GB2054581A

GB2054581A - alpha -Phenyl-2-pyrrolidinemethanol derivatives

Info

Publication number: GB2054581A
Application number: GB8022070A
Authority: GB
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1979-07-06
Filing date: 1980-07-04
Publication date: 1981-02-18
Also published as: JPS5610166A; FR2460929A1; IT1149204B; IT8049165A0; BE884176A; DE3025436A1; NL8003880A; FR2460929B1; EP0022408A1; ES8106289A1; ES493107A0

Description

SPECIFICATION a-Phenyl-2-pyrrolidinemethanol derivatives The present invention relates to new derivatives of a-phenyl 2-pyrrolidinemethanol as well as their salts, processes for their preparation, compositions containing them and their use as medicaments. According to one feature of the present invention there are provided compounds of the formula

(in which R represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms) and their acid addition salts. It is to be understood that the present invention extends to all stereoisomeric forms of the compounds of formula I, isolated or mixed, racemic or optionally active. In the general formula (I) and in what follows, the term alkyl radical containing from 1 to 5 carbon atoms includes, for example, a methyl, ethyl, propyl, isopropyl, butyl or pentyl radical. The acid addition salts with mineral or organic acids can for example be the salts formed with the following acids: hydrochloric, hydrobromic, hydriodic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic (such as methane- or ethanesulphonic), arylsulphonic (such as benzene- or paratoluenesulphonic) and arylcarboxylic. Among the products which are the subject of the invention, there are to be mentioned in particular compounds of formula (I), as well as their acid addition salts with mineral or organic acids, in which the hydroxyl groups attached to the phenyl ring are in positions 3 and 4 or 3 and 5 and R represents a hydrogen atom. Special mention should be made of 4-[a-hydroxy(pyrrolidin-2-yl)methyl]-1,2-benzenediol in all its optically active and racemic forms, as well as its salts, and in particular the acid oxalate of the A isomer of 4-[a-hydroxy(pyrrolidin-2-yl)methyl]-1,2-benzenediol in all its optically active and racemic forms. Compounds of formula (I) as defined above possess two asymmetric carbons and can therefore exist in different isomeric forms. These different isomeric forms can be obtained separately by methods known per se. The diastereoisomeric racemates will in what follows be denoted by the terms isomer A and isomer B: they can be obtained separately by known methods, for example by selective crystallization, by chromatography or by stereo-selective preparations. By convention, the isomer for which the coupling constant of the hydrogen atoms carried by the asymmetric carbons is the stronger is called isomer A, and the one for which the coupling constant is weaker is called isomer B. Examples of stereo-selective preparation and of separation by chromatography are given hereinafter. The racemates A and B can be resolved into their optically active enantiomers by known methods, such as, for example, the formation of salts by means of optically active acids. It is to be understood that the mixtures of the different isomers of the compounds of formula (I), and in particular the mixtures of the diastereo-isomeric racemates of the said compounds, come within the scope of the invention. According to a further feature of the present invention there is provided a process for the preparation of a compound according to the invention which comprises hydrolysing a compound of formula

(in which R' represents a benzyl radical or an alkyl radical containing from 1 to 5 carbon atoms) and if desired separating into its isomers and/or salifying the product thereby obtained.According to a still further feature of the present invention there is provided a process for the preparation of a compound according to the invention in which R represents an alkyl radical which comprises reacting a compound of formula I in which R represent a hydrogen atom with a compound of formula

in which R" represents an alkyl radical containing from 1 to 5 carbon atoms and Hal represent a chlorine, bromine or iodine atom and if desired separating into its isomers and/or salifying the product thereby obtained. The above processes may, for example, be incorporated in the following reaction sequences. A. 4-Bromobutyl triphenyl phosphonium bromide may be reacted with an aldehyde of formula (II):

so as to obtain a product of formula (III):

which may then be reacted with an amine of formula (IV):

(in which R' represents a benzyl radical or an alkyl radical containing from 1 to 5 carbon atoms), so as to obtain a product of formula (V):

(in which R' has the significance already indicated) which product of formula (V) may be treated with trifluoroacetic anhydride so as to obtain a product of formula (VI):

(in wich R' has the significance already indicated); the product of formula (VI) may be treated with N-bromosuccinimide so as to obtain a product of formula (VII):

(in which R' has the significance already indicated) which product of formula (VII) may be treated with an alkaline agent so as to obtain a product of formula (VIII):

(in which R' has the significance already indicated) in the form of a mixture of the isomers A (VIIIA) and B (VIIIB) which may, if desired, be separated; the product of formula (VIII), (VIIIA) or (VIIIB) is subjected to hydrogenolysis so as to obtain the desired product of formula (I), in the form of a mixture of A and B isomers which, if desired, are separated, or in the form of isomer A or B; the product of formula (I) may, if desired, be salified, --or, may (when R represents a hydrogen atom) be reacted with a halide of formula (IX):

(in which Hal represents a chlorine, bromine or iodine atom and R" represents an alkyl radical containing from 1 to 5 carbon atoms) so as to obtain a product with the formula (I'):

(in which R" has the significance already indicated) corresponding to a product of formula (I) in which R is as defined for R", in the form of a mixture of A and B isomers (which, may if desired, be separated) or in the form of isomer A or B. The product of formula (I') may, if desired, be salified. The following are preferred conditions for reaction sequence A:--4-bromobutyl triphenylphosphonium bromide is reacted with the aldehyde of formula (II), by adding them, in the solid state, to sodium hydride in a mixture of tetrahydrofuran and dimethyl sulphoxide; -the product of formula (III) is reacted with the amine of formula (IV) at a temperature of about 120.C for a period of 8 to 12 hours; -the product of formula (V) is treated with trifluoroacetic acid anhydride at ambient temperature for a period of 12 to 16 hours; -the product of formula (VI) is treated with N-bromosuccinimide in the presence of an aqueous solution of sulphuric acid, first cooled at about 12[deg]C, then at ambient temperature;-the alkaline agent utilized for the cyclization of the product of formula (VII) is an aqueous solution of sodium hydroxide, but it is also possible to utilize an aqueous solution of potassium hydroxide; -the cyclization of the product of formula (VII) is carried out in dioxan in an inert atmosphere, by refluxing the reaction mixture; -the catalytic hydrogenolysis of the product of formula (VIII) is carried out in methanol at 50[deg]C in the presence of palladized charcoal; -the optional separation of the mixture of A and B isomers of the products of formulae VIII and I is carried out by chromatography. B. For the preparation of compounds of the invention in which the hydroxyl radicals attached to the phenyl ring are in the 2,4 or 2,5 or 3,4 position, a compound of formula (X)

(in which the benzyloxy radicals are in positions 2,4 or 2,5 or 3,4 may be treated with bromine so as to obtain a compound of formula (XI):

which may be cyclized with an amine of formula (IV)

(in which R' represents a benzyl radical or an alkyl radical containing from 1 to 5 carbon atoms) so as to obtain a product of formula (XII):

(in which R' has the significance already indicated) which product of formula (XII) may be reduced so as to obtain a product of formula (XIII):

(in which R' has the significance already indicated) in the form of a mixture of isomers A (XIIIA) and B (XIIIB) which may be separated if desired. The compound of formula (XIII), (XIIIA) or (XIIIB) is subjected to hydrogenolysis, so as to obtain the desired product of formula (I), in the form of a mixture of the A and B isomers (which may if desired by separated) or in the form of isomer A or B. The product of formula (I), may if desired, be salified or may when R represents a hydrogen atom, be reacted with a halide of formula (IX):

(in which Hal and R" have the significance already indicated) so as to obtain a product of

(in which R" has the significance already indicated) corresponding to a product of formula (I) in which R is as defined for R" and the substituents OH are in positions 2,4 or 2,5 or 3,4, in the form of a mixture of A and B isomers (which may if desired, be separated) or in the form of isomer A or B. The product of formula (I") may, if desired, be salified. The following are preferred conditions for reaction sequence B: the product of formula (X) is treated with a solution of bromine in acetic acid and the reaction mixture is treated rapidly with iced water after the addition of the bromine; -the cyclization of the product of formula (XI) is carried out in toluene, but it is possible to utilize other solvents such as benzene or xylene; -the product of formula (XII) is reduced with sodium borohydride in methanol [if it is preferred to obtain the isomer A of the desired product of formula (I)] or with diethylsodiumaluminium dihydride in toluene [if it is preferred to obtain the isomer B of the desired product of formula (I)]; -the catalytic hydrogenolysis of the product of formula (XIII) is carried out at 50[deg]C in the presence of palladized carbon;-the optional separation of the A and B isomers of the products of formulae (XIII) and (I) is obtained by chromatography. C. For the preparation of compounds of the invention in the form of the A isomer, a product of formula (X):

may be treated with bromine, so as to obtain a product of formula (XI):

the said product of formula (XI) may be treated with a reducing agent so as to obtain a product of formula (XIV):

which may be treated with an alkaline alcoholate, so as to obtain a product of formula (XV):

which may be treated with an amine of formula (IV):

(in which R' represents a benzyl radical or an alkyl radical containing from 1 to 5 carbon atoms) so as to obtain a product with the formula (XIII) as previously defined, in the form of the A isomer, which product is subjected to hydrogenolysis, so as to obtain the corresponding product of formula (I) in the form of the A isomer, which product may, if desired, be salified or, when R represents a hydrogen atom, may be reacted with a halide of formula (IX):

(in which Hal and R" have the significance already indicated) so as to obtain a product of formula (I"):

(in which R" has the significance already indicated) corresponding to a product of formula I in which R is as defined for R" in the form of the A isomer. The product of formula (I"') may, if desired, be salified. The preferred conditions for reaction sequence C are as follows:-the reducing agent is sodium borohydride and the operation is carried out in methanol: -the epoxidation by the alkaline alcoholate is carried out by sodium teramylate in tetrahydrofuran: -the treatment with the amine of formula (IV) is carried out in the absence of a solvent: -the hydrogenolysis of the product with the formula (XIII) is carried out at 50[deg]C in the presence of palladized carbon. D. For the preparation of compounds of the invention in the form of the A isomer, 4bromobutyltriphenyl phosphonium bromide may be reacted with an aldehyde of formula (II):

so as to obtain a product of formula (III):

in the form of the cis isomer. The said product of formula (III) may be treated with an epoxidation agent, so as to obtain a product of formula (XV), as previously defined, and the synthesis may then be continued as described in reaction sequence C. In reaction sequence D, the preferred epoxidation agent utilized is hydrogen peroxide. The compounds of formula (I) are basic. The acid addition salts of compounds of formula (I) can advantageously be prepared by reacting a mineral or organic acid with the said compound of formula (I) in substantially stoichiometric proportions. The salts can be prepared without isolating the corresponding bases. The compounds of the present invention possess very useful pharmacological properties; they are in particular endowed with remarkable bronchodilatatory and hypotensive properties, as well as anti-depressive properties. These properties are illustrated hereinafter in the experimental part. The compounds of formula (I) and their salts may accordingly be used as medicaments. According to a further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I as hereinbefore defined or a pharmaceutically acceptable acid addition salt thereof. Preferred compositions are those wherein the active ingredient is a compound of formula (I) in which the hydroxyl groups attached to the phenyl ring are in positions 3 and 4 or 3 and 5, and R represents a hydrogen atom, or a pharmaceutically acceptable acid addition salt of such a compound. Especially preferred compositions are those wherein the active ingredient is 4-[a-hydroxy(pyrrolidin-2-yl)-methyl]-1,2-benzene-diol in its optically active or racemic forms, or a pharmaceutically acceptable acid addition salt thereof, in particular the acid oxalate of the A isomer of 4-[ahydroxy(pyrrolidin-2-yl)methyl]-1,2-benzenediol in its optically active or racemic forms. The compositions according to the invention may, for example, be used in the treatment of asthma, asthmatic bronchitis, chronic bronchitis, arterial hypertension in all its forms-permanent mild, moderate or severe-or even in the treatment of states of depression. The usual dose, variable according to the derivative utilized, the subject treated and the complaint concerned, can, for example, be from 1 mg to 50 mg per day, by oral route for man. The compositions according to the invention may, for example, be presented in a form suitable for administration by the digestive, parenteral or local route. The pharmaceutical compositions can, for example, be solid or liquid, and can be prepared in the pharmaceutical forms currently utilized in human medicine, such as for example, compressed tablets (plain or sugar-coated), capsules, granules, suppositories, injectable preparations and aerosols; they can be prepared according to conventional methods. The active ingredients can be incorporated in pharmaceutical compositions with conventional excipients, such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or nonaqueous vehicles and fatty substances of animal or vegetable origin; paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and preservatives. Compounds of formula (II), when they are not known, can for example be prepared by benzylation of an acid of formula (XIV):

followed by the conversion of the dibenzylated acid so obtained into the corresponding acid chloride by conventional processes, and finally by catalytic reduction of the acid chloride by Rosenmund's method so as to obtain the desired aldehyde. The compounds of formula (X) in which the benzyloxy radicals are in positions 2,4 or 2,5 or 3,4, when they are not known, can be prepared by a Friedel-Crafts reaction between a dihydroxybenzene in which the hydroxy radicals are in positions 1,3 or 1,4 or 1,2 and 5bromovaleric acid, followed by benzylation with benzyl bromide in the presence of an alkaline agent. An example of such a preparation is given below in the experimental part. The process of the invention enables new industrial products to be prepared, namely, in particular, the derivatives with the formulae (VI), (VII), (VIII), (XI), (XII), (XIV) and (XV), as previously defined. The following non-limiting examples illustrate the present invention. Example 1: Acid oxalate of 4-[a-hydroxy(pyrrolidin-2-yl)-methyl]-1 ,2-benzenediol (isomer A).

Over one and a half hours, a mixture of 47.8 g of 4-bromobutyl triphenyl phosphonium bromide (Mondon: Annalen der Chemie 603-1 15 (1957)) and 28.6 g of 3,4-dibenzyloxybenzaldehyde is added progressively to a suspension of 5.28 g of sodium hydride in 350 cm of tetrahydrofuran and 350 cm of dimethylsulphoxide, at a temperature of 5[deg]C; the reaction mixture is agitated for 27 hours at ambient temperature and taken to dryness by heating to 70-80[deg]C under reduced pressure. The gelatinuous mass obtained is taken up by 700 cm of ether, agitated for one hour, allowed to stand for one night, filtered and taken to dryness. The product obtained is purified by re-dissolution in benzene, then by rapid passage on 700 g of silica, and after evaporation of the solvent, 35.60 g of the product sought is obtained. Stage B: Hydrochloride of N-[5-[3,4-bis[phenylmethyl)oxy] phenyl]pent-5-en-1-yl]benzene ethanamine (cis isomer). 29.25 g of the product obtained at the previous stage is agitated for 10 hours at 120[deg]C with 72 cm of benzylamine, then the excess amine is expelled at 100[deg]C under reduced pressure; the residue is taken up by 500 cm of ether, washed with water, dried and evaporated and 36.85 g of a thick oil is obtained which is put into solution in 300 cm of ether. 22 cm of 5N hydrochloric acid in solution in alcohol is added, the hydrochloride is separated from the liquid, and washed with ether, dried under reduced pressure and purified in methylene chloride. 30 g of the expected product is obtained, melting at 150[deg]C.

cetamide (cis isomer). 30 g of the hydrochloride obtained in the previous stage is agitated in 100 cm of methylene chloride with 50 g of trifluoroacetic anhydride in the presence of 31.8 g of anhydrous sodium carbonate. After agitating for one night at ambient temperature, washing with a 10% aqueous solution of potassium bicarbonate, drying and evaporating the organic phase under reduced pressure, 28.5 g of the product sought is obtained. Thin-layer chromatography on silica, eluant : benzene-acetic acid (9/1), R. F. = 0.45.

thyl)2,2,2-trifluoroacetamide. Under inert atomosphere, to a solution of 5.6 g of the product obtained in the previous stage in 100 cm of dioxan at 10-15[deg]C, 7.2 cm of an aqueous solution of sulphuric acid of density of 1.83 and then, over 15 minutes, a solution of 1.9 g of N-bromosuccinimide in 25 cm of dioxane are added. After 15 minutes the mixture is allowed to return to ambient temperature, and is maintained under agitation overnight, diluted with 400 cm of ether, washed with water, dried, treated with activated charcoal; the organic phase is taken to dryness and 7.8 g of the product sought is obtained.

A).

18.5 g of the product obtained in the previous stage is taken to reflux in 200 cm of dioxane with 87 cm of N sodium hydroxide for one and a half hours under an inert atmosphere; the reaction mixture is allowed to stand for one night, taken up with ether, washed with water and evaporated, and 10.45 g of an oil is recovered which is chromatographed on a silica column by elution with a mixture of methylene chloride and methanol (95-5). In this way three fractions are isolated; the least mobile fraction, consisting of 2.4 g of a thick oil corresponding to the A isomer of the product sought, is recovered and is crystallized in isopropyl ether. White crystals melting at 72[deg]C are obtained. The fraction with medium mobility corresponds to the isomer A containing traces of isomer B.

Stage F: Acid oxalate of 4-[a-hydroxy(pyrrolidin-2-yl)-methyl]-1 ,2-benzenediol (isomer A). Under a pressure of 0.5 bar of hydrogen at 50[deg]C, 4.095 g of the product obtained in the previous stage is agitated for 40 minutes in 55 cm of methanol with 0.82 g of palladized charcoal. Preparation of the acid oxalate. Next, the above mixture is put under a nitrogen atmosphere, and 25 cm of a solution of oxalic acid in methanol at 4 g per 100 cm is added; the mixture is agitated for several minutes, filtered and the solvent is evaporated under reduced pressure. The residue is dried at 70[deg]C and 2.7 g of a white product is recovered which is washed with ethanol and then with ether. After drying, 2.35 g of a product corresponding to the product sought is obtained, melting with decomposition at 220-225 [deg]C.

Example 2: Acid oxalate of 4-[a-hydroxy(pyrrolidin-2-yl) methyl] 1,2-benzenediol (isomer A).

38.47 g of 5-bromo-1-[3,4-bis (phenylmethyloxy)phenyl]-1-pentanone is dissolved in 350 cm of acetic acid by heating at 60[deg]C and then cooled. A solution of 14 g of bromine in 40 cm of acetic acid is introduced drop by drop while cooling, and agitated again for 5 minutes after the ) crystallization obtained at the end of the addition, then a litre of iced water is added. After agitating for 5 minutes, separating off the liquid, washing the crystals with water, drying under reduced pressure at 60[deg]C, and re-crystallizing the 43.2 g of crystals obtained in cyclohexane, 38 g of the expected product is recovered, melting at 100[deg]C.

21.28 g of the product obtained in the previous stage is taken to reflux in 100 cm of anhydrous toluene for 4 hours with 14.12 g of benzylamine; after cooling and eliminating by filtration the precipitate formed, the filtrate is recovered and utilized as it is for the following stage.

The filtrate obtained in the previous stage is agitated for 17 hours at 65[deg]C, under inert atmosphere, with 5.12 g of 95% sodium borohydride 40 cm of 2N sodium hydroxide, 200 cm of water and 3 g of cetyltrimethylammonium bromide. After cooling, 500 cm of ether is added; by decanting, extracting the aqueous phase with ether, washing the organic phase with salt water and drying, and expelling the solvents under reduced pressure, 21.35 g of a yellow oil is recovered, which is chromatographed on silica by elution with a methylene chloridemethanol (97-3) mixture. Three fractions are obtained and the least mobile fraction corresponding to the A isomer is isolated. The A isomer recovered, recrystallized in 2.5 volumes of isopropyl ether, leads to 5.515 g of pure product, melting at 73-74[deg]C.

Stage D: Acid oxalate of 4-[a-hydroxy(pyrrolidin-2-yl)-methyl] 1, 2-benzenediol (isomer A). The product obtained in the previous stage is treated according to the process indicated in stage F of Example 1. The 5-bromo 1-[3,4-bis(phenylmethyloxy)phenyl] 1-pentanone for the start of Stage A can be prepared in the following manner: a) Preparation of 5-bromo-1-(3,4-dihydroxyphenyl)-1-pentanone. Boron trifluoride is bubbled into a suspension of 91.2 g of pyrocatechol in 695 cm of trichlorethylene with 150 g of 5-bromo valeric acid (Isenberg and Coll. Can J. 40 831 (1962)), then heated for 2 hours 40 minutes at 67 [deg]C; after bubbling in 154 g of boron trifluoride, [the mixture] is allowed under agitation to return slowly to ambient temperature overnight. The upper phase of the two phases so obtained is eliminated; the remainder is washed twice, with 100 ml of trichlorethylene, poured into 650 cm of iced water, agitated for an hour, and the crystals are separated, washed with water and dried. 186 g of crystals are recovered, which are recrystallized in toluene. 163 g of the product sought is obtained, melting at 110-115[deg]C.

A solution of 30.6 g of the product obtained in the previous stage in 390 cm of acetone is agitated under an inert atmosphere with 155g of potassium carbonate. Over 2 hours at 23.-25[deg]C, 39.1 g of benzyl bromide in solution in 300 cm of acetone is introduced drop by drop; after agitating for 21 hours 30 minutes, filtering and evaporating the filtrate under reduced pressure, 51 g of the crude product is recovered. This is purified by chromatography on silica by methylene chloride, and after drying under reduced pressure, 43 g of the desired product is obtained, which, recrystallized in cyclohexane, melts at 71 [deg]C. Example 3: Hydrochloride of 4-[alpha -hydroxy(pyrrolidin-2-yl]-methyl]-1,2-benzenediol (isomer B). Stage A: alpha [3,4-bis[(phenylmethyl)oxy]phenyl] [1-(phenylmethyl)2-pyrrolidinyl]methanone. 22.08 g of the product as obtained in Stage A of Example 2 is taken to reflux in 150 cm of anhydrous toluene, the temperature is allowed to fall to 100[deg]C and over 4 minutes a solution of 15 cm of benzylamine in 25 cm of toluene is added; after agitating again for 2 hours 30 minutes at reflux, cooling and eliminating by filtration the precipitate formed, the filtrate is utilized as it is for the following stage.

The filtrate obtained in the previous stage is agitated at 20[deg]C under inert atmosphere with 61.5 cm of a solution in toluene at 1.35 mole/litre of diethyl sodium aluminium dihydride, which is added over 5 minutes. [The mixture] is then agitated for 18 hours 30 minutes at 20-23[deg]C, then cooled to 8[deg]C, over 30 minutes 15 g of ice in small pieces is added, then, at 10.C, 250 cm of sodium hydroxide solution is introduced. After agitating for 30 minutes, decanting, extracting the aqueous phase with toluene, washing the organic phase with water, drying and expelling the solvents under reduced pressure, 20.8 g of a yellow oil is recovered which is chromatographed on silica (eluant: methylene chloride-methanol (97-3). 4 fractions are obtained, the most mobile fraction, corresponding to the isomer B is isolated and taken to dryness.The product is recrystallized in 20 cm of isopropyl ether and 7.475 g of the product sought is obtained, pure, melting at 82[deg]C.

about 95 Hz (massive) the CH2 in /? of the nitrogen.

Stage C: Hydrochloride of 4-[a-hydroxy(pyrrolidin-2-yl) methyl]- 1,2-benzenediol (isomer B). For 45 minutes under an atmosphere of hydrogen, and at a temperature of 54[deg]C, 4 g of the product obtained in the previous stage is agitated in 52 cm of dimethylformamide with 0.650 g of palladized charcoal at 9.8%. The mixture is cooled to 25[deg]C, and 2.5 cm of a solution in ethanol of 6.6 N hydrochloric acid is added. After filtering, evaporating the solvents and drying at 54[deg]C under reduced pressure, 3.5 g of a yellowish-brown oil is recovered, which is dissolved in 30 cm of water at 60.C under inert atmosphere. The solution obtained is filtered under inert atmosphere, and 2 cm of 20[deg] Be ammonia is added; after icing and allowing to crystallize during one hour 30 minutes, the crystals are washed with water, dried under reduced pressure, and 1.47 g of the product sought is recovered in the non-salified form, melting at 250[deg]C.

Preparation of the hydrochloride. 3.285 g of the product as obtained above in solution in 13 cm of absolute alcohol is agitated with 2.6 cm of a solution in ethanol of 6.6 N hydrochloric acid for one night under inert atmosphere. After icing for an hour, the crystals are separated and washed with an iced mixture of ethanol and ether, dried under vacuum and 3.41 g of the hydrochloride sought is obtained, melting at 250[deg]C.

Example 4: Acid oxalate of 4-[alpha -hydroxy(pyrrolidin-2-yl)-methyl]- ,2-benzene diol (isomer A). 5 Stage A: 3,4-bis(phenylmethoxy)-a-(1,4-dibromobutyl) benzene-methanol. 0.532 g of 2,5-dibromo 1-[3,4-bis(phenylmethoxy) phenyl]-1-pentanone (obtained in Stage A of Example 2) is put into suspension in 10.6 cm of methanol. 0.08 g of sodium borohydride is added at 0 to + 5[deg]C. The mixture is agitated for one hour 15 minutes at 0 to + 5[deg]C, then poured on to an aqueous solution of 1 N hydrochloric acid at 0[deg]C. After extracting with ether, ) drying and evaporating the solvent, 0.472 g of the expected product is obtained which is used just as it is for the following stage.

0.05 g of sodium hydride in mineral oil at 56% is put into suspension in 1 cm of 5 tetrahydrofuran, then 0.19 cm of teramyl alcohol in 1 cm of tetrahydrofuran is added. The temperature is allowed to rise to reflux, then cooled to 20[deg]C. 0.534 g of the product obtained as described in Stage A is added, and agitation is maintained for 45 minutes.After pouring on to an aqueous solution of hydrochloric acid, extracting with methylene chloride, drying the organic phase and evaporating the solvent, 0.393 g of the expected product is obtained and ) utilized as it is for the following stage. Stage C: alpha -[3,4-bis(phenylmethoxy)phenyl)1-(phenylmeihyl) 2-pyrrolidine methanol (isomer A) A mixture of 0.361 g of the product obtained in stage B and 0.343 g of benzylamine is agitated for 4 hours, then poured on to an aqueous solution of sodium hydroxide; after 5 extracting with methylene chloride, drying and evaporating the solvents, 0.3 g of the expected product is obtained, identical to the product obtained in Example 1 (Stage E) and Example 2 (Stage C). Stage D; Acid oxalate of 4-[alpha -hydroxy(pyrrolidin-2-yl)-methyl]-1,2-benzenediol (isomer A). Starting with the product obtained in Stage C above, and operating as described in Example 1 or 2, the expected product is obtained. Example 5: Acid oxalate of 4-[alpha -hydroxy-(pyrrolidin-2-yl)-methyl]-1,2-benzenediol (isomer A). Stage A: 2-[3,4-bis(phenylmethoxy)phenyl]3-(1-bromopropyl)-oxirane. At 0[deg]C, 1.55 g of metachloroperbenzoic acid in solution in 20 cm of methylene chloride is introduced into a solution of 1 g of 1,2-bis(phenylmethoxy)4-(5-bromopent-1-en-1-yl)benzene obtained as described at Stage A of Example 1, in 10 cm of methylene chloride. [The mixture] is maintained for 5 hours at 20[deg]C, then filtered, the filtrate is washed with an aqueous solution of sodium bicarbonate, dried, and the solvent evaporated. The expected product is obtained, and is utilized as it is for the following stage. Stage B: Acid oxalate of 4 [alpha -hydroxy (pyrrolidin-2-yl)-methyl]1,2-benzenediol. Starting with the product obtained in Stage A above and operating as described in Stage C for Example 4, then as described at Example 1 or 2, the expected product is obtained.

Example 6: Compressed tablets corresponding to the formulation:

(Detail of the excipient: lactose, starch, talc, magnesium stearate).

Example 7: Compressed tablets corresponding to the formulation:

(Detail of the excipient: lactose, starch, talc, magnesium stearate).

Example 8: Aerosols were preparated delivering doses each containing:

Pharmacological study. 1) Action on the isolated tracheas of guinea-pigs. The tracheas of guinea-pigs, freshly killed by a blow on the nape of the neck, are taken out, cut spirally and suspended in a Krebs Henseleit solution at a temperature of 37[deg]C, through which a mixture of 95% oxygen and 5% carbon dioxide gas is bubbled. Carbachol is added to the solution as agonist to provoke contractions. The product of Example 1 at a concentration of 3.10-6M antagonises 100% the contractions provoked by carbachol at a concentration of 0.4 Microg/ml. 2) Action on broncho-spasms provoked by histamine in guinea-pigs. Following the method of Konzett and Rossler, Arch. exp. Path. Pharmakol. 195 71 (1940), histamine is administered at a dose varying from 2 to 10 Microg/kg i.v. according to the sensitivity of the animal. The registration of the pressure produced by the air expelled is carried out by an Apelab microdynamometer. The product to be tested is injected in solution in physiological serum by i.v. route one minute before the histamine. A possible effect of the product alone and its antagonist action vis-a-vis the constrictor agent is recorded. The antagonist activity is expressed in percentage of protection as referred to the initial broncho-spasm due to the histamine. Injected at a dose of 1,ug/kg, the product of Example 1 inhibited by 52% the broncho constriction of the histamine and the product of Example 3 at this same dose inhibited it by 17%. 3) Determination of hypotensive activity. The hypotensive activity was studied on male rats of Sprague Dawley S.P.F. strain, weighing about 300 g and anaesthetized with nembutal (50 mg/kg by intravenous route). The product tested was administered by intravenous route in the jugular vein. The pressure in the carotid artery was measured before and after administration of the product tested. The following table indicates the variations expressed in percentage of the arterial pressure, after administration of the product tested, referred to the initial arterial pressure, as well as the time during which these variations were exhibited.

4) Anti-hypertensive action on conscious dogs. The study of the anti-hypertensive action was carried out on beagle dogs weighing from 12 to 14 kg, given high blood pressure by enveloping the two kidneys in cellophane, according to the technique described by Irvine H. Page in Science (1939) 89 p.273-274. The product was administered orah/ at a dose of 10 mg/kg. The arterial pressure was measured on the tails of the dogs by means of a pneumatic sleeve connected to an electronic pressure transducer. The pressure was measured before and after administration of the product. The table below indicates the variations expressed in percentages of the arterial pressure, after administration of the product, as referred to the initial control pressure.

5) Study of acute toxicity The lethal doses 50 (LD 50) of the products after administration by intra-peritoneal route to mice was evaluated. The mortality was recorded forty-eight hours after administration of the products. The lethal dose 50 (LD 50) of the product described in Example 1 is equal to 250 mg/kg; that of the product described in Example 3 is equal to 40 mg/kg. 6) Determination of the anti-depressive activity. a) Hypothermy with reserpine. The test is carried out on a group of 10 male mice to which 4 mg/kg of reserpine is administered by intra-peritoneal route. The rectal temperature of the animals is measured over 5 hours by an electric thermometer. At a dose of 10 mg/kg I.P., the product of Example 1 retards the onset of hypothermy caused by reserpine. b) Hypothermy with apomorphine. The test is carried out on a group of 10 male mice. Hypothermy is induced in the animals by intraperitoneal injection of 16 mg/kg of apomorphine hydrochloride. The compound to be tested is administered by intra-peritoneal route 30 minutes before the injection of the apomorphine; the rectal temperature of the animals is measured 30 minutes after the injection of the apomorphine. Control animals receive either physiological solution, or the apomorphine; the temperature difference is measured between the controls which received the physiological solution, the controls which received only the apomorphine and the animals which received the apomorphine and the compound to be tested. The dose of the compound which reduced by 50% the temperature difference observed between the controls is called DE 50. The DE 50 of the product of Example 1 was found equal to 25 mg/kg.

Claims

1. Compounds of the formula

(in which R represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms) and their acid addition salts.

2. Compounds as claimed in claim 1 wherein R represents a hydrogen atom and the hydroxyl groups attached to the phenyl ring are in the 3- and 4- positions or in the 3- and 5positions.

3. 4-[a-Hydroxy(pyrrolidin-2-yl)methyl]-1 ,2-benzenediol and acid addition salts thereof.

4. The acid oxalate of isomer A of 4-[a-hydroxy(pyrrolidin-2-yl)methyl]-1 ,2-benzenediol.

5. A process for the preparation of a compound as claimed in claim 1 which comprises hydrogenolysing a compound of formula

(in which R represents a benzyl radical or an alkyl radical containing from 1 to 5 carbon atoms) and if desired separating into its isomers and/or salifying the product thereby obtained.

6. A process as claimed in claim 5 wherein the hydrogenolysis is effected in the presence of palladized charcoal.

7. A process as claimed in claim 6 wherein the hydrogenolysis is carried out in methanol at about 50[deg]C.

8. A process as claimed in any of claim 5 to 7 wherein an individual isomer of a compound I of formula VIII is used.

9. A process as claimed in any of claims 5 to 8 wherein the compound of formula VIII is obtained by treating a compound of formula

(wherein R' is as defined in claim 5) with an alkaline agent. 5

10. A process as claimed in claim 9 wherein the alkaline agent is an aqueous solution of sodium hydroxide or potassium hydroxide.

11. A process as claimed in claim 9 or claim 10 wherein the treatment of the compound of formula VII with an alkaline agent is carried out in dioxan in an inert atmosphere.

12. A process as claimed in any of claims 9 to 11 wherein the compound of formula VII is obtained by treating a compound of formula

(wherein R' is as defined in claim 5) with N-bromosuccinimide.

13. A process as claimed in claim 12 wherein the treatment with N-bromosuccinimide is effected in the presence of aqueous sulphuric acid.

14. A process as claimed in claim 12 or claim 13 wherein the compound of formula VI is obtained by treating a compound of formula

(wherein R' is as defined in claim 5) with trifluoroacetic anhydride.

15. A process as claimed in claim 14 wherein the treatment with trifluoroacetic anhydride is effected at ambient temperature for a period of 12 to

16 hours. 16. A process as claimed in claim 14 or claim 15 wherein the compound of formula (V) is obtained by reacting a compound of formula

with an amine of formula

wherein R' is as defined in claim 5.

17. A process as claimed in claim 16 wherein the compounds of formulae III and IV are reacted at a temperature of about 120[deg]C for a period of from 8 to 12 hours.

18. A process as claimed in claim 16 or claim 17 wherein the compound of formula III is obtained by reaction of 4-bromobutyl triphenyl phosphonium bromide with a compound of formula

19. A process as claimed in claim 18 wherein the reaction of 4-bromobutyl triphenyl phosphonium bromide is effected by adding the reagents, in the solid state, to sodium hydride in a mixture of tetrahydrofuran and dimethyl sulphoxide.

20. A process for the preparation of a compound as claimed in claim 1 in which R represents an alkyl radical which comprises reacting a compound of formula I in which R represents a hydrogen atom with a compound of formula

in which R" represents an alkyl radical containing from 1 to 5 carbon atoms and Hal represents a chloride, bromine or iodine atom and if desired separating into its isomers and/or salifying the product thereby obtained.

21. A process as claimed in any of claims 5 to 8 for the preparation of compounds as claimed in claim 1 in which the hydroxyl groups attached to the phenyl ring are in the 2,4 or 2,5 or 3,4 portions wherein the compound of formula VIII is a compound of formula

wherein R is as defined in claim 5 and the benzyloxy radicals are in the 2,4 or 2,5 or 3,4 positions of the phenyl ring and is obtained by reduction of a compound of formula

wherein R' is as defined in claim 5 and the benzyloxy groups are in the 2,4 or 2,5 or 3,4 of the phenyl ring.

22. A process as claimed in claim 21 for the preparation of the A isomer of the desired product wherein the reduction is effected by means of sodium borohydride in methanol.

23. A process as claimed in claim 21 for the preparation of the B isomer of the desired product wherein the reduction is effected by means of diethylsodiumaluminium dihydride. 5

24. A process as claimed in claim 23 wherein the reaction is effected in the presence of toluene.

25. A process as claimed in any of claims 21 to 24 wherein the compound of formula XII is obtained by cyclisation of a compound of formula

(in which the benxyloxy radicals are in the 2,4 or 2,5 or 3,4 positions of the phenyl ring) with a compound of formula IV as defined in claim 16.

26. A process as claimed in claim 25 wherein the cyclisation is effected in the presence of toluene, benzene or xylene.

27. A process as claimed in claim 8 wherein the A isomer of a compound of formula VIII is used and is prepared by reaction of a compound of formula

with a compound of formula IV as defined in claim 16.

28. A process as claimed in claim 27 wherein the reaction of the compound of formula XV with the compound of formula IV is effected in the absence of a solvent.

29. A process as claimed in claim 27 or claim 28 wherein the compound of formula XV is prepared by treating a compound of formula

with an alkaline alcoholate.

30. A process as claimed in claim 29 wherein the alkaline alcoholate is sodium teramylate.

31. A process as claimed in claim 30 wherein the epoxidation is effected in the presence of tetrahydrofuran.

32. A process as claimed in any of claims 29 to 31 wherein the compound of formula XIV is obtained by reduction of a compound of formula

33. A process as claimed in claim 32 wherein the reduction is effected by means of sodium borohydride.

34. A process as claimed in any of claims 25, 26, 32 and 33 wherein the compound of 5 formula XI is obtained by treating a compound of formula

with bromine.

35. A process as claimed in claim 34 wherein the compound of formula X is treated with a solution of bromine in acetic acid.

36. A process as claimed in claim 27 or claim 28 wherein the compound of formula XV is obtained by reaction of a compound of formula III as defined in claim 16 in the form of a cis isomer with an epoxidation agent.

37. A process as claimed in claim 36 wherein the epoxidation agent comprises hydrogen peroxide.

38. A process as claimed in claim 36 or claim 37 wherein the compound of formula III is obtained by reaction of 4-bromobutyl triphenyl phosphonium bromide with a compound of formula II as defined in claim 18.

39. A process for the preparation of a compound as claimed in claim 1 substantially as herein described in any of Examples 1 to 3.

40. A process for the preparation of a compound as claimed in claim 1 substantially as herein described in Example 4 or Example 5.

41. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any of claims 5 to 40.

42. Pharmaceutical compositions comprising as active ingredient at least one compound of formula I as defined in claim 1 or a pharmaceutically acceptable acid solution salt thereof.

43. Compositions as claimed in claim 42 in a form suitable for administration by a digestive, parenteral or local route.

44. Compositions as claimed in claim 42 or 43 in the form of dosage units.

45. Compositions as claimed in any of claims 42 to 44 wherein the active ingredient comprises at least one compound as claimed in any of claims 2 to 4.

46. Pharmaceutical compositions substantially as herein described in any of Examples 6 to 8.

47. A compound of formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof for use as a medicament.

48. A compound of formula i as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof for use as a medicament in the treatment of asthma, asthmatic bronchitis, chronic bronchitis, arterial hypertension or depression.

49. Each and every novel compound, process, method and composition herein disclosed.