GB2040933A - Cis- and Trans-3-Aryloxy-4- Hydroxypyrrolidines and Derivatives Thereof - Google Patents

Abstract

Cis and trans-3-aryloxy-4- hydroxypyrrolidines and derivatives thereof having the formula: <IMAGE> wherein R<1> represents a hydrogen atom or a loweralkyl, benzyloxycarbonyl or N- loweralkylcarbamoyl group; R<2> represents a hydrogen atom or a loweralkyl, cycloalkyl, phenylalkyl, benzyloxycarbonyl, carbamoyl, N- loweralkylcarbamoyl, N,N- diloweralkylcarbamoyl or parafluorobenzoyl-lower-alkyl group; Ar represents a phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, 1- indenyl or 2-indenyl group; and pharmaceutically acceptable acid addition and quaternary salts thereof, variously have antidepressant, antihypertensive and antiarrythymic activity in animals and human beings.

Description

SPECIFICATION Cis and Trans-3-Aryloxy-4-Hydroxypyrrolidines and Derivatives Thereof The present invention relates to certain novel cis and trans isomers of 3-aryloxy-4hydroxypyrrolidines and derivatives thereof. Compositions prepared from these compounds are useful in treating depression, hypertension or heart arrythmias in animals.

The present invention provides novel cis and trans isomers of 3-aryloxy-4-hydroxypyrrolidines and derivatives thereof which have important pharmacological activity. The compounds of the invention are represented by the following formula:

H OyyO-Ar N2 Formula I R cis Qnd trans isomers wherein: R' represents a hydrogen atom, or a loweralkyl, benzoylcarbonyl, or N-loweralkylcarbamoyl group, R2 represents a hydrogen atom, or a loweralkyl, cycloalkyl, phenylalkyl, benzyloxycarbonyl, carbamoyl, N-loweralkyl-carbamoyl, N-di-loweralkylcarbamoyl or parafluorobenzoyl-loweralkyl group, Ar represents a phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, 1 -indenyl or 2-indenyl group, and the pharmaceutically acceptable acid addition and quaternary salts thereof. The compounds have cis or trans configuration.

The compounds of the present invention have anti-depressant, hypotensive and cardiovascular activity in animals.

Antidepressant activity was shown to be present by the procedure given by Englehardt, E. L. et al., J. Med. Chem. 11(2): 325 (1968) wherein the novel compounds of the present invention were administered to mice intraperitoneally and the effectiveness of the compounds in blocking the depressant effects which are induced in mice by intravenous administration of 2-oxo-3-isobutyl-9,1 0, dimethoxy-1 ,2,3,4,6,7-hexahydro- 1 bh-benzo[a]quinolizine (tetrabenazine) were determined.

Compounds of the invention for which pronounced antidepressant activity was observed have the formula:

HO 0-Ar 12 H Formuta Ia wherein: R2 represents a hydrogen atom or a loweralkyl or phenylalkyl group, and Ar represents a phenyl or substituted phenyl group.

Compounds preferred for their antidepressant activity have the formula:

x HO MOM n Formula Ib alkyl wherein: X represents a halogen atom and n is O to 2.

The action of certain compounds disclosed in the present invention in counteracting cardiac arrhythmia is demonstrated by the following antiarrythmia testing procedure. The procedure is carried out under barbiturate anesthesia using adult mongrel dogs of either sex weighing from 8 to 1 4 kg. A Grass Model 7 polygraph was used for recording femoral arterial blood pressure (Statham P23AC Transducer) and the electrocardiogram (Grass 7P4 Preamplifier). Ouabian was given intravenously in an initial dose of 40 y/kg in a second dose of 20 y/kg, given 30 minutes after the first dose, and in subsequent doses of 10 y/kg which were repeated at 1 5 minute intervals as required for producing cardiac arrhythmias that'persisted for at least 1 5 minutes. When arrhythmias were established, the test compounds were administered by infusion (Harvard Model 942 Infusion Pump) into a removal vein at a rate of 1 mg/kg/min. Concentrations of compounds were adjusted according to the weight of the dog to allow a volume infusion of 1 ml/min. Compounds that are considered to be active as antiarrhythmic agents cause reversion to sinus rhythm which is maintained for at least 60 minutes.

Compounds of the invention for which pronounced antiarrhythmic activity was observed have the formula:

HO yyOAr H2 Formuta Ic R wherein: R2 represents a hydrogen atom or a lower alkyl group, and Ar represents a 1 or 2-naphthyl or 4 or 5-indenyl group.

It is accordingly an object of the present invention to provide cis and trans-3-aryloxy-4hydroxypyrrolidines and derivatives thereof and methods of making the same, which have a high degree of antidepressant activity.

Another object is to provide cis and trans-3-aryloxy-4-hydroxypyrrolidines and derivatives thereof which have antiarrhythmic and antihypertensive activities in animals.

A still further object is to provide methods of using the cis and trans-3-aryloxy-4hydroxypyrrolidines as antidepressants, hypotensive agents and antiarrythmic agents in the treatment of living animals, especially mammalian subjects in need of treatment.

The present invention encompases the novel cis and trans isomers of 3-aryloxy-4hydroxypyrrolidines and derivatives thereof as set forth hereinabove in Formula I and the definitions therewith as compositions of matter and the utilisation of these novel compounds in living animals for their pharmacological effect as herein set forth.

The term "loweralkyl" as used in the specification and claims includes straight and branched chain groups of up to eight carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl isobutyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl and octyl.

The term "substituted phenyl" as used in the specification and claims includes phenyl groups substituted in one to 3 positions by one or more groups selected from halogen, O-loweralkyl, - -NHC(O)CH3,CF3, C(0)CH3, -CH2CH=CH2, alkyl, hydroxy, -OCH2 phenyl, and -C(0)NH2.

By "cycloalkyl" is meant cycloalkyl radicals having 1 to 9 carbon atoms and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Representative of phenylalkyl groups are benzyl (phenylmethyl), a-methylbenzyl, phenylethyl, phenylpropyl, and phenylbutyl.

The starting materials used in preparing the novel trans isomer compounds of Formula I are 1phenylalkyl-3, 4-epoxypyrrolidines such as 1 -benzyl-3,4-epoxypyrrolidine; 1-alkyl-3,4epoxypyrrolidines such as 1-ethyl-3, 4-epoxypyrrolidine; and 1-cycloalkyl-3,4-epoxy-pyrrolidines such as 1 -cyclohexyl-3,4-epoxypyrrolidine.

Preparatiom of these 1-substituted epoxypyrrolidines may be represented by the following equation:

X HO- " HCI R H2O H Aqueous or alcoholic base solution.

N H '[ wherein: R represents a loweralkyl, phenylalkyl or cycloalkyl group. Generally, the chlorination step is accomplished in 2 to 6 hours and the intermediate Ill need not be isolated. Crude epoxypyrrolidines may be obtained by solvent extraction and converted to crystalline salts such as oxalates. Pure free base of the epoxypyrrolidines may be obtained from the oxalate salt by partitioning between 5% aqueous sodium carbonate and methylene chloride and thereafter drying over anhydrous sodium sulphate and evaporating off the methylene chloride. The pyrrolines used in these starting preparations are prepared according to the procedure of U.S. Patent Specification No. 3,691,198 and the procedure for the preparation of 1-cyclohexyl-A3-pyrroline is given in Preparation 1.

Preparation of the epoxypyrrolidines used to prepare the trans isomers of Formula I are given in Preparations 2 to 4.

The starting material used in preparing the cis isomers of compounds of Formula I was cisbenzyl-3,4-pyrrolidinediol as given in Preparation 5. Cis-3,4-pyrrolidinediols were first prepared by A.

J. Hill et al., J. Amer. Chem. Soc. 76, 3548 (1954).

Synthesis of trans-isomer compounds of Formula I which are part of the present invention and which also serve as reactants for the preparation of other compounds of the invention was started by reacting aryloxy compounds with appropriately 1 -substituted-3,4-epoxypyrrolidines as exemplified by the following equation: Trans Isomers

t + ArOH h HOyyOAr heat h2 H 2 trans isomers H wherein: R2 represents a phenyl alkyl, alkyl or cycloalkyl group, and Ar is as defined hereinabove.

Synthesis of cis isomers which are part of the present invention and which serve as reactants for other compounds of the invention was started by reacting 1 -benzyl-3,4-pyrrolidinediol cis isomer with Ar-F compounds according to the following formula: Cis Isomers

HOg; ArF NaH HO OAr OMF N cis Ncis CH,C,H, CH2 isomers E6H wherein: Ar is as defined hereinabove.

In preparing compounds having further variations within Formula I, the following methods may be used for preparation of either trans or cis isomers.

(1) R2 = Hydrogen R1 = H or alkyl R1 oar H2 RloN/OAr M :H2 H 6H5

(2)1) alkyl OAr + OAr ]- oar CH3 CH, H3 265 CH2 1) at?0 2)H2:Pd/C, H5 H1O OAr CH3 (3) R1 alkyl OCH3 OAr OAr XOAr N CH3IN CH2 CH C6H5 C6H5 0 2 Ii 22 R2 (CH2)2 0 RO X XO-AR + (CH3)2NCH2-CH2-C U F HO 0-Ar H N C1H2CH2-C11F (5) R2 = o = C-0-CH2C6H5 HO I I OAr HO I I OAr k X + Benzylchloro X X N formate N O O= C-O-CH2C6H5 2 C6H5 5 11 C6H5CH3O CM OAR O= C-O-CH2C6H5 (6) Ar = phenol substituted with halide;

R2 = H 0 1 0 Xn N HBr X HnBr O=C-OCH2C6H5 HOMO N xn ii wherein: X represents halogen and n=1 or 2.

0 2 II (7) H = -C-NH2 HO 1 1 -Ar HO + + Nitrourea - IN H = NH2 (8) R2=-C-N(CH R2 = -C-N(CH3)2 (I \ 3/L HO OAr HO OAr J dimethyl N + carbamyt r N H chloride C=O OH N-(CH3)2 (9) R2= b (9) R=-C-N-alkyl HO 1 OAr HO j j OAr isocyanate cold, all cold H. NH CH3

0 0 2 (10) H1 - CH3NHC-O, H = -C-H(CH3)2 O J HO I I OAr CH7NHC + + methyt ambient OyȮAr isocyanate h(CH3)2 N (CH3)2

(11) R1=H; Ar = C6H5 sturting from Ar = C6H-hato

To obtain the free base of a compound prepared as a salt, the salt is partitioned.between methylene chloride and 5% sodium hydroxide (by weight aqueous). The methylene chloride layer is dried over sodium sulphate and concentrated to give the base as a residue.

The novel compounds of the present invention and the methods for their preparation are exemplified more fully by the following ilustrative preparations and examples, through the scope of the invention is, however, not limited thereto. As will be readily identifiable from a consideration of the examples and the foregoing outline, many of the compounds under the scope of Formula I may be also considered as intermediates in the synthesis of other compounds of Formula I.

Preparation 1 1 -Cyclohexyl-A3-pyrroline A solution of 5.1 9 kg (52.3 moles) of cyclohexylamine in 4.0 liters of benzene was heated to mild reflux (92"C) and then the heating discontinued. To the solution was added, dropwise, 1635 g (13.1 moles) of 1,4-dichlorobutene at a rate sufficient to maintain gentle reflux for 3 hours. Heating was continued and the reactants were heated at reflux temperature for 1 8 hours. The mixture was cooled to about 500C and filtered to remove the hydrochloride salt. Carbon dioxide was bubbled into the filtrate to precipitate excess amine carbonate salt which was removed by filtration. Solvent was removed from the filtrate by distillation under reduced pressure and the reddish fluid residue slightly contaminated with benzene weighed 1 506 g (76% yield).

Preparation 2 1 -Benzyl-3,4-Epoxypyrrolidine Oxalate A mixture of 31.8 g (0.20 mole) of N-benzyl-A3-pyrrnline 25 ml of concentrated hydrochloric acid and 300 ml of water was treated with a stream of chlorine gas for 2 hours. The solution was filtered and the filtrate was made basic with 20% sodium hydroxide (by weight aqueous). The basic solution was extracted with three 1 50 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulphate and evaporated to give 48.5 g of crude chlorohydrin as a dark oil. This oil was stirred with 200 ml of 20% sodium hydroxide for 0.5 hr, 700 ml of water was added, and the base was extracted with four 100 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulphate and concentrated to yield 34.9 g (99%) of crude epoxide as a dark oil. The oxalate salt was prepared in 81% yield.

Recrystallisation from 95% ethanol gave the salt as off-white needles, mp 1 48-90C (d). (d) means the solids method with decomposition.

Analysis: Calculated for C13H15NO5: C, 58.86; H, 5.70; N, 5.28 Found: C, 58.55; H, 5.68; N, 5.25 Preparation 3 1 -Ethyl-3,4-Epoxy-Pyrrolidine Oxalate A mixture of 61 g (0.63 mole) of 1 -ethyl-A3-pyrroline, 50 ml of concentrated aqueous hydrochloric acid and 600 ml of water was treated with chlorine gas for 2.5 hours. The mixture was filtered through cotton and the filtrate was washed with t,vo 100 ml portions of methylene chloride.

The aqueous layer was made basic with 20% sodium hydroxide, heated on a steam bath for 0.5 hour and extracted with three 100 ml portions of methylene chloride. The combined extracts were dried overanhydrous sodium sulphate and concentrated and the residue vacuum distilled to give 39.4 g (56%) of the epoxide as a clear oil (bp 75-900C at 28 mmHg). The epoxide was converted to the oxalate and the salt was recrystallised from absolute ethanol to give white needles, mp 142--40C (d).

Analysis: Calculated for CBH,3NO5: C, 47.29; H, 6.45: N, 6.89 Found: C, 47.12; H, 6.42; N, 6.82 Preparation 4 1 -Cyclohexyl-3,4-Epoxypyrrolidine Oxalate A solution of 151.3 g (1.0 mole) of N-cyclohexyl-A3-pyrroline, 100 ml of concentrated hydrochloric acid and 1.8 litres of water was treated with a stream of chlorine gas until uptake ceased (about 6 hours). The solution was washed with methylene chloride and the acidic solution was left standing overnight. The solution was then made basic with 50% sodium hydroxide and extracted with methylene chloride. The combined extracts were concentrated to give 1 85 g of chlorohydrin as residue.

The residue was slowly poured into an ethanol solution containing 20% sodium hydroxide. The mixture was stirred for 0.5 hour and then 3.5 litres of water was added. The mixture was extracted with methylene chloride and the combined extracts were dried over anhydrous sodium sulphate and concentrated to give 1 54 g (92%) of amine epoxide. An NMR analysis indicated that this residue was 86% epoxide and 14% 3,4-chloro-N-cyclohexylpyrrolidine. The residue was vacuum distilled to give the epoxide as a water-white liquid, bp 71 OC at 0.6 mmHg. A portion of the liquid was converted to the oxalate to give a white solid, mp 1 55-60C (d) when recrystallised from ethanol.

Analysis: Calculated for C12H1gNO5 C, 56.02; H, 7.44; N, 5.44 Found: C, 56.05; H, 7.50; N, 5.34 Preparation 5 1 -Phenylmethyl-3,4-Pyrrolidinediol Monohydrochloride Cis Isomer A mixture of 80 g (0.32 mole) of meso-1 ,4-dibromo-2,3-dihydroxybutane, 34 g (0.32 mole) of benzylamine, 3 g of potassium iodide and 140 g (1.0 mole) of potassium carbonate in 250 ml of 95% ethanol was heated at reflux for 1 8 hours, then cooled and filtered. The filtrate was concentrated and the residue was washed with several portions of boiiing ethyl acetate. The extracts were combined, washed with a small amount of water, dried over anhydrous sodium sulphate-and concentrated to give 30 g residue representing a 48% yield of 1 -phenylmethyl-3,4-pyrrolidinediol cis isomer. A portion was converted to the hydrochloride salt with hydrogen chloride in isopropyl alcohol and recrystallised from isopropyl alcohol as off-white granules, mp 11 5.0-11 6.50C.

Analysis: Calculated for C1,H6CINO2: C, 57.52; H, 7.02; N, 6.10 Found C, 57.16; H, 6.91; N, 6.01 Example 1 Trans-4-Phenoxy-1 -Phenylmethyl-3-Pyrrolidinol A mixture of 12.3 g of 1 -benzyl-3,4-epoxypyrrolidine, 1 3.2 g of phenol and 3 drops of water was heated at 1200sunder nitrogen gas for 20 hours. The mixture was cooled and dissolved in 100 ml ethyl ether. The ethereal solution was extracted with 2x50 ml of 5% sodium hydroxide and then washed with water. After being dried with anhydrous sodium sulphate, the solvent was evaporated and the residue weighed 14.3 g. Two crystallisations from cyclohexane gave analytically pure product melting at 101-1 040C. The yield was 24%.

Analysis: Calculated for C17H,gNO2: C, 75.81; H, 7.11; N, 5.20 Found: C, 75.71; H, 7.10; N, 5.38 Example 2 Trans-3-Hydroxy-1 -Methyl-4-Phenoxy-1 -Phenylmethylpyrrolidinium lodide A solution of 8.0 g (56 mmol) of methyl iodide in 30 ml of dry ethyl ether was added dropwise to a stirred solution of 7.0 g (26 mmol) of trans-4-phenoxy-1 -phenylmethyl-3-pyrrolidinol in 70 ml of dry diethyl ether. The mixture was stirred for two days and then concentrated under reduced pressure. The 10.7 g of crystalline residue was washed with tetrahydrofuran and dried, and gave 10.4 g (97%) of white powder, mp 122-270C.

Analysis: Calculated for C,8H221NO2: C, 52.57; H, 5.39; N, 3.41 Found: C, 52.78; H, 5.45; N 3.55 Example 3 Trans -Methyl-4-Phenoxy-3-Pyrrolidinol A solution of 9.3 g (22.5 mmol) uf trans-3-hydroxy-1 -methyl-4-phenoxy-1 - phenylmethylpyrrolidinium iodide in 200 ml of absolute ethanol and 100 ml of 1 90 ethanol was stirred at ambient temperature for 0.5 hour with 2.6 g (11.3 mmol) of silver oxide. After 0.2 g more silver oxide was added, the mixture was warmed to 450C and stirred for an additional 1 5 mins. The mixture was separated by filtration through Celite (Registered Trade Mark) and the volume of the filtrate was reduced to 200 ml. This solution was treated with about 0.5 g of 10% palladium-on-charcoal (Pd/C) catalyst and was shaken with hydrogen in a Parr reduction apparatus for 3 hours. The suspension was filtered through Celite and the filtrate was concentrated to give 4.3 g of crystalline solid. This material, when recrystallised from cyclohexane, gave 3.66 g (84%) of off-white crystals, mp 89.0-90.00C.

Analysis: Calculated for C"H,5NO2: C, 68.37; H, 7.82; N, 7.25 Found: C, 68.11; H, 7.83; N, 7.22 Example 4 Trans-3-Methoxy-4-Phenoxy-1 -Phenylmethylpyrrolidine Oxalata 8.1 g (0.03 mole) of trans-4-phenoxy-1-phenylmethyl-3-pyrrolidinol was mixed with 0.72 g (0.03 mole) of sodium hydride (1.3 g of 55% in oil, washed with 3x 10 ml diethyl ether to remove the oil) in 50 ml of dimethylformamide and stirred until hydrogen evolution ceased. 4.3 g (0.03 mole) of methyl iodide was added and the mixture was stirred for 1 8 hours. The reaction was worked up by pouring into 400 ml of water and extracting with 3 x 100 ml of diethyl ether. The diethyl ether was evaporated, leaving 7.9 g of residue. Addition of petroleum ether caused precipitation of starting material, which was removed by filtration. The residue after evaporation of the mother liquor was chromatographed on silica gel eluting the product with 10% acetone in benzene. The yield of pure product by NMR was 5.0 g (59%). A small amount was converted to the oxalate in isopropyl alcohol and recrystallised from isopropyl alcohol; mp 1 22-250C.

Analysis: Calculated for C20H23NO8: C, 64.33; H, 6.21; N, 3.75 Found: C, 63.93; H, 6.21; N, 3.69 Example 5 Trans-3-Methoxy-4-Phenoxypyrrolidine Flu karate A solution of 4.2 g (0.015 mole) of 3-methoxy-4-phenoxy-1-phenylmethylpyrrolidine in 70 ml of ethanol was treated with ca. 0.2 g of Pd/C catalyst and shaken under hydrogen at 600C in a Parr apparatus for 3 hours. After cooling, the mixture was filtered and the solvent was evaporated. The 2.9 g (100%) of crude product (good purity by NMR) was converted to the fumarate in isopropyl alcohol.

The pale yellow precipitate melted at 134-1 350C.

Analysis: Calculated for C,5H1gNO8: C, 58.25; H, 6.19; N, 4.53 Found: C, 58.15; H, 6.27; N, 4.46 Example 6 Trans-4-Phenoxy-3-Pyrrolidinol Fumarate A solution of 14.8 g of 1 -benzyl-4- phenoxy-3-pyrrolidinol in 200 ml of ethanol was treated with about 3 g of 10% Pd/C catalyst and was shaken with hydrogen at 60 C in a Parr reduction apparatus for 5 hours. The suspension was cooled, filtered and the solvent evaporated at reduced pressure. The residue was converted to the fumarate using isopropyl alcohol. The yield of product, mp 1 58--62 OC was 14.1 g (87%).

Analysis: Calculated for C,4H,7NO8: C, 56.95; H, 5.80; N, 4.74 Found: C, 56.91; H, 5.97; N, 4.78 Example 7 Trans-1 -(4-Fluorophenyl)-3-(3-Hydroxy-4-Phenoxy-1 -Pyrrolidinyl)-1 -Propanone A mixture of 3.6 g (0.02 mole) of 4-phenoxy-3-pyrrolidinol, 5 g (0.021 5 mole) of p- dimethylamino-p-fluoropropiophenone hydrochloride, 10 g of potassium carbonate and 50 ml of dimethylformamide was heated with stirring at 700C for 6 hours while nitrogen gas was bubbled through the reaction mixture. The mixture was poured into water and extracted twice with benzene.

The combined extracts were dried over anhydrous sodium sulphate and concentrated to give 6.1 g of an oil as residue. The oil was chromatographed on 130 g of silica gel. The desired compound was eluted with 20% acetone in benzene and 2.6 g (39%) of an oil which gradually crystallised upon standing was obtained. This solid was recystallised from petroleum ether diethylether to yield a white solid, mp 770--800C.

Analysis: Calculated for C1gH20FNO3 C, 69.28; H, 6.12; N, 4.25 Found: C, 69.43; H, 6.23; N, 4.18 Example 8 Trans-4-(4-Chlorophenoxy)-1 -Phenylmethyl-3-Pyrrolidinol A mixture of 12.3 g of 1 -benzyl-3,4-epoxypyrrolidine,18.0 g of p-chlorophenol and 3 drops of water was heated at 12000 under nitrogen gas for 20 hours. The mixture was cooled and dissolved in 100 ml diethyl ether. The ethereal solution was extracted with 2 x 50 ml 5% sodium hydroxide and then washed with water. After being dried with anhydrous sodium sulphate, the solvent was evaporated and the residue weighed 14.3 g. Two crystallisations from cyclohexane gave 4.7 g (29%) of analytically pure product which melted at 101-1 040C.

Analysis: Calculated for CrH8CINO2: C, 67.21; H, 5.97; N, 4.61 Found: C, 67.35; H, 6.10; N, 4.69 Example 9 trans-3-(4-Chlornphenoxy-4-{Phenylmethyl[Carbonylbis(oxy)] I-i -Pyrrolidine Carboxylic acid Phenylmethyl Ester A solution of 14.0 g (0.046 mole) of trans-4-(4-chlorophenoxy)-1-phenylmethyl-3-pyrrolidinol and 5 g (0.05 mole) of triethylamine in 200 ml of benzene was added dropwise to a cold (15 C) solution of 30.0 g (0.175 mole) of benzylchloroformate in 100 ml of benzene. The mixture was allowed to warm to room temperature and stirred overnight. The precipitate was removed by filtration and discarded and the filtrate was concentrated and the residue heated under high vacuum to remove excess reactants and by-products. The resulting gum wash chromatographed on silica gel, eluting the desired product with 20% acetone in benzene. 5 g of product was obtained after evaporation.

Example 10 Trans-4-(4-Chlorophenoxy)-3-Pyrrolidinol hydrobromide A solution of 5 g of 3-(4-chlorophenoxy)-4-(phenyl-methyl[carbonylbis(oxy)])-1- pyrrolidinecarboxylic acid phenylmethyl ester trans isomer in 30 ml of ethanol and 50 ml of 48% hydrogen bromide was heated at 115 C for 1 6 hours and then cooled and diluted with 100 ml water.

The solution was extracted with 2x50 ml of methylene chloride and the aqueous layer was evaporated to dryness. The powder that remained was the product in 82% yield with a melting point of 1 90- 920C.

Analysis: Calculated for C0Hr3NO2BrCI: C, 40.77; H, 4.45; N, 4.76 Found: C, 41.01; H, 4.46; N, 4.85 Example 11 Trans-3-(4-Chlorophenoxy)-4-Hydroxy-1 -Pyrrolidinecarboxamide A solution of 4.4 g of 4-(chlorophenoxy)-3-pyrrolidinol and 2.8 g'of nitrourea in 100 ml of 90% ethanol was heated at 500C for 20 hours. Some of the solvent was removed under vacuum and the remaining slurry was diluted with 50 ml water. The precipitate was filtered, triturated with acetone, filtered and dried. Yield 1.8 g, mp 223--2250C.

Analysis: Calculated for C"H,3N203CI: C, 51.47; H, 5.11; N, 10.91 Found: C, 51.18; H, 5.02; N, 10.88 Example 12 Trans-3-(4-Chlorophenoxy)-4-Hydroxy-N,N-Di methyl-1 -Pyrrolidinecarboxamide A solution of 3.5 g of 4-(4-chlorophenoxy)-3-pyrrolidinol, 1.8 g of dimethylcarbamyl chloride and 1.7 g of triethylamine in 300 ml of methylene chloride was stirred for 60 hours. The solvent was removed under vacuum, 300 ml of benzene was added and the mixture was refluxes for 2 hours, then filtered. After solvent evaporation, the residue was dissolved in cyclohexanebenzene and treated with charcoal. The product was then crystallised, collected by filtration and recrystallised from cyclohexanebenzene; mp 137142oC.

Analysis: Calculated for Cr3C,7N203CI: C, 54.84; H, 6.02; N, 9.84 Found: C, 54.64; H, 6.01; N, 9.77 Example 13 Trans-3-(4-Chlorophenoxy)-4-Hydroxy-N-Methyl-l -Pyrrolidinecarboxamide Hemihydrate A solution of 0.9 g of 4-(4-chlorophenoxy)-3-pyrrolidinol in 50 ml of methylene chloride was cooled to OOC and 0.24 g of methyl isocyanate in 5 ml of methylene chloride was added dropwise over the period of 10 minutes. Cooling was discontinued and stirring was continued for 1 hour. Solvent was then removed and the residue was crystallised from dimethylsulphoxidewater; mp 95.0--98.50C.

Analysis: Calculated for C,2H,5N203CI: C, 51.53; H, 5.77; N, 10.02 Found: C, 51.64; H, 5.79; N, 10.09 Example 14 Trans-3-( [(Methylamino)carbonyl]oxy)-4-(4-Chlorophenoxy)-N,N-Dimethyl-1 Pyrrolidinecarboxamide A solution of 1.0 g (0.003 mole) of

Analysis: Calculated for C10Hl2NO2BrCi2: C, 36.51; H, 3.68; N, 4.26 Found: C, 36.49; H, 3.72; N, 4.36 Example 18 Trans-4-(2,3-Dichlorophenoxy)-1 -Phenylmethyl-3-Pyrrolidinol Hydrochloride A mixture of 21.5 g (0.12 mole) of 1 -benzyl-3,4-epoxypyrrolidine, 27.8 g (0.17 mole) of 2,3dichlorophenol and 2 drops of concentrated hydrochloric acid was heated at 1 2000 overnight. The dark mixture was dissolved in methylene chloride and washed with four 100 ml portions of 5% sodium hydroxide and once with water The methylene chloride layer was dried over anhydrous sodium sulphate-potassium hydroxide and concentrated to give 35.8 g of dark gum as residue. This gum was chromatographed on 800 g of silica gel and the product was eluted with an acetone-benzene solution.

The appropriate fractions were concentrated to give 25 g (60%) of an oil. A portion of this oil was converted to the hydrochloride to yield white solid, mp 219--220C.

Analysis: Calculated for C17H18C13NO2: C, 54.50; H, 4.84; N, 3.74 Found: C, 54.53; H, 4.82; N, 3.53 Example 19 Trans-4-(2,3-Dichlorophenoxy)-1 -[(Phenylmethoxy)Carbonyl]-3-Pyrrolidinol A mixture of 8.5 g (0.023 mole) of trans-4-(2,3-dichlorophenoxy)- 1 -phenylmethyl-3-pyrrolidinol hydrochloride and 1 00 litres (100 ml) of methyl chloride was cooled and treated dropwise with a solution of 23 g (0.125 mole) of benzyl-chloroformate in 100 ml of methylene chloride. The mixture was stirred at ambient temperature for 48 hours and then washed successively with water, 2N hydrochloric acid, 5% sodium hydroxide and water. The methylene chloride layer was dried over anhydrous sodium sulphate and then subjected to vacuum distillation at 1000C at 1.0 mmHg to remove the methylene chloride, excess benzylchloroformate and benzyl chloride. An NMR analysis of the pot residue indicated only the oxygen was substituted. An additional 25 ml of benzyl-chloroformate and 100 ml of methylene chloride was added to the residue and the solution stirred at ambient temperature for 48 hours. The mixture was purified as above to give 14.6 g of residue which was chromatographed on 300 g of silica gel. The chromatography gave 5.6 g of the disubstituted compound (see Example 20) and 1.0 g of the titled compound as a white solid, mp 1302 C (recrystallised from benzene).

Analysis: Calculated for C16Ht7Ci2NO4: C, 56.56; H, 4.48; N, 3.67 Found: C, 56.80; H, 4.48; N, 3.67 Example 20 Trans-3-(2-Dichlorophenoxy)-4-{Phenylmethyl[Carbonylbis(oxy)]} 1-1 Pyrrolidine Carboxylic acid Phenylmethyl Ester This di-substituted compound resulted from chromatography separation in amount of 5-6 g in Example 1 9.

Example 21 Trans-4-(2,3-Dichlorophenoxy)-3-Pyrrolidinol Hydrobromide A mixture of 5.6 g (0.011 mole) of 3-(2-dichlorophenoxy)-4-(phenylmethyl[carbonylbis(oxy)])-1- pyrrolidine carboxylic acid phenylmethylester trans isomer, 60 ml of ethanol and 70 ml of 48% aqueous hydrogen bromide was heated at 12500 overnight. The mixture was poured into 1 50 ml of water and extracted three times with methylene chloride. The aqueous solution was concentrated to give an oily residue which crystallised upon standing. The solid was washed with isopropyl alcoholdiethylether, collected by filtration and recrystallised frmm isopropyl alcohol-diethyl ether to yield 1.5 g (45%) of pink solid, mp 1 34--8 OC.

Analysis: Calculated for C10H,2BrCI2N02: C, 36.51; H, 3.68; N, 4.26 Found: C, 36.54; H, 3.69; N, 4.32 Example 22 Trans-1-Benzyl-4-(3-Methylphenoxy)-3-Pyrrolidinol Hydrochloride A mixture of 1 7.5 g of 1 -benzyl-3,4-epoxypyrrolidine and 20 g of m-cresol was heated at 115 C for 1 8 hours under nitrogen gas. After cooling, the mixture was dissolved in benzene and washed with 5% sodium hydroxide to remove excess cresol. Stirring with 50 g of silica gel removed much of the coloured material. The solution was reduced in volume and some of the residue was converted to the hydrochloride. This salt was recrystallised from isopropyl alcohol-diethyl ether and melted at 1 63- 165 C.

Analysis: Calculated for C18H22N02CI: C, 67.60; H, 6.93; N, 4.38 Found: C, 67.39; H, 6.97; N, 4.43 Example 23 Trans-4-(3-Methylphenoxy)-3-Pyrrolidinol Oxalate A solution of 8.2 g of 1 -benzyl-4-(3-methylphenoxy)-3-pyrrolidinol in 1 50 ml of ethanol was treated with ca. 0.5 g of 10% Pd/C catalyst and was shaken with hydrogen at 600C in a Parr apparatus for 2 hours. The suspension was cooled, filtered and the solvent evaporated under vacuum. The base was converted to the oxalate in isopropyl alcohol, filtered and dried. The salt was obtained in 86% yield and melted at 150--1550C.

Analysis: Calculated for C13H,7NO5: C, 55.12; H, 6.05; N, 4.94 Found: C, 54.75; H, 6.07; N, 5.06 Example 24 Trans-4-(2,3-Dimethylphenoxy)-1 -Phenylmethyl-3-Pyrrolidinol A mixture of 17.5 g (0.10 mole) of 1 -benzyl-3,4-epoxypyrrolidine, 18.3 g (0.15 mole) of 2,3dimethylphenol and 2 drops of concentrated hydrochloric acid was heated at 1200C under a nitrogen atmosphere overnight. The reaction mixture was dissolved in methylene chloride and washed with four 100 ml portions of 5% sodium hydroxide and once with water. The methylene chloride layer was dried over anhydrous sodium sulphate-potassium hydroxide and concentrated to give 28.6 g of dark oil as residue. This oil was chromatographed on 600 g of silica gel and the product was eluted with an acetone-benzene solution. The appropriate fractions were concentrated to give an oil which crystallised upon standing. This solid was recrystallised from ligroin to give 9.1 g (31%) of white solid, mp 100 40C.

Analysis: Calculated for C19H23N02: C, 76.74: H, 7.80; N, 4.71 Found: C, 76.92; H, 7.86; N, 4.80 Example 25 Trans-4-(2;3-Dimethylphenoxy)-3-Pyrrolidinol Hydrobromide A solution of 9.1 g (0.031 mole) of trans-4-(2,3-dimethylphenoxy)- 1 -phenylmethyl-3-pyrrolidinol in 100 litres (100 ml) of ethanol was hydrogenated over 10% Pd/C at 50 psi and 600C until hydrogen uptake ceased. The mixture was filtered through Celite and the filtrate was concentrated to give an oil as residue which solidified upon standing. The solid was converted to the hydrobromide and this salt was recrystallised from isopropyl alcohol-ethylacetate-diethylether to yield 4.9 g (55%) of tan needles, mp152--30C.

Analysis: Calculated for C12H18BrNO2: C, 50.01; H, 6.30; N, 4.86 Found: C, 50.29; H, 6.42; N, 4.85 Example 26 Trans-4-(2-Methoxyphenoxy)-1 -Phenylmethyl-3-Pyrrolidinol A mixture of 40 g of crude 1 -benzyl-3,4-epoxypyrrolidine and 70 g.of guaiacol was heated at 1200C for 20 hours. Aspirator vacuum was then used to distill off the excess guaiacol. The residue was dissolved in methylene chloride and extracted with dilute sodium hydroxide. The methylene chloride solution was dried over anhydrous sodium sulphate and the solvent was evaporated. The residue weighed 54 g, and was chromatographed on 1 kg of silica gel. The product was eluted with 50% ethyl acetate in benzene and crystallised from cyclohexane. The mp was 1 15--1 170C and the yield was 27%.

Analysis: Calculated for C18H21NO3: C, 72.22; H, 7.07; N, 4.68 Found: C, 72.30; H, 7.04; N, 4.70 Example 27 Trans-4-(2-Methoxyphenoxy)-3-Pyrrolidinol Fu ma rate A solution of 11.5 g of 1-benzyl-4-(o-methoxyphenoxy)-3-pyrroiidinol in 200 ml of ethanol was treated with ca. 2 g of 10% Pd/C catalyst and was shaken with hydrogen at 600C in a Parr reduction apparatus for 5 hours. The suspension was then cooled, filtered, and the solvent evaporated at reduced pressure. The base was converted to the fumarate which melted at 158--1600C. Yield was 9.8 g (78%).

Analysis: Calculated for CsH19N07: C, 55.38; H, 5.89; N, 4.31 Found: C, 55.38; H, 5.89; N, 4.13 Example 28 Trans-4-(4-Methoxyphenoxy)-1 -Phenylmethyl-3-Pyrrolidinol A mixture of 17.5 g (0.10 mole) of 1 -benzyl-3,4-epoxypyrrolidine, 13.4 g (0.11 mole) of pmethoxyphenol, and 3 drops of water was heated on a steam bath overnight. The dark residue was dissolved in methylene chloride and the solution was washed with two 50 ml portions of 5% sodium hydroxide The methylene chloride layer was dried over anhydrous sodium sulphate and concentrated to give 23.7 g of viscous dark oil. This oil was chromatographed on 480 g of silica gel 60 and the product was eluted with a 1:1 benzene:ether solution. The appropriate fractions were concentrated to give 10.0 g of a yellow oil which crystallised upon scratching. The solid was recrystallised from cyclohexane to yield 7.2 g (24%) tan solid, mp 84--50C.

Analysis: Calculated for C18H2'NO3: C, 72.22; H, 7.07: N, 4.68 Found: C, 72.20; H, 7.15; N, 4.61 Example 29 Trans-4-(4-Methoxyphenoxy)-3-Pyrrolidinol Oxalate (3:4) A solution of 4.0 g (0.0134 mole) of trans-4-(4-methoxyphenoxy)-1 -phenylmethyl-3-pyrrolidinol in 75 litres (75 ml) of ethanol was hydrogenated over 0.4 g of 10% Pd/C at 600C overnight. The reaction mixture was cooled, filtered through Celite, and the filtrate concentrated to give the base as a white solid. This solid was converted to the oxalate and recrystallised from methanol to yield white flakes, mp 173--1750C(d).

Analysis: Calculated for C4'H53N3025: C, 52.40; H, 5.68; N, 4.47 Found: C, 52.17; H, 5.62; N, 4.66 Example 30 Trans-4-(2-Ethoxyphenoxy)-1 -Phenylmethyl-3-Pyrrolidinol A mixture of 45.5 g (0.26 mole) of 1 -benzyl-3,4-epoxypyrrolidine (60 g of 76% epoxide), 48 g (0.35 mole) of o-ethoxyphenol and 8 drops of concentrated hydrochloric acid was heated at 1450C for 1 6 hours. The mixture was cooled, dissolved in methylene chloride and washed with dilute sodium hydroxide solution. The methylene chloride layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The residue was chromatographed on 1 kg of silica gel using 20% acetone in benzene as the eluent. Two crystallisations from cyclohexane gave 8.0 g (10%) of tan needles, mp 88.5--90.00C.

Analysis: Calculated for C19H23NO3: C, 72.82; H, 7.40; N, 4.47 Found: C, 72.64; H, 7.39; N, 4.56 Example 31 Trans-4-(2-Ethoxyphenoxy)-3-Pyrrolidinol Fumarate A solution of 7.4 g (24 mmoles) of trans-4-(2-ethoxy-phenoxy)-1-phenylmethyl-3-pyrrolidinol in 1 50 ml of absolute ethanol was treated with about 0.5 g of 10% Pd/C catalyst and was shaken with hydrogen in a Parr reduction apparatus at 600C for 1.5 hours. the mixture was cooled and filtered and the filtrate was concentrated. The residue (5.3 g, 100%) was converted to the fumarate in isopropyl alcohol to give a white powder; mp 173.0--174;50C.

Analysis: Calculated for Ct6H2tNO7: C, 56.63; H, 6.24; N, 4.13 Found: C, 56.60; H, 6.27; N, 4.1,2 Example 32 Trans-4-[4-(Phenylmethoxy)Phenoxy]-1 -Phenylmethyl-3-Pyrrolidinol A mixture of 40 g of 1 -benzyl-3,4-epoxypyrrolidine and 42 g of 4-benzoxyphenol was heated at 1 3000 for 8 hours. On cooling, the mixture crystallised. Three crystallisations from petroleum ethercyclohexane gave fluffy white crystals melting at 98.0-1 00.00 C. The yield was 6.0 g (8%).

Analysis: Calculated for C24H2SNO3: C, 76.78; H, 6.71; N, 3.73 Found: C, 76.83; H, 6.82; N, 3.57 Example 33 Trans-4-(4-Hydroxyphenoxy)-3-Pyrrolidinol Hemioxalate 6 grams of 1 -benzyl-4-(4-benzoxyphenoxy)-3-pyrrolidinol in 1 50 ml of ethanol was treated with ca. 1 g of Pd/C catalyst and shaken under hydrogen at 600C in a Parr apparatus for 3 hours. The mixture was then cooled, filtered and the ethanol removed. The oxalate was made in isopropyl alcohol acetone and recrystaliised from 90% ethanol. The salt decomposed at 2350C.

Analysis: Calculated for Ct1H,4NO5: C, 55.00; H, 5.87; N, 5.83 Found: C, 54.54; H, 5.83; N, 5.65 Example 34 Trans-4-(3-Trifluoromethylphenoxy)-1 -Phenylmethyl-3-Pyrrolidinol Oxalate A mixture of 24.0 g of 1 -benzyl-3,4-epoxypyrrolidine and 22.2 g of 3-trifluoromethylphenol was heated at 1 3000 for 3 hours. The mixture was cooled, dissolved in methylene chloride and extracted with dilute sodium hydroxide. The residue after the solvent was evaporated was purified by column chromatography. The product, which was eluted using 30% ethyl acetate in benzene weighed 1 7.7 g (38%). A small portion when converted to the oxalate melted at 139--1410C.

Analysis: Calculated for C20H20NO6F3: C, 56.21; H, 4.72; N, 3.28 Found: C, 56.48: H, 4.77: N, 3.44 Example 35 Trans-4-(3-Trifluoromethylphenoxy)-3-Pyrroliidinol Hydrochloride A solution of 12.6 g of trans -benzyl-4-(3-trifluoromethylphenoxy)-3-pyrrolidinol in 200 ml of ethanol was treated with ca. 2 g of 10% Pd/C catalyst and was shaken with hydrogen at 600C in a Parr reduction apparatus for 1 6 hours. The suspension was cooled, filtered and the solvent evaporated at reduced pressure. The residue was dissolved in ether and converted to the hydrochloride. The yield of product melting at 145--80C was 9.8 g (93%).

Analysis: Calculated for C11H13NC)2CIF3: C, 46.58; H, 4.62; N, 4.94 Found: C, 46.42; H, 4.68; N, 5.07 Example 36 Trans-4-[(4-Hydroxy-1 -Phenyl methyl-Pyrrolidin-3-yl )oxy] Benzamide A mixture of 28 g of 1 -benzyl-3,4-epoxypyrrolidine and 20.6 g of 4-hydroxybenzamide was heated at 1300C for 8 hours. The cooled mixture was chromatographed on silica gel using 5% methanol in ethyl acetate to elute the product, which was then crystallised from chloroform-benzenemethanol. The yield was 19% of product melting at 133.0--6.00C.

Analysis: Calculated for C18H20N203: C, 69.21: H, 6.45; N, 8.97 Found: C, 69.11; H, 6.46; N, 8.82 Example 37 Trans-4-[(4-Hydroxy-3-pyrrolidinyl)oxy] benza mide 8.0 g of 4-[(4-benzamide)oxy]-1 -benzyl-3-pyrrolidinol was treated with ca. 1 g of 10% Pd/C catalyst and dissolved in 100 ml of ethanol and shaken with hydrogen at 600C for 4 hours. The suspension was then cooled and filtered. The precipitate was washed with hot methanol and the washings combined with the mother liquor. The solvent was evaporated to 1 50 ml and cooled overnight. The product was filtered and dried and melted at 199--2040C with decomposition. The yield was 80%.

Analysis: Calculated for C11H14N203 C, 59.45; H, 6.35; N, 12.61 Found: C, 59.47; H, 6.45; N, 12.57 Example 38 Tra ns-N-l4-[(4-Hydroxy-1 -Phenylmethyl-3-Pyrrolidinyl)oxy]phenyl Acetamide A mixture of 35.0 g of 1 -benzyl-3,4-epoxypyrrolidine, 30.2 g of p-acetamidophenol and two drops of water was heated at 12500 for 3 hours. The mixture was then cooled, dissolved in 50% ethyl acetate in benzene and washed with dilute sodium hydroxide. When the solvent was removed, the residue weighed 56 g. It was chromatographed using 370 g of silica gel and the product was eluted with ethyl acetate. After crystallisation from 50% ethyl acetate in benzene, the product melted at 130--1320C and weighed 26.1 g (40%).

Analysis: Calculated for CgH22N203: C, 69.92; H, 6.79; N, 8.58 Found: C, 69.61; H, 6.69; N, 8.44 Example 39 Trnns-N-(4-[(4-Hydrnxy-3-Pyrrolidinyl)oxy] Phenyl Acetamide Hemifumarate A solution of 12.4 g of 1 -benzyl-4-(4-acetamidophenoxy)-3-pyrrolidinol in 200 ml of ethanol was treated with ca. 2 g of 10% Pd/C catalyst and was shaken with hydrogen at 600C in a Parr reduction apparatus for 1 6 hours. The suspension was then cooled, filtered and the solvent evaporated at reduced pressure. The residue weighed 9 g and was converted to the fumarate and crystallised from isopropyl alcohol. The yield of salt was 10.2 g (90%) which melted at 200--205"C.

Analysis: Calculated for C14H1sN2Os C, 57.14; H, 6.17; N, 9.52 Found: C, 56.90; H, 6.22; N, 9.29 Example 40 Trans-4-(1-Naphthalenyloxy)-1-Phenylmethyl-3-Pyrrolidinol Oxalate A mixture of 1 7.5 g (0.10 mole) of crude 1 -benzyl-3,4-epoxypyrrolidine, 1 5.0 g (0.11 mole) of 1 naphthol and 1 drop of concentrated hydrochloric acid was heated on a steam bath overnight. The dark mixture was dissolved in methylene chloride and the solution was extracted with three 50 ml portions of 5% sodium hydroxide. the methylene chloride layer was dried over anhydrous sodium sulphate and concentrated to give 25.5 g (80%) of black gum as residue. The residue was chromatographed on 500 g of silica gel and the product was eluted with 1:1 ethyl ether:benzene to give 9.9 g (31%) of white solid, mp 1 06--8 OC when recrystallised from cyclohexane.

Analysis: Calculated for C21H2'NO2: C, 78.97; H, 6.63; N, 4.39 Found: C, 79.08 H, 6.67; N, 4.45 The oxalate was prepared as a white solid, mp 1902 C when recrystallised from nitromethane.

Analysis: Calculated for C23H23NO6: C, 67.47; H, 5.66; N, 3.42 Found: C, 67.00; H, 5.68; N, 3.57 Example 41 Trans-4-( 1 -Naphthalenyloxy)-3-Pyrrolidinol 18.0 g of 1-benzyl-4-(1-naphthoxy)-3-pyrrolidinol in 200 ml of ethanol was treated with ca. 2 g of 10% Pd/C catalyst under hydrogen at 600C for 20 hours. The mixture was cooled, filtered and ethanol removed. The residue was crystallised from benzene and had a melting point of 1 12--1 1 50C.

Analysis: Calculated for C 14H15NO2: C, 73.34; H, 6.59; N, 6.11 Found: C, 73.39; H, 6.64; N, 5.90 Example 42 Trans-4-[1 H-2.3-Dihydroinden-4-yl)oxy]-l -Phenylmethyl-3-Pyrrolidinol A mixture of 28 g of 1-benzyl-3,4-epoxypyrrolidine and 20.1 g of 4-indanol was heated at 1300C for 1 8 hours. The residue was chromatographed on silica gel using ethyl acetate to elute the product.

The yield of product after crystallisation from cyclohexane was 6%, melting at 98--1010C.

Analysis: Calculated for C20H23NO2: C, 77.64; H, 7.49; N, 4.53 Found: C, 77.41; H, 7.52; N, 4.37 Example 43 Trans-4-[1 H-2,3-Dihydroinden-4-yl)oxy]-3-Pyrrolidino Hydrochloride 1 -benzyl-4-(4-indanoxy)-3-pyrrolidinol (2.7 g) in 100 ml of ethanol was treated with ca. 0.5 g 10% Pd/C catalyst and was shaken with hydrogen at 600C in a Parr apparatus for 5 hours. The suspension was then cooled, filtered and the solvent removed. The residue was converted to the hydrochloride in ether and dried for 18 hours at 400C under vacuum. The yield of product melting at 174--180"C was 91%.

Analysis: Calculated for C13H16N02Ci: C, 61.06; H, 7.09; N, 5.48 Found: C, 60.80; H, 7.16; N, 5.46 Example 44 Trans-4-[(1,2-Dihydroinden-5-yl)oxy]-1-Phenylmethyl-3-Pyrrolidinol Hydrochloride A mixture of 35 g of 1 -benzyl-3,4-epoxypyrrolidine and 28 g of 5-indanol was heatecl at 130 C for 3 hours. The mixture was then cooled, dissolved in methylene chloride and extracted with dilute sodium hydroxide. After solvent evaporation the residue was chromatographed on silica gel, and the product was eluted with 50% ethyl acetate in benzene. The hydrochloride salt was formed in ether and was recrystallised from ethanol-acetone. The yield of salt melting at 1 53--5"C was 12.3 g (18%).

Analysis; Calculated for C20H24NO2CI: C, 69.45; H, 6.99; N, 4.05 Found: C, 69.13; H, 6.93; N, 3.99 Example 45 Trans-4-[(2,3-Dihydro-1 H-lnden-5-yl)oxy]-3-Pyrrolidinol Oxalate A solution of 6.0 g of 1 -benzyl-4-(5-indanoxy)-3-pyrrolidinol in 100 ml of ethanol was treated with ca. 0.5 g 10% Pd/C catalyst and was shaken with hydrogen at 600C in a Parr apparatus for 3 hours. The suspension was then cooled, filtered, and the solvent removed. The oxalate was prepared in isopropyl alcohol and melted at 179.0--181.00C.

Analysis: Calculated for C15H1gNO6 C, 58.25; H, 6.19; N, 4.53 Found: C, 58.13; H, 6.14; N, 4.58 Example 46 Trans -Ethyl-4-Phenoxy-3-Pyrroiidinol Oxalate Hydrate (4:1) A mixture of 22.6 g of 1 -ethyl-3,4-epoxypyrrolidine and 1 8.6 g of phenol was heated at 1 5000 for 0.5 hour, and then distilled. The product boiled at 1 200C at 0.025 mmHg. The yield of pure product was 25.0 g (60%). A portion of the base was converted to the oxalate which melted at 134--70C after it was recrystallised from isopropyl alcohol.

Analysis: Calculated for C56H78N4025: C, 55.72; H, 6.51; N, 4.64 Found: C, 55.83; H, 6.38; N, 4.63 Example 47 Trans-I -Ethyl-4-Phenoxy-3-Pyrrolidinolmethylcarbamate Ester A solution of 6.5 g of 1 -ethyl-4-phenoxy-3-pyrrolidinol and 1.9 g of methyl isocyanate in 80 ml of benzene was allowed to stand under nitrogen gas for 5 days. The crystalline solid remaining on evaporation of the benzene was recrystallised from cyclohexane. The yield of product melting at 88 940C was 6.5 g (79%).

Analysis: Calculated for Ct4H2oN203: C, 63.62; H, 7.63; N, 10.60 Found: C, 63.61; H, 7.60; N, 10.62 Example 48 Trans-4-(2-Chlorophenoxy)-1 -Ethyl-3-Pvrrolidinol Hydrochioride A mixture of 17.0 g (0.15 mole) of 1 -ethyl-3,4-epoxy-pyrrolidone, 20.5 g (0.16 mole) of o- chlorophenol and 3 drops concentrated hydrochloric acid was heated on a steam bath overnight. The oil was dissolved in methylene chloride and washed with three 50 ml portions of 5% sodium hydroxide and one 50 ml portion of water. The methylene chloride solution was dried over anhydrous sodium sulphate, concentrated and chromatographed on silica gel to give 8.9 g (25%) of an oil as residue. The oil was converted to the hydrochloride and recrystallised from ethyl acetate-acetonitrile to yield white powder, mp 108--1100C.

Analysis: Calculated for C12H17C12NO2: C, 51.81; H, 6.16; N, 5.04 Found: C, 51.65; H, 6.17; N, 5.09 Example 49 Trans-4-(2,6-Dichlorophenoxy)-1 -Ethyl-3-Pyrrolidinol Hydrochloride A mixture of 11.3 g (0.10 mole) of 1-ethyl-3,4-epoxypyrrolidine, 18.0 g (0.11 mole) of 2,6dichlorophenol and 2 drops concentrated hydrochloric acid was heated on a steam bath overnight. The oil was dissolved in methylene chloride and washed with three 50 ml portions of 5% sodium hydroxide and one 50 ml portion of water. The methylene chloride solution was dried over anhydrous sodium sulphate, concentrated and chromatographed on silica gel to give 12.9 g (47%) of an oil residue. The oil was converted to the hydrochloride and recrystallised from isopropyl alcohol-diethyl ether to yield 12.3 g (39%), mp 160--1620C.

Analysis: Calculated for C12Hl C13NO2: C, 46.10; H, 5.16; N, 4.48 Found: C, 46.10; H, 5.20; N, 4.48 Example 50 Trans-l -Ethyl-4-(3-Methylphenoxy)-3-Pyrrolidino Oxalate Hemihydrate A mixture of 17 g of 1 -ethyl-3,4-epoxypyrrolidine and 1 6.2 g of m-cresol was heated at 12500 for 45 minutes and then vacuum distilled. The yield of product boiling at 13500 at 0.02 mmHg was 37%. This was converted to the oxalate which melted at 11 6-11 900.

Analysis: Calculated for C30H44N2013: C, 56.24; H, 6.92; N, 4.37 Found: C, 56.66; H, 6.68; N, 4.15 Example 51 Trans-4-(2-Ethoxyphenoxy)-1 -Ethyl-3-Pyrrolidinol A mixture of 17.0 g (0.1 5 mole) of 1 -ethyl-3,4-epoxypyrrolidine, 22.1 g (0.1 6 mole) of o- ethoxyphenol and 3 drops of concentrated hydrochloric acid was heated on a steam bath overnight.

The oil was dissolved in methylene chloride and washed with three 50 ml portions of 5% sodium hydroxide and one 50 ml portion of water. The methylene chloride solution was dried over anhydrous sodium sulphate, concentrated and chromatographed on silica gel to give 8.1 g (21%) of an oil which crystallised on standing. The solid was recrystallised from cyclohexane to yield a tan solid, mp 73 750C.

Analysis: Calculated for C14H2lNO3: C, 66.90; H, 8.42; N, 5.57 Found: C, 66.49; H, 8.43; N, 5.48 Example 52 Trans-1 -(4[( 1 -Ethyl-4-Hydroxy-3-Pyrrolidinyl)oxy]-3-Methoxyphenyl)Ethanone Sesquioxalate A mixture of 17.0 g (0.15 mole) of acetovanillone and 1 -ethyl-3,4-epoxypyrrolidine and 3 drops of water was heated on a steam bath overnight. The mixture was dissolved in 250 ml of methylene chloride and extracted with three 1 50 ml portions of 5% sodium hydroxide and one 100 ml portion of water. The methylene chloride layer was dried over anhydrous sodium sulphate and concentrated to give 19.0 g crude oil. This oil was chromatographed on 400 g of silica gel. The desired product was eluted with acetone. The fractions were concentated to give 14.0 9 of oil which was treated with oxalic acid in isopropyl alcohol. The resulting white solid was recrystallised twice from isopropyl alcohol to yield 13.4 g (24%) of sesquioxalate, mp 1 2 1--3 OC.

Analysis: Calculated for C16H24NO1o C, 52.17; H, 5.84 N, 3.38 Found: C, 52.45; H, 5.90; N, 3.60 Example 53 Trans-1 -Ethyl-4-[2-(2-Propenyl) Phenoxy]-3-Pyrrolidinol Oxalate A mixture of 17.0 g of 1 -ethyl-3,4-epoxypyrrolidine and 20.0 g of 2-allylphenol was heated at 1300C for 1.5 hours then cooled and chromatographed on silica gel, using 20% methanol in ethyl acetate to elute the product. A portion of the total yield, 1 8.5 g (50%) was converted to the oxalate which melted at ID=17.12

Analysis: Calculated for C 15H21NO2: C, 72.84; H, 8.56; N, 5.66 Found: C, 72.92; H, 8.52; N, 5.48 Example 57 Trans-i -Ethyl-4-[( 1 H-2,3-Dihydroinden-5-yl)oxy]-3-Pyrrolidinol Maleate A mixture of 15.0 g (0.132 mole) of 1 -ethyl-3,4-epoxypyrrolidine, 20 g (0.15 mole) of 5-indanol and 1 drop of water was heated on a steam bath overnight. The oil was dissolved in methylene chloride and washed with three 50 ml portions of 5% sodium hydroxide and one 50 ml portion of water. The methylene chloride was dried over anhydrous sodium sulphate and concentrated to give 28.5 g of a dark residue. This residue was chromatographed on 500 g of silica gel and the product was diluted with methanol. This oil was converted to the maleate to yield 1 6.6 g (35%) of cream coloured needles, mp 1 47--8 0 C.

Analysis: Calculated for C1gH25NO6: C, 62.80; H, 6.93; N, 3.85 Found: C, 62.74; H, 6.88; N, 3.83 Example 58 Trans -Cyclohexyl-4-Phenoxy-3-Pyrrolidinol Compound with Cyclohexane-Sulphamic Acid A mixture of 33.5 g (0.2 mole) of N-cyclohexyl-3,4-epoxypyrrolidine, 18.8 g (0.02 mole) of phenol and 2 drops concentrated hydrochloric acid was heated on a steam bath overnight. The reaction mixture was dissolved in methylene chloride and washed with three 100 ml portions of 5% sodium hydroxide and once with 100 ml of water and dried over potassium hydroxide-anhydrous sodium sulphate. The methylene chloride solution was concentrated to give 36.4 g of oil as residue. The oil partially crystallised and the solid was washed with petroleum ether, collected by filtration and recrystallized from cyclohexane to give 11.0 g (21%) of a white solid. This solid was converted to the hexamate to yield white needles, mp 163---50C, recrystallised from isopropyl alcohol.

Analysis: Calculated for C22H36N205S: C, 59.97; H, 8.24; N, 6.36 Found: C, 59.99; H, 8.29; N, 6.30 Example 59 Cis-4-Phenoxy-l -Phenylmethyl-3-Pyrrolidinol A slurry of 2.4 g (0.1 mole) of sodium hydride (4.2 g of 57% oil dispersion, washed with ether to remove the oil) in 30 ml of dimethylformamide was stirred while a solution of 19.3 g (0.1 mole) of 1 benzyl-3,4-dihydroxypyrrolidine, cis isomer, (I) in 30 ml of dimethylformamide was added dropwise.

The mixture was heated at 500C for 1 hour, then a solution of 1 9.2 g (0.2 mole) of fluorobenzene in 30 ml of dimethylformamide was added in one portion. The mixture was heated at 900C for 1 8 hours, then cooled and concentrated under vacuum. The residue was dissolved in benzene and washed with water. The semicrystalline residue from the concentrated organic fraction was dissolved in cyclohexane and the solution was decanted from an insoluble oil (mostly 1). The cyclohexane solution was treated with charcoal to remove residual I and then crystallised as fluffy, off-white needles (mp 88.5--900C (d)) which weighed 1.2 g (4.5%).

Analysis: Calculated for C17HlgNO2 C, 75.81; H, 7.11; N, 5.20 Found: C, 75.88; H, 7.27; N, 5.16 Example 60 Cis-4-(3-Chlorophenoxy)-1 -Phenylmethyl-3-Pyrrolidinol A slurry of 1.2 g (50 mmoles) of sodium hydride (2.1 g of 57% oil dispersion, washed with ether to remove the oil) in 25 ml of dimethyl sulphoxide was stirred while 9.6 g (50 mmoles) of 1-benzyl-3,4di-hydroxypyrrolidine, cis isomer, in 25 ml of dimethyl sulphoxide was added. The mixture was stirred at ambient temperature for one hour, then 50 ml of dimethyl sulphoxide was added and the temperature was raised to 950C for 0.5 hour. Mechanical stirring of the thick slurry was necessary while 13 g (100 mmoles) of m-chlorofluorobenzene was added. During the heating period of 1 hour at 950C, all the solids dissolved. The reaction mixture was concentrated by vacuum distillation of the dimethyl sulphoxide and excess m-chlorofluorobenzene. The residue was poured into water and extracted with hot cyclohexane. The organic extracts were combined, dried over anhydrous sodium sulphate and concentrated to give 7.5 g (49%) of off-white crystals, mp 86--87.50C.

Analysis: Calculated for 017H1sCINO2: C, 67.21; H, 5.97; N, 4.61 Found: C, 67.33; H, 6.00; N, 4.56 Example 61 Cis-3-(3-Chlorophenoxy)-4-Hydroxy-1 -Methyl-1,-Phenylmethylpyrrolidinium lodide A mixture of 1 5.2 g (0.05 mole) of cis-4-(3-chlorophenoxy)-1 -phenylmethyl-3-pyrrolidinol and 56 g (0.4 mole) of methyl iodide was heated at reflux for 60 hours. Excess methyl iodide was removed under vacuum. The pasty residue was washed with ether-acetone, leaving 1 3 g (59%) of granular tan powder, mp 118--250C.

Analysis: Calculated for 018H210llN02: C, 48.51; H, 4.75; N, 3.14 Found: C, 48.27; H, 4.75; N, 3.19 Example 62 Cis-l -Methyl-4-Phenoxy-3-Pyrrolidinol A solution of 12.5 g (28 mmoles) of cis-3-(3-chlorophenoxy)-4-hydroxy- 1-methyl- 1 - phenylmethylpyrrolidinium iodide in 400 ml of ethanol; was stirred at 450C with 3.5 g (15 mmoles) of silver oxide for 1 hour. The solids were removed by filtration and the filtrate was concentrated to 100 ml, treated with 0.5 g of 10% Pd/C catalyst and was shaken under hydrogen at 600C for 3 hours. The mixture was cooled and the catalyst was collected by filtration. The filtrate was concentrated and the residue was treated with dilute sodium hydroxide and extracted into methylene chloride. The solution was concentrated and redissoved in hot cyclohexane, treated with charcoal, separated by filtration through Celite and recrystallised from cyclohexane to give 4.6 g (85%) of white needles (mp 78 81 C).

Analysis: Calculated for C 11H15NO2: C, 68.37; H, 7.82; N, 7.25 Found: C, 68.42; H, 7.87; N, 7.19 Example 63 Cis-4-Phenoxy-3-Pyrrolidinol Cis Isomer Hydrochloride Hydrate (4:1) A solution of 16.0 g (53 mmoles) of cis-4-(3-chlorophenoxy)-1 -phenylmethyl-3-pyrrolidinol in 100 ml of absolute ethanol and 5 ml concentrated hydrochloric acid was treated with 0.5 g of 10% Pd/C catalyst and was shaken under hydrogen at 600C for 1 6 hours. The mixture was cooled and the catalyst was separated by filtration through Celite. The filtrate was concentrated and the white crystalline residue was triturated with ether-acetone. A while powder, 9.8 g (86%), mp 1 28--37 OC was obtained.

Analysis: Calculated for C40H58CI4N4Og: C, 54.55; H, 6.64; N, 6.36 Found: C, 54.26; H, 6.41; N, 6.27 Effective quantities of any of the foregoing pharmacologically active compounds of Formula I may be administered to a living animal body for therapeutic purposes according to usual modes of administration and in usual forms, such as orally in solutions, emulsions, suspensions, pills, tablets and capsules in pharmaceutically acceptable carriers and parenterally in the form of sterile solutions.

For parenteral administration the carrier or excipient is a sterile, parenterally acceptable liquid; e.g., water or a parenterally acceptable oil; e.g. arachis oil contained in ampoules.

Although very small quantities of the active materials of the present invention are effective when minor therapy is involved or in cases of administration to subjects having a relatively low body weight, unit dosages are usually from five milligrams or above and preferably 25, 50, or 100 milligrams or even higher, depending, of course, upon the emergency of the situation and the particular result desired. Five to 50 milligrams appears optimum per unit dose or usual broader ranges appear to be 1 to 500 milligrams per unit dose. Daily dosages should preferably range from 10 mg to 100 mg. The active ingredients of the invention may be combined with other pharmacologically active agents as stated above. It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several unit dosage forms may be administered at about the same time. The exact individual dosages as well as daily dosages will, of course, be determined according to standard medical principles under the direction of a physician or veterinarian.

Illustrative of the antidepressant activity of compounds of Formula la are the effective dosages determined by the above described anti-tetrabenazine test.

Compound Antitetrabenazine (Mice) Example ED50 (mg/kg) 3 3.7 46 3.5 49 4.8 48 2.8 The compounds of Formula 1C have pronounced antiarrhythmic activity. The compound of Example 55 represents a preferred compound exhibiting exceptional antiarrhythmic activity at a minimum effective dose of 10.7 mg/kg using the above described antiarrythmic testing procedure.

The following formulations are representative for all of the pharmacologically active compounds of this invention.

Examples 64A to G-Capsules Capsules of 5 mg (64A), 10 mg (64B), 25 mg (64C), and 50 mg (64D) of active ingredient per capsule were prepared. With the higher amounts of active ingredient, reduction may be made in the amount of lactose.

Typical Blend for Encapsulation Per Capsule, mg Active ingredient, as salt 5 Lactose 259 Starch 126 Magnesium stearate 4 Total 394 Additional capsule formulations preferably contain a higher dosage of active ingredient and are as follows: Example 64E 64F 64G 100 250 500 mg per mg per mg per Ingredients Capsule Capsule Capsule Active ingredient, 100 250 500 as salt Lactose 214 163 95 Starch 87 81 47 Magnesium stearate 4 6 8 Total 405 500 650 In each case, the selected active ingredient was uniformly blended with lactose, starch, and magnesium stearate and the blend was encapsulated.

Example 65-Tablets A typical formulation for a tablet containing 5.0 mg of active ingredient per tablet is described.

The formulation may be used for other strengths of active ingredient by adjustment of the amount of dicalcium phosphate.

Per Tablet, mg 1. Active ingredient 5.0 2. Corn starch 15.0 3. Corn starch (paste) 12.0 4. Lactose 35.0 5. Dicalcium phosphate 132.0 6. Calcium stearate 2.0 Total 201.0 Ingredients 1, 2, 4 and 5 were uniformly blended. Ingredient 3 was prepared as a 10 percent paste in water. The blend was granulated with starch paste and the wet mass passed through a 8 mesh screen. The wet granulation was dried and sized through a 12 mesh screen. The dried granules were blended with the calcium stearate and compressed.

Example 66-Injections An injectable 2% sterile solution was made up containing the following.

Per cc Active ingredient mg 20 Preservative, e.g. 0.5 chlorobutanol, wt/mol percent Water for injection q.s.

The solution was prepared and clarified by filtration. The solution was then filled into vials, sealed and autoclaved.

Claims (107)

Claims

1. Cis and trans isomers of 2-aryloxy-4-hydroxypyrrolidine and derivatives thereof having the formula

wherein: R1 represents a hydrogen atom, or a lower alkyl, benzyloxycarbonyl or N-loweralkylcarbamoyl group, R2 represents a hydrogen atom or a lower alkyl, cycloalkyl, phenylalkyl, benzyloxycarbonyl, carbamoyl, N-loweralkylcarbamoyl or parafluorobenzoyl-loweralkyl group, Ar represents a phenyl, substituted phenyl, 1 -naphthyl, 2-naphthyl, 1 -indenyl or 2-indenyl group, and the pharmaceutically acceptable addition and quaternary salts thereof.

2. Trans-4-phenoxy-1-phenylmethyl-3-pyrrolidinol.

3. Trans-3-hydroxy-1 -methyl-4-phenoxy-1 -phenylmethylpyrrolidinium iodide.

4. Tra ns-l -methyl-4-phenoxy-3-pyrrolidinol.

5. Trans-3-methoxy-4-phenoxy-1 -phenylmethylpyrrolidine.

6. Trans-3-methoxy-4-phenoxy- I -phenylmethylpyrrolidine oxalate.

7. Trans-3-methoxy-4-phenoxypyrrolidine.

8. Trans-3-methoxy-4-phenoxypyrrolidine fumarate.

9. Trans-4-phenoxy-3-pyrrolidinol.

1 0. Trans-4-phenoxy-3-pyrrolidinol fumarate.

11. Trans -(4-fluorophenyl)-3-(3-hydroxy-4-phenoxy-1 -pyrrolidinyl)- 1 -propanone.

12. Trans-4-(4-chlorophenoxy)-1 -phenylmethyl-3-pyrrolidinol.

13. Trans-3-(4-chlorophenoxy-4-(phenylmethyl[carbonylbis(oxy] I-I -pyrrolidinecarboxylic acid phenylmethyl ester.

14. Trans-4-(4-chlorophenoxy)-3-pyrrolidinol.

1 5. Trans-4-(4-chlorophenoxy)-3-pyrrolidinol hydrobromide.

1 6. Trans-3-(4-chlorophenoxy)-4-hydroxy-1 -pyrrolidinecarboxamide.

1 7. Trans-3-(4-chlorophenoxy)-4-hydroxy-N,N-dimethyl-1 -pyrrolidinecarboxamide.

1 8. Trans-3-(4-chlorophenoxy)-4-hydroxy-N-methyl- 1 -pyrrolidinecarboxamide hemihydrate.

1 9. Trans-3-( [(methyl amino)carbonyljoxy)-4-(4-chlorophenoxy)-N,N-dimethyl-l - pyrrolidinecarboxamide.

20. Trans-4-(2,6-dichlorophenoxy)-1 -phenylmethyl-3-pyrrolidinol.

21. Trans-3-(2,6sdichlorophenoxy)-4-{phenyimethyl[carbonylbis(oxy)] i-i -pyrrolidinecarboxylic acid phenylmethyl ester.

22. Trans-4-(2,6-dichlorophenoxy)-3-pyrrolidinol.

23. Trans-4-(2,6-dichlorophenoxy)-3-pyrrolidinol hydrobromide.

24. Trans-4-(2,3-dichlorophenoxy)-1 -phenylmethyl-3-pyrrolidinol.

25. Trans-4-(2,3-dichlorophenoxy)-1 -phenylmethyl-3-pyrrolidinol hydrochloride.

26. Trans-4-(2,3-dichlorophenoxy)- 1 -[(phenylmethoxy)carbonyl]-3-pyrrnIidinol.

27. Trans-3-(2-dichlorophenoxy)-4-(phenylmethyl[carbonylbis(oxy)] )-i -pyrrolidine carboxylic acid phenyimethyi ester.

28. Trans-4-(2,3-dichlorophenoxy)-3-pyrrolidinol.

29. Trans-4-(2,3-dichlorophenoxy)-3-pyrrolidinol hydrobromide.

30. Trans-i -benzyl-4-(3-methylphenoxy)-3-pyrrolidinol.

31. Trans-i -benzyl-4-(3-methylphenoxy)-3-pyrrolidinol hydrochloride.

32. Trans-4-(3-methylphenoxy)-3-pyrrnIidinol.

33. Trans-4-(3-methylphenoxy)-3-pyrrolidinol oxalate.

34. Trans-4-(2,3-dimethylphenoxy)-1 -phenylmethyl-3-pyrrolidinol.

35. Trans-4-(2,3-dimethylphenoxy)-3-pyrrolindol.

36. Trans-4-(2,3-dimethylphenoxy)-3-pyrrolidinol hydrobromide.

37. Trans-4-(2-methoxyphenoxy)-l -phenylmethyl-3-pyrrolidinol.

38. Trans-4-(2-methoxyphenoxy)-3-pyrrolidinol.

39. Trans-4-(2-methoxyphenoxy)-3-pyrrolidinol fumarate.

40. Trans-4-(4-methoxyphenoxy)-1 -phenylmethyl-3-pyrrolidinol.

41. Trans-4-(4-methoxyphenoxy)-3-pyrrolidinol.

42. Trans-4-(4-methoxyphenoxy)-3-pyrrolidino oxalate (3:4).

43. Trans-4-(2-ethoxyphenoxy)-1 -phenylmethyl-3-pyrrolidinol.

44. Trans-4-(2-ethoxyphenoxy)-3-pyrrolidinol.

45. Trans-4-(2-ethoxyphenoxy)-3-pyrrolidinol fumarate.

46. Trans-4-[4-(phenylmethoxy)phenoxy]-l -phenylmethyl-3-pyrrolidinol.

47. Trans-4-(4-hydroxyphenoxy)-3-pyrrolidinol.

48. Trans-4-(4-hydroxyphenoxy)-3-pyrrolidinol hemioxalate.

49. Trans-4-(3-trifluoromethylphenoxy)-1 -phenylmethyl-3-pyrrolidinol.

50. Trans-4-(3-trifluoromethylphenoxy)- 1 -phenylmethyl-3-pyrrolidinol oxalate.

51. Trans-4-(3-trifluoromethylphenoxy)-3-pyrrolidinol.

52. Trans-4-(3-trifluoromethylphenoxy)-3- pyrrolidinol hydrochloride.

53. Trans-4-[(4-hydroxy- 1 -phenyl m ethylpyrro lidin-3-yl)oxy]benza m ide.

54. Trans -4-[(4-hydroxy-3-pyrrolidinyl)oxy]benzamide.

55. Trans-N-(4-[(4-hydroxy- 1 phenylmethyl-3-pyrrolidinyl)oxy]phenyljacetamide.

56. Trans-N-(4-[(4-hydroxy-3-pyrrolidinyl)oxy]phenyl lacetamide.

57. Trans-N-(4-[(4-hydroxy-3-pyrrolidinyl)oxy]phenyl )acetamide hemifumarate.

58. Trans-4-( 1 -naphthalenyloxy)- 1 -phenylmethyl-3-pyrrolidinol.

59. Trans-4-(l -naphthalenyloxy)-l -phenylmethyl-3-pyrrolidinol oxalate.

60. Trans-4-( 1 -naphth'alenyloxy)-3-pyrrolidinol.

61. Trans-4-[1 H-2,3-dihydroinden-4-yl )oxy]-l -phenylmethyl-3-pyrrolidinol.

62. Trans-4-[ 1 H-2,3-dihydroinden-4-yl)oxy]-3-pyrrolindinol.

63. Trans-4-[1 H-2,3-dihydroinden -4-yl)oxy]-3-pyrrolidinol hydrochloride.

64. Trans4-[(l ,2-dihydroinden-5-yl)oxy]-l -phenylmethyl-3-pyrrolidinol.

65. Trans-4-[(1,2-dihydroinden-5-yl)oxy]-1-phenylmethyl-3-pyrrolidinol hydrochloride.

66. Trans-4-[(2,3-dihydro-1 H-inden-5-yl)oxy]-3-pyrro!indinol.

67. Trans-4-[(2,3-dihydro-1 H-inden-5-yl)oxy]-3-pyrrolindinol oxalate.

68. Trans-l -ethyl-4-phenoxy-3-pyrrolidinol.

69. Trans-1-ethyl-4-phenoxy-3-pyrrolidinol oxalate hydrate (4:1).

70. Trans-i -ethyl-4-phenoxy-3-pyrrolidinolmethylcarbamate ester.

71. Trans-4-(2-chlorophenoxy)- 1 -ethyl-3-pyrrolidinol.

72. Trans-4-(2-chlorophenoxy)-1 -ethyl-3-pyrrolidinol Ihydrochloride.

73. Trans-4-(2,6-dichlorophenoxy)- 1 -ethyl-3-pyrrolidinol.

74. Trans-4-(2,6-dichlorophenoxy)-1 -ethyl-3-pyrrolidinol hydrochloride.

75. Trans-l -ethyl-4-(3-methylphenoxy)-3-pyrrolidinol.

76. Trans-i -ethyl-4-(3-methylphenoxy)-3-pyrrolidinol oxalate hemihydrate.

77. Trans-4-(2-ethoxyphenoxy)- 1 -ethyl-3-pyrrolidinol.

78. Trans- 1 -{ 4-[( 1 -ethyl-4-hydroxy-3-pyrrolidinyl)oxy]-3-methoxyphenyl lethanone.

79. Trans -(4-[( 1 -ethyl-4-hydroxy-3-pyrrol idinyl)oxy]-3-methoxyphenyl )ethanone sesquioxalate.

80. Trans-i -ethyl-4-[2-(2-propenyl)phenoxy]-3-pyrrolidinol.

81. Trans -ethyl-4-[2-(2-propenyl)phenoxy]-3-pyrrolidinol oxalate.

82. Trans-1-ethyl-4-[2-(2-propenyl)phenoxy]-3-pyrrolidinolethylcarbamate (ester).

83. Trans-i -ethyl-4-( 1 -naphthalenyloxy)-3-pyrrolidinol.

84. Trans -ethyl-4-( 1 -naphthalenyloxy)-3-pyrrolidi nol hydrochloride.

85. Trans- 1 -ethyl-4-[(1 H-2,3-dihydroinden-4-yl)oxy]-3-pyrrolidinol.

86. Trans-1-ethyl-4-[(1 H-2,3-dihydroinden-5-yl)oxy]-3-pyrrolidinol.

87. Trans-1-ethyl-4-[(1 H-2,3-dihydroinden-5-yl)oxy]-3-pyrrolidinol maleate.

88. Trans -cyclohexyl-4-phenoxy-3-pyrrolidinol.

89. Trans -cyclohexyl-4-phenoxy-3-pyrrolidinol compound with cyclohexane-sulphamic acid.

90. Cis-4-phenoxy-i -phenylmethyl-3-pyrrolidinol.

91. Cis-4-(3-chlorophenoxy)- 1 -phenylmethyl-3-pyrrolidinol.

92. Cis-3-(3-chlornphenoxy)-4-hydrnxy-1 -m ethyl-l -phenylmethylpyrrolidinium iodide.

93. Cis-l -methyl-4-phenoxy-3-pyrrolidinol.

94. Cis-4-phenoxy-3-pyrrolidinol.

95. Cis-4-phenoxy-3-pyrrolidinol hydrochloride hydrate (4:1).

96. A compound as claimed in Claim 1 substantially as specifically described herein with reference to any one of Examples 1 to 63.

97. A compound as claimed in Claim 1 whenever made by a method substantially as specifically described herein with reference to any one of Examples 1 to 63.

98. A pharmaceutical composition comprising as active ingredient a compound as claimed in any one of Claims 1 to 97 and a pharmaceutically acceptable carrier or diluent therefor.

99. A pharmaceutical composition as claimed in Claim 98 substantially as specifically described herein with reference to any one of Examples 64A to 64G, 65 or 66.

100. The use of a cis or trans isomer of a compound having the formula:

wherein R2 represents a hydrogen atom or a lower alkyl or phenyla!kyl group, and Ar represents a phenyl or substituted phenyl group, in an effective amount for treating depression in animals or human beings.

101. A use as claimed in Claim 100 in which the compound is trans-4-(2,6-dichlorophenoxy)-3pyrrolidinol.

102. A use as claimed in Claim 100 in which the compound is trans-1 -ethyl-4-phenoxy-3pyrrolidinol.

103. A use as claimed in Claim 100 in which the compound is trans -methyl-4-phenoxy-3pyrrolidinol.

104. A use as claimed in Claim 100 in which the compound is trans-4-(2,6-dichlorophenoxy)-1 ethyl-3-pyrrolidinol.

105. A use as claimed in Claim 100 in which the compound is trans-4-(2,3-dichlorophenoxy)-3pyrrolidinol.

106. A cis or trans isomer of a compound having the formula:

wherein R2 represents a hydrogen atom or a loweralkyl group, and Ar represents a 1 - or 2-naphthyl or a 4- or 5-indenyl group for use in the treatment of arrythmias in animals or human beings.

1 07. Trans-1-ethyl-4-(1 -naphthaleneyloxy)-3-pyrrolidinol as claimed in Claim 106.

106. The use of a cis or trans isomer of a compound having the formula:

wherein R2 represents a hydrogen atom or a loweralkyl group, and Ar represents a 1- or 2-naphthyl or a 4- or 5-indenyl group in an effective amount for treating arrythmias in animals or human beings.

107. A method as claimed in Claim 106 in which the compound is trans-i -ethyl-4-( 1 - naphthaleneyloxy)-3-pyrrolidinol.

New Claims or Amendments to Claims filed on 2 May 1980.

Superseded Claims 100 to

107.

New or Amended Claims:

100. A cis or trans isomer of a compound having the formula:

wherein R2 represents a hydrogen atom or a lower alkyl or phenylalkyl group, and Ar represents a phenyl or substituted phenyl group, for use in the treatment of depression in animals or human beings.

101. Trans-4-(2-dichlorophenoxy)-3-pyrrolidinol as claimed in Claim 100.

1 02. Trans-I -ethyl-4-phenoxy-3-pyrrolidinol as claimed in Claim 1 00.

103. Trans-1-methyl-4-phenoxy-3-pyrrolidinol as claimed in Claim 100.

104. Trans-4-(2,6-dichlorophenoxy)-l -ethyl-3-pyrrolidinol as claimed in Claim 100.

1 05. Trans-4-(2,3-dichlorophenoxy)-3-pyrrolidinol as claimed in Claim 1 00.