0-acyl-4-phenylcyclohexanol, cis/trans-isomers or their salts and pharmaceutical drug

 

(57) Abstract:

The invention relates to new cycloalkenyl exhibiting the properties of inhibitors of the biosynthesis of cholesterol, in particular, inhibitors of the enzyme 2,3-amoxicilin-lanosterol-cyclase activity and can find application in the treatment and prevention of, for example, hyperlipidemia, hypercholesterinemia, atherosclerosis, and pharmaceuticals based on them. The proposed compounds correspond to the General formula I

< / BR>
where the values of the radicals indicated in the claims.

The pharmaceutical preparation includes the active principle-0-acyl-4-phenylcyclohexanol formula I or their salts in the form of CIS-TRANS-isomers and at least a carrier and/or diluent. 2 S. and Z. p. f-crystals, 2 tab.

This invention relates to O-acyl-4-phenyl-cycloalkenyl, their salts with physiologically tolerable inorganic and organic acids, methods of producing these compounds and containing medicines and their use.

The proposed compounds are inhibitors of cholesterol biosynthesis, in particular inhibitors of the enzyme 2,3-amoxicilin-lanosterol-cyclase, a key enzyme of the biosynthesis of cholesterol.

Proposed connection pigodeath for the treatment of hyperproliferative diseases of the skin and blood vessels, tumors, gall-stone disease and mycosis.

Compounds that interfere with the biosynthesis of cholesterol, have value for the treatment of a number of paintings of the disease. It should first of all be called hypercholesterolemia and hyperlipidemia, which represent risk factors for the occurrence of atherosclerotic vascular changes and the resulting diseases, such as coronary heart disease, brain ischemia, intermittent claudication and gangrene.

Is excessively elevated serum cholesterol as a major risk factor for the occurrence of atherosclerotic changes in the vessels is well recognized. Numerous clinical studies have led to the knowledge that by reducing serum cholesterol can reduce the risk of coronary heart disease (see Current Opinion in Lipidology 2(4), page 234, 1991). Since most cholesterol is synthesized in the body and only a small part is taken together with food, the inhibition of biosynthesis is particularly attractive by lowering elevated serum cholesterol.

As an additional possible applications of inhibitors of the biosynthesis of cholesterol can be called l the but-stone disease, and mycosis. In the case of mycosis we are talking about intervention in the biosynthesis of ergosterol in fungal organisms, highly proceeding is similar to the biosynthesis of cholesterol in mammals.

The biosynthesis of cholesterol or ergosterol includes, based on the acetic acid, the greater number of reaction stages. This multi-stage process provides a number of opportunities for intervention. As examples the following:

For inhibition of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase mentioned - lactones and lactams potential antihypercholesterolemic action (see J. Antibiotics 40, page 1356, 1987, U.S. patent N 4751237, application EP N 0462667, U.S. patent N 4983597).

Inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A-reductase are 3,5-dihydroxycinnamate acid type of statin and their lactones, which are used in the treatment of hypercholesterinemia as their representatives lovastatin, simvastatin and pravastatin.

Other applications of these compounds are fungal infections (see U.S. patent N 4375475, application EP N 0113881, U.S. patent N 5106992), skin diseases (see application EP N 0369263), and gall-stone disease and neoplastic disease (see U.S. patent No. 5 is adcoy muscles with lovastatin (see Cardiovasc. Drugs Ther. 5, app. 3, page 354, 1991).

Inhibitors of the enzyme squalene synthetase are, for example, isoprenoid-(povinelli)phosphonates, the suitability of which for treating hypercholesterinemia, gall-stone disease, and neoplastic diseases described in the application EP N 0409181, and source J. Med. Chemistry 24 p. 1912, 1991, hereinafter qualitative with lower cholesterol and antimycotic activity (see J. Antibiotics 45, pp. 639-647, 1992, J. Biol. Chemistry 267 p. 11705-11708, 1992).

As inhibitors of the enzyme squalene-epoxidase known allylamine as naftifine and terbinafine, which are used as therapeutic agents against fungal diseases, as well as allylamine NB-598 with antihypercholesterolemic action (see J. Biol. Chemistry 265 p. 18075-18078, 1990 ) and derivatives forskalea with hypocholesterolemic effect (see U.S. patent N 5011859). Additionally, it describes piperidine and Azadegan with potential hypocholesterolemic and/or antifungal activity, mechanism of action which is clearly not yet identified, and represent inhibitors of squalene-epoxidase and/or 2,3-amoxicilin-lanosterol-cyclase activity (see application EP N 0420116, application EP N 0468434, U.S. patent N 5084461 and application EP N 0468457).

N 0464465), derivatives aminoethoxymethyl (see application EP N 0410359), as well as derivatives of piperidine (see J. Org. Chem. 57 p. 2794-2803, 1992 ), which has antifungal activity. Further, this enzyme in mammalian cells is hampered by decaline, isodecanol and derivatives indana (see international application WO N 89/08450, J. Biol. Chemistry 254. page 11258-11263, 1981, Biochem. Pharmacology 37, pp. 1955-1964, 1988), and 2-Aza-2,3-dihydroequilin and 2,3-aminosilane (see Biochem. Pharmacology 34, page 2765-2777, 1985), squarenose-epoxide-anglefire (see J. Chem. Soc. Perkin Trans. 1, 1988. page 461) and 29-methylidene-2,3-occidentalism (see J. Amer. Chem. Soc. 11 p. 9673 - 9674, 1991).

In addition, as inhibitors of the enzyme lanosterol - 14-demethylase which may be called " steroid derivatives with potential antihyperlipidemic action, which simultaneously affect the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A-reductase (see U.S. patent N 5041432, J. Biol. Chemistry 266 p. 20070-20078, 1991, U.S. patent N 5034548). This enzyme is also inhibited antimycotic means type asola, representing the N-substituted imidazoles and triazoles. To this class are, for example, trading antimycotic means ketoconazole and fluconazole.

Compounds of the following General formula (I) are new. Suddenly the LAZ (international classification: EC5.4.99.7).

The enzyme 2,3-amoxicilin-lanosterol-cyclase catalyzes the key step of the biosynthesis of cholesterol or ergosterol, namely the conversion of 2,3-amoxicilina in lanosterol, representing a first connection with a steroid structure in the cascade biosynthesis. Unlike inhibitors earlier stages of biosynthesis, such as, for example, synthesis of 3-hydroxy-3-methylglutaryl-coenzyme A and the recovery of 3-hydroxy-3-methylglutaryl-coenzyme A, from inhibitors of this enzyme, you can expect the advantage of higher selectivity, as inhibition of these early stages of biosynthesis leads to a decrease biosynthetic formed avalonbay acid and, as a consequence, it may also adversely affect the biosynthesis dependent on avalonbay acid substances dolichol, ubiquinone and isopentenyl-t-RNA (see J. Biol. Chemistry 265. page 18075-18078, 1990).

When braking stages of biosynthesis after the conversion of 2,3-amoxicilina in lanosterol there is a risk of accumulation of intermediate products with steroid structure in the body and the stimulation caused by this phenomenon of toxic effects. This phenomenon is described, for example, for triparanol, inhibitor desmosterol-reductase. This substance must be removed from sale (pescalis-lanosterol-cyclase activity described in some literature. The structure of these compounds, however, are completely different from the structure of the compounds of the following General formula (I).

The invention relates to antihypercholesterolemic substances suitable for the treatment and prevention of atherosclerosis and, in comparison with the known active principles, different best antihypercholesterolemic action at high selectivity and, thus, increased security. Since the proposed connection because of their high effectiveness as inhibitors of the enzyme 2,3-amoxicilin-lanosterol-cyclase activity can also inhibit the biosynthesis of ergosterol in the fungal organism, they are also suitable for the treatment of mycosis.

The object of the present invention are new O-acyl-4-phenyl-cycloalkanes General formula (I)

< / BR>
where n, m, p = 1,

R1and R2which may be identical or different, denote a hydrogen atom, an unbranched alkyl with 1-6 carbon atoms, unbranched of alkenyl with 3-6 carbon atoms, while the double bond is isolated from the nitrogen-carbon connection and the above alkyl may be substituted by a residue from the group comprising hydroxyl, alkylcarboxylic, carboxyl, alkoxycarbonyl, aminocarb the ode or the same carbon atom in position 1, or

R1and R2together with the enclosed nitrogen atom of mean 5 - to 7-membered saturated monocyclic heterocyclic ring, formed thus 6-membered saturated monocyclic heterocyclic ring one methylene group in position 4 may be replaced by oxygen atom or unsubstituted or substituted alkyl with aminogroups,

R3and R4represent a hydrogen atom,

R5is a hydrogen atom, an unbranched or branched alkyl with 1 to 4 carbon atoms or alkoxy with 1-4 carbon atoms,

R6is a hydrogen atom,

R7is a hydrogen atom, cycloalkyl with 3-7 carbon atoms, phenyl, unsubstituted, mono - or disubstituted by a residue from the group comprising fluorine atom, chlorine and bromine, alkyl, alkoxy, phenyl, nitro, amino, alkylamino, dialkylamino, trifluoromethyl, while the substituents may be the same or different, and two adjacent hydrogen atom in the phenyl group may be substituted by methylendioxyphenyl or 1,2-ethylenedioxythiophene, phenyl, substituted by two chlorine atoms or bromine and one amino group, naphthyl or tetrahydronaphthyl, thienyl, furyl or pyridyl, substituted by a halogen atom or 1 or 2 alkyl groups, and

and their CIS-TRANS-isomers, or their salts.

Compounds of General formula I belong to the category of low-toxic compounds.

Especially preferred are compounds of General formula (Ia), where

n, m and p mean 1,

R1is a hydrogen atom, an unbranched or branched alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by aminocarbonyl or in position 2, 3 or 4 hydroxyl or alkoxyl, or 2-propanole and

R2is a hydrogen atom, alkyl with 1 to 4 carbon atoms or 2-propanole, or

R1and R2together with in between the nitrogen atom signify a 5 - or 6 - membered saturated monocyclic heterocyclic ring, 6-membered saturated monocyclic heterocyclic ring one methylene group in position 4 may be replaced by oxygen atom or unsubstituted or substituted alkyl with aminogroups,

R3- R6means a hydrogen atom,

R7is a hydrogen atom, cycloalkyl with 3-6 carbon atoms, phenyl, unsubstituted or monosubstituted in position 4 the rest of the group, Lomami chlorine, one chlorine atom and one alkyl group or amino group or two CNS groups, phenyl, tizamidine two chlorine atoms and one amino group, 3,4-methylenedioxyphenyl, naphthyl or tetrahydronaphthyl, 2-furyl or unsubstituted or substituted in position 5 by a chlorine atom 2-thienyl or 3-pyridyl,

A - link, unbranched or branched alkylene with 1 to 6 carbon atoms or albaniles with 2 to 4 carbon atoms,

all of the aforementioned alkyl and CNS group, if nothing else is mentioned, may contain 1 to 3 carbon atoms, their enantiomers, diastereoisomers and geometric isomers, and their salts, particularly for pharmaceutical use the physiologically acceptable salts with inorganic or organic acids.

Particularly preferred compounds of General formula (Ia),

where

n, m and p mean 1,

R1is a hydrogen atom, an unbranched or branched alkyl with 1 to 4 carbon atoms, unsubstituted or substituted by aminocarbonyl or in position 2, 3 or 4 hydroxyl or alkoxyl, or 2-propanole,

R2is a hydrogen atom or alkyl with 1 to 4 carbon atoms,

R3- R6means a hydrogen atom,

R7- phenyl, tormentil, methoxy, phenyl and nitro, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 4-chloro-W-were, 4-amino-S-chlorophenyl-, 3,4-acid, 3,4-methylenedioxyphenyl, 4-amino-3,5-dichlorophenyl or 2-naphthyl, and

A - link, unbranched or branched alkylene with 1 to 5 carbon atoms or albaniles with 2 or 3 carbon atoms,

all of the aforementioned alkyl and CNS group, if nothing else is mentioned, may contain 1 to 3 carbon atoms, their enantiomers, diastereoisomers and geometric isomers, and their salts, particularly for pharmaceutical use the physiologically acceptable salts with inorganic or organic acids,

in particular, however, preferred compounds selected from the group including:

(1) CIS-O-(4-chlorobenzoyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(2) CIS-O-(4-phenyl-3-butenyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

(3) TRANS-O-(4-chlorophenylacetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

(4) CIS-O-(5-methylhexanoic)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(5) TRANS-O-(2-phenylpropionyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

(6) TRANS-O-(4-pertenecer)-4-(4-dimethylaminomethylphenol)- cyclohexanol

(7) TRANS-O-(3,4-dichloropheny)- cyclohexanol

(9) TRANS-O-(p-tolylacetic)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(10) TRANS-O-(4-[trifluoromethyl] -phenylacetyl)-4-(4 - dimethylaminomethylphenol)-cyclohexanol

(11) TRANS-O-(2-naphthylacetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

(12) TRANS-O-(4-nitrophenylacetic)-4-(4-dimethylaminomethylphenol)- cyclohexanol

(13) TRANS-O-(4-bromophenylacetate)-4-(4-dimethylaminomethylphenol)- cyclohexanol

(14) TRANS-O-(2,4-dichlorophenylethyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

(15) TRANS-O-([4-amino-3-chlorophenyl]acetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

(16) TRANS-O-(4-methoxyphenylacetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

(17) TRANS-O-(4-chlorophenylacetyl)-4-(4-methylaminomethyl)- cyclohexanol,

and their salts.

Ways to get

The compounds of formula (I) can be obtained, for example, in the following ways:

a) 4-phenylcyclohexanol General formula (II)

< / BR>
where n, m, p and R1- R6have the above values,

subjected to interaction with the carboxylic acid or its reactive derivatives of the General formula (III)

R7A COX

where

R7and A have the above meanings and X represents a hydroxyl or reactive is si, for example, p-toluensulfonate, N-heteroaryl, for example 1-imidazolyl or 1-benzotriazolyl, or O-isomotion, for example O-(N,N'-DICYCLOHEXYL)-smokeview.

Interaction expediently carried out in an environment of a solvent, such as, for example, benzene, toluene, xylene, diisopropyl ether, dioxane, tetrahydrofuran, dimethylformamide, dichloromethane or chloroform, and, if necessary, in the presence of a base, such as, for example, triethylamine, pyridine or 4-dimethylaminopyridine, or in the presence of acid, in particular then, if X in the General formula (III) represents a hydroxyl, for example, in the presence of mortified-epirate or acidic effects for cation-exchanger at a temperature between -10 and +150oC, preferably however at temperatures between -10 and +80oC.

If the R1and/or R2have a free hydroxyl group, amino group or carboxyl group, it is recommended before carrying out a reaction to protect them suitable way, for example, by transferring the hydroxyl group in the ester group, for example, 2-methoxyethoxymethyl group, tert.-butyl or benzyl ester group, amino group - carbamate, such as trichloroethyl, 9-fluorenylmethyl or 2,4-dichlorobenzyl the IRNA group, and the reaction to remove the protective group known methods.

b) O-acyl-4-phenylcyclohexanol General formula (IV)

< / BR>
where n, m, p, R3- R7and A have the above meanings and Y represents a reactive remove the group as, for example, halogen atom such as chlorine atom or bromine, or sulfonyloxy, for example, methylsulfonylamino,

subjected to interaction with the amine of General formula (V)

< / BR>
where R1and R2have the above values.

Interaction expediently carried out in an environment suitable solvent, such as, for example, ethanol, tert.-butanol, dimethylformamide or tetrahydrofuran, and, if necessary, in the presence of a base, such as, for example, potassium carbonate, ethanolic sodium tert.-butanolic potassium or sodium hydride, and, if necessary, in the transfer phase, at temperatures between 0 and 100oC.

To obtain compounds of General formula (I), where R1have the above meanings and R2denotes unbranched or branched alkyl with 1 to 6 carbon atoms, unsubstituted or substituted by a residue from the group comprising hydroxyl, alkoxyl, alkylcarboxylic, alkylcarboxylic, carboximide not linked to the carbon atom in position 1:

O-acyl-4-phenylcyclohexanol General formula (VI)

< / BR>
where n, m, p, R3-R7and A have the above meanings and R1has the above value,

subjected to interaction with the compound of General formula (VII)

R2'- Z1< / BR>
where R2'denotes unbranched or branched alkyl with 1-6 carbon atoms, unsubstituted or substituted by a residue from the group comprising hydroxyl, alkoxyl, alkylcarboxylic, alkylcarboxylic, carboxyl, alkoxycarbonyl, aminocarbonyl and cyano, the hydroxyl, alkoxyl, alkylcarboxylic or alkylcarboxylic not linked to the carbon atom in position 1, and Z1means reactive removable group, for example, halogen atom, such as, for example, chlorine atom or bromine, or sulfonyloxy, for example, methylsulfonylamino.

The reaction is expediently carried out in an environment of a solvent or mixture of solvents, such as, for example, ethanol, tert.-butanol, tetrahydrofuran, dimethylsulfoxide or dimethylformamide, if necessary in the presence of an acid acceptor, such as, for example, sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride, methanolic sodium tert.-butanolic potassium, triethylamine elioti in terms of transmission phases, preferably at temperatures between 0 and 100oC, for example at temperatures between 20 and 50oC.

When carrying out the above reactions may available reactive group, such as hydroxyl group, amino group, alkylamino, aminogroup or carboxyl groups can be protected during the reaction the standard protective groups are removed after completion of the reaction.

As a protective group for hydroxyl group can be applied, for example, trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.-butyl, 2-methoxy-ethoxymethyl, benzyl or tetrahydropyranyl, as a protective group for amino, alkylamino - or imino-groups, such as acetyl, benzoyl, etoxycarbonyl or benzyl, and as a protective group for the carboxyl group - complex 2,2,2-trichlorethylene. tert.-butyl or benzyl ether.

Further, if necessary, removing the used protective group is preferably carried out by hydrolysis in an aqueous solvent, such as, for example, water, a mixture of isopropanol and water, a mixture of tetrahydrofuran and water, or a mixture of dioxane and water, in the presence of acid, such as hydrochloric acid or sulfuric kislotno 0 and 100oC, preferably at the boiling temperature of the reaction mixture. Removal of the benzyl residue, however, preferably carried out by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst like palladium on coal in the environment of a solvent, such as, for example, methanol, ethanol, complex ethyl ester of acetic acid or glacial acetic acid, if necessary with the addition of acid, for example hydrochloric acid, at temperatures between 0 and 50oC, preferably, however, at room temperature, and hydrogen pressure of 1 to 7 bar, preferably, however, 3 to 5 bar.

Obtained by the above methods, compounds of General formula (I) can be cleaned and isolated by known methods, for example by crystallization or chromatography.

Then, the obtained compounds of General formula(1) can, if desired, to translate in their acid additive salts, particularly for pharmaceutical use into their physiologically acceptable salts with inorganic or organic acids. As acids are suitable for this, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid position of the substituents at cycloalkane ring or form of the substituents R1- R7you may have stereoisomers, such as diastereomers, geometric isomers or optical isomers. The invention covers both the pure stereoisomers and their mixtures.

The source connection

The initial compounds of General formula (II) can be obtained, for example, as follows:

1. by restoring 4-phenylcyclohexanone General formula (VIII)

< / BR>
where n, m, p and R1- R6have the above values.

The choice of a suitable reducing agents, such as, for example, sodium borohydride or three-Deut. -butylbromide lithium (L-selectride) you can control the reaction so that mainly formed e,e-isomer or e,a-isomer of compounds of General formula (II).

Ketones of General formula (VIII) can be obtained by known methods, for example, as a result of interaction monomethylaniline General formula (IX)

< / BR>
with an ORGANOMETALLIC compound of General formula (X)

< / BR>
where n and R1- R5have the above meanings and Me means a lithium atom or a group-MgHal, while Hal means a halogen atom, preferably a chlorine atom,

and subsequent removal of water, hydrogenation of the resulting double bond and hydrolysis katalavei group.

6means alkyl with 1 to 4 carbon atoms, for example, by alkylation ion ketone-enolate.

Another method of obtaining compounds of General formula (VIII) is cyclization by Diekmann esters of dicarboxylic acids of General formula (XI)

< / BR>
where n, m, p and R1- R6have the above meanings and R8and R9which may be identical or different, denote alkyl, aralkyl or aryl,

with subsequent saponification and decarboxylation by known techniques.

2. The initial compounds of General formula (IV) can be obtained, for example, as a result of halogenosilanes O-acyl-4-phenylcyclohexanol General formula (XII)

< / BR>
where m, p, R6-R7and A have the above values,

the corresponding aldehyde and kaleidotrope, for example, chloride or hydrogen bromide, in the presence of a catalyst of the Friedel -, for example zinc chloride, and, optionally, subsequent substitution of the halogen atom other suitable reactive removed by the group.

3. The initial compounds of General formula (VI) can be obtained, for example, O-Azania values and Z2means suitable protective group,

due to the removal of this protective group. As the protective group can be applied, for example, tert.-butoxycarbonyl, 1-(3,5-di-tert.-butylphenyl)-1-methylethanolamine or 2-(4-pyridyl)etoxycarbonyl. Compounds of General formula (XIII), for example, can be synthesized as described in method 1.

The initial compounds of formulas (III) and (V) are known or can be obtained well-known techniques.

Compounds of General formula (I) have interesting biological properties. They are inhibitors of cholesterol biosynthesis, in particular inhibitors of the enzyme 2,3-amoxicilin-lanosterol-cyclase activity. Due to their biological properties, they are particularly suitable for the treatment and prevention of hyperlipidemia, especially hypercholesterolemia, hyperlipoproteinemias and hypertriglyceridemia, and the resulting atherosclerotic vascular changes and the resulting diseases, such as coronary heart disease, brain ischemia, intermittent claudication, gangrene, and others.

For the treatment of these diseases, the compounds of General formula (I) can be applied separately for monotherapy or in combination with other sniggling drugs if necessary and in rectal preparations. The quality of the ingredients can be applied, for example,

binding of bile acid resin, how? for example, cholestyramine, holestipol and others,

connection, inhibiting the resorption of cholesterol, such as, for example, sitosterol and neomycin,

connection, and engaged in the biosynthesis of cholesterol, such as, for example, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase as lovastatin, simvastatin, pravastatin and others,

- inhibitors of squalene-epoxidase as, for example, NB-598 and similar compounds, as well as

- inhibitors of squalene synthetase as, for example, representatives of the class isoprenoid-(povinelli)phosphonates and squarestate.

As possible may be called the class of fibrates, such as clofibrate, bezafibrat, gemfibrozil and others, nicotinic acid, its derivatives and analogues as, for example, acipimox and probucol.

In addition, compounds of General formula (I) are suitable for treating diseases associated with excessive increased cell proliferation. Cholesterol is an essential part of the cell and must be available in sufficient quantities for cell proliferation, i.e., the fact is-3-methylglutaryl-coenzyme A-reductase type a statin lovastatin described, as described, for example, cells of smooth muscles.

As examples of diseases associated with excessive increased cell proliferation, should be called first tumor diseases. In experiments using cell cultures and in vivo tests have shown that lowering cholesterol in serum or intervention in cholesterol biosynthesis inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase reduces tumor growth (see Lancet 339. page 1154 - 1156, 1992). Therefore, the proposed compounds of formula (I) due to their inhibiting cholesterol biosynthesis action potentially suitable for the treatment of neoplastic diseases. Thus they can be used separately or in support of known therapeutic methods.

As additional examples of hyperproliferative skin diseases, such as psoriasis, basal cell carcinoma, squamous cell carcinoma, keratosis and disorders of keratinization. Used herein, the term "psoriasis" refers to hyperproliferative skin disease that alters the mechanism of regulation of the skin. In particular, formation damage, covering primary and secondary changes of the proliferation of the disease is possible. Psoriatic skin is morphologically characterized by increased metabolism of cells of the epidermis, thickened epidermis, abnormal keratinization of inflammatory cell infiltrates in the dermis layer and infiltration of polymorphonuclear leukocytes into the epidermis, causing the increase of the basal cell cycle. In addition, present be accompanied and parakeratotic cells.

The term "keratosis", "basal cell carcinoma", "squamous cell carcinoma" and "disorders of keratinization" treat hyperproliferative diseases of the skin, which interrupted the mechanism of regulation of proliferation and differentiation of skin cells.

The compounds of formula (I) useful as antagonists of hyperproliferative skin, i.e. as a means of impeding hyperproliferation human keratinocytes. As a result, they are suitable as a means for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization and keratosis.

For the treatment of the abovementioned diseases, the compounds of formula (I) can be used orally or topically, and can be used alone as monotherapy or in comb the parties, such as, for example, percutaneous transluminal coronary angioplasty or bypass surgery, hyperproliferative vascular diseases as stenosis and occlusion of vessels, based on the cell proliferation of smooth muscles. As mentioned above, this cell proliferation is possible, as it is known to be suppressed by inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase type of statin, such as lovastatin. Due to their inhibitory effect on cholesterol biosynthesis and compounds of General formula (I) are suitable for the treatment and prevention of these diseases, and they can be applied separately or in combination with known active substances, such as, for example, intravenously injected heparin, preferably orally.

Another area of application of the compounds of General formula (I) are the prevention and treatment of gallstone disease. The formation of gallstones is called unfavorable ratio of cholesterol and bile acids in bile, which accounts for the solubility of insufficient cholesterol and cholesterol is deposited in the form of gallstones. The effectiveness of the inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitor, lovastatin, the dissolution of gallstones, in particular in whom is unisom action of compounds of General formula (I) are also of significance for the prevention and treatment of gallstone disease. Thus they can be used separately or in combination with known therapies, such as, for example, treatment ursodeoxycholic acid or lithotripsy shock waves, preferably as oral drugs.

Compounds of General formula (I) are also suitable for the treatment of infections by pathogenic fungi, such as Candida albicans, Aspergillus niger, Trichophyton mentagrophytes, Penicillium sp., Cladosporium sp. and others. As already mentioned above, the final product of the biosynthesis of the Sterol in the fungal organism is not cholesterol and ergosterol, an essential for the integrity and functioning of the cell membranes of fungi. Therefore, the inhibition of the biosynthesis of ergosterol leads to impaired growth and, perhaps, to the mortification of the fungal organisms.

For the treatment of mycosis compounds of General formula (I) can be used orally or topically. Thus they can be used separately or in combination with known antimycotic active principles, in particular with those involved in other stages of the biosynthesis of the Sterol, such as, for example, inhibitors of squalene-epoxidase terbinafine, naftifine or inhibitors of lanosterol-14 - demethylase type Isola as, for example, ketoconazole and fluconazole.

In addition,inhibitor 3-hydroxy-3-methyl-glutaryl-coenzyme A-reductase inhibitor lovastatin chickens-laying hens are described in the source FASEB Journal 4, A 533, Abstracts 1543, 1990, Receiving poor cholesterol eggs is interesting, because the load of the body cholesterol at the expense of eggs with low cholesterol can be reduced without changing eating habits. Because of their inhibitory effect on cholesterol biosynthesis compounds of General formula (I) can also be used in poultry to obtain poor cholesterol eggs, when this substance is preferably given as an additive to feed.

Biological activity of compounds of General formula (I) was determined via the following methods:

1. Measurement of inhibition include14C-acetate in steroids besieged by digitonin

Method:

Cells human hepatoma (HEP-G2) after three days of cultivation stimulate free from cholesterol environment for 16 hours. The subjects of the substance (dissolved in dimethyl sulfoxide to a final concentration of 0.1%) are added during this phase of stimulation. After adding 200 µmol/l 2-14C-acetate incubation continue in a thermostat at a temperature of 37oC for two hours.

After separation of the cells and the saponification of esters of Sterol in the implementation of the extraction type, digitonin and produce precipitated sterols.14C-acetate, VK is asego action of the compounds was carried out at the concentrations equal to 10-7and 10-8mol/l Was found that, for example, the following compounds A - P General formula (I) possess good inhibitory effect at these concentrations, for example, at a concentration equal to 10-8mol/l, there is at least 50% braking:

A = CIS-O-(4-chlorobenzoyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

B = CIS-O-(4-phenyl-3-butenyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

In = TRANS-O-(4-chlorophenylacetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

G = CIS-O-(5-methylhexanoic)-4-(4-dimethylaminomethylphenol)-cyclohexanol

D = TRANS-O-(2-phenylpropionyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

E = TRANS-O-(4-pertenecer)-4-(4-dimethylaminomethylphenol)- cyclohexanol

W = TRANS-O-(3,4-dichlorophenylethyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

C = CIS-O-(4-forcename)-4-(4-dimethylaminomethylphenol)-cyclohexanol

And = TRANS-O-(p-tolylacetic)-4-(4-dimethylaminomethylphenol)- cyclohexanol

Th = TRANS-O-(4-[trifluoromethyl]-phenylacetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

K = TRANS-O-(2-naphthylacetyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

L = TRANS-O-(4-nitrophenylacetic)-4-(4-dimethylaminomethylphenol)- cyclohexaneacetic)-4-(4-dimethylaminomethylphenol)- cyclohexanol

About = TRANS-O-([4-amino-3-chlorophenyl]acetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

P = TRANS-O-(4-methoxyphenylacetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

P = TRANS-O-(4-chlorophenylacetyl)-4-(4-methylaminomethyl)- cyclohexanol.

Percentage inhibition include14C-acetate of the above compounds are shown in table 1:

mol/l - 10-7; 10-8< / BR>
A - -85; -51

B - -87; -58

IN - -83; -66

MR. -88; -53

DR. -89; -72

E - -86, -66

W - -89; -74

C - -86; -51

AND - -90; -72

TH - -89; -87

K - -86; -54

L - -83; -67

M - -84; -64

N - -85; -67

ON - -79; -51

P - -73; -52

R - -79; -50

As already mentioned above, in some literature describes inhibitors of the enzyme 2,3-amoxicilin-lanosterol-cyclase activity, which, however, the structure is very different from the proposed compounds of formula (I). Connection, the most similar in structure to the compounds of General formula (I) described in the application EP N 0468457. Therefore, in order to compare the test were subjected to the example 1 of this application in accordance with the above method of determining inhibition at concentrations equal to 10-5and 10-6mol/l was Found with braking components 41 and 13%, respectively the>/P>II. The definition of activity in vivo on rats after oral administration.

Inhibition of the enzyme 2,3-amoxicilin-lanosterol-cyclase activity causes an increase in the level of 2,3-amoxicilina in plasma and liver. Therefore, the number of the resulting 2,3-amoxicilina serves as a direct measure of efficiency for the animal. The determination is carried out according to the following method:

Rats-males-type Wistar (160 - 190 g body weight) injected through the mouth of the probe give the test substance suspended in a 1.5% aqueous methylcellulose. 5 hours after giving retroorbital take blood from the venous plexus. The plasma process method blajan and Dyer (see Canad. J. Biochem. Physiol. 37, page 912, 1959), clear on forbalance and analyzed by high speed liquid column chromatography. The obtained peaks identified using substances-standards and subjected to quantitative determination. An internal standard is used to check the reproducibility of the results.

The tests were carried out with concentrations of 0.1 and 1.0 mg/kg In the table below as examples are experimental data of the above substances B, C, D, M, N and P for the achieved level of 2,3-epoxysilane is provided.

The level of 2,3-amoxicilina in plasma (rat) is given in table 2.

So far in the literature are not described inhibition of the biosynthesis of cholesterol from animal one of the well-known inhibitors of the enzyme 2,3-amoxicilin-lanosterol-cyclase activity.

Compounds in therapeutic doses was quite non-toxic. So, for example, a compound In the rat, and join Th and M in the mouse after oral giving 100 mg/kg compound once a day for 5 days had no side effects.

For pharmaceutical use, the compounds of General formula (I) are well known manner amenable to the introduction of standard pharmaceutical preparations for oral and topical use.

Thus, the object of this invention is a pharmaceutical drug that has the properties of an inhibitor of the enzyme amoxickllin-lanosterol-cyclase comprising the active principle and at least an inert carrier and/or diluent, as active principle, it contains O-acyl-4-phenyl-cycloalkanes General formula (I)

< / BR>
where n, m, p = 1,

R1and R2may be the same or different and denote unbranched alkyl with 1-6 carbon atoms, or R1means a hydrogen atom and R2sachetorte,

R7- cycloalkyl with 3 to 7 carbon atoms, phenyl, unsubstituted, mono - or disubstituted by a residue from the group comprising fluorine atom, chlorine and bromine, alkyl, alkoxy, phenyl, nitro, amino, alkylamino, dialkylamino, trifluoromethyl, while the substituents may be the same or different, and two adjacent hydrogen atom in the phenyl group may be replaced by methylenedioxy group or 1,2-Ethylenedioxy group, phenyl substituted by two chlorine atoms or bromine and one amino group, a naphthyl, and

A - link, unbranched or branched alkylene with 1 to 6 carbon atoms or an unbranched albaniles with 2 to 4 carbon atoms; all the above alkyl and CNS group, if nothing else is mentioned, may contain 1 to 3 carbon atoms, and their CIS.the TRANS-isomers, or salts

Preparations for oral administration include, for example, tablets, pills and capsules, and for rectal injection preferably used suppositories.

Preparations for topical application include gels, creams, lotions, ointments, powders, aerosols and other standard composition for the application of therapeutic agents to the skin. The number of active start for local use is 1 to 50 mg/g compozitiunea the invention can also be applied in the treatment of mucous membranes, available for local treatment. Preparations for local application can be applied, for example, on the mucous membranes of the mouth, descending colon, and others.

Daily oral or rectal dose is 1 to 1200 mg for a person of 60 kg body weight, preferably, however, 5 - 100 mg Daily dose is preferably divided into 1 to 3 single doses.

The local application connections can be provided in compositions containing approximately 1 to 1000 mg, in particular 10 to 300 mg of active principle per day. The daily dose is preferably divided into 1 to 3 single doses.

For use in poultry to obtain poor cholesterol eggs active principle of General formula (I) animals given standard methods as an additive to fit the stern. The concentration of active principles in the stern ready is usually 0.01 to 1%, preferably, however, of 0.05 - 0.5%.

The active agent can be added to the feed as such. Thus, along with active early and, if necessary, along with the standard mixture of vitamins and minerals, feed for chickens hens has, for example, corn, soy flour, meat meal, feed fat and soybean oil. Food is mixed with one of the above compounds of formulas is their examples explain the invention.

In the following examples, the tests thin-layer chromatography was carried out using ready-to-tile company E. Merck, DE, namely, on

a) silica gel 60 F254< / BR>
b) aluminum oxide F254(type E).

Getting the initial connection.

Example 1

4-(4-dimethylaminomethylphenol)-cyclohexanone

a) 4-(4-dimethylaminomethylphenol)-4-oxocyclohexa-atlantta

To a cooled to -70oC to a solution of 36.4 g (to 0.17 mol) 4-bromo-N,N-dimethylbenzylamine in 250 ml of dry tetrahydrofuran in a nitrogen atmosphere under stirring was added dropwise 112 ml (0,179 mol) of a 1.6 molar solution of n-utility in hexane so that the temperature of -65oC not prevails. The orange solution is stirred for further 15 minutes at - 70oC, then for 10 minutes, mixed with a solution of 27.6 g (0,172 mol) 1,4-cyclohexadien-monoethylene-ketal in 110 ml of tetrahydrofuran, the temperature should not exceed -65oC.

The reaction mixture is stirred first for 30 minutes at -70oC, and then without external cooling to achieve +20oC. the Mixture is poured into 600 ml of ice water and extracted with 200 ml of ethyl acetate. The organic phase is separated and the aqueous phase is extracted several times with ethyl acetate. Unite isopropylalcohol ether. Get a 41.9 g (85% of theory) of 4-(4-dimethylaminomethylphenol)-4 - oxocyclohexa-etelankyla with a melting point of 84 - 86oC.

b) 1-(4-dimethylaminomethyl)phenyl-4-Ethylenedioxy-1-cyclohexen

A mixture of 22.4 g (0,077 mol) of 4-(4-dimethylaminomethylphenol)-4 - oxocyclohexa-etelankyla, 15.0 g (0.079 in mol) of p-toluenesulfonic acid in the form of a monohydrate, 39 ml of ethylene glycol and 240 ml of toluene with stirring is heated under reflux for 3.5 hours and the resulting reaction water is continuously removed. The cooled reaction mixture is poured into 200 ml of water and 2 N. sodium hydroxide adjusted to pH 12 - 13. The organic phase is separated and the aqueous phase is extracted several times with toluene. The combined organic extracts dried over sodium sulfate and concentrated in vacuum. Get 21 g (about 100%) of target compound as a yellow oil.

C) 1-(4-dimethylaminomethyl)phenyl-4-Ethylenedioxy-1-cyclohexane

A solution of 21 g (0,077 mol) of crude 1-(4-dimethylaminomethyl)phenyl-4 - Ethylenedioxy-1-cyclohexene in 200 ml of ethyl acetate and 100 ml of methanol is mixed with 5 g of a mixture of palladium and barium sulfate as catalyst and hydronaut for 1.5 hours under hydrogen pressure of 5 bar. After separation of the catalyst, concentrated in vacuum. Recip is l-cyclohexanone

A mixture of 20 g (0,077 mol) of crude 1-(4-dimethylaminomethyl)phenyl-4 - Ethylenedioxy-1-cyclohexane and 110 ml of 2 N. hydrochloric acid is stirred for 3.5 hours at room temperature. The resulting aqueous solution extracted several times with ethyl acetate. The organic extracts are removed.

The aqueous phase when cooled to 50% sodium liquor was adjusted to pH 13 to 14 and again extracted several times with ethyl acetate. The combined organic extracts washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuum. Get 14 g (79% of theory) of 4-(4-dimethylaminomethyl)phenyl-cyclohexanone with a melting point of 64 - 67oC in the form of a light yellow product. Analytical test is recrystallized from petroleum ether.

So pl.: 65 - 67oC.

C15H21NO (231,34)

Calculated: C 77,88; H 9,15; N 6,05;

Found: 77,69; to 9.32; 5,98;

Example II

TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol

To a cooled to -10oC to a solution of 11.1 g (0,048 mol) of 4-(4-dimethylaminomethylphenol)-cyclohexanone in 100 ml of absolute methanol under stirring portions add 1,82 g (0,048 mol) sodium borohydride. The reaction mixture is allowed to stand for 1.5 hours at room tempera, stirred for 30 minutes at room temperature, alkalinized 50% sodium lye and extracted several times with chloroform. The combined extracts dried over sodium sulfate and concentrated in vacuum. The residue consisting of a mixture of TRANS/CIS-isomers of 4-(4-dimethylaminomethylphenol)-cyclohexanol (the proportion of CIS-isomers < 10%), purified by column chromatography on neutral aluminum oxide with a degree of activity III, using as eluent a mixture of petroleum ether and methyl ethyl ketone in a ratio of 5: 1. Get white crystals with a melting point of 63 - 65oC.

Yield: 8.8 g (79% of theory).

WITH15H23NO (233,36)

Calculated: C 77,21; H to 9.93; N 6,00;

Found: 77,34; 10,02; of 5.89.

Example III

CIS-4-(4-dimethylaminomethylphenol)-cyclohexanol

50 ml (0.05 mol) of 1-molar solution of tri-sec.-butylbromide lithium in absolute tetrahydrofuran in a nitrogen atmosphere diluted with 100 ml of absolute tetrahydrofuran, and then at a temperature of from -65 to - 70oC under stirring for 10 minutes, mixed with a solution of 5.8 g (0,025 mol) of 4-(4-dimethylaminomethylphenol)-cyclohexanone in 50 ml of absolute tetrahydrofuran. Then the reaction mixture is left to stand in the ml of 75% aqueous ethanol and organoboron oxidized alkaline hydrogen peroxide (mixture of 10 ml of 6 M sodium hydroxide and 15 ml of 30% hydrogen peroxide). The organic phase is separated, the aqueous phase is saturated with potassium carbonate and extracted with 50 ml ethyl acetate. The combined organic extracts dried over sodium sulfate and concentrated in vacuum. Oily residue consisting of a mixture of CIS/TRANS-isomers of 4-(4-dimethylaminomethylphenol)-cyclohexanol (the share of the TRANS-isomers < 5%), purified by column chromatography on neutral aluminum oxide with a degree of activity III, using as eluent a mixture of petroleum ether and methyl ethyl ketone in a ratio of 5:1. Get the product as a colourless oil.

Yield: 4.1 g (71% of theory).

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: 1,5 - 2,0 (2m, 8H); of 2.25 (s, 6H); from 2.4 to 2.65 (m, 1H); 3,4 (s, 2H); 4.1 and 4,18 (m, 1H); 7,15 - to 7.3 (m, 4H).

Example IV

TRANS-O-acetyl-4-(4-chloromethylene)-cyclohexanol

a) 4-phenylcyclohexanol

To a cooled to -10oC to a solution of 31.4 g(0.18 mol) of 4-phenylcyclohexanone in 500 ml of absolute methanol under stirring portions added 6.8 g (0.18 mol) of sodium borohydride. The reaction mixture is left to stand for 0.5 hours at a temperature of -10oC and for 3 hours at room temperature, then concentrated in vacuo. The residue is mixed with water and acidified with 2 N. hydrochloric acid is tallitot from diisopropyl ether. Get 21 g (66 % of theory) 4-phenylcyclohexanol with a melting point of 112 - 114oC.

b) O-acetyl-4-phenylcyclohexanol

To a mixture of 20.3 g (0,115 mol) 4-phenylcyclohexanol, of 14.2 ml (0.15 mol) of acetanhydride and 29 ml of triethylamine at room temperature with stirring, add 2.3 g (0.02 mol) of 4-dimethylaminopyridine, and exothermic conditions formed a clear solution. Heated to 80oC for 3 hours, after which the reaction mixture is poured into ice water. Precipitated crystalline product is sucked off, dissolved in diethyl ether, washed with sodium bicarbonate solution, dried and concentrated in vacuum. Get 23 grams (92% of theory) of O-acetyl-4-phenylcyclohexanol. The product is obtained first in the form of oil, which, however, crystallize when standing.

So pl.: 43 - 45oC.

C) TRANS-O-acetyl-4-(4-chloromethylene)-cyclohexanol

A solution of 24.3 g (0.11 mol) of O-acetyl-4-phenylcyclohexanol in 1300 ml of methylene chloride is mixed with 26,0 g (0.86 mol) of paraformaldehyde and 26,0 g (to 0.19 mol) of chloride of zinc. In this suspension for 2.5 hours under stirring served hydrogen chloride, and the temperature rises to about 30oC and is formed in the homogeneous solution. Poshout with stirring into about 1.5 l of ice water. The organic phase is separated, the aqueous phase is again extracted with methylene chloride and the two organic phases are pooled. They are washed until neutral, dried and evaporated in vacuum. The remaining yellow oil by rubbing with diisopropyl ether is brought to crystallization and the solid product is recrystallized from diisopropyl ether. Get white crystals with a melting point of 87 - 89oC.

Yield: 12.7 g (43% of theory).

C15H19ClO2(266,77)

Calculated: C 67,53; H 7,18; Cl to 13.29;

Found: 67,68; 7,29; 13,11.

Example V

CIS/TRANS-O-(4-chlorophenylacetyl)-4-(4-N-[tert. -butoxycarbonyl] - methylaminomethyl)phenyl-cyclohexanol

a) 4-(4-methylaminomethyl)phenyl-4-oxocyclohexanecarboxylic

A solution of 94 g (0.47 mol) of 4-bromo-(N-methyl)-benzylamine in 460 ml of dry tetrahydrofuran in a nitrogen atmosphere at a temperature of -30oC to -25oC is mixed first with 300 ml (0.48 mol) of a 1.6 molar solution of n-utility in hexane and then 52,5 g (0.48 mol) of trimethylchlorosilane. The reaction mixture is stirred for a further 15 minutes at this temperature, then cooled to -75oC. Then add 320 ml (0.51 mol) of a 1.6 molar solution of n-utility in hexane so that the temperature of-70C by a solution of 76 g(0.47 mol) of 1,4-cyclohexadien-monoelemental in 200 ml of tetrahydrofuran, moreover, the temperature should not exceed -65oC. Then the reaction mixture is stirred first for 30 minutes at -70oC, and then without external cooling until a temperature of +20oC. the Mixture is subjected to decomposition in the cold, like ice, aqueous ammonium chloride solution and repeatedly extracted with methylene chloride. The combined organic extracts dried over sodium sulfate, the solvent is removed and the remainder will recrystallized from diisopropyl ether. Get 77 g (59% of theory) of 4-(4-methylaminomethyl)phenyl-4-oxocyclohexa-etelankyla with a melting point of 95 - 97oC.

b) 1-(4-methylaminomethyl)phenyl-4-Ethylenedioxy-1-cyclohexen

A mixture of 68 g (0.24 mol) of 4-(4-methylaminomethyl)-phenyl-4 - oxocyclohexa-etelankyla, 51 g (0.27 mol) of p-toluenesulfonic acid in the form of a monohydrate, 150 ml of ethylene glycol and 900 ml of toluene with stirring is heated under reflux for 2.5 hours, and the formed reaction water is continuously removed. The cooled reaction mixture is alkalinized 1 N. sodium lye (pH 12 to 13), the organic layer is separated and the aqueous phase is extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated vtogo oil.

C) 1-(4-N-[tert.-butoxycarbonyl]-methylaminomethyl)phenyl-4 - Ethylenedioxy-1-cyclohexen

A solution of 63 g (0.24 mol) of crude 1-(4-methylaminomethyl)phenyl-4 - Ethylenedioxy-1-cyclohexene in 350 ml of absolute tetrahydrofuran under stirring mixed with a solution of 58 g (0.26 mol) di-tert.-BUTYLCARBAMATE in 100 ml of absolute tetrahydrofuran, the temperature when cooled store between 15 and 20oC. After the cessation of carbon dioxide, the mixture is left to stand for a further 10 hours at room temperature, the solvent is distilled off in vacuum, the residue is mixed with water and repeatedly extracted with diethyl ether. After drying over sodium sulfate and evaporation obtain 84 g (about 100% of theory) of 1-(4-N-[tert.-butoxycarbonyl]-methylaminomethyl)phenyl-4 - Ethylenedioxy-1-cyclohexene in the form of a yellowish oil.

g) 4-(4-N-[tert.-butoxycarbonyl]-methylaminomethyl)phenyl-cyclohexanone

A solution of 84 g (0.24 mol) of crude 1-(4-N-[tert.-butoxycarbonyl]- methylamino-methyl)phenyl-4-Ethylenedioxy-1-cyclohexene in a mixture of 250 ml of methanol and 250 ml of ethyl acetate is mixed with 10 g of a mixture of palladium and barium sulfate as catalyst and hydronaut for 4 hours at room temperature and the hydrogen pressure is 3 bar. The catalyst atole add 8.5 g (0,034 mol) tosilata pyridinium heated under reflux for 15 hours. Then the solvent is distilled off in vacuum, the residue is mixed with water and repeatedly extracted with methylene chloride. After drying the organic phase over sodium sulfate and evaporation obtain 61 g (77% of theory) of 4-(4-N-[tert.- butoxycarbonyl]-methyl-aminomethyl)phenyl-cyclohexanone in the form of a pale yellow oil, which solidified after prolonged standing.

So pl.: 55 - 57oC.

d) 4-(4-N-[tert. -butoxycarbonyl] -methylaminomethyl)phenyl - cyclohexanol(mixture of CIS-/TRANS-isomers)

To a cooled to -10oC to a solution of 11 g (0.035 mol) of 4-(4-N-[tert.-butoxycarbonyl]-methylaminomethyl)phenyl-cyclohexanone in 70 ml of absolute methanol under stirring portions add 1,31 g (0.035 mol) of sodium borohydride. The reaction mixture leave to stand for 0.5 hours at -10oC and for 2 hours at room temperature, then concentrated in vacuo. The residue is mixed with water and stirred at room temperature for one hour. Resulting solid product is sucked off, dissolved in ethyl acetate and this solution is dried over sodium sulfate. After thickening, vacuum obtain 8.6 g (77% of theory) of a mixture of CIS - and TRANS-isomers of 4-(4-N-[tert. -butoxycarbonyl] -methylaminomethyl)phenyl - cyclohexanol is th aluminum oxide, with the degree of activity III, using as eluent a mixture of petroleum ether and ethyl acetate in a ratio of 3: 1.

The value of Rf(aluminum oxide, a mixture of petroleum ether and ethyl acetate in the ratio 3:1): 0,21 (TRANS) and 0.31 (CIS).

e) O-(4-chlorophenylacetyl)-4-(4-N-[tert.-butoxycarbonyl]- methylaminomethyl)phenyl-cyclohexanol(mixture of CIS-/TRANS-isomers)

A mixture of 0.54 g(0,0032 mol) 4-chlorophenylalanine acid, 0.52 g (0,0032 mol) of N, N'-carbonyldiimidazole and 20 ml of xylene with stirring during one hour and heated to 60oC. Then, to the mixture add a solution of 0.85 g (0,0027 mol) of 4-(4-N-[tert. -butoxycarbonyl]- methylaminomethyl)phenyl-cyclohexanol (mixture of CIS-/TRANS-isomers) in 10 ml of xylene and the reaction mixture is heated for another 8 hours to 160oC. After cooling, concentrated under vacuum, the residue is mixed with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated in vacuum. Obtain 1.3 g (100% of theory) of O-(4-chloro-phenylacetyl)- 4-(4-N-[tert.-butoxycarbonyl]-methylaminomethyl)phenyl-cyclohexanol (mixture of CIS-/TRANS-isomers) as a red-brown oil. The Rf-value(aluminum oxide, a mixture of petroleum ether and ethyl acetate in the ratio 3: 1): 0,78 (TRANS) and 0,85 (CIS).

EN is of IMT]- methylaminomethyl)phenyl-cyclohexanol

from TRANS-4-(4-N-[tert. -butoxycarbonyl] -methylaminomethyl)phenyl - cyclohexanol, and mixtures of 4-chlorophenylalanine acid and N,N'-carbonyldiimidazole.

White crystals.

So pl.: 94 - 96oC.

Receiving target products:

Example 1

TRANS-O-(4-chlorobenzoyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

To a solution of 1.0 g (0,0043 mol) of TRANS-4-(4-dimethylaminomethylphenol)- cyclohexanol and 0.6 ml of triethylamine in 50 ml of methylene chloride under stirring pin 0.75 g (0,0043 mol) of 4-chlorobenzylchloride and heated under reflux for 3 hours. After cooling, mixed with 50 ml of water, sodium liquor was adjusted to pH 12 - 13, methylenchloride phase is separated and the aqueous phase is again extracted with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated in vacuum. The solid residue purified by column chromatography on neutral aluminum oxide with a degree of activity III, using as eluent a mixture of petroleum ether and ethyl acetate in a ratio of 40 : 1. Get white crystals with a melting point 94 - 95oC.

Yield: 1.1 g (69% of theory).

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: of 1.55 to 1.8 (m, 4H)time synthesize the following compounds:

(1) TRANS-O-acetyl-4-(4-dimethylaminomethylphenol)-cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of acetylchloride and triethylamine. Colorless syrup.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: of 1.45 to 1.7 (m, 4H); 1.9 to 2.05 is (m, 2H); 2,05 - 2,15 (C+m, 3+2H); of 2.23 (s, 6H); from 2.4 to 2.65 (m, 1H); 3,4 (s, 2H); 4,7 - 4,9 (m, 1H); 7,1 - 7,3 (m, 4H)

(2) TRANS-O-butyryl-4-(4-dimethylaminomethylphenol)-cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of butyric acid chloride and triethylamine. A colorless oil.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: from 0.9 to 1.02 (t, 3H); 1,45 is 1.75 (m, 6H); 1,89 - 2,05 (m, 2H); 2,05 - to 2.18 (m, 2H); 2,18 - of 2.38 (s+t, 6+2H); 2,4 - 2,6 (m, 1H); 3,4 (s, 2H); 4,7 - 4,9 (m, 1H); 7,1 - 7,3 (m, 4H).

(3) TRANS-O-cyclopropanol-4-(4-dimethylaminomethylphenol)-cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of chloride cyclopropanecarbonyl acid and triethylamine. Colorless wax.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: 0,81 - 0.87 (m, 2H); 0,95 - 1,02 (m, 2H): 1,45 - 1,7 (m, 4H); 1.9 to 2.0 (m, 2H); 2,05 - of 2.15 (m, 2H); 2,24 (c, 6H); 2,4 -2,63 (2m, 2H); 3,4 (c, 2H); 4,73 of 4.83 (m, 1H); 7,12 - 7,25 (m, 4H).

(4) TRANS-O-cyclohexanol-4-(4-dimethylaminomethylphenol)-cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclog is 68oC.

(5) CIS-O-(4-chlorophenylacetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from CIS-4-(4-dimethylaminomethylphenol)-cyclohexanol and a mixture of 4-chlorophenyl-acetylchloride and triethylamine. A colorless oil.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: of 1.5 to 1.75 (m, 6H); 1,88 - 2,05 (m, 2H); of 2.25 (s, 6H); from 2.4 to 2.65 (m, 1H); 3,4 (s, 2H); the 3.65 (s, 2H); of 5.05 - of 5.15 (m, 1H); was 7.08 (d, 2H); of 7.2 to 7.4 (m, 6H).

(6) TRANS-O-(4-phenyl-3-butenyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of chloride 4-phenyl-3-butenova acid and triethylamine. White crystals.

So pl.: 90 - 91oC.

(7) CIS-O-(4-phenyl-3-butenyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from CIS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of chloride 4-phenyl-3-butenova acid and triethylamine. White crystals.

So pl.: 71 - 73oC.

Example 2

TRANS-O-(4-chlorophenylacetyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

To a mixture of 0.43 g (0,0025 mol) 4-chlorophenylalanine acid and 30 ml of xylene type of 0.41 g (0,0025 mol) of N,N'-carbonyldiimidazole, while the carbon dioxide produced white product. The reaction mixture for one hour with stirring, heat delamerian heated to 160oC for 12 hours, cooled to room temperature, mixed with water and 2 N. sodium liquor was adjusted to pH 12 - 13. Xylene phase is separated, the aqueous phase is extracted several times with ethyl acetate, the combined organic phases, dried and concentrated in vacuum. The solid residue purified by column chromatography on alkaline aluminum oxide having a degree of activity III, using as eluent a mixture of petroleum ether and ethyl acetate in a ratio of 10:1. Get white crystals with a melting point of 75 - 77oC.

Yield: 0.7 g (86% of theory).

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: 1,4 - 1,7 (m, 4H); from 1.8 to 2.15 (m, 4H); of 2.25 (s, 6H); 2,4 - 2,6 (m, 1H); to 3.38 (s, 2H); 3,6 (s, 2H); 4,7 - 4,9 (m, 1H); 7,1 -7,35 (m, 8H).

Similarly synthesize the following compounds:

(1) TRANS-O-(5-methylhexanoic)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of 5-methylhexanoic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 35 - 36oC.

(2) CIS-O-(5-methylhexanoic)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from CIS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of 5-methylhexanoic acid and N,N'-carbonyldiimidazole,88 (m, 9H); 1,95 - 2,1 (m, 2H); of 2.25 (s, 6H); 2,3 (d, 2H); 2,48 - 2,69 (m, 1H); 3,4 (s, 2H); 5.08 to by 5.18 (m, 1H); 7,12 - to 7.3 (m, 4H).

(3) TRANS-O-cyclohexylmethyl-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures cyclohexyloxy acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 37 - 39oC.

(4) TRANS-O-(2-butenyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures crotonic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 69 - 71oC.

(5) TRANS-O-(2-hexanoyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of 2-hexenoic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 40 - 42oC.

(6) TRANS-O-(3-cyclohexylpropionic)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of 3-cyclohexylpropionic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 46 - 47oC.

(7) TRANS-O-benzoyl-4-(4-dimethylaminomethylphenol)-cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures ANS-O-(4-chloro-3-methylbenzoyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and a mixture of 4-chloro-3-methylbenzoic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 100 - 102oC.

(9) TRANS-O-(2-naphtol)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures 4-naphthoic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 110 - 112oC.

(10) TRANS-O-phenylacetyl-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of phenylacetic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 38 - 40oC.

(11) TRANS-O-(4-pertenecer)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures 4-florfenicol acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 68 - 70oC.

(12) CIS-O-(4-pertenecer)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from CIS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures 4-florfenicol acid and N,N'-carbonyldiimidazole. A colorless oil.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: of 1.5 to 1.75 (m, 6H); 1.85 to 2.05 is (is cetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures 4-bromoferrocene acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 72 - 74oC.

(14) TRANS-O-(3,4-dichlorophenylethyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of 3,4-dichlorophenylamino acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 95 - 97oC.

(15) CIS-O-(3,4-dichlorophenylethyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from CIS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of 3,4-dichlorophenylamino acid and N,N'-carbonyldiimidazole. A colorless oil.

1H-NMR (200 MHz, CDCl3): signals at h/mill.: of 1.5 to 1.75 (m, 6H); 1.9 to 2.05 is (m, 2H); of 2.28 (s, 6H); from 2.4 to 2.65 (m, 1H); 3,4 (s, 2H); 3,62 (s, 2H); 5,8 - 5,17 (m, 1H); 7,05 of 7.3 (m, 5H); 7,35 - 7,49 (m, 2H).

(16) TRANS-O-(2,4-dichlorophenylethyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of 2,4-dichlorphenoxy acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 78 - 80oC.

(17) TRANS-O-(p-tolylacetic)-4-(4-dimethylaminomethylphenol)-cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexa the C.

(18) TRANS-O-(4-[trifluoromethyl] -phenylacetyl)-4-(4 - dimethylaminomethylphenol)-cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and a mixture of 4-(trifluoromethyl)-phenylacetic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 73 - 75oC.

(19) TRANS-O-(4-methoxyphenylacetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures 4-methoxyphenylacetic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 47 - 49oC.

(20) TRANS-O-(4-nitrophenylacetic)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures 4-nitrophenylarsonic acid and N,N'-carbonyldiimidazole. Yellowish crystals.

So pl.: 136 - 137oC.

(21) TRANS-O-[3-(4-forfinal)-propionyl] -4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and a mixture of 3-(4-forfinal)-propionic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 58 - 59oC.

(22) TRANS-O-[3-(4-chlorophenyl)-propionyl] -4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexano theoC.

(23) TRANS-O-(4-biphenylacetic)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures 4-biphenylacetic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 88 - 89oC.

(24) TRANS-O-(2-naphthylacetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of 2-naphthylacetic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 85 - 87oC.

(25) TRANS-O-[2-(1,2,3,4-tetrahydro)naphtol] -4-(4 - dimethylaminomethylphenol)-cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and a mixture of 2-(1,2,3,4-tetrahydro)naphthoic acid and N, N'-carbonyldiimidazole. White crystals.

So pl.: 95 - 96oC.

(26) CIS-O-[2-(1,2,3,4-tetrahydro)naphtol]-4-(4-dimethylaminomethylphenol)- cyclohexanol

from CIS-4-(4-dimethylaminomethylphenol)-cyclohexanol and a mixture of 2-(1,2,3,4-tetrahydro)naphthoic acid and N,N'-carbonyldiimidazole. A colorless oil.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: 1,55 - of 1.85 (m, 6H); 1,9 - 2,1 (m, 3H); 2,15 - 2,32 (+m 6+1H); from 2.4 to 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 of 7.3 (2m, 8H).

(27) TRANS-O-(2-phenylprop MESI 2 phenylpropionic acid and N,N'-carbonyldiimidazole. Colorless wax.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: 1,25 - 1,7 (d+m, 3+3H); from 1.8 to 2.15 (m, 5H); 2,3 (s, 6H); 2,38 of 2.6 (m, 1H); 3,4 (s, 2H); 3,7 (kV, 1H); 4,68 of 4.9 (m, 1H); to 7.15 (d, 2H); 7.18 in - 7,38 (d+m, 2+5H).

(28) CIS-O-(2-phenylpropionyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from CIS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of 2-phenylpropionic acid and N,N'-carbonyldiimidazole. A colorless oil.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: 1.3 to 1.7 (l+m, 3+6H); 1,8 - 2,05 (m, 2H); of 2.25 (s, 6H); 2,35 - of 2.58 (m, 1H); 3,4 (s, 2H); of 3.78 (q, 1H); at 5.0 to 5.1 (m, 1H); 7,0 (d, 2H); to 7.2 (d, 2H); 7,25 to 7.4 (m, 5H).

(29) TRANS-O-(4-forcename)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures 4-tortorice acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 118 - 120oC.

(30) CIS-O-(4-forcename)-4-(4-dimethylaminomethylphenol)-cyclohexanol

from CIS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures 4-tortorice acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 66 - 68oC.

(31) TRANS-O-(4-chlorocinnamoyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures 4-harkerite cinnamoyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from CIS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures 4-harkerite acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 88 - 90oC.

(33) TRANS-O-(4-[trifluoromethyl]-cynnamoyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and a mixture of 4-(trifluoromethyl)cinnamic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 134 - 136oC.

(34) CIS-O-(4-[trifluoromethyl] -cynnamoyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from CIS-4-(4-dimethylaminomethylphenol)-cyclohexanol and a mixture of 4-(trifluoromethyl)-cinnamic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 61 - 63oC.

(35) TRANS-O-(5-chloro-2-thenoyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of 5-chloro-2-thiophencarboxylic acid and N,N'-colonelgeneral. White crystals.

So pl.: 95 - 97oC.

(36) TRANS-O-nicotinoyl-4-(4-dimethylaminomethylphenol)-cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and a mixture of nicotinic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 86 - 88oC.

(37) TRANS-O-(2-fuese 2-frankenboob acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 58 - 60oC.

(38) TRANS-O-(3,4-dimethoxyphenylacetic)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of 3,4-dimethoxyphenylacetic acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 32 - 34oC.

(39) TRANS-O-(4-amino-3-chlorophenylacetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and a mixture of 4-amino-3-chlorophenylalanine acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 83 - 85oC.

(40) TRANS-O-(4-amino-3,5-dichlorophenylethyl)-4-(4 - dimethylaminomethylphenol)-cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and a mixture of 4-amino-3,5-dichlorophenylamino acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 78 - 80oC.

(41) TRANS-O-(4-chlorophenylacetyl)-4-(4-diethylaminomethyl)- cyclohexanol

from TRANS-4-(4-diethylaminomethyl)-cyclohexanol and mixtures 4-chlorophenylalanine acid and N,N'-carbonyldiimidazole. A colorless oil.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: of 1.05 (t, 6H); 1,4 - 1,72 (m, 4H); 1,9 - 2,2 (m, 4H); 2,4 - 2,6 (kV+m, 5H); 3,5 (s, 2H); 3,6 (s, 2H); 4,7 - 4,ol

from TRANS-4-(4-dipropylenetriamine)-cyclohexanol and mixtures 4-chlorophenylalanine acid and N,N'-carbonyldiimidazole. A colorless oil.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: to 0.88 (t, 6H); 1,38 to 1.7 (m, 8H); 1,9 - 2,19 (m, 4H); 2,35 (kV, 4H); 2,4 - 2,6 (m, 1H); 3,5 (s, 2H); 3,6 (s, 2H); 4,7 - 4,9 (m, 1H); and 7.1 (d, 2H); 7,15 - 7,38 (m, 6H).

(43) TRANS-O-(4-chlorophenylacetyl)-4-(4-[N-methylbutylamine] - were) cyclohexanol

from TRANS-4-(4-[N-methylbutylamine]were)-cyclohexanol and mixtures 4-chlorophenylalanine acid and N,N'-carbonyldiimidazole. A colorless oil.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: of 0.9 (t, 3H); 1,2 - 1,7 (m, 8H); from 1.8 to 2.15 (m, 4H); to 2.18 (s, 3H); 2,35 (t, 2H); 2,4 - 2,6 (m, 1H); to 3.41 (s, 2H); 3,6 (s, 2H); 4,7 - 4,9 (m, 1H); and 7.1 (d, 2H); a 7.2 to 7.35 (m, 6H).

(44) TRANS-O-(4-chlorophenylacetyl)-4-(4-diallyldimethyl)- cyclohexanol

from TRANS-4-(4-diallyldimethyl)-cyclohexanol and mixtures 4-chlorophenylalanine acid and N,N'-carbonyldiimidazole. A colorless oil.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: 1,4 - of 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); of 5.75 to 6.0 (m, 2H); for 7.12 (d, 2H); 7,15 - 7,38 (m, 6H).

(45) TRANS-O-(4-chlorophenylacetyl)-4-(4-[N-pyrrolidino] - were) cyclohexanol

from TRANS-4-(4 - [the crystals.

So pl.: 57 - 59oC.

(46) TRANS-O-(4-chlorophenylacetyl)-4-(4-[N-piperidino]were) cyclohexanol

from TRANS-4-(4-[N-piperidino]-were)-cyclohexanol and mixtures 4-chlorophenylalanine acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 87 - 89oC.

(47) TRANS-O-(4-chlorophenylacetyl)-4-(4-[N-morpholino]were) cyclohexanol

from TRANS-4-(4-[N-morpholino] were)-cyclohexanol and mixtures 4-chlorophenylalanine acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 114 - 116oC.

(48) TRANS-O-(4-chlorophenylacetyl)-4-(4-[N-methyl-N'-piperazine derivatives] were) cyclohexanol

from TRANS-4-(4-[N-methyl-N'-piperazine derivatives]were)-cyclohexanol and mixtures 4-chlorophenylalanine acid and N,N'-carbonyldiimidazole. White crystals.

So pl.: 97 - 99oC.

(49) TRANS-O-(3,4-[methylendioxy] -phenylacetyl)-4-(4 - dimethylaminomethylphenol)-cyclohexanol

from TRANS-4-(4-dimethylaminomethylphenol)-cyclohexanol and mixtures of 3,4-(methylendioxy)-phenylacetic acid and N,N'-carbonyldiimidazole. A colorless oil.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: 1,4 - 1,7 (m, 4H); 1.8 - 2.0 (m, 2H); 2.0 to to 2.15 (m, 2H); of 2.25 (s, 6H); 2,4 - 2,6 (m, 1H); to 3.38 (s, 2H); 3,5 (s, 2H); 4,7 - 4,9 (m, 1H); 5,94 (s, 2H); 6,7 - 6,85 (who 0.24 g (0.001 mol) of CIS-4-(4-dimethylaminomethylphenol)-cyclohexanol, 0,34 ml (0,0025 mol) of triethylamine and 0.12 g (0.001 mol) of dimethylaminopyridine dissolved in 20 ml of methylene chloride, mixed with 0,175 g (0.001 mol) of 4-chlorobenzylchloride and stirred at room temperature for 12 hours. The reaction mixture is mixed with water and sodium liquor was adjusted to pH 12 - 13. Methylenchloride phase is separated and the aqueous phase is repeatedly extracted with methylene chloride. The combined organic phases are washed with saturated common salt solution, dried and concentrated in vacuum. The residue is purified by column chromatography on neutral aluminum oxide with a degree of activity III, using as eluent a mixture of petroleum ether and ethyl acetate in the ratio of 45:1. White crystals.

So pl.: 96 - 97oC.

Yield: 0.27 g (73% of theory).

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: 1,7 - 2,0 (m, 6H); from 2.1 to 2.25 (m, 2H); of 2.28 (s, 6H); 2,55 is 2.75 (m, 1H); 3,4 (s, 2H); 5,33 of 5.4 (m, 1H); 7,15 - to 7.3 (m, 4H); was 7.45 (d, 2H); or 8.2 (d, 2H).

Example 4

TRANS-O-acetyl-4-(4-diethylaminomethyl)-cyclohexanol

A solution of 1 g (3.75 mmol) of TRANS-O-acetyl-4-(4-chloromethylene)- cyclohexanol in 10 ml of dimethylformamide is mixed with 0.52 g (3.75 mmol) of potassium carbonate and 0.27 g (3.75 mmol) of diethylamine. The mixture with stirring, the action phase is dried and concentrated in vacuum. The residue is purified by column chromatography on alkaline aluminum oxide having a degree of activity III, using as eluent a mixture of petroleum ether and ethyl acetate in a ratio of 15:1. A colorless oil.

Output: 0,79 g (69% of theory).

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: of 1.05 (t, 6H); 1,45 is 1.75 (m, 4H); 1,9 - 2,2 (C+m, 7H); 2,4 - 2,6 (kV+m, 5H); 3,55 (s, 2H); 4,68 of 4.9 (m, 1H); for 7.12 (d, 2H); 7,28 (d, 2H).

Similarly synthesized the following compounds:

(1) TRANS-O-acetyl-4-(4-dipropylenetriamine)-cyclohexanol

from TRANS-O-acetyl-4-(4-chloromethylene)-cyclohexanol and dipropylamine. A colorless oil.

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: of 0.9 (t, 6H); to 1.35 and 1.75 (m, 8H); 1,9 - 2,2 (C+m, 7H); 2,3 - 2,6 (kV+m, 5H); 3,5 (s, 2H); 4,65 of 4.9 (m, 1H); and 7.1 (d, 2H); to 7.25 (d, 2H).

(2) TRANS-O-acetyl-4-(4-[N-methylbutylamine]were) cyclohexanol

from TRANS-O-acetyl-4-(4-chloromethylene)-cyclohexanol and N-methylbutylamine. A colorless oil.

1H-NMR (200 MHz, CDCl3): signals at h/mill.: of 0.9 (t, 3H); 1.2 to about 1.75 (m, 10H); 1,9 - 2,2 (2C+m, 8H); of 2.38 (t, 2H); 2,4 - 2,6 (m, 1H); of 3.45 (s, 2H); 4,7 - 4,9 (m, 1H); to 7.15 (d, 2H); to 7.25 (d, 2H).

(3) TRANS-O-acetyl-4-(4-diallyldimethyl)-cyclohexanol

from TRANS-O-acetyl-4-(4-CHLOROTHALONIL.: 1,4 - of 1.7 (m, 4H); 1.9 to 2,18 (C+m, 7H); 2,4 - 2,6 (m, 1H); to 3.09 (DD, 4H); to 3.52 (s, 2H); 4,7 - 4,9 (m, 1H); 5,01 - 5,3 (m, 4H); of 5.75 to 6.0 (m, 2H); for 7.12 (d, 2H); to 7.35 (d, 2H).

(4) TRANS-O-acetyl-4-(4-[N-pyrrolidino]were) cyclohexanol

from TRANS-O-acetyl-4-(4-chloromethylene)-cyclohexanol and pyrrolidine. Colorless crystals.

So pl.: 43 - 45oC.

(5) TRANS-O-acetyl-4-(4-[N-morpholino]were) cyclohexanol

from TRANS-O-acetyl-4-(4-chloromethylene)-cyclohexanol and research. Colorless crystals.

So pl.: 53 - 55oC.

(6) TRANS-O-acetyl-4-(4-[N-piperidino]were) cyclohexanol

from TRANS-O-acetyl-4-(4-chloromethylene)-cyclohexanol and piperidine. Colorless crystals.

So pl.: 62 - 64oC.

(7) TRANS-O-acetyl-4-[N-methyl-N'-piperazine derivatives]were) cyclohexanol

from TRANS-O-acetyl-4-(4-chloromethylene)-cyclohexanol and N-methylpiperazine. Colorless crystals.

So pl.: 50 - 52oC.

Example 5

TRANS-O-(4-chlorophenylacetyl)-4-(4-methylaminomethyl)-cyclohexanol

A solution of 8.9 g (0.019 mol) of TRANS-O-(4-chlorophenylacetyl)-4-(4-N- [tert.-butoxycarbonyl] -methylaminomethyl)-phenyl-cyclohexanol in 200 ml of methylene chloride is mixed with 35 ml triperoxonane acid and stirred at kom methylene and washed with saturated sodium bicarbonate solution until neutral. The organic phase is dried over sodium sulfate and concentrated in vacuum. The remainder in the form of a yellow oil purified by column chromatography on alkaline aluminum oxide having a degree of activity III, using as eluent a mixture of petroleum ether, ethyl acetate and methanol in the ratio 10:10:1. Get yellowish-white crystals with a melting point of 65 - 67oC.

Yield: 6.4 g (91% of theory).

1H-NMR (200 MHz, CDCl3); the signals at h/mill.: 1,4 - 1,7 (m, 4H); 1,8 - 2,0 (m, 2H); of 2.0 - 2.2 (m, 2H); 2,4 - 2,6 (C+m, 3+1H); to 3.58 (s, 2H); 3,7 (s, 2H); 4,7 - 4,9 (m, 1H); 7,1 - 7,35 (m, 8H).

Similarly synthesized following link:

(1) O-(4-chlorophenylacetyl)-4-(4-methylaminomethyl) cyclohexanol (mixture of CIS-/TRANS-isomers)

from O-(4-chlorophenylacetyl)-4-(4-N-[(tert.-butoxycarbonyl]- methylaminomethyl)-phenyl-cyclohexanol (mixture of CIS-/TRANS-isomers) and triperoxonane acid. Yellowish oil.

The value of Rf(aluminium oxide; a mixture of petroleum ether, ethyl acetate and methanol in the ratio 10:10:1): 0,28 - 0,53.

Example 6

O-(4-chlorophenylacetyl)-4-(4-N-[carboxymethyl] - methylaminomethyl)-phenyl-cyclohexanol (mixture of CIS-/TRANS-isomers)

A mixture of 1.0 g (0,0027 mol) of O-(4-chlorophenylacetyl)-4-(4 - meth is onata potassium and 5 ml of dimethylformamide under stirring for 2 hours, heated to 50oC. After cooling to room temperature, mixed with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the volatile components distilled off in vacuum. The residue is purified by column chromatography on alkaline aluminum oxide having a degree of activity III, using as eluent a mixture of petroleum ether, ethyl acetate and methanol in the ratio of 60:40:2,5. Get a white crystalline product, fusible, starting with 110oC, and melting at 128 - 132oC.

1H-NMR (200 MHz, CDCl3/CD3OD); signals at h/mill.: 1,4 - of 1.75 (m, 5H); 1,8 - 2,2 (m, 3H); 2,32 (DD, 3H); 2,4 - 2,63 (m, 1H); 3,0 (DD, 2H); of 3.5 - 3.7 (DD+DD, 2+2H): 4,7 - 4,9 (m, 0.5 H); 5.08 to further 5.15 (m, 0.5 H); 7,0 - 7,4 (m, 8H).

Similarly synthesized the following compounds:

(1) TRANS-O-(4-chlorophenylacetyl)-4-(4-N-[carbetimer] - methylaminomethyl)phenyl-cyclohexanol

from TRANS-O-(4-chlorophenylacetyl)-4-(4-methylaminomethyl)- cyclohexanol, complex ethyl ester bromoxynil acid and a mixture of potassium carbonate and dimethylformamide. The solid white product.

So pl.: 40 - 42oC.

(2) TRANS-O-(4-chlorophenylacetyl)-4-(4-N-[3-oksipropil] - methylaminomethyl)-phenyl-cyclohexanol

from TRANS-O-(4-chlorophenyl. the white crystals.

So pl.: 75 - 77oC.

Example 7

Hydrochloride of TRANS-O-(4-chlorophenylacetyl)-4-(4-dimethylaminomethylphenol)- cyclohexanol

A solution of 0.39 g (0.001 mol) of TRANS-O-(4-chlorophenylacetyl)-4-(4 - dimethylaminomethylphenol)-cyclohexanol in 10 ml of diethyl ether at room temperature with stirring dropwise mixed with 1.5-fold equimolar amount of hydrogen chloride in isopropanol. The precipitation is within one hour left to stand at room temperature, sucked off, washed several times with diethyl ether and dried. Get white crystals with a melting point of 231 - 233oC.

Yield: 0.32 g (76% of theory).

C23H29Cl2NO2(422,40)

Calculated: C 65,40; H 6,92; N 3,32; Cl 16,79;

Found: 65,33; 7,06; 3,45; 16,92.

Example 8

TRANS-O-(4-chlorophenylacetyl)-4-(4-dimethylaminomethylphenol) cyclohexanol tartrate

In 7 ml of absolute ethanol is first dissolved 0.15 g (0.001 mol) of anhydrous tartaric acid, and then 0.39 g (0.001 mol) of TRANS-O-(4-chlorophenylacetyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol. A clear solution is mixed with diethyl ether until a slight turbidity, then leave to stand at a temperature of +4oC for 169 - 171oC.

Output: 0,46 g (86% of theory).

C27H34ClNO8(536,02)

Calculated: C of 60.50; H to 6.39; N, 2,61; Cl 6,61;

Found: 60,37; 6,38; 2,65; 6,73.

The following describes how to obtain pharmaceuticals at some examples.

Example I

Tablets containing 5 mg of TRANS-O-(4-chlorophenylacetyl)- 4-(4-dimethylaminomethylphenol)-cyclohexanol

Composition:

One tablet contains:

active start - 5.0 mg

milk sugar - 148,0 mg

potato starch - 65,0 mg

magnesium stearate - 2.0 mg

All 220,0 mg

Way get:

As a result of heating parts of potato starch receive 10% mucilage. The active principle, dairy residual sugar and potato starch are mixed together with mucus granularit through a sieve with openings of 1.5 mm Granulate is dried at 45oC, again passed through a sieve, mixed with magnesium stearate and pressed into tablets.

The weight of the tablet: 220 mg

Stamp: 9 mm

Example II

Tablets containing 5 mg of TRANS-O-(4-chlorophenylacetyl)-4-(4 - dimethylaminomethylphenol)-cyclohexanol

Obtained according to example I tablets according to the method covered by the shell, mainly consisting of Sahar

Suppositories containing 5 mg of TRANS-O-(4-chlorophenylacetyl)-4- (4-dimethylaminomethyl-phenyl)-cyclohexanol

Composition:

One suppository contains:

active start - 5.0 mg

the bulk of suppositories (e.g. Witepsol W 45) - 1695,0 mg

All 1700,0 mg

Way get:

Malabarismo active principle is suspended in the melted and cooled to 40oC the bulk of the suppository. When the temperature of the 37oC the mass is fed into a pre-cooled in the form of suppositories. The weight of the suppository: 1,7,

Example IV

Capsules containing 5 mg of TRANS-O-(4-[trifluoromethyl]-phenylacetyl)- 4-(4-dimethylaminomethyl-phenyl)-cyclohexanol

Composition:

One capsule contains:

active start - 5.0 mg

lactose - 82,0 mg

starch - 82,0 mg

magnesium stearate 1.0 mg

All 170,0 mg

Way get:

The powder mixture is intensively stirred and the filler serves in hard gelatin detachable capsules of size 3, and the final weight is continuously monitored.

Example V

Tablets containing 5 mg of TRANS-O-(4-bromophenylacetate)- 4-(4-dimethylaminomethyl-phenyl)-cyclohexanol

Composition:

One tablet contains:

mg

All 220,0 mg

Way get:

As a result of heating parts of potato starch receive 10% mucilage. The active principle, dairy residual sugar and potato starch are mixed together with mucus granularit through a sieve with openings of 1.5 mm Granulate is dried at 45oC, again passed through a sieve, mixed with magnesium stearate and pressed into tablets.

The weight of the tablet: 220 mg

Stamp: 9 mm

Example VI

Cream for topical application, containing 1 g of TRANS-O-(4-chlorophenylacetyl)-4-(4-dimethylaminomethyl-phenyl)-cyclohexanol

The preparation for topical application of the compounds of formula (I) may have the following composition:

1. the active principle - 1.0 g

2. stearyl alcohol 4.0 g

3. cetyl alcohol 4.0 g

4. mineral oil 3.0 g

5. Polysorbate 60 - 4.5 g

6. stearate sorbitan - 4.5 g

7. propylene glycol - 10.0 g

8. methylparaben - 0.18 g

9. propylparaben - 0.02 g

10. water to 100.00 g

Ingredients 2 - 6 heated to 80oC until complete melting. Then ingredient 1 is dissolved in the oil phase. Ingredients 7 and 10 is heated to 90oC and ingredients 8 and 9 are dissolved in the thus obtained aqueous phase. Then the aqueous phase is served in mass the project emulsion. With further stirring, the product is cooled to room temperature.

The following example describes how to obtain feed for laying hens.

Example VII

Feed for laying hens, containing as the active principle of TRANS-O-(4-chlorophenylacetyl)-4-(4-dimethylaminomethyl-phenyl)-cyclohexanol

Corn - 633 g/kg

soy flour 260 g/kg

meat flour - 40 g/kg

feed fat 25 g/kg

soybean oil - 17 g/kg

recalcitrant - 12 g/kg

calcium carbonate 6 g/kg

the mixture of vitamins and minerals to 5 g/kg

active start - 2 g/kg

As a result of intensive mixing these components in the indicated amounts get 1 kg of feed.

1. 0-acyl-4-phenylcyclohexanol General formula I

< / BR>
where n, m, p = 1;

R1and R2which may be identical or different, denote a hydrogen atom, an unbranched alkyl with 1 to 6 carbon atoms, unbranched of alkenyl with 3 to 6 carbon atoms, while the double bond is isolated from azoogleads communication and the above alkyl may be substituted by a residue from the group comprising hydroxyl, alkylcarboxylic, carboxyl, alkoxycarbonyl, aminocarbonyl, with the above-mentioned hydroxyl, alkitab>and R2together with the enclosed nitrogen atom of mean 5 - to 7-membered saturated monocyclic heterocyclic ring, formed thus 6-membered saturated monocyclic heterocyclic ring one methylene group in position 4 may be replaced by oxygen atom or unsubstituted or substituted alkyl with aminogroups;

R3and R4mean a hydrogen atom;

R5is a hydrogen atom, an unbranched or branched alkyl with 1 to 4 carbon atoms or alkoxy with 1 to 4 carbon atoms;

R6is a hydrogen atom,

R7is a hydrogen atom, cycloalkyl with 3 to 7 carbon atoms, phenyl, unsubstituted, mono - or disubstituted by a residue from the group comprising fluorine atom, chlorine and bromine, alkyl, alkoxy, phenyl, nitro, amino, alkylamino, dialkylamino, trifluoromethyl, while the substituents may be the same or different, and two adjacent hydrogen atom in the phenyl group may be substituted by methylendioxyphenyl or 1,2-ethylenedioxythiophene, phenyl, substituted by two chlorine atoms or bromine and one amino group, naphthyl or tetrahydronaphthyl, thienyl, furyl or pyridyl, substituted by a halogen atom or 1 or 2 alkyl groups;

A - link, nieroda, all of the aforementioned alkyl and CNS group, if nothing else is mentioned, may contain 1 to 3 carbon atom,

and their CIS/TRANS-isomers or their salts.

2. 0-acyl-phenylcyclohexanol General formula I on p. 1, representing a compound selected from the group including

(1) CIS-0-(4-chlorobenzoyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(2) CIS-0-(4-phenyl-3-butenyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(3) TRANS-0-(4-chlorophenylacetyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(4) CIS-0-(5-methylhexanoic)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(5) TRANS-0-(2-phenylpropionyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(6) TRANS-0-(4-pertenecer)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(7) TRANS-0-(3,4-dichlorophenylethyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(8) CIS-0-(4-forcename)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(9) TRANS-0-(p-tolylacetic)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(10) TRANS-0-(4-[trifluoromethyl]-phenylacetyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(11) TRANS-0-(2-naphthylacetyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(12) TRANS-0-(4-nitrophenylacetic)-4-(4-dimethylaminomethylene is-0-(2,4-dichlorophenylethyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(15) TRANS-0-([4-amino-3-chlorophenyl] acetyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(16) TRANS-0-(4-methoxyphenylacetyl)-4-(4-dimethylaminomethylphenol)-cyclohexanol

(17) TRANS-0-(4-chlorophenylacetyl)-4-(4-methylaminomethyl)-cyclohexanol,

and their physiologically acceptable salts with inorganic or organic acids.

3. The pharmaceutical preparation having the properties of an inhibitor of the enzyme amoxickllin-lanosterol-cyclase comprising the active principle and at least an inert carrier and/or diluent, characterized in that the active agent it contains 0-acyl-4-phenyl-cycloalkanes General formula I

< / BR>
where n, m, p = 1;

R1and R2may be identical or different, denote unbranched alkyl with 1 to 6 carbon atoms, or R1means a hydrogen atom and R2means unbranched alkyl with 1 to 6 carbon atoms;

R3, R4, R5, R6mean a hydrogen atom;

R7- cycloalkyl with 3 to 7 carbon atoms, phenyl, unsubstituted, mono - or disubstituted by a residue from the group comprising fluorine atom, chlorine and bromine, alkyl, alkoxy, phenyl, nitro, amino, alkylamino, dialkylamino, trifluoromethyl, Vice Vendicari or 1,2-ethylenedioxythiophene, phenyl substituted by two chlorine atoms or bromine and one amino group, naphthyl,

A - link, unbranched or branched alkylene with 1 to 6 carbon atoms or an unbranched albaniles with 2 to 4 carbon atoms; all the above alkyl and CNS group, if nothing else is mentioned, may contain 1 to 3 carbon atom,

and their CIS/TRANS-isomers or their salts.

 

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The invention relates to new compounds, levogyrate and programada, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -4-[(were)sulfonyl]-piperazine of the formula I:

< / BR>
the method of production of these compounds, their use as levogyrate and programalso, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -piperazine
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Derivative research // 2038353
The invention relates to compounds of amines having a high fungicidal activity, method of their production and to their use in agriculture as fungicides

The invention relates to new aralkylamines derivatives and their salts of interest as medicines, especially as a means of improving brain function, which can be shown senile dementia, Alzheimer's disease, etc

The invention relates to new compounds of the formula (I) in which R1represents a group of formula (Ia) or (IB), in which either R7represents an optionally protected hydroxy-group, alloctype, halogen, -OR10where R10represents lower alkyl, optionally protected-O(CH2)mHE, where m = 2 to 4, or-ОСОNН2and R7ais hydrogen, or R7and R7atogether represent oxoprop, R8represents a hydroxy or methoxy group, and R9- hydroxy - or alloctype; R2- hydrogen, alloctype or optionally protected hydroxy-group, and between the two carbon atoms connected by the dotted line, there is a simple or a double bond; R3is methyl, ethyl, n-propyl or allyl; or R4represents hydrogen or a hydroxy-group, and R4ais hydrogen, or R4and R4atogether represent oxoprop; or R5represents a hydroxy-group, and R5ais hydrogen, or R5and R5atogether represent oxoprop; and a represents a group of formula-CH(OR6)-CH2-(CH2)nor-CH= CH-(CH2)n- associated with carbon atom (CH2

The invention relates to new derivatives of Anthranilic acid of General formula (1) or their pharmacologically acceptable salts, where R1, R2, R3and R4- same or different and mean a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, nitro, cyano, pyrazolidine group, a group of the formula (II), where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula (III), where R13represents a hydrogen atom, a lower alkyl group, q is an integer from 0 to 2; and R2may be 1,2,4-triazoline group; R5and R6are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup, or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring; W represents a group - N = or-CH=; R7and R8are the same or different and represent a hydrogen atom, a lower alkyl group, or R1and R7together with the carbon atoms and nitrogen, respectively, to which they are attached, form the second alkyl group or a group of the formula-X-(CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-; Z represents hydrogen, halogen, phenyl group which may be substituted by lower alkyl, lower alkoxygroup, carboxypropyl or lower alkoxycarbonyl group, pyridyloxy group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, carboxypropyl, lower alkoxycarbonyl group, cycloalkyl group containing 3-8 carbon atoms which may be substituted by actigraphy, cyano, lower alkylcarboxylic, carboxypropyl or lower alkoxycarbonyl group, piperidino group, m is an integer from 0 to 6, Y is an oxygen atom; n is an integer from 0 to 6

The invention relates to new carboxamides f-ly 1, where E-N, G-H, lower alkyl, lower alkylene COOH, COO-lower alkyl, lower alkanoyl, lower alkanoyloxy, lower alkoxy, aryl-lower alkoxy, СОNH2and others, M-H, lower alkyl, lower alkenyl, aryl, heteroaryl, cycloalkyl, L-H, lower alkyl, aryl, cycloalkyl, or M and L together with the atoms to which they are linked, form a group - N (het), or E and G spot form a methylene or carbonyl group, and M represents H, lower alkyl, lower alkenyl, aryl, heteroaryl, cycloalkyl, L-H, lower alkyl, aryl , cycloalkyl, A-H, alkyl, aralkyl, Q represents a group of formula Q1or Q2T-CH2or Oh, R6and R7- H, cerboneschi alkoxy, HE

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