JP2006342114A - Condensed bicyclic pyridine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new condensed bicyclic pyridine derivative or a pharmacologically acceptable salt thereof exhibiting PPARγ modulator activities. <P>SOLUTION: The condensed bicyclic pyridine derivative represented by general formula (1) or the salt thereof exhibits excellent PPAR(peroxisome proliferator-activated receptor)γ modulator actions. A concrete example thereof is 7-benzylamino-5-(benzylthio)thieno[3,2-b]pyrimidine-6-carboxylic acid. The derivative and the salt thereof are useful as a medicine for treating, preventing or suppressing various pathologies (diabetes, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin resistance, obesity, hyperlipidemia, arteriosclerosis, involutional osteoporosis, or the like) in which the PPARγ participates. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a novel fused bicyclic pyridine derivative having PPARγ modulator activity or a pharmacologically acceptable salt thereof and a pharmaceutical use thereof.

Peroxisome proliferator-activated receptor (peroxisome proliferator
activated receptor (PPAR) is a member of the nuclear receptor family.

  In general, it is known that there are partial agonists or partial antagonists (these are collectively referred to as “modulators”) in addition to agonists and antagonists in the nuclear receptor group. Examples of other nuclear receptor family modulators include raloxifene and tamoxifen, which are partial agonists or partial antagonists for the estrogen receptor. Partial agonists have the property of having a lower transcriptional activity than agonists. In addition, when a partial antagonist is present simultaneously with an agonist, it suppresses transcription activation by the agonist, but is characterized in that the degree of suppression is smaller than that of the antagonist. In general, partial agonists often exhibit the properties of partial antagonists.

  These partial agonists and partial antagonists are often created with the intention of suppressing the tissue-specific undesirable effects exhibited by agonists and antagonists and eliciting tissue-specific desirable effects.

By the way, various thiazolidinedione derivatives are non-insulin dependent diabetes mellitus (NIDDM:
The model animal of non-insulin-dependent diabetes mellitus shows a hypoglycemic action and is expected as a new NIDDM having an action of releasing insulin resistance. Recent studies have revealed that these thiazolidinedione derivatives also act as PPARγ modulators and specifically activate PPARγ (Non-patent Document 1). Since there is a strong correlation between the PPARγ activation ability of such thiazolidinedione derivatives and the blood glucose lowering effect in hereditary obese mice, it is considered that PPARγ may be a target molecule for the pharmacological action of thiazolidinedione derivatives (non- Patent Document 2).

  PPARγ is considered to be a factor deeply involved in adipocyte differentiation (Non-patent Documents 3 and 4).

Furthermore, PPARγ regulates cell differentiation and lipid metabolism at the transcriptional level (Non-patent Documents 5 and 6), and PPRE (Peroxisomal).
Proliferator-activated receptor responsive element (DNA sequence recognized by PPAR) is apolipoprotein A-1 (Non-patent document 7) gene, lipoprotein lipase (Non-patent document 8, Non-patent document 9), etc., and affects serum lipid profile It is a gene promoter related to lipid metabolism.

  From these findings, PPARγ is deeply involved in pathological conditions such as diabetes, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin resistance, obesity, hyperlipidemia, arteriosclerosis, and regression osteoporosis. It is thought that there is. Therefore, development of novel compounds having excellent properties as pharmaceuticals, such as having excellent PPARγ modulator activity and few side effects, is desired as a preventive and therapeutic agent for various pathological conditions as described above.

Currently, the following compounds and the like are disclosed as compounds having PPARγ modulator activity.

(1) The specification of Patent Document 1 includes a formula:

Wherein R ¹ and R ² are independently H, halogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl and C ₁ -C ₁₀ alkoxy; Ar ¹ and Ar ² are aryl and heteroaryl; X , W ¹ and W ² are single bonds, Y or Y (CH ₂ ) _n Y ¹ ; Y and Y ¹ are single bonds, O, S, SO, SO ₂ and NR; R is H, C ₁ -C ₃ alkyl And C ₂ -C ₃ alkenyl.) And the like.

(2) The specification of Patent Document 2 includes the formula:

(In the formula, B represents a substituted aryl group, B represents a substituted aryl group, a substituted cycloalkyl group or a substituted heterocyclic group, R ^a represents H or an alkyl group, X represents a bond, O, S; , CH ₂ , CO, NH, SO ₂ NH, NHSO ₂ , CONH, NHCO, or OCH ₂ group, and n represents 0 or 1).

(3) The specification of Patent Document 3 includes the formula:

Wherein R ¹ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
X and Y are the same or different and each represents a bond or the like; Q represents a divalent hydrocarbon residue having q to 20 carbon atoms; ring A may further have 1 to 3 substituents W represents a divalent hydrocarbon residue having 1 to 20 carbon atoms; V represents a bond or the like; R ² represents an optionally substituted heterocyclic group or the like. ) And the like are disclosed.

(4) The specification of Patent Document 4 includes a formula:

(Wherein X is O or S; R ¹ , R ² and R ³ are hydrogen atoms, carboxyl groups, etc .; Ar is an aromatic ring or heterocycle; R ⁴ is H etc .; R ⁵ is H etc .; R ⁶ is H etc; R ⁷ is H or the like; Y is an oxygen atom or a nitrogen atom;. n is such compound represented by indicating from 1 to 4) is disclosed.

  However, none of the above publications disclose specific disclosure regarding fused bicyclic pyridine derivatives.

  On the other hand, in the specification of Patent Document 5, a compound having a CRF (Corticotropin releasing factor) antagonistic activity is represented by the formula:

(In the formula, A is N or CR ⁶ ; B is NR ¹ R ² or the like; R ¹ may have a substituent (alkyl / alkene / alkyne); and R ² has a substituent. R ³ is an alkylthio group, etc .; R ⁴ is a hydrogen atom, etc .; R ⁵ is an optionally substituted phenyl group, etc .; R ⁶ is a hydrogen atom, etc .; R ⁷ is R ⁶ or alkoxy A compound such as carbonyl group is disclosed, but there is no specific disclosure of the compound described in this patent, and there is no description or suggestion about the PPAR modulator action.

In the specification of Patent Document 6, a compound having a potassium channel opener action is represented by the formula:

Wherein W, X, Y, Z are CH or N; R ¹ is an alkylcarbonyl group, etc .; R ² and R ³ are hydrogen atoms, etc. There is no specific disclosure of the compounds described in this patent, and there is no description or suggestion about the action of PPAR modulator.

The specification of Patent Document 7 includes MCP-1 (Monocyte
chemoattractant protein-1) As a compound having an antagonistic action:

(W, X, Y are independently O, S, CR ⁶ R ⁷ or NR ⁷ ; Z is N or CR ⁸ ; R ¹ , R ² , R ⁶ , R ⁸ are independently SR ⁹ , NR ⁹ R ^{10 and the} like; R ⁹ and R ¹⁰ are aralkyl groups and the like; R ³ , R ⁴ , R ⁵ and R ⁷ independently represent a hydrogen atom and the like. There is no specific disclosure of the compounds described in this patent, and there is no description or suggestion about the action of PPAR modulator.
WO01 / 30343 pamphlet WO03 / 035602 pamphlet WO03 / 000685 pamphlet WO99 / 08501 pamphlet WO95 / 34563 pamphlet US2004192697 pamphlet WO02 / 81463 pamphlet Lehmann et al., Journal of Biological Chemistry, 1995, 270, p. 12953-12956. Willson et al., Journal of Medicinal Chemistry, 1996, Vol. 39, p. 665-668. Tontonoz et al., Genesand Development, 1994, Volume 8, p. 1224-1234. Tontonoz et al., Cell, 1994, 79, p. 1147-1156. Spiegelman, Eur. J. Med. Res., 1997, Volume 2, p. 457-464. Tontonoz & Nagy, Curr. Opin. Lipidol, 1999, Vol. 10, p.485-490. Steal, Atherosclerosis, 1998, 137 (suppulo), S19-S23. Schhnjans, EMBO J., 1996, 15 (suppulo), p.5536-5548. Lefebvre, Arterio Thrombo Vasc. Biol., 1997, Vol. 17, p. 17 56-1764.

  Currently, it has excellent PPARγ modulator action as a prophylactic and therapeutic agent for various pathological conditions such as the above-described preventive or therapeutic drugs for various pathological conditions, and is a sufficiently satisfactory pharmaceutical from the viewpoint of few side effects. No resulting compound has been found.

  The object of the present invention is to find a novel compound having a PPARγ modulator action, and various pathological conditions involving PPARγ (diabetes, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin resistance, obesity, high fat It is to provide a prophylactic or therapeutic agent for blood pressure, arteriosclerosis, regressive osteoporosis and the like.

  As a result of intensive studies, the present inventors have found that a condensed bicyclic pyridine derivative has a PPARγ modulator activity, and thus various pathological conditions involving PPARγ (diabetes, hypercholesterolemia, hypertriglyceridemia, Insulinemia, insulin resistance, obesity, hyperlipidemia, arteriosclerosis, degenerative osteoporosis, etc.) have been found to be useful for the treatment, prevention or suppression, and the present invention has been completed.

That is, the present invention
1) The following general formula (1)

(Where

Is

Or

Indicates;
W ¹ and W ² are the same or different and each represents O, S or NH;
Y ¹ and Y ² are the same or different and each represents a single bond or a C ₁ -C ₆ alkylene chain;
A ¹ and A ² are the same or different, an aryl group, a cycloalkyl group or a Hajime Tamaki (the A ¹ and A ² are the same or different, a halogen atom, C ₁ -C be substituted with a halogen atom ₆ alkyl group, an aryl group, a nitro group, one or two identical or different C ₁ -C ₆ alkyl which may be substituted with a group aminosulfonyl group, an amino group, mono- or di-substituted C ₁ -C ₆ alkylamino group, an oxo group, 1 to 3 substituents (adjacent two substituents selected independently from among good C ₁ -C ₆ alkoxy group optionally substituted by a hydroxyl group or a halogen atom May be bonded to each other to form a ring).
R ¹ represents OH or NR ⁶ R ⁷ ;
R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkyl group, an aryl group or an aralkyl group;
R ⁵ represents a hydrogen atom or a C ₁ -C ₆ alkylthio group;
R ⁶ and R ⁷ are the same or different and each represents a C _{1 to} C ₆ alkyl group which may be substituted with a hydrogen atom or a carboxyl group. A condensed bicyclic pyridine derivative represented by the following formula:

2) The condensed bicyclic pyridine derivative or the salt thereof according to 1), wherein R ¹ is OH or NH ₂ in the general formula (1),

3) In the general formula (1), at least one of W ¹ and W ² is a sulfur atom, and R ¹ is OH or NH _2. The condensed bicyclic pyridine derivative or a salt thereof according to 1) above,

4) In the general formula (1), at least one of W ¹ and W ² is a sulfur atom, Y ¹ and Y ² are the same or different and are a methylene chain or an ethylene chain, and R ¹ is OH or NH ₂ . The condensed bicyclic pyridine derivative or a salt thereof according to 1) above,

5) The following general formula (1a)

(Wherein W ¹ , W ² , Y ¹ , Y ² , A ¹ , A ² and R ¹ are the same as above), the condensed bicyclic pyridine derivative or a salt thereof according to 1) above,

5) The condensed bicyclic pyridine derivative or the salt thereof according to 5), wherein R ¹ is OH or NH ₂ in the general formula (1a),

6) In the general formula (1a), at least one of W ¹ and W ² is a sulfur atom, and R ¹ is OH or NH _2. The condensed bicyclic pyridine derivative or a salt thereof according to 5) above,

7) In the general formula (1a), at least one of W ¹ and W ² is a sulfur atom, Y ¹ and Y ² are the same or different and are a methylene chain or an ethylene chain, and R ¹ is OH or NH ₂ The condensed bicyclic pyridine derivative or a salt thereof according to 5) above,

8) The following general formula (1b)

(Wherein W ¹ , W ² , Y ¹ , Y ² , A ¹ , A ² and R ¹ are the same as above), the condensed bicyclic pyridine derivative or a salt thereof according to 1) above,

10) The condensed bicyclic pyridine derivative or the salt thereof according to 9), wherein R ¹ is OH or NH ₂ in the general formula (1b),

11) The condensed bicyclic pyridine derivative or a salt thereof according to 9), wherein in General Formula (1b), at least one of W ¹ and W ² is a sulfur atom, and R ¹ is OH or NH ₂ ,

12) In the general formula (1b), at least one of W ¹ and W ² is a sulfur atom, Y ¹ and Y ² are the same or different and are a methylene chain or an ethylene chain, and R ¹ is OH or NH ₂ The condensed bicyclic pyridine derivative or a salt thereof according to 9) above,

13) The following general formula (1c)

(Wherein W ¹ , W ² , Y ¹ , Y ² , A ¹ , A ² , R ¹ and R ² are the same as above) or the condensed bicyclic pyridine derivative or Its salt,

14) The condensed bicyclic pyridine derivative or a salt thereof according to the above 13), wherein R ¹ is OH or NH ₂ in the general formula (1c),

15) In the general formula (1c), at least one of W ¹ and W ² is a sulfur atom, and the condensed bicyclic pyridine derivative or a salt thereof according to 13) above, wherein R ¹ is OH or NH ₂ ;

16) In the general formula (1c), at least one of W ¹ and W ² is a sulfur atom, Y ¹ and Y ² are the same or different and are a methylene chain or an ethylene chain, and R ¹ is OH or NH ₂ The condensed bicyclic pyridine derivative or a salt thereof according to the above 13),

17) The following general formula (1d)

(Wherein W ¹ , W ² , Y ¹ , Y ² , A ¹ , A ² , R ¹ and R ³ are the same as above) or the condensed bicyclic pyridine derivative or Its salt,

18) The fused bicyclic pyridine derivative or a salt thereof according to 17), wherein, in the general formula (1d), R ¹ is OH or NH ₂ ;

19) The condensed bicyclic pyridine derivative or a salt thereof according to 17) above, wherein in general formula (1d), at least one of W ¹ and W ² is a sulfur atom, and R ¹ is OH or NH ₂ ;

20) In the general formula (1d), at least one of W ¹ and W ² is a sulfur atom, Y ¹ and Y ² are the same or different and are a methylene chain or an ethylene chain, and R ¹ is OH or NH ₂ The condensed bicyclic pyridine derivative or a salt thereof according to 17) above,

21) A therapeutic, preventive or suppressive agent for non-insulin-dependent diabetes mellitus, comprising the fused bicyclic pyridine derivative or a salt thereof according to any one of 1) to 20) as an active ingredient,

22) A therapeutic, prophylactic or inhibitory agent for obesity comprising the fused bicyclic pyridine derivative or a salt thereof according to any one of 1) to 20) as an active ingredient,

23) A therapeutic, prophylactic or inhibitory agent for hyperglycemia, comprising the fused bicyclic pyridine derivative or a salt thereof according to any one of 1) to 20) as an active ingredient,

24) A therapeutic, prophylactic or inhibitory agent for hyperlipidemia, comprising the fused bicyclic pyridine derivative or a salt thereof according to any one of 1) to 20) as an active ingredient,

25) A therapeutic, preventive or suppressive agent for hypercholesterolemia characterized by containing the fused bicyclic pyridine derivative or a salt thereof according to any one of 1) to 20) as an active ingredient,

26) A therapeutic, prophylactic or inhibitory agent for hypertriglyceridemia, comprising the fused bicyclic pyridine derivative or a salt thereof according to any one of 1) to 20) as an active ingredient,

27) A therapeutic, prophylactic or inhibitory agent for insulin resistance comprising the fused bicyclic pyridine derivative or a salt thereof according to any one of 1) to 20) as an active ingredient,

28) A therapeutic, prophylactic or inhibitory agent for hyperinsulinemia comprising the fused bicyclic pyridine derivative or a salt thereof according to any one of 1) to 20) as an active ingredient,

29) A therapeutic, prophylactic or inhibitory agent for arteriosclerosis, comprising the fused bicyclic pyridine derivative or a salt thereof according to any one of 1) to 20) as an active ingredient,

30) A therapeutic, prophylactic or inhibitory agent for degenerative osteoporosis characterized by containing the fused bicyclic pyridine derivative or a salt thereof according to any one of 1) to 20) as an active ingredient.

  The present invention has been found that a novel fused bicyclic pyridine derivative or a salt thereof has an excellent PPARγ modulator action.

  Furthermore, the compounds of the present invention and their salts are safe with low toxicity. Therefore, the compounds of the present invention and salts thereof are used in various pathologies involving PPARγ (diabetes, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin resistance, obesity, hyperlipidemia, arteriosclerosis, regression, Stage osteoporosis and the like) has high utility for treatment, prevention or suppression.

  The present invention is described in detail below.

Q ¹ , Q ² And Q ³ about

Is

Or

Indicates.

  preferable

As

as well as

Is mentioned.

For W ¹ and W ² , W ¹ and W ² are the same or different and represent S or NH. A preferred combination of W ¹ and W ² is preferably when W ¹ is S and W ² is NH.

With respect to Y ¹ and Y ² , Y ¹ and Y ² are the same or different and each represents a single bond or a C ₁ -C ₆ alkylene chain. Here, examples of the “C ₁ -C ₆ alkylene chain” include a methylene chain, an ethylene chain, a propylene chain, a butylene chain, a pentylene chain, and a hexylene chain. Preferred Y ¹ and Y ² include a single bond, a methylene chain, an ethylene chain and a propylene chain. More preferable Y ¹ and Y ² include a single bond and a methylene chain.

About A < ¹ > and A < ² >, in said General Formula (1), A < ¹ > and A < ² > are the same or different, and show an aryl group, a cycloalkyl group, or a heterocyclic group. A ¹ and A ² may be the same or different and may have a substituent. The substituent may be substituted at any substitutable position in the ring, and the number thereof may be about 1 to 3. Two adjacent substituents may be bonded to each other to form a ring. Examples of the substituent for A ¹ and A ² include a halogen atom, a C _{1 to} C ₆ alkyl group optionally substituted with a halogen atom, an aryl group, a nitro group, one or two identical or different C atoms. ₁ -C ₆ alkyl optionally substituted aminosulfonyl group by group, amino group, mono- or di-substituted C ₁ -C ₆ alkylamino group, an oxo group, a hydroxyl group, and may C ₁ optionally substituted by a halogen atom -C ₆ alkoxy group, and the like.

  Here, examples of the “aryl group” include an aromatic hydrocarbon group having 5 to 14 carbon atoms such as a phenyl group, an indenyl group, a naphthyl group, a phenanthrenyl group, and an anthracenyl group.

  Examples of the “cycloalkyl group” include 3 to 10-membered saturated hydrocarbon group which may be condensed such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, norbornyl group and adamantyl group. be able to.

  The “heterocyclic group” is a 5- to 7-membered heterocyclic group containing 1 to 4 atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom. For example, a furyl group, a thienyl group, a pyrrolyl group , Azepinyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, 1,2,3-oxadiazolyl group, triazolyl group, tetrazolyl group, thiadiazolyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrimidinyl And aromatic heterocyclic groups such as groups, pyrazinyl groups, and groups such as morpholyl groups, thiomorpholinyl groups, pyrrolidinyl groups, pyrrolinyl groups, imidazolidinyl groups, imidazolinyl groups, pyrazolidinyl groups, pyrazolinyl groups, piperidyl groups, piperazinyl groups, etc. Can do. The “heterocyclic group” may be condensed with another cyclic group, for example, an isobenzofuranyl group, a benzoxazolyl group, a benzoisoxazolyl group, a benzothiazolyl group, a benzoisothiazo group. Ryl, chromenyl, chromanonyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolidinyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl Quinoxalinyl group, quinazolinyl group, carbazolyl group, carbolinyl group, acridinyl group, isoindolinyl group and the like.

  “Halogen atom” includes fluorine atom, chlorine atom, bromine atom, iodine atom and the like.

Examples of the “C ₁ -C ₆ alkyl group optionally substituted with a halogen atom” include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. , Fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, 1-fluoroethyl group, 1-chloroethyl group, 2-chloroethyl group, difluoromethyl group, trifluoromethyl group, trichloromethyl group, 2,2,2- A trifluoroethyl group etc. are mentioned.

Examples of the “aminosulfonyl group optionally substituted by one or two identical or different C ₁ -C ₆ alkyl groups” include an aminosulfonyl group, a methylaminosulfonyl group, an ethylaminosulfonyl group, and a dimethylaminosulfonyl group. Etc.

Examples of the “mono- or di-substituted C ₁ -C ₆ alkylamino group” include methylamino group, ethylamino group, propylamino group, butylamino group, pentylamino group, hexylamino group, dimethylamino group, diethylamino group, dipropyl Amino group, dibutylamino group, dipentylamino group, dihexylamino group, diisopropylamino group, ethylmethylamino group, methylpropylamino group, methylbutylamino group, methylpentylamino group, methylhexylamino group, 2-hydroxyethylamino group 3-hydroxypropylamino group, 4-hydroxybutylamino group, 2-methoxyethylamino group, 3-methoxypropylamino group, 4-methoxybutylamino group, 2-aminoethylamino group, 3-aminopropylamino group, 4-aminobutylamino group Methoxycarbonylmethyl group, carboxymethyl methylamino group.

Examples of the “C ₁ -C ₆ alkoxy group optionally substituted with a halogen atom” include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, Fluoromethoxy group, chloromethoxy group, bromomethoxy group, iodomethoxy group, 1-fluoroethoxy group, 1-chloroethoxy group, 2-chloroethoxy group, difluoromethoxy group, trifluoromethoxy group, trichloromethoxy group, 2,2 , 2-trifluoroethoxy group and the like.

  As the “ring which two adjacent substituents may combine to form each other”, when the two substituents forming the ring are both present on the same carbon, for example,

And when two substituents forming a ring are adjacent to each other, for example,

Etc.

Preferable A ^{1 includes} , for example, phenyl group, pyridyl group, furyl group, thienyl group, cyclohexyl group and the like. More preferable A ¹ includes a phenyl group and the like.

Preferable A ^{2 includes} , for example, phenyl group, pyridyl group, furyl group, thienyl group, cyclohexyl group and the like. More preferable A ² includes a phenyl group and the like.

R ¹ for R ¹ represents OH or NR ⁶ R ⁷ . Preferable R ¹ includes OH.

R ³ , R ⁴ and R ⁵ are the same or different with respect to R ² , R ³ and R ⁴ and represent a hydrogen atom, a C _{1 to} C ₆ alkyl group, an aryl group or an aralkyl group. Here, the “aryl group” is the same as described above.

Examples of the “C ₁ -C ₆ alkyl group” include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like.

  Examples of the “aralkyl group” include benzyl group, phenethyl group, 3-phenylpropyl group, α-methylbenzyl group and the like.

For R ⁵ , R ² represents a hydrogen atom or a C ₁ -C ₆ alkylthio group. Here, examples of the “C ₁ -C ₆ alkylthio group” include a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, and a hexylthio group.

Regarding R ⁶ and R ⁷ , R ⁶ and R ⁷ are the same or different and represent a C _{1 to} C ₆ alkyl group which may be substituted with a hydrogen atom or a carboxyl group.
R ⁶ and R ⁷ are preferably both hydrogen atoms.

Preferred compounds of the present invention include, for example,
7-benzylamino-5- (benzylthio) thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio-7- (4-chlorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio-7- (4-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio-7- (3-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio-7- (2-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio-7- (4-methoxybenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio-7- (4-methylbenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio-7- [4- (trifluoromethoxy) benzylamino] thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio-7- (2-phenethylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio-7- [4- (trifluoromethyl) benzylamino] thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio-7- (cyclohexylmethylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio-7- (3-pyridylmethylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio-7- (2-pyridylmethylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid,
7-anilino-5- (benzylthio) thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio- (3-methoxybenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid,
5-benzylthio- (2-methoxybenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid,
Examples thereof include 4-benzylamino-6-benzylthio-1-methyl-1H-pyrazolo [3,4-b] pyrimidine-5-carboxylic acid.

When the compound of the present invention forms a salt, it means a salt with a pharmaceutically acceptable non-toxic base or acid (for example, an inorganic or organic base and an inorganic or organic acid). Salts derived from pharmaceutically acceptable non-toxic bases include inorganic bases such as aluminum, ammonium, calcium, copper, ferrous, ferric, lithium, magnesium, manganese, manganite, potassium and sodium. Salts (particularly preferably ammonium, calcium, manganese, potassium and sodium salts) or primary, secondary, tertiary amines, substituted amines (eg naturally occurring substituted amines), cyclic amines and bases Organic bases such as ionic ion exchange resins (eg, arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl) Morpholine, N-ethylpiperidine, gluca And a salt with mine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, tripropylamine, tripropylamine, tromethamine and the like. Examples of salts derived from non-toxic acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, Examples thereof include pharmaceutically acceptable salts with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid.

  Furthermore, this invention compound or its salt may exist as a hydrate or a solvate. Any of the hydrates and solvates formed by the condensed bicyclic pyridine derivative represented by the general formula (1) or a salt thereof, including the preferred compounds specifically described above, are all included in the present invention. It is included in the range. Solvents that can form solvates include methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, diisopropyl ether, and the like.

  The compound of the present invention or a salt thereof includes an optically active substance, a stereoisomer or a rotational isomer in addition to a racemate.

  The compound of the present invention can be produced by various synthetic methods. Next, typical production methods of the compound of the present invention and salts thereof will be described.

(Method A)

(First step)
This step is a step of producing the compound (c) by substituting the chloro atom of the compound (a) with the compound (b). This step is carried out in the presence or absence of an organic base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, DBU or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium acetate. The reaction can be carried out in a solvent such as dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, mesitylene, pyridine, quinoline, dichloromethane and the like. This reaction proceeds smoothly at a temperature from 0 ° C. to the boiling point of the solvent when a solvent is used.

Compound (a) is, for example, Journal of Chemical Research (Journal of Chemical Research).
Chemical Research), 1982, Vol. 6, 158, etc., or a method analogous thereto.

(Second step)
This step is a step for producing the compound (e) by substituting the chloro atom of the compound (c) with the compound (d). This step can be performed according to the first step.

(Third process)
This step is a step of producing compound (f) by hydrolyzing the ester group of compound (h).

  This step is performed in a suitable solvent in the presence of a base according to a conventional method. Examples of the base include alkali metal salts such as potassium hydroxide and sodium hydroxide. Examples of the solvent used in this reaction include tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, propanol, isopropanol, butanol, water, and the like. The reaction temperature is usually about 0 to about 150 ° C. The reaction time is usually about 0.5 to about 48 hours.

(Method B)

(First step)
This step is a step for producing the compound (h) by substituting the chloro atom of the compound (g) with the compound (b). This step can be carried out according to the first method A.

Compound (g) is, for example, Journal of Chemical Research (Journal of Chemical Research).
Chemical Research), 1985, Vol. 7, p. 214, etc., or a method analogous thereto.

(Second step)
This step is a step for producing the compound (i) by substituting the chloro atom of the compound (h) with the compound (d). This step can be performed according to the second method A.

(Third process)
This step is a step of producing compound (j) by hydrolyzing the ester group of compound (i). This step can be performed in accordance with the third step of Method A.

(C method)

(First step)
This step is a step for producing the compound (l) by converting the hydroxyl group or oxo group of the compound (k) to a chloro atom. This step is performed using thionyl chloride, phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride. When a solvent is used, an inert solvent that does not participate in the reaction, for example, N, N-dimethylformamide, sulfolane, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, toluene, pyridine and the like are used. This reaction smoothly proceeds at a temperature from room temperature to the boiling point of the chlorinating agent or the boiling point of the solvent when a solvent is used. Further, as an additive, a tertiary amine such as N, N-dimethylaniline, a quaternary ammonium salt such as benzyltriethylammonium chloride, and the like can be added.

Compound (k) is, for example, bioorganic and medicinal chemistry (Bioorganic).
& Medicinal Chemistry), 2003, Vol. 11, p. 2991, etc., or a method analogous thereto.

(Second step)
This step is a step for producing the compound (m) by substituting the chloro atom of the compound (l) with the compound (b). This step can be carried out according to the first method A.

(Third process)
This step is a step for producing the compound (n) by substituting the chloro atom of the compound (m) with the compound (d). This step can be performed according to the second method A.

(Fourth process)
This step is a step of producing the compound (o) by hydrolyzing the ester group of the compound (n). This step can be performed in accordance with the third step of Method A.

(First step)
In this step, compound (r) is produced by reacting compound (p) with compound (q). In this reaction, 1 to 50 equivalents, preferably 5 to 20 equivalents, of compound (q) is used with respect to compound (p), and 0 to 300 ° C., preferably 50, in the presence or absence of a solvent. Performed at ~ 200 ° C. When using a solvent, for example, methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, xylene, mesitylene, nitrobenzene, diphenyl ether, etc. are used. It is done.

Compound (p) is, for example, Chemical and Pharmaceutical Bulletin (Chemical
& Pharmaceutical Bulletin), 1995, 43, 788, etc., or a method analogous thereto.

(Second step)
This step is a step of producing compound (r) by cyclizing compound (q) in the molecule. This reaction is carried out in the presence of a suitable base at −50 to 200 ° C., preferably 0 to 100 ° C. When using a solvent, for example, methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, xylene, mesitylene, nitrobenzene, diphenyl ether, etc. are used. It is done. Examples of the base used in this step include alkoxides with alkali metals such as sodium methoxide and potassium methoxide, sodium hydride, potassium hydride and the like.

(Third process)
This step is a step of producing the compound (s) by converting the hydroxyl group or oxo group of the compound (r) to a chloro atom. This step can be carried out according to the first method A.

(Fourth process)
This step is a step for producing the compound (m) by substituting the chloro atom of the compound (l) with the compound (b). This step can be carried out according to the first method A.

(Fifth process)
This step is a step for producing the compound (n) by substituting the chloro atom of the compound (m) with the compound (d). This step can be performed according to the second method A.

(Sixth process)
This step is a step of producing the compound (o) by hydrolyzing the ester group of the compound (n). This step can be performed in accordance with the third step of Method A.

  The compound (1) of the present invention can be isolated and purified by ordinary separation means (for example, extraction, recrystallization, distillation, chromatography, etc.). Moreover, when the obtained compound forms a salt, various salts can be produced by a usual method or a method equivalent thereto (for example, neutralization). The compound (1) of the present invention or a salt thereof alone or mixed with an appropriate pharmacologically acceptable excipient or diluent, such as tablets, capsules, granules, powders or syrups It can be administered as a pharmaceutical composition orally or parenterally as a preparation such as an injection or suppository. These preparations are produced by known methods using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents.

  The excipient may be an organic excipient or an inorganic excipient. The organic economy is, for example, sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α starch, dextrin; cellulose derivatives such as crystalline cellulose; Dextran; or pullulan and the like. Inorganic excipients include, for example, light inorganic silicic acid, synthetic aluminum silicate, calcium silicate, magnesium silicate derivatives such as magnesium aluminate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; Alternatively, it may be a sulfate such as calcium sulfate.

  Lubricants include, for example, stearic acid, calcium stearate, magnesium stearate such as magnesium stearate; talc; colloidal silica; waxes such as bee gum; adipic acid; sulfate such as sodium sulfate; glycol; It can be an acid; sodium benzoate; DL-leucine; fatty acid sodium; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid such as anhydrous silicic acid and silicic acid hydrate; or the starch derivative.

  The binder can be, for example, hydroxypropylcellulose, hydroxymethylpropylcellulose, polyvinylpyrrolidone, macrogol, or a compound similar to the excipients described above.

  Disintegrants are, for example, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose; or chemically modified such as carboxymethyl starch, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone. Starches and celluloses.

  Stabilizers include, for example, parahydroxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenethyl alcohol; benzalkonium chloride; cresols such as phenol and cresol; thimerosal; Can be dehydroacetic acid; or sorbic acid.

  The flavoring agent can be, for example, commonly used sweeteners, acidulants, and fragrances.

  The dose varies depending on the type of the compound (1) or salt thereof, the route of administration, the age of the patient, symptoms, etc., but for example, 0.001 as the compound (1) or salt thereof for mammals including humans. ~ 500 mg / kg / day. Administration is, for example, once a day or divided into several times.

Hereinafter, based on an Example, a reference example, and a test example, this invention is demonstrated in detail. Moreover, since the novel compound is contained also in the raw material compound used for manufacture of this invention compound (1), the manufacture example of a raw material compound is demonstrated as a reference example. The compounds of the present invention are not limited to the compounds described in the following examples, and may be changed without departing from the scope of the present invention.

<Example 1>

To a solution of ethyl 7-benzylamino-5- (benzylthio) thieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 1; 51.0 mg, 0.117 mmol) in ethanol (1 mL) was added 3 mol / L aqueous potassium hydroxide solution (0.5 mL) was added, and the mixture was heated to reflux for 5 hours. Water and 2 mol / L hydrochloric acid were added to the reaction mixture to adjust to pH = 1, and the precipitated crystals were collected by filtration to give 7-benzylamino-5- (benzylthio) thieno [3,2-b] pyrimidine-6-carboxylic acid. The acid was obtained (29.6 mg, 62%).
MS (FAB ⁺ ) m / z: 407 (M + H ⁺ )
_{^{HRMS (FAB +): C 22}} H 19 N 2 O 2 S 2 Calculated: 407.0888

Actual value: 408.0883

<Example 2>

In the same manner as in Example 1, ethyl 5-benzylthio-7- (4-chlorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 2; 119 mg, 0.254 mmol) Gave 5-benzylthio-7- (4-chlorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid (111 mg, 99%).
MS (FAB ⁺ ) m / z: 441 (M + H ⁺ )
_{^{HRMS (FAB +): C 22}} H 18 ClN 2 O 2 S 2 Calculated: 441.0498

Actual value: 441.0504

<Example 3>

In the same manner as in Example 1, ethyl 5-benzylthio-7- (4-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 3; 30.0 mg, 66. From 3 μmol) gave 5-benzylthio-7- (4-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid (18.5 mg, 66%).
MS (FAB ⁺ ) m / z: 425 (M + H ⁺ )
_{^{HRMS (FAB +): C 22}} H 18 FN 2 O 2 S 2 Calculated: 425.0794

Actual value: 425.0797

<Example 4>

In the same manner as in Example 1, ethyl 5-benzylthio-7- (3-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 4; 72.5 mg, 0. 160 mmol) gave 5-benzylthio-7- (3-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid (52.3 mg, 77%).
MS (FAB ⁺ ) m / z: 425 (M + H ⁺ )
_{^{HRMS (FAB +): C 22}} H 18 FN 2 O 2 S 2 Calculated: 425.0797

<Example 5>

In the same manner as in Example 1, ethyl 5-benzylthio-7- (2-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 5; 98.4 mg, 0. 217 mmol) gave 5-benzylthio-7- (2-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid (88.5 mg, 96%).
MS (FAB ⁺ ) m / z: 425 (M + H ⁺ )
_{^{HRMS (FAB +): C 22}} H 18 FN 2 O 2 S 2 Calculated: 425.0797

Actual value: 425.0789

<Example 6>

In the same manner as in Example 1, ethyl 5-benzylthio-7- (4-methoxybenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 6; 96.7 mg, 0. 208 mmol) gave 5-benzylthio-7- (4-methoxybenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid (88.2 mg, 97%).
MS (FAB ⁺ ) m / z: 437 (M + H ⁺ )
_{^{HRMS (FAB +): C 23}} H 21 N 2 O 3 S 2 Calculated: 437.0994

Actual value: 437.1018

<Example 7>

In the same manner as in Example 1, ethyl 5-benzylthio-7- (4-methylbenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 7; 57.9 mg, 0. 129 mmol) gave 5-benzylthio-7- (4-methylbenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid (50.6 mg, 93%).
MS (FAB ⁺ ) m / z: 421 (M + H ⁺ )
_{^{HRMS (FAB +): C 23}} H 21 N 2 O 2 S 2 Calculated: 421.1044

Actual value: 421.1078

<Example 8>

In the same manner as in Example 1, ethyl 5-benzylthio-7- [4- (trifluoromethoxy) benzylamino] thieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 8; 58. 5 mg, 0.113 mmol) gave 5-benzylthio-7- [4- (trifluoromethoxy) benzylamino] thieno [3,2-b] pyrimidine-6-carboxylic acid (53.5 mg, 97% ).
MS (FAB ⁺ ) m / z: 491 (M + H ⁺ )
_{^{HRMS (FAB +): C 23}} H 18 F 3 N 2 O 3 S 2 Calculated: 491.0711

Actual value: 491.0744

<Example 9>

N, N-dimethylformamide of ethyl 5-chloro-7- (2-phenethylamino) thieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 9; 74.3 mg, 0.206 mmol) To the solution, phenylmethanethiol (24 μL, 0.207 mmol) and potassium carbonate (28.5 mg, 0.206 mmol) were added, and the mixture was heated and stirred at 100 ° C. for 8 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1). Then, 3 mol / L potassium hydroxide aqueous solution (0.5 mL) was added to the ethanol (1 mL) solution of the obtained residue, and it heated and refluxed for 5 hours. Water and 2 mol / L hydrochloric acid were added to the reaction mixture to adjust to pH = 1, and the precipitated crystals were collected by filtration to give 5-benzylthio-7- (2-phenethylamino) thieno [3,2-b] pyrimidine. -6-carboxylic acid was obtained (11.7 mg, 14%).
MS (FAB ⁺ ) m / z: 421 (M + H ⁺ )
_{^{HRMS (FAB +): C 23}} H 22 N 2 O 2 S 2 Calculated: 421.1044

Actual value: 421.1057

<Example 10>

In the same manner as in Example 9, ethyl 5-chloro-7- [4- (trifluoromethyl) benzylamino] thieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 10; 142 mg, 0.342 mmol) and phenylmethanethiol (50 μL, 0.410 mmol) give 5-benzylthio-7- [4- (trifluoromethyl) benzylamino] thieno [3,2-b] pyrimidine-6-carboxylic acid. (41.1 mg, 25%).
MS (FAB ⁺ ) m / z: 475 (M + H ⁺ )
_{^{HRMS (FAB +): C 23}} H 18 F 3 N 2 O 2 S 2 Calculated: 475.0762

Actual value: 475.0791

<Example 11>

In the same manner as in Example 9, ethyl 5-chloro-7- (cyclohexylmethylamino) thieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 11; 47.1 mg, 0.133 mmol) And phenylmethanethiol (19 μL, 0.160 mmol) gave 5-benzylthio-7- (cyclohexylmethylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid (3.2 mg, 6%) .
MS (FAB ⁺ ) m / z: 413 (M + H ⁺ )
_{^{HRMS (FAB +): C 22}} H 25 N 2 O 2 S 2 Calculated: 413.1357

Actual value: 413.1385

<Example 12>

In the same manner as in Example 9, ethyl 5-chloro-7- (3-pyridylmethylamino) thieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 12; 71.7 mg, 0. 206 mmol) and phenylmethanethiol (29 μL, 0.247 mmol) gave 5-benzylthio-7- (3-pyridylmethylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid (12.8 mg). 15%).
MS (FAB ⁺ ) m / z: 408 (M + H ⁺ )
_{^{HRMS (FAB +): C 21}} H 18 N 3 O 2 S 2 Calculated: 408.0840

Actual value: 408.0860

<Example 13>

In the same manner as in Example 9, ethyl 5-chloro-7- (2-pyridylmethylamino) thieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 13; 123 mg, 0.352 mmol) And phenylmethanethiol (50 μL, 0.387 mmol) gave 5-benzylthio-7- (2-pyridylmethylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid (25.0 mg, 24 %).
MS (FAB ⁺ ) m / z: 408 (M + H ⁺ )
_{^{HRMS (FAB +): C 21}} H 18 N 3 O 2 S 2 Calculated: 408.0840

Actual value: 408.0875

<Example 14>

To a solution of ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 24; 310 mg, 1.12 mmol) in N, N-dimethylformamide (3 mL), aniline (0. 10 mL, 1.12 mmol) and potassium carbonate (155 mg, 1.12 mmol) were added and stirred at 100 ° C. for 8 hours. The reaction mixture was diluted with ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1). To a solution of the obtained residue in N, N-dimethylformamide (1 mL), phenylmethanethiol (76 μL, 0.620 mmol) and cesium carbonate (202 mg, 0.620 mmol) were added, and the mixture was stirred with heating at 100 ° C. for 8 hours. The reaction mixture was diluted with ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1). Then, 3 mol / L potassium hydroxide aqueous solution (0.5 mL) was added to the ethanol (1 mL) solution of the obtained residue, and it heated and refluxed for 5 hours. Water and 2 mol / L hydrochloric acid were added to the reaction mixture to adjust to pH = 1, and the precipitated crystals were collected by filtration to give 7-anilino-5- (benzylthio) thieno [3,2-b] pyrimidine-6-carboxylic acid. Was obtained (15.2 mg, 3%).
MS (FAB ⁺ ) m / z: 393 (M + H ⁺ )
HRMS (FAB ⁺ ): Calculated as C ₂₁ H ₁₇ N ₂ O ₂ S ₂ : 393.0731

Actual value: 393.0774

<Example 15>

In the same manner as in Example 14, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 293 mg, 1.06 mmol), 3-methoxybenzylamine (0 .14 mL, 1.06 mmol) and phenylmethanethiol (0.13 mL, 1.10 mmol) gave 5-benzylthio- (3-methoxybenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid. (15.1 mg, 4%).
MS (FAB ⁺ ) m / z: 437 (M + H ⁺ )
_{^{HRMS (FAB +): C 23}} H 21 N 2 O 3 S 2 Calculated: 437.0994

Actual value: 437.0993

<Example 16>

In the same manner as in Example 14, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 24; 293 mg, 1.06 mmol), 2-methoxybenzylamine (0 .14 mL, 1.06 mmol) and phenylmethanethiol (0.13 mL, 1.10 mmol) give 5-benzylthio- (2-methoxybenzylamino) thieno [3,2-b] pyrimidine-6-carboxylic acid. (28.5 mg, 6%).
MS (FAB ⁺ ) m / z: 437 (M + H ⁺ )
_{^{HRMS (FAB +): C 23}} H 21 N 2 O 3 S 2 Calculated: 437.0994

Actual value: 437.1023

<Example 17>

In the same manner as in Example 1, ethyl 4-benzylamino-6-benzylthio-1-methyl-1H-pyrazolo [3,4-b] pyrimidine-5-carboxylate (the compound of Reference Example 22; 22.0 mg, From 50.9 μmol) gave 4-benzylamino-6-benzylthio-1-methyl-1H-pyrazolo [3,4-b] pyrimidine-5-carboxylic acid (20.0 mg, 97%).
MS (FAB ⁺ ) m / z: 405 (M + H ⁺ )
_{^{HRMS (FAB +): C 22}} H 21 N 4 O 2 S Calculated: 405.1385

Actual value: 405.1393

<Reference Example 1>

N, N-dimethylformamide (0.5 mL) solution of ethyl 7-benzylamino-5-chlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 14; 69.4 mg, 0.200 mmol) Were added phenylmethanethiol (25.0 mg, 0.201 mmol) and potassium carbonate (27.7 mg, 0.200 mmol), and the mixture was heated and stirred at 100 ° C. for 8 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 7-benzylamino-5- (benzylthio) thieno [3,2-b] pyrimidine- Ethyl 6-carboxylate was obtained (53.0 mg, 61%).
MS (FAB ⁺ ) m / z: 434 (M ⁺ )
_{^{HRMS (FAB +): C 24}} H 22 N 2 O 2 S 2 Calculated: 434.1123

Actual value: 434.1081

<Reference Example 2>

In the same manner as in Reference Example 1, ethyl 5-chloro-7- (4-chlorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 15; 375 mg, 0.982 mmol) And phenylmethanethiol (0.139 mL, 1.18 mmol) gave ethyl 5-benzylthio-7- (4-chlorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (199 mg, 43%).
MS (FAB ⁺ ) m / z: 469 (M + H ⁺ )
HRMS (FAB ⁺ ): Calculated as C ₂₄ H ₂₂ ClN ₂ O ₂ S ₂ : 469.0811

Actual value: 469.0815

<Reference Example 3>

In the same manner as in Reference Example 1, ethyl 5-chloro-7- (4-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 16; 189 mg, 0.518 mmol) And phenylmethanethiol (70 μL, 0.621 mmol) gave ethyl 5-benzylthio-7- (4-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (41.0 mg, 17%).
MS (EI) m / z: 452 (M ⁺ )
HRMS (EI): Calculated as C ₂₄ H ₂₂ FN ₂ O ₂ S ₂ : 452.1028

Actual value: 452.1063

<Reference Example 4>

In the same manner as in Reference Example 1, ethyl 5-chloro-7- (3-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 17; 282 mg, 0.774 mmol) And phenylmethanethiol (0.11 mL, 0.929 mmol) gave ethyl 5-benzylthio-7- (3-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (82. 0 mg, 23%).
MS (EI) m / z: 452 (M ⁺ )
HRMS (EI): Calculated as C ₂₄ H ₂₂ FN ₂ O ₂ S ₂ : 452.1028

Actual value: 452.0984

<Reference Example 5>

In the same manner as in Reference Example 1, ethyl 5-chloro-7- (2-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 18; 262 mg, 0.720 mmol) And phenylmethanethiol (0.10 mL, 0.860 mmol) gave ethyl 5-benzylthio-7- (2-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (112 mg, 34%).
MS (EI) m / z: 452 (M ⁺ )
HRMS (EI): Calculated as C ₂₄ H ₂₂ FN ₂ O ₂ S ₂ : 452.1028

Actual value: 452.1055

<Reference Example 6>

In the same manner as in Reference Example 1, ethyl 5-chloro-7- (4-methoxybenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 19; 254 mg, 0.675 mmol) And phenylmethanethiol (0.10 mL, 0.860 mmol) gave ethyl 5-benzylthio-7- (4-methoxybenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (108 mg, 34%).
MS (EI) m / z: 464 (M ⁺ )
_{HRMS (EI): C 25 H} 24 N 2 O 3 S 2 Calculated: 464.1228

Actual value: 464.1213

<Reference Example 7>

In the same manner as in Reference Example 1, ethyl 5-chloro-7- (4-methylbenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 20; 157 mg, 0.434 mmol) And phenylmethanethiol (60 μL, 0.521 mmol) gave ethyl 5-benzylthio-7- (4-methylbenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (118 mg, 60% ).
MS (EI) m / z: 448 (M ⁺ )
_{HRMS (EI): C 25 H} 24 N 2 O 2 S 2 Calculated: 448.1279

Actual value: 448.1292

<Reference Example 8>

In the same manner as in Reference Example 1, ethyl 5-chloro-7- [4- (trifluoromethyl) benzylamino] thieno [3,2-b] pyrimidine-6-carboxylate (the compound of Reference Example 21; 234 mg, 0.588 mmol) and phenylmethanethiol (80 μL, 0.706 mmol) yields ethyl 5-benzylthio-7- [4- (trifluoromethyl) benzylamino] thieno [3,2-b] pyrimidine-6-carboxylate Obtained (67.2 mg, 22%).
MS (EI) m / z: 518 (M ⁺ )
_{HRMS (EI): C 25 H} 21 F 3 N 2 O 3 S 2 Calculated: 518.0946

Actual value: 518.0910

<Reference Example 9>

In the same manner as in Reference Example 1, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 104 mg, 0.376 mmol) and phenethylamine (94 μL, 0.747 mmol) ) Gave ethyl 5-chloro-7- (2-phenethyl) thieno [3,2-b] pyrimidine-6-carboxylate (85.8 mg, 63%).
MS (FAB ⁺ ) m / z: 361 (M + H ⁺ )
HRMS (FAB ⁺ ): Calculated as C ₁₈ H ₁₈ ClN ₂ O ₂ S: 361.0778

Actual value: 361.0770

<Reference Example 10>

In the same manner as in Reference Example 1, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 104 mg, 0.376 mmol) and 4- (trifluoromethyl) Benzylamine (50 μL, 0.376 mmol) gave ethyl 5-chloro-7- [4- (trifluoromethyl) benzylamino] thieno [3,2-b] pyrimidine-6-carboxylate (33. 0 mg, 21%).
MS (EI) m / z: 414 (M ⁺ )
HRMS (EI): Calculated as C ₁₈ H ₁₄ ClF ₃ N ₂ O ₂ S: 414.0417

Actual value: 414.0455

<Reference Example 11>

In the same manner as in Reference Example 1, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 179 mg, 0.647 mmol) and cyclohexylmethylamine (84 μL, 0 .647 mmol) gave ethyl 5-chloro-7- (cyclohexylmethylamino) thieno [3,2-b] pyrimidine-6-carboxylate (51.1 mg, 22%).
MS (EI) m / z: 352 (M ⁺ )
HRMS (EI): Calculated as C ₁₇ H ₂₁ ClN ₂ O ₂ S: 352.1012

Actual value: 352.1045

<Reference Example 12>

In the same manner as in Reference Example 1, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 154 mg, 0.557 mmol) and 3-pyridylmethylamine (60 μL) 0.557 mmol) gave ethyl 5-chloro-7- (3-pyridylmethylamino) thieno [3,2-b] pyrimidine-6-carboxylate (74.7 mg, 39%).
MS (EI) m / z: 347 (M ⁺ )
HRMS (EI): Calculated as C ₁₆ H ₁₄ ClN ₃ O ₂ S: 347.0495

Actual value: 347.0476

<Reference Example 13>

In the same manner as in Reference Example 1, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 195 mg, 0.705 mmol) and 2-pyridylmethylamine (60 μL) 0.557 mmol) gave ethyl 5-chloro-7- (2-pyridylmethylamino) thieno [3,2-b] pyrimidine-6-carboxylate (125 mg, 51%).
MS (EI) m / z: 347 (M ⁺ )
HRMS (EI): Calculated as C ₁₆ H ₁₄ ClN ₃ O ₂ S: 347.0495

Actual value: 347.0493

<Reference Example 14>

In the same manner as in Reference Example 1, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 74.0 mg, 0.268 mmol) and benzylamine (145 mg, 1.35 mmol) gave ethyl 7-benzylamino-5-chlorothieno [3,2-b] pyrimidine-6-carboxylate (67.0 mg, 72%).
MS (FAB ⁺ ) m / z: 347 (M + H ⁺ )
HRMS (FAB ⁺ ): Calculated as C ₁₇ H ₁₆ ClN ₂ O ₂ S: 347.0621

Actual value: 347.0620

<Reference Example 15>

In the same manner as in Reference Example 1, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 110 mg, 0.399 mmol) and 4-chlorobenzylamine (60 μL) 0.557 mmol) gave ethyl 5-chloro-7- (4-chlorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (76.3 mg, 50%).
MS (EI) m / z: 380 (M ⁺ )
_{HRMS (EI): C 17 H} 14 Cl 2 N 2 O 2 S Calculated: 380.0153

Actual value: 380.0115

<Reference Example 16>

In the same manner as in Reference Example 1, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 120 mg, 0.399 mmol) and 4-fluorobenzylamine (60 μL) 0.557 mmol) gave ethyl 5-chloro-7- (4-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (50.8 mg, 32%).
MS (EI) m / z: 364 (M ⁺ )
HRMS (EI): Calculated as C ₁₇ H ₁₄ ClFN ₂ O ₂ S: 364.0449

Actual value: 364.0446

<Reference Example 17>

In the same manner as in Reference Example 1, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 113 mg, 0.409 mmol) and 3-fluorobenzylamine (60 μL) 0.557 mmol) gave ethyl 5-chloro-7- (3-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (30.0 mg, 20%).
MS (EI) m / z: 364 (M ⁺ )
HRMS (EI): Calculated as C ₁₇ H ₁₄ ClFN ₂ O ₂ S: 364.0449

Actual value: 364.0452

<Reference Example 18>

In the same manner as in Reference Example 1, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 127 mg, 0.460 mmol) and 2-fluorobenzylamine (50 μL) 0.460 mmol) gave ethyl 5-chloro-7- (2-fluorobenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (121 mg, 72%).
MS (EI) m / z: 364 (M ⁺ )
HRMS (EI): Calculated as C ₁₇ H ₁₄ ClFN ₂ O ₂ S: 364.0449

Actual value: 364.0468

<Reference Example 19>

In the same manner as in Reference Example 1, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 107 mg, 0.389 mmol) and 4-methoxybenzylamine (50 μL) 0.389 mmol) gave ethyl 5-chloro-7- (4-methoxybenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (65.3 mg, 44%).
MS (EI) m / z: 376 (M ⁺ )
HRMS (EI): Calculated as C ₁₈ H ₁₇ ClN ₂ O ₃ S: 376.0648

Actual value: 376.0642

<Reference Example 20>

In the same manner as in Reference Example 1, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 102 mg, 0.369 mmol) and 4-methylbenzylamine (90 μL) 0.734 mmol) gave ethyl 5-chloro-7- (4-methylbenzylamino) thieno [3,2-b] pyrimidine-6-carboxylate (41.2 mg, 31%).
MS (FAB ⁺ ) m / z: 361 (M + H ⁺ )
HRMS (FAB ⁺ ): Calculated as C ₁₈ H ₁₈ ClN ₂ O ₂ S: 361.0778

Actual value: 361.0736

<Reference Example 21>

In the same manner as in Reference Example 1, ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate (Compound of Reference Example 24; 107 mg, 0.386 mmol) and 4- (trifluoromethoxy) Benzylamine (60 μL, 0.386 mmol) gave ethyl 5-chloro-7- [4- (trifluoromethoxy) benzylamino] thieno [3,2-b] pyrimidine-6-carboxylate (26. 6 mg, 16%).
MS (EI) m / z: 430 (M ⁺ )
HRMS (EI): Calculated as C ₁₈ H ₁₄ ClF ₃ N ₂ O ₃ S: 430.0366

Actual value: 430.0350

<Reference Example 22>

In the same manner as in Reference Example 1, ethyl 4-benzylamino-6-chloro-1-methyl-1H-pyrazolo [3,4-b] pyrimidine-5-carboxylate (the compound of Reference Example 23; 80.0 mg, 0.232 mmol) and phenylmethanethiol (30.0 mg, 0.242 mmol) yielded ethyl 4-benzylamino-6-benzylthio-1-methyl-1H-pyrazolo [3,4-b] pyrimidine-5-carboxylate Obtained (50.5 mg, 50%).
MS (FAB ⁺ ) m / z: 433 (M + H ⁺ )
HRMS (FAB ⁺ ): Calculated as C ₂₄ H ₂₅ N ₄ O ₂ S: 433.1698

Actual value: 433.1707

<Reference Example 23>

In the same manner as in Reference Example 1, ethyl 4,6-dichloro-1-methyl-1H-pyrazolo [3,4-b] pyrimidine-5-carboxylate (Compound of Reference Example 26; 100 mg, 0.365 mmol) and Phenylmethanethiol (30.0 mg, 0.242 mmol) gave ethyl 4-benzylamino-6-chloro-1-methyl-1H-pyrazolo [3,4-b] pyrimidine-5-carboxylate (113 mg). 90%).
MS (FAB ⁺ ) m / z: 345 (M + H ⁺ )
_{^{HRMS (FAB +): C 17}} H 18 ClN 4 O 2 Calculated: 345.1118

Actual value: 345.1083

<Reference Example 24>

A suspension of ethyl 7-hydroxy-5-oxo-4,5-dihydrothieno [3,2-b] pyrimidine-6-carboxylate (Reference Example 27 compound; 20.0 g, 83.6 mmol) in acetonitrile (280 mL). To the mixture, benzyltriethylammonium chloride (76.2 g, 0.334 mol) and phosphorus oxychloride (36 mL, 0.384 mol) were added, and the mixture was heated to reflux at 40 ° C. for 30 minutes and subsequently for 5 hours. Water was added to the reaction solution and allowed to stand overnight, the precipitated crystals were removed, and the filtrate was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain ethyl 5,7-dichlorothieno [3,2-b] pyrimidine-6-carboxylate. Was obtained (7.87 g, 34%).

<Reference Example 25>

4-Chloro-6-oxo-6,7-dihydro-1H-pyrazolo [3,4-b] pyrimidine-5-carboxylate (compound of Reference Example 25; 3.82 g, 15.0 mmol) was added to phosphorus oxychloride. (15.0 mL, 0.161 mol) and dimethylaniline (1.90 mL, 15.0 mmol) were suspended and heated to reflux for 5 hours. The reaction solution was added to ice and stirred at room temperature for 1 hour, and then potassium carbonate was added to adjust to pH = 10. After extraction with ethyl acetate, it was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 4,6-dichloro-1H-pyrazolo [3,4-b] pyrimidine-5- Ethyl carboxylate was obtained (205 mg, 5%).
MS (FAB ⁺ ) m / z: 274 (M + H ⁺ )
_{^{HRMS (FAB +): C 10}} H 10 Cl 2 N 3 O 2 Calculated: 274.0150

Actual value: 274.0131

<Reference Example 26>

To a solution of sodium ethoxide (2.40 g, 35.3 mmol) in ethanol (15 mL) was added methyl 3-aminothiophene-2-carboxylate (1.58 g, 10.1 mmol) and stirred at room temperature for 30 minutes, Diethyl malonate (5.66 g, 35.3 mmol) was added, and the mixture was heated to reflux for 6 hours. The reaction solution was cooled to room temperature, diluted with water and washed with ethyl acetate, 3 mol / L hydrochloric acid was added to adjust to pH = 1, and the precipitated crystals were collected by filtration to give 7-hydroxy-5-oxo-4, Ethyl 5-dihydrothieno [3,2-b] pyrimidine-6-carboxylate was obtained (1.06 g, 44%).
MS (EI) m / z: 239 (M ⁺ )
HRMS (EI): Calculated as C ₁₀ H ₉ NO ₄ S: 239.0252

Actual value: 239.0266

  Next, with respect to the compounds of the present invention, the results supporting the usefulness are shown by test examples.

<Test Example 1>
Evaluation of PPARγ modulator activity
Transcriptional activation test for human peroxisome proliferator activated receptor (PPAR) γ
Expression of fusion protein of yeast transcription factor GAL4 DNA binding region and human PPARγ ligand binding region (Biochemistry, 1993, 32, 5598) in CHO-K1 cells cultured in Ham's F12 medium containing 10% fetal bovine serum Serum-free receptor plasmid (pM-hPPARγLBD) and its reporter plasmid (STRATAGENE, firefly luciferase reporter plasmid) and Renilla luciferase plasmid (Promega) for internal standard using Lipofectamine (Invitrogen) The condition was cotransfected at 37 ° C. for 2 hours. Thereafter, the test compound was added in Ham's F12 medium containing 10% defatted bovine serum, cultured for 20 hours at 37 ° C, then both luciferase activities were measured, and a dose-dependent curve was drawn using the values corrected by the internal standard . The EC ₅₀ value and ME value of the test compound are defined as follows. When the PPARγ transcription activity value of the positive control group (additional concentration of 1 μmol / L rosiglitazone alone treatment) is 100% and the PPARγ transcription activity value of the control group is 0%, the maximum value of the PPARγ transcription activity value of the test compound alone Is ME (%). At this time, the concentration of the test compound showing the value of ME / 2 is calculated as the EC ₅₀ value. The results of EC ₅₀ value and ME value calculated in this way were used for evaluation of PPARγ modulator activity. The measurement results are shown in Table 1.

  From Table 1, it can be seen that the compound (1) of the present invention or a salt thereof exhibits excellent PPARγ modulator activity.

  The present invention has been found that a novel fused bicyclic pyridine derivative or a salt thereof has an excellent PPARγ modulator action.

Furthermore, the compounds of the present invention and their salts are safe with low toxicity. Therefore, the compounds of the present invention and salts thereof are used in various pathologies involving PPARγ (diabetes, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin resistance, obesity, hyperlipidemia, arteriosclerosis, regression, It is intended to provide a highly useful drug effective for treatment, prevention or suppression of stage osteoporosis and the like.

Claims (30)

The following general formula (1)

(Where

Is

Or

Indicates;
W ¹ and W ² are the same or different and each represents O, S or NH;
Y ¹ and Y ² are the same or different and each represents a single bond or a C ₁ -C ₆ alkylene chain;
A ¹ and A ² are the same or different, an aryl group, a cycloalkyl group or a Hajime Tamaki (the A ¹ and A ² are the same or different, a halogen atom, C ₁ -C be substituted with a halogen atom ₆ alkyl group, an aryl group, a nitro group, one or two identical or different C ₁ -C ₆ alkyl which may be substituted with a group aminosulfonyl group, an amino group, mono- or di-substituted C ₁ -C ₆ alkylamino group, an oxo group, 1 to 3 substituents (adjacent two substituents selected independently from among good C ₁ -C ₆ alkoxy group optionally substituted by a hydroxyl group or a halogen atom May be bonded to each other to form a ring).
R ¹ represents OH or NR ⁶ R ⁷ ;
R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkyl group, an aryl group or an aralkyl group;
R ⁵ represents a hydrogen atom or a C ₁ -C ₆ alkylthio group;
R ⁶ and R ⁷ are the same or different and each represents a C _{1 to} C ₆ alkyl group which may be substituted with a hydrogen atom or a carboxyl group. Or a salt thereof. The condensed bicyclic pyridine derivative or a salt thereof according to claim 1, wherein, in the general formula (1), R ¹ is OH or NH ₂ . ^2. The condensed bicyclic pyridine derivative or a salt thereof according to claim 1, wherein in the general formula (1), at least one of W ¹ and W ² is a sulfur atom, and R ¹ is OH or NH ₂ . In the general formula (1), at least one of W ¹ and W ² is a sulfur atom, Y ¹ and Y ² are the same or different and are a methylene chain or an ethylene chain, and R ¹ is OH or NH _2. Item 5. The condensed bicyclic pyridine derivative or the salt thereof according to Item 1. The following general formula (1a)

(Wherein W ¹ , W ² , Y ¹ , Y ² , A ¹ , A ² and R ¹ are the same as above), the condensed bicyclic pyridine derivative or a salt thereof according to claim 1 represented by: The condensed bicyclic pyridine derivative or a salt thereof according to claim 5, wherein, in the general formula (1a), R ¹ is OH or NH ₂ . The condensed bicyclic pyridine derivative or a salt thereof according to claim 5, wherein in the general formula (1a), at least one of W ¹ and W ² is a sulfur atom, and R ¹ is OH or NH ₂ . In the general formula (1a), at least one of W ¹ and W ² is a sulfur atom, Y ¹ and Y ² are the same or different and are a methylene chain or an ethylene chain, and R ¹ is OH or NH _2. Item 6. The condensed bicyclic pyridine derivative or the salt thereof according to Item 5. The following general formula (1b)

(Wherein W ¹ , W ² , Y ¹ , Y ² , A ¹ , A ² and R ¹ are the same as above), the condensed bicyclic pyridine derivative or a salt thereof according to claim 1 represented by: The condensed bicyclic pyridine derivative or a salt thereof according to claim 9, wherein, in the general formula (1b), R ¹ is OH or NH ₂ . The condensed bicyclic pyridine derivative or a salt thereof according to claim 9, wherein, in the general formula (1b), at least one of W ¹ and W ² is a sulfur atom, and R ¹ is OH or NH ₂ . In the general formula (1b), at least one of W ¹ and W ² is a sulfur atom, Y ¹ and Y ² are the same or different and are a methylene chain or an ethylene chain, and R ¹ is OH or NH _2. Item 10. The condensed bicyclic pyridine derivative or a salt thereof according to Item 9. The following general formula (1c)

(Wherein W ¹ , W ² , Y ¹ , Y ² , A ¹ , A ² , R ¹ and R ² are the same as above) or the condensed bicyclic pyridine derivative according to claim 1 or Its salt. The condensed bicyclic pyridine derivative or a salt thereof according to claim 13, wherein, in the general formula (1c), R ¹ is OH or NH ₂ . The condensed bicyclic pyridine derivative or a salt thereof according to claim 13, wherein in the general formula (1c), at least one of W ¹ and W ² is a sulfur atom, and R ¹ is OH or NH ₂ . In the general formula (1c), at least one of W ¹ and W ² is a sulfur atom, Y ¹ and Y ² are the same or different and are a methylene chain or an ethylene chain, and R ¹ is OH or NH _2. Item 14. The condensed bicyclic pyridine derivative or a salt thereof according to Item 13. The following general formula (1d)

(Wherein W ¹ , W ² , Y ¹ , Y ² , A ¹ , A ² , R ¹ and R ³ are the same as above) or a condensed bicyclic pyridine derivative according to claim 1 or Its salt. The condensed bicyclic pyridine derivative or a salt thereof according to claim 17, wherein, in the general formula (1d), R ¹ is OH or NH ₂ . In the general formula (1d), at least one of ^{W 1} and ^{W 2} is a sulfur atom, fused bicyclic pyridine derivative or a salt thereof according to claim 17 ^{R 1} is OH or NH _2. In the general formula (1d), at least one of W ¹ and W ² is a sulfur atom, Y ¹ and Y ² are the same or different and are a methylene chain or an ethylene chain, and R ¹ is OH or NH _2. Item 18. The fused bicyclic pyridine derivative or a salt thereof according to Item 17. 21. A therapeutic, preventive or suppressive agent for non-insulin dependent diabetes mellitus, comprising the fused bicyclic pyridine derivative according to any one of claims 1 to 20 or a salt thereof as an active ingredient. A therapeutic, preventive or inhibitory agent for obesity comprising the fused bicyclic pyridine derivative according to any one of claims 1 to 20 or a salt thereof as an active ingredient. A therapeutic, preventive or suppressive agent for hyperglycemia, comprising the condensed bicyclic pyridine derivative or a salt thereof according to any one of claims 1 to 20 as an active ingredient. 21. A therapeutic, preventive or suppressive agent for hyperlipidemia, comprising the fused bicyclic pyridine derivative or a salt thereof according to any one of claims 1 to 20 as an active ingredient. 21. A therapeutic, preventive or suppressive agent for hypercholesterolemia comprising the condensed bicyclic pyridine derivative according to any one of claims 1 to 20 or a salt thereof as an active ingredient. 21. A therapeutic, preventive, or suppressive agent for hypertriglyceridemia, comprising the fused bicyclic pyridine derivative according to any one of claims 1 to 20 or a salt thereof as an active ingredient. 21. A therapeutic, prophylactic or inhibitory agent for insulin resistance comprising the fused bicyclic pyridine derivative according to any one of claims 1 to 20 or a salt thereof as an active ingredient. 21. A therapeutic, preventive or suppressive agent for hyperinsulinemia comprising the fused bicyclic pyridine derivative according to any one of claims 1 to 20 or a salt thereof as an active ingredient. A therapeutic, prophylactic or inhibitory agent for arteriosclerosis, comprising the fused bicyclic pyridine derivative or a salt thereof according to any one of claims 1 to 20 as an active ingredient. 21. A therapeutic, preventive or suppressive agent for degenerative osteoporosis, comprising the condensed bicyclic pyridine derivative according to any one of claims 1 to 20 or a salt thereof as an active ingredient.