JPH0741424A - Anti-inflammatory agent - Google Patents

Abstract

PURPOSE:To provide an agent suppressing generation of active oxygen to be produced by phagocytes including neutrophiles, thus useful for inhibiting development or progression of inflammation. CONSTITUTION:The anti-inflammatory agent containing, as the active ingredient, an isoquinolinesulfonamide derivative of formula I [R<1> is H, Cl or OH; (1) when R<1> is H, A is (1-10C alkyl-, aryl- or aralkyl-substituted) 2-6C alkylene; R<2> is H; R<3> is H, 1-6C alkyl, aryl or aralkyl; R<4> is the same as R<3>, benzoyl, cinnamyl, cinnamoyl, furoyl, of formula II (R<5> is 1-6C alkyl), of formula III (R<6> and R<7> are each H or combined into 2-4C alkylene), or R<2> and R<3> are combined into (substituted) <=4C alkylene, R<3> and R<4> are either directly or via O combined into heterocycle; (2) when R<1> is Cl or OH, A is (1-6C alkyl-substituted) 2-6C alkylene; R<2> and R<3> are each H, 1-6C alkyl or combined into (substituted) 2-3C alkylene; R<4> is H, 1-6C alkyl or amidino].

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an anti-inflammatory agent. In particular, it relates to an anti-inflammatory agent containing a compound represented by the following general formula (1) or an acid addition salt thereof as an active ingredient. The anti-inflammatory agent according to the present invention suppresses the production of active oxygen (O ₂ ⁻ ) produced by phagocyte system such as neutrophils infiltrating the inflammatory site and causes inflammation accompanied by phagocyte infiltration. Or, it is a useful drug to prevent the spread.

[0002]

2. Description of the Related Art A compound represented by the general formula (1) exhibits a vascular smooth muscle relaxing action, a blood flow increasing action, a blood pressure lowering action, a brain protecting action, a vasodilator, a cerebral circulation improving agent, and an angina treatment. It is already known that they are effective substances in agents, antihypertensive agents, prophylactic and therapeutic agents for cerebral cardiovascular thrombosis, cerebral function improving agents and the like. (For example, JP-A-57-154643, JP-A-57-200366, and JP-A-58-1.
21278, JP-A-58-112279,
JP-A-59-93054 and JP-A-60-8116
No. 8, JP 61-152658 A, JP 6
(See JP-A 1-227581, JP-A-2-256617, etc.).

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a highly safe and excellent anti-inflammatory drug which can be applied clinically.

[0004]

Means for Solving the Problems As a result of repeated studies on the compound represented by the general formula (1), the present inventors have found that the compound has a vascular smooth muscle relaxing action, a blood flow increasing action, a blood pressure lowering action, totally unexpected anti-inflammatory action from the action conventionally known such as a brain function improving action ^- found to have (O ₂ phagocytes of damaging surrounding tissue at sites of inflammation inhibiting the production), the present invention Was completed. That is, the present invention relates to an anti-inflammatory agent containing a compound represented by the following general formula (1) or an acid addition salt thereof as an active ingredient.

[0005]

[Chemical 3]

(In the formula, R ¹ represents hydrogen, chlorine or a hydroxyl group, and when R ¹ is hydrogen, A is unsubstituted or an alkyl group having 1 to 10 carbon atoms in which hydrogen bonded to a carbon atom, an aryl group, or 2 carbon atoms substituted with aralkyl groups
To 6 alkylene groups, R ² is a hydrogen atom, R ³ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, an aryl group, an aralkyl group, R
⁴ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, an aryl group, an aralkyl group, or a benzoyl group, a cinnamyl group, a cinnamoyl group, a furoyl group,

[0007]

[Chemical 4]

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, or an alkylene group having 4 or less carbon atoms, which is substituted with a phenyl group or a benzyl group. Alternatively, R ³ and R ⁴ represent groups which are 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 an unsubstituted or alkylene group having 2 to 6 carbon atoms in which hydrogen bonded to carbon is substituted with an alkyl group having 1 to 6 carbon atoms, R ² and R ³ are A hydrogen atom, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, or a hydrogen atom directly bonded to each other and having a carbon-bonded hydrogen atom substituted with an alkyl group having 1 to 6 carbon atoms; And R ⁴ represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an amidino group. In the present invention, specific compounds represented by the general formula (1) include, for example, the following compounds. (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- (N 1,} N 2 - dimethyl-amidinophenyl) -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 isoquinoline derivative represented by the general formula (1) is pharmaceutically acceptable. A non-toxic salt of
For example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid,
And organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, fumaric acid, maleic acid and methanesulfonic acid.

The compound represented by the general formula (1) can be obtained by a known method, for example, JP-A-57-156463, JP-A-57-200366, and JP-A-58-12127.
No. 8, JP-A-58-112279, JP-A-SHO-5
9-93054, JP-A-60-81168, JP-A-61-252658, and JP-A-61-2.
It can be synthesized by the method described in Japanese Patent No. 27581. As a typical example, a method of synthesizing by reacting 5-isoquinolinesulfonic acid chloride with homopiperazine is shown below.

[0010]

[Chemical 5]

When the compound represented by the general formula (1) or an acid addition salt thereof is used as an anti-inflammatory agent, 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 amount is generally 0.01-0.01 for parenteral administration.
20 mg / kg / day, 0.02-40 mg / orally
kg / day. When the compound represented by the general formula (1) is orally administered, it is in the form of tablets, capsules, powders, granules, solutions, elixirs and the like, and when parenterally administered,
Used in liquid, sterile form. When used in the form as described above, a solid or liquid non-toxic pharmaceutical carrier may be included in the composition.

Gelatin type capsules are usually used as an example of the solid carrier. In addition, the active ingredient is tableted, granulated or powdered with or without an adjuvant. Excipients used together in these cases include water:
Gelatin: Lactose, sugars such as glucose: corn, wheat,
Starch such as rice and corn starch: fatty acids such as stearic acid: fatty acid salts such as calcium stearate and magnesium stearate: talc: vegetable oil: alcohols such as stearyl alcohol and benzyl alcohol: gum: polyalkylene glycol.

These capsules, tablets, granules and powders generally contain 1-80% by weight, preferably 1-60% by weight, of the active ingredient. As the liquid carrier, generally, water, physiological saline, dextrose or similar saccharide solution, glycols such as ethylene glycol, propylene glycol and polyethylene glycol are preferable as the liquid carrier.

When administered parenterally by intramuscular injection, intravenous injection, or subcutaneous injection, the compound represented by the general formula (1) contains salt or other solute such as glucose in order to make the solution isotonic. Used as an added sterile solution. 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) and the like. In the case of these injectable solutions, the active ingredient is usually contained in an amount of 0.01 to 20% by weight, preferably 0.1 to 10% by weight.

In the case of a liquid preparation for oral administration, a suspension or syrup containing 0.01 to 20% by weight of the active ingredient is preferable. In this case, a carrier such as a flavoring agent, a syrup, an aqueous excipient such as a pharmaceutical micelle is used.

[0017]

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.

[0018]

Example 1 Phorbol Ester (PMA) or PET
Human phagocytic cells stimulated with peptide chemotactic factor (FMLP)
Of the compound of the present invention against the NADPH oxidase activity of
I examined the use. The human neutrophils provided were heparinized human powder.
Add the same amount of 3% dextran-T500 to the treetop blood at room temperature
After leaving for 15 minutes, the buffy coat is collected and neutrophils are collected.
Separation liquid Lymphophrep is layered on top and then centrifuged,
H in the sediment₂O was added to remove red blood cells and then collected.
On the other hand, HL-60 cells were treated with 10% fetal calf serum and
Human front bones per ml in F12 culture medium containing biomaterials
2 × 10 myeloid leukemia HL-60 cells^FiveFloat them individually,
Then 10^-7M1,25-dihydroxyvitamin D
₃(VD₃) Is added and 5% CO is added at 37 ° C for 3 days.₂I
Incubated in an incubator, macrophage-like
Differentiated into cells. O₂ ^-Production is measured by cytochrome c
It was carried out by the reduction method. That is, 80 μM cytochrome
Muc and 2x10^FiveIndividual / ml human neutrophils or 5 × 1
0^FiveCells / ml HL-60 cells containing 0.5 ml Han
The compound (1) or the compound (83) was added to the ks' BSS solution.
Add acid addition salt and pre-incubate for 10 minutes at room temperature
did. Next, add 10 ng / ml PMA or 1 μ to the reaction solution.
Add each MFMLP and immediately add a spectrophotometer (Hitachi,
U3210) to measure absorbance at 550 nm over time
Decided As a standard, 50 units of soot are added to the same reaction solution.
Measured by adding peroxide dismutase (SOD)
It was The results are shown in Tables 1 and 2. Compound (1) or compound
Of acid addition salt of substance (83) on PMA in human neutrophils
Sex O₂ ^-50% inhibitory concentration of production (ID ₅₀) Are each
It was 15 μM or 24 μM. Also, FMLP stimulation
Sex O₂ ^-Compound (1) was inhibited by 67 at 30 μM
%, And the compound (83) was 29%. Compound (1)
Or the acid addition salt of compound (83) in HL-60 cells.
PMA stimulation O₂ ^-Production ID₅₀Are 18μ each
M or 19 μM.

The acid addition salt of the compound (1) or the compound (83) can be used as the NADPH of human neutrophils or HL-60 cells.
By blocking the oxidase activity, PMA or FMLP-stimulated O ₂ ^- inhibited the production. In addition, the acid addition salt of compound (1) or compound (83) is HL-60.
It also suppressed PMA-stimulated O ₂ ⁻ production of cells. The compound represented by the general formula (1) or an acid addition salt thereof suppresses the production of O ₂ ⁻ produced by phagocyte system including neutrophils infiltrating the inflammation site, and causes the onset of inflammation or surrounding tissues. It was confirmed that it is effective as an anti-inflammatory agent to prevent the spread of damage to the skin.

[0020]

Example 2 A test compound was dissolved in sterilized water to give Slc: I.
The LD ₅₀ value was determined from the amount of the test compound that gave a 50% mortality rate in the mouse after a single oral administration to CR type 5-week-old male mice. The results are shown in Table 3. The LD ₅₀ value of the compound represented by the general formula (1) or the acid addition salt thereof is 300 mg /
It was kg, which was higher than the pharmacological effect expression level, and safety was confirmed.

[0021]

Example 3 Formulation Example (1) Tablet A tablet containing the following ingredients is prepared by a known method. Ingredient Preparation Example Compound (1) Hydrochloride 30 mg Crystalline cellulose 40 mg Lactose 103 mg Magnesium stearate 2 mg Carboxymethyl cellulose calcium 5 mg ───────── Total 180 mg (2) Sterile injection The following ingredients are dissolved in distilled water, Then water is added to reach the required final weight. 2 ml of this solution is sealed in an ampoule and sterilized by heating.

Ingredient Preparation Example Compound (1) Hydrochloride 50 mg Sodium chloride 16 mg Distilled water Appropriate amount ────────── Total volume is 2 ml.

[0023]

[Table 1]

[0024]

[Table 2]

[0025]

[Table 3]

[0026]

INDUSTRIAL APPLICABILITY The anti-inflammatory agent of the present invention is useful for suppressing the production of active oxygen (O ₂ ⁻ ) produced by phagocyte system such as neutrophil and preventing the onset or spread of inflammation. Is.

Claims (1)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ represents hydrogen, chlorine, or a hydroxyl group, and when R ¹ is hydrogen, A is an unsubstituted or carbon-bonded hydrogen having 1 to 10 carbon atoms, an aryl group, or an aralkyl group. A substituted alkylene group having 2 to 6 carbon atoms, R ² is a hydrogen atom, R ³ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, an aryl group, an aralkyl group, R ⁴ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, an aryl group, an aralkyl group, a benzoyl group, a cinnamyl group, a cinnamoyl group, a furoyl group, or 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. ) An anti-inflammatory agent comprising a substituted isoquinoline sulfonamide derivative or an acid addition salt thereof as an active ingredient.