CA1228548A - Pharmaceutical compositions containing as active ingredient at least one substituted quinoleine 4-carboxamide derivative - Google Patents

Abstract

The invention relates to new medicinal compositions containing an active substance and a pharmaceutically acceptable vehicle, characterized in that the active substance is a compound corresponding to the general formula (I): <IMG> (I) in which A represents an atom d 'nitrogen, B represents a CH group, R1 and R2 represent identical linear or branched alkyl groups having 1 to 4 carbon atoms, R1 and R2 can also form with the nitrogen atom to which they are attached a piperazino radical, Z represents a phenyl group optionally substituted by one or two substituents chosen from halogen atoms, alkyl groups having 1 to 3 carbon atoms, alkoxy groups having 1 to 3 carbon atoms, group CF3 and group nitro, X and Y, identical or different, represent hydrogen, halogen atoms, alkyl or alkoxy groups having 1 to 3 carbon atoms, nitro or CF3 groups, with the exception of N, N-2-diethylphenyl-quinoline carboxa mide-4, or an addition salt of this compound with pharmaceutically acceptable mineral or organic acids. These compositions are particularly useful for the treatment of anxiety states and pulmonary, renal, cardiovascular or circulatory disorders.

Description

su This is a division of the patent application Canadian born 444,273 filed December 23, 1383.
The subject of the present invention is new drug compositions, particularly useful for the treatment of anxiety states and pulmonary disorders dwarf, renal, cardiovascular or circulatory.
More particularly, the invention relates to drug compositions containing an active substance and a pharmaceutically acceptable vehicle, characterized in that the active substance is a compound corresponding to the general formula (I):
y in which A represents a nitrogen atom, represents a CH group, Ri and Ré represent alkyl groups linear or branched, identical and having 1 to 4 atoms of carbon, Ré and Ré can also form with the atom nitrogen to which they make a piperazino radical attached, Z represents an optionally substituted phenyl group by one or two substituents taken from halo atoms gene, the alkyl groups having 1 3 carbon atoms, alkoxy groups having 1 to 3 carbon atoms, Ire group CF3 and the nitro croup, X and Y, identical or different, represent hydrogen atoms, dislodged alkyl or alkoxy groups having 1 3 carbon atoms, nitro or CF3 groups, with the exception of N, N ~ diethyl-2-phenyl quinoline carboxamide-4, or an addition salt of this compound with, mineral or organic acids ceutically acceptable.

ès In formula (I) above X and Y are preferably hydrogen atoms.
The compounds of formula (I) for which A is a nitrogen atom, B is a CH group, Z is a group phenyl, X and Y are hydrogen atoms and Ri and Ré
are identical alkyl groups having 1 to 4 atoms carbon or form with the nitrogen atom to which they are linked a piperazino group are known products. (have.
English patent 10,352; Il Farmaco, vol. 29, 1974, 507-516, y article by G. PAGANI and Colt .; ROUSHDI and Colt, J. Phare.
Set. U. Arab Repu 1961, 2, 109; EIGHT and Colt., J. Orge Chef., 1942, 7, 497; SONNA, Chef. Zen-tr., 1941, 1, lq21).
Finally the compound of formula (I) for which A = N, B = CH, Z = 4-methylphenol, X = Y = H, Ri = Ré = C2H5 is known 15 (ai. JOHN and Colt., J. Prakt. Chef., 1931, 131, 301_. Among the compounds of known formula (I), only N, N-diethyl phenyl-2 quinoline-carboxamide-4 has been reported to have pharmacological properties, more specifically uricosuric and antipyretic properties (GUEULE and Colt., 20 Egypt Lighthouse. Bull., 1960, 42, 465).
The compounds of general formula (I) can be prepared by the action of an amine of formula (II):
Re HEY (II) Re in which Ri and Ré have the same meanings as Hans the formula tee), on a compound of formula (III):

X Ci W

To him (III) in which X, Y, Z, A and B have the same meanings ford in formula (I) and W represents an alkoxy group of low molecular weight, a chlorine atom or a troop low molecular weight alkoxycarbonyloxy, depending on following editorial scheme:
(1) (II) + (III) y + OH
The reaction (1) is carried out according to procedures, known per se, allowing to transform an acid ester carboxylic acid, a carboxylic acid chloride or an Andy-mixed carboxamide derivative (ai. for example CA BUEHLER and DUE. PARESSONS, Surveille of Organique Synthesis, Willy Inter science, 1970, page 804).
The compounds of formula (I) in base form free can possibly wax transformed into salts addition with mineral or organic acid per action of such an acid in an appropriate solvent.
The various clinical effects (anxiolytic, asti-convulsant, hypnotic, muscle relaxant) of benzodiazepines have been attributed the presence, in the nervous system central mammalian, saturable binding sites, to high affinity and stereospecific (C. 3RAESTRUP and Colt., Nature, 1977, 269, 702, JE TELEMANN and Colt., Science, 1980, 207, 274).
Some benzodiazepines also bind membranes of peripheral tissues like the kidney with equal-strong affinity (C. ~ RAESTRUP and Colt., Pro. Natal.
Akkad. Set. USA, 1977, 74, 3805). Benzol receptors diaz ~ pines present in these tissues differ from those marked by H diazep ~ m or H] flunitrazepam in the brain. For example, clonazepam, mistletoe has a very strong affinity for the OH] diaz ~ pam binding sites of brain is practically inactive at sites of binding of OH diaz ~ pam in the kidney. In the ~ erse chlorine derivative of diazepam, Rot is very active at ~ 85 ~ 3 peripheral level but inactive at central level. So it is possible to distinguish at least 2 types of receptors of benzodiazepines, one of the "cerebral" type, whose criterion pharmacological will be a classification by decreasing affinity in order clonazepam diazepam Rot and the other "peripheral" type, the pharmacological criterion of which will be a ranking by decreasing affinity in the Rot order 4864 ~ diazepam ~ clonazepam.
These "peripheral" type receptors are present in many organs: the heart, kidney, lung, blood platelets and also the brain (where are present the 2 types of receptors) (ai. L DEVIES and Colt., fur. J. Pharmacol., 1981, 73, 209; JET YANG and Colt., Linked Sciences, 1980, 27, 1881; JE REGAIN et Col]., Linked Science, 15 1981, 28, 991; H. SCHOEMAKER, fur. J. Pharmacol., 1981, 71, 173).
The compounds of formula (I), although having a different role structure of benzodiazepines, have the property of binding to benzodiazepine receptors.
Depending on their structure, they preferentially bind to brain receptors or peripheral receptors. By example, the compounds of formula (I) for which X and Y
are hydrogen atoms, A is a nitrogen atom, B is a CH group, Z is the phenyl group and NR1R2 is a group diethylamino or piperidino act preferentially on brain receptors, while the compounds of formula (I) for which X and Y are hydrogen atoms, æ is a phenyl or chloro-2 (or -3) phenyl group, and the killing Ri and Ré are alkyl groups having 3 or atoms of branched carbon in position relative to the atom nitrogen, preferentially act on receptors peripheral devices.
The following examples illustrate the preparation of compounds of formula (I) useful as active principle, 135 ~

in the drug compositions according to the invention.

N, N-diethyl (4-chloro-phenyl) -2 quinoline carboxamide-4 Is heated under reflux for one hour 59 of acid (4-chloro-phenyl) -2 quinoline carboxylic-4 and 15 ml of thionyl chloride. The thionyl chloride is evaporated, takes up the residue in 100 ml of toluene and evaporates to new. 20 ml of toluene are then added to the residue obtained.
then, drop by drop, with stirring, 18 ml of diethylamine.
Stir two hours at room temperature. The mixture editorial is then poured into 50 ml of water. The sentence organic is decanted and the aqueous phase is extracted by three times 100 ml of ethyl acetate. Organic phases are collected, washed with three times 30 ml of water, dried over magnesium sulfate and evaporated under reduced pressure.
After recrystallization of the residue in Luther isopropyl, 4.2 g of N, N-diethyl (4-chloro-phoenix) are isolated y quinoleinecarboxamide-4 melting at 105 C.
(4-Chloro-phenyl) -2 quinoline carboxylic acid -4 can wax prepared according to the process described by RIF. ROT
and this. J. Amer. Chief. Soc. 68, 2705 (1946).

y EXAMPLE 2:
N, N-diethyl (m ~ thoxy-4 ph ~ nyl) -2 quinoline carboxamide-4 The procedure is as in Example 1, starting from 5 g (4-methoxy-ph ~ nyl) -2 quinoline-carboxylic acid-4, 15 void of thionyl chloride and 18.4 ml of diethylamine.

~ Z ~, ~ 5 ~

After recrystallization of the residue from ether isopropyl, 3.8 g of N, N-diethyl (4-methoxy) are isolated phenyl) -2 quinoline carboxamide-4 melting at 128 C.
(4-methoxyphenyl) -2 quinoline carboxylic acid -4 can be prepared according to the process described by CAUSA and LUZZATTO, Gas. Pissed off. Vital., 44, 64 (1914).

EXAMPLE 3:
N, N-diethyl (chloro-2 phoenix ~ uinoléinecarboxamide-4 There we proceed as in Example 1 starting from 5 g (2-chloro-phenyl) -2 quinolinecarboxylic acid-4, 15 ml of thionyl chloride and 12.7 ml of diethylamine.
After recrystallization of the residue from ether isopropyli ~ eu, 3.2 g of N, N-diethyl (2-chloro-phenol) are isolated

-2 guinoléinecarboxamide-4 melting at 130 C.
(2-Chloro-phenyl) -2 quinoline carboxylic acid -4 can be prepared according to the process described by RIF. BROWN
et ci., J. Amer. Chief. Soc. 68, 2705 (1946).

EXAMPLE_:
N, N-diethyl (3-trifluoromethyl-phenyl) -2 quinoline carbon ~ amide We proceed as in example l, starting from 6 9 acid (trifluc, 3-romethylphenyl) -2 quinoleinecarboxylic-4, 18 ml of thionyl chloride and 18.5 ml of diethylamine.
After recrystallization of the residue in Luther isopropyl, 5.2 g of N, N ~ diethyl ~ trifluoromethyl are isolated

-3 phenyl) -2 qu.inoléinecarboxam.ide-4 fondant 100 C.
Acid (trifluoromethyl-3 phoenix quinoleinecar-boxylic-4 can be prepared according to the process described by SHARGIER and LALEZARI, J. Chef, Erg. Data, 8, 276 tl ~ 63).

EXAMPLE 5:
N, N-diethyl tfluoro-4 phenyl) -2 quinoleilleca.rboxamide-4 35 ~ 8 We proceed as in example l, starting from 5 g (4-fluoro-phenyl) -2 quinolinecarboxylic acid-4, 15 ml thionyl chloride and 19.2 ml of diethylamineO
After chromatography of the residue on gel silica with an eludant consisting of a hexane-acetate mixture ethyl y: 30) and recrystallization of the product as well separated in isopropyl ether, 0.86 g of NON-diAthyl tfluoro-4 phenyl) -2 quinolineca ~ boxamide-4 fondant at 114 C.
(4-fluoro-phenyl) -2 quinolinecarboxylic acid-4 can wax prepared according to the method described by Bu Ho et ci., Rock. Tram. Chié., 68, 781 (1949).

-N, N-diethyl-6,7-dimethoxy-2-phenyl quinolinecarboxamide ~ 4 The procedure is as in Example 1, starting from 2.5 g 6,7-dimethoxy-2-phenyl quinolecarboxylic acid-4, 8 ml of thionyl chloride and 8.2 ml of diethylamine.
This gives g of N, N-diethyl dimethoxy-6,7 phoenix guinoléinecarboxamide-4 in the form of an oil, which we transform, within acetone, into its chlorhy-drape by adding a hydrochloric acid solution in ether. After recrystallization from acetone, the latter has a melting point of 140 C.
Article dimethoxy-6,7 phenyl-2 quinol ~ inecarboxy-lique-4 can be prepared according to the process described by BORSCHE AND BARTENHEIMER, Ann, 548, 50 ~ 1941 ~.

EXAMPLE 7:
N, N-diethyl-methyl-6 phoenix quinoleinecarboxamide-4 The procedure is as in Example 1, starting with 3.2 g metis phoenix quinoleinecarboxylic acid - 4, 15 ml thionyl chloride and 12.5 ml of diethylamine ~
After recrystallization of the residue from ether ~ 2 ~ 35 ~

isopropyl, 3.1 g of N, N-diethyl methyl-6 are obtained phenyl-2 quinoline carboxamide-4 melting at 120 C.
Methyl] -6 acid 2-phenyl quinoline carboxylic-4 can wax prepared according to the process described by sUcHMANN and HOWTON, J. Amer. Chief. Soc., 68, 2718 (1946).

AMPLE 8:
N, N-diethyl-8-nitro-2-phenyl quinoline-carboxamide-4 The procedure is as in Example 1, starting from 32 g 8-nitro-2-phenyl quinoline-4-carboxylic acid, 9 ml of thionyl chloride and 11.5 ml of diethylamine.
After recrystallization of the residue in a mixture cyclohexane / ethyl acetate (1: 1), A g of N, N-diethyl-8-nitro-2-phenyl quinolinecarboxamide-4 fondant at 138 C.
Nitro-8-phenyl-2 quinolinecarboxylic acid ~ 4 can be prepared according to the process described by BUCHMANN ci Ai., J. Amer. Chief. Soc., 69, 380 (at 2 0 CALL 9:
N, N-di (1-methyl-propyl) (2-chloro-phenyl) -2 quinoleinecar-boxamide-4 The procedure is as in Example 1, starting from 2.83 g acid (2-chloro phoenix quinoline carboxylic-4, 10 ml of thionyl chloride and 5.16 g of N (methyl-1 propyl) butanamine-2, We obtain, after a first chromatography residue on silica gel with a cyclohexane-~ ethyl acetate (1: 1) like ~ luaIlt, then after a second pressure chromatography on silica gel with a cyclohexane mixture ~ ethyl acetate (7: 3) as alder, y 1.8 g of N, N-di metis propyl) ~ chloro-2 phoenix quinol ~ inecarboxamide-4 fondant 120 C.

~ 2Z859 ~

EXAMPLE 10:

(2-phenyl-quinolyl-4) carbonyl-1 piperazine 30 g are refluxed for four hours 2-guinoline-4-carboxylic acid in 90 ml of thionyl chloride. The thionyl chloride is evaporated, takes up the residue with 100 ml of diethyl ether and evaporates again. The residue is added in portions to a solution stirred with 51.6 g of piperazine in 250 ml of chloride methylene. Stir overnight at room temperature. The solution is then taken up in 500 ml of methylene chloride S and 400 ml of water. The organic phase is separated and the phase aqueous solution is washed with 3 times 100 ml of methylene chloride.
The organic phases are combined, washed with 150 ml of water, dried over magnesium sulfate and evaporated under reduced pressure.
The residue is taken up in 200 ml of a solution 0.1N aqueous acetic acid. The insoluble material is filtered, washed with 3 times 20 ml of the 0.1 L aqueous solution of acetic acid.
The filter and the washing solutions are combined and basified by addition of a concentrated hydroxide solution potassium lily, and extracted with 3 times 150 ml of chloride methylene. The organic phase is washed with 3 times 60 ml of water, dried over magnesium sulphate and evaporated HOU
reduced pressure. The residue is chromatographed on gel silica using a toluene /
diethylamine (9: 1).
The raw base thus obtained is dissolved in ethanol, then transformed into its dihydrochloride by addition of a solution of hydrochloric acid in ether.
After recrystallization from ethanol, 2.4 g of (2-phenyl-quinolyl-4) carbonyl-1 piperazine dihydrochloride, melting above 250 C.

EXAMPLE 11:
__ _ N, N-diethyl ~ 4-methyl phoenix quinoline carboY ~ 4-amide At 5.5 ml of diethylamine in Su ml of, titra-hydroEuranne an hydre, added at room temperature and under a nitrogen atmosphere, 22.5 ml of a 1.6 M solution of butyllithium in hexane. After 15 minutes of agitation, it is cooled to 0 C, then slowly introduced S, 25 9 ~ Z; ~ 85 ~ 3 of (4-methylphenyl) -2 ethyl quinolinecarboxylate-4.
The mixture is stirred for 2 hours at room temperature. We then add slowly, at room temperature and with stirring, acetic acid until discolored and a yellow solution. Then add 100 ml of water, evaporate tetrahydrofuran under reduced pressure, and extracted by 3 times 100 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel with a cyclohexane / ethyl acetate mixture (80:20) as an evader. After recrystallization of the product crude thus isolated in isopropyl ether, 1.1 g are obtained N, N-diethyl ~ 4-methylphenyl) -2 quinolinecarboxamide-4 melting at 145 C.
(4-methylphenyl) -2 quinolinecarboxylate-4 ethyl can be prepared by the action of ethanol on (4-methylphenyl) -2 quinolinecarboxyli acid ~ eu-4 in presence of concentrated sulfuric acid. He presents a point 52 C.
Acid ~ 4-methyl phoenix quinoline carboxylic

-4 can be prepared according to the process described by C. PRÉVOST
et ci., Compté Rend. Akkad. Set., 258d 954 ~ 1964).

JOB 12:
N, N-diethyl chloro-6 (4-chloro phenyl) -2 quinoleinecarboxa-mide-4 3 ml of diethylamine in 15 ml of tetrahedron reindeer anhydrous, added at room temperature and under nitrogen atmosphere, 12.5 ml of a 1.6M solution of butylli-thium in hexane. nearly an hour onreEroidit d -65 C, then slowly introduced 3.4 g of chloro-6 (chlorinated 4 phenyl) -2 quinolinecarboxylate-4 in lys ml of tetrahydrofuran. Shake 2:30 min. -THAN, then introduce 4 ml of glacial acetic acid, leave the ~ Z ~ 5 ~

medium temperature return to -10 C, add 50 ml of water and finally let it return to room temperature. We evaporated tetrahydrofuran, extracts the insoluble material 3 times 50 ml ethyl acetate. The organic phase is washed with water, S dried over magnesium sulfate and evaporated HOU pressure scaled down .
The residue obtained is chromatographed on gel silica with a cyclohexane / chloroform mixture (50:50) evasive rubber. After recrystallization from acetate y ethyl of the crude product thus isolated, 1.1 g of N, N-diethyl chloro-6 (4-chloro phenyl) -2 ~ uinoline carbox-mide-4 melting at 173 C.
Chloro-6 (4-chloro-phenyl) -2 quinoleinecarboxy-ethyl latex can be prepared by the action of ethanol lily on chloro-6 (chloro-4 phenyl) -2 quinoline carboxy acid lique-4, in the presence of concentrated sulfuric acid. he has a melting point of QUE.
Chloro-6 acid (chloro-4 phoenix quinoline-carboxylic-4 can be synthesized according to the process described by LUT et ci., J. Amer. Chief. Soc. y (1946) 1813-14.
EXAMPLE 13:
N, N-diethyl (3-chloro-phenyl) -2 quinolinecarboxamide-4 We proceed as in example ~ the 12, starting from 4.3 ml of diethylamine, 20 ml of a 1.6 M solution of S butyllithium in hexane, and 3.2 g of (3-chloro-phenyl) -2 methyl quinolinecarboxylate-4. 3.4 g are then obtained.
of N, N-diethyl (3-chloro-phenyl) -2 quinolinecarboxarnide-4, that lion transforms into its hydrochloride by adding to a product solution in lattons an acid solution hydrochloric acid in diethyl ether. After recrystalli-station in an ethanol / diethyl ether mixture (2: 1), this hydrochloride has a melting point of 165 C.

: ~ 2 ~ 35 ~

(3-Chloro-phenyl) -2 quinolinecarboxylate-4 methyl can wax prepared by the action of methanol on (3-chloro-phenyl) -2 quinolinecarboxylic-4 acid presence of concentrated sulfuric acid. It presents a melting point of 101 C.
(3-Chloro-phenyl) -2 quinoline carboxylic acid -4 can be prepaid according to the process described by RIF. BROWN
et ci., J. Amer Chef. Soc., 68, 2705 (1946).

EXAMPLE 14:
N, N ~ diethyl (3,4-dichloro phenyl) -2 quinoline carboxamide-4 We proceed as in Example 12, starting from 5 ml of diethylamine, 23 ml of a 1.6M solution of butyllithium in hexane and 4 g of (3,4-dichloro-phenyl) -2 quinoline-ethyl carboxylate-4. After 3 recrystallizations of the residue in isopropanol, 2.5 g of N, N-diethyl (dichloro) are isolated -3.4 phenyl) -2 quinolinecarboxamide-4 melting at 170 C.
(3,4-dichloro-phenyl) -2 quinolinecarboxylate-4 ethyl can be prepared by the action of ethanol on (3,4-dichloro-phenyl) -2 quinolinecarboxylic acid-4 in presence of concentrated sulfuric acid. He presents a point 74 C.
Acid (3,4-dichloro-phenyl) -2 q ~ inoline carboxy-lique-4 can wax prepared according to the process described by RIF.
25 BROWN et al., J. Amer. Chief. Soc., 68, 2705 (1946).

EXAMPLE 15:
-N, N-diethyl ~ 2-fluoro phenyl) -2 quinoleinecarboxamide-4 We proceed as in example 12, starting from 27 ml of diethylamine, 12.5 ml of a 1.6M solution of butyllithium donated hexane and 2 g of ~ fluoro-2 phenyl) -2 quinol ~ ethyl inecarboxylate-4. After recrystallization of the residue in isopropyl Luther, 2 of NON-di ~ thyl ~ fluoro-2 phenyl) -2 quinoleinecarboxamide-4 fondant ~ 85 ~

at 92 C.
(Eluoro-2 phenyl) -2 quinolinecarboxylate-4 ethyl can be prepared by the action of ethanol on (2-fluoro-phenyl) -2 quinolinecarboxylic-4 acid presence of concentrated sulfuric acid. It presents a melting point of 86 C.
(2-fluoro-phenyl) -2 quinoleinecarboxy-lique-4 can be prepared according to the process described by RIF.
BROWN and ci. J. Amer. Chief. Soc., 68, 2705 (1946).
EXAMPLE 16:
N, N-diiso ~ utyl (2-chloro phoenix quinoline carboxamide-4 Heat at reflux, for one hour, yg (2-chloro-phenyl) -2 quinoline carboxylic acid-4 in 10 ml of thionyl chloride. The chloride is evaporated thionyle, take up the residue in 40 ml of toluene and evaporate again. Then added to the residue obtained 20 ml of toluene and introduced dropwise, with stirring, a solution of 5.16 g of diisobutylamine in 20 ml of toluene.
zou Shake overnight at room temperature, evaporated under reduced pressure, takes up the residue in 50 ml of chloroform and 100 ml of water. The organic phase is decanted, dried over magnesium sulfate and evaporated under reduced pressure.
Ire residue obtained is dissolved in 100 ml of acetate ethyl, the organic phase is extracted with 100 ml of a normal solution of acetic acid, washed at times 100 ml of water, dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is taken up in the ballast and, after adding a solution of hydrochloric acid in Luther isolated 1.5 g of N, N-diisobutyl hydrochloride ~ 2-chloro-phenyl) -2 ~ uinolineec ~ rboxamide-4 fondant QUE.

Example 17:
N, N-dimethyl ph ~ 2-nyl-quinolinecarboxamide-4 hi To a stirred solution of 18.9 g of NON-dimethylamine in 100 ml of methylene chloride, cooled to 0 ° C., it is added in one hour, in portions, 10.7 g 2-phenyl acid chloride hydrochloride qu: inolinecarboxylic-4. Shake for one hour at 0 C. The solution is evaporated under reduced pressure. The residue is taken up in 100 ml of methylene chloride. The sentence organic is washed with 3 times 100 ml of water, dried over magnesium sulfate and evaporated under reduced pressure.
After recrystallization of the residue in milk nitrile, 7.9 g of N, N-2-dimethylphenyl quinoline are isolated.
carboxamide-4 melting at 158 C.

N, N-2-diethylphenyl-8-trifluoromethyl quinolinecarboxamide Jo We proceed as in example 1, starting from 10 g 2-phenyl-trifluoromethyl-8 quinoline carboxy acid lique-4, 30 ml of thionyl chloride and 16.2 ml of diethylamine.
close chromatography on silica gel with a cyclohexane ~ ethyl acetate mixture (70 30) as eluding and recrystallization from an isopro ether mixture pylic / petroleum ether (8: 3), 9.2 g of NON-diethyl phenyl-2 trifluoromethyl-8 quinoline carboxamide-4 fondant 3 114 C.
2-phenyl-8-trifluoromethyl quinolineacaric acid boxyli.que-4 can wax prepared according to the process described by D BOYKIN and y J. Med. Chef., 11 (2) 273-277 (1968).
PHARMACOLOGICAL CLEANLINESS

Affinity for benzodia2 ~ pine receptor sites This affinity is measured by the ability of y products to move the initiated diazepam (H-dia ~ epam) from its binding site and is expressed as a Kif value in micro moles Mû which is calculated by the formula:
HIC

Kif C

in which C represents the concentration of 3H-diazepam used, AD a constant define characteristic of the diazepam and HIC the necessary product concentration to obtain a 50 ~ inhibition of the binding of H-diazepam.
The affinity of the compounds of formula (I) for the benzodiazepine brain receptor sites has been endow-mined according to the MOULER and Colt method, Science Linked, 1977, 20, 2101, on membranes of rat brain.
The affinity of the compounds of formula (I) for the peripheral type receptor sites has been determined, using the BRAESTRUP et Collé protocol, Pro. Native.
Akkad. Set. USA, 1977, 74, 3805, on membranes of rat kidney.
As an example, we obtained the results following:
Affinity for type golds Kil Mû Products Example S 0.21 y Example 11 0.33 Example 15 0.31 Chlordiazepoxide 0.08 ; ~ 2 ~ 59 ~

Affinity for peripheral type receptor sites Kif products (ut) Example 3 0.117 Example 5 0.160 Example 9 0.072 Example y 0.117 Diazepam 0.043 Rot TOXICOLOGICAL PROPERTIES
Acute toxicities of the compounds of formula (I) were determined in the CI 1 mouse (Charles RIVER) orally. LD50 were calculated after 3 days of observation, by the cumulative method of JE REND and H.
MUENCH (Amer. J. Hi., 1938, 27, 493).
The compounds of formula (I) behave as relatively little toxic substances in the suris, since the LD50s of the compounds are between 200 and 1000 mg / kg.

THERAPEUTIC USE
Medicines according to the invention which contain a compound of formula (I) or a mixture of ster ~ oiso- compounds mothers corresponding to formula (I) or a salt of such a compound or mixture of stereoisomeric compounds with a pharmaceutical acid acceptable ticlit, associated with a pharmaceutical vehicle-acceptable, can be used in therapy therapy for the treatment of anxiety states and pulmonary, renal, cardiovascular or circulatory disorders latoires ~ They can be presented SOU all the forms in use in the field of medicaments, such as tablets, .,,

5 ~ 3 capsules, capsules, suppositories, ingestible solutions or injectable, and ...
The dosage depends on the desired effects and the route of administration uses For example, by route oral, it can wax between 10 and 500 mg of undergone active session per day, with unit doses ranging from 2,100 mg of active substance.

Claims (2)

The embodiments of the invention, concerning the-which an exclusive property or privilege is claimed, are defined as follows: 1. Drug compositions containing a active substance and a pharmaceutically acceptable carrier table, characterized in that the active substance is a compound corresponding to the general formula (I):

in which A represents a nitrogen atom, B represents a CH group, R1 and R2 represent alkyl groups linear or branched, identical having 1 to 4 atoms of carbon, R1 and R2 can also form with the nitrogen atom to which they are attached a piperazino radical, Z represents a phenyl group which is unsubstituted or substituted by one or two substituents chosen from the group consisting of halogen atoms, alkyl groups having 1 to 3 atoms carbon, the alkoxy groups having 1 to 3 carbon atoms, CF3 group and nitro group, X and Y, identical or different, represent hydrogen, halogen atoms alkyl or alkoxy groups having 1 to 3 carbon atoms, nitro or CF3 groups, with the exception of N, N-diethylphenyl-2 quinoline carboxamide-4, or an addition salt thereof posed with mineral or organic pharmaceutical acids-acceptable. 2. Compositions according to claim 1, charac-terized in that, in the general formula (I), X and Y
are hydrogen atoms.