WO2006115289A1

WO2006115289A1 - Combination of a cyanopyrrolidine with a hepatic gluconeogenesis inhibitor

Info

Publication number: WO2006115289A1
Application number: PCT/JP2006/308926
Authority: WO
Inventors: Noriyuki Miyata; Shinichiro Kumeda
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 2005-04-22
Filing date: 2006-04-21
Publication date: 2006-11-02
Also published as: JP2008115080A; TW200716096A

Abstract

A medicament comprising a cyanopyrrolidine derivative having a supeirior DPP-IV inhibitory activity in combination with a hepatic gluconeogenesis inhibitor, which medicament provides a prophylactic or therapeutic agent for diabetes having an effective hypoglycemic action with few side effects in many diabetic patients.

Description

DESCRIPT ION COMBINATION OF A CYANOPYRROLIDINE WITH A HEPATIC GLUCONEOGENESIS INHIBITOR

Technical Field

The present invention relates to prophylactic or therapeutic agents for diabetes comprising cyanopyrrolidine derivatives having superior dipeptidyl peptidase IV (DPP- IV) inhibitory activity in combination with biguanide drugs.

Background Art DPP-IV is a type of serine protease which hydrolyzes dipeptide from a peptide chain having proline or alanine at the second position from the N-terminal, and it is widely distributed in tissues such as the kidney and the liver, and in plasma. Recently, it was found that DPP-IV is involved in the metabolism of glucagon-like peptide-1 (GLP-I) . Specifically, DPP-IV inactivates GLP-I by hydrolyzing the dipeptide of the N-terminal His-Ala of GLP-I, and the decomposition product acts as an antagonist of the GLP -1 receptor.

It is known that the physiological actions of GLP-I are to promote insulin secretion from the pancreas, inhibit glucagon secretion, extend gastric emptying and suppress feeding. Thus, the inhibition of DPP-IV might be expected to increase the action of GLP-I, enhance the insulin action, improve carbohydrate metabolism and be useful for type 2 diabetes treatment. Cyanopyrrolidine derivatives have already been reported to have superior DPP-IV inhibitory effect, as described in WO2002/038541 or WO2004/020407.

Biguanide drugs inhibit gluconeogenesis in the liver and inhibit glucose absorption from the alimentary canal, causing the blood sugar level to lower without promoting insulin secretion (N Engl J Med 333, 541-549, 1995) . Therefore, they are used as diabetic drugs.

Diabetes is a chronic disease and its pathology progresses often with accompanying many complications.

Thus, to treat diabetes it is necessary to select a drug suited to the condition of each individual patient, but there are many cases where a sufficient effect is not produced and the drug selection finds difficulties. There are some reports where a combination of a

DPP-IV inhibitor and a biguanide drug was attempted to obtain an agent for effectively preventing or treating diabetes (WO2001/097808, WO2001/052825, WO2001/068603, JP-A 2003-238566, WO99/38501 and WO99/61431) . However, there are no pharmaceutical compositions known hitherto which comprise a cyanopyrrolidine derivative having superior DPP-IV inhibitory effect in combination with a biguanide drug as described above.

Disclosure of Invention

The object of the present invention is to provide a prophylactic or therapeutic agent for diabetes having effective hypoglycemic action with few side effects in a large number of diabetic patients.

As a result of diligent and intensive studies to resolve the above-mentioned problems, it was discovered that when a cyanopyrrolidine derivative having superior DPP-IV inhibitory action combined with a hepatic gluconeogenesis inhibitor, a synergistic hypoglycemic action was produced, upon which the present invention has been completed. Specifically, the present invention is described below.

(1) A medicament comprising a cyanopyrrolidine derivative represented by the general formula (I) :

[Chemical Formula (I)]

wherein R¹ is a halogen atom, a hydroxy gr-oup, an alkoxy group having 1-5 carbon atoms or an alkyl group having 1-5 carbon atoms, and

R² is a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group having 1-5 carbon atoms or an alkyl group having 1-5 carbon atoms, or R¹ and R² together form an oxo, a hydroxyimino group, an alkoxyimino group having 1-5 carbon atoms or an alkylidene group having 1-5 carbon atoms,

R³ and R⁴ are each a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group having 1-5 carbon atoms or an alkyl group having 1-5 carbon atoms, or

R³ and R⁴ together form an oxo, a hydroxyimino group, an alkoxyimino group having 1-5 carbon atoms or an alkylidene group having 1-5 carbon atoms, X is an oxygen atom or a sulfur atom, Y represents the formula of -CR⁵R⁶-, wherein R⁵ and R⁶ are the same or different, and are each a hydrogen atom_/ a halogen atom; an alkyl group having 1-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group , a hydroxyalkyl group having 1-5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1-5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, -NHR¹¹ (wherein R¹¹ is a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , -CONHR¹² [wherein R¹² is a hydrogen atom or - (CH₂) _m-R¹³ (wherein m is an integer of 1-5 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 1-5 carbon atoms or a benzyl group) ; or an alkenyl group having 2-10 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms, or alternatively, the formula of -CR⁷R⁸-CR⁹R¹⁰- wherein R⁷, R⁸, R⁹ and R¹⁰ are the same or different, and are each a hydrogen atom; a halogen atom; an alkyl group having 1-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxy group, a hydroxyalkyl group having 1-5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1-5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, -NHR¹¹ (wherein R¹¹ is a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , -CONHR¹² [wherein R¹² is a hydrogen atom or - (CH₂) _m-R¹³ (wherein m is an integer of 1-5 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 1-5 carbon atoms or a benzyl group) , or alternatively, R⁷and R⁹ together with the adjacent carbon atom form a cyclic alkyl group having 3-8 carbon atoms optionally substituted with one or more members selected the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group having 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms; a cycloalkenyl group having 4-8 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms; a bicycloalkyl group having 5-10 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms; or a bicycloalkenyl group having 5-10 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms,

Z is a hydrogen atom, or is an alkyl group having 1-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxy group, a hydroxyalkyl group having 1-5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1-5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, -NHR¹¹ (wherein R¹¹ is a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , -CONHR¹² [wherein R¹² is a hydrogen atom or - (CH₂) _m-R¹³ (wherein m is an integer from 1- 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 1-5 carbon atoms or benzyl group) , or alternatively, Y and Z together with the adjacent nitrogen atom form a cyclic amino group having 2-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a chain alkyl group having 1-5 carbon atoms and -OR¹⁵ (wherein R¹⁵ is a chain alkyl group having 1-5 carbon atoms, an aminocarbonylmethyl group or a benzyl group) , or a pharmaceutically acceptable salt thereof, in combination with a hepatic gluconeogenesis inhibitor. (2) The medicament as described in (1), wherein in the general formula (I) , R¹ is a halogen atom, a hydroxyl group, an alkoxy group having 1-5 carbon atoms or an alkyl group having 1-5 carbon atoms; and R², R³ and R⁴ are each a halogen atom, a hydroxyl group, an alkoxy group having 1-5 carbon atoms or an alkyl group having 1-5 carbon atoms.

(3) The medicament as described in (1) or (2), wherein in the general formula (I), R¹ is a fluorine atom or a chlorine atom.

(4) The medicament as described in ( 1 ) or (2 ) , wherein in the general formula ( I ) , R¹ is a fluorine atom and R² is a hydrogen atom. ( 5) The medicament as described in ( 1 ) or (2 ) , wherein in the general formula ( I ) , R¹ is a fluorine atom; and R², R³ and R⁴ are each a hydrogen atom.

( 6) A medicament comprising a cyanopyrrolidine derivative represented by the general formula ( II ) :

[Chemical Formula (II) ]

wherein X is an oxygen atom or a sulfur atom, Y represents the formula of -CR⁵R⁶- wherein R⁵ and R⁶ are the same or different, and are each a hydrogen atom; a halogen atom; an alkyl group having 1-10 carbon atoms optionally substituted with one or more- members selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1-5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1-5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, -NHR¹¹ (wherein R¹¹ is a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , -CONHR¹² [wherein R¹² is a hydrogen atom or - (CH₂) _m-R¹³ (wherein m is an integer of 1-5 and R¹³ is a hydrogen atom, a itiethoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ] and -OR¹⁴ (wherein R¹⁴ is a chain alkyl group having 1-5 carbon atoms or a benzyl group) ; or an alkenyl group having 2-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxy1 group, a carboxyl group, an amino group, an aminocarbonyl group, and a chain alkoxy group having 1-5 carbon atoms)], or alternatively, the formula of -CR⁷R⁸-CR⁹R¹⁰- wherein R⁷, R⁸, R⁹ and R¹⁰ are the same or different, and are each a hydrogen atom; a halogen atom; an alkyl group having 1-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1-5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1-5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, -NHR¹¹ (wherein R¹¹ is a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , -CONHR¹² [wherein R¹² is a hydrogen atom or - (CH₂) _m-R¹³ (wherein m is an integer of 1-5 and R¹³ is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ] and -OR¹⁴ (wherein R¹⁴ is a an alkyl group having 1-5 carbon atoms or a benzyl group) , or alternatively, R⁷and R⁹ together with the adjacent carbon atom form a cyclic alkyl group having 3-8 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms; a cycloalkenyl group having 4-8 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, a aminocarbonyl group, a chain alkyl group having 1- 5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms; a bicycloalkyl group having 5-10 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms; or a bicycloalkenyl group having 5-10 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms,

Z is a halogen atom, or an alkyl group having 1-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen group, a hydroxy group, a hydroxyalkyl group having 1-5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1-5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, -NHR¹¹ (wherein R¹¹ is a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , -CONHR¹² [wherein R¹² is a hydrogen atom or - (CH₂) _m-R¹³ (wherein m is an integer of 1-5 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 1-5 carbon atoms or a benzyl group) , or alternatively,

Y and Z together with the adjacent nitrogen atom form a cyclic amino group having 2-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a chain alkyl group having 1-5 carbon atoms and -OR¹⁵ (wherein R¹⁵ is a chain alkyl group having 1-5 carbon atoms, an aminocarbonylmethyl group or a benzyl group) , or a pharmaceutically acceptable salt thereof, in combination with a hepatic gluconeogenesis inhibitor. (7) The medicament as described in any of (I)- (6), wherein in the general formula (I) or (II) , X is an oxygen atom.

(8) The medicament as described in (7), wherein in the general formula (I) or (II), Y is -CH₂-. (9) The medicament as described in (8) , wherein in the general formula (I) or (II), Z is a branched-chain or cyclic alkyl group having 4-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a hydroxyl group and a hydroxyalkyl group having 1-5 carbon atoms.

(10) The medicament as described in (8), wherein in the general formula (I) or (II), Z is a tert-butyl group, a (1- hydroxymethy) cyclopentyl group or a (2-hydroxy-l, 1- dimethyl) ethyl group. (11) The medicament as described in (7) , wherein in the general formula (I) or (II), Y is -CR⁵R⁶- (wherein R⁵ is a hydrogen atom) , and Z is a hydrogen atom.

(12) The medicament as described in (7), wherein in the general formula (I) or (II), Y is -CR⁵R⁵- (wherein R⁵ is a hydrogen atom and R⁶ is a branched-chain or cyclic alkyl group having 3-6 carbon atoms) , and Z is a hydrogen atom.

(13) The medicament as described in (7) , wherein in the general formula (I) or (II), Y is -CH[CH(CHa)₂]-,

-CH [C (CH₃) ₃]~ or -CH[CH(CH₃)CH₂CH₃]-, and Z is a hydrogen atom.

(14) The medicament as described in any of (I)- (13), wherein in the general formula (I) or (II), the pharmaceutically acceptable salt is a benzene sulfonate. (15) The medicament as described in any of (I)- (14), wherein the hepatic gluconeogenesis inhibitor is a biguanide drug. (16) The medicament as described in (15), wherein the biguanide drug is a slow-release biguanide drug.

(17) The medicament as described in (15) or (16) , wherein the biguanide drug is metformin.

(18) The medicament as described in any of (I)- (17) which is intended for preventing or treating a disease or condition that can be improved by lowering the blood sugar level.

(19) The medicament as described in (18), wherein the disease or condition which can be improved by lowering the blood sugar level is diabetes.

According to the present invention, while the hyperglycemia resulting from diabetes can be efficiently reduced, hyperglycemia can be prevented and the onset of diabetes can be suppressed. Further, the invention is also effective for prevention and treatment of diabetic complications due to hyperglycemia, such as neuropathy, nephropathy and retinopathy. In addition, the blood sugar level can be lowered without causing excessive insulin secretion and hypoglycemia, hence there are few side effects and long-term administration will be possible.

Brief Description of Drawings Fig. 1 shows the results from the examination of the time-dependent variation of postprandial plasma glucose level when Compound A and metformin were administered simultaneously or both separately to Zucker fatty rats as a model animal with type 2 diabetes .

Fig. 2 shows the results of measuring the reduction (ΔAUC₀-2_hours (mg/h/dL blood) ) in plasma glucose level from 0-2 hours after feeding in the above rats . Fig. 3 shows the results of measuring DPP-IV activity in plasma in the rats.

Best Mode for Carrying Out the Invention

In the cyanopyridine derivative represented by the general formula (I) or (II) , or its pharmaceutically acceptable salt according to the present invention, the term "chain" refers to straight-chain or branched-chain. The term "halogen atom" represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The term "alkoxy group having 1-5 carbon atoms" refers to straight-chain, branched-chain or cyclic alkoxy groups, and they include, for example, 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 term "alkyl group having 1-5 carbon atoms" refers to straight-chain, branched-chain or cyclic alkyl groups, and they include, for examples, 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 term "alkoxyimino group having 1-5 carbon atoms" refers to straight-chain, branched-chain or cyclic imino groups substituted with alkoxy groups, and they include, for example, 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 isopentyloximino group.

The term "alkylidene group having 1-5 carbon atoms" refers to straight-chain, branched-chain or cyclic alkylidene groups, and they include, for example, 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 term "alkyl group having 1-10 carbon atoms optionally substituted" refers to substituted or unsubstituted straight-chain, branched-chain or cyclic alkyl groups having 1-10 carbon atoms, and they include, for example, 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 cyclic alkyl group having 3-10 carbon atoms (for example, 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 4-8 carbon atoms (for example, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, or a cyclooctenyl group) , a bicycloalkyl group having 5-10 carbon atoms which may be substituted (for example, a bicyclopentyl group, a bicyclohexyl group, a bicycloheptyl group, a bicyclooctyl group, a bicyclononyl group, or a bicyclodecyl group) , a bicycloalkenyl group having 5-10 carbon atoms which may be substituted (for example, a bicyclopentenyl group, a bicyclohexenyl group, a bicycloheptenyl group, a bicyclooctenyl group, a bicyclononenyl group, or a bicyclodecenyl group) , and a crosslinked cyclic hydrocarbon (for example, an adamanthyl group, a bornyl group, a norbornyl group, a pinanyl group, a thujyl group, a caryl group, or a camphanyl group) . In addition to these alkyl groups there may be mentioned the alkyl groups of which a hydrogen atom is substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1-5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1-5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group or an indolyl group, -NHR¹¹ (wherein R¹¹ is a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , -CONHR¹² [wherein R¹² is a hydrogen atom or - (CH₂) _m-R¹³ (wherein m is an integer of 1-5 and R¹³ is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ] and

-OR¹⁴ (whrein R¹⁴ is a straight-chain or branched-chain alkyl group having 1-5 carbon atoms or a benzyl group) .

By the substituted phenyl group for the term "phenyl group which may be substituted, " there is mentioned, for example, a phenyl group substituted with one or more members selected from the group consisting of a hydroxyl group and a straight-chain or branched-chain alkoxy group having 1-5 carbon atoms (e.g., a 4-hydroxyphenyl group and a 3, 4-dimethoxyphenyl group). By the substituted pyridyl group for the term

"pyridiyl group which may be substituted (e.g., a pyridin- 2-yl group)," there is mentioned, for example, a pyridyl group substituted with one or more members 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 group, a 5- chloropyridin-2-yl group, or a 5-aminocarbonylpyridin-2-yl group) .

The term "hydroxyalkyl group having 1-5 carbon atoms" refers to, for example, a hydroxymethyl group, a 1- hydroxyethyl group, a 2-hydroxyethyl group, a 1- hydroxypropyl group, a 2-hydroxypropyl group, a 3- hydroxypropyl group, a 1- (hydroxymethyl) ethyl group, a 1- hydroxy-1-methylethyl group, a 4-hydroxybutyl group or a 5- hydroxypentyl group .

The term "alkylthio group having 1-5 carbon atoms" refers to, for example, a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, a tert-butylthio group or a pentylthio group .

The term "alkenyl group having 2-10 carbon atoms optionally substituted" refers to substituted or unsubstituted straight-chain, branched-chain or cyclic alkyl groups having 1-5 carbon atoms, and they include, for example, alkenyl groups such as 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, and a cyclohexenyl group. In addition to these alkenyl groups, there may be mentioned the alkenyl groups of which a hydrogen atom is substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group and a straight-chain or branched- chain alkoxy group having 1-5 carbon atoms.

The term "cycloalkyl group having 3-8 carbon atoms optionally substituted" refers to substituted or unsubstituted cycloalkyl groups, and they include, for example, cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group. In addition to these cycloalkyl groups, there may be mentioned the cycloalkyl groups of which a hydrogen atom is substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a straight-chain or branched-chain alkyl group having 1-5 carbon atoms, and a straight-chain or branched-chain alkoxy group having 1-5 carbon atoms.

The term "cycloalkenyl group having 4-8 carbon atoms optionally substituted" refers to substituted or unsubstituted cycloalkenyl groups, and they include, for example, cycloalkenyl groups such as a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group and a cyclooctenyl group. In addition to these cycloalkenyl groups, there may be mentioned the cycloalkenyl groups of which a hydrogen atom is substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a straight-chain or branched-chain alkyl group having 1-5 carbon atoms and a straight-chain or branched-chain, alkoxy group having 1-5 carbon atoms .

The term "bicycloalkyl group having 5-10 carbon atoms optionally substituted" refers to substituted or unsubstituted bicycloalkyl groups, and they include, for example, bicycloalkyl groups such as a bicyclopentyl group, a bicyclohexyl group, a bicycloheptyl group, a bicyclooctyl group, a bicyclononyl group and a bicyclodecyl group. In addition these bicyloalkyl groups, there may be mentioned the bicycloalkyl groups of which a hydrogen atom is substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a straight-chain or branched-chain alkyl group having 1-5 carbon atoms, and a straight-chain or branched-chain alkoxy group having 1-5 carbon atoms.

The term "bicycloalkenyl group having 5-10 carbon atoms optionally substituted" refers to substituted or unsubstituted bicycloalkenyl groups, and they include, for example, bicycloalkenyl groups such as a bicyclopentenyl group, a bicyclohexenyl group, a bicycloheptenyl group, a bicyclooctenyl group, a bicyclononenyl group and a bicyclodecenyl group. In addition to these bicycloalkenyl groups, there may be mentioned bicycloalkenyl groups of which a hydrogen atom is substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a straight-chain or branched-chain alkyl group having 1-5 carbon atoms, and a straight-chain or branched-chain alkoxy group having 1-5 carbon atoms.

The term "cyclic amino group having 2-10 carbon atoms optionally substituted" refers to substituted or unsubstituted cyclic amino groups having one or more nitrogen atoms in the ring, and wherein one or more oxygen atoms or sulphur atoms may also be present, and they include, for example, cyclic amino groups 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 these cyclic amino groups, there may be mentioned the cyclic amino groups with which a benzene ring or a pyridine ring is condensed, or of which (including the benzene ring or pyridine ring condensed therewith) a hydrogen atom is substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a straight-chain or branched-chain alkyl group having 1-5 carbon atoms and -OR¹⁵ (wherein R¹⁵ is a straight-chain or branched-chain alkyl group having 1-5 carbon atoms, an aminocarbonyl methyl group or a benzyl group) . The pharmaceutically acceptable salts include a salt with a mineral acid such as sulfuric acid, hydrochloric acid, hydrobromic acid or phosphoric acid, and a salt of with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, trifluoroacetic acid or methanesulfonic acid.

Some preferred examples of the compounds of this invention will now be described.

From the viewpoint of DPP-IV inhibitory activity, R¹ is preferably a halogen atom, and more preferably a fluorine atom. R² is preferably a hydrogen atom or halogen atom, and more preferably a hydrogen atom. When, in formula (I) or (II), Y is -CH₂-, Z is preferably an alkyl group having 1-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a hydroxyl group, an alkoxy group having 1-5 carbon atoms, a hydroxyalkyl group having 1-5 carbon atoms, a phenyl group which may be substituted and -NHR¹¹ (wherein R¹¹ is a pyridyl group which may be substituted) . Further in this case, Z is preferably a branched-chain or cyclic alkyl group having 4-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a hydroxyl group, a hydroxyalkyl group having 1-5 carbon atoms and an alkoxy group having 1-5 carbon atoms. More preferably, it is a branched-chain alkyl group having 4-10 carbon atoms, a cyclic alkyl group having 4-10 carbon atoms, or an adamanthyl group each of which may be substituted with one or more members selected from the group consisting of a hydroxyl group and a hydroxyalkyl group having 1-5 carbon atoms, and still more preferably a tert-butyl group, a (1- hydroxymethyl) cyclopentyl group or a (2-hydroxy-l, 1- dimethyl ) ethyl group.

In formula (I) or (II) , when Y is of the formula -CR⁵R⁶- (wherein R⁵ is a hydrogen atom and R⁶ is an optionally substituted alkyl group having 1-10 carbon atoms) , or of the formula -CR⁷R⁸-CR⁹R¹⁰ (wherein R⁸ and R¹⁰ are a hydrogen atom, and R⁷ and R⁹ together with the adjacent carbon atom form a cyclic alkyl group having 3-8 carbon atoms), then Z is preferably H or CH₃.

In this case, preferably, when Y is of the formula -CR⁵R⁶- (wherein R⁵ is a hydrogen atom and R⁶ is a branched-chain or cyclic alkyl group having 3-6 carbon atoms optionally substituted with one or more members selected from the group consisting of a hydroxyl group and -OR¹⁴ (wherein R¹⁴ is a straight-chain or branched-chain alkyl group having 1-5 carbon atoms or a benzyl group) , Z is a hydrogen atom. More preferably, when Y is of the formula -CR⁵R⁶- (wherein R⁵ is a hydrogen atom and R⁶ is a branched-chain or cyclic alkyl group having 3-6 carbon atoms) , Z is a hydrogen atom, and still more preferably, when Y is -CH[CH(CH₃J₂]-, -CH[C (CH₃J₃] - or -CH[CH(CH₃)CH₂CH₃]-, Z is a hydrogen atom.

In formula (I) or (II), preferred examples where Y and Z together with the adjacent nitrogen atom form an optionally substituted cyclic amino group having 2-10 carbon atoms are a pyrrolidinyl group, a piperidyl group or cyclic amino groups wherein a benzene ring is condensed with these groups; and preferred substituents are a hydroxyl group and -OR¹⁵ (wherein R¹⁵ is as defined above) .

WO2002/038541 (pamphlet) discloses a detailed description (preferred conditions and production methods) related to the cyanofluoropyrrolidine compounds or their pharmaceutically acceptable salts.

In particular, from the viewpoint of stability during formulation, the benzensuplhonate of (2S, 4S) -2- cyano-4-fluoro-l- [2-hydroxy-l, 1- dimethyl) ethylamino] acetylpyrrolidine is preferred; and WO2004/02407 (pamphlet) discloses a detailed description of the compound (preferred conditions and production methods) . The term "hepatic gluconeogenesis inhibitor" as used in the present specification will then be described. In the context of the present invention, "a hepatic gluconeogenesis inhibitor" means a drug having the action of inhibiting gluconeogenesis in the liver such as a biguanide drug, including metformin, buformin, phenformin or the pharmaceutically acceptable salts of these compounds In particular, metformin is preferable from the viewpoint of hypoglycemic action and lack of side effects, and metformin hydrochloride is particularly preferred. These biguanide drugs are well-known. Specifically, metformin and its hydrochloride are disclosed in Emil A. Werner and

James Bell, J.Chem. Soc, 121, 1922, 1790-1794, and marketed as GLUCOPHAGE (registered trademark) , which can be put into use.

For the medicament according to the present invention where a cyanopyyrolidine derivative having DPP-IV inhibitory activity is combined with a hepatic gluconeogenesis inhibitor, the active ingredients may be incorporated into one formulation, or may be used separately to prepare a tablet, granule, powder, capsule, emulsion, suspension or syrup, or injectables such as a sterile solution and a sterile suspension by following ordinary techniques. When these active ingredients are formulated separately, the separate formulations can be administered simultaneously, continuously or with a time lag.

After the active ingredients are simultaneously or individually blended with an excipient such as mannitol or lactose followed by granulation, they can be filled into capsules or made into tablets, either directly, or after blending with another oral additive, specifically an excipient (e.g., a sugar or glycitol excipients such as glucose, saccharose, mannitol, milk sugar, xylitol, sorbitol, maltitol, or pullulan, a cellulose excipient such as crystalline cellulose, a starch excipient such as corn starch, or an inorganic excipient such as anhydrous calcium hydrogenphosphate) , a binder (e.g., a cellulose binder such as methyl cellulose, hydroxypropyl cellulose, or hydroxypropyl methylcellulose) , a disintegrating agent (e.g., a cellulose disintegrating agent such as carmellose calcium, low-substituted hydroxypropyl cellulose, or croscarmellose sodium, or a starch-based disintegrating agent such as partial α-starch or sodium carboxymethyl starch, a fluidizer (e.g., an inorganic fluidizer such as light silicic acid anhydride) or a lubricant (such as stearic acid, magnesium stearate, calcium stearate, talc, or sodium stearyl fumarate) .

The dosage of the medicament of the present invention varies depending on the subject and the administration method, but for example in the case of oral administration, it is preferably administered in a daily dose of 5-200 mg cyanopyrrolidone derivative and 250-3000 mg biguanide to a diabetic patient (60 kg) . If a biguanide drug is¹ selected as the hepatic gluconeogenesis inhibitor, absorption will be poor as the dosage is increased; therefore, the dose must be divided into 2-3 units. The cyanopyridine derivative is capable of maintaining its DPP- IV inhibitory action for a long time. Thus, In order to be able to prepare a medicament of the type of once-daily administration, it is preferred to use the cyanopyyrolidine derivative having superior DPP-IV inhibitory activity of the present invention in combination with "a slow-release biguanide drug."

As used herein, "a slow release biguanide drug" can be obtained by the methods known in the art. For example, according to the slow-releasing method as described in WO96/08243 or the method as described in WO2000/012097 can be used to produce slow-release forms.

The blending ratio of the cyanopyyrolidine derivative of the present invention with the gluconeogenesis inhibitor varies depending on the subject and the administration method, but for example, when the medicament of the present invention is administered to a human, a superior hypoglycemic effect to that obtained when these drugs are administered separately, can be obtained by blending 1-1000 mass parts of the gluconeogenesis inhibitor with 1 mass part of the cyanopyyrolidine derivative. It is particularly preferable to blend it in the ratio of 1.25- 600 mass parts. In this way, a sufficient effect can be obtained in a smaller amount than that with which these drugs are administered individually. In addition, since they do not cause hypersecretion of insulin or hypoglycaemia, they can be made into a medicament with few side effects.

EXAMPLES The present invention will then be described in more detail by referring to the examples, but the invention is not to be limited to these examples in any way.

Example 1 Tablets (Granulated substance) Compound A 5mg

D-mannitol lOmg

(Other oral administration additives) Metformin 500mg

Crystalline cellulose 5mg

Directly compressible D- mannitol lOOmg Low-substituted hydroxypropyl cellulose 15mg Calcium stearate 3mg

D-mannitol was blended with the benzensulphonate of (2S, 4S)-2-cyano-4-fluoro-l-[2-hydroxy-l,l- (dimethyl) ethylamino] acetylpyrrolidine (hereafter, Compound A) , and granules were obtained by using a stirring granulator (vertical granulator [VG5] manufactured by

Powrex Co., Ltd.) . After drying in a fluidized bed drier (FL-MINI manufactured by Freund Corporation), the granulated substance was mixed with other oral administration additives (including metformin) , to produce a powdered mixture. The powdered mixture was then compressed by a tablet press (VIRGOl9 manufactured by Kikusui Seisakusho Ltd.) to produce tablets of diameter 13 mm.

Example 2 Tablets Compound A lOmg

D-mannitol 20mg

(Other oral administration additives)

Metformin 500mg

Crystalline cellulose 5mg Directly compressible D-mannitol 90mg

Low-substituted hydroxypropylcellulose 15mg

Calcium stearate 3mg Tablets of diameter 13 mm were produced similarly to Example 1.

Example 3 Tablets

Compound A 20mg D-mannitol 40mg

(Other oral administration additives) Metformin 500mg

Crystalline cellulose 5mg

Directly compressible D-mannitol 70mg Low-substituted hydroxypropylcellulose 15mg Calcium stearate 3mg

Tablets of diameter 13 mm were produced similarly to Example 1.

Test Example 1 : Oral glucose tolerance test (OGTT) with the use of Zucker fatty rats

This test was performed by referring to the method described in Diabetologia Vol. 42, pp.1325 (1999) . Specifically, the method was performed as described below. (Method) Zucker fatty rats (male, 10 weeks) and Zucker lean rats (male, 10 weeks) as controls, purchased from Nihon Charles River Co., were divided into the following 5 groups (10 animals in each group) .

Group I: Vehicle group (water for injection) Group II: Compound A (0.5 mg/kg) administered group Group III: Metformin (300 mg/kg) administered group Group IV: Compound A (0.5 mg/kg + metformin 300 mg/kg) administered group Group V: Normal control group (water for injection)

In each group, the animals were fed ad lib with rat/mouse chow MF (Oriental Yeast Co., Ltd.) together with sterile water as the drinking water. The temperature- humidity were 23±3°C, 50±20%, the lighting was 12 hours (7:15 lights on to 19:15 lights off), and air ventilation frequency was 10 times or more/hour.

After the end of the acclimatization period, all rats were fasted for about 16 hours (food was removed the day before at 17:00). On the OGTT day, rats were forced to take an oral dosage of the test substance or vehicle (water for injection) with an oral sonde, and after 0.5 hours, 2g/5mL/kg of D- (+) -glucose solution was given orally for torelance. Blood was sampled at 7 points, i.e., before administration of the test substance, at 0 hours (before administration of the glucose solution), and at 0.25, 0.5, 1, 1.5 and 2 hours. The blood sampling procedure was such that 0.2 ml/animal was sampled each time using a heparin- coated blood-collecting vessel (Drummond Scientific

Company) from an eye socket vein under ether anesthesia, and the sampled blood was collected so that the final concentration of sodium heparin was 20 U/mL. After centrifugation (3,000 rpm, 10 minutes, 4⁰C), the plasma was separated and sampled. The plasma was stored in a freezer at -4O⁰C (preset temperature) until measurement. Fasting was continued after administration of the test substance until the end of the OGTT.

Measurement of glucose level in the plasma was performed by colorimetry according to the mutarotase GOD method using a glucose measurement kit (Glucose CII Test- Wako: Wako Pure Chemical Industries Co., Ltd.) . Five μL of plasma was separated, and 500 μL of Glucose CII Test Wako color development solution was added, left to stand at room temperature for 15 min or more to allow color to develop; and the absorbance (extinction wavelength at 505 nm) was measured using a spectrophotometer (Spectro Rainbow Thermo absorbance microplate reader, TECAN Austria GmbH) . A calibration curve was drawn with the standard solution of known glucose levels supplied with the kit to covert the absorbance, and the glucose level of the plasma was expressed as mean value ± standard error for each group (Table 1) .

The results are shown in Fig. 1. When Compound A was used in combination with metformin, the blood sugar level fell to a value almost equal to that in the normal control group.

Using the glucose level in plasma before administering glucose for tolerance (0 hour) in each test substance administered group as baseline, the area under the glucose concentration-time curve (ΔAUC0-2 hours (mg/h/dL) ) was computed according to the trapezoidal method from the time-dependent plasma glucose level, i.e., from glucose administration for tolerance (0 hour) to 2 hours after administration for tolerance (Table 2) , and the magnitude of hypoglycemic action was expressed as the proportion of reduction (%) relative to ΔAUC0-2 hours of the control group (Table 3) .

The results are shown in Fig. 2. It was confirmed that when Compound A was used in combination with metformin, a synergistic, hypoglycemic action was obtained.

[TABLE 1]

[TABLE 2]

[TABLE 3]

In addition, the DPP-IV activity in plasma was measured by referring to the method described in Clinical and Experimental Immunology Vol. 89, pp.193 (1992). An assay cocktail (66.7 μruol/L Gly-Pro-

Aminomethylcoumarin (AMC), 25 mmol/L HEPES, 140 mmol/L NaCl, 26.6 mmol/L MgCl₂, 1% (w/v) BSA, pH 7.8) 37.5 μL was added to 12.5 μL of plasma, and was allowed to react at room temperature in the dark for 5 minutes. Next, 50 μL of 25% acetic acid was added to stop the reaction, and the fluorescence intensity (Ex: 360nm, Em 465nm) was measured. The released AMC was calculated from a calibration curve drawn from known amounts of AMC. The DPP-IV activity was then expressed as mean value ± standard error for each group at the measuring points: before administration of the test substance or vehicle (Before) , before administration of glucose (taken as 0 min) , and at 15, 30, 60, 90 and 120 minutes after glucose administration (Table 4).

The results are shown in Fig. 3. When Compound A was used in combination with metformin, the DPP-IV inhibitory activity was almost equal to that when Compound A was administered alone.

The above results show that when Compound A was used in combination with metformin, superior hypoglycemic action can be obtained without side effects such as excessive insulin secretion or hypoglycemia.

[TABLE 4]

Industrial Applicability

The present invention offers a superior diabetes prophylactic or therapeutic agent with few side effects as well as effective hypoglycemic action for many diabetic patients. In addition, it offers a prophylactic or therapeutic agent for various diabetic complications such as neuropathy, nephropathy, retinopathy, heart failure and foot gangrene .

Claims

1. A medicament comprising a cyanopyrrolidine derivative represented by the general formula (I) : [Chemical Formula (I)]

wherein R¹ is a halogen atom, a hydroxy group, an alkoxy group having 1-5 carbon atoms or an alkyl group having 1-5 carbon atoms, and R² is a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group having 1-5 carbon atoms or an alkyl group having 1-5 carbon atoms, or

R¹ and R² together form an oxo, a hydroxyimino group, an alkoxyimino group having 1-5 carbon atoms or an alkylidene group having 1-5 carbon atoms; and

R³ and R⁴ together form an oxo, a hydroxyimino group, an alkoxyimino group having 1-5 carbon atoms or an alkylidene group having 1-5 carbon atoms,

X is an oxygen atom or a sulfur atom,

Y represents the formula of -CR⁵R⁶-, wherein R⁵ and R⁶ are the same or different, and are each a hydrogen atom; a halogen atom; an alkyl group having 1-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group , a hydroxyalkyl group having 1-5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1-5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, -NHR¹¹ (wherein R¹¹ is a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , -CONHR¹² [wherein R¹² is a hydrogen atom or - (CH₂) _m-R¹³ (wherein m is an integer of 1-5 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 1-5 carbon atoms or a benzyl group) ; or an alkenyl group having 2-10 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms, or alternatively, the formula of -CR⁷R⁸-CR⁹R¹⁰- wherein R⁷, R⁸, R⁹ and R¹⁰ are the same or different, and are each a hydrogen atom; a halogen atom; an alkyl group having 1-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxy group, a hydroxyalkyl group having 1-5 carbon atoms , a carboxyl group, a mercapto group, an alkyl thio group having 1-5 carbon atoms , a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, -NHR¹¹ (wherein R¹¹ is a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , -CONHR¹² [wherein R¹² is a hydrogen atom or - (CH₂ ) _m-R¹³ (wherein m is an integer of 1-5 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 1-5 carbon atoms or a benzyl group ) , or alternatively,

R⁷ and R⁹ together with the adj acent carbon atom form a cyclic alkyl group having 3-8 carbon atoms optionally substituted with one or more members selected the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an aminocarbonyl group, a chain alkyl group having 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms ; a cycloalkenyl group having 4-8 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms ; a bicycloalkyl group having 5-10 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms; or a bicycloalkenyl group having 5-10 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms, Z is a hydrogen atom, or is an alkyl group having 1-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxy group, a hydroxyalkyl group having 1-5 carbon^' atoms, a carboxyl group, a mercapto group, an alkylthio group having 1-5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, -NHR¹¹ (wherein R¹¹ is a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , -CONHR¹² [wherein R¹² is a hydrogen atom or - (CH₂) _m-R¹³ (wherein m is an integer from 1- 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 1-5 carbon atoms or benzyl group) , or alternatively,

Y and Z together with the adjacent nitrogen atom form a cyclic amino group having 2-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a chain alkyl group having 1-5 carbon atoms and -OR¹⁵ (wherein R¹⁵ is a chain alkyl group having 1-5 carbon atoms, an aminocarbonylmethyl group or a benzyl group) , or a pharmaceutically acceptable salt thereof, in combination with a hepatic gluconeogenesis inhibitor.

2. The medicament according to claim 1, wherein in the general formula (I) , R¹ is a halogen atom, a hydroxyl group, an alkoxy group having 1-5 carbon atoms or an alkyl group having 1-5 carbon atoms; and R², R³ and R⁴ are each a halogen atom, a hydroxyl group, an alkoxy group having 1-5 carbon atoms or an alkyl group having 1-5 carbon atoms.

3. The medicament according to claim 1 or 2, wherein in the general formula (I) , R¹ is a fluorine atom or a chlorine atom.

4. The medicament according to claim 1 or 2, wherein in the general formula (I), R¹ is a fluorine atom and R² is a hydrogen atom.

5. The medicament according to claim 1 or 2, wherein in the general formula (I), R¹ is a fluorine atom; and R², R³ and R⁴ are each a hydrogen atom.

6. A medicament comprising a cyanopyrrolidine derivative represented by the general formula (II) : [Chemical Formula ( I I ) ]

wherein X is an oxygen atom or a sulfur atom, Y represents the formula of -CR⁵R⁶- wherein R⁵ and R⁶ are the same or different, and are each a hydrogen atom; a halogen atom; an alkyl group having 1-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1-5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1-5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, -NHR¹¹ (wherein R¹¹ is a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , -CONHR¹² [wherein R¹² is a hydrogen atom or - (CH₂) _m-R¹³ (wherein m is an integer of 1-5 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 1-5 carbon atoms or a benzyl group) ; or an alkenyl group having 2-10 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms) ] , or alternatively, the formula of -CR⁷R⁸-CR⁹R¹⁰- wherein R⁷, R⁸, R⁹ and R¹⁰ are the same or different, and are each a hydrogen atom; a halogen atom; an alkyl group having 1-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a hydroxyalkyl group having 1-5 carbon atoms, a carboxyl group, a mercapto group, an alkylthio group having 1-5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, -NHR¹¹ (wherein R¹¹ is a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , -CONHR¹² [wherein R¹² is a hydrogen atom or - (CHa) _m~R¹³ (wherein m is an integer of 1-5 and R¹³ is a hydrogen atom, a methoxycarbonyl group, an ethoxycarbonyl group or a benzyloxycarbonyl group) ] and -OR¹⁴ (wherein R¹⁴ is a an alkyl group having 1-5 carbon atoms or a benzyl group) , or alternatively,

R⁷ and R⁹ together with the adjacent carbon atom form a cyclic alkyl group having 3-8 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms; a cycloalkenyl group having 4-8 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group, a aminocarbonyl group, a chain alkyl group having 1- 5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms; a bicycloalkyl group having 5-10 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms; or a bicycloalkenyl group having 5-10 carbon atoms optionally substituted with one or more members 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 1-5 carbon atoms and a chain alkoxy group having 1-5 carbon atoms, Z is a halogen atom, or an alkyl group having 1-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen group, a hydroxy group, a hydroxyalkyl group having 1-5 carbon atoms, a carboxyl -group, a mercapto group, an alkylthio group having 1-5 carbon atoms, a guanidyl group, a phenyl group which may be substituted, an imidazolyl group, an indolyl group, -NHR¹¹ (wherein R¹¹ is a hydrogen atom, a phenyl group which may be substituted, a pyridyl group which may be substituted, a tert-butoxycarbonyl group or a benzyloxycarbonyl group) , -CONHR¹² [wherein R¹² is a hydrogen atom or - (CH₂) _m-R¹³ (wherein m is an integer of 1-5 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 1-5 carbon atoms or a benzyl group) , or alternatively, Y and Z together with the adjacent nitrogen atom form a cyclic amino group having 2-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a chain alkyl group having 1-5 carbon atoms and -OR¹⁵ (wherein R¹⁵ is a chain alkyl group having 1-5 carbon atoms, an aminocarbonylmethyl group or a benzyl group) , or a pharmaceutically acceptable salt thereof, in combination with a hepatic gluconeogenesis inhibitor.

7. The medicament according to any of claims 1-6, wherein in the general formula (I) or (II), X is an oxygen atom.

8. The medicament according to claim 7, wherein in the general formula (I) or (II), Y is -CH₂-.

9. The medicament according to claim 8, wherein in the general formula (I) or (II), Z is a branched-chain or cyclic alkyl group having 4-10 carbon atoms optionally substituted with one or more members selected from the group consisting of a hydroxyl group and a hydroxyalkyl group having 1-5 carbon atoms.

10. The medicament according to claim 8, wherein in the general formula (I) or (II), Z is a tert-butyl group, a (1-hydroxymethy) cyclopentyl group or a (2-hydroxy-1, 1- dimethyl) ethyl group.

11. The medicament according to claim 7, wherein in the general formula (I) or (II), Y is -CR⁵R⁶- (wherein R⁵ is a hydrogen atom) , and Z is a hydrogen atom.

12. The medicament according to claim 7, wherein in the general formula (I) or (II), Y is -CR⁵R⁶- (wherein R⁵ is a hydrogen atom and R⁶ is a branched-chain or cyclic alkyl group having 3-6 carbon atoms) , and Z is a hydrogen atom.

13. The medicament according to claim 7, wherein

• in the general formula (I) or (II), Y is -CH[CH(CHa)₂]-/ -CH[C(CHa)₃]- or -CH[CH(CH₃)CH₂CH₃]-, and Z is a hydrogen atom.

14. The medicament according to any of claims 1- 13, wherein in the general formula (I) or (II), the pharmaceutically acceptable salt is a benzene sulfonate.

15. The medicament according to any of claims 1- 14, wherein the hepatic gluconeogenesis inhibitor is a biguanide drug.

16. The medicament according to claim 15, wherein the biguanide drug is a slow-release biguanide drug.

17. The medicament according to claim 15 or 16, wherein the biguanide drug is metformin.

18. The medicament according to any of claims 1- 17 which is intended for preventing or treating a disease or condition that can be improved by lowering the blood sugar level.

19. The medicament according to claim 18, wherein the disease or condition which can be improved by lowering the blood sugar level is diabetes.