LU80220A1 - PROCESS FOR THE PREPARATION OF CYCLOALCANONES AND CYCLOALCANOLS SUBSTITUTED IN POSITION 3 BY A GROUP 2-HYDROXYPHENYL SUBSTITUTED IN POSITION 4 AND A PHARMACEUTICAL COMPOSITION CONTAINING THEM - Google Patents

Description

D. 5o.o29

- - "-"-- GRAND DUCHY OF LUXEMBOURG

| Patent No ....... 8 U ...... £ ...... ^ Q

1 a „12 septettee 1978 (jrfft m“, ”” _, tSaKÏb de l'Économie Nationale et des Classes Moyennes, Title delivered: ..................... ................... K?

Clivai Industrial Property Service

Γ Tjj 'LUXEMBOURG

kH (/ \ AA / ^ j itf ^ emanc ^ e ^ dream ^ of invention I. Request w ....... The ..... society ... called: ..... PFIZER .. .XNC .., ..... 2.35.East ..... 42M. Street, ... to ........................ .......... (i> ^ ....... NEW-YORK, ..... State ... of .. New- York, .. United States. ... d.lMérlque, .... repre. · -.........................

~; ....... ssntée ..... by .... MQnsieur „„ .. Ja. ^ ...... agissa ^^ ........... (2) v ....... de-agent ....................................... .................................................. .................................................. .................................................. ...............................

deposit ........ this .. twelve ..... September ..... IS.oo- ^ Q.ia ^ jfeêzâlXrlmit ---------------- --------------- ® at ........... 15 ......... ... hours, at the Ministry of National Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent for an invention concerning: ........ "Process.de ... prepar.ation ..... de .... c.yc.loalcanones ..... e.fc ..... C.YSloalcanQ.ls .......... (4) .......... ..substituted ..... in ..... pos.i.tioii .... 3 .... by ..... a ...... gr.o.up.e .. ... Hydroxyphenyl ............................

............. substituted in position ..... 4 ..... and-of a ..... composition ..... pbarmac.e.utjLgue .. ........

............. the ·, .containing. ".............................. .................................................. .................................................. ...............................................- .. ........................

declares, assuming responsibility for this declaration, that the inventor (s) is (are): ........ see-over-back ............ .................................................. .................................................. .................................................. .................................................. .. (5) 2. the delegation of power, dated ..NSKr.Y.QRK ............................. ..... on ........ l.ê ..- S.QÛt, ... 19.78 ..........

3. description in French ........ language ................................... of the invention in two copies; 4 ....... He .............. ... drawing boards, in two copies; 5. the receipt of the taxes paid to the Luxembourg Registration Office on ......... 12 ..... September ..... 1978 ........... .......................................-.......... .................................................. .................................................. .................................

claims for the above patent application the priority of one (s) application (s) of (6) ...................... patent .... ........................................... filed® / i / (7 ) .......... at .. „Eta.ts-üiiis ..... d .. '. Mi.r..iqu.e ............ ..

on .......... 13 ..... September .19 7.7 ........... (No ......... 83.3 ..,. 10.2. ) ..... „efc.JL. And ..... 2.5 ..... 3.ui.l..l.efc ...... l.9..7..8 .. .................. (8) ................... (No * ...... 9.2 .6 .., .. 68.7.) ...... (cmtinuation-.inr; part ... applic! Atlori ... de ..... 83.3.,. LQ2.) ..... ....................................

on behalf of s ..... inventor s ....................................... .................................................. .................................................. .................................................. ...... (9) elect domicile for him / her and, if appointed, for their proxy, in Luxembourg ....................... .................

. ......... 35., ..... bld * ..... Royal ......................... .................................................. .................................................. .................................................. ............................ (îo) requests the issuance of a patent for the subject described and represented in the above-mentioned annexes, - with postponement of this issue to .......... 18 ............................. .month.

II. Deposit Minutes

The above application for a patent for invention has been filed with the Ministry of National Economy and the Middle Classes, Industrial Property Service in Luxembourg, dated: September 12, 197 8. ··· ....... ... ··., Pr. Minister- at 3 p.m. / National EconomyJ ^ yä ^ s -Average Classes, · / ................. K / ·· hf f '/ η M'V W ~ 7? A 65007_ (;: ........ - \ j.? _ / / _ D. 5o.o29

t CLAIM OF PRIORITY

^ of the patent application / · ΗΜ ···· ΜΙΙ ^^ ΜΜΜΗ ·· ΗΜ ······ ΜΜΜΜΜΝ · ^ Β ·· Η ^ Η ^ ΜΜ · Μ · Μ ^^ «ηΜΗ ··· Ι

Jty IN THE UNITED STATES D1AMERIQUE_

SEPTEMBER 13, 1977

Of JULY 25, 1978_ "r Brief Description filed in support of a request for

PATENT

at

Luxembourg on behalf of: PFIZER INC.

for: "Process for the preparation of cycloalkanones and cycloalkanols substituted in position 3 by a 2-hydroxyphenyl group substituted in position 4 and of a pharmaceutical composition containing them".

j I - * 1 \

The present invention relates to cycloalkanones, cycloalkanols and their unsaturated analogs having 5 to 8 carbon atoms in the cycloalkyl ring and carrying in position 3 a 2-hydroxy-4- (substituent Z-5 W) phenyl group in which Z is an alkylene radical having 1 to 13 carbon atoms or a group (alk ^ _) -0- (alk2) n ”in le-ν„ which each of the indices m and n is equal to 0 or 1 and 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 (alk ^) plus (alk2) does not exceed 13; and 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 anti-convulsants, diuretics and antidiarrheal agents in mammals, including man.

Although a number of common analgesic agents are available, there is always a search for new and improved agents, which shows that there is not an agent which can be used. to combat pain to a great extent 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 tests.

> Other analgesic agents such as d-propoxyphene, codeine and morphine present a risk of addiction.

30 It is therefore essential to find analgesics that are both powerful and without drawbacks.

U.S. Patent No. 3,576,887 describes a series of 1- (1'-hydroxy) alkyl-2-o-hydroxyphenylcyclo-hexane and -cyclohexene which can be used as intermediates for production of 6,6-dialkyltetrahydro-and-hexahydro ~ dibenzo [b, d] -pyrans exerting a depressive effect on the central nervous system.

- '2 Λ We have just discovered that certain cycloalkanones, certain cycloalkanols and their unsaturated analogues carrying in position 3 a 2-hydroxy-4- (substituent) phenyl group (formula I below) have an effect on 5 the central nervous system, in particular as analgesics, tranquilizers, sedatives and anxiolytic agents in mammals, including humans, and / or as anti-convulsants, diuretics and antidiarrheals in mammals, including humans. The invention also relates to various derivatives of these compounds which are useful for use as dosage forms of the subject compounds, intermediate compounds relating to the compounds of formula I, and methods of obtaining them.

The compounds of the invention correspond to the formula: <? R1 X., in which R represents a saturated or unsaturated cycloalkyl group corresponding to one of the formulas: AXB ΑχΒ R, R, i? ? r * 2 3 r4 r3

I-A (A, B taken individually j I-B

* he — A (Af B taken together} II-B

A B Av R4 R2 R4 R2 I- C (A, B taken individually) 1-0

II- C (A, B taken together) 11 D

3 where the dashed lines represent an optional double bond in one of the corresponding positions, in which case Rg cannot be present; Considered alone represents a hydrogen atom; B considered alone represents a hydroxy group, a hydroxymethyl 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-10 mule II) represent an oxo * methylene or alkylenedioxy group having 2 to 4 carbon atoms; R ^ is a hydrogen atom, an alkanoyloxy group having 1 to 5 carbon atoms, a benzyl group, a group -P (O) (OH) 2 or its monometallic and dimetallic salts of sodium and potassium, a group -CQ (CH2) 2COOH or its sodium and potassium salts or a group -C0- (CH2) p-NR ^ Rg in which £ is an integer having a value of 1 to 4; each of the symbols Rg and Rg represents, individually, a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; Rg and Rg form, with the nitrogen atom to which they are linked, a pentagonal or hexagonal heterocyclic ring chosen from piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino rings 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 phenyl- * alkyl group the alkyl radical of which comprises 1 to 4 atoms of carbon ; * 30 Rg is a hydrogen atom or a methyl group; R4 is a hydrogen atom or an alkyl group, having 1 to 6 carbon atoms; with the proviso that when Rg is a methyl group, R ^ is a hydrogen atom; Z represents (a) an alkylene group having 1 to 13 carbon atoms; (b) a group - (alk ^) -0- (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 carbon of (alk ^) plus (alk2) is not more than 13; each of the indices m and £ is equal to 0 or 1; and 4 W is a hydrogen atom, a pyridyl group 5 or a group of the formula: "" i in which is a hydrogen atom or a fluo-ro or chloro radical.

The dotted lines in the compounds of formula I, that is to say in formulas IA to ID, 10 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 formulas I which contain a basic group. Examples of these compounds include those in which the variable W is a pyridyl group and / or OR ^ 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; and the salts of organic acids such as citrates, acetates, sul-fosalicylates, tartrates, glycolates, malates, malonates, ma-25, pamoates, salicylates, stearates, phthalates, succi-nates, gluconates, 2-hydroxy-3 -naphthoates, lactates, mandela-ΐ tes and methanesulfonates.

Compounds of formulas IA-ID in which A and B together form an oxo group and 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 formulas IA to ID in which A represents a hydrogen atom and B is a hydroxy group have centers of asymmetry in positions 5 1) 3 and 4 and, when the cycloalkyl group is formed from 6 to 8 members, 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 group 5 (-ZW) of the phenyl ring. The cis relationship 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 the substituents 3 and 4 and the substituents 4 and 5 of the cycloalkyl group are appreciated in reason greater biological activity (greater quantitatively). For the same reason, the trans-3,4 relationship is appreciated in the compounds of formula IA-ID 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 the formulas given above, the invention also relates to various intermediate compounds of interest for use in the preparation of compounds of formula I. The intermediate compounds correspond to the following formulas II-IV: (II) ÎQ) (III) OR- / ° \ (IV)

„J fT

Ο * R2 Λ ccH2> t-w r3 (cis and trans isomers) 6 (whose stereochemistry has not been shown), formulas in which Z, W, 1 * 2 and have the definitions given above; Y is a cyano or formyl group; t_ is an integer having a value from 5 1 to 8; R7 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; and Q is chosen from -CH2-, -ch2-ch (r4) -, -ch2-ch2-ch (r4) - and -ch2-ch2-ch2-ch (r4) - groups.

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

The compounds of formulas IA-ID in which A and B together form an oxo group are appreciated for their greater biological activity compared to that of other compounds described herein. A and B considered individually represent a hydrogen atom and, respectively, a hydroxy group; R2 is a hydrogen atom or an alkyl group; 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: _Z_ m ri _W_ 25 alkylene having 8 to

11 carbon atoms - - H

alkylene having 4 to 7 carbon atoms - - pyridyle (alk ^) -0- (alk9) 0 1 "\ OVwl ', pyridyle î m ^ π' **"

30 (alk-) -0- (alk5) n 0 1 H

1 m 2 n

The compounds of formula I are preferred, in particular the saturated cycloalkyl compounds of formula I, in which: each of the symbols R 1 and R 3 is a hydrogen atom; Z is a group -C (CH3) 2 (CH2) 6 and W is a hydrogen atom; 7 * Z is a C4 to C 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 (cis and trans forms); "- A and B together form an oxo group; 10 * 2 is a hydrogen atom or a methyl, propyl or propenyl group; R ^ 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 R ^, R2, R ^, 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 preferred in which R2 is a methyl, propyl or propenyl group and each of the symbols R1 and R4 represents a hydrogen atom.

The saturated cycloalkyl compounds of the present invention which correspond to formula I in which R3 is a hydrogen atom are prepared from suitable 2-bromo-5- ”(ZW substituent) phenol by a series of reactions comprising, as a first step, 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 protecting groups are methyl, ethyl, benzyl or substituted benzyl, the substituent of which is, for example, an alkyl radical having 1 to 4 carbon atoms, a halogen (Cl, Br, F or I) or an alkoxy group 8 having 1 to 4 carbon atoms. Protecting or inhibiting groups by ether formation can be removed using hydrobromic acid in acetic acid or a 48% aqueous solution of hydrobromic acid. Reaction 5 is carried out at elevated temperatures and, advantageously, at reflux temperature. However, when Z is a group - (alk.,) - ~ 0- (alk ~) -, acids such as polyphosphoric acid or trifluoroacetic acid must be used to avoid cleavage of the ether bond. Other reagents such as hydroiodic acid, hydrochloride or pyridine hydrobromide can be used to remove protecting groups by formation of an ether such as methyl or ethyl groups. When the protecting groups are benzyl groups or substituted benzyl groups, they can be removed by catalytic hydrogenolysis. Suitable catalysts are palladium and platinum, especially when they are attached to carbon. Alternatively, the protecting groups can be removed by solvolysis using trifluoroacetic acid. Another procedure consists in carrying out a treatment with n-butyllithium in a solvent inert to the reaction, at room 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 efficacy ** of a group to protect hydroxy function, this group is used in the reaction sequences illustrated herein. 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 an activator chosen, for example, between cuprous salts such as chloride, bromide and iodide (to favor the addition at positions 1,4), 9 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 ethylene glycol dimethyl ether (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 -20oC and cuprous iodide is added, followed by the corresponding 2-cyclo-alkene-1-one, to a temperature of about 0 to -20 ° C. The amount of copper iodide that is used is not critical, but can vary between wide limits.

15 molar proportions of approximately 0.2 to approximately 0.02 mole per mole of brominated reactant give satisfactory yields of cycloalkanone in which the hydroxyphenol group is protected (formulas IA-ID, R ^ = protecting group; = H ; A + B = oxo).

The protected cycloalcanone is then treated with a reagent which is suitable for removing 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 above-mentioned methods or by treatment, for example, with pyridine hydrochloride.

When R2 is an alkenyl group, the cycloal-t cenones so produced serve as intermediates for the preparation of the corresponding cycloalkenones (IA-ID) 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 the hydroxylic solvents. such as methanol, ethanol and water so that 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 hydroxy solvent. If higher temperatures are desired or if they are required for a given reduction, isopropanol or dimethyl ether is used as diethylene glycol.

The potassium tri-sec.-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 below 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 may also be used require anhydrous conditions and non-hydroxylic solvents such as 1,2 -dimethoxyethane, tetrahydrofuran, diethyl ether and dimethyl ether of ethylene glycol.

The cycloalkanols of formula I in which A is a hydrogen atom and each of the groups B and OR 4 is a hydroxy group can naturally be obtained directly by catalytic reduction of the protected cycloalkanone * by passage over palladium fixed on carbon or by catalytic reduction or chemical reduction of the unprotected cycloalkanone 30 (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 = OR ^ = 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 cis hydroxy epimer as the main product, 11 \ * which facilitates the separation and purification of epimeric alcohols.

Compounds of formulas IA-ID whose double bond occupies positions 2, 3 are prepared by the Grignard reaction of 5-bromo-5- (ZW substituent) protected phenol corresponding with a 3-alkoxy-2-cycloalkene -l-one (having „1 to 4 carbon atoms in the alkoxy group) in a vant inert soil vis-à-vis the reaction, at a temperature of-, about -30 to + 1Q ° C. The protected cycloalkenone thus produced is then freed from the protective 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 removed from the protecting group to regenerate the phenolic hydroxy group.

Compounds of formulas IA-ID whose double bond occupies position 3, 4 are prepared from compounds of formulas IA-ID in which A + B forms an oxo group and the double bond is in position 2,3. This process consists in ketalizing the corresponding compounds of formulas IA-ID unsaturated in position 2,3 with an al-kylene glycol having 2 to 4 carbon atoms, in the presence of a dehydrating agent such as para acid. -toluenesulfonic 25 in a solvent such as benzene, which allows azeotropic removal of the water formed as a by-product. The isomerization of the double bond takes place with formation of the ketal t with unsaturation in position 3,4. Decetalization by treatment with a mild-acting acid gives the unsaturated compounds in position 3,4 of formulas IA-ID where A + B represents an oxo group. Reduction of the oxo group as described above gives the corresponding alcohol.

The protected cycloalc-2 ~ (formulas IA-ID, A + B = oxo, R ^ = protecting group) can also be used as intermediate compounds for obtaining compounds of formula I in which is a methyl group. The introduction of the substituent is obtained by the combined addition of dimethylcopper-lithium to the corresponding cycloalk-2-enone 12 *. 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 around 5 to 0 ° -20 ° C. The organometallic reagent performs the addition at position 1,4 on the protected cycloalkenone, with the formation of a tertiary carbon atom. The protected cycloalcanone carrying a substituent R ^ is then freed from -. protective group and reduced, or reduced and then freed from the protective group in accordance with the operations described above. The adduct in position 1,2 is also formed.

Compounds of formula IB in which the cycloalkyl group is saturated and 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 about -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 benzaldehyde derivative is then converted into a suitable omega- (2-hydroxy- 4- (ZW substituent) phenyl) -3-alkenone via the Wittig reaction with the suitable 1-triphenylphosphoranylidene-2-alkanoen in an inert solvent, at a temperature, the approximate value of which is chosen between the ambient 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 al-cenone. The reaction is carried out in an inert solvent such as an alcohol having 1 to 4 carbon atoms, at a temperature selected between about 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 an elevated temperature, i.e. at a temperature of about 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 para-toluenesulfonic acid.

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

Alternatively, the reaction of 5- [2-ben- 5. zyloxy-4 ~ (ZW) -phenyl] -3-alkoxy-2-cyclohexene-1-ones with the corresponding Grignard reagent R ^ MgBr followed by acid hydrolysis gives the 5- [2 ~ benzyloxy-4- (ZW) -phenyl] -3-R ^ -2- cyclohexene-1-ones which are then reduced catalytically to the corresponding cyclohexanones .

Debenzylation as described above gives 5- 5-2-hydroxy-4- (Z-W) -phenyl] -3-R4-cyclohexanones which are then reduced as indicated above to the corresponding cyclohexanols.

Compounds of formula I-C in which the cycloalkyl group is saturated and represents something other than a hydrogen atom are prepared by extension of the nucleus of the cyclohexyl derivative. The reaction of the corresponding 5- [2-benzyloxy-4- (ZW) -phenyl] ~ 3-R ^ -cyclohexanone with li-thium / dibromomethane in an inert solvent such as diethyl ether gives l- dibromomethyl-5- [2-benzyloxy-4- (ZW) -phenylj-3-R ^ -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. 10 subsequently removed from the protective group and reduced, or reduced and removed from the protective group, in accordance with the procedures described above.

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

The reactional 2-brorao-5- (ZW substituent) phenols are prepared by bromination of the corresponding 3- (ZW substituent) phenol by conventional procedures, for example by treatment with bromine in carbon tetrachloride at a temperature of about 20 to 30 ° C. The necessary 3- (Z-W) - * phenols are prepared, if not known, by methods described herein. A practical process for the preparation of reactants in which Z is an alkylene group or (alk4) m-O- (alk2) n- 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. This aldehyde is then treated with the corresponding alkyltriphenylphosphonium bromide, the alkyl group of which extends the propionaldehyde group to the desired length. In a conventional process, the reaction aldehyde is added to a 15% suspension of sodium-dimsyl and of alkyltriphenylphos-phonium bromide in dimethylsulfoxide at a temperature below 30 ° C., for example between 10 and 30 ° C approximately. When the reaction is finished; the alkene-substituted protected phenol is collected by known procedures. Hydrogenation of the alkene by passage over palladium attached to carbon then gives the desired 3- (substituent Z-W) -phenol benzyl ether. The judicious choice of starting reactants such as 3-hydroxyphenyl-substituted aldehyde and alkyltriphenylphosphonium bromide; gives the desired 3- (substituting Z-W) phenols.

The preparation of suitable 4-R2 ~ 2-cycloalkene-l-one allows the synthesis of the compounds of formulas IA-D in which is a hydrogen atom; in accordance with the 15 procedures already described. The reaction of the corresponding 1,3-cyclo-alkane-dione with an alcohol having 1 to 4 carbon atoms and an acid catalyst such as para-toluene sulfonic acid in an inert solvent such as benzene or toluene; and in the presence of an apparatus for separating the water; at temperatures at which the reaction solvent flows back; gives 3-alkoxy-2-cycloalkene-1-ones. Reaction of the corresponding 3-alkoxy-2-cycloalkene-1-one with the lithiodiisopropyl amide in an inert solvent such as tetrahydrofuran in the presence of hexamethylphosphoramide and of the suitable compound R ^ X in which X is l 'bromide or iodide ion or some other suitable leaving groups; gives 4-R2-3-alkoxy-2-cycloalkene-1-ones. Each 4-R2-3- * alkoxy-2-cycloalkene ~ l-one is then reacted with lithium aluminum hydride in a reaction solvent 30 nel such as diethyl ether; at temperatures of about -10 to 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 formula IB-ID in which the cycloalkyl group is saturated and each of the variables R 2 and R 4 represents something other than a hydrogen atom; are prepared by reaction of 5- [2-benzyloxy-4- (Z-W) -phenyl] -3-methoxy- - 16 \? 2-cyclohexene-1-one with lithium diisopropylamide in an inert solvent at low temperature, for example between -50 and -78 ° C. Hexamethylphosphoramide and suitable R2 iodide (in which R2 represents something other than a hydrogen atom) are then added to produce a 5- [2-benzyloxy-4- (ZW) -phenyl] -3- methoxy-6-R2-2-cyclohexene-1-one. The subsequent reaction of this compound with the suitable Grignard reagent R '^ MgX (in which R'4 is an alkyl group) under the usual conditions for a reaction of Gri-10 gnard gives 3- [2-benzyloxy-4 - (ZW) -phenyl3-4-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-cyclo-hexanole is obtained. Reduction of the double bond of 3- [2-.benzyloxy-4- (ZW) -phenyl] -4-R2-5-R '4-5-cyclohexene-1-one on a catalyst consisting of fixed palladium on carbon ”makes it possible to obtain the saturated derivative of cyclohexanone corresponding. 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 the 4-hydroxy group involves, as a first step, the transformation of 3- (2,4-dihydroxyphenyl) cycloalcanone a ketal. The transformation is carried out according to well known ketalization methods, for example by reaction of 3- (2,4-dihydroxyphenyl) cycloalcanone with an alcohol, in particular an alcohol having 1 to 4 carbon atoms, in the presence of an acid such as sulfuric acid, para-toluene-sulfonic acid, hydrochloric gas, under conditions suitable for removing the water formed as a by-product. A preferred procedure is to react 3- (2,4-dihydroxyphenyl) -cycloalkanone with an orthoformic ester dissolved 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 and mesyloxy radicals (CH ^ -SC ^ -O) and tosyloxy (p-CH ^ -C ^ H ^ -SC ^ -O-) „in the presence of an acid acceptor such as sodium or potassium carbonate. The alkylated ketal is then decetated by known operations, by treatment with an aqueous solution of acid.

Another process for the preparation of 3- (ZW-substituting) phenols in which Z is an alkylene group or an (alk ^) - 0- (alk2) n- group involves the Wittig reaction on a suitable phenolic aldehyde or ketone , for example 3-hydroxybenzaldehyde or a 3- (hydroxyphenyl) -alkyl ketone whose hydroxyphenolic group is protected, for example by conversion to benzyl, methyl or ethyl ether. By the proper 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 beta carbon atom of the alkylene group, is obtained by the choice of the corresponding carbalkoxy-alkylidene-triphenylphosphorane, for example (CgHs) 2P = C (R 'J-CCXX ^ Hçj. The unsaturated ester thus produced is reduced to the corresponding alcohol by reaction with lithium aluminum hydride. Alternatively, when the group protecting the phenolic function is other than a benzyl group (e.g. a methyl group), alcohol is produced by catalytic reduction of the unsaturated ester using palladium attached to carbon, the reduction being followed by treatment of the ester saturated 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 18 \ an alkali metal salt of the body corresponding reaction H0- (alk2) -W, with final elimination of g protective group, gives the desired 3- (Z-W substituent) 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 reacted with the corresponding compound H0- (alk2) -W in the presence of a suitable base 10 (synthesis of Williamson ethers).

The brominated compounds are also advantageous to use as intermediate compounds to extend the chain of the alkylene group 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-butyliithium 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, catalyzed acid-substituted aromatic substitution. 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 and then extracting it with a suitable solvent such as methylene chloride. The 2-methoxy-alkylphenol 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 5-ammonia followed by demethylation of the resulting alkylated methyl ether with boron tribromide or pyridine hydrochloride or other known demethylating agents gives 3-alkylphenol longed for.

A practical process for the preparation of compounds of the invention in which the group -Z-W is a group -0 ~ (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. We appreciate the use of the benzyl group as a protective group in this process, since it can be easily removed by catalytic hydrogenation without cleavage of the ester group -0- (alk2) n ~ W. Of course, other protecting groups can also be used such as alkyl groups (eg 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 thus produced 3 - (2,4-dibenzyloxyphenyl) cycloalcanone is then subjected to catalytic hydrogenation on carbon-bonded palladium, to produce the corresponding 3- (2,4-dihydroxy-> phenyl) cycloalcanone with its hemicetal. The hemicetal is then transformed into; The alkyl ketal corresponding to a C 1 -C alkyl group, for example methyl, by reaction with, for example, a trialkyl orthoformate such as trimethyl orthoformate in a suitable solvent such as a C 1 -C alcohol, for example methanol, in the presence of concentrated sulfuric acid.

The alkyl ketal thus produced is then alkylated with suitable alkyl or aralkyl methane sulfonate or tosylate in the presence of anhydrous sodium or potassium carbonate in a suitably inert solvent such as N, N-dimethylfor- mamide, 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 0-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) cycloalkanone which exists in balance with its hemicetal.

Since compounds of formulas IA-ID in which A and B together form an oxo group and is a hydrogen atom exist, in solution, in equilibrium with their hemicetal form and that some, in the crystalline state, exist roughly completely in the hemicetal form, compounds of formulas IA-ID in which A and B together form an oxo group and is a hydrogen atom include the hemicetal as well 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, methyltriphenyl-phosphonium 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 procedures. 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 21 in tetrahydrofuran for the hydroboration operation, since it is a commercially available form, which gives satisfactory yields of the desired hydroxy-methyl compound. The reaction is generally carried out in tetrahydrofuran or in diethylene glycol dimethyl ether (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 of forming methylide are naturally known and can be used in place of the method described above. Representative examples of these methods are given by Maercker in "Organic Reactions", 14, 270 (1965). In the oxo compounds which correspond to the formulas IA-ID, 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-ID in which is an alkanoyl group or a group -CO-ÎCl · ^) pNR ^ R ^ 25 are easy to prepare by reaction of compounds IA-ID in which is a hydrogen atom, with the corresponding alkanoic acid or an acid of formula HOOC-CCl · ^) ^ NR ^ R ^ in the presence of a condensing agent such as dicyclohexylcar-bodiimide. Alternatively, they can be prepared by reacting a compound of formula IA-ID with the corresponding alkanoic acid chloride or anhydride, for example acetyl chloride or acetic anhydride, presence of a base such as pyridine.

Esters of compounds of formulas IA-ID in which A is a hydrogen atom and B is a hydroxy or hydroxymethyl group and OR 2 is a hydroxy group, are prepared by acylation according to the procedures described above. Compounds in which the R group (R = 22 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.

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

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

The method used is the modified version after Woolfe and MacDonald, "J. Pharmacol. Exp. Ther.", 80 "15 300-307 (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 watt 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. Each mouse is dropped into a glass cylinder (diameter of 16.6 cm) resting on the heating plate and the timer is started when the animal's legs 25 come into contact with the plate. The mice are observed half an hour and two hours after treatment with the test compound, to detect the first movements of "trembling" of one or both hind legs, or else a period of 10 seconds is allowed to pass 30 in the 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 seconds after exposure to the action of the lamp. The reaction threshold, for a protective effect, is equal to 10 seconds. Each mouse is tested half an hour and 2 hours after treatment with morphine and with the test compound. Morphine has an EMP ^ Q value of between 3.2 and 5.6 mg / kg (see subcutaneous).

15 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 the "Charles River" strain CD-I 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 the dose of 56 mg / kg intraperitoneally or subcutaneously, delivered in a volume of 10 ml / kg. Before treatment with the active substance, then half an hour and 2 hours 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 undesirable tissue damage, the test is stopped and the tail is removed from the water bath after 10 seconds. The latency period of the response is expressed 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 hours of testing, the latency periods of the response are determined after 4 and 6 hours. A final measurement 10 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 phenylbenzoquinone_ 15 Groups of 5 "Carworth" breeding mice

Farms "CF-1 are pretreated with administratior / subcutaneous or oral physiological solution of salt, morphine, codeine or test compound. Twenty minutes (in case of subcutaneous treatment) or 50 minutes ( if treated orally) later, each group of mice is treated by intraperitoneal injection of phenylbenzoquinone, an irritant known for its ability to cause abdominal contractions. The mice are observed for 5 minutes to detect the presence or absence of tension, starting 5 minutes after injection of the irritant The values On ^ 0 of inhibition of tension are determined for the pre-treatments using the active substances.

Tests using nociceptive stimuli acting by pressure 30 Effect produced in the tail pinching method according to Haffner_

A variant of Haffner's method, "Experimentelle Prüfung schmerzstillender.", Deutsch Med.Wschr., 55, 731-732 (1929) is used to determine the effects of the test compound on triggered aggression responses by a stimulus consisting of a pinch of the tail. The animals used are males of albino rats (50-50 g) of the "Charles River" (Sprague-Dawley) CD strain. Before treatment with the drug, then again half an hour, 25 * 1 hour,. 2 hours and 3 hours after treatment, a "Johns Hopkins" forceps of the type is fitted to the root of the rat's tail. 6.35 cm "bulldog". The reaction threshold for each trial consists of a clear attack and bite behavior 5 directed towards the excitation stimulus, and the latency period before the attack is noted in seconds. The clamp is removed after 30 seconds if the attack has not yet taken place and it is then considered that the latency period of the reaction is 30 seconds. Morphine is active at a dose of Ί0 17.8 mg / kg (intraperitoneally)

Tests using electrical nociceptive stimuli

"Flexion-jump" test

A modified version of the jump after flexion method according to Tenen, "Psychopharmacologia", 12, 15 278-285 (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% gly-20 cerol. The animals are then placed in a room and their legs are exposed to a series of pulses lasting 1 second, delivered at increasing intensity at 30 second intervals. 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 cries and (c) the execution of a jump or rapid movement; forward, when the pulse is triggered. A single increasing series of pulse intensities are made to act on each rat just before treatment with the drug, and half an hour, 2 hours, 4 hours and 24 hours 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: 26 EMP% = time "test" - time "witness11_ l00 deletion time - time" witness "

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 suitable in almost every 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. In general, however, the initial analgesic dosage in adults may range from about 0.1 to about 750 mg per day in a single or multiple doses. In many cases, it is not necessary to exceed a dose of 100 mg per day. The preferred oral dosage range is from about 1.0 to about 300 mg / day; the preferred dose is from about 1.0 to about 50 mg / day. The preferred parenteral dose is from about 0.1 to about 100 mg / day; the preferred dose is about 0.1 to about 20 mg / day.

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.

27

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 starch or lactose, then by loading the mixture into gelatin capsules with interlocking 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 0.10 100 mg of active substance.

Suspensions and solutions of these active substances, in particular those in which (formulas I and II) is a hydroxy group, are often prepared just before administration so as to avoid problems of stability of the suspensions or solutions (for example by precipitate -20 tion) 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:

( OH

z-w R2

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

The following abbreviations have been used in the tables: PBQ = tension caused by phenyl-benzoquinone; EQ = sudden tail spread; PC = hot plate; PQR = rat tail pinch test; 28 and FS = flexion-jump.

The values reproduced individually in the tables are the DE5Q 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.

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31

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, J7, 68-73 (1976). Charles River CD-I rats (170-200 g) are grouped in cages 18 hours before the test. The animals are made to fast for approximately 16 hours, leaving them water at will, then they are made to absorb 15 castor oil. The test drug is administered subcutaneously or orally at a constant volume of 5 ml / kg body weight in a vehicle composed of 5% ethanol, 5% "Emulphor EL-620" (emulsifier based on polyoxyethylated vegetable oil from Antara Chemicals, New York, NY) and 90% physiological salt solution, and 1 hour later, the rats are subjected to a castor oil test (1 ml , orally). The animals are placed in small individual cages (20.5 x 16 x 21 cm) fitted with metal canvas hanging bottoms. A disposable cardboard sheet 25 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 hour 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 from about 0.01 to about 50 mg / kg of body weight and by observing the subsequent drop in spontaneous motor activity. The daily dosage range for 32 mammals is from about 0.01 to about 100 mg.

The anticonvulsant activity is determined by the 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 the antidiarrheal application. Groups of five mice are used. The day before the administration, the mice are made to fast throughout the night, but they are given unlimited water. The treatments are carried out at volumes of 10 ml / kg using a 10 hypodermic needle No. 25. Animals are treated with the test compound and, 1 hour after the test, they are subjected to a electroshock (50 mA, 60 Hz) applied trans-corneally. At the same time, control tests are carried out in which the mice are only made to absorb the vehicle. Electroshock treatment causes extensor tonic convulsions in all control mice, with a lag period of 1.5 to 3 seconds. Protection is considered to exist when a mouse no longer exhibits tonic convulsions of the extensors for 10 seconds after the application of the electroshock.

The anxiolytic activity is determined by a method similar to the method for determining the anticonvulsant activity, except that the substance causing the convulsions is pentylenetetrazole administered intraperitoneally at the dose of 120 mg / kg. This treatment produced clonic convulsions in less than a minute in more than 95% of the control mice treated. Protection is considered to exist when the latency period of convulsions is delayed 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. Thirty and sixty minutes after the treatment, the mice are placed on a rotating bar for a test period of one minute 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.

'33

Example 1 3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclohexanone

A solution of 75.0 g (0.193 mole) of 2- (3-benzyloxy-4-bromophenyl) -2-methyloc-5 tane in 200 ml of tetrahydrofuran is slowly added to 9.25 g (0.386 mole) of metallic magnesium in particles from 0.177 to 0.210 mm.

The resulting mixture is refluxed for 20 minutes, then cooled to -18 ° C. 1.84 g (9.7 mmol) of cuprous iodide are added and stirring is continued for 10 minutes. A solution of 18.5 g (0.193 mole) of 2-cyclohexene-1-one in 40 ml of tetrahydro-furan is added slowly to the resulting mixture at a rate chosen so that the reaction temperature is kept below from -3 ° C by cooling with a mixture of salt and ice. The reaction mixture is stirred for a further 30 minutes (temperature below 0 ° C), then poured into 500 ml of 2N hydrochloric acid and 2 liters 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 chromatography on a column of 1.6 kg of silica gel, and elution with 20% ether in cyclohexane gives 62.5 g (79.7%) of product under the form of an oil.

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

- 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 procedure J above.

3- [2-benzyloxy-4- (2- (5-phenylpentyloxy)) phenyl] -35 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.

34 / *

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

Trans-3- [2 ~ benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -4-methylcyclohexanone as an oil (5.11 g, 5 61%) from 2-b'enzyloxy -4- (1,1-dimethylheptyl) bromobenzene (7.83 g, 0.0201 mole) and 4-methylcyclohex-2-enone (2.21 g, 0.0201 mole).

Infrared spectrum: (CHCl ^) 1712, 1613 and 1575 cm "1.

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

3- [2-benzyloxy-4 - (^., L-dimethylheptyl) phenyl] -cyclopentanone in the form of an oil (3.5 g, 58%) from 2-benzyloxy-4- (l, l -dimethylheptyl) bromobenzene (6.00 g, 15.4 mmol); Rf = 0.43 (0.25 mm 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 20 (6.00 g, 15.4 mmol) and cycloheptenone (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 mole) and cyclohex-2-enone (11.1 g, 0.116 mole). The product is recrystallized from a mixture of ether and pen-tane.

r Infrared spectrum: (CHCl ^) 1709, 1618 and 1595 cm-1.

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

Analysis: C% H%

Calculated for C2eH26 ° 3 80.80 6.78

Found: 80.88 6.80 3- [2-benzyloxy-4- (1,1-dimethyloctyl) phenyl] -cyclohexanone as an oil (5.0 g, 46%) from 2 - [3-benzyloxy-4-bromophenyl) -2-methylnonane (10.4 g, 0.0258 mole) and 2-cyclohexene-1-one (2.48 g, 0.0258 mole).

/ 35

Infrared spectrum: (CHCl ^) 1715, 1618 and 1577 cm ”· 1.

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

5 3- [2-Benzyloxy-4-tert-butylphenyl) cyclohexanone in the form of an oil (27.6 g, 58%) from 2- (3-benzyloxy-4-bromophenyl) -2- methylpropane (45.4 g, 0.142 mole) and 2-cyclohexene-1-one (13.9 g, 0.145 mole).

Infrared spectrum: (CHCl ^) 1724, 1623 and 10 1582 cm-1.

Mass spectrum: 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 mole) and 2-cyclohexene-l-one (7.06 g, 0.0735 mole)

Infrared spectrum: (CHCl ^) 1718, 1618 and -1 J

1575 cm

Mass spectrum: m / e 350 (M +), 335, 321, 307, 20 259 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 mole) and 2-cyclohexene-1-one (10.5 g, 0.110 mole).

25 Infrared spectrum: (CHCl 4) 1736, 1631 and 1592 cm "1.

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

Trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) -30 phenyl] -4- (2-propenyl) cyclohexanone as an oil (58.3 g, 70%) from l-bromo-2-benzyloxy-4- (1,1-dimethyl-heptyl) bromobenzene (73.0 g, 0.188 mole) and 4- (2-propenyl) - 2-cyclohexene-l-one (25.5 g, 0.188 mole).

Infrared spectrum (CHCl ^) 1712, 1645, 1613 and 35 1575 cm “1.

Mass spectrum: m / e 446 (M1-), 360, 354 and 91.

3- [2-benzyloxy-4- (1,1-dimethylpentyl) phenyl] -cyclohexanone in the form of an oil (11.5 g, 37%) from 36 \ "from 2- (3-benzyloxy -4-bromophenyl) -2-methylhexane (29.6 g, 0.0818 mole) and 2-cyclohexene-1-one (8.63 g, 0.09 mole).

Infrared spectrum: (CHClg) 1730, 1629 and 1592 cm "1.

5 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 10 (30.2 g, 0.0806 mole) and 2-cyclohexene-1-one (8.5 g, 0.0886 mole).

Infrared spectrum: (CHCl ^) 1715, 1623 and -1 ύ 1585 cm

Mass spectrum: m / e 392 (M +), 348, 321, 301, 15 259 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 mole) and 2-cyclohexene-1-one (7.71 g, 0.0803 mole).

20 Infrared spectrum: (CHCl-s) 1715, 1623 and 1582 cm *.

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

3- [2-benzyloxy-4- (1,1-dimethyldecyl) phenyl] -25 cyclohexanone in the form of an oil (7.0 g, 17%) from 2- (3-benzyloxy-4-bromophenyl ) -2-methylundecane (40.0 g, 0.0928 mole) and 2-cyclohexene-1-one (9.8 g, 0.102 mole).

Infrared spectrum: (CHClo) 1715, 1623 and -1 1585 cm 30 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 mole) and 2-cyclohexene-1-one (6.68 g, 0.0682 mole).

35 Infrared spectrum: (CHCl ^) 1718, 1623 and 1585 cm-1.

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

* 37 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-cyclooctene-1-one (4.78 g, 38.6 mmol).

5 Infrared spectrum: (CHCl ^) 1715, 1629 and 1587 cm ”1.

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

Example 2 10 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclohexanone

A mixture of 19.5 g (0.0468 mole) of 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclohexanone is stirred under hydrogen pressure of 1 bar for 1.5 hours. , 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 on 280 g of silica gel and elution is carried out with 20% ether in cyclohexane to obtain a solid. By recrystallization 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.

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

(CHC13) 3571, 3289, 1704, 1623 and 1575 cm “1.

Mass spectrum: m / e 316 (M +), 298, 273 and 30 231.

Analysis: C% H%

Calculated for c2iH3202: 79.70 10.19

Found: 79.69 9.89 The above procedure was repeated using the corresponding reactants of Example i, and the following products were obtained: 38 3- [4- (1, 1- dimethylheptyl) -2-hydroxyphenyl] -3- methylcyclohexanone in the form of an oil (54 mg, 86%) from 80 mg (0.19 mmol) of 3- [2-benzyloxy-4- (l, 1 -di- methylheptyl) -phenyl] -3-methylcyclohexanone.

5 Infrared spectrum: (CHClO 3597, 3390, 1623 -1 0 and 1572 cm

Mass spectrum: m / e 330 (M +), 315, 287 and 245.

Trans-3 - ([4- (1,1-dimethylheptyl) -2-hydroxyphé-10 nyl] -4-methylcyclohexanone (825 mg, 99%), melting at 62-64 ° C (after recrystallization from pentane) from trans- 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenylJ-4-methylcyclo-hexanone (1.05 g, 2.50 mmol).

Infrared spectrum: (CHCl ^) 3571, 3333, 1721 15 (weak), 1626 and 1577 cm

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

Analysis: C% H% 20 Calculated for C22 ^ 34 ° 2: 79.97 10.37

Found: 80.33 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-25 4- (1,1-dimethylheptyl) phenyl] -cyclopentanone (1.50 g, 3.83 mmol).

Infrared spectrum: (KBr) 3279, 1739, 1621 and 1577 cm- ^.

Mass spectrum: m / e 302 (M +), 283, 217, 189, 30 175 and 161.

Analysis: C% H%

Calculated for C2 () H3û02: 79.42 10.00

Found: 79.65 10.03 35 3- [4- (1,1-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).

39

Infrared spectrum: (CHCl ^) 3571, 3289, 1701, 1621, 1605 and 1577 cm "1.

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

Analysis: 5 C% H%

Calculated for ^ 22 ^ 34 ^ 2 79.95 10.37

Found: 79.60 10.33

Quantitative yield of 3- [2-hydroxy-4- (2- (5-phenylpentyloxy)) phenyl] cyclohexanone as 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-1.

Mass spectrum: m / e 352 (M +), 206, 188 and 15 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 mmo-20 µl).

Infrared spectrum: (KBr) 3195, 1631 and 1603 cm 1.

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

25 Analysis: c% H%

Calculated for C- ^ 2H14 ° 3: 69.88 6.84

Found ": 69.94 6.78 3- [4- (1,1-dimethyloctyl) -2-hydroxyphenyl] -cyclo-i hexanone (0.75 g, 48%) from 2.00 g (4 , 76 mmol) of 3- [2-benzyloxy-4- (1,1-dimethyloctyl) phenyljcyclohexanone.

Melting point: 78-80 ° C (after recrystallization from pentane).

Infrared spectrum: (CHCl ^) 3571, 3333, 1709 35 (weak), 1626 and 1577 cm-1.

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

* 40

Analysis: C% H%

Calculated for C22H34 ° 2: 79.95 10.37

Found: 79.97 9.99 5 3- (4-tertio-butyl-2-hydroxyphenyl) cyclohexanone (4.22 g, 58%) from 3- (2-benzyloxy-4-tertio-butylphenyl) cyclohexanone (10.0 g, 0.0298 mole).

Infrared spectrum: (KBr) 3279, 1639 and 1592 cm “1.

10 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 "J 45%) from 3-l2-benzyloxy-4- (1,1-dimethylpropyl) phenyljcyclohexanone (7 , 50 g, 0.0214 mo-15 le) Melting point: 165-166 ° C (after recrystallization from d-isopropyl ether).

Infrared spectrum: (CHCl ^) 3636, 3401, 1724 (weak), 1634 and 1587 cm “1.

Mass spectrum: m / e 260 (M +), 242, 231, 217, 20 213 and 161.

Analysis: C% H%

Calculated for C ^ 7H24 ° 2: 78.42 9.29

Found: 78.17 9.22 25 3- [4- (1,1-dimethylbutyl) -2-hydroxyphenyl] - cyclohexanone (0.6 g, il%) from 3 - [_ 2-benzyloxy-4- ( 1,1-dimethylbutyl) phenyl] cyclohexanone (7.00 g, 0.0192 mole).

Melting point: 10l-102 ° C (after recrystallization from isopropyl ether).

30 Infrared spectrum: (CHCl ^) 3636, 3401, 1724 (weak), 1634 and 1585 cm “1.

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

Analysis: 35 C% H%

Calculated for C ^ 3H26 ° 2: 78.79 9.55

Found: 78.78 9.21 41

Trans-3- [4 ~ (1,1-dimethylheptyl) -2-hydroxyphenyl] -4-propylcyclohexanone (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).

5 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- (1,1-dimethylpentyl) -2-hydroxyphenyl] -10 cyclohexanone (4.0 g, 95%) from 3 ~ [2-benzyloxy - 4- (l, 1 - dimethylpentyl) phenyljcyclohexanone (5.5 g, 0.0146 mole).

Melting point: 124.5-125.5 ° C (after recrystallization from pentane)

Infrared spectrum: (CHCl ^) 3623, 3378, 1718 15 (weak), 1634 and 1587 cm "1.

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

Analysis: C% H%

Calculated for C ^ 9H28 ° 2: 79.12 9.79 20 Found: 79.32 9.53 3- [4- (1,1-dimethylhexyl) -2-hydroxyphenyl] -cyclo ~ hexanone (quantitative yield) from of 3- [2-benzyloxy- 4- (1,1-dimethylhexyl) phenyljcyclohexanone (2.0 g, 5.1 mmol). Melting point: 82-83 ° C.

25 Infrared spectrum: (CHCl 4) 3636, 1634, 1616 and 1585 cm "1.

Mass spectrum: m / e 302 (M +), 284, 259 and 231.

Analysis: 30 C% H%

Calculated for C20H30 ° 2: 79.42 10.00

Found: 79.16 9.75 3- [4- (1,1-dimethylnonyl) -2-hydroxyphenyl] cyclo-hexanone (2.4 g, 6%) from 3 - [_ 2-benzylxoy-4- ( 1. 1-35 dimethylnonyl) phenyl (cyclohexanone) (5.0 g, 11.5 mmol).

Melting point: 72-73 ° C.

Infrared spectrum: (CHClo) 3650, 3413, 1721 -1 J

(weak), 1639 and 1595 cm * 42

High resolution mass spectrum: m / e 344.2691 (M +), (C23H3S ° 2) ’326.2570 and 301.2168.

3- [4- (1,1-dimethyldecyl) -2-hydroxyphenyl] -cyclo-hexanone (880 mg, 55%) from 3- £ 2-benzyloxy-3- (l, 1-5 dimethyldecyl) phenyl] cyclohexanone (2.0 g, 4.46 mmol).

Melting point: 78-79 ° C.

Infrared spectrum: (CHCl ^) 3623, 1629, 1616 and 1587 cm ”^.

High resolution mass spectrum: m / e 10 358.2836 (M +), C24H38 ° 2 * 3_ [4- (1,1-dimethylundecyl) -2-hydroxyphenyl] -cyclohexanone (1.49 gj 46%) from of 3- [2-benzyloxy-4- (1,1-dimethylundecyl) phenyl] cyclohexanone (4.00 g, 8.66 mmol).

15 Melting point: 72-73 ° C.

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

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

20 Analysis: C% H%

Calculated for C25H40 ° 2: 80.59 10.82

Found: 80.70 10.84 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -25 cyclooctanone (1.92 g, 81%) from 3- [2-benzyloxy-4- ( 1,1-dimethylheptyl) -phenyl] cyclooctanone (3.02 g, 6.95 mmol).

Melting point: 118 ° C.

Infrared spectrum (CHClo) 3623, 3356, 1709, -1 30 1629 and 1587 cm.

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

Analysis: C% H% 35 Calculated for ^ 23 ^ 35 ^ 2: 80.18 10.53

Found '79.92 10.37 43 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4-methyl-2-cyclohexene-1-one (1.15 g, 70%) from 3- [2-Benzyloxy-4 - (1,1-dimethylheptyl) phenyl] -4-methyl-2-cyclo-hexene-1-one (2.10 g, 5.02 mmol).

5 Melting point: 111 ° C (after recrystallization from a mixture of diisopropyl ether and petroleum ether)>

Infrared spectrum: (CHCl ^) 3534, 3279, 1667, 1623 and 1567 cm "1.

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

Analysis:

Cor u © / / 0 Π / 0

Calculated for ^ 22 ^ 32 ° 2: 80.44 9.83

Found: 80.35 9.67 Example 3 cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyljcyclohexanol and the trans isomer

8.05 g (0.212 mole) of sodium borohydride is added in three portions to a solution at -40 ° C of 43.0 g (0.106 mole) of 3- [2-benzyloxy-4- (l, 1- dimethylheptyl) phenyl] - cyclohexanone in 500 ml of methanol and 15 ml of tetrahydro-furan. The reaction mixture is stirred for 1 hour 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 get an oil. The oil is purified by column chromatography on 400 g of silica gel which is eluted with 20% ether in cyclohexane; 5.0 g (12%) of trans-3-Γ2-benzyloxy-4- (1,1-dimethylheptyl) phenyllcyclo-35 hexanol is obtained, in order of elution.

Infrared spectrum: (CHCl ^) 3636, 3497, 1629

Mass spectrum: m / e 408 (M +)> 393, 390, 323 and 91.

and 1587 cm-1.

44

Analysis: C% H%

Calculated for ^ 28 ^ 40 ^ 2: 82.30 9.87

Found: 81.98 9.82; 5 and 22.2 g (51%) of çis-3-Γ2-benzyloxy-4- (i, 1-dimethylheptyl) phenyl] cyclohexanol.

Melting point: 75.5-76.5 ° C.

Infrared spectrum: (CHCl ^) 3636, 3497, 1629 and 1587 cm “1.

10 Mass spectrum: m / e 408 (M +), 393, 390, 323 and 91.

Analysis: c% H%

Calculated for C28H40 ° 2: 82.30 9.87 15 Found: 81.95 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-methylcyclohexanol (quantitative yield) as an oil from 3- [2-benzyloxy-4- (1 , 1-dimethylheptyl) -phenyl] -3-methylcyclohexanone (200 mg, 0.476 mmol).

Infrared spectrum: (CHClo) 3546, 3378, 1603

-1 day

and 1555 cm.

Mass spectrum: m / e 422 (M +), 337, 314, 299, 25 271 and 229.

trans, trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4 ~ methylcyclohexanol (0.225 g, 14%) in the form of an oil and 1.19 g (74%) ' cis, trans isomer from trans-3-Γ2-benzyloxy-4- (1,1-dimethylheptyl) phenyl ~ l-30 4-methylcyclohexanone (1.6 g, 3.8 mmol). trans, trans isomer: Proton magnetic resonance: ÔCDC1 0.80 (m, methyl end of the side chain and methyl in C-4), 1.27 (s, dimethyl gemine), 3.12 (m, benzyl methine) , 35 4.20 (m, carbinol methine), 5.13 (s, methylene of benzyl ether), 6.95 (m, ArH), 7.15 (d, J = 8 Hz, ArH) and 7.48 (broad s, PhH).

Infrared spectrum: (CHCl ^) 3413, 1616 and 1575 cm "1.

: 45

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

ÔTMS

CDCl * 0 70 5 (d, J = 6 Hz, methyl at C-4), 0.85 (m, methyl end of the side chain), 1.29 (s, dimethyl twin), 2.81 (m, methi - benzylne), 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).

10 Infrared spectrum: (CHCl ^,) 3571, 3390, 1618

-1 day

and 1577 cm

Mass spectrum: m / e 422, 337, 314, 272, 229 and 91.

A mixture of the cis and trans isomers of 3- £ 2-15 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 mmoles).

Mass spectrum: m / e 394 (M +), 379, 376, 309 20 and 91.

Trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] cycloheptanol (695 mg, 49%) and 380 mg (27%) of the cis isomer in the form of oils from 3- [2-Benzyloxy- 4- (1-dimethylheptyl) phenyl] cycloheptanone (1.40 g, 3.33 mmo-25 µl).

cis isomer:

c TMS

Proton magnetic resonance: 6 ^^ 0.85 (m, methyl end of the side chain), 1.30 (s, 3dimé-théméminé), 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: (CHCl ^) 3571, 3448, 1613 and 1572 cm "" ^.

Mass spectrum: m / e 422 (M +), 337, 314, 229 35 and 91.

Trans isomer:

y f TMS

Proton magnetic resonance: 0 * 86 (m, terminal methyl), 1.26 (s, twin dimethyl), ^ 46 \ 3.41 (m, benzyl methine), 4.10 (m, carblnol 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: (CHCl ^) 3534, 3390, 1613 5 and 1572 cm-'1 '.

Mass spectrum: m / e 422 (M +), 337, 331, 314, · - 246, 229 and 91.

cis-3- [2-benzy1oxy-4- (2-5-pheny1pentyloxy) -v, phenyl] cyclohexanol (1.51 g, 76%) and the trans isomer 10 (0.379 g, 19%) as d oils from 3- [2-benzyloxy-4- (2 ~ (5 ~ phenylpentyloxy)) phenyljcyclohexanone (2.0 g, 4.52 mmol).

Trans isomer: Proton magnetic resonance: 0cpci ^ * 28 15 (d, J = 6Hz, methyl), 2.68 (m, methylene benzyl), 3 ^ 45 (m, benzyl methine), 4.22 (m, methine carbinol), 4.30 (m, side chain methine), 5.09 (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 (lar-20 ge s, PhH).

Infrared spectrum: (CHCl ^) 3571, 3448, 1613 and 1590 cm- ^

Mass spectrum: m / e 444 (M +), 298, 280, 190 and 91.

25 Cis isomer: Proton magnetic resonance: 1.25 (d, J = 6 Hz, 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, „30 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: (CHC1.,) 3571, 3390, 1613 and 1587 cm

Mass spectrum: m / e 444 (M +), 298, 190 and 35 91.

cis-3- [2-benzyloxy-4- (1,1-dimethyloctyl) phenylj-cyclohexanol (1.35 g, 45%) and the trans isomer (0.34 g, 11%) from 3.00 g (7.14 mmol) of 3- [2-benzyloxy-4- (1,1-di-47 methyloctyl) phenyl] cyclohexanone and 0.90 g (30% of the cis-trans mixture.

Trans isomer: Magnetic resonance of protons: 0.87 5 (m, methyl end of the side chain), 1.25 (s, ^ dimethyl gemine), 3.50 (m, benzyl methine), 4.22 (m, carbinol methine), 5.15 (s, methylene of benzyl ether) and 6.8-7.6 (m, ArH and PhH).

Infrared spectrum: (CHC1 ~) 3497, 1623 and _1 J

10 1582 cm

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

Cis isomer:

f TMS

Proton magnetic resonance: ^ ^ DCl (m, methyl end of the side chain), 1.25 (s, semimethylimethyl), 3.10 (m, benzyl methine), 3.75 (m, methyl methine) carbinol), 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: (CHC1.J 3571, 3425, 1618 -1 to 20 and 1577 cm

Mass spectrum: m / e 422 (M +) and 323. cis-3- (2-benzyloxy-4-tertio-butylphenyl) cyclo-hexanol (7.18 g, 59%) and trans isomer (1.33 g, 11%) as well as 1.5 g (12%) of a mixture of the cis and trans isomers, from 12.0 g (0.0357 mole) of 3- (2-benzyloxÿ-4-tert-butylphenyl ) cyclohexanone.

Cis isomer: - Melting point: 78-79 ° C (after recrystallization from hexane).

c TMS

30 Proton magnetic resonance: o 1.30 (s, tert-butyl), 3.10 (m, benzyl methine), 3.72 ^ (m, carbinol methine), 5.12 (s, methylene ether benzyl), 6.97 (d, J = 2Hz, ArH), 6.97 (dd, J = 8 and 2Hz, ArH), 7.17 (d, J = 8Hz, ArH) and 7.40 (wide s, PhH).

35 Infrared spectrum: (CHC17) 3636, 3472, 1621

-1 day

and 1582 cm

Mass spectrum: m / e 338 (M +), 323, 320, 230, 215 and 91.

48

Analysis: C% H%

Calculated for ^ 23 ^ 30 ^ 2: 81 * 61 8.93

Found: 81.79 8.77 5 Trans isomer:

/ y CTMS

Proton magnetic resonance: C cdci ^ »^ 3 s, tert-butyl), 3.50 (m, benzyl methine), 4.20 ^ (m, carbinol methine), 5.02 (s, methylene ether benzyl) and 6.8-7.4 (m, ArH and PhH).

10 Infrared spectrum: (CHCl ^) 3650, 3472, 1626 and 1587 cm ”1.

Mass spectrum: m / e 338 (M +), 323, 320, 230 and 91.

ci s-3- [2-benzy1oxy-4- (1,1-dimethylpropyl) phenylJ-15 cyclohexanol (6.3 g, 78%) and the trans isomer (1.0 g, 12%) in the form d oils from 8.0 g (0.0229 mole) of 3- [2-benzyloxy-4- (1,1-dimethylpropyl) phenyl] cyclohexanone.

Cis isomer:

"",, c TMS

Proton magnetic resonance: Ö CDC1 0.67 20 (t, J = 7Hz, terminal methyl), 1.26 (s, geminated dimethyl), 3.05 (m, benzyl methine), 3.75 (m, methine of carbinol), 5.15 (s, methylene of benzyl ether), 6.92 (d, J = 2, ArH), 6.92 (dd, J = 8 and 2 Hz, ArH), 7.17 (d, J = 8Hz, ArH) and 7.42 (large s,

PhH).

25 Infrared spectrum: (CHCl ^) 3636, 3344, 1626

-1 day

and 1587 cm

Mass spectrum: m / e 352 (M +), 337, 334, 323,, 244, 215 and 91.

Trans isomer: 30 Infrared spectrum: (CHCl 4) 3636, 1626 and 1587 cm 1.

Mass spectrum: m / e 352 (M +), 337, 334, 323, 244, 215 and 91.

cis-3- [2-benzyloxy-4- (1,1-dimethylbutyl) phenyl] -35 cyclohexanol (4.16 g, 52%) and the trans isomer (0.88 g, 11%), and 0, 49 g (6.1%) of a mixture of the cis and trans isomers in the form of oils from 8.0 g (0.022 mole) of 3- [2-benzyloxy-4- (1,1-dimethylbutyl ) phenyl] cyclohexanone.

49

Cis isomer: Magnetic resonance of protons: £ 0.80 vULl Λ (m, terminal methyl), 1.23 (s, dimethyl twin), ä 3.05 (m, benzyl methine), 3.70 (m, methyl methine) carbinol), 5.08 (s, methylene of benzyl ether), 6.86 (d, J = 2 Hz,

ArH), 6.86 (dd, J = 8 and 2Hz, ArH), 7.11 (d, J = 8Hz, ArH) and - 7.35 (large s, PhH).

Infrared spectrum: (CHCIO 3623, 3448, 1621 -1 J

and 1582 cm 10 Mass spectrum: m / e 366 (M +), 351, 348, 323, 258, 215 and 91.

Trans isomer: r- TMÇ Proton magnetic resonance: û * DC1 0.83 (m, terminal methyl), 1.22 (s, geminated dimethyl), ^ 15 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: (CHCl ^) 3623, 3472, 1623 2o and 1585 cm ~ ^.

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 ~ r2 - benzyloxy-4- (1,1-dimethylheptyl) phenyll- 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 com-i 30 posed indicated in the title, in the form of an oil, followed by the cis-3-trans-4 isomer.

Trans-3, cis-4 isomer:

Infrared spectrum: (CHCl ^) 3559, 3401, 1639, 1608 and 1567 cm- ^.

35 Mass spectrum: m / e 448 (M +), 433, 430, 363, 406 and 91.

Proton magnetic resonance: 0.82 (m, terminal methyl), 1.25 (s, twin dimethyl), ^; 50 3.30 (m, benzyl methine), 4.12 (m, carbinol methine), 4.6- 5.0 (m, vinyl H), 5.06 (s, methyl 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 (broad s, 5 Ph).

Cis-3, trans-4 isomer:

Infrared spectrum: (CHClo) 3571, 3401, 1639,, _1 J 1610 and 1572 cm

Mass spectrum: m / e 448 (M +), 406, 363 and 10 91.

Proton magnetic resonance: <*) 0.82 (m, terminal methyl), 1.22 (s, twin dimethyl), 3 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-butenyl) cyclohexanol (495 mg, 82%) and 20 1 »trans-3 isomer, cis- 4 (105 mg, 18%) from trans-3- £ 2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] j- (2-butenyl) -cyclohexanone (600 mg, 1.30 mmol) . The trans-3, cis-4 isomer is eluted first.

Trans-3, cis-4:25 isomer Mass spectrum: m / e 462 (M +), 447, 444, 377 and 91.

Cis-3, trans-4 isomer:

Infrared spectrum: (CHClg) 3610, 3448, 1618 and 1577 cm 30 Mass spectrum: m / e 462 (M +), 447, 444, 377 and 91.

cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -trans-4- (2-pentenyl) cyclohexanoÎ and the trans-3 isomer, cis-4 from trans-3- (2-benzyloxy-4- (1,1-dimethylheptyl) -35 phenyl) -4- (2-pentenyl) cyclohexanone (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% of ether in penane) and 363 mg (73%) of the cis-3, trans-4 isomer (Rf = 0.13, 1.51 silica gel, 33% ether in pentane).

cis-3- [2-benzyloxy-4- (1,1-dimethylpentyl) -phenyljcyclohexanol (5.0 g, 83%) and the trans isomer (θ ', 60 g, 10%) in the form of oils from 3- [2-benzyloxy-4-5 (1,1 "dimethylpentyl) phenyl] cyclohexanone (6.0 g, 58 mmol).

Trans isomer: ^ Infrared spectrum: (CHC13) 3636, 3497, 1623 and 1582 cm “1.

Mass spectrum: m / e 380 (M).

c TMS

10 Proton magnetic resonance: ôCDC1 0.83 (m, terminal methyl), 1.24 (s, geminated dimethyl), ^ 3.5 (m, benzyl methine), 4.20 (m, carbinol methine), 5 , 09 (s, methylene benzyl) and 6.8-7.6 (m, ArH).

Cis isomer: 15 Infrared spectrum: (CHClO 3636, 1621 and 1580 cm

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

f TMS

Proton magnetic resonance: 0.75 (m, terminal methyl), 1.14 (s, twin dimethyl), ^ 20 2.90 (m, benzyl methine), 3.52 (m, carbinol methine), 4, 80 (s, methylene benzyl), 6.49 (dd, J = 8 and 2Hz, ArH), 6.49 (d, J = 2Hz, ArH), 6.72 (d, J = 8Hz, ArH) and 6 , 96 (broad s, r Ph).

cis-3- [2-benzyloxy-4- (1,1-dimethylhexyl) phenyl] -25 cyclohexanol (3.0 g, 43%) and the trans isomer (660 mg, 9%) in the form of oils from 3- [2-benzyloxy-4- (1,1-dimethylhexyl) phenyl] cyclohexanone (7.0 g, 17.9 mmol).

, Cis isomer:

Infrared spectrum: (CHCl ^) 3623, 3448, 1618, 30 and 1575 cm "1.

Mass spectrum: m / e 394 (M +).

Proton magnetic resonance; 0.82 (m, terminal methyl), 1.22 (s, twin dimethyl), ^ 3.07 (m, benzyl methine), 3.70 (m, carbinol methine), 35 5.08 (s, methylene benzyl), 6.88 (dd, J = 8 and 2Hz, ArH), 6.88 (d, J = 2Hz, ArH), 7.12 (d, J = 8Hz, ArH) and 7.37 (large S , Ph).

52 \

Trans isomer:

Infrared spectrum: (CHCl ^) 3623, 7448, 1618 and 1577 cm "1.

Mass spectrum: m / e 394 (M +).

r TMS

5 Proton magnetic resonance s ό CDC1 0.80 (m, terminal methyl), 1.27 (s, dimethyl twin), ^ »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 oils from 3- [2-benzyloxy-4- (1,1-dimethylnonyl) phenyl] cyclohexanone (8.5 g, 19.6 mmol).

Cis isomer: 15 Infrared spectrum: (CHClo) 3623, 3448, 1618 -1 Λ and 1577 cm

Mass spectrum: m / e 436 (M +).

S TMS

CDC1 °> 83 (m, terminal methyl), 1.22 (s, twin dimethyl), ^ 20 3.04 (m, benzyl methine), 3.67 (m, carbinol methine), 5.08 (s, methylene benzyl), 6.87 (dd, J = 8 and 2 Hz, ArH), 6.87 (d, J = 2 Hz, ArH) and 7.05-7.45 (m, ArH and Ph).

Trans isomer:

Infrared spectrum: (CHCl ^) 3610, 3448, 1618 25 and 1575 cm "1.

Mass spectrum: m / e 436 (M +).

Proton magnetic resonance: 0 CDCl 0 * 82! '(m, terminal methyl), 1.22 (s, twin dimethyl), ^ 3.42 (m, 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%) as oils from 3- [2-benzyloxy-4- (1,1-dimethylundecyl) phenyl] cyclohexanone (7.00 g, 15.0 mmol).

35 Cis isomer:

Infrared spectrum: (CHCl ^) 3636, 3448, 1621 and 1582 cm-1.

; 53

Mass spectrum: m / e 464 (M +).

Proton magnetic resonance: ^ CDCI ^, 95 (m, terminal methyl), 1.33 (s, twin dimethyl), ^ 3.09 (m, benzyl methine), 3.70 (m, carbinol methine), 5 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, (large s, PhH).

Trans isomer:

Infrared spectrum: (CHCl ^) 3534 (wide), 10 1618 and 1577 cm “1.

Mass spectrum: m / e 464 (M +)

ÎTMS

CDC1 85 (m, terminal methyl), 1.22 (s, twin dimethyl), ^ 3.48 (m, benzyl methine), 4.17 (m, benzyl methine), 15 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] cyclohexanone (4.5 g, 10.0 mmol).

20 Cis isomer:

Infrared spectrum: (CHC1-) 3704, 3571, 1639 and 1597 cm.

* ί "

Mass spectrum r m / e 450 (M).

r TMS

Proton magnetic resonance: ,80.86 25 (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 = 2Hz, ArH), 7.12 (d, J = 8Hz, ArH) and 7 ^ 37 (large s, Ph).

30 Trans isomer:

Infrared spectrum: (CHClO 3623, 3448, 1616 -1 and 1577 cm

Mass spectrum: m / e 450 (MH).

f TMS

Proton magnetic resonance: ÔCDC; L 0.82 35 (m, terminal methyl), 1.22 (s, sine dimethyl), ^ 3.53 (m, benzyl methine), 4.22 (m, carbinol methine) , 5.02 (s, methyl benzyl) and 6.8-7.6 (m, ArH and Ph).

54 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 d oils from 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclooctanone (7.0 g, 16.1 mmol). 5 Infrared spectrum: (CHCl ^)

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

c T * MS

Proton magnetic resonance: ôCDci 0.83 (m, terminal methyl), 1.28 (s, twin dimethyl), ^ 10 3.19 (large m, benzyl methine), 3.89 (large m, carbinol methine) , 5.10 (s, methyl benzyl), 6.83 (m, ArH), 7.08 (d, J = 8 Hz, ArH) and 7.38 (m, Ph).

Trans isomer:

Infrared spectrum: (CHCl ^) 15

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

S T MS

Cdci 0.83 (m, terminal methyl), 1.28 (s, twin dimethyl), ^ 20 3.4 (broad m, benzyl methine), 3.9 (m, carbol nol methine), 5.10 ( s, methylene benzyl), 6.85 (m, ArH), 7.08 (d, J = 8 Hz, 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 mole) is stirred under hydrogen pressure from a bar for 2 hours. of cis-3-Γ2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclohexanol, 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: (CHCl ^) 3610, 3356, 1626 35 and 1582 cm "1.

Mass spectrum: m / e 318 (M +), 300, 233 and 215.

55

Analysis: C% H%

Calculated for C21H3402: 79.19 10.76

Found: 78.96 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 re-tallization in pentane) from trans-3- [2-benzyloxy- 4- (1,1-dimethylheptyl) phenyl] cyclohexanol (4.50 g, 0.011 mole).

Infrared spectrum: (CHCl ^) 3610, 3390, 1626 and 1575 cm ”\

Mass spectrum: m / e 318 (M +), 300, 233 and 15 215.

Analysis: C% H%

Calculated for C21H34 ° 2: 79.19 10.76

Found: 78.82 10.43 20 A quantitative yield is obtained of Z-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -3-methyl 1-cyclohexanol, melting at 90-91 ° C ( after recrystallization from petroleum ether) from £ ~ 3- [2-benzyloxy-4- (1,1-di-methylheptyl) phenyl] -3-methylcyclohexanol (180 mg, 0.248 mmo-25 le).

Infrared spectrum: (CHCl ^) 3597, 3333, 1605 -1 0 and 1570 cm ’Mass spectrum: m / e 332 (M +), 314, 299, 286, 271, 247 and 229.

* 30 Analysis: C% H%

Calculated for C22H36 ° 2: 79.45 10.92

Found: 79.24 10.64

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

Infrared spectrum: (CHC1-.) 3571, 3333, 1626 56 \ -1 and 1575 cm.

Mass spectrum: m / e 332 (M +), 317, 314, 247, 233 and 229.

5 Analysis: C% H%

Calculated for C22H36 ° 2: 79.46 10.92

Found: 79.13 10.68

Cis, trans-3- [4- (1,1-dimethylheptyl) -2-hydroxy-10 phenyl] -4-methylcyclohexanol (quantitative yield), melting at 150-151 ° C (after recrystallization from pentane) at taken from the cis, trans-3-Γ2-benzyloxy-4- (l, 1-dimethylheptvl) phenyl ~] - 4-methylcyclohexanol (1.15 g, 2.72 mmol).

Infrared spectrum: (CHCl ^) 3571, 3333, 1621, 15 1605 and 1580 cm

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

Analysis: C% H% 20 Calculated for C22H36 ° 2: 79.46 10.92

Found: 79.15 10.72 cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cyclopentanol (464 mg, 55%) and 228 mg (27%) of the trans isomer under form of oils from a mixture of cis and trans iso-25 mothers of 3- [2-benzyloxy ~ 4- (1,1-dimethylheptyl) -phenyljcyclopentanol (1.10 g, 2.79 mmol).

Cis isomer:

at T MS

CDCl °> ^ 3 (m, methyl end of the side chain), 1.24 (s, ^ dimethyl * 30 them), 3.2 (m, benzyl methine), 4.52 (m, carbinol methine ), 6.75 (dd, J = 8 and 2Hz, ArH), 6.81 (large s, overlap with S 6.75, ArH) and 6.97 (d, J = 8Hz, ArH).

Infrared spectrum: (CHCl ^) 3571, 3300, 1623 and 1567 cm- ^.

35 Mass spectrum: m / e 304 (M +), 286, 219, 20! and 159.

Trans isomer:

~ ——— ç TMS

Proton magnetic resonance: Ôçpçi (m, methyl end of the side chain), 1.27 (s, dim- 57

S

twin thyle), 3.60 (m, benzyl methine), 4.55 (m, carbinol methine), 6.78 (large s, overlap with 56.88, ArH), 6.88 (dd, J = 8 and 2Hz, ArH) and 7.10 (d, J = 8Hz, ArH).

Infrared spectrum: (CHCl ^) 3571, 3333, 1621 5 and 1575 cm "'1'.

Mass spectrum: m / e 304 (M +), 286, 219 and, 201.

trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cycloheptanol (quantitative yield), melting at 55-57 ° C, from trans-3- [2-benzyloxy-4- ( 1,1-dimethylheptyl) phenyl ~ l-cycloheptanol (695 mg, 1.64 mmol).

Infrared spectrum: (CHCl ^) 3333, 1621 and 1570 cm

Mass spectrum: m / e 332 (M +), 314, 247 and 15 229.

Analysis: C% H%

Calculated for C22H36 ° 2: 79.46 10.92

Found: 79.68 10.62 20 cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] - cycloheptanol (quantitative yield), melting at 103-104 ° C (after recrystallization from pentane) at from cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cycloheptanol (380 mg, 0.900 mmol).

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

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

Analysis: 30 C% H%

Calculated for C22H35 ° 2: 79.46 10.92

Found: 79.39 10.72 cis-3- [2-hydroxy-4- (2- (5-phenylpentyloxy)) - phenyl] cyclohexanol (quantitative yield), melting at 80-35 84 ° C after recrystallization from pentane , from cis- 3- [2-benzyloxy ~ 4 ~ (2- (5-phenylpentyloxy)) phenyl] cyclohexanol (1.45 g, 3.27 mmol).

Infrared spectrum: (CHC13) 3597, 3333, 1623 and 1597 cm "1.

58

Mass spectrum: m / e 354 (M +), 336, 208, 190 and 91.

Analysis: C% H% 5 Calculated for C23H3o ° 3: 77.93 8.53

Found: 77.95 8.31 -. trans-3- [2-hydroxy-4- (2- (5-phenylpentyloxy)) - phenyl] cyclohexanol (241 mg, 90%), melting at 65-70 ° C (pen-tane) from trans-3 - [2-benzyloxy-4- (2- (5-phenylpentyl-10 oxy)) phenyl] cyclohexanol (0.355 g, 0.754 mmol).

Infrared spectrum: (CHCl ^) 3597, 3378, 1629 and 1587 cm "" · * ·.

Mass spectrum: m / e 354 (M +), 336, 208, 190 and 91.

15 Analysis: C% H%

Calculated for C23H3o ° 3: 77.93 8.53

Found: 77.53 8.40 cis-3- [4- (1,1-dimethyloctyl) -2-hydroxyphenyl] -20 cyclohexanol (0.725 g, 68%) from 1.36 g (3.22 mmol) of this £ -3- [2-benzyloxy-4- (1,1-dimethyloctyl) phenyl] cyclohexa-nol.

Melting point: 100-10l ° C (after recrystallization from hexane).

25 Infrared spectrum: (CHCl ^) 3571, 3333, 1626 and 1582 cm

Mass spectrum: m / e 332 (M +), 314, 233 and 215.

Analysis: 30 c% H%

Calculated for: 79.46 10.92

Found: 79.85 11.03 trans-3- [4- (1,1-dimethyloctyl) -2-hydroxyphenyl] -cyclohexanol (0.195 g, 100%) as an oil from 246 mg (0.582 mmol) trans-3- [2-benzyloxy-4- (1,1-dimethyloctyl) phenyl] cyclohexanol.

Melting point: 94-95 ° C (after recrystallization from petroleum ether).

Infrared spectrum: (CHCl ^) 3650, 3436, 1639 59 \ and 1582 cm-'1 '.

Mass spectrum: m / e 332 (M +), 314, 233 and 215.

5 Analysis: C% H%

Calculated for C22H36 ° 2: 79.46 10.92

Found: 79.34 10.55 cis -3- (4-tertio-butyl-2-hydroxyphenyl) cyclo-10 hexanol (3.99 g, 77%) from cis - 3- (2 - benzyloxy- 4-ter-tio-butylphenyl) cyclohexanol (7.1 g, 0.021 mole).

Melting point: 177-178 ° C (after recrystallization from isopropyl ether).

Infrared spectrum: (KBr) 3484, 3268, 1634 15 and 1592 cm- ^.

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

Analysis: C% H% 20 Calculated for cigH25 ° 2: 77.37 9.74

Found: 77.00 9.54 trans-3- (4-tertio-butvl-2-hydroxyphenyl) cyclohexanol (0.725 g, 99%) from trans-3- (2-benzyloxy-4-tertio-butylphenyl) cyclohexanol (1.25 g, 2.96 mmol).

25 Melting point: 136-137 ° C (after recrystallization from isopropyl ether).

Infrared spectrum: (CHC1 ~) 3623, 3401, 1626 -1 and 1575 cm

Mass spectrum: m / e 248 (M +), 233, 230, 215, 30 187 and 173.

at"

Analysis: C% H%

Calculated for C16H24 ° 2: 77.37 9.74

Found: 77.34 9.49 35 cis-3- [4- (1,1-dimethylpropyl) -2-hydroxyphenyl] - cyclohexanol (1.45 g, 32%) from cis-3-r2-benzyloxy- 4- (1,1-dimethylpropyl) phenyl] cyclohexanol (6.1 g (0.0173 mole).

Melting point: 166-167 ° c (after recrystallization from isopropyl ether).

Infrared spectrum: (KBr) 3509, 3279, 1629 60 \ and 1592 cm.

Mass spectrum: m / e 262 (M +), 247, 244, 233 and 215.

5 trans-3- [4- (1,1-dimethylpropyl) -2-hydroxyphé ~ nyl] cYcl ° hexanoÎ (0.50 g, 68%) from trans-3-Γ2-ben-zyloxy-4- ( 1,1-dimethylpropyl) pheny1] cyclohexanol (1.00 g, s ", 2.84 mmol).

Melting point: 124-125 ° C (after recrystallization from isopropyl ether).

Infrared spectrum: (CHCl ^) 3636, 3413, 1639

-1 day

and 1585 cm

Mass spectrum: m / e 262 (M +), 247, 244, 233 and 215.

15 Analysis: C% H%

Calculated for C47H26 ° 2: 77.82 9.99

Found: 77.51 9.87 cis-3- [4- (1,1-dimethylbutyl) -2-hydroxypheny1] -20 cyclohexanol (1.9 g, 74%) from cis-3-Γ2-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 25 and 1592 cm

Mass spectrum: m / e 276 (M +), 261, 258, 233 and 215.

trans-3- [4- (1,1-dimethylbutyl) -2-hydroxyphé-nyl] cyclohexanol (0.45 g, 87%) as an oil from trans-3-r2-benzyloxy- 4- (1,1-dimethylbutyl) phenyl] -cyclohexanol (0.700 g, 1.91 mmol).

Infrared spectrum: (CHCl ^) 3636, 3390, 1629 and 1575 cm "1.

Mass spectrum: m / e 276 (M +), 261, 258, 233 35 and 215.

trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphé-nyl] -cis-4-propylcycl ° hexanol (626 mg, 78%) from trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -cis-4- (2-propene-nyl) cyclohexanol (1.0 g, 2.23 mmol).

61

Melting point: 92-94 ° C.

Infrared spectrum (CHCl ^) 3623, 3390, 1629 and 1578 cm ”1.

Analysis: 5 C% H%

Calculated for ^ 24 ^ 40 ^ 2: 79.94 11.18

Found: 80.10 10.89 cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -trans-4-propylcyclohexanol (550 mq, 74%) from 'ci s-10 3 - [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -t £ years-4- (2-pro-penyl) cyclohexanol (930 mg, 2.07 mmol).

Melting point: 126 ° C (after recrystallization from pentane).

Infrared spectrum: (CHCl-j) 3597, 3390, 1629 15 and 1575 cm ”1.

Mass spectrum: m / e 360 (M +), 345, 342, 275 and 257.

Analysis: C% H% 20 Calculated for C24H4 () 02: 79.94 11.18

Found: 79.85 10.95 trans ~ 4-butyl-cis-3- £ 4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclohexanol (322 mg, 80%) from cls-3-1 2 -benzvloxv-4- (1,1-dimethylheptyl) phenyl1-trans-4- (2-buté-25 nyl) cyclohexanol (500 mg, 1.08 mmol).

Melting point: 131 ° C (after recrystallization from pentane).

Infrared spectrum: (CHCl ^) 3636, 3356, 1629 and 1587 cm ”1.

30 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) - 2-hydroxyphenyl ^ Jcyclohexanol (225 mg, 76%) from cîs- 3- Γ 2-benzvloxv-4 “(l, 1-dimethylheptyl) phenyl1-trans-4- (2-35 pentenyl) cyclohexanol (363 mg, 0.762 mmol).

Melting point: 135-136 ° C.

cis-3- [4- (1,1-dimethylpentyl) -2-hydroxyphenyl] -cyclohexanol (2.5 g, 60%) from cis-3- [2-benzyloxy-4—62 (1,1- dimethylpentyl) phenyl] cyclohexanol (5.5 g, 0.0144 mole).

Melting point: 112-113 ° C (after recrystallization from pentane and isopropyl ether).

Infrared spectrum: (CHC13) 3636, 3390, 1631 5 and 1592 cm "1.

Mass spectrum: m / e 290 (M +), 272, 233 and, 215.

Analysis: C% H% 10 Calculated for c ^ gH3o ° 2: 78.57 10.41

Found: 78.76 10.11 trans-3- [4- (1,1-dimethylpentyl) -2-hydroxyphé-nyl] cyclohexanoï (385 mg, 78%) from trans ~ 3-r2-ben-zyloxy- 4- (1,1-dimethylpentyl) phenyl] cyclohexanol (640 mg, 1.68 mmol).

Melting point: 114-115 ° C (after recrystallization from pentane).

Infrared spectrum: (CHC1-) 3636, 3390, 1631 -1 ύ and 1577 cm.

20 Mass spectrum: m / e 290 (M +), 272, 233 and 215.

Analysis: C% H%

Calculated for ClgH3002: 78.57 10.41 25 Found: 78.38 10.10 cis-3- [4- (1,1-dimethylhexyl) -2-hydroxyphenyl] -cyclohexanol (2.3 g, 99%) at from cis-3-t2-benzyloxy-4-; (1,1-dimethylhexyl) phenyl] cyclohexanol (3.00 g, 7.61 mmol).

Melting point: 98-100 ° C (pentane) 30 Infrared spectrum: (CHC1-) 3636, 3367, 1626

-1 day

and 1587 cm.

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

Analysis: 35 C% H%

Calculated for C2qH3202: 78.89 10.59

Found: 78.57 10.46 63 trans-3- [4- (1,1-dimethyl1hexy1) -2-hydroxypheny1] - cyclohexanol (440 mg, 86%) from trans-3-Γ2-benzyloxy- 4- (1,1-dimethylhexy1) phenyl] cyclohexanol (660 mg, 1.68 mmo-le).

5 Melting point: 113-114 ° C (pentane).

Infrared spectrum: (CHCl ^) 3636, 3390, 1631, -1 to 1616 and 1580 cm

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

10 High resolution mass spectrum: 304.2419 (C20H32 ° 2) * cis-3- [4- (1,1-dimethylnonyl) -2-hydroxyphenyl] - cyclohexanol (47o g »100%) from cis- 3-r2-benzyloxy-4- (1,1-dimethylnonyl) phenyl] cyclohexanol (5.0 g, 1.15 mmol).

Melting point: 82-83 ° C (pentane).

Infrared spectrum: (CHC1 ~) 3650, 3390, 1637 -1 J

and 1597 cm

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

20 Analysis: C% H%

Calculated for C23H38 ° 2: 79.71 11.05

Found: 79.71 11.14 trans-3- [4- (1,1-dimethylnonyl) -2-hydroxyphenyl] -25 cyclohexanol (709 mg, 89%) from trans-3-Γ2-benzyloxy- 4- (1,1-dimethylnonyl) phenyl] cyclohexanol (1.00 g, 2.29 mmo-les).

Melting point: 69-70 ° C (pentane).

Infrared spectrum: (CHCl ^) 3636, 3413, 1631, 30 1618 and 1582 cm “1.

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

Analysis: C% H% 35 Calculated for C23H38 ° 2 * 79 ^ 71 11.05

Found: 79.11 10.86 \ 64 cis-3- [4- (1,1-dimethyldecyl) -2-hydroxyphenyl] -cyclohexanol (2.02 q> 98%) from cis-3-r2-benzyloxy - 4- (1,1-dimethyldecyl) phenyl] cyclohexanol (2.6 g, 5.78 mmo-les).

5 Melting point: 93-94 ° C (pentane).

Infrared spectrum: (CHCl ^) 3636, 3390, 1629 and 1587 cm- ^.

Mass spectrum: m / e 360 (M +), 342, 288, 233 and 215.

10 Analysis: C% H%

Calculated for C24H4o ° 2: 79.94 11.18

Found: 80.12 11.39 trans-3- [4- (1,1-dimethyldecyl) -2-hydroxyphé-15 nyl] cyclohexanol (130 mg, 45%) from trans-3- (t2-benzyloxy- 4- (1,1-dimethyldecyl) phenyl] cyclohexanol (360 mg, 0.80 mmol).

Fusion point ; 76-77 ° C.

Infrared spectrum: (CHCl ^) 3636, 3425, 1631, 20 1616 and 1580 cm-1.

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

Analysis: C% H% 25 Calculated for C24H40 ° 2: 79.94 11.18

Found: 80.20 11.27 cis-3- [4- (1,1-dimethylundecyl) -2-hydroxyphenyl] -cyclohexanol (2.39 g, 85%) from cis-3- [2-benzyloxy- 4- (1,1-dimethylundecyl) phenyl] cyclohexanol (3.5 g, 7.54 mmo-30 µl).

Melting point: 85-86 ° C.

Infrared spectrum: (CHCl-.) 3636, 3390, 1634 -1 13 and 1592 cm

Mass spectrum: m / e 374 (M +), 356, 233 and 35 215.

Analysis: C% H%

Calculated for C25H42 ° 2: 80.15 11.30

Found: 80.00 11.48 65 trans-3- [4- (1,1-dimethylundecyl) -2-hydroxy-phenyllcyclohexanol (487 mq, 60%) from trans-3-r2-benzyloxy-4- ( 1,1-dimethylundecyl) phenyl] cyclohexanol (1 * 00 g "2.16 mmol).

5 Melting point; 73-74 ° C

Infrared spectrum-: (CHCl ^) 3636, 3413, 1637 and 1585 cm- ^.

Mass spectrum: m / e 374 (M +), 356, 233 and 215.

10 Analysis: C% H%

Calculated for C25H42 ° 2: 80.15 11.30

Found: 80.11 11.16 cis-3- [4- (1,1-dimethy1heptyl) -2-hydroxypheny1] -15 cyclooctanol (0.793 g, 73%) from cis-3 - Î 2-benzyloxy- '4- (1,1-dimethylheptyl) phenyl] cyclooctanol (1.36 g, 3.11 mmol).

Melting point: 89-90 ° C (after recrystallization from pentane).

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

Analysis: C% H%

Calculated for C23H38 ° 2: 79.71 11.05 25 Found: 79.90 10.89 trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphé-nyllcyclooctanol (2.62 g, 83%) from trans ~ 3-l'2-benzyl-oxy-4- (l, 1-dimethylheptyl) phenyl] cyclooctanol (4.0 g, 9.17 mmol).

30 Melting point: 76-77eC (after recrystallization from pentane).

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

Analysis 35 C% H%

Calculated for ^ 23 ^ 38 ^ 2-: 79.71 11.05

Found: 79.81 10.86 66

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) is added slowly ) -2-methyloctane in lo ml of tetrahydrofuran 360 mg (14.4 mmol) of metallic magnesium in particles from 0.177 to 0.210 mm. The resulting mixture is refluxed for 30 minutes, then cooled to 0 ° C. A solution of 1.40 g (10 mmol) of 3-ethoxy-2-cyclohexene-1-one in 3 ml of tetrahydrofuran is slowly added to this solution. The reaction mixture is stirred for 30 minutes at 0 ° C, then deactivated by the addition of 20 ml of IN sulfuric acid and heated in a boiling water bath for 30 minutes. 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 bi-carbonate 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 chromatography on a column of 170 g of silica gel eluted with a mixture of ether and pentane at 1: 1; 2.5 g (54%) of the title compound are thus obtained in the form of an oil.

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

Mass spectrum: m / e 404 (M +), 319, 313 and 25 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%) in using 3-ethoxy-6-methyl-2-cyclohexene-1-one (1.98 g, 12.9 mmol), 0.61 g 30 (25.7 mmol of magnesium) and 12.9 mmol (5, 0 g) of 2- (3-benzyloxy-4-bromophenyl) -2-methyloctane.

Infrared spectrum: (CHCl ^) 1667, 1613 and 1565 cm "1.

Mass spectrum: m / e 418 (M +), 400, 385, 333, 35 327, 299, 291 and 91.

\ 67

Example 6 3- £ 2-benzyloxy-4- (1,1-dimethylheptyl) phenyl3-3-methylcyclohexanone

5.60 mg (1.39 mmol) of 5 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 minutes, then poured into 100 ml of saturated ammonium chloride and 100 ml of ether. After stirring for 10 minutes, 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 * conducted on three plates of silica gel 20 cm x 20 cm x 2. mm, eluting with a 2: 1 mixture of cyclohexane and ether; 282 mg (48%) (higher Rf) of the compound indicated in the title are obtained, in the form of an oil, and 211 mg (36%) (lower Rf) of 3- [2-benzyloxy-4- ( 1,1-dimethylheptyl) phe-nyl] -1-methylcyclohexene-2-ol-1 in the form of an oil.

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

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

3- [2-benzyloxy-4- (l, 1-dimethylheptyl) phenyl3 ~ l-methvlcyclohexene-2-ol-l:

Infrared spectrum: (CHCl ^) 3571, 3401, 1661, 30 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 35 A mixture of 400 mg (0.988timole) of 3- is stirred under hydrogen pressure of 1 bar for 30 minutes. [2-benzyloxy-4 ~ (1,1-dimethylheptyl) phenyl] cyclohex-2-enone and 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 and gives 110 mg (35%) of the title compound, melting 5 at 122-123 ° C.

Infrared spectrum: (KBr) 3448, 1634, 1608 and 1565 cm

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

Analysis: 10 C% H%

Calculated for ^ 2 ^ Z002: 80.21 9.62

Found: 80.23 9.46

Example 8 Methylketal of 3- (2,4-dihydroxyphenyl) cyclohexanone Ί5 10 drops of concentrated sulfuric acid are added to a solution at 0 ° C of 7.0 g (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 hours 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 -1 and 1597 cm

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

Analysis: 35 C% H%

Calculated for 013Η1 & 03: 70.89 7.32

Found: 70.79 7.34 69

Example 9 3- [2-Hydroxy-4- (4-phenylbutyloxy) phenyl] methyl ketal - cyclohexanone

A mixture of 5.03 g (22.8 mmol) of 3- (2,4-di-hydroxyphenyl) cyclohexanone methyl ketal, 10.1 g (73.2 mmol) is heated at 85-100 ° C. for 4 hours. ) anhydrous potassium carbonate and 6.12 g (26.8 mmol) of 4-phenylbutyl methane sulfonate in 25 ml of N, N-dimethylformamide. The reaction mixture is cooled and added to 10,200 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 chromatography on a column of 400 g of silica gel eluted with a mixture of pen-15 tane and 2: 1 ether; 7.4 g (92%) of the title compound are thus obtained, in the form of an oil.

Infrared spectrum: (CHCl ^) 1623 and 1590 cm Mass spectrum: m / e 352 (M +) and 91.

Analysis: 20 C% H%

Calculated for C23H2803: 78.37 8.01

Found: 78.34 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%) in the form of an oil from 5.7 g ("25.9 mmol) of methyl ketal of 3- (2,4-dihydroxyphenyl) cyclohexanone and of 6.2 g (32, 3 mmol) of 2-heptyl methanesulfonate.

Infrared spectrum: (CHCl ^) 1637 and 1600 cm ”1. Mass spectrum: m / e 318 (M +), 286, 274, 220, 204 and 178.

3- [2-hydroxy-4 ~ (2-octyloxy) phenyl] -35 methyl ketal cyclohexanone as an oil (5.03 g, 58%) from 3- (2,4-dihydroxyphenyl methyl ketal) ) cyclohexanone (5.7 g, 25.9 mmol) and 7.3 g (35.1 mmol) of 2-octyl methanesulfonate.

_1 70

Infrared spectrum: (CHCl ^) 1639 and 1600 cm

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

3- [2-hydroxy-4- (2-nonyloxy) -5 phenyl] cyclohexanone methyl ketal (5.23 g * 59%) as an oil from 3- (2,4-dihydroxyphenyl methyl ketal) ) cyclohexano-ne (5 * 7 g, 25 * 9 mmol) and 2-nonyl methanesulfonate (7.9 g, 35.5 mmol).

Infrared spectrum: (CHCl 4) 1634 and 1590 cm 10 Mass spectrum; m / e 346 (M +), 314 * 220 * 188 and 161.

3- [2-hydroxy-4- (2- (4-phenyl) -butoxy) phenyljcyclohexanone methyl ketal as an oil (5.1 g * 56 "%) from 3- (2, 4-dihydroxyphenyl) cyclo-15 hexanone (5.7 g, 25 * 9 mmol) and 2- (4-phenylbutyl) methanesulfonate (8.0 g, 35.0 mmol).

Infrared spectrum: (CHCl ^) 1639 and 1603 cm

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-hydroxyphenyl) phenyl] cyclohexanone 2,4-dihydroxyphé-nyl) cyclohexanone (5.7 g, 25.9 mmol) and 2- (6-phenylhexyl) methanesulfonate (9.0 g, 35.5 mmol).

25 Infrared spectrum: (CHCl ^) 1634 and 1597 cm

Mass spectrum: m / e 380.2342 (M +, C25H32 ° 3 ^ ’220,1088, 188,0986 and 177,0550.

Example 10 3- [2-hydroxy-4- (4-phenylbutyloxy) phenyl] cyclohexanone * 30 y

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 is heated at reflux for 1 hour. 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 sulfate and evaporated to 1%. '\ 71 tion of an oily residue. The oil is purified by chromatography on a column of 400 g of silica gel eluted with a mixture of ether and cyclohexane at 1: 1; 6.4 g (98%) of the title compound are obtained in the form of an oil.

Infrared spectrum: (CHCl ^) 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%) in the form of an oil from 6.0 g (18.8 mmol) of the corresponding methyl ketal.

Infrared spectrum: (CHCl ^) 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%) as an oil from 5.0 g (15.0 mmol) of the corresponding methyl ketal.

Infrared spectrum: (CHCl ^) 3636, 3378, 1721 (weak), 1631 and 1595 cm "1.

25 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.

30 Infrared spectrum: (CHClg) 3584, 3367, 1709 (weak), 1626 and 1587 cm "1.

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

3- [4- (2- (4-pheny1) buty1oxy) -2-hydroxypheny1] -35 cyclohexanone (3.8 g, 79%) from 5.0 g (14.2 mmol) of the corresponding methyl ketal, under the shape of an oil.

Infrared spectrum: (CHCl ^) 3636, 3425, 1724 (weak), 1637 and 1600 cm "1.

72

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%) as a 5.2 g oil (5.2 g (13 , 6 mmol) of the corresponding methyl ketal.

Infrared spectrum: (CHC1-) 3636, 3390, 1718, -1 J 1637 and 1600 cm.

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

Example 11 cis-3- [2-hydroxy-4- (4-phenylbutyloxy) phenyl] cyclohexanol and 1 * 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-phenylbutyloxy) phenyl ] cyclohexanone in 25 ml of methanol. The reaction mixture is stirred for 40 minutes, 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, dried over magnesium sulfate and evaporated until an oily residue is obtained. This oil is purified by chromatography on a column of 400 g of silica gel eluted with a mixture of dichloromethane and ether at 2.5: 1; 3.37 g (70%) of the cis isomer, cris-tallized in cyclohexane, and 0.68 g (14%) of the trans isomer, crystallized in cyclohexane, are obtained, as well as 0.69 g (14%) of mixed material.

Cis isomer:

Melting point: 79-80 ° C.

5 TM S

2.70 LUv JL n (m, benzyl methylene), 3.26 (m, benzyl methine ;, 3.93 (large t, J = 6Hz, -0CH2 ~), 4.28 (m, OH ,, methine car-binol, with D-, 0 & 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) 35 and 7.22 (s, PhH).

Infrared spectrum: (CHCIO 3610, 3333, 1631 -1 J

and 1603 cm

Mass spectrum: m / e 340 (M +), 322, 190 and 91.

73 \ *

Analysis: C% H%

Calculated for C22H28 ° 3: 77.61 8.29

Found: 77.46 8.25 5 Trans isomer:

Melting point: 112-114 ° C.

Proton magnetic resonance: 2.68 (m, benzyl methylene), 3.8o (m, OH, -OCHg- »carbinol ^ methine, with D2O <£ 3.63, m, carbinol methine and S 3.90 , lO large t, J = 6Hz, ”0CH2 * -)> 6.32 (large s, overlap with £> 6.40), 6.40 (double d, J = 8 and 2Hz, ArH), 7.00 (d, J = 8Hz,

ArH) and 7.20 (s, PhH).

Infrared spectrum: (CHCl ^) 3610, 3390, 1631 and 1595 cm 15 Mass spectrum: m / e 340 (M +), 322, 190 and 91.

Analysis: C% H%

Calculated for C22H28 ^ 3: 77.61 8.29 20 Found: 77.40 8.31

The following compounds are prepared in the same way: cis-3- £ 4- (2-heptyloxy) -2-hydroxyphenylJ cyclo-hexanol and the trans isomer in the form of oils from 3 ~ [4- ( 2 ~ heptyloxy) -2 ~ hydroxyphenyl] cyclohexanone (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: 30 Infrared spectrum: (CHCl-,) 3597, 3333, 1629

-1 day

and 1600 cm

Mass spectrum: m / e 306 (M +), 208, 190, 173 and 162.

Proton magnetic resonance: "SÊi, O'82 35 (m, methyl), 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.

74

/ / rTMS

Proton magnetic resonance: 00.82 (m, methyl), 3.25 (m, benzyl methine), 4.3 3 (m, carbinoDet OH methine), 6.33 (m, ArH) and 6.94 ( d, J = 8Hz, ArH).

5 ci s-3- [4- (2-octyloxy) -2-hydroxyphenyl] cyclohexanol and the trans isomer from 3-14 (2-octyloxy) - 2-hydroxyphenyl] cyclohexanone (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.

10 Cis isomer:

Infrared spectrum: (CHCl ^) 3663, 3390, 1637 and 1608 cm ^.

Spectrum of. mass: m / e 320 (M +), 319, 208 and 190.

ÔTMS

Cdci 0.82 (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: 20 Infrared spectrum: (CHC13) 3636, 3390, 1634 and 1595 cm "1.

Mass spectrum: m / e 320 (M +), 235, 208, 190 and 173.

Proton magnetic resonance: ό ç; DC ^ 0.82 25 (m, methyl), 3.25 (m, benzyl methine), 4.1-4.9 3 (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] cyclo-hexanol and the trans isomer from 3-L4- (2-nonyloxy) -30 2-hydroxyphenyl] cyclohexanone (31.5 g , 19.48 mmol).

In the order of elution of the silica gel, 2.11 g (67%) of the cis-3 isomer and 0.32 g (lo%) of the trans-3 isomer are obtained in the form of oils.

Cis isomer: 35 Infrared spectrum: (CHC1.,) 3663, 3390, 1639

-1 day

and 1610 cm

Mass spectrum: m / e 334 (M +), 316, 208 and 190.

r TMS

Proton magnetic resonance: 0CDCI °> 88 (m, methyl), 2.85 (m, benzyl methine), 3.5-4.1 (m, meth- 75% carbinol and OH), 4.22 (m, side chain methine), 6.38 (m, ArH) and 6.97 (d, J = 8Hz, ArH).

Trans isomer;

Infrared spectrum: (CHCl ^) 3636, 3413, 1637 5 and 1592 cm ~ ^.

Mass spectrum: m / e 334 (M +), 316, 208, 206 and 190.

6TMS

CDC1 0.88 (m, methyl), 3.23 (m, benzyl methine), 3.9-4.6 ^ 10 (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 ~ hydroxyphé-nyllcyclohexanol and the trans isomer from 3—1 4— C2 - (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: (CHCl ^) 3636, 3390, 1634 and 1608 cm "" ^.

Mass spectrum: m / e 340 (M +), 322, 208, 190, 162, 147, 136 and 91.

STMS

Cdci 3 · »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 = 8Hz, ArH) and 7.20 (s, Ph).

30 Analysis:

• Y

C% H%

Calculated for C22H2803: 77.61 8.29

Found: 77.59 8.18

Trans isomer: 35 Infrared spectrum: (CHCl ^) 3623, 3390, 1637 -1 45 and 1595 cm

Mass spectrum: m / e 340 (M +), 342, 208, 190, 162, 147, 136 and 91.

76

r TMS

Proton magnetic resonance: Oqxii - ^ O (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).

5 cis-3- [4- (2- (6-phenyl) hexyloxy) -2-hydroxyphenylcyclohexanol and the trans isomer from 3-Γ4- (2- (6-phenyl) hexyloxy) -2-hydroxyphenyl ]] cyclohexanol (3.3 g, 9.01 mmol). 1.54 g (46%) of the cis-3 isomer and 274 mg (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 15 and 1592 cm "1.

Mass spectrum: m / e 368 (M +), 350, 208, 190, 162, 147, 136 and 91.

Proton magnetic resonance: oCDC1 1.30 (d, J = 6Hz, methyl), 3.6 (m, carbinol methine), ^ 20 4.2 (m, side chain methine), 6.37 (m , ArH), 6.98 (d, J = 8Hz, ArH) and 7.18 (s, PhH).

Analysis: C% H%

Calculated for C24H32 ° 3: 78.22 8.75 25 Found: 78.05 8.56

Trans isomer:

Infrared spectrum: (CHCl ^) 3636, 3413, 1634 and „'1597 cm-1.

Mass spectrum: m / e 368 (M +), 350, 208, 190, 30 162, 147, 136 and 91.

S TMS

CDC1 l'25 (d, J = 6Hz, methyl), 4.21 (m, carbinol methines and ^ of the side chain), 6.37 (m, ArH), 6.95 (d, J = 8Hz, ArH) and 7.15 (s, PhH).

77

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- (l , 1-dimethylheptyl) -2-hydroxyphenyl] -2-cyclohexenone in 60 ml of ether. The reaction mixture is stirred for a further 30 minutes at -30 ° C, then added to 1.5 liters 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 chromatography on a column of 50 g of "Florisil" eluted with ether, which gives 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.

20 Analysis: C% H%

Calculated for C21H32 ° 2 î 79.70 10.19

Found: 79.68 9.96

Example 13 Ethylene ketal of 3- ^ 4- (1,1-dimethylheptyl) -2-hydroxy-phenyl] -3-cyclohexenone

A solution of 500 mg (1.59 mmol) of 3- [4 ~ (1,1-dimethylheptyl) - 2-hydroxyphenyl] -2-cyclohexenone, 7.8 g (127 mmol) d is heated at reflux for 12 hours. ethy-30 lene glycol, 375 mg (3.18 mmol) of hydroquinone and 50 mg (0.263 mmol) of para-toluenesulfonic acid monohydrate in 50 ml of benzene using a Dean and Stark condenser Û packed with sieve molecular weight of 3 A. 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 chromatography on a column of 50 g of silica gel 78 eluted with 50% ether in petroleum ether and 393 mg (69%) of the product are obtained (after crystallization from pentane) indicated in the title.

Melting point: 97-98 ° C.

5 Mass spectrum: m / e 358 (M +), 297, 273, 245 229.

Analysis: C% H%

Calculated for C23H34 ° 3: 77.05 9.56 10 Found: 76.98 9.42

Example 14 3- [4- (1,1-dimethylheptyl) -Z-hydroxyphenylj ^ -methylcyclohex- ^ enone_

A mixture of 4.08 g (0.1 mole) of ethylene ketal of 3 - [[4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4- is stirred at 25 ° C for 6 hours methylcyclohex-3-enone, 50 ml of 2N oxalic acid and 50 ml of methanol. 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 chromatography on a column of 400 g of silica gel eluted with 50% ether in pentane, which gives the posed corn-25 indicated in the title.

Example 15 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cyclohexene-3-ol-1 • l9 g (50 mmol) of sodium borohydride is added to a solution at -18 ° C of 17 , 5 g (50 mmol) of 3- [4-v 30 (1,1-dimethylheptyl) -2-hydroxyphenyl] -cyclohex-3-enone in 50 ml of methanol. The reaction mixture is stirred for 30 minutes, 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, dehydrated over magnesium sulphate, then evaporated. The residue is purified by chromatography on a column of 400 g of silica gel eluted with 50% ether in pentane; the compound indicated in the title is obtained.

79

Example 16 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclohexene-2-l-ol

7.6 g (0.20 mole) of sodium borohydride are added to a solution at -18 ° C of 70.0 g (0.20 mole) of 3- [4-5 (1,1-dimethylheptyl) - 2-hydroxyphenyl] -cyclohex-2 "-enone in 200 ml of methanol. The reaction mixture is stirred for 30 minutes, then poured into 1 liter of saturated sodium chloride and 1 liter of ether. The phase d is washed extraction with ether 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- 3- [2-acetoxy-4- (1,1-dimethylheptyl) phenyl] cyclohexanone

A solution of 2.0 g of 3- [2-hydroxy-4- (1,1-dimethylheptyl) phenyl] cyclohexanonc in 15 ml of pyridine is treated at 10 ° C. with 10 ml of acetic anhydride and the mixture is stirred. for 18 hours under a 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-acetoxy-3- [2-acetoxy-4- (2- (5-phenyl) pentyloxy) phenyl] -cyclohexane v 20 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 the mixture is stirred under a nitrogen atmosphere for 18 hours. 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, dehydrated over magnesium sulphate, then evaporated to give the diacetic derivative- \ 80 tylé in the form of an oil.

Example 19 3- [2- (4-morpholinobutyryloxy) -4- (1,1-dimethylheptyl) phenyl] - cyclohexanol_ 5 0.227 g (1.1 mmol) of dicyclohexylcarbodiimide and 0.222 g (1.0 mmol) are added of 4- N-piperidyl-butyric acid hydrochloride to a solution of 0.300 g (1.0 mmol) of 3- [2-hydroxy-4- (1,1-dimethylheptyl) phenyl] cyclohexanone in 25 ml of chloride methylene at room temperature.

The mixture is stirred for 18 hours, 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-methylenecyclohexane _; _______

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 hours. Then added in a single portion 17.79 g (51 mmol) of methyltriphenylphosphonium bromide. The yellow solution is stirred for 30 minutes at 25 ° C., then 2.26 g (6.3 mmol) of 3- [2-acetoxy-4- (1,1-dimethylheptyl) -25 are added thereto at once. phenyljcyclohexanone dissolved in 90 ml of dimethylsulfoxide and the mixture is heated to 63-65 ° C for a further 1.5 hours.

The reaction mixture is then poured onto 150 ml of ice and water containing 25 g of sodium bicarbonate and it is extracted three times with 50 ml of ether each time. After having combined the ether extraction phases, they are dried over magnesium sulphate, discolored with charcoal and filtered through a layer of silica gel, which gives a colorless oil which treated by chromatography on 75 g of silica gel (using cyclohexane as elution solvent). A non-polar 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.

81

Example 21 3- [2 ~ hydroxy-4- (1 »1-dimethylheptyl) phenyl] -1-hydroxymethyl-cyclohexane_______

A solution of 1.03 g (3 mmol) of 3- [2-hydroxy-4- (1,1-dimethylheptyl) phenyl] -1-methylenecyclohexane in an ice-water bath is cooled to 0 ° C. 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 about 18 hours 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 minutes, then 3 ml (9 mmol) of 3N sodium acetate and then 3 ml of 30% hydrogen peroxide are added. The mixture is stirred at 0 ° C for 15 minutes, then allowed to warm to room temperature and stirred for 24 hours. The reaction mixture is poured onto 100 ml of ice and water, then it is extracted with three times 50 ml of ether. After combining 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 = cyclohexane / ether at 3: 1) and the product is obtained under the colorless foam. Example 22 trans-4-Γ 2-benzyloxy-4- (1,1-dimethylheptyl) phenyl-3-butene- 2 -o ne____ VI - "Il · Ι. · ΙΙ. ^ ΙΙΙ> ΙΙ · Ι · ™ —II - · ΙΙ ·· Ι · - I. “Il W.III ·

A solution of 65.2 g (0.193 mole) of 2-benzyloxy-4- (1,1-dimethylheptyl) benzaldehyde and 62.0 g (0.195 mole) of 1- is heated at reflux for 20 hours. triphenyl-phosphoranylidene-2-propanone in 195 ml of dichloromethane. Another portion of 15.5 g of ylide (0.047 mole) is added and heating is continued at reflux for 24 hours. 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 chromatography on a column of 1.5 kg of silica gel \ 82 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 5 1575 cm

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-10 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 is slowly added 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 hours, then cooled and evaporated under reduced pressure. The residue is diluted with ether and saturated sodium chloride and acidified with 20 IN hydrochloric acid. The extraction phase is washed with ether twice with 500 ml of saturated sodium chloride, dried over magnesium sulphate and evaporated to give 4.71 g (99%) of the indicated compound in the title.

Melting point: 108-109 ° C (after recrystallization in a mixture of petroleum ether and ether).

Infrared spectrum: (CHCl ^) 1742, 1709, 1612 and 1577 cm

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

Example 24 5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenylJ-1,3-cyclohexanedione_

A mixture of 20.8 g (43.5 mmol) of 5- [2-benzyloxy-4- (1,1-di-35 methylheptyl) phenyl3-4-carbomethoxy- is heated at 100 ° C. for 2.5 hours. 1,3-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 hour 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 title compound are obtained .

Melting point: 102-103 ° C (after recrystallization in pentane and ether).

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

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

Example 25 5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methoxy-2-cyclohexene-1-one_

A solution of 5.0 g (11.9 mmol) of 5- [2-benzyloxy-4- (l, 1-20 dimethylheptyl) phenyl] -1,3-cyclohexanedione and 200 mg is heated at reflux for 30 minutes. para-toluenesulfonic acid in 250 ml of methanol in a flask connected to a Soxhlet condenser containing a sieve

O

molecular weight of 3 A. 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 sulfate, 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: (CHCl ^) 1644, 1612, 1503, 1460 and 1379 cm “1.

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 ether 84 of 500 mg (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 2 $. The reaction mixture is stirred for 30 minutes at 0 ° C. acidified with 1N hydrochloric acid and stirred for 2 hours at room temperature The ether phase is separated, washed successively with saturated sodium bicarbonate and saturated sodium chloride dehydrate on magnesium sulfate and evaporate. The crude oil is purified by chromatography on a column of 100 g of silica gel eluted with 50% ether in pentane, which gives 353 mg (76%) of the title compound, as an oil.

Infrared spectrum: (CHCl ^) 1681, 1672, 1613, 1575 and 1479 cm “1.

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

Example 27 5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl3-3-methyl-2-cyclohexene-1-one_ A solution of 3.45 g (7.95 mmol) is added dropwise of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methoxy-2-cyclohexene-l-one in 10 ml of tetrahydrofuran to 11 ml of a 0QC solution of iodide 2.9M methylmagnesium in ether and 10 ml of tetrahydrofuran. The reaction mixture is then warmed and stirred at room temperature for 2 hours, then ice-cold IN hydrochloric acid is added thereto. After stirring for 20 minutes, 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 chromatography on a column of 100 g of silica gel eluted with 25% ether in pentane, which gives 3.08 g (93%) of the compound indicated in the title.

35 Melting point: 60-61 ° C (after recrystallization from pentane).

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

85 \ "

Likewise, the following compounds are prepared from the corresponding reactants: 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-ethyl-2-cyclohexene-1-one (2.83 g , 82%) as an oil from 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phe-nyl] -3-methoxy-2-cyclohexene-1-one (3 , 46 g, 7.97 mmol) and 10.8 ml of 2.94 M ethylmagnesium bromide (in ether).

Infrared spectrum: (CHC1-) 1698, 1666, 1623 -1 0 and 1582 cm 10 Mass spectrum: (m / e) 432 (M +), 341 and 91.

5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-n-propyl-2-cyclohexene-1-one (3.48 g, 85%) in the form of an oil from 4.00 g (9.21 mmol) of 5- [2-benzyl-oxy -4- (1,1-dimethylheptyl) phenyl] -3-met hoxy-2-cycl ohexene-1-15 one and 36 , 8 mmol of n-propylmagnesium bromide.

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

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

5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -20 3-n-hexyl-2-cyclohexene-1-one (4.11 g, 92%) in the form of an oil with from 4.00 g (9.21 mmol) of 5- [2-benzyl-oxy-4- (1,1-dimethylheptyl) phenyl] -3-methoxy-2-cyclohexene-l-one and from 7.37 ml 2.5 M n-hexylmagnesium bromide (in ether).

25 Infrared spectrum: (CHCl 4) 1678, 1661, 1633, 1618 and 1582 cm-1.

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

Example 28 cis-3-Ç 2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -5-methyl-cyclohexanone _________________

A mixture of 1.00 g (2.39 mmol) of 5- ^ 2-benzyl-oxy-4- (1,1-dimethylheptyl) phenyl] -3- is stirred under hydrogen pressure of 1 bar for 1 hour methyl-2-cyclohexene-l-one 35 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 minutes. A third portion of 500 mg of catalyst is added and agitation is continued for 13 minutes. The reaction mixture is then filtered through sodium bicarbonate and magnesium sulfate and the filtrate is evaporated. The residue is purified by chromatography on a column of 140 g of silica gel eluted with 5% 10% ether in petroleum ether, which gives 323 mg (32%) of the title compound, under the form of an oil.

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

Example 29 cis-3-f 4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-methyl-cyclohexanone_

A mixture of 283 g (6.77 mmol) of 5- [2-15 benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methyl-2 is stirred under hydrogen pressure of 1 bar for 45 minutes -cyclo-hexene-l-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.

25 Analysis: C% H%

Calculated for C22H34 ° 2: 79.95 10.37

Found: 80.22 10.28

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-ethylcyclohexanone (1.34 g, 60%) from 2.83 g (6.55 mmol) of 5- [2 ~ benzyloxy-4- (1,1-dimethylheptylIphenyl] -35 3-ethyl-2-cyclohexene-l-one.

Melting point: 106-107 ° C.

Infrared spectrum: (CHCl ^) 3597, 3333, 1709, 1626 and 1585 cm “1.

Mass spectrum: (m / e) 344 (M +), 326, 315, 87 \ * 297, 273 and 259.

Analysis: C% H%

Calculated for ^ 23 ^ 36 ^ 2 * 80.18 10.53 5 Found: 80.27 10.39 cis-3- [4- (1,1-dimethylheptyl) - ^ - hydroxyphenylj-S ^ Ë ^ SÊXl ^ Ycl ^ (1.66 g, 61%) from 3.40 g (7.62 mmol) of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-propyl-2-cyclohexene -l-one.

10 Melting point: 86.5-90.5 ° C.

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

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

15 Analysis: C% H%

Calculated for C24H38 ° 2: 80.39 10.68

Found: 80.16 10.57 ci s-3- £ 4- (1,1-dimethylhepty1) -2-hydroxyphenyl] -20 5-hexylcyclohexanone (3.06 g, 93%) from 4.00 g ( 8.2 mmol) of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-hexyl-2-cyclohexene-1-one.

Melting point: 84-85 ° C (after recrystallization from pentane).

25 Infrared spectrum: (CHC1 ~) 3571, 3333, 1703,

-1 day

1623 and 1582 cm

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

Analysis: C% H% 30 Calculated for: 80.94 11.07

Found: 80.97 10.94

Example 30 trans-3- [2-benzy1oxy-4- (1,1-dimethylheptyl) pheny1] -5-methyl-cyclohexanone 35 500 mg (1.24 mmol) solution of 5- [2 is added dropwise -benzyloxy-4 ~ (1,1-dimethylheptyl) phenyl] - 2-cyclohexene-l-one in 1.5 ml of ether in a 0 ° C solution of dimethylcopper-lithium (2.47 mmol) in 3 ml ether and 88 1/2 ml of hexane. The reaction mixture is stirred for 15 minutes, then it is poured into 300 ml of saturated aqueous ammonium chloride solution. The deactivated reaction mixture is extracted with three 50 ml portions of ether, the extraction phases at 1 ether are combined, then washed with water and with saturated sodium chloride, then they are dried over magnesium sulfate and evaporated to give 475 mg (92%) of the title compound, v as d 'an oil.

10 Infrared spectrum: (CHCl 4) 1704, 1613 and 1577 cm "1.

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

Example 31 15 trans-3-f 4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-methyl-cyclohexanone_

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-Γ2-benzyloxy-4-20 (1, 1-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 crystallizing the residue from pentane, 89 mg (64%) of the title compound is obtained.

Melting point: 99-102 ° C.

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

Example 32 cis ~ 3-f ~ 2-benzyloxy-4- (1,1-dimethylheptyl) phenyll-trans-5-methylcyclohexanol 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 txans-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 hours at -78 ° C, allowed to warm to room temperature and evaporated in vacuo. The residue is acidified with dilute hydrochloric acid and extracted with ether. The extraction phase is dried over magnesium sulfate; it is evaporated and the residue is purified on a chromatographic column of 50 g of silica gel which is eluted with 30% ether in pentane; 232 mg (77%) of the trans isomer are thus obtained in the order of elution; cis and 45; 9 mg (15%) of the cis isomer; trans.

Trans isomer; cis: 10 Mass spectrum: (m / e) 422 (M +); 337, 314, 229 and 91..

ÎTMS

CDCl (m, terminal methyl), 1.05 (d, J = 7 Hz, methyl at C-5)? 1.26 (s, twin dimethyl), 3.70 (m, benzyl methine), 15 4.05 (m, carbinol methine), 5.13 (s, methylene benzyl), 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.

STMS

CDCl 0.9 (m, terminal methyl), 1.05 (d, J = 7Hz, C-5 methyl) ^ 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).

Example 33 cis-3- [~ 2-benzyloxY-4- (1,1-dimethylheptyl) phenyll-cis-5-methylcyclohexanol and the trans isomer, trans_

160 mg (4.21 mmol) of sodium borohydride are added over 2 hours to a solution at -78 ° C of 228 mg (0.543 mmol) of çi_s-3- [2-benzyloxy-4- (l, 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 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 (R ^ 0.25, silica gel, 90% ether 33% in petroleum ether and 168 mg (Rf 0.17, silica gel, 33% ether in petroleum ether) of the cis isomer, cis.

Example 34 5- cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl ~] -cls-5-methyl- cyclohexanol_

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-dimethylheptyl) -2-hydroxyphenyl ] -5-methylcyclo-10 hexanol in 30 ml of methanol. The reaction mixture is stirred for 1 hour 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: 113-114 ° C

Infrared spectrum: (CHC13) 3636, 3390, 1631 and 1592 cm ~ ^.

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

Analysis: C% H%

Calculated for C22H36 ° 2: 79.46 10.91 25 Found: 79.79 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-ethylcyclohexanol (0.74 g, 74%) from 1.00 g 30 (2.30 mmol) of cis -3- [4- (1,1-dimethylheptyl) -2-hydroxvphé-

V

nyl] -5-ethylcyclohexanone.

Melting point: 110-111 ° C.

Infrared spectrum: (CHCl ^) 3636, 3367, 1631 and 1587 cm 35 Analysis: C% H%

Calculated for C23H3Q ° 2: 79.71 11.05

Found: 79.41 10.71 91 \ cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cis-5-n-propylcyclohexanol (0> 954 g, 71%) from cis-3-Γ 4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-n-propyl-cyclohexanone (1.34 g, 3.74 mmol).

5 Melting point: 103-104 ° C (after recrystallization from pentane).

Infrared spectrum: (CHCl ^) 3636, 3378, 1626 and 1587 cm v Mass spectrum î (m / e) 360 (M +), 342, 275, 10 257 and 161.

Analysis: C% H%

Calculated for C24H40 ^ 2: 79.94 11.18

Found: 79.88 11.22 15 cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl]) - cis-5-n-hexylcyclohexanol, after purification on 120 g of silica gel eluted with 50% ether in pentane; quantitative yield of cis-3-Γ4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-n-hexylcyclohexanone (1.20 g, 3.00 mmol) 2o in the form of an oil containing traces of the trans, trans isomer.

Infrared spectrum: (CHC1 ~) 3623, 3355, 1626 -1 Λ and 1585 cm

Mass spectrum: (m / e) 402 (M +), 384, 317 and 25,299.

Example 35 trans-3- [4- (1,1-dimethylheptyl) -2 ~ hydroxyphenyl ~ 1-cis-5-methylcyclohexanol_ '

A mixture of 220 mg (0.521 mmol) of trans- 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyll-cis-5-methyl is stirred under hydrogen pressure of 1 bar v 30 for 3 hours. -cyclohexanol 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.

92 \ *

Melting point: 111-112 ° C

Infrared spectrum: (CHC1-) 3571, 3333, 1629 and 1572 cm

Mass spectrum: (m / e) 332 (M +), 314, 246 and 5 229.

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

cis-3- [4- (l, t-dimethylheptyl) -2-hydroxyphenyl] -trans-5-methylcyclohexanol (20.0 mg, 56%) as an oil from 45 mg (0.107 mmol ) of cis-3-f2-benzyloxy- 4- (1,1-dimethylheptyl) phenyll ~ trans-5-methylcyclohexanol (in the form of an oil).

High resolution mass spectrum: (m / e) 332.2698 (M +, C22H3602), 314.2635, 247.1665 and 229.1600.

Trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -trans-5-methylcyclohexanol (28 mg, quantitative yield) from trans-3- [L2-benzyloxy-4- ( 1,1-dimethylheptyl) -phenyil-trans-5-methylcyclohexanol (36 mg, 0.0853 mmol) in the form of an oil.

20 = 0.35 (silica gel, 50% ether in pentane).

cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl]] - cis-5-methylcyclohexanol in quantitative yield from cis-3-Γ2-benzyloxy-4- (1,1-dimethylheptyl) pheny 1] -jçis-5-25 methylcyclohexanol (168 mg, 0.398 mmol). This compound is identical to the product of Example 42.

EXAMPLE 36 trans-3-Γ 4- (1,1-dimethylheptyl) -2-hydroxyphenyl1-cis-4- (2-propenyl) cyclohexanol_ A 900 mg solution is stirred for 2 days at ambient temperature (2, 0.1 mmol) of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -cis-4- (2-propenyl) -cyclohexanol and 2.74 ml of 2.2 M n-butyllithium (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 days. It is added to 250 ml of 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 chromatography 93 on a column of 20 g of silica gel eluted with 50% ether in pentane, which gives 631 mg (88%) of the compound indicated in the title.

Melting point: 85-9l ° C.

5 Infrared spectrum: (CHCl ^) 3311, 1639, 1618 and 1567 cm ^.

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

By this procedure, cis-3- [4-10 (1,1-dimethylheptyl) -2-hydroxyphenyl] -trans-4- (2-propenyl) - cyclohexanol (241 mq, 60%) is prepared from cis-3- | 2-benzyloxy-4- (1,1-dimethylheptyl) phenyl ~] -trans-4- (2-propenyl) cyclohexanol (500 mg, 1.12 mmol).

Melting point: 124-125 ° C (after recrystallization from pentane).

Infrared spectrum: (CHCl ^) 3571, 3333, 1642, 1618 and 1580.

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

20 Analysis: C% H%

Calculated for C24H38 ° 2: 80.39 10.68

Found: 80.52 10.57

Example 37 trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4- (2-propenyl) cyclohexanone_

2.59 g (12.1 ml) of pyridinium chlorochromate are added to a solution of 2.15 g (6.03 ml) of 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4- (2-propenyl) -30 cyclohexanol (mixture of isomers) in 15 ml of dichlorome-thane. The reaction mixture is stirred for 2 hours at room temperature, diluted with ether, diatomaceous earth is added thereto, then filtered through magnesium sulfate. The evaporated filtrate is purified by chromatography. 35 on a column of 200 g of silica gel eluted with 20% ether in pentane, giving 250 mg of the crude compound indicated in the title. The purification of this compound is perfected by preparative chromatography on two plates of 94 silica gel 20 cm x 20 cm x 2 mm which are eluted twice with 20% ether in pentane, to obtain 200 mg (9.3%) of the title compound, as an oil.

Infrared spectrum: (CHCl ^) 3571, 3390, 1718, 5 1650, 1626 and 1577 cm “1.

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

Analysis: C% H% 10 Calculated for C24H35 ° 2: 80.85 10.18

Found: 80.92 9.86

Example 38

Ethylene ketal of trans-3-Γ2 ~ benzyloxy-4- (l> 1-dimethvl-heptyl) phenyl] -4- (2- (propenyl) -cyclohexanone

The mixture is refluxed for 3 hours in the presence of a Dean and Stark separator a mixture of 17.0 g (38.1 mmol) of trans-3-C2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl ] -4- (2-propenyl) cyclohexanone, 47.2 g (0.762 mol) of ethylene glycol and 250 mg of para-toluenesulfonic acid monohydrate in 200 ml of benzene. The reaction mixture is cooled and poured into a mixture of 200 ml of lN 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: (CHCl ^) 1656, 1626 and 1587 cm "1.

30 Mass spectrum: (m / e) 490 (M +), 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 ____ 35 A mixture of 700 mg is refluxed for 1.5 hours (1.38 mmol) ethylene ketal of trans-3-C2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-butenyl) cyclo-hexanone, 20 ml of dioxane and 20 ml hydrochloric acid 2n.

95

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, in the form of an oil.

Infrared spectrum: (CHCl ^) 1715, 1616 and 1575 cm "1.

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

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

In the same way, the following are prepared: trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) - phenyl] -4- (2-pentenyl) cyclohexanone in quantitative yield, in the form of an oil from 540 mg (1.04 mmol) of trans-3-r2-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 ~ 1-cis-4-methyl-cyclohexanol and cis-3 - [] 4- (1,1-dimethylheptyl) -2-hydroxyphé -25 nyl] -4-methylcyclohexanone

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-dimethylheptyl) phenyl] -4-methylcyclohex-2 -r 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 chromatography on a column 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 mixture of ketones is further purified by preparative chromatography on five plates of silica gel 20 cm × 20 cm × 2 mm eluted 96 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 title 5 Melting point: 134-135 ° C.

Infrared spectrum: (CHCl ^) 3623, 3333, 1626 .. and 1585 cm \

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

10 Analysis: C% H%

Calculated for ^ 22 ^ 2, ^ 2: 79.46 10.92

Found: 79.40 10.72 Ketone indicated in the title 15 Infrared spectrum: (CHCl 4) 3623, 3390, 1634 and 1582 crrT ^.

Mass spectrum: (m / e) 330 (M +), 315, 312, 288, 273, 271 and 245.

Example 41 20 5- (2-benzyloxy ~ 4- (1,1-dimethylheptyl) phenyl) -3-methoxy-6-) ηέί1 ") γ1--2 - ογο1οΡθχθηθ - 1 - οηβ

A solution of 217 g (0.5 mole) of 5- (2-benzyloxy-4- (1,1-dimethyl-heptyl) phenyl) -3-methoxy-2-cyclohexene- is added dropwise (30 minutes) l-one in 250 ml of tetrahydrofuran in a solution at -78 ° C of 0.5 mole of lithium diisopropylamide in 500 ml of tetrahydrofuran (compound prepared from 50.5 g, i.e. 0.5 mole, diisopropylamine and 417 ml of 1.2 M n-butyllithium in ^ hexane). The reaction mixture is stirred for a further 30 minutes at -78 ° C, then 179 g (1.0 mole) of hexamé-thylphosphoramide and 78.1 g (0.55 mole) of methyl iodide are added thereto.

The reaction mixture is allowed to warm slowly to room temperature, stirred for 1 hour and is deactivated by the addition of 10 ml of water. The reaction mixture is evaporated under reduced pressure to remove the tetrahydrofuran and poured into 1 liter of ice water and 1 liter of ether. The ether extraction phase is washed with three one-liter portions of water, dried over magnesium sulfate and evaporated to give the title compound; in almost pure form. The compound indicated in the title is purified by chromatography on a column of 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- cyclohexene-1-one_

Following the procedure of Example 1; reacting 5- [2 ~ benzyloxy-4- (1,1-dimethylheptyl) phenyl] -10 3-methoxy-6-methyl-2-cyclohexene-l-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-dimethylcyclohexanol_

The debenzylated compound of Example 42 is reduced to sodium borohydride according to the procedure of Example 11 to obtain the title compound. Example 44 3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4,5-dimethyl-cycloheptanone A solution of 0.10 mole of lithium dicyclohexylamide is added dropwise over 2 hours. 100 ml of tetrahydrofuran to a solution at -78 ° C of 17.4 g (0.10 mole) of dibromomethane and 21.7 g (0.050 mole) of 3- [2-benzyloxy-4- (1,1- dimethylheptyl) phenyl] -4,5-dimethylcyclo-30 hexanone in 100 ml of tetrahydrofuran. The reaction mixture is stirred for a further 1 hour at -78 ° C and quenched by the addition of 2 ml (0.11 mole) 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 chromatography on a column of 500 g of silica gel eluted with a mixture of ether and pentane; thus obtaining pure 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -1-dibromomethy4,5- '98 \ "dimethylcyclohexanol.

47.7 ml (0.105 mole) of n-butyllithium (2.2 M in hexane) are added over 2 hours to a solution at -78 ° C of 30.4 g (0.050 mole) of 3- [2- benzyloxy-4- (1,1-dimethyl-5-heptyl) phenyl] -1-dibromomethyl-4,5-dimethylcyclohexanol in 150 ml of tetrahydrofuran. The reaction solution is stirred for a further 2 hours at -78 ° C and 10 minutes at 0 ° C, then 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 chromatography on a column of 500 g of silica gel eluted with a mixture of ether and pentane to give the compound indicated in the title.

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 1:10 ether.

The hydrobromide, sul-25 fate, nitrate, phosphate, acetate, butyrate, citrate, malona-te, maleate, fumarate, malate, glycolate, gluconate, lactate, salicylate, sulfosalicylate, succinate, pamoate, tartrate or the like are prepared in the same way. embonate.

Example 46 Sodium salt of cis-3-Γ4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclohexanol 2'-O-hemisuccinic ester

0.383 g (3.14 mmol) of 4-N, N ~ di-methylaminopyridine is added to a 0 ° C solution of 1.00 g (3.14 mmol) of cis-3-f 4— (1.1 -dimethylheptyl) -2-hydroxyphenyl "cyclo-35 hexanol in 3 ml of dichloromethane. 0.314 g (3.14 mmol) of succinic anhydride is added slowly to the resulting solution in 1 ml of dichloromethane. The reaction mixture is stirred 3.14 ml 99 lN hydrochloric acid is added thereto slowly for 4 hours at 0 ° C. The reaction mixture is stirred for a further 5 minutes, then poured into 100 ml of water and 100 ml of dichloromethane. The dichlo-romethane extraction phase is dried over magnesium sulphate and evaporated, the residue is dissolved in 5 ml of ethanol and 3.14 ml of lN sodium hydroxide is added to the solution: ethanol The addition of ether causes crystallization.

By recrystallization from a mixture of ethanol and ether, ** the compound indicated in the title is obtained.

10 Example 47

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

A solution of 1.00 g (3.14 mmol) of cis-3 ~ r4- (1,1-dimethylheptyl) -2-hydroxyphenyl1cyclohexanol 15 in 3 ml of dimethylformamide is added to a 0.16 g suspension at 0eC (3, 14 mmol) of potassium hydride in 3 ml of dimethylformamide. When the evolution of gas has ceased (about 10 minutes), 0.932 g (3.14 mmol) of dibenzyl phosphorochloridate is added slowly. The reaction mixture is stirred for 1 hour, then poured into 200 ml of ether and 100 ml of water. The extraction phase is 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 car-bone and 25 ml of ethanol and the mixture is stirred under 1 bar hydrogen pressure for 3 hours. The reaction mixture is filtered through diatomaceous earth and slowly added 3.14 ml of 1N sodium hydroxide in ethanol to the filtrate. The addition of ether causes the product to crystallize. By recrystallization in ethanol, the compound indicated in the title is obtained.

Example 48

100 mg of 3- [4- (1,1-di-methylheptyl) -2-hydroxyphenyl] cyclohexanol is intimately mixed by grinding with 3500 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.

100

Example 49

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

Sucrose 80.3 parts 5 Cassava starch 13.2 parts

Magnesium stearate 6.5 parts

A sufficient amount of healthy Jtrans-3- [2-hydroxy-4- (2- (5-phenylpentyloxy)) phenyl] - cyclohexanol is incorporated into this base to obtain tablets each containing 0.1, 10 0, 5, 1, 5, 10 and 25 mg of active substance.

Example 50

Suspensions of 3- [4- (1,1-dimé-thylheptyl) -2-hydroxyphenyl] cyclohexanone are prepared by adding sufficient amounts of active substance to 0.5% methyl cellulose to obtain suspensions containing 0.05, 0.1, 0.5, 1, 5 and 10 mg of active substance per ml.

ί

Claims (5)

1. Process for the preparation of a compound corresponding to the formula: 0RX “" roL. "In which R is a saturated or unsaturated cycloalkyl group corresponding to one of the formulas: A B A A B AB \ E H y-j \ '’ R,! R, / $ 4 - 'J R, "2" 3 P R4 R2 4 2 Krt I-A X-B I-C and I-D where A is a hydrogen atom and B is a hydroxy or alkanoyl-oxy group containing X to 5 carbon atoms; R ^ is a hydrogen atom, a benzyl group, an alkanoyl group containing 1 to 5 carbon atoms, a P (0) (011) 2 group or its monosodium, disodium, monopotassium and dipotassium salts or also a group -CO (CH2) NR ^ -R ^ in which p is an integer between 1 and 4 j each of the radicals Rj. and R ^ taken individually is a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, R ^ and R ^, taken together with the nitrogen atom to which they are linked, form a pentagonal or hexagonal heterocyclic ring (a piperidino group, a pyrrolo group, a pyrrolidino group, a morpholino group or an N-alkylpiperazino group in which the alkyl group contains 1 to 4 carbon atoms); R2 is a hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, an alkenyl group containing 3 to 6 carbon atoms, a phenyl group or a phenylalkyl group in which the alkyl group contains 1 to 4 carbon atoms; / V ·, R ^ is a hydrogen atom or a methyl group; is a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms; Z is an alkylene group containing 1 to 13 carbon atoms or a group - (alk ^) m ~ 0- (alk2) n ~ in which each of the radicals (alk ^) and (alk2) is an alkylene group containing 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 equal to O or 1 3 and v W is an atom of hydrogen, a pyridyl group or a ΓΛ group of formula: 10K in which is a hydrogen atom, a fluorine atom or a chlorine atom 3 as well as pharmaceutically acceptable acid addition salts of these compounds when R ^ is a group -CO (CEL) NR-R / · and / or when W is a pyridyl group; "P j 0 hemicetals of these compounds when A and B taken together represent an oxo group and when R ^ is a hydrogen atom, as well as ketals with alkanols (containing 1 to 4 carbon atoms) of these compounds when A and B taken together represent an oxo group and when R ^ is a hydrogen atom, characterized in that it consists in reducing a compound of formula I in which A and B taken together represent an oxo group, while R ^ R2, R ^, R ^, Z and W have the meanings defined above and optionally carry out one or more of the following steps consisting in: (a) acylating a compound of formula I in which OR ^ and / or B represents (nt ) a hydroxy group 3 (b) hydrolyzing a compound of formula I in which% ORj and / or B represents (s) an ester fraction 3. (c) preparing a pharmaceutically acceptable acid addition salt of a compound of formula I in which R ^ is a group -C0 (CH2) p-NR ^ R ^ and / or W is a pyridyl group. 2, Process for the preparation of a compound corresponding to the formula: A B OR ^ vv * R2 Z-W / v in which R ^,, Z and ¥ have the meanings defined in claim 1; β is a group -CH2-, -CH2CH (R ^) -, - (CH2) 2CHR ^ or taddis that A and B taken together represent an oxo group or a methylene group, characterized in that it consists in subjecting a compound of formula: OR »% ZW * in which R ^ 'is a group protecting the hydroxy function, while Z and W have the meanings defined above, to a Grignard reduction with a compound of formula: 0 6 in which R2 and Q have the meanings defined above, then optionally carry out one or more of the following steps consisting in: (a) removing the group protecting the hydroxy function; (b) acylating a compound of formula 1 'in which R ^ is a hydrogen atom; (c) subjecting a compound of formula I ', in which A and B taken together represent an oxo group, to a Wittig reaction with a methylide to obtain a compound in which A and B taken together represent a methylene group; . (d) subjecting a compound of formula I * in which A and B taken together represent a methylene group, to hydro-boration-oxidation; ^ (e) preparing a pharmaceutically acceptable acid addition salt of a compound of formula 1 'in which R ^ is * a group -C0 (CH2) pNR ^ R ^ and / or W is a group pyridyle " 3 · Process for the preparation of a compound corresponding to the formula: AB rL * iipi 2 zw V / / in which A, B, R ^, R2, Z, W and Ô have the sigrrifications defined in claim 2, characterized in what it consists in subjecting a compound of formula: OR, 'Br I 1' in which R ^ 'has the meaning defined in claim s. 2, to a Grignard reaction with a compound of formula: 0 O-alkyl * 2 in which "alkyl" is an alkyl group containing 1 to 4 carbon atoms, then, before or after the elimination of the group protecting the hydroxy function , optionally carry out one or more of the following steps consisting in: (a) isomerizing a compound of formula In by ketalization to obtain the corresponding unsaturated ketal in positions .3,4; (b) decetalizing the unsaturated ketal in positions 3 , 4 of step (a) 5 (c) subjecting a compound of formula I ”to a reaction with dimethyl-copper-lithium to obtain a compound of formula: ATS B °, ri Γ 2 ch3 \ ^ zw in which A, B, R. ^, R2, Z, W and Q have the meanings defined above; (d) prepare a pharmaceutically acceptable acid addition salt of a compound of formula I "in which R ^ is a group -C0 (CH2) pNR ^ Rg and / or W is a pyridyl group. / ·, 4. Process for the selective alkylation of a 3- (2,4-dihydroxyphenyl) cycloalkanone containing 5 to 8 carbon atoms in the aikyl fraction on the hydroxy group in position 4, characterized in that it comprises the steps which consist in: (a) transforming the 3- (2,4-dihydroxyphenyl) - cycloalcanone into a ketal with an alcohol containing 1 to 4 carbon atoms 5 (b) alkylating the product of step (a) with a compound, of formula: 1. WZY -Si in which Y is chosen from the group comprising a chlorine atom, a bromine atom, a mesyloxy group and a tosyloxy group; Z is a group - (all ^) which is an alkylene group containing 1 to 13 carbon atoms; and W is chosen from the group comprising a hydrogen atom, a pyridyl group and a group of formula I in which W, es * cKols! from the group comprising a hydrogen atom, a fluorine atom and a chlorine atom 5 and (c) treating the alkylated product of step (b) with a dilute acid, 5 · Process according to claim 4, characterized in that the ketal is formed by reacting 3- (2,4-dihydroxy-phenyl) -cycloalkanone with a cb trialkyl formate.