CS242879B2 - Process for preparing 3- [2-benzyloxy-4- (substituted) phenyl] -5-cyanocycloalkanone - Google Patents

Abstract

A method for preparing 3-[2-benzyloxy-4-(substituted)-phenyl]-5-cyanocycloalkanone of the general formula wherein the compound Z—W is reacted with sodium cyanide or potassium cyanide in an aqueous solvent. The compound is a valuable intermediate for the preparation of pharmaceutically active substances.

Description

The invention relates to a process for the preparation of novel 3-[2-benzyloxy-4-(substituted)phenyl-4- or 5-cyano-5-cyanocycloalkanes suitable for the preparation of novel 3-[2-hydroxy-4-(substituted)phenyl]-4-(or 5-substituted)cycloalkanones and cycloalkanols having analgesic and antiemetic properties.

Despite the current availability of numerous analgesic agents, there is a continuing need for new and improved agents for the control of a wide range of pain and discomfort with minimal side effects. The most commonly used agent, aspirin, 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, are addictive. The need for an improved and effective analgesic agent is therefore clear.

Compounds useful as analgesics, tranquilizers, sedatives, anxiolytics and/or anticonvulsants, diuretics and antidiarrheals are described in Belgian Patent Specification Nos. 870,404 and 870,402, both granted on March 12, 1977. Belgian Patent Specification No. 870,404 describes 5-[1,2-hydroxy-4-substituted-phenyl]cycloalkanones and cycloalkanols which may have an alkyl, alkenyl, phenyl or phenylalkyl substituent in the 4-position of the cycloalkanone or cycloalkanol residue; or may have an alkyl substituent in the 5-position. Belgian Patent Specification No. 870,402 describes certain phenols substituted in the 2-position with acyclic substituents, in particular 2-hydroxyalkyl-4-substituted-phenyls 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)cyclohexanes which have central nervous system depressant properties.

The co-filed patent application D.P.C. /Ph/ 6248, entitled Pharmacologically active 4- [2-hydroxy-4- /substituted/phenyl] naphthalen-2- /1H/ones and 4- |2-hydroxy-4-substituted/phenyl] naphthalen-2-ols, their derivatives and intermediates, describes a series of 4- [2-hydroxy-4- /substituted/phenyl] naphthalen-2- /1H/ones and 4-j2-hydroxy-4- /substituted/phenyl^ naphthalen-2- /1H/ols, useful as agents affecting the nervous system and useful 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 alkoxy, as intermediates for the preparation of 1-(aminoalkyl)-2-phenylcyclohexanol, which is useful as an analgesic, as a local anesthetic and as an antiemetic.

The journal Chemical Abstracts 85, 176952f /1976/ refers 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 sedative effects and can also be used as additives in antidepressants and as additives in anticonvulsants.

The active ingredients transportable using the intermediates produced by the process of this invention have the general formula I

HR _with ^0R 1 ^with í

Ύ aa are prepared from compounds of general formula II with °1 '- _Y V:.,. ^/l!/ ' zw where means

R is a hydrogen atom, a hydroxy group, an alkynyl group with 1 to 5 carbon atoms, an amino group or an acetamido group, a hydrogen atom, a benzyl group, an alkanoyl group with 1 to 5 carbon atoms, a group of the formula P/O//OH/ ₂ and its monosodium salt, disodium salt and potassium salt, a group of the formula -CO/CH ₂ / ₂ COOH and its sodium or potassium salts or a group of the formula -CO/CH^/pNR^R^, where p is zero or an integer from 1 to 4,

R^ and Rg are each individually a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, or together with the nitrogen atom to which they are attached, a five- or six-membered heterocyclic ring of piperidine, pyrrole, pyrrolidine, morpholine and N-alkylpiperazine with 1 to 4 carbon atoms in the alkyl portion, with an integer of 1 or 2,

Y a group of the general formula -CH/R^/CH/R^Z- or of the general formula CH/Rg/CH ₂ , where

R ₂ is a hydrogen atom or a methyl group,

R ₂ is a hydroxy group or the substituent X is a substituted alkyl group with 1 to 6 carbon atoms,

R ₃ represents a hydroxy group, a cyano group or an alkyl group with 1 to 3 carbon atoms substituted by a substituent X where

X a group of the general formula -ORg, -NRgR.?, -COOR^, -CONR^Rg or an oxo group, where

Rg is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms or an acetyl group,

R? and Rg are each a hydrogen atom or an alkyl group with 1 to 6 carbon atoms, provided that in the case where X represents a group of the general formula -NRgR?, -COOR?, or -CONR^Rg this group is bonded to the terminal carbon atom of the substituent R ₂ or Rg, and in the case where Rg represents an acetyl group, then R? represents a hydrogen atom,

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

where means

Wg is a hydrogen atom, a chlorine atom or a fluorine atom, provided that when W is a hydrogen atom, it means

Z a/alkylene group with 5 to 13 carbon atoms or b/ -/alk ₁ / _m -O- /alk ₂ / _n group, where each /alk k / and /alk ₂ / alkylene group with 1 to 13 carbon atoms each man is zero or the number 1, /alk j / plus /alk ₂ / is at least 5 and at most 13 and that at least with the proviso that the sum of the carbon atoms in one of the symbols man is the number 1 hydrogen, Z a/ alkylene group with 3 to 8 carbon atoms or b/ -/alk ₁ / _m -0 /alk ₂ / _ri group, and with the proviso that in the case where W does not mean an atom where each /alk ^ / and /alk ₂ / alkylene group with 1 to 8 carbon atoms and each man is zero or the number 1, provided that the sum of the carbon in /alk ₁ / plus /alk ₂ / is at least 3 and at most 8 and that at least one of the symbols man means the number 1. ,

In each of the general formulas I and II, the group of the symbol Y has a variable position in the cycloalkyl moiety in the sense that R ₂ is always a substituent in the 4-position and each R 1 and R ₃ is always a substituent in the 5-position.

As mentioned above, pharmaceutically acceptable acid addition salts of compounds of formula I or formula II which contain one or more basic groups are also effective. In general, compounds in which W is a pyridyl group and/or the group OR _x is a basic ester moiety, R ₂ is an aminoalkyl group and R is an amino group are suitable for the preparation of such acid addition salts.

Compounds of the general formula I which have more than one basic group are moreover 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, and 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 methanesulfonate.

The invention relates to a process for the preparation of intermediates for compounds of general formula I and II, which have the general formula III

where s, Z and W have the meanings given above, of general formula IV

that the compound /IV/, where the individual symbols have the above-mentioned meaning, is reacted with sodium cyanide or potassium cyanide in an aqueous solvent and optionally the oxosulfate of the general formula III is reduced to form the corresponding hydroxy compound and/or optionally the CN group of the compound of the general formula III is converted to a formyl group by reaction with diisobutylaluminum hydride and/or the formyl derivative is then reduced to the corresponding hydroxymethyl derivative.

The compounds contain an asymmetric center at positions 3, 4 and 5 in the cycloalkyl moiety and may contain additional asymmetric centers in the -Z-W moiety of the phenyl ring. The trans relationship between the substituents at positions 3a4a3a5 on the cycloalkyl moiety is preferred for quantitatively higher biological efficacy of the pharmaceutically active substances prepared from the compounds produced according to the invention.

In the above formulas, the compounds are designated as racemic. However, the general formulas given always include racemic modifications of the compounds, as well as diastereomeric mixtures, pure enantiomers and diastereomers. The usefulness of the racemic mixture, diastereomeric mixture and pure enantiomers and diastereomers is confirmed by the biological tests described below.

In view of their higher biological activity, preferred compounds of the general formula I and II are those described, where each R represents a hydroxy group or an acetamido group, R ₁ is a hydrogen atom, R 1 is a hydrogen atom or a methyl group, each and every one represents a hydroxyalkyl group, an alkoxyalkyl group, a carboalkoxyalkyl group or a dialkylaminoalkyl group, and Z and W have the meanings given below.

alkylene group with 7 to 11 carbon atoms alkylene group with 4 to 7 carbon atoms hydrogen atom group of the general formula

0.1 or a pyridyl group a group of the general formula or a pyridyl group, wherein each /alk^/ and /alk2/ represents an alkylene group with 1 to that the sum of carbon atoms in /alk^/ plus /alk^/ is at least 4 and at most carbon atoms, provided that / ^alk 2 ^/ n·

0.1 hydrogen atom, wherein each /alk^/ and /alk ₂ / represents an alkylene group having 1 to 11 carbon atoms, provided that the sum of the carbon atoms in /alk^/ plus /alk ₂ / is at least 7 and at most 11.

Preferred are compounds of general formula I and II, where means:

R ₂ and always a hydrogen atom,

Z group of the formula C/CH^/ ₂ /CH ₂ / _g a

W is a hydrogen atom;

Z an alkylene group with 4 to 7 carbon atoms and

W is a phenyl group;

Z -O-alkylene group with 7 to 9 carbon atoms and

W is a hydrogen atom;

Z -O-alkylene group with 4 to 5 carbon atoms and

W is a phenyl group;

R in general formula I represents a hydroxy group /cis and trans form/:

R ₂ is a -hydroxyalkyl group with 2 to 4 carbon atoms or a -methoxyalkyl group with 2 to 4 carbon atoms in the alkyl moiety;

R ₃ is a hydroxyalkyl or methoxyalkyl group.

Particularly preferred are compounds of the general formula I and II, wherein R, R, Z and W have the meanings given above for the preferred compounds; R is 3-hydroxypropyl or 3-methoxypropyl and R is hydroxymethyl. The 1-form of the compounds of the general formula I and II is more preferred than the d-form.

Suitable starting materials for the process according to the invention are 5-(2-benzyloxy-4-(2-N-substituted)phenyl)-2-cycloalken-1-ones, the preparation of which is described in Belgian Patent Specification No. 870,404, published on March 12, 1979. The nucleophilic addition of HCN elements in the process according to the invention to 2-cycloalken-1-one compounds by their reaction with aqueous potassium cyanide or aqueous sodium cyanide provides the corresponding trans-3-(2-benzyloxy-4-(2-N-substituted)phenyl)-5-cyanocycloalkanes, which are valuable intermediates. Reduction of the oxo group of the cycloalkanone moiety with sodium borohydride leads to the corresponding trans-cis hydroxy compound. This is converted to the corresponding trans-trans compound by refluxing in a tert-butanol solution in the presence of potassium tert-butoxide.

Stereomeric cis-3-[2-benzyloxy-4-(Z-N-substituted)phenyl]-cis-5-cyanocycloalkanols are prepared by oxidation of the transtrans stereoisomers using, for example, Jones' reagent, followed by reduction with sodium borohydride of the thus produced cis-3-[2-benzyloxy-4-(Z-N-substituted)phenyl]-5-cyanocycloalkanone.

Each of the above 5-cyanocycloalkaliol derivatives is also a valuable intermediate. The cyano group is readily converted by reduction with diisobutylaluminum hydride (DIBAL-H) to the corresponding formyl derivative. In this process, the cyano derivative is reacted with two equivalents of diisobutylaluminum hydride in toluene at low temperature, for example, at a temperature of 0 to -65 ° C, after which the reaction product is treated with a dilute acid, for example, a dilute mineral acid such as sulfuric acid. The formyl derivative is obtained by conventional methods, such as extraction with ether and evaporation of the solvent. Reduction of the formyl derivative, for example with sodium borohydride, leads to the corresponding hydroxymethyl derivative.

In the above reactions, the benzyl ether derivative of 3-(2-hydroxy-4-(Z-substituted)phenyl)-5-cyanocycloalkanol is used as a reagent to prevent reactions at the phenyl hydroxyl group. The protecting benzyl group is then removed by methods known per se in the preparation of the active compounds.

The 5-Hydroxymethyl and 5-formyl derivatives are intermediates for the preparation of other valuable compounds by the reactions described above with respect to the conversion of the hydroxyalkyl and oxoalkyl groups in the meaning of the symbol R1.

The analgesic properties of the compounds obtainable from the products prepared according to the invention are determined by tests based on a stimulus capturing noxious stimuli. It is recalled that the compounds of general formula I and II, where R ₁ represents a benzyl group, are not pharmacologically active for the purposes described, but are useful as intermediates for the compounds of general formula I and II, where R 2 represents a hydrogen atom.

Tests based on a stimulus capturing noxious thermal stimuli and/or Mouse hot plate analgesic test

This method uses a modified Woolf and MaoDonald test, described in J. Pharmacol. Exp. Ther. 80, pp. 300-307, 1944. A controlled thermal stimulus is applied to the mouse paw on a 3.175 mm thick aluminum plate. A 250 watt infrared heating bulb is placed under the bottom of the aluminum plate. A temperature controller, connected to a thermistor on the surface of the 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 the hot plate, and time is started as soon as the mouse paw touches the plate. The mouse is observed for half an hour and two hours after treatment with the test compound for the first twitch of one or both hind paws or until 10 seconds have elapsed without such movements. Morphine has a MMtJ value of up to 5.6 mg/kg /s.c./. /MMO always means the maximum possible effect./ b/ Analgesic mouse tail flick test

A modified test according to D^Airiour and Smith, described in the journal J. Pharmacol. 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 over its entire surface 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 tail. At the same time, a timer is started. A sudden twitch of the tail is detected. An untreated mouse usually reacts within 3 to 4 seconds after exposure to the heat of the bulb. The end point of protection is 10 seconds. Each mouse is tested half an hour and two hours after treatment with morphine and the test substance. Morphine has an MIC value of 3.2 to 5.6 mg/kg /s.c./.

c/ Tail immersion test

A modified method is used, as described by Bonbasset et al. in Arch. Int. Pharmacodyn., 122, p. 434, 1959. A male Charles River CD-I white mouse, weighing 19 to 21 g, is weighed and marked for identification. Five mice are usually used for treatment with the substance and a control animal. First, each test substance is 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 two 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 stopper through which the tail of each mouse is passed. The cylinder is held upright and the tail is completely immersed in a water bath at a constant temperature of 56°C. The endpoint of each test is an energetic jerk 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. A vehicle and a standard of known potency are tested in parallel with the selected subjects. If the activity of the test substance does not return to baseline values at the two-hour test, the response is determined at 4 hours and 6 hours. A final measurement is made at 24 hours if potency is still observed at the end of the test day.

Stimulus-based test capturing noxious chemical stimuli

Suppression of writhing induced by phenylbenzoquinone

A group of five Carworth Parms CF-1 mice are pretreated subcutaneously or orally with saline, morphine, codeine or the test drug. Each group is treated with an intraperitoneal injection of phenylbenzoquinone, a stimulus known to induce abdominal contractions, for 20 minutes in the case of subcutaneous treatment, and for 50 minutes in the case of oral administration. The mice are observed for writhing or not writhing 5 minutes after the phenylbenzoquinone injection. The ΜΜϋ,-θ value after treatment with the writhing-blocking drug is recorded.

Stimulus-based test capturing noxious pressure stimuli

The influence of the Haffner tail grip method

Modified Haffner tests, described in the publication Experimentelle Prufun Schmerzstillen der /Experimental testing of painkillers/, Deutsch. Med. Wschr., 55, p.

731 to 732, 1929, is used to determine the effect of the test substance on the aggressive response elicited by tail pinching. Male Charles River White (Sprague-Dawley) CD rats are used in this test. Before treatment with the test substance and then at half an hour, one hour, two hours and three hours after treatment, a 63.5 mm Johns Hopkins clamp is clamped at the base of the rat's tail; the endpoint of each test is a clear attack and biting directed against the cause

pain, if Morphine is already effective at the dose of 17.8 mg/kg /i.p./. The time to onset is recorded in seconds. The clamp is removed after 30 seconds and there is no response and the time to onset is recorded in seconds. 17.8 mg/kg /i.p./.

Test test foundation! on a stimulus capturing harmful electrical stimuli recoil - rebound

A modified test described by Tenen in the journal Psychopharmacologia is used.

12, pp. 278-285, 1968 for the determination of pain threshold. Male Charles River white (Sprague-Dawley) CD rats, weighing 175-200 g, are used in this test. Before the drug is administered, the paw of the rat is immersed in a 20% solution of glycerin and saline. The rats are placed in a chamber and their paws are given one-second shocks, which are developed 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 the electric shock. A series of shocks of increasing intensity are administered to each rat immediately 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 above tests are recorded as a percentage of the maximum possible effect /% ΜΜΰ/. The percentage of the maximum 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 from the relationship:

test start time - control time % MMU r --- -----— y. 100 test end time - control time

The compounds prepared from the intermediates of the invention are generally used in the form of preparations when used as analgesics for oral or parenteral administration. Such preparations contain a pharmaceutically acceptable carrier selected with regard to the route of administration and with regard to conventional pharmaceutical practice. For example, the active ingredient prepared from the compounds of the invention 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 suspensions, solutions, emulsions, syrups and elixirs which may contain flavourings and colourings. For oral administration of the active ingredients prepared from the intermediates of the invention, tablets or capsules containing from 0.01 to about 100 mg of active ingredient are suitable. In most cases, the active ingredient may be administered in the form of a suspension, solution, emulsion, syrup or elixir. In some cases, such doses are appropriate.

The analgesic efficacy of certain compounds is determined by the methods described above.

These compounds have the general formula:

From W

42879

P.jH11 I k.

OH ,OiI ,/('H/ /41 /CH ,/ />11 /ch ₂ / ^oih ^Lt ' /CH.,, y)IÍ'^lj; /CH ,/ OH .Cil _;//:i '|, _ř

CH

CH^CHO

CH^COOH /CH-/ /JOOH /ch _? / ₂ cooch /ch ₂ / _? cowh ₉ ch ₂ hh _? /CH ₂ / _? NH ₂ HCL

Cl^N/CHy -,HC1 /'CH ₀ / N/CH ₀ / _? HCl·

C!k ₍ CHOHCH JQ/ ''Ή . ₍ CI IOHCiI .

/Cil -,/ -/'H /Cíi.,/ ,oil 'Ci , / .oj /r:i ₂ / OH ,ch ₂ „ _V >h /oH ,1 ,( >H /CH,,/ _S OH /CH^/,OH

MMIJ ₅₀ /mg./kg./

.9 i - ·. z-w PHQ RTC HP TF FJ ¹ and í >11 1 ^C/C11 iO-Gu 1.71 1, 26 ^! < ΊΙ 1 '''''-vWu 2.58 7.85 ! Ή 1 7011 ,/ ₂ '' _h H, ₃ 0.2 9 0.46 1.11 0.55 0.63 H , tl| 1 0.06 0.1 3 0.66 0.41 H r 1 1 ^0099.3 14.6 I 9Í1 l ' ^7Cil 3 CO" ₁₃ 0.23 1.15 H i >H I -,00,03 0.55 2.64 H OH 1 '-/‘--GOOOs 0.37 1.00 11 OH 1 '- ^7ci noo ^H 13 2.59 11 011 1 C/LH ₃ / ₂ C ₍ .H ₁ , 1.21 H OH '- ^/í;! HO ^C 6 ^H 13 >56 11 OH 1 á5 6 11 OH ! ^{C ' / CH3OC6H13} 7.53 30.6 H uH 1 l /',H _j ,' ₂ C' ₆ H _{1 3} a/ 5 6 11 OH 1 c/ch ₃ / ₂ c ₆ h ₁₃ k./· 6 H OH 1 c/ch ₃ / ₂ ^c 6h ₁₃ >5 6 H OH 1 '-''«HOOOj /In ^year -> ⁶ H OH 1 c/ch ₃ / ₂ c ₆ h, ₃ 6.38 11 OH 1 ^C/rI1 //0i3 1.00 ru oll 1 C/CII ₃ / ₂ C _fi H ₁ , 77 OH Π l· (and > >H H 1 ''''^l!;'2' gi , / 1 liter c 1 ^C 'OOO . 0.9 3 11 Oh!) and '-'/O': ; o, i 0 4 7 _years 8 1 _ø M 1 0’

, 1

H '' O .? 6' 1 8 'V ¹ '' : and 'Cm .. ¹ H 0,R 1 — ^77! g3 /O -------- | 0/0:1,/ U . , 0, 7J rS} ,00 H OH ( Ί ' '......i gi n ¹ ' “ '“Yeah''' H 011 011 0 1 0 , -OdC ₆ H ₁₃ 2.87 H OH 011, ,11 i v'' ¹¹ -0-C-/CIL,/,e _r H ₅ 0.29

/a/ /-/ endriciomer /b/ /+/ enantiomer /c/ diasteromer Λ /a/ diastereomer B /θ/ /-/ enanc ioraer /o /+/ enantiomer

The following abbreviations are used in the table:

PBQ phenylbenzoquinone-induced writhing

TP tail wag

HP hot plate test

RTC tail clamp rate

FJ jump

The analgesic activity of some compounds of the general formula I, prepared from intermediates according to the invention, is determined by the methods described above. Compounds of this general formula are tested: _{Δ R}

Table II

MMŮ _5q /mg/kg/

^R 3 A B PBQ RTC HO H 0H 5.60 HO H OH 13.90 39.2 H0 iH.ll// OH H 5.80 756 NC H OH 7.20 boy ₂ Electric OH 1.21 3.34 NC *»— --0 2.87

PBQ stands for phenylbenzoquinone /pronounced swin-jen.!

RTC stands for tail clamp rate

The antiemetic efficacy of compounds of general formula L, prepared from intermediates according to the invention, is determined in unrestrained cats by the method described in the journal Proc. Soc. Expl. Biol. and Med., 140 pp. 437-440, 3979.

Compounds of general formula Ϊ, prepared from intermediates according to the invention, 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 with regard to current 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 flavorings and colorings. For the administration of therapeutic compositions containing a compound of formula I prepared from the intermediates of the invention, tablets or capsules contain from about 0.01 to about 100 mg of active ingredient; such preparations are suitable for most uses.

The physician will determine the dosages that are appropriate for each patient, taking into account age, weight, and response to the administration route. However, the usual starting 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. Preferred oral doses are about 1.0 to 300 mg/day. Preferred parenteral doses are about 0.1 to about 100 mg/day, with a dose of about 0.1 to about 20 mg/day being preferred.

The compounds of formula I prepared from the intermediates of the invention can be used to formulate liquid or solid preparations for oral or parenteral administration. Capsules containing the active ingredient of formula I are prepared by mixing one part by weight of the compound of formula I with 9 parts by weight of an excipient such as starch or lactose and then filling the mixture into gelatin capsules so that each such gelatin capsule contains 100 parts of the mixture. Tablets containing the compound of formula I 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 of formula I prepared from the intermediate of the invention.

Example 1

Trans-3-[2-benzyloxy-4-(1,1-dlmethylheptyl)phenyl]-5-cyanocyclohexanone

To a refluxing solution of 3.99 g (9.87 mmol) of 5-[2-benzyloxy-4-(1,1-dimethylheptal)phenyl]-2-cyclohexen-1-one in 6.65 ml of ethyl acetate was added a hot solution of 800 mg (11.9 mmol) of potassium cyanide in 2 ml of water and 2.3 ml of ethanol. The reaction mixture was refluxed for two hours and then an additional 2.74 mmol of potassium cyanide was added. The ethereal solution was dried over magnesium sulfate and evaporated to give an oil. The crude oil was purified by column chromatography on 160 g of silica gel eluted with 10% acetone-hexane to give 3.02 g (71% of theory) of the desired compound.

Melting point: 79 °C /petroleum ether/

IR /CHClj/ 2202, 1706, 1600 and 1552 cm ^-1

MR /m/e/ 431 /M ⁺ /, 414, 403, 346, 340 and 91.

Example 2

Trans-3-[1-benzyloxy-4-[1,1-dimethylheptyl/phenyl]-cis-5-cyanocyclohexanol

To a solution at 0 °C of 3.02 g (7.00 mmol) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-5-cyanodicyclohexanone in 50 ml of methanol was added 1.22 g (32.1 mmol) of sodium borohydride. The reaction mixture was stirred for 30 minutes at 0 °C and then added to 500 ml of saturated sodium chloride solution and 300 ml of ether. The organic extract was washed twice with 500 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give an oil. The crude oil was purified by column chromatography on 200 g of silica gel eluted with a 2:1 pentane:ether system, which gave 2.66 g (88% of theory) of the compound prepared by sequential elution.

Melting point: 94 to 102 °C /pentane/

IR (CHCl 2 ) 3413, 2222, 1612 and 1575 cm ^-1 .

MS /m/e/ 433 /M ⁺ /.

Example 3

Trans-3-]2-benzyloxy-4-[1,1-dimethylheptyl/phenyl]-trans-5-cyanocyclohexanol

A mixture of 3.12 g (7.20 mmol) of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cis-5-cyanocyclohexanol and 808 mg (7.20 mmol) of potassium t-butoxide in 70 ml of t-butanol was refluxed for 2.5 hours. The t-butanol was evaporated on a rotary evaporator and the residue was diluted with saturated sodium chloride solution. The rapidly cooled residue was extracted with ether, the extract was dried over magnesium sulfate and evaporated to give an oil. The crude oil was purified by column chromatography on 124 g of silica gel eluted with 10% acetone-hexane to give 1.53 g (44% of theory) of no compound.

Melting point: 62 to 64 °C /petroleum ether/

IR /CHCl / 2247, 1597 and 1579 cm ^-1

MS /m/e/ 433 /M ⁺ /, 348, 342, 305 and 91

TMS

PMR 0.83 (m, terminal methyl), 2.8 to 3.9 ^CDCl 3 (two methines), 4.25 (m, carbinol methine), 5.12 (s, benzylic methylene), 6.9 (m, ArH), 7.06 (d, J = 8 Hz, ArH) and 7.4 (s, phH).

Example 4

cis-3-[2-Benzyloxy-4-[1,1-dimethylheptyl]phenyl]-cis-5-cyanocyclohexanol

Using the method of Example 2, 1.11 g (2.58 mmol) of cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-5-cyanocyclohexanone yields 949 mg (84% of theory) of the desired compound as an oil.

IR /CHC1 ₃ / 3571, 3389, 2232, 1612 and 1574 cm ¹

TMS

PMR(/ 0.83 /m, terminal methyl/, 1.25 /s, gem dimethyl/, 3.70 /m, carbinol methine/ cdci ₃

5.10 /s, benzyl methylene/, 6.9 /m, ArH/, 7.09 /d, J : 8 Hz, ArH/ and 7.41 /s, PhH/.

Example 5

cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl/phenyl)-5-cis-hydroxycyclohexanecarboxaldehyde

To a solution at -65°C of 704 mg (1.62 mmol) of cis3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cis-5-cyanocyclohexanol in 30 ml of toluene was added 3.40 ml (3.40 ml (3.4 mmol) of diisobutylaluminum hydride (1M in toluene). The reaction mixture was allowed to warm to -5°C and then poured into a mixture of dilute sulfuric acid and ice. The rapidly cooled reaction mixture was extracted with ether, the extract was dried over magnesium sulfate and evaporated to give the desired compound in quantitative yield as an oil.

Ir /CHC1 ₃ / 3165, 1730, 1612 and 1574 cm ^-1

MS /m/e/ 436 /M ⁺ /, 408 and 350

TMS

PMR r 0.83 /m, terminal methyl/, 1.23 /s, gem dimethyl·/, 3.7 /m, carbinol methine/, cdci ₃

5.11 /s, benzyl methylene/, 6.85 /m, ArH/, 7.35 /m, PhH/ and 9.60 /bs, CHO/.

Example 6

cis-3-12-benzyloxy-4-(1,1-dimethylheptyl/phenyl)-cis-5-hydroxymethylcyclohexanol

Using the method of Example 2, 700 mg (1.60 mmol) of cis-3-[[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-5-cis-hydroxycyclohexanecarbosaldehyde are converted to 208 mg (30% of theory) of the desired compound in the form of an oil.

MS /m/e/ 438 /M ⁺ /

TMS

PMR0 0.83 (m, terminal methyl), 1.23 (s, gem dimethyl), 2.7 to 4.0 (m, 4H), 5.09 cdci ₃ (s, benzylic methylene), b, 90 (m, ArII), 7.10 (d, J - 8 Hz, ArH) and 7.38 (s, PhH).

Example 7

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

A mixture of 208 ml of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cis-5-hydroxymethylcyclohexyl]-5-hydroxymethyl in 10 ml of ethanol was stirred under a hydrogen pressure of 0.01 MPa for 45 minutes at room temperature. The reaction mixture was filtered through a sieve and the filtrate was concentrated under reduced pressure to give a solid. Recrystallization of the crude solid from diethyl ether afforded 127 mg of the desired compound.

Melting point: 12b to 127 'V /vi.ff - five ulcum ether/

IR /CHCl / 3597, 333 3, I 62 ij 1587 lU ¹

HRMS /m/c/ 348, 2662 /M ⁺ , calcd·· for C , JI _j( oi : 348, 2655/, 330, 299, 287, 263 and 245. PMR /CDC1 ₃ , D^-DMSO/ ¢.),85 /m, i« r no ;, ui:, i methyl/, 1.25 /s, gem dimethyl/, 3.5 /m, carbinol methylene/, 3.8 /m, carbrv.d. :·.« »nj ¹ , h,tí /m, ArH/ and 7.07 /d, J z 8 Hz, ArH/.

Claims (1)

BACKGROUND OF THE INVENTION A process for the preparation of 3- [2-benzyloxy-4- (substituted) phenyl-5-cyanocycloalkanone of general formula (I) (111), wherein s is 1 or 2 W is a hydrogen atom, a pyridyl group or a group of the formula wherein W is hydrogen, chlorine or fluorine, provided that when W is hydrogen, Z is an alkylene group having 7 to 11 carbon atoms or a group of the formula - (alk ₁ ) _m -O- (alk ₂ ) _n wherein each alk 1 and alk ₂ is an alkylene group having 1 to 11 carbon atoms, each having every zero or number 1, provided that the sum of the carbon atoms in the (alk) ^ (plus / alk ^) is not less than 7 or greater than 11 and that at least one of m and n is 1, and provided that when W is not a hydrogen atom, Z is (C až-C alky) alkylene or general moiety - (alk ₁ ) _m -O- (alk ₂ ) _n wherein each (alk (1) and (alk ₂ ) alkylene group having 1 to 7 carbon atoms, each man zero or number 1, provided that the sum of the carbon atoms in the (alk _A ) plus (alk ₂ ) is not less than 4 and not more than 7, and that at least one of m and n is 1, characterized by reacting a compound of formula (ll), wherein the symbols are as defined above , with sodium cyanide with potassium cyanide in an aqueous solvent and optionally reducing the oxo compound of formula III to give the corresponding hydroxy compound and / or optionally converting the CN group of the compound of formula III to a formyl group by reaction with diisobutylaluminum hydride and / hydroxymethyl derivative.