CS216503B2

CS216503B2 - Method of making the derivatives of the 3-+ l 2-hydroxy-4-subst.phenyl +p cycloalkanons

Info

Publication number: CS216503B2
Application number: CS808072A
Authority: CS
Inventors: Charles A Harbert
Original assignee: Pfizer
Priority date: 1977-09-13
Filing date: 1980-11-24
Publication date: 1982-11-26
Also published as: CS216504B2; CS216505B2; CS216506B2

Abstract

Způsob výroby derivátů 3-(2-hydroxy-4- -subst.fenyljcykloalkanonů. Vynález se týká způsobu výroby derivátů 3-(2-hydroxy-4-subst.fenyl jcykloalkanonů obecného vzorce katalytickou hydrogenací sloučeniny obecného vzorceProcess for producing 3- (2-hydroxy-4- -substituted phenylcycloalkanones. The invention relates to a process for the preparation of derivatives 3- (2-hydroxy-4-substitutedphenyl) cycloalkanones general formula by catalytic hydrogenation of a general compound formula

Description

216503 3 4

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of certain C 5 -C 8 cycloalkanones in a cycloalkyl ring containing a 2-hydroxy-4- (ZW-substituted phenyl group wherein Z is C 1 -C 13 alkylene or the remainder of the - (alk) m - O - (alk 2) n -, wherein each of the man symbols has a value of 0 or 1, and each of the (alki) and (alkz) symbols represents an alkylene group of 1 to 13 carbon atoms, provided the sum of the carbon atoms in the residues (alkij + (alkz) is not higher than 13 and W is hydrogen, phenyl, chlorophenyl, fluorophenyl or pyridyl, their derivatives and the intermediates needed to prepare them.

The aforementioned products are useful as central nervous system agents, in particular as analgesics, tranquilizers, sedatives and anti-anxiety agents in mammals including humans, or / and as anticonvulsants, diuretics and anti-arrheal agents for mammals, including humans. Although a number of analgesics are currently available, there is still a search and better means since there is no agent useful for the treatment of a wide range of pain conditions that would have only minimal side effects. The most commonly used substance, aspirin, is of no practical significance for the treatment of major pains, and is also known to exhibit various undesirable side effects. Other analgesics, such as d-propoxyphene, codeine and morphine, are addictive. From the above, there is a clear need for a better and more effective analgesic.

U.S. Patent No. 3,576,887 (April 27, 71) discloses a series of 1- (1'-hydroxy) alkyl-2-o-hydroxyphenylcyclohexane and -cyclohexene derivatives serving as intermediates for the preparation of 6,6-dialkyltetra -hydro- and hexahydrodibenzo [b, d] pyrans, which can be used as central nervous system depressants.

It has now been found that certain cycloalkanoes containing the 2-hydroxy-4-substituted-phenyl group (see Formula I below) are effective as central nervous system-inducing agents, particularly as analgesics, tranquilizing agents. agents, sedatives and anti-susceptibility agents in mammals, including humans, and / or as anticonvulsants, diuretics and antidiarrheal agents for mammals, including humans. The invention also discloses various derivatives of these compounds which are useful as dosage forms for such compounds, as well as intermediates for the preparation of compounds of Formula 1, including the process for their preparation.

Compounds produced by the process of the invention are those of Formula I, R. zw (wherein R is a saturated or unsaturated cycloalkyl moiety selected from the group consisting of Formulas IA, II-A, IB, II-B, IC, II-C, ID and II-D

(l ~ A)

(11-AJ

(lB) (II-B) (lC) (II-C)

Rtf. SS

wherein the dashed line represents, where appropriate, a double bond present in any of the indicated positions, wherein in the case of the presence of a double bond the radical R 3 may not be present and where 216503 5 A and B together (Formula II) represent an oxo group

R 1 represents a hydrogen atom, a C 1 -C 5 alkanoyl group, a benzyl group, a - P (O) (OH) 2 group and its mono- and di-sodium and potassium salts,

—CO (CH 2) 2 COOH and its sodium and potassium salts, or —CO— (CH 2 JP — NR 5 R 6, where p is 1 to 4, R 8 and R 6 are each independently hydrogen or alkyl of 1 to 4 atoms) carbon, or R 5 and R 6 together with the nitrogen atom to which they are attached form a five- or six-membered heterocyclic ring selected from the group consisting of a piperidine residue, a pyrrole residue, a pyrrolidine residue, a morpholine residue, and an N-alkyl-piperazine a radical containing from 1 to 4 carbon atoms;

R 2 represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 alkenyl group, a phenyl group or a C 1 -C 4 alkyl group, R 3 represents a hydrogen atom,

R 1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, Z represents an alkylene group having 1 to 13 carbon atoms or a radical of formula - (alk 1 - O - (alk 2) n -, where (alki) and (alk?) Mean in each case an alkyl group having from 1 to 13 carbon atoms, provided that the sum of the carbon atoms in the groups (alki) plus (alkz) is not more than 13 aman and is always 0 or 1, and W represents a hydrogen atom, a pyridyl group or a residue of formula 6 tates, salts with mandelic acid and methanesulfonates.

The compounds of the invention which, in the formulas II-A to II-D, in which A and B together form an oxo group and R 1 represent hydrogen, exist in solution in equilibrium with their hemiketal forms. The present invention encompasses both the keto forms and the chemical forms of such compounds of formula (I). The compounds of the present invention are preferred for the trans-arrangement of substituents at 3 and 4, since such compounds exhibit a quantitatively higher biological activity. nity.

For simplicity, the above formulas refer to racemic compounds, but it is to be understood that these formulas are meant to include racemic mixtures of the respective compounds, mixtures of diastereomers, as well as pure enantiomers of the diastereomers. The utility of racemic mixtures, mixtures of diastereomers, as well as pure enantiomers and diastereomers, is due to their biological activity as determined by the procedures described herein.

The compounds of the invention are prepared by catalytic hydrogenation of compounds of the general formula

wherein W 1 represents a hydrogen atom, a fluorine atom or a chlorine atom.

The invention also encompasses pharmaceutically acceptable acid addition salts of the compounds of Formula I which contain basic groups. Typical examples of such compounds are those wherein W is pyridyl and / or OR 1 is a basic ester residue. Of course, in the case of compounds containing two basic groups, several acid addition salts are possible. Representative examples of the aforementioned pharmaceutically acceptable acid addition salts include those with mineral acids such as hydrochlorides, hydrobromides, sulfates, phosphates, and nitrates with organic acids such as citrates, acetates, sulfosalicylates. , tartrates, glycolates, malic acid salts, malonates, maleates, pamoates, salicylates, stearates, phthalates, succinates, glyconates, 2-hydroxy-3-naphthoates, in which n is 0, 1, 2 or 3, and

R 1, R 2, R 4, Z and W are as defined above.

Suitable catalysts for this hydrogenation are palladium or platinum, preferably coal as carriers. Thus, for example, 5% palladium on carbon can be used as a catalyst. Hydrogenation is carried out under conventional conditions, for example at room temperature. It may be useful to carry out the reaction in the presence of water, for example in 50% aqueous methanol, optionally in the presence of a base, such as sodium bicarbonate. The starting materials for the process according to the invention can be obtained by the method described in our related Czechoslovak Patent Publication No. 216 502 or 216 504.

Because of their higher biological activity compared to the other compounds described herein, those in which R represents one of the above formula II-A to II-D, R 2 represents hydrogen or alkyl-as defined above 216503 7 are preferred. R 1 represents a hydrogen atom or an alkanoyl group as defined above;

From the defined alkyl group and Z and Wm are as follows:

mn W alkylene of 8 to 11 carbon atoms C 4 to 7 carbon alkylene (alk, n-0 (alk 2) n (alk, -O- (alk 2) n -hydrogen-1-pyridyl-pyridyl hydrogen

Particularly preferred compounds of general formula (I), in particular saturated cycloalkyl derivatives of formula (I), are those mentioned above, in which

R 1 is hydrogen, Z is -C (CH 3) 2 (CH 2) 6, and W is hydrogen, Z is alkylene of 4 to 7 carbon atoms, and W is phenyl, Z is -O-alkyl of 7 to 9 carbon atoms, and W is hydrogen, Z is -O-alkylene of 4 to 5 carbon atoms, and W is phenyl, A is hydrogen and B is hydroxy (cis- and trans-forms), A and B together form an oxo group R2 represents a hydrogen atom, a methyl, propyl or propenyl group, and R4 represents a hydrogen atom or a methyl group.

In terms of analgesic activity, particularly preferred compounds from the group of preferred compounds are those in which R2 is methyl, propyl or propenyl and R4 is hydrogen.

The analgesic properties of the compounds according to the invention are determined by the tests described below for the use of irritant stimuli.

Thermal Irritation Tests a) Analgesic Efficiency Test on Mouse Hot Plate

A modification of the procedure described by Woolfe and MacDonald [J. Pharmacol.Exp. Ther. 80, 300-307 (1944)]. The experiments were placed on an aluminum plate of 0.3 cm thickness, which was heated in a controlled manner, so that the paws were irritated by heat. Under the aluminum plate there is an infrared emitter with a power of 250 W. The operation of the radiator is regulated by a thermal controller coupled by the stermistors on the surface of the plate so that the plate temperature is kept constant at 57 ° C. Each experimental mouse is placed in a glass cylinder (16.5 cm diameter) settled on a hot plate, and the time the paw of the animal touches the plate begins to subtract. Experimental mice are observed at 0.5 and 2 hours after administration of the test compound to detect the first twitching movements of one or both hind paws or for 10 sec when these movements do not occur. Morphine has an IC 50 value of 4 to 5.6 mg / kg (subcutaneous administration) in this assay. (b) Mouse analgesic efficacy test, where animals move the tail from the heat-tracking site by rapid movement.

This test is a modification of the procedure described by D'Amour and Smith [J. Pharmacol. Exp.Ther. 72, 74-79 (1941)], and is used to heat the tail of mice with controlled intensity. Each mouse is placed in a sliding metal cylinder such that its tail protrudes at one end of the cylinder. The cylinder is arranged such that the protruding tail of the animal is in a horizontal position above the covered heat radiator. At the beginning of the test, the aluminum shield is removed from the emitter and the light beam is directed through the slit and focus to the end of the animal's tail. At the same time they are put into the clock. An extension of the time required for the mouse to twitch the tail to heat irritation is determined. Untreated mice usually respond to thermal irritation in 3 to 4 seconds. The endpoint of the protection provided by the test substance is 10 seconds. Each mouse is tested for 0.5 to 2 hours of administration of morphine or test compound. Morphine has an MPE 50 of 3.2 to 5.6 mg / kg (subcutaneous). c) Submerged tail test

The method used is a modification of the procedure developed by Benbasset et al. [Sheet. int.Pharmacodyn. 122, 434 (1959)]. Male white mice (Charles River CD-I strain, weight 19 to 21 g) were weighed and identified with identifying markers. Each substance is tested for a group of 5 animals each, serving as a self-control. In general, a new test substance is first administered intraperitoneally or subcutaneously at a dose of 56 mg / kg, administered in a volume of 10 ml / kg. Prior to administration of the active agent at 0.5 and 2 hours after the administration of the active ingredient, each animal is placed in a cylinder with apertures allowing adequate ventilation and closed with a circular nylon cap through which the animal's tail protrudes out of the cylinder. The column is held in a vertical position, with the incoming bath fully immersed in a constant temperature of 56 ° C. The experiment always ends with a vigorous jerking or pulling of the tail, coupled with a coherent response. In some cases, this may be less vigorous following administration of the test substance. In order to avoid unwanted tissue damage, the animal's tail is terminated from the bath after 10 seconds. The response latency is recorded in seconds with rounding to 0.5 seconds. Simultaneously, the vehicle and the known efficacy standard are tested. If the efficacy of the test substance does not fall to baseline within 2 hours after administration of the active agent, the response latency is determined to be 4 and 6 hours after administration. If, at the end of the day of the assay, the test compound still shows efficacy, the final measurement is performed 24 hours after administration.

Test using chemical stimuli

Suppression of painful spasms induced by phenylbenzoquinone

Groups of 5 mice each (Carworth Farms CF-1) are pretreated by subcutaneous or oral administration of saline, morphine, codeine, or test compound. After 20 minutes (or subcutaneous administration) or 50 minutes (in the case of oral administration), phenylbenzoquinone, known to induce abdominal contraction, is injected intraperitoneally into all groups of experimental animals. 5 minutes after the injection, the mice are observed for 5 minutes to determine whether or not they have painful cramps. They determine the MPE50 values for the individual test substances which are pre-treated to prevent painful seizures.

Tests Using Pressure Irritants Effectiveness in Haffner Test [Clamping-Cause] A modification of the procedure described by Haffner (Experimentelle PrufungSchmerzstillender, Deutsch. Med. Wschr., 55, 731-732 (1929)) is used to determine the efficacy of the test compound. Male white rats (50-60 g) of the Charles River strain (Sprague-Dawley CD) are used before the test substance is administered at 0.5, 1, 2, and 3 hours after the drug was administered, the tail of the rat's tail (John- Hopkins, a 6.35 cm bulldog clamp, is the endpoint of every attempted attack and biting towards the pain-inducing instrument, recording the response time of the response in seconds. seconds, the clamp is removed and the response latency time is recorded as 30 seconds. eritoneal administration at 17.8 mg / kg.

Tests using electrical irritation

Test in which experimental animals bounce from the site of electrical irritation To determine the pain threshold, use the procedure described by Tenen [Psychopharmacologia, 12, pp. 278-285 (1968)]. Males (175-200 g) of the Charles River (Sprague-Dawley) CD are used for the assay. Prior to administration of the test substance, the paws of all rats are immersed in a 20% glycerin solution in saline. The animals are then introduced into the cage and 1 second electric shocks increasing in current are added to their flaps in 30 second intervals. These increasing 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.In the behavior of each animal, it is recorded whether a) bounce back, b) bounce or / and c) to jump or move forward in an electric shock.

Each rat, just before administration of the test substance and at 0.5, 2, 4, and 24 hours after the test substance was administered, gave one series of shocks with increasing current intensity. The results of the above tests are reported as the maximum possible effect in% (% MPE). The% MPE values for each group are statistically compared to the% MPE values for the standard and the control values determined before the drug delivery. The% MPE values are calculated according to the following formula:

% MPE measured time - - control time - --- z -; - X 100. interruption time - - control time

When administered orally or parenterally as an analgesic, the compounds of the present invention are conveniently administered in the form of compositions containing a pharmaceutical carrier selected on the basis of the chosen route of administration and taking into account standard pharmaceutical practice. For example, the compounds described can be applied in the form of tablets, pills, powders or granules containing as carrier substances, for example, starch, milk sugar, certain types of clays and the like. which contain universes with the same or equivalent carriers. The disclosed compounds may also be presented in the form of suspensions, solutions, emulsions, syrups or elixirs for oral administration, which may contain flavoring and coloring agents. For most oral applications of the therapeutic agents, tablets or capsules containing from about 0.01 to 100 mg of active ingredient are suitable.

The most appropriate dosage for the patient to be varied depending on the patient's age, weight of response, and route of administration will be determined by the attending physician. In general, however, the initial analgesic effective dose for adult patients may range from about 0.1 to 750 mg / day, wherein the total dose may be administered in single or multiple doses. In many cases, it is not necessary to exceed a daily dose of 100mg. A suitable dosage range for oral administration is from about 1.0 to 300 mg / day, and a preferred range is from about 1.0 to 50 mg / day. A suitable dose range for parenteral administration is from about 0.1 to 100 mg / day, preferably from about 0.1 to 20 mg / day.

The invention also provides pharmaceutical compositions comprising unit dosage forms suitable for the use of the above-described compounds as analgesics and for applications thereof as described herein. These dosage forms may be formulated as single or multiple doses as described above to achieve a daily dose effective for such use.

The compounds of the invention may be formulated for administration to solid or liquid compositions for oral or parenteral administration. Capsules containing the active ingredients according to the invention can be prepared by mixing 1 part by weight of the active ingredient with 9 parts of a carrier such as starch or milk sugar and filling the plug-in gelatin capsules so that each capsule contains 100 parts of the mixture. Tablets containing the above-described compounds as active ingredients are prepared using suitable mixtures of the active ingredient and standard carrier and excipients used in the preparation of tablets, such as starch, binders and glidants, so that each tablet contains from 0.1 to 100 mg of active substance.

Suspensions and solutions of the compounds of the invention, especially those in which R 1 denotes hydrogen, are often prepared by pre-loading to avoid problems associated with the stability of the suspension or solution of the active ingredient during storage (e.g. ).

The analgesic efficacy of several compounds of the present invention was determined by the procedures described above. These compounds correspond to the general formula

For the individual tests, the following abbreviations are used in the table: FBCH = painful crust caused by phenyl-benzoquinone, DO = tail irritation by heat, HD = hot plate, SO = tail clamping (Haffner), OD = bounce in electric shock. The table shows ED50 values (if only one number is given). The number followed by the second number in parentheses meets the protection in% at the given dose. Thus, a value of 31 (56) means that the test substance dose of 56 mg / kg body weight causes 31% protection. 216503

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The diuretic efficacy of the compounds of the invention is demonstrated by the assay described by Lipschitz et al. [J. Pharmacol., 197, 97 [1943]], using rats as experimental animals. The dosage range in this use corresponds to that given above for the use of the compounds of the invention as analgesics.

Antidiarrheal efficacy was determined using a modification of the procedure described by Nei-megers et al. [Modern Pharmacology-Toxicology, Willem van Bever and HarbansLal, Edr., 7, 68-73 (1976)] .Charles River CD-I rats (170-200 g) were placed in the community for 18 hours prior to the test. Animals are fasted overnight prior to administration of castor oil, but are not limited to water intake, and are administered subcutaneously or orally at a constant volume of 5 ml / kg body weight in a 5% ethanol / 5% mixture. polyoxyethylated plant oil emulsifier and 90% salt solution, and the provocative dose (1 ml) of castor oil was orally administered for one hour and placed in small individual cages (20.5 x 16 x 21). Under a wire floor, lay a strip of cardboard, and check for any diarrhea after 1 hour after casting the castor oil. and the vehicle and the castor oil, respectively, were recorded as the number of animals injected before diarrhea for 1 hour from castor oil administration. In general, dosages using the disclosed compounds as antidiarrheal agents correspond to those used in the administration of these compounds as analgesics.

The triancvilization activity of the compounds of the invention is determined by administering the test compounds orally to rats at doses of about 0.01 to 50 mg / kg body weight and observing the following non-spontaneous motor activity. The daily dose for the mammal is about 0.01 to 100 mg.

Anticonvulsant efficacy was determined by subcutaneously injecting the test compound into mice (14 to 23 g Charles River) in a vehicle of the same type as the one used in the diarrheal assay. The compound to be tested is applied in a volume of 10 ml / kg using a hypodermic syringe No. 25. After 1 hour of administration of the test substance, electroconvulsive shock is given to the animals by transdermal injection. 50 mA (60 Hz) Simultaneously, a control experiment is carried out in which mice are challenged with a vehicle, and the electroconvulsive induces tonic convulsions of the stretcher with a laling time of 1.5 to 3 seconds in all control mice. 10 seconds after the application of electroconvulsive shock ádným tonickýmkřečím stretchy. Activity against states of anxiety zjišťujeobdobným manner as anticonvulsant efficacy vulsivní, that as the agent induces convulsions-limiting uses pentylenetetrazol, podanýintraperitoneálně 120 mg / kg. Administration of this substance produces less than 1 minute clonic convulsions in more than 95% of control mice. The test substance is considered to be effective when the latency latency is at least doubled in premedication with the agent.

Sedative / depressive efficacy is determined by administering to each group of 6 mice different doses of the test compound subcutaneously. At 30 and 60 minutes after application, the mice are placed on a rotating rod for 1 minute and their ability to hold on to this is evaluated. Inability of the treated mouse to keep the hay spinning rod Indicates the sedative / degressive efficacy of the test substance.

The invention is illustrated by the following non-limiting Examples. Example 1 cis-3- [2-Benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -5-methylcyclohexanone

A mixture of 1.00 g (2.39 mmol) of 5- [2-benzyloxy-4- (1,1-dimethylheptyl] phenyl] -3-methyl-2-cyclohexen-1-one and 500 mg of 5%). Palladium charcoal containing 50% water was stirred under a hydrogen atmosphere at 0.1 MPa for 1 hour, stirring was continued for 30 minutes after which an additional 500 mg of catalyst was added and then a third portion of catalyst (500 mg) was added. The reaction mixture was filtered through sodium bicarbonate and magnesium sulfate, and the filtrate was evaporated, and the residue was purified by chromatography (140 g silica gel, petroleum ether / 10% ethyl acetate) to give 323 mg (32%). ) of the title compound as an oil.

Mass Spectrum (m / e): 420 (M +), 402, 363, 335 and 91; PMR (CDCl 3, tetramethylsilane, δ): 0.86 (multiplet, terminal methyl), 1.28 (singlet, geminal dimethyl) , 4.06 (methyl on Cs), 3.40 (multiplet, methine benzyl residue group), 5.16 (singlet, methylene benzyl residue), 6.95 (doublet, J = 2 Hz, proton of aryl residue ), 216503 15 6.95 (double doublet, 1 = 8 Hz and 2 Hz, pro-ton of the aryl moiety), 7.43 (singlet, protons of the phenyl moiety) Example 2 cis-3- [4- (1,1 -Dimethylheptyl) -2-hydroxy-phenyl] -5-methylcyclohexanone

A mixture of 2.83 g (6.77 mmol) of 5- [2-benzyloxy-4- (1,1-dimethylheptylphenyl] -3-methyl-2-cyclohexen-1-one, 1.5 g of 5% palladium) on carbon containing 50% water and 2.8 g of sodium bicarbonate are stirred in 30 ml of methanol for 45 minutes under a hydrogen atmosphere of 0.1 MPa, the reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure. The solution was dried (MgSO4) and evaporated and crystallized from pentane to give 1.15 g (52%) of the title compound: mp 95-98 [deg.] C. PMR (CDCl3, tetramethylsilane, .alpha.): 0; 87 (multiplet, terminal methyl), 1.1 (methyl to Cs), 1.28 (singlet, geminal dimethyl), 3.25 (multiplet, methine benzyl residue), 5.62 (singlet, hydroxyl) , 6.85 (multiplet, proton aryl residue), 7.10 (doublet, J = 8 Hz, proton aryl residue).

Analysis calculated for C22H54O2: 79.95% C, 10.37% H, found: 80.22% C, 10.28% H.

Following the same procedure as above, the following compounds were prepared from the appropriate starting materials: cis-3- [4- (1,1-Dimethylheptyl) -2-hydroxy-phenyl] -5-ethylcyclohexanone

The product was prepared in 1.34 g (60%) of 2.83 g (6.55 mmol) of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-ethyl. -2-cyclohexen-1-one.

Melting point: 106-107 ° C. IR (chloroform): 3597, 3333, 1709, 1626 and 1585 cm -1.

Mass Spectrum (m / e): 344 (M +), 326, 315, 297, 273, and 259. PMR (CDCl3, tetramethylsilane, < 5): 0.83 (multiplet, terminal methyl), 16.95 (triplet) , J = 7 Hz, methyl), 1.25 (singlet, geminal dimethyl), 3.25 (multiplet, methine benzyl residue group), 5.98 (singlet, hydroxyl group), 6.90 (multiplet, aryl residue proton), 7.16 (doublet, J = 8 Hz, proton aryl residue).

Analysis: for C23H36O2 Calculated: 80.18% C, 10.53% H, found: 80.27% C, 10.39% H. cis-3- [4- (1,1-Dimethylheptyl) -2-hydride oxy-phenyl] -5-propylcyclohexanone

The product was prepared in 1.66 g (61%) of 3.40 g (7.62 mmol) of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-propionate. of 2-cyclohexen-1-one.

Melting point: 86.5-90.5 ° C. IC (chloroform): 3533, 3289, 1700, 1618 and 1577 cm -1.

Mass spectrum (m / e): 358 (M +), 340, 315, 297 and 273. PMR (CDCl 3, tetramethylsilane, δ): 0.90 (multiplet, terminal methyl), 1.22 (singlet, geminal dimethyl) , 3.25 (multiplet, methine benzyl residue group), 5.95 (singlet, hydroxyl group), 6.85 (multiplet, proton aryl residue) and 7.14 (doublet, J = 8 Hz, proton aryl residue).

Analysis: for C24H38O2 Calculated: 80.39% C, 10.68% H, found: 80.16% C, 10.57% H. cis-3- [4- (1,1-Dimethylheptyl) -2-hydride oxy-phenyl) -5-hexylcyclohexanone

The product was prepared in 3.06 g (93%) of 4.00 g (8.2 mmol) of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-hexyl- -2-cyclohexen-1-one.

Melting point: 84-85 ° C (from pentane). IC (chloroform): 3571, 3333, 1703, 1623, and 1582 cm -1.

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

Claims

216503 18 17 PMR (deuterochloroform, tetramethylsilane, δJ: 0.90 (multiplet, terminal methyls), 1.21 (singlet, geminal dimethyl), 3.20 (multiplet, methine benzyl residue), 5, 80 (singlet, hydroxyl group, 6.85 (multiplet, proton aryl residue) and 7.10 (doublet, J = 8 Hz) Analysis for C27H44O2: C, 80.94; H, 11.07; % C, 10.94% H. Example 3 cis-3- [4- (1,1-Dimethylheptyl) -2-hydroxy-phenyl] -cis-4-methylcyclohexanone and cis-3- [4- (1,1-diethylheptyl) -2-hydroxyphenyl] -4-methylcyclohexanone A mixture of 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4-methylcyclohex-2-enone and 391 mg of 5% palladium on carbon containing 50% of water are stirred in 15 ml of methanol in an atmosphere of hydrogen at a pressure of 1 bar until hydrogenation of the hydrogen is taken up. The reaction mixture is filtered through diatomaceous earth using ethyl acetate and the filtrate is evaporated. 200 g silica gel column using 50% eth The column is eluted with 758 mg of a ketone mixture of 820 mg (53%) of the title alcohol which crystallizes from cyclohexane. The ketone mixture was then purified by preparative chromatography on a thin-layer silica gel plate (20 cm x 20 cm x 2 mm) which was developed four times in dichloromethane. There was obtained 112 mg (7.2%) of the title oily ketone. The title alcohol is melting at 134-135 ° C. IC (chloroform): 3623, 3333, 1626 and 1585 cm -1. Mass spectrum (m / e): 332 (M +), 314.247 and 229. PMR (CDCl 3, tetramethylsilane, δ values): 0.69 (doublet, J = 7 Hz, methyl at C4), 0.85 (multiplet, terminal methyl), 1.26 (singlet, geminal dimethyl), 3.2 (multiplet, methine benzyl residue group), 3.8 (multiplet, methine carbinol moiety), 5.05 (singlet, hydroxyl group) and 6.7 to 7.1 (multiplet, proton of the aryl moiety). Analysis: for C22H36O2 Calculated: 79.46% C, 10.92% H, found: 79.40% C, 10.72% H. Ketone title compound IR (CDCl3): 3623, 3390, 1634 and 1582 cm @ -1 . Mass spectrum (m / e): 330 (M +), 315.312, 288, 273, 271 and 245. PMR (CDCl 3, tetramethylsilane, δ): 0.82 (multiplet, terminal methyl), 0.88 (doublet, J = 7 Hz, methyl at C4), 1.26 (singlet, geminal dimethyl) and 6.83 (singlet, all protons of the aryl moiety). E D M E T Method of producing 3- (2-hydroxy-4-substituted phenylcycloalkanone derivatives)

wherein R 1 represents a hydrogen atom, a (C 1 -C 5) alkanoyl group, a benzyl group, a group (- (Ο) (ΟΗ) ζ and its mono- and di-sodium and potassium salts, a group --CO (CHa) 2 COOH and its sodium and potassium salts, or-CO- (CH 2) p -NR 5 R 6, wherein p is 1 to 4, R 5 and R 6 are each independently hydrogen or alkyl of 1 to 4 carbon atoms, or R 5 and R 6 together with the nitrogen atom to which they are attached form a five- or six-membered heterocyclic ring selected from the group consisting of a piperidine residue, a pyrrole residue, a pyrrolidine residue, a morpholine residue and a 216503 N-alkylpiperazine residue containing in C 1 -C 4 alkyl, R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, phenyl or phenylalkyl having 1 to 4 carbon atoms in the alkyl, R d is hydrogen or an alkyl group having 1 to 6 carbon atoms, Z represents an alkylene group having 1 to 13 carbon atoms or a radical of the formula - (alki) - O - (alk 2) n -, where (alki) and (alkz) always represent an alkyl group of 1 with up to 13 carbon atoms, provided that the sum of the carbon atoms in the groups (alkij + (alkzj not greater than 13 and m and each having 0 or 1, W represents a hydrogen atom, a pyridyl group, or a radical of formula O-w ', / 20 where W 1 represents a hydrogen atom, a fluorine atom or a chlorine atom, and has a value of 0, 1, 2 or 3, provided that when n is 0, R 4 is a hydrogen atom characterized in that the compound of formula II is catalytically hydrogenated.

R 1, R 2, R 4, Z, W and n are as defined above.