Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
  • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C17/00—Preparation of halogenated hydrocarbons
  • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
  • C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
  • C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
  • C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms

Definitions

• 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
• the compounds of the present invention are effective as central nervous system depressants.
• 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.
• EXAMPLE 1 A X CPZ in mouse rage test. /2 CPZ in antiamphetamine test.
• EXAMPLE 3 2X CPZ in mouse rage test. 4 CPZ in reducing spontaneous motor activity.
• 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.
• CPZ above denotes chlorpromazine.
• 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
• 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).
• 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.
• 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.
• potassium hydroxide employed as the inorganic base the reaction proceeds as shown below:
• R, R, R and R have the same significance as in Formula I.
• the chlorohydrin (II) may be treated with cold methanolic potassium hydroxide or heated with aqueous
• 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.
• 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.
• 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.
• 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).
• 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.
• 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 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.
• 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.
• 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.
• 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 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.
• 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.
• 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 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.
• 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.
• 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.
• 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 44(a) 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• a compound according to claim 1 consisting of 1-[3- (p cyclohexylphenyl) 2 hydroxypropyl] 4-o-tolylpiperazine hydrochloride.
• a compound according to claim 1 consisting of 1-[3- (p cyclohexylphenyl) 2 hydroxypropyl]-4-m-tolylpiperazine hydrochloride.
• a compound according to claim 1 consisting of l- (p chlorophenyl) 4 [3-(p-cyclohexylphenyl)-2-hydroxypropyl]-piperazine hydrochloride.
• a compound according to claim 1 consisting of 1 o chlorophenyl 4 [3-(p-chlorhexylphenyl)-2-hydroxypropyl]-piperazine dihydrochloride.
• a compound according to claim 1 consisting of 1-[3- (p cyclohexylphenyl) Z-hydroxypropyl]-4-o-methoxyphenylpiperazine dihydrochloride.
• a compound according to claim 1 consisting of 1-[3- (p cyclohexylphenyl) 2 hydroxypropyl]-4-(m-methoxyphenyl -piperazine dihydrochloride.
• a compound according to claim 1 consisting of l- [3 (p cyclohexylphenyl)-2-hydroxypropyl]-4-phenylpiperazine dihydrochloride.
• a compound according to claim 1 consisting of 1- [3 (p cyclohexyloxyphenyl)-2-hydroxypropyl]-4-(omethoxyphenyl -piperazine hydrochloride.
• a compound according to claim 1 consisting of 1- [3 (p cyclohexylphenyl) 2-hydroxypropyl]-4-(o-fiuorophenyl)-piperazine hydrochloride.
• a compound according to claim 1 consisting of l- [3 (p cyclohexylphenyl)-2-hydroxypropyl]-4-(p-fluorophenyl -piperazine hydrochloride.
• a compound according to claim 1 consisting of 1- (m chlorophenyl) 4 [3 (p-cyclohexylphenyl)-2- hydroxypropyl]-piperazine hydrochloride.
• a compound according to claim 1 consisting of 1- [3 (p cyclohexylphenyl) 2 hydroxypropy11-4-(oethoxyphenyl)-piperazine hydrochloride.

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• 1967
  • 1967-07-05 GB GB30873/67A patent/GB1171251A/en not_active Expired
• 1968
  • 1968-06-20 IE IE734/68A patent/IE32152B1/xx unknown
  • 1968-06-27 DK DK309268AA patent/DK120998B/da unknown
  • 1968-06-28 NO NO682568A patent/NO126082B/no unknown
  • 1968-07-03 NL NL6809422A patent/NL6809422A/xx unknown
  • 1968-07-03 AT AT639368A patent/AT281038B/de not_active IP Right Cessation
  • 1968-07-04 IL IL30313A patent/IL30313A/xx unknown
  • 1968-07-04 ES ES355739A patent/ES355739A1/es not_active Expired
  • 1968-07-04 FR FR1583999D patent/FR1583999A/fr not_active Expired
  • 1968-07-05 DE DE19681770805 patent/DE1770805A1/de active Pending
  • 1968-07-05 CH CH1009968A patent/CH496005A/de not_active IP Right Cessation
  • 1968-07-05 SE SE09283/68A patent/SE352891B/xx unknown
• 1971
  • 1971-06-23 US US00156092A patent/US3732229A/en not_active Expired - Lifetime

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