JP2007224044A - Pyridyl acetic acid compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound having a peptidase inhibitory action and is useful as an agent for the prophylaxis or treatment of diabetes and having excellent properties such as efficacy of the medicine, action time, specificity, low toxicity, etc. <P>SOLUTION: The invention relates to the compound represented by the formula (I) or salts of the same, wherein R<SP>1</SP>-R<SP>3</SP>are each a C<SB>1-6</SB>alkyl group, etc., X is a -OR<SP>6</SP>or -NR<SP>4</SP>R<SP>5</SP>(R<SP>4</SP>-R<SP>6</SP>are each a hydrocarbon group or a heterocyclic group, etc.,). <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a pyridylacetic acid compound having a peptidase inhibitory effect and useful as a prophylactic / therapeutic agent for diabetes.

  Peptidases are known to be associated with various diseases. Dipeptidyl peptidase-IV (hereinafter sometimes abbreviated as DPP-IV), which is a kind of peptidase, specifically binds to a peptide containing proline (or alanine) second from the N-terminus, and the proline ( Alternatively, it is a serine protease that cleaves the C-terminal side of alanine) to produce a dipeptide. It has also been shown that DPP-IV is the same molecule as CD26 and has been reported to be related to the immune system. The role of DPP-IV in mammals has not been fully clarified, but it plays an important role in neuropeptide metabolism, T cell activation, cancer cell adhesion to endothelial cells, and HIV entry into cells. It is thought that he plays. Particularly in terms of sugar metabolism, DPP-IV plays a role in inactivation of incretins GLP-1 (glucagon-like peptide-1) or GIP (Gastric inhibitory peptide / Glucose-dependent insulinotropic peptide). Regarding GLP-1, the plasma half-life is as short as 1-2 minutes, and GLP-1 (9-36) amide, a degradation product of DPP-IV, acts as an antagonist to the GLP-1 receptor. It is known that its physiological activity is significantly impaired by being decomposed into DPP-IV, such as working. It is also known that if the degradation of GLP-1 is inhibited by inhibiting DPP-IV activity, the physiological activity of GLP-1 is enhanced, such as promoting insulin secretion in a glucose concentration-dependent manner. Based on these facts, compounds having DPP-IV inhibitory action are effective in impaired glucose tolerance, postprandial hyperglycemia, fasting hyperglycemia and associated obesity / diabetic complications observed in type 1 and type 2 diabetes It is expected.

  Examples of the compound having DPP-IV inhibitory action include compounds represented by the formula:

[Wherein X is N or CR ⁵ (R ⁵ is hydrogen or lower alkyl); R ¹ and R ² are independently hydrogen or lower alkyl; R ³ is each substituted with lower alkyl or the like; the good heterocyclic group or an aryl; R ⁴ is or a salt thereof] represents a lower alkyl or the like have been reported (see Patent Document 1).
However, there are no reports on the compounds of the present invention.

International Publication No. WO03 / 068757 Pamphlet

  Development of a compound that has a peptidase inhibitory action, is useful as a preventive / therapeutic agent for diabetes, and has excellent properties in terms of drug efficacy, action time, specificity, and low toxicity is desired.

The inventors of the present invention have an amino group via the methylene group at the 3-position of the pyridine ring, a phenyl group which may be substituted at the 4-position, an acyl group via the methylene group at the 5-position, and a C _{2-6 at the} 6-position. Formula (I) having a chemical structural feature in that the alkyl group is bonded:

[Wherein R ¹ represents a C _1-6 alkyl group which may be substituted with a C _3-10 cycloalkyl group,
R ² represents a C _2-6 alkyl group,
R ³ represents a hydrogen atom, a C _1-6 alkyl group or a halogen atom,
X represents —OR ⁶ or —NR ⁴ R ⁵ (R ⁴ and R ⁶ independently represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ⁵ represents Represents an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted hydroxy group, or R ⁴ and R ⁵ are substituted together with the adjacent nitrogen atom; Which may form a nitrogen-containing heterocyclic ring that may be present. ]
Or a salt thereof [hereinafter sometimes abbreviated as compound (I). ] Have an excellent peptidase inhibitory effect and are useful for the first time as a prophylactic / therapeutic agent for diabetes. Based on this knowledge, the present inventors have conducted intensive studies and have completed the present invention.

That is, the present invention relates to 1) Compound (I);
2) Compound (I) wherein X is —OH;
3) Compound (I) wherein R ¹ is a C _3-6 alkyl group;
4) Compound (I) wherein R ³ is a C _1-6 alkyl group;
5) [5- (Aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid;
[5- (aminomethyl) -2,6-diisobutyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid;
[5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid;
1-{[5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetyl} -L-prolinamide;
Or a salt thereof (I);
6) prodrugs of compound (I);
7) A medicament comprising compound (I) or a prodrug thereof;
8) The medicament according to 7) above, which is a prophylactic / therapeutic agent for diabetes, diabetic complications, glucose intolerance or obesity;
9) A peptidase inhibitor comprising compound (I) or a prodrug thereof;
10) The inhibitor according to 9) above, wherein the peptidase is dipeptidyl peptidase-IV;
11) Use of compound (I) or a prodrug thereof for the manufacture of a prophylactic / therapeutic agent for diabetes, diabetic complications, glucose intolerance or obesity;
12) Use of compound (I) or a prodrug thereof for producing a peptidase inhibitor;
13) A method for preventing or treating diabetes, diabetic complications, glucose intolerance or obesity in a mammal, comprising administering the compound (I) or a prodrug thereof to the mammal;
14) A method for inhibiting peptidase in a mammal, comprising administering the compound (I) or a prodrug thereof to the mammal;
15) Formula (1):

[Wherein P represents a hydrogen atom or an amino-protecting group,
R ¹ represents a C _1-6 alkyl group which may be substituted with a C _3-10 cycloalkyl group,
R ² represents a C _2-6 alkyl group,
R ³ represents a hydrogen atom, a C _1-6 alkyl group or a halogen atom. ]
Wherein the compound represented by the formula or a salt thereof is subjected to a hydrolysis reaction and a deprotection reaction:

[The symbols in the formula are as defined above. ]
A method for producing a compound represented by the formula:
And so on.

  The compound of the present invention has an excellent peptidase inhibitory action and is useful as a prophylactic / therapeutic agent for diabetes.

Hereinafter, the definition of each symbol in formula (I) will be described in detail.
As "C _1-6 alkyl group" of the "C _3-10 cycloalkyl C _1-6 alkyl group optionally substituted with a group" represented by R ^1, for example, methyl, ethyl, propyl, isopropyl, butyl , Isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl Etc.
Examples of the “C _3-10 cycloalkyl group” in the “C _1-6 alkyl group _optionally substituted with a C _3-10 cycloalkyl group” represented by R ¹ include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3 3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, adamantyl and the like.
R ¹ is preferably a C _3-6 alkyl group, more preferably a branched C _3-6 alkyl group, and particularly preferably isobutyl or neopentyl.

Examples of the “C _2-6 alkyl group” represented by R ² include ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
R ² is preferably ethyl or isobutyl.

As the “C _1-6 alkyl group” for R ³ , those exemplified for the aforementioned R ¹ can be mentioned.
Examples of the “halogen atom” represented by R ³ include fluorine, chlorine, bromine and iodine.
R ³ is preferably a C _1-6 alkyl group, more preferably methyl.

As the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ⁴ , R ⁵ or R ⁶ , for example, a C _1-10 alkyl group, a C _2-10 alkenyl group, C _{2- 10} alkynyl group, C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _4-10 cycloalkadienyl group, C _6-14 aryl group, C _7-13 aralkyl group, C _8-13 arylalkenyl group Group, C _3-10 cycloalkyl-C _1-6 alkyl group and the like.

Here, as the C _1-10 alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1 , 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.
Examples of the C _2-10 alkenyl group include ethenyl, 1-propenyl, 2-propenyl,
2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3- Pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like can be mentioned.
Examples of the C _2-10 alkynyl group include ethynyl, 1-propynyl, 2-propynyl,
1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1- Examples include heptynyl and 1-octynyl.

Examples of the C _3-10 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, and bicyclo [3. 2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, adamantyl and the like. Can be mentioned.
Examples of the C _3-10 cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.
Examples of the C _4-10 cycloalkadienyl group include 2,4-cyclopentadiene-1-
Yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like.

The above C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _4-10 cycloalkadienyl group may be condensed with a benzene ring, for example, indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl. Etc.

Examples of the C _6-14 aryl group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Of these, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.
Examples of the C _7-13 aralkyl group include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like.
Examples of the C _8-13 arylalkenyl group include styryl and the like.
Examples of the C _3-10 cycloalkyl-C _1-6 alkyl group include cyclohexylmethyl and the like.

The aforementioned C _1-10 alkyl group, C _2-10 alkenyl group, and C _2-10 alkynyl group may have 1 to 3 substituents at substitutable positions.
As such a substituent, for example,
(1) C _3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl);
(2) C _6-14 aryl group (eg, phenyl, naphthyl);
(3) substituted with 1 to 3 substituents selected from a carboxyl group, a carbamoyl group, a thiocarbamoyl group and a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl) Aromatic heterocyclic groups which may be substituted (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrazolyl, oxadiazolyl, pyrazinyl, quinolyl, indolyl);
(4) Non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl, oxodioxolyl) optionally substituted by a C _1-6 alkyl group (eg, methyl, ethyl) , Oxodioxolanyl, oxo-2-benzofuranyl, oxooxadiazolyl);
(5) C _1-6 alkyl group (eg, methyl, ethyl), C _1-6 alkyl-carbonyl group (eg, acetyl, isobutanoyl, isopentanoyl) and C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) Amino group optionally mono- or di-substituted with a substituent selected from ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl);
(6) C _1-6 alkylsulfonylamino group (eg, methylsulfonylamino);
(7) amidino group;
(8) C _1-6 alkyl-carbonyl group (eg, acetyl, isobutanoyl, isopentanoyl);
(9) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, tert-butoxycarbonyl);
(10) C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl);
(11) Mono or disubstituted with a C _1-6 alkyl group (eg, methyl, ethyl) which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) A good carbamoyl group;
(12) Mono- or di-substituted with a C _1-6 alkyl group (eg, methyl, ethyl) which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) A good thiocarbamoyl group;
(13) Mono or disubstituted with a C _1-6 alkyl group (eg, methyl, ethyl) which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine) A good sulfamoyl group;
(14) carboxyl group;
(15) hydroxy group;
(16) a C _1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
(17) a C _2-6 alkenyloxy group (eg, ethenyloxy) optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
(18) C _3-10 cycloalkyloxy group (eg, cyclohexyloxy);
(19) C _7-13 aralkyloxy group (eg, benzyloxy);
(20) C _6-14 aryloxy group (eg, phenyloxy, naphthyloxy);
(21) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy, tert-butylcarbonyloxy);
(22) a thiol group;
(23) a C _1-6 alkylthio group (eg, methylthio, ethylthio) optionally substituted by 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
(24) C _7-13 aralkylthio group (eg, benzylthio);
(25) C _6-14 arylthio group (eg, phenylthio, naphthylthio);
(26) a sulfo group;
(27) a cyano group;
(28) an azido group;
(29) a nitro group;
(30) Nitroso group;
(31) a halogen atom (eg, fluorine, chlorine, bromine, iodine);
(32) C _1-6 alkylsulfinyl group (eg, methylsulfinyl);
Etc.

Examples of the “hydrocarbon group” include C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _4-10 cycloalkadienyl group, C _6-14 aryl group, C _7-13 aralkyl. Group, C _8-13 arylalkenyl group, C _3-10 cycloalkyl-C _1-6 alkyl group may have 1 to 3 substituents at substitutable positions.
As such a substituent, for example,
Substituents exemplified as substituents in the aforementioned C _1-10 alkyl group and the like;
From halogen atoms (eg, fluorine, chlorine, bromine, iodine), carboxyl groups, C _1-6 alkoxy-carbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl), carbamoyl groups and C _1-6 alkoxy groups (eg, methoxy) A C _1-6 alkyl group _optionally substituted with 1 to 3 selected substituents (eg, methyl, ethyl);
Substituted with 1 to 3 substituents selected from a halogen atom (eg, fluorine, chlorine, bromine, iodine), a carboxyl group, a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) and a carbamoyl group An optionally substituted C _2-6 alkenyl group (eg, ethenyl, 1-propenyl);
A C _7-13 aralkyl group (eg, benzyl);
An oxo group;
Etc.

Examples of the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R ⁴ , R ⁵ or R ⁶ include an aromatic heterocyclic group and a non-aromatic heterocyclic group.
Examples of the aromatic heterocyclic group include a 5- to 7-membered monocyclic aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom. Groups and fused aromatic heterocyclic groups. Examples of the condensed aromatic heterocyclic group include a 5- to 7-membered monocyclic aromatic heterocyclic group, a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or one sulfur atom. And a group condensed with a 5-membered ring to be included.
Preferable examples of the aromatic heterocyclic group include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl ( Examples, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4- Pyrazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, oxazolyl Examples, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (eg, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (eg, 1,3,4-thiadiazole-2)
-Yl), triazolyl (eg, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3- Triazol-2-yl, 1,2,3-
Monocyclic aromatic heterocyclic groups such as triazol-4-yl) and tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl);
Quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg, 2-quinoxalyl), benzofuryl (eg, 2-benzofuryl, 3-benzofuryl) ), Benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzoxazolyl (eg, 2-benzoxazolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzothiadiazolyl (eg, benzothiazolyl) [1,2,5
] Thiadiazol-4-yl), benzimidazolyl (e.g., benzimidazol-1-yl, benzimidazol-2-yl), indolyl (e.g., indol-1-yl, indol-3-yl), indazolyl (e.g., 1H -Indazol-3-yl), pyrrolopyrazinyl (eg, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyrazin-6-yl), imidazopyridinyl ( Examples, 1H-imidazo [4,5-b] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl), imidazopyrazinyl (eg, 1H-imidazo [4,5- b] pyrazin-2-yl), and the like condensed aromatic heterocyclic group such as.

Examples of the non-aromatic heterocyclic group include a 5- to 7-membered monocyclic non-aromatic group containing 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom. Examples include heterocyclic groups and fused non-aromatic heterocyclic groups. Examples of the condensed non-aromatic heterocyclic group include these 5- to 7-membered monocyclic non-aromatic heterocyclic groups, 6-membered rings containing 1 to 2 nitrogen atoms, benzene rings, or 1 sulfur. And a group condensed with a 5-membered ring containing an atom. Non-aromatic heterocyclic groups include bridged cyclic groups.
Suitable examples of the non-aromatic heterocyclic group include pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (eg, piperidino), morpholinyl (eg, morpholino), thiomorpholinyl (eg, thiomorpholino). ), Piperazinyl (eg, 1-piperazinyl), hexamethyleneiminyl (eg, hexamethyleneimin-1-yl), oxazolidinyl (eg, oxazolidine-3-yl), thiazolidinyl (eg, thiazolidin-3-yl), imidazolidinyl (Eg, imidazolidin-3-yl), oxoimidazolidinyl (eg, 2-oxoimidazolidin-1-yl), dioxoimidazolidinyl (eg, 2,4-dioxoimidazolidin-3-yl) , Dioxooxazolidinyl (eg 2,4-dioxooxazolidin-3- 2,4-dioxooxazolidine-5-yl, 2,4-dioxooxazolidine-1-yl), dioxothiazolidinyl (eg 2,4-dioxothiazolidin-3-yl, 2, 4-dioxothiazolidin-5-yl), dioxoisoindolinyl (eg, 1,3-dioxoisoindolin-2-yl), oxooxadiazolidinyl (eg, 5-oxooxadiazolidine-3-yl) Yl), oxothiadiazolidinyl (eg, 5-oxothiadiazolidin-3-yl), oxopiperazinyl (eg, 3-oxopiperazin-1-yl), dioxopiperazinyl (eg, 2, 3-dioxopiperazin-1-yl, 2,5-dioxopiperazin-1-yl), oxodioxolyl (eg, 2-oxo-1,3-dioxol-4-yl), oxodioxolanyl Examples, 2-oxo-1,3-dioxolan-4-yl), 3-oxo-1,3-dihydro-2-benzofuranyl (eg, 3-oxo-1,3-dihydro-2-benzofuran-1-yl) ), Oxodihydrooxadiazolyl (eg, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl), oxodihydropyrazolyl (eg, 5-oxo-4,5-dihydro) -1H-pyrazol-3-yl), 4-oxo-2-thioxo-1,3-thiazolidin-5-yl, 4-oxo-2-thioxo-1,3-oxazolidine-5-yl, tetrahydropyranyl ( Example, 4-tetrahydropyranyl), 4-oxo-4,5,6,7-tetrahydro-1-benzofuranyl (eg, 4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-yl ), 1,3 (2H, 5H) -dioxotetrahydroimidazo [1,5-a] pyridinyl, 1,3 (2H, 5H) -dioxo-10,10a-dihydroimidazo [1,5-b] isoquinolinyl, Azabicyclooctyl (eg 1-A Zabicyclo [2.2.2] octane-2-yl, 1-azabicyclo [2.2.2] octane-3-yl) and the like.

Examples of the “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R ⁴ and R ⁵ together with the adjacent nitrogen atom include, for example, at least one nitrogen other than a carbon atom as a ring-constituting atom. Examples thereof include a 5- to 7-membered nitrogen-containing heterocyclic ring which contains an atom and may further contain 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Preferable examples of the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, oxopiperazine, homopiperidine, homopiperazine, thiazolidine, dihydroindole (eg, 2,3-dihydroindole ), Dihydroisoindole (eg, 1,3-dihydroisoindole), tetrahydroquinoline (eg, 1,2,3,4-tetrahydroquinoline), triazaspirodecanedione (eg, 1,3,8-triazaspiro [ 4.5] decane-2,4-dione), hexahydropyrazinooxazinone (eg, hexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one) and the like.
The nitrogen-containing heterocycle may have 1 to 3 (preferably 1 or 2) substituents at substitutable positions. Examples of such a substituent include a substituent in the C _3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ⁴ or R ^5. What was illustrated is mentioned.

Examples of the “optionally substituted hydroxy group” represented by R ⁵ include a hydroxy group which may be substituted with a hydrocarbon group.
Here, examples of the hydrocarbon group include those exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ⁴ , R ⁵ or R ⁶ .
The “optionally substituted hydroxy group” is preferably a hydroxy group, a C _1-6 alkoxy group (eg, methoxy, ethoxy) or the like.

R ⁴ and R ⁵ are the same or different and each is a hydrogen atom (only in the case of R ⁴ ), an optionally substituted C _1-10 alkyl group, and an optionally substituted C _3-10 cycloalkyl group. , An optionally substituted C _6-14 aryl group, an optionally substituted C _7-13 aralkyl group, an optionally substituted heterocyclic group and an optionally substituted hydroxy group (in the case of R ⁵ Only) is preferred. In particular,
(1) Hydrogen atom (only for R ⁴ );
(2) C _1-6 alkoxy - carbonyl group, C _1-6 alkoxy group and a Hajime Tamaki (e.g., 2-thienyl) to 1 selected from optionally substituted with 1-3 substituents C _1-10 An alkyl group (preferably methyl, ethyl);
(3) a C _3-10 cycloalkyl group (preferably indanyl, tetrahydronaphthyl) optionally condensed with a benzene ring;
(4) (4a) a halogen atom;
(4b) C _1-6 alkoxy - optionally substituted with a carbonyl group C _1-6 alkyl group;
(4c) a C _1-6 alkyl-carbonyl group;
(4d) a C _1-6 alkylsulfonyl group; and
(4e) a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
A C _6-14 aryl group (preferably phenyl) _optionally substituted by 1 to 3 substituents selected from:
(5) a C _7-13 aralkyl group (preferably benzyl) _optionally substituted with 1 to 3 C _1-6 alkylsulfonyl groups;
(6) a heterocycle optionally substituted by 1 to 3 substituents selected from a C _1-6 alkyl group, a C _6-14 aryl group, a C _7-13 aralkyl group and a C _1-6 alkoxy-carbonyl group A ring group (eg, pyridyl, isoxazolyl, pyrazolyl, thiadiazolyl, benzothiadiazolyl, oxodihydropyrazolyl, azabicyclooctyl, pyrrolidinyl); and
(7) C _1-6 alkoxy group (only for R ⁵ );
Is preferred.

Examples of the “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R ⁴ and R ⁵ together with the adjacent nitrogen atom include pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, homo Piperazine, thiazolidine, dihydroindole, dihydroisoindole, tetrahydroquinoline, triazaspirodecanedione, hexahydropyrazinooxazinone and the like are preferable.
As substituents of these nitrogen-containing heterocycles,
(1) a carbamoyl group;
(2) a C _1-6 alkyl-carbonyl group;
(3) a C _1-6 alkoxy-carbonyl group;
(4) a C _1-6 alkylsulfonyl group;
(5) C _1-6 alkoxy group and a C _1-6 alkoxy - 1 selected from carbonyl groups to three optionally substituted with a substituent C _1-6 alkyl group;
(6) non-aromatic heterocyclic group (eg, pyrrolidinyl);
(7) an amino group which may be mono- or di-substituted with a C _1-6 alkyl-carbonyl group;
(8) Halogen atoms (eg, fluorine, chlorine, bromine, iodine);
Is preferred.

R ⁶ is preferably a hydrogen atom or an optionally substituted C _1-10 alkyl group. Examples of the substituent for the C _1-10 alkyl group include a non-aromatic heterocyclic group (eg, oxodioxolyl) which may be substituted with a C _1-6 alkyl group. R ⁶ is particularly preferably a hydrogen atom.

Preferable examples of compound (I) include the following compounds.
[Compound A]
R ¹ is a C _3-6 alkyl group (preferably isobutyl, neopentyl);
R ² is a C _2-6 alkyl group (preferably ethyl, isobutyl);
R ³ is a C _1-6 alkyl group (preferably methyl);
X is -OR ⁶ or -NR ⁴ R ⁵ ,
R ⁶ is a hydrogen atom, and C _1-6 alkyl which may be have a non-aromatic Hajime Tamaki substituted with a group (e.g., oxo-benzodioxolyl) C _1-10 optionally substituted alkyl group;
R ⁴ and R ⁵ are the same or different,
(1) Hydrogen atom (only for R ⁴ );
(2) C _1-6 alkoxy-carbonyl group, C _1-6 alkoxy group and heterocyclic group (preferably 2-
A C _1-10 alkyl group (preferably methyl, ethyl) _optionally substituted by 1 to 3 substituents selected from thienyl);
(3) a C _3-10 cycloalkyl group (preferably indanyl, tetrahydronaphthyl) which may be condensed with a benzene ring;
(4) (4a) a halogen atom;
(4b) C _1-6 alkoxy - optionally substituted with a carbonyl group C _1-6 alkyl group;
(4c) a C _1-6 alkyl-carbonyl group;
(4d) a C _1-6 alkylsulfonyl group; and
(4e) a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine);
A C _6-14 aryl group (preferably phenyl) _optionally substituted with 1 to 3 substituents selected from:
(5) a C _7-13 aralkyl group (preferably benzyl) _optionally substituted with 1 to 3 C _1-6 alkylsulfonyl groups;
(6) a heterocycle optionally substituted by 1 to 3 substituents selected from a C _1-6 alkyl group, a C _6-14 aryl group, a C _7-13 aralkyl group and a C _1-6 alkoxy-carbonyl group A ring group (eg, pyridyl, isoxazolyl, pyrazolyl, thiadiazolyl, benzothiadiazolyl, oxodihydropyrazolyl, azabicyclooctyl, pyrrolidinyl); or
(7) C _1-6 alkoxy group (only for R ⁵ );
Or
R ⁴ and R ⁵ together with the adjacent nitrogen atom
(1) a carbamoyl group;
(2) a C _1-6 alkyl-carbonyl group;
(3) a C _1-6 alkoxy-carbonyl group;
(4) a C _1-6 alkylsulfonyl group;
(5) C _1-6 alkoxy group and a C _1-6 alkoxy - 1 selected from carbonyl groups to three optionally substituted with a substituent C _1-6 alkyl group;
(6) non-aromatic heterocyclic group (eg, pyrrolidinyl);
(7) an amino group optionally mono- or disubstituted with a C _1-6 alkyl-carbonyl group; and
(8) Halogen atoms (eg, fluorine, chlorine, bromine, iodine);
A nitrogen-containing heterocyclic ring optionally substituted with 1 to 3 substituents selected from (preferably pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, homopiperazine, thiazolidine, dihydroindole, dihydroisoindole, tetrahydroquinoline, Triazaspirodecanedione, hexahydropyrazinoxazinone);
Compound.
[Compound B]
Of the above [Compound A], a compound wherein X is —OH.
[Compound C]
[5- (aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (Example 1);
[5- (Aminomethyl) -2,6-diisobutyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid
(Example 2);
[5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (Example 4);
1-{[5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetyl} -L-prolinamide (Example 6);
Or its salt.

The salt of compound (I) is preferably a pharmacologically acceptable salt. Examples of such a salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and an organic acid. And salts with basic or acidic amino acids.
Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
Preferable examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid , Salts with p-toluenesulfonic acid and the like.
Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
Among the above-mentioned salts, salts with inorganic acids and organic acids are preferable, and hydrochlorides, trifluoroacetates and the like are more preferable.

A prodrug of compound (I) is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (I) upon hydrolysis by gastric acid or the like. Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated and phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound); compound Compounds in which the hydroxyl group of (I) is acylated, alkylated, phosphorylated, borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated , Dimethylaminomethylcarbonylated compound); the carboxyl group of compound (I) is esterified or amidated. (Eg, the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl Esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compound) and the like. These compounds can be produced from compound (I) by a method known per se.
In addition, the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.
Compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).
Furthermore, compound (I) may be an anhydride or a hydrate.

Compound (I) or a prodrug thereof [hereinafter sometimes abbreviated as the compound of the present invention. ] Can be used as a pharmaceutical composition with low toxicity, as it is, or mixed with a pharmacologically acceptable carrier or the like to give a mammal (eg, human, mouse, rat, rabbit, dog, cat, cow, For horses, pigs, monkeys), it can be used as a preventive or therapeutic agent for various diseases described below.
Here, as the pharmacologically acceptable carrier, various conventional organic or inorganic carrier materials are used as the formulation material, and excipients, lubricants, binders, disintegrants in solid formulations; solvents in liquid formulations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
Preferable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate and the like can be mentioned.
Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Preferable examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.
Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, light anhydrous silicic acid, low substituted hydroxypropylcellulose and the like.

Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
Preferable examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Etc.
Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone , Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.
Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate and citrate.
Preferable examples of the soothing agent include benzyl alcohol.
Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Preferable examples of the antioxidant include sulfite and ascorbate.
Suitable examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, and edible blue Nos. 1 and 2), water-insoluble lake dyes (E.g., aluminum salt of the water-soluble edible tar dye), natural dyes (e.g., [beta] -carotene, chlorophyll, bengara) and the like.
Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.

Examples of the dosage form of the pharmaceutical composition include tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, troches, syrups, emulsions, Oral preparations such as suspensions; and injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, infusions), external preparations (eg, transdermal preparations, ointments), Examples include suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), ophthalmic preparations and the like, and these are safe orally or parenterally. Can be administered.
These preparations may be controlled-release preparations such as immediate-release preparations or sustained-release preparations (eg, sustained-release microcapsules).
The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.

If necessary, the oral preparation may be coated with a coating base for the purpose of taste masking, enteric property or durability.
Examples of the coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base and the like.
As the sugar coating base, sucrose is used, and one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) Synthetic polymers such as polyvinyl pyrrolidone; polysaccharides such as pullulan.
Examples of enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) , Rohm Pharma Co., Ltd.], acrylic polymer such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.], methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co., Ltd.] A natural product such as shellac.
Examples of the sustained-release film coating base include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Rohm Pharma Co., Ltd.], ethyl acrylate-methyl methacrylate copolymer suspension Acrylic polymers such as turbid liquid [Eudragit NE (trade name), Rohm Pharma Co., Ltd.] can be used.
Two or more of the coating bases described above may be mixed and used at an appropriate ratio. Moreover, you may use light-shielding agents, such as a titanium oxide, ferric oxide, etc. in the case of coating, for example.

The compound of the present invention has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), few side effects, and mammals (eg, humans, cows, horses, dogs, cats, It can be used as a preventive or therapeutic agent for various diseases or a diagnostic agent for monkeys, mice, rats;
The compound of the present invention has an excellent peptidase inhibitory action and can suppress degradation of physiologically active substances such as peptide hormones, cytokines, and neurotransmitters by peptidases.
Examples of the peptide hormone include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), GIP, growth hormone releasing hormone (GHRH) and the like.
Examples of cytokines include chemokines such as RANTES.
Examples of neurotransmitters include neuropeptide Y.

As peptidases, for example, EC 3.4.11.1 (Leucyl aminopeptidase), EC 3.4.11.2 (Membrane alanine aminopeptidase), EC 3.4.11.3 (Cystinyl aminopeptidase), EC 3.4. 11.4 (Tripeptide aminopeptidase), EC 3.4.11.5 (Prolyl aminopeptidase), EC 3.4.11.6 (Aminopeptidase B), EC 3.4.11.7
(Glutamyl aminopeptidase), EC 3.4.11.9 (Xaa-Pro aminopeptidase), EC 3.4.11.10 (Bacterial leucyl aminopeptidase), EC 3.4.11.13 (Clostridial aminopeptidase), EC 3.4.11.14 (Cytosol alanyl aminopeptidase), EC 3.4.11.15 ( Lysyl aminopeptidase), EC 3.4.11.16 (Xaa-Trp aminopeptidase), EC 3.4.11.17 (Tryptophanyl aminopeptidase), EC 3.4.11.18 (Methionyl aminopeptidase), EC 3.4.11.19 (D-stereospecific aminopeptidase), EC 3.4.11.20 (Aminopeptidase) Ey), EC 3.4.11.21 (Aspartyl aminopeptidase), EC 3.4.11.22 (Aminopeptidase I), EC 3.4.13.3 (Xaa-His dipeptidase), EC 3.4.13.4 (Xaa-Arg dipeptidase), EC 3.4.13.5 (Xaa- methyl-His dipeptidase), EC 3.4.13.7 (Glu-Glu dipeptidase), EC 3.4.13.9 (Xaa-Pro dipeptidase), EC 3.4.13.12 (Met-Xaa dipeptidase), EC 3.4.13.17 (Non-stereospecific dipeptidase), EC 3.4.13.18 (Cytosol nonspecific dipeptidase), EC 3.4.13.19 (Membrane dipeptidase), EC 3.4.13.20 (Beta-Ala-His dipeptidase), EC 3.4.14.1 (Dipeptidyl-peptidase I), EC 3.4.14.2 (Dipeptidyl- pepti dase II), EC 3.4.14.4 (Dipeptidyl-peptidase III), EC 3.4.14.5 (Dipeptidyl-peptidase IV), EC 3.4.14.6 (Dipeptidyl-dipeptidase), EC 3.4.14.9 (Tripeptidyl-peptidase I), EC 3.4. 14.10 (Tripeptidyl-peptidase II), EC 3.4.14.11 (Xaa-Pro dipeptidyl-peptidase) and the like. Examples of peptidases include FAPα, DPP8, DPP9 and the like.
Among these, EC 3.4.14.1, EC 3.4.14.2, EC 3.4.14.4, EC 3.4.14.5, EC 3.4.14.6, EC 3.4.14.9, EC 3.4.14.10, EC 3.4.14.11 are preferable, especially EC 3.4. .14.5 (Dipeptidyl-peptidase IV) is preferred.
The compound of the present invention may have a glucagon antagonistic action or a CETP (Cholesterylester transfer protein) inhibitory action in addition to the peptidase inhibitory action. When the compound of the present invention has both of these actions, the compound of the present invention is diabetic (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, slowly progressive insulin dependent diabetes mellitus
(SPIDDM), LADA (Latent Autoimmune Diabetes in Adults), insulin secretion deficiency diabetes, obesity diabetes) and hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, postprandial hyperlipidemia) It is more effective as a preventive / therapeutic agent.

The compound of the present invention is a prophylactic / therapeutic agent for diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, slowly progressive insulin dependent diabetes mellitus (SPIDDM), LADA (Latent Autoimmune Diabetes in Adults); Prevention, treatment of hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, postprandial hyperlipidemia); prevention and treatment of arteriosclerosis; prevention of glucose tolerance [IGT (Impaired Glucose Tolerance)] It can be used as a therapeutic agent; an insulin secretagogue; and a transition inhibitor from impaired glucose tolerance to diabetes.
As for the criteria for determining diabetes, criteria for judgment have been reported by the Japan Diabetes Society, ADA (American Diabetes Association) and WHO.
According to this report, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dL or more, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dL or more. This is a state in which the blood glucose level (glucose concentration in venous plasma) at any time indicates 200 mg / dL or more. In addition, the above-mentioned diabetes does not apply, and “a fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dL or a 75 g oral glucose tolerance test (75 gOGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / A state that is not “a state indicating less than dL” (normal type) is referred to as a “boundary type”.

According to the above report, glucose intolerance is a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg / dL, and a 75-g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma). Is a state showing 140 mg / dL or more and less than 200 mg / dL. Furthermore, according to ADA reports, a state in which fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dL or more and less than 126 mg / dL is called IFG (Impaired Fasting Glucose). On the other hand, according to the report of WHO, the IFG (Impaired Fasting Glucose) is a state where the 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dL as IFG (Impaired Fasting Glycemia). Call.
The compound of the present invention is also used as a prophylactic / therapeutic agent for diabetes, borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above criteria. Furthermore, the compound of the present invention can also prevent progression from borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.

The compound of the present invention can be used, for example, for diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infection (eg, respiratory infection, Urinary tract infection, digestive organ infection, skin soft tissue infection, leg infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorder, peripheral blood circulation disorder], obesity, osteoporosis, cachexia (E.g., cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine cachexia, infectious cachexia or acquired immunodeficiency syndrome), fatty liver, High blood pressure, polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease), muscular dystrophy, myocardial infarction, angina, brain Vascular disorders (eg, cerebral infarction, stroke), Alzha Mer's disease, Parkinson's disease, anxiety, dementia, schizophrenia, insulin resistance syndrome, syndrome X, metabolic syndrome, hyperinsulinemia, hyperinsulinemia, sensory impairment, tumor (eg leukemia, breast cancer, prostate cancer) , Skin cancer), irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (eg, rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, inflammation after surgery or trauma, swelling, neuralgia, throat Headache, cystitis, hepatitis (including non-alcoholic steatohepatitis), pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), ulcerative colitis, gastric mucosal damage (caused by aspirin) Gastric mucosal damage)), small intestinal mucosal damage, malabsorption, testicular dysfunction, visceral obesity syndrome and the like.
The compound of the present invention reduces visceral fat, suppresses visceral fat accumulation, improves glucose metabolism, improves lipid metabolism, suppresses oxidized LDL production, improves lipoprotein metabolism, improves coronary artery metabolism, prevents or treats cardiovascular complications, complications of heart failure Prevention or treatment, reduction of blood remnants, prevention or treatment of anovulation, prevention or treatment of hirsutism, prevention and treatment of hyperandrogenemia, improvement of pancreatic (β cell) function, pancreatic (β cell) regeneration, pancreas (Β cells) It is also used for promoting regeneration and regulating appetite.
The compound of the present invention is also used for secondary prevention and suppression of progression of the various diseases described above (eg, cardiovascular events such as myocardial infarction).

  The compound of the present invention selectively promotes insulin secretion in hyperglycemic patients (for example, patients with a fasting blood glucose level of 126 mg / dL or higher or a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value of 140 mg / dL or higher). It is a glucose-dependent insulin secretagogue that exerts its action. Therefore, the compound of the present invention is useful as a safe prophylactic / therapeutic agent for diabetes with low risk of vascular complications and hypoglycemia induction, which are harmful effects of insulin.

The compound of the present invention is also useful as a therapeutic agent for sulfonylurea secondary ineffective diabetes. Even in a diabetic patient who cannot obtain an insulin secretion effect with a sulfonylurea compound or a fast-acting insulin secretagogue, and therefore cannot obtain a sufficient blood glucose lowering effect. Excellent insulin secretion effect and blood glucose lowering effect.
Here, examples of the sulfonylurea compound include a compound having a sulfonylurea skeleton or a derivative thereof such as tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, and glybazole.
In addition, as a fast-acting insulin secretagogue, a compound that does not have a sulfonylurea skeleton but promotes insulin secretion from pancreatic β cells in the same manner as the sulfonylurea compound, such as repaglinide, senaglinide, nateglinide, mitiglinide or a calcium salt hydrate thereof And the like.

  The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, and the like. For example, when administered orally to an adult diabetic patient, the dose is usually about 0.01 to 100 mg / kg body weight. It is preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, and it is desirable to administer this amount once to three times a day.

The compound of the present invention comprises a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent, an osteoporosis therapeutic agent, It can be used in combination with a drug (hereinafter abbreviated as a concomitant drug) such as a dementia agent, an erectile dysfunction improving agent, a urinary incontinence / frequent urination therapeutic agent, or a dysuria therapeutic agent. In this case, the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the administration subject, or may be administered with a time difference. Further, the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

Examples of the therapeutic agent for diabetes include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using E. coli or yeast; insulin zinc; protamine insulin zinc; insulin Fragments or derivatives (eg, INS-1), oral insulin preparations), insulin resistance improvers (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), reglixan (Reglixane) (JTT-501), GI-262570, Netoglitazone (MCC-555), DRF-2593, KRP-297, R-119702, Riboglitazone (CS-011), FK-614 , Compounds described in WO99 / 58510 (for example (E) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid), WO01 / 38325 A compound according tesaglitazar (Tesaglitazar) (AZ-242), Ragaguritazaru (Rag
aglitazar (NN-622), Muraglitazar (BMS-298585), ONO-5816
, Edaglitazone (BM-13-1258), LM-4156, MBX-102, Naveglitazar (LY-519818), MX-6054, LY-510929, Balaglitazone (NN-2344) , T-131 or a salt thereof, THR-0921), PPARγ agonist, PPARγ antagonist, PPARγ / α dual agonist, α-glucosidase inhibitor (eg, voglibose, acarbose, miglitol, emiglitate), biguanide agent (eg, phenformin, Metformin, buformin or their salts (eg, hydrochloride, fumarate, succinate)), insulin secretagogues [sulfonylurea (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glycine Clopyramide, glimepiride, glipizide, glybsol), repaglinide, senaglinide, nate Linide, mitiglinide or its calcium salt hydrate], GPR40 agonist, GLP-1 receptor agonist [eg, GLP-1, GLP-1MR agent, Liraglutide (NN-2211), Exenatide (AC-2993) Exendin-4) and exenatide LAR, BIM-51077, Aib (8,35) hGLP-1 (7,37) NH2, CJC-1131], amylin agonist (eg, pramlintide), phospho Tyrosine phosphatase inhibitors (eg, sodium vanadate), dipeptidyl peptidase IV inhibitors (eg, NVP-DPP-728, PT-100, P32 / 98, Vidagliptin (LAF-237), P93 / 01, TS -021, Sitagliptin (MK-0431), Saxagliptin (BMS-477118), T-6666), β3 agonists (eg, AJ-9677, AZ40140), gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibition) Agent, glucose-6-phosphatase inhibitor, glucagon Antagonists), SGLT (sodium-glucose cotransporter) inhibitors (eg, T-1095), 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498), adiponectin or agonists thereof, IKK inhibitors (eg, AS- 2868), leptin resistance improving drug, somatostatin receptor agonist (compound described in WO01 / 25228, WO03 / 42204, WO98 / 44921, WO98 / 45285, WO99 / 22735), glucokinase activator (eg, Ro- 28-1675).

Diabetes complications include aldose reductase inhibitors (eg, torrestat, epalrestat, zenarestat, zopolrestat, minarerestat, fidarestat (SNK-860), CT-112, ranirestat), neurotrophic factor and its Increaser (eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (for example, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl)- 5- [3- (2-methylphenoxy) propyl] oxazole)), nerve regeneration promoter (eg, Y-128), PKC inhibitor (eg, ruboxistaurin mesylate (LY-333531)), AGE inhibitors (eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226, pyridrin (Pyridorin), pyridoxa ), Active oxygen scavengers (eg, thioctic acid), cerebral vasodilators (eg, thiaprid, mexiletine), somatostatin receptor agonists (eg, BIM23190), inhibition of apoptosis signal regulating kinase-1 (ASK-1) Medicines.
Antihyperlipidemic agents include statins that are HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or salts thereof (eg, sodium salt, calcium salt) )), Squalene synthase inhibitors (eg, compounds described in WO97 / 10224, such as N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro- 5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds (Eg, bezafibrate, clofibrate, simfibrate, clinofibrate), ACAT inhibitors (eg, Avasimibe,
Eflucimibe), anion exchange resin (eg, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol, niceritrol),
Examples include ethyl icosapentate, plant sterols (eg, soysterol, gamma-oryzanol) and the like.

Antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril), angiotensin II receptor antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, 1-[[2 '-(2,5-Dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-1H-benzimidazole-7-carvone Acid), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channel openers (eg, lebucromakalim, L-27152, AL 0671, NIP-121), clonidine and the like.
Anti-obesity agents include, for example, central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonist (Eg, SB-568849; SNAP-7941; compounds described in WO01 / 82925 and WO01 / 87834); neuropeptide Y antagonist (eg, CP-422935); cannabinoid receptor antagonist (eg, SR-141716, SR -147778); ghrelin antagonist; 11β-hydroxysteroid dehydrogenase inhibitor (eg, BVT-3498)), pancreatic lipase inhibitor (eg, orlistat, ATL-962), β3 agonist (eg, AJ-9677, AZ40140), Peptide appetite suppressants (eg, leptin, CNTF (ciliary neurotrophic factor)
), Cholecystokinin agonist (eg, Lynchtripto, FPL-15849), antifeedant (eg, P-57), GPR40 antagonist and the like.

Examples of the diuretic include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide. , Methiclotiazide), anti-aldosterone preparations (eg, spironolactone, triamterene), carbonic anhydrase inhibitors (eg, acetazolamide), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide), azosemide, isosorbide, ethacrynic acid, Piretanide, bumetanide, furosemide and the like can be mentioned.
Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg, methotrexate, 5-fluorouracil or derivatives thereof), anticancer antibiotics (eg, mitomycin, adriamycin). Plant-derived anticancer agents (eg, vincristine, vindesine, taxol), cisplatin, carboplatin, etoposide and the like. Of these, 5-fluorouracil derivatives such as furuluron or neofluturon are preferable.
Examples of immunotherapeutic agents include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin), and cytokines obtained by genetic engineering techniques (eg, , Interferon, interleukin (IL)), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin) and the like, and interleukins such as IL-1, IL-2 and IL-12 are particularly preferable.

Antithrombotic agents include, for example, heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, aragatroban), thrombolytic agent (Eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamitepase), platelet aggregation inhibitors (eg, ticlopidine hydrochloride, cilostazol ( cilostazol), ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like.
Examples of the osteoporosis therapeutic agent include alfacalcidol, calcitriol, elcatonin, salmon calcitonin.
salmon), estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, risedronate disodium ( risedronate disodium).
Examples of the anti-dementia agent include tacrine, donepezil, rivastigmine, galanthamine and the like.
Examples of the erectile dysfunction ameliorating agent include apomorphine, sildenafil citrate, and the like.
Examples of the urinary incontinence / frequent urination therapeutic agent include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.
Examples of the dysuria therapeutic agent include acetylcholinesterase inhibitors (eg, distigmine).

  In addition, drugs that have been shown to improve cachexia in animal models and clinically: cyclooxygenase inhibitors (eg, indomethacin), progesterone derivatives (eg, megestrol acetate), carbohydrate steroids (eg, dexamethasone), metoclopramide Drugs, tetrahydrocannabinols, fat metabolism improvers (eg, eicosapentaenoic acid), growth hormone, IGF-1, or cachexia-inducing factors TNF-α, LIF, IL-6, oncostatin An antibody against M can also be used in combination with the compound of the present invention.

The combination drug is preferably an insulin preparation, an insulin resistance improving agent, an α-glucosidase inhibitor, a biguanide agent, an insulin secretagogue (preferably a sulfonylurea agent) and the like.
Two or more of the above concomitant drugs may be used in combination at an appropriate ratio. As a preferable combination in the case of using two or more kinds of concomitant drugs, for example, the following combinations may be mentioned.
1) an insulin secretagogue (preferably a sulfonylurea) and an α-glucosidase inhibitor;
2) Insulin secretion promoter (preferably sulfonylurea) and biguanide agent;
3) Insulin secretion promoter (preferably sulfonylurea), biguanide and α-glucosidase inhibitor;
4) Insulin resistance improving agent and α-glucosidase inhibitor;
5) Insulin resistance improving agent and biguanide agent;
6) Insulin resistance improving agent, biguanide agent and α-glucosidase inhibitor.
By using the compound of the present invention and a concomitant drug in combination,
(1) Compared with the case where the compound of the present invention or the concomitant drug is administered alone, the dose of the compound of the present invention and / or the concomitant drug can be reduced.
(2) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the therapeutic effect can be sustained.
(3) By using the compound of the present invention and a concomitant drug in combination, excellent effects such as a synergistic effect can be obtained.
When the compound of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of those agents. In particular, the insulin resistance improving agent, insulin secretagogue (preferably sulfonylurea) and biguanide can be reduced from the usual dose. Thus, the adverse effects that would be caused by these agents can be safely prevented. In addition, the dosage of antidiabetic complications, antihyperlipidemic agents, and antihypertensive agents can be reduced, thereby effectively preventing the adverse effects that would be caused by these agents.

Hereafter, the manufacturing method of this invention compound is demonstrated.
The compound of the present invention can be produced according to a method known per se, for example, the method described in detail below or a method analogous thereto.
Incidentally, the compounds 1 to 14 in the following formula, also included when forming a salt, as such salts, those similar to the salts of compound (I).
The compound obtained in each step in the following formula can be used in the next reaction as the reaction solution or as a crude product, but is known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, It can be easily isolated and purified from the reaction solution by crystallization, recrystallization, transfer dissolution, chromatography or the like.
Moreover, when the compound in the following formula | equation is marketed, a commercial item can also be used as it is.
In each of the following reactions, when the raw material compound has an amino group, a carboxyl group or a hydroxyl group as a substituent, these groups may be protected with a protecting group generally used in peptide chemistry or the like. . In this case, the target compound can be obtained by removing the protecting group as necessary after the reaction.
In the present specification, examples of the protecting group for the amino group include a formyl group, a C _1-6 alkyl-carbonyl group, a C _1-6 alkoxy-carbonyl group, a benzoyl group, a C _7-10 aralkyl-carbonyl group (eg, Benzylcarbonyl), C _7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted silyl group (eg, Trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C _2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkoxy group and a nitro group.
Examples of the protecting group for the carboxyl group include a C _1-6 alkyl group, a C _7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C _2-6 alkenyl groups (eg, 1-allyl) and the like.
Examples of the hydroxyl protecting group include a C _1-6 alkyl group, a phenyl group, a trityl group, a C _7-10 aralkyl group (eg, benzyl), a formyl group, a C _1-6 alkyl-carbonyl group, a benzoyl group, C _7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert- Butyldiethylsilyl), C _2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a nitro group.
Examples of the method for removing the protecting group include methods known per se, such as those described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980). Specifically, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilyl iodide, trimethylsilyl bromide, etc.) The method used, the reduction method, etc. are used.

In formula (I), compound (Ia) in which X is a hydroxyl group can be produced by the following scheme 1 or a method analogous thereto.

[The symbols in the formula are as defined above. ]
The amino-protecting group represented by P is preferably a C _1-6 alkoxy-carbonyl group (preferably a Boc (tert-butoxycarbonyl) group) or a C _7-14 aralkyloxy-carbonyl group (preferably Cbz (Benzyloxycarbonyl) group, Fmoc (9-fluorenylmethoxycarbonyl) group) and the like.
In this method, compound (Ia) is produced by hydrolyzing the cyano group of compound 1 and simultaneously or subsequently removing the protecting group for the amino group.
The hydrolysis reaction can usually be performed in the presence of an acid or a base.
Examples of the acid include mineral acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid), carboxylic acids (eg, formic acid, acetic acid, propionic acid), and the like. Of these, hydrochloric acid, sulfuric acid and the like are preferable.
Examples of the base include alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate; alkaline earth metals such as calcium hydroxide and barium hydroxide Salts; amines such as trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine; and the like. Of these, potassium hydroxide, sodium hydroxide and the like are preferable.
The amount of acid or base to be used is generally 0.01-100 mol, preferably 0.1-50 mol, per 1 mol of compound 1 .
The hydrolysis reaction is usually performed in a solvent that does not adversely influence the reaction. Examples of such solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and tert-butanol; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatics such as hexane and heptane Hydrocarbons; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and dimethoxyethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide Kind; water etc. are mentioned. These solvents may be used by mixing two or more kinds at an appropriate ratio.
The reaction temperature is usually 0 to 150 ° C, preferably 10 to 100 ° C.
While the reaction time varies depending on the acid-base reagent and solvent to be used, it is generally 0.1 to 100 hours, preferably 0.1 to 10 hours.
Removal of the amino-protecting group is carried out according to a method known per se.

In Scheme 1, compound 1 to be used as a starting compound can be prepared by a method analogous to the following Scheme 2 or it.

[Wherein R ⁷ is an optionally substituted C _1-10 alkyl group, L is a leaving group (eg, a substituted sulfonyloxy group (eg, methanesulfonyloxy group, p-toluenesulfonyloxy group), A halogen atom (for example, chlorine, bromine)) and other symbols are as defined above. ]
As good C _1-10 alkyl group optionally substituted represented by R ^7, include those exemplified as the R ^6.

Compound 1 can be produced, for example, by cyanating compound 11 using a cyanating agent. Examples of the cyanating agent used here include general cyanating agents such as potassium cyanide and trimethylsilanecarbonitrile (TMSCN). When potassium cyanide is used as the cyanating agent, the reaction efficiency can be improved by adding tetrabutylammonium bromide or the like, and when using trimethylsilanecarbonitrile, the reaction efficiency can be improved by adding tetrabutylammonium fluoride (TBAF). Can do.

Compound 11 can be produced, for example, by converting the hydroxyl group of compound 10 to a leaving group. Such conversion to a leaving group is carried out according to a conventional method, for example, by reacting with methanesulfonyl chloride in the presence of an appropriate base, or by reacting with thionyl chloride in the presence of an appropriate base. be able to. Suitable bases used for conversion to the leaving group include, for example, N, N-diisopropylethylamine (DIEA), triethylamine (TEA), pyridine, N, N-dimethylaniline and the like.
Compound 10 can be produced, for example, by protecting the amino group of compound 9 . The amino group is protected according to a method known per se.

Compound 9 , for example, subjectes compound 8 to a reduction reaction to convert the cyano group as the 5-position substituent and the substituted oxycarbonyl group as the 3-position substituent of compound 8 into an aminomethyl group and a hydroxymethyl group, respectively. Can be manufactured. The reduction reaction of the cyano group and the reduction reaction of the substituted oxycarbonyl group may be carried out sequentially or simultaneously. When the reduction reaction is carried out sequentially, it may be carried out from any of the reduction reactions. If necessary, an intermediate obtained at the end of one reduction reaction is isolated and purified, and then the intermediate is converted into the other. It may be subjected to the reduction reaction. Such a reduction reaction is performed according to a conventional method in the presence of a reducing agent in a solvent that does not adversely influence the reaction.
Examples of the reducing agent include metal hydride compounds such as sodium bis (2-methoxyethoxy) aluminum hydride and diisobutylaluminum hydride (DIBALH); sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, hydrogenation Metal hydrogen complex compounds such as aluminum sodium; and the like.
The amount of the reducing agent to be used is generally 0.1 to 20 mol with respect to 1 mol of compound 8 .
Examples of the solvent that does not adversely influence the reaction include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and tert-butanol; aromatic hydrocarbons such as benzene, toluene and xylene; hexane, heptane and the like Aliphatic ethers; diethyl ether, diisopropyl ether, tert-butyl methyl ether, ethers such as tetrahydrofuran, dioxane, dimethoxyethane; esters such as methyl acetate, ethyl acetate, n-butyl acetate, tert-butyl acetate; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone are used. These solvents may be used by mixing two or more kinds at an appropriate ratio.
The reaction temperature is generally −70 to 150 ° C., preferably −20 to 100 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 40 hours.
In addition, the reduction reaction of the cyano group does not adversely affect the reaction in the presence of a metal catalyst such as palladium-carbon, palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt, and a hydrogen source. It can also be carried out in a solvent.
The usage-amount of a metal catalyst is 0.001-1000 mol normally with respect to 1 mol of compound 8 , Preferably it is 0.01-100 mol.
Examples of the hydrogen source include hydrogen gas, formic acid, amine formate, phosphinate, hydrazine, and the like. Examples of the solvent that does not adversely influence the reaction include methanol, tetrahydrofuran, N, N-dimethylacetamide and the like.
This reaction may be performed in the presence of ammonia (eg, aqueous ammonia, ammonia-methanol) as necessary. By carrying out the reaction in the presence of ammonia, side reactions are suppressed and compound 9 can be produced in high yield.

Compound 8 can be produced, for example, by oxidizing compound 7 . Such an oxidation reaction is performed according to a conventional method in the presence of an oxidizing agent (for example, dilute nitric acid, ceric ammonium cerium nitrate (CAN)) in a solvent that does not adversely influence the reaction (for example, dioxane, acetone). .

Compound 7 is a method known per se, such as Hanzch's pyridine synthesis method described in Maruzen Publishing Co., Ltd., 1973 "New Experimental Chemistry Course (Edited by The Chemical Society of Japan), Vol. For example, it can be produced from compound 4 and compound 6 .
Compound 4 can be produced by a method known per se, for example, by subjecting compound 2 and compound 3 to a known Knoevenagel condensation.
Compound 6 is prepared by a method known per se, for example, the method described in Synthesis, (1999), 11, 1951-1960; Journal of Chemical Society Perkin Transactions 1, (2002), 1663-1671, etc. According to an equivalent method, it can be produced by reacting compound 5 with ammonia or ammonium salt.
The aforementioned compound 2 , compound 3 and compound 5 can be produced according to a method known per se.

In the formula (I), the compound (Ib) in which X is —OR ⁸ [R ⁸ represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted] is represented by the following scheme 3 Or it can manufacture by the method according to this.
The optionally substituted hydrocarbon group and optionally substituted heterocyclic group represented by R ^8, those exemplified respectively as the R ^6.

[In the formula, Dox represents a (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group, and other symbols are as defined above. ]
In this method, compound (Ib) is produced by esterifying compound 12 and removing the amino-protecting group simultaneously or successively as necessary.
Examples of esterification include per se known methods, for example, esterification with alcohol (R ⁸ —OH), esterification with O-alkylating agent (R ⁸ -L), and the like.
The esterification reaction with alcohols is performed by reacting compound 12 with alcohol in the presence of an acid catalyst or a dehydrating agent according to a conventional method. This reaction is usually carried out in a solvent that does not adversely influence the reaction, but the alcohol itself may be used as a solvent.
Examples of the acid catalyst include acids usually used as an acid catalyst in a condensation reaction, such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and boron fluoride etherate.
The amount of the acid catalyst to be used is preferably about 0.05 to about 50 mol per 1 mol of compound 12 .
Examples of the dehydrating agent include a reagent that activates the compound 12 (for example, dicyclohexylcarbodiimide (DCC), trifluoroacetic anhydride) and a reagent that activates alcohols (for example, an organic phosphorus compound (for example, triphenylphosphine)). And an electronic agent (for example, a combination with diethyl azodicarboxylate).
The amount of the dehydrating agent to be used is preferably about 1 to about 50 mol per 1 mol of compound 12 .
Examples of the solvent that does not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N -Amides such as dimethylformamide (DMF); and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is usually −30 ° C. to 150 ° C.
The reaction time is usually 0.5 to 20 hours.

The esterification reaction with an O-alkylating agent is performed according to a conventional method, for example, in the presence of a base, using an O-alkylating agent in a solvent that does not adversely influence the reaction.
Examples of such bases include bases usually used for O-alkylation of carboxyl groups, for example, amines such as triethylamine, N-methylmorpholine, N, N-dimethylaniline; sodium hydrogen carbonate, sodium carbonate, potassium carbonate, etc. And alkali metal salts of the above.
The amount of the O-alkylating agent and the base to be used is preferably about 1 to about 50 mol per 1 mol of compound 12 .
Examples of the solvent that does not adversely influence the reaction include ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N-dimethylformamide Amides such as sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.
The reaction temperature is usually −30 ° C. to 100 ° C.
The reaction time is usually 0.5 to 20 hours.
Removal of the amino-protecting group is carried out according to a method known per se.

In formula (I), compound (Ic) wherein X is —NR ⁴ R ⁵ can be produced by the following scheme 4 or a method analogous thereto.

[Each symbol in the formula is as defined above. ]
In this method, after condensing compound 12 and compound 13 , compound (Ic) is produced by removing the amino-protecting group.
The condensation reaction is performed according to a conventional method, for example, according to a general peptide coupling method. Examples of such a method include a method in which compound 12 and compound 13 are directly condensed using a condensing agent, or a method in which a reactive derivative of compound 12 and compound 13 are reacted.
Examples of the condensing agent include carbodiimide condensing reagents such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and hydrochloride thereof; diethyl cyanophosphate; Phosphoric acid condensation reagents such as diphenylphosphoryl azide; carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium tetrafluoroborate, hexafluorophosphoric acid O- (7-azabenzotriazol-1-yl) -1 1,3,3-tetramethyluronium (HATU) and the like.
Examples of the solvent used in the reaction using a condensing agent include amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; halogens such as chloroform and dichloromethane. Hydrocarbons; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane, diethyl ether and dimethoxyethane; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile and propionitrile; Water etc. are mentioned. These solvents may be mixed and used at an appropriate ratio.
The amount of compound 13 to be used is generally 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound 12 .
The amount of the condensing agent to be used is generally 0.1 to 10 mol, preferably 0.3 to 3 mol, per 1 mol of compound 12 .
When a carbodiimide-based condensing reagent is used as the condensing agent, an appropriate condensation accelerator (eg, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide) ) Can be used to improve the reaction efficiency. Moreover, when using HATU or a phosphoric acid-type condensing reagent as a condensing agent, reaction efficiency can be improved by using organic amine bases, such as a triethylamine and N, N- diisopropylethylamine.
The amount of the condensation accelerator or organic amine base used is usually 0.1 to 10 mol, preferably 0.3 to 3 mol, per 1 mol of compound 12 .
The reaction temperature is usually −30 ° C. to 120 ° C. Preferably it is -10-100 degreeC.
The reaction time is usually 0.5 to 60 hours.

Examples of the reactive derivative of compound 12 include acid anhydrides, acid halides (for example, acid chloride, acid bromide), imidazolides, mixed acid anhydrides (for example, anhydrides with methyl carbonate, ethyl carbonate, and isobutyl carbonate). Etc.
For example, when using an acid anhydride or acid halide, the reaction is usually performed in the presence of a base in a solvent that does not adversely influence the reaction.
Examples of the base include amines such as triethylamine, pyridine, N-methylmorpholine, N, N-dimethylaniline, 4-dimethylaminopyridine; lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate And alkali metal salts such as potassium carbonate.
Examples of the solvent that does not adversely influence the reaction include amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; halogenated carbonization such as chloroform and dichloromethane. Hydrogens; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane, diethyl ether and dimethoxyethane; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile and propionitrile; water and the like Is mentioned. These solvents may be mixed and used at an appropriate ratio.
In addition, when using the said amides as a solvent which does not exert a bad influence on reaction, reaction can also be performed in absence of a base.
The amount of compound 13 to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound 12 .
The amount of the base to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound 12 .
The reaction temperature is usually −30 ° C. to 100 ° C. Preferably it is -10-100 degreeC.
The reaction time is usually 0.5 to 30 hours.
When a mixed acid anhydride is used, compound 12 and chlorocarbonate (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate) are reacted in the presence of a base, and further reacted with compound 13 .
Examples of the base used here include those exemplified as the base used in the reaction of the acid anhydride or acid halide of compound 12 and compound 13 described above.
The amount of compound 13 to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound 12 .
The amount of the base to be used is generally 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound 12 .
The reaction temperature is usually −30 ° C. to 120 ° C. Preferably it is -10-100 degreeC.
The reaction time is usually 0.5 to 20 hours.
When imidazolide is used, the corresponding imidazolide is obtained from compound 12 and, for example, N, N′-carbonyldiimidazole (CDI), and further reacted with compound 13 .
The amount of compound 13 to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound 12 .
The reaction temperature is usually −30 ° C. to 120 ° C. Preferably it is -10-100 degreeC.
The reaction time is usually 0.5 to 20 hours.
Removal of the amino-protecting group is carried out according to a method known per se.

  The compound (I) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, and the like.

  In addition, when compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely, when obtained as a salt, It can be converted into a free form or other desired salt by a method known per se or a method analogous thereto.

When compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and are synthesized by a known synthesis method and separation method, respectively. Can be obtained as a single product. For example, when compound (I) has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I).
The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
As the optical resolution method, a method known per se, for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.
1) Fractional recrystallization method Racemate and optically active compound (for example, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, A salt with (−)-1-phenethylamine, cinchonine, (−)-cinchonidine, brucine), which is separated by fractional recrystallization, and if desired, a free optical isomer is obtained through a neutralization step. Method.
2) Chiral column method A method in which a racemate or a salt thereof is separated by applying to an optical isomer separation column (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Corporation), and water, various buffers (eg, phosphate buffer) The optical isomers are separated by developing an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) as a single or mixed solution. In addition, for example, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
3) Diastereomer method A mixture of racemates is converted into a mixture of diastereomers by chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (for example, fractional recrystallization, chromatography method). Then, the optical isomer is obtained by separating the optically active reagent site by chemical treatment such as hydrolysis reaction. For example, when the compound (I) has a hydroxy group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (for example, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid ], (-)-Menthoxyacetic acid) and the like are subjected to a condensation reaction to give diastereomers of ester or amide, respectively. On the other hand, when compound (I) has a carboxyl group, an amide or ester diastereomer can be obtained by subjecting the compound and an optically active amine or alcohol to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.

Compound (I) may be a crystal.
Crystals of compound (I) (hereinafter sometimes abbreviated as crystals of the present invention) can be produced by applying crystallization methods known per se to compound (I) for crystallization.
Here, examples of the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, and a crystallization method from a melt.
The “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent. In general, a method of shifting from a supersaturated state to a supersaturated state is exemplified, and specific examples include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, and a flux method. Examples of the solvent used include aromatic hydrocarbons (eg, benzene, toluene, xylene), halogenated hydrocarbons (eg, dichloromethane, chloroform), saturated hydrocarbons (eg, hexane, heptane, cyclohexane), Ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane), nitriles (eg, acetonitrile), ketones (eg, acetone), sulfoxides (eg, dimethyl sulfoxide), acid amides (eg, N, N -Dimethylformamide), esters (eg, ethyl acetate), alcohols (eg, methanol, ethanol, isopropyl alcohol), water and the like are used. These solvents are used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)).
Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like.
Examples of the “crystallization from the melt” include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method). And liquid phase epitaxy method).
As a suitable example of the crystallization method, the compound (I) or a salt thereof is dissolved in an appropriate solvent (eg, alcohols such as methanol and ethanol) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved. The method of cooling to below the temperature of time (for example, 0-50 degreeC, Preferably 0-20 degreeC) etc. are mentioned.
The crystals of the present invention thus obtained can be isolated by, for example, filtration.

In the present specification, the melting point is measured using, for example, a micro melting point measuring device (Yanako, MP-500D type or Buchi, B-545 type) or DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000). Mean melting point.
In general, the melting point may vary depending on the measuring instrument, measurement conditions, and the like. The crystal in the present specification may be a crystal having a value different from the melting point described in the present specification as long as it is within a normal error range.
The crystals of the present invention are excellent in physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of medicinal properties), and are extremely useful as pharmaceuticals. Useful.

The present invention will be described in more detail with reference to the following Reference Examples, Examples, Experimental Examples and Formulation Examples, which are not intended to limit the present invention, and may be changed without departing from the scope of the present invention. Also good.
In addition, the symbol in a reference example and an Example has the following meaning.
s: singlet, d: doublet, t: triplet
, Q: quartet, m: multiplet, J: coupling constant Further, room temperature means about 10 to 35 ° C. Unless otherwise specified, “%” indicates “% by weight”.
Mass spectra (MS) in Reference Examples and Examples were measured by electron impact ionization using Waters ZQ, ZMP or Shimadzu LCMS-2010A. Purification by silica gel column chromatography was performed by flash chromatography (mobile phase: a solvent selected from hexane, ethyl acetate, methanol or a mixed solvent thereof). Purification by HPLC was performed using a Gilson high-throughput purification system (YMC Combiprep Hydrosphere C18, S-5 μm, 50 × 20 mm; mobile phase: from 2% acetonitrile and 98% water and 0.1% trifluoroacetic acid to 95% acetonitrile and Gradient elution to 5% water and 0.1% trifluoroacetic acid).

Reference Example 1 [5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid
Step A. Methyl 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate
5-methyl-3-oxohexanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol), piperidine (0.34 g, 4.0) prepared in the same manner as EP 135252 A2 (Ex.Y) mmol)
, Acetic acid (0.48 g, 8.0 mmol) and toluene (200 mL) were heated to reflux using a Dean-Stark trap for 12 hours. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (50 mL), methyl 3-aminocrotonate (4.6 g, 40 mmol) was added, and the mixture was heated to reflux for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (7.45 g, yield 57%) as colorless crystals. Melting point 171 ° C.
Step B. Methyl 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate ice-cooled 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) -1,4 -A solution of ceric ammonium cerium nitrate (319 g, 0.58 mol) in water (300 mL) was added dropwise to a solution of methyl dihydropyridine-3-carboxylate (75.5 g, 0.23 mol) in acetone (500 mL). The resulting mixture was stirred for 1 hour under ice cooling and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane to give the title compound (69.4 g, yield 93%) as a white powder. MS 323 (M + 1).
Step C. 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinic acid
Chill
Methyl 5-cyano-6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (1.00 g, 3.10 mmol), Raney nickel (4 mL), 25% aqueous ammonia (6 mL), tetrahydrofuran (15 mL) ) And methanol (45 mL) were stirred in a sealed tube under a 0.3-0.5 MPa hydrogen atmosphere at room temperature for 6 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and 10% aqueous potassium carbonate solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.97 g, yield 95%) as pale-yellow crystals. MS 327 (M + 1).
Step D. {[5- (hydroxymethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyrid
N-3-yl] methyl} carbamate tert-butyl
A solution of methyl 5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) nicotinate (9.3 g, 29 mmol) in toluene (150 mL) was cooled to −78 ° C., and 1 M Diisobutylaluminum hydride toluene solution (100 mL, 100 mmol) was added dropwise over 30 minutes. After the temperature of the obtained mixture was raised, acetone (10 mL) and sodium sulfate decahydrate (40 g) were added at 0 ° C. The reaction mixture was stirred at room temperature overnight, and insoluble matters were filtered and washed with ethyl acetate. The filtrate and washings were combined, 1N aqueous sodium hydroxide solution (30 mL, 30 mmol) and di-tert-butyl dicarbonate (6.9 mL, 30 mmol) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (8.5 g, yield 75%) as colorless crystals. MS 399 (M + 1).
Step E. {[5- (Cyanomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} tert-butyl carbamate, ice-cooled, {[5- (hydroxymethyl)- 2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (17.4 g, 43 mmol), triethylamine (15 mL, 108 mmol), and tetrahydrofuran ( 150 mL), methanesulfonyl chloride (4.0 mL, 52 mmol) was added dropwise and stirred at 0 ° C. for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl- 4- (4-Methylphenyl) pyridin-3-yl] methyl was obtained as a crude product (20 g). The crude product (20 g) was dissolved in acetonitrile (300 mL), and trimethylsilanecarbonitrile (6.7 mL, 50 mmol) and then 1 M tetrabutylammonium fluoride tetrahydrofuran solution (50 mL, 50 mmol) were sequentially added. . The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with a mixture of hexane and diethyl ether to give the title compound (15.6 g, yield 89%) as a white powder. MS 408 (M + 1).
Step F. [5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid
{[5- (Cyanomethyl) -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridin-3-yl]
Methyl} tert-butyl carbamate (14.5 g, 36 mmol) was suspended in 6N hydrochloric acid (150 mL) and stirred at 90 ° C. for 20 hours. The reaction was cooled to room temperature and washed with diethyl ether. The aqueous layer was made alkaline (pH 8) with 8N aqueous sodium hydroxide solution, ethyl acetate (200 mL) and di-tert-butyl dicarbonate (10 mL, 44 mmol) were added, and the mixture was stirred at room temperature for 1 hr. Hydrochloric acid was added to the reaction solution for neutralization, liquid separation was performed, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (14.0 g,
(Yield 92%) was obtained as a white powder. MS 427 (M + 1).

Reference Example 2 [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylphen
Nyl) -6-neopentylpyridin-3-yl] acetic acid
Step A. 2- (3,3-Dimethylbutanoyl) -3- (4-methylphenyl) acrylonitrile
5,5-dimethyl-3-oxohexanenitrile (302 g, 2.2 mol), p-tolualdehyde (256 mL, 2.2 mol), piperidine (22 mL) prepared in the same manner as EP 135252 A2 (Ex.V) , 0.22 mol), acetic acid (25 mL, 0.43 mol) and toluene (1.4 L) were heated to reflux for 8 hours using a Dean-Stark trap. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-toluene to give the title compound (390 g, yield 75%) as a white powder. ¹ H-NMR (CDCl ₃ ) δ
: 1.10 (9H, s), 2.44 (3H, s), 2.81 (2H, s), 7.31 (2H, d, J = 8.1 Hz), 7.92 (2H, d, J = 8.3 Hz), 8.13 (1H, s).
Step B. Tert-butyl 5-cyano-2-methyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate
2- (3,3-dimethylbutanoyl) -3- (4-methylphenyl) acrylonitrile (495 g, 2.1 mol), tert-butyl 3-aminobut-2-enoate (354 g, 2.3 mol) and acetic acid ( 2.5 L) was stirred at 80 ° C. for 30 minutes. The reaction mixture was ice-cooled, and the precipitated crystals were collected by filtration, washed with 75% aqueous ethanol, and dried to give the title compound (611 g, yield 78%) as colorless crystals. Melting point 202 ° C.
Step C. Tert-Butyl 5-cyano-2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate (134 g, 89% yield) was obtained as 5-cyano-2-methyl-4- ( A white powder was obtained from tert-butyl 4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate (152 g, 0.40 mol) in the same manner as in Reference Example 1, Step B. MS 379 (M + 1).
Step D. 5-cyano-2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid
A solution of tert-butyl 5-cyano-2-methyl-4- (4-methylphenyl) -6-neopentylnicotinate (20 g, 53 mmol) in trifluoroacetic acid (50 mL) was stirred at 50 ° C. for 12 hours. . The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from hexane-ethyl acetate to give the title compound (12.1 g, yield 71%) as a white powder. MS 323 (M + 1).
Step E. 5- (hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylnicoti
Nitonitrile ice-cooled, 5-cyano-2-methyl-4- (4-methylphenyl) -6-neopentylnicotinic acid (0.83 g, 2.6 mmol), N, N-dimethylformamide (0.02 mL) and tetrahydrofuran (20 Oxalyl chloride (0.39 g, 3.1 mmol) was added dropwise to the mixture consisting of (mL). The resulting mixture was stirred at 5 ° C. for 30 minutes and then concentrated under reduced pressure. The residue was dissolved in a mixture of tetrahydrofuran (10 mL) and 1,2-dimethoxyethane (10 mL) and cooled on ice. To the ice-cooled solution,
Sodium tetrahydroborate (0.34 g, 9.0 mmol) was added and stirred. Methanol (3 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 minutes, and then the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.69 g, yield 87%) as colorless crystals. MS 309 (M + 1).
Step F. {[5- (hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyri
Gin-3-yl] methyl} carbamate tert-butyl
5- (hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylnicotinonitrile (0.61 g, 2.0 mmol), Raney nickel (2 mL), 25% aqueous ammonia (2 mL) and A mixture of methanol (50 mL) was stirred in a sealed tube for 1 hour at room temperature under a hydrogen atmosphere of 0.3-0.5 MPa. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (100 mL). Di-tert-butyl dicarbonate (0.50 mL, 2.2 mmol) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and recrystallized from diisopropyl ether-ethyl acetate to give the title compound (0.67 g, yield 82%) as a white powder. MS 413 (M + 1).
Step G. {[5- (Cyanomethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate tert-butyl Title compound (5.7 g, yield 93%) is , {[5- (hydroxymethyl) -6-methyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate tert-butyl (6.0 g, 15 mmol), reference Example 1 Colorless crystals were obtained in the same manner as in Step E. MS 422 (M + 1).
Step H. [5-{[(tert-butoxycarbonyl) amino] methyl} -2-methyl-4- (4-methylpheny
L) -6-Neopentylpyridin-3-yl] acetic acid title compound (13.0 g, 80% yield) was obtained from {[5- (cyanomethyl) -6-methyl-4- (4-methylphenyl) -2- Neopentylpyridin-3-yl] methyl} carbamate tert-butyl (15.5 g, 37 mmol)
Thus, white powder was obtained in the same manner as in Reference Example 1, Step F. MS 441 (M + 1).

Reference Example 3 [5-{[(tert-butoxycarbonyl) amino] methyl} -2,6-diisobutyl-4- (4-methyl
Tylphenyl) pyridin-3-yl] acetic acid
Step A. To a solution of dimethyl carbonate (6.3 g, 70 mmol) in 1,4-dioxane (15 mL) under a nitrogen atmosphere of methyl 5-methyl-3-oxohexanoate , sodium hydride (2.2 g, 55 mmol) was added, Heated to reflux. To the suspension was added dropwise a solution of 4-methyl-2-pentanone (2.5 g, 25 mmol) in 1,4-dioxane (5 mL), and the mixture was heated to reflux for 3 hours. The reaction solution was poured into ice water, washed with hexane, neutralized with 1N hydrochloric acid, and extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (3.9 g, yield 98%) as an orange oil. ¹ H-NMR (CDCl ₃ )
δ: 0.94 (6H, d, J = 6.6 Hz), 2.10-2.25 (1H, m), 2.42 (2H, d, J = 7.0 Hz), 3.44 (2H, s), 3.74 (3H, s).
Step B. 3-Amino-5-methylhex-2-enoic acid methyl ester
A mixture of methyl 5-methyl-3-oxohexanoate (4.0 g, 25 mmol), ammonium acetate (9.8 g, 25 mmol), acetic acid (1.5 mL, 25 mmol) and toluene (200 mL) was added to the Dean-Stark trap. And heated at reflux for 12 hours. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (3.0 g, yield 75%) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.94 (6H, d, J = 6.4 Hz), 1.80-1.95 (1H, m), 1.95-2.00 (2H, m), 3.65
(3H, s), 4.52 (1H, s).
Step C. 5-cyano-2,6-diisobutyl-4- (4-methylphenyl) nicotinic acid methyl ester
From 5-methyl-3-oxohexanenitrile (2.5 g, 20 mmol), p-tolualdehyde (2.4 g, 20 mmol) and methyl 3-amino-5-methylhex-2-enoate (3.1 g, 20 mmol) Reference example 1
In the same manner as in Step A, methyl 5-cyano-2,6-diisobutyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate was obtained as a crude product. From the crude product, Reference Example 1
The title compound (4.8 g, yield 65%) was obtained as a white powder by the same method as in Step B. ¹ H-NMR (CDCl ₃ ) δ: 0.93 (6H, d, J = 6.8 Hz), 1.00 (6H, d, J = 6.8 Hz), 2.17-2.34 (2H,
m), 2.40 (3H, s), 2.73 (2H, d, J = 7.4 Hz), 2.97 (2H, d, J = 7.2 Hz), 3.57 (3H,
s), 7.27 (4H, s).
Step D. 5-{[(tert-Butoxycarbonyl) amino] methyl} -2,6-diisobutyl-4- (4-methylphenyl) nicotinic acid methyl ester
From methyl 5-cyano-2,6-diisobutyl-4- (4-methylphenyl) nicotinate (4.8 g, 13 mmol) in the same manner as in Reference Example 1, Step C, 5- (aminomethyl) -2, 6-Diisobutyl-4- (4-
Methyl methyl phenyl) nicotinate was obtained as a crude product. To a solution of the crude product in tetrahydrofuran (60 mL) was added di-tert-butyl dicarbonate (3.4 g, 16 mmol) at room temperature and stirred for 30 minutes. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound (5.8 g, yield 95%) as a white powder. MS 469 (M + 1).
Step E. {[5- (hydroxymethyl) -2,6-diisobutyl-4- (4-methylphenyl) pyridine-3-
Yl] methyl} carbamate tert-butyl
A solution of methyl 5-{[(tert-butoxycarbonyl) amino] methyl} -2,6-diisobutyl-4- (4-methylphenyl) nicotinate (5.4 g, 12 mmol) in toluene (50 mL) at −78 ° C. Cool to 1.5 M
Diisobutylaluminum hydride in toluene (35 mL, 52 mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at -78 ° C for 30 minutes, then warmed to 0 ° C and stirred for 30 minutes. Methanol (1 mL) was added to the reaction solution, and the mixture was stirred for 15 minutes, and then sodium sulfate decahydrate (17 g) was added and further stirred for 1 hour. The insoluble material was filtered and washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.5 g, yield 49%). MS 441 (M + 1).
Step F. {[5- (Cyanomethyl) -2,6-diisobutyl-4- (4-methylphenyl) pyridin-3-yl] methyl} tert-butyl carbamate The title compound (2.4 g, 94% yield) was obtained from {[ From tert-butyl 5- (hydroxymethyl) -2,6-diisobutyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate (2.5 g, 5.7 mmol), similar to Reference Example 1, Step E Thus, a white powder was obtained. MS 450 (M + 1).
Step G. [5-{[(tert-Butoxycarbonyl) amino] methyl} -2,6-diisobutyl-4- (4-methyl
Ruphenyl) pyridin-3-yl] acetic acid title compound (1.7 g, 67% yield) was obtained from {[5- (cyanomethyl) -2,6-diisobutyl-4- (4-methylphenyl) pyridin-3-yl] Obtained as a white powder from tert-butyl methyl} carbamate (2.4 g, 5.3 mmol) by the same method as in Reference Example 1, Step F. MS 469 (M + 1).

Reference Example 4 [5-{[(tert-butoxycarbonyl) amino] methyl} -2-ethyl-4- (4-methylphenol
Nyl) -6-neopentylpyridin-3-yl] acetic acid
Step A. Methyl 3-aminopent-2-enoate
Methyl 3-oxopentanoate (3.3 g, 25 mmol), ammonium acetate (9.8 g, 127 mmol),
A mixture of acetic acid (1.45 mL, 25 mmol) and toluene (200 mL) was heated to reflux for 12 hours using a Dean-Stark trap. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a crude product (2.5 g).
Step B. 5-cyano-2-ethyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-carboxylate
5,5-dimethyl-3-oxohexanenitrile (3.5 g, 19 mmol), p-tolualdehyde (2.3 g, 19 mmol), piperidine (0.19 mL, 1.9 mmol), acetic acid (0.22 mL, 3.9 mmol) and toluene (200 mL) was heated to reflux for 3 hours using a Dean-Stark trap. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2- (3,3-dimethylbutanoyl) -3- (4-methylphenyl) acrylonitrile. Obtained as the crude product (5.7 g). The crude product (5.7 g) and the crude product (2.5 g) obtained in Reference Example 4 Step A were dissolved in acetic acid (15 mL) and stirred at 80 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from hexane-ethyl acetate to give the title compound (3.1 g, yield 45%) as a white powder. Melting point 126 ° C.
Step C. Methyl 5-cyano-2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinate
5-cyano-2-ethyl-4- (4-methylphenyl) -6-neopentyl-1,4-dihydropyridine-3-
To a solution of methyl carboxylate (3.0 g, 8.6 mmol) in acetone (75 mL), a solution of ceric ammonium cerium nitrate (11.8 g, 21 mmol) in water (15 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to give the title compound (2.5 g, yield 83%) as a white powder. MS 351 (M + 1).
Step D. 5- (Aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinic acid
Methyl
Methyl 5-cyano-2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinate (1.0 g, 2.9 mmol), Raney nickel (5 mL), 25% aqueous ammonia (5 mL) and methanol (50 mL) was stirred in a sealed tube under a hydrogen atmosphere of 0.3-0.5 MPa for 1 hour at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.00 g, yield 99%) as a white powder. MS 355 (M + 1).
Step E. {[6-Ethyl-5- (hydroxymethyl) -4- (4-methylphenyl) -2-neopentylpyri
Gin-3-yl] methyl} carbamate tert-butyl
A solution of methyl 5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylnicotinate (0.50 g, 1.4 mmol) in toluene (10 mL) was cooled to −78 ° C., and 1 M Diisobutylaluminum hydride in toluene (3.3 mL, 4.9 mmol) was added dropwise over 30 minutes. The resulting mixture was warmed and then stirred at 0 ° C. for 15 minutes. Isopropanol (2 mL) was added to the reaction solution, tetrahydrofuran (10 mL) and saturated aqueous sodium hydrogen carbonate (4 mL) were added, and the mixture was stirred at room temperature for 5 min. Di-tert-butyl dicarbonate (0.49 mL, 2.1 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine,
The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane to give the title compound (0.48 g, yield 80%) as colorless crystals. MS 427 (M + 1).
Step F. {[5- (Cyanomethyl) -6-ethyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} tert-butyl carbamate, ice-cooled, {[6-ethyl-5- (Hydroxymethyl) -4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamate tert-butyl (2.0 g, 4.8 mmol), triethylamine (1.3 mL, 9.6 mmol) and tetrahydrofuran ( 40 mL), methanesulfonyl chloride (0.56 mL, 7.2 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 30 minutes.
The reaction mixture was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium hydrogen carbonate, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methanesulfonic acid [5-{[(tert- Butoxycarbonyl) amino] methyl} -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] methyl was obtained as a crude product (2.6 g). The crude product (2.6 g) was dissolved in a mixture of acetonitrile (40 mL) and tetrahydrofuran (40 mL), trimethylsilanecarbonitrile (0.77 mL, 5.7 mmol), and then 1 M tetrabutylammonium fluoride tetrahydrofuran solution ( 5.7 mL, 5.7 mmol) was added. The resulting mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from hexane-ethyl acetate to give the title compound (1.9 g, yield 92%) as a white powder. MS 436 (M + 1).
Step G. [5-{[(tert-Butoxycarbonyl) amino] methyl} -2-ethyl-4- (4-methylpheny
) -6-Neopentylpyridin-3-yl] acetic acid
{[5- (Cyanomethyl) -6-ethyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} tert-butyl carbamate (1.9 g, 4.3 mmol) was added to 6N hydrochloric acid ( 100 mL)
Stir at 24 ° C. for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. Saturated aqueous sodium hydrogen carbonate was added to the aqueous layer to make it alkaline, tetrahydrofuran (200 mL) and di-tert-butyl dicarbonate (1.5 mL, 6.5 mmol) were added, and the mixture was stirred at room temperature for 17 hours. 1N Hydrochloric acid was added to the reaction mixture to acidify it, the phases were separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.8 g, yield 94%) as a white powder. MS 455 (M + 1).

Reference Example 5 1-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyrid
N-3-yl] acetyl} -L-prolinamide dihydrochloride
Step A. {[5- {2-[(2S) -2- (Aminocarbonyl) pyrrolidin-1-yl] -2-oxoethyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridine-3- Yl] methyl} carbamate tert-butyl
[5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (0.50 g, 1.2 mmol), L-proline Amides (0.32 g, 2.8 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium (1.1 g, 2.8 mmol) and N, N hexafluorophosphate -A mixture of dimethylformamide (20 mL) was stirred at room temperature for 16 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.49 g, 81% yield)
Was obtained as a white powder. MS 523 (M + 1).
Step B. 1-{[5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} -L-prolinamide dihydrochloride
{[5- {2-[(2S) -2- (Aminocarbonyl) pyrrolidin-1-yl] -2-oxoethyl} -2-isobutyl-6-methyl-4- (4-methylphenyl) pyridine-3- A mixture of tert-butyl [yl] methyl} carbamate (0.48 g, 0.90 mmol) and 4N hydrogen chloride 1,4-dioxane solution (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give the title compound (0.37 g, yield 82%) as a white powder. MS 423 (M + 1).

Reference Example 6 8-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridy
N-3-yl] acetyl} hexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one dihydrochloride
salt
Step A. 8-Benzylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one
(4-benzylpiperazin-2-yl) methanol (6.4 g, 30 mmol), water (100 mL) and water prepared in the same manner as described in J. Med. Chem. 1993, 36, 2075-2083. To a mixture consisting of tetrahydrofuran (100 mL), potassium carbonate (8.3 g, 60 mmol) and chloroacetyl chloride (3.6 mL, 45 mmol) were sequentially added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (100 mL), potassium hydroxide (2 g) was added, and the mixture was stirred at 50 ° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.6 g, yield 35%) as a yellow oil. MS 247 (M + 1).
Step B. Hexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one hydrochloride
To a solution of 8-benzylhexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one (2.6 g, 10.5 mmol) in methanol (50 mL), ammonium formate (3.0 g) and Palladium-carbon (10%, 1.5 g) was added and stirred at 80 ° C. for 15 minutes. The reaction solution was cooled to room temperature and then filtered to remove palladium-carbon. The filtrate was concentrated under reduced pressure, and 4N hydrogen chloride-ethyl acetate solution was added to the residue. The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (1.8 g, yield 93%) as a pale yellow powder. MS 157 (M + 1).
Step C. ({2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- [2-oxo-2- (4-oxohexahydropyrazino [2,1-c] [1,4] oxazine- 8 (1H) -yl) ethyl] pyridin-3-yl} methyl) carbamate tert-butyl
[5-{[(tert-Butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (0.43 g, 1.0 mmol) in N, N -Dimethylformamide (5 mL)
Hexahydropyrazino [2,1-c] [1,4] oxazin-4 (3H) -one hydrochloride (0.29 g, 1.5 mmol), hexafluorophosphoric acid O- (7-azabenzotriazole -1-yl) -1,1,3,3-tetramethyluronium (0.57 g, 1.5 mmol) and triethylamine (0.35 mL, 2.5 mmol) were added and stirred at room temperature for 12 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed successively with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from hexane-diethyl ether to give the title compound (0.42 g, yield 74%) as a white powder. MS 565 (M + 1
).
Step D. 8-{[5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] acetyl} hexahydropyrazino [2,1-c] [1,4 ] Oxazin-4 (3H) -one dihydrochloride
({2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- [2-oxo-2- (4-oxohexahydropyrazino [2,1-c] [1,4] oxazine- 8 (1H) -yl) ethyl] pyridin-3-yl} methyl) carbamate tert-butyl (0.42 g, 0.74 mmol) was dissolved in ethyl acetate (2 mL) and 4N hydrogen chloride in ethyl acetate solution (3 mL ) Was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and crystallized from hexane-diethyl ether to give the title compound (0.39 g, yield 98%) as a white powder. MS 465 (M + 1).

Reference Example 7 2- [5- (aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N- [3- (methylsulfonyl) phenyl] acetamide dihydrochloride salt
Step A. {[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-{[3- (methylsulfonyl) phenyl] amino} -2-oxoethyl) pyridin-3-yl] methyl} carbamine The acid tert-butyl title compound (0.59 g, 87% yield) was obtained from [5-{[(tert-butoxycarbonyl) amino] methyl} -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridine. -3-yl] acetic acid (0.50 g, 1.17 mmol)
And 3-methylsulfonylaniline hydrochloride (0.24 g, 1.17 mmol) were obtained as crystals by the same method as in Reference Example 6, Step C. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 6.6 Hz), 1.38 (9H, s), 2.18-2.27 (1H, m), 2.41 (3H, s), 2.63 (3H, s ), 2.77 (2H, d, J = 7.4
Hz), 3.05 (3H, s), 3.49 (2H, s), 4.06 (2H, d, J = 5.1 Hz), 4.23 (1H, s), 6.90 (1H, m), 7.01 (2H, d, J = 7.9 Hz), 7.25 (2H, d, J = 7.9 Hz), 7.50 (1H, t, J = 7.9
Hz), 7.64-7.67 (1H, m), 7.76 (1H, d, J = 8.7 Hz), 7.83 (1H, t, J = 1.9 Hz).
Step B. 2- [5- (Aminomethyl) -6-isobutyl-2-methyl-4- (4-methylphenyl) pyridin-3-yl] -N- [3- (methylsulfonyl) phenyl] acetamide dihydrochloride
{[2-Isobutyl-6-methyl-4- (4-methylphenyl) -5- (2-{[3- (methylsulfonyl) phenyl] amino} -2-oxoethyl) pyridin-3-yl] methyl} carbamine Tert-butyl acid (0.45 g,
To a solution of 0.78 mmol) in tetrahydrofuran (4 mL) was added 4N hydrogen chloride in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 16 hours. The precipitated crystals were collected by filtration, washed with ethyl acetate, and recrystallized from methanol-ethyl acetate to give the title compound (0.31 g, yield 56%) as crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (6H, d, J = 6.6 Hz), 2.14-2.23 (1H, m), 2.36 (3H, s), 2.80 (3H, s), 3.12-3.18 (2H, m), 3.18 (3H, s), 3.63 (2H, s), 3.79-3.84 (2H, m), 7.21 (2H, d, J = 8.0 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.55-7.64 (2H, m), 7.70-7.74
(1H, m), 8.16-8.18 (1H, m), 8.37 (3H, s), 10.6 (1H, s).

Example 1 [5- (Aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid
Step A. Methyl 5-cyano-2-ethyl-6-isobutyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate
In the same manner as in Reference Example 4, Step A, methyl 3-aminopent-2-enoate was obtained as a crude product (11.5 g) from methyl 3-oxopentanoate (12.0 g, 92 mmol).
5-methyl-3-oxohexanenitrile (11.4 g, 91 mmol), p-tolualdehyde (11.0 g, 91 mmol), piperidine (0.90 mL, 9.1 mmol), acetic acid (1.05 mL, 18 mmol) and toluene (200 mL) was heated to reflux for 12 hours using a Dean-Stark trap. The reaction mixture was cooled to room temperature, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2- (3-methylbutanoyl) -3- (4-methylphenyl) acrylonitrile as a crude product. Obtained as a product (21 g). The crude product (21 g) and the crude product of methyl 3-aminopent-2-enoate (11.5 g) were dissolved in acetic acid (20 mL) and stirred at 90 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting orange oil was washed with hexane to give the title compound (29.7 g, yield 96%) as an orange oil. MS 339 (M + 1).
Step B. 5-cyano-2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinic acid methyl ester
To a solution of methyl 5-cyano-2-ethyl-6-isobutyl-4- (4-methylphenyl) -1,4-dihydropyridine-3-carboxylate (29.7 g, 88 mmol) in acetone (750 mL), add nitric acid A solution of diammonium cerium (120 g, 0.21 mol) in water (150 mL) was added dropwise. The resulting mixture was stirred at room temperature for 5
Stir for minutes. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from hexane to give the title compound (13.9 g,
Yield 47%) was obtained as a white powder. MS 337 (M + 1).
Step C. 5- (Aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinic acid
Chill
Methyl 5-cyano-2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinate (22.7 g, 68 mmol), Raney nickel (25 mL), 25% aqueous ammonia (25 mL) and methanol (200 mL) The mixture consisting of was stirred at 50 ° C. for 4 hours in a sealed tube under a hydrogen atmosphere of 0.3-0.5 MPa. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1N hydrochloric acid and washed with ethyl acetate.
The aqueous layer was separated, made alkaline with 5% aqueous ammonia, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (20.7 g, yield 90%) as a pale orange oil. MS 341 (M + 1).
Step D. {[6-Ethyl-5- (hydroxymethyl) -2-isobutyl-4- (4-methylphenyl) pyrid
N-3-yl] methyl} carbamate tert-butyl
A solution of methyl 5- (aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) nicotinate (20.6 g, 61 mmol) in toluene (280 mL) was cooled to −78 ° C., and 1 M Diisobutylaluminum hydride toluene solution (141 mL, 0.21 mol) was added dropwise over 90 minutes. The resulting mixture was stirred at the same temperature for 10 minutes, and then ethyl acetate (20 mL) and sodium sulfate decahydrate (69 g) were sequentially added. The reaction was warmed to room temperature and stirred for 12 hours. Insoluble materials were removed by filtration and washed with toluene. The filtrate and washings were combined and concentrated under reduced pressure. The residue was tetrahydrofuran (180
in 1 mL), di-tert-butyl dicarbonate (14.5 mL, 63 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from hexane-diisopropyl ether to give the title compound (15.7 g, yield 63%) as an off-white powder. MS 413 (M + 1).
Step E. {[5- (Cyanomethyl) -6-ethyl-2-isobutyl-4- (4-methylphenyl) pyridin-3-yl] methyl} tert-butyl carbamate was ice-cooled, {[6-ethyl-5- ( Hydroxymethyl) -2-isobutyl-4- (4-methylphenyl) pyridin-3-yl] methyl} carbamate tert-butyl (15.7 g, 38 mmol), triethylamine (10.6 mL, 76 mmol) and tetrahydrofuran (150 mL ) Methanesulfonyl chloride (4.4 mL, 57 mmol) was added dropwise thereto, and the mixture was stirred at 5 ° C. for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and methanesulfonic acid [5-{[(tert-butoxycarbonyl) amino] methyl} -2-ethyl -6-Isobutyl-4- (4-methylphenyl) pyridin-3-yl] methyl was obtained as a crude product (23 g). The crude product (23 g) was dissolved in a mixture of acetonitrile (150 mL) and tetrahydrofuran (150 mL) and trimethylsilanecarbonitrile (6.1 mL,
46 mmol), and then 1 M tetrabutylammonium fluoride tetrahydrofuran solution (46 mL, 46 mmol) was added sequentially. The resulting mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (15.7 g, yield 98%) as a white powder. MS
422 (M + 1).
Step F. [5- (Aminomethyl) -2-ethyl-6-isobutyl-4- (4-methylphenyl) pyridine-3-
Il] acetic acid
{[5- (Cyanomethyl) -6-ethyl-2-isobutyl-4- (4-methylphenyl) pyridin-3-yl]
Methyl} carbamate tert-butyl (15.6 g, 37 mmol) suspended in 6N hydrochloric acid (60 mL)
For 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (150 mL) and washed with ethyl acetate. The aqueous layer was stirred at 5 ° C. and neutralized with 8N aqueous sodium hydroxide solution. The resulting suspension was stirred at the same temperature for 2 hours, and then the precipitate was collected by filtration, washed with water and dried to give the title compound monohydrate (9.1 g, yield 72%) as a pale yellow powder. It was.
Elemental analysis values Theoretical values as C ₂₁ H ₂₈ N ₂ O ₂ .H ₂ O: C, 70.36; H, 8.44; N, 7.81.
Found: C, 69.95; H, 8.18; N, 7.54.
MS 341 (M + 1).

Example 2 [5- (aminomethyl) -2,6-diisobutyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid [5-{[(tert-butoxy ] prepared in Reference Example 3 Carbonyl) amino] methyl} -2,6-diisobutyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid (0.050 g, 0.11 mmol) and 4N hydrogen chloride 1,4-dioxane solution (5 mL) The mixture consisting of was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was triturated from diisopropyl ether to give the title compound (0.048 g, yield 100%) as a pale yellow powder. MS 369 (M + 1).

Example 3 [5- (Aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid [5-{[( tert-Butoxycarbonyl) amino] methyl} -2-ethyl-4- (4-
Methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (0.14 g, 0.31 mmol) was suspended in 6N hydrochloric acid (5 mL) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was triturated from diisopropyl ether to give the title compound (0.13 g, yield 99%) as a white powder. M
S 355 (M + 1).

Example 4 [5- (Aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid
[5- (Aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid dihydrochloride (1.0 g, 2.3 mmol) dissolved in water (2 mL) The mixture was neutralized with 4N aqueous sodium hydroxide solution under ice cooling. The obtained suspension was stirred at 5 ° C. for 1 hour, and the crystals were collected by filtration. The obtained crystals were washed with cold water and dried to give the title compound (0.69 g, yield 83%) as a white powder.
MS 355 (M + 1).
[5- (Aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid dihydrochloride (3.6 g, 8.4 mmol) dissolved in water (7.2 mL) Then, 4N aqueous sodium hydroxide solution (3.5 mL) was added dropwise under ice cooling to neutralize. The obtained suspension was stirred at 5 ° C. for 1 hour, and the crystals were collected by filtration. The obtained crystals were washed 3 times with cold water (5 mL) and dried to give the title compound monohydrate (2.4 g, yield 80%) as a white powder.
Elemental analysis value Theoretical value as C ₂₂ H ₃₀ N ₂ O ₂ .H ₂ O: C, 70.94; H, 8.66; N, 7.52.
Found: C, 71.12; H, 8.52; N, 7.45.

Example 5 N- (3-acetylphenyl) -2- [5- (aminomethyl) -2-ethyl-4- (4-methylpheny
) -6-Neopentylpyridin-3-yl] acetamide dihydrochloride
Step A. {[5- {2-[(3-acetylphenyl) amino] -2-oxoethyl} -6-ethyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamic acid tert - it was prepared with butyl reference example 4 [5 - {[(tert- butoxycarbonyl) amino] methyl} -2-ethyl-4- (4-
Methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (0.35 g, 0.77 mmol) in N, N-dimethylformamide (5 mL) was added 3-aminoacetophenone (0.16 g, 1.2 mmol), N-diisopropylethylamine (0.20 mL, 1.2 mmol) and hexafluorophosphate O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium (0.44 g, 1.2 mmol) Sequentially added. The mixture was stirred at room temperature for 17 hours and then partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from diisopropyl ether-ethyl acetate to give the title compound (0.36 g, yield 82%) as a white powder. MS
572 (M + 1).
Step B. N- (3-acetylphenyl) -2- [5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetamide dihydrochloride
{[5- {2-[(3-acetylphenyl) amino] -2-oxoethyl} -6-ethyl-4- (4-methylphenyl) -2-neopentylpyridin-3-yl] methyl} carbamic acid tert -Butyl (0.32 g, 0.56 mmol) was dissolved in 4N hydrogen chloride ethyl acetate solution (5 mL), and the solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether-methanol.
The title compound (0.28 g, yield 90%) was obtained as a white powder. MS 472 (M + 1).

Example 6 1-{[5- (Aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyri
Gin-3-yl] acetyl} -L-prolinamide
Step A. {[5- {2-[(2S) -2- (Aminocarbonyl) pyrrolidin-1-yl] -2-oxoethyl} -6-ethyl-4- (4-methylphenyl) -2-neopentylpyridine-3 -Il] methyl} carbamic acid tert-butyl title compound (0.14 g, yield 98%) was prepared according to [5-{[(tert-butoxycarbonyl) amino] methyl} -2-ethyl-4 prepared in Reference Example 4. -(4-Methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (0.12 g, 0.26 mmol) and L-prolinamide (0.046 g, 0.4 mmol) by a method similar to Example 5, step A. Obtained as a white powder. MS 551 (M + 1).
Step B. 1-{[5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridy
N-3-yl] acetyl} -L-prolinamide
{[5- {2-[(2S) -2- (Aminocarbonyl) pyrrolidin-1-yl] -2-oxoethyl} -6-ethyl-4- (4-methylphenyl) -2-neopentylpyridine-3 -Yl] methyl} carbamate tert-butyl (0.14 g, 0.26 mmol) in ethyl acetate (2 mL), 4N hydrogen chloride in ethyl acetate (3 mL)
And stirred at room temperature for 3 hours. Water was added to the reaction mixture and washed with ethyl acetate.
The solution was made alkaline (pH 8.0) using a% ammonia aqueous solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from hexane-diethyl ether to give the title compound monohydrate (0.057 g, yield 42%) as a white powder.
Elemental analysis _{C 27 H 38 N 4 O 2} · H 2 O theoretically: C, 69.20; H, 8.60 ; N, 11.96.
Found: C, 69.23; H, 8.54; N, 11.53.
MS 451 (M + 1).

Example 7 2- [5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] -N- [3- (methylsulfonyl) phenyl] acetamide Hydrochloride
Step A. {[6-Ethyl-4- (4-methylphenyl) -5- (2-{[3- (methylsulfonyl) phenyl] amino} -2-oxoethyl) -2-neopentylpyridin-3-yl] methyl} [5-{[(tert-Butoxycarbonyl) amino] methyl} -2-ethyl-4- (4-) prepared in tert-butyl carbamate Reference Example 4
Methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (0.18 g, 0.40 mmol) in N, N-dimethylformamide (5 mL) was added to 3-methylsulfonylaniline hydrochloride (0.12 g, 0.59 mmol) , N, N-diisopropylethylamine (0.21 mL, 1.2 mmol) and O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (0.23 g, 0.59) mmol) were added sequentially. The mixture was stirred at room temperature for 17 hours and then partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from diisopropyl ether-ethyl acetate to give the title compound (0.19 g, yield 77%) as a pale-yellow powder. MS 608 (M + 1).
Step B. 2- [5- (Aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] -N- [3- (methylsulfonyl) phenyl] acetamide dihydrochloride The compound (0.12 g, 85% yield) was obtained from {[6-ethyl-4- (4-methylphenyl) -5- (2-{[3- (methylsulfonyl) phenyl] amino} -2-oxoethyl)- It was obtained as pale yellow crystals from tert-butyl 2-neopentylpyridin-3-yl] methyl} carbamate (0.15 g, 0.25 mmol) by the same method as in Example 5, Step B. MS 508 (M + 1).

Example 8 Methyl [5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetate dihydrochloride
[5-{[(tert-Butoxycarbonyl) amino] methyl} -2-ethyl-4- (4-methylphenyl) -6-
A mixture consisting of neopentylpyridin-3-yl] acetic acid (0.20 g, 0.44 mmol) and 10% hydrogen chloride in methanol (3 mL) was stirred with heating at 80 ° C. for 3 hours. The reaction mixture was concentrated and then partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. To the obtained colorless oil was added 4N hydrogen chloride in ethyl acetate (1 mL) and stirred, and then the precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound (0.18 g, 91% yield). Was obtained as a white powder. MS 369 (M + 1).

Example 9 [5- (Aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (5-methyl-2-oxo-1,3-dioxol- 4-yl) methyl dihydrochloride
Step A. [5-{[(tert-Butoxycarbonyl) amino] methyl} -2-ethyl-4- (4-methylpheny
) -6-Neopentylpyridin-3-yl] acetic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl
[5-{[(tert-Butoxycarbonyl) amino] methyl} -2-ethyl-4- (4-methylphenyl) -6-
Neopentylpyridin-3-yl] acetic acid (0.77 g, 1.7 mmol), 4- (chloromethyl) -5-methyl-1,3-dioxol-2-one (0.38 g, 2.5 mmol), potassium carbonate (0.35 g , 2.5 mmol) and N, N-dimethylformamide (10 mL) were stirred at 60 ° C. for 2 h. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from diisopropyl ether to give the title compound (0.67 g, yield 71%) as a white powder. MS 567 (M + 1).
Step B. [5- (Aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetic acid (5-methyl-2-oxo-1,3-dioxol-4-yl ) Methyl dihydrochloride title compound (0.60 g, 99% yield) was obtained from [5-{[(tert-butoxycarbonyl) amino] methyl} -2-ethyl-4- (4-methylphenyl) -6-neo. [Pentylpyridin-3-yl] acetic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (0.63 g, 1.1 mmol) was obtained as a white powder in the same manner as in Example 2. . MS 467 (M + 1).

Example 10 [(2,6-Diisobutyl-4- (4-methylphenyl) -5- {2- [3- (methylsulfonyl) pyrrolidin-1-yl] -2-oxoethyl} pyridin-3-yl) methyl ] Amine ditrifluoroacetate
0.12 M [5-{[(tert-butoxycarbonyl) amino] methyl} -2,6-diisobutyl-4- (4-methylphenyl) pyridin-3-yl] acetic acid N, N-dimethylformamide solution (0.5 mL , 0.060 mmol), 0.24 M 3- (methylsulfonyl) pyrrolidine N, N-dimethylformamide solution (0.5 mL, 0.12 mmol) and 0.24 M hexafluorophosphoric acid 0- (7-azabenzotriazol-1-yl)- 1,1,3,3-Tetramethyluronium N, N-dimethylformamide solution (0.5 mL, 0.12 mmol) was sequentially added, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with dichloromethane (2 mL) and washed successively with saturated aqueous sodium hydrogen carbonate and water. The organic layer was separated, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC to give the title compound (0.035 g, yield 81%). MS 500 (M + 1).

The compounds of Examples 11 to 53 were prepared in the same manner as in Example 10 using [5-{[(tert-butoxycarbonyl) amino] methyl} -2,6-diisobutyl-4- (4-methylphenyl) pyridine- 3-Ile]
Prepared from acetic acid and free amines prepared from amines corresponding to Table 3 or salts of the corresponding amines.

The compounds of Examples 54 to 94 were prepared in the same manner as in Example 10 using [5-{[(tert-butoxycarbonyl) amino] methyl} -2-ethyl-4- (4-methylphenyl) -6-neo. [Pentylpyridin-3-yl] acetic acid and the free amines prepared from the amines corresponding to Table 4 or salts of the corresponding amines.

Experimental example 1
Measurement of dipeptidyl peptidase IV inhibitory activity in rat plasma The reaction was carried out using a 96-well flat bottom plate according to the method of Raymond et al. (Diabetes, 47, 1253-1258, 1998). Performed at 30 ° C. 69 μL of water, 10 μL of 1 M Tris-HCl buffer (pH 7.5),
1 μL of a dimethyl sulfoxide solution of a test compound was added to 100 μL of a 1 mM Gly-Pro-p-NA aqueous solution to prepare a mixed solution. Next, 20 μL of plasma prepared from SD rat blood by a conventional method was added to the above mixed solution, and an enzyme reaction was started at 30 ° C. The absorbance after 0 hour and 1 hour was measured at a wavelength of 405 nm using a microplate reader, and the increase (Δ
ODs). At the same time, the increase in absorbance (ΔODc) in the reaction solution not containing the test compound and the increase in absorbance (ΔODb) in the reaction solution not containing the test compound and enzyme were determined, and the inhibition rate of the dipeptidyl peptidase IV enzyme activity was calculated. :
{1-[(ΔODs−ΔODb) / (ΔODc−ΔODb)]} × 100
Determined by
The dipeptidyl peptidase IV inhibitory activity of the test compound group was expressed as an IC ₅₀ value (nM) and shown in Table 5.

Experimental example 2
Measurement of Dipeptidyl Peptidase IV Inhibitory Activity in Rat Plasma In the same manner as in Experimental Example 1, the inhibition rate of dipeptidyl peptidase IV enzyme activity was determined using 1 μL of an N, N-dimethylformamide solution of the test compound.
The dipeptidyl peptidase IV inhibitory activity of the test compound group was expressed as an IC ₅₀ value (nM) and is shown in Table 6.

  Thus, since the compound of the present invention has excellent dipeptidyl peptidase IV inhibitory activity, it is useful as a prophylactic / therapeutic agent for diabetes.

Formulation Example 1 (Manufacture of capsules)
1) Compound of Example 1 30 mg
2) Fine powder cellulose 10 mg
3) Lactose 19 mg
4) Magnesium stearate 1mg
60 mg total
1), 2), 3) and 4) are mixed and filled into gelatin capsules.
Formulation Example 2 (Manufacture of tablets)
1) 30 g of the compound of Example 1
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethylcellulose calcium 44 g
5) Magnesium stearate 1g
1000 tablets total 140 g
The total amount of 1), 2), and 3) and 30 g of 4) are kneaded with water, vacuum dried, and sized.
14 g of 4) and 1 g of 5) are mixed with this sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

  The compound of the present invention has an excellent peptidase inhibitory action and is useful as a prophylactic / therapeutic agent for diabetes.

Claims (12)

Formula (I):

[Wherein R ¹ represents a C _1-6 alkyl group which may be substituted with a C _3-10 cycloalkyl group,
R ² represents a C _2-6 alkyl group,
R ³ represents a hydrogen atom, a C _1-6 alkyl group or a halogen atom,
X represents —OR ⁶ or —NR ⁴ R ⁵ (R ⁴ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ⁶ represents an optionally substituted group. R ⁵ represents a hydrocarbon group that may be substituted, a heterocyclic group that may be substituted, or a hydroxy group that may be substituted. Or R ⁴ and R ⁵ together with the adjacent nitrogen atom may form an optionally substituted nitrogen-containing heterocyclic ring). ]
Or a salt thereof. The compound according to claim 1, wherein R ¹ is a C _3-6 alkyl group. The compound according to claim 1, wherein R ³ is a C _1-6 alkyl group. 1-{[5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetyl} -L-prolinamide;
The compound according to claim 1, which is or a salt thereof.   A prodrug of the compound of claim 1.   1-{[5- (aminomethyl) -2-ethyl-4- (4-methylphenyl) -6-neopentylpyridin-3-yl] acetyl} -L-prolinamide or a salt thereof.   A medicament comprising the compound according to claim 1 or a prodrug thereof.   The medicament according to claim 7, which is a prophylactic / therapeutic agent for diabetes, diabetic complications, glucose intolerance or obesity.   A peptidase inhibitor comprising the compound according to claim 1 or a prodrug thereof.   The inhibitor according to claim 9, wherein the peptidase is dipeptidyl peptidase-IV.   Use of the compound according to claim 1 or a prodrug thereof for the manufacture of a prophylactic / therapeutic agent for diabetes, diabetic complications, glucose intolerance or obesity.   Use of a compound according to claim 1 or a prodrug thereof for the manufacture of a peptidase inhibitor.