NO148452B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1-PHENYL-1-PROPANOL DERIVATIVES - Google Patents

Description

The present invention relates to an analog method

in the preparation of therapeutically active 1-phenyl-l-propanol derivatives of the general formula I:

where:

(a) R, means a linear or branched (C₁-C₁) alkylthio group,

linear or branched (C 1 -C 3 ) alkylsulfinyl group, straight chain or branched (C 1* -C 3 ) alkylsulfonyl group or mercaptor residue;

(b) R2 means:

(b-1) an oxo-2-pyrrolidinyl-1 residue which may be substituted

with a hydroxy group;

(b-2) an NHR^ residue where R 3 means:

- hydrogen

- a straight-chain or branched (Cg-C^g) alkyl residue or a straight-chain (C^-C^) alkyl residue substituted with a phenyl or phenoxy group with the proviso that R-^ is not an alkylthio residue - a straight-chain or branched (C- ^-C^) alkyl residue substituted with a lower carboxy or (C-^-C-j) carb-oxy group in the iw position;

as well as non-toxic and pharmacologically tolerable salts and esters of these compounds.

Examples of compounds according to the invention are: 1-(4-isopropylsulfinylphenyl)-2-n.octylamino-1-propanol. 1-(4-isopropylthiophenyl)-2-[3-(methoxycarbonyl)propylamino]-1-propanol.

1-(4-isopropylthiophenyl)-2-3-(carboxy)propylamino]-1-propanol. 1-(4-methylthiphenyl)-2-[3-(methoxycarbonyl)propylamino]-1-propanol. 1-(4-methylthiophenyl)-2-[3-(carboxy)propylamino]-1-propanol. 1-(4-isopropylsulfinylphenyl)-2-[3-(methoxycarbonyl)propylamino]-1-propanol.

1-(4-isopropylsulfinylphenyl)-2-[3-(carboxy)propylamino]-1-propanol.

1-(4-isopropylsulfinylphenyl)-2-[1-(2-oxopyrrolidinyl)]-1-propanol.

1-(4-Mercaptophenyl)-2-n.octylamino-1-propanol.

Derivatives of formula I can be isolated as salts, especially hydrochlorides and sulfates.

Derivatives of formula I can be transferred by known methods in salts with acid and, when the derivatives are directly obtained as salts, they can also be transferred in their free base or in salts with other acids.

Particularly preferred are pharmaceutically acceptable non-toxic acid addition salts, formed with suitable inorganic acids, e.g. salts, sulfuric or phosphoric acid or with suitable organic acids such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic, carboxylic or sulphonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, giutamic acid, benzoic acid, anthranilic acid, hydroxybenzoic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, 3-hydroxypropionic acid, O-hydroxybutyric acid, oxalic acid, malonic acid, galactaric acid, galacturonic acid. These salts can also be formed from amino acids which are natural or not such as lysine, glycine, arginine, ornithine, asparagine, glutamine, alanine, valine, threonine, serine, leucine, cysteine and the like.

Most of the products that are manufactured have two centers of asymmetry. Derivatives where R-^ represents an alkylsulfinyl residue have three

centers of asymmetry.

When the products contain two asymmetric centers, two racemates corresponding to the erythro and threo configurations can be obtained, and these two racemates can be resolved by conventional methods, e.g. by forming diastereoisomeric salts by treatment with optically active acids, such as tartaric acid, diacetyltartaric acid, tartranylic acid, dibenzyltartaric acid, ditoluenetartaric acid and separation of the stereoisomeric mixture by crystallization, distillation, chromatography and then releasing optically active bases from these salts.

When the products contain three centers of asymmetry, eight optical isomers can be obtained. The same methods can be used for dissolving these mixtures.

The most active derivatives can thus be used as mixtures comprising several diastereoisomers depending on their mutual ratios or as enantiomeric pairs in equal proportions (racemic mixture) or not, or also as optically pure compounds. However, derivatives with the erythro configuration at the two asymmetric carbon atoms in the propanol chain are preferred.

The method according to the invention is characterized in that

1) a compound with formula:

where R^ is ^, YS, YSO and YS02, Y is a protecting group which may be replaced by hydrogen, condensed with 2-pyrrolidone or with an amine R^NH,,, without solvent with possible use of excess 2-pyrrolidone or of amine or in the presence of a solvent, e.g. methanol or ethanol, giving a compound of formula I in which R2 is an oxo-2-pyrrolodinyl residue or an NHR^ residue, if R^ is YS, YSO or YS02, the protecting group is removed by means of an alkali

metal, if R'^ is YS or YSO, this group is optionally oxidized first to YSO or YS02;

2) a compound with formula

where R<1>^ is R-^, YS, YSO or YS02, Y is a protecting group which can be replaced by hydrogen, is reduced to a compound of formula

if R'^ is YS, YSO or YS02, the protecting group is removed with the aid of an alkali metal, while if R1-^ is YS or YSO, this group is possibly oxidized first to YSO or YS02-

3) a compound with formula

where R'^ is , YS, YSO or YS02, Y is a protecting group which can be replaced by hydrogen, and X is a halogen atom, is reacted with an amine R^NH^ or with 2-pyrrolidone to give a compound of formula I, if R'^ is YS, YSO or YS02, the protecting group is split off with the aid of an alkali metal, while if R'^ is YS or YSO, this group is optionally oxidized first to YSO or YS02;

4) a compound with formula

where Y has the meaning mentioned above and R,- means an alkyl group, especially a lower alkyl (C^-C^) residue, is hydrolyzed in an acidic medium, the intermediate acid obtained is then oxidized to the corresponding compound of formula I, where R^ is a alkylsulfinyl or an alkylsulfonyl residue or the protecting group is cleaved giving the corresponding compound of formula I, in which R-^ is a mercaptor residue:

5) a compound with formula

in which Y has the above-mentioned meaning and R^ means an alkyl group, especially a lower alkyl (C-^-C^) residue, is hydrolyzed in an acidic medium, and the intermediate acid obtained is cyclized to a corresponding compound of formula I, in which R 2 is an oxo -2-pyrrolidinyl-1-residue;

and after which, if desired, the obtained compound of formula I is transferred in a non-toxic pharmacologically tolerable salt or an ester in a manner known per se.

The compounds with the general formula I where is an oxo-2-pyrrolidinyl-1-ring, optionally substituted with a hydroxy group or are advantageously obtained according to general reaction schemes as described in the following:

In these schemes, R^ has the predicted meaning.

In reaction (a), the condensation of an epoxide with 2-pyrrolidinone is easily carried out either without solvent with the possible use of excess 2-pyrrolidinone, or in the presence of solvents e.g. methanol or ethanol.

This procedure makes it possible to obtain alcohols with

treo configuration.

In reaction (b), the condensation of an a-bromoketone with a

ester of uj- aminobutyric acid is carried out in a solvent which meta-

nol, ethanol, chloroform, acetonitrile, benzene or a mixture thereof, preferably at room temperature.

The reduction can be done with hydrides of alkali metals, espe-

elted with NaBH^, in a solvent such as methanol or ethanol at room temperature.

The cyclization to pyrrolidinone can be carried out by impact

of an organic or inorganic base, e.g. an alkoxide or sodium or potassium hydroxide in an alcoholic or hydro-

in an alcoholic solvent such as methanol, ethanol or iso-

propanol at a temperature between room temperature and the reflux temperature of the chosen solvent, but preferably at room temperature.

This method allows the preparation of alcohols with erythrocyte configuration.

The compound of the general formula I wherein R2 is a residue of

the types NHR^ can be obtained from a compound of the general formula V:

or optionally as a result of the value of Q from a salt of a compound of this formula, where R 2 has the previously indicated meaning and Q represents one of the following groups:

in these formulas R_ has the previously given meaning while X represents a halogen atom.

In these formulas, R 1 has the predicted meaning while X represents a halogen atom.

This method can be carried out according to two embodiments

which is mainly determined by the output product, namely by the value of Q in formula V.

Embodiment A

According to a first method, an α-amino ketone is reduced by

formula V where Q means a group:

where R^ has it

previously stated meaning.

This reaction can be carried out in the usual way, most easily e.g. by the action of alkali metal hydrides such as sodium borohydride in a solvent such as methanol or ethanol, preferably at low temperature, or by the action of aluminum or lithium hydride in a solvent such as diethyl ether or tetrahydrofuran, or by the action of an aluminum alkoxide,

such as aluminum propoxide in a solvent such as isopropanol, especially at its reflux temperature. The reduction can also be carried out by hydrogenation in the presence of a catalyst such as palladium on carbon, Raney nickel, platinum oxide in a solvent such as methanol, ethanol, dioxane.

As previously mentioned, the most interesting products can have two

erythro and threo configurations. The choice of the starting amino ketone and of the reduction conditions enables both of these forms to be obtained stereoselectively. Thus, the reduction of et

amino ketone where Q means:

to an amino alcohol with erythro configuration under the conditions generally described above. To obtain a compound with the threo configuration, the reduction of an amino ketone is carried out where Q means:

in which

R., has the aforementioned meaning and R^ is a protecting group which can later be removed by hydrolysis or hydrogenolysis, such as benzyl, trityl, < acetyl, formyl, benzhydryl groups, and this reduction is then preferably carried out by the action of alkali metal hydrides such as sodium borohydride or aluminum lithium hydride.

The starting amino ketones are readily available, e.g. by the action of an amine R^Nf^ or R^R^NH on an α-halo ketone in solvents such as ether, benzene, chloroform, dioxane, methanol, isopropanol or acetonitrile.

Embodiment B

According to this production method, a compound with the general formula V is reacted where Q represents a group:

This reaction is carried out in a solvent such as alcohols, chloroform, dioxane, carbon tetrachloride, most easily in the presence of a binder for the formed hydrogen halide such as inorganic or organic bases, or in the presence of an excess of amine. It is well known that in these cases the group first gives an oxirane group of the type

as rea-

reacts with the amine compound.

The compound of formula I where is a mercaptor residue can be obtained from the compound of general formula VI:

in which R 2 has the aforementioned meaning and Y is a protecting group which can be replaced by hydrogen according to well-known methods from the literature, e.g. an alkyl group such as isopropyl, benzyl or substituted benzyl group which can be removed by the action of alkali metals such as sodium or lithium in a solvent such as ammonia, or by the action of hydrogen in the presence of hydrogenation catalysts or by the action of lead diacetate or hydrofluoric acid, a diphenylmethyl group which is substituted or not removable by the action of acids such as trifluoroacetic acid or hydrogen bromide, a triphenylmethyl group which is substituted or not removed by the action of acids such as hydrogen chloride or hydrogen bromide or by agents such as HgCl,,, AgNO^ or Hg(OAc)2 a benzylthiomethyl group which can be removed by impact of oxidizing agents such as HgCl2 or Hg(OAc)2, an acetamido-methyl group that can be removed e.g. with mercuric salts, a carboxymethyl group which can be removed by oxidizing agents in an acidic medium or a tetrahydropyranyl or tetrahydrofuranyl which can be removed by oxidizing agents such as AgNO^f Ir, SO2C12, (SCN)2~Zn or with acids.

Compounds of the general formula I, where R is an alkylsulfinyl or alkylsulfonyl residue can be obtained from compounds of the general formula I where R is an alkylthio residue by oxidation according to well-known methods from the literature.

This oxidation can be carried out at any stage of the synthesis

of the products according to the invention.

To obtain sulfoxides, oxidizing agents such as iodine, bromine in water or in the presence of acetate ions or in a complex with pyridine, peracids such as peracetic acid, monoperphthalic acid or m-chloroperbenzoic acid can be used, N-halogensuccinides such as N-bromosuccinimide, hypochlorites such as sodium, t-butyl or isopropyl hypochlorites, periodates such as sodium periodate, hydrogen peroxide in the presence of acetic anhydride or in the presence of vanadium hemipentoxide in t-butanol, nitrates such as acetyl nitrate or ammonium and cerium nitrate, oxides such as chromium (VI) oxide in pyridine or vanadium hemipentoxide in presence of oxygen or nitrogen hemipentoxide, peroxides, ozone, oxygen in the singlet or triplet state, acids such as nitric acid, chromic acid or caroic acid or further in other agents such as sulphuryl chloride, 1-chlorobenzotriazole, chloramine, N-chloronylon 66, iodobenzene dichloride, iodosobenzene, iodobenzenediaceta.t, N-chloro-triazole, 2,4,4,6-tetrabromocyclohexadienone or auric acid (HAuCl^). These oxidation reactions can be carried out in solvents such as e.g. water, acetic acid, chloroform, dichloromethane, carbon tetrachloride, methanol, t-butanol or acetone.

To obtain sulfones, oxidizing agents such as hydrogen peroxide will be used, preferably in the presence of zirconium salts, peracids such as peracetic acid, monoperphthalic acid and m-chloroperbenzoic acid (in the case of oxidation with peracids, catalysts based on transition metals will advantageously be used), potassium permanganate in acidic or basic medium, sodium or potassium dichromate, osmium tetroxide, selenium oxide, t-butyl hypochlorite, nitric acid, ozone, oxygen, advantageously in the presence of iridium or rhodium salts, iodobenzene dichloride, periodic acid or by electrochemical oxidation. These reactions will be carried out in solvents such as water, acetic acid, chloroform, dichloromethane, methanol, ethanol, isopropanol, t-butanol, dioxane or acetone.

In some cases, it may be advantageous to carry out the above-described oxidation reactions on compounds of the general formula I where R is an alkylthio group as the functions which are sensitive to the oxidizing agent used will have to be protected, e.g. e.g. by formation of esters in the case of hydroxyl groups or of ketones in the case of ketone groups.

In the following, detailed examples of the preparation of some derivatives of 1-phenyl-1-propanol according to the present invention are given. The purpose of these examples is mainly to illustrate the special features of the method according to the present invention in more detail.

Example 1

1-(4-isopropylsulfinylphenyl)-2-n-octylaminopropanol.

(Table I, no. 6)■ 14 g of 1-(4-isopropylthiophenyl)-2-n-octylaminopropanol dissolved in 250 ml of chloroform is slowly added to 6.4 g of m-chloroperbenzoic acid. The mixture is stirred overnight at room temperature, washed with an aqueous saturated solution of NaHCO 3 and evaporated under vacuum.

The resulting residue is treated with 50 ml of ether and filtered.

The organic phase is dried over MgSO 4 , filtered and evaporated. The oily residue is dried in vacuo overnight, dissolved again in anhydrous ether and the hydrochloride is obtained by passing a dry HC1 gas stream through the residue. After recrystallization with

a mixture of methanol and ether yields 8.4 g of product. Yield: 60%, melting point (°C): 167-169 .

Elementary analysis

Example 2

1-(4-isopropylthiophenyl)-2-[1-(2-oxopyrrolidinyl)]-1-propanol.

(Table I, no. J)

a) 2-methyl-3-(4- isopropylthiophenyl)oxirane.

To a solution containing 28.5 g of 2-bromo-1-(4-isopropylthiophenyl)

-1-propanone, 350 ml of ethanol and 125 ml of ethoxyethanol, 3.83 g of "JaBH4 is added slowly in water at 25°C while shaking. After the addition is complete the mixture can be slowly cooled to room temperature. P'7 stirring is continued for 1.1/2 hours. 3.8 g of KOH is added to 40 ml of water and stirring is continued for 30 minutes. The reaction mixture is diluted with water and the extract from chloroform. The chloroform solution is collected, dried and filtered, the solvent is then removed by vacuum distillation. 23.6 g of an oil are obtained, this oil is redistilled under vacuum. Weight: 19.2 g, yield: 65%, boiling point 81-84°C (0.7 mm), the NMR spectrum is consistent with 2-methyl-3 -(4-isopropylthiophenyl)oxirane b) 1-(4-isopropylthiophenyl)-2-[1-(2-oxopyrrolidinyl)]-1-propanol.

10.4 g of the above product, 4.25 g of 2-pyrrolidinone and

0.5 g of NaOH is heated under nitrogen for 17 hours at 120°C. After cooling, the resulting oil solidifies by adding petroleum ether. The solid is filtered, washed with a minimum of petroleum ether, dried and recrystallized from diethyl ether. 4.68 g of product is thus obtained. Yield: 45%, melting point (°C): 115-116.

The intended structure is checked mass spectrometrically

and NMR (threoconfiguration).

Elementary analysis

Example 3.

1-4-isopropylsulfonylphenyl)-2-[1-(2-oxopyrrolidinyl)]-1-propanol (Table I, no. 9).

A solution containing 2.93 g of 1-(4-isopropylthiophenyl)-2-[1-(2-oxopyrrolidinyl)]-1-propanol, 6.5 ml of acetic acid and 6.5 ml of 30% ^ 2®2 °PP is heated gradually to 85-90°C and held at this temperature for 2 hours. After cooling, add a solution of 6 g ^ 3.^ 20^ slowly in 15 ml of water, then dilute it with 50 ml of water. The residue is extracted from chloroform, the organic phase is dried over MgSO 4 , filtered and evaporated. The resulting oil residue solidifies by adding petroleum ether and is recrystallized with a mixture of ether and methanol.

1.95 g of product is thereby obtained.

Temp. (°C): 170.5

Elementary analysis

The NMR spectrum confirms the threo configuration.•

Example 4.

1-(4-isopropylthiophenyl)-2-[3-(carbomethoxy)propylamino]-1-propanol.

(Table I, no. 13)

17 g of 2-bromo-1-(4-isopropylthiophenyl)-1-propanone, 200 ml of methanol, 17.3 ml of triethylamine and 10 g of methyl U)-aminobutyrate (hydrochloride) are refluxed for 17 hours. The mixture is then cooled to a temperature of 5°C and 4.5 g of NaBH^ is added slowly. The reaction mixture is stirred overnight at room temperature. After vacuum evaporation of the solution and dilution of the residue with water, extract from chloroform. The chloroform solution is collected, dried and filtered. Thus 13.4 g of crude product is obtained, this crude product yields 12.4 g of product after preparing the hydrochloride in a diethyl ether-methanol (50/50) mixture. Yield: 58%, melting point (°C): 175.6.

The intended structure has been checked mass spectrometrically.

Elementary analysis.

The NMR spectrum confirms the erythro configuration.

Example 5.

1-(4-isopropylthiophenyl)-2-[3-(carboxy)propylamino]-1-propanol.

(Table I, no. 23).

Dissolve 7 g of 1-(4-isopropylthiophenyl)-2-[3-methoxycarbonyl)propylamino]-1-propanol in 70 ml of water and add 7 ml of concentrated hydrochloric acid. The mixture is heated to 80°C for 1 hour, cooled, the solvent is distilled off under vacuum, then recrystallized in a methanol/ether mixture.

Weight: 4.5 g, Yield: 68%, Melting point (°C): 197.5

Elementary analysis.

Example 6

1-( 4- isopropylthiophenyl)- 2-[ 1-( 2- oxopyrrolidinyl)]

- 1-propanol (erythro).

6 g of 1-(4-isopropylthiophenyl-2-[3-(carboxy)propylamino]-1-propanol are dissolved in a mixture containing 100 ml of methanol and 50 ml of water. The pH is brought to 13 by adding a solution ION sodium hydroxide. Stir for 1 hour at room temperature, evaporate the methanol, extract with chloroform, the organic phase is dried with MgSO4 and the solvent is evaporated. The product solidifies in petroleum ether and is recrystallized in ether. 1.3 g of product is obtained, which gives a yield of 27 %. Melting point (°C): 80. The structure is confirmed by NMR and mass spectroscopy (erythro configuration).

■RI (=>mpn-t-s>r analvsp

Example 7

1-(4-isopropylthiophenyl)-1,2-propanediol

(Table I, no. 18).

170 g of 1-(4-isopropylthiophenyl)-2-hydroxy-1-propanone are dissolved in 1500 ml of methanol. It is cooled to 0°C, 57.4 g of sodium borohydride are added slowly with stirring overnight at room temperature. The solution is evaporated, diluted with water, then extracted from chloroform and dried over MgSO4. After solution evaporation, recrystallization is carried out in the benzenehexane mixture. Weight: 66.8 g, yield: 39%, melting point (°C) 83-85.

The NMR spectrum confirms the erythro configuration of the product obtained.

Elementary analysis

Example 8

1-(4-mercaptophenyl)-2-n-octylamino-1-propanol

(Table I, no. 40).

For a solution containing 5.25 g lithium 1000 ml liquid

ammonia and 500 ml of tetrahydrofuran, a solution containing 16 g of 1-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol in 500 ml of tetrahydrofuran is added slowly. After the addition is complete, the stirring is continued for approx. 15 minutes, then 16 g of NH^Cl are added in small portions.

The ammonia' is evaporated slowly in a water bath, after which the remainder is diluted with water. The solution thus obtained is filtered and recrystallized with methanol. 12 g of 1-(4-mercaptophenyl)-2-n-octylamino-1-propanol are thus obtained. Melting point (°C): 110-112, Yield: 82.1%. Elementary analysis

As previously mentioned, the derivatives produced can be present as their salts or esters.

Special esters are those that have the formula

Both the melting point of the derivatives mentioned in the examples and other derivatives produced according to the invention have been indicated in the following table.

Example 9

1-(4-isopropylthio)-2-[1-(2-oxopyrrolidinyl)]-1-propanol.

28.9 g of 1-(4-isopropylthio)-2-bromo-1-propanol are dissolved in 200 ml of ethanol, treated with 17 g of 2-pyrrolidinone and refluxed for 7 hours.

The solvent and excess amine are removed under vacuum. The remainder is treated with 1.2 equiv. NaOH, the aqueous phase is extracted with chloroform and dried over MgSO^.

The solvent is removed under reduced pressure and the product is recrystallized in diethyl ether. Yield: 10.26 g (35%).

Temp. 113.5 - 114°C.

(1) the crystallization solution is given in parentheses.

(2) the elemental analyzes were made for the C, H, N constituents and

is in accordance with theoretical assessment.

(3) the melting point of the hydrochloride

(4) erythro configuration.

(5) treo configuration

(6) erythro/threo mixture.

The manufactured compounds, although they are not very toxic, have effects on the cardiovascular system, in particular antispasmodic, antihypertensive, peripheral vasodilatory effect, hypolipidemic, normolipoproteinemic, antithrombotic effect, an inhibitory effect against platelet aggregation. They can especially be used in the treatment of cardiovascular disorders which are or are not linked to atherosclerosis. Furthermore, they can also be used as agents for stimulating cerebral metabolism or as tranquillizers.

The effect on behavior has been investigated using a modified method from S. Irwin's. (Gordon Res. Conf. on Medicinal hem., 133, 1959). The substances in suspension in a 1% gum tragacanth were given orally by means of an intragastric tube to 5 groups of male mice (CCD1 strain, Charles River, fasted for 18 hours). If the available amount of substance allowed, the dosages were 3000, 1000 and 300 mg/kg. If the substance was active, the drug's effect was examined at 100, 30, 10 and possibly 3 mg/kg. The behavior was studied 2, 4, 6 and 24 hours after treatment. The observation was continued when symptoms were present throughout that time. Mortality was recorded in the 14-day period after treatment. The LD values were calculated according to the Hitchfield and Wilcoxon method (J.Pharmacol Exp. Ther., 96, 99, 1949) and expressed as mg/kg.

The results obtained with regard to the effects on the behavior show the minimal active dose in mg/kg (MAD) and the observed symptomatology. The LD^q values are indicated with confidence limits (p-0.95). Under these conditions a clear activity was found, especially for compounds S, 13 and 20.

The antihypertensive effect was investigated by oral administration to spontaneously hypertensive nonanesthetized rats whose systolic arterial pressure was measured for the middle coccygeal artery by a plethysmographic method (J. Roba, G. Lambelin, A. F. De Schaepdryver, Arch, int. Pharmacodyn .20_0, 182 , 1972).

Arterial pressure was measured every 30 minutes from two hours before to three hours after oral administration of the products tested at 60 mg/kg or of a placebo (1% tracaganate gum slime).

Only rats with a systolic pressure of 180 to 220 mm Hg were used. Two rats were used for each product. The treatments were given without the knowledge of the person doing the measurements. The antihypertensive effects were noted as a score followed by an index. The scoring system was as follows.

0 : reduction <10 mm Hg + : reduction of 10 to 20 mm Hg ++ : reduction of 20 to 30 mm Hg +++ : reduction of 30 to 50 mm Hg ++++ : reduction >50 mm Hg.

The index was calculated by multiplying the systolic pressure difference (cm Hg) measured every 30 minutes after the treatment by a coefficient of 1 to 6 corresponding to the time periods 30 to 180 minutes.

Under the experimental conditions, α-methyldopa scored +++ (47) at 100 mg/kg, reserpine: +++ (53) at 3 mg/kg, and guanethidine: +++

(62) at 60 mg/kg.

In these experiments, there was an interesting antihypertensive effect, especially with products 6 and 7.

The peripheral vasodilatory effect of the products was measured

on anesthetized dogs at the level of femoral artery circulation. At the end of this the femoral artery whose lateral lines had been ligated was showered with a steady stream of blood taken from the aorta. The overflow pressure measured at the height of the femoral artery thus varied as a function of the resistance of the overflow area. The test products and the corresponding solvents were

directly injected into the stream at a dose of 30 mg/kg. The blood circulation was kept constant, and a vasodilation was thus measured by an increase in the overflow pressure. The latter was noted in relation to the effect of papaverine, which was used as a standard and injected once per week. group of four products.

When they were of interest, the products were examined at other dosages under the same conditions. The vasodilatory effect was indicated as follows:

0 : inactive, reduction < 10 mm HG

+ : 1/3 of papaverine's activity ++ : 2/3 of papaverine's activity activity equal to papaverine's ++++ : activity higher than papaverine's.

Of the products according to the present invention, a peripheral vasodilatory effect equal to or higher than that of papaverine was observed especially with compounds 5, 6 and 20.

The antispasmodic effect of the studied substances was investigated on contractions in guinea pigs, the last part of the small intestine, initiated by histamine and acetylcholine. These experiments make it possible to study an antihistamine, anticholinergic or musculotropic effect. The reaction to the contraction agent (submaximal concentration) was obtained every 5 minutes before and after injection of increasing dosages of the investigated products

-7 -4

(10M to 10M). The percentage of inhibition under the influence of the investigated compounds was calculated and the theoretical concentration giving 50% inhibition was graphically determined for each investigation. These values are expressed as -log IC^0 (M). In this experiment, compounds 5 and 6 are particularly found to be active.

The platelet aggregation was studied according to the turbidimetric method of G.V.R. Born and N.J. Cross (J.Physiol., 168, 178-195, 1973). The plasma richness in the plates was preinduced 4 minutes before introduction of the inducer (Thrombofax). The smallest variations were recorded over a period of 10 minutes with an aggregometer "Upchurch". The inhibition of the amplitudes of the maximal aggregation was measured. This experiment has shown that compounds 5, 6, 13 and 14 in particular were active.

The following 5 particularly preferred compounds showed the following activities:

To investigate lipolysis inhibition, epididymal fat was taken from fasted rats. Fragments of adipose tissue (+ 150 mg) were incubated in Kreps-Ringer buffer containing 3% bovine serum albumin and the substance to be examined. A sample at time 0 was taken after an incubation of 30 minutes at 37°C. Nor-epinephrine was used to induce lipolysis. The rate of free amino acid was measured after 20 minutes of incubation (Duncombe, W.G., Clin. Chim. Acta. 8, 122, 1964). In this experiment, compounds 5,6,8 and 13 were particularly active.

The inhibition of cholesterol biosynthesis was investigated as follows: Buffered homogenates of rat liver were enriched with suitable co-factors. Aliquots were incubated 60 minutes with 1-14 C acetate and the compound to be examined. After saponification of the medium, sterols were extracted from petroleum ether and the dried residue was precipitated with digitonin in an alcohol-acetone solution. The content of 14C in the precipitate dissolved in pyridine was measured by "liquid scintillation" counting according to the method described by N. Bucher (J.Biol.Chem., 222, 1-15, 1956). Under these conditions,

a significant degree of activity shown for compounds 1, 13 and 15 in particular.

The inhibition of bioamine uptake by synaptosomes was studied by

to isolate synaptosomes from rat brain after partial subcellular fractionation in a sucrose gradient (Gray R.G. and Whittaker V.P., J.Anat. 92, 79, 1962). The uptake of 5-HT (serotonin) was done as follows: After 5 minutes of incubation of the test product with synaptosomes, the preparation was incubated for 5 minutes at 37°C in the presence of 14C-5HT, filtered on a "Millipore" filter and the filters were washed with ice-cold buffer. The radioactivity of the filtrates was measured by liquid scintillation counting. The uptake is the difference between the radioactivity measured at 37°C and that measured at 0°C. In this experiment, compounds 5,6,13 and 14 were particularly active.

The active compounds according to the present invention can be given

in conjunction with various pharmaceutical excipients orally, parenterally or rectally.

For oral administration, pills, granules,

tablets, capsules and tablets and capsules with controlled release of the active agent, and also sublingual tablets, solutions, syrups, emulsions containing traditional additives or excipients within galenic pharmacy. For parenteral administration, sterile water or oil such as peanut oil or ethyl oleate will be used. For rectal administration, suppositories or rectal capsules will be used.

These active compounds can be used alone or in conjunction with other active products with a similar or different effect.

The products produced can be used in different forms.

The following examples are illustrative of galenic formulations which as active product contain one of the following compounds, denoted by "A" in the following: 1-(4-isopropylsulfinylphenyl)-2-[1-(2-oxopyrrolidyl) ] -1-propanol

1-(4-isopropylsulfinylphenyl)-2-n-octylamino-1-propanol.

Intramuscular injections

Intravenous injection Solution for oral administration Tablets

Sublingual tablets

Capsules Soft capsules Capsules with controlled substance release

Suppositories

The meaning of some of the expressions used in the above Galenic formulations are:

- Aerosol: trade name for finely divided silicon dioxide

- Starch: STA-RX 1500: corn starch

- Lidocaine: trade name for lignocaine

- Novata 299 grade: mixture of saturated fatty acid triglycerides with partial glycerides of acetylated fatty acid - Novata B grade: mixture of saturated cn~ c±- j fatty acid tri-, di- and monoglycerides - Witepsol S 58 grade.: mixture of <C> ^2_C18 <n>aturli9e triglycerides -Eudragit E (Røhm): polymer of acrylic acid dimethylaminoethyl ester.

Depending on the case, the route of administration, the type of activity found and the present compound, 1-phenyl-l-propanol derivatives according to the present invention are administered in daily doses of 5 to 3000 mg and as an intravenous injection the 1-phenyl-l-propanol derivative according to the invention is administered in daily doses of 1 to 20 mg.

Claims (1)

1. Analogous method for the preparation of therapeutically active 1-phenyl-l-propanol derivatives with the general formula I: where: (a) means a linear or branched (C 1 -C 3 ) alkylthio group, linear or branched (C 1 -C 3 ) alkylsulfinyl group, straight or branched (C 3 -C 4 ) alkylsulfonyl group or mercaptor residue; (b) R2 means: (b-1) an oxo-2-pyrrolidinyl-1 residue which may be substituted with a hydroxy group; (b-2) an NHR residue where R^ means: - hydrogen - a straight-chain or branched (C -C ) alkyl residue 0 16 or a straight-chain (C2~C4' alkyl radical substituted by a phenyl or phenoxy group with the proviso that R-^ is not an alkylthio radical - a straight-chain or branched (C^-C.,) alkyl radical substituted by a lower carboxy or (C - C^) carbal oxy group in the co position; as well as non-toxic and pharmacologically tolerable salts and esters of these compounds, characterized in that 1) a compound with formula: where R' is R^,YS, YSO and YS02, Y is a protecting group which may be substituted with hydrogen, condensed with 2-pyrrolidone or with an amine R^NH,,, without solvent with possible use of excess 2-pyrrolidone or of amine or in the presence of a solvent, e.g. methanol or ethanol, giving a compound of formula I in which R 2 is an oxo-2-pyrrolodinyl-1-residue or an NHR^ residue, if R| is YS, YSO or YSO,,, the protecting group is removed by means of an alkali metal, if R| if YS or YSO, this group is optionally oxidized first to YSO or YS02; 2) a compound with formula where R| is R1, YS, YSO or YS02, Y is a protecting group which can be replaced by hydrogen, reduced to a compound of formula if R^ is YS, YSO or YS02, the protecting group is deprotected with an alkali metal, while if R| is YS or YSO, this group is optionally oxidized first to YSO or YS02 3) a compound with formula where R| is R1, YS, YSO or YS02, Y is a protecting group which can be replaced by hydrogen, and X is a halogen atom, is reacted with an amine J^NH^ or with 2-pyrrolidnone which gives a compound of formula I, if R| is YS, YSO or YS02, the protecting group is removed by means of an alkali metal, while if R| is YS or YSO, this group is optionally oxidized first to YSO or YS02; 4) a compound with formula where Y has the above-mentioned meaning and Rj- means an alkyl group, especially a lower alkyl (C^-C^) residue, is hydrolyzed in an acidic medium, the intermediate acid obtained is then oxidized to the corresponding compound of formula I, where R^ is an alkylsulfinyl or an alkylsulfonyl residue or the protecting group is cleaved giving the corresponding compound of formula I, in which R^ is a mercapto residue: 5) a compound with formula in which Y has the above-mentioned meaning and R^ means an alkyl group, especially a lower alkyl (C^-C^) residue, is hydrolyzed in an acidic medium, and the resulting intermediate acid is cyclized to a corresponding compound of formula I, in which R2 is an oxo- 2-pyrrolidinyl-1-residue; and after which, if desired, the obtained compound of formula I is transferred in a non-toxic pharmacologically tolerable salt or an ester in a manner known per se. 2. Process for the production of 1-(4-isopropylsulfinyl-phenyl)-2-n-octylamino-l-propanol according to claim 1, characterized in that correspondingly substituted starting materials are used. 3. Process for the production of 1-(4-isopropylthiophenyl)-2-(3-(methoxycarbonyl)-propylamino)-1-propanol according to claim 1, characterized in that correspondingly substituted starting materials are used. 4. Process for the production of 1-(4-methylthiophenyl)-2-(3-(methoxycarbonyl)-propylamino)-1-propanol according to claim 1, characterized in that correspondingly substituted starting materials are used. 5. Process for the production of 1-(4-isopropylsulfinyl-phenyl)-2-(3-(carboxy)-propylamino)-1-propanol according to claim 1, characterized in that correspondingly substituted starting materials are used. 6. Process for the production of 1-(4-mercaptophenyl)-2-n-octylamino-1-propanol according to claim 1, characterized in that correspondingly substituted starting materials are used.