SK8612000A3 - 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 analogues of 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, R<1> and R<2> 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 R<1> and R<2 >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, R<3>-R<6> can be identical or different and represent hydrogen atoms or alkyl groups, R<7> 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 R<8> represents a hydrogen atom or E represents the -C(R<9>R<10>)- group, wherein R<10> and adjacent group R<8> 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

Technical field

The invention relates to novel urethanes derived from azacycloalkanes, further to their thio- and dithioanalogues, to their salts with physiologically acceptable organic or inorganic acids, to a process for the preparation of these compounds and to pharmaceutical compositions containing said compounds.

BACKGROUND OF THE INVENTION

The compounds of the invention are inhibitors of cholesterol biosynthesis, in particular inhibitors of the enzyme 2,3-epoxyqualene-lanosterol cyclase, a key enzyme in cholesterol biosynthesis. The compounds of the invention are useful in the treatment and prophylaxis of hyperlipidemia, hypercholesterolemia and atherosclerosis. Said compounds find possible other uses in the treatment of hyperproliferative skin and vascular diseases, cancer, gallstones and mycoses.

Compounds that interfere with cholesterol biosynthesis are useful in the treatment of a variety of diseases. In particular, hypercholesterolemia and hyperlipidemia, risk factors for the development of atherosclerotic vascular changes and their subsequent diseases such as coronary heart disease, cerebral ischemia, Claudicatio intermittens and gangrenes.

The importance of elevated serum cholesterol as a major risk factor for the development of atherosclerotic vascular changes is well known. Extensive clinical studies have shown that the risk of coronary heart disease is reduced by lowering serum cholesterol (Current Opinion in Lipidology 2 (4), 234 (1991); Exp. Opin. Ther. Patents 7 (5), 441-455 (1997). )). The fact that the higher the proportion of cholesterol the body synthesizes itself and the least it eats from the diet suggests a particularly interesting way to inhibit biosynthesis and lower cholesterol levels.

In addition, other possible areas of use for inhibiting cholesterol biosynthesis are described, for example in the treatment of hyperproliferative skin and vascular diseases as well as cancer, in the treatment and prophylaxis of gallstones, and the use of the compounds in mycoses. The latter is an intervention in the biosynthesis of ergosterol in fungal organisms, which is similar to the synthesis of cholesterol in mammalian cells.

Cholesterol biosynthesis or ergosterol biosynthesis is based on acetic acid and requires a large number of reaction steps. This multi-stage process offers a variety of possibilities for interfering with it; known examples are:

for example, the antihypercholestrolemic effect of β-lactones and β-lactams on the inhibition of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase has been reported (see J. Antibiotics 40, 1356 (1987), U.S. Pat. Nos. 4,751,237 , EP-A-0 462 667, US 4,983,597).

Examples of HMG-CoA reductase enzyme inhibitors are the mevinoline-type 3,5-dihydroxycarboxylic compounds and their δ-lactones; in the treatment of hypercholesterolemia, there are applications of these compounds by their representatives Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin and Cerivastatin. Other possible areas of use for these compounds are fungal infections (U.S. Pat. Nos. 4,375,475, EP-A-0 113 881, U.S. Pat. No. 5,106,992), skin diseases (EP-A-0 369 263), gallstones and cancer (U.S. Pat. 106, 992, Lancet 339, 1154-1166 (1992)).

Suppression of smooth muscle cell proliferation by Lovastatin is described in Cardiovasc. Drugs. Ter. 5, Suppl. 3, 354 (1991). Tocotrienol, an unsaturated vitamin E analogue and analogues thereof, is another class of substances that act on HMGCoA reductase (Exp. Opin. Ther. Patents 7 (5), 446 (1997)).

Squalene synthetase enzyme inhibitors are, for example, isoprenoid (phosphinylmethyl) phosphonates; their suitability for the treatment of hypercholersterolemia, gallstones and cancer is described in EP-A-0 409 181 as well as in J. Med. Chemistry 34, 1912 (1991); other inhibitors are α-phosphosulfinate compounds (EP-A-0 698 609), compounds J-104,118 and J-104,123 (Tetrahedron 52, 13881-13989 (1996)) as well as

-3cyclobutane derivatives (WO 96/33 159). A review of squalene synthetase inhibitors can be found in Exp. Opin. Ther. Patents 7 (5): 446-44 (1997).

Allylamines, such as naphthidine and terbinafine, have been found to be used as inhibitors of the enzyme squalene epoxydase, which have found use as agents against fungal diseases, as well as allylamine NB-598 with antihypercholesterolemic activity (J. Biol. Chemistry 265, 18075-18078 (1990)) and fluqualquene derivatives with hypocholesterolemic activity (US 5,011,859). Further disclosed are piperidines and azadecalins with potentially hypocholesterolemic and / or antifungal effects; their mechanism of action is not fully elucidated but is represented by 2,3-epoxyqualene-lanosterol cyclase inhibitors (EP-A-0 420 116, EP-A-0 468 434, US-A-5 084 461 and EP-A 0 468 457). Other representatives of these inhibitors are described in Exp. Opin. Ther. Patents 7 (5): 448-449 (1997).

Examples of 2,3-epoxyqualene-lanosterol cyclase inhibitors are diphenyl derivatives (EP-A-0 464 465), aminoalkoxybenzole derivatives (EP-A 0 410 359, J. Lipid. Res. 38, 373- 390 (1997)), as well as piperidine derivatives (J. Org. Chem. 57, 2794-2923 (1992)) which have antifungal effects. In mammalian cells, this enzyme is further inhibited by decalin, azadecalin and indan derivatives (WO 89/08 450; J. Biol. Chemistry 254. 11258-11 263 (1981); Biochem. Pharmacology 37, 1955-1964 (1988); and J 64 003 144), further inhibited by 2-aza-2,3-dihydrosqualene and 2,3-epiminosqualene (Biochem.

Pharmacology 34, 2765-2777 (1985)) through squalenoid-epoxydinynyl ether (J. Chem. Soc. Perkin Trans. 1, 461 (1988)) and 29-methylidene-2,3-oxidoqualene (J. Amer. Chem. Soc., 113, 9673-9674 (1991)). Further examples of substances having said effects are pyridine or pyrimidine derivatives (WO 97/06 802), heterobicyclic alkylamines (WO 96/11201), imidazole derivatives (EP-A-0 757 988) and isoquinoline derivatives (J.

Med. Chemistry 39. 2302-2312 (1996)). Furthermore, urea (DE-A4 438 021), oximes (DE-A-412 692), a number of amides (DE-A-4 407 134), (DE-A4 407 135), (DE-A-4 407 136), (DE-A-4 407 138), (DE-A-4 407 139), (DE-A-4 437 999), (DE-A-4 438 000) , (DE-A-4,438,020), (DE-A-438,082), (DE-A-4,438,029), (DE-A-4,438,054), (DE-A-4,438,055), ( DE-A4 438 082), (DE-A-4,438,083), EP-A-0 599 203, EP-A-0 596 326 and an ester (WO

147. Further examples are described in Exp. Opin. Ther. Patents 7 (5): 448-449 (1997).

Finally, steroid derivatives with potential antihyperlipidemia effects that simultaneously affect the HMG-CoA reductase enzyme are also known as inhibitors of the enzyme lanosterol-14a-demethylase (US-A-5,041,431; J. Biol. Chemistry 266. 20070-2007 (1991); US-A-5,034,548). In addition, this enzyme is inhibited by azole-type antimycotics, N-substituted imidazoles and triazoles. This group includes, for example, the known antifungals Ketoconazole and Fluconazole.

The compounds of formula I below are novel. They have been unexpectedly found to be very potent inhibitors of the enzyme 2,3-epoxyqualene-lanosterol cyclase (International Classification: EC 5.4.99.7).

The enzyme 2,3-epoxyqualene-lanosterol cyclase catalyzes a key reaction step of cholesterol or ergosterol biosynthesis, in particular the conversion of 2,3-epoxyqualene to lanosterol, the first compound with a steroid structure in a cascade of biosynthetic reactions. In contrast to inhibitors of the preceding reaction steps, such as HMG-CoA synthase and HMG-CoA reductase, inhibitors of the above enzyme may have the advantage that they are expected to have increased selectivity; insufficient selectivity in inhibiting previous biosynthesis reaction steps may lead to a loss of biosynthetically generated mevalonic acid and thus also to a reduction in the biosynthesis of mevalonic acid dependent substances of dolichol, ubiquinone and isopentenyl-β-RNA (cf. J. Biol. ).

By inhibiting the biosynthetic steps after the conversion of 2,3-epoxyqualene to lanosterol, there may be a risk in the body of the accumulation of intermediates with a steroid structure and of their toxic effects. This has been described, for example, for triparanol, a desmosterol reductase inhibitor. Due to the occurrence of cataract, it had to be removed from the market (cited in J. Biol. Chemistry 265. 18075-18078 (1990)).

It has already been stated that 2,3-epoxyqualene-lanosterol cyclase inhibitors are known in the literature. However, no urethanes and / or thio- or dithio-analogues thereof are known as 2,3-epoxyqualene-lanosterol cyclase inhibitors.

The present invention relates to the preparation of substances with antihypercholesterolemic activity, which are suitable for the treatment or prophylaxis of atherosclerosis and, in comparison with the prior art substances, have a better antihypercholesterolemic effect with increased selectivity and thus increased safety. Since the compounds of the present invention may also inhibit ergosterol biosynthesis in fungal organisms due to their high potency as inhibitors of the 2,3-epoxyqualene-lanosterol cyclase enzyme, they may also be useful in the treatment of mycoses.

SUMMARY OF THE INVENTION

The present invention provides urethanes derived from azacylalkanes and their thio- and dithio-analogues of general formula I

(I) where m is 0 or 1, n is 1 or 2,

A is a single bond, a linear or branched Cys-alkylene, _C2 _8-alkenylene or C 2 alkynylene much, the unsaturated group is bonded directly to Y,

X is an oxygen or sulfur atom,

Y is an oxygen atom or a sulfur atom,

R ¹ is a straight or branched C 1-6 -alkyl, C 1-6 -alkenyl or C 1-6 -alkynyl group wherein the multiple bond is isolated from the nitrogen-carbon bond,

-6R ² is unbranched or branched Ci. _{A 6-} alkyl group, a C 1-4 -alkenyl group or a C 1-4 -alkynyl group wherein the multiple bond is isolated from the nitrogen-carbon bond, or

R ¹ and R ² together with the nitrogen atom form a 5 to 7 membered, saturated heterocyclic ring in which the methylene group isolated from the nitrogen may be replaced by an oxygen or sulfur atom, an -NH- group or an -N (alkyl) - group,

R ³ to R ⁶ may be the same or different and may be hydrogen atoms or alkyl groups,

R ⁷ is C ₃ . _7- cycloalkyl, phenyl or naphthyl, which may be optionally substituted by one or two halogens, alkyl, alkoxy, trifluoromethyl or cyano, and unless A is a single bond, a hydrogen atom,

E represents an oxygen or sulfur atom, a methylene group, a carbonyl group or a sulfinyl group, and

R ⁸ represents a hydrogen atom, or

E is -C (R ⁹ R ¹⁰ ) -, wherein

R ⁹ represents a hydrogen atom and

R ¹⁰ together with an adjacent R ⁸ group represents a carbon-carbon bond, wherein, unless otherwise indicated, the above alkyl groups may each contain 1 to 3 carbon atoms and the halogen atoms mentioned may be a fluorine atom, a chlorine atom or a bromine atom, enantiomers, diastereomers, mixtures thereof and salts thereof, in particular their physiologically acceptable acid addition salts.

Preferred are compounds of formula I wherein m is 1, n is 1,

A is a single bond, a branched or unbranched C 1-4 alkylene group, or a C 2-4 alkenylene group, wherein the unsaturated group is not bound directly to the radical Y,

X is an oxygen atom or a sulfur atom,

Y is an oxygen atom or a sulfur atom,

7R ¹ is a linear or branched C _v6 -alkyl, allyl or propargyl group, wherein the vicnásobná bond from the nitrogen - carbon collected.

R ² is unbranched or branched. _{A 6-} alkyl group, an allyl or propargyl group, wherein the multiple bond is isolated from the nitrogen-carbon bond, or

R ¹ and R ² together with the nitrogen atom form a 5 to 7 membered, saturated heterocyclic ring in which one methylene group isolated from the nitrogen atom may be replaced by an oxygen or sulfur atom,

R ³ to R ⁶ may be the same or different and may be hydrogen atoms or methyl groups,

R ⁷ is C 3-6 -cycloalkyl, or phenyl or naphthyl, optionally substituted with one or two halogen atoms, alkyl, alkoxy, trifluoromethyl or cyano,

E is a sulfur atom, a methylene group, a carbonyl group or a sulfinyl group, and

R ⁸ is a hydrogen atom, or

E is -C (R ⁹ R ¹⁰ ) -, wherein

R ⁹ represents a hydrogen atom and

R ¹⁰ together with an adjacent R ⁸ group represents a carbon-carbon bond, wherein, unless otherwise indicated, the above alkyl groups may each contain 1 to 3 carbon atoms and the halogen atoms mentioned may be a fluorine atom, a chlorine atom or a bromine atom, enantiomers, diastereomers, mixtures thereof and salts thereof, in particular their physiologically acceptable acid addition salts.

Very preferred are compounds of formula I wherein m is 1, n is 1,

A is a single bond, or an unbranched or branched C1-4alkylene group,

X is an oxygen atom or a sulfur atom,

Y is an oxygen atom or a sulfur atom,

-8R ¹ is a linear or branched C 3 alkyl,

R ² is a straight or branched C 1-3 alkyl group; or

R ¹ and R ² together with the nitrogen atom form a piperidine or morpholine group,

R ³ to R ⁶ are hydrogen atoms,

R ⁷ is C 3-6 -cycloalkyl, or phenyl or naphthyl, optionally substituted with one or two halogen atoms, alkyl, alkoxy, trifluoromethyl or cyano,

E is a sulfur atom, a methylene group, a carbonyl group or a sulfinyl group, and

R ⁸ is a hydrogen atom, or

E is -C (R ⁹ R ¹⁰ ) -, wherein

R ⁹ represents a hydrogen atom and

R ¹⁰ together with the adjacent R ⁸ group represents a carbon-carbon bond, further enantiomers, diastereomers, mixtures thereof and salts thereof, in particular their physiologically acceptable acid addition salts.

Most preferred are compounds of formula I wherein m is 1, n is 1,

A is a single bond or a methylene group,

X is an oxygen atom or a sulfur atom,

Y is an oxygen atom or a sulfur atom,

R ¹ is a methyl group,

R ² is a methyl group,

R ³ to R ⁶ are hydrogen atoms,

R ⁷ represents a phenyl group, optionally substituted by one or two fluorine or chlorine atoms, or a methyl group,

E is a sulfur atom, a methylene group, or a carbonyl group, and

R ⁸ is a hydrogen atom, or

E is -C (R ⁹ R ¹⁰ ) -, wherein

R ⁹ represents a hydrogen atom and

R ¹⁰ together with an adjacent R ⁸ group means a carbon-carbon bond, mixtures thereof and salts thereof, in particular their physiologically acceptable acid addition salts,

But especially compounds:

(1) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine, (2) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzoyl] piperidine, (3) / N-benzyloxycarbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine, (4) N - (4-chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine, (5) N - (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine, (6) N - (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzylidene] piperidine, (7) N - (4-chlorophenoxy) thiocarbonyl -4- [4- (dimethylaminomethyl) benzyl] piperidine, (8) N- (4-chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine, (9) N-benzyloxycarbonyl-4- [ 4- (dimethylaminomethyl) benzyl] 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, mixtures thereof and salts thereof, in particular physiologically acceptable acid addition salts, for example hydroc chlorides, methanesulfonates and tartrates.

The compounds of formula I can be prepared, for example, by the following methods:

(a) converting a compound of formula II

(CH ₂ ) _n \

NH (CH ₂ ) / (II) wherein m, n, E except the sulfinyl group, R ¹ to R ⁶ and R ⁸ are as defined above, by reaction with a compound of formula III

Gil)

-10 in which

A, X, Y and R ⁷ are as defined above and Z is a replaceable group, for example a halogen atom such as a chlorine, bromine or iodine atom.

The conversion is carried out under Shotten-Baumann or Einhorn conditions; that is, the reactants are reacted in the presence of at least one equivalent of the auxiliary base at temperatures between -50 ° C and +120 ° C, preferably between -10 ° C to +30 ° C, optionally also in the presence of solvents. Preferred auxiliary bases are alkali metal hydroxides and caustic 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 such as pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo [2.2.2] octane or 1,8- diazabicyclo [5.4.0] undec-7-ene and as solvent, for example, diethyl ether, methylene chloride, dichloromethane, ethyl acetate, toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or a mixture thereof; if alkali metal or earth-caustic hydroxides, alkali metal carbonates or alkali metal acetates are used as auxiliary bases, the addition of water as a co-solvent may be used in the reaction mixture.

(b) Preparation of compounds of formula I wherein X and Y are sulfur and m, n, A, E and R ¹ to R ⁸ are as defined above except when R ⁷ is not an optionally substituted phenyl or naphthyl group, then A means a single bond, is effected by converting compounds of formula II wherein m, n, E except for the sulfinyl group, R ¹ to R ⁸ and R ⁸ are defined above, with carbon disulphide followed by an alkylating agent of formula IV / R ⁷ ( iv)

-11 in which

A and R ⁷ are as defined above except that R ^{7 is} not an optionally substituted phenyl or naphthyl group when A is a single bond; Z ¹ represents a replaceable group, for example a halogen atom such as a chlorine, bromine or iodine atom, an alkylsulfonyloxy- group having 1 to 10 carbon atoms in the alkyl moiety, a phenylsulfonyloxy- or naphthylsulfonyloxy- group, optionally mono-, di- or trisubstituted with chlorine or bromine atoms , methyl or nitro, the substituents may be the same or different.

Conversion is conveniently effected by first converting the compound of formula II in a suitable solvent, for example tetrahydrofuran, to a lithium salt, for example by treatment with n-butyllithium at a temperature of from -20 ° C to -10 ° C, and then converting with carbon disulphide. Subsequently, the compound of formula IV is added in a suitable solvent, for example tetrahydrofuran, dimethylformamide or a mixture of both solvents, and the reaction is carried out at 20 to 60 ° C.

(c) The preparation of a compound of formula I in which E is a sulfinyl group is carried out by oxidation of a compound of formula I and the groups m, n, A, X, Y and R ¹ to R ⁸ are as defined above and E is sulfur, preferably sodium periodate.

Suitably, the oxidation is carried out with an equivalent amount of the oxidizing agent used, for example sodium periodate, in methanol and water or ethanol and water at -15 to 25 ° C.

The compounds of formula (I) prepared according to the methods can be purified and isolated by known methods, for example by crystallization, distillation or chromatography.

Further, the compounds of formula I prepared may optionally be resolved into individual enantiomers and / or diastereomers.

Thus, the prepared compounds of formula I which are racemates can be separated, for example, by known methods (see Allinger, N.L. and Eliel, E.L. in: Topics in Stereochemistry, Vol. 6, Wiley Interscience, 1971) into their optical antipodes; compounds of formula I having at least 2 asymmetric carbon atoms

12 can be separated into their diastereomers by virtue of their different physical properties and using known methods, for example by chromatography and / or fractional crystallization; when separated in racemic form, the racemate can then be resolved into the enantiomers by the methods described above.

Separation of the enantiomers is effected preferably by column separation into chiral phases, or by recrystallization from an optically active solvent, or by conversion with an optically active substance, forming salts or derivatives with racemic compounds, for example esters or amides, preferably with acid, derivatives or alcohols thereof; and separating the diastereomeric mixtures of salts or derivatives thus obtained, for example on the basis of different solubilities, in which case the free diastereomeric salts or derivatives can be released by the action of suitable substances.

Preferred optically active acids are, for example, the D- and L-forms of tartaric or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid or aspartic acid. +) or (-) menthol and as the optically active acyl residue in amides, for example, (+) or (-) mentyloxycarbonyl.

The compounds of formula I prepared can be further converted into their salts, in particular for pharmaceutical use, in the form of physiologically acceptable 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 maleic acid.

The starting compounds of the formula II in which E represents a carbonyl group can be prepared, for example, by the methods described in DE 44 07 136 A1 (pages 4 to 5).

The starting compounds of formula (II) in which E represents a methylene group or a -C (R ⁹ R ¹⁰ ) - group, wherein R ⁹ is a hydrogen atom and R ¹⁰ together with the adjacent R ⁸ group represents a carbon-carbon bond, as described in DE 44 07 138 A (5/1144) (pages 7 to 8).

Compounds of formula (II) in which E represents an oxygen atom or a sulfur atom may be prepared according to the following reaction scheme:

(CH ₂ ) _{n χ}

N (CH3) /

R ¹¹ (VI)

I

(VII) (CH ₂ ) _{n χ}

N (CH ₂ ) /

R ¹¹ (II)

Conversion of a compound of formula V wherein R ¹ to R ⁵ are as defined above and E is O or S with a compound of formula VI wherein m, n, R ⁶ to R ⁸ are as defined above, R ¹¹ represents a protecting group, for example a tert-butyloxycarbonyl group, and R ¹² represents an alkyl radical, gives the corresponding compound of formula VII which is converted to the desired compound of formula II by cleavage of the protecting group R ¹¹ .

Compounds of formula (II) in which E represents a methylene group, an oxygen or sulfur atom, R ³ to R ⁵ and R ⁸ hydrogen atoms, R ⁶ a hydrogen atom or an alkyl group and the phenyl moiety is 1,4-disubstituted can be prepared by both methods according to the following reaction schemes:

(VIII)

- 14continuation of the scheme

(II)

In one reaction sequence, the

T (II) a compound of formula VIII, wherein R ¹¹ is a protecting buying up, preferably a 2,2,2-trichloroethoxycarbonyl group, is converted by chloromethylation into a compound of formula IX. By aminolysis with an amine having the formula R ^{@ 1} R ^{@ 2} NH, the compound of formula IX is converted to a compound of formula X, which is converted to a compound of formula II by cleavage of the protecting group.

In a second sequence, a compound of formula (VIII), wherein R ¹¹ is a protecting group, preferably a trifluoroacetyl radical, converted Friedel-Crafts reaction with oxalyl chloride in the presence of aluminum chloride to a compound of formula XI. Aminolysis with an amine of formula R ¹ R ² NH gives a compound of formula XII which is converted to the desired compound of formula II by lithium aluminum hydride and cleavage of the protecting group.

Compounds of formula (II) wherein E is O or S, R ³ to R ⁵ and R ⁸ are hydrogen, R ⁶ is hydrogen or alkyl can also be prepared as follows:

(CH ₂ ) _{n χ}

N - R ¹¹ (CH ₂ ) /

R \ ⁺

N-CH ₂ Hal

R2 (XIV)

A compound of formula (XIII) wherein:

R ¹¹ is a protecting group, preferably a trityl radical, first converted to a lithium compound and then reacted with a compound of formula XIV wherein Hal is chlorine, bromine or iodine to give a compound of formula

XV. Cleavage of the protecting group yields the desired compound of formula II.

The compounds of formula I have interesting biological properties. They are inhibitors of cholesterol biosynthesis, in particular of the enzyme 2,3-epoxyqualene-lanosterol cyclase. By virtue of their biological properties, they are suitable for the treatment of diseases associated with cholesterol biosynthesis, in particular for the treatment and prophylaxis of hypercholesterolemia, hyperlipoproteinemia and hypertriglyceridemia and the resulting vascular atherosclerotic changes with subsequent diseases such as coronary heart disease, intermittent ischemia gangrens and more.

For the treatment of these diseases, the compounds of formula I may be used alone or in monotherapy, or in combination with other cholesterol or lipid lowering agents; said compounds of the formula I can advantageously be formulated

Oral preparations, optionally as suppositories for rectal administration. Combination partners are:

- resins capable of binding bile acids, such as Cholestyramine, Cholestipol and others,

- compounds that inhibit cholesterol absorption, such as Sitosterol and Neomycin,

- compounds that interfere with the role of 2,3-epoxyqualene-lanosterol cyclase in cholesterol biosynthesis by mechanisms other than suppression, for example HMF-CoAreductase inhibitors such as Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin, Cerivastatin and others,

squalene-epoxydase inhibitors, for example NB 598 and analogous compounds, and

squalene synthetase inhibitors, for example a representative of this group is isoprenoid (phosphinylmethyl) phosphonate and squalestatin.

Other possible partners for the combinations include a group of fibrates, for example Clofibrate, Bezafibrate, Gemfibrozil and others, nicotinic acid, derivatives and analogs thereof, for example Acipimox and also Probucol.

The compounds of formula I are further suitable for the treatment of diseases which are associated with excessive cell proliferation. Cholesterol is one of the essential components of the cell and must therefore be sufficiently present in the cell to multiply it, that is, to divide the cell. Inhibition of cell proliferation by inhibiting cholesterol biosynthesis has been described in the example of smooth muscle cells with the HMGCoA reductase inhibitor mevinoline-type Lovastatin, as mentioned above.

Examples of diseases associated with increased cell proliferation include cancer. In cell cultures and in vivo experiments, decreasing serum cholesterol or interfering with cholesterol biosynthesis via HMG-CoA reductase inhibitors has been shown to reduce tumor growth (Lancet 339, 1154-1166 (1992)). The compounds of the formula I according to the invention are potentially suitable for the treatment of cancer, due to their inhibitory effect on cholesterol biosynthesis. These compounds may be used alone or in support of known therapeutic principles.

Other examples of diseases are hyperproliferative skin diseases such as psoriasis, basal cell carcinoma of the skin cells, flat epithelial carcinoma, keratosis and keratinization disorders. As used herein, psoriasis refers to a hyperproliferative inflammatory skin disease that alters the regulatory mechanism of the skin. In particular, lesions are formed, including primary and secondary skin proliferation changes, inflammatory skin reactions, and changes in the expression of regulatory molecules, such as lymphokines and inflammatory factors. Psoriatic skin is characterized by a morphologically increased conversion of epidermal cells, coarse epidermis, abnormal keratinization of inflammatory cell infiltrates in the skin layer, and the presence of polymorphonuclear leukocyte infiltrates in the skin that cause an increase in the base layer cell cycle. In addition, hyperkeratosis and parakeratosis cells are present. The terms keratosis, basal cell carcinoma of the skin, flat epithelial carcinoma, and keratinization disorders refer to hyperproliferative skin diseases in which the regulatory mechanism of skin cell proliferation and differentiation is disrupted.

The compounds of formula I are effective as antagonists of cutaneous hyperproliferation, i.e., they are a tool for inhibiting the proliferation of human keratinocytes. The compounds are therefore useful as a therapeutic agent for hyperproliferative skin diseases such as psoriasis, basal cell carcinoma of the skin cells, keratosis and keratinization disorders. Compounds of formula I or in the form of oral formulations or as topical formulations may be used for the treatment of these diseases, which may be used in monotherapy alone or in combination with known active substances.

In addition, hyperproliferative vascular diseases such as stenosis and vascular obstruction caused by surgical interventions such as PCTA (percutaneous transluminal coronary angioplasty) or by-pass operations; said disorders depend on the proliferation of smooth muscle cells. It has already been mentioned that such proliferation processes can be interrupted by HMG-CoA reductase inhibitors, for example Lovastatin. In view of their inhibitory effects on cholesterol biosynthesis, the compounds of the formula I can also be regarded as suitable for the treatment and prophylaxis of the diseases mentioned, which can be used alone or in

18 in combination with known active ingredients, for example intravenously administered heparin, but preferably in a formulation for oral administration.

Another possibility of using the compounds of the invention of formula I is the prophylaxis and treatment of gallstones. The formation of gallstones is induced by exceeding the cholesterol concentration in the bile beyond the maximum solubility of cholesterol in the bile fluids, thereby excreting cholesterol in the form of gallstones. Lipid lowering agents from the fibrate class lead to increased secretion of neutral steroids in the bile and an increased susceptibility to bile stone formation.

In contrast to the latter, substances that suppress cholesterol biosynthesis such as Lovastatin or Pravastatin do not lead to increased gallstone formation, but may cause a decrease in the concentration of cholesterol in the bile and thus reduce the so-called lithogenic index, which is a measure of the likelihood of gallstones. These facts are described in Gut 31, 348-350 (1990) and in Z. Gastroenterol. 29: 242-245 (1991).

In addition, Gastroenterology 102 (4), Part 2 and 319 (1992) describes the effective effect of Lovastatin on the dissolution of gallstones, particularly in combination with ursodeoxycholic acid. The compounds of formula (I) are therefore also important for the prophylaxis and treatment of gallstones due to their mechanism of action; they can be used alone or in combination with known therapies, for example in the treatment with ursodeoxycholic acid or in lithotripsy with sound waves; The compounds of the invention herein have advantageous use in formulations for oral administration.

The compounds of the formula I are also suitable for the treatment of infections with pathogenic fungi, for example Candida albicans, Aspergillus niger, Trichophyton mentagrophytes, Penicillium sp., Cladosporium sp. and others. It has already been stated that the final product of sterol biosynthesis in fungal organisms is not cholesterol, but ergosterol is essential for the integrity and function of fungal membranes. Therefore, inhibition of egosterol biosynthesis leads to growth disturbances and possibly to death of fungal organisms.

For the treatment of mycoses, the compounds of formula I may be used or in an oral formulation or in a formulation for topical use. They can be used here

-19 or alone or in combination with known antifungal agents, in particular those which interfere with other stages of sterol biosynthesis, for example in combination with squalene-epoxydase inhibitors Terbinafine and Naftifine, or with lanosterol-14a-demethylase inhibitors, for example of the azole type, Ketoconazole and Fluconazole.

A further possibility of using the compounds of the formula I relates to their use in poultry farming. The reduction of egg cholesterol by administration of the HMG-CoA reductase inhibitor Lovastatin to laying hens is described in (FASEB Journal 4, A 533, abstract 1543 (1990)). The production of low-cholesterol eggs is interesting because cholesterol-lowered eggs can reduce the cholesterol load on the human body without altering eating habits. Owing to their inhibitory effects on cholesterol biosynthesis, the compounds of the formula I may also find use in poultry farms for the production of eggs having a low cholesterol content, the active compounds being preferably administered as feed additives.

The biological activity of the compounds of formula I was determined by the following methods:

I. Measurement of ¹⁴ C-acetate inhibition in digitonin cleavable steroids

Monitoring of the inhibitory effect was performed as described in J. Lipid. Res. 37, 148-158 (1996), the concentrations of the test substances, 10 ^-8, and 10 ^-9 mol.dm ^'3rd

The test results of compounds (A) to (R) of formula (I) and comparative compounds (U), (V) and (W) are further exemplified below; the tests were carried out at the above concentrations:

(A) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine hydrochloride, (B) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzoyl] piperidine hydrochloride, (C) N-benzyloxycarbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine hydrochloride, (D) N- (4-chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine hydrochloride, (E) hydrochloride / N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine, (F) N - (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzylidene] piperidine hydrochloride, (G) N - (4) hydrochloride - (chlorophenoxy) thiocarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine; (H) N - (4-chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine hydrochloride; benzyloxycarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine, (K) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) carbonylpiperidine hydrochloride, (L) 4- [4- (dimethylaminomethyl) hydrochloride benzyl] - N - (4-methylphenoxy) thiocarbonylpiperidine, and (M) 4- [4- (d) hydrochloride imethylaminomethyl) benzyl] - N - (4-fluorophenoxy) carbonylpiperidine, (U) 1- (4-chlorobenzoyl) -4- [4- (2-oxazolin-2-yl) benzylidene] piperidine (EP-A-0) 596,326, page 16, there Compound A; J. Lipid. Res. 38, 564-575 (1997)), (N - trans - N- (4-chlorobenzoyl) - N -methyl- [4- (4-dimethylamino) methyl) phenyl] cyclohexylamine (DE-A-44 38 020; J. Lipid, res. 37, 148-157 (1996)) and (W) trans- 7S-O- (p-tolylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol (WO 95/29 148, p. 28, there compound I).

The percentages of ¹⁴ C-acetate incorporation attenuation by the above compounds are shown in Table 1.

Table 1

compound 10 ' ^ä mol.dm · ⁰ 10 ' ^s mol.dm · ⁴ (A) 1 00 cn -53 (B) -85 -47 (C) -78 -57 (D) -86 -55

compound 10 '' mol.dm ' ^a 10 ' ^s mol-dm' · ¹ (E) -87 -47 (F) -84 -45 (G) -83 -56 (H) -80 -45 (I) -85 -47 (C) -82 -49 (L) -88 -64 (M) -84 -59 (U) -54 -07 (IN) -59 -23 (W) -72 -21

IC 50 values were determined for compounds H, I, K and M. The determined IC 50 values from these samples are compared in Table 2 with the IC ₅₀ values of the comparative compounds U, V and W.

Table 2

compound IC50 (nmol.dm ' ⁰ ) (H) 0.8 (I) 1.2 (C) 1.4 (M) 1.5 (U) 5.5 (IN) 3.8 (W) 9.6

From the values in Tab. 2 shows the significant superiority of the compounds of the present invention over these comparators.

II. Measurement of in vivo effect in rats after oral dosing

Inhibition of the enzyme 2,3-epoxyqualene-lanosterol cyclase causes an increase in the levels of 2,3-epoxyqualene in the liver and plasma. Thus, the amount of 2,3-epoxyqualene formed serves directly as a measure of effect on the whole animal. The assay was performed as described in J. Lipid. Res. 38, 564-575 (1997) at 3 and 8 hours after drug administration at concentrations of c = 0.01, 0.03, 0.1, 0.3 and 1.0 rng kg ^-1 . Table 3 below gives examples of results for the above compounds A, B, C, D, E, G, I, and K.

Table 3

2,3-Epoxyqualene concentrations [gg.dm ' ³ ] in liver (rat)

c [mg.kg- ¹ ] 0.01 0.03 t [h] 3 8 3 8 A B C 0.6 3.0 D 1.3 1.0 E 0.9 1.0 G H 1 The

Table 3 - continued

c [mg.kg- ¹ ] 0.1 0.3 1.0 t [h] 3 8 3 8 3 8 A 2.0 1.2 9.3 9.8 B 4.5 5.8 392 42.0 C 0.5 1.3 0.5 1.8 3.8 2.0 D 1.4 1.8 E 5.6 4.4 G 10.3 11.5 87.4 134.2 H 1.0 0.8 56.3 20.7 1 1.0 26.1 10.0 The 0.4 0.4 24.0 5.5

-23 No measurable levels of 2,3-epoxyqualene were detected under the same conditions in the control group of animals.

III. Decrease of lipids in normolipemic golden hamster

Lipid drop determination was performed as described in J. Lipid. Res. 38, 564-575 (1997). Finally, total cholesterol, βlipoprotein-cholesterol as well as HDL cholesterol were also determined and compared with the control group without administration of test substances.

Lipid decline was tested using the compounds H, I, K, and M described above.

The results of the tests are shown in Table 4.

Table 4

Test compound dose [mg. kg ' ¹ / day] total cholesterol [%] β-lipoprotein-cholesterol [%] HDLcholesterol [%] H 6.5 -8.3 -13.0 -3.4 19.9 -11.0 -13.2 -8.2 62.3 -32.1 -33.7 -28.5 I 47.1 -23.1 -32.9 -17.6 The 54.2 -6.8 -21.2 2.3 M 57.5 -26.8 -31.6 -20.4

The compounds of the invention did not show any toxic effects under these conditions.

IV. Determination of fungistatic effect

The fungistatic effect was determined by the dilution test. Sabouraud broth was used as the nutrient medium. A concentration of approximately 10 ⁴ to 10 ⁵ KBE per ml (KBE = colony forming units) was expected; the incubation time was 2-4 days at 26 ° C.

The lowest concentration at which growth was still observed (minimale Hemmkonzentration, MHK) was determined.

The compounds A, B, D, E, F, H, I, K, L, and M described above were tested. The results are summarized in Table 6. MHK is given in pg.m ^-1 . The following test germs were used:

Test embryos In short Cand. albicans ATCC 10231 Cand. SACCH. carlsbergensis ATCC 9080 Sacc. Rhod. rubra 49 Rhod. Asp. nigerATCC 16404 Asp. Trich. mentagrophytes ATCC 9129 Trich. Pen. notatum CBS 19746 Pen.

Table 5

Test compound MHK pg.mľ Cand. Sacc. Rhod. Asp. Trich. Pen. A 16 8 16 8 1 4 B 64 32 16 32 2 8 D 64 128 64 256 16 128 E 16 16 4 8 1 1 F 16 16 4 8 2 4 H 64 128 16 32 1 64 I 256 512 64 64 4 128 The 64 512 64 64 8 256 L 32 64 8 64 1 32 M 128 512 32 64 2 512

The compounds of formula (I) have been prepared by known methods for pharmaceutical use in conventional dosage forms for oral, rectal and topical administration.

Forms for oral administration include, for example, tablets, dragees, and capsules. For rectal administration, suppository forms of the drug are preferred. The daily dose of the drug is between 0.1 and 200 mg for a human with a body weight of 60 kg, preferably the daily dose is 1 to 100 mg per person with a 60 kg body weight. The daily dose is preferably divided into 1 to 3 individual doses.

For topical use, the compounds may be formulated in a dosage form containing from 1 to 1000 mg of active ingredient, in particular from 10 to 300 mg of active ingredient per day. The daily dose is preferably divided into 1 to 3 individual doses.

Topical formulations for use as skin medicaments include gels, creams, lotions, ointments, powders, aerosols and other conventional formulations. The amount of active ingredient for topical administration is 1 to 50 mg of active ingredient per gram of formulation, but preferably 5 to 20 mg of active ingredient per gram of formulation. In addition to using the skin preparation, the topical formulations of the invention may also be used in the treatment of mucosal mycoses available for topical administration. Topical formulations may be administered, for example, to the mucous membranes of the oral cavity, the lower intestine, and the like.

The active compounds of the formula I, when used in poultry for the production of cholesterol-lowered eggs, are administered in the customary manner as additives to suitable feedstuffs. The active compound concentration in the finished feed is normally 0.01 to 1%. preferably 0.05 to 0.5%.

Said active ingredients may be added to the feed as such. The feedstuffs thus obtained according to the invention for laying hens then contain, in addition to the active ingredient and, optionally, in addition to conventional vitamin and mineral mixtures, corn, soya flour, meat meal, feed fat and soya oil. To this feed is added one of the compounds of the formula I described above as active ingredient in a concentration of from 0.01 to 1%, preferably in a concentration of 0.05 to 0.5%.

DETAILED DESCRIPTION OF THE INVENTION

The following examples serve to illustrate the invention in more detail. The reported Rf values were determined on E. Merck, Darmstadt plates at:

a) Aluminum oxide F-254 (Type E)

b) on a silica gel 60 F-254.

Preparation of starting materials

Example A

4- [4- (dimethylaminomethyl) phenylthio] piperidine

To a solution of 4-hydroxypiperidine (7.18 g, 71 mmol) in DMF (100 mL) was added triturated potassium carbonate (19.6 g, 142 mmol) followed by trityl chloride (19.8 g, 71 mmol). The mixture was stirred at room temperature for 22 hours, then diluted to twice the volume with ethyl acetate and washed with saturated brine. The organic layer was then dried with magnesium sulfate and evaporated. The residue was recrystallized from ethyl acetate / petroleum ether (1: 4, v / v). Yield: 17.65 g (72.4% of theory) of 4-hydroxy- N -tritylpiperidine as colorless crystals, m.p. 157-158 ° C.

5.77 g of this product was dissolved in 60 ml of methylene chloride. 2.6 g of methanesulfonic acid chloride and 3.4 g of triethylamine were added dropwise. The reaction mixture was then stirred at 0 ° C for 1 hour, diluted with ether, washed with ice water (4x), dried (MgSO 4) and evaporated. 7.58 g of 4-methanesulfonyloxy- N -tritylpiperidine were obtained as a colorless foam.

This product was dissolved in 30 mL of tetrahydrofuran and added dropwise to a solution of 4-bromothiophenol sodium salt (prepared from 3.18 g of 4-bromothiophenol and 0.81 g of 55% sodium hydride in 35 mL of tetrahydrofuran). The mixture was heated at reflux for an hour, then cooled and extracted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate and evaporated. 5.28 g of 4- (4-bromophenylthio) -N-tritylpiperidine were obtained in the form of a colorless crystalline substance, m.p. 174-175 ° C.

2.57 g of the latter product were dissolved in 30 ml of tetrahydrofuran and 4 ml (6.4 mmol) of n-butyllithium (Cbutyintia = 1.6 mol.dm &^lt; ^{3 &gt;} ) solution was added dropwise to the solution at -70 [deg.] C. in n-hexane. After 1.5 hours at -70 ° C was added

1.1 g (6.4 mmol) of N, N -dimethylmethylenimmonium iodide, the cooling bath was removed and the mixture was stirred overnight. The solvent was then evaporated, the residue was triturated in water and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, evaporated and the residue purified by column chromatography (alumina, ethyl acetate / petroleum ether = 1:10, v / v). 0.9 g of 4- [4- (dimethylaminomethyl) phenylthio] -N-tritylpiperidine was obtained as a colorless crystalline substance, m.p. 163 ° C.

This product was dissolved in 30 mL of methylene chloride and 10 mL of ethereal hydrogen chloride was added. After an hour at room temperature, the mixture was concentrated, ether was added and the precipitate was filtered off with suction. The precipitate was dissolved in a little water, ether was added and the pH of the reaction mixture was adjusted to 11 with sodium hydroxide solution (cnsoh = 6 mol.dnT ³ ). The ether phase was separated, the aqueous phase was extracted once more with ether, and the combined extracts were dried over magnesium sulfate. 500 mg of 4- [4- (dimethylaminomethyl) phenylthio] piperidine are obtained in the form of colorless crystals, m.p.

Example B

4- [4- (piperidinomethyl) phenylthio] piperidine

To a solution of 10.1 g (0.1 mol) of 4-hydroxypiperidine and 11 g (0.11 mol) of triethylamine in 200 ml of ethyl acetate and 250 ml of tetrahydrofuran was added dropwise a solution of 23.3 g (0) (11 mol) 2,2,2-trichloroethyl chloroformate. The mixture was then stirred at 0 ° C for 1 hour and at room temperature for 1 hour. The precipitate was filtered off with suction, the filtrate was mixed with 12 g (0.105 mol) of methanesulfonic acid chloride at -12 to -14 ° C and a solution of 12 g (0.12 mol) of triethylamine was added dropwise at -8 to -12 ° C. in 50 ml of tetrahydrofuran. The mixture was stirred at -10 ° C for 40 minutes, then the cooling bath was removed and the mixture was stirred for another 30 minutes. After washing with water and saturated brine, the solution was dried over magnesium sulfate, evaporated and the residue was triturated in diisopropyl ether and filtered off with suction. Thus, 32.4 g (91.5% of theory) of 4-methanesulfonyloxy-N-2,2,2-trichloroethoxycarbonylpiperidine were obtained as a colorless crystalline substance, m.p. 93 ° C.

17.7 g (50 mmol) of this product was dissolved in 30 ml of dimethylformamide at room temperature, and the solution was added dropwise to a solution of potassium thiophenolate (prepared from 6 g of thiophenol and 6.2 g of potassium tert-butylate, at 20 to 60 ° C). ). The resulting jelly was mixed with 100 ml of dimethylformamide, heated to 60 ° C and allowed to stand overnight at room temperature after the addition of 30 ml of methanol. After addition of 800 ml of water, the mixture was extracted with ether, the ether extract was washed with water, dried with magnesium sulfate and concentrated. After purification of the residue by column chromatography (silica gel, petroleum ether / ethyl acetate = 5: 1, by volume), 11 g (64.3% of theory) of 4-phenylthio- N -2,2,2-trichloroethoxycarbonylpiperidine are obtained in the form of: colorless oil.

g (25 mmol) of the latter product, 6 g paraformaldehyde and 5.6 g (42 mmol) zinc chloride were mixed with 300 ml methylene chloride. Hydrogen chloride was added to the mixture at 20-22 ° C for 30 minutes. After an hour, hydrogen chloride was again fed for 10 minutes and the mixture was stirred overnight. The reaction mixture was then stirred into 300 ml of disodium hydrogen phosphate solution (c _{Na 2} H 2 PO 4 = 1 mol.dm ³ ); the methylene chloride phase was separated and the aqueous phase was extracted with methylene chloride. The organic phases were combined, washed with water, dried with magnesium sulfate and concentrated by evaporation. The residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1: 10, v / v) to give 4.5 g (43.2% of theory) of 4- [4- (chloromethyl) phenylthio] -A / -2,2,2-trichloroethoxycarbonylpiperidine as a colorless oil.

2.1 g (5 mmol) of the latter product and 1.3 g (15 mmol) piperidine were heated to reflux in 10 ml of tetrahydrofuran and 10 ml of ethanol for 2.5 hours. After evaporation, the residue was triturated with water and extracted with ether. The ether phase was washed with water, dried over magnesium sulfate and concentrated by evaporation. 2.5 g of 4- [4- (piperidinomethyl) phenylthio] -N-2,2,2-trichloroethoxycarbonylpiperidine were obtained as a crude product.

2.4 g of this crude product was dissolved in 3.5 ml of acetic acid and 18 ml of water and 5 g of zinc powder was added (vigorous effervescence upon gas evolution). The mixture was stirred at room temperature for 20 hours and at 50 ° C for one hour. After addition of 20 ml of water, the aqueous phase was overlaid with 100 ml of ether, the mixture was made alkaline with sodium hydroxide solution (cn ₉ oh = 6 mol.dm &^lt; ^{3 &gt;} ) and stirred for 20 minutes. The ether was then separated and the aqueous phase was extracted 3 times with ether. The combined extracts were dried with magnesium sulfate and concentrated by evaporation. 1.3 g of 4- [4- (piperidinomethyl) phenylthio] -N-2,2,2-trichloroethoxycarbonylpiperidine were obtained as a colorless powder. Rf value = 0.69 (alumina, methylene chloride / methanol = 10: 1, v / v).

Example C

4- [4- (dimethylaminomethyl) benzyl] piperidine

At 20-35 ° C, 100 g (0.57 mol) of 4-benzylpiperidine in 220 ml of methanol was mixed with 88 g (0.68 mol) of trifluoroacetic acid methyl ester. After two hours, the mixture was concentrated by evaporation. After crystallization of the residue from petroleum ether, 117 g (76% of th.) Of 4-benzyl-N-trifluoroacetylpiperidine were obtained as a colorless crystalline substance.

113 g (0.848 mol) of aluminum chloride in 600 ml of dichloroethane were mixed with 114 g (0.9 mol) of oxalyl chloride. 114 g of the above product in 300 ml of dichloroethane (gas evolution) were added dropwise at -4 to +4 ° C. The mixture was then stirred at room temperature for 2.5 hours; then 300 ml of a 40% aqueous dimethylamine solution was quickly added at -25 ° C (the temperature rose to 35 ° C). The resulting gel was diluted with 100 mL of dichloroethane, stirred for 20 minutes and diluted with chloroform for better phase separation. The mixture was washed with water, sodium hydroxide solution (ον ₃ οη = 2 mol.dm * ³ ), water, dilute hydrochloric acid (I want = 2 mol.dm * ³ ) and once more with water. The organic phase was dried over magnesium sulfate, concentrated by evaporation and the residue was triturated in ether. Yield: 111 g (80% of theory) of 4- [4- (dimethylaminocarbonyl) benzyl] -N-trifluoroacetylpiperidine as a colorless crystalline solid.

g of the latter product in 350 ml of tetrahydrofuran was added dropwise at 0 to 3 ° C to 70 ml of a 20% solution of lithium aluminum hydride in ether, diluted with 250 ml of ether. The mixture was then stirred at 0 ° C for 20 minutes and then heated at reflux for 1 hour. After cooling at 0 to 15 ° C, sodium hydroxide solution (cnsoh = 4 mol.dm * ³ ) was added dropwise (the mixture was strongly effervescent), then the mixture was stirred at room temperature for 30 minutes, filtered with suction and washed with the residue on the filter. ether. The combined ether phases were dried

-30 magnesium sulphate and concentrated by evaporation. Yield: 46 g (99% of theory) of 4- [4-dimethylaminomethyl) benzyl] piperidine as a colorless, slowly crystallizing oil.

_Rf value: 0.56 (aluminum oxide, methylene chloride / methanol = 10: 1, by volume).

Preparation of end products

Example 1

N - (Benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine hydrochloride

A mixture of 237 mg (0.83 mmol) of 4- [4-dimethylaminomethyl) phenylthio] piperidine, 200 mg (2 mmol) of triethylamine and 1 ml of ethanol was mixed with 150 mg (2 mmol) of carbon disulphide at room temperature. The resulting precipitate was dissolved by the addition of 1 ml triethylamine and 2.5 ml dimethylformamide. After an hour at room temperature, 160 mg (0.94 mmol) of benzyl bromide was added, the mixture was stirred overnight at room temperature and then heated at 60 ° C for 3 hours. After addition of 50 ml of water, the mixture was extracted with ethyl acetate, the organic phase was dried over magnesium sulphate and concentrated by evaporation. The residue was purified by column chromatography (alumina, petroleum ether / ethyl acetate = 4: 1, v / v). 210 mg of the title compound was obtained as a colorless oil which was converted into the hydrochloride with ethereal hydrochloric acid.

_Rf value of the free base: 0.83 (aluminum oxide, ethyl acetate / petroleum ether = 3: 1, obejmovo).

¹ H NMR (200 MHz, DMSO-d ₆ ) signals at ppm: 1.4-4.6 (m, 2H), 2.0-2.15 (m, 2H), 2.55 (d, 6H) 3.5 to 3.65 (t, 2H), 3.7 to 3.85 (m, 1H), 4.2 (d, 2H), 4.3 to 4.4 (m, 1H), 4.5 (s, 2H), 4.95-5.15 (m, 1H), 7.2-7.6 (m, 9H).

Similarly prepared:

(1) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzoyl] piperidine hydrochloride

-31 from 4- [4- (dimethylaminomethyl) -benzoyl] piperidine and benzyl bromide; the product was a colorless powder with an Rf value of the product (free base): 0.65 (alumina, ethyl acetate).

(2) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzylidene] piperidine hydrochloride from 4- [4- (dimethylaminomethyl) benzylidene] piperidine and benzyl bromide; the product was a colorless powder; mp 190 ° C.

(3) N- (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine hydrochloride from 4- [4- (dimethylaminomethyl) benzyl] piperidine and benzyl bromide; the product was a colorless powder with an Rf value of the product (free base) of: 0.26 (alumina, petroleum ether / ethyl acetate = 10: 1, v / v).

Example 2 N-Benzyloxycarbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine

Combine 250 mg (1 mmol) of 4- [4- (dimethylaminomethyl) phenylthio] piperidine in 20 ml of THF with 2 ml of sodium hydroxide _(Na OH = c 2 mol.dm ^'3) and 5 ml of water. 200 mg (1.2 mmol) of benzyl chloroformate in 5 ml of tetrahydrofuran was added slowly dropwise at room temperature. After 1.5 hours, chloroformate-free ester and sodium hydroxide were added again. After addition of 100 mL of ether, the mixture was washed with saturated brine, dried over magnesium sulfate, and concentrated by evaporation. The residue was purified by column chromatography (alumina, petroleum ether / ethyl acetate = 4: 1, v / v). The product obtained was converted to the hydrochloride by addition of an ethereal hydrochloric acid solution. 190 mg (45.1% of theory) of the title compound are obtained as a colorless powder, m.p. 144 ° C.

¹ H NMR (200 MHz, DMSO-d 6), signals at 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 (m, 1H), 3.8-4.0 (m, 2H), 4.2 (s, 2H), 5 0.05 (s, 2H); 7.3-7.6 (m, 9H).

-32 Similarly prepared:

(1) N- (4-chlorophenylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine hydrochloride from 4- [4- (dimethylaminomethyl) phenylthio] piperidine and 4-chlorophenyl chlorodithio formate; the product was a colorless powder, m.p. 178 ° C;

(2) 4- [4- (dimethylaminomethyl) phenylthio] -N-phenoxycarbonylpiperidine hydrochloride from 4- [4- (dimethylaminomethyl) phenylthio] piperidine and chloroformic acid phenyl ester; the product was a colorless powder, mp 161 ° C;

(3) N- (4-chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine hydrochloride from 4- [4- (dimethylaminomethyl) phenylthio] piperidine and 4-chlorophenyl chloroformate; the product was a colorless powder, mp 169 ° C;

(4) 4- [4- (dimethylaminomethyl) phenylthio] - N - (phenylthio) thiocarbonylpiperidine hydrochloride from 4- [4- (dimethylaminomethyl) phenylthio] piperidine and chlorodithio formate phenyl ester; the product was in the form of a colorless powder; Rf value of free base: 0.57 (alumina, petroleum ether / ethyl acetate = 4: 1, v / v);

(5) N- (4-chlorophenoxy) thiocarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine hydrochloride from 4- [4- (dimethylaminomethyl) benzyl] piperidine and chlorothioformate Ο-4-chlorophenyl ester; the product was a colorless powder, m.p. 150 ° C;

(6) N- (4-chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine from 4- [4- (dimethylaminomethyl) benzyl] piperidine and 4-chlorophenyl chloroformate; the product was a colorless powder, m.p. 104 ° C; treating the free base with hydrochloric acid to give the hydrochloride; the product was a colorless powder, mp 156 ° C;

-33 treatment of the free base with methanesulfonic acid in a mixture of ethyl acetate and ether gave the methanesulfonate as a colorless powder, m.p. 152 ° C;

treating the free base with L-tartaric acid in a mixture of methanol and ethyl acetate to give the tartrate as a colorless powder, mp 147 ° C;

(7) N- (4-chlorophenylthio) carbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine hydrochloride from 4- [4- (dimethylaminomethyl) benzyl] piperidine and chlorothioformic acid S-4-chlorophenyl ester; the product was a colorless powder, m.p. 190-191 ° C;

(8) N -benzyloxycarbonyl-4- [4- (piperidinomethyl) phenylthio] piperidine hydrochloride from 4- [4- (piperidinomethyl) phenylthio] piperidine and benzyl chloroformate; the product was a colorless powder, mp 186 ° C;

(9) N -phenoxycarbonyl-4- [4- (piperidinomethyl) phenylthio] piperidine hydrochloride from 4- [4- (piperidinomethyl) phenylthio] piperidine and phenyl chloroformate; the product was a colorless powder, m.p. 204 ° C;

(10) N -4-chlorophenoxycarbonyl-4- [4- (piperidinomethyl) phenylthio] piperidine hydrochloride from 4- [4- (piperidinomethyl) phenylthio] piperidine and 4-chlorophenyl chloroformate; the product was a colorless powder, m.p. 182 ° C;

(11) N -benzyloxycarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine from 4- [4- (dimethylaminomethyl) benzyl] piperidine and benzyl chloroformate; the free base product had a melting point of 63 ° C;

treatment with hydrochloric acid gave the hydrochloride; the product was a colorless powder, m.p. 132 ° C;

Treatment of the free base with methanesulfonic acid in a mixture of ethyl acetate and ether gave the methanesulfonate as a colorless powder, m.p. 140 [deg.] C .;

treating the free base with L-tartaric acid in a mixture of methanol and ethyl acetate to give the tartrate as a colorless powder, mp 125 ° C;

(12) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) carbonylpiperidine from 4- [4- (dimethylaminomethyl) benzyl] piperidine and 4-methylphenyl chloroformate; the free base product had a melting point of 80 ° C;

treating the free base with hydrochloric acid to give the hydrochloride; the product was a colorless powder, m.p. 185 ° C;

treating the free base with methanesulfonic acid in a mixture of ethyl acetate and ether gave the methanesulfonate as a colorless powder, m.p. 165 ° C;

treating the free base with L-tartaric acid in a mixture of methanol and ethyl acetate to give the tartrate as a colorless powder, mp 162 ° C;

(13) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) thiocarbonylpiperidine hydrochloride from 4- [4- (dimethylaminomethyl) benzyl] piperidine and chlorothioformate Ο-4-methylphenyl ester; the product was a colorless powder, mp 184 ° C;

(14) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-fluorophenoxy) carbonylpiperidine hydrochloride from 4- [4- (dimethylaminomethyl) benzyl] piperidine and 4-fluorophenyl chloroformate; the product was in the form of a colorless powder; Rf value of free base: 0.61 (alumina, petroleum ether / ethyl acetate = 6: 1, v / v).

-35Example 3

N-benzyloxycarbonyl-4- [4- (dimethylaminomethyl) phenylsulfinyl] piperidine hydrochloride

90.7 mg (0.215 mmol) of N -benzyloxy-4- [4- (dimethylaminomethyl) phenylthio] piperidine hydrochloride was dissolved in a mixture of 1 ml of methanol and 1 ml of water and 18.6 mg (0.226 mmol) were gradually added to the solution. anhydrous sodium acetate and 48.4 mg (0.226 mmol) of sodium meta-periodate. The mixture was stirred at room temperature for 6 hours, diluted with water, overlaid with ethyl acetate and saturated with sodium carbonate. The organic phase was separated, the aqueous phase was extracted with ethyl acetate; the organic phases were combined, washed with saturated brine, dried over magnesium sulfate and concentrated by evaporation. The residue was dissolved in a little methanol, treated with ethereal hydrochloric acid and the solvent was evaporated. The residue was triturated in ether, the solvent was evaporated and the residue was dried under high vacuum. Thus 85 mg (90.5% of theory) of the title compound are obtained as a colorless powder. The free base Rf was 0.43 (alumina, ethyl acetate = 1: 1, v / v);

¹ H NMR (200 MHz, DMSO-d ₆ ), signals at ppm: 1.3-1.6 (m, 3H), 1.8-2.0 (m, 1H), 2.65 (s, 6H) ), 2.7 to 3.1 (m, 3H), 3.95 to 4.15 (t, 2H), 4.35 (s, 2H), 5.05 (s, 2H), 7.3 ( s, 5H), 7.65-7.85 (q, 4H).

Similarly prepared:

(1) 4- [4- (dimethylaminomethyl) phenylsulfinyl] - N -phenoxycarbonylpiperidine hydrochloride from 4- [4- (dimethylaminomethyl) phenylthio] - N -phenoxycarbonylpiperidine hydrochloride and sodium periodate; the product was in the form of a colorless powder; _Rf value of the free base: 0.4 (aluminum oxide, ethyl acetate / petroleum ether = 1: 1, by volume).

Claims (15)

PATENT CLAIMS 1. Urethans derived from azacycloalkanes and their thio- and dithio-analogues of the general formula I R ¹ (I) wherein m is 0 or 1, n is 1 or 2, A is a single bond, unbranched or branched C1. ₈ -alkylene, C ₂ . _8- alkenylene or C ₂ . _{An 8-} alkynylene group wherein the unsaturated group is not bonded directly to Y, X is an oxygen or sulfur atom, Y is an oxygen atom or a sulfur atom, R ¹ is a straight or branched C 1-4 alkyl, C 1-4 alkenyl or C 1-4 alkynyl group wherein the multiple bond is isolated from the nitrogen-carbon bond, R ² is a straight or branched Ci_6-alkyl, CM-alkenyl or C ^ -alkynyl, whilst the multiple bond is isolated from the nitrogen - carbon isolated, or R ¹ and R ² together with the nitrogen atom form a 5 to 7 membered, saturated heterocyclic ring in which the methylene group isolated from the nitrogen may be replaced by an oxygen or sulfur atom, an -NH- group or an -N (alkyl) - group, R ³ to R ⁶ may be the same or different and may be hydrogen atoms or alkyl groups, R ⁷ is C ₃ . _7- cycloalkyl, phenyl or naphthyl, which may be optionally substituted by one or two halogens, alkyl-, -37alkoxy-, trifluoromethyl- or cyano- and, unless A is a single bond, a hydrogen atom, E represents an oxygen or sulfur atom, a methylene, carbonyl or sulfinyl group and R ⁸ represents a hydrogen atom, or E is -C (R ⁹ R ¹⁰ ) -, wherein R ⁹ represents a hydrogen atom and R ¹⁰ together with an adjacent R ⁸ group represents a carbon-carbon bond, wherein, unless otherwise indicated, the above alkyl groups may each contain 1 to 3 carbon atoms and the halogen atoms mentioned may be fluorine, chlorine or bromine, their enantiomers , diastereomers, mixtures thereof and salts thereof. Urethenes derived from azacycloalkanes and their thio- and dithio-analogues of the general formula I according to claim 1, in which m is 1, n is 1, A is a single bond, a branched or unbranched C 1 -C 4 -alkylene group, a C 2-4 -alkenylene group, wherein the unsaturated group is not bound directly to the radical Y, X is an oxygen atom or a sulfur atom, Y is an oxygen atom or a sulfur atom, R ¹ is a straight or branched C 1-6 -alkyl, allyl or propargyl group, wherein the multiple bond is isolated from the nitrogen-carbon bond, R ² is a straight or branched Ci-6-alkyl, allyl or propargyl group, whilst the multiple bond is isolated from the nitrogen - carbon isolated, or R ¹ and R ² together with the nitrogen atom form a 5 to 7 membered, saturated heterocyclic ring in which one methylene group isolated from the nitrogen atom may be replaced by an oxygen or sulfur atom, -38R ^{3 * *} to R ⁶ may be the same or different and may be hydrogen atoms or methyl groups, R ⁷ is C ₃ . _6- cycloalkyl, or phenyl or naphthyl, optionally substituted by one or two halogen atoms, alkyl, alkoxy, trifluoromethyl or cyano, E is a sulfur atom, a methylene group, a carbonyl group or a sulfinyl group, and R ⁸ is a hydrogen atom, or E is -C (R ⁹ R ¹⁰ ) -, wherein R ⁹ represents a hydrogen atom and R ¹⁰ together with an adjacent R ⁸ group represents a carbon-carbon bond, wherein, unless otherwise indicated, the above alkyl groups may each contain 1 to 3 carbon atoms and the halogen atoms mentioned may be fluorine, chlorine or bromine, their enantiomers , diastereomers, mixtures thereof and salts thereof. Urethenes derived from azacycloalkanes and their thio- and dithio-analogues of the general formula I according to claim 1, wherein m is 1, n is 1, A is a single bond, or unbranched or branched C1. _3- alkylene group, X is an oxygen atom or a sulfur atom, Y is an oxygen atom or a sulfur atom, R ¹ is unbranched or branched. _3- alkyl, R ² is a straight or branched C _1-3 -alkyl group; or R ¹ and R ² together with the nitrogen atom form a piperidine or morpholine group, R ³ to R ⁶ are hydrogen atoms, R ⁷ represents a cyclohexyl group or a phenyl or naphthyl group optionally substituted by one halogen atom, an alkyl-, alkoxy-, trifluoromethyl- or cyano- group, -39E is a sulfur atom, a methylene group, a carbonyl group or a sulfinyl group, and R ⁸ is a hydrogen atom, or E is -C (R ⁹ R ¹⁰ ) -, wherein R ⁹ represents a hydrogen atom and R ¹⁰ together with the adjacent R ⁸ group represents a carbon-carbon bond, their enantiomers, diastereomers, mixtures thereof, and salts thereof. Urethane derivatives derived from azacyclloalkanes and their thio- and dithio-analogues of the general formula I according to claim 1, in which m is 1, n is 1, A is a single bond or a methylene group, X is an oxygen atom or a sulfur atom, Y is an oxygen atom or a sulfur atom, R ¹ is a methyl group, R ² is a methyl group, R ³ to R ^{5 6} are hydrogen atoms, R ⁷ represents a phenyl group, optionally substituted by one or two fluorine or chlorine atoms, or a methyl group, E is a sulfur atom, a methylene group, or a carbonyl group, and R 8 is a hydrogen atom, or E is -C (R ⁹ R ¹⁰ ) -, wherein R ⁹ represents a hydrogen atom and R ¹⁰ together with an adjacent R ⁸ group represents a carbon-carbon bond, mixtures thereof and salts thereof. The urethanes derived from azacycloalkanes and their thio- and dithio-analogues of the general formula I according to claim 1 which are: (1) N - (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine, (2) N - (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzoyl] piperidine, (3) A N -benzyloxycarbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine, (4) N- (4-chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) phenylthio] piperidine, (5) N - (benzylthio) (6) N - (benzylthio) thiocarbonyl-4- [4- (dimethylaminomethyl) benzylidene] piperidine, (7) N- (4-chlorophenoxy) thiocarbonyl-thiocarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine; 4- [4- (dimethylaminomethyl) benzyl] piperidine, (8) N- (4-chlorophenoxy) carbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine, (9) N-benzyloxycarbonyl-4- [4- (dimethylaminomethyl) benzyl] piperidine, (10) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-methylphenoxy) carbonylpiperidine _I (11) 4- [4- (dimethylaminomethyl) benzyl] - N - ( And (12) 4- [4- (dimethylaminomethyl) benzyl] -N- (4-fluorophenoxy) carbonylpiperidine, mixtures thereof and salts thereof. 6. Urethenes derived from azacycloalkanes and their thio- and dithio-analogues of the formula I according to claims 1 to 5, in the form of their physiologically acceptable salts with inorganic or organic acids. A process for the preparation of urethanes derived from azacycloalkanes and their thio- and dithio-analogues according to at least one of claims 1 to 6, characterized in that (a) the conversion of a compound of the general formula II is carried out R ¹ (CH ₂ ) _{n χ} NH (CH ₂ ) / (Π) wherein m, n, E with the exception of the sulfinyl group, R ¹ to R ⁶ and R ⁸ are as defined in claims 1 to 5, by reaction with a compound of formula III 'A R ⁷ (III) -41 in which A, X, Y and R ⁷ are as defined in claims 1 to 5 and Z is a removable group, (b) for the preparation of compounds of the formula I in which X and Y represent a sulfur atom and m, n, A, E and R ¹ to R ⁸ are as defined in claims 1 to 5, except where R ⁷ is not optionally substituted phenyl or naphthyl the group, then A represents a single bond, is carried out to convert the compounds of the general formula II in which m, n, E with the exception of the sulfinyl group, R ¹ to R ⁶ and R ⁸ are as defined in claims 1 to 5, with carbon disulphide and an agent of formula IV And (IV) wherein A and R ⁷ are as defined in claims 1 to 5, except that R ^{7 is} not an optionally substituted phenyl or naphthyl group when A is a single bond; Z ¹ represents a exchangeable group; c) for a compound of formula I in which E represents a sulphinyl group by oxidation of a compound of formula I and the group m, n, A, X, Y and R ¹ to R ⁸ are as defined in claims 1 to 5, and E is S; and if desired, the prepared mixture of geometric isomers of the compound of formula I may be separated into its enantiomers and diastereomers, or the prepared compound of formula I may be converted into its salt with an inorganic or organic acid, in particular a physiologically acceptable salt. A pharmaceutical composition comprising a compound according to at least one of claims 1 to 5, or a physiologically acceptable salt thereof according to claim 6, and optionally one or more carriers and / or diluents. Pharmaceutical composition according to claim 8, characterized in that it comprises a compound according to at least one of claims 1 to 5, or a physiologically tolerable salt according to claim 6, in combination with one or more other substances which lower cholesterol or lipid levels. Pharmaceutical composition according to claim 9, characterized in that the other substances are selected from: - bile acid binding resins, - compounds that inhibit cholesterol absorption, - compounds which act by mechanisms other than the suppression of 2,3-epoxyqualenlanosterol cyclase in cholesterol biosynthesis, - fibrates, nicotinic acid, derivatives and analogues thereof, as well as Probucol. Layer for laying hens, characterized in that it comprises a compound according to at least one of claims 1 to 5 or a physiologically tolerable salt according to claim 6. Process for the preparation of a pharmaceutical composition according to claim 6, characterized in that the compound according to at least one of claims 1 to 6 is incorporated in a non-chemical way into one or more carriers and / or diluents. Use of urethanes derived from azacycloalkanes and their thio- and dithioanalogues according to at least one of claims 1 to 6 for the manufacture of a medicament for the treatment of diseases related to cholesterol biosynthesis. Use according to claim 12 for the manufacture of a medicament for the treatment or prophylaxis of hypercholesterolemia, hyperlipoproteinaemia, hypertriglyceridemia and the resulting atherosclerotic vascular changes with subsequent diseases such as coronary heart disease, cerebral ischemia, Claudicatio intermittens or gangrene, for the treatment of diseases cells, for the prophylaxis and treatment of gallstones, or for the treatment of mycoses. Use of urethane derived from azacycloalkanes and their thio- and dithioanalogues according to at least one of claims 1 to 6 for the preparation of feed for laying eggs for the production of cholesterol-reduced eggs.