ZA200302591B - Cyanopyrrolidine derivatives. - Google Patents

Description

~~ 0400372591 ® SPECIFICATION

CYANOPYRROLIDINE DERIVATIVES

TECHNICAL FIELD

The present invention relates to novel cyanopyrrolidine derivatives. :

BACKGROUND ART

Dipeptidyl peptidase IV (DPP IV) is a kind of serine proteases which can hydrolyze the dipeptide from the peptide chain having proline or alanine at the second position from the N-terminus. DPP IV is distributed in a variety of the tissues (including kidney or liver) and ~ plasma, and participates in the metabolisms of various physiologically active peptides.

Recently, it has been made clear that DPP IV acts on the metabolism of glucagon-like peptide-1 (GLP-1). That is,

DPP IV hydrolyzes the dipeptide of the N-terminal His-Ala of GLP-1, thereby, GLP-1 is inactivated, and the inactivated product acts as an antagonist of GLP-1 receptor.

GLP-1 has been found to have physiological actions such as an accelerating action of insulin-secretion from the pancreas, a prolonging action of gastric emptying time or an inhibitory action of eating. Accordingly, DPP IV inhibition elevates the GLP-1 effect, enhances the insulin effect and improves glucose metabolism, therefore, DPP IV inhibition is expected to be useful for treating type 2 diabetes mellitus.

In addition, DPP IV has been found to participate in the metabolism of neuropeptide Y which is a kind of

® neuropeptides, activation of T cells which are immunocompetent cells, adhesion of cancer cells to the endothelium or invasion of HIV virus into lymphocytes.

Accordingly, DPP IV inhibition is considered to be useful for treating immune diseases, etc.

Furthermore, a high level of DPP IV expression has been found in fibroblasts of the skin of human subjects of psoriasis, rheumatoid arthritis and lichen planus, and a high DPP IV activity has been found in the subjects of benign prostatic hypertrophy. Accordingly, DPP IV inhibition is also expected to be effective to skin diseases and benign prostatic hypertrophy.

Among DPP IV inhibiting compounds which have been known up to this time, there are the compounds which are substituted with a phosphorus atom at the 2-position of pyrrolidine (J. Med. Chem., 37, 3969 - 3976, 1994), and the compounds which are substituted with a boron atom at the 2-position of pyrrolidine (Biochemistry, 32, 8723 - 8731, 1993). Also are known the compounds which are substituted with a cyano group at the 2-position of pyrrolidine (Arch.

Biochem. Biophys., 323, 148 - 152, 1995; Bioorg. Med. Chem.

Lett., 6, 1163 - 1166, 1996; Biochemistry, 38, 11597 - 11603, 1999), but there is no report on any inhibitors . which have substituent(s) at the 3- or 4-position of 2- : cyanopyrrolidine derivatives.

An object of the present invention is to provide novel cyanopyrrolidine derivatives which have an excellent

DPP IV inhibition activity.

® DISCLOSURE OF THE INVENTION

As a result of the continued extensive studies in order to achieve the above-mentioned object, the present inventors have found that certain cyanopyrrolidine derivatives have an excellent DPP IV inhibition activity, and thereby the present invention has been accomplished.

One aspect of the present invention is to provide a compound represented by Formula (1) (hereinafter referred to as "the compound of the present invention” or "the present invention compound”): : x RI

H J R2 7 Ny SL (1)

R3

CN R4 [wherein Rl is a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, RZ is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, or Rl and Rr? together form an oxo, a hydroxyimino group, an alkoxyimino group having 1 to 5 carbon atoms or an alkylidene group having 1 to 5 carbon atoms,

R3 and R4 are each a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, or R3 and R% together form an oxo, a hydroxyimino group, an alkoxyimino group having 1 to 5 carbon atoms or an

® alkylidene group having 1 to 5 carbon atoms,

X is an oxygen atom or a sulfur atom,

Y is -CROR6- [wherein R5 and R6 are the same or different, and each a hydrogen atom; ‘a halogen atom; an alkyl group having 1 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of 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 § carbon atoms, a guanidyl group, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, -NHR11 (wherein Rll is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR12 {wherein R12 is a hydrogen atom or -(CHj)p-R13 (wherein m is an integer of 1 to 5, and R13 is a hydrogen . atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)} and -OR14 (wherein R14 is a chain alkyl group having 1 to 5 carbon atoms or a benzyl group): or an alkenyl group having 2 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a chain alkoxy group having 1 to 5 carbon atoms], or -CR7R8-CRIR10- (wherein R7, R8, R? and R10 are the same or different, and each a hydrogen atom; a halogen atom; or an alkyl group having 1 to 10 carbon atoms which is optionally substituted with at least one selected from the

® group consisting of 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, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, -NHR11 (wherein R11 is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR12 {wherein R12 is a hydrogen atom or -(CHj)y,-R13

(wherein m is an integer of 1 to 5, and R13 is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)} and -ORl4 (wherein R14 is a chain alkyl group having 1 to 5 carbon atoms or a benzyl group), or R7 and R? together with the carbon atom to which they are attached form a cycloalkyl group having 3 to 8 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, 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 cycloalkenyl group having 4 to 8 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, 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 5 to 10 carbon atoms which is : optionally substituted with at least one selected from the

C group consisting of a halogen atom, 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; or a bicycloalkenyl group having 5 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, 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), and

Z is a hydrogen atom; or an alkyl group having 1 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of 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, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, -NHR1l (wherein R11 is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR12 (wherein R12 is a hydrogen atom or -(CHy)p-R13 (wherein m is an integer of 1 to 5, and R13 is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)} and -OR14 (wherein R14 is a chain alkyl group having 1 to 5 carbon atoms or a benzyl group), or Y and Z together with the nitrogen atom to which they are attached form a cyclic amino group having 2 to 10

[ carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a chain alkyl group having 1 to 5 carbon atoms and -OR15 (wherein R15 is a chain alkyl group having 1 to 5 carbon atoms, an aminocarbonylmethyl group or a benzyl group)] or a pharmaceutically acceptable salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

Another aspect of the present invention is to provide the cyanopyrrolidine derivative of Formula (1) wherein Rl is a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, and RZ, R3 and R4 are each a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, or the pharmaceutically acceptable salt thereof. nL

A still another aspect of the present invention is to provide the cyanopyrrolidine derivative of Formula (1) wherein Rl is a fluorine atom or a chlorine atom, or the pharmaceutically acceptable salt thereof.

A further aspect of the present invention is to provide the cyanopyrrolidine derivative of Formula (1) wherein Rl is a fluorine atom, and R2 is a hydrogen atom, or the pharmaceutically acceptable salt thereof.

A still further aspect of the present invention is to provide the cyanopyrrolidine derivative of Formula (1) wherein Rl is a fluorine atom, and R2, R3 and R% are each a - 7 - B

® hydrogen atom, or the pharmaceutically acceptable salt thereof.

A still further aspect of the present invention is to provide a cyanopyrrolidine derivative represented by

Formula (2):

H J§ F 17 "Sy os (2)

CN wherein X, Y and Z are defined as above) or a pharmaceutically acceptable salt thereof.

A still further aspect of the present invention is to provide the cyanopyrrolidine derivative of Formula (1) or (2) wherein X is an oxygen atom, or the pharmaceutically acceptable salt thereof.

A still further aspect of the present invention is . to provide the cyanopyrrolidine derivative of Formula (1) or (2) wherein Y is -CHy-, or the pharmaceutically acceptable salt thereof.

A still further aspect of the present invention is to provide the cyanopyrrolidine derivative of Formula (1) ~ or (2) wherein Y is -CHy- and Z is a branched or cyclic alkyl group having 4 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a hydroxyl group and a hydroxyalkyl group having 1 to 5 carbon atoms, or the pharmaceutically acceptable salt thereof.

® A still further aspect of the present invention is to provide the cyanopyrrolidine derivative of Formula (1) TT or (2) wherein Y is -CHp- and Z is a tert-butyl group, a (1-hydroxymethyl)cyclopentyl group or a (2-hydroxy-1,1- dimethyl)ethyl group, or the pharmaceutically acceptable salt thereof.

A still further aspect of the present invention is to provide the cyanopyrrolidine derivative of Formula (1) or (2) wherein Y is -CROR6- (wherein RY is a hydrogen atom) and Z is a hydrogen atom, or the pharmaceutically acceptable salt thereof.

A still further aspect of the present invention is to provide the cyanopyrrolidine derivative of Formula (1) or (2) wherein Y is -CR5R6- (wherein R® is a hydrogen atom,

R6 is a branched or cyclic alkyl group having 3 to 6 carbon atoms) and Z is a hydrogen atom, or the pharmaceutically acceptable salt thereof.

A still further of the present invention is to provide the cyanopyrrolidine derivative of Formula (1) or (2) wherein Y is -CH[CH(CH3)31-, -CH[C(CH3)3]- or -CH[CH(CH3)CHCH3]- and Z is a hydrogen atom, or the pharmaceutically acceptable salt thereof.

A still further aspect of the present invention is to provide a pharmaceutical preparation which comprises as an effective ingredient the above-mentioned cyanopyrrolidine derivative or the pharmaceutically acceptable salt thereof.

A still further aspect of the present invention is

® to provide the above-mentioned pharmaceutical preparation for preventing or treating a disease or condition capable of being improved by inhibition of dipeptidyl peptidase IV.

A still further aspect of the present invention is to provide the above-mentioned pharmaceutical preparation wherein the disease or condition capable of being improved by inhibition of dipeptidyl peptidase IV is diabetes mellitus.

A still further aspect of the present invention is to provide the above-mentioned pharmaceutical preparation wherein the disease or condition capable of being improved by inhibition of dipeptidyl peptidase IV is an immune disease. : In the present invention, “chain” means a straight or branched chain.

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 straight, branched or cyclic alkoxy group, examples thereof are a methoxy group, an ethoxy group, a propoxy group, an . isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a cyclopropylmethoxy group, a pentyloxy group and an isopentyloxy group.

The alkyl group having 1 to 5 carbon atoms means a straight, branched or cyclic alkyl group, and examples thereof are a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a

® cyclobutyl group, a cyclopropylmethyl group, a pentyl group, an isopentyl group, a cyclopentyl group, a cyclobutylmethyl group and a 1-ethylpropyl group.

The alkoxyimino group having 1 to 5 carbon atoms means an imino group substituted with a straight, branched or cyclic alkoxy group, and examples thereof are a methoxyimino group, an ethoxyimino group, a propoxyimino group, an isopropoxyimino group, a butoxyimino group, an isobutoxyimino group, a tert-butoxyimino group, a cyclopropylmethoxyimino group, a pentyloxyimino group and an isopentyloxyimino group.

The alkylidene group having 1 to 5 carbon atoms means a straight, branched or cyclic alkylidene group, and examples thereof are a methylene group, an ethylidene group, a propylidene group, an isopropylidene group, a butylidene group, an isobutylidene group, a cyclopropylmethylene group and a pentylidene group.

The alkyl group having 1 to 10 carbon atoms which is optionally substituted means a straight, branched or cyclic alkyl group having 1 to 10 carbon atoms which is substituted or unsubstituted, and examples thereof are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, a cycloalkyl group having 3 to 10 carbon atoms (e.g., a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclobutylmethyl group, a cyclohexyl

[ group, a cycloheptyl group or a cyclooctyl group), a cycloalkenyl group having 4 to 8 carbon atoms (e.g., a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group or a cyclooctenyl group), a bicycloalkyl group having 5 to 10 carbon atoms which is optionally substituted (e.g., a bicyclopentyl group, a bicyclohexyl group, a bicycloheptyl group, a bicyclooctyl group, a bicyclononyl group or a bicyclodecyl group), a bicycloalkenyl group having 5 to 10 carbon atoms which is optionally substituted (e.g., a bicyclopentenyl group, a bicyclohexenyl group, a bicycloheptenyl group, a bicyclooctenyl group, a bicyclononenyl group or a bicyclodecenyl group), a bridged cyclic hydrocarbon group (e.g., an adamantyl group, a bornyl group, a norbornyl group, a pinanyl group, a thujyl group, a caryl group or a camphanyl group), and the alkyl group of which the hydrogen atom is substituted with at least one selected from the group consisting of 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, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, -NHR11 (wherein R11 is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR12 {wherein R12 is a hydrogen atom or -(CHp)p-R13 (wherein m is an integer of 1 to 5, and R13 is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a

® benzyloxycarbonyl group)} and -ORl4 (wherein R14 is a . straight or branched alkyl group having 1 to 5 carbon atoms or a benzyl group).

Examples of the substituted phenyl group of the optionally substituted phenyl group are a phenyl group substituted with at least one selected from the group consisting of a hydroxyl group and a straight or branched alkoxy group having 1 to 5 carbon atoms (e.g., a 4- hydroxyphenyl group or a 3,4-dimethoxyphenyl group).

Examples of the substituted pyridyl group of the optionally substituted pyridyl group (e.g., a pyridin-2-yl group) are a pyridyl group substituted with at least one selected from the group consisting of a cyano group. a : nitro group, a halogen atom and an aminocarbonyl group (e.g., a 5-cyanopyridin-2-yl group, a 5-nitropyridin-2-yl

S group, a chloropyridin-2-yl group or a 5- aminocarbonylpyridin-2-yl group).

Examples of the hydroxyalkyl group having 1 to 5 carbon atoms are a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxypropyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 1l- (hydroxymethyl)ethyl group, a 1-hydroxy-1l-methylethyl group, a 4-hydroxybutyl group and a 5-hydroxypentyl group.

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

The alkenyl group having 2 to 10 carbon atoms

® which is optionally substituted means a straight, branched or cyclic alkenyl group having 2 to 10 carbon atoms which is substituted or unsubstituted, and examples thereof are alkenyl groups (e.g., a vinyl group, an allyl 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 or a cyclohexenyl group) and the alkenyl group of which the hydrogen atom is substituted with at least one group selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a straight or branched alkoxy group "having 1 to 5 carbon atoms.

The cycloalkyl group having 3 to 8 carbon atoms which is optionally substituted means a cycloalkyl group which is substituted or unsubstituted, and examples thereof are a cycloalkyl group (e.g., a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group) and the cycloalkyl group of which the hydrogen atom is substituted with at least one selected from the group consisting of a halogen atom, a hydroxyl group. a carboxyl group, an amino group, an aminocarbonyl group, a straight or branched alkyl group having 1 to 5 carbon atoms and a straight or branched alkoxy group having 1 to 5 carbon atoms.

The cycloalkenyl group having 4 to 8 carbon atoms which is optionally substituted means a cycloalkenyl group which is substituted or unsubstituted, and examples thereof

® are a cylcoalkenyl group (e.g., a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group or a cyclooctenyl group) and the cycloalkenyl group of which the hydrogen atom is substituted with at least one selected from the group consisting of a halogen atom, a : hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a straight or branched alkyl group having 1 to 5 carbon atoms and a straight or branched alkoxy group having 1 to 5 carbon atoms.

The bicycloalkyl group having 5 to 10 carbon atoms which is optionally substituted means a bicycloalkyl group which is substituted or unsubstituted, and examples thereof are a bicycloalkyl group (e.g., a bicyclopentyl group, a bicyclohexyl group, a bicycloheptyl group, a bicyclooctyl group, a bicyclononyl group or a bicyclodecyl group) and the bicycloalkyl group of which the hydrogen atom is substituted with at least one selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a straight or branched alkyl group having 1 to 5 carbon atoms and a straight or branched alkoxy group having 1 to 5 carbon atoms.

The bicycloalkenyl group having 5 to 10 carbon atoms which is optionally substituted means a bicycloalkenyl group which is substituted or unsubstituted, and examples thereof are bicycloalkenyl groups (e.g., a bicyclopentenyl group, a bicyclohexenyl group, a bicycloheptenyl group, a bicyclooctenyl group, a bicyclononenyl group or a EK

( bicyclodecenyl group) and the bicycloalkenyl group of which the hydrogen atom is substituted with at least one group selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a straight or branched alkyl group having 1 to 5 carbon atoms and a straight or branched alkoxy group having 1 to 5 carbon atoms.

The cyclic amino group having 2 to 10 carbon atoms which is optionally substituted means a cyclic amino group which has at least one nitrogen atom and has optionally at least one of an oxygen atom and a sulfur atom on the ring, and is substituted or unsubstituted, and examples thereof are a cyclic amino group (e.g., an aziridyl group, an azetidyl group, a pyrrolidyl group, an imidazolidyl group, an oxazolidyl group, a thiazolidyl group, a piperidyl group, a morpholinyl group, an azabicycloheptyl group or an azabicyclooctyl group), the cyclic amino group which is condensed with a benzene ring or a pyridine ring, and the cyclic amino group (including those which are condensed with a benzene ring or a pyridine ring) of which the hydrogen atom is substituted with at least one group selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a straight or branched alkyl group having 1 to 5 carbon atoms, and -OR15 (wherein

R15 is a straight or branched alkyl group having 1 to 5 carbon atoms, an aminocarbonylmethyl group or a benzyl group) .

Examples of the pharmaceutically acceptable salt are

® salts with mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid or phosphoric acid, and salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, trifluoroacetic acid or methanesulfonic acid.

Preferred compounds of the present invention are shown as follows:

In view of DPP IV inhibition activity, Rl is preferably a halogen atom, and especially preferably a fluorine atom. RZ is preferably a hydrogen atom or a halogen atom, and especially preferably a hydrogen atom.

In Formula (1) or (2), when Y is -CHp-, Z is preferably an alkyl group having 1 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, an optionally substituted phenyl group and -NHR11l (wherein R11 is an optionally substituted pyridyl group) . In this case, Z is preferably a branched or cyclic alkyl group having 4 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms and an alkoxy group having 1 to 5 carbon atoms, and especially preferably a branched alkyl ~~ 25 group having 4 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a hydroxyl group and a hydroxyalkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 4 to

C 10 carbon atom or an adamantyl group, and most preferably a tert-butyl group, a (l-hydroxymethy)cyclopentyl group or a (2-hydroxy-1,1-dimethyl)ethyl group.

In Formula (1) or (2), it is preferable that when Y is -CRSR6- (wherein R® is a hydrogen atom, R® is an optionally substituted alkyl group having 1 to 10 carbon atoms) or -CR7R8-CRIR10- (wherein R8® and R10 are each a hydrogen atom, and R7 and RY together with the carbon atom to which they are attached form a cycloalkyl group having 3 to 8 carbon atoms), Z is H or -CHj3.

In this case, it is further preferable that when Y is -CRSR6- {wherein R® is a hydrogen atom, R6 is a branched or cyclic alkyl group having 3 to 6 carbon atoms which is optionally substituted with at least one selected from the group consisting of a hydroxyl group and -OR!4 (wherein R14 is a straight or branched alkyl group having 1 to 5 carbon atoms or a benzyl group)}, Z is a hydrogen atom. It is further preferable that when Y is -CRSR6- (wherein R® is a hydrogen atom, and R6 is a branched or cyclic alkyl group having 3 to 6 carbon atoms), Z is a hydrogen atom, and it is especially preferable that when Y is -CH[CH(CH3);1-. -CH[C(CH3)3]- or -CH[CH(CH3)CHyCH3]-, Z is a hydrogen atom.

In Formula (1) or (2), preferred examples of the optionally substituted cyclic amino group having 2 to 10 carbon atoms which is formed by Y and Z together with the nitrogen atom to which they are attached, are a pyrrolidyl group, a piperidyl group and a cyclic amino group which is formed by condensing a pyrrolidyl group or a piperidyl

® group with a benzene ring, and preferred substituent thereof includes a hydroxyl group or -OR15 (wherein RIS is defined as above).

The compounds of the present invention can inhibit dipeptidyl peptidase IV, and therefore, they increase insulin activity, improve glucose metabolism, and can contribute to inhibition of neuropeptide Y metabolism, inhibition of T-cell activity, inhibition of adhesion of cancer cells to the endothelium and prevention of invasion of HIV virus into lymphocytes.

Accordingly, the present invention is to provide a pharmaceutical preparation for preventing or treating diseases or conditions capable of being improved by inhibition of dipeptidyl peptidase IV, for example, diabetes mellitus (especially the type 2), immune diseases, arthritis, obesity, osteoporosis, conditions of glucose tolerance, benign prostatic hypertrophy or skin diseases.

The pharmaceutical preparation for immune diseases includes immunosuppresors for tissue transplantation, for example, cytokine-release inhibitors in various autoimmune diseases such as inflammatory enteritis, multiple sclerosis : or chronic rheumatoid arthritis (RA), drugs useful for preventing or treating AIDS due to prevention of invasion of HIV into T-cells, drugs for metastasis obviation, especially, metastasis obviation of breast or prostatic cancer into lung.

The pharmaceutical preparation of present invention can be administered systemically or locally, or orally or

[ parentelly such as rectally, subcutaneously, intramuscularly, intravenously or percutaneusly.

For use of the compound of the present invention as a pharmaceutical preparation, any dosage form can be properly selected as necessary from solid compositions, liquid compositions and other compositions. The pharmaceutical preparation of the present invention can be produced by combining the compound of the present invention with pharmaceutically acceptable carriers. Specifically, tablets, pills, capsules, granules, powders, fine powders, solutions, emulsions, suspensions or injections can be produced by adding convenient excipients, fillers, binders, disintegrators, coating agents, sugar coating agents, pH modulators, solublizing agents, or aqueous OX non-aqueous solvents according to the conventional pharmaceutical preparation techniques. Excipients and fillers include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, arabic gum, olive oil, sesame oil, cacao butter, ethylene glycol and other conventional materials.

Furthermore, the compounds of the present invention can be formulated into the form of an inclusion compound with a-, B- or y-cyclodextrin, or methylated cyclodextrin.

A dose of the compound of the present invention varies depending upon disease, conditions, body weight, age, sex, administration route, but the dose for adult is preferably from about 1 to about 1000 mg/kg of body weight/day for oral administration, and specifically preferably from about 10 to about 200 mg/kg of body

@ weight/day, and may be given at once or by dividing.

The compounds of Formula (1) can be prepared by the general preparation processes. [General Preparation Process] [Reaction Scheme 1] 1 1

Rb J ; R2 H J R R2 : R3 R3

Ra R¢ a Ra R* wherein X, Y, %, Rl, R2, R3 and R4 are defined as above, Ra is a cyano group, an aminocarbonyl group Or an alkoxycarbonyl group, and Rb is a protecting group of an amino group.

The deprotection can be carried out by the method described in Protective Groups in Organic Synthesis by

Theodora W. Greene and Peter G. M. Wu Ts.

For example, the compound wherein Rb is a group to be deprotected with an acid (e.g., a tert-butoxycarbonyl group, a trityl group or an o-nitrobenzenesulfenyl group) can be deprotected using an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid or methanesulfonic acid. In this case, the deprotection can be carried out using the acid which is diluted with or dissolved in an organic solvent or water. The reaction can be carried out at a temperature of -50 to 50°C. Examples of the organic solvent are ethanol, methanol, tetrahydrofuran,

N,N-dimethylformamide, dichloromethane, chloroform and 1,2-

® dichloroethane. Furthermore, for example, the compound wherein Rb is a group to be deprotected by hydrogenolysis (e.g., a benzyloxycarbonyl group) can be deprotected by hydrogenolysis using a metal catalyst (e.g., palladium).

The solvent to be used includes a reaction-inert solvent (e.g., ethanol, methanol, tetrahydrofuran or ethyl acetate).

The reaction can be carried at a temperature of 0 to 100°C.

Furthermore, this reaction can be also carried out using a hydrogen gas or using a combination of reagents (e.qg., formic acid - ammonium formate). For another example, the compound wherein Rb is a protective group to be deprotected by a base (e.g., a fluorenyloxycarbonyl group) can be deprotected using a base (e.g., diethylamine, piperidine, ammonia, sodium hydroxide or potassium carbonate). These bases can be used directly or after diluting with, dissolving or suspending in a solvent. In this case, examples of the solvent to be used are water, ethanol, methanol, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, chloroform and 1,2-dichloroethane. The reaction can be carried out at a temperature of 0 to 100°C.

In addition, the compound wherein Rb is a group to be deprotected by a metal catalyst (e.g., an allyloxycarbonyl group) can be deprotected using, for example, tetrakis(triphenylphoshine)palladium as a catalyst or a reagent in a reaction-inert solvent (e.g., dichloromethane, chloroform or tetrahydrofuran). The reaction can be carried out at a temperature of 0 to 100°C. [Reaction Scheme 2]

®

X R' X R1

Romy Ay Re Pia J ¥

RR Z Y N R3

Ra R¢ Ra R4 wherein X, ¥, Z, Rl, RZ, R3, R4 and Ra are defined as above, and Rc is a leaving group (e.g., a halogen atom or a sulfonyloxy group) or a group capable of being converted into a leaving group.

For example, the compound wherein Rc is a leaving group (e.g., a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group) can be subjected to a substitution reaction using a primary amine (Z-NHp)(e.g.. ethylamine, isopropylamine, tert-butylamine, benzylamine, a substituted benzylamine, phenethylamine, a substituted phenethylamine or a 2- (substituted pyridylamino)ethylamine). In this case, the amine may be used in an excess amount, or alternatively a base may be further added. Examples of the base to be added are an amine (e.g., triethylamine or diisopropylethylamine) or an inorganic base (e.g., : potassium carbonate). If necessary, for example, sodium iodide may be added for accelerating the reaction. The reaction solvent includes a reaction-inert solvent such as

N,N-dimethylformamide, tetrahydrofuran, dioxane, dichloromethane or chloroform. The reaction can be carried out at a temperature of 0 to 100°C.

C An example of the group, presented by Rc, capable of being converted into a leaving group, is a hydroxyl group, in this case, the above-mentioned reaction can be carried out after chlorination, bromination, iodination, methanesulfonation, p-toluenesulfonation or the like.

Examples of chlorination are a method using carbon tetrachloride and triphenylphosphine, a method using thionyl chloride or phosphorus oxychloride and a method for substituting a leaving group with lithium chloride or the like after forming the leaving group with tosyl chloride, etc. These reactions can be carried out using a reaction- inert solvent such as tetrahydrofuran, dioxane, dichloromethane, chloroform or N,N-dimethylformamide, at a temperature of -50 to 100°C. An example of bromination is a method using carbon tetrabromide and triphenylphosphine.

This reaction can be carried out by using a reaction-inert solvent such as tetrahydrofuran, dioxane, dichloromethane, chloroform or N,N-dimethylformamide, at a temperature of -50 to 50°C. An example of iodination is a method using iodine, triphenylphosphine and imidazole. This reaction can be carried out by using a reaction-inert solvent such as tetrahydrofuran, dioxane, dichloromethane, chloroform or

N,N-dimethylformamide, at a temperature of -50 to 100°C.

Methanesulfonation and p-toluenesulfonation are each carried out by a method using methanesulfonyl chloride and p-toluenesulfonyl chloride, respectively. In these cases, a suitable base can be optionally added. Examples of the base to be added are an amine (e.g., triethylamine or

® diisopropylethylamine) and an inorganic base (e.g., potassium carbonate). As the reaction solvent can be used a reaction-inert solvent (e.g., N,N-dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, chloroform or 1,2-dichloroethane), and the reaction can be carried out at a temperature of -50 to 50°C. [Reaction Scheme 3]

X A Rb X R hf AE

Y N —— 77 Sy N

R3 R3

Ra R* "Ra R* wherein X, Y, %, Rl, R2, R3, R%, Ra, Rb and Rc are defined as above.

For example, the compound wherein Rc is a leaving group (e.g., a chlorine atom, a bromine atom, iodine atom, a methanesulfonyloxy group or a p-toluenesufonyloxy group) can be subjected to substitution reaction using a compound represented by Z-NH-Rb (wherein Z and Rb are defined as above). In this case, for example, sodium hydride, potassium tert-butoxide, n-butyl lithium or lithium diisopropylamide can be used as a base. As a solvent can be used N,N-dimethylformamide, tetrahydrofuran or dioxane. ‘The reaction can be carried out at a temperature of -50 to 50°C.

An example of the group, presented by Rc, capable of being converted into a leaving group, is a hydroxyl group. :

In this case, the above-mentioned reaction can be carried

® out after chlorination, bromination, iodination, methanesulfonation or p-toluenesulfonation as illustrated in Reaction Scheme 2. [Reaction Scheme 4]

X R! | X RI

HN~ PN 2nd i J Re

Y ~~R3 or 2” Y N R3

Ra R4 L=0 Ra R4 wherein X, Y, 2, Rl, R2, R3, R4 and Ra are defined as above, and Rd is a leaving group such as a halogen atom or a sulfonyloxy group.

When Z%-Rd is used, the amino group of the material can be reacted with Z-Rd to give the object compound. For example, the compound wherein Rd is a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or the like can be reacted with an amino compound of the material in the presence of a suitable base. Examples of the base to be added are amines (e.g., triethylamine or diisopropylethylamine) and inorganic bases (e.g., potassium carbonate). Examples of the reaction solvent are N,N-dimethylformamide, tetrahydrofuran and dioxane. The reaction can be carried out at a temperature of 0 to 100°C.

In addition, when Z=0 (aldehyde or ketone compound) is used, the reaction can be carried out using a primary amino group of the material under the conditions for a suitable reduction method. The reduction method to be used

® includes a hydrogenation using a reductant (e.g., sodium borohydride or sodium cyanoborohydride) or palladium.

Examples of the solvent to be used are reaction-inert solvents (e.g., ethanol, methanol, tetrahydrofuran, dioxane or water). The reaction can be carried out at a temperature of -20 to 100°C. [Reaction Scheme 5]

R1 | ) 1

RX re Z—Rd Rb X Ko

HN J J

Sy” ON — ANN

R3 R3

Ra R* © Ra R wherein X, Y, Z, Rl, R2, R3, R4, Ra, Rb and RA are defined as above.

The protected amino group of the material is reacted with Z-Rd to give the object compound. In this case, the reaction can be carried out by adding a suitable base, examples of which are sodium hydride, potassium tert- butoxide, n-butyl lithium and lithium diisopropylamide.

Examples of the reaction solvent are N,N-dimethylformamide, tetrahydrofuran and dioxane. The reaction can be carried out at a temperature of -50 to 50°C. [Reaction Scheme 6] 1

R Rr

Re Re ~ 1 R2

N —_— Re 3 Ra N

R3

R4

CONH, CN Re o wherein Re is -C(=X)-Y-NH-Z, -C(=X)-Y-N(Rb)-Z, -C(=X)-Y-Rc or Rb, and R1, R2, R3, R4, X, Y, Z, Rb and Rc are defined as above.

The aminocarbonyl group can be converted into a cyano group by a general dehydration, an example of which is a method using trifluoroacetic anhydride. The solvent to be used herein includes a reaction-inert solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane or N,N-dimethylformamide. In this case, a base (e.g., triethylamine, diisopropylethylamine, sodium bicarbonate or potassium carbonate) can be used if necessary. The reaction can be carried out at a temperature of -50 to 50°C.

Another example is a method using phosphorus oxychloride. In this case, the solvent to be used herein includes dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane or pyridine. They can be used alone or in combination with at least two solvents thereof.

This reaction may be carried out by adding imidazole, etc., at a temperature of -50 to 50°C.

Still another example is a method using cyanuric chloride and N,N-dimethylformamide. In this case, the solvent to be used herein includes dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane or pyridine. They can be used alone or in combination with at least two solvents thereof. This reaction can be carried out at a temperature of -50 to 50°C. [Reaction Scheme 7]

® Ra ] . R

N — "Oy

R3a R3

Ra Rta Ra R¢ wherein Re, Rl, R2, R3, R4 and Ra are defined as above, and rRla, R2a, R3a and R%a are the same as Rl, R2, R3 and R%, respectively, or the groups capable of being converted into

R1, R2, R3 and R%4, respectively.

An example of modification of the pyrrolidine ring is a conversion of the substituent(s). For example, the compound wherein one of Rla, R2a, R3a and R%a is a hydroxyl group is subjected to halogenation to give a fluorine compound, a chlorine compound or a bromine compound or the like. In detail, examples of fluorination are methods using diethylaminosulfur trifluoride, dimethylsulfur trifluoride, etc. These reactions are started at a temperature of -78°C to room temperature and achieved by maintaining a temperature at room temperature to 50°C using a reaction-inert solvent such as tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane or toluene.

Another example of fluorination is a method for converting a hydroxyl group into a leaving group, followed by conversion into a fluorine atom. The conversion into the leaving group is carried out by the same method as illustrated in Reaction Scheme 2. After the conversion into the leaving group, the method for converting into a fluorine atom includes methods for reaction with o tetrabutylammonium fluoride, caesium fluoride, or the like.

These methods can be carried out using a reaction-inert solvent such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N-dimethylformamide or water at a temperature of -50 to 100°C.

Examples of chlorination are a method using carbon tetrachloride and triphenylphosphine, a method using thionyl chloride and phosphorus oxychloride and a method for converting into a leaving group using tosyl chloride, etc. and substituting it with lithium chloride, etc. These reactions can be carried out using a reaction-inert solvent such as tetrahydrofuran, dioxane, dichloromethane, chloroform and N,N-dimethylformamide at a temperature of -50 to 100°C.

Still another example is a method for sterically inverting a hydroxyl group, example of which is a Mitsunobu reaction. In this reaction, the hydroxyl group is reacted with diethyl azodicarboxylate, triphenylphosphine and a carboxylic acid such as acetic acid to give a sterically inverted ester, which is then hydrolyzed to give a inverted hydroxyl group. This reaction is carried out using a reaction-inert solvent such as tetrahydrofuran, dioxane, dichloromethane, chloroform or N,N-dimethylformamide at a temperature of -50 to 50°C.

The compound wherein Rl and R2, or R3 and R4 together form an oxo can be synthesized by an oxidation using a compound wherein one of Rla, RZa, R3a and R%a is a hydroxyl group. Examples of the oxidation are a method

() using a chromate oxidant (e.g., pyridinium chlorochromate or pyridinium dichromate) and a DMSO oxidation method using activating agents (e.g., dimethyl sulfoxide and oxalyl chloride). For example, the reaction using pyridinium chlorochromate can be carried out using a reaction-inert solvent such as dichloromethane, chloroform, N,6N- dimethylformamide, tetrahydrofuran or dioxane at a temperature of 0 to 50°C. [Reaction Scheme 8]

RI RI

R? R2

Le CC

R3 RS . Ra R¢ Ra RS wherein Rl, R2, R3, R4, Re and Ra are defined as above.

A 1l-H-pyrrolidine derivative or a salt thereof is subjected to condensation to give an amide compound, a thioamide compound or a carbamate compound. For example, amidation can be carried out using an acyl halide (e.g., an acyl chloride or an acyl bromide) in a reaction-inert solvent such as dichloromethane, chloroform, 1,2- dichloroethane, tetrahydrofuran, dioxane, toluene or ethyl acetate. In this case can be used a base, examples of which are amines (e.g., triethylamine or diisopropylethylamine), organic acid salts (e.g., sodium 2- ethylhexanoate or potassium 2-ethylhexanoate) and inorganic bases (e.g., potassium carbonate). These reactions can be carried out at a temperature of -50 to 100°C. Another o amidation can be carried out using an activating ester such as 1-benzotriazolyl ester or succinimidyl ester in a reaction solvent (e.g., dichloromethane, chloroform, 1,2- dichloroethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, toluene or ethyl acetate). The reaction can be carried out at a temperature of -50 to 50°C.

Still another amidation can be carried out by using a carboxylic acid and a condensing agent for dehydration.

Examples of the condensing agent for dehydration are 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, diphenylphosphoryl azide and carbonyldiimidazole. If necessary, an activating agent (e.g., l-hydroxybenzotriazole or hydroxysuccinimide) can be used. Examples of the reaction solvent are dichloromethane, chloroform, 1, 2-dichloroethane, N,N-dimethylformamide, tetrahydrofuran, dioxane, toluene and ethyl acetate. In this case can be used a base, examples of which are amines (e.g., triethylamine or diisopropylethylamine), organic acid salts (e.g., sodium 2-ethylhexanoate or potassium 2-ethylhexanoate) and inorganic bases (e.g., potassium carbonate). The reaction can be carried out at a temperature of -50 to 50°C.

Furthermore, for example, amidation can be carried out by using a mixed acid anhydride obtained from a carboxylic acid and a chlorocarboxylate ester. The solvent for the reaction includes reaction-inert solvents such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N- dimethylformamide, toluene or ethyl acetate. In this case

® can be used a base, examples of which are amines (e.g., triethylamine or diisopropylethylamine), organic acid salts (e.g., sodium 2-ethylhexanoate or potassium 2- ethylhexanoate) and inorganic bases (e.g., potassium carbonate). The reaction can be carried out at a temperature of -50 to 50°C.

Protection of the amino group can be carried out using di-tert-butyldicarboxylate, benzyloxycarbonyl chloride or fluorenylmethoxycarbonyl chloride in the presence of a suitable base. Examples of the base are amines (e.g., triethylamine or diisopropylethylamine) and inorganic bases (e.g., potassium carbonate). The solvents in these reactions include reaction-inert solvents such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N- dimethylformamide, toluene, ethyl acetate or water. These reactions can be carried out at a temperature of -50 to 50°C. [Reaction Scheme 9]:

Rt R!

Rey a Rex fF : -R3 R3 ‘R¢ . R4 - COORF CONH, wherein rl, RZ, R3, RY and Re are defined as above, and Rf is a hydrogen atom, a lower alkyl group. a benzyl group, an allyl group, etc.

The method is a conversion of a carboxyl group, a salt thereof or an ester thereof into an aminocarbonyl

® group. When the compound wherein COORf is a carboxyl group or a salt thereof is used as a material, ammonia can be used under an ordinary amidation condition for the synthesis. An example of the amidation is a method for converting a carboxyl group or a salt thereof into an acid chloride using thionyl chloride, phosphorus oxychloride or oxalyl chloride, followed by condensation with ammonia.

Examples of the solvent in these reactions are reaction- inert solvents such as tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N- dimethylformamide, toluene or ethyl acetate. These reactions can be carried out at a temperature of -50 to 50°C.

Another example of the amidation is a method using a condensing agent for dehydration and ammonia. In this reaction is .used a condensing agent such as l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, diphenylphosphoryl azide or carbonyldiimidazole. If necessary, an activating agent (e.g., l-hydroxybenzotriazole or hydroxysuccinimide) can be added. Examples of the solvent in these reactions are reaction-inert solvents such as tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N- dimethylformamide, toluene, ethyl acetate or acetonitrile.

These reactions can be carried out at a temperature of -50 to 50°C.

Still another example of the amidation is a method using a mixed acid anhydride (obtained from a carboxylic acid and a chlorocarbonate ester) and ammonia. Examples of

® the solvent in the reaction are reaction-inert solvents such as tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, toluene or ethyl acetate. These reactions can be carried out at a temperature of -50 to 50°C.

Conversion of COORf (which is an ester) of the compound into an aminocarbonyl group can be carried out by a direct reaction with ammonia, or can be carried out by conversion of the ester into a carboxylic acid or a salt thereof, followed by conversion of the carboxylic acid into an aminocarbonyl group according to the above-mentioned method. The conversion of an ester into a carboxylic acid or a salt thereof is carried out according to the method described in Protective Groups in Organic Synthesis by

Theodora W. Greene and Peter G. M. Wu Ts. The conversion by the direct reaction with ammonia is carried out using . ammonia gas or aqueous ammonia in a solvent (e.g., water, methanol, ethanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, N,N-dimethylformamide or toluene) or without a solvent at a temperature of 0 to 100°C and, if necessary, with sealing for preventing volatilization of ammonia. [Reaction Scheme 10]

R! RT _R? Rz

CE — LC

R® R3

Ra Rf Ra R' .

( wherein Rl, R2, R3, R%4, Ra and Rb are defined as above.

Rb (which is a protecting group of an amino group) can be deprotected, for example, by a method described in

Reaction Scheme 1. The resulting amine can be obtained as a base or an acid salt. Examples of the suitable acid to be used are hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and acetic acid.

The present invention is illustrated in more detail by the following reference examples, examples and experiments, however, being not limited thereto.

Reference Example 1

Synthesis of (2S,4S)-1-(tert-butoxycarbonyl)-4- fluoropyrrolidine-2-carboxylic acid

Referring to Tetrahedron Letter 39(10), 1169 - 1172 (1998), the title compound (4.5 g) which is the material of

Example 1(1) was obtained from methyl (2S,4R)-1-(tert- butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylate (6.8 g) by two steps.

Reference Example 2

Synthesis of (2S,4R)-1-(tert-butoxycarbonyl)-4- fluoropyrrolidine-2-carboxylic acid

Referring to Tetrahedron Letter 39(10), 1169 - 1172 (1998), the title compound (370 mg) which is the material of Example 3(1) was obtained from methyl (2S,4S)-1-(tert- butoxycarbonyl) -4-hydroxypyrrolidine-2-carboxylate (500 mg) by two steps. ' Reference Example 3

® Synthesis of (2S,4R)-2-(aminocarbonyl)-1-(tert- butoxycarbonyl) -4-hydroxypyrrolidine

In dioxane (50 mL) were suspended (2S,4R)-1-(tert- butoxycarbonyl) -4-hydroxypyrrolidine-2-carboxylic acid (2.31 g) and l-hydroxybenzotriazole monohydrate (1.51 g), and then 1-(3,3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.11 g) and 25% aqueous ammonia (0.68 mL) were added with ice-cooling. The temperature was gradually raised to room temperature, and then, the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (developing solvent; chloroform : methanol =100:3 - 100:7) to give the title compound (2.19 g) as a colorless powder.

Example 1

Synthesis of (2S,4S)-1-[(2S,3S8)-2-amino-3- methylpentanoyl]-2-cyano-4-fluoropyrrolidine hydrochloride (1) Synthesis of (25,48) -2-(aminocarbonyl)-1-(tert- butoxycarbonyl)-4-fluoropyrrolidine

In acetonitrile (50 mL) was dissolved (25,4S)-1- (tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (4.5 g) obtained in Reference Example 1, then 1- hydroxybenzotriazole monohydrate (3.6 g) and 1-(3,3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.5 g) were added with ice-cooling. The temperature was gradually raised, and then, the mixture was stirred at room temperature overnight. The reaction solution was again ice-cooled, 25% aqueous ammonia (5 mL) was added, and

® stirring was continued with ice-cooling for 30 minutes then at room temperature for 30 minutes. To the reaction solution was added acetonitrile (50 mL), and an insoluble substance was removed by filtration. The filtrate was concentrated under reduced pressure and purified by a silica gel column chromatography (developing solvent; hexane : ethyl acetate =4:1 - 1:5). To the resulting residue was added hexane to give the title compound (4.2 g) as a colorless powder.

MS(ESI pos.)m/z: 255([M+Nalt, (ESI neg.)m/z: 231([M-H]") (2) Synthesis of (2S,4S)-2-(aminocarbonyl)-4- fluoropyrrolidine hydrochloride

In 4M-hydrochloric acid-dioxane (45 mL) was suspended (2S,4S)-2-(aminocarbonyl)-1-(tert- butoxycarbonyl)-4-fluoropyrrolidine (4.2 g) and, after stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. To the residue was added toluene (50 mL), followed by further concentration under reduced pressure. This was repeated 3 times to give the title compound (3.1 g) as a colorless powder. This intermediate was used for the next reaction without purification. (3) Synthesis of (2S, 48) -2-(aminocarbonyl)-1- [(2S,3S)-2-(fluorenylmethoxycarbonylamino)-3- methylpentanoyl]-4-fluoropyrrolidine

In tetrahydrofuran (40 mL) - N,N-dimethylformamide (10 mL) were dissolved (2S,48)-2-(aminocarbonyl)-4- fluoropyrrolidine hydrochloride (2.4 g) and (2S,3S)-2-

® (fluorenylmethoxycarbonylamino)-3 -methylpentanoic acid (5.1 g). and then 1-hydroxybenzotriazole monohydrate (2.6 g), 1- (3,3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.3 g) and diisopropylethylamine (2.5 mL) were added with ice-cooling, and the temperature was gradually raised, followed by stirring at room temperature overnight. The solution was concentrated under reduced pressure, and water was added to the resulting residue. The resulting powder was collected by filtration and purified by a silica gel column chromatography (developing solvent; hexane : ethyl acetate =4:1 - 1:4) to give the title compound (6.9 g) as a pale yellow amorphous substance.

MS(ESI pos.)m/z: 490( [M+Nalt). (4) Synthesis of (2S,4S)-2-cyano-1-[(2S,3S)-2- (fluorenylmethoxycarbonylamino)-3-methylpentanoyl]-4- fluoropyrrolidine

In tetrahydrofuran (70 mL) was dissolved (2S,4S)-2- (aminocarbonyl)-1-[(2S,3S)-2- (£luorenylmethoxycarbonylamino)-3-methylpentanoyl]-4- fluoropyrrolidine (6.9 g), and trifluoroacetic anhydride (4.0 mL) was added with ice-cooling, followed by stirring with ice-cooling for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by a silica gel column chromatography (developing solvent: hexane : ethyl acetate =8:1 - 3:2) to give the title compound (6.2 g) as a pale yellow amorphous substance.

MS(ESI pos.)m/z: 472([M+Na]t) (5) Synthesis of (2S,4S8)-1-[(2S,3S)-2-amino-3-

o methylpentanoyl]-2-cyano- 4-fluoropyrrolidine hydrochloride

In 1,2-dichloroethane (90 mL) was dissolved (2S,4S)- 2-cyano-1-[(2S,3S)-2-(fluorenylmethoxycarbonylamino)-3- methylpentanoyl]-4-fluoropyrrolidine (6.2 g) and, after addition of diethylamine (10 mL) with ice-cooling, stirring was continued with ice-cooling for 30 minutes and then at room temperature for 5 hours. The solution was concentrated under reduced pressure, the residue was dissolved in a mixture of diethyl ether (100 mL), tetrahydrofuran (50 mL) and chloroform (50 mL), and then 4M hydrochloric acid - dioxane (4.0 mL) was added with ice- cooling. The resulting salt was collected by filtration and washed with diethyl ether. The resulting powder was purified by a silica gel column chromatography (developing solvent; chloroform : methanol : 25% aqueous ammonia =40:1:0.1 - 25:1:0.1). The resulting residue was dissolved in chloroform and, after addition of 4M hydrochloric acid - dioxane (4.0 mL) with ice-cooling, the resulting salt was collected by filtration, washed with chloroform and 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+Nal*), (ESI neg.)m/z: 262([M+CL]").

H-NMR (DMSO-d4, 500MHz)&; 8.59(3H,br s), 5.54(1H,br 4,

J=52.1Hz), 5.06(1H,d,J=9.4Hz), 4.07-3.77(3H,m), 2.55-2.34(2

H, m), 1.88(1H,m), 1.61(1H,m), 1.17(1H,m), 0.94(3H,d,J=6.7Hz ),0.88(3H,t,J=7.3Hz).

Example 2

® Synthesis of (2S,4S)-1-[(2S,3S)-2-amino-3- methylpentanoyl]-2-cyano-4-fluoropyrrolidine hydrobromide.

In ethanol (1 mL) was dissolved (2S,4S)-1-[(2S,38)- 2-amino-3-methylpentanoyl]-2-cyano-4-fluoropyrrolidine (0.5 g) obtained in Example 1, and the solution was added to an ice-cooled ethanol solution (2 mL) of 48% hydrobromic acid (0.26 mL). Further, ethanol (2 mL) and pentane (3 mL) were added and stirred, and the precipitated crystals were collected by filtration. The resulting crystals were dissolved in methanol (1.75 mL) and added to an ice-cooled 2-propanol (14 mL). To this was added pentane (3.5 mL), followed by stirring. The precipitated crystals were collected by filtration to give the title compound (0.28 g) as a colorless powder.

Anal. calcd for C,H, ,FN,0 HBr: C,42.87;H,6.21;N,13.63;Br, 25.93;F,6.16. Found:C,42.98;H,6.26;N,13.54;Br,25.85;F, 6.15.

Example 3

Synthesis of (2S,4R)-1-[(2S,3S)-2-amino-3- methylpentanoyl]-2-cyano-4-fluoropyrrolidine hydrochloride (1) Synthesis of (2S,4R)-2-(aminocarbonyl)-1-(tert- butoxycarbonyl)-4-fluoropyrrolidine

According to the manner similar to that of Example 1(1), the title compound (270 mg) was obtained as a colorless gummy substance from (2S,4R)-1-(tert- butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (370 mg) obtained in Reference Example 2.

MS(ESI pos.)m/z: 255([M+Nal*), (ESI neg.)m/z: 231([M-H]~) (2) Synthesis of (2S,4R)-2-(aminocarbonyl)-1-

o [(2S,3S)-2-(fluorenylmethoxycarbonylamino)-3- methylpentanoyl]-4-fluoropyrrolidine

In 4M hydrochloric acid - dioxane (3 ml) was suspended (2S,4R)-2-(aminocarbonyl)-1-(tert- butoxycarbonyl)-4-fluoropyrrolidine (260 mg) and, after stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. To the residue was added chloroform (10 ml), followed by further concentration under reduced pressure. The procedure was repeated 3 times. The resulting residue, (2S,38)-2- (£luorenylmethoxycarbonylamino)-3-methylpentanoic acid (400 mg) was dissolved in N,N-dimethylformamide (5 mL), and then 1l-hydroxybenzotriazole monohydrate (210 mg), 1-(3,3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (260 mg) and diisopropylethylamine (0.20 mL) were added with ice-cooling. The temperature was gradually raised, and then, the mixture was stirred at room temperature overnight. The reaction mixture was taken up in water and extracted with ethyl acetate. The organic phase was washed with 0.1 M aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, successively, dried over anhydrous sodium sulfate and, after removal of the drying agent by filtration, concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (hexane : ethyl acetate =1:1 - 1:4) to give the title compound (450 mg) as a colorless amorphous substance.

MS (ESI pos.)m/z: 490([M+Nal™*).

® (3) Synthesis of (2S,4R)-2-cyano-1-[(28,38)-2- (£luorenylmethoxycarbonylamino)-3-methylpentanoyl]-4- fluoropyrrolidine

According to the manner similar to that of Example 1(4), the title compound (330 mg) was obtained as a pale yellow amorphous substance from (2S, 4R)-2-(aminocarbonyl) - 1-[(2S.3S)-2-(fluorenylmethoxycarbonylamino)-3- methylpentanoyl]-4-fluoropyrrolidine (440 mg).

MS(ESI pos.)m/z: 472 ([M+Nalt). (4) Synthesis of (2S,4R)-1-[(2S,3S5)-2-amino-3- methylpentanoyl]-2-cyano-4-fluoropyrrolidine hydrochloride

According to the manner similar to that of Example 1(5), the title compound (60 mg) was obtained as a colorless powder from (2S,4R)-2-cyano-1-[(2S,38)-2- (fluorenylmethoxycarbonylamino)-3-methylpentanoyl]-4- fluoropyrrolidine (320 mg).

MS(ESI pos.)m/z: 228([M+H]7), 250 ( [M+Nal*), (ESI neg. )m/z: 262 ( [M+CL]1")

Example 4

Synthesis of (2S,4S)-2-cyano-1-[2-[(5-nitropyridin- 2-yl)amino]ethylamino]acetyl-4-fluoropyrrolidine maleate (1) Synthesis of (2S,4S)-2-(aminocarbonyl)-1- bromoacetyl-4-fluoropyrrolidine

In tetrahydrofuran (10 mL) was suspended (25,48) -2- aminocarbonyl-4-fluoropyrrolidine hydrochloride (650 mg) obtained in Example 1(2), and then potassium 2- ethylhexanoate (1.6 g) was added with ice-cooling, followed by stirring for an hour. Bromoacetyl bromide (0.37 mL) was

Claims (1)

1. ® CLAIMS

   1. A cyanopyrrolidine derivative represented by Formula X id H J ~R? LA ou NES RS CN R¢ [wherein Rl is a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, RZ is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, ox R1 and R2 together form an oxo, a hydroxyimino group, an alkoxyimino group having 1 to 5 carbon atoms or an alkylidene group having 1 to 5 carbon atoms, R3 and R% are each a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, or R3 and R% together form an oxo, a hydroxyimino group, an alkoxyimino group having 1 to 5 carbon atoms or an alkylidene group having 1 to 5 carbon atoms, X is an oxygen atom or a sulfur atom, Y is -CROR6- [wherein RS and R® are the same or different, and each a hydrogen atom; a halogen atom; an alkyl group having 1 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of 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, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, -NHR11 (wherein R11 is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), ~-CONHR12 {wherein R12 is a hydrogen atom or -(CHy)p-R13 (wherein m is an integer of 1 to 5, and R13 is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)} and -ORl14 (wherein R14 is a chain alkyl group having 1 to 5 carbon atoms or a benzyl group); or an alkenyl group having 2 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a chain alkoxy group having 1 to 5 carbon atoms], or -CR7R8-CRPR10- (wherein R7, R8, RY? and R10 are the same or different, and each a hydrogen atom; a halogen atom; or an alkyl group having 1 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of 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, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, -NHR11 (wherein Rll is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a

   ® tert-butoxycarbonyl group or a benzyloxycarbonyl group),

   ~-CONHR12 {wherein R12 is a hydrogen atom or -(CHp)p-R13 (wherein m is an integer of 1 to 5, and R13 is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)} and -ORl4 (wherein R14 is a chain alkyl group having 1 to 5 carbon atoms or a benzyl group), or R7 and R? together with the carbon atom to which they are attached form a cycloalkyl group having 3 to 8 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, 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 cycloalkenyl group having 4 to 8 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, 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 5 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, 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; or a bicycloalkenyl group having 5 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, 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), and Z is a hydrogen atom; or an alkyl group having 1 to carbon atoms which is optionally substituted with at least one selected from the group consisting of 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

   10 group, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, -NHR11 (wherein R11 is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR12 (wherein R12 is a hydrogen atom or -(CHp)p-R13 (wherein m is an integer of 1 to 5, and R13 is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) } and -OR14 (wherein R14 is a chain alkyl group having 1 to 5 carbon atoms or a benzyl group),

   or Y and Z together with the nitrogen atom to which they are attached form a cyclic amino group having 2 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a chain alkyl group having

   1 to 5 carbon atoms and -OR1® (wherein R15 is a chain alkyl group having 1 to 5 carbon atoms, an aminocarbonylmethyl group or a benzyl group)] or a pharmaceutically acceptable salt thereof.

   @® 2. The cyanopyrrolidine derivative of Formula (1) according to Claim 1 wherein Rl is a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, and R2, R3 and R%4 are each a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, or the pharmaceutically acceptable salt thereof.

   3. The cyanopyrrolidine derivative of Formula (1) according to Claim 1 or 2 wherein Rl is a fluorine atom or a chlorine atom, or the pharmaceutically acceptable salt thereof. 4, The cyanopyrrolidine derivative of Formula (1) according to Claim 1 or 2 wherein Rl is a fluorine atom, and R2 is a hydrogen atom, or the pharmaceutically acceptable salt thereof.

   5. The cyanopyrrolidine derivative of Formula (1) according to Claim 1 or 2 wherein Rl is a fluorine atom, and R2, R3 and R%4 are each a hydrogen atom, or the pharmaceutically acceptable salt thereof.

   6. A cyanopyrrolidine derivative represented by Formula (2): A 27 of 2) oN [wherein X is an oxygen atom or a sulfur atom,

   ® Y is -CRSR6- [wherein RS and R® are the same or different, and each a hydrogen atom; a halogen atom; an alkyl group having 1 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of 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, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, -NHR11

   (wherein R11 is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), - CONHR12 {wherein R12 is a hydrogen atom or -(CHy)p-R13 (wherein m is an integer of 1 to 5, and R13 is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)} and -OR14 (wherein R14 is a chain alkyl group having 1 to 5 carbon atoms or a benzyl group): or an alkenyl group having 2 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a chain alkoxy group having 1 to 5 carbon atoms], or -CR7R8-CR9R10- (wherein R7, R8, RY? and R10 are the same or different, and each a hydrogen atom; a halogen atom; or an alkyl group having 1 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1 to 5 carbon atoms, a carboxyl

   [J 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, -NHR11 (wherein R11 is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), -CONHR12 {wherein R12 jg a hydrogen atom or -(CHy)p-R13 (wherein m is an integer of 1 to 5, and R13 is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group)} and -OR14 (wherein R14 is a chain alkyl group having 1 to 5 carbon atoms or a benzyl group), or R7 and RY together with the carbon atom to which they are attached form a cycloalkyl group having 3 to 8 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, 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 cycloalkenyl group having 4 to 8 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, 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 5 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a

   9 chain alkyl group having 1 to 5 carbon atoms and a chain alkoxy group having 1 to 5 carbon atoms; or a bicycloalkenyl group having 5 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, 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), and

   Z is a hydrogen atom; or an alkyl group having 1 to

   10 carbon atoms which is optionally substituted with at least one selected from the group consisting of 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, an optionally substituted phenyl group, an imidazolyl group, an indolyl group, -NHR11 (wherein R11 is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted pyridyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), ~-CONHR12 {wherein R12 is a hydrogen atom or -(CHy)p-R13 (wherein m is an integer of 1 to 5, and R13 is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) } and -ORl4 (wherein R14 is a chain alkyl group having 1 to 5 carbon atoms or a benzyl group),

   or Y and Zz together with the nitrogen atom to which they are attached form a cyclic amino group having 2 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a halogen atom, a

   ¥ | hydroxyl group, an amino group, a chain alkyl group having 1 to 5 carbon atoms and -OR15 (wherein R15 is a chain alkyl group having 1 to 5 carbon atoms, an aminocarbonylmethyl group or a benzyl group)] or a pharmaceutically acceptable salt thereof.

   7. The cyanopyrrolidine derivative of Formula (1) or (2) according to any one of Claims 1 to 6 wherein X is an oxygen atom, or the pharmaceutically acceptable salt thereof.

   8. The cyanopyrrolidine derivative of Formula (1) or (2) according to Claim 7 wherein Y is -CHy-, or the pharmaceutically acceptable salt thereof.

   9. The cyanopyrrolidine derivative of Formula (1) or (2) according to Claim 8 wherein Z is a branched or cyclic alkyl group having 4 to 10 carbon atoms which is optionally substituted with at least one selected from the group consisting of a hydroxyl group and a hydroxyalkyl group having 1 to 5 carbon atoms, or the pharmaceutically acceptable salt thereof.

   10. The cyanopyrrolidine derivative of Formula (1) or (2) according to Claim 8 wherein Z is a tert-butyl group, a (1-hydroxymethyl)cyclopentyl group or a (2-hydroxy-1,1- dimethyl)ethyl group, or the pharmaceutically acceptable salt thereof.

   11. The cyanopyrrolidine derivative of Formula (1) or (2) according to Claim 7 wherein Y is -CROR6- (wherein R® is a hydrogen atom) and Z is a hydrogen atom, or the pharmaceutically acceptable salt thereof.

   - ] 12. The cyanopyrrolidine derivative of Formula (1) or (2) according to Claim 7 wherein Y is -CRSR6- (wherein RS is a hydrogen atom, R6 is a branched or cyclic alkyl group having 3 to 6 carbon atoms) and Z is a hydrogen atom, or the pharmaceutically acceptable salt thereof.

   13. The cyanopyrrolidine derivative of Formula (1) or (2) according to Claim 7 wherein Y is -CH[CH(CH3)31-, -CH[C(CH3)3]1- or -CH[CH(CH3)CH;CH3]- and Z is a hydrogen atom, or the pharmaceutically acceptable salt thereof.

   14. A pharmaceutical preparation which comprises as an effective ingredient the cyanopyrrolidine derivative or the pharmaceutically acceptable salt thereof according to any one of Claims 1 to 13.

   15. The pharmaceutical preparation according to Claim 14 for preventing or treating a disease or condition capable of being improved by inhibition of dipeptidyl peptidase IV.

   16. The pharmaceutical preparation according to Claim 15 wherein the disease or condition capable of being improved by inhibition of dipeptidyl peptidase IV is diabetes mellitus.

   17. ‘The pharmaceutical preparation according to Claim 15 wherein the disease or condition capable of being improved by inhibition of dipeptidyl peptidase IV is an immune disease.