JPH07149646A - Chemical mediator isolation suppressor - Google Patents

Abstract

PURPOSE:To obtain a chemical mediator isolation suppressor useful for treating allergic diseases and having high safety. CONSTITUTION:This chemical mediator isolation suppressor contains a substituted isoquinolinesulfoneamide derivative of the formula (R<1> is H or OH; R<2> is H; R<3> is H, aryl, benzoyl or R<2> and R<3> together form a 1-4C alkylene) or its acid addition salt, e.g. N-(2-aminoethyl)-5-isoquinolinesulfone amide or 1-(1-hydroxy-5-isoquinolinesulfonyl)homopiperazine as an active ingredient. The compound of the formula suppresses production or isolation of a chemical mediator such as histamine, leukotriene, thromboxane A2, prostaglandin, a neutrophil chemotactic factor, an eosinophilic leucocyte chemotactic factor, a platelet- activation factor, lymphokine, lysosome enzyme or an eosinophilic leucocyte granular protein isolated by allergic reaction.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a chemical mediator release inhibitor, more specifically, the following general formula (I)

[0002]

[Chemical 2]

(Wherein R ¹ is a hydrogen atom or a hydroxyl group, R
² represents a hydrogen atom, R ³ represents a hydrogen atom, an aryl group or a benzoyl group, or R ² and R ³ represent an unsubstituted alkylene group having 1 to 4 carbon atoms and are directly bonded to each other. The present invention relates to a chemical mediator release inhibitor containing an amide derivative or an acid addition salt thereof as an active ingredient.

[0004]

2. Description of the Related Art Heretofore, many therapeutic agents for allergic diseases, such as azelastine, which have a chemical mediator release inhibitory action, have been reported, but none have been found to be sufficient. A substituted isoquinoline sulfonamide derivative represented by the general formula (I) or an acid addition salt thereof exhibits a vasculature smooth muscle expanding action, a blood flow increasing action, a blood pressure lowering action, and a brain protecting action.
It is already known that it is an effective substance in a cerebral circulation improving agent, a therapeutic agent for angina, an antihypertensive agent, a preventive and therapeutic agent for cerebral cardiovascular thrombosis, a cerebral function improving agent, etc. 57-154643, JP-A-57-200366
JP, JP-A-58-112278, JP-A-58
-121279, JP-A-59-93054, JP-A-60-81168, and JP-A-61-15.
2658, JP-A-61-227581, JP-A-2-256617).

Further, an isoquinoline sulfonamide derivative represented by 5- (4-piperidinylmethylaminosulfonyl) isoquinoline and a substituted isoquinoline sulfonamide derivative represented by the general formula (I) or an acid addition salt thereof is used asthma. Are known to be useful substances (USP 4,857,301, JP-A-4-26403).
No. 0), these techniques improve the asthma caused by the already released chemical mediators such as histamine acting on the respiratory tract and the like, and suppress the release of chemical mediators. is not.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a highly safe chemical mediator release inhibitor which is clinically applicable and has high safety as a therapeutic agent for allergic diseases. The chemical mediator release inhibitor of the present invention means histamine, leukotriene, thromboxane A ₂ , prostaglandin, neutrophil chemotactic factor, eosinophil chemotactic factor, and platelet activating factor released by allergic reaction. , Lymphokine,
It is a drug useful for the treatment of allergic diseases by suppressing the production and release of chemical mediators such as lysosomal enzymes and eosinophil granule proteins.

More specifically, allergic rhinitis,
It is intended to provide a drug useful for treating allergic diseases such as atopic dermatitis, anaphylactic shock, drug allergy, acute urticaria, bronchial asthma, rheumatoid arthritis, and allergic contact dermatitis.

[0008]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted extensive studies on a substituted isoquinolinesulfonamide derivative represented by the general formula (I) or an acid addition salt thereof, and as a result, the compound has the above-mentioned vascular smooth muscle dilation. The present invention has been found to have a chemical mediator release inhibitory effect that is completely unexpected from the conventionally known effects such as action, blood flow increasing action, blood pressure lowering action, brain function improving action, tracheal smooth muscle dilating action, and the present invention. completed. That is, the present invention provides the following general formula (I)

[0009]

[Chemical 3]

A chemical mediator release inhibitor containing a substituted isoquinoline sulfonamide derivative represented by the formula (wherein R ¹ , R ² and R ³ have the same meanings as described above) or an acid addition salt thereof as an active ingredient. . In the general formula (I), R ¹ is a compound represented by a hydrogen atom, R ¹
Examples thereof include compounds in which ¹ is a hydroxyl group, compounds in which R ² and R ³ are hydrogen atoms, and compounds in which an unsubstituted trimethylene group in which R ² and R ³ are directly bonded to each other.

[0011] As Of these particularly preferred ^{compounds, R 1, R 2, R} 3 is a hydrogen atom N-(2-aminoethyl) -5-isoquinolinesulfonamide [Compound (1)], R ¹ is a hydroxyl group , R ² and R ³ are hydrogen atoms, N- (2-aminoethyl) -1-hydroxy-5-isoquinolinesulfonamide [compound (2)], R ¹ is a hydrogen atom, and R ² and R ³ are directly to each other. 1- (5-isoquinolinesulfonyl) homopiperazine [compound (3)] which is an unsubstituted trimethylene group bonded, R ¹ is a hydroxyl group, and R ² and R ³ are unsubstituted trimethylene groups directly bonded to each other 1- (1-hydroxy-5-isoquinolinesulfonyl) homopiperazine [compound (4)] can be mentioned.

The acid addition salt of the substituted isoquinoline sulfonamide derivative represented by the general formula (I) is
A non-toxic pharmaceutically acceptable salt, for example hydrochloric acid,
Examples thereof include inorganic acids such as hydrobromic acid, phosphoric acid and 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 substituted isoquinoline sulfonamide derivative represented by the general formula (I) can be prepared by known methods, 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.

[0014]

[Chemical 4]

When the substituted isoquinoline sulfonamide derivative represented by the general formula (I) or its acid addition salt is used as a chemical mediator release inhibitor, 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 / time, 0.02-40 mg / orally
It is 1 to 3 times / day of kg. When the substituted isoquinoline sulfonamide derivative represented by the general formula (I) or its acid addition salt is orally administered, it is in the form of tablets, capsules, powders, granules, liquids, elixirs or the like, and parenterally. In the case of, it is used in a 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.

As an example of the solid carrier, gelatin type capsules are usually used. 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 substituted isoquinoline sulfonamide derivative represented by the general formula (I) or its acid addition salt isotonic to the solution. It is 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) 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.

[0021]

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.

[0022]

Example 1 The effect of the compound of the present invention on the passive skin anaphylaxis (PCA) reaction was examined. Dinitrophenol-Ascaris (DNP-As) antiserum was added to Tad
a & Okumura et al. [J. Immunolo
gy, 106, 1002 (1971)]. 50 μl of DNP-As antiserum diluted 200-fold with physiological saline was intradermally administered to the shaved back of Wistar male rats for passive sensitization.

After 48 hours, 2.0 ml of 0.5% Evans blue containing 1 mg of DNP-As antigen was administered into the tail vein to induce PCA. The animals were fasted 24 hours before the antigen induction, and the test compound of the present invention and the theophylline test substance (dissolved in distilled water) as a control were orally administered 1 hour before the antigen induction. The animal was killed by exsanguination 30 minutes after antigen challenge, the dorsal skin was peeled off, and the blue-stained area was cut out and finely cut.
The minced tissue pieces were extracted with 2 ml of an extract (acetone: 0.15% sulfuric acid-Na aqueous solution = 7: 3) for 24 hours, and then,
The absorbance of the supernatant was measured at 620 nm. A calibration curve was prepared using a standard solution of Evans blue dissolved in the same solvent, and the amount of Evans blue leaked to the back was calculated from the calibration curve.

The results are shown in Table 1.

[0025]

[Table 1]

As shown in Table 1, the compound represented by the general formula (I) of the present invention is PCA which is one of allergic reactions.
The reaction was suppressed to the same level as or higher than that of theophylline, which has a typical chemical mediator release suppressing effect.

[0027]

Example 2 The effect of the compound of the present invention on the release of histamine from rat intraperitoneal mast cells stimulated with calcium ionophore A23187 was examined. Rat peritoneal mast cells can be prepared by the method of Marquardt et al. [J. Immuno
, 120, 871 (1987)] and Prou.
post-Danon et al. [Immunolog
y, 15, 271 (1968)], 2 × 10 ⁵
It was prepared as a suspension of cells / ml. Mast cell fluid 0.
After keeping 5 ml at 37 ° C. for 5 minutes, each test substance of the compound of the present invention, theophylline as a control, and azelastine hydrochloride was added and preincubated for 10 minutes.
23187 (final concentration 0.2 μg / ml) was added to bring the total volume to 1 ml, and the mixture was further incubated for 10 minutes.

After stopping the reaction by cooling with ice, Short
e. et al. [J. Pharmacol. Exp. The
r. , 127, 182 (1959)], and the amount of histamine released was measured. In addition, the intracellular total histamine amount and the spontaneously released histamine amount were separately measured, and the histamine release inhibition rate was calculated from these three measured values, and the inhibition rate was calculated as
The concentration of the test substance required to make it 0% or more was determined.

The results are shown in Table 2.

[0030]

[Table 2]

As shown in Table 2, the compounds of the general formula (I) of the present invention are theophylline and azelastine which have a typical chemical mediator release inhibitory effect on histamine release from rat intraperitoneal mast cells stimulated with A23187. Suppressed to the same level or more.

[0032]

[Example 3] LD ₅₀ values were determined using 5-week-old male Wistar rats. The test substance is dissolved in distilled water,
It was orally administered. The results are shown in Table 3.

[0033]

[Table 3]

The acute toxicity value of the compound represented by the general formula (I) of the present invention and the acid addition salt thereof was higher than the expression amount of the pharmacological effect, and its safety was confirmed.

[0035]

Example 4 Formulation Example (1) Tablet A tablet containing the following ingredients was 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 injectable solution The following ingredients are dissolved in distilled water, and then water is added to make the final required. Made to weight. 2 ml of this solution was sealed in an ampoule and sterilized by heating.

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

A preparation containing another compound as an active ingredient can also be obtained by preparing in the same manner by using the above-mentioned compound (1) instead.

[0038]

Industrial Applicability The chemical mediator release inhibitor of the present invention comprises histamine, leukotriene, thromboxane A ₂ , prostaglandin, neutrophil chemotactic factor, eosinophil chemotactic factor released by allergic reaction, Platelet activating factor, lymphokine, lysosomal enzyme,
It is a useful drug for the treatment of allergic diseases by suppressing the production and release of chemical mediators such as eosinophil granule protein.

More specifically, allergic rhinitis,
The drug is useful for treating allergic diseases such as atopic dermatitis, anaphylactic shock, drug allergy, acute urticaria, bronchial asthma, rheumatoid arthritis, and allergic contact dermatitis.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location C07D 401/12 243

Claims (9)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ is a hydrogen atom or a hydroxyl group, R ² is a hydrogen atom, R ³ is a hydrogen atom, an aryl group or a benzoyl group,
Or R ² and R ³ represent an unsubstituted alkylene group having 1 to 4 carbon atoms which is directly bonded to each other), a chemical mediator release inhibitor containing a substituted isoquinoline sulfonamide derivative or an acid addition salt thereof as an active ingredient. . 2. In the general formula (I) according to claim 1,
The chemical mediator release inhibitor according to claim ¹ , wherein R ¹ is a hydrogen atom. 3. In the general formula (I) according to claim 1,
The chemical mediator release inhibitor according to claim 1, wherein R ¹ is a hydroxyl group. 4. In the general formula (I) according to claim 1,
The chemical mediator release inhibitor according to claim 1, wherein R ² and R ³ are hydrogen atoms. 5. In the general formula (I) according to claim 1,
The chemical mediator release inhibitor according to claim 1, wherein R ² and R ³ are unsubstituted trimethylene groups directly bonded to each other. 6. A chemical mediator release inhibitor containing N- (2-aminoethyl) -5-isoquinolinesulfonamide or an acid addition salt thereof as an active ingredient. 7. A chemical mediator release inhibitor containing N- (2-aminoethyl) -1-hydroxy-5-isoquinolinesulfonamide or an acid addition salt thereof as an active ingredient. 8. A chemical mediator release inhibitor comprising 1- (5-isoquinolinesulfonyl) homopiperazine or an acid addition salt thereof as an active ingredient. 9. A chemical mediator release inhibitor containing 1- (1-hydroxy-5-isoquinolinesulfonyl) homopiperazine or an acid addition salt thereof as an active ingredient.