FI57595C - PROCEDURE FOR THE SUBSTANCE OF A THERAPEUTIC SUBSTITUTE SUBSTITUTE PYRIDO- (3,4-E) -AS-TRIAZINDERIVAT - Google Patents

Description

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Patent and registration office * (44) Date of issue and date. -

Patent · oeh regiiterstyrelten Antek · »utit | d och« i. * Krift * n pubikartd 30.05.80 (32) (33) (31) Pyydetty atuolkwt — Begird prlorltet (71) EGYT Gyogyszervegyeszeti Gyär, 30 Kereszturi ut, Budapest X,

Un + cari-Ungern (HU) ^ (72) Pal Benko, Budapest, Laszlo Pallos, Budapest, Andräs Messmer,

Budapest, Andräs Gelleri, Budapest, Istvan Szabo, Budapest,

Lujza E. Peto'cz, Budapest, Peter Greek, Budapest, Attila Varga,

Budapest, Hungary-Hungary (HU) (7I4) Oy Kolster Ab (5I +) Method for the preparation of therapeutically useful substituted pyridoZ'3, l + -e7-as-triazine derivatives ^ -as-triazinderivat

The present invention relates to a process for the preparation of therapeutically useful substituted pyrido [3,4-e] -as-triazine derivatives of general formula I.

wherein R represents a C5-20 alkyl group, a phenyl group substituted by a hydroxy group or 1 to 3 C1-3 alkoxy groups, a phenylalkyl group having 2 to 4 carbon atoms or a pyridyl group in the alkyl chain, and R1 and R2 represent a hydrogen atom or both together means an additional bond, and for the preparation of these pharmaceutically acceptable salts 2 57595 ·

Several pyrido f3,4-ej -as-triazine derivatives are known from the literature. A literature reference (French Patent Publication No. 1,449,770) describes the substituents (alkyl and aryl groups) in the 3-position quite extensively, but gives only one example for the preparation of a 3-methyl compound. This example mentions the photosensitizing effect of the example compound on photosensitive materials.

The therapeutic efficacy of the pyrido ε-3,4-e3-as-triazine backbone and other alkyl derivatives having 1 to 4 carbon atoms has also been described (U.S. Patent No. 3,597,427). According to the values mentioned here, these compounds have antibacterial activity at concentrations of 31 to 250 μg / ml, but at the same time their toxicity is quite high (100 to 200 mg / kg).

The process according to the invention is characterized in that the general formula II is obtained

αχ (II) rf02

a pyridine derivative of the general formula III wherein X represents a halogen atom or a C 1-4 oxy group to react with a compound of general formula III

R-CO-NH-NH2 (III)

with the acylhydrazine of formula IV, wherein the group R has the same meaning as above, is then reduced with hydrogen by catalytic hydrogenation or heating of stannous chloride in an acidic solution of the general formula IV

NH-NH-C0-R

Γ (iv) Compound according to N j, and finally cyclized in the previous case 57595 3

of general formula V

NH-NH-CO-R

The aminoacylhydrazino compound of formula is converted into a salt with a pharmaceutically acceptable acid.

The starting materials of formula IV, 3-nitro-4-acylhydrazinopyridine derivatives required in the process of the invention are prepared in one of the following ways. According to another alternative method, 4-halo-3-nitropyridine is reacted with aliphatic, araliphatic or aromatic carboxylic acid hydrazides, if desired in the presence of an acid scavenger. When no acid scavengers are used, the hydrochlorides of the compounds of general formula IV are formed. Another alternative method proved to be advantageous, in which case 4-hydrazino-3-nitropyridine is reacted with the corresponding carboxylic acid halide or carboxylic acid ester.

The 4-acylhydrazino-3-nitropyridines thus prepared are then reduced with a solution of stannous chloride in hydrochloric acid. The dihydropyrido-as-triazine-tin complex formed as an intermediate is, if desired, converted into the aromatic end product by oxidation in a basic medium, suitably with potassium ferricyanide. The catalytic reduction of 4-acyl-hydrazino-3-nitropyridine can also be carried out using palladium on charcoal as a suitable catalyst. The resulting 4-acylhydrazino-3-aminopyridines are generally prepared as hydrochlorides. They are further treated in an acidic medium, for example hydrochloric acid, or in aqueous or anhydrous ethanol, dioxane or ethyl acetate. Polyphosphoric acid or its esters can also be used as the medium for the cyclization to form hydrochlorides of 1,2-dihydropyrido [3,4-e] -azriazines.

«57595

If desired, the final oxidation step can be performed with oxygen or an oxidizing agent in the air. In the former case, the dihydro-pyrido-as-triazine is preferably separated in vacuo under a strong stream of air, in which case aromatization takes place. The latter method, on the other hand, is mainly used when dihydropyrido-Cs.A-e] -as-triazines have already been prepared as hydrochlorides. Potassium ferricyanide, hydrogen peroxide in ethanol and, in certain cases, iron (IID chloride) can be used as oxidizing agents.

The invention also relates to a process in which the compound obtained as an intermediate in one step of the process acts as a starting compound and then the missing steps of the process are carried out, or the starting material is formed under reaction conditions, or the reactants are added as salts. Thus, the aforementioned e.g. nitro, amino and dihydro compounds can be added as salts.

Preferred exemplary compounds prepared by the process of the invention are those derivatives of formula I wherein R 1 | and mean a chemical bond. When administered orally, the toxicity of these compounds is about Θ00 to 3000 mg / kg in mice. The remarkable anti-inflammatory activity of these compounds of the invention is manifested in that they are effective at a dose of 1/10 LD50 of carrageenan-induced edema in rats. The toxicity of the aromatic derivatives ranged from 800 to 4500 mg / kg (orally administered to mice).

The compounds according to the invention have been shown in animal experiments to have anti-inflammatory, analgesic, antipyretic and gastrointestinal peristalsis effects. The following table shows the effect of the substituent R of a compound of formula I on the pharmacological range of action of the compound. _

The figures show the strength of the effect in terms of comparable times.

5,57595

Table

R

Impact ______________________________________________

Octyl Phenylethyl p-anisyl

Anti-inflammatory 5 _ _

Analgesic 10-20 - - _ Fever-lowering - 5-10 -

Reducing gastrointestinal pertussis 20-50 10-50 5 - 10

The compounds according to the invention also have a strong antifungal activity in concentrations of 5-50 μg / ml mm. against the following fungi:

Trichophyton rubrum, Candida albicans, Candida tropicalis, Penicillium digitatum. Trichophyton mentagrophytes, Arpergillus flavus. Particularly effective against fungi are the compounds of the formula I in which R is 3,5-dimethoxyphenyl or p-hydroxyphenyl.

The compounds of the formula I have an antituberculous activity against concentrations of e.g. isonicotinic acid hydrazide and resistant and streptomycin-resistant strains, such as Mycobacterium cansasii, Mycobacterium Ranae and others, at concentrations of 1 to 5 μg / ml. Preferred compounds in this regard are those compounds of formula I wherein R is p-anisyl or tridecyl.

The invention is further illustrated by the following examples. Example 1 3- (p-Anisyl) pyrido [3,4-e] -az-triazine 25.0 g (0.156 mol) of 4-chloro-3-nitropyridine were reacted with anisic acid hydrazide (26.16 g, 0.156 mol) in 500 ml. in ethanol. A yellow precipitate formed which was filtered after about 60 minutes and the precipitate was washed with ethanol to give 44.9 g (66.9%) of yellow 4- (p-anisyl) hydrazino-3-nitropyridine hydrochloride, m.p. 280 ° C (ethanol).

6,57595 42.1 g (0.14 mol) of 4- (p-anisyl) hydrazino-3-nitropyridine hydrochloride were added to a solution of 90.3 g (0.44 mol) of stannous chloride hydrate in 500 ml of water, then 1000 ml of concentrated hydrochloric acid was added dropwise, and the mixture was boiled for one hour. The resulting brick-red precipitate was filtered off with suction and added wet to 480 ml of a 20% solution of potassium ferricyanide at 0 ° C, which had been made alkaline with 100 ml of concentrated ammonium hydroxide. The mixture was allowed to stand for 1 hour at 5 ° C, then the yellow precipitate was filtered. It was dried and extracted with hot chloroform. Evaporation of the solvent gave 20 g (50.2¾) of the title compound, m.p. 190-199 ° C.

Example 2 3- (Phenylethyl) pyrido [3,4-b] azetriamin

To a stirred solution of 16.4 g (0.1 mol) of phenylpropionic acid hydrazide in 400 ml of ethanol was added 15.05 (0.1 mol) of 4-chloro-3-nitropyridine. Due to a slightly exothermic reaction, the temperature rose from 23 ° C to 30 ° C with the addition of the pyridine derivative, and the reaction mixture was allowed to stand at this temperature for about 6 hours. The mixture was cooled to 10 ° C, the precipitated yellow precipitate was filtered and washed with ethanol to give 29.5 g (91.6%) of 4-phenylpropionylhydrazino-3-nitropyridine hydrochloride, m.p. 244-245 ° C (2-methoxyethanol).

To a solution of 25 g (0.087 mol) of 4-phenylpropionylhydrazino-3-nitropyridine hydrochloride and 59 g (0.26 mol) of stannous chloride hydrate in 350 ml of water was added dropwise 610 ml of concentrated hydrochloric acid at such a rate that the thio mixture remained boiling. The mixture was boiled for 1 hour, then cooled to 10 ° C, the precipitate was filtered and washed with water until acid-free. 40.5 g of a yellow tin complex were obtained, which was dried and added with stirring to a solution of 40 g (0.012 mol) of potassium ferricyanide in 320 ml of water, which solution had been made alkaline with 50 ml of concentrated ammonium hydroxide. The mixture was allowed to stand for 1 hour at 0-5 ° C, the precipitate was filtered and washed with ethanol.

It was dried and extracted into chloroform. Evaporation of the solvent gave 10.6 g (51.7%) of the title compound as glossy brown crystals, m.p. 76-77 ° C (ethanol).

Example 3 3-Nonylpyrido [3,4-e] -az-triazine 3.00 g (0.02 mol) of 4-methoxy-3-nitropyridine and 3.72 g (0.02 7,57595 mol) of capric acid hydrazine were boiled with stirring in 60 ml. in ethanol for 4 hours. The solution was filtered hot, the filtrate was cooled, the pale yellow precipitate was filtered off with suction and washed with ethanol.

Yield 3.03 g (53.6%) of 4-decanoylhydrazino-3-nitropyridine, m.p. 119-120 ° C.

To a solution of 2 g (0.1 mol) of 4-decanoylhydrazino-3-nitropyridine in 360 ml of an 18% solution of stannous chloride hydrate was added dropwise 450 ml of concentrated hydrochloric acid, and the mixture was refluxed for 1 hour. After cooling, the yellow precipitate was filtered and washed with water and then added while still wet to 450 ml of an 18% potassium ferricyanide solution made alkaline with 75 ml of concentrated ammonium hydroxide.

The mixture was allowed to stand at 0 ° C for one hour. The precipitate was then filtered, dried and extracted with chloroform to give 15 g (65.2%) of the title compound, m.p. 46-47 ° C (ethanol).

Example 4 3-Octylpyrido [3,4-e] -az-triazine 3.16 g (0.02 mol) of 4-chloro-3-nitropyridine was added to a solution of geranium acid hydrazide (3.44 g, 0.02 mol) in 80 ml. ethanol, during the addition the mixture warmed up somewhat. The reaction mixture was stirred for 4 hours at the same temperature, then filtered and the filtrate evaporated to give 45.7 g (78.8%) of yellow crystalline 4-pelargoylhydrazino-3-nitropyridine hydrochloride, m.p.

188-189 ° C.

To a solution of 40 g (0.12 moles) of 4-pelargoylhydrazino-3-nitropyridine hydrochloride and 91.7 g (0.41 moles) of stannous chloride hydrate in 500 ml of water was added dropwise 800 ml of concentrated hydrochloric acid at such a rate. that the mixture just kept boiling. Cooking was then continued for 1 hour, the yellow precipitate formed was filtered off, washed with water and added wet to a solution of potassium ferricyanide (138 g, 0.42 mol) in a mixture of water (700 ml) and concentrated ammonium hydroxide (113 ml). The mixture was stirred 0-5 It was then filtered, the precipitate was washed with water, dried and extracted with chloroform, and the solvent was evaporated and crystallized from ethanol to give 14.75 g (50%) of the title compound as red plates, mp 46-47 ° C.

Example 5 3-Triethylpyrido [3,4-e] -az-triazine 4-methoxy-3-nitropyridine (1.54 g, 0.01 mol) and myristic acid hydrazide (2.42 g, 0 .01 moles) was reacted with each other in ethanol as described in Example 3 to give 57595

B

24.6 g (67.3%) of 4-myristylhydrazino-3-nitropyridine, m.p.

211-213 ° C (ethanol).

To a solution of 36.4 g (0.1 mol) of 4-myristylhydrazino-3-nitropyridine and stannous chloride hydrate (67.5 g, 0.3 mol) in 400 ml of water was added dropwise 700 ml of concentrated hydrochloric acid. . The solution and the precipitate formed were refluxed for 90 minutes. The mixture was cooled, filtered and the precipitate was washed with water. The resulting tin complex was added wet to a solution of potassium ferricyanide (90.5 g, 0.3 mol) in 500 mL of water, which was made alkaline with 75 mL of concentrated ammonium hydroxide.

The mixture was allowed to stand for 1 hour at 0-5 ° C, the precipitate was filtered off and washed with water. The precipitate was dried and extracted with chloroform, the solvent was evaporated and the residue was crystallized from ethanol to give 19.5 g (62.2¾) of crystalline red title compound, m.p. 65-66 ° C.

Example 6 3- (4'-Pyridyl) pyrido C3,4- [alpha] -thiazine 18.85 g (0.1 mol) of 4-chloro-3-nitropyridine were reacted with isonicotinic acid hydrazide (13.71 g, 0.1 moles) in 400 ml of ethanol at 45-50 ° C. After about an hour, a precipitate began to form. After stirring for 2 hours, the precipitate was filtered and washed with ethanol. 26.9 g (90.8%) of 4-isonicotinoylhydrazino-3-nitropyridine hydrochloride were obtained, m.p. 272-273 ° C (ethanol).

The resulting compound was reduced, cyclized and oxidized as described in Examples 1-5 to give the title compound in 43.9% yield, m.p. 169-170 ° C (chloroform).

If the oxidation step was omitted, 3- (4 * -pyridyl) -1,2-dihydropyrido [3,4-e] -as-triazine hydrochloride was obtained in 95.3% yield. - '

Sp. 287-288 ° C (dimethylformamide).

Example 7 3- (3 *, 4 ', 5 * -Trimethoxyphenyl) -pyrido [3,4-e] -aziazine

To a solution of 4.35 g (0.019 mol) of 3,4,5-trimethoxybenzoic acid hydrazide in 50 ml of ethanol was added 3.05 g (0.019 mol) of 4-chloro-3-nitropyridine. Heating at 50 ° C gave a solution from which an orange-yellow precipitate separated after about an hour.

The mixture was allowed to stand at 50 ° C for 2 hours, then cooled and the precipitate was filtered. 6.5 g (97.2%) of product were obtained, m.p. 240 ° C. The crude product was treated with HCl-containing ethyl acetate, the mixture was filtered and the precipitate was recrystallized from 50 ml of ethanol.

There was obtained 4- (3 ', 4', 5'-trimethoxybenzoyl) -hydrazino-3-nitropyridine-57595 dihydrochloride, m.p. 249-250 ° C.

The obtained compound was reduced, cyclized and oxidized as described in Examples 1-5 to give the title compound as red crystals. Yield 68.2%, m.p. 204-205 ° C (chloroform).

If the oxidation step was omitted, 3- (3 ', 4 *, 5'-trimethoxy-phenyl) -1,2-dihydropyrido [3,4-e] -as-triazine hydrochloride was obtained.

Yield 95%. Sp. 266-267 ° C.

Example B

3- (3 ', 5'-Dimethoxyphenyl) -pyrido [3,4-e] -az-triazine 3.8 g (0.2 mol) of 4-methoxy-3-nitropyridine hydrochloride were reacted with 3,5-methoxybenzoic acid hydrazide (39 , 2 g) (0.2 mol) in ethanol (600 ml) at reflux for 8 hours. The mixture was cooled, the cotton-like ocher-yellow precipitate was filtered to give 62 g (87.8%) of crude product. It was recrystallized from isopropanol to give 4- (3 ', 5'-dimethoxybenzoyl) -hydrazino-3-nitropyridine hydrochloride, m.p. 252-253 ° C.

The resulting compound was reduced, cyclized and oxidized as described in Examples 1-5 to give the title compound in 93% yield, m.p. 158-159 ° C.

Example 9 3- (2 * -Hydroxy-3 * -naphthyl) -pyrido [3,4-e] astriazine 30.8 g (0.2 moles) of 4-methoxy-3-nitropyridine were reacted with 2 -hydroxy-3-naphthoic acid hydrazide (40.4 g, 0.2 mol) by co-boiling in 600 ethanol for 5 hours. The mixture was cooled, the precipitate was filtered and recrystallized from dimethylformamide. 4- (2'-Hydroxy-3, -naphthoyl) -hydrazino-3-nitropyridine was obtained as yellow crystals. Yield 57.9 g (89.4%), m.p.

261-262 ° C.

The obtained compound was reduced, cyclized and oxidized as described in Examples 1-5 to give the title compound in 38.2% yield. Sp. 256-257 ° C (dimethylformamide),

Example 10 3- (o-Hydroxyphenyl) pyrido [3,4-e] -az-triazine 19.0 g (0.1 mol) of 4-methoxy-3-nitropyridine hydrochloride were co-boiled with salicylic acid hydrazide (15.2 g, 0.1 mol). with 250 mL of ethanol for 2 hours. The mixture was cooled, the orange crystals were filtered and washed with ethanol. 29.5 g (95.2%) of 3- (o-hydroxybenzoylhydrazino-3-nitropyridine hydrochloride) were obtained.

10 57595

The obtained compound was reduced, cyclized and oxidized as described in Examples 1-5 to give the title compound as glossy crystals. Yield 69.3%, m.p. 162-183 ° C.

If the oxidation step was omitted, 3- (o-hydroxyphenyl) -1,2-dihydropyrido [3,4-e] -az-triazine hydrochloride was obtained in 93% yield, mp 29B-299 ° C (dimethylformamide).

Example 11 3- (p-Hydroxyphenyl) pyrido [3,4-e] -as-triazine 15.85 g (0.1 mol) of 4-chloro-3-nitropyridine was reacted with p-hydroxybenzoic acid hydrazide (15.2 g, 0.1 moles) in 200 ml of ethanol at 40. After 30 minutes, yellow crystals began to precipitate from the solution, which were filtered after 2 hours and washed with ethanol to give 26.0 g (83.7%) of crude 4- ( p-hydroxybenzoyl) -hydrazino-3-nitropyridine hydrochloride by reprecipitation from alkaline solution, mp 280-281 ° C.

The obtained compound was reduced, cyclized and oxidized as described in Examples 1-5 to give the title compound as brick red crystals, yield 91.7%, m.p. 288-289 ° C (ethanol).

Claims (1)

Claim: A process for the preparation of therapeutically useful substituted pyrido [β, 4-e3-a-triazine derivatives of the general formula IR is m wherein R represents a C 1-6 alkyl group substituted by a hydroxy group or a 1-3 C 1-4 alkoxy group a phenyl group, a phenylalkyl group having 2 to 4 carbon atoms in the alkyl chain or a pyridyl group, and R 1 and R 2 represent a hydrogen atom or both together represent an additional bond, and for the preparation of these pharmaceutically acceptable salts, characterized in that A pyridine derivative of the general formula III of "wherein X represents a halogen atom or a C 1-4 alkoxy group to react with an acylhydrazine of the general formula III r-co-nh-nh 2 (III)" "in which the group R has the same meaning as above, then reduced with hydrogen catalytically hydrogenated by hydrogenation or heating with stannous chloride in an acidic solution NH-NH-CO-R I of general formula IV Compound of formula I (IV), and finally cyclizing the aminoacylhydrazino compound of general formula V (NH-NH-CO-R N 1V) obtained in the previous case 57595 12 to give the final products of formula I in which and R 2 are hydrogen and, if desired, preparing such the final products of formula I in which R and R form an additional bond, the final product obtained above is preferably oxidized with potassium ferricyanide and, if desired, the compound obtained is salified with a pharmaceutically acceptable acid. 13 57595 For the preparation of a therapeutically active substance with a pyrido substituent (j3> 4-eJ-as-triazine derivatives with all of the formulas I R1 _ / R2 color R for the C 1-6 alkyl group, with a hydroxy group or 1-3 _g- an alkoxy group substituted with a phenyl group, a phenyl-alkyl group having 2-4 chapters in the alkyl group, and an alkyl group having an additional bond or an additional bond, and a pharmaceutical form of the same, II. Lytisk hydrering with a mixture or with tenn-II-chlorides in the reaction of the genome up to a reduction in the form of a compound of the formula IV-rv ^^^ - NH-NH-CO-R I II (IV) N ^ nd2