WO1997017349A1 - Five-membered fused heterocyclic azepine derivatives and pharmaceutical use thereof - Google Patents

Abstract

Five-membered fused heterocyclic azepine derivatives represented by general formula (I) or pharmacologically acceptable salts thereof, wherein R?1, R2, R3, R4 and R6¿ represent each hydrogen or lower alkyl; R5 represents hydrogen, lower alkyl or phenyl; A1 represents oxygen, sulfur or -NR7-; A2 represents -CR8R9- (wherein any one of R8 or R9 represents hydrogen with the other representing hydrogen, hydroxyl or lower alkyl); and A3 represents oxygen, sulfur, -NR11-, or a single bond; and Z represents halogeno, a heterocyclic group or the like. These compounds are excellent as prophylactic or therapeutic agents for vasopressin-related diseases, for example, congestive heart failure, edema, particularly cerebral edema, syndrome of inappropriate secretion of ADH, hypertension, etc., and as a diuretic.

Description

 Specification

 Condensed hetero 5-membered azepine derivatives and their pharmaceutical uses

 Technical field

 The present invention relates to a novel fused 5-membered heterocyclic azepine compound, and more particularly, to a novel fused 5-membered heterocyclic azepine compound having excellent vasopressin antagonism and its pharmaceutical use.

 Background art

 Vasobretsin is one of the posterior pituitary hormones, and has an antidiuretic effect by promoting the reabsorption of water in the collecting tubules of the kidney, thereby maintaining body fluid homeostasis. Some also act on the central nervous system as paracrine hormones. In addition, vasopressin exerts a vasopressor effect due to vascular smooth muscle contraction, vasoconstriction related to the circulatory system, cardiac depression, body temperature regulation, blood coagulation, hepatic protein release, mesangial mucous cell proliferation, etc. There is.

Receptors Basoburetsushin is V, and there are two types of V _2, and to be involved in each of the physiological activity expression have been revealed. V, receptors are distributed in a group of cells, including vascular smooth muscle and hepatocytes, and cause vasoconstriction and glycogenolysis via inositol phospholipid metabolism (MJ Berridge, RF Irrine, Nature, 212, 315 ( 1984). On the other hand, V ₂ receptors are distributed in the renal tubules, express activity through c AMP production system (J. Bockart et al .. J. Biol . Chem., 248, 5922

(1973).).

Excess of vasobretsin having such an effect may be caused by various pathological conditions, such as depressive 'deficiency (Pharmacological Reviews, 43, P73-108 (1991)), cerebral edema [ Stroke, 23, p 1767-1773 (1992), Life Sciences, 43, p3 991-403, (1988), cranial nerve, 44 (1), p43 ( 1992), neurosurgery, 21 (12), p 1103 (1993)), arginine vasopletsusin hypersecretion syndrome [Journal of Cardio Vascular Pharmacology] (Journal of Cardiovascular Pharmacology), 8 (Suppl. 7), pS36-S43 (19986)], hypertension and the like. Therefore, if a superior vasopletusin antagonist is developed, these diseases caused by excess vasobrethsin, such as cardiac insufficiency, edema, arginine vasobrethsin hypersecretion syndrome, renal failure, high blood pressure, ascites, cirrhosis, and low sodium As a therapeutic or preventive agent for thoremia, hypokalemia, diabetes, circulatory failure, pulmonary edema, Meniere's syndrome, okintocin-related disease, etc., and as a diuretic (kidney and dialysis, p 161 (p. ), History of Pharmaceuticals, 15 7 (3), p 16 6 (1 9)

9 1)], and various vasobretusin antagonists have been developed so far for the prevention or treatment of vasobretusin-related diseases.

 In particular, since non-peptide compounds can be orally administered unlike dipeptide compounds, clinical usefulness can be expected. Until now, Japanese Patent Application Laid-Open Nos. 7-280 and 4-1

3 2 1 669, Japanese Patent Application Laid-Open No. 4-1545765, Japanese Patent Application Laid-Open No. 6-172732, Japanese Patent Application Laid-Open No. 5-132664, W095 Z 033305 Meigong Co., Ltd., Japanese Unexamined Patent Publication No. Hei 5-321035, W094 / 124476, Japanese Unexamined Patent Publication No. Hei 6-157

No. 480, Japanese Unexamined Patent Publication No. Hei 6-21810, WO 94/14976, Japanese Patent No. WO 94/4733, Japanese Unexamined Patent Publication No. 6-1 Various compounds have been proposed in, for example, Japanese Patent Application Laid-Open No. 6643/1994, Japanese Patent Application Laid-Open No. 7-157486 / 1995, and Japanese Patent Application Laid-Open No. 7-1794430 / 1995.

In particular, Japanese Patent Application Laid-Open Nos. H4-154, 765 and H4-232169,

Are disclosed in Japanese Patent Application Laid-Open No. 7-2800. 97/17349

Me

等が開示されている。

Are disclosed.

 However, more effective ones have been demanded than these compounds.

 An object of the present invention is to provide a novel compound that antagonizes vasobretsin.

 It is another object of the present invention to provide a useful bathoburetsin antagonist.

 Disclosure of the invention

 The present inventors have conducted intensive studies in view of such circumstances, and as a result, have found that condensed hetero 5-membered ring azepine compounds achieve the above objects, and have completed the present invention.

That is, the present invention relates to a novel 5,6,7,8-tetrahydro 4 H-thieno [3,2-b] azepine derivative or an analog thereof, and a novel 5,6,7,8-tetrahydro-4H-fluoro [3 , 2-b] azepine derivatives or analogs thereof, and new 4,5,6,7,8-hexahydropyrro [3,2-b] azepine derivatives or analogs thereof, and containing these compounds Related to nasobusetsushinshin antagonist The details are as shown in the following (1) to (18),

 (1) General formula (I)

(I)

[In the formula, R ¹ represents a hydrogen atom, a hydroxyl group, a lowly treated alkyl group, a halogen atom, a formyl group or a carboxy group,

R ² represents a hydrogen atom or a lower alkyl group,

R ³ and R ⁴ may be the same or different and each represent a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkoxy group, an acyl group, a cyano group or a halogen atom;

R ⁵ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted radical, R ⁶ represents a hydrogen atom or a lower alkyl group,

A ¹ represents an oxygen atom, a sulfur atom or —NR ⁷ — (wherein R ⁷ represents a hydrogen atom or a lower alkyl group);

A ² is one of CR ⁸ R ⁹ (wherein, one of R ⁸ and R ⁹ represents a hydrogen atom, and the other is a hydrogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted or represents lower pole alkoxy group or an optionally substituted amino group, or an Okiso group becomes R ⁸ and R ⁹ gar cord) or one NR ^ie - (wherein, R ^{1 ()} is a hydrogen atom, Which may be substituted (representing an alkyl group or an acyl group); A ³ represents an oxygen atom, a sulfur atom or one NR ¹¹ — (wherein, R ¹¹ represents a hydrogen atom or a lower alkyl group) or a single bond;

Z is a halogen atom, an optionally substituted heteroaryl group, one NR ¹² R ¹³ (wherein R ¹² and R ¹³ are the same or different and represent a hydrogen atom or a lower alkyl group),

-CONR ¹² R ' ³ (wherein R' ² and R ¹³ represent the same meaning as described above), a guanidino group,

—

{In the formula, R ¹⁴ is a hydrogen atom, a low-handed alkyl group which may be substituted with a hydroxyl group, a lower alkoxycarbonyl group, a phenyl group (the phenyl group may be substituted with a hydroxyl group or a halogen atom. ), A benzyl group (the benzoyl group may be substituted by a hydroxyl group or a halogen atom), a dimethylphenyl group, —NR ¹² R ¹³ (wherein, R ¹² and R ¹³ have the same meanings as described above.) , —C〇NR ¹² R ′ ³ (wherein, R ¹² and R ¹³ have the same meanings as described above.), And C (= NH) R ¹² (where R ¹² has the same meanings as above.) Represents.) Or

(Wherein, r represents an integer of 3 to 6.), wherein A ⁴ is a carbonyl group, — NR ¹⁵ —

(In the formula, R ¹⁵ represents a hydrogen atom or a lower alkyl group.)

-R ¹⁵ CO (CH ₂ ).-(Wherein, R ¹⁵ has the same meaning as described above, s represents 0 or an integer of 1 to 6) or a single bond, and is a nitrogen atom or CH Represents a nitrogen atom or a CH group or represents an oxygen atom by W ² —R ¹⁴ , and n represents 1 to 3 Represents an integer, and p represents an integer of 0 or 1 to 3. } Or one Y—X {Y is an oxygen atom, a sulfur atom, — NR ¹⁵ — (wherein, R ¹⁵ has the same meaning as described above.), —COO— or one NHCO—, and X is a hydrogen atom A lower alkyl group {the lower alkyl group may be substituted with a halogen atom or one NR ¹² R ¹³ (wherein, R ¹² and R ¹³ have the same meanings as described above). } Or an optionally substituted heteroaryl group. Represents

m represents 0 or an integer of〗 to 6. However, when A ³ is a single bond, m represents an integer of 1 to 6. ] A fused 5-membered azepine derivative represented by the formula or a pharmacologically acceptable derivative thereof.

(2) Alpha 'is a sulfur atom, Alpha ² the salts are CH _2, A ³ is (1), wherein the hetero 5-membered to fused ring Azepin derivative or a pharmacologically oxygen atom acceptable.

(3) A 5-membered ring azepine derivative or a pharmaceutically acceptable salt thereof according to the above (2), wherein R ¹ , R ² , R ³ , R ⁴ and R ⁶ are all hydrogen atoms.

 (4) N— [2 -— (2-chloroethyne) 1-41-[(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepin-4-yl) carbonyl ] Phenyl] 1- [1, -biphenyl] 1-2-carboxamide,

 N- [2-[2-(4-Methylbiperazine-1 1-yl) Etkin] 1-41 [(

5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-4-yl) carbonyl] phenyl] — [1,1'-biphenyl] 1-2-carboxamide, ethyl 2-— [[1,1-biphenyl] 1-2-carbonyl] amino] -1-5-((5,6,7,8-tetrahydro-4H-thieno [3,2-b] azebin-14yl) carbonyl] Phenoxy acetate,

 2-[[[[1,1 * -biphenyl] -1-2-carbonyl] amino] -1-5-((5,

6, 7, 8-tetrahydro-4H-thieno [3,2-b] azepine-4-yl) carbonyl] phenoxyacetic acid,

N- [2- [2-(4-Methylbiperazine-1 1-yl) -1 2-oxotokin] 1-41-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepi Carbonyl) phenyl] — [biphenyl] 1-2-carboxamide,

 N— [2— (5-cyclopentoxy) 1-4 — [(5,6,7,8-tetrahydric-4H—thieno [3,2-b] azebin-4-yl) carbonyl] Phenyl]-[1'-biphenyl] -1-2-carboxamide,

 N- [2-[5-(4-methylbiperazine-1-yl) pentoxy] -4-1 [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] Azebine- (4-yl) carbonyl] phenyl]-[1'-biphenyl] -12-carboxamide,

 N— [2— [5— (4-Methyl Perhydro Draw 1,4—Diazepine—11-yl) Pentoxy] —4-1 — ((5,6,7,8—Tetrahydro-1-4H—thieno [3, 2 — b] azepine-4-yl) carbonyl] phenyl]-[1'-biphenyl] -2-carboxamide,

 N- [2-[2-[4- (4-fluorophenyl) piperazine-1-1yl] ethoxy] —4-1-((5,6,7,8-tetrahi draw 4H-thieno [ 3, 2-b] azepine-1-4-yl) carbonyl] phenyl] — [1,1'-biphenyl] -12-carboxamide,

 N— [2— (3-Chlorobromoxy) 1-4-1 [(5,6,7,8-tetrahydro4H-thieno [3,2-b] azepin-14-yl) carbonyl] phenyl]-[ 1, —biphenyl] -1-2-carboxamide,

 N— [2- [3- [Ν'-methyl-N '— (1—methylbiperidine-14-yl) amino] propoxy] —4 — [(5,6,7,8-tetrahydro-4 4-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl]-[1'-biphenyl] -12-carboxamide,

N— [2— (4-Chlorobutoxy) 1 4 — [(5,6,7,8—tetrahydro-1 4H—thieno [3,2—b] azebine-1-4-yl) carbonyl] phenyl U, 1'-biphenyl] 1-2-carboxamide, N- [2-[4-(4-Methylbarhi draw 1, 4-diazepine 1-1 -yl) butoxy] 1 4-[(5, 6, 7, 8-tetrahydro draw 4 H-thieno [3, 2-b ] Azebin-1-yl) carbonyl] phenyl]-[1,1'-biphenyl] -12-carboxamide,

 N— [2— [4-[Ν'-I- (2-dimethylamino) ethyl N'-methylamino] butkin] — 4-[(5,6,7,8-Tetrahydro 4 4-thieno [3,2 -b] azepine-41-yl) carbonyl] phenyl] -1- [1, -biphenyl] -12-carboxamide,

 N- [2— [4- (4-Methylbiperazine-1 1-yl) butoxy] 1-41 [(

5,6,7,8-Tetrahydrido-4H-thieno [3,2-b] azepine-4-yl) carbonyl] phenyl]-[1'-biphenyl] —2-carboxamide,

N— [2— (Pyridine-1-3-yl) Methoxy-14-1 ((5,6,7,8—Tetrahedro-1H 4H—Thieno [3,2-b] azepin-14-1yl ) Carbonyl] phenyl] 1- [1,1-biphenyl] —2-carboxamide,

 N— [2-(2-Dimethylaminoquinone) 1-41 [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-4-yl) carbonyl] phenyl] One [1,1'-biphenyl] — 2-carboxamide,

 N— [2— (2-morpholinoetkin) 1-41 [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-1 4-yl) carbonyl] phenyl [Shi 1'-biphenyl] 1-2-carboxamide,

 N— [2— [2— (4-Methyl-Bad Draw 1,4-Diazepine-1-1, E) Ethoxy] 1-4 1 [(5,6,7,8-Tetra-Hydro 4 H—Thieno 2-b] azepine-1 4-yl) carbonyl] phenyl]-1- [biphenyl]-2-carboxamide,

 N- [2— [2— [2— (cyclohexylamino) etkin] 1 4-[(5,

6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] — [s-biphenyl] 1-2-carboxamide, N— [2— [2— [1- (pyrrolidine-1-1-yl) piperidino] ethkin] -1-4-[(5,6,7,8-tetrahydro-1-4H-thieno [3,2-b ] Azepine-14-yl) carbonyl] phenyl] — [1,1'-biphenyl] -12-carboxamide,

 N— [2— [2— (4-biperidino piperidino) etokine] 1-4 — [(5,6,7,8—tetrahydric mouth 4 H—thieno [3,2—b] azepine-1-4-yl) Carbonyl] phenyl] — [1,1'-biphenyl] 1-2-carboxamide,

 N— [2— [2— [4— (4-Hydroquinphenyl) pirazin-1-yl] ethokine] —4—C (5,6,7,8—tetrahydro 4 H—thieno [3,2 — B] azepine-41-yl) carbonyl] phenyl] -1- [1,1'-biphenyl] -2-carboxamide,

 N— [2— [2 — [(4—ethoxyquincarbonyl) piperazine-1 1-yl] ethoxy] —4 — [(5,6,7,8—tetrahydro 4 H—thieno [3, 2—b] azepine-4—yl) carbonyl] phenyl] — [shibiphenyl] 121carboxamide,

 N- [2— [2— (4-Methylperhidro 1, 4—dazepine-1 1-yl) -1 2-oxotokin] 1 4 — [(5,6,7,8—Tetrahid 4H—Ceno [ 3, 2-b] azebin-4 —yl) carbonyl] phenyl) 1 [1, 1 biphenyl] — 2 -carboxamide,

 N- [2-[[[1,1'-biphenyl] -1-2-carbonyl] amino] —5 — [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] Azepine 4-yl) carbonyl] phenoxy] acetyl] -l-prolinamide,

 N— [2— [2-oxo-1—2— (4-piperidino piperidino) ethkin] 1-41 [(5,6,7,8—tetrahydro-1-4H—thieno [3,2—b] azepine 1- (yl) carbonyl] phenyl] 1- [bi-biphenyl] —2-carboxamide,

N- [2— [2-oxo-1 2— [4— (pyrrolidin-1 1-yl) piberidino] Etkin] ー 4 — [(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] — [shi—biphenyl] —2-carboxami Do

 N— [2-[2- (4-dimethylaminobiperidino) 1 2-year-old ethoxy] -4-[(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepin-4-1 Yl) carbonyl] phenyl]-[1,1,1'-biphenyl] -12-carboxamide,

 N— [2— [2 — [(1-Methyl-1H—1,2,3,4-tetrazole-5-yl) thio] etokine] 1-41 [(5.6,7,8-tetrahydro-1-4H— Thieno [3,2-b] azepine—41-yl) carbonyl] phenyl]-[biphenyl] -12-carboxamide,

 N— [2— (3-phthalimidoproxy) 1-41 [(5,6,7,8-tetrahydro 4H-thieno [3,2_b] azepin-1 4-yl) carbonyl] phenyl] — [1, perbiphenyl] 1-2-carboxamide,

 N— [2— (3-aminopropoxy) 1-4 — [(5,6,7,8—tetrahydro 4H—thieno [3,2-b] zepin-1 4-yl) carbonyl] phenyl]- [1,1'-biphenyl] 1-2-carboxamide,

 N— [2- [3- (Chloroacetylamino) propoxy] —4 — [(5,6,7,8—tetrahydro 4H—thieno [3,2—b] azepine 1-4yl) Bonyl] phenyl] 1- [biphenyl] 1-2-carboxamide,

 N— [2— [3-[(4-me. Tylbiperazine-1 1-yl) acetylamino] probokin] 1-41 [(5, 6, 7, 8—tetrahydro 4 H—thieno [3, 2— b] azepine-41-yl) carbonyl] phenyl]-[1-biphenyl] -12-carboxamide,

2 — [[[1,1'-biphenyl] -1-2-carbonyl] amino] —5 — [(5,6,7,8-tetrahydro 4H—thieno [3,2—b] azepine-1 Le) Power ponyl] phenoxyacetic acid amide, N- [2— [2— (4—Benzhydrylbiperazine-1 11-yl) Etkin] 1 4-[(5,6,7,8-Tetrahydr 4H—Thieno [3,2—b] azebin 1 4 1-yl) carbonyl] phenyl] 1- [1,1'-biphenyl] 12-carboxamide,

 N— [2— [2 — [(4-fluorene benzoyl) piperidino] ethkin] 1 4-[(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-4 —Yl) carbonyl] phenyl]-[1,1'-biphenyl] -12-carboxamide,

 Ethyl 4— [2 — [[[1,1'-liff: Lnyl] -1—2-carbonyl] amino]-5-[(5,6,7,8-tetrahydro-1H-thieno [3, 2—b] azepin-4yl) carbonyl] phenoxy] butyrate,

 4-[2-[[[1, 1 '-biphenyl] —2—carbonyl] amino] 1 5— [(5,6,7,8-tetrahydro-1H-thieno [3,2—b] Azevin-4yl) carbonyl] funoxy] butyric acid,

 N— [2— [4-(4-Methylbiperazine— 1-yl) —4-oxobutoxy]--[(5,6,7,8-tetrahydro-1H-thieno [3,2—b ] Azepin-4-yl) carbonyl] phenyl] -1- [1, -biphenyl] -12-carboxamide,

 N— [2— [4- (4-Methyl perhydro draw 1,4-diazepine) —4-oxobutoxy] —4-1 — ((5,6,7,8-tetrahydro 4H—Ceno [ 3, 2-b] azepine-14-yl) carbonyl] phenyl] — [1,1-biphenyl] — 2-carboxamide,

 N- [2— [4— (4-Dimethylaminobiperidino) 1 4-oxobutoxy]-4-[(5,6,7,8-tetrahydro α- 4H-thieno [3,2-b] Azepin-4-yl) carbonyl] phenyl] -1- [biphenyl] -12-carboxamide,

N— [2 — [(pyridin-4-yl) methoxy] 1-4 — [(5,6,7,8- Tetrahydro 4H-thieno [3,2-b] azepine-41-yl) carbonyl] phenyl]-[1'-biphenyl] —2-carboxamide,

 N— [2-[2-(Indole-1-3-yl) Etkin] 1-41 [(5,6,7,8-tetrahydro-4 H-thieno [3,2-b] azebin-1 4- Le) carbonyl] phenyl] — [し —biphenyl] 12-carboxamide,

 N— [2— [3-(4-Methylbiperazine-1 1-yl) propoxy] 1 4 1 [(5,6,7,8-tetrahydro-4 H-thieno [3,2—b] azebine 4—yl) carbonyl] phenyl] 1- [1-biphenyl] 12-carboxamito ”,

 N— [2-[3— (4-Methyl Perhydro Draw 1, 4-diazepine 1-1-yl) Probokin] 1-4 1 [(5, 6, 7, 8-tetrahydro Draw 4 H-thieno [3, 2 — b] azepine-41-yl) carbonyl] phenyl] -1- [biphenyl] -12-carboxamide,

 2 -— [[[1,1-Bifidenyl] carbonyl] Rmino] -1-5-—4 — [(5,6,7,8-tetrahydro-1-4H—thieno [3,2-b] azepine-1-4-yl ) Carbonyl] phenoxycarboxamide,

 N— [2— [3 -— (-dimethylaminopiperidino) propoxy] 1-41 [(5,6,7,8-tetrahydro-1-4H-thieno [3,2—b] azepine-1-4— Yl) carbonyl] phenyl] 1- [1-biphenyl] — 2-carboxamide,

N— [2— [4 _ (4-ethylpyperazine—11-yl) butoxy] one 4— [(

5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl]-[1'-biphenyl] -12-carboxamide,

N- [2 -— [4- (4-dimethylaminobiperidino) butoxy] 1-41- [(5,

6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] -1- [1,1'-biphenyl] -12-carboxamide,

N- [2— [4-(piperazine-1 1-yl) 1 4 1-oxobutoxy] 1 4 1 (5,6,7,8-tetrahydro 4 H-thieno [3,2-b] Hey Le) carbonyl] phenyl] mono [1,1-biphenyl] -2-carboxamide,

N-C2- [4- [4-[(pyrrolidine-111) piperidino] butoxy] -1-4-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine 4- (yl) carbonyl] phenyl]-[bi-biphenyl] -2-carboxamide,

 N- [2 -— [4- [4- [pyrrolidine-1-1-yl) piperidino] -14-oxobutoxy] — 4-[(5,6,7,8-tetrahydro- 1H-thieno [ 3,2—b] azepine-41-yl) carbonyl] phenyl] — [1,1'-biphenyl] -21-carboxamide,

 N— [2-[4-(4-piperidino piperidino) 1 4-oxobutoxy ト 1 4 1 [(5,6,7,8-tetrahydro-1H 4H-thieno [3,2-b] azebin-1 4-1 Yl) carbonyl] phenyl]-[bi-phenyl] -12-carboxamide,

 N— [2— (4—Aminobutoxy) 1 4 — [(5,6,7,8—Tetrahydro—4H—thieno [3.2—b] azepin-1-yl) carbonyl] phenyl

 [1,1'-biphenyl] 1-2-carboxamide,

 4— [2— (2-Methylbenzamide) -1-5-((5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenoxy Butyric acid,

 N— [2 -— [4- (4-dimethylaminobiperidine-1-11) 1-41-oxobutyne] 1-41 [(5,6,7,8-tetrahydro-4H-thieno [3,2- b] Rzepin-1 41-yl) carbonyl] phenyl] 1-2-methylbenzamide, ethyl 4- [5 — [[[1,1'-biphenyl] -12-carbonyl] amino] 1-2- [( 5, 6, 7, 8—tetrahydro 4H—thieno [3,2—b] zepin-4-yl) carbonyl] phenoquine] butyrate,

4-[3-[[[1, 1 * 1-biphenyl] -1 2-carbonyl] amino] 1-6-[(5,6,7,8-tetrahydro 4 H-thieno [3,2-b] Ryo Zepin 4 Yl) carbonyl] phenoxy] butyric acid,

 N- [3-C4- (4-Dimethylaminobiperidino) 14-year-old xyptoxy]-4-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine 1-41-yl) carbonyl] phenyl] -1 [1,1'-biphenyl] 1-2-carboxamide,

 N- [2-[4-(4 -Jetylamino-biperidino) 1-4-oxobutoxy]--[(5,6,7,8-tetrahydro D- 4 H-thieno [3,2-b] azepin-1 4-yl) carbonyl] phenyl] -1- [1, -biphenyl] —2-carboxamide,

 N- [2— [4-[Ν '-(3-dimethylaminoethyl) -N'-methylamino]-4-oxobutokin] 1 4-[(5,6,7,8-tetrahydro 4 4-thieno [ 3, 2-b] azepine-41-yl) carbonyl] phenyl- [1-,-biphenyl] -12-carboxamide,

 N— [2— [4-[Ν '— (2-Jethylaminoethyl) — N' —ethylamino] — 4-oxobutoxin] — 41 [(5,6,7,8—tetrahydro-1 4 Η— thieno [3,2—b] azepine—41-yl) carbonyl] phenyl] — [1 ,, — biphenyl] —2-carboxamide,

 N— [2- [4- [Ν '-(2-dimethylaminopropyl) -1-N'-methylamino] -14-oxobutoxy] -14-1 [(5,6,7,8-tetrahydro □ —4Η —Ceno [3,2-b] azepine-14-yl) carbonyl] phenyl] -1- [1,1'-biphenyl] —2-carboxamide,

 N— [2— [4- (4-Methylaminobiperidino) 1-4-oxobutoxy] 1-4-[(5,6,7,8-tetrahydric-4H-thieno [3,2-b] azepine-1 4yl) carbonyl] phenyl] 1- [biphenyl] 1-2-carboxamide,

N- [2— [4--1 (4-amino-biperidino) 1-41-oxobutokin] 1-4- [(5,6,7,8-tetrahydro 4 H-thieno [3,2-blazebine-1 41 Yl) carbonyl] .phenyl]-[1,1'-biphenyl] -1-2-carboxamito ",

 N- [2 -— [4-[4- (1-Iminoethyl) piperazine-11-yl] -4-1oxobutoxy] -4-1 [(5,6,7,8-tetrahydro-4H-thieno [3 , 2-b] azepine-4-yl) carbonyl] phenyl]-[1, -biphenyl] -12-carboxamide,

 N— [2— (4-guanidinobutoxy) 1 4 1 [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-4-yl) carbonyl] phenyl] — [ 1, 1'-biphenyl] 1-2-carboxamide and

 N— [2— [4— [4— (2-Hydroxyethyl) piperazine-11-yl] butoxy 4 -— [(5,6,7,8-tetrahydro-1-H-thieno [3, 2-b] azepine-14-yl) carbonyl] phenyl] — [1, —biphenyl] 121-carboxamide selected from the above-mentioned condensed hetero 5-membered ring azebin derivative according to (3) or a pharmacologically acceptable derivative thereof. Salt.

 (5) N- [2 -— [2- (4-Methylbiperazine-1-yl) ethoxy] 1-41-[(5,6,7,8-tetrahydro 4H-thieno [3,2- b] Rzezepine 4-yl) carbonyl] phenyl]-[1-biphenyl] -12-carboxamito ",

 2-[[[1,1'-biphenyl] -1-2-carbonyl] amino] -5-[(5,6,7,8-tetrahydro4H-thieno [3,2-b] azebin-1-4- Le) carbonyl] phenoxyacetic acid,

 N— [2-[2— (4-Methylbiperazine—11-yl) -1-2-oxoetokin]-4-[(5, 6, 7, 8—tetrahydro-1-4H—thieno [3, 2—b〗 azepi Carbonyl) phenyl]-[1,1-biphenyl] -12-carboxamide,

N- [2— [4— (4-Methylperhydro-4-1-diazepine-1-yl) butoxy] —4-1— (5,6,7,8-tetrahydro 4H-thieno [3,2- b] azepine-41-yl) carbonyl] phenyl]-[ci-biphenyl] -12-carboxamide,

 N— [2— [4-[Ν '-(2-dimethylaminoethyl) -N'-methylamino] butoxy] 1-41 [(5,6,7,8-tetrahydrido D— 4 Η-thieno [3 , 2—b] azepine-14-yl) carbonyl] phenyl] -1- [1, -biphenyl] -12-carboxamide,

 N- [2— [4— (4-Methylbiverazine-1-11yl) butoxy] 1-41 [(5,6,7,8-tetrahydro 4H-thieno [3,2—b] azepine-4 -Yl) carbonyl] phenyl] 1- [1-biphenyl] 12-carboxamide,

N— [2-[2-(4 -Methylbarhydro-1, 4-diazepine-1 1 -yl) ethoxy] 1-4 1 [(5, 6, 7, 8-tetrahydro 4 H-thieno [3, 2 -b] azepine-1-4-yl) carbonyl] phenyl] -1- [1,1'-biphenyl] 121-carboxamide,

 N—C 2-[2-[4-(pyrrolidin- 1-1-yl) piperidino] etokine] 1-4-[(5, 6, 7, 8-tetrahydro-1 4 H-thieno [3, 2-b ] Azepine — 4-yl) carbonyl] phenyl] 1- [biphenyl] 1-2-carboxamide,

 N- [2-[2— (4—piperidino piperidino) etokine] — 4 1 [(5, 6, 7. 8—tetrahydro 4 H—thieno [3, 2— b] azepin 1 4-yl ) Carbonyl] phenyl]-[1'-biphenyl] -12-carboxamide,

 N— [2— [2— (4-Methylbarhi draw 1, 4-diazepine 1—yl) 1—2-oxoethoxy] 1-41 [(5, 6, 7, 8—tetrahydro 4 H—Ceno [ 3, 2-b] azepine-4 yl) carbonyl] phenyl] 1 [1, 1 '1 biphenyl] 1 2 -carboxamide,

N— [2-[2-Okitwo 2— (4-piperidino piperidino) ethoxy] 1 4-[(5,6,7,8—tetrahi draw 4 H—thieno [3,2-b] azebine 4- (yl) carbonyl] phenyl] 1 [1,1'-biphenyl 1 1-2-carboxy Sumid,

 N— [2— [2-oxo-1—2— [4 -— (pyrrolidine—11-yl) piperidino] ethoxy] —4-1 — ((5,6,7,8-tetrahydro 4H—thieno [3, 2-b] azepine-14-yl) carbonyl] phenyl] — [1,1'-biphenyl] -12-carboxamide,

 N— [2— [2— (4-Dimethylaminobiperidino) -1-oxotokin] —4 — [(5,6,7,8—tetrahydro 4H—thieno [3,2—b] azepine Carbonyl) phenyl] [1,1'-biphenyl] —2-carboxamide,

 N- [2— [3-[(4-Methylbiperazine-1 1-yl) acetylamino] proboxy] — 4-[[5,6,7,8-tetrahydro-1 4H—thieno [3,2 — B] azepine-41-yl) carbonyl] phenyl]-[1,1-biphenyl] -2-carboxamide,

 N— [2— [4— (4-Methylbiperazine-1 11-yl) 1 4-oxobutoxy]-4-[(5, 6, 7, 8—tetrahydro 4H—thieno [3, 2— b] azepin-4-yl) carbonyl] phenyl] 1- [1,1-biphenyl] —2-carboxamide,

 N— [2 -— [4- (4-Methyl-hydroxy-1, 4-diazebine_1-yl) 1-4-oxobutoxy] 1-41 [(5,6,7,8-tetrahydro-4H— Cheno [3,2-b] azepine-4-yl) carbonyl] phenyl]-[1'-biphenyl] -12-carboxamide,

 N— [2 -— [4- (4-dimethylamino-biperidino) -141-oxobutokin]-4-[(5,6,7,8-tetrahydro 4 H-thieno [3,2-b] azepin-4 —Yl) carbonyl] phenyl) — [shi 1'-biphenyl] — 2-carboxamide,

N— [2- [3- (4-Methylbiperazine-1-yl) propoxy] -1-4 — [(5,6,7,8—tetrahydro 4 H—thieno [3,2—b] azepine One four one Carbonyl) phenyl] — [biphenyl] —2-carboxamide ',

 N- [2— [3— (4-Methylbarhi draw and 4-diazepine-11-yl) Proboxy] —4-1-((5,6.7,8—Tetrahydro 4H—thieno [3,2-b] azepine 1-41) carbonyl] phenyl] -1- [1,1'-biphenyl] -1-2-carboxamide,

 N- [2— [3— (4-Dimethylaminopiperidino) propoxy] 1 4-1 [(5,6,7,8-tetrahydro 4 H-thieno [3,2—b] azebin 1-4 Yl) carbonyl] phenyl] mono [1,1-biphenyl] -2-carboxamide and

 N— [2— [4— (4-Etylbiperazine—11-yl) butoxy] —4— [(5, 6, 7, 8—tetrahydro 4H—thieno [3, 2—b] (5) The fused hetero 5-membered azepine derivative or the pharmaceutically acceptable salt thereof according to the above (4), which is selected from carbonyl] phenyl] 1- [1'-biphenyl] -12-carboxamide.

 (6) A pharmaceutical composition comprising the condensed hetero 5-membered azepine derivative or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (5), and a carrier.

 (7) A vasopressin antagonist comprising the condensed a 5-membered azepine derivative or the pharmacologically acceptable salt thereof according to any one of the above (1) to (5).

 (8) A therapeutic drug for depressive heart failure, comprising the condensed hetero 5-membered ring azevin derivative or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (5).

 (9) A therapeutic agent for cerebral edema comprising the condensed hetero 5-membered azepine derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (5).

 (10) A method for treating arginine vasopressin hypersecretion syndrome comprising the condensed hetero 5-membered azepine derivative or the pharmacologically acceptable salt thereof according to any one of the above (1) to (5). medicine.

(11) Derivation of the composite hetero 5-membered ring azepine according to any of (1) to (5) above O 97/17349

A diuretic comprising the body or a pharmacologically acceptable salt thereof.

 (12) A therapeutic agent for renal failure comprising a heterozygous 5-membered ring azepine derivative or a pharmacologically acceptable salt thereof according to any one of the above (1) to (5).

 (13) A therapeutic agent for pulmonary edema comprising the condensed hetero 5-membered ring azepine derivative or the pharmacologically acceptable salt thereof according to any of (1) to (5).

 (14) A therapeutic drug for Meniere's syndrome comprising the condensed hetero 5-membered ring azepine derivative or the pharmacologically acceptable salt thereof according to any one of the above (1) to (5).

 (15) General formula (II)

(In the formula, R ¹⁶ ′ represents a hydrogen atom or a lower alkyl group, R ¹⁸ represents a nitro group or an amino group, and R ′, R ² , R ³ , R ⁴ , A ¹ , A ² , A ³ or And A ⁴ has the same meaning as described above.) 5-condensed azepine amide compounds c)

(16) The fused 5-membered azepine amide compound according to the above (15), wherein A ¹ is a sulfur atom.

(17) The fused 5-membered azepine amide compound according to the above (15), wherein A ¹ is an oxygen atom or an NR ⁷ group (wherein, R ⁷ has the same meaning as described above).

(18) Equation (III)

A compound represented by the formula:

 Each definition used in this specification will be described.

 The term "lower" refers to a hydrocarbon chain having 1 to 6 carbon atoms.

 The “lower alkyl group” may be straight-chain or branched, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1 — (2— or 3—) Methylpentyl group, 1,1— (1,2—, 2,2-, 1,3-, 2,3- or 3,3-) dimethylbutyl group, 1- (or 2-) ethylbutyl group, I, and 2- (or 2,2-) trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like.

Methyl group, Echiru group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl groups, C such as tert- butyl group, - ₄ alkyl group, a Riwake methyl group, Echiru group and propyl Groups are particularly preferred.

 Examples of the “halogen atom” include fluorine, chlorine, bromine and iodine, and chlorine and bromine are preferred.

Examples of the “lower alkoxy group” include a methoxy group, an ethoxyquin group, a proboxyl group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a benzyloxy group and an isopentyloxy group Tert-pentyloxy, neopentyloxy, 2-methylbutyne, 2-dimethylpropoxy, 11-ethylpropoxy, hexyloxy and the like. Among them, main butoxy group, Etokin group, Purobokishi group, Isopurobokishi group, but-Kin group, such as tert- butoxy - ₄ alkoxy groups, especially main butoxy group, is Etokin group particularly preferred.

 The "aryl group" preferably has 6 to 14 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, a biphenyl group, a fluorenyl group, an anthryl group and a phenanthryl group.

Among them, Fuweniru group, a naphthyl group, Bifuweniru group, C «such Furuoreniru group - _{1 3} ones, especially off We group, Bifuweniru group is particularly preferred.

 The “heteroaryl group” contains at least one heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom in the ring, and may be a fused ring. Specific examples of the heteroaryl group include, for example, a pyridyl group, a fluorimido group, a tetrabryl group, a quinolyl group, an isoquinolyl group, an indolyl group, a chenyl group, a benzothenyl group, a furyl group and a benzofuryl group.

 Of these, a pyridyl group, a quinolyl group, an isoquinolyl group, a phthalimid group, a tetrazolyl group, and the like are preferable, and an indolyl group, a pyridyl group, a phthalimid group, and a tetrabryl group are particularly preferable.

 The terminating silyl group may include an aroyl group. And the like.

 Of these, alkenyl groups such as an acetyl group, a formyl group, a propionyl group and a butyryl group, and a benzoyl group are preferable, and an acetyl group, a formyl group, and a propylion group are particularly preferable.

Examples of the “lower alkenyl group” include, for example, ethenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group Nyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-hexenyl, 2-hexenyl, 3- Xenenyl group, 4-hexenyl group, 5-hexenyl A 2-methyl-1-pentenyl group, a 3-methyl-1-pentenyl group, a 4-methyl-1-pentenyl group, a 2,3-dimethyl-1-butenyl group, a 3,3-dimethyl-1-butenyl group, etc. I can do it.

 Among them, ethenyl group having 2 to 4 carbon atoms, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-bromo group And the like, and particularly preferably an ethenyl group.

 Examples of the alkoxy moiety of the “alkoxycarbonyl group” include those mentioned above as the low alkoxy group. Of these, methoxy, ethoxyquin, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like are preferable, and methoxy and ethoxyquin are particularly preferable.

 As the “primary or secondary lower alkylamino group”, the above-mentioned lower alkyl groups are mono- or di-substituted with an amino group, for example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group. , Butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neopentylamino, tert-pentylamino, hexylamino, isohexylamino, dimethylamino , Acetylamino, dibutylamino, diisopropylamino, dibutylamino, diisobutylamino, di-sec-butylamino, di-tert-butylamino, dipentylamino, diisopentylamino, dineopentylamino Base , Di-tert-pentylamino, dihexylamino, diisohexylamino, methylethylamino, methylpropylamino, methylisopropylamino, methylbutylamino, methylisobutylamino, methyl-sec Butylamino, methyl-tert-butylamino, ethylpropylamino, ethylisopropylamino, ethylbutylamino, ethylisobutylamino, ethylsec-butylamino, ethyltert-butylamino and the like.

Among them, methylamino group, ethylamino group, propylamino group, isopropylamine Preferred are a lumino group, a dimethylamino group, a getylamino group, a diaminopropylamino group, a diisopropylamino group and the like, and particularly preferred are a dimethylamino group and a dimethylamino group.

 Examples of the substituent of the phenyl group or the aryl group include a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a methylamino group, a dimethylamino group, a hydroxyl group, a carboxy group, a phenoxy group, and an acyloxy group.

 Of these, a lower alkyl group, a halogen atom, an amino group, a methylamino group, a dimethylamino group and the like are preferable, and a methyl group, a dimethylamino group and an amino group are particularly preferable.

 The substitution position is not particularly limited.

 Examples of the substituent of the heteroaryl group include the aryl group and those described as the substituent of the aryl group.

 Of these, a lower alkyl group, an aryl group, a halogen atom, a dimethylamino group, a phenoxy group and the like are preferable, and a methyl group, a phenyl group and a phenoxy group are particularly preferable.

 The substitution position is not particularly limited.

As the “protecting group for hydroxyl group”, any protecting group may be used as long as it is generally used. For example, methyl group, ethyl group, propyl group, isopropyl group, η-butyl group, isobutyl group, tert-butyl group Alkyl or substituted alkyl groups such as methoxy, methoxymethyl, methoxymethyl, tert-butynemethyl, tetrahydrobilanyl (THP); benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, benzyl Aralkyl groups such as oxymethyl group and trityl group; acryl groups such as formyl group, acetyl group, propionyl group, butyroyl group, valeryl group, bivaloyl group, chloroacetyl group, trichloroacetyl group and trifluoromethyl group; trimethylsilyl Group, triethylsilyl group, triisopropyl Ryl group, dimethylisopropylsilyl group, getylisobromovirsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, Silyl groups such as diphenylmethylsilyl group, triphenylsilyl group, tribenzylsilyl group, tert-butylmethyoxyphenylurinyl group, 2- (trimethylsilyl) ethyl group, 2- (trimethylsilyl) ethoxymethyl group, and the like; methoxycarbonyl Group, ethoxyquincarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, I-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, tert-amyloxycarbonyl group, 2 , 2,2-Trichloro mouth ethoxyquincarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, benzyloxycarbonyl, ρ-methoxybenzyloxycarbonyl, 2,4-dimethylbenzyloxycarbonyl And carbonates such as groups Of these, a methyl group and an ethyl group are preferred, and a methyl group is particularly preferred.

Preferred in general formula (I) !? Hydrogen atoms and C as ^1, - ₄ alkyl group, and particularly preferably a hydrogen atom.

Preferred R ^{2 includes} a hydrogen atom and a C,-* alkyl group, and particularly preferred is a hydrogen atom.

Preferred R ³ and R ⁴ each include a hydrogen atom, a lower alkyl group and the like, and a hydrogen atom is particularly preferred.

Preferred R ^5, a hydrogen atom, is substitution with an alkyl group and a lower alkyl group include good Fuyuniru group, especially a hydrogen atom, a phenyl group which may be substituted with a methyl group or a methyl group is preferable.

Preferred R ⁶ is a hydrogen atom or a methyl group, and a hydrogen atom is particularly preferred.

Preferred substituents for the lower alkyl group or lower alkoxy group in R ⁸ , R ⁹ or ^Rie include an amino group, a lower alkylamino group, a di-lower alkylamino group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, and a 4-lower. Alkylpiperazinyl group, 4-dialkylaminobiperidino group, perhydroazepinyl group, peridot diazepinyl group, N-low-alkyl perhydroazepinyl group, pyridyl group, power The substitution position and number are not particularly limited, but the terminal is preferable. Of these, di-lower alkylamino, pyrrolidinyl, piperidino, 4 lower-alkylpiperazinyl, pyridyl and carbonyl are preferred, and dimethylamino, pyrrolidinyl and 4-methylbiperazinyl are particularly preferred. And a pyridyl group are particularly preferred.

When A ^{4 is} —NR ¹⁵ , W ¹ is preferably a CH group.

 The pharmacologically acceptable salts of compound (I) include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid) in a conventional manner. , Linoleic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ascorbic acid, etc.), inorganic bases (sodium hydroxide, potassium hydroxide, calcium hydroxide) , Magnesium hydroxide, zinc hydroxide, ammonium hydroxide, etc.), organic bases (methylamine, getylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, trishydroxymethylmethyl) Methane, quinine, guanidine, cinchonine, etc.) or amino acids (lysine, ol Ditin, arginine, alanine, etc.). In some cases, it may be a hydrate or a hydrate. It may also be a prodrug.

 The feature of the compound (I) of the present invention is that benzozepines, which are the basic skeleton of a conventionally known vasopressin antagonist compound, are converted into condensed 5-membered heterocyclic azepines, and the side chain from the central benzene ring is converted. It is a point that we succeeded in improving the activity. In particular, the compound (I) of the present invention is expected not only to have an excellent vasobrethsin antagonism but also to reduce side effects such as central toxicity.

While describing the preparation of the compounds of the present invention (I) below, the present compound manufacturing method (I) Les such to be limited to, ₀

Manufacturing method (1) Rearrangement reaction

転位反応 (TsClZ base) or acid catalyst

Rearrangement reaction

 (DIBAH reduction)

ja original reaction

 0 = Benzoylated

OR 1 6

ΝΗ ^! (6)

Alkylation

(Hal- (CH ₂ ) _m- Z)

(In the formula, R ¹⁶ represents a protecting group for a lower alkyl group or a hydroxyl group, Ha represents a halogen atom, and other symbols are as defined above.)

 (1) Reaction of compound 1 to compound 2

Starting compound 1, ie 4-oxo-1,4,5,6,7-tetrahydrothianaphthene (where A 'is a sulfur atom), 4-oxo-4,5,6,7-tetrahydro Drobenzo [b] furan (where A ¹ is an oxygen atom), and 1,5,6,7-tetrahydro-4 H-indole-4-one (where A ¹ Is NH Compounds) are commercially available or described in the literature (eg, Journal “Ob.” Organic Chemistry [J. Org. Chem.], 53 (41), p35, (1988)). The method is carried out by oxidizing _c compound 1 which can be produced by the method described in, for example, RA Zambias et al. With hydroxylamine hydrochloride in the presence of a base.

 As the base, for example, pyridine, 2,6-lutidine, triethylamine, sodium acetate and the like are used, and pyridine is particularly preferable.

 As the solvent, methanol or a base can be used as it is. The reaction is usually carried out at about O'C to room temperature, and the reaction time is about 30 minutes to 24 hours.

 (2) Reaction of compound 2 to compound 3

 The reaction for obtaining compound 3 from compound 2 is a Beckmann rearrangement reaction. Compound 2 is carried out in a suitable solvent in the presence of an acid catalyst used in a usual Beckmann rearrangement reaction, or a tosyl mouth ride, a mesyl mouth ride and a basic solvent such as pyridine, lutidine, etc. Is performed by converting tosylate or mesylate by using and then transposing by heating.

 As the acid catalyst, for example, sulfuric acid, sulfonic acid, phosphoric anhydride, phosphorus pentachloride, sulfuryl chloride, methylsulfonic acid Z phosphorus pentoxide and the like can be used.

 Any solvent can be used as long as it does not affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene.

 The reaction is preferably carried out at about 100 to 140 ° C., and is generally completed in about 30 minutes to 15 hours.

 (3) Reaction from compound 3 to compound 4

 Compound 3 is reduced using a hydride reducing agent in a suitable solvent.

Examples of the hydrogenation-reducing agent include lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, diborane, and the like. The molar amount is from 10 to 10 times the molar amount. Examples of the solvent include ethers such as tetrahydrofuran, getyl ether and diisopropyl ether (these may be used as a mixture).

 The reaction is usually completed in about 0 to 7 (TC, about 10 minutes to 15 hours).

 When lithium aluminum hydride is used as the reducing agent, use of an anhydrous solvent is preferred.

 () Reaction of compound 2 to compound 4

 Compound 4 can also be manufactured by the method of Yamamoto et al. Described in Tet rahedron Letters, 24 (43), p4711-7112, (1983). The method can be performed more efficiently than the two-stage reaction.

 That is, compound 2 is dissolved in a suitable organic solvent, preferably toluene or methylene chloride, and diisobutylaluminum hydride (DIBAH) is added thereto, whereby a rearrangement reaction occurs one-dimensionally, whereby compound 4 can be obtained. it can.

 (5) Reaction of compound 4 to compound 5

 The compound 4 (amine compound) and a suitable carboxylic acid are benzoylated by a usual amide bond formation reaction. Known conditions for amide bond formation reaction can be appropriately applied to the amide bond formation reaction.

 For example, there are a mixed acid anhydride method, an active ester method, a carbodiimide method and other methods.

Mixed acid anhydride method

 The carboxylic acid is reacted with an alkyl halocarbonate to form a mixed acid anhydride, which is then reacted with an amine (compound 4).

Active ester method

The carboxylic acid is converted into an active ester such as ρ-ditrophenyl ester, N-hydroxysuccinic acid imidoester, 1-hydroxybenbutriabule ester, etc., and reacted with amine (compound 4). Carbodimid method

 An amine (compound 4) is condensed with a carboxylic acid in the presence of an activator such as dicyclohexylcarpoimide or carbodimidazole.

Other methods

 A method in which a carboxylic acid is converted to a carboxylic anhydride with a dehydrating agent such as acetic anhydride and then reacted with an amine (compound 4). The lower alcohol ester of the carboxylic acid is reacted with the amine (compound 4) at high temperature and high pressure. A method of reacting an amide acid (compound 4) with an acid halide of a carboxylic acid, that is, a carboxylic acid halide, and reacting a carboxylic acid with an amine (compound 4) in the presence of a condensing agent for a phosphorus compound. There is a method to make it. The mixed acid anhydride used in the mixed acid anhydride method is obtained by a known method, and the compound 5 is obtained by reacting the mixed acid anhydride with an amine (compound 4) without isolation, for example.基礎 Basic and Experimental Peptide Synthesis ”, written by Nobuo Izumiya, published by Maruzen Co., Ltd.). The mixed acid anhydride method is performed in one step in a solvent. As the solvent to be used, any of the solvents used in the ordinary mixed acid anhydride method can be used. For example, halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and quinylene; ethers such as dimethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxetane; Esters such as methyl acetate and ethyl acetate, non-protonic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitril, hexamethyl phosphoric acid triamide, or mixed solvents thereof Is mentioned.

The mixed acid anhydride method is usually performed in the presence of a base compound. Examples of the basic compound include triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, and 5-diazavinclo [4.3.0] nonene-5 (DBN), 1, 8-Diazavincro [5.4.0] Pendene-1 7 (DBU) 1,4 Diazabicyclo [2.2.2] Organic bases such as octane (DABCO), inorganic bases such as potassium carbonate, sodium carbonate and sodium hydrogencarbonate A known compound such as a base can be used. Examples of the alkyl halocarbonate used in the mixed acid anhydride include methyl chloroformate, ethyl ethyl chloroformate, isobutyl chloroformate and the like.

 The use ratio of the carboxylic acid and the amine (compound 4) is usually preferably equimolar, but both the alkylhalocarbonate and the carboxylic acid are used in an amount of about 1 to 1.5 times the mol of the amine (compound 4). Can be used within IS enclosures.

 The reaction is usually carried out at about 20 to 100 ° C, preferably about 0 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours. .

 The reaction of the carboxylic acid halide with the amine (compound 4) is performed in a suitable solvent in the presence of a basic compound.

 As the basic compound, for example, known basic compounds such as a basic compound used in the mixed acid anhydride method, sodium hydroxide, lithium hydroxide, sodium hydride, and lithium hydrogen hydride are used. You.

 Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and kynene; ethers such as tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; Is exemplified. In addition, the solvents exemplified in the mixed acid anhydride method can also be used.

 The proportions of the amine (compound 4) and the carboxylic acid halide are not particularly limited and can be determined as appropriate. Usually, the carboxylic acid halide is used in an amount of at least an equimolar amount of the amide (compound 4), preferably about an equimolar to 5 times the molar amount.

 The reaction is carried out at about 120 to 180 ° C., preferably at about 0 to 150 ° C., and is generally completed in about 5 minutes to 30 hours.

Examples of the condensing agent for a phosphorus compound used in the condensation reaction between a carboxylic acid and an amine (compound 4) include, for example, triphenylphosphine, diphenylphosphinylchloride, getylchlorophosphate, and cyanophosphoric acid. Examples include getyl, diphenylphosphoric azide, N, N-bis (2-oxo-13-oxazolidinyl) phosphinic chloride. As the basic compound, the same basic compound as used in the method for reacting a carboxylic acid halide can be used.

As the solvent, the same solvent as used in the method for reacting the carboxylic acid halide with the amine (compound 4) can be used. The reaction is carried out at about 150 ° C., preferably about 0 to 100 ^e C, and the reaction is completed in 5 minutes to 30 hours at a time.

 The amount of the condensing agent and the amount of the carboxylic acid to be used are both equimolar or more, preferably about equimolar to about 2 times the molar amount of the amine (compound 4).

 (6) Reaction of compound 5 to compound 6

 The reduction of the nitro group of compound 5 to the amino group can be performed, for example, by (i) a method using a catalytic reduction catalyst in a suitable solvent, or (ii) a metal or metal salt and an acid, or It is carried out by a method using a mixture of a metal or a metal salt and an alkali metal hydroxide, sulfide, ammonium salt or the like as a reducing agent.

 Examples of the solvent used in the method (i) include alcohols such as water, acetic acid, methanol, ethanol, and 2-propanol; hydrocarbons such as hexane and cyclohexane; dioxane; tetrahydrofuran; Ethers such as getyl ether diethylene glycol and dimethyl ether; esters such as methyl acetate and ethyl acetate; non-protonic polar solvents such as N, N-dimethylformamide; and mixed solvents thereof. No.

 Examples of the reduction catalyst to be used include palladium, palladium black, palladium carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like. In general, the catalyst is preferably used in an amount of about 0.02 to 1 mol per mol of Compound 5. The reaction temperature is usually about 120 to 150, preferably about 0 to 100, and the hydrogen E is usually 1 to 10 atm. The reaction is generally completed in about 30 minutes to 10 hours.

 An acid such as hydrochloric acid may be added to the reaction.

The reducing agent in the reaction (ii) is iron, zinc, tin or stannous chloride and hydrochloric acid, A mixture with a mineral acid such as sulfuric acid, or an alkali gold hydroxide such as iron, ferrous sulfate, zinc or sodium hydride, a sulfide such as ammonium sulfide, an ammonia water, an ammonium chloride, etc. Examples include a mixture with ammonium salt, or a combination of chlorazine and hydrazine.

 The inert solvent used includes, for example, water, acetic acid, methanol, ethanol, dioxane and the like, and is preferably methanol.

 The conditions of the reduction reaction are appropriately selected depending on the reducing agent used.For example, when a mixture of iron and salt S $ is used as the reducing agent, the reaction is performed at about 0 to 10 O'C for 30 minutes to 1 minute. It is preferable to perform the reaction at about 0 hours.

 The reducing agent is used in an amount of at least equimolar to compound 5, preferably about equimolar to 20-fold molar.

 In the reduction reaction using iron chloride, it may be preferable to add activated carbon.

 (7) Reaction of compound 6 to compound 7

 This reaction is a benzoylation reaction of compound 6. The benzoylation reaction can be carried out in the same manner as in the reaction from compound 4 to compound 5.

 (8) Reaction of compound 7 to compound 8

Compound 8 can be obtained by deprotecting the hydroxyl-protecting group (OR ¹⁶ ) on the benzene ring of compound 7.

'If ⁶ is a lower alkyl group, and as a reagent to be used for deprotection, for example, boron tribromide, boron trichloride, bis one Ibburopiruchio bromide boron (: (' R as a protecting group P r S ) ₂ BB r] (Tetorahi Delon Letters, ^ _, 3, (1 9 84) compounds), iodine Kaboku Rimechirushiran (T MS- I) or aluminum chloride and the like by EJ Corey, etc. that are described.

Examples of the solvent include methylene chloride and cetonitrile. In particular, when boron tribromide is used, the reaction is carried out at 2 to 5 equivalents, preferably 3.5 equivalents, by reacting the solvent at room temperature or at room temperature using methylene chloride or the like. I can. When aluminum chloride is used, sodium iodide or the like may be added.

 When another protecting group is used, a method usually used for removing the protecting group may be used.

 (9) Reaction of compound 8 to compound 9

The reaction of the compound 8 into the target compound 9, Ru carried out in the presence or absence of a halogen-substituted aralkyl force down inductive element [H a 1- (CH ₂₎ "one Z] with a basic compound to the compound 8. In some cases, it is preferable to add an alkali metal halide such as sodium iodide and potassium iodide.

 Examples of the solvent used include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dioxane and diethylene glycol dimethyl ether, chloroform, halogenated compounds such as dichloromethane, dichloroethane and carbon tetrachloride. Hydrocarbons, alcohols such as methanol, ethanol, n-propanol, and 2-propanol, acetone, acetonitril, pyridine, dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphate triamide or these Can be exemplified.

 Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium hydride and the like. Metal hydrides, metal amides such as sodium amide, metal alcoholates such as sodium methylate and sodium methoxide, pyridine, N-ethyldiisopropylamine, dimethylaminoviridine, triethylamine, DBN, Organic bases such as DBU and DABCO can be mentioned.

The ratio of the compound 8 and the halogen-substituted alkane derivative to be used is not particularly limited and may be appropriately selected. The compound [H a1-(CH ₂ ) _n- Z] (wherein each symbol in the formula is as defined above) Equimolar or more, preferably equimolar to 10-fold molar amount, relative to compound 8. The alkylation reaction is carried out under O'C to reflux, preferably under reflux, and the reaction is completed in about 2 to 5 hours.

Manufacturing method (2)

(10) Reaction of compound 9 'to compound 10

Z is Z '{∑' is — NR ⁿ R ¹² ,

(When A ^{4 is} -NR ¹⁵ )

(CH ₂ ) _n .

 — N Ψ

(CH ₂ ),

(Α ⁴ is a single bond and W ¹ is a nitrogen atom.)

I represents 0-X (when Y is an oxygen atom), _S—X (when Y is a sulfur atom), and other symbols are as defined above. }, The compound 9 ′ where Z is a halogen atom is used, and HNR ^H R ^l2 , (CH ₂ ),

Hidden 1 5 W ² — R ¹

(CH ₂ ),

 The reaction can be carried out by subjecting H〇—X, HS—X or an alkali metal salt thereof to a nucleophilic substitution reaction.

 Examples of the reaction solvent include N, N-dimethylformamide, dioxane, tetrahydrofuran, dimethylsulfokind, acetone, and the like, and preferably N, N-dimethylformamide.

 The reaction is usually performed at room temperature or under reflux with heating, and the reaction is completed in about 30 minutes to 24 hours.

 When a base is used, for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium hydride and the like Metal hydrides, metal amides such as sodium amide, gold alcohols such as sodium methylate, sodium ethylate, pyridine, N-ethyldiisopropylamine, dimethylamino pyridine, triethylamine, Organic bases such as DBN, DBU and DABCO can be mentioned.

The iodide force Agrobacterium In this reaction, may be added iodide Natoriumu like _π Manufacturing method (3)

(式巾、 R ^{1 7}は、 低极アルキル基を表し、 その他の記号は前記と同衮。 ）

(Formula width, R ¹⁷ represents a lower alkyl group, and other symbols are as defined above.)

 Y is -C 00-, X is a hydrogen atom or Z is

To Z (CH ₂ )

— CON W ² — R

ヽ (CH ₂ ) ノ

When the compound represented by is desired, W5 can be produced by the following method S using compound 11 in which Y is —C 00 — and X is a hydrogen atom.

 (1) Reaction from compound 11 to compound 12 (compound where Y is -C 00-and X is a lower alkyl group)

 The alkyl group can be eliminated by hydrolyzing compound 11 o

 The hydrolysis of compound 11 can be carried out in a suitable solvent or without a solvent in the presence of an acid or a basic compound.

 Examples of the solvent include water, low-end alcohols such as methanol, ethanol, n-propanol and 2-propanol; ketones such as acetone and methyl ethyl ketone; ethers such as dioxane, tetrahydrofuran and ethylene glycol dimethyl ether. Octanoic acids such as acetic acid, formic acid and the like, or a mixed solution thereof and the like can be used.

 As the acid, for example, mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as formic acid, acid, and aromatic sulfonic acid can be used.

 Examples of the basic compound include metal carbonates such as sodium carbonate and potassium carbonate, and metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide.

 The hydrolysis proceeds favorably at room temperature to about 200 ° C., preferably at room temperature to about 150 ° C. The reaction is generally completed in about 10 minutes to 25 hours.

 (2) Reaction from compound 12 to compound 13

Compounds 1 and 2 , (CH ₂ ) _n \

HN W ² — R ^{1 4}

\ (CH ₂ ) _P Z

Compound 13 is obtained by a condensation reaction of the amine derivative represented by the following formula.

 Examples of the compounding agent include dicyclohexylcarbodiimide (DCC), carbonylylimidabyl, N, N-bis (2-oxo-3--3-oxazolidinyl) phosphinic chloride (B0P— Examples include C 1), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HC 1), and ethyl ethyl carbonate.

 The reaction is performed in the presence or absence of a basic compound.

 Examples of the basic compound include known basic compounds used in the mixed acid anhydride method described above, such as sodium hydroxide, sodium hydroxide, sodium hydroxide, sodium hydroxide, triethylamine, and the like. Compounds can be used.

 Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; Is exemplified. In addition, the solvents exemplified in the mixed acid anhydride method can also be used.

 The proportions of the amine derivative and compound 12 used are not particularly limited, and can be determined as appropriate. Usually, the amount of the amide derivative used is at least an equimolar amount of the compound 12, preferably about an equimolar to about 5 times the molar amount.

 The amount of the condensing agent to be used is at least equimolar to the amide derivative, and preferably about equimolar to about twice the molar amount.

 The reaction is carried out at about −20 to 15 O′C, preferably about 0 to 10O′C, and is generally completed in about 5 minutes to 30 hours.

After compound 12 is converted into a carboxylic acid halide with a reagent such as oxalyl chloride or thionyl chloride, the amine derivative is dissolved in an organic solvent such as chloroform or acetonitrile. Compound 13 can also be obtained by performing the reaction in a medium in the presence of a base such as triethylamine for about 30 minutes to about 24 hours at 0 ° C. or room temperature. Manufacturing method (4)

R to A ¹ C00R '' R ¹ A ¹ COOR ''

 Acylation

NH ₂ (C1C0 (CH ₂ ) ₂ C00R ') R ² NHC0 (CH ₂ ) ₂ C00R'

(14) (15) (16)

Ring closure reaction

 i) Base or metal hydride

 ii) Decarboxylation reaction

Vagrant

(Wherein R ′ and R ′ ′ are the same or different and represent a lower alkyl group such as a methyl group or an ethyl group or an aralkyl group such as a benzyl group, and other symbols are as defined above.) Compound 4 is represented by A ¹ Is a sulfur atom, a method known in the literature [Kunick. Arch.

Pharm. (Weinheim) 324, 579 (1991)], and then can be produced by the following reduction method.

 (1) Reaction of compound 14 to compound 16

The conversion of compound 14 to compound 16 is carried out by reacting the acyl compound (compound 15) in an appropriate solvent in the presence or absence of a basic compound. Examples of the basic compound include organic bases such as triethylamine, trimethylamine, pyridine, N, N-dimethylaniline, N-methylmorpholine, DBN, DBU, and DBACO, potassium carbonate, sodium carbonate, calcium carbonate, and carbonate. Inorganic bases such as hydrogen hydrogen and sodium hydrogen carbonate;

 Examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, getyl ether, dibutyl pill ether, tetrahydrofuran, and dimethoxyethane. Aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoric acid triamide, or a mixed solution thereof.

 Compound 15 is preferably used in an equimolar to 10-fold molar amount with respect to compound 14.

 The reaction is preferably carried out under ice-cooling to 20 ° C., and is completed in about 1 to 50 hours.

 (2) Reaction of compound 16 to compound 17

 Compound 16 is converted to compound 17 by heating 2 to 3 equivalents of metal hydride or base to compound 16 in an organic solvent such as toluene, benzene, N, N-dimethylformamide, etc. The mixture is stirred to obtain a Dieckmann condensate, which is then heated under reflux in a water-containing organic solvent in the presence of sodium chloride, potassium chloride or the like to carry out decarboxylation to obtain compound 17.

 Examples of the metal hydride include sodium hydride, potassium hydride and the like.

 Examples of the base include potassium tert-butoxide, lithium disopropylamide and the like.

 Examples of the organic solvent include dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, tetrahydrofuran, dioxane and the like.

 The heating and stirring are carried out at 60 to 100 ° C., preferably at 70 ° C., and the reaction is completed in about 30 minutes to 48 hours.

 (3) Reaction of compound 17 to compound 4

Although there is no particular limitation on the origin of compound 17, a reduction method using a hydride reducing agent is preferred. Good.

 Examples of the hydrogenation reducing agent include lithium aluminum hydride, diborane and the like.

 The amount of the reducing agent to be used is 1 mol or more, preferably 1 mol to 15 mol, per 1 mol of compound 17.

 The reaction is usually performed in a suitable solvent. Examples of the solvent include ethers such as tetrahydrofuran, getyl ether, diisopropyl ether, ethylene glycol dimethyl ether, and diglyme, and mixtures thereof. The reaction is usually carried out at 160-150'C, preferably at 130-100. C, about 10 minutes to 15 hours.

Manufacturing method (5)

Har CO (CH ₂ ) «Hal

化合物 8から化合物 1 8への反応

Reaction of compound 8 to compound 18

If desired, compound 18 (a compound in which m is 0 and Z is —C） NH ₂ ) is obtained by reacting compound 8 with chlorosulfonyl isocyanate, generally in an inert solvent. .

 Examples of the inert solvent used include, for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether; chloroform; dichloromethane; Halogenated hydrocarbons such as methanol, ethanol, 2-propanol, butanol, tert-butyl alcohol, etc., esters such as methyl acetate, ethyl acetate, acetic acid, acetone, acetonitrile, pyridine , Dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric acid triamide or a mixed solution thereof.

 The ratio of compound 8 and chlorosulfonyl isocyanate to be used is not particularly limited and may be appropriately selected, but chlorosulfonyl isocyanate is at least equimolar to compound 8, preferably at equimolar to 10-fold molar. Use the amount.

Then, the desired compound 18 is obtained by reacting water under heating ₍ production method (6)).

<CH ₂ ) _m -NH ₂

R ⁵

R ⁶

Reaction of compound 19 to compound 20

When the compound 20 (R if ^'2, R' ³ is a hydrogen atom) desired, the compound 1 9 (Z compound is a flow evening Louis Mi de), methanol, heat in an alcoholic solvent such as ethanol It can also be obtained by reacting drazine.

 The hydrazine may be used in an amount of 1 to 10 equivalents to the compound 19. The reaction is carried out under heating, preferably under reflux, and the reaction is completed in about 1 to 10 hours.

Manufacturing method (7)

 Z is

R ' ⁵ no (CH ₂ ) _n \

— N -C0 (CH ₂ ), — NW ² — R

(CH ₂ ) _P ^/

When the compound represented by is desired, the following steps may be performed using a compound in which Z is an amino group.

(CH ₂ )

(CH ₂ ) one NW ⁵

W²— R"

W ² — R "

(1) Reaction of compound 20 to compound 21

Compound _{20, Ha r CO (CH 2} ) t Ha l ( wherein, Ha l ', Ha 1 each represents a halogen atom, s is as defined above.) The compound represented by the inert solvent, By reacting in the presence or absence of a base, Z is strongly obtained as a compound 21 represented by NHCO (CH ₂ ) and Ha 1.

The use ratio of Hal * CO (CH ₂ ) and Ha 1 is preferably 1 to 2 equivalents to compound 20. The reaction is carried out under heating to reflux, preferably at 0 ° C. to heating under reflux, and the reaction is completed in about 30 minutes to 24 hours.

 The inert solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include dichloromethane, chloroform, acetone, tetrahydrofuran, N, N-dimethylformamide and the like. .

 Examples of the base include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, such as triethylamine, and N, N-diisopropylethylamine. Organic bases such as pyridine, 4-dimethylaminopyridine and the like can be used.

 (2) Reaction of compound 21 to compound 22

Compound 21 to 1 , (CH ₂ ) _n \

HN W ² — R

\ (CH ₂ ) _P Z

 (Each symbol in the formula is as defined above), the compound 22 is obtained by reacting in an inert solvent in the presence or absence of a base.

 The solvent used is not particularly limited as long as it does not affect the reaction, and examples include dichloromethane, chloroform, acetone, tetrahydrofuran, N, N-dimethylformamide and the like.

 Examples of the base include inorganic bases such as sodium hydride, potassium hydride, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, such as triethylamine, N, N-diamine. Organic bases such as isoprovirethylamine, pyridine and 4-dimethylaminoviridine can be used.

 In this reaction, it may be preferable to add sodium iodide, potassium iodide, or the like.

 (3) Reaction of compound 22 to compound 23

This step may be performed when a compound in which R ¹⁵ is a lower alkyl group is desired.

 Compound 22 is used in a solvent such as tetrahydrofuran, N, N-dimethylformamide, or cetone, and a base such as sodium hydride, potassium hydride, sodium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, etc. Compound 23 is obtained by reacting an alkylating agent such as an alkyl halide or dialkyl sulfate having a desired alkyl residue in the presence of

Manufacturing method (8)

A ² force \ one CR ⁸ R ^{9, wherein} one of R ⁸ and R ⁹ represents a hydrogen atom and the other is an optionally substituted amino group, preferably R ' ⁹

 N

2 ⁰

(In the formula, R ¹⁹ and R ² ° may be the same or different and each represents an optionally substituted alkyl group or a cycloalkyl group, or represents a ring together with a nitrogen atom to which R ¹⁹ and R ² bind. And the ring may further contain a nitrogen atom which may be substituted and an oxygen filant). If desired, the compound 17 is obtained by the following steps using compound 17 be able to.

(Wherein, R ²¹ represents a halogen atom, an alkylsulfonyl group or an arylsulfonyl group, and other symbols are as defined above)

 (1) Reaction of compound 17 to compound 24

Compound 17 is converted to water, lower alcohols such as methanol, ethanol, isopropanol, tert-butanol, ethers such as tetrahydrofuran, getyl ether, diisopropyl ether, ethylene glycol, dimethyl ether, diglyme, or a mixed solvent thereof. In, sodium borohydride, hydrogenation Compound 24 is obtained by performing a reduction reaction using a reducing agent such as sodium trimethoxyborohydride or lithium borohydride. The reaction is usually completed at about 160 to 150 ° C., preferably about 130 to 100 ° C., in about 10 minutes to 15 hours.

(2) Reaction of compound 24 to compound 25

 The ability to halogenate compound 24 with a halogenating agent such as hydrogen chloride, thionyl chloride, or oxalyl chloride in a solvent such as dichloromethane, chloroform, tetrahydrofuran, or methyl ether; triethylamine; Sulfonylating agents such as methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, anhydrous trifluoromethanesulfonyl, etc. in the presence of bases such as min, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc. Compound 25 is obtained by reacting

 (3) Reaction of compound 25 to compound 26

Compound 25 was converted to chloroform, dichloromethane, dichloroethane, benzene, toluene, xylene, getyl ether, diisopropyl ether, tetrahydrofuran, furan, dimethoxetane, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, In a solvent such as xamethylphosphoric acid triamide, in the presence of a base such as triethylamine, pyridine, N, N-dimethylaniline, N-methylmorpholine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc. Mino compounds, preferably no R ^{, s}

 HN

(Each symbol in the formula is as defined above) to give compound 26. This reaction is preferably performed under ice cooling to 200 ° C., and is completed in about 1 to 50 hours.

 (4) Reaction of compound 17 to compound 26

Compound 17 HN

(Each symbol in the formula is as defined above), to give compound 26.

 Examples of the solvent include alcohols such as methanol, ethanol, and 2-propanol; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as carbon form, dichloromethane, dichloroethane, and carbon tetrachloride; Non-protonic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, and mixtures thereof can be used.

 Examples of the dehydrating agent include desiccants used for drying ordinary solvents such as molecular sieves, mineral acids such as hydrochloric acid, sulfuric acid, and boron trifluoride, and organic acids such as p-toluenesulfonic acid. Mixtures and the like can be used.

 The reaction is usually carried out at room temperature to 250'C, preferably at about 50 to 200'C, and is generally completed in about 1 to 48 hours.

 (5) Reaction of compound 26 to compound 27

 Compound 26 is subjected to a reduction reaction using a reducing agent such as lithium aluminum hydride, diborane, or diisobutyl aluminum hydride in a solvent such as getyl ether, tetrahydrofuran, benzene, or toluene to obtain compound 27. Is obtained.

Thereafter, the reaction for obtaining compound 5 using compound 27 in production method 1 and the subsequent steps are carried out, whereby A ² power,

R ^{1 9} R ^{2 0} NO CH \

Wherein each symbol in the formula is as defined above, is obtained. In each of the above reactions, after completion of the reaction, the target compound is separated from the anti-mixture and produced by a means known in the art, such as solvent extraction, column chromatography, recrystallization, etc., as appropriate. It can be done by doing. In addition, the target compound can be produced even if it proceeds to the next step without isolation and purification of the target compound.

 When synthesizing the final target compound represented by the general formula (I), a protecting group may be introduced at an appropriate stage as necessary, and the protecting group may be removed at an appropriate stage.

 When a free form of the compound represented by the general formula (I) is converted into an acid addition salt or a weak acid salt is converted into a strong acid salt, the compound is converted into water, methanol, ethanol, n-propanol, 2 — Solvents dissolved in propanol, getyl ether, tetrahydrofuran, 1,4-dioxane, ethyl acetic acid, dichloromethane, 1,2-dichloroethane or chloroform, or a mixture of these, and the desired acid dissolved in the above solvent. Then, the precipitated crystals are collected or reduced and concentrated to obtain an acid addition salt of the compound represented by formula (I).

 When converting the acid addition salt of the compound represented by the general formula (I), the compound is converted into sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydroxide, potassium hydroxide or water. Dissolve or suspend in an aqueous solution of a base such as lithium oxide and extract with ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, or a mixed solvent thereof. The residue is then treated with water, methanol, ethanol, n-propanol, 2-propanol, getylether, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, 1,2-dichloroethane or chloroform, or The above-mentioned solvent in which the desired acid is dissolved in these mixed solvents and the like is added, and the precipitated crystals are collected by filtration or reduced E and concentrated to obtain the desired salt represented by the general formula (I). An acid addition salt of the represented compound is obtained.

Further, in the compound represented by the general formula (I) of the present invention, various isomers may exist. For example, cis-form and trans-form as geometric isomers can exist. When an asymmetric carbon atom is present, an enantiomer as a stereoisomer based on these, Diastereomers can be r-present. In some cases, tautomers may exist. Therefore, the scope of the present invention includes all these isomers and mixtures thereof. The compound (I) of the present invention and a pharmacologically acceptable salt thereof antagonize vasobretsin. It can be expected to have various effects such as an inhibitory effect and an oxytocin antagonistic effect. Therefore, hypertension, heart failure, renal failure, edema, ascites, arginine vasobretsin hypersecretion syndrome, cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, pulmonary edema, Meniere's syndrome, okintocin It is considered to be useful for treatment and prevention or prevention of diseases and the like. In particular, it is expected to be useful as a therapeutic agent for cerebral edema, congestive heart failure, arginine vasopressin hypersecretion syndrome, hypertension, renal failure, pulmonary edema, Meniere's syndrome, and the like.

 The compound (I) of the present invention or a pharmaceutically acceptable salt thereof is used in the form of a general pharmaceutical preparation. The preparations are prepared using commonly used diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and lubricants. Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, Injection (solution, suspension) and the like.

In the case of molding into tablets, various carriers known in the art can be used as carriers. Examples include excipients such as milk, white, sodium chloride, grape, urea, calcium carbonate, kaolin, crystalline cellulose, gay acid, water, ethanol, propanol, simple syrup, grape, Binders such as starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, polyoxyethylene ethylene sorbitan fatty acid ester , Sodium lauryl sulfate, stearic acid monoglyceride, dampening agents, demulsifying agents such as milk, lactic acid, encouragement, stearin, cocoa butter, degrading agents such as hydrogenated oil, quaternary ammonium base, lauryl sulfate Promotion of absorption of sodium, etc. , Moisturizers such as glycerin and starch; adsorbents such as starch, lactose, lactose, bentonite, and colloidal gay acid; lubricants such as purified talc, stearates, boric acid powder, polyethylene glycol, etc. Can be used. Further, the preparation can be a preparation coated with a usual coating, if necessary, for example, a sugar-coated tablet, a gelatin-encapsulated, enteric-coated, a film-coated tablet or a double tablet or a multilayer tablet.

 In the case of molding in the form of a pill, various carriers known in the art can be used as the carrier. Examples include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, kaolin, talc, binders such as gum arabic, tragacanth, gelatin, ethanol, and disintegrants such as laminaran and agar. Etc. can be used

 When formed into a suppository, various carriers known in the art can be used as the carrier. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, highly alcoholic esters, gelatin, and semi-synthetic glycerides.

 Capsules are usually prepared by mixing the active ingredient compound with the various carriers described above and filling the mixture into hard gelatin capsules, soft capsules and the like according to a conventional method.

When prepared as an injection, liquid preparations, emulsions and suspensions are preferably sterilized and isotonic with blood and blood, and are commonly used as diluents in this field when shaping into these forms. Everything can be used. For example, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, boroxylated isostearyl alcohol, and polyoxetylene rubine fatty acid esters can be used. In this case, a sufficient amount of salt, fluid, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and ordinary dissolution aids, buffers, soothing agents, etc. may be used. It may be added. Further, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent or the like and other pharmaceuticals may be contained in the pharmaceutical preparation, if necessary. _C The compound to be contained in the bathoburetsin antagonist of the present invention (I) Alternatively, the amount of the salt is not particularly limited and may be appropriately selected, but is usually 1 to 70 times in the pharmaceutical composition. %, Preferably about 5 to 50% by weight.

 There is no particular limitation on the method of administration of the vasobretsin antagonist of the present invention, and it is administered according to the formulation, age, sex and other conditions of the patient, degree of disease, and the like. For example, tablets, pills, solutions, suspensions, emulsions, contraceptives and capsules are orally administered. In the case of injections, they are administered intravenously, alone or in combination with ordinary fluid replacements such as voodoo and amino acids, and if necessary, intramuscularly, intradermally, subcutaneously, or intraperitoneally. Suppositories are administered rectally.

 The dosage is appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the disease, etc. Usually, the amount of the active ingredient compound is about 0.6 to 5 Omg per kg of body weight per day. Is good. It is preferable that the active ingredient compound is contained in the dosage unit form in the range of about 10 to 100 mg.

 Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to the following examples.

Example 1

 N— [2-Methoxy-1-41 [(5,6,7,8-Tetrahydr 4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl]-[S-phenyl ] 1-Carboxamide

 (Process a)

 4,5,6,7-tetrahydro 4H-benzo [b] thiophene-41-one-oxime

6,7-Dihydro 5H-benzo [b] Dissolve 4-thione-one (9.3 g) in pyridine (70 ml), add hydroxylamine hydrochloride (8.5 g), and add 3 hours The mixture was stirred at room temperature. The reaction solution is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography. Purified by Raffy (elution solvent; ethyl acetate: black form = 1: 19). g Compound (7.5 g) was obtained.

 (Process b)

 5, 6, 7, 8—tetrahydro 4H—thieno [3,2—b] azepine

工程 aで得られた 4, 5, 6, 7—テトラヒ ドロ— 4 H.—べンゾ [b] チオフ ェン一 4一オン ォキシ厶 （5 g)にアルゴン雰囲気下、 無水ジクロロメタン （500 ml) を加え、 氷冷下、 水素化ジイソブチルアルミニウム （165 ml. 0.98M へキサ ン溶液） を滴下し 2時間攪拌した。 反応液にフッ化ナトリウム （25 g) を加え、 氷冷下にて 5分攪拌した後、 水 （7.5 ml) を滴下し 2 0分攪拌した。 反応液をセ ライ ト濾過し、 セライ ト上の残渣をジクロロメタンで洗い、 滹液と洗液を合わせ、 減 0：下溶媒留去し、 標題化合物 （3.6 g)を得た。

Under an argon atmosphere, anhydrous dichloromethane (500 ml) was added to 4,5,6,7-tetrahydro-4H.-benzo [b] thiophene-one oxonium (5 g) obtained in step a. ), Diisobutylaluminum hydride (165 ml. 0.98M hexane solution) was added dropwise under ice cooling, and the mixture was stirred for 2 hours. Sodium fluoride (25 g) was added to the reaction solution, and the mixture was stirred under ice-cooling for 5 minutes, water (7.5 ml) was added dropwise, and the mixture was stirred for 20 minutes. The reaction solution was filtered through celite, and the residue on celite was washed with dichloromethane. The combined solution and the wash were combined, and the solvent was distilled off at 0: the solvent was distilled off to obtain the title compound (3.6 g).

NMR (CDC 13) (5 ppm, 300 MHz:

 1.60-1.75 (2H, m) .1.75-1.90 (2H, m), 2.65-2.80 (2H, m).

3.00-1 3.15 (2H.m), 6.31 (1H, d. J = 5.0Hz). 6.82 ClH, d. J = 5.0Hz) MS (M ⁺ ): 153

 (Process c)

4- (3-Methoxy-4,2-trobenzoyl) -5,6,7,8-tetrahydro-14H-thieno [3,2-b]

A mixture of 3-methoxy-4-nitrobenzoic acid (2 g), thionyl chloride (2 ml), chloroform (2 ml) and N, N-dimethylformamide (0.2 ml) is heated under reflux for 3 hours. After that, the mixture was concentrated under reduced pressure to obtain an acid chloride. This acid chloride was dissolved in chloroform (10 ml), and cooled with ice to give 5,6,7,8-tetrahydro D-4H-thieno [3,2-b] azepine (1.1). g :), a mixture of triethylamine (3 ml) and □ mouth form (10 ml) were added dropwise over 10 minutes. After stirring for 12 hours at room temperature, is the reaction liquid under 减? '' Distill off the solvent, add chloroform, wash with water, 1N-hydrochloric acid, saturated saline, IN-aqueous sodium hydroxide solution and saturated saline, and dry over anhydrous sodium sulfate. The residue obtained by evaporation was recrystallized from ethanol to give the title compound (2.2 g).

m p (soln.): colorless crystal, 123.4-124.6 ° C (EtOH)

 NMR (CDC 13) 5 ppm, 300 MHz:

 1.55-1.65 (2H, m), 1.75-1.85 (2H, m). 2.90-3.00 (2H, m), 3.81 (3H, s), 3.70-4.00 (2H.brs), 6.19 (1H.d, J = 5.1Hz),

 6.71 (1H.d 'J = 5.1Hz), 6.87 (1H, d, J = 8.4Hz) .7.03 (1H.s),

 7.66 (1H.d, J = 8.4Hz)

MS (M ⁺ ): 332

 (Process d)

N— [2—Methoxy 4 — [(5,6,7,8—tetrahydro 4 H—thieno [3,2—b] azepine-14-yl) carbonyl] phenyl] -1- [1, bibi Phenyl] — 2-carboxamide

2-Phenylbenzoic acid (320 mg) was dissolved in chloroform (3 ml), thionyl chloride (3 ml) was added, and the mixture was heated under reflux for 4 B. The solvent was distilled off from the reaction mixture under reduced pressure, and toluene was added to and dissolved in the remaining apricot. Then, the solvent was distilled off under reduced pressure to prepare 2-phenylbenzoyl chloride.

 On the other hand, 4- (3-Methoxy-412-trobenzyl) -1-5,6,7,8-tetrahydro-14-thieno [3,2-b] azepine obtained in step c (430 mg) Was dissolved in ethanol (30 ml), 10% palladium on carbon (43 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere of ffl for 10 hours. The reaction solution was passed through celite, the residue on the celite was washed with ethanol, the filtrate and the washing were combined, and the solvent was distilled off under reduced pressure. This was dissolved in chloroform (5 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced E to give 4- (4-methoxy-4-aminobenzoyl) —5,6, 7,8-Tetrahydro 4 H-thieno [3,2-b] azepine was obtained.

IR (KBr): 3469, 3344. 1617, 1523, 1379 cm " ¹

NMR (CDC 13) (5 ppm:

 1.67-1.79 (2H, m). 1.95-2.02 (2H.m), 2.90-2.94 (2H, m),

3.68 (3H, s). 3.80-1 4.00 (2H.brs). 3.94 (2H, brs),

6.27 (1H.d.J = 4.8Hz). 6.45-6.47 (1H.m), 6.67 (1H, d, J = 4.6Hz), 6.76-6.82 (2H, m)

MS (M ⁺ ): 302

 Then, form (5 ml) was added to the residue to form a solution. To this were added a solution of 2-phenylbenzoyl chloride previously prepared in chloroform (5 ml) and triethylamine (0.4 ml), and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off from the reaction solution under reduced pressure, and chloroform was added.The residue was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by Raffy (elution solvent: ethyl acetate: n-hexane = 1: 3) to give the title compound (420 mg).

mp (soln.): colorless needles, 157.6- 158.8. C (MeOH)

IR (KBr): 3397, 1641. 1523 cm " ¹

 NMR (CDC 13) 5 ppm, 300 MHz:

 1.73-1.82 (2H.m). 1.94-2.04 (2H.m), 2.85-2.95 (2H, m).

 3.42 (3H, s). 3.70-4.00 (2H.brs). 6.19 (1H.brs), 6.66 (1H.s), 6.75 (1H.d, J = 5.1Hz), 6.82 (1H.d.J = 7.31 ― 7.55 (8H, m), 7.68 (1H, s), 7.83 (1H, d, J = 5.9Hz), 8.26 (1H, d.J = 8.Hz)

MS (M ⁺ ): 482

Example 2

N— [2-Hydroxy-1-4-((5,6,7,8-Tetrahydric 1-4H-Cheno [3,2-b] azepine-4-1-yl) carbonyl] phenyl] -1- [ -Biphenyl] 1- 2-carboxamide

実施例 1で得られた N— [2—メ トキシ— 4一 [ (5, 6, 7, 8—テトラヒ ドロ一 4H—チエノ [3, 2— b] ァゼピン一 4一ィル） カルボニル] フエニル ] - [ 1 , 1 * ービフエ二ル] — 2—カルボキサミ ド （100 mg) にアルゴン雰 ffl 気下、 無水ジクロロメタン （5 ml) を加え、 一 78 °Cの下、 三臭化ホウ素（0.72 ml, 1.0Mへキサン溶液） を滴下し、 3時間かけて室温まで昇温した。 反応液にメ 夕ノール （1.0 ml) を加え、 5分攪拌した後、 クロ口ホルムを加え、 水、 飽和 it 塩水で洗浄、 無水硫酸ナトリウムで乾燥後、 '减圧下にて溶媒留去して得られる残 渣をシリカゲルカラムクロマトグラフィー （溶出溶媒；酢酸ェチル： n—へキサ ン= 1 ： 1) により精製し、 標題化合物 （90 mg)を得た。

N- [2-Methoxy-4-1-[(5,6,7,8-tetrahydro-1-4H-thieno [3,2-b] azepine-1-4-yl) carbonyl] phenyl obtained in Example 1 ]-[1,1 * -biphenyl] — 2-Carboxamide (100 mg) was added to anhydrous dichloromethane (5 ml) under an argon atmosphere under ffl, and boron tribromide (0.72 ml) was added at -78 ° C. , 1.0 M hexane solution) was added dropwise, and the temperature was raised to room temperature over 3 hours. To the reaction mixture, add methanol (1.0 ml), stir for 5 minutes, add chloroform, wash with water and saturated it brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 1: 1) to obtain the title compound (90 mg).

mp (soln.): amorphous solid

 I R (KB r): 3225, 1610, 1528 cm "'

NMR (CDC 13) <5 ppm, 300 MHz:

 1.71-1.81 (2H, m). 1.92-2.02 (2H, m). 2.88-2.95 (2H.m).

 3.70-4.00 (2H, brs). 6.20 (2H, brs) .6.52 (1H, brs),

 6.65 (1H, brs). 6.94 (1H.s) .7.30-7.60 (8H, m),

 7.85 (1H, d. J = 7.7Hz). 8.99 (1H, s)

MS (M +): 468 Example 3

 N— [2 -— (2-chloroethyn) 1-41-[(5,6,7,8-tetrahydro-1-4H-cheno [3,2-b] azepin-1-yl) carbonyl] phenyl] [1, 1 '-biphenyl] — 2-carboxamide

実施例 2で得られた N— [2—ヒ ドロキン一 4一 [ ( 5, 6, 7, 8—テトラ ヒ ドロー 4 H—チエノ [3, 2 - b] ァゼピン一 4一ィル） カルボニル] フエ二 ル] 一 [し 1 ' —ビフエニル] 一 2—カルボキサミ ド （3.0 g)をアセトン （25

N— [2-Hydroquinone 1-41 obtained in Example 2 ((5, 6, 7, 8-tetrahydro 4 H—thieno [3,2-b] azepine-14-yl) carbonyl] [Phenyl]-[1'-biphenyl] -12-carboxamide (3.0 g) in acetone (25

0 ml), 1-promo 2-chlorobenzene (1.3 g), lithium carbonate (2.6 g), and potassium iodide (212 mg) were added, and the mixture was refluxed for 12 hours. To the reaction mixture was added chloroform, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

Purified by ethyl acetate: n-hexane = 1: 3) to obtain the title compound (2.9 g).

mp (soln.): amorphous solid

1 R (KBr): 3403, 1640, 1521 cm " ¹

NMR (CDC 13) <5 ppm, 300 MHz:

1.72-1.82 (2H, m). 1.93-2.03 (2H, m), 2.89-2.93 (2H, m), 3.49 (2H.m), 3.83-4.00 (4H, m). 6.19 (1H, brs), 6.68 (1H.d.J = 5.1Hz). 6.75 (1H, s), 6.89 (1H.d.J = 8.4Hz).

 7.30-7.55 (8H, m), 7.71 (1H.s). 7.78 (1H.d.J = 7.7Hz).

 8.32 (1H.d, J = 8.5Hz)

MS (M +): 530

Example 4

 N- [2— [2— (4-Methylbiperazine-11-yl) ethokine] 1-41- [(5,6,7,8-tetrahydro-1 4H-thieno [3,2-b] azebin 1-yl) carbonyl] phenyl] 1- [1,1'-biphenyl] 1-2-carboxad

実施例 3で得られた N- [2— (2—クロ口エトキン） 一 4— [ (5, 6， 7 , 8—テトラヒ ドロー 4 H—チエノ [3, 2— b] ァゼビン一 4一ィル） カルボ ニル] フエニル] 一 [し 1 ' 一ビフヱニル] 一 2—カルボキサミ ド O100 mg) を N, N—ジメチルホルムアミ ド （6 ml) に溶かし、 N—メチルビペラジン （90 mg)、 ヨウ化カリウム （12 tng)を加え、 3時間加熱通流した。 反^液にクロロホ ルムを加え、 飽和炭酸水素ナトリウム水で洗浄、 無水硫酸ナトリウムで乾燥後、 减圧下にて溶媒留去して得られる残渣をシリカゲルカラムクロマトグラフィー （ 溶出溶媒； クロ口ホルム ： メタノール = 19 ： 1 ) により精製し、 標題化合物 （ 250 mg) を得た。

N- [2 -— (2-cloth ethokine) 1-4 — [(5,6,7,8-tetrahydro 4H—thieno [3,2-b] azebine 1-41 obtained in Example 3 L) Carbonyl] phenyl]-[1'-biphenyl] -12-carboxamide O100 mg) is dissolved in N, N-dimethylformamide (6 ml), N-methylbiperazine (90 mg), potassium iodide (12 tng), and the mixture was heated and flowed for 3 hours. Chloroform is added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent obtained by distilling off the solvent under reduced pressure is subjected to silica gel column chromatography (elution solvent: chloroform: methanol). = 19: 1) to give the title compound (250 mg).

mp (soln.): colorless crystal, 117.0-118.0 ° C (acetone) IR (KBr): -3404, 2934. 2800. 1673. 1640. 1523 cm " ¹

NMR (CDC 13) δ p pm, 300 MHz:

 1.72-1.82 (2H.m). 1.93-2.03 (2H, m), 2.17 (3H.s).

 2.25 (4H.brs), 2.35-2.48 (6H, m), 2.88-1.95 (2H, m).

 3.70-3.80 (2H, m). 3.70-3.91 (2H, s). 6.20 (1H, brs).

 6.67 (1H.d.J = 5.2Hz). 6.79 (1H.brs). 6.88 (1H.d.J = 8.4Hz),

7.25-7.55 (8H.m). 7.74 (1H, d, J = 6.2Hz). 8.10 (1H.brs),

 8.26 (1H.d, J = 8.5Hz)

MS (M ⁺ ): 594

Example 5

 Ethyl 2-[[[[1'-biphenyl] -1-2-carbonyl] amino] -1-5-[(5,6,7.8-tetrahydro-4H-thieno [3,2-b] azepin-14-1 Le) carbonyl] phenoxy acetate

実施例 3で得られた N— [2—ヒドロキン— 4一 [ (5， 6, 7, 8-テトラ ヒドロー 4 H—チエノ [3, 2— b] ァゼピン一 4—ィル） カルボニル] フエ二 ル] 一 [ 1 , 1 ' —ビフエニル] 一 2—カルボキサミ ド （936 mg) をァセ卜ン （ 25 ml)、 N, N—ジメチルホルムアミ ド （25 ml)の混合溶液に溶かし、 ブロモ酢 酸ェチル （500 mg) 、 炭酸カ リウム （280 mg) 、 ヨウ化ナトリウム （300 m を 加え、 5時問加熱還流した。 反応液にクロ口ホルムを加え、 水、 和食塩水で沈 浄、 無水硫酸ナトリウ厶で乾燥後、 減圧下にて溶媒留去して得られる残渣をシリ 力ゲルカラムクロマトグラフィー （溶出溶媒：酢酸ェチル ·· n—へキサン = 1 ： 3) により精製し、 標題化合物 （1.2 g)を得た。

N- [2-Hydroquin-4-1 [(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepin-14-yl) carbonyl] carbonyl obtained in Example 3 [1,1'-Biphenyl] -12-carboxamide (936 mg) was dissolved in a mixed solution of acetone (25 ml) and N, N-dimethylformamide (25 ml). Ethyl acid (500 mg), potassium carbonate (280 mg), and sodium iodide (300 m) were added, and the mixture was heated under reflux for 5 hours. To the reaction solution was added chloroform, and the mixture was washed with water and brine, and sulfuric anhydride was added. After drying over sodium, the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate · n-hexane = 1: 3) to obtain the title compound (1.2 g) was obtained.

mp (soln.): non-crystalline solid

IR (KBr): 3407. 1754, 1687, 1643 cm- ¹

NMR (CD C 13) ά p pm, 300 ΜΗ ζ:

 1.24 (3Η.t.J = 7.0Hz) .1.72-1.82 (2H, m). 1.91-2.01 (2H, m).

2.86-2.92 (2H.m). 3.70-3.90 (2H.brs), 4.18 (2H.s).

 4.19 (2H, q, J = 7.0Hz), 6.17 (1H, brs). 6.64-1 6.72 (2H, m).

 6.90 (1H.d.J = 8.4Hz) .7.22 ― 7.55 (8H.m. 7.80 (1H.d, J = 7.7Hz).

8.00 (1H.s). 8.27 (1H, d, J = 8.Hz)

MS (M ⁺ ): 554

Example 6

 2-[[[[1,1-biphenyl] -1-2-carboni] amino] -1-5-((5,6,7,8-tetrahydro 4 Η-thieno [3,2-b] azepine 1-4-yl ) Carbonyl] phenoxyacetic acid

実施例 5で得られたェチル 2— [ [ [し 1 ' —ビフヱ二ル] — 2—力儿ボ ニル] ァミ ノ] — 5— [ ( 5, 6, 7， 8—テトラヒ ドロー 4 H—チエノ [3, 2 - b] ァゼピン一 4一ィル） カルボニル] フエノキシアセテー ト （560 mg) を メタノール （100 mg) に溶かし、 水酸化カリウム （140 mg) を加え、 2時問加 還流した。 減圧下にて溶媒留去し、 反応液にクロ口ホルムを加え、 塩酸を用いて 水層を酸性とし、 抽出した有機層を飽和食塩水で洗浄した。 無水硫酸ナトリウム で乾燥後、 標題化合物 （350 mg) を得た。

Etyl 2-[[[1'-biphenyl] -2- [2-diphenyl] amino] obtained in Example 5—5 — [(5,6,7,8-tetrahydro 4H Dissolve thieno [3,2-b] azepine-141-yl) carbonyl] phenoxyacetate (560 mg) in methanol (100 mg), add potassium hydroxide (140 mg), and add 2 hours. Refluxed. The solvent was distilled off under reduced pressure, and the reaction mixture was added with chloroform. The aqueous layer was acidified with hydrochloric acid, and the extracted organic layer was washed with saturated saline. After drying over anhydrous sodium sulfate, the title compound (350 mg) was obtained.

mp (soln.): amorphous solid

IR (KB r): 3397. 1600, 1523 cm " ¹

NMR (CDC 13) (5 ppm, 30 OMH z:

 1.70-1.80 (2H.m). 1.90-2.00 (2H.m). 2.86-2.90 (2H, m).

 3.70-3.90 (2H, brs), 4.26 (2H.s), 6.16 (2H.brs).

 6.62-6.80 (3H, m). 7.30-7.55 (8H.m). 7.80 (1H.d.J = 6.6Hz),

7.97 (1H.s) .8.13 (1H, d.J = 8.4Hz)

MS (M ⁺ ): 526

Example 7

N- [2-[2 -— (4-Methylbiperazine-1 1-yl) -1-2-oxotoquine]--[(5,6,7,8-tetrahydro 4H-thieno [3,2_b] azepine 1-4-yl) carbonyl] phenyl] 1- [shi 1'-biphenyl] 1-2-force lipoxamide

実施例 6で得られた 2— [ [ [ 1 , 1 ' 一ビフヱニ儿] 一 2—カルボニル] 了 ミノ] 一 5— [ (5, 6, 7, 8—テトラヒ ドロー 4 H—チエノ [3, 2— b] ァゼピン一 4一ィル） カルボニル] フエノキシ酢酸 （180 mg) をクロ口ホルム （ 5 ml) に溶かし、 N—メチルビペラジン （37 mg)、 N, N—ビス （2—ォキフー 3—ォキサゾリジニル） ホスフィ ン酸 ク□リ ド （130 mg) 、 トリェチルァミ ン (140 ml) を加え、 1 2時間室温にて攪拌した。 反応液にクロ口ホルムを加え、 飽和炭酸水素ナトリウ厶水で洗浄、 無水硫酸ナトリウ厶で乾燥後、 減 E下にて 媒留去して得られる残渣をシリカゲルカラムクロマトグラフィー （溶出溶媒； ク ロロホルム ： メタノール = 19 ： 1 ) により精製し、 標題化合物 （127 mg) を得 m p (soln.)：無色針状結晶、 183.0 - 184.7て （イソプロピルエーテル）

2-[[[1, 1'-biphenyl] 1-2-carbonyl] rino] 1-5-[(5,6,7,8-tetrahydro 4H-thieno [3, obtained in Example 6] 2—b] azepine-41-yl) carbonyl] phenoxyacetic acid (180 mg) dissolved in chloroform (5 ml), N-methylbiperazine (37 mg), N, N-bis (2-oxofuzidinyl) ) Phosphinic acid chloride (130 mg) and triethylamine (140 ml) were added, and the mixture was stirred at room temperature for 12 hours. To the reaction mixture was added chloroform, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue obtained was distilled off using silica gel column chromatography (eluent: chloroform). : Methanol = 19: 1) to give the title compound (127 mg) mp (soln.): Colorless needles, 183.0-184.7 (isopropyl ether)

IR (KBr): 3440. 1651, 1523 cm- ¹

 NMR (CD C 13) (5 ppm, 300 MHz:

 1.72-1.82 (2H.m). 1.93-2.03 (2H, m). 2.27 (3H.s),

 2.25-2.40 (4H.m). 2.90-2.93 (2H, m), 3.27 (2H.m).

 3.59 (2H.m), 3.75-4.00 (2H, m), 4.31 (2H, s), 6.20 (1H.brs),

6.67 (1H, d, J = 5.1Hz). 6.90 (1H, d. J = 7.7Hz). 7.25-7.55 C8H.m),

7.78 (1H, d, J = 7.7Hz) .8.23 (1H, d, J = 8.4Hz). 8.48 (1H.s) MS (M ⁺ ): 608

Example 8

 N— [2— (5-chloropentoxy) 1-41 [(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepin-4-yl) carbonyl] [Phenyl] one [one 1 'one biphenyl] one two-carboxamide

実施例 2で得られた N— [2—ヒ ド oキシー 4一 [ ( 5, 6, 7, 8—テトラ ヒ ドロー 4 H—チエノ [ 3, 2— b] ァゼビン一 4一ィル） カルボニル] フエ二 ル] 一 [ し 1 ' ービフエニル] 一 2—カルボキサミ ド （1.50 g) 及び 1 一プロ モー 5—クロ口ペンタン （2.37 g) を用いて、 実施例 3と同様にして、 標題化合 物 (1.80 g) を得た。

N— [2-Hydroxy 41-[(5,6,7,8-tetrahydro 4 H-thieno [3,2-b] azebine-1-41) obtained in Example 2 carbonyl The title compound was prepared in the same manner as in Example 3 using phenyl]-[1'-biphenyl] -12-carboxamide (1.50 g) and 11-promo 5-cyclopentene (2.37 g). (1.80 g) was obtained.

m p (soln.): oily thing

IR (N eat): 1639 cm " ¹

NMR (CDC 13) 5 ppm, 300 MHz:

 1.30-1.50 (2H.m) .1.50-1.70 (2H, m), 1.70-1.90 (-1H, π, 1.90-2.10 (2Η, m), 2.80-3.00 (2H, m) .3.51 (2H, t J = 6.5Hz), 3.63 (2H. T. J = 6.4Hz), 3.70-4.10 (2H, m). 6.20 (1H, brs).

 6.67 (1H, d.J = 5.2Hz), 6.76 (1H, s), 6.83 (1H.d.J = 8.4Hz),

7.10-7.60 (8H.m), 7.66 (1H, s). 7.76 (1H.d.J = 8.3Hz). 8.29 (1H.d.J = 8.3Hz)

MS ( ⁺ ): 573

Example 9

 N— [2-[5-(4-Methylbiperazine-1 1-yl) pentoxy] 1-4 1 [(5, 6, 7, 8-tetrahydro-1 4 H-thieno [3, 2-b] azepine 1 4 I-yl) carbonyl] phenyl] I- [bi-phenyl] I-2-carboxami K

实施例 8で得られた N— [2 - ( 5—クロ口ペントキシ） 一 4 一 [ ( 5, 6, 7, 8—テトラヒ ドロー 4 H—チェノ [ 3, 2— b] 了ゼピン一 4一ィル） カル ボニル] フエニル] 一 [ 1 , ービフエニル] 一 2—カルボキサミ ド （300 mg ) 及び 1 ーメチルビペラジン （63 mg)を用いて、 実施例 4 と同様-にして、 標題化 合物 (70 mg)を得た。

N— [2-(5-chloropentyl pentoxy) obtained in Example 8 1 4 1 [(5,6,7,8—tetrahydro 4 H—Ceno [3,2—b] Yl) carbonyl] phenyl]-[1, -biphenyl] -12-carboxamide (300 mg) and 1-methylbiperazine (63 mg) in the same manner as in Example 4 to give the title compound. (70 mg).

m p (soln.): oily thing

IR (Ne at): 1640 ¹

NMR (CDC 13) δ p pm, 300 MHz:

 1.20-1.40 (2H.m), 1.40-1.65 (4H, m) .1.65-1.90 (2H, m), 1.90-2.10 (2H.m), 2.20-2.80 (13H, m), 2.80-3.00 (2H , m).

3.61 (2H.t.J = 6.6Hz). 3.65-4.20 (2H.m) .6.20 ClH.brs), 6.67 (1H.d.J = 5.2Hz), 6.75 (1H, s), 6.81 (1H.d.J = 8.3Hz).

 7.20-7.60 (8H, m), 7.67 (1H, s), 7.76 (1H, d.J = 8.3Hz),

 8.28 (1H.d, J = 8.3Hz)

MS (M +): 636

Example 10

 N— [2— [5— (4-Methylbahydro-1,4-diazepine-11-yl) pentoxy] — 4— [(5,6,7,8-tetrahydro-1H-thieno [3,2 -b] azebin-1-yl) carbonyl] phenyl] — [1,1'-biphenyl] 1-2-carboxamide

実施例 8で得られた N— [2— （5—クロ口ペントキシ） 一 4一 [ (5, 6, 7, '8—テトラヒ ドロ一 4 H—チエノ [3, 2 - b] ァゼピン一 4一ィル） カル ボニル] フエニル] 一 [し ービフエニル] 一 2—カルボキサミ ド （300 mg ) 及び 1一メチルホモピペラ'ジン （72 mg)を用いて、 実施例 4と同様にして、 標 題化合物 (100 mg) を得た。

N— [2 -— (5-chloropentoxy) 1-4 1 [(5, 6, 7, '8-tetrahydro-4 H—thieno [3,2-b] azepine-1 obtained in Example 8 1-yl) Carbonyl] phenyl] -1- [bi-phenyl] -12-carboxamide (300 mg) and 1-methylhomopiperazine '(72 mg) were used in the same manner as in Example 4 to give the title compound (100 mg). mg).

mp (soln.): amorphous solid

 I R (Ne at): 1636 cm "'

NMR (CDC 1 a) <5 ppm, 300 MHz:

1.15-1.35 (2H, m). 1.45-1.65 (4H.m), 1.65-1.85 (2H.m), 1.85-2.05 (2H.m) .2.05-2.20 (2H.m) .2.50-2.70 (5H.m)

 2.75-3.15 (10H.m), 3.64 (2H, t, J = 6.5Hz). 3.70-4.20 (2H.η, 6.20 (1H, brs). 6.69 (1H.d, J = 5.2Hz), 6.70- 6.90 (2H, m),

 7.20-7.60 (8H, m). 7.65 (1H.s), 7.77 (1H, d.J = 8.2Hz),

 8.26 (1H.d, J = 8.2Hz)

MS (M ⁺ ): 650

Example 1 1

 N— [2— [2 -— [4- (4-fluorophenyl) biradizine-11-yl] ethoxy] -4-1 [(5,6,7,8-tetrahydro 4H-thieno [3, 2—b] azepine-41-yl) carbonyl] phenyl] -1- [1, -biphenyl] -12-carboxamide

実施例 3で得られた N— [2— (2—クロ口エトキン） 一 4一 [ (5, 6, 7 , 8—テトラヒ ドロー 4 H—チエノ [ 3, 2— b] ァゼピン一 4—ィル） カルボ ニル] フエニル] 一 [ し 1' —ビフエニル] 一 2—カルボキサミ ド （200 mg) 及び 4一 （4一フルォロ） フヱニルビペラジン （68 mg)を用いて、 実施例 4と同 様にして、 標題化合物 （200 mg) を得た。

N— [2 -— (2-cloth ethokine) 1-4 1 ((5,6,7,8-tetrahydro 4H—thieno [3,2—b] azepine 1-4) obtained in Example 3 L) Carbonyl] phenyl]-[1'-biphenyl] -12-carboxamide (200 mg) and 4- (4-fluoro) phenylbiperazine (68 mg) were used in Example 4 and In the same manner, the title compound (200 mg) was obtained.

mp (soln.): amorphous solid

IR (KBr): 1638 cm " ¹ NMR (CDC 13) δ ρ τη, 300 MHz:

 1.70-1.85 (2H.m), 1.90-2.10 (2H.m), 2.50-2.60 (6H, m.

 2.80-3.00 (6H.m), 3.75-4.00 (4H.m) .6.21 (1H.brs).

 6.67 (1H, brs), 6.75-7.00 (6H.m), 7.27-7.50 C8H.m),

 7.72 (1H.d, J = 7.2Hz), 8.10 (1H, s), 8.26 (1H, d. J = 8.4Hz)

MS (M ⁺ ): 674

Example 1 2

 N— [2— (3-Chlorobroboxy) 1-41 [(5,6,7,8-tetrahydrido-4H-thieno [3,2-b] azepin-1 4-yl) carbonyl] phenyl] one [1,1-biphenyl] ― 2-carboxamide

実施例 2で得られた N— [ 2—ヒ ドロキン— 4 - [ ( 5, 6, 7, 8—テトラ ヒ ドロ一 4 H—チエノ [3, 2— b] ァゼピン一 4一ィル） カルボニル] フエ二 ル] 一 [ 1 , ービフエ二ル] — 2—カルボキサミ ド （600 mg) のアセ トン溶 液に炭酸力リウ厶 （531 mg) 、 ヨウ化カリウム （43 mg)、 1一プロモー 3—ク□ 口プロパン （0.19 ml)を加え、 還流下 1 5時間撹拌した。 放冷後、 反応液を濃^ し、 残渣を酢酸ェチルに溶解し、 水、 飽和食塩水で洗浄後無水硫酸ナトリウムで 乾燥した。 濂過後滤液を濃縮し、 残渣をシリカゲルカラムクロマ トグラフィー （ へキサン ： St酸ェチル = 3 ： 1) により精製し、 標題化合物 （581 mg) を得た。 mp (soln.)：無色結晶， 178.6 - 179.2 'C (Et₂ 0)

N— [2-Hydrokine—4 — [(5,6,7,8—tetrahydro-4H—thieno [3,2—b] azepine-14-yl) carbonyl obtained in Example 2 ] Phenyl] 1 [1, biphenyl] — 2-Carboxamide (600 mg) in acetone solution of lithium carbonate (531 mg), potassium iodide (43 mg), 1-promo Kupan propane (0.19 ml) was added, and the mixture was stirred under reflux for 15 hours. After cooling, the reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (581 mg). mp (soln.): colorless crystal, 178.6-179.2 'C (Et ₂₀ )

IR (KBr): 3403, 1621. 1523 cm " ¹

NMR (C DC 13) δ p pm, 30 O H z:

 1.69-1.81 (2H, m), 1.90-2.02 (4H, m). 2.87-2.91 (2H.m),

3.45 (2H.t, J = 6.8Hz) .3.73-3.77 (2H, m). 3.92 (2H.brs).

 6.18 (1H.brs). 6.65 (1H, d, J = 5.1Hz). 6.75 (1H.s).

 6.83 (1H, d, J = 8.4Hz). 7.27-7.57 (9H, m), 7.75 (1H. D. J = 7.5Hz).

8.30 (1H, d. J = 8.4Hz)

MS (M +): 544

Example 13

 N— [2 -— [3- [Ν'—Methyl-N '— (1-Methylbeveridine-1-yl) amino] Proboxy] 1-4-1 [(5,6,7,8-tetrahydro-1-4-) No [3,2-b] azepine-1 4-yl) carbonyl] phenyl]-[1,1'-biphenyl] -12-carboxamide

実施例 1 2で得られた N— [2— （3—クロロブ□ボキン） 一 4 - [ (5, 6 , 7, 8—テトラヒ ドロー 4H—チエノ [3, 2-b] ァゼビン一 4—ィル） 力 ルボニル] フエニル] 一 [し ービフエニル] 一 2—カルボキサミ ド （300 mg) 及び 1ーメチルー 4ーメチルァミノピペリジン （82 mg)を用いて、 実施例 4 と同様にして、 標題化合物 （80 mg)を得た。

N— [2 -— (3-chlorobuboxin) -14-[(5,6,7,8-tetrahydro 4H—thieno [3,2-b] azebine-1-4 obtained in Example 12 Example 4 Using rubonyl] phenyl]-[bibiphenyl] -12-carboxamide (300 mg) and 1-methyl-4-methylaminopiperidine (82 mg) in Example 4 In the same manner as in the above, the title compound (80 mg) was obtained.

mp (soln.): amorphous solid

 I R (Ne at t): 1639 cm "

NMR (CDC 1 a) 5 ppm, 300 MHz:

 1.45-1.85 (8H, m), 1.85-2.10 (4H, m), 2.15-2.35 C6H, m).

 2.35-2.50 (2H.m), 2.80-3.10 (5H, m) .3.55-4.05 (4H, m),

6.20 (1H, brs). 6.66 (1H.d, J = 5.1Hz). 6.75-6.85 (2H, m).

 7.20-7.35 (3H.m). 7.35-7.60 (5H, m), 7.68 (1H, s).

 7.75 (1H, d, J = 7.7Hz). 8.26 (1H.d, J = 8.2Hz)

MS (M ⁺ ): 636

Example 14

 N— [2 -— (4-Chlorobutoxy) 1-41-[(5,6,7,8-tetrahydro-1-4H-thieno [3,2-b] azepin-14-yl) carbonyl] phenyl] ―

 [1,1'-biphenyl] 1-2-carboxamide

実施例 2で得られた N— [2—ヒドロキシ— 4一 [ (5， 6, 7, 8—テトラ ヒ ドロー 4H—チエノ [3， 2— b] ァゼピン一 4一ィル） カルボニル] フエ二 ル] — [し 一ビフエニル] ― 2—カルボキサミ ド （300 mg) 及び 1一プロ モー ₄一クロロブタン （₀ u ml)を用いて、 実施例 1 2と同樣にして、 標題化合 97/17349

N- [2-Hydroxy-41-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-14-yl) carbonyl) carbonyl obtained in Example 2 L]-[S-biphenyl]-2-carboxamide (300 mg) and 1-promo- _4- chlorobutane ( ₀ uml) in the same manner as in Example 12 to give the title compound. 97/17349

(320 mg).

mp (soln.): non-crystalline solid

IR (CHC 13): 1671, 1637 cnT ¹

 NMR (CDC 13) <5 ppm, 30 OMHz:

 1.65-1.85 (6H, m). 1.90-2.10 (2H, m). 2.85-2.95 (2H, m),

 3.45-4.15 (6H.m), 6.10-6.25 (1H.m). 6.60-6.85 (3H, m),

 7.25-7.80 (10H.m) .8.25-8.40 (1H, m)

MS (M ⁺ ): 558

Example 15

 N— [2— [4-(4-Methyl-hydroxy-1, 4-—dazebine-1 1-yl) butoxy] 1-41 [(5, 6, 7, 8-tetrahydro-1 4 一 —thieno [3 . 2-b] azepine-1 4-yl) carbonyl] phenyl] — [1,1'-biphenyl] -12-carboxamide

実施例 1 4で得られた N— [2— （ 4—クロロブトキシ） — 4一 [ (5, 6, 7. 8—テトラヒ ドロー 4 H—チエノ [ 3, 2— b] ァゼピン一 4—ィル） カル ボニル] フエニル] 一 [し ービフエ二ル] — 2—カルボキサミ ド （300 mg ) のァセトニトリル （3.0 ml) 、 ジメチルホル厶ァミ ド （1.5 ml) 混合溶液にョ ゥ化カリウ厶 （9 mg) 、 1一メチルホモビぺラジン （0.09 ml)を加え、 還流下 2 4時間撹拌する。 放冷後、 反応液を濃縮し、 残渣を酢酸ェチ几に溶解し、 m 酸水素ナ ト リゥム水溶液、 水、 飽和食塩水で洗浄後無水硫酸ナト リウムで乾燥す る。 濾過後滤液を濃縮し、 残渣をシリカゲルカラムクロマトグラフィー （ク Π Π ホルム ： メタノール = 10 ： 1 ) で精製し、 標題化合物 （270 mg) を得た。 mp (soln.) ：非結晶性固体

N— [2 -— (4-chlorobutoxy) —4-[[5,6,7.8-tetrahydro 4H—thieno [3,2-b] azepine-1-4 obtained in Example 14 L) Carbonyl] phenyl]-[bi-biphenyl] -2-carboxamide (300 mg) in acetonitrile (3.0 ml) / dimethylformamide (1.5 ml) mixed solution of potassium iodide (9 mg) ), 1-Methyl homobiperazine (0.09 ml) was added and the mixture was refluxed. Stir for 4 hours. After allowing to cool, the reaction solution is concentrated, the residue is dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate, water, and saturated saline, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (270 mg). mp (soln.): non-crystalline solid

1 R (CHC 13): 1672. 1639 cm " ¹

NMR (CDC 13) δ p pm, 300 MHz:

 1.35-2.30 (12H, m), 2.35-2.55 (5H.m). 2.60-2.80 (6H, m),

2.85-3.00 (2H, m) .3.50-4.10 (4H.m). 6.10-6.30 (1H.m).

 6.60-6.90 (3H.m). 7.20-7.60 (8H.m), 7.66 (1H, brs).

 7.70-7.80 (1H, m). 8.20-8.35 (1H, m)

MS (M ⁺ ): 636

Example 16

 N— [2— [4-[Ν '-(2-dimethylaminoethyl) -1-N'-methylamino] butkin] -1-4- [(5,6,7,8-tetrahydro-1-4Η-thieno [3,

2-b] azepine-4-yl) carbonyl] phenyl] — [ani — biphenyl] 12-carboxamide

実施例 1 4で得られた N— [2— （ 4一クロロブトキシ） 一 4— 「 （ 5, 6 97/17349

N— [2 -— (4-chlorobutoxy) 1-4 — “(5,6) obtained in Example 14 97/17349

7,8-tetrahydro-4H-thieno [3,2-b] azevin-14-yl) carbonyl] phenyl]-[1,1,1'-biphenyl] -12-carboxamide (300 mg :) and N, N The title compound (103 mg) was obtained in the same manner as in Example 15 using, N'-trimethylethylenediamine (0.11 ml).

mp (soln.): non-crystalline solid

IR (CHC 13): 1672. 1640 cm " ¹

_{NMR (CDC 1 3) 5p pm} , 3 0 0 MHz:

 1.35-1.65 (4H, m). 1.80-2.10 (4H.m). 2.15-2.55 (15H, m).

 2.80-2.95 (2H, m) .3.50-4.10 (4H.m). 6.10-6.30 (1H, m).

 6.60-6.90 (3H, m). 7.20-7.60 (8H, m), 7.67 (1H.brs),

 7.70-7.80 (1H, m). 8.20-8.35 (1H.m)

MS (M ⁺ ): 624

Example 17

 N- [2- [4- [4- (4-methylbiperazine-11-yl) butoxy] 1-41-[(5,6,7.8-tetrahydro 4H-thieno [3,2-b] azebin 1-4-yl) carbonyl] phenyl] 1- [1'-biphenyl] 1-2-carboxamide

実施例 1 4で得られた N— [2— （4一クロロブトキシ） — 4— [ (5， 6, 7, 8—テ トラヒ ドロー 4 H—チエノ [ 3, 2— b] ァゼビン一 4一ィル） カル ボニル] フエニル] 一 [ 1 , —ビフエニル] — 2—カルボキサミ ド （300 mg ) 及び 1 ーメチルビペラジン （0.03 ml)を用いて、 実施例 1 5と同様にして、 β 题化合物 （150 mg) を得た。

N— [2 -— (4-Chlorobutoxy) —4 -— ((5,6,7,8—TetrahiDraw) 4H—Thieno [3,2—b] azebine obtained in Example 14 Yl) carbonyl] phenyl]-[1,2-biphenyl] -2-carboxamide (300 mg) and 1-methylbiperazine (0.03 ml) in the same manner as in Example 15 The compound (150 mg) was obtained.

m p (soln.): colorless crystal, 134.7-135.4 'C (AcOEt)

IR (CHC 13): 1672, 1639 cm " ¹

_{NMR (CDC 1 3) δ ρ} ρτη, 3 0 0 MH z:

 1.40-2.05 (10H.m), 2.20-2.65 (11H.m). 2.85-3.00 (2H.m) .3.50-4.10 (4H, m), 6.10-6.30 (1H.m). 6.60-6.90 (3H m), 7.20-7.60 C8H.m), 7.65 (1H, brs). 7.70-7.80 (1H, m).

 8.20-8.35 (1H.m)

MS (M ⁺ ): 622

Example 18

 N— [2— (pyridin-1-yl) methoxy-41-((5,6,7,8-tetrahydro 4 H-thieno [3,2-b] azepin-14-yl) Carbonyl] phenyl] 1 U, 1 biphenyl] 12-carboxamide

実施例 2で得られた N— [2—ヒドロキン一 4一 [ ( 5, 6, 7, 8—テトラ 7/17349

N— [2-Hydroquinone 4-[[5, 6, 7, 8-tetra 7/17349

Hydro-4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl]-[shi 1'-biphenyl] -12-carboxamide (140 mg) and 3-chloromethylpyridine (70 mg), and the title compound (40 mg) was obtained in the same manner as in Example 3.

mp (soin.): non-crystalline solid

IR (KBr): 3405, 1638, 1521 cnr ¹

 NMR (CDC 13) ά p pm, 30 OMH z:

 1.68-1.78 (2H, π, 1.90-2.00 (2Η, m), 2.81-2.95 (2H, m), 3.70-3.91 (2H, brs), 4.68 (2H.s). 6.15 (1H, brs),

 6.68 (1H.d, J = 5.lHz). 6.73 (1H, brs) .6.91 (1H.d.J = 8.4Hz),

 7.20-7.55 (10H.m), 7.60 (1H.brs), 7.79 (1H, d.7Hz),

 8.36 (1H.d, J = 8.4Hz), 8.44 (1H.brs). 8.61 (1H.d.J = 3.3Hz)

 MS (M +): 559

Example 19

 N— [2 -— (2-Dimethylaminoethoxy) 1-41-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl ] One [one biphenyl] ― 2-carboxamide

実施例 2で得られた N— [2 ドロキシー 4— [ (5, 6, 7, 8—テトフ ヒ ドロ一 4 H—チエノ [3, 2— b] ァゼピン一 4一ィル） カルボニル] フエ二 ル] — [ 1 , 1 ' ービフエニル] 一 2—カルボキサミ ド （140 mg) 及び 2—クロ ロェチルジメチルァミ ン （50 mg)を用いて、 実施例 3と同様にして、 標題化合物 (110 mg) を得た。

N— [2 droxy 4 — [(5,6,7,8—tetofu obtained in Example 2 Hydroxy-4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] — [1,1'-biphenyl] -12-carboxamide (140 mg) and 2-chloroethyl The title compound (110 mg) was obtained in the same manner as in Example 3 using dimethylamine (50 mg).

mp (soln.): amorphous solid

IR (KBr): 2931, 1640, 1524 cm " ¹

 N R (CD C 13) 5 p pm, 300 MHz:

 1.70-1.80 (2H, m), 1.90-2.00 (2H, m), 2.08 (6H, s),

 2.37-2.47 (2H.m). 2.85-2.95 (2H, m) .3.72-3.82 (2H.m).

 3.73-3.93 (2H, s), 6.21 (1H.brs), 6.66 (1H.brs),

 6.82 (1H, brs), 6.92 (1H, d.J = 8.4Hz) .7.30-7.55 (8H, m),

 7.70 (1H.d, J = 7.0Hz), 8.26 (1H.d, J = 8.1Hz). 8.85 (1H.brs)

 MS (M +): 539

Example 20

 N- [2- (2-Morpholinoetkin) 1-41 [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-1 4-yl) carbonyl] phenyl] one [1,1'-biphenyl] 1-2-carboxamide

実施例 3で得られた N— [2— （2—クロ口エトキン） ー 4一 [ (5, 6, 7 , 8—テトラヒ ドロー 4 H—チエノ [3, 2— b] ァゼビン一 4一ィル） カルボ ニル] フエニル] 一 [ 1 , 一ビフヱニル] 一 2—カルボキサミ ド （400 mg 及びモルホリ ン （160 mg) を用いて、 実施例 4 と同様にして、 標題化合物 （230 mg) を得た。

N— [2 -— (2-cloth ethokine) obtained in Example 3—4-1 ((5, 6, 7 , 8-Tetrahydro 4H-thieno [3,2-b] azevin-14-yl) carbonyl] phenyl]-[1,1-biphenyl] -12-carboxamide (400 mg and morpholine (160 mg) And the title compound (230 mg) was obtained in the same manner as in Example 4.

mp (soln.): non-crystalline solid

IR (KB r): 2931, 2852, 1638, 1522 cm— ¹

NMR (CD C 13) ά p pm, 30 OMH z:

 1.72-1.82 (2H.m), 1.94-2.01 (2H.m). 2.35-2.39 (4H.m).

 2.45-2.49 (2H.m). 2.88-2.95 (2H.m). 3.48-3.51 (4H.m).

 3.48-3.51 (2H, m), 3.61 one 3.91 (2H, s), 6.20 (1H, brs),

 6.66 (1H, d, J = 5.2Hz). 6.80 (1H, brs). 6.87 (1H. D. J = 8.0Hz).

 7.25-7.55 (7H.m), 7.74 (1H.d.J = 7.3Hz) .8.02 (1H.brs).

 8.26 (1H.d.J = 8.5Hz)

MS (M +): 581

Example 2 1

N- [2— [2-(4-Methyl perhydro draw 1, 4-diazepine 11-yl) ethoxy] 1-4 1 [(5,6,7,8-tetrahydro 4 4-thieno [3,2- b] azepine-1-yl) carbonyl] phenyl] -1- [1,1'-biphenyl] -1-2-carboxamide

実施例 3で得られた N— [2— （2—クロ口エトキシ） 一 4一 [ (5, 6, 7 , 8—テトラヒ ドロー 4 H—チエノ [3， 2— b] ァゼビン一 4一ィル） カルボ ニル] フエニル] 一 [1, Γ ービフエニル] —2—カルボキサミ ド （200 mg) 及び N—ホモピぺラジン （51 mg)を用いて、 実施例 4と同様にして、 標題化合物 (150 mg) を得た。

N— [2— (2-chloromouth ethoxy) 1-4 1 ((5,6,7,8-tetrahydro) 4 H—thieno [3,2-b] azebin 1-41 obtained in Example 3 L) Carbonyl] phenyl]-[1, di-biphenyl] -2-carboxamide (200 mg) and N-homopyrazine (51 mg) in the same manner as in Example 4 to give the title compound (150 mg). ).

mp (soln.): amorphous solid

IR (KBr): 3405. 2930. 1641, 1522 cm " ¹

NMR (CDC 1 a) ά p pm, 300 MHz:

 1.60-1.80 (4H, m). 1.93-2,03 (2H.m) .2.33 (3H.s),

 2.50-2.70 (10H.m). 2.87-2,93 (2H, m) .3.72 (2H.m),

 3.70-3.90 (2H, tn). 6.19 (1H, brs). 6.66 (1H, d. J = 5.3Hz),

 6.80 (1H.s), 6.86 ClH, d, J = 8.1Hz), 7.25-7.55 (8H.m),

 7.77 (1H, d. J = 7.0Hz), 8.02 (1H.s). 8.26 (1H, d. J = 8.4Hz)

MS (M ⁺ ): 608

Example 22

N- [2 -— [2-[2 -— (cyclohexylamino) ethokine] -1-[(5,6,7,8-tetrahydro 4 H-thieno [3,2-b] azebin-1-yl ) Carbonyl] phenyl]-[biphenyl] -12-carboxamide

実施例 3で得られた N— [2— （2—クロ口エトキシ） —4一 [ (5, 6, 7 , 8—テトラヒ ドロー 4 H—チエノ [3, 2— b] ァゼビン一 4一ィル） カルボ ニル] フエニル] 一 [1, 1' ービフエニル] 一 2—カルボキサミ ド （400 mg) 及びシクロへキシルァミ ン （100 mg) を用いて、 実施例 4と同様にして、 標？ S化 合物 （95 mg)を得た。

N— [2 -— (2-chloromouth ethoxy) —4—1 ((5,6,7,8—tetrahydro 4H—thieno [3,2—b] azebine—14-1) obtained in Example 3 L) [Carbonyl] phenyl]-[1,1'-biphenyl] -12-carboxamide (400 mg) and cyclohexylamine (100 mg) in the same manner as in Example 4 to obtain the target compound. An S compound (95 mg) was obtained.

mp (soln.): amorphous solid

IR (KB r): 3287, 1670. 1524 cm " ¹

NMR (CDC 1 a) δ p pm, 300 MHz:

 0.90-1.40 (1H.m), 1.50-2.00 (8H.m), 2.32 (1H.m),

 2.75 (2H.m), 2.90 (2H, m). 3.70 (2H.m), 3.80-3.90 (2H.m).

 5.79-6.00 (2H.brs), 6.19 (1H, brs), 6.66 (1H.d.J = 5.18Hz).

 6.78 (1H, s). 6.87 (1H.d.J = 8.1Hz), 7.25― 7.55 (5H, m),

7.72 (1H.d, J = 6.6Hz), 8.00-8.15 (2H, m), 8.25 (1H.d, J = 8.4Hz) MS (M ⁺ ): 593

Example 23

N— [2— [2-[4-1- (pyrrolidine-1 1-yl) piperidino] ethoxy] 1-4— [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine — 4-yl) carbonyl] phenyl] 1- [1'-biphenyl] —2-carbo Kisamide

実施例 3で得られた N— [2— （2-ク noエトキシ） 一 4— [ (5, 6, 7 , 8—テトラヒ ドロ一 4 H—チエノ [3, 2— b] ァゼピン一 4一ィル） カルボ ニル] フエニル] 一 [1, 一ビフヱニル] 一 2—カルボキサミ ド （400 mg) 及び 4 -ピロリジノピペリジン （225 mg) を用いて、 実施例 4と同様にして、 搮 题化合物 （225 mg) を得た。

N— [2 -— (2-ethoxy ethoxy) -14 — [(5,6,7,8—tetrahydro-4H—thieno [3,2-b] azepine obtained in Example 3 Yl) carbonyl] phenyl]-[1,1-biphenyl] -12-carboxamide (400 mg) and 4-pyrrolidinopiperidine (225 mg) in the same manner as in Example 4 225 mg).

mp (soln.): amorphous solid

IR (KB r): 3406. 1643, 1522 cm ' ¹

NMR (CDC 13) (5 ppm, 300 MHz:

 1.30-1.50 (4H, m), 1.50-1.82 (8H.m) .1.90-2.05 (4H.m), 2.22 (1H, m) .2.43-2.47 (4H, m). 2.82-2.92 (4H, m ).

 3.73 (2H.m). 3.80-3.95 (2H, m), 6.20 (1H.brs).

 6.55 (1H.d.J = 5.2Hz), 6.78 (1H, s). 6.85 (1H, d, J = 8.lHz),

 7.25-7.55 (8H, m), 7.74 (1H.d, J = 7.3Hz) .8.03 (1H, s).

 8.25 (1H.d, J = 8.Hz)

MS (M ⁺ ): 648

Example 24

N— [2— [2— (4-Biperidinopiperidino) Etkin] 1-41 [(5, 6 , 7,8-Tetrahydro-1H-thieno [3,2-b] azebin-1-4-yl) Power Luponyl] phenyl]-[1'-biphenyl] -12-carboxamide

実施例 3で得られた N— [2— （2—クロ口エトキン） — 4一 [ (5, 6, 7 , 8—テトラヒドロー 4 H—チエノ [ 3， 2— b] ァゼピン一 4一ィル） カルボ ニル] フエニル] 一 [ 1, 1' —ビフエニル] — 2—カルボキサミ ド （400 mg) 及び 4一ピペリジノ ピペリジン （240 mg) を用いて、 実施例 4と同様にして、 楞 题化合物 (350 mg) を得た。

N— [2 -— (2-ethylentoquin) obtained in Example 3—4- (5,6,7,8-tetrahydro-4H—thieno [3,2-b] azepine-14-yl ) Carbonyl] phenyl]-[1,1'-biphenyl]-2-carboxamide (400 mg) and 4-piperidino piperidine (240 mg) were used in the same manner as in Example 4 to obtain the compound of the compound (350). mg).

mp (soln.): amorphous solid

IR (KB r): 3405, 1633, 1523 cm— ¹

NMR (CD C 13) δ p pm, 300 MHz:

 1.30-2.10 (15H.m). 2.48-2.52 (4H.m). 2.85-2.95 (8H.m) .3.73 (2H.m. 3.70-4.00 (2H.brs). 6.20 (1H.brs),

 6.67 (1H.d, J = 4.8Hz), 6.79 (1H, s). 6.85 (1H, d, J = 8.1Hz),

 7.25-7.55 (8H.m). 7.74 (1H, d, J = 7.3Hz), 7.99 (1H, s),

 8.25 (1H, d, J = 8.1Hz)

MS (M ⁺ ): 662

Example 25

N- [2— [2— [4— (4-hydroxydiphenyl) piperazine-1 1-yl] Etkin] 1-41-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-14-yl) carbonyl] phenyl] -1 [1,1'-biphenyl] 1 2 One carboxamide

実施例 3で得られた N— [2— （2—クロ口エトキン） 一 4一 [ (5, 6, 7 ' 8—テトラヒ ドロー 4 H—チエノ [ 3, 2— b] ァゼピン一 4一ィル） カルボ ニル] フヱニル] — [1, ービフエニル] 一 2—カルボキサミ ド （500 mg) 及び 1一 （ 4ーヒ ドロキシフヱニル） ピペラジン （200 mg) を用いて、 実施例 4 と同樣にして、 標題化合物 （390 mg) を得た。

N— [2 -— (2-cloth ethokine) 1-4 [(5,6,7'8-tetrahydro 4H-thieno [3,2-b] azepine 1-41 obtained in Example 3 L) Carbonyl] phenyl] — [1, -Biphenyl] 12-carboxamide (500 mg) and 11- (4-hydroxyphenyl) piperazine (200 mg) in the same manner as in Example 4 to give the title compound (390 mg).

mp (soln.): amorphous solid

IR (KB r): 2929. 1697. 1676 cm " ¹

_{NMR (CDC 1 3) <5} p pm, 30 OMH z:

 1.72-1.82 (2H.m). 1.93-2.03 (2H, m), 2.52 (4H.m).

 2.80― 2.85 (2H, m), 2.88 (4H, s), 2.95 (4H, s), 3.79 (2H.m),

6.20 (1H.brs), 6.65-6.90 (3H, m), 7.25-7.50 (9H, m),

 7.71 (1H, d. J = 7.7Hz). 8.01 (4H, s). 8.11 (1H.s).

 8.26 (1H.d, J = 8.4Hz)

MS (M +): 672

Example 26 7/17349

N— [2-[2— [(4-ethoxycarbonyl) pidazine-1 11-yl] ethoxy] 1-4 1 [(5, 6, 7, 8-tetrahydro 4 H-thieno [3, 2 -b] R-zepin-41-yl) carbonyl] phenyl]-[di-biphenyl] 1-21-carboxamide

COOEt

実施例 3で得られた N— [2— （2—クロ口エトキン） 一 4一 [ (5, 6, 7 . 8—テトラヒ ドロー 4 H—チエノ [ 3, 2— b] ァゼピン一 4一ィル） カルボ ニル] フエニル】 一 [し 1 ' —ビフヱニル] 一 2—カルボキサミ ド （500 mg) 及び 1 一エトキンカルボ二ルビペラジン （200 mg) を用いて、 実施例 4と同 に して、 標題化合物 （400 mg) を得た。

N— [2 -— (2-cloth ethokine) 1-4 [(5,6,7.8-tetrahydro 4H-thieno [3,2-b] azepine 1-41 obtained in Example 3 L) Carbonyl] phenyl] 1- [1'-biphenyl] 12-carboxamide (500 mg) and 1-ethoxyquincarbylbiperazine (200 mg) were prepared in the same manner as in Example 4 to give the title compound ( 400 mg).

 p (soln.): Oil

1 R (Ne a): 3270. 2933, 1666, 1514 cm " ¹

_{NMR (CDC 1 3) 5 p} pm, 30 0 MHz:

 1.26 (3H, t, J = 7.1Hz), 1.72-1.82 (2H, m), 1.93-2.03 (2H, m),

2.33 (2H, m). 2.49 (2H, m). 2.87 ― 3.25 (2H.m), 3.28 (2H.brs),

3.35 (2H.m) .3.5-3.53 (4H, m) .3.75-3.85 (2H.m).

 4.16 (2H, q.J = 7.lHz) .6.20 (1H, brs) .6.62 (1H.d, J = 6.9Hz),

6.80 (1H, brs), 6.88 (1H.brs), 7.20-7.60 (7H.m),

7.70-7.80 (1H.m), 7.95 (1H.brs), 8.08 (1H.brs). 8.24 (1H.d.J = 8.4Hz)

MS (M ⁺ ): 653

Example 2 7

 N- [2 -— [2 -— (4-Methylbahydro-1,4-diazebine-11-yl) -1-2-oxoetokine] 1-41 [(5,6,7,8-tetrahydro-4H—Ceno [3 , 2-b] azepine-1 4-yl) carbonyl] phenyl] 1-[1 '1 biphenyl] 1-2-carboxamide

実施例 6で得られた 2— [ [ [ 1 , 1 ' ービフヱニル] 一 2—カルボニル] 了 ミノ] 一 5— [ (5, 6, 7, 8—テトラヒ ドロ一 4 H—チエノ [3, 2— b] ァゼビン— 4—ィル） カルボニル] フエノキシ齚酸 （200 mg) 及び N—メチルホ 乇ピペラジン （51 mg)を用いて、 実施例 7と同様にして、 標題化合物 （ 0 mg) を得た。

2-[[[1,1'-biphenyl] -12-carbonyl] dimino] -1 5-[(5,6,7,8-tetrahydro-1H-thieno [3,2] obtained in Example 6 —B] azevin-4-yl) carbonyl] phenoxydinoic acid (200 mg) and N-methyldopiperazine (51 mg) were obtained in the same manner as in Example 7 to give the title compound (0 mg). .

mp (soln.): amorphous solid

IR (KBr): 3420. 1644, 1520 cm " ¹

 NMR (CDC 13) δ p pm, 300 MHz:

1.50-1.90 (2H.brs) .1.72-1.82 (2H, m). 1.90-2.00 (2H.m), 2.36 (3H.d, J = 7.3Hz), 2.50-1.65 (4H.m). 2.89- 2.93 (2H, m), 97/17349

3.32-3.38 (2H.m) .3.57-3.61 (2H, m). 3.66 (1H.brs),

 3.70-4.00 (1H, brs), 4.32 (2H, d, J = 9.1Hz) .6.20 (1H.brs), 6.66 (2H.brs), 6.80-6.90 (2H, m), 7.25-7.50 (7H. m),

 7.78 (1H, d. J = 7.3Hz). 8.23 (1H.m). 8.56 (1H.s)

 MS (M +): 622

Example 2 8

 N— [2-[[[1,1, biphenyl] 1-2-carbonyl] amino] — 5— [(5,6,7,8-tetrahydro-4H-thieno [3,2—b] azebin-14 Le) carbonyl] phenoxy] acetyl] l-brolinamide

実施例 6で得られた 2— [ [ [ 1 , ービフエニル] 一 2—カルボニル] ァ ミノ] 一 5— [ ( 5, 6, 7, 8—テトラヒ ドロー 4 H—チエノ [ 3, 2 -b] ァゼピン— 4一ィル） カルボニル] フエノキシ酢酸 （520 mg) 及び L—プロリン アミ ド （150 mg) を用いて、 実施例 7と同様にして、 標題化合物 （380 mg) を た。

2-[[[[1, biphenyl] -12-carbonyl] amino] -15-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] obtained in Example 6 The title compound (380 mg) was obtained in the same manner as in Example 7 using [azepine-41-yl) carbonyl] phenoxyacetic acid (520 mg) and L-proline amide (150 mg).

mp (soln.): non-crystalline solid

IR (KBr): 3400. 1658. 1524 cm " ¹

NMR (CDC 13) ά p pm, 300 MHz:

1.72-1.82 (2H.m) .1.85-2.04 (4H, m), 1.95-2.05 (2H.m), 2.85-2.91 (2H, m), 3.26 (1H, m), 3.44 (1H.m),

 3.75-4.00 (2H, m). 4.30 (2H, s). 4.45 (1H, d. J = 5.5Hz).

 5.58 (1H.brs). 6.18 (1H.brs). 6.67 (1H.d, J = 4.8Hz).

 6.79 (2H, brs), 6.87 (1H.d.J = 8.4Hz), 7.25-7.55 (8H, m).

 7.76 (1H, d, J = 8.4Hz) .8.22 (1H, d, J = 8.4Hz), 8.54 (1H.s)

MS (M +): 622

Example 29

 N- [2— [2-oxo-1 2 -— (4-biperidinopiperidino) ethkin] 1-4 1 [(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-1 4-yl) carbonyl] phenyl] — [1,1-biphenyl] 1-2-carboxamide

突施例 6で得られた 2— [ [ [ 1, 1 ' 一ビフヱニル] 一 2—カルボニル] ァ ミノ] 一 5— [ (5, 6, 7, 8—テトラヒ ドロー 4H-チエノ [3, 2-b] ァゼピン— 4—ィル） カルボニル] フエノキシ酢酸 （300 mg) 及び 4一ピペリジ ノビペリジン （140 mg) を用いて、 実施例 7と同様にして、 標題化合物 （270 mg ) を得た。

2 -— [[[1,1'-biphenyl] -12-carbonyl] amino] -1-5 — [(5,6,7,8-tetrahydro 4H-thieno [3,2] -b] azepine-4-yl) carbonyl] phenoxyacetic acid (300 mg) and 4-piperidinobiperidine (140 mg) were obtained in the same manner as in Example 7 to obtain the title compound (270 mg).

mp (soln.): amorphous solid

IR (KBr): 3399, 1651, 1522 cm " ¹ 97/17349

NMR (CDC 13) 5 p pm, 300 MHz:

 1.35-1.50 (6H, m), 1.50-1.65 (4H, m). 1.75-1.90 (4H.m).

 1.95-2.00 (2H, m). 2.40-2.50 (4H.brs), 2.60 (1H, m).

 2.85-3.00 (2H, m) .3.56 (1H, d, J = 12.8Hz). 3.70-4.00 (2H.brs,

4.31 (2H, s). 4.52 (1H.d.J = 12.8Hz). 6.19 (1H, brs).

 6.67 (1H.d, J = 4.8Hz), 6.80 (1H, s). 6.91 (1H.d, J = 8.4Hz).

 7.25-7.50 (8H.m), 7.78 (1H.d, J = 7.7Hz), 8.23 (1H.d.J = 8.4Hz),

8.56 (1H, s)

MS (M +): 676

Example 30

 N— [2— [2-oxo-1—2— [4 -— (pyrrolidine—11-yl) biperidino] ethoxy] —4 — [(5,6,7,8—tetrahydro 4 H—thieno [3,2 — B] azepine— 4-yl) carbonyl] phenyl] 1- [1,1-biphenyl] 1-21-carboxamide

実施例 6で得られた 2— [ [ [1, 1 ' ービフエニル] 一 2—カルボニル] ァ ミノ] — 5— [ (5, 6, 7, 8—テトラヒ ドロー 4H—チエノ [3， 2— b] ァゼピン— 4一ィル） カルボニル] フエノキシ齚酸 （300 mg) 及び 4一ピロリジ ノ ビペリジン （150 mg) を用いて、 実施例 7と同様にして、 標題化合物 （250 mg ) を得た。

2 — [[[1,1′-biphenyl] -12-carbonyl] amino] —5 — [(5,6,7,8—tetrahydro 4H—thieno [3,2-b) obtained in Example 6 ] Azepine- (41-yl) carbonyl] phenoxydiacid (300 mg) and 4-pyrrolidino-biperidine (150 mg) in the same manner as in Example 7 to give the title compound (250 mg). ).

mp (soln.): amorphous solid

IR (KBr): 3429. 1652, 841 cm " ¹

 NMR (CDC 13) (5 ppm, 30 OMH z:

 1.55-1.65 (2H, m), 1.70-1.80 (2H, m), 1.82-2.20 (9H.m), 2.55-2.65 (2H, m), 2.85-2.95 (2H, m) .3.00-3.20 (4H , m), 3.60-3.90 (3H, m), 4.32-4.40 (2H.m) .4.45-4.50 (1H.m),

6.19 (1H.brs). 6.67 (1H.brs). 6.77 (1H, brs). 6.81-6.90 (1H, m.

7.20-7.55 (7H.m). 7.70-7.80 (2H.m), 8.15 (IH, m).

 8.48 (1H, brs)

MS (M ⁺ ): 662

Example 3 1

 N— [2— [2— (4-Dimethylamino biperidino) -1-2-oxoethoxy]--[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-41yl) Carbonyl] phenyl] — [1'-biphenyl] -1-2-carboxamide

実施例 6で得られた 2— [ [ [ 1 , 1' —ビフヱニル] 一 2—カルボニル] ァ ノ ] 一 5— [ (5, 6, 7, 8—テトラヒ ドロー 4H—チエノ [3, 2 - b] 97/17349

2-[[[1,1'-biphenyl] -12-carbonyl] ano] -1-5-((5,6,7,8-tetrahydro 4H-thieno [3,2-] obtained in Example 6 b] 97/17349

Azepine-41-yl) carbonyl] phenoxyacetic acid (300 mg) and 4-dimethylaminobiperidine (150 mg) in the same manner as in Example 7 to give the title compound (28

0 mg).

mp (soln.): amorphous solid

1 R (KB r): 3434. 1654 cm " ¹

 NMR (CDC 13) δ p pm, 30 ：:

 1.40-1.50 (4Η.m), 1.72-1.82 (2H, m). 1.90-2.00 (2H.m).

 2.49 (6H.s). 2.50-2.60 (2H, m), 2.90-3.00 (4H.m).

 3.70-3.90 (2H.m). 4.20-4.30 (2H.m). 4.54 (1H, m),

 6.19 (1H.brs). 6.66 (1H, brs). 6.80 (1H, brs). 6.90 (1H.m),

 7.25-7.60 (7H, m), 7.76-7,90 (2H, m). 8.20 (1H.m), 8.41 (1H.m)

MS (M +): 636

Example 3 2

 N— [2— [2 — [(1-Methyl-1H—1,2,3,4-tetrazole-5-yl) thio] etkin] —4-[[5,6,7,8-tetrahydro 4 H —Thieno [3,2—b] azepine-4-yl) carbonyl] phenyl] -1- [1,1'-biphenyl] -1-2-carboxamide

実施伊 13で得られた N— [2— (2—クロ口エトキン） 一 4一 [ ( 5, 6, 7 , 8—テトラヒ ドロー 4 H—チエノ [3, 2— b] ァゼビン— 4一ィル） カルボ ニル] フエニル] 一 [ 1 , 1 ' 一ビフヱニル〗 一 2—カルボキサミ ド （200 m をジメチルホル厶ァミ ド （5 ml) に溶解し、 5—メルカプト— 1 ーメチルテトラ ゾ一ル ナトリウム塩 2水和物 （78 ntg)を加え 1 0 0° (：、 4時間加熱した後、 5—メルカブト— 1 ーメチルテトラブール ナトリウム塩 2水和物 （78 mg)を 追加し 1 2 0'C、 5時間加熱した。 ジメチルホルムアミ ドを留去した後、 残?まを ク D口ホルムに溶かし水洗し、 有機層を無水硫酸マグネシウムで乾燥した。 溶媒 留去後、 シリカゲルカラムクロマトグラフィー （溶出溶媒； ^酸ェチル：へキサ ン= 2 ： 1) により精製し、 標題化合物 （130 mg) を得た。

N— [2 -— (2-cloth ethokine) obtained in Experiment 13 , 8-tetrahydro 4H-thieno [3,2-b] azevin-4'yl) carbonyl] phenyl [1- [1,1'-biphenyl] -1-2-carboxamide (200 m to dimethylformamide) (5 ml), add 5-mercapto-1-methyltetrazole sodium salt dihydrate (78 ntg), add 100 ° (:, heat for 4 hours, then add 5-mercapto-1-methyl Tetrabule sodium salt dihydrate (78 mg) was added, and the mixture was heated at 120 ° C for 5 hours. The solvent was distilled off and the residue was purified by silica gel column chromatography (elution solvent: ^ ethyl: hexane = 2: 1) to obtain the title compound (130 mg).

m p oln.): Oily substance

IR (Ne at): 1672. 1638. 1522 cm- ¹

N R (CDC 1 a) δ p pm, 30 ΟΜΗ ζ:

 1.70-1.80 (2Η.m). 1.90― 2.10 (2H.m). 2.80-3.00 (2H.m),

3.40 (2H.t, J = 6Hz). 3.60 ― 4.10 (4H, m) .3.82 (3H.s).

 6.18 (1H.brs). 6.68 (1H.d, J = 5Hz), 6.73 (1H, s).

 6.90 (1H, d.J = 8Hz), 7.30-7.60 (8H, m), 7.69 (1H, s),

 7.75-7.85 (1H.m), 8.33 (1H.d, J = 8Hz)

MS (M ⁺ ): 610

Example 3 3

N— [2— (3-phthalimidoproxy) 1-41 [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-1 4-yl) carbonyl] phenyl ] — [1, 1 '—biphenyl] — 2-carboxamide

実施例 2で得られた N— [ 2—ヒ ドロキシ— 4— [ ( 5, 6, 7, 8—テトラ ヒ ドロー 4 H—チエノ [3, 2 - b] ァゼピン一 4一ィル） カルボニル] フエ二 ル] 一 . 一ビフエニル] 一 2—カルボキサミ ド （530 mg) 及び N— ( 3 —プロモプロピル） フ夕ルイミ ド （607 mg) を用いて、 実施例 3と同様にして、 搮 ¾Β化合物 （600 mg) を得た。

N— [2-Hydroxy—4 — [(5,6,7,8-tetrahydro 4 H—thieno [3,2-b] azepine-1 4-yl) carbonyl obtained in Example 2) carbonyl] Using [phenyl] -1.1-biphenyl] -12-carboxamide (530 mg) and N- (3-bromopropyl) furimimid (607 mg) in the same manner as in Example 3 (600 mg).

m p (soln.): oily substance

 I R (Ne at): 1770. 1721, 1674. 1638 (cm

NMR (CDC 1 a) 5 ppm, 300 MHz:

 1.65-1.80 (2H, m), 1.90-2.10 (4H.m), 2.80-3.00 (2H.m),

3.50-4.10 (6H.m). 6.19 (1H, brs), 6.50-6.80 (2H.m).

 6.86 (1H.d, J = 8Hz). 7.20-7.40 (3H.m). 7.40― 7.60 (5H.m),

7.60-7.80 (6H.m), 8.29 (1H.d.J = 8Hz)

MS ( ⁺ ): 655

Example 34

N— [2— (3-Aminobroxy) 1-41 [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-1 4-yl) carbonyl] phenyl]-[1 . 1 '-biphenyl] — 2-carboxamide

実施例 3 3で得られた N— [2— （ 3—フ夕ルイミ ドブロボキン） — 4一 [ ( 5, 6, 7, 8—テトラヒ ドロー 4 H—チエノ [ 3, 2— b] ァゼピン一 4ーィ ル） カルボニル] フエニル] 一 [し 】 ' ービフエニル] 一 2—カルボキサミ ド (520 mg) をエタノール （10 ml)に溶解し、 ヒ ドラジン 1水和物 （58〃 1)を加え 3時間加熱還流した。 ヒ ドラジン 1水和物 （174 1)を追加し、 さらに 4 Β-ίίΗ]加 熱還流した。 溶媒を留去した後、 残渣に I Ν水酸化ナトリウム水 ¾液を加えた後 クロ口ホルムで抽出し、 有機層を無水硫酸マグネシウムで乾燥した。 溶媒留去 ½ シリカゲルカラムクロマトグラフィー （溶出溶媒； メタノール： クロ口ホル厶二 1 :10) により精製し、 標題化合物 （274 mg) を得た。

Example 3 N— [2— (3-fuimiimidobroboquin) —4— (5,6,7,8—tetrahydro 4 H—thieno [3,2—b] azepine obtained from 3-4 Dissolve carbonyl] phenyl] -1- [shi] '-biphenyl] -12-carboxamide (520 mg) in ethanol (10 ml), add hydrazine monohydrate (58〃1) and heat for 3 hours Refluxed. Hydrazine monohydrate (174 1) was added, and the mixture was further heated to reflux with 4Β-ίίΗ]. After the solvent was distilled off, an aqueous solution of I-sodium hydroxide was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent; methanol: ethyl acetate form 2: 1: 10) to give the title compound (274 mg).

m p (soln.): oily substance

IR (Ne at): 1672. 1633, 1523 cm " ¹

NMR (CDC 13) 5 p pm, 30 O H z:

 1.60-1.80 (4H.m). 1.90-2.10 (2H, m), 2.69 (2H.t, J = 6.6Hz),

2.80-3.00 (2H.m). 3.60-4.00 (4H, m), 6.20 (1H, brs).

 6.67 (1H.d.J = 5Hz), 6.75-6.90 (2 m). 7.20-7.60 (8H.m).

 7.73 (1H.d.J = 8Hz), 8.00 (1H.s), 8.28 (1H.d, J = 8Hz)

MS (M ⁺ ): 525

Example 3 5 97/17349

N- [2— [3 (chloroacetylamino) propoxy] -4-1 [(5,6,7,8-tetrahydro D—4H—thieno [3,2-b] azepine-14-yl) [Carbonyl] phenyl] — [1,1-biphenyl-2--1-carboxamide

実施例 3 4で得られた N— [ 2— （ 3—アミノブロボキシ〉 一 4一 [ (5, 6 , 7, 8—テトラヒドロー 4 H—チエノ [3, 2— b] ァゼピン一 4一ィル） 力 ルボニル] フエニル] — [し ービフエニル] — 2—カルボキサミ ド （2H mg) 及びトリェチルァミン （170 をクロ口ホルム （5 ml) に溶解し、 氷冷下 クロロアセチルクロリ ド （39 1)を加え、 室温で 2時間撹拌した。 冷却後反応液 に飽和炭酸水素ナトリウム水溶液を加えた後、 クロ口ホルムで抽出し、 有機層を 飽和食塩水で洗浄後、 無水硫酸マグネシウムで乾燥した。 溶媒留去後シリカゲル カラムクロマトグラフィー （溶出溶媒；酢酸ェチル：へキサン： = 2 ： 3〜 1 ： 1 ) により精製し、 標題化合物 （186 mg) を得た。

N- [2- (3-aminobromoboxyl) -141 [(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-14-yl) obtained in Example 34 Carbonyl] phenyl] — [bibiphenyl] — 2-carboxamide (2H mg) and triethylamine (170 were dissolved in chloroform (5 ml), chloroacetyl chloride (391) was added under ice cooling, and the mixture was cooled to room temperature. After cooling, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Purification by column chromatography (elution solvent: ethyl acetate: hexane: = 2: 3 to 1: 1) gave the title compound (186 mg).

mp (soln.): oil

IR (N eat): 1660. 1641 cm ' ¹

NMR (CDC 13) (5 ppm, 300 MHz:

 1.70-1.85 (4H.m) .1,90-2.00 (2H, m), 2.80-3.00 (2H, m), 3.28 (2H.q.J = 6Hz). 3.60-4.10 (4H, m). 4.10 (2H.s),

6.21 (1H.brs). 6.60 (1H, s). 6.68 (1H.d, J = 6Hz), 6.75-6.80 (1H, m), 6.85 (1H.d.J = 8.4Hz) .7.20-7.60 (8H.m), 7.62 (1H.s), 7.75-7.80 (1H, m). d, J = 8.Hz)

 MS (M +): 601

Example 36

 N— [2— [3 — [(4-Methylbiperazine-1-yl) acetylamino] broboxy] —4 — [(5,6,7,8—tetrahydric 4H—thieno [3,2-b ] Azepine-41-yl) carbonyl] phenyl] -1- [1, -biphenyl:]-2-carboxamide

実施例 35で得られた N— [2— [3 - (クロロアセチルァミノ） プロボキン ] - - [ ( 5, 6, 7, 8—テトラヒ ドロー 4 H—チエノ [3, 2— b〕 ァゼ ピン一 4—ィル） カルボニル] フエニル] 一 [1, 1' ービフエニル] 一 2—力 ルポキサミ ド （186 mg) 及び N—メチルビペラジン （55〃 1)をァセトン （5 ml) に溶解し、 ヨウ化カリウム （18 mg)を加え、 4時間加熱還流した。 冷却後反応液 に水を加えた後、 クロ口ホルムで抽出した。 有機層を飽和食塩水で洗浄後、 無水 硫酸マグネシウムで乾燥した。 溶媒留去後シリカゲルカラムクロマトグラフィー (溶出溶媒；酢酸ェチル ··へキサン = 2 ： 1) により精製し、 標題化合物 （56 m g)を得た。

N- [2- (3- (chloroacetylamino) propoquine] obtained in Example 35--[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] ase 4- (yl) carbonyl] phenyl] -1- [1,1'-biphenyl] -12-force Rupoxamide (186 mg) and N-methylbiperazine (55〃1) are dissolved in acetone (5 ml) and iodinated Potassium (18 mg) was added, and the mixture was heated under reflux for 4 hours. After cooling, water was added to the reaction solution, followed by extraction with black-mouthed form. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate · hexane = 2: 1) to obtain the title compound (56 mg).

mp (so): non-crystalline solid 97/17349

IR (KBr): 1671. 1640 cm " ¹

 NMR (CDC 13) ά p pm, 300 MHz:

 1.70-1.80 (4H.m). 1.90-2.10 (2H, m), 2.23 (3H.s),

 2.30-1 2.60 (8H.m), 2.85-3.00 (2H.m) .3.00 (2H.s).

 3.25 (2H, q, J = 6.6Hz), 3.50-4.00 (4H.m). 6.20 (1H.brs).

 6.68 (1H.d.J = 5Hz). 6.75-6.90 (2H, m), 7.10-7.20 (1H, m), 7.25-7.40 (3H, m). 7.40-7.60 (5H.m), 7.67 (1H .s).

 7.75-1 7.85 (1H, m). 8.29 (1H, d. J = 8.4Hz)

MS (M ⁺ ): 665

Example 3 7

 2-[[[[1,1-biphenyl] -2-carbonyl] amino] -1-5-((5,6,7,8-tetrahydric-4-4Η-thieno [3,2-b] azepine-1-4 -Yl) carbonyl] phenoxyacetic acid amide

実施例 2で得られた N— [2—ヒドロキシー 4— [ ( 5, 6, 7, 8—テトラ ヒ ドロー 4 H—チエノ [3, 2 - b] ァゼピン一 4一ィル） カルボニル] フエ二 ル] 一 [し 1 ' 一ビフエ二ル] ― 2—カルボキサミ ド （ 299 m g) 及び 2— プロモアセトアミ ド （ 1 76mg) を用いて、 実施例 3と同様にして、 標題化合 物 （ 1 2 Omg) を得た。

N- [2-hydroxy-4-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-14-yl) carbonyl] carbonyl obtained in Example 2 1]-[1'-biphenyl] -2-carboxamide (299 mg) and 2-bromoacetamide (176 mg) in the same manner as in Example 3 to give the title compound (12 Omg).

mp (soln.): amorphous solid

IR (KB r): 1681. 1633.] 523 cm one ¹

NMR (CDC 13) δ p pm, 300 ΜΗ ζ:

 1.60-1.85 (2Η.m), 1.85-2.05 (2H, m). 2.80-3.00 (2H, m), 3.50-4.20 (2H.m), 4.02 (2H.s), 5.38 (1H, s). 5.85 (1H.s), 6.16 (1H.brs), 6.52 (1H.s). 6.65 (1H.d, J = 5Hz),

 7.07 (1H.d, J = 5Hz), 7.20-7.60 (9H, m). 7.86 (1H.d.J = 8Hz).

 8.18 (1H.d.J = 8Hz)

MS (M +): 525

Example 38

N- [2-[2-(4-benzhydrylpyrazine-1-yl) etkin] -1 4-[(5,6,7,8-tetrahidro 4H-thieno [3,2-b] Azepine-14-yl) carbonyl] phenyl] 1- [1'-biphenyl] 1-2-carboxamide

97/17349

実施例 3で得られた N— [2- (2—クロ口エトキン） —4一 [ (5, 6, 7 , 8—テトラヒ ドロー 4 H—チエノ [ 3, 2— b] ァゼピン一 4一ィル） カルボ ニル] フエニル] 一 [1, 1' ービフエニル] 一 2—カルボキサミ ド （ 0 mg) 及び N— (ジフヱニルメチル） ビぺラジン （107 mg) を用いて、 実施例 4と同は- にして、 標題化合物 （120 mg) を得た。

N— [2- (2-—mouth ethokine) —4—1 ((5,6,7,8—tetrahydro 4H—thieno [3,2—b] azepine 1-41 obtained in Example 3) L) Carbonyl] phenyl]-[1,1'-biphenyl] -12-carboxamide (0 mg) and N- (diphenylmethyl) biperazine (107 mg), the same as in Example 4 except that The title compound (120 mg) was obtained.

mp (soln.): amorphous solid

 I R (KB r): 1673. 1641. 1596, 1522 cm "'

NMR (CDC 13) δ p pm, 300 ΜΗ ζ:

 1.60-1.80 (2Ηm), 1.80-2.05 (2H, η, 2.05-2.50 (8H.m), 2.80- 2.95 (2H, m), 3.50-4.10 (4H.m), 4.00 (2H, s) ,

 6.20 (1H, brs). 6.64 (1H, d, J = 5Hz). 6.77 (1H, s),

 6.88 (1H.d, J = 8Hz) .7.15-7.60 (18H.m), 7.70-7.75 (1H.m).

 8.17 (1H, s). 8.25 (1H, d, J = 8Hz)

MS (M +): 746

Example 39

N— [2-[2-[4-I (4-fluorobenbuyl) piberidino] Etkin]-4-[(5, 6, 7, 8-tetrahydric 1H-thieno [3, 2-b] Azepine-41-yl) carbonyl] phenyl]-[1,1'-biphenyl] -1-2-cal Boxamide

実施例 3で得られた N— [2— （2—クロ口エトキシ） — 4一 [ (5, 6, 7 , 8—テトラヒ ドロー 4 H—チエノ [3, 2— b] ァゼピン一 4—ィル） カルボ ニル] フエニル] 一 [1, 1' ービフエニル] 一 2—カルボキサミ ド （150 mg) 及び 4一 （ 4一フルォ口べンゾィル） ピペリジン （88 mg)を用いて、 実施例 4と 同はにして、 標題化合物 （120 mg) を得た。

N— [2 -— (2-chloro ethoxy) —4-1 — ((5,6,7,8—tetrahydro) 4 H—thieno [3,2-b] azepine-1— obtained in Example 3 L) Carbonyl] phenyl]-[1,1'-biphenyl] -12-carboxamide (150 mg) and 4- (4-fluorobenzoyl) piperidine (88 mg) were used to produce the same as in Example 4. The title compound (120 mg) was obtained.

mp (soln.): amorphous solid

IR (KB r): 1680, 1643, 1597 cm- ¹

_{NMR (CDC 1 3) ό p} pm, 300 MHz:

 1.50-1.85 (6H.m), 1.90-2.05 (2H.m), 2.05-2.20 (2H.m),

2.52 (2H.t.J = 6Hz). 2.80-2.95 (4H, m) .3.00-3.20 (1H, m).

 3.77 (2H.t, J = 6Hz). 3.60-4.00 (2H.m), 6.20 (1H, brs).

 6.67 (1H, d. J = 5Hz). 6.80 ClH, s), 6.85 (1H. D. J = 9Hz).

 7.10-7.20 (2H, m), 7.25-7.55 (8H, m), 7.70-7.75 (1H, m),

7.90-8.05 (3H, m), 8.26 (1H, d, J = 8Hz)

MS (M ⁺ ): 701

Example 40

Ethyl 4- [2 — [[[1,1'-biphenyl] 1-2-carbonyl] amino 97/17349

]-5-[(5,6,7,8-tetrahydrodraw / 1H-thieno [3,2-b] azepine-41-yl) carbonyl] phenoxy] butylate

実施例 2で得られた N— [2—ヒドロキシ— 4一 [ (5, 6, 7, 8—テトラ ヒ ドロー 4 H—チエノ [ 3, 2— b] ァゼピン一 4—ィル） カルボニル〕 フエ二 ル] 一 [し 1 ' —ビフエニル] 一 2—カルボキサミ ド （1.0 g)及び 4一ブロモ ブタン酸ェチルエステル （1.2 g)を用いて、 実施例 3と同様にして、 標題化合物 (921 mg) を得た。

N- [2-hydroxy-41-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-14-yl) carbonyl] carbonyl obtained in Example 2 The title compound (921 mg) was prepared in the same manner as in Example 3 by using 1- [1'-biphenyl] -12-carboxamide (1.0 g) and 4-ethylbutyrate ethyl ester (1.2 g). Obtained.

m p (soln.): colorless crystal

IR (N eat): 1731, 1675, 1639 cm " ¹

NMR (CDC 13) (5 ppm, 300 MHz:

 1.24 (3H, t.J = 7.2Hz) .1.70-2.05 (6H, m), 2.27 (2H.t.J = 7.2Hz) .2.90-3.00 (2H.π, 3.60-4.00 (4H.m). 4.08 (2H.q, J = 7.2Hz), 6.20 (1H, brs). 6.68 (1H.d.J = 5.Hz), 6.75-1.80 (1H.m),

 6.82 (1H.d.J = 9.0Hz), 7.25-7.60 (8H.m). 7.65 (1H.s).

 7.75-7.80 (1H, m), 8.30 (1H.d, J = 8Hz)

MS (M +): 583

Example 4 1

4-[2-[[[1, 1 '1-biphenyl] 1 2-carbonyl] amino] 1 5— [(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-4-yl) carbonyl] phenoxy] butyric acid

実施例 4 0で得られたェチル 4一 [2— [ [ [ 1 , 1 ' —ビフヱ二ル] — 2 —カルボニル] ァミ ノ] 一 5— [ ( 5, 6, 7, 8—テトラヒ ドロー 4 H—チェ ノ [3, 2 - b] ァゼピン一 4—ィル） カルボニル] フエノキシ] プチレー ト （ 820 mg) を用いて、 実施例 6と同様にして、 標題化合物 （6H mg) を得た。

Example 40 Etyl obtained in 40 [2 — [[[[1,1'-biphenyl] —2—carbonyl] amino] -1 5 — [(5,6,7,8-tetrahydrodraw The title compound (6H mg) was obtained in the same manner as in Example 6 using 4H-cheno [3,2-b] azepin-14-yl) carbonyl] phenoxy] petiteate (820 mg). .

m p (soln.): colorless crystal

IR (KBr): 1718, 1643, 1528 cm " ¹

_{NMR (DMSO - d 6) 0} p pm, 3 0 0 MH z:

 1.50-2.00 (6H, m), 2.25-2.40 (2H, m), 2.75-3.00 (2H, m),

3.50-4.00 (2H, m), 6.30 (1H, brs), 6.70-7.00 (3H.m).

 7.25-7.70 (9H.m). 7.70-7.85 (1H.m) .9.03 (1H.s).

 12.2 (1H, s)

MS (M ⁺ ): 554

Example 4 2

N- [2— [4-(4-Methylbiperazine-1 1-yl) 1 4-oxobutokin]--[(5,6,7,8-tetrahydro 4 H-thieno [3,2—b ] Azepine 4-1) carbonyl] phenyl] -1 [1, 1'-biphenyl] -1 2-force 97/17349

Lupoxamide

 Example 41 4- [2 — [[[1,1, '-biphenyl] -12-carbonyl] amino] -1-5 — [(5,6,7,8-tetrahydro-4H— Using thieno [3,2-b] azepine-14-yl) carbonyl] phenoxy] butyric acid (180 mg) and N-methylbiperazine (43ζ1) in the same manner as in Example 7, the title compound (131 mg ) Was obtained.

m p (soln.): 188.0-190.0 ° C (isopropanol)

IR (KBr): 1641 cm " ¹

 NMR (CDC 13) δ p pm, 300 MHz:

 1.70-1.85 (2H.m). 1.85-2.05 (4H.m), 2.20-2.40 (9H, π, 2.85-3.00 (2Η.m), 3.35 (2H.t, J = 5Hz) .3.55 (2H, m t, J = 5Hz),

3.69 (2H, t.J = 6Hz). 3.70-4.10 (2H, m), 6.20 (1H, brs),

 6.70 1 6.90 (4H, m), 7.25-7.40 (3H, m). 7.40-7.60 (5H.m), 7.70-7.80 (2H, m), 8.26 (1H, d.J = 8Hz)

MS (M ⁺ ): 636

Example 4 3

N- [2 -— [4-(4-Methyl-vinyl draw 1,4—dazepine) 1 4-oxobutoxy] 1 4— [(5,6,7,8—tetrahydro 1—4 No [3,2-b] azepine-41-yl) carbonyl] phenyl] [1,1-biphenyl] —2-carboxamide

実施例 4 1で得られた 4一 [2— [ [ [し 一ビフヱニル] 一 2—カルボ ニル] ァミノ] 一 5— [ ( 5, 6, 7, 8—テトラヒ ドロー 4 Η—チエノ [3， 2— b] ァゼピン一 4一ィル） カルボニル] フエノキシ] 酷酸 （180 mg) 及び N 一メチルホモピぺラジン （48 1)を用いて、 実施例 7と同様にして、 標題化合物 (171 mg) を得た。

Example 41 4- [2-[[[Shibibiphenyl] -12-carbonyl] amino] -15-[(5,6,7,8-tetrahydro 4 4-thieno [3, 2-b] azepine-41-yl) carbonyl] phenoxy] severe acid (180 mg) and N-methyl homopyrazine (481) were used to give the title compound (171 mg) in the same manner as in Example 7. Obtained.

mp (soln.): non-crystalline solid

IR (KBr): 1638 cm- ¹

NMR (C D C 13) <5 ppm, 300 MHz:

 1.70-2.00 (8H.m), 2.20-2.40 (5H, m), 2.40-2.60 (4H.m), 2.80-3.00 (2H.m), 3.30-3.50 (2H, m), 3.50-4.10 (6H , m), 6.20 (1H.brs). 6.60-6.70 (1H, m), 6.70-6.90 (2H.m),

7.20-7.60 (8H.m). 7.70-7.80 (2H, m), 8.27 (1H. D. J = 9Hz) MS ( ⁺ ): 650

Example 4 4

N— [2— [4- (4-Dimethylaminobiperidino) 1 4-oxobutoxy]-4-[(5, 6, 7, 8-tetrahydride a— 4 H—thieno [3, 2—b] Hazepi 97/17349

Carbonyl) phenyl] one [shi 1 one biphenyl] one 2—force

実施例 4 1で得られた 4 - [2 - [ [ [ 1 , 1 ' -ビフヱニル] ― 2—カルボ ニル] 了ミノ] — 5— [ ( 5, 6, 7, 8—テトラヒ ドロー 4H—チエノ [3, 2 - b] ァゼピン— 4—ィル） カルボニル] フヱノキシ] 酪酸 （180 mg) 及び 4 ージメチルァミ ノ ピペリジン 2塩酸塩 （89 mg)を用いて、 実施例 7と同樣にして 、 標題化合物 （98 mg)を得た。

Example 4 4- [2-[[[1,1'-biphenyl] -2-carbonyl] Rmino] obtained in Example 1—5 — [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-4-yl) carbonyl] phenoxy] butyric acid (180 mg) and 4-dimethylaminopiperidine dihydrochloride (89 mg) were prepared in the same manner as in Example 7 to give the title compound ( 98 mg).

mp (soln.): amorphous solid

 I R (KB r): 1640 cm "'

NMR (CD C 13) 5 ppm, 300 MHz:

 1.20-1.50 (2H.m). 1.50-2.10 (11H, m), 2.20-2.40 (8H, m), 2.45-2.60 (1H, m), 2.80-3.00 (2H.m). 3.60-4.20 (4H m), 4.50 (1H, d.J = 12Hz), 6.20 (1H, brs), 6.67 (1H.d.J = 5Hz),

 6.70-6.85 (2H.m). 7.25-7.60 (8H, m), 7.70-7.80 (2H, m).

 8.26 (1H, d. J = 8Hz)

MS (M ⁺ ): 664

Example 45

N— [2-[(pyridine-41-yl) methoxy] 1-41- [(5, 6, 7, 8- Tetrahydride α-4H-thieno [3,2-b] azevin-14-yl) carbonyl] phenyl] — [sibiphenyl] —2-carboxamide

実施例 2で得られた N— [2—ヒ ドロキシー 4一 [ (5, 6, 7, 8—テトラ ヒ ドロー 4 H—チエノ [3, 2— b] ァゼピン一 4一ィル） カルボニル] フエ二 ル] — [ 1 , —ビフエニル〗 一 2—カルボキサミ ド （180 mg) 及び 4—クロ ロメチルピリジン塩酸塩 (158 mg) を用いて、 実施例 3と同様にして、 標題化合 物 （201 mg) を得た。

N- [2-Hydroxy-41-[(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-1-4-yl) carbonyl] carbonyl obtained in Example 2 The title compound (201 mg) was prepared in the same manner as in Example 3 using [1,2] -biphenyl-1-2-carboxamide (180 mg) and 4-chloromethylpyridine hydrochloride (158 mg). ).

m p (soln.): non-crystalline solid

IR (KBr): 1673. 1639 cm " ¹

NMR (CDC 13) δ p pm, 300 MHz:

 1.60-1.80 (2H.m). 1.80-2.00 (2H.m), 2.60-2.80 (2H.m).

 3.50-4.00 (2H, m). 4.67 (2H.s) .6.12 (1H, brs) .6.55 (1H.s)

6.67 (1H, d, J = 5Hz). 6.90-7.05 (3H.m), 7.20-7.30 (3H.m).

 7.30-7.60 (5H.m). 7.68 (1H, s), 7.73 (1H, dd, J = 7.7Hz and 1.5Hz),

8.39 (1H, d, J = 8Hz), 8.55-8.65 (2H, m)

MS (M +): 559

Example 4 6

N— [2— [2— (indole 3—yl) etkin] 1 4— [(5, 6, 7 97/17349

, 8-Tetrahydro 4H-thieno [3,2-b] azebin-14yl) carbonyl] phenyl] -1- [biphenyl] — 2-carboxamide

実施例 2で得られた Ν— [2—ヒドロキシー 4一 [ ( 5, 6, 7, 8—テトラ ヒ ドロー 4 Η—チエノ [3, 2 - b] ァゼピン一 4一ィル） カルボニル] フエ二 ル] 一 [し 1 ' 一ビフエニル] 一 2—カルボキサミ ド （200 mg) 及び 3— （ 2 一プロモェチル） インドール （191 mg) を用いて、 実施例 1 2と同様にして、 標 题化合物 （288 mg) を得た。

Ν— [2-Hydroxy-41-[(5,6,7,8-tetrahydro 4- 4-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl obtained in Example 2 [1'-biphenyl] -12-carboxamide (200 mg) and 3- (2-promoethyl) indole (191 mg) in the same manner as in Example 12 to obtain the title compound (288 mg).

mp (soln.) _: pale yellow amorphous solid

IR (Ne at): 3399. 3316, 1632, 1523 cm ' ¹

NMR (CDC 13) <5 ppm, 300 MHz:

 1.68-1.80 (2H, m), 1.91-2.01 (2H, m), 2.84-2.88 (2H, m).

 2.98 (2H.t.J = 13.5Hz). 3.82 (2H, brs), 3.95 (2H, t, J = 13.5Hz), 6.18 (1H.brs). 6.64 (1H, d.J = 5.1Hz). 6.80-6.84 (3H.m),

 7.00-7.03 (1H.m), 7.14-7.20 (1H, m), 7.28-7.32 (5H.m), 7.40-7.59 (5H.m). 7.68-7.70 (2H, m), 7.79 (1H, s ),

 8.25 (1H, d. J = 8.4Hz)

MS (M ⁺ ): 611

Example 47 N— [2— [3 -— (4-Methylbiperazine-11-yl) broboxy] -1-4-[(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine 4yl) carbonyl] phenyl] — [1,1'-biphenyl] —2-carboxami K

実施例 1 2で得られた N— [2 - ( 3—クロロブロボキシ） 一 4一 [ (5, 6 , 7, 8—テトラヒド口一 4 H—チエノ [3， 2— b] ァゼピン一 4一ィル） 力 ルポニル] フエニル] 一 [し 一ビフヱニル] 一 2—カルボキサミ ド （280 mg) 及び N—メチルビペラジン （0.09 ml)を用いて、 実施例 1 5と同ほ-にして、 標題化合物 （260 mg) を得た。

N— [2- (3-Chlorobromoxoxy) 1-4 [(5,6,7,8-tetrahydrido) 4 H—thieno [3,2-b] azepine 1-41 obtained in Example 12 The title compound (260 mg) was prepared in the same manner as in Example 15 using luponyl] phenyl] -1- [bi-biphenyl] -12-carboxamide (280 mg) and N-methylbiperazine (0.09 ml). ).

mp (soln.): yellow amorphous solid

IR (N eat): 3404. 1640. 1522 cm " ¹

NMR (CDC) 3) 5 ppm, 300 MHz:

 1.71-1.75 (4H.m), 1.91-2.02 (2H, m). 2.30 (3H, s),

 2.32-2.35 (2H, m), 2.38-2.50 (8H, m), 2.89-2.93 (2H.m), 3.65-3.70 (2H, m), 3.83 (2H.brs). 6.20 (1H.brs).

 6.66 (1H.d.J = 5.1Hz), 6.71-6.82 (2H, m), 7.30-7.56 (8H, m), 7.65 (1H.s), 7.75 (1H.d.J = 7.5Hz). 8.25 (1H.d.J = 8.4Hz)

MS (M +): 608 97/17349 Example 4 8

 N— [2— [3— (4-Methyl-Bad Draw 1,4-Diazepine—1-Ge) Proboxy] —4-1— (5,6,7,8-tetrahydro-4H—thieno [3,2 1b] azepine-1-4-yl) carbonyl] phenyl] -1- [biphenyl] -2-carboxamide

実施例 1 2で得られた N— [ 2— （ 3—クロ口プロボキシ） — 4— [ ( 5, 6 , 7, 8—テトラヒ ドロ一 4 H—チエノ [3, 2— b] ァゼピン一 4一ィル） 力 ルポニル] フエニル] 一 [し ービフエニル] — 2—カルボキサミ ド （280 mg) 及び N—メチルホモピぺラジン （0.10 ml)を用いて、 実施例 1 5と同様にし て、 標題化合物 （244 mg) を得た。

N— [2— (3-chloropropoxy) —4 — [(5,6,7,8—tetrahydro-4H—thieno [3,2—b] azepine-1 obtained in Example 12 1-yl-proponyl] phenyl]-[bi-phenyl] —2-carboxamide (280 mg) and N-methylhomopirazine (0.10 ml) were prepared in the same manner as in Example 15 to give the title compound (244 mg).

m p (soln.): yellow oil

IR (N eat): 3404. 1639. 1522 cm— ¹

NMR (CDC 13) δ ρ pm, 300 MHz:

 1.69-2.02 (8H.m). 2.37-2.50 (2H, m), 2.2 (3H.s).

 2.65-2.74 (8H.m). 2.89-2.93 (2H.m). 3.65-3.71 (2H, m),

3.82 (2H.brs), 6.20 (1H, brs), 6.67 (1H.d, J = 5.1Hz),

 6.75-6.82 (2H.m) .7.30-7.56 (8H.m). 7.66 (1H.s),

7.75 (1H, d, J = 7.8Hz). 8.26 (1H, d, J = 7.5Hz) MS (M +): 622

Example 9

 2-[[[[1,1,1'biphenyl] carbonyl] amino] -1-5- [4-((5,6,7,8-tetrahydro-4Η-thieno [3,2-b] azepine-1 4-yl) carbonyl] phenoxycarboxamide

実施例 2で得られた N— [ 2—ヒ ドロキシ— 4一 [ ( 5， 6, 7, 8—テトラ ヒ ドロー 4 H—チエノ [3, 2 - b] ァゼピン一 4一ィル） カルボニル] フエ二 ル] 一 [し 1 ' ービフエニル〕 一 2—カルボキサミ ド （290 mg) をクロ口ホル ム （2.5 ml) に懸濁させ、 氷冷下クロロスルホニルイフシァネート （59〃1)のク ロロホルム溶液 （500 を滴下し、 氷冷下で 2 5分、 室温でさらに 2時間 1 5 分攪拌した。 反応液に水を加え、 クロ口ホルム抽出し、 有機層を無水硫酸マグネ シゥムで乾燥した。 減圧下にて溶媒留去して得られる残渣に水 （20 ml)を加え、 7 0^eCにて 3時間加熱した。 冷却後反応液をクロ口ホルム抽出し、 有機層を無水 硫酸マグネシウムで乾燥した。 滅圧下にて溶媒留去して得られる残渣をシリカゲ ルクロマトグラフィ一 （溶出溶媒： S1E酸ェチル： n—へキサン二 1: 3 ) により 精製し、 標題化合物 （37 mg)を得た。

N— [2-Hydroxy—4-1 obtained in Example 2 ((5,6,7,8—Tetrahydro 4 H—thieno [3,2-b] azepine-14-yl) carbonyl) [Phenyl]-[1'-biphenyl] -12-carboxamide (290 mg) was suspended in chloroform (2.5 ml), and chlorosulfonyl ifocyanate (59-1) in chloroform was cooled under ice-cooling. The solution (500 was added dropwise, and the mixture was stirred under ice-cooling for 25 minutes and at room temperature for another 2 hours and 15 minutes. Water was added to the reaction solution, extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. Water (20 ml) was added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was heated for 3 hours at 70 ^e C. After cooling, the reaction solution was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel chromatography (elution solvent: S1E acid ethyl). Hexane two to n-1: Purification by 3) to give the title compound (37 mg).

mp (soln.): non-crystalline solid

IR (KB r): 1729. 1651. 1632 cm ' ¹ 97/17349

NMR (CDC 1 a) 5 p pm, 30 OMH z:

 1.65-2.10 (4H.m). 2.80-3.00 (2H.m). 3.40-4.20 (2H.mX

5.00 (2H, s), 6.23 (1H, brs). 6.60-1.80 (1H.m).

 6.85-7.05 (1H.m) .7.05-7.60 (10H, m). 7.77 (1H.d, J = 7.8Hz).

8.18 (1H.d, J = 7.8Hz)

MS (M ⁺ ): 511

Example 5 0

 N— [2— [3- (4-Dimethylaminopiperidino) propoxy] 1-4 — [(5,6,7,8—tetrahydro-1 4H—thieno [3,2—b] azebin-1 4 -Yl) carbonyl] phenyl]-[bi-phenyl] — 2-carboxamide

実施例 1 2で得られた N— [2— （3—クロ口プロボキシ） 一 4— [ (5, 6 , 7, 8 -テトラヒ ドロ一 4 H—チエノ [ 3, 2— b] ァゼピン一 4一ィル） 力 ルポニル] フエニル] — [し 1 ' —ビフエニル] 一 2—カルボキサミ ド （150 mg) 及びジメチルアミノビペリジン （75 mg)を用いて、 実施例 4と同樣にして、 標題化合物 （105 mg) を得た。

N— [2 -— (3-chloropropoxy) -14-[(5,6,7,8-tetrahydro-1-4H-thieno [3,2-b] azepine-1-4 obtained in Example 12 1-yl) -Ruponyl] phenyl]-[し 1'-biphenyl] 1-2-carboxamide (150 mg) and dimethylaminobiperidine (75 mg) in the same manner as in Example 4 to give the title compound (105 mg) was obtained.

mp (soln.): amorphous solid

IR (KBr): 1641. 1522 cm " ¹

NMR (CDC 1 a) <5 p pm. PC

97/17349

1.70-1.80 (6H.m). 1.95-2.10 (6H, m) .2.34 (2H, t.J = 6.6Hz), 2.59 (6H, s). 2.70-3.00 (5H, m). 3.70-3, 75 (2H.m).

 3.75-4.00 (2H, brs). 6.19 (1H, brs), 6.69 (1H.d, J = 5.1Hz), 6.75 (1H, d. J = 8.1Hz). 6.87 (1H.s), 7.25-7.35 (3H.m),

 7.35-7.55 (5H.m). 7.64 (1H, s). 7.75 (1H, d, J = 7.3Hz).

 8.23 (1H.d, J = 8.8Hz)

 MS (M +): 636

Example 5 1

 N- [2-[4-I (4-ethylbiverazine-1-11) butoxy] 1-41 [(5,6,7,8-tetrahydro 4 H-thieno [3,2—b] azepine-1 4 —Yl) carbonyl] phenyl) 1- [bi-phenyl 12-carboxad

実施例 1 で得られた Ν— [2— （4一クロロブトキシ） 一 4一 [ (5, 6, 7, 8—テトラヒ ドロー 4 Η—チエノ [ 3, 2— b] ァゼビン一 4一ィル） カル ボニル] フエニル] — [1, ービフエニル] 一 2—カルボキサミ ド （650 mg ) 及び N—ェチルビべラジン （222 〃1)を用いて、 実施例 4と同様にして、 標題 化合物 (181 mg) を得た。

Ν— [2 -— (4-Chlorobutoxy) 1 4-1 [(5,6,7,8-tetrahydro 4) Η-thieno [3,2—b] azebine-14-yl obtained in Example 1 ) Carbonyl] phenyl] — [1, -biphenyl] 12-carboxamide (650 mg) and N-ethylbiverazine (222-1) in the same manner as in Example 4 to give the title compound (181 mg) I got

m p (soln.): oily substance

IR (Ne at): 1675, 1639 cm " ¹ 97/17349

_{NMR (CDC 1 3) δ p} pm, 3 0 0 MHz:

 1.09 (3H, t.J-7.2Hz). 1.40-1.70 (4H, m), 1.70-1.90 (2H.m). 1.90-2.10 (2H, m). 2.20-2.60 (12H.m), 2.85- 2.95 (2H.m), 3.55-4.20 (4H.m), 6.10-6.40 (1H.m), 6.60-6.90 (3H.m), 7.20-7.60 (8H.m). 7.65 (1H, s), 7.70-7.80 (1H, m),

 8.20-8.35 (1H.m)

 MS (M *): 636

Example 5 2

 N- [2-C4- (4-dimethylaminobiperidino) butoxy] -4-1-((5,6,7,8-tetrahydro-14H-thieno [3,2-b] azebin-1-yl) Carbonyl] phenyl] -1- [1,1'-biphenyl] 1-2-carboxamide

実施例 1 で得られた N— [2— (4—クロロブトキシ） 一 4— [ (5, 6, 7, 8—テトラヒ ドロー 4 H—チエノ [3, 2— b〕 ァゼピン- 4一ィル） カル ボニル] フエニル] 一 [し 1 ' —ビフエ二ル] — 2—カルボキサミ ド （300 mg

N- [2- (4-chlorobutoxy) -14-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-4yl obtained in Example 1 ) Carbonyl] phenyl] 1 [shi 1 '-biphenyl]-2-carboxamide (300 mg

) And dimethylamino piperidine (150 mg) to give the title compound (200 mg) in the same manner as in Example 4.

mp (soln.): amorphous solid

IR (KB r): 1640. 1525 cm " ¹ NMR (CDC 13) dp pm, 300 MHz:

 1.40-1.70 (11H.m), 1.75-1.85 (4H, m). 1.95-2.00 (2H.m),

2.10-2.20 (2H.m). 2.35-2.40 (2H, m). 2.60-2.65 (4H.m.

 2.90-2.95 (2H.m). 2.98-3.10 (2H, m) .3.62-3.72 (2H.brs).

6.20 (1H.brs), 6.79 (1H.m), 7.26-7.65 (10H.m),

 7.77 (1H, d. J = 7.Hz), 8.25 (1H, d. J = 6.9Hz)

MS (M ⁺ ): 650

Example 53

 N- [2-[4--(-Dimethylamino) piperidino] — 4-oxobutoxy] — 4-1- [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-1 L) carbonyl] phenyl]-[1, -biphenyl] -12-carboxamide hydrochloride

実施例 44で得られた N— [ 2— [ - [ ( 4ージメチルァミノ） ピペリジノ ] 一 4—ォキソブトキシ] 一 4一 [ ( 5， 6, 7, 8—テトラヒ ドロー 4 H-チ エノ [3, 2— b] ァゼピン一 4一ィル） カルボニル] フヱニル] 一 [し 一ビフヱニル] — 2—カルボキサミ ド（330 mg)の酢酸ェチル（3 ml)溶液に、 4N 塩化水素一酢酸ェチル （0.25 ml)を滴下した。 滴下終了後 30分間攪拌し、 析出 した固体を 取し、 アセトンを用いて再結晶を行い、 摞題化合物 （250 mg) を得 た。

N- [2-(-[(4-dimethylamino) piperidino] -14-oxobutoxy] -14-[(5,6,7,8-tetrahydro 4H-thieno [3,2] obtained in Example 44 — B] azepine-41-yl) carbonyl] phenyl]-[1-biphenyl] — 2-N-carboxamide (330 mg) in ethyl acetate (3 ml), 4N hydrogen chloride / monoethyl acetate (0.25 ml) It was dropped. After completion of the dropwise addition, the mixture was stirred for 30 minutes, and the precipitated solid was collected and recrystallized from acetone to obtain the title compound (250 mg). Was.

mp (soln,): colorless crystals, 211.5-213.5. C (aceton)

IR (KB r): 3429. 2374, 1635. 1525. 1381 cm— ¹

 NMR (CDC 13) δ ρ ρτη, 300 MHz:

 1.39-1.59 (2H, m), 1.67-1.87 (4H, brs), 1.90-2.05 (5H.m), 2.25-2.30 (3H.m). 2.46 (1H, t, J = 12.3Hz). 2.63 ( 3H, s),

 2.73 (3H, s), 2.89-3.00 (3H, m), 3.24 (1H.t.J = 12.2Hz),

 3.85 (2H.d, J = 13.2Hz), 3.87 (2H, brs). 4.67 (2H, d, J = 13.2Hz), 6.18 (1H, brs), 6.72 (1H, d, J = 5.7Hz), 7.24-7.35 (4H.m),

 7.42-7.58 (4H, m). 7.74-7.78 (2H.m), 8.24 (1H.d, J = 7.8Hz), 12.70 (1H.brs)

MS (M ⁺ ): 664

Example 5 4

 N— [4 — [(8-dimethylamino-1,5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-14-yl) carbonyl] -12-methoxyphenyl] One U, 1'-biphenyl] one 2-carboxamide

 (Process a)

 8—Hydroxy 4, 6, 7, 8—Tetrahydrothieno [3,2-b] azepin-5-one

6,7-Dihydrodreno [3,2-b] azepine-1 To the suspension of 5,8-dione (1.58 g) in methanol (30 ml), add sodium borohydride (330 mg) to the suspension, and allow to stand at room temperature for 3 hours. Stirred. Water was added to the reaction solution, and the mixture was extracted with chloroform.The organic layer was saturated with water. The extract was washed successively with brine and dried over anhydrous magnesium sulfate. Concentration 0: The mixture was concentrated underneath to give the title compound (996 mg) as an amorphous solid.

NMR (δ) p _Pm (DMSO-di. 300 MHz)

 1.95-2.25 (2H.m), 2.30-2.45 (1H.m). 2.50-2.65 (1H.m),

 4.60 (1H.t, J = 4.5Hz). 6.70 (1H, d.J = 5.Hz).

 7.39 (1H.d, J = 5.4Hz), 9.84 (1H.brs)

MS (M ⁺ ): 182

 (Process b)

 8-dimethylamino-4,6,7,8-tetrahydrothieno (3,2-b) azepin-1 5-one

工程 aで得られた 8—ヒ ドロキン- 4, 6, 7, 8—テトラヒ ドロチェノ 〔3 ， 2— b〕 ァゼピン— 5—オン（500 mg)をピリジン（20 ml) に溶かし、 氷冷下、 塩化メタンスルホニル（473 mg)を加え、 氷冷〜室温にて 4時間攪拌した。 減 下 で溶媒を留去した後、 残渣を N， N—ジメチルホルムアミ ド（30 m】） に溶かし、 氷冷下、 炭酸カリウム（3.8 g) 、 ジメチルァミ ン塩酸塩（2.2 g) を加え、 室温下 で終夜攬拌した。 反応液を減圧下溶媒留去後、 飽和炭酸水素ナトリウム水溶液を 加え、 クロ口ホルムで抽出し、 有機層を水、 飽和食塩水で順次洗浄した後、 無水 硫酸マグネシウムで乾燥した。 減圧下、 溶媒を留去して標題化合物 (270 mg)を^ た。

8-Hydroquine-4,6,7,8-tetrahydrocheno [3,2-b] azepin-5-one (500 mg) obtained in step a was dissolved in pyridine (20 ml), and the mixture was cooled on ice. Methanesulfonyl chloride (473 mg) was added, and the mixture was stirred at ice cooling to room temperature for 4 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in N, N-dimethylformamide (30 m), and potassium carbonate (3.8 g) and dimethylamine hydrochloride (2.2 g) were added under ice-cooling. The mixture was stirred overnight at room temperature. After evaporating the solvent of the reaction solution under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (270 mg).

NMR (6) p _Pra (DMSO-ds, 300 MHz)

 1.60-1.85 (1H, m), 1.95-2.15 (1H, m). 2.20 (6H, s),

2.30-2.60 (2H, m). 3.92 (1H.dd.J = 12.0Hz and 6.0Hz), 6.65 C1H.d, J = 6.OHz). 7.29 (1H.d, J = 6.0Hz). 9.69 (1H.brs)

MS (M ⁺ ): 209

 (Process c)

 8-dimethyl-1,4- (3-methoxy 412 trobenbuyl) 1,5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine

水素化アルミニウムリチウム（184 mg)のテトラヒ ドロフラン（40 ml)懸濁液に 、 工程 bで得られた 8—ジメチルァミノ— 4 , 6, 7, 8-テトラヒ ドロチェノ 〔3, 2— b〕 ァゼビン一 5—オン（510 mg)を加え、 還流下 3時間攪拌した。 放 ？合 ¾反応液をジェチルエーテル （80 ml)で希釈し、 過剰の水素化アルミニウムリ チウムを水で分解した。 溶液をセライ ト澳過し、 濾液を無水硫酸ナ トリウムで乾 燥した。 濾過後、 滤液を濃縮し、 残渣をクロ口ホルム （25 ml)に溶解し、 室温下 でトリエチルァミ ン（1.0 ml)を加えた。 ここに 3—メ トキシ— 4—ニトロ安息香 酸（575 mg)と塩化チォニル（3.0 ml)より調製した塩化 3—メ トキシー 4—ニトロ ベンゾィルを加え、 14時間攪拌した。 反応液を水、 飽和食塩水で洗浄し、 無水 硫酸ナトリウムで乾燥した。 滹過後據液を濃縮し、 残渣をシリカゲルカラムクロ マトグラフィー （へキサン ：酢酸ェチル =2 ： 1) で精製し、 非結晶性固体とし て標題化合物（884 mg)を得た。

To a suspension of lithium aluminum hydride (184 mg) in tetrahydrofuran (40 ml) was added 8-dimethylamino-4,6,7,8-tetrahydrocheno [3,2-b] azevin obtained in step b. —On (510 mg) was added, and the mixture was stirred under reflux for 3 hours. Release? The combined reaction solution was diluted with getyl ether (80 ml), and excess lithium aluminum hydride was decomposed with water. The solution was filtered through celite, and the filtrate was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, the residue was dissolved in chloroform (25 ml), and triethylamine (1.0 ml) was added at room temperature. To this was added 3-methoxy-4-nitrobenzoyl chloride prepared from 3-methoxy-4-nitrobenzoic acid (575 mg) and thionyl chloride (3.0 ml), and the mixture was stirred for 14 hours. The reaction solution was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After filtration, the resulting solution was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound (884 mg) as a non-crystalline solid.

NMR (5) _P p _m (CDC 13.300 MHz)

 1.80-2.05 (4H, m). 2.17-2.40 (1H, m), 2.37 (6H.s).

3.50-3.60 (1H, m). 3.86 (3H, s), 6.17 (1H.d.J = 3.7Hz). 6.87 (1H.d, J = 3.7Hz). 6.98 (1H, d.J = 6.8Hz), 7.13 (1H, brs).

 7.65 (1H.d, J = 6.8Hz)

MS (M ⁺ ): 375

 (Process d)

 N- [4-[[8-dimethylamino-5,6,7,8-tetrahydro4H thieno [3,2-b] azepine-41-yl) carbonyl] -1 2-Methoxyphenyl] -1 [1,1'-biphenyl] 1-2-carboxamide

工程 cで得られた 8—ジメチルアミノー 4一 （ 3—メ トキシー 4—ニトロベン ゾィル） 一 5， 6， 7, 8—テトラヒ ドロー 4 H—チエノ 〔3, 2— b〕 了ゼピ ン（417 mg)の酢酸（4.0 ml)溶液に、 還元鉄（186 mg)及び水 (0.06 ml)を加え、 5 0でにて 1時間 4 0分攪拌した後、 更に還元鉄 （62 mg)を加え、 5 O'Cにて 2時 間攪拌した。 クロ口ホルム （20 ml)で希釈した該反応液をセライ ト濾過し、 濾液 を 1 N水酸化ナトリウム水溶液（150 ml)で塩基性とした。 得られた溶液を酢酸ェ チルで抽出し、 有機層を飽和食塩水で洗浄し、 無水硫酸ナトリウムで乾燥した。 濾過後濂液を濃縮し、 残澄をクロ口ホルム （15 ml)に溶解し、 室温下にてトリェ チルアミン （0.46 ml)及び 2—フヱニル安息香酸（264 mg)より調製した塩化 2— フニ二ルペンゾィルを加え、 3時間攪拌した。 反応液を飽和炭酸水素ナトリウム 水溶液、 飽和食塩水で洗浄し、 無水硫酸マグネシウムで乾燥した。 濾過後濾液を 濃縮し、 残渣をシリカゲルカラムクロマトグラフィ一 （へキサン ：酢酸ェチル =

8-dimethylamino-4- (3-methoxy-4-nitrobenzoyl) -1,5,6,7,8-tetrahydro-4H-thieno [3,2-b] Rzepin (417) obtained in step c Reduced iron (186 mg) and water (0.06 ml) were added to a solution of (mg) in acetic acid (4.0 ml), stirred at 50 for 1 hour and 40 minutes, and then reduced iron (62 mg) was added. The mixture was stirred at 5 O'C for 2 hours. The reaction solution diluted with 20 ml of chloroform was filtered through celite, and the filtrate was basified with 1N aqueous sodium hydroxide solution (150 ml). The obtained solution was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was dissolved in chloroform (15 ml). The solution was prepared from triethylamine (0.46 ml) and 2-phenylbenzoic acid (264 mg) at room temperature. Lupenzil was added and stirred for 3 hours. The reaction solution was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, the filtrate is Concentrate and concentrate the residue on silica gel column chromatography (hexane: ethyl acetate =

Purification by 1: 1) afforded the title compound (374 mg).

m p (soln.): 168.2-168.8 ° C (getyl ether)

 I R (KB r): 1665. 1635cm

NR (ά) p _Pro (CDC 13.300 MHz)

 1.70-2.03 (4H.m), 2.14-2.30 (1H, m), 2.37 (6H.s),

 3.44 (3H, s), 3.64 (1H.s) .4.05 (1H, m), 6.15 (1H, brs).

 6.78 (1H.d.J = 5.0Hz), 6.82 (1H, s). 6.90 ClH.d, J = 8.3Hz).

 7.29-7.53 (8H.m). 7.69 (1H.s). 7.81 (1H.d.J = 7.6Hz).

 8.26 (1H, d. J = 8.3Hz)

MS (M ⁺ ): 525

Example 55

 N- [2-C4-(piperazine-1 1-yl) 1 4-oxobutoxy] 1 4 1 [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-1 4 Le) carbonyl] phenyl) — [shi 1'-biphenyl] — 2-carboxami

K

実施例 4 1で得られた 4一 〔2— 〔 〔 〔し ービフエニル〕 一 2—カルボ -ル〕 ァミ ノ〕 一 5— C (5, 6, 7, 8—テトラヒ ドロー 4H—チエノ 〔3, 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フエノキン〕 酪酸 （ 1. 1 g) 及び ピぺラジン （ 1 8 9mg) を用いて、 実施例 7と同樣にして、 標題化合物 (50

Example 41 4- [2-[[[[biphenyl] -12-carboyl] amino] -1 5-C (5,6,7,8-tetrahydro 4H-thieno [3 , 2-b] azepine-14-yl) carbonyl] phenoquine] butyric acid (1.1 g) and piperazine (189 mg) in the same manner as in Example 7 to give the title compound (50

0 mg) was obtained.

mp (soln.): amorphous solid

1 R (KB r): 3408, 1636, 1522, 1262.747 cm— ¹

N R (CDC 1 a) (5 p pm:

 1.60-2.00 (9H, m), 2.46-2.29 C2H, m). 2.74-2.80 (4H, m).

 2.89-2.92 (2H.m). 3.25-3.35 (2H, m). 3.45-3.55 (2H.m).

 3.65-3.75 (2H.m). 3.70-4.00 (2H, brs). 6.19 (1H.brs) ..

 6.67-6.78 (3H.m), 7.20-7.55 (7H, m), 7.73-7.77 (2H, m),

8.26 (1H.d.J = 7.6Hz)

MS (M ⁺ ): 622

Example 56

 N— [2— [4-1- [4-pyrrolidine-1-11yl) piberidino] butoxy] 1-4 — [(5,6,7,8-tetrahydro-1-4H-thieno [3,2-b ] Azevin-41-yl) carbonyl] phenyl) — [1,1'-biphenyl] -12-carboxamide

実施例 1 4で得られた N— 〔2— （4一クロロブトキシ） — 4一 〔 （5, 6 7, 8—テトラヒ ドロー 4 H—チエノ 〔3, 2— b〕 ァゼピン一 4一ィル） カル ボニル〕 フェニル〕 一 〔 1 , 1 ' 一ビフエニル〕 一 2—カルボキサミ ド （ 5 5 9 mg) 及び 4一ピロリジノビべリジン （227 mg) を用いて、 実施例 4と同は にして、 標題化合物 （27 Omg) を得た。

N— [2-((4-chlorobutoxy)) — 4-1 ((5,6) obtained in Example 14 7,8-tetrahydro 4 H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] 1 [1,1'-biphenyl] 12-carboxamide (555 mg) and 4 The title compound (27 Omg) was obtained in the same manner as in Example 4 using 1-pyrrolidinobiveridine (227 mg).

mp (soln.): amorphous solid

IR (KBr): 3405, 2930, 1674, 1641. 1521.746 cm " ¹

NMR (CDC 1 a) 5 p pm:

 1.40-1.50 (2H, m). 1.50-1.60 (2H.m). 1.70-1.82 (2H, m).

 1.95-2.05 (2H.m), 2.29-2.56 (12H.m), 2.88-2.95 (5H.m).

 3.59-3.63 (5H.m), 3.70-4.00 (2H, brs), 6.19 (1H.brs).

 6.66 (1H.d, J = 4.8Hz), 6.70-6.81 (2H, m). 7.20-7.56 (7H.m),

7.65 (1H, s), 7.76 (1H.d.J = 7.OHz). 8.27 (1H.d, J = 7.3Hz)

MS (M ⁺ ): 676

Example 5 7

 N— [2— [4-1-1 (4- (pyrrolidine-11-yl) piperidino] -14-oxobutoxy) 1-4- [(5,6,7,8-tetrahydro-1-4H-thieno [3, 2-b] azepine-1 4-yl) carbonyl] phenyl] 1 [1, -biphenyl] 1 21 carboxamide

実施例 4 1で得られた 4一 〔2— 〔 〔 〔1, 1¹ —ビフヱニル〕 一 2—カルボ ニル〕 ァミノ〕 一 5— 〔 （5， 6, 7, 8—テトラヒ ドロ一 4H—チエノ 〔3， 2_b〕 ァゼピン一 4一ィル） カルボニル〕 フヱノキシ〕 酪酸 （554 mg) ¾ び 4一ピロリジノピペリジン （272 mg) を用いて、 実施例 7と同ぼにして、 標題化合物 （ 607 mg) を得た。

Example 4 4 one obtained in 1 [2- [[[1, 1 ¹ - Bifuweniru] one 2-carbomethoxy sulfonyl] Amino] one 5- [(5, 6, 7, 8 Tetorahi chondroitinase 4H- thieno [3,2_b] azepine- 1 -yl) carbonyl] phenoxy] butyric acid (554 mg) and 4-pyrrolidinopiperidine (272 mg) in the same manner as in Example 7 to give the title compound (607 mg) ).

mp (soln.): amorphous solid

IR (KBr): 3411, 2926, 1638, 1522. 746 cm " ¹

N R (CDC 13) (5 p pm:

 1.40-1.60 (2H.m), 1.80-1.98 (13H, m), 2.17 (1H, brs),

 2.30 (2H.t, J = 6.5Hz). 2.55-2.65 (5H, m), 2.89-1.90 (3H.m).

3.60-4.00 (4H, m) .4.41 ClH.d, J = 10.8Hz), 6.20 (1H, brs).

 6.68 (1H.d, J = 4.6Hz). 6.66 (1H.brs), 6.77 (1H, brs).

7.26-7.60 (7H, m). 7.73-7.78 (2H.m). 8.27 (1H, d, J = 7.5Hz) MS (M ⁺ ): 690

Example 58

N— [2-C4-(4-piperidinopiperidino) 1 4-oxobutoxy) 1 4 1 [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine 1 4 1-yl) carbonyl] phenyl) 1 [shi 1'-biphenyl] 1 2

実施例 4 1で得られた 4一 〔2— 〔 C 〔 1， 1 ' —ビフヱニル〕 — 2—カルボ ニル〕 ァミノ〕 一 5— 〔 （ 5, 6, 7, 8—テトラヒ ドロー 4 H—チエノ 〔3, 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フエノキン〕 酪酸 （ 5 5 4mg) 及 び 4一ピペリジノビペリジン （3 3 6 mg) を用いて、 実施例 7と同樣にして、 標題化合物 （ 6 1 2mg) を得た。

Example 41 4- (2- [C [1,1'-biphenyl] —2-carbonyl] amino] -15-[(5,6,7,8-tetrahydro 4H-thieno obtained in Example 1 [3,2-b] azepine-41-yl) carbonyl] phenoquine] butyric acid (554 mg) and 4-piperidinobiperidine (336 mg) in the same manner as in Example 7 The title compound (612 mg) was obtained.

mp (soln.): non-crystalline solid

IR (KBr): 3408, 2930. 1638. 1522. 806 cm— ¹

NMR (CDC 13) δ p p

 1.25-1.60 (7H.π, 1.77 (4Η, m), 1.91 (2H, t.J = 5.9Hz).

 1.95-2.05 (2H, m), 2.27 (2H.t.J = 6.2Hz), 2.40-2.60 (6H.m). 2.80-2.85 (3H, m), 3.60-3.80 (6H, m), 4.53 ( 1H, d, J = 10.8Hz), 6.19 (1H, brs), 6.67 (1H, d.J = 4.6Hz). 6.78 (1H, brs),

 6.80 (1H, brs), 7.26-7,60 (7H.m). 7.75-7.77 (2H.m),

 8.26 (1H.d.J = 7.0Hz)

MS (NT): 704

Example 5 9

N— [2-((4-Aminobutoxy)) 1 4-((5,6,7,8-tetrahydro-14H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl) -1 W

C 1, 1'-biphenyl] 1-2-carboxamide

実施例 2で得られた N— 〔2—ヒ ドロキシー 4一 〔 （5, 6, 7, 8—テトラ ヒ ドロー 4 H—チエノ （3, 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フエ二 ル〕 一 U , 1 ' -ビフエニル〕 一 2—カルボキサミ ド . 8 g) 及び N— ( 一プロモブチル） フタルイミ ド （ 1. 6 g) を用いて、 実施例 3と同樣の操 : を行い N— 〔2— （4一フタルイミ ドブトキン） — 4一 〔 （5, 6, 7, 8—テ トラヒ ドロ一 4 H—チエノ 〔3, 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フ ェニル〕 一 〔し 1 ' 一ビフヱニル〕 一 2—カルボキサミ ドを得た。 ついで実施 例 34と同様の操作でヒドラジン 1水和物 （5 7 Omg) を用いて、 標題化合物

N- [2-Hydroxy-41-((5,6,7,8-tetrahydro-4H-thieno (3,2-b) azepine-14-yl) carbonyl) carbonyl obtained in Example 2 2U], 1 U, 1'-biphenyl] -12-carboxamide. 8 g) and N- (1-promobutyl) phthalimid (1.6 g) were subjected to the same operation as in Example 3 to obtain N — [2— (4-phthalimidovbutkin) — 4-[(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] 1- [1'-biphenyl] -12-carboxamide was obtained. Then, in the same manner as in Example 34, hydrazine monohydrate (57 Omg) was used to give the title compound.

(72 Omg).

 mp (soln.): amorphous solid

 I R (KB r): 3397, 2926. 1643. 1523, 747 cm— '

 1.38-1.50 (4Η.m), 1.53-1.61 (2H, m), 1.70-1.82 (2H, m),

1.90-2.02 (2H, m), 2.69 (2H, t.J = 6.5Hz), 2.80-2.92 (2H. In).

3.63 (2H, t.J = 5.9Hz). 3.70-4.00 (2H.brs). 6.20 (1H.brs).

 6.66 (1H, d, J = 5.1Hz), 6.76 (1H, s). 6.82 (1H. D. J = 7.6Hz).

7.20-1 7.60 (8H, m) .7.75-1 7.85 (1H.m) .8.28 (1H.d, J = 7.6Hz) MS (M ⁺ ): 539

Example 6 0

 N- [2-Methoxy-41-((5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] -12-methylbenzamide

実施例 1の工程 cで得られた 4一 （3—メ トキシー 4一二トロベンブイル） 一 5 , 6, 7, 8—テ トラヒ ドロー 4 H—チエノ 〔3， 2— b〕 ァゼピン （2. 0 0 g) を、 テトラヒ ドロフラン （20m l ) に溶解した後、 水 （ 1 Om 1 ) 、 塩 化アンモニゥム （ 1 6mg) 、 及び、 還元鉄 （8 4 Omg) を加え、 加熱還流下 5 Bき間攪拌した。 反応液に、 セライ ト （2 g) を加え、 室温下 30分攪拌後、 紙濾過し、 残渣をテトラヒ ドロフラン （ 1 0m l ) で洗った。 滤液と洗液を合わ せた後、 炭酸力リウム （ 1. 5 0 g) を加え、 室温下攪拌し溶解させた。 腿液 に、 塩化 2—トルオイル （ 1. 1 2 g) のテトラヒ ドロフラン （4m l ) 溶液を 加え、 室温下 1時間攢拌した。 反応液を、 有機層と水層に分層し、 有機層を 1 N —水酸化ナトリゥ厶水溶液にて洗浄後、 水洗し、 無水硫酸ナトリウムで乾燥後、 減 E下溶媒留去した。 得られた残渣を、 トルエン一へキサンにて再結晶し、 標題 化合物 （2. 3 0 g) を得た。

4- (3-Methoxy 412 trobenbuyl) -1,5,6,7,8-tetrahdro 4H-thieno [3,2-b] azepine (2.0) obtained in step c of Example 1 0 g) was dissolved in tetrahydrofuran (20 ml), water (1 Om 1), ammonium chloride (16 mg), and reduced iron (84 Omg) were added. Stirred. Cerite (2 g) was added to the reaction solution, stirred at room temperature for 30 minutes, filtered through paper, and the residue was washed with tetrahydrofuran (10 ml). After the solution and the washing solution were combined, lithium carbonate (1.50 g) was added, and the mixture was stirred and dissolved at room temperature. A solution of 2-toluoyl chloride (1.12 g) in tetrahydrofuran (4 ml) was added to the thigh fluid, and the mixture was stirred at room temperature for 1 hour. The reaction solution was separated into an organic layer and an aqueous layer, and the organic layer was washed with a 1 N aqueous solution of sodium hydroxide, washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was recrystallized from toluene-hexane to give the title compound (2.30 g).

mp (soln.): 122.5-124.5 ° C (toluene-hexane) IR (KB r): 1689, 1642. 1522. 1409, 1377 cm— ¹

 1.70-1.90 (2H.m). 1.90-2.10 (2H.m), 2.50 (3H.s),

 2.95 (2H, t. J = 4.8Hz). 3.70-4.10 (5H, m). 6.27 (1H, br).

 6.71 (1H, d.J = 5.3Hz). 6.85-7.00 (2H.m) .7.20-1 7.40 (3H.m), 7.49 (1H.d, J = 7.4Hz) .8.11 (1H, br), 8.37 (1H.br)

MS (M ⁺ ): 420

Example 6 1

 N— [2-Hydroxy 4 -— ((5,6,7,8-tetrahydro 4 H—Cheno [3,2-b] azepine-14-yl) carbonyl] phenyl) -12-Methylbenzamide

実施例 6 0で得られた N— 〔2—メ トキシー 4一 〔 （ 5， 6， 7, 8—テトラ ヒ ド□— 4 H—チエノ 〔3, 2— b〕 ァゼビン一 4一ィル） カルボニル〕 フエ二 ル〕 一 2—メチルベンズァミ ド （ 2. 3 0 g) に、 ァセ トニトリル （ 2 3m 1 ) 、 及び、 ヨウ化ナトリウム （2. 0 5 g) を加え、 室温下攪拌し溶解させた。 溶 解液を、 氷浴下 1 0分攪拌した後、 塩化アルミニウム （2. 5 6 g) を加え、 6 0 C加熱下 3時間攪拌した。 反応液を、 氷浴下 3 0分攪拌した後、 氷 （25 g) を加え、 室温下 3 0分攪拌して粗結晶を折出させた後、 濃塩酸 （ 2m l ) 加え、 更に、 室温下 3 0分攪拌した。 析出した粗結晶を據紙據取し、 水 （25m 1 ) で 洗った後、 テトラヒドロフラン— トルエンにて再結晶し、 標題化合物 （2. 08 g) を得た。

N- [2-Methoxy41- (5,6,7,8-tetrahydro □ -4H-thieno [3,2-b] azebin-14yl obtained in Example 60) To carbonyl] phenyl] -12-methylbenzamide (2.30 g) were added acetonitrile (23 ml) and sodium iodide (2.05 g), and the mixture was stirred at room temperature to dissolve. Was. The solution was stirred for 10 minutes in an ice bath, aluminum chloride (2.56 g) was added, and the mixture was stirred at 60 C for 3 hours. The reaction solution was stirred in an ice bath for 30 minutes, ice (25 g) was added, and the mixture was stirred at room temperature for 30 minutes to precipitate crude crystals, and concentrated hydrochloric acid (2 ml) was added. Further, the mixture was stirred at room temperature for 30 minutes. The precipitated crude crystals were collected, washed with water (25 ml), and recrystallized from tetrahydrofuran-toluene to obtain the title compound (2.08 g).

mp (soln.): 220.5-222.5 'C (tetrahydrofuran-toluene)

IR (KBr): 1672, 1618. 1504, 1429. 1395 cm " ¹

 NMR (CDC 13) 5 p pm:

 1.60-1.90 (2H, m), 1.90-2.10 (2H, m), 2.48 (3H, s).

 2.91 (2H.t.J = 4.8Hz), 3.60-4.10 (2H.m). 6.27 ClH.br),

 6.57 (1H.d.J = 7.5Hz). 6.70 (1H.d.J = 4.5Hz), 7.15-1.40 (3H, m),

7.46 (1H.d.J = 7.8Hz), 7.75 (1H.br), 8.19 (1H.br). 9.27 (1H.br)

MS (M +): 406

Example 62

 4- [2- (2-Methylbenzamide) -15-[(5,6,7,8-Tetrahydro 4H-thieno [3,2-b] azepine-14yl) carbonyl] phenoxy Butyric acid

実施例 6 1で得られた N— 〔2—ヒ ドロキジ一 4— 〔 （ 5, 6, 7, 8—テト ラヒ ドロー 4 H—チエノ 〔3, 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フエ ニル〕 一 2—メチルベンズアミ ド （ 1. 0 0 g) に、 4—ブロモ— n—酪酸ェチ ル （ 0. 64 g：) 、 炭酸力リウ厶 （0. 68 g：) 、 ヨウ化カリウム （0. 4 1 g ) 、 及び、 アセ トン （50m l) を加え、 加熱還流下 7時間攪拌した。 反応液を セライ ト濾過し、 残渣をアセ トン （50m l ) にて洗い、 滤液と洗液を合わせた 後、 減 E下溶媒留去した。 得られる濃縮残渣を、 クロ口ホルム （ 1 00m l ) に 溶解し、 水洗、 無水硫酸ナトリウム乾燥後、 減圧下溶媒留去した。 得られた残 ¾ に、 エタノール （45m 1 ) 、 及び、 4 N—水酸化ナトリウム水溶液を加え、 6 8 'C加熱下 3時間攪拌した。 反応液を減圧下溶媒留去後、 水 （50m l ) を加え 、 ェチルエーテルにて洗浄後、 2N -塩酸にて pH 1に調整し、 析出した粗結晶 を據紙據取し、 水 （25m l) で洗った。 得られた粗結晶を、 クロ口ホルム （5 0m l ) に溶解させ、 有機層と水層に分層し、 有機層を無水硫酸ナト リウムで乾 燥後、 減圧下溶媒留去した。 得られた残渣を、 トルエン一へキサンにて再結晶し 、 標題化合物 （し 20 g) を得た。

Example 6 N— [2-Hydroxydi-4-((5,6,7,8-TetrahiDraw 4H—thieno [3,2-b] azepine-14-yl) carbonyl obtained in 1) carbonyl [Phenyl]] 1-methylbenzamide (1.00 g) is added to 4-bromo-n-butyric acid (0.64 g :), lithium carbonate (0.68 g :), potassium iodide (0.41 g), and acetone (50 ml) were added, and the mixture was stirred under heating and reflux for 7 hours. . The reaction solution was filtered through celite, and the residue was washed with acetone (50 ml). The combined solution and washing solution were evaporated, and the solvent was distilled off under reduced pressure. The resulting concentrated residue was dissolved in chloroform (100 ml), washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (45 ml) and a 4N aqueous solution of sodium hydroxide were added to the obtained residue, and the mixture was stirred under heating at 68'C for 3 hours. After evaporating the solvent of the reaction solution under reduced pressure, water (50 ml) was added, the mixture was washed with ethyl ether, adjusted to pH 1 with 2N-hydrochloric acid, and the precipitated crude crystals were collected on a paper. ) And washed. The obtained crude crystals were dissolved in chloroform (50 ml), and the organic and aqueous layers were separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from toluene-hexane to give the title compound (20 g).

m p (soln.): 148.0-150.0 'C (toluene-hexane)

IR (KBr): 1705. 1682, 1642, 1526, 1425, 1383 cm " ¹

NMR (CDC 13) ά p pm:

 1.70― 1.90 (2H.m). 1.90― 2.15 (4H, m), 2.46 (2H.t, J = 7.5Hz) .2.51 (3H, s), 2.94 (2H, t, J = 6.OHz), 2.60-4.10 (4H.m),

 6.25 (1H.br), 6.70 (1H.d, J = 5.4Hz). 6.89 (1H, d.J = 7.8Hz),

 6.97 (1H.br). 7.10-7.40 (4H, m). 7.49 (1H.d.J = 6.6Hz),

 8.13 (1H, s), 8.34 (1H, s)

MS (M ⁺ ): 492

Example 63

N—C 2-[4- (4-dimethylaminobiperidine-11-yl) -14-oxobutoxy] 1-4- [(5,6,7,8-tetrahydro-14H-thieno [3,2-b Azebin-41-yl) carbonyl] phenyl] -1-methylbenzamide

実施例 6 2で得られた 4一 C2 - (2一メチルベンズァミ ド） 一 5 - 〔 （ 5, 6, 7, 8—テトラヒ ドロー 4 H—チエノ 〔3, 2— b〕 ァゼビン一 4—ィル） カルボニル〕 フエノキシ〕 酷酸 （ 6 0 Omg) に、 4ージメチルアミノビベリジ ン 2塩酸塩 （2 7 Omg)、 N, N—ビス （2—ォキソ一 3—ォキサゾリジニル ) ホスフィ ン酸 クロリ ド （ 3 7 5 mg) 、 卜 リエチルァミ ン （ 6 2 Omg) 、 及び、 クロ口ホルム （ 1 0 0m l ) を加え、 室温下一週間攬拌した。 反応液を^ EE下溶媒留去して得られる残澄を、 クロ口ホルム （ 1 0 0m l ) に溶 し、 水洗 後、 無水硫酸ナトリウム乾燥後、 減圧下溶媒留去した。 得られた残渣を、 シリカ ゲルカラムクロマトグラフィー （クロ口ホルム ： メタノール = 9 5 ： 5) を用い て精製し、 標題化合物 （2 5 Omg) を得た。

Example 6 4-C2- (2-Methylbenzamide) -15-[(5,6,7,8-tetrahydro4H-thieno [3,2-b] azebine-14-yl obtained in 2) ) Carbonyl] phenoxy] severe acid (60 Omg), 4-dimethylaminobiberidine dihydrochloride (27 Omg), N, N-bis (2-oxo-13-oxazolidinyl) phosphinic acid chloride (375 mg), triethylamine (62 Omg), and chloroform (100 ml) were added, and the mixture was stirred at room temperature for one week. The residue obtained by evaporating the solvent of the reaction solution under ^ EE was dissolved in chloroform (100 ml), washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (cloth form: methanol = 95: 5) to give the title compound (25 Omg).

mp (soln.): non-crystalline solid

IR (KB r): 1676. 1637, 1523, 1423, 1380 cm " ¹

 1.70-1.90 (4Η, m), 1.90-2.20 (4H.m). 2.20-2.70 (15H, m),

2.85-3.05 (3H.m), 3.60-4.10 (5H.m). 4.39 (1H, d.J = 14.1Hz).

6.26 (1H, br). 6.71 (1H.d.J = 5.1Hz), 6.90 (1H.d.J = 8.1Hz).

 6.96 (1H, s), 7.20-7.40 (3H, m), 7.51 (1H.d, J = 7.2Hz).

8.28 (1H.s). 8.35 (1H.br) MS (M +): 602

Example 6 4

 -(3-methoxy-4,12,5,6,8-tetrahydro 4H-flow [3,2-b] azebin

6,7-Dihidro 5H-Venzo [b] Furan-41-Oxoxime (4.53 g) and 3-Methoxy-4,2-nitrobenzoic acid (5.90 g) The title compound (4.31) was obtained in the same manner as in Step b and Step c of Example 1.

mp (soln.): colorless crystal, 122.5-124.0 ° C (EtOH)

IR (KBr): 1644, 1522 cm— ¹

NMR (CDC 13) ά p pm, 300 Hz:

 1.75-1.85 (2H.m), 1.95-2.10 (2H.m). 2.85-2.95 (2H, m),

3.90 (3H.s), 4.00-4.05 (2H.m), 5.56 (1H, s).

 6.90-7,00 (2H.ra), 7.19 (1H, s), 7.65-7.75 (1H.m)

MS (M ⁺ ): 316

Example 6 5

N- [2-Methoxy41-[(5,6,7,8-tetrahydro-4H-furo [3,2-b] azepine-14-yl) carbonyl] phenyl] -1- [1, -biphenyl 1-2-Carboxamide

実施例 64で得られた 4一 （3—メ トキシー 4一二トロべンゾィル） - 5, 6 , 7, 8—テトラヒドロー 4H—フロ 〔3, 2— b〕 ァゼビン （4. 00 g) 及 び 2—フヱニル安息香酸 （ 1. 1 6 g) を用いて、 実施例 1工程 dと同様にして 、 標題化合物 （2. 03 g) を得た。

4- (3-Methoxy-412-trobenzyl) obtained in Example 64-5,6,7,8-tetrahydro-4H-furo [3,2-b] azebine (4.00 g) and The title compound (2.03 g) was obtained in the same manner as in Example 1, step d, using 2-phenylbenzoic acid (1.16 g).

mp (soln.): colorless amorphous solid

IR (KBr): 1627, 1596, 1523 cm " ¹

N R (CDC 13) <5 p pm, 300 MHz:

 1.70-1.80 (2H, m), 1.85-2.10 (2H.m). 2.85-2.90 (2H.m).

 3.49 (3H.s). 3.80-3.90 (2H.m). 5.60 (1H.brs).

 6.85-7.00 (3H.m). 7.30-7.55 (8H, m). 7.71 (1H, s).

 7.85 (1H, dd, J = 1.5, 7.8Hz). 8.32 (1H.d, J = 8.1Hz)

MS (M +): 466

Example 66

N- [2-Hydroxy-4-([5,6,7,8-tetrahydro-4H-furo [3,2-b] azepin-4-yl) carbonyl] phenyl] 1 [shi-biphenyl] —2 —Carboxamide

実施例 6 5で得られた N— 〔2—メ トキシー 4一 〔 （5, 6, 7, 8—テトラ ヒ ドロ一 4 H—フロ 〔3, 2— b〕 ァゼピン一 4—ィル） カルボニル〕 フエニル 〕 ー 〔 1 , 1 ' ービフエニル〕 一 2—カルボキサミ ド （2. 0 1 g) を用いて、 実施例 2と同様にして、 標題化合物 （ 1. 8 3 g) を得た。

N- [2-Methoxy41- (5,6,7,8-tetrahydro-4H-furo [3,2-b] azepine-14-yl) carbonyl obtained in Example 6 5 [Phenyl]-[1,1'-biphenyl] -12-carboxamide (2.01 g) was obtained in the same manner as in Example 2 to obtain the title compound (1.83 g).

mp (soln.): colorless amorphous solid

NMR (DMS 0- d ₆ ) ά p pm, 300 MHz:

 1.60-1.75 (2Ηm). 1.80-1.95 (2H.m), 2.75-2.90 (2H.m).

 3.65-3.80 (2H.m), 5.73 (1H.brs). 6.74 (1H, d, J = 7.5Hz).

 6.81 (1H.s), 7.18 (1H, s). 7.30-7.65 (10H, m), 9.14 (1H, s).

9.91 (1H, s)

MS (M ⁺ ): 452

Example 6 7

4- (2-C [[1, -biphenyl] -12-carbonyl] amino] -15-[(5,6,7,8-tetrahydro-14H-flo [3,2-b] azepin-4 I-yl) carbonyl] phenoquine] butylate

実施例 66で得られた N— 〔2—ヒ ドロキシー 4— ( ( 5, 6， 7, 8—テト ラヒ ドロ一 4H—フロ 〔3, 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フエ二 ル〕 一 〔 1 , 一ビフエ二ル〕 一 2—カルボキサミ ド （ 1. 80 g) 及び 4一 ブロモブ夕ン酸ェチルエステル （ 0. 74m l ) を用いて、 実施例 3と同様にし て、 標題化合物 （2. 1 3 g) を得た。

N- [2-Hydroxy 4-((5,6,7,8-tetrahydro-1-4H-furo [3,2-b] azepine-14-yl) carbonyl) carbonyl obtained in Example 66 The title compound was prepared in the same manner as in Example 3 using 1- [1,1-biphenyl) -12-carboxamide (1.80 g) and 4-bromobutenoic acid ethyl ester (0.74 ml). The compound (2.13 g) was obtained.

mp (soln.): colorless amorphous solid

IR (KBr): 1732. 1646, 1598, 1523 cm " ¹

NMR (CDC 1 a) (5 ppm, 30 OMH z:

 1.24 (3H.t.J = 7.lHz). 1.65-1.75 (2H, m), 1.80-1.95 (4H, m), 2.29 (2H.t.J = 7.3Hz), 2.80-1.90 (2H.m ). 3.75 (2H.t, J = 6.2Hz), 3.85 (2H.brs), 4.08 (2H.q.J = 7.1Hz). 5.56 (1H, brs).

 6.80-6.95 (3H.m), 7.25-7.65 (8H, m), 7.69 (1H, s),

 7.79 (1H, d. J = 7.6Hz). 8.35 (1H, d. J = 8.4Hz)

MS (M ⁺ ): 566

Example 68

4- [2-[[[[1, -biphenyl] -12-carbonyl] amino] -5-[(5,6,7,8-tetrahydro 4H-flow [3,2-b] azebin-1 4- Le) carbonyl] phenokine] butyric acid

実施例 67で得られたェチル 4一 〔2— 〔 〔 〔1, 1 ' —ビフヱニル〕 一 2 一カルボニル〕 ァミ ノ〕 一 5— 〔 （ 5, 6, 7, 8—テトラヒ ドロー 4 H—フロ 〔3， 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フエノキシ〕 プチレート （2 . 1 0 g) を用いて、 実施例 6と同様にして、 標題化合物 （ 1. 75 g) を得た o

Etyl 4- [2-[[[1,1'-biphenyl] -12-carbonyl] amino] -15-[(5,6,7,8-tetrahydro 4H— obtained in Example 67 The title compound (1.75 g) was obtained in the same manner as in Example 6 using furo [3,2-b] azepine-14-yl) carbonyl] phenoxy] butyrate (2.10 g). o

m p (soln.): colorless crystals, 202,5-203.5 ° C (2-propanol)

IR (KBr): 1720, 1649, 1526 cm " ¹

 NMR (CDC 13) (5 ppm, 300 MHz:

 1.70-1.80 (2H.m) .1.85-2.00 (4H.m), 2.34 (2H, t, J = 7.4Hz), 2.80― 2.90 (2H, m). 3.78 (2H.t.J = 6.2Hz) , 3.85 (2H, brs),

 5.58 (1H.brs). 6.85-6.95 (3H.m), 7.25-7.60 (8H.m).

 7.67 (1H, s), 7.78 (1H.d.J = 7.8Hz), 8.35 (1H.d, J = 8.4Hz)

 MS (M +): 538

Example 69

N- [2-[[4- (4-dimethylaminobiperidino) -1-4-oxobutokin]--C (5,6,7,8-tetrahydro-1H-Flo [3,2-b] azebin-4-1y Carbonyl) phenyl) 1- [1,1'-biphenyl] 1-2-carboxamide 97/17349

実施例 68で得られた 4一 〔2— 〔 〔 〔1， 1 ' -ビフエニル〕 一 2—カルボ ニル〕 ァミノ〕 一 5— 〔 （ 5, 6, 7. 8—テトラヒ ド口一 4H—フロ （3, 2 一 b〕 ァゼピン- 4—ィル） カルボニル〕 フエノキシ〕 酪酸 （し 0 O g) 及び 4—ジメチルアミノビペリジン （286 mg) を用いて、 実施例 7と同樣にして 、 標題化合物 （ 1. 1 7 g) を得た。

4- (2-[[[[1,1'-biphenyl] -12-carbonyl] amino] -15-[(5,6,7.8-tetrahydric acid obtained in Example 68) (3,2-b) azepine-4-yl) carbonyl] phenoxy] butyric acid (0 Og) and 4-dimethylaminobiperidine (286 mg) in the same manner as in Example 7, The compound (1.17 g) was obtained.

 [0000]

mp (soln.): colorless amorphous solid

IR (KB r): 3404. 1642, 1522 cm ' ¹

NMR (CDC 13) δ p pm, 30 ΟΜΗζ:

 1.20-1.40 (2 π, 1.70-1.85 (4Η, m). 1.85-2.00 (4H, m), 2.27 (6H, s). 2.25-2.40 (3H, m), 2.45-2.60 (1H, m),

 2.80-3.00 (3H, m), 3.70-3.90 (5H, m), 4.50 (1H, d.J = 12.3Hz), 5.60 (1H, brs) .6.85-6.90 (3H, m), 7.25-7.60 ( 8H.m).

 7.75-7.80 (2H, m), 8.33 (1H.d, J = 8.7Hz)

MS (M ⁺ ): 648

Example 70

4-1 (2-methoxy 412 trobenbuyl) -1,5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine

Example 1 using 6,7-dihydro-5H-benzo [b] thiophene 4-oxoxime (3.27 g) and 2-methoxy 4-fluorobenzoic acid (3886 g). The title compound (482 g) was obtained in the same manner as in Steps b and c of Step 1.

m p (soln.): colorless crystal, 138.5-140.0 ° C (EtOH)

IR (KBr): 1649, 1524 cm ' ¹

N R (CD C 1 a) δ p pm, 300 MHz:

 1.70-1.85 (2H, m) .2.00-2.10 (2H.m). 2.85-2.95 (2H.m).

 3.77 (3H, s), 3.70 ― 4.00 (2H, brs). 6.24 (1H.d.J = 5.4Hz).

 6.58 (1H, d. J = 5.4Hz), 7.35 (1H, d. J = 8. LHz). 7.56 (1H. D. J = 1.8Hz).

7.76 (1H, dd, J = 1.8, 8.1Hz)

MS (M ⁺ ): 332

Example 7 1

N— (3-Methoxy-1-41 [(5,6,7,8-Tetrahydro 4H-thieno [3,2-b) azepine-14-yl) carbonyl] phenyl] -1 [1,1, ' -Biphenyl] 1-2-carboxamide 97/17349

実施例 70で得られた 4一 （2—メ トキシ— 4—ニトロベンブイル） 一 5, 6

4- (2-Methoxy-4-nitrobenvyl) -1,5,6 obtained in Example 70

Using 1,7,8-tetrahydro-4H-thieno [3,2-b] azepine (4.65 g) and 2-phenylbenzoic acid (3.33 g) in the same manner as in step d of Example 1 The title compound (5.53 g) was obtained.

mp (soln.): colorless amorphous solid (amorphous)

IR (KBr): 3292. 1680, 1602 cm " ¹

 NMR (CDC 13) δ ρ pm, 300 MHz:

 1.65-1.80 (2H.m), 1.90-2.05 (2H, m), 2.80-2.90 (2H, m), 3.50 (1H.brs) .3.55 (3H, s) .3.72 (1H, brs). 6.18 ( 1H.d.J = 5.4Hz), 6.25 (1H.d, J = 8.1Hz), 6.53 (1H, d, J = 5.4Hz), 6.90 ― 7.00 (3H, m). 7.30-7.60 (7H.m ). 7.85 (1H, d, J = 7.5Hz)

 MS (M +): 482

Example 7 2

N— [3-Hydroxy 4 — [(5,6,7,8-Tetrahydro 4H—Cheno [3,2-b] azepine-1 4-yl) carbonyl] phenyl] 1 Biphenyl) 1-2-Carboxamide

実施例 71で得られた N— 〔3—メ トキシー 4一 〔 （5, 6, 7, 8—テトラ ヒ ドロー 4 H—チエノ （3. 2— b〕 ァゼビン一 4—ィル） カルボニル〕 フエ二 ル〕 — U , 1 ' -ビフエニル〕 ― 2—カルボキサミ ド （ 3. 00 g) を用いて 、 実施例 2と同様にして、 標題化合物 （2. 58 g) を得た。

N- [3-Methoxy-41-((5,6,7,8-tetrahydro-4H-thieno (3.2-b) azebin-14-yl) carbonyl] phen obtained in Example 71 The title compound (2.58 g) was obtained in the same manner as in Example 2 using (2,1) -U, 1'-biphenyl] -2-carboxamide (3.00 g).

mp (soln.): colorless crystal, 216.5-218.0 ^e C (E "0)

 I R (K B r): 3447. 1614 cm "'

NMR (CDC 13) ά p pm, 300 MHz:

 1.70-1.80 (2H, m). 1.90-2.05 (2H.m). 2.90-2.95 (2H.m),

3.50-4.50 (2H, brs), 6.35 (1H, d.J = 5.1Hz), 6.40-6.70 (3H.m).

6.79 (1H, d.J = 5.1Hz), 6.84 (1H, s), 7.35-7.60 (8H.m).

 7.86 (1H, d. J = 7.5Hz), 11.17 (1H, s)

MS (M ⁺ ): 468

Example 73

 Ethyl 41-[[-[[[1,1 * -biphenyl]-2-carbonyl] amino] 1-2-[(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine I 41-yl) carbonyl] phenyl) butylate

1 3 g 97/17349

実施例 72で得られた N— 〔3—ヒ ドロキン— 4一 〔 （ 5, 6, 7, 8—テト ラヒ ドロー 4 H—チエノ 〔3, 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フエ ニル〕 一 U, Γ —ビフエ二ル〕 — 2—カルボキサミ ド （ 1. 50g)及び 4 —プロモブ夕ン酸ェチルエステル （0. 60m 1 ) を用いて、 実施例 3と同 に して、 標題化合物 （ 1. 42 g) を得た。

N- [3-Hydroquine-4-1 obtained in Example 72 [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-14-yl) carbonyl] [Phenyl] -U, Γ-biphenyl] — 2-carboxamide (1.50 g) and 4-promobutenoic acid ethyl ester (0.60 m 1) in the same manner as in Example 3 using the title The compound (1.42 g) was obtained.

mp (soln.): colorless crystal, 83.5-85.5 ^e C (EtOH)

IR (KBr): 1731. 1602, 1527 cm " ¹

NMR (CDC 13) (5 ppm, 30 OMH z:

 1.27 (3H, t.J = 7.2Hz), 1.70-1.85 (2H, m). 1.90-2.10 (4H, m),

2.47 (2H, t.J = 7.4Hz). 2.80-2.90 (2H.m), 3.82 (1H.brs).

 3.88 (2H.t, J = 6.2Hz), 4.02 (1H, brs). 4.15 (2H, q, J = 7.2Hz).

 6.21 (1H.d.J = 8.1Hz). 6.25 (1H.d, J = 5.1Hz), 6.56 (1H.d, J = 5.1Hz).

6.82 (1H, s), 6.89 (1H, d, J = 8.1Hz). 6.92 (1H, s).

 7.30-7.60 (8H, m). 7.87 (1H, d. J = 7.5Hz)

MS (M ⁺ ): 582

Example 74

4- [3-[[[[1,1-biphenyl] 1-2-carbonyl] amino] -16-[(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azebine-1 4 Yl) carbonyl] phenyl) butyric acid

実施例 7 3で得られたェチル 4一 〔5— 〔 〔 〔 1 , 1 ' 一ビフヱニル〕 一 2 —カルボニル〕 ァミ ノ〕 一 2— 〔 （ 5, 6, 7, 8—テトラヒ ドロー 4 H—チェ ノ （3, 2— b〕 ァゼビン一 4一ィル） カルボニル〕 フエノキン〕 プチレー ト （ 1 - 4 0 g) を用いて、 実施例 6と同様にして、 標題化合物 （ 1. 3 8 g) を得 た。

Ethyl 41-[[[[[1,1,1'-biphenyl] -12-carbonyl] amino] -12-[(5,6,7,8-tetrahydro 4H obtained in Example 7 —Ceno (3,2—b) azevin-41-yl) carbonyl] phenoquine] petitate (1-40 g) in the same manner as in Example 6 to give the title compound (1.38 g) ) Was obtained.

mp (soln.): colorless crystal, 150.0-152.5 'C (CHC)

IR (KBr): 1729.1600.1527 cm— ¹

 NMR (CDC 1 a) δ ρ pm, 300 MHz:

 1.70-1.85 (2H, m). 1.90-2.10 (4H, m), 2.47 (2H, t, J = 7.OHz), 2.75-2.90 (2H, m), 3.83 (2H.t, J = 5.9Hz ), 4.0-5.0 (2H.brs), 6.20-6.25 (1H, m), 6.27 (1H.d, J = 5.4Hz) .6.58 (1H.d, J = 5.4Hz). 6.77 (1H.d, J = 8.lHz), 6.90-7.60 (10H, m), 7.75 (1H, d, J = 7.4Hz)

MS (M +): 554

Example 7 5

N— [3— (4- (4-dimethylaminobiperidino) 14-oxobutoxy) 1-41 [(5,6,7,8-tetrahydro o—4H-thieno [3.2-b] azebine 4- (yl) carbonyl] phenyl] 1- (1,1'-biphenyl) 1-2-cal 97/17349

Boxamide

実施例 74で得られた 4一 〔5— 〔 〔 〔1, Γ 一ビフヱニル〕 一 2—カルボ ニル〕 ァミノ〕 一 2— C ( 5, 6, 7, 8—テトラヒ ドロー 4H-チエノ 〔3, 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フエノキン〕 酪酸 （1. 38 g) 及 び 4ージメチルァミノピぺリジン （37 Omg) を用いて、 実施例 7と同樣にし て、 標題化合物 （ 1. 1 4 g) を得た。

4- [5-[[[[1,1-biphenyl] -12-carbonyl] amino] -12-C (5,6,7,8-tetrahydro 4H-thieno [3, 2-b] azepine-41-yl) carbonyl] phenoquine] butyric acid (1.38 g) and 4-dimethylaminopiperidine (37 Omg) in the same manner as in Example 7 to give the title compound (1.14 g) was obtained.

mp (soln.): colorless amorphous solid

IR (KBr): 3468, 1638, 1527 cnT ¹

NMR (CDC 13) δ p pm, 300 MHz:

 1.20-1.35 (2H, m), 1.65-1.80 (4H, m), 1.80-2.00 (4H, m).

 2.20 (6H.s), 2.30-2.40 (1H, m), 2.43 (2H, t, J = 7.1Hz).

 2.70-2.90 (4H.m) .3.55-3.65 (2H.m). 3.90 (2H.t, J = 6.5Hz).

4.00-4.20 (2H, brs) .6.52 (1H, brs). 6.87 (1H.d, J = 5.1Hz).

 6.90-7.00 (2H, m), 7.10 (1H.s), 7.25-7.60 (9H.m).

 9.66 (1H.s)

MS (M ⁺ ): 664

Example 76

4-I (3-Methoxy 4-Nitrobenzoyl) I 5,6,7,8-Tetrahydrid Rho 1 H-pyro mouth. [3,2-b] azebine

3-Methoxy 4-nitrobenzoic acid (4.33 g), thionyl chloride (1.75 ml), toluene (2 Om I), N, N-dimethylformamide (0.1 ml) After the mixture was refluxed for 3 hours, the mixture was concentrated under reduced pressure to obtain an acid chloride.

 On the other hand, 6,7-dihydro-5H-benzo [b] pyruro 4-oxo

(3.00 g), under an argon atmosphere, anhydrous toluene (301) was added, and diisobutylaluminum hydride (100m in a 1.0M toluene solution) was added dropwise under ice cooling, and the mixture was stirred for 3 hours. did. This reaction solution was added dropwise to a 4 N aqueous solution of sodium hydroxide (5Οπ) under ice-cooling, and after stirring for 30 minutes, toluene was added, and the mixture was washed successively with water and a saturated aqueous solution of sodium chloride. The concentration was reduced to about 200 ml. To this was added a solution of triethylamine (4.2 ml) and the toluene (1 Oml) solution of the acid chloride prepared above under ice-cooling, followed by stirring at room temperature for 12 hours. The reaction mixture was evaporated under reduced pressure, the solution was distilled off, and chloroform was added. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate = 2: 1) to give the title compound (1.59 g). mp (soln.): colorless crystal, 199.5-200.5 (CHC-hexane)

IR (KB r): 3236. 1629. 1608 cm ' ¹

NMR (CDC 1 a) (5 ppm, 300 MHz:

1.70-1.85 (2H, m) .1.95-2.10 (2H, m) .2.70-2.75 (2H.m), 3.86 (3H.s), 3.85-3.95 (2H, m), 5.35-5.40 (1H, m ), 97/17349

6.20-6.25 (1H.m), 6.88 (1H.dd, J = 1.2.8.3Hz),

 7.14 (1H.d.J = 1.2Hz). 7.65 (1H, d.J = 8.3Hz). 7.80 (1H, brs)

 MS (M +): 315

Example 7 7

 4- (3-Methoxy-412-trobenzyl) 1-1-Methyl-5,6,7,8-Tetrahydro 1 H-pyro mouth [3,2-b] azepine

実施例 76で得られた 4一 （3—メ トキシー 4一二トロべンゾィル） 一 5. 6 , 7, 8—テトラヒ ドロー 1 H—ピロ口 〔3, 2— b〕 ァゼビン （2. 20 g) をテ トラヒ ドロフラン （ 1 5m l ) と N, N—ジメチルホル厶ァミ ド （ 1 m 1 ) に溶かし、 氷冷下、 水素化ナト リウム （ 3 35mg、 6 0 %鉱油分散物） を加え 、 1 0分攪拌した後、 よう化メチル （0. 8 7 m I ) を加え、 室温にて 64時問 攪拌した。 反応液にクロ口ホルムを加え、 水、 飽和食塩水で順次洗浄し、 無水硫 酸マグネシウムで乾燥後、 溶媒を減圧下留去し、 得られた残渣をシリカゲルカラ ムクロマトグラフィー （溶出溶媒：へキサン一酢酸ェチル = 5 ： 2) により精製 し、 標題化合物 （に 9 7 g) を得た。

4- (3-Methoxy-412-trobenzyl) obtained in Example 76-15.6,7,8-Tetrahydro 1H-pyro mouth [3,2-b] azebin (2.20 g) ) Was dissolved in tetrahydrofuran (15 ml) and N, N-dimethylformamide (1 ml), and sodium hydride (335 mg, 60% mineral oil dispersion) was added under ice-cooling. After stirring for 10 minutes, methyl iodide (0.87 mI) was added, and the mixture was stirred at room temperature for 64 hours. To the reaction mixture was added chloroform, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: Purification by ethyl ethyl acetate = 5: 2) gave the title compound (97 g).

mp (so): colorless crystal, 120.0-12.0. C (Ε 0)

IR (KBr): 1639, 1607 cm " ¹

NMR (CDC 13) δ ρ pm, 300 MHz:

 1.70-1.85 (2H.m), 1.95-2.10 (2H.m). 2.70-2.80 (2H, m),

3.49 (3Ηs), 3.87 (3H, s), 3.90-4.10 (2H, m),

5.27 (1H.d, J = 3.0Hz), 6.11 (1H.d, J = 3.0Hz), 97/17349

6.86 (1H.dd..J = 1.5, 8.4Hz), 7.16 (1H, d, J = 1.5Hz).

 7.65 (1H.d, J = 8.4Hz)

MS (M: 329

Example 78

 N— [2-Methoxy-1 4-— ((1-Methyl-5,6,7,8-tetrahydro 1 H-pyro [3,2-b) azepine-14-yl) carbonyl] phenyl] -1 [1 , 1'-biphenyl] -1-2-carboxamide

実施例 77で得られた 4— ( 3—メ トキシー 4一二トロべンゾィル） — 1—メ チルー 5, 6, 7, 8—テトラヒ ドロー 1 H-ピロ口 〔3， 2— b〕 ァゼピン （ 1 - 90 g)及び 2—フヱニル安息香酸 （し 37 g) を用いて、 実施例 1工程 dと同様にして、 標題化合物 （2. 20 g) を得た。

4- (3-Methoxy-412-trobenzyl) obtained in Example 77—1-Methyl-5,6,7,8-tetrahydro 1H-pyro mouth [3,2-b] azepine ( Using 1-90 g) and 2-phenylbenzoic acid (37 g), the title compound (2.20 g) was obtained in the same manner as in Example 1, step d.

m p (soln.): oil

IR (KB r): 3403. 1673, 1630 cm- ¹

NMR (CDC 13) 5 ppm, 300 MHz:

 1.70-1.85 (2H.m), 1.90-2.00 (2H, m), 2.70-2.80 (2H, m), 3.47 (3H.s), 3.48 (3H, s). 3.86 (2H.brs). 5.25 ( 1H, s).

 6.08 (1H, s), 6.70-6.80 (1H, m), 6.91 (1H, d.J = 1.5Hz),

7.20-7.55 (8H.m). 7.68 (1H, s), 7.80 (1H, d.J = 6.0Hz), 97/17349

8.20 (1H.d.J = 8.4Hz)

MS (M ⁺ ): 479

Example 79

 N- [2-Hydroxy-41-((1-Methyl-5,6,7,8-tetrahydro--1H-pyro- [3,2-b] azevin-14-yl) carbonyl] phenyl] -1 [1 , 1'-Biphenyl] -1-2-carboxamide

実施例 78で得られた N— 〔2—メ トキシ— 4一 〔 （ 1—メチルー 5, 6, 7 , 8—テトラヒ ドロ一 1 H—ピロ口 〔 3 , 2— b〕 ァゼピン一 4—ィル） カルボ ニル〕 フエニル〕 一 〔 1 , 1 ' 一ビフヱニル〕 一 2—カルボキサミ ド （ 2. 20 g) を用いて、 実施例 2と同様にして、 標題化合物 （802 mg)を得た。 mp (soln.)：非結晶性固体

N- [2-Methoxy-41-[(1-methyl-5,6,7,8-tetrahydro-1H) -pyro mouth [3,2-b] azepine-14- obtained in Example 78 L) Carbonyl] phenyl]-[1,1'-biphenyl] -12-carboxamide (2.20 g), and the title compound (802 mg) was obtained in the same manner as in Example 2. mp (soln.): amorphous solid

IR (KB r): 3404. 2934, 1609 cm " ¹

NMR (CD C 13) (5 ppm, 300 MHz:

 1.70-1.80 (2H.brs) .1.85-2,00 (2H, m), 2.65-2.75 (2H.m), 3.45 (3H, s), 3.84 (2H, brs), 5.23 (1H.s), 5.98 (1H.d.J = 7.6Hz), 6.05 (1H, s), 6.70 (1H.d.J = 7.6Hz), 6.87 (1H.s), 7.14 (1H.s), 7.0-7.60 (8H.m). 7.87 (1H, d.J = 6.9Hz), 8.89 (1H.s)

MS ( ⁺ ): 465 P

 97/17349

Example 8 0

 4- (2-[[[[1, -biphenyl] -12-carbonyl] amino] -5-[(1-methyl-1,5,6,7,8-tetrahydro-1H-pyro mouth (3,2-b) Azepine 41-yl) carbonyl] phenoquine] butyrate

実施例 7 9で得られた N— 〔2—ヒ ドロキシー 4一 〔 （ 1 ーメチルー 5, 6, 7， 8—テトラヒ ドロ一 1 H—ピロ口 〔3, 2— b〕 ァゼピン一 4一ィル） カル ボニル〕 フエニル〕 一 〔 1 , ービフエニル〕 — 2—カルボキサミ ド （ 1. 1 5 g) 及び 4一ブロモブタン酸ェチルエステル （ 0. 4 6m l ) を用いて、 実施 例 3と同様にして、 標題化合物 （ 1. 0 0 g) を得た。

N- [2-Hydroxy 41-((1-methyl-5,6,7,8-tetrahydro-1H) pyro-mouth [3,2-b] azepine-14-yl obtained in Example 7 9 ) The title was obtained in the same manner as in Example 3 using carbonyl [phenyl]-[1,-biphenyl]-2-carboxamide (1.15 g) and ethyl 4-bromobutanoate (0.46 ml). The compound (1.00 g) was obtained.

m p (soln.): oil

IR (KB r): 1731. 1676. 1631, 1522 cm " ¹

NMR (CDC 1 a) 5 ppm, 300 MHz:

 1.24 (3H, t, J = 7.2Hz), 1.70-1.80 (2H, m), 1.85-2.00 (4H.m), 2.28 (2H, t.J = 7.4Hz). 2.70-2.80 (2H,), 3.49 (3H, s),

 3.75 (2H.t.J = 6.2Hz). 3.80-3.95 (2H, m), 4.08 (2H, q.J = 7.2Hz), 5.27 (1H, s), 6.10 (1H.s), 6.80 (1H d, J = 7.2Hz). 6.91 (1H.s).

7.25-7.60 (8H.m), 7.67 (1H, s). 7.76 (1H, d.J = 7.2Hz).

8.25 (1H.d.J = 7.2Hz) 97/17349

MS (M +): 579

Example 8 1

 4-C 2-CCC 1, 1'-biphenyl] 1-2-carbonyl] amino] 5-1 ((1-methyl-5,6.7,8-tetrahydro 1) -pyro mouth [3,2b] azepine-1 4 —Yl) carbonyl] phenoxy] butyric acid

実施例 80で得られたェチル 4一 〔2— 〔 〔 〔1， 1 ' —ビフヱ二ル〕 — 2 一カルボニル〕 ァミノ〕 一 5— 〔 （ 1一メチル一 5 , 6, 7, 8—テトラヒ ドロ 一 1 H—ピロ口 〔3, 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フエノキン〕 プチレート （ 1. 00 g) を用いて、 実施例 6と同様にして、 標題化合物 （97

Ethyl 4- [2-[[[1,1'-biphenyl]-2-carbonyl] amino] -15-[(1-methyl-1,5,6,7,8-tetrahyl obtained in Example 80 The same procedure as in Example 6 was carried out using 1-H-pyrro [3,2-b] azepine-41-yl) carbonyl] phenoquine] butylate (1.00 g) to obtain the title compound (97

0 mg) was obtained.

mp (soln.): amorphous solid

1 R (KB r): 1728, 1637. 1603. 1525 cm ' ¹

NMR (CDC 13) δ p pm, 300 MHz:

 1.70-1.85 (2H.m), 1.85-2.00 (4H.m) .2.33 (2H.t, J = 7.2Hz), 2.70-2.80 (2H.m). 3.48 (3H, s). 3.66-4.00 ( 4H, m).

5.27 (1H, s), 6.10 (1H, s), 6.79 (1H, d, J = 7.5Hz) .6.95 (1H.s), 7.25-7.60 (8H.m), 7.66 (1H.s), 7.76 (1H, d. J = 7.8Hz), PC

97/17349

8.23 (1H.d, J = 7.5Hz)

MS (M +): 551

Example 82

 N— [2— CA-(4-dimethylaminobiperidino) 1 4-oxobutoxy) — 4 1 ((1-methyl-5,6,7,8-tetrahydro-1H-pyrro [3,21-b] azepine 1-41) carbonyl] phenyl) 1 [shibiphenyl 12-carboxamide

実施例 8 1で得られた 4一 〔2— 〔 〔 〔し —ビフヱニル〕 一 2—カルボ ニル〕 ァミノ〕 一 5— 〔 （ 1ーメチルー 5, 6, 7, 8—テトラヒドロー 1 H— ピロ口 〔3, 2— b〕 ァゼビン一 4—ィル） カルボニル〕 フエノキン〕 酪酸 （ 9 7 Omg) 及び 4ージメチルァミノピぺリジン （2 6 6 mg) を fIいて、 実½例 7と同様にして、 標題化合物 （5 0 4 mg) を得た。

Example 81 4- [2-[[[shi-biphenyl] -12-carbonyl] amino] -15-[(1-methyl-5,6,7,8-tetrahydro-1H-pyrro [] obtained in Example 1 3,2-b] azevin-1-yl) carbonyl] phenoquine] butyric acid (97 Omg) and 4-dimethylaminopiperidine (266 mg) were subjected to fI in the same manner as in Example 7. The title compound (504 mg) was obtained.

mp (soln.): colorless amorphous solid

I (KB r): 3408. 1634. 1523 cm " ¹

NMR (CDC 13) δ τη, 300 MHz:

 1.20-1.40 (2H.m). 1.70-1.85 (4H, m), 1.85-2.00 (4H, m), 2.27 (6H, s), 2.30-2.40 (3H, m), 2.50-2.60 (1H.m ),

2.70-2.80 (2H.m), 2.85-2.95 (1H.m). 3.49 (3H, s), 97/17349

3.70-3.90 (5H, m), 4.51 (1H, brd. J = 12.3Hz). 5.27 (1H.s,

 6.10 (1H.s), 6.77 OH, d, J = 8.2Hz). 6.92 (1H.s).

 7.25-7.60 (8H, m), 7.75-7.80 (2H.m), 8.22 (1H.d, J = 8.2Hz)

MS (M ⁺ ): 661

Example 8 3

 (Process a)

1 Benzyl 4- 4-Jetylamino piperidine dihydrochloride

(1) Dissolve 4-benzylidone (2.0 m) in 1,2-dichlorobenzene and add getylamine (1.23 m1) and acetic acid (0.62 ml) in a nitrogen stream. Was. To this was added sodium triacetoxyborohydride (3.37 g), and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were recrystallized from ethanol to give the title compound (2,08 g).

mp (soln.): colorless crystal, 232.5-234.0 ° C (EtOH)

IR (KB r): 3418, 1636, 1458 cm ' ¹

NMR (DMSO-de) 5 ppm, 300 MHz:

 1.25 (6H, t.J = 7.4Hz), 2.15-2.30 (4H, m). 2.90-3.20 (4H.m). 3.30-3.60 (5H.m). 4.20-4.30 (2H.m). 7.45- 7.50 (3H, m), 7.60-7.65 (2H, m), 10.72 (1H.brs), 11.41 (1H.brs)

MS (M +): 318

 (Process b)

4-Jetylaminopiperidine dihydrochloride

 1-benzyl-41-ethylethylaminobiperidine diphosphate (60 g) obtained in step a was dissolved in ethanol (16 m 1) and water (9 m 1). Cyclohexene (7.60 ml) and 5% palladium on carbon (32 Omg) were added thereto, and the mixture was heated under reflux in a nitrogen atmosphere for 14 hours. The reaction mixture was passed through celite and washed with ethanol. The filtrate and the washing solution were combined, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with ethyl ether to give the title compound (903 mg).

m p (soln.): colorless crystal, 231.0-235.0

 I R (KB r): 1618. 1588. 1471 cnT]

NMR (DMS 0- d «) ά p pm, 300 MHz:

 1.26 (6H, t, J = 7.2Hz), 1.85-2.10 (2H.m), 2.15-2.30 (2H, m), 2.80-3.00 (2H, m), 3.00-3.20 (2H, m), 3.20- 3.40 (2H.m).

 3.50-3.65 (1H.m), 9.19 (2H.brs), 10.72 (1H, brs)

MS (M ⁺ ): 228

 (Process c)

N— [2— ί 4-(4-Getylaminobiperidino) 1-4-oxobutoxy)--C (5,6,7,8-tetrahydro 4) -thieno (3,2-b) azepine 1-41-yl) carbonyl] phenyl] -1- [1, -biphenyl] -2-carboxamide 97/17349

実施例 4 1で得られた 4一 〔2— 〔 〔 〔し Γ ービフヱニル〕 ― 2—カルボ ニル〕 ァミノ〕 一 5— 〔 （5, 6, 7, 8—テトラヒドロー 4H—チエノ 〔3, 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フエノキシ〕 酪酸 （9 1 mg)及 び工程 bで得られた 4一ジェチルァミノピペリジン 2塩酸塩 （ 428 mg) を川 いて、 実施例 7と同樣にして、 標題化合物 （74 1 mg) を得た。

Example 41 The 4- [2-[[[diphenyl] -2-carbonyl] amino] -1 5-[(5,6,7,8-tetrahydro-4H-thieno [3,2-] obtained in Example 1 b] As in Example 7, except that azepine-41-yl) carbonyl] phenoxy] butyric acid (91 mg) and 4- (4-ethylethylaminopiperidine) dihydrochloride (428 mg) obtained in step b were used. The title compound (74 1 mg) was obtained.

mp (soln.): colorless amorphous solid

IR (KBr): 3401, 1640, 1522 cm " ¹

NMR (CDC 13) δ p pm, 300 MHz:

 1.00 (6H, t.J = 7.2Hz). 1.20-1.40 (2H.m), 1.65-2.00 (8H.m).

2.21 (2H, t, J = 7.1Hz). 2.35-2.60 (5H, m), 2.60-2.90 (4H, m),

3.55-3.95 (5H.m). 4.48 (1H.d, J = 12.6Hz), 6.13 (1H, brs).

 6.60 (1H, d. J = 4.8Hz). 6.65-6.80 (2H, m). 7.20-7.50 (8H, m),

7.65-7.70 (2H.m). 8.19 (1H.d.J = 8.1Hz)

MS (M ⁺ ): 692

Example 84

N— [2 -— [4-1- [Ν '-(2-Dimethylaminoethyl) -1-N'-methylamino] -14-oxobutoxy] -4-1 [(5,6,7,8-tetrahydro-4Η-thieno [3 , 2-b] azebine-4-yl) carbonyl] phenyl] — [1,1 -Biphenyl] 1-2-carboxamide

実施例 4 1で得られた 4一 〔2— 〔 〔 〔1, 1 ' 一ビフエ二ル〕 一 2—カルボ ニル〕 了ミ ノ〕 一 5— 〔 （5, 6, 7, 8—テトラヒ ドロー 4H—チエノ 〔3, 2— b〕 ァゼピン一 4—ィル） カルボニル〕 フヱノキシ〕 酩酸 （50 Omg) 及 び N, N, N' — トリメチルエチレンジァミ ン （0. 1 2ΙΏ 1 ) を用いて、 雄 例 7と同様にして、 標題化合物 （4 95mg) を得た。

Example 41 4- [2-[[[[1,1'-biphenyl] -12-carbonyl] lymino] -1-5-((5,6,7,8-tetrahydro) obtained in Example 1 4H-thieno [3,2-b] azepin-14-yl) carbonyl] phenoxy] drank acid (50 Omg) and N, N, N'-trimethylethylenediamine (0.12ΙΏ1) In the same manner as in Example 7, the title compound (495 mg) was obtained.

mp (soln.): colorless amorphous solid

 I R (K B r): 3402, 1641, 1522 cm— '

_{NMR (CDC 1 3) 5 p} pm, 30 OMH z:

 1.70-1.80 (2H, m). 1.85-2.10 (4H.m), 2.16 (2H, s).

 2.25-2.45 (4H, m). 2.26 (4H, m), 2.85-2.95 (5H.π,

 3.25-3.45 (2Η.m), 3.65-3.75 (2H, m), 3.85 (2H.brs),

 6.21 (1H.brs), 6.67 (1H, d, J = 5.1Hz). 6.75-6.85 (2H, m),

7.30-7.55 (8H.m). 7.65-7.80 (2Η 'm), 8.27 (1H.d, J = 7.8Hz) S (M ⁺ ): 638

Example 85

N- [2— [4— [Ν '— (2-Jetylaminoethyl) 1 N' —ethylamino] 1 4-oxobutokin] 1 4 1 [(5, 6, 7, 8—tetrahydro 4Η— 97/17349

Thieno [3,2-b) azebin-1-yl) carbonyl] phenyl] 1-(1'-biphenyl) 12-carboxamide

実施例 4 1で得られた 4一 〔2— 〔 〔 〔 1 , 1 ' -ビフヱニル〕 一 2—カルボ ニル〕 ァミノ〕 一 5— C (5, 6, 7, 8—テトラヒ ドロー 4 H—チエノ 〔3， 2— b〕 ァゼピン一 4—ィル） カルボニル〕 フヱノキシ〕 酪酸 （ 5 0 Omg) 及 び N. N, N' —トリエチルエチレンジァミ ン （0. 1 7m l ) を用いて、 実施 例 7と同様にして、 標題化合物 （ 5 2 7 mg) を得た。

Example 41 4- (2-[[[[1,1, '-biphenyl] -12-carbonyl] amino] -1 5-C (5,6,7,8-tetrahydro 4H-thieno obtained in 1 [3,2-b] azepin-14-yl) carbonyl] phenoxy] butyric acid (50 Omg) and N.N, N'-triethylethylenediamine (0.17 ml) The title compound (527 mg) was obtained in the same manner as in Example 7.

mp (soln.): colorless amorphous solid

IR (KB r): 3403, 1639, 1523 cm— ¹

_{. NMR (CDC 1 3) 5} p pm 3 0 0 MHz:

 0.93-1.11 (9H, m), 1.70-2.05 (6H.m), 2.20-2.35 (2H.m), 2,40-2.50 (2H, m), 2.50-2.65 (4H.rn). 2.90-3.00 (2H.m), 3.20-3.40 (4H, m). 3.60-3.75 (2H, m). 3.85 (2H, brs),

 6.20 (1H, brs), 6.66 (1H, d, J = 4.5Hz). 6.75-6.85 (2H.m),

 7.25-7.55 (8H.m), 7.65-7.80 (2H.m), 8.25-8.30 (1H.m)

MS (M ⁺ ): 680

Example 8 6

N— [2— (4-[Ν '-(3-dimethylaminobuticyl) one N'-methyla [Mino] 1-4-oxobutoxy) 1-4-[(5,6,7,8-tetrahydro-1-4H-thieno [3,2-b] azevin-1 4-yl) carbonyl] 1,1'-biphenyl] 1-2-carboxamide

実施例 4 1で得られた 4— 〔2— 〔 〔 〔1, 1 ' -ビフヱニル〕 一 2—カルボ ニル〕 ァミノ〕 一 5— C (5, 6, 7, 8—テトラヒ ドロ一 4 H—チエノ 〔3. 2— b〕 了ゼピン一 4一ィル） カルボニル〕 フヱノキシ〕 酩酸 （ 500 mg) 及 び N, N, N' — トリメチルプロピレンジァミ ン （ 0. 1 4m l ) を爪いて、 ¾ 施例 7と同様にして、 標題化合物 （53 1 mg) を得た。

Example 4 4- [2-[[[[1,1'-biphenyl] -12-carbonyl] amino] -1 5-C (5,6,7,8-tetrahydro-1H- Thieno [3.2-b] Rzezepine-41-yl) carbonyl] phenoxy] drip acid (500 mg) and N, N, N'-trimethylpropylenediamine (0.14 ml) Then, the title compound (53 1 mg) was obtained in the same manner as in Example 7.

mp (soln.): colorless amorphous solid

IR (KBr): 3402. 1641. 1522 cm- ¹

_{NMR (CDC 1 3) ά p} pm, 300 ΜΗ ζ:

 1.60― 2.00 (8Η.m), 2.14 (3H.s), 2.15-2.35 (4H.m),

 2.25 (3H.s). 2.85-2.95 (5H, m). 3.20-1.40 (2H, m).

 3.60-3.70 (2H.m). 3.75-3.95 (2H.brs). 6.19 (1H.brs).

 6.67 (1H.d.J = 4.8Hz), 6.70-6.85 (2H.m), 7.25-7.55 (8H.m).

7.70-7.80 (2H.m), 8.27 (1H, d.J = 8.1Hz)

MS (M ⁺ ): 652

Example 87 97/17349

N- [2—C 4-(4-Dimethylaminopiperidino) 1 4-oxobutoxy]--C (5,6,7,8-tetrahydro-1 4H-thieno [3,2-b] azepine 14-yl) carbonyl] phenyl) 1 [shi-biphenyl] 1 2--boxyboxamidomaleate

実施例 4 で得られた N— 〔 2— C - ( 4—ジメチルアミ ノ ビペリ ジノ） 一 4一ォキソブトキシ〕 一 4— 〔 （5, 6, 7, 8—テトラヒ ドロー 4 H—チエノ 〔3, 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フエニル〕 一 〔 1 , 1 ' —ビ フエニル〕 ― 2—カルボキサミ ド （5. O g) のエタノール （2 0m l ) 溶液に マレイン酸 （0. 8 7 g) エタノール （5m 1 ) 溶液を加え 1時間室温で攪 し た。 減 DE下溶媒留去し、 残渣にアセ トンを加え濃縮後アセ トン及びへブタンを加 ぇ濃槠した。 得られた粉体を滅 乾燥し標題化合物 （ 6. 0 g) を得た。

N- [2-C- (4-dimethylamino-biperidino) -14-oxobutoxy] -14-[(5,6,7,8-tetrahydro 4H-thieno [3,2] obtained in Example 4 — B] azepine-41-yl) carbonyl] phenyl] 1- [1,1'-biphenyl]-2-carboxamide (5. Og) in ethanol (20 ml) solution with maleic acid (0.8 7 g) Ethanol (5 ml) solution was added and stirred for 1 hour at room temperature. The solvent was distilled off under reduced DE, and acetone was added to the residue. After concentration, acetone and heptane were added and concentrated. The obtained powder was dried to give the title compound (6.0 g).

mp (soln.): colorless crystal, 139.5-141.5 'C (ethyl acetate)

NMR (CDC 13) δ p pm:

 1.40-1.55 (2H, m), 1.70-1.80 (2H.brs). 1.90-2.10 (6H.m), 2.67-2.31 (2H.m). 2.47 (1H.t.J = 12.3Hz), 2.70 ( 6H, s),

 2.85-3.05 (3H, m), 3.32 (1H, t.J = 11.9Hz) .3.72 (2H.brs),

 3.60-4.2 (2H.brs). 3.85 (1H.d, J = 14.2Hz).

4.67 (1H, d, J = 12.1Hz). 6.19 (1H.brs). 6.27 (2H, s). 6.68-6.79 (3H.m) .7.26-7.35 (3H, m). 7.-12-7.57 (4H.m), 7.75-7.78 (2H.m) .8.24 (1H.d, J = 8.5Hz)

 In the same manner as in Example 87, the compounds of Examples 88 to 91 were obtained.

Example 8 8

 N— [2-C4- (4-Dimethylaminobiperidino) 1-4-oxobutoxy] 1-41 ((5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-4 1 Yl) carbonyl] phenyl] 1 [shi 1'-biphenyl] 12-carboxamide methanesulfonate

N R (DMSO-cU) d p pm

 1.23 ― 1.30 (2Η. Π, 1.77 (2Η, brs). 1.85-2.10 (6H, m),

 2.40-2.55 (2H, m), 2.55-2.60 (1H, m). 2.60-3.05 (13H.m).

 3.42 (1H.brs), 3.74 (2H.brs). 3.86 (2H, m), 4.55 ― 4.65 (1H, m).

6.19 (1H, brs). 6.72 (2H.brs). 6.80 (1H, brs), 7.20-7.60 (7H, m).

7.70-7.80 (2H.m) .8.22 (1H.d.J = 7.2Hz), 10.08 (1H, brs) Example 8 9

 N- [2-C4- (4-Dimethylamino-biperidino) -14-oxobutoxy] -4-1 [(5,6,7,8-Tetrahidro 4H-thieno [3,2-b] azepi N-41) carbonyl] phenyl] -U, -biphenyl] 1-2-carboxamido fumarate

NMR (DMSO-d s) dp pm

 1.10-1.35 (2H.m), 1.60-1.95 (8H, m). 2.33 (6H, s),

 2.35-2.45 (2H.m). 2.60-2.70 (1H, m). 2.80-2.95 (4H, m), 3.80-3.85 (4H.m), 4.33 (2H, d.J = 12.3Hz), 6.29 ( 1H.brs).

 6.54 (2H.s). 6.75-6.85 (2H.m), 6.90-6.95 (1H.m),

 7.25-7.60 αθΗ, m). 7.70-7.80 (1H, m), 9.07 (1H.s)

Example 9 0

N— [2— [4-1 (4-dimethylamino biperidino) 1-41-oxobutoxy] 97/17349

1-41 ((5,6,7,8-tetrahydro-14H-thieno [3,2-b] azepin-14-yl) carbonyl] phenyl) 1 [1,1'-biphenyl] 1 2 —Carboxamido citrate

 1.15 one 1.25 (2Η.m), 1.65-1.80 (2H, m), 1.80-2.10 (6H.m),

2.30-2.40 (2H.m). 2.40-2.60 (1H, m), 2.65 (6H.brs).

 2.73 (2H.brs), 2.82 (2H.brs). 2.87 (4H.brs). 3.20-3.30 (1H.m),

3.70-3.80 (2H, brs), 3.70-3.85 (2H, m), 4.54-4.65 (1H.m),

6.16 (1H.brs), 6.67-6.80 (2H, brs), 6.82 (1H.brs),

 6.80-7.30 (2H.brs), 7.20-7.40 (4H.m). 7.40-7.60 (6H.m).

7.72 (1H, d.J = 7.5Hz), 7.81 (1H, brs), 8.18-8.22 (1H.m)

Example 9 1

 N— [2—C 4-(4-Dimethylamino biperidino) 1-4-oxobutoxy]--C (5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine 1 4 — Yl) carbonyl] phenyl) 1 [1, 1-biphenyl] 12-carboxamide L monotartrate

NMR (CDC 13) d p pm:

 1.30-1.40 (2H, m) .1.65-1.75 (2H, brs), 1.80-2, 10 (6H, m), 2.27 (3H, brs). 2.40-1.50 (1H.m), 2.63 (6H.brs) ).

 2.82 ― 3.05 (3H, m). 3.27 (1H.brs). 3.69 (2H, brs),

 3.75-3.95 (2H.m), 4.45 (2H.s), 4.57-4.65 (1H.m).

 5.60-6.10 (4H.brs), 6.16 (1H, brs), 6.68 OH, d, J = .8Hz).

 6.78 (2H, brs). 7.20-7.40 (4H, m). 7.40-7.55 (4H.m),

 7.72 (1H.d.J = 7.2Hz). 7.80 (1H, brs). 8.20 (1H.d.J = 7.5Hz) Example 9 2

Biphenyl-2-carboxylic acid {2- (4- (4-methylaminobiperidinyl) -14-oxobutoxy) -14- (5,6,7,8-tetrahydrothithieno [3, 2—b] azepine-4-carbonyl) phenyl} amide hydrochloride

 (Process a)

 (1 Benzylbiperidin-1-yl) methylcarbamic acid tert-butyl ester

メチルァミ ン 塩酸塩 （8 0 2mg) をメタノール （ 1 Om 1 ) に溶解し、 1 一ベンジル— 4ーピペリ ドン （2. 0 0m l ) を加えた。 5 %パラジウム炭素 （ 2 0 Onig) を加え、 水素雰囲気下、 室温、 3気圧で 1 8時間攪拌した。 反応液 をセライ ト滹過し、 濾液を濃縮した。 得られた残渣を 1 , 4—ジォキサン （ 1 0 . 0 0m l ) と水 （ 6. 0 0m 1 ) の混液に溶解し、 4 N -水酸化ナトリウム水 i嫌 ( 5. 94m l ) を加えた。 次いでジー t e r t—プチルジカルボネート （ 3. 0 6 g) を加え、 室温下終夜攪拌した。 有機層と水層を分離し、 水層より附 酿ェチルで抽出した。 全有機層を水、 飽和食塩水で洗浄し、 無水硫酸ナト リウム で乾燥した。 滹過後濃縮し、 残渣をシリカゲルカラムクロマトグラフィー （クロ 口ホルム ： メタノール = 20 : 1 ) で精製し、 標題化合物 （ 1. 1 8 g) を得た ο

Methylamine hydrochloride (800 mg) was dissolved in methanol (1 Om 1), and 1-benzyl-4-piperidone (2.0 ml) was added. 5% palladium on carbon (20 Onig) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature and 3 atmospheres for 18 hours. The reaction solution was passed through celite, and the filtrate was concentrated. The obtained residue was dissolved in a mixture of 1,4-dioxane (10.0 ml) and water (6.0 ml), and 4N-sodium hydroxide aqueous solution (5.94 ml) was added. Was. Then, di-tert-butyl dicarbonate (3.06 g) was added, and the mixture was stirred overnight at room temperature. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted with water. All the organic layers were washed with water and saturated saline, and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated, and the residue was purified by silica gel column chromatography (cloth form: methanol = 20: 1) to obtain the title compound (1.18 g).

m p (soln.): colorless oil

 Ή-NMR (CDC 13):

 1.45 (9H.s, 1,50-1.80 (5H.m). 1.95-2.10 (2H, m,

 2.73 (3H.s), 2.85-2.95 (2H.m). 3.49 (2H, s),

 7.20-7.35 (5H, m)

MS (M +): 304

(Process b) 97/17349

Methyl (piperidine-14-yl) carbamic acid tert-butyl ester

工程 aで得られた （ 1一ベンジルピペリジン— 4一ィル） メチルカルバミン ¾ t e r t—ブチルエステル （54 5mg) をエタノール （5. 5m l ) に溶 した。 シクロへキセン （2. 5 0m l ) , 5 %パラジウム炭素 （ 6 0 Omg) 、 1 N -塩酸水溶液 （ 1. 8 0m l ) を順次加え、 還流下終夜攪拌した。 反応液を セライ ト據過し、 滤液を濃縮した。 得られた結晶をジェチルエーテルで洗浄し、 標? S化合物 （ 3 7 1 mg) を得た。

The (1-benzylpiperidine-4-yl) methylcarbamine-tert-butyl ester (545 mg) obtained in step a was dissolved in ethanol (5.5 ml). Cyclohexene (2.50 ml), 5% palladium on carbon (60 Omg), and a 1N-hydrochloric acid aqueous solution (1.80 ml) were sequentially added, and the mixture was stirred under reflux overnight. The reaction solution was passed through celite, and the aqueous solution was concentrated. The obtained crystals were washed with getyl ether to give the target S compound (371 mg).

m p (soln.): 223 · 2. C (decomposition)

Ή-NMR (D ₂₀ ):

 1.42 (9H.s) .1.75-2.05 (4H.m), 2.74 (3H.s).

3.00-3.20 (2H, m). 3.35-3.65 (2H, m). 4.05-4.20 (1H.m) MS (M ⁺ ): 214 (M + in free form)

 (Process c)

N— [2 -— [4- (4-(Ν'-tert-butoxycarbonyl N'-methylaminobiperidino] 1-41-oxobutokin) 1-41 [(5, 6, 7, 8- Rahi Draw 4 H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl]-[1'-biphenyl] -12-carboxamide

実施例 4 1で得られた 4一 〔2— 〔 〔 〔し 一ビフヱニル〕 一 2—カルボ ニル〕 ァミノ〕 一 5— 〔 （5, 6, 7, 8—テトラヒ ドロー 4H -チエノ 〔3, 2 - b) ァゼピン一 4一ィル） カルボニル〕 フエノキン〕 酪酸 （300mg) を ジメチルホルムアミ ド （4. 00m l) に溶解し、 トリェチルァミ ン （0. 08 m】） を加えた。 氷冷下でクロロギ酸イソブチル （ 0. 08m I ) を滴下し、 1 5分攪 ft:した。 次いで工程 bで得られたメチル （ピペリジン一 4一ィル） 力ルバ ミ ン酸 t e r t—ブチルエステル 塩酸塩 （ 1 50mg) 、 トリェチルァミ ン (0. 1 7m l ) を順次加え、 室温下で 1時間攪拌した。 反応液を水にあけ、 ^ 酸ェチルで抽出した。 有機層を水、 飽和食塩水で洗浄し、 無水硫酸ナトリウムで 乾燥した。 滹過後濃縮し、 残渣をシリカゲルカラムクロマトグラフィー （酢酸ェ チル） で精製し、 標題化合物 （ 325 mg) を得た。

Example 41 4- [2-[[[[1-biphenyl] -12-carbonyl] amino] -15-[(5,6,7,8-tetrahydro 4H-thieno [3,2] -b) azepine-41-yl) carbonyl] phenoquine] butyric acid (300 mg) was dissolved in dimethylformamide (4.00 ml), and triethylamine (0.08 m) was added. Under ice cooling, isobutyl chloroformate (0.08 ml) was added dropwise, and the mixture was stirred for 15 minutes. Then, the methyl (piperidine-141-yl) -capillate tert-butyl ester hydrochloride (150 mg) and triethylamine (0.117 ml) obtained in step b were sequentially added, and the mixture was added at room temperature for 1 hour. Stirred. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (325 mg).

mp (soln.): amorphous solid

 Ή-NR (CDC 13):

 1.47 (9H, s), 1.55--1.85 (4H.π, 1.85-2.10 (5Η.m).

 2.20-2.40 (2H.m), 2.40-2.55 (1H, m). 2.65 (3H, s),

 2.85-3.05 (4H.m), 3.60-4.40 (6H, m). 4.50-4.70 (1H.m).

 6.20 (1H, brs), 6.67 (1H.d.J = 5.2Hz). 6.75-6.85 (2H.m).

7.20-7.60 (8H, m). 7.70-7.85 (2H.m). 8.26 (1H.d.J = 8.4Hz) 97/17349 S (M ⁺ ): 750

 (Process d)

 N- [2-C4- (4-methylaminobiperidino) -14-oxobutoxy] 1-41-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-1 4- (yl) carbonyl] phenyl] 1 [shi 1'-biphenyl] 12-carboxamide hydrochloride

工程 cで得られた N— 〔2— C 4 - 〔4一 （Ν' — t e r t—ブトキンカルボ 二ルー N' —メチルァミ ノビペリジノ〕 一 4—ォキソブトキシ〕 一 4一 C ( 5, 6, 7, 8—テトラヒ ドロー 4 H—チエノ 〔3, 2— b〕 ァゼビン一 4一ィル） カルボニル〕 フエニル〕 一 〔1 , 1 ' ービフエニル〕 一 2—カルボキサミ ド （ 6 O Omg) をメタノール （ 1 0m l ) に溶解し、 4 N—塩酸—酢酸ェチル溶液 （ 1. 0 0m l ) を加えた後、 室温下で 9時間攪拌した。 反応液を濃縮し、 残渣に 4 N—水酸化ナトリウム水溶液を加え、 クロ口ホルムで抽出した。 有機層を無水 硫酸ナトリウ厶で乾燥し、 滤過後濃縮した。 残渣をシリカゲルカラムクロマトグ ラフィー （クロ口ホルム ： メタノール = ι 0 ： 1 ) で精製し、 標題化合物のフリ 一体 （4 7 5mg) を得た。 これを酢酸ェチル （ 1 0m l ) に溶解し、 氷冷、 攪 拌下で 4 N -塩酸—酢酸ェチル溶液 （0. 4m l ) を加え、 3 0分攪拌した。 反 応液を濃縮、 乾燥し、 標題化合物 （4 3 l mg) を得た。 P 97/17349

N— [2-C4- (4-I (Ν'-tert-butyncarbo-2-ru N'-methylaminoviperidino) -14-oxobutoxy) obtained in step c-14-C (5,6,7,8- Tetrahydro 4H-thieno [3,2-b] azevin-14-yl) carbonyl] phenyl]-[1,1, '-biphenyl] -12-carboxamide (6O Omg) in methanol (10ml) After dissolution, 4N-hydrochloric acid-ethyl acetate solution (1.00 ml) was added, and the mixture was stirred at room temperature for 9 hours.The reaction solution was concentrated, and 4N-sodium hydroxide aqueous solution was added to the residue. The organic layer was dried over anhydrous sodium sulfate, concentrated after filtration, and the residue was purified by silica gel column chromatography (chloroform: methanol = ι0: 1) to give the title compound (free). This was added to ethyl acetate (10 ml). Then, a 4 N hydrochloric acid-ethyl acetate solution (0.4 ml) was added under ice-cooling and stirring, and the mixture was stirred for 30 minutes.The reaction solution was concentrated, dried, and the title compound (43 mg) was added. I got P 97/17349

mp (soln.): amorphous solid

IR (KBr): 3414. 1637 cm " ¹

 Ή-NMR (DMSO-d,, 100 'Ο:

 1.35― 1.50 (2Η, m), 1.65-2.05 (8H, m), 2.30-2.40 (2H.m),

2.51 (3H, s), 2.65-3.00 (4H, m). 3.10-3.20 (1H.m),

 3.65-3.75 (2H, m), 3.75-3.85 (2H.m), 4.08 (2H.brs).

 6.34 (1H, d, J = 4.0Hz). 6.70-6.85 (2H, m), 6.90 (1H.d, J = -J.2Hz).

7.25-7.50 (7H.m), 7.50-7.65 (2H.m). 7.76 (1H, d, J = 6.2Hz),

8.54 (1H, brs), 8.89 (2H, brs)

MS (M ⁺ ): 650 (Free M +)

Example 93

 Biphenyl-2-carboxylic acid {2-(4- (4-amino-biberidinyl) -14-oxobutoxy) -1 4- (5,6,7,8-tetrahydrothieno [3,2-b] azepine-1 Carbonyl) phenyl} amide hydrochloride

 (Process a)

 (1-benzylpiperidine-14-yl) carbamic acid tert-butyl ester

4Amino 1-benzylbiperidine (5.00 ml) is dissolved in a mixture of 4-dioxane (25.0 ml) and water (15.0 ml), and 4N-water sodium oxide is stirred at room temperature. An aqueous solution (2.5 ml) was added. Then, di-tert-butyl dicarbonate (6.96 g) was added, and the mixture was stirred overnight. The insolubles were separated and the base solution was concentrated. The residue was dissolved in ethyl acetate, washed successively with water and saturated saline, and dried over anhydrous sulfuric acid. 97/17349

Dried with sodium. After filtration, the mixture was concentrated, and the resulting crude crystals were reconstituted with methanol.

The title compound (41 g) was obtained.

m p (soln.): 122.8-123. C (methanol)

 Ή-NMR (CDC 13):

 1.30-1.55 (ΠΗ.m) .1.80-1.95 (2H.m) .2.00-2.20 (2H.m) .2.70-2.90 (2H.m), 3.35-3.60 (1H, m), 3.48 (3H.s ).

 4.41 (1H.brs) .7.15-7.35 (5H, m)

MS (M +): 290

 (Process b)

Biridin-4-ylcarbamic acid tert-butyl ester hydrochloride

工程 aで得られた （ 1 一べンジルビペリジン一 4—ィル） カルバミ ン酸 t e r t一ブチルエステル （ 1. 3 0 g) を出発原料として、 実施例 9 2の工程 bと 同はの手法により摞題化合物 （ 9 2 2 mg) を得た。

Starting from (1 monobenzylbiperidin-4-yl) carbamic acid tert-butyl ester (1.30 g) obtained in step a, the same procedure as in step b of Example 92 was carried out. The title compound (922 mg) was obtained.

mp (soln.): 223.5 ^e C (decomposition)

Ή-NMR (D ₂₀ ):

 1.39 (9H.s) .1.55-1.75 (2H, m), 2.00-2.15 (2H.m).

3.00-3.20 (2H, m), 3.30-3.50 (2H, m). 3.55-3.70 (1H, m) MS (M ⁺ ): 200 (M + in free form)

 (Process c)

N— [2— [4-C 4-(Ν'-tert-butoxycarbonylamino) piridino] 1 4-oxobutoxy] 1-4-[(5,6,7,8-tetrahydro 4 H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] -1 [1, -biphenyl] -12-carboxamide

実施例 4 1で得られた 4— 〔2— 〔 〔 〔1, 1 ' 一ビフヱニル〕 一 2—カルボ ニル〕 ァミノ〕 一 5— 〔 （5, 6, 7， 8—テトラヒ ドロー 4H—チエノ 〔3, 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フヱノキシ〕 酪酸 （80 Omg) 及 び、 工程 bで得られたビペリジン— 4—ィルカルバミン酸 t e r t—プチルェ ステル 塩酸塩を用いて、 実施例 92の工程 cと同様の方法により標题化合物 ( 1. 00 g) を得た。

4- [2-[[[[1,1'-biphenyl] -12-carbonyl] amino] -15-[(5,6,7,8-tetrahydro 4H-thieno obtained in Example 41 3,92-b] azepine-41-yl) carbonyl] phenoxy] butyric acid (80 Omg) and biperidine-4-ylcarbamic acid tert-butylester hydrochloride obtained in step b, Example 92 The title compound (1.00 g) was obtained in the same manner as in Step c of the above.

mp (soln.): amorphous solid

 Ή-NMR (CDC 13):

 1.05-1.35 (2H.m). 1.45 (9H.s), 1.60-2.10 (8H.m),

 2.20-2.40 (2H.m), 2.60-2.75 (1H.m). 2.85-3.10 (4H, m), 3.50-4.00 (4H.m), 4.30-4.80 (2H.m), 6.20 (1H, brs ).

 6.60-6.85 (3H, m), 7.20-7.65 (9H, m), 7.70-7.85 (2H.m), 8.26 (1H, d.J = 8.4Hz)

MS (M ⁺ ): 736

 (Process d)

N— [2-C4- (4-Aminobiperidino) -14-oxobutoxy) 1-4-[(5,6,7,8-tetrahydro-1H-thieno [3,2-b] azepine-14yl) carbonyl Phenyl) 1- [1, -biphenyl] 1-2-carboxami 97/17349

De hydrochloride

工程 cで得られた N- 〔2— 〔4— C4 - (Ν' — t e r t—ブトキシカルボ ニルァミノ） ピペリジノ〕 一 4一ォキソブトキン〕 一 4— 〔 （ 5, 6, 7, 8 - テトラヒ ドロー 4H—チエノ 〔3, 2— b〕 ァゼピン一 4一ィル） カルボニル〕 フエニル〕 一 U , 1 ' —ビフエニル〕 一 2—カルボキサミ ド （ 90 Om g) を 用い、 実施例 92の工程 dと同様の方法により標題化合物 （66 1 mg) を^た ο

N- [2- (4-C4- (Ν'-tert-butoxycarbonylylamino) piperidino]-(4-oxobutoxy)] 4-([5,6,7,8-tetrahydro 4H-) obtained in step c Thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] -1U, 1'-biphenyl] -12-carboxamide (90 Omg), using the same method as in step d of Example 92. Gave the title compound (66 1 mg)

mp (soln.): amorphous solid

IR (KBr): 3405, 1637 cm " ¹

_{Ή-NMR (DMSO - d 6} , 1 00 ° C):

 1.35-1.50 (2H.m). 1.65-2.00 (8H.m). 2.30-2.40 (2H.m), 2.65-3.00 (4H.m). 3.15-3.30 (1H, m). 3.65-3.75 (2H m), 3.75― 3.85 (2H.m), 3.90-4.10 (2H.m), 6.35 (1H, d, J = 4.1Hz), 6.75-6.85 (2H.m). 6.90 (1H.d, J 7.25-1 7.50 (7H, m), 7.50-7.65 (2H.m), 7.76 (1H, d, J = 6.2Hz), 8.03 (3H, brs),

 8.54 (1H, brs)

MS (M ⁺ ): 636 (Free M +)

Example 94 N— [2— [4-1 (1- (Iminoethyl) piperazine-1-11yl) 1-41-oxobutoxy] 1-41 C (5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-41-yl) carbonyl] phenyl] -1- [1, -biphenyl] -2-carboxamide

実施例 55で得られた N— 〔2— 〔4一 （ピペラジン一 1一ィル） 一 4一才 キソブトキシ〕 一 4一 〔 （5， 6, 7， 8—テトラヒ ドロー 4H—チエノ 〔3， 2_b〕 ァゼピン一 4一ィル） カルボニル〕 フエニル〕 一 〔し —ビフエ二 ル〕 一 2—カルボキサミ ド （35 Omg) をエタノール （ 1 Om l ) に溶解し、 トリェチルァミ ン （ 1 97mg) 、 ェチルァセトイミデ一ト塩酸塩 （1 72mg ) を加え 5時間室温攪拌した。 エタノールを留去した後、 残渣をクロ口ホルムに 溶かし飽和食塩水にて洗浄し、 有機層を無水硫酸マグネシウムで乾燥した。 沱媒 留去後シリ力ゲルカラムクロマトグラフィー （クロ口ホルム ： メタノール = 9 ： 1 ) により精製し、 標題化合物 （32 Omg) を得た。

N- [2- (4-1 (piperazine-11-yl) -14-year-old oxobutoxy) 1-41-((5,6,7,8-tetrahydro 4H-thieno [3, 2_b] azepine-41-yl) carbonyl] phenyl) 1 [shi-biphenyl] 12-carboxamide (35 Omg) dissolved in ethanol (1 Oml), triethylamine (197 mg), ethyl Acetamide hydrochloride (172 mg) was added, and the mixture was stirred at room temperature for 5 hours. After the ethanol was distilled off, the residue was dissolved in chloroform and washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off Tutuo medium, the product was purified by silica gel column chromatography (form: methanol = 9: 1) to obtain the title compound (32 Omg).

mp (soln.): amorphous solid

 R (KB r): 3401, 1626, 1522, 1423, 747 cm

 Ή-NMR (CDC 13):

1.70-1.82 (2H, m), 1.85-2.02 (4H.m), 2.22-2.32 (2H.m), 2.46 (3H, s). 2.90-2.95 (2H.m) .3.05-3.15 (1H, m ), 97/17349

3.40-4.05 C13H, m), 6.19 (1H, m .6.68 (1H.m) .6.77 C2H.brs), 7.26-7.60 (6H.m) .7.73-7.78 (1H.m). 9.80-9.95 (1H , brs)

MS (M ⁺ ): 663

Example 95

 N— [2— (4-guanidinobutoxy) 1-41 ((5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-1 4-yl) carbonyl] [Geometry] 1 U, 1'-biphenyl] 1—2-lipoxamide

実施例 5 9で得られた N- 〔2— （4一アミノブトキシ） 一 4一 〔 （5, 6, 7， 8—テトラヒ ドロ一 4 H—チエノ 〔 3， 2— b〕 ァゼピン一 4一ィル） カル ボニル〕 フエニル〕 一 〔し 1 ' 一ビフエニル〕 ― 2—カルボキサミ ド （ 350 m g) をジメチルホル厶ァミ ド （ 1 0 m 1 ) に溶解し、 トリェチルァミン （ 29 8mg) 、 3, 5—ジメチルビラゾール— 1—カルボキサミ ジ硝酸塩 （ 297 m g) を加え 60 'Cにて 1 5時間攪拌した。 ジメチルホルムアミ ドを留去した後、 残渣をクロ口ホルムに溶かし飽和食塩水にて洗浄し、 有機層を無水硫酸マグネシ ゥ厶で乾燥した。 溶媒留去後シリカゲルカラムクロマトグラフィー （クロ口ホル ム ： メタノール =9 _: 1 ) により精製し標題化合物 （347mg) を得た。 mp (soln.)：非結晶性固体

N- [2-((4-Aminobutoxy))-14-1 ((5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-1) obtained in Example 59 (Carbonyl) phenyl) [[1'-Biphenyl] -2-carboxamide (350 mg) is dissolved in dimethylformamide (10 m1), and triethylamine (298 mg), 3,5 —Dimethylvirazole-1-carboxamidinitrate (297 mg) was added, and the mixture was stirred at 60 ° C. for 15 hours. After distilling off dimethylformamide, the residue was dissolved in chloroform and washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform: methanol = 9 _: 1) to obtain the title compound (347 mg). mp (soln.): amorphous solid

IR (KBr): 3311. 3159, 1694, 1651. 1384 cm-' Ή-NMR (CDC 13):

 1.40-2.00 (8H.m), 2.89 (2H.brs). 3.16 (2H.brs).

 3.60-4.00 (4H.m) .6.00-6.20 (3H, m). 6.60-6.95 (6H, m),

7.20-7.80 (8H.m). 7.70 (1H, brs).

MS (M ⁺ ): 581

Example 96

 N- [2-[4- (4- (2-hydroxyethyl) biradizine-11-yl] butoxy] -4-1 ((5,6,7,8-tetrahydro 4H-thieno [3 , 2—b] azepine-41-yl) carbonyl] phenyl] -1- [1,1-biphenyl] 1-21-carboxamide

実施例 1 4で得られた N— 〔2— （4一クロロブトキシ） 一 4一 〔 （5， 6, 7, 8—テトラヒ ドロー 4H—チエノ 〔3, 2— b〕 ァゼピン一 4一ィル） カル ボニル〕 フエニル〕 — U , 1 ' —ビフエニル〕 一 2—カルボキサミ ド （ 559 mg) 及び 1一ピぺラジンエタノール （ 1 3 Omg) を用いて、 実施例 4と同は にして、 標題化合物 （ 1 5 Omg) を得た。

N- [2-((4-Chlorobutoxy)) 1-41 ((5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-14yl) obtained in Example 14 ) Carbonyl] phenyl] — U, 1'-biphenyl] 12-carboxamide (559 mg) and 11-piperazineethanol (13 Omg) using the same procedure as in Example 4 to give the title compound (15 Omg).

mp (soln.): amorphous solid

IR (KBr): 3404, 2933, 1673, 1640. 1522, 1381.746 cm " ¹

Ή-NMR (CDC 13): 97/17349

1.25-1.58 (6H, m). 1.79-2.04 (8H, brs). 2.20-2.30

 (3H.m), 2.61 (4H.brs), 2.83-2.92 (4H.m) .3.60-3.64 (2H.m), 3.84 (1H.brs), 6.20 (1H, brs). 6.67 (1H, d) , J = 4.6Hz) .6.71

 (1H.brs), 6.81 (1H, d, J = 7.3Hz), 7.22-7.56 (7H, m), 7.66 (1H, brs). 7.76 (1H, d.J = 7.0Hz), 8.27 (1H, d, J = 7.8Hz)

 MS (M +): 652

 Next, the compound (I) of the present invention was tested for its binding activity to vasobretsin receptor.

Test example 1

Vasopressin (VI) receptor binding

Liver of Sprague Dawley male rat (Charles River Japan) is minced and ice-cold 250 mM containing 20 m HEPES (pH 7.4), ImM EGTA, 5 μg / ml antipain and 5 μg / ml leupeptin Homogenize in 4 volumes of sucrose buffer. All the processes of de-sampling were performed in step 4. Centrifuge the homogenate at 8000g for 15 minutes. Separate the supernatant fraction and centrifuge at 40,000 g for 60 minutes. The residual pellet is suspended in 4 volumes of 20 mM (HEPES) .Ice-cold 250 sucrose buffer (pH 7.4) containing 5 g / ml antipain and 5 μg / ml leupeptin, and resuspended at 40,000 g for 60 minutes. Centrifuge. Resuspend the final pellet in ice-cold 250 // M sucrose buffer (pH 7.4) containing 20 mM HEPES, 5 ^ g / ml antipain and 5 Ug / ml leupeptin. The resulting membrane sample is stored at 1-8 (TC). The membrane sample is used for the binding test after thawing. Competition competition assay is performed using 1.0 nM [3H] monovasopressin (10 mM Tris-HCKPH 8.0) buffer. [Fenilaranil-3,4,5-3H] -Vasopressin; 40-87 Ci / gol: New England 'Nuclear 1) is carried out at equilibrium (20 minutes at 37 ° C). Measure non-specific binding using 1 U vasopressin (Peptide Institute; Osaka). After the incubation, stop the reaction by adding 2.5 ml of ice-cold lOOmM Tris-HC1 (pH 8.0) buffer, and transfer the solution quickly through a Bettmann glass filter (GF / B). Wash the filter three times with the same buffer (2.5 ml). Combine with filter The measured radioactivity is measured in a liquid scintillation counter (WALLAC 1410). Test compounds were shown in Table 1 as the concentration that inhibits 50% binding (IC _5.).

Test example 2

Vasopressin (V2) receptor binding

 The medullary papilla of the kidney of a Sprague Dawley male rat (Charles River Japan) is minced, and 10 OmM Tris-HC1 buffer (pH-pH) containing O.lmM phenylmethylsulfonyl fluoride (H-PMSF) is used. 8.0) Homogenize in a 20-fold volume. Filter the homogenate through a 150 urn diameter nylon mesh.遠 心 Centrifuge the solution at 500g for 5 minutes. Separate the supernatant fraction and centrifuge at 20000 g for 20 minutes. Resuspend the residual pellet in 20 volumes of ice-cold lOOmM Tris-HC1 (pH 8.0) buffer (containing 5 mM MgC. ImTA. 5 g / ml antipain and 5 / g / ml leupeptin) and resuspend. Centrifuge at 20000g for 20 minutes. Resuspend the final pellet in the same buffer. The obtained membrane test bridge is stored at 180 ° C. The membrane test bridge is used for the binding test after thawing. Competition assay was performed using l.Onlll [3H] 1 vasopressin ([Fenara 2 3,4,5-3H] 1 ppretzin in lOOmM Tris-HC1 (pH 8.0) buffer; 40-87 Ci / Perform at equilibrium (20 minutes at 37 ° C) using a concealer; New England 'Nuclea'.

1 Measure non-specific binding using vasopressin (Peptide Research Institute; Osaka). After incubation, add 2.5 ml of ice-cold lOOmM Tris-HC] (pH 8.0) buffer to stop the reaction, and filter quickly through a Bettmann glass filter (GFZB). Wash the filter three times with the same buffer (2.5 ml). The radioactivity bound to the filter is measured in a liquid scintillation counter (WA 1410). The concentration at which the test compound inhibits binding by 50% (IC ₅ o) is shown in Table 1.

As test compounds, Examples 2, 4, 6, 7, 15 to 17, 21, 21, 23, 24, 27, 29 to 31, 36, 42 to 44, 47, 48, 50, 51, 51 The compounds obtained in 53, 92 and 93 were used. In addition, using a known compound represented by the following formula as a control compound, the binding activity of vasobretsin receptor was examined in the same manner as in Test Examples 1 and 2.

 Table 1 shows the results.

Compound of Comparative Example 1

Compound of Comparative Example 2

Entering

OK Ζ Ό

SO 0 * 9 I

300 0 10 '0 S6

 SOO'O 900 "0 26

 2000 ΖΟΟΌ 89

 SO'O 2019

 so'o 20 Ό 09

 1000> 2008

 200.0 10 Ό

 SOO'O 900 '0

 δΟΟ Ό 20

 100 Ό 20 "0 Z

 SOO'O 刚

 V 0 'Ο 300 18

 900 0 SO 0 OS

 εοο · ο 00 · 0 62

 ruu υ on

 L6

 SOO'O 10 "0 U

 200 SOO'O zz

 900 0 800 * 0 \ z

 00 · 0 SOO'O L \

 8000 ZO O 9Ϊ

 SOO'O 10 Ό 91

 SOO'O 90 "0 L

 10Ό> 90Ό9

 10 0 10 0

 10 "0 Z

 10 0 I '0 Ϊ

(W) ^0S 3I (W) ^OS 31

 导 ¾ 'Λ

6PZLVL6 OIC0 / 96df / lDd 97/17349

Test example 3

Diuretic test

 The test compound was administered to a male Sprague-Dawley rat, which had been fasted for 18 hours, and immediately placed in a metabolic cage to measure urine output. In the case of the oral administration test, the test compound was dissolved in distilled water or 10% (v / v) dimethyl sulfoxide solution and administered, and the urine volume up to 4 hours after the addition was measured. In the case of the intravenous administration test, the test compound was dissolved in physiological saline, administered intravenously, and the total urine volume up to 2 hours later was measured. The control group was administered a solvent containing no test compound, and the urine volume was measured in the same manner.

 Table 2 shows the results.

 The same compound as the compound of Comparative Example 1 was used as a control compound. Table 2

(Note) Dose (mg / kg) Industrial applications

Compound (I) and a pharmacologically acceptable salt thereof of the present invention have as mentioned above V, receptor, V ₂ receptor together strong binding activity. Accordingly, the compound (I) of the present invention is useful for diseases associated with vasoprescin, such as congestive heart failure, edema, particularly cerebral edema, arginine vasopletusin hypersecretion syndrome (arginine vasobretsin secretion inappropriate symptom group), and hypertension. It is expected to exert excellent effects as a preventive or remedy for renal failure, pulmonary edema, Meniere's syndrome, etc., and as a diuretic.

Claims

97/17349 The scope of the claims  One-leg type (I) (I)

[In the formula, R ¹ represents a hydrogen atom, a hydroxyl group, a lower alkyl group, a halogen atom, a formyl group, or a carboxy group, R ² represents a hydrogen atom or a lower alkyl group, R ³ and R ⁴ may be the same or different and each represent a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkenyl group, a lower alkoxy group, an acyl group, a cyano group or a halogen atom; R ⁵ represents a hydrogen atom, a lower alkyl group or a phenyl group which may be substituted, R ⁶ represents a hydrogen atom or a lower alkyl group, Α ′ represents an oxygen atom, a sulfur atom or —NR ″ ¹ — (wherein R ⁷ represents a hydrogen atom or a lower alkyl group), A ² is one of CR ⁸ R ⁹ (wherein, one of R ⁸ and R ⁹ represents a hydrogen atom, and the other is a hydrogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted represents an alkoxy group or an amino group which may be substituted, or R ⁸ and R ⁹ are linked to each other to represent an oxo group) or one NR ′ ° — (where R ^ie is a hydrogen atom, Which may be substituted (representing an alkyl group or an acyl group); A ³ is an oxygen atom, a sulfur atom or one NR ¹¹ — (wherein, R ' ¹ is a hydrogen atom or a lower 97/17349 Represents a kill group. ) Or a single bond, Z is a halogen atom, an optionally substituted heteroaryl group, — NR ¹² R ¹³ (wherein R ′ ² and R ¹³ are the same or different and represent a hydrogen atom or a lower alkyl group), and one C 一 NR ¹² R ′ ³ (wherein, R ¹² and R ″ have the same meanings as described above), a guanidino group, To Z (CH ₂ ) — A ⁴ — W ¹ W ² — R  ヽ (CH {Wherein, R ¹⁴ is a hydrogen atom, a lower alkyl group which may be substituted with a hydroxyl group, a lower alkoxycarbonyl group, a phenyl group (the phenyl group may be substituted with a hydroxyl group or a halogen atom ), A benzoyl group (the benzoyl group may be substituted with a hydroxyl group or a halogen atom), a dimethylphenyl group, and one NR ^I2 R ¹³ (wherein, R ¹² and R ¹³ have the same meanings as described above). ) -. CONR ¹² R ¹³ (wherein, R ¹²及beauty R ¹³ is of the same meaning as defined above), in one C (= NH) R ¹² (wherein, R ¹² have the same meanings as defined above ) Or

(Wherein, r represents an integer of 3 to 6.), A ⁴ represents a carbonyl group, one NR ¹⁵ — (wherein R ¹⁵ represents a hydrogen atom or a lower alkyl group), — NR ′ ⁵ CO (CH ₂ ),-(wherein, R ¹⁵ has the same meaning as described above, s represents 0 or an integer of 1 to 6) or a single bond, and W represents a nitrogen atom or a CH group. Represents a nitrogen atom or a CH group or represents an oxygen atom by W ² —R ^M , n represents an integer of 1 to 3, and p represents 0 or an integer of 1 to 3. } Or one Y—X {Y is an oxygen atom, a sulfur atom, — NR ¹⁵ — (wherein, R ¹⁵ has the same meaning as described above), ——CO〇 one or one NHCO—, and X is hydrogen atom, lower pole alkyl group {said low pole alkyl group is a halogen atom or an - optionally substituted with NR ^l2 R ¹³ (wherein, R ¹² and R ¹³ have the same meanings as defined above.) 97/17349 No. } Or an optionally substituted heteroaryl group. }, m represents 0 or an integer of 1 to 6. However, when A ³ is a single bond, ΠΊ represents an integer of 1 to 6. And a pharmacologically acceptable 5-membered azepine derivative represented by the formula: 2. A heterocyclic 5-membered azepine derivative or a pharmaceutically acceptable salt thereof according to claim I, wherein A ¹ is a sulfur atom, A ² is CH ₂ , and A ³ is an oxygen atom. 3. R ', R ² , R ³ , R ⁴ , and R ^S are all hydrogen atoms. [Condensed π 5-membered azepine derivative or a pharmacologically acceptable salt thereof according to claim 2].  4. N— [2— (2-chloroethoxy) 1-4 — [(5,6,7,8—tetrahydro 4 H—thieno [3,2-b] azepine-14-yl) carbonyl〗 phenyl ]-[1, 1 biphenyl] 1 2-carboxamide,  N— [2-[2-(4-Methylbiperazine-1 1-yl) Etkin] -1 4— [( 5,6,7,8-tetrahydro-4H-thieno [3,2-b] azebine-14-yl) carbonyl] phenyl]-[biphenyl] -12-carboxamide, ethyl 2-[[[1, -Biphenyl] -1-2-carbonyl] amino-5-1-[(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenoxyacetate ,  2 — [[[[Shi-biphenyl] -1-2-carbonyl] amino] —5— [(5, 6, 7, 8-tetrahydro 4 H-thieno [3,2-b] azepine-4-yl) carbonyl] phenoxy ^ acid,  N— [2— [2- (4-Methylbiperazine-1 1—yl) 1—2-year-old ethoxylate] —4 — [(5,6,7,8—tetrahydro 4 H—thieno [3,2 — B] azepin-4-yl) carbonyl〗 phenyl] -1- [biphenyl] -12-carboxamide, N- [2 -— (5-chloropentoxy) -1-4-[(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepin-14-yl) carbonyl] phenyl] One [one 1'-biphenyl] one two-carboxamide, 97/17349 N— [2— [5— (4-Methylbiperazine-1 1-yl) pentoxy] —4—1 ((5,6,7,8—tetrahydro 4 H—thieno [3,2—b] azepine 1 4 Carbonyl) phenyl] — [C 1'-biphenyl] —2-carboxamito ”,  N- [2— [5— (4-Methyl perhydro 1,4,1-diazepine 1-yl) pentoxy] -4 — [(5,6,7,8-tetrahydro 4 H—thieno [3,2 1 b] azepine- (4-yl) carbonyl] phenyl] — [1,1'-biphenyl] -1-2-carboxamide,  N- [2— [2- [4- (4-fluorophenyl) piperazine-1-11yl] ethoxy] 1-41 [(5,6,7,8-tetrahydro-1-4H-thieno [3,2-b] azepine-41-yl) carbonyl] phenyl] -1- [1, -biphenyl] 1-2-carboxamide,  N— [2— (3-Chlorobroboxy) -1-4-((5,6,7,8-tetrahydrido — 4 H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] — [Shi-biphenyl] — 2-carboxamide,  N- [2- [3 -— [Ν'-methyl-N '-(1-methylbiperidine-1 4-amino) amino] propoxy] —4 — [(5,6,7,8—tetrahydro 4 4 —Thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] -1- [1, -biphenyl] -12-carboxamide,  N— [2— (4-chlorobutoxy) 1 4 -— [(5,6,7,8-tetrahydro—4H-thieno [3,2-b] azepine-1 4-yl) carbonyl] phenyl]  [1, -biphenyl] — 2-carboxamide,  N— [2— [4- (4-Methyl-perhydro-d- 4-D-lazebine-1-1-yl) Butoxy] 1-41-[(5,6,7,8-Tetrahi-Draw 4 H—Thieno [3,2- b] azepine-41-yl) carbonyl] phenyl]-[1-biphenyl] -12-carboxamide, N— [2-[4-CN * one (2-dimethylaminoethyl) one N '— methylamine 97/17349 [No] butoxy] 1-4 [[5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-14-yl) carbonyl] phenyl] -1- [shi1'-biphenyl] One 2—carboxamide,  N- [2— [4- (4-Methylbiperazine-1 1-yl) butoxy] 1-41 [(5,6,7,8-tetrahi draw 4 H-thieno [3,2-b] Azepine-14-yl) carbonyl] phenyl] -1- [1,1'-biphenyl] -12-carboxamide, N— [2— (pyridin-1-3-yl) methoxy 41- [(5, 6, 7, 8—tetrahi draw 4 H—thieno [3,2-b] azepin 1-4-yl) Carbonyl] phenyl] — [1,1'-biphenyl] —2-carboxamide,  N— [2— (2-Dimethylaminoquinone) 1-4 — [(5,6,7,8—tetrahydro-4H—thieno [3,2—b] azevin-1-yl) carbonyl] phenyl ] — [1, 1-biphenyl] — 2-carboxamide,  N— [2— (2-morpholinoetkin) -1-4-[(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepin-14-yl) carbonyl] phenyl] -[1,1'-biphenyl] 1-2-carboxamide,  N- [2-[2 -— (4-Methyl-hydroxy-1, 4-diazepine—11-yl) ethoxy] 1-41 [(5,6,7,8-tetrahi draw 4 H—thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] -1- [1, -biphenyl] -12-carboxamide,  N— [2-[2— [2— (cyclohexaluminamino) etokine] 1-41 ((5,6,7,8-tetrahydro 4 H-thieno [3,2—b] azepine-1 Le) carbonyl] phenyl] 1- [biphenyl] 1-2-carboxamide, N— [2- [2- [4-[(pyrrolidine-1 1-yl) piperidino] etokine] 4-([5,6.7,8-tetrahydro 4H-thieno [3,2— b] azepine-14-yl) carbonyl] phenyl] -1- [bi-phenyl] -12-carboxamide, N— [2— [2-(4—Piberi zino Biberi zino) ethoxy] 1 4 1 [(5, 6, 97/17349 7,8-tetrahydro 4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] -1- [1, Γ-biphenyl] —2-carboxamide, N— [2- [2 — [4-(4-Hydroxyphenyl) piperazine 1 1 —yl] ethoxy] 1 4 1 [(5,6,7,8—tetrahydro 1 4 H—thieno [3,2-b] Zepin (41-yl) carbonyl] phenyl]-[biphenyl] — 2-carboxamide,  N— [2— [2-[(4-ethoxycarbonyl) piperazine-1 11yl] ethoxy] 1-4 1 [(5, 6, 7, 8—tetrahydro-1 4 H—thieno [ 3, 2 -b] azepine-4 yl) carbonyl] phenyl] 1- [1, -biphenyl] — 2 carboxamide,  N- [2— [2— (4 -methylperhydro-1, -dazepine-1 1 -yl) 1 -2-oxethoxyethoxy] 1 4— [(5,6,7,8-tetrahido □ — 4 H— Ceno [3,2-b] azepine-41-yl> carbonyl] phenyl] — [shi I'-biphenyl] 12-carboxamide,  N— [2 — [[[1,1'-biphenyl] -2-carbonyl] amino] -1-5-((5,6,7,8-tetrahydro-1-4H-thieno [3,2-b ] Azepine-1 4-yl) carbonyl] phenoxy] acetyl] 1-L-prolinamide,  N- [2-[2-okitwo 2-(4-piperidino piperidino) etkin] 1 4-[(5, 6, 7. 8-tetrahi draw 4 H-thieno [3, 2-b] azepine 1-41-yl) carbonyl] phenyl]-[biphenyl] —2-carboxamide,  N- [2- [2-oxo-1-2- [4-(pyrrolidine-1-1yl) piperidino] etokine] -4-1 [(5,6,7,8-tetrahydro 4H-thieno [3, 2—b] azepine 4- (yl) carbonyl] phenyl]-[1'-biphenyl] -2-carboxamide, N- [2— [2-(4-Dimethylamino biperidino) 1 2-oxoetokine]--[(5, 6, 7, 8— tetrahi draw 4 H—thieno [3, 2— b] azepi 97/17349 1-41-yl) carbonyl] phenyl]-[1'-biphenyl] -12-carboxamide,  N— [2— [2 — [(1-Methyl-1H—1,2,3,4-tetrazol-5-yl) thio] etkin] —4-one [(5,6,7,8-tetrahydro 4 H-thieno [3,2-b] azepine-41-yl) carbonyl] phenyl]-[biphenyl] —2-carboxamide,  N— [2-(3-phthalimidoproxy) 1-41 [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-1 4-yl) carbonyl] Nil] i [i 1'-biphenyl] i 2 -carboxamide,  N— [2— (3-Aminobroboxy) -1-4-((5,6,7,8-tetrahydric-4H-thieno [3,2-b] azepin-1-4-yl) carbonyl] phenyl] One [1,1'-biphenyl] — 2-carboxamide,  N— [2-[3— (chloroacetylamino) propoxy] 1 4 1 [(5, 6, 7, 8—tetrahydro 1 4 H—thieno [3, 2— b] azepine 1 4 Le) carbonyl, phenyl]-[1, -biphenyl] -12-carboxamide,  N— [2— [3 — [(4-Methylbiperazine-1 1-yl) acetylamino] probokin] 1-41 [(5,6,7,8-tetrahydro 4 H-thieno [3,2—b ] Azepine-41-yl) carbonyl] phenyl]-[[bi-phenyl] -12-carboxamide,  2-[[[[1,1'-biphenyl] -1-2-carbonyl] amino] -1 5 — [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-1 4 — (Yl) caprolponyl] phenoxyacetic acid amide,  N— [2-[2-(4-benzhydrylbiperazine-1-yl) ethkin] -1-4-[(5,6,7,8-tetrahydr-4H-thieno [3,2-b] azepine 1-41) carbonyl] phenyl] — [1, —biphenyl] 1-2-carboxamide, N— [2-[2-[(4-Fluorobenbuil) Piberi Zino] Etkin] 1-4 97/17349 1 [(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl] — [1, -biphenyl] — 2-— ,  Ethyl 4 — [2 — [[[1,1'-biphenyl] 1-2-carbonyl] amino]-5-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] Azepine (41-yl) carbonyl] phenoxy] butyrate,  4-[2-[[[1, 1 '-biphenyl] -1-2-carbonyl] amino] 1 5 — [(5,6,7,8-tetrahidro 4 H-thieno [3,2-b ] Azebin-1-yl) carbonyl] phenoxy] butyric acid,  N— [2— [4-(4-Methylbiperazine-1 1-yl) 1-4-oxobutoxy]--[(5,6,7,8-tetrahydro 4 H-thieno [3,2—b〗 azepin- 4-yl) carbonyl] phenyl] -1- [1, -biphenyl-12-carboxamide,  N— [2— [4— (4-Methyl perhydrone 4-diazepine-1—yl) -14-oxobutoxy] 1-41-[(5,6,7,8—tetrahydro-4H—Ceno [3 , 2 -b] azebine—4—yl) carbonyl] phenyl] — [shi 1'-biphenyl] -1-2—carboxamide,  N— [2— [4- (4-dimethylaminobiperidino) -1 4—oxobutokin] -4 — [(5,6.7,8—tetrahydro 4 H—thieno [3,2—bazepine-4-1 Yl) carbonyl] phenyl] 1 [1,1'-biphenyl] -2-carboxamide,  N- [2 — [(pyridin-4-yl) methoxy] —4 — [(5,6,7,8—tetrahydro-1H-thieno [3,2—b] azebin-14-1 Yl) carbonyl] phenyl] -1- [1, -biphenyl] -12-carboxamide, N— [2-[2-(Indone 3 -yl) Etkin]] 4 — [(5, 6, 7, 8 — Tetrahi Draw 4 H—Thieno [3, 2 — b] Azepin 1 4 1-yl) carbonyl] phenyl] -1- [1,1'-biphenyl] -12-carboxamide, 97/17349 N- [2 -— [3-(4-Methylbiperazine-1-yl) propoxy] 1-41-[(5,6,7,8-tetrahydro-1-4H-thieno [3,2-b] Azebin-14yl) carbonyl] phenyl] -1- [1,1'-biphenyl] 1-2-carboxamito ",  N— [2— [3— (4-Methylbarhydr-1--1,4-dazepine-1-yl) Broboxy] 1-41 ((5,6,7,8-Tetrahydr 4H—thieno [3,21-1 b] azepine-41-yl) carbonyl] phenyl]-[biphenyl] -2-carboxamide,  2-[[[1,1 * -Biphenyl] carbonyl] amino] 1 5— [4 — [(5,6,7,8—tetrahydro-4H—thieno [3,2—b] azebin 1-41) carbonyl] phenoxycarboxamide,  N— [2— [3- (4-Dimethylaminobiperidino) propoxy] —4-[(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-4-yl) carbonyl ] Phenyl] — [shi—biphenyl] -1-2-carboxamide, N— [2-[4-(4-ethylviverazine)) Butoxy]-4— [( 5,6,7,8-tetrahydro-14H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl]-[1-biphenyl] -12-carboxamide, N— [2— [4- (4-dimethylamino-biperidino) butoxy] _ 4-1- [(5, 6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-14-yl) carbonyl] phenyl]-[1-biphenyl] -12-carboxamide, N— [2-[4-(piperazine-1 1-yl) 1-4-oxobutoxy] 1-41 (5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine 1-4 L) carbonyl] phenyl] 1- [shi 1-biphenyl] 1-2-carboxamide, N- [2- [4- [4- (4- (pyrrolidine-1-1-yl) piperidino] butkin] -1-4-((5,6,7,8-tetrahydro-1H-thieno [3,2-b] Azepine 1-41) carbonyl] phenyl] — [shi—biphenyl] —2-carboxamide, 97/17349 N— [2—C 4-[4- (Pyrrolidine-1- 1-yl) piperidino] -4 -oxobutoxy] — 4-[(5,6,7,8-tetrahydro 4H-thieno [3, 2-b] azepine-4-yl) carbonyl] phenyl]-[biphenyl]-1 -carboxamide,  N- [2— [4-(4-Biperidino piperidino) 1 4-oxobutoxy] 1 4 1 [(5,6,7,8-tetrahydro 4H-thieno [3,2—b] azebin-1 4-yl ) Carbonyl] phenyl] — [1,1′-biphenyl] —2-carboxamide,  N— [2— (4-aminobutoxy) 1-41 [(5,6,7,8-tetrahydro-1-4H-thieno [3,2-b] azepine-4-yl) carbonyl] phenyl] one  [1, -biphenyl] 1-2-carboxamide,  4- [2— (2-Methylbenzamide) -1-5-((5,6,7,8-tetrahydro 4H-thieno [3,2-b] azebin-1 4-yl) carbonyl] phenoxy Butyric acid,  N— [2— [4- (4-Dimethylaminobiperidin-1-yl) 1-14-oxobutoxy] —4-1 — ((5,6,7,8-tetrahydro-1-4H—Ceno [3, 2-b] azepine-1-4-yl) carbonyl] phenyl] -12-methylbenzamide, ethyl 4- [5 — [[[1,1-biphenyl] 1-2-carbonyl] amino] 1-2 — [(5 , 6,7,8-tetrahydro-4H-thieno [3,2-b] azepin-4-yl) carbonyl] phenoxy] butyrate,  4-[3-[[[1,1'-biphenyl] -1-2-carbonyl] amino] 1-6- [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepine I 4 —yl) carbonyl] phenoxy] butyric acid, N— [3-[4-(4-dimethylaminobiperidino) 1-4-oxobutoxy]-4-[(5, 6, 7, 8-tetrahydro 4H-thieno [3, 2-b] azepin 4 L) carbonyl] phenyl] 1- [1,1-biphenyl] 1-2-carboxamide, N- [2- [4-I- (4-Jetylamino-biperidino) -14-oxobutoxy]-4-C (5,6,7,8-tetrahydro-1H-thieno [3,2-b] azepin-4- Yl) carbonyl] phenyl-1 [1,1'-biphenyl] -12-carboxamide,  N- [2-[4-1 [Ν '— (2-dimethylaminoethyl) 1 N'-methylamino] 1-4-oxobutoxy]-4-[(5, 6, 7, 8-tetrahydro 4Η-thieno [3 , 2—b] azebin-1-yl) carbonyl] phenyl] -1- [1,1′-biphenyl] 1-2-carboxamide,  N— [2— [4-[Ν '— (2-ethylamino) — N' —ethylamino] 1 4-oxobutokin] 1-41 [(5,6,7,8-tetrahidro 4 Η— thieno [ 3, 2-b] azepine-4-yl) carbonyl] phenyl] — [shi 1'-biphenyl] 12-carboxamide,  N- [2- [4-CN'-I- (3-dimethylamino-provir) -N'-Methylamino]-4-year-old oxobutoxy] 1-4-[(5,6,7,8-tetrahydro-1-H) Thieno [3,2-b] azepine-4-yl) carbonyl] phenyl] — [1,1'-biphenyl] 1-2-carboxamide.,  N- [2— [4-(4-Methylamino biperidino) 1 4-oxobutokin 4- 1-C (5,6,7,8-tetrahedral 1 H-thieno [3,2—b ] Azebin-14-yl) carbonyl] phenyl]-[1'-biphenyl] -12-carboxamide,  N- [2-[4-(4-amino-biberidino) 14-oxobutoxy] -4-1 [(5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepine-4 1-yl) carbonyl] phenyl] — [[1'-biphenyl] 1-2-carboxamide ', N— [2-[4-[4- (4-Iminoethyl) piperazine- 1-yl] 1-4-oxobutokin] ー 4-[(5, 6, 7, 8-tetrahydric port-4H —Thieno [3,2-b] azebin-1-yl) carbonyl] phenyl]-[1,1-biphenyl -2—carboxamide,  N— [2— (4-guanidinobutoxy) 1-41 [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azepin-14-1yl) carbonyl] ] 1 [1,1'-biphenyl] 12-carboxamide and  N— [2— [4-[4- (4-hydroxyl) -pirazine] 1-child] Butoxy 4-1- [(5,6,7,8-tetrahydro-1 H-thieno [3, 2 -b] azebin-14-yl) carbonyl] phenyl]-[1, -biph-Xynl] -221carboxamide A fused 5-membered azepine derivative according to claim 3 of claim 3 selected from the claims of ifi. Or a pharmacologically acceptable salt thereof.  5. N- [2-[2-(4-Methylbiperazine-1-11yl) ethokine] 1-41 [(5,6,7,8-tetrahydro 4H-thieno [3,2-b] azebine-1 4 yl) carbonyl] phenyl) — [s 1 '1-biphenyl] 12-carboxamide',  2-[[[[1, biphenyl] -1-2-carbonyl] amino] -1 5— [(5, 6,7,8-tetrahydro 4H-thieno [3,2-b] azepine-4-yl) carbonyl] phenoxyacetic acid,  N— [2-[2-(4-Methylbiperazine _ 1-yl) 12-year-old ethoxy]--[(5, 6, 7, 8-tetrahydro 4 H-thieno [3, 2- b] azepin-4-yl) carbonyl] phenyl]-[1'-biphenyl] -12-carboxamide,  N— [2 -— [4- (4-methylperhydro-1,4-diazepine-1-yl) butoxy] 1-41-[(5,6,7,8-tetrahydro-4H-thieno [3, 2—b] azepine-41-yl) carbonyl] phenyl] — [shi 1'-biphenyl] -2-carboxamide, N— [2— [4-[Ν '— (2-dimethylaminoethyl) -N'-methylamino] butkin] 1-41 [(5, 6, 7. 8-tetrahydro 4 ド -thieno [3, 2 -b] azebin-1 4-yl) carbonyl] phenyl] — [1, -biphenyl 1] 2-carboxamide,  N— [2— [4- (4-Methylbiperazine-1 1-yl) butoxy] 1—4— [(5,6,7,8-tetrahydro-4H—thieno [3,2-b] azepine-4 Carbonyl) phenyl] 1- [1, biphenyl] 1-2-carboxamide, N- [2-[2— (4-Methyl-Bad Draw 1,4, -dazepine 1-yl) Etkin] -1 4— [(5,6,7,8-Tetra hydr 4H-thieno [3, 2-b] azepine-41-yl) carbonyl] phenyl]-[1-biphenyl] -1-2-carboxamide,  N— [2— [2-[4-(Pyrrolidine-1 1 -yl) Piberidino] Etkin] 1 4-[(5,6,7,8-tetrahydro 4 H-thieno [3,2— b ] Azebin-14-yl) carbonyl] phenyl] -1- [1, -biphenyl] —2-carboxamide,  N— [2— [2— (4-Piberidino biperidino) etokine] 1-41 ((5.6, 7,8—tetrahydro-4H—thieno [3,2—b] azepine-14) Carbonyl] phenyl]-[1, —biphenyl] -12-carboxamide,  N— [2— [2— (4-Methyl benzo o—1,4—dazepine-1—yl) -1-2-oxoequin] —4-1— (5,6,7,8—Tetrahydro 1 4 H—Ceno [3,2-b] azepine-14 yl) carbonyl] phenyl] 1 [shi 1 '— biphenyl] 1 2—carboxamide,  N— [2— [2—okifu 2— (4—piperidino piperidino) ethkin] 1-4 — [(5,6,7,8—tetrahydro-1 4 H—thieno [3,2-b] azepine- 4-yl) carbonyl] phenyl] — [shi-biphenyl] 1-2-carboxamide, N— [2- [2-oxo-1—2— [4- (pyrrolidin-1——dipipiperidino] etokin]] — 4 — [(5,6,7,8—tetrahydro 4H—thieno [3, 2—b] azepine-41-yl) carbonyl】 phenyl] -1- [1,1, '-biphenyl] -1-2-carboxamide, N— [2— [2- (4-Dimethylaminobiperidino) 1 2-oxoethoxyquin] -4 — [(5,6,7,8—tetrahydro 4 H—thieno [3,2—b] azepin-4 Yl) carbonyl] phenyl] — [shi 1'-biphenyl] 12-carboxamide,  N— [2-[3— [(4-Methylbiperazine-1 1-yl) acetyl Rmino] Proboxy] 1-41 [(5, 6, 7, 8—tetrahydro 4 H—thieno [ 3,2—b] azepine-41-yl) carbonyl] phenyl] -1- [1,1'-biphenyl] -1-2-carboxamide,  N— [2— [4-(4-Methylbiberazine-1 1-yl) 1 4-oxobutoxy]--[(5, 6, 7, 8—tetrahydro 4 H-thieno [3, 2—b] azepi Carbonyl) phenyl] one [one biphenyl] one two-box boxamide,  N- [2-[4— (4-Methyl-Bad Draw 1,4,4-Diazebine -11-yl)) 1 4-1oxobutokin] 1 4-1 [(5,6,7,8-Tetrahi Draw 4 H—Ceno [3,2-b] azepine-14-yl) carbonyl] phenyl]-[1'-biphenyl-1-2-carboxamide,  N- [2— [4-(4-Dimethyl-amino-piperidino) 1-4-oxobutokin]-4-[(5, 6, 7, 8, 8-tetrahydro 4 H-thieno [3, 2-b] azepine 4-yl) carbonyl] phenyl] 1- [1,1'-biphenyl] —2-carboxamide,  N- [2— [3- (4-Methylbiperazine-1 1-yl) propoxy] 1-41 [(5,6,7,8-tetrahydro 4H-thieno [3,2—b] azepine 1-41) carbonyl] phenyl] 1- [1'-biphenyl] 1-2-carboxamide ', N— [2— [3— (4-Methyl perhydro 1,4,1-diazepine 1-yl) Proboxy] 1-4— [(5, 6, 7, 8, 8-tetrahydro 4 H—thieno [3, 2- b] azepine (4-yl) carbonyl] phenyl] [1,1,1'-biphenyl] One 2—carboxamide,  N- [2 -— [3 -— (4-dimethylaminopiperidino) propoquine] -14-[(5,6.7,8-tetrahydro-1-4H-thieno [3,2-b] azebine-1-4- Yl) carbonyl] phenyl] -1- [1, -biphenyl] -12-carboxamide and  N- [2— [4- (4-ethyl-biperazine-1—yl) butoxy] 1-4- [( 5. 6,7,8-Tetrahydro-4H-thieno [3,2-b] azebin-14-yl) carbonyl] phenyl] — [1,1'-biphenyl] -12-carboxamide Item 5. The condensed hetero 5-membered azepine derivative or the pharmaceutically acceptable salt thereof according to Item 4.  6. A pharmaceutical composition comprising the fused hetero 5-membered azepine derivative according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a carrier.  7. A vasobretsin antagonist comprising the condensed hetero 5-membered azebine derivative according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.  8. A therapeutic drug for congestive heart failure, comprising the fused hetero 5-membered ring azepine derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.  9. A therapeutic agent for cerebral edema comprising the condensed hetero 5-membered azepine derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 to 5 in IB.  10. Treatment for hypersecretory syndrome of guinea pig vasobretsin containing the fused hetero 5-membered azebine derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 to 5. medicine.  6. A diuretic comprising the condensed hetero 5-membered ring azepine derivative according to any one of claims 1 to 5, or a pharmacologically acceptable salt thereof.  1 2. A remedy for deficiency comprising a fused hetero 5-membered azepine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 15 to 1 to 5. 1 3. A therapeutic agent for pulmonary edema comprising the fused hetero 5-membered azepine derivative or the pharmaceutically acceptable salt thereof according to any one of claims 5 to 1 to 5. 1 4. An agent for treating Meniere's syndrome comprising the fused hetero 5-membered ring azepine derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.  1 5. —General formula (II)

(Wherein, R ¹⁶ ′ represents a hydrogen atom or a lower alkyl group, R ¹⁸ represents a nitro group or an amino group, and R ¹ , R ² , R ³ , R ⁴ , A ¹ , A ² , A ³ or a 5-membered ring § peptidase Pin'ami de compounds terror into condensation represented by the representative.) the same meaning as described ⁴ in paragraph 1 range of billed respectively. 16. The fused hetero 5-membered ring azepine amide compound according to claim 15, wherein A ¹ is a sulfur atom. 1 7. A ¹ is an oxygen atom or a NR ⁷ group (wherein, R ⁷ is. Of the same meaning as defined above) 5-membered ring Azepin'ami de compounds hetero the condensation ranges first 5 claim of claim is. 1 8. Equation (I I I)

Compound represented by