CZ311796A3 - O-acyl-4-phenyl-cycloalkanols, their salts, medicament in which the compounds are comprised and their use, as well as process for preparing thereof - Google Patents

Abstract

O-acyl-4-phenyl-cyclohexanol derivs. of formula (I) and their enantiomers, diastereomers, and geometric isomers and their salts are new. n = 0-1; m = 1-2; p = 0-1; R1 and R2 each = H, 1-6C alkyl, 3-6C alkenyl, 3-6C alkynyl (opt. substd. but not on an unsatd. C and not on Cl); or NR1R2= a 5-7 membered satd. monocyclic heterocyclic ring, the 6 membered ring opt. having CH2 in position 4 replaced with O, S or alkyl-substd. imino; R3,R4 = H or 1-4C alkyl; R5 = H, 1-4C alkyl or 1-4C alkoxy; R6 = H or 1-4C alkyl; R7 = H, 3-7C cycloalkyl, Ph (opt. mono- or di-substd.), naphthyl, tetra-hydronaphthyl, thienyl, furyl or pyridyl (those last 3 gps. opt. mono-substd. for halogen or di-substd. by alkyl); A = a bond, 1-17C alkylene, 2-17C alkylene or 2-17C alkynylene; all alkyl and alkoxy gps., unless otherwise stated, contain 1-3 C atoms and halogen is F, Cl or Br.

Description

O-Acyl-4-phenyl-cycloalkanols, their salts, medicaments containing these compounds and their use, and processes for their preparation

Technical field

The present invention relates to O-acyl-4-phenyl-cycloalkanates, their salts with physiologically acceptable organic and inorganic acids, processes for the preparation of these compounds and medicaments containing them and their use.

BACKGROUND OF THE INVENTION

The compounds of the invention are inhibitors of cholesterol biosynthesis, in particular inhibitors of 2,3epoxisqualen-lanosterol cyclase, a key enzyme in cholesterol biosynthesis. The compounds of the invention are useful in the treatment and prophylaxis of hyperiipidemia, hypercholesterolemia and atherosclerosis. Another possible field of application of hyperproliferative diseases of the skin and blood vessels, gallstones and mycoses.

is the treatment of tumors,

Compounds that interfere with cholesterol biosynthesis are useful in the treatment of a number of major diseases. These include, in particular, hypercholesterolemia and hyperlipidemia, which are risk factors for the development of atherosclerotic vascular changes and their subsequent diseases such as coronary heart disease, cerebral ischemia, claudicatio intermittens and gangrene.

The importance of elevated serum cholesterol as a major risk factor for the development of atherosclerotic vascular changes is generally known. Extensive clinical studies have led to the recognition that lowering serum cholesterol may reduce the risk of coronary heart disease (Current Opinion in Lipidology 2 (4), 234 (1991)). Since an increased proportion of cholesterol is self-synthesized in the body and only a minor portion is taken with food, suppression of biosynthesis is a particularly attractive way to lower elevated cholesterol levels.

In addition, the treatment of hyperproliferative skin and vascular diseases as well as tumor diseases, the treatment and prophylaxis of gallstones and mycoses is another field of application for cholesterol biosynthesis suppressors. The latter is an intervention in ergosterol biosynthesis in fungal organisms, which is analogous to cholesterol biosynthesis in mammalian cells.

Synthesis of cholesterol resp. ergosterol proceeds by starting from acetic acid and running through a large number of reaction steps. This multi-step process provides a range of intervention options, examples of which include:

For inhibition of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) -synthase, β-lactones and β-lactams with a potential anitihypercholesterolemic effect are selected (see J. Antibiotics 40, 1356 [1987], US-A-4751237 EP-A-0462667

US-A-498,397).

HMG-CoA reductase inhibitors are the statin-type 3,5-dihydroxycarboxylic acids and their 5-lactones, their representatives lovastatin, simvastatin and pravastatin find use in the treatment of hypercholesterolemia.

Other possible uses for these compounds are fungal infections (US-A-4375475, EP-A-0113881, US-A-5106992), skin diseases (EP-A-0369263) as well as gallstones and tumor diseases (US-A Lancet 339, 1154 1156 [1992]). Another therapeutic option is to suppress the proliferation of the muscle cells by lovastatin (Cardiovasc. Drugs. Ther. 5, Suppl.3, 354 [1991]).

Squalene synthetase inhibitors are, for example, isoprenoid (phosphinylmethyl) phosphonate, the property of which for the treatment of hypercholesterolemia, gallstones and tumor diseases is described in EP-A-0409181 and J. Med. Chemistry 34, 1912 [1991]; squalestatins cholesterol-suppressing activity and antifungal activity (J. Antibiotics 45, 539-647 [1992] and J.Biol.Chemistry 267,

11705-11708 [1992].

Allylamines such as naftifine and terbinafine are known as squalene epoxidase inhibitors, which have found use as an antifungal agent in therapy, such as allylamine NB-598 with antihypercholesterolemic activity (J.Biol.Chemistry 265, 18075-18078, [1990]) and fluorsqualene derivatives with hypocholesterolemic activity (US-A-5011859). Further disclosed are piperidines and azadecalins with hypocholesterolemic and / or antifungal activity, their mechanism of action is not obvious and which are squalenepoxidase- and / or 2,3-epoxidsqualen-lanesterolcyclase inhibitors (EP-A-0420116, EP-A-0468434, US -A5084461 and EP-A-0468457).

Examples of 2,3-epoxisqualene-ianesterol cyclase inhibitors are diphenyl derivatives (EP-A-0464465), aminoalkoxybenzyl derivatives (EP-A-0410359) as well as piperidine derivatives (J. Org. Chem. 57, 2794-2803, [1992] ) that have antifungal activity. Furthermore, this enzyme is inhibited in mammalian cells by decalin, azadecalin and indander derivatives (WO 89/08450, J.Biol.Chemistry 254, 11258-11263 [1981], Biochem. Pharmacology 37, 1955-1964 [1988] and J 64 003 144) 2-aza-2,3-dihydrdsqualene and 2,3-epiminosqualene (Biochem. Pharmacology 34, 2765-2777 [1985]), squalenoxide-epoxy-enol ether (J. Chem. Soc. Perkin Trans. I, 1938, 461) and 29-methylidene-2,3-oxidosqualene (J.Amer. Chem. Soc. 113, 9673-9674 [1991]).

Finally, steroid derivatives with potential antihyperlipidemic activity that also affect HMG-CoA reductase enzyme (US-A-5041432, lanosterol-14a-demethylase) should be mentioned as inhibitors of the enzyme lanosterol-14a-demethylase.

J.Biol.Chemistry 266, 20070-20078 [1991], US-A-5034548.

In addition, this enzyme inhibits azole-type antifungal agents, which are N-substituted imidazoles and triazoles. This class includes, for example, the commercially available antifungals ketoconazole and fluconazole.

The compounds of the following formula I are novel. Surprisingly, they have been found to be very potent inhibitors of the enzyme 2,3-epoxisqualen-lanosterol-cyclase (international classification: EC5.4.99.7).

The enzyme 2,3-epoxisqualen-lanosterol cyclase catalyses a key step in cholesterol biosynthesis and biosynthesis. ergosterol, namely the conversion of 2,3-epoxisqualene to lanosterol, the first compound with a steroid structure in the biosynthesis cascade. Inhibitors of this enzyme can be expected to inhibit this early biosynthesis step to decrease biosynthetically produced mevalonic acid and thereby also negatively affect biosynthesis on mevalone synthesis dependent against inhibitors of earlier biosynthesis steps such as HMG-Co-synthesis and HMG-CoA-reduction. substances with cholesterol, ubiquinone and isopentenyl-t-RNA (cf. J.Biol.Chemistry 265, 18075-18078 [1990]).

Inhibition of the biosynthesis steps after the conversion of 2,3epoxisqualene to lanesterol creates the risk of an increased occurrence of intermediates with a steroid structure in the body and the triggering of such toxic effects. This is described, for example, for triparanol, a desmosterol reductase inhibitor. This substance had to be withdrawn from the market for cataract formation, ichthyosis and alopecia (cited in J. Biol. Chemistry 265, 18075-18078 [1990]).

As mentioned previously, 2,3-epoxisqualenlanesterol cyclase inhibitors are individually described in the literature. However, the structure of these compounds is quite different from that of the compounds of the invention of the following general formula (I).

The invention provides antihypercholesterolemic substances which are suitable for the treatment and prophylaxis of atherosclerosis and, in comparison with known active substances, are characterized by improved antihypercholesterolemic action with increased selectivity and thus increased safety. Since the compounds of the invention, as inhibitors of the enzyme 2,3epoxisqualen-lanesterol cyclase, can also inhibit ergosterol biosynthesis in fungal organisms because of their high potency, they are also useful in the treatment of mycoses.

SUMMARY OF THE INVENTION

The present invention relates to novel O-acyl-4-phenylcycloalkanols of formula I

Ί

n means numbers 0 or 1, ra means numbers 1 or 2, P means numbers 0 or 1,

R ¹ and R ² , which may be the same or different, represent a hydrogen atom, a straight or branched (C 1 -C 6) alkyl group, a straight or branched (C 3 -C 6) alkenyl or alkynyl group, the double and triple bonds thereof are isolated from the nitrogen bond and said alkyl, alkenyl and alkynyl groups may also be substituted with amino, hydroxy, alkoxy, alkylcarbonyloxy, alkylcarbonylamino, carboxyl, alkoxycarbonyl, aminocarbonyl or cyano, said amino, hydroxy -, alkoxy-, alkylcarbonyloxy- and alkylcarbonylamino groups cannot be attached to the unsaturated carbon atom and to the carbon atom at the 1-position, or

Rl and ^R2 together with the interjacent nitrogen atom form a 5- to 7-membered saturated monocyclic heterocyclic ring wherein the thus formed monocyclic ring hetsrocyklickém methylene group can be in position 4 is replaced by oxygen or sulfur or an optionally alkyl-substituted imino group,

R ³ and R ^4, which may be the same or different and represent hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms,

R ⁵ represents a hydrogen atom, a straight or branched (C 1 -C 4) alkyl group or a (C 1 -C 4) alkoxy group,

R ⁶ represents a hydrogen atom or a straight or branched (C 1 -C 4) alkyl group,

R 7 represents a hydrogen atom, a C 3 -C 7 cycloalkyl group, optionally a fluorine, chlorine or bromine atom, hydroxy-, alkyl-, alkoxy-, phenylalkoxy-, phenyl-, nitro-, amino-, alkylamino-, dialkylamino- , the alkylcarbones of lamino-, cyano-, carboxy-, alkoxycarbonyl-, aminocarbonyl-, alkylaminocarbonyl-, dialkylaminocarbonyl-, trifluoromethyl-, alkylcarbonyloxy-, aminosulfonyl-, alkylaminosulfonyl- or dialkylaminosulfonyl- mono- or disubstituted phenyl groups may be the same or a substituted phenyl group; and wherein two adjacent hydrogen atoms in the phenyl group may be replaced by methylenedioxy or 1,2-ethylenedioxy, chloro or bromo and amino substituted phenyl, naphthyl or cetrahydronaphthyl, halogen or one or two alkyl substituted thienyl, furyl or oyridyl groups and

A represents a bond, straight or branched (C 1 -C 17) alkylene or (C 2 -C 17) alkenylene or alkynyl, all of which alkyl and alkoxy moieties, unless otherwise indicated, may contain 1 to 3 carbon atoms, and said atom halogen may be fluorine, chlorine or bromine, their enantiomers, diastereomers and geometric isomers as well as their salts, in particular for the pharmaceutical use of their physiologically acceptable salts with inorganic or organic acids.

Compounds of formula Ia are preferred

, (la) where n, m and p are always 1,

R ¹ and R ² , which may be the same or different, represent a hydrogen atom, a straight or branched (C 1 -C 6) alkyl group, a straight or branched (C 3 -C 6) alkenyl or alkynyl group, the double and triple bonds thereof are isolated from a nitrogen carbon bond and said alkyl-, alkenyl- and alkynyl groups may also be substituted by amino-, hydroxy-, alkoxy-, alkylcarbonyloxy-, alkylcarbonylamino-, carboxyl, alkoxycarbonyl-, aminocarbonyl- or cyano groups, said amino-, hydroxy -, alkoxy-, alkylcarbonyloxy- and alkylcarbonylamino groups cannot be attached to the unsaturated carbon atom and to the carbon atom at the 1-position, or

R ¹ and R ² together with the intervening nitrogen atom form a 5- to 7-membered saturated monocyclic heterocyclic ring, wherein in the β-membered monocyclic heterocyclic ring thus formed, the methylene group at the 4-position may be replaced by an oxygen or sulfur atom or optionally by an alkyl an amino-substituted group,

R ³ to R ⁶ , which may be the same or different, represent a hydrogen atom or a methylene group,

R ⁷ represents a hydrogen atom, a C 3 -C 7 cycloalkyl group, optionally a fluorine, chlorine or bromine atom, a hydroxy-, alkyl-, alkoxy-, phenylalkoxy-, phenyl-, nitro-, amino-, alkylamino-, dialkylamino-, alkylcarbonylamino-, cyano-, carboxy-, alkoxycarbonyl-, aminocarbonyl-, alkylarainocarbonyl-, dialkylaminocarbonyl-, trifluoromethyl-, alkylcarbonyloxy-, aminosulfonyl-, alkylaminosulfonyl- or dialkylaminosulfonyl- mono- or disubstituted phenyl groups, wherein the substituents may be the same or two, wherein the substituents may be the same or two; adjacent hydrogen atoms in the phenyl group may be replaced by methylenedioxy- or 1,2-ethylenedioxy, two chlorine or bromine atoms and an amino substituted phenyl, naphthyl or tetrahydronaphthyl, chlorine or bromine atom, or one or two alkylsubstituted thienyl, furyl or pyridyl, and

A represents a bond, straight or branched (C1 -C10) alkylene or (C2 -C10) alkenylene or alkynylene, wherein all alkyl and alkoxy moieties, unless otherwise indicated, may contain 1 to 3 carbon atoms and their enantiomers , diastereomers and geometric isomers as well as their salts, in particular for pharmaceutical use their physiologically acceptable salts with inorganic or organic acids.

Particularly preferred are compounds of formula Ia wherein n, m and p are each 1,

R ¹ represents a hydrogen atom, a straight or branched (C 1 -C 4) alkyl group which may be substituted by an aminocarbonyl or in the 2-, 3- or 4- position may be substituted by a hydroxy or alkoxy group, or a 2-propenyl group, and

R ² represents a hydrogen atom, a C 1 -C 4 alkyl group or a 2-propenyl group, or rA and R ² together with the intervening nitrogen atom form a 5- to 2-carbon atom;

A 6-membered saturated monocyclic heterocyclic ring, wherein in the 6-membered monocyclic heterocyclic ring thus formed, the methylene group at the 4-position may be replaced by an oxygen atom or an optionally substituted alkyl group by an alkyl group,

R ³ to R ⁶ are each hydrogen, r ⁷ is hydrogen, C 3 -C 6 cycloalkyl, optionally in the 4-position with fluorine, chlorine or bromine, hydroxy-, alkyl-, alkoxy-, phenyl-, nitro- , a trifluoromethyl monosubstituted phenyl group, two chlorine atoms, a chlorine atom and an alkyl or amino group or two alkoxy groups a disubstituted phenyl group, two chlorine atoms and an amino trisubstituted phenyl group,

3,4-methylenedioxyphenyl, naphthyl or tetrahydronaphthyl, 2-furyl or optionally substituted 5-chloro-2-thienyl at the 5-position or

3-pyridyl,

A represents a bond, straight or branched (C1-C6) alkylene or (C2-C5) alkenylene, wherein all alkyl and alkoxy moieties, unless otherwise indicated, may contain 1 to 3 carbon atoms and their enantiomers, diastereomers and geometric forms isomers and salts thereof, in particular for pharmaceutical use, their physiologically acceptable salts with inorganic or organic acids.

Very particularly preferred are compounds of formula Ia wherein n, m and m are each 1,

R ¹ represents a hydrogen atom, a straight or branched (C 1 -C 4) alkyl group which may be substituted by an aminocarbonyl group or in the 2-, 3- or 4-position of a hydroxy or alkoxy group, or a 2-propenylene group,

R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,

R ³ to R ⁶ are each hydrogen or methylene,

R? is optionally at the 4-position with fluorine, chlorine or bromine, methyl, trifluoromethyl, methoxy, phenyl or nitro substituted phenyl, 3,4-dichlorophenyl,

2,4-dichlorophenyl-, 4-chloro-3-methylphenyl-, 4-amino-3-chlorophenyl-, 3,4-dimethoxyphenyl-, 3,4-methylenedioxyphenyl-, 4-amino-3,5-dichlorophenyl- or 2-naphthyl; and

A represents a bond, straight or branched (C 1 -C 5) alkylene or C 2 or C 3 alkenylene or alkynylene, all of which alkyl and alkoxy moieties, unless otherwise indicated, may contain 1 to 3 carbon atoms and their enantiomers, diastereomers and geometric isomers and their salts, in particular for the pharmaceutical use, their physiologically acceptable salts with inorganic or organic acids, in particular the compounds (1) cis-O- (4-chlorobenzoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol (2) cis-O- (4-phenyl-3-butenoyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol, (3) trans-O- (4-chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol, (4) cis-O - (5-methylhexanoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol, (5) trans-O- (2-phenylpropionyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol, (6) trans-O- (4- fluorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol, (7) trans-O- (3,4-dichlorophenylation) (8) cis-O- (4-fluorocinnamoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol, (9) trans-O- (p-tolylacetyl) -4- (4-methyl-4- (4-dimethylaminomethylphenyl) cyclohexanol); (10) trans-O- (4- [trifluoromethyl] phenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol; (11) trans-O- (2-naphthylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol; (12) trans-O- (4-nitrophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol, (13) trans-O- (4-bromophenylacetyl) -4- (4-dimethylarainomethylphenyl) -cyclohexanol, (14) trans-O- (2,4-dichlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol, (15) trans-O- ([4-amino-3-chlorophenyl] acetyl) -4- (4 dimethylaminomethylphenyl) -cyclohexanol, (16) trans-O- (4-methoxyphenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol, (17) trans-O- (4-chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclo hexanol and its salts.

Method of production:

For example, the compounds of formula (I) may be prepared as follows:

a) Reaction of 4-phenylcycloalkanol of formula II

where n, ra, p and R ¹ to R ⁵ are as defined above, with a carboxylic acid or its reactive derivatives of the general formula

III

R ⁷ -A-COX (III) wherein

R ⁷ and A are as defined above and X is a hydroxy or a reactive leaving group such as a halogen atom such as a chlorine or bromine atom, trimethylsilyloxy, a sulfonyloxy group such as a p-toluenesulfonyloxy group, an N-heteroaryl group such as a 1-imidazolyl or 1-benzotriazolyl group a group such as an O- (N, N ¹ -dicyclohexyl) isurea group.

The reaction is preferably carried out in a solvent such as benzene toluene, xylene, diisopropyl ether, dioxane, tetrahydrofuran, dimethylformamide, dichloromethane or chloroform and optionally in the presence of a base such as triethylamine, pyridine or 4-dimethylaminopyridine, or in the presence of acid, especially when X in general formula III represents a hydroxy group, for example in the presence of boron trifluoride etherate or an acid cation exchanger at a temperature between 10 and 150 ° C, but preferably at a temperature between -10 and 80 ° C.

If the residues R ¹ and / or R contain a free hydroxyl, amino or carboxyl group, it is recommended to protect against these reactions suitable manner, e.g. by converting the hydroxy into an ether group, e.g. 2-methoxyethoxymethyl, terč.butylnebo benzyletherskupinou, amino, - to a carbamate group such as a trichloroethyl, 9-fluorenyl- or 2,4-dichlorobenzylcarbamate group and a carboxyl group to an ester group such as a 2,2,2-trichloroethal-, tert-butyl- or benzyl ester group and protecting groups after the reaction is completed again cleaved by known methods.

(b)

Reaction of O-acyl-4-phenylcycloalkanol of formula IV

n, m, p, R ³ to R ' ¹ and A have Wsnara a as defined above

Y represents a reactive leaving group such as a halogen atom such as a chlorine or bromine atom, or a sulfonyloxy group, such as a methylsulfonyloxy group, with an amine of formula V

where

R ¹ and R ³ are as hereinbefore defined.

The reaction is preferably carried out in a suitable solvent such as ethanol, tert-butanol, dimethylformamide or tetrahydrofuran optionally in the presence of a base such as potassium carbonate, sodium ethanolate, potassium tert-butanolate or sodium hydride and optionally under phase transfer conditions at temperatures between 0 and Mp 100 ° C.

and c) For the preparation of compounds of the formula I in which R ¹ is as defined above and R ³ represents a straight or branched alkyl group having 1 to 6 carbon atoms, which may be

substituted by hydroxy-, alkoxy-, alkylcarbonyloxy-, alkylcarbonylamino-, carboxyl-, alkoxycarbonyl-, aminocarbonyl- or cyano, wherein the hydroxy-, alkoxy-, alkylcarbonyloxy- or alkylcarbonylamino group is not attached to the carbon atom at the 1-position:

Reaction of O-acyl-4-phenylcycloalkanol of formula VI

in which n, m, p, R ³ to R ⁷ and A are as defined above and R ³ is as defined above, with a compound of formula VII R _{2 '-} 21 (VIZ;

wherein r 2 'is a straight or branched (C 1 -C 6) alkyl group which may be substituted by hydroxy-, alkoxy-, alkylcarbonyloxy-, alkylcarbonylamino-, carboxyl-, alkoxycarbonyl-, aminocarbonyl-, or cyano, wherein hydroxy-, alkoxy-, alkylcarbonyloxy or the alkylcarbonylamino group is not attached to a carbon atom in the position Ia. Z ¹ represents a reactive leaving group such as a halogen atom, such as a chlorine or bromine atom, or a sulfonyloxy group, such as a methylsulfonyloxy group.

The reaction is preferably carried out in a solvent or solvent mixture such as ethanol, tert-butanol, tetrahydrofuran, dimethylsulfoxide or dimethylformamide, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride, sodium ethanolate, tert-butanolate potassium, triethylamine or pyridine, the latter two compounds can also be used simultaneously as solvents, optionally under phase transfer conditions, preferably at a temperature between 0 and 100 ° C, e.g. at temperatures between 20 and 50 ° C.

In such reactions, any reactive groups present, such as hydroxy, amino, alkylamino, imino or carboxyl groups, may be protected by conventional protecting groups which are cleaved again after the reaction.

Examples of protecting groups for the hydroxy group are trimethylsilyl-, acetyl-, benzoyl-, methyl-, ethyl-, tert-butyl-, 2-methoxyethoxymethyl-, benzyl- or tetrahydropyranyl-, as protecting groups for amino-, alkylamino- or the imino group acety-, benzoyl, ethoxycarbonyl- or benzyl and as the protecting group for the carboxyl group 2,2,2-trichloroethyl-, tert-butyl- or benzyl ester.

Optionally, the subsequent cleavage of the protecting residue used is preferably carried out hydrolytically in an aqueous solvent, e.g. water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as hydrochloric or sulfuric acid or in the presence of an alkali metal base such as hydroxide. sodium or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at the boiling point of the reaction mixture. However, the cleavage of the benzyl residue is preferably carried out hydrogenolytically, e.g.

hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, preferably at room temperature and hydrogen pressure 1 to 7 bar, preferably 3 to 5 bar.

The compounds of formula (I) prepared by the above process can be purified and isolated by methods known per se, for example by crystallization or chromatography.

Further, the compounds of the formula I obtained, if desired, can be converted into their acid addition salts, in particular for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

The compounds of the formula I according to the invention can be, depending on the position of the substituents on the cycloalkane ring or the ring. in the form of substituents R ¹ to R ⁷ in the form of stereoisomers, in the form of diastereomers, geometric isomers or optical isomers. The invention includes both pure stereoisomers and mixtures thereof.

Starting compounds:

For example, the starting compounds of formula (II) may be prepared as follows:

1. Reduction of 4-phenylcycloalkanones of formula VIII, (VIII)

where η, m, ρ and R ¹ to R 5 are as previously defined.

Selection of a suitable reducing agent, e.g. sodium borohydride; For example, lithium tri-sec-butylborohydride (L-seectride), the reaction can be conducted to give the ε, ε-isomers or the ε-isomers. e, α-isomers of the compound of formula II.

The ketones of formula VIII can be prepared by methods known per se, for example by reaction of the monoethylene ketals of formula IX

z (IX) with a metalloorganic compound of formula X

wherein R ¹ to R ⁵ are as defined above and Me represents lithium or -MgHal, wherein Hal represents a halogen atom, preferably a chlorine atom, and then cleavage of water, hydrogenation of the resulting double bond and hydrolysis of the ketal moiety.

The process can be varied in such a way that the ketone of formula VIII, where R 0 is hydrogen, after the above reaction sequence is converted to a ketone of formula VIII, where R ⁵ is C 1 -C 4 alkyl, for example by alkylation of a ketone -enolate ion.

Another method for preparing compounds of formula (VIII) is by Dieckmann cyclization of dicarboxylic acid esters of formula (XI)

COOR ³

CGQR ^? , (XI) wherein n, m, p and R ¹ to R ³ are as defined above and

R ³ and R ⁹ , which may be the same or different, are alkyl, aralkyl or aryl, and finally saponification and decarboxylation by known methods.

2. The starting compounds of the general formula IV can be, for example, used

I prepared by halomethylation of O-acyl-4-phenylcycloalkanols of formula XII *

wherein m-, p, R ⁵ -R ⁷ are as previously defined, with the corresponding aldehyde and hydrogen halide, ^r in the presence of a Friedei-Crafts catalyst, e.g. zinc chloride, and optionally subsequent substitution of the halogen atom with another suitable reactive leaving group.

Initial '´' sLou.csn.i.n.y J3 Maybe they.pno.vicnčpcll-3.ci ξ Ο ’^ ον '*

phenyl-cycloalkanols of the general formula XIII

wherein n, m, p, R ¹ , R ³ to R ⁷ and A are as previously defined and Z ² represents a suitable protecting group, by cleaving the protecting group. Suitable protecting groups are, for example, tert-butoxycarbonyl-, 1- (3,5-di-tert-butylphenyl) -1-methylethoxycarbonyl- or 2- (4-pyridyl) ethoxycarbonyl. For example, the compounds of formula (XIII) can be synthesized analogously to the method described in Method 1. · »

The starting compounds of formulas III and V are known in the literature or can be prepared by methods known in the literature.

The compounds of formula I exhibit interesting biological properties. They are inhibitors of cholesterol biosynthesis, in particular inhibitors of the enzyme 2,3-epoxisqualenlanosterol cyclase. Due to their biological properties, they are particularly suitable for the treatment and prophylaxis of hyperlipidemia, in particular hypercholesterolemia, hyperlipoproteinaemia and hypertriglyceridemia and the resulting atherosclerotic vascular changes with the following diseases such as coronary heart disease, cerebral ischemia, Claudicatio intermittens, gangrena.

For the treatment of these diseases, the compounds of the formula I can be used either alone as monotherapy or used in combination with other cholesterol-suppressing substances or lipids, the compounds being advantageously formulated as oral preparations or as rectal preparations. As a combination partner, the following can be considered:

- bile acid binding resins such as e.g.

cholestyramine, cholestipol and others

- compounds that inhibit cholesterol resorption, such as sitosterol and neomycin,

- compounds that inhibit cholesterol biosynthesis, such as HMG-CoA reductase inhibitors such as lovastatin, simvastatin, pravastatin and others,

squalene epoxidase inhibitors such as NB 598 and analogous compounds as well as

squalene synthetase inhibitors such as a representative of the class of isoprenoid (phosphinylmethyl) phosphonate and squalestatin.

As another possible combination partner, fibrate classes such as clofibrate, bezafibrate, gembrozil and others, nicotinic acid, derivatives and analogs thereof such as acipimox such as probucol are optional.

Further, the compounds of Formula I are useful in the treatment of diseases resulting from excessive cell proliferation. Cholesterol is an essential cellular component and must be present in sufficient quantities for cell proliferation, i.e., cell division. For example, inhibiting cell proliferation by inhibiting cholesterol biosynthesis is exemplified by smooth muscle cells with the HMG-CoA reductase inhibitor statin type lovastatin, as described previously.

Examples of diseases associated with increased cell proliferation are tumor diseases. In cell culture and in vivo experiments, decreasing serum cholesterol or interfering with cholesterol biosynthesis with HMG-CoA reductase inhibitors has been shown to attenuate tumor growth (Lancet 339, 1154-1156 [1992]). The compounds of the invention of formula I are therefore potentially useful on the basis of their cholesterol inhibiting effect for the treatment of cancer. They can be used alone or in support of known principles of therapy.

Other examples include hyperproliferative skin diseases such as psoriassis, basal cell carcinoma, platelet epithelial carcinoma, keratosis and keratinization disorders. As used herein, psoriasis refers to a hyperproliferative skin disorder that alters the regulatory mechanism of the skin. In particular, lesions are formed that

they include primary and secondary changes in proliferation in the epidermis, inflammatory skin reactions, and expression of regulator molecules such as lymphokines and inflammatory factors. Psoriatic skin is morphologically marked by an increased epidermal cell response, thickened epidermis, abnormal keratinization of an inflammatory cell infiltrate in the dermis layer, and polymorphonuclear leukocyte infiltration in the epidermis, which causes an increase in basal cell cycle. Hyperkeratotic and parakeratotic cells are additional.

The term keratosis, basal cell carcinoma, platelet 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 skin hyperproliferation, i. as agents that inhibit hyperproliferation of human keratinocytes. As a result, they are useful as a means to treat hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, keratinization disorders and keratosis.

For the treatment of these diseases, the compounds of formula I can be administered either orally or topically, either alone or in combination with known active compounds.

Surgical measures such as pTCA (percutaneous transluminal coronary angioplasty) or bypass surgery to address hyperproliferative vascular diseases such as stenosis and vascular occlusions resulting from smooth muscle cell proliferation may also be mentioned. As already mentioned, inhibition of this cell proliferation is possible with HMG27 inhibitors

Statin-type CoA reductases such as lovastatin. Due to their inhibitory action on cholesterol biosynthesis, the compounds of formula (I) are also suitable for the treatment and prophylaxis of these diseases, and can be administered either alone or in combination with known active compounds such as intravenously administered heparin, preferably by oral administration.

Another possibility of using the compounds of formula I according to the invention is the prophylaxis and treatment of gallstones. The formation of gallstones is due to an inadequate ratio of cholesterol-bile acid in the bile fluid, thereby exceeding the solubility of cholesterol and eliminating cholesterol in the form of gallstones. The efficacy of the HMG-CoAreductase inhibitor lovastatin in gallstone secretion, particularly in combination with ursodeoxycholic acid, is described in Gastroenterology 102, No. 4, pt.2, A319 [1992]. Because of their efficacy, the compounds of the formula I are therefore also suitable for the prophylaxis and treatment of gallstone diseases.

They can be used either alone or in combination with known therapies, such as ursodeoxycholic acid treatment or impact lithotripsy, preferably when administered orally.

Finally, the compounds of formula I are useful in the treatment of infections with pathogenic fungi such as Candida albicans, Aspergillus niger, Trichophyton mentagrophytes, Penicillium sp., Cladosporium sp. and more. As already mentioned, the end product of sterol biosynthesis in fungal cholesterol is not essential for the integrity and function of fungal cell membranes. Therefore, inhibition of ergosterol biosynthesis leads to growth disorders and possibly to the death of fungal organisms.

For the treatment of mycoses, the compounds of formula I are administered either orally or topically. They can be administered either alone or in combination with known antifungal agents, in particular those which interfere with other stages of sterol biosynthesis, such as squalene epoxidase, terbinafine and naftifine suppressants or azole-type lanosterol-14a-demethylase inhibitors, such as e.g. ketoconazole and fluconazole.

Another possibility of using the compounds of formula I is for use in the treatment of poultry. Reduction of egg cholesterol levels by administration of the HMG-CoA reductase inhibitor lovastatin to laying hens is described (FASEB Journal 4, A 533, Abstracts 1543 [1990]). The production of cholesterol-poor eggs is of particular interest because the body's cholesterol load on cholesterol-lowered eggs can be reduced without changing dietary habits. Due to their inhibitory action on cholesterol biosynthesis, the compounds of formula I can also be used in poultry farming for the production of cholesterol-poor eggs, the substances being preferably administered as an additive to feed.

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

I. Measurement of ¹⁴ C-acetate incorporation into digitonin-secretable steroids:

Method:

Human liver cells (HEP-G2) are stimulated for 16 hours with cholesterol-free medium after 3 days of culture. Test substances (dissolved in dimethylsulfoxide, final concentration 0.1%) are added during this stimulation phase.

Then, after addition of 200 µM / l of 2- ¹⁴ C-acetate, it is further incubated for another 2 hours at 37 ° C in the hatchery.

After aspirating the cells and saponifying the steroiester, digitonin is added after extraction and the precipitated sterol is isolated. ¹⁴ C-acetate incorporated into digitonin-precipitated sterol is determined by scintillation counting.

Determination of suppression efficiency is effected at the tested concentrations from 10moi / 1 and IQ ^'8 mol / 1st It was found that for example the following compounds A to Q of general formula I at these concentrations tested exhibit good inhibitory effect, e.g., at a test concentration of 10 ^-8 mol / 1 inhibitory effect at least 50%:

A = cis-O- (4-chlorobenzoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol

B = cis-O- (4-phenyl-3-butenoyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol,

C = trans-O- (4-chlorophenylacetyl) -4- (4-dimethylaminomethyiphenyl) cyclohexanol,

D = cis-O- (5-methylhexanoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol,

E = trans-O- (2-phenylpropionyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol,

F = trans-O- (4-fluorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol,

G = trans-O- (3,4-dichlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol,

H = cis-O- (4-fluoroinnamoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol,

1 = trans-O- (p-tolylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol,

J = trans-O- (4- [trifluoromethyl] phenylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol,

K = trans-O- (2-naphthylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol,

L = trans-O- (4-nitrophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol,

M = trans-N- (4-bromophenylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol,

N = trans-O- (2,4-dichlorophenylacetyl) -4- (4dimethylaminomethylphenyl) -cyclohexanol,

0 = trans-O - ([4-amino-3-chlorophenyl] acetyl) -4- (4-dimethylarainomethylphenyl) cyclohexanol,

P = trans-O- (4-methoxyphenylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol,

Q = trans-O- (4-chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol

The percentages expressing how the above compounds suppress incorporation are shown in the following table:

mol / 1 10 ' ⁷ 10 ' ⁸ AND -85 -51 (B) -83 -66 C -83 -66 D -88 -53 E -89 -72 F -86 - 66 G -89 -74 H -86 -51 AND -90 -72 J -89 -87 TO -86 -54 L -83 -67 M -84 -64 N -85 -67 O -79 -51 P -73 -52 Q -79 -50

As already mentioned, individual 2,3-epoxisqualen-lanosterol cyclase inhibitors are described in the literature, but which differ structurally from the compounds of formula I according to the invention. The compounds most closely related to the compounds of formula (I) are described in EP 0468 457. For comparison, Example 1 of this publication was therefore tested by the above-described method of determination at the test concentrations of 10 ⁵ mol / l and 10 'moi / l. The suppression values thus determined are 41% resp. 13% show that these compounds differ significantly from the compounds of formula I according to the invention.

II. Determination of in vivo efficacy in rats after oral administration

Inhibition of the enzyme 2,3-epoxisqualen-lanosterol-cyclase causes an increase in the level of 2,3-epoxisqualene in the liver and plasma. The amount of 2,3-epoxisqualene formed serves as a direct value for the potency of activity throughout the animal. The determination is carried out by the following method:

Male Wistar rats (160-190 g body weight) are administered as a suspension of test substance in 1.5% aqueous methylcellulose by a swallowing probe. Five hours after application, blood is obtained retroorbitally from the plexus vein. Plasma is treated according to the method of Bligh and Dyer (Canad. J. Biochem. Physiol. 37, 912 [1959]), purified through a pre-column, and then analyzed by HPLC. The peaks obtained are identified and quantified via a standard substance. An internal standard is used to test the reproducibility of results.

The tests were performed at concentrations of 0.1 and 1.0 mg / kg. For example, the following table gives the test values for the substances B, C, J, Μ, N and P mentioned above for inhibition of the level

2,3-epoxisqualene in rat plasma. In control animals, no measurable levels of 2,3-epoxisqualene are produced in experimental animals under the experimental conditions.

2,3-Epoxisqualen plasma level (rat)

2,3-epoxisqualene [/ ig / ml]

Component 0.1 mg / kg 1.0 mg / kg (B) 0.4 1.1 C 0.6 4.2 J 0.5 3.6 M 0.6 3.5 N 0.1 2.2 P 0.3 0.9

None of the 2,3-epoxisqualenlanosterol cyclase enzyme inhibitors described in the literature have yet been reported to inhibit cholesterol biosynthesis throughout the animal.

The compounds appear to be completely non-toxic at the curative dose. For example, compounds C show no side effects in rats, compounds J and M in mice after oral administration of 100 mg / kg, once daily for 5 days.

For pharmaceutical use, the compounds of formula (I) may be formulated in conventional manner into conventional pharmaceutical formulations for oral and topical administration.

Suitable formulations for oral administration are, for example, tablets, dragees and capsules, preferably suppositories for rectal administration.

Topical formulations include gels, creams, lotions, ointments, powders, aerosols and other conventional formulations for application of drugs to the skin. An effective amount for topical use is 1 to 50 mg per gram of formulation, but preferably 5 to 20 mg per gram of formulation. In addition to application to the skin, the topical formulations of the present invention may also be used in the treatment of mucous membranes that are available for topical treatment. For example, topical formulations may be applied to the mucous membranes of the mouth, lower column, and others.

The oral or rectal daily dose is between 1 and 1200 mg for humans weighing 60 kg, but preferably the daily dose is 5 to 100 mg for humans weighing 60 kg. The daily dose is preferably divided into 1 to 3 individual administrations.

For topical administration, the compounds may be administered in preparations containing about 1 to 1000 mg, in particular 10 to 300 mg, of active ingredient per day. The daily dose is preferably divided into 1 to 3 individual doses.

For use in raising poultry for the production of cholesterol-poor eggs, the active compounds of the formula I are administered to animals by conventional methods as an additive to suitable feedstuffs. The concentration of active ingredient in the finished feed is usually 0.01 to 1%, but preferably 0.05 to 0.5%.

The active ingredients may be added to the feed as such. The feed according to the invention thus contains, in addition to the active ingredient and, if appropriate, a conventional vitamin-mineral mixture, for example, maize, soybean meal, meat meal, feed fat and soybean oil. Some of the compounds of the formula I are added to this feed as active ingredient in a concentration of 0.01 to 1%, preferably 0.05 to 0.5%.

The following examples should explain the invention in more detail:

DETAILED DESCRIPTION OF THE INVENTION

In the following examples, thin-layer chromatography analysis is carried out on finished thin-layer chromatography plates from E. Merck, Darmstadt, at:

a) silica gel 60 F254

(b) aluminum oxide F254 (type E)

Production of starting materials

Example 1

4- (4-Dimethylaminomethylphenyl) -cyclohexanone

a) 4- (4-Dimethylaminomethylphenyl) -4-hydroxy-cyclohexanone-ethylene ketal

To a solution of 36.4 g (0.17 mol) of 4-bromo-N, N-dimethylbenzvlamine in 250 ml of dry tetrahydrofuran cooled to -70 ° C was added dropwise 112 ml (0.179 mol) of a 1.6 molar solution under nitrogen. n-butyllithium in hexane such that the temperature does not exceed -65 ° C. The orange-red solution was stirred for an additional 15 minutes at -70 ° C and then treated with a solution of 27.6 g (0.172 mol) over 10 minutes.

1,4-cyclohexanedione monoethylene ketal in 110 ml of tetrahydrofuran, the temperature not exceeding -65 ° C.

The reaction mixture was first stirred at -70 ° C for 30 minutes and then without external cooling to +20 ° C, poured into 600 mL of ice water and extracted with 200 mL of ethyl acetate. The organic phase was separated and the aqueous phase was extracted several times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, evaporated in vacuo and the residue recrystallized from diisopropyl ether. 41.9 g (85% of theory) of 4- (436 dimethylaminomethylphenyl) -4-hydroxycyclohexanone ethylene ketal, m.p.

b) 1- (4-Dimethylaminomethyl) phenyl-4-ethylenedioxy-1-cyclohexene

A mixture of 22.4 g (0.077 mol) of 4- (4-dimethylaminomethylphenyl) 4-hydroxycyclohexanone-ethylene ketal, 15.0 g (0.079 mol) of p-toluenesulfonic acid monohydrate, 39 ml of ethylene glycol and 240 ml of toluene is heated with stirring for 3.5 hours under reflux and the resulting reaction water was removed ontin. The cooled reaction mixture was poured into 200 mL of water and adjusted to pH 12-13 with 2N NaOH. The organic phase is separated and the aqueous phase is extracted several times with toluene. The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. 21 g (ca 100%) of the title compound are obtained as a yellow oil.

c) 1- (4-Dimethylaminomethyl) phenyl-4-ethylenedioxy-1-cyclohexane

A solution of 21 g (0.077 mol) of crude 1- (4-dimethylaminomethyl) phenyl-4-ethylenedioxy-1-cyclohexene in 200 ml of ethyl acetate and 100 ml of methanol is treated with 5 g of palladium / barium sulfate catalyst and stirred under hydrogen pressure for 1.5 hours. 0.5 MPa. After separation of the catalyst, it is distilled off under vacuum. 20 g (ca 100%) of the title compound are obtained as a tan oil.

d) 4- (4-Dimethylaminomethyl) phenyl-cyclohexanone

A mixture of 20 g (0.077 mol) of crude 1- (4-dimethylaminomethyl) phenyl-4-ethylenedioxy-1-cyclohexane and 110 ml of 2N hydrochloric acid was stirred at room temperature for 3.5 hours. The resulting aqueous solution was extracted several times with ethyl acetate; the organic extracts are discarded. The aqueous phase was adjusted to pH 13-14 with 50% sodium hydroxide while cooling and extracted several times with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated in vacuo. 14 g (79% of theory) of 4- (4-dimethylaminomethyl) phenylcyclohexanone, m.p. 64 DEG-67 DEG C., are obtained as a pale yellow product. The sample for analysis is recrystallized from petroleum ether 60/90.

Melting point: 65-67 ° C

Elemental analysis for C- ^ I ^ ,NONO (231.34) calculated C 77.33%, H 9.15%, N 6.05% found C 77.69, H 9.32%, N 5.93% .

Example 2 trans -4- (4-Dimethylaminomethylphenyl) -cyclchehanc-1

To a solution of 11.1 g (0.048 mol) of 4- (4-dimethylaminomethylphenyl) -cyclohexanone in 100 ml of absolute methanol cooled to -10 ° C was added portionwise 1.82 g (0.048 mol) of sodium borohydride. The reaction mixture was allowed to react for 1.5 hours at room temperature and then evaporated in vacuo. The residue was mixed with water, acidified with concentrated hydrochloric acid, stirred at room temperature for 30 minutes, basified with 50% sodium hydroxide and extracted several times with chloroform. The combined extracts were dried over sodium sulfate and evaporated in vacuo. The residue, consisting of a mixture of trans / cis-4- (4-dimethylaminomethylphenyl) -cyclohexanol (cis fraction <10%), is purified by column chromatography (neutral alumina, activity level III, ICN;

petroleum ether / methylethylketone = 5: 1).

White crystals of m.p. 63-65 ° C are obtained. Yield 8.8 g (79% of theory).

Elemental Analysis Found C, 77.34; H, 10.02; N, 5.39. Found: C, 77.21; H, 9.93; N, 6.00.

EXAMPLE III cis-4- (4-Dimethylaminomethylphenyl) -cyclohexano1 ml (0.05 mol) of a 1 molar solution of lithium tris-butylborohydride in absolute tetrahydrofuran is diluted under an atmosphere then 100 ml of absolute tetrahydrofuran at -65 nitrogen and 0 ° C to -70 ° C with stirring over 10 minutes with a solution of 5.3 g (0.025 mol) of 4- (4-dimethylaminomethylphenyl) cyclohexanone in 50 ml of absolute tetrahydrofuran. The reaction mixture was then allowed to react at -70 ° C for 3 hours and then warmed to room temperature over 1 hour. 20 ml were then hydrolyzed

75% aqueous ethanol and organoborane and oxidized with alkaline hydrogen peroxide (10 mL 6M NaOH / 15 mL 30% HgOg). The organic phase was separated, the aqueous phase was saturated with potassium carbonate, and three ml of ethyl acetate (CO 2) was dried over sodium sulfate and evaporated in vacuo. The remaining gooey residue, consisting of cis / trans-4- (4 dimethylaminomethylphenyl) -cyclohexanol (trans <5%), is purified by column chromatography (neutral alumina, activity level III, ION; petroleum ether / methyl ethyl ketone =

5: l).

The product precipitated as a colorless oil. Yield 4.1 g (71% of theory).

¹ H-NMR spectrum (200 MHz, CDCl ₃ ); signals at ppm: 1.5-2.0 (2m, 3H); 2.25 (s. 6H); 2.4-2.65 (m, 1H); 3.4 (s. 2H); 4.14.13 (m, 1H); 7.15-7.3 (m, 4H).

Example IV tans-O-Acetyl-4- (4-chloromethylphenyl) -cyclohexanol

(a) 4-Phenylcyclohexanol

To a solution of 31.4 g (0.18 mol) of 4-phenylcyclohexanone in 50 ml of absolute methanol cooled to -10 ° C was added portionwise with stirring, 6.8 g (0.18 mol of sodium borohydride). at -10 ° C for 0.5 hours and 3 hours at room temperature, then evaporated in vacuo, the residue was mixed with water and acidified with 2N hydrochloric acid, the resulting suspension was stirred for 1 hour and the crystalline product was filtered off with suction, dried and recrystallized from diisopropyl ether. 21 g (66% of theory) of 4-phenylcyclohexanol of melting point 112 DEG-114 DEG C. are obtained.

b) O-Acetyl-4-phenylcyclohexanol

To a mixture of 20.3 g (0.115 mol) of 4-phenylcyclohexanol, 14.2 ml (0.15 mol) of acetic anhydride and 29 ml of triethylamine is added with stirring 2.3 g (0.02 mol) of 4-dimethylaminopyridine, while exotherming. a clear solution is formed. Heat at 80 ° C for 3 hours and then pour the reaction mixture into ice water. The precipitated crystalline product is filtered off with suction, dissolved in ether, washed with sodium carbonate solution, dried and evaporated in vacuo. 23 g (92% of theory) of O-acetyl-4-phenylcyclohexanol are obtained. The product precipitates first as an oil, but crystallizes on standing.

Melting point 43-45 ° C.

c) trans-O-Acetyl-4- (4-chloromethylphenyl) -cyclohexanol

A solution of 24.3 g (0.11 mol) of O-acetyl-4-phenylcyclohexanol in 1300 ml of methylene chloride was treated with 26.0 g (0.86 mol) of paraformaldehyde and 26.0 g (0.19 mol) of zinc chloride. Hydrogen chloride is introduced into this suspension with stirring over a period of 2.5 hours, the temperature rising to about 30 ° C to form a homogeneous solution. The mixture is then allowed to react at room temperature for 15 hours and the reaction mixture is then hydrolyzed in about 1.5 L of ice water with stirring. The organic phase is separated, the aqueous phase is extracted once more with methylene chloride and the two organic phases are combined. They are washed to neutrality, dried and evaporated in a vacuum. The residual yellow oil is crystallized by trituration with diisopropyl ether and the solid product is recrystallized from diisopropyl ether. White crystals of m.p. 37-39 ° C are obtained. Yield 12.7 g (43% of theory).

Elemental analysis for C ^ HH ^ClClC (266.77) calculated C 67.53, C 7.13, C 13.29 found C 67.68, C 7.29, C 13.11 .

Example V cis / trans-O- (4-Chloro-phenylacetyl) -4- (4-N [tert-butoxycarbonyl] -methylaminomethyl) phenyl-cyclohexanol

a) 4- (4-Methylaminomethyl) phenyl-4-hydroxycyclohexanone ethylene ketal

A solution of 94 g (0.47 mol) of 4-bromo- (N-methyl) -benzylamine in 460 ml of dry tetrahydrofuran is first mixed with 300 ml (0.48 mol) of nitrogen at -30 to -25 ° C. Of a 6 molar solution of n-butyllithium in hexane and then with 52.5 g (0.48 mol) of trimethylchlorosilane. The reaction mixture was stirred for 15 minutes at this temperature and then cooled to -75 ° C. An additional 320 ml (0.51 mol) of a 1.6 molar solution of n-butyllithium in hexane is then added such that the temperature does not exceed -70 ° C. The mixture is stirred for a further 20 minutes at -7 ° C and then treated with a solution of 7.6 g (0.47 mol) of 1,4-cyclohexanedione monoethylene ketal in 200 ml of tetrahydrofuran over 20 minutes, the temperature not exceeding -65 ° C. Then the reaction mixture was stirred for 30 minutes at -70 ° C and then without external cooling until the temperature reached +20 ° C. It is then treated with an ice-cold aqueous ammonium chloride solution and extracted several times with methylene chloride. The combined organic solutions were dried over sodium sulfate, the solvent was removed and the remaining residue was recrystallized from diisopropyl ether. 77 g (59% of theory) of 4- (4-methylaminomethyl) phenyl-4-hydroxycyclohexanone ethylene ketal, m.p. 95 DEG-97 DEG C., are obtained.

b) 1- (4-Methylaminomethyl) phenyl-4-ethylenedioxy-1-cyclohexene

A mixture of 68 g (0.24 mol) of 4- (4-methylaminomethyl) phenyl-4 hydroxycyclohexanone-ethylene ketal, 51 g (0.27 mol) of p-toluenesulfonic acid monohydrate, 150 ml of ethylene glycol and 900 ml of toluene is heated with stirring for 2 hours. The reaction water is continuously removed. The cooled reaction mixture was basified with 1N sodium hydroxide (pH 12-13), the organic layer separated and the aqueous phase extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in vacuo. 63 g (ca. 100% of theory) of 1- (4-methylaminomethyl) phenyl-4-ethylenedioxy-1-cyclohexene are obtained as a yellowish oil. '

c) 1- (4-N - [(tert-Butoxycarbonyl] -methylaminomethyl) phenyl-4-ethylenedioxy-1-cyclohexene

A solution of 63 g (0.24 mol) of crude 1- (4-methylaminoraethyl) phenyl-4-ethylenedioxy-1-cyclohexene in 350 ml of absolute tetrahydrofuran was mixed with a solution of 58 g (0.26 mol) of di-tert-butyl dicarbonate in 100 ml of stirring. ml of absolute tetrahydrofuran, maintaining the temperature between 15-20 ° C under cooling. After the evolution of CO 2 ceased, it was allowed to stand for 10 hours at room temperature, the solvent was distilled off in vacuo, the residue was mixed with water and extracted several times with ether. After drying with sodium sulfate and evaporation, 84 g (ca. 100% of theory) of 1- (4- [tert-butoxycarbonyl] methylaminomethyl) phenyl-4-ethylenedioxy-1-cyclohexene are obtained as a yellowish oil.

d) 4- (4-N- [tert-Butoxycarbonyl] -methylaminomethyl) phenylcyclohexanone

A solution of 84 g (0.24 mol) of crude 1- (4-N [tert-butoxycarbonyl] -methylaminomethyl) phenyl-4-ethylenedioxy-1-cyclohexene in methanol / ethyl acetate (250 + 250 mL) was treated with 10 g of palladium / sulfate catalyst barium and hydrogenated at 50 psi for 4 hours. The catalyst was separated, the solvent was distilled off in vacuo, the oily residue was dissolved in acetone / water (1400 + 140 ml) and after addition of 8.5 g (0.034 mol) pyridinium tosylate under reflux for 15 hours. It is mixed with water and extracted several times with methylene chloride. After drying the organic phase with sodium sulfate and evaporation, 61 g (77% of theory) are obtained.

4- (4-N- [tert-butoxycarbonyl] -methylaminomethyl) phenylcyclohexanone as a pale yellow solid which solidifies upon prolonged standing.

Mp 55-57 ° C.

e) 4- (4-N- [tert -Butoxycarbones of thylaminomethyl line) phenylcyclohexanol (cis / trans-mixture)

To a solution of 11 g (0.035 mol) of 4- (4-N- [tert-butoxycarbonyl] methylaminomethyl) phenyl-cyclohexanone in 70 ml of absolute methanol cooled to -10 ° C was added portionwise with stirring, 1.31 g (0.035 mol). sodium borohydride. The reaction mixture was further allowed to react for 0.5 hours at -10 ° C and 2 hours at room temperature and then evaporated in vacuo. The residue was treated with water and stirred at room temperature for 1 hour. The solid thus formed is filtered off with suction, dissolved in ethyl acetate and dried over sodium sulphate. Evaporation in vacuo left 8.6 g (77% of theory) of a mixture of cis- and trans- form of 4- (4-N [tert-butoxycarbonyl] -methylaminomethyl) phenyl-cyclohexanol as a colorless oil. This was separated by column chromatography into pure isomers (neutral alumina, activity level III, ICN; petroether / ethyl acetate = 3: 1). R f value (alumina; petroether / ethyl acetate = 31): 0.21 (trans) and 0.31 (cis).

f) O- (4-Chlorophenylacetyl) -4- (4-N [tert-butoxycarbonyl] methylaminomethyl) phenyl cyclohexanol (cis / trans-mixture)

A mixture of 4-chlorophenylacetic acid (0.54 g, 0.0032 mol), N, N ¹ -carbonyldiimidazole (0.52 g, 0.0032 mol) and xylene (20 ml) was heated at 60 ° C for 1 hour. A solution of 0.35 g (0.0027 mol) of 4- (4-N- [tert-butoxycarbonyl] methylaminomethyl) phenyl-cyclohexanol (cis / trans-mixture) in 10 ml of xylene is then added and the reaction mixture is heated for a further 8 hours at 160 ° C. After cooling, evaporate in vacuo, mix the residue with water and extract with ethyl acetate. The organic phase is dried over sodium sulphate and evaporated in vacuo. 1.3 g (ca. 100% of theory) of O- (4-chlorophenylacetyl) -4- (4-N- [tert-butoxycarbonyl] methylaminomethyl) -phenyl-cyclohexanol (cis / trans-mixture) remained as a red-brown oil.

Rf value (alumina; petroether / ethyl acetate = 3: 1):

0.78 (trans) and 0.85 (cis).

The following substances are synthesized analogously:

(1) trans-O- (4-chlorophenylacetyl) -4- (4-N [tert-butoxycarbonyl] -methylaminomethyl) phenyl-cyclohexanol from trans-4- (4-N- [tert-butoxycarbonyl] methylaminomethyl) phenylcyclohexanol and acid 4-chlorophenylacetic acid, 4'-carbonyldiimidazole.

White crystals.

Melting point: 94-96 ° C.

Manufacture of finished products

Example 1 trans-O- (4-Chlorobenzoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol

A solution of 1.0 g (0.0043 mol) of trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 0.6 ml of triethylamine in 50 ml of methylene chloride is added dropwise with stirring to 0.75 g (0.0043 mol) of 4-chlorobenzoyl chloride. and heated under reflux for 3 hours. After cooling, it is treated with 50 ml of water, the pH is adjusted to 12-13 with sodium hydroxide, the methylene phase is separated and the aqueous phase is extracted once more with methylene chloride. The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The solid residue was purified by column chromatography (neutral alumina, activity level III, ICN; petroleum ether / ethyl acetate = 40: 1). White crystals of m.p. 94-95 ° C are obtained.

Yield 1.1 g (69% of theory) @ ¹ H-NMR spectrum (200 MHz, CDCl3); signals at ppm:

1.55-1.8 (m, 4H); 1.9-2.1 (m. 2H); 2.15-2.3 (s + m, 6 + 2H); 2.52.7 (m, IH); 3.4 (s. 2H); 4.9-5.1 (m, IH); 7.15-7.3 (m. 4H); 7.4 (d, 2 H); 8.0 (d, 2 H).

The following substances are synthesized in an analogous manner:

(1) trans-O-acetyl-4- (4-dimethylaminomethylphenyl) cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) cyclohexanol and acetyl chloride / triethylamine.

Colorless syrup.

1 H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

1.45-1.7 (m, 4H); 1.9-2.05 (m, 2 H); 2.05-2.15 (s + m, 3 + 2H);

2.33 (s, 6H); 2.4-2.55 (m, IH); 3.4 (s. 2H); 4.7-4.9 (m, 1H) 7.1-7.3 (m, 4H), (2) trans-O-butyryl-4- (4-dimethylaminomethylphenyl) cyclohexanol from trans-4- (4- dimethylaminomethylphenyl) -cyclohexanol and butyric acid / triethylamine chloride.

Colorless oil.

¹ H-NMR spectrum (200 MHz, CDCl ₃ ); signals at ppm:

0.9-1.02 (t, 3H); 1.45-1.75 (m, 6H); 1.89-2.05 (m, 2 H); 2.05 2.18 (m, 2H); 2.13-2.38 (s + t, 6 + 2H); 2.4-2.6 (m, 1H; 3.4 (s, 2H); 4.7-4.9 (m, 1H); 7.1-7.3 (m, 4H)).

(3) trans-O-Cyclopropanoyl-4- (4-dimethylaminomethylphenyl) cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) cyclohexanol and cyclopropanecarboxylic acid triethylamine chloride. Colorless wax.

¹ H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

0.81-0.87 (m, 2 H); 0.95-1.02 (m, 2H); 1.45-1.7 (m, 4H); 1.92.0 (m, 2 H); 2.05-2.15 (m, 2 H); 2.24 (s, 6 H); 2.4-2.63 (2m,

2H); 3.4 (s. 2H); 4.73-4.83 (m, 1H); 7.12-7.25 (m, 4H).

(4) trans-O-Cyclohexanoyl-4- (4-dimethylaminomethylphenyl) cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) cyclohexanol and cyclohexanecarboxylic acid / triethylamine chloride.

White crystals.

Melting point: 66-68 ° C.

(5) cis-O- (4-Chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from cis-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-chlorophenylacetyl chloride / triethylamine.

Colorless oil.

1 H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

1,5 · • 1.75 (m, 6H); 1.88-2.05 (m, 2H); 2.55 (s, he); 2,4-2, 6 5 (m, (H); 3.4 (with, 2H); 3.65 (with, 2H); 5,05-5,15 (m, 1 H); 7, 08 / (d, 2H); 7.2 7.4 (ra, 6H).

(6) trans-O- (4-Phenyl-3-butenoyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-phenyl-3-butenoic acid / triethylamine chloride. White crystals.

Melting point: 90-91 ° C.

(7) cis-O- (4-Phenyl-3-butenoyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from cis-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-phenyl-3-butenoic acid / triethylamine chloride.

White crystals.

Mp 71-73 ° C.

Example 2 · trans-O- (4-Chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol

To a mixture of 0.43 g (0.0025 mol) of 4-chlorophenylacetic acid and 30 ml of xylene was added 0.41 mol of N, N-carbonyldi imidazole to give a white product. The reaction mixture was heated to 60 ° C with stirring and then 0.5 g (0.0021 mol) of trans -4- (4-dimethylaminomethylphenyl) cyclohexanol was added. While stirring, heat to 160 ° C, cool to room temperature, mix with water and adjust the pH to 12-13 with 2N sodium hydroxide. The xylene phase was separated, extracted several times with ethyl acetate, the organic phases were combined, dried and evaporated in vacuo. The solid residue was purified by column chromatography (basic alumina, activity level III, ICN; petroleum ether / ethyl acetate = 10: 1). White crystals of m.p. 75-77 ° C are obtained.

Yield: 0.7 g (86% of theory).

1 H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

1.4-1.7 (m, 4H); 1.8-2.15 (m. 4H); 2.25 (s. 6H); 2.4-2.6 (m, 1H); 3.38 (s, 2 H); 3.6 (s. 2H); 4.7-4.9 (m, 1H); 7.1-7.35 (m, 8H).

The following compounds were synthesized in an analogous manner:

(1) trans-O- (5-Methylhexanol) -4- (4-dimethylaminomethylphenyl) cyclohexanol

from trans -4- (4-dimethylaminomethylphenyl) cyclohexanone and 5-methylhexanoic acid / N, N'-carbonyldiimidazole.

White crystals.

Melting point: 35 to 36 ° C.

(2) cis-O- (5-Methylhexanoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol from cis-4- (4-dimethylaminomethylphenyl) cyclohexanol and 5-methylhexanoic acid / N, N'-carbonyldiimidazole.

Colorless oil.

¹ H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

0.9 (d, 6H); 1.15-1.32 (m, 2 H); 1.5-1.83 (m, 9H); 1.95-2.1 (m, 2 H); 2.25 (s. 6H); 2.3 (d, 2 H); 2.43-2.69 (m, 1H); 3.4 (s. 2H); 5.08-5.13 (m, 1H); 7.12-7.3 (m, 4H).

(3) trans-Q-Cyclohexylacetyl-4- (4-dimethylaminomethylphenyl) cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) cyclohexanol and cyclohexylacetic acid / N, N ¹ -carbonyldimidazole.

White crystals.

Melting point: 37-39 ° C.

(4) trans-O- (2-Butenoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and crotonic acid Ν, Ν'-carbonyldimidazole.

White crystals.

Melting point: 69-71 ° C.

(5) trans-O- (2-Hexenoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol from trans -4- (4-dimethylaminomethylphenyl) cyclohexanol and 2-hexenoic acid / /, Ν ¹ carbonyldiimidazole.

White crystals.

Melting point: 40 to 42 ° C.

(6) trans-O- (3-Cyclohexylpropenoyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 3-cyclonexylipropenoic acid / N, N'-carbonylimidimidazole. White crystals.

Melting point: 45 to 47 ° C.

(7) trans-O-Benzoyl-4- (4-dimethylaminomethylphenyl) cyclohexanol from trans -4- (4-dimethylaminomethylphenyl) cyclohexanol and benzoic acid, N, N 'carbonyldiimidazole.

White crystals.

Melting point: 53-70 ^c C.

(3) trans-O- (4-Chloro-3-methylbenzoyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-chloro-3-methylbenzoic acid / N, N ' -carbonyldiimidazole White crystals.

Melting point: 100-102 ° C.

(9) trans-O- (2-Naphthyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) cyclohexanol and naphthoic acid / N, N ¹ -carbonylimidimidazole.

Strong crystals.

Melting point: 110-112 ° C.

(10) trans-O-Phenylacetyl-4- (4-dimethylaminomethylphenyl) cyclohexanol with trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and phenylacetic acid / N, N'-carbonyldiimidasol.

White crystals.

Melting point: 33 to 40 ° C.

(11) trans-C- (4-Fluoro-phenylacetyl) -4- (4-dimethylaminomethyl-phenyl) -cyclohexanol from trans-4- (4-dimethylaminomethyl-phenyl) -cyclohexanol and 4-fluoro-phenylacetic acid / N, N'-carbonyldiimidasol.

White crystals.

Melting point: 58-70 ^c C.

(12) cis-O- (4-Fluorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol with cis -4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-fluorophenylacetic acid / N, N ¹ -carbonyldiimidasol. Colorless oil.

¹ H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

1.5-1.75 (m, 6H); 1.35-2.05 (m, 2 H); 2.3 (s, SH3; 2.4-2.65 (m, 1H); 3.43 (s, 2H); 3.65 (s, 2H); 5.05-5.15 (m, 1H); 7.0 7.15 (m, 4H), 7.2-7.38 (m, 4H).

(13) trans-O- (4-Bromophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans -4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-bromophenylacetic acid / N, N ¹ -carbonyl-diimidazole.

White crystals.

Melting point: 72-74 ° C.

(14) trans-O- (3,4-Dichlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 3,4-dichlorophenylacetic acid, N, N- ^1- carbonyldiimidazole.

White crystals.

Melting point: 95-97 ° C.

(15) cis-O- (3,4-Dichiorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from cis-4- (4-dimethylaminomethylphenyl) -cyclohexanol and acid

3,4-Dichlorophenylacetate / N, N'-carbonyldiimidazole.

Colorless oil.

1 H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

1.5-1.75 (m, 6H); 1.9-2.05 (m, 2 H); 2.28 (s, 6H); 2.4-2.65 (m, IH); 3.4 (s. 2H); 3.62 (s, 2 H); 5.8-5.17 (m, IH); 7.057.3 (m, 5H); 7.35-7.49 (m, 2 H).

(16) trans-O- (2,4-Dichiorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 2,4-dichloro-phenylacetic acid / N, N'-carbonyl-diimidazole.

White crystals.

Melting point: 78 to 80 ° C.

(17) trans-O- (p-Toylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and p-tolylacetic acid / N, N'-carbonyldiimidazole.

White crystals.

Melting point: 40 to 42 ° C.

(18) trans-O - ([4-Trifluoromethyl] phenylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) cyclohexanol and 4- (trifluoromethyl) phenylacetic acid / N, N carbonyldiimidazoiu.

White crystals.

Melting point: 73-75 ° C.

(19) trans-O- (4-Methoxyphenylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol from trans -4- (4-dimethylaminomethylphenyl) cyclohexanol and 4-methoxyphenylacetic acid / N, N ¹ -carbonyldiimidazole. White crystals.

Melting point: 47 to 49 ° C.

(20) trans-O- (4-Nitrophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-nitrophenylacetic acid / N, N'-carbonyldiimidazole. Yellowish crystals.

M.p .: 136-137 ° C.

(21) trans-O- [3- (4-Fluorophenyl) -propionyl] -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 3- (4-fluorophenyl) -propionic acid] N, N ¹ carbonyldiimidazole.

White crystals.

58-59 ° C.

(22) trans-O- [3- (4-Chloro-phenyl) -propionyl] -4- (4-dimethylaminophenylphenyl) -cyclohexanol from trans-4 - (4-dimethylaminomethylphenyl) -cyclohexanol from 3- (4-chlorophenyl) propionic acid / N, N'-carbonyldiimidazole Strong crystals.

Melting point: 35 to 37 ° C.

(23) trans-O- (4-Bisphenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-biphenyl-acetic acid / N, N'-carbonyldiimidazole.

White crystals.

Melting point: 83-89 ° C.

(24) trans-O- (2-Naphthylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol from trans -4- (4-dimethylaminomethylphenyl) -cyclohexanol and 2-naphthylacetic acid Ν, Ν'-carbonyldiimidazole.

White crystals.

Melting point: 35 to 87 ° C.

(25) trans-O- [2- (1,2,3,4-Tetrahydro) naphthyl] -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans -4- (4-dimethylaminomethylphenyl) -cyclohexanol and 2 (1,2) 3,4-tetrahydro-naphthetic acid / N, N'-carbonyldiimidazole.

White crystals.

Melting point: 95 to 96 ° C.

(26) cis-C- [2- (1,2,3,4-Tetrahydro) naphthoyl] -4- (4-dimethylaminomethylphenyl) -cyclohexanol from cis - 4- (4-dimethylaminomethylphenyl) -cyclohexanol (1,2,3,4-tetrahydro) naphthoic acid / N, N'-carbonyldiimidazole.

¹ H-NMR spectrum (200 MHz, CDCl ₃ ); signals at ppm: 1.55-1.35 (m, 5H); 1.9-2.1 (m. 3H); 2.15-2.32 (sm, 2.4-2.6 5 im, 1H); 2.72 - 2.95 (m, 3H); 3.05 (d, 2H, 2H); 5.1-5.2 (m, 1H); 7.05-7.3 (2m, 8H).

• IK)

3,4 '27) trans- (2-phenylpropionyl) -4- (4-dimethylaminomethylphenyl) trans-4- (4-dimethylaminomethylphenyl) - cyclohexanol and 2-phenylpropionic acid / N, N'-carbonyidiimidazole.

Berber wax.

1 H-NMR spectrum (200 MHz, CDCl ₃ ); signals at ppm:

1.25-1.7 (d + m, 3 + 3H); 1.8-2.15 (m, 5H); 2.3 (s. 5H); 2.38-2.6 (m, IH); 3.4 (s. 2H); 3.7 (q, 1 H); 6.68 - 4.9 (m, 1H); 7.15 (d, 2 H); 7.18-7.33 (d + m, 2 + 5H).

(28) cis-O- (2-Phenylpropionyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol from cis-4- (4-dimethylaminomethylphenyl) cyclohexanol and 2-phenyipropionic acid / N, N- ^1- carbonyldiimidazole.

Colorless oil.

1 H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

1.3-1.7 (d + m, 3 + SH); 1.8-2.05 (m, 2 H); 2.25 (s, 5H); 2,352.58 (m, IH); 3.4 (s. 2H); 3.73 (q, IH); 5.0-5.1 µm, 1H; 7.0 (d, 2 H); 7.2 (d, 2 H); 7.25-7.4 (m, 5H).

(29) trans-O- (4-Fluorcinnamoyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans -4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-fluoro-cinnamic acid / N, N ¹ -carbonyldiimidazole.

White crystals.

Suction temperature: 113-120 ° C.

30) cis Ό (4 - π F ICI. N CTM OV 1) 4 ^_ (4 o C MS ny ismi i. CRNE of ny ny L ^R S *) -cyclohexanol from cis-4 - (4-dimethylaminomethyl) -cyclohexanol and 4-fluorosuccinic acid / N, N ¹ -carbonyldiimidazole.

White crystals.

Melting point: 65-68 ° C.

(31) trans-O- (4-Chloroinnamoyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans -4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-chlorocinnamic acid / N, N ¹ -carbonyldiimidazole.

White crystals.

Melting point: 131-133 ° C.

(32) cis- (4-Chloroinnamoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol from cis-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-chlorocinnamic acid / N, N'-carbonyldiimidazole.

White crystals.

Melting point: 88-90 ° C.

(33) trans-O- (4- [Trifluoromethyl] cinnamoyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4- (trifluoromethyl) cinnamic acid / Ν, Ν ¹ carbonyldiimidazole.

White crystals.

Melting point: 134-136 ° C.

(34) cis-O- (4- [Trifluoromethyl] cinnamoyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from cis-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4- (trifluoromethyl) -cinnamic acid / Ν, Ν ' - carbonyldiimidazole.

White crystals.

Melting point: 61-63 ° C.

(35) trans-O- (5-Chloro-2-thenoyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 5-chloro-2-thiophenecarboxylic acid / N, N ' carbonyldiimidazole.

White crystals.

Melting point: 95-97 ° C.

(36) trans-O-Nicotinyl-4- (4-dimethylaminomethylphenyl) cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and nicotinic acid Ν, Ν'-carbonyldiimidazole.

White crystals.

Melting point: 86-88 ° C.

(37) trans-O- (2-Furoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol from trans -4- (4-dimethylaminomethylphenyl) cyclohexanol and 2-furancarboxylic acid / N, N'-carbonyldiimidazole.

White crystals.

Melting point: 58-60 ° C.

(38) trans-O- (3,4-Dimethoxyphenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminoniethylphenyl) 1-cyclohexanol and 3,4-dimethoxyphenylacetic acid / N, N'-carbonyldiimidazole. White crystals.

Melting point: 32 to 34 ° C.

(39) trans-O- (4-Amino-3-chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-amino-3-chlorophenylacetic acid / N, Ν ' -carbonyldiimidazole. White crystals.

Melting point: 83-85 ° C.

(40) trans-O- (4-Amino-3,5-dichlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans -4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-amino-3,5- dichlorophenylacetic acid, N, N'-carbonyldiimidazole.

White crystals.

Melting point: 78 to 80 ° C.

(41) trans-O- (4-Chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-chlorophenylacetic acid / N, N'-carbonyldiimidazole.

Colorless oil.

1 H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

1.05 (t, 6 H); 1.4-1.72 (m, 4H); 1.9-2.2 (m. 4H); 2.4-2.5 (q + m, 5H); 3.5 (s. 2H); 3.6 (s. 2H); 4.7-4.9 (m, 1H); 7.12 (d, 2 H); 7.13-7.35 (m, 6H).

(42) trans-O- (4-Chloro-phenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-dimethylaminomethylphenyl) -cyclohexanol and 4-chlorophenylacetic acid / N, N'-carbonyldiimidazole.

Colorless oil.

1 H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

0.88 (t, 6H); 1.38-1.7 (m, 8H); 1.9-2.19 (m, 4H); 2.35 (q,

4H); 2.4-2.6 (m, 1H); 3.5 (s. 2H); 3.6 (s. 2H); 4.7-4.9 (m, 1H); 7.1 (d, 2 H); 7.15-7.38 (m, 6H).

(43) trans-O- (4-Chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4- [N-methylbutylamino] methylphenyl) -cyclohexanol and 4-chlorophenylacetic acid / N, ct'-carbonyldiimidazole . Colorless oil.

¹ H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

0.9 (t, 3 H); 1.2-1.7 (m, 8H); 1.8-2.15 (m. 4H); 2.18 (s, 3H); 2.35 (t, 2 H); 2.4-2.6 (m, 1H); 3.41 (s, 2 H); 3.6 (s. 2H); 4.7-4.9 (m, 1H); 7.1 (d, 2 H); 7.2-7.35 (m, 6H).

(44) trans-O- (4-Chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol from trans-4- (4-diallylaminomethylphenyl) - cyclohexanol and 4-chlorophenylacetic acid / N, N ¹ -carbonyldiimidazole. Colorless oil.

¹ H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

1.4-1.75 (m, 4H); 1.9-2.2 (m. 4H); 2.4-2.6 (m, IH); 3.0-3.18 (dd, 4H); 3.5 (s. 2H); 3.6 (s. 2H); 4.7-4.9 (m, IH); 5.1-5.3 (m, 4H); 5.75-6.0 (m, 2 H); 7.12 (d, 2 H); 7.15-7.38 (m, 6H).

(45) trans-O- (4-Chlorophenylacetyl) -4- (4- [N-pyrrolidino] methylphenyl) -cyclohexanol from trans-4- (4- [N-pyrrolidino] methylphenyl) -cyclohexanol and 4-chlorophenylacetic acid / N, N ¹ -carbonyldiimidazole.

White crystals.

Melting point: 57-59 ° C.

(46) trans- (4-Chlorophenylacetyl) -4- (4- [N-piperidino] methylphenyl) -cyclohexanol from trans-4- (4- [N-piperidino] methylphenyl) -cyclohexanol and 4-chlorophenylacetic acid / Ν, kyseliny ' -carbonyldiimidazole.

White crystals.

Melting point: 87-89 ° C.

(47) trans-O- (4-Chlorophenylacetyl) -4- (4- [N-morpholino] methylphenyl) -cyclohexanol from trans-4- (4- [N-morpholino] methylphenyl) -cyclohexanol and 4-chlorophenylacetic acid / N, Ν'-carbonyldiimidazole.

White crystals.

Melting point: 114-116 ° C.

(48) trans-O- (4-Chlorophenylacetyl) -4- (4- [N-methyl-N'piperazino] methylphenyl) -cyclohexanol from trans-4- (4- [N-methyl-Ν'-piperazino] methylphenyl of cyclohexanol and 4-chlorophenylacetic acid / N, N-carbonyldiimidazole.

White crystals.

Melting point: 97-99 ° C.

(49) trans-O- (3,4- [Methylenedioxy] -phenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol 1 of trans-4 - (4-dimethylaminomethylphenyl) -cyclohexanol and 3,4- (methylenedioxy) phenylacetic acid / N, N ¹ carbonyldiimidazole.

Colorless oil.

1 H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

1.4-1.7 (m, 4H), 1.8-2.0 (m, 2H), 2.0-2.15 (m, 2H), 2.25 (s,

SH), 2.4-2.5 (m, 1H), 3.33 (s, 2H), 3.5 (s, 2H), 4.7-4.9 (m,

1H), 5.94 (5, 2H), 6.7-0.85 (m, 3H), 7.1-7.3 (m, 4H).

Example 3 cis-O- (4-Chlorobenzoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol

0.24 g (0.001 mol) of cis-4- (4-dimethylaminomethylphenyl) cyclohexanol, 0.34 ml (0.0025 mol) of triethylamine and 0.12 g (0.001 mol) of dimethylaminopyridine are dissolved in 20 ml of methylene chloride, mixed with 0.175 g (0.001 mol) of 4-chlorobenzoyl chloride was stirred at room temperature for 12 hours. The reaction mixture is mixed with water and the pH is adjusted to 12-13 with sodium hydroxide. The methylene chloride phase is separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated sodium chloride solution, dried and evaporated in vacuo. The residue was purified by column chromatography (neutral alumina, activity level III, ICN; petroleum ether / ethyl acetate = 45: 1).

White crystals.

Melting point: 96 to 97 ° C.

Yield: 0.27 g (73% of theory) @ ¹ H-NMR spectrum (200 MHz, CDCl3); signals at ppm:

1.7-2.0 (m, 6H); 2.1-2.25 (m / 2H); 2.28 (s, 6H); 2.55-2.75 (m, 1H); 3.4 (s. 2H); 5.33-5.4 (m, 1H); 7.15-7.3 (m. 4H);

7.45 (d, 2 H); 3.2 (d, 2 H).

Example 4 trans-O-Acetal-4- (4-diethylaminomethylphenyl) -cyclohexanol

A solution of 1 g (3.75 mmol) of trans-O-acetyl-4- (4-chloromethylphenyl) -cyclohexanol in 10 ml of dimethylformamide is treated with 0.52 g (3.75 mmol) of potassium carbonate and 0.27 g (3, 75 mmol) of diethylamine. The mixture was heated to 50 ° C with stirring for 5 hours, then treated with water and extracted with methylene chloride. The organic phase is dried, evaporated in vacuo and the residue purified by column chromatography (alumina basic, activity level III, ICN;

petroleum ether / ethyl acetate = 15: 1).

Colorless oil.

Yield: 0.79 g (69% of theory).

¹ H-NMR spectrum (200 MHz, CDCl ₃ ); signals at ppm:

1.05 (t, 6 H); 1.45-1.75 (m, 4H); 1.9-2.2 (s + m, 7H); 2.4-2.6 (q + m, 5H); 3.55 (s, 2 H); 4.68-4.9 (m, 1H); 7.12 (d, 2 H); 7.28 (d, 2 H).

The following compounds were synthesized in an analogous manner:

(1) trans-O-acetyl-4- (4-dipropylaminomethylphenyl) cyclohexanol from trans-O-acetyl-4- (4-chloromethylphenyl) cyclohexanol and dipropylamine.

Colorless oil.

3 H-NMR spectrum (200 MHz, CDCl ₃ ); signals at ppm:

0.9 (t, 6 H); 1.35-1.75 (m, 8H); 1.9-2.2 (s + m, 7H); 2.3-2.6 (q + m, 5H); 3.5 (s. 2H); 4.65-4.9 (m, 1H); 7.1 (d, 2 H); 7.25 (d, 2 H).

(2) trans-O-acetyl-4- (4- [N-methylbutylamino] methylphenyl) cyclohexanol from trans-O-acetyl-4- (4-chloromethylphenyl) cyclohexanol and methylbutylamine.

Colorless oil.

3 H-NMR spectrum (200 MHz, CDCl ₃ ); signals at ppm:

0.9 (t, 3 H); 1.2-1.75 (m, 10H); 1.9-2.2 (2s + m, 8H); 2.33 2H); 2.4-2.6 km, IH); 3.45 (s, 2H); 4.7-4.9 (m, 1H); 7.15

2H); 7.25 (d, 2 H).

N (t, / -4 t

(3) trans-O-acetyl-4- (4-diallylaminomethylphenyl) -cyclohexanol from trans-O-acetyl-4- (4-chloromethylphenyl) -cyclohexanol and diallylamine.

Colorless oil.

3 H-NMR spectrum (200 MHz, CDCl ₃ ); signals at ppm:

1.4-1.7 (m, 4H); 1.9-2.18 (s + m, 7 H); 2.4-2.6 (m, 1H); 3.09 (dd, 4H); 3.52 (s, 2H); 4.7-4.9 (m, 1H); 5.01-5.3 (m, 4H); 5.75-6.0 (m, 2H); 7.12 (d, 2 H); 7.35 (d, 2 H).

(4) trans-O-acetyl-4- (4- [N-pyrrolidino] methylphenyl) cyclohexanol from trans-O-acetyl-4- (4-chloromethylphenyl) -cyclohexanol with pyrrolidine.

White crystals.

Melting point: 43-45 ° C.

(5) trans-O-acetyl-4- (4- [N-morpholino] methylphenyl) cyclohexanol from trans-O-acetyl-4- (4-chloromethylphenyl) cyclohexanol and morpholine.

White crystals.

Mp 53-55 ° C.

(6) trans-O-acetyl-4- (4- [N-piperidino] methylphenyl) cyclohexanol from trans-O-acetyl-4- (4-chloromethylphenyl) cyclohexanol and piperiain.

White crystals.

62-54 ° C.

(7) trans-O-acetyl-4- [N-methyl-N'-piperazino] methylphenyl) cyclohexanol from trans-O-acetyl-4- (4-chloromethylphenyl) -cyclohexanol and N methylpiperazine.

White crystals.

Melting point: 50-52 ° C.

Example 5 trans-O- (4-Chlorophenylacetyl) -4- (4-methylaminomethylphenyl) cyclohexanol

A solution of 8.9 g (0.019 mol) of trans-O- (4-chloro-phenylacetyl) -4- (4-N- [tert-butoxycarbonyl] -methylaminomethyl) -phenylcyclohexanol in 200 ml of methylene chloride was treated with 35 ml of trifluoroacetic acid and 2 hours is stirred at room temperature. The volatiles were then distilled off in vacuo, the residue was taken up in methylene chloride and washed to neutrality with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulphate and evaporated in vacuo. A yellowish oil remains, which is purified by column chromatography (alumina, activity level III, ICN;

petroleum ether / ethyl acetate / methanol = 10: 10: 1). Yellow-white crystals of m.p. 65-67 ° C are obtained.

Yield: 6.4 g (91% of theory).

1 H-NMR spectrum (200 MHz, CDCl 3); signals at ppm:

1.4 - 1.7 (m, 4H); 1.8-2.0 (m, 2H), 2.0-2.2 (m, 2H), 2.42.6 (s + m, 3 + 1H), 3.58 (s, 2H), 3.7 (s, 2H); 4.7-4.9 (ra, 1H); 7.1-7.35 (m, 8H).

The following compound was synthesized in an analogous manner:

(1) O- (4-Chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol (cis / trans-mixture) from O- (4-chlorophenylacetyl) -4- (4-N- [tert-butoxycarbonyl] methylaminomethyl) phenyl -cyclohexanol (cis / trans-mixture) and trifluoroacetic acid.

Yellow oil.

Rf value (alumina; petroleum ether / ethyl acetate / methanol = 10: 10: 1): 0.28-0.53.

Example 6

O- (4-Chlorophenylacetyl) -4- (4N- [carboxamidomethyl] methylaminomethylphenyl) -cyclohexanol (cis / trans mixture)

From a mixture of 1.0 g (0.0027 mol) of O- (4-chlorophenylacetyl) -4- (4-methylaminomethylphenyl) -cyclohexanol (cis / trans-mixture), 0.5 g (0.0027 mol) of iodoacetamide, 0.37 g (0.0027 mol) of potassium carbonate and 5 ml of dimethylformamide were heated at 50 ° C for 2 hours with stirring. After cooling to room temperature, it was treated with water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, the volatiles are distilled off in vacuo and the residue is purified by column chromatography (basic alumina, activity level III, ICN;

petroleum ether / ethyl acetate / methanol = 60: 40: 2.5).

A white crystalline product is obtained which sinters from 110 ° C and melts between 123 and 132 ° C.

1 H-NMR spectrum (200 MHz, CDCl 3 / CD 3 OD); signals at ppm:

1.4-1.75 (ra, 5H); 1.3-2.2 (m, 3H); 2.32 (dd, 3H); 2.4-2.63 (m, 1H); 3.0 (dd, 2 H); 3.5-3.7 (dd + dd, 2 + 1H); 4.7-4.9 (m,

0.5H); 5.03-5.15 (m, 0.5H); 7.0-7.4 (s, 3H).

The following compounds were synthesized in an analogous manner:

(1) trans-O- (4-chlorophenylacetyl) -4- (4-N- [carbethoxymethyl] methylaminomethyl) phenyl cyclohexanol from trans-O- (4-chlorophenylacetyl) -4- (4-methylaminomethylphenyl) cyclohexanol, ethyl ester bromoacetate and potassium carbonate / dimethylformamide.

White solid product.

Melting point: 40 to 42 ° C.

(2) trans-O- (4-chlorophenylacetyl) -4- (4-N- [3-hydroxypropyl] methyl-aminomethyl) phenyl-cyclohexanol from trans-O- (4- (chlorophenylacetyl) -4- (4-methylaminomethylphenyl) -cyclohexanol, 3-bromopropanol and potassium carbonate / dimethylformamide.

White crystals.

Melting point: 75-77 ° C.

Example 7

Trans-O- (4-chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol hydrochloride

A solution of 0.39 g (0.001 mol) of trans-O- (4-chlorophenylacetyl) 4- (4-dimethylaminomethylphenyl) cyclohexanol in 10 ml of diethyl ether is added dropwise at room temperature with stirring to

1.5 times the molar amount of hydrogen chloride in isopropanol. The precipitate formed is allowed to stand for 1 hour at room temperature, filtered off with suction, washed repeatedly with diethyl ether and dried. White crystals of m.p. 231-233 ° C are obtained. Yield: 0.32 g (76% of theory).

Elemental analysis for C 23 H 29 Cl 2 NO 2 (422.40) calculated 65.40% C, 6.92% H, 3.22% N, 16.79% Cl found 65.33% C, 7.06% H, 3.45% N, 16.92% Cl.

Example 8

Trans-O- (4-chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol tartrate

0.15 g (0.001 mol) of anhydrous tartaric acid is dissolved in 7 ml of absolute ethanol and then 0.39 g (0.001 mol) of trans-O- (4-chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) 67 cyclohexanol. The clear solution was then mixed with diethyl ether until light turbidity and allowed to stand at + 4 ° C for 8 hours. The precipitated crystalline product is filtered off with suction, washed with diethyl ether and dried.

Melting point: 169-171 ° C.

Yield 0.46 g (86% of theory).

For C27H34ClNOg (536.02):

C, 60.50; H, 6.39; N, 2.51; Cl, 6.61. Found: C, 60.37; H, 6.38; N, 2.65.

Further, the preparation of pharmaceutical dosage forms is described in several examples.

Example I

Tablets with 5 mg trans-O- (4-chlorophenylacetyl) -4- (4 dimethylaminomethylphenyl) -cyclohexanol

Ingredients:

1 tablet contains: active substance milk sugar potato starch magnesium stearate 5.0 mg 143.0 mg 65.0 mg 2.0 mg 220.0 mg Method of production:

From potato starch it is heated by heating with 10% broth. The active ingredient, milk sugar and the remaining potato starch are mixed and granulated with the above sieve through a 1.5 mm sieve. The granulate is dried at 45 ° C, rubbed once again with the aforementioned sieve and pressed into tablets.

Tablet weight: 220 mg

Punches: 9 mg

Example II

Dragee, containing 5 mg trans-O- (4-chlorophenylacetyl) -4- (4 dimethylaminomethylphenyl) -cyclohexanol

The tablets prepared according to Example I are coated with a coating consisting essentially of sugar and talc. Finished dragees are polished with beeswax.

Dragee weight: 300 mg

Example III

Suppositories with 5 mg trans-O- (4-chlorophenylacetyl) -4- (4 dimethylaminomethylphenyl) -cyclohexanol

Ingredients:

suppository contains:

active substance 5.0 mg suppository (e.g. Witepsol W 45 ^) 1S95.0 mg

Method of production:

The finely powdered active substance is suspended in the molten suppository at 40 ° C. The mass is poured at 37 ° C into slightly pre-cooled rosehip molds. Suppository weight 1,7 g.

Example IV

Capsules with 5 mg trans-O- (4- [trifluoromethyl] -phenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol

Ingredients :

capsule contains:

active ingredient 5.0 mg lactose 82.0 mg starch 82.0 mg magnesium stearate 1.0 mg

0.0 mg

Method of production:

The powder blend was intensively mixed and filled into a size 3 hard-type, gelatin capsule on a capsule apparatus, while the final weight was continuously checked.

Example V

Tablets with 5 mg trans-O- (4-bromophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol

Ingredients:

the tablet contains the active ingredient milk sugar potato starch magnesium stearate

5.0 mg 148.0 mg 65.0 mg

2.0 mg

220.0 mg

Method of production:

t

From potato starch, it is made by heating with 10% broth.

The active ingredient, milk sugar and the remaining potato starch are mixed and granulated with the abovementioned strain through a sieve with a mesh size

1.5 mm. The granulate is dried at 45 ° C, rubbed again through the aforementioned sieve, mixed with magnesium stearate and pressed into tablets.

Tablet weight: 220 mg

Punches: 9 mm

Example VI

Cream for topical application with 1 g of trans-O- (4-chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol

A composition for topical application of a compound of formula I may

have the following composition 1. the active substance i, o g 2. stearyl alcohol 4.0 g 3. cetylalkohol 4.0 g 4. mineral oil 3,0 g 5 Polysorbate 60 4.5 g 6. sorbitan stearate 4.5 g 7. propylene glycol 10,0 g 8. methylparaben 0.13 g 9. propylparaben 0,02 g 10. Water g.s. ad 100.00 g Components 2-6 are heated to 80 ° C to 80 ° C they all melt The component is then dissolved 1 in the oil phase. Components 7 and 10 are heated to 90 ° C and the aqueous thus obtained phase dissolves components 8 and 9. Then the aqueous phase is added to the oil phase; and

stirring rapidly to obtain an emulsion. This was allowed to cool slowly to 50 ° C to solidify the emulsion. With further stirring, the formulation was cooled to room temperature.

The following example describes the production of feed for laying hens:

Example VII

Feed for laying hens containing trans-O (4-chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol as active ingredient

maize 633 g / kg soya bean meal 260 g / kg meat meal 40 g / kg feed fat 25 g / kg soybean oil 17 g / kg bicalciumphosphate 12 g / kg calcium carbonate 6 g / kg Vitamin-mineral mixture substances 5 g / kg active substance 2 g / kg

These ingredients are given in the indicated amounts after careful mixing of 1 kg of feed.

Claims (4)

The phenylcycloalkyiols of general formula I, (D R ¹ and R ² , which may be the same or different, represent a hydrogen atom, a straight or branched (C 1 -C 5) alkyl group, a straight or branched (C 3 -C 10) alkenyl or alkynyl group, their double and triple the bonds are isolated from the nitrogen bond and said alkyl-, alkenyl- and alkynyl groups may also be substituted by amino-, hydroxy-, alkoxy-, alkylcarbonyloxy-, alkylcarbonylamino-, carboxy, alkoxycarbonyl-, aminocarbonyl- or cyano groups, said amino-, hydroxy, alkoxy, alkylcarbonyloxy and alkylcarbonylamino groups cannot be attached to the unsaturated carbon atom and to the carbon atom at the 1-position, or R ¹ - and R ² together with the nitrogen atom lying between them form 5- to 3-carbon atoms A 7-membered saturated monocyclic heterocyclic ring, wherein in the monocyclic heterocyclic ring thus formed, the methylene group at the 4-position may be replaced by an oxygen or sulfur atom or an optionally substituted alkyl group by an alkyl group, R ³ and R ^4, which may be the same or different and represent hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms, R 5 represents a hydrogen atom, a straight or branched (C 1 -C 4) alkyl group or a (C 1 -C 4) alkoxy group, R ⁶ represents a hydrogen atom or a straight or branched (C 1 -C 4) alkyl group, R ⁷ represents a hydrogen atom, a C 3 -C 7 cycloalkyl group, optionally a fluorine, chlorine or bromine atom, a hydroxy-, alkyl-, alkoxy-, phenylalkoxy-, phenyl-, nitro-, amino-, alkylamino-, dialkylamino-, alkylcarbonylamino-, cyano-, carboxy-, alkoxycarbonyl-, aminocarbonyl-, alkylaminocarbonyl-, dialkylaminocarbonyl-, trifluoromethyl-, alkylcarbonyloxy-, aminosulfonyl-, alkylaminosulfonyl- or dialkylaminosulfonyl- mono- or disubstituted phenyl and wherein the substituents may be the same or the substituents may be the same; two adjacent hydrogen atoms in the phenyl group may be replaced by methylenedioxy or 1,2-ethylenedioxy, chloro or bromo and amino substituted phenyl, naphthyl or tetrahydronaphthyl, halogen or one or two alkyl substituted thienyl, furyl or pyridyl, and A represents a bond, straight or branched (C 1 -C 17) alkylene or (C 2 -C 17) alkenylene or alkynylene, wherein all alkyl and alkoxy moieties, unless otherwise indicated, may contain 1 to 3 carbon atoms, and said atom halogen may be fluorine, chlorine or bromine, their enantiomers, diastereomers and geometric isoraers, as well as their salts. C-A-Cyl-4-phenyl-cyclohexanols of the general formula Ia in which n, m and m each represent the number 1, P ¹ and R ² , which may be the same or different, represent a hydrogen atom, a straight or branched alkyl group having 1 to 6 carbon atoms, a straight or branched alkenyl or alkynyl group having from 3 to 6 carbon atoms each of which the triple bonds are isolated from the nitrogen bond and said alkyl-, alkenyl- and aikinyl groups may also be substituted by amino-, hydroxy-, alkoxy-, alkylcarbonyloxy-, alkylcarbonylamino-, carboxy, alkoxycarbonyl-, aminocarbonyl- or cyano groups, said amino-, hydroxy, alkoxy, alkylcarbonyloxy and alkylcarbonylamino groups cannot be attached to the unsaturated carbon atom and to the carbon atom at the 1-position, or R ¹ and R ² together with the intervening nitrogen atom form a 5- to 7-membered saturated monocyclic heterocyclic ring, whereby the 6-membered monocyclic heterocyclic ring thus formed may be replaced by the methylene group at the 4-position by an oxygen or sulfur atom or optionally by an alkyl group substituted amino, R ³ to R ^8, which may be the same or different, and represent a hydrogen atom or a methylene group, R ⁷ is hydrogen, C 3 -C 7 cycloalkyl, optionally fluorine, chlorine or bromine, hydroxy-, alkyl-, alkoxy-, phenylalkoxy-, phenyl-, nitro-, amino-, alkylamino-, dialkylamino-, alkylcarbonylamino-, cyano-, carboxy-, alkoxycarbonyl-, aminocarbonyl-, alkylaminocarbonyl-, dialkylaminocarbonyl-, trifluoromethyl-, alkylcarbonyloxy-, aminosulfonyl-, alkylaminosulfonyl- or dialkylaminosulfonyl- mono- or disubstituted phenyl groups, wherein the substituents may be the same or two and the substituents may be the same or two; adjacent hydrogen atoms in the phenyl group may be replaced by methylenedioxy- or 1,2-ethylenedioxy, two chlorine or bromine atoms and an amino substituted phenyl, naphthyl or tetrahydronaphthyl, chlorine or bromine atom or one or two alkyl substituted thienyl, furyl or pyridyl groups, and A represents a bond, straight or branched (C1 -C10) alkylene or (C2 -C10) alkenylene or alkynylene, wherein all alkyl and alkoxy moieties, unless otherwise indicated, may contain 1 to 3 carbon atoms and their enantiomers, diastereomers and geometric isomers as well as their salts. O-Acyl-4-phenyl-cyclohexanols of formula Ia according to claim 2, wherein n, m and p are 1, R1 represents a hydrogen atom, a straight or branched (C1-C4) alkyl group which may be substituted by an aminocarbonyl or in the 2-, 3- or 4- position may be substituted by a hydroxy or alkoxy group or a 2-propenyl group, and R ² is hydrogen, alkyl having 1 to 4 carbon atoms or a 2-propenyl group, or R ¹ and R ² together with the intervening nitrogen atom form 5- to 3-membered nitrogen A 6-membered saturated monocyclic heterocyclic ring, wherein in the 6-membered monocyclic heterocyclic ring thus formed, the methylene group at the 4-position may be replaced by an oxygen atom or an optionally substituted alkyl group by an alkyl group, R ³ to R ⁶ are each hydrogen, R ⁷ represents a hydrogen atom, a C 3 -C 6 cycloalkyl group, optionally in the 4-position with a fluorine, chlorine or bromine atom, a hydroxy-, alkyl-, alkoxy-, phenyl-, nitro-, trifluoromethyl monosubstituted phenyl group, two chlorine atoms, chloro and alkyl or amino or two alkoxy disubstituted phenyl, two chlorine atoms and amino trisubstituted phenyl, 3,4-methylenedioxyphenyl, naphthyl or tetrahydronaphthyl, 2-furyl, or optionally substituted at the 5-position with chloro substituted 2-thienyl, A represents a bond, a straight or branched (C 1 -C 6) alkylene or (C 2 -C 5) alkenyl group, wherein all alkyl and alkoxy moieties, unless otherwise specified, may contain 1 to 3 carbon atoms and their enantiomers, diastereomers and geometric isomers as well as their salts with inorganic or organic acids. O-Acyl-4-phenyl-cyclohexanols of the formula Ia according to claim 2, wherein n, m and p are each 1, R ¹ represents a hydrogen atom, a straight or branched (C 1 -C 4) alkyl group which may be substituted by an aminocarbonyl group or in the 2-, 3- or 4-position of a hydroxy or alkoxy group, or a 2-propenylene group, R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R ³ to R ⁵ are each hydrogen, R ⁷ is optionally in the 4-position by fluorine, chlorine or bromine, methyl, trifluoromethyl, methoxy, phenyl or nitro substituted phenyl, 3,4-dichloro-phenyl, 2,4-dichlorophenyl-, 4-chloro- 3-methylphenyl, 4-amino-3-chlorophenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 4 amino-3,5-dichlorophenyl or 2-naphthyl; and A is a bond, straight or branched (C 1 -C 5) alkylene or C 2 or C 3 alkenylene or alkynylene, wherein all alkyl and alkoxy moieties, unless otherwise indicated, may contain 1 to 3 carbon atoms and their enantiomers, diastereomers and geometric isomers as well as their physiologically acceptable salts with inorganic or organic acids, O-Acyl-4-phenyl-cyclohexanol selected from the group consisting of (1) cis-O- (4-chlorobenzoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol (2) cis-O- (4-phenyl-3) (3) trans-O- (4-chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol; (4) cis-O- (5-methylhexanoyl) -4- (butenoyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol; (4-dimethylaminomethylphenyl) cyclohexanol, (5) trans-O- (2-phenylpropionyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol, (6) trans-O- (4-fluorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol, ( 7) trans-O- (3,4-dichlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol, (8) cis-O- (4-fluorocinnamoyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol, (9) trans-O - (p-tolylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol. (10) trans-O- (4- [trifluoromethyl] phenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol, (11) trans-O- (2-naphthylacetyl) -4- (4-dimethylaminomethylphenyl) cyclohexanol, (12) trans-O- (4-nitrophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol, (13) trans-O- (4-bromophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol, (14) trans-O- (2,4) (15) trans-O - ([4-amino-3-chlorophenyl] acetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol; (16) trans-O- (4-) -dichlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol; methoxy-phenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol; (17) trans-O- (4-chlorophenylacetyl) -4- (4-dimethylaminomethylphenyl) -cyclohexanol and its physiologically acceptable salts with inorganic or organic acids. Medicament, characterized in that it contains at least one compound according to at least one of claims 1 to 5 in addition to optionally one or more inert carriers and / or diluents. A medicament comprising at least one compound according to at least one of claims 3 to 14 5 in addition to optionally one or more inert carriers and / or diluents. Use of a compound according to at least one of claims 1 to 5 for the manufacture of a medicament for inhibiting cholesterol biosynthesis. Use of a compound according to at least one of claims 1 to 5 for the manufacture of a medicament for the treatment or prophylaxis of hyper lipidemia. Use of a compound according to at least one of Claims 1 to 5 for the manufacture of a medicament for the treatment of diseases which are caused by excessive cell proliferation. 11. for stones. Use of a compound according to at least the manufacture of a medicament for the prophylaxis and treatment of one of claims 1 to 5 for bile diseases Use of a compound according to at least one of claims 1 to 5 for the manufacture of a medicament for the treatment of mycoses. Use of a compound according to at least one of claims 1 to 5 for the manufacture of a medicament for the manufacture of a feed for laying hens for producing low-cholesterol eggs. 14. A method according to claim 6 or 7, characterized in that the compound according to at least one of claims 1 to 5 is incorporated into one or more inert carriers and / or diluents. Process for the preparation of a compound according to at least one of Claims 1 to 5, characterized in that it comprises: and) II where n, m let react 4-phenylcycloalkanol of the general formula p and ΡΛ to Ρθ are as defined in the claims (II) 1 to 4, with a carboxylic acid or reactive derivatives thereof of the general formula III R ⁷ -A-COX (III) wherein R ⁷ and A are as defined in claims 1 to 4 and X represents a hydroxy group or a reactive leaving group, at a temperature between -10 ° C and 150 ° C, bi-acyl-4-phenylcycloalkanol of formula IV R ³ , (IV) wherein n, m, p, R ^J to R ^Z and a are as hereinbefore defined and Y represents a reactive leaving group is reacted with an amine such as triethylamine formula V wherein T R ¹ and R ² are as defined in claims 1 to 4, at a temperature between 0 and 100 ° C, or c) for the preparation of a compound of the formula I in which it is as defined in claims 1 to 4 and R ² represents a straight or branched C 1 -C 6 alkyl group which may be substituted by hydroxy-, alkoxy-, alkylcarbonyloxy-. alkylcarbonylamino-, carboxyl-, alkoxycarbonyl-, aminocarbonyl- or cyano, wherein the hydroxy-, alkoxy-, alkylcarbonyloxy- or alkylcarbonylamino group is not 1 attached to the carbon atom at position 1 is reacted Q-acyl-4-phenylcycloalkanol of formula VI wherein n, m, o, R ³ to R 6 and A are as defined in claims 1 to 4 and R 1 is as defined above, with a compound of formula VII R ² (VID where R ² 'represents a straight or branched (C 1 -C 6) alkyl group which may be substituted by hydroxy-, alkoxy-, alkylcarbonyloxy-, alkylcarbonylamino-, carboxyl-, alkoxycarbonyl-, aminocarbonyl- or cyano, wherein hydroxy-, alkoxy-, alkylcarbonyloxy or the alkylcarbonylamino group is not attached to the carbon atom in the 1-position and Z ¹ represents a reactive leaving group, at temperatures between 0 and 100 ° C, and preferably hydroxy-, amino-, alkylamino- or optionally present in the compounds of formulas II to VII The carboxyl group is protected by a protecting group before the reaction, after which the protecting group is cleaved again and / or the compounds of the formula I thus obtained are converted into their salts with inorganic or organic acids.