, J = 4 Hz, 1 Hz);
[1465] 7.19-7.15 (2H, multiplet);
[1466] 7.03-6.97 (2H, multiplet);
[1467] 6.85 (1H, singlet);
[1468] 5.38 (1H, triplet, J = 2 Hz);
[1469] 3.42-3.33 (2H, multiplet);
[1470] 3.13 (1H, doublet of doublets, J = 10 Hz, 3 Hz);
[1471] 2.83-2.77 (1H, multiplet);
[1472] 2.66 (1H, doublets of doublets, J = 10 Hz, 8 Hz);
[1473] 2.57 (2H, quartet, J = 7 Hz);
[1474] 2.50-2.33 (2H, multiplet);
[1475] 2.31-2.30 (1H, multiplet);
[1476] 2.21-2.13 (1H, multiplet);
[1477] 1.38-1.30 (1H, multiplet);
[1478] 1.25 (3H, triplet, J = 7 Hz).
[1479] Example 36
[1480] 4-[(2S, 8aS) -2-ethylthio-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine -4- day) -1 H-Pyrrole (Compound No. 1-996)
[1481]
[1482] Silica gel column chromatography carried out in Example 35 above also gave 563 mg (yield: 20%) of the title compound (Rf value: 0.10) as pale pink powder.
[1483] Melting Point: 193-196 ℃ (Decomposition)
[1484] ¹ H-NMR spectrum (400 MHz, CD ₃ OD) δ ppm:
[1485] 8.37 (2H, doublet of doublets, J = 4 Hz, 2 Hz);
[1486] 7.23 (2H, doublet of doublets, J = 4 Hz, 2 Hz);
[1487] 7.21-7.15 (2H, multiplet);
[1488] 7.02-6.98 (2H, multiplet);
[1489] 6.86 (1H, singlet);
[1490] 5.27 (1H, broad singlet);
[1491] 3.54-3.49 (1H, multiplet);
[1492] 3.32 (1H, quinine, J = 8 Hz);
[1493] 3.14 (1H, doublet of doublets, J = 10 Hz, 8 Hz);
[1494] 3.08-3.02 (1H, doublets of triplets, J = 12 Hz, 5 Hz);
[1495] 2.85 (1H, triplets of doublets, J = 12 Hz, 5 Hz);
[1496] 2.78 (1H, doublets of triplets, J = 10 Hz, 8 Hz);
[1497] 2.60 (2H, quartet, J = 8 Hz);
[1498] 2.41 (1H, doublets of triplets, J = 12 Hz, 9 Hz);
[1499] 2.36-2.29 (1H, multiplet);
[1500] 2.17-2.11 (1H, multiplet);
[1501] 1.35 (1H, doublets of triplets, J = 13 Hz, 8 Hz);
[1502] 1.27 (3H, triplet, J = 8 Hz).
[1503] Example 37
[1504] 4-[(8aS) -2-ethylidene-l, 2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine-4 -Day) -1 H-Pyrrole (Compound No. 1-983)
[1505]
[1506] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (8aS) -2-ethylidene-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation 24 below) is used 474 mg (yield: 4%) of the title compound (Rf) by reaction and silica gel column chromatography (using a mixture of 100: 5: 3 each volume ratio of ethyl acetate, methanol and isopropylamine as eluent). Value = 0.50) was obtained as a white powder.
[1507] Melting Point: 244-246 ℃ (decomposition)
[1508] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1509] 8.42 (2H, doublet, J = 6 Hz);
[1510] 7.18-7.12 (4H, multiplet);
[1511] 7.10-7.07 (2H, multiplet);
[1512] 6.93 (1H, doublet, J = 3 Hz);
[1513] 5.31-5.29 (1H, broad singlet);
[1514] 5.18-5.16 (1H, broad singlet);
[1515] 3.30-3.29 (1H, multiplet);
[1516] 3.24-3.23 (1H, multiplet);
[1517] 3.19-3.10 (1H, multiplet);
[1518] 2.84-2.80 (1H, multiplet);
[1519] 2.64-2.55 (1H, multiplet);
[1520] 2.35-2.26 (2H, multiplet);
[1521] 2.10-2.07 (1H, multiplet);
[1522] 1.82-1.78 (1H, multiplet);
[1523] 1.53 (3H, doublet, J = 6 Hz).
[1524] Example 38
[1525] 2- (4-fluorophenyl) -4-[(8aS) -2,2-propylenedioxy-1,2,3,5,8,8a-hexahydro indolizin-7-yl] -3- (Pyridin-4-yl) -1 H-pyrrole (compound No. 4-57)
[1526]
[1527] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (8aS) -2,2-propylenedioxy-1,2,3,5,6,7,8,8a-octahydroindoligin-7- (prepared as described in Preparation Example 21 below) 2.11 g (yield: 29%) of title by performing reaction and silica gel column chromatography (using a mixture of 100: 10: 0.25 each volume ratio of ethyl acetate, methanol and isopropylamine as eluent) using ionic Compound (Rf value = 0.48) was obtained as a light brown powder.
[1528] Melting Point: 164-166 ℃ (Decomposition)
[1529] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1530] 11.39 (1H, broad singlet);
[1531] 8.45 (2H, doublet, J = 6 Hz);
[1532] 7.20-7.08 (6H, multiplet);
[1533] 6.91 (1H, doublet, J = 3 Hz);
[1534] 5.27-5.22 (1H, multiplet);
[1535] 3.86-3.69 (4H, multiplet);
[1536] 3.39 (1H, doublet, J = 10 Hz);
[1537] 3.27-3.19 (1H, multiplet);
[1538] 2.66-2.57 (1H, multiplet);
[1539] 2.35-2.19 (3H, multiplet);
[1540] 2.15 (1H, doublet, J = 10 Hz);
[1541] 2.06-1.96 (1H, multiplet);
[1542] 1.62-1.54 (2H, multiplet);
[1543] 1.50-1.42 (1H, multiplet).
[1544] Example 39
[1545] 2- (4-fluorophenyl) -4-[(8aS) -2,2-propylenedioxy-l, 2,3,5,6,8a-hexahydro indolizin-7-yl] -3- (Pyridin-4-yl) -1 H-pyrrole (compound No. 1-989)
[1546]
[1547] Silica gel column chromatography carried out in Example 38 above also gave 1.38 g (yield: 19%) of the title compound (Rf value: 0.22) as a light brown powder.
[1548] Melting Point: 214-216 ℃ (decomposition)
[1549] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1550] 11.40 (1H, broad singlet);
[1551] 8.43 (2H, doublet, J = 6 Hz);
[1552] 7.22-7.07 (6H, multiplet);
[1553] 6.93 (1H, doublet, J = 3 Hz);
[1554] 5.20-5.16 (1H, multiplet);
[1555] 3.85-3.70 (4H, multiplet);
[1556] 3.14-3.04 (1H, multiplet);
[1557] 3.07 (1H, doublet, J = 10 Hz);
[1558] 2.93-2.85 (1H, multiplet);
[1559] 2.62 (1H, doublet, J = 10 Hz);
[1560] 2.54-2.44 (1H, multiplet);
[1561] 2.33-2.21 (1H, multiplet);
[1562] 2.16-2.04 (2H, multiplet);
[1563] 1.68-1.44 (2H, multiplet);
[1564] 1.47 (1H, doublets of doublets, J = 13 Hz, 9 Hz).
[1565] Example 40
[1566] 4-[(8aS) -2,2- (2 ', 2'-dimethylpropylenedioxy) -1,2,3,5,8,8a-hexahydroindolizin-7-yl] -2- (4 -Fluorophenyl) -3- (pyridin-4-yl) -1 H-Pyrrole (Compound No. 4-58)
[1567]
[1568] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (8aS) -2,2- (2 ', 2'-dimethylpropylenedioxy) -1,2,3,5,6,7,8, (prepared as described in Preparation 22 below), 1.85 using 8a-octahydroindolizin-7-one to perform reaction and silica gel column chromatography (using e. g (Yield 26%) of the title compound (Rf value = 0.58) were obtained as a light brown powder.
[1569] Melting Point: 235-237 ℃ (decomposition)
[1570] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1571] 11.39 (1H, broad singlet);
[1572] 8.45 (2H, doublet, J = 6 Hz);
[1573] 7.20-7.08 (6H, multiplet);
[1574] 6.91 (1H, doublet, J = 3 Hz);
[1575] 5.27-5.22 (1H, multiplet);
[1576] 3.47-3.30 (5H, multiplet);
[1577] 3.26-3.18 (1H, multiplet);
[1578] 2.66-2.58 (1H, multiplet);
[1579] 2.36-2.19 (3H, multiplet);
[1580] 2.16 (1H, doublet, J = 10 Hz);
[1581] 2.07-1.96 (1H, multiplet);
[1582] 1.47 (1H, doublets of doublets, J = 12 Hz, 10 Hz);
[1583] 0.88 (6H, singlet).
[1584] Example 41
[1585] 4-[(8aS) -2,2- (2 ', 2'-dimethylpropylenedioxy) -l, 2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4 -Fluorophenyl) -3- (pyridin-4-yl) -1 H-Pyrrole (Compound No. 1-990)
[1586]
[1587] Silica gel column chromatography carried out in Example 40 above also gave 1.37 g (yield: 19%) of the title compound (Rf value: 0.20) as a white powder.
[1588] Melting Point: 235-237 ℃ (decomposition)
[1589] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1590] 11.40 (1H, broad singlet);
[1591] 8.43 (2H, doublet, J = 6 Hz);
[1592] 7.19-7.08 (6H, multiplet);
[1593] 6.93 (1H, doublet, J = 3 Hz);
[1594] 5.19-5.15 (1H, multiplet);
[1595] 3.47-3.29 (4H, multiplet);
[1596] 3.14-3.05 (2H, multiplet);
[1597] 2.93-2.85 (1H, multiplet);
[1598] 2.63 (1H, doublet, J = 10 Hz);
[1599] 2.54-2.45 (1H, multiplet);
[1600] 2.33-2.22 (1H, multiplet);
[1601] 2.14-2.04 (2H, multiplet);
[1602] 1.46 (1H, doublets of doublets, J = 13 Hz, 9 Hz);
[1603] 0.91 (3H, singlet);
[1604] 0.85 (3H, singlet).
[1605] Example 42
[1606] 2- (4-fluorophenyl) -4-[(2S, 8aS) -2-propyl-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridine- 4-day) -1 H-Pyrrole (Compound No. 4-7)
[1607]
[1608] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (2S, 8aS) -2-propyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation Example 28 below) 684 mg (yield: 5%) of the title compound (by using a reaction and silica gel column chromatography (using a mixture of ethyl acetate, methanol and isopropylamine in each volume ratio 100: 5: 1 as eluent) by using Rf value = 0.60) was obtained as a pale yellow powder.
[1609] Melting Point: 205-206 ℃ (Decomposition)
[1610] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1611] 11.36-11.35 (1H, broad singlet);
[1612] 8.44 (2H, doublet, J = 6 Hz);
[1613] 7.17-7.14 (4H, multiplet);
[1614] 7.13-7.09 (2H, multiplet);
[1615] 6.90 (1H, doublet, J = 3 Hz);
[1616] 5.25-5.24 (1H, broad singlet);
[1617] 3.36-3.30 (1H, multiplet);
[1618] 3.27-3.22 (1H, multiplet);
[1619] 2.74-2.72 (1H, multiplet);
[1620] 2.61-2.51 (1H, multiplet);
[1621] 2.23-2.10 (3H, multiplet);
[1622] 2.07-1.97 (3H, multiplet);
[1623] 1.38-1.20 (4H, multiplet);
[1624] 0.86 (3H, triplets, J = 7 Hz).
[1625] Example 43
[1626] 2- (4-fluorophenyl) -4-[(2S, 8aS) -2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine- 4-day) -1 H-Pyrrole (Compound No. 1-295)
[1627]
[1628] Silica gel column chromatography carried out in Example 42 above also gave 359 mg (yield: 3%) of the title compound (Rf value: 0.50) as a pale yellow powder.
[1629] Melting Point: 202-203 ℃ (Decomposition)
[1630] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1631] 11.38-11.37 (1H, broad singlet);
[1632] 8.42 (2H, doublet, J = 6 Hz);
[1633] 7.18-7.13 (4H, multiplet);
[1634] 7.12-7.09 (2H, multiplet);
[1635] 6.91 (1H, doublet, J = 3 Hz);
[1636] 5.12-5.11 (1H, broad singlet);
[1637] 3.31-3.23 (1H, multiplet);
[1638] 2.92-2.88 (1H, multiplet);
[1639] 2.67-2.61 (2H, multiplet);
[1640] 2.51-2.49 (1H, multiplet);
[1641] 2.42-2.38 (1H, multiplet);
[1642] 2.30-2.25 (1H, multiplet);
[1643] 2.02-1.89 (3H, multiplet);
[1644] 1.36-1.22 (4H, multiplet);
[1645] 0.88 (3H, doublet, J = 7 Hz).
[1646] Example 44
[1647] 4-[(2S, 8aS) -2-ethoxy-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine -4- day) -1 H-Pyrrole (Compound No. 4-16)
[1648]
[1649] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (2R, 8aS) -2-ethoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation Example 20 below) 285 mg (yield: 9%) of the title compound by using the reaction and silica gel column chromatography (using a mixture of 10: 1: 1 by volume of ethyl acetate, methanol and isopropylamine as eluents) (Rf value = 0.65) was obtained as a light brown powder.
[1650] Melting Point: 194-196 ℃ (Decomposition)
[1651] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1652] 8.46 (2H, doublet, J = 6 Hz);
[1653] 8.23 (1H, broad singlet);
[1654] 7.16 (2H, doublet, J = 6 Hz);
[1655] 7.12 (2H, doublet of doublets, J = 9 Hz, 5 Hz);
[1656] 6.97 (2H, triplet, J = 9 Hz);
[1657] 6.82 (1H, doublet, J = 3 Hz);
[1658] 5.51-5.47 (1H, multiplet);
[1659] 4.14-4.08 (1H, multiplet);
[1660] 3.62-3.53 (1H, multiplet);
[1661] 3.50-3.36 (3H, multiplet);
[1662] 2.93-2.82 (1H, multiplet);
[1663] 2.59-2.46 (1H, multiplet);
[1664] 2.32-2.15 (2H, multiplet);
[1665] 2.14-2.01 (1H, multiplet);
[1666] 2.00-1.92 (1H, multiplet);
[1667] 1.70-1.60 (1H, multiplet);
[1668] 1.19 (3H, triplet, J = 7 Hz).
[1669] Example 45
[1670] 4-[(2S, 8aS) -2-ethoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine -4- day) -1 H-Pyrrole (Compound No. 1-304)
[1671]
[1672] Silica gel column chromatography carried out in Example 44 above also gave 231 mg (yield: 7%) of the title compound (Rf value: 0.60) as a light brown powder.
[1673] Melting Point: 192-195 ℃ (Decomposition)
[1674] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1675] 8.47 (2H, doublet, J = 6 Hz);
[1676] 8.25 (1H, broad singlet);
[1677] 7.20-7.09 (4H, multiplet);
[1678] 6.97 (2H, triplet, J = 9 Hz);
[1679] 6.82 (1H, doublet, J = 3 Hz);
[1680] 5.40 (1H, doublet, J = 2 Hz);
[1681] 4.10-4.02 (1H, multiplet);
[1682] 3.50-3.34 (3H, multiplet);
[1683] 3.16 (1H, doublet of doublets, J = 11 Hz, 6 Hz);
[1684] 2.99-2.90 (1H, multiplet);
[1685] 2.80-2.65 (2H, multiplet);
[1686] 2.46-2.30 (1H, multiplet);
[1687] 2.18-2.04 (1H, multiplet);
[1688] 1.96-1.88 (1H, multiplet);
[1689] 1.69-1.60 (1H, multiplet);
[1690] 1.19 (3H, triplet, J = 7 Hz).
[1691] Example 46
[1692] (±) -4- [cyclopentanespiro-2 '-(1', 2 ', 3', 5 ', 8', 8a'-hexahydroindolizin-7'-yl] -2- (4-fluoro Rophenyl) -3- (pyridin-4-yl) -1 H-Pyrrole (compound No. 4-61)
[1693]
[1694] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (±) -cyclopentanespiro-2 '-(1', 2 ', 3', 5 ', 6', 7 ', 8', 8a '(prepared as described in Preparation Example 18 below) By using -octahydroindolizin) -7'-one, by carrying out the reaction and silica gel column chromatography (using a mixture of 100: 10: 0.25 each volume ratio of ethyl acetate, methanol and isopropylamine as eluent), 2.05 g (yield: 29%) of the title compound (Rf value = 0.53) were obtained as a light brown powder.
[1695] Melting Point: 206-208 ℃ (Decomposition)
[1696] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1697] 11.37 (1H, broad singlet);
[1698] 8.45 (2H, doublet, J = 5 Hz);
[1699] 7.20-7.07 (6H, multiplet);
[1700] 6.90 (1H, doublet, J = 3 Hz);
[1701] 5.27-5.22 (1H, multiplet);
[1702] 3.28-3.20 (1H, multiplet);
[1703] 2.90 (1H, doublet, J = 9 Hz);
[1704] 2.64-2.55 (1H, multiplet);
[1705] 2.29-2.17 (2H, multiplet);
[1706] 2.05-1.94 (2H, multiplet);
[1707] 1.80 (1H, doublets of doublets, J = 12 Hz, 6 Hz);
[1708] 1.64-1.42 (8H, multiplet);
[1709] 1.26 (1H, doublets of doublets, J = 12 Hz, 10 Hz).
[1710] Example 47
[1711] (±) -4- [cyclopentanespiro-2 '-(1', 2 ', 3', 5 ', 6', 8a'-hexahydroindolizin-7'-yl] -2- (4-fluoro Rophenyl) -3- (pyridin-4-yl) -1 H-Pyrrole (Compound No. 1-993)
[1712]
[1713] Silica gel column chromatography carried out in Example 46 above also gave 1.31 g (yield: 19%) of the title compound (Rf value: 0.19) as a light brown powder.
[1714] Melting Point: 202-204 ℃ (Decomposition)
[1715] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1716] 11.38 (1H, broad singlet);
[1717] 8.43 (2H, doublet, J = 6 Hz);
[1718] 7.20-7.08 (6H, multiplet);
[1719] 6.91 (1H, doublet, J = 3 Hz);
[1720] 5.17-5.13 (1H, multiplet);
[1721] 3.25-3.18 (1H, multiplet);
[1722] 2.92-2.85 (1H, multiplet);
[1723] 2.70 (1H, doublet, J = 9 Hz);
[1724] 2.65-2.56 (1H, multiplet);
[1725] 2.37 (1H, doublet, J = 9 Hz);
[1726] 2.34-2.23 (1H, multiplet);
[1727] 2.01-1.92 (1H, multiplet);
[1728] 1.69 (1H, doublets of doublets, J = 12 Hz, 7 Hz);
[1729] 1.61-1.39 (8H, multiplet);
[1730] 1.15 (1H, doublet of doublets, J = 12 Hz, 8 Hz).
[1731] Example 48
[1732] 4-[(2S, 8aS) -2-benzyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine- 4-day) -1 H-Pyrrole (Compound No. 1-299)
[1733]
[1734] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (2S, 8aS) -2-benzyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation 29 below) 252 mg (yield: 11%) of the title compound (by using a reaction and silica gel column chromatography (using a mixture of ethyl acetate, methanol and isopropylamine in each volume ratio of 100: 10: 2) as an eluent Rf value = 0.50) was obtained as a light brown powder.
[1735] Melting Point: 207-209 ℃ (Decomposition)
[1736] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1737] 11.39-11.38 (1H, broad singlet);
[1738] 8.46 (2H, doublet, J = 6 Hz);
[1739] 7.28 (2H, triplets, J = 8 Hz);
[1740] 7.20-7.11 (9H, multiplet);
[1741] 6.92 (1H, doublet, J = 3 Hz);
[1742] 5.14-5.13 (1H, broad singlet);
[1743] 3.39-3.21 (2H, multiplet);
[1744] 2.91-2.83 (1H, multiplet);
[1745] 2.65-2.49 (5H, multiplet);
[1746] 2.32-2.29 (2H, multiplet);
[1747] 1.99-1.87 (2H, multiplet).
[1748] Example 49
[1749] 4-[(8aS) -2-benzylidene-l, 2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridine-4 -Day) -1 H-Pyrrole (Compound No. 1-987)
[1750]
[1751] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (8aS) -2-benzylidene-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation 26 below) is used 17 mg (yield: 3%) of the title compound (Rf) by reaction and silica gel column chromatography (using a mixture of ethyl acetate, methanol and isopropylamine in each volume ratio of 100: 10: 2 as eluent) Value = 0.50) was obtained as a light brown powder.
[1752] Melting Point: 243-245 ℃ (Decomposition)
[1753] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1754] 8.41 (2H, doublet, J = 6 Hz);
[1755] 8.31-8.29 (1H, broad singlet);
[1756] 7.38-7.27 (4H, multiplet);
[1757] 7.21 (1H, triplet, J = 7 Hz);
[1758] 7.15-7.10 (4H, multiplet);
[1759] 6.97 (2H, triplet, J = 9 Hz);
[1760] 6.84 (1H, doublet, J = 3 Hz);
[1761] 6.40 (1H, singlet);
[1762] 5.50-5.49 (1H, broad singlet);
[1763] 3.65-3.58 (3H, multiplet);
[1764] 2.96-2.93 (1H, multiplet);
[1765] 2.85-2.78 (2H, multiplet);
[1766] 2.47-2.42 (1H, multiplet);
[1767] 2.36-2.21 (2H, multiplet).
[1768] Example 50
[1769] 2- (4-fluorophenyl) -4-[(2S, 8aS) -2-phenoxy-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- (pyridine -4- day) -1 H-Pyrrole (Compound No. 4-68)
[1770]
[1771] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (2S, 8aS) -2-phenoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation 23 below) 2.00 g (yield: 33%) of the title compound (Rf value = 0.63) were obtained by reaction and silica gel column chromatography (using a mixture of 19: 1 by volume ratio of ethyl acetate and methanol as eluent), using Obtained as a white powder.
[1772] Melting Point: 212-214 ℃ (Decomposition)
[1773] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1774] 11.40 (1H, broad singlet);
[1775] 8.45 (2H, doublet, J = 6 Hz);
[1776] 7.27 (2H, triplets, J = 8 Hz);
[1777] 7.21-7.08 (6H, multiplet);
[1778] 6.96-6.82 (4H, multiplet);
[1779] 5.28-5.24 (1H, multiplet);
[1780] 4.88-4.80 (1H, multiplet);
[1781] 3.34-3.27 (1H, multiplet);
[1782] 3.19-3.11 (1H, multiplet);
[1783] 2.70-2.50 (2H, multiplet);
[1784] 2.46-2.05 (4H, multiplet);
[1785] 1.47-1.37 (1H, multiplet).
[1786] Example 51
[1787] 2- (4-fluorophenyl) -4-[(2S, 8aS) -2-phenoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine -4- day) -1 H-Pyrrole (Compound No. 1-1000)
[1788]
[1789] Silica gel column chromatography carried out in Example 50 above also gave 0.90 g (yield: 15%) of the title compound (Rf value: 0.10) as a light brown powder.
[1790] Melting Point: 199-201 ℃ (Decomposition)
[1791] ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ ppm:
[1792] 11.41 (1H, broad singlet);
[1793] 8.33 (2H, doublet, J = 6 Hz);
[1794] 7.29 (2H, triplets, J = 8 Hz);
[1795] 7.21-7.08 (6H, multiplet);
[1796] 6.97-6.86 (4H, multiplet);
[1797] 5.28-5.24 (1H, multiplet);
[1798] 4.88-4.82 (1H, multiplet);
[1799] 3.21-3.14 (1H, multiplet);
[1800] 3.04-2.91 (3H, multiplet);
[1801] 2.67-2.57 (1H, multiplet);
[1802] 2.44-2.35 (1H, multiplet);
[1803] 2.33-2.23 (1H, multiplet);
[1804] 2.11-2.02 (1H, multiplet);
[1805] 1.44-1.36 (1H, multiplet).
[1806] Example 52
[1807] 2- (4-fluorophenyl) -4-[(2S, 8aS) -2-methylsulfonyl-1,2,3,5,8,8a-hexahydroindolizin-7-yl] -3- ( Pyridin-4-yl) -1 H-Pyrrole (Compound No. 4-67)
[1808]
[1809] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (2S, 8aS) -2-methylsulfonyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7- (prepared as described in Preparation Example 15 below) 30 mg (yield: 2%) of the title by carrying out reaction and silica gel column chromatography (using a mixture of 100: 1: 1 each volume ratio of ethyl acetate, methanol and isopropylamine as eluent) using a warm Compound (Rf value = 0.2) was obtained as a brown powder.
[1810] Melting Point:〉 250 ℃ (decomposition)
[1811] ¹ H-NMR spectrum (400 MHz, CD ₃ OD) δ ppm:
[1812] 8.40-8.36 (2H, multiplet);
[1813] 7.25 (2H, doublet, J = 5 Hz);
[1814] 7.22-7.15 (2H, multiplet);
[1815] 7.05-6.98 (2H, multiplet);
[1816] 6.87 (1H, singlet);
[1817] 5.39 (1H, triplet, J = 2 Hz);
[1818] 3.81-3.74 (1H, multiplet);
[1819] 3.59 (1H, doublets of doublets, J = 11 Hz, 3 Hz);
[1820] 3.49-3.44 (1H, multiplet);
[1821] 2.93 (3H, singlet);
[1822] 2.90-2.83 (1H, multiplet);
[1823] 2.67 (1H, triplet, J = 11 Hz);
[1824] 2.57-2.27 (3H, multiplet);
[1825] 2.27-2.20 (1H, multiplet);
[1826] 1.88-1.80 (1H, multiplet).
[1827] Example 53
[1828] 2- (4-fluorophenyl) -4-[(2S, 8aS) -2-methylsulfonyl-l, 2,3,5,6,8a-hexahydroindolizin-7-yl] -3- ( Pyridin-4-yl) -1 H-Pyrrole (Compound No. 1-999)
[1829]
[1830] Silica gel column chromatography carried out in Example 52 above also gave 46 mg (yield: 2%) of the title compound (Rf value: 0.05) as a brown powder.
[1831] Melting Point: 147-150 ℃ (Decomposition)
[1832] H-NMR spectrum (400 MHz, CD ₃ OD) δ ppm:
[1833] 8.39-8.35 (2H, multiplet);
[1834] 7.24 (2H, doublet, J = 5 Hz);
[1835] 7.19-7.16 (2H, multiplet);
[1836] 7.03-6.87 (2H, multiplet);
[1837] 6.86 (1H, singlet);
[1838] 5.38 (1H, triplet, J = 2 Hz);
[1839] 3.69-3.65 (1H, multiplet);
[1840] 3.62-3.56 (1H, multiplet);
[1841] 3.44-3.38 (1H, multiplet);
[1842] 2.92 (3H, singlet);
[1843] 2.82-2.78 (1H, multiplet);
[1844] 2.63-2.53 (1H, multiplet);
[1845] 2.50-2.39 (1H, multiplet);
[1846] 2.36-2.15 (3H, multiplet);
[1847] 1.92-1.76 (1H, multiplet).
[1848] Example 54
[1849] 2- (4-fluorophenyl) -4-[(8aS) -2-propylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridine-4 -Day) -1 H-Pyrrole (Compound No. 1-984)
[1850]
[1851] In a manner similar to the procedure described in Example 1 (v) above, (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one Instead, (8aS) -2-propylidene-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (prepared as described in Preparation 25 below) is used By the reaction and silica gel column chromatography (using a mixture of ethyl acetate, methanol and isopropylamine in each volume ratio 100: 5: 1 as eluent) to form the title compound as two geometric isomers of Form E and Form Z. Obtained.
[1852] Isomer A
[1853] Rf value = 0.50, 0.56 g of orange powder (yield: 4%)
[1854] Melting Point: 185-187 ℃ (Decomposition)
[1855] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1856] 11.41-11.40 (1H, broad singlet);
[1857] 8.41 (2H, doublet, J = 6 Hz);
[1858] 7.18-7.11 (4H, multiplet);
[1859] 7.10-7.07 (2H, multiplet);
[1860] 6.93 (1H, doublet, J = 3 Hz);
[1861] 5.23-5.18 (1H, multiplet);
[1862] 5.14-5.13 (1H, broad singlet);
[1863] 3.41-3.36 (1H, multiplet);
[1864] 3.22-3.13 (2H, multiplet);
[1865] 2.93-2.89 (1 H, multiplet);
[1866] 2.68-2.66 (1H, multiplet);
[1867] 2.40-2.29 (2H, multiplet);
[1868] 2.10-2.06 (1H, multiplet);
[1869] 1.97-1.87 (2H, multiplet);
[1870] 1.57-1.55 (1H, multiplet);
[1871] 0.94 (3H, doublet, J = 7 Hz).
[1872] Isomer B
[1873] Rf value = 0.45, 1.58 g of white powder (yield: 11%)
[1874] Melting Point: 249-251 ℃ (Decomposition)
[1875] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1876] 11.47-11.46 (1H, broad singlet);
[1877] 8.42 (2H, doublet, J = 6 Hz);
[1878] 7.19-7.14 (4H, multiplet);
[1879] 7.13-7.07 (2H, multiplet);
[1880] 6.92 (1H, doublet, J = 3 Hz);
[1881] 5.27-5.23 (1H, multiplet);
[1882] 5.18-5.17 (1H, broad singlet);
[1883] 4.14 (1H, quartet, J = 5 Hz);
[1884] 3.24-3.21 (1H, multiplet);
[1885] 3.13-3.10 (1H, multiplet);
[1886] 2.85-2.80 (1H, multiplet);
[1887] 2.63-2.58 (1H, multiplet);
[1888] 2.37-2.31 (2H, multiplet);
[1889] 2.11-2.07 (1H, multiplet);
[1890] 1.95-1.90 (2H, multiplet);
[1891] 1.88-1.78 (1H, multiplet);
[1892] 0.92 (3H, doublet, J = 8 Hz).
[1893] Production Example
[1894] Preparation Example 1
[1895] (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[1896]
[1897] 1 (i) (2S, 4R) -1-benzyloxycarbonyl-2-cyanomethyl-4-methoxypyrrolidine
[1898] 17.9 mL (17.9 mmol) of the 1M solution of the borane-tetrahydrofuran complex in tetrahydrofuran was stirred at 0 ° C. with (2S, 4R) -1-benzyloxycarbonyl-4-methoxy in 20 mL tetrahydrofuran. Proline was added to a solution of 2.00 g (7.16 mmol). The resulting mixture was stirred at 0 ° C. for 1 hour, then at room temperature for 3 hours and upon completion of the stirring time, the reaction mixture was cooled back to 0 ° C. Then, methanol was carefully added to the cooled mixture, and the mixture was then concentrated by evaporation under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue and the mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to give 1.82 g of a reduced product, an alcohol derivative, as a brown oil.
[1899] 1.13 mL (8.14 mmol) of triethylamine was added to a solution of the oil obtained above in 25 mL of dichloromethane, followed by 0.58 mL (7.46 mmol) of methanesulfonyl chloride was added to the ice-cooled mixture with stirring. After stirring for 30 minutes at room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to give 2.19 g of mesylated derivative as a brown oil.
[1900] 0.31 g (6.32 mmol) of sodium cyanide was added to a solution of the obtained mesylated derivative in 22 mL of dimethyl sulfoxide, and the obtained mixture was stirred at 100 ° C. for 30 minutes. Upon completion of the stirring time, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.70 g (yield: 88%) of the title compound as a light brown oil.
[1901] ¹ H-NMR spectrum (400 MHz, CDC1 ₃ ) δ ppm:
[1902] 7.43-7.28 (5H, multiplet);
[1903] 5.26-5.08 (2H, multiplet);
[1904] 4.20-4.10 (1H, multiplet);
[1905] 4.03-3.93 (1H, multiplet);
[1906] 3.90 (0.4H, doublet, J = 12 Hz);
[1907] 3.74 (0.6H, doublet, J = 12 Hz);
[1908] 3.56-3.44 (1H, multiplet);
[1909] 3.31 (1.2H, singlet);
[1910] 3.30 (1.8H, singlet);
[1911] 3.16 (0.6H, doublets of doublets, J = 17 Hz, 6 Hz);
[1912] 2.80 (0.4H, doublet of doublets, J = 17 Hz, 6 Hz);
[1913] 2.76-2.58 (1H, multiplet);
[1914] 2.39-2.30 (1H, multiplet);
[1915] 2.08-1.97 (1H, multiplet).
[1916] 1 (ii) (2S, 4R) -1-benzyloxycarbonyl-2- (3-ethoxycarbonyl-2-oxopropyl) -4-methoxypyrrolidine
[1917] 0.5 ml (4.51 mmol) of ethyl bromoacetate was added to a suspension of 57.19 g (875 mmol) of zinc powder in 600 ml of tetrahydrofuran at 90 ° C. and the resulting reaction mixture was heated under reflux for 1 hour. (2S, 4R) -1-benzyloxycarbonyl-2-cyanomethyl-4-methoxypyrrolidine [repared as described in Preparation Example 1 (i)] 30.00 g (109 mmol) in 30 ml of tetrahydrofuran A solution of and 84.9 mL (766 mmol) of ethyl bromoacetate were added sequentially to the reaction mixture, and the obtained mixture was further heated under reflux for 1.5 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure. The obtained residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The obtained residue was dissolved in a mixture of 200 ml of dioxane and 100 ml of 1N hydrochloric acid aqueous solution, and then left at room temperature for 3 hours. Upon completion of the stand time, water was added to the reaction mixture which was then extracted with ethyl acetate. The organic extract was washed with water and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 2: 3 volume ratio mixture of ethyl acetate and hexane as eluent to afford 28.23 g (yield: 71%) of the title compound as a pale yellow oil.
[1918] ¹ H-NMR spectrum (400 MHz, CDC1 ₃ ) δ ppm:
[1919] 7.43-7.27 (5H, multiplet);
[1920] 5.24-5.06 (2H, multiplet);
[1921] 4.33-4.10 (3H, multiplet);
[1922] 3.93-3.86 (1H, multiplet);
[1923] 3.78 (0.4H, doublet, J = 12 Hz);
[1924] 3.65 (0.6H, doublet, J = 12 Hz);
[1925] 3.52-3.24 (3.6H, multiplet);
[1926] 3.29 (3H, singlet);
[1927] 3.14-3.05 (0.4H, multiplet);
[1928] 2.80-2.62 (1H, multiplet);
[1929] 2.42-2.32 (1H, multiplet);
[1930] 1.84-1.73 (1H, multiplet);
[1931] 1.34-1.21 (3H, multiplet).
[1932] 1 (iii) (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[1933] 3.79 mL (45.4 mmol) of pyrrolidine, 1.50 g of molecular sieve (MS4A) and 3.75 g of 20% palladium hydroxide on carbon were dissolved in 150 mL of ethyl acetate (2S, 4R) -1-benzyloxycarbonyl-2- (3 -Ethoxycarbonyl-2-oxopropyl) -4-methoxypyrrolidine (obtained as described in Preparation Example 1 (ii) above) to a solution of 15.00 g (41.3 mmol), and then the mixture was added to a room temperature under a hydrogen atmosphere. Stirred for 2 h. Upon completion of the stirring time, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure. The obtained residue was dissolved in 150 ml of tetrahydrofuran, and the resulting solution was added dropwise with stirring to an ice cooled suspension of 4.70 g (124 mmol) of lithium aluminum hydride in 100 ml of tetrahydrofuran, followed by reaction mixture. Was further stirred at rt for 18 h. Upon completion of the stirring time, 19 ml of a 4% aqueous solution of sodium hydroxide was carefully added to the reaction mixture at 0 ° C. and after addition of 250 ml of ethanol, the resulting mixture was filtered. The obtained filtrate was concentrated by evaporation under reduced pressure, and the residue was purified by chromatography on an alumina column using ethyl acetate as eluent to give 4.13 g (yield: 59%) of the title compound as a light brown powder.
[1934] ¹ H-NMR spectrum (400 MHz, CDC1 ₃ ) δ ppm:
[1935] 4.12-4.04 (1H, multiplet);
[1936] 3.54 (1H, doublets of doublets, J = 10 Hz, 7 Hz);
[1937] 3.34-3.24 (1H, multiplet);
[1938] 3.29 (3H, singlet);
[1939] 2.63-2.30 (5H, multiplet);
[1940] 2.29-2.19 (2H, multiplet);
[1941] 2.00 (1H, doublet of doublets, J = 13 Hz, 6 Hz, 1 Hz);
[1942] 1.79-1.67 (1H, multiplet).
[1943] Preparation Example 2
[1944] (2R, 8aS) -2- (t-butyldimethylsilyloxy) -1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[1945]
[1946] 2 (i) (2R, 8aS) -2-hydroxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[1947] (2R, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one [repared as described in Preparation Example 1] 2.63 g (15.5 mmol) ) Was dissolved in 26 ml of a 47% aqueous solution of bromic acid and the resulting mixture was stirred at 100 ° C. for 8 hours. After cooling to 0 ° C., the reaction mixture was neutralized by addition of sodium carbonate and then concentrated by evaporation under reduced pressure. Ethanol was added to the residue obtained and all insoluble materials were filtered off. The obtained filtrate was concentrated by evaporation under reduced pressure, and the obtained residue was purified by chromatography on an alumina column using a 39: 1 volume ratio mixture of ethyl acetate and methanol as eluent, yielding 1.30 g of the title compound (yield: 52%) was obtained as a pale yellow oil.
[1948] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1949] 4.63-4.56 (1H, multiplet);
[1950] 3.58 (1H, doublets of doublets, J = 10 Hz, 7 Hz);
[1951] 3.31-3.24 (1H, multiplet);
[1952] 2.72-2.44 (4H, multiplet);
[1953] 2.39-2.32 (1H, multiplet);
[1954] 2.29-2.20 (2H, multiplet);
[1955] 1.97-1.70 (3H, multiplet).
[1956] 2 (ii) (2R, 8aS) -2- (t-butyldimethylsilyloxy) -1,2,3,5.6,7,8,8a-octahydroindolizin-7-one
[1957] 1.70 g (24.9 mmol) of imidazole and 1.88 g (12.5 mol) of t-butyldimethylsilyl chloride were added to (2R, 8aS) -2-hydroxy-1,2,3,5,6,7 in 30 ml of dichloromethane. , 8,8a-octahydroindolizin-7-one [obtained as described in Preparation Example 2 (i) above] was added to a solution of 1.30 g (8.1 mmol), and the obtained mixture was stirred at room temperature for 20 hours. Upon completion of the stirring time, water was added and the reaction mixture was extracted with dichloromethane. The organic extract was washed with water, concentrated by evaporation under reduced pressure, and then the residue obtained was purified by chromatography on an alumina column using a 9: 1 volume ratio mixture of hexane and ethyl acetate as eluent to yield 1.98 g (yield of the title compound). : 88%) was obtained as a colorless oil.
[1958] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1959] 4.56-4.48 (1H, multiplet);
[1960] 3.50-3.42 (1H, multiplet);
[1961] 3.30-3.23 (1H, multiplet);
[1962] 2.69-2.32 (5H, multiplet);
[1963] 2.30-2.17 (2H, multiplet);
[1964] 1.90-1.78 (2H, multiplet);
[1965] 0.88 (9H, singlet);
[1966] 0.06 (3H, singlet);
[1967] 0.05 (3H, singlet).
[1968] Preparation Example 3
[1969] (2S, 8aS) -2-chloro-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[1970]
[1971] 3.93 g (15.0 mmol) of triphenylphosphine (2R, 8aS) -2-hydroxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one in 45 ml of carbon tetrachloride [Obtained as described in Preparation Example 2 (i) above] to a solution of 1.55 g (10.0 mmol), and the obtained mixture was heated under reflux for 5 hours. After removal of the solvent by evaporation under reduced pressure, the residue was purified by chromatography on an alumina column using a 1: 1 volume ratio mixture of ethyl acetate and hexane as eluent to afford 1.52 g (yield: 88%) of the title compound as a pale yellow oil. Obtained.
[1972] ¹ H-NMR spectrum (400 MHz, CDC1 ₃ ) δ ppm:
[1973] 4.47-4.40 (1H, multiplet);
[1974] 3.39-3.31 (2H, multiplet);
[1975] 2.78-2.63 (3H, multiplet);
[1976] 2.57-2.42 (2H, multiplet);
[1977] 2.42-2.26 (3H, multiplet);
[1978] 1.94 (1H, doublet of doublets, J = 14 Hz, 10 Hz, 5 Hz).
[1979] Preparation Example 4
[1980] (8aS) -2,2-difluoro-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[1981]
[1982] (2S) -1-benzyloxy instead of (2S, 4R) -1-benzyloxycarbonyl-4-methoxyproline in a manner similar to the procedure described in Preparation Example 1 (i), (ii) and (iii) above The reaction was carried out sequentially using carbonyl-4,4-difluoroproline as starting material to give the title compound as pale yellow oil (total yield for 3 steps: 14%).
[1983] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[1984] 3.55-3.45 (1H, multiplet);
[1985] 3.33-3.24 (1H, multiplet);
[1986] 2.72-2.33 (8H, multiplet);
[1987] 2.17-2.00 (1H, multiplet).
[1988] Preparation Example 5
[1989] (±) -6,7,8,9,9a, 10-hexahydropyrido [1,2-a] indole-8-one
[1990]
[1991] 5 (i) 1-benzyloxycarbonylindolin-2-methanol
[1992] 4.6 g (212 mmol) of lithium borohydride were added three times to a solution of 33.0 g (10.6 mmol) of methyl 1-benzyloxycarbonylindolin-2-carboxylate in 450 ml of tetrahydrofuran and obtained The mixture was stirred at rt for 5 h. Upon completion of the stirring time, ice was added and the mixture was further stirred for 1 hour, then extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 2: 5 volume ratio mixture of ethyl acetate and hexane as eluent to afford 25.0 g (yield: 83%) of the title compound as a colorless oil.
[1993] ¹ H-NMR spectrum (400 MHz, CDCI ₃ ) δ ppm:
[1994] 7.47-7.2S (6H, multiplet);
[1995] 7.19-7.10 (2H, multiplet);
[1996] 6.97 (1H, triplet, J = 7 Hz);
[1997] 5.30 (2H, singlet);
[1998] 4.72-4.53 (2H, multiplet);
[1999] 3.82-3.63 (2H, multiplet);
[2000] 3.33 (1H, doublet of doublets, J = 16 Hz, 10 Hz);
[2001] 3.00-2.77 (1H, multiplet).
[2002] 5 (ii) 1-benzyloxycarbonyl-2-cyanomethylindolin
[2003] Methanesulfonylation and cyanoation reaction using 1-benzyloxycarbonylindolin-2-methanol (obtained as described in Preparation Example 5 (i) above) in a manner similar to the procedure described in Preparation Example 1 (i) above. The title compound was obtained as an orange oil (yield: 65%).
[2004] ¹ H-NMR spectrum (400 MHz, CDC1 ₃ ) δ ppm:
[2005] 7.48-7.32 (6H, multiplet);
[2006] 7.23-7.16 (2H, multiplet);
[2007] 7.02 (1H, triplet, J = 7 Hz);
[2008] 5.31 (2H, singlet);
[2009] 4.81-4.68 (1H, multiplet);
[2010] 3.50 (1H, doublets of doublets, J = 16 Hz, 10 Hz);
[2011] 3.01 (1H, doublet, J = 16 Hz);
[2012] 2.99-2.50 (2H, multiplet).
[2013] 5 (iii) 1-benzyloxycarbonyl-2- (3-ethoxycarbonyl-2-oxopropyl) indolin
[2014] In a manner similar to that described in Preparation Example 1 (ii), 1-benzyloxycarbonyl-2- instead of (2S, 4R) -1-benzyloxycarbonyl-2-cyanomethyl-4-methoxypyrrolidine The reaction was carried out using cyanomethylindolin (obtained as described in Preparation Example 5 (ii) above) to give the title compound as a yellow oil (yield: 47%).
[2015] ¹ H-NMR spectrum (400 MHz, CDC1 ₃ ) δ ppm:
[2016] 7.45-7.32 (6H, multiplet);
[2017] 7.22-7.13 (2H, multiplet);
[2018] 6.97 (1H, triplet, J = 7 Hz);
[2019] 5.28 (2H, singlet);
[2020] 4.92-4.84 (1H, multiplet);
[2021] 4.22-4.12 (2H, multiplet);
[2022] 3.46 (1H, doublet of doublets, J = 16 Hz, 9 Hz);
[2023] 3.43-3.31 (2H, multiplet);
[2024] 2.84 (1H, doublets of doublets, J = 6 Hz, 4 Hz);
[2025] 2.80 (1H, doublets of doublets, J = 6 Hz, 4 Hz);
[2026] 2.74 (1H, doublet of doublets, J = 16 Hz, 2 Hz);
[2027] 1.29 (3H, triplet, J = 7 Hz).
[2028] 5 (iv) 2- (3-ethoxycarbonyl-2-oxopropyl) indoline
[2029] In a manner similar to that described in Preparation Example 1 (iii), instead of (2S, 4R) -1-benzyloxycarbonyl-2- (3-ethoxycarbonyl-2-oxopropyl) -4-methoxypyrrolidine Palladium hydroxide on hydrogen gas and carbon was prepared by using 1-benzyloxycarbonyl-2- (3-ethoxycarbonyl-2-oxopropyl) indole [obtained as described in Preparation Example 5 (iii)]. The debenzylation reaction used was carried out to give the title compound as an orange oil (yield: quantitative).
[2030] ¹ H-NMR spectrum (400 MHz, CDCI ₃ ) δ ppm:
[2031] 7.08 (1H, doublet, J = 7 Hz);
[2032] 6.99 (1H, triplet, J = 7 Hz);
[2033] 6.68 (1H, triplet, J = 7 Hz);
[2034] 6.57 (1H, doublet, J = 7 Hz);
[2035] 4.28-4.16 (1H, multiplet);
[2036] 4.12-4.01 (2H, multiplet);
[2037] 3.39-3.18 (4H, multiplet);
[2038] 3.03-2.81 (1H, multiplet);
[2039] 2.81-2.71 (1H, multiplet);
[2040] 1.32-1.21 (3H, multiplet).
[2041] 5 (v) (±) -6,7,8,9,9a, 10-hexahydropyrido [1,2-a] indole-8-one
[2042] 14.1 mL (56.6 mmol) of a 4N solution of hydrogen chloride in dioxane was obtained from 2- (3-ethoxycarbonyl-2-oxopropyl) indole in 140 mL of dichloromethane [obtained as described in Preparation Example 5 (iv) above]. 7.0 g (28.3 mmol) was added to the solution and the resulting mixture was stirred at rt for 2 h. At the completion of the stirring time, the reaction mixture was concentrated by evaporation under reduced pressure. 2.6 ml (31.1 mmol) of pyrrolidine was added to a solution of the residue in 140 ml of ethanol, and then the mixture was stirred at room temperature for 5 hours and then under reduced pressure. Evaporation was concentrated. Then, 3.18 g (84.9 mmol) of lithium aluminum hydride was added to a solution of the obtained residue in 100 mL of tetrahydrofuran with ice cooling, and the obtained mixture was stirred at room temperature for 18 hours.
[2043] At the completion of the stirring time, 13 ml of 4% aqueous sodium hydroxide solution was carefully added to the reaction mixture at 0 ° C., 150 ml of ethanol were added, and the obtained mixture was filtered. The obtained filtrate was concentrated by evaporation under reduced pressure and the residue was purified by chromatography on an alumina column using a 1: 5 volume ratio mixture of ethyl acetate and hexane as eluent to afford 720 mg (yield: 14%) of the title compound. Obtained as a pale yellow oil.
[2044] ¹ H-NMR spectrum (400 MHz, CDC1 ₃ ) δ ppm:
[2045] 7.20-7.10 (2H, multiplet);
[2046] 6.61-6.52 (2H, multiplet);
[2047] 3.20-3.09 (2H, multiplet);
[2048] 2.74-2.33 (7H, multiplet).
[2049] Preparation Example 6
[2050] (2R, 8aS) -2-phenyl-l, 2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2051]
[2052] 6 (i) (S) -1-benzyloxycarbonyl-2-hydroxymethyl-4-phenyl-3-pyrroline
[2053] In a manner similar to that described in Preparation Example 5 (i), the methyl (S) -1-benzyloxycarbonyl-4-phenyl-3-pyrroline-2-carboxylate was reduced using lithium borohydride. , The title compound was obtained as a pale yellow powder (yield: 78%).
[2054] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2055] 7.47-7.27 (10H, multiplet);
[2056] 6.11-6.07 (0.2H, multiplet);
[2057] 6.03-5.99 (0.8H, multiplet);
[2058] 5.23 (2H, doublet of doublets, J = 16 Hz, 12 Hz);
[2059] 5.00-4.94 (0.5H, multiplet);
[2060] 4.85-4.80 (0.2H, multiplet);
[2061] 4.77-4.70 (0.2H, multiplet);
[2062] 4.65 (0.8H, triplets of doublets, J = 15 Hz, 2 Hz);
[2063] 4.56 (1H, doublet of doublets, J = 15 Hz, 5 Hz, 2 Hz);
[2064] 4.26 (1H, broad singlet);
[2065] 3.94-3.83 (1H, multiplet);
[2066] 3.80-3.74 (0.2H, multiplet);
[2067] 3.72 (0.8H, doublet of doublets, J = 12 Hz, 7 Hz).
[2068] 6 (ii) (S) -1-benzyloxycarbonyl-2-cyanomethyl-4-phenyl-3-pyrroline
[2069] In a manner similar to the procedure described in Preparation Example 1 (i), (S) -1-benzyloxycarbonyl-2-hydroxymethyl-4-phenyl-3-pyrroline [described in Preparation Example 6 (i) Methanesulfonylation and cyanoation reactions were carried out using [as obtained] to give the title compound as a pale yellow powder (yield: 80%).
[2070] ¹ H-NMR spectrum (400 MHz, CDC1 ₃ ) δ ppm:
[2071] 7.47-7.29 (10H, multiplet);
[2072] 6.17-6.11 (1H, multiplet);
[2073] 5.25 (1H, doublet, J = 12 Hz);
[2074] 5.18 (1H, doublet, J = 12 Hz);
[2075] 5.01-4.90 (1H, multiplet);
[2076] 4.77-4.60 (2H, multiplet);
[2077] 3.10 (0.7H, doublet of doublets, J = 17 Hz, 6 Hz);
[2078] 2.90 (0.7H, doublet of doublets, J = 17 Hz, 3 Hz);
[2079] 2.86-2.73 (0.6H, multiplet).
[2080] 6 (iii) (2S, 4R) -1-benzyloxycarbonyl-2-cyanomethyl-4-phenylpyrrolidine
[2081] 2.32 g of 20% palladium hydroxide on carbon (S) -1-benzyloxycarbonyl-2-cyanomethyl-4-phenyl-3-pyrroline in 150 ml of ethyl acetate [as described in Preparation Example 6 (ii) above Obtained] was added to a solution of 11.60 g (36.4 mmol), and the obtained mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. Upon completion of the stirring time, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure. The residue obtained using a 4: 1 volume ratio mixture of hexane and ethyl acetate as eluent was purified by chromatography on a silica gel column to give 8.18 g (yield: 70%) of the title compound as a light brown oil.
[2082] ¹ H-NMR spectrum (400 MHz, CDC1 ₃ ) δ ppm:
[2083] 7.44-7.17 (10H, multiplet);
[2084] 5.26-5.09 (2H, multiplet);
[2085] 4.32-4.06 (2H, multiplet);
[2086] 3.50-3.41 (1H, multiplet);
[2087] 3.37-3.26 (1H, multiplet);
[2088] 3.21 (0.7H, doublet of doublets, J = 17 Hz, 6 Hz);
[2089] 2.93 (0.3 Hz, doublet of doublets, J = 17 Hz, 6 Hz);
[2090] 2.88-2.59 (2H, multiplet);
[2091] 2.19-2.07 (1H, multiplet).
[2092] 6 (iv) (2S, 4R) -1-benzyloxycarbonyl-2- (3-ethoxycarbonyl-2-oxopropyl) -4-phenylpyrrolidine
[2093] In a manner similar to that described in Preparation Example 1 (ii), (2S, 4R) -1-benzyl instead of (2S, 4R) -1-benzyloxycarbonyl-2-cyanomethyl-4-methoxypyrrolidine The reaction was carried out using oxycarbonyl-2-cyanomethyl-4-phenylpyrrolidine [obtained as described in Preparation Example 6 (iii) above] to give the title compound as pale yellow oil (yield: 72% ).
[2094] ¹ H-NMR spectrum (400 MHz, CDC1 ₃ ) δ ppm:
[2095] 7.43-7.17 (10H, multiplet);
[2096] 5.23-5.07 (2H, multiplet);
[2097] 4.31-4.10 (4H, multiplet);
[2098] 3.55-3.20 (5H, multiplet);
[2099] 2.87-2.67 (2H, multiplet);
[2100] 1.85-1.74 (1H, multiplet);
[2101] 1.32-1.21 (3H, multiplet).
[2102] 6 (v) (2R, 8aS) -2-phenyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2103] In a manner similar to that described in Preparation Example 1 (iii), instead of (2S, 4R) -1-benzyloxycarbonyl-2- (3-ethoxycarbonyl-2-oxopropyl) -4-methoxypyrrolidine To (2S, 4R) -1-benzyloxycarbonyl-2- (3-ethoxycarbonyl-2-oxopropyl) -4-phenylpyrrolidine [obtained as described in Preparation Example 6 (iv) above] The reaction was carried out to give the title compound as pale yellow oil (yield: 27%).
[2104] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2105] 7.42-7.14 (5H, multiplet);
[2106] 3.42-3.28 (2H, multiplet);
[2107] 3.18 (1H, doublet of doublets, J = 9 Hz, 3 Hz);
[2108] 2.77-2.63 (2H, multiplet);
[2109] 2.58-2.30 (6H, multiplet);
[2110] 1.70-1.58 (1H, multiplet).
[2111] Preparation Example 7
[2112] (8aS) -2,2-ethylenedioxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2113]
[2114] 7 (i) (S) -1-benzyloxycarbonyl-4,4-ethylenedioxy-2-hydroxymethylpyrrolidine
[2115] In a manner similar to that described in Preparation Example 5 (i), (S) -1-benzyloxycarbonyl-4,4-ethylenedioxyproline methyl ester was reduced using lithium borohydride to give the title compound colorless. Obtained as an oil (yield: 85%).
[2116] ¹ H-NMR spectrum (400 MHz, CDC1 ₃ ) δ ppm:
[2117] 7.42-7.29 (5H, multiplet);
[2118] 5.14 (2H, singlet);
[2119] 4.22-4.08 (1H, multiplet);
[2120] 4.02-3.S8 (4H, multiplet);
[2121] 3.82-3.62 (2H, multiplet);
[2122] 3.59 (1H, doublet, J = 12 Hz);
[2123] 3.47 (1H, doublet, J = 12 Hz);
[2124] 2.27-2.18 (1H, multiplet);
[2125] 1.90-l. 82 (1H, multiplet).
[2126] 7 (ii) (S) -1-benzyloxycarbonyl-2-cyanomethyl-4,4-ethylenedioxypyrrolidine
[2127] In a manner similar to the procedure described in Preparation Example 1 (i), (S) -1-benzyloxycarbonyl-4,4-ethylenedioxy-2-hydroxymethylpyrrolidine [Preparation Example 7 (i) Methanesulfonylation and cyanoation reaction were carried out using [obtained as described] to give the title compound as a colorless oil (yield: 88%).
[2128] ¹ H-NMR spectrum (400 MHz, CDC1 ₃ ) δ ppm:
[2129] 7.43-7.28 (5H, multiplet);
[2130] 5.22-5.08 (2H, multiplet);
[2131] 4.30-4.21 (1H, multiplet);
[2132] 4.06-3.88 (4H, multiplet);
[2133] 3.62-3.44 (2H, multiplet);
[2134] 3.00-2.72 (2H, multiplet);
[2135] 2.41-2.29 (1H, multiplet);
[2136] 2.17-2.10 (1H, multiplet).
[2137] 7 (iii) (8aS) -2,2-ethylenedioxy-1.2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2138] In a manner similar to the procedure described in Preparation Examples 1 (ii) and 1 (iii) above, instead of (2S, 4R) -1-benzyloxycarbonyl-2-cyanomethyl-4-methoxypyrrolidine (S) Reaction was carried out sequentially using -1-benzyloxycarbonyl-2-cyanomethyl-4,4-ethylenedioxypyrrolidine (obtained as described in Preparation Example 7 (ii) above) as starting material, The title compound was obtained as a white powder (total yield for two steps: 17%).
[2139] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2140] 4.06-3.84 (4H, multiplet);
[2141] 3.32-3.24 (1H, multiplet);
[2142] 3.22 (1H, doublet, J = 10 Hz);
[2143] 2.73-2.61 (1H, multiplet);
[2144] 2.58-2.32 (6H, multiplet);
[2145] 2.23 (1H, doublets of doublets, J = 13 Hz, 6 Hz);
[2146] 1.89 (1H, doublet of doublets, J = 13 Hz, 10 Hz).
[2147] Preparation Example 8
[2148] (8aS) -2-methyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2149]
[2150] 8 (i) (S) -1-benzyloxycarbonyl-4-methylideneproline methyl ester
[2151] 4.80 g (13.4 mmol) of methyltriphenylphosphonium bromide were added to a suspension of 1.41 g (12.6 mmol) of potassium t-butoxide in 100 mL of diethyl ether and the resulting mixture was stirred at 5 ° C. for 15 minutes. Upon completion of the stirring time, a solution of 2.50 g (9.0 mmol) of (S) -1-benzyloxycarbonyl-4-oxoproline methyl ester in 30 ml of diethyl ether was added to the mixture obtained above and the mixture at 35 ° C. Further stirring for 3 hours. At the completion of the stirring time, 50 ml of saturated aqueous ammonium chloride solution was added to the reaction mixture with ice cooling, and the obtained mixture was partitioned. The organic extract obtained was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography on a silica gel column using a 1: 3 volume ratio mixture of ethyl acetate and hexanes as eluent to afford 1.80 g (yield: 72%) of the title compound as a pale yellow oil.
[2152] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2153] 7.40-7.23 (5H, multiplet);
[2154] 5.21-4.95 (4H, multiplet);
[2155] 4.60-4.50 (1H, multiplet);
[2156] 4.20-4.09 (2H, multiplet);
[2157] 3.74 (1.5H, singlet);
[2158] 3.60 (1.5H, singlet);
[2159] 3.07-2.91 (1H, multiplet);
[2160] 2.65 (1H, doublet, J = 16 Hz).
[2161] 8 (ii) (2S) -4-methylproline methyl ester
[2162] 180 mg of 10% palladium on carbon (S) -1-benzyloxycarbonyl-4-methylideneproline methyl ester in 50 ml of methanol (obtained as described in Preparation Example 8 (i) above) of 1.80 g (6.5 mmol) To the solution was added and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. Upon completion of the stirring time, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure to give 0.93 g (quantitative yield) of the title compound as a pale yellow oil.
[2163] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2164] 3.82 (1H, triplet, J = 8 Hz);
[2165] 3.74 (3H, singlet);
[2166] 3.08 (1H, doublet of doublets, J = 10 Hz, 7 Hz);
[2167] 2.60 (1H, doublets of doublets, J = 10 Hz, 8 Hz);
[2168] 2.33 (1H, doublets of triplets, J = 12 Hz, 8 Hz);
[2169] 2.28-2.15 (1H, multiplet);
[2170] 1.44-1.37 (1H, multiplet);
[2171] 1.27 (1H, doublets of doublets, J = 14 Hz, 7 Hz);
[2172] 1.02 (3H, doublet, J = 7 Hz).
[2173] 8 (iii) (2S) -1-benzyloxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine
[2174] 20 ml of an aqueous solution containing 1.89 g (22.5 mmol) of sodium bicarbonate and 1.54 ml (10.8 mmol) of benzyl chloroformate were dissolved in (2S) -4-methylproline methyl ester in 20 ml of toluene. Obtained as described in 0.93 g (6.5 mmol) and the resulting mixture was stirred overnight at room temperature. Upon completion of the stirring time, the reaction mixture was extracted with ethyl acetate. The organic extract was washed with water and concentrated under reduced pressure to give 1.78 g (yield: 99%) of (2S) -1-benzyloxycarbonyl-4-methylproline methyl ester as light yellow oil. Then, all of the obtained compounds were reduced using lithium borohydride in a manner similar to that described in Preparation Example 5 (i), to obtain 1.07 g (yield: 66%) of the title compound as a pale yellow oil.
[2175] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2176] 7.42-7.29 (5H, multiplet);
[2177] 5.14 (2H, broad singlet);
[2178] 5.07-4.90 (1H, multiplet);
[2179] 4.08-3.87 (1H, multiplet);
[2180] 3.86-3.40 (4H, multiplet);
[2181] 2.90-2.65 (1H, multiplet);
[2182] 2.40-2.05 (2H, multiplet);
[2183] 1.02 (3H, doublet, J = 6 Hz).
[2184] 8 (iv) (2S) -1-benzyloxycarbonyl-2-cyanomethyl-4-methylpyrrolidine
[2185] In a manner similar to the procedure described in Preparation Example 1 (i), (2S) -1-benzyloxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine [obtained as described in Preparation Example 8 (iii) above. Methanesulfonylation and cyanoation reactions were carried out to afford the title compound as a colorless oil (yield: 70%).
[2186] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2187] 7.50-7.30 (5H, multiplet);
[2188] 5.25-5.05 (2H, multiplet);
[2189] 4.20-3.78 (1.8H, multiplet);
[2190] 3.70-3.62 (0.2H, multiplet);
[2191] 3.15-2.88 (1.4H, multiplet);
[2192] 2.84-2.67 (1.2H, multiplet);
[2193] 2.62-2.50 (0.4H, multiplet);
[2194] 2.45-2.30 (0.8H, multiplet);
[2195] 2.23-2.00 (1H, multiplet);
[2196] 1.89-1.77 (0.2H, multiplet);
[2197] 1.60-1.49 (1H, multiplet);
[2198] 1.10-1.03 (3H, multiplet).
[2199] 8 (v) (2S) -1-benzyloxycarbonyl-2- (3-ethoxycarbonyl-2-oxopropyl) -4-methylpyrrolidine
[2200] In a manner similar to that described in Preparation Example 1 (ii), (2S) -1-benzyloxycar instead of (2S, 4R) -1-benzyloxycarbonyl-2-cyanomethyl-4-methoxypyrrolidine The reaction was carried out using carbonyl-2-cyanomethyl-4-methylpyrrolidine [obtained as described in Preparation Example 8 (iv) above] to give the title compound as pale yellow oil (yield: 66%).
[2201] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2202] 7.43-7.28 (5H, multiplet);
[2203] 5.20-4.99 (2H, multiplet);
[2204] 4.27-4.03 (3H, multiplet);
[2205] 3.56-3.40 (1.6H, multiplet);
[2206] 3.37-3.25 (0.4H, multiplet);
[2207] 3.00-2.89 (0.2H, multiplet);
[2208] 2.89-2.75 (0.8H, multiplet);
[2209] 2.75-2.56 (1H, multiplet);
[2210] 2.50-2.22 (1H, multiplet);
[2211] 2.20-2.05 (1H, multiplet);
[2212] 1.32-1.15 (4H, multiplet);
[2213] 1.08 (0.6H, doublet, J = 6 Hz);
[2214] 1.02 (2.4H, doublet, J = 6 Hz).
[2215] 8 (vi) (8aS) -2-methyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2216] In a manner similar to that described in Preparation Example 1 (iii), instead of (2S, 4R) -1-benzyloxycarbonyl-2- (3-ethoxycarbonyl-2-oxopropyl) -4-methoxypyrrolidine To (2S) -1-benzyloxycarbonyl-2- (3-ethoxycarbonyl-2-oxopropyl) -4-methylpyrrolidine [obtained as described in Preparation Example 8 (v)] above The reaction was carried out to give the title compound as a colorless oil (yield: 34%).
[2217] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2218] 3.34-3.22 (1.2H, multiplet);
[2219] 2.77 (0.8H, doublet of doublets, J = 9 Hz, 3 Hz);
[2220] 2.68-2.55 (1H, multiplet);
[2221] 2.51-2.43 (2H, multiplet);
[2222] 2.39-2.24 (5H, multiplet);
[2223] 2.20-2.10 (1H, multiplet);
[2224] 1.87-1.75 (0.8H, multiplet);
[2225] 1.57-1.51 (0.2H, multiplet);
[2226] 1.14 (2.4H, doublet, J = 7 Hz);
[2227] 1.04 (0.6H, doublet, J = 7 Hz).
[2228] Preparation Example 9
[2229] (8aS) -8-methyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2230]
[2231] 9 (i) (2S) -1-methylmalonyl-2- (1-carboxyethyl) pyrrolidine
[2232] 2.01 mL (18.7 mmol) of methyl malonyl chloride was prepared as described in (2S) -2- (1-carboxyethyl) pyrrolidine in 60 mL dichloromethane [Tetrahedron Lett., 40 , 2891-2894 (1999)]. 2.43 g (17.0 mmol) of solution and 2.61 mL (18.7 mmol) of triethylamine were added dropwise to the stirred and ice cooled mixture. The resulting mixture was stirred at the same temperature for 15 minutes, then at room temperature for 30 minutes, and then saturated aqueous sodium hydrogen carbonate solution was added. The resulting mixture was then adjusted to pH 2 with concentrated hydrochloric acid and then extracted with a 4: 1 volume ratio mixture of dichloromethane and isopropanol. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to give 4.47 g (yield: quantitative) of the title compound as light brown oil.
[2233] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[2234] 4.55-4.47 (0.4H, multiplet);
[2235] 4.34-4.25 (0.6H, multiplet);
[2236] 3.76 (2.4H, singlet);
[2237] 3.59-3.42 (4H, multiplet);
[2238] 3.25-3.16 (0.6H, multiplet);
[2239] 2.14-1.80 (5H, multiplet);
[2240] 1.18 (1.8H, doublet, J = 7 Hz);
[2241] 1.08 (1.2H, doublet, J = 7 Hz).
[2242] 9 (ii) (8aS) -6-methoxycarbonyl-8-methyl-1,2,3,5,6,7,8.8a-octahydroindoligin-5,7-dione
[2243] 4.13 g (25.5 mmol) of carbonyldiimidazole were added to (2S) -1-methylmalonyl-2- (1-carboxyethyl) pyrrolidine in 120 mL of tetrahydrofuran at room temperature. Obtained as described in 4.47 g (17.0 mmol) was added to the solution, and the obtained mixture was stirred at room temperature for 30 minutes. Upon completion of the stirring time, 3.81 mL (25.5 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene was added and the resulting mixture was further stirred for 1 hour. The reaction mixture was then concentrated by evaporation under reduced pressure and the residue was partitioned between dichloromethane and 1N aqueous hydrochloric acid solution. The separated organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to give 4.16 g (yield: quantitative) of the title compound as a brown oil.
[2244] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[2245] 3.90 (3H, singlet);
[2246] 3.89-3.82 (1H, multiplet);
[2247] 3.73-3.64 (1H, multiplet);
[2248] 3.53-3.32 (2H, multiplet);
[2249] 2.67-2.S2 (2H, multiplet);
[2250] 2.33-2.25 (0.5H, multiplet);
[2251] 2.07-1.96 (1.5H, multiplet);
[2252] 1.87-1.74 (1H, multiplet);
[2253] 1.68-1.55 (1H, multiplet);
[2254] 1.43 (1.5H, doublet, J = 7 Hz);
[2255] 1.12 (1.5H, doublet, J = 7 Hz).
[2256] 9 (iii) (8aS) -8-methyl-1,2,3,5,6,7,8,8a-octahydroindoligin-5,7-dione
[2257] (8aS) -6-methoxycarbonyl-8-methyl-1,2,3,5,6,7,8,8a-octahydroindoligin-5,7-dione [In Preparation Example 9 (ii) above Obtained as described] 4.16 g (17.0 mmol) was dissolved in 40 mL of 10% acetic acid aqueous solution, and the obtained solution was stirred at 110 ° C. for 30 minutes. After cooling to room temperature, the reaction mixture was made basic using saturated aqueous sodium hydrogen carbonate solution and then extracted with a 4: 1 volumetric mixture of dichloromethane and isopropanol. The organic extract was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure to give 2.62 g (yield: 92%) of the title compound as a brown oil.
[2258] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[2259] 4.03-3.97 (0.3H, multiplet);
[2260] 3.74-3.41 (2.7H, multiplet);
[2261] 3.27 (1.4H, singlet);
[2262] 3.26 (0.6H, singlet);
[2263] 2.73-2.67 (0.3H, multiplet);
[2264] 2.38-2.32 (0.7H, multiplet);
[2265] 2.30-2.23 (0.7H, multiplet);
[2266] 2.14-2.01 (1.3H, multiplet);
[2267] 1.96-1.86 (1H, multiplet);
[2268] 1.73-1.63 (1H, multiplet);
[2269] 1.77 (2.1H, doublet, J = 7 Hz);
[2270] 1.08 (0.9H, doublet, J = 7 Hz).
[2271] 9 (iv) (8aS) -8-methyl-7- (l-pyrrolidinyl) -1,2,3,5,8,8a-hexahydroindolizin-5-one
[2272] 2.62 mL (31.4 mmol) of pyrrolidine (8aS) -8-methyl-1,2,3,5,6,7,8,8a-octahydroindolisin-5,7-dione in 30 mL of ethanol [above] Obtained as described in Preparation Example 9 (iii)] to a solution of 2.62 g (15.7 mmol), and the obtained mixture was stirred at 80 ° C. for 30 minutes. After the reaction was completed, the solvent and excess pyrrolidine were removed from the reaction mixture by evaporation under reduced pressure to give 3.67 g (yield: quantitative) of the title compound as a brown oil.
[2273] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[2274] 4.52 (1H, singlet);
[2275] 3.80-3.65 (2H, multiplet);
[2276] 3.44-3.34 (1H, multiplet);
[2277] 3.33-3.17 (4H, multiplet);
[2278] 2.61-2.43 (1H, multiplet);
[2279] 2.02-1.89 (6H, multiplet);
[2280] 1.88-1.72 (4H, multiplet);
[2281] 1.01 (3H, doublet, J = 7 Hz).
[2282] 9 (v) (8aS) -8-methyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2283] 1.79 g (47.1 mmol) of lithium aluminum hydride (8aS) -8-methyl-7- (1-pyrrolidinyl) -1,2,3,5,8,8a-hexahydroindole in 50 ml of tetrahydrofuran Lysine-5-one [obtained as described in Preparation Example 9 (iv) above] was added several times to 3.67 g (15.7 mmol) of a stirred, ice cooled solution and the resulting mixture was stirred overnight at room temperature. At the completion of the stirring time, 7.22 mL of 1N aqueous sodium hydroxide solution was added followed by ethanol and then the insoluble material was filtered off. The filtrate obtained above was concentrated by evaporation under reduced pressure and the residue obtained using ethyl acetate as eluent was purified by chromatography on an alumina column to give 1.69 g (yield: 70%) of the title compound as a pale yellow oil.
[2284] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[2285] 3.36-3.29 (1H, multiplet);
[2286] 3.18-3.13 (1H, multiplet);
[2287] 2.72-2.63 (1H, multiplet);
[2288] 2.40-2.30 (3H, multiplet);
[2289] 2.26-2.17 (1H, multiplet);
[2290] 2.05-1.91 (3H, multiplet);
[2291] 1.87-1.78 (1H, multiplet);
[2292] 1.64-1.55 (2H, multiplet);
[2293] 1.01 (3H, doublet, J = 7 Hz).
[2294] Preparation Example 10
[2295] (2S, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2296]
[2297] 10 (i) (2S, 4S) -4-methoxy-1-methylmalonyl homoproline
[2298] 7.52 mL (54 mmol) of triethylamine was added dropwise to a suspension of 4.40 g (22.5 mmol) of (2S, 4S) -4-methoxyhomoproline hydrochloride in 100 mL of methylene chloride with ice cooling and stirring, followed by methyl malo 2.66 mL (24.8 mmol) of neil chloride was further added dropwise with ice cooling, and the obtained mixture was then stirred at the same temperature for 15 minutes. The reaction mixture was further stirred at room temperature for 2 hours, then saturated aqueous sodium hydrogen carbonate solution was added, and the pH value of the separated aqueous layer was adjusted to 2 by addition of concentrated hydrochloric acid, and the mixture was then diluted with methylene chloride 4: Extracted in 1 volume ratio mixture. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to give 5.83 g (yield: quantitative) of the title compound as a brown oil.
[2299] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[2300] 4.51-4.44 (0.8H, multiplet);
[2301] 4.36-4.30 (0.2H, multiplet);
[2302] 4.05-3.97 (1H, multiplet);
[2303] 3.78-3.73 (2.6H, multiplet);
[2304] 3.67-3.S2 (2.4H, multiplet);
[2305] 3.48-3.38 (2H, multiplet);
[2306] 3.35-3.30 (3H, multiplet);
[2307] 3.14-3.08 (0.8H, multiplet);
[2308] 3.03 (0.2H, doublets of doublets, J = 16 Hz, 9 Hz);
[2309] 2.83-2.77 (0.2H, multiplet);
[2310] 2.69 (0.8H, doublet of doublets, J = 16 Hz, 9 Hz);
[2311] 2.21-2.12 (3H, multiplet).
[2312] 10 (ii) (2S, 8aS) -2-methoxy-6-methoxycarbonyl-1,2,3,5.6,7,8,8a-octahydroindoligin-5,7-dione
[2313] 4.02 g (24.8 mmol) of carbonyldiimidazole ((2S, 4S) -4-methoxy-1-methylmalonyl homoproline in 90 mL of tetrahydrofuran [obtained as described in Preparation Example 10 (i) above) 5.83 g (22.5 mmol) was added to the suspension, and the obtained mixture was then stirred at room temperature for 30 minutes. Upon completion of the stirring time, 3.71 mL (24.8 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene was added and the resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was then concentrated by evaporation under reduced pressure and the residue obtained was partitioned between methylene chloride and 1N aqueous hydrochloric acid solution. The organic extract obtained was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to give 5.21 g (yield: quantitative) of the title compound as a brown oil.
[2314] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[2315] 4.02-3.96 (1H, multiplet);
[2316] 3.90 (3H, singlet);
[2317] 3.87-3.79 (1H, multiplet);
[2318] 3.78-3.72 (1H, multiplet);
[2319] 3.55 (1H, doublet of doublets, J = 13 Hz, 6 Hz);
[2320] 3.39-3.29 (4H, multiplet);
[2321] 2.74 (1H, doublet of doublets, J = 17 Hz, 13 Hz);
[2322] 2.59 (1H, doublets of doublets, J = 13 Hz, 4 Hz);
[2323] 2.49-2.42 (1H, multiplet);
[2324] 1.84-1.77 (1H, multiplet).
[2325] 10 (iii) (2S, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindoligin-5,7-dione
[2326] (2S, 8aS) -2-methoxy-6-methoxycarbonyl-1,2,3,5,6,7,8,8a-octahydroindoligin-5,7-dione [Preparation Example 10 ( 5.21 g (22.5 mmol) was dissolved in 50 mL of 10% acetic acid aqueous solution, and the obtained mixture was stirred at 110 ° C. for 1 hour. After cooling to room temperature, the reaction mixture was made alkaline by addition of saturated aqueous sodium hydrogen carbonate solution and then extracted with a 4: 1 volumetric mixture of methylene chloride and isopropanol. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to give 3.38 g (yield: 82%) of the title compound as a light brown oil.
[2327] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[2328] 4.06-3.90 (3H, multiplet);
[2329] 3.52 (1H, doublets of doublets, J = 12 Hz, 5 Hz);
[2330] 3.37-3.28 (5H, multiplet);
[2331] 2.73 (1H, doublet of doublets, J = 17 Hz, 3 Hz);
[2332] 2.55-2.43 (2H, multiplet);
[2333] 1.95-1.87 (1H, multiplet).
[2334] 10 (iv) (2S, 8aS) -2-methoxy-7- (l-pyrrolidinyl) -1,2,3,5,8,8a-hexahydroindolizin-5-one
[2335] 3.07 mL (36.8 mmol) of pyrrolidine was dissolved in 34 mL of ethanol (2S, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolisin-5,7- Dione (obtained as described in Preparation Example 10 (iii) above) was added to a solution of 3.38 g (18.4 mmol), and the obtained mixture was left at room temperature for 30 minutes. Upon completion of the stand time, the solvent and excess pyrrolidine were distilled off under reduced pressure to yield 4.26 g (yield: 98%) of the title compound as a brown oil.
[2336] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[2337] 4.60 (1H, singlet);
[2338] 4.05-3.96 (1H, multiplet);
[2339] 3.77-3.65 (2H, multiplet);
[2340] 3.57 (1H, doublet of doublets, J = 12 Hz, 5 Hz);
[2341] 3.34 (3H, singlet);
[2342] 3.33-3.16 (4H, multiplet);
[2343] 2.87 (1H, doublets of doublets, J = 16 Hz, 5 Hz);
[2344] 2.50-2.37 (2H, multiplet);
[2345] 2.02-1.83 (4H, multiplet);
[2346] 1.80-1.70 (1H, multiplet).
[2347] 10 (v) (2S, 8aS) -2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2348] 2.10 g (55 mmol) of lithium aluminum hydride (2S, 8aS) -2-methoxy-7- (1-pyrrolidinyl) -1,2,3,5,8,8a- in 50 ml of tetrahydrofuran Hexahydroindolizin-5-one (obtained as described in Preparation Example 10 (iv) above) was added to a solution of 4.26 g (18.1 mol) with stirring and ice cooling, and the resulting mixture was then added at room temperature for 3 hours. Stirred. Upon completion of the stirring time, 8.40 mL of 1N aqueous sodium hydroxide solution was carefully added to the reaction mixture, followed by ethanol and then insoluble material was filtered off. The obtained filtrate was concentrated by evaporation under reduced pressure and the residue obtained was purified by chromatography on an alumina column using ethyl acetate as eluent to afford 1.60 g (yield: 51%) of the title compound as light brown oil. .
[2349] ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ ppm:
[2350] 3.96-3.90 (1H, multiplet);
[2351] 3.35-3.21 (2H, multiplet);
[2352] 3.32 (3H, singlet);
[2353] 2.75-2.65 (1H, multiplet);
[2354] 2.55-2.17 (5H, multiplet);
[2355] 1.63-1.53 (2H, multiplet);
[2356] 1.32-1.20 (1H, multiplet).
[2357] Preparation Example 11
[2358] (8aS) -2-methylidene-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2359]
[2360] 11 (i) (S) -1-benzyloxycarbonyl-2-cyanomethyl-4-methylidenepyrrolidine
[2361] In a manner similar to the procedure described in Preparation Example 5 (i) above, instead of methyl-1-benzyloxycarbonylindolin-2-carboxylate (S) -1-benzyloxycarbonyl-4-methylideneproline methyl Reduction, methanesulfonylation and cyanoation reactions were carried out using an ester [obtained as described in Preparation Example 8 (i) above) to give the title compound as a colorless oil (yield: 61%).
[2362] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2363] 7.42-7.30 (5H, multiplet);
[2364] 5.20-5.02 (4H, multiplet);
[2365] 4.36-4.27 (1H, multiplet);
[2366] 4.22-3.93 (2H, multiplet);
[2367] 2.92 (1H, doublet of doublets, J = 16 Hz, 9 Hz);
[2368] 2.80-2.38 (3H, multiplet).
[2369] 11 (ii) (S) -1- (t-butoxycarbonyl) -4-methylidene homoproline ethyl ester
[2370] 7.00 g (27.3 mmol) of (S) -1-benzyloxycarbonyl-2-cyanomethyl-4-methylidenepyrrolidine (obtained as described in Preparation Example 11 (i) above) was dissolved in 100 ml of ethanol and After stirring for 1 hour at room temperature while bubbling hydrogen chloride gas into the obtained solution, the temperature was raised to 80 ° C. and hydrogen chloride gas bubbling was continued while stirring for an additional 2 hours. The ethanol was then distilled off and the residue obtained was dissolved in 100 ml of water. The aqueous layer was washed with ethyl acetate and then 50 ml of dioxane was added to the aqueous layer. The aqueous dioxane solution obtained above was neutralized by adding triethylamine. Then, 3.80 mL (27.3 mmol) of triethylamine was further added, followed by 8.95 g (41.0 mml) of di-t-butyl dicarbonate. The resulting mixture was stirred at rt for 2 h and upon completion of the stirring time the reaction mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue obtained using a 1: 3 volume ratio mixture of ethyl acetate and hexane as the eluent was purified by chromatography on a silica gel column to give 3.40 g (yield: 46%) of the title compound as a colorless oil.
[2371] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2372] 5.01 (2H, broad singlet);
[2373] 4.43-4.21 (1H, multiplet);
[2374] 4.12 (2H, doublet of doublets, J = 14 Hz, 7 Hz);
[2375] 4.08-3.90 (1H, multiplet);
[2376] 3.84 (1H, doublet of doublets, J = 15 Hz, 2 Hz);
[2377] 2.88-2.55 (2H, multiplet);
[2378] 2.41-2.29 (2H, multiplet);
[2379] 1.49 (9H, singlet);
[2380] 1.30-1.18 (3H, multiplet).
[2381] 11 (iii) (S) -4-methylidene homoproline trifluoroacetate
[2382] 18.9 mL (18.9 mmol) of 1N aqueous sodium hydroxide solution was obtained from 35 mL of ethanol (S) -1- (t-butoxycarbonyl) -4-methylidene homoproline ethyl ester [as described in Preparation Example 11 (ii) above. 3.40 g (12.6 mmol) was added to the solution and the resulting mixture was stirred at room temperature for 2 hours. Upon completion of the stirring time, the reaction mixture was concentrated by evaporation under reduced pressure and then partitioned between ethyl acetate and water. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The obtained residue was dissolved in 30 ml of methylene chloride and 9.7 ml (126 mmol) of trifluoroacetic acid were added to the obtained solution, which was then stirred at room temperature for 2 hours. Upon completion of the stirring time, the reaction mixture was concentrated by evaporation under reduced pressure to give 3.08 g (yield: 96%) of the title compound as a white powder.
[2383] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2384] 5.22-5.12 (2H, multiplet);
[2385] 4.03-3.88 (2H, multiplet);
[2386] 3.80-3.30 (3H, multiplet);
[2387] 2.91-2.79 (2H, multiplet).
[2388] 11 (iv) (8aS) -2-methylidene-1,2,3,5.6,7,8,8a-octahydroindolizin-7-one
[2389] Instead of (2S, 4S) -4-methoxyhomoproline hydrochloride in a manner similar to the procedure described in Preparation Examples 10 (i), 10 (ii), 10 (iii), 10 (iv) and 10 (v) above The reaction was carried out using (S) -4-methylidene homoproline trifluoroacetate [obtained as described in Preparation 11 (iii) above] to give the title compound as a yellow oil (yield: 39%). .
[2390] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2391] 4.97 (1H, broad singlet);
[2392] 4.94 (1H, broad singlet);
[2393] 3.72 (1H, doublet, J = 13 Hz);
[2394] 3.34-3.25 (1H, multiplet);
[2395] 3.00-2.91 (1H, multiplet);
[2396] 2.70-2.20 (8H, multiplet).
[2397] Preparation Example 12
[2398] (2S, 8aS) -2-methylthio-1,2,3.5,6,7,8,8a-octahydroindolizin-7-one
[2399]
[2400] 12 (i) (2S, 4R) -1-Benzyloxycarbonyl-2-hydroxymethyl-4- (p-toluenesulfonyloxy) -pyrrolidine
[2401] a) 37.5 mL (270 mmol) triethylamine, 49.04 g (257 mmol) p-toluenesulfonyl chloride and 2.99 g (24.5 mmol) 4-dimethylaminopyridine in (2S, 4R) -1- 600 mL methylene chloride To the solution of 77.70 g (245 mmol) of benzyloxycarbonyl-4-hydroxyproline methyl ester was added in turn, and the resulting mixture was then stirred at rt overnight. Upon completion of the stirring time, the reaction mixture was concentrated by evaporation under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue obtained using a 1: 1 volume ratio mixture of hexane and ethyl acetate as eluent was purified by chromatography on a silica gel column to give (2S, 4R) -1-benzyloxycarbonyl-4- (p-toluenesulfonyl 106.18 g (quantitative yield) of oxy) proline methyl ester was obtained as a yellow oil.
[2402] b) (2S, 4R) -1-benzyloxycarbonyl-4- (p-toluenesulfonyloxy) proline methyl ester in a similar manner to the procedure described in Preparation Example 5 (i) above [in step (a) Prepared as described] 106.18 g (245 mmol) were reduced to give 104.98 g of the title compound as a yellow oil (yield: quantitative).
[2403] 12 (ii) (2S, 4S) -1-benzyloxycarbonyl-2- (t-butyldimethylsilyloxy) methyl-4-acetylthiopyrrolidine
[2404] a) 37.4 mL (269 mmol) of triethylamine, 38.76 g (257 mmol) of t-butyldimethylsilyl chloride and 2.99 g (24.5 mmol) of 4-dimethylaminopyridine, in 610 mL of methylene chloride (2S, 4R) -1 Benzyloxycarbonyl-2-hydroxymethyl-4- (p-toluenesulfonyloxy) pyrrolidine (obtained as described in Preparation 12 (i) above) in turn to a solution of 104.98 g (245 mmol) The resulting mixture was then stirred overnight at room temperature. Upon completion of the stirring time, the reaction mixture was concentrated by evaporation under reduced pressure and the residue obtained was partitioned between ethyl acetate and water. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue obtained using a 1: 1 volume ratio mixture of hexane and ethyl acetate as eluent was purified by chromatography on a silica gel column to give (2S, 4R) -1-benzyloxycarbonyl-2- (t-butyldimethylsilyl 119.34 g (yield: 94%) of oxy) methyl-4- (p-toluenesulfonyloxy) pyrrolidine was obtained as a yellow oil.
[2405] b) 29.34 g (257 mmol) of sodium thioacetate (2S, 4R) -1-benzyloxycarbonyl-2- (t-butyldimethylsilyloxy) methyl-4- (p-toluenesulphate) in 245 ml of dimethylformamide Ponyloxy) pyrrolidine (obtained as described in step (a) above) was added to a solution of 127.17 g (245 mmol) and the resulting mixture was stirred at 60 ° C. for 1.5 h. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue obtained was chromatographed on silica gel using an 8: 1 volume ratio mixture of hexane and ethyl acetate as eluent to afford 91.67 g (yield: 88%) of the title compound as an orange oil.
[2406] 12 (iii) (2S, 4S) -1-benzyloxycarbonyl-2- (t-butyldimethylsilyloxy) methyl-4-methylthiopyrrolidine
[2407] 6.22 ml (99.9 mmol) of methyl iodide was added to (2S, 4S) -1-benzyloxycarbonyl-2- (t-butyldimethylsilyloxy) -methyl-4-acetylthiopyrrolidine in 166 ml of methanol at room temperature. To 35.26 g (83.2 mmol) of a solution, and further addition of 149 mL (41.6 mmol) of 28% sodium methoxide solution in methanol at 0 ° C., followed by Stirred at the same temperature for 1 hour. Upon completion of the stirring time, the reaction mixture was concentrated by evaporation under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography on a silica gel column using a 9: 1 volume ratio mixture of hexane and ethyl acetate as eluent to afford 30.74 g (yield: 93%) of the title compound as a yellow oil.
[2408] 12 (iv) (2S, 4S) -1-benzyloxycarbonyl-2-hydroxymethyl-4-methylthiopyrrolidine
[2409] 85.5 ml (85.5 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (2S, 4S) -1-benzyloxycarbonyl-2- (t-butyldimethylsilyloxy) methyl- in 155 ml tetrahydrofuran 4-methylthiopyrrolidine (obtained as described in Preparation 12 (iii) above) was added to a solution of 30.74 g (77.7 mmol), and the obtained mixture was stirred at room temperature overnight. Upon completion of the stirring time, the reaction mixture was concentrated by evaporation under reduced pressure and the residue obtained was partitioned between ethyl acetate and water. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue obtained using a 1: 1 volume ratio mixture of hexane and ethyl acetate as eluent was purified by chromatography on a silica gel column to give 21.87 g (yield: quantitative) of the title compound as a yellow oil.
[2410] 12 (v) (2S, 4S) -1-benzyloxycarbonyl-2-cyanomethyl-4-methylthiopyrrolidine
[2411] In a manner similar to the procedure described in Preparation Example 1 (i), (2S, 4S) -1-benzyloxycarbonyl-2-hydroxymethyl-4-methylthiopyrrolidine [Preparation Example 12 (iv) Methanesulfonylation and cyanoation reactions were carried out using Get as described to give the title compound (yield: 52%) as a yellow oil.
[2412] 12 (vi) (2S, 4S) -4-methylthiohomproline hydrochloride
[2413] 37 ml of 35% aqueous hydrochloric acid solution was dissolved in (2S, 4S) -1-benzyloxycarbonyl-2-cyanomethyl-4-methylthiopyrrolidine (obtained as described in Preparation Example 12 (v) above). 7.43 g (25.6) mmol) and the resulting solution was stirred at 80 ° C. overnight. Upon completion of the stirring time, the reaction mixture was concentrated by evaporation under reduced pressure and the residue obtained was washed with ethyl acetate and then ethanol was added. The insoluble material was removed by filtration and the filtrate was concentrated by evaporation under reduced pressure to give 5.39 g (yield: quantitative) of the title compound as a brown oil.
[2414] 12 (vii) (2S, 8aS) -2-methylthio-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2415] Instead of (2S, 4S) -4-methoxyhomoproline hydrochloride in a manner similar to the procedure described in Preparation Examples 10 (i), 10 (ii), 10 (iii), 10 (iv) and 10 (v) above The reaction was carried out sequentially using (2S, 4S) -4-methylthiohomoproline hydrochloride [obtained as described in Preparation 12 (vi) above) to give the title compound as a yellow oil (yield: 37% ).
[2416] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2417] 3.32-3.23 (2H, multiplet);
[2418] 3.17 (1H, doublet of doublets, J = 10 Hz, 2 Hz);
[2419] 2.72-2.59 (2H, multiplet);
[2420] 2.51-2.40 (2H, multiplet);
[2421] 2.37-2.31 (4H, multiplet);
[2422] 2.15 (3H, singlet);
[2423] 1.52-1.45 (1H, multiplet).
[2424] Preparation Example 13
[2425] (2S, 8aS) -2-ethylthio-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2426]
[2427] Ethyl iodide was used in place of methyl iodide and the reaction was carried out sequentially, similar to the procedure described in Preparation Examples 12 (iii), 12 (iv), 12 (v), 12 (vi) and 12 (vii), The title compound was obtained as yellow oil (yield: 8%).
[2428] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2429] 3.36-3.28 (2H, multiplet);
[2430] 3.16 (1H, doublet of doublets, J = 10 Hz, 2 Hz);
[2431] 2.74-2.57 (4H, multiplet);
[2432] 2.52-2.41 (2H, multiplet);
[2433] 2.38-2.27 (4H, multiplet);
[2434] 1.53-1.46 (1H, multiplet);
[2435] 1.28 (3H, triplets, 5 = 7 Hz).
[2436] Preparation Example 14
[2437] (2S, 8aS) -2-butylthio-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2438]
[2439] Butyl bromide was used instead of methyl iodide and the reaction was carried out sequentially, similar to the procedure described in Preparation Examples 12 (iii), 12 (iv), 12 (v), 12 (vi) and 12 (vii), The title compound was obtained as a brown oil (yield: 13%).
[2440] Preparation Example 15
[2441] (2S, 8aS) -2-methylsulfonyl-1,2.3,5,6,7,8,8a-octahydroindolizin-7-one
[2442]
[2443] 4.6 ml (9.23 mmol) of 2N sulfuric acid solution and sodium tungstate dihydrate (101 mg, 0.31 mmol) were added (2S, 8aS) -2-methylthio-1,2,3,5,6,7,8,8a-. To a methanol (15 ml) solution of octahydroindolizin-7-one [obtained by Preparation 12 above] was added, and 1.35 ml (12.3 mmol) of 30% hydrogen peroxide solution were added dropwise at 55 ° C. The mixture was stirred at the same temperature for 1 hour. At the end of the reaction, 30 ml of saturated aqueous sodium hydrogen carbonate solution was added and extracted with methylene chloride. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by alumina column chromatography using ethyl acetate as eluent to afford 945 mg of the title compound as a yellow oil (yield: 71%).
[2444] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2445] 3.62-3.55 (2H, multiplet);
[2446] 3.63-3.32 (1H, multiplet);
[2447] 2.93 (3H, singlet);
[2448] 2.69-2.56 (3H, multiplet);
[2449] 2.52-2.43 (2H, multiplet);
[2450] 2.41-2.33 (3H, multiplet);
[2451] 2.02-1.94 (1H, multiplet).
[2452] Preparation Example 16
[2453] Cyclopropanespiro-6 '-[(8a'S) -l', 2 ', 3', 5 ', 6', 7 ', 8', 8a'-octahydroindoli ] zin- 7-one
[2454]
[2455] 16 (i) 1-ethoxycarbonyl-1-[(S) -2-ethoxycarbonylmethylpyrrolidin-1-yl] methylcyclopropane
[2456] 4.25 g of 10% palladium on carbon is added to a solution of 12.74 g (43.7 mmol) of ethanol (200 ml) of (S) -1-benzyloxycarbonyl homoproline ethyl ester and the resulting mixture is added at room temperature under hydrogen atmosphere to 2 Stirred for time. At the end of the reaction, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was dissolved in 150 ml of ethanol and 6.84 g (48.1 mmol) of 1-ethoxycarbonyl-1-formylcyclopropane were added to this solution under ice cooling. The reaction mixture was stirred at 0 ° C. for 1 hour, then 1.92 g (30.6 mmol) of sodium cyanotrihydroborate were added and the mixture was stirred at room temperature for 2 hours. At the end of the reaction, 300 ml of water were added to the reaction mixture, which was then extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography using a 7: 3 (volume) mixed solution of hexane and ethyl acetate as eluent to afford 3.07 g of the title compound as a light brown oil (yield: 25%).
[2457] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2458] 4.21-4.07 (4H, multiplet);
[2459] 3.24 (1H, doublet, J = 13 Hz);
[2460] 3.22-3.12 (1H, multiplet);
[2461] 2.82-2.68 (2H, multiplet);
[2462] 2.28-2.13 (3H, multiplet);
[2463] 2.03-1.90 (1H, multiplet);
[2464] 1.82-1.64 (2H, multiplet);
[2465] 1.56-1.45 (1H, multiplet);
[2466] 1.36-1.21 (7H, multiplet);
[2467] 1.12-1.03 (1H, multiplet);
[2468] 0.84-0.70 (2H, multiplet).
[2469] 16 (ii) cyclopropanespiro-6 '-[(8a'S) -8'-ethoxycarbonyl-1', 2 ', 3', 5 ', 6', 7 ', 8', 8a'-octahydro Indolizin] -7-one
[2470] 518 mg (11.9 mmol) of 55% sodium hydride were suspended in 20 ml of toluene, 3 drops of methanol were added dropwise using a Pasteur pipette and the resulting mixture was heated to 130 ° C. 1-ethoxycarbonyl-1-[(S) -2-ethoxycarbonylmethylpyrrolidin-1-yl] methylcyclopropane [obtained by Preparation Example 16 (i) above] to the reaction mixture. g (10.8 mmol) was added and heated at reflux for 10 minutes. The reaction mixture was cooled to 0 ° C. and then partitioned between saturated aqueous sodium chloride solution and ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography using a 9: 1 (volume) mixed solution of ethyl acetate and methanol as eluent to give 2.02 g of the title compound as a colorless oil (yield: 79%).
[2471] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2472] 4.31-4.15 (2H, multiplet);
[2473] 3.32 (1H, doublet, J = 11 Hz);
[2474] 3.15 (1H, triplets of doublets, J = 9 Hz, 3 Hz);
[2475] 2.92-2.82 (2H, multiplet);
[2476] 2.67 (1H, doublet, J = l 1 Hz);
[2477] 2.29 (1H, quinine, J = 9 Hz);
[2478] 2.12-1.80 (3H, multiplet);
[2479] 1.71-1.55 (2H, multiplet);
[2480] 1.29 (3H, triplet, J = 7 Hz);
[2481] 1.09-1.02 (1H, multiplet);
[2482] 0.99-0.92 (1H, multiplet);
[2483] 0.69-0.62 (1H, multiplet).
[2484] 16 (iii) cyclopropanespiro-6 '-[(8a'S) -l', 2 ', 3', 5 ', 6', 7 ', 8', 8a'-octahydroindolizin] -7'-one
[2485] 1 ml of 1N aqueous sodium hydroxide solution was added to cyclopropanespiro-6 '-[(8a'S) -8'-ethoxycarbonyl-1', 2 ', 3', 5 ', 6', 7 ', 8', 8a ' -Octahydroindolizin] -7'-one [obtained by Preparation 16 (ii) above] 50 mg (0.21 mmol) of ethanol (1 ml) solution was added and heated under reflux for 1 hour. At the end of the reaction, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was purified by alumina column chromatography using ethyl acetate as eluent to give 10 mg of the title compound as colorless oil (yield: 29%). .
[2486] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2487] 3.17 (1H, triplets of doublets, J = 9 Hz, 3 Hz);
[2488] 2.76 (1H, doublet, J = 12 Hz);
[2489] 2.69 (1H, doublet, J = 12 Hz);
[2490] 2.67 (1H, doublet of doublets, J = 16 Hz, 3 Hz);
[2491] 2.56-2.44 (1H, multiplet);
[2492] 2.34 (1H, doublets of doublets, J = 16 Hz, 12 Hz);
[2493] 2.30-2.18 (1H, multiplet);
[2494] 2.12-1.93 (2H, multiplet);
[2495] 1.90-1.78 (1H, multiplet);
[2496] 1.64-1.50 (2H, multiplet);
[2497] 1.08-1.00 (1 H, multiplet);
[2498] 0.96-0.88 (1H, multiplet);
[2499] 0.67-0.58 (1H, multiplet).
[2500] Preparation Example 17
[2501] (8aS) -2,2-dimethyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2502]
[2503] 17 (i) (S) -l-benzyloxycarbonyl-4,4-dimethyl-2-hydroxymethylpyrrolidine
[2504] 32.35 g (226 mmol) of tetrahydrofuran (300 ml) of (S) -4,4-dimethyl-2-hydroxymethyl-5-oxopyrrolidine while maintaining a temperature of 8-17 ° C. under cooling and stirring ) Was added dropwise over 25 minutes to a suspension of 25.72 g (678 mmol) of tetraaluminum hydride (500 ml). The resulting mixture was heated at reflux for 7 hours, at the end of the reaction it was cooled to 20 ° C. and 103 ml of 4% sodium hydroxide solution was carefully added thereto. Insolubles were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The obtained residue was dissolved in 500 ml of methylene chloride, 40.94 ml (294 mmol) of triethylamine were added, followed by further addition of 38.71 ml (271 mmol) of benzyloxycarbonylchloride under cooling and stirring. The resulting mixture was stirred at the same temperature for 1 hour and then further at room temperature for 1 hour. At the end of the reaction, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and extracted with methylene chloride. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography using a 1: 1 (volume) mixed solution of hexane and ethyl acetate as eluent to give 43.97 g of the title compound as a colorless oil (yield: 74%).
[2505] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2506] 7.42-7.29 (5H, multiplet);
[2507] 5.20-5.10 (2H, multiplet);
[2508] 4.89 (1H, doublet of doublets, J = 9 Hz, 3 Hz);
[2509] 4.14-4.05 (1H, multiplet);
[2510] 3.73-3.59 (2H, multiplet);
[2511] 3.41 (1H, doublet, J = 11 Hz);
[2512] 3.06 (1H, doublet, J = 11 Hz);
[2513] 1.80 (1H, doublets of doublets, J = 13 Hz, 7 Hz, 1 Hz);
[2514] 1.33 (1H, doublets of doublets, J = 12 Hz, 10 Hz);
[2515] 1.08 (3H, singlet);
[2516] 1.02 (3H, singlet).
[2517] 17 (ii) (8aS) -2,2-dimethyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2518] (S) -l-benzyloxycarbonyl-4,4-dimethyl-2-hydroxymethyl instead of (2S, 4S) -l-benzyloxycarbonyl-2-hydroxymethyl-4-methylthiopyrrolidine Using pyrrolidine (obtained by Preparation 17 (i) above), the reaction was carried out sequentially, similar to the procedure described in Preparation 12 (v), 12 (vi) and 12 (vii), The title compound was obtained as a brown oil (yield: 36%).
[2519] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2520] 3.26-3.19 (1H, multiplet);
[2521] 2.89 (1H, doublet, J = 9 Hz);
[2522] 2.68-2.57 (1H, multiplet);
[2523] 2.49-2.25 (5H, multiplet);
[2524] 2.07 (1H, doublet, J = 9 Hz);
[2525] 1.73 (1H, doublets of doublets, J = 12 Hz, 6 Hz);
[2526] 1.40 (1H, doublets of doublets, J = 12 Hz, 10 Hz);
[2527] 1.20 (3H, singlet);
[2528] 1.07 (3H, singlet).
[2529] Preparation Example 18
[2530] Cyclopropanespiro-2 '-(l', 2 ', 3', 5'.6 ', 7', 8 ', 8a'-octahydroindolizin) -7'-one
[2531]
[2532] 18 (i) 1-cyano-l-formylmethylcyclopentane diethyl acetal
[2533] Under ice-cooling, 100 ml (157 mmol) of a 1.57 polyline n-butyllithium / hexane solution were added dropwise to 22.00 ml (157 mmol) of a tetrahydrofuran (500 ml) solution of diisopropylamine, and the reaction mixture at the same temperature. Stir for 30 minutes. At the end of the reaction, 14.89 ml (143 mmol) of cyclopentanecarbonitrile were added dropwise to the reaction mixture in a dry ice-acetone bath. The reaction mixture was stirred at −78 ° C. for 15 minutes, and at the end of the reaction, 27.31 ml (157 mmol) of a tetrahydrofuran (50 ml) solution of hexamethylphosphoramide were added dropwise. After stirring the reaction mixture at -78 ° C for 30 minutes, 23.62 ml (157 mmol) of bromoacetaldehyde diethyl acetal was added dropwise, and the reaction mixture was stirred at -78 ° C for 2 hours, and then further stirred at room temperature for 20 hours. . At the end of the reaction, ice water was added to the reaction mixture, which was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography using 19: 1 (volume) mixed solution of hexane and ethyl acetate as eluent to give 23.92 g of the title compound as a colorless oil (yield: 79%).
[2534] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2535] 4.75 (1H, triplet, J = 5 Hz);
[2536] 3.76-3.66 (2H, multiplet);
[2537] 3.61-3.52 (2H, multiplet);
[2538] 2.22-2.13 (2H, multiplet);
[2539] 1.93 (2H, doublet, 5 = 5 Hz);
[2540] 1.91-1.63 (6H, multiplet);
[2541] 1.23 (6H, triplet, J = 7 Hz).
[2542] 18 (ii) 1-aminomethyl-1 -formylmethylcyclopentane diethyl acetal
[2543] Under ice cooling and stirring, 8.66 ml (162 mmol) of concentrated sulfuric acid were added dropwise over 10 minutes to a suspension of 12.33 g (325 mmol) of tetraaluminum hydride in tetrahydrofuran (460 ml). The reaction mixture was stirred at 0 ° C. for 1 hour, and at the end of the reaction 22.88 g (108 mmol) of 1-cyano-1-formylmethylcyclopentane diethylacetal (obtained by Preparation Example 18 (i) above) was added. To the reaction mixture was added little by little and stirred at room temperature for 2 hours. At the end of the reaction, the reaction mixture was cooled back to 0 ° C. and 149.3 ml of 4% aqueous sodium hydroxide solution were carefully added. The insolubles were filtered off from the mixture and the filtrate was concentrated by evaporation under reduced pressure to give 18.69 g of the title compound as pale yellow oil (yield: 80%).
[2544] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2545] 4.51 (1H, triplet, J = 5 Hz);
[2546] 3.70-3.60 (2H, multiplet);
[2547] 3.54-3.41 (2H, multiplet);
[2548] 2.50 (2H, singlet);
[2549] 1.70 (2H, doublet, J = 5 Hz);
[2550] 1.69-1.34 (10H, multiplet);
[2551] 1.21 (6H, triplet, J = 7 Hz).
[2552] 18 (iii) cyclopropanespiro-2 '-(l', 2 ', 3', 5'.6 ', 7', 8 ', 8a'-octahydroindolizin) -7'-one
[2553] Under ice cooling and stirring, 8.67 ml (104 mmol) of methylvinylketone were dissolved in 1-aminomethyl-1-formylmethylcyclopentanediethyl acetal (obtained by Preparation Example 18 (ii) above). 18.68 g (86.7 mmol) Was added and the resulting mixture was stirred at rt for 24 h. At the end of the reaction, the reaction mixture was extracted with 200 ml of 3N hydrochloric acid aqueous solution, and the aqueous layer was stirred at 100 ° C for 3 hours. The reaction mixture was cooled to room temperature, made alkaline by addition of sodium bicarbonate and extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by alumina column chromatography using a 9: 1 (volume) mixed solution of hexane and ethyl acetate as eluent to give 5.75 g of the title compound as a colorless oil (yield: 34%).
[2554] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2555] 3.27-3.21 (1H, multiplet);
[2556] 3.03 (1H, doublet, J = 9 Hz);
[2557] 2.69-2.59 (1H, multiplet);
[2558] 2.47 (1H, doublets of triplets, J = 13 Hz, 2 Hz);
[2559] 2.42-2.26 (4H, multiplet);
[2560] 2.19 (1H, doublet, J = 9 Hz);
[2561] 1.86 (1H, doublets of doublets, J = 12 Hz, 5 Hz);
[2562] 1.80-1.46 (9H, multiplet).
[2563] Preparation Example 19
[2564] (8aS) -2-methyl-3,5,6,7,8,8a-hexahydroindolizin-7-one
[2565]
[2566] 19 (i) (S) -2-carboxymethyl-4-methyl-3-pyrroline hydrochloride
[2567] 150 ml of concentrated hydrochloric acid was added 24.00 g (93.6 mmol) of (S) -1-benzyloxycarbonyl-2-cyanomethyl-4-methylidenepyrrolidone (obtained by Preparation Example 11 (i) above). And this solution was stirred overnight at 80 degreeC. At the end of the reaction, the reaction mixture was concentrated by evaporation under reduced pressure, and ethyl acetate was added to the residue obtained. The aqueous layer was concentrated by evaporation under reduced pressure and 16.60 g of the title compound was obtained as a white powder (yield: quantitative).
[2568] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2569] 5.47-5.4 O (1 H, multiplet);
[2570] 4.60-4.47 (1H, multiplet);
[2571] 4.15-3.75 (2H, multiplet);
[2572] 3.60-3.35 (2H, multiplet);
[2573] 1.74 (3H, multiplet).
[2574] 19 (ii) (8aS) -2-methyl-3,5,6,7,8,8a-hexahydroindolizin-7-one
[2575] (S) -2-carboxymethyl-4-methyl-3-pyrroline hydrochloride (obtained by Preparation Example 19 (i) above) was used instead of (2S, 4S) -4-methoxy homoproline hydrochloride. The reaction was carried out in sequence similar to the procedure described in Preparation Examples 10 (i), 10 (ii), 10 (iii), 10 (iv) and 10 (v) above to give the title compound as an orange oil ( Yield: 10%).
[2576] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2577] 5.44-5.38 (1H, multiplet);
[2578] 3.75-3.67 (1H, multiplet);
[2579] 3.58 (1H, doublet of doublets, J = 13 Hz, 3 Hz);
[2580] 3.48-3.39 (1H, multiplet);
[2581] 3.30-3.21 (1H, multiplet);
[2582] 3.01-2.92 (1H, multiplet);
[2583] 2.63-2,49 (2H, multiplet);
[2584] 2.45-2.35 (2H, multiplet);
[2585] 1.79 (3H, singlet).
[2586] Preparation Example 20
[2587] (2R, 8aS) -2-ethoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7'-one
[2588]
[2589] Instead of (2S, 4R) -1-benzyloxycarbonyl-4-methoxyproline, (2S, 4R) -1-benzyloxycarbonyl-4-ethoxyproline was used, and Preparation Example 1 (i), The reaction was carried out in sequence similar to the procedure described in 1 (ii) and 1 (iii) to give the title compound as an orange oil (yield: 5%).
[2590] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2591] 4.21-4.13 (1H, multiplet);
[2592] 3.60-3.38 (3H, multiplet);
[2593] 3.28 (1H, doublet of doublets, J = 11 Hz, 7 Hz);
[2594] 2.66-2.20 (7H, multiplet);
[2595] 1.99 (1H, doublets of doublets, J = 13 Hz, 6 Hz);
[2596] 1.82-1,70 (1H, multiplet);
[2597] 1.20 (3H, triplet, J = 7 Hz).
[2598] Preparation Example 21
[2599] ( 8aS) -2,2-propylenedioxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2600]
[2601] The above preparation using (S) -1-benzyloxycarbonyl-4,4-propylenedioxyproline methyl ester instead of (S) -1-benzyloxycarbonyl-4,4-ethylenedioxyproline methyl ester The reaction was carried out in sequence similar to the procedure described in Examples 7 (i), 7 (ii) and 7 (iii) to give the title compound as pale yellow powder (yield: 16%).
[2602] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2603] 4.00-3.82 (4H, multiplet);
[2604] 3.51 (1H, doublet, J = 10 Hz);
[2605] 3.33-3.25 (1H, multiplet);
[2606] 2.74-2.62 (1H, multiplet);
[2607] 2.57-2.48 (2H, multiplet);
[2608] 2.43-2.31 (SH, multiplet);
[2609] 1.86-1.62 (2H, multiplet);
[2610] 1.82 (1H, doublet of doublets, J = 13 Hz, 10 Hz).
[2611] Preparation Example 22
[2612] (8aS) -2,2- (2 ', 2'-dimethylpropylenedioxy) -1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2613]
[2614] (S) -1-benzyloxycarbonyl-4,4- (2 ', 2'-dimethylpropylenedioxy) instead of (S) -1-benzyloxycarbonyl-4,4-ethylenedioxyproline methyl ester The reaction was carried out sequentially using proline methyl ester and analogous to the procedure described in Preparation Examples 7 (i), 7 (ii) and 7 (iii) above to give the title compound as pale yellow powder (Yield: 19% ).
[2615] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2616] 3.57-3.41 (5H, multiplet);
[2617] 3.31-3.24 (1H, multiplet);
[2618] 2.73-2.62 (1H, multiplet);
[2619] 2.57-2.46 (2H, multiplet);
[2620] 2.42-2.31 (5H, multiplet);
[2621] 1.82 (1H, doublets of doublets, J = 13 Hz, 10 Hz);
[2622] 1.00 (3H, singlet);
[2623] 0.96 (3H, singlet).
[2624] Preparation Example 23
[2625] (2S, 8aS) -2-phenoxy-1,2,3,5,6,7.8,8a-octahydroindolizin-7-one
[2626]
[2627] 23 (i) (2S, 4S) -l-benzyloxycarbonyl-4-phenoxyhomoproline benzyl ester
[2628] 6.53 ml (74.3 mmol) of phenol and 19.48 g (74.3 mmol) of triphenylphosphine were converted to 18.29 g (49.5 mmol) of tetrahydrofuran of (2S, 4R) -benzyloxycarbonyl-4-hydroxyhomoproline benzyl ester (300 ml) was added to the solution and the resulting mixture was cooled to 0 ° C. To the mixture was added dropwise 11.69 ml (74.3 mmol) of diethylazodicarboxylate (DEAD) at the same temperature, and the resulting mixture was stirred overnight at room temperature. At the end of the reaction, the reaction mixture was concentrated by evaporation under reduced pressure, diethyl ether was added to the residue obtained, and the insolubles were filtered off. The resulting filtrate was washed in order of saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and then concentrated by evaporation under reduced pressure. The resulting residue was purified by silica gel column chromatography using a 3: 1 (volume) mixed solution of hexane and ethyl acetate as eluent to give 11.14 g of the title compound as a colorless oil (yield: 51%).
[2629] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2630] 7.40-7.21 (12H, multiplet);
[2631] 6.97 (1H, triplet, J = 7 Hz);
[2632] 6.84 (2H, doublet, J = 8 Hz);
[2633] 5.21-4.99 (4H, multiplet);
[2634] 4.93-4.83 (1H, multiplet);
[2635] 4.48-4.38 (1H, multiplet);
[2636] 3.84-3.68 (2H, multiplet);
[2637] 3.24-3.15 (0.6H, multiplet);
[2638] 3.04-2.95 (0.4H, multiplet);
[2639] 2.92-2.76 (1H, multiplet);
[2640] 2.39-2.30 (1H, multiplet);
[2641] 2.26-2.17 (1H, multiplet).
[2642] 23 (ii) (2S, 4S) -4-phenoxyhomoproline hydrochloride
[2643] 2.22 g of 20% palladium on carbon (2S, 4S) -l-benzyloxycarbonyl-4-phenoxyhomoproline benzyl ester [obtained by Preparation 23 (i) above] 11.09 g (24.9 mmol) of tetra To the solution in hydrofuran (220 ml) was added and the reaction mixture was stirred for 6 hours at room temperature under hydrogen atmosphere. At the end of the reaction, 6.85 ml (27.4 mmol) of 4N hydrochloric acid solution in dioxane were added to the reaction mixture, and the reaction mixture was filtered. The filtrate was concentrated by evaporation under reduced pressure to give 6.39 g of the title compound as a light brown powder (yield: quantitative).
[2644] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2645] 12.70 (1H, broad singlet);
[2646] 7.33 (2H, doublet of doublets, J = 8 Hz, 7 Hz);
[2647] 6.99 (1H, triplet, J = 7 Hz);
[2648] 6.96 (2H, doublet, J = 8 Hz);
[2649] 5.16-5.09 (1H, multiplet);
[2650] 3.98-3.87 (1H, multiplet);
[2651] 3.50 (1H, doublets of doublets, J = 13 Hz, 5 Hz);
[2652] 3.42-3.28 (2H, multiplet);
[2653] 2.89 (1H, doublets of doublets, J = 18 Hz, 8 Hz);
[2654] 2.80 (1H, doublets of doublets, J = 18 Hz, 6 Hz);
[2655] 2.64-2.54 (1H, multiplet);
[2656] 1.91-1.81 (1H, multiplet).
[2657] 23 (iii) (2S, 8aS) -2-phenoxy-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2658] Preparation Example 2 Using (2S, 4S) -4-phenoxyhomoproline hydrochloride (obtained by Preparation Example 23 (ii) above) instead of (2S, 4S) -4-methoxy homoproline hydrochloride, Similarly to the procedures described in 10 (i), 10 (ii), 10 (iii), 10 (iv) and 10 (v), the reactions were carried out sequentially to give the title compound as a light brown powder (yield: 25% ).
[2659] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2660] 7.28 (2H, doublet of doublets, J = 8 Hz, 7 Hz);
[2661] 6.95 (1H, triplet, J = 7 Hz);
[2662] 6.87 (2H, doublet, J = 8 Hz);
[2663] 4.90-4.82 (IH, multiplet);
[2664] 3.4O (1H, doublet, J = 11 Hz);
[2665] 3.39-3.32 (1H, multiplet);
[2666] 2.80-2.68 (1H, multiplet);
[2667] 2.67-2.27 (7H, multiplet);
[2668] 1.86-1.74 (1H, multiplet).
[2669] Preparation Example 24
[2670] (8aS) -2-ethylidene-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2671]
[2672] Using ethyltriphenylphosphonium bromide instead of methyltriphenylphosphonium bromide, the reaction was carried out sequentially similar to the procedure described in 8 (i), followed by the resulting (S) -1-benzyloxycarbonyl-4 The reaction was carried out in sequence similar to the procedure described in 11 (i), 11 (ii), 11 (iii) and ii (iv), to give the title compound as a brown oil (yield: 9%).
[2673] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2674] 5.45-5.30 (1H, multiplet);
[2675] 3.78 (0.5H, doublet, J = 3 Hz);
[2676] 3.64 (0.5H, doublet, J = 3 Hz);
[2677] 3.37-3.28 (1H, multiplet);
[2678] 2.94-2.85 (1H, multiplet);
[2679] 2.69-2.09 (8H, multiplet);
[2680] 1.68-1.61 (3H, multiplet).
[2681] Preparation Example 25
[2682] ( 8aS) -2-prolidene-1,2,3,5,6,7,8,8a-octahydroindolizin-7'-one
[2683]
[2684] Using propyltriphenylphosphonium bromide instead of methyltriphenylphosphonium bromide, the reaction was carried out in sequence similar to the procedure described in 8 (i), followed by the resulting (S) -1-benzyloxycarbonyl-4 The reaction was carried out in sequence similar to the procedure described in 11 (i), 11 (ii), 11 (iii) and ii (iv) to yield the title compound as a brown oil (yield: 10%).
[2685] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2686] 5.37-5.25 (1H, multiplet);
[2687] 3.78 (0.5H, doublet, J = 3 Hz);
[2688] 3.62 (0.5H, doublet, J = 3 Hz);
[2689] 3.36-3.28 (1H, multiplet);
[2690] 2.94-2.85 (1H, multiplet);
[2691] 2.69-2.10 (8H, multiplet);
[2692] 2.04-1.91 (2H, multiplet);
[2693] 1.01-0.92 (3H, multiplet).
[2694] Preparation Example 26
[2695] ( 8aS) -2-benzylidene-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2696]
[2697] Using benzyltriphenylphosphonium bromide instead of methyltriphenylphosphonium bromide, the reaction was carried out sequentially similar to the procedure described in 8 (i), and then the resulting (S) -1-benzyloxycarbonyl-4 The reaction of benzylideneproline methyl ester was carried out in sequence similar to the procedure described in 11 (i), 11 (ii), 11 (iii) and ii (iv) to give the title compound as a brown oil (yield: 0.4%).
[2698] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2699] 7.41-7.26 (4H, multiplet);
[2700] 7.21-7.15 (1H, multiplet);
[2701] 6.39-6.32 (1H, multiplet);
[2702] 4.70-4.02 (1H, multiplet);
[2703] 3.89-3.72 (1H, multiplet);
[2704] 3.40-3.35 (1H, multiplet);
[2705] 3.26-3.10 (1H, multiplet);
[2706] 2.98-2.78 (1H, multiplet);
[2707] 2.75-2.38 (5H, multiplet);
[2708] 2.11-1.84 (1H, multiplet).
[2709] Preparation Example 27
[2710] (2S, 8aS) -2-ethyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2711]
[2712] Instead of (S) -1-benzyloxycarbonyl-4-methylideneproline methyl ester, (S) -1-benzyloxycarbonyl-4-ethylideneproline methyl ester (prepared by Preparation Example 24 above) was used. And the reaction was carried out in sequence similar to the procedure described in 8 (ii), 8 (iii), 8 (iv), 8 (v) and 8 (vi) to give the title compound as a brown oil (yield: 10%).
[2713] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2714] 3.28-3.23 (1H, multiplet);
[2715] 2.87 (1H, doublet, J = 9 Hz);
[2716] 2.67-2.58 (1H, multiplet);
[2717] 2.56-2.40 (2H, multiplet);
[2718] 2.32-2.26 (4H, multiplet);
[2719] 2.13-2.05 (2H, multiplet);
[2720] 1.54-1.45 (2H, multiplet);
[2721] 1.18 (1H, doublet, J = 6 Hz);
[2722] 0.90 (3H, triplet, J = 7 Hz).
[2723] Preparation Example 28
[2724] (2S, 8aS) -2-propyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2725]
[2726] (S) -1-benzyloxycarbonyl-4-propylideneproline methyl ester [repared by Preparation Example 25] was used instead of (S) -1-benzyloxycarbonyl-4-methylideneproline methyl ester And the reaction was carried out in sequence similar to the procedure described in 8 (ii), 8 (iii), 8 (iv), 8 (v) and 8 (vi) to give the title compound as a brown oil (yield: 24%).
[2727] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2728] 3.29-3.21 (1H, multiplet);
[2729] 2.87-2.73 (1H, multiplet);
[2730] 2.67-2.57 (1H, multiplet);
[2731] 2.53-2.41 (1H, multiplet);
[2732] 2.40-2.24 (3H, multiplet);
[2733] 2.22-2.09 (2H, multiplet);
[2734] 1.99-1.85 (1H, multiplet);
[2735] 1.83-1.56 (1H, multiplet);
[2736] 1.53-1.39 (2H, multiplet);
[2737] 1.37-1.22 (2H, multiplet);
[2738] 1.21-1.14 (1H, multiplet);
[2739] 0.93-0.86 (3H, multiplet).
[2740] Preparation Example 29
[2741] (2S, 8aS) -2-benzyl-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one
[2742]
[2743] (S) -1-benzyloxycarbonyl-4-benzylideneproline methyl ester [repared by Preparation Example 25] was used instead of (S) -1-benzyloxycarbonyl-4-methylideneproline methyl ester And the reaction was carried out in sequence similar to the procedure described in 8 (ii), 8 (iii), 8 (iv), 8 (v) and 8 (vi) to give the title compound as a brown oil (yield: 4 %).
[2744] ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ ppm:
[2745] 7.38-7.28 (2H, multiplet);
[2746] 7.27-7.11 (3H, multiplet);
[2747] 3.36-3.23 (1H, multiplet);
[2748] 3.04-2.88 (1H, multiplet);
[2749] 2.86-2.21 (8H, multiplet);
[2750] 2.11-2.05 (1H, multiplet);
[2751] 2.02-1.72 (2H, multiplet);
[2752] 1.34-1.25 (2H, multiplet).
[2753] Formulation example
[2754] The preparation containing the compound represented by the formula (I) of the present invention, or a pharmaceutically acceptable salt, ester or other derivative thereof can be prepared by the following method.
[2755] Formulation Example 1
[2756] powder
[2757] 5 g of the compound of Example 2, 895 g of lactose and 100 g of corn starch were mixed in a blender to prepare the desired powder.
[2758] Formulation Example 2
[2759] Granules
[2760] 5 g of the compound of Example 4, 865 g of lactose and 100 g of low-substituted hydroxypropyl cellulose were mixed, and 300 g of an aqueous 10% hydroxypropyl cellulose solution was added to the resulting mixture, followed by kneading. The obtained product was granulated using an extrusion granulator and then dried to prepare the desired granules.
[2761] Formulation Example 3
[2762] capsule
[2763] 5 g of the compound of Example 6, 115 g of lactose, 58 g of corn starch and 2 g of magnesium stearate were mixed using a V-type mixer, No. 3 capsules were selected, and the resulting mixture was added 180 mg into No. 3 capsules. Was filled and the desired capsule was prepared.
[2764] Formulation Example 4
[2765] refine
[2766] 5 g of the compound of Example 8, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate were mixed in a blender and the resulting mixture was compressed into tablets to prepare the desired tablet.
[2767] Test Example
[2768] Test Example 1
[2769] Inhibition of the production of cytokines IL-1β and TNFα in human whole blood (in vitro)
[2770] This test was performed by Hartman et al. [D.A. Hartman, S.J. Ochalski and R.P. Carlson; The effects of anti-inflammatory and antiallergic drugs on cytokine release after stimulation of human whole blood by lipopolysaccharide and zymosan A: Inflamm. Res., 44, 269 (1995)].
[2771] Peripheral blood samples were taken from heparin in the adult adult volunteers. 1000 μl of whole blood was added to an Eppendorf tube to which 2 μl of a dimethylsulfoxide solution of the test compound was previously added, followed by 10 μl of lipopolysaccharide (from E. coli O26: B6, Difco) as a stimulant (above) Final concentration of lipopolysaccharide: 10 μg / ml). It was mixed well and then incubated at 37 ° C. for 6 hours in the presence of 5% CO ₂ . After incubation, the mixture was cooled to 4 ° C. to stop the reaction and immediately centrifuged at 14,000 rpm for 5 minutes to collect supernatant plasma. IL-1β and TNFα produced and released in plasma were measured using a commercial enzyme immunoassay (ELISA) kit [Cayman (IL-1β) and Genzyme (TNFα)]. The procedure was repeated even in the absence of test compound. The inhibitory effect [IC ₅₀ (μm)] on the production of IL-1β and TNFα was determined by least squares method from the amount of cytokines prepared in the presence and absence of test compounds. The results of the TNFα production inhibitory effect is shown in Table 7 below.
[2772] TABLE 7
[2773] Inhibitory effect of TNFα production (in vitro) Test compoundIC ₅₀ [μm] Compound of Example 20.062 Compound of Example 40.054 Compound of Example 60.027 Compound of Example 120.0025 Compound of Example 140.0040 Compound of Example 160.0022 Compound of Example 190.044 Compound of Example 210.046 Compound of Example 230.0037 Compound of Example 270.0038 Compound of Example 290.0036 Compound of Example 310.0024 Compound of Example 320.0045 Compound of Example 340.046 Compound of Example 360.018 Compound of Example 370.010 Compound of Example 430.006 Compound of Example 470.010 Compound A1.90 Compound B1.73
[2774] In Table 7, Compound A and Compound B are compounds of the prior art as follows.
[2775]
[2776] The results for the inhibitory effect of IL-1β production are shown in Table 8 below.
[2777] TABLE 8
[2778] IL-1β production inhibitory effect (in vitro) Test compoundIC ₅₀ [μm] Compound of Example 20.031 Compound of Example 40.041 Compound of Example 120.0026 Compound of Example 140.0092 Compound of Example 160.0017 Compound of Example 190.0083 Compound of Example 210.018 Compound of Example 230.0038 Compound of Example 270.0014 Compound of Example 290.0010 Compound of Example 310.0046 Compound of Example 320.0027 Compound of Example 340.049 Compound of Example 360.026 Compound of Example 370.058 Compound of Example 430.008 Compound of Example 470.033
[2779] As can be seen from Table 7 and Table 8, the compounds of the present invention in this test showed excellent inhibitory activity on the production of IL-1β and TNFα in vitro.
[2780] Test Example 2
[2781] Inhibition of TNFα Production (In Vivo)
[2782] This test was performed by the method of Ochalski et al. [S.J. Ochalski, D. A. Hartman, M.T. Belfast, M.L. Walter, K.B. Glaser and R.P. Carlson; Inhibition of endotoxin-induced hypothermia and serum TNFα levels in CD-1 mice by various pharmacological agents: Agents Actions 39, C52-C54 (1993).
[2783] The production of TNFα was induced by injecting lipopolysaccharide (from E. coli O26: B6, Difeo) prepared at 0.045 mg / ml using physiological saline into the vein of mice. Saline preparations of lipopolysaccharide were administered at a rate of 10 ml / 1 Kg body weight to the tail vein of Balb / c mice (male, 5-7 weeks old, about 22 g body weight, Japan Charles River) fasted overnight from the day before the experiment. One hour after administration, the mice were opened under anesthesia, respectively, and blood was collected from the abdominal vein. Blood collection was performed using a 1 ml disposable syringe equipped with a 23 G needle and the inner wall wetted with heparin. After blood collection, blood was immediately transferred to a 1.5 ml Eppendorf tube and centrifuged at 4 ° C., 14,000 rpm to separate plasma. The plasma was stored at −20 ° C. until TNFα was measured. The amount of TNFα was measured by a commercial enzyme immunoassay (ELISA) kit (mouse TNFa ELISA KIT, Genzyme).
[2784] To determine the inhibitory activity of test compounds, each test compound was suspended in 0.5% tragacanth solution and then orally injected into Balb / c mice at a rate of 10 ml / 1 Kg body weight 30 minutes prior to injection of lipopolysaccharide. Administered. The degree of production of TNFα was measured as described above. In the control group, 0.5% tragacanth solution instead of test compound solution was administered to test mice at a rate of 10 ml / 1 Kg body weight. At least three dose concentrations of each test compound were administered to five groups of test mice for each test compound. Inhibition rates for controls were calculated at each dose concentration. From the inhibition rate and dose, ID ₅₀ values were calculated by the least squares method and the results are shown in Table 9.
[2785] TABLE 9
[2786] TNFα production inhibitory effect (in vivo) Test compoundID ₅₀ [mg / kg] Compound of Example 160.71 Compound of Example 310.36 Compound of Example 320.61 Compound of Example 430.40
[2787] As can be seen from Table 9, the compounds of the present invention showed excellent inhibitory activity on the production of TNFα in vivo.
[2788] Test Example 3
[2789] Inhibition of Production of IL-1β (In Vivo)
[2790] This test was conducted by Griffiths et al. [Richard J. Griffiths, Ethan J. Stam, James T. Downs and Ivan G. Otterness; ATP Induces The Release of IL-1 from LPS-Primed Cells In Vivo: J. Immunol., 154, 2821-2828 (1995).
[2791] Production of IL-1β was induced by intraperitoneal injection of lipopolysaccharide followed by adenosine triphosphate (ATP). Balb / c mice (male, 5-7 weeks old) fasting lipopolysaccharide (E. coli O26: B6 derived from Difco) solution prepared at 0.0045 mg / ml concentration using physiological saline overnight from the day before the experiment. This was achieved by first administering at a rate of 10 ml / 1 Kg body weight in the abdominal cavity of the Japanese Charles River). After 2 hours, 0.5 ml of ATP prepared at a concentration of 0.63 mg / ml was administered intraperitoneally using physiological saline. 0.5 hours after ATP administration, mice were suffocated with dry ice and immediately washed with phosphate buffer [heparin (10 U / ml), p-toluenesulfonyl fluoride (0.25 mM), leupesin (leupepsin; 1 μg / ml) Containing pepstatin (1 mM) and EDTA (1 mM)] intraperitoneally was washed by intraperitoneal injection. The wash solution was recovered using a 1 ml disposable syringe equipped with a 21 G needle. After recovery, the wash solution from the intraperitoneal cavity was immediately transferred to an 1.5 ml Eppendorf tube and centrifuged at 4 ° C., 7,500 rpm to separate the supernatant. This supernatant was stored at −20 ° C. until IL-1β was measured.
[2792] IL-1β amount was measured by a commercial enzyme immunoassay (ELISA) kit (Mouse TNFa ELISA KIT, Genzyme).
[2793] To determine the inhibitory activity of test compounds, each test compound was suspended in 0.5% tragacanth solution and then orally injected into Balb / c mice at a rate of 10 ml / 1 Kg body weight 30 minutes prior to injection of lipopolysaccharide. Administered. The degree of production of TNFα was measured as described above. In the control group, 0.5% tragacanth solution instead of test compound solution was administered to test mice at a rate of 10 ml / 1 Kg body weight. At least three dose concentrations of each test compound were administered to five groups of test mice for each test compound. The average inhibition rate for the control group was calculated at each dose. In this test, the compounds of the present invention showed excellent inhibitory activity on the production of IL-1β in vivo.
[2794] Test Example 4
[2795] Activity on prevention of the development of arthritis induced by adjuvant (in vivo)
[2796] This test was performed by Winder et al. (Arthritis Rheum., 12, 472-482, 1969).
[2797] A heated Mycobacterium Dryer (Difco Laboratories, Lot 679123) of Mycobacterium butyricum was pulverized in agate mortar and a 2 mg / ml suspension with dry sterilized liquid paraffin (First Class, Waco Pure Chemical Industries, Ltd.). Suspended to The resulting suspension was sonicated and used as an adjuvant. Arthritis was induced by subcutaneous injection of an adjuvant (100 μg of heated mycelia / paraffin 0.05 ml / foot) in the heel of the right hind paw of Lewis rat (male, 9 weeks old, 190 g, Japan Charles River). The test compound is suspended in 0.5% aqueous solution of sodium carboxymethyl cellulose (CMC, Daiichi Pure Chemicals, Co., Ltd.), 5 ml / kg once daily, from the injection date of the supplement (day 0) to the 20th day. Oral administration at a rate.
[2798] Using the Plethysmometer ™ (Ugo Basile), the hind feet are immersed in the Plethysmometer ™ bath from the toes to the hairline and injected with the right hind feet (adjuvant) on days 3, 5, 7, 10, 13, 15, 18 and 21 The volume of one foot) and the left hind foot (foot without injection of the adjuvant) were measured. The volume of the swollen leg (volume of the right hind paw injected with the aid-the volume of the left hind non-injected) was calculated. On day 21, the percentage inhibition of swelling of the injected legs of the treatment groups relative to the control group was calculated as follows.
[2799] % Inhibition = {1- (volume of swollen legs of compound treatment group) / (volume of swollen legs of control group)} × 100
[2800] Linear regression curves were obtained from the log of the percentage inhibition and the dose by least squares method. The ID ₅₀ value was calculated using this curve, and the results are shown in Table 10.
[2801] TABLE 10
[2802] Activity against the prevention of the development of arthritis induced by supplements (in vivo) Test compoundID ₅₀ [mg / kg] Compound of Example 122.1 Compound of Example 161.2
[2803] As can be seen from Table 10, the compounds of the present invention in this test showed excellent activity in the prevention of the development of arthritis induced by the adjuvant.
[2804] Test Example 5
[2805] Activity against the prevention of the development of arthritis induced by anti-collagen antibodies (in vivo)
[2806] In this test, a model of arthritis induced by anti-collagen antibodies in mice was employed.
[2807] 0.5 ml (antibody 2 mg) of anti-collagen antibody solution (4 mg / ml, manufactured by Arthritogenic mAb Cocktail: Immuno-Biological Laboratories Co., Ltd.) was obtained from Balb / c mice (male, 5-6 weeks old, Japan Charles River). Injection into the tail vein. Three days later, 0.1 ml [lipopolysaccharide 0.05 mg] of lipopolysaccharide solution (0.5 mg / ml, manufactured by Arthritogenic mAb Cocktail: Immuno-Biological Laboratories Co., Ltd.) was administered to mice by intraperitoneal injection.
[2808] The test compound suspended in 0.5% tragacanth solution was orally administered to the test group at a rate of 10 ml / kg body weight once daily for 7 days from the day of administration of the anti-collagen antibody. Mice in the control group received 0.5% tragacanth solution instead of the test compound solution at a rate of 10 ml / kg body weight once daily for 7 days from the day of administration of the anti-collagen antibody.
[2809] After administration of the test compound (or 0.5% tragacanth solution), the degree of edema of four paws of mice was scored according to the following criteria:
[2810] 0: normal (no edema is observed);
[2811] 1: edema observed on one of the five toes;
[2812] 2: edema observed in at least two of the five toes;
[2813] 3: All toes are swollen.
[2814] The degree of arthritis in the test mice was assessed by the total score of four edema scores. Inhibition rates were calculated from the extent of arthritis in the control and test compound treatment groups. From the inhibition rate and dose, ID ₅₀ values were calculated by the least squares method.
[2815] In this test, the compounds of the present invention showed good activity against the prevention of arthritis development induced by anti-collagen antibodies.
[2816] Test Example 6
[2817] Therapeutic activity against arthritis induced by anti-collagen antibodies (in vivo)
[2818] In this test, a model of arthritis induced by anti-collagen antibodies in mice was employed.
[2819] 0.5 ml (antibody 2 mg) of anti-collagen antibody solution (4 mg / ml, manufactured by Arthritogenic mAb Cocktail: Immuno-Biological Laboratories Co., Ltd.) was obtained from Balb / c mice (male, 5-6 weeks old, Japan Charles River). Injection into the tail vein. After 3 days, 0.1 ml [lipopolysaccharide 0.05 mg] was administered to mice by intraperitoneal injection of a lipopolysaccharide solution (0.5 mg / ml, product of Arthritogenic mAb Cocktail: Immuno-Biological Laboratories Co., Ltd.). .
[2820] Seven days after the day of administration of the anti-collagen antibody solution, the degree of four foot edema of each test mouse was scored according to the criteria shown in Test Example 5 above.
[2821] Mice with both hind edema scores of "3" were selected. Test compounds suspended in 0.5% tragacanth solution were orally administered to the selected mice at a rate of 10 ml / kg body weight once daily for three days. Mice in the control group received 0.5% tragacanth solution once daily for 3 days at a rate of 10 ml / kg body weight instead of the test compound solution.
[2822] After administering the test compound (or 0.5% tragacanth solution), the degree of edema of each test mouse was evaluated according to the method described in Test Example 5. The treatment rate of arthritis induced by anti-collagen antibodies was calculated from the degree of arthritis in the control and test compound treated groups.
[2823] From treatment rates and dosages, ID ₅₀ values were calculated by the least squares method.
[2824] In this test, the compounds of the present invention showed excellent activity in the treatment of arthritis induced by anti-collagen antibodies.
[2825] As mentioned above, the compounds of the present invention exhibit excellent activity in inhibiting the production of inflammatory cytokines, in particular the production of IL-1β and TNFα. Moreover, the compounds of the present invention exhibit satisfactory oral absorption and low toxicity. Accordingly, the compounds of the present invention are useful as medicaments for the prevention and treatment of humans and animals. For example, it can be used as an analgesic, anti-inflammatory and antiviral agent, and also chronic rheumatoid arthritis, degenerative arthritis, allergic diseases, asthma, sepsis, psoriasis, osteoporosis, autoimmune diseases (eg systemic lupus erythematosus, ulcerative colitis, crohn) Diseases, etc.), diabetes, nephritis, hepatitis, cancer, ischemic heart disease, Alzheimer's disease, arteriosclerosis.

权利要求:
Claims (80)
[1" claim-type="Currently amended] Compounds of Formula (I), or pharmaceutically acceptable salts, esters or other derivatives thereof:
[Formula I]
[Wherein A represents a pyrrole ring;
R ¹ is an aryl group defined below which may be optionally substituted with one or more substituents selected from substituent group α and substituent group β defined below, and
A heteroaryl group defined below which may be optionally substituted with one or more substituents selected from the substituent group α defined below and the substituent group β defined below;
R ² represents a heteroaryl group defined below having one or more ring nitrogen atoms, said heteroaryl group may be optionally substituted with one or more substituents selected from the substituent group α and the substituent group β defined below;
R ³ represents a group of formula (IIa), (IIb) or (IIc) shown below:
[Formula IIa]
[Formula IIb]
Formula IIc]
[Wherein m represents 1 or 2,
One of D and E represents a nitrogen atom, and the other is selected from the group consisting of the formula> C (R ⁵ )-(wherein R ⁵ is a hydrogen atom, a substituent group defined below and a substituent group Group)
B is a 4- to 7-membered heterocyclic ring having at least one ring nitrogen atom (the heterocyclic ring may be saturated or unsaturated, an aryl group as defined below, a heteroaryl group as defined below, cyclo as defined below) Alkyl groups and heterocyclyl groups defined below), optionally fused with a group selected from:
R ⁴ represents 1 to 3 substituents independently selected from the group consisting of a substituent group α defined below, a substituent group β defined below and a substituent group γ defined below, or
When B is a heterocyclic ring fused to an aryl group, heteroaryl group, cycloalkyl group or heterocyclyl group, R ⁴ may be a hydrogen atom;
Provided that the substituents R ¹ and R ³ are bonded to two atoms of the pyrrole ring adjacent to an atom of the pyrrole ring to which the substituent R ² is bonded;
Substituent group α is a hydroxyl group, a nitro group, a cyano group, a halogen atom, a lower alkoxy group defined below, a halogeno lower alkoxy group defined below, a lower alkylthio group defined below, a halogeno lower alkylthio group defined below And groups of formula -NR ^a R ^{b wherein} R ^a and R ^b are the same or different from each other, and each a hydrogen atom, a lower alkyl group defined below, a lower alkenyl group defined below, a lower alkynyl group defined below, Independently selected from the group consisting of an aralkyl group defined and a lower alkylsulfonyl group defined below, or R ^a and R ^b together with the nitrogen atom to which they are attached form a heterocyclyl group);
Substituent group β is a lower alkyl group defined below which may be optionally substituted with one or more substituents selected from substituent group α as defined above, and a lower alkenyl group defined below which may be optionally substituted with one or more substituents selected from substituent group α as defined above. A lower alkynyl group as defined below, an aralkyl group as defined below, and a cycloalkyl group as defined below, which may be optionally substituted with one or more substituents selected from the substituent group α as defined above;
Substituent group γ is an oxo group, a hydroxyimino group, a lower alkoxyimino group defined below, a lower alkylene group defined below, a lower alkylenedioxy group defined below, a lower alkylsulfinyl group defined below, a lower alkylsulfo defined below One or more substituents selected from the following defined aryl groups, the above defined substituent groups α and the above defined substituent groups β, which may be optionally substituted with one or more substituents selected from the group including the defined substituent groups α and the above defined substituent groups β An aryloxy group, a lower alkylidenyl group and an aralkylidedenyl group as defined below which may be optionally substituted with;
Wherein the optionally substituted aryl group in the definition of R ¹ , ring B and substituent group γ is an aromatic hydrocarbon group having 6 to 14 carbon atoms in at least one ring, the aryl group optionally being a cycloalkyl group having 3 to 10 carbon atoms Can be fused;
The optionally substituted heteroaryl in the definition of R ¹ and Ring B is a 5- to 7-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom, The heteroaryl group is optionally fused with another cyclic group selected from the group consisting of an aryl group as defined above and a cycloalkyl group having 3 to 10 carbon atoms;
Wherein said optionally substituted heteroaryl group having at least one ring nitrogen atom in the definition of R ² contains at least one nitrogen atom and optionally comprises one or two additional heteroatoms selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms 5- to 7-membered aromatic heterocyclic group containing;
The lower alkyl moiety of the lower alkyl group which may be optionally substituted with the lower alkyl group in the definition of R ^a , R ^b and substituent group β and one or more substituents selected from substituent group α in the definition of substituent group β A straight or branched alkyl group having 1 to 6 carbon atoms;
The lower alkenyl portion of the lower alkenyl group which may be optionally substituted with the lower alkenyl group in the definition of R ^a , R ^b and the substituent group β and at least one substituent selected from the substituent group α in the definition of the substituent group β is A straight or branched alkenyl group having 2 to 6 carbon atoms;
The lower alkynyl moiety of the lower alkynyl group which may be optionally substituted with the lower alkynyl group in the definition of R ^a , R ^b and the substituent group β, and one or more substituents from the substituent group α in the definition of the substituent group β is 2 Straight or branched alkynyl groups having from 6 to 6 carbon atoms;
Wherein in the definition of R ^a , R ^b and substituent group β the aralkyl group is one as defined above which may be optionally substituted with one to three substituents selected from the substituent group α and the substituent group β defined above Lower alkyl groups as defined above substituted with aryl groups above;
The lower alkylsulfonyl group in the definition of R ^a , R ^b and substituent group γ is a lower alkyl group as defined above bonded to a sulfonyl group;
Wherein ring B is fused with a heterocyclyl group, wherein the heterocyclyl group is a 4- to 7-membered heterocyclyl group containing 1 to 3 ring heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom;
Where R ^a and R ^b represent a heterocyclyl group together with the nitrogen atom to which they are attached, said heterocyclyl group contains one nitrogen atom and is one further selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom A 4- to 7-membered heterocyclyl group optionally containing a hetero atom of wherein the heterocyclyl group is optionally fused with another cyclyl group selected from the group consisting of an aryl group as defined above and a heteroaryl group as defined above;
The lower alkoxy group in the definition of the substituent group α is a group in which an oxygen atom is bonded to the lower alkyl group as defined above;
The halogeno lower alkoxy group in the definition of the substituent group α is a group in which a lower alkoxy group as defined above is substituted with one or more halogen atoms;
The lower alkylthio group in the definition of the substituent group α is a group in which a sulfur atom is bonded to a lower alkyl group as defined above;
The halogeno lower alkylthio group in the definition of the substituent group α is a group in which a lower alkylthio group as defined above is substituted with one or more halogen atoms;
The cycloalkyl group in the definition of substituent group β and ring B is a cycloalkyl group having 3 to 7 carbon atoms;
The lower alkoxyimino group in the definition of the substituent group γ is a group in which the hydrogen atom of the hydroxyimino group is substituted by a lower alkyl group as defined above;
The lower alkylene group in the definition of the substituent group γ is an alkylene group having 2 to 6 carbon atoms;
The lower alkylenedioxy group in the definition of the substituent group γ is a group in which an alkylene moiety which is a straight or branched chain alkylene group having 1 to 6 carbon atoms is substituted with two oxy groups;
The lower alkylsulfinyl group in the definition of the substituent group γ is a group in which a lower alkyl group as defined above is bound to a sulfinyl group;
The lower alkylideneyl group in the definition of the substituent group γ is a straight or branched alkylideneyl group having 1 to 6 carbon atoms;
Wherein the aralkylidedenyl group in the definition of substituent group γ is a lower alkylidedenyl group as defined above substituted with one or more aryl groups as defined above;
The optionally substituted aryloxy group in the definition of substituent group γ is a group in which an oxygen atom is attached to an aryl group as defined above.
[2" claim-type="Currently amended] 2. A compound according to claim 1, wherein R ¹ is an aryl group which may be optionally substituted with one or more substituents selected from substituent group α and substituent group β as defined in claim 1, or a pharmaceutically acceptable salt, ester thereof or Other derivatives.
[3" claim-type="Currently amended] A compound according to claim 1, wherein R ¹ is a phenyl or naphthyl group, said groups being a group which may be optionally substituted with one or more substituents selected from substituent group α and substituent group β as defined in claim 1, or a pharmaceutical thereof Optionally acceptable salts, esters or other derivatives.
[4" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is a phenyl group which may be optionally substituted with one or more substituents selected from substituent group α ¹ and the substituent group β ¹ defined below;
The substituent group α ¹ represents a halogen atom, a lower alkoxy group, a halogeno lower alkoxy group and ^a group of the formula -NR ^a R ^b (wherein one of R ^a and R ^b represents a hydrogen atom or a lower alkyl group, and the other Hydrogen atom, lower alkyl group or aralkyl group), wherein the lower alkyl group, lower alkoxy group, halogeno lower alkoxy group and aralkyl group are as defined in claim 1;
The substituent group β consists of a lower alkyl group, a halogeno lower alkyl group, a hydroxyl lower alkyl group, a nitro lower alkyl group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di (lower alkyl) amino lower alkyl group, and an aralkylamino lower alkyl group, Alkyl and ar of the lower alkyl group, the halogeno lower alkyl group, the hydroxyl lower alkyl group alkyl moiety, the nitro lower alkyl group, the amino lower alkyl group, the lower alkylamino lower alkyl group and the di (lower alkyl) amino lower alkyl group and the aralkylamino lower alkyl group The alkyl moiety is as defined in claim 1, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[5" claim-type="Currently amended] The compound of claim 1, wherein R ¹ may be optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a halogeno lower alkyl group as defined in claim 1 and a halogeno lower alkoxy group as defined in claim 1. A compound which is a phenyl group, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[6" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3- A compound which is a substituent selected from the group consisting of chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl group, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[7" claim-type="Currently amended] The substituent group according to any one of claims 1 to 6, wherein R ² is a 5- or 6-membered aromatic heterocyclic group having 1 or 2 nitrogen atoms, wherein said group is a substituent group as defined in claim 1 A compound that can be optionally substituted with one or more substituents selected from α and the substituent group β, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[8" claim-type="Currently amended] 7. The at least one substituent according to claim 1, wherein R ² is a pyridyl or pyrimidyl group, said group being selected from the group consisting of a substituent group α and a substituent group β as defined in claim 1. Compound, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[9" claim-type="Currently amended] The compound according to any one of claims 1 to 6, wherein R ² is a 4-pyridyl or 4-pyrimidyl group, and the group is selected from the group consisting of a substituent group α and a substituent group β as defined in claim 1. A compound that can be optionally substituted with one or more substituents selected, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[10" claim-type="Currently amended] The compound according to any one of claims 1 to 6, wherein R ² is a 4-pyridyl or 4-pyrimidyl group, and the group is selected from the group consisting of a substituent group α and a substituent group β as defined in claim 1. A compound that can be optionally substituted at its 2-position with a selected substituent, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[11" claim-type="Currently amended] The compound according to any one of claims 1 to 6, wherein R ² is a 4-pyridyl or 4-pyrimidyl group, and the group consists of a methoxy, amino, methylamino, benzylamino, and α-methylbenzylamino group. A compound, or a pharmaceutically acceptable salt, ester or other derivative thereof, which may be optionally substituted in the 2-position with a substituent selected from the group.
[12" claim-type="Currently amended] The compound of claim 1, wherein B has one ring nitrogen atom and is optionally selected from one further ring hetero atom or nitrogen atom, oxygen atom, sulfur atom,> SO and> SO ₂ . 5- or 6-membered hetero having a ring group (the ring may be saturated or unsaturated and optionally fused with an aryl group, heteroaryl group, cycloalkyl group or heterocyclyl group as defined in claim 1) Compounds that are cyclic rings, or pharmaceutically acceptable salts, esters or other derivatives thereof.
[13" claim-type="Currently amended] The aryl group according to any one of claims 1 to 11, wherein B is a D group and an E group, and 3 or 4 carbon atoms (the ring may be saturated or unsaturated, and an aryl group as defined in claim 1). , Or a 5- or 6-membered heterocyclic ring consisting of a heteroaryl group, a cycloalkyl group or a heterocyclyl group), or a pharmaceutically acceptable salt, ester or other derivative thereof.
[14" claim-type="Currently amended] The compound according to any one of claims 1 to 11, wherein B is a pyrrolidinyl ring or a pyrrolinyl ring, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[15" claim-type="Currently amended] The compound of any one of claims 1-14, wherein R ³ is a group of formula (IIa) or (IIb), or a pharmaceutically acceptable salt, ester or other derivative thereof.
[16" claim-type="Currently amended] The compound of any one of claims 1-14, wherein R ³ is a group of formula IIa, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[17" claim-type="Currently amended] The compound according to any one of claims 1 to 16, wherein m is 1, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[18" claim-type="Currently amended] 18. The compound according to any one of claims 1 to 17, wherein R ⁴ is from a group consisting of a substituent group α as defined in claim 1, a substituent group β as defined in claim 1, and a substituent group γ ¹ Is independently selected one or two substituents, wherein the substituent group γ ¹ is an oxo group, hydroxyimi, which may be optionally substituted with one or more substituents selected from the substituent group α and the substituent group β as defined in claim ¹ A compound which is a furnace group, lower alkoxyimino group, lower alkylene group, lower alkylenedioxy group, lower alkylsulfinyl group, lower alkylsulfonyl group and aryl group, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[19" claim-type="Currently amended] 18. A hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkylthio group, a halogeno lower alkoxy group, a lower alkyl group, a halo according to any one of claims 1 to 17, wherein R ⁴ is as defined in claim 1. A compound which is a substituent selected from the group consisting of an aryl group, a lower alkylenedioxy group, a lower alkylene group and a lower alkylsulfonyl group optionally substituted with one or more substituents selected from a geno lower alkyl group, an oxo group, a substituent group α and a substituent group β, or Pharmaceutically acceptable salts, esters or other derivatives thereof.
[20" claim-type="Currently amended] The hydroxyl group, fluorine atom, chlorine atom according to any one of claims 1 to 17, wherein R ⁴ may be optionally substituted with one or more substituents selected from substituent group α and substituent group β as defined in claim 1. , A methoxy group, an ethoxy group, a propoxy group, a methyl group, an ethyl group, a propyl group and a phenyl group, a compound selected from the group consisting of, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[21" claim-type="Currently amended] The compound according to any one of claims 1 to 17, wherein R ⁴ is a substituent selected from the group consisting of methoxy group, methyl group, ethyl group, propyl group and phenyl group, or a pharmaceutically acceptable salt, ester or other derivative thereof. .
[22" claim-type="Currently amended] The aryloxy group, alkylidene group according to any one of claims 1 to 17, wherein R ⁴ may be optionally substituted with one or more substituents selected from substituent group α and substituent group β as defined in claim 1. And a substituent selected from the group consisting of an aralkylidene group, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[23" claim-type="Currently amended] The compound according to any one of claims 1 to 17, wherein R ⁴ is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups, or a pharmaceutically acceptable salt, ester thereof. Or other derivatives.
[24" claim-type="Currently amended] 24. The compound according to any one of claims 1 to 23, wherein D is a formula> C (R ⁵ )-(wherein R ⁵ is a hydrogen atom, substituent group α and substituent group β as defined in claim 1). Or a pharmaceutically acceptable salt, ester or other derivative thereof.
[25" claim-type="Currently amended] The compound according to any one of claims 1 to 24, wherein the compound of formula I represents formula I-1 or I-3, or a pharmaceutically acceptable salt, ester or other derivative thereof:
[Formula I-1]
[Formula I-3] .
[26" claim-type="Currently amended] The compound according to any one of claims 1 to 24, wherein the compound of formula (I) represents formula (I-1), or a pharmaceutically acceptable salt, ester or other derivative thereof:
[Formula I-1] .
[27" claim-type="Currently amended] The compound of claim 1 wherein:
R ¹ is an aryl group which may be optionally substituted with one or more substituents selected from substituent group α and substituent group β;
R ² is a 5- or 6-membered aromatic heterocyclic group having 1 or 2 nitrogen atoms, said group optionally substituted with one or more substituents selected from substituent group α and substituent group β; And
R ³ is a group of formula (IIa) or formula (IIb) wherein m is 1 and D is of the formula> C (R ⁵ )-(wherein R ⁵ is selected from the group consisting of a hydrogen atom, a substituent group α and a substituent group β E is a nitrogen atom, R ⁴ is one or two substituents independently selected from the group consisting of a substituent group α, a substituent group β and a substituent group γ ¹ , wherein the substituent group γ ¹ is Oxo group, hydroxyimino group, lower alkoxyimino group, lower alkylene group, lower alkylenedioxy group, lower alkylsulfinyl group, lower alkylsulfo, which may be optionally substituted with one or more substituents selected from substituent group α and substituent group β A compound consisting of a silyl group and an aryl group, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[28" claim-type="Currently amended] The compound of claim 1 wherein:
R ¹ is a phenyl or naphthyl group, said group may be optionally substituted with one or more substituents selected from the group consisting of substituent group α and substituent group β;
R ² is a pyridyl or pyrimidyl group, said group may be optionally substituted with one or more substituents selected from the group consisting of substituent group α and substituent group β; And
R ³ is a group of formula (IIa) or formula (IIb) wherein m is 1 and D is of the formula> C (R ⁵ )-(wherein R ⁵ is selected from the group consisting of a hydrogen atom, a substituent group α and a substituent group β E is a nitrogen atom, R ⁴ is a hydroxy group, a halogen atom, a lower alkoxy group, a lower alkylthio group, a halogeno lower alkoxy group, a lower alkyl group, a halogeno lower alkyl group, an oxo group, a substituent group α And a substituent selected from the group consisting of an aryl group, a lower alkylenedioxy group, a lower alkylene group and a lower alkylsulfonyl group optionally substituted with one or more substituents selected from the substituent group β, or a pharmaceutically acceptable salt, ester thereof, or Other derivatives.
[29" claim-type="Currently amended] The compound of claim 1 wherein:
R ¹ is a phenyl group which may be optionally substituted with one or more substituents selected from substituent group α ¹ as defined below and substituent group β ^{1 as} defined below,
The substituent group α ¹ represents a halogen atom, a lower alkoxy group, a halogeno lower alkoxy group, and a formula —NR ^a R ^b (wherein one of R ^a and R ^b represents a hydrogen atom or a lower alkyl group, and the other is a hydrogen atom) , A lower alkyl group or an aralkyl group), wherein the lower alkyl group, lower alkoxy group, halogeno lower alkoxy group and aralkyl group are as defined in claim 1,
The substituent group β ¹ consists of a lower alkyl group, a halogeno lower alkyl group, a hydroxyl lower alkyl group, a nitro lower alkyl group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di (lower alkyl) amino lower alkyl group, and an aralkylamino lower alkyl group. , The lower alkyl group, the halogeno lower alkyl group, the alkyl portion of the hydroxyl lower alkyl group, the nitro lower alkyl group, the amino lower alkyl group, the lower alkylamino lower alkyl group and the di (lower alkyl) amino lower alkyl group, and the aralkylamino lower alkyl group The alkyl and aralkyl moieties are as defined in claim 1;
R ² is a 4-pyridyl or 4-pyrimidyl group, said group optionally substituted with one or more substituents selected from the group consisting of substituent group α and substituent group β;
R ³ is a group of formula (IIa) or formula (IIb) wherein m is 1 and D is of the formula> C (R ⁵ )-(wherein R ⁵ is selected from the group consisting of a hydrogen atom, a substituent group α and a substituent group β Is selected, E is a nitrogen atom, R ⁴ is a hydroxy group, a halogen atom, a lower alkoxy group, a lower alkylthio group, a halogeno lower alkoxy group, a lower alkyl group, a halogeno lower alkyl group, an oxo group, a substituent group α And a substituent selected from the group consisting of an aryl group, a lower alkylenedioxy group, a lower alkylene group and a lower alkylsulfonyl group optionally substituted with one or more substituents selected from the substituent group β, or a pharmaceutically acceptable salt, ester thereof, or Other derivatives.
[30" claim-type="Currently amended] The compound of claim 1 wherein:
R ¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen atoms, halogeno lower alkyl groups as defined in claim 1 and halogeno lower alkoxy groups;
R ² is a 4-pyridyl or 4-pyrimidyl group, said group may be optionally substituted at its 2-position with a substituent selected from the group consisting of substituent group α and substituent group β; And
R ³ is a group of formula (IIa), wherein m is 1, D is of formula> C (R ⁵ )-(wherein R ⁵ is selected from the group consisting of hydrogen atom, substituent group α and substituent group β) is a group, E is a nitrogen atom, R ⁴ is a substituent group α, and substituent group that β may be optionally substituted with one or more substituents selected from, a hydroxy group, a fluorine atom, a chlorine atom, a methoxy group, an ethoxy group, a propoxy group, A compound which is a substituent selected from the group consisting of a methyl group, an ethyl group, a propyl group and a phenyl group, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[31" claim-type="Currently amended] The compound of claim 1 wherein:
R ¹ is phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluoro A substituent selected from the group consisting of phenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl group;
R ² is a 4-pyridyl or 4-pyrimidyl group, said group optionally substituted at its 2-position with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α-methylbenzylamino groups; And
R ³ is a group of formula (IIa), m is 1, and D is of formula> C (R ⁵ )-(wherein R ⁵ is selected from the group consisting of hydrogen atom, substituent group α and substituent group β) And E is a nitrogen atom, R ⁴ is a substituent selected from the group consisting of methoxy group, methyl group, ethyl group, propyl group and phenyl group, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[32" claim-type="Currently amended] The compound of claim 1 wherein:
R ¹ is an aryl group which may be optionally substituted with one or more substituents selected from substituent group α and substituent group β;
R ² is a 5- or 6-membered aromatic heterocyclic group having 1 or 2 nitrogen atoms, said group optionally substituted with one or more substituents selected from substituent group α and substituent group β;
R ³ is a group of formula (IIa) or formula (IIb), in which m is 1 and D is of the formula> C (R ⁵ )-(wherein R ⁵ is selected from the group consisting of a hydrogen atom, a substituent group α and a substituent group β a group of is selected), E is a nitrogen atom, R ⁴ is a substituent group α and substituent group optionally an aryloxy group which may be substituted with one or more substituents selected from β, alkylidene group and aralkyl alkylidene group selected from the group consisting of Compounds that are substituents, or pharmaceutically acceptable salts, esters or other derivatives thereof.
[33" claim-type="Currently amended] The compound of claim 1 wherein:
R ¹ is a phenyl or naphthyl group, said group optionally substituted with one or more substituents selected from substituent group α and substituent group β;
R ² is a pyridyl or pyrimidyl group, said group optionally substituted with one or more substituents selected from substituent group α and substituent group β; And
R ³ is a group of formula (IIa) or formula (IIb) wherein m is 1 and D is of the formula> C (R ⁵ )-(wherein R ⁵ is selected from the group consisting of a hydrogen atom, a substituent group α and a substituent group β a group of is selected), E is a nitrogen atom, R ⁴ is a substituent group α and substituent group optionally an aryloxy group which may be substituted with one or more substituents selected from β, alkylidene group and aralkyl alkylidene group selected from the group consisting of Compounds that are substituents, or pharmaceutically acceptable salts, esters or other derivatives thereof.
[34" claim-type="Currently amended] The compound of claim 1 wherein:
R ¹ is a phenyl group which may be optionally substituted with one or more substituents selected from substituent group α ¹ and the substituent group β ¹ defined below,
The substituent group α ¹ represents a halogen atom, a lower alkoxy group, a halogeno lower alkoxy group, and a formula —NR ^a R ^b (wherein one of R ^a and R ^b represents a hydrogen atom or a lower alkyl group, and the other is a hydrogen atom) , Lower alkyl group or aralkyl group), the lower alkyl group, lower alkoxy group, halogeno lower alkoxy group and aralkyl group are as defined in claim 1,
The substituent group β ¹ comprises a lower alkyl group, a halogeno lower alkyl group, a hydroxyl lower alkyl group, a nitro lower alkyl group, an amino lower alkyl group, a lower alkylamino lower alkyl group, a di (lower alkyl) amino lower alkyl group, and an aralkylamino lower alkyl group , The lower alkyl group, the halogeno lower alkyl group, the alkyl portion of the hydroxyl lower alkyl group, the nitro lower alkyl group, the amino lower alkyl group, the lower alkylamino lower alkyl group and the di (lower alkyl) amino lower alkyl group, and the aralkylamino lower alkyl group The alkyl and aralkyl moieties are as defined in claim 1;
R ² is a 4-pyridyl or 4-pyrimidyl group, said group optionally substituted with one or more substituents selected from the group consisting of substituent group α and substituent group β;
R ³ is formula IIa or formula IIb, m is 1 and D is> C (R ⁵ )-(wherein R ⁵ is selected from the group consisting of hydrogen atom, substituent group α and substituent group β Is a nitrogen atom, R ⁴ is a substituent selected from the group consisting of an aryloxy group, an alkylidene group and an aralkylidene group which may be optionally substituted with one or more substituents selected from the substituent group α and the substituent group β Phosphorus compounds, or pharmaceutically acceptable salts, esters or other derivatives thereof.
[35" claim-type="Currently amended] The compound of claim 1 wherein:
R ¹ is a phenyl group optionally substituted with one or more substituents selected from the group consisting of halogen atoms, halogeno lower alkyl groups as defined in claim 1 and halogeno lower alkoxy groups;
R ² is a 4-pyridyl or 4-pyrimidyl group, said group may be optionally substituted at its 2-position with a substituent selected from the group consisting of substituent group α and substituent group β;
R ³ is a group of formula (IIa), wherein m is 1, D is of formula> C (R ⁵ )-(wherein R ⁵ is selected from the group consisting of hydrogen atom, substituent group α and substituent group β) And E is a nitrogen atom, R ⁴ is a substituent selected from the group consisting of phenoxy group, methylidene, ethylidene, propylidene and benzylidene groups, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[36" claim-type="Currently amended] The compound of claim 1 wherein:
R ¹ is phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluoro A substituent selected from the group consisting of phenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl group;
R ² is a 4-pyridyl or 4-pyrimidyl group, which may be optionally substituted at its 2-position with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α-methylbenzylamino groups There is; And
R ³ is a group of formula (IIa), wherein m is 1, D is of formula> C (R ⁵ )-(wherein R ⁵ is selected from the group consisting of hydrogen atom, substituent group α and substituent group β) And E is a nitrogen atom, R ⁴ is a substituent selected from the group consisting of phenoxy group, methylidene, ethylidene, propylidene and benzylidene groups, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[37" claim-type="Currently amended] 37. The compound according to any one of claims 27 to 36, wherein the compound of formula I is a compound of formula I-1 or formula I-3, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[38" claim-type="Currently amended] The compound of any one of claims 27-36, wherein the compound of formula I is a compound of formula I-1, or a pharmaceutically acceptable salt, ester or other derivative thereof.
[39" claim-type="Currently amended] A compound according to claim 1 or a pharmaceutically acceptable salt, ester or other derivative thereof, which is selected from:
2- (3-fluorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
2- (3-fluorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
2- (3-fluorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
2- (4-fluorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
2- (4-fluorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
2- (4-fluorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
2- (3-chlorophenyl) -4- [2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
2- (3-chlorophenyl) -4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
2- (3-chlorophenyl) -4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
4- [2-Methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
4- [2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
4- [2-methoxy-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl) -1 H -pyrrole,
2- (4-fluorophenyl) -4- [2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
2- (4-fluorophenyl) -4- [2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl)- 1 H -pyrrole,
4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
4- [2-ethyl-1,3,5,6,8a-hexahydroindolizin-7-yl] -2- (3-fluorophenyl) -3- (pyridin-4-yl) -1 H- Pyrrole,
2- (3-chlorophenyl) -4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
4- [2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3--trifluoromethylphenyl) -1 H -pyrrole,
2- (4-fluorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
2- (3-fluorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole,
2- (3-chlorophenyl) -4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H Pyrrole,
4- [2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3- (pyridin-4-yl) -2- (3-trifluoromethylphenyl)- 1 H -pyrrole,
4- [2-ethyl-3,5,6,8a-tetrahydroindolizin-7-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1 H -pyrrole,
2- (4-fluorophenyl) -4- [2-propyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole, And
2- (4-fluorophenyl) -4- [2-phenyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridin-4-yl) -1 H -pyrrole.
[40" claim-type="Currently amended] The compound of claim 1, wherein 2- (4-fluorophenyl) -4-[(2R, 8aS) -2-phenyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] Compounds selected from 3- (pyridin-4-yl) -1 H -pyrrole and pharmaceutically acceptable salts, esters and other derivatives thereof.
[41" claim-type="Currently amended] The compound of claim 1, wherein the 2- (4-fluorophenyl) -4-[(8aS) -2-methyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] -3 Compounds selected from-(pyridin-4-yl) -1 H -pyrrole and pharmaceutically acceptable salts, esters and other derivatives thereof.
[42" claim-type="Currently amended] 2. A compound according to claim 1, wherein 2- (4-fluorophenyl) -4-[(8aS) -2-methylidene-1,2,3,5,6,8a-hexahydroindolizin-7-yl]- Compounds selected from 3- (pyridin-4-yl) -1 H -pyrrole and pharmaceutically acceptable salts, esters and other derivatives thereof.
[43" claim-type="Currently amended] The compound according to claim 1, wherein 2- (4-fluorophenyl) -4-[(8aS) -2-methyl-3,5,6,8a-tetrahydroindolizin-7-yl] -3- (pyridine- 4-yl) -1 H -pyrrole and pharmaceutically acceptable salts, esters or other derivatives thereof.
[44" claim-type="Currently amended] The method of claim 1, wherein the 4-[(2S, 8aS) -2-ethyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl) -2- (4-fluorophenyl) Compounds selected from -3- (pyridin-4-yl) -1 H -pyrrole and pharmaceutically acceptable salts, esters or other derivatives thereof.
[45" claim-type="Currently amended] The compound of claim 1, wherein 2- (4-fluorophenyl) -4-[(2S, 8aS) -2-propyl-1,2,3,5,6,8a-hexahydroindolizin-7-yl] Compounds selected from -3- (pyridin-4-yl) -1 H -pyrrole and pharmaceutically acceptable salts, esters or other derivatives thereof.
[46" claim-type="Currently amended] A pharmaceutical composition comprising a carrier or diluent therefor with an effective amount of a pharmaceutically active compound, wherein the pharmaceutically active compound is a compound of formula I according to any one of claims 1 to 45 or A composition which is a pharmaceutically acceptable salt, ester or other derivative thereof.
[47" claim-type="Currently amended] 46. A compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 for use as a medicament.
[48" claim-type="Currently amended] 46. A compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 for use as a medicament that inhibits inflammatory cytokine production in a mammal, which can be human.
[49" claim-type="Currently amended] 46. A compound of formula (I) or a pharmaceutically acceptable salt, ester or other thereof according to any one of claims 1 to 45 for use as a medicament that inhibits bone resorption in a mammal, which can be human derivative.
[50" claim-type="Currently amended] 46. A compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 for use as a medicament for the treatment or prophylaxis of inflammatory diseases in a mammal, which can be human.
[51" claim-type="Currently amended] 46. A compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 for use as a medicament for the treatment or prevention of viral diseases in a mammal, which may be human. .
[52" claim-type="Currently amended] 46. A compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 for use as a medicament for alleviating pain or fever in a mammal, which may be human.
[53" claim-type="Currently amended] 46. A compound of formula (I) or a pharmaceutically acceptable salt, ester or other thereof according to any one of claims 1 to 45 for use as a medicament for the treatment or prevention of chronic rheumatoid arthritis in a mammal, which can be human. derivative.
[54" claim-type="Currently amended] 46. A compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 for use as a medicament for the treatment or prevention of osteoarthritis in a mammal, which may be human.
[55" claim-type="Currently amended] 46. A compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 for use as a medicament for the treatment or prevention of cancer in a mammal, which may be human.
[56" claim-type="Currently amended] 46. A compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 for use as a medicament for the treatment or prevention of hepatitis in a mammal, which may be human.
[57" claim-type="Currently amended] 46. The method of any of claims 1 to 45, wherein in a mammal, which may be human, allergic disease, sepsis, psoriasis, asthma, degenerative arthritis, Crohn's disease, systemic lupus erythematosus, osteoporosis, ulcers Compounds of formula (I) or pharmaceutically acceptable salts, esters thereof, used as agents for the treatment or prophylaxis of diseases selected from the group consisting of colitis, diabetes, nephritis, ischemic heart disease, Alzheimer's disease, and atherosclerosis Or other derivatives.
[58" claim-type="Currently amended] 45. Preparation of a medicament that inhibits the production of inflammatory cytokines in a mammal, which may be human, of at least one compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 Use for.
[59" claim-type="Currently amended] 45. A preparation of a medicament for inhibiting bone absorption in a mammal, which may be human, of at least one compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 Usage.
[60" claim-type="Currently amended] 45. Preparation of a medicament for the treatment or prophylaxis of an inflammatory disease in a mammal, which may be human, of at least one compound of formula (I) according to any one of claims 1 to 45 or a pharmaceutically acceptable salt, ester or other derivative thereof. Use for.
[61" claim-type="Currently amended] 45. A medicament for the treatment or prophylaxis of a viral disease in a mammal, which may be human, of at least one compound of formula (I) according to any one of claims 1 to 45 or a pharmaceutically acceptable salt, ester or other derivative thereof. Use in manufacture.
[62" claim-type="Currently amended] 45. A preparation of a medicament for the pain or fever alleviation in a mammal, which may be human, of at least one compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 Usage.
[63" claim-type="Currently amended] 45. For the treatment or prevention of chronic rheumatoid arthritis in a mammal, which may be human, of at least one compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 Use in the manufacture of a medicament.
[64" claim-type="Currently amended] 45.A preparation of a medicament for the treatment or prophylaxis of osteoarthritis in a mammal, which may be human, of at least one compound of formula (I) according to any one of claims 1 to 45 or a pharmaceutically acceptable salt, ester or other derivative thereof. Use of
[65" claim-type="Currently amended] 45. A pharmaceutical preparation for the treatment or prophylaxis of cancer in a mammal, which may be human, of at least one compound of formula (I) according to any one of claims 1 to 45 or a pharmaceutically acceptable salt, ester or other derivative thereof. Use of
[66" claim-type="Currently amended] 45.A preparation of a medicament for the treatment or prophylaxis of hepatitis in a mammal, which may be human, of at least one compound of formula (I) according to any one of claims 1 to 45 or a pharmaceutically acceptable salt, ester or other derivative thereof Use of
[67" claim-type="Currently amended] 45. In mammals, which may be human, of one or more compounds of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45, allergic diseases, sepsis, psoriasis, Use for the manufacture of a medicament for the treatment or prophylaxis of diseases selected from the group consisting of asthma, degenerative arthritis, Crohn's disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, diabetes, nephritis, ischemic heart disease, Alzheimer's disease, and atherosclerosis.
[68" claim-type="Currently amended] Inflammatory in a mammal comprising administering to a mammal, which may be a human, an effective amount of a compound of formula (I) according to any one of claims 1 to 45 or a pharmaceutically acceptable salt, ester or other derivative thereof Method of inhibiting production of cytokines.
[69" claim-type="Currently amended] Bone in said mammal comprising administering to a mammal, which may be a human, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 Absorption inhibition method.
[70" claim-type="Currently amended] 45. An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45, comprising administering to a mammal, which may be a human suffering from an inflammatory disease A method of treating or preventing inflammatory diseases in said mammal.
[71" claim-type="Currently amended] 46. An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 for administering to a mammal, which may be a human suffering from a viral disease, Comprising, a method of treating or preventing a viral disease in said mammal.
[72" claim-type="Currently amended] 46. An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 for administering to a mammal, which may be a human suffering from pain or fever Comprising, the method of alleviating pain or fever in said mammal.
[73" claim-type="Currently amended] An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45 is administered to a mammal, which may be a human suffering from chronic rheumatoid arthritis A method of treating or preventing chronic rheumatoid arthritis in a mammal, comprising.
[74" claim-type="Currently amended] 45. An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45, comprising administering to a mammal, which may be a human suffering from osteoarthritis , Method of treating or preventing osteoarthritis in said mammal.
[75" claim-type="Currently amended] 46. An effective amount of a compound of formula I or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45, comprising administering to a mammal, which may be a human suffering from cancer , Method of treating or preventing cancer in said mammal.
[76" claim-type="Currently amended] 45. An effective amount of a compound of formula I or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45, comprising administering to a mammal, which may be a human suffering from hepatitis , Method of treating or preventing hepatitis in said mammal.
[77" claim-type="Currently amended] 45. An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 45, comprising administering to a mammal, which may be a human suffering from From the group consisting of allergic disease, sepsis, psoriasis, asthma, degenerative arthritis, Crohn's disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, diabetes, nephritis, ischemic heart disease, Alzheimer's disease, and atherosclerosis in the mammal Method of treatment or prevention of selected diseases.
[78" claim-type="Currently amended] 46. A process for the preparation of a compound according to any one of claims 1 to 45, comprising
(a) adding a compound of formula III to a reaction to remove hydrogen cyanide and water from the compound of formula III to provide a desired compound of formula I:

[Wherein R ¹ , R ² and R ³ are as defined in any one of claims 1 to 45, G represents a pyrrolidinyl ring and cyano and hydroxide on said pyrrolidinyl ring The actual substituents are on the carbon atom of the ring adjacent to the nitrogen atom of the ring; And
(b) optionally incorporating the compound of formula (I) obtained in step (a) into at least one reaction to convert one or more of the substituents R ¹ , R ² and R ³ to another substituent belonging to the definition of the group And / or converting the compound of formula I into a salt, ester, or other derivative thereof.
[79" claim-type="Currently amended] A process for preparing a compound of formula (I ') or a pharmaceutically acceptable salt, ester or other derivative thereof, comprising the following steps:

Wherein R ¹ , R ² and R ³ are as defined in any one of claims 1-45;
(a) lithiating the compound of formula IV:

[Wherein R ¹ and R ² are as defined above and each R ⁷ is the same or different and each is a hydrogen atom, a lower alkyl group as defined in claim 1, an aryl as defined in claim 1 Group or an aralkyl group as defined in claim 1). Then, the obtained lithiated derivative is substituted with the formula R ³ -L, wherein R ³ is as defined above, and L is released as a nucleophilic moiety. Reacting with a compound of formula I) to provide a compound of Formula V:

Wherein R ¹ , R ² , R ³ and R ⁷ are as defined above;
(b) subjecting the compound of formula V obtained in step (a) to a desilylation reaction to provide the desired compound of formula I '; And
(c) optionally incorporating the compound of formula I 'obtained in step (b) into at least one reaction to convert one or more of the substituents R ¹ , R ² and R ³ to another substituent belonging to the definition of the group And / or converting the compound of formula I 'to a salt, ester or other derivative thereof.
[80" claim-type="Currently amended] A process for preparing a compound of formula (I ') or a pharmaceutically acceptable salt, ester or other derivative thereof, comprising the following steps:
[Formula I ']
Wherein R ¹ , R ² and R ³ are as defined in any one of claims 1-45;
(a) lithiating the compound of formula IV:
[Formula IV]
Wherein R ¹ and R ² are as defined above and R ⁷ is as defined in claim 79. Thereafter, the obtained lithiated derivative is reacted with a compound of formula VI or VII to formula VIII Or providing a compound of Formula IX:


Wherein B, D, E, R ⁴ and m are as defined in any one of claims 1 to 45.


Wherein R ¹ , R ² , R ⁴ , R ⁷ , B, D, E and m are as defined above;
(b) subjecting the compound of formula VIII or formula IX obtained in step (a) to a subsequent step of dehydrogenation and desilylation to give the desired compound of formula I '; And
(c) optionally incorporating the compound of formula I 'obtained in step (b) into at least one reaction to convert one or more of the substituents R ¹ , R ² and R ³ to another substituent belonging to the definition of the group And / or converting the compound of formula I 'to a salt, ester or other derivative thereof.

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同族专利:

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公开号 | 公开日

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AT329915T|2006-07-15|

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DE60212357T2|2007-05-31|

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CN1553911A|2004-12-08|

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PE20030197A1|2003-03-12|

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PL362896A1|2004-11-02|

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AR032511A1|2003-11-12|

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EP1377577B1|2006-06-14|

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NO20033290D0|2003-07-21|

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HU0302807A2|2003-12-29|

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ES2266500T3|2007-03-01|

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CN100371336C|2008-02-27|

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RU2003122364A|2005-03-27|

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MXPA03006515A|2003-10-15|

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DE60212357D1|2006-07-27|

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EP1377577A1|2004-01-07|

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CZ20031949A3|2003-12-17|

---

BR0206650A|2004-02-25|

---

SK9282003A3|2004-04-06|

---

WO2002057264A1|2002-07-25|

---

IL156861D0|2004-02-08|

---

EG23054A|2004-02-29|

---

NZ527099A|2004-09-24|

---

CA2435692A1|2002-07-25|

---

NO20033290L|2003-09-11|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-01-22|Priority to JPJP-P-2001-00013817

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2001-01-22|Priority to JP2001013817

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2001-03-12|Priority to US27500501P

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2001-03-12|Priority to US60/275,005

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2002-01-22|Application filed by 상꾜 가부시키가이샤

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2002-01-22|Priority to PCT/IB2002/000176

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2003-09-26|Publication of KR20030076619A

优先权:

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申请号 | 申请日 | 专利标题

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JPJP-P-2001-00013817|2001-01-22|

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JP2001013817|2001-01-22|

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US27500501P| true| 2001-03-12|2001-03-12|

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US60/275,005|2001-03-12|

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PCT/IB2002/000176|WO2002057264A1|2001-01-22|2002-01-22|Pyrrole derivates for treating cytokine mediated diseases|