HUT75706A - O-acyl-4-phenyl-cyclohexanols, medicaments containing such compounds and their use, as well as a method of preparing them - Google Patents

Abstract

The invention relates to the synthesis of cholesterol bio * <./ · "KC" &quot; h &quot;, &lt; RTI ID = 0.0 &gt; &lt; / RTI &gt; &lt; / RTI &gt; new O-acyl-4-phenylcycloalkanols and their salts including all possible isomers, processes for their preparation, pharmaceutical compositions containing them and their use. According to the invention, the compounds of formula I are. Ind n, m and p are preferably 1; R 1 and R 2 are independently hydrogen or optionally substituted alkyl, alkenyl or alkynyl; or together with the nitrogen atom to which they are attached form a saturated heterocyclic ring; R3, R4 and R6 are hydrogen or alkyl; R5 is hydrogen, alkyl or alkoxy; hydrogen, cycloalkyl, optionally mono-, di-

Description

The present invention relates to O-acyl-4-phenylcycloalkanols and their physiologically tolerable salts with organic or inorganic acids, to processes for their preparation, to pharmaceutical compositions containing them and to their use.

The compounds of the present invention inhibit cholesterol biosynthesis, in particular by virtue of their inhibitory effect on the key enzyme, 2,3-epoxysqualene cyclase, and as a medicament for the treatment and prevention of hyperlipidemia, hypercholesterolemia and atherosclerosis. Other uses of the compounds of the invention include proliferative skin and vascular diseases, cancerous diseases, gallstones, and fungal diseases.

The importance of active substances that can interfere with cholesterol biosynthesis is that they play an important role in the treatment of many disorders. These disorders include hypercholesterolemia and hyperlipidemia, which are known to be associated with atherosclerotic vascular changes and their consequences, such as coronary heart disease, cerebral blood flow disorders, periodic stroke, and gout risk.

It is now generally accepted that excessively elevated serum cholesterol levels are a major contributor to atherosclerotic vascular changes. Comprehensive clinical studies show that lowering serum cholesterol also reduces the risk of developing coronary heart disease [Current Opinion in Lipodology 2 (4), · · · ι

· · · · · ··· ······················································· ···

234 (1991)]. Because dietary intake represents a smaller proportion of cholesterol and a greater part is synthesized by the body itself, it is particularly useful as a means of reducing high cholesterol by inhibiting cholesterol biosynthesis.

In addition, inhibition of cholesterol biosynthesis may also be beneficial in other areas, such as in the treatment of proliferative skin and vascular diseases and cancer, in the treatment and prevention of gallstones, and in the treatment of fungal infections. In the latter case, the effect is based on influencing ergosterol biosynthesis in fungi, which is largely analogous to cholesterol biosynthesis in mammalian cells.

Cholesterol and ergosterol biosynthesis is a multi-step process starting from acetic acid. Many successive reaction steps provide many options for intervention, some of which are briefly described below by way of example.

It is capable of inhibiting HMG-CoA synthetase (HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A) and thus mentions β-lactones and β-lactams with potential antihypercholesterolemic activity [see J. Antibiotics 40, 1355 (1987) and US-A-4 751 237, EP-A-0 462 667 and US-A-4 983 597.

The so-called statin-type 3,5-dihydroxycarboxylic acids and their δ-lactones, such as lovastatin, simvastatin and pravastatin, which have already been used in the treatment of hypercholesterolemia, are HMG-CoA reductase. inhibitors. Other possible uses of these agents include fungal infections (US-A-4 375 475, EP-A-0 113).

881 and US-A-5 106 992), certain skin diseases (EP-A-0 369 263) and gallstones and cancer [US-A-5 106 992; 339: 1154-1156 (1992)]. Inhibition of smooth muscle cell proliferation by lovastatin [see Cardiovasc. Drugs. Ther. 5, Suppl. 3, 354 (1991)] provides an additional therapeutic option.

Squalene synthetase enzyme inhibitors, such as isoprenoid (phosphinylmethyl) phosphonates, are described and their utility in the treatment of hypercholesterolemia, cholelithiasis and cancer.

EP-A-0 409 181 and the Journal of

Medic. Chem., 1991, J. Med. Chem. 34, 1912. The cholesterol lowering and antifungal effects of squalestatin are also described in J. Antibiotics, 1992, 45, 639-641; and J. Bioi. Chemistry 267: 11705-11708 (1992)].

Inhibitors of the squalene epoxidase enzyme are known to be certain alkylamine-type compounds, such as naphthphin and terbinafine, which are active ingredients in pharmaceuticals for fungal diseases, and the anti-hypercholesterolemic agent, NB-598, of the allylamine derivative, J. Biol. Chemistry 265: 18075-18078 (1990)] and fluoro squalene derivatives found to have hypocholesterolemic activity (U.S. Pat. No. 5,011,859).

5 ··· ·· · ·. ········· · · · · · irat). In addition, piperidine and aza-decalin derivatives have been described as potential hypocholesterolemic and / or antifungal agents, although their mechanism of action is not fully elucidated and which have an inhibitor of squalene epoxidase and / or 2,3-epoxy squalene lanosterol cyclase. EP-A-0 420 116, EP-A-0 468 434, US-A-5,084,461 and

EP-A-0 468 457).

Among the inhibitors of 2,3-epoxy-squalene-lanosterol cyclase are diphenyl derivatives having antifungal activity (EP-A-0 464

465), aminoalkoxybenzyl derivatives (EP-A-0 410 359) and piperidine derivatives (J. Org. Chem. 57: 2794-2803 (1992). It has also been shown that in mammalian cells the action of this enzyme with decalin, azadecalin and indan derivatives is described in WO 89/08450; J. Bioi. Chemistry 254: 11258-11263 (1981); Biochem.

Pharmacology 37: 1955-1964 (1988); and J 64,003,144], 2-aza-2,3-dihydroqualene and 2,3-epiminoqualene (Biochem. Pharmacology 34, 2765-2777 (1985)], squalene oxide-epoxide enol ether (J. Chem. Soc. Perkin Trans. I, 461, 1988) and 2,3-epoxy-29-methylidene squalene (J. Am. Chem.

Soc., 113, 9673-9674 (1991)].

Finally, as a potentially antihyperlipidemic agent, inhibitors of lanosterol-14oc-demethylase, which are steroid derivatives and at the same time affect the action of HMG-CoA reductase, can be mentioned [U.S. Pat. No. 5,041,432; J. Bioi. Chemistry 266, 20070-20078 (1991); and US-A-5,034

548]. In addition, the enzyme in question is inhibited by so-called azole antifungal agents, which are chemically N-substituted imidazole and triazole derivatives, including the commercially available ketoconazole and fluconazole.

The compounds of formula (I) according to the invention are new compounds which have not been known so far and have surprisingly been found to be 2,3-epoxy-squalene-lanosterol cyclase (international code classification of the enzyme: EC.5.4.99.7). effective inhibitors.

2,3-epoxy-squalene-lanosterol cyclase is a key step in the biosynthesis of cholesterol and ergosterol, namely, 2,3-epoxy-squalene-lanosterol, the first compound to incorporate lanosterol in the biosynthesis of steroids. catalyses. Compounds that inhibit earlier steps of steroid biosynthesis, such as HMG-CoA synthesis or reduction, are expected to have better selectivity for inhibitors of this enzyme, and this is extremely advantageous because premature intervention in the biosynthesis process, leading to a decrease in the amount of mevalonic acid produced other biosynthetic products based on mevalonic acid, such as dolichol, ubiquinone and isopentenyl t-RNA, may also be negatively affected [see J.

Biol. Chemistry 265: 18075-18078 (1990).

However, if one of the steps of steroid biosynthesis is inhibited following the conversion of 2,3-epoxy squalene to lanosterol, there is a risk that steroid skeletal intermediates will accumulate in the body and their toxic effects will not be negligible. Reference may be made here, for example, to the active ingredient triparanol, which is an inhibitor of desmosterol reductase and which has exactly the same effect as described above. Due to its side effects such as cataracts, ichthyosis and alopecia, the active ingredient had to be withdrawn from the market [see J. Biol. Chemistry 265: 18075-18078 (1990).

As discussed in the introduction, 2,3-epoxy-squalene-lanosterol cyclase inhibitors are widely distributed in the literature, but the structure of the compounds to which this effect is attributed differs radically from the compounds of formula (I) described below. structure of compounds.

In view of the foregoing, it is an object of the present invention to provide compounds having antihypercholesterolemic activity which are useful in the treatment and prevention of atherosclerosis, superior to known active ingredients in terms of potency, and are considered to be of outstanding drug safety. It is further contemplated that the compounds of the present invention, being potent inhibitors of 2,3-epoxy-squalene-lanosterol cyclase, may also inhibit ergosterol biosynthesis in fungi and may therefore be useful in the treatment of mycoses.

The present invention therefore relates to those novel compounds of formula (I)

0-Acyl-4-phenylcycloalkanols, including their enantiomers, diastereomers and geometric isomers, and their salts, having a physiologically tolerable salt with inorganic or organic acids, having the formula:

n is 0 obsession 1; m is 0 obsession 1; P is 0 obsession 1;

R 'and R, which may be the same or different, are hydrogen or optionally amino, hydroxy, alkoxy, (alkoxycarbonyl) oxy, (alkylcarbonyl) amino, carboxy, alkoxycarbonyl; C 1 -C 6 straight or branched alkyl substituted by carbamoyl or cyano, or

C3-C6 straight or branched chain alkenyl or alkynyl, with the proviso that the alkenyl or alkynyl group may have only an isolated double or triple bond with respect to the carbon nitrogen bond, and the amino, hydroxy, alkoxy, -, (alkylcarbonyl) oxy and (alkylcarbonyl) amino may only be attached to a saturated carbon atom other than 1; obsession

R * and R ² taken together with the nitrogen atom to which they are attached form a 5-7 membered monocyclic, saturated heterocyclic group wherein the 6-membered ring at the 4-position of the methylene may be replaced by oxygen, sulfur or an alkyl optionally substituted imino;

R ⁴ and R ⁴ , which may be the same or different, are hydrogen or C 1 -C 4 linear or branched alkyl;

R 'is hydrogen, straight or branched C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;

R is hydrogen or C 1-4 straight or branched chain alkyl;

R 'is hydrogen, C 3 -C 7 cycloalkyl, optionally with fluoro, chloro or bromo, or hydroxy, alkyl, alkoxy, phenylalkoxy, phenyl, nitro, amino, alkylamino, dialkylamino, (alkylcarbonyl) amino, cyano, carboxy, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N, Ν-dialkylcarbamoyl, trifluoromethyl, ( alkylcarbonyl) oxy, sulfamoyl, N-alkylsulfamoyl or N, N-dialkylsulfamoyl mono- or disubstituted phenyl, wherein the substituents may be the same or different, and disubstituted phenyl includes phenyl, wherein the adjacent hydrogen atom of the hand is substituted by methylenedioxy or 1,2-ethylenedioxy, phenyl substituted by two chlorine or bromine atoms and one amino group, naphthyl, tetrahydronaphthyl or thienyl, furyl substituted by one or two halogen atoms - or pyridyl; and

A is a bond, a linear or branched C 1 -C 17 alkylene group or a C 2 -C 17 alkenylene or alkynylene group expressing a chemical bond;

with the proviso that, unless otherwise stated, alkyl and alkoxy may have from 1 to 3 carbon atoms and halogen means fluorine, chlorine or bromine.

Preferred are compounds of formula (Ia), including their enantiomers, diastereomers and geometric isomers, and their salts, especially those used in pharmaceutical applications, physiologically. salts thereof with acceptable inorganic or organic acids wherein n, m and p are both 1;

R ¹ and R ² , which may be the same or different, are hydrogen or optionally amino, hydroxy, (alkylcarbonyl) oxy, (alkylcarbonyl) amino, carboxy, alkoxycarbonyl, carbamoyl - either C 1-6 straight or branched chain alkyl or C 3-6 straight or branched chain alkenyl or alkynyl substituted with cyano, with the proviso that the alkenyl or alkynyl group has only a it can be an isolated double or triple bond, and the amino, hydroxy, alkoxy, (alkylcarbonyl) oxy, and (alkylcarbonyl) amino groups of the substituents can only be on saturated carbon atoms other than 1 connect; obsession

R ¹ and R ² taken together with the nitrogen atom to which they are attached form a 5-7 membered monocyclic, saturated heterocyclic group wherein the 6-membered ring at the 4-position of the methylene may be replaced by oxygen, sulfur or an alkyl optionally substituted imino;

R ³ , R ⁴ , R ⁵ and R 0, which may be the same or different, are hydrogen or methyl;

R ⁷ is hydrogen, C 3 -C 7 cycloalkyl optionally with fluoro, chloro or bromo, or hydroxy, alkyl, alkoxy, phenylalkoxy, phenyl, nitro, amino, alkylamino, dialkylamino, (alkylcarbonyl) amino, cyano, carboxy, alkoxycarbonyl, carbamoyl,

Mono with a? -Alkylcarbamoyl, N, N-dialkylcarbamoyl, trifluoromethyl, (alkylcarbonyl) oxy, sulfamoyl, N-alkylsulfamoyl or N, N-dialkylsulfamoyl group - or disubstituted phenyl, where the substituents may be the same or different, and disubstituted phenyl is understood to mean a phenyl group having two adjacent hydrogen atoms being methylenedioxy or 1,2-ethylenedioxy, two chloro or bromo atoms and one amino group. substituted phenyl, naphthyl, tetrahydronaphthyl or thienyl, furyl or pyridyl substituted with one or two chlorine or bromine; and A is a bond, a linear or branched C 1 -C 10 alkenylene or C 2 -C 10 alkenylene or alkynylene bond;

with the proviso that, unless otherwise indicated, the above alkyl or alkoxy group may have from 1 to 3 carbon atoms.

Particularly preferred are the compounds of formula (Ia), including enantiomers, diastereomers and geometric isomers, and salts thereof, in particular pharmaceutically acceptable salts of physiologically tolerated inorganic or organic acids, wherein n, m and p are both 1;

R is hydrogen, C 1 -C 4, straight or branched, having the following characteristics: "T", "T", "", "", alkyl or allyl optionally substituted by carbamoyl or in the 2-, 3- or 4-position of hydroxy or alkoxy;

R is hydrogen, (C1-C4) -alkyl or allyl; obsession

R ¹ and R ² taken together with the nitrogen atom to which they are attached form a 5- or β-membered monocyclic, saturated heterocyclic group in which the 6-membered ring may be substituted at the 4-position of the methylene by an oxygen atom or an optionally substituted imino group;

R ³ , R ⁴ , R ³ , R ⁶ are each hydrogen;

R ⁷ is hydrogen, C 3 -C 6 cycloalkyl optionally substituted in the 4-position by a fluorine, chlorine or bromine atom or an alkyl, alkoxy, phenyl, nitro or trifluoromethyl group, two chloro atoms, one chloro atom and phenyl substituted with one alkyl or amino group or two alkoxy groups, phenyl substituted with two chlorine atoms and one amino group, 3,4-methylenedioxyphenyl, naphthyl, tetrahydronaphthyl, 2-furyl, optionally in the 5-position substituted with chlorine

2-thienyl or 3-pyridyl; and

A is a bond, a linear or branched C 1 -C 6 alkylene group or a C 2 -C 5 alkenylene group expressing a chemical bond;

with the proviso that, unless otherwise indicated, the above alkyl or alkoxy group may have from 1 to 3 carbon atoms.

· Μ

Particularly preferred are the compounds of formula (Ia), including enantiomers, diastereomers and geometric isomers, and salts thereof, in particular pharmaceutically acceptable salts of physiologically acceptable inorganic or organic acids, wherein n, m and p are both 1;

R is hydrogen, C 1-4 straight or branched chain alkyl optionally substituted by carbamoyl, or 2-, 3- or 4-hydroxy or alkoxy;

R ² is hydrogen or C 1-4 alkyl;

R, R ', R and R are each hydrogen;

R 'is phenyl optionally substituted at the 4-position by a fluorine, chlorine or bromine atom or a methyl, trifluoromethyl, methoxy, phenyl or nitro group, or 3,4-dichlorophenyl, 2,4-dichloro -phenyl, 4-chloro-3-methylphenyl, 4-amino-3-chlorophenyl, 3,4-dimethoxyphenyl, 3,4- (methylenedioxy) phenyl, 4- amino-3,5-dichlorophenyl or 2-naphthyl; and

A is a bond, a linear or branched C 1 -C 5 alkylene group or a C 2 or C 3 alkenylene group;

with the proviso that, unless otherwise indicated, the above alkyl and alkoxy groups may have from 1 to 3 carbon atoms.

The following compounds and their salts are particularly preferred:

(1) cis [4- {4 - [(dimethylamino) methyl] phenyl] cyclohexyl] (4-chlorobenzoate);

···· · · * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · (·) (2) cis -} 4- {4 - [(dimethylamino) methyl] phenyl} -cyclohexyl] - (4

phenyl-3-butenoate);

(3) trans} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] [(4-chlorophenyl) acetate];

(4) cis} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - (5-methylhexanoate);

(5) trans} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] (2-phenylpropionate);

(6) trans} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] [(4-fluorophenyl) acetate];

(7) trans- {4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - [(3,4-dichlorophenyl) acetate];

(8) cis-4- {4-} (dimethylamino) methyl] phenyl} cyclohexyl] - (4-fluorocinnamate);

(9) trans} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - [(4-yl) acetate];

(10) trans- 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl]} [4- (trifluoromethyl) phenyl] acetate};

(11) trans- {4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - [(2-naphthyl) acetate];

(12) trans- 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] [(4-nitrophenyl) acetate];

(13) trans- {4- {4-} (dimethylamino) methyl] phenyl} cyclohexyl] - [(4-bromophenyl) acetate];

(14) trans- {4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] [(2,4-dichlorophenyl) acetate];

(15) trans- {4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] -15

- [(4-amino-3-chlorophenyl) acetate];

(16) trans 4 - {4 - [(dimethylamino) methyl] phenyl) cyclohexyl] [(4-methoxyphenyl) acetate]; and (17) trans 4 - {4 - [(methylamino) methyl] phenyl} cyclohexyl] [(4-chlorophenyl) acetate].

For example, the compounds of formula (I) may be prepared by the following processes:

a) A 4-phenylcycloalkanol of formula II wherein z ¹ 2 3 4 represents n, m and p and R *, R, R, R, R and R have the meanings given in the introduction, A carboxylic acid of formula III or a reactive carboxylic acid derivative wherein R and A are as defined in the introduction and X is a hydroxy group or a reactive leaving group such as a halogen such as chlorine or bromine, a trimethylsilyl oxy group, a sulfonyloxy group such as a (p-tolylsulfonyl) oxy group, an N-heteroaryl group such as 1-liridazolyl or a benzotriazol-1-yl group, or attached via its oxygen atom, isocarbamide, i.e. the compound in question may be, for example, 0-substituted N, N'-dicyclohexylisocarbamide.

The reaction is conveniently carried out in a solvent such as benzene, toluene, xylene, diisopropyl ether, dioxane, tetrahydrofuran, N, N-dimethylformamide, dichloromethane or chloroform, optionally with a base such as triethylamine, pyridine or 4- ( in the presence of dimethylamino) pyridine, or in the presence of an acid, especially when X in the formula (III) is a hydroxy group such as boron trifluoride diethyl ether (1/1) or an acid phase in the presence of a cation exchange resin at a temperature of -10 to +150 ° C, preferably -10 to +80 ° C.

When a group corresponding to R 'and / or R has a free hydroxy, amino or carboxy group, it is advisable to protect these groups in some suitable manner prior to the reaction, i.e. by protecting the hydroxy group, e.g. 2-methoxyethoxy) methyl, tert-butyl or benzyl ether is converted to the title compound or the amino group of the carbamoyl group, for example trichloroethyl, (9-fluorenyl) methyl or 2,4-dichloro. benzyl, whereby the compound is N- (trichloroethyl) carbamoyl, N - [(9-fluorenyl) methyl] carbamoyl or N- (2,4-dichlorobenzyl) carbamoyl. or by esterifying the carboxy group, for example, to form 2,2,2-trichloroethyl, tert-butyl or benzyl ester, and then removing the protecting group (s) in a known manner.

b) An O-acyl-4-phenylcycloalkanol of formula IV wherein n, m and p, and R ³ , R ⁴ , R ⁼ , R 'and R ⁷ are as defined in the introduction, Y and a reactive leaving group such as a halogen such as chlorine or bromine or a sulfonyloxy group such as a methylsulfonyl oxy group with an amine of formula V wherein R * and R meanings defined in the introduction - we react.

The reaction is conveniently carried out in a suitable solvent, such as ethanol, tert-butyl alcohol, N, N-dimethylformamide or tetrahydrofuran, optionally in the presence of a base such as potassium carbonate, sodium ethanolate, butylate) or sodium hydride, and optionally under phase-promoting conditions, at temperatures between 0 and 100 ° C.

c) When R * in the compound of formula (I) to be prepared has the meaning given in the introduction and R is C 1-6 straight or branched, optionally hydroxy, alkoxy, (alkylcarbonyl) oxy, ( alkylcarbonylamino, carboxy, alkoxycarbonyl, carbamoyl or cyano alkyl, provided that the substituents are hydroxy, alkoxy, (alkylcarbonyl) oxy and (alkylcarbonyl) -amino group can only be attached to carbon atoms other than 1, an O-acyl-4-phenylcycloalkanol of formula VI having n, m and p and R, R ' , R, R 'and R are as defined in the introduction, and R * is as defined above for a compound of formula VII, wherein R is a C 1 -C 6 straight or branched, optionally hydroxy, alkoxy, (alkylcarbonyl) oxy, (alkylcarbonyl) amino, carboxy, alkyl substituted by alkoxycarbonyl, carbamoyl or cyano, with the proviso that the hydroxy, alkoxy, (alkylcarbonyl) oxy or (alkylcarbonyl) amino group of the substituents is not substituted with carbon 1 only. and Z * is a reactive leaving group such as a halogen such as chlorine or bromine or a sulfonyloxy such as (methylsulfonyl) oxy.

The reaction is conveniently carried out in a solvent or mixture of solvents such as ethanol, tert-butyl alcohol, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide, optionally an acid acceptor such as sodium carbonate, potassium carbonate, sodium hydroxide, in the presence of sodium hydride, sodium methanolate, potassium tert-butylate, triethylamine or pyridine, both of which may also serve as solvents and optionally providing phase transfer conditions, preferably 0 ° C and 100 ° C, for example, at 20 ° C to 50 ° C.

In carrying out the above processes, prior to the reaction, the reactive groups which may be present in the molecule, such as the hydroxy, amino, alkylamino, imino or carboxy groups, may be provided with conventional protecting groups, which then, after the reaction, again removed from the molecule.

Suitable protecting groups for the hydroxy group include, for example, trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, (2-methoxyethoxy) methyl, benzyl or tetrahydropyranyl, protecting groups for amino, alkylamino and imino include, for example, acetyl, benzoyl, ethoxycarbonyl and benzyl, while protecting groups for carboxy include, for example, 2,2,2-trichloroethyl, tert-butyl or benzyl ester form.

The optional protecting group may be cleaved after the reaction, preferably by hydrolysis, in an aqueous solvent such as water, isopropyl alcohol and water, tetrahydrofuran and water or dioxane and water, an acid such as hydrochloric acid. or in the presence of sulfuric acid or a base such as an alkali such as sodium hydroxide or potassium hydroxide at a temperature of 0 ° C to 100 ° C, preferably at the reflux temperature of the reaction mixture. A preferred way of cleaving the benzyl group is by hydrogenolysis. This can be done, for example, with hydrogen gas in the presence of a catalyst such as palladium on charcoal, in a suitable solvent such as methanol, ethanol, ethyl acetate or acetic acid, optionally with an acid such as hydrochloric acid at 0 to 50 ° C, preferably at room temperature. At a pressure of -7 bar, preferably 3-5 bar.

The compounds of formula (I) obtained by the methods described above may be purified or isolated by conventional means, such as crystallization or chromatography.

In addition, the compounds of formula (I) obtained may, if desired, be converted into an acid addition salt, preferably an acid addition salt with a physiologically tolerable inorganic or organic acid, which can be used in pharmacology. For salt formation, the acid may be selected from, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

The compounds of formula I according to the invention are characterized by the position of the substituents on the cycloalkane ring.

- 90 - * as stereoisomers, depending on the particular form of the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ , such as diastereomers, geometric isomers or optical isomers. It is understood that the invention relates to both pure stereoisomers and mixtures thereof.

Preparation of starting compounds:

1. The starting compounds of formula (II) may be prepared, for example, by reacting a 4-phenylcycloalkanone of formula (VIII): wherein n, m and p are and R ¹ , R ² , R ³ , R ⁴ , The symbols R ⁵ and R ⁶ have the same meaning as in the introduction. By appropriate choice of reducing agent, such as sodium [(tetrahydroborate) bowl or lithium [tri (sec-butyl) hydroborate] (L-selectride), it can be achieved that e, e -isomer or e, a-isomeric form of the compound of formula II.

The ketones of formula (VIII) can be obtained by known methods such as a cycloalkanedione mono (ethylene acetal) of formula (IX) and an organometallic compound of formula (X): wherein n is R, R, R ', R and R is as defined in the introduction, and Me is a reaction of lithium atom or a group of the formula -MgHal where Hal is halogen, preferably chlorine, followed by removal of water from the product, followed by reduction of the double bond and finally hydrolysis to the acetal ketone. can be produced.

• · · · ·

Another embodiment of the process is that a ketone of formula VIII wherein R is hydrogen is carried out following the reaction steps described above, for example by alkylation of the ketone enolate ion, to form a ketone of formula VIII. wherein R 0 is C 1 -C 4 alkyl.

Another possibility for the preparation of compounds of formula VIII is the dicarboxylic acid esters of formula XI - a

2 3 4 5 6.

wherein n, m and p and R, R, R, R, R and R are as defined in the introduction, and R and R ', which may be the same or different, are alkyl, aralkyl or aryl - Dieckmann- cyclization followed by known hydrolysis and decarboxylation of the product obtained.

2. The starting compounds of formula (IV) are, for example, from the corresponding 0-acyl-4-phenylcycloalkanol of formula (XII) by halomethylation, i.e. in the presence of a Friedel-crafts catalyst such as zinc chloride, with an aldehyde and it may be prepared by reaction with a halide such as hydrochloride or hydrobromic acid and optionally substituted with another reactive leaving group which is more suitable for the purpose.

3. Compounds of formula (VI) may be prepared, for example, from 0-acyl-4-phenylcycloalkanol of formula (XIII) wherein n, m and p are and R ', R ^J , R ⁴ , R, R ⁶ and R ^; is as defined in the introduction, Z and ^z is a suitable protecting group such as (t-Bu • · · · 9 • 9 methoxy) carbonyl, {l- [3, 5-di (t-butyl) phenyl] -1 -methyl-ethoxy} -carbonyl or [2- (4-pyridyl) -ethoxy] -carbonyl-1, by removing this protecting group from the molecule. For example, the compounds of formula (XIII) may be prepared by the synthetic route set forth in point 1 for the preparation of compounds of formula (VIII).

The starting compounds of formulas (III) and (V) are known in the art or can be readily prepared by known methods described previously.

The compounds of formula (I) have been shown to have valuable biological properties, since they are inhibitors of the cholesterol biosynthesis, being inhibitors of the 2,3-epoxy squalene-lanosterol cyclase enzyme, and are therefore particularly suitable for the treatment of various types of hyperlipidemia. hypercholesterolemia, hyperlipoproteinemia, and hypertriglyceridemia, and atherosclerotic vascular changes resulting from such conditions, and its consequences, coronary artery disease, cerebral blood flow disorders, intermittent claudication and prevention of herniation.

For the treatment of the diseases listed above, the compounds of the formula I are preferably administered in the form of oral or, if appropriate, rectal formulations, either as monotherapy or in combination with other cholesterol or lipid lowering agents. Suitable agents for use in combination include, for example, bile acid sequestering resins such as cholestyramine, cholestipol and the like; cholesterol uptake inhibitors such as sitosterol and neomycin; compounds that affect cholesterol biosynthesis, e.g.

HMG-CoA reductase inhibitors such as lovastatin, simvastatin, pravastatin and the like; squalene epoxidase inhibitors such as NB 598 and analogues; and squalene synthetase inhibitors such as isoprenoid (phosphonylmethyl) phosphonates, and squalestatin.

Other active ingredients for use in combination therapy include fibrates such as clofibrate, bezafibrate, gemfibrozil and the like, and nicotinic acid and derivatives thereof, such as acipimox and probucol.

In addition, the compounds of formula (I) are useful in the treatment of diseases that are somehow associated with cell proliferation. Cholesterol is an essential constituent of cells, which must be available in sufficient quantities for cell proliferation, ie cell division. As discussed briefly in the introduction, for example, inhibition of smooth muscle cell proliferation by HMG-CoA reductase inhibitors, more specifically a statin-like active ingredient known as lovastatin, has been reported to exert its inhibitory effect on cholesterol biosynthesis.

Examples of diseases associated with excessive cell proliferation include, in particular, cancerous diseases. The results of both cell culture and in vivo experiments show that serum cholesterol levels decrease.

-24 se, or interference with cholesterol biosynthesis, such as with HMG-CoA reductase inhibitors, slows tumor growth (Chain 339: 1154-1156 (1992)). The compounds of formula (I) of the present invention are therefore considered to be potential antitumor agents due to their inhibition of cholesterol biosynthesis and, therefore, either alone or as adjunctive therapy to other known therapies.

Further examples of hyperproliferative skin diseases, such as psoriasis, basal cell carcinoma, planocellular squamous cell carcinoma, keratosis and cornea, are further examples of diseases associated with excessive cell proliferation.

Psoriasis or psoriasis is a hyperproliferative skin disease that alters the skin's regulatory mechanism. Above all, external lesions appear on the skin, but the disease includes primary and secondary alterations in the proliferation of the epidermis, inflammatory reactions of the skin, and expression of mediator molecules such as lymphokines and inflammatory factors. Morphological features of psoriatic skin include increased epidermis metabolism, epithelial thickening, abnormal cornea, inflammatory cell infiltrations into the skin layers and polymorphonuclear leukocyte infiltration into the epidermis, which is associated with an increase in the basal cell cycle. The presence of hyperkeratosis and parakeratosis cells is also observed.

Keratosis, left-cell carcinoma, planocellular squamous cell carcinomas and disorders of the cornea are all proliferative skin diseases that result from a break in the mechanism that regulates the proliferation and differentiation of skin cells.

The compounds of formula (I) have been found to be effective in antagonizing the hyperproliferation of the skin, i.e., agents that are capable of inhibiting the hyperproliferation of human keratinocytes. Therefore, these compounds are useful as active ingredients in pharmaceutical compositions for the treatment of hyperproliferative skin disorders such as psoriasis, basal cell carcinoma, various disorders of cornea and keratosis.

For the treatment of the above diseases, the compounds of the formula I can be administered orally or topically, either as a single active ingredient or in combination with other known active ingredients.

Excessive proliferation of smooth muscle cells is considered to be the cause of certain surgical interventions such as percutaneous transluminal coronary angioplasty (PCTA) or bypass surgery such as stenoses, vascular occlusions. As discussed in the introduction, this type of cell proliferation can be suppressed by the use of statin-type HMG-CoA reductase inhibitors such as lovastatin. Due to their inhibitory effect on cholesterol biosynthesis, the compounds of formula I according to the invention are useful in the prevention or treatment of these vascular diseases, either alone, preferably in the form of oral formulations, or in combination with other active substances such as intravenous heparin.

The compounds of formula I according to the invention are

Λ X- ··········

-2ο - · · · · · · · · · · · · · · · · · · · · · · about their role in preventing and treating gallstones. The formation of gallstones is caused by the unfavorable cholesterol / bile acid ratio in the bile secretion, whereby the cholesterol is present in the liquid in excess of its solubility and consequently precipitates in the form of gallstones. THE

Lovastatin, known as HMG-CoA reductase inhibitor (Gastroenteorology 102, No. 4, Pt.2, A319 (1992)), has been reported to be an active agent for gallstone resolution, particularly when combined with urodeoxycholic acid. From the foregoing, it follows from the mode of action of the compounds of formula (I) that they may also be used, preferably in the form of oral formulations, for the prevention and treatment of gallstones, either alone or in combination with other known active substances such as urodeoxycholic acid as a complement to rock blasting by shock wave.

Finally, the compounds of formula I are useful in the treatment of infections caused by pathogenic fungi such as Candida albicans, Aspergilus niger, Trichophyton mentagrophytes, penicillium species, Cladosporium species and others. As discussed briefly in the introduction, the end product of sterane biosynthesis in fungi is not ergosterol, which is essential for the integrity and function of fungal cell membranes, but cholesterol. Inhibition of ergosterol biosynthesis therefore causes growth disturbances in fungi and, where appropriate, leads to cell death.

For the treatment of mycoses, the compounds of formula I may be administered orally and topically. These agents can be used alone or with known antimycotics, preferably those capable of interfering with another step of sterane biosynthesis, such as terbinafine and naphthphin, which act as inhibitors of squalene epoxidase, and are known as lanosterol-14a-demethylase inhibitors. ketoconazole and fluconazole - in combination.

Still further uses of the compounds of formula I include poultry farming. As described in the literature (FASEB Journal 4, A 533, Abstracts 1543 (1990)), the cholesterol content of eggs was reduced by adding lovastatin as an HMG-CoA reductase inhibitor to laying hens. The production of cholesterol-poor eggs is of great importance as it can reduce the amount of cholesterol taken in the diet without changing the diet. In view of the inhibitory effect of the compounds of the formula I on the cholesterol biosynthesis, it is obvious that these compounds, preferably in the form of an additive to poultry feed, can also be used in poultry farming as active ingredients which enable the production of cholesterol-deficient eggs.

The following tests were conducted to determine the biological activity of the compounds of formula (I):

I. Investigation of the inhibition of the incorporation of C-acetic acid into digitonin-precipitated steroids:

Human hepatocytes (HEP-G2) were cultured for three days and then stimulated for 16 hours in cholesterol-free medium.

• · · · ·

The test substance is dissolved in dimethyl sulfoxide and a 0.1% final solution is added to the cell suspension during the stimulation phase. To the mixture was then added 200 pmoles / liter of [2- ¹⁴ C] acetic acid in acetate and incubation continued at 37 for 2 hours. Following cell depletion and hydrolysis of the sterol esters, the steroids are precipitated from the extract with digitonin, finally separated and the amount of C-acetic acid incorporated is determined by scintillation measurement.

To determine the degree of inhibition is performed in the test materials 10 mol / 1 and 10 'is ⁸ mol / 1 concentration measurements, and it was found that for example in the following list A to Q to alphabetically labeled (I) compounds of the formula they exhibit a pronounced inhibitory effect, e.g., at a concentration of 10 ~ mol / liter, the degree of inhibition is equal to or greater than 50%.

A = cis) 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - (4-chlorobenzoate)

B = cis [4- {4 - [(dimethylamino) methyl] phenyl) cyclohexyl] - (4-phenyl-3-butenoate)

C = trans- 4- {4 - [(dimethylamino) methyl] phenyl) cyclohexyl] - [(4-chlorophenyl) acetate]

D = cis) 4- {4 - [(dimethylamino) methyl] phenyl] cyclohexyl] - (5-methylhexanoate)

E = trans) 4- {4 - [(Dimethylamino) methyl] phenyl] cyclohexyl] - (2-phenylpropionate)

F = trans- [4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - [(4-fluorophenyl) acetate]

G = trans- [4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - [(3,4-dichlorophenyl) acetate]

H = cis} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - (4-fluorocinnamate)

I = trans-} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl) - [(4-tolyl) acetate]

J = trans-} 4-} 4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - {[4- (trifluoromethyl) phenyl] acetate}

K = trans} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - [(2-naphthyl) acetate]

L = trans-} 4-} 4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - [(4-nitrophenyl) acetate]

M = trans} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl]} (4-bromophenyl) acetate]

N = trans-} 4-} 4 - [(dimethylamino) methyl] phenyl} cyclohexyl]} (2,4-dichlorophenyl) acetate] = trans- 4- {4- [( dimethylamino) methyl] phenyl} cyclohexyl] - [(4-amino-3-chlorophenyl) acetate]

P = trans} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - [(4-methoxyphenyl) acetate]

Q = trans- 4- {4 - [(methylamino) methyl] phenyl} cyclohexyl] - [(4-chlorophenyl) acetate].

Table 1 shows the% values obtained for the listed compounds in the above assay.

···· • · · · ····· a a A A *

V • a * • a «

Table 1

The compound sign Inhibit incorporation ^{of 14} C-acetic acid action, if the concentration of 10 ^"7 mol / 1 Inhibition of ¹⁴ C-acetic acid incorporation at a concentration of 10® mol / L THE -85 -51 B -87 -58 C -83 - 6 6 D -88 -53 E -89 -72 F -86 -66 G -89 -74 Ή -86 -51 I -90 -72 J -89 -87 K -86 -54 L -83 -67 M -84 -64 N -85 -67 SHE -79 -51 P -73 -52 Q -79 -50

b- V ·· ·

In the introduction, it has already been mentioned that there are sporadic publications in the literature dealing with 2,3-epoxy-squalene-lanosterol cyclase inhibitors, but the structure of the known compounds differs sharply from that of the compounds of formula I according to the invention. Enzyme inhibitors of the structure most closely related to the compounds of formula I are described in EP 0 468 457. For purposes of comparison, the above compound of Example 1 was also subjected to the above assay and was found to produce 41% and 13% inhibition at concentrations of 10 ⁵ mol / l and 10 mol / l, respectively, which was well below values of compounds of formula I according to the invention.

II. Measurement of the in vivo effect in rats following oral administration

Inhibition of the enzyme 2,3-epoxy-squalene-lanosterol cyclase results in elevated concentrations of 2,3-epoxy-squalene in the liver and plasma. Thus, the amount of 2,3-epoxy squalene formed is directly related to the potency of the animal. The test procedure is as follows:

Male Wistar rats (160-190 g), suspended in 1.5% aqueous methylcellulose, were dosed by gavage with the test compound. Five hours after administration of the drug, blood is collected from the striatal orbital

Bligh and Dyer, Canad. J. Biochem. Physiol. 37, 912 (1959)], then purified on a ballast column and subjected to HPLC. THE • ·

The resulting peaks are identified and quantified using authentic materials. The reproducibility of the results is checked using an internal standard.

The test was conducted at doses of 0.1 and 1.0 mg / kg of the active compounds. Table 2 shows experimental data for compounds B, C, J, Μ, N and P. The figures show the amount of 2,3-epoxy squalene in rat plasma expressed in pg / ml. In control animals, no measurable amounts were found in plasma under the same experimental conditions

2,3-epoxy-squalene.

Table 2

Compound sign Plasma concentration (pg / ml) of 2,3-epoxy squalene when administered 0.1 mg / kg Plasma concentration (pg / ml) of 2,3-epoxy squalene when administered 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

To date, no animal-related data on the inhibitory effect of kaleolesterol biosynthesis have been reported in any animal for any of the 2,3-epoxyqualene-lanosterol cyclase inhibitors.

Therapeutic doses of the compounds of the invention did not show any toxic effect at all. For example, Compound C in rats and Compounds J and M in mice found, for example, that no oral side-effects occurred at doses of 100 mg / kg orally for 5 days.

The compounds of formula (I) may be formulated into conventional pharmaceutical compositions for oral or topical administration in a manner known per se.

Among the compositions for oral use are, for example, the talbeta, dragee and capsule, and the rectal suppository is the preferred dosage form.

Topical formulations include, for example, gels, creams, lotions, ointments, lotion, aerosol and other known pharmaceutical formulations used primarily in dermatology. Formulations for topical administration will usually contain from 1 to 50 mg, preferably from 5 to 20 mg, of active ingredient per gram. In addition to the skin, the topical formulations of the invention may also be used to treat readily accessible areas of mucous membranes, such as the mouth, lower colon, and the like.

The daily oral or rectal dosage may be in the range of from 1 to 1200 mg per person of 60 kg body weight, but preferably in the range of 100 mg. Preferably, the daily dose is administered in 1-3 divided doses.

Treatment with preparations for topical application • ·.. 4. - · ···· · · · ·

For D * T · ····································································································································································ing 1. During the course of D * T "········ is about 1 to 1000 mg, preferably 10 to 300 mg, of the active ingredient, conveniently administered in one to three single doses.

When used in poultry farms for the production of cholesterol-deficient eggs, the active ingredient of the formula I is administered to the animals in the usual manner, for example in the form of a food additive. The concentration of the active ingredient in poultry feed is usually in the range of 0.01% to 1%, preferably 0.05% to 0.5%.

The active ingredient may be added in its original form to the feed. The poultry feed according to the invention for laying hens may contain, in addition to the active ingredient and optionally the usual vitamin-mineral mixture, corn, soybean meal, meat meal, feed fat and soybean oil. One or more of the compounds of formula (I) as defined in the introduction is added to the poultry feed at a concentration of 0.01% to 1%, preferably 0.05% to 0.5%, and the components are thoroughly mixed.

The following section provides examples to illustrate the invention. For the experiments described in the examples, thin layer chromatography was performed using E. Merck, Darmstadt, under the name DC-Fertigplatten, as follows:

(a) Kieselgel 60 F ₂₅₄ and

b) Aluminum oxide F ₂₅₄ (Typ E).

The preparation of the starting compounds is described in the Examples.

• · · · • · · · · β

Reference Example 1

4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexanone

a) 4- {4 - [(Dimethylamino) methyl] phenyl} -4-hydroxycyclohexanone ethylene acetal

To a solution of 36.4 g (0.17 mol) of 4-bromo-N, N-dimethylbenzylamine in 250 ml of anhydrous tetrahydrofuran and cooled to -70 ° C was added dropwise 112 ml (0.179 mol) of nitrogen under constant stirring. A solution of 1.6 M butyl lithium in hexane was added at a temperature not exceeding -65 ° C. The resulting orange solution was then stirred for an additional 15 minutes at -70 ° C and then 27.6 g (0.172 mol) of 1,4- (27.6 g, 0.172 mol) were added over a period of 10 minutes, maintaining the temperature at or below -65 ° C. cyclohexanedione mono (ethylene acetal) in 110 ml of tetrahydrofuran. The reaction mixture was stirred for 30 minutes at -70 ° C and then, without external cooling, until the temperature reached +20 ° C, when poured into 600 ml of ice water and the product was extracted with 200 ml of ethyl acetate. The organic layer was separated, the aqueous portion was shaken a few more times with ethyl acetate, and the combined organic solvent extracts were shaken with ethyl acetate, dried over the combined organic solvent extracts, and concentrated in vacuo. The residual crude product was recrystallized from diisopropyl ether to give

41.9 g of 4- {4 - [(dimethylamino) methyl] phenyl} -4-hydroxycyclohexanone ethylene acetal are obtained. Melting point: 84-86 ° C, 85% of theory.

b) 1- {4 - [(Dimethylamino) methyl] phenyl} -4-ethylenedioxy-cyclohexene

22.4 g (0.077 mol) of 4- {4 - [(dimethylamino) methyl] phenyl} -4-hydroxycyclohexanone ethylene acetal, 15.0 g (0.079 mol) of p-toluenesulfonic acid— water (1/1), ethylene glycol (39 mL) and toluene (240 mL) were heated to reflux with stirring for 3.5 hours while continuously removing water from the system. After cooling, the reaction mixture was poured into water (200 mL), the pH of the aqueous mixture was adjusted to 12 to 13 with 2M sodium hydroxide solution, then the aqueous portion was separated and extracted several times with toluene. The combined organic solvent extracts were dried over sodium sulfate and concentrated in vacuo. The remaining 21 g of a yellow oil is the title compound in approximately 100% yield.

c) 4- {4 - [(Dimethylamino) -methyl] -phenyl} -cyclohexanone-ethylene-acetal g (0.077 mol) 1- {4 - [(dimethylamino) -methyl] -phenyl] - The crude 4- (ethylenedioxy) -cyclohexene was dissolved in a mixture of ethyl acetate (200 mL) and methanol (100 mL), treated with palladium catalyst (5 g) on barium sulfate and hydrogenated under 5 bar of hydrogen gas for 1.5 h. At the end of the reaction, the catalyst was filtered off and the filtrate was concentrated in vacuo. The resulting 20 g of a tan oil is the title compound in approximately 100% yield.

• · · · • · · · · · · ····· ·· the

d) 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexanone

The crude 4- {4 - [(dimethylamino) methyl] phenyl} -cyclohexanone-ethylene-acetal crude product (20 g, 0.077 mol) and 110 ml of 2M hydrochloric acid were weighed, and the mixture was stirred at room temperature for 3.5 hours. . The resulting solution was shaken successively with ethyl acetate and the ethyl acetate solutions discarded. The aqueous phase is adjusted to pH 13-14 with 50% sodium hydroxide solution under cooling, and then the basic mixture is extracted several times with ethyl acetate. The combined organic solvent extracts were washed with brine, dried over sodium sulfate and then concentrated in vacuo. The resulting light yellow product (14 g, m.p. 64-67 ° C) is 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanone, 79% of theory. An analytical sample was recrystallized from petroleum ether boiling at 60-90 ° C to give crystals melting at 65-67 ° C.

REFERENCE EXAMPLE 2 Trans-4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexanol

11.1 g (0.048 mol) of 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanone are dissolved in 100 ml of anhydrous methanol, followed by small portions of 1.82 g (0.048 mol) of sodium} tetrahydride. -borate] is added to the solution. The reaction mixture was added after the addition

After stirring for 1.5 hours at room temperature, the mixture was concentrated in vacuo and water was added to the residue. The aqueous mixture was acidified with concentrated hydrochloric acid, stirred for 30 minutes at room temperature, then basified with 50% sodium hydroxide solution, and extracted several times with chloroform. The combined chloroform extract was dried over sodium sulfate, then the solvent was evaporated in vacuo and the residue consisting of a mixture of trans- and cis-4- {4 - [(dimethylaminomethyl) phenyl} cyclohexanol (cis). isomer ratio below 10%), purified by column chromatography on activity III neutral alumina (ICN), eluting with 5: 1 petroleum ether / ethyl methyl ketone. M.p. 63-65 ° C; weighing 8.8 g, 79% of theory.

REFERENCE EXAMPLE 3 Cis -4- {4 - [(Dimethylamino) methyl] phenyl} -cyclohexanol lithium [tri (sec-butyl) hydroborate] (1 M in tetrahydrofuran, 0.05 mol) The solution was diluted with 100 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere and 5.8 g (0.025 mol) of 4- {4 - [(dimethylamino) was added with stirring at -65 ° C to -70 ° C for about 10 minutes. ) -methyl] -phenyl} -cyclohexanone in 50 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at -70 ° C for 3 hours, then allowed to warm to room temperature over 1 hour and quenched with 75% aqueous ethanol (20 mL). The organometallic boron compound was oxidized with a mixture of 6 ml of sodium hydroxide solution (6 ml) and 30% hydrogen peroxide (15 ml), then the organic phase was separated, the aqueous portion was saturated with potassium carbonate and extracted with 50 ml of ethyl acetate. The combined organic solvent extracts were dried over sodium sulfate, concentrated in vacuo and the sticky evaporation residue, which was cis- and trans-4- {4 - [(dimethylamino) methyl]. -phenyl] -cyclohexanol (trans isomer ratio <5%), purified by column chromatography on activity III neutral alumina (ICN), eluting with 5: 1 petroleum ether / ethyl methyl ketone. column. The product was a colorless oil, 4.1 g, 71% of theory. ¹ H-Nuclear magnetic resonance spectrum (200 MHz, CDCl ₃ , ppm): 1.5-2.0 (2m, 8H); 2.25 (s, 6H); 2.4-2.65 (m, 1H); 3.4 (s, 2H); 4.1-4.18 (m, 1H); 7.15-7.3 (m, 4H).

Reference Example 4 trans- 4- [4- (Chloromethyl-phenyl) -cyclohexyl] -acetate

a) 4-Phenylcyclohexanol

31.4 g (0.18 mol) of 4-phenylcyclohexanone are dissolved in 500 ml of anhydrous methanol, cooled to -10 ° C and 6.8 g (0.18 mol) of sodium ] tetrahydroborate]. After the addition, the reaction mixture was stirred at -10 ° C for 0.5 hour, then at room temperature for 3 hours, and then concentrated in vacuo. Water was added to the evaporation residue, acidified with 2M hydrochloric acid, and the resulting slurry was allowed to stir for 1 hour. The crystals were collected on a filter and filtered off with suction, dried and recrystallized from diisopropyl ether. The 21 g of 4-phenylcyclohexanol thus obtained have a melting point of 112-114 ° C, 66% of theory.

• · · · ·

b) (4-Phenylcyclohexyl) acetate

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 at room temperature was added 2.3 g (0.02 mol) of 4- (dimethylamino) ) -pyridine is added, which results in an exothermic reaction to form a clear crisp solution. After stirring for 3 hours at 80 ° C, the reaction mixture was poured into ice water, and the precipitated crystalline product was collected on a filter and filtered off with suction. The filtered product was dissolved in diethyl ether, washed with sodium bicarbonate solution, dried and then concentrated in vacuo. The resulting 23 g of (4-phenylcyclohexyl) acetate was initially an oil, but crystallized on standing, m.p. 43-45 ° C. The extraction

92% of what was calculated.

c) trans- 4- [4- (Chloromethyl) phenyl] cyclohexyl) acetate

To a solution of (4-phenylcyclohexyl) acetate (24.3 g, 0.11 mol) in methylene chloride (1300 mL) was added paraformaldehyde (26.0 g, 0.86 mol) and zinc chloride (26.0 g, 0.19 mol). . Hydrogen chloride was added to the resulting slurry with stirring for 2.5 hours, whereby the temperature rose to about 30 ° C and a homogeneous solution was obtained. This solution was allowed to stir at room temperature for an additional 15 hours, then quenched with ice water (approximately 1500 mL). The organic phase is separated off, the aqueous phase is extracted once more with dichloromethane, and the two solvent extracts are combined, washed neutral, dried and evaporated in vacuo. Evaporate. The residual oil was crystallized by trituration with diisopropyl ether and then recrystallized from diisopropyl ether. Yield: 12.7 g of a white crystalline product, m.p. 87-89 ° C.

43% of what is theoretically calculated.

Reference Example 5 Cis and trans- 4- [4 - {[N- (tert-Butoxycarbonyl) -N-methylamino] methyl} phenyl] cyclohexyl} - [(4-chlorophenyl) )-acetate]

a) 4-Hydroxy-4- {4 - [(methylamino) -methyl] -phenyl} -cyclohexanone-ethylene-acetal g (0.47 mol) 4-bromo-N-methyl-benzylamine in 460 ml of anhydrous solution of tetrahydrofuran in a nitrogen atmosphere,

At -30 to -25 ° C, 300 ml (0.48 mol) of a 1.6 M solution of butyllithium in hexane was added, followed by 52.5 g (0.48 mol) of chlorotrimethylsilane. The reaction mixture was stirred at this temperature for a further 15 minutes, cooled to -75 ° C, and treated with additional 320 ml (0.51 mol) of 1.6 M butyl lithium in hexane without increasing the temperature to -70 ° C. Above ° C. The mixture is allowed to stir for an additional 20 minutes at -75 ° C, then dropwise over a period of about 20 minutes at -65 ° C or 76 g (0.47 mol) of 1,4-cyclohexanedione mono ( ethylene acetal) in tetrahydrofuran (200 mL). The reaction mixture was stirred for an additional 30 minutes at -70 ° C and then, without external cooling, to a temperature of +20 ° C, then ice-cold aqueous ammonium chloride solution was added and the mixture was extracted several times with dichloromethane. . The combined organic solvent extracts were dried over sodium sulfate, then the solvent was evaporated and the crude product was recrystallized from diisopropyl ether. 77.0 g of 4-hydroxy-4- {4 - [(methylamino) methyl] phenyl} cyclohexanone ethylene acetal are obtained, m.p. 95-97 DEG C., 59% yield. a is theoretically calculated.

b) 4- (Ethylenedioxy) -1- {4 - [(methylamino) methyl] phenyl} -cyclohexene g (0.24 mol) 4-hydroxy-4- (4 - [(methylamino) ) -methyl] -phenyl} -cyclohexanone-ethylene-acetal, a mixture of 51 g (0.27 mol) of p-toluenesulfonic acid-water (1/1), 150 ml of ethylene glycol and 900 ml of toluene is heated under reflux with stirring, After 5 hours while continuously removing water from the system, the reaction mixture was cooled, basified to pH 12-13 with 1M sodium hydroxide solution, and the organic phase was separated and the aqueous layer was extracted several times with ethyl acetate. The combined organic solvent extracts were dried over sodium sulfate and concentrated in vacuo to afford 63 g of 4- (ethylenedioxy) -1- {4 - [(methylamino) methyl] phenyl} cyclohexene as a yellowish oil. yield approximately 100%.

c) 1- [4 - {[N- (tert-Butoxycarbonyl) -N-methylamino] methyl} phenyl] -4- (ethylenedioxy) cyclohexene g (0.24 mol). The ethylene dioxy) -1- {4 - [(methylamino) methyl] phenyl} cyclohexene crude product is dissolved in 350 ml of anhydrous tetrahydrofuran and stirred with cooling at 15 to 20 ° C. a solution of 58 g (0.26 mol) of di-tert-butyl dicarbonate in 100 ml of anhydrous tetrahydrofuran was added, and after the evolution of carbon dioxide had ceased, the reaction mixture was kept at room temperature for 10 hours and the solvent was evaporated in vacuo. The residue was stirred with water and extracted several times with diethyl ether, then the solvent extract was dried over sodium sulfate and evaporated to give 84 g of crude product as a yellow oil, 1- [4 - {[N- (tert-butoxycarbonyl) -N]. -methyl-amino] -methyl) -phenyl] -4- (ethylenedioxy) -cyclohexene, yield approx. most 100%.

d) 4- [4 - {[N- (tert-Butoxycarbonyl) -N-methylamino] -methyl) -phenyl] -cyclohexanone g (0.24 mol) was obtained as crude product 1- [4 - {[N - (tert-Butoxycarbonyl) -N-methylamino] -methyl) phenyl] -4-ethylenedioxy-cyclohexene was dissolved in a mixture of methanol (250 ml) and ethyl acetate (250 ml) and then barium sulphate (10 g). After the addition of a precipitated palladium catalyst, the solution was hydrogenated at room temperature under a hydrogen atmosphere of 3 bar for 4 hours. The catalyst was filtered off, the solvent was evaporated in vacuo and the residual oil was dissolved in a mixture of acetone (1400 mL) and water (140 mL). To the solution was added 8.5 g (0.034 mol) of pyridinium (4-toluenesulfonate), the mixture was refluxed for 15 hours, then the solvent was distilled off in vacuo, the residue was stirred with water and several times with methylene chloride. extraction with dichloride. The organic solvent extract of the individual organic extract was dried over sodium sulfate and evaporated to leave 61 g of a pale yellow oil. . The resulting oil, which solidifies with prolonged standing, is 4- [4 - {[N- (tert-butoxycarbonyl) -N-methylamino] methyl} phenyl] cyclohexanone, m.p. 55-57 ° C. C, 77% of theory as calculated.

e) 4- [4 - {[N- (tert-Butoxycarbonyl) -N-methylamino] methyl} phenyl] cyclohexanol (mixture of cis and trans isomers) g (0.035 mol) 4- [ 4 - {[N- (tert-Butoxycarbonyl) -N-methylamino] -methyl} -phenyl] -cyclohexanone is dissolved in 70 ml of anhydrous methanol, the solution is cooled to -10 ° C and then stirred in small portions. 1.31 g (0.035 mol) of sodium} tetrahydroborate are added. The reaction mixture was stirred at -10 ° C for 0.5 hour and then at room temperature for a further 2 hours and then concentrated in vacuo. Water was added to the evaporation residue, stirred at room temperature for 1 hour, and the resulting solid product was filtered off with suction, dissolved in ethyl acetate and dried over sodium sulfate. Evaporation of the solvent in vacuo left a mixture of cis and trans -4- [4 - {[N- (tert-butoxycarbonyl) -N-methylamino] methyl} phenyl] cyclohexanol as a colorless oil (8.6 g). , yield of 70% of theory. The isomer mixture was subjected to column chromatography,

Separated on neutral alumina (ICN), activity III, pure isomers, eluting with petroleum ether / ethyl acetate 3: 1.

The TLC _Rf: 0.21 (trans-isomer) and ···· * · · · · · · ·· • «·« «« • ♦ ··· «·« «* • ·· ·· ·

0.31 (cis-isomer); (alumina; petroleum ether: ethyl acetate = 3: 1).

f) {4- [4 - {[N- (tert-Butoxycarbonyl) -N-methylamino] methyl} phenyl] cyclohexyl} - [(4-chlorophenyl) acetate] (cis - and trans isomer mixture)

A mixture of (4-chlorophenyl) acetic acid (0.54 g, 0.0032 mol), N, Ν'-carbonyldiimidazole (0.52 g, 0.0032 mol) and xylene (20 ml) was heated at 60 ° C for 1 hour. stir. Subsequently, 0.85 g (0.0027 mol) of 4- [4 - {[N- (tert-butoxycarbonyl) -N-methylamino] -methyl) -phenyl] -cyclohexanol (cis and trans isomer a solution of 10 ml of xylene in the reaction mixture was added and the reaction was continued at 160 ° C for a further 8 hours. After cooling, the mixture was concentrated in vacuo, the residue was mixed with water and extracted with ethyl acetate. The organic solvent extract was dried over sodium sulfate and then the solvent was evaporated in vacuo. The resulting red-brown oil (1.3 g) was cis- and trans- (4- [4 - {[N- (tert-butoxycarbonyl) -N-methylamino] methyl} phenyl] cyclohexyl} -). (4-chlorophenyl) acetate] in approximately 100% yield.

The TLC _Rf: 0.78 (trans-isomer) and 0.85 (cis-isomer); alumina; petroleum ether: ethyl acetate = 3: 1).

In the same manner, trans-4- [4 - {[N- (tert-butoxycarbonyl) -N-methylamino] -methyl) -phenyl] -cyclohexanol in the presence of N, N'-carbonyldiimidazole (4-chloro) -phenyl) -acetic acid to prepare trans- 4- [4 - {[N- (tert-butoxycarbonyl) -N-methylamino] -methyl) -phenyl] -cyclohexyl) - [(4-chloro) (phenyl) acetate] which is a white crystalline solid, m.p. 94-96 ° C.

•>

. Example 4 Trans- [4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (4-chlorobenzoate)

A solution of trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol (1.0 g, 0.0043 mol) in triethylamine (0.6 ml) in dichloromethane (50 ml) was added dropwise with stirring. 4-Chlorobenzoyl chloride (0.75 g, 0.0043 mol) was added and the reaction mixture was refluxed for 3 hours. After the reaction time, the mixture was cooled, after addition of 50 ml of water, the pH was adjusted to 12 to 13 with sodium hydroxide, the dichloromethane layer was separated and the aqueous portion was extracted once more with dichloromethane. The combined organic solvent extracts were dried over sodium sulfate and concentrated in vacuo. The resulting white crystalline product, m.p. 94-95 ° C, was 1.1 g, 69% of theory.

1 H-Nuclear Magnetic Resonance Spectrum (200 MHz, CDCl ₃ , ppm): 1.55-1.8 (m, 4H); 1.9-2.1 (m, 2H); 2.15-2.3 (s + m, 6 + 2H); 2.5-2.7 (m, 1H); 3.4 (s, 2H);

4.9-5.1 (m, 1H); 7.15-7.3 (m, 4H); 7.4 (d, 2H); 8.0 (d, 2H).

The following compounds were prepared in the same manner:

(1) Trans- [4- {4 - [(Dimethylamino) -methyl] -phenyl} -cyclohexyl] -acetate · · · · · trans-4- {4 - [(Dimethylamino) -methyl] - phenyl} -cyclohexanol and acetyl chloride are reacted in the presence of triethylamine. The product is a colorless syrup.

1 H NMR (200 MHz, CDCl ₃ , ppm): 1.45-1.7 (m, 4H); 1.9-2.05 (m, 2H); 2.05-2.15 (s + m, 3 + 2H); 2.33 (s, 6H); 2.4-2.65 (m,

1H); 3.4 (s, 2H); 4.7-4.9 (m, 1H); 7.1-7.3 (m, 4H).

(2) reacting trans- [4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] butyrate with trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol; in the presence of triethylamine with butyryl chloride. The product is a colorless oil.

¹H-NMR (200 MHz, CDC1 ₃ , ppm): 0.9-1.02 (t, 3H); 1.45 -1.75 (m, 6H); 1.89-2.05 (m, 2H) ; 2.05-2.18 (m, 2 H); 2.18-2.38 (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) reacting trans- 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] cyclopropanecarboxylate with trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol. in the presence of triethylamine with cyclopropanecarbonyl chloride. The product obtained is a colorless wax.

1 H NMR (200 MHz, CDCl ₃ , ppm): 0.81-0.87 (m, 2H); 0.95-1.02 (m, 2H); 1.45-1.7 (m, 4H); 1.9-2.0 (m, 2H); 2.05-2.15 (m, 2H); 2.24 (s, 6H); 2.4-2.63 (2m, 2H); 3.4 (s, 2H); 4.73-4.83 (m,

1H); 7.12-7.25 (m, 4H).

(4) trans-} 4- {4 - [(Dimethylamino) -methyl] -phenyl} -cyclohexyl] -cyclohexanecarboxylate trans-4- {4 - [(Dimethylamino) -methyl] -phenyl} -cyclohexanol in the presence of triethylamine with cyclohexanecarbonyl chloride. The product is a white crystalline solid, m.p. 66-68 ° C.

(5) cis} 4- {4-} (dimethylamino) methyl] phenyl} cyclohexyl] - [(4-chlorophenyl) acetate] cis -4- {4 - [(Dimethylamino) ) -methyl] -phenyl} -cyclohexanol is reacted with (4-chlorophenyl) acetyl chloride in the presence of triethylamine. The product obtained is a colorless oil.

1 H NMR (200 MHz, CDCl ₃ , ppm): 1.5-1.75 (m, 6H); 1.88-2.05 (m, 2H); 2.25 (s, 6H); 2.4-2.65 (m, 1H), 3.4 (s, 2H); 3.65 (s, 2H); 5.05-5.15 (m, 1H); 7.08 (d, 2H); 7.2-7.4 (m, 6H).

(6) trans-} 4-} 4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (4-phenyl-3-butenoate) trans -4- {4 - [(Dimethylamino) - methyl] phenyl} cyclohexanol is reacted with 4-phenyl-3-butenoyl chloride in the presence of triethylamine. 90-91 ° C.

(7) cis} 4-} 4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (4-phenyl-3-butenoate)

In the presence of triethylamine, cis-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol is reacted with 4-phenyl-3-butenoyl chloride. M.p. 71-73 ° C.

• «· · · · · · · · · · · · · · · · · ·

Example 2 Trans- [4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - [(4-chlorophenyl) acetate]

To a mixture of (4-chlorophenyl) acetic acid (0.43 g, 0.025 mol) in xylene (30 ml) was added N, Ν'-carbonyldiimidazole (0.41 g, 0.025 mol) to give carbon dioxide. as it develops, a white product is formed. The reaction mixture was stirred for 1 hour at 60 ° C and then trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol (0.5 g, 0. 0021 mol) was added, followed by 160 ° C. stirring is continued for another 12 hours. After the reaction time, the mixture was cooled to room temperature, water was added and the pH was

Make up to 12-13 with M sodium hydroxide solution. The xylene layer is separated, the aqueous portion is extracted several times with ethyl acetate, and the combined organic solvent extracts are dried and concentrated in vacuo. The resulting solid crude product was purified by column chromatography on activity III, basic alumina (ICN), eluting with 10: 1 petroleum ether / ethyl acetate. This gives 0.7 g of a white crystalline solid, m.p. 75-77 ° C, 86% of theory.

1 H-Nuclear magnetic resonance spectrum (200 MHz, CDCl ₃ , 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, 2H); 3.6 (s,

2 H) ; 4.7-4.9 (m, 1H); 7.1-7.35 (m, 8H).

Following the same procedure, the following compounds were synthesized:

• · * (1) trans-} 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (5-methylhexanoate)

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and 5-methylhexanoic acid are reacted. The white crystalline product has a melting point of 35-36 ° C.

(2) cis} 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (5-methylhexanoate)

In the presence of?,? - carbonyldiimidazole, cis -4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and 5-methylhexanoic acid are reacted. The product is a colorless oil.

H NMR (200 MHz, CDCl ₃ , ppm) : 0.9 (D, 6H); 1.15-1.32 (m, 2 H); 1.5 to 1.88 (m, 9H); 1.95-2.1 (m, 2 H) ; 2.25 (s, 6H); 2.3 (d, 2 H); 2.48 to 2.69 (m, 1H); 3.4 (s, 2H); 5, 08- 5, 18 (m, 1H); 7.12 to 7.3

(m, 4H).

(3) trans- {4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] (cyclohexyl acetate)

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and cyclohexylacetic acid are reacted. The white crystalline product has a melting point of 37-39 ° C.

(4) trans-} 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (2-butenoate)

In the presence of N, N'-carbonyldiimidazole, trans-4-} 4 - [(dimethylamino) methyl] phenyl} cyclohexanol and crotonic acid are reacted. The white crystalline product has a melting point of 69-71 ° C.

• · *

• · · · «« · · · · · ·················································································· ((5) trans-] 4- {4- [(Dimethylamino) -methyl] -phenyl} -cyclohexyl] - (2-hexanoate)

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl] cyclohexanol and 2-hexenoic acid are reacted. The white crystalline product has a melting point of 40-42 ° C.

(6) trans-] 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (3-cyclohexyl acrylate)

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - ((dimethylamino) methyl] phenyl) cyclohexanol and 3-cyclohexylacrylic acid are reacted. The white crystalline product has a melting point of 46-47 ° C.

(7) Trans-] 4- {4 - [(Dimethylamino) methyl] phenyl] cyclohexyl] benzoate

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and benzoic acid are reacted. The white crystalline product has a melting point of 68-70 ° C.

(8) Trans-] 4- {4-] (Dimethylamino) -methyl] -phenyl} -cyclohexyl] - (4-chloro-3-methyl-benzoate)

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and 4-chloro-3-methylbenzoic acid are reacted. Melting point of white crystalline product:

Mp 100-102 ° C.

(9) trans- 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (2-naphthoate)

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and 2-naphthoic acid are reacted. The white crystalline product has a melting point of 110-112 ° C.

(10) trans-) 4- (4-) (Dimethylamino) methyl] phenyl} cyclohexyl] (phenylacetate)

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl] cyclohexanol and phenylacetic acid are reacted. The white crystalline product has a melting point of 38-40 ° C.

(11) trans-) 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (4-fluorophenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl}} cyclohexanol and (4-fluorophenyl) acetic acid are reacted. Melting point of white crystalline product:

68-70 ° C.

(12) cis) 4- (4- (dimethylamino) methyl] phenyl} cyclohexyl] - [(4-fluorophenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, cis-4- (4-) (dimethylamino) methyl] phenyl] cyclohexanol and (4-fluorophenyl) acetic acid are reacted. The product is a colorless oil.

1 H NMR (200 MHz, CDCl ₃ , ppm): 1.5-1.75 (m, 6H); 1.85-2.05 (m, 2H); 2.3 (s, 6H); 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- {4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - [(4-bromophenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and (4-bromophenyl) acetic acid are reacted. The white crystalline product has a melting point of 72-74 ° C.

(14) trans-} 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl]} (3,4-dichlorophenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl] cyclohexanol and (3,4-dichlorophenyl) acetic acid are reacted. Melting point of white crystalline product:

95-97 'C.

(15) cis} 4- {4-} (dimethylamino) methyl] phenyl) cyclohexyl] - [(3,4-dichlorophenyl acetate)

In the presence of N, N'-carbonyldiimidazole, cis-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and (3,4-dichlorophenyl) acetic acid are reacted. The product is a colorless oil.

1 H NMR (200 MHz, CDCl ₃ , ppm): 1.5-1.75 (m, 6H); 1.9-2.05 (m, 2H); 2.28 (s, 6H); 2.4-2.65 (m, 1H); 3.4 (s, 2H); 3.62 (s,

2 H) ; 5.8-5.17 (m, 1H); 7.05-7.3 (m. 5H); 7.35-7.49 (m, 2H).

(16) trans- {4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - [(2,4-dichlorophenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethyl-54-methylamino) -methyl] -phenyl} -cyclohexanol and (2,4-dichlorophenyl) -acetic acid are reacted. Melting point of white crystalline product:

78-80 ° C.

(17) trans- {4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - [(4-tolyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4-} (dimethylamino) methyl] phenyl] cyclohexanol and (4-tolyl) acetic acid are reacted. The white crystalline product has a melting point of 40-42 ° C.

(18) trans- {4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - {[4- (trifluoromethyl) phenyl] acetate}

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl] cyclohexanol and [4- (trifluoromethyl) phenyl] acetic acid are reacted. The white crystalline product had a melting point of 73-75 ° C.

(19) trans-} 4-} 4-} (dimethylamino) methyl] phenyl] cyclohexyl] -} (4-methoxyphenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl] cyclohexanol and (4-methoxyphenyl) acetic acid are reacted. Melting point of white crystalline product:

47-49 ° C.

(20) trans-} 4-} 4-} (dimethylamino) methyl] phenyl} cyclohexyl] - [(4-nitrophenyl) acetate]

In the presence of N, N '-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and (4-nitrophenyl) acetic acid are reacted. A yellowish crystalline product is obtained, m.p. 136-137 ° C.

(21) Trans-] 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - [3- (4-fluorophenyl) propionate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and 3- (4-fluorophenyl) propionic acid are reacted. The white crystalline product has a melting point of 58-59 ° C.

(22) Trans-] 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - [3- (4-chlorophenyl) propionate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and 3- (4-chlorophenyl) propionic acid are reacted. Melting point: 85-87 ° C, white crystalline product.

(23) trans-] 4- {4 - [(Dimethylamino) -methyl] -phenyl) -cyclohexyl] - [(4-biphenylyl) -acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and (4-biphenylyl) acetic acid are reacted. Melting point of white crystalline product:

88-89 ° C.

(24) trans-] 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - [(2-naphthyl) acetate] • · · ··

In the presence of?,? - carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and (2-naphthyl) acetic acid are reacted. Melting point: 85-87 ° C, white crystalline product.

(25) trans- {4- {4 - [(Dimethylamino) -methyl] -phenyl} -cyclohexyl] - (1,2,3,4-tetrahydro-2-naphthoate)

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and 1,2,3,4-tetrahydro-2-naphthoic acid are reacted. The white crystalline product has a melting point of 95-96 ° C.

(2 6) cis [4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] -1,2,3,4-tetrahydro-2-naphthoate)

In the presence of N, N'-carbonyldiimidazole, cis-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and 1,2,3,4-tetrahydro-2-naphthoic acid are reacted. The product is a colorless oil.

1 H NMR Spectrum (200 MHz, CDCl ₃ , ppm): 1.55-1.85 (m, 6H); 1.9-2.1 (m, 3H); 2.15-2.32 (s + m, 6 + 1H); 2.4-2.65 (m, 1H); 2.72-2.95 (m, 3H); 3.05 (d, 2H); 3.4 (s, 2H); 5.1-5.2 (m, 1H); 7.05-7.3 (2m, 8H).

(27) trans- {4- {4 - [(Dimethylamino) -methyl] -phenyl} -cyclohexyl] - (2-phenyl-propionate)

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and 2-phenylpropionic acid are reacted. The product is colorless wax.

1 H NMR (200 MHz, CDCl ₃ , ppm): 1.25-1.7 (d + m, 3 + 3H);

• ··. *

1.8 - 2.15 (m, 5H); 2.3 (s, 6H); 2.38-2.6 (m, 1H); 3.4 (s, 2H)

3.7 (q, 1H); 4.68-4.9 (m, 1H); 7.15 (d, 2H); 7.18-7.38 (d + m + 5H).

(28) cis] 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (2-phenylpropionate)

In the presence of N, N'-carbonyldiimidazole, cis -4- {4 - [(dimethyl

-amino) -methyl] -phenyl} -cyclohexanol and 2-phenylpropionic acid are reacted. The product is a colorless oil.

1 H-Nuclear magnetic resonance spectrum (200 MHz, CDCl ₃ , ppm): 1.3-1.7 (d + m, 3 + 6H)

1.8 - 2.05 (m, 2H); 2.25 (s, 6H); 2.35-2.58 (m, 1H); 3.4 (s, 2H)

3.78 (q, 1H); 5.0-5.1 (m, 1H); 7.0 (d, 2H); 7.2 (d, 2H)

7.25-7.4 (m, 5H).

(2 9) trans-] 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (4

-fluoro-cinnamate)

In the presence of N, N'-carbonyldiimidazole, trans-4- {4-] (dimethylamino) methyl] phenyl} cyclohexanol and 4-fluorocinnamic acid are reacted. The white crystalline product has a melting point of 118-120 ° C.

(30) cis] 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (4-fluorocinnamate)

In the presence of N, N'-carbonyldiimidazole, cis -4- {4 - [(dimethyl

-amino) -methyl] -phenyl} -cyclohexanol and 4-fluoro-cinnamic acid are reacted. The white crystalline product m.p. 66-68 ° C.

(31) Trans-] 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (4-chlorocinnamate)

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and 4-chloro-cinnamic acid are reacted. The white crystalline product melted at 131-133 ° C.

(32) cis} 4- {4-] (dimethylamino) methyl] phenyl} cyclohexyl] - (4-chlorocinnamate)

In the presence of N, N'-carbonyldiimidazole, cis-4- (4 - [(dimethylamino) methyl] phenyl} -cyclohexanol and 4-chloro-cinnamic acid are obtained, m.p. 88-90 ° C.

(33) trans-] 4- {4-] (Dimethylamino) methyl] phenyl} cyclohexyl] - [4- (trifluoromethyl) cinnamate]

In the presence of N, N'-carbonyldiimidazole, trans-4-] 4 - [(dimethylamino) methyl] phenyl} cyclohexanol and 4- (trifluoromethyl) cinnamic acid are reacted. Melting point of white crystalline product:

134-136 'C.

(34) cis] 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] [4- (trifluoromethyl) cinnamate]

In the presence of N, N'-carbonyldiimidazole, cis-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and 4- (trifluoromethyl) cinnamic acid are reacted. Melting point of white crystalline product:

61-63 ° C.

«<> ** • ··· · · · · · ··························································································································································· (·) 4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (5-chloro-2-tenoate)

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl) cyclohexanol and 5-chloro-2-thiophenecarboxylic acid are reacted. Melting point of white crystalline product:

95-97 'C.

(3 6) trans 4 - {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] nicotine

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl) cyclohexanol and nicotinic acid are reacted. The white crystalline product melts at 86-88 ° C.

(37) trans 4 - {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (2-furancarboxylate)

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl) cyclohexanol and 2-furancarboxylic acid are reacted. The white crystalline product melts at 58-60 ° C.

(38) Trans- [4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - [(3,4-dimethoxyphenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4/4 - [(dimethylamino) methyl] phenyl} cyclohexanol and (3,4-dimethoxyphenyl) acetic acid are reacted. The white crystalline product melts at 32-34 ° C.

• ·· «

9 · 39 (trans) 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - [(4-amino-3-chlorophenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and (4-amino-3-chlorophenyl) acetic acid are reacted. The white crystalline product melts at 83-85 ° C.

(40) trans- {4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - [(4-amino-3,5-dichlorophenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and (4-amino-3,5-dichlorophenyl) acetic acid are reacted. The white crystalline product has a melting point of 78-80 ° C.

(41) trans- {4- {4 - [(Diethylamino) methyl] phenyl} cyclohexyl] - [(4-chlorophenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4-} (diethyl-amino) -methyl] -phenyl} -cyclohexanol and (4-chlorophenyl) -acetic acid are reacted. The product is a colorless oil.

1 H-Nuclear magnetic resonance spectrum (200 MHz, CDCl 3 δ, ppm): 1.05 (t, 6H); 1.4-1.72 (m, 4H); 1.9-2.2 (m, 4H); 2.4-2.6 (q + m, 5H); 3.5 (s, 2H); 3.6 (s

2 H); 4.7-4.9 (m, 1H); 7.12 (d, 2H); 7.18-7.35 (m, 6H).

(42) trans- {4- {4-} (Dipropylamino) methyl] phenyl} cyclohexyl] - [(4-chlorophenyl) acetate]

In the presence of N, N '-carbonyldiimidazole, trans-4- {4 - [(dipropylamino) methyl] phenyl} cyclohexanol and (4-chlorophenyl) acetic acid. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The product is a colorless oil.

1 H-Nuclear magnetic resonance spectrum (200 MHz, CDCl ₂ , 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,

2 H) ; 3.6 (s, 2H); 4.7-4.9 (m, 1H); 7.1 (d, 2H); 7.15-7.38 (m,

6H).

(43) trans 4 - {4 - [(N-Butyl-N-methylamino) methyl] phenyl} cyclohexyl] - [(4-chlorophenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(N-butyl-N-methylamino) methyl] phenyl} cyclohexanol and (4-chlorophenyl) acetic acid are reacted. The product is a colorless oil. 1 H-NMR (200 MHz, CDCl ₃ , ppm): 0.9 (t, 3H); 1.2-1.7 (m, 8H); 1.8-2.15 (m, 4H); 2.18 (s, 3H); 2.35 (t, 2H); 2.4-2.6 (m,

1H); 3.41 (s, 2H); 3.6 (s, 2H); 4.7-4.9 (m, 1H); 7.1 (d, 2H);

7.2-7.35 (m, 6H).

(44) trans 4 - {4 - [(Diallylamino) methyl] phenyl} cyclohexyl] - [(4-chlorophenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(diallylamino) methyl] phenyl} cyclohexanol and (4-chlorophenyl) acetic acid are reacted. The product is a colorless oil.

1 H-Nuclear magnetic resonance spectrum (200 MHz, CDCl ₃ , ppm): 1.4-1.75 (m, 4H); 1.9-2.2 (m, 4H); 2.4-2.6 (m, 1H); 3.0-3.18 (dd, 4H); 3.5 (s, 2H); 3.6 (s, 2H); 4.7-4.9 (m, 1H); 5.1-5.3 (m, 4H); 5.75-6.0 (m, 2H);

7.12 (d, 2H); 7.15-7.38 (m, 6H).

• · »· ·

-62 (45) trans-] 4- {4-] (1-Pyrrolidinyl) methyl] phenyl} cyclohexyl] - [(4-chlorophenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(1-pyrrolidinyl) methyl] phenyl} cyclohexanol and (4-chlorophenyl) acetic acid are reacted. Melting point of white crystalline product:

57-59 ° C.

(46) trans-] 4- [4- (Piperidinomethyl) phenyl] -cyclohexyl} - [(4-chlorophenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- [4- (piperidinomethyl) phenyl] cyclohexanol and (4-chlorophenyl) acetic acid are reacted. The white crystalline product has a melting point of 87-89 ° C.

(47) trans-] 4- [4- (Morpholinomethyl) phenyl] -cyclohexyl} - (4-chlorophenyl) acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- [4- (morpholinomethyl) phenyl] cyclohexanol and (4-chlorophenyl) acetic acid are reacted. The white crystalline product melted at 114-116 ° C.

(48) trans-] 4- {4- ~ (4-Methyl-piperazin-1-yl) -methyl] -phenyl} -cyclohexyl] -] (4-chloro-phenyl) -acetate]

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(4-methylpiperazin-1-yl) methyl] phenyl} cyclohexanol and (4-chlorophenyl) acetic acid are reacted. The white crystalline product has a melting point of 97-99 ° C.

 (49) trans- {4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] {[3,4-methylenedioxyphenyl] acetate}

In the presence of N, N'-carbonyldiimidazole, trans-4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol and [3,4-methylenedioxyphenyl] acetic acid are reacted. The product is a colorless oil.

1 H NMR (200 MHz, CDCl ₃ , ppm): 1.4-1.7 (m, 4H); 1.8-2.0 (m, 2H); 2.0-2.15 (m, 2H); 2.25 (s, 6H); 2.4-2.6 (m, 1H); 3.38 (s, 2H); 3.5 (s, 2H); 4.7-4.9 (m, 1H); 5.94 (s, 2H); 6.7-6.85 (m, 3H); 7.1-7.3 (m, 4H).

Example 3 cis} 4- {4-} (Dimethylamino) methyl] phenyl} cyclohexyl] - (4-chlorobenzoate)

O, 24 g (0.001 mol) of cis -4- {4 - [(dimethylamino) methyl] phenyl} cyclohexanol, 0.34 ml (0.0025 mol) of triethylamine and 0.12 g (0.001 mol) mole) (dimethylamino) pyridine was dissolved in methylene chloride (20 ml) and 4-chlorobenzoyl chloride (0.175 g, 0.001 mole) was added. After stirring for 12 hours at room temperature, water was added and the pH was adjusted to 12 to 13 with sodium hydroxide. The methylene chloride phase is separated off and the aqueous phase is extracted several times with methylene chloride. The combined organic solvent extracts were washed with brine, dried, and evaporated in vacuo. The residue was purified by column chromatography on activity III, neutral alumina (ICN), eluting with petroleum ether / ethyl acetate 45: 1. This gave 0.27 g of white crystalline ··· ··· «· ♦ * · ·« ·. . ······ ♦♦ ··. Ad - ·········· ', m.p. 96-97 ° C, 73% of theory.

Nuclear Magnetic Resonance Spectrum (200 MHz, CDCl ₃ , 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, 2H); 8.2 (d, 2H).

Example 4 Trans- [4 - {[(Diethylamino) -methyl] -phenyl} -cyclohexyl] -acetate g (3.75 mmol) trans- 4- [4- (chloromethyl) -phenyl] - cyclohexyl} acetate in 10 ml of N, N-dimethylformamide

0.52 g (3.75 mmol) of potassium carbonate and 0.27 g (3.75 mmol) of diethylamine are added. After stirring for 6 hours at 50 ° C, water was added and the mixture was extracted with dichloromethane. The organic phase was dried, evaporated in vacuo and the residue was purified by column chromatography on activity III, basic alumina (ICN) eluting with 15: 1 petroleum ether / ethyl acetate. This gives 0.79 g of a colorless oil, 69% of theory.

1 H-Nuclear Magnetic Resonance Spectrum (200 MHz, CDCl ₃ , ppm): 1.05 (t, 6H); 1.45-1.75 (m, 4H); 1.9-2.2 (s + m, 7H); 2.4-2.6 (q + m, 5H); 3.55 (s, 2H);

4.68-4.9 (m, 1H); 7.12 (d, 2H); 7.28 (d, 2H).

The following compounds were prepared in the same manner:

(1) trans-] 4-] 4 - [(Dipropylamino) methyl] phenyl} cyclohexyl] acetate

The title compound is trans-] 4- [4- (chloromethyl) • · · * «

-phenyl] -cyclohexyl] -acetate and dipropylamine.

The product is a colorless oil.

¹ H NMR Spectrum (200 MHz, CDCl ₃ , ppm): 0.9 (t, 6H); 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, 2H); 7.25 (d, 2H).

(2) trans} 4- {4 - [(N-butyl-N-methylamino) methyl] phenyl} cyclohexyl] acetate

The compound was prepared from trans- 4- [4- (chloromethyl) phenyl] cyclohexyl] acetate and N-methylbutylamine. The product is a colorless oil.

¹ H NMR (200 MHz, CDCl ₃ , ppm): 0.9 (t, 3H); 1.2-1.75 (m,

10H); 1.9-2.2 (2s + m, 8H); 2.38 (t, 2H); 2.4-2.6 (m, 1H); 3.45 (s, 2H); 4.7-4.9 (m, 1H); 7.15 (d, 2H); 7.25 (d, 2H).

(3) trans-} 4- {4 - [(Dallyl-amino) -methyl] -phenyl} -cyclohexyl] -acetate

The compound was prepared from trans} 4- [4- (chloromethyl) phenyl] cyclohexyl} acetate and diallylamine. The product is a colorless oil.

H NMR (200 MHz, CDCl ₃ , ppm) :% 4-1,7 (m, 4H); 1.9-2, 18 (s + m, 7H); 2.4-2.6 (m, 1H); 3 Δ 9 (dd, 4H); 3.52 (s, 2H); 4.7-4.9 (m, 1H) ; 5.01-5.3 (m, 4H); 5.75-6.0 (m, 2 H) ; 7.12 (d,

2 H); 7.35 (d, 2H).

Cetate (4) trans-} 4- {4 - [(1-Pyrrolidinyl) methyl] phenyl} -cyclohexyl] -α ♦ · 5

The compound was prepared from trans- 4- [4- (chloromethyl) phenyl] cyclohexyl] acetate and pyrrolidine. Colorless crystalline product, m.p. 43-45 ° C.

(5) trans-) 4-) 4- (Morpholinomethyl) phenyl] cyclohexyl} acetate

The compound is prepared from trans- 4- [4- (chloromethyl) phenyl] cyclohexyl} acetate and morpholine. Colorless crystalline product, m.p. 53-55 ° C.

(6) trans- 4- [4- (piperidinomethyl) phenyl] cyclohexyl} acetate

The compound was prepared from trans- 4- [4- (chloromethyl) phenyl] cyclohexyl} acetate and piperidine. M.p. 62-64 ° C.

(7) trans-) 4-) 4-} (4-Methyl-piperazin-1-yl) -methyl] -phenyl} -cyclohexyl] -acetate

The compound was prepared from trans- 4- [4- (chloromethyl) phenyl] cyclohexyl} acetate and N-methylpiperazine. The colorless crystalline product has a melting point of 50-52 ° C.

Example 5 Trans-) 4- {4 - [(Methylamino) methyl] phenyl} cyclohexyl] - [(4-chlorophenyl) acetate]

8.9 g (0.019 mole) of trans- 4- [4 - {[N- (tert-butoxycarbonyl) -N-methylamino] methyl} phenyl] cyclohexyl} - [(4-chloro) (Phenyl) acetate] in methylene chloride (200 mL) was added trifluoroacetic acid (35 mL), the mixture was allowed to stir at room temperature for 2 hours and the volatiles were evaporated in vacuo. The residue was dissolved in dichloromethane and washed neutral with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate, evaporated in vacuo and the residual yellowish oil purified by column chromatography on basic alumina (ICN), activity III, eluting with 10: 10: 1 petroleum ether / ethyl acetate / methanol. . 6.4 g of a yellowish white crystalline product, m.p. 65-67 ° C, 91% of theory.

Nuclear Magnetic Resonance Spectrum (200 MHz, CDCl ₃ , ppm): 1.4-1.7 (m, 4H); 1.8-2.0 (m, 2H); 2.0-2.2 (m, 2H); 2.4-2.6 (s + m, 3 + 1H); 3.58 (s, 2H);

3.7 (s, 2H); 4.7-4.9 (m, 1H); 7.1-7.35 (m, 8H).

In a similar manner, the following compound is prepared:

(1) [4- {4 - [(Methylamino) -methyl] -phenyl) -cyclohexyl] - [(4-chlorophenyl) -acetate] (mixture of cis and trans isomers)

The compound was cis- and trans- 4- [4 - {[N- (tert-butoxycarbonyl) -N-methylamino] methyl) phenyl] cyclohexyl) - [(4-chlorophenyl) - acetate) with trifluoroacetic acid. The product is yellow oil.

TLC _Rf Rf: 0.28 to 0.53 (alumina; petroleum ether: ethyl acetate: methanol = 10: 10: 1).

Example 6 (4- [4 - {[N- (Carbamoylmethyl) -N-methylamino] methyl) phenyl] cyclohexyl} - [(4-chlorophenyl) acetate] (cis and trans isomer mixture)

1.0 g (0, 0027 mol), cis- and trans] 4- {4- [(methylamino) -68 • · · · · · · · _β • ······ .. «·

-methyl] -phenyl] -cyclohexyl] - [(4-chlorophenyl) -acetate] isomeric mixture: 0.5 g (0.0277 mole) of iodoacetamide, 0.37 g (0.0277 mole) of potassium. carbonate and 5 ml of N, N-dimethylformamide are added and the mixture is stirred for 2 hours at 50 ° C. After cooling, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic solvent extract was dried over sodium sulfate, then the volatiles were evaporated in vacuo, and the residue was purified by column chromatography on activity III basic alumina (ICN), petroleum ether, ethyl acetate 2: methanol 60: Eluting the column with 5 ratios. The white crystalline product thus obtained shrinks at 110 ° C and melts at 128-132 ° C.

1 H-Nuclear magnetic resonance spectrum (200 MHz, CDCl ₃ , + CD ₃ OD, ppm): 1.4-1.75 (m, 5H);

1.8-2.2 (m, 3H); 2.32 (dd, 3H); 2.4-2.63 (m, 1H); 3.0 (dd, 2H);

3.5-3.7 (dd + dd, 2 + 2H); 4.7-4.9 (m, 0.5H); 5.08-5.15 (m,

0.5H); 7.0-7.4 (m, 8H).

The following compounds were prepared in the same manner:

(1) trans-} 4- {4 - [{N - [(Ethoxycarbonyl) methyl] -N-methylamino] methyl] phenyl] cyclohexyl] - [(4-chlorophenyl) - acetate]

In N, N-dimethylformamide, in the presence of potassium carbonate, trans- 4- {4 - [(methylamino) methyl] phenyl} cyclohexyl] - [(4-chlorophenyl) acetate] and ethyl bromoacetate. White solid, m.p. 40-42 ° C.

(2) trans-} 4- [4- {} N- (3-Hydroxypropyl) -N-methylamino] methyl} phenyl] cyclohexyl} - [(4-chlorophenyl) acetate] • · ·· • · · ·

-69 - "

In N, N-dimethylformamide in the presence of potassium carbonate, trans- 4- {4 - [(methylamino) methyl] phenyl} cyclohexyl] - [(4-chlorophenyl) acetate] and 3-Bromopropanol is reacted. The white crystalline product had a melting point of 75-77 ° C.

Example 7 trans- 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - [(4-chlorophenyl) acetate] hydrochloride

0. 39 g (0.001 mol) of trans- 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - [(4-chlorophenyl) acetate] are dissolved in 10 ml of diethyl ether. ether, followed by stirring at room temperature with a 1.5 molar amount of hydrogen chloride in a solution in isopropyl alcohol. The resulting precipitated mixture was kept at room temperature for a further 1 hour, then the salt was collected on a filter, filtered off with suction, rinsed several times with diethyl ether and finally dried. The white crystalline product thus obtained m.p. 231-233 ° C; mass 0.32 g, 76% of theory.

Example 8 Trans-] 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - (4-chlorophenyl) acetate] tartrate Dissolve 0.15 g of anhydrous ethanol. Anhydrous tartaric acid (0.001 mol) followed by trans] 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] [(4-chlorophenyl) acetate] (0.39 g, 0.001 mol) -five. The initially clear, clear solution is slightly cloudy, then diethyl ether is added and the mixture is kept at + 4 ° C for 8 hours. The precipitated crystals are then collected on a filter, suctioned off, washed with diethyl ether and finally dried. M.p. 169-171 ° C; weighing 0.46 g, 86% of theory.

Example 9 Preparation of a tablet containing mg trans- 4- {4 - [(dimethylamino) methyl] phenyl} -cyclohexyl] - [(4-chlorophenyl) acetate]

Concatenated Composition:

Each tablet contains:

agent 5, 0 mg Milk sugar 148.0 mg potato starch 65.0 mg Magnesium stearate 2, 0 mg

220.0 mg

Preparation:

The potato starch is heated to make 10% mucus. The active ingredient, the lactose and the potato starch residue are mixed and then granulated with the above mica using a 1.5 mm mesh sieve. The granulate is dried at 45 ° C, then broken through the sieve again, finally mixed with magnesium stearate and compressed into tablets. Tablet weight: 220 mg, stamp diameter: 9 mm.

• ·

Example 10 Preparation of a dragee containing mg of trans) 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] [(4-chlorophenyl) acetate]

The tablet, prepared as described in Example 9, is coated according to one of the known methods and consists essentially of sugar and talc. The finished dragee is finally polished with beeswax. Weight of each dragee: 300 mg.

Example 11 Preparation of a suppository containing trans-) 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - (4-chlorophenyl) acetate]

Ingredients:

Each cone contains the following ingredients:

Active ingredient 5.0 mg

Suppository base (e.g. Witepsol W 45) is 1,695.0 mg

700.0 mg

Preparation:

The finely divided active ingredient is uniformly distributed in the molten supernatant and cooled to 40 ° C, and the suspension is poured into slightly pre-cooled suppository molds at 37 ° C. Weight of the suppository thus obtained: 1.7 g.

> »·

Example 12 Preparation of a capsule containing mg trans- 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] {[4- (trifluoromethyl) phenyl] acetate}

Ingredients:

Each capsule contains:

agent 5 0 mg Lactose 82 0 mg Starch 82 0 mg Magnesium stearate 1 0 mg 170 0 mg

Preparation:

The powdered materials are thoroughly mixed and the powder mixture is filled into a size 3 hard gelatin capsule consisting of two slidable parts using a capsule filling machine. The weight of the capsules is continuously monitored during the operation.

. Example 1 Preparation of a tablet containing mg trans- 4- {4 - [(Dimethylamino) methyl] phenyl} cyclohexyl] - [(4-bromophenyl) acetate]

Ingredients:

Each tablet contains:

Active ingredient 5.0 mg

Milk sugar

148.0 mg • · • · · · ·

Potato starch 65.0 mg

Magnesium stearate 2.0 mg

220.0 mg

Preparation:

The potato starch is heated to make 10% mucus. The active ingredient, the lactose and the potato starch residue are mixed and, after working with the above mucilage, the mixture is granulated using a 1.5 mm mesh sieve. The granulate is dried at 45 ° C, then broken through the sieve again, finally mixed with magnesium stearate and compressed into tablets. Each tablet weighs 220 mg and has a diameter of 9 mm.

Example 14 Preparation of a topical ointment from g trans} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] [(4-chlorophenyl) acetate]

A topical formulation containing an active ingredient of formula (I) may contain the following ingredients:

agent 1.0 Stearyl alcohol 4.0 Cetyl alcohol 4.0 petroleum 3, 0 Polysorbate 60 4.5

Sorbitan Stearate

4.5g • · • · · ·

propylene

Methyl (4-hydroxybenzoate)

Propyl (4-hydroxybenzoate)

Water as needed

10.0 g

0.18 g

0.02 g

To 100.00 g

Stearyl alcohol, cetyl alcohol, mineral oil, polysorbate 60 and sorbitan stearate are blended and the mixture is heated to 80 ° C and maintained at this temperature until all ingredients are melted. The active ingredient is dissolved in the oily mixture. Methyl and propyl (4-hydroxybenzoate) are dissolved in propylene glycol / water at 90 ° C, and the aqueous phase is then added to the oil phase with rapid stirring. An emulsion is formed which is slowly cooled to 50 ° C to solidify. The composition is then further stirred while cooling to room temperature.

Example 15

Active ingredient for laying hens containing trans- 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] [(4-chlorophenyl) acetate]

Ingredients:

Maize 633 g / kg Weave aloe 260 g / kg meat meal 40 g / kg Fat feed 25 g / kg Soybean oil 17 g / kg Calcium hydrogen phosphate 12 g / kg

• · · · ·

Calcium carbonate 6 g / kg

Vitamin-mineral mixture 5 g / kg

Active ingredient 2 g / kg

The components are carefully mixed in the above amounts to give kg of poultry feed.

Claims (16)

1. O-Acyl-4-phenylcycloalkanols of formula (I), including enantiomers, diastereomers and geometric isomers, and salts thereof, n is 0 obsession 1; m is 0 obsession 1; P is 0 obsession 1; R and R ² , which may be the same or different, are hydrogen or optionally amino, hydroxy, alkoxy, (alkoxycarbonyl) oxy, (alkylcarbonyl) amino, carboxy, alkoxycarbonyl; C 1 -C 6 straight or branched alkyl substituted by carbamoyl or cyano, or C3-C6 straight or branched chain alkenyl or alkynyl, with the proviso that the alkenyl or alkynyl group may have only an isolated double or triple bond with respect to the carbon nitrogen bond, and the amino, hydroxy, alkoxy, -, (alkylcarbonyl) oxy and (alkylcarbonyl) amino may only be attached to a saturated carbon atom other than 1; obsession R 'and R' together with the nitrogen atom to which they are attached are a 5-7 membered monocyclic, saturated heterocyclic group in which the 4-position methylene is substituted with an oxygen or sulfur atom or an alkyl optionally substituted imino group at the 6-membered ring ; '· · · • · · · · · ······ * R ³ and R ⁴ , which may be the same or different, are hydrogen or C 1 -C 4 linear or branched alkyl; R 0 is hydrogen, straight or branched C 1 -C 4 alkyl or C 1 -C 4 alkoxy; R 0 is hydrogen or C 1 -C 4 linear or branched alkyl; R 'is hydrogen, C 3 -C 7 cycloalkyl optionally with fluoro, chloro or bromo, or hydroxy, alkyl, alkoxy, phenylalkoxy, phenyl, nitro, amino, alkylamino, dialkylamino, (alkylcarbonyl) amino, cyano, carboxy, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N, Ν-dialkylcarbamoyl, trifluoromethyl, ( alkylcarbonyl) oxy, sulfamoyl, N-alkylsulfamoyl or N, N-dialkylsulfamoyl mono- or disubstituted phenyl, wherein the substituents may be the same or different, and disubstituted phenyl includes phenyl, wherein two adjacent hydrogen atoms are replaced by methylenedioxy or 1,2-ethylenedioxy, phenyl substituted by two chlorine or bromine atoms and one amino group, naphthyl, tetrahydronaphthyl or thienyl, furyl substituted by one or two halogen atoms - or pyridyl; and A is a bond, a linear or branched C 1 -C 17 alkylene group or a C 2 -C 17 alkenylene or alkynylene group expressing a chemical bond; • ·· «· -78 ··· « With the proviso that, unless otherwise noted, alkyl is an alkoxy group having 1 to 3 carbon atoms and halogen is understood to mean fluorine, chlorine or bromine. 2. O-Acyl-4-phenylcyclohexanols of formula (Ia), including enantiomers, diastereomers and geometric isomers, and their physiologically tolerable salts of inorganic or organic acids wherein n, m and p are both 1; R * and R ² , which may be the same or different, are hydrogen or optionally amino, hydroxy, (alkylcarbonyl) oxy, (alkylcarbonyl) amino, carboxy, alkoxycarbonyl, carbamoyl - either C 1-6 straight or branched chain alkyl or C 3-6 straight or branched chain alkenyl or alkynyl substituted with cyano, with the proviso that the alkenyl or alkynyl group has only a it can be an isolated double or triple bond, and the amino, hydroxy, alkoxy, (alkylcarbonyl) oxy, and (alkylcarbonyl) amino groups of the substituents can only be on saturated carbon atoms other than 1 connect; obsession R and R ² taken together with the nitrogen to which they are attached are a 5-7 membered monocyclic, saturated heterocyclic group wherein the 6-membered ring at the 4-position of the methylene may be replaced by oxygen, sulfur or an alkyl optionally substituted imino; R ² , R ⁴ , R ² and R 0, which may be the same or different, are bridged 79 or methyl; R ⁷ is hydrogen, C 3 -C 7 cycloalkyl optionally with fluoro, chloro or bromo, or hydroxy, alkyl, alkoxy, phenylalkoxy, phenyl, nitro, amino, alkylamino, dialkylamino, (alkylcarbonyl) amino, cyano, carboxy, alkoxycarbonyl, carbamoyl, Mono with N-alkylcarbamoyl, N, N-dialkylcarbamoyl, trifluoromethyl, (alkylcarbonyl) oxy, sulfamoyl, N-alkylsulfamoyl or N, N-dialkylsulfamoyl - or disubstituted phenyl, where the substituents may be the same or different, and disubstituted phenyl is understood to mean a phenyl group having two adjacent hydrogen atoms being methylenedioxy or 1,2-ethylenedioxy, with two chlorine or bromine atoms and one amino group substituted phenyl, naphthyl, tetrahydronaphthyl or thienyl, furyl or pyridyl substituted with one or two alkyl groups or one or two alkyl groups; and A is a bond, a linear or branched C 1 -C 10 alkenylene, or a C 2 -C 10 alkenylene or alkynylene moiety expressing a chemical bond; with the proviso that, unless otherwise indicated, the above alkyl or alkoxy group may have from 1 to 3 carbon atoms. O-acyl-4-phenylcyclohexanols of the formula (Ia) as claimed in claim 2, including enantiomers, diastereomers and geomeric isomers, and their physiologically tolerable salts with inorganic or organic acids of the formula: m and p are both 1; R 'is hydrogen, C 1-4 straight or branched chain alkyl optionally substituted by carbamoyl, or 2-, 3- or 4-hydroxy or alkoxy; R is hydrogen, (C1-C4) -alkyl or allyl; obsession R ¹ and R ² together with the nitrogen to which they are attached form a 5- or δ-membered monocyclic, saturated heterocyclic group in which the 4-position of the methylene group in the 6-membered ring may be replaced by an oxygen atom or an optionally substituted imino group; ^{RJ, R4,} R, R ⁶ represents a hydrogen atom; R 'is hydrogen, C3-C6 cycloalkyl optionally substituted in the 4-position with fluorine, chlorine or bromine or alkyl, alkoxy, phenyl, nitro or trifluoromethyl, with two chlorine atoms and one chlorine atom and phenyl substituted with one alkyl or amino group or two alkoxy groups, phenyl substituted with two chlorine atoms and one amino group, 3,4-methylenedioxyphenyl, naphthyl, tetrahydronaphthyl, 2-furyl, optionally 5- a 2-thienyl or 3-pyridyl group substituted with a chlorine atom; and A is a bond, a linear or branched alkylene group having from 1 to 6 carbon atoms, or a chain of 2 to 5 carbon monoxide radicals having from 2 to 5 carbon atoms. C alk alkalkenylene; with the proviso that, unless otherwise indicated, the above alkyl or alkoxy group may have from 1 to 3 carbon atoms. O-acyl-4-phenylcycloalkanols of formula (Ia) according to claim 2, including enantiomers, diastereomers and geometric isomers, and their salts with physiologically tolerable inorganic or organic acids wherein n, m and p both are 1; R ¹ is hydrogen, C 1 -C 4 straight or branched chain alkyl optionally substituted by carbamoyl, or hydroxy or alkoxy in the 2-, 3- or 4-position; R is hydrogen or C1-C4 alkyl; R ³ , R ⁴ , R ⁵ and R ⁶ are each hydrogen; ^R7 is optionally substituted at the 4-position by fluorine, chlorine or bromine atoms or methyl, trifluoromethyl, methoxy, phenyl or nitro-substituted phenyl or 3,4-dichlorophenyl, 2,4-dichlorophenyl -phenyl, 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, a linear or branched C 1 -C 5 alkylene group or a C 2 or C 3 alkenylene group; with the proviso that, unless otherwise indicated, the above alkyl and alkoxy groups may have from 1 to 3 carbon atoms. ··· «· 5. The following O-acyl-4-phenylcyclohexanols and their physiologically tolerated salts with inorganic or organic acids: (1) cis} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - (4) chloro-benzoate); (2) cis} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - (4) phenyl-3-butenoate); (3) trans} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl]} (4-chlorophenyl) acetate]; (4) cis} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - (5) methyl-hexanoate); (5) trans- {4- {4-} (dimethylamino) methyl] phenyl} cyclohexyl] - (2-phenylpropionate); (6) trans- 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] [(4-fluorophenyl) acetate]; (7) trans- {4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - [(3,4-dichlorophenyl) acetate]; (8) cis} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - (4-fluorocinnamate); (9) trans} 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl]} (4-tolyl) acetate]; (10) trans- {4- {4-} (dimethylamino) methyl] phenyl} cyclohexyl] - {[4- (trifluoromethyl) phenyl] acetate}; (11) trans- {4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] - [(2-naphthyl) acetate]; (12) trans- 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] [(4-nitrophenyl) acetate]; (13) trans-} 4- {4 - [(dimethylamino) -methyl] -phenyl} -cyclohexyl] • · ·· 9 ν Ο .83 - ……. - [(4-bromophenyl) acetate]; (14) trans] 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] [(2,4-dichlorophenyl) acetate]; (15) trans-] 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] [(4-amino-3-chlorophenyl) acetate]; (16) trans] 4- {4 - [(dimethylamino) methyl] phenyl} cyclohexyl] [(4-methoxyphenyl) acetate]; and (17) trans] 4- {4 - [(methylamino) methyl] phenyl} cyclohexyl] [(4-chlorophenyl) acetate]. A pharmaceutical composition comprising a compound according to any one of claims 1-5. A compound according to at least one of claims 1 to 6 and optionally one or more inert carriers and / or diluents. A pharmaceutical composition comprising a compound according to any one of claims 3-5. A compound according to at least one of claims 1 to 7 and optionally one or more inert carriers and / or diluents. 8. One of claims 1-5. Use of a compound according to at least one of claims 1 to 6 for the manufacture of a medicament for inhibiting cholesterol biosynthesis. 9. One of claims 1-5. Use of a compound according to at least one of claims 1 to 6 for the manufacture of a medicament for the prevention or treatment of various types of hyperlipidemia. 10. A method according to any one of claims 1-5. Use of a compound according to at least one of claims 1 to 6 for the manufacture of a medicament for the treatment of diseases associated with cell proliferation. 11. A method according to any one of claims 1-5. Use of a compound according to at least one of claims 1 to 5 for the manufacture of a medicament for the prevention or treatment of gallstone disease. 12. One of claims 1-5. Use of a compound according to at least one of claims 1 to 6 for the manufacture of a medicament for the treatment of mycoses. 13. A method according to any one of claims 1-5. Use of a compound according to at least one of claims 1 to 6 for the preparation of poultry feed for laying hens caught in the production of cholesterol-poor eggs. 14. A process for the preparation of a pharmaceutical composition according to claim 6 or 7, characterized in that a composition according to any one of claims 1-5. The compound according to at least one of claims 1 to 6, in combination with one or more inert carriers and / or diluents. 15. Procedure 1-5. A process for the preparation of compounds according to at least one of claims 1 to 3, characterized in that (a) a 4-phenylcycloalkanol of formula (II) wherein n, m and p and R, R, R ', R, R and R j are 1-4. A carboxylic acid or reactive carboxylic acid derivative of the formula (III) R ⁷ and A are as defined in claims 1-4. and X is a hydroxy group or a reactive leaving group - at a temperature of -10 ° C to +150 ° C; obsession b) an O-acyl-4-phenylcycloalkanol of formula IV wherein n, m and p, and R ³ , R ⁴ , R% R 0 and R 'are as defined in any one of claims 1-4. and Y is a reactive group - with an amine of formula (V) - in which R * and R 1-4. Significant as defined in claims 1 to 4 - reacting at a temperature of 0 ° C to 100 ° C; obsession (c) in the preparation of a compound of formula (I): R * is 1-4. and R is a linear or branched C 1 -C 6, optionally hydroxy, alkoxy, (alkylcarbonyl) oxy, (alkylcarbonyl) amino, carboxy, alkoxycarbonyl group. -, carbamoyl or cyano substituted alkyl, provided that the hydroxy, alkoxy, (alkylcarbonyl) oxy (alkylcarbonyl) amino group may only be attached to a carbon atom other than 1 - O-acyl-4-phenylcycloalkanol of formula (VI): wherein n, m and p and R, R, R ', R' and R are as defined in any of claims 1-4. and R * is as defined above for a compound of formula (VII) R ² is C 1 -C 6 straight or branched, optionally hydroxy, alkoxy, (alkylcarbonyl) oxy, (alkylcarbonyl) amino, carboxy, alkoxycarbonyl, carbamoyl or cyano-substituted alkyl, provided that the hydroxy, alkoxy, (alkylcarbonyl) oxy, or (alkylcarbonyl) amino group may only be attached to a carbon atom other than 1, and Z ' reactive exit ···· · - 86 ··· ··· ························································································· · · · · · · · · · · · · · · · and when the hydroxy, amino, alkylamino or carboxy group optionally present in the compounds of formulas II, III, IV, V, VI and VII is necessarily protected with a protecting group. then protecting groups are removed; and / or converting the compound of formula (I) thus obtained into a salt formed with an inorganic or organic acid.