WO1999020620A1

WO1999020620A1 - Isoquinoline derivative and drug

Info

Publication number: WO1999020620A1
Application number: PCT/JP1998/004781
Authority: WO
Inventors: Hiroyoshi Hidaka; Akira Matsuura
Original assignee: Nippon Shinyaku Co Ltd; Hiroyoshi Hidaka; Matsura Akira
Priority date: 1997-10-22
Filing date: 1998-10-22
Publication date: 1999-04-29
Also published as: JP4316794B2; AU9646198A

Abstract

The isoquinoline derivative represented by formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing either of them as the active ingredient. The compound (I) is useful as a preventive or remedy for cerebrovascular accident and is particularly excellent as a depressor for cerebrovascular contraction. It is also useful as a preventive or remedy for diseases accompanied by ischemic lesion.

Description

Specification

Isokinoline Inducer and Pharmaceutical Technology

The present invention relates to an isoquinoline derivative which has a cerebral vasoconstriction inhibitory action and a blood flow increasing action and is useful as a medicine. Background technology

Vascular disorders and heart disease, along with cancer, are the leading causes of death in developed countries.

Cerebrovascular disorders are broadly divided into bleeding groups and ischemic groups. In the bleeding group, subarachnoid hemorrhage due to rupture of the cerebral artery, hypertensive cerebral hemorrhage, and head trauma are typical. Subarachnoid hemorrhage causes a narrowing of the vascular lumen in the main artery of the brain that lasts 4-5 days after bleeding and lasts about 2 weeks. This is called cerebral vasospasm. There are still many unclear points about its mechanism of expression, and various physiologically active substances (eg, phytocolamin, hemoglobin, lipid peroxide, arachidonic acid metabolites, peptides, and protein kinase C) are involved. It is attributed to the interaction of these various physiologically active substances. When neurological disorders appear due to ischemia associated with vascular stenosis, it affects not only the prognosis of function but also sometimes the prognosis of life. In the ischemic group, cerebral infarction and transient ischemic attack (TIA) are typical. Vascular disorders and nerve cell damage associated with ischemia or hemorrhage may cause numbness and dyskinetic movements such as numbness and nervous and mental disorders in the acute to chronic phases. In severe cases, it may lead to impaired consciousness and death. Antithrombotic agents and cerebral circulation and metabolism improvers are used to treat these cerebrovascular disorders. However, there are few agents that suppress the damage of nerve cells that progress to lethal cerebral vasorelaxation or dementia, and therapeutic agents are expected. Fasudil hydrochloride [hexahydrol (5-isoquinolinylsulfonyl) -1H-1,4-dazepine] is the only therapeutic agent for cerebral vasoconstriction following subarachnoid hemorrhage. (See Pharmacology & Treatment, 1992, 20 (Suppl 6), 1515, etc.) are not satisfactory drugs in terms of efficacy and side effects.

On the other hand, angina is a typical example of ischemic heart disease. In angina, ischemia accompanies vascular stenosis, leading to myocardial infarction and even death. For animal treatment, vasodilators are mainly used, but many of them also have an antihypertensive effect, and there are few drugs that treat vascular changes.

Compounds in which the 5-position of the isoquinoline skeleton is substituted with cyclic aminosulfonyl are cardiovascular agents (vasodilators, cerebral circulation improvers, angina treatments, cerebral cardiovascular thrombosis). It is known to be useful as a prophylactic and therapeutic agent, a prophylactic and / or therapeutic agent for hypertension, and a cerebral function improving agent (JP-A-57-15846S, JP-A-57-200366, JP-A-57-200366) 58-121278, JP-A-58-121279, JP-A-59-93054, JP-A-60-81168, JP-A-61-152658, JP-A-61-227581 No.). It is also useful as a brain function improver (a drug that prevents, improves, or slows the progression of impairment of brain tissue function, sabotage (including metabolic capacity) and symptoms associated with it, and sequelae). It is known that this is the case (see Japanese Patent Application Laid-Open No. 2 256617).

The authors found that the 5-position of the isoquinoline skeleton was a cyclic aminosulfonyl. And a compound having a substituent at the 4-position is a superior cerebrovascular disorder preventive or therapeutic agent than these known compounds, and a patent application was previously filed (International Publication W037 / 281). No. 30). In this case, the isoquinoline skeleton has a fluorine atom at the 4-position, the 5-position is substituted with a hexahydrido-4H-1.4-dazepine-ylsulfonyl, and the hexahydro-4Η The compound of the present invention in which the 2-position of 1,4-dazepine is substituted with methyl is not specifically disclosed. Disclosure of the invention

The object of the present invention is to be highly safe and superior to existing drugs as a cerebrovascular disorder prevention and treatment agent, especially as a cerebrovascular contraction inhibitor, and as a preventive and therapeutic agent for diseases associated with ischemic lesions. To provide

-3 was ο

In order to achieve the above object, the present inventors have synthesized and studied various compounds having a novel structure, and found that a compound represented by the following formula [I] can be administered to the brain at a very low dose. The present invention has been found to have a vasoconstriction inhibitory effect and to have an excellent blood flow increasing effect by dilating coronary blood vessels and cerebral blood vessels without lowering systemic blood pressure. Therefore, the present invention provides the following formula [I]

c I]

Or a pharmaceutically acceptable salt thereof and an effective compound thereof. A pharmaceutical composition contained as a component.

A special feature of the chemical structure of the compound of the present invention is that the 4-position of the isoquinoline skeleton is substituted with fluorine, and the 5-position hexahydro-4H-1,4-azepin-1-ylsulfonyl. Hexahydro-4Η-diazepine is substituted with methyl at position 2.

The compound [I] of the present invention has an asymmetric carbon and has optical isomers. Both of these isomers and mixtures thereof are included in the present invention. Of these, the (S) body is preferred.

Examples of the “pharmaceutically acceptable salt” include 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, and cunic acid. And salts of organic acids such as fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and camphorsulfonic acid. it can.

The compound [I] of the present invention can be produced, for example, by the method described in International Publication WO097 / 28130 or the following method.

Manufacturing method 1

(In the formula, R ³¹ represents a protecting group or a leaving group.)

Examples of L ′ as the leaving group include a residue of a reactive derivative of sulfonic acid described below. Examples of the protecting group represented by R ³¹ include: Examples thereof include acyl such as formyl, acetyl and benzoyl, aralkyloxycarbonyl such as benzyloxycarbonyl, alkoxycarbonyl such as tert-butyloxycarbonyl, and aralkyl such as benzyl.

The amine represented by the formula [III] is reacted with a reactive derivative of the sulfonic acid represented by the formula [II] in a suitable solvent to remove the protecting group to produce the compound [I]. . The reaction solvent may be any solvent that does not hinder the reaction. Examples thereof include ethers such as tetrahydrofuran (THF), dioxane and getyl ether, hydrocarbons such as benzene and toluene, and chlorides. Halogenated hydrocarbons such as methylene and chloroform, non-protonic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, pyridine, and acetonitrile Ril, or a mixture thereof can be used. Sulfonic acid halides (eg, sulfonic acid chloride, sulfonic acid buideamide), sulfonic anhydride, N-sulfonylimidazolide, etc. are used as reactive sulfonic acids of sulfonic acid. It is possible. Particularly, sulfonic acid halide is preferable.

This reaction is preferably performed in the presence of a suitable base. Such bases include alkali metal bicarbonates (eg, sodium bicarbonate), alkaline metal carbonates (eg, lithium carbonate), alkali metal hydroxides (eg, Organic class S amines such as sodium hydroxide, sodium hydroxide, and sodium hydroxide, and triethylamine and triethylenediamine can be used. If a basic solvent such as gin is used, such a base is not required and is preferred.

This reaction is usually often proceeds at room temperature, cold却又if necessary by heating, - at 78-150, preferred details, this performed at 0 ~ 120 ^e C Can be. When a base is used, the amount of the amide [III] used is preferably 1 to 5 moles per mole of the reactive derivative [II], more preferably 1 to 2 moles per mole of the reactive derivative [II]. is there. The amount of base used is

It is preferably in the range of 1 to 10 moles, more preferably 1 to S moles, relative to [III]. If no base is used, reactive derivative

[II] is used in an amount equal to or less than an equimolar amount, preferably 0.5 to 0.1 times the molar amount of the amide [III]. The reaction time varies depending on the raw materials, solvent, reaction temperature, etc. used, but is usually 5 minutes to 70 hours. The protecting group is then removed in a manner known per se. The protecting group can be removed by a method known per se, such as acid treatment, alcohol treatment, and catalytic reduction.

Starting material [II] can be produced in the same manner as in Reference Example 1 described later.

Starting material [III] can be produced in the same manner as in Reference Example 2. Production method 2

[V]

[I] (In the formula, L ¹ is as defined above.)

(Step 1) Compound [IV] is produced by reacting 2-amino-1-propanol with compound [III] in the same manner as in Production Method 1.

(Second step) The hydroxy group of compound [IV] can be converted to a halogen (eg, chlorine, bromine), a sulfonyloxy (eg, methansulfonyloxy), or an acyloxy (eg, tosylquinine) by a method known per se. , Acetyloxy) and then reacting 3-amino-1-propanol in an appropriate solvent in the presence or absence of a base in the same manner as in Production Method 1 to give the compound [V ] Is manufactured.

(Third step) After protecting the nitrogen atom of the secondary amino of compound [V] by a method known per se, the compound is subjected to ring closure and deprotection in the presence of a base in an appropriate solvent to give compound [V]. I] can be obtained.

The compound [I] can also be produced by treating the compound [V] with triphenylphosphine and dialkyl abdicarboxylate and performing an intramolecular dehydration condensation reaction.

In the above-mentioned production method, the amino group is protected with a commonly used protecting group, if necessary, and after the above reaction, protected by a method known per se such as acid treatment, alkali treatment, or catalytic reduction. Examples of the amino-protecting group from which the group can be removed include benzyl, benzyloxycarbonyl, and trifluoroacetyl.

The compound [I] of the present invention is usually obtained in a racemic form. These racemic forms have pharmacological activity as they are, but can be separated into the respective isomers as desired. For example, a mixture of isomers can be subjected to a known optical resolution method, for example, an optically active carboxylic acid (eg, (10)-or (-)-tartaric acid). Acid, (10)-or (-)-ligonic acid> or a salt with an optically active sulfonic acid (eg, (+)-camphorsulfonic acid), fractional recrystallization, optically active column The optical isomer can be obtained by performing each reaction using an optically active raw material compound (S configuration or R configuration) corresponding to the raw material compound [III]. it can.

The compound [I] of the present invention can form the above-mentioned salt by a known method. For example, the hydrochloride of the compound [I] of the present invention can be obtained by dissolving the compound [I] of the present invention in an alcohol solution or hydrogen ether solution of hydrogen chloride, concentrating the solution, and collecting the precipitated crystals by filtration. Can be.

The compound of the present invention thus produced can be obtained by a method known per se in the form of a free base or an acid addition salt, for example, by concentration, liquid conversion, phase transfer, solvent extraction, crystallization, It can be isolated and purified by distillation, chromatography and recrystallization.

Since the compound of the present invention has a 脑 vasoconstriction inhibitory action and is highly safe, it is useful for the treatment of 脳 cerebrovascular disorders, particularly 予防 prevention of cerebral tissue disorders due to vascular constriction after hemorrhage 膙. In addition, since it has a blood flow increasing effect, it is also useful as an agent for preventing or treating a lesion associated with ischemic disease.

When the compound of the present invention is administered as a medicament, the compound of the present invention 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 composition is administered It may be desirable to administer in unit form. 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. Above all, intravenous administration or oral administration is preferred.

The dosage as a medicament should be adjusted in consideration of the patient's condition such as age and weight, the administration route, the nature and degree of the disease, etc., but it is usually used as a therapeutic agent for preventing cerebrovascular disease. In the case of intravenous administration, the amount of the active ingredient of the present invention for an adult is 0.1 to 100 mg / day, preferably 1 to 30 mg / human knee per day. . In the case of oral administration, the daily dose is in the range of 1-1, OOO mg / human, preferably in the range of 10-30 mg / human. As an agent for preventing or treating diseases associated with ischemic lesions, the amount of the active ingredient of the present invention for adults is preferably 0.1 to 100 mg / human in intravenous administration. Is in the range of 1-30 mg / human. For oral administration a daily dose in the range of l to 1.000 mg / human, preferably 10-30 mg / human. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It can also be administered in divided doses two to three times a day. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to the production of typical raw materials according to Reference Examples, the production of the compounds of the present invention by Examples, and Formulation Examples and Test Examples of representative compounds. It is not limited to these. The specific rotation was measured at 20 ° C.

Reference example i Synthesis of 5-chlorosulfonyl-4-fluoroysoquinoline (first step)

300 ml 29% ammonia water 1 60 ml sealed tube of copper sulfate _{(0 CuSCU · 5Η 2) 3g} , 4- blanking placed σ Moi Sokino Li down 49, 92 g, was stirred for 1 6 hours 17CTC. After cooling, add 40 ml of 2N sodium hydroxide to the reaction solution, and add 400 ml of benzene.

Extracted 5 times. The organic layer was dried over magnesium sulfate, treated with activated carbon, and then the solvent was distilled off to obtain 29.5 g of 4-aminoisoquinoline.

(2nd step)

28.8 g of 4-aminoisoquinoline was added to 42-fluorohydrofluoric acid lOOinl and dissolved. This mixture was cooled with dry ice-monoether, and when it began to solidify, 13.8 g of sodium nitrite was added over 1 hour. The reaction solution was filtered, and the obtained solid (diazonium salt) was quickly washed with ether at a low temperature to remove water as much as possible. The diabdium salt was added to xylene, heated with hot air (dryer) under stirring, and after gas generation started, the mixture was stirred at room temperature for 2 hours. Xylene was decanted from the obtained tar, and the xylene solution was extracted S times with 100 ml of dilute hydrochloric acid. The hydrochloric acid layer and the tarry substance were mixed, water (100 ml) was added to the mixture, the mixture was made alkaline with potassium carbonate, and extracted three times with 400 ml of ether. The extract was dried over magnesium sulfate, filtered, activated carbon was added, and filtered through celite. The solvent was distilled off, and the residue was purified by silica gel column chromatography (black-mouthed form). The solvent was distilled off to obtain 14.5 g of 4-fluoroisoquinoline.

(3rd step)

22,05 g of 4-fluoroisoquinoline was added to 90 ml of sulfuric acid. Under ice-cooling, a solution of 18.18 g of potassium nitrate in sulfuric acid (90 ml) was added dropwise. At room temperature 2 After stirring for an hour, the reaction solution was poured into ice, and ammonia water was added under cooling to make it basic. The precipitated crystals were collected by filtration, washed with water, and dried to give 6 g of 4-fluoro-5-2-nitrosquinoline 22.I.

(4th step)

23.04 g of 4-fluoro-5-nitroisoquinoline was suspended in 80 ml of ethanol. To this, 4 ml of concentrated hydrochloric acid U was added, and a solution of 90.24 g of stannous chloride 'dihydrate in ethanol (144 tnl) was added dropwise with stirring under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction solution was concentrated, 200 mi of ice water was added, and then 2N sodium hydroxide was added to make the mixture alkaline, and the mixture was extracted S times with 500 ml of chloroform. The extract was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to give 15.05 g of 5-amino-4-1-full-year-old leusoquinoline. .

(Fifth step)

8. 1 g of 5-amino-4-fluoroisoquinoline was suspended in 100 ml of concentrated hydrochloric acid. To this, sodium nitrite (5.18 g) was dissolved in water (20 mU) and added dropwise at -5 with the following, followed by stirring at room temperature for 30 minutes (preparation of solution A). Separately, a solution was prepared by adding a solution of 2.8 Sg of water (12.5 ml) of cupric chloride dihydrate to 62.5 mi of a sulfuric acid gas-saturated acetic acid solution, and the A solution was added dropwise thereto. The reaction was then stirred at room temperature for 1 hour and then warmed on a water bath at 30 to remove unreacted sulfur dioxide. The reaction solution was extracted three times with 400 ml of black hole. The extract was neutralized and washed with a sodium hydrogencarbonate aqueous solution, dried, and then the solvent was distilled off to obtain 9.6 g of 5-mouth rosulfonyl-4-fluoroysoquinoline.

Reference example 2 (s) Synthesis of 1-hexahydryl 4- (tert-butoxycarbonyl) — 2-methyl-1H—1,4-diazepine

(First step)

(S)-(+)-2-Amino-1 15 g of monopropanol was dissolved in 150 ml of chloroform, and triethylamine 20 and 2 were added. A solution prepared by dissolving 34.07 g of benzyloxycarbonyl chloride (ZC1) in 50 ml of clogged form was gradually added dropwise with stirring under ice-cooling, and the mixture was stirred at room temperature overnight. 200 ml of water was added to the reaction solution, and the mixture was extracted three times with 200 ml of black form. The organic solution was washed twice with 200 ml of saturated saline, dried over magnesium sulfate, and the solvent was distilled off. 200 ml of n-hexane was added to the obtained crystalline residue, and the residue was crushed. The residue was collected, washed with n-hexane, dried and dried (S> -2-benzylbenzene). 37.04 g of xycarbonylamino-1-propanol was obtained.

(2nd step)

36.52 g of (S) -2-benzyloxycarbonylamino-1-bromophenol was dissolved in 140 ml of methylene chloride, and 18.67 g of triethylamine was added. Was dissolved in 60 ml of methylene chloride, and the mixture was gradually added while stirring forever and stirred for 20 minutes.200 ml of water was added to the reaction solution, and the mixture was extracted three times with 200 ml of chloroform at the mouth. After drying with magnesium sulfate, the solvent was distilled off to obtain 49.53 g of (S) -2-benzyloxycarbonylamino-1-methanesulfonyloxypropane.

(3rd step)

Dissolve 70.0 g of 3-amino-1-propanol in 60 ml of tetrahydrofuran (THF) and add (S) -2-benzyloxycarbonylamino at room temperature. 1-Methanesulfonyloxypropane 48. A suspension of 7 g of S in 140 ml of THF was added. The mixture was heated to reflux overnight at 80 ° C. with stirring. After cooling, 200 ml of water was added to the reaction solution, and the mixture was extracted S times with a 200-ml black hole form. The organic layer was washed twice with 200 ml of a saturated saline solution and dried over magnesium sulfate. The solvent was distilled off, and the (S) -6-benzyloquincarbonylamino-4-4-azaheptanol was removed. 37.6 was obtained as a pale yellow oil. The oil crystallized on standing for a while.

(4th step)

(S) -6-Benzyloxycarbonylamino-4-azaheptane-1-ol S7-lg was dissolved in 150 ml of THF, and 34.7 g of di-tert-butyl carbonate was added thereto under stirring with water cooling. Was dissolved in 50 ml of THF, and the mixture was stirred overnight at room temperature. The reaction mixture was added with 200 inl of water and extracted three times with 200 ml of chloroform. The organic layer was washed twice with 200 ml of a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was purified using silica gel column chromatography (eluent: Cogel C-200 / registered trademark lkg, chloroform: methanol = 100: 1 100: 5) and purified by (S 44) 42 g of) -6-benzyloquincarbonylamino--4- (tert-butoxycarbonyl) -4-azaheptan-1-ol as a pale yellow oil was obtained.

(Fifth step)

Dissolve (S) -6-benzyloxycarbonylamino-4- (tert-butoxycarbonyl) -4-azaheptane-l-lO.Og in 50 ml of methylene chloride and add 3.0 g of tritylamine. The mixture was stirred on ice. To this was added a solution of 32.g of mesyl chloride in 25 ml of methylene chloride, and the mixture was stirred at room temperature for 10 minutes. 200 ml of water is added to the reaction solution, and And extracted three times. The organic layer was washed with 200 ml of a saturated saline solution, dried over magnesium sulfate, the solvent was distilled off, and [S) -6-benzyloxycarbonylamino--4- (tert-butoxycarbonyl) -4- 11.74 g of azaheptyl methanesulfonate was obtained as a pale yellow oil.

(Step 6)

Dissolve 11.74 g of (S) -8-benzyloxycarbonylamino-4- (tert-butoxycarbonyl) -4-azaheptyl methanesulfonate in dimethyl sulfoxide (DMS0) and hydrogenate 60% After adding 2.2 g of sodium and stirring at room temperature for 30 minutes, water and ethyl acetate were added to the reaction solution, the mixture was separated, and the organic layer was washed with water, washed with 200 ml of saturated saline 5 times, and sulfuric acid was added. The residue was purified by silica gel column chromatography (using 200 g of Co-gel C-200 / registered trademark, eluted with a gel form). Then, 8.53 g of (S) -hexahydro 1-benzyloxycarbonyl-4- (tert-butoxycarbonyl) -2-methyl-1H-1,4 diazepine was obtained as a pale yellow oil.

(Step 7)

(S) -Hexahydritol benzyloxycarbonyl-4- (tert-butoxycarbonyl) -2-methyl-1H-1,4-dazepine 8.53 g in a 500 ml atmospheric pressure reduction apparatus Was dissolved in 80 nil, and 4.0 g of 5% palladium / carbon was added, and the mixture was catalytically reduced at room temperature under normal pressure.After 6 hours, the mixture was passed through celite, the solvent was distilled off, and (S)- Hexahydro-4- (tert-butoxycarbonyl) -2-methyl-1H-1,4-dazepine was obtained as a pale yellow oil (3.97 g).

In the same manner, (R) -hexahydro-4-1- (tert-butoxycarbonyl) -12-methyl-1H-1,4-diazepine and hexahydro 1- (tert-butoxycarbonyl) -2-methyl-1H- and 4-diazepine were synthesized.

Example 1

Hexahydro 1- (4-fluoro-^ _- isoquinolinosulfonyl) 2-methyl-1H—1,4-diazepine

(1) Hexahydro-4- (tert-butoxycarbonyl) -2-methyl-1H-1,4-dazepine 0.51 g and triethylamine 0.30 g are dissolved in a solution of methylene chloride in 10 ml. 0.49 g of sulfonyl-4-fluorosoquinoline was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with water, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (form π-formaldehyde: 100/1), and hexahydro-4- (tert-butoxycarbonyl) -1- (4-fluoro- There was obtained 0.51 g of 5- (isoquinolinsulfonyl) -2-methyl-1H-1,4-dazepine.

(2) 0.99 g of the compound obtained in (1) was dissolved in 10 ml of methylene chloride, 10 ml of trifluoroacetic acid was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The port-form layer was dried over magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (formula formanol = 10/1) to obtain 0.24 g of the desired compound.

NMR spectrum (CDCla): δ Cppm) d.91 (SH, d), 1.69-1.88 (3H.m), 2.47-2.77C2H, nO, 3.13-3.36 (3H, m), 3.92-4.10 (2H, m), 7.73C1H, t), 8.22 (1H, dd), 8.57C1H, d), 8.84 (1H, d>, 9.15C1H, s)

Example 2 1 (S) — (1) 1-hexahydro 1 1 (4-fluoro-5-isoquinolinosulfonyl) 1 2 — _methyl ^ ^ JH-1 1,4 1-dazebine hydrochloride

(1) (S)-Hexahydro-4-(tert-butoxycarbonyl) 1-2-Methyl-1H-1,4-1-diazepine 0.54 g and triethylamine 0.38 g are salified. To a solution dissolved in 10 ml of methylene was added 0.62 g of 5-neck α-sulfonyl-41-fluoroysoquinoline, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with water, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform Z methanol-100/1), and (S) -hexahi draw 41- (tert-butoxycarbonyl) -1 0.99 g of 1- (4-fluoro-5-isoquinolinin sulfonyl) -1-2-methyl-1H-1,4-dazepine was obtained.

(2) 0.99 g of the compound obtained in (1) was dissolved in 10 ml of methylene chloride, and trifluoroacetic acid was added dropwise, followed by stirring at room temperature for 2 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with chloroform. The port-form layer was dried over magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (formula nominol = 10/1) to give (S) -hexahydro-11- (4-fluoro-15-isoquinolinylsulfonyl) -1 0.58 g of 2-methyl-1H-1.4-diazepine was obtained.

NMR spectrum (CDC>: δ (ppm) 0.91C3H, d), 1.69-1.88 (3H, m), 2.47-2.77C2H.m), 3.13-3.36C3H, m), 3.92-4.10C2H, m ), 7.73C1H, t), 8.22C1H, dd) .8.57C1H.d), 8.84UH, d). 9.15 (1H, S)

(3) 0.58 g of the compound obtained in (2) was dissolved in 10 ml of methanol, and 1.80 ml of a 1N aqueous hydrochloric acid solution was added thereto.

Elemental analysis as _{_{_{(C 15 H 1 B PN 3}}} 0 2 S ■ HCI)

Calculated value (%) C: 50.01H: 5.32N: 1.1.68 Actual value (%) C: 50.26H: 5.60N: 1.1.44 [N] _D = one 9.02. (C = l.086, H _z 0)

Example S

_ (p)-+ —Hexahi Draw 1-1 (4-Fluoro-5—isonolinsulfonyl) —1-2-Methyl-1-H—_1, —4-Diazepine hydrochloride

C 1) (R) 1-hexahydryl 4- (tert-butoxycarbonyl) 12-methyl-1H-1,4-diazepine Using 0.54 g, Examples 2 (1) and (2) By the same operation, (R)-(10) 1-hexahydro 1- (4-fluoro-5-isoquinolininsulfonyl) -1-methyl-1H-1,4-diazepine was obtained.

NMR spectrum (CDCl _a ): δ (ppm) 0.91C3H, d), 1.69-1.88 (3H, m), 2.47-2.77C2H, m), 3.1S-3.36C3H, in), S.92- 4.10 (2H, m), 7.73UH, t), 8.22C1H, dd), 8.57C1H, d), 8.84 (1H, d), 9.15C1H, s)

(2) The compound obtained in (1) was operated in the same manner as in Example 2 (3) to obtain 0.45 g of the desired compound.

Elemental analysis useful (C ₁₅ H _{1 4} FN3Q ₂ S ■ HC1)

Calculated value (%) C: 50.01H: 5.S2N: 11.668 Actual value (%) C: 50.27H: 5.05N: 11.82 [Na] _D = 7, 70 ° (c-1.116, HiO)

Example 4

— (S) (1) Hexahi draw 1- (4-Fluoro-5-isoquinolinylsulfonyl)-2-methyl- 1 H— 1,4-diazepine hydrochloride (Alternative method)

(1) Dissolve 3.00 g of (S)-(+)-2-amino-1-propanol and 6.06 g of triethylamine in 100 ml of methylene chloride, and add 9.82 g of 5-chlorosulfonyl-4-fluorooysoquinoline The reaction mixture was washed with water, dried over magnesium sulfate, and concentrated, and the precipitated crystals were washed with iso-α-pyruether to give (S) -4-fluoro-5- [Ν- There was obtained 7.96 g of (1-hydroxybutane-2--2-yl) aminosulfonyl] isoquinoline.

(2) 1.42 g of the compound obtained in (1) and 0.76 of triethylamine were dissolved in 30 ml of methylene chloride, and under ice cooling, 0.63 g of methyl sulfonyl chloride was added dropwise, followed by stirring at room temperature for 1 hour. The solution was washed with water, dried over magnesium sulfate, and concentrated, 20 ml of THF was added to the residue, 1.88 g of 3-aminopropanol was added dropwise, and the mixture was stirred at room temperature for 12 hours. Purified by Rica gel lacquer α-matography (methylene chloride, methanol 29% ammonia water = 90/10/1), and (S) -4-fluoro-5- [Ν- (1 Thus, 1.56 g of [1-hydroxyquin-4-yl) aminoquinosulfonyl] isoquinoline was obtained.

(3) 1.54 g of the compound obtained in (2) and 1.77 g of triphenylphosphine were dissolved in 15ral of THF, and 3.41 g of a 40% toluene solution of absodicarboxylic acid diisopropyl ester was added dropwise, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated, ethyl acetate was added to the residue, and the mixture was extracted with 1N hydrochloric acid. The water is made slightly alkaline with sodium bicarbonate, and the resulting oil Extracted. The extract was washed with water, dried over magnesium sulfate, and concentrated. The residue was dissolved in ethanol, a 1N hydrogen chloride ether solution was added, and the precipitated crystals were collected. The crystals were washed with ethanol to obtain 0.60 g of the desired product. Elemental analysis value (C, ₅ _Hle FN _a 0 ₂ S ■ HC1)

Calculated value (%) C: 50.0 1 H: 5.32 N: 11.68 Actual value (%) C: 4 9. S 2 H: 5.2 1 N: 1 1.4 3 With a melting point of 2 5 8 to 2 6 0

Formulation Example 1

Prescription (in lml)

3 mg of the compound of Example 2

9mg sodium chloride

Water for injection ---

lml

Preparation method

The compound of Example 2 and sodium chloride were dissolved in water for injection at the above ratio, filtered using a membrane filter (0.22μπι), filled into the sample, sterilized, and sterilized with an aqueous elution agent. I do.

Formulation Example 2

Prescription (per vial)

3 mg of the compound of Example 2

Mannitol 50mg

Preparation method

After dissolving the compound of Example 2 and mannitol in the water for injection in the above ratio, the mixture was sterilized using a membrane filter (0.22 m), filled into a vial, and then freeze-dried by a conventional method. , Dissolving injection for use And

Formulation Example 3

Prescription (1 tablet 1 in 80mg)

Compound of Example 2 l Omg

Lactose l OOmg

Corn starch 55mg

Low substitution degree π xybu mouth pill cellulose 9mg

Polyvinyl alcohol (partially genated) 5mg

Magnesium stearate img

Preparation method

After the above components except polyvinyl alcohol and magnesium stearate are uniformly mixed in the above ratio, granules for tableting are manufactured by a wet granulation method using an aqueous solution of polyvinyl alcohol as a binder. . After mixing with magnesium stearate, each tablet is weighed to 180 mg using a tableting machine to give internal tablets.

Formulation Example 4

Prescription 0 capsules in 220mg)

Compound of Example 2 l Omg

Lactose 187rag

Microcrystalline cellulose 20mg

Magnesium stearate Smg

220mg

Preparation method

After uniformly mixing the components in the above ratio, the capsule is filled with the above-mentioned 220 mg into a hard capsule with a capsule filling machine to obtain a hard capsule. Formulation Example 5

Formulation (granules in l g)

10 mg of the compound of Example 2

Lactose 880mg

Low-substituted hydroxyquine propyl cellulose 70mg

t-Droquine propyl cellulose _ 40mg

l OOOmg

Preparation method

In the above ratio, the above-mentioned components except for π-pidipropylcellulose are uniformly mixed, and then kneaded with an aqueous solution of hydroxyp-sipircellose as a binder, and then granulated with a granulator to obtain granules. And

Next, test examples of typical compounds of the present invention are shown. The test food was the compound of Example 2, and the comparative control compound was a compound specifically disclosed in the prior art W097 / 28130, a hexahydrodraw that is structurally closest to the compound of the present invention. 1 — (4 —Fluoro-5 —isoquinolinin sulfonyl) — 1 Η— 1,4 —Dazebine hydrochloride (hereinafter referred to as compound 化合物) and a commercially available product, fasudil hydrochloride were used. Test example 1

Effects of rat aorta on calcium ionophore contraction

Rats anesthetized with ether (SD, male, 10-14 weeks old) were sacrificed by exsanguination, and the thoracic aorta (about 3 cm) was removed. After removal of fat and connective tissue, an infusion specimen of about 3 band width was obtained, and the lumen was rubbed to remove intracellular blood cells. The specimen was mounted on an isometric tension transducer in a Magnus bath filled with nutrient solution and a lg static tension was applied. The nutrient solution in the Magnus tank is maintained at 37 under aeration of a mixed gas (95% 0 ₂ + 5¾C 0 ₂ ) and nourished about every 20 minutes. The sample was allowed to stabilize for about 1 hour while changing the solution. Calcium myonophore A23187 was administered to the sample to a final concentration of 1 // M, and after the contraction was stabilized, the test compound was cumulatively administered. The contraction-relaxation reaction was recorded during this period, and the 50% inhibitory concentration (IC _{B 0} (^ M)) of the test compound on A23187 vasoconstriction was determined. As a result, I of the compound of Example 2 was obtained. Was 1.7. On the other hand, the ICs of Compound A as a control compound and Fasudil hydrochloride. Were 10.6 and 7.4, respectively. The composition of the nutrient solution used in the experiment is as follows. NaCl 115.9m C or less the same); KC 1 5.9; CaCla 2.5 ; MgCl 2 1.2; NaHjP0 4 1,2; NaHC0 8 25.0; glucose 11.5. These were dissolved in distilled deionized water. The pH when the mixed gas was saturated was 7.4.

The compound of the present invention has an action of relaxing blood vessels contracted by calcium ionophore, and the action intensity was much higher than that of the comparative compound, compound A and fasudil hydrochloride.

Test example 2

Increases blood flow in rat middle cerebral artery

The head of a rat (SD, male, 11-12 weeks old) anesthetized with urethane was fixed, the striated muscle was separated, and the tibia was exposed. Using a dental drill, a hole with a diameter of about 5 was drilled in the skull just above the middle cerebral artery (MC A) so that the MC A could be seen directly. The probe (diameter: 1.0 yield) of the laser Doppler blood flow meter was brought close to the MC A, and the change in the MC A blood flow was measured. The test compound was dissolved and diluted in physiological saline, and Smg / kg was administered from the femoral vein via a force nebulizer for 5 minutes. The effect of each compound was indicated by the blood flow increase rate before drug administration. As a result, the blood flow increase rate of the compound of Example 2 was 18.8%. On the other hand, The increase in blood flow of compound A and fasudil hydrochloride were 12.4% and 5.2%, respectively. The test compound was administered for 30 minutes, and the blood flow increase rate was measured in the same manner. As a result, the compound of Example 2 significantly increased the blood flow to 5.2 化合物, 9.6% by administering lmg / kg and 3mg / kg, respectively, while the increase of fasudil hydrochloride was observed at 3nig / kg. However, a significant 5.4% increase was seen with l Omg / kg.

The compound of the present invention had an effect of increasing rat middle cerebral artery blood flow, and the effect was much greater than that of the comparative compound A and fasudil hydrochloride.

Test example 3

Relief action of cerebral vasorelaxation in a submucosal hemorrhage model in dog

According to the method of Varsos et al., U. Neurosurgery 58, 11-17 (1983)], a model dog was injected twice in the autologous blood tank. On the first day of the experiment, under pentobarbital anesthesia, the axillary artery blood vessels before compound administration were photographed by angiography. Thereafter, 4 ral cerebrospinal fluid was removed from the cisterna magna and the same volume of autologous blood was injected at a rate of 2 ml / min. After the blood injection, the head was tilted 30 degrees downward for 30 minutes, and the blood was uniformly distributed from the basilar artery to the Circle of Willis. On the third day of the experiment, another 4 ml of autologous blood was injected into the cisternal. On the 7th day of the experiment, cerebral angiography was performed under pentobarbital anesthesia, and after confirming that delayed cerebral vasoconstriction was induced, the drug was evaluated. The test compound was administered from the left femoral vein over 1 minute. Angiography was performed over time. Regarding the action of each compound, the maximum value of the diameter of the most constricted portion of the basilar artery was shown, and the diameter of the same site on the first day of the experiment was defined as 100.

As a result, the compound of Example 2 showed a significant remission effect on vasoconstriction at a dose of 0.3 mg / kg or more, and completely attenuated the plaque at 3 mg / kg. Was. Blood pressure did not change significantly at 0.3 mg / kg, but decreased at Img / kg and above. On the other hand, fasudil hydrochloride at lOmg / kg showed a significant remission effect only immediately after infusion, and blood pressure decreased at 3 mg / kg or more. That is, 3 mg / kg of the compound administration group of Example 2 was used in Test Example A (number of animals used = 5), and the comparative control compound, fassil hydrochloride 3 mg / kg group was used in Test Example B (number of animals used-4). Assuming that the / kg administration group is Test Example C (the number of animals used = 4), the blood vessel diameter before drug administration on Day 7 was 58% in Test Example A. On the other hand, in Test Examples B and C, they were 58% and 57, respectively. Intravenous administration of the compound of Example 2 increased the constriction blood vessels to 107% by intravenous administration to the inner diameter before blood injection. On the other hand, Fasudil hydrochloride did not show a clear remission effect when administered intravenously at 3 mg / kg, and only 82% was resolved when administered intravenously at 10 mg / kg.

The compound of the present invention significantly relieved vasospasm at a very low dose of 0.3 g / kg and at a dose that did not cause a change in blood pressure.

Test example 4

Effects on ^ infarction due to rat middle cerebral artery occlusion

An incision was made in the common carotid artery of a male SD rat (210-240 g, 7 weeks old, 12 per group) under anesthesia with Hakosen, and nylon was used from the same site through the internal carotid artery to the root of the middle cerebral artery. The obturator was inserted. After the middle cerebral artery blood flow was interrupted, the anesthesia was stopped, and two hours later, the blood flow was resumed by removing the nylon obturator. Six hours after resuming blood flow, the brain was excised, the infarct area was determined by TTC (2, S, 5-triphenyltetrazolium chloride) staining, and the infarct volume was measured separately for the cerebral cortex and the upper brain stem other than the cortex. And Dunnett's test. The total amount of 0.3, lmg / k of the compound of Example 2 and 3 mg / kg of fasudil hydrochloride were immediately applied for 30 minutes immediately after occlusion of the middle cerebral artery-reperfusion. A gun was administered intravenously. As a result, the compound of Example 2 significantly reduced the infarction in the cerebral cortex from 298.7 mra ^s to 181.7 に対して³ in the cerebral infarction due to transient middle cerebral artery occlusion at the dose of 1 mg / kg (P 0.05). On the other hand, fasudil hydrochloride only showed a tendency to suppress cerebral infarction at 3 mg / kg.

Test example 5

Effects of rat permanent middle cerebral artery occlusion on cerebral infarction

A small hole was made in the bottom of the temporal bone under halothane anesthesia and the main trunk of the left middle cerebral artery was cauterized and cut by electrocoagulation in an SD male rat (210-240 g, 7 weeks old, 10-11 animals per group) 48 hours after occlusion of the middle cerebral artery, the brain was excised, the infarct area was determined by TTC staining, the infarct volume was measured separately for the cerebral cortex and the striatum, and tested by Dunnett's test. Compound 0.03, 0.1, 0.3 or lmg / kg and 酿 fasudil 1 or 3mg / kg were administered intravenously continuously over 30 minutes immediately after occlusion of the middle cerebral artery, resulting in cerebral cortex and striatum. in the compound of example 2 was significantly inhibited each stroke body穑administration of O. Smg / kg from 341, 0 mm ³ to 198, 0m 141.8mm ³ or al 103.8膽^s (P rather 0.01) , 103.7Mr from fasudil hydrochloride is 3 mg / kg 224.7 negation ^s the infarct volume from 3 .0Mm ^s for large腦皮quality in the administration of, in striatum 141, 8imn ^a no gaps in significantly suppressed in a ^s (P rather 0.01>. That is, the compound of Example 2 has a strong work甩on 10 more than double compared to the hydrochloride off § twisting.

Test example 6

Effects of rat on photochemically induced thrombus in cerebral infarction

A hole was made in the skull just above the middle cerebral artery of an SD male rat (7 weeks, 8 animals per group) so that the middle cerebral artery could be seen directly. Rose bengal Was administered intravenously, and the light source for preparing a thrombus model was brought close to the middle cerebral artery, and irradiated with blue light. The drug was administered intravenously immediately after the end of green light irradiation.

Twenty-four hours later, the brain was removed, an irregular coronal section was prepared, and stained with a TTC solution. As a result, the compound of Example 2 showed a cerebral infarction inhibitory action in both the cerebral cortex and the striatum, and the action was clear in the cerebral cortex. In other words, 0.3 and l mg / kg cerebral infarct volume was reduced to agree to 64.51 ^ ³ and 55.6 ⁸ 86. 3 mm ⁸ (P rather each 0.05 in cerebral quality in the administration of, P rather 0.01), administration of ling / kg significantly reduced the infarct volume in the striatum from 5S.2mm ^s to 37.Smm ¹¹ (P <0,05). Hand, fasudil hydrochloride is Atsuta only significantly inhibited in 1 and 3Nig / respectively infarct volume in the striatum from 59.9 Yuzuru ³ administration of 43.5 (11111 ⁸ and 44.5111111 ³ ( P <0.01).

The compound of Example 2 showed a far superior improvement effect on cerebral thrombotic cerebral infarction than fasudil hydrochloride.

Test example 7

Effect of the compound of Example 2 on coronary blood flow in anesthetized open chest dogs

experimental method

Beagle dogs weighing 12.3 to 13.41 tg (four per group) were anesthetized with pentobarbital lunatum (30 nig / kg i.v.) and fixed in the ^ position. Pentobarbital sodium (3 to 5 mg / kg / hr) was continuously infused from a force knuckle placed in the right cephalic vein to maintain blood pressure. The chest is opened between the 4th and 5th ribs under artificial respiration (tidal volume 15 ml / kg, respiratory frequency 2 Dbreaths / min), then the pericardium is opened, and the heart is hammerock-shaped. Hanged and fixed. An electromagnetic blood flow probe was attached to the anterior descending coronary artery of the left coronary artery. Coronary blood flow was measured using an electromagnetic blood flow meter and a bioelectric probe, and recorded on a recticorder. The compound of Example 2 and fasudil hydrochloride were dissolved in physiological saline at the time of use so that the dose volume per animal was 30 ml, and it took 30 minutes from a cannula previously placed in the left cephalic vein. Was injected with a gun. The percent change relative to the value before the start of continuous infusion was calculated. The measurement was performed for 60 minutes including during the administration. As a result, saline administration showed almost no change in coronary artery blood flow. The time course of the coronary artery blood flow after the start of intravenous administration of the test drug was observed. 5 to 10 minutes after the start of administration, the compound of Example 2 showed significant increases of 29.7%, 69.3% and 86.7% at 0.1, 0.3 and 1 mg / kg, respectively. . On the other hand, the control compound fasudil hydrochloride showed an increasing tendency at 3 mg / kg, and only a significant increase of 53.1 at 10 mg / k.

As is clear from Test Examples 1 to 7, the compounds of the present invention exhibited remarkably excellent cerebral vasoconstriction / relaxation effects, blood flow increasing effects, etc. as compared with known compounds similar to the compounds of the present invention.

Test example 8

Acute toxicity

It was performed according to the Weyl method using a rat. The test drug was administered to a 6-week-old male sic SD rat (5 cases per group) via the tail vein over 60 seconds, and the presence or absence of death was observed for 24 hours thereafter. Test drug, dissolved in physiological saline, _Q result of using diluted, acute toxicity of the compound of Example 2 was low.產 Commercial availability As described above, the compound of the present invention shows a stronger cerebral vasoconstriction at a much lower dose and at a dose that does not show a change in blood pressure as compared with the control compound, Compound A or fassil hydrochloride, which is similar to the compound of the present invention. It showed a remission effect. Moreover, the compound of the present invention completely restored the pancreatic blood vessels to the inner diameter before blood injection. From this fact, the compound of the present invention is useful for the prevention and treatment of cerebrovascular disorders, particularly brain tissue disorders due to cerebral vasospasm after cerebral hemorrhage. In addition, the compound of the present invention is characterized in that the above cerebral blood vessels! ^ In addition to the action of shrinking, it has excellent organ organ selectivity at a much lower dose compared to the control compound puasudil hydrochloride, blood vessel and cardiovascular dilation action, blood flow increasing action, and ぴ ischemic nerve Since it also has a cytoprotective effect, it is useful as a prophylactic or therapeutic agent for diseases associated with ischemic lesions. That is, the compound of the present invention dilates cerebral blood vessels, has an effect of increasing axillary blood flow and a protective effect on ischemic nerve cells, and is therefore useful in patients with cerebral hemorrhage, cerebral infarction, transient ischemic attack, head trauma, etc. It is useful as a prophylactic or therapeutic agent for symptoms (eg, exercise hemp). Furthermore, it expands coronary blood vessels and exhibits an excellent effect of increasing coronary blood flow, which is useful for the prevention and treatment of myocardial infarction and angina pectoris.

Claims

The scope of the claims

1. The following equation [I]

[I]

Or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the absolute configuration is the S configuration, or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is a prophylactic or therapeutic agent for cerebrovascular disease.

5. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is an agent for preventing or treating a disease associated with ischemic lesions.

6. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is a cerebral vasospasm inhibitor.

7. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is an ischemic protective agent for neuronal necrosis.

8. The pharmaceutical composition according to claim 3, wherein the cerebrovascular disorder is cerebral infarction.

9. The pharmaceutical composition according to claim 3, wherein the type of cerebrovascular disorder is a transient ischemic attack. ―

10. The pharmaceutical composition according to claim 3, wherein the type of cerebrovascular disorder is cerebral hemorrhage and head injury.

11. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is a preventive or a remedy for sequelae associated with cerebral hemorrhage and head injury.

12. The pharmaceutical composition according to claim S, wherein the pharmaceutical composition is an agent for preventing or treating ischemic heart disease.

13. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is a myocardial infarction inhibitor.

1 4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is a therapeutic agent for angina pectoris.