Patent EA-003298-B1 (EA)
Title: Urethanes, thio and dithio analogues, the salts thereof, medicaments containing said compounds, use and method for the production thereof
Inventor: MAIER ROLAND
IPC: C07C333/06
Filed: 1998-12-08
Abstract: 1. Urethanes and the thio and dithio analogues thereof of the general formula wherein m denotes the numbers 0 or 1, n denotes the numbers 1 or 2, A denotes a single bond, a straight-chained or branched C1-8-alkylene group, a C2-8-alkenylene or C2-8-alkynylene group, whilst an unsaturated group is not directly bound to the group Y, X denotes an oxygen or sulphur atom, Y denotes an oxygen or sulphur atom, R<1> denotes a straight-chained or branched C1-8-alkyl group, a C1-6-alkenyl group or a C1-6-alkynyl group, whilst the multiple bond is isolated from the nitrogen-carbon bond, R<2> denotes a hydrogen atom, a straight-chained or branched C1-8-alkyl group which may be substituted by a hydroxy or alkoxy group, a C1-6-alkenyl group or a C1-6-alkynyl group, whilst a hydroxy and alkoxy substituent is not bound in the 1-position and a multiple bond is isolated from the nitrogen-carbon bond, or R<1> and R<2> together with the nitrogen atom denote a 5- to 7-membered, saturated heterocyclic ring wherein a methylene group isolated from the nitrogen atom may be replaced by an oxygen or sulphur atom or by an -HH- or -N(alkyl)- group, R<3> to R<6>, which may be identical or different, denote hydrogen atoms or alkyl groups, R<7> denotes a straight-chained or branched C1-6-alkyl group, a C1-6-alkenyl group or a C1-6-alkynyl group, whilst the multiple bond is isolated from the nitrogen-carbon bond, R<8> denotes a C3-7-cycloalkyl group, a phenyl or naphthyl group optionally substituted by one or two halogen atoms or by an alkyl, alkoxy, triftoromethyl or cyano group or, if A does not denote a single bond, R<8> also denotes a hydrogen atom, whilst, unless otherwise stated, alkyl groups contained in the groups mentioned above may contain 1 to 3 carbon atoms and a halogen atom mentioned above may be a fluorine, chlorine or-bromine atom, the enantiomers, diastereomers, the mixtures thereof and the salts thereof, with the proviso that A and R<8> together cannot denote a tert.-butyl group if X and Y both denote an oxygen atom. 2. Compounds of general formula I according to claim l, wherein m denotes the number 1, n denotes the number 1, A denotes a single bond, a straight-chained or branched C1-6-alkylene group, X denotes an oxygen or sulphur atom, Y denotes an oxygen or sulphur atom, R<1> denotes a straight-chained or branched C1-6-alkyl group, R<2> denotes a hydrogen atom, a straight-chained or branched C1-6-alkyl group which may be substituted by a hydroxy group, a C1-4-alkenyl group or a C1-4-alkynyl group, whilst the hydroxy group is not bound in the 1 position and the multiple bond is isolated from the nitrogen-carbon bond, or R<1> and R<2> together with the nitrogen atom denote a 5- to 7-menibered, saturated heterocyclic ring wherein a methylene group isolated from the nitrogen atom may be replaced by an oxygen atom, R<3> to R<6>, which may be identical or different, denote hydrogen atoms or methyl groups, R<7> denotes a straight-chained or branched C1-6-alkyl group or a C1-4-alkenyl group, whilst the multiple bond is isolated from the nitrogen-carbon bond, R<8> denotes a C3-6-cycloalkyl group, a phenyl or naphthyl group optionally substituted by one or two halogen atoms or by an alkyl, alkoxy, trifluoromethyl or cyano group or, if A does not denote a single bond, R<8> also denotes a hydrogen atom, whilst, unless otherwise stated, alkyl groups contained in the groups mentioned above may each contain l to 3 carbon atoms and a halogen atom mentioned above may be a fluorine, chlorine or bromine atom, the enantiomers, diastereomers, the mixtures thereof and the salts thereof, with the proviso that A and R<8> together cannot denote a tert.-butyl group if X and Y both denote an oxygen atom. 3. Compounds of general formula I according to claim 1, wherein m denotes the number 1, n denotes the number 1, A denotes a single bond or a methylene group, X denotes an oxygen or sulphur atom, Y denotes an oxygen or sulphur atom, R<1> denotes a methyl or ethyl group, R<2> denotes a methyl, ethyl, allyl or propargyl group or R<1> and R<2> together with the nitrogen atom denote a pyrrolidine or piperidine ring, R<3> to R<6> denote hydrogen atoms, R<7> denotes a methyl group, R<8> denotes a phenyl group optionally substituted by a chlorine or fluorine atom or by a methyl group, the mixtures and the salts thereof. 4. The following compounds of general formula I according to claim 1: (1) trans-S-(4-chlorophenyl)-N-4-[4-(dimethylaminomethyl)-phenyl]cyclohexyl-N-methyldithiocarbamate, (2) trans-S-(3-fluorobenzyl)-N-4-(4-(dimethylaminomethyl)-phenyl]cyclohexyl-N-methyldithiocarbamate, (3) trans-S-(4-fluorobenzyl)-N-4- [4- (dimethylaminomethyl)-phenyl]cyclohexyl-N-methyldithiocarbamate, (4) trans-S-(4-chlorobenzyl)-N-4-[4-(dimethylaminomethyl)-phenyl]cyclohexyl-N-methyldithiocarbamate, (5) trans-O-(4-chlorophenyl)-N-4-[4-(dimethylaminomethyl)-phenyl]cyclohexyl-N-methylcarbamate, (6) cis-S-benzyl-N-4-[4-(dimethylaminomethyl) phenyl]-cyclohexyl-N-methyldithiocarbamate, (7) trans-O-(4-chlorophenyl)-N-4-[4-(dimethylaminomethyl)-phenyl] cyclohexyl-N-methylthiocarbamate, (8) trans-S-(4-chlorophenyl)-N-4- [4-(dimethylaminomethyl)-phenyl] cyclohexyl-N-methylthiocarbamate, (9) trans-O-(4-chlorophenyl)-N-methyl-N-4-[4-(piperidinomethyl)phenyl]cyclohexylcarbamate, (10) trans-O-(4-chlorophenyl)-N-methyl-N-4-[4-(pyrrolidinomethyl)phenyl]cyclohexylcarbamate, (11) trans-O-(4-chlorophenyl)-N-4-[4-(diethylaminomethyl)-phenyl]cyclohexyl-N-methylcarbamate, (12) trans-O-(4-chlorophenyl)-N-methyl-N-4-[4-(N-methyl-N-allylaminomethyl)phenyl]cyclohexylcarbamate, (13) trans-O-(4-chlorophenyl)-N-methyl-N-4-[4-(N-methyl-N-propargylaminomethyl) phenyl]cyclohexylcarbamate, (14) trans-N-4-[4-(dimethylaminomethyl)phenyl] cyclohexyl-N-methyl-O-(4-methylphenyl)carbamate, (15) trans-N-4-[4-(dimethylaminomethyl)phenyl]cyclohexyl-N-methyl-O-(4-methylphenyl) thiocarbamate, (16) trans-N-methyl-O-(4-methylphenyl)-N-4-[4-(piperidinomethyl)phenyl]cyclohexylthiocarbamate and (17) trans-N-4-[4-(dimethylaminomethyl)phenyl]cyclohexyl-O-(4-fluorophenyl)-N-methylcarbamate, the mixtures thereof and the salts thereof. 5. Physiologically acceptable salts of the compounds according to any one of claims 1 to 4 with inorganic or organic acids. 6. Pharmaceutical compositions containing a compound according to any one of claims 1 to 4 or a physiologically acceptable salt according to claim 5, together with one or more inert carriers and/or diluents. 7. Pharmaceutical compositions according to claim 6, suitable for treating diseases in which cholesterol biosynthesis plays a part. 8. Pharmaceutical compositions according to claim 7, containing a compound according to any one of claims 1 to 4 or a physiologically acceptable salt according to claim 5 in combination with one or more other active substances with a cholesterol or lipid-lowering activity. 9. Pharmaceutical compositions according to claim 8, characterised in that the other active substances are selected from resins which bind bile acid, which inhibit cholesterol absorption, compounds which are involved in cholesterol biosynthesis by a mechanism other than the inhibition of 2,3-epoxysqualene-lanosterol-cyclase, fibrates, nicotinic acid, the derivatives and analogues thereof, and probucol. 10. Pharmaceutical compositions according to any one of claims 7 to 9, suitable for the treatment or prophylaxis of hypercholesterolaemia, hyperlipoproteinaemia, hypertriglyceridaemia and the resulting atherosclerotic vascular changes with their consequent diseases such as coronary heart disease, cerebral ischaemia, Claudicatio intermittens or gangrene, for treating diseases connected with excessive cell proliferation, for the prophylaxis and treatment of gallstone problems or for treating mycoses. 11. Use of a compound according to any one of claims 1 to 5 for preparing a pharmaceutical composition according to any one of claims 7 to 10. 12. Feed for laying hens, containing a compound according to any one of claims 1 to 4 or a physiologically acceptable salt according to claim 5. 13. Use of a compound according to any one of claims 1 to 5 for preparing a feed for laying hens for producing low-cholesterol eggs. 14. Process for preparing a pharmaceutical composition according to claim 6, characterised in that a compound according to any one of claims 1 to 5 is incorporated in one or more insert carriers and/or diluents by a non-chemical method. 15. Process for preparing the compounds of general formula I according to any one of claims 1 to 5, characterised in that a compound of general formula wherein m, n and R<1> to R<7> are defined as in claims 1 to 4, is reacted with a compound of general formula wherein X and Y each denote a sulphur atom and m, n, A and R<1> to R<8> are defined as in claims 1 to 4, with the proviso that R<8> does not represent an optionally substituted phenyl or naphthyl group if A denotes a single bond, a compound of general formula (II) wherein m, n and R<1> to R<7> are defined as in claims 1 to 4, is reacted with carbon disulphide and then with an alkylating agent of general formula wherein A and R<8> are defined as in claims 1 to 4, with the proviso that R<8> does not represent an optionally substituted phenyl or naphthyl group if A denotes a single bond, and Z<1> denotes a leaving group and any protecting groups used are subsequently cleaved and if desired a mixture of the geometric isomers of a compound of general formula I thus obtained is resolved into its enantiomers and diastereomers or a compound of general formula I thus obtained is converted into a salt thereof with an inorganic or organic acid, particularly into the physiologically acceptable salts thereof.