Aliphatic Nitrogenous Five-Membered Ring Compounds

专利摘要:
The present invention discloses an aliphatic nitrogen-containing five-membered ring compound represented by the following formula (I) or a pharmacologically acceptable salt thereof, a method for preparing the compound, and a pharmaceutical composition comprising the compound as an active ingredient. <Formula I> In the formula, A represents -CH 2 -or -S-, R 1 represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, X represents -N (R 3 )-, -O- or -CO-, R 3 represents a hydrogen atom or a lower alkyl group, R 2 is (1) a cyclic group which may be substituted, or (2) The amino group which may be substituted is shown.
公开号:KR20030041149A
申请号:KR10-2003-7004829
申请日:2001-10-05
公开日:2003-05-23
发明作者:고스께 야스다；히로시 모리모또；사부로 가와나미；마사따까 히꼬따；다께시 마쯔모또；겐지 아라까와
申请人:다나베 세이야꾸 가부시키가이샤；
IPC主号:

专利说明:

Aliphatic Nitrogenous Five-Membered Ring Compounds
[2] Dipeptidylpeptidase IV (DPPIV) is a type of serine protease that specifically hydrolyzes the dipeptides of Xaa-Pro or Xaa-Ala (Xaa can be any amino acid) at the N terminus of the polypeptide chain.
[3] There are various reports on the role of DPPIV (also called CD26) in vivo and its relationship to disease (Holst et al., Diabetes, Vol. 47, pp. 1663-1670, 1998; Augustyns et al., Current Medicinal). Chemistry, vol. 6, pp. 311-327, 1999: Meester et al., Immunol.Today, vol. 20, pp. 367-375, 1999; Fleicher et al., Immunol.Today, Vol. 15, 180-184 P. 1994).
[4] GLP-1 (glucagon-type peptide 1) is a peptide hormone having a function of amplifying insulin secretion mainly in glucose-dependent manner, and is mainly secreted from the lower part of the small intestine to act on the pancreas. There are also reports suggesting that GLP-1 has a feeding inhibitory effect. DPPIV hydrolyzes and inactivates this GLP-1 while generating a peptide that acts as an antagonist of GLP-1.
[5] Substances that inhibit the enzyme activity of DPPIV enhance the action of endogenous GLP-1 through its inhibitory action, thereby enhancing insulin secretion response to oral glucose load and improving impaired glucose tolerance.
[6] For this reason, the DPPIV inhibitor is considered to be useful for the prevention and treatment of diabetes (particularly type 2 diabetes). In addition, other diseases caused or impaired by impaired glucose tolerance (hyperglycemia (e.g. postprandial hyperglycemia), hyperinsulinemia, diabetes complications (e.g. kidney failure, neuropathy), lipid metabolism abnormalities, obesity, etc.) The effect in prevention and treatment is expected.
[7] In addition, the effect in the prevention and treatment of diseases (overeating, obesity, etc.) for which improvement is expected by enhancing the feeding inhibitory effect of GLP-1 is also expected.
[8] In addition, DPPIV (CD26), which is present on the surface of T cells, induces expression in response to activation of T cells in immune system cells, and plays an important role in activation and proliferation of T cells. It is known that blocking DPPIV (CD26) with antibodies or inhibitors inhibits T cell activation. In addition, the relationship between the enzyme and the condition in collagen metabolic abnormalities or immune abnormal diseases is interesting. For example, the positive rate of DPPIV (CD26) of peripheral blood T cells increases in rheumatoid patients, and high DPPIV activity is detected in the urine of nephritis patients. In addition, DPPIV (CD26) is thought to play an important role in the entry of HIV into lymph cells.
[9] For this reason, a substance that inhibits DPPIV (CD26) has a prophylactic or therapeutic effect on autoimmune diseases (eg, arthritis, chronic joint rheumatism), osteoporosis, acquired immunodeficiency syndrome (AIDS), rejection of transplanted organs and tissues, and the like. Is expected.
[10] On the other hand, as compounds having a DPPIV inhibitory action, international publications WO98 / 19998 and WO00 / 34241 describe 2-cyanopyrrolidine derivatives having a DPPIV inhibitory action.
[11] The present invention provides a novel aliphatic nitrogen-containing five-membered ring compound having excellent DPPIV inhibitory action.
[1] The present invention relates to a novel aliphatic nitrogen-containing five-membered ring compound having excellent dipeptidyl peptidase IV (DPPIV) inhibitory action and useful as a medicament.
[12] MEANS TO SOLVE THE PROBLEM In order to solve a subject, this inventor discovered the novel aliphatic nitrogen-containing five-membered ring compound which has a DPPIV inhibitory effect, and completed this invention.
[13] That is, the present invention
[14] An aliphatic nitrogen-containing five-membered ring compound represented by the following formula (I) or a pharmacologically acceptable salt thereof.
[15]
[16] In the formula, A represents -CH ₂ -or -S-,
[17] R ¹ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group,
[18] X represents -N (R ³ )-, -O- or -CO-,
[19] R ³ represents a hydrogen atom or a lower alkyl group,
[20] R ² is (1) a cyclic group which may be substituted, wherein the cyclic moiety is
[21] (i) monocyclic, bicyclic or tricyclic hydrocarbon groups or
[22] (ii) a group which is a monocyclic, bicyclic or tricyclic heterocyclic group, or
[23] (2) The amino group which may be substituted is shown.
[24] <Best Mode for Carrying Out the Invention>
[25] In the compound I of the present invention, optical isomers based on subsidiary carbon may be present, but the present invention includes all of these optical isomers and also mixtures thereof. In addition, there are isomers (cis or trans) based on the relative position of the substituent relative to the reference plane of the cyclic group, but the present invention includes all of these isomers and also mixtures thereof.
[26] In this invention, as a lower alkyl group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkoxy group, and a lower alkylamino group, a C1-C6 linear or branched thing is mentioned, Especially a C1-C4 thing is mentioned. Can be. Moreover, as a lower alkanoyl group and a lower alkanoylamino group, a C2-C7, especially C2-C5 linear or branched thing is mentioned. Examples of the lower cycloalkyl group and the lower cycloalkenyl group include those having 3 to 8 carbon atoms, particularly those having 3 to 6 carbon atoms. As a lower alkylene group, a C1-C6, especially C1-C4 linear or branched thing is mentioned. Examples of the lower alkenyl group and the lower alkenylene group include those having 2 to 7 carbon atoms, particularly those having 2 to 5 carbon atoms. Examples of the halogen atom include fluorine, chlorine, bromine or iodine.
[27] In the objective compound I of this invention, a hydrogen atom, a methyl group, etc. are mentioned as a specific example of the hydrogen atom or lower alkyl group represented by R < ³ >. Among these, hydrogen atoms are more preferable.
[28] In the compound I of this invention, as a specific example of the "hydrogen atom, lower alkyl group, hydroxy lower alkyl group, or lower alkoxy lower alkyl group" represented by R < ¹ >, a hydrogen atom, a methyl group, a hydroxymethyl group, a methoxymethyl group, etc. are mentioned, for example. Can be mentioned. Among these, a hydrogen atom is preferable.
[29] In the compound I of the present invention, the cyclic group moiety of the "substituted cyclic group" represented by R ² includes (i) a monocyclic, bicyclic or tricyclic hydrocarbon group and (ii) a monocyclic, bicyclic or tricyclic heterocyclic group. Can be mentioned.
[30] Examples of such a monocyclic, bicyclic or tricyclic hydrocarbon group include those having 3 to 15 carbon atoms in which part or all of them may be saturated.
[31] Examples of the monocyclic hydrocarbon group include those having 3 to 7 carbon atoms, and specific examples thereof include a phenyl group, a cyclohexyl group, a cyclopentyl group, a cyclobutyl group and a cyclopropyl group.
[32] Examples of the bicyclic hydrocarbon group include those having 9 to 11 carbon atoms, and specific examples thereof include an indanyl group, an indenyl group, a naphthyl group, a tetrahydronaphthyl group, and a cyclic group in which some or all of them are saturated.
[33] As a tricyclic hydrocarbon group, a C12-C15 thing is preferable, A fluorenyl group, an anthryl group, a phenanthryl group, and the cyclic group etc. which the one part or all these are saturated are mentioned.
[34] As a monocyclic, bicyclic or tricyclic heterocyclic group, for example, monocyclic, bicyclic or tricyclic containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, some or all of which may be saturated Heterocyclic group can be mentioned.
[35] As a monocyclic heterocyclic group, as a heterocyclic group containing 1-2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, the heterocyclic group containing a saturated or unsaturated 5-7 membered ring is mentioned, Specifically, Is pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, oxolanyl group, thiolanyl group, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group , Triazolyl group, tetrazolyl group, furyl group, oxazolyl group, isoxoxazolyl group, oxadiazolyl group, thienyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, piperidyl group, piperazinyl Group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, pyranyl group, tetrahydropyridyl group, dihydropyridazinyl group, perhydroazinyl group, perhydro Thiazinyl groups, and parts thereof Or a cyclic group in which all are saturated.
[36] As a bicyclic heterocyclic group, as a heterocyclic group containing 1-3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, the heterocyclic group formed by condensation of two saturated or unsaturated 5- to 7-membered rings, Specifically, indolinyl group, isoindolinyl group, indolyl group, indazolyl group, isoindolyl group, benzimidazolyl group, benzothiazolyl group, benzoxazolyl group, benzodioxolanil group, benzothienyl group, Benzofuryl group, thienopyridyl group, thiazolopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, quinazolinyl group, phthalazinyl group, cinnaline And a cyclic group in which some or all of them are saturated, such as a silyl group, a chromanyl group, an isochromenyl group, a naphthyridinyl group, and the like.
[37] As a tricyclic heterocyclic group, as a heterocyclic group containing 1-4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, the heterocyclic group formed by condensation of three saturated or unsaturated 5-7 membered rings is mentioned. Specific examples thereof include a benzooxolanopyrimidinyl group, β-carbolinyl group, carbazolyl group, phenothiazinyl group, phenoxazinyl group, and a cyclic group in which some or all of them are saturated.
[38] Among these cyclic groups (monocyclic, bicyclic or tricyclic hydrocarbon groups or monocyclic, bicyclic or tricyclic heterocyclic groups),
[39] "(I) monocyclic hydrocarbon group having 3 to 7 carbon atoms,
[40] (ii) a bicyclic hydrocarbon group having 9 to 11 carbon atoms,
[41] (iii) a monocyclic heterocyclic group comprising 1-2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or
[42] (iv) a bicyclic heterocyclic group comprising 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, wherein 5 to 7 membered rings are condensed two times;
[43] Is preferable, and as a specific example of such a group,
[44] "Phenyl group, cyclohexyl group, cyclopentyl group, cyclobutyl group, cyclopropyl group, indanyl group, indenyl group, naphthyl group, tetrahydronaphthyl, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, jade Solanyl group, thiolanyl group, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, furyl group, oxazolyl group, isoxazolyl Group, oxadiazolyl group, thienyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, pyra Genyl group, pyridazinyl group, pyranyl group, tetrahydropyridyl group, dihydropyridazinyl group, perhydroazinyl group, perhydrothiazepinyl group, indolinyl group, isoindolinyl group, indolyl group, indazolyl group , Isoindolyl group, benzimidazolyl group, benzothiazole Group, benzoxazolyl group, benzodioxolanyl group, benzothienyl group, benzofuryl group, thienopyridyl group, thiazolopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, quinolyl group, isoquinolyl group , Quinoxalinyl group, quinazolinyl group, phthalazinyl group, cinnolinyl group, chromanyl group, isochromenyl group, naphthyridinyl group, and a cyclic group in which some or all of them are saturated.
[45] Among these, as a more preferable specific example,
[46] "Phenyl group, cyclohexyl group, pyrrolidinyl group, tetrazolyl group, furyl group, thienyl group, thiazolyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group , Pyrazinyl group, pyridazinyl group, perhydroazinyl group, indolinyl group, isoindolinyl group, benzothienyl group, thienopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, quinolyl group, Isoquinolyl group, quinoxalinyl group, and a cyclic group in which some or all of them are saturated ”, and the like, and as a more preferred specific example,
[47] "Pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, indolinyl group, isoindolinyl group, pyrrolopyridyl group, dihydropyrrolopyrrole Dill groups and cyclic groups in which some or all of them are saturated ”.
[48] Among these, as a particularly preferable specific example,
[49] "1-pyrrolidinyl group, 1-piperidyl group, 1-piperazinyl group, 4-morpholinyl group, 4-thiomorpholinyl group, 2-pyridyl group, 2-pyrimidinyl group, 2-isoindoli And a 1, indolinyl group, and a 2,3-dihydro-1H-pyrrolo [3,4-b] pyridin-2-yl group.
[50] The "substituted cyclic group (monocyclic, bicyclic or tricyclic hydrocarbon group or monocyclic, bicyclic or tricyclic heterocyclic group)" represented by R ² may be unsubstituted, but may have the same or different 1 to 3 substituents. have.
[51] Although the substituent in the said cyclic group is not specifically limited, Specifically, the substituent selected from the following "A group substituent" is mentioned, for example, "A 'group substituent" is more preferable among them.
[52] In the objective compound I of the present invention, the "substituted amino group" represented by R ² may be unsubstituted, but may be an amino group (mono or di-substituted amino group) having the same or different 1-2 substituents.
[53] Although the substituent in the said amino group is not specifically limited, Specifically, the substituent selected from the following "group B substituents" is mentioned, for example, "B 'group substituent" is more preferable among them.
[54] As the "substituted amino group" represented by R ² , a substituted amino group (mono or di-substituted amino group) is preferable and more specifically
[55] The same or different 1 to 2 selected from the group consisting of lower alkyl groups (methyl group, ethyl group, isopropyl group, butyl group, etc.), lower cycloalkyl group, lower alkoxy substituted lower alkyl group, pyrimidinyl group, thiazolyl group and thiadiazolyl group Amino group substituted with two substituents ”is preferable. double,
[56] "(I) amino group di-substituted with the same or different substituents selected from lower alkyl groups (methyl group, ethyl group, isopropyl group, butyl group, etc.), lower cycloalkyl group and lower alkoxy substituted lower alkyl group; or
[57] (ii) an amino group mono-substituted with a substituent selected from a pyrimidinyl group, a thiazolyl group and a thiadiazolyl group ”is more preferable,
[58] Particular preference is given to "amino groups di-substituted with the same or different substituents selected from lower alkyl groups (methyl groups, ethyl groups, isopropyl groups, butyl groups, etc.), lower cycloalkyl groups and lower alkoxy substituted lower alkyl groups.
[59] --Group A substituent: -------------
[60] Examples of the group A substituents include the following ones:
[61] Halogen atoms (Cl, F, Br, etc.); Cyano group; Nitro group; Oxo group; Hydroxyl group; Carboxyl groups; Oxydyl group; Amino group: carbamoyl group; Aminosulfonyl group; Lower alkyl groups; Lower alkoxy group; Lower alkanoyl groups;
[62] Lower alkoxycarbonyl group; Lower alkoxy substituted lower alkanoyl groups;
[63] Lower alkoxycarbonyl substituted lower alkoxy groups;
[64] Lower alkoxycarbonyl substituted lower alkoxycarbonyl group;
[65] Lower alkylthio groups;
[66] Lower alkylsulfonyl groups;
[67] Di lower alkylamino substituted lower alkoxy groups;
[68] Di lower alkylaminocarboxy group;
[69] Lower alkyl groups substituted with groups selected from amino groups, carbamoyl groups, halogen atoms, hydroxy groups, carboxy groups, lower alkoxy groups, and mono or di-substituted amino groups
[70] (The substituents in the substituted amino group moiety are not all particularly limited, but specific examples include substituents in the following C group);
[71] Mono or di-substituted amino groups, and mono or di-substituted carbamoyl groups
[72] (The substituents in the substituted amino group or the substituted carbamoyl group are not particularly limited, but specific examples thereof include substituents of the following C group.);
[73] A substituted or unsubstituted lower cycloalkyl group,
[74] Substituted or unsubstituted lower cycloalkyl-CO-,
[75] A substituted or unsubstituted lower cycloalkyl-lower alkyl group,
[76] Substituted or unsubstituted phenyl group,
[77] Substituted or unsubstituted phenyl-O-,
[78] Substituted or unsubstituted phenyl-CO-,
[79] Substituted or unsubstituted phenyl-lower alkyl group,
[80] A substituted or unsubstituted phenyl-O-lower alkyl group,
[81] A substituted or unsubstituted phenylsulfonyl group,
[82] Substituted or unsubstituted phenyl lower alkoxy group,
[83] Substituted or unsubstituted phenyl lower alkoxycarbonyl group,
[84] A substituted or unsubstituted lower cycloalkenyl group (cyclobutenyl group, etc.),
[85] Substituted or unsubstituted bicyclic heterocyclic group,
[86] Substituted or unsubstituted monocyclic 5 to 6 membered heterocyclic group,
[87] Substituted or unsubstituted monocyclic 5 to 6 membered heterocyclic group -O-,
[88] Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-CO-,
[89] A substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-CO-lower alkyl group and
[90] Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-lower alkyl group
[91] (The substituents in the substituted lower cycloalkyl group moiety, substituted phenyl group moiety, substituted lower cycloalkenyl group moiety, substituted bicyclic heterocyclic moiety moiety, or substituted monocyclic 5 to 6 membered heterocyclic moiety moiety are not particularly limited. For example,
[92] And halogen atoms (Cl, F, Br, etc.), cyano groups, nitro groups, oxo groups, and substituents of the following C group substituents.
[93] Moreover, as a monocyclic 5-6 membered heterocyclic group part, the monocyclic 5-6 membered heterocyclic group containing 1-2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom is mentioned, Specifically,
[94] Piperidyl, piperazinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolyl, imida A sleepy group, a pyrazolyl group, a thiazolyl group, a thiadiazolyl group, a thienyl group, etc. are mentioned.
[95] The bicyclic heterocyclic group moiety includes a bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and formed by condensation of two 5 to 6 membered rings. An indolinyl group, an indolinyl group, etc. are mentioned.).
[96] --A 'group substituent (especially preferred group A substituent): --------
[97] As a more preferable group A substituent, the following are mentioned:
[98] Halogen atoms (Cl and the like); Cyano group; Nitro group; Oxo group; Carbamoyl groups; Lower alkyl groups; Lower alkoxy group; Lower alkanoyl groups; Lower alkoxycarbonyl group; Lower alkoxy substituted lower alkyl groups,
[99] Mono or di-substituted amino groups (such as lower cycloalkylcarbonyl-substituted amino groups),
[100] Mono or di substituted carbamoyl groups (such as phenyl substituted carbamoyl groups),
[101] Lower cycloalkyl-CO-,
[102] Substituted or unsubstituted phenyl group (phenyl group, halophenyl group, etc.),
[103] A substituted or unsubstituted phenyl-lower alkyl group (phenyl lower alkyl group, halophenyl lower alkyl group, etc.),
[104] Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group (such as thienyl group),
[105] Substituted or unsubstituted monocyclic 5 to 6 membered heterocyclic group -O- (pyrimidinyloxy group, halopyrimidinyloxy group, etc.),
[106] Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group -CO- (pyridylcarbonyl group, thienylcarbonyl group, etc.).
[107] (In the above, as each monocyclic 5-6 membered heterocyclic group part, the monocyclic 5-6 membered heterocyclic group containing 1-2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom is mentioned, Specifically, As a pyridyl group, a pyrimidinyl group, a thienyl group, etc. are mentioned.)
[108] --- Group B substituents: ---------------------
[109] Examples of the group B substituent include the following ones:
[110] Lower alkyl groups; Lower alkoxy substituted lower alkyl groups; Lower alkoxycarbonyl substituted lower alkyl group; Hydroxy lower alkyl group; Carboxy lower alkyl groups;
[111] A substituted or unsubstituted lower cycloalkyl group,
[112] A substituted or unsubstituted lower cycloalkyl-lower alkyl group,
[113] Substituted or unsubstituted phenyl group,
[114] Substituted or unsubstituted phenyl-lower alkyl group,
[115] Substituted or unsubstituted bicyclic hydrocarbon group,
[116] Substituted or unsubstituted monocyclic 5 to 6 membered heterocyclic group,
[117] A substituted or unsubstituted monocyclic 5 to 6 membered heterocyclic group-lower alkyl group, and
[118] Substituted or unsubstituted bicyclic heterocyclic group-lower alkyl group
[119] (The substituents in the substituted lower cycloalkyl group moiety, substituted phenyl moiety moiety, substituted bicyclic hydrocarbon moiety moiety, substituted monocyclic 5 to 6 membered heterocyclic moiety moiety, or substituted bicyclic heterocyclic moiety moiety are not particularly limited. The substituent of the following C group substituent is mentioned.
[120] As a bicyclic hydrocarbon group part, a C9-11 bicyclic hydrocarbon group is mentioned, Specifically, an indanyl group etc. are mentioned, for example.
[121] Moreover, as a monocyclic 5-6 membered heterocyclic group part, the monocyclic 5-6 membered heterocyclic group containing 1-2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom is mentioned, Specifically,
[122] Piperidyl, piperazinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolyl, imida A sleepy group, a pyrazolyl group, a thiazolyl group, a thiadiazolyl group, a thienyl group, etc. are mentioned.
[123] Moreover, as a bicyclic heterocyclic group part, the heterocyclic group which contains 1-3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and is formed by condensing two 5-6 membered rings of saturated or unsaturated, Specifically, a benzodioxolanyl group etc. are mentioned, for example.)
[124] --- B 'group substituent (more preferable group B substituent): -----
[125] As a more preferable group B substituent, the following are mentioned:
[126] Lower alkyl groups (methyl group, ethyl group, isopropyl group, butyl group, etc.), lower cycloalkyl group, lower alkoxy substituted lower alkyl group, pyrimidinyl group, thiazolyl group and thiadiazolyl group.
[127] Particularly preferred group B substituents include the followings:
[128] In the case where R ² is a di-substituted amino group,
[129] Lower alkyl groups (methyl group, ethyl group, isopropyl group, butyl group, etc.), lower cycloalkyl group, lower alkoxy substituted lower alkyl group; And
[130] When R ² is a mono substituted amino group,
[131] Pyrimidinyl, thiazolyl and thiadiazolyl.
[132] ---- C group substituent: --------------------
[133] Examples of the group C substituent include the following ones:
[134] Lower alkyl groups; Hydroxy lower alkyl group; Lower alkanoyl groups; Lower cycloalkylcarbonyl group; Lower alkoxy groups: lower alkoxycarbonyl groups; Lower alkylsulfonyl groups; Di lower alkyl substituted carbamoyl groups; Di lower alkylamino substituted lower alkanoyl groups; And
[135] Substituted or unsubstituted phenyl group,
[136] Substituted or unsubstituted phenyl-O-,
[137] Substituted or unsubstituted phenyl-CO-,
[138] Substituted or unsubstituted phenyl lower alkanoyl group,
[139] A substituted or unsubstituted phenyl lower alkyl group,
[140] Substituted or unsubstituted phenyl lower alkoxy group,
[141] Substituted or unsubstituted monocyclic 5 to 6 membered heterocyclic group,
[142] Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group -O- (pyridyloxy group, etc.),
[143] Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group -CO- (pyridylcarbonyl group, etc.) and
[144] Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-substituted amino group (such as pyridylamino group)
[145] (The substituents in the substituted phenyl group moiety or the substituted monocyclic 5 to 6 membered heterocyclic group moiety are not particularly limited. Specifically, for example,
[146] Halogen atoms (Cl, F, Br, etc.), cyano groups, nitro groups, oxo groups, lower alkyl groups, lower alkoxy groups, lower alkanoyl groups, lower alkoxycarbonyl groups, and the like.
[147] Moreover, as a monocyclic 5-6 membered heterocyclic group part, the monocyclic 5-6 membered heterocyclic group containing 1-2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom is mentioned, Specifically,
[148] Piperidyl, piperazinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolyl, imida Sleepy group, pyrazolyl group, thiazolyl group, thiadiazolyl group and thienyl group.
[149] In the objective compound I of this invention, as R <^2> when X is -N (R <^3> )-or -O-, a preferable example is a cyclic group which may be substituted.
[150] In addition, in the objective compound I of this invention, as R <^2> when X is -CO-, a chemical formula Preferred examples include the monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic group which may be substituted by (1) or the amino group which may be substituted by (2).
[151] In addition, in the target compound I of the present invention,
[152] Of the two types of cis-trans isomers having the cyclohexyl ring as the reference plane in the structure of [I], the trans isomer compound is more preferable in that a higher DPPIV inhibitory activity can be obtained. That is, for the objective compound I of the present invention, a compound having the following partial structure or a pharmacologically acceptable salt thereof is preferable.
[153]
[154] In particular, the superiority of such a trans body is remarkable in the compound whose X group is -CO-.
[155] As a compound group of one of the compounds of the present invention,
[156] R ² may have the same or different 1 to 3 substituents selected from (1) group A substituents, wherein the cyclic moiety may be (i) monocyclic, bicyclic or tricyclic hydrocarbon group or (ii) monocyclic, Bicyclic or tricyclic heterocyclic groups, or
[157] (2) The compound which is an amino group which has the same or different 1-2 substituent selected from group B substituent is mentioned. (Compound Group 1)
[158] In addition, as another compound group, in the compound I or the compound group 1, R ² is
[159] (1) A cyclic group which may be substituted, wherein the cyclic group portion is selected from the following (i) to (iv)
[160] (i) monocyclic hydrocarbon groups having 3 to 7 carbon atoms,
[161] (ii) a bicyclic hydrocarbon group having 9 to 11 carbon atoms,
[162] (iii) a monocyclic heterocyclic group comprising 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and
[163] (iv) a bicyclic heterocyclic group comprising 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, wherein 5 to 7 membered rings are condensed two times; or
[164] (2) The compound which is a substituted amino group is mentioned. (Compound Group 2)
[165] In the compound group 2, R ² is
[166] (1) A cyclic group which may be substituted, wherein the cyclic group portion is
[167] Phenyl group, cyclohexyl group, cyclopentyl group, cyclobutyl group, cyclopropyl group, indanyl group, indenyl group, naphthyl group, tetrahydronaphthyl, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, oxola Nyl group, thiolanyl group, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, furyl group, oxazolyl group, isoxazolyl group , Oxadiazolyl group, thienyl group, thiazolyl group, isothiazolyl group, thiadiazolyl, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, pyrazinyl group , Pyridazinyl group, pyranyl group, tetrahydropyridyl group, dihydropyridazinyl group, perhydroazinyl group, perhydrothiazepinyl group, indolinyl group, isoindolinyl group, indolyl group, indazolyl group, iso Indolyl group, benzimidazolyl group, benzothiazolyl group, Benzoxazolyl group, benzodioxolanil group, benzothienyl group, benzofuryl group, thienopyridyl group, thiazolopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, quinolyl group, isoquinolyl group, quinoxol A group selected from a salinyl group, a quinazolinyl group, a phthalazinyl group, a cynolinyl group, a chromanyl group, an isochromenyl group, a naphthyridinyl group, and a cyclic group in which some or all of them are saturated; or
[168] (2) The compound which is a substituted amino group is mentioned. (Compound Group 3)
[169] In the compound group 3, as a more preferable compound group, R ² is
[170] (1) A cyclic group which may be substituted, wherein the cyclic group portion is
[171] Phenyl, cyclohexyl, pyrrolidinyl, tetrazolyl, furyl, thienyl, thiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridyl, pyrimidinyl, Pyrazinyl group, pyridazinyl group, perhydroazinyl group, indolinyl group, isoindolinyl group, benzothienyl group, thienopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, quinolyl group, iso A group selected from the group consisting of a quinolyl group, a quinoxalinyl group, and a cyclic group in which some or all of them are saturated; or
[172] (2) The compound which is a substituted amino group is mentioned. (Compound Group 4)
[173] In the compound group 4, as a more preferable compound group, R ² is
[174] (1) A cyclic group which may be substituted, wherein the cyclic group portion is
[175] Pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, indolinyl group, isoindolinyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group And a group selected from the group consisting of a cyclic group in which some or all of them are saturated; or
[176] (2) The compound which is a substituted amino group is mentioned. (Compound Group 5)
[177] In addition, among the compound I, as a more preferable group of other compounds, R ² is
[178] (1) a cyclic group which may have the same or different 1-3 substituents selected from A 'group substituents, wherein the cyclic moiety is
[179] Pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, indolinyl group, isoindolinyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group And a group selected from the group consisting of a cyclic group in which some or all of them are saturated; or
[180] (2) The compound which is an amino group substituted by the same or different 1-2 substituent selected from B 'group substituent is mentioned. (Compound Group 6)
[181] In addition, in the compound I or each compound group 1, 2, 3, 4, 5 or 6,
[182] And a group of compounds in which R ² when X is —N (R ³ ) — or —O— may be a cyclic group which may be substituted. (Compound Group 7)
[183] In addition, in the compound I or each compound group 1, 2, 3, 4, 5 or 6,
[184] R ² when X is -CO- is a chemical formula The compound group which is (1) monocyclic, bicyclic or tricyclic nitrogen containing heterocyclic group which may be substituted, or (2) amino group which may be substituted is mentioned. (Compound Group 8)
[185] Moreover, as a more preferable compound group among the compound I or said each compound group 1, 2, 3, 4, 5, 6, 7 or 8,
[186] A group of compounds in which X is -CO- or -O- and A is -CH _2- ;
[187] A group of compounds in which X is -CO- or -O-, A is -CH _2- , and R ¹ is a hydrogen atom;
[188] A group of compounds in which X is -CO-, A is -CH _2- , and R ¹ is a hydrogen atom;
[189] A group of compounds in which X is -CO-, A is -CH _2- , R ¹ is a hydrogen atom, and R ² may be substituted;
[190] A group of compounds in which X is -CO-, A is -CH _2- , R ¹ is a hydrogen atom, and R ² is a substituted amino group;
[191] A group of compounds in which X is -CO- or -O- and A is -S-;
[192] A group of compounds in which X is -CO- or -O-, A is -S-, and R ¹ is a hydrogen atom;
[193] A group of compounds in which X is -CO-, A is -S-, and R ¹ is a hydrogen atom;
[194] A group of compounds in which X is -CO-, A is -S-, R ¹ is a hydrogen atom, and R ² may be substituted;
[195] The compound group etc. whose X is -CO-, A is -S-, R <^1> is a hydrogen atom and R <^2> is a substituted amino group are mentioned.
[196] Moreover, in each said compound group, the compound group which has the following partial structure is mentioned as a more preferable compound group.
[197]
[198] Moreover, the following compounds are mentioned as a preferable specific compound among the compound I;
[199] (S) -2-cyano-1- [trans-4- (5-nitro-2-pyridylamino) cyclohexylamino] acetylpyrrolidine;
[200] (S) -2-cyano-1- [trans-4- (5-cyano-2-pyridyloxy) cyclohexylamino] acetylpyrrolidine;
[201] (S) -2-cyano-1- [trans-4- (dimethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
[202] (S) -2-cyano-1- [trans-4- (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine;
[203] (S) -2-cyano-1- [trans-4- (5-bromo-2-pyrimidinyloxy) cyclohexylamino] acetylpyrrolidine;
[204] (S) -2-cyano-1- [trans-4- (5-pyrimidinylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
[205] (S) -2-cyano-1- [trans-4- (N-ethyl-N-methoxyethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
[206] (S) -2-cyano-1- [trans-4- (N-ethyl-N-isopropylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
[207] (S) -2-cyano-1- [trans-4- (N-methyl-N-butylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
[208] (S) -2-cyano-1- [trans-4-[(S) -2-methoxymethylpyrrolidin-1-ylcarbonyl] cyclohexylamino] acetylpyrrolidine:
[209] (S) -2-cyano-1- [trans-4- (3-carbamoylpiperidinocarbonyl) cyclohexylamino] acetylpyrrolidine;
[210] (S) -2-cyano-1- [trans-4- (3-nitro-2-pyridylamino) cyclohexylamino] acetylpyrrolidine;
[211] (S) -2-cyano-1- [trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
[212] (S) -2-cyano-1- [trans-4- (2-isoindolinylcarbonyl) cyclohexylamino] acetylpyrrolidine;
[213] (S) -2-cyano-1- [trans-4- [4- (3-pyridylcarbonyl) piperazin-1-ylcarbonyl] cyclohexylamino] acetylpyrrolidine;
[214] (S) -2-cyano-1- {trans-4- [4- (3-tennoyl) piperazin-1-ylcarbonyl] cyclohexylamino} acetylpyrrolidine;
[215] (S) -2-cyano-1- {trans-4- [4- (4-chlorophenyl) piperazin-1-ylcarbonyl] cyclohexylamino} acetylpyrrolidine;
[216] (S) -2-cyano-1- [trans-4- (cis-2,6-dimethylmorpholinocarbonyl) cyclohexylamino] acetylpyrrolidine;
[217] (S) -2-cyano-1- [trans-4- (5-nitro-2-isoindolinylcarbonyl) cyclohexylamino] acetylpyrrolidine;
[218] (S) -2-cyano-1- [trans-4- (piperidinocarbonyl) cyclohexylamino] acetylpyrrolidine;
[219] (S) -2-cyano-1- [trans-4- (4-carbamoylpiperidinocarbonyl) cyclohexylamino] acetylpyrrolidine;
[220] (S) -2-cyano-1- [trans-4- (1-pyrrolidinylcarbonyl) cyclohexylamino] acetylpyrrolidine;
[221] (S) -2-cyano-1- [trans-4- (4-cyclopropylcarbonylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
[222] (S) -2-cyano-1- [trans-4- (4-propionylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
[223] (S) -2-cyano-1- [trans-4- (1-indolinylcarbonyl) cyclohexylamino] acetylpyrrolidine;
[224] (S) -2-cyano-1- [trans-4- (2,3-dihydro-1H-pyrrolo [3,4-b] pyridin-2-ylcarbonyl) cyclohexylamino] acetylpyrroli Dean;
[225] (S) -2-cyano-1- [trans-4- [4- (2-pyrimidinyloxy) piperidinocarbonyl] cyclohexylamino] acetylpyrrolidine;
[226] (S) -2-cyano-1- {trans-4- [4- (5-bromo-2-pyrimidinyloxy) piperidinocarbonyl] cyclohexylamino] acetylpyrrolidine;
[227] (S) -2-cyano-1- [trans-4- (cis-3,5-dimethyl-4-benzylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
[228] (S) -2-cyano-1- [trans-4- (4-cyclohexylcarbonylaminopiperidinocarbonyl) cyclohexylamino] acetylpyrrolidine;
[229] (S) -2-cyano-1- {trans-4- [4- (N-phenylcarbamoyl) piperazin-1-ylcarbonyl] cyclohexylamino} acetylpyrrolidine;
[230] (S) -2-cyano-1- [trans-4- (4-ethoxycarbonylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
[231] (S) -2-cyano-1- {trans-4- [4- (2-thienyl) piperidinocarbonyl] cyclohexylamino} acetylpyrrolidine;
[232] (S) -2-cyano-1- [trans-4- (1,1-dioxoperhydro-1,4-thiazin-4-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
[233] (R) -4-cyano-3- [trans-4- (5-nitro-2-pyridylamino) cyclohexylamino] acetylpyrrolidine;
[234] (R) -4-cyano-3- [trans-4- (5-cyano-2-pyridyloxy) cyclohexylamino] acetylthiazolidine;
[235] (R) -4-cyano-3- [trans-4- (dimethylaminocarbonyl) cyclohexylamino] acetylthiazolidine;
[236] (R) -4-cyano-3- [trans-4- (2-isoindolinylcarbonyl) cyclohexylamino] acetylthiazolidine;
[237] (R) -4-cyano-3- [trans-4- (morpholinocarbonyl) cyclohexylamino] acetylthiazolidine; And
[238] (R) -4-cyano-3- [trans-4- (pyrrolidinylcarbonyl) cyclohexylamino] acetylthiazolidine.
[239] Compound I or a pharmacologically acceptable salt thereof of the present invention has an excellent inhibitory effect on the enzymatic activity of DPPIV. In particular, it has an excellent inhibitory effect on human DPPIV. It also exhibits high selectivity for DPPIV (ie, type IV dipeptidyl peptidase) among various serine proteases (eg, plasmin, thrombin, proline endo peptidase, trypsin, dipeptidyl peptidase II, etc.).
[240] In addition, Compound I or a pharmacologically acceptable salt thereof of the present invention, through its DPPIV inhibitory action, improves the insulin secretory response to oral glucose load.
[241] Accordingly, Compound I or a pharmacologically acceptable salt thereof of the present invention can be used for the prevention of diseases related to DPPIV (disorders mediated by DPPIV), i.e., diseases in which improvement of the condition is expected by inhibiting the enzymatic activity of DPPIV or It is useful as a therapeutic drug.
[242] Such diseases include, for example, diabetes (for example, type 1 diabetes, type 2 diabetes, etc.), hyperglycemia (for example, postprandial hyperglycemia, etc.), hyperinsulinemia, diabetes complications (for example, kidney failure and neuropathy). ), Obesity, overeating, lipid metabolism abnormalities (e.g., hyperlipidemia such as hypertriglyceridemia), autoimmune diseases (e.g., arthritis, chronic arthritis rheumatoid, etc.), osteoporosis, acquired immunodeficiency syndrome (AIDS), Rejection of transplanted organs and tissues.
[243] Objects of the present invention Compound I or a pharmacologically acceptable salt thereof is particularly useful as a prophylactic or therapeutic agent for diabetes (particularly type 2 diabetes).
[244] In addition, the compound of the present invention is low in toxicity and has high safety when used as a pharmaceutical compound. It also exhibits pharmacokinetic properties (bioavailability, in vitro metabolic stability (stable in human homogenates), P450 inhibitory activity, binding to proteins, etc.).
[245] The DPPIV inhibitory action of the compounds of the present invention and the medicinal effects based thereon (anti-glycemic effect, improving insulin secretion response to glucose load, etc.) are known or equivalent methods (WO98 / 19998; WO00 / 34241; Holst). Diabetes, vol. 47, pp. 1663-1670, 1998; Augustynes et al., Current Medicinal Chemistry, vol. 6, pp. 311-327, 1999; Meester et al., Immunol. Today, vol. 20, 367 P. -375, 1999; Fleicher et al., Immunol. Today, Vol. 15, pp. 180-I84, 1994).
[246] Objects of the Invention Compounds I can be used in medicinal applications either in free form or in the form of pharmacologically acceptable salts. Pharmacologically acceptable salts of Compound I include, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate or male. Organic acid salts such as acid salts; and the like. Moreover, when it has substituents, such as a carboxyl group, salt with a base (For example, alkali metal salts, such as a sodium salt and potassium salt, or alkaline earth metal salts, such as a calcium salt), are mentioned.
[247] Objects I or salts thereof of the present invention include all intramolecular salts or adducts thereof, solvates or hydrates thereof, and the like.
[248] Object of the Invention Compound I or a pharmacologically acceptable salt thereof can be administered orally or parenterally and can be used as a conventional pharmaceutical preparation such as tablets, granules, capsules, powders, injections, inhalants and the like. For example, the compounds of the present invention can be used by formulating in a conventional manner using excipients or diluents such as binders, disintegrants, extenders, fillers, lubricants and the like which are acceptable in general medicine.
[249] Dosages of Compound I or a pharmacologically acceptable salt thereof for the purposes of the present invention, depending on the method of administration, the age, weight and condition of the patient, are usually from about 0.01 to 300 mg / kg, in particular from about 0.1 to 30 mg / kg per day. It is preferable to make it to an extent.
[250] Although the objective compound I of this invention can be manufactured by the following A method or the B method, it is not limited to these.
[251] <A law>
[252] The objective compound I of the present invention can be prepared by reacting a compound represented by the formula (II) with a compound represented by the formula (III) or a salt thereof, and making the product a pharmacologically acceptable salt according to the purpose.
[253]
[254] In the formula, Z ¹ represents a reactive moiety, and A has the same meaning as above.
[255]
[256] In formula, R <^1> , R <^2> and X have the same meaning as the above,
[257] As the salt of the compound III, salts with inorganic bases such as inorganic acids such as hydrochloride and sulfate, or alkali metal salts and alkaline earth metal salts can be used.
[258] As the reactive moiety of Z ¹ , conventional reactive moieties such as a halogen atom, a lower alkylsulfonyloxy group, and an arylsulfonyloxy group can be preferably used, but a halogen atom is particularly preferable.
[259] The reaction of compound [II] with compound [III] or a salt thereof can be carried out in a suitable solvent or without solvent in the presence or absence of a deoxidizer.
[260] The solvent may be a solvent which does not adversely affect the reaction, for example, acetonitrile, methanol, ethanol, isopropyl alcohol, propyl alcohol, acetone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ether, dioxane, acetic acid Ethyl, toluene, methylene chloride, dichloroethane, chloroform or a mixed solvent thereof can be suitably used.
[261] The reaction proceeds preferably at 0 to 120 ° C, in particular at room temperature to 80 ° C.
[262] Examples of the deoxidizer include inorganic bases such as alkali metal hydrides such as sodium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium methoxide, alkali metals such as sodium, sodium hydroxide and potassium hydroxide, and the like. Alkali metal hydroxides and the like) or an organic base (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine and the like) can be preferably used.
[263] <B law>
[264] In addition, the compound represented by the formula (Ia) of the objective compound I of the present invention, by reacting the compound represented by the formula (IV) or salts thereof with the compound represented by the formula (V) or salts thereof, the compound represented by the formula (VI) or salts thereof It can also be obtained by removing the amino group protecting group (R ⁴ ) of the product to make the product a pharmacologically acceptable salt according to the purpose.
[265]
[266] Wherein R ²¹ is (1) monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic group which may be substituted, or (2) an amino group which may be substituted, R ¹ and A have the same meaning as described above.
[267]
[268] In formula, R <^4> represents the protecting group of an amino group, and R <^1> and A have the same meaning as the above.
[269] R ²¹ -H
[270]
[271] In formula, R <^1> , R <^4> , R <^21> and A have the same meaning as the above.
[272] As salts of the compounds IV to VI, for example, salts with inorganic bases such as hydrochloric acid salts and sulfates or inorganic bases such as alkali metal salts and alkaline earth metal salts can be used.
[273] As a protecting group of the amino group of R <^{4>, all} the usual amino group protecting groups, such as t-butoxycarbonyl group, benzyloxycarbonyl group, trifluoroacetyl group, chloroacetyl group, and 9-fluorenylmethyloxycarbonyl group, can be used preferably.
[274] The reaction of Compound IV or a salt thereof with Compound V or a salt thereof can be carried out in a suitable solvent or without solvent in the presence or absence of a condensing agent.
[275] The solvent may be a solvent which does not adversely affect the reaction, for example, acetonitrile, methanol, ethanol, isopropyl alcohol, propyl alcohol, acetone, dimethylformamide, tetrahydrofuran, ether, dioxane, ethyl acetate, toluene, Methylene chloride, dichloroethane, chloroform or a mixed solvent thereof can be suitably used.
[276] The reaction proceeds preferably at 0 to 120 ° C, in particular at room temperature to 80 ° C.
[277] As the condensing agent, O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate, DCC (dicyclohexylcarbodiimide), EDC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide), chloroformate esters (for example, ethyl chloroformate, isobutyl chloroformate), carbonyldiimidazole, and the like can be preferably used.
[278] In addition, in order to accelerate the reaction, a base (sodium carbonate, sodium bicarbonate, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7 -En, etc.), 1-hydroxybenzotriazole, 1-hydroxysuccinimide, etc. can also be added to the said condensing agent.
[279] Subsequent removal of the amino group protecting group (R ⁴ ) of Compound VI can be carried out by a conventional method, but can be carried out by, for example, acid treatment, base treatment or catalytic reduction in a suitable solvent or solvent-free.
[280] The solvent may be a solvent that does not adversely affect the reaction, for example methanol, ethanol, isopropyl alcohol, propyl alcohol, dioxane, methylene chloride, chloroform, dichloroethane, ether, tetrahydrofuran, ethyl acetate, toluene or these The mixed solvent of can be used suitably.
[281] The reaction proceeds preferably at -78 to 80 ° C, in particular at 0 ° C to room temperature.
[282] As the acid, organic acids such as inorganic acids such as hydrochloric acid and sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid can be preferably used.
[283] Examples of the base include inorganic bases such as alkali metal hydrides such as sodium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium methoxide, alkali metals such as sodium, sodium hydroxide and potassium hydroxide, and the like. Alkali metal hydroxides and the like) or an organic base (e.g., triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, pyridine, piperidine, dimethylaniline, dimethylaminopyridine, etc.) Can be used.
[284] The catalytic reduction reaction can be carried out by preferably using palladium carbon, palladium hydroxide carbon, platinum oxide, Raney-nickel or the like in a hydrogen atmosphere.
[285] The raw material compound II of this invention can be manufactured according to the method described, for example in international publication patent WO98 / 19998, WO00 / 34241, the following reference example (reference example 1 or 2), etc.
[286] For example, compound II reacts the compound represented by the formula (10) with the compound represented by the formula (11) in the presence of a deoxidizer (for example, triethylamine, etc.) to obtain a compound represented by the formula (12), and further It can obtain by processing with a dehydrating agent (for example, phosphorus oxy chloride, trifluoroacetic anhydride etc.) by a conventional method.
[287]
[288] In formula, A has the same meaning as the above.
[289] Z ² -CH ₂ CO-Z ³
[290] Wherein Z ² and Z ³ represent reactive moieties which may be the same or different.
[291]
[292] In formula, Z <^2> and A have the same meaning as the above.
[293] As the reactive residue of Z ² or Z ³ , the same conventional reactive residues as Z ¹ can be preferably used.
[294] Raw material compound III can be manufactured specifically similarly to the method described, for example in the following reference examples (Reference Examples 3-14).
[295] For example, compound III, wherein X is -N (R ³ )-or -O-, is a deoxidizer (e.g. triethyl It can be manufactured by making it react in presence or absence of organic bases, such as amine and diisopropylethylamine, inorganic bases, such as sodium hydride and potassium carbonate, etc., and deprotection of the protecting group of an amino group by a conventional method as needed.
[296]
[297] In the formula, V ¹ represents a -NH (R ³ )-or hydroxy group, and R ¹ and R ³ have the same meaning as above.
[298] R ² -Z ⁴
[299] In the formula, Z ⁴ represents a reactive moiety, R ² has the same meaning as above,
[300] As a protecting group of an amino group, all the common protecting groups similar to said R <^4> can be used preferably.
[301] As the reactive residue of Z ⁴ , the same conventional reactive residue as Z ¹ can be preferably used.
[302] For example, X is -CO- and R ² is of the formula The compound III represented by the above formula represents a compound represented by the formula (15), an amino group protecting group or salts thereof, and a compound represented by the formula (16) or a salt thereof as a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) It can be manufactured by making it react in presence of a body imide, etc., and if necessary, deprotecting the protecting group of an amino group by a conventional method.
[303]
[304] In the formula, V ² represents -COOH, and R ¹ has the same meaning as above.
[305] R ²² -H
[306] Wherein R ²² is (1) Monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic group which may be substituted, or (2) The amino group which may be substituted is represented, and a cyclic or linear amine is formed with a hydrogen atom.
[307] Alternatively, the compound III in which X is -CO- may be a compound represented by the formula (17), an amino group protecting group or salt thereof, and a compound represented by the formula (18) with a palladium catalyst (for example, dichlorobis (triphenylphosphine) palladium, etc.). It can obtain by making it react in presence of).
[308]
[309] In the formula, Z ⁵ represents a reactive moiety and has the same meaning as the R ¹ group,
[310] R ² -Sn (R ⁵ ) ₃
[311] In formula, R < ⁵ > represents a lower alkyl group and R <^2> has the same meaning as the above.
[312] As a protecting group of an amino group, all the common protecting groups similar to said R <^4> can be used preferably. In addition, as a reactive residue of Z <^5> , the same conventional reactive residue as Z <^1> can be used preferably.
[313] Alternatively, compound III wherein X is -N (R ³ )-may be substituted with a compound represented by the formula (19), an amino group protecting group thereof or a salt thereof and a compound represented by the formula (20) in the presence of a reducing agent (such as sodium triacetoxy borohydride). It can be manufactured by making it react and deprotecting a protecting group of an amino group by a conventional method as needed.
[314]
[315] In formula, R <^1> has the same meaning as the above.
[316] R ² -V ³
[317] In the formula, V ³ represents -N (R ³ ) H, and R ² has the same meaning as above.
[318] As a protecting group of an amino group, all the common protecting groups similar to said R <^4> can be used preferably.
[319] Raw material compounds 10-20 can be manufactured by carrying out similarly to the well-known method or the method of the following reference example.
[320] When obtaining raw material compound III of the trans body which makes a cyclohexane ring a reference plane, the raw material cyclohexane compound (compound 13, 15, 17 etc.) of a trans body can be used, respectively.
[321] In addition, raw material compound IV can be manufactured similarly to or according to the method described in the following Example (Example 3-1 (1)-(3)), for example like the following table | surface. (In the scheme, Z ⁶ represents a reactive moiety, R ⁴ represents an amino group protecting group, and the other symbols have the same meanings as above.)
[322] As the reactive moiety of Z ⁶ , the same conventional reactive moieties as Z ¹ can be preferably used.
[323]
[324] The compound I of the present invention or the raw material compound thereof prepared as described above is isolated and purified as a free or salt thereof. Salts can be prepared by carrying out the commonly used salt treatment.
[325] Isolation and purification can be carried out by applying conventional chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, and various chromatography.
[326] In addition, in the compound of the present invention, optical isomers such as racemates, optically active agents and diastereomers may be present alone or in a mixture. Stereochemically pure isomers can be derived by using stereochemically pure raw compounds or by separating optical isomers by conventional racemic fractionation. In addition, the mixture of diastereomers can be separated by a conventional method, for example, fractional crystallization or chromatography.
[327] <Example>
[328] Hereinafter, although an Example demonstrates this invention still in detail, these Examples do not limit this invention.
[329] <Example 1a-1>
[330] (S) -1-bromoacetyl-2-cyanopyrrolidine (Reference Example 1 below) 100 mg and N- (5-nitro-2-pyridyl) -trans-1,4-cyclohexanediamine (see below) Example 3-1) 327 mg of acetonitrile-methanol solution was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with chloroform. The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by diol column chromatography (solvent: 0 to 10% methanol-chloroform) to obtain an oily substance. This was dissolved in 0.5 ml of ethyl acetate-0.5 ml of chloroform, 1.0 ml of 2N hydrochloric acid ether and then 2 ml of ether were added, and the precipitated precipitate was filtered off and washed with ether, (S) -2-cyano-1 -[Trans-4- (5-nitro-2-pyridylamino) cyclohexylamino] acetylpyrrolidine dihydrochloride (Example 1a-1 of Table 1a) was obtained.
[331] <Examples 1a-2 to 1d-152>
[332] (S) -1-Bromoacetyl-2-cyanopyrrolidine and the corresponding raw material compound, and the same treatment as in Example 1a-1 to give Tables 1a to 1d (Examples 1a-2 to 1a-89). , 1b-1 to 1b-71, 1c-1 to 1c-52, and 1d-1 to 152) were obtained. In addition, the corresponding raw material compound was obtained by the method similar to the following reference example, a well-known method, or the combination of these.
[333] Only the compound of Example 1d-77 was obtained by using trans-4- (1-piperazinylcarbonyl) cyclohexylamine as a raw material.
[334] In addition, the compound of Example 1c-39 (ie, (S) -2-cyano-1- {trans-4-[(N-carboxymethyl-N-methylamino) carbonyl] cyclohexylamino} acetylpyrroli Dine hydrochloride) is a compound of Example 1c-38 (i.e., (S) -2-cyano-1- {trans-4-[(N-tert-butoxycarbonylmethyl-N-methylamino) carbonyl Cyclohexylamino} acetylpyrrolidine) was obtained by treatment with trifluoroacetic acid followed by hydrochloric acid.
[335] In addition, the compound of Example 1d-14 (that is, (S) -2-cyano-1- [trans-4- (1-piperazinylcarbonyl) cyclohexylamino] acetylpyrrolidine dihydrochloride) Example 1 d-70 Free Compound ((S) -2-cyano-1- [trans-4- (4-benzyloxycarbonyl-1-piperazinylcarbonyl) cyclohexylamino] acetylpyrrolidine ) Was treated with trimethylsilyl iodide.
[336] <Examples 2-1 to 2-2>
[337] (1) 4-tert-butoxycarbonylamino-4-methylcyclohexanone (compound of Reference Example 6-1 (3)) 600 mg, sodium triacetoxy borohydride 783 mg, 3-cyanoaniline 343 mg , A mixture of 159 mg of acetic acid and 6 ml of dichloroethane were stirred at room temperature for 16 hours. Dilution with saturated aqueous sodium hydrogen carbonate solution was followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane-ethyl acetate 4: 1-> 1: 1) to N-tert-butoxycarbonyl-1-methyl-c-4- (3-cyano-phenyl 304 mg of amino) -r-1-cyclohexylamine and 292 mg of N-tert-butoxycarbonyl-1-methyl-t-4- (3-cyano-phenylamino) -r-1-cyclohexylamine Got it.
[338] (2) 243 mg of N-tert-butoxycarbonyl-1-methyl-c-4- (3-cyano-phenylamino) -r-1-cyclohexylamine obtained in the above (1) with 4N hydrochloric acid / In a liquid mixture of 2 ml of dioxane and 2 ml of ethanol, the mixture was stirred at room temperature for 15 hours.
[339] After concentrating the reaction solution, 320 mg of (S) -1-bromoacetyl-2-cyanopyrrolidine, 0.6 ml of triethylamine, 3.5 ml of acetonitrile and 1 ml of methanol were added to the residue, followed by 15 hours at room temperature. Stirred. Dilution with saturated aqueous sodium hydrogen carbonate solution was followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol (50: 1)) to treat 154 mg of the obtained compound in hydrochloric acid, and (S) -2-cyano-1- [1-methyl-c-4 -(3-cyano-phenylamino) -r-1-cyclohexylamino] acetylpyrrolidine dihydrochloride (Table 2: Example 2-1) was obtained.
[340] (3) Using N-tert-butoxycarbonyl-1-methyl-t-4- (3-cyano-phenylamino) -r-1-cyclohexylamine obtained in the above (1), (2) (S) -2-cyano-1- [1-methyl-c-4- (3-cyano-phenylamino) -r-1-cyclohexylamino] acetylpyrrolidine dihydrochloride ( Example 2-2 of Table 2 was obtained.
[341] <Examples 2-3 to 2-8>
[342] Using the corresponding starting compound, the same treatment as in Examples 2-1 to 2-2 was carried out to obtain the compounds of Examples 2-3 to 2-8 shown in Table 2.
[343] <Example 3-1>
[344]
[345] (1) 5.0 g of trans-4-ethoxycarbonylcyclohexylamine hydrochloride were dissolved in water, made alkaline by adding potassium carbonate, and then extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. A mixture of the residue and 5.1 g of p-toluenesulfonic acid monohydrate and 50 ml of allyl alcohol was heated to reflux for 48 hours. The reaction solution was concentrated and then diluted with chloroform. The chloroform solution was washed with aqueous potassium carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: chloroform-methanol-ammonia water (500: 10: 1)) to obtain 3.29 g of trans-4- (2-propenyloxycarbonyl) cyclohexylamine.
[346] (2) of 507 mg of the compound obtained in (1), 400 mg of (S) -1-bromoacetyl-2-cyanopyrrolidine, 714 mg of N, N-diisopropylethylamine, and 4 ml of acetonitrile The mixture was stirred at 50 ° C for 12 h. After cooling to room temperature, 476 mg of N, N-diisopropylethylamine and 4 ml of acetonitrile solution of 803 mg of di-tert-butyldicarbonate were added to the reaction solution, followed by stirring at room temperature for 3 hours. The reaction solution was concentrated and diluted with ethyl acetate. The ethyl acetate solution was washed with 10% aqueous citric acid solution, water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: chloroform-methanol (100: 1)) to give (S) -2-cyano-1- [N-tert-butoxycarbonyl-trans-4- (2 -658 mg of propenyloxycarbonyl) cyclohexylamino] acetylpyrrolidine was obtained.
[347] (3) A mixture of 600 mg of the compound obtained in the above (2), 165 mg of tetrakis (triphenylphosphine) palladium, 271 mg of ammonium formate and 6 ml of dioxane was stirred at 50 ° C. for 1 hour. After cooling, the reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: chloroform-methanol (50: 1)) to give (S) -2-cyano-1- (N-tert-butoxycarbonyl-trans-4-carboxycyclo 394 mg of hexylamino) acetylpyrrolidine was obtained.
[348] (4) 150 mg of the compound obtained in (3), 64 mg of 2-aminomethylpyridine, 114 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, and 1-hydroxybenzotriazole 80 A mg solution of 2 ml of N, N-dimethylformamide was stirred for 24 hours at room temperature. Saturated sodium bicarbonate water was added to the reaction mixture, which was then extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 3 ml of acetonitrile, and 1 ml of acetonitrile solution of 118 mg of trimethylsilyl iodide was added dropwise under ice cooling, followed by stirring at room temperature for 30 minutes. Methanol and water were added to the reaction mixture, the mixture was stirred briefly, neutralized with saturated sodium hydrogencarbonate water, and extracted with chloroform. The extract was washed with saturated sodium bicarbonate water, water and brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by diol chromatography (solvent: chloroform) to obtain an oily substance. This was dissolved in 1 ml of ethyl acetate, 0.5 ml of 1 N hydrochloric acid ether and then 2 ml of ether were added, and the precipitated precipitate was washed with ether to give (S) -2-cyano-1- [trans-4- 106 mg of (2-pyridylmethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine dihydrochloride (Example 3-1 in Table 3) were obtained.
[349] <Examples 3-2 to 3-12>
[350] (S) -2-cyano-1- (N-tert-butoxycarbonyl-trans-4-carboxycyclohexylamino) acetylpyrrolidine (compound of item (3) of Example 3-1 above) and the corresponding Using the starting compound, the same process as in (4) of Example 3-1 was carried out to obtain the compounds of Examples 3-2 to 3-12 of Table 3.
[351] <Examples 4-1 to 4-32>
[352] 100 mg of (R) -3-chloroacetyl-4-cyanothiazolidine (compound of Reference Example 2 below) and N- (5-nitro-2-pyridyl) -trans-1,4-cyclohexanediamine 372 A solution of mg acetonitrile 2 ml-methanol was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by diol column chromatography (solvent: 0-5% methanol-chloroform) to obtain an oily substance. This was dissolved in 0.5 ml of ethyl acetate 0.5 ml, chloroform, 1.0 ml of 2N hydrochloric acid-ether, then 2 ml of ether was added, and the precipitated precipitate was filtered and washed with ether (R) -4-cyano-3 -173 mg of [trans-4- (5-nitro-2-pyridylamino) cyclohexylamino] acetylthiazolidine dihydrochloride (Example 4-1 of Table 4) was obtained.
[353] In addition, the compound of Examples 4-2 to 4-32 of Table 4 was obtained in the same manner as above using the corresponding starting compound.
[354] Reference Example 1
[355] According to the method described in (WO98 / 19998), (S) -1-bromoacetyl-2-cyanopyrrolidine was obtained by reacting L-prolineamide (commercially available product) and bromoacetylbromide, followed by dehydration reaction.
[356] Reference Example 2
[357] L-thioprolineamide hydrochloride was synthesized according to the method described in Ashworth et al., Bioorg. Med. Chem. Lett., Vol. 6, pp. 2745-2748, 1996. 2.36 ml of chloroacetyl chloride was added to the obtained 5.00 g of L- thioprrolineamide hydrochloride and 150 ml of dichloromethane of 8.67 ml of triethylamine under ice-cooling, and it stirred at room temperature for 1 hour. A dichloromethane solution of 4.8 ml of pyridine and 8.4 ml of trifluoroacetic anhydride was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was washed with 10% aqueous HCl solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then the residue was crystallized from ether to give (R) -3-chloroacetyl-4-cyanothiazolidine 4.82 g was obtained as tan crystals.
[358] <Reference Examples 3-1 to 3-40>
[359] An ethanol (15 ml) -tetrahydrofuran (10 ml) solution of 5-nitro-2-chloropyridine (2.50 g) and trans-1,4-cyclohexanediamine (5.40 g) was stirred at room temperature for 5 days. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol-condensed aqueous ammonia (20: 4: 1) and crystallized from ethyl acetate to give N- (5-nitro-2-pyridyl) -trans-1,4 -Cyclohexanediamine (Reference Example 3-1 in Table 5) was obtained.
[360] In addition, using the corresponding starting compound, the same treatment as described above to obtain the compounds of Reference Examples 3-2 to 3-40 of Table 5.
[361] <Reference Examples 3-41 to 3-44>
[362] A solution of N, N-dimethylacetamide (30 ml) of 4-nitrofluorobenzene (1.69 g) and trans-1,4-cyclohexanediamine (4.1 g) was stirred at 144 ° C. for 3 days. After cooling, saturated aqueous potassium carbonate solution was added to the reaction solution, the reaction mixture was extracted with ethyl acetate, the extract was dried over anhydrous potassium carbonate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: chloroform-methanol-ammonia (90: 10: 1)), and the solvent was distilled off to trans-N- (4-nitrophenyl) -1,4-cyclohexane Diamine (Reference Example 3-41 in Table 5) (2.31 g) was obtained.
[363] In addition, the compounds of Reference Examples 3-42 to 3-44 of Table 5 were obtained in the same manner using the corresponding starting compounds.
[364] <Reference Examples 3-45 to 3-47>
[365] A 25 mL solution of 1.23 g of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine, 1.0 g of 2-chloro-3-nitropyridine 1-oxide and 700 mg of dimethylaminopyridine under argon atmosphere It was heated to reflux for 2 hours.
[366] After cooling, the reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (solvent: chloroform-methanol (30: 1)) to obtain a red powder. The obtained compound was dissolved in 5 ml of trifluoroacetic acid and stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (solvent: ammonia water saturated chloroform-methanol (10: 1)) to give N- (3-nitropyridin-1-oxide-2-yl). 110 mg of -trans-1,4-cyclohexanediamine (Reference Example 3-45 in Table 5) was obtained.
[367] In addition, the compounds of Reference Examples 3-46 to 3-47 of Table 5 were obtained by the same treatment using the corresponding starting compounds.
[368] <Reference Examples 3-48 to 3-49>
[369] 168 mg of N-tert-butoxycarbonyl-trans-4-[(6-chloro-3-pyridazinyl) amino] cyclohexylamine (Reference Example 3-46) and 0.5 ml of triethylamine with 5 ml of ethanol It was dissolved in 4 ml of tetrahydrofuran mixed solvent. 50 mg of 10% palladium carbon was added and stirred for 1 day at room temperature under a hydrogen atmosphere at atmospheric pressure. After filtration of the catalyst, the solvent was distilled off and the residue was stirred in 2 ml of trifluoroacetic acid for 3 hours. The solvent was distilled off, 10% aqueous sodium hydroxide solution was added to the residue, the mixture was extracted with chloroform, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain trans-4- (pyridazin-3-ylamino) cyclohexyl. 61 mg of amine (Reference Example 3-48 of Table 5) were obtained.
[370] In addition, the compound of Reference Example 3-49 in Table 5 was obtained by treating the corresponding starting compound (Reference Example 3-47) in the same manner.
[371] <Reference Examples 3-50 to 3-58>
[372] In the same manner as in Reference Example 9-50 or Reference Example 9-55, the compounds of Reference Examples 3-50 to 3-58 in Table 5 were obtained.
[373] Reference Example 3-59
[374] 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester and N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine in the same manner as in Reference Example 3-49 N-tert-butoxycarbonyl-trans-4- (5-ethoxycarbonyl-2-phenyl-4-pyrimidinylamino) cyclohexylamine was obtained by reacting in ethanol in the presence.
[375] By treating this compound in the same manner as in (1) and (2) of Reference Example 9-56, trans-4- (5-morpholinocarbonyl-2-phenyl-4-pyrimidinylamino) cyclohexylamine ( Reference Example 3-59) in Table 5 was obtained.
[376] Reference Example 4
[377] (1) 15 ml of triethylamine are added to a 150 ml suspension of 10 g of tetra-4-aminocyclohexanol and tetrahydrofuran of 2-chloro-5-nitropyridine is added under ice cooling. After stirring, the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: ethyl acetate-hexane (2: 1)) to obtain 8.52 g of trans-4- (5-nitro-2-pyridylamino) cyclohexanol.
[378] (2) 1.8 ml of triethylamine was added to a 10 ml solution of 1.0 g of dichloromethane obtained in the above (1), and 0.65 ml of methanesulfonyl chloride was further added under ice-cooling, followed by stirring for 1 hour. Saturated sodium bicarbonate solution was added to the reaction mixture, which was then extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Sodium azide 1.37 g was added to a 10 ml solution of the residue's dimethylformamide, and the mixture was stirred at 50 ° C for 3 days. After cooling, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: ethyl acetate-hexane (1: 5)) to obtain 758 mg of cis-4-azide-N- (5-nitro-2-pyridyl) cyclohexylamine. .
[379] (3) A solution of 640 mg of the compound obtained in the above (2) and 704 mg of triphenylphosphine 10 ml-water 1 ml of tetrahydrofuran was stirred at room temperature for 2 days. The reaction mixture was concentrated and the residue was purified by silica gel flash column chromatography (solvent: ethyl acetate-methanol (10: 1)) to give N- (5-nitro-2-pyridyl) -cis-1,4-cyclo 531 mg of hexanediamine (compound of Reference Example 4 in Table 5) were obtained.
[380] <Reference Examples 5-1 to 5-6>
[381] (1) 60.0 g of trans-4-tert-butoxycarbonylaminocyclohexyl methanesulfonate and 20.1 g of sodium azide were suspended in 600 ml of dimethylformamide and stirred at 90 ° C. for 6 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 47.9 g of cis-4-azide-N- (tert-butoxycarbonyl) cyclohexylamine was obtained.
[382] (2) 500 mg of the compound obtained in the above (1) and 100 mg of palladium-carbon (wet) were suspended in 8 ml of tetrahydrofuran and stirred vigorously for 1.5 hours at room temperature under a hydrogen atmosphere. On the way, hydrogen in the system was replaced twice. Insolubles were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (solvent: chloroform-methanol (20: 1)) followed by chloroform-methanol-ammonia water (100: 10: 1)) to N-tert-butoxycarbonyl-cis-1,4- 395 mg of cyclohexanediamine were obtained.
[383] (3) 2.0 g of the compound obtained in the above (2), 1.63 g of 2-chloro-3-nitropyridine and 1.95 mL of diisopropylethylamine were stirred at 80 ° C. for 1 day. The reaction mixture was concentrated under reduced pressure, then water was added and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: chloroform and then chloroform-ethyl acetate (7: 1)). Hydrochloric acid-dioxane was added to the ethanol suspension of the obtained compound, stirred at room temperature for 18 hours, and the precipitate was filtered and N- (3-nitro-2-pyridyl) -cis-1,4-cyclohexanediamine dihydrochloride ( 2.15 g of Reference Example 5-1) in Table 5 were obtained.
[384] In addition, the compound of Reference Examples 5-2 to 5-6 of Table 5 was obtained similarly using the corresponding raw material compound.
[385] Reference Example 6-1
[386]
[387] (1) According to the method described in JP83-118577, methyl 1,4-dioxaspiro [4.5] decane-8-carboxylic acid is reacted with methyliodide in the presence of LDA (lithium diisopropylamide) , 8-methyl-1,4-dioxaspiro [4.5] decane-8-carboxylic acid methyl (compound 1 of the above scheme) was obtained.
[388] (Raw compounds are described in Rosemmund et al. (Chem. Bel., 1975, Vol. 108, pp. 1871-1895) and Black et al. (Synthesis, 1981, pp. 829). What was synthesized according to the method was used.)
[389] (2) A mixture of 3.80 g of the compound obtained in (1), 3.55 g of sodium hydroxide, 16 mL of methanol and 25 ml of water was heated to reflux for 2 hours. The reaction solution was ice-cooled, brought to pH 5 with 2N hydrochloric acid and 10% citric acid aqueous solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 8-methyl-1,4-dioxaspiro [4.5] decane-8-carboxylic acid (compound of the above scheme). 2) 3.46 g were obtained.
[390] (3) A mixture of 16.19 g of the compound obtained in the above (2), 24.51 g of diphenylphosphoryl azide, 9.00 g of triethylamine, and 160 ml of toluene was heated to reflux for 2.5 hours. The reaction solution was ice-cooled, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 9.55 g of tert-butoxy potassium was slowly added to 100 mL solution of the obtained compound of dimethylacetamide under ice-cooling, and it stirred at room temperature for 1 hour. The reaction solution was poured into ice water, and the precipitated crystals were filtered, washed with water and dried. 100 ml of 30.87 g of p-toluenesulfonic acid hydrate was added to a 100 ml solution of tetrahydrofuran of the obtained compound, followed by stirring at room temperature for 16 hours. After diluting with saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 10.41 g of 4-tert-butoxycarbonylamino-4-methylcyclohexanone (Compound 3 in Scheme 3). Got it.
[391] (4) A mixture of 10.41 g of the compound obtained in the above (3), 11.01 g of sodium triacetoxy borohydride, 5.10 ml of benzylamine, and 150 ml of methylene chloride was stirred at room temperature for 16 hours. After diluting with saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the methanol 15 mL solution of the obtained compound, 3.32 g of p-toluenesulfonic acid hydrate and then 160 ml of ether were added. The precipitate was filtered off, washed with ether and dried, N-benzyl-t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine p-toluenesulfonate (compound of the above scheme) 4) 7.49 g was obtained.
[392] (5) A mixture of 16.63 g of the compound obtained in (4), 5.0 g of 10% palladium carbon, and 400 ml of methanol was stirred for 24 hours under a hydrogen atmosphere (1 atmosphere). 10% palladium carbon was filtered off and the filtrate was concentrated. The obtained residue was dissolved in a mixture of 50 ml of 10% aqueous sodium hydroxide solution and 300 ml of ether, the ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, t-4- 6.87 g of tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (Compound 5 of the above scheme) were obtained.
[393] (6) The filtrate of step (4) was treated with an aqueous sodium hydroxide solution, and extracted with chloroform. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH-silica gel column chromatography (solvent: hexane-ethyl acetate (30: 1-> 3: 1)) to N-benzyl-c-4-tert-butoxycarbonylamino-4-methyl- r-1-cyclohexylamine was obtained. This was then treated as in (5) above to obtain c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (Compound 6 in the above scheme).
[394] Reference Example 6-2
[395] Except for using benzyloxymethyl chloride in place of methyl iodide in the step (1) of Reference Example 6-1, the same procedure as in (1) to (5) or (6) of Reference Example 6-1 4-tert-butoxycarbonylamino-4-hydroxymethyl-r-1-cyclohexylamine or c-4-tert-butoxycarbonylamino-4-hydroxymethyl-r-1-cyclohexylamine Got it.
[396] In addition, except that methoxymethyl chloride is used instead of methyl iodide in the step of (1) of Reference Example 6-1, as in (1) to (5) or (6) of Reference Example 6-1. T-4-tert-butoxycarbonylamino-4-methoxymethyl-r-1-cyclohexylamine or c-4-tert-butoxycarbonylamino-4-methoxymethyl-r-1-cyclo Hexylamine was obtained.
[397] <Reference Examples 7-1 to 7-18>
[398] t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (compound obtained in (5) of Reference Example 6-1) 1.70 g, 2-chloropyrimidine 2.04 g, A mixture of 3.24 mL of diisopropylethylamine and 13 ml of 2-propanol was heated to reflux for 12 hours. After cooling, the reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate-hexane (30: 70-50: 50)). The obtained compound was dissolved in 4 mL of dioxane, 10 ml of 4N hydrochloric acid-dioxane was added, and stirred for 8 hours. The reaction solution was diluted with ether, and the precipitated crystals were filtered off and washed with ether.
[399] The obtained crystals were dissolved in water, saturated with potassium carbonate and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 1-methyl-t-4- (2-pyrimidinylamino) -r-1-cyclohexylamine (Reference Example 7-1 in Table 5) 587 mg was obtained.
[400] In addition, the compound of Reference Examples 7-2 to 7-5 of Table 5 was obtained similarly using the corresponding raw material compound.
[401] In addition, it is the same using c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (compound obtained by (6) of the said Reference Example 6-1), and a corresponding raw material compound. The compounds of Reference Examples 7-6 to 7-9 of Table 5 were obtained.
[402] In addition, it uses the t- or c-4-tert-butoxycarbonylamino-4-hydroxymethyl-r-1-cyclohexylamine (Reference Example 6-2), and the corresponding raw material compound, Compounds of 7-10 to 7-18 were obtained.
[403] <Reference Examples 7-19 to 7-23>
[404] 4-tert-butoxycarbonylamino-4-methylcyclohexanone (compound 3 of Reference Example 6-1) and a corresponding starting compound (amine compound) were stirred for 16 hours at room temperature in the presence of sodium triacetoxyborohydride. After the reaction, an acid treatment was performed to remove the protecting group (t-butoxycarbonyl group) to obtain the compounds of Reference Examples 7-19 to 7-23 in Table 5.
[405] <Reference Examples 8-1 to 8-4>
[406] (1) To a 160 ml solution of 16.93 g of 4- (tert-butoxycarbonylamino) cyclohexanone and 160 ml of 10.55 ml of N-methylbenzylamine, 19.08 g of sodium triacetoxyborohydride were added by ice-cooling, and room temperature Stirred for 14 hours. The reaction solution was diluted with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was suspended in hexane and filtered. The mother liquor was concentrated, the residue was purified by NH-silica gel chromatography (solvent: hexane-ethyl acetate (97: 3-83: 17)), and the residue was suspended in hexane and combined with what was previously filtered. 13.55 g of N'-benzyl-N-tert-butoxycarbonyl-N'-methyl-trans-1,4-cyclohexanediamine was obtained.
[407] Suspension in 13.53 g of this compound and 2.00 g of palladium hydroxide-carbon in methanol was added by catalytic hydrogenation at normal temperature over 5 hours at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain 9.93 g of N-tert-butoxycarbonyl-N'-methyl-trans-1,4-cyclohexanediamine.
[408] (2) Using the compound obtained in the above (1) and the corresponding raw material compound (chloride), reacted by heating under reflux for 12 hours in the presence of diisopropylethylamine in 2-propanol in the same manner as in Reference Example 7-1, The obtained compound was acid treated with hydrochloric acid and neutralized with potassium carbonate to obtain the compounds of Reference Examples 8-1 to 8-4 in Table 5.
[409] <Reference Examples 9-1 to 9-45>
[410] To a 150 ml solution of tetrahydrofuran of 10.0 g of trans-4- (tert-butoxycarbonylamino) cyclohexanol and 7.35 g of 2-chloro-5-nitropyridine, 2.04 g of 60% sodium hydride was slowly added, followed by dimethyl 30 ml of sulfoxide were added and then stirred at room temperature for 1 day. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform alone from chloroform-ethyl acetate (20: 1)), and the obtained powder crystals were suspended in an ethyl acetate-hexane mixed solution and filtered to give trans-1-tert- 12.20 g of butoxycarbonylamino-4- (5-nitro-2-pyridyloxy) cyclohexane were obtained. A 2 ml solution of 2N hydrochloric acid-dioxane was added to a 10 ml suspension of 800 mg of ethanol of this compound, and stirred for 18 hours at room temperature. The precipitate was filtered to give 568 mg of trans-4- (5-nitro-2-pyridyloxy) cyclohexylamine hydrochloride (Reference Example 9-1 in Table 6).
[411] In addition, the compounds of Reference Examples 9-2 to 9-45 in Table 6 were obtained in the same manner as above using the corresponding starting compound.
[412] <Reference Examples 9-46 to 9-47>
[413] 60% sodium hydride was added to a 10 ml suspension of 1.00 g of tetra-4-aminocyclohexanol hydrochloride and heated to reflux for 1 hour. After cooling to room temperature, 2-chloropyrimidine was slowly added and stirred at room temperature for 6 hours. The reaction mixture was poured into iced water and extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH-silica gel column chromatography (solvent: chloroform alone from ethyl acetate-hexane (1: 4)) to trans-4- (2-pyrimidinyloxy) cyclohexylamine (Reference Example 9 in Table 6). -46) 788 mg was obtained.
[414] In addition, the compound of Reference Example 9-47 in Table 6 was obtained in the same manner as above using the corresponding starting compound.
[415] <Reference Example 9-48>
[416] In the same manner as in Reference Example 9-1, trans-1-tert-butoxycarbonylamino-4- (3-nitro-2-pyridyloxy) cyclohexane was obtained. Then, a 30 ml suspension of 3.35 g of this compound of ethanol was stirred at 50 ° C., and 155 mg of palladium-carbon (dry) and 1.6 ml of hydrazine monohydrate were added. The reaction mixture was stirred for 10 minutes, then 185 mg of remaining palladium-carbon was added and heated to reflux for 40 minutes. After cooling the reaction mixture to room temperature, the insolubles were removed by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized with ethanol-water (1: 1) and the crystals were filtered off to obtain 2.58 g of trans-1-tert-butoxycarbonylamino-4- (3-amino-2-pyridyloxy) cyclohexane. Got it.
[417] Subsequently, hydrochloric acid-dioxane is added to the ethanol solution of this compound, followed by acid treatment to give trans-4- (3-amino-2-pyridyloxy) cyclohexylamine hydrochloride (Reference Example 9-48 in Table 6). Got it.
[418] <Reference Example 9-49>
[419] Trans-4- (5-ethoxycarbonyl-2-methylthio by treating in the same manner as Reference Example 9-1 using trans-4- (tert-butoxycarbonylamino) cyclohexanol and the corresponding starting compound Pyrimidin-4-yloxy) cyclohexylamine hydrochloride was obtained.
[420] The hydrochloride compound was made into an aqueous solution, treated with potassium carbonate and extracted with chloroform to obtain its vitreous body (Reference Example 9-49 in Table 6).
[421] <Reference Examples 9-50 to 9-54>
[422] N-tert-butoxycarbonyl-trans-4- (5-ethoxycarbonyl-2-methylthiopyrimidin-4-yloxy) cyclohexylamine (deprotection in Reference Example 9-49 (hydrochloric acid-di 2.75 g of the compound before oxane treatment) were dissolved in 50 ml of chloroform, 1.73 g of 75% -methchlorochlorobenzoic acid was added, and stirred at room temperature for 30 minutes. Then, 1.14 g of dimethylamine hydrochloride and 2.79 ml of triethylamine were added, and it stirred for further 5 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by stirring. The chloroform layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash chromatography (solvent: hexane-chloroform (50:50 to 100: 0)) to give N-tert-butoxycarbonyl-trans-4- [5-ethoxycarbonyl-2- ( 2.74 g of dimethylamino) pyrimidin-4-yloxy] cyclohexylamine were obtained.
[423] The compound was deprotected by treatment with hydrochloric acid-dioxane and then neutralized with potassium carbonate to be trans-4- [5-ethoxycarbonyl-2- (dimethylamino) pyrimidin-4-yloxy] cyclohexylamine ( Reference Example 9-50 of Table 6 was obtained.
[424] In the same manner as above, the compounds of Reference Examples 9-51 to 9-54 in Table 6 were obtained.
[425] <Reference Examples 9-55 to 9-57>
[426] (1) N-tert-butoxycarbonyl-trans-4- [5-ethoxycarbonyl-2- (dimethylamino) pyrimidin-4-yloxy] cyclohexylamine (desorption in Reference Example 9-50 2.675 g of compound before protective treatment) were dissolved in 15 ml of ethanol, and 3.27 ml of 3 N-sodium hydroxide aqueous solution was added at room temperature, and stirred overnight. After diluting the reaction solution with water, citric acid was added until the liquidity became neutral. The precipitated crystals were filtered off, diluted with water and dried under reduced pressure to yield N-tert-butoxycarbonyl-trans-4- [5-carboxy-2- (dimethylamino) pyrimidin-4-yloxy] cyclohexylamine 2.015 g was obtained.
[427] (2) The compound obtained in the above (1) was used as a raw material, and was reacted with the raw amine compound in the same manner as in Reference Example 11-1. The obtained compound (hydrochloride) was made into an aqueous solution, treated with potassium carbonate, and extracted with chloroform to obtain a vitreous.
[428] Thus, the compounds of Reference Examples 9-55 to 9-57 in Table 6 were obtained.
[429] <Reference Examples 9-58 to 9-64>
[430] (1) 0.494 ml of DMSO was slowly added dropwise at −78 ° C. under argon gas atmosphere to 0.5 ml of oxalyl chloride 10 ml of methylene chloride. After 15 minutes from the end of the dropwise addition, 30 ml of a methylene chloride suspension of trans-4-tert-butoxycarbonylaminocyclohexanol was added dropwise, and after 30 minutes, 2.52 ml of triethylamine was added, and at -78 ° C for 30 minutes, It stirred at 0 degreeC for 15 minutes. Heavy water was added to the reaction mixture, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was suspended in a hexane-isopropyl ether mixed solvent and filtered to obtain 0.903 g of 4- (tert-butoxycarbonylamino) cyclohexanone. .
[431] (2) 313 ml of 1.0 M diisobutylaluminum hydride toluene solution was added dropwise at -78 ° C to 350 ml of 33.05 g of toluene of the compound obtained in the above (1), followed by stirring at room temperature for 4 hours. Excess reagent was added dropwise to decompose 33 ml of methanol, and 100 ml of water was added thereto, stirred for 1 hour, and the precipitated insolubles were filtered off. The organic layer of the filtrate was separated and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was suspended in a chloroform-isopropylether mixed solvent under heating, and the insolubles were filtered off. After the filtrate was concentrated, the same operation was performed with isopropyl ether. The obtained filtrate was concentrated and the residue was purified by silica gel flash column chromatography (solvent: ethyl acetate (1: 2-1: 1)), and the resultant colorless crystals were heat-suspended in a hexane-isopropyl ether mixed solvent. . Filtration at 0 ° C yielded 6.95 g of cis-4-tert-butoxycarbonylaminocyclohexanol.
[432] (3) Using the cis-4-tert-butoxycarbonylaminocyclohexanol and the corresponding starting compound obtained above, in the same manner as in Reference Example 9-1, Reference Examples 9-58 to 9-64 of Table 6 were used. The compound was obtained.
[433] <Reference Example 10-1>
[434] (1) A mixture of 9.13 g of 4-tert-butoxycarbonylamino-4-methylcyclohexanone, 3.05 g of sodium borohydride and 100 ml of isopropyl alcohol was stirred at room temperature for 1 hour. The reaction solution was diluted with saturated aqueous ammonium chloride solution under ice-cooling, and extracted with ethyl acetate. The obtained extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to give t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol and c. 9.20 g of a mixture of -4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol were obtained.
[435] (2) A mixture of 9.20 g of the compound obtained in (1), 8.26 g of p-methoxybenzoic acid chloride, 5.93 g of dimethylaminopyridine and 100 ml of methylene chloride was heated to reflux for 20 hours. After cooling, the reaction solution was washed with saturated aqueous sodium bicarbonate solution, 10% aqueous citric acid solution, water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was crystallized from n-hexane and c-4-tert-butoxycarbonylamino-4-methyl-O- (4-methoxyphenylcarbonyl) -r-1-cyclohexanol (cis compound) 0.68 g was obtained.
[436] The residue was further purified by silica gel column chromatography [solvent: ethyl acetate / n-hexane (1/10)] to give the compound (cis compound) and t-4-tert-butoxycarbonylamino-4-methyl. 3.50 g of a mixture (1: 5) of -O- (4-methoxyphenylcarbonyl) -r-1-cyclohexanol (trans compound) was obtained.
[437] (3) A mixture of 10.68 g of the cis compound obtained in (2), 6.10 g of sodium hydroxide, 150 ml of methanol, and 120 ml of water was heated at an external temperature of 75 ° C. for 1 hour. After cooling the reaction solution, the solvent was distilled off under reduced pressure and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to thereby c-4-tert-butoxycarbonylamino-4-methyl-r-1-. 6.61 g of cyclohexanol were obtained.
[438] (4) t-4-tert-butoxycarbonylamino-4-methyl by using 3.50 g of the mixture (1: 5) of the cis body and the trans body obtained in the above (2) as in (3) above. 1.77 g of -r-1-cyclohexanol was obtained.
[439] <Reference Examples 10-2 to 10-8>
[440] In the same manner as in Reference Example 9-1 using t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol (Reference Example 10-1 (4)) and a corresponding starting compound The compounds of Reference Examples 10-2 to 10-3 of Table 6 were obtained. In addition, c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol (Reference Example 10-1 (3)) was used, and in the same manner, Reference Example 10-4 in Table 6 To 10-8 were obtained.
[441] <Reference Examples 11-1 to 11-38 and 12-1 to 12-96>
[442] 500 mg of trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid and 250 mg of N-methyl-benzylamine, 434 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, A mixture of 306 mg of 1-hydroxybenzotriazole and 5 ml of N, N-dimethylformamide was stirred at room temperature for 15 hours. An aqueous sodium hydrogencarbonate solution was added to the reaction solution to make it alkaline, and then extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 691 mg of N-benzyl-trans-4-tert-butoxycarbonylamino-N-methylcyclohexanecarboxamide. Got. A mixture of 670 mg of this compound and 5 ml of 4N hydrochloric acid-dioxane and 5 ml of dioxane was stirred at room temperature for 12 hours. The reaction solution was concentrated to give 585 mg of trans-4-amino-N-benzyl-N-methylcyclohexanecarboxamide hydrochloride (Reference Example 11-1 in Table 7).
[443] In addition, the corresponding raw material amine compounds (cyclic amine compounds such as chain amine compounds or piperidine compounds, piperazine compounds, etc.) were used in the same manner as described above, and the reference examples 11-2 in Tables 7 and 8 below. To 11-38 and 12-1 to 12-96. (However, the free compound can be obtained by saturating an aqueous solution of a hydrochloride compound with potassium carbonate, extracting with chloroform, drying the extract with sodium sulfate, and distilling off the solvent under reduced pressure.)
[444] (A raw material amine compound (piperidine compound, piperazine compound, etc.) is synthesized by the following Reference Examples 15-1 to 15-11 or a known method or a combination thereof.)
[445] <Reference Example 12-97>
[446] (1) 4.5 g of trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid, 2.29 g of thiomorpholine, 3.90 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1 A mixture of 2.74 g of hydroxybenzotriazole and 30 ml of N, N-dimethylformamide was stirred at room temperature for 4 hours.
[447] An aqueous sodium hydrogencarbonate solution was added to the reaction solution to make it alkaline, and then extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was suspended in diisopropyl ether, and the precipitated precipitate was filtered off to obtain N-tert-butoxycarbonyl-trans-4- (4-thiomorpholinylcarbonyl) cyclohexylamine.
[448] (2) 8.9 g of 75% -methchlorochlorobenzoic acid was added to a 50 ml solution of 5.4 g of chloroform obtained in the above (1) under ice-cooling, and stirred at room temperature for 1 hour. An aqueous sodium hydrogencarbonate solution was added to the reaction solution to make it alkaline, and then extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was suspended in diisopropyl ether and the precipitated precipitate was filtered off.
[449] This compound was then suspended in 25 mL of dioxane, 4N hydrochloric acid-dioxane solution (25 ml) was added and stirred at room temperature for 16 hours. Ether was added to the reaction solution, and the precipitated precipitate was filtered and dissolved in water. The mixture was made alkaline by adding potassium carbonate and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was suspended in diisopropyl ether and the precipitate precipitated was filtered to give trans-4- (1,1-dioxo-4-thiomorpholinylcarbonyl) cyclohexylamine (Reference Example 12-97 in Table 8). Got.
[450] <Reference Examples 13-1 to 13-7>
[451] To 50 ml suspension of methylene chloride of 5.07 g of trans-4- (benzyloxycarbonylamino) cyclohexanecarboxylic acid, 4.0 ml of thionyl chloride and 0.3 ml of N, N-dimethylformamide were added and stirred at room temperature for 1 hour. .
[452] 500 mg of the solid obtained by concentrating the reaction liquid under reduced pressure was added to 8 ml solution of 207 mg of 2-cooled 2-aminopyrimidine and 0.4 ml of triethylamine. After stirring at room temperature for 2 hours, water was added to the reaction solution, followed by extraction with chloroform. The residue obtained by concentrating the extract under reduced pressure was purified by silica gel column chromatography (solvent: chloroform-methanol (50: 1)). 240 mg of N-benzyloxycarbonyl-trans-4-[(pyrimidin-2-ylamino) carbonyl] cyclohexylamine was obtained.
[453] This compound was deprotected to obtain trans-4-[(pyrimidin-2-ylamino) carbonyl] cyclohexylamine (Reference Example 13-1 in Table 8).
[454] In addition, the compound of Reference Examples 13-2 to 13-7 of Table 8 was obtained by using the corresponding starting compound instead of 2-aminopyrimidine and treating as described above.
[455] Deprotection was performed as follows using hydrobromic acetic acid. That is, the compound was stirred for 4 hours at 50 ° C. in 3 ml of a 30% hydrobromic acetic acid solution. 30 ml of diisopropyl ether was added to the reaction solution, and the precipitate was filtered off to obtain hydrobromide of the deprotected compound. This hydrobromide solution was used as an aqueous solution, saturated with potassium carbonate, and extracted with chloroform to obtain a vitreous.
[456] However, deprotection of the compound of Reference Example 13-2 was performed as follows using palladium carbon. In other words, a 10% palladium carbon catalyst and ammonium formate were added to the methanol-tetrahydrofuran suspension of the compound to be heated to reflux. Insolubles were filtered off and the filtrate was concentrated under reduced pressure.
[457] <Reference Examples 13-8 to 13-16>
[458] Under argon atmosphere, a mixture of 1.0 g of trans-4- (benzyloxycarbonylamino) cyclohexanecarboxylic acid chloride, 1.92 g of tributylphenyl tin, 61 mg of dichlorobis (triphenylphosphine) palladium and 10 mL of dioxane was charged. It stirred by heating at 12 degreeC. After cooling, the reaction solution was concentrated with a centrifugal concentrator, and the residue was dissolved in tetrahydrofuran and concentrated to dryness with 5 g of silica gel. The obtained residue was purified by silica gel flash column chromatography (solvent: ethyl acetate-hexane (1: 2) to (1: 1)) to obtain 883 mg of N-benzyloxycarbonyl-trans-4-benzoylcyclohexylamine. .
[459] 870 mg of this compound was stirred for 2 hours at room temperature with 1.0 g of trimethylsilyl iodide and 5 ml of chloroform under argon atmosphere. Disappearance of the raw material was confirmed by TLC, 0.17 ml of methanol and 5 ml of diethyl ether were added to the reaction solution, and the mixture was stirred at room temperature for 3 days. The precipitate obtained was filtered off, washed with anhydrous diethyl ether and dried to give 830 mg of trans-4-benzoylcyclohexylamine (Reference Example 13-8 in Table 8).
[460] In the same manner as the above, the compounds of Reference Examples 13-9 to 13-16 in Table 8 were obtained.
[461] <Reference Example 13-17>
[462] (1) Trans-4-methoxycarbonylcyclohexane-1-carboxylic acid chloride was obtained from 5 g of trans-4-methoxycarbonylcyclohexane-1-carboxylic acid and oxalyl chloride. To this 50 mL solution of methylene chloride, 7.58 g of morpholine was added dropwise under ice cooling, followed by stirring for 2 hours. The reaction solution was poured into 10% aqueous citric acid solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: ethyl acetate-hexane (1: 1)) and ethyl acetate-chloroform (1: 1)) and crystallized from hexane to give trans-1-methoxycarbonyl-4 6.49 g of-(morpholinocarbonyl) cyclohexane were obtained.
[463] (2) To 40 mL (0.024 mol) of a hexane-tetrahydrofuran (3: 5) solution of LDA (lithium diisopropylamide) prepared in use under an argon atmosphere, the compound obtained in (1) at -78 ° C. 10 ml of 2.0 g of tetrahydrofuran solution was dripped, and it heated up to -30 degreeC and stirred over 2 hours. The reaction solution was cooled again to -78 ° C, reacted with 1.46 ml of methyl iodide, and heated up to water temperature, then water was added and extracted with ethyl acetate. The extract was washed sequentially with 10% aqueous citric acid solution, water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: ethyl acetate-hexane (1: 2) to (1: 1)) and 1-methoxycarbonyl-1-methyl-4- (morpholinocarbonyl 1.47 g of isomeric mixtures of cyclohexane were obtained. This mixture was stirred in a mixture of 158 mg sodium hydroxide, 1 ml ethanol and 1 ml water for 12 hours at room temperature. The reaction solution was extracted with diethyl ether, the extract was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from a diethyl ether-hexane mixed solvent to obtain 592 mg of a single isomer of 1-methoxycarbonyl-1-methyl-4- (morpholinocarbonyl) cyclohexane.
[464] (3) 546 mg of the compound (monoisomer) obtained in the above (2) was heated and stirred at 110 ° C. for 2 hours in a mixture of 251 mg of sodium hydroxide, 5 ml of methanol, and 10 mL of water. After cooling, the reaction solution was adjusted to pH 3 with 10% hydrochloric acid, extracted three times with chloroform, the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 479 mg of the obtained compound (carboxylic acid), 550 mg of diphenylphosphonyl azide, and 216 mg of toluene 5 ml of benzyl alcohol were stirred by heating for 12 hours. After cooling, 10% aqueous citric acid solution was added to the reaction solution, the toluene layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (solvent: ethyl acetate-hexane (1: 2) to (1: 1)) to obtain N-benzyloxycarbonyl-1-methyl-4- (morpholinocarbonyl). 387 mg of cyclohexylamine was obtained.
[465] This compound was treated with trimethylsilyl iodide to deprotect it to obtain 1-methyl-4- (morpholinocarbonyl) cyclohexylamine (Reference Example 13-17 in Table 8).
[466] <Reference Examples 13-18 to 13-21>
[467] Trans-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid and piperazine were treated in the same manner as in Reference Example 11-1 to N-tert-butoxycarbonyl-trans-4- (1-pipera Genylcarbonyl) cyclohexylamine was obtained.
[468] Methyl chlorocarbonate was added dropwise to 400 ml of this compound, 260 mg of triethylamine, and 8 ml of methylene chloride under ice-cooling, followed by stirring at room temperature overnight. The reaction solution was washed sequentially with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. 410 mg of N-tert-butoxycarbonyl-trans-4- (4-methoxycarbonyl-1-piperazinylcarbonyl) cyclohexylamine was obtained by suspending the obtained residue in isopropyl ether. Got.
[469] The compound was deprotected under acidic conditions in accordance with a conventional method, and returned to basicity to give trans-4- (4-methoxycarbonyl-1-piperazinylcarbonyl) cyclohexylamine (Reference Example 13- in Table 8). 18).
[470] In addition, the compounds of Reference Examples 13-19 to 13-21 in Table 8 were obtained in the same manner as described above.
[471] Reference Example 13-22
[472] 623 mg of N-tert-butoxyquixycarbonyl-trans-4- (piperazinocarbonyl) cyclohexylamine, 340 mg of 3,4-diethoxy-3-cyclobutene-1,2-dione and 5 ml of ethanol The mixture was stirred for 2.5 days at room temperature. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (solvent: chloroform-methanol (50: 1)) and then triturated with ether.
[473] The compound was deprotected by treatment with hydrochloric acid-dioxane and trans-4- [4- (4-ethoxy-1,2-dioxo-3-cyclobuten-3-yl) piperazinylcarbonyl] cyclo Hexylamine (Reference Example 13-22 in Table 8) was obtained.
[474] <Reference Example 13-23>
[475] (1) A mixture of 1101 mg of N-benzyloxycarbonylpiperazine, 1131 mg of 3,4-dibutoxy-3-cyclobutene-1,2-dione and 5 ml of ethanol was stirred at room temperature for 25 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (19: 1)) to thereby yield 1-benzyloxycarbonyl-4- (4-butoxy-1,2-. 1570 mg of dioxo-3-cyclobuten-3-yl) -piperazine were obtained.
[476] The compound was deprotected by treatment with palladium carbon in a hydrogen atmosphere in the presence of 3 ml of 10% hydrochloric acid and 4- (4-butoxy-1,2-dioxo-3-cyclobuten-3-yl) -piperazine Got.
[477] (2) N-benzyloxycarbonyl-trans-4- by reacting the compound obtained in the above (1) with trans- (4-benzyloxycarbonylamino) cyclohexanecarboxylic acid chloride in methylene chloride in the presence of triethylamine. [4- (4-butoxy-1,2-dioxo-3-cyclobuten-3-yl) piperazinocarbonyl] cyclohexylamine was obtained.
[478] (3) N-benzyloxycarbonyl-trans-4- [4- (4-dimethylamino-1,2-dioxo by reacting the compound obtained in the above (2) with dimethylamine hydrochloride in ethanol in the presence of triethylamine. 3-cyclobuten-3-yl) piperazinylcarbonyl] cyclohexylamine was obtained. The compound was deprotected by treatment with trimethylsilane iodide and trans-4- [4- (4-dimethylamino-1,2-dioxo-3-cyclobuten-3-yl) piperazinylcarbonyl] cyclohexyl An amine (Reference Example 13-23 in Table 8) was obtained.
[479] <Reference Example 13-24>
[480] Triethyl (N-benzyloxycarbonyl-trans-4-[(5-hydroxymethyl-2-isoindolinyl) carbonyl] cyclohexylamine 0.31 g of tetrahydrofuran-methylene chloride in a suspension of 10 ml of triethyl under ice-cooling 0.15 ml of amine and 0.07 ml of methanesulfonyl chloride were added and stirred for 1 hour under ice-cooling. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. 5 ml of dimethylformamide and 0.25 ml of morpholine were added to the residue, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: chloroform-methanol = 100: 1). This compound was treated with palladium carbon in a hydrogen atmosphere to give trans-4-[(5-morpholinomethyl-2-isoindolinyl) carbonyl] cyclohexylamine (Reference Example 13-24 in Table 8).
[481] <Reference Examples 13-25 to 13-29>
[482] (1) 20 g of manganese dioxide was added to a 120 ml solution of 4.0 g of N-benzyloxycarbonyl-trans-4-[(5-hydroxymethyl-isoindolinyl) carbonyl] cyclohexylamine. Stirred for time. Manganese dioxide was filtered off with celite, and the solvent was distilled off under reduced pressure. The residue was suspended in hexane-ethyl acetate and the crystals were filtered off to obtain N-benzyloxycarbonyl-trans-4-[(5-formyl-2-isoindolinyl) carbonyl] cyclohexylamine.
[483] (2) After adding 2.75 g of the compound obtained in the above (1) and 110 ml of ethanol to an aqueous solution of 3.35 g of silver nitrate under ice cooling, an aqueous solution of 2.61 g of potassium hydroxide was added dropwise. The mixture was stirred for 1 hour under ice-cooling, separated by filtration through celite, and the solvent was distilled off under reduced pressure. 50 ml of 1 N hydrochloric acid was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was suspended in hexane-ether and the crystals were filtered to give N-benzyloxycarbonyl-trans-4-[(5-carboxy-2isoindolinyl) carbonyl] cyclohexylamine.
[484] (3) Condensation with a raw amine compound in the same manner as in Reference Example 11-1 using the compound obtained in the above (2), followed by treatment with palladium carbon in a hydrogen atmosphere to provide trans-4-[(5-dimethylaminocarba). Bonyl-2-isoindolinyl) carbonyl] cyclohexylamine (Reference Example 13-25 in Table 8) was obtained.
[485] In the same manner, the compounds of Reference Examples 13-26 to 13-29 in Table 8 were obtained.
[486] <Reference Examples 13-30 to 13-33>
[487] (1) N-benzyloxycarbonyl-trans-4-[(5-formyl-2-isoindolinyl) carbonyl] cyclohexylamine (compound obtained in (1) of Reference Example 13-25) 3.0 g To a suspension of 25 ml of acetonitrile, 2.6 g of tert-butylcarbamate, 3.5 ml of triethylsilane, and 1.15 ml of trifluoroacetic acid were added and stirred at room temperature overnight. Water was added to the reaction mixture and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was suspended in hexane-ethyl acetate and the crystals were filtered off to obtain N-benzyloxycarbonyl-trans-4-[(5-tert-butoxycarbonylaminomethyl-2-isoindolinyl) carbonyl] cyclohexyl An amine was obtained.
[488] (2) trans-4-[(5-tert-butoxycarbonylaminomethyl-2-isoindolinyl) carbonyl] cyclohexylamine by treating the compound obtained in (1) with palladium carbon in a hydrogen atmosphere. Reference Example 13-30) in Table 8 was obtained.
[489] (3) N-benzyloxycarbonyl-trans-4-[(5-aminomethyl-2-isoindolinyl) carbonyl] cyclohexyl by treating the compound obtained in (1) with 4N hydrochloric acid-dioxane An amine hydrochloride was obtained.
[490] (4) 0.25 ml of cyclopropanecarbonyl chloride was added to 5 ml of methylene chloride-pyridine 5 g of the compound (hydrochloride) obtained in said (3), and it stirred at room temperature for 4 hours. Dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: chloroform-methanol = 50: 1) to obtain a crystal. This compound was treated with palladium carbon in a hydrogen atmosphere to thereby convert trans-4-[(5-cyclopropylcarbonylaminomethyl-2-isoindolinyl) carbonyl] cyclohexylamine (Reference Example 13-31 in Table 8). Got it.
[491] In addition, the compounds of Reference Examples 13-32 to 13-33 in Table 8 were obtained in the same manner.
[492] <Reference Example 13-34>
[493] (1) 0.3 g of N-benzyloxycarbonyl-trans-4-[(5-formyl-1-isoindolinyl) carbonyl] cyclohexylamine (compound obtained in (1) of Reference Example 13-25) 0.08 g of hydroxylamine hydrochloride and 0.09 g of sodium formate were added to a solution of 3 ml of formic acid, and the mixture was heated to reflux for 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel chromatography (solvent: chloroform-ethyl acetate = 50: 1) to treat the compound obtained with iodide trimethylsilane to give trans-4-[(5-cyano-2-isoindolinyl) carbine. Bonyl] Cyclohexylamine hydroiodic acid salt (Reference Example 13-34 of Table 8) was obtained.
[494] <Reference Examples 13-35 to 13-46>
[495] (1) 6.08 g of N-benzyloxycarbonyl-trans-4-[(6-nitro-1-indolinyl) carbonyl] cyclohexylamine (compound before deprotection obtained by the same method as Reference Example 13-1) 17.33 g of stannous chloride was added to a suspension of brine ethanol (120 ml of ethanol + 1.2 ml of water), and the mixture was heated to reflux for 4.5 hours under argon atmosphere. An aqueous 10% sodium hydroxide solution was added to the reaction solution to pH 9-10, diluted with 300 ml of chloroform, dried over anhydrous magnesium sulfate, and the insolubles were filtered out. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (2: 1)) to obtain N-benzyloxycarbonyl-trans-4-[(6-amino-1- 4.72 g of indolinyl) carbonyl] cyclohexylamine was obtained.
[496] (2) 0.12 ml of pyridine and 0.104 ml of acetic anhydride were added to a 10 ml solution of 396 mg of methylene chloride of the compound obtained in (1) above at room temperature, and stirred for 5 hours. 5% hydrochloric acid was added to the reaction solution, followed by extraction with chloroform. The extract layer was washed sequentially with water and saturated sodium bicarbonate water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (1: 1)).
[497] This compound was treated with palladium carbon and deprotected to obtain trans-4-[(6-acetylamino-1-indolinyl) carbonyl] cyclohexylamine (Reference Example 13-35 in Table 8).
[498] In the same manner, the compounds of Reference Examples 13-36 to 13-37 in Table 8 were obtained.
[499] (3) 0.085 ml of methanesulfonyl chloride was added to a 10 ml solution of 400 mg of the compound obtained in the above (1) at room temperature, followed by stirring for 5 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform, washed sequentially with 5% hydrochloric acid, water and saturated sodium bicarbonate water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (2: 1)).
[500] This compound was treated with palladium carbon and deprotected to obtain trans-4-[(6-methylsulfonylamino-1-indolinyl) carbonyl] cyclohexylamine (Reference Example 13-38 in Table 8).
[501] (4) The compound 403 mg obtained in the above (1), 169 mg of N, N-dimethylglycine hydrochloride, 243 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride, 1-hydroxybenzotria A solution of 173 mg of sol and 0.181 ml of triethylamine 15 ml of N, N-dimethylformamide was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with saturated sodium bicarbonate water, water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol (50: 1)).
[502] This compound was treated with palladium carbon and deprotected to obtain trans-4-[[6- (dimethylamino) methylcarbonyl-1-indolynyl] carbonyl} cyclohexylamine (Reference Example 13-39 in Table 8). .
[503] (5) To 10 ml suspension of 402 mg of acetonitrile of the compound obtained in the above (1), 0.8 ml of 37% aqueous formalin solution and 635 mg of sodium triacetoxyborohydride were added at room temperature and stirred for 1.5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (2: 1)).
[504] This compound was treated with palladium carbon and deprotected to obtain trans-4-[(6-dimethylamino-1-indolynyl) carbonyl] cyclohexylamine (Reference Example 13-40 in Table 8).
[505] (6) N-benzyloxycarbonyl-trans-4-[(5-nitro-1-indolinyl) carbonyl] cyclohexylamine (compound obtained by the same method as Reference Example 13-1) using as starting material A compound of Reference Examples 13-41 to 13-46 in Table 8 was obtained in the same manner as in the above (1) to (5).
[506] <Reference Examples 13-47 to 13-52>
[507] N-benzyloxycarbonyl-trans-4-[(5-hydroxy-1-indolinyl) carbonyl] cyclohexylamine (compound obtained by the same method as Reference Example 13-1) 400 mg of N, N-dimethyl 451 mg of potassium carbonate and 238 mg of 2- (dimethylamino) ethylchloride hydrochloride were added to a 5 ml solution of formamide, and the mixture was stirred at 50 ° C for 9 hours. The reaction solution was concentrated under reduced pressure, and the resulting chloroform solution was washed with water, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol (30: 1)).
[508] The compound was heated to reflux for 17 hours by adding 100 mg of 10% palladium carbon catalyst and 920 mg of ammonium formate to 10 ml of methanol 10 ml-tetrahydrofuran suspension. The insolubles were separated by filtration and the filtrate was concentrated under reduced pressure, thereby trans-4-{[5- (2-dimethylaminoethyl) oxy-1-indolinyl] carbonyl} cyclohexylamine (Reference Example 13- in Table 8). 47) 281 mg were obtained.
[509] In addition, the compounds of Reference Examples 13-48 to 13-52 in Table 8 were obtained in the same manner as described above.
[510] <Reference Examples 14-1 to 14-16>
[511] 400 mg of cis-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid, 216 mg of 4-hydroxypiperidine, 244 mg of 1-hydroxybenzotriazole, O-benzotriazol-1-yl A mixture of 686 mg of -N, N, N ', N'-tetramethyluronium hexafluorophosphate, 398 μl of N-methylmorpholine and 11 ml of N, N-dimethylformamide was stirred at room temperature for 14 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with 10% aqueous citric acid solution, water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 5 ml of dioxane, 6 ml of 4N hydrochloric acid-dioxane was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, methanol was added to the residue, and concentrated under reduced pressure. Subsequently, ether was added to the residue and concentrated under reduced pressure to obtain cis-4- (4-hydroxypiperidinocarbonyl) cyclohexylamine hydrochloride (Reference Example 14-1 in Table 8).
[512] In addition, the compound of Reference Examples 14-2 to 14-16 of Table 8 were obtained by treating as described above using the corresponding starting compound. (However, the free compound was obtained by saturating an aqueous solution of a hydrochloride compound with potassium carbonate, extracting with chloroform, drying the extract with anhydrous sodium sulfate, and distilling off the solvent under reduced pressure.)
[513] Reference Example 15-1
[514] Potassium carbonate (742 mg) and butyl iodide (1.09 g) were added to a solution of dimethylformamide (7 ml) of N- (tert-butoxycarbonyl) piperazine (1.0 g), followed by stirring at room temperature for 15 hours. N-tert-butoxycarbonyl-N-butyl piperazine was obtained by making it react. An acid treatment of this with hydrochloric acid gave N-butyl piperazine dihydrochloride.
[515] In the same manner, N-isopropyl piperazine dihydrochloride was obtained.
[516] Reference Example 15-2
[517] To a solution of 4- (tert-butoxycarbonyl) piperidone (1.0 g) in methylene chloride (10 ml) was added dimethylamine hydrochloride (430 mg), and also triethylamine (0.84 ml) and triacetoxybo under ice-cooling. Lohydride (1.17 g) was added, and it stirred for 3 hours at room temperature, and obtained N-tert-butoxycarbonyl-4- dimethylamino piperidine by reaction. An acid treatment of this with hydrochloric acid gave 4- (dimethylamino) piperidine dihydrochloride.
[518] Reference Example 15-3
[519] To a methylene chloride (50 ml) solution of N-formyl piperazine (5.08 g) and cyclohexanecarboxyaldehyde (7.50 g), sodium triacetoxyborohydride (10.51 g) is added under ice cooling, followed by stirring at room temperature for 18 hours. 1-formyl-4-cyclohexylmethylpiperazine was obtained by making it react, and 1- (cyclohexylmethyl) piperazine hydrochloride was obtained by acid-treating this with hydrochloric acid.
[520] Reference Example 15-4
[521] Slowly add 60% sodium hydride (0.232 g) to a tetrahydrofuran (4.5 ml) solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (0.900 g), 2-chloropyrimidine (0.666 g). After 2 hours, dimethyl sulfoxide (1.0 ml) was added, followed by stirring for 1 day at room temperature to give 1-tert-butoxycarbonyl-4- (2-pyrimidinyloxy) piperidine. The acid treatment of this compound with hydrochloric acid yielded 4- (2-pyrimidinyloxy) piperidine hydrochloride.
[522] In the same manner, the following compounds were obtained.
[523] 4- (5-cyano-2-pyridyloxy) piperidine hydrochloride
[524] 4- (5-Bromo-2-pyrimidinyloxy) piperidine hydrochloride
[525] 4- (p-nitrophenoxy) piperidine hydrochloride
[526] Reference Example 15-5
[527] N- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (700 mg), morpholine (319 μL), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (702 mg), a mixture of 1-hydroxybenzotriazole (495 mg) and N, N-dimethylformamide (9 ml) was stirred at room temperature for 16 hours to react the resulting compound with acid treatment with hydrochloric acid to give 4- (morpholi Nocarbonyl) piperidine hydrochloride was obtained.
[528] In addition, the following compounds were obtained in the same manner as above.
[529] 4- (diethylaminocarbonyl) piperidine hydrochloride
[530] 4- (N-methyl-N-benzylaminocarbonyl) piperidine hydrochloride
[531] 4- (p-chlorophenylaminocarbonyl) piperidine hydrochloride
[532] Reference Example 15-6
[533] Of 4-amino-1- (tert-butoxycarbonyl) piperidine (700 mg), benzoic acid (512 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (804 mg) A mixture of 1-hydroxybenzotriazole (567 mg) and N, N-dimethylformamide (10 ml) is obtained by reacting by stirring at room temperature for 16 hours. The compound was acid treated with hydrochloric acid to obtain 4- (benzoylamino) piperidine hydrochloride.
[534] In addition, the following compounds were obtained in the same manner as above.
[535] 4- (2-pyridylcarbonylamino) piperidine hydrochloride
[536] 4- (cyclohexylcarbonylamino) piperidine hydrochloride
[537] Reference Example 15-7
[538] A solution of acetonitrile (7 ml) of N- (tert-butoxycarbonyl) piperazine (700 mg), N-methyl-N-phenylcarbamoylchloride (700 mg) and triethylamine (1.05 ml) was prepared at room temperature. The compound obtained by making it react for 15 hours by stirring in the acid was hydrochloric acid, and 1- (N-methyl-N-phenylaminocarbonyl) piperazine hydrochloride was obtained.
[539] Reference Example 15-8
[540] To methylene chloride (50 ml) solution of N-formyl piperazine (5.08 g) and triethylamine (6.85 ml), methanesulfonyl chloride (3.65 ml) was added under ice-cooling, and stirred at room temperature for 18 hours to react. 1-formyl-4-methanesulfonylpiperazine was obtained. This compound was acid-treated with hydrochloric acid, and 1-methanesulfonyl piperazine hydrochloride was obtained. In addition, 1- (phenylsulfonyl) piperazine hydrochloride was obtained in the same manner using the corresponding starting compound.
[541] Reference Example 15-9
[542] To a 10 ml solution of 0.99 g of 2-tert-butoxycarbonyl-5- (hydroxymethyl) isoindolin, tetrahydrofuran, 0.84 ml of triethylamine and 0.37 ml of methanesulfonyl chloride were added under ice cooling, and under ice cooling. Stirred for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. 20 ml of ethanol and 1.02 ml of diisopropylethylamine were added to the residue, and the mixture was heated to reflux for 30 minutes. The reaction solution was concentrated under reduced pressure, and extracted with ethyl acetate and 5% hydrochloric acid. The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: hexane-ethyl acetate = 4: 1) to obtain an oily substance. This was dissolved in 5 ml of dioxane, 8 ml of 4N hydrochloric acid-dioxane was added and stirred at room temperature. 20 ml of ether was added, and the precipitated precipitate was filtered and washed with ether to obtain 5- (ethoxymethyl) isoindolin hydrochloride.
[543] In addition, the following compounds were obtained in the same manner as above.
[544] 5- (methoxymethyl) isoindoline hydrochloride
[545] 5- (isopropyloxymethyl) isoindoline hydrochloride
[546] Reference Example 15-10
[547] 0.85 ml of triethylamine and 0.35 ml of methyl chlorocarbonate were added to an 8 ml solution of 0.72 g of 5-amino-2-tert-butoxycarbonylisoindolin, and stirred for 5 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: chloroform-ethyl acetate = 2: 1) to obtain an oily substance. This was dissolved in 5 ml of dioxane, 8 ml of 4N hydrochloric acid-dioxane was added and stirred at room temperature. 20 ml of ether was added, and the precipitate which precipitated was filtered and washed with ether to obtain 5- (methoxycarbonylamino) isoindolin hydrochloride.
[548] In addition, the following compounds were obtained in the same manner as above.
[549] 5- (acetylamino) isoindolin-hydrochloride
[550] Reference Example 15-11
[551] 5- (dimethylamino) by reacting 2-tert-butoxycarbonyl-5-aminoisoindolin (compound obtained in the same manner as WO00 / 23428) and dimethylglycine as raw materials, and reacting in the same manner as in Reference Example 11-1. Methylcarbonylamino) isoindolin was obtained.
[552] In Tables 1a to 1d and Tables 2 to 8 below, the chemical structural formulas, physical properties and the like of the compounds of Examples and Reference Examples are shown. ("Me" shows a methyl group in a table. In addition, MS, APCI (m / z) shows a mass spectrometry value (atmospheric pressure chemical ionization mass spectrum.).)
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权利要求:
Claims (32)
[1" claim-type="Currently amended] Aliphatic nitrogen-containing five-membered ring compounds represented by formula (I) or pharmacologically acceptable salts thereof
<Formula I>

In the formula, A represents -CH ₂ -or -S-,
R ¹ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group,
X represents -N (R ³ )-, -O- or -CO-,
R ³ represents a hydrogen atom or a lower alkyl group,
R ² is (1) a cyclic group which may be substituted, wherein the cyclic moiety is
(i) monocyclic, bicyclic or tricyclic hydrocarbon groups or
(ii) a group which is a monocyclic, bicyclic or tricyclic heterocyclic group, or
(2) The amino group which may be substituted is shown.
[2" claim-type="Currently amended] The cyclic group according to claim 1, wherein R ² may have the same or different 1 to 3 substituents selected from Group A substituents of (1) or less, wherein the cyclic moiety is (i) monocyclic, bicyclic or tricyclic hydrocarbon. Or (ii) a group which is a monocyclic, bicyclic or tricyclic heterocyclic group, or
(2) a compound which is an amino group which may have the same or different 1 to 2 substituents selected from the following Group B substituents:
<Group A substituent>
Halogen atom; Cyano group; Nitro group; Oxo group; Hydroxyl group; Carboxyl groups; Oxydyl group; Amino group; Carbamoyl groups; Aminosulfonyl group; Lower alkyl groups; Lower alkoxy group; Lower alkanoyl groups; Lower alkoxycarbonyl group; Lower alkoxy substituted lower alkanoyl groups;
Lower alkoxycarbonyl substituted lower alkoxy groups;
Lower alkoxycarbonyl substituted lower alkoxycarbonyl group;
Lower alkylthio groups;
Lower alkylsulfonyl groups;
Di lower alkylamino substituted lower alkoxy groups;
Di lower alkylaminocarboxy group;
Lower alkyl groups substituted with a group selected from an amino group, a carbamoyl group, a halogen atom, a hydroxy group, a carboxyl group, a lower alkoxy group and a mono or di-substituted amino group;
Mono or di-substituted amino groups;
Mono or di substituted carbamoyl groups;
Substituted or unsubstituted lower cycloalkyl group;
Substituted or unsubstituted lower cycloalkyl-CO-;
A substituted or unsubstituted lower cycloalkyl-lower alkyl group;
Substituted or unsubstituted phenyl group;
Substituted or unsubstituted phenyl-O-;
Substituted or unsubstituted phenyl-CO-;
A substituted or unsubstituted phenyl-lower alkyl group;
A substituted or unsubstituted phenyl-O-lower alkyl group;
Substituted or unsubstituted phenylsulfonyl group;
Substituted or unsubstituted phenyl lower alkoxy group;
Substituted or unsubstituted phenyl lower alkoxycarbonyl group;
Substituted or unsubstituted lower cycloalkenyl group;
Substituted or unsubstituted bicyclic heterocyclic group;
Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group;
Substituted or unsubstituted monocyclic 5-6 membered heterocyclic group -O-;
Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-CO-;
A substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-CO-lower alkyl group; And
Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-lower alkyl group
<Group B substituent>
Lower alkyl groups; Lower alkoxy substituted lower alkyl groups; Lower alkoxycarbonyl substituted lower alkyl group; Hydroxy lower alkyl group; Carboxy lower alkyl groups;
Substituted or unsubstituted lower cycloalkyl group;
A substituted or unsubstituted lower cycloalkyl-lower alkyl group;
Substituted or unsubstituted phenyl group;
A substituted or unsubstituted phenyl-lower alkyl group;
Substituted or unsubstituted bicyclic hydrocarbon group;
Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group;
A substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-lower alkyl group; And
Substituted or unsubstituted bicyclic heterocyclic group-lower alkyl group.
[3" claim-type="Currently amended] 3. The substituent of claim 2, wherein when the "substituent selected from group A substituent" is a mono or di substituted amino lower alkyl group, a mono or di substituted amino group or a mono or di substituted carbamoyl group, the substituent of the substituent Is selected from;
"Substituent selected from group A substituent" is substituted lower cycloalkyl group, substituted lower cycloalkyl-CO-, substituted lower cycloalkyl-lower alkyl group, substituted phenyl group, substituted phenyl-O-, substituted phenyl-CO-, substituted phenyl-lower Alkyl group, substituted phenyl-O-lower alkyl group, substituted phenylsulfonyl group, substituted phenyl lower alkoxy group, substituted phenyl lower alkoxycarbonyl group, substituted lower cycloalkenyl group, substituted bicyclic heterocyclic group, substituted monocyclic 5 to 6 membered heterocyclic group, substituted group Cyclic 5-6 membered heterocyclic group-O-, substituted monocyclic 5-6 membered heterocyclic group-CO-, substituted monocyclic 5-6 membered heterocyclic group-CO- lower alkyl group or substituted monocyclic 5-6 membered heterocyclic group-lower When an alkyl group, the substituent which the said substituent has is selected from a halogen atom, a cyano group, a nitro group, an oxo group, and the following C group substituents;
"Substituent selected from group B substituent" is substituted lower cycloalkyl group, substituted lower cycloalkyl-lower alkyl group, substituted phenyl group, substituted phenyl-lower alkyl group, substituted bicyclic hydrocarbon group, substituted monocyclic 5- to 6-membered heterocyclic group, substituted monocyclic When the 5- to 6-membered heterocyclic group-lower alkyl group or a substituted bicyclic heterocyclic group-lower alkyl group, the substituent having a substituent is selected from the following Group C substituents:
<Group C substituent>
Lower alkyl groups; Hydroxy lower alkyl group; Lower alkanoyl groups; Lower cycloalkylcarbonyl group; Lower alkoxy group; Lower alkoxycarbonyl group; Lower alkylsulfonyl groups; Di lower alkyl substituted carbamoyl groups: di lower alkylamino substituted lower alkanoyl groups;
Substituted or unsubstituted phenyl group;
Substituted or unsubstituted phenyl-O-;
Substituted or unsubstituted phenyl-C0-;
Substituted or unsubstituted phenyl lower alkanoyl group;
Substituted or unsubstituted phenyl lower alkyl group;
Substituted or unsubstituted phenyl lower alkoxy group;
Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group;
Substituted or unsubstituted monocyclic 5-6 membered heterocyclic group -O-;
Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-CO-; And
Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group substituted amino group;
(In the group C substituent, the substituent of the substituted phenyl group portion or the substituted monocyclic 5 to 6 membered heterocyclic group portion is a halogen atom, cyano group, nitro group, oxo group, lower alkyl group, lower alkoxy group, lower alkanoyl group and lower group) Alkoxycarbonyl group).
[4" claim-type="Currently amended] The compound according to any one of claims 1 to 3, wherein R ² is
(1) a group in which the cyclic group moiety is selected from the following (i) to (iv) as a cyclic group which may be substituted
(i) monocyclic hydrocarbon groups having 3 to 7 carbon atoms,
(ii) a bicyclic hydrocarbon group having 9 to 11 carbon atoms,
(iii) a monocyclic heterocyclic group comprising 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and
(iv) a bicyclic heterocyclic group comprising 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, wherein 5 to 7 membered rings are condensed two times; or
(2) A compound which is a substituted amino group.
[5" claim-type="Currently amended] The compound of claim 4, wherein R ² is
(1) A cyclic group which may be substituted, wherein the cyclic group portion is
Phenyl group, cyclohexyl group, cyclopentyl group, cyclobutyl group, cyclopropyl group, indanyl group, indenyl group, naphthyl group, tetrahydronaphthyl, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, oxola Nyl group, thiolanyl group, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, furyl group, oxazolyl group, isoxazolyl group , Oxadiazolyl group, thienyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, pyrazinyl Group, pyridazinyl group, pyranyl group, tetrahydropyridyl group, dihydropyridazinyl group, perhydroazinyl group, perhydrothiazepinyl group, indolinyl group, isoindolinyl group, indolyl group, indazolyl group, Isoindolyl group, benzimidazolyl group, benzothiazolyl , Benzoxazolyl group, benzodioxolanil group, benzothienyl group, benzofuryl group, thienopyridyl group, thiazolopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, quinolyl group, isoquinolyl group, A group selected from a quinoxalinyl group, a quinazolinyl group, a phthalazinyl group, a cinnalinyl group, a chromanyl group, an isochromenyl group, a naphthyridinyl group, and a cyclic group in which some or all of them are saturated; or
(2) A compound which is a substituted amino group.
[6" claim-type="Currently amended] The compound of claim 5, wherein R ² is
(1) A cyclic group which may be substituted, wherein the cyclic group portion is
Phenyl, cyclohexyl, pyrrolidinyl, tetrazolyl, furyl, thienyl, thiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridyl, pyrimidinyl, Pyrazinyl group, pyridazinyl group, perhydroazinyl group, indolinyl group, isoindolinyl group, benzothienyl group, thienopyridyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group, quinolyl group, iso A group selected from the group consisting of a quinolyl group, a quinoxalinyl group, and a cyclic group in which some or all of them are saturated; or
(2) A compound which is a substituted amino group.
[7" claim-type="Currently amended] The compound of claim 6, wherein R ² is
(1) A cyclic group which may be substituted, wherein the cyclic group portion is
Pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, indolinyl group, isoindolinyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group And a group selected from the group consisting of a cyclic group in which some or all of them are saturated; or
(2) A compound which is a substituted amino group.
[8" claim-type="Currently amended] The compound according to any one of claims 1 to 3, wherein R ² is
(1) a cyclic group which may have the same or different 1 to 3 substituents selected from the following A ′ group substituents, wherein the cyclic moiety is
Pyrrolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyridyl group, pyrimidinyl group, indolinyl group, isoindolinyl group, pyrrolopyridyl group, dihydropyrrolopyridyl group And a group selected from the group consisting of a cyclic group in which some or all of them are saturated; or
(2) a compound which is an amino group substituted with the same or different 1-2 substituents selected from the following B 'group substituents:
<A 'group substituent>
Halogen atom, cyano group, nitro group, oxo group, carbamoyl group, lower alkyl group, lower alkoxy group, lower alkanoyl group, lower alkoxycarbonyl group, lower alkoxy substituted lower alkyl group, mono or di substituted amino group, mono or di substituted carbamo diary,
Lower cycloalkyl-CO-,
Substituted or unsubstituted phenyl group,
Substituted or unsubstituted phenyl-lower alkyl group,
Substituted or unsubstituted monocyclic 5 to 6 membered heterocyclic group,
Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group-O-, and
Substituted or unsubstituted monocyclic 5- to 6-membered heterocyclic group -CO-.
<B 'group substituent>
Lower alkyl groups, lower cycloalkyl groups, lower alkoxy substituted lower alkyl groups, pyrimidinyl groups, thiazolyl groups and thiadiazolyl groups.
[9" claim-type="Currently amended] The compound of any one of claims 1 to 8, wherein X is -N (R ³ )-or -O- and is a cyclic group which may be R ² -substituted.
[10" claim-type="Currently amended] The compound of claim 1, wherein X is —CO—, and R ² is of the formula A compound which is (1) a monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic group which may be substituted, or (2) an amino group which may be substituted.
[11" claim-type="Currently amended] The compound of claim 1, wherein X is —CO— or —O— and A is —CH ₂ —.
[12" claim-type="Currently amended] The compound according to any one of claims 1 to 8, wherein X is -CO- or -O-, A is -CH ₂ -and R ¹ is a hydrogen atom.
[13" claim-type="Currently amended] The compound of any one of claims 1 to 8 wherein X is -CO-, A is -CH ₂ -and R ¹ is a hydrogen atom.
[14" claim-type="Currently amended] The compound according to any one of claims 1 to 8, wherein X is -CO-, A is -CH _2- , R ¹ is a hydrogen atom, and R ² is a cyclic group which may be substituted.
[15" claim-type="Currently amended] The compound according to any one of claims 1 to 8, wherein X is -CO-, A is -CH _2- , R ¹ is a hydrogen atom, and R ² is a substituted amino group.
[16" claim-type="Currently amended] The partial structure according to any one of claims 1 to 15, wherein Compound having a.
[17" claim-type="Currently amended] (S) -2-cyano-1- [trans-4- (5-nitro-2-pyridylamino) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (5-cyano-2-pyridyloxy) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (dimethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (5-bromo-2-pyrimidinyloxy) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (5-pyrimidinylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (N-ethyl-N-methoxyethylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (N-ethyl-N-isopropylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (N-methyl-N-butylaminocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4-[(S) -2-methoxymethylpyrrolidin-1-ylcarbonyl] cyclohexylamino] acetylpyrrolidine:
(S) -2-cyano-1- [trans-4- (3-carbamoylpiperidinocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (3-nitro-2-pyridylamino) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (4-acetylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (2-isoindolinylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- [4- (3-pyridylcarbonyl) piperazin-1-ylcarbonyl] cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- {trans-4- [4- (3-tennoyl) piperazin-1-ylcarbonyl] cyclohexylamino} acetylpyrrolidine;
(S) -2-cyano-1- {trans-4- [4- (4-chlorophenyl) piperazin-1-ylcarbonyl] cyclohexylamino} acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (cis-2,6-dimethylmorpholinocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (5-nitro-2-isoindolinylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (piperidinocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (4-carbamoylpiperidinocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (1-pyrrolidinylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (4-cyclopropylcarbonylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (4-propionylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (1-indolinylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (2,3-dihydro-1H-pyrrolo [3,4-b] pyridin-2-ylcarbonyl) cyclohexylamino] acetylpyrroli Dean;
(S) -2-cyano-1- [trans-4- [4- (2-pyrimidinyloxy) piperidinocarbonyl] cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- {trans-4- [4- (5-bromo-2-pyrimidinyloxy) piperidinocarbonyl] cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (cis-3,5-dimethyl-4-benzylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (4-cyclohexylcarbonylaminopiperidinocarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- {trans-4- [4- (N-phenylcarbamoyl) piperazin-1-ylcarbonyl] cyclohexylamino} acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (4-ethoxycarbonylpiperazin-1-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(S) -2-cyano-1- {trans-4- [4- (2-thienyl) piperidinocarbonyl] cyclohexylamino} acetylpyrrolidine;
(S) -2-cyano-1- [trans-4- (1,1-dioxoperhydro-1,4-thiazin-4-ylcarbonyl) cyclohexylamino] acetylpyrrolidine;
(R) -4-cyano-3- [trans-4- (5-nitro-2-pyridylamino) cyclohexylamino] acetylthiazolidine;
(R) -4-cyano-3- [trans-4- (5-cyano-2-pyridyloxy) cyclohexylamino] acetylthiazolidine;
(R) -4-cyano-3- [trans-4- (dimethylaminocarbonyl) cyclohexylamino] acetylthiazolidine;
(R) -4-cyano-3- [trans-4- (2-isoindolinylcarbonyl) cyclohexylamino] acetylthiazolidine;
(R) -4-cyano-3- [trans-4- (morpholinocarbonyl) cyclohexylamino] acetylthiazolidine; And
(R) -4-cyano-3- [trans-4- (pyrrolidinylcarbonyl) cyclohexylamino] acetylthiazolidine A compound selected from the group consisting of pharmacologically acceptable salts thereof.
[18" claim-type="Currently amended] The aliphatic nitrogen-containing five-membered ring compound represented by the formula (I), or a compound thereof, characterized by reacting a compound represented by the formula (II) with a compound represented by the formula (III) or a salt thereof and making the product a pharmacologically acceptable salt according to the purpose. Preparation of Pharmacologically Acceptable Salts.
<Formula II>

In the formula, A represents -CH ₂ -or -S-, and Z ¹ represents a reactive moiety.
<Formula III>

In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group,
X represents -N (R ³ )-, -O- or -CO-,
R ³ represents a hydrogen atom or a lower alkyl group,
R ² is (1) a cyclic group which may be substituted, wherein the cyclic moiety is
(i) monocyclic, bicyclic or tricyclic hydrocarbon groups or
(ii) a group which is a monocyclic, bicyclic or tricyclic heterocyclic group, or
(2) The amino group which may be substituted is shown.
<Formula I>

In formula, R <^1> , R <^2> and A have the same meaning as the above.
[19" claim-type="Currently amended] The compound represented by the formula (IV) or a salt thereof is reacted with a compound represented by the formula (V) or a salt thereof to obtain a compound represented by the formula (VI) or a salt thereof, and then the amino group protecting group R ⁴ is removed to thereby pharmacologically remove the product according to the purpose. A method for producing an aliphatic nitrogen-containing five-membered ring compound represented by the formula (Ia) or a pharmacologically acceptable salt thereof, characterized by an acceptable salt thereof.
<Formula IV>

In the formula, A represents -CH ₂ -or -S-,
R ¹ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R ⁴ represents a protecting group of an amino group.
<Formula V>
R ²¹ -H
Wherein R ²¹ is (1) Monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic group which may be substituted, or (2) The amino group which may be substituted is represented.
<Formula VI>

In formula, R <^1> , R <^4> , R <^21> and A have the same meaning as the above,
<Formula I-a>

In formula, R <^1> , R <^21> and A have the same meaning as the above,
[20" claim-type="Currently amended] A method of inhibiting dipeptidyl peptidase IV activity using the compound of any one of claims 1 to 17.
[21" claim-type="Currently amended] A method of treating or preventing a disease comprising administering to a patient an effective amount of a compound according to any one of claims 1 to 17.
[22" claim-type="Currently amended] The method of claim 21, wherein the disease is a disease in which the condition is expected to be improved by inhibition of dipeptidylpeptidase IV activity.
[23" claim-type="Currently amended] The method of claim 21, wherein the disease is diabetes.
[24" claim-type="Currently amended] The method of claim 21, wherein the disease is type 2 diabetes.
[25" claim-type="Currently amended] Use of the compound according to any one of claims 1 to 17 as a dipeptidyl peptidase IV inhibitor.
[26" claim-type="Currently amended] Use of the compound according to any one of claims 1 to 17 as a pharmaceutically active ingredient.
[27" claim-type="Currently amended] Use of the compound according to any one of claims 1 to 17 for the manufacture of a medicament.
[28" claim-type="Currently amended] Use according to claim 26 or 27, wherein the medicament is a medicament for the treatment or prophylaxis of diseases in which the condition is expected to be improved by inhibiting dipeptidyl peptidase IV activity.
[29" claim-type="Currently amended] Use according to claim 26 or 27, wherein the medicament is a medicament for the treatment or prevention of diabetes.
[30" claim-type="Currently amended] Use according to claim 26 or 27, wherein the medicament is a medicament for the treatment or prevention of type 2 diabetes.
[31" claim-type="Currently amended] A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 as an active ingredient.
[32" claim-type="Currently amended] The pharmaceutical composition according to claim 31, which is a dipeptidyl peptidase IV inhibitor.

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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:
2000-10-06|Priority to JPJP-P-2000-00308528

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2000-10-06|Priority to JP2000308528

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2000-10-12|Priority to JP2000312562

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2000-10-12|Priority to JPJP-P-2000-00312562

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2001-03-30|Priority to JP2001099251

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2001-03-30|Priority to JPJP-P-2001-00099251

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2001-10-05|Application filed by 다나베 세이야꾸 가부시키가이샤

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2001-10-05|Priority to PCT/JP2001/008803

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2003-05-23|Publication of KR20030041149A

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2005-11-08|Application granted

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2005-11-08|Publication of KR100526091B1

优先权:

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申请号 | 申请日 | 专利标题

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JPJP-P-2000-00308528|2000-10-06|

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JP2000308528|2000-10-06|

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JP2000312562|2000-10-12|

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JPJP-P-2000-00312562|2000-10-12|

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JP2001099251|2001-03-30|

---

JPJP-P-2001-00099251|2001-03-30|

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PCT/JP2001/008803|WO2002030891A1|2000-10-06|2001-10-05|Aliphatic nitrogenous five-membered ring compounds|