MXPA00004622A - Urethanes derived from azacycloalkanes, thio and dithio analogues, production and use thereof as 2,3 epoxysqualene lanesterol cyclase inhibitors - Google Patents

Abstract

The present invention relates to urethanes derived from azacycloalkanes in addition to thio and dithio analoguesof general formula (I), wherein m=0 or 1, n=1or 2, A is a single bond, a straight-chain or branched C1-8 alkylene group, a C2-8 alkenylene or C2-8 alkylene group, whereby an unsaturated group is not directly bonded to radical Y;X and Y is an oxygen or sulphur atom, R1 and R2 are a straight-chain or branched C1-6 alkyl group, a C1-4 alkenyl group or a C1-4 alkinyl group, whereby a multiple bond is isolated from the nitrogen-carbon bond, or R1 and R2 together with the nitrogen atom represent a 5-7 membered saturated heterocyclic ring, whereby one methylene group isolated from the nitrogen atom can be replaced by an oxygen or sulphur atom or by an -NH or -N (alkyl) group, R3-R6 can be identical or different and represent hydrogen atoms or alkyl groups, R7 is a C3-7 cycloalkyl group, optionally a phenyl or naphtyl group substituted by two halogen atoms, an alkyl, alkoxy, trifluoromethyl or cyano group or a hydrogen atom, provided that A does not represent a single bond, E is an oxygen or sulphur atom, a methylene, carbonyl or sulfinyl group and R8 represents a hydrogen atom or E represents the -C(R9R10)- group, wherein R10 and adjacent group R8 represent a carbon-carbon bond. The invention also relates to enantiomers, diastereomers and salts thereof, especially physiologically acceptable acid additive salts with valuable properties such as exhibiting an inhibiting effect on cholesterol biosynthesis, in addition to medicaments containing said compounds, the use thereof and a method for the production thereof.

Description

NEW URETANOS DERIVED FROM AZACICLOALCANOS, ITS ANALOGS UNCLE AND DIET, YOUR SALTS, MEDICATIONS THAT CONTAIN THESE COMPOUNDS AND THEIR EMPLOYMENT AS WELL AS PROCEDURES FOR PREPARATION The present invention relates to novel urethanes derived from azacycloalkanes, their thio and dithio analogs, their salts with physiologically compatible organic and inorganic acids, processes for the preparation of preparations and medicaments containing them. The compounds according to the invention represent inhibitors of cholesterol biosynthesis, in particular inhibitors of the enzyme 2, 3-e p or x i e s c u a 1 e no-1 ano s t e r 1 - c i c a s a, - a key enlia in the biosynthesis of cholestex al. The compounds according to the invention are suitable for the treatment and prophylaxis of hypersensitivity, hypersensitivity and atherosclerosis. Other possible fields of application are for the treatment of diseases. of the skin and vascular diseases, tumors, cholelithiasis as well as my ero sis.

Compounds involved in the biosynthesis of cholesterol are of importance for the treatment of a series of pathological conditions. In this case, hypercholesterolemias and hyperlipidemias, the risk factors for the appearance of atherosclerotic variations of the vessels and their deuteropathies, represented, for example, by coronary heart disease, cerebral ischemia, and chronic claudication, should be mentioned. er my tente and gangrene. The importance of increased levels of serum cholesterol as a major factor in the development of vascular variations is generally recognized. NLume r o s or clinical studies have led to re c o n ojc. Thus, by decreasing serum cholesterol, the risk of coronary heart disease can be reduced (Current Opinion in Lipidology 2 (4), 234 [1991]; Exp. Opin. Ther. Patents 7 (5), 441-455 [1997]). Since most cholesterol is synthesized in the body itself and a small part is absorbed with food, the inhibition of biosynthesis represents a particularly attractive way to reduce the increased level of cholesterol. _ In addition to the above, other possible applications of inhibitors of cholesterol biosynthesis include the treatment of hyperproductive diseases of the skin and vessels - as well as tumor diseases, treatment and prophylaxis. < Aelitiasis as well as the use in mycosis. In this case it is, in the latter case, an intervention in the biosynthesis of ergosterol in fungi, which runs largely analogous to the biosynthesis of cholesterol in mammalian cells. The biosynthesis of coiesterol or - that of ergosterol runs, starting from acetic acid, through a large number of reaction stages. This multi-stage process offers a series of possibilities of interaction, to which we can mention, as examples: For the inhibition of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA). -sintasa ß-lactones and ß-lactnmas are mentioned with an effect at n t i h ip e r co 1 e s t er potential eemy (see J.

Antibiotics 40-, 1356 [1987], US-A-4,751,237, EP-A-0 462 667, US-A-4,983,597). Examples of H-GC enzyme inhibitors or A-re du ctasa are represented by 3,5-dihydric oxycarboxylic acids of the mevinolin type and their d-lactones, the representatives of which are lovastatin, if mva statin, pra va statin, f 1 uvastatin, atorvastatin as well as cerivastatin find application in the therapy of hypercholesterolemia.

Other possible areas of application of these compounds are fungal infections (documents (US-A-4,375,475, EP-A-0 113 881, U S-A-5,106,992), skin diseases (EP-A-0 369 263) as well as cholelithiasis and tumor diseases (US-A-5,106,992; Lancet 339, 1154-1156

[1992]). The inhibition of the proliferation of smooth muscle cells by lovastatin is described in Cardiovasc. Drugs Ther. 5, Suppl. 3, 3 4 [1991]. The toc < > trienol ', an unsaturated analogue of vitamin E, and its analogs represent another class of substances acting on the HMG-CoA-r educ rate (Exp. Opin. Ther.Patents 7 (5), 446 [1997]). Inhibitors of the enzyme 1-en-synthetase are, for example, isaprene-de (phosphinylmethyl) -phosphonates, whose suitability for the treatment of hypercholesterolemias, cholelithiasis and tumor arl diseases is described in EP-A-0 409 181 as well as in A Med. Chemistry 34, 1912 [1991] and, in addition, compounds of α-phosphon and its 1-in (EP-A-0 698 609), the compounds J-104, TI 8 and J - ~ 104, 123 (Tetrahedron 52, 13881-13894, [1996]) as well as cyclobutane derivatives (clocume nt 10 96/331759. A compilation on squalene 1-enzyme-sitetase inhibitors is found in Exp. Opin. Ther. Patents 7 (5), 446-448 [1997] As inhibitors of the enzyme squalene-epoxidase are known alkylamines such as naph tidine and terbinafine that have found access to therapy-as agents against diseases, fungi, as well as allylamine NB-598 with an effect on the iridoemic co-1 (J. Biol. Chemistry 265, 18075-18078 [1990] ) and "fluorescelenic-hydrogel derivatives" (US-A-5,011,859). In addition, piperidines and izadecalines are described as having a cholesemic and / or functional antibacterial effect, whose action mechanism is not clearly explained and which they represent. inhibitors of 1-ene-epoxy da-say / or 2,3-epoxysqualene-lanosterol-cyclase inhibitors (EP-A-0 420 116, EP-A-0-468 434, US-5,084,461 and EP-A -0 468 457). Other representatives are described in Exp. Opin. Ther. Patents 7 (5), 448-44 ^ [1997].

Examples of inhibitors of the enzyme 2,3-epoxiesc ua 1 ene-1 anostero 1-cic 1 asa are diphenyl derivatives (EP-A-0 464 465), aminoalkoxybenzene derivatives (EP-A-0 v.) 10 359, J. Lipid, Res. 38, 373-390, [1997]), as well as piperidine derivatives (J. Org. Chem. 57, 2794-2903 [1992] which possess an antifungal effect. , this enzyme is inhibited in mammalian cells by decalins, azadecalins and indane derivatives (WO 89/08450; J. Biol. Chemistry 254, 11258-11263 [1981]; Biochem. Pharmacology 37, 1955-15.64 [1988] ] and J 64 003 144), in addition on the part of 2-aza-2, 3 -dihi dr oes cua 1 ene and 2, 3-ep imi noe sc ua le no (Bio chem. Pharmacology 34, 2765-2777 11985] ), by squalenoid-epoxide-vinyl ether (J. Chem. 'Soc. Perkin Trans. I, 461 [1988]) and 29-methylidene-2, 3-oxide-squalene (J. Amer. Chem. Soc. 113, 9673-9674

[1991]). Other examples are pyridine or pyrimidine derivatives (WO 97/06802), heteroaryl alkylamines (WO 96/11201, imidazole derivatives (EP-A-0 757 988) as well as derivatives of isoquinoline (J. Med. Chemistry, 39, 2302 -Til 2, [1996]). In addition, "ureas" are described (DE-A-4 438 021), oximes (DE-A-4 412). 692 j, a series of amides (DE-A-4 407 134, DE-A-4 407 135, DE-A-4 407 136, DE-A-4 407 138, DE-A-4 407 139, DE -A-4 412 691, DE-A-4 437 999, DE-A-4 438 000, DE-A-4 438 020, DE-A-4 438 082, DE-A-4 438 029, DE-A -4 438 054, DE-A-4 438 ~ 055, ~ DE- ~ A-4 438 082, DE-A-4 438 083, EP-A-0 599 203, EP-A-0"596 326) as well as esters (document _W_Q_ 93/29148) A Other examples are described in Exp. Opin. Ther.Patents 7 (5), 448-449 [1997] .Finally, as inhibitors of the enzyme 1 year old 1-14 rx - d eme ti 1 asa have yet to be mentioned, deriv a_d o, s steroids with an effect-a ntihi pe r 1 i p i d e i c o potential that, at the same time, influence the enzyme HMG-CoA reductase (document-US-A-5,041,431; J. Biol. Chemistry 266, 20070-20078 [1991-]; US-A-5,034 48). In addition, this enzyme is inhibited by the anritipicotics of the rI: ol type, which represent N-substituted imidazoles and triazoles, and belong, for example, to the ketoconazole and lucoña.zol antimycotics that are commercially available. compounds of the following general formula I are new, Surprisingly, they have been found to represent very efficient inhibitors of the enzyme 2,3-epoxysqualenolanosterol-cyclase (International Classification: EC 5.4.99.7).

The enzyme 2, 3 -epa xies qua 1 ene-1 to non-stero 1 -cyclase catalyses a clav step of the biosynthesis of clesool or ergosterol, namely the transformation of 2, 3-ep oxies cu to 1 ene in the lanosterol, the first compound with a steroid structure in the cascade of biosynthesis. Inhibitors of this enzyme allow us to expect the advantage of greater selectivity with respect to inhibitors of previous stages of biosynthesis such as, for example, HMG-CoA synthase and HMG-CoA reductase, since the inhibition of these early stages of biosynthesis leads to the decrease of mevalonic acid formed by biosynthesis and, thus, can also negatively influence the biosy iitesis of the substances dependent on the mevalonic acid dolichol, ubiquinone and is ape nteni 1-t-RNA (see J. Biol. Chemistry 265, 1 ^ 075-18078 [1990]). In the case of the inhibition of the biosynthesis stages after the transformation of 2,3-epoxysqualene into lanosterol, there exists the risk of the accumulation of intermediate products with structure in the body and the development of conditioned toxic effects. thus. This is described, for example, for Lriparanol, an inhibitor of desmosterol-reductase. This substance had to be withdrawn from the market due to the formation of cataracts, ichthyosis and alopecia (cited in J. Biol. Chemistry 265, 18075-18078"[1990].) As already explained at the beginning, the inhibitors 2 , 3-ep oxysqua 1 ene-1 anostero 1 -cic 1 to s_a have already been described in the bibliography, however, no type of urethanes as well as thio or dithio analogues are known as inhibitors of the 2, 3-epoxiesuqua 1 e no-1 ano stero 1-cic 1 asa The invention relates to the provision of anti-infective substances 1 or 1 which are suitable for the treatment and reofilaxis of the atherosclerosis and which, in comparison with known active substances, are distinguished by a better hypercholesterolemic effect with an increased selectivity and, thereby, an increased safety, since the compounds according to the invention, by virtue of its the evade efficiency as inhibitors the enzyme 2, 3-epa x i e s to 1 e o - 1 to no s te r 1-cyclase, can also inhibit the biosynthesis of ergosterol in fungi, are also suitable for the treatment of mycosis.

The present invention relates to 1 or more urethanes derived from azacycloalkanes, as well as to their thio and dithio analogs of the formula g e n e r a l in 1 a.m.-m means the numbers 0 or 1, n means the numbers 1 or 2, A means a single bond, a straight-chain or branched-chain alkylene group C? _H, a C2-8 alkenylene group or C-? _ 8, not being a directly unsaturated group - attached to the radical Y, X means an oxygen or sulfur atom, Y means an oxygen atom to sulfur, R1 means a C j alkyl group. Linear or branched chain, an alkenyl group CL_ or a C 1 alkynyl group, the multiple bond being isolated from the nitrogen bonding bond, R 'means a straight or branched chain C alkyl group, a C 1-4 alkenyl group or a C 1-4 alkynyl group, with a multiple bond of the nitrogen-carbon bond being isolated, or R 1 and R ~, together with the nitrogen atom, mean a saturated heterocyclic ring of 5-7 members, wherein a methylene group isolated from the nitrogen atom can be replaced by an oxygen or sulfur atom or by an -NH group or -N (alkyl), R3 to R °, which can be identical or different, denote hydrogen atoms or alkyl groups, R7 means a C3_7 cycloalkyl group, a phenyl or naphthyl group optionally substituted by one or two halogen atoms , with an alkyl, aleo xi, trifluoromethyl or VO group, or if A does not represent a simple 11 or, also means a hydrogen atom, E means an oxygen or sulfur atom, a methylene, carbonyl or sulfinyl group and R8 means a hydrogen atom, or E means the group -C (RR 1 o) -, where R9 represents a hydrogen atom and R 1 or together with the contiguous group R represents a carbon or carbon bond, where, unless otherwise mentioned, the alkyl groups contained in the radicals mentioned above may contain in each case from 1 to 3 carbon atoms and a halogen atom mentioned above can mean a fluorine, chlorine or bromine atom, its enantiomers, diastereoisomers, mixtures thereof and its salts, in particular its salts by the addition of acids physiologically compatible. Preference is given to compounds of the general formula I, in which m means the number 1, n means the number 1, A means a bond cercillo, uA alkylene group C ± -, straight chain • branched or a group alque ileno C2_4, no being an unsaturated group directly attached to the radical Y, X means a xenon or sulfur atom, Y means an oxygen to sulfur atom, R "means a straight or branched chain group, allyl or propargyl group, the multiple bond of the nitrile no-carbon bond being isolated, R 'means a straight or branched chain alkyl group C i-e, an allyl opioparyl group, the multiple linkage being isolated from the nitrogen or nitrogen bond, or R1 and R ~, together with the nitrogen atom, mean a saturated 5- to 7-membered heterocyclic ring, in which a methylene group isolated from the nitrogen atom may be replaced by a nitrogen atom. oxygen or sulfur, R3 to R6 which may be the same or different, meaning hydrogen atoms or methyl groups, R7 means a C3_6alkyl group, a phenyl or naphthyl group optionally substituted by one or two halogen atoms, with an alkyl group, alkoyl, trifluoromethyl or cyano, E means a sulfur atom, a methylene, carbonyl or sulfinyl group R8 means a hydrogen atom, or E means the group -C (R 'R10) -, where R9 represents a hydrogen atom and R10, together with the adjacent group R8, represents a carbon-carbon bond, where, if not mentioned otherwise, the alkyl groups contained in the radicals mentioned above can each contain from 1 to 3 carbon atoms and The aforementioned halogen atom can mean a fluorine, chlorine or bromine atom, its enantiomers, diastereomers, its mixtures and its salts, in particular its salts by the addition of physiological acids. you compatible. Particularly preferred are the compounds of the general formula I, in which m means the number 1, n means the number 1, A means a single bond or a straight or branched chain C1-3 alkylene group, X means an oxygen atom or sulfur, Y means an atom of xigene to sulfur, R1 means an alkyl group A-3 branched chain line, R2 means a straight or branched chain C1-3 alkyl group, or R1 and R2, together with the nitrogen atom , they mean a piperidino or morpholino group, R3 a Rr >; they mean hydrogen atoms, R7 means a cyclohexyl group or a phenyl group and it is not replaced by an atom. of halogen, with an alkyl group, alkoxy otrif 1 uro romethyl, E means a sulfur atom, a methylene, carbonyl or sulfinyl group and R8 means a hydrogen atom, or E means the group -C (R <R10) -, wherein R9 represents a hydrogen atom and R10, together with the adjacent group R8, represents a carbon-carbon bond, its enantiomers, diastereomers, its mixtures and its salts, in particular its salts by addition of physiologically compatible acids. The compounds of the general formula I are particularly preferred, where m means the number 1, n means the number 1, A means a single bond or a methylene group, X means an oxygen or sulfur atom, Y means an atom from oxygen to sulfur, R1 and R2 signify in each case a methyl group, R3 to R6 signify hydrogen atoms, R7 sig means a phenyl group optionally substituted with a fluorine or chlorine atom or with a methyl group, E means an atom of sulfur, a methylene or carbonyl group and R8 means a hydrogen atom, or E means the group -C (R ° R10) -, where R9 represents a hydrogen atom and R10, together with the adjacent group R8, represents a carbon-carbon bond, their mixtures and their salts, in particular their salts by the addition of compatible organic acids, but especially the compounds. (1 N- (benzylthio) thiocarbonyl-4- [4- (dimethyl-am in orne-phenyl-thio] piperidine, (2 N- (benzylthio) thiocarbonyl-4- [4- (dimethylammonium orne-benzoyl] piperidine, (3-N-benzyloxycarbonyl-4- [4- ('dimethylamino-methyl) phynyl] piperidine, N- (4-chlorophenoxy) carbonyl-4- [4- (dimethyl-ami nomethyl phenylthio] piperidine, ( 5 N- (benzylthio) thiocarbonyl-4- [4- (dimethyl-amine n-benzyl) piperidine, - (6 N- (benzylthio) thiocarbonyl-4- [4- (dimethyl-amine nyl-benzylidene] piperidine, ( 7 N- (4-chlorophenoxy) thiocarbonyl-4- [4-dimethylaminomethyl) benzyl] piperidine, (8) N- (4-chlorophenoxy) carbonyl-4- [4- (dimethyl-ami nome ti 1) be nci 1] piperidine, (9) N-benzylaxycarbonyl-4- [4- (dimethylamino-me ti 1) be nci 1] piperidine, (10) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) carbonylpiperidine, (11) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) thiocarbonylpiperidine and (12) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-fluorophenoxy) carbonylpiperidine,, their mixtures and its salts, in particular its salts by the addition of physiologically compatible acids, for example its hydrochlorides, do not contain any salts and tartrates. The compounds of the general formula I can be prepared, for example, according to the following methods: a) Reaction of a compound of the general formula e n l a q u e m, n, E with the exception of the sulfinyl group, R 1 to R s and R 8 are defined as mentioned at the beginning, with a compound of the general formula z ?? AR '(III), wherein A, X, Y and R7 are defined as mentioned at the beginning, and Z means a leaving group, for example a halogen atom such as the chlorine, bromine or iodine atom. The reaction is carried out under conditions of S cho 11 in-B to null or Einhorn urn, ie the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between -50 ° C and +120 ° C, preferably between _ = 10 ° C and + 30 ° C, and optionally in the presence of diso 1 v_e ntes. Suitable auxiliary bases are alkali metal and alkaline earth metal hydroxides, for example sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, for example sodium carbonate, potassium carbonate or cesium carbonate, alkali metal acetates, for example sodium or potassium acetate, as well as tertiary amines, for example pyridine, 2,4,6-tr ime ti lp iridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diaz ab i ci cio [2, 2, 2] oc t an o 1, 8 - di az ab icic 1 or [5,, 0] -undec-7-ene and, as solvents, for example, diethyl ether, methylene chloride, dichloromethane, ethyl acetate, toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-1-methyl or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as auxiliary bases, water may also be added to the reaction mixture as a mixture or 1 ve n t e. b) For the preparation of compounds of the. general formula (I), in which X and Y signify in each case a sulfur atom and m, n, A, E and R1 to R8 are defined as mentioned at the beginning, with the proviso that R1 does not represent any phenyl or optionally substituted naphthyl group, in case A means a single bond: reaction of compounds of the general formula (II), in which m, n, E with the exception of the sulfinyl group, R1 to R6 and R8 are defined as mentioned at the beginning, with carbon disulphide and then with an alkylating agent of the general formula (IV), A wherein A and R are defined as mentioned at the beginning, with the proviso that R7 does not represent any phenyl or optionally substituted naphthyl group, in case A means a single bond, and Z1 means a leaving group, for example a halogen atom such as the chlorine, bromine or iodine atom, a group a 1 qu i 1 su 1 f on i 1 axi with 1 to 10 carbon atoms in the alkyl part, a group f in i 1 su 1 f on i 1 axio na fti 1 su 1 foni 1 ai mono-, di-tri-us us tit ui do possibly with atoms of c 1 o r_o or bromine, with methyl or nitro groups, being able to be. equal or different substituents. The reaction is conveniently carried out so that a compound of the general formula (II) in a suitable solvent, for example in a drier, dioxane, hexane or toluene, is first converted into the lithium salt, for example with n-butyl 1-1, at a temperature of -20 to -10 ° C and then reacted with carbon disulfide. Next, a compound of the general formula (IV) is added in a suitable solvent, for example in tetrahydrofuran, dimethylformamide, di me ti 1 su 1 f or ix or a mixture thereof, and the reaction is carried out at 20-60 ° C. c) For the preparation of compounds of the general formula (I), in which E means a sulfinyl group: Oxidation of a compound of the generic formula aA (I), wherein m, n, A, X, Y and R1 to R8 are defined as mentioned at the beginning and E means a sulfur atom, preferably with sodium periodate. The oxidation is conveniently carried out with an equivalent of the oxidizing agent used, for example with sodium tetrahydrate, in aqueous methanol or ethanol at 15. to 25 ° C. The compounds of the general formula I prepared according to the preceding processes can be purified and isolated according to known methods, for example by crystallization, distillation or chromatography.

In addition, the compounds of the general formula I obtained can optionally be separated into their enantiomers and / or d i a s t e r e or i s. Thus, for example, the compounds of the general formula I obtained, which are manifested in racemates, can be separated according to methods known per se (see Allinger N. L. and Eliel E. L. in Topics in S t e r eo chemi s t r y, vol. 6 Wiley I nters cience, 1971)), in their optical antipodes, and compounds of the general formula I with at least 2 asymmetric carbon atoms can be separated, by virtue of their physical-chemical differences ", according to methods known per se, for example by chromatography and / or fractional crystallization, in their eosomeric days which, if they result in racemic form, can then be separated into the enantiomers as mentioned above. The enantiomers are preferably effected by column separation in chiral phases or by rectalization in an optically active solvent or by reaction with an optically active substance which forms with the racemic compound salts or derivatives such as, for example, esters or amides, particular S-acid and its activated derivatives or alcohols, and separation of the mixture of salts derived from the obtained derivative in this manner, for example in vir It has different solubilities, and free antipodes can be liberated from the pure salts or from the derivatives by the action of suitable agents. Particularly customary optically active acids are, for example, the D and L forms of tartaric acid or dibenzayltartaric acid, di-o-tolyl tartaric acid, acid, malic, mandelic acid, hydrophilic acid, glutamic acid, acid aspartic or quinaic acid. As optically active alcohol, for example, it comes into consideration (+) - or (-) -mentol and, as an optically active acyl radical in amides, for example (+) - or (-) -me nti 1 ox ic arb on 1 o. Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular for the pharmaceutical application, into their physiologically compatible salts with inorganic or organic acids. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maceic acid. The starting compounds of formula I to general formula II, in which E means a group c a r b or ni 1 o, can be prepared according to the methods described in DE 44 07 136 Al (pages 4 - 5). The starting compounds of the general formula II, in which E means a methylene group or the group -C (R 9 R 10) -, wherein R 9 represents a hydrogen atom and R 10, together with the group R 8 contiguous, represents a hydrogen bond bono-ca r bo no, can be prepared according to the methods described in document DE 4 07 138 Al (5/1144) (pages 7 - 8). Compounds of the general formula II, in which E means an oxygen or sulfur atom, can be prepared according to the following scheme of r e a c clon: -The reaction of a compound of the formula V, wherein R1 to R5 are defined as mentioned at the beginning and E means an oxygen or sulfur atom, with a compound of the signature VI, wherein m, n, R6 and R8 are defined as mentioned at the beginning, R11 signifies a protective group, for example the tere-bu ti1-X-carbonyl group, and R12 signifies an alkyl radical, provides a corresponding compound of the formula VII which can be converted into a compound of the formula II by removal of the protective radical R11. Compounds of the general formula II, in which E means a methylene group, an oxygen or sulfur atom, R3 to R5 and R8 mean hydrogen atoms, R means a hydrogen atom or an alkyl group, and the phenyl radical is disubstituted in positions 1, 4, they can be prepared according to the two methods shown in the following reaction scheme: (II) (II) On the one hand, a compound of formula VIII, in which R 11 represents a protecting group, preferably a 2.2.2-tri-c-methoxy-carborxyl group, can be converted to a compound of formula IX by chloro Orne ti 1 aci ón. Aminolysis with an amine of the formula RXR2NH provides a compound of the formula X which can be converted to a compound of the formula II by removal of the protecting group. On the other hand, a compound of the formula VIII, in which R 11 represents a protecting group, preferably the trifluoride radical, can be converted into a compound of the formula XI by a Fpedel-Craft reaction with oxalyl chloride in the presence of aluminum chloride. Aminolysis with an amine of the formula R 1 R 2 NH yields a compound of the formula, XII which can be converted into a compound of the formula II by reduction with lithium aluminum hydride and removal of the radical-protector. _ Compounds of formula II, e? that E means an oxygen or sulfur atom, R3 to R5 and Rβ signify hydrogen atoms and R6 signifies a hydrogen atom or an alkyl group, can also be prepared according to the following method: (XV) A compound of formula XIII, wherein R represents a protective group, preferably a trifyl radical, is first transformed into the lithium compound and is then reacted with a compound of the formula XIV, in which Hal is a chlorine, bromine or iodine atom, for give a_ compound of formula XV. The separation of the protecting group gives a compound of the f or rmu 1 a II. . The compounds of the general formula I possess interesting biological properties. They represent inhibitors of cholesterol biosynthesis, in particular inhibitors of the enzyme 2, 3-e po xlescualeno-lánosterol-oirl.asa. By virtue of their biological properties, they are suitable for the treatment of diseases in which the biosynthesis of cholesterol plays a role, in particular for the treatment and prophylaxis of hypercholesterolemia, the hyper 1 ipopr ote inemi and the hypertrig 1 icer idem of the atherosclerotic variations of the vessels that result from them with their deuteropathies such as coronary heart disease, cerebral ischemia, intermittent claudication, gangrene and others. "For the treatment of these diseases, the compounds of the general formula I can be used alone for the monotherapy or be used in combination with other substances network cholesterol or 1 ip idos, can be administered the ^ compounds preferably in the form of an oral formulation, optionally also in the form of suppositories as a rectal formulation As part of the combination, the following may be used, for example: bile acid-binding resins such as, for example, co-stretch amine, colestipol and others, - compounds that inhibit the resorption of cholesterol such as, for example, sitosterol and neomycin, - compounds that are involved in the biosynthesis of cholesterol through another mecan is not the inhibition of cholesterol. , 3-epox i is qualeno-1 ano ster ol-cyc sa such as, for example, inhibitors of the HMG -CoA- r educ rate such as lovastatin, s imva statina , pra va stati na, f 1 u va stt ina, ato rva stat in a, ceri va stat ina and others, inhibitors of the espo 1 ene-epopoxide sa such _cojr? o, for example, NB 598 and analogous compounds, as well as - 1-enzyme synthetase inhibitors, such as, for example, representatives of the class of isoprenoi of - (phosphinylmethyl) -phosphonates and stannane. As other possible participants in the combination, there must also be mentioned the class of fibrates such as clofibrate, bezafibrate, .gemfibrozil and others, nicotinic acid, its derivatives and analogues such as, for example, acipimox, as well as probucol.

In addition, the compounds of the general formula I are suitable for the treatment of diseases that are related to increased cell proliferation. Cholesterol is an essential component of cells and has an ester present in sufficient quantity for cell proliferation, ie cell division. The inhibition of cell proliferation by the inhibition of cholesterol biosynthesis is described, as mentioned at the beginning, in the example of smooth muscle cells with the HMG-CoA reductase inhibitor of the mevinolin type, lovastatin. As examples of diseases that are related to an increased cell proliferation, tumoral diseases should be mentioned first. In experiments with cell cultures and in vivo, it was shown that the reduction of serum cholesterol or the intervention in the biosynthesis of Cole-esterol by inhibitors of HMG-C or A-r educ rate reduces the development of the tumor (Lancet). 339, 1154-1156 [1992]). The compounds of the. Formula I according to the invention are, therefore, by virtue of their eJf e c_t or inhibitor of cholesterol biosynthesis, potentially suitable for the treatment of tumor diseases. In this case, ^ can find application alone or for the support of known therapeutic principles. As other examples, skin diseases such as, for example, psoriasis, basal cell carcinoma, squamous cell carcinoma, keratysis, and disorders of the skin have to be mentioned. The term "psoriasis" used herein designates an inflammatory skin disease h ip e r p r o 1 i f e r a t i va that modifies the mechanism of skin regulation. In particular, lesions involving primary and secondary proliferation of epidermal proliferation are formed, • inflamed reactions of the skin and the expression of regulatory molecules such as lymphokines and inflammation factors. Psoriatic skin is distinguished by a reinforced transformation of the cells of the epidermis, a hypertrophied epidermis, one that causes abnormal infiltration of inflammatory cell infiltrates in the dermis layer and a poor infiltration of the skin. 1 ear of leukocytes in the epidermis that conditions an increase in the cycle of the basal cells. Additionally, hypersensory cells are present that are phytic and p a r a r t t t ca s. The terms "keratosis", "basal cell carcinoma", "flat cell carcinoma" and "keratinization disorders" refer to skin diseases - hyperproliferative in the "what" the regulation mechanism for proliferation and differentiation is interrupted of the skin cells - The compounds of the formula I are active as antagonists of the hyperproliferation of the skin, that is to say as agents that inhibit the hyperproliferation of human ratinocites. suitable as agents for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, keratinization disorders and keratoses For the treatment of these diseases, the compounds of the formula I can be applied orally or topical, being able to be used alone in the form of monotherapy or in co-ination with known active substances In addition, hyperproliferative diseases of the vessels triggered by surgical measures such as PTCA (percutaneous transluminal coronary artery) or arterial bridging operations such as stenoses and occlusions of the vessels that are I based on the proliferation of smooth muscle cells. As mentioned at the beginning, this cell proliferation can be suppressed in a manner known by inhibitors of HMG-CoA-reductase of the mevinolin type such as lovastatin. By virtue of its inhibitory effect on f cholesterol biosynthesis, the compounds of the General formula I are also suitable for the treatment and prophylaxis of these diseases, being able to find application alone or in combination with known active substances such as e, or, for example, heparin applied intravenously, preferably in the oral application. Another possibility of using the compounds of the general formula I according to the invention is the prophylaxis and treatment of cholelithiasis. The formation of gallstones is triggered that the concentration of cholesterol in the gall bladder exceeds the maximum solubility of cholesterol. in the liquid. bile, with which the precipitation of cholesterol takes place in the form of biliary calculations. Lipid reducers of the class of fibrates lead to an increased secretion of.

Neutral steroids through the gallbladder and increase the tendency to the formation of gallstones. In contrast to this, inhibitors of cholesterol biosynthesis such as lovastatin. or pravastatin do not lead to an increased formation of gallstones, but, on the contrary, they determine a reduction of the. concentration of cholesterol in the gallbladder and, therefore, decrease the so-called lithogenic index; a measure of the likelihood of gallstone formation. This is described in Gu t _3_1, 3463 -_ 350 [199Q] as well as in Z. Ga s t r o e n t e r o 1. 2_9_, 242-245_ [1991]. In addition, in Ga s t r oen erology 102, No. 4, Pt. 2, A 319 [1992] describes the activity of lovastatin in the dissolution of gallstones, in particular in combination with acid or oxidase. By virtue of its mode of action, the compounds of the. General formula I are therefore also of importance for the prophylaxis and the t a t t of cholelithiasis. In this case, you can find application alone or. in combination with . known therapies such as, for example, treatment with uric acid oxides coli co or shock wave lithotripsy, preferably in oral application. Finally, the compounds of the. General formula I are suitable for the therapy of infections by pathogenic fungi such as, for example, Candida albicans, Aspergillus niger, Trichophyton me n t a g r op h y t e s, Penicillium sp. , Cladosporium sp. and others. As mentioned before, the final product of the biosynthesis of the sterol in the fungus is not cholesterol, but the e r g o s t e r, or 1 essential for the integrity and function of the cell membranes of the fungus. Therefore, the inhibition of ergosterol biosynthesis leads to growth disorders and, eventually, to the extermination of fungi. For the treatment of mycosis, the compounds of the general formula i. Can be administered orally or topically. In this case, they can be used alone or in combination with known antifungal active substances, in particular with those which are involved in other stages of steroid biosynthesis, such as, for example, inhibitors of es cu 1 in o-ep. oxi da sa terbinafine and naftifine, or inhibitors of 1 anostero 1-14 a- of sme ti 1-aa of the azole type such as, for example, ketoconazole and fluconazole. Another possibility of application of the compounds of the general formula I refers to the application in poultry farming. The decrease in cholesterol content of eggs is described by administration of the HMG-CoA reductase inhibitor lovastatin to laying hens (FASEB Journal 4_, A 533, Abstracts 1543 [1990]). The production of eggs low in cholesterol is of interest. since the cholesterol load of the body can be reduced by eggs with reduced cholesterol content without v a r i a r _ ALo s h J dit = s = feeding. By virtue of their inhibiting effect on cholesterol biosynthesis, the compounds of general formula I can also find application in poultry farming to produce eggs poor in cholesterol, the substances being administered preferably in the form of a fat additive. The biological effect of compounds of the general formula I was determined according to the following methods: I. Measurement of the Inhibition of the incorporation of 14C-acetate in the precipitable steroids with digi onine: The investigation of the inhibitory effect was carried out according to the method described in. JA Lipid. Res. 37, 148-157 [1996] at test concentrations of 10 ~ 8 and 10 ~ 9 moles / 1. By way of example, the test results of the following compounds (A) to (M) of the general formula I and of the comparative substances (U), (V) and (W) at these test concentrations are indicated: ( A) N- (Benzylthio) -thiocarbonyl-4- [4- (dimethyl-aminomethyl) phenyltio] -piperidine hydrochloride, (B) N- (benzylthio) thio carbonyl hydrochloride 4- [4- (dimethyl- aminomethyl) benzoyl] - piper üina, "(C) N-be cycloxychloride 1 oxycarboni 1 - 4 - [4- (dimethyl-aminomethyl) phenylthio] piperidine, (D) N- (4-c 1 orofenoxi) hydrochloride ) - carbonyl-4- [4- (dimethyl-aminomethyl) phenylthio] - pipe r id i na, (E) N- (benzyl t, io) - ^ thiocarbonyl-4- [4- (dimethyl-aminomethyl) hydrochloride) benzyl] - piperidma, (F) N- (benzylthio) -5-thiocarbonyl-4- [4- (dimethyl-aminomethyl) benzylidene] -piperidine hydrochloride, (G) N- (4-c 1 orof enox i) hydrochloride - thiocarbonyl-4- [4- (dimethylaminomethyl) benzyl] -) piperidine, 10 (H) N - hydrochloride 4-c 1 orof enox i) - carbonyl, -4- [4- (dimethyl-aminomethyl) -benzyl] - pipe ridin, (I) N-benzyl hydrochloride 1 ox i ca r bon i 1 - 4 - [ 4- (dimethylaminomethyl) benzyl] piperidine, 15 (K) H oc dr of 4 - [4 - (di me t ylamethylmethyl) benzyl] - N - (4-methylphenoxy) carbonylpiperidine, (L) Hydrochloride 4- [4- (dimethylaminomethyl) bnc] N- (4-methylphenoxy) thiocarbonyl-piperidine, 20 (M) 4 - [4 - (dimethylammethylmethyl) benzyl] -N- hydrochloride ( 4-fluorophenoxy) carbonylylpiperidine (U) 1- (4-chlorobenzayl) -4- [4- (2-oxazolin-2-yl) -benzyl-1 iden] -p ipe ri dine (EP-A-0 596 326, page 16, and there the compound A; J. _ Lipid. 25 Res. 38, 564-575 [1997]), (V) trans-N- (4-chlorobenzayl) -N-methyl- [4 - (4-d methylaminoethyl) phenyl] cyclohexylamine (DE-A- 44 38 020; J. Lipid, Res. 37, 148- 157 [1996]) and (W) trans-0- (p-tolyl-acetyl) -4- (_ 4 -dimethyl-ami n orne ti 1) fei 1 cic 1 ohe a no 1 (WO 95/29148, page 28, and there the compound I). The percentages for inhibiting the incorporation of 1 4 C-acetate in the above compounds are indicated in Table 1.

Table 1 Of the compounds H, I, K and M, the IC 50 values are determined. These are indicated in Table 2 together with the IC 50 values of the compounds U, V and W.

Table 2 From Table 2 one can observe a significant superiority of the compounds according to the invention with respect to the comparative substances described above. _ II. Measurement of the effect in vivo in the rat after oral administration The inhibition of the enzyme 2,3-epoxy is qu1a1-no to 1-s1 1-ci c1 asa 'determines an increase in the level of 2,3-epoxysqualene in the liver and in the plasma. Therefore, the amount of 2, 3-epoxies that is formed serves as a direct measure of the power of action in the whole animal. The determination was carried out according to the method described in J. Lipid. Res. 38, 564-575 [1997] after t = 3 or 8 hours after administration of the substance with concentrations of c = 0.01, 0.03, 0.1, 0.3 and 1.0 mg / kg. In the following Table 3 the results for the substances A, B, C, D, E, G, H, I and K mentioned above are given by way of example.

Table 3 Concentration of 2.3 epoxysqualene [μg / g] in the liver (rat) In control animals, no medial level of 2,3-epaxyesqualene was observed under these conditions.

III. Reduction of lipids in the normolipémico golden hamster This determination was carried out according to the method described in J. Lipid. Res. 38, 564-575, (1997). At the end of the test, tctal, ß-1 and popula rt cholesterol were determined as well as HDL-cholesterol and compared to the values of a control group fed without the test substance. The lipid reducing effect of compound H mentioned above was examined. The results are compiled in Table 4.

Table 4 Under these conditions, the compounds showed no toxic effect IV. Determination of the fungistatic effect The -fungistatic effect was determined through the serial dilution test (microtitre system). Sabouraud broth served as a nutrient medium. The inoculum amounted to ipro imada at 104 to 105 CFU / ml (CFU = units form colonies); the culture time amounted to 2 to 4 days at 26 ° C. The lowest concentration that no longer allowed a vi s i b 1 e development (minimum inhibitory concentration MIC) was determined. Compounds A, B, D, E were added, F, H, I, K, L and M mentioned above. The results are compiled in the following Table 5. The MIC is indicated in μg / ml. The following test germs were used: Table 5 For the pharmaceutical application, the compounds of the general formula I can be incorporated, in a manner known per se, into the forms of usual pharmaceutical preparations for oral, rectal and topical administration.

Formulations for oral administration include, for example, tablets, dragees and capsules. For rectal administration, suppositories are preferably considered. The daily dose ranges from 0.1 to 200 mg for a human being with a body weight of 60 kg but a daily dose of 1 to AL0_D mg is preferred for a human being with a body weight of 60 kg. The daily dose is preferably divided into 1 to 3 individual doses. In the case of topical application, the compounds can be administered in preparations containing approximately 1 to 1000 mg, in particular 10 to 300 mg of active substance per day. The daily dose is preferably divided into 1 to 3 individual doses. _ Topical formulations include gels, creams, 1 or c or n_e_s, ointments, powders, lerosols and other customary formulations for the application of therapeutic and curative agents on the skin. The amount of active substance for topical administration. it yields 1 to 50 mg per gram of formulation, but preferably at 5 to 20 mg per gram of formulation. In addition to the application on the skin, the topical formulations of the present invention can also be applied in the treatment of mucosae that are accessible to topical treatment. For example, topical formulations can be applied to the mucous membranes of the mouth, lower colon and others. For the application in poultry farming for the production of eggs low in cholesterol, the active substances of the general formula I are administered to the animals according to the usual methods as additive to suitable feeds. The concentration of the active substances in the finished feed normally amounts to 0.01 to 1% but preferably to 0.05 to 0.5%. The active substances can be added as such to the feed. Thus, the incenses according to the invention for laying hens with 11 in, along with the active substance and possibly together with a usual mixture of v 11 ami-s-mine nera 1 is, for example corn, meal of so a, meat meal, feed fat and soybean oil. To this feed is added by mixing one of the compounds of the formula I mentioned at the beginning as active substance in a concentration of 0.01 to 1% but preferably 0.05 to 0.5%.

The following Examples are used for the more detailed explanation of the invention. The indicated Rf values were determined on finished plates from the firm E. Merck, Darmstadt, namely n a) aluminum oxide F-254 (type E b) silica gel 60 F-254 Examples for the preparation of starting materials: E jep lo, A 4- [4- (dimethylaminomethyl) phenylthio] piperidine To a solution of 7.18 g (71 mmol) of 4-hydroxypiperidine in 100 ml of dimethylformamide was added. First, add 19.6 g 142 mmol) of powdered potassium carbonate and then add 19.8 g (71 mmol) of triflyl chloride. Stir for 22 hours at room temperature, it is diluted with acetic acid ethyl ester to twice the volume, washed with water and sodium chloride solution, dried with magnesium sulfate and concentrated by evaporation. The residue is recrystallized from ethyl acetate, acetic acid / petroleum ether (1: 4, v: v). 17.65 g (72.4% of theory) are obtained from 4-hydroxy-Nt-rity Ip ipe ridine in the form of colorless crystals of melting point 157-158 ° C. 5.77 g of this product are dissolved in 60 ml of methylene chloride, 2.6 g of methylene chloride are added, and 3.4 g of riethylamine are slowly added dropwise, stirring is continued for 1 hour at 0 ° C. ° C, it is diluted with ether, washed with ice / water (4 times), dried over magnesium sulfate and concentrated by evaporation to give 7.58 g of 4-me tanosu, 1 of 11 oxi. N-triti Ipidiperidine in the form of a colorless foam. The product is dissolved in 30 ml of tetrahydrofuran and added dropwise to a solution of the sodium salt of 4-bromothiophenol (prepared from 3.18 g of 4-br omo tiofe no 1 and 0.81 g of 55% sodium hydride in 35 ml of tetrahydrofuran). The mixture is heated for 1 hour up to 1 hour, after cooling it is recited in ethyl acetate, washed with water and saturated sodium chloride, dried with magnesium sulfate and concentrated. by evaporation. 5.28 g of 4 - (4-b r omo f e n i 11 i o) - N-t r i t i Ip ipe r idi in the form of colorless crystals are obtained, of melting point 174-175 ° C. 2.57 g (5 mmol) of this product are dissolved in 30 ml of tetrahydrofuran and, at -70 ° C, 4 ml (6.4 millimoles) of a 1.6 molar solution of n-buty are added dropwise. 1 - 1 itio in nrhexane. After 1.5 hours at -70 ° C, 1.1 g (6.4 mmol) of N, N-d-ime-1-methyl-1-iodide is added, the cooling bath is removed and It is stirred overnight. The solvent is evaporated, the residue is triturated with water and extracted with ethyl acetate. The organic phase is dried with magnesium sulfate, concentrated by evaporation and the residue is purified by column chromatography (aluminum oxide, acetic acid ethyl ester / petroleum ether = 1: 1, v: v). 0.9 g of 4 - [4- (dimethylaminomethyl) phenylthio] -N-t-ethylpiperidine are obtained in the form of colorless crystals of melting point 163 ° C. This product dissolves in. 3Q_ mi of methylene chloride and 10 ml of ethereal hydrochloric acid are added. After 1 hour at room temperature, concentrate, mix with ether and the precipitate is filtered with suction. This dissolves in a little water, se. add ether and adjust to pH 11 with 6N sodium hydroxide solution. The etheric phase is separated, the aqueous phase is extracted again with ether and the combined extracts are dried with magnesium sulfate. 500 mg of 4- [4- (d ime t i 1 ami nome t i 1) f in i 11 i o] p i pe r i di na are obtained in the form of colorless crystals with a melting point of 52 ° C.

E n emp lo B 4- [4- (piperidinomethyl) phenylthio] piperidine 10, 1 g (0.1 mole) of 4-hydroxypiperidine and 11 g (0.11 mole) of triethylamine are previously prepared in 200 ml of ester acetic acid ethyl ester and 250 ml of tetrahydrofuran and, at 0-4 ° C, a solution of 23.3 g (0.11 mole) of ether 2.2.2 - tic 1 oroethane is added dropwise. of chloroformic acid. Stirring is continued for 1 hour at 0 ° C and for 1 hour at room temperature. The precipitate is filtered off with suction, the filtrate is mixed at -12 to -14 ° C with 12 g (0.105 mol) of methanesulfonic acid chloride and, at -8 to 12 ° C, are added dropwise 12 g (0.12 mol) of trie tjla.m_i_n_a in 50 ml of .tetrahydrofura no. For 40 minutes at -10 ° C, the cooling bath is removed and stirred for 30 minutes. After the reaction with water and sodium chloride solution, it is dried with magnesium sulfate, concentrated by evaporation, the residue is triturated with diis or opium, and filtered with suction. 32.4 g (91.5% of theory) of 4-methanesulfonyloxy-N-2.2.2-tri-chloro e ~ or icarbonyl-piperidine in the form of colorless crystals of melting point 93 ° C. 17.7 g (50 mmol) of this product in 30 ml of dimethylformamide are added dropwise, at room temperature, to a solution of thiophenolate potassium (prepared from 6 g thiophenol and 6.2 g terpene). -butyrate of potassium in 50 ml of dimethylformamide at 20-60 ° C). The resulting jelly is mixed with 100 ml of 1 ml of milk, heated to 60 ° C and, after the addition of 30 ml of methanol, allowed to stand overnight at room temperature. After the addition of 800 ml of water, it is extracted with ether, the ethereal extract is washed with water, dried with magnesium sulfate and concentrated by evaporation. After purification by column chromatography (silica gel, petroleum ether / acetic acid ethyl ester = 5: 1,, v: v), 11 g (64.3% of theory) of 4-phenylthioate are obtained. N-2.2.2-trichloroethoxycarbonylpiperidine in the form of a colorless oil. 9 g (25 millimoles) of this product, 6 g of p a r a ox ox ldehyde and 5.6 g (42 millimoles) of. Zinc chloride is previously placed in 300 ml of methylene chloride. At 20-22 ° C, hydrogen chloride is introduced for 30 minutes, after one hour, hydrogen chloride is added again for 10 minutes and the mixture is stirred overnight. 300 ml of a 1 molar solution of disodium hydrogen peroxide, the methylene chloride phase is separated and the aqueous phase extracted with chloride of m e.t i 1jg no. The organic phases are combined, washed with water, dried with magnesium sulfate and concentrated by evaporation. After purification - by column chromatography (silica gel, acetic acid ethyl ester / petroleum ether = 1:10, v: v), 4.5 g (43.2% theoretical A ) rde 4 - [4 - (chloromethyl) phenylthio] -N-2.2.2-tri chloroef or icarbonylpiperidine as a colorless oil. 2.1 g (5 millimoles) of eAe product and 1.3 g (15 millimoles) of piperidine are heated under reflux for 2.5 hours in 10 ml of trahydrofuran and 10 ml of ethanol. After evaporation, it is mixed with water and extracted, with ether. The ether phase is washed with water, dried with magnesium sulfate and concentrated by evaporation. 2.5 g of 4- [4- (piperidinometyl) phenylthio] -2.2.2-trichloroethoxycarbonylpiperidine are obtained as a crude product 2.4 g of this product are dissolved in 3.5 ml of acetic acid and 18 ml of water and add 5 g of zinc powder (intense foaming), stir for 20 hours at room temperature and for 1 hour at 50 ° C. After the addition of 20 ml of water, it is coated with 100 ml of water. The ether is strongly alkalized with 6N sodium hydroxide solution and stirred for 20 minutes.The ether is separated and the aqueous phase is extracted 3 times with ether.The dry components are dried with magnesium sulfate. , they are concentrated by evaporation, 1.3 g of 4 - [4 - (piperi di nome 111) f enyl thio] pi pe rid ina ~~ eT "is obtained from a powder - green. _ Rf value: 0.69 (aluminum oxide, methylene chloride / methanol = 10: 1, v: v).

Example C 4- [4- (dimethylaminomethyl) benzyl] piperidine 100 g (0.57 mol) of 4-benzyl piperidin in 220 mA of methanol are mixed at 20 to 35 ° C with 88 g (0, 68 moles) of trifluoroacetic acid methyl ester. After 2 hours, concentrate by evaporation. After crystallization of the residue from petroleum ether, 117 g (76% of theory) of 4-benzyl-N-trifluoroacetylpiperidine are obtained as colorless crystals. 113 g (0.848 moles) of aluminum chloride in 600 ml of dichloroethane are mixed with 114 g (0.9 mls) of oxalyl chloride. At -4 to + 4 ° C, 114 g of the above product are added dropwise to 300 ml of dichloroethane (gas evolution). The mixture is stirred for 2.5 hours at room temperature and then 300 ml of a 40% aqueous solution of imethylamine are added rapidly at -25 ° C (increase in temperature up to 35 ° C). The resulting jelly is diluted with 100 ml of dichloroethane, stirred for 20 minutes and c. Dilute with chloroform for better phase separation. It is washed with water, 2N sodium hydroxide solution, water, 2 N hydrochloric acid and again with water. The organic phase is dried with magnesium sulfate, concentrated by evaporation and the residue is triturated with ether. 111 g (80% of theory) of 4- [4 - (d ime t i 1 ami n or c a r b on i 1) -benzyl] -N-trifluoroacetylpiperidin.a are obtained in the form of colorless crystals. 64 g of this product in 350 ml of tetrahydrofuran are added dropwise, at 0 to 3 ° C, to 70 ml of a 20% solution of lithium hydride and aluminum in ether, diluted with 250 ml of ether. It is stirred for 20 minutes at 0 ° C and then heated to reflux for 1 hour. At 0 ° to 15 ° C., 40 ml of 4 N sodium hydroxide solution (strong foaming) are added dropwise, the mixture is stirred at room temperature for 30 minutes, filtered off with suction and the filter residue is washed with ether. The combined ether phases are dried with magnesium sulfate and concentrated by evaporation. • 46 g A cA of the theoretical) of • I- [4- (dimethylamino-methyl) benzyl piperidine are obtained in the form of a colorless oil which slowly stirred. Rf value: 0.56 (aluminum oxide, meOH odor / me t a n o 1 = 10: 1, v: v).

Examples for the preparation of the final products: Example 1 Hydr or N- (benzylthio) thiocarbonyl-4- [4 - (dimethylaminomethyl) phenylthio] iperidine chloride A mixture of 237 mg (0.03 mg / ml) of 4- [4- (dimethylaminomethyl) phenylthio] piperidine, 200 mg (2 mmol) of triethylamine and 1 ml of ethanol are mixed at room temperature with 150 mg (2 mmol) of carbide sulfide.The resulting precipitate is to solution by the addition of 1 ml of triethylamine and A ml of dimethylformamide.After 1 hour at room temperature, 160 mg (0.94 mmol) of benzyl bromide is added, stirred overnight at room temperature. and then it is heated for 3 hours to 60 ° C. After the addition of 50 ml of water, it is extracted with ethyl ester - acetic acid, the organic phase is combined with magnesium sulphate and concentrated by evaporation. the purification of the residue by chromatography >; = n column (aluminum oxide, ethereal ether or acetic acid ethyl ester = 4: 1, v: v),. and obtain 210 mg of the title compound as a colorless oil which is converted to the hydrochloride with ethereal hydrochloric acid. Rf value of the base lie: 0, 83 (aluminum oxide, ethyl ester of acetic acid / petroleum ether = 3: 1, v: v). Spectrum of LH-NMR (200 MHz, DMS0-d6), signals in ppm: 1.4-1, 6 (m, 2H), 2.0-2.15 (m, 2H), 2.55 (d, 6H), 3.5-3, 65 (t, 2H), 3.7-3.85 (m, 1H), 4.2 (d, 2H), 4, 3-4.4 (m, 1H) , 4.5 (s, 2H), 4.95-5, 15 (m, 1H), 7.2-7.5 (m, 9H) Analogously, one obtains (1) N- (benzylthio) hydrochloride - thiocarbonyl-4- [4- (dimethylaminomethyl) -benzoyl] -piperidine, from 4- [4- (dimethylaminomethyl) -benzoyl] piperidine and benzyl bromide; colorless powder .; Rf value of the free base: 0.65 (aluminum oxide, acetic acid ethyl ester) (2) N- (benzylthio) -thiocarbonyl-4- [4- (dimethylaminomer il) benzylidene] -'piperidine hydrochloride, a from 4- [4- (dimethylaminomethyl) -benzylidene] piperidine and benzyl bromide; colorless powder; melting point: 190 ° C (3) N- (benzylthio) thiocarbon hydro nAi 1-4- [4- (dimethylaminomethyl) benzyl] -piperidine, from 4- [4- (dimethylaminomethyl) benzyl] - piperidine and benzyl bromide; colorless powder; f value of the free base: 0.26 (aluminum oxide, petroleum ether or ethyl ester of ascetic acid = 10: 1,: v) E xample 2 N-benzyloxycarbonyl-4- [ 4- (tell me you laminóme til) -phenylthio] piperidine 250 mg (1 millimole) of 4- [4- (di me ti 1 ami n ome ti 1) feni 11 io] piperidine in 20 ml of tetrahydrofuran are mixed with 2 ml of soda lye 2zr N and 5 ml of water. At room temperature, 200 mg (1.2 mmol) of benzyl ester of cyclophoric acid in 5 ml of tetrahydrofuran are slowly added dropwise. After 1.5 hours at room temperature, some chloroformic acid Joencyl ester and soda lye are again added. After the addition of 100 ml of ether, it is washed with saturated aqueous chloruronic solution, the exothermic phase is dried with sulfa or magnesium and concentrated by evaporation. The product obtained after purification by column chromatography (aluminum oxide, petroleum ether / acetic acid ethyl acetate = 4: 1, v: v) is converted to the hydrochloride with ethereal hydrochloric acid. 190 mg (45.1% of theory) of the title compound are obtained in the form of a colorless powder of melting point - 144 ° C. XH-NMR spectrum (200 MHz, DMSO-d,), signals in ppm: 1.3-1.5 (m, 2H), 1.85-2.0 (m, 2H), 2.65 (s, 6H), 2, 95-3, 15 (t, 2H), 3.5-3.65 (, 1H), 3.8-4.0 (m, 2H), 4.2 (s, 211), 5.05 (s, '2H), 7.3-7, 6 (m, "9" H) Analogously, the following are obtained: (1) N- (4-chlorofenylthio) - hydrochloride. thiocarbonyl-4- [4- (dimethylaminomethyl) phenylthio] -piperidine, from 4- [4- (dimethylaminomethyl) -f n i 1 t i o] p i p e r i n a and ester 4 - c 1 o r o f e n i i c o c o cio cyclic acid; colorless powder; melting point: 178 ° C ~ _ "" "i" A "(2) 4- [4- (Dimethylaminomethyl) -phenylthio] -N-phenoxycarbonylpiperidine hydrochloride ~, - - from 4- [4- (dimethylaminomethyl ) -phenylthio] piperidine and chloroformic phenyl ester, colorless ol, melting point: 11 ° C (3) N- (4-chlorophenoxy) -carbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine hydrochloride, from 4- [4- (dimethylaminomethyl) -pheni 11 io] piperidine and ester 4-c 1 orphene 1 i of chloric acid; colorless powder; melting point: 169 ° C (4) 4- [4- (dimethylaminomethyl) -phenylthiol-N- (phenylthio) thiocarbonylpiperidine hydrochloride, from 4- [4- (.dimethylaminomethyl) -phenol ti op ipe ridine and phenyl ester of "chlorodithioformic acid", colorless powder, R-value of the Aibre base: 0.57 (aluminum oxide, ether-petrol e_o / ethyl ester-acetic acid = 4: 1, v: v) (5) ) N - 4 - (4 - c 1 orophenoxy) -. Thiocarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine hydrochloride from 4- [4- (dimethylaminomethyl) benzyl] -piperidine and ester 4-c 1 gold ti of o rmi co-O-4-chlorophenyl, colorless powder, melting point: 150 ° C (6) M - (4-chlorophenoxy) ca bonyl-4- [4- (dimethyl-iminomethyl) benzyl] piperidine, , 4- (4- (4- (4-dimethyl-methyl) benzyl) -piperidine ester and 4-c-1-orofol in chloroformic acid, melting point of the mixture, free: 104 ° C Hydrochloric acid was obtained by hydrochloric acid treatment uro Colorless powder, melting point: 156 ° C. By treating the free base with jae t a sulfonic acid in an ester mixture. Ethyl, acetic acid and ether were obtained by ethanesulfonate. Colorless powder; melting point: 152 ° C. By treating the free base with L-tartaric acid in a mixture of methane 1. and ethyl acetate, the tartrate was obtained. Colorless powder; melting point: 147 ° C (7) N- (4-chlorofenylthio) -carbonyl hydrochloride 1-4 - [4- (dimethylaminomethyl) benzyl] piperidine, from 4 - [4 - (d ime ti 1 ami nome ti 1) be nci 1] -piperidine and S-4-chlorophenyl ester of c 1 oro thioformic acid; colorless powder; melting point: 190-191 ° C (8) N - be nc il or xi ca rbon i 1 - 4 - [4- (piperidinomethyl) phenylthio] piperidine hydrochloride,. from 4- [4- (piperidinomethyl) phenylthio] -piperidine and benzyl ester of chloroformic acid; colorless powder; melting point: 186 ° C (9) N-f-enoxica hydrochloride i-4 - [4 - (piperidinomethyl) phenylthio] piperidine, from 4- [4- (piperi the inomethyl) phenylthio] - piperidine and phenyl ester. of acid. _ci o ro.f o r my c o; colorless powder; melting point: 204 ° C (10) Hydrochloride of N-4 - c lo rof enoxi -carbonyl-4- [4- (piperidinomethyl) phenylthio] piperidine, from 4- [4- (piperidinomethyl) phenylthio] - piperidine and • ester 4-c 1 orop nor 1 i co of chloroic acid; colorless powder; melting point: 182 ° C (11) M-benzyloxycarbonyl-4- [4- (dimethylamino-me ti 1) e nc ii] pi pe ri dina, from 4 - [4 - (dime 11 laminóme 111) benc 11] -piperidine and benzyl ester of chloroformic acid; melting point of the free base: 63 ° C. The hydrochloride was obtained by treatment with hydrochloric acid. Colorless powder; melting point: 132 ° C. _ _ _ By treating the free base with. Methanesulfonic acid in a mixture of ethyl ester of acetic acid and methanesulfonate was obtained. Colorless powder; melting point: 140 ° C. The tartrate was obtained by treating the base li-b with AL-tartaric acid in a mixture of metanol and ethyl ester of acetic acid. Pol or colorless; melting point: 125 ° C (12) 4- [4- (dimethylammethyl) benzyl] -N- (4-methyl-phenoxy) carbonylpiperidine, from 4- [4- (d? met? laminomet (I) benzyl] -piperidine and 4-methyl-1-phenol ester of chloroformic acid; melting point of the free base :, 80 ° C. The hydrochloride was obtained by treatment with hydrochloric acid. Colorless powder; melting point: 185 ° C. By treating the free base with methane sulphonic acid in a mixture of acetic acid ethyl ester and methanesulfonate was obtained. Colorless powder; melting point: 165 ° C. - By treatment of the base 11b re with. L-tartaric acid in one. mixture of methanol and acetic acid ethyl ester, the tea was obtained. _ Colorless powder; melting point: 162 ° C _ (13) 4- [4- [Dimethylaminomethyl] _b_e, nyl] - N - (4-methylphenoxy) thiocarbonyl-piperidine hydrochloride, from 4- [4- (dimethylamino-met il) -_ _ benzyl] piperidine and 0-4-methylphenyl ester of c 1 oro thio phormi c; colorless powder; melting point J: 184 ° C (14) Hydrochloride of 4 - [4 - (di me ti 1 to my non-methyl) benzyl] -N- (4-fluorofenoxi) carbonylpiperidine, from 4 - [4 - (d ime t 11 ami nome ti 1) be nci 1] -piperidine and 4-fluorophenic ester of chloric acid; colorless powder; -alt Rt of the free base: 0, 61. (aluminum oxide, petroleum ether / acetic acid ethyl ester = 6: 1., v: v).

Use 3 N-benzyloxycarbonyl-4 - [4 - (dimethyl-1-aminomethyl) phenyl sulfinyl] piperidine hydrochloride 90.7 mg (0.215 mmol) of 5 N-benzyloxy-4- [4- (dimethylaminomethyl) hydrochloride ) phenol] - piperidine are dissolved in a mixture of 1 ml of methanol and 1 ml of water and are added, firstly, 18, 6 mg (0.226 mmol) of anhydrous ethyl sod ium i v then 48, 4 mq (0.226 mmol) of metaperiodate sodium. Stir for 6 h r i s at room temperature, diluted with water, and coated with ethyl acetate and saturated with sodium. The organic phase is separated, the aqueous phase is extracted with ethyl acetate, the organic phases fE combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated oncentran c. The residue is dissolved in a little methylene chloride, mixed with ethereal hydrochloric acid and the solvent is evaporated. He The residue is mixed by triturating with ether, the solvent is evaporated and the residue is dried under high vacuum. HE. they obtain 85 mg (90.5% of theory) of the title compound in the form of a colorless powder.

Rf value of the free base: 0.43 (aluminum oxide, acetic acid ethyl ester / petroleum ether = 1: 1, v: v). Spectrum of XH-NMR (200 MHz, DMS0-d6), signals in ppm: 1, 3-1, 6 (m, 3H), 1.8-2.0 (m, 1H), 2.65 (s, 6H), 2.7-3 1 (m, 3H), 3.95-4.15 (t, 2H), 4.35 (s, 2H), 5.05 (s, 2H), 7.3 (s, 5H), 7, 65-7,85? q, 4H) Analogously, we obtain: (1) 4- [4- (Dimethylammo-methyl) f-enylsulfinyl] -N-phenoxycarbonylpiperidine hydrochloride, from 4- [4- (dimethylamino-methyl) phenylthio] -N-phenoxycarbonyl-piperidine hydrochloride and sodium maleate; colorless powder; "UKR Rf lu free base: 0.4 'aluminum oxide, -ethyl ester or ACE t i c / eb -of oil = 1: 1, v: v).

Claims (16)

1. Urethanes derived from azacycloalkanes, as well as their thio and di thio analogues of the general formula • in which m means the numbers 0 or 1, n means the numbers 1 or 2, A means a single bond, or "straight-chain or branched chain N-linear alkyl group, a C2_8 alkenylene group or C2-alkynylene group" t, not being an unsaturated group directly linked to the radical X means an oxygen atom or azurofre, Y means an oxygen atom to sulfur, R1 means a straight or branched chain alkyl group CL-6, an alkenyl group C i or a C 1 alkynyl group, the multiple bond of the nitrile or noncarbonate bond, R means a straight or branched chain C 1-6 alkyl group, a lkenyl group C i or an alkynyl group C i _ 4, a multiple bond of the nitrogen-carbon bond being isolated , or R1 and R-, together with the nitrogen atom, mean a saturated heterocyclic ring. from 5 to 7 members, in which a methylene group isolated from the nitrogen atom may be replaced by an oxygen or sulfur atom or by a group -NH or N (a alkyl), R3 to R ", which may be the same or different, they mean hydrogen atoms or alkyl groups, R7 signifies a group: ic 1 or 1 qui 1 or _ C3-7, a g phenyl c aftilo event at the mind substituted with one or two halogen atoms, r ^ A alkyl, alkoxy, trifluoromethyl or cyano group or, if A does not represent a single elace, also means an atom of hydrogen, E means a xylene or sulfur atom, a methylene, carbonyl or sulfanyl group and R8 means an atom of hydrogen, or E means the group -C (R9R10) -, where R9 represents a hydrogen atom and R10, together with the adjacent R8, represents a carbon-carbon link, where, if not mentioned otherwise, the alkyl groups contained in the radicals mentioned above may each contain and 1 to 3 carbon atoms and a halogen atom mentioned above can mean a fluorine, chlorine or bromine atom, its enantiomers, d i a s t e r eo s, its mixtures and its salts.

2. Compounds of the general formula I according to claim 1, wherein m means the number 1, n means the number 1, A means a single bond, a C 1 - alkylene group, straight or branched chain or an alkenylene group C 2 - , not being an unsaturated group directly attached to the radical Y, X means an atom of oxygen or sulfur, Y means an atom of oxygen to sulfur, R1 means a C1-D straight or branched chain alkyl group, an allyl group or propargyl, the multiple bond of the nitrogen-carbon bond being isolated, R 'means a straight or branched chain alkyl group 1-6, an allyl or propargyl group, the multiple bond of the nitr or genocarbon bond being isolated, or R1 and R ", together with the nitrogen atom, mean a saturated 5- to 7-membered heterocyclic ring, in which a methylene group isolated from the nitrogen atom may be replaced by an oxygen or sulfur atom, R3 to R6 , which can be R7 denotes a C3_6 cycloalkyl group, a phenyl or naphthyl group optionally substituted with one or two halogen atoms, with an alkyl, alkoxy, trifluoromethyl or cyano group, E means a Sulfur atom-, a methylene, carbonyl or sulfinyl group R8 means a hydrogen atom, or E means the group -C (R'R10) -, where R9 represents a hydrogen atom and _R10, together with the group Contiguous R3 represents a non-calo bon connection, where, unless otherwise mentioned, the alkyl groups contained in the abovementioned radicals may each contain 1 to 3 carbon atoms and one carbon atom. The aforementioned halogen can mean a fluorine, chlorine or bromine atom, its enantiomers, di aster or isomers, its mixtures and its salts.

3. Compounds of the general formula I according to claim 1, wherein ___m means the number 1, n means the number 1, A means a single bond or an alkylene group Ci- straight or branched chain, X means a carbon atom, Oxygen or sulfur, Y means an oxygen atom to sulfur, R1 means a straight or branched chain C? -3 alkyl group, R2 means a straight or branched chain C? _3 alkyl group, or R1 and R ", together with the nitrogen atom, they mean a piperidino or morpholino group, R3 to R6 mean hydrogen atoms, R7 means a cyclohexyl group or a phenyl group optionally substituted with a halogen atom, with an alkyl, alkoxy or trifluoromethyl group, E means a sulfur atom, a methylene, carbonyl or sulfinyl group and R8 means an atom, of hydrogen, or E means the group -C (P'R10) -, where R9 represents a hydrogen atom and R10, together with the group R8 contiguous, represents a link ca rb ono - c a r b o n o, its enantiomers, d i a t e r eo i s, its mixtures and its salts.

4. Compounds of the general formula I according to claim 1, wherein m means the number 1, n means the number 1, A means a single bond or a me t 11 group in o, X means an oxygen or sulfur atom, Y means an oxygen atom to sulfur, R1 and R2 signify in each case a methyl group, R3 to R "signify hydrogen atoms, R7 means a phenyl group optionally substituted with a fluorine or chlorine atom or with a methyl group, E means a sulfur atom, a methylene or carbonyl group, and R8 means a hydrogen atom, or E means the group -C (R'R10) -, where R9 represents a hydrogen atom and R10, together with the group R8 contiguous, represents a carbon-carbon bond, its meclas and its salts.

5. The following compounds of the general formula I according to claim 1. 1: ti- (benzylthio) thioca? Bonil-4- [4- (dimethyl aminomethylphenylthio] piperidine, (2 N- (benzylthio) thiocarbonyl-4- [4- (dimethyl aminometryl benzoyl-1] piperidine, (3N -benzyloxycarbonyl-4- [4- (d? methyl-ininomethyl phenylthio] piperidine, (4 N- (4-chlorophenoxy) carbonyl-4- [4 - (dimethylaminomethyl) phenylthio] piperidine, N- (benzylthio) thiocarbonyl-4- [4 - (dimethylaminomethyl) benzyl] piperirline, (6) N- (benzyl) c) thiocarbonyl-4- [4- (dimethylaminomethyl) benzylidene] piperidine, (7) N- (4-chlorophenoxy) thio ca rbonyl-4- [4 - (dimethylaminomethyl) benzyl] piperidine, (8) N- (4-chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine, (9) N-benzyloxycarbonyl-4- [4- (dimethyl aminomethyl) benzyl] ] piperidine, (10) 4 - [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) carbonylpiperidine, (11) 4 - [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) thi or carbonylpiperidine and ( 12) 4 - [4- (dimethylaminomethyl) benzyl] -N- (4-fluorine or ~ phenoxy) carbonylpiperidine, its m ezclas and their salts.

6. Physiologically compatible salts of the compounds according to at least one of the following indications 1 to 5 with inorganic organic acids.

7. Medicament containing a compound according to at least one of claims 1 to 5 or a physiologically compatible salt according to claim 6 together with optionally one or more support substances and / or inert diluents.

8. Medicine according to the indication 7, suitable for the treatment of diseases in which cholesterol biosynthesis plays a role.

9. The medicament according to claim 8, which contains a compound according to at least one of claims 1 to 5 or a physiologically compatible salt according to claim 6 in combination with one or more active substances with cholesterol or lipid reducing activity.

10. A drug according to claim 9, characterized in that the other active substances are chosen from biliary acid-binding resins, compounds that inhibit the resorption of cholesterol., compounds that, through other mechanism than the inhibition of 2,3 - "ep oxl squalene - lanosterol - cyclase, intervene in - the biosynthesis of cholesterol, fibrates, nicotinic acid, its derivatives and analogues, as well as as probucol-

11. A drug according to claim 8, 9 or 10, suitable for the treatment or prophylaxis of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia and variations at the level of the skin. of the vessels that result from them with their deuteropathies such as coronary heart disease, cerebral ischemia, intermittent claudication or gangrene, for the treatment of diseases that are related to an increased proliferation of cells, for the prophylaxis and treatment of cholelithiasis or for the treatment of mycosis.

12. Use of a compound according to at least one of claims 1 to 5, for the preparation of a medicament according to one of claims 8 to 11.

13. Feed for laying hens, which contains a compound according to at least one of claims 1 to 5 or a physiologically compatible salt according to claim 6.

14. Use of a compound according to at least one of claims 1 to 6, for the preparation of a feed for laying hens to produce eggs poor in cholesterol.

15. Process for the preparation of a medicament according to claim 7, characterized in that, by non-chemical route, a compound according to at least one of claims 1 to 6 is incorporated in one or more support substances and / or inert diluent carriers.

16. Process for the preparation of the compounds according to at least one of claims 1 to 6, characterized in that a) s reacts a compound of the general formula in which, with the exception of the sulfinyl group, R1 Rr and R "are defined as in claims 1 with a compound of the general formula z? VR '(III), wherein A, X, Y and R7 are defined as in claims 1 to 5 and Z means a labile group, or .'b) for the preparation of compounds of the general formula (I), in the that X e? mean in each case a sulfur atom and m, n, A, E and R1 to R8 are defined as defined in claims 1 to 5, with the proviso that R7 does not represent any Añyl or "naphthyl" group optionally substituted, in case A means a single link, - reacts a compound of the general formula fl), wherein m, n, " E with the exception of the sulfonyl group, R1 to R6 and R8 are defined as in rei indications 1 to 5, with carbon sulfide and, a < Next, with an alkylating agent of the general formula Z'-AR '(IV), wherein A and R7 are defined as in claims 1 to 5, with the proviso that R7 does not represent any phenyl or optionally substituted naphthyl group, in case A means a single bond, and Z1 means a group 1 bi 1, oc) for the preparation of compounds of the general formula (I), in which E means a sulphonyl group, a compound of the general formula (I) is oxidized, wherein. , n, A, 'X, Y and R1 to R are defined as in claims 1 to 5 and E means a sulfur atom, and, if desired, a mixture of the geometric isomers of a compound of the general formula I, thus obtained, is separated into its enantiomers and diastereoisomers, or "~ - - - a compound of the general formula I, thus obtained, is transformed into its salt with an inorganic or organic acid, in particular in its physiologically compatible salts.