KR790001002B1 - Heterocyclic compounds - Google Patents

Abstract

Antigen - antibody reaction - inhibiting(no data) cinnolines I(R = OH, OMe, OEt, 2-EtOEtO, 2-Et NHOEt, PhO, NH2, NHNH2, NHOH, 1,2,3,4-tetrazol amino-5-ylamino; A = Me, Et, n-Pr, n-Bu, cyclohexyl, OMe, NHCHMe, NHAc, MeO C6H4, (O2N)2 C6H3, F, C1, Br) were prepd. by aromatization reaction of dihydro pyridazine ring of II by oxidn. or hydrolysis of III(Y = alkoxy carbonyl, phenylalkony carbonyl, PhOCO, CN, carbanyl, Thio carbamoyl).

Description

Preparation of Heterocycle Compound

The present invention relates to a method for preparing a heterocycle-based compound represented by the following general formula (1), and more particularly, a cinnoline derivative effective as an inhibitor of an effect accompanying a combination of an antibody such as a ligand and an antigen. It relates to a manufacturing method of.

In the formula,

[R is hydroxy, C _1-6 alkoxy, C _3-6 alkoxyalkoxy, C _4-10 dialkylaminoalkoxy, C _7-10 phenylalkoxy, phenoxy, amino, hydrazino, hydroxyamino, (C _{1 -6} alkoxy) carbonylmethylamino or 1,2,3,4-tetrazol-5-ylamino group, benzene ring A is C _1-5 alkyl, C _5-7 cycloalkyl, C _1-3 alkoxy May optionally contain one or two substituents selected from benzyl, amino, C _1-4 alkylamino, C _2-5 alkanoylamino and benzyloxycarbonylamino groups and nitro groups, halogen atoms and phenyl groups, the substituents being phenyl groups Is optionally substituted with one or two substituents selected from C _1-3 alkoxy groups and nitro groups and halogen atoms.]

The present invention includes pharmacologically acceptable salts of the compound represented by the general formula (1) but includes cinnaline-3-ylcarboxylic acid and ethyl esters thereof, ethyl 6-chlorocinnoline-3-yl carboxylate and ethyl 7- Chlorocinnolin-3-yl carboxylates and their pharmacologically acceptable salts are not included.

Suitable as substituents are, for example, hydroxy, methoxy, ethoxy, 2-ethoxyethoxy, 2-diethylaminoethoxy, phenoxy, benzyloxy, amino, hydrazino, hydroxyamino, methoxycarbonylmethylamino Or 1,2,3,4-tetrazol-5-ylamino and the like.

Benzene ring A is, for example, methyl, ethyl, n-propyl, n-butyl, cyclohexyl, methoxy, benzylamino, isopropylamino, acetylamino and benzyloxycarbonylamino groups, and nitro groups and phenyl, methoxyphenyl, di It may optionally contain one or two substituents which can be selected from nitrophenyl and chlorophenyl and fluorine, chlorine and bromine atoms.

According to one method of the present invention, R has a substituent as described above and the benzene ring A optionally contains two methyl groups in the 7,8-position (refering to the sinnorin nucleus) or, for example, the 6-position (sinorin nucleus). Methyl, ethyl, n-propyl, n-butyl, cyclohexyl, methoxy, benzyl, amino, isopropylamino, acetylamino or benzyloxy carbonylamino groups or nitro groups or phenyl, methoxyphenyl, di A compound of the general formula (1) containing a nitrophenyl or chlorolphenyl group or chlorine bromide and pharmacologically acceptable salts thereof are obtained, in which case cinnaline-3-ylcarboxylic acid and its ethyl ester, ethyl 6-chlorocinnoline 3-ylcarboxylic acid and 6-chlorocinnorin-3-yl carboxylic acid and 7-chlorocinnoline 3-yl carboxylate and pharmacologically acceptable salts thereof are excluded.

According to a suitable process of the invention R is a hydroxy, methoxy, ethoxy, 2-diethylaminoethoxy, phenoxy, hydroxyamino, or 1,2,3,4-tetrazol-5-ylamino group Benzene ring A contains ethyl, n-propyl, cyclohexyl, amino, acetylamino, phenyl, P-chlorophenyl or dinitrophenyl or the chlorine or bromine atom at the 6-position (associated with the new norin nucleus). Compounds of formula (1) and pharmacologically acceptable salts thereof are obtained, in which case ethyl 6-chlorocinnorin-3-yl carboxylate and pharmacologically acceptable salts thereof are excluded.

Particularly suitable compounds as general formula (1) that can be prepared by the present invention are 6-bromosinolin-3-yl carboxylic acid and 6-phenylcinnorin-3-yl carboxylic acid and pharmacologically acceptable compounds thereof. Salts. Suitable salts according to the invention are pharmacologically acceptable acid addition salts derived from inorganic or organic acids when the compound of formula (1) is sufficiently basic. Examples of such acid addition salts include hypochloride, hypobromide, tartarate and citrate.

Suitable salts are those salts in which the anion moiety is derived from the compound of general formula (1) and is a cation moiety that is a pharmacologically acceptable cation when the compound of formula (1) is sufficiently acidic. Examples of such acid addition salts include ammonium salts, alkali metal salts, alkaline earth metal salts, aluminum salts and pharmacologically acceptable organic bases such as N-methylglucamine, triethanolamine or 2-amino-2-hydroxymethyl-1,3- Salts with propanediol.

According to the method of the present invention, the compound of formula (2) is optionally oxidized in the presence of an oxidization catalyst to aromatize the dihydropyridazine ring to produce the desired compound of formula (1).

In the formula, R and A are as described above.

Suitable oxidizing agents include, for example, tetraacetate, manganese dioxide, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and diethyl azodicarboxylate, and the other oxidizing agents include oxygen.

The reaction is carried out in an organic solvent such as lower alkyl lower alkanoates of up to 8 carbon atoms, ie ethyl acetate or aromatic hydrocarbons such as toluene. The reaction temperature can be carried out at a moderately elevated temperature, such as reflux. The base material of formula (2) may be prepared according to the following reaction, for example as described in Example 1.

In the formula, A and R are as described above.

Another method of the present invention is to prepare a compound of formula (1) wherein A represents hydroxy and R represents hydroxy by hydrolyzing the compound of formula (5).

In the formula,

[A is as described above,

Cy represents an alkoxycarbonyl, phenylalkoxycarbonyl, phenoxycarbonyl, cyano, carbamoyl or thiocarbamoyl group.]

Hydrolysis is carried out in the presence of water, and an organic solvent such as ethanol may also be present. Suitable hydrolysing agents are, for example, sodium hydroxide or inorganic acids such as bearded acid. The reaction can be carried out at a moderately elevated temperature, for example at a temperature of approximately 100 ° C.

The ester of the general formula (5) to be used as the basic substance can be prepared by the method described herein, and other basic substances of the general formula (5) can be prepared by known general synthetic methods. According to another method of the present invention, a compound of formula (1) wherein R is as described above and benzene ring A contains one or two amino groups and pharmacologically acceptable salts thereof can be prepared. The benzene ring A is supposed to carry out catalytic hydrogenation of the corresponding compound which contained one or two nitro groups. Suitable hydrogenation catalysts are, for example, palladium supported on carbon. Hydrogenation is carried out in a suitable organic solvent such as C _1-4 alkanol, ie ethanol.

According to another method of the invention A is as described above and R is amino, hydrazino, hydroxyamino, (C _1-4 alkoxy) carbonylmethylamino or 1,2,3,4-tetrazol-5 -A compound of formula (1) representing a monoamino group and a pharmacologically acceptable salt thereof are obtained. This method is to react a corresponding acid halide with a compound of formula RH (R: as described above). .

Suitable acid halides are, for example, acid chlorides, which can be prepared by conventional methods from the corresponding acids. Reactions involving an acid halide are carried out in a suitable organic solvent such as pyridine or methylenechloride (in the presence of triethylamine).

According to another method of the present invention, a compound of formula (1) wherein R is as described above and benzene ring A contains one or two C _2-5 alkanoylamino groups and pharmacologically acceptable salts thereof are obtained. This method is supposed to acylate the corresponding compound in which the benzene ring A contains one or two amino groups. Suitable assimilating agents include, for example, acid halides or acid anhydrides derived from C _2-5 alkanoic acid. The reaction can be carried out in the presence of a suitable organic solvent such as pyridine and can be carried out at a moderately elevated temperature such as 100 ° C.

According to another method of the present invention, A is the same as described above, and R is an amino, hydrazino, hydroxyamino or a (C _1-4 alkoxy) carbonylmethylamino group. Acceptable salts are obtained, which process reacts the corresponding esters in which R is a C _1-6 alkoxy group with ammonia, hydrazine, hydroxyami or (C _1-4 alkoxy) carbonylmethylamine. The reaction is usually carried out in the presence of a suitable organic solvent such as anhydrous (C _1-3 alkanol) such as ethanol.

According to another method of the present invention, a compound of formula (1) wherein R is as described above and benzene ring A is a nitrophenyl or dinitrophenyl group and a pharmacologically acceptable salt thereof are obtained. It is supposed to nitrate the corresponding compound containing an unsubstituted phenyl group. The nitration reaction is carried out, for example, with concentrated nitric acid and concentrated sulfuric acid under reflux.

According to another method of the invention, R is C _1-6 alkoxy, C _3-6 alkoxyalkoxy, C _4-10 dialkylaminoalkoxy, C _7-10 phenylalkoxy or phenoxy group, as described above. Compounds of formula (1) and their pharmacologically acceptable salts are obtained, which is to esterify the corresponding acid. The esterification reaction is carried out in a conventional manner, for example an acid halide or an acid anhydride such as an acid chloride is reacted with a suitable alcohol (RH) in a suitable organic solvent such as anhydrous tetrahydrofuran. The reaction is carried out at moderately elevated temperatures, such as reflux.

According to another method of the present invention, a compound of formula (1) wherein R is as described above and benzene ring A contains one or two C _1-4 alkylamino groups and a pharmacologically acceptable salt thereof are obtained. The process involves the preparation of the corresponding compound in which the benzene ring A contains one or two amino groups in the presence of hydrogen and a hydrogenation catalyst such as platinum catalyst or an alkali metal borohydride such as sodium borohydride or sodium. Reaction with an aldehyde or ketone of the general formula R ¹ COR ² (R ¹ is alkyl, R ² is hydrogen or an alkyl group in the presence of cyanoborohydride, provided that R ¹ COR ² does not contain 4 or more carbon atoms) It is supposed to be.

The aforementioned reductive alkylation process is optionally carried out in a suitable organic solvent such as ethanol.

The action of the compound represented by the general formula (1) described above is the ability to inhibit passive skin hypersensitivity induced by antibodies such as lysine to egg albumin using Bordetella Pertussis as an adjuvant in mice. Proven. The action of the individual compounds represented by formula (1) in this test depends on the exact chemical structure, but generally speaking each compound exhibits its action at a dose of 0.2-20 mg / kg body weight. No toxic effect or other unwanted effect was observed in each compound at an effective amount in the test as described above. One of the important features of the compound represented by the general formula (1) according to the present invention is that it is effective upon oral administration.

The compound of formula (1) according to the present invention may be used for the treatment of a disease or syndrome caused by the reaction of an antigen with an antibody of a chronic asthma (non-allergic) or an antigen of a warm-blooded mammal, such as a human body, such as allergic asthma, high fever, urticaria. (Damage) or used in the treatment of autoimmune diseases.

The compounds according to the invention can be administered (1) orally at a dose of 5-250 mg every six hours per day or (2) inhaling at a dose of 0.01 mg / kg-1.0 mg / kg every six hours per day, or It is recommended to administer (3) intravenously in a total dose of 10-100 mg per day, or (4) as a suppository in a dose of 5-250 mg.

R in formula (1) is hydroxy, C _1-6 alkoxy, C _3-6 alkoxyalkoxy, C _4-10 dialkylaminoalkoxy, C _7-10 phenylalkoxy, phenoxy, amino, hydrazino, hydroxy Amino (C _1-4 alkoxy) carbonylmethylamino or 1,2,3,4-tetrazol-5-ylamino group, and the benzene ring A is optionally C _1-5 alkyl, C _5-7 cycloalkyl, _One selected from C _1-3 alkoxy, benzyl, amino, C _1-4 alkylamino, C _2-5 alkanoylamino, benzyloxycarbonylamino, nitro, halogen and optionally C _1-3 alkoxy, nitro, halogen or A pharmaceutical composition can be used in combination with a compound or a pharmacologically acceptable inert diluent or carrier containing one or two substituents selected from phenyl containing two substituents.

The pharmaceutical composition is used in the form of a unit dosage form that can be administered orally, such as a tablet or capsule, particularly a tablet containing 5-50 mg of the active ingredient. Alternatively it can be used in the form of inhalants and in a form suitable for intravenous administration, for example as a sterile solution or a suspension or in the form of suppositories. In addition, the compound according to the present invention can be used by combining one or more known compounds effective for the treatment of asthma. Examples of such compounds are as follows.

(1) bronchodilators such as atropine or β-adrenergic agonists such as isoprenin, adrenaline, salbutamol, orchiprelinin, or isotacin

(2) corticosteroids such as beclomethasone dipropionate or betamethasone valerate

(3) phosphodiesterase inhibitors such as theophylline or aminophylline; And

(4) α-adrenergic agonists such as phentolamine;

(5) prostaglandins E ₁ or E ₂ ;

(6) 3-acetamide-6-methyl-8-n-propyl-S-triazolo- [4,3-a] pyrazine;

(7) 2-amino-4,6-di-C _1-4 alkyl-5-oxo-4,5-dihydro-S-triazolo [1,5-a] pyrimidine and

(8) 6,8-di-C _1-4 alkyl-5,6-dihydro-5-oxo-S-triazolo [4,3-c] pyrimidine.

The pharmaceutical composition may contain 1.0-50% of the compound of formula (1) or a pharmacologically acceptable salt thereof.

The present invention will be described in detail by way of examples.

Example 1-3

(Example 1)

Lead tetraacetate (13 g) was added to a solution of ethyl 6-ethyl-1,4-dihydrocinnolin-3-yl carboxylate (4.25 g) dissolved in ethyl acetate (400 ml) and the suspension was stirred for 2 hours. After stirring at room temperature, water (400 ml) was added thereto, followed by shaking to separate the reaction mixture. The ethyl acetate layer was washed with water (3 × 200 ml), dried (MgSO ₄ ) and filtered until the filtrate became 20 ml. The mixture was evaporated and petroleum ether (boiling point 40-60 ° C., capacity 50 ml) was filtered to afford ethyl 6-ethylcinnorin-3-yl carboxylate. Melting Point: 71-3 ℃

Ethyl ester used as starting material was prepared as follows.

Thionyl chloride (35 ml) and dimethylformamide (1 drop) were added to ethyl 6-ethyl-4-hydroxycinnoline-3-yl carboxylate (1.23 g), and the mixture was gradually heated to boiling point to release gas. After boiling under reflux until the end, the solution was evaporated under reduced pressure to dissolve the residue in anhydrous toluene (20 ml), and the solution was evaporated to remove the remaining solid (ethyl 4-chloro-6-ethylcinnoline-3-ylcarboxylate). ) Dissolved in dimethylformamide (10 ml) and ethyl acetate (25 ml), the solution was stirred, and sodium borohydride (0.76 g) was added thereto. The reaction mixture was stirred for 2 hours and then added to a mixture of 1N hydrochloric acid (30 ml) and ethyl acetate (150 ml), the ethyl acetate layer was washed with water (3 x 50 ml), dried (MgSO ₄ ) and filtered Was evaporated under reduced pressure until it became a small amount, and petroleum ether (boiling point, 40-60 ° C.) was added to give crystalline ethyl 6-ethyl-1,4-dihydrocinnolin-3-yl carboxylate. Melting Point: 171-3 ℃

In a similar manner to the above, the following compounds were prepared using suitable starting materials instead of ethyl 6-ethylcinnorin-3-yl carboxylate.

Example 2

Thin layer chromatography was performed on silica (Keselgel GF 254: E. Merck, Darmstadt) using ethyl 6-n-butylcinnolin-3-yl carboxylate, ether as cleaning agent, and the Rf was 0.55.

Example 3

Ethyl 6-P-chlorophenylcinnolin-3-yl carboxylate, melting point 150-2 ° C

This starting material was used to prepare the following two compounds.

Ethyl 6-n-butyl-1, 4-dihydrocinnoline-3-yl carboxylate (melting point 150-152 ° C.), and ethyl 6-p-chlorophenyl-1, 4-dihydrocinnoline-3- One carboxylate (melting point 254-256 ° C.) was obtained by a method analogous to the preparation of ethyl 6-ethyl-1,4-dihydrocinnolin-3-yl carboxylate described above.

Ethyl 6-P-chlorophenyl-4-hydroxycinnolin-3-yl carboxylate used as starting material for the preparation of chlorophenyl derivatives was prepared as follows.

Thionyl chloride (35 ml) was added dropwise, anhydrous ethanol (250 ml) was stirred, cooled to -40 ° C, stirred at this temperature for 10 minutes, and then stirred at -40 ° C to 6-P-chlorophenyl-4-hydroxy. Cincinnarin-3-yl carboxylic acid (4.5 g) was added and stirring continued to warm the reaction mixture to room temperature overnight, then heated to reflux for 1 hour, cooled, filtered and the filtrate was evaporated to dryness under reduced pressure to obtain a solid residue. Recrystallization was carried out from a mixture of ethyl acetate and petroleum ether (boiling point 60-80 ° C.). Melting Point 259-261 ℃

Example 4

To a solution of ethyl 6-ethylcinnorin-3-yl carboxylate (2.3 g) dissolved in ethanol (10 ml) was added 1N-sodium hydroxide (10 ml), and the reaction mixture was stirred at room temperature overnight, approximately half After evaporation under reduced pressure until the volume of the solution was reduced, the mixture was diluted with water (20 ml), filtered, the filtrate was cooled to 0-5 ° C., acidified to pH 2 with concentrated hydrochloric acid, and the precipitated precipitate was separated by filtration, washed with water and dried in vacuo. The residue was recrystallized in a mixed solution of ethyl acetate and petroleum ether (boiling point 40-60 ° C.) to give 6-ethylcinnolin-3-yl carboxylic acid. Melting Point, 176-8 ℃ (Decomposition)

Example 5

6-n-butylcinnorin-3-yl carboxylic acid (melting point, 131-3 ° C.) was obtained from the corresponding 6-n-butyl derivative by a method similar to that described in Example 4.

Example 6

Thionyl chloride (15 ml) and dimethylformamide (1 drop) were added to ethyl 4-hydroxy-6-phenylcinnolin-3-yl carboxylate (0.30 g), and the mixture was slowly warmed to boiling point to release gas. After heating under reflux until the end, the solution was evaporated under reduced pressure to dissolve the residue in anhydrous toluene (20 ml) and the solution was evaporated. After repeating this operation, the residue was dissolved in a mixture of dimethylformamide (5 ml) and ethyl acetate (30 ml), the solution was stirred, and sodium borohydride (0.25 g) was added thereto, followed by stirring for 2 hours, followed by 1N-hydrochloric acid ( 10 ml) and ethyl acetate (50 ml) were added, the mixture was separated, the ethyl acetate layer was washed with water, dried (MgSO ₄ ), filtered and the filtrate was evaporated under reduced pressure, followed by residue (ethyl 6-phenyl-1, 4-di). Hydrocinnoline-3-yl carboxylate) was dissolved in anhydrous toluene (50 ml), and this solution was added with lead tetraacetate (1 g) and stirred for 2 hours, and then the mixture was separated by shaking with water (50 ml) and an organic layer. Was washed with water (3 × 50 ml), dried (MgSO ₄ ), filtered and the filtrate was evaporated under reduced pressure. The residue was then determined from a mixture of ethyl acetate and petroleum ether (boiling point, 60-80 ° C.). Norin-3-yl carboxylate is obtained It was. Melting Point 160-2 ℃

Example 7-9

(Example 7)

A mixture of cinnano-3-yl carboxylic acid (5 g), corn starch (65 g) calcium phosphate (130 g) and magnesium stearate (1 g) was softened and passed through a 16 mesh screen (1,373 pages of the British Pharmacopoeia, 1968 edition, page 1,373). Granulated and then compressed into tablets containing 50mg of active ingredient per tablet. In a similar manner, a tablet containing 50 mg of ethyl cinnaline-3-chlorocinnoline-3-yl carboxylate (Example 9) was obtained.

Example 10

The solution of ethyl 6-bromo-1,4-dihydrocinnolin-3-yl carboxylate dissolved in ethyl acetate was heated to reflux, and manganese dioxide (10 g) was added thereto to reflux the reaction mixture for 30 minutes. After heating, the filtrate was evaporated until the filtrate became approximately 25 ml, and petroleum ether (60-80 ° C.) was added. As a result, crystalline ethyl 6-bromosinolin-3-yl carboxylate (melting point, 151 ° C.) was separated. It was.

The solution used as starting material was prepared as follows.

Thionyl chloride (2ml) was added dropwise, anhydrous ethanol (50ml) was stirred and cooled to -40 ° C, and the solution was stirred at -40 ° C for 10 minutes and then 6-bromo-4-hydroxycinnoline-3- One carboxylic acid (3.0 g) was added and stirring continued to warm the reaction mixture to room temperature overnight, then heated under reflux for 1 hour, cooled to freezing and filtered to wash the solid residue with anhydrous ethanol, resulting in ethyl 6-bromo 4-hydroxycinnoline-3-yl carboxylate was obtained (melting point, 253 ° C).

Ethyl 6-bromo-4-hydroxycinnoline-3-yl carboxylate (3.0 g) was added to thionyl chloride (35 ml) and dimethylformamide (1 drop). The mixture was slowly warmed to the boiling point. After heating under reflux until the end, the residue was suspended in anhydrous toluene (25 ml) and evaporated, and the solid residue (ethyl 6-bromo-4-chlorocinnorin-3-yl carboxylate) was diluted with dimethylformamide (10 ml). After dissolving in ethyl acetate (90 ml), the solution was cooled to 0-5 ° C. and stirred to add sodium borohydride (1.5 g), and then the reaction mixture was stirred for 2 hours, followed by 1 N hydrochloric acid (100 ml) and ethyl acetate. (150 ml) was added, the ethyl acetate layer was washed with water (2 × 100 ml), dried (MgSO ₄ ), and filtered.

Example 11-15

The following compounds were prepared using suitable starting materials in a similar manner as described in Example 10.

Example 16

To a solution of ethyl 6-bromosinolin-3-yl carboxylate dissolved in ethanol (20 ml) was added 1N-sodium hydroxide (50 ml), and the solution was boiled in air to remove most of the ethanol and then at 100 ° C. After heating for 30 minutes, the reaction mixture was cooled to room temperature, acidified to pH 2 by adding concentrated hydrochloric acid, and the resulting solid precipitate was separated by filtration, washed with water, and recrystallized from an aqueous ethanol solution. 6-bromosinolin-3-yl Carboxylic acid was obtained. Melting point, 203-4 ℃

Example 17

In a similar manner to Example 16, 6-cyclohexylcinnolin-3-yl carboxylic acid was obtained. Melting point 159-161 ℃

Example 18

To a solution of ethyl 6-phenylcinnolin-3-yl carboxylate (1.0 g) dissolved in ethanol (15 ml) was added 1N-sodium hydroxide (50 ml), and the solution was boiled in air to remove most of the ethanol. After removing and heating at 100 DEG C for 30 minutes, the reaction mixture was cooled to room temperature, acidified to pH 2 with concentrated hydrochloric acid, and the solid precipitate was washed with water and dried to obtain 6-phenylcinnolin-3-yl carboxylic acid. Melting Point, 216-8 ℃

Example 19

In a similar manner to Example 18, 6-chlorocinnolin-3-yl carboxylic acid was obtained. Melting Point, 207-8 ℃

Example 20

Heat a solution of ethyl 6-nitro 1,4-dihydrocinnorin-3-yl carboxylate (described below) to reflux temperature, add manganese dioxide (20 g) to reflux for 30 minutes, heat, filter and filtrate Was evaporated to a small amount (approximately 25 ml) and petroleum ether (boiling point 60-80 ° C .; 75 ml) was added and the mixture was filtered to afford ethyl 6-nitrocinnorin-3-yl carboxylate. Melting point, 154-6 ℃

The solution used as starting material was prepared as follows.

Thionyl chloride (35 ml) and dimethylformamide (1 drop) are added to ethyl 4-hydroxy-6-nitrosinorin-3-yl carboxylate (3.0 g), and the mixture is slowly heated to boiling point to release the gas. After heating under reflux until the end, the solution was evaporated under reduced pressure, the residue was suspended in anhydrous toluene (25 ml) and evaporated to give a solid residue (ethyl 4-chloro-6-nitrosinolinrin-3-yl carboxylate). Was dissolved in dimethylformamide (10 ml) and ethyl acetate (90 ml), the solution was cooled to 0-5 ° C. and stirred, and sodium borohydride (1.6 g) was added thereto. The reaction mixture was stirred for 2 hours, added to a mixed solution of 1N hydrochloric acid (100 ml) and ethyl acetate (150 ml), and the ethyl acetate layer was washed with water (2 × 100 ml), dried (MgSO ₄ ), and filtered.

Example 21

In an analogous manner to Example 20, ethyl 6-n-propylcinnolin-3-yl carboxylate was obtained. Melting point, 88-9 ℃

Example 22

Ethyl 6-nitrosinorin-3-yl carboxylate (150 mg) was dissolved in ethanol (20 ml), and 30 wt% palladium catalyst (20 ml) supported on carbon was added to the solution, followed by theoretical analysis in a hydrogen stream at room temperature and atmospheric pressure. After shaking until a large amount of hydrogen was absorbed, the catalyst was filtered off, the ethanol solution was evaporated to dryness to obtain a yellow solid, and this solid was washed with ethyl acetate as a washing agent using ethyl-gel gel 60 (E. Merck, Darmstadt). Purification was carried out by chromatography on a column containing, and the washings were combined and evaporated to dryness to afford ethyl 6-aminocinnorin-3-yl carboxylate. Melting Point, 204-6 ℃

Example 23

A solution of 5-amino-1,2,3,4-tetrazole (0.425 g) dissolved in anhydrous pyridine (10 ml) was added to 6-ethylcinnorin-3-yl carbonyl chloride (1.1 g), and this solution After standing at room temperature overnight, water (50 ml) and 1N hydrochloric acid (50 ml) were added, and the mixed solution was filtered and the solid residue was washed with water to determine an aqueous dimethylformamide solution. As a result, 6-ethyl-N- (1,2, 3,4-tetrazol-5-yl) cinnolin-3-yl carboxamide was obtained. Melting point above 250 ℃

The acid chloride used as starting material was prepared in the same manner as in Example 26, which describes a method for preparing 6-bromosinolinrin-3-yl carbonyl chloride.

Example 24

A mixture of glycinemethyl ester hydrochloride (2.5 g) and triethylamine (2.6 ml) added to anhydrous methylene chloride (10 ml) was dissolved in anhydrous methylene chloride (10 ml) in a 6-ethylcinnorin-3-yl carbonyl chloride solution. The solution was left at room temperature for 5 hours, diluted with methylene chloride (80 ml), washed successively with 1N hydrochloric acid, water and sodium carbonate solution in 10 W / W%, and again with water and dried (MgSO ₄ ), And the solvent was evaporated to determine the solid residue from an aqueous ethanol solution. As a result, 6-ethyl-N- (methoxycarbonylmethyl) -cinnolin-3-ylcarboxamide was obtained. Melting point, 135-7 ℃

Example 25

6-ethylcinnorine-3-carbonyl chloride (1.12 g) in which a mixture of hydroxylamine hydrochloride (0.85 g) and triethylamine (2 ml) added to anhydrous methylene chloride (15 ml) was dissolved in anhydrous methylene chloride (15 ml). The solution was left at room temperature for 3 hours, the solvent was evaporated in vacuo, the white solid residue was dissolved in excess 1N sodium hydroxide, acidified to pH5 with concentrated hydrochloric acid and filtered, and the solid residue was cooled with cold water. Washing and crystallization from ethanol anhydride gave 6-ethylcinnorine-3-hydroxyamic acid. Melting point, 195-7 ℃

Example 26

A solution of 6-bromosinolin-3-carbonyl chloride (1.07 g) dissolved in anhydrous tetrahydrofuran (15 g) dissolved in anhydrous tetrahydrofuran (15 ml). The solution was heated under reflux for 2 hours, the solvent was evaporated in vacuo to dissolve the solid residue in water (50 ml), the solution was extracted with ethyl acetate (3 × 100 ml) and the combined extracts were dried (MgSO _4). ), And then evaporated to a small amount. Petroleum ether (boiling point, 60-80 ° C., 50 ml) was added thereto, and the mixture was filtered to give 2-diethylaminoethyl 6-bromosinolin-3-yl carbox. Cyxlate was obtained as a solid residue. Melting point, 90-3 ℃

Acid chloride used as starting material was prepared as follows.

To 6-bromosinorin-3-yl carboxylic acid (1 g) thionyl chloride (15 ml), the mixture was heated under reflux until gas evolution was completed, and excess thionyl chloride was evaporated in vacuo to the desired acid chloride. Was obtained as a solid.

Example 27

The mixture of 6-ethylcinnorin-3-yl carboxylic acid (0.60 g) and thionyl chloride (30 ml) was heated under reflux for 20 minutes in a steam bath, and then the solution was evaporated under reduced pressure to give a yellow crystalline solid. To the solid was added a solution of phenol (1.13 g) dissolved in anhydrous tetrahydrofuran (20 ml), the mixture was heated under reflux for 2 hours in a steam bath and the solution was evaporated to race the residue over ether (2 x 50 ml). The residue was dissolved in ethanol acetate (50 ml), washed successively with 5 W / V% sodium bicarbonate (10 ml) and water (2 × 10 ml), and the ethyl acetate solution was dried (MgSO ₄ ) and filtered. , The remaining oil was washed with ethyl acetate and petroleum ether (boiling point, 60-80 ℃) on a silica cylinder (Kieselgel 60, 30g) with a mixture of 50W / V%, and the oil was evaporated to prepare phenyl 6-ethylcinnoline. 3-yl carboxylate was obtained, which was added to It was recrystallized from aqueous play.

Melting Point, 143-5 ℃

Example 28

In a manner similar to Example 27, 2-methoxy ethyl 6-bromosinolin-3-yl carboxylate was obtained.

Example 29

A solution of ethyl 6- (benzylbathylcarbonylamino) -1,4-dihydrocinnolin-3-yl carboxylate (prepared as described below) dissolved in ethyl acetate was heated to reflux temperature and manganese dioxide (20 g) was added, the mixture was heated at reflux for 30 minutes, and then the filtrate was evaporated in vacuo until the filtrate became approximately 20 ml, petroleum ether (boiling point, 60-80 ° C., 75 ml) was added, and the mixture was filtered to give ethyl 6 -(Benzyloxycarbonylamino) cinnorin-3-yl carboxylate was obtained as a solid residue. Melting point, 205 ℃

The solution used as starting material was prepared as follows.

A palladium catalyst (30 wt%; 0.5 g) supported on carbon was added to a solution of ethyl 4-hydroxy-6-nitrosinorin-3-yl carboxylate (10 g) dissolved in anhydrous pyridine (250 ml). The mixture was shaken in a stream of hydrogen under atmospheric pressure at room temperature until the desired amount of hydrogen was absorbed and then filtered through Celite to evaporate the filtrate to a volume of approximately 100 ml. The solution was subjected to benzylchloroformate ( 30 ml) was added, followed by heating at 100 ° C. for 1 hour, and the solvent was evaporated in vacuo to recrystallize the residue from an aqueous ethanol solution, resulting in ethyl 6- (benzyloxycarbonylamino) -4-hydroxycinnoline-3-yl carboxyl. The rate was obtained. Melting point, 250-2 ℃

Ethyl 6- (benzyloxy carbonylamino) -4-hydroxycinnorin-3-yl carboxylate (4 g) was suspended in thionyl chloride (90 ml), and dimethylformamide (0.1 ml) was added to the suspension. Slowly warm until boiling, then heated to reflux until gas evolution, excess thionyl chloride is evaporated in vacuo to dissolve the residue in toluene (30 ml), and the solution is evaporated to dryness in vacuo to give the residue ethyl. The mixture was added to a mixture of acetate (250 ml) and 1N hydrochloric acid (250 ml), and the separated organic layer was washed with water and dried (MgSO ₄ ).

Example 30

Ethyl 6-aminocinnorin-3-yl carboxylate (prepared as described below) was dissolved in acetic anhydride (25 ml), the solution was heated at 100 ° C. for 6 hours, cooled to room temperature, and then the reaction mixture was Filtration gave ethyl 6-acetylaminocinnolin-3-yl carboxylate as a solid residue. Melting point, 256-8 ℃

Ethyl ester used as starting material was prepared as follows.

To a solution of ethyl 6- (benzyloxycarbonylamino) cinnolin-3-yl carboxylate (1 g) dissolved in anhydrous ethanol (25 ml) was added a palladium catalyst (30% by weight; 100 mg) supported on carbon. The solution was shaken in a hydrogen stream for 24 hours under atmospheric pressure at room temperature, and then the reaction mixture was filtered to evaporate the filtrate under vacuum to afford ethyl 6-aminocinnorin-3-yl carboxylate as a solid residue.

Example 31

The solution of ethyl 6- (methoxyphenyl) -1,4-dihydrocinnorin-3-yl carboxylate dissolved in ethyl acetate was heated to the boiling point, followed by addition of manganese dioxide (15 g) under reflux for 30 minutes. The filtrate was evaporated in vacuo until the filtrate became approximately 1 ml, and the residue was washed on a silica cylinder (Kieselgel 60; 30 g) with a 50% by volume mixture of ethyl acetate and petroleum ether (boiling point, 60-80 ° C.), and the oils were combined. Ethyl 6- (methoxyphenyl) cinnolin-3-yl carboxylate (presumed to be a mixture of isomers that resulted in a change in the methoxy group position on the phenyl substituent) after evaporation in vacuo and the crystalline residue was recrystallized from an aqueous ethanol solution Was obtained. Melting Point, 143-5 ℃

Ethyl esters used as starting materials were prepared as follows (this particular subject matter is the subject compound of British Patent Application No. 48,206 / 74):

Amyl nitrite (2 ml) is added to a suspension of ethyl 6-amino-4-hydroxycinnoline-3-yl carboxylate suspended in anisole (250 ml) and stirred for 3 hours in water vapor. After heating, the filtrate was filtered and the filtrate was evaporated. The residue was washed with a 10% by volume mixture of anhydrous ethanol and chloroform on a cylinder of silica (Kieselgel 60, 100 g) to evaporate the oil, and then a solid residue [ethyl 4-hydroxy 6- ( Methoxyphenyl) cinnorin-3-yl carboxylate] is dissolved in thionyl chloride (50 ml) and dimethylformamide (5 drops) is added to heat the solution under reflux until gas evolution is complete, and then the solution is After evaporation under reduced pressure, the residue was dissolved in anhydrous toluene (20 ml), evaporated to dryness, the residue was dissolved in a mixture of dimethylformamide (2 ml) and ethyl acetate (50 ml), stirred at room temperature for 2 hours, and then 1N hydrochloric acid (10 ml). ) And on Washing the separated ethyl acetate layer was added to a mixture of acetate (50ml) in water (3 × 20ml), dried (MgSO _4), filtered and used as a starting material ethyl 6- (methoxyphenyl) -1,4-dihydro A solution of cinnarin-3-yl carboxylate (presumed to be a mixture of isomers which resulted in a change in the methoxy group on the phenyl substituent) was obtained.

Example 32

Hydrazine hydrate (0.5 ml) was added to a solution of ethyl 6-bromosinolin-3-yl carboxylate (1.08 g) dissolved in anhydrous ethanol (25 ml), and after a while, the white solid precipitated was filtered off. Recrystallization from ethanol afforded 6-bromosinolinrin-3-yl carboxyhydrazide. Melting point above 250 ℃

Example 33

6-phenylcinnolin-3-yl carboxylic acid (0.25 g) was dissolved in concentrated sulfuric acid (1 ml) at 0 ° C. in an ice bath, and concentrated nitric acid (specifically 1.42; 0.5 ml) was added to the solution for 5 hours in a steam bath. After heating under reflux, the pale brown solution was poured into a mixture of crushed ice and water (50 ml), and the precipitated solid was filtered, washed with water (3 x 10 ml) and determined from an aqueous ethanol solution. 6- (dinitrophenyl) cinnoline 3-yl carboxylic acid was obtained. Melting point, 196-8 ° C. (presumed to be a mixture of isomers which change at the position of the two nitro groups in the phenyl substituent)

Example 34

Aqueous ammonia solution (0.88: 10 ml in specific gravity) was added to 6-ethylcinnorin-3-yl carbonyl chloroide (1 g), the suspension was stirred at room temperature overnight, and then the mixture was filtered to determine the solid residue from an aqueous ethanol solution. Ethylcinnor-3-yl carboxamide is obtained. Melting point, 215-6 ℃

Example 35

Benzyl 6-bromosinolin-3-yl carboxylate was obtained in the same manner as in Example 27. Melting point, 171 ° C

Example 36

A mixture of ethyl 6-nitrosinorin-3-ylcarboxylate (0.7 g) and platinum oxide (100 mg) added to anhydrous ethanol (20 ml), acetone (20 ml) and glacial acetic acid (0.5 ml) was stirred for 24 hours at room temperature and atmospheric pressure. After shaking under hydrogen stream for a while, the mixture was heated to boiling point in a steam bath, and manganese dioxide (10 g) was added to the boiling solution (a very small amount of 1,4-dihydrocinnoline derivative was produced under the above-mentioned reducing conditions, Manganese dioxide was used to convert these derivatives to the corresponding cinnanor derivatives). The suspension was heated at reflux for 30 minutes, filtered through celite, and the mixture was evaporated to dryness by adding Kigelgur 60 (1 g), and the residue was washed with ethyl acetate on a silica gel cylinder (50 g) and Kigelgur 60). The oil was evaporated and recrystallized from an aqueous ethanol solution to give ethyl 6-isopropylaminocinnolin-3-yl carboxylate. Melting Point, 167-8 ℃

Example 37

In the same manner as in Example 10, methyl 6-methylcinnolin-3-yl carboxylate was obtained. Melting point, 170-2 ℃

Example 38

A mixture of 6-bromosinolin-3-yl carboxylic acid (10 g), corn starch (65 g), calcium phosphate (130 g) and magnesium stearate (1 g) is compacted and the compacted mixture is 16-mesh After passing through the screen into granules, the granules were compressed into tablets containing 25 mg of active ingredient per tablet.

Claims (1)

As described above in the text, the compound of formula (2) is oxidized to aromatize the dihydropyridazine ring, or the compound of formula (5) is hydrolyzed to give the cinnorine derivative of formula (1) How to prepare.

In the formula, [R is hydroxy, C _1-6 alkoxy, C _3-6 alkoxyalkoxy, C _4-10 dialkylaminoalkoxy, C _7-10 phenylalkoxy, amino, hydrazino, hydroxyamino, (C _1-4 alkoxy ) Carbonylmethylamino or 1,2,3,4-tetrazol-5-ylamino group, benzene ring A is C _1-5 alkyl, C _5-7 cycloalkyl, C _1-3 alkoxy, benzyl, One or two substituents selected from amino, C _1-4 alkylamino, C _2-5 alkanoylamino and benzyloxycarbonylamino groups and nitro groups, halogen atoms and phenyl groups may optionally be included, and when the substituent is a phenyl group May optionally contain one or two substituents selected from C _1-3 alkoxy groups and nitro groups and halogen atoms in the phenyl group itself, Y represents an alkoxycarbonyl, phenylalkoxycarbonyl, phenoxycarbonyl, cyano, carbamoyl or thiocarbamoyl group.]