US3732229A - 3-cyclohexyl phenyl-2-hydroxypropyl-4-phenyl piperazines - Google Patents

Abstract

WHEREIN R IS HYDROGEN OR ALKOXY HAVING FROM 1 TO 8 CARBON ATOMS, R1 IS ALKYL HAVING UP TO 10 CARBON ATOMS, ALKOXY HAVING UP TO 10 CARBON ATOMS, CYCLOALKYL HAVING FROM 5 TO 7 CARBON ATOMS, CYCLOALKYLOXY HAVING FROM 5 TO 7 CARBON ATOMS, CYCLOALK-1-ENYL HAVING FROM 5 TO 7 CARBON ATOMS, PHENYL, PHENOXY OR HALOGEN, R2 IS HYDROGEN OR METHYL, R3 IS 2-HYDROXYCYCLOHEXYL, 2-PYRIDYL, PHENYL, DIMETHOXYPHENYL, CHLORONITROPHENYL, CHLOROMETHOXYPHENYL, AND METHYLDISULPHAMOLYPHENYL, PHENYL SUBSTITUTED WITH A GROUP SELECTED FROM THOSE CONSISTING OF ALKYL HAVING UP TO 4 CARBON ATOMS, ALKOXY HAVING FROM 1 TO 4 CARBON ATOMS, FLUORINE, CHLORINE, BROMINE, NITRO, AMINO, SULPHAMOYL, HYDROXY, TRIFLUOROMETHYL AND ACETAMIDO, AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS.

1-((R,R1-PHENYL)-CH2-C(-R2)(-OH)-CH2-),4-R3-PIPERAZINE

NOVEL SUBSTITUTED PIPERAZINE COMPOUNDS OF THE FORMULAE

Description

United States Patent US. Cl. 260-268 PH 13 Claims ABSTRACT OF THE DISCLOSURE Novel substituted piperazine compounds of the formulae -omo on 011216 N-R R1 wherein R is hydrogen or alkoxy having from 1 to 8 carbon atoms;

R is alkyl having up to 10 carbon atoms, alkoxy having up to 10 carbon atoms, cycloalkyl having from 5 to 7 carbon atoms, cycloalkyloxy having from 5 to 7 carbon atoms, cycloalk-l-enyl having from 5 to 7 carbon atoms, phenyl, phenoxy or halogen;

R is hydrogen or methyl;

R is Z-hydroxycyclohexyl, 2-pyridyl, phenyl, dimethoxyphenyl, chloronitrophenyl, chloromethoxyphenyl, and methyldisulphamoylphenyl, phenyl substituted with a group selected from those consisting of alkyl having up to 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms, fluorine, chlorine, bromine, nitro, amino, sulphamoyl, hydroxy, trifluoromethyl and acetamido; and

Their pharmaceutically acceptable acid addition salts.

The compounds of the present invention are effective as central nervous system depressants.

This is a continuation of application Ser. No. 740,881, filed June 28, 1968, now abandoned. This invention relates to organic compounds and has particular reference to substituted piperazines.

It is an object of the invention to provide new piperazine derivatives having the general Formula I below, which are of particular value as drugs acting on the central nervous system.

The compound 1-[3-(p-cyclohexylphenyl)-2-hydroxypropyl] 4 o-methoxyphenylpiperazine dihydrochloride, the product of Example 8, is a central nervous system depressant. Thus it was twice as active as morphine in the mouse tail-pinch test, three times as active as chlorpromazine in the mouse rage test and twice as active as chlorpromazine in the anti-amphetamine test.

Furthermore the products of the examples listed below have shown similar central nervous system activity:

EXAMPLE 1 A X CPZ in mouse rage test. /2 CPZ in antiamphetamine test.

EXAMPLE 2 1.7 X CPZ in reducing spontaneous motor activity.

EXAMPLE 3 2X CPZ in mouse rage test. 4 CPZ in reducing spontaneous motor activity.

3,732,229 Patented May 8, 1973 EXAMPLE 4 1.5 X morphine in tailpinch test. AXCPZ in mouse rage test.

EXAMPLE ll /3 X CPZ in reducing spontaneous motor activity.

EXAMPLE 14 1.8 X CPZ in mouse rage test.

EXAMPLE 16 2.5 x CPZ in mouse rage test.

EXAMPLE 22 Equals CPZ in mouse rage test. /2 x CPZ in reduction of spontaneous motor activity.

EXAMPLE 24 73 CPZ in mouse rage test. 1A CPZ in reduction of spontaneous motor activity.

EXAMPLE 25 2x CPZ in mouse rage test.

EXAMPLE 26 6 X CPZ in mouse rage test. Active in antiamphetamine test.

EXAMPLE 30 Equals CPZ in mouse rage test.

EXAMPLE 31 Equals CPZ in mouse rage test.

CPZ above denotes chlorpromazine.

According to the present invention there are provided novel piperazine derivatives having the general formula where R=hydrogen or alkoxy (containing from 1-8 carbon atoms in a straight or branched chain) R =alkyl, either straight or branched chain containing up to 10 carbon atoms; alkoxy, either straight or branched chain up to 10 carbon atoms; cycloalkyl containing from 5-7 carbon atoms; cycloalkyloxy containing from 5-7 carbon atoms; cycloalk-l-enyl (e.g. cyclohex-lenyl), containing from 5-7 carbon atoms; phenyl, phenoxy or halogen R =hydrogen or methyl R =2-hydroxycyclohexyl; phenyl or mono-, dior trisubstituted phenyl (such substituents include alkyl, containing up to 4 carbon atoms; alkoxy, containing from 1-4 carbon atoms; fluorine; chlorine; bromine; nitro; amino; acylamino; tn'fiuoromethyl; sulphamoyl and hydroxy).

In addition the group R may represent a 2-pyridy1 nucleus.

The compounds of the present invention may be used as the free bases or in the form of their salts with inorganic or organic acids, which in general will be pharmaceutically acceptable in their own right, such for example as hydrochloric, sulphuric, phosphoric, benzoic, citric, maleic, tartaric or salicylic acids.

According to the present invention there is provided a process for the preparation of piperazine derivatives having the general Formula I above which process comprises reacting a chlorohydrin having the formula @wmbwmomcr B1 (where R, and R and R have the same meaning as above) and a base and a substituted piperazine having the formula HN N-R (III) (where R has the same meaning as above) The base is an inorganic base such as potassium hydroxide or sodium carbonate or an organic base in the form of an excess of the substituted piperazine. In the latter case the reaction .may be carried out employing 2 mole equivalents of the substituted piperazine. When potassium hydroxide is employed as the inorganic base the reaction proceeds as shown below:

where R, R, R and R have the same significance as in Formula I.

In some instances it may be convenient to react the chlorohydrin (II) initially with the inorganic base thereby forming the corresponding epoxide (IV) which is subsequently reacted with the substituted piperazine. Thus for example the chlorohydrin (II) may be treated with cold methanolic potassium hydroxide or heated with aqueous The process may be carried out in a variety of solvents such as, for example, alcohols, hydrocarbons, ethers or aqueous alcohols. Reaction temperatures are not critical, but in most cases it was found satisfactory to heat the reactants in ethanol or .methanol at reflux temperature for several hours. The products may be purified by distillation at reduced pressure or by crystallisation from an appropriate solvent. In some cases it was found most convenient to convert the basic product into a suitable salt which could then be purified by crystallisation.

Chlorohydrins of Formula II employed as starting materials in the present invention are described in our British specification No. 1,040,735 together with their preparation.

Following is a description by way of example of methods of carrying the invention into effect.

EXAMPLE 1 1-[3-(p-cyclohexylphenyl)-2-hydroxypropyl]-4-o-tolylpiperazine hydrochloride A solution of 1-chloro-3-(p-cyclohexylphenyl)propan 2-01 (10.1 g.) in methanol (50 ml.) was treated with a solution of potassium hydroxide (11.2 g.) in methanol ml.) followed by l-o-tolylpiperazine dihydrochloride (10 g.). The mixture was heated under reflux for 2 hours and excess of methanol was boiled off and the residue diluted with water. The resultant oil was isolated with chloroform, the chloroform extracts were washed with water and the solvent distilled off, last traces being removed at reduced pressure (25 mm.). The residual oil was dissolved in isopropanol (80 ml.) and treated with a slight excess of hydrogen chloride. The solution was diluted with ether and cooled to 5 C. overnight. The product (9.8 g.) was collected and crystallised from water containing a small amount of ethanol. It had M.P. 23 3235 C.

EXAMPLE 2 1- [3 (p-eyclohexylphenyl -2-hydroxypropyl] -4-m-tolylpiperazine hydrochloride A solution of l-chloro-3-(p-cyclohexylphenyl)propan- 2-01 (10.1 g.) in ethanol (50 ml.) was treated with a solution of 85% potassium hydroxide (10.5 g.) in methanol (60 ml.) followed by a solution of l-(m-tolyl) piperazine dihydrochloride hydrate (10.7 g.) in ethanol (50 ml.) and the mixture was heated under reflux for 10 hours. The excess of alcohol was boiled off, the residue diluted with water and the oil extracted with chloroform. The chloroform extract was washed with water, concentrated, and the last traces of solvent distilled off at reduced pressure (20-25 mm.). The resultant residue was dissolved in 2 volumes of warm ethanol, treated with a slight excess of hydrogen chloride and the solution diluted with ether. The resultant crystalline solid was collected (13 g.) and purified by recrystallisation from a mixture of methanol and ether. It had M.P. 203-205 C.

EXAMPLE 3 l-(p-chlorophenyl) -4-[3-(p-cyclohexylphenyl)-2- hydroxypropyl]piperazine hydrochloride A solution of 1-chloro-3 (p-cyclohexylphenyl)-propan- 2-ol (10.1 g.) in ethanol (50 ml.) was treated with a solution of 85% potassium hydroxide (10.5 g.) in methanol (50 ml.) followed by a solution of l-(p-chlorophenyl) piperazine dihydrochloride (10.8 g.) in ethanol (50 ml.) and the mixture was heated under reflux for 20 hours. The mixture was concentrated to remove most of the alcohol and was then diluted with water. The resultant oily material was extracted with chloroform, the chloroform extract was washed with water and the solvent was distilled off, first at atmospheric pressure and then at reduced pressure. The residual gum Was dissolved in isopropanol treated with a slight excess of hydrogen chloride and the solution diluted with ether. Crystalline material was collected (12 g.) and recrystallised from a mixture of ethanol and ether. It had M.P. 193-195 C.

EXAMPLE 4 1-o-chlorophenyl-4- 3- (p-cyclohexylphenyl) -2-hydroxypropyl] -piperazine dihydrochloride Reaction of 1-chloro-3-p-cyclohexylphenylpropan-Z-ol (6.3 g.) with l-(o-chlorophenyl)piperazine hydrochloride hydrate (6.3 g.) in ethanol ml.), containing 85% potassium hydroxide (3.6 g.), at reflux temperature for 5 hours, followed by isolation of the crude base and treatment of this with hydrogen chloride as described in Example 1, yielded the dihydrochloride (4.7 g.) which had M.P. 177-179 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 5 1- [3- (p-biphenylyl -2-hydroxypropy1] -4-o-chlorophenylpiperazine hydrochloride A solution of 1-p-biphenylyl-3-chloropropan-2-ol (6.2 g.) in ethanol (120 ml.) was treated with a solution of 85 potassium hydroxide (3.6 g.) in methanol (40 ml.) followed by 1-(o-chlorophenyl)-piperazine hydrochloride hydrate (6.3 g.) and the mixture was heated at reflux temperature for 5 hours. The basic product was isolated with chloroform and converted into its hydrochloride salt as described in Example 1. This product (7.3 g.) had M.P. 190-191 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 6 1phenyl-4- 3 2-n-butoxy-5 -phenyl) phenyl-2- hydroxypropyl] piperazine A solution of 1-chloro-3--(2'-n-butoxy-5'-phenyl)-phen ylpropan-2-ol (9.5 g.) in ethanol (100 ml.) was treated With 1- phenyl-piperazine (4.9 g.) followed by a solution of 85% potassium hydroxide (2.1 g.) in methanol (25 ml.) and the mixture was boiled under reflux for 5 hours. It was filtered hot to remove potassium chloride and the base crystallised from the filtrate on cooling. The crystalline material was collected and washed with water to remove admixed potassium chloride. It was then crystallised from ethanol to yield the product (11.8 g.), M.P. 111-113 C.

EXAMPLE 7 1-o-chlorophenyl-4- 3- (p-cyclohexl-enylphenyl) -2- hydroxypropyl]-piperazine hydrochloride A solution of 1-chloro-3-(p-cyclohex-l-enylphenyl)propan-Z-ol (6.25 g.) in ethanol (120 ml.) was treated with a solution of 85% potassium hydroxide (3.6 g.) in methanol (40 ml.) followed at once by l-(o-chlorophenyl) piperazine hydrochloride hydrate and the mixture was heated under reflux for 5 hours. The base was then isolated with chloroform as in previous examples, dissolved in ethanol (75 ml.) and treated with a slight excess of hydrogen chloride. The hydrochloride salt separated on cooling. It (5.8 g.) had M.P. 194.5l96.5 C. after crystallisation from a mixture of isopropanol and ether.

EXAMPLE 8 1- 3- (p-cyclohexylphenyl -2-hydroxypropyl] -4-omethoxyphenylpiperazine dihydrochloride A solution of 1-chloro-3-(p-cyclohexylphenyl)propan- 2-01 (8.8 g.) in ethanol (100 ml.), was treated with a solution of 85% potassium hydroxide (7.25 g.) in methanol (70 ml.) followed by l-(o-methoxyphenyl)-piperazine dihydrochloride (9.3 g.) and the mixture was heated under reflux for 5 hours. The precipitated potassium chloride was filtered off and the ethanol was distilled off, last traces being removed at reduced pressure. The residual base, isolated with chloroform as described'in Example 1, was dissolved in ethanol and treated with a slight excess of hydrogen chloride. The dihydrochloride salt separated from the solution on cooling. It 8.5 g.) had M.P. 181-183 C. after crystallisation from anhydrous ethanol.

EXAMPLE 9 1- [3-(o-biphe11ylyl) -2-hydroxypropyl] -4-o-chlorophenylpiperazine A solution of 1-(o-biphenyly1) 3 chloropropan-2-ol (7.4 g.) in ethanol (140 ml.) was treated with a solution of 85% potassium hydroxide (4.1 g.) in methanol (40 ml.) followed by l-(o-chlorophenyl)-piperazine hydrochloride hydrate (7.5 g.) and the mixture was heated under reflux for 5 hours. The base was isolated with chloroform as described in Example 1. It was purified by crystallisation from ethanol and had M.P. 106l08 C. (yield-78 g.).

EXAMPLE 10 1- 3- (p-biphenylyl -2-hydroxypropyl] -4-o-chlorophenylpiperazine hydrochloride a) 3-(p-biphenylyl) 1,2 epoxypropane.A suspension of l-(p-biphenylyl)-3-chloropropan-2-ol (49.3 g.) in water (1 litre) and ethanol (250 ml.) containing sodium carbonate (42.4 g.) was heated with efficient stirring for 4 hours with free evaporation of the ethanol. The resultant oil was isolated with chloroform to yield the epoxide (37.2 g.) B.P. 130132 C. at 0.35 mm., M.P. 51 C. (from methanol).

(b) A solution of 3-(p-biphenylyl)-1,2-epoxypropane (2.10 g.) in benzene (20 ml.) was treated with a solution of 1-(o-chlorophenyl)piperazine (1.97 g.) in benzene (20 ml.) and the solution Was heated at reflux temperature for 3 hours. The solution was cooled and treated with a slight excess of hydrogen chloride gas. The hydrochloride salt which separated was collected (3.0 g.) and purified by crystallisation from a mixture of ethanol and ether. It had M.P. 190191 C. and was identical with the material described in Example 5.

EXAMPLE 11 l- (o-methoxyphenyl -4- 3- (p-phenoxyphenyl -2- hydroxypropyl] piperazine dihydrochloride A solution of 1-chloro-3-(p-phenoxyphenyl)-propan-2- 01 (8.15 g.) in methanol (20 ml.) was treated with a solution of 85 potassium hydroxide (3.82 g.) in methanol (30 ml.) followed by l-(o-methoxyphenyl) piperazine dihydrochloride (8.51 g.) and the mixture was heated at reflux temperature for 20 hours. The excess of methanol was boiled off, the residual oil extracted with ether and the extract Washed With Water and dried with anhydrous sodium sulphate. The ether was distilled off, the residual oil was dissolved in a small volume of ethanol and treated with a slight excess of hydrogen chloride gas. Dilution with ether furnished the dihydrochloride salt (7.6 g.). The product had M.P. 188-l91 C. after crystallisation from ethanol.

EXAMPLE 12 1-(2-hydroxycyclohexyl)-4-[3 (p-cyclohexylphenyl)-2- hydroxypropyl] piperazine dihydrochloride A solution of 1-chloro-3-(p-cyclohexylphenyl)propan- 2-ol (10.1 g.) in ethanol ml.) was treated with a. solution of potassium hydroxide (2.8 g.) in methanol (20 ml.) followed by l-(o-hydroxycyclohexyl) piperazine (7.36 g.) and the mixture heated under reflux for 12 hours. It was then concentrated to remove most of the alcohol, water was added and the basic product isolated with ether and converted into the dihydrochloride salt as described in Example 11. The product (7.8 g.) had M.P. 256260 C. after crystallisation from methanol.

EXAMPLE 13 l-(p-chlorophenyl) -4-[3-(p-cyclohex-1-enylphenyl)-2- hydroxypropyl] -piperazine dihydrochloride A solution of 1-chloro-3-(p-cyclohex-l-enylphenyl)- propan-Z-ol (7.5 g.) in ethanol ml.) was treated with a solution of 85 potassium hydroxide (6.6 g.) in methanol (40 ml.) followed by l-(p-chlorophenyl) piperazine dihydrochloride (8.1 g.) and the mixture heated under reflux for 12 hours. The basic product was isolated with chloroform as described in earlier examples and converted into the dihydrochloride in ethanolic solution. The product (3.8 g.) had M.P. 209-211 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 14 1- [3 (p-cyclohexylphenyl -2-hydroxypropyl] -4- (m-methoxyphenyl)piperazine dihydrochloride A solution of 1-chloro-3-(p-cyclohexylphenyl) propan- 2-01 (10.1 g.) in ethanol (150 ml.) was treated with 1- 7 (m-methoxyphenyl)piperazine dihydrochloride (10.6 g.) followed by a solution of 85 potassium hydroxide (8.6 g.) in methanol (50 ml.) and the mixture refluxed for 12 hours. The base was isolated with chloroform and converted into the dihydrochloride as described in earlier examples. The product (9.85 g.) had M.P. 216217 C. after crystallisation from ethanol.

EXAMPLE 15 1- [3- (p-cyclohexylphenyl) -2-hydroxypropyl -4- (p-methoxyphenyl) -piperazine dihydrochloride This compound was prepared in the same way as the m-methoxyphenyl analogue described in Example 14 except that l-(p-methoxyphenyl)-piperazine dihydrochloride was used in place of 1-(m-methoxyphenyl)-piperazine dihydrochloride. The dihydrochloride g.) had M.P. 195- 197 C. after crystallisation from the mixture of ethanol and ether.

EXAMPLE 16 1- [3- (p-cyclohexylphenyl) -2-hydroxypropyl]-4- phenylpiperazine dihydrochloride A solution of 1-chloro-3-(p-cyclohexyl)phenylpropan- 2-01 (10.1 g.) in ethanol (150 ml.) was treated with 1- phenylpiperazine (6.5 g.) followed by a solution of 85% potassium hydroxide (2.8 g.) in methanol (25 ml.) and the mixture was refluxed for 12 hours. The base was isolated with chloroform and converted into a dihydrochloride as described in earlier examples. The product (5 g.) had M.P. 103105 C. after crystallisation from methanol.

EXAMPLE 17 1-(o-chlorophenyl)-4-[3- (p-chlorophenyl)-2- hydroxypropyl] piperazine hydrochloride A solution of l-(o-chlorophenyl) piperazine hydrochloride hydrate (6.3 g.) in ethanol (60 ml.) was treated with a solution of 1-chloro-3-(p-chlorophenyl)-propan- 2-01 (5.1 g.), in ethanol (40 m1.) followed by a solution of 85% potassium hydroxide (3.6 g.) in methanol (40 ml.) and the mixture was heated under reflux for 5 hours. The precipitated potassium chloride was filtered off, the filtrate concentrated to remove ethanol, and the basic residue partitioned between chloroform and water. The chloroform extract was concentrated, the residual oil was dissolved in an equal volume of ethanol and treated with a slight excess of hydrogen chloride. Dilution with ether yielded the hydrochloride (8.4 g.) which had M.P. 181- 183 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 18 1- 3-p-hexylphenyl -2-hydroxypropyl] -4- (o-methoxyphenyl)piperazine hydrochloride (a) l-(p-bromophenyl)hexane.-Bromine (74.2 g.) was added dropwise with stirring to l-phenylhexane (71.6 g.) in the presence of iron powder (2.5 g.) as catalyst. After the addition was complete the mixture was allowed to stand overnight when chloroform (100 ml.) was added and the liquid washed with water, sodium hydroxide solution, sodium sulphite solution and twice more with water. The liquid was then dried with anhydrous sodium sulphate and the solvent distilled off at reduced pressure. The residual liquid was fractionally distilled at reduced pressure to give the product in 57% yield, B.P. 87-89" C. at 0.65 mm.

(b) 1-chloro-3-(p-hexylphenyl)propan-2-ol.A solution of 1-(p-bromophenyl)hexane (90.4 g.) in ether (325) ml.) plus tetrahydrofuran (75 ml.) and ethyl bromide (20.5 g.) was added dropwise to activated magnesium (13.5 g.). When the reaction was complete the mixture was stirred for 2 hours and treated with epichlorohydrin (117 g.) added dropwise during 1 hour, then the mixture was stirred for 2 hours further. It was then cooled in icewater and decomposed by the dropwise addition of 5 N 8 hydrochloric acid (300 ml.). The organic layer was separated, washed twice with water and dried over anhydrous sodium sulphate. It was then concentrated and the residual oil distilled at reduced pressure to give the chlorohydrin, B.-P. 132-134 C. at 0.08 mm. in 69.2% yield.

(c) The foregoing chlorohydrin (11.2 g.) was added to a solution of 1-(o-methoxyphenyl)piperazine (11.3 g.) and potassium hydroxide (8 g.) in ethanol ml.) and the mixture was heated under reflux for 12 hours. The ethanol was boiled off and the residue partitioned between chloroform and water. The chloroform layer was washed with water, dried over anhydrous sodium sulphate and the chloroform distilled off. The residual oil was treated with a slight excess of ethanolic hydrogen chloride and the solution diluted with ether when the hydrochloride crystallised. It (8.6 g.) had M.P. 133 to 135 C., after crystallisation from isobutyl methyl ketone.

EXAMPLE l9 1-[ 3-p-cyclohexylphenyl) -2-hydroxypropyl] -4- (ptolyl)piperazine hydrochloride Reaction of 1-chloro-3-p-cyclohexylphenylpropan-Z-ol (12.6 g.) with l-p-tolylpiperazine hydrochloride (10.6 g.) in ethanol (100 ml.) containing 85 potassium hydroxide (7.5 g.) at reflux temperature for 10 hours, followed by isolation of the crude base and treatment of this with ethanolic hydrogen chloride as described in Example 1, yielded the hydrochloride (4.5 g.) which had M.P. 204206 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 20 1(m-bromophenyl)-4-[3-(p-cyclohexy1phenyl) -2- hydroxypropyl]piperazine hydrochloride (a) 1-(m-bromophenyl)piperazine hydrochloride.A mixture of rn-bromoaniline (68.8 g.) and bis-(2-chloroethyl) amine hydrochloride (71.4 g.) in ethanol (250 ml.) was heated at reflux temperature for 10 hours when anhydrous sodium carbonate (21.2 g.) was added to the mixture and heating was continued for a further 10 hours. The mixture was filtered hot, concentrated to half-bulk and cooled when the product separated. It (22.7 g.) had M.P. 2172l9 C. after crystallisation from ethanol.

(b) The title compound was obtained in 43% yield by reaction of 1-chloro-3-p-cyclohexyl phenylpropan-Z- 01 with m-bromophenylpiperazine hydrochloride in ethanolic potassium hydroxide solution followed by conversion of the base obtained into the hydrochloride and had M.P. 192-194 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 21 1- [3 (p-cyclohexylphenyl -2-hydroxypropyl -4- (onitrophenyl) piperazine hydrochloride This compound (12.8 g.) was obtained by reaction of 1-chloro-3-p-cyclohexylphenylpropan-Z-ol (10.1 g.) with l-o-nitrophenylpiperazine (8.3 g.) in ethanol (70 ml.) containing potassium hydroxide at reflux temperature for 8 hours. The crude base was isolated and converted into the hydrochloride which had M.P. 180182 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 22 1- [3- (p-cyclohexylphenyl) -2-hydroxypropyl]-4- (2- pyridyl) piperazine hydrochloride This compound was prepared in 66% yield by reaction of 1-chloro-3-pcyclohexylphenylpropan-Z-ol with 1-(2'- pyridyl) piperazine in ethanol in the presence of potassium hydroxide followed by conversion of the base into the hydrochloride as described in earlier Examples. The hydrochloride had M.P. 223224 C. after crystallisation from isopropanol.

EXAMPLE 23 1-[3-p-(cyclohexylphenyl)-2-hydroxy-2-methylpropy1]- 4-o-methoxy-phenylpiperazine hydrochloride (a) 1-chloro-3-(p-cyclohexylphenyl) 2 methylpropan-2-ol.--To a Grignard solution prepared from magnesium (4.8 g.) and p-bromophenylcyclohexane (48 g.) in ether (250 ml.), fl-methylepichlorohydrin (44.4 g.) was added dropwise with stirring during 1 hour and stirring was continued for a further 2 hours. The mixture was then cooled and decomposed by the careful addition of 5 N hydrochloric acid (85 ml.). The ether layer was washed with water, dried over anhydrous sodium sulphate, the ether was distilled off and the residual oil distilled at reduced pressure to yield the chlorohydrin (18.6 g.), B.P. 150-153 C., at 0.4 mm.

(b) The foregoing chlorohydrin g.) was added to a solution of l-(o-methoxyphenyl) piperazine dihydrochloride (10 g.) in ethanol (50 ml.) and this was treated with a solution of 80% potassium hydroxide (8 g.) in methanol (50 ml.). The mixture was heated at reflux temperature for 12 hours when the crude basic product was isolated and converted into the hydrochloride salt as described in earlier examples to give the hydrochloride in 58% yield, M.P. 222-224" C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 24 1- [3 (p-cyclohexyloxyphenyl) -2-hydroxypropyl] -4- omethoxyphenyl) piperazine hydrochloride (a) 1-chloro-3-(p-cyclohexyloxyphenyl)propan-Z-oL- A Grignard solution was prepared from p-bromophenoxycyclohexane (92.9 g.) and magnesium (13.2 g.) in ether 400 ml. This solution was stirred and treated with epichlorohydrin (102 g.) added at such a rate that the reaction was maintained at gentle reflux temperature. The mixture was allowed to stand overnight when it was cooled and decomposed by the careful addition of 5 N hydrochloric acid (250 ml.). The ether layer was Separated, washed with water, dried over anhydrous sodium sulphate and the ether was boiled off. The residual oil was distilled at reduced pressure to yield the chlorohydrin (46.2 g.), B.P. 144-146 C. at 0.2 mm.

(b) Reaction of the foregoing chlorohydrin with 1-(omethoxyphenyl) piperazine as described in earlier exam ples gave the product, isolated as the hydrochloride, in 52% yield, M.P. 147-149 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 25 1- [3 p-cyclohexylphenyl -2-hydroxypropyl] -4- (ofiuorophenyl) piperazine hydrochloride This compound was prepared by reaction of l-chloro- 3-(p-cyclohexylphenyl)-propan-2-ol with 1-(0 fluorophenyl)piperazine using the experimental procedure described in Example 3. It was obtained in 47% yield and had M.P. 192.5-193.5 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 26 1- [3- (p-cyclohexylphenyl) -2-hydroxypropyl] -4- (pfiuorophenyl) piperazine hydrochloride This compound was obtained in 59% yield by reaction of 1-chloro-3-(p-cyclohexylphenyl)propan-2-ol with 1-(p fluorophenyl)-piperazine as described in earlier examples. It had M.P. 179-180 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 27 1- [3-(p-cyclohexylphenyl) -2-hydroxypropyl] -4- (mtrifluoromethylphenyl) piperazine hydrochloride Reaction of 1-chloro-3-(p-cyclohexylphenyl)-propan- 2-o1 with 1-(m-trifluorornethylphenyl)piperazine using the method described in Example 3 gave this product in 10 50% yield, M.P. 189-191 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 28 l- (o-aminophenyl) -4- 3- (p-cyclohexylphenyl) -2- hydroxypropyl] piperazine hydrochloride A solution of 1-[3-(p-cyclohexylphenyl)-2-hydroxypropyl]-4-(o-nitrophenyl) piperazine hydrochloride (11.5 g.) (Example 21) in ethanol (100 ml.) was treated with 5% palladised charcoal catalyst (2 g.) and hydrogenated at atmospheric pressure when 1520 ml. of hydrogen was absorbed in 1 hour. The mixture was filtered, concentrated and diluted with ether to yield the product (5.61 g.) M.P. 229-231 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 29 1-[3-(p-2-ethylbutylphenyl) -2-hydroxypropyl] -4- (omethoxyphenyl) piperazine hydrochloride (a) 3-(p-bromobenzyl) pentane.Bromine (24 g.) was added dropwise with stirring to 3-benzylpentane (24.5 g.) in the presence of iron powder (2 g.) as catalyst. When the addition was complete, stirring was continued for 6 hours and the mixture was allowed to stand overnight. It was then diluted with chloroform (50 mL), washed successively with water, dilute sodium bicarbonate solution and water and dried over anhydrous sodium sulphate. The chloroform was distilled off at reduced pressure and the residual oil distilled at 0.15 mm. pressure to give the product (54.5% yield), B.P. 63 C.

(b) 1-chloro-3- [4- (Z-ethylbutyl phenyl] propan-2-ol. A Grignard reagent was prepared from the foregoing bromo compound (18.8 g.), ethyl bromide (2.7 g.) and magnesium (2.4 g.) in ether (100 ml.). This was stirred and treated with epichlorohydrin (18.5 g.) added dropwise during 30 minutes and stirring was continued for 2 hours further. The reaction mixture was then cooled and decomposed by the careful addition of 5N hydrochloric acid (100 ml.). The ether layer was separated, washed with water, dried over anhydrous sodium sulphate and the ether distilled off. The residual oil was distilled at reduced pressure to yield the chlorohydrin (12.5 g.), B.P. 124 C. at 0.1 mm.

(c) A solution of the foregoing chlorohydrin (7.0 g.) in ethanol (50 ml.) was treated with 1-(o-methoxyphenyl) piperazine (6.3 g.) followed by a solution of potassium hydroxide (3.92 g.) in methanol (30 ml.) and the mixture was heated under reflux for 10' hours. The basic product was isolated as described in earlier examples and converted into the hydrochloride in ethanolic solution. This (3.89 g.) had M.P. 137-139 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 30 1- (m-chlorophenyl) -4- [3 (p-cyclohexylphenyl) -2-hydroxypropyl]-piperazine hydrochloride This compound was prepared in 20.5% yield by reaction of l-ch1oro-3- (p-cyclohexylphenyl)-propan-2-ol with l-(m-chlorophenyl) piperazine in a mixture of ethanol and methanol containing potassium hydroxide followed by conversion of the basic product into the required hydrochloride. This had M.P. 202204 C. after crystallisation from isopropanol.

EXAMPLE 31 1- 3-(p-cyclohexylphenyl -2-hydroxypropyl] -4- (oethoxyphenyl) piperazine hydrochloride (a) 1 (o-ethoxyphenyl)piperazine hydrochloride.o- Phenetidine (13.6 g.) was added to a solution of bis-(2- chloroethyl)amine hydrochloride (22.2 g.) in n-butanol (60 ml.) and the mixture heated for 30 hours with the addition of two 5.3 g. samples of anhydrous sodium carbonate at 10 hour intervals. The mixture was filtered hot and the filtrate concentrated to half bulk. The product 1 1 (9.7 g.) which crystallised on cooling had M.P. 207209 C. after crystallisation from isopropanol.

(b) The title compound was obtained in 26.7% yield by reaction of 1-chloro-3-(p-cyclohexylphenyl)-propan-2- 01 with l-(o-ethoxyphenyl) piperazine hydrochloride in a mixture of ethanol and methanol containing potassium hydroxide, followed by conversion of the basic product into the required hydrochloride. This had M.P. 170-172" C. after crystallisation from a mixture of isopropanol and ether.

EXAMPLE 32 1- o-butoxyphenyl -4- [3- (p-cyclohexylphenyl -2-hydroxy-propyl] piperazine hydrochloride (a) 1-(o-butoxyphenyl)piperazine hydrochloride.The product (15.6 g.) was obtained by reaction of bis-(Z-chloroethyl)amine hydrochloride (31.5 g.) with o-butoxyaniline (23.8 g.) in n-butanol (100 ml.) in the presence of anhydrous sodium carbonate (14.8 g.) as described for l-(o-ethoxyphenyl) piperazine hydrochloride in Example 31. It had M.P. 144146 C. after crystallisation from a mixture of isopropanol and ether.

-(b) The title compound was obtained in 32% yield by reaction of 1 chloro-3-(p-cyclohexylphenyl)-propan-2-ol with l-(o-butoxyphenyl) piperazine hydrochloride using the procedure described in earlier examples. It had M.P. 174-176 C. after crystallisation from a mixture of 1,2- dichloroethane and light petroleum (B.P. 6080 C.).

EXAMPLE 33 1-[3-(p-cyclohex-1-enylphenyl)-2-hydroxypropyl]-4- (o-methoxyphenyl) piperazine hydrochloride This compound Was obtained in 25% yield by reaction of 1-chloro-3-(pcyclohex-1-enylphenyl)-propan-2-ol with l-(o-methoxyphenyl) piperazine in a mixture of methanol and ethanol in the presence of potassium hydroxide, following the procedure described in earlier examples. It had M.P. 179-180 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 34 1- [3 -(p-cyc1opentylphenyl) -2-hydroxypropyl] -4-(omethoxyphenyl) piperazine hydrochloride This compound was prepared in 16% yield by reaction of 1 chloro-3-(p-cyclopentylphenyl)-propan-2-ol with 1- (o-methoxyphenyl) piperazine in ethanolic solution in the presence of potassium hydroxide followed by conversion of the basic product into the hydrochloride. It had M.P. 174176 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 35 1-[3-(p-cyclohept-l-enylphenyl)-2-hydroxypropyl-4-(ornethoxyphenyl) piperazine hydrochloride This product was prepared in 26% yield by reaction of 1-chloro-3-(p-cyclohept-l-enylphenyl)-propan-2-ol with l-(o-methoxyphenyl)-piperazine following the procedure described in earlier examples. It had M.P. 152153 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 36 1 [3-(p-cyclopentl-enylphenyl)-2-hydroxypropyl] -4- (omethoxyphenyl) piperazine hydrochloride This compound was prepared in 17% yield by reaction of 1-chloro-3-( p-cyclopentl-enylphenyl) -propan-2-ol with l (o-methoxyphenyl) piperazine using the method described in earlier examples. It had M.P. 183-185 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 37 1- [3 (2'-n-butoxy-5-phenyl )phenyl-2-hydroxypropyl]- 4-(o-methoxyphenyl) piperazine hydrochloride This compound was prepared by reaction of l-chloro 3-(2'-n-butoxy-5'-phenyl)-phenylpropan-2-ol with l-(omethoxyphenyl) piperazine as described in earlier examples. It was obtained in 35% yield and had M.P. 160- 162 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 38 1- (m-chlorophenyl -4- 3- (o-methoxyphenyl -2- hydroxypropyl] piperazine A solution of l-(m-chlorophenyl) piperazine dihydrochloride (13.5 g.) in ethanol (100 ml.) was treated with 1-chlor0-3-(o-methoxyphenyl)-propan-2-ol (10 g.) followed at once by a solution of 85% potassium hydroxide (9.5 g.) in methanol ml.) and the mixture was heated under reflux or 10 hours. It was then filtered, concentrated and the residue partitioned between chloroform and water. The chloroform layer was washed with water, dried over anhydrous sodium sulphate and the chloroform was then distilled off at reduced pressure. The viscous residue was dissolved in ethanol (40 ml.) when the basic product crystallised (yield 12 g.). It had M.P. 899l C. after crystallisation from ethanol.

EXAMPLE 39 1-[3-(2'-n-butoxy-5'-cyclohexylphenyl) 2 hydroxypropyl]-4-(o-methoxyphenyl) piperazine hydrochloride (a) 2-bromo-4-cyclohexylphenol.A solution of pcyclohexylphenol (44 g.) in chloroform (500 ml.) was stirred and treated during 30 minutes with a solution of bromine (13 ml.) in chloroform (15 ml.) and reaction was completed by heating at reflux temperature for 2 hours. The solvent was distilled oil? at reduced pressure and the residual oil was distilled at 0.05 mm. pressure to yield the product (40.5 g.) B.P. 102104 C.

(b) 2-n-butoxy-5-cyclohexylbromobenzene.A solution of 2-bromo-4-cyclohexylphenol (51 g.) in ethanol (300 ml.) containing potassium hydroxide (13.2 g.) was treated with n-bromobutane (28 g.) and the mixture was heated under reflux for 5 hours. It was then concentrated, poured into water (500 ml.) and the product isolated with chloroform. The chloroform solution was washed with water, dried over anhydrous sodium sulphate and the chloroform was distilled off at reduced pressure. The residual oil was fractionated at 0.3 mm. pressure to yield the product, B.P. 151 C. (yield 44.6 g.).

(c) 1-chloro-3-(2-n-butoxy 5 cyclohexyl)-phenylpropan-2-ol.-To a Grignard reagent prepared from 2-nbutoxy-5-cyclohexylbromobenzene (28.2 g.), ethyl bromide (3.4 ml.) and magnesium (3.25 g.) in a mixture of ether (225 ml.) and tetrahydrofuran (75 ml.) was added a solution of epichlorohydrin (33.3 g.) in a mixture of ether (20 ml.) and tetrahydrofuran (10 ml.) during 30 minutes. The mixture was stirred for 2 hours and was then cooled and decomposed by the careful addition of 5 N hydrochloric acid ml.). The ether layer was separated, washed with water and dried over anhydrous sodium sulphate. The ether was distilled oflf and the residual oil distilled at 0.05 mm. pressure to yield the chlorohydrin (14.1 g.), B.P. 168 C.

((1) Reaction of the foregoing chlorohydrin with l-(omethoxyphenyl) piperazine as described in earlier examples gave the title compound in 37.5% yield, M.P. l8l-183 C., after crystallisation from a mixture of ethanol and ether.

EXAMPLE 40 1- [3- (o-cyclohexyloxyphenyl -2-hydroxypropyl] -4- (omethoxyphenyl) piperazine hydrochloride (a) l-chloro 3 (o-cyclohexyloxyphenyl)-propan-2- ol.A Grignard reagent was prepared from o-cyclohexyloxybromobenzene (40.7 g.), ethyl bromide (6.2 ml.) and magnesium (5.75 g.) in ether (400 ml.). This was stirred and treated with a solution of epichlorohydrin (59.2 g.) in ether (50 ml.), added during 30 minutes.

Stirring was continued for a further 2 hours then the mixture was cooled and decomposed by the careful addition of N hydrochloric acid (100 ml.). The ether layer was separated, washed twice with water, dried over sodium sulphate and the ether distilled off. The residual oil was distilled at 0.075 mm. pressure to yield the chlorohydrin (23.3 g.), B.P. 138-140 C.

(b) Reaction of the foregoing chlorohydrin with l- (o-methoxyphenyl) piperazine by the method described in earlier examples gave a 24% yield of the title compound, M.P. 174176 C., after crystallisation from a mixture of ethanol and ether.

EXAMPLE 41 1- 3 (p-cyclohexylphenyl) -2-hydroxypropyl] -4- (2,4- dimethoxyphenyl) piperazine (a) 1 (2,4 dimethoxyphenyl)piperazine hydrochloride.-This compound (28.2 g.) was obtained by reaction of bis-(2-chloroethyl)amine hydrochloride (55.7 g.) with 2,4-dimethoxyaniline (38.25 g.) in n-butanol (180 ml.) in the presence of anhydrous sodium carbonate (26.5 g.) as described for the preparation of 1-(o-ethoxyphenyl) piperazine hydrochloride in Example 31. It had M.P. 228-230 C. after crystallisation from ethanol.

(b) A solution of 1-chloro-3-(p-cyclohexylphenyl) propan-2-ol (12.6 g.) in ethanol (110 ml.) was treated with 1-(2,4-dimethoxyphenyl)piperazine hydrochloride (12.93 g.) followed by a solution of 85% potassium hydroxide (6.91 g.) in methanol (40 m1.) and the mixture was heated under reflux for 12 hours. The mixture was cooled, poured into water and the oil extracted with three portions of chloroform. The chloroform extracts were washed with water, dried with anhydrous sodium sulphate and the chloroform distilled off, last traces of solvent being removed at reduced pressure. The residual oil was dissolved in warm ethanol when the title compound crystallised. It (10.6 g.) had M.P. 112-l14 C. after crystallisation from ethanol.

EXAMPLE 42 1- (o-acetamidophenyl) -4- [3 (p-cyclohexylphenyl) -2- hydroxypropyl] piperazine hydrochloride This product was prepared in 40% yield by reaction of 1-( o-aminophenyl)-4-[3-(p-cyclohexylphenyl) 2 hydroxypropyl]piperazine hydrochloride with acetyl chloride in 1,2-dichloroethane in the presence of pyridine. It had M.P. 174-176 C. after crystallisation from a mixture of 1,2-dichloroethane and light petroleum (B.P. 40- 60 C.).

EXAMPLE 43 1-(4-chloro-2-nitrophenyl) -4-[S-(p-cyclohexylphenyl)-2- hydroxypropyl] piperazine hydrochloride (a) 1-(4 chloro-2-nitrophenyl)piperazine hydrochloride.A mixture of anhydrous piperazine (51.6 g.) and 2,5-dichloronitrobenzene (38.4 g.) dissolved in n-butanol (250 ml.), was heated at reflux temperature for 6 hours. It was then cooled, poured into water and basified by the addition of a solution of sodium hydroxide (10 g.) in water (100 ml.). The mixture was extracted with four, 100 ml. portions of ether and the ether extracts were combined and concentrated. The residual oil was dissolved in a small amount of ethanol and treated with a slight excess of ethanolic hydrogen chloride. The product (26.5 g.) which separated had M.P. 239-240 C. after crystallization from a mixture of ethanol and ether.

(b) The title compound was prepared in 65% yield by reaction of 1 chloro-3-(p-cyclohexylphenyl)propan-Z-ol with 1 (4-chloro-2-nitrophenyl)piperazine hydrochloride in a mixture of methanol and ethanol containing 2 equivalents of potassium hydroxide, as described in earlier examples. It had M.P. 215-216 C. after crystallisation from a mixture of ethanol and ether.

1 4 EXAMPLE 44 1- 3- (p-cyclohexylphenyl) -2-hydroxypropyl] -4- (omethoxyphenyl) piperazine monohydrochloride (a) A solution of 1-chloro-3-(p-cyclohexylphenyl)propan-2-ol (25.2 g.) in ethanol (250 ml.) was treated with a solution of potassium hydroxide (14.5 g.) in methanol (100 ml.) followed by 1- (o-methoxyphenyD-piperazine monohydrochloride (22.8 g.) and the mixture was heated under reflux for 5 hours. The free base was isolated with chloroform as described in Example 8. It was then dissolved in a minimum of ethanol and treated with a solution of hydrogen chloride (3.7 g.) in ethanol (20 ml.). The crystalline product (28 g.) which separated on dilution of the solution with ether was purified by crystallisation from a mixture of 1,2-dichloroethane and light petroleum (B.P. 60-80 C.) and yielded the monohydrochloride, M.P. 199-201 C.

(b) The same product was obtained in 47% yield when l-chloro-3-(p-cyclohexylphenyl)propan-2-ol (5.05 g.) was reacted with 1-(o-methoxyphenyl)piperazine hydrochloride (4.37 g.) in tertiary butanol ml.) containing 85% potassium hydroxide (3.08 g.) at reflux temperature for 2 hours followed by isolation of the base as described in earlier examples and conversion into the monohydrochloride as described above.

(0) The preparation described in Example 44(a) was carried out in more concentrated solution viz in ethanol ml.) and methanol (50 ml.) and the mixture was allowed to stand at room temperature for 6 days. The free base was isolated and converted into the monohydrochloride as described in Example 44(a). The product (34 g.), M.P. 199-201 C. [after crystallisation from a mixture of 1,2-dichloroethane and light petroleum (B.P. 60-80 C.)], was identical with that described in Example 44(a).

EXAMPLE 45 1- [3- (p-biphenylyl) -2-hydroxypropyl] -4- (m-fluorophenyl) piperazine hydrochloride a) l-(p-biphenylyl)-2,3-epoxypropane.-A suspension of l-(p-biphenylyl) 3 chloropropan-Z-ol (49.3 g.) in mixed solutions of water (1 litre) and ethanol (250 ml.) containing sodium carbonate (42.4 g.), was heated with vigorous stirring and the ethanol was allowed to boil ofi. during 1 hour. Heating at 95 C. was then continued for 2 /2 hours. The oil was isolated with chloroform and the chloroform extract was washed with water. The chloroform was distilled off and the residual oil distilled at reduced pressure to yield the epoxide (37.2 g.), B.P. 132 C. at 0.35 mm., M.P. 51 C., after crystallisation from a small amount of methanol.

(b) A solution of the foregoing epoxide (5.65 g.) in toluene (10 ml.) was treated with a solution of 1-(mfluorophenyl)piperazine (4.87 g.) in toluene (20 ml.) and the mixture was allowed to stand at room temperature for 2 days. The toluene was distilled off at reduced pressure and the residual oil was dissolved in ether and treated with hydrogen chloride. The resultant solid (9.6 g.) was crystallised from a mixture of ethanol and ether to yield the hydrochloride, M.P. 200 to 202 C.

EXAMPLE 46 1 [3- (p-cyclohexylphenyl) -2-hydroxypropyl]-4- (o fluorophenyl) piperazine hydrochloride (a) l-(p-cyclohexylphenyl)-2,3-epoxypropane.-A suspension of 1 chloro-3-(p-cyclohexylphenyl)-propan-2-ol (37.8 g.) in water (1 litre) and ethanol (250 ml.) was converted into the epoxide using the method described in Example 45 (a). The epoxide had B.P. 104 C. at 0.1 mm.

(b) A solution of the foregoing epoxide (4 g.) in toluene (20 ml.) was added to a solution of l-(o-fiuorophenyl)piperazine (3.31 g.) in toluene (15 ml.) and the mixture was heated on the steam bath for 4 hours. The toluene was distilled off at reduced pressure and the residual oil was dissolved in dry ethanol and treated with hydrogen chloride. Dilution with ether furnished the hydrochloride salt (5.2 g.). This had M.P. 195197 C. after crystallisation from a mixture of ethanol and ether. It was identical with the product described in Example 25.

EXAMPLE 47 1 chloro 2-methoxyphenyl)-4-[3-(p-cyclohexylphenyl -2-hydroxypropyl] piperazine hydrochloride (a) 1 (5 chloro 2 methoxyphenyDpiperazine hydrochloride.Tl1is compound (10.4 g.) was obtained by reaction of bis-(2-chloroethyl)amine hydrochloride (55.7 g.) with 5-chloro-2-methoxyaniline (39.4 g.) in n-butanol (180 ml.) in the presence of anhydrous sodium carbonate (27.5 g.) as described for the preparation of l-(o-ethoxyphenyl)-piperazine hydrochloride in Example 31. It had M.P. 218220 C. after crystallisation from 1,2-dichloroethane.

(b) A solution of 1-chloro-3-(p-cyclohexylphenyl) propan-Z-ol (12.6 g.) in isopropanol (125 ml.) was treated with a solution of 85% potassium hydroxide (6.91 g.) in methanol (40 ml.) followed by 1-(5-chloro- 2-methoxyphenyl)piperazine hydrochloride (13.16 g.) and the mixture was heated under reflux for 8 hours. The base was isolated with chloroform and converted into the hydrochloride as described in earlier examples. This (14.4 g.) has M.P. l84186 C. after crystallisation from 1,2-dichloroethane.

EXAMPLE 48 1- [3- p-cyclohexylphenyl -2-hydroxypropyl -4- 5 methyl-2,4-disulphamoylphenyl piperazine To a solution of 1-chloro-3-(p-cyclohexylphenyl)- propan-2-ol (10.1 g.) in 2-methoxyethanol (20 ml.) was added a solution of 1-(5-methyl-2,4-disulphamoyl) piperazine (10.3 g.) in 2-methoxyethanol (230 ml), followed by a solution of 80% potassium hydroxide (2.8 g.) in methanol (30 ml.) and the mixture was heated at reflux temperature for hours. The solvent was distilled 01f at reduced pressure and the residual solid was extracted with boiling ethanol. Dilution of the ethanol with ether yielded the solid product (8.4 g.) which had M.P. 130-131" C. (decomp.) after crystallisation from a mixture of toluene and light petroleum (B.P. 80100 C.).

EXAMPLE 49 1- 3- p-cyclohexy1phenyl -2-hydroxypropyl] -4- (p-hydroxyphenyl)piperazine hydrochloride The title compound was prepared in 55% yield by reaction of 1 ehloro 3-(p-cyclohexylphenyl)propan-Z-ol with l-(m-fluorophenyl) piperazine in a mixture of ethanol and methanol in the presence of potassium hydroxide as described in earlier examples. It had M.P. 228230 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 50 1- 3-(pcyclohexylphenyl -2-hydroxypropyl] -4- (p-hydroxylphenyl)piperazine hydrochloride The title compound was prepared in 74% yield by reaction of 1-chloro-3-(p-cyclohexylphenyl)propan-Z-ol (11.6 g.) with l-(p-hydroxyphenyl) piperazine dihydrobromide (13.3 g.) in a mixture of ethanol (50 ml.) and methanol (50 ml.) in the presence of 85% potassium hydroxide (9.8 g.). The mixture was heated at reflux for 6 hours then poured into water. Neutralisation gave the 16 free base which, on dissolving in ethanol and treatment with hydrogen chloride, yielded the title compound. This (12.4 g.) had M.P. 2479 C. after crystallisation from a mixture of ethanol and ether.

EXAMPLE 5 1 1- [3 (p-cyclohexylphenyl -2-hydroxypropyl] -4- (p-nitrophenyl) piperazine hydrochloride The title compound was prepared by treating a solution of 1-chloro-3-(p-cyclohexylphenyl)propan-Z-ol (13.1 g.) in ethanol (120 ml.) with potassium hydroxide (4.0 g.) in methanol (25 ml.), below 10 C., followed by l-(p-nitrophenyl)piperazine. The mixture stood 6 days at room temperature. Isolation of the base and conversion into the hydrochloride, as described in Example 2, yielded the title compound (11.6 g.) which had a M.P. 156- 158 C., after crystallisation from a mixture of 1,2-dichloroethane and light petroleum (B.P. 6080 C.).

We claim:

1. A piperazine compound of the formula -ornon on onm wherein R is selected from the group consisting of cycloalkyl having from 5 to 7 carbon atoms and cycloalkoxy having from 5 to 7 carbon atoms,

R is selected from the group consisting of phenyl and phenyl substituted with a group selected from those consisting of alkyl having from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms, fluorine, chlorine, and trifluoromethyl; and their pharmaceutically acceptable acid addition salts.

2. A compound according to claim 1 consisting of 1-[3- (p cyclohexylphenyl) 2 hydroxypropyl] 4-o-tolylpiperazine hydrochloride.

3. A compound according to claim 1 consisting of 1-[3- (p cyclohexylphenyl) 2 hydroxypropyl]-4-m-tolylpiperazine hydrochloride.

4. A compound according to claim 1 consisting of l- (p chlorophenyl) 4 [3-(p-cyclohexylphenyl)-2-hydroxypropyl]-piperazine hydrochloride.

5. A compound according to claim 1 consisting of 1 o chlorophenyl 4 [3-(p-chlorhexylphenyl)-2-hydroxypropyl]-piperazine dihydrochloride.

6. A compound according to claim 1 consisting of 1-[3- (p cyclohexylphenyl) Z-hydroxypropyl]-4-o-methoxyphenylpiperazine dihydrochloride.

7. A compound according to claim 1 consisting of 1-[3- (p cyclohexylphenyl) 2 hydroxypropyl]-4-(m-methoxyphenyl -piperazine dihydrochloride.

8. A compound according to claim 1 consisting of l- [3 (p cyclohexylphenyl)-2-hydroxypropyl]-4-phenylpiperazine dihydrochloride.

9. A compound according to claim 1 consisting of 1- [3 (p cyclohexyloxyphenyl)-2-hydroxypropyl]-4-(omethoxyphenyl -piperazine hydrochloride.

10. A compound according to claim 1 consisting of 1- [3 (p cyclohexylphenyl) 2-hydroxypropyl]-4-(o-fiuorophenyl)-piperazine hydrochloride.

11. A compound according to claim 1 consisting of l- [3 (p cyclohexylphenyl)-2-hydroxypropyl]-4-(p-fluorophenyl -piperazine hydrochloride.

12. A compound according to claim 1 consisting of 1- (m chlorophenyl) 4 [3 (p-cyclohexylphenyl)-2- hydroxypropyl]-piperazine hydrochloride.

13. A compound according to claim 1 consisting of 1- [3 (p cyclohexylphenyl) 2 hydroxypropy11-4-(oethoxyphenyl)-piperazine hydrochloride.

References Cited UNITED STATES PATENTS Pollard 260268 Heywood 260268 Janssen 260268 Janssen 260--268 Parcell 260268 Geschicter et a1. 260268 18 Shapiro 260268 Ash et a1. 260268 De Stevens 260268 PH Hansen 260268 PH Fauran 260268 G Umeomoto 260268 R DONALD G. DAUS, Primary Examiner US. Cl. X.R.