SE190893C1 - - Google Patents

Description

CLASS INTERNATIONAL SWEDISH C 07 d12 p: PATENT AND REGISTRATION AGENCY one. 11 851/1960 filed on 7/12 1960 posted on 23/12 1963 E C TAYLOR, PRINCETON, N.J. and J WEINSTOCK, PHOENIXVILLE, PENN., USA Procedure for Preparation of 6-Pteridine Hydrazide Derivatives Priority Proposed on December 29, 1959 (USA) The present invention relates to novel 6-pteridine hydrazide derivatives having diuretic and natriuretic activity.

The novel pteridine derivatives of the invention are represented by the following basic formula Formula I.

R 1, R 2, R 2 N 2 -NH-1-1Y y O / N \ R, R, in which R 1, R 2, R 4 and R 1, represent hydrogen atoms or lower alkyl groups having up to 4 carbon atoms, preferably methyl groups, and Ar means a phenyl, chlorophenyl, tolyl, methylphenyl, α, α, atrifluorotolyl, hydroxyphenyl, aminophenyl, thienyl or pyridyl group.

Lamping compounds of this invention are represented by the following formula Formula II.

N NR, -XI \\ (\ / 17 0 NH, van in R1 and R, dro vate or methyl, and R6 dr vate, chlorine, methyl, methoxy, hydroxy, amino or trifluoromethyl A compound which is particularly advantageous and which 4,7-diamino-2-phenyl-6-pteridinecarboxylic acid methyl hydrazide is preferred.

The pteridine hydrazides of this invention are prepared from the corresponding carbonic acid esters by reaction with hydrazine or an alkyl substituted hydrazine. When the monoalkylhydrazines, such as methylhydrazine, are used in the reaction, the methyl group of the final product, as is known to those skilled in the art, may be substituted on the nitrogen atom into the carbon atom of the carbonyl in 6-staining, or in the liquid atom. Both of these isomers have diuretic effect and are encompassed by the invention. In fact, it has been found that a mixture of the two isomers is formed. For convenience, these compounds are referred to as the compounds substituted by the duct atom.

The preferred hydrazide derivatives are prepared by reacting a 6-pteridinecarboxylic acid ester, preferably the methyl or ethyl ester, with a hydrazine in a hydroxyl-containing polar organic solvent having less than 6 carbon atoms, such as ethoxyethanol, methoxyethanol, ethylene glycol or propylene glycol at about 70 ° C. ° C, preferably about 90-150 ° C for from about 10 minutes to 8 hours. The acid hydrazides formed often separate on cooling and are isolated by filtration. The carboxylic acid ester used as starting material is prepared by reacting a 4,6-diamino-2-aryl-5-nitrosopyrimidine with a cyanoacetic acid ester, which will be described in more detail in the examples below.

The pharmaceutically usable salts of the hydrazides of the invention, which are formed with non-toxic acids such as hydrochloric acid, sulfuric acid, carbonic acid, maleic acid, methylsulfonic acid, citric acid, phosphoric acid with several acids, can be used alternately with the parent substances. These salts can be prepared in many ways, but most advantageously by preparing the bases with the desired acid in a lower alcohol, then evaporating the alcohol solvent to obtain the residual salt. Alternatively, salt formation can occur in water slurry or rising.

Example 1. To a boiling solution of 6.45 g of 4,6-diamino-2-phenyl-5-nitrosopyrimidine in 400 ml of methanol is added 2.94 ml of methyl cyanoacetate, and 2-drop 1.78 g of sodium methoxide. The resulting mixture is refluxed for one hour. Yellow crystals are collected by filtration of the hot mixture and extracted with 300 ml of boiling water. Recrystallization from dimethylformamide gives guk crystals of methyl 4-7-diamino-2-phenyl-6-pteridinecarboxylate, m.p. 28 ° C.

Methyl hydrazine (5.0 g) was added to a refluxing solution of 3.0 g of methyl 4-7-diamino-2-phenyl-6-pteridinecarboxylate in 300 ml of 2-ethoxyethanol. The resulting mixture is refluxed for 1 minute. Cooling, drip filtration and recrystallization of the precipitate from aqueous dimethylformamide give a mixture of 4,7-diamino-2-phenyl- 6- (pteridinecarboxylic acid 2-methylhydrazide) and the corresponding 1-methylhydrazide.

A solution of the methyl hydrazide (500 mg) was reacted with an equivalent amount of maleic acid in ethanol on the steam bath. Evaporation gives the salt of malonic acid.

Example 2. A mixture of 2.0 g of methyl 4-7-diamino-2-phenyl-6-pteridinecarboxylate prepared as in Example 1, in 200 ml of ethylene glycol is treated with 4.5 g of hydrazine. The resulting mixture is heated to 150-160 ° C for 30 minutes. Cooling, dilution with water, filtration of the solids and recrystallization from aqueous dimethylformamide give 4,7-diamino-2-phenyl-6-pteridinecarboxylic acid hydrazide.

The hydrazine (1 g) in ethanol was reacted with hydrochloric acid. Evaporation and pulverization with ether give the chloride.

Example 3. To a solution with stirring of 9 g of p-chlorobenzamidine hydrochloride in 200 ml of methanol was slowly added 11.1 g of the silver salt of isonitrosomalononitrile. The resulting mixture is stirred for one hour and filtered. The filtrate is evaporated to dryness at 30-35 ° C. To the residue was added 1 ml of a solution of 5-ethyl-2-methylpyridine and 2-picoline (2: 1). The resulting solution is refluxed for 20 minutes. Addition of water and ethanol precipitates a ground solid which is isolated by filtration and washed with ethanol to give 4,6-diamino2- (p-chlorophenyl) -5-nitrosopyrimidine.

A refluxing solution of 7.8 g of the pyrimidine prepared above in 500 ml of methanol is treated with 2.8 g of methyl cyanoacetate and 1.78 g of sodium methoxide, and refluxed for one hour. Work-up as in Example 1 gives methyl-4,7-diamino-2- (p-chlorophenyl) -6-pteridinecarboxylate.

Methyl hydrazine (4 g) was added to a refluxing solution of 2 g of the carboxylate in 250 ml of 2-ethylethanol. After a one hour surface period, 4,7-diamino-2- (chlorophenyl) -6-pteridinecarboxylic acid methyl hydrazide is precipitated on cooling.

Example 4. A rimming of 4.65 g of p-anisamidine hydrochloride in 50 ml of methanol is treated with 5.5 g of the silver salt of isonitrosomalononitrile and the resulting mixture is stirred for one hour. The mixture is filtered and the filtrate is concentrated to dryness in vacuo at 40 ° C. The remaining dry substance is boiled for four minutes in ml of 5-ethyl-2-methylpyridine. The solution is cooled, diluted with ethanol and filtered. The spruce solid obtained is 4,6-diamino-2- (p-methoxyphenyl) -5-nitrosopyrimidine, m.p. 278 ° C (sanderfall).

Treatment of a methanol solution of the pyrimidine prepared above with methyl cyanoacetate and sodium methoxide gives methyl 4-4,7-diamino-2- (p-methoxyphenyl) -6-pteridine carboxylate.

A mixture of 2 g of ester, 2 g of hydrazine and 200 ml of methoxyethanol is heated under reflux for four hours. The desired 4,7-diamino-2- (p-methylphenyl) -6-pteridinecarboxylic acid hydrazide separates on cooling.

Example 5. Dry chlorate is introduced into a cooled solution of 54.5 g of 3-thiophenecarbonitrile in 75 ml of absolute ethanol and the resulting loading is allowed to stand. for 48 hours. To the solid was added portionwise an 8% solution of dry ammonia in absolute ethanol containing 12 g of ammonia. The reaction mixture is shaken for 24 hours, stirring. for 48 hours and filtered. The filtrate is allowed to evaporate into dryness in the open air. Atersto it is read in water. The aqueous solution is acidified with concentrated hydrochloric acid, treated with alcohol, filtered and concentrated. The crystals formed are isolated by filtration to 3-thiophenecarboxamidine hydrochloride.

To a solution of 8.1 g of 3-thiophenecarboxamidine hydrochloride in 80 ml of methyl alcohol was added 11.1 g of the silver salt of isonitrosomalononitrile. The resulting mixture is stirred for 30 minutes and filtered. The filtrate is evaporated to dryness in vacuo. The residue is refluxed with 50 ml of 5-ethyl-2-methylpyridine for twenty minutes. The mixture is cooled, diluted with 100 ml of ethanol and filtered to give 4,6-diamino-5-nitroso-2- (3-thienyl) pyrimidine.

To a surfactant solution of 4.4 g of 4,6-diamine-5-nitroso-2- (3'-thienyl) pyrimidine in 300 ml of methanol was added 1.9 g of methyl cyanoacetate and. 1.2 g sodium methoxide. The resulting solution is refluxed for one hour. The hot weld is filtered. The solid is extracted with hot water and recrystallized from dimethylformamide to form methyl 4,4-diamino-2 (3'-thienyl) -6-pteridine carhoxylate.

A mixture of 1 g of the carboxylate, 2.0 g of asymmetric dibutylhydrazine and 150 ml of ethoxyethanol is heated under reflux for 3 hours. Upon cooling, the desired 4,7-diamino-2- (3'-thienyl) 6-pteridinecarboxylic acid dibutyl hydrazide precipitates.

Example 6. Treatment of 54.5 g of 2-thiophenecarbonitrile in ethanolic solution with dry chlorine and then with an ethanolic solution of ammonia, and work-up as in Example 5 gives 2-thiophenecarb oxamidine hydrochloride.

The chloride (4.0 g) prepared above was reacted with 5.6 g of the silver salt of isonitrosomalononitrile I methanol solution and cyclized by subsequent refluxing with 35 ml of 5-ethyl-2-methylpyridine as in Example 5 to 4,6-diamino-5- nitroso-2- (2'-thienyl) pyrimidine.

This pyrimidine (4.4 g) in 350 ml of refluxing n-propanol is treated with 2.5 g of n-propyl cyanoacetate (prepared by refluxing cyanoacetic acid with n-propanol and concentrated sulfuric acid), and 1.2 g of sodium methoxide. . The mixture is refluxed for one hour. The crystals are filtered off from the hot solution, extracted with hot water and recrystallized from dimethylformamide to give n-propyl-4,7-diamino-2- (2'-thienyl) -6-pteridinecarboxylate.

A mixture of 500 mg of the carboxylate, 1 g of propylhydrazine and 50 ml of ethoxyethanol is heated under hot water for one hour. Cooling gives the desired 4,7-diamino-2- (2'-thienyl) -6-pteridinecarboxylic acid propyl hydrazide.

Example 7. To a solution of 8.5 g of m-toluamidine hydrochloride in 80 ml of methanol was added 11.1 g of the silver salt of isonitrosomalononitrile. The mixture is stirred for one hour, filtered and the filtrate is concentrated in vacuo. The residue is refluxed with a mixture of 100 ml of 5-ethyl-2-methylpyridine and 50 ml of 2-picoline, and worked up as described above to give 4,6-diamino-5-nitroso-2- (m-tolyl) pyrimidine.

Sodium methoxide (1.78 g) was added to a refluxing solution of 6.87 g of 4,6-diamino-5-nitroso-2- (m-tolyl) pyrimidine and 2.8 g of methyl cyanoacetate in 400 ml of methanol. The resulting mixture is refluxed for 45 minutes. The crystals are collected by filtering the hot mixture. Washing with hot water and recrystallization from dimethylformamide gives methyl 4,7-diamino-2- (m-tolyl) -6-pteridinecarboxylate.

A mixture of 3 g of the ester, 4 g of hydrazine and 400 ml of methoxymethanol is heated under reflux for two hours, and cooled to give 4,7-diamino-2- (m-tolyl) -6-pteri-dicarboxylic acid hydrazide.

The hydrazide (500 mg) in methanol is reacted with a stoichiometric amount of phosphoric acid to give the phosphate.

Example 8. To a solution with stirring of 5.0 g of o-fluorobenzamidine hydrochloride in 75 ml of ethanol is added portionwise 5.55 g of the silver salt of isonitrosomalinitrile. The resulting mixture is stirred for one hour and filtered. The filtrate is evaporated to dryness and the residue is refluxed for ten minutes in 50 ml of 5-ethyl-3-methylpyridine, cooled and treated with 50 ml of ethanol. Collection of the solid by filtration gives 4,6-diamino-2- (o-fluorophenyl) -5-nitrosopyrimidine.

Addition of 2.2 g of ethyl cyanoacetate, then 1.5 g of sodium ethoxide to a refluxing solution of 5.2 g of 2- (o-fluorophenyl) -5-nitrosopyrimidine in 300 ml of ethanol, refluxing the resulting mixture for one hour, and work-up as described above gives ethyl-4,7-diamino-2- (o-fluorophenyl) -6-pteridinecarboxylate, which (1 g) is reacted with 1 g of methylhydrazine in ethoxyethanol under reflux to 4,7-diamino-1- (o -fluorophenyl) -6-pteridinecarboxylic acid methyl hydrazide.

Example 9. To a solution of 8.5 g of m-aminobenzamidine hydrochloride in 150 ml of methanol was slowly added 11.1 g of the silver salt of isonitrosomalononitrile. The resulting mixture is stirred for one hour and filtered. The filtrate is evaporated in vacuo at 30-35 ° C. The residue is refluxed with a solution of 5-ethyl-2-methylpyrimidine (100 ml) and 2-picoline (50 ml) for 20 minutes. The mixture was cooled and diluted with water and ethanol. The precipitate is isolated by filtration and washed with ethanol to give a dark green substance, 4,6-diamine-2- (m-aminophenyl) -5-nitrosopyrimidine.

Treatment of this pyrimidine in methanol solution with methyl cyanoacetate and sodium methoxide and work-up as in Example 1 to give methyl 1-4,7-diamino-2- (m-aminophenyl) 6-pteridine carboxylate, which (2 g) is reacted with 3 g of hydrazine in methoxyethanol to give give the acid hydrazides.

Example 10. Treatment of 22.0 g of α, α, α-trifluoro-p-tolunitrile in ethanol solution with dry chloroate and darpa with ethanol ammonia solution, and work-up as described above gives α, α, α-trifluoro toleamidine hydrochloride.

This hydrochloride is reacted with the silver salt of isonitrosomalononitrile in methanol solution and cyclized by refluxing with 5-ethyl-2-methylpyridine as described, to give 4,6-diamino-5-nitroso-2- (α, α, α-trifluoro-β- ) pyrimidine.

To a refluxing solution of 5.6 g of the pyrimidine prepared above in 250 ml of methanol were added 1.8 g of methyl cyanoacetate and 1.2 g of sodium methoxide. The resulting mixture is heated under reflux for one hour. The hot mixture is filtered and the obtained crystals are washed with hot water and recrystallized from dimethylformamide to methyl 1-4,7-diamino-2- (α, α, α-trifluoro-p-tolyl) -6-pteridine carboxylate, which (2 g) is treated under AterflOde with 1 g of methylhydrazine in ethoxyethanol for one hour to 4,7-diamino2- (α, α, α-trifluoro-β-tolyl) -6-pteridinecarboxylic acid methylhydrazide. A solution of 500 mg of the hydrazide and an equivalent amount of maleic acid in ethanol is evaporated on a steam bath to the maleate.

Example 11. To a mixture of 20 g of 6-amino2-phenyl-4-pyrimidol and 10 ml of dimethylaniline was added 100 ml of phosphorus oxychloride. The resulting mixture is refluxed for eight hours, and concentrated in vacuo. The residue is dissolved in water and treated with an excess of concentrated ammonium hydroxide. After heating the mixture on a steam bath for one hour, concentrating in vacuo and cooling, the precipitate is filtered off, washed with water and grated in a mortar with 15 ml of 1-n sodium hydroxide. The solid is filtered off and washed with water to give 6-amino-4-chloro-2-phenyl-pyrimidine. g of 6-amino-4-chloro-2-phenylpyrimidine and 25 ml of 25% methylamine in water are heated in a bomb at 125 ° C for four hours. The product, 6-amino-4-methylamino-2-phenylpyrimidine, is isolated by filtration.

A mixture of 11.4 g of 6-amino-4-methylamino2-phenylpyrimidine and 100 ml of 10% acetic acid is heated to 90 ° C and filtered. The solution is cooled to 3 ° C and treated with a solution of 5.0 g of sodium nitrite 115 ml of water added in portions. After one hour at 0 ° C and one hour at room temperature, the mixture is filtered. The solid is washed with water and - - dried to give 6-amino-4-methylamino-5-nitroso-2-phenylpyrimidine.

Sodium methoxide (1.2 g) was added to a refluxing methanol solution of 4.6 g of 6-amino-4-methylamino-5-nitroso-2-phenylpyrimidine and 1.8 g of methyl cyanoacetate. The resulting mixture is refluxed for one hour. Work-up as described gives methyl 7-amino-4-methylamino-2-phenylpteridinecarboxylate. This ester, (500 mg) is heated with 1 g of methylhydrazine in 50 ml of ethoxyethanol for 2 hours. Cooling gives the methyl hydrazide.

Example 12. A mixture of 8.0 g of 6-amino-4-chloro-2-phenylpyrimidine, prepared as described in Example 11, and 30 ml of 25% dimethylamine in water is heated in a bomb at 125 ° C for four hours. 6-Amino-4-dimethylamino-2-phenyl-pyrimidine is isolated from the mixture by filtration. g of 6-amino-4-dimethylamino-2-phenylpyrimidine and 150 ml of 10% acetic acid are heated to 90 ° C and filtered. The mixture is cooled to 0 ° C. A solution of 4.0 sodium nitrite in 10 ml of water is added in portions, and the resulting mixture. The reaction is allowed to stand for one hour at 0 ° C and for one hour at room temperature. The precipitate is filtered off, washed with water and dried over 6-amino-4-dimethylamino-5-nitroso-2-phenylpyrimidine.

Treatment of the nitrosopyrimidine (4.8 g) prepared above in refluxing methanol solution with 1.8 g of methyl cyanoacetate and 1.2 g of sodium methoxide, and work-up as described, gives methyl 7-amino-4-dimethylamino-2-phenylpteridine carboxylate, which is transferred to the hydrazide by reaction with hydrazine in ethoxyethanol as described above.

Example 13. The silver salt of isonitrosomalononitrile (11.1 g) was added to a solution of 7.8 g of isonicotinamidine hydrochloride in 100 ml of methanol and the resulting mixture was stirred for 30 minutes and filtered. The filtrate is evaporated to dryness in vacuo at 30-35 ° C. The residue is refluxed with 100 ml of 5-ethyl-2-methylpyridine for two minutes. Addition of water and ethanol and filtration of the solid give 4,6-diamino-5-nitroso-2- (4'-pyridyl) pyrimidine.

Methyl cyanoacetate (2.8 g) and sodium methoxide (1.78 g) were added to a boiling solution of 6.45 g of 4,6-diamino-5-nitroso-2- (4'-pyridyl) pyrimidine 400 ml of methanol. Refluxing the resulting mixture for 30 minutes, filtering off the crystals, extracting with hot water and recrystallizing from dimethylformamide gives methyl 4,7-diamino-2- (4'-pyridyl) -6-pteridinecarboxylate.

A mixture of 2 g of methyl-4,7-diamino-2- (4'-pyridyl) -6-pteridinecarboxylate, 3 g of dimethylhydrazine and 400 ml of ethoxyethanol is heated under reflux for 5 hours, and cooled to give the desired 4 7-Diamino-2- (4'-pyridyl) -6-pteridinecarboxylic acid dimethyl hydrazide.

Example114. 10 g of 6-amino-4-1dor-2-phenylpyrimidine, prepared as in Example 11, and 7.5 g of dibutylamine in aqueous solution are refluxed for four hours. Filtration of the resulting mixture gives 6-amino-4-dibutylamino-2-phenylpyrimidine.

A mixture of 10.0 g of the pyrimidine prepared above and 150 ml of acetic acid is heated to 90 ° C, filtered clear and cooled to 0 ° C. 4 g of sodium nitrite in aqueous lysis were added in portions. The mixture is allowed to stand for one hour at 0 ° C and one hour at room temperature, and the precipitated 6-amino-4-dibutylamino-5-nitroso-2-phenylpyrimidine is removed by filtration.

To a refluxing solution of 9.8 g of 6-amino-4-dibutylamino-5-nitroso-2-phenylpyrimidine in 500 ml of ethanol was added 3.3 g of ethyl cyanoacetate, and. darpa 2.2 g sodium ethoxide. The resulting mixture is refluxed for one hour. The crystals are collected by filtration, washed with hot water and recrystallized from dimethylformamide to ethyl 7-7-amino-4-dibutylamino-2-phenyl-6-pteridinecarboxylate which (500 mg) is reacted with an excess of hydrazine in ethoxyethanol to give the desired acidic hydrazide.

Example115. To a solution with stirring of 4.3 g of m-hydroxybenzamidine hydrochloride in 100 ml of ethanol was slowly added 5.55 g of the silver salt of isonitrosomalononitrile. The resulting mixture is stirred for one hour and filtered. The filtrate is evaporated to dryness, and the residue is refluxed for ten minutes with 50 ml of 5-ethyl-2-methylpyridine and treated darpa with 50 ml of ethanol. Collection of the solid by filtration gives 4,6-diamino-2- (m-hydroxyphenyl) -5-nitrosopyrimidine.

Treatment of the above-prepared pyrimidine (2.3 g) in refluxing methanol solution with 0.93 g of methyl cyanoacetate and 0.59 g of sodium methoxide and work-up as described gives methyl 1-4,7-diamino-2- (m-hydroxyphenyl) -6- pteridine carboxylate, which (1 g) is reacted with 1 g of methylhydrazine in ethoxyethanol, after which the methyl hydrazide is obtained on cooling.

Claims (6)

Patent claim: Process for the preparation of pteridine derivatives having diuretic and natriuretic activity, characterized in that a pteridine of the structural formula NN NH, - "1 ', /) -Ar X- / \ R4 RI which Ar represents a phenyl-, chlorophenyl-, tolyl- , methoxyphenyl, α, α, α-trifluorotolyl, aminophenyl, thienyl or pyridyl group, R 1 and R 2 each represent a hydrogen atom or an alkyl group having up to 4 carbon atoms and X represents an alkoxycarbonyl group having up to 4 carbon atoms, reacted with a hydrazine by the formula R1R2N-NH2 van in R, and R, each denote a hydrogen atom or an alkyl radical having - - up to 4 carbon atoms, to form a formation of the formula N \ / h — Ar 0 / \ R. R van iR „R4, R, and As have the meanings given above, and that the base thus prepared may be neutralized to form a salt. Process according to Claim 1, characterized in that a 6-pteridinecarboxylic acid ester is reacted with a hydrazine in a hydroxyl-containing polar solvent having less than 6 carbon atoms at a temperature ranging from 70-200 ° C to give the corresponding hydrazide derivative. Process according to claim 2, characterized in that a methyl or ethyl ester is used. Procedure according to any one of the preceding patent claims, characterized in that the reaction is carried out at a temperature ranging from 90 to 150 ° C. Cited publications: Patent Specifications from the United Kingdom 598,453, 699,644; USA. 2,716,663, 2,763,684, 2,963,478-2,963,481. Other publications: Encyclopedia of chemical technology. Oath. by R E Kirk & D F Othmer. Vol. 7. New York 1951, p.58 5. Chemical society. London. Journal 1955, pp. 203 6.