WO2003095425A1 - Cyanopyrrolidine derivatives - Google Patents

Abstract

Cyanopyrrolidine derivatives represented by the general formula (1) or pharmaceutically acceptable salts thereof: (1) wherein W is an acyl group derived from a natural amino acid, a group represented by the general formula (2): (2) (wherein W1 is C1-5 alkanoyl, optionally substituted arylcarbonyl, or C1-5 alkyl; and W2 is hydrogen or C1-5 alkyl), or a group represented by the general formula (3): (3) (wherein W3 and W4 are each hydrogen or C1-5 alkyl); X is oxygen or sulfur; Y is -CR5R6- (wherein R5 and R6 are each independently hydrogen, halogeno, or the like) or -CR7R8-CR9R10- (wherein R7, R8, R9, and R10 are each independently hydrogen, halogeno, or the like); and Z is hydrogen or optionally substituted C1-10 alkyl, or Y and Z together with the nitrogen atom adjacent to them may form an optionally substituted cyclic amino group having 2 to 10 carbon atoms.

Description

Technical field

The present invention relates to a novel Mi derivative _(Background Art

 Dipidyl peptidase IV (DPP IV) is a type of serine protease that hydrolyzes dipeptides from peptide chains having proline or alanine at the second position from the N-terminus. DPP IV is widely distributed in tissues such as kidney and liver and plasma, and is involved in the metabolism of various bioactive peptides.

 Recently, it was revealed that DPP IV is involved in the metabolism of glucagon-like peptide 11 (GLP-1). In other words, DPPIV inactivates GLP-1 by hydrolyzing the dipeptide at the N-terminal His-Ala of GLP-1, and the inactivated form acts as an antagonist of the GLP-1 receptor. I have.

 It is known that GLP-1 has physiological actions of promoting secretion of insulin from the kidney, prolonging the gastric emptying time, and suppressing feeding. Therefore, inhibition of DPPIV can enhance the action of GLP-1, enhance insulin action and improve glucose metabolism, and is expected to be useful for the treatment of type 2 diabetes.

 In addition, DPP IV is involved in the metabolism of neuropeptide Y, a neuropeptide, activation of T cells, which are immunocompetent cells, adhesion of cancer cells to endothelium, and entry of HIV virus into lymphocytes. Are known. Therefore, inhibition of DPHV is considered to be useful for treating immune diseases and the like.

 Also, high levels of DPPIV expression have been found in fibroblasts on human skin from patients with psoriasis, rheumatoid arthritis and flat plaques, and high DPPIV activity is found in patients with benign prostate hyperplasia. Has been issued. Therefore, inhibition of DPP IV is expected to be effective for skin diseases and benign prostatic hyperplasia.

Until now, as a DRP IV inhibitor, the 2-position of pyrrolidine was substituted with phosphorus Compounds (J. Med. Chem. 37, 3969-3976, 1994), boron-substituted compounds (Biochemistry 32, 8723-8731, 1993) and the like are known. Compounds in which the 2-position of pyrrolidine is substituted with a cyano group (Arch. Biochem. Biophys. 323, 148-152, 1995; Bioorg. Med. Chem. Lett. 6, 1163-1166, 1996; Biochemistry 38, 11597-11603, 1999), but there are no reports of 2-cyanopyrrolidine derivatives having a fluorine atom at the 4-position. Disclosure of the invention

 An object of the present invention is to provide a novel cyanopia lysine derivative exhibiting excellent DPPIV inhibitory activity in a living body and having physical properties required for a drug such as stability.

 The present inventors have conducted intensive studies to achieve the above object, and as a result, certain cyanopyrrolidine derivatives show excellent DPPIV inhibitory activity in vivo and also have the physical properties required for a drug such as stability. And completed the present invention.

 According to one embodiment of the present invention, the present invention provides a compound of formula (1)

Wherein W is an acyl group derived from a natural amino acid;

(式中、 W¹は炭素数 1〜 5のアルカノィル基、 置換されてもよいァリールカル ポニル基又は炭素数 1〜 5のアルキル基示し、 W²は水素原子又は炭素数 1〜 5 のアルキル基を示す。 ） で表される基、 又は式

(Wherein, W ¹ represents an alkanoyl group having 1 to 5 carbon atoms, an arylcarbonyl group which may be substituted or an alkyl group having 1 to 5 carbon atoms, and W ² represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. A group represented by) or a formula

(Wherein, W ³ and W ⁴ are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.)

 X represents an oxygen atom or a sulfur atom,

Y is the formula — CR ⁵ R ⁶ — [wherein R ⁵ and R ⁶ are the same or different and are a hydrogen atom; a halogen atom; a halogen atom, a zK acid group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carboxyl group. , A mercapto group, an alkylthio group having 1 to 5 carbon atoms, a guanidyl group, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, one NHR ¹¹ (wherein R ¹¹ is a hydrogen atom, an optionally substituted phenyl group Represents an optionally substituted pyridyl group, tert-butoxycarbonyl group or benzyloxycarbonyl group.), -CONHR ¹² (wherein, R ¹² is a hydrogen atom or — (CH ₂ ) _m -R ¹³ ( In the formula, m represents an integer of 1 to 5, and R ¹³ represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group. } And —〇R ¹⁴ (wherein, R ¹⁴ represents a linear alkyl group or a benzyl group having 1 to 5 carbon atoms). The carbon number 1 which may be substituted with one or more groups selected from the group consisting of To 10 alkyl groups; or may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a propyloxyl group, an amino group, an aminocarbonyl group and a linear alkoxy group having 1 to 5 carbon atoms. It represents an alkenyl group having 2 to 10 carbon atoms. Or a formula — CR ⁷ R ⁸ — CR ⁹ R ^1Q — (wherein R ⁷ , R ⁸ , R ⁹ and R ¹ ° are the same or different and are a hydrogen atom; a halogen atom; a halogen atom, a hydroxyl group, C1-C5 hydroxyalkyl group, carboxyl group, mercapto group, C1-C5 alkylthio group , Guanidyl group, phenyl group which may be substituted, imidazolyl group, indolyl group

, —NHR ¹¹ (wherein, R ¹¹ represents a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarpenyl group or a benzyloxycarponyl group), —CONHR ¹² {wherein, R ¹² represents a hydrogen atom or — (CH ₂ ) _m -R ¹³ (where m represents an integer of 1 to 5, R ¹³ represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxy And a carboxyl group. } And one OR ¹⁴ (wherein, R ¹⁴ represents a linear alkyl group or a benzyl group having 1 to 5 carbon atoms), and one or more groups selected from the group consisting of A halogen atom, a hydroxyl group, a hydroxyl group, an amino group, an aminocarbonyl group, a chain having 1 to 5 carbon atoms, which represents an alkyl group of up to 10 or R ⁷ and R ⁹ together with an adjacent carbon atom; A cycloalkyl group having 3 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of an alkyl group and a linear alkoxy group having 1 to 5 carbon atoms; a halogen atom, a hydroxyl group, a carbonyl group, an amino group Group, an aminocarbonyl group, a linear alkyl group having 1 to 5 carbon atoms, and a carbon number of 4 to 8 which may be substituted with one or more groups selected from the group consisting of a linear alkoxy group having 1 to 5 carbon atoms. A cycloalkenyl group; a halogen atom, a hydroxyl group A carbon atom which may be substituted with at least one group selected from the group consisting of a carbonyl group, an amino group, an aminocarbonyl group, a linear alkyl group having 1 to 5 carbon atoms and a linear alkoxy group having 1 to 5 carbon atoms. A bicycloalkyl group having a number of 5 to 10; or a halogen atom, a hydroxyl group, a propyloxyl group, an amino group, an aminocarboxy group, a linear alkyl group having 1 to 5 carbon atoms, and a linear alkoxy group having 1 to 5 carbon atoms. Forming a bicyclic alkenyl group having 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of: ),

Z is a hydrogen atom; or a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, and imidazolyl. A group, an indolyl group, —NH R ¹¹ (wherein, R ¹¹ represents a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), One CONHR ¹² (wherein, R ¹² is a hydrogen atom or one (CH ₂ ) -R ¹³ (formula In the formula, m represents an integer of 1 to 5, and R ¹³ represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group. .). } And one or more carbon atoms which may be substituted with one or more groups selected from the group consisting of OR ¹⁴ (wherein R ¹⁴ represents a linear alkyl group or a benzyl group having 1 to 5 carbon atoms). Represents an alkyl group of 1 to 10 or

Or Y and Z are joined together with an adjacent nitrogen atom to form a halogen atom, a hydroxyl group, an amino group, a chain alkyl group having 1 to 5 carbon atoms and one OR ¹⁵ (wherein, R ¹⁵ is a group having 1 to ⁵ carbon atoms) And 5 represents a chain alkyl group, an aminocarbonylmethyl group or a benzyl group.5) which forms a cyclic amino group having 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of: ] The compound which is a cyanopyrrolidine derivative represented by these, or its pharmacologically acceptable salt is provided.

According to another aspect of the present invention, there is provided a compound which is a cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom in the formula (1). And a compound of the formula (1), wherein Y is —CH ₂ — in formula (1), or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention, there is provided a compound according to the present invention, wherein in formula (1), Y is —CH ₂ —, and Z is selected from the group consisting of a hydroxyl group and a hydroxyalkyl group having 1 to 5 carbon atoms. Provided is a cyanopyrrolidine derivative which is a branched or cyclic alkyl group having 4 to 10 carbon atoms, or a pharmaceutically acceptable salt thereof, which may be substituted.

According to another aspect of the present invention, the present invention provides a compound of the formula (1) wherein Y is —CH ₂ — and Z is a tert-butyl group, a (1-hydroxymethyl) cyclopentyl group or a (2-hydroxy_1 A compound which is a cyanopyrrolidine derivative which is a (1,1-dimethyl) ethyl group or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention, there is provided a cyanopyrrolidine derivative represented by the formula (1), wherein Y is -CR ⁵ R ⁶ — wherein R ⁵ is hydrogen and Z is a hydrogen atom. Or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention, the present invention provides a compound of the formula (1), wherein Y is one CR ⁵ R ⁶ — (wherein R ⁵ is hydrogen and R ⁶ is a branched or branched C 3-6 carbon atom. A cyclic alkyl group), wherein Z is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention, the present invention provides a compound of the formula (1) wherein Y is —CH [CH (CH ₃ ) ₂ ] —, CH (C (CH ₃ ) ₃ ] — or —CH [GH (CH ₃ ) A compound which is CH ₂ CH ₃ ] — and is a cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof, wherein Z is a hydrogen atom.

 According to another aspect of the present invention, there is provided a medicament comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

 According to another aspect of the present invention, there is provided the aforementioned medicament for preventing or treating a disease or condition that can be ameliorated by inhibiting dipeptidyl peptidase IV.

 According to another aspect of the present invention, there is provided the medicament wherein the disease or condition that can be ameliorated by inhibiting the dipeptidyl peptidase IV is diabetes.

 According to another aspect of the present invention, there is provided the medicament wherein the disease or condition ameliorated by inhibiting the dipeptidyl peptidase IV is an immune disease. BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, the term “chain” means a linear or branched chain.

 Asyl groups derived from natural amino acids include, for example, alanine, arginine, asparagine, aspartic acid, cystine, glutamine, glutamic acid, glycine (i.e., aminoacetyl group), histidine, isoleucine, leucine, lysine, methionine, fenylalanine, Examples include acyl groups derived from proline, serine, threonine, tyrosine, valine and the like.

The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The alkoxy group having 1 to 5 carbon atoms means a linear, branched or cyclic alkoxy group, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, Butoxy, isobutoxy, tert-butoxy, cyclopropylmethoxy, pentyloxy, isopentyloxy and the like.

 The alkanoyl group having 1 to 5 carbon atoms means a linear or branched alkanoyl group, such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group. And so on.

 The arylcarbonyl group which may be substituted means a substituted or unsubstituted arylcarbonyl group, for example, a benzyl group, an 11-naphthoyl group, a 2-naphthoyl group and the like. An arylcarbonyl group in which the hydrogen atom of these aryl groups is substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, an alkyl group having 1 to 5 carbon atoms, and an alkoxy group having 1 to 5 carbon atoms; For example, an o-toluyl group can be mentioned.

The alkyl group having 1 to 5 carbon atoms means a linear, branched or cyclic alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group. And sec-butyl, tert-butyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, cyclopentyl, cyclobutylmethyl, and 1-ethylpropyl. The alkyl group having 1 to 10 carbon atoms which may be substituted means a substituted or unsubstituted linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, for example, a methyl group, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, noel, decyl, carbon number 3-10 cycloalkyl groups (for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclobutylmethyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, etc.), cycloalkenyl group having 4-8 carbon atoms (For example, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group, cyclooctenyl group, etc.), carbon 5 to 0 bicycloalkyl group (e.g., Bishikuropenchiru group, a bicyclo hexyl group, heptyl group bicyclo, Bishikurookuchiru group, bicyclononyl group, vicinal Crodecyl group, etc.), bicycloalkenyl group having 5 to 10 carbon atoms (for example, bicyclopentenyl group, bicyclohexenyl group, bicycloheptenyl group, bicyclooctenyl group, bicyclononel group, bicyclodecel group, etc.), cross-linked cyclic hydrocarbon (For example, adamantyl group, porunyl group, norpolnyl group, pinanyl group, phenyl group, caryl group, carphanyl group, etc.), and hydrogen atoms of these alkyl groups are replaced with halogen atoms, hydroxyl groups, 1 to 1 carbon atoms. 5, a hydroxyalkyl group, a carbonyl group, a mercapto group, an alkylthio group having 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, one NHR ¹¹ (wherein R ¹¹ Is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl Group, a ter t-Butokishikarupo sulfonyl group or a base Nji Ruo carboxymethyl Cal Po two Le ^{group), - CO NH R 1 2} { wherein R ^{1 2} is hydrogen atom or _{- (CH 2) m - R} 1 3 ( wherein Wherein m represents an integer of 1 to 5, R ¹³ represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)} and one OR ¹⁴ (where R ¹⁴ is A straight-chain or branched-chain alkyl group having 1 to 5 carbon atoms or a benzyl group), and an alkyl group substituted with one or more groups selected from the group consisting of:

 The substituted phenyl group of the phenyl group which may be substituted is, for example, substituted with one or more groups selected from the group consisting of a hydroxyl group and a linear or branched alkoxy group having 1 to 5 carbon atoms. Phenyl groups (eg, 4-hydroxyphenyl group, 3,4-dimethoxyphenyl group, etc.).

 The substituted pyridyl group of a pyridyl group which may be substituted (for example, a pyridine-2-yl group) is, for example, selected from the group consisting of a cyano group, a nitro group, a halogen atom, and an aminocaprol group. Pyridyl groups substituted with one or more of the following groups (for example, 5-cyanopyridine-12-yl group, 5-ditropyridine-12-yl group, 5-cyclopentylpyridine-2-yl group, Minocarbonylpyridine-2-yl group).

Hydroxyalkyl groups having 1 to 5 carbon atoms include hydroxymethyl group, 1-hydroxyl group, 2-hydroxyethyl group, 1-hydroxypropyl group and 2-hydrido Roxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) ethyl, 1-hydroxy-1-methylethyl, 4-hydroxybutyl, 5-hydroxypentyl and the like.

 Examples of the alkylthio group having 1 to 5 carbon atoms include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, a tert-butylthio group, and a pentylthio group.

 The optionally substituted alkenyl group having 2 to 10 carbon atoms means a substituted or unsubstituted linear, branched or cyclic alkenyl group having 2 to 10 carbon atoms, for example, a vinyl group or an aryl group. Alkenyl groups such as a benzyl group, a propenyl group, an isopropenyl group, a butenyl group, an isobutenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, a cyclopentenyl group, and a cyclohexenyl group. Is replaced by one or more groups selected from the group consisting of halogen atoms, hydroxyl groups, carboxyl groups, amino groups, aminocarbonyl groups, and linear or branched alkoxy groups having 1 to 5 carbon atoms. Alkenyl groups can be mentioned.

 The optionally substituted cycloalkyl group having 3 to 8 carbon atoms means a substituted or unsubstituted cycloalkyl group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexyl group. In addition to cycloalkyl groups such as butyl group and cyclooctyl group, hydrogen atoms of these cycloalkyl groups can be replaced with halogen atoms, hydroxyl groups, hydroxyl groups, amino groups, aminocarbonyl groups, linear or branched carbon atoms. Examples thereof include a cycloalkyl group substituted with one or more groups selected from the group consisting of an alkyl group having 1 to 5 prime numbers and a linear or branched alkoxy group having 1 to 5 carbon atoms.

Carbon atoms which may be substituted: a cycloalkenyl group having up to 8 means a substituted or unsubstituted cycloalkenyl group, for example, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group, cyclooctenyl group, etc. In addition to the above cycloalkenyl group, hydrogen atoms of these cycloalkenyl groups are replaced by halogen atoms, hydroxyl groups, propyloxyl groups, amino groups, aminocarbonyl groups, linear or branched alkyl groups having 1 to 5 carbon atoms and Linear or branched C1-C5 alkoxy group And cycloalkenyl groups substituted with one or more groups selected from the group consisting of:

 The optionally substituted bicycloalkyl group having 5 to 10 carbon atoms means a substituted or unsubstituted bicycloalkyl group, for example, a bicyclopentyl group, a bicyclohexyl group, a bicycloheptyl group, a bicyclooctyl group, In addition to bicycloalkyl groups such as a bicyclononyl group and a bicyclodecyl group, hydrogen atoms of these bicycloalkyl groups are replaced with halogen atoms, hydroxyl groups, carbonyl groups, amino groups, aminoamino groups, linear or branched carbon atoms of 1 to 1. Examples thereof include a bicycloalkyl group substituted with one or more groups selected from the group consisting of an alkyl group of 5 and a linear or branched alkoxy group having 1 to 5 carbon atoms.

 The optionally substituted bicycloalkenyl group having 5 to 10 carbon atoms means a substituted or unsubstituted bicycloalkenyl group, for example, a bicyclopentenyl group, a bicyclohexenyl group, a bicycloheptenyl group, a bicyclo In addition to bicycloalkenyl groups such as octenyl group, bicyclononel group and bicyclodecel group, hydrogen atoms of these bicycloalkenyl groups are replaced with halogen atoms, hydroxyl groups, carbonyl groups, amino groups, aminoamino groups, linear or branched chains. And a bicycloalkenyl group substituted with at least one group selected from the group consisting of an alkyl group having 1 to 5 carbon atoms and a linear or branched alkoxy group having 1 to 5 carbon atoms. .

The optionally substituted cyclic amino group having 2 to 10 carbon atoms refers to a substituted or unsubstituted amino group having one or more nitrogen atoms in the ring and optionally having one or more oxygen atoms and sulfur atoms. Means a substituted cyclic amino group, such as a cyclic group such as an aziridyl group, an azetidyl group, a pyrrolidyl group, an imidazolidyl group, an oxazolidyl group, a thiazolidyl group, a piperidyl group, a morpholyl group, an azabicycloheptyl group, and an azabicyclooctyl group. In addition to the amino group, a hydrogen atom of a cyclic amino group in which a benzene ring or a pyridine ring is condensed to these cyclic amino groups or a hydrogen atom of a cyclic amino group (including a benzene ring or a pyridine ring condensed with a cyclic amino group) is a halogen atom, a hydroxyl group, an amino group, or the like. Group, a linear or branched alkyl group having 1 to 5 carbon atoms and one OR ¹⁵ (wherein R ¹⁵ is a linear or branched alkyl group having 1 to 5 carbon atoms) Group, aminocarbonylmethyl group or benzyl group) And a cyclic amino group substituted with one or more groups selected from the group. Also, pharmaceutically acceptable salts include, for example, salts with mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, and phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, and trifluoroacetic acid. And salts with organic acids such as methanesulfonic acid. The preferred embodiment of the compound of the present invention is shown.

In the formula (1), when Y is —CH ₂ —, Z represents a hydroxyl group, an alkoxyl group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, a phenyl group which may be substituted and NH R ^{1 1} may be substituted with (wherein R ^{1 1} is a pyridyl group which may be substituted) of the group consisting of one or more, preferably an alkyl group having a carbon number of 1 to 1 0. In this case, Z is preferably substituted with one or more of a group consisting of a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms and an alkoxyl group having 1 to 5 carbon atoms. A branched or cyclic alkyl group, more preferably a substituted or unsubstituted alkyl group having 4 to 10 carbon atoms, which may be substituted with at least one of a group consisting of a hydroxyl group and a hydroxyalkyl group having 1 to 5 carbon atoms. A cycloalkyl group having 4 to 10 carbon atoms or an adamantyl group, more preferably a tert-butyl group, a (1-hydroxymethyl) cyclopentyl group or a (2-hydroxy-1,1-dimethyl) ethyl group. is there.

In the formula (1), Y is a group represented by the formula —CR 5 R ⁶ — (wherein R ⁵ is hydrogen and R ⁶ may be substituted with an alkyl group having 1 to 10 carbon atoms or a group represented by the formula CR ⁷ R ^s _ CR ⁹ R ¹ ° — (where R ⁸ and R ^{1 Q} are hydrogen, and R ⁷ and R ⁹ are taken together with adjacent carbon atoms to form a cycloalkyl group having 3 to 8 carbon atoms) In the formula, Z is preferably H or CH ₃ .

In this case, preferably, Y is a group represented by the formula _CR ⁵ R ⁶ — {wherein R ⁵ is hydrogen, R ⁶ is a hydroxyl group and one OR ¹⁴ (where R "is a linear group having 1 to 5 carbon atoms) Or a branched or branched alkyl group or a benzyl group), which is a branched or cyclic alkyl group having 3 to 6 carbon atoms which may be substituted with one or more selected from the group consisting of Z is a hydrogen atom, more preferably Y is CR ⁵ R ⁶ — wherein R ⁵ is hydrogen , R ⁶ is a branched or cyclic alkyl group having 3 to 6 carbon atoms), Z is a hydrogen atom, and still more preferably, Y is one CH [CH (CH ₃ ) ₂ ] _, When it is one CH [C (CH ₃ ) 3] — or one CH [CH (CH ₃ ) CH ₂ CH ₃ ] —, Z is a hydrogen atom.

In the formula (1), preferred examples of the case where Y and Z together with an adjacent nitrogen atom form a cyclic amino group having 2 to 10 carbon atoms which may be substituted include a pyrrolidyl group and a piperidyl group A group or a cyclic amino group in which a benzene ring is condensed to these groups, and preferred substituents include a hydroxyl group and one OR ¹⁵ (wherein R ¹⁵ is as defined above).

 In the compound of the present invention, the basicity of the nitrogen atom is attenuated by the presence of W, and the instability of the compound derived from the basicity of the nitrogen atom is improved. Although the presence of W greatly reduces the dipeptidyl peptidase IV inhibitory activity of the compound of the present invention, the W portion is eliminated by an enzyme or the like in vivo, and the dipeptidyl peptidase IV activity is reduced. Strongly inhibits. That is, using a general expression, the compound of the present invention belongs to the category of a prodrug. In addition, the introduction of W has effects such as improvement of oral absorbability and continuation of drug activity, and enables reduction of the dose and the number of times of administration.

 INDUSTRIAL APPLICABILITY The compound of the present invention can suppress dipeptidyl peptidase IV in a living body, thereby enhancing insulin action and improving glucose metabolism. It can contribute to suppressing cell activation, suppressing adhesion of cancer cells to endothelium, and preventing HIV virus from entering lymphocytes.

 Therefore, the present invention relates to a disease or condition that can be improved by inhibiting dipeptidyl peptidase IV, for example, diabetes (particularly type 2), immune disease, arthritis, obesity, osteoporosis, glucose tolerance damage. The present invention provides the above-mentioned medicament for preventing or treating conditions, benign prostatic hypertrophy, skin diseases and the like.

Pharmaceuticals for immune diseases include immunosuppressive agents in tissue transplantation; for example, cytokine inhibitory inhibitors in various autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis (RA); Drugs useful in the prevention and treatment of AIDS by preventing HIV from entering cells, preventing metastasis, especially preventing breast and prostate tumors from metastasizing to the lungs Drugs and the like.

 The medicament of the present invention can be administered systemically or locally orally or rectally, subcutaneously, intramuscularly, intravenously, transdermally, or the like.

 In order to use the compound of the present invention as a medicament, it may be in any form of a solid composition, a liquid composition, and other compositions, and an optimum one is selected as necessary. The medicament of the present invention can be produced by compounding a pharmaceutically acceptable carrier with the compound of the present invention. Specifically, conventional excipients, extenders, binders, disintegrants, coating agents, sugar coatings, pH adjusters, solubilizers, or aqueous or non-aqueous solvents, etc. are added, and by conventional formulation techniques, They can be prepared into tablets, pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections, and the like. Excipients and bulking agents include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa batata, ethylene glycol, and others. You can give something.

 Further, the compound of the present invention can be formulated by forming an inclusion compound with j3, arcyclodextrin, methylated cyclodextrin and the like. The dose of the compound of the present invention varies depending on the disease, symptom, body weight, age, sex, administration route and the like, but is preferably about 1 to about 100 mg / person / day for oral administration to an adult. More preferably, the dose is about 10 to about 200 mg / day, which can be administered once or several times a day. The compound of the formula (1) can be produced by the following general production method.

[General manufacturing method] 式, expression

(Wherein WW ² , X, Y, Z, are the same as above. A represents a leaving group such as a halogen atom.)

This method is a method of introducing an oxypropyl group into an amino group, and further converting A, which is a leaving group, to W ¹ .

 For example, an oxycarbonyl group can be introduced using 1-chloroalkyl formate in the presence of a suitable base. Examples of the base include amines such as triethylamine and disopropylethylamine, and inorganic bases such as carbonated lime. Examples of the reaction solvent include dichloromethane, chloroform, 1,2-dichloromethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, ethyl acetate and the like. The reaction can be performed at -50 to 50 ° C.

An example of converting A, which is a leaving group, to W ¹ is a method of introducing an acyloxy group using a carboxylic acid sodium salt when A is a chlorine atom. At this time, sodium iodide, potassium iodide, or the like that promotes the reaction can be used. Examples of the reaction solvent include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, and ethyl acetate. The reaction can be performed at -50 to 50 ° C. Anti

(Wherein WW ² , X, Υ, and ζ are the same as described above.)

 This method is to introduce an oxypropyl group into an amino group.

 For example, if 1-acyloxyalkyl ρ-ditrophenyl carbonate is used, a 1-acyloxyalkoxycarbonyl group can be introduced. At this time, an appropriate base can be used. Examples of the base include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate. Examples of the reaction solvent include dichloromethane, chloroform, 1,2-dichloroethane, Ν, Ν-dimethylformamide, tetrahydrofuran, dioxane, ruene, and ethyl acetate. The reaction can be carried out at a temperature of 50-50 ° C. Reaction formula 3

(Wherein X, Υ, and 、 are the same as described above. W ⁵ represents an acyl group derived from a natural amino acid and having an amino group protected, and W ⁵ represents an acyl group derived from a natural amino acid. Represents a group. )

 In this method, an acyl group derived from a natural amino acid and having an amino group protected is introduced and further deprotected. For example, the amidation reaction can be carried out using an acyl halide such as acyl chloride or bromide in a solvent that does not participate in the reaction, such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, and ethyl acetate. At this time, the reaction can be performed using a base. Examples of the base include amines such as triethylamine and diisopropylethylamine, sodium 2-ethylhexanoate, and lithium 2-ethylhexanoate. Inorganic bases such as organic acid salts and potassium carbonate; These reactions can be performed at 150-100 ° C.

 As another example of the amidation reaction, the reaction can be carried out using an active ester such as 1-benzotriazolyl ester / succinimidyl ester. Examples of the reaction solvent include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, and ethyl acetate. The reaction can be performed at -50 to 50 ° C.

In addition, for example, amidation can be performed using a carboxylic acid and a dehydrating condensing agent. Examples of the dehydration condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexyl carbodiimide, diphenylphosphoryl azide, and phenyldiimidazole. Activators such as 1-hydroxybenzotriazole and hydroxysuccinimide can be used accordingly. Examples of the reaction solvent include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, and ethyl acetate. In this case, the reaction can be carried out using a base. Examples of the base include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate. The reaction can be carried out at a temperature of 150 to 50 ° C. Further, for example, amidation can be carried out using a mixed acid anhydride obtained from carboxylic acid and chlorocarbonate. The solvent for these reactions is Examples of solvents that do not participate in the reaction include furan, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, toluene, and ethyl acetate. In this case, the reaction can be carried out using a base. Examples of the base include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as carbon dioxide lime. These reactions can be performed at —50-50 ° C.

 In addition, as a method for deprotecting the protecting group of the amino group, a method described in PROTECTIVE GROUPS IN 0 RGANIC SYNTHESIS, THEODORA. GREENE and PETER G. M. WUTS can be used.

 For example, compounds in which the protecting group is a group that can be deprotected by an acid such as a tert-butoxycarbonyl group, a trityl group, an o-nitrobenzenesulfenyl group, are hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid It can be deprotected using an acid such as methanesulfonic acid or the like. At this time, the deprotection can be carried out by diluting or dissolving the acid with an organic solvent or water, and the reaction can be carried out at -50 to 50 ° C. Examples of the organic solvent include ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloromethane, and the like. Further, for example, the protecting group is benzyloxy Compounds that are deprotected by a hydrogenolysis reaction such as a carbonyl group can be deprotected by a hydrogenolysis reaction using a metal catalyst such as palladium. As the solvent, a solvent that does not participate in the reaction, such as ethanol, methanol, tetrahydrofuran, and ethyl acetate can be used. The reaction can be performed at O-100 ° C. In addition, hydrogen gas can be used for this reaction, or the reaction can be performed using a combination of reagents such as ammonium formate and formate.

Further, for example, for a compound in which the protecting group is a protecting group such as a fluorenyloxycarbonyl group which is deprotected with a base, a base such as getylamine, piperidine, ammonia, sodium hydroxide, potassium carbonate or the like is used. Can be deprotected. These bases can be used alone or diluted, dissolved or suspended in a solvent. At this time, water, ethanol, methanol, tetrahydrofuran, N, N —Dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane and the like can be used. The reaction can be performed at O-100 ° C.

 Further, for example, a compound in which the protecting group is a group that can be deprotected by a metal catalyst such as an aryloxy group, can be deprotected by using tetrakis (triphenylphosphine) palladium as a catalyst or a reagent. At this time, the reaction can be carried out in a solvent that does not participate in the reaction, such as dichloromethane, chloroform, tetrahydrofuran, and the like. The reaction can be performed at 0-1 oo ° c. Reaction formula 4

(Wherein, W ³ ,, X, Υ, Ζ are the same as described above.)

In this method, W ³ —C〇—CH2C (W ⁴ ) — (where W ³ and W ⁴ are each a hydrogen atom or an alkyl group having 1 to 5 carbon atoms) is introduced into an amino group. . For example, it can be synthesized by a dehydration-condensation reaction of a / 3-diketone such as acetylacetone with an amine compound. At this time, the reaction can be performed using a base or an acid. Examples of the base include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate. Examples of the acid include hydrochloric acid, acetic acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like. Solvents for these reactions include solvents that do not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, toluene, and ethyl acetate. These reactions can be performed at 0 to 50 ° C. Reaction formula 5

(Wherein, X, Υ, and で are the same as described above. Ra represents a cyano group, an aminocarboyl group or an alkoxyl group, and Rb represents a protecting group for an amino group. R ¹ represents a fluorine atom or a hydroxyl group.

 For this deprotection, the method shown in Reaction Example 3 can be used. Reaction formula 6

R

(In the formula, X, Y, Z, and RRa are the same as described above. Rc represents a leaving group such as a halogen atom or a sulfonyloxy group, or a group that can be converted to a leaving group.) For example, compounds in which R c is a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, are ethylamine, isopropylamine, tert-butylamine, benzylamine, substituted benzylamine, The substitution reaction can be performed using primary amines (Z-NH ₂ ) such as phenethylamine, substituted phenethylamine, and 2- (substituted pyridylamino) ethylamine. At this time, these amines may be used in excess or a base may be separately added. Examples of the base to be added include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate. Also, in some cases, Sodium iodide or the like can be added to proceed. As the reaction solvent

, N, N-dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, chloroform, and other solvents that do not participate in the reaction. The reaction can be performed at 0-100 ° C.

Examples of a group that can convert R c to a leaving group include a hydroxyl group. In this case, after performing chlorination, bromination, iodination, methanesulfonylation, p-toluenesulfonylation, etc. The above reaction can be performed. Examples of the chlorination reaction include a method using carbon tetrachloride and triphenylphosphine, a method using phosphorous chloride, or a method using tosyl chloride or the like as a leaving group, followed by replacement with lithium salt or the like. can give. In these reactions, a solvent that does not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, or the like can be used. These reactions can be performed at —50-100 ° C. An example of the bromination reaction is a method using carbon tetrabromide and triphenylphosphine. This reaction can be carried out at 150 to 50 ° C. using a solvent which does not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide and the like. Examples of iodination reactions include methods using iodine, triphenylphosphine and imidazole. This reaction can use a solvent that does not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, and the like. These reactions can be performed at —50 to 100 ° C. Methanesulfonylation and p-toluenesulfonylation can be carried out using methanesulfonyl chloride, p-toluenesulfonyl chloride and the like, respectively. At this time, a suitable base may be added. Examples of the base to be added include amines such as triethylamine and diisopropylethylamine and inorganic bases such as carbonated lime. Examples of the reaction solvent include solvents that do not participate in the reaction, such as N, N-dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, and the like. Can be done in C. Reaction formula 7

(Wherein, X, Y, Z, R ¹ , R a, R b, and R c are the same as described above.) For example, when R c is a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, p The compound which is a leaving group such as —toluenesulfonyloxy group is subjected to a substitution reaction using a compound represented by Z—NH—R b (wherein Z and R b are the same as described above). Can be. At this time, sodium hydride, potassium tert-butoxide, n-butyllithium, lithium diisopro R pyramide and the like can be used as the base. As the solvent, N, N-dimethylformamide, tetrahydrofuran, dioxane and the like can be used. The reaction can be performed at -50 to 50 ° C.

 Examples of a group that can convert R c to a leaving group include a hydroxyl group. In this case, chlorination, bromination, iodination, methanesulfonation, p — After toluenesulfonylation, etc., the above reaction can be carried out. Reaction formula 8

 (In the formula, X, Y, Z, and RRa are the same as described above. Rd represents a leaving group such as a halogen atom or a sulfonyloxy group.)

When Z—Rd is used, the target product can be obtained by allowing Z—Rd to act on the amino group of the raw material. For example, when R d is a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, or the like, the reaction can be carried out with an amino form as a raw material in the presence of a suitable base. Examples of the base to be added include: Examples thereof include amines such as triethylamine and disopropylethylamine, and inorganic bases such as lithium carbonate. Examples of the reaction solvent include N, N-dimethylformamide, tetrahydrofuran, dioxane and the like. The reaction can be performed at O to 100 ° C.

 When Z = 0 (aldehyde compound or ketone compound) is used, the reaction can be carried out under conditions using a primary amino group as a raw material and an appropriate reduction method. Examples of the reduction method used include a reducing agent such as sodium borohydride and sodium cyanoborohydride, and hydrogenation using palladium. As a solvent to be used, a solvent that does not participate in the reaction, such as ethanol, methanol, tetrahydrofuran, dioxane, and water can be used. The reaction can be carried out at a temperature between 20 and 100 ° C. Reaction formula 9

(In the formula, X, Y, Z, R ¹ , R a, R b, and R d are the same as described above.) By reacting Z—R d with the protected amino group of the raw material, the desired product is obtained. Obtainable. At this time, the reaction is carried out by adding an appropriate base. Examples of the base include sodium hydride, potassium tert-butoxide, n-butyllithium, lithium diisopropylamide and the like. Examples of the reaction solvent include N, N-dimethylformamide, tetrahydrofuran, dioxane and the like. The reaction can be performed at a temperature of 50 to 50 ° C. Reaction formula 10

 {Where, R e is C (= X) — Y— NH— Z, or one C (= X) —Y— N (R b) one Z, or — C (= X) one Y _ R c , Or Rb. Further, X, Y, Ζ, Rb and Rc are the same as described above. }

 It can be produced by converting an aminocarbonyl group into a cyano group by a general dehydration reaction. An example of this is a method using trifluoroacetic anhydride. Examples of the solvent to be used include solvents that do not participate in the reaction such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, and N, N-dimethylformamide. At this time, if necessary, a base such as triethylamine, diisopropylethylamine, sodium hydrogencarbonate or potassium carbonate can be added. The reaction can be performed at -50 to 50 ° C.

 Another example is a method using phosphorus oxychloride. At this time, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, pyridine and the like can be used alone or as a mixture of two or more kinds as solvents. In this reaction, imidazole and the like may be added. This reaction can be carried out at a temperature of 50-50 ° C.

Another example is a method using Shiidan Cyanur and N, N-dimethylformamide. At this time, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, pyridine and the like can be used alone or as a mixture of two or more. This reaction can be carried out at a temperature of from 50 to 50 ° C. Reaction formula 1

 (Wherein, Re and Ra are the same as described above.)

 This is a method of converting a hydroxyl group into a fluorine atom. Examples of the fluorination method include a method using methylaminosulfur trifluoride / dimethylsulfur trifluoride or the like. In these reactions, the reaction is started at a temperature of from 78 ° C to room temperature using a solvent that does not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, and toluene. Achieved by continuous reaction.

 Another example of fluorination is a method of converting a hydroxyl group into a leaving group and then converting it into a fluoro group. Conversion to a leaving group can be carried out in the same manner as described in Scheme 6. As a method of converting to a fluoro group after converting to a leaving group, a method of reacting tetrabutylammonium fluoride, cesium fluoride or the like can be mentioned. These reactions can be carried out using a solvent that does not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, and water. Reaction formula 1 2

 (Where R R e, a is as defined above.)

Using a 1-H-pyrrolidine derivative or its salt, an amide or Amides or olebamates can be produced. For example, the amidation reaction uses acyl octyl chloride, such as acyl chloride,

The reaction can be performed in a solvent that does not participate in the reaction, such as chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, toluene, and ethyl acetate. In this case, the reaction can be performed using a base. Examples of the base include amines such as triethylamine and diisopropylethylamine, sodium 2-ethylhexanoate, and 2-ethylhexanoic acid rim. Inorganic bases such as organic acid salts and carbonated lime are mentioned. These reactions can be performed at —50-100 ° C.

 As another example of the amidation reaction, for example, the reaction can be carried out using an active ester such as 1-benzotriazolyl ester or succinimidyl ester. Examples of the reaction solvent include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, and ethyl acetate. The reaction can be performed at -50 to 50 ° C.

 In addition, for example, amidation can be performed using a carboxylic acid and a dehydrating condensing agent. Examples of the dehydrating condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexyl carbodiimide, diphenylphosphoryl azide, and lipoeldiimidazole. Activators such as 1-hydroxybenzotriazole and hydroxysuccinimide can be used accordingly. Examples of the reaction solvent include dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, and ethyl acetate. In this case, the reaction can be carried out using a base. Examples of the base include amines such as triethylamine and diisopropylethylamine, sodium salts such as sodium 2-ethylhexanoate, and organic acid salts such as sodium 2-hexylhexanoate, And inorganic bases such as potassium carbonate. The reaction can be carried out at a temperature of 50 to 50 ° C.

Further, for example, amidation can be performed using a mixed acid anhydride obtained from a carboxylic acid and chlorocarbonate. Solvents for these reactions include tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylform. Solvents that do not participate in the reaction, such as muamide, toluene, and ethyl acetate. In this case, the reaction can be carried out using a base. Examples of the base include amines such as triethylamine and diisopropylethylamine, sodium 2-ethylhexanoate, and 2-ethylhexanoic acid rim. Inorganic bases such as organic acid salts and carbonated lime are mentioned. These reactions can be carried out at a temperature of 50 to 50 ° C.

 The protection of the amino group can be carried out using di-tert-butyldicarboxylate, benzyloxycarboechloride, fluorenylmethoxycarbonyl chloride or the like in the presence of a suitable base. Examples of the base include amines such as triethylamine and diisopropylethylamine, and inorganic bases such as carbonated lime. Solvents for these reactions include solvents that do not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, toluene, ethyl acetate, and water. These reactions can be carried out at a temperature of from 50 to 50 ° C.式, Equation 1 3

_Λ

_Λ

(In the formula, R Re is the same as described above. R f represents a hydrogen atom or a lower alkyl group, a benzyl group, an aryl group, or the like.)

This is a method for converting a carbonyl group, a salt thereof, or an ester thereof into an aminocarbonyl group. When a compound in which COOR f is a carbonyl group or a salt thereof is used as a raw material, synthesis can be performed using ammonia under general amidation conditions. As an example of amidation, there is a method in which a carboxyl group or a salt thereof is converted to an acid chloride using thionyl chloride, phosphorus oxychloride, oxalyl chloride or the like, and then condensed with ammonia. Solvents for these reactions include Solvents that do not participate in the reaction include butane, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, toluene, and ethyl acetate. These reactions can be performed at -50 to 50 ° C.

 Another example is amidation using a dehydrating condensing agent and ammonia. For example, a reaction using a condensing agent such as 11-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexyl carbodiimide, diphenylphosphoryl azide, carboxydiimidazole, etc. Activators such as 1-hydroxybenzotriazole and hydroxysuccinimide can be added. Solvents for these reactions include solvents that do not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, toluene, ethyl acetate, and acetonitrile. . These reactions can be carried out at a temperature of 50 to 50 ° C.

 Further, for example, amidation can be carried out using ammonia and a mixed acid anhydride obtained from carboxylic acid and chlorocarbonate. Solvents for these reactions include solvents that do not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N, N-dimethylformamide, toluene, and ethyl acetate. These reactions can be performed at —50-50 ° C.

The conversion of a compound in which COORί is an ester to an aminocarbonyl group can be carried out by directly reacting with ammonia, or can be once converted to a carboxylic acid or a salt thereof and then converted to an aminocarbonyl group by the above method. it can. As a method for converting an ester to a carboxylic acid or a salt thereof, the method described in PROTECTIVE GROUPS IN ORGAN IC SYNTHESIS, THEODORA W. GREENE and PETER GM WU TS can be used. The reaction of direct conversion with ammonia uses ammonia gas or ammonia water in a solvent such as water, methanol, ethanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, or toluene, or without solvent. , O can be performed in a temperature range of 100 ° C. In some cases, it can be carried out in a sealed system to prevent the volatilization of ammonia. Reaction formula 14

 (Wherein, R Ra and Rb are the same as above.)

 Rb, which is a protecting group for an amino group, can be deprotected by, for example, the method described in Reaction Scheme 3. The resulting amine can be removed as a base or as a salt of a suitable acid. Suitable acids include, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid and the like. Furthermore, the present invention will be described with reference examples, examples, and test examples, but the present invention is not limited to these examples.

 Reference example 1

 Synthesis of (2 S, 4 S)-1-[(2 S, 3 S) 12-amino-13-methylpentanoyl] 12-cyano 4-fluoropyrrolidine hydrochloride

 (1) Synthesis of (2 S, 4 S) -2- (aminopyruponyl) 1-111 (tert-butoxycarponyl) 1.41-fluoropyrrolidine

 (2 S, 4 S)-1-(tert-Butoxycarponyl) -4-fluoropyrrolidin-2-Rubonic acid (4.5 g) is dissolved in acetonitrile (50 inL) and 1-hydroxybenzotriazole 1 under ice cooling Hydrate (3.6 g) and 11- (3,3-dimethylaminopropyl) -13-ethylcarboimide hydrochloride (4.5 g) were added, and the temperature was slowly raised, followed by stirring at room temperature for 1 hour. The reaction solution was ice-cooled again, 25% aqueous ammonia (5 虬) was added, and the mixture was stirred under ice-cooling for 30 minutes and at room temperature for 30 minutes. After adding acetonitrile (50 mL) to the reaction solution, insolubles were filtered off. The filtrate is concentrated under reduced pressure, and silica gel column chromatography

(Developing solvent; hexane: ethyl acetate = 4: 1 to 1: 5). Hexane was added to the selected residue to give the title compound (4.2 g) as a colorless powder. MS (ESI pos.) M / z: 255 ([M + Na] ⁺ ), (ESI neg.) M / z: 231 ([M-H] one)

 (2) Synthesis of (2S, 4S) -2- (aminopyruponyl) -141-fluoropyrrolidine hydrochloride

 (2S, 4S) 12- (aminoaminopropyl) -11- (tert-butoxycarbonyl) -41-fluoropyrrolidine (4.2g) was suspended in 4M hydrochloric acid-dioxane (45mL) and room temperature. After stirring for 2 hours, the reaction solution was concentrated under reduced pressure. Toluene (50 mL) was added to the residue, and the mixture was concentrated again under reduced pressure. This was repeated three times to obtain the title compound (3.1 g) as a colorless powder. This intermediate was used for the next reaction without purification.

 (3) (2 S, 4 S) 1 2— (amino diphenyl) 1 1— [(2 S, 3 S) 1 2 1 (fluorenylmethoxycarbonylamino) —3-methylpentanoyl] Synthesis of 1 4-fluoropyrrolidine

 (2S, 4S) -1-2- (Aminophenol) -4-fluoropyrrolidine hydrochloride (2.4g), (2S, 3S) -2- (fluorenylmethoxycarbonylamino) -1- 3-Methylpentanoic acid (5.1 g) was dissolved in tetrahydrofuran (40 niL) and N, N-dimethylformamide (1 OmL), and 1-hydroxybenzotriazole monohydrate (2.6 g) was added under ice cooling. 1- (3,3-Dimethylaminopropyl) -13-ethylcarbodiimide hydrochloride (3.3 g) and diisopropylethylamine (2.5 inL) were added, the temperature was slowly raised, and the mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, water was added to the obtained residue, and the resulting powder was collected by filtration. This was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 4: 1 to 1: 4) to obtain the title compound (6.9 g) as a pale yellow amorphous.

MS (ESI pos.) M / z: 490 ([M + Na] ⁺ )

 (4) (2 S, 4 S) 1-2-cyano 1-[(2 S, 3 S)-2- (fluorenylmethoxycarbonylamino)-1-3-methylpentanoyl]-4-fluoropyrrolidine Synthesis

(2 S, 4 S) 1 2— (Amino propylonyl) — 1 _ [(2 S, 3 S) 1 2— (Fluorenylmethoxycarbonylamino) 1-methylpentyl] —4-fluoropyrrolidine (6.9 g) dissolved in tetrahydrofuran (70 mL) and dried under ice-cooling Trifluoroacetic acid (4.0) was added, and the mixture was stirred under ice cooling for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 8: 1 to 3: 2) to give the title compound (6.2 g) as a pale yellow amorphous. .

MS (ESI pos.) M / z: 472 ([+ Na] ⁺ )

 (5) Synthesis of (2 S, 4 S) -1-1 [(2 S, 3 S) — 2-amino-1- 3-methyl-pentyl] 1-2-cyano 4-fluoropyrrolidine hydrochloride

 (2 S, 4 S) — 2-Cyanone 1 — [(2 S, 3 S) 1-2 — (Fluorenylmethoxycarbonylylamino) -3-methylpentanoyl] 14 _fluoropyrrolidin (6.2 g) Dissolve in 1,2-dichloroethane (90 mL) and cool with ice

(lOmL), and the mixture was stirred for 30 minutes on ice and for 5 hours at room temperature. The solution was concentrated under reduced pressure, and the residue was treated with getyl ether (100 mL), tetrahydrofuran (50 mL),

(50raL) and added 4M hydrochloric acid-dioxane (4. OmL) under ice-cooling. The resulting salt was collected by filtration and washed with Jetil ether. The obtained powder was purified by silica gel column chromatography (developing solvent; chloroform: methanol: 25% aqueous ammonia = 40: 1: 0.1 to 25: 1: 0.1), and (2S, 4S) 1-[(2S, 3S) -1-2-amino-3-methylpentanoyl] -2--2-ano-4-fluoropyrrolidine was obtained. This was dissolved in black-mouthed form, 4M mono-dioxane hydrochloride (4. OmL) was added under ice cooling, and the resulting salt was filtered off and washed with black-mouthed form. The crystals were dried under reduced pressure to give the title compound (2.9 g) as a colorless powder. .

MS (ESI pos.) M / z: 228 ([M + H] ⁺ ), 250 ([M + Na] ⁺ ), (ESI neg.) M / z: 262 ([+ CL]-) ¹ H- _{NMR (DMS0-d 6, 500MHz} ) 58.59 (3Η, br s), 5.54 (1H, br d, J = 52.1Hz), 5.06 (1H, d, J = 9.4Hz), 4.07-3.77 (3H, m) , 2.55-2.3 (2H, m), 1.88 (1H, m), 1 61 (1H, m), l.17 (1H, ra), 0.94 (3H, d, J = 6.7Hz), 0.88 (3H , T, J = 7.3Hz)

MS (ESI pos.) M / z: 228 ([M + H] ⁺ )> 250 ([M + Na] ⁺ )> (ESI neg.) M / z: 262 ([M + CL] ") Reference example Two

(2 S, 4 S) — 1 [(2 S) 1 2-amino-3-methylbutanoyl] 1 2- Synthesis of 4-anofluoropyrrolidine hydrochloride

 (1) Synthesis of (2 S, 4 S) 1 2— (Aminoforce Ruponyl) 1 1 1 [(2 S)-2-(t ert—butoxycarponylamino) 1 3 1-Methylbutanol] 1 4 1-Fluoropyrrolidine

 Reference Example 1 In the same manner as in (3), (2S, 4S) -12- (aminocarbonyl) -14-fluoropyrrolidine hydrochloride (2.33g) and (2S) -2 (-tert- The title compound (4.22 g) was obtained as colorless amorphous from butoxyl-propionylamino) -3-methylbutanoic acid (3.00 g).

MS (ESI pos.) M / z: 354 ([M + Na] ⁺ ), (ESI neg.) M / z: 330 ([M-H] —)

 (2) Synthesis of (2 S, 4 S) 1 1 _ [(2 S)-2-(tert-butoxycarbonylamino) 1-3-methylbutynoyl] -12-cyano 4-fluoropyrrolidine

(2 S, 4 S) —2— (Amino-L-Ruponyl) 1-1 1 ((2 S)-2- (tert-butoxycarponylamino) _ 3-Methyl-butynoyl) -1 4-Fluoropyrrolidin (4.03 g) Was dissolved in N, N-dimethylformamide (16 mL), and cyanuric chloride (1.35 g) was added, followed by stirring at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the title compound (3.49 g) as a colorless solid.

MS (ESI pos.) M / z: 336 ([M + Na] ⁺ ), (ESI neg.) M / z: 312 ([MH] ~)

 (3) Synthesis of (2 S, 4 S)-1-[(2 S) —2-Amino-3_methylbutynoyl] -1-2-Cyanol 4-fluoropyrrolidine hydrochloride

(2 S, 4 S) — 1 _ [(2 S) —2— (tert-butoxycarbonylamino) 13 _methylbutynoyl] -2-cyano 4 Fluoropyrrolidine (1.70 g) in methanol (LlmL) and cooled with ice. A 4M aqueous hydrochloric acid solution (llmL) was added, the temperature was raised to room temperature, and the mixture was stirred for 1 minute. The methanol was concentrated under reduced pressure, and the obtained aqueous solution was washed with ethyl acetate. A 4M aqueous sodium hydroxide solution (12 mL) and sodium chloride were added to the aqueous phase, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline. After the obtained organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off and concentrated under reduced pressure to obtain a colorless solid (2S, 4 S) -1-1 [(2S) -1-2-amino-3-methylbutanoyl] -2-cyano-14-fluoropyrrolidine (0.80 g) was obtained. A portion (0.60 g) of this was dissolved in methanol and added to a solution of 4M hydrochloric acid (ethyl acetate solution, 0.77 mL) in diisopropyl ether (22 mL) under ice-cooling. The solution was stirred at room temperature for 1 hour, and the precipitated insolubles were collected by filtration to give the title compound (0.75 g) as a colorless powder.

MS (ESI pos.) M / z: 214 ([M + H] +), 236 ([M + Na] +), (ESI neg.) M / z: 248 ([M + CL]-) ¹ H _{-NMR (DMSO - d 6, 500MHz} ) (58.57 (3H, br s), 5.55 (1H, br d, J = 51.8Hz), 5.06 (1H, d, J = 9.2Hz), 4.08-3.90 (2H, m), 3.83 (1H, d, J = 7.3Hz), 2.55-2.3 (2H, m), 2.12 (1H, m), 1.01 (3H, d, J = 6.7Hz), 0.98 (3H, d , J = 6.7Hz) Reference example 3

 Synthesis of (2 S, 4 S) I 2-cyano 1- [2 — [(5-Nitropyridine-2-yl) -amino] ethylamino] acetyl—4-fluoropyrrolidine maleate

(1) Synthesis of (2 S, 4 S) -2- (aminoaminopropyl) -1-1-bromoacetyl_4-1fluoropyrrolidine

 Reference Example 1 (2S, 4S) -2-aminopropyl 4-fluoropyrrolidine hydrochloride (650 mg) obtained in (2) was suspended in tetrahydrofuran (10 mL) and added to 2-ethyl under ice cooling. Potassium xanate (1.6 g) was added and stirred for 1 hour. Under ice cooling, bromoacetyl bromide (0.37 mL) was added, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 1 hour. To the reaction mixture was added chloroform-methanol (10: 1, 50 mL), and the mixture was stirred at room temperature for 15 minutes. The precipitated salt was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 40: 1 to 25: 1) to give the title compound (570 mg) as a colorless amorphous.

MS (ESI pos.) M / z: 275 ([M + Na] ⁺ ), 277 ([M + Na] ⁺ )

 (2) Synthesis of (2 S, 4 S) — 1-bromoacetyl — 2-cyano — 4-fluoropyrrolidine

(2S, 4S) 1-2- (Aminocarbonyl) -1-bromoacetyl_4_fluoropyrrolidine (560mg) was dissolved in tetrahydrofuran (6mL) and dried under ice-cooling. After addition of trifluoroacetic acid (0.62 mL), the mixture was stirred for 1 hour under ice cooling. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 50: 1 to 30: 1) to give the title compound (540 mg) as a colorless solid.

MS (ESI pos.) M: 257 ([M + Na] ⁺ ), 259 ([MINa] ⁺ )

 (3) (2 S, 4S) — Synthesis of 2-cyano 1- [2 — [(5-ditropyridine-1 2-yl) amino] ethylamino] acetyl-41-fluoropyrrolidine maleate

 2- (2-Aminoethylamino) -1-nitropyridine (580 mg) is dissolved in tetrahydrofuran (10 mL) and cooled with ice (2 S, 4 S) — 1-bromoacetyl-2-cyano — 4 A solution of 1-fluoropyrrolidine (250 nig) in tetrahydrofuran (2.5 mL) was added, and the temperature was slowly raised, followed by stirring at room temperature for 1 hour. The solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 50: 1 to 25: 1) to give (2S, 4S) —2-cyano 1 One [2 — [(5—nitropyridine-12-yl) amino] ethylamino] acetyl—4_fluoropyridine was obtained. This was dissolved in ethanol (lmL), and a solution of maleic acid (52mg) in ethanol (lmL) was added. Getyl ether was added to the reaction solution, the supernatant was discarded, and the precipitate was washed with getyl ether. The residue was dried under reduced pressure to give the title compound (160 mg) as a yellow powder.

MS (ESI pos.) M / z: 337 ([M + H] ⁺ )> 359 ([M + Na] ⁺ )> (ESI neg.) M / z: 335 ([MH] -I) Reference Example 4

 Synthesis of (2 S, 4 S) — 1— (tert-butylamino) acetyl — 2-cyano-141-fluoropyrrolidine hydrochloride

 Dissolve tert-butylamine (0.47g) in tetrahydrofuran (10mL) and cool under ice-cooling (2S, 4S) -11-bromoacetyl-2-cyano 4-fluoropyrrolidine

(0.30 g) in tetrahydrofuran (3 mL) was added, the temperature was slowly raised, and the mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added to the obtained residue. In addition, it was extracted with black-mouthed form. The organic phase was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The obtained residue was suspended in getyl ether, and the insoluble material was collected by filtration. As a colorless powder, (2S, 4S) -1-1 (tert-butylamino) acetyl-2-cyano-14-fluoropyrrolidine (0.26g) ). This part (0.25 g) was added to an ice-cooled getyl ether solution of 4 M hydrochloric acid (ethyl acetate solution, 0.3 mL), and the mixture was stirred at room temperature for 1 hour. The insolubles were collected by filtration to give the title compound (0.28 g) as a colorless powder.

MS (ESI pos.) M / z: 228 ([M + H] ⁺ ) ₁ 250 ([M + Na] ⁺ ), (ESI neg.) M / z: 226 ([MH]-), 262 ([ M + CL]-)

¹ H-丽 R (DMS0-d ₆ , 500MHz) δ 9.10 (2H, br s), 5.56 (IH, br d, J = 52.9Hz), 5.09-5.06 (1 H, m), 4.16 (IH, dd , J = 24.4, 12.5Hz), 4.12 (IH, d, J = l 6.5Hz), 3.88 (1H, d, J = 16.5Hz), 386 (IH, ddd, J = 39.9, 12.5, 3.3Hz) ), 2.54-2.40 (2H, m), 1.33 (9H, s) Reference example 5

 Synthesis of (2S, 4S) -1-2-cyano 4-fluoro-1-[(2-hydroxy-1,1, dimethyl) ethylamino] acetylpyrrolidine hydrochloride

 In the same manner as in Reference Example 4, 2-amino-2-methyl-1-propanol (0.71 g) and (2S, 4S) -1-bromoacetyl-2-cyano-14-fluoropyrrolidine (0.54 g) Thus, (2S, 4S) -2-cyano 4-monofluoro-1 _ [(2-hydroxy-1,1dimethyl) ethylamino] acetylpyrrolidine and the hydrochloride of the title compound (0.62 g) were obtained.

MS (ESI pos.) M / z: 244 ([M + H] ⁺ )> 266 ([M + Na] ⁺ )> (ESI neg.) M / z: 242 ([MH] ")> 278 ( [M + CL] ") Example 1

(2 S, 4 S) — 1 [[2 S, 3 S) -2-[(1-acetoxethoxytoxylponyl) amino] — 3-methylpentanoyl] —2-cyano 4-fluoropyrrolidine Synthesis of (2 S, 4 S)-1-[(2 S, 3 S) 12-amino-13-methylpentyl] _ 2-cyano 4-fluoropyrrolidine (2.0 g) in tetrahydrofuran

(2 OmL) and cooled to -2 with dry ice-acetone. Diisopropylethylamine (1.53 mL) was added, and 1-chloroethyl chloroformate (0.95 mL) was added dropwise over 15 minutes. This solution was stirred at -20 to 15 ° C for 1 hour. The reaction solution was poured into a saturated saline solution (5 OmL), and extracted with ethyl acetate (5 OmL). The organic layer was washed with a mixed aqueous solution of a 6 M aqueous hydrochloric acid solution (1 mL) and a saturated saline solution (5 OmL), and then washed twice with a saturated saline solution (5 OmL). After the organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. Dissolve the residue in acetone (3 OmL) and add sodium iodide (1.32 g) and sodium acetate.

(1.08 g) was added and the mixture was stirred at room temperature for 4 hours. Acetone was distilled off, and the residue was dissolved in water (10 OmL) and ethyl acetate (10 OmL). The organic layer was washed successively with a 1% aqueous solution of sodium hydrogen sulfite (50 mL) and a saturated saline solution (50 mL × 2). After the organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate =

3: 4 to 1: 1) to give the title compound (0.2

4 g) was obtained as a diastereomer mixture (ratio approximately 3: 2 by NMR).

MS (ESI) m / z: 380 ([M + Na] tens), (ES_) m / z: 356 ([M-1] —)

 IH-band R (CDC 13, 300MHz) 66.76 and 6.74 (lH, q each, J = 5.4Hz each), 5.46 (IH, br d, J = 9.2Hz), 5.43 (IH, br d, J = 51.8Hz) ), 5.01 (IH, d, J = 9.3Hz), 4.22-3.92 (3H, m), 2.66 (IH, t, J = 15.6Hz), 2.50-2.22 (IH, m), 2.06 and 2.03 ( 3H, s each), 1.84 (lH, m), 1.63 (IH, m), 1.46 and 1.44 (3H, d each, J = 5.4Hz each), 1.0 (IH, m), 1.01 and 1.00 (3H, d each, J = 6.8Hz each), 0.94 and 0.93 (3H, t each, J = 7.4Hz each) Example 2

(2 S, 4 S) — Synthesis of 1-[(2 S) -2-[(1-acetoxyshethoxycarponyl) amino] -13-methylbutanoyl] 1-2-cyano-14-fluoropyrrolidine (2 S, 4 S) — 1 [(2 S, 3 S) 1 2-amino-3-methylpentanoyl] 1-cyano 4-fluoropyrrolidine (2 S, 4 S) — The title compound was obtained in the same manner as in Example 1 using 1-[(2S) -1-2_amino-3-methylbutanol] -2-cyano 4-fluoropyrrolidine. Example 3

 (2 S, 4 S) 1 1 1 [N— (1-Acetoxyethoxycarbonyl) -N- [2 — [(5-Ditropyridine — 2-yl) —Amino] ethyl] Amino] acetyl— 2 Synthesis of 4-cyano 4-pyrrolidine pyrrolidine

 (2 S, 4 S) 1 1-[(2 S, 3 S) 1-2-amino-1-3 -methylpentanoyl]-1-2-cyano 4 _ Instead of fluorfluoropyrrolidine, (2 S, 4 S) 1 2-Cyano 1_ [2 _ [(5-nitropyridin-2-yl) 1-amino] ethylamino] acetyl-4-Fluoropyrrolidine was used to give the title compound in the same manner as in Example 1. Obtained. Example 4

 Synthesis of (2 S, 4 S) — 1 [N— (1—acetoxetethoxycarponyl) 1 N— (tert-butyl) amino] acetyl-2—cyano _ 4 1-fluoropyrrolidine

 (2 S, 4 S)-1-[(2 S, 3 S) 1-2-amino-3-methylpentanoyl]-2-cyano 14-Instead of fluoropyrrolidine, (2 S, 4 S The title compound was obtained in the same manner as in Example 1 using 1 1 _ (tert-butylamino) acetyl-2-cyano 4-fluoropyrrolidine. Example 5

 (2 S, 4 S) 1 1 1 [N— (1-acetoxetoxycarponyl) —N— [(2-hydroxy-1,1 dimethyl) ethyl] amino] acetyl—2-cyano—4—fluoropyrrolidine

(2 S, 4 S) 1 1 1 [(2 S, 3 S) — 2-amino-1 3-methylpentanoy (1S) instead of 4-cyano 4-fluoropyrrolidine (2S, 4S) —2—cyano _4-monofluoro [1-1 ((2-hydroxy-11,1dimethyl) ethylamino] acetylpyrrolidine And the title compound was obtained in the same manner as in Example 1. Test Example 1 [Dipidyl peptidase IV activity inhibition experiment]

Dipeptidyl peptidase IV (DPP IV) activity inhibition experiments were performed according to the method described in Diabetes, 47, 764-769, 1998. Plasma containing dipeptidyl peptidase IV was prepared by collecting blood from healthy volunteers and centrifuging. The enzymatic reaction was carried out using a 96-well flat bottom plate in a buffer consisting of 25 mM HEPES, 14 OmM NaC 1% BSA, pH 7.8. IOOMG 1 y_Pro— 4-Methylcumaryl-1 7-amide (manufactured by Peptide Research Laboratories) Solution 25 1, 133 mM magnesium chloride solution 7.5 n 1, test compound 51 mixed, then 1/100 with the above buffer One-half diluted plasma 12.5 1 was added. After reacting at room temperature for 2 hours, the reaction was stopped by adding 50 1 of 25% acetic acid aqueous solution. The amount of the released 7-amino-4-methylcoumarin was measured at 460 nm when excited at 390 nm using a fluorescence plate reader (1420 ARVOTM Multi-absorber; Wa11ac). The fluorescence intensity when the reaction time was set to 0 minutes after the addition of the solvent was defined as a blank value, and the value obtained by subtracting the blank value from each measured value was defined as the specific fluorescence intensity. From the obtained specific fluorescence intensity, the inhibition rate (%) of dipeptidyl peptidase IV activity was determined by the following equation. The test compound was prepared by preparing a dimethylsulfoxide solution having a 1000-fold higher concentration, and diluting it with the above buffer. From the inhibition rate at each concentration, the concentration of the compound showing 50% inhibition ( _IC5Q value) was calculated. As a result, the compound of Reference Example 1 exhibited an excellent DPPIV inhibitory activity with an IC ₅₀ of 0.6 nM.

 Inhibition rate (%) = A ÷ BX 100

 (A = Fluorescence intensity when solvent is added-Fluorescence intensity when analyte compound is added)

(Fluorescence intensity upon addition of B solvent). Test Example 2 [Effect of dipeptidyl peptidase IV inhibitor in oral glucose tolerance test (OGTT) in Zucker fatty rats]

 OGTT in Zucker fatty rats was carried out with reference to the method described in Diabetologia, 42, 1324-1331, 1999. For the test, 10-week-old male Zucker fatty rats (Nippon Charus Riva) were used after a 16-hour fast. Water was taken freely until immediately before use, and thereafter water was cut off until the end of the test. Blood was collected via heparin-treated blood collection tube (Drummond Scientific) before the start of the test; blood was collected from the fundus vein. The test compound was orally administered as a solution. Sugar was dissolved in water for injection in the Japanese Pharmacopoeia and administered orally as a sugar at a dose of 1 g / kg body weight or 2 gZkg body weight 15 or 30 minutes after administration of the test compound and water for injection. Blood was collected from the fundus vein at 15, 30 and 60 minutes after glucose administration. The blood sample was immediately mixed with heparin (manufactured by Shimizu Pharmaceutical), centrifuged at 3000 rpm for 15 minutes at 4 ° C, and the plasma was collected and immediately frozen.

 The blood glucose level (mg / dl) of the frozen sample was measured with a glucose CII test II (manufactured by Wako Pure Chemical Industries, Ltd.) and the area under the curve (min * mgZd 1) was calculated. (However, the blood glucose level of the sample obtained by blood collection before the test was started was used as the 0-minute blood glucose level.)

 The compounds of the examples suppressed an increase in blood glucose level. Industrial applicability

 According to the present invention, it is possible to provide a compound having stable and excellent dipeptidyl peptidase IV (DPPIV) inhibitory activity, and the compound of the present invention is useful as a prophylactic or therapeutic agent for diabetes, immune disease and the like.

Claims

The scope of the claims  1. Equation (1)

[Wherein, w is an acyl group derived from a natural amino acid;

(In the formula, W ¹ represents an alkanoyl group having 1 to 5 carbon atoms, an arylcarbonyl group which may be substituted or an alkyl group having 1 to 5 carbon atoms, represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. )) Or a group represented by the formula

(Wherein, W ³ and are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.)  X represents an oxygen atom or a sulfur atom, Y is a group of the formula CR ⁵ R ⁶ — wherein R ⁵ and R ⁶ are the same or different and are a hydrogen atom; a halogen atom; a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms, Xyl group, mercapto group, alkylthio group having 1 to 5 carbon atoms, guanidyl group, phenyl group which may be substituted, imidazolyl group, indolyl group, -NHR ¹¹ (wherein, R ¹¹ is a hydrogen atom and may be substituted A phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group.), -CONHR ¹² {wherein, R ¹² is a hydrogen atom or 1 (CH ₂ ) _m —R ¹³ (in the formula, m represents an integer of 1 to 5, R ¹³ represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group.) And _OR "(wherein R ¹⁴ represents a chain alkyl group having 1 to 5 carbon atoms or a benzyl group.) An alkyl group having 1 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of Or having 2 to 2 carbon atoms which may be substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyl group, an amino group, an aminocarboxy group and a linear alkoxy group having 1 to 5 carbon atoms. Indicate 10 alkenyl groups. ] Or the formula-. ! ^ ⁷ ! ^-. ! ^! ^. — (Wherein, R ⁷ , R ⁸ , R ⁹ and R ¹¹¹ are the same or different and are a hydrogen atom; a halogen atom; a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carboxyl group, a mercapto group, and a carbon number 1 to 5 alkylthio groups, guanidyl groups, optionally substituted phenyl groups, imidazolyl groups, indolyl groups, -NHR ¹¹ (wherein R ¹¹ is a hydrogen atom, optionally substituted phenyl groups, optionally substituted Represents a pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group.),, —CONHR ¹² {wherein R ¹² is a hydrogen atom or — (CH ₂ ) _ffl -R ′ ³ (where m is an integer And R ¹³ represents a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group.) And —OR ¹⁴ (wherein R ¹⁴ has 1 to 5 carbon atoms). Chain alkyl group Or properly represents an alkyl group which may carbons 1-10 be substituted with one or more groups selected from the group consisting of a benzyl group.), Or together with the carbon atom to which R ⁷ and R ⁹ adjacent In addition, one selected from the group consisting of a halogen atom, a hydroxyl group, a propyloxyl group, an amino group, an aminocarbonyl group, a linear alkyl group having 1 to 5 carbon atoms, and a linear alkoxy group having 1 to 5 carbon atoms. A cycloalkyl group having 3 to 8 carbon atoms which may be substituted with one or more groups; a halogen atom, a hydroxyl group, a carbonyl group, an amino group, an aminocarbonyl group, a carbon atom A cycloalkyl group having 4 to 8 carbon atoms which may be substituted with one or more groups selected from the group consisting of a chain alkyl group having 1 to 5 chain atoms and a chain alkoxy group having 1 to 5 carbon atoms; A carbon atom which may be substituted with one or more groups selected from the group consisting of a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group having 1 to 5 carbon atoms and a chain alkoxy group having 1 to 5 carbon atoms. A bicycloalkyl group having a number of 5 to 10; or a halogen atom, a hydroxyl group, a propyloxyl group, an amino group, an aminocarbonyl group, a linear alkyl group having 1 to 5 carbon atoms, and a linear alkoxy group having 1 to 5 carbon atoms. A bicycloalkenyl group having 5 to 10 carbon atoms which may be substituted with one or more groups selected from the group is formed. ), Z is a hydrogen atom; or a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carbonyl group, a mercapto group, an alkylthio group having 1 to 5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, An imidazolyl group, an indolyl group, —NH R "(wherein R ¹¹ is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group; . shown), one CO NH R ^{1 2} {wherein, R ^{1 2} is a hydrogen atom or one ^{_{(CH 2) m - R 1}} 3 ( wherein, m represents an integer 1 to 5, R ^{1 3} is a hydrogen atom , A methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group.)} And —OR ¹⁴ (wherein, R ¹⁴ is a linear alkyl group having 1 to 5 carbon atoms or Represents a benzyl group.) Selected from the group consisting of In one or more groups or an alkyl group having a carbon number of 1 to 1 0 may be substituted that, Or Y and Z are joined together with an adjacent nitrogen atom to form an octylogen atom, a hydroxyl group, an amino group, a chain alkyl group having 1 to 5 carbon atoms, and 1 R ¹⁵ (where R ¹⁵ is a carbon atom A linear alkyl group, an aminocarbonylmethyl group or a benzyl group having 1 to 5), which forms a cyclic amino group having 2 to 10 carbon atoms which may be substituted with one or more groups selected from the group consisting of I do. Or a pharmaceutically acceptable salt thereof. 2. The cyanopyrrolidine derivative according to claim 1, wherein in the formula (1), X is an oxygen atom. A conductor or a pharmaceutically acceptable salt thereof. 3. The cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y in the formula (1) is —CH ₂ —. 4. In the formula (1), Z is a branched or cyclic alkyl group having 4 to 10 carbon atoms, which may be substituted with one or more selected from the group consisting of a hydroxyl group and a hydroxyalkyl group having 1 carbon atom. 4. The cyanopyrrolidine derivative according to any one of 1 to 3, or a pharmaceutically acceptable salt thereof. 5. In the formula (1), Z is a tert-butyl group, a (1-hydroxymethyl) cyclopentyl group or a (2-hydroxy-1,1-dimethyl) ethyl group. Cyanopyrrolidine derivative or its pharmaceutically acceptable 6. In the formula (1), Y is —CR ⁵ R ⁶ — (where R ⁵ is hydrogen.); 2. The cyanopyrrolidine derivative according to claim 1, wherein Z is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 7. In the formula (1), Y is —CR ⁵ R ⁶ — (wherein, R ⁵ is hydrogen and R ⁶ is a branched or cyclic alkyl group having 3 to 6 carbon atoms), and Z is 3. The cyanopyrrolidine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein is a hydrogen atom. 8. In the formula (1), Y is _CH [CH (CH ₃ ) ₂ ] —, -CH [C (CH ₃ ) ₃ ] — or one CH [CH (CH ₃ ) CH ₂ CH ₃ ] —, and Z The cyanopyrrolidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein is a hydrogen atom. 9. The cyanopyrrolidine derivative according to any one of claims 1 to 8, or a pharmaceutical thereof. A medicament comprising a pharmaceutically acceptable salt as an active ingredient. 10. The medicament according to claim 9, for preventing or treating a disease or condition that can be improved by inhibiting dipeptidyl peptidase IV. 11. The medicament according to claim 10, wherein the disease or condition that can be ameliorated by inhibiting dipeptidyl peptidase IV is diabetes. 12. The medicament according to claim 10, wherein the disease or condition that can be improved by inhibiting dipeptidyl peptidase IV is an immune disease.