JPH1036374A - Thienopyridine derivative and medicine containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new thienopyridine derivative being the specific one, having an anti-inflammatory effect, depression of bone resorption and depression of production of immune cytokine and useful as an anti-flammatory agent such as an agent for treating arthritis, an agent for depressing the bone resorption, an immunosuppressant, etc. SOLUTION: This thienopyridine derivative is the new one of formula I G is a halogen; X is O, S which may be oxidized or a group of the formula (CH2 )q [(q) is 0-5]; R is a (substituted) amino or a (substituted) heterocyclic ring; the ring B is a (substituted) 5 to 7-membered ring containing nitrogen; M is H, a (substituted) hydrocarbon residue, a (substituted) acyl, a (substituted) (thio)carbamoyl or a (substituted) sulfonyl; (n) is 0 or 1; the ring A may have a substituted group} and useful as an anti-flammatory agent, especially an agent for treating arthritis, an agent for depressing the bone resorption, an immunosuppressant, etc. The compound is obtained by reacting a thienopyridine compound of formula II (Q is an eliminable group) with a compound of the formula R-X<1> H in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a disease useful as an anti-inflammatory agent, particularly as a therapeutic agent for arthritis, has a bone resorption inhibiting effect, is useful as a therapeutic agent for preventing and treating osteoporosis, and furthermore, it is considered that the disease is considered to be involved in immunity. The present invention relates to a novel thienopyridine derivative or a salt thereof, which is useful for the prophylactic treatment or the like of thienopyridine.

[0002]

2. Description of the Related Art Arthritis is an inflammatory disease of the joint, and the main diseases include rheumatoid arthritis and related diseases in which inflammation is recognized in the joint. In particular, rheumatoid arthritis is also referred to as rheumatoid arthritis and is a chronic polyarthritis whose main lesion is inflammatory changes in the synovium of the capsule inner layer. Arthritis, such as rheumatoid arthritis, is progressive and causes joint disorders such as joint deformation and tonicity,
If they get worse without effective treatment, they often lead to severe physical disability. Conventionally, in the treatment of these arthritis, steroids such as corticosteroids (eg, cortisone, etc.), non-steroidal anti-inflammatory drugs (eg, aspirin, piroxicam, indomethacin, etc.), gold preparations (eg, gold) Thiomalate, etc.), antirheumatic agents (eg, chloroquine preparations, D-penicillamine, etc.), anti-gout agents (eg, colchicine, etc.), immunosuppressants (eg, cyclophosphamide, azathioprine, methotrexate, levamisole, etc.) are used. I have been.

[0003]

However, these drugs have side effects that make serious or long-term use difficult, are ineffective, or have been used for arthritis that has already developed. There were problems such as not being effective. Therefore, in the clinical practice of arthritis, a drug with low toxicity and excellent in prevention and treatment of arthritis is still desired. Conventionally, thieno [2,3-b] pyridine derivatives include, for example, Buretin of the Chemical Society of Japan [(Bull. Chem. Soc. Jpn.), 6
1, 4431 (1988)], Chemical and Pharmaceutical Buretin [(Chem. Pharm. Bull.), 36
Vol.4, p.389 (1988)], Phosphorus, Sulfur, and Silicon
73, 127 (1992)], Chemical and Pharmaceutical Buretin [(Chem. Pharm. Bull.), 40
Volume 1, p. 1376 (1992)] and Kim Geterotsikl Soedin [(Khim. Geterotsikl. Soedin.), Vol. 1, p. 124 (1987)]. However, in these, the substituent at the 6-position of the thieno [2,3-b] pyridine skeleton is limited to a methyl group. In addition, there is no description of an anti-inflammatory effect, a bone resorption suppressing effect, and an immunosuppressive effect with respect to these known thienopyridine derivatives.

[0004]

Means for Solving the Problems The present inventors have developed a novel thienopyridine derivative represented by the general formula (I) which has an anti-arthritic effect, acts as a joint destruction inhibitor, and acts directly on bone. The present invention was found to have a bone resorption inhibitory effect and to be useful as a bone resorption inhibitor and further as an immunosuppressant, and completed the present invention. That is, the present invention provides: (1) General formula (I):

Embedded image Wherein G is a halogen atom, X is an oxygen atom, a sulfur atom which may be oxidized, or-(CH ₂ ) q- (q is an integer of 0 to 5), and R is a substituted Represents an optionally substituted amino group or an optionally substituted heterocyclic group.
Ring B represents a 5- to 7-membered ring containing an optionally substituted nitrogen atom, and M represents a hydrogen atom, an optionally substituted hydrocarbon residue, an optionally substituted acyl N represents 0 or 1 for a group, a carbamoyl group which may be substituted, a thiocarbamoyl group which may be substituted or a sulfonyl group which may be substituted; Ring A may have a substituent. Or a salt thereof, (2) an optionally substituted amino group represented by R:
—N (R ¹ ) (R ² ) (wherein, R ¹ and R ² are the same or different and each is a hydrogen atom, a hydrocarbon residue which may be substituted, an acyl group, a sulfonyl group or a heterocyclic ring; R ¹ and R ² may be bonded to each other to form a 5- to 7-membered nitrogen-containing ring), and each of the optionally substituted heterocyclic groups represented by R is the same Or differently, an aromatic monocyclic heterocyclic group, an aromatic fused heterocyclic group or a non-aromatic heterocyclic group, wherein the optionally substituted 5- to 7-membered ring represented by ring B is substituted. 6-membered heterocyclic ring containing one nitrogen atom, wherein ring A is a halogen atom, a nitro group, an optionally substituted alkyl group, an optionally substituted hydroxy group, an optionally substituted A good thiol group, an optionally substituted amino group,
A compound according to the above (1) or a salt thereof, which may be substituted with an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic ring group, (3) R ¹ or a hydrocarbon residue which may be substituted represented by R ² is a C _1-6 alkyl group which may be substituted, it may be substituted represented by R ¹ or R ² complex The compound or a salt thereof according to the above (2), wherein the ring group is an aromatic 5-membered heterocyclic group containing 2 to 3 heteroatoms, (4) an optionally substituted heterocyclic group represented by R,
(i) a 5-7 membered heterocyclic group containing one sulfur, nitrogen or oxygen atom, (ii) a 5-6 membered heterocyclic group containing 2-4 nitrogen atoms, (iii) 1-2 A 5- or 6-membered heterocyclic group containing a nitrogen atom and one sulfur or oxygen atom, or (iv)
Any heterocyclic group containing no more than 2 nitrogen atoms 6
Membered ring, or a salt thereof those 5 membered combined ring condensed above (1) further comprising a benzene ring or one sulfur atom, (5) X is - (CH ₂₎ q- (q is 0 Represents an integer of 3)
The compound according to the above (1) or a salt thereof,

(6) The compound according to the above (5) wherein q is 0 or a salt thereof; (7) the compound according to the above (1) or a salt thereof wherein G is a chlorine atom; (8) a substituent of ring A Is a C _1-6 alkoxy group or a hydroxy group, or a salt thereof; (9) a compound of the formula (I) is 7-benzyl-3
-Chloro-4- (3,4-dimethoxyphenyl) -2-
(2-oxo-1-piperidinylmethyl) -5,6,
7,8-tetrahydrothieno [2,3-b: 5,4-
c ′] dipyridine, 7-benzyl-3-chloro-4-
(3,4-dimethoxyphenyl) -2- (2-oxohexamethyleneinomimethyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c ′] dipyridine, 7- Benzyl-3-chloro-4- (3,4-dimethoxyphenyl) -2- (2-oxo-1-pyrrolidinylmethyl) -5,6,7,8-tetrahydrothieno [2
3-b: 5,4-c '] dipyridine or 7-benzyl-3-chloro-4- (4-hydroxy-3-methoxyphenyl-2- (2-oxo-1-pyrrolidinylmethyl) -5 , 6,7,8-Tetrahydrothieno [2,3-
b: 5,4-c ′] dipyridine, the compound according to the above (1), (10) 7-benzyl-3-chloro-2- (2,5-dioxopyrrolidin-1-ylmethyl) -4- ( 3,4-
Dimethoxyphenyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c ′] dipyridine according to the above (1), (11) 3-chloro-4- (3 , 4-Dimethoxyphenyl) -2- (2-oxopyrrolidin-1-ylmethyl)
The compound according to the above (1), which is thieno [2,3-b: 5,4-c ′] dipyridine, (12) a compound of the formula (II-1):

Embedded image [Wherein, M ¹ is an optionally substituted hydrocarbon residue, an optionally substituted acyl group, an optionally substituted alkyl group, an optionally substituted carbamoyl group or an optionally substituted carbamoyl group. A good thiocarbamoyl group, Q is a leaving group, and G is a halogen atom. In a solvent, in the presence of a base, a compound represented by the formula (III): R—X ¹ H wherein X ¹ represents an oxygen atom or a sulfur atom. And a compound represented by the formula (I-1):

Embedded image Wherein M ¹ , G and X ¹ are the same as defined above,
R represents an optionally substituted amino group or an optionally substituted heterocyclic group. Or a compound of formula (II-2):

Embedded image Wherein p represents an integer of 1 to 6, and M ¹ , G and Q
Is the same as defined above. A compound of formula (IV) in a solvent in the presence of a base:

Embedded image [Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom, an optionally substituted hydrocarbon residue, an acyl group, a sulfonyl group or a heterocyclic group, or R ¹ and R ² May be bonded to each other to form a nitrogen-containing 5- to 7-membered ring. With a compound represented by the formula (I-2):

Embedded image [Wherein, M ¹ , G, R ¹ , R ² and p are the same as defined above. Or a compound of the formula (I-
3):

Embedded image [Wherein, M ² represents an optionally substituted acyl group;
X is an oxygen atom, oxidized have good sulfur atom or be - (CH ₂₎ q- (q is 0 to an integer of 5) indicates, G and R are as defined above. To a compound represented by formula (I-4):

Embedded image [Wherein, G, R and X are the same as defined above. Or a compound of the formula (I-4) in a solvent in the presence of a base of the formula (VII): R ⁵ -Q wherein R ⁵ is substituted And Q is the same as defined above. And a compound represented by the formula (I-9):

Embedded image [Wherein, R, R ⁵ , G and X are the same as defined above. Or a compound of formula (IX):

Embedded image Wherein M ¹ is the same as defined above. A compound represented by the formula:
Formula (X):

Embedded image And sulfur in a solvent in the presence of a base to give a compound of the formula (XI):

Embedded image [Wherein, M ¹ is the same as defined above. Then, a compound represented by the formula (XI) is converted to a compound represented by the formula (XII): QCH ₂ COCH ₂ -G, wherein G and Q are the same as defined above. With a compound represented by the formula (II-
3):

Embedded image Wherein G, M ¹ and Q are as defined above. Wherein a compound represented by the general formula (I) is obtained:

Embedded image [Wherein, G, X and R are the same as defined above. Ring B represents a 5- to 7-membered ring containing an optionally substituted nitrogen atom, and M represents a hydrogen atom, an optionally substituted hydrocarbon residue, an optionally substituted acyl N represents 0 or 1 for a group, a carbamoyl group which may be substituted, a thiocarbamoyl group which may be substituted or a sulfonyl group which may be substituted; Ring A may have a substituent. (13) General formula (I):

Embedded image Wherein G is a halogen atom, X is an oxygen atom, a sulfur atom which may be oxidized, or-(CH ₂ ) q- (q is an integer of 0 to 5), and R is a substituted Represents an optionally substituted amino group or an optionally substituted heterocyclic group.
Ring B represents a 5- to 7-membered ring containing an optionally substituted nitrogen atom, and M represents a hydrogen atom, an optionally substituted hydrocarbon residue, an optionally substituted acyl N represents 0 or 1 for a group, a carbamoyl group which may be substituted, a thiocarbamoyl group which may be substituted or a sulfonyl group which may be substituted; Ring A may have a substituent. A pharmaceutical composition comprising a compound represented by the formula or a pharmaceutically acceptable salt thereof,

(14) The pharmaceutical composition according to the above (13) for preventing or treating inflammation, (15) the above (13) for preventing or treating arthritis.
(16) The above (1) for the prevention or treatment of rheumatism.
3) The pharmaceutical composition according to the above (13), for preventing or treating rheumatoid arthritis, the pharmaceutical composition according to the above (13), (19) The above (1) for prevention or treatment of osteoporosis.
3) The pharmaceutical composition according to the above, (20) the above-mentioned (1) which has a cytokine production inhibitory action.
3) The pharmaceutical composition according to the above, (21) the pharmaceutical composition according to the above (13) for prevention or treatment of an autoimmune disease, and (22) the above (1) for the prevention of rejection after organ transplantation.
3) The pharmaceutical composition according to the above.

A description of the above general formulas and definitions included within the scope of the present invention and preferred examples thereof are set forth below. In the above formula (I), the optionally substituted amino group represented by R is -N (R ¹ ) (R ² ) (wherein R ¹ and R ² are the same or different and each represents hydrogen Represents an optionally substituted hydrocarbon residue, an acyl group, a sulfonyl group or a heterocyclic group, or represents that R ¹ and R ² are bonded to form a nitrogen-containing ring). You. Examples of the hydrocarbon residue in the optionally substituted hydrocarbon residue represented by R ¹ or R ² include an aliphatic hydrocarbon residue, an alicyclic hydrocarbon residue, and an alicyclic-aliphatic hydrocarbon. Residues, araliphatic hydrocarbon residues, aromatic hydrocarbon residues and the like.

The aliphatic hydrocarbon residue includes a C _1-8 saturated aliphatic hydrocarbon residue (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl) , Neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.) and _C2-8 unsaturated aliphatic hydrocarbon residues (e.g., vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2- Butenyl, 3-butenyl,
2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl,
2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2
-Propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, -Heptynyl, 1-octynyl and the like) and the like.

The alicyclic hydrocarbon residue includes a C _3-7 saturated alicyclic hydrocarbon residue (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) and a C _5-7 unsaturated aliphatic hydrocarbon residue. Cyclic hydrocarbon residues (e.g., 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2
-Cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl and the like). As the alicyclic-aliphatic hydrocarbon residue, those in which the alicyclic hydrocarbon residue and the above-mentioned aliphatic hydrocarbon residue are bonded to each other have 4 to 9 carbon atoms (for example, cycloalkyl). Propylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl , Cycloheptylethyl, etc.). Examples of the araliphatic hydrocarbon residue include _C7-9 phenylalkyl (for example, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, etc.) and _C11-13. And naphthylalkyl (for example, α-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl, β-naphthylethyl, etc.). Examples of the aromatic hydrocarbon residue include phenyl, naphthyl (α
-Naphthyl, β-naphthyl) and the like.

The acyl group represented by R ¹ or R ² includes (i) formyl or (ii) a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group or an aromatic group. And a carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl Benzoyl, nicotinoyl and the like). As the sulfonyl group represented by R ¹ or R ² ,
Examples thereof include a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, or a combination of an aromatic group and a sulfonyl group (eg, methanesulfonyl, ethanesulfonyl, benzenesulfonyl, etc.). The heterocyclic group in the optionally substituted heterocyclic group represented by R ¹ or R ² includes, for example, (i) a heterocyclic group containing 5 sulfur atoms, 1 nitrogen atom or 1 oxygen atom. 7-membered heterocyclic group, (ii) 2-
A 5- to 6-membered heterocyclic group containing 4 nitrogen atoms, or (ii)
i) 5- to 6-membered heterocyclic groups containing one or two nitrogen atoms and one sulfur or oxygen atom; and (iv) these heterocyclic groups are six-membered rings containing not more than two nitrogen atoms. , A benzene ring or a 5-membered ring containing one sulfur atom. Examples of the heterocyclic group in the optionally substituted heterocyclic group represented by R ¹ or R ² include an aromatic monocyclic heterocyclic group, an aromatic fused heterocyclic group and a non-aromatic heterocyclic group. No.

Specific examples of the optionally substituted heterocyclic group represented by R ¹ or R ² include (i)
Aromatic monocyclic heterocyclic groups (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-
Oxadiazolyl, 1,2,4-oxadiazolyl, 1,
3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-
Thiadiazolyl, 1,2,3-triazolyl, 1,2,4-
Triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.),
(ii) aromatic fused heterocyclic groups (eg, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisothiazolyl, 1H -Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothininyl, phenazidinyl Nyl, thianthrenyl, phenanthrinyl, phenanthrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2
-A] pyridyl, imidazo [1,5-a] pyridyl, imidazo
[1,2-b] pyridazinyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b]
Pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,
2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl and the like) and (iii)
Non-aromatic heterocyclic group (eg, oxiranyl, azetidinyl,
Oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like.

R ¹ and R ² may combine with each other to form a ring, especially a nitrogen-containing 5- to 7-membered ring.
Examples of N (R ¹ ) (R ² ) include 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-piperidyl (piperidino), 1-piperazinyl, 4-morpholinyl (morpholino), 4-thiomorpholinyl, and homopiperazine -1-yl, pyrazol-1-yl, imidazole-
1-yl, 1,2,4-triazol-1-yl, 1,2,
4-triazol-4-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, tetrazol-1-yl, benzimidazol-1-yl,
Indole-1-yl, 1H-indazol-1-yl and the like.

The hydrocarbon residue in the optionally substituted hydrocarbon residue represented by R ¹ or R ² is
More preferred are _1-6 straight or branched chain alkyl, especially C _1-4 straight chain alkyl or C _1-4 branched chain alkyl. Specifically, a methyl, ethyl, propyl, isopropyl, butyl group and the like are preferable. When R ¹ and R ² combine to form a nitrogen-containing ring,
N (R ¹ ) (R ² ) includes 1,2,4-triazole-1-
Preferred are yl, imidazol-1-yl, morpholino (4-morpholinyl), piperidino (1-piperidyl), pyrrolidino and the like.

The hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ² have 1 to 3 substituents at any substitutable position on the chain or ring. May be. Examples of the substituent on the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ² include an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group, an aryl group and an aromatic group. Heterocyclic group, non-aromatic heterocyclic group,
Halogen atom, optionally substituted amino group, amidino group, optionally substituted acyl group, optionally substituted hydroxy group, optionally substituted thiol group, esterified or amidified Carboxyl group, aralkyl group (eg, aryl C _1-6 alkyl group, etc.), carbamoyl group, N-monosubstituted carbamoyl group
(Eg, methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, etc.), N, N-disubstituted carbamoyl group
(N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, piperidinocarbamoyl, morpholinocarbamoyl, etc.), sulfamoyl group, N-monosubstituted sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, phenylsulfamoyl) Moyl, p-toluenesulfamoyl, etc.), N, N-disubstituted sulfamoyl group (N, N
-Dimethylsulfamoyl, N-methyl-N-phenylsulfamoyl, piperidinosulfamoyl, morpholinosulfamoyl, etc.), mercapto group, sulfo group, cyano group, azido group, nitro group, nitroso group and the like. Can be

The aliphatic hydrocarbon group as a substituent for the hydrocarbon residue, acyl group, sulfonyl group or heterocyclic group represented by R ¹ or R ² includes a linear or branched aliphatic group. Group hydrocarbon groups such as alkyl groups (preferably C
_1-10 alkyl group), alkenyl group (preferably C _2-10 alkenyl group), alkynyl group (preferably C _2-10 alkynyl group) and the like. Preferred examples of the alkyl group include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,
Examples include 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, decyl and the like. Preferred examples of the alkenyl group include, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl,
3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3
-Pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like. Preferred examples of the alkynyl group include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
Examples thereof include 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

The alicyclic hydrocarbon group as a substituent for the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ² includes a saturated or unsaturated C _3-8
An alicyclic hydrocarbon group such as a C _3-8 cycloalkyl group,
_Examples thereof include a _3-8 cycloalkenyl group and a C _4-8 cycloalkadienyl group. Preferred examples of the C _3-8 cycloalkyl group include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo
[2.2.2] octyl, bicyclo [3.2.1] octyl and the like. Preferred examples of the C _3-8 cycloalkenyl group include, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl
Cyclopenten-1-yl, 2-cyclohexen-1-
Yl, 3-cyclohexen-1-yl and the like. Preferred examples of the C _4-8 cycloalkadienyl group include, for example, 2,4-cyclopentadien-1-yl,
4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like.

The aryl group as a substituent for the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ² means a monocyclic or condensed polycyclic aromatic hydrocarbon group. Preferred examples include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like.
-Naphthyl and the like are more preferred. Preferred examples of the aromatic heterocyclic group as a substituent for the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ² include an aromatic monocyclic heterocyclic group (for example, furyl ,
Thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.) and aromatic Fused heterocyclic groups (eg, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2
-Benzisoxazolyl, benzothiazolyl, 1,2
-Benzoisothiazolyl, 1H-benzotriazolyl,
Quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,
Purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrrolo
[1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a]
Pyridyl, imidazo [1,2-b] pyridazinyl, imidazo
[1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3
-A] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl and the like.

Preferred examples of the non-aromatic heterocyclic group as a substituent for the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ² include oxiranyl, azetidinyl, oxetanyl, Thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. R ¹ or R ²
Examples of the halogen atom as a substituent for the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by are fluorine, chlorine, bromine and iodine, and fluorine and chlorine are particularly preferred.

The amino group which may be substituted as a substituent for the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ² includes an amino group and an N-monosubstituted amino group. And N, N-disubstituted amino groups. Examples of the substituted amino group include C
_{A 1-10} alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, an aromatic group, a heterocyclic group or a C _1-10 acyl group;
Or two amino groups as substituents (eg, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino Benzoylamino, nicotinoylamino, etc.).

The acyl as a substituent for the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ² includes (i) formyl or (ii) a C _1-10 alkyl group. , A C _2-10 alkenyl group, a C _2-10 alkynyl group or an aromatic group and a carbonyl group bonded thereto (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl) , Cyclopentanecarbonyl, cyclohexanecarbonyl,
Cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl and the like).

The hydroxy group which may be substituted as a substituent of the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ² includes a hydroxy group and an appropriate Examples include a hydroxy group having a substituent, particularly one used as a protecting group (for example, alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyloxy, aryloxy, etc.). The alkoxy includes C _1-10 alkoxy
(E.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-
Butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy,
Cyclohexyloxy) is preferred. Examples of the alkenyloxy include C _2-10 alkenyloxy (eg, allyl (al
lyl) oxy, crotyloxy, 2-pentenyloxy,
3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy, etc.) are preferred.
The alkynyloxy includes C _2-10 alkynyloxy
(Eg, ethynyloxy, 2-propynyloxy, etc.) are preferred. As the aralkyloxy, for example, phenyl-C _1-4 alkyloxy and the like (eg, benzyloxy, phenethyloxy and the like) are preferable. Examples of the acyloxy include C _2-4 alkanoyloxy (eg, acetyloxy,
Propionyloxy, butyryloxy, isobutyryloxy, etc.), C _3-4 alkenoyloxy or C _3-4 alkinoyloxy are preferred. As the aryloxy,
Phenoxy, 4-chlorophenoxy and the like are preferred.

The thiol group which may be substituted as a substituent of the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ² includes a thiol group and an appropriate thiol group. Examples include thiol groups having substituents, particularly those used as protecting groups (eg, alkylthio, alkenylthio, alkynylthio, aralkylthio, acylthio, arylthio, and the like). Examples of the alkylthio include C _1-10 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, Nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.) are preferred. As the alkenylthio, for example, C _2-10 alkenylthio (eg, allyl thio, crotylthio, 2-pentenylthio, 3-hexenylthio, 2-cyclopentenylmethylthio, 2-cyclohexenylmethylthio, etc.) is preferable. As the alkynylthio, for example, C _2-10 alkynylthio (eg, ethynylthio, 2-propynylthio, etc.) is preferable. Examples of the aralkylthio include phenyl -C _1-4 alkylthio (e.g., benzylthio, phenethylthio, etc.). As the acylthio, for example, C
_2-4 alkanoylthio (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.) is preferred. Examples of the arylthio include phenylthio, 4
-Chlorophenylthio and the like are preferred.

The carboxyl group which may be esterified as a substituent of the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ² includes:
In addition to the carboxyl group, for example, an alkyloxycarbonyl group, an alkenyloxycarbonyl, an alkynyloxycarbonyl, an aralkyloxycarbonyl group, an acyloxycarbonyl group, an aryloxycarbonyl group and the like can be mentioned. Examples of the alkyl group in the alkyloxycarbonyl group include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl, etc.). Examples of the alkenyl group in the alkenyloxycarbonyl group include a C _2-6 alkenyl group (eg, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 2-methylallyl, etc.). The alkynyl group in the alkynyloxycarbonyl group includes C.I.
_2-6 alkynyl group (eg, ethynyl, 2-propynyl, etc.)
Is mentioned. The aralkyl group in the aralkyloxycarbonyl group means an aryl-alkyl group.
As the aryl group in the aryl-alkyl group,
For example, phenyl, naphthyl and the like may be mentioned, and these may have the same substituent as the aryl group exemplified as the hydrocarbon group represented by R ¹ or R ² . The alkyl group in the aryl-alkyl group is preferably a C _1-6 alkyl group (eg, methyl, ethyl, propyl, butyl, etc.). Preferable examples of the aralkyl group, that is, the aryl-alkyl group include benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like. preferable. Examples of the acyl group in the acyloxycarbonyl group include formyl, C
Examples include a _2-4 alkanoyl group, a C _3-4 alkenoyl group, and a C _3-4 alkinoyl group. Examples of the aryl group in the aryloxycarbonyl group include phenyl and naphthyl. The amidated carboxyl group as a substituent for the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ² includes -C
And ON (R ¹ ) (R ² ) (R ¹ and R ² are as defined above).

The above-mentioned substituents on the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ² may further have one suitable substituent at any substitutable position. As described above, preferably, 1 to 3 may be provided. Examples of the substituent include hydrocarbon residues represented by R ¹ or R ^2, an acyl group, similar to those exemplified as a substituent on sulfonyl group and heterocyclic group, C _1-10 alkyl group, C _{2 -10} alkenyl group, C _2-10 alkynyl group, C
_3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C
_4-8 cycloalkadienyl group, aryl group, aromatic heterocyclic group, non-aromatic heterocyclic group, aralkyl group (eg, aryl C _1-6 alkyl group, etc.), amino group, N-monosubstituted amino group, N, N-disubstituted amino group, amidino group, acyl group,
Carbamoyl group, N-monosubstituted carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, etc.), N, N-disubstituted carbamoyl group (N, N-
Dimethylcarbamoyl, N, N-diethylcarbamoyl, piperidinocarbamoyl, morpholinocarbamoyl, etc.), sulfamoyl group, N-monosubstituted sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, phenylsulfamoyl, p-toluene) Sulfamoyl, etc.), N, N-disubstituted sulfamoyl group (N, N-dimethylsulfamoyl, N-methyl-N-phenylsulfamoyl, piperidinosulfamoyl, morpholinosulfamoyl, etc.), carboxyl group , A C _1-10 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), a hydroxy group, a C _1-10 alkoxy group,
_2-10 alkenyloxy group, C _3-7 cycloalkyloxy group, aralkyloxy group, aryloxy group, mercapto group, C _1-10 alkylthio group, aralkylthio group, arylthio group, sulfo group, cyano group, azide group, Examples include a nitro group, a nitroso group, and a halogen.

In the above formula (I), examples of the heterocyclic group in the optionally substituted heterocyclic group represented by R include the same as those defined for R ¹ or R ² above. No. Examples of the heterocyclic group in the optionally substituted heterocyclic group represented by R include (i) a 5- to 7-membered heterocyclic ring containing one sulfur atom, one nitrogen atom or one oxygen atom. The group, (ii) 5 containing 2 to 4 nitrogen atoms
A 6-membered heterocyclic group, or (iii) a 5- to 6-membered heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur or oxygen atom, and (iv) these heterocyclic groups are 2 It may be condensed with a 6-membered ring containing not more than nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom. These heterocyclic groups may have a substituent group of 1 to 3 at any substitutable position on the ring.
You may have one. Such substituents include the above R ¹
Or similar to those defined as substituents on the hydrocarbon residue and heterocyclic group represented by R ^2, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3- 8}
Cycloalkyl group, C _3-8 cycloalkenyl group, C _4-8 cycloalkadienyl group, aryl group, aromatic heterocyclic group,
Non-aromatic heterocyclic group, aralkyl group (eg, aryl C _1-6
Alkyl group, etc.), amino group, N-monosubstituted amino group,
N, N-disubstituted amino group, amidino group, acyl group, carbamoyl group, N-monosubstituted carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, etc.), N, N-disubstituted carbamoyl group (N, N -Dimethylcarbamoyl, N, N-diethylcarbamoyl, piperidinocarbamoyl, morpholinocarbamoyl, etc.),
Sulfamoyl group, N-monosubstituted sulfamoyl group
(E.g., methylsulfamoyl, ethylsulfamoyl,
Phenylsulfamoyl, p-toluenesulfamoyl, etc.), N, N-disubstituted sulfamoyl groups (N, N-dimethylsulfamoyl, N-methyl-N-phenylsulfamoyl, piperidinosulfamoyl, morpholino) Sulfamoyl, etc.), carboxyl group, C _1-10 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), hydroxy group, C _{1 -10} alkoxy group, C _2-10
Alkenyloxy group, C _3-7 cycloalkyloxy group,
Aralkyloxy group, aryloxy group, mercapto group, C _1-10 alkylthio group, aralkylthio group, arylthio group, sulfo group, cyano group, azide group, nitro group,
Examples include a nitroso group and a halogen.

The substituents on these heterocyclic groups may further have one or more, preferably 1 to 3 suitable substituents at any substitutable positions. C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _4-8 cycloalk Dienyl group, aryl group, aromatic heterocyclic group, non-aromatic heterocyclic group, aralkyl group (eg, aryl C _1-6 alkyl group),
Amino group, N-monosubstituted amino group, N, N-disubstituted amino group, amidino group, acyl group, carbamoyl group, N-monosubstituted carbamoyl group, N, N-disubstituted carbamoyl group, sulfamoyl group, N-mono Substituted sulfamoyl group, N, N-disubstituted sulfamoyl group, carboxyl group, C _1-10 lower alkoxycarbonyl group, hydroxy group, C _1-10 lower alkoxy group, C _2-10 lower alkenyloxy group, C _3-7 cyclo Alkyloxy group, aralkyloxy group, aryloxy group, mercapto group, C _1-10 lower alkylthio group, aralkylthio group, arylthio group,
Examples thereof include a sulfo group, a cyano group, an azide group, a nitro group, a nitroso group, and a halogen.

Examples of the optionally substituted heterocyclic group represented by R include 2-imidazolyl, 1,2,4-triazol-3-yl, 2-thiazolyl, 2-oxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-
Benzimidazolyl and the like are preferred. In the above formula (I),
X represents an oxygen atom, oxidized optionally also good sulfur atom, or - (CH ₂₎ q- (q is an integer of 0 to 5, preferably 0
3 represents an integer of 3). Examples of the optionally oxidized sulfur atom represented by X include a thio group, a sulfinyl group, and a sulfonyl group, among which a thio group is preferable. As-(CH ₂ ) q- represented by X, q is preferably 0. In the above formula (I), G represents a halogen atom (chlorine, bromine, iodine or fluorine).
Preferably, G is chlorine.

In the above formula (I), M represents a hydrogen atom, a hydrocarbon residue which may be substituted, an acyl group which may be substituted, a carbamoyl group which may be substituted, Shows a good thiocarbamoyl group or a sulfonyl group which may be substituted. Examples of the optionally substituted hydrocarbon residue represented by M include the same as the hydrocarbon residue represented by R ¹ or R ² . Examples of the optionally substituted hydrocarbon residue represented by M include methyl, ethyl, isopropyl, propyl, butyl,
Benzyl, phenethyl, 2-, 3- or 4-pyridylmethyl and the like are preferred. Examples of the optionally substituted acyl group represented by M include those exemplified as the acyl group as a substituent for the hydrocarbon residue, acyl group, sulfonyl group and heterocyclic group represented by R ¹ or R ^2. The same acyl group is mentioned, and benzoyl, acetyl and the like are particularly preferable. Examples of the optionally substituted carbamoyl group represented by M include those represented by R ¹ NHCO (R ¹ is as defined above). Examples of the optionally substituted thiocarbamoyl group represented by M include R ¹ NHCS
(R ¹ is as defined above).
Examples of the optionally substituted sulfonyl group represented by M include those represented by R ¹ SO ₂ (R ¹ is as defined above).

In the above formula (I), ring B together with the carbon double bond of the adjacent thiophene ring forms a 5- to 7-membered ring containing an optionally substituted nitrogen atom. But more preferably a 6-membered ring containing an optionally substituted nitrogen atom. That is, specifically as ring B and (M) _n, for example,

Embedded image And the like.

In the above formula (I), ring A may be the same or different at any substitutable position on the ring.
It may have up to 4, preferably 1 or 2 substituents. Examples of the substituent on the ring A include a halogen atom, a nitro group, an optionally substituted alkyl, an optionally substituted hydroxy group, an optionally substituted thiol group, an optionally substituted amino A group, an acyl group, a carboxyl group which may be esterified, or an aromatic ring group which may be substituted is used. Examples of halogen as a substituent of ring A include fluorine, chlorine,
Bromine and iodine are mentioned, with fluorine and chlorine being particularly preferred. The alkyl group which may be substituted as a substituent on ring A includes a C _1-10 linear alkyl group,
_3-10 branched chain alkyl, may be any of C _3-10 cyclic alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, Octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like can be mentioned.

The hydroxy group which may be substituted as a substituent of the ring A includes a hydroxy group and a substituent having an appropriate substituent on the hydroxy group, particularly those having a substituent used as a protecting group for the hydroxy group (for example, alkoxy group). ,
Alkenyloxy, alkynyloxy, aralkyloxy, acyloxy, aryloxy, etc.).
Examples of the alkoxy include C _1-10 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,
Pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.). The alkenyloxy includes C _2-10 alkenyloxy (eg, allyl)
Oxy, crotyloxy, 2-pentenyloxy, 3-
Hexenyloxy, 2-cyclopentenylmethoxy, 2
-Cyclohexenylmethoxy and the like) are preferred. Examples of the alkynyloxy include C _2-10 alkynyloxy (eg,
Ethynyloxy, 2-propynyloxy, etc.) are preferred. As the aralkyloxy, for example, phenyl-
C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.). As the acyloxy, C _2-4 alkanoyloxy (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.) is preferable. Examples of the aryloxy include phenoxy, 4-chlorophenoxy and the like.

Examples of the thiol group which may be substituted as a substituent of ring A include thiol groups and those having an appropriate substituent on the thiol group, particularly those having a thiol group used as a protecting group (for example, alkylthio group). Alkenylthio, alkynylthio, aralkylthio, acylthio, arylthio, etc.). Examples of the alkylthio include C _1-10 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio , Cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.) are preferred. The alkenylthio includes C
_2-10 alkenylthio (eg, allyl thio, crotylthio, 2-pentenylthio, 3-hexenylthio,
-Cyclopentenylmethoxy, 2-cyclohexenylmethoxy, etc.) are preferred. As the alkynylthio,
C _2-10 alkynylthio (eg, ethynylthio, 2-propynylthio, etc.) is preferred. Examples of the aralkylthio include phenyl -C _1-4 alkylthio (e.g., benzylthio, phenethylthio, etc.). As the acylthio, an alkanoylthio having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.) is preferable. As the arylthio, phenylthio, 4-chlorophenylthio and the like are preferable.

The optionally substituted amino group as a substituent on ring A includes, in addition to an amino group, a substituted amino group,
For example, an amino group having one or two C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, aromatic group, heterocyclic group or C _1-10 acyl group as a substituent (eg, methyl Amino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino and the like. Examples of the acyl group as a substituent of ring A include formyl, or a C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or aromatic group bonded to a carbonyl group (eg, acetyl, propionyl) , Butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-
Cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.).

The carboxyl group which may be esterified as a substituent on ring A includes, in addition to a carboxyl group, for example, an alkyloxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group,
An aralkyloxycarbonyl group, an acyloxycarbonyl group, an aryloxycarbonyl group, and the like, which are represented by the formula —COOR ³ (R ³ is a hydrogen atom, a C _1-6 alkyl group, an aryl C _1-6 alkyl group or an aryl group) expressed. As the alkyl group in the alkyloxycarbonyl group, a C _1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, etc.). The aralkyl group in the aralkyloxycarbonyl group means an aryl-alkyl group. Examples of the aryl group in the aryl-alkyl group include phenyl, naphthyl and the like, which have the same substituents as the aryl group exemplified as the hydrocarbon group represented by R ¹ or R ^2. It may be. As the alkyl group in the aryl-alkyl group, a C _1-6 alkyl group (eg, methyl, ethyl, propyl, butyl, etc.)
Is preferred. Preferred examples of the aralkyl group, i.e., the aryl-alkyl group include benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like, among which benzyl, phenethyl and the like. preferable.

Examples of the aromatic ring group which may be substituted as a substituent of ring A include pyridyl, furyl, thienyl, imidazolyl, and C _6-14 aromatic hydrocarbon residues such as phenyl, naphthyl and anthryl. And heteroaromatic residues such as thiazolyl. The substituent on ring A is preferably
Located at position 3 and / or 4 of ring A. When these substituents are adjacent to each other is a substituent on ring A is linked substituents adjacent, - (CH _{2) m} - or -O- (C
H ₂ ) _l —O— [wherein, m represents an integer of 3 to 5, and l represents an integer of 1 to 3], and the ring may be a carbon atom of a benzene ring. 5 formed with atoms
Including a 7-membered ring. Ring A is preferably substituted with at least one C _1-6 alkoxy group, preferably a C _1-3 alkoxy group, especially a methoxy group or a hydroxy group. More preferably, ring A is the same or different
Substituted with two alkoxy groups, preferably two C _1-3 alkoxy groups, especially two methoxy groups. Specifically, for example, a ring A in which both the 3-position and the 4-position are substituted with a methoxy group is particularly preferable. The above formula (I)
Of the compounds represented by the following formulas, particularly preferred are those wherein n is 1, M is a hydrogen atom or benzyl, Ring B is a 6-membered ring containing a nitrogen atom, G is a chlorine atom, and -XR is 2-oxo-. 1
-Pyrrolidinyl, 2-oxo-1-piperidinyl, 2-
Oxohexamethyleneimino, N, N-diethylamino, 1,2,4-triazol-1-yl or 1-methylimidazol-2-ylthio, a compound in which both the 3-position and 4-position of ring A are substituted with a methoxy group It is.

The salt of the desired compound (I) of the present invention is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base,
Examples thereof include salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred 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; and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like.
Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be

The target compound (I) of the present invention is mixed with a pharmaceutically acceptable carrier, and is orally administered as a solid preparation such as tablets, capsules, granules and powders; or a liquid preparation such as syrups and injections. Or it can be administered parenterally. Pharmaceutically acceptable carriers include various organic or inorganic carrier materials commonly used as pharmaceutical materials, such as excipients, lubricants, binders, and disintegrants in solid preparations; solvents and dissolution aids in liquid preparations. , A suspending agent, an isotonic agent, a buffer, a soothing agent and the like. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.

Preferred examples of the excipient include lactose,
Sucrose, D-mannitol, starch, crystalline cellulose,
Light silicic anhydride and the like can be mentioned. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferred examples of the binder include bound cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.

Preferred examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, and the like.
Examples include sodium carbonate and sodium citrate. Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, Examples include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like. Suitable examples of the buffer include phosphate, acetate, carbonate, and the like.
Buffers such as citrate are exemplified. Preferred examples of the soothing agent include benzyl alcohol and the like. Preferable examples of the preservative include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like. The above compound (I) can be produced, for example, as follows. That is,

Method A

Embedded image [In the formula, M ¹ is an optionally substituted hydrocarbon residue, an optionally substituted acyl group, an optionally substituted alkyl group, an optionally substituted carbamoyl group or an optionally substituted carbamoyl group. A good thiocarbamoyl group, Q is a leaving group, X ¹ is an oxygen atom or a sulfur atom, and other symbols are as defined above. In the general formula (II-1), as the leaving group represented by Q,
For example, halogen, preferably chlorine, bromine or iodine or a hydroxy group activated by esterification,
For example, organic sulfonic acid residues (eg, p-toluenesulfonyloxy group, methanesulfonyloxy group, etc.) and organic phosphoric acid residues, diphenylphosphoryloxy group, dibenzylphosphoryloxy group, dimethylphosphoryloxy group, etc. optionally substituted hydrocarbon residue represented by M ^1, optionally substituted acyl group, an alkyl group which may be substituted, may be also be a carbamoyl group or a substituted substituted Examples of the thiocarbamoyl group include an optionally substituted hydrocarbon residue represented by M, an optionally substituted acyl group, an optionally substituted alkyl group, an optionally substituted carbamoyl group, The same as those exemplified as the thiocarbamoyl group which may be substituted are exemplified.

In the present method, (II-1) is converted to (I-1) in the presence of a base.
To produce (I-1). (II-
The reaction between 1) and (III) is performed in an appropriate solvent. Examples of the solvent include benzene, toluene, aromatic hydrocarbons such as xylene, dioxane, tetrahydrofuran,
Ethers such as dimethoxyethane, alcohols such as methanol, ethanol and propanol, ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), Examples include chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone, and a mixed solvent thereof. The reaction between (II-1) and (III) is carried out by alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, silver carbonate (Ag ₂ CO ₃ ), sodium hydride, hydride Potassium, pyridine, triethylamine, N, N-dimethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,
The reaction is carried out in the presence of an appropriate base such as amines such as 4-diazabicyclo [2.2.2] octane and 1,8-diazabicyclo [5.4.0] unde-7-ene. I
It is preferably about 1 to 5 molar equivalents based on I-1). This reaction is carried out usually at -20 ° C to 150 ° C, preferably at about -10 ° C to 100 ° C. The thienopyridine derivative (I-1) thus obtained can be obtained by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography and the like.

Method B

Embedded image [In the formula, p represents an integer of 1 to 6, and the other symbols have the same meanings as described above. In this method, (I-2) is produced by reacting (II-2) with (IV) in the presence of a base. The reaction between (II-2) and (IV) is performed in an appropriate solvent. As the solvent, for example, benzene, toluene, aromatic hydrocarbons such as xylene,
Ethers such as dioxane, tetrahydrofuran, dimethoxyethane, methanol, ethanol, propano-
Alcohols such as ethyl, ethyl acetate, acetonitrile,
Pyridine, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), chloroform, dichloromethane,
Examples thereof include 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone, and a mixed solvent thereof. The reaction between (II-2) and (IV) is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate,
Alkali metal salts such as sodium bicarbonate, pyridine,
The reaction is carried out in the presence of an amine such as triethylamine or N, N-dimethylaniline, or an appropriate base such as sodium hydride or potassium hydride, and the amount of the base to be used is 1 to 5 mol based on compound (II-2). About equivalent weight is preferable. This reaction is usually carried out at -20 ° C to 150 ° C, preferably about -1 ° C.
It is performed at 0 ° C to 100 ° C. This reaction is also performed by using an excess amount of (IV) as a base. The thienopyridine derivative (I-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method C

Embedded image [Wherein, M ² represents an optionally substituted acyl group;
Other symbols are as defined above. In the general formula (I-3), examples of the optionally substituted acyl group represented by M ² include the same groups as those exemplified as the optionally substituted acyl group represented by M. . In this method, (I-3) is subjected to a hydrolysis reaction in the presence of an acid to produce (I-4). The hydrolysis reaction of (I-3) is performed in a water-containing solvent. Examples of the solvent include ethers such as dioxane, tetrahydrofuran and dimethoxyethane, methanol, ethanol and propanol.
, Butanol, alcohols such as 2-methoxyethanol, acetonitrile, N, N-dimethylformamide (D
MF), dimethyl sulfoxide (DMSO), acetone, 2-butanone, acetic acid, and a mixed solvent thereof. Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and the like.
These acids are used in large excess with respect to compound (I-3),
About 5 to 50 molar equivalents are preferred. This reaction is carried out usually at 30 ° C to 150 ° C, preferably at about 50 ° C to 120 ° C, and the reaction time is usually 1 to 100 hours. The thienopyridine derivative (I-4) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method D

Embedded image [Wherein the symbols have the same meanings as described above. In this method, (I-4) is subjected to an oxidation reaction to produce (I-5). This reaction is performed in an appropriate solvent in the presence of an oxidizing agent. Examples of the solvent include benzene, toluene, aromatic hydrocarbons such as xylene, dioxane, tetrahydrofuran, ethers such as dimethoxyethane, ethyl acetate, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2, Examples include 2-tetrachloroethane and a mixed solvent thereof. Examples of the oxidizing agent include manganese dioxide, nitric acid, and the like.
It is preferable to use a large excess amount, about 5 to 50 molar equivalents, relative to 4). The reaction is usually carried out at 30 ° C. to 150 ° C., preferably at about 50 ° C. to 120 ° C., and the reaction time is usually 1 to 1
00 hours. The thienopyridine derivative (I-5) thus obtained can be obtained by a known separation and purification means such as concentration,
It can be isolated and purified by concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method E

Embedded image [Wherein the symbols have the same meanings as described above. In this method, (I-4) is subjected to the same oxidation reaction as in method D,
(I-6) is produced. This reaction is carried out in the same manner as in Method D. The thienopyridine derivative (I-6) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method F

Embedded image [In the formula, R ⁴ represents a hydrocarbon residue which may be substituted or a heterocyclic group which may be substituted, and other symbols have the same meanings as described above. In general formula (V), the optionally substituted hydrocarbon residue represented by R ⁴ or the optionally substituted heterocyclic group represented by R ¹ is represented by R ^1. The same as those exemplified as the residue or the optionally substituted heterocyclic group can be mentioned. In this method, (I-4) is reacted with (V) in the presence of a base to produce (I-7).
The reaction between (I-4) and (V) is performed in an appropriate solvent.
Examples of the solvent include benzene, toluene, aromatic hydrocarbons such as xylene, dioxane, tetrahydrofuran, ethers such as dimethoxyethane, ethyl acetate,
Acetonitrile, pyridine, N, N-dimethylformamide
(DMF), dimethyl sulfoxide (DMSO), chloroform,
Examples include dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone, and a mixed solvent thereof. The reaction between (I-4) and (V) is an alkali metal salt such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, silver carbonate (Ag ₂ CO ₃ ), sodium hydride, hydride Potassium, pyridine, triethylamine, N, N-dimethylaniline, 1,
Amines such as 5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, and 1,8-diazabicyclo [5.4.0] unde-7-ene; The reaction is carried out in the presence of a base, and the amount of the base to be used is preferably about 1 to 5 molar equivalents relative to compound (I-4). This reaction is usually carried out at -20 ° C to 150 ° C, preferably at about -10 ° C to 100 ° C.
Done in The thienopyridine derivative (I-7) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The G method

Embedded image [Wherein the symbols have the same meanings as described above. In the present method, (I-8) is obtained by the reaction of (I-4) and (VI).
To manufacture. The reaction between (I-4) and (VI) is performed in an appropriate solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane;
Ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), chloroform, dichloromethane, 1,2-dichloroethane, 1,
Examples thereof include 1,2,2-tetrachloroethane, acetone, 2-butanone, and a mixed solvent thereof. The amount of (VI) to be used is preferably about 1 to 5 molar equivalents relative to compound (I-4).
This reaction is generally carried out at -50 ° C to 150 ° C, preferably about-
It is carried out at 20 to 100 ° C. The thienopyridine derivative (I-8) thus obtained can be obtained by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

H method

Embedded image [Wherein, R ⁵ represents an optionally substituted hydrocarbon residue, and the other symbols have the same meanings as described above. In formulas (I-9) and (VII), the optionally substituted hydrocarbon residue represented by R ⁵ is exemplified by the optionally substituted hydrocarbon residue represented by M The same thing as the thing is mentioned. In this method, (I-4) is reacted with (VII) in the presence of a base to produce (I-9). The reaction between (I-4) and (VII) is performed in an appropriate solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol;
Ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), chloroform, dichloromethane, 1,2-dichloroethane, 1,
Examples thereof include 1,2,2-tetrachloroethane, acetone, 2-butanone, and a mixed solvent thereof. (I-4) and (VI
The reaction of I) is an alkali metal salt such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, silver carbonate (Ag ₂ CO ₃ ), sodium hydride,
Potassium hydride, pyridine, triethylamine, N, N-dimethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4 .0] The reaction is carried out in the presence of an appropriate base such as an amine such as unde-7-ene, and the use amount of these bases is preferably about 1 to 5 molar equivalents relative to compound (I-4). This reaction is usually carried out at -20 ° C to 150 ° C, preferably about -1 ° C.
It is performed at 0 ° C to 100 ° C. The thienopyridine derivative (I-9) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method I

Embedded image [Wherein the symbols have the same meanings as described above. In this method, (I-10) is produced by reacting compound (VIII) or a reactive derivative at the carboxyl group or a salt thereof with compound (I-4). Suitable reactive derivatives at the carboxyl group of compound (VIII) include acid halides, acid anhydrides, activated amides, activated esters and the like. Preferred examples of the reactive derivative include acid chloride; acid azide; substituted phosphoric acid such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, and dialkyl phosphite. , Sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acids such as methanesulfonic acid, for example, acetic acid, propionic acid, butyric acid, pivalic acid isobutyrate, pentanoic acid,
Mixed acid anhydrides with acids such as aliphatic carboxylic acids such as isopentanoic acid and trichloroacetic acid or aromatic carboxylic acids such as benzoic acid; symmetric acid anhydrides; imidazole;
Activated amides with substituted imidazoles, dimethylpyrazoles, triazoles or tetrazoles; or, for example, cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, tri- Chlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester,
Phenylthioester, p-nitrophenylester, p-
Activated esters such as cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, or N, N-dimethylhydroxyamine, 1-
Examples thereof include esters with N-hydroxy compounds such as hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, and 1-hydroxy-1H-benzotriazole. These reactive derivatives can be arbitrarily selected depending on the type of the compound (VIII) to be used. Suitable salts of the reactive derivative of compound (VIII) include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salts such as trimethylamine salt and triethylamine salt And base salts such as organic base salts such as pyridine salt, picoline salt, dicyclohexylamine salt and N, N-dibenzylethylenediamine salt. The reaction is usually carried out with water, for example, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide and pyridine. The reaction is carried out in any conventional solvent, but the reaction can be carried out in any other organic solvent that does not adversely affect the reaction. These conventional solvents may be used as a mixture with water. In this reaction, when compound (VIII) is used in the form of a free acid or a salt thereof, N, N′-dicyclohexylcarbodiimide; N-cyclohexyl-N′-morpholinoethylcarbodiimide; N-cyclohexyl-N ′ -(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N
-Ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis (2-methylimidazo-
Pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; Diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; for example, ethyl chloroformate; lower alkyl haloformate such as isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5- ( m-sulfophenyl) isoxazolium hydroxide inner salt; N-hydroxybenzotriazole; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; N, N'-dimethyl Formamide and thionyl chloride, phosgene, trichloromethyl chloroformate, ox It is desirable to carry out the reaction in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by reaction with phosphorus chloride or the like. The reaction is also carried out in the presence of an inorganic or organic base such as alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) -alkylmorpholine, N, N-di (lower) alkylbenzylamine, etc. You may go to. The reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or heating. The thienopyridine derivative (I-10) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. The starting compound used for producing the compound (I) can be produced, for example, by the following method.

The J method

Embedded image [Wherein the symbols have the same meanings as described above. Compound (XI) is selected from the journal of medicinal
Chemistry (Journal of Medicinal Chemistry), 17
The compound (IX), the compound (X) and sulfur are reacted in a solvent in the presence of a base according to the method described in Vol. 624, p. 1974 (1974). Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol; chloroform; Examples include dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and a mixed solvent thereof. Examples of the base include triethylamine, diethylamine, morpholine,
The reaction is carried out in the presence of an appropriate base such as an amine such as piperidine or N, N-dimethylaniline. The use amount of these bases is preferably about 1 to 5 molar equivalents relative to compound (IX). This reaction is carried out usually at -20 ° C to 150 ° C, preferably at about -10 ° C to 100 ° C. Next, compound (II-3) is produced from the reaction of compound (XI) with compound (XII). The reaction between (XI) and (XII) is carried out in the presence of a suitable acid such as a Lewis acid such as aluminum chloride and zinc chloride, hydrochloric acid, sulfuric acid, trifluoroacetic acid and p-toluenesulfonic acid.
Performed in a solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol and propanol, and ethyl acetate. , N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and a mixed solvent thereof. Compound (XI
The amount of I) to be used is preferably about 1.0 to 2.0 molar equivalents relative to compound (XI). The amount of the acid to be used is preferably about 0.05 to 2.0 molar equivalents relative to compound (XI). This reaction is carried out usually at 0 ° C to 200 ° C, preferably at about 20 ° C to 1 ° C.
Performed at 20 ° C. The reaction time is 0.5 to 20 hours, preferably 1 to 10 hours. The thienopyridine derivative (II-3) thus obtained can be obtained by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

The K method

Embedded image [In the formula, each symbol has the same meaning as described above.] In this method, compound (II-1) is converted to formylamino form (I-11) by reaction with sodium diformylimide, and then to amino form by reaction with acid. (I-12) is produced. The reaction between compound (II-1) and diformylimide sodium salt is carried out in the same manner as in Method A. (I-
11) can be obtained as compound (I-12) in the same manner as in Method C. A sulfonylamino compound is produced from compound (I-12) according to method F, and an acylamino compound is produced according to method I.

When the thienopyridine derivative produced by Method A to Method K has an isopropoxy group as a substituent of ring A, the isopropoxy group can be converted to a hydroxy group by treating with titanium tetrachloride. This reaction is carried out in a solvent such as chloroform, dichloromethane and carbon tetrachloride at -50 to 30C, preferably at -10 to 20C.

The compound (I) or a salt thereof provided by the present invention has an anti-inflammatory effect, and furthermore has an excellent anti-arthritic effect in an experimental model of adjuvant arthritis which develops arthritis similar to human rheumatoid arthritis. Was confirmed. Further, the compound of the present invention has an excellent inhibitory action on bone resorption, and is useful for prevention and treatment of bone destruction, osteoporosis and the like accompanying arthritis. Furthermore, the compound of the present invention has an inhibitory effect on the production of immune cytokines, and is also effective for the prevention and treatment of diseases considered to be involved in immunity, and / or the prevention of rejection after organ transplantation. . Also, the compounds of the present invention have low toxicity. Accordingly, the compound of interest of the present invention can be used as a prophylactic and therapeutic agent for all arthritis exhibiting inflammatory symptoms in the joints of mammals including humans (eg, humans, horses, cows, pigs, dogs, cats, etc.) as bone destruction or therapeutic agents. It can be used as a prophylactic or therapeutic agent for osteoporosis and the like, and as an immunosuppressant. The immunosuppressive agent or the pharmaceutical composition of the present invention may be used, in particular, for an immune cytokine [eg, interleukin-
2 (IL-2), interferon-γ (IFN-γ)
Etc.) has the effect of suppressing the production of
It is useful for the treatment or prevention of diseases in which immunity is considered to be involved, including autoimmune diseases in mammals including humans.
Such target diseases include, for example, systemic erythematosus, inflammatory bowel disease (ulcerative colitis, Crohn's disease), multiple sclerosis, psoriasis, chronic hepatitis, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia , Chronic myelogenous leukemia, colorectal cancer, colon cancer, rectal cancer, Helicobacter pylori infection, Hodgkin's disease, insulin-dependent diabetes, malignant melanoma, multiple myeloma, non-Hodgkin's lymphoma, non-small cell lung cancer, ovarian cancer , Peptic ulcer, prostate cancer, septic shock, tuberculosis, infertility, arteriosclerosis, Behcet's disease, asthma, atopic dermatitis, nephritis, systemic fungal infection, acute bacterial meningitis, acute myocardial infarction, acute pancreatitis, Acute viral encephalitis, adult respiratory distress syndrome, bacterial pneumonia, chronic pancreatitis, herpes simplex virus infection, varicella-zoster virus infection, AID , Human papilloma virus infection, influenza, invasive staphylococcal infection, peripheral vascular diseases, sepsis, interstitial liver diseases, relay station ileitis, and the like multiple sclerosis. The immunosuppressive agent of the present invention is particularly useful for preventing or treating systemic lupus erythematosus, chronic hepatitis, interstitial liver disease, asthma, psoriasis, ulcerative colitis, Crohn's disease, localized ileitis or multiple sclerosis. On the other hand, it is preferably used. In addition, the immunosuppressant of the present invention is also useful in preventing rejection after organ transplantation. The dose of compound (I) used in the present invention can be variously selected depending on the administration route and the condition of the patient to be treated. Usually, the dose is 5 mg to 1000 mg per adult per oral administration.
In the case of parenteral administration, it can be selected from the range of 1 mg to 100 mg, and these can be divided and administered once to three times a day.

[0054]

BEST MODE FOR CARRYING OUT THE INVENTION Next, test methods for confirming the pharmacological action of the compound (I) of the present invention or a salt thereof and the results thereof will be described. Test Example 1 Effect on rat adjuvant arthritis Male Lewis rats (7 weeks old, CLEA Japan)
Complete Freund's adjuvant [Fresh] in the skin of the right hind footpad
und's complete adjuvant (liquid paraffin suspension of 0.5% tuberculosis killed bacteria)] was injected for sensitization. Test drug (6.25 mg / kg or 3.13 mg / kg)
Is suspended in 0.5% methylcellulose immediately before sensitization (day
0) orally once a day for 14 days. Immediately before sensitization (Day
On day 0) and 14 days (Day 14), the left hind limb volume and body weight were measured using a preseismometer (Ugo Basile
Made in Italy) and electronic balance (EB-3200D, made in Shimadzu,
Japan), and the rate of inhibition of footpad swelling (%) and the rate of weight gain (%) for non-sensitized rats were determined. Table 1 shows the results
Shown in The results were expressed as the mean ± SE of each group (N = 6) and compared and tested by the Dunnet method. In addition, a risk rate of less than 5% was regarded as significant.

[0055]

[Table 1]

Test Example 2 Bone Resorption Inhibitory Effect The bone resorption effect was measured by the method of Lois [Journal of
Clinical Investigation (J. Clin. Inves
t.), 44 , 103-116 (1965)]. Ie, pregnancy 1
One Sprague-Dawley rat on day 8 was injected subcutaneously with 50 μCi of ⁴⁵ Ca (Ca isotope, CaCl ₂ solution),
The following day, the abdomen was opened, the fetal rat was aseptically removed, and the left and right forearms (radius and ulna) of the fetal rat were cut off from the trunk under a dissecting microscope, and a bone culture sample was prepared by removing connective tissue and cartilage as much as possible. BGJb Medium (Fitton-Jackson
modification; GIBCO Laboratories, USA) supplemented with bovine serum albumin (final concentration 2mg / ml) 0.6ml
Was added to each piece, and cultured at 37 ° C. for 24 hours. The bone was cultured for 2 days in the above medium to which a compound (final concentration: 10 μM) was added. The ratio (%) of ⁴⁵ Ca released from the bone into the medium was determined by measuring the radioactivity of ⁴⁵ Ca in the medium and the radioactivity of ⁴⁵ Ca in the bone, and according to the equation (1).

(Equation 1)

A bone obtained from a fetus of the same litter was similarly cultured for 2 days without adding any compound, to obtain a symmetric group. The average value ± standard deviation of the values obtained from five bones in each group was determined, and the ratio (%) of this value to the value of the symmetric group was determined.

[Table 2] Hereinafter, the present invention will be described in more detail by reference examples and examples, but the present invention is not limited thereto.

Reference Example 1 Ethyl 3,4-dimethoxybenzoate (17.8 g) and acetonitrile (7.0 g) in toluene (30 ml)
The solution was added dropwise at 100 ° C. to a suspension of oily sodium hydride (60%, 6.8 g) in toluene (170 ml) and N, N-dimethylformamide (DMF) (17 ml). After the dropwise addition, the mixture was further stirred at 100 ° C. for 3 hours, the reaction mixture was poured into ice-water, and the organic layer was separated. The aqueous layer was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure.
-Cyano-3,4-dimethoxyacetophenone (14.
(0 g, 80%) and recrystallized from ethyl acetate. Colorless needles. 141-142 ° C.

Reference Example 2 ω-cyano-3,4-dimethoxyacetophenone (1
0.0g), sulfur (1.7g), 1-benzyl-4-
A mixture of piperidone (10.1 g), morpholine (4.7 g) and ethanol (50 ml) was stirred under reflux for 2 hours. Pour the reaction mixture into ice-water and add 2N HC
1, 1N KOH and water in that order, and then dried (MgSO
₄ ) After that, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography. From the part eluted with chloroform-ethyl acetate (20: 1, v / v), 2-
Amino-6-benzyl-3- (3,4-dimethoxybenzoyl) -4,5,6,7-tetrahydrothieno [2,
3-c] pyridine (8.4 g, 42%) was obtained and recrystallized from ethanol. Yellow prism crystals. Melting point 149-1
50 ° C.

Reference Example 3 2-amino-6-benzyl-3- (3,4-dimethoxybenzoyl) -4,5,6,7-tetrahydrothieno [2,3-c] pyridine (10.0 g), 1 A mixture of 3,3-dichloroacetone (3.4 g), concentrated sulfuric acid (2.6 g) and acetic acid (200 ml) was stirred at 90 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with 2N NaO
After making it alkaline with H, it was extracted with dichloromethane. The dichloromethane layer was washed with water, dried (MgSO ₄ ), and the solvent was distilled off. The residue was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (1: 1, v / v), 7-benzyl-3-chloro-2-chloromethyl-4- (3,4-dimethoxyphenyl) -5,
6,7,8-tetrahydrothieno [2,3-b: 5,4
-C '] dipyridine (following the structural formula) (3.5 g, 29
%) And recrystallized from ethyl acetate-hexane. Colorless prism crystals. 171-172 ° C.

[0061]

Embedded image REFERENCE EXAMPLE 4 In the same manner as in Reference Example 2, 2-amino-6-benzoyl-3- (3,3) 4-dimethoxybenzoyl) -4,5
6,7-Tetrahydrothieno [2,3-c] pyridine was obtained. Recrystallized from ethanol. Light yellow prism crystal.
143-145 ° C. Reference Example 5 The compound (1.0 g) obtained in Reference Example 4, 1,3-dichloroacetone (0.331 g), p-toluenesulfonic acid 1
A mixture of hydrate (0.045 g) and benzene (15 ml) was heated under reflux for 6 hours and then concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (3: 2,
v / v), 7-benzoyl-3-chloro-2-chloromethyl-4- (3,4-dimethoxyphenyl) -5,6,7,8-tetrahydrothieno [2,
3-b: 5,4-c ′] dipyridine (0.484 g, 4
0%) and recrystallized from ethyl acetate-hexane. Colorless prism crystals. 208-209 ° C.

Reference Example 6 In the same manner as in Reference Example 1, ω-cyano-2,3-dimethoxyacetophenone was obtained by reaction with ethyl 2,3-dimethoxybenzoate and acetonitrile, and recrystallized from ethyl acetate-hexane. . Colorless needles. Melting point 94 ~
95 ° C. Reference Example 7 In the same manner as in Reference Example 2, 2-amino-6-benzyl- was reacted with ω-cyano-2,3-dimethoxyacetophenone, 1-benzyl-4-piperidone and sulfur.
3- (2,3-dimethoxybenzoyl) -4,5,6
7-tetrahydrothieno [2,3-c] pyridine is obtained,
Recrystallized from ethyl acetate-hexane. Light yellow prism crystal. 172-173 ° C. Reference Example 8 In the same manner as in Reference Example 5, by reacting the compound obtained in Reference Example 7 with 1,3-dichloroacetone, 7-benzyl-3-chloro-2-chloromethyl-4- (2,3- Dimethoxyphenyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c ′] dipyridine was obtained and recrystallized from ethyl acetate-hexane. Colorless prism crystals.
137-138 ° C.

Reference Example 9 In the same manner as in Reference Example 1, ω-cyano-4-isopropoxy-3-methoxyacetophenone was obtained by reaction with ethyl 4-isopropoxy-3-methoxybenzoate and acetonitrile. -Recrystallized from hexane. Colorless needles. 114-115 ° C. Reference Example 10 In the same manner as in Reference Example 2, ω-cyano-4-isopropoxy-3-methoxyacetophenone, 1-benzoyl-4
Reaction of 2-amino-6-benzoyl-3- (4-isopropoxy-3-methoxybenzoyl) -4,5,6,7-tetrahydrothieno [2,3-c] pyridine by reaction with piperidone and sulfur. Obtained and recrystallized from ethyl acetate-hexane. Yellow prism crystals. Melting point 158-1
60 ° C. Reference Example 11 In the same manner as in Reference Example 5, 7-benzoyl-3-chloro-2-chloromethyl-4- (4-isopropoxy) was reacted with the compound obtained in Reference Example 10 and 1,3-dichloroacetone. -3-methoxyphenyl) -5,6,7,8
-Tetrahydrothieno [2,3-b: 5,4-c '] dipyridine was obtained as an oil. NMR (δppm in CDCl ₃ ):
1.41 (6H, d, J = 6.0Hz), 2.09-2.35 (2H, m), 3.30-3.81
(2H, m), 3.89 (3H, s), 4.30-4.70 (3H, m), 4.96 (2H, s),
6.78 (1H, d, J = 1.8Hz), 6.80 (1H, dd, J = 8.0 & 1.8Hz), 6.
97 (1H, d, J = 8.0Hz), 7.35-7.55 (5H, m).

Reference Example 12 In the same manner as in Reference Example 2, ω-cyano-4-isopropoxy-3-methoxyacetophenone, 1-benzyl-4-
Reaction with piperidone and sulfur gives 2-amino-
6-Benzyl-3- (4-isopropoxy-3-methoxybenzoyl) -4,5,6,7-tetrahydrothieno [2,3-c] pyridine was obtained and recrystallized from ethyl acetate-hexane. Yellow prism crystals. Melting point 113-114
° C. Reference Example 13 In the same manner as in Reference Example 5, 7-benzyl-3-chloro-2-chloromethyl-4- (4-isopropoxy) was reacted with the compound obtained in Reference Example 12 and 1,3-dichloroacetone. -3-methoxyphenyl) -5,6,7,8-
Tetrahydrothieno [2,3-b: 5,4-c '] dipyridine was obtained and recrystallized from ethyl acetate-hexane. Light yellow prism crystal. 173-174 ° C.

Example 1 A mixture of the compound (1.5 g) obtained in Reference Example 3, an aqueous solution of ethylamine (70%, 4.8 g) and N, N-dimethylformamide (50 ml) was stirred at room temperature for 3 days. Concentrated under reduced pressure. Water was poured into the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and the solvent was distilled off. The residue was subjected to silica gel column chromatography. From the part eluted with ethyl acetate, 7-benzyl-
3-chloro-4- (3,4-dimethoxyphenyl) -2
-Ethylaminomethyl-5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c '] dipyridine (the following structural formula) (0.5 g, 33%) was obtained. Recrystallized from ethanol. Colorless prism crystals. 135-136
° C.

Embedded image Example 2 A mixture of the compound (1.5 g) obtained in Reference Example 3, diethylamine (1.1 g) and tetrahydrofuran (50 ml) was stirred under reflux for 10 hours, and then concentrated under reduced pressure. Water was poured into the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and the solvent was distilled off. The residue was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate, 7-benzyl-3-chloro-2-
(N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c ′] dipyridine (structural formula below) (0.5 g, 33%). Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 150-15
1 ° C.

Embedded image

Example 3 A mixture of the compound (1.0 g) obtained in Reference Example 3, tert-butylamine (2.9 g), potassium carbonate (0.276 g) and acetone (30 ml) was stirred at room temperature for 2 days. And concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and 7-benzyl-2- (tert-butylaminomethyl) -3-chloro-4- (3,4-dimethoxyphenyl) -5,6 was eluted with ethyl acetate. , 7,8-Tetrahydrothieno [2,3-b: 5,4-c '] dipyridine (0.68
g, 64%) and was recrystallized from isopropyl ether. Colorless prism crystals. 134-135 ° C. Example 4 In the same manner as in Example 3, the compound obtained in Reference Example 3 and t
By reaction with ert-amylamine, 2- (tert-amylaminomethyl) -7-benzyl-3-chloro-4-
(3,4-Dimethoxyphenyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c ′] dipyridine was obtained. Recrystallized from isopropyl ether. Colorless prism crystals. 128-129 ° C. Example 5 In the same manner as in Example 3, the compound obtained in Reference Example 3 and
By reaction with cyclopropylamine, 7-benzyl-
3-chloro-2- (cyclopropylaminomethyl) -4
-(3,4-dimethoxyphenyl) -5,6,7,8-
Tetrahydrothieno [2,3-b: 5,4-c '] dipyridine was obtained. Recrystallized from isopropyl ether.
Colorless prism crystals. 131-132 ° C.

Example 6 To a solution of 2-hydroxypyridine (0.297 g) in N, N-dimethylformamide (20 ml) was added oily sodium hydride (60%, 0.125 g), and the mixture was stirred at room temperature for 15 minutes. Then, the compound (1.2 g) obtained in Reference Example 3 was added, and the mixture was stirred at 80 ° C. for 30 minutes, and then poured into water and extracted with ethyl acetate. Wash and dry the ethyl acetate layer
(MgSO ₄ ) and concentrated under reduced pressure. Silica gel residue
The residue was subjected to column chromatography and eluted with ethyl acetate-hexane (2: 1, v / v) to give 7-benzyl-3-chloro-4- (3,4-dimethoxyphenyl).
-2- (2-pyridyloxymethyl) -5,6,7,8
-Tetrahydrothieno [2,3-b: 5,4-c '] dipyridine (0.13 g, 10%) was obtained. Ethyl acetate
Recrystallized from hexane. Light yellow prism crystal. Melting point 1
65-167 ° C. Example 7 In the column chromatography of Example 6, 7-benzyl-
3-chloro-4- (3,4-dimethoxyphenyl) -2
-(1,2-dihydro-2-oxopyridin-1-ylmethyl) -5,6,7,8-tetrahydrothieno [2,
3-b: 5,4-c ′] dipyridine (1.0 g, 75
%) As a colorless powder.

Example 8 In the same manner as in Example 2, the compound obtained in Reference Example 5 and t
Upon reaction with ert-butylamine, 7-benzoyl-2
-(Tert-butylaminomethyl) -3-chloro-4-
(3,4-Dimethoxyphenyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c ′] dipyridine was obtained. 204-205 ° C. Example 9 The compound obtained in Reference Example 11 and
By reaction with tert-butylamine, 7-benzoyl-
2- (tert-butylaminomethyl) -3-chloro-4-
(4-isopropoxy-3-methoxyphenyl) -5
6,7,8-tetrahydrothieno [2,3-b: 5,4
-C '] dipyridine was obtained. 165-166 ° C. Example 10 After stirring the compound obtained in Example 8 (3.0 g), an aqueous potassium hydroxide solution (4N, 6.8 ml) and 2-methoxyethanol (50 ml) at 100 ° C for 10 hours, the mixture was concentrated under reduced pressure. Was. Water was poured into the residue and extracted with dichloromethane. The dichloromethane layer was washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the portion eluted with ethyl acetate, 2-
(Tert-butylaminomethyl) -3-chloro-4-
(3,4-Dimethoxyphenyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c ′] dipyridine (1.25 g, 51%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 162-
163 ° C.

Example 11 In the same manner as in Example 10, from the compound obtained in Example 9,
2- (tert-butylaminomethyl) -3-chloro-4-
(4-isopropoxy-3-methoxyphenyl) -5
6,7,8-tetrahydrothieno [2,3-b: 5,4
-C '] dipyridine was obtained. Recrystallized from ethyl acetate-hexane. Light yellow prism crystal. 157-158
° C. Example 12 In the same manner as in Example 3, 7-benzyl-3-chloro- was reacted with the compound obtained in Reference Example 8 and piperidine.
4- (2,3-dimethoxyphenyl) -5,6,7,8
-Tetrahydro-2-piperidinomethylthieno [2,3
-B: 5,4-c '] dipyridine was obtained and treated with hydrochloric acid-ethanol to form a hydrochloride. Colorless powder. 173-174 ° C. Example 13 By reacting the compound obtained in Reference Example 8 and morpholine in the same manner as in Example 3, 7-benzyl-3-chloro-
4- (2,3-dimethoxyphenyl) -2-morpholinomethyl-5,6,7,8-tetrahydrothieno [2,3
-B: 5,4-c '] dipyridine was obtained and treated with hydrochloric acid-ethanol to form a hydrochloride. Pale yellow powder. 176-177 ° C. Example 14 In the same manner as in Example 2, the compound obtained in Reference Example 3 and N
Reaction with 2-acetylpiperazine gives 2- (4-acetylpiperazin-1-ylmethyl) -7-benzyl-3
-Chloro-4- (3,4-dimethoxyphenyl) -5,
6,7,8-tetrahydrothieno [2,3-b: 5,4
-C '] dipyridine was obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. 183-184 ° C.

Example 15 The compound (1.0 g) obtained in Reference Example 3 and pyrrolidine (0.
A mixture of 284 g) and ethanol (30 ml) was heated under reflux for 3 hours and then concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (2: 1, v / v), 7-benzyl-3-chloro-4-
(3,4-dimethoxyphenyl) -2- (1-pyrrolidinylmethyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c ′] dipyridine (0.65
g, 61%). Recrystallized from ethyl acetate-hexane. Colorless prism crystals. 157-158 ° C. Example 16 A mixture of the compound obtained in Reference Example 3 (3.0 g), sodium diformamide [NaN (CHO) ₂ ] (0.856 g) and N, N-dimethylformamide (40 ml) was mixed at 80 ° C. with 3
Stir for hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1, v / v).
From the part eluted in v), 7-benzyl-3-chloro-
2- (Diformylaminomethyl) -4- (3,4-dimethoxyphenyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c ′] dipyridine (1.0
g, 31%). Colorless powder. Elemental analysis Calculated for C ₂₈ H ₂₆ N ₃ O ₄ SCl · 1 / 2H ₂ O: C, 61.70; H, 4.99; N, 7.71 Analytical values: C, 61.94; H, 5.30; N, 7.35

Example 17 In the column chromatography of Example 16, 7-benzyl-3-chloro-4- (3,4-dimethoxyphenyl) was obtained from the portion eluted following the compound of Example 16.
-2-Formylaminomethyl-5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c '] dipyridine (0.7 g, 23%) was obtained as a colorless powder. Elemental analysis Calculated value for C ₂₇ H ₂₆ N ₃ O ₃ SCl · 1 / 4H ₂ O: C, 63.27; H, 5.21; N, 8.20 Analytical value: C, 63.27; H, 5.54; N, 7.85 A mixture of the compound (0.9 g) obtained in Example 16 and hydrochloric acid-ethanol (5%, 6 ml) was heated under reflux for 1 hour, and then concentrated under reduced pressure. The residue was made alkaline with 2N NaOH and extracted with dichloromethane. The dichloromethane layer was washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the fraction eluted with ethyl acetate-ethanol (5: 1, v / v), 2-aminomethyl-7-benzyl-3 was obtained.
-Chloro-4- (3,4-dimethoxyphenyl) -5,
6,7,8-tetrahydrothieno [2,3-b: 5,4
-C '] dipyridine (0.59 g, 81%). Colorless powder.

Example 19 The compound obtained in Example 18 (0.35 g), triethylamine (0.096 g) and dichloromethane (6 ml)
To a mixture of benzenesulfonyl chloride (0.1
After stirring for 1 hour, the reaction mixture was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and 7-benzyl-3-chloro-4- (3,4-dimethoxyphenyl) -2 was eluted with ethyl acetate-hexane (1: 1, v / v). -Phenylsulfonylaminomethyl-5,6
7,8-tetrahydrothieno [2,3-b: 5,4-
c ′] dipyridine (0.25 g, 55%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. 153-154 ° C. Example 20 N-hydroxybenzotriazole (HOBt) (0.427
g) and 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide (WSC) (0.535 g) obtained in Example 18 (1.0 g), (1,2,4-triazol-1-yl) ) Acetic acid (0.325 g) and N, N-
The mixture was added to an ice-cooled mixture of dimethylformamide (DMF) (20 ml), stirred at room temperature for 8 hours, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl acetate-methanol (20:
1, v / v), 7-benzyl-3-
Chloro-4- (3,4-dimethoxyphenyl) -5
6,7,8-tetrahydro-2- (1,2,4-triazol-1-ylacetylaminomethyl) thieno [2,
3-b: 5,4-c ′] dipyridine (0.55 g, 50
%). Recrystallized from ethyl acetate-hexane. Colorless powder. 101-102 ° C.

Example 21 The compound (0.3 g) obtained in Example 18 and acetic anhydride (0.
A mixture of 142 g) and pyridine (2.5 ml) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the part eluted with ethyl acetate, 2-acetylaminomethyl-7-benzyl-3-chloro-4- (3,4
-Dimethoxyphenyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c '] dipyridine was obtained as an oil. This oil was treated with hydrochloric acid-ethanol to form a hydrochloride. Recrystallized from dichloromethane-ethyl ether. Pale yellow powder. 172-174 ° C. Example 22 Compound (0.29 g) obtained in Example 18 containing pyridine (4
nicotinic acid chloride hydrochloride (0.18 g)
After stirring at room temperature for 1 hour, the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. From the part eluted with ethyl acetate, 7-
Benzyl-3-chloro-4- (3,4-dimethoxyphenyl) -2- (nicotinoylaminomethyl) -5,6
7,8-tetrahydrothieno [2,3-b: 5,4-
c ′] dipyridine (0.2 g, 51%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. 124-125 ° C.

Example 23 A solution of 2-pyrrolidone (0.839 g) in N, N-dimethylformamide (50 ml) was added with oily sodium hydride (6 ml).
0%, 0.394 g) and stirred at room temperature for 20 minutes. Next, the compound (4.0 g) obtained in Reference Example 11 was added, and the mixture was stirred at 60 ° C. for 20 minutes, and then the reaction mixture was poured into water, and the precipitated solid was collected by filtration. The crystals were subjected to silica gel column chromatography, and from the portion eluted with ethyl acetate-hexane (4: 3, v / v), 7-benzyl-3-chloro-4- (4-isopropoxy-3-methoxyphenyl) was obtained. ) -2- (2-Oxo-1-pyrrolidinylmethyl) -5,6,7,8-tetrahydrothieno [2,3
-B: 5,4-c '] dipyridine (0.72 g, 17
%). Recrystallized from ethyl acetate-hexane. Colorless prism crystals. 140-141 ° C. Example 24 In the same manner as in Example 23, by reacting the compound obtained in Reference Example 3 with 2-piperidone, 7-benzyl-3-
Chloro-4- (3,4-dimethoxyphenyl) -2-
(2-oxo-1-piperidinylmethyl) -5,6,
7,8-tetrahydrothieno [2,3-b: 5,4-
c ′] dipyridine was obtained. Recrystallized from ethanol-isopropyl ether. Light yellow prism crystal. Melting point 11
3-114 ° C.

Example 25 In the same manner as in Example 23, the compound obtained in Reference Example 3 was reacted with ε-caprolactam to give 7-benzyl-
3-chloro-4- (3,4-dimethoxyphenyl) -2
-(2-oxohexamethyleneiminomethyl) -5,
6,7,8-tetrahydrothieno [2,3-b: 5,4
-C '] dipyridine was obtained. Recrystallized from ethyl acetate-hexane. Light yellow prism crystal. Melting point 113-114
° C. Example 26 Compound (2.5 g) obtained in Reference Example 3, 1H-1,2,4
-Triazole (0.414 g), potassium carbonate (0.
A mixture of 691 g) and acetone (50 ml) was stirred under reflux for 10 hours, and then concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and 7-benzyl-3-chloro-4- (3,4-dimethoxyphenyl)-was eluted with ethyl acetate.
5,6,7,8-Tetrahydro-2- (1,2,4-triazol-1-ylmethyl) thieno [2,3-b:
5,4-c '] dipyridine (1.93 g, 73%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. 165-166 ° C. Example 27 In the column chromatography of Example 26, 7-benzyl-3-chloro-4- (3,4-dimethoxyphenyl) was obtained from a portion eluted following the compound of Example 26.
-5,6,7,8-tetrahydro-2- (1,2,4-
Triazol-4-ylmethyl) thieno [2,3-b:
5,4-c '] dipyridine (0.22 g, 8%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 176-177 [deg.] C.

Example 28 A solution of 2-pyrrolidone (0.204 g) in N, N-dimethylformamide (15 ml) was added with oily sodium hydride (6 ml).
0%, 0.088 g) and stirred at room temperature for 15 minutes. Then, the compound (1.0 g) obtained in Reference Example 3 was added,
After stirring at 90 ° C. for 20 minutes, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (MgSO
₄ ) Then, the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and 7-benzyl-3-chloro-4- (3,4-dimethoxyphenyl) -2- (2-oxo-1-pyrrolidinidine was eluted with ethyl acetate. Methyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c ′] dipyridine (0.21
g, 19%). Recrystallized from ethyl acetate-hexane. Colorless prism crystals. 139-140 ° C. Example 29 A dichloromethane (10 ml) solution of titanium tetrachloride (6.3 g) was added dropwise to a solution of the compound obtained in Example 23 (3.8 g) in dichloromethane (75 ml) under ice-cooling. Stir for hours. The reaction mixture was poured into ice-saturated aqueous sodium hydrogen carbonate solution, and the insoluble matter was removed by filtration.
It was dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl acetate-
From the part eluted with hexane (7: 3, v / v), 7-
Benzyl-3-chloro-4- (4-hydroxy-3-methoxyphenyl) -2- (2-oxo-1-pyrrolidinylmethyl) -5,6,7,8-tetrahydrothieno [2,3-b : 5,4-c '] dipyridine (0.89
g, 25%). Recrystallized from ethanol. Colorless prism crystals. 190-191 ° C.

Example 30 In the same manner as in Example 28, the compound obtained in Reference Example 3 was
By reaction with hydroxy-2-oxopyrrolidine, 7
-Benzyl-3-chloro-4- (3,4-dimethoxyphenyl) -2- (4-hydroxy-2-oxopyrrolidin-1-ylmethyl) -5,6,7,8-tetrahydrothieno [2,3- b: 5,4-c '] dipyridine was obtained as an amorphous solid. NMR (δ ppm in CDCl ₃ ): 1.90-2.1
5 (2H, m), 2.40-2.68 (3H, m), 2.82 (1H, dd, J = 17.6 & 5.4
Hz), 3.50 (1H, dd, J = 10.6 & 4.0Hz), 3.66 (2H, s), 3.71
(2H, s), 3.87 (3H, s), 3.96 (3H, s), 4.45-4.65 (2H, m),
5.15 (1H, d, J = 16.6 & 3.6Hz), 6.68-6.85 (2H, m), 6.95
(1H, dd, J = 7.8 & 2.0Hz), 7.20-7.48 (5H, m). Example 31 In the same manner as in Example 28, the compound obtained in Reference Example 3 and 5-
By reaction with methyl-2-oxopyrrolidine, 7-benzyl-3-chloro-4- (3,4-dimethoxyphenyl) -2- (5-methyl-2-oxopyrrolidine-1-
(Ilmethyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c '] dipyridine was obtained as an amorphous solid. NMR (δ ppm in CDCl ₃ ): 1.22 (3H, d, J =
6.2Hz), 1.94-2.08 (2H, m), 2.20-2.63 (6H, m), 3.3.65
(2H, s), 3.70 (2H, s), 3.78-4.05 (7H, m), 4.42 (1H,
d, J = 16.8Hz), 5.24 (1H, d, J = 16.8Hz), 6.73 (1H, d, J = 1.
8Hz), 6.77 (1H, dd, J = 8.0 & 1.8Hz), 6.94 (1H, d, J = 8.0H
z), 7.20-7.42 (5H, m).

Example 32 In the same manner as in Example 28, the compound obtained in Reference Example 3 was
By reaction with oxo-1-phenylpyrazolidine, 7
-Benzyl-3-chloro-4- (3,4-dimethoxyphenyl) -2- (1-phenyl-2-pyrazolin-3-
(Iloxymethyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c '] dipyridine was obtained.
Recrystallized from ethyl acetate-hexane. Colorless prism crystals. 157-158 ° C. Example 33 In the column chromatography of Example 32, 7-benzyl-3-chloro-4- (3,4-dimethoxyphenyl) was obtained from a portion eluted following the compound of Example 32.
-2- (3-oxo-1-phenylpyrazolidine-2-
(Ilmethyl) -5,6,7,8-tetrahydrothieno [2,3-b: 5,4-c '] dipyridine was obtained as an amorphous solid. NMR (δ ppm in CDCl ₃ ): 1.90-2.10 (2H,
m), 2.57 (2H, t, J = 5.8Hz), 2.71 (2H, t, J = 7.6Hz), 3.66
(2H, s), 3.71 (2H, s), 3.85 (3H, s), 3.94 (3H, s), 4.
12 (2H, t, J = 7.6Hz), 4.98 (2H, s), 6.68 (1H, d, J = 1.8H
z), 6.75 (1H, dd, J = 8.2 & 1.8Hz), 6.93 (1H, d, J = 8.2Hz),
6.98-7.15 (3H, m), 7.25-7.50 (5H, m).

Example 34 In the same manner as in Example 28, the compound obtained in Reference Example 3 was
By reaction with methyl-5-oxo-2-pyrazoline,
7-benzyl-3-chloro-4- (3,4-dimethoxyphenyl) -2- (3-methyl-5-oxo-2-pyrazolin-1-ylmethyl) -5,6,7,8-tetrahydrothieno [ 2,3-b: 5,4-c ′] dipyridine was obtained as an amorphous solid. NMR (δ ppm in CDCl ₃ ): 1.82
-2.08 (2H, m), 2.25 (3H, s), 2.50-2.63 (2H, m), 3.66
(2H, s), 3.71 (2H, s), 3.87 (3H, s), 3.95 (3H, s), 5.3
0-5.62 (3H, m), 6.70-6.85 (2H, m), 6.94 (1H, d, J = 7.8H
z), 7.20-7.43 (5H, m).

Example 35 A mixture of the compound (1.0 g) obtained in Reference Example 3, succinimide (0.238 g), potassium carbonate (0.276 g) and N, N-dimethylformamide (10 ml) was added at 100 ° C. for 1 hour. After stirring for an hour, the mixture was poured into water and extracted with ethyl acetate. Wash the ethyl acetate layer with water and dry (MgSO ₄ )
And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1: 1).
1, v / v), 7-benzyl-3-
Chloro-2- (2,5-dioxopyrrolidin-1-ylmethyl) -4- (3,4-dimethoxyphenyl) -5
6,7,8-tetrahydrothieno [2,3-b: 5,4
-C '] dipyridine (0.65 g, 58%). Recrystallized from ethanol-hexane. Light yellow prism crystal. 128-130 ° C.

Example 36 A mixture of the compound obtained in Example 28 (3.0 g), palladium-carbon (5%, 5 g), nitrobenzene (1.3 g) and xylene (100 ml) was stirred under reflux for 4 hours. Thereafter, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography,
From the part eluted with ethyl acetate, 3-chloro-4-
(3,4-dimethoxyphenyl) -2- (2-oxopyrrolidin-1-ylmethyl) thieno [2,3-b: 5
4-c '] dipyridine (0.25, 10%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals.
228-230 ° C.

[0082]

Industrial Applicability According to the present invention, it has an excellent anti-inflammatory effect, is useful as an anti-inflammatory agent, particularly a therapeutic agent for arthritis such as rheumatoid arthritis, and has an effect of inhibiting bone resorption, It is useful for the prevention and treatment of osteoporosis and the like, and furthermore, has an inhibitory effect on the production of immune cytokines, and prevents or treats diseases that are considered to be involved in immunity, and / or prevents rejection after organ transplantation. Novel Thienopyridine Derivative Effectively Also, a Method for Producing the Same, and an Anti-inflammatory Agent Containing the Same, Especially an Arthritis Treatment Agent, a Bone Destruction, a Prevention and Treatment Agent for Osteoporosis, and an Agent for Prevention and Treatment of Diseases Involved in Immunity Can be provided.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 31/435 ABJ A61K 31/435 ABJ ADT ADT

Claims (22)

[Claims] 1. A compound of the general formula (I): Wherein G is a halogen atom, X is an oxygen atom, a sulfur atom which may be oxidized, or-(CH ₂ ) q- (q is an integer of 0 to 5), and R is a substituted Represents an optionally substituted amino group or an optionally substituted heterocyclic group.
Ring B represents a 5- to 7-membered ring containing an optionally substituted nitrogen atom, and M represents a hydrogen atom, an optionally substituted hydrocarbon residue, an optionally substituted acyl N represents 0 or 1 for a group, a carbamoyl group which may be substituted, a thiocarbamoyl group which may be substituted or a sulfonyl group which may be substituted; Ring A may have a substituent. Or a salt thereof. 2. An optionally substituted amino group represented by R is —N (R ¹ ) (R ² ) (wherein R ¹ and R ² are the same or different and are each a hydrogen atom, A hydrocarbon residue, an acyl group, a sulfonyl group or a heterocyclic group which may be substituted, or R ¹ and R ² may be bonded to each other to form a nitrogen-containing 5- to 7-membered ring) Wherein the optionally substituted heterocyclic group represented by R is the same or different and is an aromatic monocyclic heterocyclic group, an aromatic condensed heterocyclic group or a non-aromatic heterocyclic group; The optionally substituted 5- to 7-membered ring represented by is a 6-membered heterocyclic ring containing one optionally substituted nitrogen atom, wherein Ring A is a halogen atom, a nitro group, Alkyl group, an optionally substituted hydroxy group, an optionally substituted An all group, an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted aromatic ring group. 2. The compound according to 1 or a salt thereof. Wherein R ¹ or a hydrocarbon residue which may be substituted represented by R ² is substituted is also C _1-6 alkyl group, substituted represented by R ¹ or R ² The compound according to claim 2, wherein the heterocyclic group which may be an aromatic 5-membered heterocyclic group containing 2 to 3 heteroatoms or a salt thereof. 4. An optionally substituted heterocyclic group represented by R is (i) a 5- to 7-membered heterocyclic group containing one sulfur, nitrogen or oxygen atom, and (ii) 2 to 4 heterocyclic groups. 5 including nitrogen atom
A 6-membered heterocyclic group, (iii) a 5- to 6-membered heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur or oxygen atom, or (i)
v) The compound according to claim 1, wherein any one of the three heterocyclic groups is condensed with a 6-membered ring containing not more than 2 nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom. Or its salt. 5. The compound according to claim 1, wherein X is-(CH ₂ ) q-, wherein q is an integer of 0 to 3, or a salt thereof. 6. The compound according to claim 5, wherein q is 0, or a salt thereof. 7. The compound according to claim 1, wherein G is a chlorine atom, or a salt thereof. 8. The compound according to claim 2, wherein the substituent on ring A is a C _1-6 alkoxy group or a hydroxy group, or a salt thereof. 9. A compound represented by the formula (I): 7-benzyl-3-chloro-4- (3,4-dimethoxyphenyl) -2- (2-oxo-1-piperidinylmethyl) -5 , 6,7,8-Tetrahydrothieno [2,3-
b: 5,4-c '] dipyridine, 7-benzyl-3-chloro-4- (3,4-dimethoxyphenyl) -2- (2-oxohexamethyleneinomimethyl) -5,6,7,8 -Tetrahydrothieno [2,3
-B: 5,4-c '] dipyridine, 7-benzyl-3-chloro-4- (3,4-dimethoxyphenyl) -2- (2-oxo-l-pyrrolidinylmethyl) -5,6, 7,8-tetrahydrothieno [2,3-
b: 5,4-c '] dipyridine or 7-benzyl-
3-chloro-4- (4-hydroxy-3-methoxyphenyl-2- (2-oxo-1-pyrrolidinylmethyl)-
5,6,7,8-tetrahydrothieno [2,3-b:
5,4-c '] dipyridine. 10. 7-Benzyl-3-chloro-2-
(2,5-dioxopyrrolidin-1-ylmethyl) -4
-(3,4-dimethoxyphenyl) -5,6,7,8-
The compound according to claim 1, which is tetrahydrothieno [2,3-b: 5,4-c '] dipyridine. 11. It is 3-chloro-4- (3,4-dimethoxyphenyl) -2- (2-oxopyrrolidin-1-ylmethyl) thieno [2,3-b: 5,4-c ′] dipyridine. A compound according to claim 1. 12. A compound of formula (II-1): [Wherein, M ¹ is an optionally substituted hydrocarbon residue, an optionally substituted acyl group, an optionally substituted alkyl group, an optionally substituted carbamoyl group or an optionally substituted carbamoyl group. A good thiocarbamoyl group, Q is a leaving group, and G is a halogen atom. In a solvent, in the presence of a base, a compound represented by the formula (III): R—X ¹ H wherein X ¹ represents an oxygen atom or a sulfur atom. And a compound represented by the formula (I-1): Wherein M ¹ , G and X ¹ are the same as defined above,
R represents an optionally substituted amino group or an optionally substituted heterocyclic group. Or a compound of the formula (II-2): Wherein p represents an integer of 1 to 6, and M ¹ , G and Q
Is the same as defined above. In a solvent in the presence of a base, a compound represented by the formula (IV): [Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom, an optionally substituted hydrocarbon residue, an acyl group, a sulfonyl group or a heterocyclic group, or R ¹ and R ² May be bonded to each other to form a nitrogen-containing 5- to 7-membered ring. With a compound represented by the formula (I-2): [Wherein, M ¹ , G, R ¹ , R ² and p are the same as defined above. Or a compound of the formula (I-
3): embedded image [Wherein, M ² represents an optionally substituted acyl group;
X is an oxygen atom, oxidized have good sulfur atom or be - (CH ₂₎ q- (q is 0 to an integer of 5) indicates, G and R are as defined above. Is subjected to a hydrolysis reaction in a water-containing solvent in the presence of an acid to give a compound of the formula (I-4): [Wherein, G, R and X are the same as defined above. Or a compound of the formula (I-4) in a solvent in the presence of a base of the formula (VII): R ⁵ -Q wherein R ⁵ is substituted And Q is the same as defined above. And a compound represented by the formula (I-9): [Wherein, R, R ⁵ , G and X are the same as defined above. Or a compound of formula (IX): Wherein M ¹ is the same as defined above. A compound represented by the formula:
Formula (X): And sulfur in a solvent in the presence of a base to give a compound of the formula (XI): [Wherein, M ¹ is the same as defined above. Then, a compound represented by the formula (XI) is converted to a compound represented by the formula (XII): QCH ₂ COCH ₂ -G, wherein G and Q are the same as defined above. With a compound represented by the formula (II-
3): embedded image Wherein G, M ¹ and Q are as defined above. Wherein a compound represented by the general formula (I) is obtained: [Wherein, G, X and R are the same as defined above. Ring B represents a 5- to 7-membered ring containing an optionally substituted nitrogen atom, and M represents a hydrogen atom, an optionally substituted hydrocarbon residue, an optionally substituted acyl N represents 0 or 1 for a group, a carbamoyl group which may be substituted, a thiocarbamoyl group which may be substituted or a sulfonyl group which may be substituted; Ring A may have a substituent. ] The manufacturing method of the compound represented by this. 13. A compound of the general formula (I): Wherein G is a halogen atom, X is an oxygen atom, a sulfur atom which may be oxidized, or-(CH ₂ ) q- (q is an integer of 0 to 5), and R is a substituted Represents an optionally substituted amino group or an optionally substituted heterocyclic group.
Ring B represents a 5- to 7-membered ring containing an optionally substituted nitrogen atom, and M represents a hydrogen atom, an optionally substituted hydrocarbon residue, an optionally substituted acyl N represents 0 or 1 for a group, a carbamoyl group which may be substituted, a thiocarbamoyl group which may be substituted or a sulfonyl group which may be substituted; Ring A may have a substituent. Or a pharmaceutically acceptable salt thereof. 14. The pharmaceutical composition according to claim 13, for preventing or treating inflammation. 15. The pharmaceutical composition according to claim 13, for preventing or treating arthritis. 16. The pharmaceutical composition according to claim 13, for preventing or treating rheumatism. 17. The pharmaceutical composition according to claim 13, for preventing or treating rheumatoid arthritis. 18. The pharmaceutical composition according to claim 13, which has a bone resorption inhibiting effect. 19. The pharmaceutical composition according to claim 13, which is for preventing or treating osteoporosis. 20. The pharmaceutical composition according to claim 13, which has an inhibitory effect on cytokine production. 21. The pharmaceutical composition according to claim 13, which is for preventing or treating an autoimmune disease. 22. The pharmaceutical composition according to claim 13, which is for preventing rejection after organ transplantation.