GB1565080A - Amino-alcohol derivatives and their preparation - Google Patents

Abstract

Aminoalcohol derivatives corresponding to the formula (I) <IMAGE> in which Q is a group <IMAGE> and the other substituents have the meaning shown in Claim 1 are prepared by reaction with a compound of formula I, in which Q represents a group <IMAGE> or <IMAGE>, with an amine of type R3R4NH, Z being a halogen. The alcohol can then be esterified by reaction with an acid or an anhydride as defined in Claim 1. The compounds obtained have activities on the cardiovascular system, for example antihypertensive and/or antispasmodic activities, peripheral vasodilative activity, protective activity against myocardial anoxia, hypolipidemiating activity, antithrombotic activity, beta -lytic activity or platelet aggregation inhibiting activity, and/or activity on the central nervous system, for example a tranquillising activity.

Description

(54) AMINO-ALCOHOL DERIVATIVES, AND THERM PREPARATION (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 including substituted amino-alcohols, esters of these amino-alcohols and salts thereof, to their preparation, to pharmaceutical compositions containing at least one of said derivatives, as well as to uses thereof.

The invention provides an amino-alcohol derivative having the formula:

wherein: (a) R, represents hydrogen, one or two linear or branched C, to C3 alkyl radicals, a phenyl radical or a carboxy radical; (b) R2 is a linear or branched C, to C3 alkyl radical; (c) R3 is: -a mono or polyunsaturated C3 to C18 alkenyl radical; -a mono or polyunsaturated C3 to C,2 alkenyl radical substituted by phenyl and/or containing an oxygen or sulfur linkage; -a mono or polyunsaturated C3 to C,8 alkynyl radical; -a mono or polyunsaturated C3 to C,2 alkynyl radical substituted by phenyl and/or containing an oxygen or sulfur linkage; -a cycloalkyl C3 to C,0 radical -a C2 to C30 linear or branched alkyl radical; -a linear or branched C2 to C,8 alkyl radical, containing at least one oxygen or sulfur linkage and/or substituted with one or more Ct to C3 alkoxycarbonyl, pyrrolidine, pyrrolidinone, imidazolidone, phenyl, phenoxy, phenylthio benzoyl, indanyloxy, naphthyloxy, or phenyl, phenoxy, phenylthio or benzoyl radicals substituted by one or more C, to C4 alkyl or C, to C4 alkoxy radicals, by one or two halogen atoms, or by a nitrile, hydroxy, amino, C3 to C6 alkylcarbonyl, C3 to C4 acylamino, C2 to C8 alkoxycarbonyl, or C, to C4 alkylsulfonamido radical, or by an alkoxycarbonyl alkyl in which both the alkoxy and alkyl moieties contain from 1 to 4 carbon atoms, or alkoxycarbonyl alkoxy in which each alkoxy moiety contains from 1 to 4 carbon atoms, or is in accordance with the definition of R4 below; (d) R4 is hydrogen or when taken with R3 and adjacent nitrogen atom, forms a morpholine, pyrrolidine, piperidine radical or a piperidine radical substituted by one or two C, to C4 alkyl, phenyl or phenylalkyl (C, to C4) radicals, or a piperazine radical substituted in position 4 by a phenyl radical or by a phenyl radical itself substituted by one or (C, to C4) two alkyl or (C, to C4) alkoxy radicals, one or two halogen atoms, or a trifluoromethyl radical; (e) R5 is a hydrogen, halogen, or a C, to C3 alkyl radical; (f) R8 is a hydrogen or a linear or branched C3 to C" alkylcarbonyl radical or a C3 to C8 cycloalkyl carbonyl radical; (g) n is 1, 2 or 3; (h) X is sulfur, oxygen, a CH2 radical or a NH radical (i) Y is a CH2 radical or sulfur provided that when simultaneously X is oxygen, Y is a CH2 group, n is 2, R, and R5 are hydrogen, R3 is methyl and R8 is hydrogen or an alkyl carbonyl radical, R4 does not form a substituted piperazine radical with R3 and the adjacent nitrogen atom.

The term "cycloalkyl" used in this specification includes "adamantyl".

This invention advantageously includes derivatives of formula I, wherein: (a) R1 is hydrogen or an alkyl (C, to C3) radical; (b) R2 is an alkyl (C, to C3) radical; (c) R3 is: -a mono or polyunsaturated alkenyl (C3 to C,8 radical; -a mono or polyunsaturated alkynyl (C3 to C,8) radical; -a cycloalkyl (C3 to C8) radical; -an alkyl (C2 to C,8) radical; -an alkyl (C2 to C,8) radical substituted by (1) a phenylthio radical, an alkoxy (C, to C,) radical, an alkylthio (C, to C8) radical, a phenoxy radical, a benzoyl radical, one or two phenyl radicals, (2) a phenyl, benzoyl, phenylthio or phenoxy radical each substituted by an alkyl (C, to C3) or a halogen, (3) a phenoxy radical substituted by a nitrile or an alkylcarbonyl (C2 to C3) radical, or is as required by the definition of R4 below; (d) R4 is hydrogen or when considered with R3 and the adjacent nitrogen atom forms (1) a piperazine radical substituted by a phenyl radical which is in turn substituted by an alkyl (C, to C3) radical, or (2) a piperidine radical substituted by an alkyl (C, to C3) radical which is itself substituted by a phenyl radical; (e) R8 is hydrogen or an alkyl (C, to C3) radical; (f) R6 is hydrogen, a linear or branched alkylcarbonyl (C2 to C8) radical or a cycloalkylcarbonyl (C3 to C8) radical; (g) n is equal to 1, 2 or 3; (h) X is sulfur, oxygen or a NH radical; (i) Y is a CH2 radical or sulfur.

Compounds included within the invention are those of formula I in which: R, represents hydrogen, or one or two linear or branched C1 to C3 alkyl radicals; R is as defined in claim 1; R3 is: -a C3 to C,8 alkenyl radical; -a C3 to C,O alkynyl radical; -a C3 to C,0 cycloalkyl radical; -a linear or branched C3 to C,8 alkyl radical; -a linear or branched C2 to C,8 alkyl radical containing one or more oxygen or sulfur linkages, and/or substituted by at least one alkoxycarbonyl, pyrrolidine, pyrrolidinone or imidazolidone radical, by one or two phenyl, phenoxy, phenylthio, indanyloxy radicals, by a phenyl, phenoxy, phenylthio radical substituted by one or two C, to C4 alkyl or C, to C4 alkoxy radicals, by one or two halogen atoms by a nitrile, hydroxy, amino, C2 to C8 alkyl carbonyl, C3 to C4 acylamino, alkoxycarbonyl, or C, to C4 alkylsulfonamido radical, or by an alkoxycarbonyl alkyl in which the alkyl and alkoxy moieties contain from I to 4 carbon atoms, or alkoxy carbonyl alkoxy in which each alkoxy moiety contains from 1 to 4 carbon atoms; R4 and R8 are as defined in claim I; R8 is hydrogen; n is sulfur, oxygen or a CH3 radical; and Y is a CH2 radical.

Preferred compounds are those in which R1 is hydrogen, R2is methyl, R3 is a n-octyl, phenylbutyl, phenexypropyl, (phenoxy)ethyl, (chlorophenoxy)ethyl or (fluorobenzoyl)propyl radical, R4 and R5 are hydrogen, n is equal to 1 or 2, X and Y each represent a CH3 radical, and R8 is hydrogen or a C2 to C8 alkyl carbonyl or C3 to C8 cycloalkylcarbonyl radical.

A preferred class of compounds according to formula I comprises those compounds wherein R1 is hydrogen or methyl, and/or R2 is methyl or ethyl, and/or R3 is an alkyl (C2 to C,8) radical, C4 to C,4 alkynyl, C8 to C,8 alkenyl or an alkyl (C2 to C,0) radical substituted by (l) a phenyl, phenylthio, phenoxy or benzoyl radical or (2) a phenyl, phenylthio, phenoxy or benzoyl radical each substituted by one or two alkyl (C, to C3) radicals or halogen, R4 and R8 are hydrogen, R8 is hydrogen, an alkylcarbonyl (C2 to C8) radical or a cycloalkylcarbonyl (C3 to C8) radical, n is equal to 1, 2 or 3, X is sulfur and Y is CH2.

Preferred R3 groups include C8 to C,O alkenyl or alkynyl radicals containing an oxygen linkage.

R3 and R4 may together form with the adjacent nitrogen atom a piperazine radical substituted by a phenyl radical which is in turn substituted by a C, to C3 alkyl radical or a piperidine radical substituted by a C, to C3 alkyl radical which is itself substituted by a phenyl radical.

Preferred R8 groups include C3 to C5, e.g. C2 to C4 alkylcarbonyl radicals and C3 to C8 cycloalkylcarbonyl radicals, e.g. propyl carbonyl or cyclohexylcarbonyl.

Examples of derivatives according to the invention are: 1 - (6 - thiochromanyl) - 2 - n - octylamino - 1 - propanol 1 - (6 - thiochromanyl) - 2 - (4 - phenylbutylamino) - 1 - propanol 1 - (6 - thiochromanyl) - 2 - [2 - (phenoxy)ethylaminol - 1 - propanol 1 - (2,3 - dihydro - 5 - benzo[b]thienyl) - 2 - n - octylamino - 1 - propanol 1 - (2,3 - dihydro - 5 - benzo[b] thienyl) - 2 - (4 - phenylbutylamino) - 1 - propanol 1 - (2,3 - dihydro - 5 - benzo[b]thienyl) - 2 - [4 - (p - chlorophenyl)butylamino] 1 - propanol 1 - (2 - methyl - 2,3 - dihydro - 5 - benzo[b]thienyl) - 2 - (4 - phenylbutylamino) 1 - propanol 1 - (2 - methyl - 2,3 - dihydro - 5 - benzo[b]furanyl) - 2 - n - octylamino - 1 - propanol 1 - (2,3,4,5 - tetrahydrobenzo[b]thiepin - 7 - yl) - 2 - (4 - phenylbutylamino) - 1 propanol 1 - (2,3 - dihydro - 5 - indolyl) - 2 - n - octylamino - 1 - propanol 1 - (2,3 - dihydro - 5 - benzo[b]thienyl) - 2 - (4 - phenylbutylamino) - 1 - propionyl oxypropane 1 - (2,3 - dihydro - 5 - benzo[b]thienyl) - 2 - (4 - phenylbutylamino) - 1 - cyclohexyl carbonyloxypropane 1 - (5 - indanyl) - 2 - (4 - phenylbutylamino) - 1 - propanol 1 - (5 - indanyl) - 2 - [2 - (4 - chlorophenoxy)ethylamino] - 1 - propanol 1 - (5 - indanyl) - 2 - [2 - (4 - fluorobenzoyl)propylamino] - 1 - propanol Satls of compounds of formula I falling within the invention include salts obtained by reacting the derivative with an inorganic acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, or perchloric acids or with an organic acid, such as ascorbic acid or a carboxylic or sulfonic acid, such as formic, acetic, propionic, glycollic, lactic, fumaric, maleic, pamoic, succinic, tartaric, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic, methanesulfonic, ethanedisulfonic, or glucuronic acid. This may be due in a solvent such as an alcohol, the reaction being followed by precipitation of the salt by addition of another solvent which is miscible with the first one and in which the salt is insoluble, for example ether, or by neutralisation of an ethereal solution of the acid or derivative by means of the derivative or acid respectively.

The more active products according to the invention having two asymmetry centres, two racemates can be obtained corresponding to erythro and threo configurations respectively; both said racemates can be resolved by conventional methods, for example by forming diastereoisomer salts by action of optically active acids, such as tartaric, diacetyltartaric, tartranilic, dibenzoyltartaric, ditoluoyltartaric acids, and separation of the diastereoisomer mixture by crystallization, distillation, chromatography, then liberation of optically active bases from said salts.

The same processes can be used when compounds according to the invention comprise more than two asymmetry centres.

The more active derivatives of the invention can thus be used either as racemates of configuration erythro or threo or as a mixture of these forms, or still as optically active compounds of each of both said forms.

In general, amino-alcohol derivatives according to the invention have some activity on the cardiovascular system, such as antihypertensive and/or antispasmodic activities, a peripheral vasodilator activity, a protecting activity against myocard anoxy, hypolipidemic, antithrombotic, p-lytic activities, a plateletaggregation inhibitory activity and/or activities on the central nervous system, for example a tranquillising activity.

These properties allow the use of products according to the invention in the treatment of hypertension and cardiovascular diseases, such as atherosclerosis.

More particularly, it has been found that certain derivatives according to the invention are endowed inter alia with very high antihypertensive, hypolipidemic and antithrombotic activities.

Active compounds according to the invention can be administered in association with various pharmaceutical excipients, e.g. diluent or carriers, orally, or parenterally.

For oral administration, coated pills, granules, tablets, capsules, solutions, syrups, emulsions and suspensions will be used, containing additives and excipients which are usual in galenic pharmacy. For parenteral administration, a liquid such as sterile water or an oil, such as peanut oil or ethyl oleate, will be used.

These active compounds can be used alone or in combination with other active products having a similar or different activity.

The new compounds according to the invention may be prepared following the general process forming also a part of the invention and defined as follows.

The new derivatives may be prepared from a compound having formula (II):

or optionally, according to the meaning of Q, from a salt of a compound of this formula (II), wherein R1, R5, Y, X and n have the hereinabove mentioned meaning and Q represents one of the following groups:

In these groups, R2, R3 and R4 have also the meaning such as mentioned hereinbefore, while z is a halogen atom, such as Cl or Br.

This general process can be carried out according to two methods which are essentially determined by the starting product, namely by the meaning of Q in formula (II).

According to a first preparation method, a a-aminoketone having formula (II) in which Q represents a group

R2 and R3 having the meaning already given, R7 has the meaning of R4 or is a protecting group which can be removed later by hydrolysis or hydrogenolysis, such as benzyl, trityl, acetyl, formyl, benzhydryl groups, is reduced.

This reduction can be made in an 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 aluminum and lithium hydride in a solvent such as diethyl ether or tetrahydrofuran, or also by action of an aluminium alkoxide, such as aluminum isopropoxide, in a solvent such as isopropanol, most advantageously at reflux thereof. 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.

As mentioned before, the most interesting products of the invention can have two configurations, namely erythro and threo. The selection of the starting aminoketone and of reduction conditions allow to obtain either of these two forms stereo-selectively. Thus reduction of an aminoketone in which

and R4 hydrogen leads to a compound with erythro configuration under the general conditions hereinbefore described.

In order to obtain a compound with threo configuration, reduction is made on an aminoketone in which

where R2 and R3 have the hereinbefore defined meaning and R7 is a protecting group which can be removed later by hydrolysis or hydrogenolysis, such as benzyl, trityl, acetyl, formyl, benzhydryl groups. This reduction is then preferably made by action of alkali metal hydrides, such as sodium borohydride, or aluminum and lithium hydride.

Starting aminoketones are easily obtainable, for example by action of an amine R3R4NH on a a-halogenoketone in solvents such as ether, benzene, chloroform, dioxan, methanol, isopropanol or acetonitrile.

It is however well known in the literature that a reaction of this kind generally gives low yields, this being due to formation of many secondary products and to instability of c-aminoketones. According to this invention, a synthesis method has been studied allowing to obtain amino-alcohols of general structure (I) with excellent yields, this being obtained preferably without isolating intermediate aminoketone; a particularly good solvent for this type of reaction reveals to be an alcohol, such as methanol, ethanol or isopropanol. In this connection, according to the invention, a a-halogenoketone of formula (II) wherein

is reacted with an amine R3R4NH, so as to obtain an aminoketone corresponding to formula (II) where

and this aminoketone is reduced as hereinbefore without being previously isolated.

According to a second preparation method, a compound of general formula (II) wherein Q is a group

is reacted with an amine of the kind R3R4NH, in which formulas R2 to R4 and Z have the hereinbefore defined meaning.

This reaction is carried out in a solvent, such as alcohols, chloroform, dioxan, carbon tetrachloride, most easily in the presence of an agent able to capture formed hydrogen halide, such as tertiary inorganic or organic bases or in the presence of excess amine. It is well known that in these cases, the group

first produces an oxirane of the type

which reacts with the amino compound.

The present process thus also includes preparation of amino-alcohols from oxiranes; this process can advantageously be used for preparing amino-alcohol derivatives having threo configuration.

Salts of amino-alcohols of formula (I) can be prepared, according to the invention, as previously mentioned by the general process such as hereinbefore described.

This process allows several variants. Generally, these salts can be formed by well known methods of this general process, such as for example reaction of equimolecular amounts of the amino-alcohol with an acid in a suitable solvent, such as an alcohol for example, then precipitation of the salt by addition of another solvent which is miscible with the first one and in which the salt is insoluble, for example ether, or also by neutralisation of an ethereal solution of the acid or base with the base or acid. Acids which are used are as well organic as inorganic acids.

As inorganic acids, one preferably uses hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and the like.

Organic acids are carboxylic acids or sulfonic acids, such as formic, propionic, glycollic, lactic, citric, fumaric, maleic pamoic, succinic, tartaric, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic, glucuronic acids and the like. Ascorbic acid may be used.

Esters of amino-alcohols according to formula I, where R8 is an alkylcarbonyl or cycloalkylcarbonyl radical are prepared by reacting an amino-alcohol or a salt thereof with excess of suitable acid chloride or anhydride preferably at a temperature between 50"C and reflux temperature of acid chloride or anhydride.

According to another method, an amino-alcohol or a salt thereof is reacted with an equimolecular amount or a slight excess of suitable acid chloride or anhydride, for example in a solvent such as acetonitrile, benzene and toluene.

Hereinafter, some detailed examples are given relating to the preparation of amino-alcohol derivatives according to the invention. These examples have more particularly for their object to more completely illustrate the particular features of the process according to the invention Example 1.

1 -(6-Thiochromanyl)-2-n-octylamino-1 i,roprniol a) To 35 gr. of aluminum chloride in 500 ml of 1 ,2-dichloroethylene, 19.7 ml of propionyl chloride are added, then slowly while stirring 36,5 gr. of thiochromane in 150 ml of 1,2-dichloroethylene, the temperature being maintained at about 10"C.

After addition, the mixture is stirred for 3 hours at room temperature, then decomposed by addition of ice and hydrochloric acid.

The organic phase is separated and the aqueous phase is extracted with 1,2dichloroethylene. The combined organic phases are dried on MgSO4, filtered and solvent is evaporated in vacuo. The residue so obtained is solidified by addition of petroleum ether; 32,5 gr. of 6-propionyl-thiochromane are so obtained.

MP ("C): 63-65 Yield: 69% (MP = Melting Point) b) To a solution of 32 gr. of 6-propionyl-thiochromane in 400 ml of anhydrous ether, 8 ml of bromine are dropwise added, temperature being maintained at +50C.

After addition, the mixture is still stirred for 2 to 3 hours at room temperature, then an aqueous saturated NaRCO3 solution is slowly added. The aqueous phase is twice extracted with 100 ml ether, combined organic phases are dried on MgSO4, filtered, and solvent is evaporated in vacuo. The residue so obtained is treated with 100 ml of petroleum ether; 38 gr. of a-bromo-6-propionyl-thiochromane are obtained.

MP ("C): 71-73. Yield 86% c) 20 gr. of the preceding product, 15 ml of n-octylamine and 200 ml of ethanol are refluxed for 4 hours. The mixture is cooled to +5"C and 5,2 gr. of sodium borohydride are gradually added. After addition, the mixture is still stirred for I or 2 hours at room temperature, then solvent is evaporated in vacuo. The residue is taken up with 200 ml of water and extracted with 3 x 100 ml of chloroform. The combined organic phases are water washed, dried on MgSO4, filtered, and solvent is evaporated in vacuo. The residue obtained is recrystallized from acetone. 13,3 gr. of 1-(6-thiochromanyl)-2-n-octylamino-1-propanol are obtained.

MP ("C): 115-1 16. Yield: 60% Centesimal analysis: C H N % calculated 71,58 9,91 4,17 %found 71,70 9,85 4,05 Example 2.

1-(2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1-propanol a) To 0,3 M of aluminum chloride in 500 ml of 1,2-dichloroethylene, 0,21 M of propionyl chloride are added, then slowly while stirring 0,2 M of 2,3 dihydrobenzo[b]thiophene are added, temperature being maintained at about 10 C. The mixture is then still stirred for 3 hours at room temperature, then decomposed with a mixture of ice and hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with 1 ,2-dichloroethylene. The combined organic phases are dried on MgSO4, filtered and solvent is evaporated in a vacuum. The residue obtained is solidified by addition of petroleum ether; 25 gr. of 5-propionyl-2,3-dihydrobenzo[b3thiophene are so obtained.

MP ("C): 5--52 Yield: 55%. b) To 12,5 gr. of the preceding product in 150 ml of anhydrous tetrahydrofuran, 3,3 ml of bromine are dropwise added while agitating at a temperature of +10 C. Agitation is still continued for 1 hour at room temperature, then 50 ml of an aqueous 10% NaH CO solution are added. The organic phase is separated, dried and evaporated. The oily residue obtained is solidified by addition of petroleum ether; 30 gr. of 5-(a-bromopropionyl)-2,3-dihydrobenzo[b]thiophene are obtained.

MP (OC): 6466 c) 15 gr. of 5-(&alpha;-bromopropionyl)-2,3-dihydrobenzo[b]thiophene, 16 gr. of 4phenylbutylamine and 150 ml of methanol are refluxed for 3 hours. The solution is cooled to +5 C and 5 gr. of sodium borohydride are slowly added. After addition, stirring is still continued for 3 to 4 hours at room temperature, then solvent is evaporated in vacuum. The residue is treated with 200 ml of water and extracted with chloroform. The organic phase is water washed, dried on MgSO4, filtered and solvent is evaporated in vacuo. The solid residue is recrystallized from acetone, 9,9 gr. of product are so obtained.

MP ("C): 113--115 Yield: 55% Centesimal analysis: C H N % calculated 73,85 7,97 4,10 % found 73,50 7,95 3,90 Example 3.

1-(2,3,4,5-tetrahydrobenzo[b]thiepin-7-yl)-2-(4-phenylbutylamino)-1-propanol a) To 0,27 M of aluminium chloride in 500 ml of 1,2-dichloroethylene, 0,25 M of propionyl chloride are added, then slowly while stirring 0,25 M of 2,3,4,5 tetrahydrobenzo[b]thiepine, temperature being maintained at about 10"C. The mixture is then stirred for 3 to 4 hours at room temperature, then decomposed with a mixture of ice and hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with 1,2-dichloroethylene. The combined organic phases are dried on MgSO4, filtered and solvent is evaporated in vacuum. The residue is distilled in vacuo. 30 gr. of dense oil are obtained. Yield: 60%; boiling point: BP: 130135 (0,4 mm). The NMR spectrum (nuclear magnetic resonance) is conform to the structure 7-propionyl-2,3,4,5-tetrahydrobenzo[b]thiepine. b) To 11 gr. of the preceding product in 150 ml of anhydrous tetrahydrofuran (THF), 2,6 ml of bromine are dropwise added at a temperature of +iO"C. The mixture is then still stirred for 1 hour at room temperature, then 30 ml of an aqueous 10% NaRCO3 solution are added. The organic phase is separated, dried and evaporated 13,2 gr. of 7 - (a - bromopropionyl) - 2,3,4,5 - tetrahydrobenzo[b]thiepine (fluid yellow oil) are so obtained, the homogeneity of which is verified by TLC (thin layer chromatography). c) 10 gr. of 7-(et-bromopropionyl)-2,3,4,5-tetrahydrobenzo[b]thiepine, 150 ml of methanol and 10 gr. of 4-phenylbutylamine are refluxed for 4 hours. The solution is then cooled to +5 C, and 4 gr. of sodium borohydride are slowly added while stirring. After addition, the mixture is allowed to stand overnight at room temperature, then solvent is evaporated in vacuo. The so obtained oily residue is treated with 200 ml of water and extracted with chloroform. The organic phase is washed with water, dried on Na2SO4, filtered and solvent is evaporated in vacuo.

The residue so obtained is recrystallized from acetone. 7,5 gr. of product are obtained.

MP (OC): 87-89 Yield: 53%.

Centesimal analysis: C H N % calculated 74,74 8,45 3,79 % found 74,85 8,65 3,70 Example 4.

1-(2-methyl-2,3-dihydrobenzo[b]thienyl)-2-[2-(chlorophenyoxy)-ethylaminol-1-propanol To 0,15 M of aluminum chloride, 0,11 M of propionyl chloride and 150 ml of 1,2-dichloroethylene, 0,1 M of 2-methyl 2,3-dihydrobenzo[b]-thiophene (prepared -according to method of Petropoulos, J. Am. Chem. Soc., 75, 1130, 1953) are added slowly, temperature being maintained at +100C. After addition, the mixture is still stirred for 3 hours at room temperature, then a mixture of ice and HCl is added.

The mixture is extracted with 1,20-dichloroethylene, dried on MgSO4 and solvent is evaporated. The oily residue is stripped in vacuum. 14 gr. of 5-propionyl-2-methyl2,3-dihydrobenzo[b]thiophene are so obtained.

BP (0,2 mm): 110115 Yield: 70%.

The NMR spectrum is conform to the structure. b) To 7 gr. of the preceding product dissolved in 100 ml of anhydrous THF, 1,8 ml of bromine are added dropwise while stirring and maintaining the temperature at about 10"C. After addition, the mixture is still stirred for 1 hour at room temperature, then an aqueous NaRCO3 solution is added. The organic phase is separated, dried and evaporated. 8,5 gr. of 5-(a-bromopropionyl)-2-methyl-2,3- dihydrobenzo[b]thiophene are obtained.

MP (OC): 52-54 Yield: 88% The NMR spectrum is conform to the structure and the product appears to be homogeneous in TLC (silica gel-C8H8). c) 16 gr. of the preceding product, 12 gr. of a-(p-chlorophenoxy)-ethylamine and 200 ml of ethanol are refluxed for 3 hours. The solution is cooled to +5 C and 5 gr. of NaB H4 are added slowly. After addition, the mixture is still stirred for 2 to 3 hours at room temperature, solvent is evaporated and the residue is extracted with CHCl3. The organic phase is dried on MgSO4, filtered, evaporated and the so obtained residue is recrystallized from acetone. 5,5 gr. of products are so obtained.

MP ("C): 108-109 Centesimal analysis: C H N % calculated 63,56 6,40 3,70 % found 63,70 6,45 3,85 The structure of the product is confirmed by mass, NMR and IR spectra.

Example 5.

I 3-rneth4-6-thiochromanyl)-242-(phenoxy)ethylamino]-1 -propanol a) To 0,13 M of AlCI3, 0,12 M of propionyl chloride in 150 ml of 1,2dichloroethylene, 0,1 M (16,4 gr.) of 3-methyl-thiochromane are dropwise addd at a temperature of #5 C. After agitating the mixture for 3 hours at room temperature, a mixture of ice and HCl is added and extraction is made with CHCl3. The organic phase is dried on MgSO4, filtered and evaporated. 17,3 gr. of 6propionyl-3-methyl thiochromane are so obtained, the homogeneity of which is verified by TLC and the structure of which is verified by NMR spectrum. b) To 22 gr. of the preceding product in 150 ml of THF, 5.2 ml of bromine are dropwise added while stirring at #5 C. The solution is treated according to the already described method. 26 gr. of 6-(&alpha;-bromopropionyl)-3-methyl thiochromane are obtained.

MP ( C): 60-63 (MeOH) Yield: 85% The NMR spectrum is conform to the structure. c) 11 gr. of the preceding product, 15 gr. of 2-phenoxyethylamine and 150 ml of ethanol are refluxed for 2 hours. The mixture is cooled to +5 C and 6 gr. of NaB H4 are slowly added. The solution is treated according to the already described method. After recrystallization from acetone, 5 gr. of product are obtained.

MP ( C): 85-87 Centesimal analysis: C H N % calculated 70,54 7,61 3,91 % found 70,42 7,60 3,90 The NMR, IR and mass spectra are conform to the structure.

Example 6.

1-(8-methyl-6-thiochromanyl)-2-n-octylamino-1-propanol a) 165 gr. of 8-methyl-thiochromane are treated with propionyl chloride in the presence of AICI3 in 1,2-dichloroethylene according to the method already described in the preceding examples. 107,4 gr. of product are so obtained.

BP: 140155 (0,50 mm). The product solidifies.

MP (PC): 48-51 Yield: 50% The NMR spectrum is conform to the structure. b) 107,4 gr. of the preceding product in 800 ml of THF are brominated with 25 ml of bromine according to the already described process. 91,7 gr. of 6-(a- bromopropionyl)-8-methyl-thiochromane are obtained.

MP ( C): 79-80 (Petroleum ether) Yield: 63%.

The NMR spectrum is conform to the structure. c) 2,0 gr. of the preceding product, 20 gr. of n-octylamine and 300 gr. of methanol are refluxed for 4 hours. The mixture is cooled to +0 C and 9,5 gr. of NaBH4 are slowly added. After usual treatment, 14 gr. of product are obtained.

MP ( C): 129-130 (CHCl3) Centesimal analysis: C H N % calculated 72,15 10,09 4,01 % found 72,05 9,75 3,85 The NMR, mass and IR spectra are conform to the structure.

Example 7.

1-(2-methyl-2,3-dihydro-5-benzo[b]furanyl-2-[4-(p-chlorophenyl)butylamino] I -propanol a) 100 gr. (0,75 mole) of 2-methyl-2,3-dihydrobenzo[b]furane are added at 10 C and while agitating to a mixture obtained by successive addition of 108 gr. (0,8 mole) of aluminum chloride and 71,6 gr. (0,75 mole) of propionyl chloride to 1000 ml of dichloromethane. At the end of the addition, agitation is continued for 3 hours at room temperature. The final medium is formed with caution on ice mixed with a little concentrated hydrochloric acid. The organic phase is decanted, dried then dry evaporated. The oily residue is distilled. 91,3 gr. (0,48 mole) of the ketonic derivative are collected.

BP: 119"C/0,5 Torr. The nuclear magnetic resonance spectrum is in agreement with structure. b) To a solution of 57 gr. (0,3 mole) or 2-methyl-5-propionyl-2,3dihydrobenzo[b]furane in 600 ml of diethyl ether, maintained at 10 C, a trace of benzoyl peroxide is added, then 47,9 gr. (0,3 mole) of bromine. The mixture is then stirred for 2 hours at room temperature. The final medium is washed with an aqueous 10% sodium hydrogen carbonate solution, with water. Then it is dried and dry evaporated. The solid residue is recrystallized from a 1:1 hexane/cyclohexane mixture. 67,3 gr. (0,25 mole, 83%) of brominated ketone are so obtained.

MP (OC): 79.6. The nuclear magnetic resonance spectrum is in agreement with the expected structure. c) A solution of 8,2 gr. (45 mmoles) of p-chlorophenylbutylamine in 100 ml of acetonitrile is stirred and refluxed. 12,4 gr. (90 mmoles) of potassium carbonate are added thereto, then over one hour a solution of 12 gr. (45 mmoles) of the preceding brominated ketone in 80 ml of acetonitrile. After the end of the addition, reflux is maintained for 1,5 hour. To the medium at room temperature, a solution of 1,8 gr.

(48 mmoles) of sodium borohydride in 10 ml of water basified with a drop of 40% aqueous NaOH is dropwise added. The solid is filtered and the filtrate is dry evaporated. The residue is a solid. The latter added to the first one is recrystallized from a 1:1 hexane/cyclohexane mixture. 5,1 gr. (14 mmoles, 31%) of a product are obtained, the melting point of which being 107,80C. The NMR spectrum confirms the expected structure.

Centesimal analysis: C H N Oo calculated 70,70 7,60 3,72 Ó found 70,40 7,60 3,60 Example 8.

I (2-metvl-6-thiochrnmanyl)-2-(4-phenyThutyiarnino )-1 -prnpanol a) 83 gr. (0,5 M) of 2-methyl-thiochromane are treated with 43,2 ml of propionyl chloride (0,5 M) in the presence of 73 gr. of AICI3 (0,55 M) in 750 ml of 1,2-dichloroethylene in the already described preceding examples. 62 gr. of 2methyl-6-propionyl-thiochromance are obtained.

MP ("C): 65-66 (petroleum ether) Yield: 58%. The NMR spectrum is conform to the structure. b) 64 gr. of the preceding product in 500 ml of absolute methanol are treated with 14,9 ml of bromine according to the already described process. 82 gr. of 6-(abromopropionyl)-2-methyl-thiochromane are obtained.

MP ("C): 78-79 Yield: 95%.The NMR spectrum is conform to the structure. c) 15 gr. of the preceding product, 9 gr. of 4-phenylbutylamine and 200 ml of methanol are refluxed for 4 hours. The mixture is cooled to +OOC and 4 gr. of NaBH4 are slowly added. After usual treatment and recrystallization from methanol, 6 gr. of I -(2-methyl-6-thiochromanyl)-2-(4-phenylbutylamino)- 1 - propanol are obtained.

MP ("C): 118-I 19. Yield: 35 Ó Centesimal analysis: C H N % calculated 74,74 8,45 3,79 % found 74,80 8,45 3,70 The NMR, mass and IR spectra are conform to the structure.

Example 9.

1-(2,3-dihydro-5-benzo[b]furanyl)-2-(4-phenylbutylamino)-1-propanol a) 8.8 gr of 2,3-dihydro-6-propionylbenzo[b]furane in 50 ml of anhydrous THF are treated with 2.6 ml of bromine according with already described process. The product so obtained is recrystallized from methanol; 8 gr of 6-(&alpha;-bromopropionyl- 2,3-dihydrobenzo[b]furane are obtained.

MP ( C): 65-66 Yield: 40% b) 10 gr. of the preceding product, 6 gr of 4-phenylbutylamine and 100 ml of methanol are refluxed for 3 hours. The mixture is cooled to #0 C and 4 gr of NaBH4 are slowly added. After usual treatment and recrystallization form acetone, 7.7 gr of product are obtained.

MP ( C): 131-133 Yield: 50% Centesimal analysis: C H N % calculated 77.49 8.36 4.30 % found 77.25 8.25 4.10 The NMR, mass and IR spectra are conform to the structure.

Example 10.

1 -[(2 3-aihydro 1,4-BenzodithEin)-6-yl]-2-(4-phenylbutylamino)-1-propanol a) To 0.12 M of aluminum chloride in 250 ml of 1.2-dichloroethylene, 0.12 M of propionyl chloride are addd, then slowly while agitating and at a temperature of # 15 C, 0,1 M of 2,3-dihydro-1,4-benzodithiin in 100 ml of 1,2-dichloroethylene.

After addition, the mixture is stirred for 1 hour at room temperature, then is decomposed with a mixture of ice and hydrochloric acid. After usual treatment, 12 gr of 6-propionyl-2,3-dihydro-1,4-benzodithiin are obtained.

BP: 145-150 (0.2 mm) Yield: 60% b) To 10 gr of the preceding product dissolved in 100 ml of anhydrous THF, 2.3 ml of bromine are dropwise added while stirring at a temperature of #10 C. After usual treatment, 11 gr of 6-(&alpha;-bromopropionyl)-2,3-dihydro-1,4-benzodithiin are obtained.

MP ( C): 72-73 Yield: 80% c) 10 gr of the preceding product, 100 ml of methanol and 10 gr of 4phenylbutylamine are refluxed for 3 hours. The solution is cooled to +500C and 7 gr of NaBH4 are added. Then the solvent is evaporated, the residue is diluted with water and extraction is made with chloroform. The organic phase is dried on MgSO4, filtered and evaporated. The solid so obtained is recrystallized from methanol, 7.5 gr of the final product are so obtained.

MP ( C): 138-140 Yield: 55% Centesimal analysis: C H N % calculated 67.50 7.28 3.75 % found 67.25 7.45 4.00 Example 11.

1-(2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1-propanol (threo form) 4 gr of 1-(2,3-dihydro-5-benzo[b]thienyl-2-bromo-1-propanol, 100 ml of ethanol and 20 gr of 4-phenylbutylamine are refluxed for 5 hours. The solvent and excess amine are evaporated in vacuo and the residue obtained is treated with ether. The solid is recrystallized from a mixture of methanol and ether, and the corresponding free base is obtained by treatment with a diluted NaOH solution and recrystallized from acetone. 1.05 gr of final product are so obtained.

MP ( C): 85-87 Centesimal analysis: C H N % calculated: 73.80 7.95 4.10 Ó found: 73.40 7.90 4.20 The threo configuration of the product is confirmed by examination of the NMR spectrum (JR1, 112 9 cps; H1 = 4.04 ppm: CDCL3 - 1% TMS).

Example 12.

1 -(5-indanyl)-2-(4-phenylbutylamino)-l -propanol a) To 17.4 gr of 5-propionylindane in 100 ml of anhydrous THF, 5.12 ml of bromine (at +10 C) are dropwise added. The mixture is then still stirred for 1 hour, at room temperature, then 100 ml of an aqueous NaRCO3 solution are added.

The separated organic phase is dried on MgSO4, filtered and evaporated. 13 gr of a fluid oil are so obtained, the homogeneity of which is verified in TLC and the structure of which is verified by NMR spectrum. b) 13 gr of the preceding product, 10 gr of 4-phenylbutylamine and 100 ml of methanol are refluxed for 3 hours. The solution is then cooled to +50C and then 6 gr. of NaBH4 are slowly added while stirring.

The solvent is evaporated, the mixture is diluted with H2O and extracted with CHCl3. The organic phase is dried, filtered, evaporated and the residue is recrystallized from acetone 4 gr of product are so obtained.

MP ( C): 108-110.

Centesimal analysis: C H N % calculated 81.65 9.05 4.35 %found 81.40 9.05 4.60 The structure of the product is confirmed by mass, NMR and IR spectra.

Example 13.

1-[6-(1,2,3,4-tetrahydronaphthyl)]-2-(4-phenylbutylamino)-1-propanol A mixture of 21.4 gr of 6-(2-bromopropionyl)-1,2,3,4-tetrahydronaphthalene (obtained by an acylation reaction of tetralin by means of 2-bromopropionyl bromide; MP ( C): 60.4 ), 15 gr of 4-phenylbutylamine and 100 ml of methanol are refluxed for 3 hours. To the solution cooled to # 5 C, 12 gr of NaBH4 are added.

The amino-alcohol is then isolated and purified as described in Example 12.

Weight: 5.3 gr. MP ( C): 99.7 .

Centesimal analysis C H N % calculated: 81.9 9.3 4.2 elo found: 81.7 9.3 3.9 The structure of the product is confirmed by mass, NMR and IR spectra.

Exmaple 14.

1-(2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1-propionyloxypropane A mixture comprising 7 ml (7.4 gr; 80 mmoles) of propionyl chloride, 10gr of 1 (2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1-propanol hydrochloride and 10 ml of toluene is heated for 3 hours at reflux temperature. The final medium is dry evaporated under reduced pressure and the residue is recrystallized from acetonitrile.

5.9 of final product are so obtained, the structure of which is confirmed by examination of NMR and IR spectra.

MP ("C): 169.9 Centesimal analysis: C H N % calculated: 66.40 7.40 3.10 Ó found: 66.54 7.60 3.40 Example 15.

15 gr of 1-(2.3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1-propanol are dissolved in 750 ml of toluene and 150 ml of chloroform, and a stream of dry gaseous HCI is bubbled therein for 2 hours. The mixture is then still stirred for 2 hours at room temperature, the precipitate so obtained is filtered, washed with icecooled pentane and dried. 15 gr of hydrochloride are so obtained.

MP ("C): 208-209.

Centesimal analysis: C H N % calculated: 66.72 7.40 3.70 % found: 66.70 7.50 3.65 Example 16.

16 gr of l-(6-thiochromanyl)-2-n-octylamino-l-propanol are dissolved in 600 ml of toluene and a stream of anhydrous HCI is passed through for 1.5 hours. The precipitate so obtained is filtered, washed with water-cooled pentane and dried. 17 gr of hydrochloride are obtained.

MP (OC): 227 Centesimal analysis: C H N % calculated: 64.60 9.15 3.77 % found: 64.60 9.15 3.65 Example 17.

2 gr of l-(6-thiochromanyl)-2-(4-phenylbutylamino)-l-propanol are dissolved in 100 ml of anhydrous ether. A stream of dry gaseous HCI is passed through for 15 minutes, the resulting precipitate is filtered and dried. 2.1 gr of hydrochloride are so obtained.

MP ("C): 204-205 Example 18.

28.0 gr (0.144 M) of D-glucuronic acid are dissolved in 340 ml of water heated to 50"C and 34.1 gr (0.1 M) of 1-(2.3-dihydro-5-benzo[b]thienyl)-2-(4- phenylbutylamino)-l-propanol are added portionwise with vigorous stirring.

Stirring is continued until dissolution is complete which requires about 20 minutes.

A clear solution which can be diluted at will with distilled water is so obtained.

The melting points of compounds described in Examples, as well as of other compounds prepared according to the invention are cited in following Table I.

Pharmacological results of a large number of compounds according to the invention are given in following Table II. The results given in Table II have to be interpreted in the following manner: (1) The acute toxicity was determined on fasted male mice. The tested substances were orally administered and LD50 values (lethal dose for 50 Ó of animals) were calculated according to the method of Litchfield and Wilcoxon (J.

Pharmacol. exp. Ther. 96, 94113, 1949). These LD50 values are given in mg/kg and also, when possible, with their confidence limits for p = 95%.

(2) The antihypertensive activity was measured on unanaesthetized, hypertension-suffering rat.

The tested substances were orally given at a rate of 60 mg/kg. The systolic arterial pressure was measured every 30 minutes for 2 hours before and for 3 hours after the tested product was given. Results are expressed as follows: 0 : no reduction of arterial pressure.

+ : reduction lower than 10 mm Hg.

++ : reduction of 10 to 20 mm Hg. t++ ++ : reduction higher than 20 mm Hg.

(3) The vasodilator activity was measured at the level of femoral artery on anaesthetized dog (technique of perfused paw). The tested substances were given intra-arterially at the rate of 30 mg/kg. Results are expressed with respect to papaverine tested at the same dose.

0 : no action.

+ : slight activity.

++ effect equal to half the effect of papaverine.

: : effect equal to that of papaverine.

++++ : effect higher than that of papaverine.

(4) The antispasmodic activity was measured in vitro, on guinea-pig ileum, the contractions of which were caused by histamine (Hist.), acetylcholine (Achol) or barium chloride (BaCI2). The tested products were added to perfusion bath 15 minutes before the spasm-inducing agents.

The dose is given in micrograms (ug) per ml of bath causing complete spasm inhibition.

In Table II the numbers given in column 1 correspond to numbers of column 1 in Table I. The same numbers concern the same compounds.

The products of the invention can be used in various forms.

Examples of Compositions.

The following Examples are no limitative and relate to galenic recipes containing, as active product designated by reference "A" hereinafter, one of the following compounds 1 -(2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)- I - propanol; 1 (64hiochromanyl)-2-(4-phenylbutylamino)- 1 -propanol; 1-(2,3,4,5- tetrahydrobenzo [b]thiepin-7-yl)-2-(4-phenylbutylamino)- 1 -propanol; 1 -(2,3 dihydro - 5 - benzo[blthienyl - 2 - (4 - phenylbutylamino) - 1 - cyclohexylcarbonyloxypropane.

Intramuscular injection A 100 mg Isopropyl myristate 0.75 ml Peanut oil q.s. 3 ml A 50 mg Ethyl alcohol 0.50 ml Polyethylene glycol 400 0.25 ml Propylene glycol 0.50 ml 10% acetic acid 1.125 ml 70% Sorbitol 0.75 ml Distilled water, q.s. 3 ml Solution for oral administration A 5 ml Ethyl alcohol 0.1 ml Propylene glycol 0.05 ml 10% acetic acid 0.05 ml Simple syrup (65 ó saccharose), q.s. I ml A 50 mgr Aerosil 2.5 mgr Corn starch 25 mgr Lecithin 1.5 mgr Methocel 2.5 mgr STA-RX 2 mgr Avicel 6 mgr A 50 mgr Corn starch 50 mgr Sodium acetate 15 mgr Magnesium stearate 2 mgr Aerosil 3 mgr Starch STA-RX 1500 80 mgr Capsules A 50 mgr Starch STA-RX 1500 94 mgr Magnesium stearate 1 mgr Sodium Lauryl sulfate 5 mgr A 50 mgr Microcrystalline cellulose 70 mgr Corn starch 30 mgr Peanut oil 0.01 mgr Sodium lauryl sulfate 5 mgr A 50 mgr Sodium lauryl sulfate 5 mgr Microcrystalline cellulose 70 mgr Magnesium oxide 20 mgr A 50 mgr Starch STA-RX 1500 100 mgr Magnesium stearate 1 mgr Sodium lauryl sulfate 10 mgr Microcrystalline cellulose 30 mgr Aerosil I mgr A 50 mgr Aerosil 2.5 mgr Corn starch 25 mgr Lecithin 1.5 mgr Methocel 2.5 mgr Soluble starch 13 mgr Tale 7 mgr Suppositories A 100 mgr Witepsol (triglycerides), q.s. 2.3 mgr A 100 mgr Syndermin GIC (triglycerides) 200 mgr Witepsol, q.s. 2.3 mgr A 100 mgr Polyethylene glycol 6000 1 mgr Polyethylene glycol 1540, q.s. 2.7 mgr A 100 mgr Peanut oil 1.5 mgr Soya lecithin 5 mgr 2-Octyldodecanol 5 mgr Gelatin-glycerin, q.s. for one capsule Tablets A 50 mgr Lactose 20 mgr Aerosil 2 mgr Starch STA-RX 1500 18 mgr Calcium phosphate (CaRPO4) 25 mgr Microcrystalline cellulose 100 mgr Sodium acetate 15 mgr A 50 mgr Microcrystalline cellulose 80 mgr Sodium acetate 25 mgr Auby-gel X 52 20 mgr Corn starch 50 mgr A 50 mgr Microcrystalline cellulose 100 mgr Starch STA-RX 1500 99 mgr Aerosil 1 mgr A 50 mgr Aerosil 2.5 mgr Corn starch 25 mgr Lecithin 1.5 mgr Methocel 2.5 mgr STA-RX 2 mgr Avicel 6 mgr A 50 mgr Corn starch 50 mgr Sodium acetate 15 mgr Magnesium stearate 2 mgr Aerosil 3 mgr Starch STA-RX 1500 80 mgr Aerosil, Methocel, Avicel, Witepsol, and Syndermin are Registered Trade Marks.

Amongst the products of the invention, the compounds having an antihypertensive activity can be used by humans, orally at daily doses of 50 to 3000 mgr.

On various studied animal species, the secondary effects which were observed for these compounds, were characterised by sedation. The latter is obtained with substantially higher doses than therapeutical doses. The ratio between active dose and sedative does is strongly in favour of the products of the invention with respect to those ratios observed for refercncce products such as a-methyldopa and propanolol.

H3 -NHnC8H17 H H 115-116 (acetone H3 -NH-(CH2)4-# H H 131-133 (acetone H3 -NHnC8H17 H H 118-120 (acetone H3 -NHnC8H17 H H 116-117 (CH3OH) H3 -NH-(CH2)4-# H H 118-119 (CH3OH) H3 -NH-(CH2)2-# H H 134-137 (acetone H3 -NH-(CH2)4-# H H 113-115 (acetone H3 -NH-(CH2)5-# H H 119-120 (CH3OH) H3 -NH-(CH2)2-# H H 125-126 (CH3OH) # U U ú U U U U U 1 S CH2 2 H 2 S CH2 2 H 3 S CH2 1 H 4 S CH2 2 2CH3 5 S CH2 2 2CH3 6 S CH2 1 H 7 S CH2 1 H 8 S CH2 2 H 9 S CH2 2 2CH3 R3 R1 R2 -N R5 R4 2CH3 CH3 N N # H CH3 H CH3 -NHnC8H17 H H CH3 -NH-(CH2)4-# H H CH3 -NH-(CH2)2-# H H CH3 -NH-(CH2)2-# H H CH3 -N N # H CH3 # H CH3 -NH-(CH2)2-CH H # H CH3 -NH-(CH2)3-# H R3 @(1) (4) N X Y n R1 R2 -N R5 R6 MP ( C) R4 19 S CH2 @ 2CH3 CH3 -NH-(CH2)4-# H H 89-90 (MeOH) 20 S CH2 2 H CH3 -NH-CH2CH2-O-# H H 117-118 (acetone) # 21 S CH2 2 H CH3 -NHCH2CH H H 119-121 (CH3OH) # 22 S CH2 2 H CH3 -NHCH2CH2#OCHE H H 131-133 (acetone) OCH3 23 5 CH2 2 H CH3 -NH-(CH2)4-#-Cl H H 106-107 (acetone) 24 S CH2 2 H CH3 -NH-(CH2)4O-# H H 141-144 (AcOEt) 25 S CH2 2 H CH3 -NH-(CH2)4S-# H H 141-142 (CHCl3) 26 S CH2 2 H CH3 -N#CH2-# H H 126-127 (acetone) 27 S CH2 2 H CH3 -NHcycloC8H15 H H 88-89 (C6H6 - Petroleum ether 19 S CH2 1 H CH3 -NH-(CH2)4-#-Cl H H 120-122 (acetone) 30 S CH2 3 H CH3 -NH (CH2)4#-CH3 H H 90-92 (acetone) 31 S CH2 1 H CH3 -NH-(CH2)4S-# H H 146-148 (MeOH-CH@ 32 S CH2 1 H CH3 NH-(CH2)4-#-CH3 H H 128-130 (MeOH) 33 S CH2 1 H CH3 -NHisoC3H7 H H 127-129 (acetone) 34 S CH2 2 H CH3 -NH-(CH2)4-#-CH3 H H 126-127 (MeOH-CH@ 35 O CH2 1 H CH3 -NH-(CH2)4-# H H 131-133 (acetone) 36 S CH2 3 H CH3 -NH-(CH2)2O-# H H 90-92 (MeOH) 37 S CH2 2 H CH3 NH-(CH2)3S-# H H 95-96 (acetone) R3 (1) (4) N X Y n R1 R2 -N R5 R6 MP ( C) R4 38 S CH2 3 H CH3 -NHisoC3H7 H H 107-109 (acetone) 39 S CH2 3 H CH3 -NH-(CH2)3S-# H H 102-104 (acetone) 40 S CH2 2 H CH3 -NH-(CH2)2O#-Cl H H 123-124 (acetone) 41 S CH2 2 H CH3 -NH-# H H 97-98 (hexane-Et2O) 42 S CH2 2 H CH3 -NHCH-(CH2)3-# H H 94-95 (Et2O) CH3 43 S CH2 2 3CH3 CH3 -NHnC8H17 H H 70-72 (acetone) CH3 (2) 44 S CH2 2 H CH3 NH-C-C#CH H H 226-227 (Et2O-MeOH) CH3 45 S CH2 2 3CH3 CH3 -NH (CH2)4-# H H 108-110 (acetone) 46 S CH2 2 H CH3 -NH-(CH2)2OCH2-# H H 96-98 (acetone) 47 S CH2 1 H CH3 -NH-(CH2)2O-# H H 131-132 (acetone) R3 (1) (4) R1 R2 -N R5 R6 MP ( C) R4 3CH3 CH3 -NH-(CH2)3-# H H 100-102 (acetone) 3CH3 CH3 -NH-(CH2)2O-# H H 85-87 (acetone) H CH3 -NH(CH2)3O(CH2)3CH3 H 89,0 (hexane) H CH3 -NHcycloC3H5 H H 96-97 (acetone) H CH3 -NHadamantyl-(1) H H 114-115 (acetone) H CH3 -NH-(CH2)2O-#-OCH3 H H 109-110 (acetone) H CH3 -NH-(CH2)2O-#-CH3 H H 132-133 (acetone) 2CH3 CH3 -NHnC8H17 H H 94,5 (acétonitrile) H CH3 -NH-(CH2)3-# H H 101-102 (acetone) R3 (1) (4) N X Y n R1 R2 -N R5 R6 MP ( C) R4 58 S CH2 1 2CH3 CH3 NH-(CH2)2O#-Cl H H 108-109 (acetone) (3) 59 S CH2 2 H CH3 -NH-(CH2)3N# H H 258,5 (MeOH-Et2O) 60 S CH2 1 H CH3 -NH-(CH2)3S-# H H 109-110 (acetone) 61 S CH2 1 2CH3 CH3 -NH-(CH2)2O-# H H 109-111 (MeOH) (3) 62 O CH2 1 2CH3 CH3 -NH-(CH2)3-N# H H 250,8 (EtOH) (2) 63 S CH2 1 H CH3 -NHCH(CH2)3-# H H 175-178 (MeOH-Et2O) CH3 (2) 64 S CH2 1 2CH3 CH3 -NH-(CH2)3O-# H H 177-179 (MeOH-Et2O) 65 O CH2 1 2CH3 CH3 -NH-(CH2)4-#-Cl H H 107,8 (cyclohexane) R3 (1) (4) X Y n R1 R2 -N R5 R6 MP ( C) R4 S CH2 1 2CH3 CH3 -NH-(CH2)2O-#-OCH3 H H 121-122 (acetone) S CH2 1 2CH3 CH3 -NH-(CH2)3-# H H 85-87 (Et2O) S CH2 1 2CH3 CH3 -NH-(CH2)4-#-Cl H H 88-90 (Et2O) O CH2 1 2CH3 CH3 -NH-(CH2)3-# H H 96,9 (isoPrOH-hxar (ne) O CH2 1 2CH3 CH3 -NH-(CH2)4-# H H 110,7 (cyclohexane) S CH2 1 2CH3 CH3 -NH-(CH2)4-#-CH3 H H 86-88 (acetone) S CH2 2 H CH3 -NH-9CH2)3O(CH2)2OnC4H9 H H 82,0 (pentane-cyclo (hexane) S CH2 2 H CH3 -NH-(CH2)IOCOOCH3 H H 108-109 (MeOH) (2) O CH2 1 2CH3 CH3 -NH-(CH2)3O-(CH2)3CH3 H H 152,3 (C6H6-cyclohexane) TABLE I (Cont. 8) R3 (1) (4) N X Y n R1 R2 -N R5 R6 MP ( C) R4 75 S CH2 2 H CH3 -NH-(CH2)3O-# H H 113-114 (acetone) 76 S CH2 2 H CH3 -NHnC14H29 H H 110-112 (MeOH) 77 S CH2 2 H CH3 -NH-(CH2)3-N# H H 102-104 (acetone) O 78 S CH2 2 H CH3 -NH-(CH2)3-#-Cl H H 84-86 (acetone) 79 S CH2 1 2CH3 CH3 -NH-(CH2)2O-#-CH3 H H 129-130 (acetone) 80 S CH2 2 H CH3 -NH-(CH2)3S(CH2)3CH3 H H 93,6 (hexane) 81 S CH2 2 H CH3 -NH-(CH2)3O(CH2)2OCH3 H H 79,0 (cyclohexane) TABLE I (Cont. 9) R3 N X Y n R1 R2 -N R4 82 O CH2 1 2CH3 CH3 -NHCH(CH2)3-# CH3 83 S CH2 2 H CH3 -NH-(CH2)2O-# 84 O CH2 1 2CH3 CH3 -NH-(CH2)2O-# 85 S CH2 1 H CH3 -NH-(CH2)2O-# 86 S CH2 1 H CH3 -NH-(CH2)2O-# 87 S CH2 2 H CH3 -NH-(CH2)2O-# 88 S CH2 2 H CH3 -NH-(CH2)2O-# R3 (1) (4) N X Y n R1 R2 -N R5 R6 MP ( C) R4 89 O CH2 1 2CH3 CH3 -NH-(CH2)2O-# H H 99,1 (cyclohexane) 90 O CH2 1 2CH3 CH3 -NH-(CH2)4-#-CH3 H H 108,9 (cyclohexane) 91 S CH2 2 H CH3 -N#-# H H 116,1 (cyclohexane) 92 S CH2 1 H CH3 -NH-(CH2)9-CH=CH2 H H 107-109 (méthanol) 93 S CH2 2 H CH3 -NHnC8H17 8CH3 H 129-130 (CHCl3) 94 S CH2 2 H CH3 -NH(CH2)4-# 8CH3 H 131-132 (CHCl3) 95 S CH2 2 H CH3 -NH(CH2) 2O-# 8CH3 H 136-137 (CHCl3-Et2O 96 S CH2 2 H CH3 -NH(CH2)3S-# 8CH3 H 121-122 (CHCl3-Et2O TABLE I (Cont. II) R3 (1) (4) N X Y n R1 R2 -N R5 R6 MP ( C) R4 (5) 97 S CH2 1 H CH3 -NHnC8H17 H H 81-83 (acetone) 98 S CH2 1 H CH3 -NH(CH2)4-# H H 85-87 (acetone) (5) (2) 99 S CH2 1 H CH3 -NH(CH2)4-# H COC(CH3)3 177-179 (isoPrOH) 100 S S 2 H CH3 -NH(CH2)4-# H H 138-140 (MeOH) 101 S S 2 H CH3 -NHnC8H17 H H 108-109 (acetone) (2) 102 S CH2 2 H CH3 -NH(CH2)3CO-#-F H H 181,6 (MeOH/isoPrOH) 103 S CH2 1 H CH3 -NH(CH2)2O-#-NMSO2CH3 H H 160-161 (MeOH) 104 S S 2 H CH3 -NH(CH2)2O-# H H 130-132 (CHCl3) (2) 105 O CH2 1 2CH3 CH3 -NH(CH2)3CO-#-F H H 184,9 (MeOH/isoPrOH) TABLE I (Cont. 12) R3 (1) (4) N X Y n R1 R2 -N R5 R6 MP ( C) R4 107 S CH2 2 H CH3 -NH(CH2)2O-#-C(CH3)3 H H 138,0 (hexane) (2) 108 S CH2 1 H CH3 -NH(CH2)2O-#-CCC2H5 H H 176-177 (MeOH-Et2O) 109 S CH2 1 3CH3 CH3 -NH(CH2)4-# H H 102-103 (MeOH) 110 S CH2 2 H CH3 -N#O H H 200,3 (MeOH/AcOEt) CH3 C6H5 (2) 111 S CH2 1 H CH3 -NH(CH2)3CO-#-F H H 178-179 (MeOH) (2) 112 S CH2 1 H CH3 -NH(CH2)4-# H COCH3 159,1 (acetonitrile) (5)(2) 113 S CH2 1 H CH3 -NH(CH2)4-# H COCH3 179,1 (MeOH/Et2O) 114 S CH2 2 H CH3 -NH(CH2)2O-#-COOCH3 H H 113-115 (acetone) 115 S CH2 1 H C2H5 -NH(CH2)4-# H H 72-73 (MeOH) (2) 116 S CH2 1 2CH3 CH3 -NH(CH2)2O-#-COC2H5 H H 191-192 (MeOH-Et2O) (aceton@ (aceton@ (MeOH) 15 (MeOH@ 72 (MeO@ (MeOH) 18 (MeO@ (2) 125 S CH2 1 H CH3 -NH(CH2)3S nC4H9 H H 196,2 (acetonitrile/ (EtOH) 126 S CH2 1 H C2H5 -NH(CH2)2O-# H H 86-88 (acetone) (5) 127 S CH2 2 H CH3 -NHnC8H17 H H 52-53 (hexane) (2) 128 S CH2 2 H C2H5 -NHnC8H17 H H 167-168(Et2O-MeOH) (2) 129 S CH2 I H CH3 -NH(CH2)3O(CH2)2OCH3 H H 152,2 (acetonitrile) (2) 130 S CH2 1 H CH3 -NH(CH2)4-# H COnC3H7 151,4 (acetonitrile) (2) 131 S CH2 2 H CH3 -NHnC8H17 H COC2H5 139,4 (AcOEt) (2) 132 S CH2 1 H CH3 -NH(CH2)4-# H COcyclo- 131,7 (AcOEt) C4H7 (2) 133 S CH2 1 H CH3 -NH(CH2)4-# H COnC7H15 145,2 (acetonitrile/ isoPrOH) R3 (1) (4) N X Y n R1 R2 -N R5 R6 MP ( C) R4 (2) 134 5 CH2 2 H CH3 -NHnC8H17 H COnC3H7 156,2 (AcOEt) 135 S CH2 2 H C2H5 -NH(CH2)4-# H H 72-73 (MeOH) (2) 136 S CH2 2 H CH3 -NHnC8H17 H COnC7H15 151,5 (AcOEt) (2) 137 S CH2 I H CH3 -NH(CH2)4-# H COcyclo- 158-160 (AcOEt) C5H9 (2) 138 S CH2 I H CH3 -NH(CH2)4-# H COcyclc- 148-150 (acetonitrile C6H11 (2) 139 S CH2 2 H CH3 -NHnC8H17 H COCH(CH3)2 126,6 (AcOEt) (2) 140 S CH2 2 H CH3 -NHnC8H17 H COCH3 148,5 (AcOEt) 141 S CH2 2 H CH3 -NH(CH2)8CH=CH-nC8H17 H H 97-98 (acetone) (2) 142 S CH2 2 H CH3 -NHnC8H17 H COcyclo- 156,5 (AcOEt) C@H@ TABLE I (Cont. 16) R3 (1) (4) N X Y n R1 R2 -N R5 R6 MP ( C) R4 143 S CH2 2 H CH3 -NHCH2CH=C-(CH2)2CH= H H 75-77 (Et2O) CH3 C(CH3)2 (2) 144 S CH2 2 H CH3 -NHnC8H17 H COC(CH3)3 149,4 (AcOEt) (2) 145 S CH2 2 H CH3 -NHnC8H17 H COcyclo- 144,6 (AcOEt) C4H7 (2) 146 S CH2 2 H CH3 -NHnC8H17 H COcyclo- 182,9 (AcOEt) C6H11 147 S CH2 2 H CH3 -NHnC18H37 H H 122-123 (CHCl3) Cl 148 S CH2 1 H CH3 -NH(CH2)2O-#-Cl H H 118,1 (isoPrOH-hexane) 149 S CH2 2 H CH3 -NHnC12H25 H H 93-101 (MeOH-CHCl3) (2) 150 S CH2 3 H CH3 -NH(CH2)4-# H COC2H5 150-152 (MeOH-Et2O) R3 -N R5 CH3 -NH-(CH2)3O-C-C#CH H CH3 -NH-(CH2)6C#CH H -NH-(CH2)4-# H -NHnC8H17 H -NH-(CH2)6C#CH H CH3 -NH-(CH2-CH=C-CH2)2-CH2-CH=C CH3 CH3 -NH-(CH2)4-# H -NH-(CH2)2O-# H -NH-(CH2)2O-# H -NH-(CH2)4-# H R3 (1) (4) N X Y n R1 R2 -N R5 R6 MP ( C) R4 161 S CH2 2 2 COOH CH3 -NH-nC8H17 H H 125-127 (MeOH-Et2O) 152 S CH2 2 H CH3 -NH-(CH2)6-C# C-nC4H9 H H 86-88 (MeOH) 163 CH2 CH2 1 H CH3 -NH-(CH2)4-# H H 108-110 (acetone) 164 CH2 CH2 1 H CH3 -NHnC8H17 H H 98-100 (acetone) 165 CH2 CH2 1 H CH3 -NH-(CH2)3-# H H 111,9 (acetonitrile) 166 CH2 CH2 1 H CH3 -NH-(CH2)4-#-CH3 H H 126,6 (hexane) 167 CH2 CH2 1 H CH3 -NH-(CH2)4-#-Cl H H 109-110 (acetone) 168 CH2 CH2 1 H CH3 -NH-(CH2)2O-# H H 122,2 (hexane) 169 CH2 CH2 1 H CH3 -NH-(CH2)2O-#-Cl H H 132,4 (acetone) 170 CH2 CH2 2 H CH3 -NHnC8H17 H H 97,2 (acetone) 171 CH2 CH2 2 H CH3 -NH-(CH2)4-# H H 99,7 172 CH2 CH2 1 H CH3 -N#-CH2-# H H 112,9 (acetone) R3 (1) (4) N X Y n R1 R2 -N R5 R6 MP ( C) R4 (2) 173 CH2 CH2 1 H CH3 -NH-CH-(CH2)3-# H H 213 (isoPrOH) CH3 (2) 174 CH2 CH2 1 H CH3 -N#-# H H 210,8 (isoPrOH) (2) 175 CH2 CH2 1 H CH3 -NH(CH2)3CO-#-F H H 180,7 (MeOH/isoPrOH) 176 CH2 CH2 1 H CH3 -NH(CH2)2O-#-C(CH3)3 H H 102,2 (hexane) CH3 C6H5 (2) 177 CH2 CH2 1 H CH3 -N#O H H 177,1 (MeOH/AcOEt) 178 CH2 CH2 1 H CH3 -NH(CH2)3SnC4H9 H H 82,1 (acetone) (2) 179 CH2 CH2 1 H CH3 -NH(CH2)3O(CH2)2OCH3 H H 134,9 (benzene cyclohexane) (2) 180 CH2 CH2 1 H CH3 -NH(CH2)2O-# H COCH3 129-131 (acetonitrile) 181 CH2 CH2 1 H CH3 -NH(CH2)4-# H CO(CH2)6CH3 oil (2)(5) 182 CH2 CH2 1 H CH3 -NH(CH2)2O-# H COCH3 140-141 (acetonitrile (I) The recrystallization solvent is given between brackets; the melting point mentioned is that of the free base, unless contrary mention. The melting points were taken with a TOTTOLI apparatus or a METTLER FP5 apparatus.

(2) Melting point of the hydrochloride.

(3) Melting point of the dihydrochloride.

(4) The elemental analyses were made for elements C, H, N and conform to the theoretical values.

(5) Threo form.

Mettler is a Registered Trade Mark.

ANTIHYPERTENSIVE VASODILATOR N ACUTE TOXICITY (1) ACTIVITY (2) ACTIVITY (3) HIST. ACHOL. BaCl2 1 > 4000 ++ ++++ 3.3 3.3 1.7 2 > 4000 +++ ++++ 1.7 8.3 16.7 3 4450 (3903-5073) +++ +++ 8.3 16.7 8.3 4 4000 (3138-4280) 0 +++ > 16.7 5 3600 (3068-4212) ++ ++++ 3.3 6 500 + +++ 3.3 7 860 (754-980) +++ ++++ 1.7 1.7 8 0 ++++ 0.8 1.7 0.8 9 #2750 0 +++ 3.3 3.3 0.8 10 > 4000 +++ ++ 0.33 16.7 8.3 11 3300 (3133-3498) +# +++ 0.8 1.7 3.3 12 5200 (2789-10880) +++ ++++ 0.33 0.8 0.8 13 0 ++ 3.3 0.8 3.3 14 0 +++ 1.7 3.3 1.7 15 +++ +++ 0.8 3.3 -16.7 16 @4000 ++ +++ 0.3 0.8 0.33 ANTIHYPERTENSIVE VASODILATOR N ACUTE TOXICITY (1) ACTIVITY (2) ACTIVITY (3) HIST. ACHOL.

17 > 4000 +++ +++ 0.8 1.7 18 3350 (2233-5025) +++ ++++ 0.8 0.33 19 1550 (1130-2108) +++ +++ 0.8 1.7 20 > 4000 +++ +++ 8.3 3.3 21 0 +++ 0.33 0.33 22 3700 (3458-3959) 0 3.3 8.3 23 # 2100 +++ ++++ 0.8 1.7 24 > 4000 0 +++ 0.33 1.7 25 @4000 0 0.8 0.8 26 +++ 0.017 1.7 27 0 ++ 1.7 1.7 28 580 (411-818) 0 + 0.8 1.7 29 1750 (1336-2292) +++ ++ 1.7 1.7 30 +++ +++ 1.7 0.8 31 > 4000 0 0.17 1.7 ANTIHYPERTENSIVE VASODILATOR ACUTE TOXICITY (1) ACTIVITY (2) ACTIVITY (3) 4000 (3419-4680) +++ 355 (317-398) 0 +++ #4000 +++ +++ 430 (187-989) +++ ++ @4000 +++ +++ @4000 +++ +++ 240 (210-274) @40000 ++ +++ > 4000 +++ +++ 0 +++ +++ 3300(2062-5280) 0 +++ +++ ++ @4000 + +++ 4000 (3418-4680) 0 +++ @4000 ++ ++++ ANTIHYPERTENSIVE VASODILATOR N ACUTE TOXICITY (1) ACTIVITY (2) ACTIVITY (3) HIST. ACHOL.

48 > 4000 +# 0.8 1.7 49 # 3700 +++ +++ 3.3 1.7 50 900 (818-990) 0 +++ 1.7 1.7 51 0 ++ 8.3 16.7 52 0 +++ 1.7 1.7 53 > 4000 0 +++ 3.3 1.7 54 4000 ++ +++ 3.3 3.3 55 350 (226-543) +++ +++ 3.3 8.3 56 0 ++ -16.7 -16.7 57 @2000 ++ +++ 1.7 1.7 58 @4000 +++ +++ 1.7 1.7 59 1125 (986-1282) 0 +++ 3.3 3.3 60 2000 +++ +++ 3.3 1.7 61 # 4000 +++ ++ 3.3 3.3 62 885 (799-991) 0 0 -16.7 -16.7 63 1850 (1480-2312) +# ++ 0.8 0.8 ANTIHYPERTENSIVE VASODILATOR N ACUTE TOXICITY (1) ACTIVITY (2) ACTIVITY (3) HIST. ACHOL.

64 +++ +++ 1.7 1.7 65 160 (124-206) +++ +++ 0.8 1.7 66 0 ++ 1.7 3.3 67 +++ +++ 1.7 1.7 68 @500 +++ +++ 3.3 0.8 69 +++ ++ 8.3 16.7 70 285 (247-327) +++ ++ 1.7 1.7 71 +++ +++ 0.8 0.8 72 880 (628-1232) 0 ++ 1.7 1.7 73 > 4000 0 +++ 3.3 1.7 74 + ++ 8.3 8.3 75 @4000 +++ +++ 0.8 1.7 76 @4000 + 77 235 (97-564) 0 0 0.8 1.7 78 725 (671-783) +++ ++++ 0.8 1.7 79 0 1.7 0.8 ANTIHYPERTENSIVE VASODILATOR N ACUTE TOXICITY (1) ACTIVITY (2) ACTIVITY (3) HIST. ACHOL.

80 5000(4065-6150) +++ ++ 0.8 1.7 81 +++ ++ 16.7 16.7 82 0 ++ 0.3 1.7 83 > 4000 0 +++ 1.7 0.8 84 1200 (952-1518) +++ +++ 8.3 3.3 85 +++ +++ 8.3 16.7 86 1425 (1319-1539) +# +++ 1.7 16.7 87 0 +++ 8.3 16.7 88 > 4000 0 +++ 1.7 1.7 89 550 (500-605) +++ +++ 8.3 8.3 90 +++ ++++ 0.8 1.7 91 +# +++ 0.8 1.7 92 > 4000 ++ 16.7 16.7 93 > 4000 0 0.8 0.8 94 > 4000 +++ +++ 0.8 0.8 95 > 4000 +++ ANTIHYPERTENSIVE VASODILATOR N ACUTE TOXICITY (1) ACTIVITY (2) ACTIVITY (3) HIST. ACHOL.

96 > 4000 +++ 0.8 1.7 97 # 98 + 99 0 8.3 1.7 100 > 2000 +++ ++++ 8.3 1.7 101 ++ +++ 0.8 0.8 102 > 4000 +++ +++ 0.8 0.3 103 0 3.3 16.7 104 4000 +++ 8.3 16.7 105 # 360 +++ +++ 3.3 3.3 106 @4000 ++ +++ 1.7 1.7 107 @4000 0 +++ 0.8 0.8 108 > 4000 ++ +++ 0.8 3.3 109 # 2750 +++ +++ 0.17 0.8 110 + 0 0.8 3.3 111 # 700 ++ +++ 0.3 0.8 ANTIHYPERTENSIVE VASODILATOR N ACUTE TOXICITY (1) ACTIVITY (2) ACTIVITY (3) HIST.

112 +++ +++ 0.3 113 + 114 2000 0 +++ 0.8 115 # 2500 +++ +++ 0.8 116 > 4000 ++ ++ 0.17 117 2200 (294-3740) +++ ++++ 1.7 118 2020 (1897-2151) +++ ++ 0.8 119 1800 (1171-2790) 0 ++++ 0.3 120 # 1450 ++ +++ 0.8 121 0 +++ 0.8 122 1650 (1375-1980) +++ ++++ 0.3 123 > 4000 +++ ++++ 0.8 124 0 ++ 1.7 125 3400 (3063-3774) 0 ++ 1.7 126 > 4000 +++ 127 0 ANTIHYPERTENSIVE VASODILATOR N ACUTE TOXICITY (1) ACTIVITY (2) ACTIVITY (3) 128 4000 129 250 (176-355) +++ 130 3700 (2242-6105) +++ 131 > 4000 + 132 1900 (1496-2413) +++ 133 2600 (1926-3510) +++ 134 > 4000 +++ 135 > 4000 +++ 136 > 4000 0 137 # 1750 +++ 138 > 4000 +++ ACTIVITY ANTIHYPERTENSIVE VASODILATOR N ACUTE TOXICITY (1) ACTIVITY (2) ACTIVITY (30 HIST. ACHOL 164 1750 (1129-2713) ++ +++ 0.8 0.8 165 3800 (3699-3914) +++ +++ 1.7 1.7 166 ++ +++ 0.8 0.8 167 # 270 +++ +++ 0.8 0.8 168 > 2000 +++ +++ 3.3 3.3 169 > 4000 +++ +++ 3.3 0.8 170 # 2300 0 +++ 1.7 0.8 171 + +++ 0.8 0.8 172 1900 (1310-2755) +++ +++ 0.08 1.7 173 2600 (1838-3692) 0 ++ 0.8 0.8 174 2150 (1720-2687) +# +++ 0.8 175 +++ ++ 0.8 0.8 176 > 4000 0 +++ 0.17 0.8 177 ++ # 1.7 1.7

Claims (42)

WHAT WE CLAIM IS:

1. An amino-alcohol derivative having the formula: R1 5 (cX ly I R (I) 3 OR6 4 wherein: (a) R, represents hydrogen, one or two linear or branched C, to C3 alkyl radicals, a phenyl radical or a carboxy radical; (b) R2 is a linear or branched C, to C3 alkyl radical; (c) R3 is: -a mono or polyunsaturated C3 to C,8 alkenyl radical; -a mono or polyunsaturated C3 to C,2 alkenyl radical substituted by phenyl and/or containing an oxygen or sulfur linkage; -a mono or polyunsaturated C3 to C,8 alkynyl radical; -a mono or polyunsaturated C3 to C,2 alkynyl radical substituted by phenyl and/or containing an oxygen or sulfur linkage; -a cycloalkyl C3 to C10 radical; -a C2 to C20 linear or branched alkyl radical; -a linear or branched C2 to C,8 alkyl radical; containing at least one oxygen or sulfur linkage and/or substituted with one or more C, to C3 alkoxycarbonyl, pyrrolidine, pyrrolidinone, imidazolidone, phenyl, phenoxy, phenylthio, benzoyl, indanyloxy, naphthyloxy, or phenyl, phenoxy, phenylthio or benzoyl radicals substituted by one or more C, to C4 alkyl or C, to C4 alkoxy radicals, by one or two halogen atoms, or by a nitrile, hydroxy, amino, C2 to C6 alkylcarbonyl, C2 to C4 acylamino, C2 to C8 alkoxycarbonyl, or C, to C4 alkylsulfonamido radical, or by an alkoxycarbonyl alkyl in which both the alkoxy and alkyl moieties contain from 1 to 4 carbon atoms, or alkoxycarbonyl alkoxy in which each alkoxy moiety contains from 1 to 4 carbon atoms, or is in accordance with the definition of R4 below; (d) R4 is hydrogen or when taken with R3 and the adjacent nitrogen atom, forms a morpholine, pyrrolidine, piperidine radical or a piperidine radical substituted by one or two C, to C4 alkyl, phenyl or phenylalkyl (C, to C4) radicals, or a piperazine radical substituted in position 4 by a phenyl radical or by a phenyl radical itself substituted by one or two (C, to C4) alkyl or C, to C4 alkoxy radicals, one or two halogen atoms, or a trifluoromethyl radical; (e) R8 is a hydrogen, halogen, or a C, to C3 alkyl radical; (f) R8 is a hydrogen or a linear or branched C2 to C" alkylcarbonyl radical or a C3 to C8 cycloalkyl carbonyl radical;, (g) n is 1, 2 or 3; (h) X is sulfur, oxygen, a CH2 radical or a NH radical' (i) Y is CH2 radical or sulfur provided that when simultaneously X is oxygen, Y is a CH2 group, n is 2, R1 and R8 are hydrogen, R2 is methyl and R8 is hydrogen or an alkylcarbonyl radical, R4 does not form a substituted piperazine radical with R3 and the adjacent nitrogen atom.

2. A derivative as claimed in claim 1, wherein R, is hydrogen or methyl.

3. A derivative as claimed in claim 1 or claim 2, wherein R2 is methyl or ethyl.

4. A derivative as claimed in any preceding claim wherein R3 is a linear or branched C2 to C,8 alkyl radical or a linear or branched C2 to C8 alkyl radical substituted by a phenyl, phenoxy, phenylthio, or benzoyl, group each being optionally substituted by one halogen atom or methyl group.

5. A derivative as claimed in any preceding claim, wherein R3 is a C4 to C,4 alkynyl radical or a C3 to C,8 alkyl radical, a C3 to C,8 alkenyl radical, a C5 to C8 cycloalkyl radical, or a C2 to C10 alkyl radical substituted as defined in claim 1.

6. A derivative as claimed in any preceding claim, wherein R4 when taken with R3 and the adjacent nitrogen atom forms a piperazine radical substituted by a phenyl radical which is in turn substituted by a C, to C3 alkyl radical or a piperidine radical substituted by a C, to C3 alkyl radical which is itself substituted by a phenyl radical.

7. A derivative as claimed in any preceding claim, wherein R6 is a hydrogen or C2 to C6 alkylcarbonyl radical or a C3 to C8 cycloalkylcarbonyl radical.

8. A derivative as claimed in claim 7, wherein Ra is a C3 to C4 alkylcarbonyl radical.

9. A derivative as claimed in claim 8, wherein Ra is a propylcarbonyl or cyclohexylcarbonyl radical.

10. A derivative as claimed in any preceding claim wherein n is 2.

11. A derivative as claimed in any preceding claim wherein any halogen atoms present are chlorine or fluorine.

12. A derivative as claimed in claim 1, wherein R, is hydrogen, R3 is methyl, R3 is a n-octyl, phenylbutyl, phenoxypropyl, (phenoxy)ethyl, (chlorophenoxy)ethyl, or (fluorobenzoyl)propyl radical, R4 and R5 are hydrogen, n is equal to 1 or 2, X and Y each represent a CH2 radical, and R6 is hydrogen or a C2 to C5 alkylcarbonyl or C3 to C6 cycloalkylcarbonyl radical.

13. A derivative as claimed in claim 1, which is one of: I -(6-thiochromanyl)-2-n-octylamino- 1 -propanol I -(6-thiochromanyl)-2-(4-phenylbutylamino)- 1 -propanol I -(6-thiochromanyl)-2- [2-(phenoxy)ethylamino] - 1 -propanol I -(2,3-dihydro-5-benzo[blthienyl)-2-n-octylamino- 1 -propanol 1-(2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1-propanol 1-(2,3-dihydro-5-benzo[b]thienyl)-2-[4-(p-chlorophenyl)butylamino]-1-propanol 1-(2-methyl-2,3-dihydro-5-benzo[b]thienyl)-2-(4-phenylbutylamino)-1-propanol 1-(2-methyl-2,3-dihydro-5-benzo[b]furanyl)-2-n-octylamino-1-propanol 1-(2,3,4,5-tetrahydrobenzo[b]thiepin-7-yl)-2-(4-phenylbutylamino)-1-propanol, and 1-(2,3-dihydro-5-indolyl)-2-n-octylamino-1-propanol.

14. A derivative as claimed in claim 1, which is: I - (2,3 - dihydro - 5 - benzo[blthienyl) - 2 - (4 - phenylbutylamino) - I - pro- pionyloxypropane, or 1 - (2,3 - dihydro - 5 - benzo[b]thienyl) - 2 - (4 - phenylbutylamino) - 1 - cyclo hexanoyloxypropane

15. A derivative as claimed in claim 1, which is one of: I -(5-indanyl)-2-(4-phenylbutylamino)- 1 -propanol 1-(5-indanyl)-2-[2-(4-chlorophenoxy)ethylamino]-1-propanol, and 1-(5-indanyl)-2-[3-(4-fluorobenzoyl)propylamino]-1-propanol.

16. A derivative as claimed in claim 1, wherein in formula I: R, represents hydrogen, or one or two linear or branched C, to C3 alkyl radicals; R3 is as defined in claim 1; R3 is: -a C3 to C,8 alkenyl radical; -a C3 to C10 alkynyl radical; -a C3 to C10 cycloalkyl radical; -a linear or branched C3 to C.8 alkyl radical; -a linear or branched C3 to C,8 alkyl radical containing one or more oxygen or sulfur linkages, and/or substituted by at least one alkoxycarbonyl, pyrrolidine, pyrrolidinone or imidazolidone radical, by one or two phenyl, phenoxy, phenylthio, indanyloxy radicals, by a phenyl, phenoxy, phenylthio radical substituted by one or two C, to C4 alkyl or C, to C4 alkoxy radicals, by one or two halogen atoms, by a nitrile, hydroxy, amino, C2 to C6 alkylcarbonyl, C3 to C4 acylamino, alkoxycarbonyl, or C, to C4 alkylsulfonamido radical, or by an alkoxycarbonylalkyl in which the alkyl and alkoxy moieties contain from 1 to 4 carbon atoms, or alkoxycarbonyl alkoxy in which each alkoxy moiety contains 1 to 4 carbon atoms; R4 and R5 are as defined in claim 1; R6 is hydrogen; n is as defined in claim I, X is sulfur, oxygen or a CH2 radical; and Y is a CH2 radical.

17. A derivative as claimed in claim 1 and substantially as described in any one of the examples.

18. A process for preparing a derivative having the formula (I), which process comprises reducing to -OH the carbonyl group of a compound of the formula: in which R1, R2, R3, R5, n, X and Y are as defined in claim 1, and R7 is a group of the formula R4 as defined in claim I or is a protecting group removable by hydrolysis.

19. A process as claimed in claim 18, wherein R, is a benzyl, trityl, acetyl, formyl, or benzhydryl group.

20. A process as claimed in claim 18 or claim 19, wherein reduction is carried out by the action of an alkali metal hydride, lithium aluminium hydride or by the action of an aluminium alkoxide.

21. A process as claimed in claim 20, wherein the reduction is carried out using sodium borohydride in methanol, ethanol or isopropanol, lithium aluminium hydride in diethyl ether or tetrahydrofuran, or aluminium isopropoxide in isopropanol.

22. A process as claimed in claim 20 or claim 21, wherein the reduction is carried out under reflux.

23. A process as claimed in claim 18, wherein the reduction is carried out by catalytic hydrogenation.

24. A process as claimed in claim 23, wherein the catalyst for the hydrogenation is palladium or carbon, Raney nickel, or platinum oxide and the reaction is performed in methanol, ethanol or dioxane.

25. A process as claimed in any one of claims 18 to 24 wherein the compound of formula II is itself obtained by the reaction of a compound of the formula: 1 5 (CH2) (IV) O R2 wherein Z is halogen, with an amine of the formula R3R4NH wherein R3 and R4 are as defined in claim 1, and the compound of formula II so obtained is reduced without being isolated, R1, R3, R5, n, X and Y being as defined in claim 1.

26. A process as claimed in claim 25, wherein the compound of formula IV is reacted with the amine in an alcohol solvent.

27. A process as claimed in claim 26, wherein the said solvent is methanol, ethanol or isopropanol.

28. A process for preparing a derivative having the formula I comprising reacting a compound of the formula: wherein Z is halogen, with an amine of the formula R3R4NH, R1, R2, R3, R4, R5, n, X and Y being as defined in claim 1.

29. A process as claimed in claim 28, wherein the reaction is carried out in the presence of a compound able to capture hydrogen halide formed in the reaction.

30. A process as claimed in claim 29, wherein compound able to capture 5 hydrogen halide is an inorganic or organic base or excess amine.

31. A process as claimed in claim 29 or claim 30, wherein the reduction is carried out in an alcohol or chloroform, dioxane or carbon tetrachloride as solvent.

32. A process for preparing a derivative having the formula I comprising reacting a compound of the formula: 10 R1 (cm2) I CH-CH-R2 with an amine of the formula R3R4NH wherein R1, R2, R3, R4, R5, n, X and Y are as defined in claim 1.

33. A process for preparing a salt of the derivative having the formula (I), comprising reacting the derivative with an inorganic acid, such as hydrochloric, 15 hydrobromic, sulfuric, phosphoric, or perchloric acids or with an organic acid. such as ascorbic acid or a carboxylic or sulfonic acid, such as formic, acetic, propionic, glycollic, lactic, fumaric, maleic, pamoic, succinic, tartaric, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic, methanesulfonic, ethanedisulfonic, or glucuronic acid in a suitable solvent, such as 20 an alcohol, the reaction being followed by precipitation of the salt by addition of another solvent which is miscible with the first one and in which the salt is insoluble, for example ether, or by neutralisation of an ethereal solution of the acid or derivative by means of the derivative or acid respectively.

34. A process for preparing a derivative having formula (I), where R8 is a linear 25 or branched C2 to C" alkylcarbonyl radical or a C3 to C8 cycloalkyl carbonyl radical, wherein an amino-alcohol having formula (I) wherein R6 is hydrogen, or a salt thereof is reacted with an equimolar amount or an excess of suitable acid chloride or an hydride.

35. A process for the preparation of an amino-alcohol derivative having the 30 formula I or a salt thereof substantially as set forth in any one of the foregoing examples.

36. A derivative having the formula I or an acid addition salt thereof prepared by a process as claimed in any one of claims 18 to 35.

37. An acid addition salt of a derivative as claimed in any one of claims 1 to 17. 35

38. A pharmaceutical composition comprising a derivative as claimed in any one of claims 1 to 17 or claim 36 or a salt thereof as claimed in claim 37 and a carrier or diluent therefor.

39. A composition as claimed in claim 38 in unit dosage form.

40. A composition as claimed in claim 38 or claim 39 in the form of an 40 injectable solution, a solution for oral administration, a suppository tablet, capsule, syrup, emulsion, suspension or granules.

41. A pharmaceutical composition substantially as hereinbefore described in any one of the "Examples of Composition".

42. A method of treating cardiovascular disease or hypertension in a non- 45 human animal which comprises administering to the animal a derivative as claimed in any one of claims 1 to 17 or claim 36 or a salt as claimed in claim 37 or a composition as claimed in any one of claims 38 to 41.

1,565,080 CONTINENTAL PHARMA, Per Boult, Wade & Tennant, 34, Cursitor Street, London, EC4A IPQ.

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