NL8303358A - CYCLOAL CANNONS, THEIR UNSATURATED ANALOGS AND METHODS FOR THEIR PREPARATION AND USE. - Google Patents

Description

// • ψ

Cycloalkanones, their unsaturated analogs and methods of their preparation and use.

The invention relates to certain cycloalkanones, and their unsaturated analogs having 5-8 carbon atoms in the cycloalkyl ring and to the 3-position a 2-hydroxy-4- (ZW-substituted) phenyl group in which Z alkylene has 1 to 13 carbon atoms or (alk.) -0- (alko), wherein each m and n are 0 or 1 and (alk.) and 1 m z η 1 (alk2> any alkylene of 1-13 carbon atoms with the proviso that the sum of the carbon atoms in (alk ^) plus (alkj) are not greater than 13, and W is hydrogen, phenyl, chlorophenyl, fluorophenyl, or pyridyl, as well as on derivatives thereof, intermediates thereof and method of their preparation. CNS agents, in particular as analgesics, tranquilizers, sedatives and anti-anxiety agents for mammals, including humans, and / or as anti-seizure agents, as diuretics and as anti-diarrheal agents in mammals including humans.

Despite the fact that maninally different analgesics are available, the search for new and improved agents continues, indicating the lack of an agent which can be used to manage all kinds of pains and which exhibits a minimum of side effects. The most commonly used, i.e. aspirin, has no practical significance for controlling severe pain and is known to exhibit a variety of undesirable side effects. Other analgesics, such as d-propoxyphene, codeine and morphine, are likely to cause addiction. So it is clear that there is a need for improved and powerful analgesics.

In U.S. Patent 3,576,887, f? ~ ~ ~ - a

'· »* ·' *!> \ J

* .... - a range of 1- (11-hydroxy) alkyl-2-o-hydroxyphenylcyclohexane or compounds described as intermediates for the preparation of 6,6-dialkyltetrahydro and hexahydro-dibenzo / b, d / -pyran, which can be used as depressants for the central nervous system.

It has now been found that certain cycloalkanones and their unsaturated analogs having a 2-hydroxy-4- (substituted) phenyl group (see formula 1 of the formula sheet) in the 3-position are effective as CNS agents, in particular as analgesic tranquilizers , sedative and anti-anxiety agents in mammals, including humans, and / or as anti-congestion agents, as diuretics and anti-diarrheal agents in mammals, including humans. Also included within the invention are a variety of derivatives of said compounds, which may become as dosage forms of said compounds, intermediates for compounds of formula 1, and methods of their preparation. The compounds have formula 1 of the formula sheet, wherein R is a saturated or unsaturated cycloalkyl portion of any one of formulas IA through 1D, the dotted lines representing an optional double bond at one of said positions, in which case R 4 is not present could be; R ^ hydrogen, alkanoyloxy of 1-5 carbon atoms, benzyl, -P (0) (0H) 2 and its mono and disodium and potassium salts, -CO (C ^) 2COOH and the sodium and potassium salts and is -CO- (CH_) -NRCRC, wherein p is an integer from 1-4; z p do each R 1 and R 9, when taken separately, is hydrogen or alkyl of 1 to 4 carbon atoms, R 1. and Rg when taken together with the nitrogen atom to which they are attached are a 5- or 6-membered heterocyclic ring, such as piperidino, pyrrolo, pyrrolidino, mofolino or N-alkylpiperazino having 1-4 carbon atoms in the alkyl group; R2 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 3-6 carbon atoms, phenyl or phenylalkyl of 1-4 carbon atoms in the alkyl portion os; R1 is hydrogen or methyl; R 1 is hydrogen or alkyl of 1 to 6 carbon atoms, provided that if R 1 is methyl, R 1 is hydrogen; Z (a) alkylene of 1-13 carbon atoms, (b) - (alk.) 1m ~

^ * o -> v V

• i - 3 - -O- (alk-) -is, wherein each (alk.) And (alk-) alkylene contains 1-13 z n i z.

carbon atoms, with the proviso that the sum of the carbon atoms in (alk ^) plus (alkj) is not greater than 13; each m and n is 0 or 1; and W is hydrogen, pyridyl or the group "T" p-W "wherein 5 is hydrogen, fluorine or chlorine.

The dotted lines in formulas 1-A to 1-D represent the possible presence of a double bond at one of said sites.

The invention also includes the pharmaceutically acceptable acid addition salts of the compounds of formula 1 wherein a basic group is present. Typical examples of such compounds are those in which the variable W is pyridyl and / or OR 1 represents a basic ester moiety. Polyacid addition salts are of course possible in compounds with two basic groups. Typical examples of such pharmaceutically acceptable acid addition salts are the mineral acid salts such as the hydrochloride, hydrobromide, sulfate, phosphate, nitrate; organic acid salts such as the citrate, acetate, sulfosyl licylate, tartrate, glycolate, malate, malonate, maleate, pamoate, salicylate, stearate, phthalate, succinate, gluconate, 2-hydroxy-4-naphthoate, lactate, mandelate and methanesulfonate.

Compounds of formula 1-A to 1-D and hydrogen exist in solution in equilibrium with their hemiketal forms. The keto and hemiketal forms of the compounds of Formula 1 are included in the invention.

Compounds of formulas 1-A to 1-D contain asymmetric centers in the 3- and 4-position and, when the cycloalkyl group has 6-8 members, in the 5-position, in the cycloalkyl part and they can , of course, contain even more asymmetric centers 30 in the 4- and 5-position substituents and in (-ZW) of the phenyl ring.

Trans-linkage between the 3 and 4 substituents and the 4 and 5 substituents on the cycloalkyl moiety is preferred because of the larger (quantitative) biological S. 7.

* * -4- activity.

For the sake of convenience, the racemic compounds are represented by said formulas. However, with the above formulas, the compounds are intended to be shown as species and include the racemic modifications of the compounds of the invention, the diastereomeric mixtures, the pure enantiomers and diastereomers thereof. The utility of the reacemic mixture, the diastereomeric mixture and also of the pure enantiomers and diastereomers is determined by the biological test methods to be described.

In addition to the above formulas, all kinds of intermediates which can be used in the preparation of compounds of formula 1 are also included in the invention. The intermediates have formulas 2-4 of the formula sheet (cis and trans isomers), which do not depict stereochemistry, and wherein Z, W, R2 and R1 have the meanings already cited; Y is cyano or formyl; is an integer from 1-8; hydrogen or alkyl of 1-4 carbon atoms and Q-CH2-. -CH2-CH (R4) -, -CH2-CH2-CH2 (R4) - and -CH2-CH2-CH2-CH. (R ^.

Compounds of formula 4 represent the hemiketal and ketal forms of the saturated cycloalkyl compounds of formula 1 (A-D).

Because of their greater biological activity over that of other compounds described herein, preference is given to compounds of formula wherein R 2 is hydrogen or alkyl, R 1 is hydrogen or alkanoyl, R 1 is hydrogen or methyl, R 4 is hydrogen or alkyl, and Z and W have the meanings given below.

_Z__ m__n W_

alkylene with 8-11 carbon - - H

material atoms 30 alkylene with 4-7 carbon - - Wx, pyridyl material atoms (alk1) m-0- (alk2) n o i Wj, pyridyl

(alk.) -0- (alk_) 0 1 H

lm 2 n - Λ ~ C.

F -j V -J * - 5 -

Preference is given to the saturated cycloalkyl compounds of the formula I, wherein R 1 and R 5 are hydrogen, ZC is (CHg) g- (C 1 Jg and W is hydrogen; ZC is 1- alkylene and W is phenyl. alkyl is 7-9 carbon atoms and W is hydrogen ZO-alkyl-5 is 4-5 carbon atoms and W is phenyl R2 is hydrogen, methyl, propyl or propenyl, Rg is hydrogen and is hydrogen or methyl.

As for analgesic activity, preference is given to compounds wherein R2 is methyl, propyl or propenyl and each R1 and R. is hydrogen.

The saturated cycloalkyl compounds of the invention of formula 1 wherein Rg is hydrogen are prepared from the appropriate 2-bromo-5- (ZW-substituted) phenol in a series of reactions involving protection in the first step of the phenol group. Typical examples of such protecting groups are methyl, ethyl, benzyl or substituted benzyl, wherein the substituent is, for example, alkyl with 1-4 carbon atoms, halogen (Cl, Br, F, I,) or alkoxy with 1-4 carbon atoms is. The protecting groups can be removed using 48% aqueous hydrobromic acid in acetic acid or hydrobromic acid.

The reaction is carried out at elevated temperatures and advantageously at the reflux temperature. However, when Z is -Calkyl] -O-ialAl, acids such as polyphosphoric acid or trifluoroacetic acid should be used to avoid cleavage of the ether bond. Other reagents, such as hydroiodic acid, pyridine hydrochloride or hydrobromide, can be used to remove protecting ether groups, such as methyl or ethyl groups. When the protecting groups are benzyl or substituted benzyl groups, they can be removed by catalytic hydrogenolysis. Suitable catalysts are palladium or platinum, especially on a support. They can also be removed by solvolysis using trifluoroacetic acid. In another method, it is treated with n-butyl lithium in an inert solvent at room temperature.

The correct chemical structure of the protecting group is not critical to the invention because its meaning is C "^ ~" Λ

V * *, y -J

4 V.

- 6 - lies in its ability to behave in this way. Methyl and benzyl are preferred as protecting groups because they are easily removed.

The protective 2-bromo-5- (ZW-substituted) phenol is then added with magnesium in an inert solvent and, as a rule, in the presence of a promoter, for example cuprous salts such as the chloride, bromide and iodide (to promote 1, 4 addition) reacted with the appropriate 4-R2-2-cycloalken-1-one (e.g., 4-R2-2-cyclohexen-1-one). Useful solvents which are inert to the reaction are cyclic and acyclic ethers, such as, for example, tetrahydrofuran, dioxane and dimethyl ether of ethylene glycol (diglyme). The Grignard reagent is formed in known manner, for example by refluxing a mixture of 1 mol part of the bromine reactive component and 2 models of magnesium in an inert solvent, for example tetrahydrofuran. The resulting mixture is then cooled to 0 to 20 ° C and cupro iodide, followed by the appropriate 2-cycloalkan-1-one is added at 0 to -20 ° C. The amount of iproiodide used is not critical, but can vary widely.

Molar amounts of about 0.2 to 0.02 moles per mole of bromine reactive component yield good yields of the cycloalkanone in which the phenolic hydroxy group is protected (formula 1-A to 1-D; R ^ is a protecting group , R ^ is H and A + B is oxo)

Then the cycloalkanone protecting is treated with a suitable reagent to remove the protecting group. The benzyl group is effectively removed by the method already described. When the protecting group is an alkyl group (methyl or ethyl), it is removed by the methods already described or by treatment with, for example, pyridine hydrochloride.

When R2 is an alkenyl group, the resulting cycloalkanones serve as intermediates for the preparation of the respective cycloalkanones, wherein R2 is alkyl.

Q '' Q v „vvo · -.

«Fc - 7 -

Compounds of formula 1, wherein the double bond is at the 2,3 positions, are prepared by Grignard reaction of the appropriately protected 2-bromo-5- (ZW-substituted phenol with a 3-alkoxy-2-cycloalkanone ( with 1-4 carbon atoms in the alkoxy group) in a reaction-inert solvent at a temperature of about -30 to + 10 ° C. The protected cycloalkanone compound thus prepared is then deprotected in the manner already described.

Compounds of formula 1 in which the double bond is in the 3,4 position are prepared from compounds of formula 1 in which the double bond is in the 2,3 position.

The method involves ketalizing the correct 2,3-unsaturated compounds of formula 1 with an alkylene glycol of 1-4 carbon atoms in the presence of a dehydrating agent, such as p-toluenesulfonic acid, in a solvent such as benzene, whereby the by-product water can be azeotroped deleted. Isomerization of the double bond to the 3,4-unsaturated ketal derivative takes place. Decalization by treatment with weak acid gives the 3,4-unsaturated compounds of formula 1A-1D.

The protected cycloalk-2 anons (Formula 1 R 1 is protecting group) also serve as intermediates for compounds of Formula 1, wherein R 1 is methyl. The substituent is introduced by conjugated addition of dimethyl copper lithium to the appropriate cycloalk-2-enone. In this method, the appropriate protected cycloalkanone is reacted with dimethyl copper lithium in an inert solvent, such as cyclic and acyclic ethers, and especially in tetrahydrofuran, at 0 to -20 ° C. The organometallic reagent accomplishes 1,4 addition to the described cyclalkenone to form a tertiary carbon atom. The R 3 -30 substituted protected cycloalkanone is then deprotected. The 1,2 addition product is also formed.

Compounds of formula 1B, in which the cycloalkyl portion is saturated and in which R 1 is slightly other than hydrogen, are prepared by using the appropriate 2-bromo-5- (Z-W-substituted) phenol,

O - '- 7 ~ O

In which the phenol group is protected in an effective manner with magnesium reaction, so that the Gripnard reagent is formed, as already described. The Grignard reagent is then treated with Ν, Ν-dimethylformamide without isolation at a reduced temperature, for example +10 to -20 ° C, 5. The reaction mixture is then allowed to come to room temperature and the product, namely a protected 2-hydroxy-4- (2-W-substituted) benzaldehyde, is recovered by known methods. The benzaldehyde derivative is then converted to a (— (2-hydroxy-4- (ZW-substituted) phenyl) -3-alkenone-10 via the Wittig reaction with the appropriate 1-triphenylphosphoranylidene-2-alkanone in an inert solvent at room temperature to the reflux temperature of the solvent. The cyclohexyl part can be formed by the said 2-propanone derivative. The arylalkenone so prepared is then reacted with a dialkyl malonate, preferably one in which the alkyl groups have 1-4 carbon atoms to cyclize the alkenone. The reaction is carried out in an inert solvent, such as an alcohol of 1-4 carbon atoms, at 25 ° C to the reflux temperature of the solvent.

The prepared carbalkoxy substituted cycloalkanedione-20 compound is then decarboxylated by treating it with aqueous sodium or potassium hydroxide at elevated temperature, i.e., about 50-100 ° C, after which the cycloalkanedione derivative is isolated by known methods. It is then catalyzed by reaction with methanol or other alcohol of up to 4 carbon atoms, or an alkylene glycol of 2-4 carbon atoms, in the presence of a dehydrating acid such as p-toluenesulfonic acid.

In the case of the cyclohexyl derivative, the 3-methoxy-2-cyclohexan-1-one derivative is then treated with lithium aluminum hydride in a reaction-inert solvent such as diethyl ether, dioxane, tetrahydrofuran or diglyme, at a temperature of approximately -10 to + 10 ° C reacted and worked up with dilute mineral acid. The resulting aryl substituted 2-cyclohexan-1-ones are then mixed with the appropriate dialkyl copper-lithium in an inert solvent such as hexane, diethyl ether or λ - - »λ V, *« / - 3 '. / * _ - * t *. Mixtures of these solvents or in cyclic ethers, such as tetrahydrofuran, are treated at temperatures from about 0 to -20 ° C. The protected 3- / 4- (Z-W-) -substituted-2-hydroxyphenyl-7-S-R-cycloalkanone is then deprotected.

Also the reaction of the 5- / 2-benzyloxy-4- (ZW) phenyl7-3-alkoxy-2-cyclohexen-1-ones with the appropriate Grignard reagent gives R 1 MgBr followed by hydrolysis with acid to give the corresponding 5 - / 2-benzyloxy-4- (ZW) -phenyl-7-3-R 2 -2-cyclohexen-1-ones, which are then catalytically reduced to the corresponding 10 cyclohexanones. Debenxylation in the manner already described gives the 5- / 2-hydroxy-d- (2-W) -phenyl / -3-R 1 -cyclohexanones.

Compounds of formula 1C, in which the cycloalkyl portion is saturated and in which R4 is other than hydrogen, are prepared by ring enlargement of the cyclohexyl derivative.

Reaction of the appropriate 5- / 2-benzyloxy-4- (ZW) -3-R-cyclohexanone with lithium dibromomethane in an inert solvent, such as diethyl ethers, gives the 1-dibromomethyl-5- / 2-benzyloxy-4 - (ZW) -phenyl / - 3-R'-cyclohexanol. Upon further reaction of the 1-dibromomethyl-cyclohexanol in a reaction-inert solvent, such as tetrahydrofuran, with n-butyl lithium, 3- / 2-hydroxy-4- (ZW) -phenyl-7-5-R4 -7 cycloheptanones, which are then deprotected.

Compounds of formula 1D, in which the cycloalkyl portion is saturated, and wherein R 1 is other than hydrogen, are prepared by ring enlargement of the cycloheptyl derivative using the methods already described.

When R. in the structure 1A-IC is hydrogen, it is possible according to the methods already described to effect ring enlargement of these structures to the ring with a methylene, ie to 1B-1D, respectively.

The 2-bromo-5- (Z-W-substituted) phenol reactive components are prepared by bromination of the appropriate 3- (Z-W-substituted) phenol by known methods, such as, for example, treatment with bromine in carbon tetrachloride at 20 to 30 ° C.

- 10 -

The required 3- (Z-W-substituted) phenols, if not yet known, are prepared by methods described herein.

A suitable method for the preparation of such reagents in which the portion Z is alkylene or (alk.) -0- (alk ") - consists in that the Whitea reaction is applied to a suitable aldehyde, such as 2- (3-hydroxyphenyl) -2-methylpropionaldehyde, the hydroxy group of which is protected by the formation of benzyl ether. This aldehyde is then treated with the appropriate alkyl triphenylphosphonium bromide, the alkyl group of which increases the propionaldehyde-10 group to the desired length. In a typical process, the reactive aldehyde is added to a suspension of sodium dimsyl and alkyl triphenylphosphonium bromide in dimethyl sulfoxide at a temperature below 30 ° C, e.g. 10-30 ° C. When the reaction is complete, the olefin-substituted protected phenol is recovered by known methods. Hydrogenation of the olefin over palladium-on-carbon then yields the desired 3- (2-W-substituted) phenol benzyl ether. By judicious selection of the starting material (3-hydroxyphenyl) substituted aldehyde and alkyl triphenylphosphonium bromide as reactive components, the required 3- (Z-W-substituted) phenol reagents are obtained.

The preparation of the appropriate 4-R2-2cycloalken-1-one allows the synthesis of the structures of formula 1A-D, wherein is hydrogen, using the methods already described. Reaction of the appropriate 1,3-cycloalkanedione with an alcohol of 1-4 carbon atoms and an acid such as p-toluenesulfonic acid as a catalyst in an inert solvent such as benzene or toluene and with a water separator at temperatures, the reaction solvent boiling under reflux gives 3-alkoxy-2-cycloalkan-1-ones. Reaction of the appropriate 3-alkoxy-2-cycloalkan-1-one with lithiodiisopropylamide in a reaction-inert solvent, such as benzene or toluene, and with a water separator at temperatures, the reaction solvent being below O Λ ~ -

J V V V V 'J

- 11 -

refluxing yields 3-alkoxy-2-cycloalkan-1-ones. Reaction of the appropriate 3-alkoxy-2-cycloalkan-1-one with lithium diisopropylamide in a reaction-inert solvent, such as tetrahydrofuran, in the presence of hexamethylphosphoramide and the appropriate compound R2X, wherein X

bromide or iodide or other suitable disappearing group gives 4-R2-3-alkoxy-2-cycloalkan-1-ones. Then the 4-R 2 -3-alkoxy-2-cycloalkan-1-one is reacted with lithium aluminum hydride in an inert solvent, such as diethyl ether, at temperatures from about -10 to + 10 ° C and worked up with dilute mineral acid. The 4-R2-2-cycloalkan-1-one obtained is then reacted by the known methods already described.

Compounds of formula 1B-1D, in which the cycloalkyl portion is saturated and in which R2 and R1 are each other than hydrogen, are prepared by reaction of the appropriate 5- / 2-benzyloxy-4- (ZW) -phenyl7 -3-methoxy-2-chlohexan-1-one with lithiodiisopropylamine in an inert solvent at low temperature, such as, for example, -50 to -78 ° C. Hexamethylphosphoramide and the appropriate R2 iodide (wherein R2 is not hydrogen) are then added so that a 5- / 2-benzyloxy-4- (ZW) -phenyl-7-methoxy-6-R2-2-cyclohexan-1- on arises. Upon further reaction of this compound with the appropriate Grignard reagent R 1 'MgX (wherein R 1' is alkyl) under conventional conditions for Grignard reactions, a 3- / 2-benzyloxy-4- (ZW-) phenyl / -4-R2- 5-) R 1 1-5 -cyclohexen-1-one obtained. Reduction of the double bond of the 3- / 2-benzyloxy-4- (Z-W) -phenyl-7-4-R2-5-R-5-cyclohexen-1-one over Pd / C yields the corresponding saturated cyclohexanone derivative. The latter derivatives serve as intermediates for the preparation of corresponding cycloheptanone and the cyclooctane derivatives by the ring enlargement already described.

An effective method, which permits selective alkylation of 3- (2,4-dihydroxyphenyl) cycloalkanones in the 4-hydroxy group, comprises, as a first step, the conversion of the 1 '»* 7> - -, -12- Ψ h 3- (2,4-dihydroxyphenyl) cycloalkanone in a ketal. The reaction is carried out by methods known for ketalization, such as reaction of the 3- (2,4-dihydroxyphenyl) cycloalkanone with an alcohol, in particular an alcohol with 1-4 carbon atoms, in the presence of an acid, such as sulfuric acid, p-toluenesulfonic acid , hydrochloric acid, under conditions in which the by-product water is removed. A preferred method comprises reacting the 3- (2,4-dihydroxyphenyl) cycloalkanone with an orthoformic acid ester in solution in an alcohol corresponding to the alcohol portion of the orthoformic acid ester. Trimethyloryhormate and methanol are preferably used as gentia with concentrated sulfuric acid, anhydrous hydrochloric acid or ammonium chloride as the catalyst.

The ketal thus prepared is then alkylated with a suitable alkylating agent, such as WZX, where W and Z have the meanings referred to, and X chlorine, bromine, mesyloxy (CH2 -SC ^ -O) and tosyloxy (p-CH2. -Cg-H 2 -SC 2 -O-) can be in the presence of an acid binding agent such as, for example, sodium or potassium carbonate. The alkylated ketal is then decetalized by known methods by treatment with aqueous acid.

Another method for preparing 3- (ZW-substituted) phenols, wherein Z is alkylene or (alk.) -0- (alk 4) n 1 XQ 6, involves the Witti reaction with a suitable phenolic aldehyde or ketone, such as 3-hydroxybenzaldehyde or a 3- (hydroxyphenyl) alkyl ketone, in which the phenolic hydroxy group is protected, for example by conversion to the benzyl, methyl or ethyl ether. Compounds with straight or branched alkylene groups (Z) can be prepared by an effective choice of reagents. When a ketone, for example 3-hydroxyacetonphenone, is used as a reagent, compounds in which Z has a methyl group on the carbon atom next to the phenyl group are obtained.

Substitution of a methyl or ethyl group to other places, for example the β-carbon atom of the alkylene group, ... «-1 · **»

... V V

r ....................................... I "s * - 13 - is reached by choose the appropriate carboalkoxyalkylidene triphenylphosphorane, for example, (C 8 H 3) ^ = O (R ') - CCXX ^ H ;.

The unsaturated ester thus prepared is reduced to the corresponding alcohol by reaction with lithium aluminum hydride.

When the phenolic protecting group is other than benzyl (eg methyl), the alcohol is also formed by catalytic reduction of the unsaturated ester with palladium carbon followed by treating the ester thus prepared with lithium aluminum hydride. Conversion of the alcohol thus prepared into the corresponding tosylate or mesylate, followed by alkylation of the tosylate or mesylate with an alkali metal salt of the appropriate HOialkjJ-W reactive component and finally removal of the protecting group yields the quenched 3- (ZW-substituted) phenol on.

A variant of this series includes bromination of the alcohol rather than converting it to a tosylate or mesylate. Phosphorus tribromide is a suitable brominating agent. The bromo derivative is then reacted with the appropriate B0 (alk2) -W in the presence of a suitable base (Williamson ether synthesis).

The bromine compounds also serve as intermediates to increase the chain length of the alkylene moiety in the above reactions to give compounds wherein Z is alkylene-W. The method involves treating the bromo derivative with triphenylphosphine to produce the corresponding triphenylphosphonium bromide. Reactions of the triphenylphosphonium bromide with the appropriate aldehyde or ketone in the presence of a base, such as sodium hydride or n-butyl lithium, yield an unsaturated derivative, which is then catalytically dehydrogenated to the corresponding saturated compound.

Another method of introducing an alkyl or aralkyl group into the aromatic core, and in particular such a group, wherein the carbon atom next to the aromatic core is a - 14 - tertiary carbon atom, involves the acid-catalyzed electrophilic aromatic substitution of guajacol with a tertiary alcohol in the presence of an acid, such as methanesulfonic acid. The general method consists in reacting a mixture of 5-methanesulfonic acid and equimolar amounts of guajacol and tertiary alcohol at temperatures of 30-80 ° C until the reaction is nearly complete. The product is isolated by pouring the reaction mixture on ice and then extracting with a solvent such as methylene chloride. Then the 2-methoxy-4-alkyl-phenol is converted to the desired 3-alkyl-phenol by removing the phenolic hydroxy group. The method involves converting the hydroxy group to a dialkyl phosphate group by reaction with a dialkyl chlorophosphonate, such as, for example, diethyl chlorophosphonate, or with diethyl phosphonate and triethylamine. Treatment of the dialkyl phosphate with lithium / ammonia followed by demethylation of the resulting alkylated methyl ether with boron tribromide or pyridine, hydrochloride or other known demethylating agents. gives the desired 3-alkylphenol.

In an effective method of preparing compounds of the invention, wherein -Z-W-CMalk1 -W is used, 3-bromo resorcinol is used as starting material. The method includes protecting the two hydroxy groups of resorcinol by benzene by known methods. The benzyl group 25 is preferred as a protecting group because it can be easily cleaved off by catalytic hydrogenation without cleavage of the ether group -O- (alk2) n-W-. Other protecting groups, such as alkyl (e.g. methyl or ethyl) can also be used. However, the benzyl protecting group is more preferred because it has fewer side reactions. The protected 4-bromo resorcinol is then subjected to the Griqnard reaction and reacted with the appropriate cycloalkanone in an inert solvent as described above. The 3- (2,4-dibenzyloxyphenyl) -cycloalkenone --λ '7 ^' q * s * -, v - * - 15 - thus prepared is then subjected to catalytic hydrogenation over palladium op-carbon, whereby the corresponding 3- (2,4-dihydroxyphenyl) -cycloalkenone is formed, which exists in equilibrium with its hemiketal. The hemiketal is then converted to the corresponding C 1-4 alkyl (eg methyl ketal by reaction with, for example, a trialkyl orthoformate, such as trimethyl orthoformate, in a suitable solvent, such as a C 1-4 alcohol, eg methanol, in the presence of concentrated sulfuric acid .

The alkyl ketal thus prepared is then alkylated with the appropriate alkyl or aralkyl methanesulfonate or tosylate in the presence of anhydrous sodium or potassium carbonate in an inert solvent, such as N, N-dimethylformamide, at 75-100 ° C. This method has the advantage that simpler compounds can be used throughout the reaction sequence. Thereafter, the 0-alkylated or aralkylated ketal is decetalized by reaction with, for example, hydrochloric acid to give the corresponding 3- (2-hydroxy-4) / 0- (alk9) 7-phenyl-cycloalkanone, which exists in equilibrium with its hemi-metal .

Since the compounds of formula 1, wherein R 1 is hydrogen, exist in solution in equilibrium with the hemiketal form and simmigen, in crystalline state, exist substantially entirely in the hemiketal form, it is intended that among compounds of formula 1, in which hydrogen is also the hemiketal and keto form.

Esters of compounds of formula 1 wherein R 1 is alka-25 noyl or -CO- (C 1) ^ NR ^ R 9 are readily prepared by compounds of formula 1A-1D, wherein R 1 is hydrogen, with the appropriate alkanoic acid or acid with formula H00C- (CH2 NR ^ Rg in the presence of a condensing agent, such as dicyclohexylcarbodiimide). They can also be prepared by reacting a compound of formula 1A-1D with the appropriate alkanoic acid chloride or anhydride, such as for example, acetyl chloride or acetic anhydride, in the presence of a base, such as pyridine.

F * * _ ** V ** ^ * «" V * «-" 'j - 16 -' I * is acylating, VverèregeSeSoorarin only the 9 «βρ R (Requirement OH, CB2OH> mild hydrolysis of the corresponding diacyl ^ derivative advantageously making use of the easier hydrolysability of the phenolic acyl group The compounds thus prepared can then be further acylated with another part of the cycle to give a double esterified compound having different ester groups.

The analgesic properties of the compounds of this invention are determined by tests using nociceptive stimuli.

Tests using thermal nociceptive stimuli a) Analgesic examination of hot plate mice

The method used is modified according to Woolfs and MacDonald (see J. Pharmacol. Exp. Ther. 8 (5 (1944), 300-307). Controlled heat stimulus was applied to the legs of a mouse on a approximately 3 mm thick sheet of aluminum. An infrared reflector lamp of 250 watts was placed under the bottom of the aluminum plate 15. A heat controller, connected to thermistors on the plate surface, programs the heat lamp so that the temperature is kept constant at 57 ° C. Each mouse was placed in a cylinder glass (diameter approx. 17 cm) resting on the hot plate, released and the timing starts as soon as the animal's legs touch the plate The mouse is observed for half an hour and 2 hours after the treatment with the compound to be examined. first "pulling" movements of either or both hind legs, or until 10 seconds have passed without such movements Morphine has an MPE50 = 4-5.6 mg / kg (sc).

B) Analgesic study in mice on tail pulling

The mouse pull tail assay is modified according to D'Amour and Smith (see J. Pharmacol. Exp. Ther. 72 (1941) 74-79, applying heat at a controlled high intensity to the tail. Each mouse is placed in a form-fitting metal cylinder with its tail protruding through one end This cylinder is arranged so that the tail lies flat on a hidden heat lamp At the start of the study an aluminum "flag" is placed over the lamp withdrawn so that the beam can pass through the slit and focus on the end of the tail At the same time, a timer is triggered The latency of a ^ ^ -w * Λ -: · <, v & v tv 'v <♦ * -17- - sudden tail pulling is detected · Untreated mice usually respond within 3-4 seconds after exposure to the lamp The end point of protection is 10 seconds Each mouse is half hours and 2 hours after treatment with morphine and the compound to be investigated. Morphine has an MPEg of 3.2-5.6 mg / kg (s.c.).

c) Method of dipping the tail

The method is a modification of the "vessel" method developed by Benbasset et al. (See Arch. Int. Pharmacodyn. 122 (1959), 434).

10 Albino male mice (19-21 grams) of the Charles River CO-1 strain are weighed and marked for identification. Five animals are usually used in each drug treatment group, each animal serving as its own control. For general guidance, new investigational agents are first administered at a dose of 56 mg / kg intraperitoneally or subcutaneously given in a volume of 10 ml / kg. Before the drug treatment and half an hour and 2 hours after, each animal is placed in the cylinder. Each cylinder is provided with holes, allowing good ventilation, and closed with a round nylon stopper, through which the animal's tail protrudes. The cylinder is held vertical and the tail is fully immersed in the constant temperature waterbed (56 ° C). The end point of each test is a strong tug or pull of the tail coupled with a motor response. In some cases, the endpoint after drug administration may be less potent. To avoid unnecessary tissue damage, the test is terminated and the tail removed from the waterbed within 10 seconds. The latency in response is recorded to 0.5 seconds in seconds. A carrier check and a standard.

of known force are examined simultaneously with the examination of candidates. If the activity of an agent to be investigated has not returned to the baseline values at the time of 2 hours of the test, latencies at 4 and 6 hours are determined. A final measurement is taken at 24 hours, when activity is still observed at the end of the study.

Investigation using nociceptive stimuli 35 Suppression of the phenylbenzoquinone irritant causes shrinkage

Groups of 5 Carworth Farms CF-1 mice are first sub-1 * T <»-ΤΛ f * \ \ '' J 'V *> w, -18- * t 9 cutaneous or oral with saline, morphine, codeine or the treated compound. 20 minutes (in the case of subcutaneous treatment) or 50 minutes (in the case of oral treatment) each group is treated by intraperitoneal injection of phenyl benzoquinone, an irritant, 5 of which is known to cause abdominal contractions. The mice are observed for the occurrence or contraction of the skin for 5 minutes, starting 5 minutes after the injection of the irritant. The MPEGs of the drug pretreatment anti-crease blocking agents are determined.

10 Tests using pressure nociceptive stimuli Effect on the tail pinch method according to Haffner

A modification of Haffner's method (see Experimental-le Prüfung Schaerzstillender + Deutsch Med. Waschr. 55_ (1929), 731-732) is used to determine the effector; of the compound to be tested for aggressive attack reactions caused by a stimulus squeezing the tail. Albino male rats (50-60 grams) are used in the Charles River (Sprague-Dawley) CO strain. Before drug treatment and also for 0.5, 1, 2 and 3 hours thereafter, a approximately 6.5 cm large "bulldog" clamp from Johns Hopkins is clamped on the implantation of the tail 20. The end point of each trial is a distinctly offensive and caustic behavior, which is directed towards the stimulating stimulus, incorporating attack latency in seconds. The clamp is removed in 30 seconds when no attack has taken place yet and the latency in response is recorded as 30 seconds. Morphine is active at 17.8 mg / kg (i.p.).

Tests using electrical nociceptive stimuli The "Trek-Spring" test

A modification of the Tenen pull-jump method (see Psychopharmacology 1_2 (1968), 278-285) is used to determine 30 pain thresholds. Albino male rats (175-200 grams) of the Charles River (Sprague-Dawley) CO strain are used. Before obtaining the drug, the legs of each rat are dipped in a 20% glycerol / salt solution. The animals are then placed in a room and exposed to a series of 1-second shocks to the 35 legs, which increase at 30-second intervals with increasing intensity.

R, Ί> ‘A

«-> * -19 - # - λ are given. These intensities are 0.26, 0.30, 0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04 mA. Each animal's behavior is monitored for the occurrence of (a) pulling, b) jerking, and (c) jumping up or rapid forward movement at the onset of shocks.

Each rat is exposed to simple ascending series of shock intensities just before and at 0.5, 2, 4 and 24 hours after drug treatment.

The results of the tests described above are noted as a maximum effect maximum percentage (% MPE). The% MPE of each group 10 is statistically compared to the% MPE of the standard and the control values before drug treatment. The / MPE is served as follows:

% MPE = Pr ° eftija - checkout χ I0Q

If the compounds of the invention are used as analgesics by oral or parenteral administration, they are usually administered in the form of a preparation. Such formulations include, inter alia, a pharmaceutical carrier selected according to the mode of administration selected and known pharmaceutical methods.

2Q They can be administered, for example, in the form of tablets, pills, powders or capsules containing excipients, such as starch, milk sugar, certain types of clay, etc. They can be administered in capsules, as mixtures with the same or equivalent excipients. They can also be administered in the form of oral suspensions, solutions, emulsions, syrups and elixirs, which may contain flavors and colors. For oral administration of the therapeutics of the invention for most applications are tablets or capsules containing about 0.01-100 mg. -.

fit. . '

The physician determines the dosage most suitable for a particular patient and varies with the age, weight and response of the particular patient and the route of administration. In general, the initial dose of the analgesic in adults is about 0.1-750 mg per day, in single or divided doses. In many cases it is not necessary to give more than 100 mg per day. Preferably, an oral dose of about 1.0-300 mg / day is given, and most preferably about 1.0-50 mg / day. The preferred parenteral dose - 20 - is about 0.1-100 mg / day and most preferably about 0.1-20 mg / day.

The invention also provides pharmaceutical compositions, such as, among others, unit doses, which are suitable for the use of the compounds described herein as analgesics and other uses mentioned herein. The dosage form can be given in one or more doses, as already mentioned, so that the daily dose effective for a particular application is achieved.

The compounds (drugs) described herein can be formulated into a solid or liquid form suitable for ral or parenteral administration. Capsules containing medicines according to the invention are prepared by mixing 1 part by weight of medicine with 9 parts by weight of excipient, such as starch or 15% milk sugar, and then transferring the mixture into telescoping gelatin capsules, so that each capsule contains 100 parts of the mixture. Tablets containing these compounds are prepared by mixing together suitable mixtures of drug and standard ingredients used in the preparation of tablets, such as starch, binders and lubricants, such that each tablet 0.10-100 mg of drug per tablet.

Suspensions and solutions of these drugs, especially those in which R ^ (formula 1) is hydroxy, are often prepared just prior to their use in order to avoid stability problems of the suspension or solution (eg sag) of the drug in case of storage to prevent. Formulations suitable for this are, as a rule, dry solid formulations which are reconstituted for administration by injection.

Using the methods described above, the analgesic activity of various compounds of this invention is determined. The compounds have formula 5. The results are shown in Table A.

~ ^ ~ * -Λ <- 21 -

The following abbreviations are used in the table: PGQ = phenylbenzoquinone induced cringe TF = tail pulling HP = hot plate? RTC = clamp on rat tail and F3 = pull-up jump.

5 Single values in the table are ED ^ q's. A number followed by a second number in brackets indicates the percentage of protection observed at a given dose. For example, 31 (56) represents 31% protection at a dose of 56 mg / kg body weight.

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Their activity as diuretics is determined by the method of Lipschitz et al. (See J. Pharmacol. 197 (1943), 97, using rats as test animals. The dosage for this application is the same as that mentioned above for the use of the compounds described herein as analgesics.

The utility against diarrhea is determined by a modification of the method of Neimegeers et al. (See Modern Pharmacology-Toxicology, Willem van Bever and Harbans Lal, Eds. 7 (1976) 68-73). Charles River CD-I rats (1702Θ0 grams) are placed in group cages 18 hours before the study. The animals were not fed overnight, but water was sufficiently available before recinus oil is administered. The drug to be tested is administered subcutaneously or orally at a constant volume of 5 ml / kg body weight in a 5% ethanol, 5% = Emulphor El-620 "(a polyoxyethylated vegetable oil as an emulsifying agent, available from Antara Chemicals, New York, NY) and 90% saline as a carrier, followed an hour later by administration of castor oil (Iml.oraal) .The animals are transferred into small individual cages (20.5xl6x21cm) with hanging mesh floors.20 Under the mesh floors, a disposable sheet of cardboard is placed and examined one hour after the administration of castor oil for the occurrence of diarrhea. A group treated with carrier and castor oil serves as a control in the examination every day. The results are recorded as the number of animals, which is one hour Is protected after the administration of castor oil In general, the dosages for use of these compounds as anti-diarrheal agents are similar to those in case of use. ssing as analgesics.

The tranquilizer activity of the compounds of the invention is determined by administering them orally to rats at doses of 0.01-50 mg / kg body weight and then monitoring the decrease in spontaneous motivity. The daily dose for mammals is 0.01-100 mg.

The activity against convulsion is determined by the compound to be tested in a carrier, such as for use against *** 7 *.

- Λ - <'* v> \ J v _ 24 _ diarrhea is used, to be administered subcutaneously to Swiss male mice (Charles River) weighing 14-23 grams.

The mice are used in groups of five. The day before use, get the. mice do not eat overnight, but enough water. The treatments are given in volumes of 10 ml per kg using a hypodermic injection needle No. 25. The test animals are treated with the test compound and an electroconvulsive shock of 50 mA at 60 Hz is administered transcomally 1 hour after administration. Controls are performed simultaneously and herein the mice receive only the vehicle as control treatment. Electroconvulsive shock treatment produces tonic extensor convulsions with a latency of 1.5-3 seconds in all control mice. Protection is noted when a mouse does not experience a tonic extensor convulsion 10 seconds after electroconvulsive shock administration.

The activity against anxiety states is determined in a manner similar to that for investigating the activity against convulsion, except that the convulsant to be administered is pentylene tetrazole administered with 120 mg / kg intraperitoneate. This treatment causes clonic seizures in less than 1 minute in more than 95% of treated control mice. Protection is noted when the latency to convulsions is delayed at least 2 times by drug pretreatment.

The sedative / depressant activity is determined by treating groups of six mice subcutaneously with different doses of investigative agents 30 and 60 minutes after treatment, the mice are placed on a rotating rod for 1 minute and judged on their behavior on the rotating rod . The mice's inability to remain in the spinning mode is seen as evidence of sedative / depressant activity.

Example I

3- / 2-Benzyloxy-4- (1,1-dimithylheptyl) phenyl7cyclohexanone

A solution of 75.0 grams (0.193 mol) of 2- (3-benzyloxy-4-bromophenyl / -2-methyloctane in 200 ml of tetrahydrofuran was added a-? + Λ 5 »Λ::" · ··.

V v y v v -j v - 25 - slowly added to 9.25 grams (0f386 mol) of magnesium metal of 70-80 mesh. The resulting mixture was refluxed for 20 minutes and then cooled to -18 ° C. 1.84 Gram (9.7mmol) cuprous iodide was added and stirred for an additional 10 minutes. A solution of 18.5 grams (0.193 mol) of 2-cyclohexen-1-one in 40 ml of tetrahydrofuran was slowly added to the resulting mixture at such a rate that the reaction temperature was kept below -3 ° C, with salt / ice was cooled. The reaction mixture was stirred for an additional 30 minutes (temperature below 0 ° C) and then added to 500 ml of 2 normal hydrochloric acid and 2 liters of ice water. The cooled reaction mixture was extracted three times with 500 ml of ether each time. The combined extracts were washed twice with 100 ml of water each, twice with 100 ml of saturated saline each, dried over magnesium sulfate and evaporated to leave an oil. The oil was purified by column chromatography over 1.6 kg of silica gel, eluted with 20% ether cyclohexane to yield 62.5 grams (yield 79.7%) of oil as product.

IR: (CHCl 3) 1709, 1613 and 1575 cm -1.

MS: ra / s 406 (M +), 362, 321, 315 and 91.

The compounds listed below were prepared from suitable 20-benzyloxy-4-Z-W-bromobenzenes and suitable cycloalkones according to the method described above.

3- ^ ~ 2-Benzyloxy-4- (2- (5-genylpentyloxy)) phenyl-7cyclohexanone as oil (3.6 grams, yield 87%) from 2-benzyloxy-4 - / - 2- (5-phenylpentyloxy) 7- bromobenzene (4.0 grams, 9.4 mmol).

IR: (CHCl 3) 1712, 1616 and 1592 cm -1.

MS: m / e 422 (M +), 351, 323, 296, 278, 252, 205 and 91.

Trans-3 - / "benzyloxy-4- (1,1-dimethylheptyl) phenyl-7-4-methyl-cyclohexanone as oil (5.11 grams, yield 61%) from 2-benzyloxy-4- (1,1-dimethylheptyl) Bromobenzene (7.83 grams, 0.0201 mol) and 4-methylcyclohexan-30-1-anone (2.21 grams, 0.0201 mol).

IR: (CHCl 3) 1712, 1613 and 1575 cm -1.

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

3- / 2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl / cyclopentanone as oil (3.5 grams, 58%) from 2-benzyloxy-4- (1,1-dimethylheptybromo-35 benzene (6.00 gram, 15.4 mmol); RF® 0.43 (0.25 mm silica gel, eluted with 1: 1 ether: hexane.

3- / 2-Benzyloxy-4- {1,1-dimethylheptyl) phenyl / cycloheptanone as oil (2.94 grams, yield 46%) from 2-benzyloxy-4- (1,1-dimethylheptylX-bromobenzene (6.00 grams) , 15.4 mmol) and cycloheptanone (1.69 grams, 15.4 mmol).

- - ** -1 b - 26 -% 3- (2,4-Dibenzyloxyphenyl) cyclohexanone as a solid (17.9 grams, yield 40%), mp 108-109 ° C; from 1-bromo-2,4-dibenzyl-oxybenzene (43 grams, 0.116 mol) and cyclohex-2-enone (11.1 grams, Q116 mol). The product was recrystallized from ether: pentane.

IR: (CHCl 3) 1709, 1618 and 1595 cm -1.

MS: m / e 295, 181 and 91.

Analysis for C26H26 ° 3:

Calculated: C 80.80%; H 6.78%.

Found: C 80.88%; H 6.80%.

3- / "2-Benzyloxy-4- (1,1-dimethyloctyl) phenyl-7cy <= lohexanone as oil (5.0 grams, yield 46%) from 2- (3-benzyloxy-4-bromo-enyl) -2- methyl nonane (10.4 grams, 0.0258 mol) and 2-cyclohexan-1-one (2.48 grams, 0.0258 mol). IR: (CHCl 3) 1715, 1618 and 1577 cm -1.

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

3- / 2-Benzyloxy-4-tert-butylphenyl) cyclohexanone as oil (27.6 grams, yield 58%) from 2- (3-benzyloxy-4-bromophenyl) -2-methylpropane (45.4 grams 0.142 mol) and 2-cyclohexan-1-one (13.9 grams, 0.146 mol).

IR: (CHCl 3) 1724, 1623 and 1582 cm-1.

MS: 336 (M +), 321, 293, 245 and 91.

3- / 2-Benzyloxy-4-1,1-dimethylpropyl) phenyl / cyclohexanone as oil (15.8 grams, yield 63%) from 2 (3-benzyloxy-4-bromophenyl) -2-methylbutane (24.0 gram, 0.0721 mol) and 2-cyclohexan-1-one (7.06 gram, 0.0735 mol).

IR: (CHCl 3) 1718, 1618 and 1575 cm-1.

MS: m / s 350 (M +), 335, 321, 307, 259 and 91.

3- / ~ 2-Benzyloxy-4- (1,1-dimethylbutyl) phenyl-7-cyclohexanone as oil (15.4 grams, yield 42%) from 2- (3-benzyloxy-4-bromophenyl) -2-methylpropane (34 .8 grams, 0.100 mol) and 2-cyclohexan-1-one (10.5 grams, 0.110 mol).

IR: (CHCl 3) 1736, 1631 and 1592 cm -1.

MS: m / e 364 (M +), 231, 273 and 91.

Trans-3- / ~ 2-benzyloxy-4- (1,1-dimethylheptyl) phenyl-7-4- (2-propanyl) cyclohexanone as oil (58.3 grams, yield 70%) from 1-bromo-2-benzyloxy- 4- (1,1-dimethylheptyl) bromobenzene (73.0 grams, 0.188 mol) and s Λ ~ 3

.. · ··. · -J V

27 _ * c. 4 .. (2-propenyl) -2-cyclohexan-1-one (25.5 grams, 0.188 mol).

IR: (CHCl 3) 1712, 1645, 1613 and 1575cm 1.

; MS: m / e 446 (M +), 360, 354 and 91.

3- / ~ 2-Benzyloxy-4- (1,1-dimethylpentyl) phenyl-7-cyclohexanone 5 as oil (11.5 grams, yield 37%) from 2- (3-benzyloxy-4-bromophenyl) -2-methylhexane ( 29.6 grams, 0.0818 mol) and 2-cyclohexan-1-one (8.63 grams, 0.09 mol).

IR: (CHCl 3) 1730, 1629 and 1592 cm -1, MS: m / e 378 (M *), 335, 321, 287 and 91.

3- / _ 2-Benzyloxy-4- (1,1-dimethylhexyl) phenyl-7-cyclohexanone as 1 oil (11.0 grams, yield 35%) from 2- (3-benzyloxy-4-bromophenyl) -2-methyl- heptane (30.2 grams, 0.0806 mol) and 2-cyclohexan-1-one (8.5 grams, 0.0886 µm mol) ·: IR: (CHCl 3) 1715, 1623 and 1585 cm 1 .

MS: m / e 392 (M +), 348, 321, 301, 259 and 91.

3- / ~ 2-Benzyloxy-4- (1,1-dimethylnonyl) phenyl / cyclohexanone as oil (13.5 grams, yield 43%) from 2- {3-benzyloxy-4-bromophenyl (-2-methyldecane (30 .5 grams, 0.073 mol) and 2-cyclohexan-1-one (7.71 grams, 0.0803 mol) .: 20 IR: (CHCl 3) 1715, 1623 and 1582 cm-1; MS: m / e 434 ( M +), 342, 321 and 91.

3- / ~ 2-Benzyloxy-4- {1,1-dimethyldecyl) phenyl-7cyclohexanone as oil (7.0 grams, yield 17%) from 2- (3-benzyloxy-4-bromophenyl) -2-methyl-undecane (40 .0 grams, 0.0928 mol) and 2-cyclohexan-1-one (.98 grams, 0.102 mol).

IR: (CHCl 3) 1715, 1623 and 1585 cm-1.

MS: m / e 448 (M +), 321 and 91.

3- / ~ 2-Benzyloxy-4- (1,1-dimethyl-undecyl) phenyl-7-cyclohexanone as oil (11.5 grams, yield 40%) from 2- (3-benzyloxy-4-bromophenyl) -2-30 methyl dodecene ( 27.5 grams, 0.062 mol) and 2-cyclohexan-1-one (6.68 grams, 0.0682 mol).

IR: (CHCl 3) 1718, 1623 and 1585cm 1.

MS: m / e 462 (M +), 417, 371, 321, and 91.

3- / ~ 2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl-7-cyclooctanone as oil (10.6 grams, yield 63%) from 2- (3-benzyloxy-4-bromophenyl) -2-methyl octane (15, 0 grams, 38.6 mmol) and 2-cycloocten-1-one (4.78 grams, 38.6 - ».» »* * C - ^ U · '” ft - 28 - »mmol).

IR: (CHCl 3) 1715, 1629 and 1587 cm -1.

MS: ra / e 434 (M +), 477, 363, 349, 343, 326, and 91.

Example II

5 3- / 4- (1,1-Dimethylheptyl) -2-hydroxyphenyl_7cyclohexanone

A mixture of 19.5 grams (0.0468 mol) of 3- / 2-benzyloxy-4- (1,1-dimethylheptyl) phenyl / cyclohexanone, 12.3 grams of sodium bicarbonate, 3.00 grams of 10% palladium-op carbon and 250 ml of ethanol were stirred under 1 atmosphere of hydrogen pressure for 1.5 hours. The reaction mixture was then filtered through diatomaceous earth with ethyl acetate and the. I filtrate evaporated to a solid. The crude solid was measured with

j I

Column chromatography purified on 280 grams of silica gel, eluting with 20% ether / cyclohexane to give a solid.

| Upon recrystallization of this solid from aqueous methanol

9.1 grams (yield 62%) of the desired product, m.p. 87 ° C

obtained mainly in the hemiketal form.

IR: (KBr) 3226, 1629 and 1580 cm-1, (CHCl 3) 3571, 3289, 1704, 1623 and 1576 cm-1, MS: m / s 316 (M +), 298, 273 and 231.20 Analysis for C2iH32 ° 2:

Calculated: C 79.70%; H 10.19%;

Found: C 79.69%; H 9.89%.

The above procedure was repeated except that the appropriate reactive components of Example I were used, yielding the 25. the following products were obtained: 3- / ~ 4- (1,1-Dimethylheptyl) -2-hydroxybenzyl) -3-methylcyclohexanone as oil (54 mg, yield 86%) from 80 mg, (0.19 mmol) 3 - / 2-benzyloxy-4- (1,1-dimethylheptyl) phenyl-7-3-methylcyclohexanone.

IR: (CHCl 3) 3597, 3390, 1623 and 1572 cm -1.

30 MS: m / e 330 (M +), 315, 287, and 245.

Trans-3 - / - 4- (1,1-dimethylheptyl) -2-hydroxyphenyl 7-4-methylcyclohexanone (825 mg, yield 99%) mp 62-64 ° C (recrystallized from pentane) from trans-3- 2-benzyloxy-4- (1,1-dimethyl-1-heptyl) phenyl-74-methylcyclohexanone (1.05 grams, 2.50 mmol).

- - y - ·: * - · - '·> 35 -29: - *! IR: (CHCLi) 3571, 3333, 1721 (weak), 1626 and 1577 can "1 MS: m / e 330 (M +), 312, 288, 273, 245, 203 and 161

Analysis for C22H34 ° 2:

Calculated: C 79.97%; H 10.37%; 5 Found: C 80.33%; H 10.30%.

3- / 4- (1,1-Dimethylheptyl) -2-hydroxyphenyl / cyclopentanone (0.54 grams, yield 47%), melting point 61-62 ° C (from pentane) from 3-2 2-benzyloxy-4- ( 1,1-dimethylheptyl) phenyl 7-cyclopentanone (1.50 grams, 3.83 mmol).

IR: (KBr) 3,279, 1739, 1621, and 1577 cm-1; MS: m / e 302 (M +), 283, 217, 189, 175, and 161.

3- / ~ 4- (1,1-Dimethylheptyl) -2-hydroxyphenyl / cycloheptanone (795 mg, yield 63%), mp 78-79 ° C (from pentane) from 3- / 2-benzyloxy-4- (1,1-dimethylheptyl) phenyl / cycloheptanone (1.60 grams, 3.80 mmoles).

IR: (CHCl 3) 3571, 3289, 1701, 1621, 1605 and 1577 cm-1 MS: m / e 330 (M +) and 245.

Analysis for: C22H34 ° 2:

Calculated: C79.95%; H 10.37%; 20 Found: C 79.60%; H 10.33%.

Quantitative yield of 3 - / - 2-hydroxy-4- (2- (5-phenylpentyl-oxy)) phenyl / cyclohexanone as an oil from 3- / 2-benzyloxy-4- (2- (5-phenylpen-tyloxy)) phenyl cyclohexanone (1.0 gram, 2.26 mmol).

IR: (CHCl 3) 3571, 3333, 1709, 1623 and 1586 cm-1.

MS: m / e 352 (M +), 206, 188 and 91.

3_ (2,4-dihydroxyphenyl) cyclohexanone as solid (8.5: grams, yield 94%), melting point 158 ° C (from isopropyl ether) from 3- (2,4-dibenzyloxyphenyl) cyclohexanone (16.9 grams) , 43.7 mmol).

IR: (KBr) 3195, 1631, and 1603 cm-1.

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

Analysis for: C12H14 ° 3:

Calculated: C 69.88%; H 6.84%.

Found: C 69.94%; H 6.78%.

3 - / ** 4- (1,1-Dimethylocty 1) -2-hydroxyphenyl-7cyclohexanone 35 (0.75 grams, yield 48%) from 2.00 grams (4.76 mmol) 3- / 2-benzyloxy- 4- b ”" ~ ~ ~ .............. ...........

T. \ ^; - 30 - * (1,1-dimethyloctyl) phenyl-7cyclohexanone; mp 78-80 ° C (from oentane).

IR: (CHCl 3) 3571, 3333, 1709 (weak), 1626 and 1577 cm-1 MS: m / e 330 (M +), 314, 312, 287 and 231.

Analysis for C22H34 ° 2: j Calculated: C 79.95%; H 10.37%;

Found: C 79.97%; H 9.99%.

3- (4-tert-butyl-2-hydroxyphenyl) cyclohexanone (4.22 g / am, yield 58%) from 3- (2-benzyloxy-4-tert-butylphenyl) cyclohexanone (10.0 g. 0298 mol); mp 177-1.78 ° C (from isopropyl ether); IR: (KBr) 3279, 1639, 1582 cm-1 MS: m / e 246 (M +), 231, 228, 215, 213, 203, 189, 176 and 161 3- / ~ 4- (1,1-Dimethylpropyl -2-hydroxyphenyl-7-cyclohexanone (2.52 grams, yield 45%) from 3- / 2-benzyloxy-4- (1,1-dimethylpropyl) phenyl 7cyclohexanone (7.50 grams, .0214 mol); mp 165-166 ° C (from isopropyl ether).

IR: (CHCl 3) 3636, 3401, 1724 (weak), 1634 and 1587 cm -1; MS: m / e 260 (M +), 242, 231, 217, 213 and 161

Analysis for C17 H24 ° 2: 20 Calculated: C 78.42%; H 9.29%.

Found: C 78.17%; H 9.22%.

3- / 4- (1,1-Dimethylbutyl) -2-hydroxyphenyl 7cyclohexanone (0.6 grams, yield 11%) from 3- / 2-benzyloxy-4- (1,1-dimethylbutyl) 1- phenyl / cyclohexanone (7.00 grams, 0.0192 mol); mp 101-102 C (from 25 isopropyl ether); IR: (CHCl 3) 3636, 3401, 1724 (weak), 1634 and 1585 cm -1.

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

Analysis for cjgH26 ° 2:

Calculated: C 78.79%; H 9.55%; 30 Found: C 78.78%; H 9.21%.

Trans-3- / 4- (1,1-dimethylheptyl) -2-hydroxyphenyl 7-4-propylcyclohexanone (1.0 gram, yield 76%) as oil from trans-3- / 2-benzyloxy-4- (1, 1-dimethylheptyl) phenyl / -4- (2-propenyl) cyclohexanone (1.65 g, 3.69 ramcl).

35. IR: (CHCl 3) 3610, 3390, 1718 (weak), 1629 and 1577 cm -1.

0, j ^ ·· "x -H - - ... .......—.. —................

Q vyvv <^ - 31 - w MS: m / e 358 (M +), 340, 288, 273, 255, 203 and 161 3- / 4- (1,1-Dimethylpentyl) -2-hydroxyphenyl 7cyclohexanone (4.0 gram, yield 95%) from 3- / 2-benzyloxy-4- (1,1-dimethylpentyl) phenyl-cyclohexanone (5.5 grams, 0.0146 mol); mp 124.5-125.5 C (5 from pentane).

IR: (CHCl 3) 3623, 3378, 1718 (weak), 1634 and 1586 can "1 MS: m / e 288 (M +), 245 and 231.

Analysis for cjgH28 ° 2:

Calculated: C 79.12%; H 9.79%.

Found: C, 79.32%; H 9.53%, 3- / 4- (1,1-Dimethylhexyl) -2-hydroxyphenyl-7cyclohexanone (quantitative) from 3- / 2-benzyloxy-4- (1,1-dimethylhexyl) phenyl-7cyclohexanone (2.0 grams, 5 , 1 mmol); mp 82-83 ° c.

IR: (CHCl 3) 3636, 1634, 1616 and 1585 cm -1.

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

Analysis for C20H30 ^ 2:

Calculated: C 79.42%; H 10.00%;

Found: C 79.16%; H 9.75%.

3- / ~ 4- (1,1-Dimethylnonyl) -2-hydroxyphenyl7-cyclohexanone 20 (2.4 grams, yield 61%) from 3- / 2-benzyloxy-4- (1,1-dimethylnonyl) phenyl / cyclohexanone (5.0 grams, 11.5 mmol); mp 72-73 ° C.

IR: (CKCl 3) 3650, 3413, 1721 (weak), 1639 and 1595 cm -1 MS: m / e 344.2691, (M *), (C ^ H. ^), 326.2570 and 301.2168.

3- / 4- (1,1-Dimethyldecyl) -2-hydroxyphenyl-7-cyclohexanone (880-25 mg / yield 55%) from 3- / ~ 2-benzyloxy-3- (1,1-dimethyl-decyl) -phenyl-7-cyclohexanone (2.0 gram, 4.46 mmol); mp 78-79 ° C.

IR: (CHCl-) 3623, 1629, 1616 and 1587 cm -1; MS: m / e 358.2836 (Μ) & 24Ε38Ό2 * '3- / 4- (1,1-Dimethylundecyl) -2-hydroxyphenyl-7cyclohexanone 30 (1, 49 grams, yield 46%) from 3- / 2-benzyloxy-4- (1,1-dimethyl-undecyl) -phenyl / cyclohexanone (4.00 grams, 8.66 mmol), mp 72-73 ° C.

IR: (KBr) 3268, 1629 and 1580 cm-1 MS: m / e 372 (M +), 354, 329 and 231.

Analysis for c25H40 ° 2: 35 Calculated: C 80.59%; H 10.82%.

Found: C 80.70%; H 10.84%.

"Λ 7 * T" "-. -. . ..... _____________ ... ___ _ ____ t 1, ·· - 32. -

USA

; ·! 3- / ~ 4- (1'-Dimethylheptyl) -2-hydroxyphenyl-7-cyclooctanone (1.92 grams, yield 81%; from 3- / 2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl / cycloctanone (3.02 grams, 6.95 mmol), mp 118 ° C.

IR; (CHCl 3) 3623, 3356, 1709, 1629 and 1587 cm-1 MS: m / e 344 (M +), 329, 326> 283, 273, 259 and 241.

Analysis for c23H3g02:

Calculated: C 80.18%; H 10.53%.

Found: C 79.92%; H 10.37%.

3- / 4- (1,1-Dimethylheptyl) -2-hydroxyphenyl 7-4-methyl-2-10 i cyclohexen-1-one (1.15 grams, yield 70%) from 3- / 2-benzyloxy-4 - (1,1-dimethylheptyl) phenyl 7-4-methyl-2-cyclohexen-1-one (2.10 grams, 5.02 mmol); mp 111 ° C (from diisopropyl ether: petroleum ether).

; IR; (CHCl 3) 3534, 3279, 1667, 1623 and 1567 cm -1, MS: m / e 328 (M +), 313 and 243.

15 | Analysis for C22 H32 O2: j Calculated: C 80.44%; H 9.83%.

Found: C 80.35%; H 9.67%.

Λ "7."

V

- 33 -

Example III

3- / S-Benzyloxy-U- (1,1-dimethylheptyl) phenyl7cyclohexanone

A solution of 3.98 grams (10 msol) of 2- (3-10 benzyloxy-1-bromophenyl) -2-methyloctane in 10 ml of tetrahydrofuran was added

slowly added to 360 mg (1U, H mmol} 70-80 mesh magnesium metal. The resulting mixture was refluxed for 30 minutes and then cooled to 0 ° C. To this solution a solution of 1.1 * 0 grams (10 mmol) of 3-ethoxy-2-cyclohex-1-one in 3 ml of tetrahydrofuran 15 slowly added in. The reaction mixture is evaporated at 0 ° C for 30 minutes

stirred and then quenched by adding 20 ml of 1 standard sulfuric acid and heating on a steam bath for 30 minutes. Then it is cooled and added to 200 ml of ether and 200 ml of water. The organic extract was successively diluted with 200 ml of saturated sodium carbonate and 200 ml of saturated sodium chloride, dried over magnesium sulphate and evaporated to leave an oil. The product is purified by column chromatography on 170 grams of silica gel, then diluted with 1: 1 ether: pentane to leave 2.5 grams (yield 5 W of the given compound as oil).

IR (CHCl 3) 1667, 1610 and 1558 cm -1; MS: m / e UoU (M +), 319, 313 µg91.

Similarly, oil 3- / 5-benzyl-oxy-1- (1,1-dimethylheptyl) phenyl-7-methylcydohex-2-enone (U, 1U gram, yield 77%) prepared from 3-ethoxy -6-methyl-2-cyclohexen-1-one 80 (1.98 grams, 12.9 mmol), magnesium (0.61 grams, 25.7 mmol) and 12.9 mol (5.0 grams 2- ( 3-benzyloxy-k-bromophenyl) -2-methyloetane.

IR (CHCl 3) 1667, 1613 and 1565 cm -1; MS: m / e h18 (M +), fcOO, 385, 327, 333, 299, 291 and 91.

Example IV

- ** “·. ~ - 34 - *

I

3- / 2-Benzyloxy-1 * - (1,1-dimethylheltyl) phenyl7-3-methylcyclohexanone

To a solution of 17 mmol dimethyl copper lithium in 10 ml tetrahydrofuran cooled to -10 to -5 ° C, 5,60 mg (1.39 mmol) 3- / 5-benzyloxy-1 * - (1,1-dimethylheptyl) phenyl7cyclo- 5 hex-2-enone in 5 ml of tetrahydrofuran added slowly. The reaction mixture was stirred for an additional 30 minutes and then added to 100 ml of saturated ammonium chloride and 100 ml of ether. After stirring for a further 10 minutes, the reaction mixture is extracted with 200 ml of ether. The ether extract was washed with 100 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated to leave an oil *

Distribute the oil by preparative layer chromatography on three plates of 20 cm x 20 cm x 2 mm silica gel, eluted with 2: 1 cyclohexane: ether to give 282 mg (yield 1 * 8 JS) (higher Rf) of the given compound as oil and 211 mg (Z $% yield) (lower Rf) 3- / 2-benzyl-15-oxy-1 * - (1,1-dimethylheptyl) phenyl-7-methylcyclohex-2-en-1-ol as oil left over .

Data compound: IR (CHCl 3) 170U, 1610, 1565cm -1; MS: m / e 1 * 20 (M +), 1 * 05, 377, 335, and 329.

3- / 2-Benzyloxy-1 * - (1,1-dimethylheptyl) phenyl-1-methylcyclohex-2-en-1-ol IR (CHCl 3) 3571, 311, 1661, 1608 and 1585 cm-1; MS: m / e 1 * 20 (M +), 1 * 02, 335 and 317.

Example v 3-A- (1,1-Dimethylheptyl) -2-hydroxy-phenyl-7-cyclohex-2-enone 25 A mixture of 1 * 00 mg (0.988 mmol) 3- / S-benzyloxy-1 * - (1, 1-dimethylheptyl) phenyl-7-cyclohex-2-enone and 20 mg of 5 µl palladium-on-carbon are stirred under 1 atmosphere of hydrogen pressure for 30 minutes. The reaction mixture was then diluted with ether through diatomaceous earth and the filtrate evaporated to a solid matter remaining. The crude solid was recrystallized from petroleum ether to leave 110 mg (yield 35 *) of the yielding compound, mp 122-123 ° C.

IR (KBr) 31 * 1 * 8, 163I *, 1608 and 1565 cm -1; • MS: m / e 311 * (M +), 299 and 229.

35 Analysis for C21H3002:.> "7 Λ '1 TT ^.. V' i, VV ^ - -------- ------ ---------- - ------------------------------------------------ - ----- - 35 -

Calculated: C 80.21 $; H 9 * 62 $;

Found: C 80.23 $; H 9, ^ 6 $.

Example vi 3- (2,1 * -Dihydroxyphenyl) cyclohexanone, methylketal 5 To a solution of 7.0 grams (33.0 mmol) of 3- (2,4-dihydroxyphenyl) cyclohexanone in 100 alm of methanol cooled to 0 ° C and 15 al trimethyl orthoformate then added 10 drops of concentrated sulfuric acid. The reaction mixture was stirred without cooling for 3 hours at which the temperature was allowed to rise to room temperature, then was quenched by addition of solid sodium bicarbonate. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in 200 ml of water and 250 ml of ether.

The ether extract was washed once with 150 ml of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated. The remaining oil was crystallized from ether-pentane to leave 5.7 µg (yield 77%) of the desired compound, mp 129-130 ° C.

IR (KBr) 3289, 1629, 1613, and 1597cm -1; m: 220 (M +), 205, 203, 188, 177, 161 and 136.

20 Analysis for C, 3H.6 ° 3:

Calculated: C 70.89 $; H 7.32 $;

Found: C 70.79 $; H 7.3 ^ $

Example of 3- / 2-Hydroxy- ((- - phenylbutyloxy) phenyl 7 cyclohexanone, methyl ketal. A mixture of 5.03 grams (22.8 mmol) 3- (2, U-dihydroxyphenyl) cyclohexanone, methyl grams, 10.1 grams (73.2 mmole) anhydrous potassium carbonate and 6.12 grams (26.8 mmole) k-phenylbutylmethane sulfonate in 25 ml Ν, Ν-dimethylformamide were heated for hour to 85-100 ° C. The reaction mixture was cooled and added to 200 ml of water and 200 ml of ether. The ether extract was washed twice with 200 ml of water, dried over magnesium sulphate and evaporated to leave an oil. The oil was purified by column chromatography over 100 grams of silica gel, with 2: 1 pentane: ether being eluted so that 7 k grams (yield 92 $) of the desired compound if oil 35 remained.

~ '-. *' -. ·. V ^ ------ · - · - - - —..... - - - - - -% - 36 -

• I

IR (CHCl 3] 1623 and 1590cm -1; MS: m / e 352 (M +) and 91.

Analysis for C23H28 ° 3:

Calculated: C 78.375 ?; H 8.01!?;

Found: C 78.3 ^ 5 ?; H 8.075.

The compounds below were prepared in a similar manner, except that the appropriate mesylate derivative was used instead of U-phenylbutylmethanesulfonate.

3- / 2-hydroxy-U- (2-heptyloxy) phenyl 7 cyclohexa-non methyl ketal (6.13 grams yield 755?) As oil from 5.7 grams (25.9 mmol) 3- (2, h- dihydroxyphenyl) -cyclohexanone methyl ketal and (2-hep-10-tyl) methanesulfonate (6.2 grams, 32.3 mmol).

IR (CHCl 3) 1637 and 1600cm -1; MS: m / e 318 (M +), 286, 27¾, 220, 20U and 178.

3- / 5-Hydroxy - ^ - (2-octyloxy) phenyl-7-cyclohexanone methyl ketal as oil (5.03 grams, yield 585?) From 3- (2, U-dihy-15-hydroxyphenyl) cyclohexanone methyl ketal (5.7 grams, 25.9 mmol) and (2-octyl) methanesulfonate (7.3 grams, 35.1 mmol).

IR (CHCl 3) 1639 and 1600cm -1; MS: m / e 332 (M +), 300, 289, 272 and 220.

3- / 2-Hydroxy-1 * - (2-nonyloxy) phenyl 17 cyclohexanone 20 methyl ketal (5.23 grams, yield 59%) as oil from 3- (2, U-dihydroxyphenyl) cyclohexanone methyl ketal ( 5.7 grams, 25.9 mmol) and (2-nonyl) methanesulfonate (7.9 grams, 35.5 mmol).

1 IR (CHCl 3) 1631 & 1590 cm -1; MS: m / e 3U6 (M +), 31 ^, 220, 188 and 161.

3- / 2-Hydroxy - ^ - (2- (lt-phenyl) butoxy) phenyl-7-cyclohexanone methyl ketal as oil (5.1 grams, yield 56%) from 3- (2,1-dihydroxyphenyl) cyclohexanone methyl ketal (5.7 grams, 25.9 mmol) and 2- (t-phenylbutyl) methanesulfonate (8.0 grams, 35.0 mmol).

IR (CHCl 3) 1639 eb 1603 cm -1, 30 MS: m / e 352 (M +), 320, 220 and 188, 3- / 2-Hydroxy-k- (2- (6-phenyl) hexyloxy) phenyl7cy- / clohexanone methyl ketal (5.3 grams, yield 5 ^%) as oil from 3- (2, It-dihydroxyphenyl) cyclohexanone methyl ketal (5.7 grams, 25.9 mmol) 'J' J * 'i »-37 - and 2- (6-phenylhexyl) methanesulfonate (9.0 grams, 35.5 mmol).

IR (CHCl 3) 163 U and 1597 cm -1; MS: m / e 380.2342 (M +, 220.1088, 188.0986 and 177.0550.

Example VIII

3- / 2-Hydroxy-4- (4-phenylbutyloxy) phenyl-7cyclohexanone

A mixture of 6.8 grams (19.3 mmol) of 3- / 2-hydroxy-4- (4-phenylbutyloxy) -phenyl-7-cyclohexanone methyl ketal, 100 ml of 2 normal hydrochloric acid and 60 ml of dioxane was heated at reflux for 1 hour. the reaction mixture is cooled and added to 300 ml of ether and 500 ml of saturated sodium chloride The ether extract is washed once with 500 ml of saturated sodium bicarbonate and once with 500 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated to leave an oil. • 15 matography purified over 400 grams of silica gel, eluting additionally with 1: 1 ether: cyclohexane, leaving 6.4 grams (yield 98%) of the desired compound as oil.

IR (CHCl 3) 3571, 3333, H18, (pocket), 1626 and 1595 cm -1; MS: m / e 388 (M +), 320, 310, 295, 268, and 91.

The following compounds were prepared in the same manner from suitable ketals of Example IX: 3- / S- (2-Heptyloxy) -2-hydroxyphenylcyclohexane (4.7 grams, yield 82%) as oil from 6.0 grams (18, 6 mmol) of the corresponding methyl ketal; IR (CHClJ 3636, 3390, 1724 (zvak), 1639 and * 1600 cm); MS: m / e 304 (M +), 206, 188, 171, 163 and 137.

3 - /) 1- (2-Octyloxy) -2-hydroxyethyl en 7 cyclohexanone 30 (4.1 grams, yield 85%) as oil from 5.0 grams (15.0 mmol) of the corresponding methyl ketal: IR (CHCl 3) 3636, 3378, 1721 (pocket), 1631 and 1595 cm -1; MS: m / e 318 (M +), 206, 188, 178 and 163.

33 3-A- (2-Nonyloxy) -2-hydroxy-phenyl-7-cyclohexanone - 38- • 4 (^ »35 grams, yield 89?) As oil from 5.1 grams (11.7 mmol) of the relevant methyl kettle IR (CHCl 3) 3581, 336j, 1709 (pocket), 1626 and

1587 cm "S

MS: m / e 332 (M +), 206, 187 and 17T.

3- / µ- (2- (1'-phenyl) butyloxy) -2-hydroxyphenyl7 cyclohexanone (3.8 grams, yield 79?) From 5.0 grams (15.2 mmol) of the corresponding methyl ketal, as oil: IR (CHCl 3) 3636, 31 + 25, 1721 (weak), 1637 and 1600 cm-2 MS: m / e 338 (M +), 206, 188, 132, 117 and 91.

3- / 5- (2- (6-Phenyl) hexyloxy) -2-hydroxyphenyl 7 cyclohexanone (1 +, 1 »5 grams, yield 89?) As oil from 5.2 grams (13.6 mmol) of the respective methyl ketal: 15 IR (CHCl 3) 3636, 3390, 1718, 1637 and 1600 cm; MS: m / e 366 (M), 206, 188 and 91 * - - - - "- - * ·" * <* · -; • ".j * V ^ - 39 -

Example 3- / 5. (It1-Dimethylheptyl) -2-hydroxyphenyl7-3-cyclohexanone ethylene ketal

A solution of 500 mg (1.59 mmol) 3- / 5- (1,1-dimethylheptyl) -2-hydroxyphenyl7-2-cyclohexanone, 7.8 grams (127 mmol) ethylene glycol, 375 mg (3.18 mmol) hydroquinone and 50 mg of 5 (0.263 mmol) p-toluenesulfonic acid monohydrate in 50 ml of benzene refluxed for 12 hours, using a Dean-Stark condenser filled with 3A molecular sieve material. The reaction mixture was cooled and added to 500 ml of saturated sodium bicarbonate.

The quenched mixture was extracted three times with 150 ml of ether each time, dried over magnesium sulphate and evaporated, leaving a solid. This solid was purified by column chromatography on 50 g of silica gel, eluting additionally with 50 µl of petroleum ether, so that after recrystallization from pentane 393 mg (yield 69%) of the desired product, mp 97-98 ° C, remained: MS: m / e 358 (M +), 297, 273, 255, and 229.

Analysis for C23H3503 * "

Calculated: C, 77.05; Η 9.56ί;

Found: C 76.98ί; H 9.52ί.

Example X.

20 3- / 5- (1 ^ -Dime * hylheptyl) -2-hydroxyphenyl7-5-methylcyclohex-3-enone

A mixture of 5.00 (0.1 mol) 3- / 5- (1,1-dimethylheptyl) -2-hydroxyphenyl-7-methyl-cyclohex-3-enone ethylene ketal, 50 ml 2 normal oxalic acid and 50 ml of methanol stirred at 25 ° C. The reaction mixture was added to 500 ml of water and 250 ml of ether. The ether extract is diluted once with 250 ml of saturated sodium bicarbonate, washed once with 250 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography over 500 grams of silica gel, eluting with 50% ether pentane to afford the desired compound.

- - - * ·>. .0 _______________________________ - '40 -

Example 3- / 2-Acetoxy-U- (1,1-dimethylhepty1) phenyl7 cyclohexanone

A solution of 2.0 grams of 3- / 2-hydroxy-fc- (1,1-dimethyl-heptyl) phenyl-7-cyclohexanone in 15 ml of pyridine was treated with 10 ml of acetic anhydride at 5 ° C and the mixture was stirred under nitrogen for 18 hours. Then it is poured on ice / water and acidified with dilute hydrochloric acid. The acidified mixture was extracted twice with 100 ml of ethyl acetate each time, the extracts were combined, washed with brine and dried over magnesium sulfate. On evaporation under reduced pressure, the yielding product is obtained as an oil.

Example. xii

Trans-WS-benzyloxy-k- (1,1-dimethylheptyl) -phenyl-3-but en-2-one 15 A solution of 2-benzyloxy-i- (1,1-dimethyl heptyl) benzaldehyde (65.2 grams, 0.193 mmol) and of 1-triphenylphosphoranylidene-2-propanone (62.0 grams, 0.195 mmol) in dichloromethane (195 ml) and refluxed for 20 hours. A further 15.5 grams of ylide (15.5 grams, 0.0U7 mol) was added and then refluxed for an additional 20 hours. The reaction mixture is cooled, evaporated and diluted with ether. The resulting precipitate of triphenylphosphine oxide is filtered off. The crude oil was purified by column chromatography on 1.5 kg of silica gel, eluting additionally with 20 μl ether-hexane, so that 53.9 grams (yield 7%) of the yielding compound were obtained as oil.

IE (CHCl 3) 1681, 1621 and 1575 cm -1; MS: m / e 378 (M +), 36 ^, 337, 293, 271, 251 and 91.

- · ·. , v -) - - ....... .................

- 41 -

Example xill 5- / 2-Benzyloxy-k- {1-dimethylheptyl) phenyl7-k-carbomethoxy-1,3-cyclohexanedione.

A solution of trans-1 + - / 2 was slowly added to a solution of sodium methoxide (0.67 grams, 12.1 + mmol) and dimethyl malonate (1.85 grams, 1U, 1 mmol) in methanol (U, 75 µl). -benzyloxy-k- (1,1-dimethylheptyl) phenyl-7-buten-2-one (3.75 grams, 9.92 nmol) in U ml of methanol. The reaction mixture was refluxed for 3 hours, then cooled and cooled under reduced pressure. Dilute the residue with ether and saturated sodium chloride and acidify with 1 normal hydrochloric acid. The ethereal extract is washed twice with 500 ml of saturated sodium chloride each time, dried over magnesium sulphate and evaporated to give 0.71 g (yield 99%) of the yielding compound; mp 108-109 ° C (from petroleum 1 * - 42 ether tether): IR (CHCl 3) 17-2, 1709, 1612, and 1577cm -1; MS: m / e U78 (M +), M »6, U19, 393, 387 and 91.

Analysis for C 1 H 3 O 5 Calculated C 75.28; H 8.00 ?;

Found: C 75.05 ?; H 7.97 ?.

Example xiv.1.5- / 2-Benzyloxy - ^ - (1,1-dimethylheptyl) phenyl7-1,3-cyclohexanedione

A mixture of 5- / 2-benzyloxy-U- (1,1-di-10-methylheptyl) phenyl-7-carbomethoxy-1,3-cyclohexanedione (20.8 grams, 1: 3.5 mmol), U0 ml dioxane and 10 ml of 20% sodium hydroxide was heated to 100 ° C for 2 hours. It was cooled in an ice bath and acidified with concentrated hydrochloric acid. The mixture was heated to 100 ° C for 1 hour, cooled to 0 ° C and then neutralized with sodium bicarbonate. The resulting mixture was added to saturated sodium bicarbonate and ether. The ether extract was dried over magnesium sulfate and evaporated to leave an oil. This oil was purified over 1 kg of silica gel by column chromatography, eluting with 10% acetone: ether to give 10.9 grams (yield 60%) of the desired compound; mp 102-103 ° C (from pentane: ether).

IR (CHCl 3) 3636-2222 (broad), 1739, 1712, 1613 (broad) and 1577 (shoulder; MS: m / e k20 (M +), 335, 329, and 91. Analysis for CggH ^ gO ^: 25 Calculated: C 79.96; H 8.63;

Found: C 79.87 ?; H 8.5 ^.

Example xv 5- / 2-Benzyloxy-U- (1,1-dimethylheptyl) phenyl7-3-methoxy-2-cyclohexan-1-one

A solution of 5.0 grams (11.9 mmol) 5- / 2-30 benzyloxy-t- (1,1-dimethylheptyl) phenyl-1,3-cyclohexanedione and 200 mg p-toluenesulfonic acid in 250 ml methanol in a flask which was connected to a Soxhlet condenser containing 3A molecular sieve material, was refluxed for 30 minutes. The reaction mixture was cooled, evaporated under reduced pressure and the residue was diluted with saturated sodium bicarbonate and ether. The ether extract is washed successively with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate and evaporated to give 5.15 grams (99% yield). the desired compound if oil remained.

IR (CHCl 3) 16UU, 1612, 1503, 60 and 1379 cm-1; MS: m / e k3h (M +), 3 ^ 9, 31 * 3 and 91.

Similarly, the remaining compounds of Example XXIV were converted to compounds of Formula 6, wherein Z and W have the meanings listed in Example XXIV and 10 is methyl. If the methanol is replaced with ethanol, isobutanol or propanol, the corresponding alkoxy derivative is obtained.

Example XVI

5- / 5-Benzyloxy-1 * - (1,1-dimethylheptyl) phenyl7-2-cyclohexan-1-one 15 To a solution of the compound 5- / 5- cooled to 0 ° C in the title of Example XXV. benzyloxy-U- (1,1-dimethy-heptyl) phenyl7-3-methoxy-2-cyclohexen-1-one (500mg, 1.15mmol) in 20ml ether became lithium & aluminum hydride (20mg, 0.53mmol) added. The reaction mixture was stirred at 0 ° C for 30 minutes, acidified with 20 L normal hydrochloric acid and stirred at room temperature for 2 hours.

The ether phase was removed, washed successively with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate and evaporated. The crude oil was purified by column chromatography over 100 grams of silica gel, eluting with 50 µl ether: pentane to give 353 mg (yield 76%) of the desired compound as an oil.

IR (CHCl 3) 1681, 1672, 1613, 1575, and 1U79 cm -1; MS: m / e 10U (M +), 319, 313, and 91.

Example XVII

5- / 2-Benzyloxy-k- (1,1-dimethylheptyl) phenyl7-3-methyl-2-cyclohexen-1-one

To a solution of methyl magnesium iodide (11 ml of 2.9 M in ether) and 10 ml of tetrabydrofuran cooled to 0 ° C was added dropwise a solution of 5- / 2-benzyloxy-U- (1,1-dimethylheptyl) phenyl7-3-methoxy-2-cydohexen-1-one (3.5 grams, 7.95 mmol) 35 in 10 ml tetrahydrofuran. The reaction mixture was then filled with "7 * - * · * • y v v ^ ..... -. -. · - - - - -44 - heated and stirred at room temperature for 2 hours, after which it was added to ice cold 1 Normal hydrochloric acid. After the hydrolysis mixture was stirred for 20 minutes, it was extracted with ether. The ether extract was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate and evaporated.

The crude product was purified by column chromatography over 100 grams of silica gel, eluting with 25% ether: pentane to give 3.08 grams (93% yield) of the desired compound, m.p. 60 DEG C. (from pentane). : MS: m / e U18 (M), 333, 327, and 91 · 10 Similarly, the following compounds were prepared from appropriate reactive components: 5- / 2-Benzyloxy-1- (1,1-dimethylheptyl) phenyl7- 3-ethyl-2-cyelohexen-1-one (2.83 grams, yield 82%) as oil from 5- / 5-benzyloxy-k- (1,1-dimethylheptyl) phenyl7-3-methoxy-2-cyclohexen- 1-15 one (3.16 grams, 7.97 mmol) and 10.8 m2, 2.9 * + ethyl magnesium magnesium bromide (in ether).

IR (CHCl 3) 1698, 1666, 1623 and 1582 cm -1; MS: m / e k32 (M +), 3 ^ 1 and 91.

5- / 2-Benzyloxy-h- (1,1-dimethylheptyl) phenyl7-20 3-n-propyl-2-cyclohexen-1-one (3, 8 grams, yield 85%) as oil from 5- / 2 -benzyloxy-U- (1,1-dimethylheptyl) phenyl-7-methoxy-2-cyclohexen-1-one (0.00 grams, 9.21 mmol) and n-propyl magnesium bromide (36.8 mmol).

IR (CHCl 3) 1661, 1631, 1612 and 1575 cm -1; MS: m / e UU6 (M +), 355 and 91 * 25 5- / 5-Benzyloxy-lt- (1,1-dimethylheptyl) phenyl7-3- n-hexyl-2-cyclohexen-1-one (U, 11 grams, yield 92¾) as oil from 5- / 2-benzyloxy-1 + - (1,1-dimethylheptyl) phenyl7-3-methoxy-2-cyelohexen- 1 -one (0.00 grams, 9.21 mmol) and 7.37 ml of 2.5 molar n-hexylmagnesium bromide (in ether).

IR (CHCl 3) 1678, 1661, 1633 and 1582 cm -1; MS: m / e U88 (M +), U03, 397 and 91.

Example XVIII

Cis-3- / S-benzyloxy-U- (1,1-dimethylheptyl) phenyl7-5-methyl-cyclohexanone

A mixture of 5- / 2-benzyloxy-U- (1,1-dimethyl-35-heptyl) phenyl7-3-methyl-2-cyclohexan-1-one (1.00 grams, 2.39 mmol) and η · · > _ 45 _ 500 mg 5% palladium on charcoal / 50 * water stirred under 1 atmosphere hydrogen pressure for 1 hour. A second 500 mg portion of catalyst was added and stirring continued for an additional 30 minutes. A third portion of 500 mg of catalyst was added and then stirred for an additional 13 minutes. The reaction mixture was then filtered through sodium bicarbonate and magnesium sulfate and the filtrate evaporated. The residue was purified by column chromatography over 100 grams of silica gel, eluting with 10% ether: petroleum ether to give 323 mg (yield 32 *) of the desired compound as an oil; 10 MS: m / e 1 * 20 (M +), 1 * 02, 363, 335, 329 and 91.

Example xix.

Cis-3-A- (1,1-dimethylheptyl) -2-hydroxyphenyl7-5-methyl-cyclohexanone

A mixture of S 2 -benzyloxy-1-1,1-dimethyl-heptyl) phenyl-3-methyl-2-cyclohexan-1-one (2.83 grams, 6.77 mmol), 1.5 grams 5 * - Palladium-on-carbon / 50% water and 2.8 grams of sodium bicarbonate in 30 ml of methanol were stirred under 1 atmosphere of hydrogen pressure for 1 * 5 minutes. The reaction mixture was filtered through dietomaceous earth and the filtrate was evaporated under reduced pressure. The residue was dissolved in ether, dried with magnesium sulfate and evaporated. Crystallization of the residue with pentane gave 1.15 grams (yield 52%) of the desired compound, mp 95-9 ° C.

Analysis for C2 ^ 3k®2:

Calculated: C 79.95 * 4 H 10.37 *;

Found: C 80.22 *; H 10.28 *.

By the method described above, the following compounds were prepared from appropriate reactive components of Example XXVI.

Cis-3- / E- (1,1-dimethylheptyl) -2-hydroxyphenyl7-5-ethylcyclohexanone (1.3 ** grams, yield 60 *) from 5- / 2-benzyloxy-1 * - (1,1- dimethylheptyl) phenyl7-3-ethyl-2-cyelohexen-1 * one (2.83 grams, 6.55 mmol) mp 106-107 ° C.

IR (CHCl 3) 3597, 3333, 1709, 1626 and 1585 cm -1; MS: m / e 3M * (M +), 326, 315, 297, 273, and 259.

Analysis for C23H36 ° 2: 35. Calculated: C 80.18 *; H 10.53 *; i \. «- v- - ·; -----. . - .....

"V * * -, * _ · ^ - 46 -

Found: C 80.27 *; ,3 10.39 *.

Cis-3-Α-ί 1,1-dimethylheptyl) -2-hydroxyphenyl7-5-propylcyclohexanone (1.66 grams, yield 61 *) from 5- / 2-benzyloxy-U- (1,1-dimethylheptyl) phenyl7- 3-propyl-2-cyclohexan-1-one (3.0 grams, 7 * 62 mmol); mp 86.5-90.5 ° C.

IR (CHCl 3) 3533, 3289, 1700, 1618 and 1577 cm -1; MS: m / e 358 (M +), 3U0, 315, 297 and 273.

Analysis for C2UH38 ° 2:

Calculated: C 80.39 *; H, 10.68 *; Found: C, 80.16 *; H 10.57 *.

Cis-3-A- {1,1-dimethylheptyl) -2-hydroxyphenyl7-5-hexylcyclohexanone (3.06 grams, yield 93 *) from 5- / 2-benzyloxy-U- (1,1-dimethylheptyl) phenyl7- 3-hexyl-2-cyclohexan-1-one (0.00 grams, 8.2 mmol); mp 8U-85 ° C (from pentane) 15 IR (CHCl 3) 3571, 2222, 1703, 1623 and 1582 cm -1; MS: ffl / 1 1 ^ 00 (M +), 382, 315.

Analysis for C ^ H ^ Og:

Calculated: C 80.9 ^ *; H 11.07 *

Found: C 80.97 *; H 10.91 * *. -

Example XX

Trans-3- / 2-benzyloxy - ^ - (1,1-dimethyl-heptyl) phenyl-7-5-methyl-cyclohexanone.

A solution of 5- / 2-benzyloxy-U- (1,1-dimethyl-heptyl) was added dropwise to a solution of dimethyl copper lithium (2, k7 mmol) cooled to 0 ° C in 3 ml ether and 2 ml hexane. phenyl 7-cyclohexan-1-one (500 mg, 1.2¼ mmol) in 1.5 ml ether. The reaction mixture was stirred for 15 minutes and then poured into 300 ml of saturated ammonium chloride solution. The quenched reaction mixture was extracted three times with 50 ml of ether each, then the ether extracts combined with each other were washed with water and with saturated sodium chloride, dried over magnesium sulfate and evaporated to give 1:75 mg (yield 92 *) of the desired compound as oil was obtained.

IR (CHCl 3) 170¼, 1613 and 1577cm -1; 35 MS: m / e ¼20 (M +), 1Λ2, 363, 335 and 329.

R T * - - :: O

w V v '-j ^ * ...... .....— - -----—............... - ------ ----- _ 47 _

Example .ΧχΙ

Trans-3- / ¢ - (1,1-dimethylheptyl) -2-hydroxyphenyl7-5-methyl-cyclohexanone.

A mixture of trans-3- / 2-benzyloxy-U- (1,1-dimethyl-heptyl) phenyl-7-methylcyclohexanone (175 mg, 0.117 mmol) and => 175 mg 5Js-palladio-on-charcoal / 50 / ί water in 8 ml of methanol was stirred under 1 atmosphere of hydrogen pressure until no more hydrogen was taken up. »The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated under reduced pressure. When the residue crystallized in pent, 89 mg (yield 6k) %) of the desired compound mp 99-102 ° C, MS: m / e 330 (M +), 312, 273 and 2U5.

Example xxii.

Trans-3- / 2-benzyloxy-1 * - (1,1-dimethylheptyl) -phenyl7- (2-butenyl) cyclohexanone.

15 A mixture of trans-3- / 2-benzyloxy-1 * - (1,1-dimethylheptyl) phenyl7-1 * - (2-butenyl) cyclohexanone ethylene ketal (700 mg, 1.38 mmol) 20 ml dioxane and 20 ml 2 Normal hydrochloric acid was refluxed for 15 hours. The reaction mixture was cooled, poured into 500 ml of ice water and extracted with 300 ml of ether. The ether-20 extract was washed twice with 200 ml of saturated sodium bicarbonate each time, dried over magnesium sulfate and evaporated to give the desired compound as oil in quantitative yield.

IR (CHCl 3) 1715, 1616 and 1575 cm -1; 25 MS: m / e k60 (M +), U03, 375, 369, 363, 313, 273, 271 and 91.

Rj! 0.1 * 3 (silica gel, 25% ether: pentane).

In a similar manner was prepared: trans-3- / 2-benzyloxy-1 * - (1,1-dimethylheptyl) phenyl 7-1 * - (2-pentenyl) cyclo-hexanone with preferential yield as oil from trans-3- 2-benzyloxy-U- (1,1-dimethylheptyl} phenyl-7 * - (2-pentenyl} cyclohexanone ethylene ketal (5l * 0 mg, 1.0U mmol); Rf 0.57 (silica gel, 33% ether: pentane) Example xxill

Cis-3- / 3- (1,1-dimethylheptyl) -2-hydroxy-phenyl7-cis-1-methyl-cyclohexa-35 nol and cis-3- / S- (1,1-dimethyl-heptyl) -2-hydroxy-phenyl7 -l * -methylcyclo- • Λ Λ ·· »Λ ï * η. Λ

V V v '/ * J W

48 Hexanone.

A mixture of 3- / 2-benzyloxy-U- (1,1-dimethyl-heptyl) phenyl-7-methyl-cyclohex-2-enone and 391 mg of 5% palladium on carbon / 505? water in 15 ml of methanol was stirred under 1 atmosphere of hydrogen-5 pressure until no more hydrogen was taken up. The reaction mixture was filtered through diatomaceous earth with ethyl acetate and evaporated. The residue was purified by column chromatography over silica gel (200 grams), using 505? ether-hexane was eluted to give, in order of elution, 758 mg of a mixture of ketones and 1020 mg (yield 535?) of the desired alcohol crystallized from cyclohexane. The ketone mixture was further purified by preparative layer chromatography on five 20cm x 20cm x 2mm silica gel plates, four times. eluted with dichloromethane to give 112 mg (yield 7.25?) of the desired ketone as oil.

Desired alcohol, mp 13-1355 ° C

IR (CHCl 3) 3623, 3333, 1626 and 1585 cm -1; MS: m / e 332 (M +), 311, 2U7 and 229.

Analysis for 20 Calculated: C 79: H 10, 925 ?;

Found: C 79. ^ 05 ?; H 10.725 ?.

Desired ketone IR (CHCl 3) 3623, 3390, 163U and 1582 cm -1; MS: m / e 330 (M +), 315, 312, 288, 273, 271 and 21 * 5.

♦

Example xxiv 5- / 2-Benzyloxy-k- (1,1-dimethylheptyl) phenyl-7-methoxy-6-methyl-2-cyclohexan-1-one.

To a solution of 0.5 mol of lithiodiisopropylamide cooled to -78 ° C in 500 ml of tetrahydrofuran (from 50.5 grams, 0.5 mol of diisopropylamine and U17 ml of 1.2 molar n-butyl lithium in hexane) was added dropwise (30 mm ) a solution of 217 grams (0.5 mol) of 5- (2-benzyloxy-1 + - (1,1-dimethylheptyl) phenyl-7-methoxy-2-cyclohexan-1-one in 250 ml of tetrahydrofuran was added. -35 mixture was stirred for an additional 30 minutes at -78 ° C, after which 178 grams (1.0 mol)

"J - ij" - J - - J

49 hexamethyl phosphate and 78 grams (0.55 mole) methyl iodide were added. The reaction mixture was allowed to slowly come to room temperature, stirred for 1 hour and quenched by adding 10 ml of water. The reaction mixture was evaporated under reduced pressure to remove the tetrahydrofuran and added to 1 liter of ice water and 1 liter of ether. The ether extract was washed three times with 1 liter of water each time, dried over magnesium sulfate and evaporated to give the desired compound in substantially pure form. Dilute the desired compound by column chromatography on 2 kg silica gel, eluting with etherspentane.

Example xxv 5- / 2-Benzyloxy-li- (1,1-dimethylheptyl) phenyl7-3 * U-dimethyl-2-cyclohexan-1-one

The process of Example 1 diluted 5- / 2-benzyloxy-1- (1,1-dimethylheptyl) phenyl-7-methoxy-6-methyl-2-cyclohexan-1-one reacted with the Grignard reaction with methyl * magnesium iodide to give the desired compound.

The corresponding phenol was obtained by debenzylating the product according to the procedure of Example II.

Example xxvi-3- / 2-Benzyloxy- (1,1-dimethylheptyl) phenyl-1, 5-dimethylcycloheptanone.

To a solution cooled to -78 ° C of 17.1 grams (0.10 mol) dibromomethane and 21.7 grams (0.050 mol) 3- / 2-b and zyloxy-U- (1,1-dimethylheptyl) phenyl7 - 5-dimethylcyclohexanone 25 in 100 ml tetrahydrofuran was added dropwise over 2 hours a solution of lithium dicyclohexylamide (0.10 mol) in 100 ml tetrahydrofuran. The reaction mixture was stirred at -78 ° C for an additional hour and quenched by adding 2 ml (0.11 mol) of water. The reaction mixture is added to 300 ml of ether and 200 ml of water. The ether-30 extract is dried over magnesium sulfate and evaporated. The crude product was purified by column chromatography on 500 grams of silica gel, eluting with ether pentane to give pure 3- / 2-benzyloxy- (1,1-dimethylheptyl) phenyl7- 1-dibromomethyl-U, 5-dimethyl-cyclohexanol was obtained.

5 '30 µg (0.050 mol) 3- / 2-benzyloxy-U- (1,1-dimethylheptyl) phenyl7-1-dibromomethyl-3,5-dimethylcyclohexanol solution in 150 ml cooled to a -T8 ° C tetrahydrofuran was slowly added 1 * 7.7 ml (0.105 mol) n-butyl lithium (2.2 Molar in hexane) over 2 hours. The reaction solution was stirred at -78 ° C for an additional 2 hours and at 0 ° C for an additional 10 minutes, after which it was quenched by pouring it into 300 ml of ice-cold 1 Normal hydrochloric acid. The quenched reaction mixture was extracted twice with 250 ml of ether each time, the combined ether extracts were washed with 250 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography over 500 grams of silica gel, eluting with ether: pentane to give the desired compound.

Example XXVII

General method of forming hydroxide salts. Excess hydrogen chloride was passed into a solution of the appropriate compound of formula 1A-1D with a pyridyl group and the resulting precipitate was separated and recrystallized from a suitable solvent such as methanol: ether 1:10. -sed.

Likewise, the hydrobromide, sulfate, nitrate, phosphate, acetate, butyrate, citrate, malonate, maleate, fumarate, malate, glycolate, gluconate, lactate, salicylate, sulfosalicylate, succinate, pamoate, tartrate and embonate salts.

Example XXVIII

Suspensions of 3- / ~ 4- (1,1-dimethylheptyl) -2-hydroxyphenyl / cyclohexanol were prepared by adding drug in sufficient amounts to S3 f. · ”Ξ -> - · & ------- ---------- - --------- ------.......

V V V * V K »- 51 0.5% methyl cellulose was added to yield suspensions containing 0.05, 0.1, 0.5, 1.5 and 10mg of drug per ml.

- J · 's

V V V V '^ J

Claims (21)

A compound of formula 1 of the formula sheet, wherein R is a saturated or unsaturated cycloalkyl portion of the group of formula IA, IB, 1C and 1D, hydrogen, benzyl, alkanoyl of 1-5 carbon atoms, P (0) (OH) 2 and its mono- and disodium and 5 potassium salts, -OC (CH2) 2- COOH and its sodium and potassium salts and -CO (CH2) p is NR ^ Rg, where p is an integer 1-4, Rg and Rg, when taken separately, are each hydrogen or alkyl of 1-4 carbon atoms or R8 and Rg, when taken together with the nitrogen atom to which they are attached, a heterocyclic 5- or 6-ring (piperidino, pyrrolo, pyrrolidino , morpholino and N-alkylpiperazino with 1-4 carbon atoms in the alkyl group); R2 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 3-6 carbon atoms, phenyl and phenylalkyl of 1-4 carbon atoms in the alkyl portion; R1 is hydrogen or methyl; R 1 is hydrogen or alkyl 15 of 1-6 carbon atoms, provided that, if R 1 is methyl, R 1 is hydrogen; Z (a) alkylene of 1-13 carbon atoms, (b) - (alk,) -O (alk_) - 1m zn of 1-13 carbon atoms, provided that the sum of the carbon atoms in (alkj) plus (alk2) is not greater then 13 and m and n are each 0 or 1, and W is hydrogen, pyridyl or the group wherein hydrogen is 20, fluorine or chlorine, as well as the pharmaceutically acceptable acid addition salts of the compounds wherein R. -CO (CH_ NR_R_ and / or 1. p 5 o W is pyridyl; the hemiketals of the compounds wherein A and B v. taken together are oxo and R 4 is hydrogen and the ketals with al-channels having 1 to 4 carbon atoms of the compounds wherein A and B taken together are oxo and R 2 hydrogen is. A compound according to claim 1, characterized in that R is a saturated cycloalkyl portion; Z is alkylene and R 2 is hydrogen. Compound according to claim 1, characterized in that 30 Z is alkylene with 8-11 carbon atoms, W and R 1 are each hydrogen and x is 1 or 2. A compound according to claim 3, characterized in that R is the group 2B and ZC (CH 2) 2 (CH 2) g, wherein the compound is 3- / 4- (1,1-dimethylheptyl) -2-hydroxyphenyl / - cyclohexanone. _, _ r-. ^ v w; -v v ~ ^ τ * - 53. A compound according to claim 3, characterized in that R is the group of formula 1 B and Z -C (CH 3) 2 (CH 2) g, wherein the compound is 3- / 4- (1,1-dimethylheptyl) -2- hydroxyphenyl-7-cycloheptanone. A compound according to claim 2, characterized in that R 2 is methyl and Z alkylene of 5-9 carbon atoms, R 3, and W are each hydrogen and R is the group of formula 2B or 2C. 7. A compound according to claim 6, characterized in that R is the group of formula 2C and Z (CH2) g, wherein the compound is 3- / 4- (1,1-dimethylheptyl) -2-hydroxyphenyl-7-methyl-cycloheptanone. is. 8. A unit dose pharmaceutical composition, characterized in that it is composed of a pharmaceutically acceptable carrier or diluent and an arialgesic, tranquilizer, sedative, anti-anxiety and anti-seizure agent. effective amount of a compound of formula 1, wherein R is a saturated or unsaturated cycloalkyl portion of the group of formula IA, IB, 1C and 1D, R 1 hydrogen, benzyl, alkanoyl of 1-5 carbon atoms, P (O) (OH ) 2 and its mono and disodium and potassium salts, -CO (CH2) 2COOH and its sodium and potassium salts or -C0 (CH2) NR ^ Rg, where p is an integer 1-4, Rg and Rg when taken together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring (piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having 1-4 carbon atoms in the alkyl group); R2 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 3-6 carbon atoms, phenyl or phenylalkyl of 1-4 carbon atoms in the alkyl portion; R1 is hydrogen or methyl; R 1 is hydrogen or alkyl of 1-6 carbon atoms provided that, if R 1 is methyl, R 1 is hydrogen; Z (a) alkylene of 1-13 carbon atoms, (b) - (alk.) -O- (alk-) is 1m zn wherein (alk ^) and (alk2) is each alkylene of 1-13 carbon atoms provided the sum of the carbon atoms in (alk ^ and (alk2) are not greater than 13 and m and n are each 0 or 1 and W is hydrogen, ^ v - - - "-54- pyridyl or the group - © -W ^, wherein hydrogen , fluorine or chlorine, as well as the pharmaceutically acceptable acid addition salt of the compound wherein R 1 is -CO (CH 2) pNR 5 Rg and / or W pyridyl. Pharmaceutical preparation according to claim 8, characterized in that R is a saturated cycloalkyl part. CHR 2 or - (C 1 ^) 3 CHR 4 is characterized in that a compound of formula 7, in which R * 'is a hydroxy protecting group and Z and W have the meanings already mentioned, is subjected to a Grignard reduction with a compound of formula 8, wherein R2 and Q have the meanings already mentioned and then, if desired, one or more of the following treatments are carried out: (a) the hydroxy protecting group is removed; (b) a compound of formula 1 ', wherein R ^ is hydrogen, is acylated? (c) a compound of formula 1 'wherein A and B taken together are oxo is subjected to a Wittig reaction with a methylide to give a compound wherein A and B taken together are methylene; (d) a compound of formula 1 ', wherein A and B taken together are methylene, is subjected to hydroboration oxidation; (e) a pharmaceutically acceptable acid addition salt of a compound of formula 1', wherein R, Co (CEL) NRCR 4 and / or 1 p OO is 25. pyridyl is prepared. · Pharmaceutical preparation according to claim 9, characterized in that, R 1, R 1 and W are each hydrogen, R 2 is hydrogen or methyl and Z is alkylene. Pharmaceutical preparation according to claim 11, 10, characterized in that R is the group of formula IB or 1C and Z is alkylene of 8-11 carbon atoms. Pharmaceutical preparation according to claim 8, characterized in that A and B, taken together, are oxo. Pharmaceutical preparation according to claim 12, characterized in that R is the group of formula IB or 1C, R 1, R 8, R 1 and W are each hydrogen, R 2 is hydrogen or methyl and Z alkylene. Pharmaceutical preparation according to claim 13, characterized in that Z is alkylene of 8-11 carbon atoms, Pharmaceutical preparation according to claim 14, characterized in that R is the group of formula 1B, R 2 is methyl and Z is -C (CH 2) 2 (CH 2) g, wherein the compound is 3- / 4- (1,1 dimethyl) -heptyl) -2-hydroxyphenyl / -4-methylcyclohexanone. Pharmaceutical preparation according to claim 12, characterized in that R is the group of formula 1C, R 2 is hydrogen and ZC (CH 2) 2 (CH 2) g, wherein the compound is 3- / 4- (1,1-dimethyl-) heptyl) -2-hydroxyphenyl / cycloheptanone. 17. Process for the selective alkylation of a 3- (2,4-dihydroxyphenyl) cycloalkane with 5-8 carbon atoms in the cycloalkyl portion on the 4-hydroxy group, characterized in that (a) the 3- (2,4- dihydroxyphenyl) cycloalkanone is converted into a ketal with an alcohol of 1-4 carbon atoms; (b) the product of step (a) is alkylated with a compound WZY, wherein Y is chlorine, bromine, mesyloxy or tosyloxy, is Z- (alk2> -, where Λ —f Λ 7 t Q fj \ r> * Λ Ce V * - "J w Λ * -55 - (alk2) alkylene of 1 - 13 carbon atoms and W is hydrogen, pyridyl or - 0 - W, wherein hydrogen is fluorine or chlorine, and (c) the alkylated product from step (b) is treated with dilute acid. 18. Process according to claim 17, characterized in that the ketal is formed by reacting the 3- {2,4-dihydroxy-phenyl) cycloalkanone with a trialkyl formate. 19. A process for the preparation of a compound of formula 1 of the formula sheet, wherein, Η ^, Z and W have the meanings already mentioned in claim 1? Q-CE ^ -i-C ^ CHiR ^), - ((^) 2 Process for the selective alkylation of a 3- (2,4-dihydroxyphenyl) cycloalkanol with 5-8 carbon atoms in the cycloalkyl portion on the 4-hydroxy group, characterized in that (a) the 3- (2,4-dihydroxyphenyl) cycloalkanol is converted into a ketal with an alcohol of 1-4 carbon atoms; (b) the product of step (a) is alkylated with a compound WZY wherein chlorine is bromine, methyloxy or tosyloxy, is Z- (alk2) - wherein (alk?) is alkylene of 1-3 carbon atoms and W hydrogen, pyridyl or <D -Wj, wherein W1 is hydrogen, fluorine or chlorine, and (c) the ratio -O; For the alkylated product of step (b), it is treated with dilute acid. Process according to claim 20, characterized in that the ketal is formed by reacting the 3- (2,4-dihydroxy-phenyl) cycloalkanone with a trialkyl formate. n "7 7; 5