GB2050358A - Derivatives of phenylcyclohexane - Google Patents

Abstract

Antidepressants and central nervous system equilibrating agents having the general formula: <IMAGE> wherein A and B are different and can be phenyl or cyclohexyl, X is an aliphatic residue and Y and Y' are hydrogen or an alkyl radical possibly bound to a cyano group or can be replaced by a single radical connected to the N atom by a double bond.

Description

SPECIFICATION Derivatives of phenylcyclohexane This invention relatives to a series of amine derivatives carrying the phenylcyclohexane radical, which can display interesting pharmacological properties e.g. as analgesics, antidepressants, and central nervous system equilibrating agents.

The general formula of these compounds is the following:

wherein A and B are different from one another and are selected from phenyl and cyclohexyl; Xis an aliphatic radical containing from 1 to 5 carbon atoms; and Y and Y' are the same or different and are selected from hydrogen and straight and branched alkyl radicals containing from 1 to 5 carbon atoms and possibly a -CN group, or are replaced by a single radical connected to the nitrogen atom by a double bond. X can be straight or branched chain or comprise a cycloaliphatic ring.

Thus, two sub-series of compounds can be obtained, one with A=phenyl and B=cyclohexyl, and vice versa: when B is cyclohexyl, the compounds can take either the "cis" or the "trans" configuration.

Compounds of this invention have been tested for the inhibition of reserpine-induced hypothermia in mice, according to the procedure of Askew, B.M., Life Sci., 2,725(1963), and have proven active.

A representative compound of the series, alpha, alpha-dimethyl-(4-phenylcyclohexyl)-methylamine, at a dosage of 40 micromol/kg b.w. has caused a temperature increase of 15.5"C, and at 160 micromol/kg b.w. the increase was 18.4"C. Another compound, alpha-methyl-(4-phenylcyclohexyl)-methylamine, has given, at the same dosages indicated above, temperature increases of 14.6"C and 23.6"C, respectively. A third compound, alpha-methyl-N-2-cyanoethyl-(4-phenylcyclohexyl )-methylamine, has caused buddy temperature increases of 10.6on and by 19.2"C, respectively.

The compounds of this invention may also be effective in inhibiting the eyelid ptosis induced by reserpine in mice according to the procedure of Wilson, S.P., and Tislo, R., Proc. Soc. Exp. Biol. Med., 109,847 (1962).

The compounds in question can increase the hyperthermia caused by 5-hydroxytryptophan in rats previously treated by the procedure of Jori, A. and Garattini, S., J. Pharm.Pharmacol., 17,480 (1965), and can increase the behavioral modifications induced in mice by 5-hydroxytryptophan according to the disclosure of Lippmann, W., and Prigsley, T.A., Arch. Int. Pha rmacodyn., 227,324(1977).

The three substances which have been more closely investigated did not display any influence on the spontaneous motility of mice, as tested by the procedure disclosed by Cantarelli, G., Carissimi, M., Cattaneo, A., D'Ambrosio, R., Grumelli, E., Milla E., Panelli, M., and Ravenna, F., II Farmaco, Ed. Sc., 24, 123(1969), nor do they inhibit monoaminooxidase when tested according to the procedure described by Tedeschi, D. H. and Tedeschi, R.E., Fellows E.J., Proc.Soc.Exp. Biol. Med., 103,608 (1960).

The pharmacological properties set forth above permit the characteristics of antidepressive drugs in humans to be attributed to the compounds of the present invention.

A number of procedures have been followed for preparing the antidepressive drugs of the present invention, e.g.

a) Treatment of an aromatic halomethyl derivative with hexamethylene tetramine; b) Reduction of a ketoxime; c) Reduction of a nitroderivative; d) Condensation of acrylonitrile with a primary amine; e) Reaction of dimethylformamide with a ketone; f) Reaction of formic acid and formaldehyde with a primary amine; g) Ritter's reaction on a tertiary alcohol; h) Condensation of an aliphatic aldehyde with a primary amine, followed by catalytic hydrogenation of the double bond.

The first of these methods has permitted preparation of the methylamine derivatives in particular, whereas the second and the third methods have been used to prepare both the ethylamine derivatives and those having a longer carbon atom chain.

The thus prepared primary amines have been condensed with an appropriate carbonyl derivative and the product thus obtained has been reduced in order to prepare the N-substituted derivatives. Formaldehyde has been used for preparing the N-methyl derivative.

Afew examples are given to illustrate the invention without limiting same.

EXAMPLE 1 4-cyclohexylbenzylamine . - To a solution of 52 grams (g) of hexamethylenetetramine in one litre of chloroform, maintained at 50"C, there was added slowly, over 3 hours, a solution of 4-cyclohexyl-alpha-chlorotoluene in 2 litres of chloroform. After a 24-hour stirring at 50"C, the mixture was evaporated to a volume of about 1 litre and poured into 3 litres of ethyl ether and the resulting solid was filtered off, washed with ether and dried.

Into a solution of 45 g of the adduct in 1.6 litres of ethanol there was dripped 900 mls of conc. HCI and the mixture was refluxed with stirring for 24 hrs. and then evaporated to dryness under reduced pressure; the residue was taken up with water, treated with soda to an alkaline pH and extracted with ethyl acetate. The extracts were combined, washed with water and dried over sodium sulfate and evaporated, to give an oil which was distilled, b.p. 1 18'C - 119"C under 0.9 millimetres of mercury (mmHg).

EXAMPLE 2 Al pha-methyl-4-cyclohexyl benzylamine . a) 4-cyclohexylacetophenoneoxime . - A solution of 41 g (0.2 mol) of 4-cyclohexylacetophenone in 500 mls of Abs. EtOH was admixed with a solution of 21 g of hydroxylamine hydrochloride in 100 mls of water had dripped continuously thereinto 32 g of NaOH in 100 mis of water. The mixture was subsequently brought to the boil for 5 hrs., allowed to cool and poured into 3 litres of water. Upon cooling, the precipitate was collected on a filter, washed with water and recrystallized from 50% EtOH. Yield : 37.3 g (85% of theory) - M.p. 1 18"C.

b) alpha-methyl-4-cyclohexylbenzylamine.- A solution of 7.5 g of 4-cyclohexylacetophenoneoxime in 100 mis of abs. EtOH was treated with 750 milligrams (mg) of 10% Pd on activated charcoal and hydrogenated in a Parr apparatus at room temperature and under a pressure of 4 atmospheres. After removal of the catalyst and evaporation of the solvent, an oil was left, which was distilled. B.p. 122"C-123"C under 0.7 mm Hg.

EXAMPLE 3 Trans-alpha-methyl-4-phenylcyclohexylmethylamine . - a) Trans-1-acetyl-4-phenylcyclohexane.- Into a suspension of 8 g. of lithium in small pieces in 300 mls ethyl ether (anhydrous), under a nitrogen blanket, there was slowly dripped a solution of 82.4 g of methyl iodide in 300 mls of anh.ethyl ether. On completion of the addition, the mixture was stirred for one hour at room temperature and quickly filtered on glass wool under a nitrogen blanket and introduced over about 3 hrs. into a solution of 31 g of trans-4-phenylcyclohexanecarbonic acid in 2.2 litres of anh. ethyl ether. The suspension thus obtained was brought to the boil with stirring for 8 hrs., then allowed to cool and poured into water.The organic layer was separated and the water layer washed with ether. The combined ethereal extracts were washed with a 5% solution of sodium bicarbonate and then with water, dried on sodium sulfate and then evaporated. The residual oil was distilled at 1340C under 0.7 mmHg. Yield 28.5 g (93% of theory).

b) Trans- 1-acetyl-4-phenylcyclohexaneoxime. The procedure is akin to that described in EXAMPLE 2, item a). The product melts at 184 C-186 C (from 95% EtOH). Yield is 76% of theory.

c) Trans-alpha-methyl-4-pnenylcyclohexylmethylamine. - To a suspension of 11.2 g of lithium and aluminum hydride in 500 mls of anh.ether there were slowly added 16 g of trans-1-acetyl-4-phenylcyclohexaneoxime dissolved in 500 mis of tetrahydrofuran and 400 mls ethyl ether and the mixture was brought to the boil with stirring for 11 hrs. Upon cooling, there were cautiously added 12 mls of water, 12 mls of 15% NaOH soln. and eventually 35 additional mls of water, and the suspension was allowed to stand with stirring for 30 mins. at room temperature.The resulting solid was filtered off, washed thoroughly with ethyl acetate and the filtrates were combined, dried over sodium sulfate, and evaporated, and the oily residue distilled. B.p. 125"C-128"C under 0.8 mmHg.

EXAMPLE 4 Trans-alpha-methyl-rN-2-cyanoethyl-4-phenylcycloheXylJ-methylamine . 46 g of trans-alpha-methyl-(4-penylcyclohexyl)-methylamine base was brought to the boil with 60 mls of acrylonitrile for 6 hrs. The solution was evaporated under vacuum and the residue dissolved in ethyl ether, converted into its hydrochloride and recrystallized from 95% EtOH. Yield : 3.6 g (60% of theory). M.p. 231"C 233"C.

EXAMPLE 5 Trans-alpha-methyl-(N-methyl-4-phenylcyclohexyl)-methylamine . - A mixture of 18.6 g of trans-1 -acetyl-4-phenylcyclohexane, 23.6 g of N-methylformamide and 15 mls of 99% formic acid was heated with stirring to 1 950C for 24 hrs. Upon cooling, there were added 100 mls of conc. HCI and the resultant mixture was refluxed again for 12 hours, diluted with 200 mis of water and extracted with ethyl ether. The watery liquors, when treated with soda and extracted with ether, gave an oily base which was converted into its hydrochloride, then purified with EtOH-ethyl ether. Yield 19.780 (85% of theory). M.p. 192"C-194"C.

EXAMPLE 6 Trans-alpha-methyl-6N,N-dimethyl-4-phenylcycloheXylJ-methylamine . - A mixture of 13.8 g of trans-alpha-methyl-4-phenylcyclohexylmethylamine hydrochloride, 43.05 g of 99% formic acid and 78.5 mls of a 39% solution of formaldehyde was heated with stirring to 1 OO"C for 10 hrs.

Upon cooling the mixture was diluted with water, made alkaline with conc. NaOH and extracted with ethyl acetate. The residue obtained on evaporation of the organic phase was dissolved in ethyl ether and converted into its hydrochloride, then recrystallized from acetone. Yield : 9.7 g (63% of theory) - M.p. 176"C 178"C.

EXAMPLE 7 Trans-alpha, alpha-dimethyl-(4-phenylcyclohexyl)-methylamine . - a) Trans-r4-phenylcyclohexylJ-alpha,alpha-dimethyl-methanol.- To a suspension of 8 g of lithium in 180 mls anh.ethyl ether there was slowly added under a nitrogen stream 82.4 g of methyl iodide in 250 mls ethyl ether. After 30 mins. heating at room temperature there was dripped thereinto 32.6 g of trans-4-phenyl-cyclohexane-carbonic acid chloride in 1.3 litres of anh.ethyl ether.

Heating was continued with stirring, still under a nitrogen stream, for 9 hrs. and the mixture, upon cooling, was quickly filtered under a nitrogen stream on glass wool to remove the unreacted Li, and slowly diluted with 1.3 litres of water, the organic phase being separated. Upon cooling and evaporation under vacuum, a solid was obtained which could be recrystallized from 500 mls of petroleum ether at -25"C. Yield : 63% of theory - M.p. 68"C - 69"C - B.p. 151"C under 1 mmHg.

b) Trans-alpha, alpha-dimethyl-(4-phenylcyclohexyl)-methylamine. To 4.77 g of potassium cyanide there was added a solution of 13.08 g of trans-(4-phenylcyclohexyl)alpha,alpha-dimethylmethanol in 18 mls of acetic acid, whereafter, without exceeding 50"C, there was added dropwise with stirring a cold solution of 15 mls of conc. sulfuric acid and 11 mls of glacial acetic acid. After 6-hour stirring at 50"C, the contents of the flask were poured into water and the resulting solid was collected on a filter, dried and washed with ether. The ultimate purification was carried out by recrystallization from water and washing with methanol-ethyl ether. Yield : 8.9 g (59% of theory) - M.p. 306"C-307"C.

EXAMPLE 8 Trans-alpha-methyl-(n-propyl-4-phenylcyclohexyl )-methylamine . a) Trans-N-propylidene-alpha-methyl-4-phen ylcyclohexylmethylamine . A solution of 7.2 g oftrans-alpha-methyl-(4-phenylcyclohexyl)-methylamine in 500 mls anh.benzene was treated with 3.08 g of propionaldehyde in 10 mls benzene, refluxed for 20 hrs., and evaporated. The residue, as obtained, was used as such for the subsequent reduction, without any purification step.

b) Trans-alpha-methyl-{N-propyl-4-phenylcyclohexylJ-methylamine.- A solution of 9.1 g oftrans-alpha-methyl-(N-propylidene-4-phenylcyclohexyl)-methylamine in 100 mix of ethyl acetate, to which there had been added 0.8 g of PtO2, was hydrogenated at room temperature and under a pressure of 3.5 atmospheres. Upon removal of the catalyst by filtration, the solution was evaporated under vacuum, the residue was dissolved in ethyl ether, filtered on activated charcoal and converted to its hydrochloride: the latter was collected on a filter and recrystallized from isopropanol. Yield : 2.8 g (27% of theory) - M.p. 215'C - 217 C.

EXAMPLE 9 Trans-alpha-butyl-(4-phenylcyclohexyl)-methylamine.- a) Trans- l-(4-phenylcyclohexyl)-pentanone . Under a nitrogen blanket, 21.92 g of butyl bromide in 160 mls of ethyl ether was dripped into a mixture of 4.32 g of magnesium shavings in 160 mls ethyl ether. After 30 mins. of heating, there was added 16.32 g of trans-4-phenyl-cyclohexanecarbonitrile in 200 mis of anh. benzene. The internal temperature was brought to 60 C by distilling off the volatile fraction, whereafterthe mixture was brought to the boil for 3 hrs.Upon cooling, there were added 40 mis of glacial acetic acid and 20 mls of water : the mixture was boiled for 3 additional hours. The mixture was then poured into iced water and extracted with benzene. Upon drying and evaporation under vaccum, an oily product was isolated. Yield 16 g (75% of theory) - B.p. 149C under 0.3 mmHg. The 2,4-dinitrophenylhydrazone melts at 136 C - 137"C.

b) Trans- l-(4-phenylcyclohexyl)-pentanoneoxime. - The procedure is akin to that described in EX. 2 item a).

The product melts at 96"C-98"C. Yield : 6.25 g (75% of theory).

c) Trans-alpha-butyl-4-phenylcyclohexylmethylamine . - To a mixture of 3.3 g of lithium and aluminum hydride in 150 mls of anh. ethyl ether, there were added dropwise 5.7 g ofthetrans-1-(4-phenylcyclohexyl)-pentanoneoxime in 150 mls of tetrahydrofuran and 120 mls ethyl ether. Subsequently, the whole mixture was refluxed with stirring for 20 hrs. Upon cooling, the excess hydride was destroyed by the addition of 5 mls of water, 5 mls of 5% NaOH and 15 mls of water. Upon dilution with ethyl acetate, the mixture was filtered and the lithium and aluminum hydroxides were washed away with additional solvent and, upon drying on sodium sulfate, the organic phase was evaporated under vacuum.The residue was dissolved in ethyl ether, filtered with activated charcoal and converted to its corresponding hydrochloride. Upon cooling, the precipitate was collected on a filter, washed with ether, dried over phosphorus pentoxide and recrystallized from acetone. Yield : 3.53 g (57% of theory) - M.p. 187"C 189"C.

EXAMPLE 10 Trans-alpha-cycloprnpyl-4-phenyl-cyclohexanemethylamine . - a) Trans-(4-phen ylcyclohexyl)-cyclopropylketone. - Under a nitrogen blanket, to 6.48 g of Mg slurried in 200 mls of ethyl ether, there was added 57.36 g of 4-phenylcyclohexyl bromide in 250 mls of ethyl ether. Afterrefluxing for 2 hrs there was added dropwise 8.88 g of cyclopropyl cyanide in 150 mls of ethyl ether, whereafter the solution was brought to the boil for 8 hours. Subsequently, there were added 50 mls of acetic acid, 20 mls of conc. HCI and 50 mls of water and, still under a nitrogen blanket, the mixture was refluxed for 3 hrs.Upon cooling, there were added water and ice and extraction with ethyl acetate was carried out. The extracts were combined and evaporated and the residual oil distilled. It has a b.p. of 148"C - 152"C under 0.1 mmHg.

By purification by chromatography on a column filled with silica gel (eluant hexane and ethyl acetate (v/v 9:11)) there was obtained 5 g of a pure product having a m.p. of 82"C, to which the "trans" structure has been attributed.

b) Trans-(4-phenylcyclohexyl)-cyclopropylketoneoxime, - The procedure is akin to that described in EXAMPLE 2, item a).

The product melts at 189eC - 1 71"C - Yield : 2.4 g (42% oftheory).

c) Trans-alpha-cyclopropyl-4-phenylcyclohexanemethylamine . To a solution of 0.55 g of LiAIH4 in 25 mls anh. ethyl ether there were added dropwise 0.89 g of trans-(4-phenylcyclohexyl)-cyclopropylketoneoxime dissolved in 25 mls of tetrahydrofuran and 25 mls ether and the mixture was brought to the boil for 20 hrs with stirring. Upon cooling there were added, in the order given, 1 ml of water, 1 ml of 5%-NaOH and 3 mls of water: stirring was applied for a short time, and the Al and Li hydroxide were filtered off and washed with ether. The organic phase was evaporated and the oily residue, converted to its hydrochloride, was recrystallized from isopropanol. Yield : 0.37 g (38% of theory) M.p.265 C- 267 C.

EXAMPLE 11 1 -(4-cyclohexyl phenyl)-2-aminopropane . a) 4-cyclohexylbenzaldehyde. A mixture of 350 mis of glacial acetic acid, 350 mls of water, 172 g of 4-cyclohexyl-alpha-chlorotoluene and 231 g of hexamethylenetetramine was refluxed with stirring for 2 hrs. Upon cooling, there were added 280 mls of dil. HCI and the mixture was brought to the boil for 15 additional minutes, whereafter it was cooled, diluted with water and repeatedly extracted with ethyl ether.

The combined extracts were washed with water, 10% sodium bicarbonate and with water again, dried and evaporated under vacuum. The oily residue was distilled at 122 C-125 C under 0.5 mmHg. Yield:113 g (72% of theory) b) l-(4)cyclohexylphenylj-2-nitropropene . - A mixture of 50 g of 4-cyclohexylbenzaldehyde, 24 g of freshly distilled nitroethane and 16.2 g of ammonium acetate in 200 mls of glacial acetic acid was brought to the boil with stirring for 5 hrs., and, upon cooling, poured into cold water and allowed to cool. The water layer was decanted and the oil lying on the bottom extracted with ethyl acetate and washed with water. Upon drying on sodium sulfate and evaporation of the solvent, the oily residue was distilled.After a head fraction which essentially contained the unreacted aldehyde, there distilled between 160"C and 180;C a fraction which was very rich in the expected product. It was percolated on a Nylon column filled with silica gel (2-metre high, 5 cm dia.) using benzene as the extractant. As the solution reached the column bottom, the yellow-colored sections were cut away and extracted with acetone and 25 g of product (39% of theory) were obtained, having a b.p. of 161"C-1 68"C under 0.5 mmHg.

c) l-(4-cyclohexylphenyl)-2-aminopropane. - To a suspension of 9.3 g of LiAIH4 in 500 mls of anh. ethyl ether there was slowly added dropwise 10 g of 1 -(4-cyclohexylphenyl)-1 -nitropropene in 150 mis ethyl ether (an hydrous) and the mixture was refluxed with stirring for 7 hrs. Upon cooling, there were slowly added, in the order given, 11 mls of water, 11 mls of 15% NaOH and lastly 35 mls of water. After a 30-min. stirring at room temp., the precipitate was collected on a filter and washed with ethyl acetate and the combined filtrates were dehydrated (sodium sulfate). By evaporation, an oil was obtained, which distilled at 118"C-123"C under 0.6 mmHg.It was converted to its hydrochloride which has a m.p. 2540C.

EXAMPLE 12 Trans-1 -(4-phenylcyclohexyl)-2-aminopropane . a) Trans- l-(4-phen ylcyclohexyl)-2-nitropropene . A mixture of 25 g of trans-4-phenylcyclohexanealdehyde, 11 g of freshly distilled nitroethane and 8.3 g of ammonium acetate in 75 mls of glacial acetic acid was refluxed under a nitrogen blanket for 22 hrs, then poured in water; the oily residue lying on the bottom was extracted with ether and the ethereal solution washed with sodium carbonate, then with water, dried and evaporated. The oily residue was purified by recrystallizing it from isopropanol.

Yield 11.6 g (38% of theory) of a product which is virtually pure by thin-layer chromatography.

By distillation (b.p. 170"C-172"C under 0.9 mmHg) a pure product was obtained, which had a m.p. of 102"C-1 04"C.

b) Trans- l-(4-phen ylcyclohexyl)-2-aminopropane. - The procedure is akin to that described in EXAMPLE 11, item c).

The trans-1 -(4-phenylcyclohexyl -2-aminopropane melts at 261 C-263 C (when recrystallized from isopro panol).

Claims (8)

1. A compound of the formula:

wherein one of A and B is phenyl and the other is cyclohexyl, Xis an aliphatic radical containing from 1 to 5 carbon atoms, and Y and Y' are the same or different and are selected from hydrogen and alkyl radicals containing from 1 to 5 carbon atoms and possibly a -CN group, or are replaced by a single radical connected to the nitrogen atom by a double bond.

2. Trans-alpha-methyl-4-phenylcyclohexylmethylamine.

3. Cis-alpha-methyl-4-phenylcyclohexylmethylamine.

4. Trans-alpha,alpha-dimethyl-4-phenylcyclohexylmethylamine.

5. Trans-alpha-methyl-N-(2-cyanoethyl )-4-phenylcyclohexylmethylamine.

6. A compound according to claim 1 substantially as hereinbefore described in any one of the Examples.

7. A method of preparing a compound according to claim 1, the method being substantially as hereinbefore described.

8. A method of preparing a compound according to claim 1, the method being substantially as hereinbefore described in any one of the Examples.