WO1994005290A1 - Platelet aggregation inhibitor - Google Patents

Abstract

A platelet aggregation inhibitor containing an isoquinolinesulfonamide derivative represented by general formula (I) or a salt thereof, wherein R1 represents H, Cl or OH; A, R?2, R3 and R4¿ represent each a substituent selected dependent on R1, among which A represents C¿1?-C6 alkylene which may be substituted by alkyl, cinnamyl, phenyl or benzyl, R?2 and R3¿ represent each independently H, C¿1?-C6 alkyl, C6 or lower cycloalkyl, cinnamyl, phenyl or benzyl, or alternatively R?2 and R3¿ may be combined together to represent alkylene, and R4 represents H, C¿1?-C6 alkyl, phenyl, benzyl, benzoyl, cinnamyl, cinnamoyl, furoyl, (a) or (b), or alternatively R?4¿ may be combined with R3 to represent a carbon chain in which an oxygen atom may be interposed; R5 represents C¿1?-C6 alkyl; and R?6 and R7¿ are each selected dependent on R1 to represent H or CH¿3?, or alternatively R?6 and R7¿ may be combined together to represent C¿2?-C4 alkylene.

Description

 Specification

 Platelet aggregation inhibitor

Technical field

 The present invention relates to a novel use of an isoquinoline sulfonamide derivative. More specifically, the present invention relates to a platelet aggregation inhibitor containing a specific isoquinoline sulfonamide derivative or an acid addition salt thereof as an active ingredient.

 The platelet aggregation inhibitor of the present invention provides platelet aggregation induced by changes in basic substances (cells, intima, etc.) that constitute blood vessels (eg, blockage of blood vessels due to atherosclerosis, damage to blood vessels by vascular surgery). When administered to a patient suffering from various diseases caused by the above, platelet aggregation of the patient can be inhibited, which is effective for prevention and treatment of the above various diseases. Therefore, the platelet aggregation inhibitor of the present invention can be used for ischemic symptoms such as ulceration of terminal tissues or cold sensation due to chronic arterial occlusion, thrombosis associated with vascular surgery and extracorporeal blood circulation, venous thrombosis, and terminal limbs. It is useful for prevention and treatment of thrombosis and pulmonary thromboembolism.

Background art

Conventionally, certain isoquinoline sulfone amide derivatives have shown vasorelaxant relaxing action, blood flow increasing action, blood pressure lowering action, cerebral protective action, vasodilator, cerebral circulation improving agent, therapeutic agent for angina pectoris, It is already known that it is a useful substance as an antihypertensive, an agent for preventing and treating thrombosis of the cerebrocardiovascular system, and an agent for improving cerebral function. These are described in, for example, Japanese Patent Application Laid-Open No. 57-156643, USP 4,456,757, Japanese Patent Application Laid-Open No. 57-200366, US Pat. , 560, 755, JP-A-584-1

No. 2 1 278 and Japanese Unexamined Patent Publication No. Sho 58-121 2 279, U

SP 4, 525, 589, Japanese Patent Application Laid-Open No. 60-81,168

(Corresponding USP 4, 634, 770); Japanese Patent Application Laid-Open No. 2-565617, J. Pharmacol. Ep. Ther., Vol. 241, 1, 1033 Br. J. Pharmacol., Vol. 98, 109 (1 89 9); Blood vessels (bloodvessel), Vol.

M eth. Find In Exp. C ln. Pharmaco 1., Vol. 12, 443 (1990); Br. J. Pharmacol., Vol. . 103, 1 9 3 5

J. Pharmacol. Exp. T her., Vol. 25, 738 (1991); Eur. J. Pharmaco 1., Vol. 1 (1991); Eur. J. Pharmacol. Vol. 209, 39

Acta N eurochir., Vol. 110, 185 (1991); J. Pharmacol. Exp. Ther., Vol. 231, 1 41 (19984); J. Pharmacol. Exp. Ther., Vo]. 2333, 454 (19985), and the like.

More specifically, for example, for example, 11 (5—isoquinoline Sulfonyl) homopidazine and i- (1-hydroxyl-5-isoquinolinosulfonyl) isoquinoline sulfonamide derivatives such as homopidazine provide vascular smooth muscle relaxing action, blood flow increasing action, and blood pressure lowering action. And it has been reported that it has a cerebral protective action, etc. [Japanese Patent Application Laid-Open Nos. 61-115,8585 and 61-222,581] Corresponding USP 4,678,7783)].

 Also, it has been reported that isoquinoline sulfonamide derivatives such as N— (2-guanidinoethyl) -15-isoquinoline sulfonamide have a vascular smooth muscle relaxing action and a blood flow increasing action. [See Japanese Unexamined Patent Publication No. Sho 59-93054 (corresponding to US Pat. Nos. 4,634,770)].

 In addition, regarding certain isoquinoline sulfone amide derivatives, the above USP 4, 634, 770 describes effects on the mesenteric artery extirpated from egrets, canine femoral artery and vertebral artery blood. Examples of increasing effect on blood flow are disclosed, and the above-mentioned USP 4,678,783 discloses effects on the upper mesenteric artery isolated from the heron, increasing effect on canine femoral artery and vertebral artery blood flow, and natural effects. An example of the effect on blood pressure of an onset hypertensive rat is disclosed. These disclosures indicate that the isoquinoline sulfonamide derivative has various effects such as a vascular smooth muscle relaxing action and a blood flow increasing action.

However, there is a need for isoquinoline sulfone amide derivatives. The above reports relate to vascular smooth muscle relaxing action, blood flow increasing action, blood pressure lowering action, and cerebral protective action, and no report has been made to teach or suggest a platelet aggregation inhibitory action.

 As a result of various studies on new uses of the isoquinoline sulfone amide derivative, the present inventors have surprisingly discovered that a specific isoquinoline sulfone derivative has a platelet aggregation inhibitory activity, Due to its activity, it is caused by chronic arterial occlusion due to changes in basic substances (cells, intima, etc.) that constitute blood vessels (eg, occlusion of blood vessels due to atherosclerosis, or damage to blood vessels due to vascular surgery). Prevention and treatment of various ischemic symptoms such as ulcers or cold sensation in the terminal tissues of arteries, thrombosis associated with vascular surgery and extracorporeal blood circulation, venous thrombosis, terminal limb thrombosis, pulmonary thromboembolism Was found to be effective.

 More specifically, the addition of adenosine nitric acid and 9,11-dioxy 9α, 11α-metanoepoxy prostaglandin to human platelet-rich plasma induces platelet aggregation, It was surprisingly found that platelet aggregation was significantly suppressed when an isoquinoline sulfonamide derivative was added thereto. Platelet aggregation is induced when adenosine diphosphate is administered to a rat, but platelet aggregation is significantly suppressed when an isoquinoline sulfonamide derivative is added thereto. Was unexpectedly found.

Thus, the isoquinoline sulfone amide derivative is converted to cerebral heart blood. It is already known that it is effective for the prevention and treatment of vascular thrombosis. This is due to the vasodilator effect of the derivative, and as described above, the isoquinoline sulfone amide derivative is It is surprisingly surprising that it has platelet aggregation inhibitory activity and is effective in preventing and treating various diseases caused by changes in basic substances (cells, intima, etc.) that constitute blood vessels. It is to be done

 The present invention has been made based on these findings. Accordingly, an object of the present invention is to provide a novel platelet aggregation inhibitor which is clinically applicable and highly safe.

 According to the present invention, there is provided a platelet aggregation inhibitor comprising an effective amount of an isoquinoline sulfonamide derivative represented by the formula (I) or a pharmaceutically acceptable acid addition salt thereof.

In the formula (I), R ¹ represents a hydrogen atom, a chlorine atom or a hydroxyl group;

When R ¹ is a hydrogen atom, A is an alkyl having 2 to 6 carbon atoms. The alkylene group is unsubstituted or at least one hydrogen bonded to carbon is an alkyl, cinnamyl, phenyl or benzyl group having 1 to 10 carbon atoms. R ² is a hydrogen atom or a cycloalkyl group having 6 or less carbon atoms; R ³ is a hydrogen atom, a straight or branched alkyl group having 1 or 6 carbon atoms; group, cinnamyl group, full Eniru group or downy § in Njiru group Li; R ⁴ is a hydrogen atom, an alkyl group branches also is properly six linear 1 -C min, phenyl group benzyl group, Benzoiru group, thinner Mi Group, cinnamoyl group, floor group, formula

CH

一

one

(Wherein, R ⁵ is a straight-chain or branched alkyl group having 1 to 6 carbon atoms)

(In the formula, R ⁶ and R ⁷ are each independently a hydrogen atom or a methyl group, or R ⁶ and R ⁷ are directly bonded to each other to form an alkylene group having 2 or 4 carbon atoms.) Amidino group Alternatively, R ² and R ³ are directly bonded to each other to form an alkylene group having 4 or less carbon atoms, and this alkylene group is unsubstituted or has at least one hydrogen atom bonded to carbon atom. It may be substituted with 1 to 10 alkyl groups, phenyl groups or benzoyl groups;

Alternatively, R ³ and R ⁴ are bonded directly or via an oxygen atom to form a 5- to 6-membered heterocyclic ring with an adjacent nitrogen atom;

(式中、 R ⁶及び R ⁷は、 それぞれ独立に水素原子またはメチ ル基を表わす） で表わされるアミ ジノ基である。 When R ¹ is a chlorine atom or a hydroxyl group, A is an alkylene group having 2 to 6 carbon atoms, and this alkylene group is unsubstituted or has at least one hydrogen atom bonded to a carbon atom. R ² and R ³ are each independently a hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a carbon atom having 1 to 6 carbon atoms, Represents a cycloalkyl group having a number of 6 or less, or R ² and R ³ are directly bonded to each other to form an ethylene group or a trimethylene group, and these ethylene groups or In the trimethylene group, at least one hydrogen atom bonded to carbon may be substituted with 1 to 6 carbon atoms; R ⁴ is a hydrogen atom, 1 to 6 carbon atoms. An alkyl group of the formula

(Wherein, R ⁶ and R ⁷ each independently represent a hydrogen atom or a methyl group).

 Further, according to the present invention, an effective amount of an isoquinoline sulfone amide derivative represented by the formula (I) or an acid addition salt thereof is administered to a patient suffering from a myocardial disease and / or a myocardial cell disorder or a living body at risk thereof. There is provided a method for treating or preventing a myocardial disease and / or a myocardial cell disorder, which comprises administering.

In the formula (I), R ¹ is preferably a hydrogen atom or a hydroxyl group. When R ¹ is a hydrogen atom, A is an ethylene group or a trimethylene group, R ² and R ³ are directly bonded to each other, and when A is an ethylene group, a trimethylene group, A When is a trimethylene group, it forms an ethylene group, and .R ⁴ is preferably hydrogen.

When R ¹ is a hydroxyl group, A is an ethylene group or a trimethylene group, R ² and R ³ are directly bonded to each other, and when A is an ethylene group, the trimethylene group is When A is a trimethylene group, it preferably forms an ethylene group, and R ⁴ is preferably hydrogen.

 In the present invention, the following compounds can be mentioned as preferred specific examples of the isoquinoline sulfonamide derivative represented by the formula (I).

(1) 1- (5—isoquinoline sulfonyl) homopidazine (2) 1 — (5 — isoquinolinosulfonyl) 1 2 — methylphomopiperazine

 (3) 1 — (5 — isoquinolinin sulfonyl) 1 3 — Metylphomo piperazine

 (4) 1 — (5 — isoquinolinosulfonyl) 1 6 — methylphomo piperazine

 (5) 1 (5—isoquinoline sulfonyl) 1, 2, 3—dimethyl homopyrazine

 (6) 1 — (5 — isoquinolinosulfonyl) 1-3, 3 — dimethinole homopiperazine

 (7) 1 — (5 — isoquinolinosulfonyl) 1 3 — etilphomopiperazine

 (8) 1 — (5 — isoquinoline insulinorephonyl) _ 3 — propyl homo homopyrazine

 (9) 1 1 (5—isoquinolinosulfonyl) 1 3—isoptinolehomopyrazine

 (1 0) 1 — (5 — isoquinolinylsulfonyl) 1 3 — phe-homomopiperazine

 (1 1) 1- (5-isoquinolinosulfonyl) 1-3-benzyl homopiperazine

 (1 2) 1 — (5—isoquinolinosulfonyl) 1 6 —ethyl homopyrazine

(1 3) 1 — (5 — isoquinoline sulfonyl) 1 6 — propyl Norehomo pirazine.

(1 4) 1 — (5 — isoquinoline sulfonyl) 1-6 — butyl homopyrazine

 (1 5) 1 — (5 — isoquinolinin sulfonyl) 1 6 — pentyne homophopiperazine

 (16) 1 — (5 — isoquinolinylsulfonyl) 1 6 — hexylhomopiperazine

 (1 7) 1 1 (5-isoquinolinosulfonyl) 1 6-Phenolehomopirazine

 (18) 1 — (5 — isoquinolinosulfonyl) 1 6 — benzo-norrehomopirazine

 (1 9) 1 — (5 — isoquinoline sulfonyl) 1-41 methyl homopyrazine

 (2 0) 1 — (5 — isoquinoline snorlefonyl) 1 4 1-ethyl homopyrazine

 (2 1) 1 — (5—isoquinoline snorrephonyl)

 (2 2) 1- (5-isoquinolinosulfonyl) 1-4-butyl homopyrazine

 (2 3) 1 — (5 — Isoquinolinosulfonyl) 1 4 — Hexinolehomopirazine

(2 4) N- (2—aminoethyl) 1 1—chlor 5—isoquinoline sulfonamide (25) N— (4-aminobutyl) 1-1—chlor-5—isoquinoline sulfonamide

 (26) N-(2-amino 1-methylethyl) 1 1-chloride 5-isoquinoline sulfone amide

 (2 7) N-(2-Amino 1-methylpentyl) 1 1-Black 5-Isoquinoline

(2 8) N-(3-amino 2-methylbutyl) 1-1-chloro- _5- isoquinoline sulfonamide

 (2 9) N— (3—di-n-butylamino propyl) 1 1—Chlorenole 5—isoquinoline

 (30) N-(N-cyclohexyl N-methylaminoethyl) 1-1 chloronore 5-isoquinoline

 (3 1) N— (2 — guanidinoethyl) 1 1 — Chronole 1 5 — Isoquinoline sulfone amide

 (3 2) N-(4-guanidino butyl) 1 1-Chronol 5-Isoquinoline sulfonamide

 (3 3) N-(2 — guanidino 1-methylethyl) 1 1 — black 5 — iso-nore

 (3 4) N— (1—guanidinomethylpentyl) 1 1 1 chloro 5—isoquinoline sulfonamide

 (3 5) N-(2 — guanidino 1-3-methyltyl) 1 1-chlor 5-isoquinoline sulfonamide

(3 6) N-(3 — guanidino 1 2 — methylpropyl) 1 1 — Chlorine 5 — Isoquinoline sulfonamide

 (3 7) N— (41 guanidino 1 — methyltyl) 1 1 — Chlor 1 5 — isoquinoline sulfonamide

 (3 8) 2 — Methyl 1 4 1 (1 1 1 5 6 1 — Isoquinoline Snorehoninole) Pirazine

 (3 9) 2 —Ethyl 1 4 — (1 1 Chlor 1 5 —Isoquinoline Snorehoninore) Pirazine

 (4 0) 2 —isobutyl-1- 4 — (1-chloro-1 5 —isoquinoline sulfonyl) piperazine

 (4 1) 2, 5 — dimethyl 1 4 — (1 — chloro 1 5 — isoquinoline sulfonyl) piperazine

 (4 2) 1-methyl 4-1 (1-1 chloro-1 5-isoquinoline snorehoninole) piperazine

 (4 3) 1 — Amidino 1 4 1 (1 — Chronolé 5 — Isoquinoline Snorrehoninole) Pirazine

 (4 4) 1 Amidino 1 4 — (1 — Chlorine 5 — Isoquinoline Sonolehoninole) Homopyrazine

 (4 5) 1 Amidino 3 — Methyl 4 — (1 — Chronole 5 — Isoquinoline sulfonyl) piperazine

 (4 6) 1 Amidino 1, 2, 5 — Dimethyl 1 4 — (1 — Chloro 5 — Isoquinoline Snorrehonyl) Pyrazine

(4 7) N— (2—aminoethyl) 1 1—hydroxy 1 5—isoquinoline sulfonamide (4 8) N— (4-amino butyl) 1 1—hydroxy 1 5—isoquinoline sulfonamide

 (4 9) N-(2-amino 1-methylethyl) 1 1-hydroxy 5-isoquinoline sulfonamide

 (5 0) N— (2-amino 1-methyl heptyl) 1 1-hydroxy 1 5-isoquinoline sulfonamide

 (5 1) N-(3-amino 2-methyl butyl) 1-1-hydrid 5-isoquinoline sulfonamide

 (52) N— [3— (N, N-dibutylamino) propyl] —1—hydroxy-5-isoquinoline sulfonamide

 (53) N- [2- (N-cyclohexyl-N-methylamino) ethyl] — 1—hydroxy-5-isoquinoline sulfone amide

 (5 4) N-(2-guanidinoethyl) 1 1-Hydroxy 5-Isoquinoline

 (55) N- (4-guanidinobutyl) 1-1 -Hydroxyxy 5 -Isoquinoline sulfone amide

 (5 6) N-(2-guanidino 1-methylethyl) 1 1-Hydroxy 5-isoquinoline sulfonamide

 (5 7) N-(1-guanidinomethylpentyl) 1-1-Head mouth 5-Isoquinoline sulfonamide

(5 8) N— (2—guanidino 1-3—methylbutyl) 1 1—hydroxy 5—isoquinoline sulfonamide (5 9) N- (3-guanidino-1-methylpropyl) 1-1-hydroxy-1 5-isoquinoline sulfonamide

 (60) N— (4-guanidino-3—methylbutyl) 1-1—hydroxy-5—isoquinoline sulfonamide

 (6 1) 2 — methyl 4 — (1 — hydroxy 1 5 — isoquinoline snorrephonyl) piperazine

 (6 2) 2 —Ethyl 1 4 — (1 —Hydroxy 1 5 —Isoquinoline sulfonyl) piperazine

 (6 3) 2-isobutyl 1-4 (1-hydroxy 5-isoquinoline sulfonyl) pirazine

 (6 4) 2, 5-dimethyl 1-1 (1-hydroxy 5-isoquinoline snorrehonyl) piperazine

 (6 5) 1 —methyl 4 — (1 —hydroxy 5 —isoquinoline sulfonyl) piperazine

 (66) 1 Amidino 4 — (1 — Hydroxy 1 5 — Isoquinoline Sulfonyl) Pirazine

 (67) 1 Amidino 1 4 — (1 -hydroxy 1 5 — Isoquinolinosulfonyl) Homopiperazine '

 (68) 1 Amidine 3 — Methyl 4 — (1-Hydroxy — 5 — Isoquinoline Sulfonyl) Piperazine

 (6 9) 1 Amidine 2, 5 — Dimethyl 4 — (1 — Hidden mouth 5 — Isoquinolinin sulfonyl) Pyrazine

(7 0) N— (2 — methylaminoethyl) 1 1 1 Chlor 1 5 I-Sokinoline Sulfonamide

 (71) N- (2-ethylethylamino) 1 1-chloro-5-isoquinoline sulfonamide

 (7 2) N— (2—propylaminoethyl) 1 1—chloro-5—isoquinoline sulfonamide

 (73) N- (2-butylaminoethyl) 11-chloro-1 5-isoquinoline sulfonamide

 (7 4) N-(2-hexylaminoethyl) 1-1-chloro-1 5-isoquinoline sulfonamide

 (7 5) 1 1 (1 1 chloro no 1-5 — isoquinoline rinsolefonyl) piperazine

 (7 6) 1 1 (1-chloro-5-isoquinoline sulfonyl) homopyrazine

 (77) N— (2—methylaminoethyl) 1 1—hydroxy 1 5—isoquinoline sulfonamide

 (7 8) N— (2—ethinoreaminoethyl) 1-1—hydroxy-1-5—isoquinoline sulfonamide

 (7 9) N— (2—Propylaminoethyl) 1-1—Hydroxy1-5—Isoquinolinosulfonamide

 (80) N— (2-Butylaminoethyl) 1-1—Hydroxy —5—Isoquinoline sulfonamide

(8 1)-(2-hexylaminoethyl) 1 1-Hydroxy 1 5-Isoquinoline sulfonamide (8 2) 1 1 (1-Hydroxyxy 5—isoquinoline sulfonyl) Piperazine

 (83) 1 — (1-hydroxy-5-isoquinoline sulfonyl) homopiperazine

 (8 4) 1 — (5 — isoquinolinosulfonyl) 1-4 — methyl piperazine

 (8 5) 1 — (5 — isoquinolinylsulfonyl) ー 4 n- to xylbiperazine

 (8 6) 1 1 (5—isoquinolinin sulfonyl) 1 4—cinnaminole biperazine

 (8 7) 1 1 (5—isoquinoline sonolefonyl) piperazine (8 8) N- (2—amino ethyl) 1 5—isoquinoline sulfonamide

 (8 9) N— (4—aminobutyl) 1-5_isoquinoline sulfonamide

 (9 0) N— (3 —di-n-butylaminopropyl) — 5— Isoquinoline sulfonamide

 (9 1) 1 — (5 — isoquinolinosenorefonyl) 1 3 — methylpiperazine

 (92) 1 1 (5—isoquinoline sulfonyl) 1 3—isobutylpiperazine

(93) 1 1 (5—isoquinoline sulfonyl) 1,2,5—dimethyl biperazine (9 4) N— (3 — guanidino 1 2 — phenylpropyl) — 5 — isoquinoline sulfone amide

 (9 5) N— (6 — guanidino 1-1 -methyl heptyl) 1-5-isoquinoline sulfone amide

 (9 6) 2 — [2 — (5 — isoquinoline sulfonamide) ethylamino] — 2 — imidazoline

 (9 7) 2 — amidino 1-1 (5-isoquinoline sulfonyl) piperazine

 (98) 4—Amidino 1,2,5—Dimethyl 1 (5—Isoquinoline sulfonyl) piperazine

 (9 9) 4-amidino 1-1 (5-isoquinoline sulfonyl) homopyrazine

(100) 4 1 (N ¹ , N ² —dimethylthiomidino) 1 1 — (5 —isoquinoline sulfonyl) piperazine

 (1 0 1) 4 Amidine 3 — butyl 1 1 — (5 — isoquinoline snorephonyl) piperazine

 (1 0 2) 4 —Hexyl 1 1 (5—Isoquinoline sulfonol) Ethylenediamine

 (10 3) N— (4-guanidinobutyl) 1-5—isoquinoline

(10 4) N- (2—guanidinoethyl) 1 5—isoquinoline The isoquinone sulfone amide derivative as an active ingredient of the platelet aggregation inhibitor of the present invention also includes an acid addition salt of the isoquinolin sulfone amide derivative represented by the formula (I). These salts are pharmaceutically acceptable non-toxic salts, for example, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and acetic acid, citric acid, tartaric acid, lactic acid, succinic acid Salts of organic acids such as acid, fumaric acid, maleic acid and methansulphonic acid can be mentioned.

 In the present invention, the method for producing the isoquinoline sulfonamide derivative represented by the formula (I) is not critical, and it can be produced by various methods. For example, Japanese Unexamined Patent Publication Nos. Sho 61-1526585 and Sho 61-227581 (corresponding US Pat. Nos. 4,678,783) and Sho 5 7 — 1 5 6 4 6 Publication, USP 4, 456, 757, Japanese Patent Application Laid-Open No. 57-200366, USP 4, 560, 755, Japanese Patent Application Japanese Patent Publication No. Sho 58-122 and Japanese Patent Laid-Open Publication No. Sho 58-121, 79, USP 4,525,589, Japanese Patent Publication No. 59-993504 And the methods disclosed in Japanese Patent Application Laid-Open No. 60-81116 (corresponding US Pat. Nos. 4,634,770) can be referred to.

For example, 1- (5-isoquinolinylsulfonyl) homopyrazine represented by the formula (IV) can be converted into 5- (isoquinolinesulfonic acid chloride) represented by the formula (V) according to the following reaction formula. Can be obtained by reacting with a homopirazine represented by the formula (VI).

 (V) (VI) This method can be carried out according to the method described in USP 4, 676, 783.

 The acid addition salt of an isoquinoline sulfonamide derivative can be easily produced by reacting the above-mentioned isoquinoline sulfonamide derivative product with an inorganic acid or an organic acid, and conversely. When the produced compound is originally an acid addition salt and the target compound is desired in the form of a free form, it can be easily converted to a free form by treating with an alcohol. You.

 The isoquinoline sulfonine amide derivative represented by the formula (I) or an acid addition salt thereof, which is an active ingredient of the platelet aggregation inhibitor according to the present invention, may be administered alone or may be pharmaceutically acceptable. May be administered as a composition with the carrier, diluent or excipient used. The component ratio in the composition can be appropriately determined depending on the administration route, administration plan and the like.

 Further, the isoquinoline sulfonamide derivative represented by the formula (I) may be used in combination with other drugs depending on the patient's symptoms.

When the isoquinoline sulfone amide derivative represented by the formula (I) is orally administered, tablets, capsules, powders, granules, It can be used in the form of solutions, elixirs and the like, or, for parenteral administration, in the form of injections, suppositories, ointments or nasal drops.

 Solid carriers used for oral administration include, for example, oligosaccharides such as lactose sucrose and mannitol; starches such as corn and potato crystalline cellulose, calcium phosphate, and synthetic calcium carbonate; Agent: sodium or calcium salt of carboxymethyl cellulose; fatty acid salt such as magnesium stearate; Agar, gum, sodium alginate; polyethylene dalicol.

 In the case of capsules, tablets, granules, and powders, they are formulated so as to generally contain 1 to 80% by weight, preferably 1 to 60% by weight of an isoquinoline sulfonamide derivative as an active ingredient. .

 When the oral administration is in liquid form, it is preferable to use a solution containing 0.11 to 20% by weight of the active ingredient and a syrup. In this case, the carrier is water or ethanol. In addition, it is desirable to add fragrances and sweeteners.

When administered parenterally by intramuscular injection, intravenous injection, or subcutaneous injection, the isoquinoline sulfonamide derivative represented by the formula (I) as an active ingredient is used to make the solution isotonic. Used as a sterile solution to which other solutes such as salt or glucose are added. Suitable solvents for injection include sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, glucose, liquid for intravenous injection, electrolyte solution (for intravenous injection), etc. Is mentioned. In the case of these liquid for injection is normally 0.0 1-2 0% by weight, is preferred properly containing from 0.1 to 1 0 weight _^0/0 Lee Sokino Li main routine Hon'a Mi de derivative as an active ingredient It is preferable to do so.

 When administered as a suppository or ointment (transdermal), it is preferable to prepare a preparation containing 1 to 80% by weight of an isoquinoline sulfonamide derivative as an active ingredient. Examples include animal and plant fats and oils such as serine, paraffin, dense roast, lanolin, and cocoa butter; synthetic fats and oils such as macrogol and witetbuzole; emulsifiers; preservatives; Accelerators and the like can be added.

 For nasal administration, the active ingredient can be formulated with an emulsifier or other enhancer, along with the carriers used in the solutions described above.

The dosage of the isoquinoline sulfonamide derivative represented by the formula (I) is determined by the patient's age, health condition, weight, degree of symptoms, type of concurrent treatment, if any, treatment frequency, and desired treatment. Although it varies depending on the nature of the effect, it is generally 0.01 to 40 mg Z kg (body weight) · day. In particular, in the case of oral administration, a dose of 0.02 to 40 mg / kg (body weight) · day is preferred, and in the case of parenteral administration, 0.1 mg / kg (body weight) 'day is preferred. I like it. Also, the frequency of administration may be once or several times a day. It is. In the case of intravenous administration, an injection containing the isoquinolinosulfonyl derivative represented by the formula (I) can be administered, for example, for 30 to 60 minutes at a time.

 The platelet aggregation inhibitor of the present invention can surely inhibit platelet aggregation as shown in the following Examples.

BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. Example 1

Inhibitory effect on human platelet agglutination

3.8% sodium citrate (10% of the volume of blood to be collected) was added to the syringe barrel of the syringe in advance and the blood collected from the human vein was rotated 1000 times. After centrifugation for 5 minutes, platelet-rich plasma (PlateRich Plasma, hereinafter referred to as “PRP j”) was prepared.PRP 200 μl was added to the cuvette of the platelet aggregometer. 25 μl of the test compound dissolved in pure water was added, mixed, and incubated at 37 ° C. for 3 minutes, and then adenosine diphosphate (ADP) as a platelet aggregation-inducing substance with stirring. Solution (final concentration Ι Ο μ Μ) and 9,11-dioxy-9α, 11-methyl-1-epoxy-prostaglandin F 2a (U-4666-19) solution (final concentration) 25 μΜ) was added, and the change in permeability due to platelet aggregation was measured. The measurement was carried out with various changes as shown in Table 1, and the concentration of the compound that inhibits blood / J-plate aggregation by 50% in this measurement system, IC ₅ . The value was determined. The results are shown in Table 1.

 Table 1

As shown in Table 1, it was found that compound (1) and compound (83) suppressed platelet aggregation by ADΡ. It was confirmed that the compound represented by the formula (I) was effective as a platelet aggregation inhibitor. Example 2

 Effects on acute pulmonary thromboembolism in mice

The test compound was orally administered to 20 ddy mice (male, 5 weeks old) that had been fasted the previous day, and then allowed to stand for 15 minutes, followed by a platelet aggregation inducer, adenosine diphosphate (ADP). The solution (Note 1) was administered via the tail vein to induce acute pulmonary thromboembolism. Then, the number of deaths within 10 minutes after the administration of the ADP solution was observed, and the compound showing 50% suppression of the mortality of the control group (Note 2) was just observed. Concentration IC ₅ of things. The value was determined. The results are shown in Table 2 Table 2

註 1) * ： ADP溶液は 400mg/10mfi (生理食塩水）/ kg (体重） を投与した。 註 2 ) * ： 対照群に於ける死亡率が 80%になるよ う に、

Note 1) *: ADP solution was administered at 400mg / 10mfi (physiological saline) / kg (body weight). Note 2) *: The mortality rate in the control group was 80%.

 The concentration of the ADP solution and the dose were set.

As shown in Table 2, compound (1) and compound (83) were found to significantly reduce the mortality in a mouse acute pulmonary thromboembolism model. It has been confirmed that the compound represented by the formula (I) is a useful drug for prevention and treatment of various diseases caused by platelet aggregation induced by changes in basic substances constituting blood vessels.

EXAMPLE 3 Test compound was dissolved in pure water, S 1 c: oral single dose to ICR strain 5-week old male mice, LD ₅ from the test compound amount mouse mortality is 50%. The value was determined. Table 3 shows the results. Table ύ

第 3表に示す通り 、 式 （ I ) に示す化合物は、 薬理効果発 現量と L D ₅。の値に 1 0倍の開きがぁリ 、 該化合物の安全性 が確認された。 計

As shown in Table 3, the compounds shown in formula (I), the pharmacological effect onset expression level and LD _5. The value of 倍 was 10-fold larger, confirming the safety of the compound. Total

Example 4

 1

 8

 Formulation example o

(1) Tablets Tablets containing the following ingredients are prepared by a known method. Ingredients Preparation Example Compound (1) Hydrochloride 30 mg Crystalline Senolerose 40 mg Lactose 0 3 mg Magnesium stearate 2 mg Canoleboximetinolenelorero -Scanoresium 5 mg (2) Sterile injection

Dissolve the following components in distilled water, then add distilled water to the required final volume. The obtained solution is sealed in a predetermined number of samples each of 2 mβ, and sterilized by heating. The composition of one ampoule is as follows. Ingredient Preparation Example Compound (1) Hydrochloride 50 mg Sodium chloride 6 mg Distilled water Amount that total volume becomes 2 mβ

Industrial applicability

 The platelet aggregation inhibitor of the present invention containing an effective amount of a specific isoquinoline sulfonamide derivative or an acid-added salt thereof is effective for the change of basic substances (cells, inner membrane, etc.) constituting blood vessels. Various diseases caused by platelet aggregation induced by ischemia, such as ischemic symptoms such as ulceration of terminal tissues or cold sensation due to chronic arterial occlusion, thrombosis associated with vascular surgery and extracorporeal blood circulation, venous thrombosis, It is useful for prevention and treatment of terminal limb thrombosis and pulmonary thromboembolism.

Claims

The scope of the claims .  1. A platelet aggregation inhibitor comprising an effective amount of an isoquinoline sulfone amide derivative represented by the formula (I) or a pharmaceutically acceptable acid addition salt thereof.

In the formula (I), R ¹ represents a hydrogen atom, a chlorine atom or a hydroxyl group; When R ¹ is a hydrogen atom, A is an alkylene group having 2 to 6 carbon atoms, and this alkylene group is unsubstituted or has at least one hydrogen atom bonded to a carbon atom. May be substituted with 1 to 10 alkyl groups, cinnamyl groups, phenyl groups or benzyl groups; R ² is a hydrogen atom or a cycloalkyl group having 6 or less carbon atoms; R ³ Is a hydrogen atom, a linear or branched alkyl, cinnamyl, phenyl or benzyl group having 1 to 6 carbon atoms; R ⁴ is a hydrogen atom, 1 to 6 carbon atoms Straight-chain or branched alkyl, phenyl, benzyl, benzoyl, cinnamyl, cinnamoyl, furoyl,

(Wherein, R ⁵ is a straight-chain or branched alkyl group having 1 to 6 carbon atoms)

(Wherein, R ⁶ and R ⁷ are each independently a hydrogen atom or a methyl group, or R ⁶ and R ′ ⁷ are directly bonded to each other to form an alkylene group having 2 or 4 carbon atoms). The amidino group represented or R ² and R ³ are directly bonded to each other to form an alkylene group having 4 or less carbon atoms, and this alkylene group is unsubstituted or at least one bonded to carbon. May be substituted with an alkyl group having 1 to 10 carbon atoms, a phenyl group or a benzoyl group; Alternatively, R ³ and R ⁴ are bonded directly or via an oxygen atom to form a 5- to 6-membered heterocyclic ring with an adjacent nitrogen atom; When R ¹ is a chlorine atom or a hydroxyl group, A is an alkylene group having 2 to 6 carbon atoms, and this alkylene group is unsubstituted. Or at least one hydrogen atom bonded to carbon atom may be substituted by an alkyl group having 1 to 6 carbon atoms; R ² and R ³ each independently represent a hydrogen atom, 1 to 6 carbon atoms Represents a straight-chain or branched alkyl group or a cycloalkyl group having 6 or less carbon atoms, or R ² and R ³ are directly bonded to each other to form an ethylene group or a trimethylene group. These ethylene or trimethylene groups are formed and at least one hydrogen atom bonded to carbon may be replaced by an alkyl group having 1 to 6 carbon atoms; R ⁴ is hydrogen. Atom, alkyl group of 1 to 6 carbon atoms, or formula

(Wherein, R ⁶ and R ⁷ each independently represent a hydrogen atom or a methyl group). 2. In the formula (I), R ¹ is a hydrogen atom, A is an ethylene group or a trimethylene group, R ² and R ³ are directly bonded to each other, and when A is an ethylene group, Application Benefits methylcarbamoyl alkylene group, a forms a ethylene lens group when the Application Benefits methylcarbamoyl alkylene group, R ⁴ is a platelet aggregation inhibitor according to claim 1 Ru hydrogen der. 3. In the formula (I), R ¹ is a hydroxyl group, A is an ethylene group or a trimethylene group, and R ² and R ³ are directly linked to each other. 290  3 1 Combined with a platelet aggregation inhibitor according to claim 1 when drill main styrene group, A is the Application Benefits main styrene groups form an ethylene group, R ⁴ is hydrogen when A is an ethylene group.  4. A composition comprising an effective amount of an isoquinoline sulfone amide derivative represented by the formula (I) or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. The platelet aggregation inhibitor according to any one of claims 1 to 3, which is a substance.  5. A method for inhibiting platelet aggregation by administering to a living body an effective amount of an isoquinoline sulfone amide derivative represented by the formula (I) or an acid addition salt thereof.

In the formula (I), R ¹ represents a hydrogen atom, a chlorine atom or a hydroxyl group; When R ¹ is a hydrogen atom, A is an alkylene group having 2 to 6 carbon atoms, and this alkylene group is unsubstituted or has at least one hydrogen atom bonded to carbon having 1 to 6 carbon atoms. Replace with 10 alkyl, cinnamyl, phenyl or benzyl groups R ² may be a hydrogen atom or a cycloalkyl group having 6 or less carbon atoms; R ³ may be a hydrogen atom, a linear or branched alkyl group having 1 or 6 carbon atoms. , cinnamyl group, full Eniru group or downy § in Njiru group Li; R ⁴ is a hydrogen atom, an alkyl group branches properly even six linear 1 -C min, Fuyuniru group, a benzyl group, Benzoiru group, thinner Mill group, cinnamoyl group, floyl group, formula CH ゥ

one (Wherein, R ⁵ is a straight-chain or branched alkyl group having 1 to 6 carbon atoms)

(Wherein R ⁶ and R ⁷ are each independently a hydrogen atom or a methyl group, or R ⁶ and R ⁷ are directly bonded to each other to form an alkylene group having 2 or 4 carbon atoms) R ² and R ³ are directly bonded to each other to form an alkylene group having 4 or less carbon atoms, and this alkylene group is at least unsubstituted or bonded to carbon. One hydrogen has 1 to 1 carbon atoms Optionally substituted with 0 alkyl, phenyl or benzoyl groups; Alternatively, R ³ and R ⁴ are bonded directly or via an oxygen atom to form a 5- to 6-membered heterocyclic ring with an adjacent nitrogen atom; When R ¹ is a chlorine atom or a hydroxyl group, A is an alkylene group having 2 to 6 carbon atoms, and this alkylene group is unsubstituted or has at least one hydrogen atom bonded to a carbon atom. R ² and R ³ may each independently be a hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, or a carbon number having 1 to 6 alkyl groups; Represents 6 or less cycloalkyl groups, or R ² and R ³ are directly bonded to each other to form an ethylene or trimethylene group, and these ethylene or trimethyl groups are formed. The methylene group may be one in which at least one hydrogen atom bonded to carbon is replaced by an alkyl group having 1 to 6 carbon atoms; R ⁴ is a hydrogen atom and 1 to 6 carbon atoms. Alkyl group, or formula

(Wherein, R ⁶ and R ⁷ each independently represent a hydrogen atom or a methyl group). 6. In the formula (I), R ¹ is a hydrogen atom, A is an ethylene group or a trimethylene group, R ² and R ³ are directly bonded to each other, and A is an ethylene group. 6. The method according to claim 5, wherein a trimethylene group is formed when A is a trimethylene group, an ethylene group is formed when A is a trimethylene group, and R ⁴ is hydrogen. 7. In formula (I), R ¹ is a hydroxyl group, A is an ethylene group or a trimethylene group, R ² and R ³ are directly bonded to each other, and when A is an ethylene group, Application Benefits main styrene group, a is when the Application Benefits main styrene groups form an ethylene group, the method of claim 5 R ⁴ is hydrogen.