JPH07277979A - Therapeutic or preventive agent for hyperviscosity syndrome - Google Patents

Abstract

PURPOSE:To obtain a medicine containing, as active ingredient, a compound useful as an excellent therapeutic or preventive agent for hyperviscosity syn drome, high in safety and clinically applicable, as well as having cardioprotective and blood platelet coagulation inhibitory activities. CONSTITUTION:This therapeutic or preventive agent for hyperviscosity syndrome containing, as active ingredient, a compound of the formula (R<1> is H, Cl or OH; when R<1> is H, A is a 2-6C alkylene; R<2> is H; R<3> is H, a 1-6C alkyl, allyl or aralkyl; R<4> is H, a 1-6C alkyl, aryl, aralkyl, benzoyl, etc.; when R<1> is Cl or OH, A is a 2-6C alkylene; R<2> and R<3> each is H, a 1-6C alkyl, etc.; R<4> is H, a 1-6C alkyl or amidino) or an acid-added salt thereof. The compound of the formula is pref. 1-(5-isoquinolinesulfonyl)homopiperazine or 1-(1-hydroxy-5- isoquinolinesulfonyl)homopiperazine, and can be obtained, for example, by reaction between 5-isoquinolinesulfonic acid chloride and homopiperazine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic or preventive agent for hyperviscosity syndrome. In particular, it relates to a therapeutic or prophylactic agent for hyperviscosity syndrome, which comprises a substituted isoquinolinesulfonamide derivative represented by the following general formula (I) or an acid addition salt thereof as an active ingredient.

[0002]

2. Description of the Related Art In recent years, blood viscosity as a risk factor has attracted attention as blood viscosity measurement has become popular in clinical tests. New Physiology, Physiology of Blood (Vol. 15, p1-
p18, 1990, edited by Ichiro Nakama, Akikazu Takada, Medical School)
, Blood viscosity, hyperviscosity syndrom
e) is described in detail.

Blood viscosity is considered to be influenced by determinants such as hematocrit value, plasma composition and viscosity, red blood cell deformability, red blood cell aggregate formation, blood coagulation, and red blood cell and platelet aggregation. Elevated blood viscosity due to possible causes of the above determinants may result in circulatory disorders (Wells, R. Syndro
mes of hyperviscosity.New Engl. J. Med., 283: 183-
186 (1970)). The hyperviscosity group means diseases in which blood viscosity is increased due to various causes. For example, it is widely known that blood viscosity increases when hypertension, Raynaud's disease, diabetes mellitus, myocardial infarction, erythropoietin, or the use of drugs showing similar drug efficacy.

The causative diseases that occur in hyperviscosity syndrome based on the above-mentioned determinants can be summarized as follows. Increased erythrocyte count, erythrocytosis due to high hematocrit, dehydration, etc .; abnormal plasma protein, multiple myeloma due to promotion of erythrocyte aggregation, collagen disease, high fibrinogen, etc .; abnormal erythrocyte due to abnormal erythrocyte, decreased deformability Illness,
Polymerized hemoglobin, Heinz bodies, etc .; promotion of blood coagulation system based on irreversible aggregation of red blood cells, etc .; diabetes, myocardial infarction, etc. based on other complex factors.

Although the causative diseases are various, the symptoms that appear are, for example, cardiovascular symptoms (decreased pulse pressure, peripheral edema, and more advanced heart failure); ocular symptoms (venous dilation, meandering, microaneurysm, Retinopathy); hemorrhagic diathesis (mucosal hemorrhage); neurological symptoms (headache, dizziness, and more advanced central nervous system disorders)
And so on. However, at present, there is no definitive treatment for hyperviscosity syndrome.

On the other hand, the substituted isoquinoline sulfonamide derivative represented by the general formula (I) exhibits a vascular smooth muscle relaxing action, a blood flow increasing action, a blood pressure lowering action and a brain protecting action, and is a vasodilator and improves cerebral circulation. It is already known that it is an effective substance in agents, angina therapeutic agents, antihypertensive agents, prophylactic and therapeutic agents for cerebral cardiovascular thrombosis, cerebral function improving agents, etc. [eg JP-A-57-156463]. Publication, JP-A-5
7-200366, JP-A-58-112278, JP-A-58-112279, and JP-A-59-
93054, JP 60-81168 A, JP 61-152658 A, JP 61-2275 A.
No. 81, No. 2-256617, No. 4
-264030, J. Pharmacol. Ex
p. Ther. 231, 141 (1984), J. Ph
armacol. Exp. Ther. 233,454
(1985), J. Pharmacol. Exp. Th
er. 241, 1033 (1987), Br. J. Ph
armacol. 98, 1091 (1989), blood vessels
13, 199 (1990), Meth. Find Ex
p. Cln. Pharmacol. 12, 443 (19
90), Br. J. Pharmacol. 103, 19
35 (1991), J. Pharmacol. Exp.
Ther. 259, 738 (1991), Eur. J.
Pharmacol. 195, 267 (1991), E
ur. J. Pharmacol. 209, 39 (199
1), Acta Neurochir. 110, 185
(1991)]. These techniques described above are applied to the isolated superior mesenteric artery of the rabbit, the effect on the canine femoral artery, the vertebral artery and the coronary blood flow, the effect on the blood pressure of spontaneously hypertensive rats, the effect on the brain mitochondrial respiration control rate, and the hypoxic brain. Action on the mouse
It was inferred from the examples of the action on hippocampal nerve deficient gerbils and the action on smooth muscle proliferation, but no indication of the therapeutic or preventive agent for the hyperviscosity syndrome group of the present invention has been found.

[0007]

DISCLOSURE OF THE INVENTION Previously, the substituted isoquinoline sulfonamide derivative represented by the general formula (I) was found to have a cardioprotective effect and a platelet aggregation inhibitory effect. An object of the present invention is to provide an excellent therapeutic or prophylactic agent for hyperviscosity syndrome which is different from the above cardioprotective effect or platelet aggregation inhibitory effect and which can be applied clinically and has high safety.

[0008]

Means for Solving the Problems The present inventors have conducted extensive research on a substituted isoquinolinesulfonamide derivative represented by the general formula (I), and as a result, the compound has the above-mentioned vascular smooth muscle relaxing action and increase in blood flow. The present invention was completed by discovering that it has a therapeutic or preventive effect on hyperviscosity syndrome, which is completely unexpected from the conventionally known effects such as action, blood pressure lowering action, brain function improving action and tracheal smooth muscle relaxing action.
That is, the present invention is represented by the following general formula (I).

[0009]

[Chemical 4]

(In the formula, R ¹ represents hydrogen, chlorine or a hydroxyl group, and when R ¹ is hydrogen, A is an alkylene group having 2 to 6 carbon atoms and an alkyl group having 1 to 10 carbon atoms; It may have a substituent such as an aryl group or an aralkyl group, R ² is a hydrogen atom, R ³ is a hydrogen atom or an alkyl group having a straight or branched chain having 1 to 6 carbon atoms, Group, aralkyl group, R ⁴ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, aryl group, aralkyl group, or benzoyl group, cinnamyl group, cinnamoyl group, furoyl group Or a group represented by the general formula (II)

[0011]

[Chemical 5]

(Wherein R ⁵ is a linear or branched lower alkyl group having 1 to 6 carbon atoms), or a group represented by the general formula (III)

[0013]

[Chemical 6]

(In the formula, R ⁶ and R ⁷ are hydrogen atoms or are directly bonded to each other and are alkylene groups having 2 to 4 carbon atoms),
Alternatively, R ² and R ³ are directly bonded to each other to form an unsubstituted or alkyl group having 1 to 10 carbon atoms, a phenyl group, an alkylene group having 4 or less carbon atoms substituted with a benzyl group, or R ³ , R ⁴ represent a group which is bonded directly or via an oxygen atom to form a heterocycle with the adjacent nitrogen atom. When R ¹ is chlorine or a hydroxyl group, A is unsubstituted or the hydrogen bonded to carbon has 1 carbon atom.
To an alkylene group having 2 to 6 carbon atoms, which is substituted with an alkyl group having 1 to 6 carbon atoms, R ² and R ³ are hydrogen atoms, an alkyl group having 1 to 6 carbon atoms and having a straight chain or a branched chain, , Or an ethylene group or a trimethylene group, which are directly bonded to each other and in which a hydrogen atom bonded to a carbon atom may be substituted with an alkyl group having 1 to 6 carbon atoms, R ⁴ is a hydrogen atom, or 1 to 6 carbon atoms It represents an alkyl group or an amidino group. ) Is a substituted isoquinolinesulfonamide derivative or an acid addition salt thereof as an active ingredient, a therapeutic or prophylactic agent for hyperviscosity syndrome.

In the present invention, specific compounds represented by the general formula (I) include, for example, the following compounds. And, preferably, in the general formula (I), R ¹ is a hydrogen atom, R ² and R ³ are directly bonded to each other to have an alkylene group having 2 carbon atoms, and A is an unsubstituted alkylene group having 3 carbon atoms, The following compound (1) in which R ⁴ is a hydrogen atom
And a compound in which R ¹ is a hydroxyl group, R ² and R ³ are directly bonded to each other and has 2 carbon atoms, A is an unsubstituted 3 alkylene group, and R ⁴ is a hydrogen atom (83)
Is mentioned. (1) 1- (5-isoquinolinesulfonyl) homopiperazine (2) 1- (5-isoquinolinesulfonyl) -2-methylhomopiperazine (3) 1- (5-isoquinolinesulfonyl) -3-methylhomopiperazine (4) 1- (5-isoquinolinesulfonyl) -6-methylhomopiperazine (5) 1- (5-isoquinolinesulfonyl) -2,3-
Dimethylhomopiperazine (6) 1- (5-isoquinolinesulfonyl) -3,3-
Dimethylhomopiperazine (7) 1- (5-isoquinolinesulfonyl) -3-ethylhomopiperazine (8) 1- (5-isoquinolinesulfonyl) -3-propylhomopiperazine (9) 1- (5-isoquinolinesulfonyl) -3 -Isobutylhomopiperazine (10) 1- (5-isoquinolinesulfonyl) -3-phenylhomopiperazine (11) 1- (5-isoquinolinesulfonyl) -3-benzylhomopiperazine (12) 1- (5-isoquinolinesulfonyl)- 6-Ethylhomopiperazine (13) 1- (5-isoquinolinesulfonyl) -6-propylhomopiperazine (14) 1- (5-isoquinolinesulfonyl) -6-butylhomopiperazine (15) 1- (5-isoquinolinesulfonyl) -6-Pentylhomopiperazine (16) 1- (5- Isoquinolinesulfonyl) -6-hexylhomopiperazine (17) 1- (5-isoquinolinesulfonyl) -6-phenylhomopiperazine (18) 1- (5-isoquinolinesulfonyl) -6-benzylhomopiperazine (19) 1- (5 -Isoquinolinesulfonyl) -4-methylhomopiperazine (20) 1- (5-isoquinolinesulfonyl) -4-ethylhomopiperazine (21) 1- (5-isoquinolinesulfonyl) -4-propylhomopiperazine (22) 1- ( 5-isoquinolinesulfonyl) -4-butylhomopiperazine (23) 1- (5-isoquinolinesulfonyl) -4-hexylhomopiperazine (24) N- (2-aminoethyl) -1-chloro-5-
Isoquinoline sulfonamide (25) N- (4-aminobutyl) -1-chloro-5-
Isoquinoline sulfonamide (26) N- (2-amino-1-methylethyl) -1-
Chlor-5-isoquinolinesulfonamide (27) N- (2-amino-1-methylpentyl) -1
-Chloro-5-isoquinoline (28) N- (3-amino-2-methylbutyl) -1-
Chlor-5-isoquinolinesulfonamide (29) N- (3-di-n-butylaminopropyl)-
1-chloro-5-isoquinolinesulfonamide (30) N- (N-cyclohexyl-N-methylaminoethyl) -1-chloro-5-isoquinolinesulfonamide (31) N- (2-guanidinoethyl) -1-chloro −
5-Isoquinolinesulfonamide (32) N- (4-guanidinobutyl) -1-chloro-
5-Isoquinolinesulfonamide (33) N- (2-guanidino-1-methylethyl)-
1-chloro-5-isoquinolinesulfonamide (34) N- (1-guanidinomethylpentyl) -1-
Chlor-5-isoquinolinesulfonamide (35) N- (2-guanidino-3-methylbutyl)-
1-chloro-5-isoquinolinesulfonamide (36) N- (3-guanidino-2-methylpropyl)
-1-Chloro-5-isoquinolinesulfonamide (37) N- (4-guanidino-3-methylbutyl)-
1-Chloro-5-isoquinolinesulfonamide (38) 2-Methyl-4- (1-chloro-5-isoquinolinesulfonyl) piperazine (39) 2-Ethyl-4- (1-chloro-5-isoquinolinesulfonyl) piperazine ( 40) 2-Isobutyl-4- (1-chloro-5-isoquinolinesulfonyl) piperazine (41) 2,5-Dimethyl-4- (1-chloro-5-isoquinolinesulfonyl) piperazine (42) 1-Methyl-4- (1-Chloro-5-isoquinolinesulfonyl) piperazine (43) 1-Amidino-4- (1-chloro-5-isoquinolinesulfonyl) piperazine (44) 1-Amidino-4- (1-chloro-5-isoquinolinesulfonyl) Homopiperazine (45) 1-amidino-3-methyl-4- (1-chloro-5-isoquinoline Ruhoniru) piperazine (46) 1-amidino-2,5-dimethyl-4- (1-
Chlor-5-isoquinolinesulfonyl) piperazine (47) N- (2-aminoethyl) -1-hydroxy-
5-Isoquinolinesulfonamide (48) N- (4-aminobutyl) -1-hydroxy-
5-Isoquinolinesulfonamide (49) N- (2-amino-1-methylethyl) -1-
Hydroxy-5-isoquinolinesulfonamide (50) N- (2-amino-1-methylheptyl) -1
-Hydroxy-5-isoquinolinesulfonamide (51) N- (3-amino-2-methylbutyl) -1-
Hydroxy-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-isoquinolinesulfonamide (54) N- (2-guanidinoethyl) -1-hydroxy-5-isoquinolinesulfonamide (55) N- (4-guanidinobutyl) -1- Hydroxy-5-isoquinolinesulfonamide (56) N- (2-guanidino-1-methylethyl)-
1-Hydroxy-5-isoquinolinesulfonamide (57) N- (1-guanidinomethylpentyl) -1-
Hydroxy-5-isoquinolinesulfonamide (58) N- (2-guanidino-3-methylbutyl)-
1-Hydroxy-5-isoquinolinesulfonamide (59) N- (3-guanidino-2-methylpropyl)
-1-Hydroxy-5-isoquinolinesulfonamide (60) N- (4-guanidino-3-methylbutyl)-
1-hydroxy-5-isoquinolinesulfonamide (61) 2-methyl-4- (1-hydroxy-5-isoquinolinesulfonyl) piperazine (62) 2-ethyl-4- (1-hydroxy-5-isoquinolinesulfonyl) piperazine ( 63) 2-isobutyl-4- (1-hydroxy-5-
Isoquinolinesulfonyl) piperazine (64) 2,5-dimethyl-4- (1-hydroxy-5)
-Isoquinolinesulfonyl) piperazine (65) 1-methyl-4- (1-hydroxy-5-isoquinolinesulfonyl) piperazine (66) 1-amidino-4- (1-hydroxy-5-isoquinolinesulfonyl) piperazine (67) 1- Amidino-4- (1-hydroxy-5-isoquinolinesulfonyl) homopiperazine (68) 1-amidino-3-methyl-4- (1-hydroxy-5-isoquinolinesulfonyl) piperazine (69) 1-amidino-2,5 -Dimethyl-4- (1-
Hydroxy-5-isoquinolinesulfonyl) piperazine (70) N- (2-methylaminoethyl) -1-chloro-5-isoquinolinesulfonamide (71) N- (2-ethylaminoethyl) -1-chloro-5-isoquinoline Sulfonamide (72) N- (2-propylaminoethyl) -1-chloro-5-isoquinolinesulfonamide (73) N- (2-butylaminoethyl) -1-chloro-5-isoquinolinesulfonamide (74) N -(2-Hexylaminoethyl) -1-chloro-5-isoquinolinesulfonamide (75) 1- (1-chloro-5-isoquinolinesulfonyl) piperazine (76) 1- (1-chloro-5-isoquinolinesulfonyl) homo Piperazine (77) N- (2-methylaminoethyl) -1-hydroxy-5-iso Norrinsulfonamide (78) N- (2-ethylaminoethyl) -1-hydroxy-5-isoquinolinesulfonamide (79) N- (2-propylaminoethyl) -1-hydroxy-5-isoquinolinesulfonamide (80) N- (2-butylaminoethyl) -1-hydroxy-5-isoquinolinesulfonamide (81) N- (2-hexylaminoethyl) -1-hydroxy-5-isoquinolinesulfonamide (82) 1- (1-hydroxy -5-Isoquinolinesulfonyl) piperazine (83) 1- (1-hydroxy-5-isoquinolinesulfonyl) homopiperazine (84) 1- (5-isoquinolinesulfonyl) -4-methylpiperazine (85) 1- (5-isoquinolinesulfonyl) ) -4-n
-Hexylpiperazine (86) 1- (5-isoquinolinesulfonyl) -4-cinnamylpiperazine (87) 1- (5-isoquinolinesulfonyl) piperazine (88) N- (2-aminoethyl) -5-isoquinolinesulfonamide ( 89) N- (4-aminobutyl) -5-isoquinolinesulfonamide (90) N- (3-di-n-butylaminopropyl)-
5-isoquinolinesulfonamide (91) 1- (5-isoquinolinesulfonyl) -3-methylpiperazine (92) 1- (5-isoquinolinesulfonyl) -3-isobutylpiperazine (93) 1- (5-isoquinolinesulfonyl) -2 5,
-Dimethylpiperazine (94) N- (3-guanidino-2-phenylpropyl) -5-isoquinolinesulfonamide (95) N- (6-guanidino-1-methylheptyl)
-5-isoquinolinesulfonamide (96) 2- [2- (5-isoquinolinesulfonamide) ethylamino] -2-imidazoline (97) 2-amidino-1- (5-isoquinolinesulfonyl) piperazine (98) 4-amidino -2,5-dimethyl-1- (5-
Isoquinolinesulfonyl) piperazine (99) 4-amidino-1- (5-isoquinolinesulfonyl) homopiperazine (100) 4- (N1, N2-dimethylamidino) -1
-(5-Isoquinolinesulfonyl) piperazine (101) 4-amidino-3-butyl-1- (5-isoquinolinesulfonyl) piperazine (102) 4-hexyl-1- (5-isoquinolinesulfonyl) ethylenediamine (103) N- ( 4-guanidinobutyl) -5-isoquinolinesulfonamide (104) N- (2-guanidinoethyl) -5-isoquinolinesulfonamide Further, the acid addition salt of the substituted isoquinoline derivative represented by the general formula (I) is Pharmaceutically acceptable non-toxic salts, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, fumaric acid, maleic acid, Organic acids such as methanesulfonic acid can be mentioned.

The substituted isoquinoline sulfonamide derivative represented by the general formula (I) can be prepared by a known method, for example,
JP-A-57-154643 and JP-A-57-200
366, JP-A-58-112278, JP-A-58-112279, and JP-A-59-93054.
JP-A No. 60-81168, JP-A No. 61-
It can be synthesized by the method described in JP-A No. 152658, JP-A No. 61-227581, or the like.
As a typical example, a method of synthesizing by reacting 5-isoquinolinesulfonic acid chloride with homopiperazine is shown below.

[0017]

[Chemical 7]

When the substituted isoquinoline sulfonamide derivative represented by the general formula (I) or its acid addition salt is used as a therapeutic or prophylactic agent for hyperviscosity syndrome, it is administered alone or in combination with a pharmaceutically acceptable carrier. .
The composition is determined by the administration route, administration schedule and the like. The dose is determined according to the age, health condition, weight, degree of symptom of the patient, the type of concurrent treatment, if any, the desired effect, and the like.

The therapeutic dose generally ranges from 0.01 to 0.01% for parenteral administration.
20 mg / kg / day, 0.02-40 mg / orally
kg / day. The administration frequency is once a day or divided into several times for administration. In the case of intravenous administration, the general formula (I)
The injection solution containing the substituted isoquinoline sulfonamide derivative represented by is administered, for example, once for 30 to 60 minutes.

When the substituted isoquinoline sulfonamide derivative represented by the general formula (I) is orally administered, it is in the form of tablets, capsules, powders, granules, liquids, elixirs and the like, and parenterally. , Injections, suppositories, ointments or nasal drops. When used in the form as described above, a solid or liquid non-toxic pharmaceutical carrier may be included in the composition.

Examples of solid carriers used for oral administration include oligosaccharides such as lactose, sucrose and mannitol; starches such as corn and potato, crystalline cellulose, calcium phosphate,
Synthetic aluminum silicate and other excipients; sodium or calcium salts of carboxymethylcellulose; fatty acid salts such as magnesium stearate; talc; modified starch such as hydroxypropylmethylcellulose and methylcellulose; gelatin, agar, gum, sodium alginate, etc .; polyethylene Examples thereof include glycol. These carriers include tablets, capsules, active ingredients and adjuvants,
It can be used for granules, powders and the like.

These capsules, tablets, granules and powders generally contain 1-80% by weight, preferably 1-60% by weight, of the active ingredient. In the case of a liquid preparation for oral administration, 0.01 to 20
A solution or syrup containing the active ingredient by weight is preferable, and in this case, it is desirable to add a fragrance, a sweetener and the like in addition to water and ethanol as a pharmaceutical carrier.

When administered parenterally by intramuscular injection, intravenous injection or subcutaneous injection, the substituted isoquinoline sulfonamide derivative represented by the general formula (I) contains sodium chloride or glucose in order to make the solution isotonic. Etc. is used as a sterile solution to which other solutes have been added. Suitable solvents for injection include sterile water, lidocaine hydrochloride solution (for intramuscular injection),
Examples include physiological saline, glucose, liquid for intravenous injection, electrolyte solution (for intravenous injection), and the like. In the case of these injection solutions, it is usually 0.01 to 20% by weight, preferably 0.1.
It is preferable to contain 10 to 10% by weight of the active ingredient.

When administered as a suppository or ointment (transdermal agent), it is preferable to prepare a preparation containing the present active ingredient in an amount of 1 to 80% by weight, and its carrier is petrolatum, paraffin, beeswax, lanolin. Animal and vegetable oils and fats such as cacao butter; synthetic oils and fats such as macrogol and Witepsol; emulsifiers; preservatives; absorption promoters and the like. For intranasal administration, the active ingredient may be formulated with an emulsifying agent or other enhancer together with the carrier as previously described liquid.

The drug containing the substituted isoquinolinesulfonamide derivative represented by the general formula (I) prepared as described above as an active ingredient can be used, for example, in patients with an increase in blood viscosity or in patients with signs of the symptoms. On the other hand, it is used as a therapeutic or prophylactic agent for hyperviscous syndrome used for the purpose of lowering blood viscosity.

[0026]

EXAMPLES The present invention will be described in detail below based on examples. However, the present invention is not limited to the following examples unless it exceeds the gist.

[0027]

Example 1 Effect on Blood Viscosity (I) Test drugs (Compound 1 and Compound 83) were dissolved in distilled water and orally administered to Wistar rats aged 10 to 12 weeks. 30 minutes after oral administration (Pentoxifylline is 2.5
Time later), under ether anesthesia, EDTA from the abdominal aorta
Blood was collected at -2K. Blood collection within 5 minutes under constant temperature of 37 ° C using a cone plate rotational viscometer (Tokyo Keiki) for 0.5 ml of blood at a rotation speed of 10 rpm (shear rate of 75 s).
Blood viscosity was measured by ec ⁻¹ ). The results of blood viscosity measurement are shown in Table 1.

[0028]

[Table 1]

Compound (1) and compound (83) reduced blood viscosity.

[0030]

Example 2 Effect on Blood Viscosity (II) Test drugs (Compound 1 and Compound 83) were dissolved in physiological saline and intraperitoneally administered to Wistar rats aged 10 to 12 weeks. 30 minutes after intraperitoneal administration (Pentoxifylline
2.5 hours after oral administration), blood was collected from the abdominal aorta with EDTA-2K under ether anesthesia. After incubating the blood at 37 ° C. for 2 hours, the blood viscosity was measured using a cone plate rotational viscometer (Tokyo Keiki Co., Ltd.) for 0.5 ml of blood at a rotation speed of 10 rpm (shear rate of 75 sec ⁻¹ ). The results of blood viscosity measurement are shown in Table 2 (blood viscosity after 2 hours of incubation).

[0031]

[Table 2]

In the case of the control physiological saline, the blood viscosity was increased by the incubation for 2 hours, but the compound (1) and the compound (83) prevent the increase in the blood viscosity by the incubation for 2 hours. Suppressed. From Examples 1 and 2, the substituted isoquinoline sulfonamide derivative represented by the general formula (I) reduced blood viscosity and suppressed the increase in blood viscosity, and therefore, is effective for the treatment and prevention of hyperviscosity syndrome. It has been shown.

Pentoxifylline, a vasodilator and a red blood cell deformability improver, which was used for comparison, did not reduce blood viscosity. It was shown that the blood viscosity lowering action of the general formula (I) is not based on the vasodilator action.

[0034]

Example 3 Effect on Erythrocyte Deformability Based on Viscosity Measurement of Washed Erythrocytes Wistar rats aged 10 to 12 weeks were anesthetized with ether, and blood was collected from the abdominal aorta with sodium citrate. After the addition of the phosphate buffer, the mixture was centrifuged at 20 ° C. and 2500 rpm for 5 minutes, and then the supernatant and the buffy coat were removed. After repeating this operation twice, it was adjusted to 1.2 × 10 ⁷ cells / μl. 1/20 volum of test drug dissolved in physiological saline
e and added, and incubated at 37 ° C for 6 hours, the viscosity of the washed red blood cells was adjusted to 20 rpm (shear speed 5
It was measured at a high shear rate of ⁰ sec ^-1 ). Since the decrease in viscosity at high shear rates is mainly due to the deformation of red blood cells, the result of this change in viscosity of washed red blood cells is mainly based on the effect on red blood cell deformability (new physiological system, physiology of blood ( Volume 15, p1-p18, 1990, edited by Ichiro Nakama, Akikazu Takada, Medical Institute)). The results of the viscosity of washed red blood cells are shown in Table 3.
It was shown to.

[0035]

[Table 3]

Compound (1) decreased the viscosity of washed red blood cells in an experiment in which the effect on the red blood cell deformability using washed red blood cells was investigated. From Examples 1, 2 and 3, the blood viscosity-lowering effect of the substituted isoquinolinesulfonamide derivative represented by the general formula (I) is not due to the vasodilatory effect but due to the enhanced erythrocyte deformability. It has been shown that the substituted isoquinoline sulphonamide derivatives of general formula (I) are particularly preferred for hyperviscosity syndrome with reduced erythrocyte deformability.

[0037]

Example 4 Oral Toxicity The test drug was orally administered to 10-week-old Wistar rats and examined for death. The results are shown in Table 4.

[0038]

[Table 4]

The substituted isoquinoline sulfonamide derivative represented by the general formula (I) showed no mortality even when a sufficient amount of the pharmacological effect was orally administered, and the safety of the compound was confirmed. .

[0040]

Example 5 Formulation Example (1) Tablet A tablet containing the following ingredients was prepared by a known method. (2) Aseptic injection The following ingredients are dissolved in distilled water, and then water is added to make the required final weight. 2 ml of this solution was sealed in an ampoule and sterilized by heating.

[0041]

[0042]

INDUSTRIAL APPLICABILITY The therapeutic agent for hyperviscosity syndrome of the present invention is administered to a patient whose blood viscosity is elevated due to various causes, or to a patient whose blood viscosity is expected to be elevated, by treating or prophylactically administrating the hyperviscous syndrome. It is useful for the treatment and prevention of emerging disorders such as cardiovascular symptoms, ocular symptoms, hemorrhagic diathesis, and neurological symptoms.

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Claims (3)

[Claims] 1. A compound represented by the general formula (I):(In the formula, R¹Represents hydrogen, chlorine or a hydroxyl group, and R¹But
When hydrogen, A is an alkylene group having 2 to 6 carbon atoms
And is an alkyl group having 1 to 10 carbon atoms, aryl
A group or an aralkyl group may have a substituent, R²
Is a hydrogen atom, R ³Is a hydrogen atom or 1 to 6 carbon atoms
Alkyl groups having a straight chain or branched chain, aryl
Group, aralkyl group, R^FourIs a hydrogen atom or has 1 carbon atom
Alkyl group having 6 straight or branched chains,
Ryl group, aralkyl group, or benzoyl group, cinna
Mill group, cinnamoyl group, furoyl group, or one of the following
A group represented by the general formula (II):(In the formula, R^FiveIs a straight or branched chain having 1 to 6 carbon atoms
Lower alkyl group) or the following general formula (II
A group represented by I):(In the formula, R⁶, R⁷Are hydrogen atoms or direct bonds to each other
And has 2 to 4 carbon atoms), or R
², R³Are directly bonded to each other and are unsubstituted or have carbon number
1 to 10 alkyl groups, or phenyl groups, benzene
Alkylene having 4 or less carbon atoms substituted with a dil group
Group or R³, R^FourIs directly or through an oxygen atom
Bond to form a heterocycle with adjacent nitrogen atoms
Represents a group. R¹When A is chlorine or hydroxyl, A is absent
Or hydrogen bonded to carbon has 1 to 6 carbon atoms
Alkyl having 2 to 6 carbon atoms substituted with an alkyl group
Xylene group, R², R³Is a hydrogen atom, having 1 to 6 carbon atoms
Is a straight-chain or branched alkyl group of
Or hydrogen atoms directly bonded to each other and bonded to carbon
Ethyl which may be substituted with an alkyl group of 1 to 6
Group, trimethylene group, R^FourIs hydrogen atom, carbon number
Represents 1 to 6 alkyl groups or amidino groups. )
Substituted isoquinoline sulfonamide derivative represented by
Treatment of hyperviscosity syndrome containing the body or its acid addition salt as an active ingredient
A therapeutic or preventive agent. 2. In the general formula (I) according to claim 1,
Substituted isoquinoline sulfonamide in which R ¹ is a hydrogen atom, R ² and R ³ are directly bonded to each other, an alkylene group having 2 carbon atoms, A is an unsubstituted alkylene group having 3 carbon atoms, and R ⁴ is a hydrogen atom. The therapeutic or preventive agent for hyperviscosity syndrome according to claim 1, which is a derivative. 3. In the general formula (I) according to claim 1,
R¹Is a hydroxyl group, R²And R³Is a direct bond and has 2 carbon atoms
Alkylene group, A is an unsubstituted alkylene having 3 carbon atoms
Group, R ^FourA substituted isoquinoline sulphone in which is a hydrogen atom
The treatment for hyperviscosity syndrome according to claim 1, which is a honamide derivative.
A therapeutic or preventive agent.