JP3268242B2 - Pharmaceuticals containing fused heterocyclic compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a hyperlipidemia, hyperglycemia, obesity, impaired glucose tolerance comprising a fused heterocyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.
ed glucosetolerance: IGT), hypertension, osteoporosis, cachexia, fatty liver, diabetic complications (eg, retinopathy,
Nephropathy, neurosis, cataract, coronary artery disease, etc.), arteriosclerosis,
Prophylactic and / or therapeutic drugs for cataracts and the like, and gestational diabetes mellitus other than the above diseases
: GDM), polycystic ovary syndrome (polycysticovary syn)
prophylactic and / or therapeutic agents for diseases caused by insulin resistance such as drome: PCOS), and inflammatory diseases (eg, osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory enteritis, etc.), acne, Sunburn, psoriasis, eczema,
Cell damage caused by allergic disease, asthma, GI ulcer, cardiovascular disease (for example, ischemic heart disease), atherosclerosis and ischemic disease (for example, brain damage caused by stroke) And the like for prophylactic and / or therapeutic agents.

[0002]

2. Description of the Related Art Conventionally, as an agent for treating diabetes and hyperglycemia,
Insulin and sulfonylurea compounds such as tributamide and glipizide have been used. Recently, thiazolidinedione derivatives have been known as therapeutic agents for insulin-independent diabetes.

(1) Numerous thiazolidine compounds having a blood glucose lowering effect are known. For example, JP-A-55-22636 (JP-B-62-42903)
No.), Japanese Unexamined Patent Publication No. 60-511189 (JP-B 2-3107)
No. 9), Y. KAWAMATSU et al., Chem. Pharm. Bull., 30
Vol., 3580-3600 (1982), European Patent Publication No. 0441605, and the like.

(2) Further, as a compound containing a heterocyclic group, for example, JP-A-61-286376, JP-A-5-5-2
No. 13913, WO92 / 07850A (= Tokuheihei 6
-502144), WO92 / 07839A (= Japanese Translation of PCT Application No. 6-502146), and JP-A-61-85372.
JP-A-1-131169, JP-A-2-83384
No., etc.

(3) Oxazolidine-2,4-dione compounds having a blood glucose lowering effect are disclosed in
478, WO92 / 02520A and the like. (4) Further, an N-hydroxyureido group or 3,5-
A compound containing a dioxooxadiazolidine-2-ylmethylphenyl group and having the same activity is described in WO9.
It is disclosed in 2 / 03425A (= Tokuhyohei 5-508654). However, these compounds have drawbacks such as insufficient activity and safety issues. Further, clinically more powerful and safe drugs for preventing and / or treating these diseases are desired.

[0006] The relationship between thiazolidine compounds and various diseases is described in, for example, the following documents. The effects of thiazolidine compounds on hyperglycemia
es., 32 (9) , 804-810 (1983); Diabetes., 37 (11) , 154.
9-1558 (1988); Prog. Clin. Biol. Res., 265 , 177-192 (198
8); Metabolism., 37 (3) , 276-280 (1988); Arzneimitte
lforschung., 40 (1) , 37-42 (1990), Arzneimittelforsch
ung., 40 (2 Pt 1) , 156-162 (1990); Arzneimittelforsc
hung., 40 (3) , 263-267 (1990).

The use of thiazolidine compounds for hyperlipidemia
The action is Diabetes.,40 (12), 1669-1674 (1991); Am.J.Ph
ysiol.,267 (1 Pt 1), E95-E101 (1994); Diabetes.,43
(Ten), 1203-1210 (1994).

[0008] Insufficient glucose tolerance and insulin resistance
Arzneimittelforschun
g.,40 (2 Pt 1), 156-162 (1990); Metabolism.,40 (1
0), 1025-1230 (1991); Diabetes.,43 (2), 204-211 (199
4); N. Engl. J. Med.,331 (18), 1226-1227 (1994), etc.
It has been tell.

The use of thiazolidine compounds for hypertension
The action is Metabolism.,42 (1), 75-80 (1993); Am. J. Phy
siol.,265 (4 Pt 2)Diabetes., R726-R732 (1993);43
(2), 204-211 (1994).

The action of thiazolidine compounds on cachexia is described in Endocrinology., 135 (5) , 2279-2282 (1994);
docrinology., 136 (4) , 1474-1481 (1995).

The effect of thiazolidine compounds on nephropathy is reported in Diabetes, Vol. 38, Extra Issue (1995).

The effect of thiazolidine compounds on coronary artery disease has been reported by Am. J. Physiol., 265 (4 Pt 2) , R726-R732 (19 ) .
93), Hypertension., 24 (2) , 170-175 (1994).

The effects of thiazolidine compounds on arteriosclerosis are described in Am. J. Physiol., 265 (4 Pt 2) , R726-R732 (19 ) .
93).

Furthermore, in recent years, a normal person having insulin resistance without glucose intolerance has a high risk of developing diabetes [insulin resistance non-insulin intolerance (insulin resist).
antnon-IGT: NGT). ], N.Engl.J.Me
d., 331 (18) , 1226-1227 (1994). It is suggested that a drug that improves insulin resistance is useful as a preventive drug for the onset of diabetes in normal individuals as described above.

[0015]

SUMMARY OF THE INVENTION An object of the present invention is to provide a condensed heterocyclic compound having the following general formula (1) or a pharmacologically acceptable salt thereof as an active ingredient: hyperlipidemia, hyperglycemia, Obesity, glucose intolerance, hypertension, osteoporosis, cachexia, fatty liver, diabetic complications, arteriosclerosis, cataracts and other prophylactic and / or therapeutic agents, and other diseases,
Prophylactic and / or therapeutic agent for diseases caused by insulin resistance such as gestational diabetes mellitus, polycystic ovary syndrome, etc., and inflammatory diseases, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcers, heart An object of the present invention is to provide a preventive and / or therapeutic agent for cell damage caused by vascular disease, atherosclerosis and ischemic disease.

[0016]

According to the present invention, there is provided (1) a compound represented by the following general formula:

[0017]

Embedded image

The present invention relates to a medicament containing a fused heterocyclic compound having the formula or a pharmaceutically acceptable salt thereof. However, in the above formula, X represents a benzimidazole ring group, which may have 1 to 5 substituents (a) described later,
Represents an oxygen atom or a sulfur atom, and Z is

[0019]

Embedded image

(Hereinafter, these are referred to as 2,4-dioxothiazolidine-5-ylenylmethyl group, 2,4-dioxothiazolidine-5-ylmethyl group, 2,4-dioxooxazolidine-5-ylmethyl group, 3,5 -Dioxooxadiazolidine-2-ylmethyl group and N-hydroxyureidomethyl group), wherein R is a hydrogen atom,
A straight-chain or branched alkyl group having 1 to 4 carbon atoms, a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, a hydroxy group,
A nitro group or an amino group which may have a substituent (b) (the substituent (b) is a straight-chain or branched alkyl group having 1 to 8 carbon atoms, Straight or branched aralkyl group having 6 carbon atoms
Aryl group having 1 to 10 carbon atoms, linear or branched aliphatic acyl group having 1 to 11 carbon atoms, araliphatic acyl group having 8 to 12 carbon atoms, or 7 to 11 carbon atoms And an aromatic acyl group having the formula: ) Or a linear or branched aralkyl group having 7 to 11 carbon atoms, and m represents an integer of 1 to 5.
Here, the substituent (a) is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, A benzyloxy group, a halogen atom, a hydroxy group, an acetoxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, and a substituent (b). An amino group (optional), wherein the substituent (b) is a linear or branched alkyl group having 1 to 8 carbon atoms,
A linear or branched aralkyl group having one,
An aryl group having 6 to 10 carbon atoms, a linear or branched aliphatic acyl group having 1 to 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms, or 7 carbon atoms And represents an aromatic acyl group having from 1 to 11. ), An aryl group having 6 to 10 carbon atoms which may have a substituent (c) (the substituent (c) is a straight-chain or branched-chain having 1 to 4 carbon atoms) Having an alkyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group or a substituent (b); Or a straight-chain or branched aralkyl group having 7 to 11 carbon atoms which may have a substituent (c).

Among the above compounds, preferred compounds include
(2) In the above (1), R is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms,
A linear or branched alkoxy group having 1 to 4 carbon atoms, a condensed heterocyclic compound which is a halogen atom or a pharmacologically acceptable salt thereof;
A condensed heterocyclic compound wherein Y is an oxygen atom or a pharmacologically acceptable salt thereof, (4) wherein in (1), Z is 2,
4-dioxothiazolidine-5-ylmethyl group, 2,4
A condensed heterocyclic compound which is a dioxothiazolidine-5-yridenylmethyl group or a 2,4-dioxooxazolidine-5-ylmethyl group or a pharmacologically acceptable salt thereof; (5) In (1), wherein R is a hydrogen atom A linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, and Y is oxygen A condensed heterocyclic ring wherein Z is a 2,4-dioxothiazolidine-5-ylmethyl group, a 2,4-dioxothiazolidine-5-ylidenylmethyl group or a 2,4-dioxooxazolidin-5-ylmethyl group The compound or a pharmacologically acceptable salt thereof, (6) In (1), Z is
A condensed heterocyclic compound or a pharmacologically acceptable salt thereof which is a 2,4-dioxothiazolidine-5-ylmethyl group or a 2,4-dioxothiazolidine-5-yridenylmethyl group, (7) A condensed heterocyclic compound which is a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom or a pharmacologically acceptable salt thereof; (8) In the above (1), m is an integer of 1 to 3 A condensed heterocyclic compound or a pharmaceutically acceptable salt thereof, (9) In (1), Y is an oxygen atom,
Z is a 2,4-dioxothiazolidine-5-ylmethyl group or a 2,4-dioxothiazolidine-5-yridenylmethyl group, and R is a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom. Atom,
a condensed heterocyclic compound wherein m is 1, 2 or 3, or a pharmacologically acceptable salt thereof, (10)
Is a benzimidazole ring group which may have 1 to 5 substituents (a ') below, wherein the substituent (a') has 1 carbon atom
Linear or branched alkyl group having 1 to 4 carbon atoms, linear or branched alkoxy group having 1 to 4 carbon atoms, benzyloxy group, halogen atom, phenylthio group, 1 carbon atom A linear or branched alkylthio group having from 4 to 4, a trifluoromethyl group,
A condensed heterocyclic compound which is a hydroxy group, an acetoxy group, a benzyl group or a phenyl group or a pharmaceutically acceptable salt thereof, (11)
A condensed heterocyclic compound which is a 4-dioxooxazolidine-5-ylmethyl group or a pharmaceutically acceptable salt thereof, (1
2) In (1), R is a hydrogen atom, a methyl group or a methoxy group, or a pharmaceutically acceptable salt thereof. (13) In (1), X is 1 to 5 A benzimidazole ring group optionally having a substituent (a '): the substituent (a') is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, and having 1 to 4 carbon atoms; Straight or branched chain alkoxy group, benzyloxy group, halogen atom, phenylthio group, straight or branched chain alkylthio group having 1 to 4 carbon atoms, trifluoromethyl group, A hydroxy group, an acetoxy group, a benzyl group or a phenyl group, Y is an oxygen atom, Z is a 2,4-dioxooxazolidin-5-ylmethyl group,
Is a hydrogen atom, a methyl group or a methoxy group;
Is an integer of 1 to 3, or a pharmacologically acceptable salt thereof, (14)
Wherein a benzimidazole ring group optionally having 1 to 5 substituents (a ″): a substituent (a ″) is a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, A condensed heterocyclic compound which is a propoxy group, an isopropoxy group, a benzyloxy group, a fluorine atom, a chlorine atom, a phenylthio group, a methylthio group, an ethylthio group, a hydroxy group, an acetoxy group, a benzyl group or a phenyl group; Acceptable salts, (15) (1)
In the above, a condensed heterocyclic compound wherein R is a hydrogen atom or a pharmaceutically acceptable salt thereof, (16) In the above (1), the fused heterocyclic compound wherein m is 1 or 2 or a pharmaceutically acceptable salt thereof As particularly preferred compounds,
(17) In (1), X is a benzimidazole ring group which may have 1 to 5 substituents (a ″) below: The substituent (a ″) is a methyl group, an ethyl group, Isopropyl, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, fluorine, chlorine, phenylthio, methylthio, ethylthio, hydroxy, acetoxy, benzyl or phenyl. Y is an oxygen atom and Z is 2,
A 4-dioxothiazolidine-5-ylmethyl group,
A condensed heterocyclic compound wherein R is a hydrogen atom and m is 1 or 2, or a pharmaceutically acceptable salt thereof, (18)
In (1), X represents 1 to 5 substituents (a ′ ″)
) May have a benzimidazole ring group: the substituent (a ''') is a methyl group, a methoxy group, a hydroxy group,
A condensed heterocyclic compound which is an acetoxy group or a benzyl group, or a pharmaceutically acceptable salt thereof, (19)
In (1), a fused heterocyclic compound wherein m is 1 or a pharmaceutically acceptable salt thereof, (20) In (1), X is 1 to 5 substituents (a ''') A benzimidazole ring group which may be present: Substituent (a ''')
Is a methyl group, a methoxy group, a hydroxy group, an acetoxy group or a benzyl group, Y is an oxygen atom, Z is a 2,4-dioxothiazolidine-5-ylmethyl group, and R is A condensed heterocyclic compound or a pharmaceutically acceptable salt thereof, wherein m is 1 or a hydrogen atom, or (21) 5- [4- (1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4
-Dione, (22) 5- [4- (6-methoxy-1-)
Methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, (23) 5-
[4- (5-Methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4
-Dione, (24) 5- [4- (1-benzylbenzimidazol-5-ylmethoxy) benzyl] thiazolidine-2,4-dione, (25) 5- [4- (5-hydroxy-1,4,6). , 7-Tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-
2,4-dione and (26) 5- [4- (5-acetoxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-
2,4-dione or a pharmacologically acceptable salt thereof, (2
7) A preventive agent for a disease caused by insulin resistance, which contains the condensed heterocyclic compound described in any one of the above (1) to (26) or a pharmaceutically acceptable salt thereof as an active ingredient and / or Therapeutic agent, (28) A prophylactic and / or therapeutic agent for hyperglycemia containing, as an active ingredient, the fused heterocyclic compound or the pharmaceutically acceptable salt thereof described in any one of the above (1) to (26). medicine,
(29) a prophylactic and / or therapeutic drug for diabetic complications comprising as an active ingredient the condensed heterocyclic compound or a pharmaceutically acceptable salt thereof described in any one of the above (1) to (26); (30) The above (1) and (2)
6) A prophylactic and / or therapeutic agent for arteriosclerosis, comprising as an active ingredient the condensed heterocyclic compound or the pharmacologically acceptable salt thereof described in any one of the above 6), (31) above (1) to (26). ) A prophylactic and / or therapeutic agent for hyperlipidemia, which comprises, as an active ingredient, the condensed heterocyclic compound described in any one of the above or a pharmacologically acceptable salt thereof. (32) The above (1) to (26) (33) a prophylactic and / or therapeutic agent for obesity, comprising as an active ingredient the condensed heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (26); (34) any one of the above (1) to (26), which comprises the condensed heterocyclic compound described in any one of the above or a pharmacologically acceptable salt thereof as an active ingredient; Or A hypertension-preventing and / or therapeutic agent comprising as an active ingredient the condensed heterocyclic compound or the pharmacologically acceptable salt thereof described in [1],
(35) a prophylactic and / or therapeutic agent for polycystic ovary syndrome, comprising as an active ingredient the condensed heterocyclic compound or the pharmaceutically acceptable salt thereof described in any one of the above (1) to (26); (36) The above (1) and (2)
6) A preventive and / or therapeutic agent for gestational diabetes mellitus, comprising as an active ingredient the condensed heterocyclic compound or the pharmacologically acceptable salt thereof described in any one of 6), (37) above, (1) to (26). (38) A preventive and / or therapeutic agent for insulin-resistant non-glucose intolerance, comprising as an active ingredient the condensed heterocyclic compound or a pharmaceutically acceptable salt thereof described in any one of (1) to (3). (2
6) A prophylactic and / or therapeutic agent for an inflammatory disease, comprising as an active ingredient the condensed heterocyclic compound described in any one of 6) or a pharmacologically acceptable salt thereof, (39) above (1) to (26). A cataract preventive and / or therapeutic agent comprising, as an active ingredient, the condensed heterocyclic compound or a pharmaceutically acceptable salt thereof described in any one of the above.

In the above, when X represents a benzimidazole ring group, examples of the benzimidazole ring group include 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl and the like.

When R and the substituent (a) and / or the substituent (c) are the same or different and represent a straight-chain or branched alkyl group having 1 to 4 carbon atoms, the alkyl group Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl and the like. Preferably it is methyl, ethyl, most preferably methyl.

When R and the substituent (a) and / or the substituent (c) are the same or different and represent a linear or branched alkoxy group having 1 to 4 carbon atoms, the alkoxy group Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy and the like. Preferably it is methoxy, ethoxy, propoxy, isopropoxy, more preferably methoxy, ethoxy and most preferably methoxy.

When R and the substituted component (a) and / or the substituted component (c) are the same or different and represent a halogen atom, examples of the halogen atom include a bromine atom, a chlorine atom and a fluorine atom. Preferably a chlorine atom,
It is a fluorine atom, most preferably a fluorine atom.

When R and the substituent (a) and / or the substituent (b) are the same or different and each represent an aralkyl group having 7 to 11 carbon atoms, the aralkyl group has an alkylene moiety having 1 carbon atom. And 5 straight-chain or branched alkylenes such as benzyl, 2-phenylethyl, 1-phenylethyl,
-Phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, 4-phenylbutyl, 1-phenylbutyl, 5-phenylpentyl, 1-naphthylmethyl, 2-
And naphthylmethyl. Preferably it is benzyl.

When R, the substituent (a) and / or the substituent (c) are the same or different and represent an amino group which may have a substituent (b), the substituent (b)
When 1) represents a linear or branched alkyl group having 1 to 8 carbon atoms, examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, and t. -Butyl, pentyl,
2-pentyl, 3-pentyl, 2-methylbutyl, 3-
Methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1
-Dimethylbutyl, 1,2-dimethylbutyl, 1,3-
Dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-
Trimethylpropyl, 1,2,2-trimethylpropyl, heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 3,3-dimethylpentyl, octyl, 1-methylheptyl, 2-ethylhexyl, 1,1,3 3-tetramethylbutyl and the like can be mentioned. Preferably, it is a linear or branched alkyl group having 1 to 6 carbon atoms. Most preferably, it is a linear or branched alkyl group having 1 to 4 carbon atoms. Particularly preferred are a methyl group and an ethyl group.

2) When a straight or branched aralkyl group having 7 to 11 carbon atoms is shown, the aralkyl group is the same as the aralkyl group described in the above-mentioned substitution (a).

3) When an aryl group having 6 to 10 carbon atoms is shown, examples of the aryl group include phenyl, 1-naphthyl and 2-naphthyl.

4) When a linear or branched aliphatic acyl group having 1 to 11 carbon atoms is shown, examples of the aliphatic acyl group include formyl, acetyl, propionyl, butyryl, isobutyryl and pivaloyl. Pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl and the like. Preferred are formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl.

5) When an araliphatic acyl group having 8 to 12 carbon atoms is shown, examples of the araliphatic acyl group include phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, and 5-phenylpentane. Noyl, 6-phenylhexanoyl, α-methylphenylacetyl, α, α-dimethylphenylacetyl and the like can be mentioned. Preferably it is phenylacetyl.

6) When an aromatic acyl group having 7 to 11 carbon atoms is shown, examples of the aromatic acyl group include benzoyl, 1-naphthoyl, 2-naphthoyl and the like. Preferably it is benzoyl.

Therefore, here, R, substitution (a) and / or
Alternatively, when the substituted moiety (c) is the same or different and represents an amino group which may have the substituted moiety (b), examples of the amino group include the following groups.

1) Methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, 2-pentylamino, 3-pentylamino, 2-methylbutyl Amino, 3-methylbutylamino, 1,1-dimethylpropylamino, 1,2-dimethylpropylamino, 2,2-dimethylpropylamino,
Hexylamino, 2-hexylamino, 3-hexylamino, 2-methylpentylamino, 3-methylpentylamino, 4-methylpentylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3
-Dimethylbutylamino, 2,2-dimethylbutylamino, 2,3-dimethylbutylamino, 3,3-dimethylbutylamino, 1,1,2-trimethylpropylamino, 1,2,2-trimethylpropylamino, heptyl Amino, 2-heptylamino, 3-heptylamino, 4
Heptylamino, 3,3-dimethylpentylamino,
Substituted amino groups consisting of a combination of a hydrogen atom and an alkyl such as octylamino, 1-methylheptylamino, 2-ethylhexylamino, and 1,1,3,3-tetramethylbutylamino can be mentioned.

2) Benzylamino, 2-phenylethylamino, 1-phenylethylamino, 3-phenylpropylamino, 2-phenylpropylamino, 1-phenylpropylamino, 4-phenylbutylamino, 1-phenylbutylamino, 5-phenylpentylamino, 1
And substituted amino groups comprising a combination of a hydrogen atom and aralkyl, such as -naphthylmethylamino and 2-naphthylmethylamino.

3) Substituted amino groups consisting of a combination of a hydrogen atom and aryl such as phenylamino, 1-naphthylamino and 2-naphthylamino.

4) Formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pivaloylamino, pentanoylamino, hexanoylamino, heptanoylamino, octanoylamino, nonanoylamino, decanoylamino, undecanoyl Examples include a substituted amino group consisting of a combination of a hydrogen atom such as amino and an aliphatic acyl.

5) phenylacetylamino, 3-phenylpropionylamino, 4-phenylbutyrylamino,
5-phenylpentanoylamino, 6-phenylhexanoylamino, α-methylphenylacetylamino,
Examples of the substituted amino group include a combination of a hydrogen atom and an araliphatic acyl such as α, α-dimethylphenylacetylamino.

6) Substituted amino groups comprising a combination of a hydrogen atom and an aromatic acyl such as benzoylamino, 1-naphthoylamino and 2-naphthoylamino can be mentioned.

7) Dimethylamino, diethylamino, N
And substituted amino groups composed of a combination of alkyl and alkyl such as -methyl-N-ethylamino and N-methyl-N-pentylamino.

8) N-ethyl-N-benzylamino, N
-T-butyl-N-benzylamino, N-hexyl-N
-A substituted amino group consisting of a combination of an alkyl and an aralkyl such as benzylamino.

9) N-methyl-N-phenylamino, N
And substituted amino groups comprising a combination of alkyl and aryl such as -ethyl-N-phenylamino and N-octyl-N-phenylamino.

10) Substituted amino groups such as N-propyl-N-acetylamino, N-pentyl-N-propionylamino and N-ethyl-N-hexanoylamino, which are composed of a combination of alkyl and aliphatic acyl. be able to.

11) Alkyl and aromatic fats such as N-ethyl-N-phenylacetylamino, N-isopropyl-N- (2-phenylpropionyl) amino, N-methyl-N- (6-phenylhexanoyl) amino And a substituted amino group consisting of a combination with a group acyl.

12) A substituted amino group consisting of a combination of an alkyl and an aromatic acyl such as N-methyl-N-benzoylamino, Ns-butyl-N-benzoylamino and N-heptyl-N-benzoylamino I can give it.

13) Dibenzylamino, N-benzyl-
N- (3-phenylpropyl) amino, N-benzyl-
A substituted amino group consisting of a combination of aralkyl and aralkyl such as N- (2-naphthylmethyl) amino can be exemplified.

14) Substituted amino groups comprising a combination of aralkyl and aryl such as N-benzyl-N-phenylamino and N- (3-phenylpropyl) -N-phenylamino can be mentioned.

15) Substituted amino groups comprising a combination of an aralkyl and an aliphatic acyl such as N-benzyl-N-acetylamino, N-benzyl-N-propionylamino, N-benzyl-N-pentanoylamino. be able to.

16) A substituted amino group comprising a combination of an aralkyl and an araliphatic acyl such as N-benzyl-N-phenylacetylamino and N-benzyl-N- (4-phenylbutyryl) amino may be mentioned. it can.

17) Substituted amino groups comprising a combination of aralkyl and aromatic acyl, such as N-benzyl-N-benzoylamino and N- (2-phenylethyl) -N-benzoylamino, can be mentioned.

18) Diphenylamino, N- (1-naphthyl) -N-phenylamino, N- (2-naphthyl)-
A substituted amino group consisting of a combination of an aryl and an aryl such as N-phenylamino can be mentioned.

19) Substituted amino groups comprising a combination of an aryl and an aliphatic acyl such as N-phenyl-N-acetylamino, N-phenyl-N-propionylamino, N-phenyl-N-hexanoylamino. be able to.

20) Substituted amino groups comprising a combination of an aryl and an araliphatic acyl such as N-phenyl-N-phenylacetylamino and N-phenyl-N- (4-phenylbutyryl) amino may be mentioned. it can.

21) Substituted amino groups comprising a combination of an aryl and an aromatic acyl such as N-phenyl-N-benzoylamino and N-phenyl-N- (2-naphthoyl) amino can be mentioned.

22) diacetylamino, N-acetyl-
Examples of the substituted amino group include a combination of an aliphatic acyl and an aliphatic acyl such as N-propionylamino and N-butyryl-N-hexanoylamino.

23) Aliphatic acyl and araliphatic acyl such as N-acetyl-N-phenylacetylamino, N-acetyl-N- (4-phenylbutyryl) amino, N-butyryl-N-phenylacetylamino And substituted amino groups consisting of combinations of the above.

24) Substituted amino groups comprising a combination of an aliphatic acyl and an aromatic acyl such as N-acetyl-N-benzoylamino and N-butyryl-N- (2-naphthoyl) amino can be mentioned.

25) Aromatic acyl such as N, N-diphenylacetylamino, N-phenylacetyl-N- (2-phenylpropionyl) amino, N-phenylacetyl-N- (4-phenylbutyryl) amino And a substituted amino group composed of a combination of acetylene and an araliphatic acyl.

26) Substituted amino groups comprising a combination of araliphatic acyl and aromatic acyl such as N-phenylacetyl-N-benzoylamino and N-phenylacetyl-N- (2-naphthoyl) amino Can be.

27) Substituted amino groups comprising a combination of aromatic acyl and aromatic acyl such as dibenzoylamino and N-benzoyl-N- (2-naphthoyl) amino can be mentioned.

When the substituent (a) represents a linear or branched alkylthio group having 1 to 4 carbon atoms, examples of the alkylthio group include methylthio, ethylthio, propylthio, isopropylthio and butylthio. , Isobutylthio, s-butylthio, t-butylthio and the like.

When the substituent (a) represents an aryl group having 6 to 10 carbon atoms which may have a substituent (c), examples of the aryl group include phenyl and 1-
Examples include naphthyl and 2-naphthyl. A substituted or unsubstituted (C) linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, When it is a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group, or an amino group which may have a substituent (b), a linear or branched alkyl having 1 to 4 carbon atoms The group, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom and an amino group which may have a substituent (b) have already been described above.

When the substituent (a) represents an aryl group having 6 to 10 carbon atoms which may have the substituent (c), examples of the aryl group include the following groups. be able to.

1) For example, 4-methylphenyl, 4-
Ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-isobutylphenyl, 4-s-butylphenyl, 4-t-butylphenyl, 4-methyl-1-naphthyl, 5-ethyl-1 -Naphthyl, 8-propyl-1-naphthyl, 4-isopropyl-1-naphthyl, 5-butyl-1-naphthyl, 4-isobutyl-1-naphthyl, 4-s-butyl-1-naphthyl, 4-t-butyl -1-naphthyl, 4-methyl-2-
Naphthyl, 5-ethyl-2-naphthyl, 8-propyl-
2-naphthyl, 4-isopropyl-2-naphthyl, 5-
Butyl-2-naphthyl, 8-isobutyl-2-naphthyl, 4-s-butyl-2-naphthyl, 5-t-butyl-
An aryl group having a linear or branched alkyl having 1 to 4 carbon atoms such as 2-naphthyl; 2) for example, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4- Isopropoxyphenyl, 4-butoxyphenyl, 4-isobutoxyphenyl, 4-s-butoxyphenyl, 4-t-butoxyphenyl, 4-methoxy-1-naphthyl, 5-ethoxy-1-naphthyl, 8-propoxy-1 -Naphthyl, 4-
Isopropoxy-1-naphthyl, 5-butoxy-1-naphthyl, 4-isobutoxy-1-naphthyl, 4-s-butoxy-1-naphthyl, 4-t-butoxy-1-naphthyl, 4-methoxy-2-naphthyl , 5-ethoxy-2-
Naphthyl, 8-propoxy-2-naphthyl, 4-isopropoxy-2-naphthyl, 5-butoxy-2-naphthyl, 8-isobutoxy-2-naphthyl, 4-s-butoxy-2-naphthyl, 5-t-butoxy An aryl group having a linear or branched alkoxy having 1 to 4 carbon atoms such as -2-naphthyl; 3) for example, 4-bromophenyl, 4-phenylchloride,
4-fluorophenyl, 4-phenyliodide, 3-phenylchloride, 3-phenylphenyl, 3-bromophenyl, 3-phenyliodide, 4-naphthyl-1-naphthyl, 4-chloro-1-
Naphthyl, 4-fluoro-1-naphthyl, 4-iodide-1-
Naphthyl, 5-chloro-1-naphthyl, 5-fluorin-1-
Naphthyl, 5-brom-1-naphthyl, 8-naphthyl chloride-8-naphthyl, 4-naphthyl-2-naphthyl, 2-naphthyl 4-bromide, 2-naphthyl 4-naphthyl, 4-iodide- Aryl groups having a halogen atom such as 2-naphthyl, 5-brom-2-naphthyl, 5-naphthyl-2-naphthyl, 5-fluoro-2-naphthyl, 5-naphthyl-2-naphthyl; 4) For example, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-1-naphthyl, 5-hydroxy-1-naphthyl, 8-hydroxyphenyl
Hydroxy-containing aryl groups such as hydroxy-1-naphthyl, 4-hydroxy-2-naphthyl, 5-hydroxy-2-naphthyl, 8-hydroxy-2-naphthyl; 5) for example, 2-nitrophenyl, 3-nitro Phenyl, 4-nitrophenyl, 4-nitro-1-naphthyl,
Nitro-containing aryl groups such as 5-nitro-1-naphthyl, 8-nitro-1-naphthyl, 4-nitro-2-naphthyl, 5-nitro-2-naphthyl, 8-nitro-2-naphthyl; 6) For example, 3-phenylphenyl, 4-phenylphenyl, 4-phenyl-1-naphthyl, 5-phenyl-
1-naphthyl, 8-phenyl-1-naphthyl, 4-phenyl-2-naphthyl, 5-phenyl-2-naphthyl, 8
An aryl group having a phenyl such as -phenyl-2-naphthyl; 7) for example, 3-trifluoromethylphenyl, 4-
Trifluoromethylphenyl, 4-trifluoromethyl-1-naphthyl, 5-trifluoromethyl-1-naphthyl, 8-trifluoromethyl-1-naphthyl, 4-trifluoromethyl-2-naphthyl, 5-trifluoromethyl Aryl groups having trifluoromethyl such as -2-naphthyl, 8-trifluoromethyl-2-naphthyl; 8) for example, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 4-amino-1-naphthyl ,
Aryl groups having unsubstituted amino, such as 8-amino-2-naphthyl; aryl groups having substituted amino include: i) e.g. 3-methylaminophenyl, 4-ethylaminophenyl, 3-propylaminophenyl, 3- Isopropylaminophenyl, 4-butylaminophenyl, 3
Aryl having a substituted amino consisting of a combination of a hydrogen atom and an alkyl such as -isobutylaminophenyl; ii) for example, 4-benzylaminophenyl, 4- (2-
Composed of a combination of a hydrogen atom and aralkyl such as phenylethylamino) phenyl, 4- (1-phenylethylamino) phenyl, 4- (4-phenylbutylamino) phenyl, and 4- (1-naphthylmethylamino) phenyl. Aryl having a substituted amino; iii) for example 4-phenylaminophenyl, 4- (1
Aryl having a substituted amino consisting of a combination of a hydrogen atom and an aryl such as -naphthylamino) phenyl; iv) for example, 4-formylaminophenyl, 4-acetylaminophenyl, 4-butyrylaminophenyl, 4-
Aryl having a substituted amino consisting of a combination of a hydrogen atom and an aliphatic acyl, such as pivaloylaminophenyl, 4-hexanoylaminophenyl, 4-octanoylaminophenyl, 4-undecanoylaminophenyl; v) for example 4-phenylacetylaminophenyl, 4-
(4-phenylbutyrylamino) phenyl, 4- (6-
Phenylhexanoylamino) phenyl, 4- (α-methylphenylacetylamino) phenyl, 4- (α, α
Aryl having a substituted amino consisting of a combination of a hydrogen atom and an araliphatic acyl, such as -dimethylphenylacetylamino) phenyl; vi) for example 4-benzoylaminophenyl, 4- (1
Aryl having a substituted amino consisting of a combination of a hydrogen atom and an aromatic acyl such as -naphthoylamino) phenyl, 4- (2-naphthoylamino) phenyl; vii) for example, 4-dimethylaminophenyl, 4-diethylaminophenyl Aryl having a substituted amino consisting of a combination of alkyl and alkyl, such as, 4- (N-methyl-N-ethylamino) phenyl; viii) for example, 4- (N-ethyl-N-benzylamino) phenyl, Aryl having a substituted amino consisting of a combination of alkyl and aralkyl, such as (Nt-butyl-N-benzylamino) phenyl, 4- (N-hexyl-N-benzylamino) phenyl; ix) for example 4- ( N-methyl-N-phenylamino)
Phenyl, 4- (N-octyl-N-phenylamino)
Aryl with substituted amino consisting of a combination of alkyl and aryl such as phenyl; x) for example 4- (N-propyl-N-acetylamino)
Aryl having a substituted amino consisting of a combination of an alkyl and an aliphatic acyl, such as phenyl, 4- (N-ethyl-N-hexanoylamino) phenyl; xi) for example 4- (N-ethyl-N-phenylacetylamino ) Aryl having substituted amino consisting of a combination of alkyl and araliphatic acyl, such as phenyl, 4- [N-methyl-N- (6-phenylhexanoyl) amino] phenyl; xii) for example 4- (N- Aryl with substituted amino consisting of a combination of alkyl and aromatic acyl, such as methyl-N-benzoylamino) phenyl, 4- (N-heptyl-N-benzoylamino) phenyl; xiii) for example 4-dibenzylaminophenyl , 4-
[N-benzyl-N- (2-naphthylmethyl) amino]
Aryl having a substituted amino consisting of a combination of aralkyl and aralkyl such as phenyl; xiv) for example 4- (N-benzyl-N-phenylamino) phenyl, 4- [N- (3-phenylpropyl)-
Aryl having a substituted amino consisting of a combination of an aralkyl and an aryl such as [N-phenylamino] phenyl; xv) for example 4- (N-benzyl-N-acetylamino) phenyl, 4- (N-benzyl-N-penta Aryl having a substituted amino consisting of a combination of an aralkyl and an aliphatic acyl such as noylamino) phenyl; xvi) for example, 4- (N-benzyl-N-phenylacetylamino) phenyl, 4- [N-benzyl-N- (4
Aryl having a substituted amino consisting of a combination of an aralkyl and an araliphatic acyl, such as -phenylbutyryl) amino] phenyl; xvii) for example 4- (N-benzyl-N-benzoylamino) phenyl, 4- [N- (2-phenylethyl)
Aryl having a substituted amino consisting of a combination of an aralkyl and an aromatic acyl such as -N-benzoylamino] phenyl; xviii) for example 4- (diphenylamino) phenyl, 4- [N- (2-naphthyl) -N- Aryl having a substituted amino consisting of a combination of aryl and aryl such as phenylamino] phenyl; xix) for example 4- (N-phenyl-N-acetylamino) phenyl, 4- (N-phenyl-N-hexanoylamino ) Aryl having a substituted amino consisting of a combination of an aryl such as phenyl and an aliphatic acyl; xx) for example, 4- (N-phenyl-N-phenylacetylamino) phenyl, 4- [N-phenyl-N- (4 −
Aryl having a substituted amino consisting of a combination of an aryl such as phenylbutyryl) amino] phenyl and an araliphatic acyl; xxi) aryl and aromatic such as, for example, 4- (N-phenyl-N-benzoylamino) phenyl Aryl having a substituted amino in combination with acyl; xxii) for example, 4-diacetylaminophenyl, 4-
Aryl having a substituted amino consisting of a combination of an aliphatic acyl and an aliphatic acyl such as (N-butyryl-N-hexanoylamino) phenyl; xxiii) for example 4- (N-acetyl-N-phenylacetylamino) phenyl , 4- (N-butyryl-N-
Aryl having a substituted amino consisting of a combination of an aliphatic acyl and an araliphatic acyl such as phenylacetylamino) phenyl; xxiv) for example, 4- (N-acetyl-N-benzoylamino) phenyl, 4- [N-butyryl Aryl having a substituted amino consisting of a combination of an aliphatic acyl and an aromatic acyl such as -N- (2-naphthoyl) amino] phenyl; xxv) for example, 4- (N, N-diphenylacetylamino) phenyl, 4- [N-phenylacetyl-N- (4
Aryl having a substituted amino consisting of a combination of an araliphatic acyl and an araliphatic acyl, such as -phenylbutyryl) amino] phenyl; xxvi) for example, 4- (N-phenylacetyl-N-benzoylamino) phenyl, Aryl having a substituted amino consisting of a combination of an araliphatic acyl and an aromatic acyl such as-[N-phenylacetyl-N- (2-naphthoyl) amino] phenyl; xxvii) for example, 4-dibenzoylaminophenyl;
Aryl having a substituted amino which is a combination of an aromatic acyl and an aromatic acyl such as 4- [N-benzoyl-N- (2-naphthoyl) amino] phenyl;

When the substituent (a) represents an aralkyl group having 7 to 11 carbon atoms which may have a substituent (c), the aralkyl group may have an alkylene moiety having 1 to 5 carbon atoms. Straight-chain or branched-chain alkylene having, for example, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl,
-Phenylpropyl, 1-phenylpropyl, 4-phenylbutyl, 1-phenylbutyl, 5-phenylpentyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. A substituted or unsubstituted (C) linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, Hydroxy group, nitro group,
When it is a phenyl group, a trifluoromethyl group or an amino group which may have a substituent (b), it has 1 to 4 carbon atoms.
Or a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms, a halogen atom, and a substituent (b). The amino group has already been described above.

When the substituent (a) represents an aralkyl group having 7 to 11 carbon atoms which may have the substituent (c), examples of the aralkyl group include the following groups. be able to.

1) For example, 4-methylbenzyl, 4-
Ethylbenzyl, 4-propylbenzyl, 4-isopropylbenzyl, 4-butylbenzyl, 4-isobutylbenzyl, 4-s-butylbenzyl, 4-t-butylbenzyl, 4-methyl-1-naphthylmethyl, 5-ethyl-
1-naphthylmethyl, 8-propyl-1-naphthylmethyl, 4-isopropyl-1-naphthylmethyl, 5-butyl-1-naphthylmethyl, 4-isobutyl-1-naphthylmethyl, 4-s-butyl-1-naphthyl Methyl, 4-
t-butyl-1-naphthylmethyl, 4-methyl-2-naphthylmethyl, 5-ethyl-2-naphthylmethyl, 8-
Propyl-2-naphthylmethyl, 4-isopropyl-2
-Naphthylmethyl, 5-butyl-2-naphthylmethyl,
Linear or branched having 1 to 4 carbon atoms, such as 8-isobutyl-2-naphthylmethyl, 4-s-butyl-2-naphthylmethyl, and 5-t-butyl-2-naphthylmethyl. An aralkyl group having an alkyl; 2) for example, 4-methoxybenzyl, 4-ethoxybenzyl, 4-propoxybenzyl, 4-isopropoxybenzyl, 4-butoxybenzyl, 4-isobutoxybenzyl, 4-s-butoxybenzyl, -T-butoxybenzyl, 4-methoxy-1-naphthylmethyl, 5-ethoxy-1-naphthylmethyl, 8-propoxy-1-naphthylmethyl, 4-isopropoxy-1-naphthylmethyl, 5-butoxy-1-naphthyl Methyl, 4-isobutoxy-1-naphthylmethyl, 4-s-butoxy-1-naphthylmethyl, 4-t- Butoxy-1-naphthylmethyl, 4-methoxy-2-naphthylmethyl, 5-ethoxy-2-naphthylmethyl, 8-propoxy-2-naphthylmethyl, 4-isopropoxy-2-naphthylmethyl, 5
-Butoxy-2-naphthylmethyl, 8-isobutoxy-
Aralkyl having a linear or branched alkoxy having 1 to 4 carbon atoms, such as 2-naphthylmethyl, 4-s-butoxy-2-naphthylmethyl, 5-t-butoxy-2-naphthylmethyl. A group; 3) for example, 4-benzyl bromide, 4-benzyl chloride,
4-benzyl fluoride, 4-benzyl iodide, 3-benzyl chloride, 3-benzyl fluoride, 3-benzyl bromide, 3-benzyl iodide, 4-naphthylmethyl 4-bromide, 4-chloride-1 -Naphthylmethyl, 4-fluoro-1-naphthylmethyl, 4-iodo-1-naphthylmethyl, 5-chloro-1-naphthylmethyl, 5-fluoro-1-naphthylmethyl, 5-naphthylmethyl
1-naphthylmethyl bromide, 8-naphthylmethyl 8-chloride, 2-naphthylmethyl 4-fluoride, -2 bromide-2
-Naphthylmethyl, 4-naphthyl-2-naphthylmethyl, 4
2-naphthylmethyl iodide, 2-naphthylmethyl bromide, 5-naphthylmethyl chloride, 5-naphthylmethyl, 5-fluoride-
Aralkyl groups having a halogen atom such as 2-naphthylmethyl and 5-naphthyl-2-naphthylmethyl; 4) for example, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 4-hydroxy-1-naphthyl Methyl, 5-hydroxy-1-naphthylmethyl, 8-hydroxy-1-naphthylmethyl, 4-hydroxy-2-naphthylmethyl, 5-hydroxy-2-
Aralkyl groups having hydroxy such as naphthylmethyl, 8-hydroxy-2-naphthylmethyl; 5) for example, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-nitro-1-naphthylmethyl, 5- Nitro-1-naphthylmethyl, 8-nitro-
1-naphthylmethyl, 4-nitro-2-naphthylmethyl, 5-nitro-2-naphthylmethyl, 8-nitro-2
Aralkyl groups having a nitro such as -naphthylmethyl; 6) for example, 3-phenylbenzyl, 4-phenylbenzyl, 4-phenyl-1-naphthylmethyl, 5-phenyl-1-naphthylmethyl, 8-phenyl-1- Aralkyl groups having a phenyl such as naphthylmethyl, 4-phenyl-2-naphthylmethyl, 5-phenyl-2-naphthylmethyl, 8-phenyl-2-naphthylmethyl; 7) for example, 3-trifluoromethylbenzyl, −
Trifluoromethylbenzyl, 4-trifluoromethyl-1-naphthylmethyl, 5-trifluoromethyl-1-
Naphthylmethyl, 8-trifluoromethyl-1-naphthylmethyl, 4-trifluoromethyl-2-naphthylmethyl, 5-trifluoromethyl-2-naphthylmethyl, 8
Aralkyl groups having trifluoromethyl, such as -trifluoromethyl-2-naphthylmethyl; 8) for example 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 4-amino-1-naphthylmethyl, 8-amino Aralkyl groups having an unsubstituted amino such as -2-naphthylmethyl; aralkyl groups having a substituted amino include: i) for example, 3-methylaminobenzyl, 4-ethylaminobenzyl, 3-propylaminobenzyl, 3-isopropylamino Benzyl, 4-butylaminobenzyl, 3
Aralkyl having a substituted amino consisting of a combination of a hydrogen atom and an alkyl such as -isobutylaminobenzyl; ii) for example, 4-benzylaminobenzyl, 4- (2-
It consists of a combination of a aralkyl with a hydrogen atom such as phenylethylamino) benzyl, 4- (1-phenylethylamino) benzyl, 4- (4-phenylbutylamino) benzyl, 4- (1-naphthylmethylamino) benzyl. Aralkyl having a substituted amino; iii) for example, 4-phenylaminobenzyl, 4- (1
Aralkyl having a substituted amino consisting of a combination of a hydrogen atom and an aryl such as -naphthylamino) benzyl; iv) e.g. 4-formylaminobenzyl, 4-acetylaminobenzyl, 4-butyrylaminobenzyl, 4-
Aralkyl having a substituted amino consisting of a combination of a hydrogen atom and an aliphatic acyl, such as pivaloylaminobenzyl, 4-hexanoylaminobenzyl, 4-octanoylaminobenzyl, 4-undecanoylaminobenzyl; v) for example 4-phenylacetylaminobenzyl, 4-
(4-phenylbutyrylamino) benzyl, 4- (6-
Phenylhexanoylamino) benzyl, 4- (α-methylphenylacetylamino) benzyl, 4- (α, α
Aralkyl having a substituted amino consisting of a combination of a hydrogen atom and an araliphatic acyl such as -dimethylphenylacetylamino) benzyl; vi) for example 4-benzoylaminobenzyl, 4- (1
Aralkyl having a substituted amino consisting of a combination of a hydrogen atom and an aromatic acyl such as -naphthoylamino) benzyl, 4- (2-naphthoylamino) benzyl; vii) for example, 4-dimethylaminobenzyl, 4-diethylaminobenzyl Aralkyl having a substituted amino consisting of a combination of alkyl and alkyl, such as, 4- (N-methyl-N-ethylamino) benzyl; viii) for example, 4- (N-ethyl-N-benzylamino) benzyl, 4- Aralkyl with substituted amino consisting of a combination of alkyl and aralkyl, such as (Nt-butyl-N-benzylamino) benzyl, 4- (N-hexyl-N-benzylamino) benzyl; ix) for example 4- ( N-methyl-N-phenylamino)
Benzyl, 4- (N-octyl-N-phenylamino)
Aralkyl having a substituted amino consisting of a combination of alkyl and aryl such as benzyl; x) for example 4- (N-propyl-N-acetylamino)
Aralkyl having a substituted amino consisting of a combination of an alkyl and an aliphatic acyl, such as benzyl, 4- (N-ethyl-N-hexanoylamino) benzyl; xi) for example 4- (N-ethyl-N-phenylacetylamino ) Aralkyls having a substituted amino consisting of a combination of an alkyl and an araliphatic acyl, such as benzyl, 4- [N-methyl-N- (6-phenylhexanoyl) amino] benzyl; xii) e.g. Aralkyl with substituted amino consisting of a combination of alkyl and aromatic acyl, such as methyl-N-benzoylamino) benzyl, 4- (N-heptyl-N-benzoylamino) benzyl; xiii) for example 4-dibenzylaminobenzyl , 4-
[N-benzyl-N- (2-naphthylmethyl) amino]
Aralkyl having a substituted amino consisting of a combination of aralkyl and aralkyl such as benzyl; xiv) for example 4- (N-benzyl-N-phenylamino) benzyl, 4- [N- (3-phenylpropyl)-
Aralkyl having a substituted amino consisting of a combination of an aralkyl and an aryl such as [N-phenylamino] benzyl; xv) for example 4- (N-benzyl-N-acetylamino) benzyl, 4- (N-benzyl-N-penta Aralkyl having a substituted amino consisting of a combination of an aralkyl and an aliphatic acyl such as noylamino) benzyl; xvi) for example, 4- (N-benzyl-N-phenylacetylamino) benzyl, 4- [N-benzyl-N- (4
Aralkyl having a substituted amino consisting of a combination of an aralkyl such as -phenylbutyryl) amino] benzyl and an araliphatic acyl; xvii) for example, 4- (N-benzyl-N-benzoylamino) benzyl, 4- [N- (2-phenylethyl)
Aralkyl having a substituted amino consisting of a combination of an aralkyl and an aromatic acyl, such as -N-benzoylamino] benzyl; xviii) for example, 4-diphenylaminobenzyl,
Aralkyl having a substituted amino consisting of a combination of aryl and aryl, such as-[N- (2-naphthyl) -N-phenylamino] benzyl; xix) for example 4- (N-phenyl-N-acetylamino) benzyl, Aralkyl having a substituted amino consisting of a combination of an aryl and an aliphatic acyl such as 4- (N-phenyl-N-hexanoylamino) benzyl; xx) for example 4- (N-phenyl-N-phenylacetylamino) benzyl , 4- [N-phenyl-N- (4-
Aralkyl having a substituted amino consisting of a combination of an aryl such as phenylbutyryl) amino] benzyl and an araliphatic acyl; xxi) aryl and aromatic such as, for example, 4- (N-phenyl-N-benzoylamino) benzyl Aralkyl having a substituted amino in combination with acyl; xxii) for example, 4-diacetylaminobenzyl, 4-
Aralkyl having a substituted amino consisting of a combination of an aliphatic acyl and an aliphatic acyl such as (N-butyryl-N-hexanoylamino) benzyl; xxiii) for example 4- (N-acetyl-N-phenylacetylamino) benzyl , 4- (N-butyryl-N-
Aralkyl having a substituted amino comprising a combination of an aliphatic acyl and an araliphatic acyl such as phenylacetylamino) benzyl; xxiv) for example, 4- (N-acetyl-N-benzoylamino) benzyl, 4- [N-butyryl Aralkyl having a substituted amino consisting of a combination of an aliphatic acyl and an aromatic acyl such as -N- (2-naphthoyl) amino] benzyl; xxv) for example, 4- (N, N-diphenylacetylamino) benzyl, 4- [N-phenylacetyl-N- (4
Aralkyl having a substituted amino consisting of a combination of an araliphatic acyl and an araliphatic acyl such as -phenylbutyryl) amino] benzyl; xxvi) for example, 4- (N-phenylacetyl-N-benzoylamino) benzyl, Aralkyl having a substituted amino consisting of a combination of an araliphatic acyl and an aromatic acyl such as-[N-phenylacetyl-N- (2-naphthoyl) amino] benzyl; xxvii) for example, 4-dibenzoylaminobenzyl,
Aralkyl having a substituted amino consisting of a combination of an aromatic acyl and an aromatic acyl such as 4- [N-benzoyl-N- (2-naphthoyl) amino] benzyl;

When a substituent (a) is present at the 1-position and / or 2-position of the benzimidazole ring group represented by X, the substituent (a) preferably has 1 to 4 carbon atoms. A linear or branched alkyl group, an aryl group having 6 to 10 carbon atoms which may have a substituent (c), or a carbon atom optionally having a substituent (c) It is a linear or branched aralkyl group having 7 to 11 groups.

Therefore, when X is 1 to 5 substituents (a)
Examples of the benzimidazole ring group having
-Methylbenzimidazol-2-yl, 1-ethylbenzimidazol-2-yl, 1-propylbenzimidazol-2-yl, 1-isopropylbenzimidazol-2-yl, 1-butylbenzimidazol-2-
Yl, 6-methoxy-1H-benzimidazole-2-
Yl, 5-methoxy-1H-benzimidazole-2-
Yl, 6-methoxy-1-methylbenzimidazole-
2-yl, 5-methoxy-1-methylbenzimidazol-2-yl, 1-ethyl-6-methoxybenzimidazol-2-yl, 1-ethyl-5-methoxybenzimidazol-2-yl, 6-methoxy- 1-propylbenzimidazol-2-yl, 5-methoxy-1-propylbenzimidazol-2-yl, 1-isopropyl-6-methoxybenzimidazol-2-yl, 1-isopropyl-5-methoxybenzimidazol-2-yl Yl, 1-isobutyl-6-methoxybenzimidazol-2-yl, 1-isobutyl-5-methoxybenzimidazol-2-yl, 6-ethoxy-1-methylbenzimidazol-2-yl, 5-ethoxy-1- Methylbenzimidazol-2-yl, 1-methyl-6-propoxybenzimida Lumpur-2-yl, 1-methyl-5-
Propoxybenzimidazol-2-yl, 6-isopropoxy-1-methylbenzimidazol-2-yl,
5-isopropoxy-1-methylbenzimidazole-
2-yl, 6-butoxy-1-methylbenzimidazol-2-yl, 5-butoxy-1-methylbenzimidazol-2-yl, 6-isobutoxy-1-methylbenzimidazol-2-yl, 5-isobutoxy- 1-methylbenzimidazol-2-yl, 6-s-butoxy-1-methylbenzimidazol-2-yl, 5-s-
Butoxy-1-methylbenzimidazol-2-yl,
6-t-butoxy-1-methylbenzimidazole-2
-Yl, 5-t-butoxy-1-methylbenzimidazol-2-yl, 6-butoxy-1-propylbenzimidazol-2-yl, 5-butoxy-1-propylbenzimidazol-2-yl, 6-benzyl Oxy-1
-Methylbenzimidazol-2-yl, 5-benzyloxy-1-methylbenzimidazol-2-yl, 5
-Methoxy-1,6-dimethylbenzimidazole-2
-Yl, 6-methoxy-1,5-dimethylbenzimidazol-2-yl, 6-bromo-5-methoxy-1-methylbenzimidazol-2-yl, 5-bromo-6
Methoxy-1-methylbenzimidazol-2-yl,
5-ethoxy-6-fluoro-1-methylbenzimidazol-2-yl, 6-ethoxy-5-fluoro-1-
Methylbenzimidazol-2-yl, 5,7-difluoro-1-methylbenzimidazol-2-yl, 4,
6-difluoro-1-methylbenzimidazole-2-
Yl, 6-fluoro-1-methylbenzimidazole-
2-yl, 5-fluoro-1-methylbenzimidazol-2-yl, 5-chloro-1,6-dimethylbenzimidazol-2-yl, 6-chloro-1,5-dimethylbenzimidazol-2-yl, 5-chloro-1,6-
Diethylbenzimidazol-2-yl, 6-chloro-
1,5-diethylbenzimidazol-2-yl, 5-
Ethyl-1-methylbenzimidazol-2-yl, 6
-Ethyl-1-methylbenzimidazol-2-yl,
5-bromo-1-methylbenzimidazol-2-yl, 6-bromo-1-methylbenzimidazol-2-yl
Yl, 7-bromo-1-methyl-5-trifluoromethylbenzimidazol-2-yl, 4-bromo-1-methyl-6-trifluoromethylbenzimidazole-2
-Yl, 7-chloro-1-methyl-5-trifluoromethylbenzimidazol-2-yl, 4-chloro-1-
Methyl-6-trifluoromethylbenzimidazole-
2-yl, 1-methyl-7-trifluoromethylbenzimidazol-2-yl, 1-methyl-4-trifluoromethylbenzimidazol-2-yl, 1-methyl-
5-trifluoromethylbenzimidazol-2-yl, 1-methyl-6-trifluoromethylbenzimidazol-2-yl, 5-bromo-1,6,7-trimethylbenzimidazol-2-yl, 6-bromo- 1,
4,5-trimethylbenzimidazol-2-yl, 5
-Fluoro-6-chloro-1-methylbenzimidazol-2-yl, 6-fluoro-5-chloro-1-methylbenzimidazol-2-yl, 5-bromo-1,7-
Dimethylbenzimidazol-2-yl, 6-bromo-
1,4-dimethylbenzimidazol-2-yl, 6-
t-butyl-1-methylbenzimidazol-2-yl, 5-t-butyl-1-methylbenzimidazole-
2-yl, 6-hydroxy-1-methylbenzimidazol-2-yl, 5-hydroxy-1-methylbenzimidazol-2-yl, 1,7-dimethylbenzimidazol-2-yl, 1,4-dimethylbenz Imidazol-2-yl, 6,7-dichloro-1-methylbenzimidazol-2-yl, 4,5-dichloro-1-methylbenzimidazol-2-yl, 5,6,7-trifluoro-1-methyl Benzimidazol-2-yl, 4,
5,6-trifluoro-1-methylbenzimidazol-2-yl, 5-bromo-6-benzyloxy-1-methylbenzimidazol-2-yl, 6-bromo-5
Benzyloxy-1-methylbenzimidazole-2-
Yl, 7-chloro-1-methylbenzimidazole-2
-Yl, 4-chloro-1-methylbenzimidazole-
2-yl, 6-hydroxy-1,5,7-trimethylbenzimidazol-2-yl, 5-hydroxy-1,
4,6-trimethylbenzimidazol-2-yl, 1
-Methylbenzimidazol-6-yl, 1-ethylbenzimidazol-6-yl, 1-propylbenzimidazol-6-yl, 1-isopropylbenzimidazol-6-yl, 1-butylbenzimidazol-6
Yl, 1-benzylbenzimidazol-6-yl, 1
-Methylbenzimidazol-7-yl, 1-ethylbenzimidazol-7-yl, 1-benzylbenzimidazol-7-yl, 1-methylbenzimidazol-
4-yl, 1-methylbenzimidazol-5-yl,
1,2-dimethylbenzimidazol-6-yl, 5-
Hydroxy-1,4,6,7-tetramethylbenzimidazol-2-yl, 1-ethyl-5-hydroxy-
4,6,7-trimethylbenzimidazol-2-yl, 1-benzylbenzimidazol-5-yl, 5-
And a benzimidazole ring group such as acetoxy-1,4,6,7-tetramethylbenzimidazol-2-yl.

The compound having the general formula (1) of the present invention can be converted into a pharmacologically acceptable salt according to a conventional method. Such salts include, for example, hydrofluoric acid, hydrochloric acid,
Salts of hydrohalic acids such as hydrobromic acid and hydroiodic acid; inorganic salts such as nitrates, perchlorates, sulfates and phosphates or salts of methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid Salts of lower alkanesulfonic acids such as benzenesulfonic acid, salts of arylsulfonic acids such as p-toluenesulfonic acid; salts of amino acids such as glutamic acid and aspartic acid; acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, Malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid,
Organic acid salts such as salts of carboxylic acids such as citric acid can be mentioned.

Further, the compound having the general formula (1) can be converted into a metal salt according to a conventional method. Examples of such salts include salts of alkali metals such as lithium, sodium and potassium; salts of alkaline earth metals such as calcium, barium and magnesium; and inorganic salts such as aluminum salts.

The compound having the general formula (1) has various isomers. That is, when Z represents a 2,4-dioxothiazolidine-5-ylmethyl or 2,4-dioxooxazolidine-5-ylmethyl group, the 5-position of the thiazolidine ring and the 5-position of the oxazolidine ring are asymmetric carbon atoms. is there. In the general formula (1), all stereoisomers based on these asymmetric carbon atoms and mixtures of equivalent and unequal amounts of these isomers are represented by a single formula. Therefore, in the present invention, all of these isomers and a mixture of these isomers are also included.

Further, in the compound having the general formula (1), Z is 2,4-dioxothiazolidine-5-ylmethyl, 2,4-dioxooxazolidine-5-ylmethyl, 2,4-dioxothiazolidine- When referring to 5-yridenylmethyl, 3,5-dioxooxadiazolidine-2-ylmethyl, the existence of various tautomers is conceivable. For example, as shown below.

[0074]

Embedded image

[0075]

Embedded image

[0076]

Embedded image

[0077]

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In the above general formula (1), tautomers based on these and equal and unequal mixtures of these isomers are all represented by a single formula. Therefore, in the present invention, all of these isomers and a mixture of these isomers are also included.

Further, in the present invention, when the compound having the general formula (1) or a pharmacologically acceptable salt thereof forms a solvate (for example, hydrate), it also includes all of them.

Further, in the present invention, all compounds which are metabolized in vivo and converted into the compound having the above general formula (1) or a salt thereof, so-called prodrugs are also included.

Specific examples of the compound having the general formula (1) of the present invention include the compounds shown in the following table. However, the present invention is not limited to these compounds. is not.

Table 1

[0083]

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[0084]

[Table 1]

[0085]

[Table 2]

[0086]

[Table 3]

[0087]

[Table 4]

[0088]

[Table 5]

[0089]

[Table 6]

[0090]

[Table 7]

[0091]

[Table 8]

[0092]

[Table 9]

[0093]

[Table 10]

[0094]

[Table 11]

[0095]

[Table 12]

[0096]

[Table 13]

[0097]

[Table 14]

[0098]

[Table 15]

[0099]

[Table 16]

[0100]

[Table 17]

[0101]

[Table 18]

[0102]

[Table 19]

[0103]

[Table 20]

[0104]

[Table 21]

[0105]

[Table 22]

[0106]

[Table 23]

[0107]

[Table 24]

[0108]

[Table 25]

[0109]

[Table 26]

[0110]

[Table 27]

[0111]

[Table 28]

[0112]

[Table 29]

Table 2

[0114]

Embedded image

[0115]

[Table 30]

[0116]

[Table 31]

[0117]

[Table 32]

[0118]

[Table 33]

[0119]

[Table 34]

[0120]

[Table 35]

[0121]

[Table 36]

[0122]

[Table 37]

[0123]

[Table 38]

[0124]

[Table 39]

[0125]

[Table 40]

[0126]

[Table 41]

[0127]

[Table 42]

[0128]

[Table 43]

[0129]

[Table 44]

[0130]

[Table 45]

[0131]

[Table 46]

[0132]

[Table 47]

[0133]

[Table 48]

[0134]

[Table 49]

[0135]

[Table 50]

[0136]

[Table 51]

[0137]

[Table 52]

[0138]

[Table 53]

[0139]

[Table 54]

[0140]

[Table 55]

[0141]

[Table 56]

Table 3

[0143]

Embedded image

[0144]

[Table 57]

[0145]

[Table 58]

[0146]

[Table 59]

[0147]

[Table 60]

[0148]

[Table 61]

[0149]

[Table 62]

[0150]

[Table 63]

[0151]

[Table 64]

[0152]

[Table 65]

[0153]

[Table 66]

[0154]

[Table 67]

[0155]

[Table 68]

[0156]

[Table 69]

[0157]

[Table 70]

[0158]

[Table 71]

[0159]

[Table 72]

[0160]

[Table 73]

[0161]

[Table 74]

[0162]

[Table 75]

[0163]

[Table 76]

[0164]

[Table 77]

[0165]

[Table 78]

[0166]

[Table 79]

[0167]

[Table 80]

[0168]

[Table 81]

[0169]

[Table 82]

[0170]

[Table 83]

Table 4

[0172]

Embedded image

[0173]

[Table 84]

[0174]

[Table 85]

[0175]

[Table 86]

[0176]

[Table 87]

[0177]

[Table 88]

[0178]

[Table 89]

[0179]

[Table 90]

[0180]

[Table 91]

[0181]

[Table 92]

[0182]

[Table 93]

[0183]

[Table 94]

[0184]

[Table 95]

[0185]

[Table 96]

[0186]

[Table 97]

[0187]

[Table 98]

[0188]

[Table 99]

[0189]

[Table 100]

[0190]

[Table 101]

[0191]

[Table 102]

[0192]

[Table 103]

[0193]

[Table 104]

[0194]

[Table 105]

[0195]

[Table 106]

[0196]

[Table 107]

[0197]

[Table 108]

[0198]

[Table 109]

[0199]

[Table 110]

Table 5

[0201]

Embedded image

[0202]

[Table 111]

[0203]

[Table 112]

[0204]

[Table 113]

[0205]

[Table 114]

[0206]

[Table 115]

[0207]

[Table 116]

[0208]

[Table 117]

[0209]

[Table 118]

[0210]

[Table 119]

[0211]

[Table 120]

[0212]

[Table 121]

[0213]

[Table 122]

[0214]

[Table 123]

[0215]

[Table 124]

[0216]

[Table 125]

[0219]

[Table 126]

[0218]

[Table 127]

[0219]

[Table 128]

[0220]

[Table 129]

[0221]

[Table 130]

[0222]

[Table 131]

[0223]

[Table 132]

[0224]

[Table 133]

[0225]

[Table 134]

[0226]

[Table 135]

[0227]

[Table 136]

[0228]

[Table 137]

Abbreviations in Tables 1 to 5 are as follows. Me = methyl, Et = ethyl, Pr = propyl, iPr = isopropyl, Bu = butyl, iBu = isobutyl, sBu = secondary-butyl, tBu = tertiary butyl, Bz = benzyl, Ac = acetyl.

In the above table, preferably, exemplified compound numbers: 1-11, 1-16, 1-18, 1-22, 1-2
7, 1-49, 1-50, 1-54, 1-56, 1-9
8, 1-100, 1-109, 1-129, 1-14
6, 1-155, 1-156, 1-229, 1-23
7, 1-238, 1-247, 1-250, 2-11,
2-49, 2-146, 2-229, 2-237, 2-
250, 3-11, 3-49, 3-146, 3-22
9, 3-237, 3-250, 4-11, 4-49, 4
-146, 4-229, 4-237, 4-250, 5-
11, 5-49, 5-146, 5-229, 5-23
7, 5-250 compounds.

More preferably, Exemplified Compound No .: 1-1
1, 1-16, 1-18, 1-22, 1-27, 1-4
9, 1-50, 1-54, 1-56, 1-98, 1-1
00, 1-109, 1-129, 1-146, 1-22
9, 1-237, 1-238, 1-247, 1-250
2-11, 2-49, 2-146, 2-229, 2-2
37, 2-250, 3-11, 3-49, 3-146,
3-229, 3-237 and 3-250.

Even more preferably, Exemplified Compound No .: 1-
11, 1-16, 1-27, 1-49, 1-50, 1-
54, 1-98, 1-100, 1-109, 1-12
9, 1-146, 1-229, 1-237, 1-23
8, 1-250.

Most preferably, Exemplified Compound No. 1-11:
5- [4- (1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, 1-49: 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) Benzyl] thiazolidine-2,4-dione, 1-146: 5- [4- (5-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, 1-229: 5- [4- (1-benzylbenzimidazol-5-ylmethoxy) benzyl] thiazolidine-
2,4-dione, 1-237: 5- [4- (5-hydroxy-1,4,4
6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, and 1-250: 5- [4- (5-acetoxy-1,4,4).
6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione.

[0234]

Next, a method for producing a compound having the general formula (1) will be described.

Production method (I)

[0236]

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The first step is a step for producing a compound having the general formula (3) (wherein X and m have the same meanings as described above). , X
And m have the same meanings as described above, and R 'represents a linear or branched alkyl group having 1 to 5 carbon atoms. ) Is reduced.

As the linear or branched alkyl group having 1 to 5 carbon atoms represented by R ', the same groups as described for the substituent (b) can be mentioned. Preferably, they are methyl, ethyl and n-butyl. The reaction is usually carried out by hydrogenation in the presence of a reducing agent. Examples of the reducing agent used include metal hydrides such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride and diisopropylaluminum hydride.

The reaction is usually and preferably effected in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; dimethylformamide Amides such as dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; or a mixed solvent thereof is preferably used.

The reaction is carried out under cooling or heating.
The reaction time varies depending on the reaction reagent, reaction temperature, etc.
Usually 0.5 hours to several days.

The reaction is preferably carried out in the presence of lithium borohydride in an alcohol or a mixed solvent with an alcohol for 1 hour to 1 day at room temperature to reflux, or in the presence of a hydrocarbon or ether. In the solvent,
The reaction is carried out under cooling or warming for 1 hour to 10 hours in the presence of lithium aluminum hydride or diisobutylaluminum hydride.

In the second step, the above-mentioned general formula (5) wherein X,
Y, R and m are as defined above, and Z ′ is

[0243]

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(Wherein, Tr represents a triphenylmethyl group). A compound having the general formula (3) (where X and m have the same meanings as described above) and a compound having the general formula (4) (wherein Y , R and Z 'have the same meanings as described above) with a conventional Mitsunobu reaction [O.
Mitsunobu, Synthesis, page 1, 1981
Year)].

The reaction is usually carried out in the presence of a solvent in the presence of an azo compound and a phosphine. As the azo compounds of the reaction reagent, diethyl azodicarboxylate, 1,1′-
(Azodicarbonyl) dipiperidine and the like are used.
As phosphines, triphenylphosphine, tributylphosphine and the like are used.

The reaction is usually and preferably effected in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; and halogenated hydrocarbons such as chloroform, dichloromethane, and 1,2-dichloroethane. Hydrogens; ethers such as diethyl ether, tetrahydrofuran, and dioxane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used.

The reaction is carried out at room temperature to under heating, preferably at room temperature to 60 ° C. The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually several hours to several days, preferably 5 hours to 3 hours.
Days.

In the third step, the above-mentioned general formula (1) (where X,
Y, Z, R and m have the same meaning as described above. Where Z is a group —CH ₂ N (OH) C (＝ O) —NH
₂ , excluding those that are. Wherein the compound having the general formula (5) (where X, Y, R, m and Z ′ have the same meanings as described above) is added to a compound having the general formula (5) in the presence of a solvent. Alternatively, it is carried out by reacting with an acid such as trifluoroacetic acid, trifluoromethanesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid and the like in the absence.

When a solvent is used, the solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; chloroform, dichloromethane and tetrachloride. Halogenated hydrocarbons such as carbon; ethers such as diethyl ether, tetrahydrofuran, dioxane; dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric acid triamide; esters such as ethyl acetate and methyl acetate; water; and a mixed solvent thereof are preferably used. The reaction temperature is under ice cooling or heating. Reaction time depends on the reaction reagent, reaction temperature,
Although it depends on the solvent and the like, it is usually from tens of minutes to tens of hours, preferably from 0.5 to 10 hours.

This step can also be achieved by subjecting a compound having the general formula (5) to a catalytic hydrogenation reaction. Examples of the catalyst used include palladium-carbon, palladium black, platinum oxide, platinum black, and the like.
Preferably it is palladium-carbon.

The reaction is generally and preferably effected in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; and halogenated hydrocarbons such as chloroform, dichloromethane, and carbon tetrachloride. Diethyl ether, tetrahydrofuran,
Ethers such as dioxane; alcohols such as methanol, ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used.

The reaction temperature is from room temperature to heating. The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually from several hours to several days, preferably from 1 hour to 1 day.

Production method (II)

[0254]

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In the fourth step, the above-mentioned general formula (6) (where X,
R and m have the same meaning as described above. Wherein a base such as sodium hydride is allowed to act on the general formula (3) (wherein X and m have the same meanings as described above) (first). Stage)
Then, 2-methoxy-4-fluorobenzaldehyde, 3
P- such as -methyl-4-fluorobenzaldehyde
It is achieved by reacting with a fluorobenzaldehyde derivative (second step).

The first step is usually suitably performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; dimethylformamide Amides such as dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used.

The reaction is carried out under ice cooling or heating.
The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually several tens of minutes to 1 day, preferably 1 hour to 10 hours.

The second step is carried out by, after the completion of the first step reaction, adding a p-fluorobenzaldehyde derivative to the reaction mixture and reacting at room temperature or under heating.

The reaction time varies depending on the reaction reagent, reaction temperature and the like, but is usually several tens of minutes to several days.

In the fifth step, the above-mentioned general formula (7) (where X,
R and m have the same meaning as described above. ), Wherein X, R and m have the same meanings as described above.
And thiazolidine-2,4-dione.

The reaction is carried out in the presence or absence of a catalyst. When the reaction is carried out in the presence of a catalyst, the catalyst used includes, for example, sodium acetate, piperidinium acetate, piperidinium benzoate and the like.

The reaction is generally and preferably effected in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; methanol, ethanol Alcohols such as, isopropanol; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; dichloromethane, chloroform, 1,2-
Halogenated hydrocarbons such as dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as ethyl formate and ethyl acetate; or a mixed solvent thereof is preferably used.

The reaction is usually carried out under heating. The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually 1 hour to 50 hours.

In the sixth step, the general formula (8) (where X,
R and m have the same meaning as described above. ), Wherein X, R and m have the same meanings as described above.
By subjecting the compound having the following formula to reduction by catalytic hydrogenation reaction. The catalyst used is, for example, palladium-carbon, palladium black, and preferably palladium-carbon.

The reaction is generally and preferably effected in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, dioxane, and tetrahydrofuran; Alcohols such as acetic acid, ethanol and isopropanol; organic acids such as formic acid, acetic acid and propionic acid; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide, or a mixed solvent thereof.

The reaction is carried out at room temperature or under heating. The reaction is usually carried out under atmospheric pressure or under pressure, preferably under pressure. The reaction time varies depending on pressure, temperature, catalyst and the like, but is usually several hours to several days, preferably one hour to one day.

The step can also be achieved by reacting a metal hydride. The reaction is usually carried out in WO 93/13
09A can be carried out according to the method disclosed.

Production method (III)

[0269]

Embedded image

In the seventh step, the above-mentioned general formula (9) (where X,
R and m have the same meaning as described above. ), Wherein X, R and m have the same meanings as described above.
Is reacted with hydroxylamine (preferably hydroxylamine hydrochloride) and then reduced.

The reaction of the compound having the general formula (6) with hydroxylamine (hydrochloride) is usually suitably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, dioxane, and tetrahydrofuran; Alcohols such as ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; acetonitrile and propionitrile Such nitriles; esters such as ethyl formate and ethyl acetate; amines such as pyridine, triethylamine, N, N-diisopropyl-N-ethylamine; and a mixed solvent thereof are preferably used.

The reaction is carried out at room temperature or under heating. The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually several hours to several tens of hours.

Next, the reduction reaction is carried out by hydrogenation in the presence of a reducing agent. Examples of the reducing agent used include metal hydrides such as lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride, sodium borohydride and sodium cyanoborohydride.

The reaction is generally and preferably effected in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, dioxane and tetrahydrofuran; dimethylformamide Amides such as dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; or a mixed solvent thereof is preferably used.

The reaction is carried out under cooling or heating.
The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually several tens of minutes to one day.

In the eighth step, the general formula (10) (wherein
X, R and m have the same meaning as described above. ) Wherein the compound has the general formula (9)
Wherein X, R and m have the same meanings as described above, and trimethylsilyl isocyanate (trimethylsilyl isocyanate).

The reaction is generally and preferably effected in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, dioxane and tetrahydrofuran; dimethylformamide Amides such as dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; or a mixed solvent thereof.

The reaction is carried out under cooling or heating.
The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually several tens of minutes to several days.

The ninth step is the same as in the above formula (11), wherein
X, R and m have the same meaning as described above. Wherein the compound having the general formula (9) (where X, R and m have the same meanings as described above) is reacted with N- (chlorocarbonyl) isocyanate. Obtained by:

The reaction is generally and preferably effected in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; dimethylformamide Amides such as dimethylacetamide and hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ethyl formate and ethyl acetate. Such esters: or a mixed solvent thereof is suitably used.

The reaction is carried out under cooling or heating.
The reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually several tens of minutes to several tens of hours.

Production method (IV)

[0283]

Embedded image

In the tenth step, the above-mentioned general formula (14) (wherein
Y, R and m have the same meaning as described above, Y 'represents an oxygen atom or a sulfur atom, and Q represents a lower alkoxycarbonyl group, a formyl group, a protected formyl group, a carboxyl group or a hydroxy group. Is a process for producing a compound having the general formula (12)
Has the same meaning as described above, and Halo represents a halogen atom. ) And a compound having the general formula (13) (wherein, Y, Y 'and R have the same meanings as described above) in the presence of a base.

The base used includes, for example, inorganic bases such as sodium hydride, potassium hydride, potassium carbonate, cesium carbonate and organic bases such as triethylamine.

The reaction is usually and preferably effected in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; dimethylformamide Amides such as dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent thereof is preferably used.

The reaction is carried out under cooling or heating.
The reaction time varies depending on the reaction reagent, reaction temperature, etc.
Usually 0.5 hours to several days.

The reaction is preferably carried out in an amide or a mixed solvent with an amide in the presence of sodium hydride for 1 hour to 10 hours under cooling or heating.

The compound having the general formula (14) produced by this step is an important intermediate since other target compounds can be produced via them. In addition, the compound in which Q is a carboxyl group or a hydroxy group can be easily produced from a lower alkoxycarbonyl group, a formyl group or a protected formyl group by an ordinary method.

In the eleventh step, the general formula (15) (wherein
X, Y, Y ', R and m are as defined above. (A) the above-mentioned general formula (14) (wherein, Y, Y ′, R and m have the same meaning as described above, and Q represents a lower alkoxycarbonyl group) And a 1,2-diaminobenzene derivative.

When Q represents a lower alkoxycarbonyl group, the group is preferably a linear or branched lower alkoxycarbonyl group having 2 to 7 carbon atoms, for example, methoxycarbonyl, ethoxycarbonyl , Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s
-Butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, 2-methylbutoxycarbonyl, 1-ethylpropoxycarbonyl, 4-
Methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl,
Examples thereof include 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl, 2-ethylbutoxycarbonyl, hexyloxycarbonyl, and isohexyloxycarbonyl. Of these, preferred are linear or branched lower alkoxycarbonyl groups having 2 to 5 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl. And more preferably methoxycarbonyl and ethoxycarbonyl.

The reaction is usually performed in the presence or absence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, and xylene; diethyl ether,
Ethers such as tetrahydrofuran and dioxane;
Amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and butanol; acids such as acetic acid and propionic acid; and mixed solvents thereof are preferably used.

The reaction is carried out under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but is usually 3 hours to several days. The reaction is preferably carried out in the absence of a solvent.
The reaction is carried out at 0 ° C. to 150 ° C. for 5 hours to 2 days while heating.

(B) The above general formula (14) (where Y,
Y ', R and m have the same meaning as described above, and Q represents a formyl group. ) Is reacted with a 1,2-diaminobenzene derivative, and then treated with an oxidizing agent.

The reaction is usually and preferably effected in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; diethyl ether, tetrahydrofuran, dioxane,
Ethers such as dimethoxyethane; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; alcohols such as methanol, ethanol and isopropanol; acids such as acetic acid and propionic acid; Sulfoxides; or a mixed solvent thereof is preferably used. The reaction is carried out at room temperature or under heating for 1 hour to several days, and then treated with an oxidizing agent.

Examples of the oxidizing agent include iodine, silver oxide, lead tetraacetate and the like, with iodine being preferred. The treatment with an oxidizing agent is usually suitably performed in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not affect the reaction, and for example, the solvents described above are used. Preferred are ethers. The treatment is preferably for one hour to several days under warming.

(C) Formula (14) (wherein Y,
Y ', R and m are as defined above, and Q is a protected formyl group. )), When Q is a protected formyl group, for example, dimethoxymethyl, diethoxymethyl, 1,3-dioxan-2-yl, 1,3-dioxolan-2-yl, 1,3-dithian-2-yl , 1,3
-Dithiolan-2-yl, which can be subjected to a reaction after deprotection prior to the reaction in the eleventh step. The deprotection reaction is a conventional deprotection reaction, such as TWGree
n, Protective Groups in Organic Synthes
is), John Wiley &Sons; JFWMcOmie, Protective Groups in Organic Chemistry, Plenum
Achieved by performing according to Press.

Production method (V)

[0299]

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The production method (V) is a method for producing a compound having the general formula (14) (wherein Q, Y, Y ', R and m have the same meanings as described above).

In the twelfth step, the general formula (17) (wherein
Q, m, Y and R are as defined above. Wherein the compound having the general formula (12) (wherein Q, m and Halo have the same meanings as described above) and the compound having the general formula (16) (wherein Y And R
Is as defined above. ) In the presence of a base. The reaction is carried out according to the tenth step shown in the above production method (IV).

In the thirteenth step, the general formula (18) (wherein
Q, m, Y and R are as defined above. Is a step of producing a compound having the general formula (17). The reaction is carried out by using a usual catalytic hydrogenation reaction and a zinc-acetic acid method or a tin-hydrochloric acid method, which is a general method for reducing a nitro group.

In the fourteenth step, the above-mentioned general formula (19) (wherein
Q, m, Y, R, R 'and Halo are as defined above. Is a step of producing a compound having the general formula (18).
It is obtained by performing a rylation reaction.

The reaction is usually carried out by the method of JP-A-55-22657 and the method of S. Oae et al. (Bull. Chem. Soc.
65 pages (1980)).

In the fifteenth step, the above-mentioned general formula (14) (wherein
Q, m, Y, Y 'and R have the same meaning as described above. Is a process for producing a compound having the general formula (1)
Reacting the compound having 9) with urea or thiourea,
Then, it is performed by subjecting it to a hydrolysis reaction. The reaction is usually carried out according to the method described in JP-A-55-22657.

The thus obtained general formula (1)
4) The compound having the formula (wherein Q, m, Y, Y 'and R have the same meanings as described above) undergo the same reaction as described in the above-mentioned eleventh step (a) or (b). By adding, the above general formula (15) (where X, Y, Y ′, R
And m have the same meaning as described above. Is obtained.

The compound having the general formula (2), which is a starting compound in the above production method (I), is represented by the following general formula (2)
-1):

[0308]

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[In the formula, the 2-position, 4-position of the benzimidazole ring
The 5-, 6-, and 7-positions may be substituted with a substituent (a), and m and R 'have the same meanings as described above. Here, when the 2-position of the benzimidazole ring is substituted with a substituent (a), the substituent (a) is preferably a straight-chain or branched-chain having 1 to 4 carbon atoms. An alkyl group, an aryl group having 6 to 10 carbon atoms which may have a substituent (c), or a linear group having 7 to 11 carbon atoms which may have a substituent (c); It is a branched aralkyl group. ], The compound can be synthesized according to the following method.

[0310]

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In the sixteenth step, the 2-, 4-, 5-, 6- and 7-positions of the benzimidazole ring in the above formula (22) may be substituted with a substituent (a). here,
When the 2-position of the benzimidazole ring is substituted with a substituent (a), the substituent (a) is preferably a linear or branched alkyl group having 1 to 4 carbon atoms,
An aryl group having 6 to 10 carbon atoms which may have a substituent (c) or a linear or branched chain having 7 to 11 carbon atoms which may have a substituent (c) Aralkyl group. Wherein the benzene ring moiety in formula (20) may have 1 to 4 substituents (a). And a compound having the general formula (21) wherein the carbon atom may have a substituent (a) instead of a hydrogen atom, and R ″ represents a hydrogen atom or a lower alkyl group. . When the carbon atom in the formula has a substituent (a) instead of a hydrogen atom, the substituent (a) is preferably a straight-chain or branched group having 1 to 4 carbon atoms. Chain alkyl group, carbon number 6 which may have substituent (c)
An aryl group having from 1 to 10 or a linear or branched aralkyl group having from 7 to 11 carbon atoms which may have a substituent (c). Is carried out according to the above-mentioned eleventh step.

When R ″ represents a lower alkyl group,
The group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
s-butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl,
4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1, Examples thereof include 3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl, and isohexyl. It is preferably an alkyl group having 1 to 4 carbon atoms, more preferably methyl or ethyl.

In the seventeenth step, the 2-, 4-, 5-, 6- and 7-positions of the benzimidazole ring may be substituted with a substituent (a) in the general formula (2-1). , M and R 'have the same meaning as described above. Here, when the 2-position of the benzimidazole ring is substituted with a substituent (a), the substituent (a) is preferably a straight-chain or branched-chain having 1 to 4 carbon atoms. An alkyl group, an aryl group having 6 to 10 carbon atoms which may have a substituent (c), or a linear group having 7 to 11 carbon atoms which may have a substituent (c); It is a branched aralkyl group. Wherein the 2-, 4-, 5-, 6- and 7-positions of the benzimidazole ring are substituted with a substituent (a). Is also good. ], Wherein Halo, m and R 'have the same meanings as described above. In accordance with a known method (for example, Liebigs Ann. Chem., P. 1078 (1983)).

The compound having the general formula (2), which is a raw material compound in the above production method (I), is represented by the following general formula (2-2):

[0315]

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[In the formula, the benzimidazole ring group may have 1 to 5 substituents (a), and m and R 'have the same meanings as described above. When the imidazole ring moiety is substituted with a substituent (a), the substituent (a) is preferably a straight-chain or branched alkyl group having 1 to 4 carbon atoms, An aryl group having 6 to 10 carbon atoms which may have a substituent (c) or a linear or branched chain having 7 to 11 carbon atoms which may have a substituent (c) Aralkyl group. Can be synthesized according to the following method.

[0317]

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In the eighteenth step, the above-mentioned general formula (25) wherein the benzene ring moiety may have 1 to 3 substituents (a), and the amino group in the formula It may be substituted at the minute (a), and m and R ′ have the same meaning as described above. When the amino group in the formula is substituted by one substituent (a), the substituent (a) is preferably a straight-chain or branched-chain having 1 to 4 carbon atoms. An alkyl group having 6 to 10 carbon atoms which may have a substituent (c) or a linear group having 7 to 11 carbon atoms which may have a substituent (c) Alternatively, it is a branched aralkyl group. Wherein the compound has the general formula (2)
4) [The benzene ring moiety in the formula may have 1 to 3 substituents (a), and the amino group in the formula may be substituted with 1 substituent (a); m and R 'have the same meaning as described above. However, one of the ortho positions of the amino group is always a hydrogen atom, and when the amino group in the formula is substituted with one substitution (a), the substitution (a) is preferably A linear or branched alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms which may have a substituent (c), or a substituent (c); 7 to 1 carbon atoms which may be
It is a linear or branched aralkyl group having one. By nitration. This nitration reaction can be performed by a known method, for example, Hogett, JG; Moodie,
RB; Peton, JR; Schofield, K., Nitrationand Aroma
tic Reactivity, Cambridge University Press, Cambrid
ge, 1971, Schofield, K., AromaticNitration, Cambrid
ge University Press, Cambridge, 1980, PBDde la
Mareand J.H. Ridd, Aromatic Substitution, Nitration
and Halogenation, Academic Prees, New York, 195
9.AVTopchiev, Nitration of Hydrocarbonsand Othe
r Organic Compounds, Pergamon Press, New York, 195
9.LFAlbright, in Kirk-Othmer, Encyclopedia of C
chemicalTechnology, 2nd ed.Vol.13, The Interscienc
e Encyclopedia, Inc., New York, p. 784, 1967, HALub
s, Chemistry of Synthetic Dyes and Pigments, Reinh
old PublishingCorp., New York, 1955, pp.12,71,350
And the like.

In the nineteenth step, the benzene ring moiety in the formula (26) may have 1 to 3 substituents (a), and one amino group in the formula is May be substituted with (a), and m and R ′ are as defined above. Here, when one amino group in the formula is substituted with one substituent (a), the substituent (a) is preferably a straight-chain or branched group having 1 to 4 carbon atoms. A branched alkyl group, an aryl group having 6 to 10 carbon atoms which may have a substituent (c) or 7 to 1 carbon atoms which may have a substituent (c)
It is a linear or branched aralkyl group having one. Wherein the benzene ring moiety may have 1 to 3 substituents (a), and the amino group in the formula is 1 to 3
And m and R ′ may be the same as those described above. When the amino group in the formula is substituted by one substituent (a), the substituent (a) is preferably a straight-chain or branched-chain having 1 to 4 carbon atoms. An alkyl group having 6 to 10 carbon atoms which may have a substituent (c) or a linear group having 7 to 11 carbon atoms which may have a substituent (c) Alternatively, it is a branched aralkyl group. By reducing the compound having the formula:

As the reducing agent, tin and hydrogen chloride, zinc and alcoholic alkali, zinc and acetic acid, sodium amalgam and water, or a combination of sodium borohydride and tin can be used.

The reaction is usually suitably carried out in the presence or absence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, tetrahydrofuran, and dioxane; Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and the like; methanol, ethanol,
Alcohols such as propanol and t-butanol; esters such as ethyl acetate; water; and mixed solvents thereof.

The reaction is carried out under cooling or heating. The reaction time varies depending on the reaction reagent, reaction temperature, etc.
Usually 0.5 hours to several days.

This step can also be carried out by a catalytic hydrogenation reaction. Examples of the catalyst used include Raney nickel, palladium-carbon, palladium black, ruthenium, platinum oxide and the like.

The reaction is usually and preferably effected in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, tetrahydrofuran, and dioxane; Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and the like; methanol, ethanol, propanol,
Alcohols such as ethylene glycol; halogenated hydrocarbons such as chloroform and methylene chloride; water or a mixed solvent thereof can be suitably used.

The reaction is carried out at room temperature or under heating. The reaction time varies depending on the reaction reagent, reaction temperature and the like, but is usually 0.5 hours to several days.

In the twentieth step, the benzimidazole ring group may have 1 to 5 substituents (a) in the general formula (2-2); Shows the same meaning as When the imidazole ring moiety is substituted with a substituent (a), the substituent (a) is preferably a straight-chain or branched alkyl group having 1 to 4 carbon atoms, An aryl group having 6 to 10 carbon atoms which may have a substituent (c) or a linear or branched chain having 7 to 11 carbon atoms which may have a substituent (c) Aralkyl group. Wherein the compound has the general formula (2)
6) [The benzene ring moiety in the formula may have 1 to 3 substituents (a), and one amino group in the formula is 1
And m and R ′ may be the same as those described above. Here, when one amino group in the formula is substituted with one substitution (a),
The substituent (a) is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, the substituent (c)
An aryl group having 6 to 10 carbon atoms which may have a carbon atom having 7 to 10 carbon atoms which may have a substituent (c);
And 11 straight-chain or branched aralkyl groups. Having the general formula (21)
[The carbon atoms in the formula are substituted (a) instead of hydrogen atoms.
R ″ represents a hydrogen atom or a lower alkyl group. And the reaction according to the eleventh step.

In the above production method (VI), the 1,2-diaminobenzene derivative used in the eleventh step can be synthesized by the following method.

[0328]

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In the twenty-first step, the above-mentioned general formula (28) [wherein the benzene ring moiety may have 1 to 4 substituents (a), and the amino group in the formula has one substituent It may be replaced by minute (a). Here, when the amino group in the formula is substituted with one substitution (a), the substitution (a)
Is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms which may have a substituent (c), or a substituent. (C) is a linear or branched aralkyl group having 7 to 11 carbon atoms which may have (c). Wherein the benzene ring moiety may have 1 to 4 substituents (a), and the amino group in the formula has 1 to 4 substituents (a). May be substituted with (a). However, one of the ortho positions of the amino group is always a hydrogen atom,
When the amino group in the formula is substituted with one substituent (a), the substituent (a) is preferably a straight-chain or branched alkyl having 1 to 4 carbon atoms. A group, an aryl group having 6 to 10 carbon atoms which may have a substituent (c) or a linear or branched group having 7 to 11 carbon atoms which may have a substituent (c). It is a branched aralkyl group. By nitrating a compound having the formula: This nitration reaction is the same as in the above-mentioned 18th step.
It is performed according to the process.

In the twenty-second step, the general formula (20) (wherein the benzene ring moiety may have 1 to 4 substituents (a), and one amino group in the formula has one Wherein one amino group in the formula is substituted with one substituent (a),
The substituent (a) is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, the substituent (c)
An aryl group having 6 to 10 carbon atoms which may have a carbon atom having 7 to 10 carbon atoms which may have a substituent (c);
And 11 straight-chain or branched aralkyl groups. Wherein the benzene ring moiety may have 1 to 4 substituents (a), and the amino group in the formula has 1 to 4 substituents (a). May be substituted with (a).
Here, when the amino group in the formula is substituted with one substituent (a), the substituent (a) is preferably a linear or branched chain having 1 to 4 carbon atoms. Alkyl group having 6 to 1 carbon atoms which may have a substituent (c)
An aryl group having 0 or a linear or branched aralkyl group having 7 to 11 carbon atoms which may have a substituent (c). By reducing the compound having the formula: The reaction is carried out according to the above-mentioned nineteenth procedure.

After completion of the reaction, the target compound obtained in each of the above steps can be purified, if necessary, by a conventional method, for example, column chromatography, recrystallization, reprecipitation, or the like. For example, a solvent is added to the reaction mixture for extraction, and the solvent is distilled off from the extract. The obtained residue is purified by subjecting it to column chromatography using silica gel or the like, whereby a pure product of the target compound can be obtained.

The fused heterocyclic compound having the general formula (1) or a pharmacologically acceptable salt thereof according to the present invention includes insulin resistance, hyperlipidemia, hyperglycemia, gestational diabetes mellitus, obesity, impaired glucose tolerance. Ameliorates diabetic complications, arteriosclerosis, cataract, polycystic ovary syndrome, etc. and further has an aldose reductase inhibitory action, a 5-lipoxygenase inhibitory action and a lipid peroxide production inhibitory action, and Disease, hyperglycemia, obesity, impaired glucose tolerance, hypertension, osteoporosis, cachexia, fatty liver, diabetes complications, arteriosclerosis, cataracts and other prophylactic and / or therapeutic agents, and other diseases, Prophylactic and / or therapeutic agent for diseases caused by insulin resistance such as gestational diabetes mellitus, polycystic ovary syndrome, etc., and inflammatory diseases, acne, sunburn, psoriasis, eczema, allergic diseases Asthma is useful as GI ulcers, cardiovascular diseases, prophylactic agents of cell damage such as is caused by atherosclerosis and ischemic diseases and / or therapeutic agents.

The dosage form of the fused heterocyclic compound having the general formula (1) of the present invention or a pharmaceutically acceptable salt thereof may be, for example, oral administration such as tablets, capsules, granules, powders or syrups, or Parenteral administration by injection, suppository, eye drop or the like can be mentioned. These preparations are manufactured by a known method using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents.

[0334] As the excipient, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; corn starch, potato starch, α-
Starch derivatives such as starch, dextrin, carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked sodium carboxymethylcellulose; gum arabic; dextran; Organic excipients such as pullulan; and silicate derivatives such as light silicic anhydride, synthetic aluminum silicate, magnesium metasilicate aluminate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; And inorganic excipients such as sulfates.

Examples of the lubricant include metal stearates such as stearic acid, calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as veegum and gay wax; boric acid: adipic acid; Sodium sulfate, DL-leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate, magnesium lauryl sulfate; silicic acids such as silicic anhydride, silicic acid hydrate; And the above-mentioned starch derivatives.

Examples of the binder include polyvinylpyrrolidone, macrogol and the same compounds as the above-mentioned excipients.

Examples of the disintegrant include the same compounds as the above-mentioned excipients and chemically modified starch and cellulose such as croscarmellose sodium, sodium carboxymethyl starch and crosslinked polyvinylpyrrolidone.

As the stabilizer, for example, methyl paraben,
Paraoxybenzoic esters such as propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. be able to.

Examples of the flavoring agent include, for example, commonly used sweeteners, sour agents, flavors and the like.

The amount of the compound of the present invention having the general formula (1) or a pharmacologically acceptable salt thereof varies depending on the condition, age, administration method and the like.
For adults, a minimum of 0.1 mg (preferably 1 mg) and a maximum of 2000 mg (preferably 500 mg, more preferably 100 mg) per day, divided into one or several doses, depending on the symptoms Is desirable. In the case of intravenous administration, for adults,
It is desirable to administer 0.01 mg (preferably 0.1 mg) as the lower limit and 500 mg (preferably 50 mg) as the upper limit once or several times depending on the symptoms.

The preparation of the present invention containing the compound having the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient can be produced, for example, by the following method.

Formulation Example 1 Powder 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-
4 g of 2,4-dione (Exemplary Compound No. 1-49: hereinafter referred to as “Compound A”), 10 g of polyvinylpyrrolidone and hydroxypropylmethylcellulose (trade name, T
When 0.5 g of C-5E (Shin-Etsu Chemical Co., Ltd.) is mixed and pulverized for 30 minutes using a vibration mill, a powder is obtained.

Formulation Example 2 Capsules 20 g of compound A and 20 g of polyvinylpyrrolidone are dissolved in a mixed solvent of 100 g of acetone and 100 g of ethanol, and the mixed solution is sprayed on 200 g of croscarmellose sodium using a fluidized bed granulator to obtain granules.
0.1 g of hydroxypropyl methylcellulose (trade name, TC-5E; manufactured by Shin-Etsu Chemical Co., Ltd.) is added to 10 g of the granules.
g and lactose 1.9 g. A gelatin capsule is then filled with 0.24 g of this mixture,
A capsule is obtained. The capsule contains 0.1 g of Compound A per capsule.

Formulation Example 3 Tablets 1 g of compound A and 1 g of polyvinylpyrrolidone are dissolved in a mixed solvent of 5 g of acetone and 5 g of ethanol, and the organic solvent is distilled off under reduced pressure using a rotary evaporator. When the solid thus obtained is pulverized, fine particles are obtained. 0.2 g of crystalline cellulose was added to 1 g of the fine particles.
g, low-substituted hydroxypropylcellulose 0.25
g, hydroxypropyl methylcellulose (trade name, T
C-5E; Shin-Etsu Chemical Co., Ltd.) 0.05 g, lactose 0.18 g and magnesium stearate 0.2 g
Are mixed and then tableted using a tablet machine to obtain tablets.

[0345]

Next, the present invention will be described in more detail with reference to Examples, Reference Examples and Production Examples, but the present invention is not limited thereto.

Example 1 Hypoglycemic Action Each compound was administered to male KK mice showing a hyperglycemic state with a body weight of 40 g or more, polyethylene glycol 400: water = 1: 1.
The mixture was orally administered after mixing with the above solvent, and allowed to stand for 18 hours under saturated conditions. Subsequently, blood was collected from the tail vein under anesthesia, and glucose analyzer GL-101 (trade name, Mitsubishi Kasei Co., Ltd.)
Blood glucose level was measured using Glucloader-F (trade name, manufactured by Shino Test Co., Ltd.). The blood glucose lowering rate was determined by the following equation. Hypoglycemic rate (%) = [(solvent-administered group blood glucose level-compound-administered group blood glucose level) / solvent-administered group blood glucose level] x 100 The results are shown below.

Table 6 II Reference Example No. Dose (mg / kg) Hypoglycemia Rate (%) １ 1 1 36.2 2 1 27.2 3 1 11 0.241 19.3} From the above results, the compounds of the present invention are excellent. Showed the effect.

Example 2 Inhibition of aldose reductase The aldose reductase of bovine lens was determined by S. Hyman and JH
Kinoshita [J. Biol. Chem., 240, 877 (1965)
] And K. Inagaki, I. Miwa and J. Okuda [Arch. Bioc
Chem. Biophys., 216, 337 (1982)]. Its activity is determined by Varma et al. [Biochem. Pharmac., 25, 2505.
(1976)]. Inhibition of enzyme activity was measured at a concentration of 5 μg / ml of the compound of the invention. The results are shown in the table below.

Table 7 Reference Example No. IC ₅₀ inhibition rate at 5 μg / ml concentration (%) (Μg / ml) １ 1 80.3 0.77 3 79 0.6 1.40 ─────────────────────────────────.

Example 3 Male rats of the F344 strain were used as toxicity experimental animals. Five groups were used for the experiment. The test compound is administered orally to each animal at 50
mg / ml body weight was administered for 2 weeks. The test compound is the compound obtained in Reference Examples 1 and 2. Animals were observed for two weeks after dosing. During that period, no abnormality due to the test compound was observed. In terms of the effective dose for each animal, a mortality of 0 indicates that the compound of the invention is very toxic.

Reference Example 15- [4- (1-methylbenzimidazol-2-yl
Methoxy) benzyl] thiazolidine-2,4-dione
(Exemplary Compound No. 1-11) N-methyl-1,2-phenylenediamine 1.0 g, 5
-[4- (ethoxycarbonylmethoxy) benzyl] thio
Azolidine-2,4-dione 3.8 g, concentrated hydrochloric acid 20 m
l, 1,4-dioxane 10 ml and water 10 ml
The mixture was heated at reflux for 5 hours. Precipitated from the reaction mixture
The insoluble material is collected by filtration and dissolved in tetrahydrofuran.
Water was added thereto and neutralized with sodium hydrogen carbonate. Obtained
The solution was extracted with ethyl acetate. Extract solution with saline
And then dried over anhydrous sodium sulfate. Extraction
The residue obtained by distilling off the solvent from the liquid is applied to a silica gel column.
Chromatography (ethyl acetate → ethanol)
And the resulting product is further treated with tetrahydrofuran and vinegar.
Recrystallization twice with ethyl acid gave a melting point of 230 ° C.
1.3 g of the title compound having a temperature of 231 ° C. were obtained.

Reference Example 25- [4- (6-methoxy-1-methylbenzimidazo)
2-ylmethoxy) benzyl] thiazolidine-
2,4-dione (Exemplary Compound No. 1-49) 5-methoxy-N-methyl-1,2-phenylenediamide
21.8 g, 5- (4-methoxycarbonylmethylo)
Xybenzyl) thiazolidine-2,4-dione 63.4
g, 1,4-dioxane 250 mg and concentrated hydrochloric acid 750
The mixture was heated to reflux for 60 hours. The reaction mixture
After cooling on ice, the precipitate was collected by filtration. 5% carbonic acid
Add 800 ml of aqueous sodium hydrogen solution and leave at room temperature for 2 hours
Stirred. The insoluble matter is collected by filtration, and N, N-dimethylform
Mix of amide 1000ml and methanol 200ml
The mixture was dissolved in the solution, and activated carbon was added to remove the color. Activated carbon
After removal, the solvent was concentrated to about 50 ml. This is Jie
750 ml of chill ether was added and left at room temperature for 2 days
Thereafter, the precipitate was collected by filtration to give a melting point of 267 ° C. to 271 ° C.
° C, Rf value = 0.68 (silica gel thin layer chromatography
Eye with 5% ethanol-methylene chloride solution)
20.1 g of the target compound were obtained.

Reference Example 3 5- [4- (5-hydroxy-1,4,6,7-tetra
Methylbenzimidazol-2-ylmethoxy) benzene
Ru] thiazolidine-2,4-dione (Exemplary Compound No. 1
-237) 1.0 g of 4-acetoxy-N-methyl-3,5,6-trimethyl-1,2-phenylenediamine, 2.7 g of 5- (4-methoxycarbonylmethyloxybenzyl) thiazolidine-2,4-dione 5 ml of 1,4-dioxane
And 25 ml of concentrated hydrochloric acid was heated under reflux for 2 days.
The reaction mixture was added to ice water, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off from the extract, the residue was purified by silica gel column chromatography (ethyl acetate), and the fraction containing the target compound was collected. The solvent was distilled off from this fraction to obtain a red oily substance. 150 ml of diethyl ether was added to the oil, and ultrasonic vibration was applied for 5 minutes, and the precipitate was collected by filtration. This precipitate was dissolved in 300 ml of tetrahydrofuran, and the solvent was concentrated to about 10 to 20 ml. After adding 200 ml of ethyl acetate to this,
When ultrasonic vibration was applied for 20 minutes, a precipitate was formed. The precipitate was collected by filtration and had a melting point of 240 ° C. to 244 ° C., R
f-value = 0.44 (silica gel thin layer chromatography;
0.52 g of the desired compound having (ethyl acetate) was obtained.

Reference Example 4 5- [4- (5-hydroxy-1,4,6,7-tetra
Methylbenzimidazol-2-ylmethoxy) benzene
Ru] thiazolidine-2,4-dione hydrochloride (exemplified compound
Object number hydrochloride 1-237) 5-4 [4- (5-hydroxy-4,6,7-tetramethyl-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 0.12g A suspension suspended in 3 ml of a normal hydrogen chloride-ethyl acetate solution was stirred at room temperature for 3 hours, and then left overnight. The insolubles were collected from the reaction mixture by filtration, tetrahydrofuran, ethyl acetate,
Subsequent washing with diethyl ether yielded 0.11 g of the desired compound having a melting point of 228 ° C to 231 ° C.

Reference Example 5 5- [4- (5-acetoxy-1,4,6,7-tetra
Methylbenzimidazol-2-ylmethoxy) benzene
Ru] thiazolidine-2,4-dione (Exemplary Compound No. 1
-250) 5- [4- (5-Hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 0.12 g of pyridine solution in 2 ml of pyridine anhydride was added. 0.032 ml at room temperature,
Stir for 3 hours and leave overnight. After the solvent was distilled off from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. After evaporating the solvent from the extract, diethyl ether was added to the precipitate, and the precipitate was collected by filtration and washed with diethyl ether to obtain 0.12 g of the desired compound having a melting point of 250 ° C to 253 ° C.

Reference Example 65- [4- (5-methoxy-1-methylbenzimidazo)
2-ylmethoxy) benzyl] thiazolidine-
2,4-dione (Exemplary Compound No. 1-146) 4-methoxy-N-methyl-1,2-phenylenediamine
1.17 g, 5- (4-methoxycarbonylmethoxy)
Benzyl) thiazolidine-2,4-dione 3.0 g,
A mixture of 20 ml of 1,4-dioxane and 60 ml of concentrated hydrochloric acid
The mixture was heated at reflux for 2 days. Add the reaction mixture to ice water.
After neutralizing with sodium bicarbonate,
Extracted. After washing the extract with saturated saline, anhydrous
Dried over sodium sulfate. Solvent is distilled off from the extract
The residue was subjected to silica gel column chromatography (3%
Purification by methylene chloride containing ethanol)
Point 209 ° C to 210 ° C, Rf value = 0.56 (5%
Target compound having methylene chloride containing methanol) 0.3
g was obtained.

Reference Example 7 5- [4- (1-benzylbenzimidazole-5-i
Rumethoxy) benzyl] thiazolidine-2,4-dione
1/2 hydrate (1/2 water of Exemplified Compound No. 1-229)
Hydrates) 5- [4- (1-benzyl-5-ylmethoxy) benzyl] -3-triphenylmethyl-thiazolidine-2,4-dione 0.26 g, a mixture of acetic acid 3ml, and water 1 ml, 50 ° C. oil Stirred on the bath for 3 hours. The reaction mixture was neutralized with an aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and the extract was washed with saturated saline. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was recrystallized from a mixture of ethanol and methanol to give 116 mg of the desired compound having a melting point of 185 ° C to 187 ° C.

Production Example 1 Methyl 4-nitrophenoxyacetate 56 g of 4-nitrophenol, methyl bromoacetate 90
g, potassium carbonate 100 g and dimethylformamide 500 ml were stirred at room temperature for 2 days. After completion of the reaction, dimethylformamide was distilled off from the reaction mixture under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water, it was dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, the residue was crystallized from hexane to obtain 63.3 g of the desired compound having a melting point of 98 ° C to 99 ° C.

Production Example 2 Methyl 4 -aminophenoxyacetate Methyl 4-nitrophenoxyacetate (see Production Example 1) 3
Hydrogen gas was introduced into a mixture of 0.8 g, 5.0 g of 10% palladium-carbon and 500 ml of methanol for 6 hours. After completion of the reaction, insolubles were filtered off from the reaction mixture, and the filtrate was distilled off under reduced pressure to obtain 25.8 g of the desired compound having an Rf value of 0.79 (silica gel thin layer chromatography; ethyl acetate).

Production Example 3 4- (2-bromo-2-butoxycarbonylethyl-1)
-Yl) methyl phenoxyacetate 25.8 g of methyl 4-aminophenoxyacetate (Production Example 2)
263m containing methanol-acetone (2: 5)
98 g of 47% hydrobromic acid was added dropwise to the solution of 1 under ice-cooling,
Then 33m of aqueous solution containing 12.8g of sodium nitrite
1 was added dropwise. After stirring for 30 minutes under ice cooling, 18.2 g of butyl acrylate was added to the reaction mixture, and the mixture was cooled under ice cooling for 30 minutes.
After stirring for 3.2 minutes, 3.2 g of copper (I) bromide was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off from the reaction mixture,
A saline solution was added to the obtained residue, and the mixture was extracted with ethyl acetate.
The extract was washed with saline and then dried over anhydrous sodium sulfate. When the solvent was distilled off from the extract, the Rf value was 0.1.
46 (silica gel thin layer chromatography; hexane:
51.7 g of a crude product containing the target compound having (ethyl acetate = 5: 1) were obtained.

Production Example 4 5- [4- (ethoxycarbonylmethoxy) benzyl]
Thiazolidine-2,4-dione 4- (2-bromo-2-butoxycarbonylethyl-1
-Yl) methyl phenoxyacetate (see Production Example 3) 100
g, 22 g of thiourea and 200 ml of ethanol were heated under reflux for 2.5 hours. The reaction mixture was then added to 2
N hydrochloric acid was added, and the mixture was heated under reflux for 5 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture, water was added to the obtained residue, extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off from the extract, and silica gel column chromatography (ethyl acetate: hexane = 2: 5)
Purification by purification afforded 19.4 g of the desired compound having a melting point of 105 ° C. to 106 ° C.

Production Example 5 5-Methoxy-2-nitroaniline A solution of 25 g of 5-chloro-2-nitroaniline in 500 ml of 1,4-dioxane was treated with 28% of sodium methoxide.
70 ml of a methanol solution was added at room temperature, and the mixture was heated under reflux for 4 hours. The solvent was distilled off from the reaction mixture, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4 → 1: 2) to obtain 16.3 g of the desired compound having a melting point of 124 ° C. to 128 ° C. Was done.

Production Example 6 N-tert-butoxycarbonyl-5-methoxy-2
- nitroaniline 5-methoxy-2-nitroaniline 16g of anhydrous tetrahydrofuran 500ml to di tert- butyl dicarbonate 25 g, pyridine 15 ml, 4-dimethylaminopyridine 0.6g was added at room temperature and stirred for 2 hours. The solvent was distilled off from the reaction mixture, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to give the desired compound 1 having a melting point of 112 ° C. to 114 ° C.
2.5 g were obtained.

Production Example 7 N-tert-butoxycarbonyl-N-methyl-5
12.0 g of sodium methoxy-2-nitroaniline hydride (containing 55% or more) was suspended in 300 ml of anhydrous N, N-dimethylformamide, and N-tert-butoxycarbonyl-5-methoxy was added to the suspension under ice-cooling. A solution of 49.6 g of 2-nitroaniline in 300 ml of anhydrous N, N-dimethylformamide was added,
Stirred at room temperature for 30 minutes. This mixture contains methyl iodide 1
7.2 ml was added at room temperature, and after stirring for 1 hour, the mixture was left at room temperature overnight. After concentrating the reaction mixture to about 1/5 volume, it was added to ice water and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract to obtain 52.1 g of the desired compound having a melting point of 122 ° C to 124 ° C.

Production Example 8 N-methyl-5-methoxy-2-nitroaniline N-tert-butoxycarbonyl-N-methyl-5
To 52 g of methoxy-2-nitroaniline was added 750 ml of a 4N hydrogen chloride-1,4-dioxane solution at room temperature, and 2
Stirred for hours. After evaporating the solvent from the reaction mixture, water and ethyl acetate were added, and the mixture was neutralized with sodium hydrogen carbonate. Ethyl acetate was further added to the mixture for extraction, and the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract to obtain 35.3 g of the desired compound having a melting point of 107 ° C to 110 ° C.

Production Example 9 5-methoxy-N-methyl-1,2-phenylenediamine
N -methyl-5-methoxy-2-nitroaniline 35 g
900 ml of tert-butanol solution and ethyl acetate 1
346 g of tin (II) chloride dihydrate in a mixture of 00 ml
Was added at room temperature, followed by stirring at 60 ° C. for 2 hours. To this mixture, 11 g of sodium borohydride was added little by little at 60 ° C. over about 1 hour, stirred at 60 ° C. for 3 hours, and left at room temperature for 2 days. After the reaction mixture was added to ice water, it was neutralized with sodium hydrogen carbonate. Ethyl acetate was added to the mixture for extraction, and the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and silica gel column chromatography (ethyl acetate: n-
Purification by hexane = 3: 2) gave an Rf value of 0.2.
21. Compound of interest (Silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 1)
9 g were obtained.

Production Example 10 Trimethylbenzoquinone Trimethylhydroquinone 20 g acetone 150 ml
A suspension of 25.6 g of iron (III) chloride in 50 ml of water was added to the solution at room temperature, stirred for 1 hour, and left for 2 days. After concentrating the solvent to about half, water was added and extracted with ethyl acetate. The extract was washed with water and saturated saline,
Dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, the extract was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 6).
16.9 g of the target compound having an Rf value of 0.48 (silica gel thin layer chromatography; ethyl acetate: n-hexane = 1: 6) were obtained.

Production Example 11 Methanol solution of 16.9 g of 2,3,6-trimethylbenzoquinone-4-oximetrimethylbenzoquinone 1
In 50 ml, hydroxylamine hydrochloride (7.04 g)
Was added at room temperature, stirred for 2 hours, and left for 2 days. After adding 1000 ml of water to the reaction mixture, the precipitate was collected by filtration. The precipitate was recrystallized from a mixture of ethyl acetate and n-hexane to obtain 11.2 g of the desired compound having a melting point of 188 ° C to 190 ° C.

Production Example 12 4-Hydroxy-2,3,5-trimethylaniline 2,3,6-trimethylbenzoquinone-4-oxime 3
6.15 g and 880 ml of 1N aqueous sodium hydroxide solution
After adding 152 g of sodium hydrosulfite to the mixture under ice-cooling, the mixture was stirred at room temperature for 1 hour and left overnight. The reaction mixture is added to ice, and p
After adjusting H to 4 to 5, it was neutralized with sodium hydrogen carbonate. This was extracted with ethyl acetate, and the extract was washed with saturated saline and dried over anhydrous sodium sulfate. Solvent was distilled off from the extract, and isopropyl ether was added to the resulting crystals, which was collected by filtration and washed with isopropyl ether.
30. The target compound having a melting point of 131 ° C. to 134 ° C.
1 g was obtained.

Production Example 13 N-tert-butoxycarbonyl-4-hydroxy-
2,3,5-trimethylaniline 4-hydroxy-2,3,5-trimethylaniline 20
g of tetrahydrofuran in 500 ml of a solution at room temperature was added with 22.0 ml of triethylamine.
After adding 34.6 g of butyl dicarbonate and stirring for 6 hours, the mixture was left overnight. After evaporating the solvent from the reaction mixture, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate.
The solvent was distilled off from the extract, n-hexane was added to the crystals obtained, and the crystals were collected by filtration and washed with n-hexane to give the target compound having a melting point of 158 ° C to 161 ° C, 31.9.
g was obtained.

Production Example 14 N-methyl-4-hydroxy-2,3,5-trimethyl
N-ter was added to a suspension of 6.8 g of lithium aluminum hydride in 300 ml of aniline anhydrous tetrahydrofuran.
t-butoxycarbonyl-4-hydroxy-2,3,5
After adding 200 ml of a solution of 15 g of trimethylaniline in anhydrous tetrahydrofuran under ice-cooling, the mixture was stirred at room temperature for 3 hours and refluxed for 2 hours. A mixture of 10 ml of water and 30 ml of tetrahydrofuran was added dropwise to the reaction mixture under ice cooling,
Excess lithium aluminum hydride was decomposed. After the reaction mixture was stirred at room temperature for 1.5 hours, insolubles were removed by filtration using Celite. The insolubles were washed with ethyl acetate,
The washing solution and the filtrate were combined and dried over anhydrous sodium sulfate. After evaporating the solvent from this solution, silica gel column chromatography (ethyl acetate: n-hexane = 1: 1).
Purification by 3) gives a melting point of 120 ° C. to 122 ° C.
5.1 g of the title compound having the formula were obtained.

Production Example 15 N-tert-butoxycarbonyl-N-methyl-4-
Hydroxy-2,3,5-trimethylaniline N-methyl-4-hydroxy-2,3,5-trimethylaniline 5.0 g of triethylamine and 7.92 g of di-tert-butyldicarbonate were added to 70 ml of a solution of 5.0 g of tetrahydrofuran. 30 ml of a tetrahydrofuran solution was added at room temperature, stirred for 1 hour, and left overnight. After evaporating the solvent from the reaction mixture, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the extract, n-hexane was added to the crystals obtained, and the crystals were collected by filtration and washed with n-hexane to give 7.35 g of the desired compound having a melting point of 163 ° C to 166 ° C. .

Production Example 16 N-tert-butoxycarbonyl-N-methyl-4-
Acetoxy-2,3,5-trimethylaniline N-tert-butoxycarbonyl-N-methyl-4-
Hydroxy-2,3,5-trimethylaniline 7.2 g
In anhydrous tetrahydrofuran solution (100 ml), anhydrous triethylamine (5.64 ml) and acetyl chloride (2.9 m).
was added at room temperature, stirred for 1 hour, and left overnight. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off from the extract, the residue was crystallized by adding ice-cooled n-hexane. Ice-cooled n-hexane was added, and the crystals were collected by filtration and washed with ice-cooled n-hexane to obtain 6.25 g of the desired compound having a melting point of 103 ° C to 104 ° C.

Production Example 17 N-methyl-4-acetoxy-2,3,5-trimethyl
Aniline hydrochloride N-tert-butoxycarbonyl-N-methyl-4-
Acetoxy-2,3,5-trimethylaniline 5.45
g in 4N hydrogen chloride-1,4-dioxane solution 100
ml was added at room temperature and stirred for 3 hours. The solvent was distilled off from the reaction mixture, isopropyl ether was added to the resulting crystals, and the crystals were collected by filtration and washed with isopropyl ether to obtain 4.36 g of the desired compound having a melting point of 172 ° C to 176 ° C.

Production Example 18 N-methyl-4-acetoxy-2,3,5-trimethyl
4.3 g of -6-nitroaniline N-methyl-4-acetoxy-2,3,5-trimethylaniline hydrochloride was added to ice-cooled concentrated nitric acid, and the mixture was stirred under ice-cooling for 10 minutes and further at room temperature for 10 minutes. Stirred. The reaction mixture was added to ice water, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. After the solvent was distilled off from the extract, 50 ml of isopropyl ether and 50 ml of n-hexane were added to the residue, and ultrasonic vibration was applied for 5 minutes. A mixed solution of isopropyl ether: n-hexane (= 1: 1) was added to the insoluble crystals, and the crystals were collected by filtration.
1) Washing with a mixture, melting point 143 ° C to 146 ° C
2.76 g of the target compound having the formula were obtained.

Production Example 19 4-Acetoxy-N-methyl-3,5,6-trimethyl
-1,2-phenylenediamine N-methyl-4-acetoxy-2,3,5-trimethyl-6-nitroaniline 2.65 g of ethanol 20 ml
20 ml of ethyl acetate and 0.2 g of platinum oxide were added to the solution, and hydrogen gas was introduced into the mixture at room temperature for 3.5 hours, and further at 40 ° C. for 3 hours. Next, platinum oxide was filtered off from the reaction mixture, and the solvent was distilled off from the filtrate. The residue was subjected to silica gel column chromatography (ethyl acetate:
Purification by n-hexane = 1: 1) gave a melting point of 11
1.3 g of the title compound having a temperature between 3 ° C. and 116 ° C. are obtained.

Production Example 20 5- (4-methoxycarbonylmethoxybenzyl) -3
-Triphenylmethylthiazolidine-2,4-dione 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 126 g of cesium carbonate was added to 2.5 liter of acetone solution of 120 g, and bromoacetic acid was further added. 36 ml of methyl was added at room temperature and stirred for 1 hour. After the solvent was distilled off from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the extract, 1 liter of diethyl ether was added to the oily residue, and ultrasonic vibration was applied for 10 minutes. The precipitated solid was collected by filtration to obtain 126.3 g of the desired compound having a melting point of 158 ° C to 162 ° C.

Production Example 21 5- (4-methoxycarbonylmethoxybenzyl) thia
Zolidine-2,4-dione 5- (4-methoxycarbonylmethoxybenzyl) -3
-Triphenylmethylthiazolidine-2,4-dione 3
To a suspension of 44 g in 400 ml of 1,4-dioxane, 1700 ml of acetic acid and then 400 ml of water were added at room temperature, and the mixture was stirred at 80 ° C. for 5 hours. The solvent was distilled off from the reaction mixture, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 → 2: 1 → ethyl acetate only).
161.7 g of the target compound having a temperature of 06 ° C. are obtained.

Production Example 22 N-tert-butoxycarbonyl-4-methoxy-2
To a suspension of 0.72 g of sodium nitroaniline hydride (containing 55% or more) in 30 ml of anhydrous N, N-dimethylformamide was added 2.5 g of 4-methoxy-2-nitroaniline in anhydrous N, N -30 ml of a dimethylformamide solution was added at room temperature, and the mixture was stirred for 10 minutes. Next, a solution of 3.57 g of di-tert-butyl dicarbonate in 20 ml of anhydrous N, N-dimethylformamide was added to the reaction mixture at room temperature, followed by stirring for 1 hour. The reaction mixture was added to ice water and extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 20) to obtain an Rf value = 0.39 (ethyl acetate: n-hexane = 1). : 20) was obtained.

Production Example 23 N-tert-Butoxycarbonyl-N-methyl-4-
0.46 g of sodium methoxy-2-nitroaniline hydride (containing 55% or more), 15 ml of anhydrous N, N-dimethylformamide, 0.66 ml of methyl iodide and N-tert-butoxycarbonyl-4-methoxy-2-nitroaniline Using 1.9 g of anhydrous N, N-dimethylformamide solution 15 ml,
When the reaction and the post-treatment are carried out according to Production Example 7, the Rf value =
2.0 g of the title compound having 0.34 (ethyl acetate: n-hexane = 1: 5) were obtained.

Production Example 24 N-methyl-4-methoxy-2-nitroaniline N-tert-butoxycarbonyl-N-methyl-4-
When 2.0 g of methoxy-2-nitroaniline and 30 ml of a 4N hydrogen chloride-1,4-dioxane solution were used to carry out the reaction and post-treatment according to Production Example 8, the Rf value was 0.1.
1.17 g of the title compound having 62 (ethyl acetate: n-hexane = 1: 5) were obtained.

Production Example 25 4-methoxy-N-methyl-1,2-phenylenediia
Min N-methyl-4-methoxy-2-nitroaniline 1.1
Hydrogen gas was introduced into a mixture of 6 g, 10% palladium-carbon catalyst 0.3 g and ethanol 50 ml at room temperature for 3 hours. After removing the 10% palladium-carbon catalyst from the reaction mixture by filtration, the solvent was distilled off, thereby obtaining 1.17 g of the target compound having an Rf value of 0.50 (ethyl acetate: n-hexane = 1: 3). .

Production Example 26 Methyl 5-benzimidazolecarboxylate A mixture of 10 g of 5-benzimidazolecarboxylic acid, 150 ml of methanol and 100 ml of a 4N hydrogen chloride-1,4-dioxane solution was subjected to ultrasonic vibration for 4 hours.
After the solvent was distilled off from the reaction mixture under reduced pressure, 300 ml of methanol and 3.5 g of lithium borohydride were added to the residue.
Was added and stirred for 1 hour. After evaporating the solvent from the reaction mixture under reduced pressure, brine was added to the residue, and the mixture was extracted with ethyl acetate. The solvent was distilled off from the extract to obtain 5.44 g of the desired compound having a melting point of 136 ° C to 138 ° C.

Production Example 27 1-Benzyl-5-benzimidazolecarboxylic acid methyl ester
Le 5- benzimidazole carboxylate 2.8 g, benzyl bromide 3.52 g, a mixture of potassium carbonate 3g and 50ml of acetone was stirred at room temperature for 3 days. The solvent was distilled off from the reaction mixture, brine was added to the residue, and the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was recrystallized from a mixture of ethyl acetate and n-hexane.
0.94 g of the target compound having a temperature of 2 ° C. was obtained.

Production Example 28 1-Benzyl-5-benzimidazole To a suspension of 0.23 g of methanolic lithium aluminum hydride in 10 ml of anhydrous tetrahydrofuran was added 0.87 g of methyl 1-benzyl-5-benzimidazolecarboxylate.
g of anhydrous tetrahydrofuran solution (18 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. Further, 0.11 g of lithium aluminum hydride and 10 ml of anhydrous tetrahydrofuran were added to the reaction mixture, and the mixture was added at room temperature for 1 hour.
Then, the mixture was stirred on a 50 ° C. oil bath for 4.5 hours, and further heated under reflux for 2 hours. After allowing the reaction mixture to cool, an excess amount of sodium sulfate decahydrate was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered using celite, and the solvent was distilled off from the filtrate. The residue was recrystallized from a mixture of ethanol and diisopropyl ether to give a melting point of 148 ° C to 150 ° C.
383 mg of the target compound having a temperature of ℃ are obtained.

Production Example 29 5- [4- (1-benzylbenzimidazole-5-i
Rumethoxy) benzyl] -3-triphenylmethylthia
Zolidine-2,4-dione 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione 822 mg, azodicarbonyldipiperidine 454 mg, anhydrous toluene 6 m
A mixture of 1 and 0.44 ml of tributylphosphine was stirred at room temperature for 30 minutes. 1-benzyl- was added to the reaction mixture.
349 mg of 5-benzimidazole methanol was added,
After stirring for 3 hours, the mixture was left at room temperature for 10 days. The solvent was distilled off from the reaction mixture, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 3: 1 → 1:
Purification by 0) gave 0.32 g of the desired compound having a softening point of 90 ° C. to 91 ° C.

[0387]

Industrial Applicability The fused heterocyclic compound having the general formula (1) of the present invention or a pharmaceutically acceptable salt thereof is useful for insulin resistance, hyperlipidemia, hyperglycemia, gestational diabetes, obesity, glucose tolerance. Ameliorates insufficiency, diabetic complications, arteriosclerosis, cataract, polycystic ovary syndrome, etc. and has an aldose reductase inhibitory action, 5-lipoxygenase inhibitory action and lipid peroxide production inhibitory action, Prophylactic and / or therapeutic drugs for blood, hyperglycemia, obesity, impaired glucose tolerance, hypertension, osteoporosis, cachexia, fatty liver, diabetic complications, arteriosclerosis, cataract, etc. , Gestational diabetes mellitus, prophylactic and / or therapeutic agent for diseases caused by insulin resistance such as polycystic ovary syndrome, and inflammatory diseases, acne, sunburn, psoriasis, eczema, allergic diseases Asthma is useful as GI ulcers, cardiovascular diseases, prophylactic agents of cell damage such as is caused by atherosclerosis and ischemic diseases and / or therapeutic agents.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 3/10 A61P 3/10 9/10 101 9/10 101 27/12 27/12 C07D 235/06 C07D 235/06 413 / 12 413/12 417/12 417/12 (72) Inventor Hiroaki Yanagisawa 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Koichi Fujimoto 1-2-2 Hiromachi, Shinagawa-ku, Tokyo No. 58 Sankyo Co., Ltd. (72) Inventor Toshihiko Fujiwara 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Daigo Noguchi 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Takao Yoshioka 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (56) References JP-A-10-72371 (JP, A) JP-A 2000-1487 (JP) , A) (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 235/12 C07 D 235/06 C07D 413/12 C07D 417/12 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (37)

(57) [Claims] 1. A compound of the general formula A preventive and / or therapeutic agent for a disease caused by insulin resistance, comprising a condensed heterocyclic compound having the formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. However, in the above formula, X represents a benzimidazole ring group, and the group is 1 to 5
Y may represent an oxygen atom or a sulfur atom, and Z may be represented by the following formula: R represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, halogen An atom, a hydroxy group, a nitro group, an amino group which may have a substituent (b) (the substituent (b) is a straight-chain or branched alkyl group having 1 to 8 carbon atoms, A linear or branched aralkyl group having 7 to 11 carbon atoms, an aryl group having 6 to 10 carbon atoms, a linear or branched aliphatic group having 1 to 11 carbon atoms An acyl group, an araliphatic acyl group having 8 to 12 carbon atoms or an aromatic acyl group having 7 to 11 carbon atoms.) Or a linear or branched chain having 7 to 11 carbon atoms. And m is an integer of 1 to 5 Show. Here, the substituent (a) is a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, A benzyloxy group, a halogen atom, a hydroxy group, an acetoxy group, a phenylthio group, a linear or branched alkylthio group having 1 to 4 carbon atoms, a trifluoromethyl group, a nitro group, and a substituent (b). An amino group (optional), wherein the substituent (b) is a linear or branched alkyl group having 1 to 8 carbon atoms,
A linear or branched aralkyl group having one,
An aryl group having 6 to 10 carbon atoms, a linear or branched aliphatic acyl group having 1 to 11 carbon atoms, an araliphatic acyl group having 8 to 12 carbon atoms, or 7 carbon atoms And represents an aromatic acyl group having from 1 to 11. ), An aryl group having 6 to 10 carbon atoms which may have a substituent (c) (the substituent (c) is a straight-chain or branched-chain having 1 to 4 carbon atoms) Having an alkyl group, a linear or branched alkoxy group having 1 to 4 carbon atoms, a halogen atom, a hydroxy group, a nitro group, a phenyl group, a trifluoromethyl group or a substituent (b); Or a straight-chain or branched aralkyl group having 7 to 11 carbon atoms which may have a substituent (c). 2. The method according to claim 1, wherein R is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkyl group having 1 to 4 carbon atoms. A preventive and / or therapeutic agent for a disease caused by insulin resistance, comprising a condensed heterocyclic compound having a chain alkoxy group or a halogen atom or a pharmaceutically acceptable salt thereof as an active ingredient. 3. A preventive and / or therapeutic agent for a disease caused by insulin resistance comprising a fused heterocyclic compound wherein Y is an oxygen atom or a pharmaceutically acceptable salt thereof as an active ingredient. . 4. The method according to claim 1, wherein Z is 2,4-dioxothiazolidine-5-ylmethyl group, 2,4-dioxothiazolidine-5-yridenylmethyl group or 2,4-dioxothiazolidine-5-ylidenylmethyl group.
A preventive and / or therapeutic agent for a disease caused by insulin resistance, comprising a condensed heterocyclic compound which is a dioxooxazolidine-5-ylmethyl group or a pharmaceutically acceptable salt thereof as an active ingredient. 5. The method according to claim 1, wherein R is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkyl group having 1 to 4 carbon atoms. A chain alkoxy group or a halogen atom, Y is an oxygen atom, Z is a 2,4-dioxothiazolidine-5-ylmethyl group, a 2,4-dioxothiazolidine-5-yridenylmethyl group or 2, A preventive and / or therapeutic agent for a disease caused by insulin resistance, comprising a condensed heterocyclic compound which is a 4-dioxooxazolidin-5-ylmethyl group or a pharmaceutically acceptable salt thereof as an active ingredient. 6. The fused heterocyclic compound according to claim 1, wherein Z is a 2,4-dioxothiazolidine-5-ylmethyl group or a 2,4-dioxothiazolidine-5-yridenylmethyl group, or a pharmaceutically acceptable compound thereof. A preventive and / or therapeutic agent for a disease caused by insulin resistance, comprising a salt as an active ingredient. 7. The method according to claim 1, wherein R is a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom, or a pharmaceutically acceptable salt thereof as an active ingredient. A preventive and / or therapeutic agent for a disease caused by insulin resistance. 8. A preventive agent for a disease caused by insulin resistance, comprising a condensed heterocyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient, wherein m is an integer of 1 to 3, and / or Or therapeutic drugs. 9. The method according to claim 1, wherein Y is an oxygen atom, Z is a 2,4-dioxothiazolidine-5-ylmethyl group or a 2,4-dioxothiazolidine-5-yridenylmethyl group, Is a hydrogen atom, a methyl group, a methoxy group, an ethoxy group,
A preventive and / or therapeutic agent for a disease caused by insulin resistance, which contains, as an active ingredient, a condensed heterocyclic compound or a pharmacologically acceptable salt thereof, wherein m is an integer of 1 to 3; medicine. 10. The compound according to claim 1, wherein X is a benzimidazole ring group which may have 1 to 5 substituents (a '), wherein the substituent (a') has 1 to 4 carbon atoms. A linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a benzyloxy group, a halogen atom, a phenylthio group,
Linear or branched alkylthio groups having
Trifluoromethyl group, hydroxy group, acetoxy group,
A preventive and / or therapeutic agent for a disease caused by insulin resistance, comprising as an active ingredient a condensed heterocyclic compound or a pharmaceutically acceptable salt thereof, which is a benzyl group or a phenyl group. 11. The method according to claim 1, wherein Z is a 2,4-dioxooxazolidin-5-ylmethyl group, or a condensed heterocyclic compound or a pharmacologically acceptable salt thereof as an active ingredient. Prophylactic and / or therapeutic agents for diseases that occur. 12. The method according to claim 1, wherein R is a hydrogen atom, a methyl group or a methoxy group, or a pharmacologically acceptable salt thereof as an active ingredient. Drugs and / or therapeutics. 13. The method according to claim 1, wherein X is a benzimidazole ring group having 1 to 5 substituents (a ′), wherein the substituent (a ′) has 1 to 4 carbon atoms. A linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 4 carbon atoms, a benzyloxy group, a halogen atom, a phenylthio group,
Linear or branched alkylthio groups having
Trifluoromethyl group, hydroxy group, acetoxy group,
A benzyl group or a phenyl group, Y is an oxygen atom, Z is a 2,4-dioxooxazolidin-5-ylmethyl group, and R is a hydrogen atom, a methyl group or a methoxy group. A preventive and / or therapeutic agent for a disease caused by insulin resistance, which comprises, as an active ingredient, a fused heterocyclic compound or a pharmaceutically acceptable salt thereof, wherein m is an integer of 1 to 3. 14. The compound according to claim 1, wherein X is a benzimidazole ring group optionally having 1 to 5 substituents (a ″): wherein the substituent (a ″) is a methyl group, an ethyl group, Group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, benzyloxy group, fluorine atom, chlorine atom,
Diseases caused by insulin resistance containing, as an active ingredient, a fused heterocyclic compound or a pharmaceutically acceptable salt thereof, which is a phenylthio group, a methylthio group, an ethylthio group, a hydroxy group, an acetoxy group, a benzyl group or a phenyl group. Prophylactic and / or therapeutic agents. 15. A preventive and / or therapeutic agent for a disease caused by insulin resistance comprising a fused heterocyclic compound wherein R is a hydrogen atom or a pharmaceutically acceptable salt thereof as an active ingredient. . 16. A preventive and / or therapeutic agent for a disease caused by insulin resistance which comprises a fused heterocyclic compound wherein m is 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. medicine. 17. The method according to claim 1, wherein X is a benzimidazole ring group optionally having 1 to 5 substituents (a ″): wherein the substituent (a ″) is a methyl group, an ethyl group, Group, isopropyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, benzyloxy group, fluorine atom, chlorine atom,
A phenylthio group, a methylthio group, an ethylthio group, a hydroxy group, an acetoxy group, a benzyl group or a phenyl group, Y is an oxygen atom, and Z is a 2,4-dioxothiazolidine-5-ylmethyl group. Wherein R is a hydrogen atom, m is 1 or 2, and a prophylactic and / or therapeutic agent for a disease caused by insulin resistance containing a condensed heterocyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient. medicine. 18. The method according to claim 1, wherein X is a benzimidazole ring group optionally having 1 to 5 substituents (a ′ ″): wherein the substituent (a ′ ″) is a methyl group , A methoxy group, a hydroxy group, an acetoxy group or a benzyl group, a preventive and / or therapeutic agent for a disease caused by insulin resistance, which contains a condensed heterocyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient. . (19) A prophylactic and / or therapeutic agent for a disease caused by insulin resistance, which comprises a fused heterocyclic compound wherein m is 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 20. The method according to claim 1, wherein X is a benzimidazole ring group which may have 1 to 5 substituents (a ′ ″), wherein the substituent (a ′ ″) is a methyl group. , A methoxy group, a hydroxy group, an acetoxy group or a benzyl group, Y is an oxygen atom, Z is a 2,4-dioxothiazolidine-5-ylmethyl group, and R is a hydrogen atom A prophylactic and / or therapeutic agent for a disease caused by insulin resistance, comprising a condensed heterocyclic compound or a pharmaceutically acceptable salt thereof wherein m is 1 as an active ingredient. 21. 5- [4- (1-Methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-
2,4-dione, 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-
2,4-dione, 5- [4- (5-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-
2,4-dione, 5- [4- (1-benzylbenzimidazol-5-ylmethoxy) benzyl] thiazolidine-2,4-dione, 5- [4- (5-hydroxy-1,4,6,7- Tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione or 5- [4-
(5-acetoxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof caused by insulin resistance containing as an active ingredient Prophylactic and / or therapeutic agents for diseases that occur. 22. 5- [4- (1-Methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-
An agent for preventing and / or treating a disease caused by insulin resistance, comprising 2,4-dione or a pharmacologically acceptable salt thereof as an active ingredient. 23. Insulin resistance containing 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof as an active ingredient. A preventive and / or therapeutic agent for a disease caused by sex. 24. Insulin resistance containing 5- [4- (5-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof as an active ingredient. A preventive and / or therapeutic agent for a disease caused by sex. 25. 5- [4- (1-benzylbenzimidazol-5-ylmethoxy) benzyl] thiazolidine-
An agent for preventing and / or treating a disease caused by insulin resistance, comprising 2,4-dione or a pharmacologically acceptable salt thereof as an active ingredient. 26. 5- [4- (5-hydroxy-1,4,4)
6,7-Tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof as an active ingredient, a preventive and / or therapeutic agent for a disease caused by insulin resistance. medicine. 27. 5- [4- (5-acetoxy-1,4,4)
6,7-Tetramethylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof as an active ingredient, a preventive and / or therapeutic agent for a disease caused by insulin resistance. medicine. 28. A prophylactic and / or therapeutic drug for hyperglycemia, comprising as an active ingredient the fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27. 29. A prophylactic and / or therapeutic drug for diabetic complications comprising the fused heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 27 as an active ingredient. 30. A prophylactic agent for arteriosclerosis, comprising as an active ingredient the condensed heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27 and / or
Or therapeutic drugs. 31. A prophylactic and / or therapeutic agent for hyperlipidemia containing the condensed heterocyclic compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient. 32. A prophylactic and / or therapeutic agent for obesity comprising the condensed heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 27 as an active ingredient. 33. A preventive drug for impaired glucose tolerance comprising the condensed heterocyclic compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient.
Or therapeutic drugs. 34. A prophylactic and / or therapeutic agent for hypertension comprising the fused heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 27 as an active ingredient. 35. A preventive agent for gestational diabetes mellitus comprising the condensed heterocyclic compound according to any one of claims 1 to 27 or a pharmacologically acceptable salt thereof as an active ingredient.
Or therapeutic drugs. 36. A prophylactic and / or therapeutic agent for insulin-resistant non-glucose intolerance comprising the fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27 as an active ingredient. medicine. 37. A cataract preventive and / or therapeutic agent comprising the fused heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 27 as an active ingredient.