CH521984A - Pyrids-pyrimidine medicaments - Google Patents

Abstract

Novel pyrido-pyrimidine derivs of formula: (where R is H, 1-5 C alkyl or Ph; R1 is 1-6 C alkyl, 3-6 C cycloalkyl, allyl, methallyl or propargyl; xy is the group -C(R2)=N-or -CHR2-NH- where R2 is phenyl or substituted phenyl of the formula: (where Y is fluorine, chlorine or bromine or 1-4C alkyl or alkoxy and Y is H, fluorine, chlorine or bromine or 1-4 C alkyl or alkoxy) have anti-inflammatory activity and are used in pharmaceutical compositions together with the usual carriers and are administered orally, enterally or parenterally. Specified compounds are 1-tert. butyl (or methyl, isopropyl, cyclopropyl, ethyl)-4-phenyl-1, 2-dihydro-pyrido 2,3-d pyrimidine-2-one, 1-isopropyl (or cyclopropyl)-4-phenyl-1,2,3,4-tetra hydro-pyrido- 2,3-d pyrimidine-2-one, 1-siopropyl-7-methyl-4-phenyl- 1,2-dihydro-pyrido- 2,3,-d pyrimidine-2-one-and 1-isopropyl-4, 6-diphenyl-1,2-dihydro-pyrido 2,3-d pyrimidine-2-one.

Description

  

  Process for the preparation of 4-phenyl-1,2,3,4-tetra-hydropyrido [2,3-d] pyrimidin-2-ones The invention relates to a process for the preparation of 4-phenyl-1,2,3, 4-tetrahydropyrido [2,3-d] pyrimidin-2-ones of the formula I,
EMI0001.0002
    where R is hydrogen or alkyl with 1-5 carbon atoms, R1 is alkyl with 1-6 atoms, cycloalkyl with 3-6 carbon atoms, allyl, methallyl or propargyl and R2 is phenyl or a group of the formula II
EMI0001.0005
    denotes where Y denotes fluorine, chlorine, bromine, alkyl or alkoxy each with 1-4 carbon atoms and Y1 denotes hydrogen, fluorine, chlorine, bromine, alkyl or alkoxy each with 1-4 carbon atoms.



  The inventive method is characterized in that compounds of the formula III
EMI0001.0006
    reduced in an inert organic solvent. The reduction can be carried out, for example, with the aid of a borohydride, preferably an alkali borohydride such as sodium borohydride, furthermore with lithium aluminum hydride, or by hydrogenation in the presence of Raney nickel, platinum or palladium. The solvent used is suitably a lower aliphatic alcohol such as methanol or ethanol, but in particular, ethanol, or a cyclic ether such as tetrahydrofuran.

   If necessary, other solvents such as methylene chloride, chloroform or water can also be used. If compounds of the formula I are to be prepared in which R represents an unsaturated group, it is advantageous to use an alkali borohydride as the reducing agent. Here, the ring double bond is hydrogenated without changing the unsaturated side group. A range from -20 to +80 ° C. is expediently used as the reduction temperature. When using a borohydride, it is advantageous to carry out the reduction at temperatures between 10 and 80 ° C., preferably 20-4.0 ° C.

    A reduction with lithium aluminum hydride is preferably carried out at temperatures between -20 and +80 C, preferably between +15 and +70 C. About one equivalency of the lithium aluminum hydride is usually used here. The catalytic hydrogenation is conveniently carried out at temperatures between 15 and 60 ° C., preferably between 20 and 50 ° C., preferably between 20 and 50 ° C. The hydrogen pressure should be between 1 and 10 atmospheres, palladium is the preferred catalyst.



  The compounds of the formula I are isolated and purified from the reaction mixtures in a manner known per se.



  The starting materials of the formula III can be obtained by adding compounds of the formula IV,
EMI0002.0000
    where R, R1 and R2 have the above meaning, reacts with carboxylic acid derivatives.



  Suitable carboxylic acid derivatives for reaction with compounds of the formula IV can be either a) phosgene or b) a 1,1'-carbanyldiimidazole. a) Compounds of the formula IV are conveniently dissolved in an inert organic solvent, for example an aromatic hydrocarbon such as benzene, toluene or xylene, but preferably benzene, and the resulting solution, if appropriate in the presence of an acid-binding agent such as sodium or potassium carbonate or a tert.

   Amine, such as trialkylamine or pyridine, but preferably triethylamine, at temperatures between 0 and 50 C, but preferably between 10 and 3 (YC, mixed with a solution of phosgene in the same or a different inert organic solvent The molar ratio between compounds of the formula IV and phosgene is not critical, but it is beneficial to use an excess of phosgene, since this gives higher yields of the end product.



  b) The reaction of compounds of the formula IV with 1,1'-carbonyldümidazal is conveniently carried out in an inert organic solvent, for example an aromatic hydrocarbon such as benzene, toluene or xylene, or a cyclic ether such as tetrahydrofuran. The reaction can be carried out at room temperature or at elevated temperatures of up to 120 ° C., although reaction temperatures between 60 and 90 ° C. are preferred. The molar ratio of 1,1'-carbonyldümidazole to compounds of the formula IV is not critical, but it is advantageous to use an excess of 1,1'-carbonyldümidazole.



  The starting materials of the formula IV can be obtained by adding compounds of the formula V,
EMI0002.0007
    where R and R1 have the above meaning, with compounds of the formula IV, R 2Q VI where R2 has the above meaning and Q is lithium or an -MgX group, where X is chlorine, bromine or iodine, and the reaction product then hydrolyzed.



  The reaction of compounds of the formula V with compounds of the formula VI is preferably carried out in an inert organic solvent, for example a straight-chain or cyclic ether such as diethyl ether, dioxane or tetrahydrofuran, but preferably in one of the cyclic ethers mentioned. The reaction temperature should be between 20 and 100.degree. C., preferably between 40 and 80.degree.



  An aryl magnesium bromide is preferably used as the compound of the formula VI. However, if compounds of the formula IV are to be prepared which carry alkyl in positions 4 and 6 of the ring, it is advantageous to use aryl lithium compounds as compounds of the formula VI. The reaction time should be between 3 and 15 minutes, preferably between 5 and 12 minutes, and the reaction should be started at room temperature. The subsequent hydrolysis should expediently take place in an alkaline medium in a manner known per se.



  Compounds of the formula V can be obtained by adding compounds of the formula VII,
EMI0002.0011
    in which R has the above meaning with compounds of the formula VIII, R1NH2 VI? I in which R1 has the above meaning, reacted.



  The reaction of compounds of the formula VII with compounds of the formula VIII is expediently carried out at an elevated temperature, but in particular at a temperature between 100 and 150.degree. An inert organic solvent or an excess of compounds of the formula VIII is suitable as the reaction medium. The compounds of the formula V obtained according to the process can be isolated from the reaction mixture in a manner known per se and, if necessary, subsequently purified in a manner known per se.



  The compounds of the formula IV obtained can be isolated and purified in a manner known per se.



  The compounds of the formula VII are either known or can be prepared from known starting compounds by known processes (Org Synth., Col.Vol. IV, pp. 166 and 704 ff and J.Am.Chem.Soc. 69, 2574). Compounds of the formula VII in which R in position 4 or 6 of the ring is alkyl can preferably be obtained by reacting corresponding 3-cyanopyridines with phosphorus oxychloride in the absence of significant proportions of phosphorus pentachloride.



  The compounds of the formula I according to the invention have extraordinarily favorable pharmacodynamic properties. In particular, they are characterized by an anti-inflammatory effect. The amount to be administered daily should be between 25 and 1000 mg, which is preferably used in several (2-4.) Daily doses of 9-500 mg or in sustained-release form.



  The compounds prepared according to the invention can be used as medicaments alone or in appropriate medicament forms for oral or parenteral administration. Oral administration can be in the form of tablets, capsules, elixirs, suspensions or solutions and parenteral administration in the form of injection solutions or suspensions.



  A preferred tablet composition consists of 50 parts of 1-isopropyl-4-phenyl-1,2,3,4-tetrahydropyrido- [2,3-d] pyrimidin-2-one, 2 parts of tragacanth, 39.5 parts of lactose, 5 Parts of corn starch, 3 parts of talc and 0.5 part of magnesium stearate.



  Of the compounds of the formula I, those which contain an isopropyl group in the 1 position are preferred.



  <I> Example 1 </I> 1-Isopropyl-4-phenyl-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidin-2-one a) 2-isopropylamino-nicotinonitrile A solution of 15 g 2-Chloro-nicotinonitrile in 75 ml of isopropylamine is heated to 130-140 ° C. in an autoclave for 4 hours. The mixture is then cooled, placed in a flask together with chloroform and evaporated to dryness therein. The residue is dissolved in chloroform, the solution is extracted twice with water, the organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in 100 ml of pentane and kept at 0 ° C. for 17 hours, the 2-isopropylaminonicotinonitrile having a melting point of 50 ° -55 ° C. crystallizing out.



  b) 3- (2-Isopropylamino) pyridyl-phenyl-ketoneimine A solution of phenylmagnesium bromide in tetrahydrofuran is added (prepared from 9.0 g magnesium and 59 g bromobenzene in 150 ml tetrahydrofuran). The resulting mixture is refluxed for 24 hours, then cooled and poured onto 1 kg of ice. The resulting mixture is extracted three times with methylene chloride, the organic phases are combined, washed with water, dried over sodium sulfate and evaporated in vacuo, the 3- (2-isopropylamino) pyridyl-phenyl-ketone imine being obtained.



  c) 1-Isopropyl-4-phenyl-1,2-dihydropyrido [2,3-d] -pyrimidin-2-one To a solution of 32 g of 3- (2-isopropylamino) pyridylphenyl-ketoneimine and 60 ml of triethylamine in 600 ml of benzene are given 183 ml of a 12.5% oigen Phos gene solution in benzene. After a few minutes a yellow precipitate is obtained and the mixture is stirred for 30 minutes. The precipitate is then filtered off, washed with benzene, dissolved in methylene chloride and the solution extracted once with 50 ml of an aqueous 2N sodium hydroxide solution and three times with water.

   The solution is then dried over sodium sulfate and evaporated in vacuo to give a crude product which is recrystallized twice from methylene chloride / diethyl ether, a 1.-isopropyl-4-phenyl-1,2-dihydropyrido [2, 3-d] pyrimidin-2-one of melting point 193-195 ° C. is obtained. An additional end product is obtained when the benzene wash solution is worked up.



  d) 1-Isopropyl-4-phenyl-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidin-2-one A solution of 2.65 g of 1-isopropyl-4-phenyl-1,2- dihydropyrido [2,3-d] pyrimidine-2-one in 50 ml of 95% ethanol is stirred and 2.0 g of sodium borohydride are added in portions. The mixture is then stirred for 3 hours at room temperature, 200 ml of water are added, a precipitate which is filtered off, washed with water and dried at 50 ° C. (0.5 mm Hg). The crude product obtained is recrystallized from methylene chloride / ether (1: 1), the 1-isopropyl-4-phenyl-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidin-2-one being dated M.p. 148-150 ° C.



  <I> Example 2 </I> 1-Cyclopropyl-4-phenyl-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidin-2-one Analogous to the method described in Example 1 and using from 1-cyclopropyl-4-phenyl-1,2-dihydropyrido [2,3-d] pyrimidin-2-one in approximately equivalent amounts, the title compound is obtained after crystallization from methanol / pentane with a melting point of 179-181 'C.



  <I> Example 3 </I> 1-Isopropyl-4-phenyl-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidin-2-one 3 g of lithium aluminum hydride powder are suspended in 100 ml of dry tetrahydrofuran and this A slurry of 10 g of 1-isopropyl-4-phenyl-1,2-dihydropyrido [2,3-d] pyrimidine-2-one in 300 ml of warm tetrahydrofuran was added to the suspension with stirring over a period of 30 minutes.

   The mixture is then refluxed for 4 hours and then left to stand for 17 hours. Excess lithium aluminum hydride is decomposed by the dropwise addition of 50 ml of 6N hydrochloric acid with cooling. The mixture obtained is filtered off and the filtrate is evaporated to remove the organic solvent. The oily mixture obtained is purified by chromatography by filtering through a short silica gel acid. The eluent used is a 6: 1 mixture of benzene and chloroform.

    The first fractions contain the desired 1-isopropyl-4-phenyl-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidin-2-one with a melting point of 148-150 C.

 

Claims (1)

PATENT CLAIM Process for the preparation of 4-phenyl-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidin-2-ones of the formula I, EMI0004.0014 where R is hydrogen or alkyl with 1-5 carbon atoms, R1 is alkyl with 1-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, allyl, methallyl or propargyl and R2 is phenyl or a group of the formula II EMI0004.0015 means where Y is fluorine, chlorine, bromine, alkyl or alkoxy each with 1-4 carbon atoms and Y1 hydrogen, fluorine, chlorine, bromine, alkyl or alkoxy each with 1-4 carbon atoms, characterized in that compounds of Formula III EMI0004.0017 reduced in an inert organic solvent.