WO1999064011A1

WO1999064011A1 - Drugs

Info

Publication number: WO1999064011A1
Application number: PCT/JP1999/003137
Authority: WO
Inventors: Hiroyoshi Hidaka; Manabu Takagi; Takushi Matsuzaki
Original assignee: Hiroyoshi Hidaka; Manabu Takagi; Takushi Matsuzaki
Priority date: 1998-06-11
Filing date: 1999-06-11
Publication date: 1999-12-16
Also published as: JP4212149B2; JPH11349482A

Abstract

Preventive or therapeutic agents for asthma containing as the active ingredient isoquinoline derivatives represented by general formula (I) or salts thereof, wherein R1 is alkyl, alkenyl, alkynyl, alkoxy, hydroxy, cyano or halogeno; R2 is hydrogen, hydroxy or halogeno; R3 is hydrogen, alkyl or amidino; and A is optionally substituted, five- to eleven-membered cyclic amino which may be bridged between any two of the carbon atoms constituting the cyclic amino.

Description

Specification

Pharmaceutical technology field

The present invention relates to a medicament containing an isoquinoline derivative as an active ingredient. Background technology

Bronchial asthma is a chronic inflammatory disease of the respiratory tract, with persistent inflammation of the respiratory tract and frequent attacks of airway asphyxia. The primary etiology of bronchial asthma is the type I allergic response to antigenic stimulation, but asthma attacks can also be triggered by external stimuli (eg, infection, exercise, smoke, cold, stress). Bronchial asthma involves many cells, especially mast cells, eosinophils and T lymphocytes. Steroidal anti-inflammatory drugs, especially inhaled steroid drugs, are the basic drug treatment. In addition, oral antiallergic agents are used. These drugs are used as prophylactic / maintenance drugs (controllers) to reduce respiratory tract inflammation and reduce seizures. Bronchodilators (02 stimulants) such as theophylline have been used as remedies for acute attacks (Releiva-1). Long-acting bronchodilators, such as sustained-release aminophylline preparations, are used as prophylactic / maintenance drugs because they can easily maintain optimal blood levels.

Neurotransmitters and hormones that cause smooth muscle contraction, after binding to receptors on smooth muscle cell membranes, increase Ca2 ⁺ concentration and activate intracellular protein phosphatase, activating the contractile mechanism I do.

Substance P is one of the neuropeptides, the oldest and smoothest It was isolated from the intestinal tract in 1931 as a substance with muscle contractile activity, and in 1971 its structure was determined as a peptide consisting of 11 amino acids. Substance P is widely distributed in the central and peripheral nervous systems, functions as a pain transmitter from the periphery to the center, and regulates the transmission system of dopamine and adrenaline in the brain. In the periphery, it is widely involved in immunity and inflammation as a regulator of macrophage dysm- piocyte activation and site force in (IL-1, TNF, IL-6). Furthermore, involvement in bronchial asthma has been suggested. External stimulation releases substance P and neurokinin A from nerve terminals distributed to smooth muscle, capillaries, and glands, causing inflammatory symptoms such as increased vascular permeability, plasma leakage, and glandular stimulation. Therefore, if the activity of substance P is inhibited, it can be used for treating asthma.

It is known that arachidonic acid is metabolized in mammals by two different pathways, namely cyclooxygenase and lipoxygenase. Numerous leukotrienes are produced by the lipoxygenase metabolic pathway. Leukotrienes are involved in the inflammatory response, exhibit chemotactic activity, stimulate the release of lysosomal enzymes, and act as key factors in immediate hypersensitivity reactions. For example, Roy co-door Li E down D ₄ is, has been known and strongly contraction child bronchial muscle of humans. Recently, developed mouth I co Application Benefits E down C ₄ - D ₄ of · E ₄ antagonists plan Lucas with or ICI 204, 219 and MK 571 is obvious clinical efficacy against both bronchial asthma Has been confirmed.

Asthma attacks are due in part to abnormal contraction of tracheal smooth muscle cells. Thus, compounds that inhibit smooth muscle contraction may be potential therapeutics for asthma. Smooth muscle contraction ■ Relaxation is regulated by increasing or decreasing intracellular Ca ion concentration. In addition, the mechanism that enhances the sensitivity of muscle fibers to Ca ions also regulates the contraction and relaxation of smooth muscle.

Rho, one of the low molecular weight GTP-binding proteins, is activated by signals from various cell membrane receptors. Activated Rho functions as a molecular switch for various cellular phenomena such as smooth muscle contraction, cell motility, cell adhesion, cell morphology change, and cell proliferation via the actomyosin system. It has been revealed. Therefore, by inhibiting Rho kinase (Rho-associate dkinase), which is considered to be present downstream of the Rho-mediated signaling pathway, Rho inhibits the response of various cellular phenomena caused by Rho, and It is thought to be a therapeutic drug for the diseases involved.

Rho kinase is a protein phosphatase activated by Rho that acts on intracellular signal transduction. Rho kinase is present in cells, and when activated, smooth muscle contracts. Specific inhibition of this enzyme selectively inhibits G-protein (guanine-nucleotide binding regulatory protein) -mediated increase in Ca ion sensitivity and decreases intracellular Ca ion sensitivity, resulting in smooth muscle relaxation. I do.

Rho kinase has been shown to selectively act on Ca-sensitivity, a mechanism of contraction that is independent of intracellular Ca concentration (Natur e 389 (1997): 990-994 j ₀ Therefore, compounds that inhibit Rho kinase are promising as new therapeutic agents for asthma and hypertension, which exert their effects by reducing Ca ion sensitivity.

In addition, Rho kinase is present not only in smooth muscle but also in cancer cells It is said that activation activates stress fibers and adhesion molecules. Therefore, if Rho kinase is inhibited, cell motility can be controlled, and it may be used as a therapeutic agent for autoimmune diseases or as a cancer cell metastasis inhibitor.

According to the aforementioned document [Natur e 389 (1997): 990-994], Y-27632 [(R)-(+)-trans-N- (4-pyridyl) -4- (1-aminoethyl) sic Rohexanecarboxamide) and fasudil hydrochloride (hexahydro-1- (5-isoquinolininsulfonyl) -1H-1,4-diazepine hydrochloride having a structure similar to that of the compound of the general formula [I]. ) It has been reported that Rho kinase is specifically inhibited to inhibit smooth muscle contraction by inhibiting Ca ion sensitivity enhancement. Further, the same is disclosed in WO 98/06433.

It is known that compounds containing isoquinoline skeleton, including fassil hydrochloride, in which the 5-position of the isoquinoline skeleton is substituted with cyclic aminosulfonyl are useful as circulating organ agents (see 57-156463, JP-A-58-121276, JP-A-61-227581, etc.).

Further, in WO 97/28130, isoquinoline represented by the general formula (I) described below, wherein the 5-position of the isoquinoline skeleton is substituted with a cyclic aminosulfonyl and the 4-position has a substituent. It is disclosed that a phosphorus derivative has a cell necrosis inhibitory action.

Lee Sokino Li down锈導body Sabusuta Nsu P antagonism of the general formula [I], Roy co preparative Lin D ₄ antagonism has a Rho kinase inhibitory activity, that as well as asthma prophylactic or therapeutic agent having a smooth muscle relaxant activity The usefulness is not disclosed or suggested in the above-mentioned documents or patent gazettes. Disclosure of the invention

An object of the present invention is to provide a novel agent for preventing or treating asthma.

In order to achieve the above object, the present inventors have found that, in a process of searching for various compounds, an isoquinoline derivative represented by the following general formula [I] has an excellent substance P antagonistic activity, co DOO Lin D ₄ antagonism has a Rho kinase inhibitory action and smooth muscle relaxant action, find a useful this in the prevention or treatment of asthma, the present invention has been completed.

Accordingly, the present invention provides the following general formula [I]

Represents hydroxy, cyano or halogen. R ² represents hydrogen, hydroxy or halogen. R ³ represents hydrogen, alkyl or amidino.潆 A represents an optionally substituted 5- to 11-membered cyclic amino. Such a cyclic amino may be bridged between any two carbons at any position. ) A prophylactic or therapeutic agent for asthma, a smooth muscle relaxant, an antiallergic agent, a substance P antagonist, leukotriene D, which contains, as an active ingredient, an isoquinoline derivative represented by _{4) An} antagonist and a Rho kinase inhibitor.

A feature of the present invention is that the 4-position of the isoquinoline skeleton has an alkyl or aryl group. Isoquinoline derivatives substituted by a substituent selected from the group consisting of phenyl, alkynyl, alkoxy, hydroxy, cyano and halogen, and the aforementioned cotolitri, which was not known for fasudil hydrochloride, emissions D ₄ antagonism, that it combines Sabusuta Nsu P antagonism and Rho kinase inhibitory activity, and inhibit the contraction of bronchial smooth muscle, that were useful as a asthma prophylactic or therapeutic agent It is in.

Hereinafter, the present invention will be described in detail.

The “prophylactic or therapeutic agent for asthma” in the present invention refers to a drug which has an action as a controller or a releaser, or has both actions, and is useful for the prevention or treatment of asthma.

"Smooth muscle relaxant" refers to a drug that suppresses abnormal contraction of smooth muscle. “Antiallergic agent” refers to a drug that suppresses a type I, II, II, or IV allergic reaction.

“Substance P antagonist” refers to a drug that is effective in ameliorating the symptoms of various diseases caused by substance P by suppressing a disorder induced by the activity of substance P.

"Roy co preparative Lin D ₄ antagonist" refers Ri by the suppressing disorders more induced activity of Roy co preparative Lin D _4, the symptoms of various diseases caused by Roy co Application Benefits E down D ₄ Refers to drugs that are effective in improving.

“Rho kinase inhibitors” are defined as physiological disorders or diseases involving Rho kinase (eg, asthma, peripheral circulatory disorders, retinopathy, hypertension, inflammation, immune diseases, autoimmune diseases, cancer, AIDS, bacterial It refers to the prevention or treatment of gastrointestinal infections, arteriosclerosis, osteoporosis, pathological diseases of cerebral dysfunction, fertilization and biological phenomena such as implantation of fertilized eggs. P99 / 03137

The “alkyl” in the present invention is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopopenol pinole, n-butynole, and isobutynole. , Sec-butinole, tert-butinole, π-pentyl, isopentyl, n-hexyl, isohexinole. Of these, alkyl having 1 to 4 carbon atoms is preferable, and methyl is particularly preferable.

The “alkenyl” is a straight-chain or branched-chain one having 2 to 6 carbon atoms, for example, vinyl, arylene, isopropenyl, 2-metharyl, 2-butenyl, 3- Butul can be mentioned. Of these, anorecanyl having 2 to 4 carbon atoms is preferred.

As the "alkynyl", a straight-chain or branched-chain one having 2 to 6 carbon atoms, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butyninole, 2-butenyl, 3-butynyl, 3-Methyl-2-butynyl can be mentioned. Among them, alkynyl having 2 to 4 carbon atoms is preferable.

"Alkoxy" refers to a straight or branched chain having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t ert—butoxy.

“Halogen” includes chlorine, fluorine, bromine, and iodine. Of these, fluorine is preferred.

Examples of the “ring A” include a saturated 5- to 11-membered monocyclic or bridged ring containing two nitrogen atoms as a ring-forming heteroatom. For example, 1-imidazolidinyl, piperazino, hexahydro-1H-1,4-diazepine-11-yl, 1,5-diazacyclooctane-1-1,3,6-diazabicyclo 3.2. . 2] Nonan-3-yl, 3,6-diazabicyclo [3.2.1] octane-3-yl, 2,5-diazabicyclo [2.2.1] heptane-2-yl or 2,5-diazabicyclo [2.2.2] octane Tan-2-yl can be mentioned. Such ring A may have 1 to 4 identical or different substituents at any position selected from the group consisting of anolequinole, halogen, phenyl and aminoanorexyl. Examples of the alkyl portion of the aminoalkyl include the aforementioned alkyl.

As R ¹ , alkyl having 1 to 4 carbon atoms and halogen are preferable, and methyl and fluorine are particularly preferable. As R ² and R ³ , hydrogen is preferable.澴 As A, hexahydro-1H-1,4-dazepine-1-yl is preferable, and in particular, 2- or 7-methylhexahydrid-1H-1, 4-dazepine_1-yl is preferable. More preferred.

— Salts of the isoquinoline derivatives of the general formula [I] include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid and acetic acid. Tartaric acid, lactic acid, cunic acid, fumaric acid, maleic acid, konnoic acid, methansnoleonic acid, ethansnoleonic acid, benzenesnolefonic acid, tonoreensnolefonic acid, naphthalenesnolefonic acid, camphorsnolefonic acid, etc. Organic acid salts can be mentioned.

Some of the isoquinoline derivatives of the general formula [I] have an asymmetric carbon and may have optical isomers. Each of these isomers and mixtures thereof are included in the present invention.

The isoquinoline derivative of the general formula [I] is described, for example, in International Publication WO wo

It can be manufactured according to the method described in 97/28130. —The isoquinoline derivative of the general formula [I] has a leukotriene D ₄ antagonistic action, a substance P antagonistic action, and a Rho kinase inhibitory action, Since it inhibits abnormal contraction of smooth muscle cells, it is useful as a prophylactic or therapeutic agent for bronchial asthma.

When the isoquinoline derivative of the general formula [1] is administered as a medicament, the isoquinoline derivative of the general formula [I] may be used as it is or in a pharmaceutically acceptable non-toxic and inert carrier. For example, it is administered to mammals including humans as a pharmaceutical composition containing 0.1% to 99.5%, preferably 0.5% to 90%.

As the carrier, one or more solid, semi-solid or liquid diluents, fillers, and other prescription auxiliaries are used. The pharmaceutical compositions are preferably administered in dosage unit forms. The pharmaceutical composition of the present invention can be administered orally, intraosseously, topically (such as transdermally), or rectally. Of course, they are administered in dosage forms suitable for these administration methods. Of these, oral administration or inhalation administration is preferred.

The dosage as a prophylactic or therapeutic agent for asthma or other diseases should be adjusted in consideration of the patient's condition such as age and weight, the administration route, the nature and extent of the disease, etc. Usually, the amount of the active ingredient of the present invention for an adult is, in the case of oral administration, in the range of l to l, 000 tng / adult per day, preferably in the range of 10 to 100 mgZ adult. . In the case of inhaled administration, the range is 0.1 to 100 mgZ adult, preferably 1 to 30 mg_ adult per day. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It can also be divided into two or three divided doses.

For oral administration, solid or liquid dosage units, such as powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, and other dosage forms Can be done by The powder is produced by making the compound of the general formula [I] into appropriate fine particles. Powders are prepared by mixing the compound of general formula [I] with a suitable finely divided and then with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as starch, mannitol and the like. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added.

Force capsules are prepared by first filling powdered powders, powders or granules as described in the section on tablets, as described above, into a capsule shell such as a gelatin capsule. It is manufactured by this. Lubricants and glidants, such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol are mixed with the powdered form, The filling operation can be performed later. Disintegrants and solubilizers, such as urenoboximetinoresenorelose, canoleboximetinoresenorelose kanoresum, low substituted hydroxypropinoresenorelose, cross-force noremelose sodium, carboxy The addition of methyl starch sodium, calcium carbonate, sodium carbonate can improve the efficacy of the medicine when the capsule is taken.

Also, a fine powder of the compound of the general formula (I) is suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant, and this is wrapped in gelatin sheet to form a soft capsule. Can be. Tablets are made by adding an excipient to form a powder mixture, granulating or slugging, then adding a disintegrating or lubricating agent and compressing. Powder mixtures can be obtained by mixing appropriately powdered substances with the diluents and bases mentioned above and, if necessary, binding agents (eg, carboxymethyl cellulose Ream, methinoresenorelose, ^3- hydroxy hydroxif pinoremetinoresenorelose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol), dissolution retardant (eg, paraffin), resorbent (eg, A quaternary salt or an adsorbent (eg, bentonite, kaolin, dicalcium phosphate) may also be used in combination. The powder mixture can be first moistened with a binder, for example, syrup, starch paste, gum arabic, cellulose solution or polymer solution, stirred and mixed, dried and pulverized into granules. Instead of granulating the powder in this way, it is also possible to first apply a tableting machine and then crush the imperfect slag obtained into granules. The granules thus produced can be prevented from adhering to each other by adding stearic acid, stearate, talc, mineral oil or the like as a lubricant. The lubricated mixture is then tableted. The uncoated tablets thus produced can be coated with a film coating or sugar coating.

Further, the compound of the general formula [I] may be directly compressed after being mixed with a fluid inert carrier without going through the steps of granulation and slag formation as described above. Transparent or translucent protective coatings consisting of a shellac hermetic coating, coatings of sugar or polymeric materials, and polishing coatings made of wax may also be used. Other oral dosage forms such as solutions, syrups and elixirs can also be presented in dosage unit form so that a given quantity contains a fixed amount of the drug. Syrup is produced by dissolving the compound of the general formula [I] in an appropriate aqueous flavor solution, and elixir is produced by using a non-toxic alcoholic carrier. The suspension is

—Formulated by dispersing the compound of the general formula [I] in a non-toxic carrier. Solubilizers and emulsifiers (eg, ethoxylated isostear If necessary, preservatives, flavoring agents (eg, palmit oil, saccharin) and the like can also be added if necessary.

Where necessary, dosage unit formulations for oral administration may be microencapsulated. The formulation can also provide an extended period of action or sustained release by coating or embedding in a polymer wax or the like.

For parenteral administration, inhalants, injections, suppositories and the like can be used. It can be carried out by using a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection, for example, a solution or suspension form. For these, a certain amount of the compound is suspended or dissolved in a non-toxic liquid carrier compatible with the purpose of injection, such as an aqueous or oily medium, and the suspension or solution is then sterilized. It is manufactured by Non-toxic salts or salt solutions may be added to make the injection solution isotonic. Further, a stabilizer, a preservative, an emulsifier and the like can be used in combination.

For rectal administration, a compound of the general formula [I] may be used as a low-melting, water-soluble or insoluble solid, for example, polyethylene glycol, cocoa butter, semi-synthetic fat (for example, Witepzol, registered trademark) Higher esters (eg, myristyl palmitate) and suppositories produced by dissolving or suspending them in a mixture thereof can be used. BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in more detail with reference to Test Examples and Formulation Examples for representative compounds of the isoquinoline derivative according to the present invention. PC so-called picture 37

It is not limited to them.

The test included hexahydro-1 7-methyl-1_ (4-methyl-5-isoquinolinin sulfonyl) -1H-1,4-diazepine hydrochloride (Compound 1) as the test drug, and (S) — (-)-Hexahydro 7-methyl-1- (4-methyl-5-isoquinolinin sulfonyl)-1H-1,4-diazepine hydrochloride '(Compound 2), Hexahydro-1 2 -Methyl-1- (4-methyl-5-isoquinolinosulfonyl) -1H-1,4-diazepine hydrochloride (compound 3), (S)-(+)-hexahydro-2-methyl Tyl-1- (4-methyl-5-isoquinolinin sulfonyl) -1H-1,4-dazepine hydrochloride (compound 4), (R)-(-)-hexahydro — 2-methyl-1 -(4-Methyl-5-isoquinolininsulfonyl) -1H-1, 4-diazepine hydrochloride (di-conjugated compound 5) and (S)-(-)-hexahydro-1-(4- Fluoro-5-isoquinoline sulfonyl) —2-methyl-1H-1,4-dazepi With hydrochloric acid salt (Compound 6). Fasudil hydrochloride (hexahydro-1- (5-isoquinolinin sulfonyl) -1H-1,4-diazepine hydrochloride) was used as a control compound.

Test example 1

Effect of guinea pig isolated ileum preparation on substance P 锈 contraction

The test was performed according to the method of Holzer et al. (Eur. J. Pharmacol. 91, 83-88 (1983)).

The ileum was removed from a guinea pig and a section specimen was prepared. The specimen was suspended by adding the load of lg Magnus bath satisfies the Krebs solution (32 ° C, 95% 0 2 + 5% C0 2, pH 7 · 4) were recorded contraction of the specimen. Atre pin (0.35 μΜ) was co-present in the Krebs solution. First, after recording contraction due to substance Ρ (3 ηΜ), the specimen was thoroughly washed. Substance サブ (3πΜ) is injected again in the presence of the test drug, and the substance in the absence of the test drug is injected. PC so-called picture 37

Compared with P shrinkage. As a result, Compound 6 exhibited 100% inhibitory activity at 30 μΜ.

Test example 2

Effects of oral guinea pig isolated ileum specimen on oral-trien-induced contraction

The test was performed according to the method of Holroyde et al. (Eur. J. Pharmacol. 1983, 90, 251-255).

The ileum was removed from a guinea pig and a section specimen was prepared. The specimen

A Magnus bath filled with Krebs solution (32 ° C, 95% O ₂ + 5% C 0 ₂ , pH 7.4) was suspended under a load of lg, and the shrinkage of the specimen was recorded. First, after recording the contraction by Roy co Application Benefits E down _{D 4 (0. 01 μ M)} , washed thoroughly specimens.

Again Roy in the presence of a test drug co Application Benefits ene 0 ₄ (injecting 0.01, compared to the mouth I co preparative Lien ₄ contraction in the absence the test agent. As a result, I spoon compound 6 30 μ 98 showed 98% inhibitory effect.

Test example 3

Rho kinase inhibitory action

1. Preparation of GST-RhoK-cat (Daltathione-S-transferase gene and catalytic site of Rho kinase gene)

After culturing SF-9 cells (insect-derived cells) for 3 days, the cells were infected with baculovirus into which the GST-RhoK-cat gene was introduced. After sonication of the cells ⁶⁰ hours after infection, the supernatant obtained by centrifugation (100,000 g × 1 hr) was adsorbed onto a glutathione-sepharose column, and the column was washed with a buffer containing daltathione. Elution was performed using the eluate. T / JP99 / 03137

2. Kinase Atsushi

The composition of the Atsushi system is as follows.

Tris-HCl (pH = 7.5) 50mM, MgCl ₂ 5mM, EDTA linM, EGTA ImM, DTT 1mM, Substrate (S6-peptide) 40μΜ, GST-RhoK-cat 26pg, hot ATP 100μM (0.2μCi) .

3. Protocol

The reaction solution was prepared by removing the substrate and ATP from the eluate. The substrate and radioactive ATP were added to the system and reacted at 30 ° C for 10 minutes. The reaction solution was spotted on a P81 filter (manufactured by Whatman), washed with a 75 mM phosphoric acid solution, and radioactivity was measured. Table 1 shows the results.

table 1

50% inhibitory concentration against Rho Kina-1Γ

(IC ₅₀ : μ Μ) Compound 1 0.15

Compound 2 0.05

Compound 3 0.08

Compound 4 0.015

Compound 5 0.10

Compound 6 0.2

Control compound 1.5 As is clear from Table 1, the Rho kinase inhibitory activity of the isoquinoline derivative of the general formula (II) was much higher by 7.5 to 100 times than that of the control compound, fasudil hydrochloride. . And its activity is professional CT / JP99 / 03137

The inhibitory activity on tin kinase A (PKA), protein kinase C (PKC), and myosin light chain kinase (MLCK) was much stronger and the selectivity was excellent. On the other hand, fasudil hydrochloride did not show selectivity for these kinases.

Test example 4

Effects on isolated guinea pig trachea specimen

The test was performed according to the method of Wasserman et al. (Eur. J. Pharmacol. 1977, 46, 303-313).

The trachea was removed from the guinea pig and a section specimen was prepared. The specimen

A Magnus bath filled with Krebs solution (37. C, 95% 0 ₂ + 5% C 0 ₂ pH 7.4) was suspended under a load of lg, and the generated tension of the sample was recorded. After the tension of the specimen became stable, the test drug (30 μM) was injected into the Magnus bath. The relaxation effect of the test drug was studied with the relaxation caused by 1.6 μe epinephrine as 100%. As a result, Compound 6 exhibited a relaxing action of 30 to 94%.

As apparent from the above弒験example, Lee Sokino re down derivatives of the general formula [I], Sabusuta Nsu P induced contractions inhibition, Roy co preparative Lin D ₄ induced shrinkage suppression effect, intracellular Rho kinase inhibitory action Indicated. It also suppressed the contraction of bronchial smooth muscle.

Formulation Example 1

Prescription (1 tablet in 180mg)

Compound 2 10mg

Lactose l OOnig

Corn starch 55mg

Low-substituted hydroxypro pinoresenorelose ⁹ mg

Polyvinyl alcohol (partially saponified) 5mg Stearin Tortoise Magnesium 1E &

180mg

Preparation method

After uniformly mixing the above components except for polyvinyl alcohol and magnesium stearate, granules for tableting are manufactured by a wet granulation method using an aqueous polyvinyl alcohol solution as a binder. After mixing magnesium stearate with this, it is molded into 180 mg per tablet using a tableting machine to make internal tablets.

Formulation Example 2

Prescription (220g per force)

Compound 4 10mg

Lactose 187 mg

Microcrystalline Senoru mouth 20 rag

Magnesium stearate 3mg

220mg

Preparation method

After the above components are uniformly mixed, 220 capsules are filled into hard capsules using a force capsule filling machine to obtain hard capsules.

Formulation Example 3

Formulation (granules in l g)

Compound 6 10mg

Lactose 880mg

Low-substituted hydroxypro pinoresenorelose ⁷⁰ mg

l OOOmg 03137

Preparation method

After uniformly mixing the above components except for hydroxypropyl cellulose, kneading the mixture as a binder for aqueous solution of hydroxypropyl cellulose, granulating with a granulator to obtain granules. Industrial availability

More than one time, as Lee Sokino re down derivatives of the general formula [I], Sabusuta Nsu P induced contraction inhibitory action, Roy co preparative Lin D ₄ antagonism have Rho quinic over peptidase inhibitory action, also bronchial smooth muscle Showed an action of suppressing shrinkage. By having these actions in combination, the isoquinoline derivative of the general formula [I] is an advantageous agent for preventing or treating asthma.

Further, the isoquinoline derivative represented by the general formula [I] inhibits the contraction of vascular smooth muscle, and is therefore useful as a hypotensive agent for treating malignant or severe hypertension. It also improves microcirculation and is therefore useful as a therapeutic agent for glaucoma.

Furthermore, by having excellent selective Rho kinase inhibitory activity, it can suppress the activation of stress fibers and adhesion molecules, control the movement of cancer cells, and act as a cancer cell metastasis inhibitor. Or for autoimmune diseases.

Claims

The scope of the claims

1. The following general formula [I]

[I]

(In the formula, R ¹ represents anoalkyl, anorecheninole, anoreckininole, anorecoxy, hydroxy, cyano, or halogen. R ² represents hydrogen, hydroxy, or halogen. R ³ represents hydrogen, alkyl, or amidino. Ring A represents an optionally substituted 5- to 11-membered amino group. Such a cyclic amino group may be bridged between two carbon atoms at any position. A prophylactic or therapeutic agent for asthma, comprising an isoquinoline derivative or a salt thereof as an active ingredient.

2. A smooth muscle relaxant comprising the isoquinoline derivative or a salt thereof according to claim 1 as an active ingredient.

3. An antiallergic agent comprising the isoquinoline derivative according to claim 1 or a salt thereof as an active ingredient.

4. A substance P antagonist comprising, as an active ingredient, the isoquinoline derivative according to claim 1 or a salt thereof.

5. I Sokino Li down derivative ranging first claim of claim or Roy co preparative Riwen 0 ₄ antagonist to a salt thereof as an active ingredient.

6. A Rho kinase inhibitor comprising, as an active ingredient, the isoquinoline derivative according to claim 1 or a salt thereof.