Thiazolidine derivative and medicinal use thereof

专利摘要:
The present invention can be provided as a prophylactic or therapeutic agent for diabetes, or a prophylactic or therapeutic agent for diabetes, since the thiazolidine derivatives of the general formula (I) and pharmaceutically acceptable salts thereof exhibit potent DPP-IV inhibitory activity. Formula I In the above formula, X is a substituent selected from the following formula (I-a) or (I-b), Y represents methylene, sulfur atom and the like, Z represents hydrogen atom or cyano. Formula I-a Formula I-b M represents an integer of 1 or 2, n represents an integer from 1 to 5, X 'represents a hydrogen atom, etc., Y' represents an aryl substituted amino group, a heterocycle, etc., and A represents a carbon atom or nitrogen An atom is represented, Q represents an aryl etc.
公开号:KR20040033048A
申请号:KR10-2004-7003689
申请日:2002-09-13
公开日:2004-04-17
发明作者:히로시 사카시타；도모히로 요시다；히로시 기타지마；마사히로 다케우치；요시히토 다나카；다쿠야 요시무라；후미히코 아카호시；요시하루 하야시
申请人:미츠비시 웰파마 가부시키가이샤；
IPC主号:

专利说明:

Thiazolidine derivatives and their pharmaceutical uses {THIAZOLIDINE DERIVATIVE AND MEDICINAL USE THEREOF}
[1] Technical field
[2] The present invention relates to thiazolidine derivatives or salts thereof which exhibit dipeptidyl peptidase IV (DPP-IV) inhibitory action and are useful for the treatment or prevention of diseases involving DPP-IV, in particular diabetes or obesity.
[3] Background technology
[4] DPP-IV is a serine protease that recognizes an amino acid sequence having proline (alanine or hydroxyproline) at the N-terminus and produces dipeptid Xaa-Pro. (Xaa represents any amino acid, Pro represents L-proline). DPP-IV is widely distributed in mammalian tissues and is known to be particularly present in blood, kidneys, intestinal epithelium and placenta.
[5] Although the physiological role of DPP-IV in mammals is not fully elucidated, the degradation of neuropeptides [Heymann et al., FEBS Letters , Vol. 91, pages 360-364 (1978)], activation of T cells [Literature] Schon et al., Biomedica Biochimica Acta , Vol. 44, K9-K15 (1985)], Adhesion of Metastatic Tumor Cells to Endothelial [Johnson et al., Journal of Cell Biology , Vol. 121, 1423-1432 (1993). ), The invasion of lymphocytes into lymphocytes (Callebaut et al., Science , Vol. 262, pp. 2045-2050 (1993)) has been shown to be involved in a wide range of biological functions. Among them, the role of DPP-IV as an enzyme having a strong insulin secretion ability and inactivating the in vivo substance glucagon peptide (GLP-1), which is responsible for post-prandial blood sugar control, has been attracting attention [Deacon et al., Journal of Clinical Endocrinology and Metabolism , Vol. 80, pp. 952-957 (1995)].
[6] GLP-1 is known to metabolize in vivo within minutes. Among others, metabolism by DPP-IV is important, and GLP-1 is rapidly cleaved to produce inactive GLP-1 [Deacon et al., American Journal of Physiology , Vol. 271, E458-E464 (1996). ]. In addition, it is thought that the physiological action of GLP-1 is further attenuated because this inactive GLP-1 antagonizes the GLP-1 receptor [Knudsen et al., European Journal of Pharmacology , Vol. 318, 429. -435 pages (1996). Therefore, the method of suppressing the degradation of GLP-1 by DPP-IV inhibition is considered to be the best as an approach to enhancing GLP-1 action. In other words, DPP-IV inhibitors are expected to be an excellent treatment method for correcting postprandial hyperglycemia in patients with insulin-independent diabetes mellitus (type 2 diabetes) without the side effects such as natural hypoglycemia. .
[7] The following is a patent application regarding a DPP-IV inhibitor.
[8] Japanese Patent Laid-Open No. 9-509921 discloses 1- [N-ε- (hydroxysuccinyl) -L-lysyl] pyrrolidine. This L-lysine moiety is limited to acyl substituents.
[9] Japanese Patent Laid-Open No. 9-509921 discloses a (S) -2-cyano-1-L-prolinepyrrolidine derivative. The L-α-amino acids corresponding to the L-proline moieties of the compounds disclosed in this document are characterized by having hydrophobic side chains.
[10] WO 99/61431 also discloses that a compound consisting of a natural amino acid and thiazolidine or pyrrolidine exhibits a DPP-IV inhibitory action.
[11] Although many DPP-IV inhibitors have been reported to date [Augustyns et al., Current Medicinal Chemistry , Vol. 6, pp. 311-327 (1999)], none of the compounds have sufficient inhibitory activity, stability and safety in vivo. Can't be said and can't be satisfied as a medicine. Therefore, there is a demand for the development of a compound having a therapeutic effect by the DPP-IV inhibitory action and satisfying as a medicine.
[12] Disclosure of the Invention
[13] The present inventors earnestly examined for the purpose of the development of a novel DPP-IV inhibitor in view of the above. As a result, the present inventors found that thiazolidine derivatives having a hydrophilic amino group introduced into the side chain and derivatives having a substituent at the γ position of proline have a strong DPP-IV inhibitory effect, thereby further enhancing the stability to complete the present invention. It was.
[14] Accordingly, the present invention relates to the following compounds.
[15] [1] a thiazolidine derivative of formula (I) or a pharmaceutically acceptable salt thereof.
[16]
[17] In the above formula, X is a substituent selected from formula (I-a) or formula (I-b);
[18] Y is methylene, hydroxymethylene, sulfur atom, sulfinyl or sulfonyl;
[19] Z is a hydrogen atom or cyano;
[20] Provided that when X is a substituent of formula (I-a), Z is a hydrogen atom;
[21]
[22]
[23] Where m is an integer of 1 or 2,
[24] n is an integer of 1 to 5,
[25] X 'is an alkyl optionally having a hydrogen atom or substituent (s),
[26] Y ′ is —NR ¹ R ² , wherein R ¹ is aryl optionally having substituent (s) or heteroaryl optionally having substituent (s), R ² is a hydrogen atom, alkyl optionally having substituent (s), substituent Aryl optionally with (s), arylalkyl optionally with substituent (s), heteroaryl optionally with substituent (s) or heteroarylalkyl optionally with substituent (s) or R ¹ and R ² are bonded to each other carbon And a heterocycle having one or more nitrogens, optionally optionally having other hetero atom (s) and substituent (s), wherein the aromatic ring optionally bearing substituent (s) to this heterocycle may be optionally substituted or fused. Can and
[27] Is a single bond or a double bond,
[28] A is a carbon atom or a nitrogen atom,
[29] Wherein i) when A is a carbon atom, A is optionally substituted with a hydroxyl group, carboxy or alkoxycarbonyl, and ii) when A is a nitrogen atom, Is a single bond,
[30] Q is aryl or heteroaryl selected from compounds of formula II to formula XII,
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42] only,
[43] (i) in formula (II), a, b, c and d are one to three nitrogen atom (s), the remainder is carbon atom (s) or both are nitrogen atoms,
[44] R ^1a is alkyl, phenyl, pyridyl, pyrimidinyl, imidazolyl or oxazolyl, wherein these groups are optionally substituted with one or more from alkyl, alkoxy, halogen or cyano,
[45] R ^2a is a hydrogen atom, alkyl or haloalkyl, provided that
[46] (i-1) when b is a nitrogen atom, R ^2a is absent;
[47] (i-2) when c and d are both nitrogen atoms, a and b are both carbon atoms, R ^1a is phenyl and R ^2a is alkyl, then R ^1a comprises one or more of the substituents described above;
[48] (i-3) when a and d are both nitrogen atoms, b and c are both carbon atoms and R ^1a is unsubstituted phenyl, then R ^2a is alkyl or haloalkyl,
[49] (i-4) where a, b, c and d are all nitrogen atoms and R ^1a is phenyl, (1) A in formula (Ib) is a carbon atom, R ^1a has no substituents as defined above, or (2 ) R ^1a is substituted with one or more of alkyl and halogen,
[50] (ii) In formula (III), one of e and f is a nitrogen atom, the other is a carbon atom, or both are carbon atoms, and 0 "to 1 of e and f are nitrogen atoms, and the other is carbon atom (s Is the same as ")",
[51] R ³ and R ⁴ may be the same or different and each is a hydrogen atom, alkyl, phenyl or pyridyl,
[52] (iii) In formula IV, j is a sulfur atom, an oxygen atom or a nitrogen atom, h and i may be the same or different, each being a nitrogen atom or a carbon atom and [0-2 of h and i are Nitrogen atom (s), the remainder being carbon atom (s) ",
[53] R ⁵ and R ⁷ may be the same or different and each is a hydrogen atom, phenyl or pyridyl, provided that when h is a nitrogen atom, R ⁷ is absent;
[54] R ⁶ is a hydrogen atom or an alkyl, provided that when i is a nitrogen atom R ⁶ is absent;
[55] (iv) In formula (V), k, l and n 'may be the same or different and each is a carbon atom or a nitrogen atom, where at least one is a carbon atom and 0 to 2 of ["k, l and n' Dog is nitrogen atom (s), the remainder being carbon atom (s) ",
[56] R ⁸ is hydrogen atom, phenyl, pyridyl or nitro, provided that when R is a nitrogen atom, R ⁸ is absent;
[57] R ^8a is a hydrogen atom or phenyl,
[58] R ⁹ is a hydrogen atom, haloalkyl or cyano,
[59] R ¹⁰ is a hydrogen atom or cyano, provided that when l is a nitrogen atom, R ¹⁰ is absent;
[60] (iv-1) when k and n 'are both nitrogen atoms, (1) A in formula (Ib) is a nitrogen atom, and R ^8a , R ⁹ and R ¹⁰ are all hydrogen atoms, or (2) R ^8a is phenyl R ⁹ is haloalkyl,
[61] (iv-2) when k, l and n 'are all carbon atoms, R ⁸ is phenyl or pyridyl,
[62] (iv-3) when k is a nitrogen atom and l and n 'are both carbon atoms, then (1) R ⁸ is phenyl or nitro or (2) R ⁹ is cyano,
[63] (iv-4) when l is a nitrogen atom, one of k and n 'is a nitrogen atom,
[64] (v) in formula VI, p is a nitrogen atom or a carbon atom,
[65] R ¹¹ is hydrogen atom, phenyl or pyridyl, provided that when p is a nitrogen atom, R ¹¹ is phenyl or pyridyl;
[66] R ¹² is hydrogen or alkyl, provided that when p is a nitrogen atom, R ¹² is absent;
[67] When R ¹³ and R ¹⁴ are both hydrogen atoms or one of them is a hydrogen atom, the other is cyano, alkoxy or halogen,
[68] (vi) in formula VII, one of r and s is a nitrogen atom, the other is a carbon atom,
[69] R ¹⁵ is hydrogen atom, alkyl or phenyl, provided that when r is nitrogen atom R ¹⁵ is absent;
[70] R ¹⁶ is a hydrogen atom or alkyl, provided that when s is a nitrogen atom, R ¹⁶ is absent;
[71] R ¹⁷ is a hydrogen atom, haloalkyl or cyano,
[72] (vii) In formula (VIII), r 'and s' may be the same or different and each is a carbon atom or a nitrogen atom, provided that at least one of them is a nitrogen atom and from 1 to 1 of ["r 'and s' Two are nitrogen atom (s), and the other are carbon atom (s) ",
[73] R ^15a is a hydrogen atom, alkyl or phenyl, provided that when r 'is a nitrogen atom, R ^15a is absent;
[74] R ^16a is a hydrogen atom or alkyl, provided that when r 'and s' are both nitrogen atoms, R ^16a is a hydrogen atom;
[75] R ^17a is a hydrogen atom, haloalkyl or cyano,
[76] (viii) In formula (IX), t is a sulfur atom or an oxygen atom,
[77] u is a carbon atom or a nitrogen atom,
[78] R ¹⁸ and R ¹⁹ are both hydrogen atoms or one of them is a hydrogen atom and the other is cyano, alkoxy or halogen,
[79] (viii-1) when u is a carbon atom, one of R ¹⁸ and R ¹⁹ is cyano, alkoxy or halogen and is the same as "" R ¹⁸ and R ¹⁹ are not simultaneously hydrogen atoms ",
[80] (viii-2) when t is a sulfur atom, A in formula (Ib) is a carbon atom, R ¹⁹ is a hydrogen atom, R ¹⁸ is methoxy or cyano,
[81] (viii-3) when A in formula (Ib) is a nitrogen atom, t is an oxygen atom, R ¹⁹ is a hydrogen atom, u is a carbon atom, R ¹⁸ is alkoxy or halogen,
[82] (viii-4) when A in formula (Ib) is a carbon atom, R ¹⁹ is a hydrogen atom, u is a carbon atom, t is an oxygen atom, R ¹⁸ is halogen,
[83] (ix) In formula (X), v, w, x and y may be the same or different, each being a carbon atom or a nitrogen atom, provided that at least two are carbon atoms and [<v, w, x and Y 0-2 are nitrogen atom (s), the remainder being carbon atom (s) ",
[84] R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ may be the same or different and 1-3 are haloalkyl, methoxy, ethoxy, isopropoxy, trifluorome Oxy, 2,2,2-trifluoroethoxy, hydroxy, cyano or halogen, the remainder is hydrogen atom (s), provided that when v is a nitrogen atom, R ²⁰ is absent and w is In the case of a nitrogen atom, R ²² is not present, when x is a nitrogen atom, R ²³ is not present and when y is a nitrogen atom, R ²⁵ is not present;
[85] (ix-1) when v is a nitrogen atom and w, x and y are all carbon atoms, R ²² is haloalkyl,
[86] (ix-2) when v and w are both nitrogen atoms and x and y are both carbon atoms, R ²¹ is cyano,
[87] (ix-3) when w is a nitrogen atom and v, x and y are all carbon atoms, (1) R ²¹ is a hydrogen atom, R ²⁰ is cyano or (2) R ²¹ is haloalkyl, R ²³ is hydroxy, ethoxy, isopropoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy or (3) R ²¹ is haloalkyl and both R ²³ and R ²⁵ are methoxy (4) R ²¹ is haloalkyl, R ²⁴ is hydroxy, chloro or trifluoromethyl, (5) R ²¹ is haloalkyl, R ²⁵ is hydroxy or trifluoromethoxy, or (6) R ²¹ is haloalkyl, R ²⁶ is methoxy, or (7) R ²¹ is cyano, R ²³ is methoxy,
[88] (x) In formula (XI), R ²⁷ and R ²⁸ may be the same or different and each is haloalkyl or alkoxy.
[89] [2] In the above [1], Y 'in formula (Ia) is -NR ¹ R ² , wherein R ¹ is aryl optionally having substituent (s) or heteroaryl optionally having substituent (s), and R ² is Hydrogen atom, alkyl optionally with substituent (s), aryl optionally with substituent (s), arylalkyl optionally with substituent (s), heteroaryl optionally with substituent (s) or heteroaryl optionally with substituent (s) Alkyl, or R ¹ and R ² may combine with each other to form a heterocycle having one or two nitrogen atom (s) or oxygen atom (s) and optionally having substituent (s), wherein Thiazolidine derivatives or pharmaceutically acceptable salts thereof, wherein the aromatic ring optionally having s) may be optionally substituted or fused.
[90] [3] The thiazolidine derivative or pharmaceutically acceptable salt thereof according to [1] or [2], wherein X in formula (I) is a substituent of formula (I-a), and Z is a hydrogen atom.
[91] [4] The thiazolidine derivative or a pharmaceutically acceptable salt thereof of [1], wherein X of formula (I) is a substituent of formula (I-b).
[92] [5] The thiazolidine derivative or a pharmaceutically acceptable salt thereof of [3], wherein Y 'of formula (I-a) is a substituent selected from formulas (II-a) to (II-d).
[93]
[94]
[95]
[96]
[97] In the above formula, Is a single bond or a double bond, R ² is as defined in claim 1, R ^3a and R ^4a are the same or different and each independently represent a hydrogen atom, an alkyl optionally having substituent (s), a substituent ( Aryl optionally having substituent (s), arylalkyl optionally having substituent (s), heteroaryl optionally having substituent (s), heteroarylalkyl optionally having substituent (s), halogen, haloalkyl, cyano, nitro, -NR ^5a R ^6a , -NHSO ₂ R ^7a , -OR ^8b , -COOR ^9a , -CONHSO ₂ R ^10a , -SO ₂ OR ^11a , -SO ₂ R ^12a or -CONR ^13a R ^14a , wherein R ^5a , R ^6a , R ^7a , R ^8b , R ^9a , R ^10a , R ^11a , R ^12a , R ^13a and R ^14a are the same or different, each independently a hydrogen atom, an alkyl optionally having substituent (s), substituent (s) Optionally has cycloalkyl, optionally substituted with cyclo (alkyl) optionally substituted with cyclo (alkyl), optionally substituted with aryl, optionally substituted substituent (s) Is arylalkyl, heteroaryl optionally having substituent (s), heteroarylalkyl or haloalkyl optionally having substituent (s), R ^5a and R ^6a , and R ^13a and R ^14a are bonded to each other to form carbon and one or more nitrogen And optionally form a heterocycle having other hetero atom (s) and optionally having substituent (s), wherein an aromatic ring optionally bearing substituent (s) may be optionally substituted or fused to such a heterocycle. A ', b', c ', d', e ', f' and g 'are all carbon atoms, or any one or two of them are nitrogen atom (s) and the rest are carbon atoms (S), m 'is 0, 1, 2 or 3, A' is a carbon atom or a nitrogen atom, provided i) when A 'is a carbon atom, A' is a hydroxyl group, carboxy or alkoxycarbonyl And ii) when A 'is a nitrogen atom, Is a single bond.
[98] [6] In the above [5], R ^3a and R ^4a in Formulas II-a, II-b, II-c, and II-d may be the same or different, and each independently a hydrogen atom. , Alkyl optionally with substituent (s), aryl optionally with substituent (s), arylalkyl optionally with substituent (s), heteroaryl optionally with substituent (s), heteroarylalkyl optionally with substituent (s), Halogen, haloalkyl, cyano, nitro, -NR ^5a R ^6a , -NHSO ₂ R ^7a , -OR ^8b , -COOR ^9a , -CONHSO ₂ R ^10a , -SO ₂ OR ^11a , -SO ₂ R ^12a or -CONR ^13a R ^14a , wherein R ^5a , R ^6a , R ^7a , R ^8b , R ^9a , R ^10a , R ^11a , R ^12a , R ^13a and R ^14a are the same or different and each independently represent a hydrogen atom, a substituent Alkyl optionally having (s), cycloalkyl optionally having substituent (s), cycloalkylalkyl optionally having substituent (s), aryl optionally having substituent (s), substituent (s) Arylalkyl having optionally, a heteroaryl having substituent (s) optionally, a heteroaryl-alkyl or halo-alkyl having a substituent (s) optionally to combine with each other R ^5a and R ^6a, and R ^13a and R ^14a 1 or 2 nitrogen Heterocycles optionally having atom (s) or oxygen atom (s) and optionally having substituent (s) may be formed, and aromatic rings optionally having substituent (s) on such heterocycles may be optionally substituted or fused Thiazolidine derivatives or pharmaceutically acceptable salts thereof.
[99] [7] The thiazolidine derivative or pharmaceutically acceptable salt thereof according to [3], wherein Y is a sulfur atom and X 'is a hydrogen atom.
[100] [8] In the above [3], Y is a sulfur atom, X 'is a hydrogen atom, and Y' is phenylamino, 2-pyridylamino or 4- (1-isoquinolyl) optionally having substituent (s). Thiazolidine derivative or pharmaceutically acceptable salt thereof, which is -1-piperazinyl.
[101] [9] A pharmaceutical composition comprising a thiazolidine derivative according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.
[102] [10] A DPP-IV inhibitor comprising a thiazolidine derivative according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof.
[103] [11] A therapeutic agent for a disease involving DPP-IV, wherein the thiazolidine derivative according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof is used as an active ingredient.
[104] [12] The therapeutic agent of [11], wherein the disease involving DPP-IV is diabetes or obesity.
[105] Each symbol used in the present specification is described below.
[106] X ', R ^1a , R ² , R ^2a , R ³ , R ^3a , R ⁴ , R ^4a , R ^5a , R ⁶ , R ^6a , R ^7a , R ^8b , R ^9a , R ^10a , R ^11a , R ¹² Alkyl represented by R ^12a , R ^13a , R ^14a , R ¹⁵ , R ¹⁶ , R ^15a or R ^16a is preferably a straight or branched chain alkyl containing 1 to 8 carbon atom (s) such as methyl, ethyl , Propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and the like. Of these, methyl is preferred.
[107] Alkyl which may be substituted in the group represented by R ^1a , provided that when R ^1a is alkyl, it is not a substituent, may be illustrated as similar to that exemplified above.
[108] Cycloalkyls preferably have 3 to 7 carbon atoms and include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Among these, cyclohexyl is preferable.
[109] Cycloalkylalkyl is a cycloalkyl moiety as described above, wherein the alkyl moiety is preferably a straight or branched cycloalkylalkyl having 1 to 3 carbon atom (s), such as cyclopropylmethyl, 2-cyclobutylethyl, 3 -Cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl and the like. Among these, cyclohexylmethyl is preferable.
[110] Aryl preferably means aryl having 6 to 14 carbon atoms, preferably containing 8 to 10 ring atoms in a phenyl, naphthyl, ortho-fused bicyclic group and at least one ring being an aromatic ring or the like (Eg, indenyl group). Among these, phenyl is preferable.
[111] In the case of arylalkyl, the same as the aryl moiety described above, the alkyl moiety is preferably a straight or branched chain having 1 to 3 carbon atom (s), for example benzyl, benzhydryl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 3- (2-naphthyl) propyl and the like. Among these, benzyl is preferred.
[112] In the case of heteroaryl, for example, it has a 5- or 6-membered ring group having carbon and 1-4 hetero atom (s) (oxygen, sulfur or nitrogen), or having 8 to 10 ring atoms derived therefrom. Ortho-fused bicyclic heteroaryls, especially those derived from fusion to benz derivatives and propenylene, trimethylene or tetramethylene groups, and stable N-oxides thereof and the like. For example, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, 1,3,5-oxadiazolyl, 1 , 2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl (2-, 3-, 4-pyridyl), pyrazinyl, pyrimidinyl , Pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benz Imidazolyl, oxazolopyridyl, imidazopyridazinyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, benzothienyl, chromenyl, isoindolinyl, indolyl, indolinyl, Indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinolinyl, 2,1,3-benzoxadiazolyl, benzoxazinyl and the like. Among these, pyridyl and pyrimidinyl are preferable.
[113] In the case of heteroarylalkyl, the heteroaryl moiety is as described above, and the alkyl moiety is straight or branched chain having 1 to 3 carbon atom (s). Examples thereof include 2-pyrrolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 2- (2-pyridyl) ethyl, 2- (3-pyridyl ) Ethyl, 2- (4-pyridyl) ethyl, 3- (2-pyrrolyl) propyl, 4-imidazolylmethyl and the like. Among these, 2-pyridylmethyl is preferable.
[114] The heterocycle contains carbon and one or more nitrogens and may include other hetero atom (s) (oxygen or sulfur), preferably 1-2 nitrogen atom (s) or oxygen atom (s) , Saturated or unsaturated. This includes not only monocycles, but also spiro rings, preferably 4 to 7 membered ring groups or 10- or 11-membered ring groups as spiro rings. As the heterocyclic ring, for example, azetinyl, pyrrolidinyl, piperidino, piperazinyl, morpholino, 1,4-diazepanyl, 1,2,5,6-tetrahydropyridyl, thiomor Polyno, oxothiomorpholino, dioxothiomorpholino, 3-azaspiro [5,5] undecyl, 1,3,8-triazaspiro [4,5] decyl, and the like. Among these, piperidino and piperazinyl are preferable.
[115] In addition, in the aforementioned heterocycle, an aromatic ring optionally having a substituent may be substituted or fused. Examples of the aromatic ring in the aromatic ring optionally including a substituent include a benzene ring, a pyridine ring and the like, with a benzene ring being preferred. The aromatic ring may have one or more of the following substituents, and the substituent is preferably cyano or trifluoromethyl. Specific examples of the fused ring include indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, phthalimide, indolyl, and the like. have. Among them, indolinyl and 1,2,3,4-tetrahydroquinolyl are preferable.
[116] The alkoxy represented by R ¹³ , R ¹⁴ , R ¹⁸ , R ¹⁹ , R ²⁷ and R ²⁸ may preferably be straight or branched chain containing 1 to 8 carbon atom (s). Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, octyloxy and the like. Of these, methoxy and isopropoxy are preferred.
[117] When A and A 'are carbon atoms, examples of the alkoxycarbonyl capable of substituting carbon atoms include alkoxycarbonyl in which the alkoxy moiety is as described above.
[118] Examples of alkoxy which may be substituted in the group represented by R ^1a are as described above.
[119] Examples of halogen represented by R ^3a , R ^4a , R ¹³ , R ¹⁴ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ include chlorine, bromine, fluorine and Iodine and the like. Among these, chlorine and fluorine are preferable.
[120] Examples of the halogen which may be substituted with the group represented by R ^1a include those described above.
[121] R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8b , R ⁹ , R ^9a , R ^10a , R ^11a , R ^12a , R ^13a , R ^14a , R ¹⁷ , R ^17a , R ²⁰ , Haloalkyl represented by R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ or R ²⁸ is alkyl substituted with one or more halogen (s), wherein halogen and alkyl are as defined above. same. Examples thereof include trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like. Among them, trifluoromethyl and 2,2,2-trifluoroethyl are preferable.
[122] Among the foregoing substituents, alkyl represented by X ', R ² , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8b , R ^9a , R ^10a , R ^11a , R ^12a , R ^13a and R ^14a , Cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and heterocycles may each be substituted with one or more substituent (s) set forth below.
[123] As these substituents, for example, alkyl in halogen (R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8b , R ^9a , R ^10a , R ^11a , R ^12a , R ^13a and R ^14a) Substituents except for halogen), hydroxyl groups, nitro, cyano, trifluoromethyl, alkyl (but not alkyl as substituents of alkyl described above), alkoxy, alkylthio, formyl, acyloxy, Oxo, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl (except for phenyl as a substituent for alkyl, 2-, 3-, 4-pyridyl), 4-piperidinyl, 2- morpholinoethyl, 3-picolyl, _{arylalkyl, -COOR a, -CH 2 COOR a} , -OCH 2 COOR a, -CONR b R c, -CH 2 CQ'NR b R c (Q ' is = O Or = S), -OCH ₂ CONR _b R _c , -COO (CH ₂ ) ₂ NR _e R _f , -SO ₂ T ₁ , -CONR _d SO ₂ T ₁ , -NR _e R _f , -NR _g CHO , -NR _g COT ₂ , -NR _g COOT ₂ , -NR _g CONR _i R _j , -NR _k SO ₂ T ₃ , -SO ₂ NR _l R _m , -SO ₂ NR _n COT ₄ , methylenedioxy, ethylene Oxy and the like, halogen, nitro, cyano, triple Etc. oro methyl, -SO ₂ T ₁ is preferred.
[124] These substituents may further comprise substituent (s). Phenyl, 2-pyridyl and 4-piperidinyl with substituent (s) are, for example, 4-cyanophenyl, 4-chlorophenyl, 4-methoxyphenyl, 5-cyano-2-pyridyl, 1- Ethoxycarbonyl-4-piperidinyl etc. are mentioned.
[125] Here, among the substituents mentioned above, halogen, alkyl and arylalkyl include those mentioned above.
[126] Alkoxy may preferably be straight or branched chain containing from 1 to 8 carbon atom (s). Examples thereof include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, octyloxy and the like. Alkylthio may preferably be straight or branched chain containing from 1 to 8 carbon atom (s). Examples thereof include methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, octylthio and the like. Acyloxy may preferably be straight or branched chain containing 1 to 8 carbon atom (s). Examples thereof include formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy, hexanoyloxy, benzoyloxy and the like.
[127] R _a to R _n represent hydrogen, alkyl (as described above) or arylalkyl (as described above). R _b and R _c , R _e and R _f , R _i and R _j and R _l and R _m of -NR _b R _c , -NR _e R _f , -NR _i R _j and -NR _l R _m Heterocyclic, preferably containing one or two nitrogen atom (s) or oxygen atom (s), comprising carbon and one or more nitrogens, and optionally comprising other hetero atom (s) (oxygen or sulfur) Summons may be formed, wherein the heterocycle is optionally fused to an aromatic ring optionally having substituent (s) (as described above, which may be substituted with substituents mentioned as substituents of the aforementioned heterocycles), and —NR _e R _f is heteroaryl having ═O (eg 2-pyrrolidinone-1-yl, succinimide, oxazolidin-2-one-3-yl, 2-benzoxazolinone-3- Phthalimide, cis-hexahydrophthalimide, and the like). T ₁ -T ₄ represents a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or haloalkyl, which are the aforementioned alkyl, cycloalkyl, cycloalkylalkyl, aryl and aryl It may be substituted with substituents mentioned as substituents of alkyl.
[128] The ^{pyridyls represented by} R ^1a , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ and R ¹¹ include 1-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
[129] ^Examples of pyrimidinyl represented by R ^1a include 1-pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl and 5-pyrimidinyl.
[130] The imidazolyl represented by R ^1a includes 1-imidazolyl, 2-imidazolyl and 4-imidazolyl.
[131] Examples of oxazolyl represented by R ^1a include 2-oxazolyl, 4-oxazolyl and 5-oxazolyl.
[132] In formula (II), "when c and d are both nitrogen atoms, a and b are both carbon atoms, R ^1a is phenyl and R ^2a is alkyl, then R ^1a contains one or more substituents described above. has the same meaning as "If c and d are both nitrogen atoms, a and b are both carbon atoms and R ^2a is alkyl, then R ^1a is not unsubstituted phenyl.
[133] In formula (II), “when a, b, c and d are all nitrogen atoms and R ^1a is phenyl, (1) A in formula (Ib) is a carbon atom, R ^1a has no substituents described above, or (2 ) R ^1a is substituted with at least one of alkyl and halogen "means that when all of a, b, c and d are nitrogen atoms, (1) A in formula (Ib) is a carbon atom, and R ^1a represents Or (2) R ^1a is not phenyl substituted with one or more from alkoxy and cyano, and is not unsubstituted phenyl. ”
[134] In compounds of the present invention, in compounds wherein X is a substituent of formula (Ia) and Z is a hydrogen atom, Y 'is preferably of formula (II-a), (II-b), (II-c) or (II-d) Substituent, and more preferably is phenylamino, 2-pyridylamino or 4- (1-isoquinolyl) -1-piperazinyl optionally having substituent (s). Y is preferably a sulfur atom and X 'is preferably a hydrogen atom.
[135] In compound (I), wherein X is formula (Ib) Due to the absent carbon to which each symbol is as described above, the compound I can exist as diastereomeric mixture or in optically active form. These diastereomeric mixtures can be separated in optically active form, respectively, by known methods.
[136] Compound I may exhibit a polymorph and may exist as one or more tautomers.
[137] Therefore, the present invention includes any stereoisomer, optical isomer, polymorph, tautomer, any mixture of the foregoing, and the like.
[138] As pharmaceutically acceptable salts of compound I, inorganic acid addition salts (e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, salts with phosphoric acid, etc.), organic acid addition salts (e.g. methanesulfonic acid, benzenesulfonic acid, p- Toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, methyl sulfate, etc. ), And salts with amino acids (eg, salts with glutamic acid, aspartic acid).
[139] Thiazolidine derivatives of the present invention can be produced by the following method. In Compound I, wherein X is Formula Ia and Z is a hydrogen atom, the process for preparing the compound wherein R ¹ is aryl or heteroaryl is described in Scheme 1 below.
[140]
[141] In the above scheme, P ¹ and P ² are amino acid-protecting groups [e.g. t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), (9H-fluorine-9-yl) methyloxycarbonyl (Fmoc Or the like) or a solid carrier (eg, Wang resin via a carbonyl group), Hal is halogen (preferably fluorine), and other symbols are as described above.
[142] Step a :
[143] Reacting compound III-a with compound IV-a to produce the amide compound V-a
[144] As a condensing agent for activating the carboxylic acid of compound III-a, for example, dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC) or Hydrochloride thereof, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxyquinoline (EEDQ), carbodiimidazole (CDI), diethylphosphoryl cyanide, benzotriazol-1-yloxytri Spirolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide (DPPA), isobutyl chloroformate, diethylacetyl chloride, trimethylacetyl chloride, and the like, with EDC being preferred. Such condensing agents may be used alone or as additives such as N-hydroxysuccinimide (HONSu), hydroxybenzotriazole (HOBT), 3-hydroxy-4-oxo-3,4-dihydro-1 , 2,3-benzotriazine (HOOBT), 4-dimethylaminopyridine (DMAP) and the like, preferably used in combination with HOBT.
[145] The amount of compound IV-a to be used is generally 90 to 300 mol%, preferably 100 to 150 mol%, based on compound III-a.
[146] The amount of the condensing agent used is generally 100 to 300 mol%, preferably 100 to 200 mol%, based on compound III-a.
[147] The amount of the additive to be used is generally 100 to 200 mol%, preferably 100 to 150 mol%, based on compound III-a.
[148] This reaction is generally carried out in a solvent that is inert to the reaction, and any inert solvent to be used may be used if it is aprotic. Acetonitrile, tetrahydrofuran, dichloromethane, chloroform, N, N-dimethylformamide (DMF) and the like are preferred. This condensation reaction is generally carried out at a temperature of -30 ° C to 80 ° C, preferably -10 ° C to 25 ° C.
[149] Step b :
[150] Deprotection of compound V-a to produce compound VI-a
[151] In this reaction, when protecting group P ² is a Boc group, for example, the deprotection reaction may be a solvent inert to the deprotection reaction, such as acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, methanol, ethanol, dichloro Acids such as hydrogen chloride, trifluoroacetic acid and the like in methane and chloroform can generally be used at -30 ° C to 60 ° C for 10 minutes to 24 hours.
[152] The amount of acid to be used is generally 100 to 3,000 mol%, preferably 100 to 1,000 mol%, based on compound V-a.
[153] When the protecting group P ² is a Cbz group, for example, contact hydrogen in the presence of a catalyst such as palladium in a solvent inert to the deprotection reaction such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, ethyl acetate and the like. Trifluoroacetic acid or in the presence of thioanisole or anisole in a solvent which is subjected to a reduction reaction, or reacted with hydrobromic acid-acetic acid, or in an inert solvent such as dichloromethane, chloroform, etc., if necessary, for example. It can be deprotected by reacting with trifluoromethanesulfonic acid, preferably trifluoromethanesulfonic acid.
[154] The amount of thioanisole or anisole used is generally 100 to 2,000 mol%, preferably 100 to 1,000 mol%, based on compound V-a.
[155] The amount of trifluoroacetic acid or trifluoromethanesulfonic acid to be used is generally 100 to 20,000 mol%, preferably 100 to 10,000 mol%, based on compound V-a.
[156] When the protecting group P ² is a Fmoc group, for example, bases such as ammonia, piperidine, and morpholine in a solvent inert to the deprotection reaction such as N, N-dimethylformamide, tetrahydrofuran, etc., if necessary, Preferably, piperidine can be used to deprotect by usually reacting at 130 ° C to 60 ° C for 5 minutes to 1 hour.
[157] The amount of base used is generally 100 to 2,000 mol%, preferably 100 to 500 mol%, based on compound V-a.
[158] Step c :
[159] Reacting compound VI-a with compound VII-a to produce compound VIII-a
[160] The reaction is carried out with N-methyl-2-pyrrolidone, N, N-dimethylformamide, tetrahydrofuran, etc. in the presence of a base such as triethylamine, diisopropylethylamine, preferably diisopropylethylamine. It is preferably performed at 0 ° C to 80 ° C at a temperature near the boiling point of the solvent in a solvent inert to the solvent.
[161] The amount of compound VII-a to be used is generally 100 to 500 mol%, preferably 100 to 200 mol%, based on compound VI-a.
[162] The amount of base used is generally 100 to 500 mol%, preferably 120 to 300 mol%, based on compound VI-a.
[163] Step d :
[164] Deprotecting compound VIII-a to produce compound I-a1
[165] In this case, it is carried out under the same reaction conditions as in step b.
[166] In the case where the solid carrier P ¹ is a Wang resin via a carbonyl group, additives such as thioanisole, anisole, phenol or ethylenedithiol may be necessary, for example, in a solvent inert to the reaction, such as dichloromethane, if necessary. The solid carrier can be separated by adding to the mixture and reacting with trifluoroacetic acid as a solvent, usually at room temperature for 1 to 24 hours.
[167] In the compound I in which X is a formula I-a and Z is a hydrogen atom, a compound in which the substituent Y 'is a formula II-b or a formula II-d can be produced by the method shown in Scheme 2 below.
[168]
[169] In the above scheme, L represents a leaving group such as halogen, tosylate (OTs), mesylate (OMs), triflate (OTf) and the like, and each other symbol is the same as above.
[170] Step e :
[171] Reacting Compound X-a or Compound X-b with Compound IX-a to produce Compound XI-a or Compound XI-b
[172] The reaction is carried out in the presence of a base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, preferably potassium carbonate, N-methyl-2-pyrrolidone, N, N-dimethylform In a solvent inert to the above reactions such as amide and tetrahydrofuran, the reaction is carried out at a temperature near the boiling point of the solvent, preferably 0 ° C to 80 ° C.
[173] The amount of compound X-a or compound X-b used is generally 100 to 500 mol%, preferably 100 to 200 mol%, based on compound IX-a.
[174] The amount of the base used is generally 100 to 500 mol%, preferably 100 to 300 mol%, based on compound IX-a.
[175] Step f :
[176] Deprotecting Compound XI-a or Compound XI-b to produce Compound I-a2 or Compound I-a3
[177] Perform the same method as in step b.
[178] In addition, the compound I whose X is a chemical formula I-a and Z is a hydrogen atom can also be manufactured by the method shown by Reaction Scheme 3 and Reaction 4.
[179]
[180] In the above scheme, each symbol is the same as above.
[181] Step g :
[182] Reacting compound XII-a with compound XIII to produce compound XIV
[183] The reaction is carried out in the presence of a base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, preferably diisopropylethylamine, N-methyl-2-pyrrolidone, N, N -In a solvent inert to the above reactions, such as dimethylformamide and tetrahydrofuran, at a temperature near the boiling point of the solvent, preferably 0 ° C to 80 ° C.
[184] The amount of compound XIII to be used is generally 100 to 500 mol%, preferably 100 to 200 mol%, based on compound XII-a.
[185] The amount of base used is generally 100 to 500 mol%, preferably 100 to 300 mol%, based on compound XII-a.
[186] Step h :
[187] Deprotecting Compound XIV to Generate Compound I-a1
[188] It is carried out in the same manner as step b.
[189]
[190] In the above scheme, each symbol is the same as above.
[191] Step i :
[192] Oxidizing Compound XV to produce Compound XVI
[193] The reaction is preferably a method using pyridine sulfur trioxide complex and dimethylsulfoxide at room temperature, for example, but other useful methods include, for example, a solution of alkaline potassium permanganate solution; Methods using oxalyl chloride, dimethyl sulfoxide and tertiary amines; Using acetic anhydride and dimethylsulfoxide; Using dichloroacetic acid as a catalyst and using DCC or EDC and dimethyl sulfoxide; A method of using chromium oxide (VI) pyridine complex in dichloromethane; And a method of using an aqueous sodium hypochlorite solution in ethyl acetate or toluene in the presence of sodium bromide using a TEMPO free radical as a catalyst.
[194] Step j :
[195] Reacting compound XVI with compound XIII followed by reduction to produce compound XIV
[196] The reaction is carried out in the presence of reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, preferably sodium triacetoxyborohydride, methanol, ethanol, dichloromethane, 1,2-dichloroethane, chloroform Acidic catalysts such as acetic acid, p-toluenesulfonic acid and boron trifluoride / diethyl ether complex, if necessary, in a solvent inert to the above reactions such as tetrahydrofuran, acetonitrile and 1,4-dioxane, preferably May be performed using acetic acid, and is usually performed at 0 ° C to 100 ° C for 10 minutes to 10 hours.
[197] The amount of compound XIII to be used is usually 100 to 300 mol%, preferably 100 to 200 mol%, based on compound XVI.
[198] The amount of the reducing agent used is usually 100 to 500 mol%, preferably 100 to 300 mol%, based on compound XVI.
[199] Step k :
[200] Deprotecting Compound XIV to Generate Compound I-a1
[201] Follow the same procedure as in step b.
[202] The raw material compound XII-a in Scheme 3 condensates the carboxylic acid compound represented by the formula (XVII) and compound IV-a in the same manner as in step a, as shown in Scheme 5, or halogenated or , Methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride and the like can be synthesized by sulfonylation. Moreover, the compound whose L of the raw material compound XII-a is halogen can also be manufactured by making sodium nitrite or nitrite ester react in presence of the halogenated alkali metal salt corresponding to the compound represented by General formula (IX-a).
[203] The hydroxy body represented by the formula (XV) can be condensed with the corresponding N-protected hydroxyamino acid XVIII and compound IV-a in the same manner as in step a, or N-protected aspartic acid, N-protected glutamic acid, 2-protected aminoadip Dipeptide compound XIX composed of an acid or 2-protected aminopimelic acid and compound IV-a can be prepared by treatment with a reduction reaction using lithium borohydride or the like.
[204]
[205] In the above scheme, R ¹⁵ represents alkyl (same as above) or arylalkyl (same as above), the others are the same as above.
[206] Scheme 6 shows a method for preparing compound I, wherein X is formula I-b.
[207]
[208] In the above scheme, R ³⁵ represents a protecting group of amino acids [eg t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz)], and -OSO ₂ R ³⁷ represents a leaving group [eg tosylate (OTs) , Mesylate (OMs), triflate (OTf)], and Hal represents halogen. Each other symbol is the same as above.
[209] Step f ' :
[210] Sulfonylation of the hydroxyl group of compound XIII-a to produce compound XIV-a
[211] This reaction is carried out in the presence of a base such as pyridine, triethylamine, or the like using di-chloro using sulfonyl chlorides such as p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, preferably methanesulfonyl chloride. In a solvent inert to the reaction, such as methane and 1,2-dichloroethane, the reaction is usually performed at a temperature of -30 to 60 ° C for 10 minutes to 24 hours.
[212] The amount of sulfonyl chloride is generally 100 to 300 mol%, preferably 100 to 200 mol% based on compound XIII-a.
[213] Step g ' :
[214] Azideing Compound XIV-a to Generate Compound XV-a
[215] The reaction is carried out in a solvent such as N, N-dimethylformamide using a metal azide such as sodium azide at a temperature of 0 ° C to 120 ° C for 30 minutes to 24 hours.
[216] The amount of metal azide used is generally 100 to 300 mol%, preferably 100 to 150 mol%, based on compound XIV-a.
[217] Step h ' :
[218] Producing compound XV-a directly from compound XIII-a
[219] The reaction is carried out in the presence of phosphines such as triphenylphosphine or tributylphosphine and azodicarboxylic acid diester, such as azide reagent such as hydrogen azide, DPPA, azide zinc bispyridine complex salt, preferably DPPA. In a solvent inert to the above reactions, such as toluene and tetrahydrofuran, at a reaction temperature of -30 ° C to 100 ° C.
[220] The amount of phosphine used is usually 100 to 300 mol%, preferably 100 to 200 mol% based on compound XIII-a.
[221] The amount of azodicarboxylic acid diester used is usually 100 to 300 mol%, preferably 100 to 200 mol%, based on compound XIII-a.
[222] The amount of azide reagent used is usually 100 to 300 mol%, preferably 100 to 200 mol%, based on compound XIII-a.
[223] Step i ' :
[224] Reducing compound XV-a to produce compound XVI-a
[225] Examples of the reaction include contact hydrogenation in the presence of palladium, platinum, nickel, and the like, reduction with metal hydrides, reduction with triphenylphosphine, thiols, sulfides, diborane, or transition metals, and the like. Preferably, contact hydrogenation using palladium is mentioned.
[226] Step j ' :
[227] Reacting compound XVI-a with compound XVII-a to produce compound XIX-a
[228] The reaction is carried out in the presence of a base such as triethylamine, diisopropylethylamine, preferably diisopropylethylamine, such as N-methyl-2-pyrrolidone, N, N-dimethylformamide, tetrahydrofuran or the like. In a solvent inert to the solvent, the temperature is performed at a temperature near the boiling point of the solvent, preferably from 0 ° C to 80 ° C.
[229] The amount of compound XVII-a to be used is usually 100 to 500 mol%, preferably 100 to 200 mol%, based on compound XVI-a.
[230] The amount of base used is usually 200 to 1000 mol%, preferably 200 to 500 mol%, based on compound XVI-a.
[231] Step k ' :
[232] Reacting compound XVI-a with compound XVIII-a followed by reduction to produce compound XIX-a
[233] This reaction is carried out in the presence of a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, preferably sodium triacetoxy borohydride, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane In an inert solvent such as tetrahydrofuran, acetonitrile, 1,4-dioxane, etc., if necessary, using an acidic catalyst such as acetic acid, p-toluenesulfonic acid, boron trifluoride diethyl ether complex, or the like. You may carry out, and it is normally performed at the temperature of 0 to 100 degreeC for 10 to 20 hours.
[234] The amount of compound XVIII-a to be used is usually 100 to 300 mol%, preferably 100 to 200 mol%, based on compound XVI-a.
[235] The amount of the reducing agent used is usually 200 to 1,000 mol%, preferably 200 to 500 mol%, based on compound XVI-a.
[236] Step m :
[237] Oxidation of compound XIII-a to yield compound XX
[238] The reaction is preferably a method using pyridine sulfur trioxide complex and dimethyl sulfoxide at room temperature, for example, but other useful methods include, for example, a method of using alkaline potassium permanganate solution; Methods using oxalyl chloride, dimethyl sulfoxide and tertiary amines; Using acetic anhydride and dimethylsulfoxide; Using dichloroacetic acid as a catalyst and using DCC or EDC and dimethyl sulfoxide; A method of using a chromium (VI) pyridine complex in dichloromethane; And a method of using an aqueous sodium hypochlorite solution in ethyl acetate or toluene in the presence of sodium bromide using a TEMPO free radical as a catalyst.
[239] Step n :
[240] Reacting Compound XX with Compound XXI followed by reduction to produce Compound XIX-a
[241] This reaction is carried out in the presence of reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, preferably methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, Acid solvents, such as acetic acid, p-toluenesulfonic acid, a boron trifluoride diethyl ether complex, as needed in a solvent inert to the said reaction, such as tetrahydrofuran, acetonitrile, 1, 4- dioxane, Preferably It may be carried out using acetic acid, and is usually carried out for 10 minutes to 20 hours at a temperature of 0 ° C to 100 ° C.
[242] The amount of compound XXI to be used is generally 100 to 300 mol%, preferably 100 to 200 mol%, based on compound XX.
[243] The amount of reducing agent used is generally 100 to 500 mol%, preferably 100 to 300 mol%, based on compound XX.
[244] Compound XXI can be synthesized by known methods.
[245] Step o :
[246] Deprotecting compound XIX-a to produce compound I-b1
[247] In this reaction, when the protecting group R ³⁵ is a Boc group, for example, hydrogen chloride or trifluoroacetic acid in a solvent such as acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, methanol, ethanol, dichloromethane, chloroform, and the like. It can be deprotected by reacting normally at -30 degreeC-60 degreeC for 10 minutes-24 hours using acids, such as these.
[248] The amount of acid used is usually 100 to 3,000 mol%, preferably 100 to 1,000 mol%, based on compound XIX-a.
[249] When the protecting group R ³⁵ is a Cbz group, for example, catalytic hydrogen reduction in the presence of a catalyst such as palladium in a solvent inert to the deprotection reaction such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, ethyl acetate and the like Trifluoroacetic acid or triacetic acid in the presence of thioanisole or anisole in a solvent which is subjected to a reaction, or reacted with hydrobromic acid-acetic acid, or, if necessary, in an inert solvent such as dichloromethane, chloroform, etc. Deprotection may be achieved by reaction with fluoromethanesulfonic acid, preferably trifluoromethanesulfonic acid.
[250] The amount of thioanisole or anisole used is usually 100 to 2,000 mol%, preferably 100 to 1,000 mol%, based on compound XIX-a.
[251] The amount of trifluoroacetic acid or trifluoromethanesulfonic acid used is usually 100 to 20,000 mol%, preferably 100 to 10,000 mol%, based on compound XIX-a.
[252] Scheme 7 shows another method for preparing compound I, wherein X of the present invention is formula I-b.
[253]
[254] In the above reaction formula, R ⁴⁰ represents alkyl such as methyl, ethyl, benzyl and the like, and each other symbol is the same as described above.
[255] Step v is identical to the method for converting compound XIX-a from compound XIII-a in Scheme 6.
[256] Step w :
[257] Deprotecting the ester protected carboxyl group of compound XXXIII to generate compound XXXIV
[258] The reaction may use a conventional deprotection reaction, but for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like, preferably hydrolyzed under alkaline conditions of sodium hydroxide, or when R ⁴⁰ is benzyl, platinum, palladium, or the like. In the presence of, it may be deprotected by carrying out contact hydrogenation or the like in a solvent inert to the reaction, such as methanol and ethanol.
[259] Process x :
[260] Reacting compound XXXV with compound XXXIV to produce compound XIX-a
[261] The reaction can use the condensing agent shown in step a, preferably EDC. Condensing agents alone or in combination with the additives indicated in step a, preferably HOBT, usually in a solvent inert to the reaction, such as acetonitrile, tetrahydrofuran, dichloromethane, chloroform, N, N-dimethylformamide, etc. It is carried out at a temperature of 30 ° C to 80 ° C, preferably at -10 ° C to 25 ° C.
[262] The amount of compound XXXV used is usually 90 to 300 mol%, preferably 100 to 150 mol%, based on compound XXXIV.
[263] The amount of the condensing agent used is usually 100 to 300 mol%, preferably 100 to 200 mol%, based on the compound XXXIV.
[264] The amount of the additive used is usually 100 to 200 mol%, preferably 100 to 150 mol%, based on the compound XXXIV.
[265] In addition, the compound represented by the formula (XIII-a) in Scheme 6, or the compound represented by the formula (XXXII) in Scheme 7 as a raw material Here, each symbol is the same as the above. The manufacturing method of the compound I whose X of the formula Ib in which the member carbon to which the member carbon couple | bonded is represented by S arrangement is represented.
[266] In addition to the foregoing, a compound of the formula (XIII'-a) or a compound of the formula (XXXII ') as a raw material The compound of the following general formula (I'-b1) in which this bonded carbon is represented by an R configuration can also be produced.
[267]
[268]
[269]
[270] In the above formula, each symbol is as defined above.
[271] In addition, when Z represents cyano in each chemical formula, Z of each chemical formula up to each intermediate may be prepared as a carbamoyl group, and dehydrated by a known method to be converted into a cyano group.
[272] This reaction is carried out in an inert solvent such as dichloromethane, pyridine and the like using diphosphorous pentoxide, phosphorus oxychloride-imidazole, trifluoroacetic anhydride, p-toluenesulfonyl chloride-pyridine and the like as a dehydrating agent.
[273] The thiazolidine derivatives of the general formula (I) of the present invention prepared as described above may be collected as any purity by appropriately performing known separation and purification means such as concentration, extraction, chromatography, reprecipitation, recrystallization, and the like. Can be.
[274] In addition, the thiazolidine derivatives of the above formula (I) are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, tri Acid addition salts with organic acids such as fluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid and methyl sulfuric acid can be used. It also exists as solvates such as hydrates.
[275] The compounds represented by the general formula (I) of the present invention or pharmacologically acceptable salts thereof (pharmaceutically acceptable salts) have an excellent inhibitory effect of DPP-IV on mammals (eg, humans, dogs, cats, rats, etc.).
[276] Compound I of the present invention or its pharmacologically acceptable salt (pharmaceutically acceptable salt) is useful as an inhibitor of DPP-IV because it exhibits potent DPP-IV inhibitory activity, as shown by the following experiment, and is thought to be involved in GLP-1. It is useful for the prevention and treatment of various diseases in which DPP-IV is involved, including the prevention and treatment of diseases such as diabetes, obesity and the like. Examples of diseases in which DPP-IV is involved include diabetes and obesity.
[277] In addition, the compound I of the present invention may be administered to the same subject at the same time as other antidiabetic drugs, diabetic complications, antihyperlipidemic agents or hypertensive agents, and at the same time. When the compound of the present invention is used in combination with other agents, the compounding ratio may be appropriately selected depending on the subject to be administered, the age and weight of the subject to be administered, the symptoms, the time of administration, the formulation, the method of administration, the combination, and the like.
[278] When the compound I of the present invention and its pharmacologically acceptable salts (pharmaceutically acceptable salts) are used as the aforementioned medicaments, they are mixed with themselves or with appropriate pharmacologically acceptable carriers, excipients, diluents, etc. It may be administered orally or parenterally in the form of a drug or injection. In the formulation, an effective amount of Compound I or a pharmacologically acceptable salt thereof (pharmaceutically acceptable salt) is combined.
[279] The dosage of the compound I or its pharmacologically acceptable salt (pharmaceutically acceptable salt) also varies depending on the route of administration, the subject disease, the symptoms, the weight or age of the patient, and the compound used, and can be appropriately set according to the purpose of administration. When orally administered to an adult normally, it is preferable to administer 0.01-1,000 mg / kg body weight / day, preferably 0.05-500 mg / kg body weight / day in 1 to several times a day.
[280] Example
[281] The invention will be described in detail with reference to the following Reference Examples and Examples, but should not be considered as limiting.
[282] ¹ H-NMR was measured at 300 MHz unless otherwise noted. Chemical shifts of ¹ H-NMR were measured using tetramethylsilane (TMS) as the internal standard and expressed as relative delta (δ) in parts per million (ppm). For coupling constants, s (single line), d (double line), t (triple line), q (quartet), quint (quintet), m (multiple line), dd (double line of doublets), td ( The triplet of doublet), brs (wide singlet), etc. were used to show the apparent multiplicity in hertz. Thin layer chromatography was performed using silica gel manufactured by Merck, and column chromatography was performed using silica gel manufactured by Fuji Silysia Chemical Limited. Purification by HPLC was performed using Develosil Combi-RP. For drying the organic solution in the extraction, sodium sulfate or anhydrous magnesium sulfate was used unless otherwise specified.
[283] Reference Example 1
[284] Synthesis of 3-[(S) -6-amino-2- (benzyloxycarbonyl) aminohexanoyl] -1,3-thiazolidine
[285] (1) N- (α-benzyloxycarbonyl-N-ε-t-butoxycarbonyl-L-lysine (19 g) was dissolved in dichloromethane (200 mL), thiazolidine (3.91 mL), HOBT monohydrate (11.5 g) and EDC hydrochloride (14.4 g) were added sequentially The mixture was stirred overnight The reaction solution was concentrated under reduced pressure and 10% aqueous citric acid solution was added The mixture was extracted with ethyl acetate. The extraction solution was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried.The solvent was evaporated under reduced pressure to obtain 3-[(S) -6- (t-butoxycarbonyl) amino- 2- (benzyloxycarbonyl) aminohexanoyl] -1,3-thiazolidine was obtained.
[286] (2) Trifluoroacetic acid (100 mL) was added to the above-mentioned compound and the mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, the solution was dried and concentrated under reduced pressure to afford the title compound (17 g).
[287] MS (ESI) m / z: 352 [M−H] ⁺
[288] Reference Example 2
[289] Synthesis of 3-{(S) -2-amino-6-[(9H-fluoren-9-yl) methyloxycarbonyl] aminohexanoyl} -1,3-thiazolidine
[290] (1) N-α-t-butoxycarbonyl-N-ε- (9H-fluoren-9-yl) methyloxycarbonyl-L-lysine (3.7 g) was dissolved in dichloromethane (200 mL) , Thiazolidine (740 μl), HOBT monohydrate (1.8 g) and EDC hydrochloride (2.3 g) were added. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The extract solution was washed successively with 10% aqueous citric acid solution, saturated aqueous solution of sodium bicarbonate and saturated brine, dried and concentrated under reduced pressure to afford 3-{(S) -2- (t-butoxycarbonyl) amino-6- [(9H-Fluoren-9-yl) methyloxycarbonyl] aminohexanoyl} -1,3-thiazolidine was obtained.
[291] (2) Trifluoroacetic acid (10 mL) was added to the above-mentioned compound and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with ethyl acetate. The extract solution was washed successively with saturated brine, dried and concentrated under reduced pressure to afford the title compound (1.68 g).
[292] MS (ESI) m / z: 440 [M−H] ⁺
[293] Reference Example 3
[294] Synthesis of 3-((S) -1-t-butoxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl) -1,3-thiazolidine
[295] (1) Nt-butoxycarbonyl-L-trans-4-hydroxyproline (69.4 g) and thiazolidine (29.4 g) are dissolved in DMF (300 mL), HOBT (50.5 g) and EDC hydrochloride ( 63.3 g) was added continuously. The mixture was stirred at rt for 18 h. The reaction solution was concentrated and saturated brine and saturated aqueous sodium hydrogen carbonate solution were added to the concentrate. The mixture was extracted with ethyl acetate. The extraction solution was dried and the solvent was evaporated under reduced pressure to give 3-((2S, 4R) -1-t-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl) -1, a colorless transparent oil. 3-thiazolidine (56.3 g) was obtained.
[296] (2) The aforementioned compound (55.4 g) and triethylamine (46 mL) were dissolved in dichloromethane (350 mL) and a solution of pyridine sulfur trioxide complex (52.4 g) in dimethyl sulfoxide (150 mL) was added under ice cooling. And the mixture was stirred for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution. The mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (30.3 g) as a white solid.
[297] ¹ H-NMR (CDCl ₃ ) δ 1.47 (9H, s), 2.45-2.57 (1H, m), 2.70-2.93 (1H, m), 2.97-3.22 (2H, m), 3.66-3.78 (0.6H, m), 3.80-4.10 (3H, m), 4.28-4.38 (0.4H, m), 4.45-5.08 (3H, m).
[298] Example 1
[299] Synthesis of 3-[(S) -2-amino-6- (2-nitrophenylamino) hexanoyl] -1,3-thiazolidinetrifluoroacetic acid salt
[300] (1) The title compound (351 mg) of Reference Example 1 was dissolved in DMF (5 mL), and diisopropylethylamine (0.258 mL) and 1-fluoro-2-nitrobenzene (141 mg) were added. The mixture was stirred overnight at 80 ° C. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added to the residue obtained above. After stirring for 10 minutes, the reaction mixture was added to Chem Elut (Valian) and extracted with ethyl acetate for 10 minutes. The eluate was concentrated under reduced pressure and the residue was purified by HPLC to give 3-[(S) -2-benzyloxycarbonylamino-6- (2-nitrophenylamino) hexanoyl] -1,3-thiazolidine ( 140 mg).
[301] (2) The compound (140 mg) described above was dissolved in trifluoroacetic acid (7 mL) and thioanisole (0.35 mL) was added. The mixture was allowed to stand overnight. Trifluoroacetic acid was evaporated and water was added. After washing with diethyl ether, the pH was adjusted to 8 by addition of 5% aqueous ammonia and the mixture was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (55.2 mg) as a yellow solid.
[302] MS (ESI) m / z: 339 [M−H] ⁺
[303] Example 2
[304] Synthesis of 3-[(S) -2-amino-6- (3-nitropyridin-2-ylamino) hexanoyl] -1,3-thiazolidinetrifluoroacetic acid salt
[305] (1) 3-[(S) -2-benzyloxy using the title compound (351 mg) and 2-chloro-3-nitropyridine (158 mg) of Reference Example 1 in the same manner as in Example 1 (1) Carbonylamino-6- (3-nitropyridin-2-ylamino) hexanoyl] -1,3-thiazolidine (284 mg) was obtained.
[306] (2) The title compound (108 mg) was obtained as a yellow solid using the compound (284 mg) described above in the same manner as in Example 1 (2).
[307] MS (ESI) m / z: 340 [M−H] ⁺
[308] Example 3
[309] Synthesis of 3-[(S) -2-amino-6- (2-cyano-3-fluorophenylamino) hexanoyl] -1,3-thiazolidinetrifluoroacetic acid salt
[310] (1) In the same manner as in Example 1 (1), using the title compound (351 mg) and 2,6-difluorobenzonitrile (139 mg) in Reference Example 1, 3-[(S) -2- Benzyloxycarbonylamino-6- (2-cyano-3-fluorophenylamino) hexanoyl] -1,3-thiazolidine (250 mg) was obtained.
[311] (2) The title compound (110 mg) was obtained as a white solid using the compound (250 mg) described above in the same manner as in Example 1 (2).
[312] MS (ESI) m / z: 337 [M−H] ⁺
[313] Example 4
[314] Synthesis of 3-[(S) -2-amino-6- (4-nitrophenylamino) hexanoyl] -1,3-thiazolidine
[315] (1) In the same manner as in Example 1 (1), 3-[(S) -2-benzyloxycarrine using the title compound (351 mg) and 4-fluoronitrobenzene (141 mg) in Reference Example 1 Bonylamino-6- (4-nitrophenylamino) hexanoyl] -1,3-thiazolidine (298 mg) was obtained.
[316] (2) In the same manner as in Example 1 (2), the trifluoroacetic acid aqueous solution of the title compound was obtained using the compound (298 mg) described above. To this was added potassium carbonate and the mixture was extracted with ethyl acetate. The solution was dried and concentrated under reduced pressure to give the title compound (66 mg).
[317] MS (ESI) m / z: 337 [M−H] ⁺
[318] Example 5
[319] Synthesis of 3-[(S) -2-amino-6- (4-cyano-2-nitrophenylamino) hexanoyl] -1,3-thiazolidine
[320] (1) In the same manner as in Example 1 (1), 3-[(S) -2- using the title compound (351 mg) and 4-chloro-3-nitrobenzonitrile (183 mg) in Reference Example 1 Benzyloxycarbonylamino-6- (4-cyano-2-nitrophenylamino) hexanoyl] -1,3-thiazolidine (404 mg) was obtained.
[321] (2) Using the compound (404 mg) described above in the same manner as in Example 1 (2), an aqueous solution of trifluoroacetate salt of the title compound was obtained. To this was added potassium carbonate and the mixture was extracted with ethyl acetate. The solution was dried and concentrated under reduced pressure to give the title compound (124 mg).
[322] MS (ESI) m / z: 364 [M−H] ⁺
[323] Example 6
[324] Synthesis of 3-[(S) -2-amino-6- (5-cyanopyridin-2-ylamino) hexanoyl] -1,3-thiazolidine dihydrochloride
[325] (1) In the same manner as in Example 1 (1), using the title compound (2.00 g) and 2-chloro-5-cyanopyridine (1.38 g) in Reference Example 1, 3-[(S) -2- Benzyloxycarbonylamino-6- (5-cyanopyridin-2-ylamino) hexanoyl] -1,3-thiazolidine (1.65 g) was obtained.
[326] (2) The compound (1.64 g) described above was dissolved in trifluoroacetic acid (15 mL) and thioanisole (2.1 mL) was added. The mixture was stirred overnight. Trifluoroacetic acid was evaporated and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with chloroform. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the resulting oily substance was dissolved in ethyl acetate. Hydrochloric acid / ethyl acetate was added and the precipitated solid was collected by filtration to give the title compound (0.443 g) as a white solid.
[327] MS (ESI) m / z: 319 [M−H] ⁺
[328] Example 7
[329] Synthesis of 3-[(S) -2-amino-6- (4-methanesulfonylphenylamino) hexanoyl] -1,3-thiazolidine
[330] (1) The title compound (1.68 g) of Reference Example 2 was dissolved in dichloromethane (25 mL), and p-nitrophenyl carbonate Wang resin (2.15 g) was added. The mixture was stirred for 3 days. The solvent was removed and the resin was washed successively with DMF once, methanol and dichloromethane three times and three times methanol, and dried under reduced pressure. 20% piperidine / DMF was added to the resulting resin and the mixture was stirred for 5 minutes, then the resulting resin was collected by filtration and this operation was repeated three times. The resin was washed three times with DMF, three times with dichloromethane and three times with methanol and dried under reduced pressure.
[331] (2) N-methylpyrrolidone (7 ml) was added to the resin (700 mg) obtained in the above operation, and 4-fluorophenylmethylsulfone (543 mg) and diisopropylethylamine (0.544 ml) were added. It was. The mixture was stirred overnight at 100 ° C. The resin was collected by filtration, washed three times with DMF, alternating with methanol and dichloromethane three times, and three times with methanol. 50% trifluoroacetic acid / dichloromethane (7 mL) was added to the resulting resin and the mixture was stirred for 2 hours. The resin was removed by filtration and the residue was concentrated under reduced pressure. The residue obtained was purified by HPLC and potassium carbonate was added to the eluent. The mixture was extracted with ethyl acetate, the solution was dried and concentrated under reduced pressure to give the title compound (26.9 mg).
[332] MS (ESI) m / z: 372 [M−H] ⁺
[333] Example 8
[334] Synthesis of 3-[(S) -2-amino-6- (2-cyanophenylamino) hexanoyl] -1,3-thiazolidine
[335] In the same manner as in Example 7 (2), the title compound (3 mg) was obtained using the resin (700 mg) and 2-fluorobenzonitrile (0.277 mL) in Example 7 (1).
[336] MS (ESI) m / z: 319 [M−H] ⁺
[337] Example 9
[338] Synthesis of 3-[(S) -2-amino-6- (4-cyanophenylamino) hexanoyl] -1,3-thiazolidine
[339] In the same manner as in Example 7 (2), the title compound (6.8 mg) was obtained using the resin (700 mg) and 4-fluorobenzonitrile (0.277 mL) in Example 7 (1).
[340] MS (ESI) m / z: 319 [M−H] ⁺
[341] Example 10
[342] Synthesis of 3-[(S) -2-amino-6- (4-bromo-2-cyanophenylamino) hexanoyl] -1,3-thiazolidine
[343] In the same manner as in Example 7 (2), the title compound (24.8 mg) was obtained using the resin (700 mg) and 2-fluoro-5-bromobenzonitrile (480 mg) in Example 7 (1).
[344] MS (ESI) m / z: 397, 399 [M−H] ⁺
[345] Example 11
[346] Synthesis of 3-{(S) -2-amino-6- [4-cyano-2- (trifluoromethyl) phenylamino] hexanoyl} -1,3-thiazolidine
[347] The title compound (18.8 mg) using the resin of Example 7 (1) and 4-fluoro-3- (trifluoromethyl) benzonitrile (453 mg) in the same manner as Example 7 (2) )
[348] MS (ESI) m / z: 387 [M−H] ⁺
[349] Example 12
[350] Synthesis of 3-{(S) -2-amino-6- [3-chloro-5- (trifluoromethyl) pyridin-2-ylamino] hexanoyl} -1,3-thiazolidine
[351] Using the resin of Example 7 (1) and 2,3-dichloro-5- (trifluoromethyl) pyridine (516 mg) in the same manner as Example 7 (2), the title compound (16.1 mg )
[352] MS (ESI) m / z: 397, 399 [M−H] ⁺
[353] Example 13
[354] Synthesis of 3-{(S) -2-amino-6- [4-cyano-3- (trifluoromethyl) phenylamino] hexanoyl} -1,3-thiazolidine
[355] In the same manner as in Example 7 (2), using the resin of Example 7 (1) (700 mg) and 4-fluoro-2- (trifluoromethyl) benzonitrile (453 mg) in the title compound (80.7 mg) )
[356] MS (ESI) m / z: 387 [M−H] ⁺
[357] Example 14
[358] Synthesis of 3-[(S) -2-amino-6- (5-nitropyridin-2-ylamino) hexanoyl] -1,3-thiazolidine
[359] In the same manner as in Example 7 (2), the title compound (20 mg) was obtained using the resin (700 mg) and 5-nitro-2-chloropyridine (379 mg) in Example 7 (1).
[360] MS (ESI) m / z: 340 [M−H] ⁺
[361] Example 15
[362] Synthesis of 3-[(S) -2-amino-6- (2-cyano-4-fluorophenylamino) hexanoyl] -1,3-thiazolidine
[363] In the same manner as in Example 7 (2), the title compound (7.9 mg) was obtained using the resin (700 mg) and 2,5-difluorobenzonitrile (334 mg) in Example 7 (1).
[364] MS (ESI) m / z: 337 [M−H] ⁺
[365] Example 16
[366] Synthesis of 3-[(S) -2-amino-6- (4-cyano-2-fluorophenylamino) hexanoyl] -1,3-thiazolidine
[367] In the same manner as in Example 7 (2), the title compound (24 mg) was obtained using the resin (700 mg) and 3,4-difluorobenzonitrile (334 mg) in Example 7 (1).
[368] MS (ESI) m / z: 337 [M−H] ⁺
[369] Example 17
[370] Synthesis of 3-[(S) -2-amino-6- (3-chloro-2-cyanophenylamino) hexanoyl] -1,3-thiazolidine
[371] In the same manner as in Example 7 (2), the title compound (18.7 mg) was obtained using the resin of Example 7 (1) (700 mg) and 2-chloro-6-fluorobenzonitrile (372 mg).
[372] MS (ESI) m / z: 353, 355 [M−H] ⁺
[373] Example 18
[374] Synthesis of 3-[(S) -2-amino-6- (3-chloro-4-cyanophenylamino) hexanoyl] -1,3-thiazolidine
[375] The title compound (52.7 mg) was obtained using the resin (700 mg) and 2-chloro-4-fluorobenzonitrile (372 mg) in Example 7 (1) in the same manner as in Example 7 (2).
[376] MS (ESI) m / z: 353, 355 [M−H] ⁺
[377] Example 19
[378] Synthesis of 3-[(S) -2-amino-6- (4-chloro-2-cyanophenylamino) hexanoyl] -1,3-thiazolidine
[379] In the same manner as in Example 7 (2), the title compound (77.3 mg) was obtained using the resin (700 mg) and 5-chloro-2-fluorobenzonitrile (372 mg) in Example 7 (1).
[380] MS (ESI) m / z: 353, 355 [M−H] ⁺
[381] Example 20
[382] Synthesis of 3-[(S) -2-amino-6- (2-bromo-4-cyanophenylamino) hexanoyl] -1,3-thiazolidine
[383] In the same manner as in Example 7 (2), the title compound (80.3 mg) was obtained using the resin (700 mg) and 3-bromo-4-fluorobenzonitrile (477 mg) in Example 7 (1).
[384] MS (ESI) m / z: 397, 399 [M−H] ⁺
[385] Example 21
[386] Synthesis of 3-[(S) -2-amino-6- (2-cyano-5-bromophenylamino) hexanoyl] -1,3-thiazolidine
[387] In the same manner as in Example 7 (2), the title compound (54.9 mg) was obtained using the resin (700 mg) and 2-fluoro-4-bromobenzonitrile (477 mg) in Example 7 (1).
[388] MS (ESI) m / z: 397, 399 [M−H] ⁺
[389] Example 22
[390] Synthesis of 3-[(S) -2-amino-6- (2-cyano-4-trifluoromethylphenylamino) hexanoyl] -1,3-thiazolidine
[391] The title compound (73.9 mg) using the resin of Example 7 (1) and 2-fluoro-5- (trifluoromethyl) benzonitrile (454 mg) in the same manner as Example 7 (2) )
[392] MS (ESI) m / z: 397 [M−H] ⁺
[393] Example 23
[394] Synthesis of 3-[(S) -2-amino-6- (5-trifluoromethylpyridin-2-ylamino) hexanoyl] -1,3-thiazolidine
[395] In the same manner as in Example 7 (2), the title compound (10 mg) was obtained using the resin (700 mg) and 2-chloro-5-trifluoromethylpyridine (434 mg) in Example 7 (1).
[396] MS (ESI) m / z: 363 [M−H] ⁺
[397] Example 24
[398] Synthesis of 3-[(S) -2-amino-6- (pyrimidin-2-ylamino) hexanoyl] -1,3-thiazolidine
[399] In the same manner as in Example 7 (2), the title compound (13.2 mg) was obtained using the resin (700 mg) and 2-chloropyrimidine (274 mg) in Example 7 (1).
[400] MS (ESI) m / z: 296 [M−H] ⁺
[401] Example 25
[402] Synthesis of 3-[(S) -2-amino-6- (4-trifluoromethylpyrimidin-2-ylamino) hexanoyl] -1,3-thiazolidine
[403] In the same manner as in Example 7 (2), the title compound (54.6 mg) was obtained using the resin (700 mg) and 2-chloro-4-trifluoromethylpyrimidine (437 mg) in Example 7 (1). .
[404] MS (ESI) m / z: 364 [M−H] ⁺
[405] Example 26
[406] Synthesis of 3-[(S) -2-amino-6- (3-cyanopyridin-2-ylamino) hexanoyl] -1,3-thiazolidine
[407] In the same manner as in Example 7 (2), the title compound (30.8 mg) was obtained using the resin (700 mg) and 2-chloro-3-cyanopyridine (331 mg) in Example 7 (1).
[408] MS (ESI) m / z: 320 [M−H] ⁺
[409] Example 27
[410] Synthesis of 3-[(S) -2-amino-6- (2-cyano-4-nitrophenylamino) hexanoyl] -1,3-thiazolidine
[411] In the same manner as in Example 7 (2), the title compound (59.4 mg) was obtained using the resin (700 mg) and 2-fluoro-5-nitrobenzonitrile (398 mg) in Example 7 (1).
[412] MS (ESI) m / z: 364 [M−H] ⁺
[413] Example 28
[414] 3-{(S) -2-amino-6- [4- (2-trifluoromethyl-4-quinolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine dihydrochloride Synthesis of
[415] (1) N-α-benzyloxycarbonyl-N-ε-t-butoxycarbonyl-L-lysine (8.60 g) was dissolved in formic acid (50 mL) and the mixture was stirred at rt overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetic acid (100 mL) and sodium acetate (1.85 g) and sodium nitrite (4.68 g) were added. The mixture was stirred overnight at 40 ° C. The reaction solution was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with chloroform. The solution was dried and concentrated under reduced pressure to give (S) -6-acetoxy-2- (benzyloxycarbonyl) aminohexanoic acid (3.52 g).
[416] (2) The compound (3.23 g) described above was dissolved in DMF (60 mL) and thiazolidine (0.79 mL), HOBT monohydrate (1.68 g) and EDC hydrochloride (2.1 g) were added sequentially. The mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate. The extraction solution was washed successively with brine, dried and concentrated under reduced pressure to afford 3-[(S) -6-acetoxy-2- (benzyloxycarbonyl) aminohexanoyl] -1,3-thiazolidine ( 1.5 g) was obtained.
[417] (3) The compound (1.5 g) described above was dissolved in methanol (15 mL) and potassium carbonate (0.69 g) was added. The mixture was stirred at rt for 2 h. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the colorless oil 3-[(S) -2- (benzyloxycarbonyl) amino-6-hydroxyhexanoyl] -1,3-thiazolidine (0.64 g) Got.
[418] (4) The compound (590 mg) and triethylamine (0.26 mL) described above were dissolved in dichloromethane (10 mL) and methanesulfonyl chloride (0.14 mL) was added dropwise. The mixture was stirred at rt for 3 h. The reaction solution was washed with water, dried and concentrated under reduced pressure. The residue was dissolved in DMF (10 mL) and 1- (2-trifluoromethyl-4-quinolyl) piperazine (469 mg) and potassium carbonate (461 mg) were added. The mixture was stirred at 80 ° C for 6 h. The reaction solution was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate and the extraction solution was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-{(S) -2-benzyloxycarbonylamino-6- [4- (2-trifluoromethyl-4-quinolyl) piperazin-1-yl ] Hexanoyl} -1,3-thiazolidine (270 mg) was obtained.
[419] (5) The compound (260 mg) described above was dissolved in trifluoroacetic acid (5 mL) and thioanisole (0.5 mL) was added. The mixture was stirred overnight at room temperature. Trifluoroacetic acid was evaporated and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with chloroform. The extract solution was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the oil obtained was dissolved in ethyl acetate. Hydrochloric acid / ethyl acetate was added. The precipitated solid was collected by filtration to give the title compound (22.9 mg) as a white solid.
[420] MS (ESI) m / z: 481 [M−H] ⁺
[421] Example 29
[422] Synthesis of 3-{(2S, 4S) -4- [4- (2-pyrimidinyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidinetrichloride
[423] (1) The title compound (1.50 g) and 2- (1-piperazinyl) pyrimidine (0.903 g) of Reference Example 3 were dissolved in 1,2-dichloroethane (25 mL), acetic acid (0.29 mL) and Triacetoxy sodium borohydride (2.12 g) was added. The mixture was stirred at rt for 16 h. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the white solid 3-{(2S, 4S) -1-t-butoxycarbonyl-4- [4- (2-pyrimidinyl) -1-piperazinyl ] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (2.12 g) was obtained.
[424] (2) The aforementioned compound (2.12 g) was dissolved in 5.6 mol / L hydrochloric acid-ethanol solution (10 mL), and the mixture was stirred at room temperature for 22 hours. The reaction solution was concentrated under reduced pressure to give the title compound (2.05 g) as a white solid.
[425] ¹ H-NMR (DMSO-d ₆ ) δ 2.33 (1H, m), 2.92-4.33 (15H, m), 4.47-4.77 (5H, m), 6.79 (1H, t, J = 4.8 Hz), 8.46 ( 2H, d, J = 4.8 Hz), 9.14 (1H, brs), 11.01 (1H, brs).
[426] Example 30
[427] 3-{(2S, 4S) -4- [4- (4-trifluoromethyl-6-phenyl-2-pyrimidinyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1 Synthesis of 3,3-thiazolidine Dihydrochloride
[428] (1) 4,4,4-trifluoro-1-phenyl-1,3-butanedione (10.8 g) and urea (6.01 g) are dissolved in ethanol (25 mL) and concentrated hydrochloric acid (5 mL) Added. The mixture was heated to reflux for 2.5 hours. The reaction solution was concentrated under reduced pressure and water was added. The mixture was washed with chloroform. A saturated aqueous solution of sodium hydrogen carbonate was added to the aqueous layer, and the precipitate was collected by filtration to give 2-hydroxy-4-phenyl-6-trifluoromethylpyrimidine (5.03 g) as a pale pink crystalline powder.
[429] (2) Phosphorous oxychloride (7.8 ml) was added to the compound (5.03 g) described above, and the mixture was stirred at 100 ° C. for 9 hours. Ice was added to the reaction solution and the solution was made basic by addition of 5 mol / L aqueous sodium hydroxide solution. The precipitate was collected by filtration to give 2-chloro-4-phenyl-6-trifluoromethylpyrimidine (5.71 g) as a white solid.
[430] (3) Piperazine (25.8 g) was melted at 130 ° C. and compound (13.1 g) described above was added. The mixture was stirred for 2 hours. Water was added to the reaction solution and the mixture was extracted with chloroform. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. Hexane was added to the residue, and the precipitate was collected by filtration to give 1- (4-trifluoromethyl-6-phenyl-2-pyrimidinyl) piperazine (2.92 g) as a white solid.
[431] (4) 3-{(2S, 4S) -1-t- which was a white solid using the title compound (0.601 g) of Reference Example 3 and the compound (0.678 g) described above in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (4-trifluoromethyl-6-phenyl-2-pyrimidinyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thia Zolidine (1.18 g) was obtained.
[432] (5) The title compound (1.02 g) as a white powder was obtained using the compound (1.18 g) described above in the same manner as in Example 29 (2).
[433] ¹ H-NMR (DMSO-d ₆ ) δ 2.29 (1H, m), 2.90-4.05 (15H, m), 4.37-4.86 (5H, m), 7.54-7.65 (3H, m), 7.76 (1H, s ), 8.27-8.30 (2H, m), 9.15 (1H, brs), 10.76 (1H, brs).
[434] Example 31
[435] 3-{(2S, 4S) -4- [4- (2-trifluoromethyl-4-pyrimidinyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thia Synthesis of Zolidine Dihydrochloride
[436] (1) Phosphorous oxychloride (15 mL) was added to 2-trifluoromethyl-4-hydroxypyrimidine (2.50 g) and the mixture was stirred at 60 ° C. for 1 hour. The mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure to give 2-trifluoromethyl-4-hydroxypyrimidine (0.600 g) as a brown oil.
[437] (2) Piperazine (845 mg) was dissolved in DMF (6 mL) while heating, and a DMF solution (1 mL) of the compound (597 mg) described above was added at 40 ° C. The mixture was stirred at rt for 2 h. The reaction solution was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with chloroform. The extraction solution was washed with saturated brine, dried and concentrated under reduced pressure to give 1- (2-trifluoromethyl-4-pyrimidinyl) piperazine (680 mg) as a brown solid.
[438] (3) 3-{(2S, 4S) -1-t- which is a pale brown solid, using the title compound (0.832 g) and the compound (0.676 g) described in Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (2-trifluoromethyl-4-pyrimidinyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (1.28 g) was obtained.
[439] (4) The compound (1.27 g) described above was dissolved in ethanol (3 mL) and 4.1 mol / L hydrochloric acid-ethanol solution (3 mL) was added. The mixture was stirred at rt for 13 h. The reaction solution was concentrated under reduced pressure and ethyl acetate was added to the residue. The precipitate was collected by filtration to give the title compound (1.02 g) as a white solid.
[440] ¹ H-NMR (DMSO-d ₆ ) δ 2.15-2.33 (1H, m), 2.90-4.05 (16H, m), 4.45-4.78 (3H, m), 7.24 (1H, d, J = 6.3 Hz), 8.45 (1H, doublet, J = 6.3 Hz), 9.12 (1H, brs), 10.83 (1H, brs), 12.7 (1H, brs).
[441] Example 32
[442] 3-((2S, 4S) -4- {4- [1- (4-methoxyphenyl) -2-imidazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1, Synthesis of 3-thiazolidinetrichloride
[443] (1) 1-benzyloxycarbonylpiperazine (6.35 g) was dissolved in acetone (40 mL) and 4-methoxyphenyl isothiocyanate (5.19 g) was added under ice cooling. The mixture was stirred at rt for 2 days. The reaction solution was concentrated under reduced pressure and the residue was dissolved in dichloromethane (80 mL). Methyl iodide (2.7 mL) was added under ice cooling and the mixture was stirred at rt for 17 h. The reaction solution was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The extraction solution was washed with saturated brine, dried and concentrated under reduced pressure to give 1-benzyloxycarbonyl-4-[(methylthio) (4-methoxyphenyl) iminomethyl] piperazine (12.8 g) as a brown oil. Got.
[444] (2) The compound (12.8 g) and aminoacetaldehyde dimethyl acetal (6.1 mL) described above were dissolved in pyridine (60 mL). The mixture was heated and stirred at 110 ° C. for 25 h. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with chloroform. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. The residue was dissolved in 2 mol / l hydrochloric acid (120 mL) and the mixture was heated at 100 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-benzyloxycarbonyl-4- [1- (4-methoxyphenyl) -2-imidazolyl] piperazine (7.91 g) as a brown oil.
[445] (3) The aforementioned compound (7.91 g) and thioanisole (6 mL) were dissolved in trifluoroacetic acid (60 mL) and the mixture was stirred at rt for 6 h. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with chloroform. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by HPLC to give 1- [1- (4-methoxyphenyl) -2-imidazolyl] piperazine (0.628 g) as a colorless transparent oil.
[446] (4) 3-((2S, 4S) -1-t- which was a white solid using the aforementioned compound (624 mg) and the title compound (601 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- {4- [1- (4-methoxyphenyl) -2-imidazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazoli Dean (416 mg) was obtained.
[447] (5) The compound (411 mg) described above was dissolved in ethyl acetate (1 mL) and 4 mol / L hydrochloric acid-ethyl acetate (1 mL) was added. The mixture was stirred at rt for 18 h. The precipitate was collected by filtration to give the title compound (413 mg) as a white powder.
[448] ¹ H-NMR (DMSO-d ₆ ) δ 2.04-2.20 (1H, m), 2.82-4.00 (16H, m), 4.42-4.75 (3H, m), 7.15 (1H, d, J = 8.9 Hz), 7.42-7.47 (2H, m), 7.59 (1H, doublet, J = 8.9 Hz), 9.04 (1H, brs), 10.88 (1H, brs), 14.1 (1H, brs).
[449] Example 33
[450] 3-{(2S, 4S) -4- [4- (1-phenyl-5-pyrazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine-3 Synthesis of Hydrochloride
[451] (1) Ethyl 3,3-diethoxypropionate (5.34 g) was dissolved in tetrahydrofuran (60 mL) and 1 mol / L aqueous sodium hydroxide solution (29 mL) was added at room temperature. The mixture was stirred for 12 hours. The reaction solution was concentrated under reduced pressure and the residue was suspended in DMF (60 mL). HOBT (5.16 g), EDC hydrochloride (6.46 g) and 1-benzyloxycarbonylpiperazine (6.20 g) were added at room temperature and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The extraction solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the oil 1-benzyloxycarbonyl-4- (3,3-diethoxypropionyl) piperazine (10.0 g).
[452] (2) The aforementioned compound (3.28 g) was dissolved in chloroform (30 mL) and 50% aqueous trifluoroacetic acid solution (20 mL) was added under ice cooling. The mixture was stirred at rt for 24 h. The reaction solution was extracted with chloroform. The extract solution was washed successively with water and saturated brine and dried. The solvent was evaporated under reduced pressure and the residue was dissolved in ethanol (60 mL). Phenylhydrazine (0.886 mL) and methanesulfonic acid (0.060 mL) were added and the mixture was stirred at rt for 3 h. Pyridine (1 mL) was added to the reaction solution and the solvent was evaporated under reduced pressure. The residue was dissolved in pyridine (50 mL) and phosphorus oxychloride (1.68 mL) was added. The mixture was stirred at rt for 18 h. The reaction solution was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The extraction solution was washed with saturated brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give the oil 1-benzyloxycarbonyl-4- (1-phenyl-5-pyrazolyl) piperazine (0.218 g).
[453] (3) The compound (218 mg) described above was dissolved in methanol (10 mL) and 10% palladium on carbon (200 mg) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 1- (1-phenyl-5-pyrazolyl) piperazine (137 mg) as a white powder.
[454] (4) 3-{(2S, 4S) -1-t- which was a white powder using the compound (137 mg) mentioned above and the title compound (180 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (1-phenyl-5-pyrazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (204 mg) was obtained. .
[455] (5) The compound (204 mg) described above was dissolved in methanol (10 mL) and 4 mol / L hydrochloric acid / ethyl acetate (3 mL) was added at room temperature. The mixture was stirred for 64 hours. The reaction solution was concentrated under reduced pressure and the residue was dissolved in methanol. Ethyl acetate was added and the precipitate was collected by filtration to give the title compound (170 mg) as a white solid.
[456] ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 2.10-2.30 (1H, m), 2.80-4.10 (16H, m), 4.46-4.74 (3H, m), 6.10 (1H, d, J = 1.7 I), 7.34-7.37 (1H, m), 7.49-7.52 (2H, m), 7.56 (1H, d, J = 1.7 kPa), 7.79-7.81 (2H, m), 9.07 (1H, brs), 10.65 (1H, brs).
[457] Example 34
[458] 3-((2S, 4S) -4- {4- [1- (4-fluorophenyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3 -Synthesis of Thiazolidine Trichloride
[459] (1) The product of Example 33 (1) (5.70 g) and 4-fluorophenylhydrazine (1.05 g), an oil, 1-benzyloxycarbonyl-4- [1, in the same manner as in Example 33 (2) -(4-fluorophenyl) -5-pyrazolyl] piperazine (0.075 g) was obtained.
[460] (2) 1- [1- (4-fluorophenyl) -5 which is a white powder using the aforementioned compound (62 mg) and 10% palladium / carbon (10 mg) in the same manner as in Example 33 (3). -Pyrazolyl] piperazine (40 mg) was obtained.
[461] (3) 3-((2S, 4S) -1-t- which is a white powder using the compound (40 mg) described above and the title compound (48 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- {4- [1- (4-fluorophenyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine (76 mg) was obtained.
[462] (4) The title compound (56 mg) was obtained as a white solid using the compound (76 mg) described above in the same manner as in Example 33 (5).
[463] ¹ H-NMR (DMSO-d ₆ ) δ 2.00-2.33 (1H, m), 2.80-4.10 (16H, m), 4.45-4.74 (3H, m), 6.11 (1H, d, J = 1.8 Hz), 7.29-7.36 (2H, m), 7.56 (1H, doublet, J = 1.8 mm 3), 7.78-7.85 (2H, m), 9.04 (1H, brs), 10.51 (1H, brs).
[464] Example 35
[465] 3-((2S, 4S) -4- {4- [1- (4-fluorophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) Synthesis of -1,3-thiazolidinetrichloride
[466] (1) 1-t-butoxycarbonylpiperazine (103 g) was dissolved in DMF (600 mL) and diketene (56 mL) was added at room temperature over 20 minutes. The mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. The mixture was washed with water and saturated brine and dried. The solvent was evaporated under reduced pressure to give 1-acetoacetyl-4-t-butoxycarbonyl piperazine (129 g) as a light brown powder.
[467] (2) The compound (3.92 g) described above was dissolved in ethanol (200 mL), and 4-fluorophenylhydrazine hydrochloride (2.36 g) and molecular sieve 3A (10 g) were added at room temperature. The mixture was stirred for 4 hours. Molecular sieves were removed by filtration and pyridine (4 mL) was added to the filtrate. The solvent was evaporated under reduced pressure. The residue was dissolved in pyridine (200 mL) and phosphorus oxychloride (3.0 mL) was added at room temperature. The mixture was stirred for 18 hours. The reaction solution was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the brown oil 1-t-butoxycarbonyl-4- [1- (4-fluorophenyl) -3-methyl-5-pyrazolyl] piperazine (2.03 g) Got.
[468] (3) The compound (2.03 g) described above was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (4 mL) was added at room temperature. The mixture was stirred for 18 hours. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with ethyl acetate, the solution was dried and concentrated under reduced pressure to give 1- [1- (4-fluorophenyl) -3-methyl-5-pyrazolyl] piperazine (1.42 g) as a brown oil. .
[469] (4) 3-((2S, 4S) -1-t- which is a white powder using the compound (1.42 g) described above and the title compound (1.36 g) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- {4- [1- (4-fluorophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3 -Thiazolidine (1.85 g) was obtained.
[470] (5) The aforementioned compound (1.85 g) was dissolved in methanol (10 mL) and chloroform (5 mL) and 4 mol / L hydrochloric acid-ethyl acetate solution (5 mL) was added. The mixture was stirred for 18 hours. The reaction solution was concentrated under reduced pressure to give the title compound (1.37 g) as a white solid.
[471] ¹ H-NMR (DMSO-d ₆ ) δ 2.17 (3H, s), 2.20-2.40 (1H, m), 2.90-4.35 (16H, m), 4.43-4.82 (3H, m), 5.95 (1H, s ), 7.21-7.37 (2H, m), 7.74-7.89 (2H, m), 9.13 (1H, brs), 11.10 (1H, brs).
[472] Example 36
[473] 3-((2S, 4S) -4- {4- [1- (2-fluorophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) Synthesis of -1,3-thiazolidinetrichloride
[474] (1) The product of Example 35 (1) (1.92 g) was dissolved in ethanol (50 mL) and 2-fluorophenylhydrazine hydrochloride (1.16 g) was added at room temperature. The mixture was stirred for 4 hours. Pyridine (1 mL) was added to the reaction solution and the solvent was evaporated under reduced pressure. The residue was dissolved in pyridine (30 mL) and phosphorus oxychloride (1.33 mL) was added at room temperature. The mixture was stirred for 19 hours. The solution was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The extraction solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the oil 1-t-butoxycarbonyl-4- [1- (2-fluorophenyl) -3-methyl-5-pyrazolyl] piperazine (0.640 g). Got it.
[475] (2) The compound (640 mg) described above was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added at room temperature. The mixture was stirred for 3 hours. The solvent was evaporated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with chloroform. The extract solution was dried, concentrated under reduced pressure, and an oil, 1- [1- (2-fluorophenyl) -3-methyl-5-pyrazolyl] piperazine (430 mg) was obtained.
[476] (3) 3-((2S, 4S) -1-t- which is a pale yellow powder using the compound (430 mg) described above and the title compound (472 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- {4- [1- (2-fluorophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3 -Thiazolidine (778 mg) was obtained.
[477] (4) The compound (778 mg) described above was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added at room temperature. The mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (20 mL). To this solution was added 4 mol / l hydrochloric acid / ethyl acetate (1.5 mL) and the precipitate was collected by filtration to give the title compound (608 mg) as a white solid.
[478] ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 2.03-2.25 (1H, m), 2.16 (3H, s), 2.72-4.00 (16H, m), 4.45-4.71 (3H, m), 5.91 ( 1H, s), 7.32-7.35 (1H, m), 7.40-7.44 (1H, m), 7.51-7.57 (2H, m), 9.02 (1H, brs), 10.41 (1H, brs).
[479] Example 37
[480] 3-((2S, 4S) -4- {4- [1- (3-fluorophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) Synthesis of -1,3-thiazolidinetrichloride
[481] (1) Yellow solid 1-t-butoxycar using the product of Example 35 (1) and 3-fluorophenylhydrazine hydrochloride (3.22 g) in the same manner as in Example 36 (1) Bonyl-4- [1- (3-fluorophenyl) -3-methyl-5-pyrazolyl] piperazine (1.55 g) was obtained.
[482] (2) 1- [1- (3-fluorophenyl) -3-methyl-5-pyrazolyl] piperazine which is an oil using the compound (1.55 g) described above in the same manner as in Example 36 (2) ( 1.12 g) was obtained.
[483] (3) 3-((2S, 4S) -1-t- which is a white powder using the compound (1.12 g) described above and the title compound (1.17 g) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- {4- [1- (3-fluorophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3 -Thiazolidine (1.97 g) was obtained.
[484] (4) The title compound (1.60 g) was obtained as a white solid using the compound (1.97 g) described above in the same manner as in Example 36 (4).
[485] ¹ H-NMR (DMSO-d ₆ ) δ 2.10-2.35 (1H, m), 2.17 (3H, s), 2.90-4.15 (16H, m), 4.46-4.76 (3H, m), 5.98 (1H, s ), 7.11-7.19 (1H, m), 7.47-7.55 (1H, m), 7.59-7.64 (1H, m), 7.70-7.73 (1H, m), 9.09 (1H, brs), 10.79 (1H, brs ).
[486] Example 38
[487] 3-((2S, 4S) -4- {4- [1- (4-chlorophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl)- Synthesis of 1,3-thiazolidinetrichloride
[488] (1) A brown solid, 1-t-butoxycarbonyl, using the compound of Example 35 (1) (5.0 g) and 4-chlorophenylhydrazine hydrochloride (3.5 g) in the same manner as in Example 35 (2) 4- [1- (4-chlorophenyl) -3-methyl-5-pyrazolyl] piperazine (2.2 g) was obtained.
[489] (2) 1- [1- (4-chlorophenyl) -3-methyl-5-pyrazolyl] piperazine which is a brown oil using the aforementioned compound (2.2 g) in the same manner as in Example 36 (2) 1.7 g) was obtained.
[490] (3) 3-((2S, 4S) -1-t- which is a white solid using the compound (1.7 g) described above and the title compound (1.5 g) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- {4- [1- (4-chlorophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3- Thiazolidine (2.8 g) was obtained.
[491] (4) The compound (2.8 g) described above was dissolved in ethyl acetate (20 mL) and 4 mol / L hydrochloric acid-ethyl acetate (40 mL) was added at room temperature. The mixture was stirred for 3 hours. The precipitate was collected by filtration to give the title compound (2.2 g) as a white powder.
[492] ¹ H-NMR (DMSO-d ₆ ) δ 2.17 (3H, s), 2.25-2.40 (1H, m), 2.95-4.15 (17H, m), 4.46-4.77 (3H, m), 5.97 (1H, s ), 7.48-7.53 (2H, m), 9.13 (1H, brs), 11.01 (1H, brs).
[493] Example 39
[494] 3-((2S, 4S) -4- {4- [1- (4-cyanophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) Synthesis of -1,3-thiazolidinedihydrochloride
[495] (1) In the same manner as in Example 35 (2), using the product of Example 35 (1) (5.0 g) and 4-cyanophenylhydrazine hydrochloride (3.3 g), 1-t-butoxycar as a pale yellow solid Bonyl-4- [1- (4-cyanophenyl) -3-methyl-5-pyrazolyl] piperazine (2.7 g) was obtained.
[496] (2) 1- [1- (4-cyanophenyl) -3-methyl-5-pyrazolyl] piperazin as a pale yellow solid using the compound (2.7 g) described above in the same manner as in Example 36 (2) (2.1 g) was obtained.
[497] (3) 3-((2S, 4S) -1-t- which is a white solid using the compound (2.1 g) described above and the title compound (1.8 g) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- {4- [1- (4-cyanophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3 -Thiazolidine (3.2 g) was obtained.
[498] (4) The title compound (2.3 g) was obtained as a white powder using the compound (3.2 g) described above in the same manner as in Example 38 (4).
[499] ¹ H-NMR (DMSO-d ₆ ) δ 2.19 (3H, s), 2.20-2.40 (1H, m), 2.95-4.15 (17H, m), 4.46-4.77 (3H, m), 6.05 (1H, s ), 7.91 (2H, d, J = 9.0 μs), 8.08 (2H, d, J = 9.0 μs), 9.13 (1H, brs), 10.09 (1H, brs).
[500] Example 40
[501] 3-((2S, 4S) -4- {4- [3-methyl-1- (2-pyridyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl)- Synthesis of 1,3-thiazolidine dihydrochloride
[502] (1) The product of Example 35 (1) (3.92 g) was dissolved in ethanol (200 mL), 2-hydrazinopyridine (1.58 g), methanesulfonic acid (0.094 mL) and molecular sieve 3A (10 g) Was added at room temperature. The mixture was stirred for 18 hours. The molecular sieve was filtered off and pyridine (4 mL) was added to the filtrate. The solvent was evaporated under reduced pressure. The residue was dissolved in pyridine (200 mL) and phosphorus oxychloride (3.0 mL) was added at room temperature. The mixture was stirred for 18 hours. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-t-butoxycarbonyl-4- [3-methyl-1- (2-pyridyl) -5-pyrazolyl] piperazine (230 mg).
[503] (2) The compound (230 mg) described above was dissolved in dichloroethane (10 mL), and trifluoroacetic acid (2 mL) was added at room temperature. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with chloroform. The solution was dried and concentrated under reduced pressure to give 1- [3-methyl-1- (2-pyridyl) -5-pyrazolyl] piperazine (180 mg).
[504] (3) 3-((2S, 4S) -1-t- which is a pale yellow oil using the compound (180 mg) described above and the title compound (222 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- {4- [3-methyl-1- (2-pyridyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3- Thiazolidine (284 mg) was obtained.
[505] (4) The compound (284 mg) described above was dissolved in methanol (4 mL) and chloroform (2 mL), and 4 mol / L hydrochloric acid-ethyl acetate solution (6 mL) was added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to give the title compound (176 mg) as a white solid.
[506] ¹ H-NMR (DMSO-d ₆ ) δ 2.19 (3H, s), 2.24-2.44 (1H, m), 2.88-4.20 (16H, m), 4.42-4.80 (3H, m), 5.99 (1H, s ), 7.30-7.40 (1H, m), 7.77 (1H, d, J = 8.3 kPa), 7.92-8.01 (1H, m), 8.46-8.54 (1H, m), 9.14 (1H, brs), 11.05 ( 1H, brs).
[507] Example 41
[508] 3-((2S, 4S) -4- {4- [3-methyl-1- (3-pyridyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl)- Synthesis of 1,3-thiazolidine-trimaleate
[509] (1) 3-Aminopyridine (20 g) was dissolved in concentrated hydrochloric acid (125 mL), and an aqueous solution of sodium nitrite (15 g) (40 mL) was added at -10 ° C over 20 minutes. The mixture was stirred at 0 ° C for 2 h. This solution was added to a solution of tin (II) chloride (80 g) in concentrated hydrochloric acid (200 mL) at -2 ° C over 20 minutes. The mixture was stirred for 14 hours. The precipitate was removed by filtration and ice was added. The mixture was made strong base with 50% aqueous potassium hydroxide solution and extracted with dichloromethane. The extract solution was dried and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (400 mL) and 4 mol / L hydrochloric acid-ethyl acetate (55 mL) was added under ice cooling. The precipitate was collected by filtration to obtain 3-hydrazinopyridine dihydrochloride (18 g) as a pale yellow solid.
[510] (2) The compound (3.5 g) described above was suspended in ethanol (100 mL) and the product of Example 35 (1) (5.0 g), molecular sieve 3A (10 g) and pyridine (20 mL) were added at room temperature It was. The mixture was stirred for 2 hours. Pyridine (100 mL) was added to the reaction mixture and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was suspended in pyridine (100 mL) and phosphorus oxychloride (3.8 mL) was added at room temperature. The mixture was stirred for 13 hours. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with chloroform. The extraction solution was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the brown solid 1-t-butoxycarbonyl-4- [3-methyl-1- (3-pyridyl) -5-pyrazolyl] piperazine (1.3 g). Got it.
[511] (3) 1- [3-methyl-1- (3-pyridyl) -5-pyrazolyl] piperazine which is a brown oil using the aforementioned compound (1.3 g) in the same manner as in Example 36 (2) ( 876 mg).
[512] (4) 3-((2S, 4S) -1-t- which is a brown oil using the aforementioned compound (0.876 g) and the title compound (0.900 g) of Reference Example 3 in the same manner as in Example 29 (1) Butoxycarbonyl-4- {4- [3-methyl-1- (3-pyridyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3- Thiazolidine (1.5 g) was obtained.
[513] (5) The compound (1.5 g) described above was dissolved in ethyl acetate (20 mL) and 4 mol / L hydrochloric acid-ethyl acetate (40 mL) was added at room temperature. The mixture was stirred for 14 hours. After the reaction, water and 1 mol / L hydrochloric acid were added. The aqueous layer was separated and made strong base using 10 mol / L aqueous sodium hydroxide solution. The mixture was extracted with chloroform. The extract solution was dried and concentrated under reduced pressure. The residue was dissolved in ethanol (100 mL) and a maleic acid (950 mg) solution in ethanol (20 mL) was added under ice cooling. The precipitate was collected by filtration to give the title compound (1.0 g) as a white powder.
[514] ¹ H-NMR (DMSO-d ₆ ) δ 1.60-1.78 (1H, s), 2.17 (3H, s), 2.50-3.90 (20H, m), 4.42-4.71 (4H, m), 5.91 (1H, s ), 6.19 (6H, s), 7.49-7.53 (1H, m), 8.12-8.16 (1H, m), 8.18-8.50 (1H, m), 8.98-8.99 (1H, m).
[515] Example 42
[516] 3-((2S, 4S) -4- {4- [3-methyl-1- (4-pyridyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl)- Synthesis of 1,3-thiazolidine-trimaleate
[517] (1) 4-chloropyridine hydrochloride (14 g) was added to hydrazine monohydrate (50 mL) and the mixture was stirred at 120 ° C. for 1 hour. 1 mol / L aqueous sodium hydroxide solution (100 mL) and sodium chloride were added to the reaction solution. The mixture was extracted with ethyl acetate and the extraction solution was dried and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and 4 mol / L hydrochloric acid-ethyl acetate (50 mL) was added under ice cooling. The precipitate was collected by filtration to obtain 4-hydrazinopyridine dihydrochloride (16 g) as a pale yellow solid.
[518] (2) 1-t-butoxycarbonyl-4- which is a pale yellow solid using the compound (3.5 g) described above and the product (5.0 g) of Example 35 (1), in the same manner as in Example 41 (2). [3-Methyl-1- (4-pyridyl) -5-pyrazolyl] piperazine (3.4 g) was obtained.
[519] (3) 1- [3-methyl-1- (4-pyridyl) -5-pyrazolyl] piperazin as a pale yellow solid using the compound (3.4 g) described above in the same manner as in Example 36 (2) 2.4 g) was obtained.
[520] (4) 3-((2S, 4S) -1-t- which is a white solid using the compound (2.4 g) described above and the title compound (2.5 g) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- {4- [3-methyl-1- (4-pyridyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3- Thiazolidine (4.1 g) was obtained.
[521] (5) The title compound (4.3 g) was obtained as a white powder using the compound (4.1 g) described above in the same manner as in Example 41 (5).
[522] ¹ H-NMR (DMSO-d ₆ ) δ 1.60-1.80 (1H, m), 2.18 (3H, s), 2.55-3.90 (20H, m), 4.43-4.72 (4H, m), 5.98 (1H, s ), 6.18 (6H, s), 7.92-7.94 (2H, m), 8.61-8.63 (2H, m).
[523] Example 43
[524] 3-((2S, 4S) -4- {4- [1- (5-cyano-2-pyridyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrroli Synthesis of Genylcarbonyl) -1,3-thiazolidine Dihydrochloride
[525] (1) 2-Chloro-5-cyanopyridine (5.0 g) was dissolved in THF (100 mL) and added to hydrazine monohydrate (9.0 mL). The mixture was refluxed for 3 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution and sodium chloride were added to the residue. The mixture was extracted with ethyl acetate, the solution was dried and concentrated under reduced pressure to give 2-cyano-5-hydrazinopyridine (4.3 g) as a light brown solid.
[526] (2) The aforementioned compound (2.6 g) was suspended in ethanol (200 mL), and the product of Example 35 (1) (5.0 g), molecular sieve 3A (10 g) and methanesulfonic acid (2.6 g) were added. It was. The mixture was stirred at rt for 18 h. Pyridine (10 mL) was added to the reaction mixture and molecular sieve 3A was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was dissolved in pyridine (200 mL) and phosphorus oxychloride (3.8 mL) was added at room temperature. The mixture was stirred for 15 hours. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The extract solution was washed successively with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the pale yellow solid 1-t-butoxycarbonyl-4- [1- (5-cyano-2-pyridyl) -3-methyl-5-pyrazolyl] piperazine. (1.3 g) was obtained.
[527] (3) 1- [1- (5-cyano-2-pyridyl) -3-methyl-5-pyra as a brown solid using the compound (1.3 g) described above in the same manner as in Example 36 (2) Zolyl] piperazine (1.1 g) was obtained.
[528] (4) 3-((2S, 4S) -1-t- which is a white solid using the aforementioned compound (1.1 g) and the title compound (0.900 g) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- {4- [1- (5-cyano-2-pyridyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine (1.6 g) was obtained.
[529] (5) The title compound (1.3 g) as a white powder was obtained using the compound (1.6 g) described above in the same manner as in Example 38 (4).
[530] ¹ H-NMR (DMSO-d ₆ ) δ 2.21 (3H, s), 2.25-2.45 (1H, m), 2.95-4.19 (17H, m), 4.47-4.77 (3H, m), 6.05 (1H, s ), 7.97 (1H, d, J = 8.7 μs), 8.37 (1H, dd, J = 8.7,2.3 μs), 8.93 (1H, d, J = 2.3 μs), 9.15 (1H, brs), 10.80 (1H , brs).
[531] Example 44
[532] 3-{(2S, 4S) -4- [4- (3-trifluoromethyl-1-phenyl-5-pyrazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1, Synthesis of 3-thiazolidinetrichloride
[533] (1) 1-benzyloxycarbonylpiperazine (19.0 g) was dissolved in pyridine (150 mL) and acetic anhydride (9.0 mL) was added at room temperature. The mixture was stirred for 18 hours. The reaction solution was concentrated under reduced pressure and 10% aqueous citric acid solution was added to the residue. The mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure to give 4-acetyl-1-benzyloxycarbonylpiperazine (22.6 g) as an oil.
[534] (2) The above-mentioned compound (7.12 g) was dissolved in tetrahydrofuran (150 mL), and 1 mol / L of lithium bis (trimethylsilyl) amide-tetrahydrofuran solution (41 mL) was 40 minutes at -78 ° C. Dropwise over. After stirring for 1 hour at this temperature, a solution of ethyl trifluoroacetic acid salt (4.85 mL) in tetrahydrofuran (20 mL) was added to the reaction solution. The mixture was gradually warmed to room temperature and stirred for 18 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-benzyloxycarbonyl-4-trifluoroacetoacetylpiperazine (7.35 g) as a pale yellow solid.
[535] (3) 1-benzyloxycarbonyl-4- (3-trifluoromethyl-1) as an oil using the compound (1.96 g) and phenylhydrazine (0.540 mL) described above in the same manner as in Example 36 (1). -Phenyl-5-pyrazolyl) piperazine (0.416 g) was obtained.
[536] (4) 1- (3-trifluoromethyl-1-phenyl-5-pyrazolyl) piperazine (286 mg) as a white solid using the compound (416 mg) described above in the same manner as in Example 33 (3). )
[537] (5) 3-{(2S, 4S) -1-t- which is a light brown powder using the compound (286 mg) described above and the title compound (280 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (3-trifluoromethyl-1-phenyl-5-pyrazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazoli Dean (322 mg) was obtained.
[538] (6) The title compound (294 mg) was obtained as a white solid using the compound (322 mg) described above in the same manner as in Example 33 (5).
[539] ¹ H-NMR (DMSO-d ₆ ) δ 2.00-2.28 (1H, m), 2.80-4.00 (16H, m), 4.44-4.74 (3H, m), 6.64 (1H, s), 7.44-7.49 (1H , m), 7.54-7.59 (2H, m), 7.77-7.79 (2H, m), 9.03 (1H, brs), 10.55 (1H, brs).
[540] Example 45
[541] 3-{(2S, 4S) -4- [4- (1H-indazol-3-yl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine-3 Synthesis of Hydrochloride
[542] (1) 3, which was a colorless transparent oil using 1- (1H-indazol-3-yl) piperazine (178 mg) and the title compound (264 mg) of Reference Example 3 in the same manner as in Example 29 (1) -{(2S, 4S) -1-t-butoxycarbonyl-4- [4- (1H-indazol-3-yl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1 , 3-thiazolidine (442 mg) was obtained.
[543] (2) The compound (442 mg) described above was dissolved in methanol (10 mL) and chloroform (5 mL), and 4 mol / L hydrochloric acid-ethyl acetate solution (5 mL) was added. The mixture was stirred for 18 hours. The reaction solution was concentrated under reduced pressure to give the title compound (210 mg) as a white solid.
[544] ¹ H-NMR (DMSO-d ₆ ) δ 2.20-2.48 (1H, m), 2.90-4.30 (16H, m), 4.41-4.80 (3H, m), 7.02 (1H, t, J = 6.9 Hz), 7.25-7.46 (2H, m), 7.79 (1H, d, J = 8.4 μs), 9.20 (1H, brs), 10.78 (1H, brs), 12.26 (1H, s), 12.34 (1H, brs).
[545] Example 46
[546] 3-{(2S, 4S) -4- [4- (4-trifluoromethyl-6-methoxy-2-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1 Synthesis of 3,3-thiazolidine Dihydrochloride
[547] (1) p-anisidine (10 g) was dissolved in toluene (100 mL) and ethyl trifluoroacetoacetic acid salt (12 mL) and molecular sieve 4A (5.0 g) were added. The mixture was refluxed for 2 hours. Molecular sieve 4A was removed by filtration and the filtrate was concentrated under reduced pressure. 75% polyphosphoric acid (40 mL) was added to the residue and the mixture was stirred at 130 ° C. for 2 hours. The reaction solution is poured into ice, the precipitate is collected by filtration, dried and washed with a solution of chloroform-ether (1: 2) to give a white solid, 4-trifluoromethyl-2-hydroxy-6-methoxyquinoline. (4.9 g) was obtained.
[548] (2) The compound (4.9 g) described above was added to phosphorus oxychloride (8.0 mL) and the mixture was stirred at 100 ° C. for 3 hours. After the ice was added to the reaction solution, the mixture was strongly basic by adding 4 mol / L aqueous sodium hydroxide solution. The precipitate was collected by filtration to give 2-chloro-4-trifluoromethyl-6-methoxyquinoline (4.9 g) as a white solid.
[549] (3) Piperazine (10 g) was melted at 130 ° C. and compound (4.9 g) described above was added. The mixture was stirred for 2 hours and water was added to the reaction mixture. The mixture is extracted with ethyl acetate and chloroform. The extraction solution was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 1- (4-trifluoromethyl-6-methoxy-2-quinolyl) piperazine (5.7 g) as a yellow solid.
[550] (4) 3-{(2S, 4S) -1-t- which is a white solid using the compound (1.1 g) described above and the title compound (0.900 g) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (4-trifluoromethyl-6-methoxy-2-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thia Zolidine (1.7 g) was obtained.
[551] (5) The title compound (1.6 g) as a yellow powder was obtained using the compound (1.7 g) described above in the same manner as in Example 38 (4).
[552] ¹ H-NMR (DMSO-d ₆ ) δ 2.30-2.45 (1H, m), 2.95-3.17 (3H, m), 3.25-4.25 (15H, m), 4.48-4.78 (5H, m), 7.16 (1H , brs), 7.45 (1H, dd, J = 9.0, 2.4 kPa), 7.74 (1H, s), 7.80 (1H, d, J = 9.0 kPa), 9.16 (1H, brs), 11.06 (1H, brs) .
[553] Example 47
[554] 3-{(2S, 4S) -4- [4- (4-trifluoromethyl-8-methoxy-2-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1 Synthesis of 3,3-thiazolidinetrichloride
[555] (1) Orthoanisidine (50 g) and ethyl 4,4,4-trifluoroacetoacetic acid salt (71.3 mL) are dissolved in benzene (800 mL), and p-toluenesulfonic acid monohydrate (7.72 g) is dissolved. Added. The mixture was heated to reflux for 20 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. 75% polyphosphoric acid (300 mL) was added to the residue, the mixture was stirred at 90 ° C. for 6 hours, the reaction solution was poured into ice water (3 L) and the precipitated solid was collected by filtration. The solid was dissolved in ethyl acetate and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried and concentrated under reduced pressure to afford a light brown solid, 4-trifluoromethyl-2-hydroxy-8-. A mixture (31.7 g) containing methoxyquinoline was obtained.
[556] (2) Phosphorous oxychloride (48.6 mL) was added to the mixture (31.7 g) described above and the mixture was stirred at 100 ° C. for 2 hours. Ice was added to the reaction solution and the mixture was made basic by addition of 5 mol / L sodium hydroxide. The precipitate was collected by filtration to give a mixture (34.2 g) comprising a light brown solid, 2-chloro-4-trifluoromethyl-8-methoxyquinoline.
[557] (3) Piperazine (25.8 g) was melted at 130 ° C. and compound (13.1 g) described above was added. The mixture was stirred for 3 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract solution was dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give a pale yellow solid, 1- (4-trifluoromethyl-8-methoxy-2-quinolyl) piperazine (5.21 g )
[558] (4) 3-{(2S, 4S) -1-t- which is a yellow solid using the compound (0.933 g) described above and the title compound (0.891 g) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (4-trifluoromethyl-8-methoxy-2-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thia Zolidine (1.82 g) was obtained.
[559] (5) The above-mentioned compound (1.82 g) was dissolved in 4.1 mol / L hydrochloric acid-ethanol solution (1 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with chloroform. The extraction solution was washed with saturated brine and dried. The solvent was evaporated and the residue was purified by HPLC. 4.1 mol / l hydrochloric acid-ethanol solution (1 mL) was added and the mixture was concentrated under reduced pressure to afford the title compound (0.310 g) as a white powder.
[560] ¹ H-NMR (DMSO-d ₆ ) δ 2.11 (1H, m), 2.67-3.92 (20H, m), 4.29-4.78 (3H, m), 7.04 (1H, m), 7.17-7.25 (2H, m ), 7.55 (1H, s), 8.98 (1H, brs), 10.46 (1H, brs).
[561] Example 48
[562] 3-{(2S, 4S) -4- [4- (2-trifluoromethyl-6-hydroxy-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1 Synthesis of 3,3-thiazolidine Dihydrochloride
[563] (1) p-anisidine (10 g) was dissolved in toluene (100 mL) and ethyl trifluoroacetoacetic acid salt (12 mL) and molecular sieve 4A (5.0 g) were added. The mixture was refluxed for 2 hours. Molecular sieve 4A was removed by filtration and the filtrate was concentrated under reduced pressure. 75% polyphosphoric acid (40 mL) was added to the residue and the mixture was stirred at 130 ° C. for 2 hours. The reaction solution was poured into ice and the precipitate was collected by filtration. The precipitate was dried, a mixed solution of chloroform-ether (1: 2) was added and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to give a mixture (8.1 g) containing the oil, 2-trifluoromethyl-4-hydroxy-6-methoxyquinoline.
[564] (2) In the same manner as in Example 46 (2), using the mixture (8.1 g) and phosphorus oxychloride (12 mL) described above, 4-chloro-2-trifluoromethyl-6-methoxy is a white solid. Quinoline (4.2 g) was obtained.
[565] (3) 1- (2-trifluoromethyl-6-methoxy-4- as a pale yellow solid using the compound (4.2 g) and piperazine (10 g) described above in the same manner as in Example 46 (3). Quinolyl) piperazine (3.6 g) was obtained.
[566] (4) 3-{(2S, 4S) -1-t- which was a white solid using the aforementioned compound (2.2 g) and the title compound (1.7 g) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (2-trifluoromethyl-6-methoxy-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thia Zolidine (3.6 g) was obtained.
[567] (5) The above-mentioned compound (3.6 g) was dissolved in ethyl acetate (20 mL) and 4 mol / L hydrochloric acid-ethyl acetate (100 mL) was added at room temperature. The mixture was stirred for 10 hours. The precipitate was collected by filtration, which was dissolved in water. The mixture was washed with chloroform and its aqueous solution was made basic using saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with chloroform. The solution was dried and concentrated under reduced pressure to afford the white solid 3-{(2S, 4S) -4- [4- (2-trifluoromethyl-6-methoxy-4-quinolyl) -1-piperazinyl ] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (2.8 g) was obtained.
[568] (6) The compound (1.1 g) described above was dissolved in dichloromethane (40 mL) and boron tribromide (0.96 mL) was added at -78 ° C. The mixture was stirred at rt for 4 h. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution. The mixture was extracted with ethyl acetate. The extraction solution was washed with saturated brine, dried and the residue was purified by HPLC. The purified product was dissolved in ethyl acetate and 4 mol / l hydrochloric acid-ethyl acetate was added. The precipitate was collected by filtration to give the title compound (236 mg) as a pale yellow powder.
[569] ¹ H-NMR (DMSO-d ₆ ) δ 2.10-2.39 (1H, m), 2.89-3.99 (17H, m), 4.48-4.77 (3H, m), 7.25 (1H, s), 7.32 (1H, d , J = 2.4 Hz), 7.43 (1H, dd, J = 9.0, 2.4 Hz), 7.98 (1H, d, J = 9.0 Hz), 9.09 (1H, brs), 10.42 (1H, brs), 10.53 (1H , brs).
[570] Example 49
[571] 3-{(2S, 4S) -4- [4- (6-trifluoromethoxy-2-trifluoromethyl-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} Synthesis of -1,3-thiazolidinedihydrochloride
[572] (1) 4-trifluoromethylaniline (25.0 g) and ethyl trifluoroacetoacetic acid salt (22.7 mL) were dissolved in acetic acid (140 mL) and the mixture was stirred at rt for 23 h. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with chloroform. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. Diphenyl ether (140 mL) was added to the residue and the mixture was stirred at 250 ° C. for 1.5 h. Hexane (140 mL) was added to the reaction solution, and the precipitate was collected by filtration to give 6-trifluoromethoxy-2-trifluoromethyl-4-hydroxyquinoline (12.0 g) as a white crystalline powder.
[573] (2) Using the compound (12.0 g) described above in the same manner as in Example 46 (2), 4-chloro-6-trifluoromethoxy-2-trifluoromethylquinoline (12.1 g) was obtained. .
[574] (3) In the same manner as in Example 46 (3), using the compound (12.1 g) described above as a pale yellow solid, 1- (6-trifluoromethoxy-2-trifluoromethyl-4-quinolyl) pipepe Obtained Razine (14.3 g).
[575] (4) 3-{(2S, 4S) -1-t- which was a white solid using the compound (402 mg) described above and the title compound (300 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (6-trifluoromethoxy-2-trifluoromethyl-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3 -Thiazolidine (601 mg) was obtained.
[576] (5) The title compound (521 mg) as a yellow fine powder was obtained using the compound (601 mg) described above in the same manner as in Example 29 (2).
[577] ¹ H-NMR (DMSO-d ₆ ) δ 2.46 (1H, m), 3.03-3.25 (3H, m), 3.31-4.05 (13H, m), 4.24 (1H, m), 4.52-4.85 (3H, m ), 7.52 (1H, s), 7.92 (1H, d, J = 9.2 Hz), 8.02 (1H, s), 8.31 (1H, d, J = 9.2 Hz), 9.25 (1H, brs), 10.19 (1H , brs).
[578] Example 50
[579] 3-{(2S, 4S) -4- [4- (2-trifluoromethyl-8-hydroxy-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1 Synthesis of 3,3-thiazolidinetrichloride
[580] (1) Orthoanisidine (50 g) and ethyl 4,4,4-trifluoroacetoacetic acid salt (71.3 mL) are dissolved in benzene (800 mL), and p-toluenesulfonic acid monohydrate (7.72 g) is dissolved. Added. The mixture was heated to reflux for 20 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. 75% polyphosphoric acid (300 mL) was added to the residue, the mixture was stirred at 90 ° C. for 6 hours, the reaction solution was poured into ice water (3 L) and the precipitated solid was collected by filtration. The solid was dissolved in ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried and concentrated under reduced pressure to give a pale brown solid, 2-trifluoromethyl-4-hydroxy-8-meth. A mixture (31.7 g) containing oxyquinoline was obtained.
[581] (2) Phosphorous oxychloride (48.6 mL) was added to the compound (31.7 g) described above, and the mixture was stirred at 100 ° C. for 2 hours. Ice was added to the reaction solution and the solution was made basic by addition of 5 mol / l sodium hydroxide. The precipitate was collected by filtration to give a mixture (34.2 g) containing 4-chloro-2-trifluoromethyl-8-methoxyquinoline as a light brown solid.
[582] (3) Piperazine (25.8 g) was melted at 130 ° C. and the aforementioned mixture (13.1 g) was added. The mixture was stirred for 3 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract solution was dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give a yellow solid, 1- (2-trifluoromethyl-8-methoxy-4-quinolyl) piperazine (8.48 g )
[583] (4) 3-{(2S, 4S) -1-t- which was a white solid using the compound (0.933 g) described above and the title compound (0.891 g) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (2-trifluoromethyl-8-methoxy-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thia Zolidine (1.54 g) was obtained.
[584] (5) The title compound (109 mg) as a yellow powder was obtained in the same manner as the Example 48 (6) using the compound (394 mg) described above.
[585] ¹ H-NMR (DMSO-d ₆ ) δ 2.34 (1H, m), 2.90-4.23 (17H, m), 4.48-4.81 (3H, m), 7.22 (1H, dd, J = 1.5, 7.2 Hz), 7.36 (1H, s), 7.49-7.59 (2H, m), 9.15 (1H, brs), 10.16 (1H, brs), 10.77 (1H, brs).
[586] Example 51
[587] 3-{(2S, 4S) -4- [4- (8-ethoxy-2-trifluoromethyl-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1 Synthesis of 3,3-thiazolidinetrichloride
[588] (1) The product of Example 50 (3) (4.86 g) was dissolved in dichloromethane and boron tribromide (7.39 mL) was added at -78 ° C. The mixture was stirred at rt for 3 h. The reaction solution was poured into water and the pH was adjusted to 8 by addition of sodium bicarbonate. The mixture was extracted with chloroform. The extraction solution was washed with saturated brine, dried and concentrated under reduced pressure to give 1- (2-trifluoromethyl-8-hydroxy-4-quinolyl) piperazine (1.52 g) as a pale yellow solid.
[589] (2) 3-{(2S, 4S) -1-t- which is a pale yellow solid, using the compound (0.648 g) described above and the title compound (0.595 g) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (2-trifluoromethyl-8-hydroxy-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thia Zolidine (1.30 g) was obtained.
[590] (3) Sodium hydride (40 mg) was suspended in DMF (1 mL) and the aforementioned compound (291 mg) was added under ice cooling. The mixture was stirred for 10 minutes. Ethyl p-toluenesulfonate (200 mg) was added to the reaction mixture and the mixture was stirred at 70 ° C. for 4 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the pale yellow solid 3-{(2S, 4S) -1-t-butoxycarbonyl-4- [4- (8-ethoxy-2-trifluoromethyl- 4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (280 mg) was obtained.
[591] (4) The title compound (141 mg) as a yellow powder was obtained using the compound (280 mg) described above in the same manner as in Example 47 (5).
[592] ¹ H-NMR (DMSO-d ₆ ) δ 1.57 (3H, t, J = 6.9 Hz), 2.54 (1H, m), 3.02-4.17 (16H, m), 4.19-4.46 (3H, m), 4.51- 5.18 (3H, m), 7.42 (1H, m), 7.51 (1H, s), 7.73-7.77 (2H, m), 9.33 (1H, brs), 10.94 (1H, brs).
[593] Example 52
[594] 3-{(2S, 4S) -4- [4- (2-trifluoromethyl-8-isopropoxy-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl}- Synthesis of 1,3-thiazolidinetrichloride
[595] (1) In the same manner as in Example 51 (3), 3-{(2S), which was a colorless oil using the product of Example 51 (2) (291 mg) and p-toluenesulfonic acid isopropoxy ester (161 mg). , 4S) -1-t-butoxycarbonyl-4- [4- (2-trifluoromethyl-8-isopropoxy-4-quinolyl) -1-piperazinyl] -2-pyrrolidinyl Carbonyl} -1,3-thiazolidine (28 mg) was obtained.
[596] (2) The title compound (10 mg) was obtained as a yellow powder using the compound (28 mg) described above in the same manner as in Example 29 (2).
[597] ¹ H-NMR (DMSO-d ₆ ) δ 1.43 (3H, s), 1.45 (3H, s), 2.45 (1H, m), 3.04-3.26 (6H, m), 3.61-4.03 (10H, m), 4.22 (1H, m), 4.50-4.97 (4H, m), 7.40 (1H, m), 7.44 (1H, s), 7.67-7.69 (2H, m), 9.24 (1H, brs), 10.99 (1H, brs).
[598] Example 53
[599] 3-{(2S, 4S) -4- [4- (8-trifluoromethoxy-2-trifluoromethyl-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} Synthesis of -1,3-thiazolidinedihydrochloride
[600] (1) 8-trifluoromethoxy-2-trifluoromethyl-4-hydroxyquinoline as a white powder using 2-trifluoromethylaniline (5.10 g) in the same manner as in Example 47 (1) 0.345 g) was obtained.
[601] (2) In the same manner as in Example 47 (2), using the compound (345 mg) described above, 4-chloro-8-trifluoromethoxy-2-trifluoromethylquinoline (316 mg) was obtained as an orange oil. .
[602] (3) 1- (8-trifluoromethoxy-2-trifluoromethyl-4-quinolyl) piperazine which is a yellow oil using the compound (316 mg) described above in the same manner as in Example 47 (3). (349 mg) was obtained.
[603] (4) 3-{(2S, 4S) -1-t- which was a white solid using the compound (349 mg) described above and the title compound (261 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (8-trifluoromethoxy-2-trifluoromethyl-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3 -Thiazolidine (513 mg) was obtained.
[604] (5) The title compound (365 mg) was obtained as a white powder using the compound (513 mg) described above in the same manner as in Example 47 (5).
[605] ¹ H-NMR (DMSO-d ₆ ) δ 2.26 (1H, m), 2.80-4.19 (17H, m), 4.30-4.72 (3H, m), 7.38 (1H, s), 7.68 (1H, dd, J = 7.9, 7.9 kPa), 7.82 (1H, d, J = 7.9 kPa), 8.06 (1H, d, J = 7.9 kPa), 9.06 (1H, brs), 10.84 (1H, brs).
[606] Example 54
[607] 3-((2S, 4S) -4- {4- [8- (2,2,2-trifluoroethoxy) -2-trifluoromethyl-4-quinolyl] -1-piperazinyl} Synthesis of 2-pyrrolidinylcarbonyl) -1,3-thiazolidine dihydrochloride
[608] (1) The product of Example 51 (2) (345 mg) was dissolved in DMF (3 mL), potassium carbonate (164 mg) and methanesulfonic acid 2,2,2-trifluoroethyl ester (212 mg) Was added. The mixture was stirred at 100 ° C. for 5 hours. Water was added to the reaction solution and the mixture was extracted with chloroform. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the yellow oil 3-((2S, 4S) -1-t-butoxycarbonyl-4- {4- [8- (2,2,2-trifluoro Ethoxy) -2-trifluoromethyl-4-quinolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine (283 mg) was obtained.
[609] (2) In the same manner as in Example 47 (5), the title compound (19 mg) was obtained as a white powder using the compound (283 mg) described above.
[610] ¹ H-NMR (DMSO-d ₆ ) δ 2.34 (1H, m), 2.92-4.21 (17H, m), 4.49-4.79 (3H, m), 5.03 (2H, q, J = 9.0 Hz), 7.44 ( 1H, s), 7.51 (1H, d, J = 7.5 μs), 7.68 (1H, dd, J = 7.5, 8.4 μs), 7.78 (1H, d, J = 8.4 μs), 9.16 (1H, brs), 10.84 (1H, broad singlet).
[611] Example 55
[612] 3-{(2S, 4S) -4- [4- (2-trifluoromethyl-6,8-dimethoxy-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} Synthesis of -1,3-thiazolidinedihydrochloride
[613] (1) 2,4-dimethoxyaniline (30 g) was dissolved in benzene (400 mL) and ethyl trifluoroacetoacetic acid salt (34 mL) and p-toluenesulfonic acid monohydrate (3.7 g) were added. . The mixture was refluxed for 21 hours. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. 75% polyphosphoric acid (150 mL) was added to the residue and the mixture was stirred at 130 ° C. for 2 hours. The reaction solution was poured into ice and the mixture was extracted with ethyl acetate. The extract solution was washed successively with saturated aqueous sodium hydrogen carbonate solution, 1 mol / l hydrochloric acid and saturated brine, dried and concentrated under reduced pressure. Ethanol was added to the residue and the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to give an oil, 2-trifluoromethyl-4-hydroxy-6,8-dimethoxyquinoline (12 g).
[614] (2) 4-chloro-2-trifluoromethyl-6,8-dimethine as a white solid using the compound (12 g) and phosphorus oxychloride (17 mL) described above in the same manner as in Example 46 (2). Obtained oxyquinoline (13 g).
[615] (3) 1- (2-trifluoromethyl-6,8-dimethoxy- which is a pale brown solid using the compound (13 g) and piperazine (23 g) described above in the same manner as in Example 46 (3). 4-quinolyl) piperazine (13 g) was obtained.
[616] (4) 3-{(2S, 4S) -1-t- which was a white powder using the aforementioned compound (1.2 g) and the title compound (0.900 g) of Reference Example 3 in the same manner as in Example 29 (1) Butoxycarbonyl-4- [4- (2-trifluoromethyl-6,8-dimethoxy-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3 -Thiazolidine (2.1 g) was obtained.
[617] (5) The title compound (1.4 g) as a pale yellow powder was obtained using the compound (1.8 g) described above in the same manner as in Example 38 (4).
[618] ¹ H-NMR (DMSO-d ₆ ) δ 2.25-2.43 (1H, m), 2.97-3.18 (3H, m), 3.25-4.20 (20H, m), 4.48-4.70 (3H, m), 6.84 (1H , d, J = 2.4 Hz), 6.95 (1H, d, J = 2.4 Hz), 7.38 (1H, s), 9.14 (1H, brs), 10.70 (1H, brs).
[619] Example 56
[620] 3-{(2S, 4S) -4- [4- (3,5-dimethyl-1-pyrazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidinetrichloride Synthesis of
[621] (1) t-butyl carbazite (26.4 g) was dissolved in ethanol (100 mL) and a solution of 1-ethoxycarbonyl-4-piperidone (34.2 g) in ethanol (80 mL) was added. The mixture was stirred for one day, 5% palladium on carbon (2 g) was added and the mixture was stirred under 1 atm of hydrogen at room temperature. Palladium on carbon was removed by filtration and 4 mol / l hydrochloric acid-dioxane solution (200 mL) was added to the filtrate. The mixture was warmed to 50 ° C. The solution was cooled with ice and the precipitate was collected by filtration to give white crystals 1-ethoxycarbonyl-4-hydrazinopiperidine dihydrochloride (44.4 g).
[622] (2) The above compound (2.9 g) was dissolved in methanol (10 mL), and triethylamine (3.1 mL) and acetylacetone (1.1 g) were added. The mixture was stirred at room temperature. The reaction solution was concentrated under reduced pressure and saturated brine was added. The mixture was extracted with ethyl acetate. The extraction solution was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated under reduced pressure to give 1-ethoxycarbonyl-4- (3,5-dimethyl-1-pyra as an oil. Zolyl) piperidine (2.69 g) was obtained.
[623] (3) The compound (2.6 g) described above was dissolved in 30% hydrogen bromide-acetic acid (25 mL) and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, neutralized with aqueous potassium carbonate solution and extracted with ethyl acetate. The extract solution was dried over potassium carbonate and concentrated under reduced pressure to afford the oil 4- (3,5-dimethyl-1-pyrazolyl) piperidine (1.12 g).
[624] (4) 3-{(2S, 4S) -1-t- which was a white solid using the aforementioned compound (592 mg) and the title compound (901 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (3,5-dimethyl-1-pyrazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (834 mg) was obtained.
[625] (5) The above-mentioned compound (834 mg) was dissolved in methanol (20 mL) and chloroform (10 mL), and 4 mol / L hydrochloric acid-ethyl acetate solution (10 mL) was added. The mixture was stirred for 18 hours. The reaction solution was concentrated under reduced pressure to give the title compound (415 mg) as a white solid.
[626] ¹ H-NMR (DMSO-d ₆ ) δ 1.90-2.55 (11H, m), 2.90-4.00 (10H, m), 4.24-4.80 (4H, m), 5.81 (1H, m), 9.12 (1H, brs ), 10.89 (1H, broad singlet).
[627] Example 57
[628] 3-{(2S, 4S) -4- [4- (3-methyl-5-phenyl-1-pyrazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine Synthesis of Trichloride
[629] (1) The product of Example 56 (1) (5.2 g) was dissolved in methanol (25 mL) and triethylamine (5.6 mL) and dibenzoylacetone (3.2 g) were added. The mixture was stirred for 3 days at room temperature. The reaction solution was concentrated under reduced pressure and saturated brine was added. The mixture was extracted with ethyl acetate. The extract solution was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-ethoxycarbonyl-4- (3-methyl-5-phenyl-1-pyrazolyl) piperidine (3.74 g).
[630] (2) Crystalline 4- (3-methyl-5-phenyl-1-pyrazolyl) piperidine was obtained using the compound (3.1 g) described above in the same manner as in Example 56 (3).
[631] (3) 3-{(2S, 4S) -1-t- which was a white solid using the compound (0.796 g) described above and the title compound (0.901 g) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (3-methyl-5-phenyl-1-pyrazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (1.43 g) Got it.
[632] (4) In the same manner as in Example 31 (4), the title compound (1.17 g) as a pale yellow powder was obtained using the compound (1.42 g) described above.
[633] ¹ H-NMR (DMSO-d ₆ ) δ 1.95-2.12 (2H, m), 2.20 (3H, s), 2.22-2.37 (1H, m), 2.87-3.27 (5H, m), 3.38-4.05 (9H , m), 4.33-4.76 (4H, m), 6.13 (1H, s), 7.42-7.57 (5H, m), 9.09 (1H, brs), 10.79 (1H, brs), 11.79 (1H, brs).
[634] Example 58
[635] 3-{(2S, 4S) -4- [4- (3,5-diphenyl-1-pyrazolyl) piperidin-1-yl] -2-pyrrolidinylcarbonyl} -1,3-thia Synthesis of Zolidine Dihydrochloride
[636] (1) The product of Example 56 (1) (2.6 g) was dissolved in methanol (10 mL) and triethylamine (2.8 mL) and dibenzoylmethane (2.2 g) were added. The mixture was stirred at 60 ° C. for one day. The reaction solution was concentrated under reduced pressure and water was added. The precipitated crystals were collected by filtration to give the crystal 1-ethoxycarbonyl-4- (3,5-diphenyl-1-pyrazolyl) piperidine (2.71 g).
[637] (2) Crystalline 4- (3,5-diphenyl-1-pyrazolyl) piperidine (2.14 g) was obtained using the compound (2.7 g) described above in the same manner as in Example 56 (3).
[638] (3) 3-{(2S, 4S) -1-t as a colorless transparent oil using the compound (1.00 g) described above and the title compound (0.901 g) of Reference Example 3 in the same manner as in Example 29 (1) -Butoxycarbonyl-4- [4- (3,5-diphenyl-1-pyrazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (1.12 g) Got it.
[639] (4) The compound (1.12 g) described above was dissolved in methanol (20 mL) and chloroform (10 mL) and 4 mol / L hydrochloric acid-ethyl acetate solution (10 mL) was added. The mixture was stirred for 18 hours. The reaction solution was concentrated under reduced pressure to give the title compound (0.804 g) as a white solid.
[640] ¹ H-NMR (DMSO-d ₆ ) δ 2.00-2.70 (5H, m), 2.82-4.10 (12H, m), 4.37-4.80 (4H, m), 6.85 (1H, s), 7.25-7.63 (8H , m), 7.74-7.95 (2H, m)
[641] Example 59
[642] 3-{(2S, 4S) -4- [4- (3-trifluoromethyl-1-phenyl-5-pyrazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thia Synthesis of Zolidine Dihydrochloride
[643] (1) Ethyl trifluoroacetic acid salt (6.32 g) was dissolved in t-butyl methyl ether (10 mL), 28% sodium methoxide-methanol solution (9.40 g) and t-butyl methyl ether (20 mL) A solution of 4-acetylpyridine (4.90 g) in water was added continuously at room temperature. The mixture was stirred for 22 hours. A 10% aqueous citric acid solution was added until the pH of the reaction solution was about 4, and the precipitate was collected by filtration, washed with water, dried and a yellow solid, 4-trifluoroacetoacetylpyridine (5.46 g) was obtained. .
[644] (2) The above-mentioned compound (760 mg) was suspended in ethanol (20 mL), and phenylhydrazine (0.380 mL) was added at room temperature. The mixture was stirred for 23 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4- (3-trifluoromethyl-1-phenyl-5-pyrazolyl) pyridine (470 mg) as an oil.
[645] (3) The compound (470 mg) described above was dissolved in acetonitrile (50 mL) and benzyl chloride (0.380 mL) was added. The mixture was heated to reflux for 24 hours. The reaction solution was concentrated under reduced pressure and diethyl ether was added to the residue. The precipitate was collected by filtration. It was dissolved in ethanol (30 mL) and sodium borohydride (130 mg) was added under ice cooling. The mixture was stirred at rt for 22 h. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the oil 1-benzyl-4- (3-trifluoromethyl-1-phenyl-5-pyrazolyl) -1,2,3,6-tetrahydropyridine (142 mg )
[646] (4) The compound (142 mg) and ammonium formate (240 mg) described above were dissolved in methanol (20 mL) and 10% palladium on carbon (150 mg) was added. The mixture was heated to reflux for 2 hours under a nitrogen atmosphere. Insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. The solution was dried and concentrated under reduced pressure to afford the oil 4- (3-trifluoromethyl-1-phenyl-5-pyrazolyl) piperidine (90 mg).
[647] (5) 3-{(2S, 4S) -1-t- which is a white powder using the compound (90 mg) described above and the title compound (90 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (3-trifluoromethyl-1-phenyl-5-pyrazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (134 Mg).
[648] (6) The title compound (96 mg) was obtained as a white solid using the compound (134 mg) described above in the same manner as in Example 33 (5).
[649] ¹ H-NMR (500 MHz, DMSO-d ₅ ) δ 1.90-2.30 (5H, m), 2.83-4.00 (13H, m), 4.46-4.71 (3H, m), 6.78 (1H, s), 7.57- 7.62 (5H, m), 9.07 (1H, brs), 10.45 (1H, brs), 11.82 (1H, brs).
[650] Example 60
[651] 3-{(2S, 4S) -4- [4- (1-phenyl-1H-tetrazol-5-yl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine Synthesis of Dihydrochloride
[652] (1) Dissolve 1-benzyloxycarbonylisonifeptic acid (13.1 g), HOBT (11.4 g) and EDC hydrochloride (11.4 g) in tetrahydrofuran (200 mL) and add aniline (5.0 mL) It was. The mixture was stirred at rt for 17 h. The reaction solution was concentrated under reduced pressure and 0.5 mol / l hydrochloric acid was added. The mixture was extracted with ethyl acetate. The extraction solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried. The solvent was evaporated under reduced pressure to give 1-benzyloxycarbonylisonifeptic acid anilide (17.0 g) as a white solid.
[653] (2) The above-described compound (2.00 g), triphenylphosphine (3.10 g) and 40% diisopropylazodicarboxylate-toluene solution (6.00 g) are dissolved in tetrahydrofuran (50 mL) and trimethyl Silyazide (1.57 mL) was added under ice cooling. The mixture was stirred for 5 days at room temperature. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography to give the brown oil 1-benzyloxycarbonyl-4- (1-phenyl-1H-tetrazol-5-yl) piperidine (4.09 g )
[654] (3) The compound (4.09 g) described above was dissolved in methanol (50 mL) and the mixture was stirred at room temperature under 1 atm of hydrogen in the presence of 10% palladium on carbon (420 mg). The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give 4- (1-phenyl-1H-tetrazol-5-yl) piperidine (1.42 g) as a gray solid.
[655] (4) 3-{(2S, 4S) -1-t- which was a white solid using the compound (0.757 g) described above and the title compound (0.901 g) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (1-phenyl-1H-tetrazol-5-yl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (1.07 g) Got it.
[656] (5) The compound (1.06 g) described above was dissolved in ethanol (4 mL) and 7.4 mol / L hydrochloric acid-ethanol solution (3 mL) was added. The mixture was stirred at rt for 11 h. The precipitate was collected by filtration to give the title compound (0.688 g) as a white powder.
[657] ¹ H-NMR (DMSO-d ₆ ) δ 1.93-2.34 (5H, m), 2.85-3.95 (13H, m), 4.43-4.77 (3H, m), 7.69 (5H, s), 9.12 (1H, brs ), 10.74 (1H, brs), 12.04 (1H, brs).
[658] Example 61
[659] 3-((2S, 4S) -4- {4- [1- (4-fluorophenyl) -1H-tetrazol-5-yl] piperidino} -2-pyrrolidinylcarbonyl) -1, Synthesis of 3-thiazolidine dihydrochloride
[660] (1) isonifecotic acid (19.0 g) is dissolved in water (150 mL) and 1,4-dioxane (300 mL), and 1 mol / L aqueous sodium hydroxide solution (150 mL) and di-t-butyl Dicarbonate (35.3 g) was added under ice cooling. The mixture was stirred for 3 days at room temperature. 1,4-dioxane was evaporated under reduced pressure and 5% aqueous sodium hydrogen sulfate solution was added to the residue. The precipitated solid was collected by filtration to give 1-t-butoxycarbonylisonifeptic acid (33.0 g) as a white solid.
[661] (2) The compound (2.43 g), HOBT (1.95 g) and EDC hydrochloride (2.44 g) described above were dissolved in DMF (50 mL) and 4-fluoroaniline (1.00 mL) was added. The mixture was stirred at rt for 5 h. Water was added to the reaction solution, and the precipitate was collected by filtration to give 4-fluorophenylamide 1-t-butoxycarbonylisonipate (2.82 g) as a white solid.
[662] (3) 1-t-butoxycarbonyl-4- [1- (4-fluorophenyl) -1H- which is a white solid using the compound (2.82 g) described above in the same manner as in Example 60 (2). Tetrazol-5-yl] piperidine (0.916 g) was obtained.
[663] (4) 4- [1- (4-fluorophenyl) -1H-tetrazol-5-yl] piperi, which is a light brown solid, using the compound (916 mg) described above in the same manner as in Example 36 (2). Dean (342 mg) was obtained.
[664] (5) 3-((2S, 4S) -1-t- which was a white powder using the compound (338 mg) mentioned above and the title compound (373 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- {4- [1- (4-fluorophenyl) -1H-tetrazol-5-yl] piperidino} -2-pyrrolidinylcarbonyl) -1,3-thiazoli Dean (514 mg) was obtained.
[665] (6) The compound (512 mg) described above was dissolved in methanol (10 mL) and chloroform (5 mL). 4 mol / l hydrochloric acid-dioxane (3 mL) was added at room temperature and the mixture was stirred for 17 hours. The reaction solution was concentrated under reduced pressure and the residue was dissolved in methanol. Ethyl acetate was added and the precipitate was collected by filtration to give the title compound (318 mg) as a white solid.
[666] ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 1.90-2.40 (5H, m), 2.70-3.95 (13H, m), 4.46-4.72 (3H, m), 7.52-7.55 (2H, m), 7.77-7.79 (2H, m), 9.09 (1H, brs), 10.57 (1H, brs), 11.92 (1H, brs).
[667] Example 62
[668] Synthesis of 3-{(2S, 4S) -4- [4- (1H-indazol-1-yl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine dihydrochloride
[669] (1) 2-fluorobenzaldehyde (2.48 g) was dissolved in methanol (20 mL) and the product of Example 56 (1) (8.2 g) and a solution of triethylamine (7.5 mL) in methanol (20 mL) Was added drop wise. After stirring for 1 hour at room temperature, the mixture was concentrated under reduced pressure and saturated brine was added to the residue. The mixture was extracted with ethyl acetate. The extract solution was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried. The solvent was evaporated and copper iodide (I) (0.38 g) and tetrahydrofuran (40 mL) were added to the residue. In addition, a solution of potassium t-butoxide (3.8 g) in tetrahydrofuran (20 mL) was added under ice cooling. The mixture was stirred at rt for 4 days. The reaction solution was neutralized with 10% aqueous citric acid solution (20 mL) and extracted with ethyl acetate. The extract solution was washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the oil 1-ethoxycarbonyl-4- (1H-indazol-1-yl) piperidine (1.04 g).
[670] (2) The compound (0.90 g) described above was dissolved in 30% hydrogen bromide-acetic acid (10 mL) and the mixture was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure and the residue was neutralized with aqueous potassium carbonate. The mixture was extracted with ethyl acetate and the extraction solution was dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4- (1H-indazol-1-yl) piperidine (0.42 g) as an oil.
[671] (3) 3-{(2S, 4S) -1-t as a colorless transparent oil using the compound (420 mg) described above and the title compound (570 mg) of Reference Example 3 in the same manner as in Example 29 (1) -Butoxycarbonyl-4- [4- (1H-indazol-1-yl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (468 mg) was obtained.
[672] (4) The compound (468 mg) described above was dissolved in methanol (10 mL) and chloroform (5 mL) and 4 mol / L hydrochloric acid-ethyl acetate solution (5 mL) was added. The mixture was stirred for 18 hours. The reaction solution was concentrated under reduced pressure to give the title compound (283 mg) as a white solid.
[673] ¹ H-NMR (DMSO-d ₆ ) δ 2.00-2.70 (5H, m), 2.90-4.15 (12H, m), 4.42-4.80 (3H, m), 4.90-5.20 (1H, m), 7.17 (1H , t, J = 7.4 Hz), 7.42 (1H, t, J = 7.3 Hz), 7.67-7.85 (2H, m), 8.12 (1H, s).
[674] Example 63
[675] 3-{(2S, 4S) -4- [4- (3-methyl-1H-indazol-1-yl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine Synthesis of Dihydrochloride
[676] (1) The product of Example 56 (1) (8.4 g) was dissolved in methanol (35 mL) and triethylamine (9.5 mL) and 2'-fluoroacetophenone (4.05 g) were added. The mixture was heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure and saturated brine was added to the residue. The mixture was extracted with ethyl acetate. The extraction solution was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried. The solvent was evaporated. Copper iodide (I) (0.6 g) and tetrahydrofuran (80 mL) were added to the residue, and potassium t-butoxide (6 g) was further added under ice cooling. The mixture was stirred at rt for 5 days. The reaction solution was neutralized with 10% aqueous citric acid solution (40 mL) and the mixture was extracted with ethyl acetate. The extraction solution was washed with saturated brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-ethoxycarbonyl-4- (3-methyl-1H-indazol-1-yl) piperidine as an oil.
[677] (2) Using the compound (2.3 g) described above in the same manner as in Example 56 (3), the oil 4- (3-methyl-1H-indazol-1-yl) piperidine (1.1 g) was obtained. .
[678] (3) 3-{(2S, 4S) -1-t- which was a white solid using the compound (710 mg) mentioned above and the title compound (901 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (3-methyl-1H-indazol-1-yl) piperidin-1-yl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine ( 793 mg).
[679] (4) The title compound (580 mg) was obtained as a white solid using the compound (793 mg) described above in the same manner as in Example 62 (4).
[680] ¹ H-NMR (DMSO-d ₆ ) δ 2.00-2.70 (8H, m), 2.92-4.27 (12H, m), 4.38-4.80 (3H, m), 4.80-5.12 (1H, m), 7.13 (1H , t, J = 7.2 μs), 7.40 (1H, t, J = 7.5 μs), 7.56-7.81 (2H, m), 9.15 (1H, brs), 10.80 (1H, brs), 12.14 (1H, brs) .
[681] Example 64
[682] 3-{(2S, 4S) -4- [4- (5-trifluoromethyl-1-benzimidazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine Synthesis of Trichloride
[683] (1) 1-fluoro-4-trifluoromethyl-2-nitrobenzene (5.1 g) was dissolved in tetrahydrofuran (100 mL), diisopropylethylamine (5.5 mL) and 4-amino-1 -t-butoxycarbonylpiperidine (5.37 g) was added. The mixture was stirred at rt for 3 h. The reaction solution was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate, the solution was dried and concentrated under reduced pressure to afford 1-t-butoxycarbonyl-4- (4-trifluoromethyl-2-nitrophenyl) aminopiperidine.
[684] (2) The compound described above was dissolved in ethanol (350 mL) and anhydrous tin chloride (II) (61 g) was added. The mixture was stirred for 3 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the precipitated insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract solution was dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4- (2-amino-4-trifluoromethylphenyl) amino-1-t-butoxycarbonylpiperidine (3.58 g).
[685] (3) Trimethyl orthoformate (12 mL) and p-toluenesulfonic acid (0.010 g) were added to the compound (1.5 g) described above, and the mixture was stirred at 90 ° C. for 90 minutes. The reaction solution was concentrated under reduced pressure to give 1-t-butoxycarbonyl-4- (5-trifluoromethyl-1-benzimidazolyl) piperidine.
[686] (4) The above-mentioned compound was dissolved in trifluoroacetic acid (10 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with ethyl acetate and the extraction solution was dried and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give 4- (5-trifluoromethyl-1-benzimidazolyl) piperidine (960 mg).
[687] (5) 3-{(2S, 4S) -1-t- which was a white solid using the compound (646 mg) described above and the title compound (601 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (5-trifluoromethyl-1-benzimidazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (795 mg) Got.
[688] (6) The title compound (558 mg) was obtained as a white powder using the compound (791 mg) described above in the same manner as in Example 60 (5).
[689] ¹ H-NMR (DMSO-d ₆ ) δ 2.25-2.43 (3H, m), 2.60-2.78 (2H, m), 2.98-3.21 (3H, m), 3.27-4.15 (9H, m), 4.47-4.80 (3H, m), 4.91-5.07 (1H, m), 7.75 (1H, d, J = 8.6 kPa), 8.14 (1H, s), 8.28 (1H, d, J = 8.6 kPa), 8.96 (1H, s), 9.21 (1H, brs), 10.87 (1H, brs), 12.51 (1H, brs).
[690] Example 65
[691] 3-{(2S, 4S) -4- [4- (5-trifluoromethyl-2-methyl-1-benzimidazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3 -Synthesis of Thiazolidine Trichloride
[692] (1) The product of Example 64 (2) (1.9 g) was dissolved in dichloromethane (15 mL) and acetic anhydride (0.500 mL) was added. The mixture was stirred overnight. The reaction solution was concentrated under reduced pressure to give 4- (2-acetylamino-4-trifluoromethylphenyl) amino-1-t-butoxycarbonylpiperidine.
[693] (2) The above compound was dissolved in acetic acid (15 mL) and the mixture was stirred at 80 ° C. overnight. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with ethyl acetate and the extraction solution was dried and concentrated under reduced pressure. The residue was purified by ISOLUTE FLUSH SIL to give 1-t-butoxycarbonyl-4- (5-trifluoromethyl-2-methyl-1-benzimidazolyl) piperidine.
[694] (3) The compound described above was dissolved in trifluoroacetic acid (20 mL) and left to stand for 4 hours. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with ethyl acetate and the extraction solution was dried and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexanes to give 4- (5-trifluoromethyl-2-methyl-1-benzimidazolyl) piperidine (730 mg).
[695] (4) 3-{(2S, 4S) -1-t- which was a white solid using the compound (614 mg) described above and the title compound (601 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (5-trifluoromethyl-2-methyl-1-benzimidazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (902 mg) was obtained.
[696] (5) The title compound (818 mg) as a white powder was obtained in the same manner as the Example 31 (4) using the compound (898 mg) described above.
[697] ¹ H-NMR (DMSO-d ₆ ) δ 2.20-2.40 (3H, m), 2.87 (3H, s), 2.91-3.20 (5H, m), 3.25-4.20 (9H, m), 4.48-4.79 (3H , m), 4.95-5.09 (1H, m), 7.73 (1H, d, J = 8.6 Hz), 8.11 (1H, s), 8.62 (1H, d, J = 8.6 Hz), 9.23 (1H, brs) , 10.90 (1H, brs), 12.75 (1H, brs).
[698] Example 66
[699] Synthesis of 3-{(2S, 4S) -4- [4- (6-fluoro-2-benzoxazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine
[700] (1) To a mixed solution of ethanol (76 g) and chloroform (110 mL) was added acetyl chloride (107 mL) dropwise under ice cooling. After stirring for 30 minutes, a solution of 1-benzyloxycarbonyl-4-cyanopiperidine (12.2 g) in chloroform (110 mL) was added under ice cooling. The mixture was stirred at rt for 1 h. The reaction solution was concentrated under reduced pressure to give 1-benzyloxycarbonyl-4- (ethoxycarbonimidoyl) piperidine hydrochloride (15.4 g) as a white solid.
[701] (2) The aforementioned compound (3.07 g) and 2-amino-5-fluorophenol (1.64 g) were dissolved in ethanol (60 mL) and the mixture was heated to reflux for 10 hours. The reaction solution was concentrated under reduced pressure and 1.0 mol / l hydrochloric acid was added to the residue. The mixture was extracted with ethyl acetate. The extraction solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 1-benzyloxycarbonyl-4- (6-fluoro-2-benzoxazolyl) piperidine (2.51 g) as a brown solid.
[702] (3) In the same manner as in Example 33 (3), using the compound (2.50 g) described above, 4- (6-fluoro-2-benzoxazolyl) piperidine (1.46 g) was obtained as a brown solid.
[703] (4) 3-{(2S, 4S) -1-t- which was a white solid using the aforementioned compound (529 mg) and the title compound (601 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (6-fluoro-2-benzoxazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (879 mg) was obtained.
[704] (5) The compound (874 mg) described above was dissolved in ethanol (3 mL) and the mixture was stirred at 7.4 mol / L hydrochloric acid-ethanol solution (1.5 mL) for 14 hours at room temperature. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with chloroform, the extraction solution was dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography and crystallized from diethyl ether to give the title compound (213 mg) as a white powder.
[705] ¹ H-NMR (DMSO-d ₆ ) δ 1.52-1.63 (1H, m), 1.70-1.87 (2H, m), 2.02-2.23 (4H, m), 2.25-2.36 (1H, m), 2.68-3.12 (8H, m), 3.57-3.98 (3H, m), 4.40-4.71 (2H, m), 7.71-7.27 (1H, m), 7.66-7.76 (2H, m).
[706] Example 67
[707] 3-{(2S, 4S) -4- [4- (6-methoxy-2-benzoxazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidinetrichloride Synthesis of
[708] (1) 1-benzyloxycar which is a brown oil using the product of Example 66 (1) (1.54 g) and 2-amino-5-methoxyphenol (1.01 g) in the same manner as Example 66 (2) Bonyl-4- (6-methoxy-2-benzoxazolyl) piperidine (1.61 g) was obtained.
[709] (2) In the same manner as in Example 33 (3), 4- (6-methoxy-2-benzoxazolyl) piperidine (0.951 g) as a reddish brown solid was obtained using the compound (1.60 g) described above.
[710] (3) 3-{(2S, 4S) -1-t- which was a white solid using the compound (557 mg) described above and the title compound (601 mg) of Reference Example 3 in the same manner as in Example 29 (1). Butoxycarbonyl-4- [4- (6-methoxy-2-benzoxazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine (885 mg) was obtained.
[711] (4) The compound (881 mg) described above was dissolved in ethyl acetate (2 mL), and 4 mol / L hydrochloric acid-ethyl acetate solution (4.3 mL) was added. The mixture was stirred at rt for 14 h. The precipitate was collected by filtration to give the title compound (780 mg) as a white solid.
[712] ¹ H-NMR (DMSO-d ₆ ) δ 2.10-2.45 (6H, m), 2.91-4.08 (15H, m), 4.45-4.78 (3H, m), 6.96 (1H, dd, J = 8.7, 2.3 ㎐ ), 7.34 (1H, d, J = 2.3 Hz), 7.59 (1H, d, J = 8.7 Hz), 9.13 (1H, brs), 10.72 (1H, brs), 12.08 (1H, brs).
[713] Example 68
[714] 3-((2S, 4S) -4- {4- [3-trifluoromethyl-1- (4-methoxyphenyl) -5-pyrazolyl] -1,2,3,6-tetrahydropyridine- Synthesis of 1-yl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine dihydrochloride
[715] (1) In the same manner as in Example 59 (2), using the compound of Example 59 (1) (1.54 g) and 4-methoxyphenylhydrazine hydrochloride (1.36 g) and pyridine (630 mL), the oil was 4- [3-trifluoromethyl-1- (4-methoxyphenyl) -5-pyrazolyl] pyridine (2.26 g) was obtained.
[716] (2) In the same manner as in Example 59 (3), using the compound (2.26 g) and benzyl chloride (1.63 mL) described above, a pyridinium salt was obtained, which was reduced to sodium borohydride (0.540 g) to give an oil of 1 -Benzyl-4- [3-trifluoromethyl-1- (4-methoxyphenyl) -5-pyrazolyl] -1,2,3,6-tetrahydropyridine (1.79 g) was obtained.
[717] (3) The above compound (1.65 g) was dissolved in dichloromethane (40 mL) and 1-chloroethyl carbonate (0.520 mL) was added under ice cooling. The mixture was stirred at rt for 24 h. The reaction solution was concentrated under reduced pressure and methanol (30 mL) was added to the residue. The mixture was heated to reflux for 1 hour. The solvent was evaporated under reduced pressure and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with chloroform. The extract solution was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the oil 4- [3-trifluoromethyl-1- (4-methoxyphenyl) -5-pyrazolyl] -1,2,3,6-tetrahydropyridine ( 1.10 g) was obtained.
[718] (4) 3-((2S, 4S) -1-t- which is a pale yellow powder using the aforementioned compound (1.05 g) and the title compound (0.890 g) of Reference Example 3 in the same manner as in Example 29 (1) Butoxycarbonyl-4- {4- [3-trifluoromethyl-1- (4-methoxyphenyl) -5-pyrazolyl] -1,2,3,6-tetrahydropyridin-1-yl} 2-pyrrolidinylcarbonyl) -1,3-thiazolidine (1.70 g) was obtained.
[719] (5) The title compound (648 mg) as a pale yellow solid was obtained using the compound (762 mg) described above in the same manner as in Example 36 (4).
[720] ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 2.00-2.65 (2H, m), 2.78-4.10 (13H, m), 3.83 (3H, s), 4.46-4.72 (3H, m), 5.72 (1H, s), 7.03 (1H, s), 7.52-7.55 (2H, m), 7.07 (2H, d, J = 8.9 kPa), 7.45 (2H, d, J = 8.9 kPa), 9.04 (1H, brs), 10.35 (1H, brs).
[721] The structures of the compounds obtained in the above examples are shown in Tables 1 to 9 below.
[722]
[723]
[724]
[725]
[726] TABLE 5
[727]
[728]
[729] TABLE 6
[730]
[731]
[732]
[733]
[734]
[735] The following compounds can be synthesized by methods similar to those of the foregoing examples.
[736] 3-[(S) -2-amino-6- (4-benzenesulfonylphenylamino) hexanoyl] -1,3-thiazolidine,
[737] 3-{(S) -2-amino-6- [N- (4-methanesulfonylphenyl) -N-methylamino] hexanoyl} -1,3-thiazolidine,
[738] 3-{(S) -2-amino-6- [N- (5-cyanopyridin-2-yl) -N-methylamino] hexanoyl} -1,3-thiazolidine,
[739] 3-{(S) -2-amino-6- [N- (5-cyanopyridin-2-yl) -N-benzylamino] hexanoyl} -1,3-thiazolidine,
[740] 1-[(S) -2-amino-6- (4-methanesulfonylphenylamino) hexanoyl] pyrrolidine,
[741] 1-[(S) -2-amino-6- (5-cyanopyridin-2-ylamino) hexanoyl] pyrrolidine,
[742] 3-[(S) -2-amino-6- (5,6-dicyanopyridin-2-ylamino) hexanoyl] -1,3-thiazolidine,
[743] 3-[(S) -2-amino-6- (3,4-dicyanophenylamino) hexanoyl] -1,3-thiazolidine,
[744] 3-{(S) -2-amino-6- [4- (4-nitrophenyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[745] 3-{(S) -2-amino-6- [4- (3,5-dichlorophenyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[746] 3-{(S) -2-amino-6- [4- (pyridin-2-yl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[747] 3-{(S) -2-amino-6- [4- (pyridin-4-yl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[748] 3-{(S) -2-amino-6- [4- (4-cyanopyridin-2-yl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[749] 3-{(S) -2-amino-6- [4- (5-cyanopyridin-2-yl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[750] 3-{(S) -2-amino-6- [4- (5-nitropyridin-2-yl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[751] 3-{(S) -2-amino-6- [4- (5-trifluoromethylpyridin-2-yl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[752] 3-{(S) -2-amino-6- [4- (5-carboxypyridin-2-yl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[753] 3-((S) -2-amino-6- {4- [5- (ethoxycarbonyl) pyridin-2-yl] piperazin-1-yl} hexanoyl) -1,3-thiazolidine,
[754] 3-{(S) -2-amino-6- [4- (5-carbamoylpyridin-2-yl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[755] 3-{(S) -2-amino-6- [4- (3,5-dichloropyridin-4-yl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[756] 3-{(S) -2-amino-6- [4- (1-phenyl-2-imidazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[757] 3-{(S) -2-amino-6- [4- (1-phenyl-5-pyrazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[758] 3-{(S) -2-amino-6- [4- (3-methyl-1-phenyl-5-pyrazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[759] 3-((S) -2-amino-6- {4- [1- (pyridin-2-yl) -5-pyrazolyl] piperazin-1-yl} hexanoyl) -1,3-thiazolidine ,
[760] 3-((S) -2-amino-6- {4- [4- (4-cyanophenyl) -2-thiazolyl] piperazin-1-yl} hexanoyl) -1,3-thiazolidine ,
[761] 3-{(S) -2-amino-6- [4- (1-phenyl-1H-tetrazol-5-yl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[762] 3-{(S) -2-amino-6- [4- (1-isoquinolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[763] 3-{(S) -2-amino-6- [4- (4-cyano-1-isoquinolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[764] 3-{(S) -2-amino-6- [4- (4-quinolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[765] 3-{(S) -2-amino-6- [4- (2-methyl-4-quinolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[766] 3-{(S) -2-amino-6- [4- (2-trifluoromethyl-6-methoxy-4-quinolyl) piperazin-1-yl] hexanoyl} -1,3-thia Jolidine,
[767] 3-{(S) -2-amino-6- [4- (2-trifluoromethyl-8-methoxy-4-quinolyl) piperazin-1-yl] hexanoyl} -1,3-thia Jolidine,
[768] 3-{(S) -2-amino-6- [4- (6-chloro-2-trifluoromethyl-4-quinolyl) piperazin-1-yl] hexanoyl} -1,3-thiazoli Dean,
[769] 3-{(S) -2-amino-6- [4- (2-trifluoromethyl-6,8-dimethoxy-4-quinolyl) piperazin-1-yl] hexanoyl} -1,3 Thiazolidine,
[770] 3-{(S) -2-amino-6- [4- (2-cyano-4-quinolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[771] 3-{(S) -2-amino-6- [4- (4-quinazolinyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[772] 3-{(S) -2-amino-6- [4- (2-trifluoromethyl-4-quinazolinyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[773] 3-{(S) -2-amino-6- [4- (2-benzimidazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[774] 3-{(S) -2-amino-6- [4- (5-cyano-2-benzimidazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[775] 3-{(S) -2-amino-6- [4- (1-methyl-2-benzimidazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[776] 3-{(S) -2-amino-6- [4- (1-phenyl-2-benzimidazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[777] 3-{(S) -2-amino-6- [4- (2-benzoxazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[778] 3-{(S) -2-amino-6- [4- (5-cyano-2-benzoxazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[779] 3-{(S) -2-amino-6- [4- (5-methoxy-2-benzoxazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[780] 3-{(S) -2-amino-6- [4- (2-benzothiazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[781] 3-{(S) -2-amino-6- [4- (5-cyano-2-benzothiazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[782] 3-{(S) -2-amino-6- [4- (5-methoxy-2-benzothiazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[783] 3-{(S) -2-amino-6- [4- (5-chloro-2-benzothiazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[784] 3-{(S) -2-amino-6- [4- (6-cyano-2-benzothiazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[785] 3-{(S) -2-amino-6- [4- (6-methoxy-2-benzothiazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[786] 3-{(S) -2-amino-6- [4- (6-chloro-2-benzothiazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[787] 3-{(S) -2-amino-6- [4- (3-benz [d] isoxazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[788] 3-{(S) -2-amino-6- [4- (5-cyano-3-benz [d] isoxazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine ,
[789] 3-{(S) -2-amino-6- [4- (3-benz [d] isothiazolyl) piperazin-1-yl] hexanoyl} -1,3-thiazolidine,
[790] 3-{(S) -2-amino-6- [4- (1-phenyl-5-pyrazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[791] 3-{(S) -2-amino-6- [4- (3-methyl-1-phenyl-5-pyrazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[792] 3-((S) -2-amino-6- {4- [1- (pyridin-2-yl) -5-pyrazolyl] piperidino} hexanoyl) -1,3-thiazolidine,
[793] 3-((S) -2-amino-6- {4- [4- (4-cyanophenyl) -2-thiazolyl] piperidino} hexanoyl) -1,3-thiazolidine,
[794] 3-{(S) -2-amino-6- [4- (1-phenyl-1H-tetrazol-5-yl) piperidino] hexanoyl} -1,3-thiazolidine,
[795] 3-{(S) -2-amino-6- [4- (2-benzimidazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[796] 3-{(S) -2-amino-6- [4- (2-benzimidazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[797] 3-{(S) -2-amino-6- [4- (5-cyano-2-benzimidazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[798] 3-{(S) -2-amino-6- [4- (1-methyl-2-benzimidazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[799] 3-{(S) -2-amino-6- [4- (1-phenyl-2-benzimidazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[800] 3-{(S) -2-amino-6- [4- (2-benzoxazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[801] 3-{(S) -2-amino-6- [4- (5-cyano-2-benzoxazolyl) piperidino] hexanoyl} -1,3-thiazoldine,
[802] 3-{(S) -2-amino-6- [4- (5-methoxy-2-benzoxazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[803] 3-{(S) -2-amino-6- [4- (5-chloro-2-benzoxazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[804] 3-{(S) -2-amino-6- [4- (2-benzothiazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[805] 3-{(S) -2-amino-6- [4- (5-cyano-2-benzothiazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[806] 3-{(S) -2-amino-6- [4- (5-methoxy-2-benzothiazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[807] 3-{(S) -2-amino-6- [4- (5-chloro-2-benzothiazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[808] 3-{(S) -2-amino-6- [4- (6-cyano-2-benzothiazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[809] 3-{(S) -2-amino-6- [4- (6-methoxy-2-benzothiazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[810] 3-{(S) -2-amino-6- [4- (6-chloro-2-benzothiazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[811] 3-{(S) -2-amino-6- [4- (3-benz [d] isoxazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[812] 3-{(S) -2-amino-6- [4- (5-cyano-3-benz [d] isoxazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[813] 3-{(S) -2-amino-6- [4- (3-benz [d] isothiazolyl) piperidino] hexanoyl} -1,3-thiazolidine,
[814] 3-{(2S, 4S) -4- [4- (5,6-dicyano-2-pyridyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazoli Dean,
[815] 3-{(2S, 4S) -4- [4- (3-nitro-2-pyridyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[816] 3-{(2S, 4S) -4- [4- (2-cyano-4-pyrimidinyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine ,
[817] 3-{(2S, 4S) -4- [4- (4-cyano-2-phenylphenyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[818] 3-{(2S, 4S) -4- [4- (4-cyano-2-pyridylphenyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine ,
[819] 3-{(2S, 4S) -4- [4- (5-cyano-3-phenyl-2-pyridyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3- Thiazolidine,
[820] 3-{(2S, 4S) -4- [4- (1-phenyl-2-pyrrolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[821] 3-{(2S, 4S) -4- [4- (4-methyl-1-phenyl-2-pyrrolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thia Jolidine,
[822] 3-((2S, 4S) -4- {4- [1- (2-pyridyl) -2-pyrrolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3- Thiazolidine,
[823] 3-((2S, 4S) -4- {4- [4-methyl-1- (2-pyridyl) -2-pyrrolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl)- 1,3-thiazolidine,
[824] 3-{(2S, 4S) -4- [4- (1,3-dimethyl-5-pyrazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine ,
[825] 3-((2S, 4S) -4- {4- [1- (2-pyridyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3- Thiazolidine,
[826] 3-((2S, 4S) -4- {4- [3-methyl-1- (2-methylphenyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1 , 3-thiazolidine,
[827] 3-((2S, 4S) -4- {4- [3-methyl-1- (3-methylphenyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1 , 3-thiazolidine,
[828] 3-((2S, 4S) -4- {4- [3-methyl-1- (4-methylphenyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1 , 3-thiazolidine,
[829] 3-((2S, 4S) -4- {4- [1- (2-methoxyphenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine,
[830] 3-((2S, 4S) -4- {4- [1- (3-methoxyphenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine,
[831] 3-((2S, 4S) -4- {4- [1- (4-methoxyphenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine,
[832] 3-((2S, 4S) -4- {4- [1- (2-chlorophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl)- 1,3-thiazolidine,
[833] 3-((2S, 4S) -4- {4- [1- (3-chlorophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl)- 1,3-thiazolidine,
[834] 3-((2S, 4S) -4- {4- [1- (2-cyanophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine,
[835] 3-((2S, 4S) -4- {4- [1- (3-cyanophenyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine,
[836] 3-((2S, 4S) -4- {4- [3-methyl-1- (2-pyrimidinyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine,
[837] 3-((2S, 4S) -4- {4- [3-methyl-1- (4-pyrimidinyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine,
[838] 3-((2S, 4S) -4- {4- [1- (2-imidazolyl) -3-methyl-5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine,
[839] 3-((2S, 4S) -4- {4- [3-methyl-1- (2-oxazolyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl)- 1,3-thiazolidine,
[840] 3-((2S, 4S) -4- {4- [3-trifluoromethyl-1- (2-pyridyl) -5-pyrazolyl] -1-piperazinyl} -2-pyrrolidinylcar Carbonyl) -1,3-thiazolidine,
[841] 3-{(2S, 4S) -4- [4- (4-methyl-1-phenyl-2-imidazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3- Thiazolidine,
[842] 3-((2S, 4S) -4- {4- [1- (2-pyridyl) -2-imidazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3 Thiazolidine,
[843] 3-((2S, 4S) -4- {4- [1- (3-pyridyl) -2-imidazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3 Thiazolidine,
[844] 3-((2S, 4S) -4- {4- [1- (4-pyridyl) -2-imidazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3 Thiazolidine,
[845] 3-((2S, 4S) -4- {4- [4-methyl-1- (2-pyridyl) -2-imidazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine,
[846] 3-((2S, 4S) -4- {4- [4-methyl-1- (3-pyridyl) -2-imidazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine,
[847] 3-((2S, 4S) -4- {4- [4-methyl-1- (4-pyridyl) -2-imidazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine,
[848] 3-{(2S, 4S) -4- [4- (2-phenyl-1,2,4-triazol-3-yl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1 , 3-thiazolidine,
[849] 3-{(2S, 4S) -4- [4- (5-methyl-2-phenyl-1,2,4-triazol-3-yl) -1-piperazinyl] -2-pyrrolidinylcar Carbonyl} -1,3-thiazolidine,
[850] 3-((2S, 4S) -4- {4- [2- (2-pyridyl) -1,2,4-triazol-3-yl] -1-piperazinyl} -2-pyrrolidinyl Carbonyl) -1,3-thiazolidine,
[851] 3-((2S, 4S) -4- {4- [5-methyl-2- (2-pyridyl) -1,2,4-triazol-3-yl] -1-piperazinyl} -2 -Pyrrolidinylcarbonyl) -1,3-thiazolidine,
[852] 3-{(2S, 4S) -4- [4- (5-phenyl-4-oxazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[853] 3-{(2S, 4S) -4- [4- (2-methyl-5-phenyl-4-oxazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thia Jolidine,
[854] 3-((2S, 4S) -4- {4- [5- (2-pyridyl) -4-oxazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1,3- Thiazolidine,
[855] 3-((2S, 4S) -4- {4- [2-methyl-5- (2-pyridyl) -4-oxazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl)- 1,3-thiazolidine,
[856] 3-{(2S, 4S) -4- [4- (2-methyl-5-phenyl-4-thiazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thia Jolidine,
[857] 3-((2S, 4S) -4- {4- [2-methyl-5- (2-pyridyl) -4-thiazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl)- 1,3-thiazolidine,
[858] 3-{(2S, 4S) -4- [4- (2-methyl-5-phenyl-1H-imidazol-4-yl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1 , 3-thiazolidine,
[859] 3-((2S, 4S) -4- {4- [2-methyl-5- (2-pyridyl) -1H-imidazol-4-yl] -1-piperazinyl} -2-pyrrolidinyl Carbonyl) -1,3-thiazolidine,
[860] 3-{(2S, 4S) -4- [4- (4-cyano-1-naphthyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[861] 3-{(2S, 4S) -4- [4- (4-chloro-1-naphthyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[862] 3-{(2S, 4S) -4- [4- (4-trifluoromethyl-1-naphthyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazoli Dean,
[863] 3-{(2S, 4S) -4- [4- (4-trifluoromethyl-1-isoquinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thia Jolidine,
[864] 3-{(2S, 4S) -4- [4- (3-cyano-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[865] 3-{(2S, 4S) -4- [4- (2-cyano-8-methoxy-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3 Thiazolidine,
[866] 3-{(2S, 4S) -4- [4- (7-chloro-2-trifluoromethyl-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1, 3-thiazolidine,
[867] 3-{(2S, 4S) -4- [4- (2-trifluoromethyl-7-hydroxy-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1 , 3-thiazolidine,
[868] 3-((2S, 4S) -4- {4- [2,7-bis (trifluoromethyl) -4-quinolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1 , 3-thiazolidine,
[869] 3-{(2S, 4S) -4- [4- (2-trifluoromethyl-5-methoxy-4-quinolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1 , 3-thiazolidine,
[870] 3-{(2S, 4S) -4- [4- (2-cyano-4-quinazolinyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine ,
[871] 3-{(2S, 4S) -4- [4- (2-trifluoromethyl-1,8-naphthyridin-4-yl) -1-piperazinyl] -2-pyrrolidinylcarbonyl}- 1,3-thiazolidine,
[872] 3-{(2S, 4S) -4- [4- (2-trifluoromethyl-1,6-naphthyridin-4-yl) -1-piperazinyl] -2-pyrrolidinylcarbonyl}- 1,3-thiazolidine,
[873] 3-{(2S, 4S) -4- [4- (1H-indol-2-yl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[874] 3-{(2S, 4S) -4- [4- (1-phenyl-1H-indol-2-yl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazoli Dean,
[875] 3-((2S, 4S) -4- {4- [1- (2-pyridyl) -1H-indol-2-yl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1 , 3-thiazolidine,
[876] 3-{(2S, 4S) -4- [4- (3-methyl-1-phenyl-1H-indol-2-yl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1, 3-thiazolidine,
[877] 3-{(2S, 4S) -4- [4- (1-phenyl-2-benzimidazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine ,
[878] 3-((2S, 4S) -4- {4- [1- (2-pyridyl) -2-benzimidazolyl] -1-piperazinyl} -2-pyrrolidinylcarbonyl) -1, 3-thiazolidine,
[879] 3-{(2S, 4S) -4- [4- (5-cyano-1-phenyl-2-benzimidazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1, 3-thiazolidine,
[880] 3-{(2S, 4S) -4- [4- (5-methoxy-1-phenyl-2-benzimidazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1, 3-thiazolidine,
[881] 3-{(2S, 4S) -4- [4- (5-chloro-1-phenyl-2-benzimidazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3 Thiazolidine,
[882] 3-{(2S, 4S) -4- [4- (6-cyano-1-phenyl-2-benzimidazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1, 3-thiazolidine,
[883] 3-{(2S, 4S) -4- [4- (6-methoxy-1-phenyl-2-benzimidazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1, 3-thiazolidine,
[884] 3-{(2S, 4S) -4- [4- (6-chloro-1-phenyl-2-benzimidazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3 Thiazolidine,
[885] 3-{(2S, 4S) -4- [4- (5-methoxy-2-benzoxazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine ,
[886] 3-{(2S, 4S) -4- [4- (5-chloro-2-benzoxazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[887] 3-{(2S, 4S) -4- [4- (6-cyano-2-benzoxazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine ,
[888] 3-{(2S, 4S) -4- [4- (6-methoxy-2-benzoxazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine ,
[889] 3-{(2S, 4S) -4- [4- (6-chloro-2-benzoxazolyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[890] 3-{(2S, 4S) -4- [4- (6-methoxy-2-oxazolo [4,5-b] pyridyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[891] 3-{(2S, 4S) -4- [4- (6-cyano-2-oxazolo [4,5-b] pyridyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[892] 3-{(2S, 4S) -4- [4- (5-cyano-2-oxazolo [4,5-b] pyridyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[893] 3-{(2S, 4S) -4- [4- (1-methyl-2-phenyl-1H-indol-3-yl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1, 3-thiazolidine,
[894] 3-{(2S, 4S) -4- [4- (9-acridinyl) -1-piperazinyl] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[895] 3-{(2S, 4S) -4- [4- (2-phenyl-1,2,4-triazol-3-yl) piperidino] -2-pyrrolidinylcarbonyl} -1,3- Thiazolidine,
[896] 3-{(2S, 4S) -4- [4- (5-methyl-2-phenyl-1,2,4-triazol-3-yl) piperidino] -2-pyrrolidinylcarbonyl}- 1,3-thiazolidine,
[897] 3-((2S, 4S) -4- {4- [2- (2-pyridyl) -1,2,4-triazol-3-yl] piperidino} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine,
[898] 3-((2S, 4S) -4- {4- [5-methyl-2- (2-pyridyl) -1,2,4-triazol-3-yl] piperidino} -2-pyrroli Genylcarbonyl) -1,3-thiazolidine,
[899] 3-{(2S, 4S) -4- [4- (5-phenyl-4-oxazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[900] 3-{(2S, 4S) -4- [4- (2-methyl-5-phenyl-4-oxazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[901] 3-((2S, 4S) -4- {4- [5- (2-pyridyl) -4-oxazolyl] piperidino} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine ,
[902] 3-((2S, 4S) -4- {4- [2-methyl-5- (2-pyridyl) -4-oxazolyl] piperidino} -2-pyrrolidinylcarbonyl) -1,3 Thiazolidine,
[903] 3-{(2S, 4S) -4- [4- (5-phenyl-4-isooxazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[904] 3-((2S, 4S) -4- {4- [5- (2-pyridyl) -4-isooxazolyl] piperidino} -2-pyrrolidinylcarbonyl) -1,3-thiazoli Dean,
[905] 3-{(2S, 4S) -4- [4- (5-phenyl-4-thiazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[906] 3-{(2S, 4S) -4- [4- (2-methyl-5-phenyl-4-thiazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[907] 3-((2S, 4S) -4- {4- [5- (2-pyridyl) -4-thiazolyl] piperidino} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine ,
[908] 3-((2S, 4S) -4- {4- [2-methyl-5- (2-pyridyl) -4-thiazolyl] piperidino} -2-pyrrolidinylcarbonyl) -1,3 Thiazolidine,
[909] 3-{(2S, 4S) -4- [4- (2-phenyl-1-pyrrolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[910] 3-((2S, 4S) -4- {4- [2- (2-pyridyl) -1-pyrrolyl] piperidino} -2-pyrrolidinylcarbonyl) -1,3-thiazolidine ,
[911] 3-{(2S, 4S) -4- [4- (2-phenyl-1-imidazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[912] 3-((2S, 4S) -4- {4- [2- (2-pyridyl) -1-imidazolyl] piperidino} -2-pyrrolidinylcarbonyl) -1,3-thiazoli Dean,
[913] 3-{(2S, 4S) -4- [4- (4-methyl-2-phenyl-1-imidazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine ,
[914] 3-((2S, 4S) -4- {4- [4-methyl-2- (2-pyridyl) -1-imidazolyl] piperidino} -2-pyrrolidinylcarbonyl) -1, 3-thiazolidine,
[915] 3-((2S, 4S) -4- {4- [1- (4-methylphenyl) -1H-tetrazol-5-yl] piperidino} -2-pyrrolidinylcarbonyl) -1,3- Thiazolidine,
[916] 3-((2S, 4S) -4- {4- [1- (2-fluorophenyl) -1H-tetrazol-5-yl] piperidino} -2-pyrrolidinylcarbonyl) -1, 3-thiazolidine,
[917] 3-((2S, 4S) -4- {4- [1- (3-fluorophenyl) -1H-tetrazol-5-yl] piperidino} -2-pyrrolidinylcarbonyl) -1, 3-thiazolidine,
[918] 3-((2S, 4S) -4- {4- [1- (2-pyridyl) -1H-tetrazol-5-yl] piperidino} -2-pyrrolidinylcarbonyl) -1,3 Thiazolidine,
[919] 3-{(2S, 4S) -4- [4- (1-phenyl-2-benzimidazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[920] 3-{(2S, 4S) -4- [4- (5-cyano-1-phenyl-2-benzimidazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thia Jolidine,
[921] 3-{(2S, 4S) -4- [4- (5-chloro-1-phenyl-2-benzimidazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazoli Dean,
[922] 3-{(2S, 4S) -4- [4- (5-methoxy-1-phenyl-2-benzimidazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thia Jolidine,
[923] 3-{(2S, 4S) -4- [4- (5-chloro-2-benzoxazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[924] 3-{(2S, 4S) -4- [4- (5-cyano-2-benzothiazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[925] 3-{(2S, 4S) -4- [4- (5-methoxy-2-benzothiazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[926] 3-{(2S, 4S) -4- [4- (2-oxazolo [4,5-b] pyridyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine ,
[927] 3-{(2S, 4S) -4- [4- (6-cyano-2-oxazolo [4,5-b] pyridyl) piperidino] -2-pyrrolidinylcarbonyl} -1, 3-thiazolidine,
[928] 3-{(2S, 4S) -4- [4- (2-phenyl-1-benzimidazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thiazolidine,
[929] 3-{(2S, 4S) -4- [4- (5-trifluoromethyl-2-phenyl-1-benzimidazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3 Thiazolidine,
[930] 3-{(2S, 4S) -4- [4- (5-cyano-2-phenyl-1-benzimidazolyl) piperidino] -2-pyrrolidinylcarbonyl} -1,3-thia Zolidine.
[931] 3-L-lysyl-1,3-thiazolidine-trifluoroacetic acid salt as the comparative compound 1 was synthesize | combined by the following method.
[932] 50% trifluoroacetic acid / dichloromethane (8 mL) was added to the resin (1209 mg) of Example 7 (1) and the mixture was stirred for 2 hours. The resin was removed by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by ISOLUTE FLUSH C18 to give the title compound (280 mg).
[933] MS (ESI) m / z: 218 [M−H] ⁺
[934] Compounds of the present invention have potent DPP-IV inhibitory activity as exemplified in Experimental Example 1 below.
[935] Experimental Example 1 (Plasma DPP-IV Inhibitory Activity)
[936] Plasma DPP-IV inhibitory activity of humans and rats was measured under fluorescence assay and the conditions of Table 10 below. Using Gly-Pro-MCA (Peptide Institute, Inc.) as the DPP-IV specific fluorescent substrate, the reaction solution of the following composition containing various concentrations of test substance was incubated at room temperature for 60 minutes and measured (SPECTRA). FLUOR, Tecan Group, Limited) to fluorescence intensity (excitation 360 nm / emission 465 nm) as DPP-IV activity.
[937] Rat or human plasma (10-fold dilution)20 μl / well Fluorescent Substrate (100 μmol / ℓ)20 μl / well Test substance20 μl / well Buffer (PBS containing 0.003% Brij-35)140 μl / well Total amount200 μl / well
[938] The inhibition rate for the solvent addition group was calculated and IC ₅₀ values were determined by logistic analysis.
[939] The IC ₅₀ values of the plasma DPP-IV inhibitory activity of the present invention obtained by the above method are shown in Tables 11 and 12 below.
[940] Example Compound NumberHuman Plasma DPP-IV Inhibitory Activity IC ₅₀ (nM)Rat Plasma DPP-IV Inhibitory Activity IC ₅₀ (nM) 52819 63429 71513 136640 142918 283549 Comparative Compound 1856719
[941] Example Compound NumberHuman Plasma DPP-IV Inhibitory Activity IC ₅₀ (nM)Rat Plasma DPP-IV Inhibitory Activity IC ₅₀ (nM) 400.630.72 480.250.37 550.240.30 560.911.17
[942] Comparative Compound 1 is a compound included in WO99 / 61431. As shown in Table 11, plasma DPP-IV inhibitory activity is not sufficient.
[943] In addition, as shown in Table 13, the plasma DPP-IV inhibitory activity of the compounds of JP-T-9-509921 and the compounds of WO99 / 61431 is insufficient.
[944] Known CompoundHuman plasma DPP-IV inhibitory activity IC ₅₀ (nM) (S) -2-cyano-1-L-prolylpyrrolidine hydrochloride2.9 3-L-prolyl-1,3-thiazolidine538
[945] Industrial availability
[946] From the above experimental examples and pharmacological experiments, the present invention shows potent DPP-IV inhibitory activity and is useful for the prevention, treatment of diabetes or the prevention and treatment of obesity.
[947] This application is based on Japanese Patent Application No. 2001-279084 and Japanese Patent Application No. 2001-304650 filed in Japan, the contents of which are incorporated herein by reference.

权利要求:
Claims (12)
[1" claim-type="Currently amended] Thiazolidine derivatives of formula (I) or a pharmaceutically acceptable salt thereof.
Formula I

In the above formula, X is a substituent selected from formula (I-a) or formula (I-b);
Y is methylene, hydroxymethylene, sulfur atom, sulfinyl or sulfonyl;
Z is a hydrogen atom or cyano;
Provided that when X is a substituent of formula (I-a), Z is a hydrogen atom;
Formula I-a

Formula I-b

Where m is an integer of 1 or 2,
n is an integer of 1 to 5,
X 'is an alkyl optionally having a hydrogen atom or substituent (s),
Y ′ is —NR ¹ R ² , wherein R ¹ is aryl optionally having substituent (s) or heteroaryl optionally having substituent (s), R ² is a hydrogen atom, alkyl optionally having substituent (s), substituent Aryl optionally with (s), arylalkyl optionally with substituent (s), heteroaryl optionally with substituent (s) or heteroarylalkyl optionally with substituent (s) or R ¹ and R ² are bonded to each other carbon And a heterocycle having one or more nitrogens, optionally optionally having other hetero atom (s) and substituent (s), wherein the aromatic ring optionally bearing substituent (s) to this heterocycle may be optionally substituted or fused. Can and
Is a single bond or a double bond,
A is a carbon atom or a nitrogen atom,
Wherein i) when A is a carbon atom, A is optionally substituted with a hydroxyl group, carboxy or alkoxycarbonyl, and ii) when A is a nitrogen atom, Is a single bond,
Q is aryl or heteroaryl selected from compounds of formula II to formula XII,
Formula II

Formula III

Formula IV

Formula V

Formula VI

Formula VII

Formula VIII

Formula IX

Formula X

Formula XI

Formula XII

only,
(i) in formula (II), a, b, c and d are one to three nitrogen atom (s), the remainder is carbon atom (s) or both are nitrogen atoms,
R ^1a is alkyl, phenyl, pyridyl, pyrimidinyl, imidazolyl or oxazolyl, wherein these groups are optionally substituted with one or more from alkyl, alkoxy, halogen or cyano,
R ^2a is a hydrogen atom, alkyl or haloalkyl, provided that
(i-1) when b is a nitrogen atom, R ^2a is absent;
(i-2) when c and d are both nitrogen atoms, a and b are both carbon atoms, R ^1a is phenyl and R ^2a is alkyl, then R ^1a comprises one or more of the substituents described above;
(i-3) when a and d are both nitrogen atoms, b and c are both carbon atoms and R ^1a is unsubstituted phenyl, then R ^2a is alkyl or haloalkyl,
(i-4) where a, b, c and d are all nitrogen atoms and R ^1a is phenyl, (1) A in formula (Ib) is a carbon atom, R ^1a has no substituents as defined above, or (2 ) R ^1a is substituted with one or more of alkyl and halogen,
(ii) in Formula III, one of e and f is a nitrogen atom, the other is a carbon atom, or both are carbon atoms,
R ³ and R ⁴ may be the same or different and each is a hydrogen atom, alkyl, phenyl or pyridyl,
(iii) in formula IV, j is a sulfur atom, an oxygen atom or a nitrogen atom, h and i can be the same or different, each is a nitrogen atom or a carbon atom,
R ⁵ and R ⁷ may be the same or different and each is a hydrogen atom, phenyl or pyridyl, provided that when h is a nitrogen atom, R ⁷ is absent;
R ⁶ is a hydrogen atom or an alkyl, provided that when i is a nitrogen atom R ⁶ is absent;
(iv) in formula V, k, l and n 'may be the same or different, each being a carbon atom or a nitrogen atom, wherein at least one is a carbon atom,
R ⁸ is hydrogen atom, phenyl, pyridyl or nitro, provided that when R is a nitrogen atom, R ⁸ is absent;
R ^8a is a hydrogen atom or phenyl,
R ⁹ is a hydrogen atom, haloalkyl or cyano,
R ¹⁰ is a hydrogen atom or cyano, provided that when l is a nitrogen atom, R ¹⁰ is absent;
(iv-1) when k and n 'are both nitrogen atoms, (1) A in formula (Ib) is a nitrogen atom, and R ^8a , R ⁹ and R ¹⁰ are all hydrogen atoms, or (2) R ^8a is phenyl R ⁹ is haloalkyl,
(iv-2) when k, l and n 'are all carbon atoms, R ⁸ is phenyl or pyridyl,
(iv-3) when k is a nitrogen atom and l and n 'are both carbon atoms, then (1) R ⁸ is phenyl or nitro or (2) R ⁹ is cyano,
(iv-4) when l is a nitrogen atom, one of k and n 'is a nitrogen atom,
(v) in formula VI, p is a nitrogen atom or a carbon atom,
R ¹¹ is hydrogen atom, phenyl or pyridyl, provided that when p is a nitrogen atom, R ¹¹ is phenyl or pyridyl;
R ¹² is hydrogen or alkyl, provided that when p is a nitrogen atom, R ¹² is absent;
When R ¹³ and R ¹⁴ are both hydrogen atoms or one of them is a hydrogen atom, the other is cyano, alkoxy or halogen,
(vi) in formula VII, one of r and s is a nitrogen atom, the other is a carbon atom,
R ¹⁵ is hydrogen atom, alkyl or phenyl, provided that when r is nitrogen atom R ¹⁵ is absent;
R ¹⁶ is a hydrogen atom or alkyl, provided that when s is a nitrogen atom, R ¹⁶ is absent;
R ¹⁷ is a hydrogen atom, haloalkyl or cyano,
(vii) In formula (VIII), r 'and s' may be the same or different, each being a carbon atom or a nitrogen atom, provided that at least one of them is a nitrogen atom,
R ^15a is a hydrogen atom, alkyl or phenyl, provided that when r 'is a nitrogen atom, R ^15a is absent;
R ^16a is a hydrogen atom or alkyl, provided that when r 'and s' are both nitrogen atoms, R ^16a is a hydrogen atom;
R ^17a is a hydrogen atom, haloalkyl or cyano,
(viii) In formula (IX), t is a sulfur atom or an oxygen atom,
u is a carbon atom or a nitrogen atom,
R ¹⁸ and R ¹⁹ are both hydrogen atoms or one of them is a hydrogen atom and the other is cyano, alkoxy or halogen,
(viii-1) when u is a carbon atom, one of R ¹⁸ and R ¹⁹ is cyano, alkoxy or halogen,
(viii-2) when t is a sulfur atom, A in formula (Ib) is a carbon atom, R ¹⁹ is a hydrogen atom, R ¹⁸ is methoxy or cyano,
(viii-3) when A in formula (Ib) is a nitrogen atom, t is an oxygen atom, R ¹⁹ is a hydrogen atom, u is a carbon atom, R ¹⁸ is alkoxy or halogen,
(viii-4) when A in formula (Ib) is a carbon atom, R ¹⁹ is a hydrogen atom, u is a carbon atom, t is an oxygen atom, R ¹⁸ is halogen,
(ix) In formula (X), v, w, x and y may be the same or different, each being a carbon atom or a nitrogen atom, provided that at least two are carbon atoms,
R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ may be the same or different and 1-3 are haloalkyl, methoxy, ethoxy, isopropoxy, trifluorome Oxy, 2,2,2-trifluoroethoxy, hydroxy, cyano or halogen, the remainder is hydrogen atom (s), provided that when v is a nitrogen atom, R ²⁰ is absent and w is In the case of a nitrogen atom, R ²² is not present, when x is a nitrogen atom, R ²³ is not present and when y is a nitrogen atom, R ²⁵ is not present;
(ix-1) when v is a nitrogen atom and w, x and y are all carbon atoms, R ²² is haloalkyl,
(ix-2) when v and w are both nitrogen atoms and x and y are both carbon atoms, R ²¹ is cyano,
(ix-3) when w is a nitrogen atom and v, x and y are all carbon atoms, (1) R ²¹ is a hydrogen atom, R ²⁰ is cyano or (2) R ²¹ is haloalkyl, R ²³ is hydroxy, ethoxy, isopropoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy or (3) R ²¹ is haloalkyl and both R ²³ and R ²⁵ are methoxy (4) R ²¹ is haloalkyl, R ²⁴ is hydroxy, chloro or trifluoromethyl, (5) R ²¹ is haloalkyl, R ²⁵ is hydroxy or trifluoromethoxy, or (6) R ²¹ is haloalkyl, R ²⁶ is methoxy, or (7) R ²¹ is cyano, R ²³ is methoxy,
(x) In formula (XI), R ²⁷ and R ²⁸ may be the same or different and each is haloalkyl or alkoxy.
[2" claim-type="Currently amended] The compound of claim 1, wherein Y ′ in formula (Ia) is —NR ¹ R ² , wherein R ¹ is aryl optionally having substituent (s) or heteroaryl optionally having substituent (s), R ² is a hydrogen atom, Alkyl optionally with substituent (s), aryl optionally with substituent (s), arylalkyl optionally with substituent (s), heteroaryl optionally with substituent (s) or heteroarylalkyl optionally with substituent (s), or R ¹ and R ² may be bonded to each other to form a heterocycle having 1 or 2 nitrogen atom (s) or oxygen atom (s) and optionally having substituent (s), and the substituent (s) may be A thiazolidine derivative or pharmaceutically acceptable salt thereof, wherein the aromatic ring optionally having may be optionally substituted or fused.
[3" claim-type="Currently amended] The thiazolidine derivative or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X in formula (I) is a substituent of formula (I-a), and Z is a hydrogen atom.
[4" claim-type="Currently amended] The thiazolidine derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein X in formula (I) is a substituent of formula (I-b).
[5" claim-type="Currently amended] The thiazolidine derivative or pharmaceutically acceptable salt thereof according to claim 3, wherein Y 'of formula (I-a) is a substituent selected from formulas (II-a) to (II-d).
Formula II-a

Formula II-b

Formula II-c

Formula II-d

In the above formula, Is a single bond or a double bond, R ² is as defined in claim 1, R ^3a and R ^4a are the same or different and each independently represent a hydrogen atom, an alkyl optionally having substituent (s), a substituent ( Aryl optionally having substituent (s), arylalkyl optionally having substituent (s), heteroaryl optionally having substituent (s), heteroarylalkyl optionally having substituent (s), halogen, haloalkyl, cyano, nitro, -NR ^5a R ^6a , -NHSO ₂ R ^7a , -OR ^8b , -COOR ^9a , -CONHSO ₂ R ^10a , -SO ₂ OR ^11a , -SO ₂ R ^12a or -CONR ^13a R ^14a , wherein R ^5a , R ^6a , R ^7a , R ^8b , R ^9a , R ^10a , R ^11a , R ^12a , R ^13a and R ^14a are the same or different, each independently a hydrogen atom, an alkyl optionally having substituent (s), substituent (s) Optionally has cycloalkyl, optionally substituted with cyclo (alkyl) optionally substituted with cyclo (alkyl), optionally substituted with aryl, optionally substituted substituent (s) Is arylalkyl, heteroaryl optionally having substituent (s), heteroarylalkyl or haloalkyl optionally having substituent (s), R ^5a and R ^6a , and R ^13a and R ^14a are bonded to each other to form carbon and one or more nitrogen And optionally form a heterocycle having other hetero atom (s) and optionally having substituent (s), wherein the aromatic ring optionally having substituent (s) on such heterocycle may be optionally substituted or fused. A ', b', c ', d', e ', f' and g 'are all carbon atoms, or any one or two of them are nitrogen atom (s) and the rest are carbon atoms (S), m 'is 0, 1, 2 or 3, A' is a carbon atom or a nitrogen atom, provided that i) when A 'is a carbon atom, A' is a hydroxyl group, carboxy or alkoxycar May be substituted with carbonyl, and ii) when A 'is a nitrogen atom, Is a single bond.
[6" claim-type="Currently amended] The compound of claim 5, wherein R ^3a and R ^4a of Formula II-a, Formula II-b, Formula II-c, and Formula II-d may be the same or different, and each independently represent a hydrogen atom, a substituent ( Alkyl optionally with substituent (s), aryl optionally with substituent (s), arylalkyl optionally with substituent (s), heteroaryl optionally with substituent (s), heteroarylalkyl optionally with substituent (s), halogen, halo Alkyl, cyano, nitro, -NR ^5a R ^6a , -NHSO ₂ R ^7a , -OR ^8b , -COOR ^9a , -CONHSO ₂ R ^10a , -SO ₂ OR ^11a , -SO ₂ R ^12a or -CONR ^13a R ^14a Wherein R ^5a , R ^6a , R ^7a , R ^8b , R ^9a , R ^10a , R ^11a , R ^12a , R ^13a and R ^14a are the same or different, each independently hydrogen atom, substituent (s) Alkyl optionally having, cycloalkyl optionally having substituent (s), cycloalkylalkyl optionally having substituent (s), aryl optionally having substituent (s), substituent (s) Arylalkyl having optionally, a heteroaryl having substituent (s) optionally, a heteroaryl-alkyl or halo-alkyl having a substituent (s) optionally to combine with each other R ^5a and R ^6a, and R ^13a and R ^14a 1 or 2 nitrogen Heterocycles optionally having atom (s) or oxygen atom (s) and optionally having substituent (s) may be formed, and aromatic rings optionally having substituent (s) on such heterocycles may be optionally substituted or fused Thiazolidine derivatives or pharmaceutically acceptable salts thereof.
[7" claim-type="Currently amended] The thiazolidine derivative or pharmaceutically acceptable salt thereof of claim 3, wherein Y is a sulfur atom and X 'is a hydrogen atom.
[8" claim-type="Currently amended] 4. The compound of claim 3, wherein Y is a sulfur atom, X ′ is a hydrogen atom, and Y ′ is phenylamino, 2-pyridylamino or 4- (1-isoquinolyl) -1- optionally having substituent (s). Thiazolidine derivative or pharmaceutically acceptable salt thereof, which is piperazinyl.
[9" claim-type="Currently amended] A pharmaceutical composition comprising a thiazolidine derivative according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.
[10" claim-type="Currently amended] A DPP-IV inhibitor comprising a thiazolidine derivative according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.
[11" claim-type="Currently amended] A therapeutic agent for a disease involving DPP-IV, wherein the thiazolidine derivative according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof is used as an active ingredient.
[12" claim-type="Currently amended] The therapeutic agent of claim 11, wherein the disease involving DPP-IV is diabetes or obesity.

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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:
2001-09-14|Priority to JP2001279084

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2001-09-14|Priority to JPJP-P-2001-00279084

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2001-09-28|Priority to JPJP-P-2001-00304650

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2001-09-28|Priority to JP2001304650

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2002-09-13|Application filed by 미츠비시 웰파마 가부시키가이샤

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2002-09-13|Priority to PCT/JP2002/009419

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2004-04-17|Publication of KR20040033048A

优先权:

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申请号 | 申请日 | 专利标题

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JP2001279084|2001-09-14|

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JPJP-P-2001-00279084|2001-09-14|

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JPJP-P-2001-00304650|2001-09-28|

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JP2001304650|2001-09-28|

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PCT/JP2002/009419|WO2003024942A1|2001-09-14|2002-09-13|Thiazolidine derivative and medicinal use thereof|