DE2745320A1 - 5-Alkoxyphenyl-oxazolidine-2-one and sulphur analogues - useful as neuroleptics and phospho-di:esterase inhibitors - Google Patents

Abstract

Oxazolidinone derivs. of formula (I) and their thio analogues are new. In the formula, R1 is lower alkyl or cycloalkyl; R2 is H, lower alkyl, cycloalkyl, aryl, aralkyl, alkenyl or heterocyclyl; R3 is H, lower alkyl, alkenyl, alkynyl, aryl, aralkyl or acyl; R4 is H or lower alkyl; R5 is lower alkyl, lower alkoxycarbonyl or H; and X is O or S. They are prepd. e.g. by reacting O=CX'Y (or thio analogue) with an appropriate 2-amino-1-phenylethanol (X' and Y = Cl, Br, imidazolyl or OR;R = alkyl, aryl or aralkyl or together 2R are alkylene). (I) have CNS depressant, antidopaminergic, antinociceptive and anticonvulsant activities but have reduced extrapyramidal side effects compared with usual neuroleptics. They also inhibit phosphodiesterases (modify cyclic nucleotide metabolism) so are useful in treating proliferative and immunological disorders such as psoriasis and bronchial asthma. A typical cpd. is 5-(3-benzyloxy-4-methoxyphenyl)-oxazolidin-2-one.

Description

5- (noun phenyl) -oxazolidinones and their sulfur

analogs and processes for their preparation II In the main patent (patent application P 26 55 369.5) new 5- (subst. phenyl) -oxAzolidinones and their sulfur analogs of the general formula I R1 is lower alkyl or cycloalkyl, R2 is hydrogen, lower alkyl, cycloalkyl, aryl, aralkyl or alkenyl, R3 is hydrogen, lower alkyl, alkenyl, alkynyl, aryl, aralkyl or acyl, R4 is hydrogen or lower alkyl and X is oxygen or sulfur, and a process for them Manufacture described.

The compounds of the general formula I are asymmetrical Carbon atom and can therefore be used both as racemates and as optical antipodes are present.

Lower alkyl is understood to mean alkyl groups with up to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Pentyl, 2-methylbutyl, 2,2-dimethylpropyl and hexyl. Alkenyl and alkynyl groups are 7r.B. 1-propenyl, 2-propenyl, 3-methyl-2-propenyl, vinyl and propargyl.

The lower alkyl groups can also be substituted one or more times be, for example by halogen, especially fluorine, chlorine and bromine. Examples for halogen-substituted alkyl groups are 2-chloroethyl, 3-chloropropyl, 4-bromobutyl, Difluoromethyl, trifluoromethyl, 1,1,2-trifluoro-2-chloroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 1,1,1,3,3,3-hexafluoro-2-propyl. As a substituent of Alkyl groups can also be hydroxy groups, for example as 2-hydroxyethyl or 3-hydroxypropyl, carboxy groups, for example as carboxymethyl or carboxyethyl, Alkoxy groups, where each alkoxy group can contain 1 to 5 carbon atoms, for example as ethoxymethyl, isopropoxymethyl, 2-methoxyethyl, 2-isopropoxyethyl, 2-butoxyethyl, 2-isobutoxyethyl, 3-pentoxypropyl. The alkoxy groups but can also be ring-closed (cyclic ether residues), such as the 3-tetrahydropyranyl residue.

The lower alkyl groups can also be terminally substituted with amino groups, in which the nitrogen is optionally replaced by alkyl groups preferably 1 to 5 carbon atoms can be mono- or disubstituted or a component a 4- to 7-membered ring. Examples of N-substituted alkyl groups are aminomethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 3-dimethylaminopropyl, 3-thylmethylaminopropyl, pyrrolidino, piperidino, N-methylpiperazino, Hexamethyleneimino, etc.

Cycloalkyl or cycloalkyl-alkyl groups preferably contain 3 up to 7 carbon atoms. Preferred are the cyclopropyl, cyclopropylmethyl, cyclopentyl and cyclohexyl groups.

Particularly suitable aryl or aralkyl groups are the phenyl and the Benzyl group in question, which is optionally substituted in a manner known per se could be.

All residues of physiologically compatible ones come as acyl Carboxylic acids in question. Preferred are those which differ from alkanoic acids with 1-18 Carbon atoms, preferably 2-8 carbon atoms, derive, such as monobasic alkanoic acids such as formic acid, acetic, propionic, butyric, Isobutter, a-ethylbutter, pivaline, valerian, isovalerian, a-ethylvalerian, Trimethylacetic, 2-methylbutter, 3-ethylbutter, Capron, triethylacetic, Gnanth- or caprylic acid, or cyclic acids, preferably cycloaliphatic acids, like the Cyclopropylidenessig-, Cyclobutylcarbon-, Cyclopentylcarbon-, Cyclopentylessig-, ß-Cyclopentylpropionic, cyclohexylcarbonic or cyclohexyl acetic acid or also carbocyclic acid Aryl or aralkyl acids such as benzoic, 2-, 3- or 4-methylbenzoic acid.

Since the chemical character of the acyl group for the properties of the Compounds according to the invention is not critical as long as the acyl group is not has a toxic effect, other aliphatic and aromatic are unsubstituted and substituted, mono-, di- and polybasic carboxylic acids, saturated and unsaturated aliphatic, araliphatic and aromatic carboxylic acids with up to 18 carbon atoms, preferably up to 8 carbon atoms, suitable.

Examples include the undecyl, dodecane, tetradecane, Hexadecane, octadecane, palmitic, stearic and ß-cyclohexylpropionic acid, 2.3-, 2.4-, 2.6-, 3.4- and 3.5-dimethylbenzoic, ethylbenzoic, naphthoic, 3-methyl-a-naphthoic, ß-phenylpropionic, diphenylacetic and α-naphthylacetic or carbamic acids such as the carbamine, phenylcarbamine, n-butylcarbamine, dimethylcarbamine, diethylcarbamine and Ällophansäure or heterocyclic acids such as the ß-furyl carbon, pyrrole carbon, ß-pyrrolidinopropion-, N-methylpyrrolidino-2-carbon-, 6-hydroxy-indolyl-3-acetic, N-methylmorpholino-2-carboxylic and pyrrole-2-carboxylic acids. The acyl residues can also be substituted one or more times. The following are examples of substituents Rests called: Hydroxy, Aralkoxy, Halo, Alkoxy, gAcyloxy, Sulfonyloxy, Amido, Sulfato, Nitro, mercapto and cyano, such as in the acyl residues of Glgvol, milk, lemon, Tartaric, maleic, glyceric, mannonic, gluconic and salicylic acid or acyl residues of Amino acids such as glycine, aminopropionic, diglycol amino and triglycol amino acids, methylglycine, Dimethylglycine, diethylglycine. The acyl residues of the p-aminosalicylic, p-aminobenzoic, ethyl mercaptoacetic, benzyl mercaptoacetic, chloroacetic, fluoroacetic, Trichloroacetic, trifluoroacetic, thioglycol, m-nitrobenzoic, 2,3,4-trimethoxybene zoic, phenoxyacetic and α-naphthyloxyacetic acids. Also mentioned are the alkoxylated and aralkoxylated acyl radicals of formic acid ie e.g. carbethoxy and Carbobenzyloxy.

In a further development of this invention it has now been found that 5- (3.4-Subst. phenyl) -oxazolidinones are particularly good biologically effective, even if the 4-position on the oxazolidine ring is substituted.

The present invention thus relates to a further embodiment of the invention according to the main patent (patent application P 26 55 369.5) new 5- (sub-phenyl) -4-R5-oxazolidinones of the general formula IV in which R1 4 and X have the meaning given in formula I and R stands for lower alkyl or lower alkoxycarbonyl.

5 Under lower alkyl or lower alkoxy are groups with up to to 6 carbon atoms, as already mentioned above.

The compounds of the general formula IV according to the invention have valuable pharmacological properties. They show central depressive, antidopaminergic, antinociceptive and anticonvulsant Effects and thus have a some resemblance to neuroleptics such as chlorpromazine or ilaloperidol. The invention However, compounds differ from classic neuroleptics in one different influencing of receptor-dependent, monoaminergic feedback mechanisms (Reduction of extrapyramidal side effects).

In addition, the compounds according to the invention have strong phosphodiesterase inhibitors Properties and thus influence the metabolism of cyclic nucleotides. There controlled cell growth is decisively regulated by cyclic nucleotides (Pastan et al., 1975) and cyclic nucleotides in uncontrolled proliferating tissue z. T. are reduced (Ryan and Heidrick, 1974, Voorhees et al., 1974), are suitable the compounds for the treatment of hyperproliferative and uncontrolled cell growth associated diseases such as psoriasis, polycythemia vera, neuroblastoma, immunological diseases such as bronchial asthma and thromboembolic diseases, who have a disturbance in the metabolism of cyclic nucleotides (Tateson, J.E .; Trist, D.G. Inhibition of adenosine-3 ', 5'-cyclic monophosphate phosphodiesterase by potential antiallergic compounds in Life Sci. 18: 153-162, 1976; De Gaetano, G.

Pharmacology of platelet aggregation; Pharmacol. Res. Commun.

7, 301-309, 1975).

Due to the effects described, the inventive Compounds in the form of pharmaceutical preparations for treating the aforesaid Diseases are applied.

The preparations are made with those for enteral or parenteral administration, usual carriers, such as water, alcohol, Gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable Oils, polyalkylene glycol, etc. The preparations can be in solid form as tablets, capsules, Dragees, suppositories or in liquid form as solutions, suspensions or emulsions are present.

The invention also relates to a process for the preparation of compounds of the formula IV according to the main patent (patent application P 26 55 369.5) by a known conversion of 2-knino-1- (3.ls-disubst. Phenyl) -4-R - Ethanols 5 of the general formula V 11 5 have the meaning given above, with a carbon 1-5 acid or thiocarbonic acid derivative of the general formula III X and Y stand for OR, chlorine1 bromine or imidazole (with R meaning alkyl1 aryl1 aralkyl and together as alkylene), in an inert solvent in the heat in the presence of a basic catalyst and, if necessary, the cleavage of an araliphatic ether group that is present Raney nickel or with a noble metal catalyst or alkylation of a free hydroxy group or exchange of the ring oxygen and / or the oxygen of the 2-carbonyl group for sulfur or, if R3 is hydrogen, N-acylation or N-alkylation.

The ring closure reaction in compounds of the formula V can per se with all carbonic acid or thick carbon acid derivatives of the general formula III are executed. R can be the same or different. So it means lower Alkyl or aralkyl such as methyl, ethyl and benzyl. R can also be an alkylene radical, such as propylene or iso-butylene.

The solvents used are expediently over against the Reactants inert. Ethers such as diethyl ether and glycol dimethyl ether may be mentioned, for example or diethylene glycol dimethyl ether, aliphatic and aromatic hydrocarbons such as dioxane, benzene, toluene, xylene and mesitylene, but also alcohols such as methanol, Ethanol, propanol, butanol and dimethyl sulfoxide, glycol monomethyl ether and diethylene glycol monomethyl ether.

The reaction is expediently carried out in the heat.

The temperature should be above room temperature and range up to to the boiling point of the reaction mixture, the temperature range 60-2000, preferably 100-1600C is applied.

The cyclization reaction is carried out in the presence of a basic catalyst executed. Suitable basic catalysts are alkali metal and alkaline earth metal carbonates and especially alcoholates such as sodium methylate and potassium carbonate. Are suitable but also organic bases such as pyridine, triethylamine, alkali metal and alkaline earth metal hydroxides such as sodium hydroxide, especially Y in the event that X4I is halogen. For the Case that X and Y are halogen, such as. B. chlorine, the addition of a basic Catalyst is also omitted. When X and Y are imidazole residues will preferably worked at room temperature, the solvent being dimethylformamide, Tetrahydrofuran, methylene chloride are suitable. The possibly subsequent reductive An araliphatic ether group, such as the benzyl group, is split off with all common metal catalysts, such as platinum, palladium, rhodium or nickel, both in pure form and on carrier materials such as carbon, calcium carbonate and barium sulfate. As a solution, all those can be used that are opposite the reducing agents are inert under the conditions according to the invention. Called for example organic acids such as acetic acid and propionic acid are lower Alcohols such as methanol and ethanol, esters such as ethyl acetate, aliphatic, cycloaliphatic and aromatic hydrocarbons such as hexane, cyclohexane and benzene.

The possibly subsequent O-alkylation (R3 means hydrogen) is also carried out according to methods known per se. Alkylation is preferred carried out with the corresponding R3 halide, mesylate or tosylate. As halides the chlorides, bromides and iodides are suitable. The hydroxy compound is used for the alkylation of the formula V, for example, dissolved in a polar solvent and in the presence a base with the alkylating agent heated to temperatures between 30 and 1500C. as Bases are, for example, sodium hydride, potassium carbonate, alkali alcoholates, such as sodium ethylate, potassium butylate and potassium tert-butylate, are suitable. As a solvent come dimethylformamide, dimethylacetamide, hexamethylphosphoric acid triamide, acetonitrile, Dimethyl sulfoxide, tetrahydrofuran, dioxane, ketones such as acetone and methyl isobutyl ketone, as well as alcohols such as ethanol, butanol and tert-butanol in question.

The exchange of carbonyl oxygen or ring oxygen in Compounds of the formula IV against sulfur is such as by methods known per se z. B. after Scheeren et al. Synthesis 1973, 149 carried out.

For example, a polysulfide such as phosphorus pentasulfide is suitable for this purpose in a solvent or solvent mix in the presence of a base. The reaction can also be carried out in a suspension. Suitable solution or suspension agents are, for example, acetonitrile, tetrahydrofuran, diethyl ether, Glycol dimethyl ether and pyridine. The bases are sodium hydrogen carbonate, potassium carbonate etc. suitable. At 30 to 120 ° C., the reaction is complete after about 3 to 24 hours.

Any subsequent N-acylation or N-alkylation (R3 = H) is also carried out according to methods known per se. So will the Amino compound dissolved in a polar solvent and in the presence of a salt former with an alkyl or aryl or. Acyl halide or acyl anhydride to 40 to 150 ° C heated.

As polar solvents, dimethylformamide, dimethylacetamide, Detrahydrofuran, dioxane, and alcohols such as ethanol and butanol can be used. Suitable salt formers are, for example, sodium hydride, potassium carbonate, alkali alcoholates, such as sodium ethylate, kallum-tert. butylate, etc. The reaction with haloaryl, for example Iodobenzene, can also be used without a solvent, preferably in the presence of copper powder, be performed.

The following examples are intended to explain the invention.

Example 1 5- (3,4-Dimethoxyphenyl) -4-methyl-2-oxazolidininone 5.5 mmol 2-Amino-1- (3.4-dimethoxyphenyl) propanol are dissolved in 50 ml of Chlorofor and mixed with 1.05 g (6.5 mmol) of carbonyldiimidazole were stirred for 2 hours with exclusion of moisture.

After standing overnight, 50 ml of distilled water are added extracted, dried, filtered and concentrated.

After the residue has been chromatographed over 50 S silica gel with chloroform / methanol (95: 5) is obtained as a mobile phase and crystallization from ethyl acetate / petroleum ether one in 24% yield 5- (3,4-dimethoxyphenyl) -4-methyl-2-oxazolidinone of melting point 98-99 ° C.

The starting material 2-amino-1- (3,4-dimethoxy) propanol was as prepared as follows: To 100 mM 3,4-dimethoxypropiophenone in 160 ml of methylene chloride 10 ml of sulfuryl chloride in 80 ml of methylene chloride are added dropwise at room temperature added. The mixture is then stirred for a further 3.5 hours at room temperature. To Removal of the solvent and recrystallization of the residue from cyclohexane / petroleum ether 2'-chloro-3,4-dimethoxypropiophenone is obtained from the melting point in 89% yield 56-57 ° C.

43.86 mM each of 2'-chloro-3,4-dimethoxypropiophenone dissolved in 230 ml of acetone, with 437 mg potassium iodide and 87.72 ml dibenzylamine under Exclusion of moisture stirred for 7 days. The batch is made up of 1 1 solution with diethyl ether diluted, filtered and concentrated. The residue is drawn up on silica gel and the silica gel first stirred with chloroform and then with ethanol and sucked off. The chloroform phase is over 500 S silica gel with chloroform chromatographed as the mobile phase and gives 2'-N, N-dibenzylamino- 3. 4- dirne thoxypropiophenone as 01.

12.39 g (31.8 mmol) of 2'-N, N-dibenzylamino-3,4-dimethoxypropiophenone are dissolved in 75 ml of isopropanol and treated with 1133 g (35.05 mmol) of sodium boronate. After stirring for 1 hour at room temperature, the mixture is refluxed for 2 hours. To When it cools, the batch is filtered off with suction and the residue is boiled with ethyl acetate. After filtration, 2 '- (N, N-dibenzylamino) -1- (3,4-dimethoxyphenyl) propanol crystallizes from the filtrate in a yield of 59% from a melting point of 151-152 ° C.

1312 mmol of the dibenzyl compound are in 50 ril ethanol p.a. with 2.64 g of palladium / carbon (10%) for 3 hours at 90 ° C. under a 10 atm. Hydrogen atmosphere hydrogenated. After suctioning off, it is concentrated and recrystallized from ethanol. That makes 2-Alnillo-1- (3,4-dimethoxyphenyl) propanol with a melting point of 64% yield 131-132 OC.

Example 2 5- (3,4-Dimethoxyphenyl) -2-oxo-oxazolidine-4-carboxylic acid ethyl ester 6 mmol of 2-amino-4- (3,4-dimethoxyphenyl) -3-hydroxypropionic acid ethyl ester with 12 mEI carbonyldiimidazole in 60 ml chloroform for 4 hours at room temperature stirred with exclusion of moisture. It is then used 1 time against 50 ml of water extracted, dried over silica gel overnight, filtered and concentrated.

The residue is over 130 g of silica gel with chloroform / methanol (90:10) chromatographed as the eluent. Recrystallization from ethyl acetate / ethanol gives 5- (3,4-dimethoxyphenyl) -2-oxooxazolidine-4-carboxylic acid ethyl in 34% yield esters of melting point 188-189 OC.

The starting material is ethyl 2-amino-4- (3,4-dimethoxyphenyl) -3 hydroxy-propionate was prepared as follows: 44.37 mmol of ethyl 3,4-dimethoxyglycidate (prepared according to W.Schneider et al., Arch. Pharm. 299, 817 (1966)) with 97.61 ml of dibenzylamine refluxed in 100 ml of ethanol for 4.5 hours with exclusion of moisture. After standing for 3 days at room temperature, the batch is concentrated and the Residue over 400 g of silica gel with chloroform / ethanol (98: 2) as the eluent chromatographed. Repeated Chromatography of the corresponding Combined fractions yields 2-N, N-dibenzyl-4- (3,4-dimethoxyphenyl) -3-hydroxypropionic acid ethyl ester as an oil in 89% yield.

22.2 mmoles of 2-N, N-dibenzylamino-4- (3,4-dimethoxyphenyl) -3-hydroxypropionic acid ethyl ester are with 4.44 g of palladium / carbon 10% in 100 ml of non-gelled ethanol for 3 hours hydrogenated at 90 ° C under 10 atii of hydrogen pressure. After filtering off the catalyst is narrowed. Recrystallization from undenatured ethanol gives a yield of 80% 2-Amino-4- (3,4-dimethoxyphenyl) -3-hydroxypropionic acid ethyl ester of melting point 211-212 OC (decomposition).

Claims (5)

Claims Further development of the process according to the main patent (patent application P 26 55 369.5) for the production of 5- (subst. Phenyl) -oxazolidinones and their sulfur analogues of the general formula IV R1 lower alkyl or cycloalkyl, n2 hydrogen, lower alkyl1 cycloalkyl, aryl, aralkyl or alkenyl, n hydrogen, lower alkyl, alkenyl, alkynyl, aryl, 3 aralkyl or acyl, R4 hydrogen or lower alkyl and R5 lower alkyl and lower alkoxycarbonyl and X oxygen or sulfur, characterized in that 2-amino-1- (3,4-disubst. phenyl) ethanols of the general formula V are used in a manner known per se R1-5 have the meaning given above, with a carbonic acid or thick carbonic acid derivative of the general formula III X and Y stand for OR, chlorine, bromine or imidazole (with R in the meaning of alkyl, aryl, aralkyl and together as alkylene), reacted in an inert solvent in the heat in the presence of a basic catalyst and optionally followed by a present araliphatic ether group is split off reductively with Raney nickel or with a noble metal catalyst or a free hydroxyl group is alkylated or the ring oxygen and / or oxygen and / or oxygen of the 2-carbonyl group is exchanged for sulfur or if 113 is hydrogen, N-acylated or N- alkylated. 2. 5- (Subst. Phenyl) -oxazolidinones and their sulfur analogues of the general formula V R1 lower alkyl or cycloalkyl, R2 hydrogen, lower alkyl, cycloalkyl, aryl, aralkyl, alkenyl or heterocyclic radicals, R hydrogen, lower alkyl, aryl, aralkyl or acyl, 3 R4 hydrogen or lower alkyl, R lower alkyl and lower alkoxycarbonyl and 5 X oxygen or sulfur. 3. 5- (3,4-Dimethoxyphenyl) -4-methyl-2-oxazolidinone 4. 5- (3. 4-Dimethoxyphenyl) -2-oxazolidinone-4-carboxylic acid ethyl ester 5. Medicaments based on compounds according to claims 2-4.