IE46435B1 - 5-(substituted phenyl)-oxazolidinones and sulphur analogues thereof and also a process for their production - Google Patents

Abstract

Novel 5-(subst. phenyl)-oxazolidinones and their sulphur analogs of the general formula I in which the substituents are defined in Claim 1, are obtained by reacting 2-amino-1(3,4-disubst. phenyl)-ethanols with a carbonic acid derivative or a thiocarbonic acid derivative in an inert solvent while heating in the presence of a basic catalyst. The novel compounds of the general formula I possess valuable pharmacological properties. They exhibit antidopaminergic, antinociceptive and anticonvulsive effects and have a depressant action on the central nervous system and thus have a certain similarity to neuroleptic agents such as chlorpromazine or haloperidol. In addition, the novel compounds possess strong phosphodiesterase-inhibiting properties and thus affect the metabolism of cyclic nucleotides. The compounds are also suitable for treating hyperproliferative diseases and diseases associated with uncontrolled cell growth.

Description

The present invention provides 5-(substituted phenyl)oxazolidinones and sulphur analogues thereof of the general formula (I) in which R.j represents a substituted or unsubstituted lower alkyl, cycloakyl or cycloalkylalkyl radical, Rg represents hydrogen or a substituted or unsubstituted lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, alkenyl or heterocyclic radical, Ιθ R3 represents hydrogen or a substituted or unsubstituted lower alkyl, alkenyl, alkynyl, aryl, aralkyl or acyl radical, - 2 -afcd; represents hydrogen or a substituted or unsubstiuted 1ower alkyl radical, Rg represents hydrogen, or a substituted or unsubstituted lower alkyl or lowe* alkoxycarbonyl radical, and X represents oxygen or sulphur, and the two X moieties may be the same or different.

The compounds of the general formula (I) have an asymmetrical carbon atom and can therefore exist both as racemates and also as optical antipodes.

Substituents of the radicals represented by R-| to may be halogen, nydroxy, alkoxy, carboxyl, alkyl, amino, substituted amino and cyclic ether groups. One or more substituents may be present in each radical.

By the term “lower alkyl radicals there is meant herein alkyl radicals containing up to 6 carbon atoms.

There may be mentioned, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary-butyl, pentyl, 2-methylbutyl, 2,2-dimethylpropyl and hexyl groups. Alkenyl and alkynyl groups are, for exampla, 1-propenyl, 2-propenyl, 3-methyl-2-propenyl, vinyl and propargyl groups. The lower alkyl radicals may be substituted one or more times, for example, by halogen, especially fluorine, chlorine and bromine. Examples of halogen-substituted alkyi grouos are 2-chloroeihy1, 3-chioropropyl, 1-b-Oir.chi'! y!, di f 1 uoronethy 1. trifluoromethyl, 1,1 ,2-trifluoro-2-chlorcethyl, 3,3,3-trif1uoropropyl, 2,2,3,3,3-pentaf1uoropropy1, 1,1,1,3,3,3-hexafluoro4 6 4 3 5 2-propyl. As substituted alkyl radicals there also come into consideration hydroxyl-substituted alkyl radicals such, for example, as 2-hydroxyethyl and 3hydroxypropyl groups, carboxyl-substituted alkyl radicals such, for example, as carboxymethyl and carboxyethyl groups, alkoxy-substituted alkyl radicals, in which each alkoxy group may contain 1 to 5 carbon atoms such, for example, as ethoxymethyl, isopropoxymethyl, 2methoxyethyl, 2-isopropoxyethyl, 2-butoxyethyl, 210 isobutoxyethyl and 3-pentoxypropyl groups. The substituent may also be a cyclic group containing oxygen (a cyclic ether radical) such, for example, as the 3tetrahydropyranyl radical.

The lower alkyl radicals may also be substituted terminally by amino groups, of which the nitrogen may be mono- or di-substituted by alkyl groups having preferably 1 to 5 carbon atoms or may be a member of a 4- to 7-membered ring which may contain other nitrogen atoms. Examples of N-substituted alkyl groups are aminomethyl, 2-methylami noethyl, 2-dimethylaminoethyl-, 2-diethylaminoethyl, 3-dimethylaminopropyl, 3-ethylmethylaminopropyl, pyrrolidino, piperidino, N-methyl-piperazino and hexamethylene-imino groups.

Cycloalkyl and cycloalkylalkyl groups perferably contain 3 to 7 carbon atoms. There may be mentioned, more especially cyclopropyl, cyclopropylmethyl, cyclopentyl and cyclohexyl groups.

A643 As aryl or aralkyl groups there come into consideration more especially unsubstituted and substituted phenyl and benzyl groups.

As acyl radicals there come into consideration radicals of carboxylic acids yielding physiologically tolerable compounds. Preferable are those derived from alkanoic acids containing 1 to IS carbon atoms, and especially 2 to 3 carbon atoms, such, for example, as monobasic alkanoic acids such, for example, as formic, acetic, propionic, butyric, isobutyric, i-ethylbutyric, pivaiic, valeric, isovaleric, -x-ethylvaleric, trimethylacetic, 2-methylbutyrie, 3-ethylbutyric, caproic, triethylacetic, oenanthic or caprylic acid, or cyclic acids, preferably cycloaliphatic acids, such, for example, as cyclopropylideneacetic, cyclobutyl carboxylic, cyclopentyl carboxyli cyclopentylacetic, β-cyclopentylpropionic, cyclohexyl carboxylic or cyclohexylacetic acid or also carbocylic aryl or aralkyl acids such, for example, as benzoic, 2-, 3- or 4-methylbenzoid acid.

As the chemical character of the acyl group is not critical with regard to the properties of the compounds of the invention, provided that the acyl group is not toxic, there are also suitable other aliphatic and aromatic unsubstituted or substituted, mono-,di- and poly-basic carboxylic acids, saturated and unsaturated aliphatic, araliphatic and aromatic carboxylic acidb containing up to 18 carbon atoms and preferably up to 8 carbon atoms.

There may be mentioned, for example, the undecylic, dodecanoic, tetradecanoic, hexadecanoic, octadecanoic, palmitic, stearic and β-cyclohexylpropionic acid, 2,3-, 2,4-, 2,6-, 3,4- and 3i5-dimethylbenzoic, ethylbenzoic, naphthoic, 3-methyl-a-naphthoic, β-phenylpropionic, diphenylacetic and α-naphthylacetic acid or carbamic acids such, for example, as carbamic, phenyl-carbamic, η-butylcarbamic, dimethylcarbamic, diethylcarbamic and allophanic acid, or heterocyclic acids such, for example, as β-furylcarboxylic, pyrrole carboxylic, β-pyrrolidinopropionic, N-methylpyrrolidino-2-carboxylic, 6-hydroxy-indolyl-3-acetic, N-methylmorpholino-2-carboxylic and pyrrole-2-carboxylic acid. The acyl radicals may be substituted one or more times. As substituents there may be mentioned, for example, the following radicals: hydroxyl, halogen, alkoxy, aralkoxy, acyloxy, sulphonyloxy, amido, sulphato, nitro, mercapto and cyano such, for example, as in the acyl radicals of glycollic, lactic, citric, tartaric, maleic, glycerinic, mannonic, gluconic and salicylic acid, or acyl radicals of amino acids such, for example, as glycine, aminopropionic, diglycollamino and triglycollamino acid, methyl-glycine, dimethylglycine, diethylglycine. There may also be mentioned the acyl radicals of para-amino-salicylic, para-aminobenzoic, ethylmercaptoacetic, benzyl-mercaptoacetic, chloracetic, fluoracetic, trichloracetic, trifluoracetic, ΐ ο 4 3 ΰ thioglyccllic, meta-πitrobenzoic, 2,3,4-triniethoxybenzoic, phenoxyacetic and α-naphthyloxyacetic acid. There may also be mentioned the alkoxylated and aralkoxylated acyl radicals of formic acid such, for example, as ethoxycaroonyl and oenzoxyca;bunyl. It .s io be understood that the term ’‘acyl is used herein to include alkoxycarbonyl, aralkoxycarbonyl and other ester groups. The term also includes carbamoyl groups, for example, a CgHg-Rn-CO- grouo.

Trie compounds of tne invention of the general formula (I) are new compounds and have valuable pharmacological properties. They exhibit central depressive, antidopaminergi c, antinociceptive and an ti cor.vu 1 si ve actions, and thus have a certain similarity to neubleptics such, for example, as chlorpromaz ir.e and haloperidol. However, the compounds of the invention differ from the classical neuroleptics in having a different kind or influence on receptor-dependent, monoaminergic feedback mechanisms (decrease or extrapyramidal side effects).

Furthermore, the compounds of the invention have strong du phosphodiesterase-inhibiting properties and thus influence the metabolism of cyclic nucleotides. As controlled cell growth is decisively regulated by cyclic nucleotides (Pastau et. al., 1975) and cyclic nucleotides are partially decreased in uncontrol led proliferating tissue (Ryan and Hsidrick, 1374. Voorhees et. al., 7974). the compounds are suitable for the treatment of diseases .. 7 .. a ν » « u that are hyperproliferative and proceed with uncontrolled cell growth such as psoriasis, polycythaemia vera, neuroblastoma, immunological diseases such as asthma, and bronchial and thromboembolic diseases, in which there is a disturbance of the metabolism of cyclic nucleotides (Tateson, J.E.: Trist, D.G. Inhibition of adenosine-3', 5'-cyclic monophosphate phosphodiesterase by potential antiallergic compounds; Life Sci. 18, 153-162, 1976; De Gaetano, G. Pharmacology of platelet aggregation, Pharmacol. Res. Commun. 7, 301-309, 1975).

The compounds of the invention may be made up in the form of pharmaceutical preparations for the treatment of the aforesaid diseases. Accordingly, the invention also provides a pharmaceutical preparation which comprises a compound of the general formula (I) in admixture of conjunction with a pharmaceutically suitable carrier. As carriers there may be used substances known to be suitable for enteral and parenteral application such, for example, as water, alcohol, gelatine, gum arabic, lactose, starches, magnesium stearate, talcum, vegetable oils, a’nd polyalkylene glycol. The preparations may be in solid form as tablets, capsules, dragees, suppositories or in liquid form as solutions, suspensions or emulsions.

The invention also provides a process for the production of compounds of the general formula (I) wherein a 2-amino1-(3,4-disubstituted phenyl)-ethanol of the general in which R, to Rg have tho meanings given above, is reacted witn a carbonic acid derivative or thiocarbor.ic acid derivative of the general formula (i'll) ¢///) in which L and Y each represents chlorine or bromine or an imidazole radical, or represents the group OR (in which R represents alkyl, aryl, aralkyl or together represent alkylene), usually in an inert solvent in the presence of a basic catalyst, and if desired an aralkyl group in an ether group present is subsequently split off by reduction with Raney nickel or with a noble meta! catalyst or s free hydroxyl 0R2 is alkylated θρ converted into another radical ORg or the ring-oxygen and/ or oxygen of the 2-carbonyl group is exchanged for sulphur or, when R3 represents hydrogen, N-acylation or N-alkylation or other substitution at the N atom is carried out.

The ring-closing reaction for compounds of the formula (II) may be carried out with all carbonic acid derivatives or thiocarbonic acid derivatives of the general formula (III). The R's may be identical or different. R may represent a lower alkyl or aralkyl radical such, for example, as methyl, ethyl and benzyl. The two R's together may also represent an alkylene residue such, for example, as propylene or iso-butylene.

The solvents used are preferably inert towards the reactants. There may be mentioned, for example, ethers such, for example, as diethyl ether, glycol dimethyl ether or diethylene glycol dimethyl ether, aliphatic and aromatic hydrocarbons such, for example, as hexane, benzene, toluene, xylene and mesitylene, but also alcohols such, for example, as methanol, ethanol, propanol, butanol and also dimethyl sulphoxide, glycol monomethyl ether and diethylene glycol monomethyl ether.

The reaction is preferably carried out at a raised temperature, in the range from above room temperature to the boiling point of the reaction mixture, preferably in the range of from 60 to 200°C, and especially 100 to 160°C. 6 4 3 6 The ring-closing reaction is carried out in the presence of a basic catalyst except in the case mentioned below when its presence is optional. Suitable basic catalysts are alkali metal and alkaline earth metal carbonates and especially alcoholates such, for example, as sodium methylate and potassium carbonate. However, there are also suitable organic bases such, for example, as pyridine and triethylamine and alkali metal and alkaline earth metal hydroxides such, for example, as sodium hydroxide especially when Z or Y represents halogen.

When Z and Y are halogen such, for example, as chlorine, the addition of a basic catalyst may, however, be dispensed with. When Z and Y are imidazole radicals it is preferable to work at room temperature, and dimethylformamide, tetrahydrofuran and methylene chloride are suitable as solvents. The subsequent optional reductive splitting off of an aralkyl group such, for example, as the benzyl group, may be carried out with any of the usual metal catalysts such, for example, as platinum, palladium, rhodium or nickel, either in the pure form of on carrier materials such for example, as carbon, calcium carbonate and barium sulphate. As solvents there may be used those that are inert towards the reducing agents under the reaction conditions. There may be mentioned, for example, organic acids such, for example, as acetic acid and propionic acid, lower alcohols such, for example, as methanol and ethanol, esters such, for example, as ethyl acetate, aliphatic, A643S cycloaliphatic and aromatic hydrocarbons such, for example, as hexane, cyclohexane and benzene.

The optional subsequent O-alkylation (Rg represents hydrogen) may also be carried out by methods in themselves known. The alkylation is perferably carried out with the appropriate Rg-halide, -mesylate or -tosylate. As halides there are suitable chlorides, bromides and iodides. For alkylation the hydroxycompound of the formula (II) is dissolved, for example, in a polar solvent and is heated in the presence of a base with the alkylating agent at temperatures between 30 and 150°C. As bases there are suitable, for example, sodium hydride, potassium carbonate, alkali metal alcoholates, such as sodium ethylate, potassium butylate and potassium tertiarybutylate. As solvents there come into consideration dimethyl-formamide, dimethylacetamide, hexamethylphosphoric acid triamide, acetonitrile, dimethyl sulphoxide, tetrahydrofuran, dioxan, ketones such, for example, as acetone and methyl isobutyl ketone, and also alcohols, such for example, as ethanol, butanol and tertiary-butanol.

The exchange of the carbonyHoxygen or the ring-oxygen in compounds of the general formula (I) for sulphur may be carried out by methods in themselves known such, for example, as according to Scheeren et al. Synthesis 1973, 149.

For this purpose there is suitable, for example, a polysulphide such, for example, as phosphorus pentasulphide in a solvent or solvent mixture in the presence of a base. The reaction may also be carried out in a suspension. Suitab’o solvents or suspension media are, for example, acetonitrile, tetrahydrofuran, diethyl ether, glycol dimethyl ether and pyridine. As bases there are suitable, for example, sodium hydrogen carbonate and potassium carbonate. Tne reaction is complete after about 3 to 24 hours at 30 to 120°C.

The subsequent optional N-acylation cr N-alkylation (Rj = H) may also be carried out by methods in themselves known. Thus, the amino-compound is dissoved in a polar solvent and heated at 40 - 150°C in the presence of a salt former with, for example, an alkyl halide or aryl halide, or acyl halide or acyl anhydride. As polar solvents there may be used, for example, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxan, and also alcohols such, for example, as ethanol and butanol. Suitable salt formers are, for example, sodium hydride, potassium carbonate, alkali metal alcoholates such, for example, as sodium ethylate and potassium tertiary-butylate. The reaction with an aryl halide, for example, iodobenzene, may also be carried out without a solvent, preferably in the presence of copper powder. 4θ)·=υ The following Examples illustrate the invention: EXAMPLE I -(3-Benzyloxy-4-methoxy-phenyl)-2-oxazolidinone 318.4 mMol of 3-benzyloxy-4-methoxybenzaldehyde are dissolved in 1200 ml of ether. A solution of 558 mMol of potassium cyanide in 300 ml of water is added at room temperature. After cooling to 0°C., 237 mMol of 2N-sulphuric acid are added dropwise to the well stirred mixture, and the reaction mixture is stirred for 12 hours at room temperature. After separating the aqueous phase, the ether is washed several times with 50 ml of semi-saturated sodium chloride solution and dried well over calcium chloride. After filtering off the drying agent and subsequent washing twice with 100 ml of ether the combined organic phases, which contain crude 2-(3-benzyloxy4-methoxyphenyl)-2-hydroxy-acetonitrile, are used in the next stage.

In an analogous manner 2-(3,4-dimethoxyphenyl)-2hydroxyacetonitrile was prepared from 3,4-dimethoxybenzaldehyde and 2-(3-cyclopentyloxy-4-methoxyphenyl)-2hydroxyacetonitrile was prepared from 3-cyclopentyloxy -4-methoxybenzaldehyde. 1.3 Mol of lithium aluminium hydride are suspended in portions in 1 litre of absolute ether and, while cooling and stirring well, the ethereal solution of 2-(3-benzyloxy-4-methoxyphenyl)-2-hydroxyacetonitrile - 14 is introduced dropwise in a manner such that only slight refluxing occurs. After stirring at room temperature overnight, there is added dropwise to the mixture while cooling,firstly 400 ml of ethyl acetate and later 600 ml of water. The precipitate that forms is then filtered off with suction and the residue is washed twice with 200 ml of ethanol: water (1:1) each time. The collected filtrates are strongly concentrated and taken up in 300 ml of semi-concentrated hydrochloric acid. This solution is extrated twice with 200 ml of ethyl acetate each time. The ethyl acetate phase is discarded, and the hydrochloric acid solution is cooled and rendered alkaline with potassium hydroxide solution (any precipitating aluminium salt being filtered off with suction) and extraction by agitation three times with 400 ml of ether each time is carried out. The combined organic phases are dired, concentrated after filtration, and recrystallised from ethyl acetate.

The 2-amino-l-(3-benzyloxy-4-methoxyphenyl)-ethanol, obtained in a yield of 20S!, melts at 101 to 1Q2°C.

In an anologous manner 2-amino-l-(3,4-dimethoxyphenyl) -ethanol, (M.p. 80-81°C.,benzene) is obtained in a yield of 49% from 2-(3,4-dimethoxyphenyl)-2-hydroxy25 acetonitrile, and 2-amino-l,-(3-cyclopentyloxy-4 -methoxyphenyl)-methanol (an oil) is obtained in a yield of 70% from 2-(3-cyclopentyloxy-4-methoxyphenyl) -2-hydroxyacetoni tri 1e. 2-Amino-l-(3-benzyloxy-4-methoxyphenyl)-ethanol can also be prepared as follows: mMol of 3-benzyloxy-4~methoxybenzaldehyde and 55 mMol of trimethylsilyl cyanide are heated at 90°C. with 0.567 mMol of anhydrous zinc iodide for 4 hours under nitrogen and with the exclusion of moisture. The mixture is then taken'up in 15 ml of absolute tetrahydrofuran, and this solution is added dropwise to a suspension of 60 mMol of lithium aluminium hydride in 35 ml of tetrahydrofuran. After heating the mixture for one hour at 60°C., working up is carried out as described above. After recrystallisation from ethyl.acetate, 2-amino-1-(3-benzyloxy-4-methoxyphenyl)-ethanol melting at 100-102°C. is isolated at a yield of 30%. mMol of 2-amino-l-(3-benzyloxy-4-methoxyphenyl)ethanol are suspended with 50 mMol of sodium methylate and 91.4 mMol of diethyl carbonate in 120 ml of absolute toluene, and the whole is heated for 2 hours at a bath temperature of 110°C. With the exclusion of mositure, methanol and .ethanol being distilled off. The toluene is subsequently distilled off finally under an oil pump vacuum. The residure is taken up iri 150 ml of chloroform and distribution against 100 ml of water is carried out. The aqueous phase is extracted twice with 150 ml of chloroform each time, the combined - 16 • chloroform extracts are washed with 100 ml of water dired, filtered, concentrated and recrystallised from ethyl acetate. There is obtained 5-(3-benzy1oxy-4methoxyphenyl)-2-oxaζο 1idinone melting at 132- 133°C. (91’/ yield).

Example 2 In a manner analogous to that in Example 1 there are prepared from the corresponding amino-alcohols the oxazolidinones given in the following Table. (Rg = hydrogen).

RlR2R3R4 Yield m Mp. (°C) Recrystallised from -ch3 -ch3 -H -H 63 114-117 methanol -ch3 -ch3 -ch3 -H 41 132-134 ethanol -ch3 -H -H 45.8 141-143 ethyl acetate/ether -CH, <1 -H -H 52 111-112 .5 ethyl acetate/ethe Example 3 -(3-benzyloxy-4-methoxyphenyl )-2-oxazolidinone 88.3 mMol of 2-amino-l-(3-benzyloxy-4-methoxyphenyl)ethanol are dissolved in 200 ml of absolute tetrahydrofuran and 92.6 mMol of carbonyl-diimidazole are added with the exclusion of moisture. The clear solution is stirred overnight at room temperature. After distilling off the tetrahydrofuran the residue is taken up in 300 ml of ethyl acetate, the mixture is extracted by agitation twice with IR-hydorchloric acid and is then washed neutral with saturated sodium chloride solution, dried, filtered and concentrated.

By recrystallisation from ethyl acetate 5-(3-benzyloxy4- methoxyphenyl)-2-oxazolidinone melting at 83-91°C. is obtained in a yield of 56%. This product, which is the same product as in Example 1, exists in several crystal modifications which have different melting points.

EXAMPLE 4 - (3-Hydroxy-4-methoxyphenyl)-2-oxazolidinone 40.6 mMol of 5-(3-benzyloxy-4-methoxyphenyl)-2-oxazolidinone are dissolved in 700 ml of ethanol and hydrogenated in the presence of 8 gms of Raney nickel (Bl13, Fa. Degussa, Frankfurt) for 2.2 hours at room temperature under a pressure of hydrogen of 100 atmospheres. After filtering off the catalyst, evaporation is carried out and the residue is recrystallised from methanol. 6.74 Gms of 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone melting at 157° - 160°C (methanol) are obtained.

EXAMPLE 5 : -(3-Cyclopentyloxy-4-methoxyphenyl)-2-oxazolidinone 7,2 mMol of 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone are dissolved in 10 ml of absolute dimethylformamide and the solution is stirred with 7.9 mMol of sodium hydride for 1 hour at 50°C. After cooling the mixture 8.6 mMol of cyclopentyl bromide are added, and then - 18 Λ6435 the whole is stirred for 2 hours at 80°C. When the reaction has terminated the dimethylformamide is removed in vacuo at 40°C. The residue is taken up in 100 ml of a 2N-solution of sodium hydroxide and extracted three times with 150 ml of chloroform. The combined chloroform phases are washed with water, dried, filtered and concentrated. The residue is recrystallised from ethyl acetate/ether. 5-(3-Cyclopentyloxy-4-methoxyphenyl)-2-oxazolidinone melting at 111-112°C. is obtained in a yield of 70%.

EXAMPLE 6 By the method given in Example 5 the compounds ^3=^4 = Rg=H) given in the following Table are prepared from 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone and the halide or tosylate of RgZ1.

The symbols have the following meanings: DMF = Dimethylformamide Petr. = Petroleum ether Chlf. = Chloroform Tos. = Tosylate NaH = Sodium Hydride NaOEt = Sodium ethylate. ' 4 6 4 3 5b p ω £, P r0 XX.

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EXAMPLE 8 -(3,4-Di methoxyphenyl)-2-thiazolidinone mMol of 2-amino-l-(3,4-dimethoxyphenyl)-ethanol are dissolved in 6 ml of pyridine and, while cooling at 0°C. 11 mMol of carbon disulphide in 10 mMol of triethylamine are added dropwise, the temperature rising strongly. The mixtrue is stirred for one hour at 0°C. and then at 4643 5 the same temperature 10 mMol of benzyl chloride are added dropwise. After stirring overnight at 0°C., the mixture is taken up in 40 ml of 3N-sulphuric acid and extracted 3 times with 50 ml of chloroform each time. The combined chloroform phases are washed in succession with sodium hydrogen carbonate and water, dried, filtered and concentrated. The residue that crystallises spontaneously is recrystallised from benzene and ethyl acetate. £2-(3,4-Dimethoxyphenyl)-2 -hydroxy-ethyfj-dithiocarbamic acid benzyl ester melting at 130-132°C is obtained in a quantitative yield.

To 6.07 mMol of (2-(3s4-dimethoxyphenyl)-2-hydroxyethylj-dithiocarbamic acid benzyl ester in 50 ml of absolute ether are added dropwise at +5°C. 2.14 mMol of phosphorus tribromide. After stirring the mixture for 20 hours at 5°C., 10 ml of methanol/water are added dropwise, while cooling, in a manner such that the temperature does not exceed 20°C. The reaction mixture is then cautiously stirred into 20 ml of sodium hydrogen carbonate solution. Extraction three times With 50 ml of chloroform each time is carried out and the combined organic phases are washed in succession with 50 ml of sodium hydrogen carbonate solution and 50 ml of water, dried, filtered and concentrated. 2-Benzylthio-5-(3,4dimethoxyphenyl)-1,3,-thiazol-2-ine is obtained in the form of an oil in a yield of 80%, This oil is dissolved in 20 ml of ethanol, 20 ml of 6N-hydrochloric acid are added and the whole is boiled for 4 hours under reflux. After concentrating the residue is taken up in 25 ml of ethanol. 19 ml of a IN-solution of sodium hydroxide are added and the mixture is stirred for 3 hours at room temperature. The reaction mixture is then neutralised with 2N-hydroehloric acid, the ethanol is removed and extraction by agitation three times with 100 ml of chloroform each time is carried out. The chloroform phase is washed with water, dried and concentrated. The residure is chromatographed over 50 gms of silica gel with the eluant chloroform/ methanol (96:4). The appropriate fractions are recrystallised from methanol, and 50% of 5-(3,4-dimethoxyphenyl)-2thiazolidinone melting at 167-169°C. is obtained.

EXAMPLE 9 -(3,4-Dimethoxyphenyl)-2-oxazolidinon -3-carboxylic acid, anilide 0.5 mMol of 5-(3,4-dimethoxyphenyl)-2-oxazolidi none is heated at 160°C in 3 ml of phenyl isocyanate for 3 hours. After cooling the reaction mixture is concentrated in vacuo and chromatographed over 50 gms of silica gel with cyclohexane/ethyl acetate (1:1). Oy recrystallisation of the appropriate fractions from ethyl acetate 5-(3,4dimethoxyphenyl)-2-oxazolidinon-3-carboxylic acid anilide melting at 175-182°C. is obtained in a yield of 60%.

EXAMPLE 10 -(3,4-0imethoxyphenyl)-2-0xazolidinone 100 mMol of 2-amino-l-(3,4-dimethoxyphenyl)-ethanol are dissolved in 100 ml of chloroform. After cooling to 0°C a solution of 100 mMol of phosgene in 100 ml of chloroform is slowly added dropwise in a manner such that the internal temperature does not exceed 5°C. After stirring for one hour at 5-10°C. 200 mMol of pyridine in 100 ml of chlorform are added dropwise and stirred for 3 hours. After washing the organic phase with a semi-saturated solution of sodium chloride, evaporation and recrystallisation from methanol are carried out. 5(3,4-Dimethoxyphenyl)-2-oxazolidinone melting at 114-117°C is obtained in a yield of 75%.

EXAMPLE 11 -(3,4-Dimethoxyphenyl)-2-oxazolidinone mMol of 2-amino-l-(3,4-dimethoxyphenyl)-ethanol are dissolved in 5 ml.of a 2N-solution of sodium hydroxide.

To the solution, cooled to 0°C, are added dropwise 10 mMol of chloroformic acid ethyl ester. Uhen the addition is complete, the mixture is stirred for 30 minutes at o°C. The crystals formed are filtered off with suction, washed with water and dried. 2-(3,4-Dimethoxyphenyl)2-hydroxyethyl-carbamic acid ethyl ester melting at 90-92°C. is obtained in a yield of 86%. 3 mMol of 2-(3,4-Dimethoxyphenyl)-2-hydroxyethylcarbamic acid ethyl ester are suspended with 4 mMol 6 435 of sodium ethylate in 12 ml of toluene, and the whole is heated for 2 hours at a bath temperature of 110°C. with the exclusion of moisture. Methanol and ethanol distil off. The toluene is then removed in vacuo, the residue is zaken up in 50 ml of chloroform, and distribution is carried out against 10 ml of water.

After drying, filtering and concentrating the organic phase recrystallisation from methanol is carried out. -(3,4-Dimethoxyphenyl)-2-oxazolidinone melting at 11410 117°C. is obtained in a yield of 80%.

EXAMPLE 12 3-Acetyl-5-(3,4-dimethoxyphenyl)-2-oxazolidinone To 8.9 mMol of 5-(3,4-dimethoxyphenyl)-2-oxazo1idinone are added 10 ml of acetic anhydride and 5 ml of pyridine, and the whole is heated for 5 hours at 100°C. After concentrating recrystallisation from ethyl acetate is carried out. 3Acetyl-5-(3,4-dimethoxyphenyl)-2-oxazol idinone melting at 175-182°C. is obtained in a yield of 73%.

EXAMPLE 13 -(3,4-Dimethoxyphenyl)-5-propyl-2-oxazolidinone mMol of 3,4-dimethoxybutyrophenone and 61.4 mMol of trimethylsilyl cyanide with the addition of 200 mg (627 mMol) of anhydrous zinc iodide are heated at 90°C. for 4 hours under nitrogen and with the exclusion of moisture. The reaction mixture is taken up in 15 ml of absolute tetrahydrofuran and added dropwise to a suspension of 60 mMol of lithium aluminium hydride in ml of absolute tetrahydrofuran, the mixture is heated for one hour at 50°C under nitrogen and the excess of lithium aluminium hydride is decomposed by the dropwise addition of ethyl acetate and water. The precipitate is filtered off with suction over silica gel, washed well with ethanol and the mother liquor is concentrated. The residue is taken up in ethyl acetate, acidified with 4N-hydrochloric acid and extracted by agitation. The aqueous phase is adjusted to a pHvalue of 9 with sodium carbonate, saturated with sodium chloride and extracted with chloroform. The chloroform phase is washed neutral with a saturated solution of sodium chloride and, after drying over sodium sulphate, the solvent is distilled off. 5-Amino-4-(3,4-dimethoxyphenyl)-4 -pentanol is obtained in the form of an oil in a yield of 75.5%. -An analysis test portion in the form of the hydrochloride melts at 175-176°C. 17.35 mMol of 5-amino-4-(3,4-dimethoxyphenyl)-4-pentanol are dissolved in 10 ml of absolute dimethylformamide and reacted with 18.3 mMol of carbonyl-diimi dazol e of 98% strength in 100 ml of absolute tetrahydrofuran for 4 days at room temperature with the exclusion of moisture. After distilling off the solvent the residue is taken up in ethyl acetate, extracted by agitation twice with IN-hydrochloric acid and washed neutral with a saturated solution of sodium chloride. The oil so obtained is purified over a column of silica gel (350 6435 gms) in the system chloroform/methanol 30:1 5-(3,4Dimethoxyphenyl)-5-propyl-2-oxazolidinone is obtained in the form of an oil in a yield of 81.7%.

EXAMPLE 14 -(3,4-Di methoxyphenyl)-5-methyl-2-oxazolidinone In a manner analogous to that in Example 13 5-(3,4dimethoxyphenyl)-5-methyl-2-oxazolidinone is obtained from 3,4-dimethoxyacetophenone in a total yield of 30% melting at 98-101°C.

EXAMPLE 15 -(3,4-Dimethoxypheny1)-3-methyl-2-oxazolidinone mMol of 5-(3,4-dimethoxyphenyl)-2-oxazolidinone are dissolved in 20 ml of absolute dimethyl-formamide and 11 mMol of sodium hydride are added. The mixture is then stirred for 40 minutes at 40°C. After cooling, mMol of methyl iodide in 5 ml of dimethylformamide are added dropwise and, after the addition, the mixture is stirred for 6 hours at 50°C. After removing the dimethylformamide, the mixture is taken up in chloroform, washed first with a little water and then with a saturated solution of sodium chloride, dried filtered and concentrated. The residue is chromatographed over 60 gms of silica gel with chloroform/methanol (96:4) as eluant. After recrystallisation from ethanol, 5-(3,4-dimethoxyphenyl) -3-methy1-2-oxazo1idinone melting at 132-133°C. is obtained in a yield of 60%.

EXAMPLE 16 -(3,4-Dimethoxyphenyl)-2-oxazolidinon-3carboxylic acid benzyl ester I 6.25 mMol of 5-(3,4-dimethoxyphenyl)-2-oxazolidinone are dissolved in 30 ml of dioxan and 6.25 ml (12.50 mM) of a 2N-solution of sodium hydroxide are added. At +4°C 12.5 ml of benzoxycarbonyl chloride are added to the mixture, and the whole is stirred for 4 hours at this temperature.

After the addition of 50 ml of a 2N-solution of sodium hydroxide, extraction three times with 50 ml of ethyl acetate each time is carried out. The ethyl acetate phase is washed once with 50 ml of a 2N-solution of sodium hydroxide and twice with 50 ml of water each time, dried over Sikkonw, filtered and concentrated. After removing the benzoxycarbonyl chloride still present at 100°C. .under 1 Torr, the residue is recrystallised from ethyl acetate/petroleum ether and 5-(3,4-dimethoxy20 phenyl)-2-oxazolidinon-3-carboxylic acid benzyl ester melting at 124-125?C. is obtained in a yield of 64%.

EXAMPLE 17 -(3,4-Dimethoxyphenyl)-2-oxazolidinon-3-carboxylic acid ethyl ester To 5mMol of 5-(3,4-dimethoxyphenyl)-oxazolidinone in ml of toluene (absolute) are applied 10 mMol of triethylamine at 0°C. with the exclusion of moisture.

The the mixture are added 10 mMol of chloroformic acid ethyl ester, and the mixture is boiled under reflux for 4 hours and allowed to stand overnight. The product that crystallises out, after being liltered off with suction, is again boiled with 7.6 mMol of triethylamine and 7.6 mMol of chloroformic acid ethyl ester. The product that crystallises out is again filtered off with suction. The combined filtrates are evaporated.

Chromatography of the residue over 80 gms of silica gel with cyclohexane-ethyl acetate 1:1 as eluant gives 5-(3,4-dimethoxyphenyl)-2-oxazolidinon-1-carboxyli c acid ethyl ester melting at 181-185°C in a yield of 43%.

EXAMPLE 18 In a manner analogous to that in Example 15 the oxazolidinones mentioned in the following Table are prepared from 5-(3,4dimethoxyphenyl)-2-oxazolidinone: - 29 <4 Ο 4 Ο Ο of moisture. After allowing the mixture to stand overnight, it is extracted with 50 ml of distilled water, dried, filtered and concentrated. By chromatography of the residue over 50 gms of silica gel with chioroform/methanol (95:5) as eluant and recrystallisation from ethyl acetate/petroleum ether, -(3-4-dimethoxypheny1)-4-methyl-2-oxazolidinone me!ting at 98-99°C is obtained in a yield of 24%.

The starting material 2-amino-l-(3,4-dimethoxy)-propanol was prepared as follows: To 100 mMol of 3,4-dimethoxypropiophenone in 160 ml of methylene chloride are added dropwise at room temperature 10 ml of sulphuryl chloride in 80 ml of methylene chloride. The mixture is then further stirred for 3.5 hours at room temperature. By removing the solvent and recrystallisation of the residue from cyclohexane/petroleum ether 2‘-chloro3,4-dimethoxypropiophenone melting at 56-57°C. is obtained in a yield of 89%.

Each 43.86 mMol of 2'-chloro-3,4-dimethoxypropiophenone dissolved in 230 ml of acetone is stirred for 7 days with 437 mg of potassium iodide and 87.72 mMol of dibenzylamine with the exclusion of moisture. The mixture is diluted with diethyl ether to 1 litre of solution, filtered and concentrated. The residue is absorbed onto silica gel and the silica gel is stirred first with chloroform and then with ethanol and filtered off with suction each time. The chloroform phase is chromatographed over 500 gms of silica gel with chloroform as eluant and give 2'-N,N-dibenzylamino-3,4-dimethoxypropiophenone in the form of an oil in a yield of 49%. 12.39 gms .(31.8 mMol) of 2'-H,N-dibenzylainino-3,4dimethoxypropiophenone are dissolved in 75 ml of isopropanol and 1.33 gms (35.05 mMol) of sodium boranate are added.

After being stirred for one hour at room temperature, the mixture is heated for 2 hours under reflux. After cooling, the mixture is filtered with suction and the residue is extracted at the boil with ethyl acetate. After filtration, 2'-(Ν,Ν-dibenzylamino)-1-(3,4-dimethoxyphenyl)propanol melting at 151-152°C crystallises out of the filtrate in a yield of 59%. 13.2 mMol of the dibenzyl-compound in 50 ml of ethanol (analytically pure) are hydrogenated with 2.64 gms of palladium/carbon (10%) for 3 hours at 90°C under an atmosphere of hydrogen of 10 atmospheres gauge. After filtering with suction, concentration and recrystallisation from ethanol are carried out, 2-Amino-l-(3,4-dimethoxyphenyl )> -propanol melting at 131-132°C is obtained in a yield of 64%.

EXAMPLE 20 -(3,4-Dimethoxyphenyl)-2-oxo-oxazolidin-4-carboxylic acid ethyl ester mMol of 2-amino-3-(3,4-dimethoxyphenyl)-3-hydroxy-propionic acid ethyl ester are stirred with 12 mMol of carbonyl diimidazole in 60 ml of chloroform for 4 hours at room temperature with the exclusion of moisture. Then the mixture is extracted once with 50 ml of water, dried over silica gel overnight, filtered and concentrated.

The residue is chromatographed over 130 gms of silica gel with chioroform/methanol (90:10) as eluant. Reerystallisation from ethyl acetate/ethanol gives 5-(3,4-dimethoxyphenyl)-2-oxo-oxazolidin-4-carboxyli c acid ethyl ester melting at 188-189°C in a yield of 34%.

The starting material 2-amino-3-(3,4-dimethoxyphenyl) -3-hydroxy-propionic acid ethyl ester was prepared as foilows: 44.37 mMol of 3,4-dimethoxyphenylglycidic acid ethyl ester (prepared according to W. Schneider et al., Arch.

Pharm. 299,817(1966) are boiled under reflux with 97.61 mMol of dibenxylamine in 100 ml of ethanol for 4.5 hours with the exclusion of moisture. After being allowed to stand for 3 days at room temperature the mixture is concentrated, and the residue is chromatographed over 400 gms of silica gel with chloroform/methanol (98:2) as eluant. Chromatography of the appropriate collected fractions gives 2-N,N-dibenzylamino-4-(3,4dimethoxyphenyl)-3-hydroxypropionic acid ethyl ester in the form of an oil in a yield of 89%. 22.2 mMol of 2-N,N-dibenzylamino-3-(3,4-dimethoxyphenyl) -3hydroxypropionic acid ethyl ester are hydrogenated with 4.44 gms of palladium/carbon of 10% strength in 100 ml undenatured ethanol for 3 hours at 90°C under hydrogen at 10 atmospheres gauge. After filtering off the catalyst with suction, the mixture is concentrated.

Recrystallisation from undenatured ethanol gives 2-amino -4-(3,4-dimethotxyphenyl )-3-hydroxypropionic acid ethyl ester melting at 211-212%. (with decomposition) in a yield of 80%.

Claims (35)

1. WHAT WE CLAIM IS:1. A 5-(substituted phenyl)-oxazolidinone or sulphur analogue thereof of the general formula (I) (Ό in which R·] represents a substituted or unsubstituted lower alkyl, cycloalkyl or cycloalkylalkyl radical, R 2 represents hydrogen or a substituted or unsubstituted lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, alkenyl or heterocylic radical, R 3 represents hydrogen or a substituted or unsubstituted lower alkyl, alkenyl, alkynyl, aryl, aralkyl or acyl radical, 4 ό 4 3 S represents hydrogen or a substituted or unsubstituted lower alkyl radical, R g represents hydrogen or a substituted or unsubstituted lower alkyl or lower alkoxycarbonyl radical and 5 X represents oxygen or sulphur, and the two X moieties may the same or different.

2. 5-(3-Benzyloxy-4-methoxyphenyl)-2-oxazolidinone.

3. 5-(3,4-Dimethoxypheny!)-2-oxazolidinone.

4. 3-Methyl-5-(3,4-dimethoxyphenyl)-2-oxazolidinone.

5. 5-(3-Methoxy-4-cyclopentyloxyphenyl)-2-oxazo1idinone.

6. 5-(3-Cyclopentyloxy-4-methoxypheny1)-2-oxazolidinone.

7. 5-(3-Hydroxy-2-methoxyphenyl)-2-oxazolidinone.

8. 5-(3-Propyloxy-4-methoxyphenyl)-2-oxazolidinone.

9. 5-(3-Isobutyloxy-4-methoxyphenyl)-2-oxazolidinone.

10. 5-(3-Cyclobutyloxy-4-methoxyphenyl)-2-oxazol idinone.

11. 5-(3-n-Butoxy-4-methoxyphenyl)-2-oxazolidinone.

12. 5-(3-Allyloxy-4-methoxyphenyl)-2-oxazolidinone. - 3S 4643

13. 5-(3-Propargyloxy-4-methoxyphenyl)-2-oxazolidinone.

14. 5-(3-Methylallyloxy-4-methoxyphenyl)-2-oxazolidi none

15. 5-(3-Phenyloxy-4-methoxyphenyl)-2-oxazolidinone.

16. 5-(3-(3-Tetrahydrofuranyloxy)-2methoxyphenyl )-2oxazolidinone.

17. 5-(3,4-Dimethoxyphenyl-2-oxazolidinthione.

18. 5-(3,4-Di methoxyphenyl )-2-thiazolidinone.

19. 5-(3,4-Di methoxypheny1)-2-oxazolidinon-3-carboxyli c acid anilide.

20. 3-Acety1-5-(3,4-dimethoxyphenyl)-2-oxazolidinone.

21. 5-(3,4-Di methoxyphenyl)-5-methyl-2-oxazolidinone.

22. 5-(3,4-Di methoxyphenyl)-5-propyl-2-oxazolidinone.

23. 5-(3,4-Di methoxyphenyl)-2-oxazolidinon-3-carboxylic acid benzyl ester.

24. 5-(3,4-Di methoxyphenyl)-2-oxazoli dinon-3-carboxyli c acid ethyl ester.

25. 5-(3,4-Dimethoxyphenyl)-3-isopropy!-2-oxazolidinone. 37 >4-643 5

26. 5-(3,4“Dimethoxyphenyl)-3-benzyl-2-oxazolidinone.

27. 5-(3,4-Dimethoxyphenyl )-3- [2,3,4-dimethoxyphenyl) ethylj -2-oxazolidinone.

28. 5-(3,4-Dimethoxy!phenyl)-4-methyl-2-oxazolidone. 5

29. 5-(3,4-Dimethyoxyphenyl)-2-oxo-oxazolidin-4carboxylic acid ethyl ester

30. A process for the manufacture of 5-(substituted phenyl)-oxazolidinones and sulphur analogues thereof of the general formula (I) 10 in which R.j Rg and X have the meanings given in claim 1, wherein a 2-amino-l-(3,4-disubstituted phenyl)-ethanol of the general formula (III) in which to Rg have the meanings given in claim 1, is reacted with a carbonic of thiocarbonic acid derivative of the general formula (III) = (III) 5 in which - ί' ’ · ’ Z and Y each represent chlorine or bromine or an imidazole radical or represents tffe group OR (in which -iR represents an alky, aryl or aralkyl radical or the two R‘s together represent an alky-Jene radical), and 10 if desired an aralkyl group in an ether group is split off by reduction with Raney nickel or d free hydroxyl group (0R 2 ) is alkylated or qonvertecl into another radical ORg or the ring-oxygen and/or oxygqn of the 2-carbonyl group is exchanged fior sulphur or, when 15 R 3 represents hydrogen, N-acylation or N-alkylation or other substitution is carried out at the N atom, the ring-closing reaction being carried out in the presence of a basic catalyst which, if desired, may be omitted when Z and Y represent halogen. 20

31. A compound of the general formula (I) when obtained - 39 46435 by the process claimed in claim 30.

32. A pharmaceutical preparation which comprises a compound as claimed in any one df claims 1 to 29 and 31, in admixture of conjunction with a pharmaceutically 5 suitable carrier.

33. A pharmaceutical preparation as claimed in claim 32, which is in dosage unit form.

34. A pharmaceutical preparation as claimed in claim 32 or claim 33, which is in the form of a tablet, capsule, 0 dragee of suppository.

35. A pharmaceutical preparation as claimed in claim 32 or claim 33, which is in the form of a solution, suspension or emulsion.