CS243480B2 - Method of new 3-(2-hydroxy-4/-(substituted)phenyl-4 or 5substituted) cycloalkanes prepararation - Google Patents

Abstract

They prepare and intermediates for analgesic active ingredients and anti-emesis agents. The compounds prepared have the general formula Ø, hydrogen, benzyl, alkanoyl β 1 to 5 atoms 1 carbon, and number 1 or 2, and Y is -CH (R 1) (CH 2 R 5) - -CH / R ^ / CH ,, - where it means R 2 "hydrogen or methyl, R10 is hydroxyalkyl of 1 to 6 carbon atoms; Rj is hydroxyalkyl of 1 to 3 carbon atoms; V is hydrogen, pyridyl or a group wherein each is alk (a) alk (alkylene) and 1 to 13 carbon atoms and each ft and n are zero or number 1, provided that the sum of atpms carbon v / alk, (plus / alk) / is at least 5 and at most 13 and at least one of the symbols m and n mean 1, and provided that v is when W does not mean hydrogen means FROM α / C 3 -C 8 alkylene or b) - alk, (m-O-) alk2, where each is / alk, / a / alkg / alkylene of 1 to 8 atoms carbon and each man zero or I, provided that the sum of the carbon atoms v / alk, / plus / alkj / is at least 3 and at most is 8 β ϊβ at least one man means number 1.

Description

The invention relates to a process for the preparation of novel 3- [2-hydroxy-4- (substituted) phenyl] -4) or 5- (substituted) cycloelkenones which are suitable for the preparation of the corresponding cycloalkenols and their derivatives, which are effective as analgesic and anti-vomiting agents. .

Not seeking the simultaneous availability of numerous enalgesic agents, new and improved means are still being sought to reduce the wide range of pain and discomforts associated with minimal side effects. The most commonly used formulation, aspirin, which is a non-acetylsilyl-acid-based formulation, has no practical significance against major pain and is known to have various, unwanted side effects. Other analgesic agents, such as meperidine, codeine, and morphine, show a habit of administration. The need for an improved and effective analgesic composition is therefore clearly clear.

Compounds useful as analgesic agents, tranquillizers, sedatives, anti-anxiety and / or anti-seizure agents, as diuretics, and as anti-diarrhea agents are described in Belgian Patent Nos. 870,404 and 870,402, both of which have been granted. 12, March 1979. Belgian Patent No. 870,404 discloses 3- [2-hydroxy-4- (substituted) phenyl} cyclohexanones and cycloalkanols, which may have an alkyl, alkenyl, phenyl group as substituent at the 4-position of the cycloalkenone or cycloalkanol moiety. or a phenylalkyl group; or may have a 5-position alkyl substituent. Belgian patent specification 670,402 discloses certain phenols substituted in the 2-position by acyclic substituents, in particular 2- (hydroxyalkyl) -4- and substituted phenyl phenols and 2- (oxyalkyl-4-) substituted phenols.

U.S. Pat. No. 3,575,887, issued April 27, 1971, discloses a series of 1- (1'-hydroxy) alkyl-2- (o-hydroxyphenyl) cyclohexenes having central nervous system depressant properties.

The phermacological activity of 4- (2-hydroxy-4- (substituted) phenyl) naphthalen-2-ol and 4- (2-hydroxy-4- (substituted) phanyl) naphthalen-2-ol), which are useful as agents affecting central nervous system and as anti-vomiting agents.

U.S. Pat. No. 3,974,157 discloses 2-phenyloyclohexanones which may have up to two substituents on the phenyl core of the alkyl, hydroxy-acetyl or alkoxy substituents, as intermediates for the preparation of 1- (sminoalkyl) -2-phenylcyclohexanol useful as an analgesic as a local anesthetic and as an anti-arrhythmia.

In the journal Chemical Abstracts fifi, 176 952 (1976), it refers to numerous 3-phenyl and 3-phenylalkylcyclohexanones as intermediates for the preparation of 2-aminomethyl-3-phenylcyclohexanones or 2-aminomethyl-3-phenylalkylcyclohexanones having analgesic and aedative action and which may also be used as antidepreasing and antispasmodic.

The invention, on the other hand, relates to a process for the preparation of compounds of formula II

where is where

R, hydrogen, benzyl, C 1 -C 5 alkanoyl, with an integer of 1 or 2,

Y 'is a group of the general formula

-ch (r ₂ ) ch (r ₂ °) or of the general formula ch (r ₃₎ / ch ₂ , where is

R ₂ is hydrogen therefrom ™ methyl, 2 & ° hydroxyalkyl group having 1 to 6 carbon atoms,

R ₃ ° hydroxyalkyl group having 1-3 carbon atoms

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

where it means

W | a hydrogen atom, a chlorine atom or a fluorine atom, provided that in the case where W represents a hydrogen atom, Z represents a (a) alkylene group of 5 to 13 carbon atoms or b) - (alk ₁ ) _n -O- (alk ₂ ) _{n a} group wherein each (alk,) and (alkg) alkylene group is 9 to 13 carbon atoms, each man is zero or a number 1, provided that the sum of the carbon atoms in (alk, / plus) alkg is at least 5 and at most 13 and that at least one of m and n is 1, and provided that when W is not a hydrogen atom, Z is an a / alkylene group of β 3 to 8 carbon atoms or b / - (alki) ^O-Zalkg (jj) a group wherein each is an (alk,) and (alkg) alkylene group having 1 to 8 carbon atoms, each man zero or a number 1, provided that the sum of the carbon atoms in (alk, (plus) alk ₎ is at least 3 and at most 8 and that at least one of the symbols man represents 1 »

The radical Y * in the cycloalkyl moiety has a variable position in the sense that & 2 c is always substituted at the 4-position and each of Rg and R ^ ⁰ is always a substituent at the 5th

As mentioned above, the invention also relates to a process for the preparation of pharmaceutically acceptable acid addition salts of compounds of formula II which contain one or more basic groups. As a rule, those compounds in which W represents a pyridyl group and / or the OR group represents a basic ester moiety are suitable for the preparation of such acid addition salts.

Compounds of formula II having more than one basic group are suitable for the preparation of polyaddition salts with acids.

Typical examples of such pharmaceutically acceptable acid addition salts include salts with mineral acids such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate; and salts with organic acids such as citrate, acetate, sulfosalicylate, tartrate, glycolate, malonate, malate, maleate, pamoate, salicylate, stearate, phthalate, succinate, gluconate, 2-hydroxy-3-naphthoate, lactate, mandelate and methylsulfonate.

Compounds of formula II wherein R 1 is hydrogen are generally in solution in equilibrium form with their hemiketal forms. The ketoforms and hemiketal forms of the 243480 nin of Formula II are included within the scope of the invention.

The compounds of formula (II) contain an asymmetric center in the 3,4,4-cycloalkyl moiety and may contain an additional asymmetric center in the (-Z-W) -phenyl core moiety.

The ®trans relationship removes the substituents at the 3 β 5 β 3 5 5 position on the cycloalkyl moiety is more preferred, since in these cases the quantitative greater biological action of the active ingredients obtainable from the products of the invention having this configuration is achieved.

In the above-mentioned formulas, racemic compounds are indicated. The formulas II are, however, considered to be general and include racemic modifications of the compounds prepared by the process of the invention, diaztereomeric mixtures, pure enantiomers, and diaatsreoaers. The usefulness of the racemic mixture, the dlastereomeric amesis and the pure enantiomers and diasteraomers is determined by the biological evaluation, which is described below.

The compounds prepared by the process according to the invention can be converted to the corresponding cycloalkanols by the method described in the Czechoslovak patent specification (PV 6764-81).

and

With respect to the larger ones the biological activity of the compounds which may Sisko, the compounds of this invention are preferred compounds of vsoree II wherein R is _(hydrogen atom, R₂ is hydrogen or a methyl radical, each R g ⁰ and R ⁰ each hydroxyalkyl group and Z and W have this meaning;

Z mn is an alkylene group of 7 to 11 carbon atoms

Z is an alkylene group having 4 to 7 carbon atoms / alki / _B- O- (elkg) _n

hydrogen atom

The group of general vsoree

-hQHw, or a pyridyl group of the general formula above - <ζθ ^ —w,

0,1 L or pyridyl wherein each (alkj) and (alkg) is an alkylene group and 1 provided that the sum of the carbon atoms in (alk,) and (alkg) is at least 5 to 7 carbon atoms, and is at most 7,

- (80k, [ _m -O-] elkg) _n 0.1 hydrogen atom wherein each (alk) (a) (alkg) represents an alkylene group and (1) the condition that the sum of the carbon atoms in (alk () a) (alkg) is at least 7 to 11 carbon atoms, s and not more than 11.

Preferred are compounds of formula (II), wherein

Rg and Rj are each hydrogen,

Z is a group of formula C / CH3 / g / CH3 / g and

W hydrogen atom,

Z is (C 4 -C 7) alkylene;

W phenyl;

OF

W

Z w

-O-alkylene of 7 to 9 carbon atoms and hydrogen,

C 4 -C 5 -alkylene and phenyl, C 2 -C 4 -hydroxyalkyl hydroxyalkyl.

Particularly preferred compounds of formula (IX) are those wherein R 1, Z and% are as defined above for preferred compounds, R 8 is 3-hydroxypropyl, and R ¹⁰ is hydroxymethyl. The 1-form of the compounds of formula (II) is more preferably than the d-form.

Compounds of formula II wherein T * is a group of formula

-CH (Rg VCH (Sg ^O) ) are prepared from the appropriate 2-bromo-5- (W-eubstituted) phenols by a series of reactions that include the first step of protecting the phenolic group. Suitable are protecting groups which do not interfere with the subsequent reaction and which can be removed from conditions that do not lead to undesired reactions at other sites of the optional compounds or products prepared therefrom.

Examples of such protecting groups include phenol protecting groups described in Haalam, Chapter 4, Protective Goups in Orgenic Ghemistry, J. F. M. McOmie, Plenum Press, London and New York (1973). Preferred are methyl, ethyl, tetrahydropyranyl, benzyl or substituted benzyl, the substituents being, for example, C 1 -C 4 alkyl, halogen atoms such as chlorine, bromine, fluorine or iodine and C 1 -C 4 alkoxy. .

The ether protecting or blocking groups can be removed using hydrobromic acid in acetic acid or using aqueous 48® hydrobromic acid. The reaction is carried out at elevated temperature and optionally at reflux temperature. When Z is a radical of formula

- / alk / _B -0- / alk ₂ / _n must be used acids such as trifluoroacetic acid or polyphosphoric acid to prevent wear cleavage bond. Other reagents such as hydroiodic acid, pyridine hydrochloride or pyridine hydrobromide can be used to remove protecting ether groups such as methyl or ethyl. If the protecting groups are benzyl or substituted benzyl, they can be removed by catalytic hydrogenolysis. Suitable catalysts are palladium or platinum, especially on carbon as supports. Alternatively, these protecting groups can be removed by solvolysis using trifluoroacetic acid.

The saline step involves treatment with n-butyllithium in a reaction-inert solvent β at room temperature.

The precise chemical structure of the protecting group is not critical in the process of the present invention, since its meaning is based solely on the ability to process as described above. The choice and identification of a suitable protecting group is easy for the person skilled in the art and does not cause problems. The suitability and effectiveness of a group, such as a hydroxyl protecting group, is determined using such a group in the reaction sequence illustrated. However, it is intended to be a group which is readily removed by releasing the hydroxyl group.

243480 6

Preferred hydroxyl protecting groups are methyl, tetrahydropyrenyl and benzyl, as they can be easily removed.

The protected 2-bromo-5- (W-substituted) phenol is then reacted with magnesium in a solvent in an inert and general reaction in the presence of a promoter, such as a copper salt, for example cuprous chloride, cuprous bromide and cuprous iodide, to promote 1. 4-addition, with a suitable 4-R 2 -2-cycloalken-1-one, such as 4-R 2 -2-cyclohexen-1-one, ^{wherein R a} represents an alkenyl group or an alkyl group substituted with X ', where X * represents a group X or a precursor thereof, for example -O-benzyl as a precursor of a hydroxyl group or a group of the formula

CH / O _3/2 or -HCOCI ^ C ^ O as a precursor to a group -CHO.

Suitable inert solvents are, for example, cyclic and acyclic ethers, such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether (diglyme).

The Grignard reagent is formed in a manner known per se, for example by maintaining a reflux temperature of a mixture of one molar portion of the reagent and two molar portions of magnesium in a reaction inert solvent such as tetrahydrofuran. The resulting mixture was then cooled to about 0 ° C to -20 ° C. The amount of copper (I) iodide used is not critical and may vary within wide limits. Molar proportions of about 0.2 to 0.02 moles per mole of bromine reagent give satisfactory results with respect to cycloalkanone yield, wherein the phenolic hydroxy group is protected (Formula II, R 1 is a protecting group).

Alternatively, the compounds of formula (II) may be prepared by reacting a derivative of a suitable 3- (W-eubetitulated) phenol whose hydroxy group is suitably protected, with a suitable cycloalk-2-en-1 substituted at the 4-position or the 5-position. -onene in a reaction-inert solvent at low temperature, not below -20 ° C. Suitable protecting groups are the same as described above except that the benzyl or substituted benzyl group is removed during the preparation of the precursor of the lithium derivative of 3- (Z-W) -phenol. copper. A particularly suitable protecting group for this method of preparation is the tetrahydropyrenyl group. This tetrahydropyranyl group ae is readily incorporated into the phenol reactant, is stable under the conditions of the following reactions, in which the protected compound is used as an intermediate and is readily removed by hydrolysis.

The 3- (ZW-eubetitmated) phenol ee derivative is prepared from a lithium derivative of this phenol by treatment of the derivative with 1-hexylene copper. It is subject to a 1,4-addition non-conjugated α-c = o cycloalk-2-en-1-one reagent. in contrast to the characteristic 1,2-addition of the corresponding lithium derivative.

This alternative 1,4-addition method leads, moreover, to the same compound as the Grignard reaction described above. In general, it provides better yields of compounds of formula II.

Accordingly, the compounds of formula (II), wherein each symbol is as defined above, are prepared by ketalizing a compound of formula (IIB)

O

(II Β) zw where s, R ₁ , Z and W are as defined above and wherein X is a group of the general formula

-ch / k ₂ (ch / r ₂ °) or

-gh / h ₃ ° / s ₂ where H ₂ is as defined above and wherein R ₂ ° and R ⁰ represents an alkenyl radical having at most 6 carbon atoms, thus formed is hydrated Ketel hydroboration-oxidation at 0 to 50 ° C a reaction inert solvent, or by conventional or demercuration using mercuric acetate in a reaction inert solvent at room temperature, whereupon the hydroxymercury intermediate is reduced with sodium borohydride and the ketal protecting group is removed.

If the reaction according to the invention is not avail appropriate 4-R-2-cycloalken-1-one, or if not readily obtainable by known methods, as intermediates for all compounds of formula II, the compound of formula II wherein R ⁰ is oxoaubstituované alkyl group having 1 to 6 carbon atoms in the alkyl group and particularly ⁰ Rg is formyl.

Compounds in which R 1 is an alkenyl group are converted to the corresponding hydroxyalkyl derivatives by hydroboration oxidation using hydrogen boron in tetrahydrofuran or diethylene glycol dimethyl ether (diglyme) at 0 to 50 ° C. The borane intermediate is not isolated, but is directly oxidized with Alkaline hydrogen peroxide with alcohol; the alcohols thus produced correspond to the anti-Markovnikov addition of the double bond water elements.

Hydroxyalkyl derivatives can also be prepared by oxymercuration-demeruration using mercuric acetate in water, followed by reduction, for example sodium borohydride, of the hydroxy-mercuric derivative formed as an intermediate. This reaction is carried out at ambient temperature using aqueous mercuric acetate-tetrahydrofuran medium. The intermediate is not separated but is reduced in situ with alcohol. The addition occurs on the opposite side with respect to the hydroboration-oxidation reaction; namely the Markovnikov edition, in which the elements of the water are double-bonded in the opposite manner to the hydroboration-oxidation reaction, leading to secondary alcohols.

Compounds of formula II wherein R ₂ ° and R ⁰ is oxo substituted alkyl are conveniently prepared by oxidation of corresponding compounds wherein R or R ⁰ is an alkenyl group having one carbon atom more than the group R ₂ ° and R ⁰ in the compound of formula II. As the oxidizing agent, a sodium meta periodate and a catalytic amount of osmium tetroxide in aqueous tetrahydrofuran or dioxane at ambient temperature is suitable, since there is minimal oxidation above the aldehyde stage. However, in spite of the relatively mild oxidation conditions compared to, for example, oxidation with the sodium meta periodate-potassium permanganate system, some oxidation to the corresponding acid and the corresponding hydroxyketone occurs in some cases. In the above reactions, the keto group of cycloalkanone is generally protected by ketalization.

Conversion to ketal and e is carried out by known methods for ketalization, such as the reaction of 3- (2,4-dihydroxyphenyl) cycloelkanone and an alcohol, especially an alcohol and 1 to 4 carbon atoms, in the presence of an acid such as sulfuric acid, p-toluenesulfonic acid acid and hydrogen chloride, by-product removal conditions. In a preferred method, the reaction of 3- (2,4-dihydroxyphenyl) cyclohexanone is carried out with orthoformic acid in the form of an ester in an alcohol solution corresponding to the alcohol fraction of the orthoformate ester. Preferred reactants are triethyl ortho formate and methanol together with concentrated sulfuric acid, anhydrous hydrochloric acid or ammonium chloride as catalyst.

The ketal thus produced is alkylated by reaction with a suitable alkylating agent, such as a compound of formula

WZX wherein Z and W are as defined above, and wherein X ** is selected from the group consisting of chlorine atom, bromine atom, meeyloxy group (CH ₂ SO ₂ O) and tosyloxy group of formula p-ch ₃ -c ₆ h ₄ -so ₂ -in the presence of a binder an acid such as sodium carbonate or potassium carbonate. The alkylated ketal is then decetalized by acid treatment in a manner known per se.

The 3- 2-hydroxy-4 - [- O - [( ₂ -N-aubetitulated) phenyl] -4- (R) -substituted cycloalkanone thus prepared is converted to the corresponding cycloalkanol as described above.

It has been found that compounds of formula II, wherein Rg represents a group of the formula ⁰ / CH / ^ OH -ZW group of formula

-c / CH _3/2 / CH _2/5 CH ₃ and R is benzyl / C ^ H? / can be resolved into diastereomers A and B by reacting a D-mandelic acid, AA, p-toluenesulfonic acid in benzene with azeotropic water odetraňčvání . Hydrolysis of d-mandate esters of diastereomers A and B, for example using potassium carbonate in a methanol-water system, results in enantiomers A and B.

In a similar manner, reaction of enantiomers B with 1-mandelic acid e with p-toluenaulfonic acid in benzene under azeotropic removal of water affords diestereomer A of the bis-mandelate derivative. Hydrolysis as described above gives enantiomer B. Removal of the benzyl protecting group yields the corresponding enenciomeric alcohols.

Acyl derivatives of compounds of formula II wherein R _f is hydrogen and each R ₂ or R ₃ is hydroxyalkyl are prepared by acylation with a suitable alkanoic acid in the presence of a condensation agent such as dicyclohexylkerbodiimide or by reaction with a suitable alkanoic acid chloride or reaction with an anhydride of a suitable alkanoic acid in the presence of a base such as pyridine. Depending on the reactivity of the acylable R groups, the alcoholic hydroxyl group is the first, followed by the phenolic hydroxy group and the secondary hydroxy group.

Esters of compounds of formula II, wherein R ⁰ or R ⁰ contain no acylovetelnou group, are prepared by acylation as described above.

The analgesic properties of the compounds prepared by the process according to the invention of the general formula II and the products prepared therefrom are determined by tests based on the stimulus capturing the noxious stimuli. It is recalled that compounds of formula II wherein R 1 is benzyl and the products prepared therefrom are not pharmacologically active for the purposes described are, however, useful as intermediates for compounds of formula II wherein R 1 is hydrogen.

Tests based on stimulus to capture thermal harmful stimuli

a) Analgesic hot plate assay of mice

This method uses the modified tests of Voolfe and Mac Donald described in J. Pharmacol. Exp. Ther. 80. 300-307, 1944, controlled heat stimulus is applied to the mySl pack on a 3.175 mm thick aluminum plate. A 250-watt infrared heating lamp is placed under the bottom of the aluminum plate. The thermal controller, coupled to the thermistor on the aluminum plate surface, programs to maintain a constant plate surface temperature of 57 ° C. Each myS is lowered into a 165 mm diameter glass cylinder resting on a hot aluminum plate and time is measured as the mouse paw touches the aluminum plate. The MyS is observed half an hour and two hours after treatment with the test compound, taking into account the first jerk with one or both hind paws or 10 seconds without such movements. Morphine has an MM11 value of 4 to 5.6 mg (kg / s.c.). / IOtó always means maximum effect. /

b) Tail flick analgesic test

The modified assays of NON Amour and Smith described in J. Phermacol are used. Exp. Ther., 72, pp. 74-79 (1941), utilizing the controlled action of intense heat on the mouse tail. Each mouse is placed on the foot of a metal cylinder with the tail extended. The cylinder is trimmed so that the tail is completely on the shaded heater bulb. At the beginning of the test, the aluminum plate covering the heating bulb is withdrawn and a light beam is passed through the slit, with the focus on the tail. At the same time the timer will turn on. A sudden tail jerk is detected. An untreated mouse typically responds within 3 to 4 seconds after exposure to the heat of the bulb. The protected endpoint is 10 seconds. Each mouse is tested half an hour and two hours after treatment with morphine and test substance. Morphine has a Pour value of 3.2 to 5.6 mg / kg (s.c.).

(c) Tail immersion test

The modified method described by Benbasset et al. in Arch. int. Pharmacodyn, 122, 434 (1959). Male Charles River CD-1 white mice, weighing 19-21 g, are weighed and labeled for identification. Usually, five mice are used to treat the same substance and control animal. First, each test substance is administered in an amount of 56 mg / kg intraperitoneally or subcutaneously in the form of 10 ml / kg. Each mouse is placed in a roller before treatment with each drug, and half an hour and two hours after administration. Each cylinder is provided with apertures for adequate ventilation and is closed with a nylon plug through which each mouse is drawn through its tail.

The cylinder is held upright and the tail is fully immersed in a water bath at a constant temperature of 56 ° C. The end point of each test is an energetic jerk or tail twitch associated with a motor response. In some cases, the endpoint may be less pronounced for administration of the active agent. To prevent unwanted tissue damage, each test is terminated within 10 seconds and the tail is removed from the bath. The response shall be recorded in seconds to the nearest half second. The carrier and the standard of known efficacy are tested simultaneously with the selected individuals. If the activity of the test drug does not return to baseline in the test after two hours, the response is determined at 4 hours and at 6 hours.

The last measurement was carried out after 24 hours if efficacy was still observed at the end of the test day.

Test based on stimulus to capture harmful chemical stimuli

Suppression of Winding Induced by Phenylbenzoquinone

A group of five Carworth Farma CF-1 mice are pretreated subcutaneously or orally with brine, morphine, codeine, or test drug. In the case of subcutaneous treatment of 20 minutes, in the case of oral administration at 50 minutes, each group is treated by intraperitoneal injection of phenylbenzoquinone; it is known that this irritation causes abdominal contractions. The mice are observed for 5 minutes with respect to whether or not they are wound from 5 minutes after the phenylbenzoquinone injection. It is recorded after treatment with the winder blocking agent.

Test based on stimulus to capture harmful pressure stimuli

Influence of Haffner's tail grip

Modified Haffner Tests, described in Experlmentelle Prüfung Schmerzstillender, Deutsch. Copper. Wschr.,

55, pp. 731-732 (1929) is used to determine the effect of a test drug on the aggressive tail-induced response. White male Charles River / Spregue-Dewlex / CD are used in this assay. A 63.5 mm John Hopkins clamp is then clamped to the root of the rat tail at half an hour, an hour, two and three hours after treatment with the test drug. The end point of each test is a clear attack and biting directed against the cause of the pain, which is recorded in seconds. The clamp is removed after 30 seconds if no response is observed and the response time is recorded in seconds. Morphine is effective at a dose of 17.8 mg / kg (i.p.). Test based on stimulus to capture harmful electrical stimuli.

Reversing test - rebound.

The modified assay described by Tenen in Psychopharmecologia, 12, pp. 278-285 (1968) is used to determine the pain threshold. Male white Charles River / Sprague-Dawley / CD rats weighing 175-200 g are used in this test. Prior to drug administration, each rat was immersed in a 20% glycerin-brine solution.

Rats are placed in the chamber and treated with one-second shocks on their paw, which develop with increasing intensity at 30 second intervals. These intensities are 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.

Observe the behavior of each rat with respect to (a) backing, (b) squeaking, and (c) bouncing or moving fast forward after inducing an electric rival. A series of increasing intensities are treated on each rat prior to treatment with the test compound and at half an hour, two hours, four hours, and 24 hours after treatment with the test compound.

The shore test results are recorded as a percentage of the maximum possible effect (% MMU). The percentage of the maximum possible effect of each group is statistically compared to the percentage of the maximum possible effect of the standard and pre-drug values. The percentage of the maximum possible effect is calculated using the relation:

test start time - inspection time% MMU · = - x 100 test end time - inspection time

The compounds of the formula (II) prepared according to the process of the invention and the products made therefrom, when used as analgesics for oral or parenteral administration, are generally used in the form of preparations. Such compositions comprise a pharmaceutically acceptable carrier selected with respect to the mode of administration and with respect to conventional pharmaceutical practice.

For example, the active ingredient prepared by the process of the invention and the products made therefrom may be administered in the form of tablets, pills, powders or granules containing excipients such as starch, milk sugar and certain types of clay. They may be administered in the form of bands in admixture with the same or equivalent excipients. They can also be administered in the form of oral suspensions, solutions, emulsions, syrups and elixirs, which may contain flavoring and coloring agents. Tablets or bands containing from 0.01 to about 100 mg of the active ingredient are suitable for oral administration of the active ingredients prepared according to the invention from the products made therefrom: in most cases such doses are suitable.

The analgesic activity of some compounds of formula (II) and products prepared therefrom are determined by the methods described above. These compounds have the general formula.

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The analgesic activity of certain compounds of formula (II) and products prepared therefrom is determined by the methods described above. The compounds of the general formula:

In table ae it uses these abbreviations:

PBQ phenylbenzoquinone induced writhing, TP tail flick,

HP hot plate test,

HTC tail grip rate,

FJ dodging

Table II

MMtf ₅₀ mg / kg «3 AND (B) PBQ HTC HIM - H OH 5.60 HIM """ H OH- 13.90 39.2 MO mni OH H 5.80 > 56 NC - H OH 7.20 HOCH ^ bfc ~ H OH 1,21 3.34 NC. 0. 2.87

PBQ means phenylbenzoquinone-induced writhing

HTC refers to the degree of tail tightness, the efficacy of compounds prepared from compounds of formula II against vomiting is determined in non-anesthetized, unrestricted cats as described in Proc. Soc. Exptl. Biol. and Med., 160, pp. 437-440, 1979.

The compounds of formula (II) and the products prepared therefrom are effective against vomiting by oral administration or by parenteral administration in the form of pharmaceutical preparations. Such formulations comprise pharmaceutically acceptable carriers selected with respect to the mode of administration and the pharmaceutical practice. For example, they may be administered in the form of tablets, pills, powders, or granules containing excipients such as starch, milk sugar, certain types of clay, and the like. They may be administered in the form of capsules in admixture with the same or equivalent excipients. They may also be administered in the form of oral suspensions, dispersions, solutions, emulsions, syrups and elixirs, which may contain flavoring and coloring agents. For the administration of therapeutic compositions containing products prepared from compounds of Formula II, the tablets or capsules contain from about 0.01 to about 100 mg of the active ingredient: such compositions are suitable for most uses.

The physician determines the doses that are most appropriate for each patient and controls their age, weight, response and route of administration. In general, however, the initial analgesic dose for adults is about 0.1 to about 750 mg per day in single or divided doses. Suitable oral doses are about 1.0 to 300 mg / day. Dosages of about 1.0 to 50 mg / day are preferred. A preferred parenteral dose is about 0.1 to about 100 mg / day: about 0.1 to about 20 mg / day is preferred.

!>

Thus, the compounds of formula (II) prepared by the process of the invention are suitable intermediates for the preparation of enalgesically active substances administered in the form of pharmaceutical compositions, including unit dosage forms. The dosage form may be a single dose or a plurality of doses to achieve a daily amount for appropriate purposes.

The compounds of formula (II) may also be used as intermediates for the preparation of active compounds for the formulation of liquid or solid preparations for oral or parenteral administration. Capsules containing the active ingredient are prepared by mixing one part by weight of the active ingredient with 9 parts of an excipient such as starch or milk sugar and filling the gelatin capsule mixture so that each such gelatin capsule contains 100 parts of the mixture.

Tablets containing the active ingredient are prepared by formulating a suitable mixture of the active ingredient and standard ingredients used in the preparation of tablets, such as starch, binders and lubricants, so that each tablet contains about 0.1 to 100 mg of the active ingredient.

Example 1

Cis-3- [2-benzyloxy-4- [1,1-dimethylheptyl] phenyl] trans-4- (3-hydroxypropyl) cyclohexanol

To a mechanically stirred solution of 2.0 g (4.46 mmol) of cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] trans-4- (2-propenyl) cyclohexanol in 20 ml of tetrahydrofuran at temperature 9 ml (8.92 mmol) of borantetrahydrofuran complex (111 in tetrahydrofuran) were added at 0 ° C. The reaction mixture was allowed to warm to 25 ° C and then stirred for 30 minutes at 25 ° C. The reaction mixture was cooled to 0 ° C and oxidized by addition of 1 mL of water, 2.66 mL (5.34 mmol) of 2N sodium hydroxide solution and 0.92 mL (10.7 mmol) of 30% hydrogen peroxide. The reaction mixture was allowed to warm to 25 ° C, stirred for 35 minutes and added to 200 mL of saturated sodium chloride solution and 200 mL of ether. The ether extract was washed twice with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a fume hood to give an oil. The crude oil was purified by column chromatography on 40 g of silica gel, eluting with ether to give 2.0 g (96%) of the title compound as an oil.

IR / CHCl j / 3623, 3425, 1623 and 1580 cm ^- '

MS (m / e) 466 (M ^& lt ^{; +} & gt ^; ), 448, 381, 363, 358, 357, and 91

TMS 0.82 (m, terminal methyl), 1.24 (s), gem dimethyl (2.90) m, benzylic

CDCl3 methine, 3.2-3.9 (m, carbinol tin e methylene), 5.08 (s), benzylic methylene), 6.86 (d, J = 2 Hz, ArH), 6.86 (d, J = 8 and 2 Hz, ArH / and 7.05 (d, J = 8 Hz, ArH).

Example 2

Trans-3- (2-benzyloxy-4- (1,1-dimethylheptyl) phenyl) -4- (2-propenyl) cyclohexanone ethylene ketal

A mixture of 17 g (38.1 mmol) of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-propenyl) cyclohexanone, 47.2 g (0.762 mol) of ethylene glycol and 250 g mg of p-toluenesulfonic acid monohydrate in 200 ml of benzene was maintained at reflux for three hours using a Dean-Stark trap. The reaction mixture was cooled and added to 20 ml of 1H sodium hydroxide solution, 100 ml of ether and 100 ml of pentane. The organic extract was washed twice with 200 ml portions of water, twice with 200 ml portions of saturated sodium chloride solution, dried over magnesium sulfate and evaporated (in a fume hood) to give the title compound in quantitative yield.

IR (CHCl3) 1656, 1626 and 1587 cm ^{@ -1}

MS (m / e) 490 (t ₊ ), 475, 450, 449, 448, 446, 407, 405, 399, 383, and 91

TMS

PMR ό 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.1 (m, benzylic ^CDCl 3 meth), 3.90 (s, ethylene ketal), 4.6 to 5, 0 and 5.2 to 6.0 (m, vinyl H),

5.07 (s, benzylic methylene), 6.81 (d, J = 2 Hz, ArH), 6.81 (ddm),

J = 8 and 2 Hz, ArH / and 7.02 (d, J = 8 Hz, ArH).

In a similar manner, 45 g (9.8 mmol) of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-propenyl) cyclohaptanone was converted to trans- 3- [2-benzyloxy-4- [1,1-dimethylheptyl] phenyl] -4- (2-propenyl) cycloheptenone ethylene ketal, which was obtained as an oil.

IR / CHC1 _3/1 650 1613, 1550, 1504 and 1460 cm ^-1

MS (m / e) 504 (M _& lt _{; +} & gt _; )

PMR δ

TMS cdci ₃

0.80 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.20 (m, benzylic methine), 3.80 (bs, ethylene), 4.6-6.0 (m), olefinic (5.07 (e, benzylic methylene), 6.85 (m &lt; 2 > ArH), 7.02 (d, &lt; 1 &gt; Hz), ArH / [beta] &gt; 38 (m, PhH).

Example 3

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

A mixture of 4.0 g (9.56 mmol) of trans-3- 4- (1,1-dimethylheptyl) -2-hydroxyphenyl-4- (3-hydroxypropyl) cyclohexanone ethylene ketal, 50 ml of 2N hydrochloric acid and 100 ml of tetrahydrofuran is kept at the reflux temperature for two hours. The reaction mixture was cooled and added to 500 mL of saturated sodium chloride solution and 250 mL of ether. The ether extract was separated and washed once with 500 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to an oil (fume hood). The crude oil was purified by column chromatography on 200 g of silica gel eluting with 80% ether-hexene to give 2.93 g (82% of theory) of the title compound as an oil.

IR / CHC1 _3/3 521 3333, 1709, 1616 and 1567 cm ¹

MS (m / e) 374 (M +), 356, 289, 273, 247, 203, and 161

TMS

PMR 6 0.82 (m, terminal methyl), 1.28 (s, gem dimethyl (3.76) m, alcoholic methylene), 6.8 (9, ArH) and 6.99 (d, J = 8 Hz) , ArH /.

Similarly, the following compounds are obtained from the appropriate ketals:

I • Η

G a

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I • rl r4 • H «

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X ⁺ a

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Honors Honors o - o

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CD t \ b — 1 * * * CM CM >> >> >> >> IA IA IA IA IA IA IA IA IA IA IA

X3 o X5

Θ O 'S Φ AJ Ai h0 r-1 O

CO · Η a W «o b CO (M vo

Q · - n ffi \ ov in w-mtrvfvrb cvi σν «- b

IA xt VO VO tA γί m v - to • 1-1 o

hO to P

VO b> σν oo to A C to r — I

Ϊ?

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CDCl-β-MR δ

Example 4

Trens-3- [R-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-oxoethyl) cyclohexannonethylene ketyl

17.0 g (34.7 mmol) of trans-3-β-2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-propenyl) cyclohexenonethylenketel, 44.5 (0.208 mmol) of sodium meteperiodate. and 176 mg (0.69 mmol) of OsO2 in 340 ml of tetrahydrofuran and 100 ml of water are stirred at room temperature for 3.5 hours. The reaction mixture was then added to 1000 mL of 15% sodium sulfite and 1000 mL of age. The organic phase is separated, washed twice with 500 ml of saturated sodium bicarbonate solution each time, dried over magnesium sulphate and evaporated (in a fume hood). The residue was purified by column chromatography on 400 g of silica gel eluting with 33-75% ether-petroleum ether to give 10.0 g (59% of theory) of the title compound as an oil.

IR ZCHC1 _3/1 730, 1621 and 1577 cm ¹

MS (m / e) 492 (M ^& lt ^{; +} & gt ^; ), 464, 448, 407, 401, 357, 339, 332, 319, 317, 271, and 91.

0.83 (m, terminal methyl), 1.23 (a, gem dimethyl), 3.2 (m, benzylic meth, 3.94 (s, ethylene ketal), 5.10 (a, benzylic methylene), 6, 85 / d,

J * 8 and 2 Hz, ArH /, 6.85 (d, J = 2 Hz, ArH), 7.07 (d, J = 8 Hz, ArH), and 9.57 / t, J with 1.5 Hz, CHO.

Further elution gave 5.53 g of a mixture of the two compounds. This mixture was dissolved in 500 ml of ether, washed with 4 x 250 ml of 1N sodium hydroxide solution. The ether phase was washed with magnesium sulfate and evaporated (in a fume hood) to give 2.7 g of an oil. This oil was further purified by column chromatography on 100 g of silica gel eluting with 50% ether-pantane to give 2.16 g (12% of theory) of trans-3- 2-benzyloxy-4- (1,1-dimethylphthyl) phenyl- 4- (3-hydroxy-2-oxopropyl) cyclohexanone ethylene ketal as an oil. This basic extract was acidified with ice-cold 6N hydrochloric acid and extracted with 500 ml of ether. The ether extract was washed twice with 200 ml of water, once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give 2.4 g of an oil which was purified by column chromatography on 100 g of silica gel, eluting with 33% ethyl acetate. pentane to give 1.51 g (9% of theory) of trens-3- [2-bezyloxy-4- (1,1-dimethylpeptyl) -phenyl] -4-carboxymethyl] cyclohexanone ethylene ketal.

Trans-3- (2-benzyloxy-4- (1,1'-dimethylheptyl) phenyl) -4- (3-hydroxy-2-oxypropyl) cyclohexanone ethylene ketal:

IS / CHCl j / 3484, 1724, 1613 and 1575 cm ¹

MS (m / e) 522 (t ⁺ ), 491, 448, 432, 407, 358, 99, 91, and 86

IMS? MS 8 0.82 (terminal methyl), 1.22 (s, gem, dimethyl), 2.17 (t, methylene alpha ^CDCl 3, not ketone), 2.88 (t, -J = 5 Hz), OH (3.82), overlap 3.90 (3.90) s, ocylene (5.03) and benzylic methylene (6.83 (m, ArH), 7.02 (d)) = 8 Hz, ArH / and 7.40 (m, PhH)

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

1H, 'CRCi 3 636 to 2 273 (broad), 1 724, 1 6? 1 and 1 487 cm ^-1

MS (m / e) 508 (M ^& lt ^{; +} & gt ^; ), 449, 424, 418, 403, 402, 99, 9! »36

243480 20

TMS

PMR 8 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.2 (m, benzylic ^GDC1 3 meth), 3.93 (s, ethylene), 5.10 (s), benzylic methylene / 6.85 (m, ArH),

7.10 (d, J = 8 Hz), ArH] and 7.41 (m, PhH).

Similarly, by oxidation of 2.60 g (5.80 mmol) of cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] trans-4- (2-propenyl) cyclohexanol, and yielding 1.4 g (54 g). % of theory (cis -3- 2-benzyloxy-4- (1,1-dimethylheptyl) phenyl trans-4- (2-oxoethyl) cyclohexanol); 409 mg (15% of theory).

cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] trane-4- (3-hydroxy-2-oxypropyl) cyclohexanol and 120 mg (4.9%) eie-3- [2- benzyloxy-4- (1,1-dimethylheptyl) phenyl] trans-4- (carboxymethyl) cyclohexanol.

2-Oxoethyl compound:

Ife / CHC1 _3/3 610 3425, 1623 and 1582 cm _'!

MS (m / e) 450 (M ^& lt ^{; +} & gt ^; ), 422, 405, 365, 359, 342 and 91

TMS

PMR 8 0.82 (m, terminal methyl), 1.23 (s, gem dimethyl), 3.00 (m, benzylic meth)

CDCl 3 ζ, ΊΟ / m, carbinol whisk, 5.09 (s, benzylic methylene), 6.88 (d),

J = 2 Hz, ArH / 6.88 (ad, J = 8 and 2 Hz, ArH), 7.10 (d, J 8 Hz, ArH),

7.40 (s, PhH) and 9.53 (t, J = 1.5 Hz, CHO).

alpha-hydroxyketone:

IR / CHC1 _3/3 448 1721, 1618 and CA 1580 ~ ¹

MS (m / e) 480 (M ^& lt ^{; +} & gt ^; ), 466, 450, 449, 406, and 91

TMS

PMR 8 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.75 (m, carbinol)

Metin CDC1 ₃ /, 3.86 / bs, hydroxymethylene /, 5.08 /, and, benzylic methylene /, 6.95 / m, Ar-H /, 7.05 / d, J «8 Hz, Ar-H and / 7.38 / s, PhH /

Acid:

Rf = 0.32 (0.25 mm, silica gel - ether)

In a similar manner, 3,4-trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -5-methyl-4- (2-propenyl) cyclohexanone ethylene ketal is oxidized to the corresponding 4- / 2- oxoethyl / cyclohexanone ethylene ketal is oxidized to the corresponding 4- (2-oxoethyl) cyclohexanone derivative. The corresponding 4- (3-hydroxy-2-oxopropyl) and 4- (2-carboxymethyl) cyclohexanone derivatives are also prepared.

Example 5

Trans-3- (2,4-dibenzyloxyphenyl) -4- (2-propenyl) cyclohexanethyl ketal

A mixture of 5.0 g (11.73 mmol) of trans-3- (2,4-dibenzyloxyphenyl) -4- (2-propenyl) cyclohexanone,

6.5 ml (117 mmol) of ethylene glycol and 223 mg (1.17 mmol) of p-toluenesulfonic acid in 50 ml of benzene are maintained at reflux for 1.5 hours. Water is removed in a soxhlet extractor filled with molecular sieve. The reaction mixture was cooled and added to 500 mL of saturated sodium bicarbonate solution and 300 mL of ether. The ether phase is separated, dried over magnesium sulphate and evaporated. Trituration with diisopropylether-hexane gave 5.31 g (96%) of the title compound.

Melting point 112-113 ° C.

HHIS / m / e / 470, 2520 / M ^+, Calcd for C3, H34O4: 470/2448 /, 387, 379, 303, 181 and 91 Analysis for C3i ^H 34 ° 4:

H, 7.28. Found: C, 79.13; H, 7.02

Example 6

Trans-3,4-trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-hydroxypropyl) -5-methylcyclohexanone ethylene ketal.

To a mixture of 25 ° C containing 3.28 g (10.3 mmol) of mercuriacetate in 50 ml

50% aqueous tetrahydrofuran was added with 5.2 g (10.3 mmol) of trans-3,4-trans-4,5-2-benzyloxy-4- (1,1-dimethylheptyl) phenyl-5-methyl-4-. Of 2-propenyl / cyclohexanone ethylene ketal in 25 mL of tetrahydrofuran. An additional 25 ml of water was added to the auxiliary solution and stirred. An additional 1.5 β (4.7 mmol) of mercuric acetate ee is added in 2 hours and 24 hours. The reaction mixture is stirred for a total of 64 hours at 25 ° C and then reduced by adding 20 ml of 3N sodium hydroxide solution and 20 ml of 0, 5U sodium hydroxide solution. The reaction mixture is stirred for an additional 30 minutes and then added to 250 ml of ether and 300 ml of saturated sodium chloride solution. The ether extract was dried over magnesium sulfate and evaporated to an oil.

The crude product was purified by column chromatography on 300 g of silica gel eluting with 50% ether-hexane to give 1.5 g (30%) of the title compound as an oil.

HBMS (m / e) 522, 3712 (M ⁺⁾ , calculated for C ₃₄ H ₅₀ ^O 4 ^: 522.3 696 /, 431, 407, 372, 113 and 9 (100%).

PMR (CDCl3 ₎ (0.75) m, terminal methyl), 0.92 (d, J = 6 Hz, C-5 methyl), 1.24 (s, gem dimethyl), 3.35 (bm), carbinol and byzylic methylenes (3.90 (bs, ethylene ketal), 5.03 (s), benzylic methylene) and 6.6 to 7.5 (m, ArH).

Trans-3,4-trans-4,5-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-hydroxypropyl) -5-methyl-cycloheptanone ethylene ketal is also prepared in this manner from the corresponding 4 - (2-Propenyl) cycloheptanone ethylene ketal.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of the novel 3- 2-hydroxy-4- (substituted) (phenyl-4) or 5- (substituted) cycloelkanones of the general formula (11): Hj is a hydrogen atom, a benzyl group, an alkanoyl group having 1 to 5 carbon atoms, an integer of 1 or 2, A group of the general formula -CH (R ₂₎ (CH (R ₂ )) or of the general formula -CH (R 3) / CH ₂ -, where is R 1 is a hydrogen atom or a methyl group, Rg ⁰ hydroxyalkyl group having 1 to 6 carbon atoms, R 1 is a C 1 -C 3 hydroxyalkyl group, W is a hydrogen atom, a pyridyl group, or a group of the formula ^W 1 wherein is W, hydrogen, chlorine or fluorine, provided that when W is hydrogen, Z is (a) an alkylene group of 5 to 13 carbon atoms; or b) - / ALK / _ln -O- / alk ₂ / _n where each is / alk / a / alk ₂ / alkylene group having 1 to 13 carbon atoms, each of m and n is zero or 1, provided that the sum of carbon the carbon in (alkj) plus (alkg) is at least 5 and at most 3, and that at least one of m and n is 1, and provided that when W is not hydrogen, it is Z (a) C 3 to C 8 alkylene; or b) - (alkj) - (O) - (alk), (a) wherein each is an (alkj) and (alkg) alkylene group having 1 to 8 carbon atoms, each man zero or number 1, provided that the sum of the carbon atoms v (alk) (plus) alkg) is at least 3 and at most 8 and that at least one of m and n is 1, characterized by catalysing a compound of formula IIB wherein s, Rp Z and W are as defined above and wherein Y is a group of the general formula -CH / R ₂ / CH / R ₂ ° / - or -CH / R ₃ ° / CH ₂ wherein R is as defined above and wherein R ₂ ° and R ⁰ represents an alkenyl radical and at most 6 carbon atoms, thus formed The ketal is hydrated by hydroboration oxidation at 0-50 ° C in a reaction inert solvent or by organomercuration and demeruration using mercuric acetate in a reaction inert solvent at ambient temperature, whereupon the hydroxy-mercury intermediate sodium borohydride is reduced and the ketal protecting group is removed. 2. The process according to item 1 for the preparation of 3- [2-hydroxy-4- (substituted) phenyl] -4) or 5- (substituted) cycloalkanones of the general formula II, wherein s, Rp Z and W have the meanings given in e where it means X * a group of the general formula -CH ₂ CHB ₂ ° - or -CH / R ₃ ° / CH ₂ wherein each R ₂ ° and R ₃ ° represents a hydroxyalkyl group of at most and 6 carbon atoms, characterized in that the compound of formula 11B is hydrated, wherein s, R p Z and W are as defined above and where is X is a group of formula -CHgCH / RG ⁰ - or -CH / R / CHgkde represents each R ₂ ° and R ° ₃ alkenyl group with at most 6 carbon atoms. 3. Process according to claim 1 for preparing compounds of formula II where p s, Z, W are as defined above, wherein R g and R ⁰ means respectively ₃ ° oxoalkyl having not more than 6 carbon atoms, wherein the oxidation of a compound of general of formula IB, wherein s, Rp Z and W are as defined above and a X. represents a group of the general formula -CH / R ₂ / CH / R ₂ ° / - or -CH / R ₃ ° / CH ₂ wherein R g is as defined above and each R ₂ ° and R ₃ ° represents an alkenyl group of not more than 6 6 sodium metaphosphate and catalytic the amount of osmium tetroxide in a solvent inert to the reaction at 10 to 80 ° C. 4. The process of item 3 for preparing a compound of formula 11 wherein s, Rp and W are as defined in item 1 and wherein X 'is a group of formula CH ₂ CH / R ₂ ° / or -CH / R ₂ ° / GH ₂ wherein each Hg ⁰ and R ₃ ° represents an oxoalkyl group of at most β 6 carbon atoms, characterized in that a compound of formula IIB is oxidized wherein s, Rp Z and V are as defined above and where is X is a group of formula -CH ₂ -CH / R ₂ ⁰ / - or -CH / R ₃ ° / CH ₂ wherein each R ₂ ° and R ° ₃ represents an alkenyl group having not more than 6 carbon atoms.