CS243480B2 - A process for preparing new 3- [2-hydroxy-4- (substituted) phenyl] -4 or 5- (substituted) cycloalkanones - Google Patents

Abstract

They also prepare intermediates for analgesic active substances and for antiemetics. The compounds prepared have the general formula Ø, hydrogen, benzyl, alkanoyl β 1 to 5 carbon atoms, and the number 1 or 2, and Y group -CH/Rj^/CH/Rj /- hebo -CH/R^/CH,,- where R2" means hydrogen or methyl, Rj0 hydroxyalkyl with 1 to 6 carbon atoms, Rj° hydroxyalkyl with 1 to 3 carbon atoms, V hydrogen, pyridyl group or group where each /alk,/ and /alk»/ means alkylene and 1 to 13 carbon atoms and each ft and n is zero or the number 1, provided that the sum of carbon atoms in /alk,/ plus /alk,,/ is at least 5 and at most 13 and that at least one of the symbols m and n means 1, and provided that v occurs when W does not mean hydrogen, Z means a/ alkylene with 3 to 8 carbon atoms or b/ -/alk,/m-0-/alk2/, where each /alk,/ and /alkg/ represents an alkylene with 1 to 8 carbon atoms and each man represents zero or the number 1, provided that the sum of the carbon atoms in /alk,/ plus /alkj/ is at least 3 and at most 8 β ϊβ and at least one of the symbols man represents the number 1.

Description

The invention relates to a process for the preparation of novel 3-[2-hydroxy-4-substituted-phenyl]-4- or 5-substituted-cycloalkenones which are suitable for the preparation of the corresponding cycloalkenols and their derivatives which are effective as analgesics and antiemetics.

Despite the current availability of numerous analgesic agents, new and improved agents are still being sought for the control of a wide range of pain and discomforts with minimal side effects. The most commonly used agent, aspirin, which is an acetylsalicylic acid-based agent, is of no practical use against severe pain and is known to have various undesirable side effects. Other analgesic agents, such as meperidine, codeine and morphine, exhibit a habit-forming effect. The need for an improved and effective analgesic agent is therefore clear.

Compounds useful as analgesics, as tranquilizers, as sedatives, as antianxiety agents and/or as anticonvulsants, as diuretics and as antidiarrheal agents are described in Belgian Patent Application Nos. 870,404 and 870,402, both filed on March 12, 1979. Belgian Patent Application No. 870,404 describes 3-[2-hydroxy-4-(substitutional)phenyl}cyclohexanones and cycloalkanols which may have an alkyl, alkenyl, phenyl or phenylalkyl substituent in the 4-position of the cycloalkenone or cycloalkanol radical; or may have an alkyl substituent in the 5-position. Belgian Patent No. 670,402 describes certain phenols substituted in the 2-position with acyclic substituents, in particular it describes 2-(hydroxyalkyl)-4-substituted phenols and 2-(oxyalkyl-4-substituted) phenols.

U.S. Patent No. 3,576,887, issued April 27, 1971, describes a series of 1-(1'-hydroxy)alkyl-2-(o-hydroxyphenyl)cyclohexenes which have central nervous system depressant properties.

The pharmacological activity of 4-(2-hydroxy-4-(substituted)phenyl)naphthalen-2-ols and 4-(2-hydroxy-4-(substituted)phenyl)naphthalen-2-ols is also known, and they are useful as agents affecting the central nervous system and as antiemetics.

U.S. Patent No. 3,974,157 describes 2-phenylcyclohexanones, which may have up to two substituents on the phenyl ring from the group consisting of alkyl, hydroxy or sulfoxy, as intermediates for the preparation of 1-(aminoalkyl)-2-phenylcyclohexanol, which is useful as an analgesic, a local anesthetic and an antiarrhythmic agent.

In the journal Chemical Abstracts fifi, 176 952 f /1976/, reference is made to numerous 3-phenyl and 3-phenylalkylcyclohexanones as intermediates for the preparation of 2-aminomethyl-3-phenylcyclohexanones or 2-aminomethyl-3-phenylalkylcyclohexanones, which have analgesic and aedative effects and which can also be used as antidepressant and anticonvulsant additives.

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

where means where means

R, a hydrogen atom, a benzyl group, an alkanoyl group with 1 to 5 carbon atoms, with the integer 1 or 2,

Y' group of general formula

-ch/r ₂ /ch/r ₂ °/ or the general formula ch/r ₃ °/ch ₂ , where means

R ₂ is a hydrogen atom, a methyl group, a C 2 -C 6 hydroxyalkyl group with 1 to 6 carbon atoms,

R ₃ ° hydroxyalkyl group with 1 to 3 carbon atoms

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

where means

W| hydrogen atom, chlorine atom or fluorine atom, provided that in the case where W represents a hydrogen atom, Z represents a/ alkylene group having 5 to 13 carbon atoms or a b/ -/alk ₁ / _n -O-/alk ₂ / _n group, where each /alk,,/ and /alkg/ alkylene group means 9 1 to 13 carbon atoms, each man is zero or the 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 the symbols man is 1, and provided that in the case where W does not represent a hydrogen atom, Z represents a/ alkylene group β 3 to 8 carbon atoms or a b/ -/alkj/^O-Zalkg/jj group, where each /alk,/ and /alkg/ alkylene group means 1 to 8 carbon atoms, each man is zero or the number 1, provided that the sum of carbon atoms in /alk,/ plus /alk ₂ / is at least 3 and at most 8 and that at least one of the symbols man means 1»

The Y* group has a variable position in the cycloalkyl moiety in the sense that &2° is always a substituent at position 4 and each Rg and R^ ⁰ is always a substituent at position 5.

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. In general, compounds in which W represents a pyridyl group and/or the group OR^ represents a basic ester moiety are suitable for the preparation of such acid addition salts.

Compounds of general formula II which have 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 R1 is hydrogen, are generally in equilibrium with their hemiketal forms in solution. The ketoforms and hemiketal forms of compounds of formula II are included within the scope of the invention.

Compounds of general formula II contain asymmetric centers at the 3,4,5 positions of the cycloalkyl moiety and may contain additional asymmetric centers at the (-Z-W) portion of the phenyl nucleus.

The ®trans relationship of the substituents in position 3 β 5 β 3 · 5 in the cycloalkyl moiety is more advantageous, since in these cases a quantitatively greater biological effect of the active substances preparable from the products according to the invention having this configuration is achieved.

In the above figures, racemic compounds are indicated. Formulae II are, however, considered to be general and include racemic modifications of the compounds prepared by the process of the invention, diastereomeric mixtures, pure enantiomers and diastereomers. The utility of racemic mixtures, diastereomeric mixtures and mixtures of pure enantiomers and diastereomers is determined by biological evaluation, which is described hereinafter.

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

and

In view of the greater biological activity of the compounds which can be obtained with the compounds prepared by the method according to the invention, preferred compounds are of the general formula II wherein R ₍ is a hydrogen atom, Rg is a hydrogen atom or a methyl group, each Rg ⁰ and R^ ⁰ is a hydroxyalkyl group and Z and W have this meaning;

Z m n alkylene group with 7- to 11 carbon atoms

Z an alkylene group with 4 to 7 carbon atoms ./alki/ _B -O-/elkg/ _n w

hydrogen atom

In the group of general vsoree

-hQHw, or pyridyl group a group of general vsoree —<ζθ^—w,

0.1 1 or a pyridyl group, wherein each /alkj/ and /alkg/ represents an alkylene group and 1 the condition that the sum of the carbon atoms in /alkj/ and /alkg/ is at least 5 to 7 carbon atoms, and at most 7,

-/8lk,/ _m -O-/elkg/ _n 0.1 hydrogen atom, wherein each /alkj/ and /alkg/ represents an alkylene group and 1 .conditions that the sum of carbon atoms in /alk^/ and /alkg/ is at least 7 to 11 carbon atoms, and at most 11.

Preferred are compounds of general formula II, where means

Rg and Rj are always hydrogen atoms,

Z group of the formula C/CH^/g/CHg/g a

W hydrogen atom,

Z an alkylene group with 4 to 7 carbon atoms and

W is a phenyl group;

FROM

W

From w

-O-alkylene group with 7 to 9 carbon atoms and a hydrogen atom,

-O-alkylene group with 4 to 5 carbon atoms and phenyl group, o>-hydroxyalkyl group with 2 to 4 carbon atoms and hydroxyalkyl group.

Particularly preferred compounds of formula IX are those wherein R1, Z and R2 are as defined above for the preferred compounds, ^R3 is 3-hydroxypropyl and R4 is hydroxymethyl. The 1-form of the compounds of formula II is more preferred than the d-form.

Compounds of general formula II, where T* represents a group of general formula

-CH/RgVCH/Sg ⁰ /are prepared from suitable 2-bromo~5-/ZW-substituted/phenols by a series of reactions which involve the first step of protecting 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 lead to undesirable reactions at other sites of the eventual compounds or products prepared therefrom.

Examples of such protecting groups include the phenolic protecting groups described in Haalam, Chapter 4, Protective Groups in Organic Chemistry, 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, alkyl having 1 to 4 carbon atoms, halogen atoms such as chlorine, bromine, fluorine or iodine, and alkoxy having 1 to 4 carbon atoms.

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. However, if Z represents a group of the general formula

-/alk,/ _B -0-/alk ₂ / _n acids such as polyphosphoric or trifluoroacetic acid must be used to prevent cleavage of the shear 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 groups. If the protecting groups are benzyl or substituted benzyl groups, they can be removed by catalytic hydrogenolysis. Suitable catalysts are palladium or platinum, especially on carbon as a support. Alternatively, these protecting groups can be removed by solvolysis using trifluoroacetic acid.

The SalS1 step involves treatment with n-butyllithium in a solvent inert to the β reaction at room temperature.

The exact chemical structure of the protecting group is not of decisive importance in the process of the invention, since its importance is based solely on the ability to be processed in the manner described above. The selection and identification of a suitable protecting group is easy and straightforward for a person skilled in the art. The suitability and effectiveness of a group, for example a hydroxyl protecting group, is determined by using such a group in the reaction sequence being described. However, it should be a group that is readily removed to release the hydroxyl group again.

243480 6

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

The protected 2-bromo-5-(ZW-substituted)phenol is then reacted with magnesium in a reaction inert solvent and generally in the presence of a promoter, such as a metal salt, for example, metal chloride, metal bromide and metal iodide, to promote the 1,4-addition, with a suitable 4-R1-2-cycloalken-1-onene (such as 4-R2-2-cyclohexen-1-onene), ^{where R1} represents an alkenyl group or an alkyl group substituted by a substituent X', where X* represents a group X or a precursor thereof, for example an -O-benzyl group as a precursor of a hydroxyl group or a group of the formula

-CH/OCH ₃ / ₂ or -HCOCI^C^O as a precursor of the -CHO group.

Suitable inert solvents include, 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 at reflux a mixture of one molar proportion of the reagent and two molar proportions of magnesium in a reaction-inert solvent, such as tetrahydrofuran. The resulting mixture is then cooled to a temperature of about 0°C to -20°C. The amount of copper iodide used is not critical and can vary within wide limits. Molar proportions of about 0.2 to 0.02 moles per mole of bromine reagent give satisfactory results in terms of the yield of the cycloalkanone, the phenolic hydroxy group being protected (general formula II, Rj represents a protecting group).

Alternatively, compounds of formula II may be prepared by reacting a suitable 3-(Z-N-eubutylated) phenol derivative, the hydroxy group of which is suitably protected, with a suitable 4- or 5-substituted cycloalk-2-en-1-onene in a reaction-inert solvent at low temperature, for example below -20°C. Suitable protecting groups are the same as those mentioned above, except that the benzyl or substituted benzyl group is removed during the preparation of the lithium 3-(Z-N)-phenol precursor. A particularly suitable protecting group for this method of preparation is the tetrahydropyrenyl group. This tetrahydropyranyl group is readily introduced into the phenolic reactant, is stable under the conditions of subsequent reactions in which the protected compound is used as an intermediate and is readily removed by hydrolysis.

The copper derivative of 3-/Z-W-eubetiminated/phenol ee is prepared from the lithium derivative of this phenol by treating the derivative with copper 1-hexyne. It undergoes 1,4-addition to the conjugated system of the oc-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 to the same compound as the Grignard reaction described above. It generally provides better yields of compounds of general formula II.

Compounds of general formula II, where the individual symbols have the meanings given above, are prepared according to the invention by ketalizing a compound of general formula IIB

O

(II Β) zw where s, R ₁ , Z and W have the meanings given above and where X represents a group of the general formula

-ch/k ₂ /ch/r ₂ °/or

-gh/h ₃ °/ch ₂ where H ₂ has the above meaning and where each R ₂ ° and R ^ ⁰ represents an alkenyl group with up to 6 carbon atoms, the ketal thus formed is hydrated by hydroboration oxidation at a temperature of 0 to 50 °C in a solvent inert to the reaction, or by organomercuration and demercuration using mercuric acetate in a solvent inert to the reaction at room temperature, after which the hydroxymercuric intermediate is reduced with sodium borohydride and the ketal protecting group is removed.

If a suitable 4-R^-2-cycloalken-1-one is not available in the reaction according to the invention, or if it is not easily prepared by methods known per se, a compound of the general formula II is used as an intermediate for all compounds of the general formula II, where ^Rg0 is an oxo-substituted alkyl group with 1 to 6 carbon atoms in the alkyl moiety and in particular ^Rg0 is a formyl group.

Compounds in which Rj, represents an alkenyl group are converted to the corresponding hydroxyalkyl derivatives by hydroboration oxidation using borohydride in tetrahydrofuran or in diglyme at a temperature of 0 to 50°C. The borane intermediate is not isolated but is directly oxidized with slkslic hydrogen peroxide to the alcohol; the alcohols thus produced correspond to the anti-Markovnikov addition of water elements to the double bond.

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

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

The conversion to the ketal is carried out by known methods for ketalization, such as the reaction of 3-(2,4-dihydroxyphenyl)cycloalkanone with an alcohol, especially an alcohol with 1 to 4 carbon atoms, in the presence of an acid, such as sulfuric acid, p-toluenesulfonic acid and hydrogen chloride, under conditions for removing the water formed as a by-product. 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 content of the orthoformic acid ester. Preferred reactants include triethyl orthoformate and methanol together with concentrated sulfuric acid, anhydrous hydrogen chloride or ammonium chloride as a catalyst.

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

WZX where Z and W are as defined above and where X** represents a group selected from the group consisting of chlorine, bromine, methyloxy (CH2SO4O) and tosyloxy of the formula p- _ch3 - _c6h4 - _so2 - _ov in the presence of an acid-binding agent, such as sodium carbonate or potassium carbonate. The alkylated ketal is then deketalized by treatment with acid in a manner known per se.

_The 3-2-hydroxy-4-(O-[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,299,29,29,29,29,29,29,29,29,29,29,29,29,29,29,29

It has been found that compounds of general formula II, where Rg is ^a group of the formula /CHg/^OH, -ZW a group of the formula

-c/ch ₃ / ₂ /ch ₂ / ₅ ch ₃ and R, the benzyl group /C^H?/ can be separated into diastereomers A and B by reaction with d-mandelic acid and p-toluenesulfonic acid in benzene with azeotropic removal of water. Hydrolysis of the d-mandelic esters of diastereomers A and B, for example using potassium carbonate in the methanol-water system, leads to enantiomers A and B.

In a similar manner, the reaction of enantiomers B with 1-mandelic acid and with p-toluenesulfonic acid in benzene with azeotropic removal of water gives the bis-mandlate derivative diastereomer A. Hydrolysis as described above gives enantiomer B. Removal of the benzyl protecting group gives the corresponding enantiomeric alcohols.

Acyl derivatives of compounds of general formula II, where R _f represents a hydrogen atom and each R ₂ ° or R ₃ ° represents a hydroxyalkyl group, are prepared by acylation with a suitable alkanoic acid in the presence of a condensing agent, such as, for example, dicyclohexylcarbodiimide or by reaction with a chloride of a suitable alkanoic acid or by reaction with an hydride of a suitable alkanoic acid in the presence of a base, such as, for example, pyridine. According to the reactivity of the acyl-releasing groups R, the alcoholic hydroxyl group is in first place, then the phenolic hydroxyl group and the secondary hydroxyl group.

Esters of compounds of general formula II, where Rg ⁰ or Rj ⁰ does not contain any acylatable group, are prepared by acylation as described above.

The analgesic properties of the compounds prepared according to the invention of formula II and the products prepared therefrom are determined by tests based on a stimulus capturing noxious stimuli. It is recalled that the compounds of formula II, where R, represents a benzyl group and the products prepared therefrom are not pharmacologically active for the purposes described, but are suitable as intermediates for compounds of formula II, where R, represents a hydrogen atom.

Thermal stimulus-based tests Noxious stimuli

a) Hot plate analgesia test in mice

This method uses a modified test according to Woolf and Mac Donald, described in the journal J. Pharmacol. Exp. Ther. 80. 300-307, 1944, a controlled thermal stimulus is applied to the mouse paw on an aluminum plate 3.175 mm thick. A 250 watt infrared heating bulb is placed under the bottom of the aluminum plate. A thermal controller, connected to a thermistor on the surface of the aluminum plate, is programmed to maintain a constant surface temperature of 57 °C. Each mouse is lowered into a 165 mm diameter glass cylinder resting on a hot aluminum plate, and time is started as soon as the mouse paw touches the aluminum plate. MyS is observed half an hour and 2 hours after treatment with the test compound, taking into account the first twitch of one or both hind paws or when 10 seconds have passed without such movements. Morphine has a value of MMlJ » 4 to 5.6 mg/kg/s.c./. /100 always means the maximum possible effect./

b) Mouse Tail Flick Analgesic Test

A modified test by d'Amour and Smith, described in J. Phermacol. Exp. Ther., 72, pp. 74-79, 1941, is used, using the controlled application of intense heat to the mouse tail. Each mouse is placed on the foot of a metal cylinder with the tail extended at one end. The cylinder is adjusted so that the tail lies entirely on a shaded heating bulb. At the beginning of the test, the aluminum plate covering the heating bulb is removed and a light beam is passed through the slit, the focus being on the mouse's tail. At the same time, a timer is started. A sudden twitch of the tail is recorded. An unconditioned mouse usually reacts within 3 to 4 seconds after exposure to the heat of the bulb. The end point is protected at 10 seconds. Each mouse is tested half an hour and two hours after treatment with morphine and the test substance. Morphine has an oral value of 3.2 to 5.6 mg/kg/s.c./.

c) Tail immersion test

A modified method is used, as described by Benbasset et al. in Arch. Int. Pharmacodyn., 122, p. 434, 1959. A male Charles River CD-1 white mouse, weighing 19 to 21 g, is weighed and marked for identification. Five mice are usually used for treatment with the test substance and a control animal. Each test substance is first administered at a dose of 56 mg/kg intraperitoneally or subcutaneously in the form of 10 ml/kg. Before treatment with each active substance and for half an hour and 2 hours after its administration, each mouse is placed in a cylinder. Each cylinder is provided with holes for adequate ventilation and is closed with a nylon plug through which the tail of each mouse is passed.

The cylinder is held upright and the tail is fully immersed in a water bath at a constant temperature of 56°C. The endpoint of each test is a vigorous twitch or twitch of the tail, associated with a motor response. In some cases, the endpoint may be less pronounced for the administration of the active substance. To avoid unwanted tissue damage, each test is terminated within 10 seconds and the tail is removed from the bath. The response is recorded in seconds to the nearest half second. The vehicle and a standard of known potency are tested simultaneously with the selected individuals. If the activity of the active substance under test does not return to baseline values at the two-hour test, the response is determined at 4 hours and 6 hours.

The last measurement is made after 24 hours if efficacy is still observed at the end of the test day.

Stimulus-based test capturing harmful chemical stimuli

Suppression of writhing induced by phenylbenzochlorine

A group of five Carworth Farma CF-1 mice are pretreated subcutaneously or orally with saline, morphine, codeine or the test substance. Each group is treated with an intraperitoneal injection of phenylbenzoquinone, which is known to induce abdominal contractions, for 20 minutes if subcutaneous, or 50 minutes if oral. The mice are observed for 5 minutes for writhing or not, starting 5 minutes after the phenylbenzoquinone injection. The values after treatment with the writhing-blocking substance are recorded.

Test based on a stimulus capturing noxious pressure stimuli

The influence of the Haffner tail grip method

Modified Haffner tests, described in the publication Experlmentelle Prúfung Schmerzstillender /Experimental testing of painkillers/, Deutsch. Med. Wschr.,

55, pp. 731-732, 1929, is used to determine the effect of the test substance on the aggressive response elicited by tail pinching. In this test, white male Charles River (Spregue-Dewlex) CD rats are used. Before treatment with the test substance and then half an hour, one hour, two and three hours after treatment, a 63.5 mm John Hopkins clamp is clamped at the base of the rat's tail. The end point of each test is a clear attack and biting directed against the cause of pain, this attack being recorded in seconds. The clamp is removed after 30 seconds when no response is observed and the time of the response is recorded in seconds. Morphine is effective at a dose of 17.8 mg/kg (i.p.). The test is based on a stimulus capturing noxious electrical stimuli.

Recoil - rebound test.

A modified test described by Tenen in Psychopharmecologia, 12, pp. 278-285, 1968, is used to determine the pain threshold. Male Charles River white rats (Sprague-Dawley/CD), weighing 175 to 200 g, are used in this test. Before administration of the active substance, the paw of each rat is immersed in a 20% solution of glycerin and saline.

Rats are placed in a chamber and their paws are given one-second shocks that are delivered 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.

The behavior of each rat is observed for a) backing away, b) squeaking, and c) jumping or rapid forward movement after the application of an electric shock. A series of shocks of increasing intensity are applied to each rat before treatment with the test substance and at half an hour, two hours, four hours, and 24 hours after treatment with the test substance.

The results of the shore tests are recorded as a percentage of the maximum possible effect /% MMU/. The percentage of the maximum possible effect of each group is statistically compared with the percentage of the maximum possible effect of the standard values and the values before the administration of the active substances. The percentage of the maximum possible effect is calculated using the relationship:

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

The compounds of formula II prepared by 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 preparations contain a pharmaceutically acceptable carrier selected with regard to the route of administration and in accordance with standard pharmaceutical practice.

For example, the active ingredient prepared by the method 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, lactose and certain types of clay. 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, solutions, emulsions, syrups and elixirs which may contain flavourings and colourings. For oral administration of the active ingredients prepared by the method of the invention and the products made therefrom, tablets or capsules containing from 0.01 to approximately 100 mg of active ingredient are suitable: in most cases such doses are suitable.

The analgesic activity of some compounds of general formula II and products prepared therefrom is determined by the methods described above. These compounds have the general formula •*fr c?

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The analgesic activity of some compounds of the general formula II and products prepared therefrom is determined by the methods described above. The compounds of this general formula are tested:

In the table ae uses the following abbreviations:

PBQ phenylbenzoquinone-induced writhing, TP tail flicking,

HP test on hot plate,

HTC tail grip rate,

FJ jump

Table II

MMtf ₅₀ /mg/kg/ «3 A B PBQ HTC HO — H OH 5.60 HO ««« H OH- 13.90 39.2 MO monks OH H 5.80 >56 NC — H OH 7.20 HOCH^bfc~ H OH 1.21 3.34 NC. 0 . 2.87

PBQ stands for phenylbenzoquinone-induced writhing.

HTC means tail clamp rate. The antiemetic efficacy of compounds prepared from compounds of general formula II is determined in unanesthetized, unrestrained cats as described in the journal 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 when administered orally or parenterally in the form of pharmaceutical preparations. Such preparations contain pharmaceutically acceptable carriers, selected with regard to the route of administration and to pharmaceutical practice. For example, they may be administered in the form of tablets, pills, powders or granules containing excipients such as starch, lactose, certain types of clays 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 flavourings and colourings. For the administration of therapeutic compositions containing products prepared from compounds of formula II, tablets or capsules contain from about 0.01 to about 100 mg of active ingredient: such preparations are suitable for most uses.

The physician determines the dosages most suitable for the individual patient and is guided by his 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; in many cases it is not necessary to exceed a daily dose of 100 mg. Suitable oral doses are about 1.0 to 300 mg/day. Doses of about 1.0 to 50 mg/day are preferred. A preferred parenteral dose is about 0.1 to about 100 mg/day; preferred is about 0.1 to about 20 mg/day.

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

The compounds of general formula II can also be used as intermediates for the preparation of active ingredients 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 lactose and filling the mixture into gelatin capsules 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 tablet excipients such as starch, binders and lubricants so that each tablet contains approximately 0.1 to 100 mg of the active ingredient.

Example 1

Cis-3-[2-benzyloxy-4-[t,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 0 °C was added 9 ml (8.92 mmol) of boranetetrahydrofuran complex (III in tetrahydrofuran). 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 adding 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 sulphate 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 theory) of the desired compound as an oil.

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

MS /m/e/ 466 /M ⁺ /, 448, 381, 363, 358, 357 and 91

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

CDClj methine/, 3.2 to 3.9 /m, carbinol tin e methylene/, 5.08 /s, benzylic methylene/, 6.86 /d, J = 2 Hz, ArH/, 6.86 /d, J = 8 e 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)/cyclohexane 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 mg of p-toluenesulfonic acid monohydrate in 200 ml of benzene was refluxed 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 hood) to give the desired compound in quantitative yield.

IR /CHClj/ 1656, 1626 and 1587 cm ^-1

MS /m/e/ 490 /tó ₊ /, 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 ^CDC1 3 methine/, 3.90 /s, ethylene ketal/, 4.6 to 5.0 and 5.2 to 6.0 /m, vinylic H/,

5.07 /s, benzyl 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, 4.5 g (9.8 mmol) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-propenyl)cyclohaptanone are converted in quantitative yield to trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-propenyl)cycloheptenone ethylene ketal, which is obtained in the form of an oil.

IR /CHC1 ₃ / 1650, 1613, 1550, 1504 and 1460 cm ^-1

MS /m/e/ 504 /M ₊ /

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 to 6.0 /m, olefinic/, 5.07 /e, benzylic methylene/, 6.85 /m> ArH/, 7.02 /d, J»í Hz, ArH/ β 7>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)cyclohexanoneethylene ketal, 50 ml of 2N hydrochloric acid and 100 ml of tetrahydrofuran was refluxed 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 (in a fume hood). The crude oil was purified by column chromatography on 200 g of silica gel eluted with 80% ether-hexene to give 2.93 g (82% theory) of the desired compound as an oil.

IR /CHC1 ₃ / 3 521, 3 333, 1 709, 1 616 and 1 567 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).

In a similar manner, the following compounds are obtained from suitable ketals:

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Example 4

Tris-3-[α-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-[2-oxoethyl]cyclohexanoneethyleneketyl

A mixture of 17.0 g (34.7 mmol) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl)-4-(2-propenyl)cyclohexenone ethylene ketal, 44.5 (0.208 mmol) of sodium meteperiodate and 176 mg (0.69 mmol) of osmium tetroxide in 340 ml of tetrahydrofuran and 100 ml of water was stirred at room temperature for 3.5 hours. The reaction mixture was then added to 1,000 ml of 15% sodium sulfite and 1,000 ml of starch. The organic phase was separated, washed twice with 500 ml of saturated sodium bicarbonate solution, dried with magnesium sulfate and evaporated (in a hood). The residue is purified by column chromatography on 400 g of silica gel eluted with 33 to 75% ether-petroleum-ether to give 10.0 g (59% of theory) of the desired compound in the form of an oil.

IR ZCHC1 ₃ / 1 730, 1 621 and 1 577 cm ¹

MS/m/e/ 492 /M ⁺ /, 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 methine, 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 four 250 ml portions of 1N sodium hydroxide solution. The ether phase was dried over 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 eluted with 50% ether-pentane to give 2.16 g (12% of theory) of trans-3-2-benzyloxy-4-(1,1-dimethyl-heptyl)phenyl-4-(3-hydroxy-2-oxopropyl)cyclohexanoneethylene 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 is 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 is purified by column chromatography on 100 g of silica gel, eluted with 33% ethyl acetate-pentane, to give 1.51 g (9% of theory) of trans-3-[2-benzyloxy-4-(1,1-dimethylpeptyl)-phenyl]-4-carboxymethyl]cyclohexanone ethylene ketal.

Trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl]-phenyl]-4-(3-hydroxy-2-oxypropyl)cyclohexanoneethylene ketal:

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

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

IMS ?MS 8 0.82 /terminal.methyl/, 1.22 /s, gem, dimethyl/, 2.17 /ta, methylene alpha ^CDC1 3 not ketone/, 2.88 /t, -J = 5 Hz, OH/, 3.82 /&, overlap 3.90/, 3.90 /s, otylene/, 5.03 /a, benzylic methylene/, 6.83 /m, ArH/, 7.02 /d, J = 8 Hz, ArH/ and 7.40 /m, PhH/

Trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-carboxymethyl)cyclohexenone ethylene ketal

1H ,'CRCy 3 636 to 2 273 /broad/, 1 724, 1 6?1 and 1 487 cm ^-1

MS /m/e/ 508 /M ⁺ /, 449, 424, 418, 403, 402, 99, 9! » 36

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PMR 8 0.82 /m, terminal methyl/, 1.22 /s, gem dimethyl/, 3.2 /m, benzylic ^GDC1 3 methine/, 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, oxidation of 2.60 g (5.80 mmol) of cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl] trans-4-(2-propenyl)cyclohexanol yields 1.4 g (54% of theory) of 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%) of eie-3-[2-benzyloxy-4-(1,1-dimethylheptyl/phenyl)-trans-4-/carboxymethyl/cyclohexanol.

2-Oxoethyl compound:

Ife /CHC1 ₃ / 3 610, 3 425, 1 623 and 1 582 cm' _!

MS /m/e/ 450 /M ⁺ /, 422, 405, 365, 359, 342 and 91

TMS

PMR 8 0.82 /m, terminal methyl/, 1.23 /s, gem dimethyl/, 3.00 /m, benzylic methine/

CDClj ζ,ΊΟ /m, carbinol broom/, 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, 1 721, 1 618 and 1 580 ca~ ¹

MS /m/e/ 480 /M ⁺ /, 466, 450, 449, 406 and 91

TMS

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

CDCl ₃ methine/, 3.86 /bs, hydroxymethylene/, 5.08 /a, benzylic methylene/, 6.95 /m, ArH/, 7.05 /d, J « 8 Hz, ArH/ 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. In this manner, the corresponding 4-(3-hydroxy-2-oxopropyl) and 4-(2-carboxymethyl)cyclohexanone derivatives are prepared.

Example 5

Trans-3-/2,4-dibenzyloxyphenyl/-4-/2-propenyl/cyclohexaneethyl 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 heated at reflux temperature for 1.5 hours. The water is removed in a Soxhlet extractor filled with molecular sieves. The reaction mixture is cooled and added to 500 ml of saturated sodium bicarbonate solution and 300 ml of ether. The ether phase is separated, dried over magnesium sulfate and evaporated. Trituration with diisopropyl ether-hexane gives 5.31 g (96%) of the desired compound,

Melting point 112 to 113 °C.

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

calculated: C 79.12 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 at 25 °C containing 3.28 g (10.3 mmol) of mercuric acetate in 50 ml

To 50% aqueous tetrahydrofuran was added 5.2 g (10.3 mmol) of trans-3,4-trans-4,5-2-benzyloxy-4-(1,1-dimethylheptyl)phenyl-5-methyl-4-(2-propenyl)cyclohexanoneethylene ketal in 25 ml of tetrahydrofuran. Another 25 ml of water was added to the auxiliary solution and stirred. An additional 1.5 g (4.7 mmol) of mercuric acetate ee was added after 2 hours and after 24 hours. The reaction mixture was 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 0.5N sodium hydroxide solution. The reaction mixture was stirred for a further 30 minutes and then poured into 250 ml of ether and 300 ml of saturated sodium chloride solution. The ether extract was dried over magnesium sulfate and evaporated to give an oil.

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

HBMS /m/e/ 522.3712 /M ⁺ , calculated _{for C34H5O4} ^: 522.3696/, 431, 407, 372, 113 and ⁹ , /100%/

PMR /CDC1 ₃ / 0.75 /m, terminal methyl/, 0.92 /d, J « 6, Hz, C-5 methyl/, 1.24 /s, gem dimethyl/, 3.35 /bm, carbinol and benzylic methyls/, 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-methylcycloheptanone 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.