GB1603378A - Derivatives of amino-alcohols - Google Patents

Description

(54) DERIVATIVES OF AMINO-ALCOHOLS (71) We, CONTINENTAL PHARMA, a Belgian Body Corporate, of 135 Avenue Louise, Brussels, Belgium, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement :- This invention relates to amino-alcohol derivatives, more particularly aminoalcohol esters, and also to processes for preparing these derivatives, and pharmaceutical compositions comprising at least one of these derivatives.

Derivatives according to the invention have the general formula :

wherein : (a) R, is a linear or branched alkyl C,-Cs radical or a ccyloalkyl C5-C6 radical ; (b) R2 is alkyl C,-C2 radical ; (c) R, is a linear or branched alkyl C3-C18 radical, a linear or branched alkyl C,-C, radical substituted by a phenyl, Phenoxy, p halogenophenoxy or p-halogenobenzyl group, a linear or branched alkenyl C6-C18 radical, or a ccyloalkyl C5-C9 radical; (d) R4 is an acyl group having the formula :

in which Rs represents : a linear or branched alky C, C6 radical a cycloalkyl C3-Cs radical, or a linear or branched alkyl C,-C4 radical substituted by a Phenyl, p methoxyphenyl or cyclohexyl group.

Preferred derivatives of formula I are those wherein : (a) R, is a linear or branched alkyl C,-Cs radical or a cycloalkyl Cs-CB radical ; (b) R2 is an alkyl C, C2 radical (c) R3 is a linear or branched alkyt Ce-C, z radical, or a linear or branched alkyl C,-C, radical substituted by phenyl radical ; and (d) R, is an acyl group having the formula :

in which R. is a linear or branched alkyl C,-Ce radical or cycloalkyl C3-Ce radical.

A preferred class of compounds of formula I comprises those compounds wherein : R, is a linear or branched alkyl Ce to C, radical, or a linear or branched alkyl C2 to C, radical substituted by a phenyl radical and R4 is an acyl group having the formula :

in which R, is a linear or branched C, to Ce alkyl radical or cycloalkyl C, to C. radical.

Examples of compounds according to the invention are : I-butyryloxy-l- (4-isopropylthiophenyl)-2-n. octylaminopropane I-cyclohexanecarbonyloxy-I- (4-isopropylthiophenyl)-2- n. octylaminopropane.

I-cyclobutanecarbonyloxy-I- (4-isopropylthiophenyl)-2- (4phenylbutylamino) propane I-neopentylcarbonyloxy-1- (4-isopropylthiophenyl)-2- n. octylaminopropane I-p-methoxyphenylacetyloxy-1- (4-isopropylthiophenyl)-2-n. octyl- aminopropane.

As the most active products according to the invention have two asymmetry centers, two racemates corresponding to erythro and threo configurations respectively may be obtained. Both said racemates may be resolved by usual processes, for example by forming diastereoisomer salts through the action of optically active acids, such as tartaric, diacetyltartaric, tartranilic, dibenzoyltartaric, ditoluoyltartaric acids, and separation of the diastereoisomer mixture by crystallisation, distillation, chromatrography, and the liberation of optically active bases from these salts.

Similar processes may be used when compounds of the invention comprise more than two asymmetry centers.

The most active derivatives of the invention may thus be used either as racemates of erythro or threo configuration, or as a mixture of both said forms, or still as optically active compounds of each of both said forms. Preferred compounds are however amino-alcohol derivatives of erythro configuration.

In general, amino-alcohol derivatives according to formula I are prepared by transforming in said derivatives a compound of the general formula 1I :

wherein Q represents one of the groups :

In these groups, R2 to Rs are also as defined above, while X represents a halogen atom, such as Cl or Br, and Re is a protective group which can be later removed by hydrolysis or hydrogenolysis, such as a benzyl, trityl, acetyl, formyl, or benzhydryl group.

Advantageously, amino-alcohol derivatives as esters are prepared by reacting an amino-alcohol or corresponding salt of such an amino-alcohol corresponding to formula II, wherein Q represents :

and R, to R, have the hereabove mentioned meanings with an acid R, COOH or an active derivative of the latter, preferably a halide, anhydride, ester or amide of such an acid, wherein R, represents a linear or branched alkyl C,-C6 radical, a cycloalkyl C3 Cg radical, a linear or branched alkyl C, C4 radical substituted by a phenyl, p-methoxyphenyl or cyclohexyl group.

The reaction temperature is advantageously between room temperature and reflux temperature of the acid or of the active derivative thereof.

An equimolecular amount or a slight excess of the acid or of the derivative thereof with respect to the amount of amino-alcohol can be used.

The reaction with an acid can be carried out in the presence of esterification catalysts such as for example hydrochloric acid, sulfuric acid, thionyl chloride, phosphoric acid, phosphorus oxychloride, p-toluenesulfonic acid, benzenesulfonyl chloride, boron trifluoride and complexes with esters, acid ion exchange resins, molecular sieves or phase transfer catalysts, such as quaternary ammonium salts or crown compounds.

This reaction with an acid can also advantageously be carried out by eliminating formed water by azeotropic distillation with a suitable solvent such as for example benzene, toluene, xylene, chloroform, carbon tetrachloride or methylene chloride. In this case, esterification catalysts, such as previously described, may also be used. The elimination of water formed in the reaction may also be made by working in the presence of an anhydrous salt, for example iron, magnesium or zinc sulfate.

The reaction with an acid can also be carried out in the presence of a condensation agent, such as for example dicyclohexylcarbodiimide or N, N'carbonyldiimidozole, preferably in solvents such as chloroform, ether, methylene chloride, methanol, benzene or carbon tetrachloride. This latter reaction may be catalyse by a basic agent such as pyridine for example. Again in the case of reaction with an acid, the latter may be as one of its salts, for example sodium salt or quaternary ammonium salt, in order to make the esterification reaction easier.

The reaction with an acid chloride will be advantageously made in a solvent such as acetonitrile, acetic acid, trifluoroacetic acid, benzene, toluene at a temperature between room temperature and reflux temperature of the selected solvent, or without any solvent by using in such a case an excess of acid halide or in aqueous medium in the presence of a basic agent, such as sodium or potassium hydroxide.

This reaction can also be carried out in the presence of agents fixing the acid halide being formed in the reaction, for example organic bases, such as pyridine, cotlidine, piperidine, dimethylaniline, sodium alkoxides or inorganic bases such as carbamates, hydroxides or oxides of alkali metals, alkaline-earth metals or magnesium.

The efficiency of the reaction with an acid halide may be improved by previously reacting said acid halide with a Lewis acid so as to form an acylium salt, for example CH CO@SbF69.

The acid halide may also be formed in situ in a selected reaction medium by treating in the presence of an agent such as phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride or oxalyl chloride.

The reaction with an anhydride can also be carried out in solvents, such as benzene, toluene, acetonitrile, pyridine, in the acid corresponding to the anhydride or in an excess of anhydride. This reaction may be catalyse with agents such as sulfuric acid, chlorosulfonic acids, zinc chloride, acetyl chloride, sodium acetate, boric acid, ferric sulfate, alkoxides of alkali and alkaline-earth metals pyridine, acetic acid, p-toluenesulfonic acid, perchloric acid and dimethylaniline.

The reaction can also be carried out with a mixed anhydride, for example by adding trifluoroacetic anhydride in the reaction medium, in order to form a very reactive compound of the kind RSCO-OCOCF,.

According to a way of proceeding, anhydride could be made in situ in the selected reaction medium, for example from the acid chloride and a derivative such as benzenesulfonyl chloride.

The reaction with an ester can be carried out by using reactive esters of the kind R ; COX wherein X is for example a p-nitrophenol or trimethylsilyl group, in the presence of condensation agents, such as organic or inorganic bases and organic or inorganic acids.

The reaction with an amide may also be made by using for example corresponding N-acyl derivatives of compounds such as acylimidazolides or acylhydantoins, in the presence of condensation agents, such as organic or inorganic bases.

According to a way of proceeding, a compound of the following general formula :

wherein R, to Rs have the above-mentioned meanings can be isomerised. The migration N-0 of the acyl group R ; CO may be made according to known processes, for example by action of an inorganic acid such as hydrochloric acid in a solvent such as methanol or by action of an agent such as thionyl chloride.

According to another way of proceeding, compounds of the invention can be obtained from compounds of the following general formula :

wherein R, to R, have the above-mentioned meanings and R6 is a protective group such as for example a benzyl, trityl, benzhydryl, carbobenzyloxy, trimethylsilyl group. This group R. may be replace by hydrogen according to well known processes depending on the kind of the group R. and preferably by hydrogenolysis or hydrolysis.

According to another way of proceeding, a compound of the following general formula :

may also be reacted with an amine of the kind R, NH2 or R, R, NH.

R, to R. have the previously mentioned meanings and X is a halogen atom such as bromine for example.

The reaction is preferably carried out in a solvent such as benzene, toluene, xylene, dimethylformamide, by an extended heating in the presence of an excess of the amine compound or of a basic agent fixing the formed acid halide.

According to a last way of proceeding, the products of the invention can be obtained from a compound of the following general formula :

wherein R,, R and R, have the above-mentioned meanings, by transforming the NH2 group into a NHR, group either by reductive alkvlation in the presence of the suitable cetone or aldehyde or by alkylation with a suitable halide or by acylation followed by a reduction.

The amino-alcohols which are necessary for preparing esters of general formula I are preferably obtained by usual processes, more particularly from a compound of the general formula :

wherein Rl, R2, R3 and R, have the previously mentioned meanings.

This reduction may be carried out in the usual manner, most easily for example by action of alkali metal hydrides, such as sodium borohydride, in a solvent, such as methanol or ethanol, preferably at low temperature, or aluminium and lithium hydride in a solvent such as diethyl ether or tetrahydrofuran, or still by action of an aluminium alkoxide, such as aluminium isopropoxide. in a solvent, such as isopropanol, most advantageously at the reflux of the latter. The reduction can also be made by hydrogenation in the presence of a catalyst, such as palladium on carbon, Raney nickel, platinum oxide in a solvent, such as methanol, ethanol, dioxan, acetic acid.

Detailed preparation processes of some aminoalcohol derivatives according to the invention are described hereinafter. These examples are given for more completely illustrating particular features of the process according to the invention.

Example I I-Acetyloxy-1- (4-isopropylthiophenyl)-2-n-octylaminopropane hydrochloride.

To 15 gr (40 mol) of I- (4-isopropylthiophenyl)-2-n-octylamino-Ipropanol hydrochloride, 12, 6 gr (160 mmol) of acetyl chloride are added. Heating is provided for I hour at reflux temperature, then 30 ml of benzene are added, reflux being maintained for two further hours. When cooling, the resulting solution abandons a white solid. The latter is filtered, then recrystallised from benzene. The product then weighs 11. 5 gr (28 mmol, 70 ) and melt at 167. 5 C.

The IR, NMR and mass spectra are in agreement with the structure.

Elementary analysis C H N % calculated 63. 5 9. 2 3. 4 % found 63. 6 9. 2 3. 4 Example 2 I-Butyryloxy-1- (4-isopropylthiophenyl)-2-n-octylaminopropane hydrochloride A mixture made of 10 gr (27 mmol) of 1- (4-isopropylthiophenyl)-2-n octylamino-I-propanol hydrochloride and 11. 4 gr (107 mmol) of butyryl chloride is heated at reflux temperature until a limpid solution is obtained. 10 ml of acetonitrile are added and reflux is maintained for about 2 hours. The solution so obtained is diluted with 40 ml of acetonitrile before being cooled. The white solid if filtered off. After recrystallisation from acetonitrile, the product weighs 6. 4 gr (14 mmol, 52%) and has a melting point of 104. 1 C.

The IR, NMR and mass spectra confirm the structure.

Elementary analysis C H N % calculated 64. 9 9. 5 3. 2 % found 64. 6 9. 3 3. 0 Example 3 1-Acetyloxy-1- (4-isopropylthiophenyl)-2-n-octylaminobutane hydrochloride.

To 20 ml of acetonitrile, 5 gr (13 mmol) of I- (4-isopropylthiophenyl)-2- n-octylamino-I-butanol hydrochloride and 5. 3 g (52 mmol) of acetic anhydride are added successively. The mixture is refluxed for 2. 5 hours. When cooling, it abandons a while solid. The latter is filtered off and twice recrystallised from acetonitrile.

Weight : 4. 1 g (9. 4 mmol, 72%) ; M. P. : 135. 0 C.

The IR, NMR and mass spectra confirm the structure.

Elementary analysis C H N % calculated 64. 2 9. 1 3. 3 % found 64. 0 9. 0 3. 5 The embodiment of process according to the invention which is the most interesting from an industrial point of view for preparing derivatives according to the invention as esters is the variant consisting of reacting a corresponding aminoalcohol or a salt thereof with an acid RsCOOH or with a reactive derivative of an acid such as hereinabove described with more details. It is, however, to be noted that such estes can also advantageously be prepared according to the other embodiments of the process according to the invention, such as described hereinabove.

The melting points of the derivatives described in the Examples and of other derivatives prepared according to the invention are given in the following Table.

N 1 R1 R 2 NHR 3 1 4-isoC3H7 CH3 NHnC8H17 COC (CH3) 3 109. 0 (isopropanol) 2 4-isoC3H7 CH3 NHn8H17 COCH2CH3 143. 5 (cyclohexane) 3 4-isoC3H7 CH3 NHnC8H17 COCH3 167. 7 (benzene) 4 4-isoC3H7 CH3 NHnC8H17 COCH (CH3) 2 104. 9 (cyclohexane) S 4-isoC3H7 CH3 NHnC8H17 CO (CH2) 2CH3 140. 1 (CH3CN) 6 4-isoC3H7 CH3 NHnC8H17 CO e 132. 4 (CH3CN) 7 4-isoC3H7 CH3 NHnC8H17 CO 6 131. 8 (CH3CH) 8 4-isoC 3H7 CH 3 NHNC 8H17 co 145. 6 (CH3CN) 9 4-1soC3H7 CH3 NH (CH2) 4 4 CO 4 150. 6 (AcOEt) V 10 4~ @ CH3 NHnC8H17 COCH2CH3 146. 3 (AcOEt) 11 4-CH3 CN3 NHnC8H17 COCH (CH3 ? 2 109. 5 (AcOEt) 12 4-isoC3H7 C2H5 NHnC8H17 COCH3 135. 0 (CH3CN) 13 4-isoC4Hg CH3 NHnC8H17 CO 6 119. 2 (cyclohexane) 14 4-O CH3 NHnC8H17 COCH3 162. 3 (CH CN) 15 4-isoC3H7 CH3 nC10 21 COCH (CH3) 2 104. 7 (CH3CN) 16 2 5 CH3 NHnC8H17 COCH2CH3 111. 7 (CH CN) 17 4-i50C3H7 CHj NH (CH2) 20 4 COCH (CH3) 2 167. 0 (isopropane) 18 4-isoC3H7 CH3 NH (CH2) 4 e (C 2) 2CH3 i19 5 (AcOEt)

N 0 R R2 NHR 3 R 4 MP (0c) (1) (2) N R1 RZ NHR3 19 4-isoC 3H7 CH 3 NH (CH 220 C/CO (CH 2) 2CH3 148. 7 (AcOEt) 20 4-isoC3H7 CH3-NH (CH212 t COCH3 142. 9 tAcOEt) 21 4-isoC3H7 CH3 NH (CH2) t COCH (CH3) 2 128. 3 (AcOEt) 22 4-isoC3H7 CH3 NH (CH2) 4 t COCH3 160. 0 (isopropanol 23 4-isoC3H7 CH3 NHnC8H17 COX 159, 8 (AcOEt) 24 4-isoC3H7 CH3 NHnC8H17 C 6 148. S (CH3CN) (threo) J 25 4-isoC3H7 CH3 NHnCaHl7 COCH2C (CH313 147. 8 (CHjCN) 26 4-isoC3H7 CH3 NHnC8H17 |CO (CH2) 2 e 132. 2 (CH3CN) 27 1 4-isoC3H7 CH3 NHnC8H17 COCH2 e 129. 6 (CH3CN) 3 7 3 8 17 28 4-isoC3H7 CH3 NHnC8H17 COCH2-.. p3 138. 0 (CH3CN) 29 4-isoC3H7 CH3 NHnC8H17 00 (CH2) 3 t 114. 6 (CH3CN) 30 4-isoC3H7 CH3 NHnC8H17 COCH2 e 152. 1 (CH3CN) 31 4-isoCHcHNHisoC3-3-5 (AcOEt) 32 4-isoC3H7 CH3 NHisoC3H7 C0CH2CH3 161. 2 (AcOEt) 1 33 |4-isoC3H7 CH3 NH (CH2) 3C O F COCH3 158. 1 (AcOEt) ( 34 J4-isoCcHNHcycloCgH00-198. 3 (AcOEt) 35 ! 4-isoCcHNHnCgHCOCH131. 8 (CH3CN) 36 i4-isoC3H CH NHnC H CO H 133. 6 (CH3CN) 3 18 37 1 37 g-isoC3H7 CH3 tNH (CH2) 8 < a > CHnC8Hl7 COCH2CH3 189.

38 4-isoC3H7 CH3 NH-CH (CH3) nC6H13 COCH3 153. 9 (CH3CN) 39 4-LsoC3H7 CH3 NH-(CH2) 2ClH-(CH2) 3 [CH3 COCH2CH3 oLl, > c=ol745 cm 1 CH3 CH3 40 4-isoC3H7 CH3 NH-(CH219-CH=CH2 COCH2 e 31. 4 (CH3CN) I

.-MP (C) 11 (2 ? N R1 R2 NHR3 4 41 4-isoC3H7 CH3 NH-(CH2) 9-CH=CH2 COCH3 1 oil ; KQ 1742 cm 1 42 4-isoC3H7 CH3 NH-(CH2) 8CHa C8Hl7 COCH (CH CN) 3 7 3 2 8 8 17 3 2 3 43 4-isoC3H7 CH3 NH (CH2) 3CO-| F OCCH2C (CH3) 3 1 132. 9 (AcOEt) H 44 4-isoC CH3 NE1CH2Q-I (Cfi2) 2 3 COCH3 141. 141. (CH3CN) \3. uH3 45 4-tsoC3H7 CH3 NH-cycloC6Hll COCH3 203. 5 (MeOH/Et20) 46 4-isoC3H7 CH3 NHcycloC6Hll COCH (CH3) 2 184. 7 (acetone) 47 4-isoC-H CH, NHnC. H.., COCH-Q (threo) 126 8 (isopropanol) The products according to the invention have various pharmaceutical activities, mainly on the cardiovascular system.

Their antihypertensive activity was tested by oral administration to non anesthetized, spontaneously hypertensed rats, on which the systolic arterial pressure is measured at the level of the median coccygeal artery by means of a plethysmographic method (J. Roba, G. Lambelin, A. F. DeSchaepdryver, Arch. int. Pharmacodyn., 200, 182, 1972). The arterial pressure was measured every 30 minutes from two hours before to three hours after oral administration of 60 mgr/kg of the tested products or of a placebo (1% tragacanth gum mucilage). When being of interest, the products were tested at other doses under similar conditions. Only rats having a systolic pressure of 180 to 220 mm Hg were used. Two rats were used for each product. The treatments were made without the knowledge of the person making the measures. The anti-hypertensive effects were rated 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 Under the test conditions, a-methyidopa was rated +++ at 100 mgr/kg, reserpine +++ at 3 mgr/kg and guanethidine +++ at 60 mgr/kg.

Products 7, 6, 9, 22, 20, 19, 25, 27, 28, 30, and 33 have shown a suitable antihypertensive activity.

The peripheral vasodilator activity of the products according to the invention was measured on anaesthetized dog at the level of the femoral arterial circulation.

To this end, the femoral artery the collaterals of which were ligaturated was perfused with a constant flow rate of blood taken from aorta. Thus the perfusion pressure measured at the level of the femoral artery, varied as a function of the resistance of perfused area. The tested products and the corresponding solvents were directly injected in the system at the dose of 30, ug/kg. The blood circulation rate being maintained constant, a vasodilation was thus measured by a decrease of the perfusion pressure. The latter is rated in comparison with the action of papaverine considered as standard and injected once per group of 4 products.

When being of interest, the products were tested at other doses under the same conditions. The vasodilation activity was rated as follows : 0 : inactive (reduction cl0 mm Hg) + : 1/3 of the papaverine activity ++ : 2/3 of the papaverine activity +++ : activity equal to that of papaverine (i. e. 30 to 40 mm Hg) ++++ : activity higher than that of papaverine.

Amongst the products according to the invention, compounds 3, 4, 5, 8, and 14, 18, 21 and 22 have shown a peripheral vasodilator activity which is at least equal to that of papaverine.

The antispasmodic activity of the products according to the invention were tested against contractions of guinea pig ileum, such as induced by histamine and acetylcholine. These tests allow to reveal an antihistaminic activity, an anticholinergic activity or a musculotrope antispasmodic activity. The response to the contracting agent (sub-maximum concentration) was repeated every 5 minutes before and after injection of increasing doses of the tested products (IO-8 to 10-5M). The various doses were made at intervals of 20 minutes or of the time necessary to the development of the maximum effect.

The percentage of inhibition under the influence of tested products was calculated and the theoretical concentration ensuring 50"inhibition was graphically determined for each experience. These values are ex ressed as-log CIso (M). The standard value for papaverine was 4. 50, namety an effective concentration of 30, uM.

All the products according to the invention have some antispasmodic activity of musculotrope type, namely without anticholinergic or antihistaminic component.

Compounds, 1, 2, 3, 4, 5, 8, 9, 10, 14, 17, 18, 19, 21, 22, 23, 24, 25, and 28, have ICso values higher than 6, corresponding to concentrations lower than, uM.

The effect on the in vitro induced lipolysis in the epididymal fat of the rat was measured by colorimetry of fatty acids liberated during the tissue incubation under the experimental conditions such as described hereinafter.

Male Sprague-Dawley rats weighing about 250 gr were sacrifice by cervical dislocation after a fasting period of 18 hours. The quickly taken-off epididymal fat was placed in a Krebs-Ringer phosphate buffer at pH 7. 4, containing 1 , albumin.

The tissue was cut into fragments of 20 mgr, which were dried on filter paper and homogeneously distributed in groups of 150 mgr weighed with precision.

Each group was pre-incubated (15 minutes, 37 C, stirring) in 5 ml of Krebs-Ringer phosphate buffer (pH 7. 4) containing 7% of bovine albumin and the product to be tested.

After pre-incubation, I ml of the medium is taken off for determining the amount of basic lipolysis. The induction agent in solution in 0. 1 ml of phosphate buffer is then added to 4 ml of the remaining medium and after incubation of 90 minutes under the same conditions, liberated fatty acids are titrated in I ml of medium according to a variant of the colorimetric method of W. G. Duncombe (Biochem. J., 83, 6P, 1962 ; Bigchem. J., 88, 7-10, 1963 ; Clin. Chem. Acta, 9, 122125, 1964).

Under the experimental conditions, compound I is seen to be active.

The blood platelet agglutination was studied according to the Born Method (J. Physiol.,/68, 178, 1963). Nine volumes of human venous blood were taken off and anticoagulated with one volume of a trisodium citrate solution (0. 129 M). The blood was centrifuged at 200 g for 10 minutes (22 C) for preparing the platelet rich plasma (PRP). Methanol or acetone was used in order to obtain 2x 10-2M solutions of the various involved products, 24, ul of each product were added to 300 ul of PRP. For controls, 24, ul of the various hereinabove mentioned solvents were used.

The products were pre-incubated in the presence of PRP for 4 minutes at 37 C under continuous stirring (1100 rpm). After this incubation period, the platelet agglutination was induced by addition of 100 pl of thrombofax or collagen. The agglutination phenomenon was quantified by graphical determination of the agglutination amplitude (A).

The inhibition percentage of the agglutination amplitude was calculated as follows : A., A ( O inhibition) : 100 xl00 Ao A. : value of agglutination amplitude in the presence of examined products A. : value of agglutination amplitude for controls Under these experimental conditions, compounds 3 and 25 show a strong agglutinating effect.

The acute toxicity of the products according to the invention was also determined after oral administration (cramming of a 1 , Ó tragacanth gum mucilage) to male mice (Charles River CDI, fasting of 18 hours).

Groups of 10 mice were used and received one of the following doses : 500, 1000, 1500, 2000 or 4000 mgr/kg. The behaviour of the animals was studied 2 and 10 hours after administration, and after 24 hours or even more in case of persistent symptoms. The behaviour examination was carried out according to a method deriving from that of Irwin (Gordon Research Conf. on Medicinal Chem., 133, 1959). The mortalities were registered for the period of 14 days following the treatment. The LD ; o vatues werre calculated according to the Litchfield and Wilcoxon method (J. Pharmacol., Exp. Ther., 96, 99, 1949) and expressed as mgr/kg.

The products according to the inventionare not very toxic. The LDgo are above 3000 mgr/kg in most cases.

The observed behaviour modifications mainly consist in tranquilizing accompanied with sedation at higher doses.

From the preceeding, it results that compounds according to the invention, while being not very toxic, are generally endowed with activities on the cardiovascular system, in particular antispasmodic, antihypertensive, peripheral vasodilation activities, a protecting activity against myocardium anoxia, hypolipidemic, normolipoproteinemic, antithrombotic activities, an inhibition activity against platelet aggregation and/or tranquillizing activities, and are more particularly used in the treatment of hypertension and cardiovascular affections, such as atherosclerosis.

Preferably, the derivatives according to the invention as amino-alcohol esters are particularly useful due to their pronounced antihypertensive activities by comparison with those of corresponding amino-alcohols.

The active compounds according to the invention may be administered in association with various pharmaceutical excipients orally, parenterally or rectally.

For oral administration, pills, granules, tablets, capsules, solutions, syrups, mulsions or suspensions containing usual additives or excipients in galenic pharmacy will be used.

For parenteral administration, sterile water or an oil will be used, such as peanut oil or ethyl oleate. For rectal administration, suppositories or rectal capsules will be used.

These active compounds may be used atone or in association with other active products having a similar or different activity.

The products according to the invention may be used as different forms. The following examples are not limitative and relate to galenic formulations containing as active product, designated by"A"hereinafter, one of the following compounds : I-neopentylcarbonyloxy-I- (4-isopropylthiophenyl)-2-n- octylaminopropane (hydrochloride) I-butyryloxy-I- (4-isopropylthiophenyl)-2-n-octylaminopropane (hydrochloride Intramuscular injection A 10 mg Isopropyl Myristate 0. 75 ml Peanut oil, q. s. ad 3 ml A 10 mg D-glucuronic acid 6 mg Benzyl alcohol 50 mg Distilled water, q. s. ad 5 ml A 10 mg Ethyl alcohol 0. 50 mi Polyethylene glycol 400 0. 25 ml Propylene glycol 0. 50 ml 10% acetic acid 0. 125 ml 70 ; o sorbitol 0. 75 ml Distilled water, q. s. ad 3 ml Solution for oral administration.

A 5mg Ethylic alcohol 0. 1 ml Propylene glycol 0. 05 ml 10% acetic acid 0. 05 ml Simple syrup (65% saccharose) q. s. ad 1 ml A 5 mg Ethyl alcohol 0. 2 mi 10% acetic acid 0. 04 ml Simple syrup, q. s. ad A 10 mg Ethyl alcohol 0. 25 ml 10% acetic acid 0. 04 ml Simple syrup, q. s. ad 1 ml Tablets A 50 mg Lactose 20 mg Aerosil (Registered Trade Mark) 2 mg Starch STA-RX 1500 18 mg Calcium phosphate (CaHPO4) 25 mg Microcrystalline cellulose 100 mg Sodium acetate 15 mg A 50 mg Microcrystalline cellulose 80 mg Sodium acetate 25 mg Auby-gel X 52 20 mg Corn starch 50 mg A 50 mg Microcrystalline cellulose 100 mg Starch STA-RX 1500 99 mg Aerosil ! mg A 50 mg Corn starch 50 mg Sodium acetate 15 mg Magnesium stearate 2 mg Aerosil 3 mg Starch STA-RX 1500 80 mg Capsules A 50 mg Starch STA-RX 1500 94 mg Magnesium stearate 1 mg Sodium lauryl sulfate 5 mg A 50 mg Microcrystalline cellulose 70 mg Corn starch 30 mg Peanut oil 0.01 mg Sodium lauryl sulfate 5 mg A 50 mg Sodium lauryl sulfate 5 mg Microcrystailine cellulose 70 mg Magnesium oxide 20 mg A50 mg Starch STA-RX 1500 100 mg Magnesium stearate Img Sodium lauryl sulfate 10 mg Microcrystalline cellulose 30 mg Aerosil I mg Suppositories A 00 mg Lidocaine 20 mg Novata 299 grad. 2000 mg A 100 mg Lidocaine 20 mg Cutina GMS (Registered Trade Mark) 100 mg Novata B grad. 2000 mg A 100 mg Witepsol S 58 grad. (Registered Trade Mark) 2000 mg The meaning of some terms used in the above galenic formulas is given hereinafter :- Aerosil : trade name for finely divided silicium dioxide Starch STA-RX 1500 : corn starch Auby-gel X 52 : carregheen derivative Lidocaine : trade name for lignocaine Novata 299 grad. : mixture of saturated C,,-~, 7 fatty acid triglycerides with partial glycerides of acetylated fatty acids.

Novata B grad. : mixture of tri-, di-and monoglycerides of saturated C,,-C,, fatty acids.

Cutina GMS : glyercin monostearate Witepsol S 58 grad. : mixture of C, 2C, 8 natural triglycerides.

Depending on the case and the kind of desired activity and of the specific com pound used, the amino-alcohol derivatives according to the invention are administered at daily dosages of 50 to 3000 mgr.

Claims (19)

1. WHAT WE CLAIM IS : 1. An amino-alcohol derivative of the formula :

   wherein : (a) R, is a linear or branched alkyl C,-Cs radical or a cycloalkyl Cs-Ce radical ; (b) R2 is alkyl C1C2 radical ; (c) R, is a linear or branched alkyl C,-C,, radical ; a linear or branched alkyl C,-C, radical substituted by a phenyl, phenoxy, phalogenophenoxy or p-halogenobenzoyl group ; a linear or branched alkenyl C6-C18 radical, or a cycloalkyl Cs-C, radical ; (d) R, is an acyl group having the formula :

   in which R, represents : a linear or branched alkyl C1-C6 raidcal, a cycloalkyl C3-Ce radical, or a linear or branched alkyl C,-C, radical substituted by a phenyl, p methoxyphenyl or cyclohexyl group.
2. 2. A derivative as claimed in Claim 1, wherein : (a) R, is a linear or branched alkul, C1-C5 radical or a cycloatkyl CS-C6 radical ; (b) R2 is an alkyl C, C2 radical ; (c) R3 is a linear or branched alkyl Ce-C, Z radical, or a linear or branched alkyl C,-C, radical substituted by a phenyl radical ; and (d) Rs is an acyl group having the formula :

   in which R5 is a linear or branched alkyl C, C6 radical or cycloaikyl C3C6 radical.
3. 3. A derivative as claimed in Claim 2 wherein R, is a linear or branched alkyl Ce to C, radical, or a linear or branched alkyl C2 to C, radical substituted by a phenyl radical and R, is an acyl group having the formula :

   in which R, is a linear or branched C, to C, alkyl radical or cycloalkyl C, to C, radical.
4. 4. A derivative as claimed in any one of Claims I to 3, wherein in formula I, R, S is in position para.
5. 5. A derivative as claimed in Claim 1, wherein in formula I ; (a) R, represents an isopropyl radical, (b) R2 represents a methyl radical, (c) R, represents a n-octyl radical, (d) R, represents an acyl group corresponding to the formula :

   in which R, represents : a linear or branched alkyl C,-C, radical, a cycloalkyl C3-C, radical, or alkyl C1C2 radical substituted by a phenyl para-methoxyphenyl or cyclohexyl group.
6. 6.1 - Butyloxy - 1 - (4 - isorpropylthiophenyl) - 2 - n - octylaminopropane.
7. 7. 1-Cyclohexanecarbonyloxy-I- (4-isopropylthiophenyl)-2-n-octyl- aminopropane.
8. 8. 1-p-Methoxyphenylacetyloxy-I- (4-isopropylthiophenyl)-2-noctylaminopropane.
9. 9. 1 - Neopentylacarbonyloxy - 1 - (4 - isopropylthiophenyl) - 2 - n - octylaminopropane.
10. 10. A process for preparing an amino-alcohol derivative of formula I, in which R, to Rs are as defined in Claim l, which method comprises transforming into such a derivative, a compound of general formula
11. II :

    wherein Q represents one of the following groups :

    wherein R2 to R. are as defined in Claim 1, while X represents a halogen atom, and Re is a protective group which is later removable by hydrolysis or hydrogenolysis.

    II. A process as claimed in Claim 10, wherein an amino-alcohol or the corresponding salt of this amino-alcohol of formula II, in which

    R, to R, are as defined in Claim 1, is reacted with an acid R5COOH or an active derivative thereof, wherein R, is as defined in Claim 1.
12. 12. A process as claimed in Claim 11, wherein a slight excess of acid or of the active derivative thereof is used at a temperature between room temperature and reflux temperature of the acid or active derivative thereof.
13. 13. A process as claimed in Claim 1 I or Claim 12, wherein an acid chloride is used as the active derivative.
14. 14. A process as claimed in Claim 10, wherein a compound of formula 11, in which Q represents

    and R, to R, are as defined in Claim I is isomerised by action of an inorganic acid in a solvent, or by action of a chlorination agent.
15. 15. A process as claimed in Claim 10, wherein a compound of formula II in which Q is a group

    is reacted with an amine of the formula R, NH, or R, R. NH in which X, and R, to R. are as defined in Claim 10, by extended heating in the presence of an excess of the amine or in the presence of a basic agent for reacting with the formed acid halide and where Q is

    the resulting amino alcohol is suitably esterified, and where Q is

    the resulting amino ketone is reduced to an amino alcohol and suitably esterified.
16. 16. A process as claimed in Claim 10, wherein the NH2 radical of the group

    of a compound of formula II is transformed into a NHR3 radical by a reductive alkylation in the presence of the appropriate ketone or aldehyde or by an alkylation with a suitable halide or by acylation followed by reduction.
17. 17. A pharmaceutical composition, comprising, as an active product, one or more derivatives as claimed in Claim 1, in association with one or more suitable excipients and optionally with other therapeutic agents.
18. 18. An amino alcohol derivative as claimed in Claim 1 or a composition comprising such a derivative, substantially as herebefore described in any one of the Examples.
19. 19. A process for preparing an amino alcohol derivative as claimed in Claim 10 substantially as hereinbefore described in any one of the Examples.