DE3017815A1 - DERIVATIVES OF PHENYLCYCLOHEXANE WITH ANTIDEPRESSIVE EFFECT - Google Patents

Description

DiPL.-lNG. Wilfrid RAECK

PATENT ADVERTISER 7 STUTTGART 1, MOSERSTRASSE 8 TELEPHONE (0711) 244003 -

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MAGGIONI FARMACEUTICI S.p.A. Via Giuseppe Colombo, 40 - MdlarW / Italy

Derivatives of phenylcyclohexane with an antidepressant effect

The invention relates to a series of Armin = _s derivatives in which the Phenylcyclohexangruppe is j, and the interesting pharmacological properties as analgesics and antidepressants have these compounds "The general formula is as follows:

-Y

X-N-

The rings A and B are each different and represent a cyclohexyl ring and a Phenylrlng _s represents wherein A and B AELS can stand for "phenyl" or "cyclohexyl" both.

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X is a straight-chain or branched aliphatic group, containing 1 to 5 carbon atoms, a portion thereof can form a cycloaliphatic ring.

Y and Y 'can be either the same or different and consist of hydrogen and straight-chain or branched alkyl groups which contain 1 to 5 carbon atoms and possibly a CN group. These'alkyl groups can optionally also be replaced by a group which is bonded to the nitrogen atom via a double bond.

In this way you can create two subsets of connections will be obtained:

one with A = phenyl

and B = cyclohexyl

and vice versa. .

When B = cyclohexyl, the compounds can either adopt the cis configuration or the trans configuration.

The compounds of the invention were tested for the inhibition of reserpine-induced hypothermia in mice, as in the procedure of Askew, B.M., Life Sci., _2, 725 (1963) is indicated and its activity is determined.

A representative compound from this series: alpha, alpha-dimethyl - (^ - phenylcyclohexyD-methylamine has caused an increase in temperature of 15.5 ⁰ C at a dose of 40 micromoles per kg weight, at 160 micromoles per kg weight increase of 18 4 ⁰ C.

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Another compound: alpha-methyl- (4-phenyl-cyclohexyl) methylamine produced in the same dosages as stated above, increases in temperature of 14.6 ⁰ C and 23.6 ° C. A third connection: alpha-methyl-N-2-cyanoethyl (4-phenylcyclohexyl) methylamine has caused increases in body temperature of 10.6 ⁰ C and 19.2 ° C.

The compounds of this invention are also very effective in inhibiting those caused by reserpine Eyelid ptosis in mice, what after

Method of Wilson, SP and Tislov, R., Proc. Soc.Exp., BIoI ₁ Med., L_0_9, 847 (1962).

A recent test according to the method of Jovi, A. and Garattini, S., J. Pharm. Pharmacol., 17 . 480 (1965) showed that the compounds in question increase hyperthermia produced in rats by 5-hydroxytryptophan and also increase behavioral deviations produced in mice by 5-hydroxytryptophan. This was found in agreement with the discovery of Lippmann, W. and PPrigsley, TA, Arch. Int, Pharmacodyn ,, 227 »324 (1977).

The three substances that were examined in more detail did not show any influence on the spontaneous mobility of mice, as after that of Cantarelli, G., Carissimi, M., Cattaneo A., D'Ambrosio, R., Grumelli E., Mi11a E., Cattaneo A., Panelli M., and Ravenna F., Il Farmaco, Ed. Sc, 2-4 (1969) discovered method was found, nor do they inhibit the monoamine oxidase in the test Tedeschi D.H. and Tedeschi R.E., Fellows E.J., Proc.Soc. Exp. Biol. Med., IO3, 608 (1960).

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The above-expressed pharmacological properties typical of antidepressants, like them used in humans can be attributed to the newly discovered drugs of the invention.

To the antidepressant drugs of the present invention a number of procedures were used to manufacture:

a) reaction of an aromatic calogen methyl derivative with hexamethylenetetramine;

b) reduction of a ketoxime;

c) reduction of a nitro derivative;

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 reaction with a tertiary alcohol;

h) Condensation of an aliphatic aldehyde with a primary amine and subsequent catalytic hydrogenation the double bond.

The first of these methods was more likely to produce the methylamine derivatives, while the second did and third methods made it possible to produce both the ethyl amine derivatives and the longer carbon chain derivatives.

The primary amines thus prepared were condensed with a suitable carbonyl derivative, the resulting Products were reduced to produce the N-substituted derivatives. For the production of the N-methyl derivative Formaldehyde was used.

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A few examples are given to explain the invention - without restricting the interpretation.

EXAMPLE 1 4-cyclohexylbenzylamine.

A solution of 52 g of hexamethylenetetramine in 1 liter Chloroform were slow at a temperature of 50 ° C, over 3 hours, a solution of 4-cyclohexylalpha-chlorotolnol added in 2 liters of chloroform. After stirring at 50 ° C for 24 hours, the mixture became evaporated to a volume of approx. 1 liter and then poured into 3 liters of ethyl ether. The resulting solid was filtered off, washed with ether and dried. The solid was found on following without further purification Way converted into the amine:

900 ml of concentrated hydrochloric acid were added dropwise to a solution of 5 g of the solid in 1.6 l of ethanol and the mixture was then refluxed for 2k hours with stirring. The mixture was then evaporated to dryness under reduced pressure, the residue was taken up in water, brought to an alkaline pH value with soda and extracted with ethyl acetate. The extracts were combined, washed with water, dried over sodium sulfate and evaporated. The resulting oil was distilled. Bp. 118 ⁰ C - 119 ° C with 0.9 mm Hg column.

EXAMPLE 2

alpha methy 1-k -eyelohexylbenzylamine.

a) ^ -eyelohexy1-acetophenonoxine.

A solution of ¹ Il g (0.2 mol) ^ -Cyclohexylacetophenon in 500 ml of absolute ethanol was with a solution

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of 21 g of hydroxylamine hydrochloride mixed in 100 ml of water and then uniformly dripped into a solution of 32 g of NaoII in 100 ml of water. The mixture was then boiled for 5 hours, cooled and poured into 3 liters of water. After cooling, the deposited precipitate was collected on a filter, washed with water and recrystallized from 50% ethanol. Yield: 37.3 g (85 % of theory), pp. 118 ° C.

b) alp ha-methy 1 - *! - cy clohexylbenzylamine.

A solution of 7.5 g ^ -cyclohexylacetophenone oxime in 100 ml abs. Ethanol was added 750 mg of 10 £ palladium-charcoal and hydrogenated Parr apparatus at room temperature and atmospheric pressure in k. After removal of the catalyst and evaporation of the solvents an oil remained which was distilled. Bp. 122 - 123 ⁰ C with 0.7 mm Hg column.

EXAMPLE 3

trans-alpha-methyl-4-phenylcyclohexylmethylamine.

a) trans-l-acetyl - ^ - phenylcyclohexane «

A solution of 82.4 g of methyl iodide in 300 ml of anhydrous ethyl ether was slowly added dropwise to a suspension of 8 g of finely divided lithium in 300 ml of anhydrous ether under a nitrogen atmosphere. After the addition was complete, the mixture was stirred at room temperature for one hour and quickly filtered through glass wool under a nitrogen atmosphere. It was then added in the course of three hours to a solution of 31 g of trans-JJ-phenylcyclohexanecarboxylic acid in 2 _S 2 1 of anhydrous ethyl ether. The suspension obtained in this way was boiled for eight hours while stirring, then cooled

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and poured into water. The organic phase was separated off and the aqueous phase was washed with ether. The combined ether extracts were washed first with sodium bicarbonate solution and then 5 #iger _s washed with water, dried with sodium sulfate and "evaporated The residual oil was at 13 ^ ⁰ C under a pressure of 0.7 mm Hg distilled.
Yield: 28.5 g (93 % of theory).

b) trans-1-acetyl - ^ - phenylcyclohexanoxlm

The procedure is similar to that already described in Example 2 »Part a). The product melts at 184-186 ° C (from 95 tiger ethanol). Yield 76 % of theory "

c) trans-alpha-met hy 1-4-pfieny Icy clohexylmet hy lamin.

A reading of 16 g of trans-1-acetyl - ^ - phenylcyclohexanoxime in 500 ml of tetrahydrofuran and 400 ml of ethyl ether was slowly added to a suspension of 11.2 g of lithium aluminum hydride in 500 ml of anhydrous ether, and the mixture was boiled for 11 hours with stirring 12 ml of water were carefully added to cooling, then 12 ml of 15% sodium hydroxide solution, finally a further 35 ml of water and the suspension was stirred at room temperature for 30 minutes. The solid formed was filtered off, carefully washed with ethyl acetate, the filtrates were combined with sodium sulfate dried, evaporated and the oily residue distilled «
Kp, 125 - 128 ° C with 0.8 mm Hg column,

EXAMPLE 4

trans-alpha-methyl- (N-2-cyanoethy1-4-phenylcyclohexyl) -

methylamine.

4.6 g of trans-alpha-methyl- (4-phenylcyclohexyl) -methylamine base were heated to the boil for 6 hours together with 60 ml of acrylonitrile. The solution was evaporated in vacuo, the residue was dissolved in ethyl ether > converted into the hydrochloride and this was recrystallized from 95% ethanol.
Yield: 3.6 g (60 % of theory). Mp. 231-233 ° C.

EXAMPLE 5

trans-alpha-methyl- (N-methy1-4-phenylcyclohexyl) -methylamine.

A mixture of 18.6 g of trans-1-acetyl - ^ - phenyl-cyclohexane, 23.6 g of N-methylformamide and 15 ml of formic acid was heated to 195 ° C. for 2k hours with stirring. After cooling, 100 ml of concentrated HCl were added and the resulting mixture was refluxed for a further 12 hours, then diluted with 200 ml of water and extracted exclusively or subsequently with ethyl ether. An oily base could be separated off from the aqueous phase by adding soda and extraction with ether, which base was converted into the hydrochloride and then purified with ethanol-ethyl ether.
Yield: 19.78 g (85 % of theory) pp. 192 -

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EXAMPLE 6

trans-alpha-methyl-CN ^ N-dimethyl - ^ - pheny! cyclohexyl) methylamine.

A mixture of 13.8 g of trans-alpha-methyl - ^ - phenylcyclohexylmethylaminhydrochlorid, 3 ^ ₉ Ο5 99 g formic acid and 78 "5 ml of 39% ± ger formaldehyde solution was heated with stirring for 10 hours at 100 ⁰ C" After cooling, the mixture was diluted with water, made alkaline with concentrated NaOH and extracted with ethyl acetate. The residue obtained after evaporation of the solvent was dissolved in ethyl ether and converted into its hydrochloride, then recrystallized from acetone. Yield: 9,7 g (63 % of theory) mp ₀ 176-178 ⁰ C.

EXAMPLE 7

trans- alpha "alpha-dimethyl" (^ ° pheny! cyclohexyl) methylamine.

a) trans- (4-Pheny! cy clohexyl) -alpha »alpha-dimethy! methanol.

_{A solution of 82 tons of} 4 g of methyl iodide in 250 ml of ethyl ether was slowly added to a suspension of 8 g of lithium in 180 ml of anhydrous ethyl ether under a stream of nitrogen. After the mixture had been kept at room temperature for 30 minutes, 32 ₈ 6 g of trans - ^ - Phenylcyclohexanecarboxylic acid dissolved in 1.3 anhydrous ethyl ether _{8 was} added dropwise. The heating was continued with stirring nine hours ₉ while the mixture was kept under a nitrogen stream ₈ the mixture after cooling rapidly under a stream of nitrogen through glass wool "filtered to unreacted lithium to remove _s then slowly treated with 1.3 1 of water, and the organic phase

- η-

severed. After cooling and evaporation in vacuo, a solid was obtained consisting of 500 ml Petroleum ether could be brought to crystallization at -25 ° C. ·

Yield: 63 % of theory.
M.p. 68-69 ° C. Bp 151 ° C with a 1 mm Hg column.

b) trans-alpha, alpha-dimethyl - (^ - pheny! cyclohexyl) -methylamine.

A solution of 13.08 g of trans- ( k -phenylcyclohexyl) -alpha, alpha-dimethylmethanol in 18 ml of acetic acid was added to 4.77 g of potassium cyanide. A cold mixture of 15 ml of concentrated sulfuric acid and 11 ml of glacial acetic acid was then added dropwise without letting the temperature rise above 50 ° C. After stirring at 50 ° C. for six hours, the mixture was poured into water, and the solid formed in the process was filtered off, dried and washed with ether. The final cleaning was done by recrystallization from water and then washing with a mixture of methanol-ethyl ether.
Yield: 8.9 g (59 % of theory). Mp 306 -. 307 ⁰ C. -

EXAMPLE 8

trans-alpha-methyl- (N-prophyl-4-phenylcyclohexyl) -methylamine. a) trans-N-propylidene-alpha-methy1-4-phenyIcyclohexylmethylariin.

A solution of 7.2 g of trans-alpha-methyl- (4-phenylcyclohexyl) methylamine in 500 ml of anhydrous Bezonl was with a solution of 3.08 g of propionaldehyde in 10 ml of benzene are added, the mixture is refluxed for 20 hours and then evaporated. The residue

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was used directly for the subsequent reduction without further purification.

b) trans-alpha-methyl ° (N-propy1-4-phenylcyclohexyl) methylamine.

A solution of 9 _S 1 g of trans-alpha-methyl- (N-propylidene-4-phenylcyclohexyl) -methylamine in 100 ml of ethyl acetate, to which ₈ 8 g of PtO 2 had been added, was at room temperature under a pressure of 3 »5 atmospheres hydrogenated. After filtering off the catalyst

_{if β} the solution was evaporated in vacuo, then the residue was dissolved in ethyl ether, purified over activated charcoal and converted into its hydrochloride. This was collected on a filter and recrystallized from isopropanol. Yield: 2.8 g (27 % of theory) mp 215-217 ° C.

EXAMPLE 9

trans-alpha-butyl- (4-phenylcyclohexyl) methylamine.

a) trans-1- (4-phenylcyclohexyl) pentanone.

Under a nitrogen atmosphere, the weight was 21.92 g Butyl bromide dissolved in 160 ml of ethyl ether, in a mixture of 4.32 g of magnesium turnings and 160 ml Ethyl ether was added dropwise. After heating for 30 minutes, 16.32 g of trans-4-phenylcyclohexanecarboxylic acid were added in 200 ml of water

free benzene added. The temperature was brought to 60 ^° C. and the volatile fraction was distilled off. The mixture was then boiled for three hours. After cooling, 40 ml of glacial acetic acid and 20 ml of water were added, then the mixture was boiled for a further three hours. Then the mixture was poured into ice water and extracted with benzene. After the solution has dried

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viorden, it was evaporated under vacuum

and an oily product was isolated in the process, yield: 16 g (75 % of theory) kp 149 ° C. with a 0.3 mm Hg column. The 2,4-dinitrophenylhydrazone melts at 136-137 ° C

b) trans-1- (4-phenylcyclohexy1) pentanone oxide.

The procedure is similar to that already described in example 2, part a).

The product melts at 96 - 98 ⁰ C.

Yield: 6.25 g (75 % of theory).

c) trans-alpha-butyl - ^ - phenylcyclohexylmethylamine.

A mixture of 3.3 g lithium aluminum hydride and 150 ml of anhydrous ethyl ether was added dropwise to a solution of 5.7 g of trans-1 - (^ - phenylcyelohexyl) pentanone oxime added in 15O ml of tetrahydrofuran and 120 ml of ethyl ether. Subsequently was

the mixture was heated under reflux with stirring for 20 hours. After cooling, the excess hydride was decomposed by adding 5 ml of water, 5 ml of 5% NaOH and 15 ml of water. After dilution with ethyl acetate, the mixture was filtered, and the lithium hydroxide and aluminum hydroxide were washed out with further solvent. The combined organic phase was then dried with sodium sulfate and evaporated in vacuo. The residue was dissolved in ethyl ether, filtered through activated charcoal and converted into the corresponding hydrochloride. After cooling, the precipitate was collected on a filter, washed with ether, dried over phosphorus pentoxide and the acetone was recrystallized. Yield: 3.53 g (57 % of theory, melting point 187-189 ° G.

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EXAMPLE 10

trans-alpha-cyclopropyl-C4- pheny / cyclohexyl) methylamine,>

a) tj ^ atns ^ (4 = Phen y! cycl ohexyl) -cyclopropylketone

6 _S 48 Mg-turnings in 200 ml of ethyl ether was added under nitrogen atmosphere a solution of 57a36 g 4 = Phenylcyclohexylbromid in 250 ml of ethyl ether added "After two hours at reflux erwär ^m t was were added dropwise 8 _s 88 g Cyclopropylcyamidj dissolved in I50 ml of ethyl ether , added, then the solution was heated to boiling for eight hours. Then 50 ml of acetic acid, 20 ml of KOnz. HCl and 50 ml of water were added and the mixture was refluxed for a further three hours - still under a nitrogen atmosphere. After cooling, water and ice were added and extracted with ethyl acetate. The extracts were combined and evaporated. The remaining oil was distilled. It had a boiling point of 148-152 ⁰ C under 0.1 mm Hg. In the purification on a chromatography column filled with silica gel (eluent: ethyl acetate in a ratio of 9:11 and Hexau), a pure product having a melting point of 82 ⁰ C.. It has been assigned the trans structure.

b) trans - (^ - phenylcyclohexyD-cyclopropylketone oxime

The procedure is similar to that already described in Example 2, part a).

The product melts at I69 - 171 ⁰ C. Yield: 2.4 g (42% of theory).

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c) trans-alpha-cyclopropyl- (4-phenylcyclohexyl) -triethylamine.

A solution of 0.89 g of trans (4-phenylcyclohexyl) cyclopropyl ketone oxime in 25 ml of tetrahydrofuran and 25 ml of ether was added dropwise to a solution of 0.55 g of LiAlH ^ in 25 ml of anhydrous ethyl ether, and the resulting mixture was then added with stirring Heated to the boil for 20 hours. After cooling, 1 ml of water, 1 ml of 5% NaOH and 3 ml of water were added in the order given and the mixture was stirred for a short time. The hydroxides of Al and Li were filtered off and washed out with ether. The organic phase was evaporated, the oily residue converted into the hydrochloride and this was recrystallized from isopropanol. Yield: 0.34 g (38 % of theory). Mp. 265-267 ⁰ C ₀ "

EXAMPLE 11

1- (4-Cyclohexy! Phenyl) ° 2 ° Aminopropano a) 4-Cyclohexy! Benzaldehydes

A mixture of 350 ml of glacial acetic acid ^ 350 ml of water, 172 g 4-Cyclohexyl-alpha <= chlorotoluene and 231 g of hexamethylene tetramin was refluxed for 2 hours while stirring « After cooling, 280 ml of dilute HCl were added - = " added and the mixture boiled for a further 15 minutes »Then it was cooled« diluted with water and again = fetches extracted with ethyl ether «

The combined extracts were washed with water, 10 # strength sodium bicarbonate solution and then after once with water, dried and evaporated in vacuo. The oily residue was distilled, bp. 122 - 125 ⁰ C under 0.5 μ Hg column yield; 113 g (72 % of theory) o

b) 1- (4-Cyclohexylphenyl -) - 2-nitropropene.

A mixture of 50 g of 4-cyclohexylbenzaldehyde ₉ 24 g of freshly distilled nitroethane and 16 _{seconds of} 2 g of ammonium acetate in 200 ml of glacial acetic acid was heated to boiling for 5 hours while stirring. After cooling, the mixture was poured into cold water and cooled again. Then, the light aqueous phase was decanted extracted "the heavier oily phase with Ethylace'sat and the solution washed with water. After drying with sodium sulfate and after evaporation of the solvent, the oily residue was distilled. After a course that contained predominantly unreacted aldehyde, a fraction distilled over between 160 ° C. and 180 ° C. which was rich in the expected product. This was _s filtered through a column filled with Silicagal nylon column (2 meters long ₉ 5 cm diameter) while benzene was used as extractant. When the solution reached the end of the column _{i is} the yellow-colored parts were separated and extracted with acetone. 25 g of the product were obtained (39 % of theory),
kp. 161 - 168 ⁰ C below 0 _s 5 mm Hg column.

c) 1- (4-Cyclohexalphenyl) -2-aminopropane.

To a suspension of 9 _S 3 LiAIhU g in 500 ml ethyl ether was slowly viasserfreiern _s dropwise a solution of 10 g (l- (4 ~ cyclohexylphenyl) -1-nitropropene in 150 ml of anhydrous ethyl ether

and the mixture was refluxed for seven hours with stirring. After cooling were Slowly add 11 ml of water in the order given

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11 ml of 15% NaOH and finally 35 ml of water were added. After stirring at room temperature for 30 minutes, the precipitate formed was collected on a filter and washed with ethyl acetate. The combined filtrates were dried exclusively with sodium sulfate. Evaporation gave an oil. This distilled at 118 to 123 ⁰ C under a pressure of 0.6 mm Hg over. It was converted into its hydrochloride. This has a m.p. of 25 ^ ⁰ C.

EXAMPLE 12

trans -1- (4-pheny / cyclohexyl) -2-aminopropane.

a) trans-lC ^ -phenylcyclohexyl ^^ - nitropropene.

A mixture of 25 g of trans-if-phenylcylohexylaldehyde, 11 g of freshly distilled nitroethane and 8.3 g of ammonium acetate in 75 ml of glacial acetic acid was added under a nitrogen atmosphere at reflux for 2.5 hours heated. The mixture was then poured into water. The heavier, sunken oily layer was with Ether extracted, the ethereal solution washed first with soda solution, then with water. Afterward the solution was dried and evaporated. The oily residue was crystallized from isoprepanol.

Yield: 11.6 g (38 % of theory) of a product which is pure according to thin-layer chromatography. In the De-stillation (kp. 170 - 172 ⁰ C under 0.9 mm Hg) to obtain a product having a mp of 102 - having 1OiI ⁰ C..

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b) trans-1 "(^" phenylcyclohexyl) "2" aminoproparu

The procedure is similar to that already described in example H ₀ part c). The trans-1C ^ phenylclohexyl) -2 = aminopropane melts after recrystallization from isopropanol at 261-263 ⁰ C ₀ . .......

Claims (5)

Claims IJ Newly composed substances for use as ^ antidepressants and balancing agents for the central nervous system ₈ with the general formula wherein A and B different from each other and represent alternatively from phenyl and cyclohexyl group selected members, and the compounds in the ice = configuration or the trans-Konflguration _s occur when B is cyclohexyl; X represents a straight-chain or branched aliphatic group _A containing 1 to 5 carbon atoms, _s part of which may take the form of a cycloaliphatic ring; Y and Y 'can be identical or different and consist of hydrogen and straight-chain or branched alkyl groups with 1 to 5 carbon atoms and possibly a CN = group _s where Y and Y' can be replaced by a group _s bonded to the nitrogen atoms via a double bond is ₀ 2. trans-alpha-methyl - ^ - phenylcyclohexylmethylamine. 3. cis-alpha-methyl-it-phenylcyclohexylmethylamine. 4. trans-alpha, alpßa-dimethyl-4-phenylcyclohexylmethylamine. 5. trans-alpha-methyl-N- (2-cyanoethyl) -4-phenyl cyclohexylmethylamine. 030048/0677