NO140821B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRIDO-PYRIMIDINE DERIVATIVES - Google Patents

Description

The present invention relates to a method for the production of new pyrido-[1,2-a]-pyrimidine derivatives.

The new compounds produced according to the present invention have the formula:

or are salts and quaternary salts thereof,

where R^ is hydrogen or C^-C^-alkyl,

I 2 is hydrogen or C 1 -C 4 alkyl;

R is carboxy or -C 1 -C 4 -Alkoxycarbonyl, carbamoyl, phenyl-lower alkylcarbamoyl optionally substituted with one or two C 1 -C 4 -Alkoxy groups; or a carboxylic acid hydrazido group; and n is 1 or 2.

The salts of the compounds of formula I can be formed with inorganic

ic or organic acids, such as hydrochloric acid, hydrogen bromide, phosphoric

acid, sulfuric acid, perchloric acid, formic acid, acetic acid, citric acid, malic acid, glutamic acid, amygdalic acid, salicylic acid, etc.

The quaternary salts of the compounds of formula I are formed with conventional quaternizing agents, e.g. alkyl halides (e.g. methyl iodide, ethyl iodide, etc), dialkyl sulfates (e.g. dimethyl-

sulphate) or alkyl or aryl benzene sulphonates or p-toluene sulphonates.

The compounds of formula I and salts and quaternary salts

thereof, is produced according to the invention by reducing a compound

else with the formula:

where , R2, Rg and n are as indicated above, to a compound with the formula:

where the R^ group can optionally be transferred to other meanings of the R^ group, after which a thus obtained compound of formula I is transferred to its acid addition salt or quaternary salt, or a compound of formula I is released from its acid addition salt or quaternary salt.

The reduction can preferably be carried out by catalytic hydrogenation. The hydrogenation can be carried out at a temperature between 0° and 100°C and under atmospheric pressure or under a pressure of 1 - 50 atm.

The reaction is carried out in a solvent. The reaction medium can be water, alkanols (e.g. methanol or ethanol), esters (e.g. ethyl acetate), ketones (e.g. acetone or methylethyl ketone) or organic acids ( e.g. acetic acid), or mixtures thereof, are used.

As a catalyst, conventional hydrogenation catalysts can be used. It is preferred to use a palladium-on-charcoal catalyst, Raney nickel, platinum or platinum oxide.

During the hydrogenation, the pyridine ring in the starting material with formula II becomes saturated and takes up 2 moles of hydrogen. After the absorption of the calculated amount of hydrogen, the catalyst is removed (preferably by filtration, late rifugation, sedimentation or decantation), and the solvent is distilled off. The thus obtained compound of formula III or its acid addition salt can be recrystallized from a suitable solvent if necessary.

In the connection with formula III, if desired, an R^ group can be transferred to other meanings of the R^ group by methods known per se. An alkoxycarbonyl group can thus be transferred to the carboxyl group by hydrolysis. The reaction can preferably be carried out under alkaline conditions, by using an alkali hydroxide, preferably an aqueous sodium or potassium hydroxide solution. An alkoxycarbonyl group can over-

is converted to an acid hydrazide group by treatment with hydrazine;

since the latter can preferably be used in the form of an alcoholic hydrazine solution; or salts and the hydrate of hydrazine may be used. The carboxyl group can be transferred to an alkoxycarbonyl group (eg, ethoxycarbonyl) by treatment with an alcohol (eg, ethanol) in the presence of a solvent (eg, benzene). The carboxyl group can be transferred to an acid amide by reaction with the corresponding amine, possibly in the presence of a solvent (e.g. xylene). The free carboxylic acid can be transferred to acid chlorides by treatment with a halogenating agent (e.g. thionyl chloride, phosphorus oxychloride, etc.). The acid halides can be transferred to the free acids by treatment with water, or to alkoxycarbonyl esters by treatment with the corresponding alcohol, or acid amides by treatment with the corresponding amine.

The compounds of formula I can be converted to their acid addition salts and quaternary salts by methods known per se. One can proceed by reacting the base of formula I with a suitable equimolar amount of the corresponding acid or quaternizing agent in the presence of an organic solvent. Both organic and inorganic acids are suitable as acid, e.g. hydrochloric acid, hydrogen bromide, phosphoric acid, sulfuric acid, perchloric acid, formic acid, acetic acid, citric acid, amygdalic acid, malic acid, glutamic acid, salicylic acid, etc. As a quaternizing agent, e.g. alkyl halides (such as methyl iodide, ethyl iodide), dialkyl sulphates (e.g. dimethyl sulphate), alkyl and aryl benzene sulphonates and p-toluene sulphonates.

The starting materials of formula II can be prepared by ring-closing a compound of the formula:

where R^ , R^ p R^°9 n are as indicated above, and Rg is alkoxycarbonyl. The cyclization can be carried out in the presence of an inert solvent or an acidic condensing agent, e.g. phosphorus oxychloride, phosphorus trihalides, polyphosphoric acid, etc., at a temperature between 25° and 4oO o C'. The production of the starting material is described in DOS 2,315,422.

The compounds of formula I have useful therapeutic properties and exhibit analgesic, anti-inflammatory and antipyretic effects, and exert other desired effects on the central nervous system (e.g. narcotic and psychosedative effects, etc.).

The process compounds can be used to prepare pharmaceutical preparations comprising as active ingredient a compound of formula I or an acid addition salt or quaternary salt thereof in mixture with suitable inert solid or liquid carriers or diluents.

Example 1

4>4 g (0.02 mol) 3-(carboxymethyl)-6-methyl^-oxo^H-pyrido-1^1,2-a]-pyrimidine was suspended in 60 ml of glacial acetic acid and hydrogenated under atmospheric pressure in the presence of 1.5 g of charcoal.

The calculated amount of hydrogen was absorbed within 30 minutes, after which the catalyst was filtered off and the solution evaporated to dryness in vacuo. The 8>2 g of remaining oil was recrystallized from 9 ml of 96% alcohol. 3.3 g (75%) of the white colored 3-(carboxymethyl)-6-methyl-4-oxo-6,7,8>9-tetrahydro-4H-pyrido-[1,2-a]- pyrimidine with melting point 193 - 194°C. The melting point remained unchanged upon recrystallization.

Analysis:

Example 2

6.0 g (0.15 mol) of sodium hydroxide was dissolved in 60 ml of water.

To the solution thus obtained was added 14.4 9 (0.05 mol) 3-(ethoxycarbonyl-methyl)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1, 2-a ] - pyrimidine hydrochloride added, and the solution was stirred at room temperature for 3 hours, after which the pH value was adjusted with hydrochloric acid 1:1 (approx. 8 ml) and the solution was decolorized with charcoal. The pH value of the decolorized solution was set to 4 (at a lower pH value the acid dissolves). The solution was left for a few hours in a refrigerator, and the precipitated crystals were filtered off. 3.6 g (32%) of 3-(carboxymethyl)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidine were obtained with melting point 191°C The aqueous mother liquor was evaporated and the residue of 10 g was dissolved in 20 ml of water by heating. On cooling, 3.5 g (30%) of the acid was obtained, with a melting point of 192°C. The total yield was 7.1 g (62%). The melting point rises to 193 - 194°C on recrystallization from 96% alcohol.

The crystals thus obtained do not cause any melting point depression with the product obtained according to example 1.

When in the above method 3~(ethoxycarbonyl-methyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidine is used as starting material, 3-( carboxymethyl)-4-oxo-6,7 > 8 > 9-t a rahydro-4H-pyrido-[1,2-a]-pyrimidine with melting point 174 - 175°C in a yield of 80%.

Example 3

53.7 g (0.2 mol) of 3-(ethoxycarbonyl-methyl)-4-oxo-4H-pyrido-[1,2-a]-pyrimidine hydrochloride was dissolved in 250 ml of water. After adding 10 ml of hydrochloric acid and 20 g of palladium-charcoal catalyst, the hydrogenation was carried out at a pressure of 5 - 10 atm. The calculated amount of hydrogen was absorbed, the catalyst was filtered off and the pH

set to 7 by adding a 20% sodium carbonate solution. The resulting solution was decolorized with charcoal and filtered. The clear solution was extracted three times with 300 ml of benzene.

The combined extracts were dried over sodium sulfate, the solution was filtered and the filtrate was evaporated to dryness. 32.0 g (68%) of a crystalline product was obtained, which melted at 63-66°C. Extraction of the aqueous mother liquor with chloroform and work-up

of the extract obtained, gave a further 2.89 (5.5fø) of the product obtained, a total yield of 73.5%. Recrystallization of the product from an alcohol-petroleum ether mixture gave snow white 3-

(ethoxyca rbonyImethyl)-4~oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidine with melting point 65 - 66°C.

Analysis:

When 3-(ethoxycarbonyl1-methyl)-7-methyl-4-oxo-4H-pyrido-[1,2-a]-pyrimidine hydrochloride is used as starting material, 3-(ethoxycarbonyl1-methyl)-7-methyl-4 -oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidine in the form of a non-crystallizable oil. The melting point of the hydrochloride is 146 - 147°C.

When 3-(ethoxycarbonylmethyl)-8-methyl-4-oxo-4H-pyrido-[1,2-a]-pyrimidine hydrochloride is used as starting material, 3-(ethoxycarbonyl-methyl)-8-methyl-4-oxo is obtained -4H-pyrido-[1,2-a]-pyrimidine with melting point 44 - 45°C.

Example 4

0.25 g (1 mmol) of 3-(ethoxycarbonyl-methyl)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidine was dissolved in 1 ml of absolute alcohol and 0.1 ml (2 mmol) of 100% hydrazine hydrate were added. After standing for 1 day at room temperature, the solution was evaporated to dryness, and the remaining, slowly crystallizing product was recrystallized from an alcohol-ether mixture. 0.17 g (72%) of white colored 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidine-3-(methyl-carbohydrazide) was obtained with melting point 132 - 133°C.

The melting point is not changed by recrystallization.

Analysis:

Example 5

25.0 g (0.1 mol) of 3-(ethoxycarbonyl-methyl)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidine was dissolved in 50 ml of absolute acetone and 13.2 g (0.105 mol) of freshly distilled dimethyl sulfate was added to the solution. The solution was kept for 10 minutes at 4o°C and then left at room temperature. The next day, the precipitated crystals were filtered off and washed with a small amount of absolute acetone. The product obtained was recrystallized from a double amount of absolute alcohol. Thus, 21 g were obtained

(56%) off-white 3~(ethoxycarbonyl-methyl)-1,6-dimethyl-4-oxo-6,7,8,9-t rahydro -4H-pyrido-[1,2-a]-pyrimidinium-met ho sulfate with melting point 150°C. The melting point is not changed by recrystallization.

Analysis:

When in the above method 3-(ethoxycarbonyl-methyl)-4-oxo-6,7,8,9-tetrahydro~4H-pyrido-[1,2-a]-pyrimidine is used as starting material, 3-(ethoxycarbonyl -methyl)-1-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidinium methosulphate with melting point 141 - 142°C

Example 6

In an apparatus equipped with a water separation column, 22.2 g (0.1 mol) of 3-(carboxymethyl)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[ 1, 2-α].-pyrimidine, 12.1 g (0.1 mol) of 2-phenylethylamine and 100 ml of xylene were refluxed for 3 hours, while 1.8 ml of water was collected in the condenser. The solution was then evaporated to dryness. 32.3 g (99%) of 3"(N-2-phenyl-ethyl)-carboxamido-methyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1 ,2-a]-pyrimidine in the form of a non-crystallizing oil. By dissolving 3.35 g (3.01 mol) of the oil in 3 ml of alcohol and adding 1.5 ml of 70% perchloric acid, 3 was obtained .0 g (71%) of the pale yellow 3-(N-2-phenyl-methyl)-carboxamido-methyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[ 1,2-a]-pyrimidinium perchlorate with a melting point of 174 - 176° C. The melting point rises after recrystallization from an 8 times greater amount of ethanol to 176 - 177° C.

Analysis:

By the above procedure using 2-(3,4-dimethoxy-phenyl)-ethylamine as the amine component, 3~[N-2-(3,4-dimethoxy-phenyl)-ethyl]-carboxamido-methyl-6-methyl- 4-oxo-6,7,8,9-tet rahydro-4H-pyrido-[1,2-a]-pyrimidine in a yield of 99% in the form of a non-crystallizing oil.

Example 7

2.6 g (0.01 mol) of 3-(ethoxycarbonyl-methyl)-6,8-dimethyl-4-oxo-4H-pyrido-[1,2-a]-pyrimidine are dissolved in 30 ml of ethanol and hydrogenated under atmospheric pressure in the presence of 1.0 g of neutral, 10% palladium-containing palladium-charcoal catalyst. After adsorption of the calculated amount of hydrogen, the reaction ends, after which the catalyst is filtered off and the alcoholic solution is evaporated. In this way, 2.2 g (84.5%) of 3-(ethoxycarbonyl-methyl)-6,8-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2 -α]-pyrimidine as a colorless oil.

Analysis:

0.5 g (0.0019 mol) of the above ester is heated to boiling with 5 ml of 5% hydrochloric acid for 0.5 hours, and then the solution is evaporated in vacuo. The crystalline residue is dried in a desiccator over phosphorus pentoxide to constant weight. 4.3 g (-95.5%) of white crystalline 3-(carboxymethyl)-6,8-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2- α]-pyrimidine with melting point 120°C and decarboxylation at 144°C.

Analysis:

Example 8

2.46 g (0.01 mol) of 3-(2-ethoxycarbonyl-ethyl)-4-oxo-4H-pyrido-[1,2-a]-pyrimidine are dissolved in 100 ml of ethanol and hydrogenated in the presence of 1.0 g 10% palladium-charcoal catalyst. After the calculated amount of hydrogen has been adsorbed, the catalyst is filtered off and the alcoholic solution is evaporated. 2.0 g (80%) of white, crystalline 3-(2-ethoxycarbonyl-ethyl)-4-oxo-6,7,8,9~tetrahydro-4H-pyrido-[1,2-a]- pyrimidine with melting point 48 - 50°C.

Analysis:

When 3-(2-ethoxycarbonyl-ethyl)-6-methyl-4-oxo-ifH-pyrido-[1,2-a]-pyrimidine is used as starting material, 3-(2-ethoxycarbonyl-ethyl)-6- methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidine in the form of a non-crystallizable colorless oil. Dividend: 8.5%. Melting point of the hydrochloride 130 - 132°C. Analysis:

Example 9

4.45 g (0.02 mol) of 3-(carboxy-methyl)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidine are suspended in 60 ml of methanol and saturated with anhydrous gaseous hydrogen chloride at 5 - 10°C. The reaction mixture is allowed to stand overnight, and the pale yellow solution is evaporated and the residue is dissolved in 30 ml of water, after which the pH is adjusted to 7 by adding a saturated sodium carbonate solution. The solution is de-coloured with charcoal which is filtered off. The clear solution is extracted with 3 x 40 ml of benzene. The combined benzene extracts are dried over sodium sulphate, the solution is filtered off and evaporated. 3.0 g (63.5%) of a light yellow oil is obtained which is dissolved in 2 ml of ethanol, and 2 ml of ethanol containing 25% hydrogen chloride is added to the solution. The precipitated white 6-methyl-3-(methoxycarbonyl-methyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidine is filtered off. Melting point: 222°C.

Analysis:

Example IO

3.54 g (0.015 mol) of 3-(ethoxycarbonyl-methyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidine is dissolved in 5 ml of acetone, and 3.0 ml of methyl iodide is added to the solution. The solution is stirred and left for 5 days in a dark room. The precipitated crystalline product is filtered off and washed with acetone. 4.9 g (86.5%) of light yellow crystals are obtained, which melt at 150 - 153°C. After recrystallization from ethanol, the melting point of 3-(ethoxycarbonyl-

methyl )-1-methyl-4-oxo-6,7,8,9-t rahydro-4H-pyrido-[1,2-a]-pyrimidine iodide 154-155°C.

Analysis:

Example 11

2.18 g (0.01 mol) of 4-oxo-4H-pyrido-[1,2-a]-pyrimidine-3-(methyl-carbohydrazide) (m.p. 228 - 229°C) are dissolved in 700 ml of ethanol under heating, after which 10.0 g of a Raney nickel catalyst is added, and the reaction mixture is refluxed until the evolution of ammonia gas ceases (3 - 3.5 hours). The catalyst is filtered off, and the filtrate is evaporated. White, crystalline 3-(carbamoyl-methyl)-4-oxo-6,7,8>9-tetrahydro-4h-pyrido-[1,2-a]-pyrimidine is obtained. Melting point: 182 - 183°C after recrystallization from ethanol. Yield: 95%.

Analysis:

Example 12

1.6 g (6.5 mmol) of 6-methyl-4-oxo-6,7,8>9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidine-3-(methyl-carbohydrazide) is dissolved in 50 ml of ethanol in the presence of 10 g of Raney nickel catalyst. The reaction mixture is boiled under reflux for 2 hours, after which the catalyst is filtered off and the alcoholic filtrate is evaporated. 1.4 g of light yellow oil is obtained which is treated with 10 ml of ethanol containing 20% hydrogen chloride. The precipitated crystals are filtered off and dried. 1.15 g (68%) of 3-(carbamoyl-methyl)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidine- hydrochloride with melting point 235 - 236°C. The melting point remains unchanged after recrystallization from ethanol containing hydrogen chloride. Analysis:

Example 13

Preparation of starting materials:

A) 14.6 g (0.05 mol) of 2-[(5-methyl-2-pyridyl)-amino-methylene]-succinic acid diethyl ester is dissolved in 100 ml diphyllo oil at 130°C. The solution is heated to 250°C and stirred at this temperature. The ethanol formed is continuously evaporated from the reaction mixture. The calculated amount of alcohol can evaporate in 30 - 40 minutes. Preparation: the cooled reaction mixture is diluted with 10 ml of petroleum ether and extracted with 3 x 100 ml of 20% hydrochloric acid. After neutralization and extraction with benzene, the hydrochloric acid phase is obtained

5% 3-(ethoxycarbonyl-methyl)-4-oxo-7-methyl-4H-pyrido-[1,2-a]-pyrimidine phase. Yield: 50 - 55%. Melting point of the base after recrystallization from a double quantity of anhydrous alcohol: 128 - 130°C.

Ana light:

From the 20% hydrochloric acid phase, 1-(5-methyl-2-pyridyl)-3-ethoxycarbonyl-2-pyrrolin-5-one is prepared as described above. The product is recrystallized from an equal volume of alcohol. Yield: 25 - 28%. Melting point: 96 - 98°C.

Analysis:

B) When 2-[(3-methyl-2-pyridyl)-amino-methylene]-succinic acid diethyl ester is used as starting material in the above process, 3-(ethoxycarbonyl-methyl)-4-oxo-9-methyl-4H- pyrido-[1,2-a]-pyrimidine with melting point 88 - 90°C. C) When 2-(2-quinolyl-amino-methylene)-succinic acid diethyl ester is used as starting material, 3-(ethoxycarbonyl-methyl)-4-oxo-4H-pyrido-[1,2-a]-pyrimidine is obtained (m.p. . 121 - 122°C) in a yield of 60% (m.p. 121 - 122°C) and 1-(2-quinolyl)-3-ethoxycarbonyl-2-pyrrolin-5-one in a yield of 7% (m.p. .110 - 112°C).

D) 10.8 9 (0.1 mol) 2-amino-6-methyl-pyridine and 20.2 g

(0.1 mol) 2-formyl-succinic acid is dissolved in 150 ml diphyllo oil. The solution is stirred and heated to 250°C for 1 hour. First the water distills off and then the ethanol from the reaction mixture. After evaporation of the calculated amount of water and ethanol, the solution is cooled and treated according to the method described in example A). The product is purified by column chromatography (Merck silica gel: particle size: 0.063 - 0.125 mm). 3-(ethoxycarbonyl-methyl)-4-oxo-6-methyl-4H-pyrido-[1,2-a]-pyrimidine is obtained in a yield of 25%. Melting point 89 - 90°C (eluted with benzene).

Analysis:

In addition, 1-(6-methyl-2-pyridyl)-3-ethoxycarbonyl-3-pyrrolin-5-one is obtained in a yield of 15 - 20%. Melting point: 98 - 100°C. Analysis:

Claims (1)

Analogous procedure for the preparation of therapeutically active compounds with the formula: and salts and quaternary salts thereof, where R^ is hydrogen or C-^-C^-alkyl, R 2 is hydrogen or C 1 -C 4 alkyl; R 8 is carboxy or C 1 -C 8 alkoxycarbonyl, carbamoyl, phenyl-lower alkylcarbamoyl optionally substituted with one or two C 1 -C 4 alkoxy groups} or a carboxylic acid hydrazido group; and n is 1 or 2, characterized in that a compound with the formula: where R^, R^, R^ and n are as indicated above; is reduced, and optionally subjected to a thus obtained compound of formula i in order to obtain other meanings of R^, one or more of the following reactions: a) hydrolysis of an alkoxycarbonyl group to a carboxyl groupj b) reaction of an alkoxycarbonyl group with hydrazine to a carboxylic acid hydrazido group; c) transferring a carboxyl group to an alkoxycarbonyl group, preferably by treatment with an alcohol; d) transferring a carboxyl group to an acid amide by treatment with an amine; e) halogenation of a carboxylic acid group to an acid halide and transfer of the thus obtained acid halide to an ester by treatment with alcohol, or to an amide by treatment with an amine; and/or f) transfer of a compound of formula I to its salt or quaternary salt, or a salt of a compound of formula I is released from its salt.