DE3000625A1 - CIS AND TRANS ISOMERS OF 3-ARYLOXY- 4-HYDROXYPYRROLIDINES AND THEIR DERIVATIVES, METHODS FOR THE PRODUCTION THEREOF AND THEIR USE - Google Patents

Description

The present invention relates to certain new cis and trans isomers of 3-aryloxy-4-hydroxypyrrolidines and derivatives of these compounds which are useful in preparations made therefrom for the treatment of depression, hypertension or cardiac arrhythmias in animals.

Compounds of the present invention have not previously been available. German Offenlegungsschrift 2,738,477 describes certain trans-3-aryloxy-4-hydroxypyrrolidines and piperidines which are related to the present invention, but this is a more recent publication. None of the compounds described in this laid-open specification are cis isomers. Certain compounds of the present invention also differ in that they are substituted on the pyrrolidinyl nitrogen by alkyl, phenylalkyl and cycloalkyl.

The present invention provides new cis and trans isomers of 3-aryloxy-4-hydroxypyrrolidines and derivatives of these compounds which have important pharmacological activity. The compounds of the present invention are represented by General Structural Formula I below

reproduced in which

R [high] 1 hydrogen, lower alkyl, benzoyloxycarbonyl or N-lower alkylcarbamoyl,

R [high] 2 hydrogen, lower alkyl, cycloalkyl, phenylalkyl, benzyloxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N-di-lower alkylcarbamoyl or p-fluorobenzoyl-lower alkyl,

and

Ar is phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, 1-indenyl or 2-indenyl.

The pharmaceutically acceptable acid addition salts and the quaternary salts of these compounds are also included. The compounds have a cis or trans configuration.

The compounds of the present invention have antidepressant, hypotensive, and cardiovascular activity in animals.

The presence of the antidepressant activity was determined by the method of Englehardt, E.L. et al., J. Med. Chem., 11 (2): 325 (1968) in which the new compounds of the present invention were administered intraperitoneally to mice and the effectiveness of the compounds in blocking the depressive effects produced in mice by intravenous administration of 2-oxo-3-isobutyl-9,10-dimethoxy-1,2,3,4,6 , 7-hexahydro-11bh-benzo [a] -quinolizine (tetrabenazine) was determined.

Compounds according to the invention for which a pronounced antidepressant activity has been observed have the general formula Ia wherein R [high] 2 is hydrogen, lower alkyl or phenylalkyl, and

Ar is phenyl or substituted phenyl.

Compounds preferred for their antidepressant activity have the general formula Ib

The effective doses which were determined by means of the aforementioned anti-tetrabenazine test are illustrative of the antidepressant activity of compounds of the general formula Ia.

The effect of certain compounds disclosed in the present invention for the control of cardiac arrhythmias is demonstrated by the following method. The procedure is performed on adult bastard dogs of both sexes weighing 8 to 14 kg under barbiturate anesthesia. A Grass Model 7 polygraph was used to record femoral artery blood pressure (Statham P23AC transducer) and the electrocardiogram (Grass 7P4 preamplifier). g-strophanthin was administered intravenously in an initial dose of 40 small gamma / kg, in a second dose of 20 small gamma / kg given 30 minutes after the first dose, and in subsequent doses of 10 small gamma / kg which at 15 minute intervals as needed to produce cardiac arrhythmias that persisted for at least 15 minutes. Once the arrhythmias developed, the compounds to be tested were administered by infusion (Harvard Model 942 Infusion Pump) into a femoral vein at a rate of 1 mg / kg / min. The concentrations of the compounds were adjusted according to the weight of the dogs to allow a volume infusion of 1 ml / min. Compounds considered to be active antiarrhythmic agents reverse sinus rhythm, which is sustained for at least 60 minutes.

Compounds according to the invention for which a pronounced antiarrhythmic activity has been observed have the general formula Ic wherein R [high] 2 is hydrogen or lower alkyl, and Ar is 1- or 2-naphthyl or 4- or 5-indenyl.

The compound of Example 55 is a preferred compound that is exceptional antiarrhythmic

Shows activity at a minimum effective dose of 10.7 mg / kg using the aforementioned method.

It is therefore an object of the present invention to provide cis- and trans-3-aryloxy-4-hydroxypyrrolidines and derivatives thereof which have a high degree of antidepressant activity and processes for their preparation.

Furthermore, according to the present invention, cis- and trans-3-aryloxy-4-hydroxypyrrolidines and derivatives thereof are provided which have antiarrhythmic and hypotensive activity in animals.

Furthermore, according to the present invention, methods for using the cis- and trans-3-aryloxy-4-hydroxypyrrolidines as antidepressant, antihypertensive and antiarrhythmic agents in the treatment of living animals, especially mammals, in the event of a treatment emergency are provided. Other advantages of the invention will be apparent to one skilled in the art and are discussed below.

The present invention includes the new cis and trans isomers of 3-aryloxy-4-hydroxypyrrolidines and their derivatives of these compounds of the above general formula I and the preparations produced with these compounds, as well as the use of these new compounds because of their pharmacological action in living animals, as has been explained above and below.

The term "lower alkyl" as used in the description and claims includes straight-chain and branched-chain radicals of up to 8 carbon atoms including, examples of which are groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl , Amyl, isoamyl, hexyl, heptyl, octyl, and the like can be listed.

The term "substituted phenyl" as used in the description and the claims includes phenyl which is substituted in the 1 to 3 positions by one or more radicals, namely halogen, O-lower alkyl, -NHC (O) CH [deep ] 3, CF [deep] 3, -C (O) Ch [deep] 3, -CH [deep] 2CH = CH [deep] 2, alkyl, hydroxy, -OCH [deep] 2-phenyl and / or -C (O) HH [deep] 2, is substituted.

"Cycloalkyl" is to be understood as meaning cycloalkyl radicals having 1 to 9 carbon atoms, including, for example, radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Representative phenylalkyl radicals are benzyl (phenylmethyl), small alpha-methylbenzyl, phenylethyl, phenylpropyl, phenylbutyl, and the like.

The starting materials used to prepare the new trans isomeric compounds of general formula I are 1-phenylalkyl-3,4-epoxypyrrolidines, such as, for example, 1-benzyl-3,4-epoxypyrrolidine, 1-alkyl-3,4-epoxypyrrolidines, such as 1 -Ethyl-3,4-epoxypyrrolidine, and 1-cycloalkyl-3,4-epoxypyrrolidines, such as 1-cyclohexyl-3,4-epoxypyrrolidine.

The preparation of these 1-substituted epoxypyrrolidines is shown by the following reaction equation: in which R is lower alkyl, phenylalkyl or cycloalkyl. The chlorination step is usually carried out in 2 to 6 hours and there is no need to isolate intermediate III. Crude epoxypyrrolidines are obtained by solvent extraction and converted into crystalline salts such as oxalates. The pure free base of the epoxypyrrolidines can be obtained from the oxalate salt by partitioning between 5% aqueous sodium carbonate and methylene chloride and then drying over anhydrous sodium sulfate and evaporating the methylene chloride. The pyrrolines used in this initial manufacturing process are prepared by the process of US Pat. No. 3,691,196, and the process for preparing 1-cyclohexyl-large delta [high] 3-pyrroline is given in Preparation 1.

The preparation of the epoxypyrrolidines used to prepare the trans isomers of the general formula I is given in preparation processes 2 to 4.

The starting material used to prepare the cis isomers of the compounds of the general formula I was cis-benzyl-3,4-pyrrolidinediol, which is described in preparation process 5. cis-3,4-pyrrolidinediols were first described by Hill, A. J. et al., J. Amer. Chem. Soc. 76, 3548 (1954).

Manufacturing process 1

1-Cyclohexyl-large delta [high] 3-pyrroline

A solution of 5.19 kg (52.3 moles) of cyclohexylamine in 4.0 liters of benzene was heated to mild reflux (92 ° C) and then the heating was discontinued. To the solution, 1635 g (13.1 mol) of 1,4-dichlorobutene was added dropwise at a rate sufficient to maintain a gentle reflux, which required 3 hours. Heating was continued and the reactants refluxed for 18 hours. The mixture was cooled to about 50 ° C and filtered to remove the hydrochloride salt. Carbon dioxide gas was bubbled into the filtrate to precipitate the excess amine carbonate salt, which was removed by filtration. The solvent was removed from the filtrate by distillation under reduced pressure, and a reddish liquid residue which was slightly contaminated with benzene weighing 1506 g was obtained (yield 76%).

Manufacturing process 2

1-benzyl 3,4-epoxypyrrolidine oxalate

Into a mixture of 31.8 g (0.20 mol) of N-benzyl-large delta [high] 3-pyrroline, 25 liters of concentrated hydrochloric acid and 300 ml

Gaseous chlorine was passed into water for 2 hours. The solution was filtered and the filtrate made basic with 20% sodium hydroxide. The basic solution was extracted with three 150 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate 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 hour, 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 sulfate and concentrated to give 34.9 g of crude epoxide as a dark oil (99%). The oxalate salt was produced in 81% yield. Recrystallization from 95% ethanol gave the salt in the form of almost white needles; 148 ° to 149 ° / degree.

Analysis for C [deep] 13H [deep] 15NO [deep] 5:

Calculated: C 58.86%, H 5.70%, N 5.28%;

Found: C 58.55%, H 5.68%, N 5.25%.

Manufacturing process 3

1-ethyl-3,4-epoxypyrrolidine oxalate

A mixture of 61 g (0.63 mol) of 1-ethylpyrroline, 50 ml of concentrated aqueous hydrochloric acid and 600 ml

Water was treated with chlorine gas for 2½ hours. The mixture was filtered through cotton and the filtrate washed with two 100 ml portions of methylene chloride. The aqueous layer was basified with 20% sodium hydroxide, heated on a steam bath for 1/2 hour, and extracted with three 100 ml portions of methylene chloride. The combined extracts were dried over anhydrous sodium sulfate and concentrated, and the residue was distilled in vacuo. 39.4 g (56%) of the epoxide were obtained as a clear oil (boiling point 75 ° to 90 ° at 28 mm). The epoxide was converted to the oxalate and the salt was recrystallized from absolute ethanol. White needles were obtained; Melting point 142 ° to 144 ° / degree.

Analysis for C [deep] 8H [deep] 13NO [deep] 5:

Calculated: C 47.29%, H 6.45%, N 6.89%;

Found: C 47.12%, H 6.42%, N 6.82%.

Manufacturing process 4

1-cyclohexyl-3,4-epoxypyrrolidine oxalate

A solution of 151.3 g (1.0 mol) of N-cyclohexyl-large Delta [high] 3-pyrroline, 100 ml of concentrated hydrochloric acid and 1.8 liters of water was treated with chlorine gas until absorption ceased (tilde, proportional 6 hours). The solution was washed with methylene chloride and the acidic solution was left to stand overnight.

The solution was then basified with 50% sodium hydroxide and extracted with methylene chloride. The combined extracts were concentrated and 185 g of chlorohydrin were obtained as a residue. The residue was slowly poured into an ethanol solution containing 20% sodium hydroxide. The mixture was stirred for ½ hour and then 3.5 liters of water was added. The mixture was extracted with methylene chloride and the combined extracts dried over anhydrous sodium sulfate and concentrated. 154 g (92%) of amine epoxide were obtained. An NMR analysis shows that this residue is 86% epoxide and 14% 3,4-dichloro-N-cyclohexylpyrrolidine. The residue was distilled in vacuo and the epoxide was obtained as a water-white liquid, boiling point 71 ° C. at 0.6 mm. A portion of the liquid was converted into the oxalate and a white solid was obtained after recrystallization from ethanol; Melting point 155 ° to 156 ° / degree.

Analysis for C [deep] 12H [deep] 19NO [deep] 5:

Calculated: C 56.02%, H 7.44%, N 5.44%;

Found: C 56.05%, H 7.50%, N 5.34%.

Manufacturing process 5

1-Phenylmethyl-3,4-pyrrolidinediol monohydrochloride cis isomer

A mixture of 80 g (0.32 mol) of meso-1,4-dibromo-2,3-dihydroxybutane,

34 g (0.32 mol) of benzylamine, 3 g of potassium iodide and 140 g (1.0 mol) of potassium carbonate in 250 ml of 95% strength ethanol were refluxed for 18 hours, then cooled and filtered. The filtrate was concentrated and the residue was washed with several portions of boiling ethyl acetate. The extracts were combined, washed with a small amount of water, dried over anhydrous sodium sulfate and concentrated. 30 g of a residue were obtained which represented 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 recrystallized from isopropyl alcohol. Almost white granules were obtained; Melting point 115.0 ° to 116.5 °.

Analysis for C [deep] 11H [deep] 16ClMO [deep] 2:

Calculated: C 57.52%, H 7.02%, N 6.10%;

Found: C 57.16%, H 6.91%, N 6.01%.

The synthesis of trans-isomeric compounds of the general formula I, which form part of the present invention and also serve as reactants for the preparation of other compounds of the invention, starts from the reaction of aryloxy compounds with suitable 1-substituted 3,4- Epoxypyrrolidinen, as exemplified by the following equation:

wherein R [high] 2 is phenylalkyl, alkyl and cycloalkyl, and Ar has the same meaning as above.

The synthesis of the cis isomers which are part of the present invention and which serve as reactants for other compounds of the present invention proceeded from the reaction of 1-benzyl-3,4-pyrrolidinediol cis isomer with Ar-F compounds according to the following reaction equation wherein Ar has the same meaning as above.

For the preparation of further varied compounds that fall under the general formula I, the following processes can be used either for the preparation of the trans or of the cis isomers are used:

(1) R [high] 2 = hydrogen, R [high] 1 = hydrogen or alkyl

(2) R [high] 2 = alkyl

(3) R [high] 1 = alkyl

(4)

(5)

(6) Ar = halogen-substituted phenyl R [high] 2 = hydrogen

(7)

(8th)

(9)

(10)

(11) [high] 1 = hydrogen; Ar = C [deep] 6H [deep] 5, starting from Ar = C [deep] 6P [deep] 4-Hal

To obtain the free base of a compound prepared as a salt, the salt is partitioned between methylene chloride and 5% sodium hydroxide. The methylene chloride layer is dried over sodium sulfate and concentrated, the base being obtained as a residue.

In summary, the present invention relates to cis- and trans-3-aryloxy-4-hydroxypyrrolidines and derivatives of this compound of the general formula wherein R [high] 1 is hydrogen, lower alkyl, benzyloxycarbonyl or N-lower alkylcarbamoyl, R [high] 2 is hydrogen, lower alkyl, cycloalkyl, phenylalkyl, benzyloxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,

N-di-lower alkylcarbamoyl or p-fluorobenzoyl-lower alkyl, and Ar is phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, 1-indenyl or 2-indenyl, and pharmaceutically acceptable acid addition salts and quaternary salts thereof. The compounds have antidepressant, antihypertensive and antiarrhythmic activity in animals.

The new compounds of the present invention and the processes for their preparation are illustrated in more detail by the following examples, which, however, are not intended to limit the scope of the present invention. As can be readily seen from a consideration of the examples and the description above, many of the compounds falling under the general formula I can also be regarded as intermediates in the synthesis of the other compounds of the formula I.

example 1

trans -4-phenoxy-1-phenylmethyl-3-pyrrolidinol

A mixture of 12.3 g of 1-benzyl-3,4-epoxypyrrolidine, 13.2 g of phenol and 3 drops of water was heated to 120 ° C. for 20 hours under nitrogen. The mixture was cooled and dissolved in 100 ml of ethyl ether. The essential solution was extracted with 2 × 50 ml of 5% sodium hydroxide and then washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated and a residue weighing 14.3 g was obtained. Two recrystallizations from cyclohexane yielded an analytically pure product with a melting point of 101 ° to 104 ° C. The yield was 24% of theory.

Analysis for C [deep] 17H [deep] 19NO [deep] 2:

Calculated: 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-phenylmethyl-pyrrolidinium iodide

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 admitted. The mixture was stirred for 2 days and then concentrated under reduced pressure. The 10.7 g of the crystalline residue was washed with tetrahydrofuran and dried to give 10.4 g (97%) of a white powder;

Melting point 122 ° to 127 ° C.

Analysis for C [deep] 18H [deep] 22JNO [deep] 2:

Calculated: C 52.57%, H 5.39%, N 3.41%;

Found: C 52.78%, H 5.45%, N 3.55%.

Example 3

trans -1-methyl-4-phenoxy-3-pyrrolidinol

A solution of 9.3 g (22.6 mmol) of trans-3-hydroxy-1-methyl-4-phenoxy-1-phenylmethylpyrrolidinium iodide in 200 ml of absolute ethanol and 100 ml of 190-ethanol was at room temperature for ½ hour with 2.6 g (11.3 mmol) of silver oxide stirred. After an additional 0.2 g of silver oxide had been added, the mixture was heated to 45 ° C. and stirred for an additional 15 minutes. The mixture was separated by filtration through Celite and the volume of the filtrate was reduced to 200 ml. The solution was treated with approximately 0.5 g of 10% Pd / C catalyst and shaken with hydrogen in a Parr reducer for 3 hours. The suspension was filtered through Celite and the filtrate was concentrated. 4.3 g of a crystalline solid were obtained which, after recrystallization from cyclohexane, gave 3.66 g (84%) of almost white crystals; Melting point 89.0 ° to 90.0 ° C.

Analysis for C [deep] 11H [deep] 15NO [deep] 2:

Calculated: 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 oxalate

8.1 g (0.03 mol) of trans-4-phenoxy-1-phenylmethyl-3-pyrrolidinol was treated with 0.72 g (0.03 mol) of sodium hydride (1.3 g of 55% NaH in oil, with 3 x washed 10 ml of diethyl ether) mixed in 50 ml of dimethylformamide and stirred until the evolution of hydrogen ceased. 4.3 g (0.03 mol) of methyl iodide was added and the mixture was stirred for 18 hours. The reaction mixture was worked up by pouring it into 400 ml of water and extracting it three times with 100 ml of diethyl ether. The diethyl ether was evaporated and 7.9 g of a residue were obtained. Addition of petroleum ether caused precipitation of the starting material, which was removed by filtration. After evaporation of the mother liquor, the residue was chromatographed on silica gel and the product was eluted with 10% acetone in benzene. The yield of pure product according to NMR analysis was 5.0 g (59%). A small amount was converted to the oxalate in isopropyl alcohol and recrystallized from isopropyl alcohol; Melting point 122 ° to 125 ° C.

Analysis for C [deep] 20H [deep] 23NO [deep] 6:

Calculated: 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 fumarate

A solution of 4.2 g (0.015 mol) of 3-methoxy-4-phenoxy-1-phenylmethylpyrrolidine in 70 ml of ethanol was treated with about 0.2 g of Pd / C catalyst and treated with hydrogen at 60 ° C. in the Parr -Apparatus shaken for 3 hours. After cooling, the mixture was filtered and the solvent was evaporated. The 2.9 g (100%) of the crude product (good purity according to NMR analysis) was converted into the fumarate in isopropyl alcohol. The pale yellow precipitate had a melting point of 134-136 ° C.

Analysis for C [deep] 15H [deep] 19NO [deep] 6:

Calculated: 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% palladium-on-carbon catalyst and treated with hydrogen at 60 ° C in the Parr Reducer shaken for 5 hours. The suspension was cooled, filtered and the solvent evaporated under reduced pressure. The residue was converted to the fumarate using isopropyl alcohol. The yield of product was 14.1 g (37%), melting point 158-162 ° C.

Analysis for C [deep] 14H [deep] 17NO [deep] 16:

Calculated: 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 mol) of 4-phenoxy-3-pyrrolidinol, 5 g (0.0215 mol) of small beta-dimethylamino-p-fluoropropiophenone hydrochloride, 10 g of potassium carbonate and 50 ml of dimethylformamide was stirred at 70 C. for 6 hours with nitrogen gas bubbling through the reaction mixture. The mixture was poured into water and extracted twice with benzene. The combined extracts were dried over anhydrous sodium sulfate and concentrated to give 6.1 g of an oil as a residue. The oil was chromatographed on 130 g of silica gel. The desired compound was eluted with 20% acetone in benzene to give 2.6 g (39%) of an oil which gradually crystallized on standing. The solid was recrystallized from petroleum ether / diethyl ether and a white solid was obtained;

Melting point 77 ° to 80 ° C.

Analysis for C [deep] 19H [deep] 20FNO [deep] 3:

Calculated: C 69.28%, H 6.12%, N 4.25%;

Found: C 69.43%, N 6.23%, N 4.18%.

Example 8

trans -4- (4-chlorophenoxy) -1-phenylmethyl-3-pyrrolidinol

A mixture of 12.3 g of 1-penzyl-3,4-epoxypyrrolidine, 18.0 g of p-chlorophenol and 3 drops of water was heated at 120 ° C. under nitrogen gas for 20 hours. The mixture was cooled and dissolved in 100 ml of diethyl ether. The ethereal solution was extracted twice with 50 ml of 5% sodium hydroxide and then washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated and a residue of 14.3 g was obtained. Two recrystallizations from cyclohexane gave 4.7 g (29%) of an analytically pure product with a melting point of 101 ° to 104 ° C.

Analysis for C [deep] 17H [deep] 18ClNO [deep] 2:

Calculated: C 67.21%, H 5,, 97%, N 4.61%;

Found: C 67.35%, H 6.10%, N 4.69%.

Example 9

phenylmethyl trans -3 (4-chlorophenoxy-4- {phenylmethyl [carbonylbis (oxy)]} - 1-pyrrolidinecarboxylate

A solution of 14.0 g (0.046 mol) of trans-4- (4-chlorophenoxy) -1-phenylmethyl-3-pyrrolidinol and 5 g (0.05 mol) of triethylamine in 200 ml of benzene was added dropwise to a cold (15 ° C) A solution of 30.0 g (0.175 mol) of benzyl chloroformate in 100 ml of benzene was added. The mixture was allowed to warm to room temperature and stir overnight. The precipitate was removed by filtration and discarded and the filtrate concentrated and the residue heated under high vacuum to remove excess reactants and by-products. The gum obtained was chromatographed on silica gel, the desired product eluted with 20% acetone in benzene. 5 g of the product were obtained after evaporation.

Example 10

trans -4- (4-chlorophenoxy) -3-pyrrolidinol hydrobromide

A solution of 5 g of 3- (4-chlorophenoxy) -4- {phenylmethyl [carbonylbis (oxy)]} - 1-pyrrolidinecarboxylic acid phenylmethyl ester-trans isomer in 30 ml of ethanol and 50 ml of 48% strength hydrogen bromide was at 115 ° for 16 hours C heated, then cooled and diluted with 100 ml of water. The solution was extracted twice with 50 ml of methylene chloride and the aqueous layer was evaporated to dryness. The powder that remained was the desired product in 82% yield; Melting point 190 ° to 192 ° C.

Analysis for C [low] 10H [low] 13NO [low] 2
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Calculated: C 40.77%, H 4.45%, N 4.76%;

Found: C 41.01%, H 4.46%, N 4.85%.

Example 11

trans -5 (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 to 50 ° C. for 20 hours. A portion of the solvent was removed in vacuo and the remaining slurry diluted with 50 ml of water. The precipitate was filtered off, triturated with acetone, filtered and dried. Yield: 1.8 g; Melting point 223 ° to 225 ° C.

Analysis for C [deep] 11H [deep] 13N [deep] 2O [deep] 3Cl:

Calculated: 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-dimethyl-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 in vacuo, 300 ml of benzene was added and the mixture was refluxed for 2 hours and then filtered. After evaporation of the solvent, the residue was dissolved in cyclohexane / benzene and treated with activated charcoal. The product was then recrystallized, the crystals were filtered off and again recrystallized from cyclohexane / benzene; Melting point 137-142 ° C.

Analysis for C [deep] 13H [deep] 17N [deep] 2O [deep] 3Cl:

Calculated: 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-1-pyrrolidine-carboxamide hemihydrate

A solution of 0.9 g of 4- (4-chlorophenoxy) -3-pyrrolidinol in 50 ml of methylene chloride was cooled to 0 ° C. and 0.24 g

Methyl isocyanate in 5 ml of methylene chloride was added dropwise over a period of 10 minutes. Cooling was continued and stirring continued for 1 hour. The solvent was then removed and the residue was recrystallized from dimethyl sulfoxide / water; Melting point 95.0 ° to 98.5 ° C.

Analysis for C [deep] 12H [deep] 15N [deep] 2O [deep] 3Cl:

Calculated: 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 mol) of trans -3- (4-chlorophenoxy) -4-hydroxy-N, N-dimethyl-1-pyrrolidinecarboxamide and 1.0 g (0.02 mol) of methyl isocyanate in 20 ml of methylene chloride was allowed to stand at room temperature for 48 hours. The solution was concentrated to an oil which crystallized on standing. The solid was recrystallized from benzene / cyclohexane and 0.6 g (50%) of a white solid was obtained; Melting point 132-134 ° C.

Analysis for C [deep] 15H [deep] 20ClN [deep] 3O [deep] 4:

Calculated: C 52.71%, H 5.90%, N 12.29%;

Found: C 53.09%, H 5.96%, N 12.28%.

Example 15

trans -4- (2,6-dichlorophenoxy) -1-phenylmethyl-3-pyrrolidinol

A mixture of 35.0 g of 1-benzyl-3,4-epoxypyrrolidine and 32.6 g of 2,6-dichlorophenol was heated to 125 ° C. for 3 hours. The mixture was cooled, dissolved in methylene chloride and extracted with dilute sodium hydroxide. The solvent was evaporated and the residue was purified by column chromatography. The product was eluted with 30% ethyl acetate in benzene and recrystallized from cyclohexane. The yield was 43 g (64%); Melting point 78 ° to 80 ° C.

Analysis for C [deep] 17H [deep] 17NO [deep] 2Cl [deep] 2:

Calculated: C 60.37%, H 5.07%, N 4.14%;

Found: C 60.42%, H 5.06%, N 4.12%.

Example 16

phenylmethyl trans -3 (2,6-dichlorophenoxy) -4- {phenylmethyl [carbonylbis (oxy)]} - 1-pyrrolidinecarboxylate

To a solution of 3.4 g of trans-1-benzyl-4- (2,6-dichlorophenoxy) -3-pyrrolidinol and 1.05 g of triethylamine in 25 ml of benzene, a solution of 4.0 g of benzyl chloroformate in 20 ml of benzene were added. When the addition was complete, the mixture was stirred for 30 minutes, then filtered and the solvent evaporated under reduced pressure. The residue was dissolved in 50 ml of methylene chloride and 6.0 g of benzyl chloroformate were added. The mixture was stirred overnight, then the solvent was evaporated and the residue was chromatographed on silica gel. The product was eluted with 20% ethyl acetate in benzene and then stirred with petroleum ether until it crystallized out. The white crystals weighed 4.7 g (90%); Melting point 93 ° to 95 ° C.

Analysis for C [deep] 26H [deep] 23NO [deep] 6Cl [deep] 2:

Calculated: C 60.48%, H 4.49%, N 2.71%;

Found: C 60.61%, H 4.55%, N 2.76%.

Example 17

trans -4- (2,6-dichlorophenoxy) -3-pyrrolidinol hydrobromide

A solution of 12.2 g of 3- (2,6-dichlorophenoxy) -4- {phenylmethyl [carbonylbis (oxy)]} - 1-pyrrolidinecarboxylic acid phenylmethyl ester trans isomer in 120 ml of ethanol and 140 ml of 48% strength hydrogen bromide was at 125 ° C for 16 hours, then cooled and diluted with 300 ml of water. The solution was then extracted twice with 100 ml of methylene chloride each time and the aqueous layer was evaporated to dryness. Trituration with 30% diethyl ether in isopropyl alcohol gave 7.4 g (95%) of the white, crystalline hydrobromide;

Melting point 192 ° to 195 ° C.

Analysis for C [deep] 10H [deep] 12NO [deep] 2BrCl [deep] 2:

Calculated: 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 mol) of 1-benzyl-3,4-epoxypyrrolidine, 27.8 g (0.17 mol) of 2,3-dichlorophenol and 2 drops of concentrated hydrochloric acid was left at 120 ° C overnight heated. The dark mixture was dissolved in methylene chloride and washed four times with 100 ml of 5% sodium hydroxide each time and once with water. The methylene chloride layer was dried over anhydrous sodium sulfate / potassium hydroxide and, after concentration, was obtained
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in the form of a dark rubber. This rubber was on
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Chromatographed silica gel and the product eluted with an acetone / benzene solution. The appropriate fractions were concentrated and 25 g (60%) of an oil were obtained. A portion of this oil was converted to the hydrochloride to give a white solid; Melting point 219 ° to 222 ° C.

Analysis for C [deep] 17H [deep] 18Cl [deep] 3NO [deep] 2:

Calculated: 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 mol) of trans-4- (2,3-dichlorophenoxy) -1-phenylmethyl-3-pyrrolidinol hydrochloride and 100 ml of methyl chloride was cooled and treated dropwise with a solution of 23 g (0.125 mol) of benzyl chloroformate in Treated 100 ml of methylene chloride. The mixture was stirred for 48 hours at room temperature and then successively with water,
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Hydrochloric acid, 5% sodium hydroxide and water. The methylene chloride layer was dried over anhydrous sodium sulfate and then distilled in vacuo at 100 ° / 1.0 mm to remove the methylene chloride, the excess benzyl chloroformate and the benzyl chloride. An NMR analysis of the distillation residue indicates that only the oxygen was substituted. A further 25 ml of benzyl chloroformate and 100 ml of methylene chloride were added to the residue, and the solution was stirred at room temperature for 48 hours. The mixture was purified as above to give 14.6 g of a residue which was chromatographed on 300 g of silica gel. Chromatography provided 5.6 g of the disubstituted compound (see Example 20) and 1.0 g of the title compound as a white solid; Melting point 130 ° to

132 ° C (recrystallized from benzene).

Analysis for C [deep] 16H [deep] 17Cl [deep] 2NO [deep] 4:

Calculated: C 56.56%, H 4.48%, N 3.67%;

Found: C 56.80%, H 4.48%, N 3.67%.

Example 20

phenylmethyl trans -3 (2-dichlorophenoxy) -4- {phenylmethyl [carbonylbis (oxy)]} - 1-pyrrolidinecarboxylate

This disubstituted compound was obtained from the chromatographic separation of Example 19 in an amount of 5 to 6 g.

Example 21

trans -4- (2,3-dichlorophenoxy) -3-pyrrolidinol hydrobromide

A mixture of 5.6 g (0.011 mol) of 3- (2-dichlorophenoxy) -4- {phenylmethyl [carbonylbis (oxy)]} - 1-pyrrolidinecarboxylic acid phenylmethyl ester trans isomer, 60 ml of ethanol and 70 ml of 48% aqueous hydrogen bromide was heated to 125 ° C overnight. The mixture was poured into 150 ml of water and extracted three times with methylene chloride. The aqueous solution was concentrated to give an oily residue which crystallized on standing. The solid was washed with isopropyl alcohol / diethyl ether, collected by filtration and recrystallized from isopropyl alcohol / diethyl ether. 1.5 g (45%) of a pink solid were obtained; Melting point 134-138 ° C.

Analysis for C [deep] 10H [deep] 12BrCl [deep] 2NO [deep] 2:

Calculated: 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 17.5 g of 1-benzyl-3,4-epoxypyrrolidine and 20 g of m-cresol was heated to 115 ° C. for 18 hours under nitrogen gas. After cooling, the mixture was dissolved in benzene and washed with 5% sodium hydroxide to remove the excess cresol. Stirring with 50 g of silica gel removed a large amount of the colored material. The solution was concentrated and part of the residue was converted into the hydrochloride. This salt was recrystallized from isopropyl alcohol / diethyl ether and had a melting point of 163 ° to 165 ° C.

Analysis for C [deep] 18H [deep] 22NO [deep] 2Cl:

Calculated: 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 150 ml of ethanol was treated with approx ° C in the Parr Reducer for 2 hours. The suspension was cooled, filtered and the solvent evaporated in vacuo. The base was converted to the oxalate in isopropyl alcohol, filtered and dried. The salt was obtained in 86% yield; Melting point 150-155 ° C.

Analysis for C [deep] 13H [deep] 17NO [deep] 5:

Calculated: 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 mol) of 1-benzyl-3,4-epoxypyrrolidine, 18.3 g (0.15 mol) of 2,3-dimethylphenol and 2 drops of concentrated hydrochloric acid was left on overnight under a nitrogen atmosphere Heated to 120 ° C. The reaction mixture was dissolved in methylene chloride and added with four 100 ml portions of 5% sodium hydroxide and once with water washed. The methylene chloride layer was dried over anhydrous sodium sulfate / potassium hydroxide and, after concentration, afforded 28.6 g of a dark oil as a 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 and an oil was obtained which crystallized on standing. This solid was recrystallized from ligroin to give 9.1 g (31%) of a white solid; Melting point 100 ° to 104 ° C.

Analysis for C [deep] 19H [deep] 23NO [deep] 2:

Calculated: 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 mol) of trans-4- (2,3-dimethylphenoxy) -1-phenylmethyl-3-pyrrolidinol in 100 ml of ethanol was poured over 10% palladium-on-charcoal at 50 psi (3, 5 kg / cm [high] 2) and hydrogenated at 60 ° C. until the uptake of hydrogen ceased. The mixture was filtered through Celite, the filtrate was concentrated and the residue obtained was an oil which solidified on standing. The solid was converted into the hydrobromide and this salt from isopropyl alcohol / ethyl acetate / diethyl ether recrystallized. 4.9 g (55%) of yellow-brown needles were obtained; Melting point 152-153 ° C.

Analysis for C [deep] 12H [deep] 18BrNO [deep] 2:

Calculated: 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-epozypyrrolidine and 70 g of guaiacol was heated to 120 ° C. for 20 hours. An 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 sulfate and the solvent was evaporated. The residue weighing 54 g was chromatographed on 1 kg of silica gel. The product was eluted with 50% ethyl acetate in benzene and recrystallized from cyclohexane. The melting point was 115 ° to 117 ° C and the yield was 27%.

Analysis for C [deep] 18H [deep] 21NO [deep] 3:

Calculated: 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 fumarate

A solution of 11.5 g of 1-benzyl-4-6-methoxyphenoxy) -3-pyrrolidinol in 200 ml of ethanol was treated with about 2 g of 10% palladium-on-charcoal catalyst and with hydrogen at 60 ° C in Shaken on the Parr Reducer for 5 hours. The suspension was then cooled, filtered and the solvent evaporated under reduced pressure. The base was converted into the fumarate, which had a melting point of 158-160 ° C. The yield was 9.8 g (78%).

Analysis for C [deep] 15H [deep] 19NO [deep] 7:

Calculated: 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 mol) 1-benzyl-3,4-epoxypyrrolidine, 13.4 g (0.11 mol) p-methoxyphenol 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 twice with 50 ml of 5% sodium hydroxide each time. The methylene chloride layer was over anhydrous sodium sulfate dried and concentrated to give 23.7 g of a viscous dark oil. This oil was chromatographed on 480 g of silica gel 60 and the product was eluted with a benzene / ether solution (1: 1). The appropriate fractions were concentrated to give 10.0 g of a yellow oil which crystallized on rubbing with a glass rod. The solid was recrystallized from cyclohexane and 7.2 g (24%) of a yellow-brown solid were obtained; Melting point 84 ° to 85 ° C.

Analysis for C [deep] 18H [deep] 21NO [deep] 3:

Calculated: C 72.225%, 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 mol) of trans-4- (4-methoxyphenoxy) -1-phenylmethyl-3-pyrrolidinol in 75 ml of ethanol was overnight at 60 ° C using 0.4 g of a 10 Hydrogenated% palladium catalyst on activated carbon. The reaction mixture was cooled, filtered through Celite and the filtrate concentrated. The base was obtained in the form of a white solid. This solid was converted to the oxalate and recrystallized from methanol. White flakes with a melting point of 173 ° to 175 ° C / degree were obtained.

Analysis for C [deep] 41H [deep] 53N [deep] 3O [deep] 25:

Calculated: 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 grams (0.26 moles) of 1-benzyl-3,4-epoxypyrrolidine (60 grams of a 76% epoxide), 48 grams (0.35 moles) of o-ethoxyphenol, and 8 drops of concentrated hydrochloric acid was added 16 Heated to 145 ° C for 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 sulfate 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 recrystallizations from cyclohexane yielded 8.0 g (10%) of dark brown needles with a melting point of 88.5 ° to 90.0 ° C.

Analysis for C [deep] 19H [deep] 23NO [deep] 3:

Calculated: C 72.82%, H 7.40%, H 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 mmol) of trans-4- (2-ethoxyphenoxy) -1-phenylmethyl-3-pyrrolidinol in 150 ml of absolute ethanol was treated with about 0.5 g of 10% palladium-on-charcoal catalyst and shaken with hydrogen in the Parr reducer at 60 ° C 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 the salt as a white powder; Melting point 173.0 ° to 174.5 ° C.

Analysis for C [deep] 16H [deep] 21NO [deep] 7:

Calculated: C 56.63%, H 6.24%, N 4.13%;

Found: C 56.60%, H 6.27%, N 4.12%.

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 to 130 ° C. for 8 hours. The mixture crystallized out on cooling. Three recrystallizations from petroleum ether / cyclohexane gave fluffy white ones

Crystals with a melting point of 98.0 ° to 100.0 ° C.

The yield was 6.0 g (8%).

Analysis for C [deep] 24H [deep] 25NO [deep] 3:

Calculated: 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 g of 1-benzyl-4- (4-benzoxyphenoxy) -3-pyrrolidinol in 150 ml of ethanol were treated with approx. 1 g of palladium-on-charcoal catalyst and with hydrogen at 60 ° C. for 3 hours in the Parr reduction apparatus shaken. The mixture was then cooled, filtered and the ethanol removed. The oxalate was prepared in isopropyl alcohol / acetone and recrystallized from 90% ethanol. The salt decomposed at 235 ° C.

Analysis for C [deep] 11H [deep] 14NO [deep] 5:

Calculated: 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 to 130 ° C. for 3 hours. The mixture was cooled, dissolved in methylene chloride and extracted with dilute sodium hydroxide. The residue obtained after evaporation of the solvent was purified by column chromatography. The product, eluted using 30% ethyl acetate in benzene, weighed 17.7 g (38%). A small portion was converted to the oxalate, which had a melting point of 139 ° to 141 ° C.

Analysis for C [deep] 20H [deep] 20NO [deep] 5F [deep] 3:

Calculated: 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-pyrrolidinol hydrochloride

A solution of 12.6 g of trans-1-benzyl-4- (3-trifluoromethylphenoxy) -3-pyrrolidinol in 200 ml of ethanol was treated with about 2 g of 10% palladium-on-charcoal catalyst and with hydrogen in the Parr reducer shaken for 16 hours at 60 ° C. The suspension was cooled, filtered and the solvent evaporated under reduced pressure. The residue was dissolved in ether and converted to the hydrochloride. The yield of product was 9.8 g (93%); Melting point 145 ° to 148 ° C.

Analysis for C [deep] 11H [deep] 13NO [deep] 2ClF [deep] 3:

Calculated: 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-phenylmethyl-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 to 130 ° C. for 8 hours. The cooled mixture was chromatographed on silica gel using 5% methanol in ethyl acetate as the fluidizing agent for the product and the eluted product was recrystallized from chloroform / benzene / methanol. The yield was 19%; Melting point 133.0 ° to 136.0 ° C.

Analysis for C [deep] 18H [deep] 20N [deep] 2O [deep] 3:

Calculated: 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] benzamide

8 g of 4 - [(4-benzamid) oxy] -1-benzyl-3-pyrrolidinol were dissolved in 100 ml of ethanol, about 1 g of 10% strength palladium-on-charcoal catalyst were added and hydrogenation was carried out for 4 hours shaken for a long time at 60 ° C. The suspension was then cooled and filtered. The precipitate was washed with hot methanol and the wash waters combined with the mother liquor. The solvent was evaporated to 150 ml and refrigerated overnight. The product was filtered and dried; Melting point 199 ° to 204 ° C (decomp.). The yield was 80%.

Analysis for C [deep] 11H [deep] 14N [deep] 2O [deep] 3:

Calculated: C 59.45%, H 6.35%, N 12.61%;

Found: C 59.47%, H 6.45%, N 12.57%

Example 38

trans N - {([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 2 drops of water was heated to 125 ° C. for 3 hours. The mixture was then cooled, dissolved in 50% ethyl acetate in benzene and washed with dilute sodium hydroxide. After removing the solvent, the residue weighed 56 g. It was chromatographed using 370 g silica gel and the product eluted with ethyl acetate. After recrystallization from 50% ethyl acetate in benzene, the product had a melting point of 130 ° to 132 ° C. and weighed 26.1 g (40%).

Analysis for C [deep] 19H [deep] 22N [deep] 2O [deep] 3:

Calculated: C 69.92%, H 6.79%, O 14.7%, N 6.58%;

Found: C 69.61%, H 6.60%, N 8.44%.

Example 39

trans N- {4 - [(4-Hydroxy-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 mixed with about 2 g of 10% palladium-on-charcoal catalyst for 16 hours in the Parr reduction apparatus shaken with hydrogen at 60 ° C. The suspension was then cooled, filtered and the solvent evaporated under reduced pressure. The residue weighed 9 g and was converted to the fumarate and recrystallized from isopropyl alcohol. The yield of the salt was 10.2 g (90%); Melting point 200 ° to 205 ° C.

Analysis for C [deep] 14N [deep] 18N [deep] 2O [deep] 5:

Calculated: 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 17.5 g (0.10 mol) of crude 1-benzyl-3,4-epoxypyrrolidine,

15.0 g (0.11 mol) 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 extracted three times with 50 ml of 5% sodium hydroxide each time. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated to give 25.5 g (80%) of a black gum as a residue. This residue was chromatographed on 500 g of silica gel and the product was eluted with ethyl ether / benzene (1: 1). 9.9 g (31%) of a white solid were obtained which, after recrystallization from cyclohexane, had a melting point of 106 ° to 108 ° C.

Analysis for C [deep] 21H [deep] 21NO [deep] 2:

Calculated: C 78.97%, H 6.63%, N 4.39%;

Found: C 79.08%, H 6.67%, N 4.45%.

The oxalate was obtained as a white solid which, after recrystallization from nitromethane, had a melting point of 190 ° to 192 ° C.

Analysis for C [deep] 23H [deep] 23NO [deep] 6:

Calculated: 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 g of 1-benzyl-4- (1-naphthoxy) -3-pyrrolidinol in 200 ml of ethanol were shaken with about 2 g of a 10% palladium-on-charcoal catalyst under hydrogen for 20 hours at 60 ° C. The mixture was cooled, filtered and the ethanol removed. The residue was recrystallized from benzene and had a melting point of 112 ° to 115 ° C.

Analysis for C [deep] 14H [deep] 15NO [deep] 2:

Calculated: C 73.34%, H 6.59%, N 6.11%;

Found: C 73.39%, H 6.64%, N 5.90%.

Example 42

trans -4- [1H-2,3-dihydroinden-4-yl) oxy] -1-phenylmethyl-3-pyrrolidinol

A mixture of 28 g of 1-benzyl-3,4-epoxypyrrolidine and 20.1 g of 4-indanol was heated to 130 ° C. for 8 hours. The residue was chromatographed on silica gel using ethyl acetate to elute the product. The yield of product after recrystallization from cyclohexane was 6%; Melting point 98 ° to 101 ° C.

Analysis for C [deep] 20H [deep] 23NO [deep] 2:

Calculated: C 77.64%, H 7.49%, N 4.53%;

Found: C 77.41%, H 7.52%, N 4.37%.

Example 43

trans -4- [1H-2,3-dihydroinden-4-yl) oxyl-3-pyrrolidinol hydrochloride

1-Benzyl-4- (4-indanoxy) -3-pyrrolidinol (2.7 g) in 100 ml of ethanol was mixed with about 0.5 g of 10% palladium on charcoal catalyst with hydrogen in the Parr reduction apparatus Shaken for 5 hours at 60 ° C. The suspension was then cooled, filtered and the solvent removed. The residue was converted to the hydrochloride in ether and dried under vacuum at 40 ° C for 18 hours. The yield of product with a melting point of 174 ° to 180 ° C. was 91%.

Analysis for C [deep] 13H [deep] 16NO [deep] 2Cl:

Calculated: 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 heated to 130 ° C. for 3 hours. The mixture was then cooled, dissolved in methylene chloride and extracted with dilute sodium hydroxide. To

Removal of the solvent, the residue was applied to a silica gel column and the product was eluted with 50% ethyl acetate in benzene. The hydrochloride salt was prepared in ether and recrystallized from ethanol / acetone. The yield of salt with a melting point of 153-155 ° C was 12.3 g (18%).

Analysis for C [deep] 20H [deep] 24NO [deep] 2Cl:

Calculated: 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-1H-inden-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 mixed with approx Shaken with hydrogen at 60 ° C for hours. The suspension was then cooled, filtered and the solvent removed. The oxalate was made in isopropyl alcohol and melted at 179.0 ° to 181.0 ° C.

Analysis for C [deep] 15H [deep] 19NO [deep] 6:

Calculated: C 58.25%, H 6.19%, N 4.53%;

Found: C 58.13%, H 6.14%, N 4.58%.

Example 46

trans-1-ethyl-4-phenoxy-3-pyrrolidinol oxalate, hydrate (4: 1)

A mixture of 22.6 g of 1-ethyl-3,4-epoxypyrrolidine and 18.6 g of phenol was heated to 150 ° C. for 0.5 hours and then distilled. The product had a boiling point of 120 ° / 0.025 mm. The yield of the pure product was 25.0 g (60%). Part of the base was converted into the oxalate, which had a melting point of 134 ° to 137 ° C. after recrystallization from isopropyl alcohol.

Analysis for C [deep] 56H [deep] 78N [deep] 4O [deep] 25:

Calculated: C 55.72%, H 6.51%, N 4.64%;

Found: C 55.83%, H 6.38%, N 4.63%.

Example 47

trans -1-ethyl-4-phenoxy-3-pyrrolidinol methyl carbamate 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 left to stand under nitrogen for 5 days. The crystalline solid remaining after evaporation of the benzene was recrystallized from cyclohexane. The yield of product was 6.5 g (79%); Melting point 88 ° to 94 ° C.

Analysis for C [deep] 14H [deep] 20N [deep] 2O [deep] 3:

Calculated: 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-pyrrolidinol hydrochloride

A mixture of 17.0 g (0.15 mol) 1-ethyl-3,4-epoxypyrrolidine, 20.5 g (0.16 mol) o-chlorophenol and 3 drops of concentrated hydrochloric acid was heated on a steam bath overnight. The oil was dissolved in methylene chloride and washed three times with 50 ml of 5% sodium hydroxide each time and once with 50 ml of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel. 8.9 g (25%) of an oil were obtained as a residue. The oil was converted into the hydrochloride and recrystallized from ethyl acetate / acetonitrile. A white powder with a melting point of 108 ° to 110 ° C. was obtained.

Analysis for C [deep] 12H [deep] 17Cl [deep] 2NO [deep] 2:

Calculated: 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 mol) 1-ethyl-3,4-epoxypyrrolidine, 18.0 g (0.11 mol) 2,6-dichlorophenol and 2 drops concentrated hydrochloric acid was heated on a steam bath overnight. The oil was dissolved in methylene chloride and washed three times with 50 ml of 5% sodium hydroxide each time and once with 50 ml of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel. 12.9 g (47%) of an oily residue were obtained. The oil was converted into the hydrochloride and recrystallized from isopropyl alcohol / diethyl ether. 12.3 g (39%) with a melting point of 160 ° to 162 ° C. were obtained.

Analysis for C [deep] 12H [deep] 16Cl [deep] 3NO [deep] 2:

Calculated: C 46.10%, H 5.16%, N 4.48%;

Found: C 46.10%, H 5.20%, N 4.48%.

Example 50

trans -1-ethyl-4- (3-methylphenoxy) -3-pyrrolidinol oxalate.hemihydrate

A mixture of 17 g of 1-ethyl-3,4-epoxypyrrolidine and 16.2 g of m-cresol was heated to 125 ° C. for 45 minutes and then distilled in vacuo. The yield of product, which had a boiling point of 135 ° C./0.02 mm, was 37%. The product was converted to the oxalate, which had a melting point of 116 ° to 119 ° C.

Analysis for C [deep] 30H [deep] 44N [deep] 2O [deep) 13:

Calculated: 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 (0.15 mol) of 1-ethyl-3,4-epoxypyrrolidine, 22.1 g (0.16 mol) 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 three times with 50 ml of 5% sodium hydroxide and once with 50 ml of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel. 8.1 g (21%) of an oil were obtained which crystallized out on standing. The solid was recrystallized from cyclohexane to give a tan solid; Melting point 73 ° to 75 ° C.

Analysis for C [deep] 14N [deep] 21NO [deep] 3:

Calculated: 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} ethanol. sesquioxalate

A mixture of 17.0 g (0.15 mol) of acetovanillon and

1-Ethyl-3,4-epoxypyrrolidine and 3 drops of water were heated on a steam bath overnight. The mixture was dissolved in 250 ml of methylene chloride and extracted three times with 150 ml of 5% sodium hydroxide each time and once with 100 ml of water. The methylene chloride layer was dried over anhydrous sodium sulfate and upon concentration afforded 19.0 g of a crude oil. This oil was chromatographed on 400 g of silica gel. The desired product was eluted with acetone. The fractions were concentrated to give 14.0 g of an oil which was treated with oxalic acid in isopropyl alcohol. The white solid obtained was recrystallized twice from isopropyl alcohol. 13.4 g (24%) of sesquioxalate were obtained; Melting point 121 ° to 123 ° C.

Analysis for C [deep] 16H [deep] 24NO [deep] 10:

Calculated: 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 to 130 ° C. for 1.5 hours, then cooled and chromatographed on silica gel, with 20% methanol in ethyl acetate for the elution of the product have been used. A portion of the total yield, 18.5 g (50%), was converted to the oxalate, which has a melting point from 142 ° to 145 ° C.

Analysis for C [deep] 17H [deep] 23NO [deep] 6:

Calculated: C 60.52%, H 6.87%, N 4.15%;

Found: C 60.30%, H 6.79%, N 3.98%

Example 54

trans-1-ethyl-4- [2- (2-propenyl) phenoxy] -3-pyrrolidinol ethyl carbamate (ester)

A mixture of 7.3 g of trans-4- (2-allylphenoxy) -1-ethyl-3-pyrrolidinol and 2.5 g of ethyl isocyanate in 30 ml of benzene was stirred for 48 hours. The benzene was replaced with petroleum ether and the solution quenched. The yield of precipitate, which had a melting point of 53 ° to 56 ° C., was 78%.

Analysis for C [deep] 18H [deep] 16N [deep] 2O [deep] 3:

Calculated: C 67.90%, H 8.23%, N 8.80%;

Found: C 67.91%, H 8.08%, N 8.79%.

Example 55

trans -1-ethyl-4- (1-naphthalenyloxy) -3-pyrrolidinol hydrochloride

A mixture of 22.6 g of 3,4-epoxy-1-ethylpyrrolidine and 28.8 g of 1-naphthol was heated to 130 ° C. for 1 hour.

The mixture was cooled, dissolved in benzene and extracted with dilute sodium hydroxide. The benzene was evaporated and the residue chromatographed on silica gel, eluting the product with 40% methanol in ethyl acetate. The hydrochloride of the product was prepared and recrystallized from ethanol / acetone. The yield of salt was 17.5 g (30%); Melting point 206 ° to 207 ° C.

Analysis for C [deep] 16H [deep] 20NO [deep] 2Cl:

Calculated: C 65.415%, H 6.86%, N 4.77%;

Found: C 65.29%, H 6.93%, N 4.70%.

Example 56

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

A mixture of 17 g of 1-ethyl-3,4-epoxypyrrolidine and 20 g of 4-indanol was heated to 125 ° C. for 1 hour, then cooled, dissolved in ethyl acetate and chromatographed on silica gel, using 25% methanol in ethyl acetate for the elution became. The yield of product after recrystallization from cyclohexane was 15 g (40%); Melting point 87 ° to 90 ° C.

Analysis for C [deep] 15H [deep] 21NO [deep] 2:

Calculated: C 72.84%, H 8.56%, N 5.66%;

Found: C 72.925%, H 8.52%, N 5.48%.

Example 57

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

A mixture of 15.0 g (0.132 mol) 1-ethyl-3,4-epoxypyrrolidine, 20 g (0.15 mol) 5-indanol and 1 drop of water was heated on a steam bath overnight. The oil was dissolved in methylene chloride and washed three times with 50 ml of 5% sodium hydroxide each time and once with 50 ml of water. The methylene chloride was dried over anhydrous sodium sulfate and, after concentration, gave 28.5 g of a dark residue. This residue was chromatographed on 500 g of silica gel and the product was eluted with methanol. This oil was converted into the maleate and 16.6 g (35%) of cream-colored needles were obtained; Melting point 147 ° to 148 ° C.

Analysis for C [deep] 19H [deep] 25NO [deep] 6:

Calculated: C 62.80%, H 6.93%, N 3.85%;

Found: C 62.74%, H 6.88%, N 3.83%.

Example 58

trans-1-Cyclohexyl-4-phenoxy-3-pyrrolidinol compound with cyclohexanesulfamic acid

A mixture of 33.5 g (0.2 mol) of N-cyclohexyl-3,4-epoxy-pyrrolidine, 18.8 g (0.02 mol) of phenol and 2 drops of concentrated

Hydrochloric acid was heated on a steam bath overnight. The reaction mixture was dissolved in methylene chloride and washed three times with 100 ml of 5% sodium hydroxide each time and once with 100 ml of water and dried over potassium hydroxide / anhydrous sodium sulfate. The methylene chloride solution was concentrated and gave 36.4 g of an oil as a residue. The oil partially crystallized out and the solid was washed with petroleum ether, collected by filtration and recrystallized from cyclohexane. 11.0 g (21%) of a white solid were obtained. This solid was converted into the hexamate and, after recrystallization from isopropyl alcohol, gave white needles; Melting point 163 ° to 165 ° C.

Analysis for C [deep] 22H [deep] 36N [deep] 2O [deep] 5S:

Calculated: C 59.975%, H 8.24%, N 6.36%;

Found: C 59.99%, H 8.29%, N 6.30%.

Example 59

cis -4-phenoxy-1-phenylmethyl-3-pyrrolidinol

A slurry of 2.4 g (0.1 mol) of sodium hydride (4.2 g of a 57% oil dispersion which had been washed with ether to remove the oil) in 30 ml of dimethylformamide was stirred while a solution of 19.3 g (0.1 mol) of 1-benzyl-3,4-dihydroxypyrrolidine, cis-isomer (I) in

30 ml of dimethylformamide was added dropwise. The mixture was heated to 50 ° C. for 1 hour and then a solution of 19.2 g (0.2 mol) of fluorobenzene in 30 ml of dimethylformamide was added all at once. The mixture was heated to 90 ° C. for 18 hours, then cooled and concentrated in vacuo. 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 off from an insoluble oil (mainly I). The cyclohexane solution was treated with activated charcoal to remove residual I and then crystallized out in the form of flaky, almost white needles. The yield was 1.2 g (4.5%); Melting point 88.5 ° to 90 ° C / degree.

Analysis for C [deep] 17H [deep] 19NO [deep] 2:

Calculated: 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 mmol) of sodium hydride (2.1 g of a 57% oil dispersion which had been washed with ether to remove the oil) in 25 ml of dimethyl sulfoxide was stirred while 9.6 g (50 mmol) 1-Benzyl-3,4-dihydroxypyrrolidine, cis isomer in 25 ml of dimethyl sulfoxide were added. The mixture was stirred at room temperature for 1 hour, then 50 ml of dimethyl sulfoxide were added and the temperature was raised to 95 ° C. for ½ hour. 13 g (100 mmoles) of m-chlorofluorobenzene were added, requiring mechanical agitation of the thick slurry. During the heating period of 1 hour at 95 ° C, all of the precipitate was dissolved. The reaction mixture was concentrated in vacuo by distilling off the dimethyl sulfoxide and the excess m-chlorofluorobenzene. The residue was poured into water and extracted with hot cyclohexane. The organic extracts were combined, dried over anhydrous sodium sulfate, and upon concentration gave 7.5 g (49%) of almost white crystals; Melting point 86 ° to 87.5 ° C.

Analysis for C [deep] 17H [deep] 18ClNO [deep] 2:

Calculated: 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-phenyl-methyl-pyrrolidinium iodide

A mixture of 15.2 g (0.05 mol) cis -4- (3-chlorophenoxy) -1-phenylmethyl-3-pyrrolidinol and 56 g (0.4 mol) methyl iodide was refluxed for 60 hours. Excess methyl iodide was removed in vacuo and the paste-like residue was washed with ether / acetone. 13 g (59%) of a granular yellow-brown powder were obtained; Melting point 118 ° to 125 ° C.

Analysis for C [deep] 18H [deep] 21ClJNO [deep] 2:

Calculated: C 48.51%, H 4.75%, N 3.14%;

Found: C 48.27%, H 4.75%, N 3.19%.

Example 62

cis -1-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 mixed with 3.5 g (15 mmoles) of silver oxide for 1 hour stirred at 45 ° C. The solids were removed by filtration and the filtrate was shaken with 0.5 g of a 10% palladium on activated carbon catalyst for 3 hours at 60 ° C. under hydrogen. The mixture was cooled and the catalyst collected by filtration. The filtrate was concentrated and the residue treated with dilute sodium hydroxide and extracted into methylene chloride. The solution was concentrated and redissolved in hot cyclohexane, treated with activated charcoal, filtered through Celite and recrystallized from cyclohexane. 4.6 g were obtained

(85%) product in the form of white needles; Melting point 78 ° to 81 ° C.

Analysis for C [deep] 11H [deep] 15NO [deep] 2:

Calculated: 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-isomeres-hydrochloride.Hydrate (6: 1)

A solution of 16.0 g (53 mmol) of cis -4- (3-chlorophenoxy) -1-phenylmethyl-3-pyrrolidinol in 100 ml of absolute ethanol and 5 ml of concentrated hydrochloric acid was dissolved with 0.5 g of 10% palladium - Activated carbon catalyst shaken under hydrogen at 60 ° C for 16 hours. The mixture was cooled and the catalyst separated by filtration through Celite. The filtrate was concentrated and the white crystalline residue was triturated with ether / acetone. The weight of the white powder obtained was 9.8 g (86%); Melting point 128-137 ° C.

Analysis for C [deep] 40H [deep] 58Cl [deep] 4N [deep] 4
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Calculated: C 54.55%, H 6.64%, N 6.36%;

Found: C 54.26%, H 6.41%, N 6.27%.

Formulation and administration

For therapeutic purposes, effective amounts of any of the above pharmacologically active compounds of general formula I can be given to the living animal in conventional routes of administration and in conventional forms, such as orally in solutions, emulsions, suspensions, pills, tablets and capsules in pharmaceutical compatible carriers, and parenterally in the form of sterile solutions.

For parenteral administration, the carrier or excipient can be a sterile, porenterally acceptable liquid, e.g. B. water, or a parenterally acceptable oil, e.g. B. peanut oil, in ampoules.

Although even very small amounts of the active materials of the present invention are effective when treatment is less important, or in cases of administration to subjects of relatively low body weight, unit doses are usually in the range of 5 mg or more, preferably 25 , 50 or 100 mg, or even higher, of course depending on the particular situation and the particular result desired. Per unit dose, 5 to 50 mg appears to be optimal, or common broader ranges appear to be in the range of 1 to 500 mg per unit dose. The daily dose should preferably be in the range from 10 mg to 100 mg. The active ingredients of the present invention can be combined with other pharmacologically active agents as noted above. All that is required is that the active ingredient be an effective amount; H. such that a suitable effective dose is obtained which is compatible with the dosage form employed. Obviously, several unit dose forms can be administered at about the same time. The exact individual doses as well as the daily doses will of course be determined according to standard medical principles under the guidance of a doctor or veterinarian.

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

Formulations

1. Capsules

Capsules of 5 mg, 10 mg, 25 mg and 50 mg of active ingredient per capsule are produced. With higher amounts of active ingredient, the amount of lactose can be decreased.

Additional capsule formulations preferably contain a higher dose of active ingredient as follows:

In either case, mix the selected active ingredient evenly with lactose, starch and magnesium stearate and then encapsulate the mixture.

2. Tablets

The following is a typical formulation for a tablet containing 5.0 mg of active ingredient per tablet. The formulation can be used for other active ingredient levels by adjusting the weight of the dicalcium phosphate.

Mix 1, 2, 4 and 5 evenly. Prepare 3 as a 10% paste in water. The mixture is granulated with corn starch paste and the moist mass is passed through an 8 mesh sieve (mesh size approx. 2.4 mm). The moist granulate is dried and classified through a 12 mesh sieve (mesh size approx. 1.4 mm). The dried granulate is mixed with the calcium stearate and pressed.

3. Injectable 2% sterile solution

The solution is prepared, clarified by filtration, filled into ampoules, sealed and treated in an autoclave.

It will be apparent to one skilled in the art that numerous modifications can be made to the formulations and methods of the present invention, but are still within the scope of the present invention. It is therefore understood that the present invention can only be limited by the appended claims.

Claims (96)

1. Cis and trans isomers of 3-aryloxy-4-hydroxypyrrolidines and their derivatives of the general formula in which R [high] 1 hydrogen, lower alkyl, benzyloxycarbonyl or N-lower alkylcarbamoyl, R [high] 2 is hydrogen, lower alkyl, cycloalkyl, phenylalkyl, benzyloxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or p-fluorobenzoyl-lower alkyl, Ar is phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, 1-indenyl or 2-indenyl, and the pharmaceutically acceptable addition salts and quaternary salts thereof. 2. trans -4-phenoxy-1-phenylmethyl-3-pyrrolidinol. 3. trans -3-hydroxy-1-methyl-4-phenoxy-1-phenylmethyl-pyrrolidinium iodide. 4. trans -1-methyl-4-phenoxy-3-pyrrolidinol. 5. trans -3-methoxy-4-phenoxy-1-phenylmethylpyrrolidine. 6. trans -3-methoxy-4-phenoxy-1-phenylmethylpyrrolidine oxalate. 7. trans -3-methoxy-4-phenoxypyrrolidine. 8. trans -3-methoxy-4-phenoxypyrrolidine fumarate. 9. trans -4-phenoxy-3-pyrrolidinol. 10. trans -4-phenoxy-3-pyrrolidinol fumarate. 11. trans -1- (4-fluorophenyl) -3- (3-hydroxy-4-phenoxy-1-pyrrolidinyl) -1-propanone. 12. trans -4- (4-chlorophenoxy) -1-phenylmethyl-3-pyrrolidinol. 13. phenylmethyl trans -3- (4-chlorophenoxy-4- {phenylmethyl [carbonylbis (oxy)]} - 1-pyrrolidinecarboxylate. 14. trans -4- (4-chlorophenoxy) -3-pyrrolidinol. 15. trans -4- (4-chlorophenoxy) -3-pyrrolidinol hydrobromide. 16. trans -3- (4-chlorophenoxy) -4-hydroxy-1-pyrrolidinecarboxamide. 17. trans -3- (4-chlorophenoxy) -4-hydroxy-N, N-dimethyl-1-pyrrolidinecarboxamide. 18. trans -3 (4-chlorophenoxy) -4-hydroxy-N-methyl-1-pyrrolidinecarboxamide hemihydrate. 19. trans -3 - {[(methylamino) carbonyl] oxy} -4- (4-chlorophenoxy) -N, N-dimethyl-1-pyrrolidinecarboxamide. 20. trans -4- (2,6-dichlorophenoxy) -1-phenylmethyl-3-pyrrolidinol. 21. phenylmethyl trans -3- (2,6-dichlorophenoxy) -4- {phenylmethyl [carbonylbis (oxy)]} - 1-pyrrolidinecarboxylate. 22. trans -4- (2,6-dichlorophenoxy) -3-pyrrolidinol. 23. trans -4- (2,6-dichlorophenoxy) -3-pyrrolidinol hyarobromide. 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-pyrrolidinol. 27. trans -3- (2-dichlorophenoxy) -4- {phenylmethyl [carbonylbis (oxy)]} - 1-pyrrolidinecarboxylic acid phenylmethyl ester. 28. trans -4- (2,3-dichlorophenoxy) -3-pyrrolidinol. 29. trans -4- (2,3-dichlorophenoxy) -3-pyrrolidinol hydrobromide. 30. trans -1-Benzyl-4- (3-methylphenoxy) -3-pyrrolidinol. 31. trans -1-Benzyl-4- (3-methylphenoxy) -3-pyrrolidinol hydrochloride. 32. trans -4- (3-methylphenoxy) -3-pyrrolidinol. 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-pyrrolidinol. 36. trans -4- (2,3-dimethylphenoxy) -3-pyrrolidinol hydrobromide. 37. trans -4- (2-methoxyphenoxy) -1-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-pyrrolidinol 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] -1-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-phenylmethylpyrrolidin-3-yl) -oxy] -benzamide. 54. trans -4 - [(4-Hydroxy-3-pyrrolidinyl) oxy] benzamide. 55. trans- N- {4 - [(4-Hydroxy-1-phenylmethyl-3-pyrrolidinyl) -oxy] phenyl} -acetamide. 56. trans- N- {4 - [(4-Hydroxy-3-pyrrolidinyl) oxy] phenyl} acetamide. 57. trans- N- {4 - [(4-Hydroxy-3-pyrrolidinyl) oxy] phenyl} acetamide hemifumarate. 58. trans -4- (1-naphthalenyloxy) -1-phenylmethyl-3-pyrrolidinol. 59. trans -4- (1-naphthalenyloxy) -1-phenylmethyl-3-pyrrolidinol oxalate. 60. trans -4- (1-naphthalenyloxy) -3-pyrrolidinol. 61. trans -4- [1H-2,3-dihydroinden-4-yl) oxy] -1-phenylmethyl-3-pyrrolidinol. 62. trans -4- (1H-2,3-dihydroinden-4-yl) oxy] -3-pyrrolidinol. 63. trans -4- [1H-2,3-dihydroinden-4-yl) oxy] -3-pyrrolidinol hydrochloride. 64. trans -4 - [(1,2-dihydroinden-5-yl) oxy] -1-phenylmethyl-3-pyrrolidinol. 65. trans -4 - [(1,2-dihydroinden-5-yl) oxy] -1-phenylmethyl-3-pyrrolidinol hydrochloride. 66. trans -4 - [(2,3-Dihydro-1H-inden-5-yl) oxy] -3-pyrrolidinol. 67. trans -4 - [(2,3-Dihydro-1H-inden-5-yl) oxy] -3-pyrrolidinol oxalate. 68. trans -1-ethyl-4-phenoxy-3-pyrrolidinol. 69. trans -1-ethyl-4-phenoxy-3-pyrrolidinol oxalate hydrate (4: 1). 70. trans -1-ethyl-4-phenoxy-3-pyrrolidinol methyl carbamate ester 71. trans -4- (2-chlorophenoxy) -1-ethyl-3-pyrrolidinol. 72. trans -4- (2-chlorophenoxy) -1-ethyl-3-pyrrolidinol hydrochloride. 73. trans -4- (2,6-dichlorophenoxy) -1-ethyl-3-pyrrolidinol. 74. trans -4- (2,6-dichlorophenoxy) -1-ethyl-3-pyrrolidinol hydrochloride. 75. trans -1-ethyl-4- (3-methylphenoxy) -3-pyrrolidinol. 76. trans -1-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} -ethanone. 79. trans -1 {4 - [(1-ethyl-4-hydroxy-3-pyrrolidinyl) oxy] -3-methoxyphenyl} -ethanone sesquioxalate. 80. trans -1-ethyl-4- [2- (2-propenyl) phenoxy] -3-pyrrolidinol. 81. trans -1-ethyl-4- [2- (2-propenyl) phenoxy] -3-pyrrolidinol oxalate. 82. trans -1-ethyl-4- [2- (2-propenyl) phenoxy] -3-pyrrolidinol ethyl carbamate (ester). 83. trans -1-ethyl-4- (1-naphthalenyloxy) -3-pyrrolidinol. 84. trans -1-ethyl-4- (1-naphthalenyloxy) -3-pyrrolidinol hydrochloride. 85. trans -1-ethyl-4 - [(1H-2,3-dihydroinden-4-yl) oxy] -3-pyrrolidinol. 86. trans -1-ethyl-4 - [(1H-2,3-dihydroinden-5-yl) oxy] -3-pyrrolidinol. 87. trans -1-ethyl-4 - [(1H-2,3-dihydroinden-5-yl) oxy] -3-pyrrolidinol maleate. 88. trans -1-cyclohexyl-4-phenoxy-3-pyrrolidinol. 89. trans-1-cyclohexyl-4-phenoxy-3-pyrrolidinol compound with cyclohexanesulfamic acid. 90. cis -4-phenoxy-1-phenylmethyl-3-pyrrolidinol. 91. cis -4- (3-chlorophenoxy) -1-phenylmethyl-3-pyrrolidinol. 92. cis -3- (3-chlorophenoxy) -4-hydroxy-1-methyl-1-phenylmethylpyrrolidinium iodide. 93. cis -1-methyl-4-phenoxy-3-pyrrolidinol. 94. cis -4-phenoxy-3-pyrrolidinol. 95. cis -4-phenoxy-3-pyrrolidinol hydrochloride hydrate (4: 1). 96. Pharmaceutical preparation, characterized in that it (a) a compound of the general formula wherein R [high] 1 hydrogen, lower alkyl, benzyloxycarbonyl or N-lower alkylcarbamoyl, R [high] 2 hydrogen, lower alkyl, cycloalkyl, phenylalkyl, benzyloxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or p-fluorobenzoyl-lower alkyl, Ar is phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, 1-indenyl or 2-indenyl, the pharmaceutically acceptable addition salts and the quaternary salts thereof, and (b) a pharmaceutical carrier for includes.