Piperazines and Homopiperazines, N-Substituted by an Aromatic Heterocyclic Group, and Their Use in Therapeutics

The present invention relates to new piperidinic, piperazinic and homopiperazinic derivatives, N-substituted by a heterocyclic group of the benzimidazole, indole, purine or benzotriazole type, the process for preparing same and the use thereof in therapeutics.

More precisely, the new derivatives of the invention correspond to the formula: ##STR1## in which: the pair (X,n) assumes any one of the following values: (N,1), (N,2), (CH,1); R represents:

a hydrogen atom,

an alkylcarbonyl or alkyloxycarbonyl group in which the alkyl residue is linear or branched and comprises from 1 to 5 carbon atoms,

a heterocyclic-carbonyl group (heterocyclic-CO) in which the heterocycle is a furyl, thienyl, tetrahydrofuryl, pyridyl or [(methylthio-2) oxadiazole-1,3,4yl]-5 nucleus,

a benzoyl, trimethoxy-3,4,5 cinnamoyl, allyloxycarbonyl, (methyl-2 propene-1yl-3) oxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl chain, or

a phenylthio group, except in the case where X represents the CH group; and

Ar represents any one of the following nucleii: benzimidazolyl-4(7); (alkyl-2) benzimidazolyl-4(7) in which the alkyl residue comprises from 1 to 4 carbon atoms; (phenyl-2) benzimidazolyl-4(7); (benzyl-2) benzimidazolyl-4(7); purinyl-6, except in the case where the pair (X,R) takes on the value (N,H); benzotriazolyl-4(7); indolyl-7; indolyl-4, but only in the case where the pair (X, n) takes on the value (N, 1).

The invention also relates to the organic or mineral acid addition salts of the derivatives of formula (I).

Among these derivatives in accordance with the invention may be more particularly mentioned those in which the set (X, n, R) assumes the value (N, 1, H) and Ar represents a benzimidazolyl-4(7); benzotriazolyl-4(7); indolyl-4 or indolyl-7 group.

The present invention also relates to the processes for preparing the derivatives of formula (I) and their salts.

Thus:

A/ The compounds of formula (I) in which Ar represents the benzimidazolyl-4(7) nucleus, the pair (X,n) takes on the value (N,1), (N,2) or (CH,1) and R has the same meanings as in formula (I), the pair (X,R) not however being able to take on the values (N,H) and (N, phenylthio), are obtained by a process which consists in a cyclising reduction with hydrogen in the presence of formic acid, preferably in an autoclave at ambient temperature and in the presence of palladium on charcoal (10% of palladium), of the compounds of formula: ##STR2## in which n, X, R have the same meanings as in formula (I), the pair (X, R) not however being able to take on the value (N, H) or (N, phenylthio).

The compounds of formula (II) are obtained by condensation of chloro-3 nitro-2 aniline, preferably in solution in an organic solvent such as DMF, acetonitrile, acetone, an alcohol or toluene for example, in the presence of a basic agent such as potassium carbonate or triethylamine, with the compounds of formula: ##STR3## in which n, X and R have the same meanings as in formula (II).

The compounds of formula (III), as far as they are concerned, are either already known or are prepared in accordance with one of the conventional methods described in the literature.

B/ The compounds of formula (I) for which Ar represents the nucleii: (alkyl-2) benzimidazolyl-4(7) in which the alkyl residue comprises 1 to 4 carbon atoms, (phenyl-2) benzimidazolyl-4(7) or (benzyl-2) benzimidazolyl-4(7), the pair (X, n) takes on the value (N,1), (N,2) or (CH,1) and R has the same meanings as in formula (I), the pair (X, R) not however being able to take on the values (N,H) and (N,phenylthio), are obtained by cyclization of the compounds of formula: ##STR4## in which n, X and R have the same meanings as in formula (II), preferably in an alcohol solution (ethanol for example), with the hydrochloride of the imidates of formula: ##STR5## in which R.sub.1 represents an alkyl group with 1 to 4 carbon atoms, a phenyl group or a benzyl group.

The compounds of formula (IV) are obtained by hydrogenation, preferably in an alcohol medium and in the presence of palladium on charcoal (10% of palladium), of the compounds of formula (II).

C/ The compounds of formula (I) for which Ar represents the purinyl-6 nucleus, the pair (X, n) takes on the value (N,1), (N,2) or (CH,1) and R has the same meanings as in formula (I), the pair (X,R) not however being able to take on the values (N, H) and (N, phenylthio), are obtained by condensation, preferably in n-butanol, of the compounds of formula (III) with chloro-6 purine.

D/ The compounds of formula (I) for which Ar represents the benzotriazolyl-4(7) nucleus, the pair (X, n) takes on the value (N, 1), (N,2) or (CH,1) and R has the same meanings as in formula (I), the pair (X, R) not however being able to take on the values (N, H) and (N, phenylthio), are obtained by condensation of the compounds of formula (IV) with an alkaline metal nitrite such as sodium nitrite, preferably in aqueous media and in the presence of acetic acid.

E/ The compounds of formula (I) for which Ar represents the indolyl-7 nucleus, the pair (X, n) takes on the value (N, 1), (N, 2) or (CH,1) and R has the same meanings as in formula (I), the pair (X, R) not however being able to take on the values (N, H) and (N, phenylthio), are obtained by cyclizing reduction with hydrogen--preferably in an ethyl acetate medium in the presence of palladium on charcoal (10% of palladium) and in autoclave--of the compounds of formula: ##STR6## in which X, n and R have the same meanings as in formula (III).

The compounds of formula (VI) are obtained by condensation of the compounds of formula (III) with chloro-3 nitro-2 phenylacetonitrile obtained by the action of sodium cyanide, preferably in an alcohol medium, on bromomethyl-1 nitro-2 chloro-3 benzene.

F/ The compound of formula (I) for which Ar represents the indolyl-4 nucleus, the pair (X, n) takes on the value (N, 1) and R represents the hydrogen atom, is obtained by hydrogenolysis--preferably in an ethanol medium and in the presence of palladium on charcoal (5% of palladium)--of the formula (I) compound having the particular structure: ##STR7## obtained by aromatization with an alkaline metal ferricyanide such as potassium ferricyanide, more especially in an aqueous medium, of indoline of formula: ##STR8## This latter is obtained by acid hydrolysis, especially with 1N hydrochloride acid, of the compound of formula: ##STR9## obtained by condensation, in DMF and in the presence of triethylamine, of benzylchloroformiate with the compound of formula: ##STR10## itself obtained by condensation, in butoxy-ethanol, in the presence of potassium carbonate and potassium fluoride, of bischloroethylamine hydrochloride with the compound of formula: ##STR11##

The compound of formula (X) is obtained by catalytic reduction in the presence of palladium on charcoal (10% of palladium), in an ethanol medium, of the compound of formula: ##STR12## which is obtained by acetylation with acetic anhydride of nitro-4 indoline. This latter is prepared by a 3 stage synthesis consisting in treating dinitro-2, 6 toluene with paraformaldehyde in the presence of sodium ethylate, in solution in DMSO, then in treating the (dinitro-2,6) phenyl-2 ethanol thus obtained with sodium sulfide, in the presence of sodium bicarbonate, in solution in water and methanol and finally in cyclizing the (amino-2-nitro-6) phenyl-2 ethanol obtained with 48% hydrobromic acid.

G/ The compounds of formula (I) for which Ar represents the benzimidazolyl-4(7) nucleus, the (alkyl-2) benzimidazolyl-4(7) nucleus in which the alkyl residue comprises 1 to 4 carbon atoms, the (phenyl-2) benzimidazolyl-4(7) nucleus, the (benzyl-2) benzimidazolyl-4(7) nucleus, the purinyl-6 nucleus, the benzotriazolyl-4(7) nucleus or the indolyl-7 nucleus and the set (X, n, R) takes on the value (N, 1, H), or (N, 2, H) are obtained:

either by treating with hydrobromic acid, preferably at 48%, the compounds of formula (I) having the particular structure: ##STR13## in which n takes on the value 1 or 2 and Ar represents the groups mentioned immediately above,

or by treating with aqueous baryte [Ba(OH).sub.2 ] the compounds of formula (Ib),

the compounds of formula (Ib) being prepared in accordance with the processes described under points A/ to E/ above.

H/ The compounds of formula (I) for which the set (X, n, R) takes on the value (N, 1, phenylthio) or (N, 2, phenylthio) are obtained by condensation of N-phenylthiophthalimide with the compounds of formula (I) having the particular structure: ##STR14## in which n takes the values 1 or 2 and Ar has the same meanings as in formula (I).

The compounds of formula (Ic) are obtained in accordance with the method described in paragraphs G/ and F/ above.

I/ The compounds of formula (I) having the particular structure: ##STR15## in which Ar has the same meanings as in formula (I) and R.sub.2 represents an alkyl or alkyloxy group in which the alkyl residue comprises 1 to 5 carbon atoms, a phenyl, furyl, thienyl, pyridyl, tetrahydrofuryl, [(methylthio-2) oxadiazole-1,3,4yl]-5 or trimethoxy-3,4,5 styryl nucleus or an alkyloxy, (methyl-2 propene-1yl-3) oxy, phenoxy or benzyloxy group already obtained in accordance with the methods described in paragraphs A/ to E/ above may also be obtained, depending on the nature of R.sub.2, by condensation of the compounds of formula (Ic) with the acid chlorides (or chloroformiates) or the acid anhydrides having respectively the formula:

in which R.sub.2 has the same meanings as in formula (Id), this condensation being preferably carried out in pyridine or in an aprotic organic solvent such as methylene chloride, DMF or THF and in the presence of triethylamine.

As was pointed out above, the salts of the derivatives of formula (I) may be formed with organic and mineral acids. Among the organic acids there may be more especially mentioned maleic acid and among the mineral acids, hydrobromic acid and hydrochloric acid may be mentioned.

These salts may be prepared by simple reaction of the derivative of formula (I) with the acid, both being possibly in solution in an appropriate solvent such as acetone or ethanol for example.

The following preparations are given by way of example to illustrate the invention.

Code number: 13

1st step: (carbethoxy-4 piperazino-1)-3 nitro-2 aniline (II)

A suspension of 6.9 g of chloro-3 nitro-2 aniline, 5.7 g of N-carbethoxy-piperazine [(III)] and 5 g of potassium carbonate in 15 ml of DMF is brought to reflux for 15 hours. Then it is poured into iced water, extracted with ethyl acetate, dried on sodium sulfate, filtered, the filtrate is evaporated and the residue crystallized in isopropylic ether. Thus 7 g of the expected compound are isolated.

Yield: 69%

Melting point: 110.degree. C.

By the same process but from the corresponding reagents, the compounds of formula (II) of the invention are obtained which are required for the synthesis of the compounds of formula (I) and more especially the following:

(acetyl-4 piperazino-1)-3 nitro-2 aniline (melting point: 142.degree. C.)

[(methyl-2) propionyl-4 piperazino-1]-3 nitro-2 aniline (melting point: 143.degree. C.)

[(furoyl-2)-4 piperazino-1]-3 nitro-2 aniline (melting point: 155.degree. C.)

[(thienoyl-2)-4 piperazino-1]-3 nitro-2 aniline (melting point: 138.degree. C.)

(benzoyl-4 piperazino-1)-3 nitro-2 aniline (melting point: 190.degree. C.)

[(tetrahydrofuranoyl-2)-4 piperazino-1]-3 nitro-2 aniline (melting point: 156.degree. C.)

(nicotinoyl-4 piperazino-1)-3 nitro-2 aniline (melting point: 188.degree. C.)

(carbethoxy-4 homopiperazino-1)-3 nitro-2 aniline (oil)

(carbethoxy-4 piperidino)-3 nitro-2 aniline (melting point: 77.degree. C.)

2nd step: (carbethoxy-4 piperazino-1)-4 (7) benzimidazole, maleate (I)

A suspension of 7 g of (carbethoxy-4 piperazino-1)-3 nitro-2 aniline (II) obtained in the previous step and 1.4 g of a 50% suspension in water of palladium on charcoal (10% of palladium), in 200 ml of 99% formic acid is left under agitation for two hours, in an autoclave at ambient temperature and under hydrogen pressure. Then 4 ml of 11N hydrochloric acid are added and the whole is brought to reflux for two and a half hours, then it is filtered, the filtrate is evaporated and the residue taken up in water, neutralized with NH.sub.4 OH, extracted with chloroform, the extract is washed with water, dried on sodium sulfate, filtered, the filtrate is evaporated, the residue is dissolved in acetone and a solution of 2.6 g of maleic acid in 20 ml of acetone is added. The precipitate obtained is filtered and recrystallized in ethanol. 4 g of the expected compound are isolated.

By the same process but from the corresponding reagents, the compounds of formula (I) are obtained shown in Table I below under the code numbers: 2 to 12, 14 to 23 and 30.

Code number: 28

1st step: (diamino-2,3 Phenyl)-4 carbethoxy-1 piperazine (IV)

A suspension of 5 g of (carbethoxy-4 piperazino-1)-3 nitro-2 aniline [(II)] and 0.5 g of palladium on charcoal (10% of palladium) in 100 ml of ethanol is hydrogenated in an autoclave at ambient temperature and at a pressure of 150 millibars for one and a half hour. Then it is filtered, the filtrate evaporated and the residue crystallized in ethyl ether. Thus 2.8 g of the desired compound are isolated.

Yield: 63%

Melting point: 107.degree. C.

By the same process but from the corresponding reagents the compounds of formula (IV) are obtained which are required for the synthesis of the compound of formula (I).

2nd step: phenyl-2(carbethoxy-4 piperazino-1)-4 (7) benzimidazole (I)

A solution of 2.7 g of (diamino-2,3 phenyl)-4 carbethoxy-1 piperazine obtained in the preceding step and 2.2 g of phenylimidate hydrochloride [(V), R.sub.1 =C.sub.6 H.sub.5 ] in 30 ml of ethanol is brought to reflux for 30 minutes. Then the solvent is evaporated, the residue is taken up in water, extracted with ethyl acetate, the extracte is washed with water, dried on sodium sulfate, filtered, the filtrate is evaporated and the residue crystallized in an ethyl acetate and isopropylic ether mixture. Thus 2.6 g of the expected compound are isolated.

By the same process, but from the corresponding reagents, the compounds of formula (I) are obtained which are shown in Table I below under code numbers: 26 and 27.

Code number: 25

A solution of 1.5 g of chloro-6 purine and 3.3 g of N-carbethoxypiperazine [(III)] in 15 ml of butanol is brought to 60.degree. C. for 30 minutes. Then the reaction mixture is filtered, the filtered precipitate is rinsed with ethyl ether, then washed with water and recrystallized in ethanol. Thus, 2 g of the expected compound are obtained.

Code number: 38

To a mixture of 17 ml of acetic acid and 35 ml of water are added 7.5 g of (diamino-2,3 phenyl)-4 carbethoxy-1 piperazine [(IV) obtained in the first step of example 2], then the solution is cooled to 0.degree. C. to which is then added a solution of 2.3 g of sodium nitrite in 7.6 ml of water and it is left to return to room temperature. After 2 hours at room temperature, the reaction medium is neutralized with NH.sub.4 OH and filtered. The filtrate is saturated with sodium chloride, then extracted with chloroform. The product obtained by filtration is added to the chloroform phase, the chloroform phase obtained is dried on sodium sulfate, filtered and the filtrate evaporated. The residue is chromatographed on a silica column (medium pressure liquid chromatography), elution being carried out with ethyl acetate. The product resulting from this chromatography is then recrystallized in an isopropyl ether (50%)--isopropyl alcohol (50%) mixture; 5.6 g of the expected product are thus isolated.

Code number: 29

1st step: chloro-3 nitro-2 phenylacetonitrile

A solution of 2.2 g of bromomethyl-1 nitro-2 chloro-3 benzene and 0.5 g of sodium cyanide in 40 ml of absolute alcohol is left under agitation for 24 hours at room temperature. Then it is filtered, the filtrate evaporated, the residue is taken up in methylene chloride, the obtained solution is dried on sodium sulfate, filtered, the filtrate is evaporated and the residue chromatographed on a silica column [eluent: n-heptane (75%)--ethyl acetate (25%)]. Thus 1 g of the expected compound is obtained:

Yield: 60%

Melting point: 62.degree. C.

Empirical formula: C.sub.7 H.sub.5 ClN.sub.2 O.sub.2

Molecular weight: 184.58

2nd step: (carbethoxy-4 piperazino-1)-3 nitro-2 phenylacetonitrile (VI)

A mixture of 3 g of chloro-3 nitro-2 phenylacetonitrile obtained in the preceding step and 50 ml of N-carbethoxy piperazine [(III)] is brought to 130.degree. C. for 4 hours. Then it is thrown on ice, extracted with ethyl acetate, the mixture obtained is dried on sodium sulfate, filtered, the filtrate is evaporated and the residue is chromatographed on a silica column [eluent: n-heptane (70%)--ethyl acetate (30%) ]. Thus, 2.6 g of the expected product are obtained.

Yield: 50%

Melting point: 85.degree. C.

Empirical formula: C.sub.15 H.sub.18 N.sub.4 O.sub.4

Molecular weight: 318.33

3rd step: (carbethoxy-4 piperazino-1)-7 indole (I)

A suspension of 1.9 g of formula (VI) compound, obtained in the preceding step, and 0.9 g of palladium on charcoal (10% of palladium) in 60 ml of ethyl acetate is hydrogenated in an autoclave at a pressure of 20 kg and at 80.degree. C. for 3 hours. Then the reaction mixture is filtered, the filtrate is evaporated and the residue chromatographed on a silica column [eluent: n-heptane (60%)--ethyl acetate (40%)]. Thus 1 g of the expected compound is obtained.

Code number: 41

A suspension of 5.7 g of (benzyloxycarbonyl-4 piperazino-1)-4 indole [(Ia) code No. 40] and 0.6 g of palladium on charcoal (5% of palladium) in 100 ml of ethanol is hydrogenated under pressure at room temperature. Then the reaction mixture is filtered, the filtrate evaporated and the residue is chromatographed on a silica column (medium pressure liquid chromatography) [elution by the mixture: CH.sub.2 Cl.sub.2 (90%)--methanol (9%)--NH.sub.4 OH (1%)]. The resulting product is then sublimated (sublimation point=160.degree. C. under 0.05 mm of Hg). Thus 2 g of the expected product are isolated.

Code number: 40

To a solution, brought to reflux, of 9.5 g of potassium ferricyanide in 200 ml of water are added 9.5 g of (benzyloxycarbonyl-4 piperazino-1)-4 indoline (VII). Then it is left at reflux for 2 hours and a further portion of 9.5 g of potassium ferricyanide in 100 ml of water is added. The reaction mixture is left at reflux for three hours, then filtered and extracted with ethyl acetate. The organic phases are evaporated and the residue is chromatographed on a silica column (medium pressure liquid chromatography), the eluent being formed by a 40% ethyl acetate -60% n-heptane mixture. Thus 5.7 g of the expected product are isolated.

A solution of 12.5 g of acetyl-1 (benzyloxy-carbonyl-4 piperazino-1)-4 indoline (VIII) in 400 ml of 1N hydrochloric acid is heated to 80.degree. C. for 3 hours. After cooling, the reaction mixture is neutralized with NH.sub.4 OH, extracted with ethyl acetate, the organic phase is evaporated and the residue chromatographed on a silica column (medium pressure liquid chromatography), elution being carried out with the ethyl acetate/heptane (60/40) mixture. Thus 9.4 g (yield=81%) of the expected product are obtained.

NMR spectrum .delta.ppm (CDCl.sub.3)=7.35, s and 5.2, s (7 H: COOCH.sub.2 C.sub.6 H.sub.5) 7.0, m and 6.25, m (3 aromatic H) 3.55, m and 2.9, m (12 H: ##STR16## and --CH.sub.2 --CH.sub.2 --)

To a solution, cooled to 0.degree. C., of 13 g of acetyl-1 piperazino-4 indoline (IX) in 450 ml of DMF are added 23 ml of triethylamine, then 11 ml of benzyl chloroformiate. The reaction mixture is agitated at room temperature for 20 minutes, then the solvent is evaporated and the residue taken up in a mixture of water and ethyl acetate, decanted, the organic phase is dried on sodium sulfate, filtered and the filtrate evaporated. The residue is chromatographed on a silica column (medium pressure liquid chromatography), elution being carried out with the ethyl acetate/heptane (50/50) mixture. Thus, 13 g (yield=70%) of the expected product are obtained.

Melting point: 150.degree. C.

Empirical formula: C.sub.22 H.sub.25 N.sub.2 O.sub.3

Molecular weight: 365.44

To a solution, brought to reflux, of 15.1 g of bischloroethylamine hydrochloride in 400 ml of butoxyethanol are added 11.8 g of potassium carbonate, then 5 g of potassium fluoride, then 14.8 g of amino-4 acetyl-1 indoline (X). The reaction mixture is left at reflux for 9 hours, then the solvent is evaporated and the residue chromatographed on a silica column (medium pressure liquid chromatography), elution being carried out with a 93% chloroform--6.5% methanol-0.5% NH.sub.4 OH mixture. Thus 4.3 g (yield=21%) of the expected product are isolated.

Melting point: 160.degree. C.

Empirical formula: C.sub.14 H.sub.19 N.sub.3 O

Molecular weight: 245.32

A suspension of 20 g of acetyl-1 nitro-4 indoline (XI) and 4 g of palladium on charcoal (10% of palladium) in 600 ml of ethanol is hydrogenated under a hydrogen pressure of 40 kg at a temperature of 80.degree. C. Then the reaction mixture is filtered and the filtrate evaporated. A crystallized product is obtained which corresponds to the expected product.

Melting point: 178.degree. C.

Yield: .about.100%

Empirical formula: C.sub.10 H.sub.12 N.sub.2 O

Molecular weight: 176.21

35 g of nitro-4 indoline are dissolved in 100 ml of acetic acid anhydride then, the obtained mixture is diluted with isopropylic ether and the precipitate obtained is filtered which corresponds to the expected compound.

Melting point: 143.degree. C.

Yield: .about.100%

Empirical formula: C.sub.10 H.sub.10 N.sub.2 O.sub.3

Molecular weight: 206.20

A mixture of 42 g of (amino-2 nitro-6) phenyl-2 ethanol in 500 ml of 48% hydrobromic acid is brought to reflux for 15 hours. Then the reaction mixture is diluted with 2 liters of water and filtered, the aqueous phase is neutralized with NH.sub.4 OH, extracted with ethyl acetate, the extract is dried on sodium sulfate, filtered and the filtrate is evaporated. The residue is chromatographed on a silica column (medium pressure liquid chromatography), elution being carried out with the 85/15 ethyl acetate/heptane mixture. Thus 8.2 g of bromo-7 nitro-4 indoline are obtained (melting point=112.degree. C.), then 14.2 g of nitro-4 indoline (melting point=105.degree. C).

It should be noted here that bromo-7 nitro-4 indoline acetylated as in example 12 then hydrogenated as in example 11 also leads to acetyl-1 amino-4 indoline (X).

A solution of 53 g of (dinitro-2,6) phenyl-2 ethanol in 600 ml of methanol is heated to 55.degree.-60.degree. C., to which is then added a solution of 216 g of sodium sulfide and 67.2 g of sodium bicarbonate in 750 ml of water. The obtained reaction mixture is left for 1 hour at 60.degree. C. then diluted with 2 liters of water, extracted with ethyl acetate, the extract is dried on sodium sulfate, filtered and the filtrate evaporated. Thus 42.1 g (yield=92%) of the expected product (crystallized) are obtained.

Melting point: 92.degree. C.

Empirical formula: C.sub.8 H.sub.10 N.sub.2 O.sub.3

Molecular weight: 182.18

To a solution of 76 g of dinitro-2,6 toluene in 400 ml of DMSO are added 12.6 g of paraformaldehyde, then 28.5 g of sodium ethylate. The solution is left under agitation at room temperature for 96 hours, then the reaction medium is poured on 2 kg of ice, neutralized with hydrochloric acid, filtered, the aqueous phase is extracted with ethyl acetate and the precipitate obtained during filtration is added to the organic phase. The organic phase obtained is dried on sodium sulfate and the filtrate is evaporated. The residue is chromatographed on a silica column [medium pressure liquid chromatography--eluent: (90/10)heptane-ethyl acetate mixture]. Thus, 77 g of the expected product are obtained.

Yield: 87%

Melting point: 68.degree. C.

Empirical formula: C.sub.7 H.sub.8 N.sub.2 O.sub.5

Molecular weight: 212.16

Code number: 1

A solution of 1.5 g of the formula (I) compound, code No. 13, prepared in example 1, in 60 ml of 48% hydrobromic acid is heated at 110.degree. C. for 3 hours. Then the solvent is evaporated in a vacuum, the residue is crystallized in ethanol and filtered. 2 g of the expected compound are isolated.

By the same process, but from the corresponding reagents, the compounds of formula (I) were obtained, shown under code numbers 32 to 37, 39 and 42 in Table I below.

Code number: 39

A solution of 3.6 g of (ethoxycarbonyl-4 piperazino-1)-4 (7) benzotriazole [(I), code No. 38] in 200 ml of 0.5N Ba(OH).sub.2 is brought to reflux for 2 hours. Then a further 200 ml of 0.5N Ba(OH).sub.2 is added, the reaction medium is left for 2 hours and again 50 ml of 0.5N Ba(OH).sub.2 are added and left for 3 hours at reflux. After cooling, the reaction mixture is neutralized by bubbling carbonic gas through said reaction mixture, then it is filtered, the filtrate is evaporated, the filtration precipitate and the residue are dissolved in chloroform, the chloroform phase is dried on sodium sulfate, filtered and the filtrate evaporated. This residue is chromatographed on a silica column [medium pressure liquid chromatography--eluent: 80% methyl chloride--19% methanol--1% NH.sub.4 OH mixture]. The product thus isolated is then crystallized in the minimum of ethanol. Thus, 1.55 g of product is obtained which is dissolved in 50 ml of warm ethanol. 4 ml of 8N hydrochloric ethanol are added and the precipitate obtained is filtered. Thus, 1.21 g of expected product are obtained.

By the same process, but from the corresponding reagents, compounds (I) are obtained, shown under code numbers 1, 32 to 37 and 42 in Table I.

Code number: 24

A suspension of 6.1 g of formula (I) compound, code No. 1 and prepared in example 16, of 8.4 g of N-phenylthiophthalimide in 300 ml of benzene and 30 ml of ethanol is heated to reflux for 4 hours, then it is cooled to 10.degree. C., filtered, the filtrate is evaporated, and the residue taken up in ethylacetate, the organic phase obtained is filtered, the filtrate is evaporated and the residue chromatographed on a silica column (eluent: ethyl acetate). 2.9 g of the expected product are obtained after crystallization in ethyl ether.

Code number: 5

To a solution, cooled to 0.degree. C., of 5.2 g of the compound of formula (I), code No. 1, prepared in example 16, in 100 ml of DMF are added over 10 minutes, 9.5 ml of triethylamine and the reagents are left in contact for 30 minutes, then 1.9 ml of n-pentanoic acid chloride are added over 15 minutes and the reagents are left in contact for one and a half hour, then the reaction mixture is poured into iced water, the mixture obtained is extracted with chloroform, the chloroform phase is dried on sodium sulfate, filtered, the filtrate is evaporated and the residue is crystallized in a 50/50 isopropyl ether-isopropyl alcohol mixture. Thus, 1.1 g of the expected compound is isolated.

By the same process, but from the corresponding reagents, the compounds of formula (I) are obtained, shown in Table I below under code numbers 2 to 4, 6 to 23, 38 and 40. ##STR17## (I) NumberCode Ar ##STR18## Form formulaEmpirical weightMolecular (.degree.C.)pointMelting (%)Yield % C LEMENTARY ANALYSIS 1 ##STR19## ##STR20## tribrom-hydrate C.sub.11 H.sub.17 Br.sub.3 N.sub.4 445.01 >260 83 Cal.Obt. 29.6929.78 3.253.89 12.5912.69 2 " ##STR21## base C.sub.13 H.sub.16 N.sub.4 O 244.29 173 30 Cal.Obt. 63.9163.92 6 6.60.60 22.9422.84 3 " ##STR22## base C.sub.15 H.sub.20 N.sub.4 O 272.34 154 45 Cal.Obt. 66.1566.18 7 7.40.66 20.5720.36 4 " ##STR23## base C.sub.16 H.sub.22 N.sub.4 O 286.37 214 42 Cal.Obt. 67.1066.86 8 7.74.07 19.5719.37 5 " ##STR24## base C.sub.16 H.sub.22 N.sub.4 O 286.37 107 23 Cal.Obt. 67.1066.96 8 7.74.04 19.5719.52 6 " ##STR25## base C.sub.16 H.sub.16 N.sub.4 O.sub.2 296.32 200 61 Cal.Obt. 64.8564.68 5.445.44 18.9119.20 7 " ##STR26## base C.sub.16 H.sub.16 N.sub.4 OS 312.39 199 36 Cal.Obt. 61.5161.48 5.165.24 17.9418.14 8 " ##STR27## base C.sub.18 H.sub.18 N.sub.4 O 306.36 230 52 Cal. Obt. 70.5670.42 5.926.10 18.2918.28 9 " ##STR28## base C.sub.16 H.sub.20 N.sub.4 O.sub.2 300.35 220 35 Cal.Obt. 63.9863.76 6.716.76 18.6618.87 10 " ##STR29## base C.sub.17 H.sub.17 N.sub.5 O 307.35 204 46 Cal.Obt. 66.4366.41 5 5.58.49 22.7922.51 11 " ##STR30## base C.sub.23 H.sub.26 N.sub.4 O.sub.4 422.47 219 50 Cal.Obt. 65.3065.66 6.206.28 13.2613.15 12 " ##STR31## base C.sub.15 H.sub.16 N.sub.6 O.sub.2 S 344.39 170 45 Cal.Obt. 52.3152.06 4.684.65 24.4024.34 13 ##STR32## ##STR33## maleate C.sub.18 H.sub.22 N.sub.4 O.sub.6 390.39 173 45 Cal.Obt. 55.3855.47 5.685.80 14.3514.25 14 " ##STR34## maleate C.sub.19 H.sub.24 N.sub.4 O.sub.6 404.41 157 70 Cal.Obt. 56.4256.57 5.986.05 13.86 13.85 15 " ##STR35## base C.sub.13 H.sub.16 N.sub.4 O.sub.2 260.29 144 56 Cal.Obt. 59.9859.83 6.206.10 21.5321.43 16 " ##STR36## base C.sub.15 H.sub.18 N.sub.4 O.sub.2 286.33 160 71 Cal.Obt. 62.9262.84 6.346.24 19.5719.44 17 " ##STR37## base C.sub.16 H.sub.20 N.sub.4 O.sub.2 300.25 142 77 Cal.Obt. 63.9863.78 6.716.82 18.6618.92 18 " ##STR38## base C.sub.15 H.sub.20 N.sub.4 O.sub.2 288.34 159 67 Cal.Obt. 62.4862.40 6.997.12 19.4319.64 19 " ##STR39## base C.sub.16 H.sub.22 N.sub.4 O.sub.2 302.37 110 68 Cal.Obt. 63.5563.63 7.337.13 18.5318.76 20 " ##STR40## base C.sub.16 H.sub.22 N.sub.4 O.sub.2 302.37 209 65 Cal.Obt. 63.5563.75 7.337.32 18.5318.70 21 " ##STR41## base C.sub.16 H.sub.22 N.sub.4 O.sub.2 302.37 160 45 Cal.Obt. 63.5563.49 7.337.51 18.5318.34 22 " ##STR42## base C.sub.19 H.sub.20 N.sub.4 O.sub.2 336.38 153 51 Cal.Obt. 67.8467.58 5.995.91 16.6616.92 23 " ##STR43## base C.sub.18 H.sub.18 N.sub.4 O.sub.2 322.36 197 64 Cal.Obt. 67.0666.85 5.635.70 17.3817.46 24 " ##STR44## base C.sub.17 H.sub.18 N.sub.4 S 310.41 145 31 Cal.Obt. 65.7765.66 5 5.85.73 18.0517.74 25 ##STR45## ##STR46## base C.sub.12 H.sub.16 N.sub.6 O.sub.2 276.30 >260 71 Cal.Obt. 52.1651.99 5.845.77 30.4230.56 26 ##STR47## " chlorhydrate C.sub.15 H.sub.21 ClN.sub.4 O.sub.2 324.81 202 55 Cal.Obt. 55.4655.16 6.526.39 17.2517.43 27 ##STR48## " base C.sub.21 H.sub.24 N.sub.4 O.sub.2 364.43 158 55 Cal.Obt. 69.2169.26 6.646.85 15.315.64 28 ##STR49## " base C.sub.20 H.sub.22 N.sub. 4 O.sub.2 350.41 171 73 Cal.Obt. 68.5568.76 6.336.46 15.9916.02 29 ##STR50## " base C.sub.15 H.sub.19 N.sub.3 O.sub.2 273.23 154 60 Cal.Obt. 65.9365.95 7.017.13 15.3815.08 30 ##STR51## ##STR52## base C.sub.15 H.sub.19 N.sub.3 O.sub.2 273.23 168 47 Cal.Obt. 65.9365.78 7.017.06 15.3815.47 32 ##STR53## ##STR54## hydratedbase C.sub.12 H.sub.16 N.sub.4+ 0.7% H.sub.2 O 217.81 206 32 Cal.Obt. 66.1766.09 7.497.65 25.7225.29 33 ##STR55## " base C.sub.13 H.sub.18 N.sub.4 230.31 212 43 Cal.Obt. 67.7967.50 8 7.88.18 24.3324.06 34 ##STR56## " base C.sub.14 H.sub.20 N.sub.4 244.33 226 70 Cal.Obt. 68.8268.67 8 8.25.39 22.9322.63 35 ##STR57## " base C.sub.15 H.sub.22 N.sub.4+ 0.7% H.sub.2 O 260.18 148 48 Cal.Obt. 69.2469.06 8.608.48 21.5421.43 36 ##STR58## ##STR59## base C.sub.12 H.sub.16 N.sub.4 216.80 190 45 Cal.Obt. 66.4866.75 7.447.26 25.8526.05 37 ##STR60## ##STR61## hydrateddichlorhy-drated C.sub.17 H.sub.20 Cl.sub.2 N.sub.4+ 0.7% H.sub.2 O 353.72 >266 53 Cal.Obt. 57.7257.23 5.785.86 15.8415.18 38 ##STR62## ##STR63## base C.sub.13 H.sub.17 N.sub.5 O.sub.2 275.31 158 73 Cal.Obt. 56.7156.80 6.226.32 25.4425.74 39 " ##STR64## diHCl C.sub.10 H.sub.15 Cl.sub.2 N.sub.5 276.17 196 57 Cal.Obt. 43.4943.77 5.475.45 25.3625.62 40 ##STR65## ##STR66## base C.sub.20 H.sub.21 N.sub.3 O.sub.2 335.38 135 62 ##STR67## 41 " ##STR68## base C.sub.12 H.sub.15 N.sub.3 201.26 208 58 Cal.Obt. 71.6171.45 7.517.56 20.8820.70 42 ##STR69## " base C.sub.12 H.sub.15 N.sub.3 201.26 174 29 Cal.Obt. 71.6171.49 7 7.51.71 20.8820.89

The derivatives of formula (I) and their acid addition salts were tested on laboratory animals and showed pharmacological activities, in particular in the cardiovascular field, more especially as antihypertensive agents.

The antihypertensive activity was revealed by oral administration of the compounds of the invention to S.H.R. rats (genetically hypertensive). The arterial blood pressure was recorded on an APELAB-BP recorder 8002-and an electromechanical counter provided a direct reading of the heartbeat rate. The measurements were taken at 0 hour, 2 hours, 4 hours, 6 hours and 24 hours after administration of the compounds tested.

Acute toxicity was assessed intravenously in mice according to the method of MILLER and TAINTER described in Proc. Soc. Exp. Biol. Med. 57, 261 (1944).

To illustrate the invention, the results obtained with some of the compounds of the invention are shown in Table II below in which the symbols AHY, .DELTA.PA and .DELTA.FC have the following meanings:

AHY=% of rats whose arterial blood pressure drops by a value greater than or equal to 20% of the initial value or is brought down to a value less than 150 mmHg,

.DELTA.PA=% variation of the arterial blood pressure in all the animals tested with respect to the initial blood pressure,

.DELTA.FC=% variation of the heart-beat rate of all the animals tested with respect to the initial rate.

As Table II shows, the compounds of the invention, showing little toxicity, present a sufficiently interesting antihypertensive activity for use in therapeutics.

The present application also relates to the use, as medicaments, of the derivatives of formula (I) and their pharmaceutically acceptable acid addition salts, more especially for the treatment of troubles of the cardiovascular system and in particular as antihypertensive medicaments.

The invention finally relates to pharmaceutical compositions containing, as active ingredient(s), at least one of the above-defined medicaments in association with a pharmaceutically acceptable medium. These compositions will be normally administered orally in the form of tablets, pills, capsules taken in one or several doses up to a total of 500 mg/day of active principle.