FR2665162A1 - 6H-Pyrido[3,2-b]carbazole derivatives, process for their preparation and their application in therapeutics - Google Patents

Abstract

Antineoplastic derivatives corresponding to the formula: in which: - R2 = H, halogen, OH, CH3O or carbethoxyoxy, and - the -A----B- linkage represents (i) , in which case R3 denotes: *) either OH or Cl; R and R1, which can be identical or different, each then representing: H, C1-C4 alkyl; methoxymethyl or methoxyethyl; -(CH2)n-COR4 where n = 0, 1, 2 or 3 and R4 = OH, C1-C4 alkoxy or hydrazino; or benzyl; *) or C1-C4 alkoxy or C2-C5 acyloxy; R and R1, which can be identical or different, then representing H or C1-C4 alkyl; or ii) , in which case R3 = OH and R1 = H. m

Description

Derivatives of 6H-pyrido [3,2-b] carbazole, process for their preparation and their therapeutic application
The present invention relates to novel 6Hpyrido [3,2-b] carbazole derivatives, to a process for their preparation and to their therapeutic application.

dans laquelle - R2 représente un atome d'hydrogène ou d'halogène ou un groupe hydro
xyle, méthoxy ou carbéthoxyoxy, et - l'enchaînement -A---B- représente

auquel cas R3 désigne *) soit un groupe hydroxyle ou un atome de chlore ; R et R1,
qui peuvent être identiques ou différents, représentant
alors chacun
. un atome d'hydrogène
. un groupe alkyle en Ct-C4
. un groupe méthoxyméthyle ou méthoxyéthyle
. un groupe de formule -(CH2)n-COR4 Où n = O, 1, 2 ou 3
et R4 représente un groupe hydroxyle, alkoxy en C1-C4
ou hydrazino, ou
. un groupe benzyle *) soit un groupe alkoxy en Ct-C4 ou acyloxy en C2-C5 ;R et R1
qui peuvent être identiques ou différents, représentant
alors un atome d'hydrogène ou un groupe alkyle en Ct-C4 ; ou

auquel cas R3 représente un groupe hydroxyle et R1 repré
sente un atome d'hydrogène.The derivatives according to the invention correspond more precisely to the formula

in which - R2 represents a hydrogen or halogen atom or a hydro group
xyl, methoxy or carbethoxyoxy, and - the sequence -A --- B- represents

in which case R3 denotes *) either a hydroxyl group or a chlorine atom; R and R1,
which may be the same or different, representing
then everyone
. a hydrogen atom
. a C 1 -C 4 alkyl group
. a methoxymethyl or methoxyethyl group
. a group of formula - (CH2) n-COR4 Where n = O, 1, 2 or 3
and R4 represents a hydroxyl, C1-C4 alkoxy group
or hydrazino, or
. a benzyl group *) is a C 1 -C 4 alkoxy group or a C 2 -C 5 acyloxy group; R and R 1
which may be the same or different, representing
then a hydrogen atom or a C 1 -C 4 alkyl group; or

in which case R3 represents a hydroxyl group and R1 represents
feels a hydrogen atom.

dans laquelle - R2 = H, OH, CH3O, halogène ou OCO2C2H5, - R = H, alkyle en Gl-C4, méthoxyméthyle, méthoxyéthyle, COOH ou
(CH2)n-C00-alkyle en Cl-C4 où n = 0, 1, 2 ou 3, et - Rai = H, alkyle en Cl-C4, COOH, (CH2)n-C00-alkyle en C1-C4 où
n = 0, 1, 2 ou 3, (CH2)n-CO-NH-NH2 où n = 0, 1, 2 ou 3 ou
benzyle

dans laquelle - Rb2 = H ou halogène, - Rb = H, alkyle en Cl-C4, méthoxyméthyle, méthoxyéthyle ou
(CH2)n-COO-alkyle en Cl-C4 où n = 0, 1, 2 ou 3, et - Rh1 = H, alkyle en Cl-C4 ou (CH2)n-COO-alkyle en Cl-C4 où
n = 0, 1, 2 ou 3

dans laquelle - RC = H ou alkyle en Ct-4, - Rcl = H ou alkyle en Cl-C4, - RC2 = H ou halogène, et - RC3 = alcoxy en Cl-C4 ou acyloxy en C2-Cs i

dans laquelle Rd2 = H ou halogène.In the scope of formula (I) above, include derivatives of formulas (II) to (V) below

in which - R2 = H, OH, CH3O, halogen or OCO2C2H5, - R = H, C1-C4 alkyl, methoxymethyl, methoxyethyl, COOH or
(CH2) n-C00-C1-C4alkyl wherein n = 0, 1, 2 or 3, and - Rai = H, C1-C4alkyl, COOH, (CH2) n-C00-C1-C4alkyl wherein
n = 0, 1, 2 or 3, (CH 2) n -CO-NH-NH 2 where n = 0, 1, 2 or 3 or
benzyl

in which - Rb2 = H or halogen, - Rb = H, C1-C4 alkyl, methoxymethyl, methoxyethyl or
(CH 2) n-COO-C 1 -C 4 alkyl wherein n = 0, 1, 2 or 3, and - Rh 1 = H, C 1 -C 4 alkyl or (CH 2) n -COO-C 1 -C 4 alkyl wherein
n = 0, 1, 2 or 3

in which - RC = H or C 1 -C 4 alkyl, - R 1 C = H or C 1 -C 4 alkyl, - RC 2 = H or halogen, and - RC 3 = C 1 -C 4 alkoxy or C 2 -C 4 acyloxy

where Rd2 = H or halogen.

 The present invention also relates to the physiologically acceptable acid addition salts of the derivatives of formula (I). These are the mineral acid addition salts such as hydrochlorides, hydrobromides, sulphates and phosphates, as well as organic acid addition salts such as acetates, oxalates, methanesulphonates, pyruvates, lactates, tartrates, malates, citrates, benzoates, sulfosalicylates and mandelates.

où R et R1, qui peuvent être identiques ou différents, représentent chacun H, méthoxyméthyle, méthoxyéthyle, alkyle en Cl-C4, benzyle ou (CH2)n-COR4 où n = 0, 1, 2 ou 3 et R4 = OH, alkoxy en C1-C4 ou hydrazino, respectivement sur les composés de formule

où R2 = H, halogène, OH, CH3O ou OC02C2H5, cette condensation étant de préférence effectuée à chaud, dans un solvant organique tel que le benzène et en presence d'acide acétique, ce qui conduit aux dérivés de formule (I) de structure particulière ::

dans laquelle R et R1 ont la même signification que dans la formule (VI) et R2 a la même signification que dans la formule (VII),
b) l'hydrolyse basique, de préférence par la soude aqueuse, des dérivés de formule (Ia) pour lesquels R2 = H, OH, OCH3 ou halogène et l'un au moins parmi R et R1 représente un groupe (CH2)n-COR'4 où n = O, l, 2 ou 3 et R'4 = alcoxy en C1-C4, ce qui conduit aux dérivés de formule (I) et de structure particulière

où R'2 = H, halogène, OH ou OCH3 et l'un au moins parmi R' et R't représente (CH2)n-COOH où n = O, 1, 2 ou 3 et l'autre represente H, alkyle en Cl-C4, méthoxyméthyle, méthoxyéthyle ou benzyle,
c) l'action de l'hydrazine sur les derives de formule (I'a), ce qui conduit aux dérivés de formule (I) et de structure particulière

où R'2 = H, halogène, OH ou OCH3 et l'un parmi R" et R"1 représente (CH2)n-COR"4 où n = O, 1, 2 ou 3 et R"4 = NH-NH2 et l'autre représente
H, alkyle en C1-C4, méthoxyméthyle, méthoxyéthyle ou benzyle,
d) la chloro déshydroxylation des dérivés de formule (la), par l'oxychlorure de phosphore ou la cyclisation, de préférence par l'oxychlorure de phosphore, des composes de formule

où R et Ri ont la même signification que dans la formule (VI) et R2 a la même signification que dans la formule (VII), ce qui conduit aux dérivés de formule (I) et de structure particulière

où R et Ri ont la même signification que dans la formule (VI) et R2 a la même signification que dans la formule (VII),
e) la condensation d'un composé d'alkylation du type (alkyle en Cl-C4)-X où X représente un groupe electrophile bon partant (tel qu'un atome d'halogène) ou d'un composé d'acylation du type (acyle en
C2-C5)-C1, (acyle en C2-Cs)20 ou ester activé de l'acide (acyle en C2-Cs)-OH, sur les dérivés de formule (Ia) pour lesquels R et R1 représentent indépendamment H ou alkyle en Cl-C4, ce qui conduit aux dérives de formule (I) de structure particulière

où R et R1 représentent indépendamment H ou alkyle en C1-C4, R2 a la même signification que dans la formule (VII) et R3 = alkoxy en Cl-C4 ou acyle en C2-C5
f) le chauffage des composés de formule (VIII) où R1 = CO2C2Hs, de préférence à une température de 220 à 2500 C, ce qui conduit aux dérivés de formule (I) et de structure particulière

où R et R2 ont les mêmes significations que dans la formule (Ic) et R1 = H,
g) la cyclisation par le malonate de diéthyle des composes de formule (VII), ce qui conduit aux dérivés de formule (I) de structure particulière :

où R2 = H, halogène OH, CH30 ou OCO2C2H5, et/ou
h) la salification par un acide organique ou minéral des dérivés de formule (Ia), (l'a), (I"a), (lob), (Ic), (I'c) ou (Id).The process for synthesizing the derivatives of formula (I), comprises
a) condensation of compounds of formula

where R and R1, which may be the same or different, each represents H, methoxymethyl, methoxyethyl, C1-C4 alkyl, benzyl or (CH2) n-COR4 where n = 0, 1, 2 or 3 and R4 = OH, alkoxy C1-C4 or hydrazino, respectively on compounds of formula

where R2 = H, halogen, OH, CH3O or OC02C2H5, this condensation being preferably carried out hot, in an organic solvent such as benzene and in the presence of acetic acid, which leads to the derivatives of formula (I) of structure particular ::

in which R and R 1 have the same meaning as in formula (VI) and R 2 has the same meaning as in formula (VII),
b) the basic hydrolysis, preferably with aqueous sodium hydroxide, of the derivatives of formula (Ia) for which R 2 = H, OH, OCH 3 or halogen and at least one of R and R 1 represents a (CH 2) n-group; COR'4 where n = O, l, 2 or 3 and R'4 = C1-C4 alkoxy, which leads to the derivatives of formula (I) and of particular structure

where R'2 = H, halogen, OH or OCH3 and at least one of R 'and R't represents (CH2) n-COOH where n = O, 1, 2 or 3 and the other represents H, alkyl C1-C4, methoxymethyl, methoxyethyl or benzyl,
c) the action of hydrazine on the derivatives of formula (I'a), which leads to the derivatives of formula (I) and of particular structure

where R'2 = H, halogen, OH or OCH3 and one of R "and R" 1 represents (CH2) n-COR "4 where n = O, 1, 2 or 3 and R" 4 = NH-NH2 and the other represents
H, C1-C4 alkyl, methoxymethyl, methoxyethyl or benzyl,
d) the chloro dehydroxylation of the derivatives of formula (Ia), with phosphorus oxychloride or cyclization, preferably with phosphorus oxychloride, compounds of formula

where R and R 1 have the same meaning as in formula (VI) and R 2 has the same meaning as in formula (VII), which leads to derivatives of formula (I) and of particular structure

where R and R 1 have the same meaning as in formula (VI) and R 2 has the same meaning as in formula (VII),
e) the condensation of a (C 1 -C 4) alkyl-alkylating compound wherein X represents a good leaving electrophilic group (such as a halogen atom) or an acylating compound of the type (acyl
C2-C5) -C1, (C2-C8 acyl) or activated ester of the acid (C2-C8 acyl) -OH, on the derivatives of formula (Ia) for which R and R1 independently represent H or alkyl in Cl-C4, which leads to the drifts of formula (I) of particular structure

where R and R 1 are independently H or C 1 -C 4 alkyl, R 2 has the same meaning as in formula (VII) and R 3 = C 1 -C 4 alkoxy or C 2 -C 5 acyl
f) heating the compounds of formula (VIII) wherein R1 = CO2C2Hs, preferably at a temperature of 220 to 2500 C, which leads to the derivatives of formula (I) and of particular structure

where R and R2 have the same meanings as in formula (Ic) and R1 = H,
g) cyclization with diethyl malonate of the compounds of formula (VII), which leads to the derivatives of formula (I) of particular structure:

where R2 = H, OH halogen, CH30 or OCO2C2H5, and / or
h) salification with an organic or inorganic acid of the derivatives of formula (Ia), (a), (I "a), (lob), (Ic), (I'c) or (Id).

où R2 = H, halogène, OH, 0H30 ou OC02C2H5, par exemple par le chlorure stanneux et l'acide chlorhydrique, ou par l'hydrogène en présence d'un catalyseur d'hydrogénation comme le charbon palladié.Moreover, the compounds of formula (VII) above can be obtained by reducing the nitro group of compounds of formula

where R2 = H, halogen, OH, OH or OCO2C2H5, for example by stannous chloride and hydrochloric acid, or by hydrogen in the presence of a hydrogenation catalyst such as palladium on carbon.

The compounds of formula (IX) can be obtained by nitration with nitric acid compounds of formula

By reduction with sodium borohydride, in an alcohol such as methanol, the compound of formula (IX) for which
R2 = OCO2C2H5, the compound of formula (IX) is obtained for which
R2 = OH.

 Treatment of the latter with diazomethane is another means of access to the compound of formula (IX) for which R2 = OCH3.

Finally, the treatment of the compound of formula (IX) for which
R2 = OH by ethyl chloroformate, in an organic solvent such as toluene and in the presence of a base such as triethylamine, leads to the compound of formula (IX) for which R 2 = OCO 2 O 2 H 5.

 The following preparations are given by way of purely illustrative and nonlimiting examples of the derivatives according to the invention.

Example 1: 1,4-Dimethyl-3-nitro-6-ethoxycarbonyloxy-9H-carbazole
[(IX), R2 = OOO202H5]
Code number: i
Method A
20 g (0.076 mole) of 1,4-dimethyl-6-ethoxycarbonyloxy-9H-carbazole (X) are dissolved in 50 ml of acetic anhydride and then, at 30 ° C., 1 equivalent of nitric acid (d = 1.52) is added. and the solution is allowed to stir for 3 hours. The precipitate formed is filtered off, washed with ether, dried and recrystallized from acetonitrile. 16 g of the expected compound are thus obtained (yield: 69%).

. Melting point: 226 ° C
Elemental analysis (CHN): C17H16N205
Method B
20 g (0.0781 mol) of 1,4-dimethyl-6-hydroxy-3-nitro-9H-carbazole (3) are refluxed in 600 ml of toluene with 1 equivalent of ethyl chloroformate in the presence of an excess of of triethylamine. After cooling, the solution is taken up in 200 ml of water, the toluene phase is dried and then concentrated under reduced pressure. The precipitate formed is recrystallized from acetonitrile. 21 g of the expected compound are thus isolated (yield 82%), melting at 226 C.

Example 2 1,4-dimethyl-6-methoxy-3-nitro-9H-carbazole
[(IX), R2 = OCH3]
Code number: 2
0 g (0.044 mol) of 1,4-dimethyl-6-hydroxy-3-nitro carbazole (3) is stirred at 0 ° C. in 200 ml of ether in the presence of a large excess of diazomethane. The residue is recrystallized from acetonitrile.

11 g of the expected compound are thus obtained (yield: 92%).

, Melting point:> 270 ° C
Elemental Analysis (CHN): ClsHt4N203
Example 3 1,4-dimethyl-6-hydroxy-3-nitro-9H-carbazole [(IX), R 2 = OH]
Code number: 3
Refluxed with 20 g (0.0609 mol) of 1,4-dimethyl-6-ethoxycarbonyloxy-3-nitro-9H carbazole (i) in 250 ml of methanol in the presence of 2 equivalents of sodium borohydride. After extraction, the precipitate is recrystallized from acetonitrile and 13 g of the expected compound are isolated (yield: 83%).

Melting point: 258 ° C
Elemental analysis (CHN): C14H12N2O3.

Example 4: 3-amino-1,4-dimethyl-6-ethoxycarbonyloxy-9H-carbazole
[(VII), R2 = OCO2C2H5], Code number: 4
Method A
50 g (0.15 mole) of 1,4-dimethyl-6-ethoxycarbonyloxy-3-nitro-9H-carbazole (1) are dissolved at 150 ° C. in 60 ml of N, N-dimethylformamide, and this solution is then added to a mixture of 100 ml of concentrated hydrochloric acid and 30 ml of acetic acid containing 10 equivalents of stannous chloride. After 2 hours at 70 ° C., the suspension is poured into a 30% aqueous solution of sodium hydroxide. The precipitate formed is drained, washed with water, dried and recrystallized from ethanol. 25 g of the expected compound are thus obtained (yield: 56%).

Melting point: 185 ° C
Elemental Analysis (CHN): C17H18N203
Method B
20 g (0.0609 mol) of 1,4-dimethyl-6-ethoxycarbonyloxy-3-nitro-9H-carbazole (1), dissolved in 250 ml of ethanol in the presence of 7 g of toluene, are stirred at 60 ° C. in an autoclave. 5% palladium on carbon under 70 kg / cm2 (70.105 Pa) of hydrogen. After degassing the solution is evaporated under reduced pressure, and after recrystallization of the residue in ethanol, 15 g of the expected compound (yield: 82.5%) having a melting point of 185 ° C. are obtained.

Example 5: 3-amino-1,4-dimethyl-6-hydroxy-9H-carbazole
[(VII), R2 = OH]
Code number: 5
Method A
5.75 g (0.15 mole) of sodium borohydride are added to a solution of 10 g (0.03 mole) of 1,4-dimethyl-6-ethoxycarbonyloxy-3-nitro-9H-carbazole (1) in 300 ml of methanol. After reflux for 2 h, the solution is evaporated under vacuum, the residue is taken up in 100 ml of water, stirred, filtered, dried and recrystallized from ethanol to give 4 g of the expected compound (yield: 60%).

, Melting point: 250 ° C
Elemental Analysis (CHN): Ct4H14N20
Method B
70 g in an autoclave are stirred at 20 g (0.078 mol) of 1,4-dimethyl-6-hydroxy-3-nitro-9H-carbazole (3) in solution in 300 ml of absolute ethanol in the presence of 10 g of 5% palladium on carbon under 70 kg / cm2 (70.105 Pa) of hydrogen. After degassing, the solution is filtered, evaporated under reduced pressure and by recrystallization of the residue in ethanol, 13 g of the expected compound are obtained (yield 74%). whose melting point is 250 ° C.

Example 6: $ 3-amino-1,4-dimethyl-6-methoxy-9H-carbazole
[(VII), R2 = OCH3]
Code number: 6
Using Method B of Example 5 and starting from 15 g (0.055 mol) of 1,4-dimethyl-6-methoxy-3-nitro-9H-carbazole (2), 10 g of the expected compound are obtained ( Yield: 76%) with a melting point of 200 C.

Example 7 2,3,5,11-tetramethyl-4-hydroxy pyrido [3,2-b] carbazole
[(Ia), R = R1 = CH3, R2 = H]
Code number: 7
A mixture of 13 g (0.0062 mol) of 3-amino-1,4-dimethyl-9H-carbazole [(VII), R2 = H] and 13.40 g (0.093 mol) is refluxed for 3 hours. ) of ethyl 2-methyl acetoacetate in 800 ml of benzene in the presence of 0.7 ml of acetic acid. The solution is filtered and concentrated under vacuum. The residual oil is poured into 50 ml of diphenyl ether preheated to 230 ° C. After cooling, the solution is poured into 800 ml of ethyl ether and stirred for 1 hour.

The precipitate formed is drained, dried and recrystallized from acetonitrile, which gives the expected derivative with a yield of 65% (melting point: 265 ° C.).

Example 8: 9-Ethoxycarbonyloxy-4-hydroxy-2,3,5,11-tetramethyl-6H pyrido [3,2-b] carbazole
[(Ia), R = R1 = CH3, R2 = OCO2C2H5]
Code number: 8
15 g (0.050 mol) of 3-amino-1,4-dimethyl-6-ethoxycarbonyloxy-9H-carbazole (4) and 19.50 g (0.15 mol) of 2-methylacetoacetate are refluxed for 3 hours. of ethyl in 300 ml of benzene in the presence of 2 ml of acetic acid. After cooling, the solution is concentrated under reduced pressure, the residual oil obtained is heated at 250 ° C. for 10 minutes in 70 ml of diphenyl ether. After cooling, the solution is poured into 600 ml of anhydrous ether, stirred and then filtered. The precipitate formed is dried and recrystallized from acetonitrile to give 13 g of the expected derivative (yield: 69%) in the form of yellow crystals.

. Melting point:> 270 C
. Elemental analysis: C22H22N204
By operating as in Examples 7 and 8 above, it is possible to prepare the derivatives of code numbers 11 to 38 assembled in the
Table I below.

Example 9: 9-Chloro-4-hydroxy-3-carboxy-5,11-dimethyl-6H-pyrido [3,2-b]
carbazole
[(a), R '= H, R'2 = C1, R'1 = COOH]
Code number: 9
The mixture is heated at 100 ° C. for 3 hours in 150 ml of 15% sodium hydroxide, 6 g (0.016 mol) of 9-chloro-4-hydroxy-3-carbethoxy-5,11-dimethyl pyrido [3,2-b]. ] carbazole (36) After cooling, the solution is acidified to pH = 1 with dilute hydrochloric acid The precipitate formed is drained, washed with water, dried and recrystallized from acetonitrile. melting point> 280 ° C.) is thus obtained with a yield of 65%.

Example 10: 9-Chloro-4-hydroxy-3-carbohydrazidoethyl-2,5,11-trimethyl-6H-pyrido [3,2-b] carbazole
[(I "a), R" = CH3, R'2 = C1, R "1 = CH2CH2CONHNH2]
Code number: 10
80 g for 2 hours in 60 ml of ethanol and 40 ml of hydrazine hydrate, 2 g (0.0048 mol) of 9-chloro-4-hydroxy-3-carbethoxyethyl-2,5,11-trimethyl are brought to 80 ° C. for 2 hours. -6H-pyridol [3,2-b] carbazole (33). After cooling, the precipitate is filtered off, washed with 30 ml of ethanol, dried and recrystallized from acetonitrile, which gives the expected derivative (melting point> 280 ° C.) in a yield of 55%.

Example 11: 4-Chloro-3-carbethoxy-5,11-dimethyl-6H-pyrido [3,2-b]
carbazole
[(Ib), R = H, R1 = CO2C2H5, R2 = H]
Code number: 39
Method A
5 g (0.013 mol) of 3- (1,1-dicarbethoxyethylidene amino) -1,4-dimethyl carbazole [(VIII) are heated at reflux for 1 hour,
R = R 2 = H, R 1 = COOC 2 H 5] in 80 ml of phosphorus oxychloride. The solution is evaporated to dryness and hydrolysed with 100 g of ice and 25 ml of aqueous ammonia. The precipitate formed is drained, washed with water, dried and recrystallized from acetonitrile, which gives the expected derivative (mp 195 ° C.) with a yield of 70%.

Method B
By treating as in Method A, 5 g (0.014 mole) of 4-hydroxy-3-carbethoxy-5,11-dimethyl-6H-pyrido [3,2-b] carbazole (19) with 60 ml of oxychloride. phosphorus, the expected derivative is obtained (mp 195 ° C.) with a yield of 75%.

 In the same way, derivatives of code numbers 40 to 44 are obtained in Table II.

Example 12: 4-acetoxy-2,5,11-trimethyl-6H-pyrido [3,2-b] carbazole
[(Ic), R = CH3, R1 = R2 = H, R3 = OCOCH3]
Code number: 45
The reaction mixture is heated at 80 ° C. for 15 minutes in 30 ml of acetic anhydride to 1.5 g (0.0054 mol) of 4-hydroxy-2,5,11-trimethyl-6H pyrido [3,2-b] carbazole (22). ). The solution is cooled, stirred in 120 ml of a saturated solution of potassium hydrogencarbonate and extracted with 150 ml of ethyl acetate. The organic phase is dried and then concentrated under vacuum; the crystals formed are recrystallized from a mixture of ethyl ether (4) and ethyl acetate (6), which gives the expected derivative (melting point: 170 ° C.) in a yield of 54%.

 In the same way, the code number derivative 46 listed in Table III is obtained.

Example 13 4-ethoxy-5,11-dimethyl-6H-pyrido [3,2-b] carbazole
[(Ic), R = R1 = R2 = H, R3 = OC2H5]
Code number: 47
0.5 g (0.0013 mol) of 3- (1,1-dicarbethoxyethylideneamino) 1,4-dimethylcarbazole [(VIII), R = R 2 = H, R 1 = COOC 2 H 5] are heated at 220 ° C. for 5 minutes then sublimated under 0.05 mm Hg. The expected derivative (mp 265 ° C.) is thus obtained in the form of yellow crystals with a yield of 19%.

Derivatives of code numbers 48 and 49 listed in the
Table III are obtained analogously.

Example 14: 1,2-Dihydro-2-oxo-4-hydroxy-5,11-dimethyl pyrido [3,2-b]
carbazole
[(Id), R2 = H]
Code number: 50
4 g (0.019 mol) of 3-amino-1,4-dimethyl-9H-carbazole [(VIl), R 2 = H] in 4.30 ml of diethyl malonate are heated at 130 ° C. for 20 minutes. The solution is then poured into 30 ml of diphenyl ether heated at 230 ° C. After 12 minutes at this temperature, the solution is cooled and then poured into 500 ml of ether. The precipitate formed is drained, dried and recrystallized from acetonitrile, which gives the expected compound (mp 265 ° C.) in a yield of 19%.

 The derivatives of code numbers 51 and 52 listed in Table IV are obtained analogously.

Example 15: 4-hydroxy-2,5-11-trimethyl-6H-pyrido [3,2-b] carbazole tartrate
[(Ia), R = CH3, R1 = R2 = H]
Code number: 53
Refluxed for 1 hour in 60 ml of isopropyl alcohol 1 g (0.0036 mol) of 4-hydroxy-2,5,11-trimethyl-6H-pyrido [3,2-b] carbazole (22) with 1.4 equivalents of tartaric acid.

After cooling, the precipitate formed is filtered off and washed with ether, which gives the expected salt (mp 265 ° C.) in a yield of 60%.

Example 16: 9-Chloro-4-hydroxy-2,3,5,11-tetramethyl-6H-pyrido [3,2-b] carbazole methanesulfonate
[(Ia), R = R1 = CH3, R2 = Cl]
Code number: 54
25 g (0.061 mole) of 9-chloro-4-hydroxy-2,3,5,11-tetramethyl-6H-pyrido (3.2 g) are dissolved in 1 liter of absolute ethanol and 200 ml of DMSO at 70 ° C. bgcarbazole (13) and 2 equivalents of methanesulfonic acid are added. The heating at 70 C is maintained for 10 minutes and then left at room temperature 2 hours. The light yellow precipitate formed is drained, washed with 75 ml of cold ethanol and 500 ml of ethyl ether, dried and recrystallized 3 times in acetonitrile. The expected salt is obtained (mp 260 ° C.) under reflux. yellow crystal form with a yield of 77%.

Derivatives of code numbers 55 to 81 listed in the
Table V are obtained analogously.

Example 17 3- (1,1-dicarbethoxyethylidene amino) -1,4-dimethyl
carbazole [(VIII), R = R2 = H, R1 = COOC2Hs]
A mixture of 5 g (0.024 mol) of 3-amino-1,4-dimethyl-9H-carbazole and 6 ml (0.028 mol) of diethyl ethoxymethylidene malonate in 50 ml of sodium hydroxide is refluxed for 1 hour. absolute ethanol.

After cooling, the precipitate is filtered off, dried and recrystallized from acetonitrile. 7.25 g of the expected compound (Yield: 79%) are thus obtained in the form of a white powder whose melting point is 230.degree.

 The other compounds of formula (VIII) are obtained analogously from the appropriate starting materials.

TABLE I

<tb> No. <SEP> of <SEP> R2 <SEP> R <SEP> Rt <SEP><SEP> Point of <SEP> Yield
<tb><SEP> Code <SEP> Merge <SEP> (%)
<tb><SEP> (C)
<tb><SEP> 7 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> 265 <SEP> 65
<tb><SEP> 8 <SEP> OCO2C2H5 <SEP> CH3 <SEP> CH3 <SEP>><SEP> 270 <SEP> 69
<tb><SEP> 9 <SEP> Cl <SEP> H <SEP> COOH <SEP>><SEP> 280 <SEP> 65
<tb><SEP> 10 <SEP> C1 <SEP> CH3 <SEP> (CH2) 2CONHNH2 <SEP>><SEP> 280 <SEP> 55
<tb><SEP> 11 <SEP> OCH3 <SEP> CH3 <SEP> CH3 <SEP>><SEP> 270 <SEP> 70
<tb><SEP> 12 <SEP> OH <SEP> CH3 <SEP> CH3 <SEP>><SEP> 270 <SEP> 20
<tb><SEP> 13 <SEP><SEP> CH3 <SEP> CH3 <SEP>><SEP> 270 <SEP> 60
<tb><SEP> 14 <SEP> Br <SEP> CH3 <SEP> CH3 <SEP>><SEP> 270 <SEP> 50
<tb><SEP> 15 <SEP><SEP> CH3 <SEP> CH3 <SEP>><SEP> 270
<tb><SEP> 16 <SEP> H <SEP> (CH2) 2CH3 <SEP> H <SE> 268 <SEP> 60
<tb><SEP> 17 <SEP> H <SEP> CH20CH3 <SEP> H <SEP>><SEP> 280 <SEP> 60
<tb><SEP> 18 <SEP> H <SEP> CH (CH3) 2 <SEP> H <SEP> 240 <SEP> 50
<tb><SEP> 19 <SEP> H <SEP> H <SEP> C02C2H5 <SEP>><SEP> 280 <SEP> 45
<tb><SEP> 20 <SEP> H <SEP> CH3 <SEP> CH2C6Hs <SEP>><SEP> 280 <SEP> 60
<tb><SEP> 21 <SEP> H <SEP> C2H5 <SEP> H <SEP>><SEP> 280 <SEP> 33
<tb><SEP> 22 <SEP> H <SEP> CH3 <SEP> H <SEP>><SEP> 280 <SEP> 50
<tb><SEP> 23 <SEP> Br <SEP> CH20CH3 <SEP> H <SEP>><SEP> 280 <SEP> 70
<tb><SEP> 24 <SEP> Br <SEP> CH (CH3) 2 <SEP> H <SEP>><SEP> 280 <SEP> 65
<tb><SEP> 25 <SEP> Br <SEP> H <SEP> CO2C2H5 <SEP>><SEP> 280 <SEP> 60
<tb><SEP> 26 <SEP>#<SEP> Br <SEP> C02C2H5 <SEP> CH3 <SEP>><SEP> 280 <SEP> 30
<tb><SEP> 27 <SEP>#<SEP> Br <SEP> CH3 <SEP> H <SEP>><SEP> 280 <SEP> 70
<tb><SEP> 28 <SEP> Br <SEP> CH3 <SEP> CH2C6H5 <SEP>><SEP> 280 <SEP> 40
<Tb>
TABLE I (Continued)

<tb> No. <SEP> of <SEP> R2 <SEP> R <SEP> Rt <SEP><SEP> Point of <SEP> Yield
<tb> Code <SEP> Merge <SEP> (%)
<tb><SEP> (C)
<tb> 29 <SEP> Br <SEP> (CH2) 3CO2C2H5 <SEP> H <SEP> 194 <SEP> 40
<tb><SEP> 30 <SEP> Br <SEP> CH3 <SEP> (CH2) 2C02C2H5 <SEP>><SEP> 280
<tb> 31 <SEP> Cl <SEP> C1H5 <SEP> H <SEP>> 280 <SEP> 60
<tb> 32 <SEP> Cl <SEP> (CH2) 2CH3 <SEP> H <SEP>><SEP> 280 <SEP> 35
<tb><SEP> 33 <SEP> Cl <SEP> CH3 <SEP> (CH2) 2C02C2H5 <SEP> 240 <SEP> 20
<tb> 34 <SEP> Cl <SEP> (CH2) 3CO2C2H5 <SEP> H <SEP> 220 <SEP> 70
<tb> 35 <SEP> Cl <SEP> CH2OCH3 <SEP> H <SEP>><SEP> 280 <SEP> 60
<tb> 36 <SEP> C <SEP> H <SEP> C02C2H5 <SEP>><SEP> 280 <SEP> 70
<tb> 37 <SEP> Cl <SEP> CH3 <SEP> H <SEP>><SEP> 280 <SEP>#<SEP> 75
<tb> 38 <SEP> OC02C2H5 <SEP> H <SEP> C02C2H5 <SEP>><SEP> 280 <SEP> 65
<Tb>
TABLE II

<tb> No. <SEP> of <SEP> R2 <SEP> R <SEP> R1 <SEP><SEP> Point of <SEP> Yield
<tb> Code <SEP> Merge <SEP> (%)
<tb><SEP> (C)
<tb><SEP> 39 <SEP> H <SEP> H <SEP> CO2C2H5 <SEP> 195 <SEP> 70
<tb> 40 <SEP> Br <SEP> CH3 <SEP> CH3 <SEP> 190 <SEP> 60
<tb> 41 <SEP> Br <SEP> CO2C2H5 <SEP> CH3 <SEP> 220 <SEP> 54
<tb> 42 <SEP> Br <SEP> (CH2) CO2C2H5 <SEP> H <SEP> 170 <SEP> 47
<tb> 43 <SEP> Cl <SEP> CH3 <SEP> CH3 <SEP> 180 <SEP> 60
<tb> 44 <SEP> H <SEP> CH2OCH3 <SEP> H <SEP> 190 <SEP> 70
<Tb>
TABLE III

<tb> No. <SEP> of <SEP> R <SEP> R1 <SEP> R2 <SEP> R3 <SEP><SEP> Point of <SEP> Yield
<tb><SEP> Code <SEP> merge <SEP> (C) <SEP> (%)
<tb><SEP> 45 <SEP> CH3 <SEP> H <SEP> H <SEP> OCOCH3 <SEQ> 170 <SEP> 54
<tb><SEP> 46 <SEP> CH3 <SEP> CH3 <SEP> H <SEP> OCOCH3 <SEQ> 184 <SEP> 63
<tb><SEP> 47 <SEP> H <SEP> H <SEP> H <SEP> OC2H5 <SEP> 265 <SEP> 19
<tb><SEP> 48 <SEP> H <SEP> H <SEP> Br <SEP> OC2H5 <SEP> 270 <SEP> 20
<tb><SEP> 49 <SEP> H <SEP> H <SEP> Cl <SEP> OC2H5 <SEP> 265 <SEP> 23
<Tb>
TABLE IV

<tb> No. <SEP> of <SEP> R2 <SEP><SEP> Point of <SEP> Yield
<tb><SEP> Code <SEP> merge <SEP>(<SEP> C) <SEP> (%) <SEP>
<tb><SEP> 50 <SEP> H <SEP> 265 <SEP> 19
<tb><SEP> 51 <SEP> Cl <SEP> 250 <SEP>#<SEP> 28
<tb><SEP> 52 <SEP> Br <SEP> 235 <SEP> 36
<Tb>
TABLE V

<SEP> No. <SEP> of <SEP> R2 <SEP> R <SEP> R1 <SEP> R3 <SEP> X- <SEP> Point <SEP> of <SEP> Yield
<tb><SEP> merge <SEP> (%)
<tb><SEP> (C)
<tb> 53 <SEP> H <SEP> CH3 <SEP> H <SEP> OH <SEP> tartrate <SEP> 265 <SEP> 60
<tb><SEP> 54 <SEP> Cl <SEP> CH <SEP> CH <SEP> OH <SEP> Methane- <SEP> 260 <SEP> 77
<tb><SEP> 3 <SEP> sulfonate
<tb><SEP> 55 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> OCOCH3 <SEP> oxalate <SEP> 265 <SEP> 70
<tb> 56 <SEP> Br <SEP> CH2OCH3 <SEP> H <SEP> OH <SEP> oxalate <SEP> / <SEP> 280 <SEP> 60
<tb> 57 <SEP> Br <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> methane- <SEP>> 280 <SEP> 70
<tb><SEP> sulfonate
<tb><SEP> 58 <SEP> Br <SEP> H <SEP> CO2C2H5 <SEP> OH <SEP> Methane <SEP>> 280 <SEP> 64
<tb><SEP> sulfonate
<tb><SEP> 59 <SEP> Br <SEP> CO2C2H5 <SEP> CH3 <SEP> OH <SEP> methane- <SEP>> 280 <SEP> 50
<tb><SEP> sulfonate
<tb><SEP> 60 <SEP> Br <SEP> (CH2) 3CO2C2H5 <SEP> H <SEP> OH <SEP> methane- <SEP>> 280 <SEP> 75
<tb><SEP> sulfonate
<tb><SEP> 61 <SEP> Br <SEP> CH3 <SEP> (CH2) 2CO2C2H5 <SEP> OH <SEP> xalate <SEP> 250 <SEP> 60
<tb><SEP> 62 <SEP> Br <SEP> CH3 <SEP> (CH2) 2CO2C2H5 <SEP> OH <SEP> methane- <SEP> 270 <SEP> 40
<tb><SEP> sulfonate
<tb><SEP> 63 <SEP> F <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> methane- <SEP>> 280 <SEP> 73
<tb><SEP> sulfonate
<tb><SEP> 64 <SEP> Cl <SEP> C2H5 <SEP> H <SEP> OH <SEP> Methane- <SEP>> 280 <SEP> 35
<tb><SEP> sulfonate
<tb><SEP> 65 <SEP> Cl <SEP> CH20CH3 <SEP> H <SEP> OH <SEP> oxalate <SEP>#<SEP> 265 <SEP> 45
<tb><SEP> 66 <SEP> Cl <SEP> H <SEP> CO2C2H5 <SEP> OH <SEP> methane- <SEP>> 280 <SEP> 50
<tb><SEP> sulfonate
<tb><SEP> 67 <SEP> Cl <SEP> CH3 <SEP> H <SEP> OH <SEP> Methane- <SEP>> 280 <SEP> 75
<tb><SEP> sulfonate
<tb><SEP> 68 <SEP> Cl <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> HCl <SEP>> 280 <SEP> 80
<tb><SEP> 69 <SEP> Cl <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> H3PO4 <SEP> H3PO4 <SEP>> 280 <SEP> 50
<Tb>
TABLE V (continued)

<tb> NÔ. <SEP> d <SEP> R2 <SEP> R <SEP> R1 <SEP> R3 <SEP> X <SEP> Rornt <SEP> of <SEP> Re "dnt
<tb> code <SEP> fÙsim <SEP> (%)
<tb> c <SEP>('C)
<tb><SEP> 70 <SEP> Cl <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> H2S04 <SEP>><SEP> 280 <SEP> 30
<tb><SEP> 71 <SEP> Cl <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> CH3COOH <SEP>> 280 <SEP> 45
<tb><SEP> 72 <SEP> Cl <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> CH3OOooH <SEP>) 280 <SEP> 40
<tb><SEP> 73 <SEP> Cl <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> OcHH3CH-CO2H <SEP>) 280 <SEP> 45
<tb><SEP> 3
<tb><SEP> 74 <SEP> Cl <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> (CHCaICOJI), <SEP>><SEP> 280 <SEP> 55
<tb><SEP> 3
<tb><SEP> 75 <SEP> Cl <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> citrate <SEP> / <SEP> 280 <SEP> 25
<tb><SEP> 76 <SEP> Cl <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> picrate <SEP> 7 <SEP> 280 <SEP> 40
<tb><SEP> 77 <SEP> Cl <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> sulphosali- <SEP>><SEP> 280 <SEP> 40
<tb><SEP> 3 <SEP> cylate
<tb><SEP> 78 <SEP> Cl <SEP> CH3 <SEP> CH3 <SEP> Cl <SEP> methane- <SEP> 265 <SEP> 75
<tb><SEP> 79 <SEP> C 2c2H; <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> HCl <SEP>><SEP> 280 <SEP> 80
<tb><SEP> 80 <SEP> C 2c2H: <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> methane- <SEP>><SEP> 280 <SEP> 70
<tb><SEP> - <SEP> Sulfonate
<tb><SEP> 81 <SEP> 0CH3 <SEP> CH3 <SEP> CH3 <SEP> OH <SEP> Methane- <SEP>><SEP> 280 <SEP> 75
<tb><SEP> sulfonate
<Tb>
The derivatives of formula (I) and their physiologically acceptable salts exhibit an antitumor activity.

 This activity was demonstrated on leukemia cells L 1210 and leukemia P 388, as well as on a solid tumor, melanoma B 16.

 By way of example, the antineoplastic activity of the code number derivative 54 is described below in detail.

a) In vitro chemosensitivity of murine leukemia L 1210
The in vitro tests on L 1210 are carried out by cloning the cells on a semi-solid medium (agar) according to an adaptation of the Salmon and Hamburger technique. The cells are incubated for one hour at 37 ° C. in the presence of the test product before being cultured (brief exposure), or placed in culture directly in the presence of the product to be treated (continuous exposure). The reading is made 5 to 7 days after cloning and the results are expressed as a percentage of the number of clones formed relative to the controls. In both cases, all experiments on treated cells and controls are done in triplicate. The cell concentration is set at 40,000 cells / ml. The results obtained are shown in FIG.

b) Antitumor activity in mice bearing experimental tumors
tales
(i) The code number derivative 54 was administered to mice carrying L 1210 leukemia and the ratio of the median survival times of the treated animals to controls (T / C%) was determined. The results obtained are collated in Table VI.

The antitumor activity is clearly significant since the T / C ratio is equal to 204% (prolongation of the survival [ILS%] = 104%). In addition, three out of ten survivors were observed at the DL dose (DL = 320 mg / kg, ie 0.76 mM / kg) and one in ten survivors at the dose
DL / 2, beyond 90 days.

 (ii) Under the same conditions, this derivative was tested on mice carrying P 388. The antitumor activity is clearly positive, the T / C being equal to 186% (see Table VII).

(iii) The results of in vivo tests performed on melanoma
B 16, indicate that the code number derivative 54 is very active on this tumor. The T / C ratio is 177% with one in ten survivors in the group of animals treated with the DL dose (see Tables VIII and
IX).

c) Mutagenicity using the Ames test
Mutagenicity of code number derivative 54 was tested using Salmonella typhimurium strains with and without metabolic activation: TA 100 reverse by a base pair substitution mechanism; TA 98, TA 1537 and TA 1977 which reverse by code read offset.

 This derivative and most of the compounds according to the invention are not or only slightly mutagenic, since the mutations generated hardly exceed three times the spontaneous reversion rate (TRS) of the corresponding strain. The results (average number of revertants calculated on three plates) obtained with the derivative 54 appear in Table X. The concentrations used are: O (controls), 2, 20, 100, 200 and 400 / g / ml (-S9: without activation, + S9: with metabolic activation).

Under these conditions, even at the highest doses, the number of revertants obtained with the derivative 54 remains always less than three times the control (TRS).

TABLE VI
LEUKEMY L 1210 - IN VIVO TRIAL
TUMOR: Leukemia L 1210 Solvent: Glucose Injection 5%
Graft: 105 cells / mouse + Klucel 0.4% and DMSO 10%
Way: ip Evaluation day: J 30
Race-sex: CDF1 Female Day of toxicity: J 5

<tb> Dose <SEP> Survivor (s) <SEP> VPM.test <SEP> VPM.ctrl. <SEP> Time <SEP> median <SEP> T / C <SEP> (%)
<tb><SEP> of <SEP> survival
<tb> mg / kg / <SEP> to <SEP> J <SEP> 5 <SEP> J5-J1 <SEP> J5-J1 <SEP> Test <SEP> Control
<tb><SEP> ip <SEP> (g) <SEP> (g)
<tb><SEP> 60 <SEP> 10/10 <SEP> + <SEP> 0.6 <SEP> + <SEP> 1.1 <SEP> 10.7 <SEP> 8.8 <SEE> 121, 6
<tb> 120 <SEP> 10/10 <SEP> + <SEP> 0.2 <SEP> + <SEP> 1.1 <SEP> 11 <SEP> 8.8 <SEP> 125
<tb> 160 <SEP> 10/10 <SEP> - <SEP> 0.6 <SEP> + <SEP> 1.1 <SEP> 12 <SEP> 8.8 <SEP> 136.4a
<tb> 240 <SEP> 10/10 <SEP> - <SEP> 1 <SEP> + <SEP> 1.1 <SEP> 13.3 <SEP> 8.8 <SEQ> 151.1
<tb> 320 <SEP> 10/10 <SEP> - <SEP> 3.7 <SEP> + <SEP> 1.1 <SEP> 18 <SEP> 8.8 <SEP> 204.5b
<Tb>
VMP: Variation in mean weight of treated mice (test) and controls
(ctrl) at the 5th day after inoculation of the tumor, expressed in
grams.

T / C (): Median survival of treated mice (T) compared with
controls (C), expressed in percent.

a: 1/10 survivor (> 90 days) in the group treated with 160 mg / kg b: 3/10 survivors (> 90 days) in the group treated with 320 mg / kg
TABLE VII
LEUKEMY P 388 - IN VIVO TRIAL
TUMOR: Leukemia P 388 Solvent: Glucose Injection 5 E
Graft: 106 cells / mouse + Klucel 0.4% and DMSO 10%
Way: ip Evaluation day: J 30
Race-sex: CDF1 Female Day of toxicity: J 5

<tb> Dose <SEP> Survivor (s) <SEP> VPM.test <SEP> VPM.ctrl. <SEP> Time <SEP> median <SEP> T / C <SEP> (%)
<tb><SEP> of <SEP> survival
<tb> mg / kg / <SEP> to <SEP> J <SEP> 5 <SEP> J5-J1 <SEP> J5-J1 <SEP> Test <SEP> Control
<tb><SEP> ip <SEP> (g) <SEP> (g)
<tb> 80 <SEP> 10/10 <SEP> + <SEP> 1 <SEP> + <SEP> 1.4 <SEP> 12 <SEP> 10.2 <SEQ> 117.6
<tb><SEP> 160 <SEP> 10/10 <SEP> - <SEP> 0.3 <SEP> + <SEP> 1.4 <SEP> 13.75 <SEP> 10.2 <SE> 134, 8
<tb> 200 <SEP> 10/10 <SEP> - <SEP> 0.3 <SEP> + <SEP> 1.4 <SEP> 14.25 <SEP> 10.2 <SEQ> 139.7
<tb> 280 <SEP> 10/10 <SEP> - <SEP> 1.5 <SEP> + <SEP> 1.4 <SEP> 17.75 <SEP> 10.2 <SEP> 174
<tb><SEP> 320 <SEP> 10/10 <SEP> - <SEP> 2.4 <SEP> + <SEP> 1.4 <SEP> 19 <SEP> 10.2 <SEP> 186.3
<Tb>
VMP: Variation in mean weight of treated mice (test) and controls
(ctrl) at the 5th day after tumor inoculation, expressed in
grams.

T / C (%): Median survival of treated mice (T) compared with
controls (C), expressed in percent.

TABLE VIII
MELANOME B 16 - IN VIVO TEST
TUMOR: Melanoma B 16 Solvent: Glucose Injection 5%
Graft: 0.5 ml (1:10) / mouse + Klucel 0.4% and DMSO 10%
Way: ip Evaluation day: J 30
Race-sex: CDF1 Female Day of toxicity: J 5

<tb> Dose <SEP> Survivor (s) <SEP> VPM.test <SEP> VPM.ctrl. <SEP> Time <SEP> median <SEP> T / C <SEP> (%)
<tb><SEP> of <SEP> survival
<tb> mg / kg / <SEP> to <SEP> J <SEP> 5 <SEP> J5-J1 <SEP> J5-J1 <SEP> Test <SEP> Control
<tb> ip <SEP> (g) <SEP> (g)
<tb><SEP> 60 <SEP> 10/10 <SEP> + <SEP> 0.4 <SEP> + <SEP> 1 <SEP> 18.7 <SE> 15.1 <SE> 123.8
<tb><SEP> 120 <SEP> 10/10 <SEP> + <SEP> 0.2 <SEP> + <SEP> 1 <SEP> 19.3 <SEP> 15.1 <SE> 127.8
<tb> 240 <SEP> 10/10 <SEP> - <SEP> 2,3 <SEP> + <SEP> 1 <SEP> 21.8 <SEP> 15.1 <SEP> 144.4
<tb> 280 <SEP> 10/10 <SEP> - <SEP> 2.6 <SEP> + <SEP> 1 <SEP> 24.9 <SEP> 15.1 <SEP> 164.9 *
<Tb>
VMP: Variation in mean weight of treated mice (test) and controls
(ctrl) at the 5th day after tumor inoculation, expressed in
grams.

T / C (%): Median survival of treated mice (T) compared with
controls (C), expressed in percent.

 1/10 surviving (> 60 days) in the group treated with 280 mg / kg.

TABLE IX
MELANOME B 16 - IN VIVO TEST
TUMOR: Melanoma B 16 Solvent: Glucose Injection 5%
Graft: 105 cells / mouse + Klucel 0.5% and DMSO 10%
Way: ip Evaluation day: J 30
Race-sex: BDF1 Female Day of toxicity: J 5

<tb> Dose <SEP> Survivor (s) <SEP> VPM.test <SEP> VPM.ctrl. <SEP> Time <SEP> median <SEP> T / C <SEP> (%)
<tb><SEP> of <SEP> survival
<tb> mg / kg / <SEP> to <SEP> J <SEP> 5 <SEP> J5-J1 <SEP> J5-J1 <SEP> Test <SEP> Control
<tb><SEP> ip <SEP> (g) <SEP> (g)
<tb><SEP> 80 <SEP> 10/10 <SEP> + <SEP> 0.4 <SEP> + <SEP> 1.3 <SEP> 19 <SEP>#<SEP> 15.7 <SEP> 121
<tb> 160 <SEP> 10/10 <SEP> + <SEP> 0.2 <SEP> + <SEP> 1.3 <SEP> 19.9 <SEP> 15.7 <SE> 126.8
<tb> 320 <SEP> 10/10 <SEP> - <SEP> 1.4 <SEP> + <SEP> 1.3 <SEP> 27.75 <SEP> 15.7 <SEQ> 176.8 * <September>
<Tb>
VMP: Variation in mean weight of treated mice (test) and controls
(ctrl) at the 5th day after tumor inoculation, expressed in
grams.

T / C (%): Median survival of treated mice (T) compared with
controls (C), expressed in percent.

 1/10 surviving (> 60 days) in the group treated with 320 mg / kg.

PAINTINGS
EVALUATION OF MUTAGENIC POWER WITH THE TESTING OF AMES
Solvent: Dimethylsulfoxide

<tb><SEP> S
<tb><SEP> O <SEP> DOSE <SEP> / <SEP> SOITE
<tb><SEP> U
<tb><SEP> C <SEP> 0 <SEP> g <SEP> 2 <SEP> g <SEP> 20 <SEP> g <SEP> 100 <SEP> g <SEP> 200 <SEP> g <SEP> 400 <SEP> g
<tb><SEP> H
<tb><SEP> E <SEP> -69 <SEP> -159 <SEP> -69 <SEP> -169 <SEP> -69 <SEP> -169 <SEP> -69 <SEP> -169 <SEP> -69 <SEP> -159 <SEP> -69 <SEP> -159
<tb><SEP> 22 <SEP> 34 <SEP> 24 <SEP> 54 <SEP> 25 <SEP> 49 <SEP> 29 <SEP> 66 <SEP> 25 <SEP> 69 <SEP> 23 <SEP> 71
<tb><SEP> TA <SEP> 98 <SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#
<tb><SEP> 3 <SEP> 3 <SEP> 3 <SEP> 9 <SEP> 4 <SEP> 3 <SEP> 1 <SEP> 6 <SEP> 5 <SEP> 6 <SEP> 4 <SEP> 10
<tb><SEP> 83 <SEP> 109 <SEP> 102 <SEP> 98 <SEP> 101 <SEP> 113 <SEP> 105 <SEP> 117 <SEP> 103 <SEP> 129 <SEP> 106 <SEP> 130
<tb><SEP> TA <SEP> 100 <SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP>#<SEP>#<SEP>#<SEP><SEP>#<SEP><SEP>#<SEP>#<SEP>#
<tb><SEP> 7 <SEP> 7 <SEP> 16 <SEP> 3 <SEP> 16 <SEP> 2 <SEP> 10 <SEP> 9 <SEP> 1 <SEP> 3 <SEP> 4 <SEP> 7
<tb><SEP> 7 <SEP> 7 <SEP> 6 <SEP> 9 <SEP> 14 <SEP> 9 <SEP> 16 <SEP> 14 <SEP> 11 <SEP> 9 <SEP> 9 <SEP> 10
<tb> TA <SEP> 1537 <SEP>#<SEP>#<SEP>#<SEP>#<SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#
<tb><SEP> 3 <SEP> 2 <SEP> 3 <SEP> 3 <SEP> 3 <SEP> 4 <SEP> 6 <SEP> 2 <SEP> 3 <SEP> 2 <SEP> 2 <SEP> 1
<tb><SEP> 5 <SEP> 8 <SEP> 7 <SEP> 12 <SEP> 6 <SEP> 9 <SEP> 5 <SEP> 8 <SEP> 3 <SEP> 8 <SEP> 3 <SEP> 7
<tb><SEP> TA <SEP> 1977 <SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP><SEP>#<SEP>#<SEP>#
<tb><SEP> 2 <SEP> 1 <SEP> 3 <SEP> 4 <SEP> 1 <SEP> 3 <SEP> 2 <SEP> 3 <SEP> 2 <SEP> 5 <SEP> 1 <SEP> 4
<Tb>
Ames test: The results are expressed in number of colonies
revertants per box (mcyenne calculated on three boxes)
for the four strains, at the doses indicated with (+ S9)
and without (-59) metabolic activation
A toxicity study of the derivatives and salts according to the invention has moreover shown that there exists a large difference between the therapeutically active doses and the toxicity.

 By way of example, the in vivo toxicity study carried out on the derivative of code number 54 is described below.

Toxicity in healthy mice
Acute and subacute toxicity studies were performed on healthy CDF1 mice (randomly divided into groups of 10 mice / dose) by intraperitoneal administration of derivative 54 according to the different protocols.
- one injection (day 1)
- 3 intermittent injections (days 1, 5, 9)
- 9 consecutive injections (days 1-9)
The derivative was solubilized in a 5% glucose / injectable solution containing 0.4% Klucel and 10% dimethylsulfoxide.

 The DLso and the DLlo are determined by the graphical method by representing the percentage of dead animals on the ordinate and the corresponding doses on the abscissa on a logarithmic scale. The results obtained as well as the correlation coefficients (r) are shown in Table XI below.

TABLE XI
Derivative toxicity 54 in CDFi mice

<tb> Injections <SEP> DLlo <SEP> (mg / kg) <SEP> LDso <SEP> (mg / kg) <SEP> r
<tb> Day <SEP> 1 <SEP> 395 <SEP> 493 <SEP> 0.98
<tb> Day <SEP> 1.5, <SEP> 9 <SEP> 384 <SE> 466 <SEP> 0.99
<tb> Day <SEP> 1-9 <SEP> 263 <SEP> 310 <SEP> 0.99
<Tb>
Therefore, the derivatives of formula (I) and their physiologically acceptable salts, find their application in human or animal therapy, as antineoplastic agents, for the treatment of tumor diseases.

 In particular, these derivatives and salts are useful for the preparation of medicaments for the treatment of the abovementioned conditions, and in particular for pharmaceutical or veterinary compositions which comprise at least one of these derivatives and salts in combination with a physiologically acceptable carrier or excipient. suitable for said compounds.

 These compositions may for example be formulated for oral, parenteral or rectal administration.

 For oral administration, said compositions may take the form of tablets, dragees or capsules prepared by the usual techniques using known carriers and excipients such as diluents (for example, polyethylene glycol, lactose, dextrose), binders ( for example, starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone), fillers, lubricants (for example, magnesium or calcium stearate, stearic acid, talc, silica) and disintegrating agents (e.g. starch, alginic acid, alginate). These compositions, for oral administration, may also take the form of solutions, syrups or suspensions; the syrups may contain, for example, sucrose with, for example, glycerin and / or mannitol and / or sorbitol, the suspensions may contain, for example, a natural gum, agar, sodium alginate, pectin or methylcellulose; the solutions may be aqueous solutions.

 For parenteral administration, the compositions according to the invention may take the form of solutions, suspensions or injectable emulsions comprising a liquid, oily or aqueous vehicle, parenterally acceptable (for example sterile water, olive oil, oleate of ethyl, propylene glycol in the case of intramuscular injection forms and sterile water or sterile isotonic aqueous saline solutions in the case of intravenous injection forms).

 Finally for rectal administration, the compositions according to the invention can take the form of suppositories comprising the usual bases for suppositories (for example, cocoa butter, polyethylene glycol).

 The dose at which the active ingredients, that is to say the derivatives of formula (I) and their salts, can be administered to humans or to any warm-blooded animal, depends especially on the route of administration, the body weight and the pathological state of the patient and the therapeutic power of the derivatives and salts used. Generally, oral doses may reach 500 mg of active ingredient per day (in one or more doses); parenterally, doses may reach 250 mg of active ingredient per day (in one or more daily injections) and rectally, doses may reach 350 mg of active ingredient per day (in one or more suppositories).

Claims (16)

 1. Derivatives of 6H-pyrido [3,2-b] carbazole, corresponding to the formula

 in which - R2 represents a hydrogen or halogen atom or a hydro group  xyl, methoxy or carbethoxyoxy, and - the sequence -A --- B- represents

 in which case R3 denotes *) either a hydroxyl group or a chlorine atom; R and R1,  which may be the same or different, representing  then everyone  . a hydrogen atom  . a C 1 -C 4 alkyl group  . a methoxymethyl or methoxyethyl group  . a group of formula (CH2) n-COR4 where n = O, 1, 2 or 3  and R4 represents a hydroxyl, C1-C4 alkoxy group  or hydrazino, or  . a benzyl group *) is a C 1 -C 4 alkoxy or C 2 -C 5 acyloxy group; R and R  which may be the same or different, representing  then a hydrogen atom or a C1-C4 alkyl group; or

 in which case R3 represents a hydroxyl group and R1 represents  hydrogen, as well as the physiologically acceptable acid addition salts of these derivatives.  2. Derivatives according to claim 1, of particular structure

 benzyl and their physiologically acceptable acid addition salts.  n = 0, 1, 2 or 3, (CH 2) n -CO-NH-NH 2 where n = 0, 1, 2 or 3 or  - Rai = H, C1-C4 alkyl, COOH, (CH2) n-COO-C1-C4 alkyl where  (CH 2) n-COO-C 1 -C 4 alkyl wherein n = O, 1, 2 or 3, and  R = H, C 1 -C 4 alkylene, methoxymethyl, methoxyethyl, COOH or  R2 = H, OH, CH30, halogen or OCO2C2Hs,  in which  3. Derivative according to claim 2, wherein Ra = R 1 = CH 3 and R 2 = Cl, and its physiologically acceptable acid addition salts.  4. Derivatives according to claim 1, of particular structure

 n = 0, 1, 2 or 3 as well as their physiologically acceptable acid addition salts.  - Rbi = H, C1-C4 alkyl or (CH2) n-COO-C1-C4 alkyl where  (CH 2) n-COO-C 1 -C 4 alkyl wherein n = O, 1, 2 or 3, and  Rb = H, C1-C4 alkyl, methoxymethyl, methoxyethyl or  - Rb2 = H or halogen,  in which  5. Derivatives according to claim 1, of particular structure

 - Rc = H or C1-C11 alkyl = H or C1-C4 alkyl, - RC2 = H or halogen, and - RC3 = C1-C4 alkoxy or C2-Cs acyloxy) and their addition salts physiologically acceptable acid.  in which  6. Derivatives according to claim 1, of particular structure:

 wherein Rd2 = H or halogen, as well as their physiologically acceptable acid addition salts.  7. Pharmaceutical or veterinary composition, characterized in that it comprises at least one derivative or salt according to one of claims 1 to 6, in combination with a carrier or excipient physiologically acceptable and suitable for said derivative or salt.  8. Use of the derivatives and salts according to one of claims 1 to 6 for the manufacture of a medicament for the treatment of tumor disorders.  9. Process for the preparation of the derivatives according to claim 1 of formula (I) of particular structure:

 or: - R and R1, which may be the same or different, each represents H, methoxymethyl, methoxyethyl, C1-C4 alkyl, benzyl or (CH2) n-COR4 where n = 0, 1, 2 or 3 and R4 = OH , C1-C4 alkoxy or hydrazino, and - R2 = H, halogen, OH, CH3O or OC02C2H5, as well as salts of these derivatives, characterized in that it comprises the condensation of compounds of formula

 where R and R 1 have the same meaning as above, respectively on compounds of formula

 where R2 = H, halogen, OH, CH3O or OC02C2H5, and optionally the salification with an organic or inorganic acid derivatives thus obtained.  10. Process for preparing the derivatives according to claim 1 of formula (I) of particular structure

 where R'2 = H, halogen, OH or OCH3 and at least one of R 'and R'1 represents (CH2) n ~ COOH where n = O, 1, 2 or 3 and the other represents H, alkyl C1-C4, methoxymethyl, methoxyethyl or benzyl, as well as salts of these derivatives, characterized in that it comprises the basic hydrolysis of the derivatives of formula (Ia) defined in claim 9 for which R2 = H, OH, 0CH3 or halogen and at least one of R and R1 represents a group (CH2) n -CORtL where n = O, 1, 2 or 3 and R'4 = C1-C4 alkoxy, and optionally salification with an acid organic or mineral derivatives thus obtained.  11. Process for preparing the derivatives according to claim 1 of formula (I) of particular structure:

 where R'2 = H, halogen, OH or OCH3 and one of R "and Rtt1 is (CH2) n-COR" 4 where n = 0, 1, 2 or 3 and R "4 = NH-NH2 and other represents H, (C1-C4) alkyl, methoxymethyl, methoxyethyl or benzyl, as well as salts of these derivatives, characterized in that it comprises the action of hydrazine on the derivatives of formula (I'a) defined in claim 10 and optionally the salification with an organic or inorganic acid of the derivatives thus obtained.  12. Process for the preparation of the derivatives according to claim 1 of formula (I) of particular structure:

 where - R and R1, which may be the same or different, each represents H, methoxymethyl, methoxyethyl, C1-C4 alkyl, benzyl or (CH2) n-COR4 where n = O, 1, 2 or 3 and R4 = OH, C 1 -C 4 alkoxy or hydrazino, and - R 2 = H, halogen, OH, OCH 3 or OCO 2 C 2 H 5, as well as salts of these derivatives, characterized in that it comprises chloro dehydroxylation, with phosphorus oxychloride, derivatives of formula (Ia) defined in claim 9, and optionally salification with an organic or inorganic acid derivatives thus obtained.  13. Process for preparing the derivatives according to claim 1 of formula (I) of particular structure

 where - R and R 1, which may be the same or different, each represent H, methoxymethyl, methoxyethyl, C 1 -C 4 alkyl, benzyl or (CH 2) n-COR 4 where n = 0, 1, 2 or 3 and R 4 = OH, C 1 -C 4 alkoxy or hydrazino, and - R 2 = H, halogen, OH, OCH 3 or OCO 2 C 2 H 5, as well as salts of these derivatives, characterized in that it comprises the cyclization, by phosphorus oxychloride, of the compounds Formula

 and optionally the salification with an organic or inorganic acid of the derivatives thus obtained.  14. Process for the preparation of the derivatives according to claim 1 of formula (I) of particular structure:

 where R and R1 independently represent H or C1-C4 alkyl, R2 = H, halogen, OH, CH3O or OC02C2H5 and R3 = C1-C4 alkoxy or C2 acyl; C5, as well as salts of these derivatives, characterized in that it comprises the condensation of a compound of formula  (C1-C4 alkyl) -X wherein X represents a good leaving electrophilic group, or a compound of formula  (C2-C5 acyl) -Cl, or  (C2-C5 acyl) or an activated ester of the acid (C2-C5 acyl) -OH, on the derivatives of formula (Ia) defined in claim 9 for which R and R independently represent H or C1-C4 alkyl, and optionally the salification with an organic or inorganic acid derivatives obtained.  15. Process for preparing the derivatives according to claim 1 of formula (I) of particular structure

 where R = H or C1-C4 alkyl, R1 = H and R2 = H, halogen, OH, CH3O or OC02C2H5, as well as salts of these derivatives, characterized in that it comprises heating the compounds of formula (VIII) defined in claim 13 for which R1 = CO2C2H5, and optionally the salification with an organic or inorganic acid derivatives and obtained.  16. Process for the preparation of the derivatives according to claim 1 of formula (I) of particular structure:

 where R2 = H, halogen, OH, CH3O or OCO2C2H5, as well as salts of these derivatives, characterized in that it comprises the cyclization by diethyl malonate compounds of formula (VII) defined in claim 9, and optionally the salification with an organic or mineral acid of the derivatives thus obtained.