CH635812A5 - CYCLOALCANONES AND CYCLOALCANOLS SUBSTITUTED IN POSITION 3 BY A GROUP 2-HYDROXYPHENYL SUBSTITUTED IN POSITION 4 AND PHARMACEUTICAL COMPOSITION CONTAINING THEM. - Google Patents

Description

The present invention relates to cycloalkanones, cycloal-canols and their unsaturated analogs having 5 to 8 carbon atoms in the cycloalkyl ring and carrying in position 3 a 2-hydroxy-4- (substituent ZW) phenyl group in which Z is a radical. alkylene having 1 to 13 carbon atoms or a group (alk ^ —O— (alk2) n— in which each of the indices m and n is equal to 0 or 1 and each of the radicals (alkj and (alk2) is an alkylene radical having 1 to 13 carbon atoms, provided that the sum of the carbon atoms of (alkj) plus (alk2) does not exceed 13; W is a hydrogen atom, a phenyl, chlorophenyl, fluorophenyl or pyridyl group; their derivatives, intermediate compounds and methods for obtaining them. The products of the invention act on the central nervous system, in particular as analgesics, tranquilizers, sedatives and anxiolytic agents in mammals, including humans, and / or as anticonvulsants, diuretics and antidiarrheal agents ch and mammals, including humans.

Although there are a number of common pain relievers, there is always a search for new and improved agents, which shows that there is not one that can be used to combat pain to a large degree while producing minimal side effects. The most commonly used agent, that is, aspirin, is of no practical use in combating acute pain and it is known that this substance has various undesirable side effects. Other analgesic agents such as d-propoxyphene, codeine and morphine are at risk of addiction. It is therefore essential to find painkillers that are both powerful and without drawbacks.

U.S. Patent No. 3,576,887 describes a series of 1- (1'-hydroxy) alkyl-2-o-hydroxyphenylcyclohexane and -cyclo-hexene which can be used as intermediates for the production of 6.6 -dialkyltétrahydro- and -hexahydrodi-benzo [b, d] pyrannes exerting a depressive effect on the central nervous system.

We have just discovered that certain cycloalcanones, certain cy-cloalcanols and their unsaturated analogs carrying in position 3 a 2-hydroxy-4- (substituent) phenyl group (formula I below) exert an effect on the central nervous system, in particular as analgesics, tranquilizers, sedatives and anxiolytic agents in mammals, including humans, and / or as anticonvulsants, diuretics and antidiarrheals in mammals, including humans. The invention also relates to various derivatives of these compounds which are advantageous to use as dosage forms of the compounds in question, intermediate compounds relating to the compounds of formula I, and methods for obtaining them.

The compounds of the invention correspond to the formula:

(I)

Z -W

in which R represents a saturated or unsaturated cycloalkyl group corresponding to one of the formulas:

60

I-A (A, B taken individually)

II-A (A, B taken together)

I-B

II-B

635,812

4

I-C (A, B taken individually)

II-C (A, B taken together)

where the dashed lines represent an optional double bond in one of the corresponding positions, in which case R3 cannot be present;

Considered alone represents a hydrogen atom;

B considered alone represents a hydroxy group, a hy-droxymethyl group or an alkanoyloxy group having 1 to 5 carbon atoms (series of compounds of formula I);

A and B taken together (series of compounds of formula II) represent an oxo, methylene or alkylenedioxy group having 2 to 4 carbon atoms;

Rj is a hydrogen atom, an alkanoyloxy group having 1 to

5 carbon atoms, a benzyl group, a group - P (0) (0H) 2 or its monometallic and dimetallic salts of sodium and potassium, a group --CO (CH2) 2COOH or its sodium and potassium salts or a group - CO— (CH2) p — NR5R6 in which p is an integer having a value of 1 to 4; each of the symbols Rs and R6 represents, individually, a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; Rs and Re form,

with the nitrogen atom to which they are linked, a heterocyclic pentagonal or hexagonal nucleus chosen from piperidino nuclei,

pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino in which the alkyl radical contains 1 to 4 carbon atoms;

R2 is a hydrogen atom, an alkyl group having 1 to

6 carbon atoms, a phenyl group or a phenylalkyl group in which the alkyl radical contains 1 to 4 carbon atoms;

R3 is a hydrogen atom or a methyl group;

R4 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, provided that when R3 is a methyl group, R4 is a hydrogen atom;

Z represents: a) an alkylene group having 1 to 13 carbon atoms; b) a group - (alk,) m — O— (alk2) n— in which each of the radicals (alk ^ and (alk2) is an alkylene radical having 1 to 13 carbon atoms, provided that the sum of the atoms of carbon of (alkj plus (alk2) is not more than 13; each of the indices m and n is 0 or 1, and

W is a hydrogen atom, a pyridyl group or a group of formula:

W1

in which W! is a hydrogen atom or a fluoro or chloro radical.

The dotted lines in the compounds of formula I, that is to say in the formulas I-A to I-D, indicate the possible presence of a double bond in one of the positions in question.

The invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I which contain a basic group. Examples of these compounds include those in which the variable W is a pyridyl group and / or ORj represents a basic ester group. For compounds having two basic groups, addition salts of polyacids are naturally possible. Representative examples of these pharmaceutically acceptable acid addition salts are the salts of mineral acids such as hydrochlorides, hydrobromides, sulfates, phosphates, nitrates; the salts of organic acids such as citrates, acetates, sulfosalicylates, tartrates, glycolates, malates, malonates, succinates, gluconates, 2-hydroxy-3-naphthoates, lactates, mandelates and methanesulfonates.

Compounds of formula I-A to I-D in which A and B together form an oxo group and Rt is a hydrogen atom exist, in solution, in equilibrium with their hemicetal forms. The keto and hemicetal forms of the compounds of formula I are within the scope of the present invention.

Compounds of one of the formulas IA to ID in which A represents a hydrogen atom and B is a hydroxy group have centers of asymmetry in positions 1, 3 and 4 and, when the cycloalkyl group is formed of 6 with 8 links, in position 5 of the cycloalkyl group, and they can naturally have other centers of asymmetry in the substituents in positions 4 and 5 and in the group (—Z — W) of the phenyl ring. The relationship eis between the substituent in position 1 of the cycloalkyl group and the phenolic or phenolic group substituted in position 3 is appreciated and the trans relationships between substituents 3 and 4 and the substituents 4 and 5 of the cycloalkyl group are appreciated due to greater biological activity (greater quantitatively). For the same reason, the trans-3,4 relationship is appreciated in the compounds of formula I-A to I-D where A and B together represent an oxo group.

For convenience, the formulas given above represent the racemic compounds. However, these formulas are considered to be general formulas which cover the racemic forms of the compounds of the invention, the diastereoisomeric mixtures, and the enantiomorphs and pure diastereoisomers. The value of the racemic mixture, of the diastereoisomeric mixture as well as of the enantiomorphs and pure diastereoisomers is determined by the biological evaluation methods described below.

In addition to the compounds of formulas given above, various intermediate compounds of interest are also described here for use in the preparation of compounds of formula I. The intermediate compounds correspond to the following formulas II-IV:

GOLD.

(II)

(III)

(CH

(eis and trans isomers)

(the stereochemistry of which has not been shown), formulas in which Z, W, R2 and R3 have the definitions given above; Y is a cyano or formyl group;

t is an integer having a value from 1 to 8;

R7 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and

Q is chosen from groups - CH2 -, - CH2 — CH (R4) -, -CH2-CH2-CH (R4) - and -CH2-CH2-CH2 (R4) -.

The compounds of formula IV represent the hemicetal forms and the ketal forms of the saturated cycloalkyl compounds of formula I (A-D) or A and B together form an oxo group.

The compounds of formulas I-A to I-D in which A and B together form an oxo group are appreciated for their greater biological activity compared with that of other compounds described in the present specification; A and B, taken individually, represent a hydrogen atom and, respectively, a hydroxy group; R2 is a hydrogen atom or an alkyl group; Rx is a hydrogen atom or an alkanoyl group; R3 is a hydrogen atom or a methyl group; R4 is a hydrogen atom or an alkyl group; and Z and W have the values indicated below:

5

10

15

20

25

30

35

40

45

50

55

60

65

5

635,812

Z

m n

W

alkylene having 8 to 11 carbon atoms alkylene having 4 to 7 carbon atoms

(alk1) m-0- (alk2) n

(alkl) m- ° - (alk2) n

0 0

1 1

H

- <^ 3) * - Wi, pyridyle pyridyle

H

The compounds of formula I are appreciated, in particular the saturated cycloalkyl compounds of formula I, in which:

each of the symbols and R3 is a hydrogen atom;

Z is a group - C (CH3) 2 (CH2) e and W is a hydrogen atom;

Z is a C4 to C7 alkylene group and W is a phenyl group;

Z is an —O — alkylene group having 7 to 9 carbon atoms and W is a hydrogen atom;

Z is an —O — alkylene group having 4 or 5 carbon atoms and W is a phenyl group;

A is a hydrogen atom and B is a hydroxy group (eis and trans forms);

A and B together form an oxo group;

R2 is a hydrogen atom or a methyl, propyl or propenyl group;

R3 is a hydrogen atom, and

R4 is a hydrogen atom or a methyl group.

Particularly preferred are the saturated cycloalkyl compounds of formulas IB and IC in which R15 R2, R3, R4, Z and W have the definitions given for the preferred compounds, and A and B, considered individually, represent respectively hydrogen and a hydroxy group.

Likewise, with regard to the analgesic activity, a group of compounds formed from the preferred compounds mentioned above is particularly appreciated in which R2 is a methyl, propyl or propenyl group and each of the symbols R3 and R4 represents an atom d 'hydrogen.

The saturated cycloalkyl compounds of the present invention which correspond to formula I in which R3 is a hydrogen atom can be prepared from suitable 2-bromo-5- (Z-W substituent) phenol by a series of reactions comprising,

as a first step, the protection of the phenolic group. Suitable protecting groups are those which do not interfere with subsequent reactions and which can be removed under conditions which do not trigger adverse reactions at other sites of these compounds or of products formed from these compounds. Representative examples of these protective groups are methyl, ethyl, benzyl or substituted benzyl groups, the substituent of which is, for example, an alkyl radical having 1 to 4 carbon atoms, a halogen (Cl, Br, F or I) or a alkoxy group having 1 to 4 carbon atoms. The protecting or inhibiting groups by formation of an ether can be eliminated by using hydrobromic acid in acetic acid or a 48% aqueous solution of hydrobromic acid. The reaction is carried out at elevated temperatures and, advantageously, at reflux temperature. However, when Z is a group - (alk ^ —O— (alk2) n—, acids such as polyphosphoric acid or trifluoroacetic acid must be used to avoid cleavage of the ether bond. Other reagents such that hydroiodic acid, hydrochloride or pyridine hydrobromide can be used to remove the protective groups by formation of an ether such as methyl or ethyl groups. When the protective groups are benzyl groups or substituted benzyl groups, can be eliminated by catalytic hydrogenolysis. Suitable catalysts are palladium and platinum, especially when they are fixed on carbon. Alternatively, the protecting groups can be removed by solvolysis using trifluoroacetic acid. procedure consists in carrying out a treatment with n-butyllithium in a solvent inert with respect to the reaction, at ambient temperature.

The exact chemical structure of the protecting group is not critical to the invention, since its importance lies in its ability to behave as described above. The choice and identification of suitable protecting groups is without difficulty for those skilled in the art. To determine the ability and the effectiveness of a group to protect the hydroxy function, this group is used in the reaction sequences illustrated here. Naturally, it must be an easy group to eliminate in order to regenerate the hydroxy groups. The methyl and benzyl groups are preferred protecting groups, since they are easily removed.

The protected 2-bromo-5- (ZW substituent) phenol is then reacted with magnesium in an inert solvent and generally in the presence of a chosen activator, for example between cuprous salts such as chloride, bromide and l 'iodide (to favor the addition at positions 1,4), with the corresponding 4-R2-2-cycloalkene-1-one (for example 4-R2-2-cyclohexene-1-one). Suitable inert solvents are cyclic and acyclic ethers such as, for example, tetrahydrofuran, dioxane and the dimethyl ether of ethylene glycol (diglyme). The Grignard reagent is formed in a known manner, for example by heating under reflux of a mixture of a molar proportion of the brominated reaction substance and two molar proportions of magnesium in an inert solvent such as tetrahydrofuran. The resulting mixture is then cooled to a temperature of about 0 to -20 ° C and cuprous iodide is added, followed by the corresponding 2-cycloalkene-1-one, to a temperature of about 0 to - 20 ° C. The amount of copper iodide used is not critical, but can vary between wide limits. Molar proportions of approximately 0.2 to approximately 0.02 mol per mole of brominated reaction substance give satisfactory yields of cycloalkanone in which the hydroxyphenolic group is protected (formulas IA to ID, Rj = protective group; R3 = H; A + B = oxo).

The protected cycloalcanone is then treated with a reagent which is suitable for the removal of the protective group. The benzyl group is advantageously removed by the process described above. If the protecting group is an alkyl group (methyl or ethyl), it is removed by the methods mentioned above or by treatment, for example, with pyridine hydrochloride.

When R2 is an alkenyl group, the cycloalkenones thus produced serve as intermediate compounds for the preparation of the corresponding cycloalkenones (I-A to I-D) in which R2 is an alkyl group.

The cycloalkanoic compounds of formula I are prepared from protected cycloalcanones, by a reduction process. Sodium borohydride is advantageous to use as a reducing agent in this operation, since it not only gives satisfactory yields of the desired product, but it maintains the protective group on the hydroxyphenolic function and reacts relatively slowly with hydroxyl solvents such only methanol, ethanol and water so they can be used as solvents. Temperatures are generally used from about -40 to about 30 ° C. Lower temperatures, even lowering to about -70 ° C, can be used to increase the selectivity of the reduction. Higher temperatures cause the sodium borohydride to react with the hydroxylic solvent. If higher temperatures are desired or if they are necessary for a given reduction, isopropanol or dimethyl ether of diethylene glycol is used as solvents. Potassium trisec.-butylborohydride is sometimes advantageously used as a reducing agent, since it promotes the stereoselective formation of trans-1,3-phenylcycloalkanol. The reduction is carried out in anhydrous tetrahydrofuran at a temperature

5

10

15

20

25

30

35

40

45

50

55

60

65

635,812

6

less than about - 50 ° C using equimolar amounts of the ketone compound and the reducing agent.

Reducing agents such as lithium borohydride, diisobutylaluminum hydride and lithium aluminum hydride which can also be used require anhydrous conditions and non-hydroxylic solvents such as 1,2-dimethoxyethane, tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether.

The cycloalkanols of formula I in which A is a hydrogen atom and each of the groups B and ORj is a hydroxy group can naturally be obtained directly by catalytic reduction of the cycloalkanone protected by passage over palladium fixed on carbon or by catalytic reduction or chemical reduction of unprotected cycloalcanone (formula I, A + B = oxo, OR! = OH) using the reducing agents indicated above.

In actual practice, it is preferable to produce the unprotected cycloalkanols of formula I (A = H, B = ORt = OH) by reduction of the cycloalcanones protected by a benzyl group (formula I, A + B = oxo, OR! = benzyloxy) as described above, because one can thus exert a stereochemical influence on the reduction and on the formation of the eis hydroxy epimer as main product, which facilitates the separation and the purification of alcohols epimers.

Compounds of formulas IA to ID whose double bond occupies positions 2,3 are prepared by the Grignard reaction of the 2-bromo-5- (ZW substituent) corresponding protected phenol with a 3-alkoxy-2-cycloalkene-1- one (having 1 to 4 carbon atoms in the alkoxy group) in a solvent inert to the reaction, at a temperature of about -30 to 4-10 ° C. The protected cycloalkenone thus produced is then freed of the protecting group as described above and reduced to the corresponding cycloalkenol. Alternatively, the protected cycloalkenone is chemically reduced, for example using sodium borohydride, to the protected cycloalkenol which is then stripped of the protective group to regenerate the phenolic hydroxy group.

Compounds of formulas I-A to I-D whose double bond occupies positions 3,4 are prepared from compounds of formula I-A to I-D in which A + B forms an oxo group and the double bond is in positions 2,3. This process consists in ketalizing the corresponding compounds of formulas IA to ID unsaturated in positions 2, 3 with an alkylene glycol having 2 to 4 carbon atoms, in the presence of a dehydrating agent such as paratoluenesulfonic acid in a solvent such than benzene, which allows azeotropic elimination of the water formed as a by-product. The isomerization of the double bond takes place with formation of the unsaturated ketal in positions 3,4. Decetalization by treatment with a mild-acting acid gives the unsaturated compounds in positions 3,4 of formulas I-A to I-D where A + B represents an oxo group. Reduction of the oxo group as described above gives the corresponding alcohol.

The protected cycloaIc-2-enones (formulas I-A to I-D, A + B = oxo, Rj = protective group) can also be used as intermediate compounds for obtaining compounds of formula I in which R3 is a methyl group. The introduction of the substituent R3 is obtained by the combined addition of dimethylcopper-lithium to the corresponding cycloalk-2-enone. The process consists in reacting the suitably protected cycloalkenone with dimethylcopper-lithium in an inert solvent such as a cyclic or acyclic ether and in particular in tetrahydrofuran, at a temperature of about 0 to - 20 ° C. The organometallic reagent performs the addition at positions 1,4 on the protected cycloalkenone, with the formation of a tertiary carbon atom. The protected cycloalcanone carrying an R3 substituent is then freed from the protective group and reduced, or reduced and then freed from the protective group in accordance with the operations described above. The adduct in positions 1,2 is also formed.

Compounds of formula IB in which the cycloalkyl group is saturated and R4 represents something other than a hydrogen atom are prepared by reaction of the corresponding 2-bromo-5- (substituent ZW) phenol, the phenolic group of which is advantageously protected from as described above, with magnesium to form the Grignard reagent as previously indicated. The Grignard reagent thus obtained is then treated, without isolation, at reduced temperature, for example at a temperature of +10 to approximately - 20 ° C, with N, N-dimethylformamide. The reaction mixture is then allowed to warm to room temperature and the product, which is a protected 2-hydroxy-4- (Z-W substituent) benzaldehyde, is collected by known procedures. The ben-zaldehyde derivative is then converted to a <a- (2-hydroxy-4- (ZW substituent) phenyl) -3-alkenone via the Wittig reaction with suitable 1-triphenylphosphoranylidene-2-alkanone in a inert solvent, at a temperature whose approximate value is chosen between room temperature and the reflux temperature of the solvent. The 2-propanone derivative mentioned above allows the formation of the cyclohexyl group. The arylalkenone thus produced is then reacted with a dialkyl malonate, the alkyl groups of which preferably have 1 to 4 carbon atoms, to cyclize the alkenone. The reaction is carried out in an inert solvent such as an alcohol having 1 to 4 carbon atoms, at a temperature chosen between approximately 25 ° C. and the reflux temperature of the solvent.

The carbalkoxy-substituted cycloalcanedione which is produced is then decarboxylated by treatment with an aqueous solution of sodium or potassium hydroxide at elevated temperature, that is to say at a temperature of approximately 50 to 100 ° C., and the cycloalcanedione derivative is isolated by conventional procedures. It is then ketalized by reaction with methanol or with another alcohol having up to 4 carbon atoms or with an alkylene glycol having 2 to 4 carbon atoms, in the presence of a dehydrating acid such as paratoluenesulfonic acid.

In the case of the cyclohexylic derivative, 3-methoxy-2-cyclo-hexene-1-one is then reacted with lithium aluminum hydride in an inert solvent such as diethyl ether, dioxane , tetrahydrofuran or diglyme at a temperature of -10 to + 10 ° C, then treated with dilute mineral acid. The resulting aryl-substituted 2-cyclo-hexene-1-ones are then treated with the corresponding dialkylcopper-lithium in a suitable inert solvent such as hexane, diethyl ether or mixtures of these solvents or in cyclic ethers such as tetrahydrofuran, at a temperature of approximately 0 to approximately - 20 ° C. The protected 3- [4- (ZW substituent) -2-hydroxyphenyl] -5-R4-cycloalkanone is then freed from the protective group and reduced, or else reduced and then freed from the protective group, in accordance with the procedures described above.

As a variant, the reaction of 5- [2-benzyloxy-4- (ZW) -phenyl] -3-alkoxy-2-cyclohexene-1-ones with the corresponding Grignard reagent R4MgBr followed by acid hydrolysis gives the 5- [2-Benzyloxy-4- (ZW) -phenyl] -3-R4-2-cyclohexene-1-corresponding ones which are then catalytically reduced to the corresponding cyclo-hexanones. Debenzylation as described above gives the 5- [2-hydroxy-4- (Z-W) -phenyl] -3-R4-cyclo-hexanones which are then reduced as indicated above to the corresponding cyclohexanols.

Compounds of formula I-C in which the cycloalkyl group is saturated and R4 represents something other than a hydrogen atom are prepared by extension of the nucleus of the cyclohexylic derivative. The reaction of the corresponding 5- [2-benzyloxy-4- (ZW) -phenyl] -3-R4-eyclohexanone with lithium / dibromomethane in an inert solvent such as diethyl ether gives l-dibromomethyl-5- [2-benzyloxy-4- (ZW) -phenyl] -3-R4-cyclohexanol. By continuing the reaction of 1-dibromomethylcyclohexanol in an inert solvent such as tetrahydrofuran with n-butyllithium, the 3- [2-hydroxy-4- (ZW) -phenyl] -5-R4-cycloheptanones are obtained, which are then freed of the protective group and reduced, or else reduced and freed from the protective group, in accordance with the procedures described above.

5

10

15

20

25

30

35

40

45

50

55

60

65

7

635,812

Compounds of formula I-D in which the cycloalkyl group is saturated and R4 represents something other than a hydrogen atom are prepared by extension of the nucleus of the cycloheptyl derivative, in accordance with the operations described above.

When R4 is a hydrogen atom in formula IA to IC, it is possible, in accordance with the operations already described, to carry out the extension of the nucleus of these formulas into a larger nucleus of a methylene group, which corresponds , respectively, to structures IB to ID.

The reactional 2-bromo-5- (ZW substituent) phenols are prepared by bromination of the corresponding 3- (ZW substituent) phenol by conventional operations, for example by treatment with bromine in carbon tetrachloride at a temperature of about 20 at 30 ° C. The necessary 3- (ZW substituent) phenols are prepared, if not known, by the methods described herein. A practical process for the preparation of reactants in which Z is an alkylene group or (alk ^ —O— (alk2) „- involves the Wittig reaction on a suitable aldehyde such as 2- (3-hydroxyphenyl) -2- methylpropionaldehyde, the hydroxy group of which is protected by the formation of benzyl ether, which is then treated with the corresponding alkyltriphenylphosphonium bromide, the alkyl group of which extends the propionaldehyde group to the desired length. The reaction aldehyde is added to a suspension of sodium dimethyl and alkyltriphenylphosphonium bromide in di-methylsulfoxide at a temperature below 30 ° C., for example between 10 and 30 ° C. When the reaction is complete, the phenol alkene-substituted protected is collected by known procedures Hydrogenation of the alkene by passage over palladium fixed on carbon then gives the desired 3- (benzine ZW) phenol benzyl ether. udicious starting reactants such as aldehyde with 3-hydroxy-phenyl substituent and alkyltriphenylphosphonium bromide, gives the 3- (Z-W substituent) phenols.

The preparation of suitable 4-R2-2-cycloalkene-1-one allows the synthesis of the compounds of formulas I-A to I-D in which R4 is a hydrogen atom, in accordance with the procedures already described. Reaction of the corresponding 1,3-cycloalcanedione with an alcohol having 1 to 4 carbon atoms and an acid catalyst such as paratoluenesulfonic acid in an inert solvent such as benzene or toluene, and in the presence of an apparatus allowing to separate the water, at temperatures at which the reaction solvent flows back, gives the 3-alkoxy-2-cycloalkene-1-ones. Reaction of the corresponding 3-alkoxy-2-cycloalkene-1-one with lithio-diisopropyl amide in an inert solvent such as tetrahydrofuran in the presence of hexamethylphosphoramide and of the suitable compound R2X in which X is the bromide ion or iodide or a few other suitable leaving groups, gives 4-R2-3-alkoxy-2-cycloalkene-1-ones. Each 4-R2-3-alkoxy-2-cycloalkene-1-one is then reacted with lithium aluminum hydride in a reaction solvent such as diethyl ether, at temperatures of about - 10-10 ° C and the reaction product is treated with dilute mineral acid. The resulting 4-R2-2-cycloalkene-1-one is then transformed in accordance with the procedures already described.

Compounds of formulas IB to ID in which the cycloalkyl group is saturated and each of the variables R2 and R4 represents something other than a hydrogen atom, are prepared by reaction of 5- [2-benzyloxy-4- (ZW) - phenyl] -3-methoxy-2-cyclohexene-1-one with lithium diisopropylamide in an inert solvent at low temperature, for example between -50 and - 78 ° C. Hexamethylphosphor-amide and suitable R2 iodide (in which R2 represents something other than a hydrogen atom) are then added to produce a 5- [2-benzyIoxy-4- (ZW) -phenyl] -3-methoxy-6-R2-2-cyclohexene-1 -one. The subsequent reaction of this compound with the suitable Grignard reagent R'4MgX (in which R'4 is an alkyl group) under the usual conditions of a Grignard reaction gives 3- [benzyloxy-4- (ZW) -phenyl ] -4-R2-5-R'4-5-cyclohexene-1-one. By debenzylation and reduction of this compound according to the procedures described above, the desired 3- [2-hydroxy-4- (Z-W) -phenyl] -4-R2-5-R'4-cyclohexanole is obtained. The reduction of the double bond of 3- [benzyloxy-4- (ZW) -phenyl] -4-R2-5-R'4-5-cyclohexene-1-one on a catalyst consisting of palladium fixed on carbon, allows to obtain the corresponding saturated cyclohexanone derivative. Derivatives of this type can be used as intermediate compounds for the preparation of the corresponding derivatives of cycloheptanone and cyclooctanone by the nucleus extension method described above.

A practical procedure which allows the selective alkylation of

3- (2,4-dihydroxyphenyl) cycloalcanones at group level

4-hydroxy involves, as a first step, the transformation of 3- (2,4-dihydroxyphenyl) cycloalcanone into a ketal. The transformation is carried out in accordance with well known methods of ketalization, for example by reaction of 3- (2,4-dihydroxyphenyl) cyclo-alkanone with an alcohol, in particular an alcohol having 1 to 4 carbon atoms, in the presence of an acid such as sulfuric acid, paratoluenesulfonic acid, hydrochloric gas, under conditions capable of removing the water formed as a by-product. A preferred procedure consists in reacting 3- (2,4-dihydroxyphenyl) -cycloalkanone with an orthoformic ester in solution in an alcohol corresponding to the alcoholic group of the orthoformic ester. Trimethyl orthoformate and methanol are preferred reactants as are concentrated sulfuric acid, anhydrous hydrochloric gas or ammonium chloride as catalyst.

The ketal thus produced is then alkylated by reaction with a suitable alkylating agent such as a compound of formula WZX in which W and Z have the definitions given above, and X is chosen from chloro, bromo, mesyloxy (CH3 - SO2 — O) and tosyloxy (p-CH3 — C6H4 — SO2 — O—) in the presence of an acid acceptor such as sodium or potassium carbonate. The alkylated ketal is then decetalized by known operations, by treatment with an aqueous acid solution.

Another process for the preparation of 3- (substituent ZW) phenols in which Z is an alkylene group or a group (alk ^ ,,, —O— (alk2) n— involves the Wittig reaction on a suitable phenolic aldehyde or ketone , for example 3-hydroxybenzaldehyde or a 3- (hydroxyphenyl) alkylketone in which the hydroxyphenolic group is protected, for example by conversion into benzyl, methyl or ethyl ether. By the suitable choice of reactants, compounds bearing straight or branched chain alkylene groups (Z) can be produced. When a ketone such as 3-hydroxyacetophenone is used as the reactant, compounds are obtained in which Z carries a methyl group on the carbon atom adjacent to the phenyl group.

The substitution of a methyl or ethyl group at other sites, for example on the carbon atom of the alkylene group, is obtained by the choice of the corresponding carbalkoxyalkylidenetriphenylphosphorane, for example (C6H5) 3P = C (R ') —COOC2H5. The unsaturated ester thus produced is reduced to the corresponding alcohol by reaction with lithium aluminum hydride. As a variant,

when the group protecting the phenolic function is other than a benzyl group (for example a methyl group), the alcohol is produced by catalytic reduction of the unsaturated ester using palladium fixed on carbon, the reduction being followed by treatment of the saturated ester thus formed with lithium aluminum hydride. The transformation of the alcohol thus produced into the corresponding tosylate or mesylate, followed by the alkylation of the tosylate or methylate with an alkali metal salt of the corresponding HO— (alk2) —W reaction group, with final elimination of the protective group , gives the desired 3- (substituent ZW) phenol.

A variant relating to the above procedure involves the bromination of the alcohol instead of its transformation into a tosylate or a mesylate. Phosphorus tribromide is an advantageous brominating agent to use. The brominated derivative is then brought to react

5

read

15

20

25

30

35

40

45

50

55

60

65

635,812

8

with the compound HO— (alk2) —W corresponding in the presence of a suitable base (synthesis of Williamson ethers).

The brominated compounds are also advantageous to use as intermediate compounds for extending the chain of the alkyleni-group as in the above reaction sequence, in order to obtain compounds in which Z is an —alkylene — W group. The process involves treating the brominated derivative with triphenylphosphine to produce the corresponding triphenylphosphonium bromide. The reaction of triphenylphosphonium bromide with the suitable aldehyde or ketone in the presence of a base such as sodium hydride or n-butyllithium gives the unsaturated derivative which is then hydrogenated catalytically to the corresponding saturated compound.

Another method of introducing an alkyl or aralkyl group into the aromatic ring, and especially a group in which the carbon atom adjacent to the aromatic ring is a tertiary carbon atom, involves electrophilic aromatic substitution, catalyzed by an acid. , guaiacol with a tertiary alcohol in the presence of an acid such as methanesulfonic acid. The general procedure is to react a mixture of methanesulfonic acid and equimolar amounts of guaiacol and tertiary alcohol at temperatures of about 30 to about 80 ° C until the reaction is substantially complete. The product is isolated by pouring the reaction mixture onto ice, then extracting it with a suitable solvent such as methylene chloride. The 2-methoxyalkylphenol is then converted to the desired 3-alkylphenol by removal of the phenolic hydroxy group. The process involves converting the hydroxy group to a dialkylphosphate group by reaction with a dialkyl chlorophosphonate such as diethyl chlorophosphonate or with diethyl phosphonate and triethylamine. Treatment of the dialkylphosphate with lithium and ammonia followed by demethylation of the resulting alkylated methyl ether with boron tribromide or pyridine hydrochloride or other known demethylating agents gives the desired 3-alkylphenol.

A practical process for the preparation of compounds of the invention in which the group - Z - W is a group - O - (alk2) n - W consists in using 4-bromoresorcinol as a starting compound. The process involves protecting the two hydroxy groups of resorcinol by benzylation according to conventional procedures. The use of the benzyl group as a protecting group in this process is appreciated, since it can be easily removed by catalytic hydrogenation without cleavage of the ester group —O— (alk2) n — W. Naturally, other protective groups can also be used, such as alkyl groups (for example methyl or ethyl). However, the protective benzyl group is appreciated because it causes fewer side reactions. The protected 4-bromoresorcinol is then subjected to the Grignard reaction and reacted with the suitable cycloalkenone in an inert solvent, as described above. The 3- (2,4-dibenzyloxyphenyl) cycloalcanone thus produced is then subjected to a catalytic hydrogenation on palladium fixed on carbon, to produce the corresponding 3- (2,4-dihydroxyphenyl) cycloalcanone which exists in equilibrium with its hemicetal. The hemic-tal is then transformed into the alkyl ketal corresponding to an alkyl group in Q to C4, for example methyl, by reaction with, for example, a trialkyl orthoformate such as trimethyl orthoformate in a suitable solvent such as a C1 to C4 alcohol, for example methanol, in the presence of concentrated sulfuric acid. The alkyl ketal thus produced is then alkylated with the appropriate alkyl or aralkyl methanesulfonate or tosylate in the presence of anhydrous sodium or potassium carbonate in a suitably inert solvent such as N, N-dimethylformamide, at a temperature of about 75 to 100 ° C. This process offers the advantage of allowing the use of simpler compounds throughout the duration of the reactions. The O-alkylated or aralkylated ketal is then decetalized by reaction with, for example, hydrochloric acid, to produce the corresponding 3- (2-hydroxy-4- [0— (alk2) n] phenyl) cycloalcanone which exists in equilibrium with its hemicetal.

Since compounds of formulas I-A to I-D in which A and B together form an oxo group and R! is a hydrogen atom, in solution, in equilibrium with their hemicetal form and that some, in the crystalline state, exist almost completely in the hemicetal form, compounds of formulas IA to ID in which A and B form together an oxo and R group! is a hydrogen atom encompassing hemicetal as much as the ketone form.

Compounds of the invention in the formula of which A and B together form a methylene group are easy to prepare from the corresponding oxo compounds by Wittig reaction with methylenetriphenylphosphorane or another suitable methylide. The usual procedure consists in generating the Wittig reagent, that is to say the methylide, in situ and, immediately after its formation, in reacting it with the corresponding oxo compound. A practical method for generating methylide is to react sodium hydride with dimethylsulfoxide (sodium / dimsyl) at a temperature of about 50 to 80 ° C, usually until the evolution of hydrogen has ceased, then reacting the resulting methylsulfinyl (dimsyl) carbanion solution with, for example, methyltriphenylphosphonium bromide at a temperature of about 10 to about 80 ° C. The corresponding oxo compound is then added to the thus produced solution of the ylide and the mixture is stirred at temperatures the value of which is approximately between room temperature and 80 ° C. The methylene compound thus produced is isolated by known operations . A hydroboration / oxidation operation of the methylenic compound then gives the hydroxymethyl derivative taken as an example in the present specification. We appreciate the use of borane in tetrahydrofuran for the hydroboration operation, since it is a commercially available form, which gives satisfactory yields of the desired hydroxymethyl compound. The reaction is generally carried out in tetrahydrofuran or in dimethyl ether of diethylene glycol (diglyme). The borane obtained as a product is not isolated, but directly oxidized to the hydroxymethyl compound with an alkaline solution of hydrogen peroxide.

Other methods for forming methylide are naturally known and can be used in place of the method described above. Representative examples of these methods are given by Maerc-ker in "Organic Ractions", 14, 270 (1965). In the oxo compounds which correspond to formulas I-A to I-D, the hydroxyphenolic group can be protected, if necessary, for example by conversion into an alkanoyloxy derivative. Other protective groups can of course be used. The hydroxy group can be converted to ethers such as, for example, tetrahydropyrannyl ethers. However, protection of the hydroxyphenolic group is not absolutely necessary if a sufficient amount of a base is present to convert the hydroxyphenolic group to an alcoholate.

Esters of compounds of formulas IA to ID in which Rj is an alkanoyl group or a group —CO— (CH2) pNR5R6 are easy to prepare by reaction of compounds IA to ID in which Rt is a hydrogen atom, with the Corresponding alkanoic acid or an acid of formula HOOC— (CH2) pNR5R6 in the presence of a condensing agent such as dicyclohexylcarbodiimide. Alternatively, they can be prepared by reacting a compound of formulas IA to ID with the corresponding alkanoic acid chloride or anhydride, for example acetyl chloride or acetic anhydride, in the presence of a base such as pyridine.

Esters of compounds of formulas I-A to I-D, in which A is a hydrogen atom and B is a hydroxy or hydroxy-methyl group and ORj is a hydroxy group, are prepared by acylation according to the procedures described above. Compounds in which the R group (R = OH, CH2OH) is only acylated are obtained by gentle hydrolysis of the corresponding diacylated derivative, thus taking advantage of the greater ease with which the phenolic acyl group is hydrolyzed. The products thus formed can then be acylated with a different acylating agent to produce a diesterified compound carrying different ester groups.

5

10

15

20

25

30

35

40

45

50

55

60

65

9

635,812

The analgesic properties of the compounds of the invention have been demonstrated by tests using nociceptive stimuli.

Tests using thermal nociceptive stimuli a) Analgesic test of the hot plate (mouse)

The method used is the modified version from Woolfe and MacDonald, "J. Pharmacol. Exp. Ther. ”, 80, 300-307 (1944). A thermal stimulus of controlled size is made to act on the paws of mice placed on an aluminum plate 3.17 mm thick. A 250 W infrared heater with a reflector is placed under the aluminum plate. A thermal regulator, connected to thermistors placed on the surface of the plate, programs the heating radiator to maintain a constant temperature of 57 ° C. We drop each mouse in a glass cylinder (diameter of 16.6 cm) in support on the heating plate and the timer is started when the animal's legs come into contact with the plate. The mice are observed 'At h and 2 h after treatment with the test compound, to detect the first trembling movements of one or both of the hind legs, or else a period of 10 s is allowed to pass by. absence of such movements. Morphine has an EMP50 value of 4 to 5.6 mg / kg (subcutaneously).

b) Analgesic test for sudden tail spreading (mouse)

The sudden tail spreading test in mice is the modified version from D'Amour and Smith, "J. Pharmacol. Exp. Ther. ”, 72, 74-79 (1941), in which a high intensity thermal excitation, of set value, is applied to the tail. Each mouse is placed in a suitably adjusted metal cylinder, the tail projecting from one end. This cylinder is arranged so that the tail is laid flat on a heat lamp which is hidden. At the start of the test, an aluminum shutter placed on the lamp is removed; the light beam can thus pass through the slit and can be focused on the end of the tail. A stopwatch is simultaneously activated. The latency period is determined before carrying out an abrupt spreading of the tail. Usually, untreated mice react 3 to 4 s after exposure to the action of the lamp. The reaction threshold, for a protective effect, is equal to 10 s. Each mouse is tested for 1 h and 2 h after treatment with morphine and with the test compound. Morphine has an EMP50 value between 3.2 and 5.6 mg / kg (subcutaneous).

c) Tail immersion method

This method is a modified version of the receptacle method developed by Benbasset et al., As described in "Arch. int. Pharmacodyn. ”, 122, 434 (1959). Males of albino mice (19-21 g) of Charles River CD-1 strain are weighed and marked for identification. Five animals are normally used in each treatment group using the active substance, each animal constituting its own control. For general selection purposes, new test substances are first administered at a dose of 56 mg / kg intraperitoneally or subcutaneously, delivered in a volume of 10 ml / kg. Before treatment with the active substance, then Vi h and 2 h after this treatment, each animal is placed in the cylinder. Each cylinder has holes which provide satisfactory ventilation and is closed with a circular nylon plug through which the tail of the animal projects. The cylinder is kept in a vertical position and the tail is completely immersed in the water bath at constant temperature (56 ° C). The reaction threshold in each trial consists of an energetic jerking or a tightening of the tail, together with a motor response. In some cases, the reaction threshold may be less vigorous after administration of the active substance. To prevent unwanted tissue damage, the test is stopped and the tail is removed from the water bath after 10 s. The latency period of the response is ex-primed in seconds, rounded to the nearest half-second. A control (vehicle) and a reference substance of known potency are tested at the same time as the candidates for selection. If the activity of a test substance has not returned to the basic values after 2 h of the test, the response lag periods are determined after 4 and 6 h. A final measurement is made after 24 hours if there is still activity at the end of the test day.

Test using chemical nociceptive stimuli

Suppression of tension caused by irritation with phe-nylbenzoquinone

Groups of 5 Carworth Farms CF-1 farmed mice are pretreated by subcutaneous or oral administration of physiological solution of salt, morphine, codeine or the test compound. 20 min (in case of subcutaneous treatment) or 50 min (in case of oral treatment) later, each group of mice is treated by intraperitoneal injection of phenylbenzoquinone, an irritant substance known for its ability to cause abdominal contractions. The mice are observed for 5 min to detect the presence or absence of tension, starting 5 min after the injection of the irritant. The EMP50 values for inhibition of tension are determined for the pretreatments using the active substances.

Tests using pressure-stimulating nociceptive stimuli

Effect produced in the Haffner tail pinch method

A variant of Haffner's method, "Experimentelle Prüfung schmerzstillender.", In "Deutsch Med. Wschr. ”, 55, 731-732 (1929) to determine the effects of the test compound on the aggressiveness responses triggered by a tail pinching stimulus. The animals used are male albino rats (50-60 g) of Charles River (Sprague-Dawley) CD strain. Before treatment with the drug, then again At 1 a.m., 1 a.m., 2 a.m. and 3 a.m. after treatment, a 6.35 cm Johns Hopkins bulldog clip is fitted to the root of the rat's tail. The reaction threshold for each trial consists of a clear attack and bite behavior directed towards the excitation stimulus, and the latency period before the attack is noted in seconds. The clamp is removed after 30 s if the attack has not yet taken place and it is then considered that the reaction latency period is 30 s. Morphine is active at a dose of 17.8 mg / kg (intraperitoneally).

Tests using electrical nociceptive stimuli Flex-jump test

A modified version of the jump after flexion method according to Tenen, "Psychopharmacologia", 12, 278-285 (1968) is used to determine the pain thresholds. The animals used are males of albino rats (175-200 g) of Charles River strain (Sprague-Dawley) CD. Before the administration of the active substance, the legs of each rat are immersed in a physiological salt solution containing 20% glycerol. The animals are then placed in a room and their legs are exposed to a series of pulses lasting 1 s, delivered at increasing intensity at intervals of 30 s. These intensities are equal to 0.26, 0.39, 0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3 , 04 mA. The behavior of each animal is noted by observing; a) the execution of a sag, b) the emission of shouts, and c) the execution of a jump or a rapid movement forward, when the impulse is triggered. A single increasing series of pulse intensities is made to act on each rat just before treatment with the drug as well as Vi h, 2 h, 4 h and 24 h after.

The results of the above tests were expressed by the maximum possible effect (EMP%). The EMP% value of each group was compared by a statistical method to the EMP% value of the reference substance and that of the control before administration of the drug. The EMP% value is calculated according to the following relation:

5

10

15

20

25

30

35

40

45

50

55

60

65

635,812

10

EMP%

test time — control time deletion time — control time x 100

When the compounds of the invention are used as analgesic agents by oral or parenteral administration, they are advantageously administered in the form of a composition. The compositions contain a pharmaceutical carrier selected according to the desired route of administration and normal pharmaceutical practice. For example, they can be administered in the form of tablets, pills, powders or granules containing excipients such as starch, lactose, certain types of clay, etc. They can be administered in capsules, in admixture with the same or equivalent excipients. They can also be administered in the oral form of suspensions, solutions, emulsions, syrups and elixirs, which may contain perfumes and dyes. For oral administration of the therapeutic agents of the invention, tablets or capsules containing from about 0.01 to about 100 mg are almost suitable in each case.

The physician is able to determine the dosage which is most suitable for an individual and which varies with the age, weight and reaction of the particular patient as well as the route of administration. However, in general, the initial analgesic dosage in adults can range from about 0.1 to about 750 mg / d in a single or multiple doses. In many cases, it is not necessary to exceed a dose of 100 mg / d. The preferred oral dosage range is from about 1.0 to about 300 mg / d; the preferred dose is from about 1.0 to about 50 mg / d. The preferred parenteral dose ranges from about 0.1 to about 100 mg / d; the preferred dose is from about 0.1 to about 20 mg / d.

The invention also relates to pharmaceutical compositions, including their unit dosage form, which advantageously allow the use of the new compounds as analgesics and in other applications indicated herein. The dosage form can be administered in one or more doses, as indicated above, to cover the effective daily dosage for a particular application. 35

The compounds (drugs) described herein can be formulated for administration in solid or oral or parenteral liquid compositions. Capsules containing the medicaments of the invention are prepared by mixing one part by weight of medicament with 9 parts of an excipient such as 40

starch or lactose, then loading the mixture into interlocking gelatin capsules so that each capsule contains 100 parts of the mixture. Tablets containing these compounds are prepared by formulating suitable mixtures of medicament and ingredients conventionally used in the preparation of tablets, for example starch, binders and lubricants, so that each tablet contains 0 , 10 to 100 mg of active substance.

Suspensions and solutions of these active substances, in particular those in which Ri (formulas I and II) is a 50 hydroxy group, are often prepared just before administration so as to avoid problems of stability of the suspensions or solutions (for example by precipitation) of the active substance during storage. Advantageous compositions for use for this purpose are generally dry powder compositions, which are reconstituted for administration by injection.

The analgesic activity of various compounds of the invention was determined by the above methods. These compounds correspond to the following formula:

The following abbreviations have been used in the tables: PBQ = tension caused by phenylbenzoquinone; EQ = sudden tail spread; PC = hot plate; PQR = rat tail pinch test and FS = flexion-jump.

The values reproduced individually in the tables are the ED50 doses. A number followed by another number in parentheses indicates the percentage of protection observed for a given dose. Thus, 31 (56) corresponds to 31% protection for a dose of 56 mg / kg of body weight.

-o fi

I £

S O

S 1

hî Q

a • S *

a s: q z-w

Table I: A = H, B = OH; Table II: A + B = oxo.

PQR

4.7

5.6

7.7

CO

you

O "" fr "n rf vf en

EQ

6.8

65 (10) 32 (10)

PC

IA (10) 27 (10)

PBQ

in m ïnin * o vo> -h

A \ s 8 - S £ 3 S A \ V / V /

£

KS as KÏÏUÛJIÏÏÏSÛUÏ

NOT

“Pï V — s / - • s N M

"" O HH M <0 <© "O" "O <0 ✓ -— s / —s tH HH N / —S." "- n

N N C * r \ r Ì tS M (S (S rs N MMMUvmhhmmm HH HH HH HH HH HH HU HH HH HH

uuu - ^^ ouuuu u

"" N "" "N K K" "" N

/ -— s / —s / —N r ^ ri 'N / ■ "-" "—N" --S

f) I ci W WfOfOfOfONtSfO

ÜUÜOnUUUUU Ö, y, -U UUUOOUUUUUOO

"

fO

SB u

V)

vs

<S

m n

X s u u

CA CO

c c aSGKEKEEK S S SES

m cis-OH

trans-OH

cis-OH

trans-OH

cis-OH

trans-OH

cis-OH

cis-OH

trans-OH

trans-OH

trans-OH

cis-OH

cis-OH

X

11

635,812

PQR

4.4

C / 3 b

10.8

EQ

15.3 58 (10)

PC

31 (56) 33 (10)

PBQ

4.5 H

20 (56)

> 56

20 (56)

2.15

15 (56)

32 (56)

43 (56)

1.51

£

£

ÏÏSUÏEÏÏÏÏ

NOT

fO

/ —S

NOT

O «« M «« «<0

S / —v «v | ± | S / —S. — S s

NOT

HH Nrt HH W HH HH HH HH hH HH HH 'w' HH HH HH NH

YES ^ UUU u

V "W 'W M \ w- s« / V «/ N N N> i (C4 N N s r r - / - V s /» V

"Wj s" / f) <o f) (o

EEEhH-SKSC X UOUrjUUU u

-W -W N— 'VW N—' S— '_ _

uuuouuuoou f)

not

ïusx «usn

M

"

X

u i

u

MM> H HH HH M M NH HH HH HH HH MH MH HH HH HH HH HH O

II

"S

4 * o <

oooooooooo x

"

o G

"4>

M

a X O

<u a

= 1

or

W)

3

* o

Ì?

s <.

<D

u s • • o BO, u O

D3 -U

B

£ cd

Their activity as diuretic agents was determined by the method of Lipschitz et al., "J. Pharmacol. ”, 197.97 (1943) which uses rats as test animals. The dosage range for this application is the same as that indicated above with regard to the use of the compounds of the invention as analgesic agents.

The antidiarrheal activity is determined by a modified version of the method of Neimegeers and collaborators described in "Modem Pharmacology-Toxicology", edition Willem van Bever and Harbans Lai, 7, 68-73 (1976). Charles River CD-1 5 rats (170-200 g) are grouped in cages 18 h before the test. The animals are made to fast for approximately 16 h by leaving them water at will, then they are made to absorb castor oil. The test drug is administered subcutaneously or orally at a constant volume of 5 ml / kg of body weight in a vehicle composed of 5% ethanol, 5% Emulphor EL-620 (emulsifier based on polyoxyethylated vegetable oil from the firm Antara Chemicals, New York, NY) and 90% of physiological salt solution and, 1 h later, the rats are subjected to a castor oil test (1 ml, orally). The animals are installed in small individual cages-15 (20.5 x 16 x 21 cm) fitted with funds suspended in wire cloth. A disposable cardboard sheet is placed below the wire mesh bottoms and examined 1 hour after the castor oil test for the presence or absence of diarrhea. A group treated with the vehicle and castor oil is used as a control for each test day. The results are expressed by the number of animals protected 1 h after the test. In general, the doses of administration of these compounds as antidiarrheal agents are parallel to the doses used in analgesic applications.

The tranquilizing activity of the compounds of the invention is determined by oral administration of these compounds to rats, at doses of about 0.01 to about 50 mg / kg of body weight and observing the subsequent decrease in activity spontaneous motor. The daily dosage range for mammals is from about 0.01 to about 100 mg.

Anticonvulsant activity is determined by subcutaneous administration of the test compound to males of Swiss (Charles River) mice weighing 14-23 g in a vehicle of the type used for antidiarrheal application. Groups of five mice are used. 35 The day before the administration, the mice are made to fast throughout the night, but they are given water at will. The treatments are carried out at volumes of 10 ml / kg using a hypodermic needle No. 25. Animals are treated with the test compound and, 1 h after the test, they are subjected to an electric shock 40 (50 mA, 60 Hz) applied transcorneally. At the same time, control tests are carried out in which the mice are only made to absorb the vehicle. The electroshock treatment causes tonic convulsions of the extensors in all the control mice, with a latency period of 1.5 to 3 s. It is considered that there is protection when a mouse no longer exhibits tonic convulsions of the extensors for 10 s after the application of the electroshock.

The anxiolytic activity is determined by a method similar to the method for determining the anticonvulsant activity, with the difference that the substance causing the convulsions is pentylenet-trazole administered intraperitoneally at a dose of 120 mg / kg. This treatment produced clonic convulsions in less than 1 min in more than 95% of the control mice treated. Protection is considered to exist when the latency period of convulsions is delayed s5 by at least a factor of 2 by prior treatment with the active substance.

The sedative / depressive activity is determined by treating groups of six mice by subcutaneous administration of various doses of the active substances. 30 and 60 min after the treatment, the mice are placed on a rotating bar for a test period of 1 min and their behavior is assessed on this bar. The inability of mice to stand on the rotating bar is considered to be evidence of sedative / depressive activity.

Example 1:

65

3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenylJcyclohexanone

A solution of 75.0 g (0.193 mol) of 2- (3-benzyloxy-4-bromophenyl) -2-methyloctane in 200 ml of tetrahy- is slowly added

635,812

12

drofuran to 9.25 g (0.386 mol) of metallic magnesium in particles of 0.177 to 0.210 mm. The resulting mixture is refluxed for 20 min, then cooled to -18 ° C. 1.84 g (9.7 mmol) of cuprous iodide are added and stirring is continued for 10 min. A solution of 18.5 g (0.193 mol) of 2-cyclohexene-1-one in 40 ml of tetrahydrofuran is slowly added to the resulting mixture at a rate chosen so that the reaction temperature is kept below -3 ° C by cooling with a mixture of salt and ice. The reaction mixture is stirred for a further 30 min (temperature below 0 ° C), then it is poured into 500 ml of 2N hydrochloric acid and 21 of ice water. The deactivated reaction mixture is extracted three times with 500 ml portions of ether. The combined extracts are washed twice with 100 ml portions of water, twice with 100 ml portions of saturated sodium chloride, dried over magnesium sulfate and evaporated leaving an oil. The oil is purified by column chromatography on 1.6 kg of silica gel, and elution with 20% ether in cyclohexane gives 62.5 g (79.7%) of product in the form of an oil.

Infrared spectrum: (CHC1,) 1709, 1613 and 1575 cm-1.

Mass spectrum: m / e 406 (M +), 362, 321, 315 and 91.

The compounds listed below were prepared from 2-benzyloxy-4-Z-W-bromobenzenes and corresponding cycloalkenones, following the above procedure.

3- [2-Benzyloxy-4- (2- (5-phenylpentyloxy) j phenyl] cyclohexanone in the form of an oil (3.6 g, 87%) from 2-benzyloxy-4- [2- ( 5-phenylpentyloxy)] - bromobenzene (4.0 g, 9.4 mmol).

Infrared spectrum: (CHC13) 1712, 1616 and 1592 cm-1.

Mass spectrum: m / e 422 (M +), 351, 323, 296, 278, 253, 205 and 91.

Trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4-methyl-cyclohexanone as an oil (5.11 g, 61%) from 2-benzyloxy-4 - (1,1-dimethylheptyl) bromobenzene (7.83 g, 0.0201 mol) and 4-methylcyclohex-2-enone (2.21 g, 0.0201 mol).

Infrared spectrum: (CHC13) 1712, 1613 and 1575 cm-1.

Mass spectrum: m / e 420 (M +), 363, 335, 329, 273, 271 and 91.

3-f 2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclopentanone in the form of an oil (3.5 g, 58%) from 2-benzyloxy-4- (1,1-dimethylheptyl ) bromobenzene (6.00 g, 15.4 mmol); Rf = 0.43 (0.25 ml of silica gel, elution with a 1/1 mixture of ether and hexane).

3- [3-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] cycloheptanone in the form of an oil (2.94 g, 46%) from 2-benzyloxy-4- (1,1-dimethylheptyl ) bromobenzene (6.00 g, 15.4 mmol) and cyclo-heptenone (1.69 g, 15.4 mmol).

3- (2,4-Dibenzyloxyphenyl) cyclohexanone in the form of a solid substance (17.9 g, 40%), melting at 108-109 ° C, from l-bromo-2,4-dibenzyloxybenzene (43 g, 0.116 mol) and cyclohex-2-enone (11.1 g, 0.116 mol). The product is recrystallized from a mixture of ether and pentane.

Infrared spectrum: (CHC13) 1709, 1618 and 1595 cm-1.

Mass spectrum: m / e 295, 181 and 91.

O

Analysis for C26H26O3:

Calculated: C 80.80 H 6.78%

Found: C 80.88 H 6.80%

3- [2-Benzyloxy-4- (1,1-dimethyloctyl) phenyl] cyclohexanone in the form of an oil (5.0 g, 46%) from 2- [benzyloxy-4-bromophenyl) -2- methylnonane (10.4 g, 0.0258 mol) and 2-cyclohexene-1-one (2.48 g, 0.0258 mol).

Infrared spectrum: (CHC13) 1715, 1618 and 1577 cm- '.

Mass spectrum: m / e 420 (M +), 377, 329 and 321.

3- [2-Benzyloxy-4-tertiobutyIphenyl] cyclohexanone in the form of an oil (27.6 g, 58%) from 2- (3-benzyloxy-4-bromo-phenyl) -2-methylpropane (45 , 4 g, 0.142 mol) and 2-cyclohexene-1-one (13.9 g, 0.145 mol).

Infrared spectrum: (CHC13) 1724, 1623 and 1582 cm-1.

Mass spectrum: m / e 336 (M +), 321, 293, 245 and 91.

3- [2-Benzyloxy-4- (1,1-dimethylpropyl) phenyl] cyclohexanone in the form of an oil (15.8 g, 63%) from 2- (3-benzyloxy-4-bromophenyl) - 2-methylbutane (24.0 g, 0.0721 mol) and 2-cyclo-hexene-1-one (7.06 g, 0.0735 mol).

Infrared spectrum: (CHC13) 1718, 1618 and 1575 cm-1.

Mass spectrum: m / e 350 (M +), 335, 321, 307,259 and 91.

3- [2-Benzyloxy-4- (1,1-dimethylbutyl) phenyl] cyclohexanone in the form of an oil (15.1 g, 42%) from 2- (3-benzyloxy-4-bromophenyl) - 2-methylpentane (34.8 g, 0.100 mol) and 2-cyclohexene-1-one (10.5 g, 0.110 mol).

Infrared spectrum: (CHC13) 1736, 1631 and 1592 cm-1.

Mass spectrum: m / e 364 (M +), 321, 273 and 91.

Trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-propé-nyl) cyclohexanone in the form of an oil (58.3 g, 70%) from 1 -bromo-2-benzyloxy-4- (1,1-dimethylheptyl) bromobenzene (73.0 g, 0.188 mol) and 4- (2-propenyl) -2-cyclohexene-l-one (25.5 g, 0.188 mol).

Infrared spectrum: (CHC13) 1712,1645, 1613 and 1575 cm-1.

Mass spectrum: m / e 446 (M +), 360, 354 and 91.

3- [2-BenzyIoxy-4- (1,1-dimethylpentyl) phenyl] cyclohexanone in the form of an oil (11.5 g, 37%) from 2- (3-benzyloxy-4-bromophenyl) - 2-methylhexane (29.6 g, 0.0818 mol) and 2-cyclohexene-1-one (8.63 g, 0.09 mol).

Infrared spectrum: (CHC13) 1730, 1629 and 1592 cm-1.

Mass spectrum: m / e 378 (M +), 335, 321, 287 and 91.

3- [2-Benzyloxy-4- (1,1-dimethylhexyl) phenyl] cyclohexanone in the form of an oil (11.0 g, 35%) from 2- (3-benzyloxy-4-bromophenyl) - 2-methylheptane (30.2 g, 0.0806 mol) and 2-cyclo-hexene-1-one (8.5 g, 0.0886 mol).

Infrared spectrum: (CHC13) 1715, 1623 and 1585 cm-1.

Mass spectrum: m / e 392 (M +), 348, 321, 301, 259 and 91.

3- [2-Benzyloxy-4- (1,1-dimethylnonyl) phenyl] cyclohexanone in the form of an oil (13.5 g, 43%) from 2- (3-benzyloxy-4-bromophenyl) - 2-methyldecane (30.5 g, 0.073 mol) and 2-cyclo-hexene-1-one (7.71 g, 0.0803 mol).

Infrared spectrum: (CHC13) 1715, 1623 and 1582 cm-1.

Mass spectrum: m / e 434 (M +), 342, 321 and 91.

3- [2-Benzyloxy-4- (1,1-dimethyldecyl) phenyl] cyclohexanone in the form of an oil (7.0 g, 17%) from 2- (3-benzyloxy-4-bromophenyl) - 2-methylundecane (40.0 g, 0.0928 mol) and 2-cyclohexene-1-one (9.8 g, 0.102 mol).

Infrared spectrum: (CHC13) 1715, 1623 and 1585 cm-1.

Mass spectrum: m / e 448 (M +), 321 and 91.

3- [2-Benzyloxy-4- (1,1-dimethylundecyl) phenyl] cyclohexanone in the form of an oil (11.5 g, 40%) from 2- (3-benzyloxy-4-bromophenyl) - 2-methyldodecane (27.5 g, 0.062 mol) and 2-cyclo-hexene-1-one (6.68 g, 0.0682 mol).

Infrared spectrum: (CHC13) 1718, 1623 and 1585 cm-1.

Mass spectrum: m / e 462 (M +), 417, 371, 321 and 91.

3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclooctanone in the form of an oil (10.6 g, 63%) from 2- (3-benzyloxy-4-bromophenyl) - 2-methyloctane (15.0 g, 38.6 mmol) and 2-cyclo-octene-1-one (4.78 g, 38.6 mmol).

Infrared spectrum: (CHC13) 1715, 1629 and 1587 cm-1.

Mass spectrum: m / e 434 (M +), 477, 363, 349, 343, 326 and 91.

Example 2:

3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] cyclohexanone

A mixture of 19.5 g (0.0468 mol) of 3- [2-benzyloxy-4- (1,1-dimethyl-heptyl) phenyl] cyclohexanone is stirred under hydrogen pressure of 1 bar for 1.5 h , 12.3 g of sodium bicarbonate, 3.00 g of 10% palladium fixed on carbon and 250 ml of ethanol. The reaction mixture is then filtered through diatomaceous earth using ethyl acetate and the filtrate is evaporated to dryness. The crude solid is purified by column chromatography of 280 g of silica gel and elution is carried out with 20% ether in cyclohexane to obtain a solid. By recristal5

io

15

20

25

30

35

40

45

50

55

60

65

13

635,812

lization of this solid substance in aqueous methanol, 9.1 g (62%) of the product indicated in the title are obtained, melting at 87 ° C., mainly in the hemicetal form.

Infrared spectrum: (KBr) 3226,1629 and 1580 cm-1.

(CHC13) 3571, 3289, 1704, 1623 and 1575 cm- '.

Mass spectrum: m / e 316 (M +), 298,273 and 231.

Analysis for C2 iH3202:

Calculated: C 79.70 H 10.19%

Found: C 79.69 H 9.89%

The above procedure was repeated using the corresponding reactants of Example 1, and the following products were thus obtained:

3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] -3-methylcyclo-hexanone in the form of an oil (54 mg, 86%) from 80 mg (0.19 mmol) of 3 - [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methylcyclohexanone.

Infrared spectrum: (CHC13) 3597, 3390, 1623 and 1572 cm-1. Mass spectrum: m / e 330 (M +), 315, 287 and 245.

Trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4-methyl-cyclohexanone (825 mg, 99%), melting at 62-64 ° C (after recrystallization from pentane) from trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4-methylcyclohexanone (1.05 g, 2.50 mmol).

Infrared spectrum: (CHC13) 3571, 3333,1721 (weak), 1626 and 1577 cm-1.

Mass spectrum: m / e 330 (M +), 312, 288, 273, 245, 203 and 161.

Analysis for C22H34O2:

Calculated: C 79.97 H 10.37%

Found: C 80.33 H 10.30%

3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] cyclopentanone (0.54 g, 47%), melting at 61-62 ° C (after recrystallization from pentane) from 3- [2- benzyloxy-4- (1,1-dimethylheptyl) phenyl] -cyclopentanone (1.50 g, 3.83 mmol).

Infrared spectrum: (KBr) 3279, 1739, 1621 and 1577 cm "1. Mass spectrum: m / e 302 (M +), 283.217, 189, 175 and 161.

Analysis for C20H30O2:

Calculated: C 79.42 H 10.00%

Found: C 79.65 H 10.03%

3- [4- (1,] - Dimethylheptyl) -2-hydroxyphenyl] cycloheptanone (795 mg, 63%), melting at 78-79 ° C (after recrystallization from pentane) from 3- [2-benzyloxy- 4- (1,1-dimethylheptyl) phenyl] -cycloheptanone (1.60 g, 3.80 mmol).

Infrared spectrum: (CHC13) 3571, 3289, 1701, 1621, 1605 and 1577 cm- '.

Mass spectrum: m / e 330 (M +) and 245.

Analysis for C22H34O2:

Calculated: C 79.95 H 10.37%

Found: C 79.60 H 10.33%

Quantitative yield of 3- [2-hydroxy-4- (2- (5-phenylpentyl-oxy)) phenyl] cyclohexanone in the form of an oil from 3- [2-benzyloxy-4- (2- (5 -phenylpentyloxy)) phenyl] cyclohexanone (1.0 g, 2.26 mmol).

Infrared spectrum: (CHC13) 3571, 3333, 1709, 1623 and 1587 cm- '.

Mass spectrum: m / e 352 (M +), 206,188 and 91.

3- (2,4-Dihydroxyphenyl) cyclohexanone in the form of a solid substance (8.5 g, 94%), melting at 158 C (after recrystallization from isopropyl ether) from 3- (2 , 4-dibenzyloxyphenyl) -cyclohexanone (16.9 g, 43.7 mmol).

Infrared spectrum: (KBr) 3195, 1631 and 1603 cm- '.

Mass spectrum: m / e 206 (M +), 188,163,149 and 136.

Analysis for C12H1403:

Calculated: C 69.88 H 6.84%

Found: C 69.94 H 6.78%

3- [4- (1,1-Dimethyloctyl) -2-hydroxyphenyl] cyclohexanone (0.75 g, 48%) from 2.00 g (4.76 mmol) of 3- [2-benzyloxy-4- (1,1-dimethyloctyl) phenyl] cyclohexanone. Melting point: 78-80 ° C (after recrystallization from pentane).

Infrared spectrum: (CHC13) 3571, 3333,1709 (weak), 1626 and 1577 cm- '.

Mass spectrum: m / e 330 (M +), 314, 312, 287 and 231.

Analysis for C22H34O2:

Calculated: C 79.95 H 10.37%

Found: C 79.97 H 9.99%

3- (4-Tertiobutyl-2-hydroxyphenyl) cyclohexanone (4.22 g, 58%) from 3- (2-benzyloxy-4-tertiobutylphenyl) cyclohexanone (10.0 g, 0.0298 mmol).

Infrared spectrum: (KBr) 3279, 1639 and 1592 cm- '.

Mass spectrum: m / e 246 (M +), 231, 228, 215, 213, 203, 189, 176 and 161.

3- [4-1,1-Dimethylpropyl) -2-hydroxyphenyl] cyclohexanone (2.52 g, 45%) from 3- [2-benzyloxy-4- (1,1-dimethylpropyl) -phenyljcyclohexanone (7, 50 g, 0.0214 mol). Melting point: 165-166 ° C (after recrystallization from isopropyl ether).

Infrared spectrum: (CHC13) 3636, 3401, 1724 (weak), 1634 and 1587 cm- '.

Mass spectrum: m / e 260 (M +), 242, 231, 217, 213 and 161.

Analysis for Ci7H2402:

Calculated: C 78.42 H 9.29%

Found: C 78.17 H 9.22%

3- [4- (1,1-Dimethylbutyl) -2-hydroxyphenyl] cyclohexanone (0.6 g, 11%) from 3- [2-benzyloxy-4- (1,1-dimethylbutyl) phenyl] cyclo- hexanone (7.00 g, 0.0192 mol). Melting point: 101-102 ° C (after recrystallization from isopropyl ether).

Infrared spectrum: (CHC13) 3636, 3401, 1724 (weak), 1634 and 1585 cm-1.

Mass spectrum: m / e 274 (M +), 256, 231 and 213.

Analysis for C18H2602:

Calculated: C 78.79 H 9.55%

Found: C 78.78 H 9.21%

Trans-3-] 4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4-propyl-cyclohexanone (1.0 g, 76%) as an oil from trans-3- [2 -benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-propenyl) -cyclohexanone (1.65 g, 3.69 mmol).

Infrared spectrum: (CHC13) 3610, 3390,1718 (weak), 1629 and 1577 cm-1.

Mass spectrum: m / e 358 (M +), 340, 288, 273, 255, 203 and 161. 3- [4- (l, 1-Dimethylpentyl) -2-hydroxyphenyl] cyclohexanone (4.0 g, 95% ) from 3- [2-benzyloxy-4- (1,1-dimethylpentyl) -phenyljcyclohexanone (5.5 g, 0.0146 mol). Melting point: 124.5-125.5 ° C (after recrystallization from pentane).

Infrared spectrum: (CHC13) 3623, 3378, 1718 (weak), 1634 and 1587 cm- '.

Mass spectrum: m / e 288 (M +), 245 and 231.

Analysis for Ch, H2802:

Calculated: C 79.12 H 9.79%

Found: C 79.32 H 9.53%

3- [4- (1,1-Dimethylhexyl) -2-hydroxyphenyl] cyclohexanone (quantitative yield) from 3- [2-benzyloxy-4- (1,1-dimethylhexyl) -cyclohexanone (2.0 g, 5.1 mmol). Melting point: 82-83 ° C.

Infrared spectrum: (CHC13) 3636,1634,1616 and 1585 cm-1. Mass spectrum: m / e 302 (M +), 284, 259 and 231.

5

10

15

20

25

30

35

40

45

50

55

60

65

635,812

14

Analysis for C20H30O2:

Calculated: C 79.42 H 10.00%

Found: C 79.16 H 9.75%

3- [4- (1,1-Dimethylnonyl) -2-hydroxyphenyl] cyclohexanone (2.4 g, 61%) from 3- [2-benzyloxy-4- (1,1-dimethylnonyl) phenyl] cyclo- hexanone (5.0 g, 11.5 mmol). Melting point: 72-73 ° C.

Infrared spectrum: (CHC13) 3650, 3413, 1721 (weak), 1639 and 1595 cm-1.

High resolution mass spectrum: m / e 344.2691 (M +), (C23H3602), 326.2570 and 301.2168.

3- [4- (1,1-Dimethyldecyl) -2-hydroxyphenyl] cyclohexanone (880 g, 55%) from 3- [2-benzyloxy-3- (1,1-dimethyldecyl) -phenyljcyclohexanone (2,0 g, 4.46 mmol). Melting point: 78-79 ° C. Infrared spectrum: (CHC13) 3623, 1629, 1616 and 1587 cm-1. High resolution mass spectrum: m / e 358.2836 (M +),

c24h38o2.

3- [4- (1,1-Dimethylundecyl) -2-hydroxyphenyl] cyclohexanone (1.49 g, 46%) from 3- [2-benzyloxy-4- (1,1-dimethylundecyl) -phenyljcyclohexanone (4 , 00 g, 8.66 mmol). Melting point: 72-73iC.

Infrared spectrum: (KBr) 3268, 1629 and 1580 cm-1.

Mass spectrum: m / e 372 (M +), 354, 329 and 231.

Analysis for C25H40O2:

Calculated: C 80.59 H 10.82%

Found: C 80.70 H 10.84%

3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] cyclooctanone (1.92 g, 81%) from 3- [2-benzyloxy-4- (1,1-dimethylheptyl) -phenyljcyclooctanone (3 , 02 g, 6.95 mmol). Melting point: 118 ° C.

Infrared spectrum: (CHC13) 3623, 3356, 1709, 1629 and 1587 cm-1.

Mass spectrum: m / e 344 (M +), 329, 326, 283, 273, 259 and 241.

Analysis for C23H3602:

Calculated: C 80.18 H 10.53%

Found: C 79.92 H 10.37%

3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenylJ-4-methyl-2-cyclo-hexene-1-one (1.15 g, 70%) from 3- [2-benzyloxy-4 - (1,1-dimethylheptyl) phenyl] -4-methyl-2-cyclohexene-1-one (2.10 g, 5.02 mmol). Melting point: 111 ° C (after recrystallization from a mixture of diisopropyl ether and petroleum ether).

Infrared spectrum: (CHC13) 3534,3279,1667, 1623 and 1567 cm-1.

Mass spectrum: m / e 328 (M +), 313 and 243.

Analysis for C22H3202:

Calculated: C 80.44 H 9.83%

Found: C 80.35 H 9.67%

Example 3:

Cis-3- [2-ben: yloxy-4- (1,1-dimethylheptyl) phenyl] cyclohexanol and the trans isomer

8.05 g (0.212 mol) of sodium borohydride are added in three portions to a solution at - 40 ° C of 43.0 g (0.106 mol) of 3- [2-benzyloxy-4- (1,1 dimethylheptyl) phenyl cyclohexanone in 500 ml of methanol and 15 ml of tetrahydrofuran. The reaction mixture is stirred for 1 h at -40 ° C, allowed to warm to -10 C, then deactivated by the addition of 100 ml of saturated sodium chloride. The deactivated reaction mixture is poured into 1500 ml of water and extracted with three 450 ml portions of ether. After having combined the ether extraction phases, they are washed with three portions of 100 ml of water and 2 portions of saturated sodium chloride solution, they are dried over magnesium sulphate and evaporated to obtain an oil. The oil is purified by column chromatography on 400 g of silica gel which is eluted with 20% ether in cyclohexane; we obtain, in order of elu-

tion: 5.0 g (12%) of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] cyclohexanol.

Infrared spectrum: (CHC13) 3636, 3497, 1629 and 1587 cm-1. Mass spectrum: m / e 408 (M +), 393, 390, 323 and 91.

Analysis for C2SH40O2:

Calculated: C 82.30 H 9.87%

Found: C 81.98 H 9.82%

and 22.2 g (51%) of cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -cyclohexanol. Melting point: 75.5-76.5 ° C.

Infrared spectrum: (CHC13) 3636, 3497, 1629 and 1587 cm-1. Mass spectrum: m / e 408 (M +), 393, 390, 323 and 91.

Analysis for C28H40O2:

Calculated: C 82.30 H 9.87%

Found: C 81.95 H 9.74%

The following compounds are prepared in the same way from the corresponding ketones of Example 1.

Z-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methylcyclo-hexanol (quantitative yield) in the form of an oil from

3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methylcyclohexa-none (200 mg, 0.476 mmol).

Infrared spectrum: (CHC13) 3546, 3378,1603 and 1,555 cm-1. Mass spectrum: m / e 422 (M +), 337, 314,299,271 and 229.

Trans, trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -

4-methylcyclohexanol (0.225 g, 14%) as an oil and 1.19 g (74%) of the isis, trans from trans-3- [2-benzyloxy-4- (l, l-dimethylheptyl) phenyl] -4-methylcyclohexanone (1.6 g,

3.8 mmol).

Trans, trans isomer:

Proton magnetic resonance: S 0.80 (m, methyl end of the side chain and methyl at C-4), 1.27 (s, geminated dimethyl), 3.12 (m, benzyl methine), 4.20 ( m, carbinol methine), 5.13 (s, methylene of benzyl ether), 6.95 (m, ArH), 7.15 (d, J = 8Hz, ArH) and 7.48 ( large s, PhH).

Infrared spectrum: (CHC13) 3413.1616 and 1575 cm-1.

Mass spectrum: m / e 422 (M +), 407, 337, 314, 272, 229 and 91.

Isis eis, trans:

Proton magnetic resonance: 5 çqq 0.70 (d, J = 6Hz,

C-4 methyl), 0.85 (m, methyl end of the side chain), 1.29 (s, dimethyl twin), 2.81 (m, benzyl methine), 3.75 (m, carbinol methine ), 5.13 (s, methylene of benzyl ether), 6.93 (m, ArH), 7.15 (d, J = 8 Hz, ArH) and 7.43 (broad s, PhH).

Infrared spectrum: (CHC13) 3571, 3390, 1618 and 1577 cm-1. Mass spectrum: m / e 422 (M +), 337, 314, 272, 229 and 91. A mixture of the isis and trans isomers of 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclopentanol ( 1.1 g, 85%) as an oil from 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -cyclopentanone (1.32 g, 3.37 mmol).

Mass spectrum: m / e 394 (M +), 379, 376, 309 and 91. Trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclohepta-nol (695 mg, 49%) and 380 mg (27%) of the isomer eis in the form of an oil from 3- [2-benzyloxy-4- (1-dimethylheptyl) phenyl] -cycloheptanone (1.40 g, 3.33 mmol ).

Eis isomer:

Proton magnetic resonance: 5 çqq 0.85 (m, methyl end of the side chain), 1.30 (s, geminated dimethyl), 3.15 (m, benzyl methine), 3.90 (m, carbinol methine ), 5.15 (s, methylene of benzyl ether), 6.8-7.4 (m, ArH) and 7.45 (broad s, PhH). Infrared spectrum: (CHC13) 3571, 3448, 1613 and 1572 cm-1. Mass spectrum: m / e 422 (M +), 337, 314, 229 and 91.

5

10

15

20

25

30

35

40

45

50

55

60

65

15

635,812

Trans isomer:

Proton magnetic resonance: 8 0.86 (m, terminal methyl), 1.26 (s, twin dimethyl), 3.41 (m, benzyl methine), 4.10 (m, carbinol methine), 5.17 (s, methylene benzyl), 6.8-7.2 (m, ArH), 7.18 (d, J = 8 Hz, ArH) and 7.45 (broad s, PhH).

Infrared spectrum: (CHC13) 3534, 3390, 1613 and 1572 cm-1. Mass spectrum: m / e 422 (M +), 337, 331, 314, 246, 229 and 91. Cis-3- [2-benzyloxy-4- (2-5-phenylpentyloxy) phenyl] cyclohexanol (1.51 g , 76%) and the trans isomer (0.379 g, 19%) in the form of oils from 3- [2-benzyloxy-4- (2- (5-phenylpentyloxy)) phenyl] cyclo-hexanone ( 2.0 g, 4.52 mmol).

Trans- isomer.

Proton magnetic resonance: 8 1.28 (d, J = 6Hz,

methyl), 2.68 (m, benzyl methylene), 3.45 (m, benzyl methine), 4.22 (m, carbinol methine), 4.30 (m, side chain methine), 5.09 (s, methylene of benzyl ether), 6.45 (s, methylene of benzyl ether), 6.45 (dd, J = 8Hz and 2Hz, ArH), 6.55 (large s, ArH ), 7.10 (d, J = 8Hz, ArH), 7.25 (s, PhH) and 7.45 (large s, PhH). Infrared spectrum: (CHC13) 3571, 3448,1613 and 1590 cm- '. Mass spectrum: m / e 444 (M +), 298,280,190 and 91.

Eis isomer:

Proton magnetic resonance: 8 1.25 (d, J = 6Hz,

methyl), 3.0 (m, benzyl methine), 3.77 (m, carbinol methine), 4.38 (m, side chain methine), 5.10 (s, benzyl ether methine ), 6.50 (dd, J = 8 and 2Hz, ArH), 6.58 (large s, ArH), 7.12 (d, J = 8Hz, ArH), 7.32 (s, PhH) and 7 , 43 (s, PhH).

Infrared spectrum: (CHC13) 3571, 3390, 1613 and 1587 cm-1. Mass spectrum: m / e 444 (M +), 298,190 and 91. Cis-3- [2-benzyloxy-4- (1,1-dimethyloctyl) phenyl] cyclohexanol (1.35 g, 45%) and the isomer trans (0.34 g, 11%) from 3.00 g (7.14 mmol) of 3- [2-benzyloxy-4- (1,1-dimethyloctyl) phenyl] cyclo-hexanone and 0.90 g (30% of the cis-trans mixture).

Trans isomer:

Proton magnetic resonance: S 0.87 (m, methyl l_J_xV_.Ì3

side chain terminal), 1.25 (s, twin dimethyl), 3.50 (m, benzyl methine), 4.22 (m, carbinol methine), 5.15 (s, methyl ether benzyl) and 6.8-7.6 (m, ArH and PhH).

Infrared spectrum: (CHC13) 3497, 1623 and 1582 cm-1.

Mass spectrum: m / e 422 (M +) and 323.

Eis isomer:

Proton magnetic resonance: 8 0.85 (m, methyl end of the side chain), 1.25 (s, geminated dimethyl), 3.10 (m, benzyl methine), 3.75 (m, carbinol methine) , 5.12 (s, methylene of benzyl ether), 6.91 (dd, J = 8 and 2Hz, ArH), 6.91 (d, J = 2Hz, ArH), 7.17 (d, J = 8Hz, ArH) and 7.42 (broad s, PhH).

Infrared spectrum: (CHCI3) 3571, 3425, 1618 and 1577 cm- '. Mass spectrum: m / e 422 (M +) and 323. Cis-3- (2-benzyloxy-4-tertiobutylphenyl) cyclohexanol (7.18 g, 59%) and the trans isomer (1.33 g, 11% ) as well as 1.5 g (12%) of a mixture of the isis and trans isomers, from 12.0 g (0.0357 mol) of 3- (benzyloxy-4-tertiobutylphenyl) cyclohexanone.

Eis isomer:

Melting point: 78-79 "C (after recrystallization from hexane). Proton magnetic resonance: 8 ™ 1.30 (s, tertio-

L-JJC-13

butyl), 3.10 (m, benzyl methine), 3.72 (m, carbinol methine),

5.12 (s, methylene of benzyl ether), 6.97 (d, J = 2 Hz, ArH), 6.97 (dd, J = 8 and 2 Hz, ArH), 7.17 (d, J = 8Hz, ArH) and 7.40 (broad s, PhH).

Infrared spectrum: (CHC13) 3636, 3472, 1621 and 1582 cm-1. Mass spectrum: m / e 338 (M +), 323, 320, 230, 215 and 91.

Analysis for C23H30O2:

Calculated: C 81.61 H 8.93%

Found: C 81.79 H 8.77%

Trans isomer:

Proton magnetic resonance: 8 çqq 1,23 (s, tertio-

butyl), 3.50 (m, benzyl methine), 4.20 (m, carbinol methine), 5.02 (s, benzyl ether methylene) and 6.8-7.4 (m, ArH and PhH). Infrared spectrum: (CHC13) 3650, 3472, 1626 and 1587 cm-1. Mass spectrum: m / e 338 (M +), 323, 320, 230 and 91. Cis-3- [2-benzyloxy-4- (1,1-dimethylpropyl) phenyl] cyclohexanol (6.3 g, 78%) and the trans isomer (1.0 g, 12%) in the form of oils from 8.0 g (0.0229 mol) of 3- [2-benzyloxy-4- (1,1-dimethyl- propyl) phenyl] cyclohexanone.

Eis isomer:

Proton magnetic resonance: 8 0.67 (t, J = 7Hz,

terminal methyl), 1.26 (s, twin dimethyl), 3.05 (m, benzyl methine), 3.75 (m, carbinol methine), 5.15 (s, methylene benzyl ether), 6, 92 (d, J = 2Hz, ArH), 6.92 (dd, J = 8 and 2Hz, ArH),

7.17 (d, J = 8Hz, ArH) and 7.42 (large s, PhH).

Infrared spectrum: (CHC13) 3636, 3344, 1626 and 1587 cm-1. Mass spectrum: m / e 352 (M +), 337, 334, 323, 244, 215 and 91.

Trans isomer:

Infrared spectrum: (CHC13) 3636, 1626 and 1587 cm-1.

Mass spectrum: m / e 352 (M +), 337, 334, 323, 244, 215 and 91. Cis-3-f 2-benzyloxy-4- (1,1-dimethylbutyljphenyl] cyclohexanol (4.16 g, 52 %) and the trans isomer (0.88 g, 11%), and 0.49 g (6.1%) of a mixture of the eis and trans isomers in the form of oils from 8.0 g (0.022 mol) of 3- [2-benzyloxy-4- (1,1-dimethylbutyl) phenyl] -cyclohexanone.

Eis isomer:

Proton magnetic resonance: 8 0.80 (m, terminal methyl), 1.23 (s, twin dimethyl), 3.05 (m, benzyl methine), 3.70 (m, carbinol methine), 5.08 (s, methylene of benzyl ether), 6.86 (d, J = 2Hz, ArH), 6.86 (dd, J = 8 and 2Hz, ArH), 7.11 (d, J = 8Hz, ArH) and 7.35 (broad s, PhH).

Infrared spectrum: (CHC13) 3623, 3448, 1621 and 1582 cm-1. Mass spectrum: m / e 366 (M +), 351, 348, 323,258,215 and 91.

Trans isomer:

Proton magnetic resonance: 8 0.83 (m, terminal methyl), 1.22 (s, geminated dimethyl), 3.40 (m, benzyl methine),

4.18 (m, carbinol methine), 5.09 (s, benzyl ether methylene), 6.86 (d, J = 2Hz, ArH), 6.86 (dd, J = 8 and 2Hz, ArH) , 7.11 (d,

J = 8Hz, ArH) and 7.39 (m, PhH).

Infrared spectrum: (CHC13) 3623, 3472, 1623 and 1585 cm-1. Mass spectrum: m / e 366 (M +), 351, 348, 323, 258, 215 and 91. Trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -cis-4- ( 2-propenyl) cyclohexanol (1.9 g, 13%) and the cis-3 isomer, trans-4 (7.3 g, 51%) in the form of oils from trans-3- [2- benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-propenyl) cyclohexanone (14.3 g, 32.1 mmol). The order of elution on silica gel with a mixture of pentane and ether at 2: 1 is as follows: trans-3, cis-4 isomer of the compound indicated in the title, in the form of an oil , followed by the cis-3-trans-4 isomer.

5

10

15

20

25

30

35

40

45

50

55

60

65

635,812

16

Trans-3, cis-4 isomer:

Infrared spectrum: (CHC13) 3559,3401,1639,1608 and 1567 cm-1. Mass spectrum: m / e 448 (M +), 433,430, 363,406 and 91.

Proton magnetic resonance: 8 0.82 (m, terminal methyl), 1.25 (s, twin dimethyl), 3.30 (m, benzyl methine), 4.12 (m, carbinol methine), 4.6 -5.0 (m, vinyl H), 5.06 (s, methylene benzyl), 5.2-6.1 (m, vinyl H), 6.82 (d, J = 2Hz, ArH), 6.82 (dd, J = 8 and 2Hz, ArH), 7.07 (d, J = 8Hz, ArH) and 7.38 (large s, Ph).

Cis-3, trans-4 isomer:

Infrared spectrum: (CHC13) 3571, 3401, 1639, 1610 and 1572 cm-1.

Mass spectrum: m / e 448 (M +), 406, 363 and 91.

Proton magnetic resonance: 8 0.82 (m, terminal methyl), 1.22 (s, twin dimethyl), 2.90 (m, benzyl methine), 3.73 (m, carbinol methine), 4.6 -5.1 (m, vinyl H), 5.02 (s, methylene benzyl), 5.3-6.3 (m, vinyl H), 6.75 (d, J = 2Hz, ArH), 6, 75 (dd, J = 8 and 2Hz, ArH), 6.99 (d, J = 8Hz, ArH) and 7.25 (large s, Ph).

Cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -trans-4- (2-bu-tenyljcyclohexanol (495 mg, 82%) and the isomer trans-3, cis-4 ( 105 mg, 18%) from trans-3- [2-benzyIoxy-4- (1,1-dimethylheptyl) -phenyl] - (2-butenyl) cyclohexanone (600 mg, 1.30 mmol). trans-3 isomer, cis-4 is eluted first.

Trans-3, cis-4 isomer:

Mass spectrum: m / e 462 (M +), 447, 444, 377 and 91.

Cis-3, trans-4 isomer:

Infrared spectrum: (CHC13) 3610, 3448, 1618 and 1577 cm-1. Mass spectrum: m / e 462 (M +), 447,444, 377 and 91. Cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -trans-4- (2-pentenyl) cyclohexanol and the trans-3, cis-4 isomer from trans-3- (2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-pentenyl) cyclo-hexanone (497 mg, 1 , 04 mmol). In the order of elution, 84 mg (17%) of the trans-3 isomer, cis-4 are obtained (Rf = 0.26, silica gel, 33% ether in the pentane) and 363 mg (73%) of the cis-3, trans-4 isomer (Rf = 0.13, silica gel, 33% ether in pentane).

Cis-3- [benzyloxy-4- (1,1-dimethylpentyl) phenyl] cyclohexanol (5.0 g, 83%) and the trans isomer (0.60 g, 10%) as oils from 3- [2-Benzyloxy-4- (1,1-dimethylpentyl) phenyl] cyclo-hexanone (6.0 g, 58 mmol).

Trans isomer:

Infrared spectrum: (CHC13) 3636, 3497, 1623 and 1582 cm-1. Mass spectrum: m / e 380 (M +).

Proton magnetic resonance: S 0.83 (m, terminal methyl), 1.24 (s, twin dimethyl), 3.5 (m, benzyl methine), 4.20 (m, carbinol methine), 5.09 (s, methylene benzyl) and 6.8-7.6 (m, ArH).

Eis isomer:

Infrared spectrum: (CHC13) 3636,1621 and 1580 cm- '.

Mass spectrum: m / e 380 (M +).

Proton magnetic resonance: 8 0.75 (m, terminal methyl) 1.14 (s, twin dimethyl), 2.90 (m, benzyl methine), 3.52 (m, carbinol methine), 4.80 ( s, methylene benzyl), 6.49 (dd, H = 8 and 2Hz, ArH), 6.59 (d, J = 2Hz, ArH), 6.72 (d, J = 8Hz, ArH) and 6.96 (large s, Ph).

Cis-3- [2-benzyloxy-4- (1,1-dimethylhexyl) phenyl] cyclohexanol (3.0 g, 43%) and the trans isomer (660 mg, 9%) in the form of

from 3- [2-benzyloxy-4- (1,1-dimethylhexyl) phenyl] cyclohexa-none (7.0 g, 17.9 mmol).

Eis isomer:

Infrared spectrum: (CHC13) 3623, 3448, 1618 and 1575 cm-1. Mass spectrum: m / e 394 (M +).

Proton magnetic resonance: 8 0.82 (m, terminal methyl), 1.22 (s, twin dimethyl), 3.07 (m, benzyl methine), 3.70 (m, carbinol methine), 5.08 (s, methylene benzyl), 6.88 (dd, J = 8 and 2Hz, ArH), 6.88 (d, J = 2Hz, ArH), 7.12 (d, J = 8 Hz, ArH) and 7 , 37 (large s, Ph).

Trans isomer:

Infrared spectrum: (CHC13) 3623, 3448, 1618 and 1577 cm- '. Mass spectrum: m / e 394 (M +).

Proton magnetic resonance: 8 0.80 (m, terminal methyl), 1.27 (s, twin dimethyl), 3.42 (m, benzyl methine), 4.12 (m, carbinol methine), 5.02 (s, methylene benzyl), 6.83 (m, ArH), 7.04 (d, J = 8 Hz, ArH) and 7.34 (large s, ArH).

Cis-3- [2-benzyloxy-4- (1,1-dimethylnonyl) phenyl] cyclohexanol (5.0 g, 59%) and the trans isomer (1.0 g, 12%) in the form of oils from 3- [2-benzyloxy-4- (1,1-dimethylnonyl) phenyl] cyclo-hexanone (8.5 g, 19.6 mmol).

Eis isomer:

Infrared spectrum: (CHC13) 3623,3448, 1618 and 1577 cm-1. Mass spectrum: m / e 436 (M +).

Proton magnetic resonance: 8 çqq 0.83 (m, terminal methyl), 1.22 (s, geminated dimethyl), 3.04 (m, benzyl methine), 3.67 (m, carbinol methine), 5, 08 (s, methylene benzyl), 6.87 (dd, J = 8 and 2Hz, ArH), 6.87 (d, J = 2Hz, ArH) and 7.05-7.45 (m, ArH and Ph) .

Trans isomer:

Infrared spectrum: (CHC13) 3610, 3448, 1618 and 1575 cm-1. Mass spectrum: m / e 436 (M +).

Proton magnetic resonance: 8 0.82 (m, methyl

CL / CI3

terminal), 1.22 (s, twin dimethyl), 3.42 (m, benzyl methine), 4.16 (m, carbinol methine), 5.02 (s, benzyl methine), 4.16 (m, carbinol methine), 5.02 (s, methylene benzyl) and 6.7-7.5 (m, ArH and Ph).

Cis-3- [2-benzyloxy-4- (1,1-dimethylundecyl) phenyl] cyclohexanol (3.5 g, 50%) and the trans isomer (1.0 g, 14%) in the form of oils from 3- [2-benzyloxy-4- (1,1-dimethylundecyl) phenyl] cyclo-hexanol (7.00 g, 15.0 mmol).

Eis isomer:

Infrared spectrum: (CHC13) 3636, 3448, 1621 and 1582 cm-1. Mass spectrum: m / e 464 (M +).

Proton magnetic resonance: 8 0.95 (m, terminal methyl), 1.33 (s, twin dimethyl), 3.09 (m, benzyl methine), 3.70 (m, carbinol methine), 5.20 (s, methylene benzyl), 6.99 (dd, J = 8 and 2Hz, ArH), 6.99 (dd, J = 8 and 2Hz, ArH), 7.22 (d, J = 8Hz, ArH) and 7.50 (broad s, PhH).

Trans isomer:

Infrared spectrum: (CHC13) 3534 (wide), 1618 and 1577 cm-1. Mass spectrum: m / e 464 (M +).

Proton magnetic resonance: 8 ™ 0.85 (m, methyl

»I3

5

10

15

20

25

30

35

40

45

50

55

60

65

17

635,812

terminal), 1.22 (s, twin dimethyl), 3.48 (m, benzyl methine), 4.17 (m, benzyl methine), 5.08 (s, methylene benzyl) and 6.75-7.55 (m, ArH and Ph).

Cis-3- [2-benzyloxy-4- (1,1-dimethyldecyl) phenyl] cyclohexanol (2.66 g, 59%) and the trans isomer (0.36 g, 8%) in the form of oils from 3- [2-benzyloxy-4- (1,1-dimethyldecyl) phenyl] cyclo-hexanone (4.5 g, 10.0 mmol).

Eis isomer:

Infrared spectrum: (CHC13) 3704, 3571, 1639 and 1597 cm-1. Mass spectrum: m / e 450 (M +).

Proton magnetic resonance: 8 TJ ??. 0.86 (m, terminal methyl), 1.25 (s, twin dimethyl), 3.08 (m, benzyl methine), 3.74 (m, carbinol methine), 5.08 (s, methylene benzyl) , 6.88 (dd, J = 8 and 2Hz, ArH), 6.88 (d, J = 8Hz, ArH) and 7.37 (large s, Ph).

Trans isomer:

Infrared spectrum: (CHC13) 3623, 3448, 1616 and 1577 cm-1. Mass spectrum: m / e 450 (M +).

Proton magnetic resonance: 8 ïîf ™ 0.82 (m, terminal methyl), 1.22 (s, twin dimethyl), 3.53 (m, benzyl methine), 4.22 (m, carbinol methine), 5 , 02 (s, methylene benzyl) and 6.8-7.6 (m, ArH and Ph).

Cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclooctanol (13.6 g, 19%) and the trans isomer (4.12 g, 59%) in the form of oils from 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclo-octanone (7.0 g, 16.1 mmol).

Infrared spectrum: (CHC13)

Mass spectrum: m / e 436 (M +), 421, 418, 351, 328, 300, 243 and 91.

Proton magnetic resonance: 8 0.83 (m, methyl

VUCI3

terminal), 1.28 (s, twin dimethyl), 3.19 (large m, benzyl methine), 3.89 (large m, carbinol methine), 5.10 (s, methylene benzyl), 6.83 ( m, ArH), 7.08 (d, J = 8Hz, ArH) and 7.38 (m, Ph).

Trans isomer:

Infrared spectrum: (CHC13)

Mass spectrum: m / e 436 (M +), 421, 418, 351, 328, 243 and 91. Magnetic resonance of the protons: S 0.83 (m, methyl

VL / L / I3

terminal), 1.28 (s, twin dimethyl), 3.4 (broad m, benzyl methine), 3.9 (m, carbinol methine), 5.10 (s, methylene benzyl), 6.85 (m , ArH), 7.08 (d, J = 8Hz, ArH) and 7.36 (m, Ph).

Example 4:

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclohexanol

A mixture of 22.0 g (0.0539 mol) of cis-3- [2-benzyloxy-4- (1,1-di-methylheptyl) phenyl] cyclohexanol is stirred under hydrogen pressure of 1 bar for 2 h , 12.0 g of sodium bicarbonate and 2.0 g of 10% palladium fixed on carbon. The reaction mixture is filtered through diatomaceous earth using ethyl acetate and the filtrate is evaporated to dryness. The solid residue is recrystallized from hexane and 13.2 g (77%) of the product indicated in the title are thus obtained, melting at 109-110 ° C.

Infrared spectrum: (CHC13) 3610, 3356, 1626 and 1582 cm-1. Mass spectrum: m / e 318 (M +), 300, 233 and 215.

Analysis for C21H3402:

Calculated: C 79.19 H 10.76%

Found: C 78.96 H 10.59%

Following the above procedure, the compounds indicated below were prepared from the corresponding reactants of Example 3.

Trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclohexanol (2.47 g, 71%), melting at 124-125 ° C (after recrystallization from pentane) from trans-3 - [2-benzyIoxy-4- (1,1-dimethylheptyl) -phenyljcyclohexanol (4.50 g, 0.011 mol).

Infrared spectrum: (CHC13) 3610, 3390, 1626 and 1575 cm-1. Mass spectrum: m / e 318 (M +), 300, 233 and 215.

Analysis for C21H3402:

Calculated: C 79.19 H 10.76%

Found: C 78.82 H 10.43%

Z-3- [4- (1,1-dimethyl-heptyl) -2-hydroxyphenyl] -3-methylcyclohexanol melting at 90-91 ° C (after recrystallization from petroleum ether) is obtained in quantitative yield. from Z-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methylcyclohexanol (180 mg, 0.248 mmol).

Infrared spectrum: (CHC13) 3597, 3333, 1605 and 1570 cm-1. Mass spectrum: m / e 332 (M +), 314, 299, 286, 271, 247 and 229.

Analysis for C22H3602:

Calculated: C 79.45 H 10.92%

Found: C 79.24 H 10.64%

Trans, trans-3-l4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4-methylcyclohexanol (quantitative yield), melting at 134-135 ° C (after recrystallization from pentane) from trans, trans- 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4-methylcyclohexanol (190 mg, 0.450 mmol).

Infrared spectrum: (CHC13) 3571, 3333, 1626 and 1575 cm- '. Mass spectrum: m / e 332 (M +), 317, 314,247,233 and 229.

Analysis for C22H3602:

Calculated: C 79.46 H 10.92%

Found: C 79.13 H 10.68%

Cis, trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4-methyl-cyclohexanol (quantitative yield), melting at 150-151 ° C (after recrystallization from pentane) from cis , trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4-methylcyclohexanol (1.15 g, 2.72 mmol).

Infrared spectrum: (CHC13) 3571, 3333, 1621, 1605 and 1580 cm-i.

Mass spectrum: m / e 332 (M +), 314, 272, 247, 233 and 229.

Analysis for C22H3602:

Calculated: C 79.46 H 10.92%

Found: C 79.15 H 10.72%

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclopentanol (464 mg, 55%) and 228 mg (27%) of the trans isomer in the form of oils from a mixture of the cis and trans isomers of 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclopentanol (1.10 g, 2.79 mmol).

Cis isomer:

Proton magnetic resonance: 8 çqq 0.83 (m, methyl end of the side chain), 1.24 (s, geminated dimethyl), 3.2 (m, benzyl methine), 4.52 (m, carbinol methine ), 6.75 (dd, J = 8 and 2HZ, ArH), 6.81 (broad s, overlap with 8 6.75, ArH) and 6.97 (d, J = 8Hz, ArH).

Infrared spectrum: (CHC13) 3571, 3300, 1623 and 1567 cm-1. Mass spectrum: m / e 304 (M +), 286, 219, 201 and 159.

Trans isomer:

Proton magnetic resonance: 8 0.83 (m, methyl

L / ULI3

side chain terminal), 1.27 (s, twin dimethyl), 3.60 (m,

5

10

15

20

25

30

35

40

45

50

55

60

65

635,812

18

benzyl methine), 4.55 (m, carbinol methine), 6.78 (broad s, overlap with 8 6.88, ArH), 6.88 (dd, J = 8 and 2Hz, ArH) and 7.10 (d, J = 8Hz, ArH).

Infrared spectrum: (CHC13) 3571, 3333, 1621 and 1575 cm-1. Mass spectrum: m / e 304 (M +), 286,219 and 201. Trans-3- [4- (I, l-dimethylheptyl) -2-hydroxyphenyl] cycloheptanol (quantitative yield), melting at 55-57 ° C, at from trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cycloheptanol (695 mg, 1.64 mmol).

Infrared spectrum: (CHC13) 3333, 1621 and 1570 cm-1.

Mass spectrum: m / e 332 (M +), 314, 247 and 229.

Analysis for C22H3602:

Calculated: C 79.46 H 10.92%

Found: C 79.68 H 10.62%

Cis-3- [4- (I, 1-dimethylheptyl) -2-hydroxyphenyl] cycloheptanol (quantitative yield), melting at 103-104 ° C (after recrystallization from pentane) from cis-3- [2-benzyloxy -4- (1,1-dimethyl-heptyl) phenyl] cycloheptanol (380 mg, 0.900 mmol).

Infrared spectrum: (CHC13) 3571, 3311,1621,1605 and 1580 cm-1.

Mass spectrum: m / e 332 (M +), 314,247 and 229.

Analysis for C22H3502:

Calculated: C 79.46 H 10.92%

Found: C 79.39 H 10.72%

Cis-3- [2-hydroxy-4- (2- (5-phenylpentyloxy)) phenyl] cyclohexanol (quantitative yield), melting at 80-84 ° C (after recrystallization from pentane) from cis-3- [ 2-benzyloxy-4- (2- (5-phenylpentyl-oxy)) phenyl] cyclohexanol (1.45 g, 3.27 mmol).

Infrared spectrum: (CHC13) 3,597.3333,1623 and 1,597 cm-1. Mass spectrum: m / e 354 (M +), 336,208,190 and 91.

Analysis for C23H30O3:

Calculated: C 77.93 H 8.53%

Found: C 77.95 H 8.31%

Trans-3- [2-hydroxy-4- (2- (5-phenylpentyloxy)) phenylJcyclohexanol (241 mg, 90%), melting at 65-70 ° C (pentane) from trans-3- [2-benzyloxy -4- (2- (5-phenylpentyloxy)) phenyl] cyclohexanol (0.355 g, 0.754 mmol).

Infrared spectrum: (CHC13) 3597, 3378, 1629 and 1587 cm-1. Mass spectrum: m / e 354 (M +), 336, 208, 190 and 91.

Analysis for C23H30O3:

Calculated: C 77.93 H 8.53%

Found: C 77.53 H 8.40%

Cis-3- [4- (I. 1-dimethyloctyl) -2-hydroxyphenyl] cyclohexanol (0.725 g, 68%) from 1.36 g (3.22 mmol) cis-3- [2-benzyloxy- 4- (1,1-dimethyloctyl) phenyl] cyclohexanol. Melting point: 100-10rC (after recrystallization from hexane).

Infrared spectrum: (CHC13) 3571, 3333, 1626 and 1582 cm-1. Mass spectrum: m / e 332 (M +), 314, 233 and 215.

Analysis for C22H3602:

Calculated: C 79.46 H 10.92%

Found: C 79.85 H 11.03%

Trans-3- [4- (1,1-dimethyloctylJ -2-hydroxyphenyl] cyclohexanol (0.195 g, 100%) as an oil from 246 mg (0.582 mmol) of trans-3- [2- benzyloxy-4- (1,1-dimethyloctyl) phenyl] -cyclohexanol Melting point: 94-95 ° C (after recrystallization from petroleum ether).

Infrared spectrum; (CHC13) 3650, 3436, 1639 and 1582 cm-1. Mass spectrum: m / e 332 (M +), 314, 233 and 215.

Analysis for C22H3602:

Calculated: C 79.46 H 10.92%

Found: C 79.34 H 10.55%

Cis-3- (4-tertiobutyl-2-hydroxyphenyl) cyclohexanol (3.99 g, 77%) from cis-3- (2-benzyloxy-4-tertiobutylphenyl) cyclohexanol (7.1 g, 0.021 mol). Melting point: 177-178 ° C (after recrystallization from isopropyl ether).

Infrared spectrum: (KBr) 3484, 3268, 1634 and 1592 cm-1.

Mass spectrum: m / e 248 (M +), 233,230,215,187,176,173 and 161.

Analysis for C16H2502:

Calculated: C 77.37 H 9.74%

Found: C 77.00 H 9.54%

Trans-3- (4-tertiobutyl-2-hydroxyphenyl) cyclohexanol (0.725 g, 99%) from trans-3- (2-benzyloxy-4-tertiobutylphenyl) cyclo-hexanol (1.25 g, 2.96 mmol ). Melting point: 136-137 ° C (after recrystallization from isopropyl ether).

Infrared spectrum: (CHC13) 3623, 3401, 1626 and 1575 cm-1. Mass spectrum: m / e 248 (M +), 233, 230, 215, 187 and 173.

Analysis for C16H2402:

Calculated: C 77.37 H 9.74%

Found: C 77.34 H 9.49%

Cis-3- [4- (1,1-dimethylpropyl) -2-hydroxyphenyl] cyclohexanol (1.45 g, 32%) from cis-3- [2-benzyloxy-4- (1,1-dimethylpropyl) -phenyl] cyclohexanol (6.1 g, 0.0173 mol). Melting point: 166-167 ° C (after recrystallization from isopropyl ether).

Infrared spectrum: (KBr) 3509, 3279,1629 and 1592 cm-1.

Mass spectrum: m / e 262 (M +), 247, 244, 233 and 215. Trans-3- [4- (1,1-dimethylpropyl) -2-hydroxyphenyl] cyclohexanol (0.50 g, 68%) at from trans-3- [2-benzyloxy-4- (1,1-dimethyl-propyl) phenyl] cyclohexanol (1.00 g, 2.84 mmol). Melting point: 124-125 ° C (after recrystallization from isopropyl ether).

Infrared spectrum: (CHC13) 3636, 3413.1639 and 1585 cm-1. Mass spectrum: m / e 262 (M +), 247, 244, 233 and 215.

Analysis for C17H2602:

Calculated: C 77.82 H 9.99%

Found: C 77.51 H 9.87%

Cis-3- [4- (1,1-dimethylbutyl) -2-hydroxyphenyl] cyclohexanol (1.9 g, 74%) from cis-3- [2-benzyloxy-4- (1,1-dimethylbutyl) -phenyl] cyclohexanol (3.39 g, 9.26 mmol). Melting point: 138-139 ° C (after recrystallization from pentane).

Infrared spectrum: (KBr) 3509, 3279,1629 and 1592 cm-1. Mass spectrum: m / e 276 (M +), 261, 258, 233 and 215. Trans-3- [4- (1,1-dimethylbutyl) -2-hydroxyphenyl] cyclohexanol (0.45 g, 87%) under as an oil from trans-3- [2-benzyl-oxy-4- (1,1-dimethylbutyl) phenyl] cyclohexanol (0.700 g, 1.91 mmol). Infrared spectrum: (CHC13) 3636, 3390, 1629 and 1575 cm-1. Mass spectrum: m / e 276 (M +), 261, 258, 233 and 215.

Trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cis-4-propyl-cyclohexanol (626 mg, 78%) from trans-3- [2-benzyloxy-4- (l, 1-dimethylheptyl) phenyl] -cis-4- (2-propenyl) cyciohexanol (1.0 g, 2.23 mmol). Melting point: 92-94 ° C.

Infrared spectrum: (CHC13) 3623,3390, 1629 and 1578 cm-1.

Analysis for C24H40O2:

Calculated: C 79.94 H 11.18%

Found: C 80.10 H 10.89%

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] trans-4-propyl-cyclohexanol (550 mg, 74%) from cis-3- [2-benzyloxy-4- (l, 1-di-methylheptyl) phenyl] trans-4- (2-propenyl) cyclohexanol (930 mg, 2.07 mmol). Melting point: 126 ° C (after recrystallization from pentane).

Infrared spectrum: (CHC13) 3597, 3390, 1629 and 1575 cm-1. Mass spectrum: m / e 360 (M +), 345, 342, 275 and 257.

5

10

15

20

25

30

35

40

45

50

55

60

65

19

635,812

Analysis for C24H40O2:

Calculated: C 79.94 H 11.18%

Found: C 79.85 H 10.95%

Trans-4-butyl-cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cyclohexanol (322 mg, 80%) from cis-3- [2-benzyloxy-4- (l , 1-di-methylheptyl) phenyl] trans-4- (2-butenyl) cyclohexanol (500 mg, 1.08 mmol). Melting point: 131 ° C (after recrystallization from pentane).

Infrared spectrum: (CHC13) 3636, 3356, 1629 and 1587 cm-1. Mass spectrum: m / e 374 (M +), 356, 302, 289, 272, 271, 257, 247,233,217,187 and 161.

Trans-4-pentyl-cis-3- [4- (1,1-dimethylheptyl j -2-hydroxyphenyl] -cyclohexanol (225 mg, 76%) from cis-3- [2-benzyloxy-4- (l , 1-di-methylheptyl) phenyl] trans-4- (2-pentenyl) cyclohexanol (363 mg, 0.762 mmol), mp: 135-136 ° C.

Cis-3- [4- (1,1-dimethylpentyl) -2-hydroxyphenyl] cyclohexanol (2.5 g, 60%) from cis-3- [2-benzyloxy-4- (1,1-dimethylpentyl) -phenyl] cyclohexanol (5.5 g, 0.0144 mol). Melting point: 112-113 ° C (after recrystallization from pentane and isopropyl ether). Infrared spectrum: (CHC13) 3636, 3390, 1631 and 1592 cm-1. Mass spectrum: m / e 290 (M +), 272, 233 and 215.

Analysis for C19H30O2:

Calculated: C 78.57 H 10.41%

Found: C 78.76 H 10.11%

Trans-3- [4- (1,1-dimethylpentylj -2-hydroxyphenyl] cyclohexanol (385 mg, 78%) from trans-3- [2-benzyloxy-4- (1,1-dimethyl-pentyl) phenyl ] cyclohexanol (640 mg, 1.68 mmol), melting point: 114-115 ° C (after recrystallization from pentane).

Infrared spectrum: (CHC13) 3636, 3390, 1631 and 1577 cm-1. Mgsse spectrum: m / e 290 (M +), 272, 233 and 215.

Analysis for Ci9H30O2:

Calculated: C 78.57 H 10.41%

Found: C 78.38 H 10.10%

Cis-3- [4- (1,1-dimethylhexyl) -2-hydroxyphenyl] cyclohexanol (2.3 g, 99%) from cis-3- [2-benzyloxy-4- (1,1-dimethylhexyl) -phenyljcyclohexanol (3.00 g, 7.61 mmol). Melting point: 98-100 ° C (pentane).

Infrared spectrum: (CHC13) 3636, 3367, 1626 and 1587 cm-1. Mass spectrum: m / e 304 (M +), 286, 233 and 215.

Analysis for C2oH3202:

Calculated: C 78.89 H 10.59%

Found: C 78.57 H 10.46%

Trans-3- [4- (1,1-dimethylhexyl) -2-hydroxyphenyl] cyclohexanol (440 mg, 86%) from trans-3- [2-benzyloxy-4- (1,1-dimethyl-hexyl) phenyl] cyclohexanol (660 mg, 1.68 mmol). Melting point: 113-114 ° C (pentane).

Infrared spectrum: (CHC13) 3636, 3390, 1631, 1616 and 1580 cm-1.

Mass spectrum: m / e 304 (M +), 286, 233 and 215.

High resolution mass spectrum: 304, 2419 (C20H32O2). Cis-3- [4- (1,1-dimethylnonyl) -2-hydroxyphenyl] cyclohexanol (4.0 g, 100%) from cis-3- [2-benzyloxy-4- (1,1-dimethylnonyl) -phenyljcyclohexanol (5.0 g, 1.15 mmol). Melting point: 82-83 ° C (pentane).

Infrared spectrum: (CHC13) 3650, 3390, 1637 and 1597 cm -1. Mass spectrum: m / e 346 (M +), 328, 233 and 215.

Analysis for C23H3g02:

Calculated: C 79.71 H 11.05%

Found: C 79.71 H 11.14%

Trans-3- [4- (1,1-dimethylnonyl) -2-hydroxyphenyl] cyclohexanol (709 mg, 89%) from trans-3- [2-benzyloxy-4- (1,1-dimethyl-

nonyl) phenyl] cyclohexanol (1.00 g, 2.29 mmol). Melting point: 69-70 ° C (pentane).

Infrared spectrum: (CHC13) 3636, 3413, 1631, 1618 and 1582 cm-1.

Mass spectrum: m / e 346 (M +), 328, 233 and 215.

Analysis for C23H3802:

Calculated: C 79.71 H 11.05%

Found: C 79.11 H 10.86%

Cis-3- [4- (1,1-dimethyldecyl) -2-hydroxyphenyl] cyclohexanol (2.02 g, 98%) from cis-3- [2-benzyloxy-4- (1,1-dimethyldecyl) -phenyl] cyclohexanol (2.6 g, 5.78 mmol). Melting point: 93-94 ° C (pentane).

Infrared spectrum: (CHC13) 3636, 3390, 1629 and 1587 cm-1. Mass spectrum: m / e 360 (M +), 342, 288, 233 and 215.

Analysis for C24H40O2:

Calculated: C 79.94 H 11.18%

Found: C 80.12 H 11.39%

Trans-3- [4- (1,1-dimethyldecyl) -2-hydroxyphenyl] cyclohexanol (130 mg, 45%) from trans-3- [2-benzyloxy-4- (1,1-dimethyl-decyl) phenyl] cyclohexanol (360 mg, 0.80 mmol). Melting point: 76-77 ° C.

Infrared spectrum: (CHC13) 3636, 3425, 1631, 1616 and 1580 cm-1.

Mass spectrum: m / e 360 (M +), 342, 233 and 215.

Analysis for C24H40O2:

Calculated: C 79.94 H 11.18%

Found: C 80.20 H 11.27%

Cis-3- [4- (1,1-dimethylundecyl) -2-hydroxyphenyl] cyclohexanol (2.39 g, 85%) from cis-3- [2-benzyloxy-4- (1,1-dimethyl- undecyl) phenyl] cyclohexanol (3.5 g, 7.54 mmol). Melting point: 85-86 ° C.

Infrared spectrum: (CHC13) 3636, 3390, 1634 and 1592 cm-1. Mass spectrum: m / e 374 (M +), 356, 233 and 215.

Analysis for C25H4202:

Calculated: C 80.15 H 11.30%

Found: C 80.00 H 11.48%

Trans-3- [4- (1,1-dimethylundecyl) -2-hydroxyphenyl] cyclohexanol (487 mg, 60%) from trans-3- [2-benzyloxy-4- (1,1-dimethyl-undecyl) phenyl] cyclohexanol (1.00 g, 2.16 mmol). Melting point: 73-74 ° C.

Infrared spectrum: (CHC13) 3636, 3413, 1637 and 1585 cm-1. Mass spectrum: m / e 374 (M +), 356, 233 and 215.

Analysis for C25H4202:

Calculated: C 80.15 H 11.30%

Found: C 80.11 H 11.16%

Cis-3-f 4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclooctanol (0.793 g, 73%) from cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl ] cyclooctanol (1.36 g, 3.11 mmol). Melting point: 89-90 ° C (after recrystallization from pentane).

Mass spectrum: m / e 346 (M +), 328, 261 and 243.

Analysis for C23H3802:

Calculated: C 79.71 H 11.05%

Found: C 79.90 H 10.89%

Trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclooctanol (2.62 g, 83%) from trans-3- [2-benzyloxy-4- (1,1-dimethyl- heptyl) phenyl] cyclooctanol (4.0 g, 9.17 mmol). Melting point: 76-77 ° C (after recrystallization from pentane).

Mass spectrum: m / e 346 (M +), 328, 261 and 243.

5

10

15

20

25

30

35

40

45

50

55

60

65

635,812

20

Analysis for C23H3S02:

Calculated: C 79.71 H 11.05%

Found: C 79.81 H 10.86%

Example 5:

3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclohex-2-enone

A solution of 3.89 g (10 mmol) of

2- (3-benzyloxy-4-bromophenyl) -2-methyloctane in 10 ml of tetrahydrofuran at 360 mg (14.4 mmol) of metallic magnesium in particles from 0.177 to 0.210 mm. The resulting mixture is refluxed for 30 min, then cooled to 0 ° C. A solution of 1.40 g (10 mmol) of 3-ethoxy-2-cyclo-hexene-1-one in 3 ml of tetrahydrofuran is added slowly to this solution. The reaction mixture is stirred for 30 min at 0 ° C., then it is deactivated by the addition of 20 ml of IN sulfuric acid and it is heated in a boiling water bath for 30 min. It is then cooled and poured into

200 ml of ether and 200 ml of water. The organic extract is washed successively with 200 ml of saturated sodium bicarbonate and 200 ml of saturated sodium chloride; it is then dried over magnesium sulphate and evaporated, leaving an oily residue. The crude product is purified by column chromatography on 170 g of silica gel eluted with a mixture of 1/1 ether and pentane; 2.5 g (54%) of the title compound are thus obtained, in the form of an oil.

Infrared spectrum: (CHC13) 1667,1610 and 1558 cm-1.

Mass spectrum: m / e 404 (M +), 319, 313 and 91.

Likewise, 3- [2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -4-methylcyclohex-2-enone is prepared in the form of an oil (4.12 g, 77%) using 3-ethoxy-6-methyl-2-cyclohexene-l-one (1.98 g, 12.9 mmol), 0.61 g (25.7 mmol magnesium) and 12.9 mmol (5.0 g ) of 2- (3-benzyloxy-4-bromophenyl) -2-methyloctane.

Infrared spectrum: (CHC13) 1667, 1613 and 1565 cm-1.

Mass spectrum: m / e 418 (M +), 400, 385, 333, 327,299,291 and 91.

Example 6:

3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methylcyclo-hexanone

5.60 mg (1.39 mmol) of 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclohex-2-enone in 5 ml of tetrahydrofuran is slowly added to a solution cooled to between -10 and - 5 ° C of 4.17 mmol of dimethylcopper-lithium in 10 ml of tetrahydrofuran. The reaction mixture is stirred for a further 30 min, then poured into 100 ml of saturated ammonium chloride and 100 ml of ether. After stirring for 10 min, the reaction mixture is quenched and extracted with 200 ml of ether. The ether extraction phase is washed with 100 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated until an oily residue is obtained. The oil is purified by preparative layer chromatography, carried out on three plates of silica gel 20 cm × 20 cm × 2 mm, eluting with a 2/1 mixture of cyclohexane and ether; 282 mg (48%) (upper Rf) of the title compound, in the form of an oil, are obtained and 211 mg (36%) (lower Rf) of 3- [2-benzyloxy-4- (l , 1-di-methylheptyl) phenyl] -1-methylcyclohexene-2-ol-1 in the form of an oil.

Infrared spectrum: (CHC13) 1704, 1610, 1565 cm-1.

Mass spectrum: m / e 420 (M +), 405, 377, 335 and 329.

3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -1-methylcyclo-hexene-2-ol-1:

Infrared spectrum: (CHC13) 3571, 3401, 1661, 1608 and 1585 cm-1.

Mass spectrum: m / e 420 (M +), 402, 335 and 317.

Example 7:

3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] cyclohex-2-enone

A mixture of 400 mg (0.988 mmol) of 3- [2-benzyloxy-4- (1,1-dimethyl-heptyl) phenyl] cyclohex-2-enone and of 20 mg of 5% palladium fixed on carbon. The reaction mixture is then filtered through diatomaceous earth using ether and the filtrate is evaporated to dryness. The crude residue is recrystallized from petroleum ether to give 110 mg (35%) of the title compound, melting at 122-123 ° C.

Infrared spectrum: (Kr) 3448, 1634, 1608 and 1565 cm-1.

Mass spectrum: m / e 314 (M +), 299 and 229.

10

Analysis for C2iH30O2:

Calculated: C 80.21 H 9.62%

Found: C 80.23 H 9.46%

15 Example 8:

3- (2,4-Dihydroxyphenyl) cyclohexanone methyl ketal

10 drops of concentrated sulfuric acid are added to a 0 ° C solution of 7.0 (33.0 mmol) of 3- (2,4-dihydroxyphenyl) cyclohexanone in 100 ml of methanol and 15 ml of trimethyl orthoformate. The reaction mixture is then stirred for 3 h without cooling, allowing its temperature to rise to room temperature,

then it is deactivated by the addition of excess solid sodium bicarbonate. The reaction mixture is evaporated under reduced pressure and the residue is dissolved in 200 ml of water and 250 ml of ether. The ether extraction phase is washed once with 150 ml of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated. The oily residue is crystallized from a mixture of ether and pentane; 5.74 g (77%) of the title compound are thus obtained, melting at 129-130 ° C.

30 Infrared spectrum: (KBr) 3289,1629, 1613 and 1597 cm -1.

Mass spectrum: m / e 220 (M +), 205, 203, 188, 177, 161 and 136.

Analysis for C13H1603:

Calculated: C 70.89 H 7.32%

35 Found: C 70.79 H 7.34%

Example 9:

3- [2-Hydroxy-4- (4-phenylbutyloxy) phenyl] cyclohexanone methyl ketal

40

Heated at 85-100 ° C for 4 h a mixture of 5.03 g (22.8 mmol) of methyl ketal of 3- (2,4-dihydroxyphenyl) cyclo-hexanone, 10.1 g (73.2 mmol) anhydrous potassium carbonate and 6.12 g (26.8 mmol) of 4-phenylbutyl methanesulfonate in 45 ml of N, N-dimethylformamide. The reaction mixture is cooled and added to 200 ml of water and 200 ml of ether. The ether extraction phase is washed twice with 200 ml of water, dried over magnesium sulfate and evaporated, leaving an oily residue. The oil is purified by column chromatography of 50,400 g of silica gel eluted with a mixture of pentane and 2/1 ether; 7.4 g (92%) of the title compound are thus obtained, in the form of an oil.

Infrared spectrum: (CHC13) 1623 and 1590 cm-1.

Mass spectrum: m / e 352 (M +) and 91.

55 Analysis for C23H2803:

Calculated: C 78.37 H 8.01%

Found: C 78.34 H 8.07%

The following compounds were prepared in the same way, but using the corresponding mesylate in place of 4-phenylbutyl methanesulfonate:

3- [2-Hydroxy-4- (2-heptyloxy) phenyl] cyclohexanone methyl ketal (6.13 g, 75%) as an oil from 5.7 g (25.9 mmol) methyl ketal of 3- (2,4-dihydroxyphenyl) cyclo-65 hexanone and 6.2 g (32.3 mmol) of 2-heptyl methanesulfonate.

Infrared spectrum: (CHC13) 1637 and 1600 crrr1.

Mass spectrum: m / e 318 (M +), 286, 274, 220, 204 and 178.

3- [2-Hydroxy-4- (2-octyloxy) phenyl] cyclo methyl ketal

21

635,812

hexanone as an oil (5.03 g, 58%) from the methyl ketal of 3- (2,4-dihydroxyphenyl) cyclohexanone (5.7 g, 25.9 mmol) and 7.3 g ( 35.1 mmol) of 2-octyl methanesulfonate.

Infrared spectrum: (CHC13) 1639 and 1600 cm-1.

Mass spectrum: m / e 332 (M +), 300, 289, 272 and 220.

3- [2-hydroxy-4- (2-nonyloxy) phenyl] cyclohexanone methyl ketal (5.23 g, 59%) as an oil from 3- (2,4-dihydroxyphenyl methyl ketal ) cyclohexanone (5.7 g, 25.9 mmol) and 2-nonyl methanesulfonate (7.9 g, 35.5 mmol).

Infrared spectrum: (CHC13) 1634 and 1590 cm-1.

Mass spectrum: m / e 346 (M +), 314, 220, 188 and 161.

3- [2-hydroxy-4- (2-phenyl) butoxy) phenyl] cyclohexanone methyl ketal as an oil (5.1 g, 56%) from 3- (2,4-dihydroxyphenyl methyl ketal) ) cyclohexanone (5.7 g, 25.9 mmol) and 2- (4-phenylbutyl) methanesulfonate (8.0 g, 35.0 mmol).

Infrared spectrum: (CHC13) 1639 and 1603 cm-1.

Mass spectrum: m / e 352 (M +), 320, 220 and 188.

3- [2-hydroxy-4- (2- (6-phenyl) hexyloxy) phenyl] -cyclohexanone methyl ketal (5.3 g, 54%) as an oil from 3- (2 methyl ketal , 4-dihydroxyphenyl) cyclohexanone (5.7 g, 25.9 mmol) and 2- (6-phenylhexyl) methanesulfonate (9.0 g, 35.5 mmol).

Infrared spectrum: (CHC13) 1634 and 1597 cm-1.

Mass spectrum: m / e 380.2342 (M +, C25H3203), 220.1088, 188.0986 and 177.0550.

Example 10:

3- [2-Hydroxy-4- (4-phenylbutyloxy) phenyl] cyclohexanone

A mixture of 6.8 g (19.3 mmol) of 3- [2-hydroxy-4- (4-phenylbutyloxy) -phenyl] cyclohexanone methyl ketal, 100 ml of 2N hydrochloric acid and 60 ml of dioxane. The reaction mixture is cooled and poured into 300 ml of ether and 500 ml of saturated sodium chloride. The ether extraction phase is washed once with 500 ml of saturated sodium chloride and once with 500 ml of saturated sodium bicarbonate, it is dried over magnesium sulphate and evaporated to 1%. 'obtaining an oily residue. The oil is purified by column chromatography of 400 g of silica gel eluted with a mixture of ether and 1/1 cyclohexane; 6.4 g (98%) of the title compound are obtained in the form of an oil.

Infrared spectrum: (CHC13) 3571, 3333, 1718 (weak), 1626 and 1595 cm-1.

Mass spectrum: m / e 388 (M +), 320, 310, 295, 268 and 91.

The following compounds were prepared in the same way from the corresponding ketals of Example 9:

3- [4- (2-Heptyloxy) -2-hydroxyphenyl] cyclohexane (4.7 g, 82%) as an oil from 6.0 g (18.8 mmol) of the corresponding methyl ketal.

Infrared spectrum: (CHC13) 3636, 3390; 1724 (weak), 1639 and 1600 cm-1.

Mass spectrum: m / e 304 (M +), 206.188, 171, 163 and 137.

3- [4- (2-Octyloxy) -2-hydroxyphenyl] cyclohexanone (4.1 g, 85%) in the form of an oil from 5.0 g (15.0 mmol) of the corresponding methyl ketal.

Infrared spectrum: (CHC13) 3636, 3378, 1721 (weak), 1631 and 1595 cm-1.

Mass spectrum: m / e 318 (M +), 206, 188, 178 and 163.

3- [4- (2-Nonyloxy) -2-hydroxyphenyl] cyclohexanone (4.35 g, 89%) in the form of an oil from 5.1 g (14.7 mmol) of the corresponding methyl ketal.

Infrared spectrum: (CHC13) 3584, 3367,1709 (weak), 1626 and 1587 cm-1.

Mass spectrum: m / e 332 (M +), 206,187 and 171.

3- [4- (2- (4-Phenyl) butyloxy) -2-hydroxyphenyl] cyclohexanone (3.8 g, 79%) from 5.0 g (14.2 mmol) of the corresponding methyl ketal, in the form of an oil.

Infrared spectrum: (CHC13) 3636, 3425, 1724 (weak), 1637 and 1600 cm-1.

Mass spectrum: m / e 338 (M +), 206,188,132,117 and 91. 3- [4- (2- (6-Phenyl) hexyloxy) -2-hydroxyphenyl] cyclohexanone (4.45 g, 89%) in the form d '' an oil from 5.2 g (13.6 mmol) of the corresponding methyl ketal.

Infrared spectrum: (CHC13) 3636, 3390, 1718, 1637 and 1600 cm-1.

Mass spectrum: m / e 366 (M +), 206, 188 and 91.

Example 11:

Cis-3- [2-hydroxy-4- (4-phenylbutyloxy j phenyl] cyclohexanol and the trans isomer

0.539 g (14.2 mmol) of sodium borohydride is added to a solution at -18 ° C of 4.8 g (14.2 mmol) of 3- [2-hydroxy-4- (4-phenyl-butyloxy) phenyl] cyclohexanone in 25 ml of methanol. The reaction mixture is stirred for 40 min, then poured into 250 ml of saturated sodium chloride and 250 ml of ether. The ether extraction phase is washed once with 150 ml of saturated sodium chloride, it is dried over magnesium sulfate and evaporated until an oily residue is obtained. This oil is purified by column chromatography on 400 g of silica gel eluted with a mixture of dichloromethane and 2.5 / 1 ether; 3.37 g (70%) of the cis isomer, crystallized from cyclohexane, and 0.68 g (14%) of the trans isomer, crystallized from cyclohexane, are obtained, as well as 0.69 g (14%) ) of mixed material.

Cis isomer:

Melting point: 79-80 ° C.

Proton magnetic resonance: S 2.70 (m, benzyl methylene), 3.26 (m, benzyl methine), 3.93 (large t, J = 8 Hz, —OCH2 -), 4.28 (m, OH, carbinol methine, with D20 8 4.25, m, carbinol methine), 6.42 (dd, J = 8 and 2Hz, ArH), 6.45 (d, J = 2Hz, ArH), 7.03 ( d, J = 8Hz, ArH) and 7.22 (s, PhH).

Infrared spectrum: (CHC13) 3610, 3333, 1631 and 1603 cm-1. Mass spectrum: m / e 340 (M +), 322, 190 and 91.

Analysis for C22H2803:

Calculated: C 77.61 H 8.29%

Found: C 77.46 H 8.25%

Trans isomer:

Melting point: 112-114 ° C.

Proton magnetic resonance: 8 2.68 (m, benzyl methylene), 3.80 (m, OH, - OH2 -, carbinol methine, with D20 8 3.63, m, carbinol methine and 8 3.90, large t, J = 6Hz, —OCH2 -), 6.32 (large s, overlap with 8 6.40), 6.40 (double d, J = 8 and 2Hz, ArH), 7.00 (d, J = 8Hz, ArH) and 7.20 (s, PhH).

Infrared spectrum: (CHC13) 3610, 3390, 1631 and 1595 cm-1. Mass spectrum: m / e 340 (M +), 322,190 and 91.

Analysis for C22H2803:

Calculated: C 77.61 H 8.29%

Found: C 77.40 H 8.31%

The following compounds are prepared in the same way: Cis-3- [4- (2-heptyloxy) -2-hydroxyphenyl] cyclohexanol and Visomother trans in the form of oils from 3- [4- (2- heptyloxy) -2-hydroxyphenyljcyclohexanone (5.2 g, 13.6 mmol). 854 mg (36%) of the cis-3 isomer and 107 mg (3%) of the trans-3 isomer are obtained in the order of elution of the silica gel.

Cis isomer:

Infrared spectrum: (CHC13) 3597, 3333, 1629 and 1600 cm-1. Mass spectrum: m / e 306 (M +), 208, 190, 173 and 162.

Proton magnetic resonance: 8 0.82 (m, methyl),

5

10

15

20

25

30

35

40

45

50

55

60

65

635,812

22

2.8 (m, benzyl methine), 3.7 (m, carbinol methine and OH), 4.1 (m, methine), 6.38 (m, ArH) and 6.93 (d, J = 8Hz, ArH ).

Trans isomer:

Mass spectrum: m / e 306 (M +), 208 and 190.

Proton magnetic resonance: 5 çqq 0.82 (m, methyl),

3.25 (m, benzyl methine), 4.3 (m, carbinol methine and OH), 6.33 (m, ArH) and 6.94 (d, J = 8Hz, ArH).

Cis-3- [4- (2-octyloxy) -2-hydroxyphenyl] cyclohexanol and the trans isomer from 3- [4- (2-octyloxy) -2-hydroxyphenyl] cyclo-hexanone (2.92 g , 9.18 mmol). 1.58 g (54%) of the cis-3 isomer and 0.57 g (19%) of the trans-3 isomer are obtained in the order of elution of the silica gel.

Cis isomer:

Infrared spectrum: (CHC13) 3663, 3390, 1637 and 1608 cm-1. Mass spectrum: m / e 320 (M +), 319, 208 and 190.

Proton magnetic resonance: S 0.83 (m, methyl),

2.81 (m, benzyl methine), 3.8 (m, carbinol methine), 4.1 (m, side chain methine and OH), 6.35 (m, ArH) and 6.96 (d , J = 8Hz, ArH).

Trans isomer:

Infrared spectrum: (CHC13) 3636, 3390, 1634 and 1595 cm-1. Mass spectrum: m / e 320 (M +), 235, 208, 190 and 173.

Proton magnetic resonance: ô 3 ^ 5 ^. 0.82 (m, methyl),

CL / LI3

3.25 (m, benzyl methine), 4.1-4.9 (m, carbinol and side chain methines and OH), 6.35 (m, ArH) and 6.96 (d, J = 8Hz , ArH).

Cis-3- [4- (2-nonyloxy) -2-hydroxyphenyl] cyclohexanol and the trans-mother from 3- [4- (2-nonyloxy) -2-hydroxyphenyl] cyclo-hexanone (31, 5 g, 19.48 mmol). In the order of elution of the silica gel, 211 g (67%) of the cis-3 isomer and 0.32 g (10%) of the trans-3 isomer are obtained in the form of oils.

Cis isomer:

Infrared spectrum: (CHC13) 3663, 3390, 1639 and 1610 cm-1. Mass spectrum: m / e 334 (M +), 316,208 and 190.

Proton magnetic resonance: 8 ïîf ™ 0.88 (m, methyl),

2.85 (m, benzyl methine), 3.5-4.1 (m, carbinol methine and OH), 4.22 (m, side chain methine), 6.38 (m, ArH) and 6 , 97 (d, J = 8Hz, ArH).

Trans isomer:

Infrared spectrum: (CHC13) 3636, 3413, 1637 and 1592 cm-1. Mass spectrum: m / e 334 (M +), 316, 208,206 and 190.

Proton magnetic resonance: 8 0.88 (m, methyl),

3.23 (m, benzylic methine), 3.9-4.6 (m, carbinol and side chain methines and OH), 6.36 (m, ArH) and 6.96 (d, J = 8Hz , ArH).

Cis-3- [4- (2- (4-phenyl) butyloxy) -2-hydroxyphenyl] cyclohexanol and the trans isomer from 3- [4- (2- (4-phenyl) butyloxy) -2- hydroxyphenyl] cyclohexanone (2.9 g, 8.23 mmol). 1.29 g (44%) of the cis-3 isomer and 241 mg (8%) of the trans-3 isomer are obtained in the order of elution of the silica gel.

Cis isomer:

Melting point: 96-105 ° C (after recrystallization from pentane).

Infrared spectrum: (CHC13) 3636, 3390, 1634 and 1608 cm-1. Mass spectrum: m / e 340 (M +), 322, 208,190,162,147, 136 and

91.

Proton magnetic resonance: 8 1.30 (d, J = 6Hz,

methyl), 3.75 (m, carbinol methine), 4.23 (m, side chain methine), 6.21 (d, J = 2Hz, ArH), 6.38 (double d, J = 8 and 2Hz, ArH), 6.98 (d, J = 8H, ArH) and 7.20 (s, Ph).

Analysis for C22H2803:

Calculated: C 77.61 H 8.29%

Found: C 77.59 H 8.18%

Trans isomer:

Infrared spectrum: (CHC13) 3623,3390, 1637 and 1595 cm-1. Mass spectrum: m / e 340 (M +), 342,208,190,162,147,136 and 91.

Proton magnetic resonance: 8 1.30 (d, J = 6Hz,

methyl), 3.3 (m, benzyl methine), 4.23 (m, carbinol and side chain methines), 6.38 (m, ArH), 6.94 (d, J = 8Hz, ArH) and 7.18 (s, Ph).

Cis-3- [4- (2- (6-phenyl) hexyloxy) -2-hydroxyphenyl] cyclohexanol and the trans isomer from 3- [4- (2- (6-phenyl) hexyloxy) -2-hydroxyphenyl ] cyclohexanol (3.3 g, 9.01 mmol). 1.54 g (46%) of the cis-3 isomer and 274 g (8%) of the trans-3 isomer are obtained in the order of elution of the silica gel.

Cis isomer:

Melting point: 99-113 ° C (after recrystallization from pentane).

Infrared spectrum: (CHC13) 3636, 3367, 1631 and 1592 cm-1. Mass spectrum: m / e 368 (M +), 350, 208,190,162,147, 136 and 91.

Proton magnetic resonance: 8 1.30 (d, J = 6Hz,

methyl), 3.6 (m, carbinol methine), 4.2 (m, side chain methine), 6.37 (m, ArH), 6.98 (d, J = 8Hz, ArH) and 7 , 18 (s, PhH).

Analysis for C24H3203:

Calculated: C 78.22 H 8.75%

Found: C 78.05 H 8.56%

Trans isomer:

Infrared spectrum: (CHC13) 3636, 3413, 1634 and 1597 cm-1. Mass spectrum: m / e 368 (M +), 350, 208,190,162,147,136 and 91.

Proton magnetic resonance: 8 1.25 (d, J = 6Hz,

methyl), 4.21 (m, carbinol and side chain methines), 6.37 (m, ArH), 6.95 (d, J = 8Hz, ArH) and 7.15 (s, PhH).

Example 12:

3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] -2-cyclohexenol

6.3 ml of a 1M diisobutylaluminum hydride solution (in toluene) are added dropwise to a solution at -30 ° C of 1.00 g (3.18 mmol) of 3- [4- ( 1,1-dimethylheptyl) -2-hydroxy-phenyl] -2-cyclohexenone in 60 ml of ether. The reaction mixture is stirred for a further 30 min at -30 ° C, then added to 1.51 of water. The deactivated solution is extracted with three 400 ml portions of ether and the combined extracts are washed twice with 125 ml of saturated sodium chloride and dried over magnesium sulfate. After evaporation, the crude product is purified by column chromatography on 50 g of Florisil eluted with ether, to give an oil. By crystallization of the oil in pentane, 256 mg (25%) of the product indicated in the title are obtained. Melting point: 87-88 ° C.

Mass spectrum: m / e 316 (M +), 298, 231 and 213.

5

10

15

20

25

30

35

40

45

50

55

60

65

23

635,812

Analysis for C2lH3202:

Calculated: C 79.70 H 10.19%

Found: C 79.68 H 9.96%

Example 13:

3- [4- (1,1-dimethy! Heptal) -2-hydroxyphenyl] -3-cyclohexenone ethylenetetyl

A solution of 500 mg (1.59 mmol) of 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -2-cyclo-hexenone, 7.8 g (127 mmol) is heated at reflux for 12 hours. ) ethylene glycol, 375 mg (3.18 mmol) of hydroquinone and 50 mg (0.263 mmol) of paratoluenesulfonic acid monohydrate in 50 ml of benzene using a Dean and Stark condenser packed with 3 A molecular sieve. The reaction mixture is cooled and poured into 500 ml of saturated sodium bicarbonate. The deactivated mixture is extracted with three 150 ml portions of ether, then it is dried over magnesium sulfate and evaporated to dryness. The solid residue is purified by column chromatography of 50 g of silica gel eluted with 50% ether in petroleum ether and 393 mg (69%) of the indicated product are obtained (after crystallization from pentane). in the title. Melting point: 97-98 ° C.

Mass spectrum: m / e 358 (M +), 297.273, 245, 229.

Analysis for C23H3403:

Calculated: C 77.05 H 9.56%

Found: C 76.98 H 9.42%

Example 14:

3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] -4-methylcyclohex-3-enone

A mixture of 4.08 g (0.1 mol) of ethylene ketal of 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4-methylcyclohex-3- is stirred at 25 ° C. for 6 h. enone, 50 ml of 2N oxalic acid and 50 ml of me-thanol. The reaction mixture is added to 500 ml of water and 250 ml of ether. The ether extraction phase is washed once with 250 ml of saturated sodium bicarbonate and once with 250 ml of saturated sodium chloride, then it is dried over magnesium sulfate and evaporated. The residue is purified by column chromatography of 400 g of silica gel eluted with 50% ether in pentane, to give the title compound.

Example 15:

3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] cyclohexene-3-ol-1

1.9 g (50 mmol) of sodium borohydride are added to a solution at -18 ° C. of 17.5 g (50 mmol) of 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclohex -3-enone in 50 ml of methanol. The reaction mixture is stirred for 30 min, then poured into 250 ml of saturated sodium chloride and 250 ml of ether. The ether extraction phase is washed once with 250 ml of saturated sodium chloride, dried over magnesium sulfate, then evaporated. The residue is purified by column chromatography on 400 g of silica gel eluted with 50% ether in pentane; the compound indicated in the title is obtained.

Example 16:

3- [4 (1,1-Dimethylheptyl) -2-hydroxyphenyl] cyclohexene-2-l-ol

7.6 g (0.20 mol) of sodium borohydride are added to a solution at -18 ° C of 70.0 g (0.20 mol) of 3- [4- (1,1-dimethylheptyl) -2 -hydroxyphenyl] cyclohex-2-enone in 200 ml of methanol. The reaction mixture is stirred for 30 min, then poured into 11 of saturated sodium chloride and 11 of ether. The ether extraction phase is washed once with 500 ml of saturated sodium chloride, it is dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a column of 500 g of silica gel eluted with 50% ether in pentane; the compound indicated in the title is thus obtained.

Example 17:

3- [2-Acetoxy-4- (1,1-dimethylheptyljphenyl] cyclohexanone

A solution of 2.0 g of 3- [2-hydroxy-4- (1,1-dimethylheptyl) phenyl] cyclohexanone in 15 ml of pyridine is treated at 10 ° C. with 10 ml of acetic anhydride and the mixture is stirred. for 18 h under nitrogen atmosphere. It is then poured onto a mixture of ice and water and acidified with dilute hydrochloric acid. The acidified mixture is extracted with twice 100 ml of ethyl acetate, the extracts are combined, washed with brine, then dried over magnesium sulfate. By evaporation under reduced pressure, the product indicated in the title is obtained in the form of an oil.

Example 18:

1-A ketoxy-3- [2-acetoxy-4- (2- (5-phenyl) pentyloxy) phenyl] cyclohexane

20 ml of acetic anhydride are added to a solution of 2.0 g of 3- [2-hydroxy-4- (2- (5-phenyl) pentyloxy) phenyl] cyclohexanol in 20 ml of pyridine at 10 ° C and stir the mixture under nitrogen for 18 h. It is then poured onto a mixture of ice and water and acidified with dilute hydrochloric acid. The product is isolated by extraction with ethyl acetate (twice 100 ml). The combined extracts are washed with brine, dried over magnesium sulfate, then evaporated to give the diacetylated derivative in the form of an oil.

Example 19:

3- [2- (4-Morpholinobutyryloxy) -4- (1,1-dimethylheptyl) phenyl] cyclohexanol

0.227 g (1.1 mmol) of dicyclohexylcarbodiimide and 0.222 g (1.0 mmol) of 4-N-piperidyl-butyric acid hydrochloride are added to a solution of 0.300 g (1.0 mmol) of 3- [2 -hydroxy-4- (1,1-di-methylheptyl) phenyl] cyclohexanone in 25 ml of methylene chloride at room temperature. The mixture is stirred for 18 h, then cooled to 0 ° C and filtered. Evaporation of the filtrate gives the product indicated in the title in the form of its hydrochloride.

Example 20:

3- [2-Hydroxy-4- (1,1-dimethylheptyl) phenyl] -1-methylenecyclo-hexane

90 ml of anhydrous dimethyl sulfoxide are added to 50% sodium hydride in mineral oil (2.28 g, 48 mmol) (washed with three 25 ml portions of pentane) and the mixture is heated to 70 ° C for 0.75 h. 17.79 g (51 mmol) of methyltriphenylphosphonium bromide are then added in a single portion. The yellow solution is stirred for 30 min at 25 ° C., then 2.26 g (6.3 mmol) of 3- [2-acetoxy-4- (1,1-dimethylheptylphenyl] -cyclohexanone) are added thereto at once. dissolved in 90 ml of dimethyl sulfoxide and the mixture is heated to 63-65 ° C. for a further 1.5 h, then the reaction mixture is poured onto 150 ml of ice and water containing 25 g of sodium bicarbonate and is extracted three times with 50 ml of ether each time. After having combined the ether extraction phases, they are dried over magnesium sulfate, they are discolored with charcoal and filtered through a layer of silica gel, which gives a colorless oil which is treated by chromatography on 75 g of silica gel (using cyclohexane as the eluting solvent). A nonpolar impurity is first eluted; the polarity of the solvent is then raised to that of a mixture of ether and cyclohexane at 1:10 and the product indicated in the title is thus obtained in the form of a colorless oil.

Example 21:

3- [2-Hydroxy-4- (1,1-dimethylheptyl) phenylJ-1-hydroxymethylcyclo-hexane

A solution of 1.03 g (3 mmol) of 3- [2-hydroxy-4- (1,1-dimethylheptyl) phenyl] -l- is cooled to 0 ° C. in an ice-water bath.

5

10

15

20

25

30

35

40

45

50

55

60

65

635,812

24

methylenecyclohexane in 25 ml of anhydrous tetrahydrofuran. 4.5 ml (4.5 mmol, 1M solution) of borane and tetrahydrofuran complex are added and the colorless solution is stirred for approximately 18 h at room temperature. The mixture is cooled to ice and 8 ml of water are added to decompose the excess reagent. The mixture is stirred for 15 min, then 3 ml (9 mmol) of 3N sodium acetate are added, then 3 ml of 30% hydrogen peroxide. The mixture is stirred at 0 ° C for 15 min, then allowed to warm to room temperature and stirred for 24 h. The reaction mixture is poured onto 100 ml of ice and water, then it is extracted with three times 50 ml of ether. After having combined the extraction phases with ether, they are washed with sodium sulfite until the starch and potassium iodide test is negative, they are dried over magnesium sulfate and evaporated to dryness to obtain a pale yellow oil which is chromatographed on 50 g of silica gel (elution solvent = cyclo-hexane / 3/1 ether) and the product is obtained in the form of 'a colorless foam.

Example 22:

Trans-4- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-butene-2-one

A solution of 65.2 g (0.193 mol) of 2-benzyloxy-4- (1,1-dimethylheptyl) benzaldehyde and 62.0 g (0.195 mol) of l-triphenylphosphoranylidene-2- are heated at reflux for 20 h. propanone in 195 ml of dichloromethane. Another portion of 15.5 g of ylide (0.047 mol) is added and heating is continued at reflux for 24 h. The reaction mixture is cooled, evaporated and diluted with ether. The resulting triphenylphosphine oxide precipitate is removed by filtration. The crude oil is purified by column chromatography on 1.5 kg of silica gel eluted with 20% ether in hexane; 53.9 g (74%) of the title compound are thus obtained, in the form of an oil.

Infrared spectrum: (CHC13) 1681,1621 and 1575 cm-1.

Mass spectrum: m / e 378 (M +), 364, 337, 293, 271, 251 and 91.

Example 23:

5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4-carbomethoxy-1,3-cyclohexanedione

A solution of 3.75 g (9.92 mmol) of trans-

4- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-butene-2-one in 4 ml of methanol to a solution of sodium methylate (0.67 g, 12.4 mmol) and 1.86 g (14.1 mmol) of dimethyl malonate in 4.75 ml of methanol. The reaction mixture is heated to reflux for 3 h, then cooled and evaporated under reduced pressure. The residue is diluted with ether and saturated sodium chloride and acidified with 1N hydrochloric acid. The extraction phase is washed with ether twice with 500 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated to give 4.71 g (99%) of the indicated compound in the title. Melting point: 108-109 ° C (after recrystallization from a mixture of petroleum ether and ether).

Infrared spectrum: (CHC13) 1742, 1709,1612 and 1577 cm-1.

Mass spectrum: m / e 478 (M +), 446,419, 393, 387 and 91.

Example 24:

5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -1,3-cyclohexanedione

A mixture of 20.8 g (43.5 mmol) of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4-carbomethoxy-1 is heated at 100 ° C. for 2.5 h. 3-cyclohexanedione, 40 ml of dioxane and 40 ml of 20% sodium hydroxide. The mixture is cooled in an ice bath and acidified with concentrated hydrochloric acid. This mixture is heated for 1 h at 100 ° C, cooled to 0 ° C, then neutralized with sodium bicarbonate. The resulting mixture is added to saturated sodium bicarbonate and ether. The ether extraction phase is dried over magnesium sulfate and evaporated to give an oil. By purification of this oil on a chromatographic column of one kilogram of silica gel eluted with 10% acetone in ether, 10.9 g (60%) of the compound indicated in the title are obtained. Melting point: 102-103 ° C (after recrystallization from pentane and ether).

Infrared spectrum: (CHC13) 3636-2222 (wide), 1739, 1712, 1613 (wide) and 1577 (shoulder).

Mass spectrum: m / e 420 (M +), 335, 329 and 91.

Example 25:

5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methoxy-2-cyclo-hexene-l-one

A solution of 5.0 g (11.9 mmol) of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -1,3-cyclohexanedione and 200 mg d is heated at reflux for 30 min. paratoluenesulfonic acid in 250 ml of methanol in a flask connected to a soxhlet condenser containing a 3 Å molecular sieve. The reaction mixture is cooled, concentrated under reduced pressure and the residue is diluted with saturated sodium bicarbonate and ether. The ether extraction phase is washed successively with saturated sodium bicarbonate and saturated sodium chloride, it is dried over magnesium sulphate, then it is evaporated to give 5.15 g (99%) of the compound indicated in the title, in the form of an oil.

Infrared spectrum: (CHC13) 1644, 1612, 1503, 1460 and 1379 cm-i.

Mass spectrum: m / e 434 (M +), 349, 343 and 91.

Example 26:

5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -2-cyclohexene-1-one

20 mg (0.53 mmol) of lithium aluminum hydride are added to a solution at 0 ° C. in 20 ml of 500 mg ether (1.15 mmol) of 5- [2-benzyloxy-4 - (1,1-dimethylheptyl) phenyl] -3-methoxy-2-cyclohexene-1-one (compound indicated in the title of Example 25). The reaction mixture is stirred for 30 min at 0 ° C, acidified with IN hydrochloric acid and stirred for 2 h at room temperature. The ether phase is separated, washed successively with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate and evaporated. The crude oil is purified by column chromatography on 100 g of silica gel eluted with 50% ether in pentane to give 353 mg (76%) of the title compound, as 'an oil.

Infrared spectrum: (CHC13) 1681,1672, 1613,1575 and 1479 cm-1.

Mass spectrum: m / e 404 (M +), 319, 313 and 91.

Example 27:

5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methyl-2-cyclo-hexene-1-one

A solution of 3.45 g (7.95 mmol) of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methoxy-2-cyclo-hexene-1 is added dropwise one in 10 ml of tetrahydrofuran to 11 ml of a 0 ° C solution of 2.9M methylmagnesium iodide in ether and 10 ml of tetrahydrofuran. The reaction mixture is then warmed and stirred at room temperature for 2 h, then ice-cold IN hydrochloric acid is added thereto. After stirring for 20 min, the hydrolyzed mixture is extracted with ether. The ether extraction phase is washed with saturated sodium bicarbonate and saturated sodium chloride, then dried over magnesium sulfate and evaporated. The crude product is purified by column chromatography of 100 g of silica gel eluted with 25% ether in pentane to give 3.08 g (93%) of the title compound. Melting point: 60-61 ° C (after recrystallization from pentane).

Mass spectrum: m / e 418 (M +), 333, 327 and 91.

Likewise, the following compounds are prepared from the corresponding reactants:

5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-ethyl-2-cyclo-

5

10

15

20

25

30

35

40

45

50

55

60

65

25

635,812

hexene-1-one (2.83 g, 82%) as an oil from 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methoxy-2- cyclohexene-1-one (3.46 g, 7.97 mmol) and 10.8 ml of 2.94M ethyl magnesium bromide (in ether).

Infrared spectrum: (CHC13) 1698, 1666, 1623 and 1582 cm-1.

Mass spectrum: m / e 432 (M +), 341 and 91.

5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-n-propyl-

2-cyclohexene-l-one (3.48 g, 85%) in the form of an oil from 4.00 g (9.21 mmol) of 5- [2-benzyloxy-4- (l, l -dimethylheptyl) -phenyl] -3-methoxy-2-cyclohexene-1-one and 36.8 mmol of n-propylmagnesium bromide.

Infrared spectrum: (CHC13) 1661,1631,1612 and 1575 cm-1.

Mass spectrum: m / e 446 (M +), 355 and 91.

5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-n-hexyl-2-cyclo-hexene-1-one (4.11 g, 92%) in the form of an oil from 4.00 g (9.21 mmol) of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -

3-methoxy-2-cyclohexene-1-one and 7.37 ml of 2.5M n-hexylmagnesium bromide (in ether).

Infrared spectrum: (CHC13) 1678, 1661, 1633,1618 and 1582 cm-1.

Mass spectrum: m / e 488 (M +), 403, 397 and 91.

Example 28:

Cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -5-methylcyclo-hexanone

A mixture of 1.00 g (2.39 mmol) of 5- [2-benzyloxy-4- (1,1-dimethyl-heptyl) phenyl] -3- is stirred under hydrogen pressure of 1 bar for 1 h. methyl-2-cyclohexene-l-one and 500 mg of 5% palladium fixed on carbon with 50% water. A second portion of 500 mg of catalyst is added and stirring is continued for 30 min. A third portion of 500 mg of catalyst is added and stirring is continued for 13 min. The reaction mixture is then filtered through sodium bicarbonate and magnesium sulfate and the filtrate is evaporated. The residue is purified by column chromatography of 140 g of silica gel eluted with 10% ether in petroleum ether, to give 323 mg (32%) of the title compound, as of an oil.

Mass spectrum: m / e 420 (M +), 402, 363, 335, 329 and 91.

Example 29:

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-methylcyclo-hexanone

A mixture of 283 g (6.77 mmol) of 5- [2-benzyloxy-4- (1,1-dimethyl-heptyl) phenyl] -3-methyl- is stirred under hydrogen pressure of 1 bar for 45 min. 2-cyclohexene-1-one, 1.5 g of 5% palladium on carbon with 50% water and 2.8 g of sodium bicarbonate in 30 ml of methanol. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure. The residue is dissolved in ether, the solution is dried over magnesium sulfate and evaporated. By crystallization of the residue in pentane, 1.15 g (52%) of the compound indicated in the title are obtained. Melting point: 95-98 ° C.

Analysis for C22H3402:

Calculated: C 79.95 H 10.37%

Found: C 80.22 H 10.28%

By following the above procedure, the compounds indicated below are prepared from the corresponding reactants of Examples 32 and 34.

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-ethylcyclo-hexanone (1.34 g, 60%) from 2.83 g (6.55 mmol) from 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-ethyl-2-cyclohexene-1-one. Melting point: 106-107 ° C.

Infrared spectrum: (CHC13) 3597, 3333,1709,1626 and 1585 cm-1.

Mass spectrum: m / e 344 (M +), 326, 315,297, 273 and 259.

Analysis for C23H3602:

Calculated: C 80.18 H 10.53%

Found: C 80.28 H 10.39%

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-propylcyclo-hexanone (1.66 g, 61%) from 3.40 g (7.62 mmol) from 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-propyl-2-cyclo-hexene-1-one. Melting point: 86.5-90.5 ° C.

Infrared spectrum: (CHC13) 3533, 3289, 1700,1618 and 1577cm-1.

Mass spectrum: m / e 358 (M +), 340, 315, 297 and 273.

Analysis for C24H3802:

Calculated: C 80.39 H 10.68%

Found: C 80.16 H 10.57%

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-hexylcyclo-hexanone (3.06 g, 93%) from 4.00 g (8.2 mmol) from 5- [2-benzyl-oxy-4- (1,1-dimethylheptyl) phenyl] -3-hexyl-2-cyclohexene-1-one. Melting point: 84-85 ° C (after recrystallization from pentane).

Infrared spectrum: (CHC13) 3571, 3333, 1703,1623 and 1582 cm-1.

Mass spectrum: m / e 400 (M +), 382 and 315.

Analysis for C27H4402:

Calculated: C 80.94 H 11.07%

Found: C 80.97 H 10.94%

Example 30:

Trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -5-methylcyclo-hexanone

A solution of 500 mg (1.24 mmol) of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -2-cyclohexene-1 -one in 1.5 ml of is added dropwise. ether with a solution at 0 ° C. of dimethylcopper-lithium (2.47 mmol) in 3 ml of ether and 2 ml of hexane. The reaction mixture is stirred for 15 min, then poured into 300 ml of saturated aqueous ammonium chloride solution. The deactivated reaction mixture is extracted with three 50 ml portions of ether, the ether extraction phases are combined, then washed with water and with saturated sodium chloride, then they are dried over sodium sulfate. magnesium and evaporated to give 450 mg (92%) of the title compound, as an oil.

Infrared spectrum: (CHC13) 1704,1613 and 1577 cm-1.

Mass spectrum: m / e 420 (M +), 402, 363, 335 and 329.

Example 31:

Trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-methylcyclo-hexanone

Stirred under pressure of hydrogen gas at 1 bar, until the absorption of hydrogen has ceased, a mixture of 175 mg (0.417 mmol) of trans-3- [2-benzyloxy-4- (l, l-dimethylheptyl) phenyl] -5-methylcyclohexanone and 175 mg of 5% palladium fixed on carbon with 8 ml of 50% water in methanol. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure. By crystallization of the residue in pentane, 89 mg (64%) of the compound indicated in the title are obtained. Melting point: 99-102 ° C.

Mass spectrum: m / e 330 (M +), 312, 273 and 245.

Example 32:

Cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] trans-5-methyl-cyclohexanol and the trans isomer, cis

216 mg (5.68 mmol) of sodium borohydride are added over 1 hour to a solution at -78 ° C of 300 mg (10.714 mmol) of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl ) phenyl] -5-methylcyclohexanone in 15 ml of methanol and 5 ml of tetrahydrofuran. The reaction mixture is stirred for a further 2 h at -78 ° C, allowed to warm to room temperature and evaporated in vacuo. We

5

10

15

20

25

30

35

40

45

50

55

60

65

635,812

26

acidifies the residue with dilute hydrochloric acid and extract it with ether. The extraction phase is dried over magnesium sulfate, evaporated and the residue is purified on a column chromatographed with 50 g of silica gel which is eluted with 30% ether in the glass. pentane; 232 mg (77%) of the trans, cis isomer and 45.9 mg (15%) of the cis, trans isomer are thus obtained in the elution order.

Trans, cis isomer:

Mass spectrum: m / e 422 (M +), 337, 314,229 and 91.

Proton magnetic resonance: 8 0.86 (m, terminal methyl), 1.05 (d, J = 7 Hz, methyl at C-5), 1.26 (s, dimethyl twin), 3.70 (m, methine benzyl), 4.05 (m, carbinol methine), 5.13 (s, benzyl methylene), 6.8-7.0 (m, ArH) and 7.1-7.6 (m, ArH and Ph ).

Cis, trans isomer:

Mass spectrum: m / e 422 (M +), 337, 314,229, 206 and 91.

Proton magnetic resonance: 8 qqq 0.9 (m, methyl 20

terminal), 1.05 (d, J = 7 Hz, methyl at C-5), 3.1-4.3 (m, benzyl methines and carbinol), 5.13 (s, methylene benzyl), 5.40 (s, OH) and 6.8-7.7 (m, Ph and ArH).

25

Example 33:

Cis-3-f2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cis-5-methylcyclo-hexanol and the trans, trans isomer

160 mg (4.21 mmol) of sodium borohydride are added over 2 h to a solution at -78 ° C of 228 mg (0.543 mmol) of cis-3- [2-benzyl-oxy-4- (1, 1-dimethylheptyl) phenyl] -5-methylcyclohexanone in 10 ml of methanol. The reaction mixture is allowed to warm to room temperature, then poured into a mixture of ether and saturated sodium chloride. The ether phase is dried over magnesium sulfate and evaporated under reduced pressure. The residue 35 is purified by preparative chromatography on five 20 cm x 20 cm x 0.5 mm silica gel plates eluted with 50% ether

in pentane, which gives 36 mg (16%) of the trans, trans isomer (Rf 0.25, silica gel, 33% ether in petroleum ether) and 168 mg (Rf 0.17, silica gel, 33% ether in petroleum ether) of the cis isomer, cis.

Example 34:

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cis-5-methylcyclo-hexanol

805 mg (21.8 mmol) of sodium borohydride are added to a solution at -78 ° C of 896 mg (2.13 mmol) of cis-3- [4- (1,1-dimethyl-heptyl) -2 -hydroxyphenyl] -5-methylcyclohexanol in 30 ml of methanol. The reaction mixture was stirred for 1 h at -78 ° C, allowed to warm to room temperature and poured into ether and saturated sodium chloride. The ether extraction phase is dried over magnesium sulfate and evaporated to give an oil. By crystallization from pentane, 589 mg (65%) of the title compound is obtained. Melting point: 53 113-114 ° C.

Infrared spectrum: (CHC13) 3636, 3390, 1631 and 1592 cm-1.

Mass spectrum: m / e 332 (M +), 314,247,229 and 95.

Analysis for C22H3602:

Calculated: C 79.46 H 10.91%

Found: C 79.79 H 10.62%

The following compounds were prepared in the same manner from the corresponding reactants.

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cis-5-ethylcyclo-hexanol (0.74 g, 7%) from 1.00 g (2.30 mmol) of cis -3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-ethylcyclohexanone. Melting point: 110-lirC.

Infrared spectrum: (CHC13) 3636, 3367, 1631 and 1587 cm- '.

Analysis for C23H3802:

Calculated: C 79.71 H 11.05%

Found: C 79.41 H 10.71%

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cis-5-n-propyl-cyclohexanol (0.954 g, 71%) from cis-3- [4- (l, l -dimethyl-heptyl) -2-hydroxyphenyl] -5-n-propylcyclohexanone (1.34 g, 3.74 mmol). Melting point: 103-104 ° C (after recrystallization from pentane).

Infrared spectrum: (CHC13) 3636, 3378, 1626 and 1587 cm-1.

Mass spectrum: m / e 360 (M +), 342,275,257 and 161.

Analysis for C24H40O2:

Calculated: C 79.94 H 11.18%

Found: C 79.88 H 11.22%

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cis-5-n-hexyl-cyclohexanol, after purification on 120 g of silica gel eluted with 50% ether in pentane ; quantitative yield of cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-n-hexylcyclohexanone (1.20 g, 3.00 mmol) in the form of an oil containing traces of the trans, trans isomer.

Infrared spectrum: (CHC13) 3623, 3355, 1626 and 1585 cm-1.

Mass spectrum: m / e 402 (M +), 384, 317 and 299.

Example 35:

Trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cis-5-methylcyclo-hexanol

A mixture of 220 mg (0.521 mmol) of trans-3- [2-benzyloxy-4- (1,1-di-methylheptyl) phenyl] cis-5-methylcyclohexanol is stirred under hydrogen pressure of 1 bar for 3 h and 220 mg of 5% palladium fixed on carbon with 50% water in methanol (8 ml). The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated. By crystallization of the residue in petroleum ether, 91 mg (53%) of the title compound are obtained. Melting point: 111-112 ° C.

Infrared spectrum: (CHC13) 3571, 3333, 1629 and 1572 cm-1.

Mass spectrum: m / e 332 (M +), 314, 246 and 229.

The following compounds are prepared in the same way from the corresponding reactants.

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] trans-5-methyl-cyclohexanol (20.0 mg, 56%) as an oil from 45 mg (0.107 mmol ) of cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] trans-5-methylcyclohexanol (in the form of an oil).

High resolution mass spectrum: m / e 332.2698 (M +, C22H3e02), 314.2635, 247.1665 and 229.1600.

Trans-3- [4- (1,1-dimethylheptyl-2-hydroxyphenyl] trans-5-methyl-cyclohexanol (28 mg, quantitative yield) from trans-3- [2-benzyloxy-4- (l, l -dimethylheptyl) phenyl] trans-5-methylcyclohexanol (36 mg, 0.0853 mmol) in the form of an oil.

Rf = 0.35 (silica gel, 50% ether in pentane).

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenylJ cis-5 -methylcyclohexanol in quantitative yield from cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cis-5-methylcyclohexanol (168 mg, 0.398 mmol). This compound is identical to the product of Example 42.

Example 36:

60

Trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cis-4- (2-propenyl) cyclohexanol

A solution of 900 mg (2.01 mmol) of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) -65 phenyl] cis-4- (2- is stirred for 2 d at room temperature. propenyl) cyclohexanol and 2.74 ml of 2.2M n-butyl lithium (in hexane) in 3 ml of ether. A second 2.0 mmol portion of n-butyllithium is added and the reaction mixture is stirred for a further 2 d. It is added to 250 ml of

27

635,812

saturated sodium chloride and the mixture is extracted with ether. The ether extraction phase is dried over magnesium sulfate and evaporated. The residue is purified by column chromatography of 20 g of silica gel eluted with 50% ether in pentane to give 631 mg (88%) of the title compound. Melting point: 85-91 ° C.

Infrared spectrum: (CHC13) 3311, 1639, 1618 and 1567 cm-1.

Mass spectrum: m / e 358 (M +), 343, 340, 316, 299, 273 and 255.

By this procedure, cis-3- [4- (1,1-dimethyl-heptyl) -2-hydroxyphenyl] trans-4- (2-propenyl) cyclohexanol (241 mg, 60%) is prepared from cis -3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -trans-4- (2-propenyl) cyclohexynol (500 mg, 1.12 mmol). Melting point: 124-125 ° C (after recrystallization from pentane).

Infrared spectrum: (CHC13) 3571, 3333, 1642, 1618 and 1580 cm- '.

Mass spectrum: m / e 358 (M +), 340,298, 286, 273 and 255.

Analysis for C24H3802:

Calculated: C 80.39 H 10.68%

Found: C 80.52 H 10.57%

Example 37:

Trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4- (2-propenyl) -cyclohexanone

2.59 g (12.1 mmol) of pyridinium chlorochromate is added to a solution of 2.15 g (6.03 mmol) of 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4 - (2-propenyl) cyclohexanol (mixture of isomers) in 15 ml of dichloromethane. The reaction mixture is stirred for 2 h at room temperature, diluted with ether, diatomaceous earth is added thereto, then filtered through magnesium sulfate. The evaporated filtrate is purified by column chromatography on 200 g of silica gel eluted with 20% ether in pentane to give 250 mg of the crude compound indicated in the title. The purification of this compound is perfected by preparative chromatography on two plates of silica gel 20 cm × 20 cm × 2 mm which are eluted twice with 20% ether in pentane, to obtain 200 mg ( 9.3%) of the title compound, in the form of an oil.

Infrared spectrum: (CHC13) 3571, 3390, 1718, 1650,1626 and 1577 cm-1.

Mass spectrum: m / e 356 (M +), 341, 338, 314, 288, 271, 257, 253 and 229.

Analysis for C24H3602:

Calculated: C 80.85 H 10.18%

Found: C 80.92 H 9.86%

Example 38:

Trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -4- (2-propenyl) cyclohexanone ethyl ketal ketal

Heated at reflux for 3 h in the presence of a Dean and Stark separator a mixture of 17.0 g (38.1 mmol) of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl ] -4- (2-propenyl) cyclo-hexanone, 47.2 g (0.762 mmol) of ethylene glycol and 250 mg of paratoluenesulfonic acid monohydrate in 200 ml of benzene. The reaction mixture is cooled and poured into a mixture of 200 ml of IN sodium hydroxide, 100 ml of ether and 100 ml of pentane. The organic extract is washed twice with 200 ml portions of water, then twice with 200 ml portions of saturated sodium chloride; it is dehydrated over magnesium sulphate and evaporated, giving in quantitative yield the compound indicated in the title.

Infrared spectrum: (CHC13) 1656, 1626 and 1587 cm-1.

Mass spectrum: m / e 490 (+), 475,450,449,448,446,407,405, 399, 383 and 91.

Example 39:

Trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-butenyl) -cyclohexanone

A mixture of 700 mg (1.38 mmol) of ethylene ketal from trans-3- [2-benzyloxy-4- (1,1-dimethyl-heptyl) phenyl] -4- is heated at reflux for 1.5 h. 2-butenyl) cyclohexanone, 20 ml of dioxane and 20 ml of 2N hydrochloric acid. The reaction mixture is cooled, poured into 500 ml of ice water and extracted with 300 ml of ether. The extraction phase is washed with ether with two 200 ml portions of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to give the title compound in quantitative yield, the shape of an oil.

Infrared spectrum: (CHC13) 1715, 1616 and 1575 cm-1.

Mass spectrum: m / e 460 (M +), 403, 375, 369, 363, 313, 273, 271 and 91.

Rf: 0.43 (silica gel, 25% ether in pentane).

We prepare in the same way:

trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-pen-tenyl) cyclohexanone in quantitative yield, in the form of an oil from 540 mg ( 1.04 mmol) of trans-3- [2-benzyloxy-

4- (1,1-dimethylheptyl) phenyl] -4- (2-pentenyl) cyclohexanone. Rf: 0.57 (silica gel, 33% ether in pentane).

Example 40:

Cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cis-4-methylcy clo-hexanol and cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4- methyl-cyclohexanone

Agitation is carried out under hydrogen pressure of one bar until the absorption of gas has ceased a mixture of 3- [2-benzyloxy-4- (1,1-di-methylheptyl) phenyl] -4-methylcyclohex -2-enone and 391 mg of 5% palladium fixed on carbon with 50% water in methanol (15 ml). The reaction mixture is filtered over diatomaceous earth with ethyl acetate and evaporated. The residue is purified by column chromatography of 200 g of silica gel eluted with 50% ether in hexane to obtain, in order of elution, 758 mg of a mixture of ketones and 820 mg (53 %) of the alcohol indicated in the title, crystallized from cyclohexane. The ketone mixture is further purified by preparative chromatography on five 20 cm x 20 cm x 2 mm silica gel plates eluted four times with dichloromethane; 112 mg (7.2%) of the ketone indicated in the title are obtained in the form of an oil.

Alcohol indicated in the title Melting point: 134-135 ° C.

Infrared spectrum: (CHC13) 3623, 3333, 1626 and 1585 cm-1. Mass spectrum: m / e 332 (M +), 314, 247 and 229.

Analysis for C22H3602:

Calculated: C 79.46 H 10.92%

Found: C 79.40 H 10.72%

Ketone indicated in the title

Infrared spectrum: (CHC13) 3623, 3390, 1634 and 1582 cm-1. Mass spectrum: m / e 330 (M +), 315, 312, 288, 273, 271 and 245.

Example 41:

5- (2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methoxy-6-methyl-2-cyclohexene-l-one

A solution of 217 g (0.5 mol) of 5- (2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methoxy-2-cyclohexene-l- is added dropwise (30 min) one in 250 ml of tetrahydrofuran to a solution at - 78 ° C of 0.5 mol of lithium diisopropylamide in 500 ml of tetrahydrofuran (compound prepared from 50.5 g, i.e. 0.5 mol , diisopropylamine and 417 ml of 1.2M n-butyllithium in hexane) The reaction mixture is stirred for a further 30 min at -78 ° C., then 179 g (1.0 mol) are added thereto.

5

10

15

20

25

30

35

40

45

50

55

60

65

635,812

28

of hexamethylphosphoramide and 78.1 g (0.55 mol) of methyl iodide. The reaction mixture is allowed to warm slowly to room temperature, stirred for 1 hr and quenched by the addition of 10 ml of water. The reaction mixture is evaporated under reduced pressure to remove the tetrahydrofuran and it is poured into 11 of ice water and 11 of ether. The ether extraction phase is washed with three 11-portion portions of water, dried over magnesium sulfate and evaporated to give the title compound, in an almost pure form. The title compound is purified by column chromatography on 2 kg of silica gel eluted with a mixture of ether and pentane.

Example 42:

5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3,4-dimethyl-2-cyclo-hexene-1-one

Following the procedure of Example 1, the 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methoxy-6-methyl- is reacted.

2-cyclohexene-1-one by Grignard reaction with methylmagnesium iodide to obtain the compound indicated in the title.

Debenzylation of the product obtained in accordance with the procedure of Example 2 gives the corresponding phenol.

Example 43:

3- [2-Hydroxy-4- (1,1-dimethylheptyl) phenyl] -4,5-dimethylcyclo-hexanol

The deben2ylated compound of Example 42 is reduced to sodium borohydride in accordance with the procedure of Example 11 to obtain the compound indicated in the title.

Example 44:

3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4,5-dimethylcyclo-heptanone

A solution of 0.10 mol of lithium dicyclohexylamide in 100 ml of tetrahydrofuran is added dropwise over 2 hours to a solution at -78 ° C of 17.4 g (0.10 mol) of dibromomethane and 21.7 g (0.050 mol) of 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4,5-dimethylcyclohexanone in 100 ml of tetrahydrofuran. The reaction mixture was stirred an additional 1 h at -78 ° C and quenched by the addition of 2 ml (0.11 mol) of water. The reaction mixture is added to 300 ml of ether and 200 ml of water. The ether extraction phase is dried over magnesium sulfate and evaporated. The crude product is purified by column chromatography on 500 g of silica gel eluted with a mixture of ether and pentane; thus obtaining 3- [2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -1-dibromomethyl-4,5-dimethylcyclohexanolpur.

47.7 ml (0.105 mol) of n-butyllithium (2.2M in hexane) are added over 2 h to a solution at -78 ° C. of 30.4 g (0.050 mol) of 3- [2-benzyloxy -4- (1,1-dimethylheptyl) phenyl] -1-dibromomethyl-4,5-dimethylcyclohexanol in 150 ml of tetrahydrofuran. The reaction solution is stirred for a further 2 h at -78 ° C and 10 min at 0 ° C, then it is deactivated by pouring it into 300 ml of ice-cold IN hydrochloric acid. The deactivated reaction mixture is extracted with two 250 ml portions of ether, the combined extracts are washed with 250 ml of saturated sodium chloride, then they are dried over magnesium sulfate and evaporated. The residue is purified by column chromatography of 500 g of silica gel eluted with a mixture of ether and pentane to give the title compound.

Example 45:

General hydrochloride formation

Excess hydrochloric gas is passed through a solution of the chosen compound of formula IA-ID carrying a pyridyl group and the resulting precipitate is separated, then it is recrystallized from a suitable solvent such as a mixture of methanol and d '' 1/10 ether.

The hydrobromide, sulfate, nitrate, phosphate, acetate, butyrate, citrate, malonate, maleate, fumarate are prepared in the same way,

malate, glycolate, gluconate, lactate, salicylate, sulfosalicylate, succi-nate, pamoate, tartrate or embonate.

Example 46:

Sodium salt of cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclohexanol 2'-O-hemisuccinic ester

0.383 g (3.14 mmol) of 4-N, N-dimethylamino-pyridine is added to a solution at 0 ° C. of 1.00 g (3.14 mmol) of cis-3- [4- (l, l-dimethylheptyl) -2-hydroxyphenyl] cyclohexanol in 3 ml of dichlo-romethane. 0.314 g (3.14 mmol) of succinic anhydride in 1 ml of dichloromethane is added slowly to the resulting solution. The reaction mixture is stirred for 4 h at 0 ° C., then 3.14 ml of IN hydrochloric acid is slowly added thereto. The reaction mixture is stirred for a further 5 min, then poured into 100 ml of water and 100 ml of dichloromethane. The dichloromethane extraction phase is dried over magnesium sulfate and evaporated. The residue is dissolved in 5 ml of ethanol and 3.14 ml of IN sodium hydroxide in ethanol is added to the solution. The addition of ether causes crystallization. By recrystallization from a mixture of ethanol and ether, the compound indicated in the title is obtained.

Example 47:

Sodium salt of cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclohexanol 2'-O-phosphoric ester

A solution of 1.00 g (3.14 mmol) of cis-3- [4- (1,1 -di-methylheptyl) -2-hydroxyphenyl] cyclohexanol in 3 ml of dimethylformamide is added to a suspension at 0 ° C of 0.126 g (3.14 mmol) of potassium hydride in 3 ml of dimethylformamide. When the evolution of gas has ceased (approximately 20 min), 0.932 g (3.14 mmol) of dibenzyl phosphorochloridate is added slowly. The reaction mixture is stirred for 1 h, then poured into 200 ml of ether and 100 ml of water. The extraction phase was washed with ether with two 100 ml portions of water, dried over magnesium sulfate and evaporated to obtain a residue. The latter is mixed with 1.0 g of 5% platinum fixed on carbon and 25 ml of ethanol and the mixture is stirred under hydrogen pressure of 1 bar for 3 h. The reaction mixture is filtered through diatomaceous earth and 3.14 ml of 1N sodium hydroxide in ethanol is slowly added to the filtrate. The addition of ether causes the product to crystallize. By recrystallization from ethanol, the compound indicated in the title is obtained.

Example 48:

100 mg of 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyljcyclohexanol are intimately mixed by grinding with 900 mg of starch. The mixture obtained is then loaded into interlocking gelatin capsules, so that each capsule contains 10 mg of active substance and 90 mg of starch.

Example 49:

A base for tablets is prepared by mixing the ingredients indicated below:

Sucrose 80.3 parts

Cassava starch 13.2 parts

Magnesium stearate 6.5 parts

Sufficient trans-3- [2-hydroxy-4- (2- (5-phenylpentyloxy)) phenyl] cyclohexanol is incorporated into this base to obtain tablets each containing 0,1,0,5,1,5, 10 and 25 mg of active substance.

Example 50:

Suspensions of 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclohexanone are prepared by adding sufficient amounts of active substance to 0.5% methylcellulose to obtain suspensions containing 0.05.0 , 1, 0.5, 1, 5 and 10 mg of active substance per milliliter.

5

10

15

20

25

30

35

40

45

50

55

60

65

R

Claims (15)

635,812 CLAIMS 1. Therapeutically active compounds of formula: GOLD Z-W in which R is a saturated or unsaturated cycloalkyl group corresponding to one of the formulas: R 2 2. Compound according to Claim 1, characterized in that R is a saturated cycloalkyl group, B is a hydroxy group, R! is a hydrogen atom and Z is an alkylene group having 4 to 2 I-C I-d R where A is a hydrogen atom and B is a hydroxy, alka-nucloyloxy group having 1 to 5 carbon atoms or hydroxymethyl; or A and B, taken together, form an oxo, methylene or C2-C4 alkylenedioxy group; Rj is a hydrogen atom or a benzyl or alkanoyl group having 1 to 5 carbon atoms, a P (0) (0H) 2 group or its monometallic or dimetallic sodium and potassium salts or a group —CO (CH2) pNR5R6 in which p is an integer having a value of 1 to 4, each of the symbols R5 and R6, considered individually, is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or else R5 and R6 form with the nitrogen atom to which they are linked a penta-gonal or hexagonal heterocyclic ring chosen from piperidino, pyrrolo, pyrrolidino, morpholino or N-alkylpiperazino in which the alkyl radical contains 1 to 4 carbon atoms; R2 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 3 to 6 carbon atoms, a phenyl group or a phenylalkyl group the alkyl radical of which comprises 1 to 4 carbon atoms; R3 is a hydrogen atom or a methyl group; R4 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, provided that when R3 is a methyl group, R4 is a hydrogen atom; Z represents: a) an alkylene group having 1 to 13 carbon atoms, or b) a group - (alk ^ —O— (alk2) n— in which each of the radicals (alk,) and (alk2) is an alkylene radical having 1 to 13 carbon atoms, provided that the sum of the carbon atoms of (alkj) plus (alk2) is not more than 13; each of the symbols m and n is 0 or 1, and W is a hydrogen atom, a pyridyl group or a group of formula: - @ - wi in which Wj is a hydrogen atom or a fluorine or chlorine atom, or a pharmaceutically acceptable acid addition salt of this compound when R! is a group —CO (CH2) p — NR5R6 and / or W is a pyridyl group, or a hemi-ketal of the compounds in which A and B together form an oxo group and R! is a hydrogen atom, or the ketal formed with alkanols having 1 to 4 carbon atoms of a compound in which A and B together form an oxo and R group! is a hydrogen atom. 3 635,812 in which A and B together form an oxo, methylene or alkylenedioxy group having 2 to 4 carbon atoms, or a pharmaceutically acceptable acid addition salt of this compound when Rj is a group - CO (CH2) p —NR5R6 and / or W is a pyridyl group, or a hemicetal of compounds in which A and B together form an oxo group and R, is a hydrogen atom, or the ketal formed with alkanols having 1 to 4 atoms carbon of a compound in which A and B together form an oxo group and Rt is a hydrogen atom. 3. Compound according to claim 2, characterized in that Z is an alkylene group having 8 to 11 carbon atoms and each of the symbols W and R3 represents a hydrogen atom. 3 R. R 4. Compound according to claim 3, characterized in that each of the symbols R2 and R4 represents a hydrogen atom and Z is a group C (CH3) 2— (CH2) 6. 4 5 5 carbon atoms and W is a phenyl group. 5. 3- [2-hydroxy-4- (1,1-dimethylheptyl) phenyl] cyclohexanol or 3- [2-hydroxy-4- (1,1-dimethylheptyl) phenyl] cycloheptanol according to claim 4. 6. Compound according to claim 3, characterized in that R2 is an alkyl group, each of the symbols R3 and R4 is a hydrogen atom and Z is a group C (CH3) 2— (CH2) 6. 7. Compound according to claim 3, characterized in that R is an I-B group, R2 is an alkenyl group, R4 is a hydrogen atom and Z is a group C (CH3) 2— (CH2) 6. 8. A compound according to claim 1, characterized in that B is a hydroxy group, R is a saturated cycloalkyl group, Rj is a hydrogen atom, Z is a group (alkj),!, - O— (alk2) n— and W is a group of formula: —W-}. 9. Compound according to claim 8, characterized in that Z is a group - O— (alk2) - in which (alk2) comprises 4 or 10 15 20 25 30 35 40 45 50 55 60 65 10. Compound according to claim 1, characterized in that R is an unsaturated cycloalkyl radical, B is a hydroxy group, each of the symbols W and Rj is a hydrogen atom and Z is an alkylene group having 8 to 11 atoms of carbon. 11. Compound according to claim 1 of formula: GOLD. R Z-W in which R is a saturated or unsaturated cycloalkyl group corresponding to one of the formulas: AB AB AT II-C 11 carbon atoms. 12. Pharmaceutical composition in unit dosage form, characterized in that it contains a pharmaceutically acceptable carrier or diluent and an amount with analgesic, tranquilizing, sedative, anxiolytic or anticonvulsant effect of a compound of formula : (I) Z-W according to claim 1. 13. Process for the preparation of a compound of formula I according to claim 1 in which R is a saturated or unsaturated cycloalkyl group of formula: I-A nr I-C or I-B I-d where A is a hydrogen atom and B is a hydroxy group, characterized in that it consists in reducing a compound of formula I in which A and B together form an oxo group and, if necessary, in preparing a salt of pharmaceutically acceptable acid addition of a compound of formula I obtained, wherein Rj is a group —CO (CH2) p — NR5R6 and / or W is a pyridyl group. 14. Process for the preparation of a compound of formula I according to claim 1, in which A is hydrogen and B is a C 1 -C 5 alkanoyloxy group, characterized in that the process of claim 13 is carried out , the compound obtained is subjected to acylation and, where appropriate, a pharmaceutically acceptable acid addition salt of a compound of formula I in which R! is a group —CO (CH2) p — NR5R6 and / or W is a pyridyl group. 15. Process for the preparation of a compound of formula I according to claim 1 in which Rj is a hydrogen atom, characterized in that the process of claim 13 is carried out to prepare a compound of formula I in which Rj is one of the ester groups indicated, this compound is subjected to hydrolysis and, where appropriate, a pharmaceutically acceptable acid addition salt of a compound of formula I obtained in which W is a pyridyl group is prepared .