CH643243A5 - CIS- AND TRANS-3-ARYLOXY-4-HYDROXYPYRROLIDINES AND DERIVATIVES THEREOF, ESPECIALLY USEFUL IN VETERINARY MEDICINE AS ANTIDEPRESSANTS. - Google Patents

Description

The present invention relates to certain novel cis and trans isomers of 3-aryloxy-4-hydroxypyrrolidines and their derivatives, which are useful in the treatment of depression, hypertension and cardiac arrhythmias in animals, and pharmaceutical compositions comprising them. contain.

The compounds of the invention were not available before the invention. Patent application of the Federal Republic of Germany (first publication) DT-OS No. 2738477 described certain trans-3-aryloxy-4-hydroxypyrrolidines and -piperidines which correspond to the invention, but this description is subsequent to the 'invention. None of the compounds described in this reference are cis isomers. Some of the compounds of the invention also differ by an alkyl, phenylalkyl or cycloalkyl substituent on the nitrogen of Pyrrolidine.

The invention relates to novel cis and trans isomers of 3-aryl-oxy-4-hydroxypyrrolidines and their derivatives which have significant pharmacological activity. The compounds of the invention are represented by the following structural formula:

—O-Ar

The antidepressant activity of the compounds of formula la is illustrated by the effective doses determined by the antitetrabenazine test above. The following results are obtained:

Compound

Anti-tetrabenazine effect

(mouse), Deso (mg / kg)

Example 3

3.7

Example 46

3.5

Example 49

4.8

Example 48

2.8

30

RjO-

(I)

R „

(cis and trans isomers)

in which:

Rj represents hydrogen or a lower alkyl, benzyloxycarbonyl, or N- (lower alkyl) carbamoyl group;

R2 represents hydrogen or a lower alkyl, cycloalkyl, phenylalkyl, benzyloxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di (lower alkyl) carbamoyl or parafluoro-benzoylalkyl group;

Ar represents a phenyl or substituted phenyl, 1-naphthyl, 2-naphthyl, 4-indanyl or 5-indanyl group,

and their pharmaceutically acceptable acid addition salts and quaternary ammonium salts. The compounds have the cis or trans configuration.

The compounds of the invention have antidepressant, hy-potensive and cardiovascular activity in animals.

The existence of antidepressant activity has been shown according to the procedure given by Englehardt, E.L. et al. In "J. Med. Chem. ”, 11 (2), p. 325 (1968), by administering the new compounds of the invention intraperitoneally to mice and by determining the effectiveness of the compounds in blocking the depressant effects induced in mice by the intravenous administration of 2-oxo-3-isobutyl -9.10, dimethoxy-1,2,3,4,6,7-hexahydro-1 lbh-benzo [a] quinolizine (tetrabenazine).

The compounds of the invention for which an increased antidepressant activity has been observed correspond to the formula: HO—, O-Ar

The action of certain compounds of the invention is opposed to cardiac arrhythmia, as shown in the following procedure. One operates under barbiturate anesthesia using adult mongrel dogs of both sexes weighing 8 to 14 kg. A Grass Model 7 polygraph recording device is used to record blood pressure in the femoral artery (Statham P23AC Transducer) and the electrocardiogram (Grass 7P4 Preamplifier). Ouabain is administered intravenously at an initial dose of 40 y / kg and a second dose of 20 y / kg, after 30 min after the first dose, and in subsequent doses of 10 y / kg repeated at an interval of 15 min as needed to produce cardiac arrhythmias that persist for at least 15 min. When the arrhythmias are established, the test compounds are administered by infusion (using a Harvard Model 942 Infusion Pump) into a femoral vein at a rate of 1 mg / kg / min. The concentrations of the compounds are adjusted according to the weight of the dog to allow an infusion volume of 1 ml / min.

Compounds which are considered effective as antiarrhythmic agents cause a reversal of the sinusoidal rhythm which is retained for at least 60 min.

The compounds of the invention for which a pronounced antiarrhythmic activity has been observed correspond to the formula:

55

Okv

(the)

I

Ro

(the)

wherein R2 is hydrogen or a lower alkyl group, and Ar represents a 1- or 2-naphthyl or 4- or 5-indenyl group. The compound of Example 55 represents a preferred compound exhibiting exceptional antiarrhythmic activity at a minimum effective dose of 10.7 mg / kg in the preceding procedure.

The subject of the invention is therefore cis- and trans-3-aryloxy-4-hydroxypyrrolidines and their derivatives having a high antidepressant activity, and their methods of manufacture.

The invention also relates to cis- and trans-3-aryloxy-4-hydroxypyrrolidines and their derivatives which have antiarrhythmic and hypotensive activities in animals.

643,243

4

The invention also relates to a medicinal composition comprising the cis- and trans-3-aryloxy-4-hydroxypyrrolidines as antidepressants, hypotensors and antiarrhythmics usable in the treatment of animals, in particular mammals, in need of treatment. Other objects of the invention will appear on reading the description which follows.

The invention relates to new cis and trans isomers of 3- * aryloxy-4-hydroxypyrrolidines and their derivatives represented by formula I above, as new products, and their use in animals for their pharmacological effect as indicated above. and below.

In the present description, the term lower alkyl is understood to denote the radicals with straight or branched chain up to C8 inclusive, for example methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, amyl, isoamyl, hexyl , heptyle, octyle, etc.

The term substituted phenyl is intended to denote a group

Cl,

ho-

HCl h2o

R

phenyl substituted in 1 to 3 positions by at least one radical chosen from halogens and lower alkoxy groups, - NHC (0) CH3, CF3, - C (0) CH3, - CH2CH = CH2, alkyl, hydroxy, benzoxy and - C (0) NH2.

The term cycloalkyl is intended to denote cy-cloalkyl radicals at C3-C9, for example cyclopropyl, cyclobutyl, cyclo-pentyl, cyclohexyl, etc.

Examples of phenylalkyl radicals are benzyl, α-methylbenzyl, phenylethyl, phenylpropyl, phenylbutyl, etc.

The starting materials used in the preparation of the new trans isomers and formula I are l-phenylalkyl-3,4-epoxypyrroli-dines such as l-benzyl-3,4-epoxypyrrolidine; 1-alkyl-3,4-epoxypyrrolidines such as 1-ethyl-3,4-epoxypyrrolidine; and l-cycloalkyl-3,4-epoxypyrrolidines such as l-cyclohexyl-3,4-epoxypyrrolidine.

The preparation of these 1-substituted epoxypyrrolidines is represented by the following equation:

(IV)

I

R (III)

Cl

0

base in aqueous or alcoholic solution

R

(II)

wherein R is a lower alkyl, phenylalkyl or cycloalkyl group. Generally, the chlorination step is carried out in 2-6 h 30 and it is not necessary to isolate intermediate III. The crude epoxypyrrolidines are obtained by solvent extraction and transformed into crystallized salts such as Oxalates. The pure free bases of the epoxypyrrolidines can be obtained from the oxalate by distribution between a 5% aqueous solution of carbonate of 35

sodium and methylene chloride, and then drying over anhydrous sodium sulfate and evaporation of methylene chloride. The Pyrrolidines used in these starting preparations are prepared according to the procedure of United States Patent No. 3691198, and the procedure for the preparation of 1-cyclo-40 hexyl-A3-pyrroline is given in preparation 1 below.

The preparation of the epoxypyrrolidines used to prepare the trans isomers of formula I is indicated in preparations 2 to 4.

The starting product used in the preparation of the cis isomers of the compounds I is cisbenzyl-3,4-pyrrolidinediol indicated in preparation 5. The cis-3,4-pyrrolidinediols were prepared the first time by AJ Hill et al, "J. Bitter. Chem. Soc. ”, 76, p. 3548 (1954).

Preparation 1:

50

l-Cyclohexyl-A3-pyrroline

A solution of 5.19 kg (52.3 mol) of cyclohexylamine in 4.0 l of benzene is heated to a gentle reflux (92 ° C.), then the heating is stopped. 1635 g (13.1 mol) of 1,4-dichlorobutene are added dropwise to the solution at a rate sufficient to maintain gentle reflux, the time required being 3 h. Continue to heat and bring to reflux for 18 h. The mixture is cooled to about 50 ° C and filtered to separate the hydrochloride. Carbon dioxide is bubbled through the filtrate to precipitate the excess amine carbonate which is separated by filtration. The solvent is removed from the filtrate by distillation under reduced pressure and 1506 g (yield 76%) of a reddish fluid residue slightly contaminated with benzene are obtained.

Preparation 2: ^

1-Benzyl-3,4-epoxypyrrolidine oxalate

A mixture of 31.8 g (0.20 mol) of N-benzyl-A3-pyrroline, 25 ml of concentrated hydrochloric acid and 300 ml of water is treated with a stream of chlorine gas for 2 h. The solution is filtered and the filtrate is made alkaline with 20% sodium hydroxide. The basic solution is extracted with 3 portions of 150 ml of methylene chloride. The chloromethylenic extracts are combined and dried over magnesium sulfate and evaporated to obtain 48.5 g of crude hydrochloride in the form of a dark oil. This oil is stirred with 200 ml of 20% sodium hydroxide for 1 h, 700 ml of water are added and the base is extracted with 4 portions of 100 ml of methylene chloride. The chloromethylenic extracts are combined, dried over magnesium sulfate and concentrated to obtain 34.9 g (99% yield) of crude epoxide in the form of a dark oil. The oxalate is prepared with a yield of 81%.

Recrystallization from 95% ethanol gives the salt in the form of dirty white needles. M 148-149 ° C / decomposition.

Elementary analysis for C13Hi5N05:

Calculated: C 58.86 H 5.70 N 5.28%

Found: C 58.55 H 5.68 N 5.25%

Preparation 3:

Ethyl-3,4-epoxypyrrolidine oxalate

A mixture of 61 g (0.63 mol) of I-ethylpyrroline, 50 ml of concentrated aqueous hydrochloric acid and 600 ml of water is treated with chlorine gas for 21 h. The mixture is filtered on cotton and the filtrate is washed with 2 portions of 100 ml of methylene chloride. The aqueous layer is made alkaline with 20% sodium hydroxide, heated in a steam bath for 1 h and extracted with 3 portions of 100 ml of methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulphate and concentrated and the residue is distilled under vacuum to obtain 39.4 g (yield 56%) of the epoxide in the form of a clear oil (E 75- 90 ° C / 28 mmHg). It is transformed into Oxalate and the salt is recrystallized from absolute ethanol to obtain white needles. F 142-144 ° C / decomposition.

Elementary analysis for C8H13N05:

Calculated: C 47.29 H 6.45 N 6.89%

Found: C 47.12 H 6.42 N 6.82%

5

643,243

Preparation 4:

1-Cyclohexyl-3,4-epoxypyrrolidine oxalate

A solution of 151.3 g (1.0 mol) of N-cyclohexyl-A3-pyrroline, 100 ml of concentrated hydrochloric acid and 1.8 l of water is treated with a stream of chlorine gas until absorption ceases (approximately 6 h). The solution is washed with methylene chloride and the acid solution is left to stand overnight. The solution is then made alkaline with 50% sodium hydroxide and extracted with methylene chloride. The extracts are combined and concentrated to obtain 185 g of hydrochlorine as a residue. The residue is slowly poured into an ethanolic solution containing 20% sodium hydroxide. The mixture is stirred for 1 h and then 3.5 l of water are added. The mixture is extracted with methylene chloride and the combined extracts are dried over anhydrous sodium sulfate and concentrated to obtain 154 g (92% yield) of the amine epoxide. NMR analysis indicates that this residue consists of 86% epoxide and 14% 3,4-dichloro-N-cyclohexylpyrrolidine. The residue is distilled in vacuo to obtain the epoxide in the form of a clear liquid such as water (E 71 ° C / 0.6 mmHg). One portion of the liquid is transformed into Oxalate to obtain a white solid. M 155-156 ° C / decomposition, by recrystallization from ethanol.

Elementary analysis for C12H19N05:

Calculated: C 56.02 H 7.44 N 5.44%

Found: C 56.05 H 7.50 N 5.34%

HO-

+ ArF

NaH

DMF

OAr

CH2C6H5

I isomeres eis ch „

c6h5

in which Ar is as defined above.

In preparing the compounds having various other substituents according to formula I, the following methods can be used to prepare either the cis or trans isomers.

15 ï) R2 = H, Rj = H or alkyl

R 3.0—, - OAr Rj.0—, r — OAr

J

2) R2--25 RlO-

ca alkyl

NOT-

I

Chai

h5

Ha

Pd / C

NOT-

I

H

Preparation 5:

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

Heated at reflux for 18 h a mixture of 80 g (0.32 mol) 30 of meso-1,4-dibromo-2,3-dihydroxybutane, 34 g (0.32 mol) of benz-ylamine, 3 g of potassium iodide and 140 g (1.0 mol) of potassium carbonate in 250 ml of 95% ethanol, then cooled and filtered. The filtrate is concentrated and the residue is washed with several portions of boiling ethyl acetate. The extracts are combined, washed with a small amount of water, dried over anhydrous sodium sulfate and concentrated to obtain 30 g of residue, representing a yield of 48% in 1-benzyl-3,4-pyrrolidinediol, cis isomer. 1 portion of the product is converted into the hydrochloride by hydrogen chloride in isopropyl alcohol and recrystallized from isopropyl alcohol in the form of dirty white granules, mp 115.0-116.5 ° C.

Elementary analysis for C11H16C1N02:

Calculated: C 57.52 H 7.02 N6.10%

Found: C 57.16 H 6.91 N6.01%

The synthesis of the trans isomers of formula I which form part of the invention and which also serve as reagents for the preparation of other compounds of the invention begins with the reaction of aryloxy compounds with suitable 1-substituted 3,4-epoxypyrrolidines as the following equation indicates:

Trans isomers

O,

-OAr x N -1

CHa csh5

ch3i

RiO-

. OAr

CîC ^ CH2CrH

I

6 ^ 5

1) Ag20 \

2) Ha, Pd / c *

RxO.

OAr

3) Rj = alkyl

HO.

-NOT'

I

ch3

-Or

OCH3

• N ^

I

cha c6h5

NaH

.OAr

CH3I

+ Ar OH

at

HO_

OAr

I

ch3 1

cah

R „

ï

(4) ra = (cha) a -

O 11 C

trans isomers

Ria in which R2 is a phenylalkyl, alkyl or cycloalkyl group, and Ar is as defined above.

The synthesis of the cis isomers which form part of the invention and which serve as reagents for the preparation of other compounds of the invention begins with the reaction of l-benzyl-3,4-pyrrolidinediol, cis isomer, with compounds of formula Ar — F according to the following equation:

-O-Ar + (CH3) 2 N-CH2 -CHa -C

V-

U

-O-Ar r?

CHaCHs-C

643 243 6

(5) R = U or COOCH_C, Hcj R_ = COOOUC.H-1 26 5 2 265

HO _

NOT •

I

CHs I

c6h5

OAr HO Ch lo ro f o rmia t e de benzyle ^

.OAr

CsHsCHaO-CO

^ N-I

O = C-0-CHaC6H5 +

OAr

We

L

O = C-0-CHSC6H5

(6) Ar = halosubstituted phenyl; Ri = R2 ° H

O

C6H5CH20-C-0-

vs

(halo) i_2

O = C-0CHaC6Hs \ HBr

\ l

HO.

u

(halo)

O

I

H

1-2

(7) Ra = -C-NH2

HO-

O - Ar

+ Nitrourée

HO

.OAr

H

I

C = O

I

NH2

(8) Rs = -Ç-N (CH3) 2 Ö

HO.

O

• N 'I

H

■ OAr chloride

+ dimethyl-carbamyl

O H II I

(9) Ra = -C-N-alkyl

HO.

O

.OAr

NOT •

I

C = 0

1 /

N- CH3 a

HO-

■ OAr

-N 'I

H

cold isocyanate

+ alkyl

HO.

0 ° C

.OAr

-OR

C = O I

NH I

CH3

(lo) ri = CH3NHC-; ra = -c-n (ch3) 2

HO

■ OAr

■ N ^

I

C = 0

n (ch3) ì

methyl isocyanate *

0 II

CH3NHC-O

temperature *

ambient

(11) Ri = H; Ar = CbH5j from Ar = CeH-i-halo

643,243

.OAr n <

I

c = 0

n (ch3) 2

HO

I

CHs

I

c6h5

This

Pd / Ç ,, Hs

HO

.0.

• not-

I

H

To obtain the free base of a compound prepared in the form of a salt, the salt is distributed between methylene chloride and 5% sodium hydroxide. The chloromethylenic layer is dried over sodium sulfate and concentrated to obtain the base as a residue.

The following examples illustrate the invention without, however, limiting its scope. As will be readily seen from the examples and from the above, several of the compounds of formula I can also be considered as intermediates in the synthesis of other compounds of formula I.

Example 1:

Trans-4-phenoxy-1-benzyl-3-pyrrolidinol

A mixture of 12.3 g of 1-benzyl-3,4-epoxypyrrolidine, 13.2 g of phenol and 3 drops of water is heated at 120 ° C. under a nitrogen atmosphere for 20 h. The mixture is cooled and dissolved in 100 ml of ethyl ether. The ethereal solution is extracted with 2 x 50 ml of 5% sodium hydroxide and then washed with water. After drying over anhydrous sodium sulfate, the solvent is evaporated and 14.3 g of residue are obtained. After two crystallizations from cy-clohexane, the analytically pure product is obtained. Mp 101-104 ° C. Yield 24% of theory.

Analysis for C17HlgN02:

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-benzylpyrrolidinium iodide

A solution of 8.0 g (56 mmol) of methyl iodide in 30 ml of anhydrous ethyl ether is added dropwise to a stirred solution of 7.0 g (26 mmol) of trans-4-phenoxy-1 -benzyl-3-pyrrolidinol in 70 ml of anhydrous ethyl ether. The mixture is stirred for 2 d and then concentrated under reduced pressure. 10.7 g of a crystalline residue are obtained which are washed with tetrahydro-furan and dried and 10.4 g (97% yield) of a white powder are obtained. Mp 122-127 ° C.

Analysis for C, 8H22IN02:

Calculated: C 52.57 H 5.39 N3.41%

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-benzylpyrrolidinium iodide in 200 ml of absolute ethanol is stirred at ambient temperature for /% h and 100 ml of 85% ethanol with 2.6 g (11.3 mmol) of silver oxide. After adding another 0.2 g of silver oxide, the mixture is heated to 45 ° C. and stirred for a further 15 min. The mixture is separated by filtration on celite and the filtrate is concentrated to 200 ml. This solution is treated with about 0.5 g of 10% palladium-on-carbon as catalyst and stirred in hydrogen in a Parr reduction apparatus for 3 h. The suspension is filtered through celite and the filtrate is concentrated to give 4.3 g of a crystallized solid. After recrystallization from cyclohexane, 3.66 g (84% yield) of dirty white crystals are obtained. F. 89.0-90.0 ° C.

Analysis for Ci, H15N02:

Calculated: C 68.37 H 7.82 N 7.25%

Found: C68, ll H 7.83 N 7.22%

Example 4:

Trans-3-methoxy-4-phenoxy-1-benzylpyrrolidine oxalate

8.1 g (0.03 mol) of trans-4-phenoxy-1-benzyl-3-pyrrolidinol are mixed with 0.72 g (0.03 mol) of sodium hydride (1.3 g of suspension at 55% in oil, washed with 3 x 10 ml of ethyl ether) in 50 ml of dimethylformamide and the mixture is stirred until the evolution of hydrogen is stopped. 4.3 g (0.03 mol) of methyl iodide are added and the mixture is stirred for 18 h. The reaction mixture is treated by pouring it into 400 ml of water and extracting with 3 x 100 ml of ethyl ether. The ethyl ether is evaporated, which leaves 7.9 g of residue. The addition of petroleum ether causes precipitation of the starting product, which is separated by filtration. After evaporating the mother liquor, the residue is chromatographed on 60 silica gel, eluting the product with 10% acetone in benzene. 5.0 g (yield 59%) of the crude product are obtained, according to the NMR spectrum. A small amount of the product is converted to Oxalate in isopropyl alcohol and recrystallized from i-PrOH. Mp 122-125 ° C.

65

Analysis for C20H23NO6:

Calculated: C 64.33 H 6.21 Found: C 63.93 H 6.21

35

40

N 3.75% N 3.69%

643,243

8

Example S. trans-3-methoxy-4-phenoxypyrrolidine fumarate

A solution of 4.2 g (0.015 mol) of 3-methoxy-4-phenoxy-1-benzylpyrrolidine in 70 ml of ethanol is treated with approximately 0.2 g of palladium on carbon as catalyst and the mixture is stirred under a hydrogen atmosphere. at 60 ° C in the Parr apparatus for 3 h.

After cooling, the mixture is filtered and the solvent is evaporated. 2.9 g (100% yield) of crude product are obtained (good purity, according to the NMR spectrum) which is converted to fumarate in isopropyl alcohol. A pale yellow precipitate is obtained. M 134-136 ° C.

Analysis for C15H19N06:

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-pyrrol-idinol in 200 ml of ethanol is treated with approximately 3 g of 10% palladium-on-carbon as catalyst and the mixture is stirred under a hydrogen atmosphere. 60 ° C in the Parr apparatus for 5 h. The suspension is cooled, filtered and the solvent is evaporated off under reduced pressure. The residue is transformed into fumarate using isopropyl alcohol. 14.1 g (product 87%) are obtained. Mp 158-162 ° C.

Analysis for C14H17N06:

Calculated: C 56.95 H 5.80 N 4.74%

Found: C 56.91 H 5.97 N 4.78%

Example 7:

Trans-p-fluoro-y- (3-hydroxy-4-phenen-1-pyrrolidinyl) propiophenone

Heated with stirring at 70 ° C for 6 h a mixture of 3.6 g (0.02 mol) of 4-phenoxy-3-pyrrolidinol, 5 g (0.0215 mol) of P-dimethylamino-p- hydrochloride fluoropropiophenone, 10 g potassium carbonate and 50 ml dimethylformamide, bubbling nitrogen through the reaction mixture. The mixture is poured into water and extracted twice with benzene. The combined extracts are dried over anhydrous sodium sulfate and concentrated to give 6.1 g of an oil as a residue. The oil is chromatographed on 130 g of silica gel. The desired compound is eluted with 20% acetone in benzene and 2.6 g (yield 39%) of an oil are obtained which gradually crystallizes on standing. This solid is recrystallized from a petroleum ether / ethyl ether mixture to obtain a white solid. Mp 77-80 ° C.

Analysis for C19H2oFN03:

Calculated: 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-benzyl-3-pyrrolidinol

Heated to 120 ° C under a nitrogen atmosphere, for 20 h, a mixture of 12.3 g of 1-benzyl-3,4-epoxypyrrolidine, 18.0 g of p-chlorophenol and 3 drops of water. The mixture is cooled and dissolved in 100 ml of ethyl ether. The ethereal solution is extracted with 2 x 50 ml of 5% sodium hydroxide and then washed with water. After drying over anhydrous sodium sulfate, the solvent is evaporated and 14.3 g of a residue are obtained. After two crystallizations from cyclohexane, 4.7 g (yield 29%) of the analytically pure product are obtained. Mp 101-104 ° C.

Analysis for C17H18C1N02:

Calculated: C 67.21 H 5.97 N 4.61%

Found: C 67.35 H 6.10 N 4.69%

Example 9:

Trans-3- (4-chlorophenoxy-4- {benzyl [carbonylbis (oxy)]} - Benzyl l-pyrrolid-inecarboxylate

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

Example 10:

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

A solution of 5 g of trans 3- (4-chlorophenoxy) -4- {benzyl [carbonylbis (oxy)]} - benzyl [benzyl [carbonylbis (oxy)]} - 1-pyrrol-idinecarboxylate in 30 ml of ethanol and 50 ml of 48% hydrogen bromide, then cooled and diluted with 100 ml of water. The solution is extracted with 2 x 50 ml of methylene chloride and the aqueous layer is evaporated to dryness. There remains a powder consisting of the desired product (yield 82%). F. 190-192 ° C.

Analysis for C10H13NO2BrCl:

Calculated: C 40.77 H 4.45 N 4.76%

30 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- (4-35 chlorophenoxy) -3-pyrrolidinol and 2.8 g of nitro-urea in 100 ml of 90% ethanol is heated at 50 ° C. for 20 h. A little of the solvent is removed in vacuo and the resulting suspension is diluted with 50 ml of water. The precipitate is filtered and triturated with acetone, filtered and dried. 1.8 g of product are obtained. M. 223-225 ° C.

40

Analysis for CnH13N203Cl:

Calculated: C 51.47 H 5.11 N 10.91%

Found: C 51.18 H 5.02 N 10.88%

45 Example 12:

Trans-3- (4-chlorophenoxy) -4-hydroxy-N, N-dimethyl-1-pyrrolidine-carboxamide

A solution of 3.5 g of 4- (4-chlorophen-50 oxy) -3-pyrrolidinol, 1.8 g of dimethylcarbamyl chloride and 1.7 g of triethylamine in 300 ml of methylene chloride is stirred for 60 h. . The solvent is removed in vacuo, 300 ml of benzene are added and the mixture is heated to reflux for 2 h, then filtered. After evaporation of the solvent, the residue is dissolved in a mixture of cyclohexane / benz-55 ene and treated with charcoal. The product is then crystallized, collected by filtration and recrystallized from a cyclohexane / benzene mixture. Mp 137-142 ° C.

Analysis for C13H17N203C1:

Calculated: C 54.84 H 6.02 N 9.84%

60

Found: C 54.64 H 6.01 N9.77%

Example 13:

Trans-3- (4-chlorophenoxy) -4-hydroxy-N-methyl-1-pyrrolidinecarb-65 oxamide hemihydrate

A solution of 0.9 g of 4- (4-chlorophenoxy) -3-pyrrolidinol in 50 ml of methylene chloride is cooled to 0 ° C. and 0.24 g of methyl isocyanate in 5 ml is added dropwise chloride

methylene in 10 min. The cooling is stopped and the stirring is continued for 1 hour. The solvent is then removed and the residue is crystallized from the dimethyl sulfoxide / water mixture. Mp 95.0-98.5 ° C.

Analysis for C12H1SN203C1:

Calculated: C 51.53 H 5.77 N 10.02%

Found: C 51.64 H 5.79 N 10.09%

Example 14:

Trans-3 - {[(methy lamino) carbonyl] oxy} -4- f 4-chlorophenoxy) -N, N-dimethyl-1-pyrrolidinecarboxamide

A solution of 1.0 g (0.003 mol) of trans-3- (4-chlorophenoxy) -4-hydr-oxy-N, N-dimethyl-1-pyrrolidinecarboxamide and 1 is allowed to stand at room temperature for 48 h. 0 g (0.02 mol) of methyl isocyanate in 20 ml of methylene chloride. The solution is concentrated to obtain an oil which crystallizes on standing. The solid is recrystallized from the benzene / cyclohexane mixture to obtain 0.6 g (50% yield) of a white solid. M. 132-134 ° C.

Analysis for C1sH20C1N3O4:

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-benzyl-3-pyrrolidinol

A mixture of 35.0 g of 1-benz-yl-3,4-epoxypyrrolidine and 32.6 g of 2,6-dichlorophenol is heated at 125 ° C. for 3 h. The mixture is cooled, dissolved in methylene chloride and extracted with dilute sodium hydroxide. After evaporation of the solvent, the residue is purified by column chromatography. The product is eluted with 30% ethyl acetate in benzene and crystallized from cyclohexane. 43 g (product 64%) are obtained. Mp 78-80 ° C.

Analysis for Ci7H17N02C12:

Calculated: C 60.37 H 5.07 N4.14%

Found: C 60.42 H 5.06 N 4.12%

Example 16:

Trans-3- (2,6-dichlorophenoxy) -4- {benzyl [carbonylbis (oxy)]} - benzyl l-pyrrolidinecarboxylate

To a solution of 3.4 g of trans-1-benzyl-4- (2,6-dichlorophen-oxy) -3-pyrrolidinol and 1.05 g of triethylamine in 25 ml of benzene is added dropwise a solution of 4.0 g of benzyl chloroformate in 1 ml of benzene. The mixture is stirred for 30 min when the addition is complete; then filtered and the solvent is evaporated off under reduced pressure. The residue is dissolved in 50 ml of methylene chloride and 6.0 g of benzyl chloroformate are added. The mixture is stirred overnight; the solvent is then evaporated and the residue is chromatographed on silica gel. The product is eluted with 20% ethyl acetate in benzene and then stirred in petroleum ether until it crystallizes. 4.7 g (90% yield) of white crystals are obtained. Mp 93-95 ° C.

Analysis for C26H23N06C12:

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

Stirred at 125 ° C for 16 h a solution of 12.2 g of the trans isomer of 3- (2,6-dichlorophenoxy) -4- [benzyl (carbonylbis (oxy))] - 1-pyrrolidinecarboxylate in 120 ml of ethanol and 140 ml of 48% hydrogen bromide, then cooled and diluted with 300 ml of water. The solution is then extracted with twice 100 ml of methylene chloride and the aqueous layer is evaporated to dryness. Trituration with 30% ethyl ether in isopropyl alcohol

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that gives 7.4 g (95% yield) of white crystallized hydrobromide. M.p. 192-195 ° C.

Analysis for Ci0Hi2NO2BrCl2:

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-benzyl-3-pyrrolid-inol hydrochloride

Heated to 120 ° C overnight a mixture of 21.5 g (0.12 mol) of l-benzyl-3,4-epoxypyrrolidine, 27.8 g (0.17 mol) of 2,3-dichlorophenol and two drops of concentrated hydrochloric acid. The dark mixture is dissolved in methylene chloride and washed with 4 portions of 100 ml of 5% sodium hydroxide and once with water. The chloromethylen layer is dried over anhydrous sodium sulphate / potassium hydroxide and concentrated to obtain 35.8 g of a dark gum as residue. This gum is chromatographed on 800 g of silica gel and the product is eluted with an acetone / benzene solution. The appropriate fractions are concentrated to obtain 25 g (yield 60%) of an oil. One portion of this oil is transformed into the hydrochloride to obtain a white solid. M 219-222 ° C.

Analysis for C ^ Hj 8C13N02:

Calculated: C 54.50 H 4.84 N 3.74%

Found: C 54.53 H 4.82 N3.53%

Example 19:

Trans-4- (2,3-dichlorophenoxy) -1 - [(benzoxy) carbonyl] -3-pyrrolidi-nol

A mixture of 8.5 g (0.023 mol) of trans-4- (2,3-dichlorophenoxy) -1-benzyl-3-pyrrolidinol hydrochloride and 100 ml of methylene chloride is cooled and treated dropwise with a solution of 23 g (0.125 mol) of benzyl chloroformate in 100 ml of methylene chloride. The mixture is stirred at room temperature for 48 h, and then washed successively with water, with 2N hydrochloric acid, with 5% sodium hydroxide and with water. The chloromethylenic layer is dried over anhydrous sodium sulfate and then subjected to vacuum distillation at 100 ° C / 1.0 mmHg to remove methylene chloride, excess benzyl chloroformate and benzyl chloride. NMR analysis of the distillation residue indicates that oxygen alone has been substituted. Another 25 ml of benzyl chloroformate and 100 ml of methylene chloride are added to the residue and the solution is stirred at room temperature for 48 h. The mixture is purified as above to obtain 14.6 g of a residue which is chromatographed on 300 g of silica gel. Chromatography gives 5.6 g of the disubstituted compound (see Example 20) and 1.0 g of the desired compound as a white solid. Mp 130-132 ° C (recrystallized from benzene).

Analysis for: C18H17C12N04:

Calculated: C 56.56 H 4.48 N 3.67%

Found: C 56.80 H 4.48 N 3.67%

Example 20:

Trans-3- (2,3-dichlorophenoxy) -4- {benzyl [carbonylbis (oxy)]} -! - benzyl pyrrolidinecarboxylate

This disubstituted compound is obtained in the chromatographic separation of Example 19 in an amount of 5.6 g.

Example 21:

Trans-4- (2,3-dichlorophenoxy) -3-pyrrolidinol hydrobromide A mixture of 5.6 g (0.011 mol) of 3- (2,3-dichlorophenoxy) trans isomer is heated to 125 ° C overnight ) -4- {benzyl- [carbonylbis (oxy)]} - Benzyl 1-pyrrolidinecarboxylate, 60 ml of ethanol and 70 ml of 48% aqueous hydrogen bromide. We pour

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the mixture in 150 ml of water and extracted three times with methylene chloride. The aqueous solution is concentrated to obtain an oily residue which crystallizes on standing. The solid is washed with an isopropyl alcohol / ethyl ether mixture, it is collected by filtration and it is recrystallized from the isopropyl alcohol / ethyl ether mixture to obtain 1.5 g (45% yield) of a pink solid. Mp 134-138 ° C.

Analysis for C10H12BrCl; NO2:

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 is heated at 115 ° C. for 18 h under nitrogen atmosphere. After cooling, the mixture is dissolved in benzene and washed with 5% sodium hydroxide to separate the excess cresol. By stirring with 50 g of silica gel, a large part of the colored material is removed. The solution is concentrated and part of the residue is converted into the hydrochloride. This salt is recrystallized from an isopropyl alcohol / ethyl ether mixture. Mp 163-165 ° C.

Analysis for C18H22N02C1:

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 is treated with approximately 0.5 g of 10% palladium on carbon as catalyst and stirred with hydrogen at 60 ° C in the Parr apparatus for 2 h. The suspension is cooled, filtered and the solvent is evaporated in vacuo. The base is transformed into Oxalate in isopropyl alcohol, filtered and dried. The salt is obtained with a yield of 86%. Mp 150-155 ° C.

Analysis for CI3H17NOs:

Calculated: C 55.12 H 6.05 N4.94%

Found: C 54.75 H 6.07 N 5.06%

Example 24:

Trans-4- (2,3-dimethylphenoxy) -1-benzyl-3-pyrrolidinol

Heated to 120 ° C under a nitrogen atmosphere overnight a mixture of 17.5 g (0.10 mol) of l-benzyl-3,4-epoxypyrrolidine, 18.3 g (0.15 mol) of 2 , 3-dimethylphenol and 2 drops of concentrated hydrochloric acid. The reaction mixture is dissolved in methylene chloride and washed with 4 portions of 100 ml of 5% sodium hydroxide and once with water. The chloromethylen layer is dried over anhydrous sodium sulfate / potassium hydroxide and concentrated to obtain 28.6 g of a dark oil as a residue. This oil is chromatographed on 600 g of silica gel and the product is eluted with an acetone / benzene solution. The appropriate fractions are concentrated to give an oil which crystallizes on standing. This solid is recrystallized from ligroin to obtain 9.1 g (31% yield) of a white solid. M.p. 100-104 ° C.

Analyst for Ci9H23N02 '.

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-benzyl-3-pyrrolidinol is hydrogenated in 100 ml of ethanol on 10% palladium carbon under a pressure of 3 , 5 bar and at 60 ° C

until the absorption of hydrogen stops. The mixture is filtered on celite and the substrate is concentrated to obtain, as residue, an oil which solidifies on standing. The solid is transformed into hydrobromide and this salt is crystallized from an isopropyl alcohol / ethyl acetate / ethyl ether mixture to obtain 4.9 g (55% yield) of brown needles. Mp 152-153 ° C.

Analysis for C12Hi8BrN02:

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) -l-benzyl-3-pyrrolidinol

A mixture of 40 g of crude 1-benzyl-3,4-epoxypyrrolidine and 70 g of guaiacol is heated at 120 ° C. for 20 h. The vacuum tube is then used to remove excess guaiacol by distillation. The residue is dissolved in methylene chloride and extracted with dilute sodium hydroxide. The chloromethylene solution is dried over anhydrous sodium sulfate and the solvent is evaporated. 54 g of residue are obtained which is chromatographed on 1 kg of silica gel. The product is eluted with 50% ethyl acetate in benzene and it is crystallized from cyclohexane. Yield 27%. Mp 115-117 ° C.

Analysis for C18H2: N03:

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 l-benzyl-4- (o-methoxyphen-oxy) -3-pyrrolidinol in 200 ml of ethanol is treated with approximately 2 g of 10% palladium on carbon as catalyst and stirred in l at 60 ° C in the Parr reduction apparatus for 5 h. The suspension is then cooled, filtered and the solvent is evaporated off under reduced pressure. The base is transformed into fumarate. M.p. 158-160 ° C. The yield is 9.8 g (78%).

Analysis for C! 5Hi9N07:

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) -l-benzyl-3-pyrrolidinol

A mixture of 17.5 g (0.10 mol) of l-benzyl-3,4-epoxypyrrolidine, 13.4 g (0.11 mol) of p-methoxyphenol and 3 drops are heated in the steam bath overnight. of water. The dark residue is dissolved in methylene chloride and the solution is washed with 2% of 50 ml of 5% sodium hydroxide. The chloromethylen layer is dried over anhydrous sodium sulfate and concentrated to obtain 23.7 g of a dark viscous oil. This oil is chromatographed on 484 g of silica gel and the product is eluted with a 1/1 benzene / ether solution. Concentrate the appropriate fractions to obtain 10.0 g of a yellow oil which crystallizes by scraping the container. The solid is recrystallized from cyclohexane to obtain 7.2 g (24% yield) of a brown solid. Mp 84-85 ° C.

Analysis for ClsH2iN03:

Calculated: C 72.22 H 7.07 N 4.68%

Found: C 72.20 H 7.15 N 4.61%

Example 29:

Oxalate (3: 4) -trans-4- (4-methoxyphenoxy) -3-pyrrolidinol

The solution of 4.0 g (0.0134 mol) of trans-4- (4-methoxyphenoxy) -1-benzyl-3-pyrrolidinol is hydrogenated in 75 ml of ethanol on 0.4 g of 10% palladium on carbon at 60 ° C overnight. The reaction mixture is cooled, filtered through silica and the filtrate is concentrated to obtain the base in the form of a white solid. We trans-

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forms this solid in Oxalate and is recrystallized from methanol to obtain white flakes. Mp 173-175 ° C / decomposition.

Analysis for C41H53N3025:

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) -l-benzyl-3-pyrrolidinol

A mixture of 45.5 g (0.26 mol) of l-benzyl-3,4-epoxypyrrolidine (60 g of 76% epoxy), 48 g (0.35 mol) is heated at 145 ° C. for 16 h. ) o-ethoxyphenol and 8 drops of concentrated hydrochloric acid. The mixture is cooled, dissolved in methylene chloride and washed with a dilute solution of sodium hydroxide. The chloromethylenic layer is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The residue is chromatographed on 1 kg of silica gel using 20% acetone in benzene as the eluent. Two recrystallizations from cyclohexane give 8.0 g (10% yield) of brown needles. Mp 88.5-90.0 ° C.

Analysis for Q9H23NO3:

Calculated: C 72.82 H 7.40 N 4.47%

Found: C 72.64 H 7.39 N4.56%

Example 31:

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

A solution of 7.4 g (24 mmol) of trans-4- (2-ethoxy-phenoxy) -1-benzyl-3-pyrrolidinol in 150 ml of absolute ethanol is treated with approximately 0.5 g of palladium-on-carbon. 10% as catalyst and stirred in hydrogen in a Parr reduction apparatus at 60 ° C for A h. The mixture is cooled, filtered and the filtrate is concentrated. The residue (5.3 g, 100% yield) is transformed into fumarate in isopropyl alcohol to give a white powder. F. 173.0-174.5 ° C.

Analysis for Ci6H21N07:

Calculated: C 56.63 H 6.24 N 4.13%

Found: C 56.60 H 6.27 N4.12%

Example 32:

Trans-4- [4- (phenylmethoxy) phenoxy J-1-benzyl-3,4-pyrrolidinol

A mixture of 42 g of 1-benzyl-3,4-epoxypyrrolidine and 42 g of 4-benzoxyphenol is heated at 130 ° C. for 8 h. The mixture crystallizes on cooling. Three crystallizations from a petroleum ether / cyclohexane mixture give fluffy white crystals. Mp 98.0-100.0 ° C. The yield is 6.0 g (8%).

Analysis for C24H25NO3:

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 l-benzyl-4- (4-benzoxyphenoxy) -3-pyrrolidinol in 150 ml of ethanol are treated with approximately 1 g of palladium on charcoal and the mixture is stirred in hydrogen at 60 ° C. in the apparatus. from Parr for 3 h. The mixture is then cooled, filtered and the ethanol is removed. The Oxalate is prepared in an isopropyl alcohol / acetone mixture and recrystallized from 90% ethanol. The salt decomposes at 235 ° C.

Analysis for Ci [H ^ NOs:

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) -l-benzyl-3-pyrrolid-inol oxalate

A mixture of 24.0 g of 1-benzyl-3,4-epoxypyrrolidine and 22.2 g of 3-trifluoromethylphenol is heated at 130 ° C. for 3 h. The mixture is cooled, dissolved in methylene chloride and extracted with dilute sodium hydroxide. After evaporation of the solvent, the residue is purified by column chromatography. Eluted with 30% ethyl acetate in benzene to obtain 17.7 g (yield 38%) of the product. We transform a small portion into Oxalate. Mp 139-141 ° C.

Analysis for C20H20NO6F3:

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-trifluoro-methylphenoxy) -3-pyrrolidinol in 200 ml of ethanol is treated with approximately 2 g of 10% palladium on charcoal as catalyst and the mixture is stirred in hydrogen at 60 ° C. in the Parr reduction apparatus for 16 h. The suspension is cooled, filtered and the solvent is evaporated off under reduced pressure. The residue is dissolved in ether and converted to the hydrochloride. 9.8 g (product 93%) are obtained. Mp 145-148 ° C.

Analysis for CUH13N02C1F3:

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-benzyl-pyrrolidine-3-yl) oxy Jbenzamide

A mixture of 28 g of 1-benzyl-3,4-epoxypyrrolidine and 20.6 g of 4-hydroxybenzamide is heated at 130 ° C. for 8 h. The cooled mixture is passed through a column of silica gel using 5% methanol in ethyl acetate to elute the product which is then crystallized from the chloroform / benzene / meth-anol mixture. The yield is 19% in product. F. 133.0-136.0 ° C.

Analysis for C18H20N2O3:

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 Jbenzamide

8 g of 4- (4-carbamylphenoxy) -1-benzyl-3-pyrrolidinol are treated with approximately 1 g of 10% palladium on charcoal and dissolved in 100 ml of ethanol and stirred with hydrogen at 60 ° C for 4 h. The suspension is then cooled and filtered. The precipitate is washed with hot methanol and the washing liquors and the mother liquor are combined. The solvent is evaporated to 150 ml and cooled overnight. The product is filtered and dried. F. 199-204 ° C / decomposition. The yield is 80%.

Analysis for CnH ^ NjO- ,:

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- [(4-hydroxy-1-benzyl-3-pyrrolidinyl) oxyJphenyl} aca-mide

A mixture of 35.0 g of 1-benzyl-3,4-epoxypyrrolidine, 30.2 g of p-acetamidophenol and two drops of water is heated at 125 ° C. for 3 hours. The mixture is then cooled, dissolved in 50% ethyl acetate in benzene and washed with hydroxide

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diluted sodium. After removing the solvent, a residue of 56 g remains. It is chromatographed using 370 g of silica gel and the product is eluted with ethyl acetate. After crystallization from 50% ethyl acetate in benzene, 26.1 g (40% yield) of product are obtained. F. 130-132 ° C.

Analysis for C19H22N203:

Calculated: C 69.92 H 6.79 N8.58%

Found: C 69.61 H 6.69 N 8.44%

Example 39:

Trans-N- {4 - [(4-hydroxy-3-pyrrolidinyl) oxy] phën-yljacetamide hemifumarate

A solution of 12.4 g of l-benzyl-4- (4-acetamidophen-oxy) -3-pyrollidinol in 200 ml of ethanol is treated with approximately 2 g of 10% palladium on charcoal as catalyst and stirred in hydrogen at 60 ° C in a Parr reduction apparatus for 16 h. The suspension is then cooled, filtered and the solvent is evaporated off under reduced pressure. A 9 g residue is obtained which is converted into fumarate and crystallized from isopropyl alcohol. 10.2 g (90% yield) of the salt are obtained. M.p. 200-205 ° C.

Analysis for Ci4H18N205:

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-naphthoxy) -l-benzyl-3-pyrrolidinol oxalate

A mixture of 17.5 g (0.10 mol) of crude l-benzyl-3,4-epoxypyrrolidine, 15.0 g (0.11 mol) of 1-naphthol and a drop of concentrated hydrochloric acid. The dark mixture is dissolved in methylene chloride and the solution is extracted with 3 portions of 50 ml of 5% sodium hydroxide. The chloromethylenic layer is dried over anhydrous sodium sulfate and concentrated to obtain 25.5 g (80% yield) of a black gum as residue. This residue is chromatographed on 500 g of silica gel and the product is eluted with a 1/1 ethyl ether / benzene mixture to obtain 9.9 g (31% yield) of a white solid. Mp 106-108 ° C, after recrystallization from cyclohexane.

Analysis for C21H21N02:

Calculated: C 78.97 H 6.63 N 4.39%

Found: C 79.08 H 6.67 N 4.45%

The oxalate is prepared in the form of a white solid. Mp 190-192 ° C, after recrystallization from nitromethane.

Analysis for C23H23N06:

Calculated: C 67.47 H 5.66 N3.42%

Found: C 67.00 H 5.68 N 3.57%

Example 41:

Trans-4- (1-naphthoxy) -3-pyrrolidinol

18 g of l-benzyl-4- (1-naphthoxy) -3-pyrrolidinol in 200 ml of ethanol are treated with approximately 2 g of 10% palladium on charcoal in hydrogen at 60 ° C for 20 h. The mixture is cooled, filtered and the ethanol is removed. The residue is crystallized from benzene. Mp 112-115 ° C.

Analysis for C14H15N02:

Calculated: C 73.34 H 6.59 N6, ll%

Found: C 73.39 H 6.64 N 5.90%

residue on silica gel using ethyl acetate to elute the product. After crystallization from cyclohexane, the product is obtained with a yield of 6%. Mp 98-101 ° C.

Analysis for C20H32NO2:

Calculated: Found:

Example 43:

CUM H 7.49 N4.53% C 77.41 H 7.52 N4.37%

Trans-4- hydrochloride [1 H- (2,3-dihydro-indene-4-yl) oxy] -3-pyrrolidinol

2.7 g of 1-benzyl-4- (4-indanoxy) -3-pyrrolidinol in 100 ml of ethanol are treated with approximately 0.5 g of 10% palladium on charcoal and the mixture is stirred in hydrogen at 60 ° C in the Parr apparatus for 5 h. The suspension is then cooled, filtered and the solvent is removed. The residue is converted into ether hydrochloride and dried for 18 h at 40 ° C under vacuum. The product is obtained with a yield of 91%. Mp 174-180 ° C.

20 Analysis for C13H16N02C1:

Calculated: C 61.06 H 7.09 N 5.48%

Found: C 60.80 H 7.16 N5.46%

Example 42:

Trans-4- [1H- (2,3-dihydro-indene-4-yl) oxy] -l-benzyl-3-pyrrolidinol

A mixture of 28 g of I-benzyl-3,4-epoxypyrrolidine and 20.1 g of 4-indanol is heated at 130 ° C. for 8 h. We chromatograph the

Example 44:

Trans-4 hydrochloride - [(1,2-dihydro-indene-5-yl) oxy] -1-benzyl-3-pyrrolidinol

A mixture of 35 g of 1-benzyl-3,4-epoxypyrrolidine and 28 g of 5-indanol is heated at 130 ° C. for 3 h. The mixture is then cooled, dissolved in methylene chloride and extracted with dilute sodium hydroxide. After evaporation of the solvent, the residue is chromatographed on silica gel and the product is eluted with 50% ethyl acetate in benzene. The hydrochloride is formed from ether and recrystallized from the ethanol / acetone mixture. 12.3 g (18% yield) of the salt are obtained. F. 153-155 ° C.

Analysis for C20H24NO2Cl:

Calculated: C 69.45 H 6.99 N 4.05%

40 Found: C 69.13 H 6.93 N 3.99%

Example 45:

Trans-4- [(2,3-dihydro-l H-indene-5-yl) oxy] -3-pyrrolidinol oxalate 45 A solution of 6.0 g of l-benzyl-4- (5-indanoxy) is treated ) -3-pyrrolidinol in 100 ml of ethanol with approximately 0.5 g of 10% palladium on charcoal and the mixture is stirred in hydrogen at 60 ° C. in the Parr apparatus for 3 h. The solution is then cooled, filtered and the solvent is removed. The oxalate is prepared in iso-50 propyl alcohol. F. 179.0-181.0 ° C.

Analysis for C15H19N06:

Calculated: C 58.25 H 6.19 N 4.53%

Found: C 58.13 H 6.14 N 4.58%

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Example 46:

Trans-1-ethyl-4-phenoxy-3-pyrrolidinol hydrated oxalate (4: 1) A mixture of 22.6 g of 1-60 ethyl-3,4-epoxypyrrolidine and 18.6 is heated at 150 ° C for 30 min , 6 g of phenol and then distilled. The product boils at 120 ° C under 0.025 mmHg. The yield of pure product is 25.0 g (60%). We transform 1 portion of the base into Oxalate. Mp 134-137 ° C, after recrystallization from isopropyl alcohol.

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Analysis for CS6H78N4025:

Calculated: C 55.72 H 6.51 N 4.64%

Found: C 55.83 H 6.38 N 4.63%

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Example 47:

Trans-1-ethyl-4-phenoxy-3-pyrrolidinyl n-methylcarbamate

The mixture is left to stand in a nitrogen atmosphere for 5 d of a solution of 6.5 g of 1-ethyl-4-phenoxy-3-pyrrolidinol and 1.9 g of methyl isocya-nate. Evaporation of the benzene leaves a crystalline solid which is recrystallized from cyclohexane. 6.5 g (product 79%) are obtained. Mp 88-94 ° C.

Analysis for Ci4H20N2O3:

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) of 1-ethyl-3,4-epoxypyrrolidine, 20.5 g (0.16 mol) of o-chlorophenol and 3 is heated in the steam bath overnight. drops of concentrated hydrochloric acid. The oil is dissolved in methylene chloride and washed with 3 portions of 50 ml of 5% sodium hydroxide and 1 portion of 50 ml of water. The chloromethylene solution is dried over sodium sulfate, concentrated and chromatographed on silica gel to give 8.9 g (25% yield) of an oil as residue. The oil is converted into the hydrochloride and recrystallized from an ethyl acetate / acetonitrile mixture to obtain a white powder. Mp 108-110 ° C.

Analysis for C12H17C12N02:

Calculated: C 51.81 H 6.16 N 5.04%

Found: C 51.65 H 6.17 N5.09%

Example 49:

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

A mixture of 11.3 g (0.10 mol) of 1-ethyl-3,4-epoxypyrrolidine, 18.0 g (0.11 mol) of 2,6-dichlorophenol and is heated in a steam bath overnight. two drops of concentrated hydrochloric acid. The oil is dissolved in methylene chloride and washed with 3 portions of 50 ml of 5% sodium hydroxide and 1 portion of 50 ml of water. The chloromethylene solution is dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel to give 12.9 g (47% yield) of an oily residue. The oil is converted into the hydrochloride and recrystallized from an isopropyl alcohol / ethyl ether mixture to obtain 12.3 g (yield 39%) of the salt. Mp 160-162 ° C.

C12Hi6Cl3N02 pump analysis:

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-pyrrolidinolhèmihy-drate oxalate

The mixture is heated at 125 ° C. for 45 min, then distilled under vacuum, a mixture of 17 g of 1-ethyl-3,4-epoxypyrrolidine and 16.2 g of m-cresol. A product boiling at 135 ° C. under 0.02 mmHg is obtained with a yield of 37%. We transform it into Oxalate. Mp 116-119 ° C.

Analysis for C30H44N2O13:

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) -l-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 is heated in the steam bath overnight. drops of concentrated hydrochloric acid. The oil is dissolved in methylene chloride and washed with 3 portions of 50 ml of 5% sodium hydroxide and 1 portion of 50 ml of water. The chloromethylene solution is dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel to give 8.1 g (21% yield) of an oil which crystallizes on standing. The solid is recrystallized from cyclohexane to obtain a brown solid. Mp 73-75 ° C.

Analysis for C14H21N03:

Calculated: C 66.90 H 8.42 N 5.57%

Found: C 66.49 H 8.43 N5.48%

Example 52:

4 - [(trans-1-ethyl-4-hydroxy-3-pyrrolidinyl) oxy] -3-methoxyacetophenone sesquioxalate

Heated in a steam bath overnight a mixture of 17.0 g (0.15 mol) of 1-ethyl-3,4-epoxypyrrolidine, 28.0 g (0.17 mol) of acetovanillone and 3 drops of 'water. The mixture is dissolved in 250 ml of methylene chloride and extracted with 3 portions of 150 ml of 5% sodium hydroxide and 1 portion of 100 ml of water. The chloromethylen layer is dried over anhydrous sodium sulfate and concentrated to obtain 19.0 g of a crude oil. This oil is chromatographed on 400 g of silica gel. The desired product is eluted with acetone. The fractions are concentrated to obtain 14.0 g of an oil, which is treated with oxalic acid in isopropyl alcohol. The resulting white solid is recrystallized twice from isopropyl alcohol to obtain 13.4 g (24% yield) of the sesquioxalate. Mp 121-123 ° C.

Analysis for C16H24NO10:

Calculated: C 52.17 H 5.84 N3.38%

Found: C 52.45 H 5.90 N3.60%

Example 53:

Trans-1-ethyl-4- (2-allylphenoxy) -3-pyrrolidinol oxalate

The mixture is heated to 130 ° C. for Ah, then cooled and chromatographed on silica gel using 20% methanol in ethyl acetate to elute the product. 18.5 g (50% yield) of product are obtained, a portion of which is transformed into Oxalate. Mp 142-145 ° C.

Analysis for C17H23NOe:

Calculated: C 60.52 H 6.87 N 4.15%

Found: C 60.30 H 6.79 N3.98%

Example 54:

Trans-1-ethyl-4- (2-allylphenoxy) -3-pyrrolidinyl N-ethylcarbamate

A mixture of 7.3 g of trans-4- (2-allyl-phenoxy) -1-ethyr-3-pyrrolidinol and 2.5 g of ethyl isocyanate in 30 ml of benzene is stirred for 48 h. The benzene is replaced by petroleum ether and the solution is cooled. A precipitate is obtained with a yield of 78%. Mp 53-56 ° C.

Analysis for C18H28N203:

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 1-4- (1-naphthoxy) -3-pyrrolidinol hydrochloride

A mixture of 22.6 g of 3,4-epoxy-1-ethylpyrrolidine and 28.8 g of 1-naphthol is heated at 130 ° C. for 1 hour. The mixture is cooled, dissolved in benzene and extracted with dilute sodium hydroxide. The benzene is evaporated and the residue is chromatographed on silica gel, eluting the product with 40% methanol in ethyl acetate. The hydrochloride is prepared and recrystallized from the methanol / acetone mixture. 17.5 g (30% yield) of the salt are obtained. Mp 206-207 ° C.

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Analysis for C16H20NO2Cl:

Calculated: C 65.41 H 6.86 N 4.77%

Found: C 65.29 H 6.93 N 4.70%

Example 56:

Trans-1-ethyl-4- [(1 H-2,3-dihydro-indene-4-yl) oxyJ-3-pyrrolidinol

A mixture of 17 g of 1-ethyl-3,4-epoxypyrrolidine and 20 g of 4-indanol is heated at 125 ° C. for 1 hour, then cooled and dissolved in ethyl acetate and chromatographed on a gel. silica using 25% methanol in ethyl acetate to elute the product. 15 g (product 40%) are obtained. Mp 87-90 ° C, after recrystallization from cyclohexane.

Analysis for C15H21N02:

Calculated: C 72.84 H 8.56 N 5.66%

Found: C 72.92 H 8.52 N 5.48%

Example 57:

Trans-1-ethyl-4 - [(1H-2,3-dihydro-indene-5-yl) oxy] -3-pyrrolidinol maleate

A mixture of 15.0 g (0.132 mol) of 1-ethyl-3,4-epoxypyrrolidine, 20 g (0.15 mol) of 5-indanol and a drop of water is heated in the steam bath overnight. The oil is dissolved in methylene chloride and washed with 3 portions of 50 ml of 5% sodium hydroxide and 1 portion of 50 ml of water. The chloromethylene solution is dried over anhydrous sodium sulfate and concentrated to obtain 28.5 g of a dark residue. This residue is chromatographed on 500 g of silica gel and the product is eluted with methanol. This oil is transformed into maleate to obtain 16.6 g (yield 35%) of cream-colored needles. Mp 147-148 ° C.

Analysis for Ci9H25N06:

Calculated: C 62.80 H 6.93 N3.85%

Found: C 62.74 H 6.88 N3.83%

Example 58:

Trans-1-cyclohexyl-4-phenoxy-3-pyrrolidinol cyclamate

Heated in a steam bath overnight a mixture of 33.5 g (0.2 mol) of N-cyclohexyl-3,4-epoxypyrrolidine, 18.8 g (0.02 mol) of phenol and 2 drops of concentrated hydrochloric acid. The reaction mixture is dissolved in methylene chloride and washed with 3% of 100 ml of 5% sodium hydroxide and once with 100 ml of water and dried over potassium hydroxide / anhydrous sodium sulfate. The chloromethylenic solution is concentrated to give 36.4 g of an oily residue. The oil partially crystallizes and the solid is washed with petroleum ether, it is collected by filtration and recrystallized from cyclohexane to obtain 11.0 g (yield 21%) of a white solid. This solid is transformed into a cyclamate to obtain white needles. Mp 163-165 ° C, after recrystallization from isopropyl alcohol.

Analysis for C22H36N205S:

Calculated: C 59.97 H 8.24 N 6.36%

Found: C 59.99 H 8.29 N 6.30%

Example 59:

Cis-4-phenoxy-1-benzyl-3-pyrrolidinol

A suspension of 2.4 g (0.1 mol) of sodium hydride (4.2 g of 57% oil dispersion, washed with ether to separate the oil) in 30 ml of dimethylformamide by adding dropwise a solution of 19.3 g (0.1 mol) of the cis isomer of 1-benzyl-3,4-dihydroxypyrrolidine (I) in 30 ml of dimethylformamide. The mixture is heated at 50 ° C for 1 h, then a solution of 19.2 g (0.2 mol) of fluorobenzene in 30 ml of dimethylformamide is added all at once. The mixture is heated at 90 ° C for 18 h, then cooled and concentrated in vacuo. The residue is dissolved in benzene and washed with water. By concentrating the organic fraction, a semi-crystalline residue is obtained which is dissolved in cyclohexane and the solution is decanted to separate the insoluble oil (essentially compound I). The cyclohexane solution is treated with charcoal to separate the residual compound I and then crystallized to obtain 1.2 g (4.5% yield) of fluffy dirty white needles. Mp 88.5-90 ° C, decomposition.

Analysis for C17H19N02:

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-benzyl-3-pyrrolidinol

A suspension of 1.2 g (50 mmol) of sodium hydride (2.1 g of 57% oil dispersion, washed with ether to separate the oil) in 25 ml of dimethylsulfoxide is stirred. adding 9.6 g (50 mmol) of cis-isomer of 1-benzyl-3,4-dihydroxypyrrolidine in 25 ml of dimethyl sulfoxide. The mixture is stirred at room temperature for 1 h, then 50 ml of dimethyl sulfoxide is added and the temperature is raised to 95 ° C for 30 min. Mechanical agitation of the thick slurry is necessary while adding 13 g (100 mmol) of n-chlorofluorobenzene. During the 1 hour heating period at 95 ° C, all of the precipitate dissolves. The reaction mixture is concentrated by vacuum distillation of dimethylsulfoxide and excess m-chlorofluorobenzene. The residue is poured into water and extracted with hot cyclohexane. The organic excesses are combined, dried over anhydrous sodium sulfate and concentrated to obtain 7.5 g (yield 49%) of dirty white crystals. Mp 86-87.5 ° C.

Analysis for Ct 7H18C1N02:

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-benzyl-pyrrolidinium iodide

A mixture of 15.2 g (0.05 mol) of cis-4- (3-chlorophenoxy) -l-benzyl-3-pyrrolidinoI and 56 g (0.4 mol) of iodide is heated at reflux for 60 h. methyl. Excess methyl iodide is removed in vacuo. The pasty residue is washed with an ether / acetone mixture; there remains 13 g (yield 59%) of a granular brown powder. Mp 118-125 ° C.

Analysis for C18H21C1IN02:

Calculated: C 48.51 H 4.75 N 3.14%

Found: C 48.27 H 4.75 N3.19%

Example 62:

Cis-1-methyl-4-phenoxy-3-pyrrolidinol

A solution of 12.5 g (28 mmol) of cis-3- (3-chlorophenoxy) -4-hydroxy-1-methyl-1-benzylpyrrolidinium iodide in 400 ml of ethanol with 3 is stirred at 45 ° C. , 5 g (15 mmol) of silver oxide for 1 h. The solids are separated by filtration and the filtrate is concentrated to 100 ml, treated with 0.5 g of 10% palladium on pea charcoal as catalyst and stirred in hydrogen at 60 ° C for 3 h. The mixture is cooled and the catalyst is collected by filtration. The filtrate is concentrated, the residue is treated with dilute sodium hydroxide and extraction is carried out in methylene chloride. The solution is concentrated and redissolved in hot cyclohexane, treated with charcoal which is separated by filtration on celite and recrystallized from cyclohexane to obtain 4.6 g (85% yield) of white needles . Mp 78-81 ° C.

Analysis for Cj, H15N02:

Calculated: C 68.37 H 7.82 N 7.25%

Found: C 68.42 H 7.87 N 7.19%

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Example 63:

Hydrated hydrochloride (4: 1) cis-4-phenoxy-3-pyrrolidinol

A solution of 16.0 g (53 mmol) of cis-4- (3-chloro-phenoxy) -1-benzyl-3-pyrrolidinol in 100 ml of absolute ethanol and 5 ml of concentrated hydrochloric acid is treated with 0 , 5 g of 10% palladium on charcoal as catalyst and stirred in hydrogen at 60 ° C for 16h. The mixture is cooled and the catalyst is separated by filtration on celite. The filtrate is concentrated and the white crystallized residue is triturated with an ether / acetone mixture. 9.8 g (86% yield) of a white powder are obtained. F. 128-137 ° C.

Analysis for C4oH58Cl4N409:

Calculated: C 54.55 H 6.64 N 6.36%

Found: C 54.26 H 6.41 N6.27%

Formulation and administration

An animal may be administered effective amounts of one of the above compounds of formula I with pharmacological activity for therapeutic purposes according to the usual modes of administration and in the usual forms, for example by the oral route 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 may be a sterile acceptable liquid, for example water, or a parenteral acceptable oil, for example peanut oil, in ampoules.

Although very small amounts of the active compounds of the invention are effective in the case of minor therapy or in the case of administration to subjects with relatively low body weight, the unit doses are usually 5 mg or more and preferably 25, 50 or 100 mg or even more, depending on the urgency of the case, of course, and the particular result desired. A dose of 5 to 50 mg per unit dose seems to be an optimal value; usual wider ranges appear to be 1 to 500 mg per unit dose. The daily doses should preferably be 10 to 100 mg. The active ingredients of the invention can be combined with other pharmacologically active agents as indicated above. It is only necessary that the active ingredient constitutes an effective amount, that is to say such that a suitable effective dose is obtained in accordance with the dosage form used. Of course, several forms of unit doses can be administered at approximately the same time. The exact individual doses as well as the daily doses are, of course, determined according to conventional medical principles under the guidance of a doctor or a veterinarian.

The following formulations are characteristic for all the compounds with pharmacological activity of the invention.

Formulations 1. Capsules

Capsules containing 5, 10, 25 and 50 mg of active ingredient are prepared per capsule. Above 5 mg of active ingredient, the amount of lactose can be reduced.

Characteristic mixture for encapsulation mg per capsule

Active ingredient in salt form

5

Lactose

259

Starch

126

Magnesium stearate

4

Total

394

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

Ingredients

100 mg per capsule

250 mg per capsule

500 mg per capsule

Active ingredient under

salt form

100

250

500

Lactose

214

163

95

Starch

87

81

47

Magnesium stearate

4

6

8

Total

399

500

650

In each case, the active ingredient chosen is uniformly mixed with the lactose, starch and magnesium stearate and the mixture is put into capsules.

2. Tablets

A typical formulation for tablets is given below containing 5.0 mg of active ingredient per tablet. The formulation can be used for other active ingredient contents by adjusting the weight of dicalcium phosphate.

Ingredient mg per tablet

1. Active ingredient

5.0

2. Corn starch

15.0

3. Corn starch (dough)

12.0

4. Lactose

35.0

5. Dicalcium phosphate

132.0

6. Magnesium stearate

2.0

Total

202.0

Ingredients 1, 2, 4 and 5 are mixed uniformly. Ingredient 3 is prepared in the form of a 10% paste in water. The mixture is granulated with the starch paste and the wet mass is passed through a sieve of 2.38 mm of mesh opening. The wet granulated mixture is dried and passed through a 1.68 mm sieve. The dried granules are mixed with the calcium stearate and pressed into tablets.

3. 2% sterile solution for injection per ml

Active ingredient (mg) 20

Preservative, e.g. chlorobutanol

(% by weight by volume) 0.5

Water for injection q.s.

The solution is prepared, adjusted, clarified by filtration, filled with vials which are sealed and autoclaved.

It is understood that the invention is not limited to the preferred embodiments described above by way of illustration and that a person skilled in the art can make various modifications and various changes without however departing from the scope nor the spirit of the invention.

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Claims (15)

643,243 2 1. Cis- and trans-3-aryloxy-4-hydroxypyrroIidines and their derivatives, characterized in that they correspond to the general formula: - OAr R-jO. (I) with a compound of formula ArF in which Ar is as defined above, in the presence of sodium hydride in dimethylformamide. 10. Process for the preparation of the cis or trans compounds according to claim 1, in which R2 is hydrogen and R is hydrogen or an alkyl group, characterized in that a compound of general formula is reduced: - OAr Ri 0 r, in which £ ■ R 1 represents hydrogen or a lower alkyl, benzyl-oxycarbonyl, or N- (lower alkyl) carbamoyl group; R2 represents hydrogen or a lower alkyl, cycloalkyl, phenylalkyl, benzyloxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di (lower alkyl) carbamoyl or paralluoro-benzoylalkyl group; Ar represents a phenyl or substituted phenyl, 1-naphthyl, 2-naphthyl, 4-indanyl or 5-indanyl group, their acid addition salts and their quaternary ammonium salts. 2. Compound according to claim 1, characterized in that it consists of trans-l-methyl-4-phenoxy-3-pyrrolidinol. 3. Compounds according to claim 1, characterized in that they consist of trans-4- (2,6-dichlorophenoxy) -3-pyrrolidinol and its hydrobromide. 4. Compounds according to claim 1, characterized in that they consist of trans-4- (2,3-dichlorophenoxy) -3-pyrrolidinol and its hydrobromide. 5. Compounds according to claim 1, characterized in that they consist of trans-1-ethyl-4-phenoxy-3-pyrrolidinol and its hydrated oxalate 0.25 H2O. 6. Compounds according to claim 1, characterized in that they consist of trans-4- (2-chlorophenoxy) -1-ethyl-3-pyrrolidinol and its hydrochloride. 7. Compounds according to claim 1, characterized in that they consist of trans-4- (2,6-dichlorophenoxy) -1-ethyl-3-pyrrolidinol and its hydrochloride. 8. A process for preparing the trans isomers of the compounds according to claim 1, in which R2 is a phenylalkyl, alkyl or cycloalkyl group, and Ar is as defined in claim 1, characterized in that a 3 is reacted, 1-substituted 4-epoxypyrrolidine: i5 CH „ I 2 c6h5 in which: Rt and Ar are as defined above, by hydrogen on palladium-on-carbon. 11. Process for the preparation of the cis or trans compounds according to claim 1, in which R2 is an alkyl group and Rt and Ar are as defined above, characterized in that a pyrrolidine of the general formula is quaternized: OAr 40 in which: Rj and Ar are as defined above with an alkyl iodide, then the pyrrolidinium iodide obtained is treated with Ag20, then with hydrogen on palladium carbon. 12. Process for the preparation of the cis or trans compounds according to claim 1, in which R! is an alkyl group, characterized in that a compound of formula: HO- .OAr in which: R2 is as defined above, with a phenol of formula ArOH in which Ar is as defined above, on heating. 9. Process for the preparation of the cis isomers of the compounds according to claim 1, in which R2 is a benzyl group and Ar is as defined above, characterized in that the 3,4-l-benzyl is reacted -pyrrolidinediol of formula: HO. -OH 50 1 CH7 i " Ss 55 in which: Ar is as defined above, by an alkyl iodide in the presence of sodium hydride. 13. Pharmaceutical composition, characterized in that it contains a cis or trans isomer of the compound corresponding to the formula: -Or R10 • (I) cis CH9 CrHc 2 6 5 in which: R. 3 643,243 R represents hydrogen or a lower alkyl, benzyl-oxycarbonyl or N- (lower alkyl) carbamoyl group; R2 represents hydrogen or a lower alkyl, cycloalkyl, phenylalkyl, benzyloxycarbonyl, carbamoyl, N- (lower alkyl) carbamoyl, N, N-di (lower alkyl) carbamoyl or parafluoro-benzoylalkyl group; Ar represents a phenyl or substituted phenyl group, 1-naphthyl, 2-naphthyl, 4-indanyl or 5-indanyl, or one of its acid addition salts or a quaternary ammonium salt. wherein R2 is hydrogen or a lower alkyl or phenylalkyl group, and Ar is a phenyl or substituted phenyl group. The preferred compounds for their antidepressant activity correspond to the formula: (Halo) (0-2) HO—, r-0 SN ' (Ib) alkyl