FR2632861A1 - 4-Amino-3-carboxyquinoline and -naphthyridine derivatives, process for preparing them and their application as medicaments - Google Patents

Abstract

The invention relates to compounds of formula I in which R1 and R2, which may be identical or different, represent a hydrogen atom, a C1 to C6 alkyl group or a phenyl or benzyl group, or R1 and R2, with the nitrogen atom to which they are attached, form a saturated C4 to C8 heterocycle, R3 represents a C1 to C6 alkyl or C7 to C9 phenylalkyl group, R4 and R7 represent, independently of one another, a hydrogen atom or a C1 to C4 alkyl group, R5 and R6, which may be identical or different, represent a hydrogen or halogen atom, a C1 to C3 alkyl or alkoxy group or a nitro or trifluoromethyl group, R8 represents a hydrogen atom, a C1 to C4 alkyl group or a phenyl group; n represents 0, 1 or 2, and one of the symbols A, B, C, D represents N and the others CH, or A, B, C, D each represent CH, as well as their addition salts with pharmaceutically acceptable acids or bases. Medicaments.

Description

 The present invention relates to new derivatives of 4-amino-3-carboxyquinolines and naphthyridines, their process of preparation and their therapeutic application.

dans laquelle R1, R2, R3, R4 sont H ou des groupes hydrocarbonés : alkyle. aryle. aralkyle. We already know naphthyridine derivatives and especially quinolines useful in therapy for pharmacological activities-s very diverse, such as antibacterial, antihypertensive, anxiolytic, anti-inflammatory, and analgesic. activities essentially dependent on groups substituting aromatic rings. Among these, some derivatives have been reported to bind to the benzodiazepine receptors:
-4-amino-3-carbamoyl quinolines, described in EP-A-0 245 054, of formula A

in which R1, R2, R3, R4 are H or hydrocarbon groups: alkyl. aryle. aralkyl.

the quinolines, described in FR-A-2 582 514. of formula B

in which R1, R2 R3, R4 represent H or alkyl or aryl groups. Z represents a group
aryl and X represents CH-R4, N-R4 SO, S02, 0 or S and
V and W represent H, halogen, alkyl, alkoxy, NO2 or CF3.

dans laquelle R représente un groupe cycloalkyle, hétéroaryle, phényle substituté ou non, A représente
N, S, SO, ou O et R1, R2 représentent notamment H ou un groupe alkyle.The naphthyridines, described in EP-AO 234 971, of formula C

in which R represents a cycloalkyl, heteroaryl, substituted or unsubstituted phenyl group, A represents
N, S, SO, or O and R1, R2 represent in particular H or an alkyl group.

dans laquelle R1, R2, R3 représentent H, un groupe alkyle ou aryle, et R4 représente OH, un groupe OR ou un alkyle.- The quinolines, described in FR-A-2 581 382, of formula D

wherein R1, R2, R3 represent H, an alkyl or aryl group, and R4 represents OH, an OR group or an alkyl.

 It has now been found that a modification of formula D makes it possible to obtain compounds which do not bind, at pharmacologically significant doses, to central benzodiazepine receptors such as compounds D, but which bind only to type receptors peripheral which we know that activation leads to pharmacological activities different from those resulting from the activation of central receptors.

dans laquelle
R1 et R 2' identiques ou différents, représentant 1 atome d'hydrogène, un groupe aikyle en C1 à C6, un groupe phényle ou benzyle, ou R1 et R2 forment avec l'atome d'azote auquel ils sont attachés un héterocyle saturé en C4 à C8,
R3 représente un groupe alkyle en C1 a C6 ou phénylalkyle en C7 à Cg,
R4 et R7 représentent, indépendamment l'un de l'autre, l'atome d'hydrogène ou un groupe alkyle en- C1 à C4,
R5 et R6, identiques ou différents représentent un atome d'hydrogène ou d halogène. un groupe alkyle ou alkoxy en C1 à C3, un groupe nitro, trifluorométhyle, cyclohexyle ou ensemble un groupe methylènedioxy,
R8 représente l'atome d'hydrogène, un groupe alkyle en
C1 à C 4 ou groupe phényle n représente 0,1 ou 2. et l'un des symboles A,B,C,D représente N et les autres
CH ou A,B,C,D représentent chacun CH, ainsi que leurs sels d'addition avec les acides ou les bases pharmaceutiquement acceptables.The invention relates to compounds corresponding to formula I

in which
R1 and R 2 ', identical or different, representing 1 hydrogen atom, a C1 to C6 alkyl group, a phenyl or benzyl group, or R1 and R2 form with the nitrogen atom to which they are attached a heterocyle saturated in C4 to C8,
R3 represents a C1 to C6 alkyl group or a C7 to C6 phenylalkyl group,
R4 and R7 represent, independently of one another, the hydrogen atom or an C1-C4 alkyl group,
R5 and R6, identical or different, represent a hydrogen or halogen atom. a C1 to C3 alkyl or alkoxy group, a nitro, trifluoromethyl, cyclohexyl group or together a methylenedioxy group,
R8 represents the hydrogen atom, an alkyl group
C1 to C 4 or phenyl group n represents 0.1 or 2. and one of the symbols A, B, C, D represents N and the others
CH or A, B, C, D each represent CH, as well as their addition salts with pharmaceutically acceptable acids or bases.

 Among the acids. mention may be made of hydrohalic, nitric, sulfuric, phosphoric acids or carboxylic acids such as acetic or formic acid. succinic, tartaric, oxalic and aspartic or sulfonic acids such as methanesulfonic or benzenesulfonic acid; the salts with the bases can be alkaline, alkaline-earth salts or salts with hands such as lysine, piperazine or ethanolamine.

 The alkyl groups can be linear, branched or cyclic.

 The phenyl or benzyl groups can be substituted by halogens, C1 to C3 alkoxy or C1 to C3 alkyl groups.

Among the preferred products which are the subject of the invention, there may be mentioned the quinoline or naphthyridine-1,5 esters of formula I in which R8 is H,
R3 represents a C1 to C 3 alkyl and more particularly the methyl group, n is O and R4 represents
H.

Another subject of the invention is the process for preparing the compounds of formula I which consists in reacting on the amine of formula II

dans lesquelles R1, R2, R3, R4, R5, R6, R7, R8, A, B,
C, D, et n ont les mêmes significations nue dans la formule I et X représente un halogène tel que Cl ou Br
ou un groupe sulfonate RSO3 dans lequel R est un grou
pe alkyle ou benzyle. I derived from formula III

in which R1, R2, R3, R4, R5, R6, R7, R8, A, B,
C, D, and n have the same meanings naked in the formula I and X represents a halogen such as Cl or Br
or a RSO3 sulfonate group in which R is a group
eg alkyl or benzyl.

The substitution of the amine II can be carried out under conventional conditions, at a temperature of between 80 ° C. and t80-C., preferably in the presence, to complex the acid formed, of a base such as a tertiary amine or an alkali carbonate is generally carried out in an organic solvent, such as a hydrocarbon such as toluene, such as an alcohol such as ethanol or isopropanol, such as an ether such as dioxane, or such as a solvent polar aprotic, such as dimethylformamide; the reaction can also be carried out at a pressure higher than atmospheric pressure, between 5 and 70 x 10
Pa, in a closed enclosure.

Certain derivatives of formula II have already been described, such as 2-amino NN-diethylpropanamide in
J. Chem. Soc. p. 2972-2980 (19521. The others can, among other things, be prepared from known products by applying conventional methods and for example - from IV amino acid derivatives, the amino function of which is protected in the form of labile carbamate and the acid function is activated by a succinimidoyl group as described by GW Anderson in JACS

86 p. 1839-1842 (1964).

(dans laquelle R1, R2 R3 R4, et n ont la meme signification que dans la formule I et R est un alkyle), avant d'éliminer le groupement carboxylique protégeant l'amine terminale par action d'un acide tel que les acides trifluoroacétique, sulfurique ou chlorhydrique; - à partir d'amides de formule VI

(dans laquelle X représente Cl ou Br, et R1, R2, R3 et n ont les mêmes significations qu'à la formule I) qui peuvent etre préparés selon le procédé décrit dans
Synthetic Organic Chemistry - chap. 19; ; R.B. Wagner et
H.D. Zook (1953), publié par J. Wiley et Sons.in which R3 R4, and n have the same meanings as in formula I and R represents a C1 to C4 alkyl group, on which the amine is reacted
HN R1 R2, to give the compound of formula V

(in which R1, R2 R3 R4, and n have the same meaning as in formula I and R is an alkyl), before eliminating the carboxylic group protecting the terminal amine by the action of an acid such as trifluoroacetic acids , sulfuric or hydrochloric; - from amides of formula VI

(in which X represents Cl or Br, and R1, R2, R3 and n have the same meanings as in formula I) which can be prepared according to the process described in
Synthetic Organic Chemistry - chap. 19; ; RB Wagner and
HD Zook (1953), published by J. Wiley and Sons.

 The compound of formula VI is reacted with the amine R4-N H2, at a temperature between 60 ° C. and 130 ° C., in solution in an alcohol or an ether, at atmospheric pressure or between 5 and 40 × 105 Pa.

Certain starting quinolines or the hydroxylated derivatives in 4 correspondents (formula III
A = B = C - D = CH; X = OH or Cl) are known compounds described in particular in J. Med. Chem. li. 7 p.

816-823 (1979) or in FR-A-2 581 382, previously cited; and those in which R is different from H, can be prepared by the method described by R.P.

Staiger and EB Miller in J. Org. Chem. 24, p. 1214
(1959).

The naphthyridines of formula III, in which X = OH are prepared by conventional methods, previously described, for example in Heterocyclic compounds - vol. 7 (1961): naphthyridines
(Chap. 2) Ed. J. Wiley.

The compounds of formula III in which X = halogen are prepared, for example by the action of
POX3 or PX3 on the corresponding hydroxylated derivatives, according to a conventional technique.

 The invention also relates to medicaments comprising at least one compound of formula I or one of its pharmaceutically acceptable salts.

 These compounds have, in effect, an in vitro and in vivo affinity for the peripheral type benzodiazepine receptors without exhibiting a specific affinity for the central receptors and their pharmacological activities will be those of the peripheral type receptor ligands of the benzodiazepines, that is to say, anxiolytics, vasodilators or immunomodulators.

 The medicaments of the invention will be administered, for example, orally, in the form of tablets, capsules or granules, or rectally - in the form of suppositories or parenterally in the form of an injectable solution, at a rate of 1 mg to 400 mg per day. in one or more doses according to the structure of the compound, the age of the patient and the nature and severity of the disease.

 The compounds of formula I, or their salts, will be associated with the usual excipients compatible with their chemical structure.

 The following examples illustrate the invention. The elementary analyzes of the isolated products meet the usual standards. The products are characterized by their instantaneous melting points possibly by their NMR spectrum (m signifies solid, d doublet, s singlet, t triplet and (x H) that the band corresponds to x protons) the internal reference is Si (CH3) 4 ); the infrared spectra show the characteristic bands of the expected structures.

Preparation of amines of formula II
a) N, N-dipropyl (2-amino) propanamide
(formula II: R1 = R2 = C3H7, R3 = CH3, R4
H, n = 1)
58g of N- (terbutoxycarbonyl) alanine, prepared from racemic alanine, 33g of N-hydroxysuccinimide and 59g of dicyclohexylcarbodiimide, dissolved in 1400 ml of dioxane, are stirred for 6 hours. The precipitate is then separated and the solvent is evaporated off under reduced pressure. The residue is washed with a 5% aqueous Na2CO3 solution
After drying, 819 of compound of formula IV are isolated (R 3 = CH 3 'R4 = H, R = C2H5, n = 1) which melts at 143 C.

 (From L-alanine, a product melting at 168-C is obtained under the same conditions).

80 g of this product are dissolved in 700 ml of tetrahydrofuran containing 140 ml of dipropylamine and the mixture is left stirring for 48 hours. The solvent is then evaporated off under reduced pressure and 80 g of compound of formula V are obtained after washing with water and drying in which R1 = R2 = C3 H ?, R3 = CH3, R4 = H, R
C2H5, n = 1, which melts at 92 ° C.

(The product prepared from product IV derived from L - alanine does not crystallize).

This compound is dissolved in 400ml of chloro form; 160 ml of trifluoroacetic acid in solution in 200 ml of chloroform are added thereto to 5 Cl, and after 3 hours of stirring, the solvent is evaporated off under reduced pressure. Water is poured onto the residue and neutralized by adding NaOH before extracting the expected product in dichloromethane. 299 yellow oil are thus obtained. Spectrum (H-NMR-: 60 MHz, OMSOd6)
# (ppm): 0.6 - 1.2 (m, 9H); 1.2 - 1.8 (m, 4H); 2.2 2.6 (s, 2H exchangeable); 3 - .3.4 (m.5H).

(The amine derived from Lalanine or its trifluoroacetate is isolated in the same way after evaporation of the chloroform)
b) N, N-dibutyl (2-amino) propanamide:
79 of the compound of formula IV. prepared in a) are dissolved in 100 ml of tetrahydrofuran containing 30 ml of N, N-dibutylamine; after 30 hours with stirring, the solvent is removed by distillation and the residue is washed with water to give 7.59 of product of formula V, in which R1 = R2 = C4H9, R3 = CH3.

R4 = H, R = C2H5 and n = 1, which melts at 80 C.

 This product is dissolved in 100 ml of CHCl3 containing 28 ml of CF @ -COOH at 0 C: and treated as its analog.

c) N-methyl N- (chloro-4) phenyl (2-amino) propanamide
17.6 ml of chloro-2propionyl chloride are slowly introduced at 5 ° C. into a solution, in 50 ml of ethyl ether, of 24.2 ml of N-methyl (chlo ro-4) phenylamine and 30 ml of triethylamine; the mixture is allowed to return to ambient temperature, with stirring; 5 hours after the end of the addition the precipitate is separated, the solvent is evaporated under reduced pressure and the residue is dissolved in ethyl ether; the organic solution is washed with an aqueous HCl solution (0.5 N) and then with water before removing the solvent to give. with 55Z of yield, the product of formula VI, in which R1 = CH3 R2 = (Cl-4) C6H4, R3 = CH3, n = o X = Cl.

 59 of this compound are maintained at 100-C, for 3 hours, in a 100 ml autoclave containing 60 ml of liquid ammonia. After 12 hours, during which the medium returns to room temperature, the ammonia is eliminated and the sought-after amine is extracted into ethyl ether.

 2.5 g of oil are thus obtained.

1H NMR (60 mHz, CDCl3) #: 1.1 - 1.2 (d, 6H); 2 - 2.3 (m, 2H exchangeable); 3.2 (s, 3H); 3.3 - 3.6
(m, 1H); 6.9 - 7.5 (m, 4H).

d) N, N-dipropyl (2-amino) -3-phenyl-propanamide
(formula II: R1 = R2 = C3H7, R3 = CH2 C6
H5, R4 = H, n = 0)
26.5 g of N- (tert-butoxycarbonyl) phenyl alanine (F = 110-C), prepared by the action of ditert-butyldicarbonate on the racemic phenyl alanine, 11.59 of N-hydroxysuccinimide, 20.6 g of dicyclohexylcarbodiimide are introduced into 500ml of dioxane; after 4 hours of stirring, the insoluble material is separated and the solvent evaporated under reduced pressure. The corresponding product of formula IV is obtained, melting at 138 ° C.

 After reaction with 12 g of dipropylamine, the corresponding product of formula V is obtained, melting at 94 ° C., which by the action of trifluoroacetic acid in chloroform, gives the trifluoroacetate of the amide of formula II sought, melting at 108 ° C., with an overall yield of 40%.

Example 1 {[N, N-dipropylcarbamoyl) -1 ethylamino] -4 trifluoromethyl-7 quinolinyl-3} ethyl carboxylate (formula I: R1 = R2 = C3H7; R3 = CH3, R4 = H, n = o,
R5 = H, R6 = 7-CF3, R8 = H, R7 = C2H5, A = B = C = D =
CH) reference number: SR 26241.

Heated for 6 hours at its reflux temperature, a solution in 100 ml of ethanol, of 2.6y of
N, N-dipropyl (2-amino) propanamide, 3 g of (4-chloro-7-trifluoromethyl-3-quinolinyl) carboxylate (F = 60 C) and 2 ml of triethylamine.

 After removing the solvent, the residue is taken up in water and dichloromethane. The organic phase is decanted, the solvent evaporated and the residue purified by chromatography on a silica column, eluting with isopropyl ether. After recrystallization from hexane, the desired product is obtained with 327. yield; F = 100 C.

H NMR (80 mHz, CDCl3) #: 0.6-1 (m, 6H); 1.3-1.8 (m, 10H); 2.9-3.8 (m, 4H); 4.3-4.7 (Q, 2H); 4.9-5.3 (m, 1H); 7.5-8.35 (m, 3H); 9.2 (s, 1H); 9.5-9.7 (d, 1H exchangeable).

Examples 2 to 24: Quinoline derivatives
These examples of compounds of formula I in which A = B = C = D = CH and n = O, appear in Table I; the products were prepared by applying the method described in example 1.

EXAMPLE 25
{[Chloro-6 (N, N-dipropylcarbamoyl) -1 ethylamino) -4 naphthyridine-1,5] yl-3} ethyl carboxylate.

(formula I: R1 = R2 = C3H7, R3 = CH3, 3 R4 = H, R6 = 6-Cl-, R7 = C2H5, R8 = H, A = N, B = C = D = CH n = o)
Reference: SR 26293
Maintaining for 1 hour, at its reflux temperature, a solution in 30 ml of ethanol of 2.7 g of [(dichloro-4,6 naphthirydine-1,5) yl-3] ethyl carboxylate F = 114 C , 2.2 g of N, N-dipropyl (2-amino) propanamide hemisulfate and 3.1 ml of triethylamine.

 The solvent is then removed under reduced pressure and the residue is dissolved in 50 ml of dichloromethane; the organic solution is washed with 2 times 10 ml of water, then the solvent is removed, after drying.

 The residue is purified by chromatography on a silica column, eluting with a mixture of toluene and ethanol (99/1).

 After recrystallization from cyclohexane, the expected product melts at 133 C.

H NMR (60MH, CDCl3) #: 0.6-1 (t, 6H); 1.1-1.8 (m, 10H); 2.8-3.8 (m, 4H); 4.1-4.6 (q, 2H); 6.1-6.5 (m, 1H); 7.27.5 (d, 1H); 7.7-8 (s, 1H); 8.95 (s, 1H); 10.4-10.7 (d, 1H exchangeable).

Example 26:
{[chloro-6 (N, N-dipropylcarbamoylmethyl) -1 ethylamino) -4 naphthyridine-1,5] -yl-3} ethyl carboxylate (formula I: R1 = R2 = C3H7, R3 = CH3; R4 = R5 = H; = 6-Cl; R7 = C2H5; R8 = H; A = N, B = C = D = CH; n = 1) Reference: SR 26331.

-TABLE I
Characteristics
physical
Ex N SR R1 R2 R3 R4 R5 R6 R7 R8 FC (salt) [α] 20
2 26399 C 3H7 C3H7 CH3 H H- 5-C1 C2H5 H 94
3 26058 C3H7 C3 H7 CH3 HH 6-Cl C2H5 (C.SOLVANT) H 59
4 26274 C3H7 C3H7 CH3 HH 6-Cl C2H5 H 170 (HCl) - 19 (1; H2O)
5 26310 C3H7 C3H7 CH3 HH 7-Cl C2H5 H 83
6 26378 C3H7 C3H7 CH3 HH 7-Cl C2H5 H 160 (HCl) -0.9 (1;
CH3OH)
7 26422 C3H7 C3H7 CH3 HH 7-Cl C2H5 H 175 (HCl) +1.9 (1 ;;
CH3OH)
8 26351 C3H7 C3H7 CH3 HH 8-Cl C2H5 H 98
9 26377 C3H7 C3H7 CH3 HH 7-Br C2H5 H 160 (HCl, H2O)
10 26421 C3H7 C3H7 CH3 H 6-CH3 7-CH3 C2H5 H 170 (HCl, H2O)
11 26492 C3H7 C3H7 CH3 H 6-Cl 7-Cl C2H5 H 106
12 26357 C3H7 C3H7 CH3 HH 6-OCH3 C2H5 H 140 (maleate)
13 26522 C3H7 C3H7 CH3 HH 7-OCH3 C2H5 H 102
14 25552 C3H7 C3H7 CH3 H 6,7-OCH2-O C2H5 H 130 (maleate H2O)
15 26426 C3H7 C3H7 CH3 HHH C2H5 H 170 (maleate)
16 26487 C3H7 C3H7 CH3 HH 6-cyclo- C2H5 H 100
hexyl
17 26449 C3H7 C3H7 CH3 HH 7-Cl C4H9 H 84
18 26454 C2H5 C2H5 CH3 HH 7-Cl C 2H5 H 100
19 26362 C4H9 C4H9 CH3 HH 7-CF3 C2H5 H 140
20 26423 CH3 (Cl-4) - CH3 HH 7-Cl C2H5 H 146
-C6H4
21 26306 C3H7 C3H7 C2H5 HH 7-CF3 C2H5 H 60
22 26258 C3H7 C3H7 C6H5 HH 7-CF3 C2H5 H 95
23 26319 C3H7 C3H7 CH3 HH 6-Cl CH3 CH3 oil
24 26 269 C3H7 C3H7 CH3 HH 6-Cl CH3 C6H5 110
By applying the procedure described in the example
25, we obtain with 37% yield, the product re
sought which melts at 102 ° C. after recrystallization from ethyl acetate.

H NMR (80 MHz, CDCl3) #: 0.55-1.00 (E, 6H); 1.15-1.80
(m, 10H); 2.50-2.95 (m, 2H); 3.00-3.50 (m, 4H); 4.10-4.50
(q, 2H); 5.40-5.80 (m, 1H); 7.30-7.50 (d, 1H); 7.90-8.10
(d, 1H); 9.01 (s, 1H); 9.40-9.60 (d, 1H).

Example 27
{[bromo-7 (N, N-dipropylcarbamoylethylamino) -4 dine-1,5] yl-3} ethyl carboxylate) -4 naphthyri
(formula I: R1 = R2 = C3 H7, R3 = CH3, R4 = R5 = R8 =
H, R6 = 7-Br, R7 = C2H5, n = O, A = N, B = C = D =
CH). Reference: SR 26579.

a) ethyl (7-bromo-4-chloro-1,5-naphthyridine) yl37carboxylate
Prepared by the action of POCl3 on ethyl (7-bromo-4-hydroxy-naphthyridine-1,5) yl-3 carboxylate.

This product melts at 130 C.

 b) 3.019 of naphthyridine thus prepared, 2.86 of N trifluoroacetate, 2-N-dipropylamino-propanamide and 2.7 ml of triethylamine are dissolved in 50 ml of ethanol and the solution is brought to reflux for one hour. The solvent is evaporated; a solution of the residue in methylene chloride is washed with water and the solvent evaporated.

 The expected product, after recrystallization from cyclohexane melts at 96 C.

Example 28
{[chloro-7 (N, N-dipropylcarbamoylmethylamino) -4 naphthyridine-1,87-yl-3} ethyl carboxylate (formula I: R1 = R2 = C3H7, R3 = CH3, R4 = R5 = R8 = H, R6 = 7 7-Cl, R = C 2H5, A = B = C = CH. D = N, n =
O). Reference: SR 26493.

a) ethyl [(dichloro-4,7 naphthyridine-1,8) yl-3] carboxylate
109 of (7-chloro-4-hydroxy-1,8-naphthyridine) yl-3 ethyl carboxylate are brought to reflux for 1 hour in 100 ml of POCl3. When the reaction is over, the excess of
POCl3 is eliminated and the residue taken up in dichloromethane is neutralized with a solution of concentrated sodium hydroxide. The product is purified by chromatography on a silica column, eluting with a mixture of toluene and 98/2 ethanol. After recrystallization from cyclohexane, it melts at 134-136-C.

 b) 39 of the naphthyridine previously obtained, 2.59 of N, N-dipropyl- (amino-2) hemi-sulphate and 3.6 ml of triethylamine are introduced into 30 ml of isopropanol and the mixture is maintained for 3 hours at reflux. The solvent is evaporated; the residue, dissolved in. methylene chloride is washed with water and then chromatographed on a silica column, eluting with a mixture of cyclohexane and ethyl acetate (80/20). After recrystallization from ethyl ether, it melts at 93-C.

 The compounds of the preceding examples are not very toxic, and. in mice their LD50 is generally greater than 1000 mg / kg, orally; thus that of the compound of Example 1 is 1100 mg / kg.

 We also studied their in vitro affinity for the central benzodiazepine receptors and those of the peripheral type according to the methods described below; the determined values of the concentrations of the product studied inhibiting 50Z of the specific binding of the labeled ligand on its receptor (IC 50) are shown in Table II; they show that the products of the invention have a specific affinity for the peripheral receptors but do not bind to the central receptors.

a) determination of the concentration of the product studied inhibiting 507. of the specific binding of the peripheral type receptor of (2-chloro-phenyl) -1N-methyl N- (methylpropyl) isoquinolyl-3 carboxamide
(or PK 11195)
The technique is analogous to that described by J. Benavides et Coll. in Brain Res. Bull. 13 p.

 69-77 (1984).

 Cat brain membrane protein suspensions were prepared as described by J.

 Benavides.

The binding fixation inhibition tests
[H] PK11195 on the receptors by the products to be tested were carried out at 4C. on 2 ml of suspension containing 0.05 mg of protein and 0.5 nM of [H] PK11195; the incubations lasted 2 hours 30 minutes.

 The specific binding was determined by replacing the product of the invention with 10 μM of chloro-7 dihydro-1,3 methyl-1 (chloro-4 phenyl) -5 2H-benzodiazepine-t, 4 one-2 or RO 5 -4864.

 The concentrations of test product inhibiting 50% of the specific binding of PK11195 to the receptor (IC50), were calculated by applying the logit-log method described by Finney in Probit analysis-Cambridge University Press. 1979.

 b) determination of the concentration of the product studied inhibiting 50% of the specific binding of flunitrazepam to the central receptor.

The brains of rats, taken after pickling: - tation, are ground and then suspended in an aqueous solution of sucrose (0.32 M). The mixture is centrifuged and the pellet resuspended homogeneously in a solution buffered with TRIS-HCl '(5'0mM;
PH = 7.4). Aliquots of this suspension are incubated at 4 ° C. after introduction of [H] flunitrazepam, alone or with increasing amounts of the test compound. The quantity of labeled product fixed on the membranes separated from the incubation medium by fixing on a glass fiber filter is determined by liquid scintillation and calculated by the logit-log method the IC50; the non-specific fixation of flunitrazepam is determined by introducing 2 μm of clonazepam.

TABLE II
SR CI50nM CI50nM
(peripheral) (central)
26241 3> 20000
26399 7 12700
26310 1> 20000
26351 6 30000
26377 1> 20000
26421 5 53000
26492 1> 20000
26522 11> 20000
26552 31 12400
26487 39> 20000
26378 1> 20000
26579 1> 20000
26493 12> 20000
26449 1> 20000
26-362 3> 20000
26423 1 12600
26306 11> 20000
26 319 8 14 000
26269 16> 20000
PK11195 1.3 21400
R05-4864 44 inactive
DIAZEPAM 523 11
CHLORDIAZE- inactive 654
POXIDE
The affinity for the peripheral type receptors of the compound of example 5 was also studied, in vivo, in mice, using the ligand? H)
PK11195.

 The products to be tested, suspended in an aqueous solution of carboxymethylcellulose (1 x w / v) are administered orally to groups of 4 mice 25 minutes before the intravenous injection of [H] PK11195, at a rate of 200 pCi / kg (specific activity 66 Ci / mmol). 5 min after the injection, the animals are sacrificed by decapitation and the various organs are removed and ground in 10 ml of buffer based on Tris-HCl <50 mM; pH- = 7.4) to give homogeneous.

 The control groups receive the carboxymethylcellulose solution and the injection of 3H2PK11195.

We determine for each organ by scintigraphy
1 - the quantity of radioactive ligand present in an organ by measuring the radioactivity of an aliqu-ote part of the homogenate.

 2 - the quantity of radioactive ligand fixed on the membrane tissues of an organ by measuring the radioactivity fixed on a glass fiber filter by filtration of another aliquot of the homogenate.

 3 - the quantity of radioactive ligand fixed not specifically on the membrane tissues by incubating a control homogenate with an excess of RO54864, followed by the fixing of the membranes on the filter and measurement of the radioactivity.

 The inhibition of specific binding, noted FS, is equal to the difference of the radioactivities measured in 2 and 3 divided by the measurement in 1.

The inhibition percentages determined for a compound of the invention and the reference products are shown in Table III; they are given by the formula
FS (witness) - FS (product)
100 x
FS (witness)
TABLE III
PRODUCT DOSE% INHIBITION OF SPECIFIC FIXING
IN
mg / kg BRAIN: RATE: THYMUS: KIDNEY: HEART
SR26310 25 76 52 31 39
PK11195 25 71 29 30 27
Ro 5-4864 15 74 Il 28 73 27

Claims (8)

CH or A, B, C, D each represent CH, as well as their addition salts with pharmaceutically acceptable acids or bases. C1 to C4 or phenyl group n represents 0.1 or 2, and one of the symbols A, B, C, D represents N and the others R8 represents the hydrogen atom, an alkyl group R5 and R6, identical or different, represent a hydrogen or halogen atom, a C1 to C3 alkyl or alkoxy group, a nitro, trifluoromethyl, cyclohexyl group or together a methylenedioxy group, R4 and R7 represent, independently of one another, the hydrogen atom or a C1- to C4 alkyl group, R3 represents a C1 to C6 alkyl group or a C7 to C6 phenylalkyl group,  in which R1 and R2, which are identical or different, represent the hydrogen atom, a C1 to C6 alkyl group, a phenyl or benzyl group or R1 and R2 form with the nitrogen atom to which they are attached a heterocycle saturated in C4 to

 CLAIMS 1. Compounds of Formula I  2. Compounds of formula I according to claim 1, in which A = B = C = D = CH.  3. Compounds of formula I according to claim 1, in which one of A, B, C, D represents  feel N and the other CHs.  4. Compounds according to claim 3 in  which A is N.  5. Compounds of formula I according to one of claims 1 to 4, in which R7 represents a C1-alkyl group. at C4,  6. Compounds of formula I according to one of the preceding claims, in which R3 is a C1 to C3 alkyl group, R4 is a hydrogen atom and n is o.  7. Process for the preparation of the compounds of one of claims 1 to 6, characterized in that the amine of formula is reacted

 with a derivative of formula III

 in which R1, R2, R3, R4, R5, R6, R7, R8, A, B, C, D and n have the same meanings as in formula I and X represents a halogen or a sulfona group.  8. Pharmaceutical composition comprising a product according to one of claims 1 to 6.