PIPERIDINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATION CONTAINING THEM

Abstract: The pure enantiomeric form of a compound of the formula wherein Y is OH, R¹COO, R²R³NCOO- or R⁴O whereby R¹ is an aliphatic hydrocarbon residue having 1-17 carbon atoms, a phenyl, 2,6-dimethylphenyl or 3- or 4-hydroxyphenyl group or a 3- or 4-alkanoyloxyphenyl group with the formula wherein R⁵ is an alkyl group having 1-6 carbon atoms, or R¹ is a group wherein R⁶ is hydrogen, an alkyl group having 1 to 5 carbon atoms or a phenyl group, R⁷ is hydrogen, an alkyl group having 1 to 5 carbon atoms or an acyl group and R⁸ is hydrogen or an alkyl group having 1 to 5 carbon atoms, R² is hydrogen, an alkyl group having 1-5 carbon atoms, a phenethyl, benzyl or phenyl group which may be mono- or disubstituted in the aromatic part with a methyl, methoxy, hydroxy, nitro or cyano group or a halogen, R³ is H, an alkyl group having 1 to 5 carbon atoms or a phenyl group, or R² and R³ together with the nitrogen atom form a 5, 6 or 7 membered ring that may contain 1 to 3 double bonds and/or 1 or 2 further heteroatoms selected frm N, O and S, and R⁴ is an allyl or benzyl group, said enantiomer having the same absolute configuration at the asymmetric carbon atom (x) as that of the (-)-enantiomer of the compound of formula I wherein Y is OH, as bases and pharmaceutically acceptable acid additiion salts thereof, processes for their preparation and pharmaceutical preparations and methods of treatment employing such compounds. The compounds are useful for treatment of disorders in the central nervous system.

Description: New compounds, processes for preparation and ph@@ ceutical preparations for such compounds DESCRIPTION Technical field The present invention is related to new enantiomers of substituted phenylazacycloalkanes, to processes for preparing such compounds as well as to pharmaceutical preparations thereof and methods of treatment employing such compounds. An object of the invention is to provide compounds for therepeutic use, especially having a therapeutic activity in the central nervous system. Background Art EP-A1-0030526 and Hacksell et al. in J. Med. Chem., vol. 24, p. 1475-1482 (1981) describe compounds of the formula EMI1.1 wherein n is 1 or 2, Y is OH, RÚCOO, RêR NCOO- or R whereby is an alkyl group having 1-5 carbon atoms or a possibly substituted phenyl group, R is an alkyl group having 1-5 carbon atoms, a phenethyl, Denzyl cr pnEnvl group, R is h or an alkyl group having 1-5 carbon atonis, and P 4 is an allyl or benzyl group, and R is an alkyl group having 1-5 carbon atoms, a hydroxyalkyl, dimethylaminoalkyl or methylthioalkyl group having 2-6 carbon atoms in the alkyl part and having the heteroatom bound in a position other than the 1 position, or an alkenyl group having 2-5 carbon atoms other than a 1-alkenyl group, as bases and pharmaceutically acceptable acid addition salts thereof, which compounds are potent neuropharma- cological agents. Thus said compounds are active as pre synaptic-dopamine receptor agonists when administered to animals including man. Said compounds are thus useful for treatment of disorders in the central nervous system, expecially psychotic disorders in man. In particular compounds of the above formula wherein R represents n-propyl are described. EP-A1-0030526 refers to and covers in general the pure enantiomers as well as mixtures thereof. However, the enantiomers are not speci filly disclosed. Disclosure of Invention According to the present invention it has been found that the pure enantiomeric forms of compounds of the formula EMI2.1 wherein Y is Ooh, RlCOO, R êR NCOO- or R40 whereby R1 is an aliphatic nyorocarbon residue having 1-17 carbon. atoms, a phenyl, 2,6-dimEthylphenyl or 3- or 4-hydroxyphenyl group or a - cr 4-alkanoyloxyphenyl group with the formula EMI2.2 wherein R5 is an alkyl group having 1-6 carbon atoms, or RÚ is a group EMI2.3 wherein R6 is hydrogen, an alkyl group having 1 to 5 carbon 7 atoms or a phenyl group, P is hydrogen, an alkyl group 8 having 1 to 5 carbon atoms or an acyl group and P is hydrogen or an alkyl group having 1 to 5 carbon atoms, R is hydrogen, an alkyl group having 1-5 carbon atoms, a phenethyl, benzyl or phenyl group which may be mono- or disubstituted in the aromatic part with a methyl, methoxy, hydroxy, nitro or cyano group or a halogen, R is H, an alkyl group having 1 to 5 carbon atoms or a phenyl group or P2 and P3 together with the nitrogen atom form a 5, 6 or 7 membered ring that may contain 1 to 3 double bonds and/or 1 to 2 further heteroatoms selected from N, 0 and S, and 4 P is an allyl or benzyl group, said enantiomer having the same absolute configuration at the asymmetric carbon atom I ) as that of the (-)-enantiomer of the compound of formula I wherein Y is OH, as bases and pharmaceutically acceptable acio adcition salts thereof, possess unexpected valuable therapeutical properties in addition to those previously described. The (-)-enantiomer of the compounc of formula I wherein Y is OH is the levo rotameric form. Compounds of the invention having Y other than OH have the same absolute configuration as said (-)-enantiomer, it being understood that said latter compounds are not necessarily the (-) or levo rotameric forms. In the pure enantiomers of the invention Y is in particular OH, R COO, êR NCOO- or R O whereby RÚ is an alkyl group having 1-5 carbon atoms or a phenyl, 2,6-dimethylphenyl or 3- or 4-hydroxyphenyl group or a 3- or 4-alkanoyloxyphenyl group, Rê is an alkyl group having 1-5 carbon atoms, a phenethyl, benzyl or phenyl group, R is H or an alkyl group having 1-5 carbon atoms, and P is an allyl or benzyl group. 6y X-ray crystallography the absolute configuration of the (-)-enantiomer of the compound of formula I wherein Y is Oh has been determined to be the S configuration. Thus, the compounds of the invention according to formula I all have S configuration. An alkyl group may be a straight alkyl group or a branched alkyl group having at least 3 carbon atoms. An acyl group R7 is a formyl, acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl group. An aliphatic hydrocarbon P1 residue R may be saturated or unsaturated. symbols for numbers, atoms or groups referred to below have the broadest meaning previously assigned unless specified otherwise. both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids are sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, pamoic, ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acid. These salts are readily prepared by methods known in the art. In a preferred embodiment the invention is related to pure enantiomeric compounds of the formula I as defined above wherein Y is OH, RÚCOO- or P23NCOO-, whereby R , R2 and R3 are as defined above. Compounds to be specifically mentioned are: (-)-3-(3-Hydroxyphenyl)-N-n-propylpiperidine, (-)-N-n-propyl-3-[3-(4-pivaloyloxybenzzyloxy)phenyl- piperidine, (-)-N-n-propyl-3-(3-allyloxyphenyl)piperidine, (-)-3-(3-cecanoyloxyphenyl)-1-propylpiperidine, S-3-(3-pivaloyloxyphenyl)-N-n-propylpiperidine, S-3-(3-acetoxyphenyl)-N-n-propylpiperidine, S-3-(3-benzyloxyphenyl)-N-n-propylpiperidine, S-3-(3-N',;i'-dimethylcarbamoyloxyphenyl)-N-n-propylpiperidine, S-3-(3-N'-phenylcarbamoyloxyphenyl)-N-n-prop{lpipEridineJ and S-3-(3-N'-cenzyloxycarbonylalanylphenyl)-N-n-propylpiperidine. The invention takes into consideration that compounds which structurally deviate from the formula I, after administration to a living organism may be transformed to a compound of the formula I and in this structural form exert their effects. This consideration is a further aspect of the invention. Likewise, certain compounds of formula I may be metabolized into other compounds of formula I before. exerting their effect. Compounds of the invention wherein Y is RlCOO, R2R3NCOO or R40 are thus believed to exert their main activity after metabolism to the compound wherein Y is OH. Methods of Preparation The compounds of the invention may be obtained by one of the following methods constituting a further aspect of the invention. a) A pure enantiomer cf an ether or ester of the formula EMI5.1 having the appropriate absolute configuration at the (*) wherein @a asymmetric carbon atom , wherein P represents a hyoro- carbon or acyl residue, preferably an alkyl group having 1-5 carbon atoms, or an alkylcarbonyl group having 2-6 carbon atoms defined above may be cleaved to form the compound of formula I wherein Y is a hydroxy group, in the desired (-)-enantiomeric form. When a is a hydrocarLon residue the cleavage may be carried out by treating the compound cf formula II with an acidic nucleophilic reagent such as aqueous HBr, ol HI, HBr/CH3COOH, BBR3, AlCl3, pyridine-HCl or (CH3)3 Sil, or with a basic nucleophilic reagent such as CH3C6H4-S# or C2H5-S#. When Ra is an acyl rEsidue the cleavage may be carried out by.hydrolysis in an aqueous acid or base or by reduction1 preferably by LiAlH4. b) In a pure enantiomer of a compound of the formula EMI6.1 having the appropriate absolute configuration at the asymmetric carbon atom ), wherein Z represents S03H, Cl or NH2, a hydroxy group may be substituted for the group Z to the formation of a compound of formula I wherein Y represents a hydroxy group and in the desired (-)-enantiomeric form. When 2 is S03H or Cl said reaction may be carried out by treatment with a strong alkali under heating, suitably with an alkali melt such as KOH when Z is S03H, and with a strong aqueous alkali such as NaOH or KOH when Z is Cl. When Z is Nv2 the reaction may be carried out by treatment with aqueous nitrous acid to the formation of an intermediats diazonium compound which is then subjected to hydrolysis in water. c) The (-)-enantiomeric form of thE compound of formula I EMI6.2 wherein Y is OH may be converted into a compound of the same formula and the same absolute configuration at the asymmetric carbon atom(*) wherein Y is RÚCOO, RêR NCOO or R4O by treating the firstmentioned compound with an appropriate carboxylic acid halide RÚCOX or anhydride (RÚCO)2O or with an appropriate carbamoyl halide RêR NCOX or isocyanate RêNCO in the presence of a base such as triethylamine or pyridine or an acid such as H2S04 or CF3COOH or with an appropriate allyl or benzyl halide R4X in the presence of a base such as triethylamine, pyridine or potassium t-butoxide. X represents a halogen, preferably Cl or Br. Alternatively, when conversion of Y = OH into P 1 COO is intended and R1 is R5CDo EMI7.1 a compound of formula I wherein Y is OH may first be converted to a compound of formula I wherein Y is HO EMI7.2 which is then treated with an appropriate carboxylic acid halide PUD COX or an 5 hydride (R5CO)20 in the presence of a base or an acid. d) A pure enantiomer of a compound of the formula EMI7.3 having the appropriate absolute configuration may be converted into a compound of formula I having the desired absolute configuration at the asymmetric carbon at by alkylation of the nitrogen atom with an appropriate alkylating agent. Thus the starting compound may be treated with a n-propyl halide or tosylate RXÚ, wherein XÚ represents C1, Br, I or OS02 EMI8.1 CH3 in an organic solvent such as acetonitrile or acetone and in the presence of a base such as K2C03 or NaOH, or the starting compound may be treated with a n-propionic acid NaBH4 complex. e) A pure enantiomer of a carbonyl compound of the formula EMI8.2 having the appropriate absolute configuration, wherein M1 and M2 are the same or different and each represents -CH2or EMI8.3 and the dashed lines represent bonds, one of which, when adjacent to a group EMI8.4 may be open and replaced by hydrogen atoms, and M3 is EMI8.5 when M1 and M2 are both -CH - and in other cases M is n-C H, and Rd is H or RÚCOê, may be converted into a compound, of the formula I having the desired absolute configuration at the asymmetric carbon atom ) and wherein Y is a hydroxy, allyl- oxy or benzyloxy group by reduction of the amide or imide function, and the ester function R1COD if piesent. Thus the compound of formula V may be treated with a reducing agent, preferably a hydride reducing agent such as LiAlH4 or BH3 in an etheral solvent or a metal reducing agent such as Na in an alcoholic solvent such as n-butanol when ring closure is not required. When one of the dashed lines in formula V represents an open bond, the reduction comprises ring closure in a compound of the formula EMI9.1 and may be done by catalytic hydrogenation. f) A compound of the formula EMI9.2 with either a C2-C3 or a C3-C4 double bond and wherein Re is H or benzyl may be converted by reduction into a compound of formula I wherein Y is OH and having the desired (-)-enantiomeric form. The reduction may preferably be carried out by catalytic hydrogenation with an appropriate chiral homogenous phase catalyst such as a Rh-complex with chiral phosphines. If required, the product may be purified to obtain only the desired enantiomer in a pure form. g) A pure enantiomer of a compound according to the formula EMI9.3 having the appropriate absolute configuration, wherein one of the group zl and z2 is a leaving group X and the other is NH(CH2)2CH3 or Z and Z are both leaving groups X, and X is a leaving group such as C1, Br, I or -OSOzC6H4CH3, may be converted to a compound of formula I wherein Y is OH and having the desired (-)-enantiomeric form by treating 1 2 the compound of formula VII, or when one of Z and Z is NH(CH2)2CH3 an acid addition salt thereof, with a base such as (C2H5)3N or K2C03, whereby the compound of formula VII is treated together with an equivalent amount of an amine CH3(CH2)2-NH2 or en acid addition salt thereof when ZÚ and Zê are both X. The conversion is carried out in a solvent such as tetrahydrofuran, dioxan or acetonitrile, if necessary with simultaneous or subsequent heating of the mixture. h) A racemic mixture or a mixture partly enriched on one of the enantiomers of a compound of formula EMI10.1 may be subjected to enantiomeric separation to obtain the desired enantiomer of compound I. This may be done by methods known in the art. These methods include recrystallization of diastereomeric salts with pure enantiomers of acids such as tartaric acid, O,O'-dibenzoyltartaric acid, mandelic acid and camphor-lO-sulphonic acid. Free bases formed may subsequently be converted into their acid addition salts, and acid addition salts formed may subsequently be converted into the corresponding bases or other acid addition salts. Preparation of Starting Materials Starting materials for the methods of preparation described above may be obtained by several methods known in the art in particular in EP-Al-O 030 526, and/or described below. The starting material for method a) according to formula II above may be prepared by the following method: EMI11.1 A compound of formula VIII (racemic mixture) wherein Ra is an alkyl group having 1-5 carbon atoms or an acyl group having 2-E carbon atoms is resolved either by first conversion into the N-benzyl analogue IX followed by recrystallization of the (+)-tartaric acid salt and debenzylation by hydrogenation, or (when Ra is alkyl) by first conversion into the (-)-O-methylmandelic acid amide X followed by chromatographic separation of the two diastereomers and cleavage by KDBu in tetrahydrofuran with traces of water. The enantiomer with the desired absolute configuration XI is then alkylated by propionylation followed by LiAlH4 reduction to the formation of compound II having the appropriate absolute configuration at the asymmetric carbon(*) atom. The starting material for method b) may be prepared by the following method EMI12.1 In a compound of formula XII a group n-C3H7 may be introduced as previously described with previous (method A) or subsequent (method h) resolvation into the desirtd enantiomer whereupon the compound is treated with Cl2, H2S04 or HNO3 followed by reduction to the formation of an isomeric mixture XIII, from which the compound III wherein Z is Cl, S03H or NH2 is obtained by chromatographic separation. D) The starting materials for method d) may be prepared according to method A) above. A starting material for method e) may be prepared by the following method EMI13.1 A compound of formula XV may be formed by N-acyiation of a corresponding compound of formula XIV, preparable according to A above, with C2H5COCl in the presence of a base. The ether function of compound XV is then cleaved with BBr3 to the formation of a compound of formula V wherein M1 and M2 are both -CH2- and Pd is H. If desired the hydroxy group may then be acylated with an acyl chloride to form a compound of formula V wherein P is RÚCO, or alkylated with an allyl or benzyl halide to form a compound of formule V wherein Rd is allyl or benzyl. The starting material for method f) may be prepared by the following method. EMI14.1 A Grignard reaction with compounds XVI and XVII followed by elimination of the hydroxy-group produces compound VI. Starting materials for method g) may be prepared by enantiomeric separation of the corresponding racemate or a precursor thereof. Pharmaceutical preparations Pharmaceutical preparations of the compounds of the invention constitute a further aspect of the invention. For such preparations reference is made to pages 23 to 25 of EP-Al 003052B. In therapeutical treatment the suitable daily doses of the compounds of the invention are 200-10000 mg for oral application, preferentially 1000-6000 mg, and 1-1000 mg for parenteral application, preferentially 50-500 mg. Working examples The following examples will further illustrate the invention. Temperatures are in C. Preparation of intermediates Example I1. (+)-3-(3-Methoxyphenyl)piperidine hydrochloride (Method A). (+)-Dibenzoyl-D-tartaric acid (28.2 g, 0.075 mol) in hot methanol (350 ml) was added to N-benzyl-3-(3-methoxyphenyl)piperidine (21.1 g, 0.075 mcl) in hot methanol ( 100 ml). After two days the salt that separated was recrystallized three times from methanol. The collected salt (8.3 g) was treated with 1M NaOH (250 Tlj and the free amine was extracted with ether (3x150 ml). The combined ether layers were dried (K2C03) and the solvent evaporated. The residual amine was then passed through a short alumina column with ether as eluant and then converted to the hydrochloride. One recrystallization from methanol-ether gave (-)-N-benzyl -3-(3-methoxyphenyl)-piperidine hydrochloride (3.8 g), m.p. 164-165 C ; [&alpha;]D22-43.1 (C 2.1, CH3OH). (-)-N-benzyl-3-(3-methoxyphenyl)piperidine hydrochloride (3.B , 0.012C mcl) was dissolved in ethanol (BO ml), 10 o Pd/C was adce and the mixture was hydrogenated at room temperature and atmosphEric pressure (28 h). The catalyst was removed (Celite) by filtration, the solvent was evaporated off and the crystalline residue was recrystallized from methanol-ether giving the desired (+)-3-(3-methoxv- phenyl)-piperidine hydrochloride (2.54 g, 30 % total yield of the maximal theoretical) m.p. 175.5-177 C ; [&alpha;]D22 + 10.1 (C 2.1, CH3OH). Exam-le 12. (+)-3-(3-Methoxyphenyl)piperidine hydrochloride (Method A). R-(-)-a-Methoxyphenylacetic acid (11.0 g, 0.066 mol) and SOCl2 (85 ml) was mixed under ice-cooling and the mixture was stirred at 200 for 2 h. Excess of SOCl2 was evaporated off (at 200! and the residual acid chloride oil was dissolved in CH2Cl2. The solution was added at 200 to a stirred mixture of 3-(3-methoxyphenyl)piperidine hydrochloride (15.1 g, 0.066 mol), CH2Cl2(280 ml) and 2.5 % aqueous NaOH (560 ml). After 10 min. stirring the phases were separated and the organic phase was washed once with water and dried (Na2S04). Filtration and evaporation of the solvent gave l-(R-a-methoxyphenylacetyl)-3-(3-methoxyphenyl)piperidine as a crude oil (21.8 g). The crude oil of 1-(R-&alpha;-methoxyphenylacetyl)-3-(3-methoxy- phenyl)-piperidine (21.8 g) was chromatographed on a SiO column (600 g Si02) with light petroleum-ether (starting with 50:50 mixture and successive increasing the ether content to 100 %) as eluant. The fractions containing that one of the two diastereomers, which is eluated first, in nearly pure form were combined and the solvent evaporated off giving the desired diastereomeric amide as an oil (7.7 g, 0.023 mmol) (containing 0.5 % of the other diastereomer according to HPLC). This was dissolved in dry tetrahydrofuran (400 ml) and potassium-tert-butoxide (16.1 g, 0.144 mol) and water (1.33 g, 0.074 mol) was added under stirring at room temperature. The mixture was stirred at this temperaturE over night and then the mixtire was partitioned between Ether and water. After drying (Na2S04) of the organic phase excess of HC1-saturated E,hanol was added and the solvent was evaporated off. The residue was redissolved twice in absolute ethanol and the so vent evaporated, giving a crystalline residue. RecryE allization from ethanol ether gave the desired (+)-3-(3-methXxyphenyl)piperidine hydrochloride (4,0 g, 53 Ó total yiE:d of the maximal theo retical), m.p. 175.5-l770C; [a]O = +10.10 (C 2.1, CH30H). Example 13. (- ) -3- (3-Methoxyphenyl) -N-n-propylpiperidine hydrochloride (Method A, E and e) (+)-3-(3-Methoxyphenyl)piperidine hydrochloride (1.5 g, 0.0066 mol) was treated with 2 N NaOH (50 ml) and the free amine was extracted with ether. After drying (K2C03), filtering and evaporation the residual free amine oil (1.2 g) was dissolved in dry ether (50 ml) and the triethylamine (1.4 ml, 0.0010 mol) was added. Then propionyl chloride (0.87 ml, 0.0010 mol) dissolved in dry ether (5 ml) was slowly added at 0 under stirring, and the mixture was stirred at room temperature for 30 min. The precipitate was filtered off and the solvent was evaporated giving an oily residue. This residue was dissolved in dry tetrahydrofuran (50 ml) and added to a suspension of LiAlH4 (0.75 g, 0.0020 mol) in dry tetrahydrofuran (75 ml) under N2. After refluxing for 4 h. the mixture was hydrolysed, the precipitate was filtered off and the solvent was evaporated. The residue was dissolved in ether and passed through an alumina column with ether as eluant. Addition of HCl-saturated ethanol, evaporation of the solvent and recrystallization gave (-)-3-(methoxyphenyl)-N-n-propylpiperidine hydrochloride (1.45 g, 83 %), 200,5-202 C; [o(J02-6.7(C 2.1, CH30H). Example 14. (-)-3-(3-methoxyphenyl)-N-n-propyl piperidine hydrochloride (Method A and d). NaOH4 (0.61 g, 0.016 mol) was added portionwise under stirring to a solution of propionic acid (3.8g, 0.051 mol) in dry benzene (15 ml). The temperature was kept below 150 C for 2 h and then (+)-3-(3-methoxyphenyl)-piperidine (0.61 g, 0.0032 mol) dissolved in dry benzene (10 ml) was added and the mixture was refluxed for 3 h. The reaction mixture was allowed to reach room temperature and was then extracted with 2.5 M NaOH (20 ml). The aqueous phase was extracted with benzene, all the benzene phases mixed, dried (Na2S04) and the solvent evaporated giving an oily residue. The product was precipitated as hydrochloride and recrystallized from methanol/ether, yielding the pure product (0.60 g, 73 %), mp. 200-2020C. Preparation of end compounds Example El. (-)-3-(3-Hydroxyphenyl)-N-n-propylpiperidine hydrochloride (Method a). (-)-(3-Methoxyphenyl)-N-n-propylpiperidine hydrochloride (1.20 g, 0.0044 mol) in 48 % aqueous HBr was heated at 1200 for 4 h under N2. The volatiles were removed in vacuo and the residue was recrystallized from methanol-ether giving (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine hydrobromide (1.10 g) mp. 166-1670C; [a]22-5 . 8(C 2.0, CH30H). The hydro 0 bromide was alkalinized with saturated NaHC03 (25 ml) and the mixture was extracted with ether (4x20 ml). The combined ether layers were dried (Na2SO4), filtered and HCl-saturated ether was added giving a precipitate which was recrystallized giving (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine hydro 22 chloride (0.84 g, 75 %), mp. 187-188 C; [a)0 - 7.1 (C 2.2, CH30H) Example E2. (-)-3-(3-Hydroxyphenyl)-N-n-propylpiperidine hydrochloride (Method a). (-)-3-(3-Methoxyphenyl)-N-n-propylpiperidine (1.50 g, 0.0064 mol) was dissolved in CH2C12 (25 ml) and cooled to -78 . BBr3 (3.0 ml, 0.031 mol) was added under stirring. The cooling medium was removed and the mixture was allowed to reach room temperature. Alkalinization with excess 10 % Na2C03, extraction with CH2C12, drying (Na2SO4) and evapo ration of the solvent gave a yellow oil (1.5 g). The oil was dissolved in abs. ethanol and excess of HCl-saturated ethanol was added. Evaporation to dryness followed by recrystallization from ether-ethanol gave (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine hydrochloride [1.05 g, 64 %), mp. 187-188 C. Example E3. (-)N-n-Propyl-3-[3-(4-pivaloyloxybenzoyloxy) -phenyl]piperidine hydrochloride (Method c). (-)N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrochloride (0.400 g, 1.56 mmol) was suspended in dry dichloromethane (4 ml). Pivaloyloxybenzoylchloride (0.413 g, 1.72 mmol) was dissolved in a mixture of dichloromethane (4 ml) and pyridine (0.136 g, 1.72 mmol). The solution was added to the suspension and the mixture was refluxed for 20 hours. The clear solution was cooled, washed with aqueous NaHCO3 and dried with Na2SO4. After evaporation the residual oil was dissolved in ethanol, one enuivai ent HCl-saturated ethanol was added and the product precipitated by adding ether. Filtering and drying yielded 360 mg (50 %) of the pure desired hydrochloride. Mp. 226-2290C [&alpha;]Dê (C = 1.5, MeOH) (-)9.05c. Example E4. (-)N-n-Propyl-3-(3-allyloxyphenyl)piperidine hydrochloride (Method c). (-)N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrochloride (0.255 , 1 mmcl) and tetrabutylammonium hydrogen sulphate (0.340 g 1 mmol) were suspended in dichloromethane (2 ml! and allylbromide (0.:3 , 1.1 mmol). 2-M NaOH (2 mi) was added during two minutes and the mixture was stirred at room temperature for half an hour. The layers were separated and the organic layer was dried over Na2SO4. After removal of the solvent by distillation, the residual oil was dissolved in ether (50 ml). A theoretical quantity of tetrabutylammonium iodios was precipitated. The precipitate was filtered off and to the filtrate was added one equivalent HCl-saturated ether. White crystals of the desired compound was obtained. The crystals were filtered, washed on the filters with ether and dried. Yield 190 mg (65 %). Mp. 136-138 C [&alpha;]D20 (C = 1.5 MeOH) (-)7.6 . 0 Example E5. (-)-N-n-Propyl-3-(3-hydroxyphenyl)piperidine hydrochloride (Method b) To a solution of the appropriate enantiomeric form of N-npropyl-3-(3-aminophenyl)piperidine (0.27 g, 0.0013 mol) in 6M H2S04 (1 ml) NaN02 (0.077 g, 0.0011 mol) dissolved in water (0.2 ml) was added dropwise at 5 0C and then the mixture was stirred at 50C for 1 h. The resulting mixture was added dropwise to refluxin 10 % H2S04 (1.5 ml) and the reflux was continued for 5 min. Cooling, alkalising (Na2C03), extraction with ether, drying and evaporation of the organic phase gave the desired product as a free base. Conversion to the hydrochloride followed by recrystallization gave 0.059 g (20 %) of (-)-N-n-propyl-3-(3-hydroxyphenyl)- piperidine hydrochloride, m.p. 176-177 0C. Example E6. (-)-N-n-Propyl-3-(3-allyloxyphenyl)piperioine hydrochloride (Method e) A solution of the appropriate enantiomeric form of N-n- propionyl-3-(3-allyloxyphenyl)piperidine (0.04 g, 0.16 mmol) in dried ether (5 ml) was dropped to a suspension of LiAlH4 (0.04 g) in dried ether under nitrogen and stirring, and the mixture was refluxed for 30 min. H20 (0.0 ml), 15 % NaOH (0.04 ml) and H20 (0.2 ml) were adoed and the precipitated crystals were filtered off and washed with Ether. The solution was dried with Na2SO4, Evaporation to drness gave an oily residue which was dissolved in ether. Addition of HCl-saturated ether resulted in precipitatisn of white crystals. The crystals were centrifugates anc treated with light pietrolurn, centrifugated and dried Yield 0.02 g of the end compound having physical properties in accordance with Example E4. Example E7. (-)-3-(3-Decanoyloxyphenyl)-1-propylpiperidine hydrochloride (-)-3-(3-hydroxyphenyl)-1-propylpiperidine hydrochloride (1.5 g, 5.86 mmol) was suspended in dry dichloromethane (15 ml). Decanoylchloride (1.2 g, 6.29 mmol) was dissolved in a mixture of dichloromethane (15 ml) and pyridine (0.5 , 6.32 mmol). The solution was added to the suspension and the mixture was refluxed for 20 hours. The clear solution was cooled, washed with aqueous NaHCO3 and dried with Na2SO4. After evaporation the residual oil was dissolved in ether and precipitated as hydrochloride salt with one equivalent HC1 in ether. The salt was recrystallized twice from aceton. Yield : 0.7 g (30%). M.p. 142-144 C. [&alpha;]D20 (C=1.8, MeOH) = = - 5.6 . MS(70 eV): m/z 373 (5%), 344 (100%), 190 (7%). Example E8. (1)-3-(3-Phenylcarbamoyloxyphenyl)-1-propyl piperidine The title compound was prepared by esterification of (-)-3 -(3-hydroxyphenyl)-1-propylpiperidine. [&alpha;] - 8.0 . M.p. (HCl) 194-195 C. The following examples illustrate how the compounds of the present invention may be included into pharmaceutical preparations. Example P1. Preparation of soft gelatine capsules. 500 g of active substance are mixed with 500 g of corn oil, whereupon the mixture is filled in soft gelatine capsules, each capsule containing 100 mg of the mixture (i.e. 50 mg of active substance). Example P2. Preparation of tablets. 0.5 kg of.active substance are mixed with 0.2 kg of silicic acid of the trade mark Aerosil. 0.45 kg of potato starch and 0.5 kg of lactose are mixed therewith and the mixture is moistened with a starch paste prepared from 50 g of potato starch and distilled water, whereupon the mixture is granulated through a sieve. The granulate is dried and sieved, whereupon 20 g of magnesium stearate are mixed into it. Finally the mixture is pressed into tablets each weighing 172 mg. Example P3. Preparation of a syrup. 100 g of active substance are dissolved in 300 g of 95 % Ethanol, whereupon 300 g of glycerol, aroma and colouring agents (q.s.) and 1000 ml of water are mixed therein. A syrup is obtained. Example P4. Preparation of an injection solution. Active substance (hydrochloride) (1 g), sooiumchloride t ) and ascorbic acid (0.1 g) are dissolved in sufficient amount of distilled water to give 100 ml of solution. This solution, which contains 10 mg of active substance per ml, is used in filling ampoules, which are sterilized by heating at 1200C for 20 minutes. Pharmacological evaluation Among the compounds described in EP-A1-0030526, the compound N-n-propyl-3- (3-hydroxyphenyl) -piperidine, hereinafter referred to as 3-PPP, was presented in greatest detail. It was shown that 3-PPP and its congeners are capable of inhibiting the physiological activity of central dopaminergic .neurons by activating a subpopulation of dopaminergic receptors presumably located on the dopaminergic neuron itself, i.e. presynaptic receptors or autoreceptors. The effect proved to be selective, in that no concomitant activation of the classical postsynaptic dopaminergic receptors could be detected. These observations were made on racemic mixtures. The two enantiomers of 3-PPP have now been tested separately. Surprisingly the levorotatory enantiomer, (-)-3-PPP, not only was capable of activating the presynaptic dopaminergic receptors (autoreceptors) but concomitantly reduced the sensitivity of the postsynaptic dopaminergic receptors to dopaminergic agonists. By the combined activation of presynaptic receptors and partial blockade of postsynaptic receptors thE inhibitory action on dopaminergic neurotransmission will be stronger than by either effect alone. In other words, the levorotatory enantiomer is superior to the racemic mixture as an inhibitor of dopaminergic neurotransmission by acting both presynaptically as an agonist and postsynaptically as an antagonist. The reason for the difference in pharmacological profile between the levorotatory enantiomer and the racemic mixture has been clarified: the dextrorotatory enantiomer was found to be a dopaminergic receptor agonist by activating both the presynaptic and the postsynaptic receptors. Thus, the two enantiomers antagonize each other on the postsynaptic dopaminergic receptor. As a consequence, the racemic mixture will be active only'own the presynaptic receptor (autoreceptor). The pharmacological tests demonstrating the properties of the two enantiomers of 3-PPP are presented below. 1. Evidence for presynaptic dopaminergic receptor (autoreceptor) agonist activity of both enantiomers of 3-PPP. Both enantiomers of 3-PPP cause a dose-dependent decrease in spontaneous exploratory motor activity of rats. In male Sprague-Dawley rats injected subcutaneously with either enantiomer of 3-PPP and 5 min later placed in Motron boxes for measurement of motor activity the number of counts during the first 30 min was recorded at doses between 0.053 and 64 mg/kg. Both enantiomers cause a.decrease of locomotor activity to 30-40 a of control. However, the (+) -enantiomer causes a decrease only after doses between 0.25 and 4 mg/kg s.c. After 8 mg/kg there is no effect, and after 64 mg/kg there is a significant increase to more than 200 t of control. In contrast, the (-)-enantiomer causes a decrease after all these doses, with no reversal of the effect after larger doses. In the dopaminergic neurotransmission L-tyrosine is hydroxy lated to L-dopa, which is decarboxylated to the transmitter substance dopamine. After inhibition of the aromatic amino acid decarboxylase by means of 3-hydroxybenzylhydrazine HC1 (NSD 1015) both enantiomers of 3-PPP cause a dose-dependent decrease at doses between 0.053 and 64 mg/kg in the formation of dopa in dopamine-rich brain regions of rats pretreated with reserpine or gamma-butyrolactone (GBL). Pretreatment with GBL and probably also reserpine precludes thE influence of postsynaptic dopamine receptors on dopa formation and thus provides the opportunity to study the .inflsnce of presynaptic autoreceptors separately (cf. Hjorth et al., Life Sci. Vol 28, pp. 1225-1238, 1981). The effect of both enantiomers on dopa formation is blocked by the dopamine-receptor antagonist haloperidol. These findings provide strong evidence for stimulation of presynaptic dopamine receptors (autoreceptors). In rats not pretreated with GBL or reserpine the two enan tiomers act differently on dopa formation at doses between 0.053 and 64 mg/kg: the (+)-form causes a decrease, whereas the (-)-form causes an increase in dopa formation in the striatum and no change in the limbic region. These changes in dopa formation are matched by corresponding changes in the levels of the dopamine metabolites 3,4-dihydroxyphenyl acetic acid and homovanillic acid. This differential action of.the two enantiomers will be commented below. 2. Evidence for postsynaptic dopaminergic receptor agonist activity of (-)-3-PPP. In reserpine-treated rats t+)-3-PPP causes a marked stimula tion of locomotor activity at doses between 0.25 and 64 mg/kc The effect is blocked by haloperidol. These findings provide strong evidence for a stimulating action of (+)-3-PPP on postsynaptic dopaminergic receptors. The (-)-form causes only a very weak stimulation of motor activity in reserpine- -pretreated rats, indicating virtual absence of stimulating action on postsynaptic dopaminergic receptors. 3. Evidence for postsynaptic dopaminergic receptor antagonist activity of (-)-3-PPP. The locomotor stimulating action of the dopamine receptor agonist apomorphine is antagonized by (-)-3-PPP. This effect is clearcut after a dose of 8 mg/kg s.c. of (-)-3-PPP. but not after 2 mg/kg. Thus the postsynaptic receptor antagonist activity requires 2 large dose than the presynaptic receptor agonist activity, which is evident after doses,down to 0.25 mg/kg. The abovementioned ability of (-)-3-PPP to stimulate dopa formation and to raise dopamine-metabolite levels in rat striatum provides further evidence for blockade of postsynaptic dopamine receptors, resulting in feedback-mediated stimulation of dopaminergic neurons. Further, (-)-3-PPP and racemic 3-PPP have been compared regarding antagonism of apomorphine-induced locomotor stimulation. Either form of 3-PPP was injected subcutaneously in a dose of a mg/kg 20 min and apomorphine in a dose of 1 mg/kg subcutaneously 5 min before placing the rats in the Motron for 30 min. Shown are the counts per 30 min, means + s.e.m. and number of experiments (n). As demonstrated in Table 1 (-)-3-PPP antagonized said stimulation while the racemate did not. The (-)-form of 3-PPP has a striking antagonistic action against the locomotor stimulating activity of (+)-amphetamine. This effect is probably the result of the simul tenuous stimulation of presynaptic dopaminergic rEceptors and partial blockade of postsynaptic dopaminergic receptors. All the- major antipsychotic agents in current use are potent amphetamine antagonists, and such activity is considered to be predictive of antipsychotic action. Conclusion ThE compounds under consideration are centrally acting selective dopamine autoreceptor simulating agents, and thus of great clinical interest in the treatment of psychotic disorders such as schizophrenia and a number of other disease states such as tardive dyskinesia, Huntington's chorea, alcoholism and drug abuse, said psychotic disorders and other-disease states possibly being associated with a pathological increase in central dopamine transmission. Extrapyramidal motor disturbances of choreatic type are avoided with the compounds of the invention. As compared with the known racemates, the pure enantiomers of the invention have a better efficacy in the suggested treatment in having an unexpected postsynaptic dopamine antagonist activity in addition the presynaptic dopamine agonist activity. Table 1 Antagonism of apomorphine-induced locomotor stimulation. Vehicle (control) 174 t 15 (10) Apomorphine 513 + 35 (10) a) (-)-3-PPP+Apomorphine 276 + 50 (5) b) (-)-3-PPPiApomorphine 443 - 26 (5) c) a) differs from control, p 40.001 b) differs from apomorphine, p 40.005 c) not significantly different from apomorphine; differs from control, p 40.001 Best mode of carrying out the invention The compound (-)-N-n-propyl-3-(3-hydroxyphenyl)piperidine and its salts, processes for preparing said compound and methods of employing said compound in therapy represent the best moce of carrying out the invention.

Claims: CLAIMS 1. A pure enantiomer of a compound of the formula EMI28.1 wherein Y is OH, RÚCOO, RêR NCOO- or R4O whereby RÚ is an aliphatic hydrocarbon residue having 1-17 carbon atoms, a phenyl, 2,6-aimethylphenyl or 3- or 4-hydroxyphenyl group or a 3- or 4-alkanoyloxyphenyl group with the formula EMI28.2 wherein R5 is an alkyl group having 1-6 carbon atoms, or RÚ is a group EMI28.3 wherein R6 is hydrogen, an alkyl group having 1 to 5 carbon atoms or a phenyl group, R7 is hydrogen, en alkyl group having 1 to 5 carbon atoms or an acyl group and R8 is hydrogen or an alkyl group having 1 to 5 carbon atoms, R is hydrogen, an alkyl group having 1-5 carbon atoms, a phenEthyl, benzyl or phenyl group which may be mono- or oisubstituted in the aromatic part with a methyl, methoxy, 3 hyoroxy, nitro or cyano group or a halogen, P is H, an alkyl group having 1 to 5 carbon atoms or a phenyl group or Rê and R together with the nitrogen atom form a 5, 6 or 7 mem@ereo ring that may contain 1 to 3 double bonds arid/or ) or 2 further heteroatoms selected from N, 0 and S, and P is an allyltor benzyl group, said enantiomer having the same absolute configuration at the asymmetric carbon atom (+) as that of the (-)-enentiomer of the compound of formula I wherein Y is OH, as the base or a pharmaceutically acceptable acid addition salt thereof. 2. A pure enantiomer according to claim 1 wherein Y is OH, R1COO, R2R3NCCO- or R O whereby R1 is an alkyl group having 1-5 carbon atoms or a phenyl, 2,6-dimethylphenyl or 3- or 4-hydroxyphenyl group or a 3- or 4-alkanoyloxyphenyl group, @ê is an alkyl group having 1-S carbon atoms, a phenethyl, benzyl or phenyl group, R is H or an alkyl group having 1-5 carbon atoms, and R4 is an allyl or benzyl group, as the base or a pharmaceutically acceptable acid addition salt thereof. 3. A pure enantiomer according to claim 1 or 2 characterized in that Y is OH, P1COO- or R2R NCOO-, as the base or a pharmaceutically acceptable acid addition salt thereof. 4. The compound according to claim 1 (-)-N-n-propyl-3-(3 -hydroxyphenyl)piperidine, as the base or a pharmaceutically acceptable acid addition salt thereof. 5. A process for preparation of a pure enantiomer of a compound of the formula EMI29.1 wherein Y is OH, Slcoo, R2R3NCOU- or R40 whereby R1 is an aliphatic hydrocarbon residue having 1-17 carbon atoms, a phenyl, 2,6-dimethylphenyl or 3- or 4-hydroxyphenyl group or a 3- or 4-alkanoyloxyphenyl group it the formula EMI30.1 5 wherein R is an alkyl group having 1-6 carbon atoms, or R1 is a group EMI30.2 wherein R6 is hydrogen, an alkyl group having 1 to 5 carbon atoms or a phenyl group, R7 is hydrogen, an alkyl group having 1 to 5 carbon atoms or an acyl group and R8 is hydrogen or an alkyl group having 1 to 5 carbon atoms, Rê is hydrogen, an alkyl group having 1-5 carbon atoms, a phenethyl, benzyl or phenyl group which may be mono- or disubstituted in the aromatic part with a methyl, methoxy, hydroxy, nitro or cyano group or a halogen, R is H, an alkyl group having 1 to 5 carbon atoms or a phenyl group or Rê and R together with the nitrogen atom form a 5, 6 or 7 membered ring that may contain 1 to 3 double bonds and/or 1 or 2 further heteroatoms selected from N, O and S, and R4 is an allyl or benzyl group, said enantiomer having the same absolute configuration at the asymmetric carbon atom ) as that of the (-)-enantiomer of the compound of formula I wherein Y is OH, as the base or a pharmaceutically acceptable acid addition salt thereof, characterized in that a) a pure enantiomer of an ether or ester of the formula EMI30.3 having the appropriate absolute configuration at the (*) a asymmetric carbon atom , wherein P represents a hydrocarbon or acyl residue, is cleaved to form the compound of formula I wherein y is a hydroxy group, in (-)-enantio- meric form, or b) n a pure enantiomer of a compound of the formula EMI31.1 having the appropriate absolute configuration at the asymmetric carbon atom ), , wherein Z represents SD3H, C1 or NH7, a hydroxy group is substituted for the group Z to the formation of a compound of formula I wherein Y represents a hydroxy group and in (-)-enantiomeric form, or c) the (-)-enantiomeric form of the compound of formula I EMI31.2 wherein Y is OH is converted into a compound of the same formula and the same absolute configuration at the asymmE- tric carbon atom ) wherein Y is RlCOO, R2R3NCOO or R4O by treating the firstmentioned compound with an appropriate carboxylic acid halide RÚCOx or anhydride (RÚCO)2O or with an appropriate carbamoyl halide RêR NCOX or isocyanate RêNCO in the presence of a base such as triethylamine or pyridine or an acid such as H2SO4 or CF3COOH or with an appropriate allyl or benzyl halide R4X in the presence of a base such as triethylamine, pyridine or potassium tbutoxìde whereby X represents a halogen, or d) a pure enantiomer of a compound of the formula EMI32.1 having the appropriate absolute configuration is converted into a compound of formula I having the desired (*) absolute configuration at the asymmetric carbon atom by alkylation of the nitrogen atom with an appropriate alkylating agent, or a a pure enantiomer of a carbonyl compound of the formula EMI32.2 having the appropriate absolute configuration, wherein p; ;l and N2 are the same or different and each represents -Ch- or EMI32.3 and the dashed lines represent bonds, one of which, when adjacent to a group EMI32.4 may be open and replaced by hydrogen atoms, and M is EMI32.5 when MÚ and M2 are both -CH2-, and in other cases M3 is n-C3H7, and Pd is H or P1 CO, is converted into a compound of the formula I having thE desired absolute configuration at the asymmetric carbon atom ) and wherein Y is a hydroxy, allyl- oxy or benzyloxy group by reduction of the amide or imide function, and the ester function R1COO if present, or f) a compound of the formula EMI33.1 with either a C2-C3 or a C3-C4 double bond and wherein Re is H or benzyl is converted by reduction into a compound of formula I wherein Y is OH and having the desired (-)enantiomeric form, or g) a pure enantiomer of a compound according to the formula EMI33.2 having the appropriate absolute configuration, wherein one 1 2 of the group 2 and 2 is a leaving group and the other is NH(CH2)2CH3 or 21 and Zê are both leaving groups, is converted to a compound of formula I wherein Y is OH and having the desired t-)-enantiomeric form by treating the compound of formula VII, or when one of zl and Zê is NH(CH2)2CH3 an dcid addition salt thercof, with a base such as tC2H5)3N or K2C03. whereby the compound of formula VII is treated together with an equivalent amount of an amine CH3(CH2)2-NH2 or an acid addition salt thereof when ZÚ and Zê are both leaving groups, or h) a racemic mixture our a mixture partly enriched on one of the enantiomers of a compound of formula EMI34.1 is subjected to enantiomeric separation to obtain the desired enantiomer of compound I; whereupon optionally a base obtained is converted to a pharmaceutically acceptable acid addition salt or a salt obtained is converted to the base or to a different, pharmaceutically acceptable acid addition salt. 6. A process according to claim 6, characterized in preparing a compound according to one of claims 2 to 4. 7. A pharmaceutical preparation comprising as an active ingredient the pure enantiomeric form of a compound according to one or more of claims 1 to 4, in conjunction with a pharmaceutically acceptable carrier. CLAIMS FOR AUSTRIA 1. A process for preparation of a pure enantiomer of a compound of the formula EMI35.1 wherein Y is OH, R1COO, RêRêNCOO- or R40 whereby R1 is an aliphatic hydrocarbon residue having 1-17 carbon atoms, a phenyl, 2,6-dimethylphenyl or 3- or 4-hydroxyphenyl group or a 3- or 4-alkanoyloxyphenyl group with the formula EMI35.2 wherein R5 is an alkyl group having 1-6 carbon atoms, or R1 is a group EMI35.3 wherein R6 is hydrogen, an alkyl group having 1 to 5 carbon atoms or a phenyl group, R7 is hydrogen, an alkyl group having 1 to 5 carbon atoms or an acyl group and R8 is hydrogen or an alkyl group having 1 to 5 carbon atoms, R2 is hydrogen, an alkyl group having 1-5 carbon atoms, a phenethyl, benzyl or phenyl group which may be mono- or disubstituted in the aromatic part with a methyl, methoxy, hydroxy, nitro or cyano group or a halogen, R is H, an alkyl group having 1 to 5 carbon atoms or a phenyl group or R2 and R3 together with the nitrogen atom form a 5, 6 or 7 membered ring that may contain 1 to 3 double bonds and/or 1 or 2 further heteroatoms selected from N, 0 and S, and P is an allyl or benzyl group, said enantiomer having the same absolute configuration at the asymmetric carbon atom *) as that of the (-)-enantiomer of the compound of formula I wherein Y is OH, as the base or a pharmaceutically acceptable acid addition salt thereof, characterized in that a) a pure enantiomer of an ether or ester of the formula EMI36.1 having the appropriate absolute configuration at the (*) wherein Ra asymmetric carbon atom , wherein P represents a hydrocarbon or acyl residue, is cleaved to form the compound of formula I wherein Y is a hydroxy group, in (-)-enantiomeric form, or b) dn a pure enantiomer of a compound of the formula EMI36.2 having the appropriate absolute configuration at the asymmetric carbon a tom whel'± in Z represents S03H, C1 or NH2, hydroxy group is substituted for the group 2 to the formation of E, compound of formula I wherein Y represents a hydroxy group and in (-)-enantiomeric form, or c) the (-)-enantiomeric form of the compound of formula I EMI37.1 wherein Y is OH is converted into a compound of the same formula and the same absolute configuration at the asymmetric carbon atom ) wherein Y is R1COO, R2R3NCOo or R4O by treating the firstmentioned compound with an appropriate carboxylic acid halide RÚCOX or anhydride (RÚCO)2O or with 23 an appropriate carbamoyl halide RêR@NCOX or isocyanate RêNCO in the presence of a base such as triethylamine or pyridine or an acid such as H2SO4 or CF3COOH or with an 4 appropriate allyl or benzyl halide R X in the presence of a base such as triethylamine, pyridine or potassium tbutoxide whereby X represents a halogen, or d) a pure enantiomer of 2 compound of the formula EMI37.2 having the appropriate absolute configuration is converted into a compound of formula I having the desired absolute configuration at the asymmetric carbon atom(*) by alkylation of the nitrogen atom with an appropriate alkylating agent, or e) a pere enantiomer of a carbonyl compound of the formula EMI38.1 having the appropriate absolute configuration, wherein MÚ and Mê are the same or different and each repressents -CH2- or EMI38.2 and the dashed lines represent bonds, ore of which, when adjacent to a group EMI38.3 may be open and replaced by hydrogen atoms, and M5 is EMI38.4 when M1 and Mê are both -CH2 -, and in other cases M3 is n-C3H7, and is is H or RlCO, is converted into a compound of the formula I having the desired absolute configuration at the asymmetric carbon atom (*) and wherein Y is a hydroxy, allyloxy or benzyloxy group by reduction of the amide or imide function, and tne ester function R1COO if present, or a ) a compound of the formula EMI38.5 with either a C2-C3 or a C3-C4 double bond and wherein Re is @ or benzyl is converted by reduction into a compound of formula I wherein Y is OH and having the desired (-)- nantiomeric form, or g) a pure enantiomer of a compound according to the formula EMI39.1 having the appropriate absolute configuration, wherein one of the group zl and Z is a leaving group and the other is NH(CH2)2CH3 or Z and Z are both leaving groups, is converted to a compound of formula I wherein Y is OH and having the desired (-)-enantiomeric form by treating the compound of formula VII, or when one of Z and z2 is NH(CH2)2CH3 an acid adoition salt thereof, with a base such as (C2H5)3N or K2C03, whereby the compound of formula VII is treated together -with an equivalent amount of an amine CH3(CH2)2-NH2 or an acid addition salt thereof when Z and z2 are both leaving groups, or h) a racemic mixture or a mixture partly enriched on one of the enantiomers of a compound of formula EMI39.2 is subjected to enantiomeric separation to obtain the desired enantiomer of compound I; whereupon optionally a base obtained is converted to a pharmaceutically acceptable acid addition salt or a salt obtained is converted to the base or to a different, pharmaceutically acceptable acid addition salt. 2. A process according to claim 1, characterized in preparing a pure enantiomertof a compound of formula I wherein Y is OH, R COO, RêR NCOO- or R4O whereby R1 is an alkyl group raving 1-5 carbon atoms or a phenyl, 2,6-dimethylphenyl or 3- or 4-hydroxyphenyl group or a 3- or 4-alkanoyloxyphenyl 2 group, R is an alkyl group having 1-5 carbon atoms, a 3 phenethyl, benzyl or phenyl group, P is H or an alkyl group naving 1-5 carbon atoms, and R is an allyl or benzyl group, as the base or a pharmaceutically acceptable acid addition salt thereof. 3. h process according to claim 1 or 2 characterized in preparing a pure enantiomer of a compound of formula I wherein Y is OH, RÚCOO- or R2R3NCOO-, as the base or a pharmaceutically acceptable acid addition salt thereof. 4. A process according to claim 1 characterized in preparing (-)-N-n-propyl-3-(-3-hydroxyphenyl)piperidine, as the base or a pharmaceutically acceptable acid addition salt thereof.

Inventors: ARVIDSSON, FOLKE LARS-ERIK, CARLSSON, PER ARVID EMIL, HACKSELL, ULI ALF, HJORTH, JOHN STEPHAN MIKAEL, JOHANSSON, ANETTE MARGARETA, LINDBERG, PER LENNART, NILSSON, JOHN LARS GUNNAR, SANCHEZ, DOMINGO, SVENSSON, KJELL ANDERS IVAN, WIKSTROEM, HAKAN VILHELM, Wikström, Hakan Vilhelm 
Applicants: CARLSSON, PER ARVID EMIL
Application year: 1983
Main classification: C07D211
IPC codes: A61K31, A61P25, C07D211