DE2243803A1 - Phenyl and naphthyl cyclohexylamino butyrophenones - - useful as medicaments - Google Patents

Abstract

Titile cpds. of formula (I):- (where R = CH3S or are prepd. by condensn of the corresp. substd. cyclohexenylamine with the 2,2-dimethyl1-, 3-propanediol ketal of 4-chloro-4'-fluorobutylrophenone in the presence of KI and K2CO3, followed by hydrolysis with HCl to liberate the ketone.

Description

[(3-Cyclohexen-1-yl) -amino] -butyrophenones substituted in the 4-position by an aromatic radical, their acid addition salts and process for the preparation of these compounds Addition to P 21 42 480. 6 In patent application P 21 42 480. 6 are derivatives of 3-cyclohexenylamine with the general formula which are substituted in the 4-position by an aromatic radical described, in which R is a hydrogen, fluorine, (thlor or bromine atom, the methyl, ethyl or trifluoromethyl group or an alkoxy radical with 1 to 4 carbon atoms, A1 is hydrogen or an alkyl radical with 1 to 4 carbon atoms and n eie integer from 1 to 6 means.

These compounds and their acid addition salts have depressive effects Effect on the central nervous system. they seem sedative, muscle relaxing and antispasmodic and are therefore suitable for the treatment of indestructible states and schizophrenia.

Because of their calming effect, they can also be used to treat aggressive behavior. Their therapeutic properties were in the locomotion, chimney, bowl and codest test as well as the loss of the Rehabilitation reflexes demonstrated, see Boissiers et al., Medicina Experimentalie gl. 4, (1361), p. 145.

As they lower the levels of satecholamine in the heart and brain, they also cause a resulting lowering of the old pressure.

It has now been found that these effects also include compounds of the general formula and their acid addition salts, in which A denotes the p-methylthiophenyl, the p-fluoro-o-tolyl and the 1-naphthyl radical.

They are prepared according to the general process described in patent application P 21 42 480.6 by reacting a 3-cyclohexenylamine of the general formula which is substituted in the 2-position and is present in the form of the free base or an acid addition salt in which A has the meaning given above, with the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyprophenone of the formula and subsequent hydrolysis of the reaction product. Isolation from the reaction mixture is carried out in the customary manner, for example when using a water-miscible solvent by pouring it into water. The precipitated precipitate can be filtered off or extracted with a water-immiscible solvent. Further cleaning can also be carried out in the usual way, 2.-3.

by elution chromatography using an adsorption column and a suitable solvent such as acetone, ethyl acetate, ether, methylene chloride, Hexane hydrocarbons or mixtures of these solvents.

The compounds according to the invention and their acid addition salts can be administered orally and parenterally alone or in admixture with other active ingredients will. The doses used are from about 0.1 to about 100 mg / kg, depending on the Severity of the disease and the patient's response. The administration can take place in a liquid or solid carrier in which the active ingredients are dissolved, suspended or dispersed. Fixed formulations can do the Take the form of tablets, powders, capsules, or pills. To simplify administration these are preferably produced in unit doses. As liquid formulations are used for solutions, emulsions, suspensions, syrups or ttlixirs.

example 1 4'-fluoro-4 - {[4- (p-methylthiophenyl) -3-cyclo- hexen-1 -ylJ -amin3 -butyrophenone hydrochloride 2.7 n g of 4- (p-14ethylthiophenyl) -3-cyclohexen-1-ylamine hydrochloride in ether and 100 ml of sodium hydroxide solution are stirred until the solid has dissolved. The organic layer is washed with brine and evaporated to dryness. 1.64 g of potassium carbonate, 0.98 g of potassium iodide and 1.47 g of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone are added successively to a solution of the residue in 30 ml of dimethylformamide given. The mixture is stirred in an oil bath at about 900 ° C. for about 18 hours.

It is then allowed to cool and the solvent is removed in vacuo. The residue is dissolved in benzene and water and the organic layer becomes washed with water and brine and then evaporated to dryness.

The gummy residue obtained is dissolved in 30 ml of Ilethanol, then 15 ml of 2.5N hydrochloric acid solution are added. The mixture will be about Stirred for 1 hour and then concentrated in vacuo. The precipitated solid will collected on a filter and using saturated ammonium chloride Chromatographed methylene chloride as the eluting solvent over 200 ml of silica gel.

Fraction 13 is dissolved in ether, then a slight excess of a 4.8 N hydrogen chloride solution in ether is added. The mixture is evaporated to dryness, whereupon one 4'-fluoro-4 - {[4- (p-methylthiophenyl) -3-cyclohexen-1-yl] - ami-butyrophenone hydrochloride-from melting point 171 to 175 C.

Analysis: Calculated for C23H27ClFNOS C, 65.77; H 6.48; N 3.34 found: C 65.59; If 6.47; H 3.09 The corresponding 4- (p-ethylthiophenyl) -, 4- (p-Propylthiophenyl) - and 4- (p-Butylthiophenyl) derivatives.

The 4- (p-methylthiophenyl) -3-cyclohexen-1-ylamine hydrochloride used as the starting material in the above process is obtained in the following way: To an ice-cold solution of p-methylthiophenylmagnesium bromide, made from 53.5 g of 4-bromothioanisole and 6.34 g of magnesium in 400 ml of tetrahydrofuran 10 g of 4-hydroxy-cyclohexanone are added to 100 ml of tetrahydrofuran. To Place at room temperature for about 17 hours and add 100 ml of saturated aqueous Ammonium chloride added. The organic layer is made with water and saline washed and evaporated to dryness. The residue is poured into 200 ml of hexane hydrocarbons three times suspended, the supernatant liquid being decanted off each time. Of the The residue gives 11.13 g of cis- and trans-4- (p-thioanisyl) -1,4-cyclohexanediol, the can also be referred to as 4- (p-1fethylthiophenyl) -1, 4-cyclohexanediol.

11 g of cis- and trans-4- (p-thioanisyl) -1,4-cyclohexanediol are added to 50 ml of trifluoroacetic acid solved. After about 15 minutes the solution is dissolved in 500 ml of saturated aqueous sodium bicarbonate solution poured. The precipitate is dissolved in ether and washed with saturated aqueous sodium bicarbonate solution washed neutral. After washing with water and saline the solution becomes evaporated to dryness. The crude product is made over 1.2 l synthetic magnesium silicate chromatographed, eluting acetone in hexane hydrocarbons used. The more polar fractions are combined and recrystallized. You get 3.51 g of 4- (p-methylthiophenyl) -3-cyclohexen-1-ol with a melting point of 127 to 130.degree.

Analysis: Calculated for C13H16OS C 70.36; H 7.32 Found: G 70.48; H 7.41 To an ice-cold solution of 3.51 g of the 4- (p-methylthiophenyl) -3-cyclohexen-1-ol obtained 3.5 ml of fiethansulfonyl chloride are added dropwise to 40 ml of pyridine. To Standing in the cold for about six hours will make the mixture with water diluted. The precipitated residue is collected on a filter and dried and recrystallized from a mixture of methylene chloride and HexankohlenxfasserstoÎfen. 4- (p-Methylthiophenyl) -3-cyclohexen-1-ol methanesulfonate with a melting point is obtained 136 to 1380 C in 90% yield.

Analysis: Calculated for C13H18O3S2 C, 54.51; H 6.33; s 22.39; found: C 55.70; ii 6.18; S 21.70 To a solution of 5.23 g of 4- (p-methylthiophenyl) -3-cyclohexen-1-ol methanesulfonate 5 g of sodium acid are added to 50 ml of dimethylformamide. The suspension will be fine stirred and heated in an oil bath to about 85 to about 90 ° C for about 12 hours. That Solvent is removed under vacuum using a rotary evaporator and the residue dissolved in benzene and water. The organic layer is made with water and brine and evaporated to dryness. 4- (p-Methylthiophenyl) -3-cyclohexen-1-ylaaid is obtained from melting point 45 to 470 C.

A solution of the 4- (p-methylthiophenyl) -3-cyclohexen-1-ylaside so prepared in 70 ml of tetrahydrofuran is added dropwise to a well-stirred suspension of 0.7 g of lithium aluminum hydride was added to 10 ml of tetrahydrofuran. After about four hours Stirring at room temperature, the mixture is cooled in ice. Subsequently, one after the other 0.7 ml of water, 0.7 l of the above aqueous sodium hydroxide solution and 1.4 ml of water were added. The precipitated gel is collected on a filter and washed well with methylene chloride washed.

The organic filtrates are combined and evaporated to dryness. The residue is dissolved in ether and treated with a small excess of 4.8 N hydrogen chloride solution mixed in ether. The failed product is on a filter collected and recrystallized from ethanol. 4- (p-Nethylthiophenyl) is obtained -3-cyclohexen-1 -yl-amine hydrochloride with a melting point of about 3000 C.

Analysis: Calculated for C13H18ClNS C, 61.03; EI 7.09; N 5.48; Found: C, 61.01; H 7.08; N 5.45 Example 2 4'-fluoro-4 - {[4- (p-fluoro-o-tolyl) -3-cyclohexene- 1-yl] amino} butyrophenone hydrochloride 0.61 g of the above solution of sodium hydride in mineral oil are added to a suspension of 3.42 g of 4- (p-tluoro-o-tolyl) -3-cyclohexen-1-ylamine hydrochloride in 60 ml of dimethylformamide . After stirring for about one hour, 4 g of potassium carbonate, 2.4 g of potassium iodide and 3.6 g of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4-fluorobutyrophenone are added in succession. The mixture is stirred in an oil bath at about 900 ° C. for about 18 hours. It is then allowed to cool and the solvent is removed in vacuo. The residue is dissolved in benzene and water, the organic layer washed with water and brine and evaporated to dryness. The gummy residue obtained is dissolved in 40 ml of methanol, treated with 20 ml of 2.5N hydrochloric acid solution, the mixture is stirred for about 3 hours and then concentrated in vacuo. The precipitated solid is collected on a filter. Recrystallization from a mixture of methanol and 2,5-N hydrochloric acid solution gives 3.18 g of 4'-fluoro-4 - {[4- (p-fluoro-o-tolyl) -3-cyclo- hexen-1-yl] amino} butyrophenone from melting point 218 to 220 ° C.

Analysis: Calculated for C23H26ClF2 C, 68.05; H 6.46; N'3.45.

found: C, 67.96; 4 6.92; N 3.88 In the same way the corresponding 4- (p-fluoro-o-ethyl) -phenyl- and 4- (p-chloro-o-ethyl) = phenyl derivatives The 4- (p-fluoro-o-tolyl) -3-cyclohexen-1-ylamine hydrochloride used as the starting material in the above process is obtained in the following way: A solution of 18.9 g of 2-bromo-5-fluorotoluene and 2.4 :) g of magnesium in 150 mm tetrahydrofuran produced Grignard reagent is chilled in ice. This solution becomes a solution of the tetrahydropyranyloxyether added, obtained from 10 g of 4-hydroxycyclohexanone in 100 ml of tetrahydrofuran became. After standing at room temperature for about 17 hours, the mixture is placed in ice cooled and treated with 100 ml of saturated aqueous ammonium chloride solution. the organic layer is washed with water and brine and dried to dryness evaporated. A solution of the gummy residue obtained in 100 ml of methanol is stirred for about 1 hour with 10 ml of 2.5N hydrochloric acid. The main crowd the solvent is removed under vacuum and the organic layer becomes Evaporated dry. The residue is combined with the separated solid and suspended in 200 ml of acetone. This suspension. is cooled, stirred and between treated with 30 ml of Jones reagent for about 5 and 10 minutes. The solvent will removed in vacuo and the residue dissolved in water and saline and evaporated to dryness. The residue obtained in this way is treated with water and ether. The ether-insoluble solid is collected on a filter. The organic Layer is washed with water and brine and evaporated to dryness. The residue is treated with 20 ml of ether and the solid that remains is filtered off. The two solid fractions are combined and made from acetone-hexane hydrocarbons recrystallized. 4- (p-Fluoro-o-tolyl) -4-hydroxycyclohexanone is obtained from melting point 158 to 1600 C.

Analysis: Calculated for C13H15FO2 C 70.25; Ft 6.80; Found: C, 70.42; if 6.96 5 g of the above obtained are added to 25 ml of well-stirred trifluoroacetic acid 4- (p-Fluoro-o-tolyl) -4-hydroxycyclohexanone given. Do about 10 minutes that will Pour mixture into excess aqueous sodium bicarbonate solution. The unusual one Material is extracted with ether, the extract washed with water and brine and then evaporated to dryness. 4- (p-Fluoro-o-tolyl) -3-cyclohexen-1-one is obtained.

A solution of L g of the 4- (p-fluoro-o-tolyl) -3-cyclohexen-1-one obtained above and 2.5 g of sodium borohydride in 150 ml of ethanol is about 4 hours at room temperature touched.

Most of the solvent is removed using a rotary evaporator removed and the residue dissolved in ether and water. The organic layer will washed with water and brine and evaporated to dryness.

Jan 1 receives 4- (p-fluoro-o-tolyl) -3-cyclohexen-1-ol from the melting point 36 to 410 C in 97 41 yield.

To an ice-cooled solution of 4.73 g of 4- (p-fluoro-otolyl) -3-cyclohexeni-ol 5 ml of 1-ethanesulfonyl chloride are added dropwise to 45 ml of pyridine. To Standing in the cold for about 7 hours, the mixture is diluted with water.

The precipitated rubbery material is extracted with ether, and the extract is successively mixed with water, 2.5N hydrochloric acid, water and Washed saline.

Then the extract is evaporated to dryness, whereupon 4-tp-fluoro-o-tolyl) -3-cyclohexen-1-olethanesulfonate as Gummy I-1 material is obtained in 97% yield. NMR: complex aromatic range at 7.0 to 7.3 # (3H), broad singlet at 6.6 # (1H), signs at 3.05 # (3H), wide multiplet at 3.3 to 2.22 (10H).

To a solution of 0.65 g of 4- (p-fluoro-o-tolyl) -3-cyclohexen-1-ol methanesulfonate 6.65 g of sodium azide are added to 35 ml of dimethylformamide. This suspension will stirred well and heated to about 85 to about 900 C in an oil bath for about 12 hours. The solvent is removed in vacuo using a rotary evaporator, the residue was washed with water and brine and then evaporated to dryness. 4- (p-Fluoro-o-tolyl) -3-cyclohexen-1-ylazide is obtained as a mobile oil.

A solution of 4- (p-fluoro-o-tolyl) -3-cyclohexen-1-ylazide in 10 ml Tetrahydrofuran is added dropwise to a suspension of 0.95 g of lithium aluminum hydride given in 10 ml of tetrahydrofuran. After stirring for about 4.5 hours at room temperature the mixture is cooled in ice, then successively 1 ml of water, 1 ml of 15% aqueous sodium hydroxide solution and 3 ml of water were added. The precipitated gel will collected on a filter and washed well with methylene chloride. The organic Filtrates are combined and evaporated to dryness. The residue is in ether dissolved and with a small excess of a 3.9 N hydrogen chloride solution in ether mixed. The precipitated product is collected on a filter and from a Mixture, recrystallized from methanol and ethyl acetate. 4- (p-Fluoro-tolyl) -3-cyclohexen-1-ylamine hydrochloride is obtained from melting point 246 to 2500 C.

Analysis: Calculated for C13H17ClFN C, 64.59; fl 7.09; N 5.80; found: C 64.58; H 7.06 "; N 5.88.

Example 3 4'-fluoro-4 - {[4- (1-naphthyl) -3-cyclohexene-1- yl] amino} butyophenone hydrochloride 0.14 g of a 57.7 above sodium hydride solution in mineral oil are added to a suspension of 0.85 g of I + - (1-naphthyl) -3-cyclohexen-1-ylamine hydrochloride in 15 ml of dimethylformamide.

After stirring for about one hour, 0.93 g of potassium carbonate, 0.56 g of potassium iodide and 0.9 g of the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4'-fluorobutyrophenone are added one after the other. The mixture is stirred in an oil bath at about 900 ° C. for about 18 hours. It is then allowed to cool and the solvent is removed in vacuo. The residue is dissolved in benzene and water, the organic layer is washed with water and weekly salt solution and then evaporated to dryness. The gummy material that remains is dissolved in 20 ml of methanol, then 10 ml of 2.5N chlorohydroic acid solution are added. The mixture is stirred for about 1.5 hours, then concentrated in vacuo and the precipitated solid collected on a filter. Recrystallization from a mixture of methanol and 2.5N chlorine hydrofluoric acid solution gives 0.7 g ethyl) -3-cyclohexen-1-ylj-amino} -hutyrophenone hydrochloride from melting point 196 to 199u C.

Analysis: Calculated for C28H27FNO # 1 / 2H2O C, 73.59; H 6.18; N 3.07; found: C 73.63; H 6.47; N 3.23 The 4- (1-naphthyl) -2-cyclohexen-1-ylamine hydrochloride used as starting material in the above process is made in the following way: To an ice-cold solution of 1-naphthylmagnesium bromide, that of 40 g of α-bromonaphthalene and 4.65 g of magnesium in 300 ml of tetrahydrofuran was prepared, 10 g of 4-hydroxycyclohexanone are added to 100 ml of tetrahydrofuran. After about 17 hours of standing at room temperature are 100 ml added saturated aqueous ammonium chloride solution. The organic layer will washed with water and brine and then evaporated to dryness. The residue is dissolved in 200 ml of acetone and cooled in an ice bath. During about 5 to about About 30 ml of Jones reagent is added for 10 minutes. The solvent will then removed in vacuo; and the residue dissolved in water and ether. The organic Layer is washed with water and brine and then evaporated to dryness. The residue is chromatographed over 1 liter of synthetic magnesium silicate and first with 2 l of a mixture of 5 i; j acetone in iexane hydrocarbons and then eluted with 4 liters of a mixture of 20 'acetone in hexane hydrocarbons. The solids recovered from fractions 9, 10, 11 and 12 are combined and recrystallized twice from acetone-hexane hydrocarbons. Ran receives 4- (1-naphthyl) -4-hydroxycyclo hexanone from melting point 170 to 1740 C.

Analysis: Calculated for C16H16O2 C 79.97; H 6.71; found: C, 80.06; H 7.04 To 7 ml of well-stirred trifluoroacetic acid, 1.42 g of the above obtained 4- (1-Naphthyl) -4-hydroxycyclohexanone given. After about 10 minutes the mixture becomes poured into an excess of aqueous sodium bicarbonate solution. The failing solid Material is extracted with ether, the extract washed with water and brine and evaporated to dryness. 4- (1-Naphthyl) -3-cyclohexen-1-one with a melting point is obtained 117 to 1200 C.

A solution of the resulting crystalline 4- (1-naphthyl) -3-cyclohexen-1-one and of .10 g of sodium borohydride in 40 ml of ethanol is about 40 minutes at room temperature touched.

Most of the solvent is on a rotary evaporator removed and the tickstand diluted with water.

The precipitated solids are extracted with ethanol, the extract is washed with water and brine and then evaporated to dryness. The solid residue obtained is recrystallized from hexane hydrocarbons.

an receives 4- (1-naphthyl) -3-cyclohexen-1-ol with a melting point of 84 bis 870 C in 91% yield.

Analysis: Calculated for C16H16O C 85.76; H 7.19; Found: C, 85.39; H 7.78 To a solution, cooled with to, of 1.21 g of 4- (1-naphthyl) 3-cyclohexen-1-ol 1.2 ml of methanesulfonyl chloride are added to 6 ml of pyridine. After about 17 hours When standing in the cold, the mixture is diluted with water. The precipitated solid is collected on a filter and dried.

4- (1-Naphthyl) -3-cyclohexen-1-ol methanesulfonate with a melting point is obtained 114 to 1180 C in 96% yield.

To a solution of 1.56 g of 4- (1-naphthyl) -1-ol-methanesulfonate in 15 1.6 g of sodium azide are added to ml of dimethylformamide.

The suspension is stirred well and placed in an oil bath for about 12 hours heated to about 85 to about 900 C. The solvent is made using a Rotary evaporator removed in vacuo. The residue obtained is dissolved in benzene and water dissolved, the organic layer washed with water and brine and evaporated to dryness. 4- (1-Napthyl) -3-cyclohexene-1-ylazide is obtained as moving 01.

A solution of the 4- (1-naphthyl) -3-cyclohexen-1 ylazids obtained in 20 ml of tetrahydrofuran is added dropwise to a well-stirred suspension of 0.7 g lithium aluminum hydride given in 5 ml of tetrahydrofuran. To Stirring for about 5 hours at room temperature, the mixture is cooled in z.i s, then are successively 0.3 ml of water, 0.3 ml of aqueous sodium hydroxide solution and 0.9 ml of water was added. The precipitated gel is collected on a filter and well washed with methylene chloride. The organic filtrates are combined and used Evaporated dry. The residue obtained is dissolved in ether and treated with a small excess of 4.9 N hydrogen chloride solution mixed in ether. The precipitated one Product is collected on a filter and made from a mixture of methanol and Recrystallized ethyl acetate.

4- (1-Naphthyl) -3-cyclohexen-1-ylamine hydrochloride with a melting point is obtained 304 to .3060 c.

Analysis: Calculated for C16H18ClN c 73.97; H 6.95; N 5.39 found: C 73.72; H 7-15; N 5.67

Claims (1)

Claims 1. Compounds of the general formula in which A denotes the p-methylthiophenyl, p-fluoro-o-tolyl or the 1-naphthyl radical, and their acid addition salts. 2. 4'-Fluoro-4 - {[4- (p-methylthiophenyl) -3-cyclohexen-1-yl] - amine} butyrophenone hydrochloride. 3. 4'-Fluoro-4 - {[4- (p-fluoro-o-tolyl) -3-cyclohexen-1-yl] -amine} - butyrophenone hydrochloride. 4. 4'-Fluoro-4 - {[4- (1-naphthyl) -3-cyclohexen-1-yl] amine} - butyrophenone hydrochloride. Process for the preparation of the compounds according to Claims 1 to 4, characterized in that a 3-cyclohexenylamine of the general formula in which A has the meaning given, or its acid addition salt with the 2,2-dimethyl-1,3-propanediol ketal of 4-chloro-4-fluorobutyrophenone of the formula and the reaction product obtained is hydrolyzed. 6. 4- (p-ethylthiophenyl) -3-cyclohexen-1-ylamine hydrochloride. 7. 4- (p-fluoro-o-tolyl) -3-cyclohexen-1-ylamine hydrochloride. 8. 4- (1-Naphthyl) -3-cyclohexen-1-ylamine hydrochloride. 9. Therapeutic preparation containing one or more compounds according to claim 1 to 4 as an active ingredient and customary carrier and auxiliary materials.