WO2004113345A1

WO2004113345A1 - Fused pyrrole compound and medicinal use thereof

Info

Publication number: WO2004113345A1
Application number: PCT/JP2004/008917
Authority: WO
Inventors: Takeshi Nakamura; Masaki Takagi; Toshihiro Kiguchi; Taku Ikenogami; Nobuhisa Ueda
Original assignee: Japan Tobacco Inc.
Priority date: 2003-06-20
Filing date: 2004-06-18
Publication date: 2004-12-29

Abstract

A fused pyrrole compound represented by the general formula (1): (1) (wherein the symbols have the same meanings as in the description), a prodrug thereof, or a pharmaceutically acceptable salt of either. The compound (1), prodrug, and salt are useful as a therapeutic agent for diabetes which has HLGPa inhibitory activity.

Description

Condensed pial compound and its pharmaceutical use

Technical field

The present invention relates to a novel condensed pyrrole compound having HLGPa (Human LiverGlycogenPhosphhory1asea) inhibitory activity and a pharmaceutical use thereof. Furthermore, the present invention relates to a therapeutic agent for diabetes comprising a compound having a condensed pyrrole structure or a pharmaceutically acceptable salt thereof.

Background art

Diabetes is a chronic disease that results from abnormal sugar, lipid, and amino acid metabolism due to a lack of insulin action. If left untreated, it will show hyperglycemia and urine sugar. Diabetes is divided into insulin-dependent and non-insulin-dependent. Approximately 90% of diabetics have insulin-independent diabetes.

Insulin-dependent diabetes mellitus is susceptible to ketemia and acidosis due to the loss of insulin secretion, and if left untreated, falls into diabetic coma. Diet and oral hypoglycemic drugs have no therapeutic effect and can only be treated with insulin.

On the other hand, non-insulin dependent diabetes mellitus (NIDDM) has a lower than normal insulin action, but has a low tendency to ketemia and acidosis, and does not necessarily require insulin for treatment.

Currently, hypoglycemic drugs used to correct hyperglycemia include insulin, sulfururea (eg, dalibenclamide, tolptamide), biguanides (eg, metformin), insulin sensitizers (eg, Troglitazone) and a-Darcosidase inhibitors (eg, acarpose) have been used.

Insulin preparations are used for insulin-dependent diabetes mellitus, and they certainly lower blood glucose, but they must be administered by injection and may cause hypoglycemia.

Sulfo-lurea agents stimulate the knee) 3 cells and promote endogenous insulin secretion Force The timing and amount of insulin secretion are determined by the administration timing and dose of the drug, regardless of the blood glucose level. This often results in hypoglycemia as a side effect due to the prolonged action of the drug. In addition, digestive symptoms such as anorexia appear. Contraindicated in patients with severe ketosis or liver or dysfunction.

The biguanide drugs do not have i) three-cell stimulation, and do not cause hypoglycemia in healthy individuals and diabetic patients when administered alone. Possible mechanisms of action include increased sugar utilization by anaerobic glycolysis, suppression of gluconeogenesis, and suppression of intestinal absorption of sugar. As a side effect, relatively severe lactic acidosis is likely to occur.

Drugs that improve insulin resistance include thiazolidine derivatives, but thiazolidine derivative compounds have no insulin secretion-promoting action, have an increased insulin action, activate insulin receptor kinase, and take up glucose in peripheral tissues. It has a stimulatory effect and an improvement in the state of increased hepatic glucose production, but it is known that gastrointestinal symptoms and edema occur as side effects, and a decrease in red blood cell count, hematocrit, hemoglobin, and an increase in LDH .

α-Darcosidase inhibitors delay the digestion and absorption of carbohydrates in the gastrointestinal tract and suppress the postprandial rise in blood sugar, but have side effects such as bloating, wheezing, and diarrhea. 521-522, see JOSL IN 'SDI ABETES ME LLI TUS 13 Th Edition.

Thus, the use of these drugs has been limited due to the occurrence of some side effects and the ineffective patients, and a hypoglycemic drug with a new mechanism of action has been desired.

In recent years, it has been known that NIDDM patients have an increased amount of glucose released from the liver during fasting compared to healthy subjects. This suggests that hepatic sugar release may be a potential target for drug treatment of NI DDM.

The source of sugar in the release of sugar from the liver is glucose produced by gluconeogenesis and glycogenolysis. In diabetic patients, it was reported that glycogenolysis was significantly involved in the release of glucose from the liver, and that the rate of fasting glycogenolysis was 75% higher than in healthy subjects. In NI DDM patients, glucose output from the liver transiently increased after glucose loading, suggesting that dalicogen degradation is involved in this increase. In addition, glycogen disease type IV (liver glycogen phosphorylase deficiency) is also known to cause fasting hypoglycemia. These reports suggest that glycogenolysis plays an important role in hepatic sugar release.

On the other hand, this glycogenolysis is catalyzed by HLGPa, and by perphosphorylating glycogen (n glucose units), glucose monomonophosphate (G 1-P) and glycogen (EL—one glucose Unit) is known.

Therefore, the development of a new mechanism for the treatment of diabetes having a new mechanism of inhibiting HLGPa, which is greatly involved in glycogenolysis, has been promoted. However, at present, no satisfactory activities have been found.

By the way, the following compounds are known as compounds having a structure similar to the present invention.

For example, it is disclosed that the following compounds are useful as pest control agents.

The patent document does not disclose a fused-ring pyrrole compound as in the present patent application, and has completely different uses (see, for example, JP-A-5-39253).

Further, the following dihydrhydrazine compounds having a structure similar to that of the present invention are disclosed.

However, there is no disclosure in the literature that the fused-ring pyrrole compound as described in the present application has HLGPa inhibitory activity or that the compound is effective for the treatment of diabetes (eg, tetrahedron letter (Te trahedron letter). Letter) (1972), vol. 23, p. 2333—2335).

However, the literature does not disclose that the fused ring pyrrole compound as described in the present application has an HLGPa inhibitory activity. There is no disclosure that the compound is effective as an antidiabetic agent (for example, Ya oxue Xuebao (1984) , 19 (10), 737-7). On the other hand, the following general formula is disclosed as a compound having a darikogen phosphorylase inhibitory activity having the same action as that of the present invention.

(Where R ₄ is a phenylalkyl group, etc., R ₅ is a hydrogen atom, etc., R ₆ is an alkoxy group, R ₂ is a hydrogen atom, R _10s R _w are independently a hydrogen atom, a halogen atom, etc. , R ₃ is a hydrogen atom, etc., A is —N = etc.). Further, the following compounds are disclosed as specific compounds.

However, the structural feature of the invention is an indole hydrazine structure, which is different from the structure having a condensed pyrrole ring and diacyl hydrazine as in our invention. Also there is no disclosure of a compound having the structure as of our invention (e.g., Kokusaioyake Hirakidai 96Z39384 No. Panfuretsuto (Kohyo 10 51 1687 JP) see) ₀

In addition, the following general formula is disclosed as a compound having the same action (glycogen phosphorylase inhibitory activity) as the present invention and having the structure of diacylhydrazine. Is <

And R ⁷ is

(Where X is = 0, A is a single bond, B is an optionally substituted aryl group, etc.)

Further, the following compounds are disclosed as specific compounds.

The invention is characterized by having a dihydryl hydrazine structure and requiring an indole structure. On the other hand, the present application is characterized in that a condensed pyrrole ring is indispensable in addition to the dihydryl hydrazine structure, and the two are different (for example, see WO 03/37864 pamphlet).

Furthermore, the following general formula is disclosed as a compound having the same action (glycogen phosphorylase inhibitory activity) as the present invention and having a condensed pyrrole ring structure.

(here,

One X—Y—Z—is —S— CR ⁴ = CR ⁵ —, — CR ⁴ = CR ⁵ — S—, one O— C R4

N One, one NR ⁶ — CR ⁴ = CR ⁵ — oh — CR ⁴ = CR ⁵ — NR ⁶ — where R ⁴ and R ⁵ are independently hydrogen, halo, nitro, cyano, human Doroki death, Furuoromechiru, Jifuruoromechiru, triflate Ruo Russia methyl, Torifuruorome butoxy, Amino, force / Repokishi, mosquito ^^ Pamoiru, main mercaptopurine, vinegar ^ "Famoinore, © Ray de, ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, Ji ₆ alkoxy, - 6 Arukanoiru, C i-6 alk Noi Ruo alkoxy, N-- 6 alkyl Le) amino, N, N-- 6 alkyl) ₂ amino, ₆ alk Noi Rua amino -. N -— 6 alkyl) Carpamoyl, N, N — (Ci- ₆ alkyl) ₂ carpamoyl, Ci — ₆ alkyl S (O) _a (where a is 0-2), Ci — ₆ alkoxycarpo- Le, Ji ₆ alkoxycarbonyl § Mino, N_ (C - ₆ alkyl .) S Rufamoiru, N, N-(C Preparative ₆ Anorekiru) ₂ sulphamoyl, _alkyl Suruhoniruamino Contact Yopi ^ - ₆ alkyl sulfonyl Lou N-(C i_ ₆ alkyl) is selected from § amino;

R ⁶ is hydrogen or Ci_ ₆ alkyl;

R ¹ is hydrogen, halo, nitro, Shiano, human Dorokishi, Amino, carboxy, Cal Pamoiru, mercapto, sulfamoyl, ureido, C ₆ alkyl, C ₂ - ₆ § alkenyl, C ₂ - ₆ alkynyl, C丄_ ₆ alkoxy , CI- ₆ Arukanoiru, C _ ₆ alkanoyloxymethyl Noi Ruo alkoxy, N- (C ₆ alkyl) amino, N, N-! (C - 6 alkyl le) ₂ amino, C ^ ₆ alkanoyloxy Noi Rua amino, N-(C — ₆ alkyl) carpamoyl, N, N— (Ο ^ ₄ alkyl) ₂ carpamoyl. ₆ alkyl S (O) _a (In here, a is a 0 to 2), C ₆ alkoxycarbonyl, C i_ ₆ alkoxy force Ruponiruamino, N-- 6 alkyl) sulphamoyl, N, N- (C ^ ₆ § alkyl) ₂ sulphamoyl, C i_ ₆ alkylsulfonyl § amino and C i_ ₆ Al Kirusuruho two Lou N-(C - ₆ alkyl) amino, C ₃ _ ₈ cycloalkyl, C ₃ - ₈ Shikuroarukiru Ji ₁ - ₆ Arukiru, Ariru, Aryl — ₆ alkyl, heterocyclic group (heterocyclic group) C — selected from ₆ alkyl; where: ¹ is substituted on carbon by one or more groups selected from P Often, when the heterocyclic group contains one NH— moiety, the nitrogen may be substituted by a group selected from R; R ² is hydrogen, halo, nitro, cyano, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, amino, carboxy, carpamoyl, mercapto, sulfamoyl, ureido, Ci- ₆ alkyl, C ₂

- ₆ alkenyl, C ₂ - ₆ alkynyl, - 6 alkoxy, CI- ₆ Arukanoiru, C DOO ₆ alkanoyloxy Noi Ruo carboxymethyl, N-(C - ₆ alkyl) Amino, N, N-(. Bok ₆ § alkyl) ₂ Amino ,. Bok ₆ Arca Noi Rua amino, N- (CI- _C6 alkyl) Scarpa carbamoyl, N, N- (Bok ₄ alkyl) ₂ power Rubamoiru, N- (Ji ₆ alkyl) - N-(CI- ₆ alkoxy) Karupamoiru, Ci — _6- alkyl S (O) _a (where a is from 0 to 2), ₆ alkoxycarbonyl, C ₆ alkoxylamine, N— (C ^ _6- anolekyi) sulfamoyl, N, N— — 6 alkyl Le) ₂ sulphamoyl, sulfamoyl § amino, N-(C - ₆ alkyl) Sulf Amoiruamino, N, N-(C - ₆ alkyl) ₂ sulfamoyl § amino, - ₆ alkylsulfonyl § amino, C i_ ₆ alkylsulfonyl § amino carbo - Le one ₆ alkylsulfonyl Interview Lou N-- is selected from 6-alkyl) amino and _E- F- G- H;

(Here, E and G are independently a direct bond, One O-, one _{S-, -SO-, - S0 2 -} , -OC (O) primary, one C (O) O-, one C (O) —, — NR ^a —, one N aC (O) —, -C (O) NR ^a —, one S0 ₂ NR ^a —, one NR ^a SO ₂ —, one NR ^a C (O) one, one ^{OC (O) NR a -,} -NR a C (O) O-, one ^{_{^{NR a SO 2 NR b -,}}} -SO 2 NR a C (O) - and single ^{_{C (O) NR a S0 2}} - from Wherein R ^a and R ^b are independently selected from hydrogen or alkyl optionally substituted by group V;

F is C- ₆ alkylene or a direct bond optionally substituted by one or more Q;

H is Ariru, is selected from C ₃ _ ₈ cycloalkyl Contact Yopi heterocyclic group;. Wherein H may be optionally substituted on carbon by one or more selected from S said heterocyclic group If it contains one NH— moiety, the nitrogen atom may be substituted by a group selected from T;

R ³ is hydrogen or Ci- ₆ alkyl; n is selected from 0-4; wherein the values of R ¹ may be the same or different; and the values of R ³ may be the same or different;

P, S and Q are independently halo, nitro, Shiano, human Dorokishi, Torifuruo Romechiru, Torifuruorome butoxy, Amino, carboxy, Karupamoiru, Melka script, sulfamoyl, ureido, Ji ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, - ₆ alkoxy, C i _ ₆ Arukanoiru, ₆ Arukanoiruoki Shi, N-(C - ₆ alkyl) Amino, N, N- (C ^ ₆ alkyl) ₂ Amino,. C — ₆ alkanoylamino, N— (C ^ e alkyl) carpamoyl, N, N— (C ₁

— ₄ alkyl) ₂ Carpamoyl, N— (C— ₆ alkyl) — N— — 6 alkoxy) Carpamoyl,. _6- alkyl S (O) _a (where a is from 0 to 2), C — 6 alkoxycarbonyl, — 6 alkoxycarbonylamino, N— (C — ₆ alkyl) sulfamoyl, N, N — ( ! C Bok ₆ alkyl) ₂ sulphamoyl, C 6 alkylsulfamoyl § amino, C ₆ alkylsulfonyl one N-(C _ ₆ alkyl) amino, c ₃ _ ₈ cycloalkyl, is selected Ariru and to the heterocyclic group; Here, P, S and Q may be independently substituted on carbon by one or more selected from V, and when the heterocycle contains one NH— moiety, a nitrogen atom May be substituted by a group selected from U;

V is halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carpamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino —Methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-getylcarpamoyl, N-methyl-1-N-ethyl / recarpamoiole, Metinorecio, Echirechio, Methyl / Less / Refinil, Echinoles Luffiel, Mesyl, Echinoresulfur, Methoxycarbonyl, Ethoxycanoleponyl, N-Methylsulfamoyl, N-Ethylsulfamoyl, N, N— Methylcarbamoyl Rusurufamoiru, N, N- GETS chill sulfamoyl, N- methyl-N- Echiru sulfamoyl, morpholino, morpholino force Ruponiru, selected from N- benzyl Scarpa Moi Le and 4-hydroxycarboxylic piperidinocarbonyl; R, T and U are independently — 4 alkyl, ₄ alkanoyl,. § alkylsulfonyl, C丄- ₄ alkoxy force Ruponiru, Karupamoiru, N- (! C _ ₄ alkyl) Karupamoiru, N, N-(Ji ₄ alkyl) Karupamoiru, phenyl, benzyl, benzyl O propoxycarbonyl Interview le, Benzoiru Oyo Diphenyls / levonyl, wherein R, T and U may be independently substituted on carbon by one or more groups selected from V;

However, when i) — X— Y— Z— is one S— CH—CH—, R ² _ (CR ^ ³ ) n— is amino, 1-phenyl-1-5-methyl-1 H—1,5 —Venzodiazepine-1,4 (3H, 5H) dione-3-yl, 1-methyl-5-phenyl-2, oxo-1,2,3-dihydro-1H—Venzo (E) ( 1,4) diazepine-1 3-yl, 2- (4-phenyl-1,2,5,6-tetrahydropyridine 1-11) ethinole, 3— (4-phenyleno 1,2,5) , 6-tetrahydropyri'zin-1-yl) propyl, 2- (4-furpiperazine-1-11) ethyl, 2- (N-methylamino) ethyl, 2-morpholinoethyl or 2- (N —Methyl-N-benzylamino) not ethyl;

ii) When _X— Y—Z— is one CH = CH— S—, R ² — (CR ^ ³ ) n one is amino or 1-methyl-5-phenyl-12-oxo-1,2,3-dihydro 1 H—Venzo (E) (1, 4) Not diazepine-3-yl;

iii) when one X—Y—Z— is one CH = C (SO ₂ NH ₂ ) —S—, then R ² — (CRiR ³ ) _n — is not methyl or isoptyl; and

iv) one X—Y—Z—is defined as in the beginning, n is 1 and R ¹ is arylmethyl, substituted arylmethyl, (heterocyclic group) methyl and substituted (heterocyclic group) methyl, And when R ³ is hydrogen, R ² is a group (C = 0) — A or a group CH (OH) — C (= 0) —A (where A is NR ^d R ^d , one NR ^a CH ₂ CH ₂ OR ^{a or}

(Wherein each R ^a Oyopi scale ¹⁵ are independently hydrogen or a C - Ri Cs alkyl der; each R ^d is independently hydrogen, CI- C ₈ alkyl, CI- Cs alkoxy, § Each R ^c is independently hydrogen, one C (= O) OR ^a , one OR ^a , one SR ^a , -NR ^a ; each n Are independent:! ~ 3, and

X ¹ is not NR ^a , _CH ₂ —, O or S). )

Further, the following compounds are disclosed as specific compounds.

The feature of the present invention lies in that it has a fused pyrrole ring and has an amide structure as shown in the title of the present invention.

During該明Saisho, in particular, ^1, R ² and are mentioned a number of exemplified as the substituents of R ^3, among them, a hydrogen atom as R ^1, and one E- F- G_H (E as R ² In addition, one NR ^a C (O) is disclosed), and a hydrogen atom is certainly disclosed as R ³ . However, there is no disclosure of specific examples of the compound having a diacylhydrazine structure as in the invention of the present application, and further no disclosure of a production method suggesting this. There is no specific disclosure or suggestion of selecting RR ² and R ³ to have a structure similar to the present invention among many substituents (for example, WO 02/20530). No. paflet).

At present, the development of a therapeutic agent for diabetes by inhibiting HLGPa is underway, but its activity has not yet been satisfactory. In addition, oral absorption and metabolic stability were not yet satisfactory.

Therefore, there has been a strong demand for the development of HLGPa inhibitors that are more active, have no side effects, and are more excellent in oral absorbability and metabolic stability than conventional diabetes therapeutics.

Therefore, an object of the present invention is to provide an HLGPa inhibitor which is more active, has no side effects, and is excellent in oral absorption and metabolic stability as compared with conventional drugs for treating diabetes. It is to be.

Disclosure of the invention

The present invention has been made in view of the above problems, and as a result of intensive studies to search for a therapeutic agent for diabetes having a useful HLGPa inhibitory activity, surprisingly, They have found that they have HLGPa inhibitory activity, and have completed the present invention.

More specifically, it is as shown in [1] to [2 2] below.

[1] General formula (1)

(In the formula,

R ¹ is a hydrogen atom or an acyl group;

R ² is a hydrogen atom or an alkyl group;

R ³ is a hydrogen atom or a C—e alkyl group;

One G “G ₂ -G ₃ — is one S-C (R ⁵ ) = C (R ⁶ ) one, — C (R ⁵ ) = C (R ⁶ ) — S—, one O — C (R ⁵ ) = C ( ⁶ ) one, -C (R ⁵ ) = C (R ⁶ ) one 0-one N (R ⁷ ) -C (R ⁵ ) = C (R ⁶ ) one, one C (R ⁵ ) = C (R ⁶ ) one N (R ⁷ ) one, one N = C (R ⁵ ) — S— or one S— C (R ⁵ ) = N— (where R ^s and ぴ R ⁶ are Same or different and independently represents a hydrogen atom, a halogen atom, a C ₆ -alkyl group, a Ci- ₆ alkoxy group, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, an aralkyloxy group or a thiazolyl group ( The thiazolyl group may be substituted by —6 alkyl group or amino group), and R ⁷ is a hydrogen atom or an acyl group);

R ⁴ is

{Where = X is = 0, = S or -NH;

A is one N (R ⁸ )-(where R ⁸ is a hydrogen atom, a Ci-e alkyl group or an aryl group which may have a substituent), one C (R ⁹ ) (R ¹⁰ (Where R ⁹ and R ¹⁰ are the same or different and are independently a hydrogen atom, a hydroxyl group, an amino group,

6 alkyl group, C - ₆ hydroxyalkyl group, C ₂ - ₇ alkoxycarbonyl amino or a group or Ashiruamino group, or R ⁹及Pi R ^{1 ()} such together with the carbon atom to which the adjacent connexion, C ₃ - ₇ (which may form a cycloalkyl group), — (CH ₂ ) _m —NH— (where m is an integer of 1 to 4), one CO— or a single bond;

B is

d

(Where I ¹¹ , R ¹² , ¹³ , R ¹⁴ and R ¹⁵ are the same or different and independently represent a hydrogen atom, a halogen atom, an alkyl group, a C- ₆ alkoxy group, a nitro group, a hydroxyl group, A cyano group, a haloalkyl group, an aralkyl group, an aryl group which may have a substituent, an aryloxy group, a tetrazolyl group, a triazolyl group,

H ₂ ) _p -CO-R ¹⁹ (where p is 0 or an integer of 1 to 4, and R ¹⁹ is an aryl group which may have a substituent, a hydroxyl group, a C- ₆ alkoxy group or -N (R ²⁰ )

(R ²¹ ) (where R ²⁰ and R ²¹ are the same or different and are each independently a hydrogen atom,

C E - ₆ alkyl group, Ararukiru group or C ₃ - i ₃ alkoxycarbonylalkyl group Or: ^{2 G} and R ²¹ together with the adjacent nitrogen atom,

(Where, q is an integer from 1 to 3, R ²² is a hydrogen atom, a hydroxyl group, C - 6 alkoxy group, an amino group, at C ₂ _ ₁₂ dialkylamino group or a C ₂ _ ₇ alkoxycarbonyl two Ruamino group ), -O- (CH ₂ ) _r -R ²³ (where r is an integer of 1 to 4, R ²³ is a hydroxyl group, an amino group, a C ₂ _ ₇ Alkyl group Ruponioxy group or one CO—R ²⁴ (where R ²⁴ is a hydroxyl group, —6 alkoxy group or one N (R ²⁵ ) ( ²⁶ ) (where R ²⁵ and R ²⁶ are the same or different Or a hydrogen atom, an alkyl group or an aralkyl group, or R ²⁵ and R ²⁶ together with an adjacent nitrogen atom

(Where q, and R ²² ′ may be synonymous with q and R ²² ), respectively)), -O-CO-R ²⁷ (where R ²⁷ is - 6 Arukirua an amino group or a C ₂ one ₁₂ dialkylamino group), or one ^{^{N (R 28) (R 29}} ) ( in here, R ²⁸及Pi R ²⁹ are the same or different, a hydrogen atom, C -6 alkyl group, aryl group which may have a substituent, acyl group, (CH ₂ ) _p , — COO— R ³

⁰ (where p and p have the same meanings as p, and R ³ ° is a hydrogen atom, a substituted or unsubstituted aryl group or —6 alkyl group (the ₆ alkyl group is a hydroxyl group, a trifluoromethyl group, Which may be substituted with an aryl group, a morpholino group or a carboxyl group which may have a substituent)) CON (R ³¹ ) (R ³² ) (where R

³¹ and R ³² are the same or different, a hydrogen atom, CI_ ₆ have an alkyl group or a substituted group is also good Ariru group), -CO-R ³³ (wherein, R ³³ is. ₆ § alkyl Or an aryl group which may have a substituent) or one CO— (CH

₂₎ _r> -R ³⁴ (where, r, have the same meanings as r, R ³⁴ Haji ₆ alkylamino group, C ₂ - ₁₂ dialkylamino group, CI_ ₆ alkoxy group or C ₂ - ₇ alkyl Cal A bonyloxy group)),

1 ^ ¹⁶¹³ to 1 ^ ¹⁶⁶ and 1 ¹⁷¹⁵ to 1 ^ ¹⁷⁸ are the same or different and are each a hydrogen atom, a halogen atom, an alkyl group, an amino group, a hydroxyl group, a —6 alkoxy group, a COOR ³⁵ (here, R ³⁵ They are the same or different, a hydrogen atom or a - 6 alkyl group der Ru) or single ^{CON (R 31 ') (R} 32') ( wherein, R ³¹ 'and R ^32' are R ³¹及Pi R ³ ² Is synonymous with)

Y is one S-, one O- or one N (R ³⁶⁾ i (wherein, R ³⁶ is a hydrogen atom or a 0 E one ₆ alkyl group (the - ₆ alkyl group, substitution at the carboxyl group or tetrazolyl group May be))

n is 0 or an integer from 1 to 4), or

R ³ and R ⁴ together with the adjacent nitrogen atom

(i) (ϋ) ()

Or

(iv) (v)

{Wherein, R ³⁷及Pi R ³⁸ are the same or different, a hydrogen atom, a halogen atom, C丄_ ₆ alkyl group, - ₆ alkoxy group, an amino group, a nitro group, a hydroxyl group, C ₂ - ₇ § alkoxy Karuboeru group, carboxyl group, C ₂ - ₇ haloalkylcarbonyl § amino group or one O- CO-:. ⁴² (wherein, R ⁴² is, CI- ₆ alkyl group, DOO ₆ alkyl Ruamino group or 0 ₂ - ₁₂ dialkyl An amino group);

Z is — CH ₂ — CH ₂ —, — C (R ⁴³ ) = CH—, — C (R ⁴³ ') = N—, one N

= N—, one CO—, one CO—CH ₂ —, one CO—O—, one CO—CH ₂ — O—,

— CH ₂ — CO— NH—, one C (R ⁴³ ") (R ⁴⁴ ) — N (R ⁴⁵ ) one (where: ⁴ 3, R ⁴³ \ R ⁴³ '' and R ⁴⁴ are the same or different and are each a hydrogen atom, a C- ₆ alkyl group or an aryl group which may have a substituent, and R ⁴⁵ is a hydrogen atom, - ₆ alkyl group (said C _ ₆ Arukiru groups force Rupokishiru group or a C ₂ may be substituted with _ ₇ alkoxy force Ruponiru group) or C ₂ _ ₇ alkoxycarbonyl Interview le group), one C (= U ) — N (R ⁴⁸ ) — (where = U is = 0 or = S, and R ⁴⁸ is synonymous with R ⁴⁵ ) or one (CH ₂ ) s—O— (where s is 1 A methylene group may be substituted with an oxo group) (provided that each group is described on the left end with an atom adjacent to a nitrogen atom on the condensed ring of the formula (i));

R ³⁹ is a hydrogen atom, an aryl group which may have a substituent or a heterocyclic group;

R ^4.及Pi R ⁴¹ are the same or different, a hydrogen atom, CI- ₆ alkyl group, CI- ₆ § alkoxy group or a C ₂ - ₇ alkoxycarbonyl - or a group, or R ⁴ °及Pi R ⁴ ¹ is Together with adjacent carbon atoms,

(Where the bonding position is not particularly limited);

Q is one (CH ₂ ) t— (where t is 2 or 3 and the methylene group may be substituted with an oxo group), one CO—NH—CH ₂ — or one CH ₂ — NH— CO—

W is one CO—, one CS— or one CH ₂ —;

V is one CO—, one CS— or one CH ₂ —;

V ₂ is one O—, one CH ₂ — or one N (R ⁴⁶ ) — (where R ⁴⁶ is a hydrogen atom, a C i-6 alkyl group or an optionally substituted aryl group) ) Is;

V ₃ is one CH (R ⁴⁷ ) one or one N (R ⁴⁷ ′) one (where R ⁴⁷ and R ⁴⁷ ′ are A hydrogen atom, an aralkyl group, a heterocyclic group, or an aryl group which may have a substituent), or a condensed pyrrole compound represented by the formula: Pharmaceutically acceptable salts.

[2] Y is 1 S—, 1 O— or 1 N (R ³⁶ ) 1 (where R ³⁶ is a hydrogen atom or —6 alkyl group);

Z is one CH ₂ — CH ₂ —, -C (R ⁴³ ) = CH—, one C (R ⁴³ ') = N—, — N = N—, one CO—, one CO— O—, one CO — CH ₂ — O—, one CH ₂ — CO—NH one, one C (R ⁴³ ") (R ⁴⁴ ) one N (R ⁴⁵ )-(where R ⁴³ , R ⁴³ ', R ⁴³ " and R ⁴⁴ is the same or different and is a hydrogen atom, a Ci-e alkyl group or an aryl group which may have a substituent, and R ⁴⁵ is a hydrogen atom, a C- ₆ alkyl group (the C i _ ₆ Arukiru group a carboxyl group or a C ₂ - a ₇ alkoxycarbonyl group), one C (= U) - - ₇ may be substituted by alkoxy force Ruponiru group) or a C ₂ N (R ⁴⁸⁾ i (where , = U is = 0 or = S, and R ⁴⁸ is synonymous with R ⁴⁵ ) or one (CH ₂ ) s -O- (where s is an integer of 1 to 3, and a methylene group is Which may be substituted with a oxo group)

1 ⁴ °及Pi 1 ⁴¹ are the same or different, a hydrogen atom, an alkyl group, - 6 carbon § alkoxy or a group or a C ₂ _ ₇ alkoxycarbonyl group, or R ⁴ °及Pi R ⁴ ¹ is adjacent Connecting with the atoms,

The condensed pyrrole compound according to the above [1], which may form ^N or, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[3] The condensed pyrrole compound according to the above [1] or [2], wherein R ¹ and R ² are hydrogen atoms, a prodrug thereof or a pharmaceutically acceptable salt thereof.

[4] R ⁴ is

{Where X is synonymous with [1] above;

A shows an N (R ⁸ ") - (wherein, R ⁸ '' is a hydrogen atom, an alkyl group or an optionally substituted Ariru ^{group), -C (9") (} R 10 ") One (where R ⁹ ′ ′ and R ^{1 ()} ″ are the same or different and are independently a hydrogen atom, a hydroxyl group, an amino group, a Ci- ₆ alkyl group, a hydroxyalkyl group or a C ₂ — ₇ alkoxycarbonyl two Ruamino a group force or R ⁹ ''及Pi R ¹⁰ "is a together with the adjacent carbon atoms connexion,, C ₃ - ₇ may form a cycloalkyl group), - (CH ₂₎ _m — NH— (where m is as defined in the above [1]), one CO— or a single bond;

B is

(f2 ') (g,)

^{^{(Where, 11 ', R 12',}} R 13 ', R 14'及Pi R ¹⁵ 'are the same or different, and independent, hydrogen atom, halogen atom, C - ₆ alkyl group, Ci-s Alkoxy group, two Toro, hydroxyl, cyano, haloalkyl, aralkyl, optionally substituted aryl, aryloxy, tetrazolyl, triazolyl,

(CH ₂ ) _p -CO-R ¹⁹ (where p and R ¹⁹ are as defined in the above [1]) O— (CH ₂ ) _r -R ²³ (where r and R ²³ are the same as the above [1] 1]), -O-CO-R ²⁷ (where R ²⁷ is the same as the above [1]) or one N (R ² ⁸ ") (R ²⁹ ") (where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom,

₆ alkyl groups, aryl groups which may have a substituent, — (CH ₂ ) _p , —CO—R ³ . "(Where i>, is synonymous with p and R ^3. " Is a hydrogen atom or a —6 alkyl group (the d- ₆ alkyl group is substituted with a hydroxyl group, a trifluoromethyl group or a carboxyl group. also may) be), one ^{^{CON (R 31) (R 32}} ) ( wherein, R ³ ¹ and R ³² are as defined in the above [1]), -CO-R 33 ( wherein, R ³³ is the same as the above [1]) or one CO— (CH ₂ ) _r> ^-34 (where r and R ³⁴ are the same as the above [1]);

! ^^ ~! ^ Okay! ^ ~! ^ Is synonymous with [1] above,

Y, is one S— or one N (R ³⁶ ) one (where R ³⁶ is the same as the above [1]), and Ν <

η is the same as in [1] above)

R ³ and R ⁴ together with the adjacent nitrogen atom

(ί ') (ϋ') (iii ')

1 又は or 0 Η

(iV) (V) (νί ')

Wherein R ^37> and R ³⁸ ′ are the same or different and are a hydrogen atom, a halogen atom, — A _6- alkyl group, a _6- alkoxy group, an amino group, a hydroxyl group or —O—CO—R ⁴² (where R ⁴² is as defined in the above [1]);

Z, is one CH ₂ — CH ₂ —, -C (R ⁴³ ) = CH—, one N = N—, one CO—,

— CO— CH ₂ —, one CO— O—, —CO-CH—O CH. One CO—NH

-, -C (R ⁴³ ") (R ⁴⁴ ) -N (R ⁴⁵ *)-(where R ⁴³ , R ⁴³ " and R ⁴⁴ are as defined in the above [1], and R ⁴⁵ 'is a le group), one C (= U) - - hydrogen atom, _alkyl group or C ₂ one ₇ alkoxy force Lupo N (R ⁴⁸ ') one (here, = U is = 0 or = S, R ⁴⁸ ′ has the same meaning as R ⁴⁸ ) or 1 (CH ₂ ) s — O 1 (wherein s is an integer of 1 to 3, and the methylene group may be substituted with an oxo group) ;

R ³⁹ ′ is a hydrogen atom or an aryl group which may have a substituent;

R ^4G '及Pi R ^41' are the same or different, a hydrogen atom, CI- ₆ alkyl group or a C ₂ one ₇ alkoxy or a carbonyl group, or together with the carbon atom to及Pi R ⁴¹ 'is adjacent Natsu,

May form;

Q ′ is one (CH ₂ ) t-(where t is 2 or 3 and the methylene group may be substituted with an oxo group), one CO—NH—CH ₂ — or one CH ₂ — NH — CO— is;

W is one CO— or one CH ₂ —;

V _x 'and V _2, have the same meanings as and V ₂ of the above-mentioned [1];

V ₃ , is one CH (R ⁴⁷ ") one or one N (R ⁴⁷ "')-(where R ⁴⁷ "and R ⁴

⁷ '"is the same or different and is a hydrogen atom or an aryl group which may have a substituent. The condensed pyrrole compound according to the above [3], a prodrug thereof, or a pharmaceutically acceptable salt thereof, which may form a).

[5] Y, but one S- or one N (R ³⁶⁾ i (wherein, R ³⁶ is a hydrogen atom or a. Interview an _alkyl group),

Z,, one CH ₂ — CH ₂ —, -C (R ⁴³ ) = CH—, one N = N—, one CO—, one CO—O—, one CO—CH ₂ —O—, one CH ₂ — CO—NH—, one C (R ⁴³ ") (R ⁴⁴ ) one N (R ⁴⁵ ')-(where R ⁴³ , R ⁴³ " and R ⁴⁴ are as defined in the above [1], and R ⁴⁵ 'is a hydrogen atom, _alkyl group or C ₂ - ₇ is alkoxycarbonyl group), one C (= U) - N ( R 48') - ( wherein, = U is = O or = S- There, R ⁴⁸ 'has the same meaning as R ⁴⁸⁾ or one (CH ₂₎ s- O- (wherein, s is 1-3 integer, a methylene group may be substituted with Okiso group) And R ⁴ . 'And R ^41' force the same or different, a hydrogen atom, a CI- ₆ alkyl or C ₂ _ ₇ alkoxycarbonyl group, or R ^4. 'And R ⁴¹ ' together with the adjacent carbon atom,

, Or

The condensed pyrrole compound according to the above [4], a prodrug thereof or a pharmaceutically acceptable salt thereof.

[6] The above where one — G ₂ — G ₃ — is one S — C (R ⁵ ) = C (R ⁶ ) —

The fused pyrrole compound according to any one of [1] to [5], a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[73 — Gi— G ₂ — G ₃ — is one C (R ⁵ ) = C (R ⁶ ) one S—

[8] — Gi— G ₂ — G ₃ — where O—C ( ⁵ ) = C (R ⁶ ) —

The fused pyrrole compound according to any one of [1] to [5], a prodrug thereof, or a pharmaceutically acceptable salt thereof. [9] The above where one Gi— G ₂ — G ₃ — is one C (R ⁵ ) = C (R ⁶ ) —O—

The fused pyrrole compound according to any one of [I] to [5], a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[10] — Gi— G ₂ — G ₃ — is one N (R ⁷ ) -C (R ⁵ ) = C (R ⁶ ) one The condensation according to any one of the above [1] to [5] Pyrrole compounds, prodrugs thereof or pharmaceutically acceptable salts thereof.

[II] The fused pyrrole according to any one of the above [1] to [5], wherein one —G ₂ —G ₃ — is one C (R ⁶ ) = C (R ⁶ ) —N (R ⁷ ) A compound, a prodrug thereof or a pharmaceutically acceptable salt thereof.

[1 2] The fused pyrrole compound according to any one of the above [1] to [5], wherein one G — G ₂ — G ₃ — is one N = C (R ⁵ ) one S—, a prodrug thereof or Their pharmaceutically acceptable salts.

[1 3] — The fused pyrrole compound according to any one of the above [1] to [5], wherein Gi—G ₂ —G ₃ — is one S—C ( ⁵ ) = N—, a prodrug thereof, or a prodrug thereof A pharmaceutically acceptable salt of

[14] A medicament comprising the condensed pyrrole compound according to any of [1] to [13], a prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Composition.

[15] The condensed pyrrole compound according to any one of the above [1] to [13], a prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. HLGP a inhibitor.

[16] The condensed pyrrole compound according to any one of the above [1] to [13], a prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Diabetes remedy.

[17] The pharmaceutical composition of the above-mentioned [14], which is used in combination with a therapeutic agent for hyperlipidemia.

[18] The pharmaceutical composition of the above-mentioned [17], wherein the therapeutic drug for hyperlipidemia is a statin drug.

[1 9] The statin drug is selected from the group consisting of oral pastatin, simpastatin, pravastatin, flupastatin, atorpastatin and seripastatin The pharmaceutical composition according to the above [18].

[20] The pharmaceutical composition of the above-mentioned [14] for use in combination with a therapeutic agent for diabetes.

[21] The above-mentioned [20], wherein the antidiabetic drug is selected from the group consisting of an insulin preparation, a sulfururea drug, an insulin secretagogue, a sulfonamide drug, a biguanide drug, an _α- dalcosidase inhibitor and an insulin sensitizer. Pharmaceutical composition.

[2 2] The antidiabetic agent is insulin, dalibenclamide, tolptamide, daliclopyramide, acethexamide, glimepiride, tolazamide, daliclazide, nateglinide, gribuzole, metformin hydrochloride, pformin hydrochloride, poglipoise, acapulose hydrochloride and pioglitazone hydrochloride. [20] The pharmaceutical composition according to the above [20], which is selected from the group consisting of:

DETAILED DESCRIPTION OF THE INVENTION

The definition of each substituent used in this specification is as follows.

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

"Alkyl group" means an alkyl group having 1 to 6 carbon atoms which may be linear or branched, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group or hexyl group, etc., preferably having 1 to 4 carbon atoms, which may be linear or branched It is an alkyl group.

The fC-ealkyl group in R ³⁰ and R ³⁰ ″ is substituted with a hydroxyl group, a trifluoromethyl group, an aryl group which may have a substituent (synonymous with the “aryl group” below), a morpholino group or a carboxyl group The substitution position is not particularly limited as long as it can be substituted. The number of substituents is not particularly limited. Hydroxyl, triflate Ruoromechiru group which may have a substituent Ariru group, the C i _ ₆ alkyl group substituted by a morpholino group or Cal Bokishiru group, such as 2-hydroxyethyl E butyl group, 3-hydroxypropyl Group, 4-hydroxybutyl, 2,3-dihydroxypropyl; 2-hydroxypropyl or 2,2-dicarboxypropyl; 2,2,2-trifluoroethyl; benzyl; And a morpholinomethyl group. R ³ "0 ^ 6 alkyl group" in ^6, a carboxyl group or a tetrazolyl group

(As defined below), and the substitution position is not particularly limited as long as substitution is possible. The number of substituents is not particularly limited.

In R ^{4 5}及Pi R ^{4 5} '' 0 - ₆ alkyl group "may be substituted with a carboxyl group or a C ₂ _ ₇ alkoxycarbonyl group (hereinafter synonymous), the substitution position is if possible substitution There is no particular limitation. The number of substituents is not particularly limited.

The ". Preparative ₆ alkoxy group" represents a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, for example, main butoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, tert- Putokishi Group, pentyloxy group, tert-pentyloxy group or hexyloxy group, preferably a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms, for example, methoxy group, ethoxy group, isopropoxy group, Butoxy group and tert-butoxy group.

The “C ₂ _ ₇ alkoxycarbonyl group” refers to an alkoxycarbonyl group in which the alkyl moiety has 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) and is linear or branched. , Methoxycarbonyl group, ethoxycarbonyl group, propoxyl-proponyl group, isopropoxycanoleponyl group, butoxycarbonyl group, isopoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexylol A xycarbol group;

“C ₂ _ ₇ alkoxycarbonylamino group” refers to an alkoxycarbonylamino group in which the alkyl portion has 1 to 6 carbon atoms (preferably 1 to 4) and is linear or branched. For example, a methoxycarbonylamino group, an ethoxycarbonylamino group, a propoxycarbonylamino group, an isopropoxycarbonylamino group, a putoxycarbolamino group, an isopoxycarbonylamino group, a tert-butoxycarbonylamino group, pentyl And a carboxycarbonylamino group and a hexoxycarbonylamino group.

“C ₃ _ ₁₃ alkoxycarbylalkyl group” means that both alkyl portions (alkoxy portion and alkyl portion) have 1 to 6 (preferably 1 to 4) carbon atoms, and Represents an alkoxycarbonylalkyl group which is a branched chain, for example, methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl Tyl group, ethoxycarbonylethyl group, propoxycarbonylmethyl group, isopropoxycarbonyl group, butoxycarbonylmethyl group, isopoxycarbonyl group, tert-butoxy group / leponinolemethinole group, pentinoleoxycanolepol-methyl group And a hexyloxy group.

The - "C ₂ ₇ alkylcarbonyl O alkoxy group", the alkyl portion is 1 to 6 carbon atoms

(Preferably 1 to 4), and represents a linear or branched alkyl alkyl group, for example, a methylcarboxy group, an ethylcarboxy group, a propylcarboxy group. A isopropylcarbonyloxy group, a butylcarbonyloxy group, an isobutylcarbonyl / reoxy group, a tert-butylcarbo-noreoxy group, a pentinorecanoleponinoleoxy group, a hexinolecanoleponyloxy group, and the like.

The - _"6 hydroxyalkyl group", Ri Oh straight-chain or branched-chain alkyl group is substituted with 1 or 2 or more hydroxyl groups group having 1 to 6 carbon atoms (preferably 1-4), The substitution position of the hydroxyl group is not particularly limited. For example, a hydroxymethyl group; 1 or more 2-hydroxyethyl groups; 1-, 2- or 3-hydroxypropyl groups; 1-, 2-, 3- or 4-hydroxybutyl groups; 3-, 4- or 5-hydroxypentynole group; 11, 2-, 3-, 4-, 5- or 6-hydroxyhexynole group; 2-hydroxy-2-methylethyl group; 1,2-dihydroxy And an ethyl group.

The “haloalkyl group” is a group in which a straight-chain or branched-chain alkyl group having 1 to 6 (preferably 1 to 4) carbon atoms is substituted with one or more halogen atoms (as defined above). Yes, the substitution position is not particularly limited. For example, trifluoromethyl group, 1- or 2-chloroethyl group, 1- or 2-bromoethyl group, 1- or 2-fluoroethyl group, 11, 2- or 3-chloropropyl group, 1 1, 2- or 3-promopropyl tomb, 1, 2- or 3-fluoropropyl, 1, 2-, 3- or 4-chlorobutyl, 1, 2-, 3- or 4-promobutyl A 11, 2-, 31- or 4-fluorobutyl group.

The "0 ^ 6 alkylamino group" is an amino group monosubstituted by a linear or branched alkyl group having 1 to 6 (preferably 1 to 4) carbon atoms, for example, methylamino And a phenylamino group, a propylamino group, a butylamino group, a pentylamino group or a hexylamino group.

“C ₂ _ ₁₂ dialkylamino group” refers to an amino group disubstituted with a straight-chain or branched-chain alkyl group having 1 to 6 (preferably 1 to 4) carbon atoms, wherein the alkyl portions are the same. But they may be different. For example, a dimethylamino group, a acetylamino group, a dipropylamino group, a dibutylamino group, a dipentylamino group, a dihexylamino group, and the like.

“. ₃ _ ₇ cycloalkyl group” means a cycloalkyl group having 3 to 7 (preferably 3 to 6) carbon atoms, and specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, And a cyclohexyl group or a cycloheptyl group. Preferred is a cycloalkyl group having 3 to 6 carbon atoms, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

The term "acyl group" refers to an alkylcarbyl group such as an acetyl group, a propioyl group, a petyryl group, a piperyl group or the like (the alkyl moiety preferably has 1 to 6, more preferably 1 to 4 carbon atoms. A carbonyl group such as a benzoyl group or a naphthoyl group (preferably the carbon number of the aryl moiety is 6 to 12, more preferably 6 to 10; Group)).

The “factory aryl group” preferably has 6 to 12 carbon atoms, more preferably 6 to 10 carbon atoms, such as a fuel group and a naphthyl group. The aryl group includes a phenyl group, a haloalkyl group (similar to the above-mentioned “0 ^ 6 haloalkyl group”), a halogen atom (as defined above), an alkyl group (as defined above), and a _6- alkoxy group. (As defined above), a C ₂ _ ₇ alkoxycarbonyl group (as defined above), a thiol group, a cyano group, a carbonyl group, a hydroxyl group, an amino group, an alkylamino group (as defined above), and a dialkylamino group (as defined above) ₁ to 6 identical or different substituents selected from the same as the above-mentioned “0 to ₁₂ dialkylamino group”), and the position of the substituent is arbitrary. There is no restriction. The phenyl group in the above substituents is further substituted at 1 to 6 identical or different substituents selected from the above substituent groups (excluding the phenyl group) at the substitutable position. May be done. The "aryloxy group" preferably has 6 to 12 carbon atoms, more preferably 6 to 10 carbon atoms, and examples thereof include a phenoxy group and a naphthyloxy group. Ariru group in said Ari Ruokishi group, Hue group, a haloalkyl group (the - include those similar to the "^ ₆ haloalkyl group"), a halogen atom (as defined above), a C ^ ₆ alkyl group (the Synonymous), — ₆ alkoxy (as defined above), C ₂ _ ₇ alkoxycarbonyl (as defined above), nitro, cyano, propyloxyl, hydroxyl, amino, amino, ₆ alkylamino ( (As defined above) and di-C i -ealkylamino group (as defined above for “C _{2 —} ₁₂ dialkylamino group”) Force ^ Even if substituted with 1 to 6 selected or different substituents Good. The substitution position is not particularly limited as long as it can be substituted. The phenyl group in the above substituents may be further substituted with 1 to 6 identical or different substituents selected from the above substituent groups (excluding the phenyl group). The substitution position is not particularly limited as long as it can be substituted.

An “aralkyl group” is a straight- or branched-chain alkyl having an aryl moiety of a phenyl group and an alkyl moiety having 1 to 6 (more preferably 1 to 4) carbon atoms. A benzyl group, a phenylpropyl group, a phenylbutyl group or a phenylhexyl group. The phenyl group includes a haloalkyl group (the same as the above-mentioned “ _6- haloalkyl group”), a halogen atom (as defined above), a —6 alkyl group (as defined above).丄§ alkoxy group (as defined above), C ₂ one ₇ alkoxycarbonyl group (as defined above), a nitro port group, Shiano group, a carboxyl group, a hydroxyl group, an amino group, C - ₆ alkylamino group

May be substituted with 1-6 identical or selected from - ( _{"1 2} dialkyl amino group C _2" defined in the above) different substituents (as defined above)及Piji alkylamino group. The substitution position is not particularly limited as long as it can be substituted.

The “aralkyloxy group” is a straight- or branched-chain alkoxy group in which the aryl part is a fuel group and the alkoxy part preferably has 1 to 6 (more preferably 1 to 4) carbon atoms. And is, for example, a benzyloxy group, a phenylpropoxy group, a phenylbutoxy group or a phenylhexyloxy group. Further, the Hue - le group, a haloalkyl group (the - include those similar to the "0 ₆ Haroaru kill group"), a halogen atom (as defined above), Al Kill group (as defined above), an alkoxy group (as defined above), C _{2 7} alkoxy force Ruponiru group (as defined above), a nitro group, Shiano group, forces Rupokishiru group, a hydroxyl group, § amino group, an alkylamino group (the Synonymous with) dialkylamino group

It may be substituted with 1-6 amino 'identical or different substituents selected from (synonymous with the "C ₂ _ _{1 2} dialkylamino group"). The substitution position is not particularly limited as long as it can be substituted.

The “acylamino group” has preferably 2 to 13 carbon atoms, more preferably 2 to 11 carbon atoms, for example, alkylcarbonylamino having 2 to 7 carbon atoms (for example, acetylamino, propionyl Amino, petyrylamino, piperoylamino, etc.).

The "C _{2 7} haloalkylcarbonyl § amino group", haloalkyl portion is the above-mentioned "C

A haloalkynolecanoleponinoleamino group having a preferred number of carbon atoms of 2 to 5, which is synonymous with "6 haloalkyl group".

"Heterocyclic group" is a heterocyclic group having one or more, preferably 1 to 3, hetero atoms such as nitrogen atom, sulfur atom, and oxygen atom, and is preferably a 4- to 7-membered ring, It is preferably a 5- to 6-membered ring. Specifically, chenyl, furyl, imidazolyl, pyrrolyl, oxazolyl, isosoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thioxazolyl, diazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazilyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl Rajur, morpholinyl, azepinil, and oxebul.

The triazolyl group includes both 1,2,3-form and 1,2,4-form. .

Examples of the tetrazolyl group include a 1-tetrazolyl group and a 5-tetrazolyl group.

The position of the bond of the thiazolyl group, triazolyl group or tetrazolyl group is not particularly limited as long as it is possible.

A thiazolyl group in R ⁵ and R ⁶ may be replacement by C E _ ₆ alkyl group or an Amino group, the number of the substituents, the position of substitution is not particularly limited. Examples of the group represented by “1- (CH ₂ ) s—O— (wherein s is an integer of 1 to 3, and the methylene group may be substituted with an oxo group)” include, for example, CH ₂ — O—, one CO— CH ₂ — O—, one CH ₂ — CO— O—, one (CH ₂ ) ₃ — 0— and the like. The number and position of the oxo groups are not particularly limited.

Examples of the group represented by “one (CH ₂ ) t — (where t is 2 or 3 and a methylene group may be substituted with an oxo group)” include, for example, one CH ₂ —CH ₂ — , — CO— CH ₂ —, one CH ₂ — CO—, one CO—CO—,-(CH ₂ ) ₃ —, —CO— (CH ₂ ) ₂ —, one (CH ₂ ) ₂ — CO— No. The number and position of the oxo group are not particularly limited.

“Pharmaceutically acceptable salts” include, for example, salts with inorganic bases [eg, alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium, etc.) Salts), ammonium salts, etc.]; various inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate or nitrate; acetate, propionate, succinate, glycolate, Lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate or ascorbate Mechanical acid addition salts; salts with various amino acids such as aspartate or glutamate; hydrochloride, methanesulfonate, benzenesulfonate, p- E Nsuruhon salt, sodium salt preferably, particularly preferably p- toluenesulfonyl emissions salt, sodium salt. In some cases, it may be a hydrate, a hydrate or a solvate.

Here, the compound (1) of the present invention may be a hydrate or a solvate in some cases, and also includes a prodrug and a metabolite thereof.

The “prodrug” in the present invention is a derivative of the compound (1) of the present invention, has a group that can be chemically or metabolically degraded, and is hydrolyzed or solvolyzed, or under physiological conditions. The present invention provides the compound (1) of the present invention that exhibits pharmacological activity when decomposed, and is not particularly limited. For example, (1). For the hydroxyl group of the compound,

- CO- alkyl, One C0 ₂ - alkyl, - CONH- alkyl, -CO- an alkenyl one CO ₂ - Arukeniru one CONH- Aruke - le, One CO- Ariru, - C0 ₂ - Ariru one CONH- Ariru, -CO- heterocyclic, -C0 ₂ - ring, - CONH- heterocycle (wherein alkyl, alkenyl, Ariru, heterocycle, halo gen atom, an alkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, an amino group, § amino acid residue, mono PO ₃ H _2, one S0 ₃ H, one OP0 ₃ H _2, may be substituted by one OS0 ₃ H and the like.) one CO- polyethylene glycol residue, mono CO ₂ - or those polyethylene glycol monoalkyl ether residue or one PO ₃ H ₂ or the like has been substituted, - polyethylene glycol residue, mono CO- polyethylene da recall monoalkyl ether residue, mono C0 ₂

(2) to the amino group of compound one CO- alkyl, - CO ₂ - alkyl, - CO- Arukeniru, - CO ₂ - alkenyl one co ₂ - Ariru, -CO- § Li

—, —CO—heterocycle, —CO ₂ —heterocycle (the alkyl, alkenyl, aryl, and heterocycle are halogen, alkyl, hydroxyl, alkoxy, ethoxyl, amino, amino acid, . the P0 ₃ H _2, one S0 ₃ H, one OPO ₃ H _2, may be substituted by one OS0 ₃ H, etc.), single CO- polyethylene glycol residue, mono CO ₂ - polyethylene glycol residue, mono CO- polyethylene glycol monoalkyl E one ether residue, mono CO ₂ - one polyethylene da recall monoalkyl ether residue or one P0 ₃ H ₂ or the like has been substituted, or

(3) With respect to the carboxy group of the compound, an alkoxy group, an aryloxy group (the alkoxy group or the aryloxy group is a halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, a carboxyl group, an amino group, an amino acid residue, -PO ₃ H _2, one S0 ₃ H, one OPO ₃ H _2, one OS0 may be substituted with ₃ H and the like.), or polyethylene glycol residue or a polyethylene da recall monoalkyl ether residue is substituted And others.

The compound (1) of the present invention is useful as a medicament, for example, as an HLGPa inhibitor or a therapeutic agent for diabetes mellitus.

When the present invention is used as a therapeutic agent for diabetes, it is administered systemically or locally, orally or parenterally. Dosage varies depending on age, body weight, symptoms, therapeutic effects, etc. 1 Usually, one adult is administered once to several times a day, in the range of 1 mg to lg at a time. The compound (1) of the present invention is a diluent suitable for preparing a composition for oral administration (for example, a solid composition or a liquid composition) or a preparation such as an injection for parenteral administration. , Dispersants, adsorbents, solubilizers and the like can be mixed.

The `` pharmaceutically acceptable carrier '' to be added to the pharmaceutical composition, HLGPa inhibitor, antidiabetic agent, etc. of the present invention is not particularly limited as long as it is a pharmaceutically acceptable carrier. Excipients, binders, disintegrants, flavoring agents, flavoring agents, emulsifiers, diluents, solubilizing agents, and the like.

Further, the compound (1) of the present invention can be used for the treatment and prevention of diabetes in humans as well as animals other than humans, for example, mammals.

The compound (1) of the present invention can be used in combination with one drug or a plurality of other drugs by a general method commonly used in medicine. Although there are various drugs that can be used in combination with the compound (1) of the present invention, drugs for treating hyperlipidemia and drugs for treating diabetes are particularly preferred.

Examples of the therapeutic drug for hyperlipidemia that can be used in combination include statins, and specific examples include oral pastatin, simpastatin, prapastatin, funovavastatin, atonorepastatin, and seripastatin.

Similarly, antidiabetic drugs that can be used in combination include insulin preparations, sulfonylureas, insulin secretagogues, sulfonamides, biguanides, a-dalcosidase inhibitors, insulin sensitizers, etc. Specific examples of the drug are as follows. For example, insulin is used as an insulin preparation, insulin is used as a sulfolurine, dalibenclamide, tolptamide, glicloviramide, acetohexamide, glimepiride, tolazamide, daliclazide, nateglinide, etc. Α-Dalcosidase inhibitors such as metformin hydrochloride and pformin hydrochloride; poglipose and acarbose; and insulin sensitizers such as pioglitazone hydrochloride.

In addition, the present inventors have demonstrated that the combined use of an HLGPa inhibitor, which has not been used in combination with a diabetes treatment drug, has a synergistic effect on the treatment of diabetes compared with the case of using each drug alone. I found that I can do it. That is, it is useful in terms of effects to use the compound (1) of the present invention together with a therapeutic agent for diabetes. Next, an example of a method for producing the condensed pyrrole compound represented by the compound (1) will be described, but the production method of the present invention is not limited thereto.

In performing the reaction described below, the functional group other than the site may be protected beforehand as necessary, and may be deprotected at an appropriate stage.

The amount of the solvent used in each step is not particularly limited as long as the reaction mixture can be stirred. In addition, as a reagent used in each step, a hydrate or a salt thereof can be used as long as the desired reaction is not inhibited.

Furthermore, in each step, the reaction may be carried out by a usual method, and the isolation and purification may be carried out by appropriately selecting or combining conventional methods such as crystallization, recrystallization, column chromatography, and preparative HPLC. Just do it.

Manufacturing method 1

In general formula (1),

— G — G ₂ — G ₃ — is one S— C (R ⁵ ) = C (R ⁶ ) one, and

R ⁴ is — C (= O) partial D or one C (—NH) — ring D (where ring D is a group selected from groups represented by formulas (a) to (g)) The method for producing the compound is exemplified below.

Manufacturing method 1

(Wherein ¹ , RR ⁵ and R ⁶ are as defined above, and R ³ ′ is a hydrogen atom, a Ci- ₆ alkyl group or an aralkyl group (the aralkyl group may be substituted with a halogen atom). And 3 ^ is a halogen atom, X ₂ is a halogen atom or a hydroxyl group, and ring D is a group selected from the groups represented by formulas (a) to (g).)

Process 1 1 1

The compound represented by the general formula (3) can be obtained by reacting the compound represented by the general formula (2) with N, N-dimethylformamide (DMF) in a solvent in the presence of a base. .

Examples of the base used in the reaction include η-butyl lithium, tert-butyl lithium, and the like. Use as a hexane solution is preferred because of easy handling. Particularly preferred is n-butyllithium (hexane solution).

Examples of the solvent used for the reaction include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethyloxetane, and diglyme; and hydrocarbon solvents such as benzene, toluene, hexane, and xylene. These can be used alone or in combination. A preferred solvent in this reaction is THF.

The reaction temperature is usually from 100 ° C. (: to 50 ° C., preferably from 80 ° C. to room temperature. The reaction time is usually from 0.1 hour to 10 hours, preferably from 0.5 hour to 5 hours. It is more preferably 1 hour to 2 hours.

Step 1—2

The compound represented by the general formula (4) can be obtained by reacting the compound represented by the general formula (3) with ethyl azidoacetate in a solvent in the presence of a base. Examples of the solvent used in the reaction include getyl ether, THF, dioxane,

Examples include ether solvents such as 1,2-dimethoxetane and diglyme; and alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol. These may be used alone or in combination. A preferred solvent in this reaction is ethanol.

Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide, sodium methoxide, potassium hydride Alkali metal alkoxides such as tert-butoxide; lithium metal amides such as lithium diisopropylamide, sodium amide, and lithium bistrimethylsilyl amide; and sodium methoxide is preferable.

The reaction temperature is usually from −20 ° C. to 50 ° C., preferably from 0 ° C. to room temperature.

The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours. Process 1 1 3

It is a five-membered ring closure reaction. The compound represented by the general formula (5) can be obtained by reacting the compound represented by the general formula (4) in a solvent.

Examples of the solvent used for the reaction include hydrocarbon solvents such as benzene, toluene, hexane, and xylene, and these can be used alone or in combination. A preferred solvent in this reaction is xylene.

The reaction temperature is usually from 110 ° C to 200 ° C, preferably from room temperature to 150 ° C. The reaction time is generally 10 minutes or more, preferably 30 minutes to 24 hours, and more preferably 30 minutes to 2 hours.

Process 1 1 4

The compound represented by the general formula (6) can be obtained by hydrolyzing the compound represented by the general formula (5) in a solvent in the presence of a base.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; polar solvents such as acetate, DMF, dimethyl sulfoxide, and water. These can be used alone or in combination. A preferred solvent in this reaction is methanol.

Examples of the base used in the reaction include lithium hydroxide, sodium hydroxide, and alkali metal hydroxides such as hydroxide hydroxide, and sodium hydroxide is preferable.

The reaction temperature is usually from −30 ° C. to 100 ° C., preferably from 0 ° C. to 50 ° C. The reaction time is generally 0.1 hour to 48 hours, preferably 0.5 hour to 12 hours.

Process 1-5

By reacting the compound represented by the general formula (5) with the compound represented by the general formula (7) in a solvent in the presence of a base, the compound represented by the general formula (8) can be obtained. .

Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium ethoxide, sodium methoxide, potassium tert-butoxide; n-butyllithium; Alkyl lithium such as butyl lithium; alkali metal amides such as lithium disopropylamide, sodium amide and lithium bistrimethylsilyl amide; alkali metal carbonates such as sodium carbonate and carbon dioxide; sodium hydrogen carbonate, potassium hydrogen carbonate Alkali metal bicarbonates; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and hydroxylated lime; Alkali metal carboxylate salts such as sodium acetate and acetic acid; Sodium phosphate, potassium phosphate, etc. The phosphoric acid Organic metal bases such as triethylamine, pyridine, N-methylmorpholine and the like, preferably sodium hydride; .

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate A polar solvent such as acetone, DMF, dimethyl sulfoxide and the like, which can be used alone or in combination. A preferred solvent in this reaction is DMF.

The reaction temperature is usually from 150 ° C to 50 ° C, preferably from 120 ° C to room temperature.

The reaction time is generally 0.1 hour to 10 hours, preferably 0.5 hour to 5 hours, more preferably 1 hour to 2 hours.

Process 1-6 The compound represented by the general formula (9) is obtained by reacting the compound represented by the general formula (6) with the compound represented by the general formula (7) in the same manner as in step 115. Can be.

Process 1-7

The compound represented by the general formula (11) can be obtained by reacting the compound represented by the general formula (8) with the compound represented by the general formula (10) in a solvent. Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Pi-based solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol-based solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; esters such as ethyl acetate, methyl acetate, and butyl acetate System solvents; polar solvents such as acetone, DMF, dimethyl sulfoxide and the like can be mentioned, and these can be used alone or in combination. A preferred solvent in this reaction is ethanol.

The reaction temperature is usually from 20 ° C to 100 ° C, preferably from room temperature to 50 ° C.

The reaction time is generally 0.1 hour to 24 hours, preferably 0.5 hour to 2 hours.

Process 11 8

The compound represented by the general formula (11) is obtained by reacting the compound represented by the general formula (9) with the compound represented by the general formula (10) in a solvent in the presence of a condensing agent. be able to.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and ethyl acetate; acetone, DMF, and dimethyl Examples thereof include polar solvents such as sulfoxide, and these can be used alone or in combination. The preferred solvent in this reaction is DMF. The condensing agent used in the reaction may be any condensing agent used in a usual peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, a method using a carbodiimide type reagent), and among them, 1-hydroxy Preferred is a combination of benzotriazo monohydrate (HOB t · H ₂ O) and 11- (3- (dimethylamino) propyl) -13-ethylcarposimid hydrochloride (EDC).

The reaction temperature is usually from 20 ° C to 50 ° C, preferably from 0 ° C to room temperature.

The reaction time is generally 1 hour to 48 hours, preferably 2 hours to 24 hours. Process 11 9

By reacting a compound represented by the general formula (11) with a compound represented by the general formula (12) using a condensing agent in a solvent, the compound represented by the general formula (111) ) Can be obtained. In addition, a base can be used to make this reaction proceed smoothly. For example, in the general formula (12), when X ₂ is a hydroxyl group, a condensing agent is used, but a base may be used for smoothly proceeding the reaction. When X ₂ is a halogen atom, the reaction can proceed smoothly by using a base without using a condensing agent.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane and chloroform. Halogen solvents such as oral form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and ethyl acetate; acetone, DMF, Examples thereof include polar solvents such as dimethyl sulfoxide, and these can be used alone or in combination. Preferred solvents in this reaction are DMF and THF.

The condensing agent used in the reaction may be any condensing agent used in a conventional peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, a method using a carbodiimide type reagent), and among them, 1-hydroxy Preferred is a combination of benzotriazole monohydrate and 11- (3- (dimethylamino) propyl) -13-ethylcarbodiimide hydrochloride.

Bases used in the reaction include, for example, triethylamine, N-methylmorpholine. And organic bases such as sodium bicarbonate; and inorganic bases such as sodium bicarbonate. Triethylamine is preferable.

The reaction temperature is usually from 10 to 60 ° C, preferably from 0 ° C to room temperature.

The reaction time is generally 10 minutes or more, preferably 1 hour to 48 hours, more preferably 3 hours to 24 hours, and further preferably 3 hours to 15 hours.

Process 1-10

By reacting the compound represented by the general formula (11) with a compound represented by the general formula (13) or a reagent equivalent thereto (eg, methylbenzimidate hydrochloride) in a solvent, the target compound is obtained. Thus, the compound represented by the general formula (1-2) can be obtained.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone , DMF, dimethyl sulfoxide and the like, and these can be used alone or in combination. A preferred solvent in this reaction is methanol. '

The reaction temperature is usually in the range of 30 ° C to 50 ° C, preferably 0 ° C to room temperature.

The reaction time is generally 0.5 hour to 48 hours, preferably 1 hour to 12 hours. Process 1 1 1 1

The compound represented by the general formula (12) is subjected to a condensation reaction with the compound represented by the general formula (12) using a condensing agent in a solvent using a condensing agent. You can get things.

Examples of the solvent used in the reaction include getyl ether, THF, dioxane,

Ether solvents such as 1,2-dimethoxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; halogen solvents such as dichloromethane, chloroform, tetrachloride carbon, and 1,2-dichloroethane Alcoholic solvents such as isopropyl alcohol and tert-butanol; ethyl acetate, methyl acetate, and butyl acetate Ester solvents such as tyl; polar solvents such as acetone, DMF, and dimethyl sulfoxide; and the like, and these can be used alone or in combination. The preferred solvent in this reaction is DMF.

The condensing agent used in the reaction may be any condensing agent used in a usual peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, a method using a carbodiimide type reagent), and among them, 1-hydroxy Preferred is a combination of benzotriazole monohydrate and 11- (3- (dimethylamino) propyl) -13-ethylcarbodiimide hydrochloride.

The reaction temperature is usually from 130 ° C to 50 ° C, preferably from 120 ° C to room temperature.

The reaction time is generally 1 hour to 48 hours, preferably 2 hours to 6 hours.

Process 1— 1 2

The compound represented by the general formula (1 2 ′) is subjected to a condensation reaction with a compound represented by the general formula (9) using a condensing agent in a solvent to obtain a compound represented by the general formula (1) -The compound represented by 1) can be obtained.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone, DMF, and dimethyl Examples thereof include polar solvents such as sulfoxide, and these can be used alone or in combination. A preferred solvent in this reaction is DMF.

The condensing agent used in the reaction may be a condensing agent used in a usual peptide condensing method (for example, an acid chloride method, a mixed acid anhydride method, a method using a carbodiimide type reagent, etc.). Preferred is a combination of hydroxybenzotriazole monohydrate and 1- (3- (dimethylamino) propyl) -13-ethylcarbodiimide hydrochloride.

The reaction temperature is usually from 130 ° C. to 50 ° C., preferably from −20 ° C. to room temperature.

The reaction time is generally 1 hour to 48 hours, preferably 1 hour to 24 hours. Manufacturing method 2

In general formula (1),

— — G ₂ — G ₃ — is one C (R ⁵ ) = C (R ⁶ ) — S— and

R ^{4 is} —C (= 0) —ring D or one C (= NH) part D (where ring D is a group selected from groups represented by formulas (a) to (g)) The method for producing the compound is exemplified below.

Manufacturing method 2

(1-3) (1-4) (In the formula, the definition of each symbol is as defined above.)

Step 2-1

This is a general reduction reaction. By reacting the compound represented by the general formula (14) with a reducing agent in a solvent, the compound represented by the general formula (15) can be obtained.

Examples of the reducing agent used in the reaction include lithium aluminum hydride, sodium borohydride, diisobutyl aluminum hydride and the like, preferably lithium aluminum hydride.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane and diglyme. The preferred solvent in this reaction is THF.

The reaction temperature is usually −20 ° C. to 50 ° C., preferably 110 ° C. to room temperature.

The reaction time is generally 1 hour to 12 hours, preferably 2 hours to 8 hours.

Process 2— 1

This is a normal oxidation reaction. The compound represented by the general formula (16) can be obtained by reacting the compound represented by the general formula (15) in a solvent using an oxidizing agent.

The oxidizing agent used in the reaction includes, for example, manganese dioxide, pyridi-dimethylchromate and the like, and is preferably manganese dioxide.

Solvents used for the reaction include, for example, halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane, and the like. Ether solvents such as diglyme; and hydrocarbon solvents such as benzene, toluene, hexane, and xylene. These can be used alone or in combination. A preferred solvent in this reaction is chloroform.

The reaction temperature is usually from 20 ° C to 100 ° C, preferably from 0 ° C to 60 ° C.

The reaction time is generally 1 hour to 10 hours, preferably 1 hour to 5 hours.

Process 2—2

In the same manner as in Steps 1 and 2 of Production Method 1, from the compound represented by the general formula (16), The compound represented by the general formula (17) can be obtained.

Process 2—3

The compound represented by the general formula (18) can be obtained from the compound represented by the general formula (17) in the same manner as in Steps 1-3 of Production Method 1.

Process 2—4

The compound represented by the general formula (19) can be obtained from the compound represented by the general formula (18) in the same manner as in Steps 1-4 of Production Method 1.

Process 2-5

The compound represented by the general formula (20) is reacted with the compound represented by the general formula (18) and the compound represented by the general formula (7) in the same manner as in Steps 1 to 5 of the production method 1. A compound can be obtained.

Process 2-6

The compound represented by the general formula (21) is reacted with the compound represented by the general formula (19) and the compound represented by the general formula (7) in the same manner as in Step 1-6 of Production Method 1. A compound can be obtained.

Process 2-7

The compound represented by the general formula (22) is reacted with the compound represented by the general formula (20) and the compound represented by the general formula (10) in the same manner as in the step 117 of the production method 1. A compound can be obtained.

Process 2-8

The compound represented by the general formula (22) is obtained by reacting the compound represented by the general formula (21) with the compound represented by the general formula (10) in the same manner as in Steps 18 of Production Method 1. A compound can be obtained.

Process 2—9

By reacting the compound represented by the general formula (22) with the compound represented by the general formula (12) in the same manner as in step 11 of production method 1, The compound represented by the formula (1-3) can be obtained.

Process 2—10

The compound represented by the general formula (22) was obtained in the same manner as in Steps 1 to 10 of Production Method 1. By reacting with a compound represented by the general formula (13) or a reagent equivalent thereto (for example, methylbenzimidate hydrochloride, etc.), the compound represented by the general formula (13)

The compound represented by (1-4) can be obtained.

Process 2— 1 1

By reacting the compound represented by the general formula (12 ') with the compound represented by the general formula (21) in the same manner as in Steps 1 to 12 of the production method 1, the compound represented by the general formula The compound represented by (1-3) can be obtained.

Manufacturing method 3

When the compound represented by the general formula (1) is combined with a nitrogen atom adjacent to R ³ and R ⁴ ,

(Wherein, Z, R ³⁷ and R ³⁸ are the same as described above).

(Wherein, R ¹ R ² , R ³ ′, G _x , G ₂ , G ₃ , R ⁴⁸ and ring D are the same as described above, and R ³⁷ ″ and R ³⁸ ″ are a hydrogen atom, a halogen atom. An atom, an alkyl group, a C ^ alkoxy group or a hydroxyl group, and R ⁴³ "'is a ₆ alkyl group).

Process 3-1 The general formula (1,) obtained in Steps 1-9, 1-10, 2-9 or 2-10 (where the general formula (1,) is the general formula (1-1), (1-2) , (1-3) or (1-4) is the same), the ring D is

(Where R ¹² ′ and R ¹³ ′ are the same or different and are each a hydrogen atom, a halogen atom, a C- ₆ alkyl group, an alkoxy group or a hydroxyl group (R ¹² ′ and R ¹³ ′ are R ³⁷ is synonymous with R ³⁸ ), and R ⁴⁸ is synonymous with R ⁴⁵ ) in a solvent, a phosgene equivalent (eg, carbopimidazole, diphosgene, triphosgene, etc.) By performing the reaction using triphosgene), a compound represented by the general formula (1-5), which is one of the target compounds, can be obtained. As the reagent, besides the above-mentioned phosgene equivalent, ethyl methyl carbonate and the like can be used.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate A polar solvent such as acetone, DMF, dimethyl sulfoxide, water and the like, and these can be used alone or in combination. A preferred solvent in this reaction is a mixture of DMF, THF and water.

In this reaction, it is preferable to use a base. Examples of usable bases include inorganic bases such as sodium hydroxide, sodium bicarbonate, and potassium carbonate; and organic bases such as triethylamine, 1,8-diazabicyclo [5.4.0] indene-7-ene. And preferably sodium bicarbonate.

The reaction temperature is usually from 110 ° C to 60 ° C, preferably from 0 ° C to room temperature. The reaction time is generally 1 hour or longer, preferably 1 hour to 24 hours, more preferably 3 hours to 24 hours, and preferably 6 hours to 12 hours.

Process 3-2

Among the compounds represented by the general formula (1 ′), when the ring D is

(Where R ¹² ′ and R ¹³ ′ are as defined above) by subjecting the compound represented by the general formula (1— The compound represented by 6) can be obtained.

Process 3—3

(Where R ¹² ′, R ¹³ ′, and R ⁴⁸ are the same as described above) in a solvent with a thiocarbonyl compound to form a compound represented by the general formula ( The compound represented by 1-7) can be obtained.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone , DMF, dimethyl sulfoxide, polar solvents such as water, and the like, and these can be used alone or in combination. A preferred solvent in this reaction is THF.

Examples of the thiocarbonyl compound used in the reaction include thiocarbonyldiimidazole, carbon disulfide, thiophosgene, and the like. It's Midazo.

In this reaction, use of a base may be desired. Examples of the base to be used include inorganic bases such as sodium hydroxide, sodium hydrogencarbonate and carbonated carbonate; triethylamine, 1,8-diazabicyclo [5.4.0]

It is an organic base such as 7-ene.

The reaction temperature is usually from 110 ° C to 60 ° C, preferably from 0 to room temperature.

The reaction time is generally 1 hour to 12 hours, preferably 2 hours to 6 hours.

Process 3—4

In the compound represented by the general formula (1 ′), the ring D is

(Where R ¹² ′ and R ¹³ ′ are the same as described above) by reacting the compound with orthoacetate, formic acid or a derivative thereof in the presence of an acid in a solvent. A compound represented by the general formula (118), which is one of the target compounds, can be obtained.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone , DMF, dimethyl sulfoxide, formic acid and the like, and these can be used alone or in combination. The preferred solvent in this reaction is DMF.

Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; and organic acids such as trifluoroacetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid, and preferably methanesulfonic acid. is there.

As the orthoacetate, methyl orthoacetate is preferred.

Formic acid and its derivatives include, for example, formic acid and ethyl formate. Among them, formic acid is preferred.

The reaction temperature is usually from 10 ° C to 100 ° C, preferably from 0 ° C to room temperature.

The reaction time is generally 30 minutes to 12 hours, preferably 30 minutes to 6 hours, and more preferably 1 hour to 6 hours.

Process 3-5

(Where R ¹² ′ and R ^13> are the same as above) by reacting the compound represented by the formula with formic acid or orthoformate such as triethyl orthoformate under heating to obtain one of the target compounds The compound represented by the general formula (1-9) can be obtained.

The reaction temperature is usually 80 ° C to 300. C, preferably between 100 ° C and 200 ° C. The reaction time is generally 4 hours to 24 hours, preferably 5 hours to 12 hours. Process 3-6

(Where R ^12> and R ¹³ ′ are the same as above) in a solvent in the presence of an organic base (for example, pyridine, triethylamine, sodium hydrogen carbonate, etc.), a haloacetyl halide compound (Eg, chloroacetyl chloride, bromoacetyl bromide, etc.). (2) A compound represented by the general formula (1-10), which is one of the target compounds, can be obtained by cyclization using a base and sodium iodide without isolating the obtained compound. Can be.

Examples of the solvent in (1) and (2) include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; and hydrocarbon solvents such as benzene, toluene, hexane, and xylene. ; Dichloromethane, chloropho Halogen solvents such as lume, carbon tetrachloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; acetone, D

Examples thereof include polar solvents such as MF and dimethyl sulfoxide, and these can be used alone or in combination. A preferred solvent in this reaction is a solvent that is THF, ethyl acetate or DMF, or a mixed solvent thereof.

Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide; n-butyllithium Alkyl lithium such as butyllithium, sec-butyllithium, etc .; Alkali metal amides such as lithium diisopropylamide, sodium amide, lithium bistrimethylsilyl azide; Alkali metal carbonates such as sodium carbonate, carbonated lime; sodium hydrogen carbonate, hydrogen carbonate Alkali metal bicarbonates such as potassium; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal salts of carboxylic acids such as sodium acetate and potassium acetate; sodium phosphate and potassium phosphate Phosphoric acid Alkali metal salts; Toryechiruamin, pyridine, N- methylmorpholine, 1, 8-Jiazabishikuro [.. 5 4 0] Undeka 7 E emission and organic bases such as the levator Gerare, preferably potassium carbonate.

The reaction temperature is usually from 130 ° C to 100 ° C. The temperature is preferably 0 ° C. to 80 ° C., and more preferably 0 ° C. to room temperature.

The reaction time is generally 1 hour to 24 hours, preferably 1 hour to 15 hours, and preferably 2 hours to 12 hours.

Process 3-7

In the compound represented by the general formula (1 ′), the ring D is C00H

R12,

One R13 '

(Where R ¹² ′ and R ¹³ ′ are as defined above) in a solvent, By cyclizing in the presence of a condensing agent, a compound represented by the general formula (111), which is one of the target compounds, can be obtained.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate A polar solvent such as acetone, DMF, dimethyl sulfoxide and the like, and these can be used alone or in combination. The preferred solvent in this reaction is DMF.

The condensing agent used in the reaction may be any condensing agent used in a usual peptide condensation method (for example, an acid chloride method, a mixed acid anhydride method, a method using a carbodiimide type reagent), and among them, 1-hydroxy Preferred is a combination of benzotriazole monohydrate and 1- (3- (dimethylamino) propyl) -13-ethylcarbodiimide hydrochloride.

The reaction temperature is usually from 30 ° C to 60 ° C, preferably from 0 ° C to room temperature.

The reaction time is generally 5 hours to 24 hours, preferably 10 hours to 20 hours. Process 3-8

In the formula, one G ₃ —G 2 G ₃ is one C (R ⁵ ) = C (R ⁶ ) one S—, and R ¹ R ² , R ^37> ′, and R ³⁸ ″ are as defined above. is there.

The general formula (1 ') obtained in step 2-9 (where the general formula (1') is

The same as 3)), the ring D is

(Wherein, X ₃ is a halogen atom or one OSO ₂ - alkyl, or is one o S 0 ₂ 7 Lil, R ^{1 2} '及Pi R ^{1 3'} is the same as) a compound represented by The compound is dissolved in a solvent and cyclized with a base and, if necessary, an alkali metal halide such as sodium iodide, to give one of the target compounds represented by the general formula (1-116) Can be obtained. X ₃ is preferably a bromine atom.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethyloxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; Halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ethyl acetate, methyl acetate, butyl acetate, etc. And a polar solvent such as acetone, N, N-dimethylformamide (DMF), dimethylsulfoxide, and formate. These can be used alone or in combination. A preferred solvent in this reaction is DMF.

Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium ethoxide, sodium methoxide, potassium tert-butoxide; n-butyllithium; Alkyl lithium such as sec-butyl lithium; Alkali metal amide such as lithium diisopropylamide, sodium amide, lithium bistrimethylsilyl amide; Alkali metal carbonate such as sodium carbonate, carbon dioxide lime; sodium hydrogencarbonate, carbonate Alkali metal bicarbonates such as potassium hydrogen; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and hydroxide hydroxide; alkali metal salts of carboxylic acids such as sodium acetate and potassium acetate; sodium phosphate, phosphorus Phosphoric acid such as potassium acid Alkali metal salts; Toryechiruamin, pyridine, N- methylmorpholine, Organic bases such as 1,8-diazabicyclo [5.4.0] pendene-l-ene (DBU) and the like are preferable, and potassium carbonate is preferable.

The reaction temperature is usually from 20 ° C to 300 ° C, preferably from 60 ° C to 200 ° C. The reaction time is generally 1 hour to 48 hours, preferably 2 hours to 24 hours. Process 3-9

(1-17)

(twenty five)

(Wherein each symbol is as defined above)

The compound (23) synthesized according to WO 03/068743 is dissolved in a polar solvent such as acetone, an ether solvent, or a halogen solvent such as chloroform, and the reaction is carried out by adding an acid chloride such as acetyl chloride and then reacting. Compound (24) can be obtained by the above operation.

The compound (24) is dissolved in an acid such as acetic acid or polyphosphoric acid alone or in a solvent containing an acid, and then the compound (25) is added and reacted to obtain a compound represented by the general formula (1-1) The compound represented by 7) can be obtained.

Examples of the acid used for the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; Organic acids such as oral acetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like, and acetic acid is preferred.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone, DMF, dimethyl sulfoxide, and formate. Alternatively, the above-mentioned acids can be used as a solvent. These can be used alone or in combination. The preferred solvent in this reaction is acetic acid.

The reaction temperature is usually from 40 ° C to 300 ° C, preferably from 60 ° C to 200 ° C.

The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 12 hours.

Manufacturing method 4

Compound represented by the general formula (1) is, R ³ and: R ⁴ together with the adjacent nitrogen atom,

(Wherein, W, R ³ R ^{4 Q} and R ^{4 1} has the same meaning as defined above) are illustrated below method for manufacturing a case of forming a.

Manufacturing method 4

(Wherein, G ₁ G ₂ , G ₃ , RR ² , R ³ ′, R ³⁹ , R ⁴⁰ and R ⁴¹ are as defined above, and boc is a tert-butoxycarbonyl group).

Process 4 1 1

Step 17 The compound represented by the general formula (31) and the compound represented by the general formula (32) obtained in the same manner as in step 7 or 1-8 are subjected to the same condensation reaction as in step 1-9. By adding the compound, a compound represented by the general formula (33) can be obtained.

Process 4-2

The tert-butoxycarbonyl group of the compound represented by the general formula (33) is removed with an acid (for example, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, etc.). After protection, the obtained amino compound is cyclized with a phosgene equivalent (for example, carbonyldiimidazole, triphosgene, etc.) in the presence of a base to obtain a compound represented by the general formula (1-1-2) which is one of the target compounds. ) Can be obtained.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, diglyme, and diphenyl ether; and hydrocarbon solvents such as benzene, toluene, hexane, and xylene. ; Jikurorome Tan, black hole Holm, carbon tetrachloride, black hole benzene, 1, 2-halogen-based solvents such as Jikuroroetan; methanol, ethanol, isopropyl alcohol, t _e alcohol solvents rt over butanol; DM F, dimethyl sulfoxide, Examples thereof include polar solvents such as water. These can be used alone or in combination, or the reaction can be carried out without a solvent. A preferred solvent used in this reaction is THF.

Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide; n-butyllithium, sec. Alkyl lithium such as monobutyllithium; alkali metal amides such as lithium disopropylamide, sodium amide and lithium bistrimethylsilyl amide; alkali metal carbonates such as sodium carbonate and carbon dioxide rim; sodium hydrogencarbonate, hydrogencarbonate Alkali metal bicarbonates such as potassium; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and hydrating hydroxide; Alkali metal carboxylate such as sodium acetate and potassium acetate; Sodium phosphate, phosphoric acid Phosphoric acid such as potassium Alkali metal salts; organic bases such as triethylamine, pyridine, N-methylmorpholine, and 1,8-diazabicyclo [5.4.0] indene-7-ene; and the like, with preference given to triethylamine.

The reaction temperature is usually 0 ° C to 100 ° C, preferably room temperature to 60 ° C.

The reaction time is generally 1 hour to 48 hours, preferably 1 hour to 25 hours, more preferably 2 hours to 24 hours.

Process 4 1 3

In the same manner as in Step 4-2, the tert-butyrate of the compound represented by the general formula (33) Deprotection of the xycarpoxyl group with an acid (eg, trifluoroacetic acid, hydrochloric acid, etc.), and then cyclization with a thiocarbonylation reagent (eg, thiocarbonyl diimidazole, carbon disulfide, thiophosgene, etc.) in the presence of a base. As a result, a compound represented by the general formula (1-13), which is one of the target compounds, can be obtained.

Process 4—4

The compound represented by the general formula (36) can be obtained by reacting the compound represented by the general formula (34) with the compound represented by the general formula (35) in acetonitrile.

The reaction temperature is usually 50 ° C to 200 ° C, preferably 80: to 100 ° C. The reaction time is generally 1 hour to 10 hours, preferably 2 hours to 5 hours.

Process 4 1 5

By reacting the compound represented by the general formula (31) with the compound represented by the general formula (36) in the same manner as in Steps 1 and 9, the compound represented by the general formula (37) is obtained. Obtainable.

Process 4 1 6

-One of the target compounds by cyclizing a compound represented by the general formula (37) with a phosgene equivalent (eg, triphosgene, carbonyldiimidazole, diphosgene, etc.) in a solvent in the presence of a base. The compound represented by the general formula (1-14) can be obtained.

Solvents used in the reaction include, for example, ether / solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, diglyme, diphene / leate / le; benzene, toluene, hexane, xylene, etc. Hydrocarbon solvents; dichloromethane, chloroform, formaldehyde, carbon benzene, carbon tetrachloride, 1,2-dichloroethane, etc .; halogen solvents; methanol, ethanol, isopropyl alcohol, tert-butanol, etc .; DMF, dimethyl Examples thereof include polar solvents such as sulfoxide and water, and dimethylfurin. These can be used alone or in combination, or the reaction can be carried out without a solvent. A preferred solvent used in the present reaction is THF.

Examples of the base used in the reaction include, for example, sodium hydride, potassium hydride, and the like. Alkali metal hydrides; alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide; alkyl lithiums such as n-butyl lithium, sec-butyl lithium; lithium diisopropylamide, sodium amide, lithium Alkali metal amides such as pistrimethylsilyl amide; alkaline metal carbonates such as sodium carbonate and carbon dioxide; alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydroxide, sodium hydroxide Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal salts of carboxylic acids such as sodium acetate and potassium acetate; alkali metal phosphates such as sodium phosphate and potassium phosphate; triethylamine, pyridine, N-methylmorpholine , 1, 8— Zabishikuro [5.4. 0] Undeka 7 E emission and organic bases such elevation Gerare, preferably a Toriechiruamin.

The reaction temperature is usually 0 ° C to 100 ° C, preferably 0 ° C to room temperature.

The reaction time is generally 1 hour to 24 hours, preferably 4 hours to 10 hours. Process 4-7

By cyclizing the compound represented by the general formula (37) with a formalin equivalent (eg, paraformaldehyde, dimethoxymethane, dibromomethane, etc.) in a solvent, one of the target compounds represented by the general formula ( The compound represented by 1-15) can be obtained.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, diglyme, and diphenyl ether; and hydrocarbon solvents such as benzene, toluene, hexane, and xylene. A halogen-based solvent such as dichloromethane, chloroform-form, carbon tetrachloride, carbon-benzene, and 1,2-dichloroethane; an alcohol-based solvent such as methanol, ethanol, isopropyl alcohol, tert-butanol; DMF, dimethyl sulfoxide, water, etc. And polar solvents, dimethylaniline and the like. These can be used alone or in combination, or the reaction can be carried out without solvent. Preferred solvents used in this reaction are methanol and ethanol. .

This reaction is preferably performed in the presence of an acid or a base.

The reaction temperature is usually 0 ° C to 100 ° C, preferably 0 ° C to room temperature. The reaction time is generally 1 hour to 10 days, preferably 1 day to 10 days, more preferably 1 day to 3 days.

The compound represented by the general formula (1-15) (where R ³⁹ is a hydrogen atom) can be produced not only by the method of the above step 417 but also by the following method. ：

Expression

(1-15 ')

(Wherein each symbol is as defined above)

Is reduced. The reduction can be carried out by a conventional method.

The desired compound can be produced by reacting the compound represented by (1-15) with a reducing agent such as sodium cyanoborohydride.

Manufacturing method 5

In the compound represented by the general formula (1), R ³ and R ⁴ are combined with an adjacent nitrogen atom,

(Wherein, R ⁴⁷ ′ has the same meaning as described above).

Process 5-1

(Wherein each symbol is as defined above)

The compound represented by the general formula (50) is reacted in a solvent using a phosgene equivalent (eg, lipodidiimidazole, triphosgene, diphosgene, or the like, preferably triphosgene) to obtain an intermediate of the target compound. One compound represented by the general formula (51) can be obtained.

As the reagent, besides the above-mentioned phosgene equivalent, ethyl ethyl carbonate and the like can be used.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone , DMF, dimethyl sulfoxide, polar solvents such as water and the like, and these can be used alone or in combination. A preferred solvent in this reaction is dioxane.

The reaction temperature is usually from 10 ° C to 60 ° C, preferably from 0 ° C to room temperature.

The reaction time is generally 1 hour or more, preferably 1 hour to 12 hours.

Process 5-2

(52) (53)

(Wherein each symbol is as defined above)

The presence of an organic base (eg, pyridine, triethylamine, etc.) or an inorganic base (eg, sodium hydrogen carbonate, etc.) in a solvent containing the compound represented by the general formula (52) By conducting a reaction using a phosgene equivalent (for example, diphosgene, triphosgene, or the like, preferably triphosgene), a compound represented by the general formula (53), which is one of the target compounds, can be obtained. .

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as n-tan; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone, DMF, dimethyl sulfoxide, water, etc. These can be used alone or in combination. The preferred solvent in this reaction is toluene.

The reaction temperature is usually from 120 ° C to 150 ° C, preferably from 5 ° C to 70 ° C.

The reaction time is generally 1 hour or more, preferably 1 hour to 3 hours.

Process 5-3

(Wherein each symbol is as defined above)

After reacting the compound represented by the general formula (51) in a solvent in the presence of a base, the reaction is carried out using the compound represented by the general formula (53), thereby obtaining one of the target compounds. The compound represented by the formula (54) can be obtained.

Examples of the solvent used in the reaction include getyl ether, THF, dioxane,

Ether solvents such as 1,2-dimethoxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; halogen solvents such as dichloromethane, chloroform, tetrachlorocarbon and 1,2-dichloroethane Ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone, DMF, dimethyl sulfoxide, and water; and the like, which can be used alone or in combination. The preferred solvent in this reaction is DMF.

Examples of the base used in the reaction include, for example, sodium hydride, potassium hydride, and the like. Alkali metal hydrides; alkali metal alkoxides such as sodium methoxide, sodium methoxide and potassium tert-butoxide; alkali metal amides such as lithium diisopropylamide, sodium amide and lithium bistrimethylsilyl amide; And preferably hydrogenated sodium.

The reaction temperature is generally 0 ° C. to 300 ° C., preferably room temperature to 100 ° C.

The reaction time is usually 30 minutes or more, preferably 1 hour to 12 hours.

Process 5—4

(Wherein each symbol is as defined above)

A compound represented by the general formula (55) can be obtained by reacting the compound represented by the general formula (54) in a solvent in the presence of an acid.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone , DMF, dimethyl sulfoxide and the like, and these can be used alone or in combination. A preferred solvent in this reaction is ethanol.

Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; and organic acids such as trifluoroacetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid. is there.

The reaction temperature is usually 0 ° C to 300 ° C _N, preferably 50 ° C to 200 ° C.

Manufacturing method 6 In the compound represented by the general formula (1), R ⁴ ° and R ⁴¹ together with an adjacent carbon atom form

Examples of the manufacturing method for forming

Process 6-1

(31) (62)

(63)

(Wherein G ₂ , G ₃ , R ¹ and R ² are as defined above, and Ra is a hydrogen atom, a _6- alkyl group, an aralkyl group or an aryl group which may have a substituent, Rb is an alkyl group, an aralkyl group or a substituted or unsubstituted aryl group.)

First step

Dissolve 4-amino-thiophene-3-carboxylic acid esters such as methyl 4-aminothiophene-l-oxypropylate or their salts (for example, hydrochloride) in a solvent, and in the presence of a base, first make phosgene equivalent (Eg, carbodiimidazole, triphosgene, etc., preferably triphosgene), and then the compound represented by the general formula (3)

By reacting with the compound represented by 1 ′), an intermediate compound represented by the general formula (62), which is one of the target compounds, can be obtained.

Examples of the solvent used in the reaction include ether solvents such as getyl ether, THF, dioxane, 1,2-dimethoxetane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane; Halogen solvents such as form, carbon tetrachloride, and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; polar solvents such as acetone, DMF, and dimethyl sulfoxide; Or they can be used in combination. In this reaction A preferred solvent is black form.

Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide; lithium disopropylamide Alkali metal amides such as sodium amide, sodium amide and lithium bistrimethylsilyl amide; Al metal hydrides such as sodium bicarbonate; Organic compounds such as 2,6-lutidine and pyridine Bases and the like are preferred, and 2,6-lutidine or pyridine is preferred.

2nd step

The reaction of the second step can be performed by dissolving the compound represented by the general formula (62) in a solvent and treating with a base.

Solvents that can be used in the reaction include, for example, alcohol solvents such as methanol and ethanol, ether solvents such as getyl ether, THF, dioxane, 1,2-dimethyloxetane, and diglyme; benzene, toluene, hexane, xylene, and the like. Hydrocarbon solvents; Halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate, and butyl acetate; acetone, N, N-dimethylform Polar solvents such as amide (DMF) and dimethyl sulfoxide.

Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium tert-butoxide; lithium disodium Alkali metal amides such as propyl amide, sodium amide, and lithium pistrimethylsilyl amide; Al metal hydrides such as sodium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide; pyridine, DBU, etc. And the like. Preferred is sodium hydroxide.

When a salt of the compound of the present invention (1) is desired, the free compound of the present invention (1) obtained by the above Production Methods 1 to 6 can be converted into a salt according to a conventional method.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto. Not something.

Example 1

2-Amino-4 monofluorobenzoic acid N, ― (2,3-dichloro-1H-thieno [3,2-b] pyrrole-1-5-caprolponyl) hydrazine

a) 4,5-Dichlorothiophene-2-carboxyaldehyde

Compound 1 (2,3-dichlorothiophene) (3.00 g) was dissolved in THF (15 ml) and cooled to 178 ° C. To this solution was added a 1.6 M hexane solution of n-butyllithium (13 ml), and the mixture was stirred at 178 ° C for 1 hour. DMF (1.7 ml) was added dropwise to the reaction solution, and the mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was added to a saturated aqueous ammonium chloride solution (25 ml), extracted with ethyl acetate, the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried and concentrated under reduced pressure. The obtained oil was purified by column chromatography to give the title compound 2 (2.92 g, yield 82%) as a brown solid.

b) 2,3-Dichloro-4H-thieno [3,2-b] pyrroyl-5-carboxylate

20% sodium ethoxide ethanol solution (9.87 g) was added to ethanol (1

0 ml) and cooled to 0 ° C. To this solution was added dropwise a solution of compound 2 (1.31 g) obtained in a) of Example 1 and ethanol solution (5 ml) of ethyl azidoacetate (3.73 g). And stirred for 30 minutes. The reaction mixture was added to a saturated aqueous ammonium chloride solution (400 ml), and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure. The resulting oil is Compound 3 ((2-azido-3- (2,3-dichlorothiophene-2-yl) ethyl estenole acrylate) (861 mg) was obtained as a brown solid.

Next, compound 3 (86 lmg) was dissolved in xylene (4 ml) and refluxed for 30 minutes. After allowing the reaction mixture to cool to room temperature, hexane (8 ml) was added, and the precipitated solid was collected by filtration and washed with hexane. The filtrate was dried to give the title compound 4 (321 mg, yield in two steps 19%) as yellow crystals.

c) 2,3-Dichloro-1 4 H-thieno [3,2-b] pyrrole-5-poturonic acid hydrazide

Compound 4 (14 lmg) obtained in b) of Example 1 was dissolved in ethanol (2 ml), hydrazine monohydrate (0.5 ml) was added, and the mixture was refluxed for 5 hours. After the reaction mixture was concentrated under reduced pressure, water (6 mL) was added, and the precipitated solid was collected by filtration and washed with water. The filtrate was dried under reduced pressure to give the title compound 23 (104 mg, yield 77%) as yellow crystals.

Chromatography NMR ([delta] value, 400MHz, DMSO- d ₆₎

4.44 (2H, brs), 7.13 (1H, s), 9.58 (1H, brs), 12.47 (1H, brs).

d) 2-Amino-4 monofluorobenzoic acid N, 1- (2,3-dichloro-4H-thieno [3,2-b] pyrroyl-5-capillonyl) hydrazine

Compound 23 obtained in c) of Example 1 (104mg), 4 one Furuoroantora Interview le acid (90mg), HOB t · Η 2 Ο a (100 mg) was dissolved in DMF (3. 5m l), in which EDC (112 mg) was added, and the mixture was stirred at room temperature for 14 hours. Ethyl acetate and aqueous saturated sodium hydrogen carbonate solution were added to the reaction solution, and the separated organic layer was separated. Washed with water. The solid obtained by concentrating the organic layer under reduced pressure was boiled with ethyl acetate-water, allowed to cool, and collected by filtration. The filtrate was dried to give the title compound 28 (8 Omg, yield 36%) as a yellow amorphous.

Example 11

2-Amino-4-fluorobenzoic acid N, 1- (2-chloro-4H-thieno [3,2-b] pyrrol-1-5-carbonyl) hydrazine

a) 2-Hydrogen 4 H-thieno [3,2-b] pyrrole-5-potassium benzoate

The title compound 15 (1.54 _g , 49% yield in two steps) was obtained from 5-chlorothiophene 12-aldehyde 13 (2.00 g) in the same manner as in Example 1 b). Obtained as crystals.

^X H-NMR ^(δ value, 400MHz, CDC 1 ₃₎

1.38 (3H, t, J = 7.2Hz), 4.36 (2H, d, J = 7.2Hz),

6.87 (1H, s), 7.03 (1H, s), 9.19 (1H, brs).

b) 2-Hydroxy-4H-thieno [3,2-b] pyrrole-5-Carponic acid hydrazide

The title compound 25 (184 mg, yield 81%) was synthesized from compound 15 (24 Omg) in the same manner as in c) of Example 1.

^ -NMR (δ value, 400MHz, DMS O- d ₆₎

4.45 (2Η, b rs), 7.00 (1Η, d, J = 2.4 Hz), 7.04

(1H, d, J = 1.2 Hz), 9.53 (1H, s), 1 1.85 (1 H, s) c) 2-Amino-4 monofluorobenzoic acid N, 1 (2 4H—Thieno [3,2-b] pyrrole-5-potassium) hydrazine

In the same manner as in Example 1, d), the title compound 30 (80 mg, 84%) was obtained as a yellow amorphous substance from compound 25 (316 mg) and 4-fluoroanthranilic acid.

Example 11

2-Amino-4-fluoro-benzoic acid N, 1- (2-chloro-4H-thieno [3,2-b] pyrroyl-5-capillonyl) hydrazine

a) 2-Methyl-4H-thieno [3,2-b] pyruroyl 5-5-ethyl rubenoate

In the same manner as in Example 1 b), the title compound 18 (316 mg, two-step yield: 19%) was obtained as yellow crystals from 5-methylthiophene-2-carboxyaldehyde 16 (1.0 g). Was.

XH-NMR (δ value, 400MHz, CDC 1 ₃₎

1.38 (3H, t, J = 7.2Hz), 2.55 (3H, s), 4.36 (2H, d, J = 7.2Hz), 6.63 (1H, s), 7.04 (1H, s), 9.03 (1H, brs).

b) 2-Methyl-14H-thieno [3,2-b] pyruroyl 5-carboxylic acid hydrazide

The title compound 26 (208 mg, 70%) was obtained as yellow crystals from the compound 18 (316 mg) in the same manner as in c) of Example 1.

iH- NMR (δ value, 400MHz, DMSO- d ₆₎

2.47 (3H, s), 4.35 (2H, brs), 6.69 (1H, s), 6.94 (1H, s), 9.37 (1H, brs), 11. 52 (1 H, brs). C) 2-Amino-4-fluorobenzoic acid N, 1- (2-methyl-4H-thieno [3,2-b] pyrroyl-1-5-carbo-norre) hydrazine

In the same manner as in d) of Example 1, the title compound 31 (80 mg, 45%) was obtained as a yellow amorphous from compound 26 (316 mg).

Example 11

2-Aminobenzoic acid N,-(2-Chloro-4H-thieno [3,2-b] pyrroyl 5- 5-pyruponyl) hydrazine

The title compound 32 (154 mg 82%) was obtained from compound 25 (123 mg) and anthralic acid in the same manner as in Example 1 d) (obtained in the same manner as in Example 1-2 b). Obtained as yellow morphus.

Example 11

Benzoic acid N, 1 (2-chloro-1,4-H-thieno [3,2-b] pyrrole-1-5-luponyl) hydrazine

(Obtained in the same manner as in Example 1-2 b)) Compound 25 (13.5 mg) was suspended in THF (2 ml) and cooled in an ice bath. Benzoyl chloride (8 μl) was added to this suspension and stirred at room temperature for 1 hour. When ice-cooled saturated aqueous sodium hydrogen carbonate was added to the reaction solution, a pale yellow solid precipitated. This was separated and washed sequentially with water and getyl ether. The solid was dried under reduced pressure to give the title compound 34 (1 6.Omg,

33%).

Example 11

N, 1-benzoic acid (4H-thieno [3,2-b] pyrrole-5-potassyl) hydrazine

a) 4H-thieno [3,2-b] pyrrole-5-carboxylic acid ethyl ester

In the same manner as in Example 1-3, a), the title compound 20 was synthesized from thiophene-2-carboxaldehyde.

XH-NMR (δ value, 400MH z, CDC 1 ₃₎

1.39 (3H, t, J = 7.2Hz), 4.37 (2H, q, J = 7.2Hz) 6.96 (1H, dd, J = 5.7, 1 OH z), 7.14 (1H, m), 7.32 (1H, d, J = 5.7Hz), 9.16 (1H, brs).

b) 4H-thieno [3,2-b] pyrrole-5-carboxylic acid

The title compound 22 was synthesized by hydrolyzing the compound 20 obtained in a) of Example 16 with sodium hydroxide. One NMR ([delta] value, 400ΜΗζ, DMSO- d ₆₎

6.97 (1 H, d, J = 5.3 Hz), 7.04 (1 H, d, J = 1.6 Hz),

7.49 (1H, d, J = 5.3Hz), 11.9 (1H, s), 12.5 (1H, s).

c) N, 1-benzoic acid (4H-thieno [3,2-b] pyruroyl 5-carbonyl) hydrazine

The title compound 35 (154 _mg , 82%) was obtained by reacting the compound 20 obtained in Example 16-b) with benzoic acid hydrazide in the same manner as in Example 1 c). Obtained as Amorphous.

Example 11

2-Amino-4 monofluorobenzoic acid N, ― (3-Promo-4H-Flo [3,2-1b] Pyruroyl 5-caprolponyl) hydrazide

The title compound was obtained in the same manner as in d) of Example 1.

Example 2

2-Amino-4 monofluorobenzoic acid N, 1 (2-chloro-6H-thieno [2,

3-b] pyrrole-5-carbonyl) hydrazine

a) 5-chlorothiophene-3-carboxylic acid methyl ester

Compound 5 (3-thiophenecarponic acid methyl ester) (2.14 g) was dissolved in acetonitrile (20 ml) and cooled to 0 ° C. Sulfuryl chloride (1.81 ml) was added dropwise to this solution, and the mixture was stirred at room temperature overnight. Add 10% thiosulfuric acid to this reaction solution. An aqueous sodium acid solution (100 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with getyl ether, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried and concentrated under reduced pressure. The obtained oil was purified by column chromatography to give the title compound 6 (1.26 g, yield 48%).

b) (5-chlorothiophene 3-inole)

Lithium aluminum hydride (270 mg) was suspended in THF (10 ml), cooled to 0 ° C., and a THF solution (5 ml) of compound 6 (1.25 g) obtained in a) of Example 2 was added. ) Was added dropwise, and the mixture was stirred at 0 ° C for 2 hours. To this reaction solution was added 1N hydrochloric acid (50 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure. The obtained oil was purified by column chromatography to give the title compound 8 (579 mg, yield 55%).

c) 5-chlorothiophene 3-carboxyaldehyde

Compound 8 (576 mg) obtained in b) of Example 2 was dissolved in chloroform (10 ml), manganese dioxide (2.88 g) was added, and the mixture was stirred at 50 ° C for 2 hours. The reaction solution was filtered through celite and concentrated under reduced pressure. The obtained oil was purified by column chromatography to give the title compound 10 (303 mg, yield 53%).

d) 2-Chloro-6H-thieno [2,3-b] pyrroyl 5-5-pyruvonic acid

In the same manner as in Example 1, b), the title compound 1 was obtained from compound 10 (293 mg). 2 (205 mg, 45% yield in two steps) was obtained as yellow crystals.

One NMR ([delta] value, 400MHz, CDC 1 ₃₎

1.38 (3H, t, J = 7.2Hz), 4.34 (2H, d, J = 7.2Hz): 6.90 (1H, s), 7.00 (1H, s), 9 .41 (1H, brs).

e) 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid hydrazide

The title compound 24 (71 mg, 84%) was obtained as yellow crystals from the compound 12 (9 Omg) in the same manner as in c) of Example 1.

XH-NMR (δ value, 400MHz, DMSO- d ₆₎

4.41 (2H, rs), 6.93 (1H, s), 7.14 (1H, s), 9.53 (1H, brs), 11.86 (1H, brs).

f) 2-Amino-4-fluorobenzoic acid N, 1- (2-chloro-6H-thieno [2,3-b] pyrrol-1-5-carbonyl) hydrazine

In the same manner as in Example 1, d), the title compound 29 was obtained from compound 24 (9 Omg).

(33 mg, 28%) was obtained as a yellow amorphous.

Example 2 could also be produced by the following method.

a) 2-Amino-4 monofluorobenzoic acid hydrazide

4 monofluoroanthranilic acid (7.0 g), HOB t'H ₂ O (8.29 g),

After dissolving EDC (9.49 g) in DMF (98 ml), hydrazine monohydrate was added.

(21.92 ml) was added, and the mixture was stirred at room temperature for 3 hours. Add water to the reaction, Organics were extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution and dried. This was concentrated under reduced pressure, and getyl ether was added to the obtained residue. The obtained solid was collected by filtration and dried under reduced pressure to give the title compound (2.78 g, 36%) as a white solid.

b) 2-Amino-4 monofluorobenzoic acid N, I (2-HCl-6H-thieno

[2,3-b] pyrrole-5-potassium) hydrazine

Compound 12 was hydrolyzed by a conventional method to give compound 50. Compound

Compounds 50 and 51 were reacted in the same manner as in Example 1 d) to obtain Compound 29 (yield 90%).

Example 2-2

2-Aminobenzoic acid N, 1 (6H-thieno [2,3-b] pyrroyl 5-carboyl) hydrazine

a) 6 H-thieno [2,3-b] pyrrolidine 5-carboxylate

The title compound 19 was synthesized from thiophene-3-carboxyaldehyde in the same manner as in Example 1 b).

One NMR ([delta] value, 400MHz, DMSO- d ₆₎

1.30 (3 H, t, J = 7.2 Hz), 4.27 (2H, q, J = 7.2 Hz): 6.99-7.02 (2H, m), 7.12 (1 H, d, J = 5.5 Hz), 12, 2 (1H, s).

b) 6H-thieno [2,3-b] pyrroyl 5- 5-pyruvonic acid

The title compound 21 was synthesized by hydrolyzing the compound 19 obtained in a) of Example 2-2 with sodium hydroxide.

^ -NM (δ value, 400 MHz, DMSO—d ₆ )

6.94 (1 H, d, J = 1.9 Hz), 7.00 (1 H, d, J = 5.6 Hz),

7.08 (1 H, d, J = 5.6 Hz), 12.1 (1 H, s), 12.5 (1 H, b rs).

c) 6H-thieno [2,3-b] pyrroyl 5- 5-pyruvonic acid hydrazide

Compound 21 (584 mg), hydrazine monohydrate (2.18 ml), EDC (688 mg) and HOB t · H ₂₀ (550 mg) obtained in b) of Example 2_2 were added to DMF. (10 ml) for 12 hours. Ice water was added to the reaction solution, and the precipitated solid was separated. The solid was washed successively with water and ether, and dried under reduced pressure to obtain the title compound 27 (416 mg, yield 66%).

XH-NM ([delta] value, 400MHz, DMSO- d ₆₎

4.36 (2H, s), 6.97-7.01 (3H, m), 9.43 (1H, s), 1 1.85 (1H, s).

d) 2-Aminobenzoic acid N, 1- (6H-thieno [2,3-b] pyrrole-1-5-caprolponyl) hydrazine

In the same manner as in Example 1, d), the title compound 33 (154 mg, 82%) was obtained as a yellow amorphous from compound 27 (123 mg) and anthranilic acid ² . Example 2-3

2-Amino-6-methylbenzoic acid N '-(2-Chloro-6H-thieno [2,3-1b] pyrroyl-5-capillonyl) hydrazide

The title compound was obtained in the same manner as in Example 2, f).

Example 2-4

2-amino-4-fluorobenzoic acid N, ― (2-fluoro-6H-thieno [2

3-b] Pyruyl 5- (Luponyl) hydrazide

The title compound was obtained in the same manner as in Example 2, f).

Example 2-5

3,4-Difluorobenzoic acid N, 1- (2-chloro-6H-thieno [2,3-b] pyrroyl-5-capillonyl) hydrazide

The title compound was obtained in the same manner as in f) of Example 2.

Example 2-6

Thiophene 1-3-Rubonic acid N, 1- (2-Chloro-6H-thieno [2,3b] pyrroyl 5-5-Rupoyl) hydrazide

In the same manner as f) of Example 2, _c to afford the title compound Example 2-7

2- {2- [N, 1- (2-chloro-6H-thieno [2,3-b] pyrroyl-5-potassium hydronyl) hydrazinocarbol] phenoxy} acetic acid

The title compound was obtained by a method similar to the method disclosed in Jouran alofOrganic Chemistry, 1991, 56, Vol. 6, page 2260, and WO 03Z037864. .

Example 3

6H-thieno [2,3-b] pyruroyl 5-carboxylic acid (2,4-dioxo-1,4-dihydro 2H-quinazoline-3-yl) amide

Compound 32 (86 mg) obtained in the same manner as in Example 14 was suspended in THF (3 ml), and sodium bicarbonate (64 mg) and water (0.12 ml) were added to the suspension. After the mixture was cooled on ice, triphosgene (27 mg) was added. After stirring this mixture for 1 hour, ethyl acetate and water were added. The separated organic layer was washed with water, dried and filtered. The filtrate was concentrated, and ether was added to precipitate crystals. This was collected by filtration and dried under reduced pressure to give the title compound 36 (75 mg, 83%).

Example 3-2

3-((6H-thieno [2,3-b] pyrrole-5-potassyl) amino) 1,2,4-dioxo-1,4-dihydro-1 2H-quinazoline

As in Example 3, 37 (75 mg, 83%) of the title compound was obtained from compound 33 (86 mg) (obtained in the same manner as in Example 2-2).

Example 3-3

a) 2- (2-Promoethoxy) benzoic acid methyl ester

After dissolving methyl salicylate (3.04 g) in dimethylformamide (DMF) (20 ml), add potassium carbonate (3.32 g) and 1,2-dipromoethane (5.2 ml) at room temperature. added. This solution was heated and stirred at 80 ° C. overnight. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride in that order, dried and concentrated under reduced pressure. The obtained oil was purified by column chromatography 1 to give the title compound ( _{1.15 §} , yield 22%) as a colorless liquid. ^X H-NMR (δ value, 300 MHz, DMS O-d ₆ )

3.78 (2Η, t, J = 5.5Hz), 3.78 (3H, s), 4.38 (2H, t, J = 5.5Hz), 7.06 (1H, dd, J = 7.3, 7.3Hz), 7.17 (1H, d, J = 8.4Hz), 7.53 (1H, ddd, J = l. 8, 7, 3, 8.4H z), 7.65 (1H, dd, J = 1.8, 7.3Hz).

b) 2— (2-promoethoxy) benzoic acid

Br Br

COOMe C00H

Methyl 2- (2-bromoethoxy) benzoate (1.15 g) was dissolved in a mixed solvent of methanol (8.80 ml) and tetrahydrofuran (8.80 ml), and 4N aqueous solution was added. Add lithium oxide (L i OH) (2.20 ml) and add at room temperature Stirred overnight. After concentrating the reaction mixture, the mixture was acidified by adding INHC1 under ice-cooling. The precipitated solid was collected by filtration to give the title compound (590 mg, yield 55%) as a white solid.

^ -NMR (δ value, 400MHz, DMSO- d ₆₎

3.78 (2H, t, J = 5.6Hz), 4.37 (2H, t, J = 5.6Hz), 7.03 (1H, dd, J = 7.4, 7.4Hz) , 7.13 (1H, d, J = 7.6Hz), 7.48 (1H, ddd, J = 1.8, 7.4, 7.6Hz), 7.62 (1H, dd , J = 1.8, 7.4Hz), 12.58 (1H, s).

c) 2- (2-Promoethoxy) benzoic acid N, 1- (2-chloro-6H-thieno [2,3-b] pyrrole-1-5-luponyl) hydrazide

twenty four

The title compound (170 mg, yield 7, 6%) was obtained from 2- (2-bromoethoxy) benzoic acid (126 mg) and compound 24 (111 mg) in the same manner as in d) of Example 1. Obtained as beige crystals.

— NMR (δ value, 300MHz, DMSO— d ₆ )

4.07 (2H, t, J = 5.5Ηζ), 4.45 (2Η, t, J = 5.5Hz): 7.1 1-7.25 (4H, m), 7.54 (1H, ddd, J = 1.8, 7.3, 7.5 Hz), 7.81 (1H, dd, J = 1.8, 7.7Hz), 9.92 (1H, brs), 10.51 (1 H, brs), 12. 04 (1 H, brs). D) 2-H-I-OH 6H-thieno [2,3-b] pyruro-l-5-5-pyruvonic acid (5 l-oxo-l, 2,3 —Dihydro-5H—benzo [f] [1,4] oxazepine-4-yl) amide

2- (2-promoetoxy) benzoic acid N, 1- (2-chloro-6-H-thieno [2,3-b] pyrroyl-5-capillonyl) hydrazide (167 mg) to dimethylformamide (DMF) (3 5 ml), potassium carbonate (226 mg) and a catalytic amount of sodium iodide were added thereto, and the mixture was heated and stirred at 80 ° C overnight. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure. Purification by column chromatography gave the title compound (112 mg, yield 82%) as a white solid.

Example 3-4

2—Black mouth _ 6 H—Thieno [2,3-b] Pyro 1-5-Ironoleponic acid (6—Fluoro 1,3-Dioxo-1,3,4-Dihydro 1 H—Isoquinoline 1 Amide

101 102

Compound 101 (300 mg) synthesized according to WO 03/068743 was dissolved in 6 ml of acetone. To this solution was added 0.5 ml of acetyl chloride, and the mixture was stirred. After that, the reaction solution was concentrated to obtain Compound 102.

After dissolving Compound 102 in 7 ml of acetic acid, Compound 24 was added, and the mixture was heated to 130 ° C and stirred for 3 hours. After the reaction solution was cooled to room temperature, 7 ml of water was added, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (259 _mg , 53%) as a white solid.

Example 3-5

2-chloro-6H-thieno [2,3b] pyrrole-5-potassic rubonic acid (8-fluoro-2,5-dioxo-1,1,2,3,5-tetrahydrobenzo [e] [1, 4] Jazepine 1—Innole) Amid

29 Compound 29 (335 mg) was dissolved in a mixed solvent consisting of 20 ml of THF and 0.5 ml of pyridine. The solution was cooled in an ice bath, 0.1 ml of chloroacetyl chloride was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The obtained organic layer was washed sequentially with a 1 N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution. The solution was dried and concentrated under reduced pressure to obtain an oil (199.1 mg). After dissolving this oil in 4 ml of DMF, 10 mg of sodium iodide and 276 mg of potassium carbonate were added. The mixture was heated to C and stirred for 2 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate (60 ml). The obtained organic layer was washed with a saturated aqueous solution of sodium chloride and dried. This was concentrated under reduced pressure, and hexane was added to the obtained residue. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (86. Omg, 22%) as a white solid.

Example 3-6

6.H-thieno [2,3-b] pyrroyl-5-carboxylic acid (7-fluoro-2,4-dioxo-1,4, dihydro-1 2H-quinazoline-1-3-yl Amid

The title compound was obtained from compound 29 in the same manner as in Example 3.

Example 3-7

2-chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid (5-methyl-1,4-dioxo-1,4-dihydro 2H-quinazoline-13-yl) ,

The title compound was obtained in the same manner as in Example 3.

Example 3-8

2-Chloro-6H-thieno [2,3-b] pyrro-noreno-5-potenolevonic acid (6-hydroxy-1,2,4-dioxo-1,4-dihydro-2H-quinazoline-13-yl) amide

The title compound was obtained in the same manner as in Example 3-2 (or Example 3).

Example 3-9

2,3-Dichloro-4H-thieno [3,2-b] pyruroyl 5-carboxylic acid (7-fluoro-2,4-dioxo-1,4 dihydro 2H-quinazoline-13-yl) amide

In the same manner as in Example 3, the title compound was obtained from the compound of Example 1.

Example 3-10

2-Chloro-4H-furo [3,2-b] pyro-mono-5-canoleponic acid (7-funoleol 2,4-dioxo-1,4-dihydro-1 2H-quinazoline-13-yl)

The title compound was obtained in the same manner as in Example 3.

Example 3—1 1

2-Fluoro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid (7-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazoline-13-yl) amide

The title compound was obtained in the same manner as in Example 3.

Example 3-12

2H-thieno [2,3-b] pyrrole-5-carboxylic acid (5,7-dioxo-1,4,7-dihydro 5H-thiazolo [5,4-d] pyrimidine-1 6— Yl) Amid

The title compound was obtained from compound 24 in the same manner as in WO 03/037864 and Example 3.

Example 3-13

(2-Chloro-6H-thieno [2,3-b] pyrrole-1-5-carboxylic acid) N, 1 (4-methoxycarbonylthiophene-3-aminocarbonyl) hydrazide

Methyl 4 primary amino Chio phen one ₃ - suspended carboxylate hydrochloride (29 lmg) in black port Holm was cooled in an ice bath. 2,6-lutidine

(2,6-Lutidine) (0.58 ml) and triphosgene (149 mg) were added in this order. The mixture was stirred at room temperature for 1 hour. Compound 24 (323 mg) was added to the mixture, and the mixture was stirred at room temperature overnight. Ice water and ethyl acetate were added to the reaction mixture. The precipitated solid was collected by filtration. The solid was dried under reduced pressure to obtain the title compound (446 mg).

Example 3-14

2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid (2,4-dioxo1-1,2-dihydro-4H-thieno [3,4-d] pyrimidine-1-3 Le) Amid

The compound obtained in Example 3-13 was suspended in methanol (3 ml). To this mixture was added a 4N aqueous sodium hydroxide solution (0.43 ml), and the mixture was stirred at room temperature for 30 minutes. The mixture was ice-cooled, and 6N hydrochloric acid aqueous solution (0.33 ml) was added. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give 274 mg of the title compound as a pale yellow solid. Example 4

2-chloro-4H-thieno [3,2-b] pyrroyl 5-carboxylic acid N, 1- (iminophenol) hydrazine methanesulfonate

Compound 25 (62 mg) was suspended in methanol (0.6 ml). To this was added thiobenzimidic acid methyl ester hydroiodide (83 mg), and the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the obtained solid was washed with water and subsequently with ether. This solid was suspended in methanol (2.0 ml). Methanesulfonic acid (30 μl) was added to this to give a clear solution. When ether was added to this solution, fine needle-like crystals were obtained. This was separated, washed with ether, and dried under reduced pressure to give the title compound 38 (94 mg, 80%) as white crystals.

Example 4-1

2-Aminobenzoic acid N, 1- (2-chloro-4H-thieno [3,2-b] pyrroyl-1-5-propyl) hydrazine r> -Toluenesulfonate

Compound 32 (63.7 mg) obtained in Example 14 was suspended in THF (5 ml), and p-toluenesulfonic acid monohydrate (54 mg) was added thereto. When the resulting clear solution was allowed to stand, needle crystals precipitated. This was separated, washed with ether and dried under reduced pressure to give the title compound 39 (86 mg, 89%).

Example 4 1-3

2-Amino-4 monofluorobenzoic acid N,-(2-bromo-6H-thieno [2,3-b] pyrroyl-5-carbonyl) hydrazide p-toluenesulfonate

A salt was prepared in the same manner as in Example 4 to give the title compound.

Example 4

2-amino-4 monofluorobenzoic acid N,-(2-chloro-6H-thieno [2,

3-b] pyrrole-5-capillonyl) hydrazide p-toluenesulfonate

The title compound was obtained from compound 29 in the same manner as in f) of Example 2 and Example 4-2.

Example 41

Sodium 2- {2- [N,-(2-chloro-6H-thieno [2,3-b] pi-5-5-potanol) hydrazinocarponyl] phenoxy} acetate

The compound of Example 2-7 was converted to a sodium salt according to an ordinary method to obtain the title compound.

Example 5

a) 5-(2-black 6H-thieno [2,3-b] pyrroyl 5-yl) 1 3H-[1, 3, 4] oxaziazol 1-2-one

Compound 24 (265 mg) was dissolved in dioxane (50 ml), cooled to 0 ° C, and triphosgene (135 mg) was added. The reaction solution was warmed to room temperature, stirred for 4 hours, concentrated, and dried under reduced pressure to obtain the title compound (245 mg, 82%) as a pale yellow substance.

iH—NMR (δ value, 400 MHz, DMS O—d ₆ )

6.83 (1 H, s), 7.16 (1 H, s), 12.39 (1 H, s), 12.43 (1 H, s).

b) N—Feniru N — ((E) ostyryl) carbamoyl chloride

105

Compound 105 (1.99 g) was dissolved in toluene (40 ml), pyridine (3 ml) was added, and after cooling with ice, triphosgene (2.10 g) was added. The reaction solution was heated to 130 ° C. and stirred for 2 hours. After the reaction solution was cooled to room temperature, insolubles were removed. The obtained solution was concentrated and dried under reduced pressure to give the title compound (2.58 g, 99%) as a brown solid.

c) 5- (2-Chloro-6H-thieno [2,3-b] pyrroyl-5-yl) -2-oxo-1 [1,3,4] oxaziazolu-l 3-carboxylate N-phenyl-1N ,-[1-Phenyl-methy (E) -Liden] hydrazide

5- (2-Chloro-6H-thieno [2,3-b] pyrrole-1-yl) -13H- [1,3,4] oxaziazol-12-one (245 mg) in anhydrous DMF (4 ml) Was dissolved. To this solution was added 60% sodium hydride (44 mg), and the mixture was heated to 55 ° C and stirred for 1 hour. The reaction mixture was cooled on ice, and a solution of N-phenyl (N-((E) styryl)) rubamoyl chloride (285 mg) in ethyl acetate (2.5 ml) was added. The temperature was raised to 70 ° C. And stirred for 5 hours. 2 Oml of water was added to the reaction solution, and extracted with ethyl acetate (20 ml). The obtained organic layer was washed with a saturated aqueous solution of sodium chloride (10 ml), dried and concentrated under reduced pressure. The obtained oil was purified by column chromatography to give the title compound (221 mg) as a brown oil.

d) 2-Methyl 6H-thieno [2,3-b] pyrrole-5-carboxylic acid (3,5-dioxo1-1-phenyl-1- [1,2,4] triazolidine-1-yl) amide ,

5- (2-Chloro-6H-thieno [2,3-b] pyrrole-1-5-yl) 1-2-oxo-1 [1,3,4] oxadiazo-1-3 3-Rubonate N-phenyl-1 N,- [1—Fenilumechi (E) —Liden] Hydrazide (221 mg) was dissolved in ethanol (10 ml). To this solution was added 6 N hydrochloric acid (2 ml), the temperature was raised to 100 ° C., and the mixture was stirred for 3 hours. After the reaction solution was cooled to room temperature, the precipitated solid was collected by filtration to give the title compound (127 mg, 33%) as a solid.

The compounds obtained above are shown in Tables 1-2.

table 1

06

.T6800 ^ 00Zdf / X3d εεπ / ΐθο OAV Table-2

J =

, S).

(δ value, 400MHz, DMSO-de)

HH ^H 2 ^N 2.33 (3H, s), 5.60 (2H, m), 6.69 (lH, m),-2 6.84 (lH, m), 7.08-7.16 (5H, m), 7.46 (2H, m),

H

7.66 (lH, m), 10.25 (2H, m), 12.0 (lH, m).

(δ value, 400MHz, DMSO-de)

HH. . H ₂ N

2.29 (3H, s 6.37 (1H td, J = 8.5, 2.5 Hz), d /-

SN 0 0 ^W 6.50 (IH, dd, J = 11.8, 2.6 Hz), 7.10-7.11 (3H-3 H

m 7.29 (1H s 7.47 (2H d, J = 8.3 Hz), 7.66

H ₃ C ^}-S ^P -0H (IH, t, J = 7.7 Hz), 10.10 (IH, s 10.14 (1H,

0

s), 12.01 (IH, s).

(δ value, 400MHz, DMSO-de)

2.29 (3H s), 6.35-6.53 (2H, m), 7.10-7.12-4 (3H m 7.20 (IH, s 7.48 (2H, d, J = 7.9 Hz),

7.67 (1H dd, J = 8.6 6.7 Hz), 10.12 (1H s

10.16 (1H s 12.02 (IH, s).

(δ value, 400MHz, DMSO-de)

0

r-K 4.42 (2H s 7.03 (1H dd, 7 = 5.6, 12.5Hz), H H 00-Na

-5 7.10-7.22 (3H m), 7.43 (IH, m), 7.73 (1H d,

SN 0 0 ^W 7 = 7.9 Hz), 10.18 (1H s 12.03 (IH, s 12.48 H

(IH, s).

(δ value, 400MHz, DMSO-de)

7.20-7.28 (3H m 7.47-7.54 (2H, m 7.58- 7.62 (2H, m 11.13 (1H s 11.70 (IH, s), 12.35 (1H s). Example 5-2 to 5-5

The compounds of Examples 5-25-5 can be obtained in the same manner as in Examples 1-17-1 and 2-27 and Example 5, or a method analogous thereto. The obtained compounds are shown in Table 3. Table-3

Examples 6 to 6—14

Compounds of Examples 6 to 6-14 can be obtained by a method similar to or a method analogous to Examples 3 to 3-14. The compounds obtained are shown in Table 4.

Examples 7 to 7 6

The compounds of Examples 7 to 76 can be obtained by a method similar to or a method analogous to Examples 1 to 7 and 2-2-7. The compounds obtained are shown in Table 5.

Table-5

Test Example (1) Method for measuring liver glycogen phosphorylase activity

The measurement of glycogen phosphorylase activity was performed by measuring the concentration of phosphoric acid generated during the reverse reaction, ie, the reaction of glycogen phosphorylase to synthesize G1-P into glycogen. As an enzyme solution of human liver glycogen phosphorylase, a cell lysate of Sf9 cells in which recombinant human liver glycogen phosphorylase was forcibly expressed was imM imidazole-hydrochloride buffer (ρΗ7.0, 0.2 mM PMS F , 25 OmM NaC 1, containing 0.025% BSA) to a protein amount of 80 g gZniL. As substrate solution, 25mM T ris- H 1 buffer (1) 117. 2, 25 OmM KC 1, 6. 25 mM Mg C 1 2, 6. 25 mM EGTA, 1. 25 mM glucose- 1- hosphate, 2.5 mg Zmlglycogen, containing 7.5 mM glcose). The test drug was dissolved in 0.5% dimethyl sulfoxide (DMSO). The enzyme reaction was started by adding 20 μl of the enzyme solution to a mixture of the test drug 101 and 20 μl of the substrate solution. As a control, 0.5% DMSO was added instead of the test drug. A sample without addition of the enzyme was used as a blank. After allowing the reaction to proceed at room temperature for 60 minutes, adding 500 l of malachite green solution, and further reacting at room temperature for 20 minutes, the absorbance at 650 ηm was measured. The enzyme solution was added to the blank at the same time as the malachite green solution, and the measurement was performed in the same manner. The inhibition rate (%) of the test drug was calculated by ((control value−test drug value) / (control value−blank value)) XI 00 (%).

Table 6 shows the test results of the above test examples.

Table 6

The enzyme inhibitory activity against HLGPa is +, when IC 50 (nM) is 100 nM or more and less than 1000 nM,

Indicated by ++. Test example (2) Measurement method of glycogen phosphorylase activity

Measurement of glycogen phosphorylase activity, row ivy by a method using a normal reaction ₀

The measurement of Daricogen phosphorylase activity using the forward reaction system was performed by the following method. Glucose-1-phosphate (hosphate), which is produced from glycogen by glycogen phosphorylase, is used to convert glucose-1-: hosphate to phospho-hognogolecomtase (h. Glucose 6-phosphate dehydrogenase (G6 PDH)] to conduct a transphosphorylation reaction and dehydrogenation reaction, and to obtain a Darconau δ-lactone 6-phosphate (g 1 uc ο η ο

— Δ—lactone 6-phosphate). At this time, G6 NAD PH generated from NAD P during the dehydrogenation of P DH was detected. As an enzyme solution of human liver glycogen phosphorylase, a cell lysate of Sf9 cells in which recombinant human liver glycogen phosphorylase was forcibly expressed was used as a 10 Ommo1 / LBES buffer solution (pH 6.8, 2 mm o 1 / L EDTA) was used. As substrate solution, using phosphoric acid buffer solution _{(1 6 mm ol ZL KH 2} PO 4, 2 4 mm o 1 / LN a 2 HP 0 4 containing). A mixture of 8 UZmL phosphoglucomutase 60 15 / m LG 6 PDH was prepared in BES buffer. Reaction buffer (1. 4 mm ol ZL NAD P , 3 0 mm o 1 / L Mg C 1 2, 8 / imol / L glucose one 1, 6 Jihosufue Ichito (G lucose- 1, 6- diphosphate) , 8 mg / mL glycogen, 40 mmol ZL BES, containing 0.8 mmo1 / L EDTA, and glucose solution (TS mmol ZL gnorecose, 100 mmo1 / LBES, 2 mmo) 1 / L EDTA). The test substance was dissolved in an aqueous solution containing 1% DMSO.

A mixture of 20 μL of glucose solution, 20 L of substrate solution, 100 L of reaction buffer, and 20 μL of test substance, combined with 20 μL of recombinant human liver glycogen phosphorylase solution and phosphognorecomtase (Phosphoglcomutase) and 20 L of a mixed solution of G6PDH were added to start the enzyme reaction. As a control, an aqueous solution containing l% DMS O was added instead of the test substance. The one without the substrate was used as a blank. Immediately after the start of the reaction, the absorbance at 340 nm was measured. After reacting at room temperature for 75 minutes, the absorbance at 340 nm was measured again. The value obtained by subtracting Planck from the absorbance change for 75 minutes was defined as the enzyme activity. The inhibition rate (%) of the test substance was calculated from “(11 (enzyme activity of test substance) / (enzyme activity of control)) XI 00”.

IC _5. The value was calculated from the concentration obtained from the intersection with the 50% inhibition rate by calculating a linear equation from the concentration points before and after the 50% inhibition rate.

Table 7 shows the test results of the above test examples. Table-7

The enzyme inhibitory activity against HLGPa is indicated by ++ when the IC 50 (nM) is not less than Ι Ο ΜηΜ and less than 100 OnM, and is indicated by ++ when the IC 50 (nM) is less than 100 OnM.

Test example (3) Measurement method of plasma glucose concentration

The effect of the compound (1) of the present invention on plasma glucose concentration was examined using db / db mice, which are obese diabetes models. The plasma glucose concentration of dbZdb mice (10 to 15 weeks of age) was measured, and the mice were divided into groups of 5 animals so that there was no difference in the average value of the plasma glucose concentration of each group. After a 4-hour fast, dbZdb mice were orally administered an example compound or a solvent (0.5% methylcellulose), and plasma glucose levels were measured 1 and 3 hours after administration. Evaluation of the hypoglycemic action of the example compound was performed by performing a significant difference test between the solvent administration group and the example compound administration group at each time interval (Dunnett test).

The test results of the above test examples are shown in Table 8 below.

Table 1 8

The hypoglycemic effect was indicated by 10 when the minimum effective dose was 100 mg Zkg or less, and by ++ when the minimum effective dose was 1 Omg / kg or less. Industrial applicability

As is clear from the above test, the novel compound of the present invention and its pharmaceutically acceptable salt strongly inhibited human liver glycogen phosphorylase. Having such an action mechanism, the compound (1) of the present invention is useful as a therapeutic drug for diabetes. In addition, the compound of the present invention is useful in combination with another drug for treating diabetes or a drug for treating hyperlipidemia. This application is based on a patent application No. 2003-1777213 filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims

1. General formula (1)

(In the formula,

R ¹ is a hydrogen atom or an acyl group;

R ² is a hydrogen atom or a Ci-e alkyl group;

R ³ is a hydrogen atom or a Ci-e alkyl group;

One — G ₂ — G ₃ — is —S— C (R ⁵ ) = C (R ⁶ ) —, -C ( ⁵ ) = C (R ⁶ ) — S—, -OC (R ⁵ ) = C ( ⁶ ) One, -C (R ⁵ ) = C (R ⁶ ) one O--. One N (R ⁷ ) one C (R ⁵ ) = C ( ⁶ ) one, -C (R ⁵ ) = C (R ⁶ ) One N (R ⁷ ) —, -N = C (R ⁵ ) —S— or one S—C ( ⁵ ) = N— (where R ⁵ and ぴ R ⁶ are the same or different, Independently, a hydrogen atom, a halogen atom, an alkyl group, a ₆ alkoxy group, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, an aralkyloxy group or a thiazolyl group (the thiazolyl group is an alkyl group or an amino group) R ⁷ is a hydrogen atom or an acyl group);

R ⁴ is

{Where = X is = O, = S or = NH;

A is —N (R ⁸ ) one (where R ⁸ is a hydrogen atom, —6 alkyl group or aryl group which may have a substituent), —C (R ⁹ ) (R ¹⁰ ) -(Where R ⁹ and R ¹⁰ are the same or different and are independently a hydrogen atom, a hydroxyl group, an amino group, ₆ alkyl groups, C WINCH ₆ hydroxyalkyl group, c ₂ - ₇ alkoxycarbonyl amino group or Ashiruamino a group force or R ⁹及Pi R ^1G is a together with the carbon atom adjacent connexion, C _3, - ₇ cycloalkyl An alkyl group), one (CH ₂ ) _m —NH— (where m is an integer of 1 to 4), one CO— or a single bond;

B is

(Where ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are the same or different and are independently a hydrogen atom, a halogen atom, a C ₆ alkyl group, a Ci- ₆ alkoxy group, a nitro group, a hydroxyl group , A cyano group, a haloalkyl group, an aralkyl group, an aryl group which may have a substituent, an aryloxy group, a tetrazolyl group, a triazolyl group, one (CH ₂ ) _p to CO- ¹⁹ (where p is 0 or 1 R ¹⁹ is an aryl group which may have a substituent, a hydroxyl group, a C ₆ alkoxy group or —N (R ²⁰ ) (R ²¹ ) (where R ²⁰ and R ²¹ are same or different, independently represent a hydrogen atom, C i _ ₆ alkyl group, or a Ararukiru group or c ₃ _ i ₃ alkoxy Cal Poni Le alkyl group, or summer together with the nitrogen atom to which R ^2G and R ²¹ are adjacent hand,

(Where, q is an integer from 1 to 3, R ²² is a hydrogen atom, a hydroxyl group, C - ₆ alkoxy group, an amino group, at C ₂ one ₁₂ dialkylamino group or a C ₂ _ ₇ alkoxycarbonyl two Ruamino group O) (CH _¾ ) _r -R ²³ (, In this, r is an integer from 1 to 4, R ²³ is a hydroxyl group, an amino group, C ₂ _ ₇ alkyl force Lupo - Ruokishi group or one CO- R ²⁴ (wherein, R ²⁴ represents a hydroxyl group, Bok ₆ an alkoxy Group or one of N (R ²⁵ ) ( ²⁶ ) (where R ²⁵ and R ²⁶ are the same or different and are a hydrogen atom, an alkyl group or an aralkyl group, or R ²⁵ and R ²⁶ are adjacent Together with the nitrogen atom,

(Where (1, and R ²² 'may be synonymous with q and R ²² , respectively))), -O-CO-R ²⁷ (where R ²⁷ is Arukirua amino group or a C ₂ one ₁₂ dialkylamino group), or one ^{^{N (R 28) (R 29}} ) ( in here, R ²⁸ and R ^29, same or different, a hydrogen atom, C - ₆ alkyl group which may have a location substituent Ariru group, Ashiru group one _{_{(CH 2) p> -COO-}} R 3 0 ( wherein, p 'is synonymous with p, R ³ ° represents hydrogen atom, it may also have a substituent group I Ariru group or _{C l} _ ₆ alkyl group (the alkyl group, a hydroxyl group, triflate Oromechiru group which may have a substituent Ariru group, a morpholino group or a carboxyl also may) be substituted with group), one ^{^{CON (R 31) (R 32}} ) ( wherein, R ³¹及Pi R ³² are the same or different, a hydrogen atom, an alkyl group or a substituted Is an aryl group which may have a group), -CO-R ³³ (where R ³³ is a C-alkyl group or an aryl group which may have a substituent) or _{_{-. (CH 2) r -R}} 34 ( where, r, have the same meanings as r, R ³⁴ is C alkylamino group, C ₂ - ₁₂ dialkylamino group, an alkoxy group or a C ₂ - ₇ alkyl Cal Poniruokishi group Is) is)), and

R ^16b to R ^16g and R ^17b to R ^{17 g} are the same or different, a hydrogen atom, a halogen atom, CI- ₆ alkyl group, an amino group, a hydroxyl group, Bok ₆ alkoxy groups, one COOR ³⁵ (where; ³⁵ , same or different, a hydrogen atom or an alkyl group Ru der) or single ^{CON (R 31>) (R} 32 ') ( wherein, R ^31'及Pi R ^32> is R ³¹ and R ³ ² synonymous Is)

Y is one S—, one O— or one N (R ³⁶ ) one (where R ³⁶ is a hydrogen atom or one ₆ alkyl group (said CI_ ₆ alkyl group, a carboxyl is substitution with a group or tetrazolyl group may also be) and a),

n is 0 or an integer from 1 to 4), or

R ³ and R ⁴ together with the adjacent nitrogen atom

(i) (ii) (iii)

(iv) (v) (vi)

{Wherein, R ³⁷及Pi R ³⁸ are the same or different, a hydrogen atom, a halogen atom, C丄- ₆ alkyl group, - 6 alkoxy group, an amino group, Yutoro group, hydroxyl group, C ₂ - ₇ § alkoxy Karuponiru group, forces Rupokishiru group, C ₂ - ₇ haloalkyl force Ruponiruamino group or one O-CO- R ⁴² (wherein, R ⁴² is - 6 alkyl group, - 6 is alkyl Ruamino group or C i ₂ dialkylamino group ) Is;

Z is one CH ₂ — CH ₂ —, -C (R ⁴³ ) = CH—, one C (R ⁴³ ') = N—, one N

N—, -CO CO— CH ₂ —, one CO— O—, CO-CH, O

— CH ₂ — CO— NH—, one C (R ⁴³ ") (R ⁴⁴ ) one N (R ⁴⁵ )-(where ' ³ , R ⁴³ ', R ⁴³ '' and R ⁴⁴ are the same or Differently, a hydrogen atom, a —6 alkyl group or an aryl group which may have a substituent, and R ⁴⁵ is a hydrogen atom,

₆ alkyl group (said C 3_ one ₆ alkyl groups force Rupokishiru group or C ₂ - may be substituted with ₇ alkoxy force Ruponiru group) or C ₂ - a ₇ alkoxycarbonyl group),

— C (= U) — N (R ⁴⁸ )-(where = U is = O or = S and R ⁴⁸ is synonymous with R ⁴⁵ ) or one (CH ₂ ) s -O- (formula Wherein s is an integer of 1 to 3, and the methylene group may be substituted with an oxo group. The atom adjacent to the nitrogen atom on the fused ring is described at the left end);

R ³⁹ is a hydrogen atom, an aryl group which may have a substituent or a heterocyclic group.

R ⁴ ° and R ⁴¹ are the same or different, a hydrogen atom, C - ₆ alkyl group, ₆ § alkoxy group or a C ₂ _ ₇ alkoxy force Lupo - or a group, or adjacent R ^4G及Pi R ¹ Together with the carbon atom

May form;

Q is one (CH ₂ ) t— (where t is 2 or 3 and the methylene group may be substituted by an oxo group), one CO—NH—CH ₂ — or one CH ₂ — NH— CO—

W is one CO—, one CS— or —CH ₂ —;

V is one CO—, one CS— or one CH ₂ —;

V ₂ is one O—, one CH ₂ — or one N (R ⁴⁶ ) — (where R ⁴⁶ is a hydrogen atom, a C 丄 -6 alkyl group or an optionally substituted aryl group) V ₃ is one CH (R ⁴⁷ ) one or one N ( ⁴⁷ ′) — (where R ⁴⁷ and R ⁴⁷ ′ each have a hydrogen atom, an aralkyl group, a heterocyclic group or a substituent. Or a pharmaceutically acceptable salt thereof.) A condensed pyrrole compound represented by the formula:

2. Y is one S—, one O— or one N ( ³⁶ ) — (where R ³⁶ is a hydrogen atom or

— A 6-alkyl group)

Z is one CH ₂ — CH ₂ —, -C (R ⁴³ ) = CH—, C (R ⁴³ ') = N—, N = N—, one CO—, one CO—O—, one CO— CH ₂ — O—, one CH ₂ — CO—NH—, one C (R ^{43 >>} ) (R ⁴⁴ ) one N (R ⁴⁵ ) I (where R ⁴³ , R ⁴³ ′, R ⁴³ ”and R ⁴⁴ are the same or different and are each a hydrogen atom, an alkyl group or an aryl group which may have a substituent, and R ⁴⁵ is hydrogen, CI- ₆ alkyl group (those the C _ ₆ Arukiru groups force Rupokishiru group or C ₂ - ₇ alkoxy force Rupoyuru group may be substituted) or C ₂ - a ₇ alkoxycarbonyl Cal Poni Le group), one C (= U) one N (R ⁴⁸ )-(where = U is = 0 or = S, and R ⁴⁸ is synonymous with R ⁴⁵ ) or one (CH ₂ ) s—O— (wherein s is an integer of 1 to 3, and the methylene group may be substituted with an oxo group.

R ^4. And R ⁴¹ are the same or different, a hydrogen atom, _alkyl group, ₆ § alkoxy group or a C ₂ - and the carbon atom to which either a group, or R ^4D及Pi R ⁴ ¹ is adjacent - ₇ alkoxy force Lupo Together,

The condensed pyrrole compound according to claim 1, a prodrug thereof or a pharmaceutically acceptable salt thereof.

3. The fused pyrrole compound according to claim 1, wherein R ¹ and R ² are a hydrogen atom, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

4. R ⁴ is

{Where X is as defined in claim 1;

A is, - N (R ⁸ ") one (. Wherein, R ⁸ '' is a hydrogen atom, Bok ₆ have an alkyl group or a substituted group is also good Ariru group), -C ^(9") (R ¹⁰ "') one (where R ⁹ '' and R ^{1 ()} '' are the same or different and are each independently a hydrogen atom, a hydroxyl group, an amino group, an alkyl group, a hydroxyalkyl group or a C ₂ _ ₇ alkoxycarbonylamino group, or R ⁹ "and such together with the carbon atom adjacent connexion, it may form a C ₃ _ ₇ cycloalkyl group), in one (CH ₂₎ _m -NH- (here, m is claim 1 Synonymous with), one CO— or a single bond;

B is

(f2 ') (g')

^{^{(Wherein, R i, R 12 ',}} R 13', R 14 '及Pi R ^15' are the same or different, and independent, hydrogen atom, halogen atom, C ^ e alkyl group, 0 ^ ₆ Alkoxy group, nitro group, hydroxyl group, cyano group, haloalkyl group, aralkyl group, optionally substituted aryl group, aryloxy group, tetrazolyl group, triazolyl group,-

(CH ₂ ) _p —CO—R ¹⁹ (where p and R ¹⁹ are as defined in claim 1),

— O— (CH ₂ ) _r -R ²³ (where r and R ²³ are as defined in claim 1),

-O-CO-R ²⁷ (where R ²⁷ is as defined in claim 1) or one N (R ²⁸ ") (R ²⁹ ") (where R ^28> 'and R ²⁹ ''' are Same or different, hydrogen atom, one Alkyl group, aryl group optionally having substituent (s), one (CH ₂ ) COO

-R ³⁰ "(where, p, is!) And has the same meaning, R ³⁰ '' is a hydrogen atom or an alkyl Le group (the - ₆ alkyl groups, hydroxyl group, substituted with triflate Ruo Russia methyl group or a carboxyl group ), -CON (R ³¹ ) (R ³² ) (where R ³¹ and R ³² are the same as in claim 1), -CO-R ³³ (where R ³³ is Is synonymous with claim 1) or one CO— (CH ₂ ) _r . -R ³⁴ (where r and R ³⁴ are synonymous with claim 1);

1 ₆ 1 ₃ to ₁ ^ ₁及Pi _{1 1} to _{1 1} is as defined in claim 1,

Y, is one S— or one N (R ³⁶ ) 1 (where R ³⁶ is as defined in claim 1);

η is the same as in claim 1).

R ³ and R ⁴ together with the adjacent nitrogen atom

(! ') (Π') (iii ':

(iV) (ν ') (νί')

{Wherein, R ³⁷ ′ and R ³⁸ ′ are the same or different and are each a hydrogen atom, a halogen atom, a 6 alkyl group, a Ci- ₆ alkoxy group, an amino group, a hydroxyl group, or —O—CO—R ⁴² (where R ⁴² is as defined in claim I);

Z 'is one CH CH, — C (R ⁴³ ) = CH—, one N = N—, one CO—, one CO—CH ₂ —, one CO—O—, one CO—CH ₂ — O—, One CH ₂ — CO— NH

^{-, -C (43 ") (} R 44) - N (45 ') - ( wherein, R ^43, R ^43"及Pi R ⁴⁴ has the same meaning as claim I, R ^45' represents a hydrogen atom, - 6 alkyl or C ₂ one ₇ § Is a alkoxycarbonyl group), one C (= U) - N ( R 48 ') - ( wherein, = U is = 0 or = S, R ^48' has the same meaning as R ⁴⁸⁾ or one (CH ₂ ) s -O- (wherein s is an integer of 1 to 3, and the methylene group may be substituted with an oxo group);

R ^39> is a hydrogen atom or an aryl group which may have a substituent;

1 ⁴ ° '及Pi 1 ^41> are the same or different, a hydrogen atom, - 6 alkyl or C ₂ - ₇ alkoxy force Lupo - or a group, or R ⁴ °' adjacent及Pi R ⁴¹ ' Together with the carbon atom

May form;

Q ′ is one (CH ₂ ) t— (where t is 2 or 3 and the methylene group may be substituted with an oxo group), one CO—NH—CH ₂ — or one CH ₂ — NH — CO— is;

W is one CO— or one CH ₂ —;

Y and V ₂ 'have the same meanings as Oyopi ₂ of claim 1;

V _3, one CH (R ^{47 >>)} one or one N (R ⁴⁷ '") one (wherein, R ^47"及Pi R ⁴ ⁷ ... are the same or different, have a hydrogen atom or a substituent The fused pyrrole compound, the prodrug thereof or the pharmaceutically acceptable salt thereof according to claim 3, which is an aryl group which may be optionally substituted).

5. Y, one S— or one N (R ³⁶ ) —, where R ³⁶ is a hydrogen atom or an alkyl group;

Z 'force — CH ₂ — CH ₂ —, -C (R ⁴³ ) = CH—, — N = N—, —CO—, — CO— O—, — CO— CH ₂ — O—, one CH ₂ — CO— NH—, one C (R ⁴³ ") (R ⁴⁴ ) one N (R ^45> ) ― (where R ⁴³ , R ^43> 'and R ⁴⁴ are as defined in claim 1, and R ⁴⁵ ' is a hydrogen atom, a Ci- ₆ alkyl group or a C ₂ _ ₇ alkoxycarbonyl group), one C (= U) — N (R ⁴⁸ ') one (where = U is = O or = S, and R ⁴⁸ ' is synonymous with R ⁴⁸ ) or one (CH ₂ ) s -O- (where s is A methylene group may be substituted with an oxo group), and R ^4. 'And: ⁴¹ ' are the same or different and are a hydrogen atom, a Ci- ₆ alkyl group or C ₂ — _{7 is an} alkoxycarbonyl group, or R ⁴ ° 'and R ⁴¹ ' are taken together with an adjacent carbon atom,

, Nu

The condensed pyrrole compound according to claim 4, which may form a prodrug thereof or a pharmaceutically acceptable salt thereof.

6. The fused pyrrole compound according to any one of claims 1 to 5, wherein one Gi—G ₂ —G _3— is one S—C ( ⁵ ) = C (R ⁶ ) —, a prodrug thereof, or a prodrug thereof. Pharmaceutically acceptable salts.

7. The fused pyrrole compound according to any one of claims 1 to 5, wherein one Gi—Gs—G _3— is one C (R ⁵ ) = C (R ⁶ ) one S—, or a prodrug thereof, or Pharmaceutically acceptable salts.

8. The condensed pyrrole compound according to any one of claims 1 to 5, wherein Gi—G ₂ —G ₃ — is one O—C ( ⁵ ) = C (R ⁶ ), a prodrug thereof, or a prodrug thereof. Pharmaceutically acceptable salts.

9. — Gi— G ₂ — G ₃ — is one C (R ⁵ ) = C ( ⁶ ) —O— 6. The fused pyrrole compound according to any one of 5 to 5, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

10. — the condensed pyrrole compound according to any one of claims 1 to 5, wherein — Gi— Gs— G ₃ — is one N (R ⁷ ) —C ( ⁵ ) = C (R ⁶ ) — A prodrug thereof or a pharmaceutically acceptable salt thereof.

1 1. The fused pyrrole compound according to any one of claims 1 to 5, wherein one Gi—G ₂ —G ₃ — is one C (R ⁵ ) = C (R ⁶ ) one N (R ⁷ ) A prodrug thereof or a pharmaceutically acceptable salt thereof.

1 2. — G — G ₂ — G ₃ _ is one N = C (R ⁵ ) one S—, the fused pyrrole compound according to any one of claims 1 to 5, a prodrug thereof, or a pharmaceutical thereof. Acceptable salt.

Five

1 3. — Gi— G ₂ — G ₃ — is one S—C (R ⁶ ) = N—, the fused pyrrole compound according to any one of claims 1 to 5, a prodrug thereof, or a medicament thereof. Acceptable salt. 0 14. A pharmaceutical composition comprising the fused pyrrole compound according to any one of claims 1 to 13, a prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. .

1 5. HLGPa comprising the fused pyrrole compound according to any one of claims 1 to 13, its prodrug, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Inhibitors.

1 6. It shall not contain the fused pyrrole compound according to any one of claims 1 to 13, a prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Drugs for diabetes.

17. The pharmaceutical composition according to claim 14, which is used in combination with a therapeutic agent for hyperlipidemia. 18. The pharmaceutical composition according to claim 17, wherein the therapeutic drug for hyperlipidemia is a statin drug.

19. The pharmaceutical composition according to claim 18, wherein the statin drug is selected from the group consisting of oral pastatin, simpastatin, prapastatin, flupastatin, atorpastatin and seripastatin.

20. The pharmaceutical composition according to claim 14, which is used in combination with a therapeutic agent for diabetes.

21. The method according to claim 2, wherein the antidiabetic drug is selected from the group consisting of insulin preparations, sulfonylureas, insulin secretagogues, sulfonamides, biguanides, ¾darcosidase inhibitors and insulin sensitizers. 0. The pharmaceutical composition according to 0.

2 2. Antidiabetic drugs include insulin, dalibenclamide, tolptamide, glicroviramide, acethexamide, glimepiride, tolazamide, daliclazide, nateglinide, gribuzole, metformin hydrochloride, buformin hydrochloride, voglipose, acapulose and hydrochloride. The pharmaceutical composition according to claim 20, which is selected from the group consisting of pioglitazone.