AU7012400A - Ascididemin derivatives and their therapeutic applications - Google Patents

Abstract

The invention concerns a pharmaceutical composition comprising an efficient amount of a compound selected among the compounds of formulae (I) and (Ia) wherein: R1, R2, R3, R4, R5, R6 and R7 are as defined in Claim 1. Said compounds have interesting cytotoxic properties leading to a therapeutic use as antitumoral medicines.

Description

WO 01/12631 PCT/FROO/02312 Ascididemin derivatives and therapeutic uses thereof The present invention relates to pharmaceutical compositions based on polyaromatic compounds that are 5 useful especially as antitumor drugs. In 1999, the cytotoxic treatments (chemotherapy) used to reduce the size of cancer tumors, to curtail the development of the tumor process or even, in all to few 10 cases still, to eliminate the lumps of cancerous cells and the risk of metastases, combine recently introduced chemical substances with others that have been used for several decades. For example, 5-fluorouracil (5-FU), which has been known for nearly 40 years as one of the 15 most active treatments in colorectal cancer, can be replaced one or other of the specific topoisomerase I inhibitors (irinotecan or topotecan) when the tumor is no longer sensitive to 5-FU. More generally, the therapeutic arsenal available to treat colorectal 20 tumors will also be enriched by the availability of oxaliplatin, novel in situ "donors" of 5-FU or selective inhibitors of thymidylate synthase. This co-existence is not limited to the treatment of colorectal cancers, since the chemotherapy of cancer of 25 the breast, of the ovaries or of the lungs now also widely uses the family of taxane derivatives (paclitaxel and docetaxel). The need for treatments that are more effective and better tolerated, thus improving the survival and the quality of life of the 30 patients, is imperative since, taking once again the example of colorectal tumors, it has been estimated (S.L. Parker, T. Tong, S. Bolden et al., CA Cancer J. Clin., 1997) that in the United States alone, more than 131 000 new cases were diagnosed in 1997, 54 000 35 of which wre responsible for the death of the patients. It is the knowledge of this situation which has incited the inventors to become interested in a family of polyaromatic compounds that are still relatively poorly - 2 studied, identified in Ascidians of warm seawaters, to develop a novel medicinal chemistry intended to select synthetic compounds derived from a design/chemical modulation study and having significant therapeutic 5 cytotoxic activity. The seas and oceans which cover more than 70% of the surface of the globe harbor marine plants and sponges whose gradual systematic pharmacognosic study shows 10 that these living species can contain complex alkaloids that have advantageous pharmacological properties. For example, the sponges Cryptotheca crypta and Halichondria okadai have been the subject of extensive studies since the discovery of the presence, in their 15 cells, of cytarabine or of halichondrine B. This is likewise the case for the family of tunicates, since the isolation of aplidin from the tunicate Aplidium albicans which lives in the Balearic islands (Spain). Alkaloids of tetrahydroisoquinolone structure have been 20 isolated from the ascidian Ecteinascidia turbinata. Among these, ecteinascidin-743 has been the subject of extensive preclinical studies (E. Igbicka et al., NCI-EORTC symposium, 1998; Abst. 130 p. 34), and also clinical trials intended to define its therapeutic 25 potential as an anticancer drug (A. Bowman et al., NCI-EORTC symposium, 1998; Abst. 452 p. 118; M. Villanova-Calero et al., NCI-EORTC symposium, 1998; Abst. 453 p. 118; M.J.X. Hillebrand et al., NCI-EORTC symposium, 1998; Abst. 455 p. 119; E. Citkovic et al., 30 NCI-EORTC symposium, 1998; Abst. 456 p. 119) . Novel pentacyclic acridine derivatives have also been the subject of pharmacochemical studies (D.J. Hagan et al., J. Chem. Soc., Perkin Transf., 1997; 1: 2739-2746). 35 Another natural alkaloid of marine origin, ascididemin, has been extracted from the tunicate Didemnum sp. (J. Kobayashi et al., Tetrahedron, lett. 1988; 29: 1177-80) and from the ascidian Cystodytes dellechiajei (I. Bonnard et al., Anti-cancer Drug design 1995; 10: - 3 333-46). Ascididemin possesses antiproliferative properties demonstrated on the model of mouse leukemia (lines P388 or L1210) and described by F. Schmitz et al. (J. Org. Chem. 1991; 56: 804-8), B. Lindsay et al. 5 (Bioorg. Med. Chem. Lett. 1995; 5: 739-42) and J. Kobayashi et al. (Tetrahedron lett. 1988; 29: 1177 80) and on the model of human leukemia described by I. Bonnard et al. (Anti-cancer Drug design 1995; 10: 333-46). Several routes for synthesizing ascididemin 10 have been reported by various authors: F. Bracher et al. (Heterocycles 1989; 29: 2093-95), C.J. Moody et al. (Tetrahedron Lett. 1992; 48: 3589-602) and G. Gellerman et al. (Synthesis 1994; 239-41). 15 Mention may also be made of 2-bromoleptoclinidone (according to the naming by S.J. Bloor et al. 1987) isolated from the ascidian Leptoclinides sp. by S.J. Bloor et al. (J. Ann. Chem. Soc. 1987; 109: 6134-6) and synthesized by F. Bracher et al. 20 (H6t6rocycles 1989; 29: 2093-95) and then by M.E. Jung et al. (H6t6rocycles 1994; 39; 2: 767-778). 2-Bromoleptoclinidone shows cytotoxicity on the cellular model of leukemia with an ED 5 o of 0.4 pg/ml. The cytotoxic properties were confirmed by F. Bracher 25 (Pharmazie 1997; 52: 57-60) both in vitro - on sixty tumor cell lines in culture - and in vivo on models of xenographs of human tumor cell lines (colon tumors SW 620 and HTC116, renal tumor A498 and melanoma LOX IM VI) implanted into mice. 30 Other compounds derived from ascididemin, such as 11-hydroxy ascididemin, 11-methoxy ascididemin, 11-phenyl and 11-nitrophenyl ascididemin, 1-nitro and 3-nitro ascididemin and neocalliactin have been 35 chemically described (according to the numbering by S.J. Bloor et al. 1987) by various teams such as those of F.J. Schmitz (J. Org. Chem. 1991; 56: 804-8) and Y. Kitahara et al. (Heterocycles 1993; 36: 943-46; Tetrahedron Lett. 1997; 53, 17029-38), G. Gellerman et al. (Tetrahedron lett. 1993; 34: 1827-30), S. Nakahara et al (Heterocycles 1993; 36: 1139-44), I. Spector et al. (US Patent Number: 5,432,172, Jul. 11, 1995). 5 One subject of the present invention is a pharmaceutical composition comprising an effective amount of a compound chosen from the compounds of general formulae I and Ia below: x R1 X R1 N R2 R7 N R2 N / 4 NR Formula i Formula la 10 in which: - X is chosen from oxygen, an =NH group and an =N-OH group, 15 - Ri is chosen from hydrogen, halogens, a nitro group and groups -NR 8

R

9 in which R 8 and R 9 are chosen, independently of each other, from hydrogen and (Ci-C4) alkyl groups, - R 2 is chosen from hydrogen and halogens, 20 - R 3 is chosen from hydrogen, halogens, (Ci-C4) alkyl groups, (C1-C6) alkoxy groups, a guanidino group, groups -NR 10

R

11 in which R 10 and R 11 are chosen, independently of each other, from hydrogen, (Ci-C4) alkyl groups, (Ci-C4) phenylalkyl groups and groups 25 -(CH 2 )n-Y with Y being chosen from halogens and CN, -CH(O-Et) 2 , (C 1

-C

6 ) alkoxy, -O-(CH 2

)

2

-N(CH

3

)

2 and -N(CH 3

)

2 groups and n = 1 to 3, - R 4 is chosen from hydrogen, halogens, nitro groups and groups -NR 12

R

1 3 in which R 12 and R 13 are 30 chosen, independently of each other, from hydrogen and (Ci-C4) alkyl groups, - 5 - R 5 , R 6 and R 7 are chosen from: hydrogen or a halogen atom, Ci-C6 alkyl, hydroxyl, C1-C6 alkoxy, (C1-C6) alkoxy (C1-C6) alkyl, (C 1

-C

4 ) alkylcarbonyloxy (C 1

-C

4 ) alkyl, 5 -CHO, -COOH, -CN, -C0 2

R

1 4 , -CONHR 1 4 and -CONR 1 4

R

1 5 groups,

-NHCOR

1 4 and -NR 14

R

15 in which R 1 4 and R 15 are chosen, independently of each other, from hydrogen and (C1-C6) alkyl, -phenyl-CO-CH 3 and -CH 2

-CH

2

-N(CH

3 )2 groups, -phenyl-CO-CH 3 or -phenyl-CO-CH=CH-N (CH 3 ) 2, 10 morpholino, nitro or SO 3 H groups, groups: -CH2-N-COOR 16 , -CH2-N-COR 1 6 1 C1- COOR 17 CH2-Ar 15 R 16 and R 1 7 being chosen from C1-C6 alkyl groups and Ar being a C6-C14 aryl group, with the exclusion of the compounds of formula I containing the combination: X = 0, 20 and, either: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 = H, or : R 1 , R 3 , R 4 , R 5 , R 6 , R 7 = H and R 2 = Br, and with the exclusion of the compound formula Ia containing the combination X = 0 and R 1 , R 2 , R 3 , R 4 , R 5 ,

R

6 , R 7 = H, 25 and the addition salts of these compounds with pharmaceutically acceptable acids. The present invention relates more particularly to a pharmaceutical composition comprising an effective 30 amount of a compound chosen from the compounds of formula I in which: - X is chosen from oxygen, an =NH group and an =N-OH group, - Ri is chosen from hydrogen, halogens, a nitro 35 group and groups -NR 8

R

9 in which R 8 and R 9 are chosen, independently of each other, from hydrogen and (C1-C4) alkyl groups, - 6 independently of each other, from hydrogen and (C1-C4) alkyl groups, - R 2 is chosen from hydrogen and halogens, - R 3 is chosen from hydrogen, halogens, (C1-C4) 5 alkyl groups, (Cl-CE) alkoxy groups, a guanidino group, groups -NR 10

R

11 in which R 10 and R 11 are chosen, independently of each other, from hydrogen, (C1-C4) alkyl groups, (C1-C4) phenylalkyl, -(CH 2

)

2

-N(CH

3

)

2 , and - (CH 2 ) 2-0- (CH 2 ) 2 -N (CH 3 ) 2 groups, 10 - R 4 is chosen from hydrogen, halogens, nitro groups and groups -NR 12

R

13 in which R 1 2 and R 1 3 are chosen, independently of each other, from hydrogen and (C1-C4) alkyl groups, - R 5 , R 6 and R 7 are chosen from: 15 hydrogen or a halogen atom, Ci-C alkyl, hydroxyl, C1-C6 alkoxy, -CHO, COOH, -CN, -C0 2

R

1 4 , -CONHR 14 and -CONR 1 4

R

15 groups, NHCOR 1 4 and -NR 1 4

R

15 groups in which R 1 4 and R 15 are chosen, independently of each other, from hydrogen and 20 (C1-C6) alkyl and -CH 2

-CH

2

-N(CH

3

)

2 groups, -phenyl-CO-CH 3 or -phenyl-CO-CH=CH-N (CH 3

)

2 , morpholino, nitro or SO 3 H groups, groups: -CH2 -N -COOR 1 , -CH2-N-COOR 1 6 , CH2- COOR 1 7 C2-Ar 25

R

16 and R 17 being chosen from C1-C6 alkyl groups and Ar being a C6-C14 aryl group, with the exclusion of the compounds in which X = 0, 30 and, either : R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 = H, or : R 1 , R 3 ,

R

4 , R 5 , R 6 , R 7 = H and R 2 = Br, and the addition salts of these compounds with pharmaceutically acceptable acids. 35 One subject of the present invention is more particularly a pharmaceutical composition comprising an - 7 effective amount of a compound chosen from the compounds of formula I in which: - X represents oxygen, - R 1 is chosen from hydrogen and an amino 5 group, - R 2 is chosen from hydrogen and halogens, - R 3 is chosen from hydrogen, halogens, (C 1

-C

4 ) alkyl groups, (C1-C6) alkoxy groups, a guanidino group, groups -NR 1 oR 11 in which R 10 and R 11 are chosen, 10 independently of each other, from hydrogen, methyl groups, (C 1

-C

4 ) phenylalkyl, - (CH 2 ) 2 -N (CH 3 ) 2, (CH 2 ) 2-0

(CH

2 ) 2 -N (CH 3

)

2 groups, - R 4 is chosen from hydrogen, halogens and nitro and amino groups, 15 - R 5 , R 6 and R 7 represent a hydrogen, with the exclusion of the compounds in which R 1 ,

R

2 , R 3 , R 4 , R 5 , R 6 , R 7 = H, or R 1 , R 3 , R 4 , R 5 , R 6 , R 7 = H and R 2 = Br, and the addition salts of these compounds with 20 pharmaceutically acceptable acids. In its preferred form, one subject of the present invention is more particularly a pharmaceutical composition comprising an effective amount of a 25 compound chosen from the compounds of formulae I and Ia in which: - X represents oxygen, - R 1 is chosen from hydrogen and an amino group, 30 - R 2 is chosen from hydrogen and halogens, - R 3 is chosen from hydrogen, halogens, (C1-C4) alkyl groups, (C1-C6) alkoxy groups, a guanidino group, groups -NR 1 oR 11 in which R 10 and R 11 are chosen, independently of each other, from hydrogen, methyl 35 groups, (C1-C4) phenylalkyl groups and groups -(CH 2 )n-Y with Y being chosen from halogens and groups CN, -CH(O Et) 2 , (C1-C6) alkoxy, -O-(CH 2

)

2

-N(CH

3

)

2 and -N(CH 3

)

2 and n = 1 to 3, - 8 - R 4 is chosen from hydrogen, halogens, and nitro and. amino groups, - R 5 is chosen from a hydrogen, a halogen and a methoxy group, 5 - R 6 and R 7 are chosen from hydrogen and Ci-C 6 alkoxy, (Cl-C6) alkoxy (Ci-C 6 ) alkyl and -CH 2 0COCH 3 groups, with the exclusion of the compounds of formula I in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 = H or R 1 , R 3 , R 4 , R 5 ,

R

6 , R 7 = H and R 2 = Br, and of the compound of formula 10 Ia in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 = H, and the addition salts of these compounds with pharmaceutically acceptable acids. A subject of the present invention is also the 15 compounds of formula I as defined above, with the exclusion of the compounds in which X = 0, and either R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 = H, or R 1 , R 3 , R 4 , R 5 , R6, R 7 = H and R 2 = Br, or R 1 , R 2 , R 4 , R 5 , R 6 , R 7 = H and R 3 = OCH 3 , 20 or R 1 , R 2 , R 3 , R 4 , R 6 , R 7 = H and R 5 = OH or OCH 3 , or Ri = NO 2 and R 2 , R 3 , R 4 , R 6 , R 7 = H, and the addition salts of these compounds with pharmaceutically acceptable acids. 25 A subject of the present invention is also the compounds of formula Ia as defined above, with the exclusion of the compound in which X = 0 and R 1 , R 2 , R 3 ,

R

4 , R 5 , R6, R 7 = H, and the addition salts of these compounds with 30 pharmaceutically acceptable acids. The expression "addition salts with pharmaceutically acceptable acids" denotes salts which give the biological properties of the free bases, without having 35 any adverse effects. These salts may be especially those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; acidic metal salts, such as disodium - 9 orthophosphate and monopotassium sulfate, and organic acids. In general, the compounds of formula I are obtained 5 according to the general reaction scheme described by F. Bracher et al. (Heterocycles 1989; 29: 2093-95) for ascididemin. According to this scheme, the compounds are prepared by oxidative amination of a 5,8-quinone substituted with a substituted ortho-aminoacetophenone, 10 followed by cyclization of the diarylamine obtained (compounds of the formula II) into an intermediate tetracyclic quinone (compounds of formula III) . The enamine formed by reaction of the compound of formula III with dimethylformamide diethyl acetal gives the 15 final derivative by cyclization: Scheme I R O R R 5 0 H

H

2 N

R

2 CeCl3,7H20 R7 0-R3 R 7 O R3 0

CH

3

R

4 0

CH

3 R4 Formula i R1 O Ri 6 N R2

H

2

SO

4 conc./AcOH HCOC2Hs2N(CH32 reflux N /3 DM, 120"C O CH3 Formula! Il R6 N R2 NH4CI N R2 AcOH ./\\ R7 NR3 R7 R3 N(CH3 2 Formula I 20 - 10 Ascididemin (or 9-H-quino[4,3,2-de] [1,10]phenanthrolin 9-one) was prepared according to the process described by F. Bracher et al. (Heterocycles 1989; 29: 2093-95) and is referenced, in the present document, under the 5 number CRL 8274. Certain compounds may be prepared directly from ascididemin or from a compound of formula I used as a synthetic intermediate. 10 Thus, in particular, the compounds of formula I in which R 3 is a group -NRioRii, where R 10 and/or R 11 are other than hydrogen, may be obtained from a compound of formula I in which R 3 is an -NH 2 group. 15 Similarly, the compounds of formula Ia may be obtained according to the general reaction scheme II. According to this scheme, the compounds are prepared by coupling a substituted chlorobenzoic acid and dimethoxyaniline 20 to form the compounds of formula IIa. After conversion of the acid function to a methyl ketone, cyclization and then oxidation, an intermediate tricyclic quinone (compound of formula IIIa) is obtained. A Diels-Alder cycloaddition with a 1-azediene leads to the formation 25 of a tetracyclic quinone (compound of formula IVa). The addition of dimethylformamide diethyl acetal to this quinone gives an enamine intermediate which is cyclized, in the presence of ammonium chloride, to the final compound of formula Ia. 30 - 11 Scheme I OMe R,

NH

2 a R OMe H Cu~ N N. . -, H0 2 C R Me HO 2

R

3 Formula Ila OMe ROMe R

LJCH

3 HH R2 FN R

CH

3 0 , D OMe R4e \/ 0 0 R I

R

2

R

7 N R 2 IN N N 0 P4Rs 0 R Form ula Ilia Formula IVa DMFDEA, NH.C1 Formula ia - 12 Certain compounds may be prepared directly from the ascididemin isomer known as 9-H-quino[4,3,.2-de] [l,7]phenanthrolin-9-one, or from a compound of formula Ia used as a synthetic intermediate. 5 Certain compounds may be prepared directly from the ascididemin isomer known as 9-H-quino[4,3,2-de] [1,7]phenanthrolin-9-one, or from a compound of formula Ia used as a synthetic intermediate. 10 Thus, in particular, the compounds of formula Ia in which R 3 is a group -NRioRii, in which Rio and/or R 11 are other than hydrogen, may be obtained from a compound of formula Ia in which R 3 is a -NH 2 group. 15 A - Preparation of the intermediate products of formula II (Scheme I) 20 A-1 - Synthesis of 6-(2-acetyl-4-methylphenylamino) quinoline-5,8-dione (Intermediate A 1 ) (CRL 8322) A solution of 5,8-quinolinedione (0.215 g, 1.35 mmol) in 12 ml of ethanol is added slowly to a solution of cerium chloride (1 g, 2.7 mmol) and 5-methyl-2-amino 25 acetophenone (0.402 g, 2.7 mmol) in 5 ml of ethanol. The reaction medium (red) is stirred overnight at room temperature. The resulting medium is hydrolyzed with 30 ml of aqueous 10% acetic acid solution and extracted 4 times with chloroform. The organic phases are dried 30 over MgSO 4 and then evaporated. The crude product obtained is purified by flash chromatography on a column of silica (95/5 CH 2 Cl 2 /MeOH) to give 0.405 g of the expected tricyclic compound in the form of a powder: 35 e Yield = 98% e 'H NMR (CDCl 3 ): 2.42 (s, 3H), 2.77 (s, 3H), 6.86 (s, 1H), 7.38 (dd, 1H, J = 8 and 1.6 Hz), 7.52 (d, 1H, J = 8 Hz), 7.61 (dd, 1H, J = 5.2 and 7.6 Hz), 7.74 (d, - 13 1H, J = 1.6 Hz), 8.46 (dd, 1H, J = 7.6 and 5.2 Hz), 9.02 (dd, 1H, J = 2 and 5.2 Hz), 11.18 (s, 1H). A-2 - Synthesis of 6-(2-acetyl-4 5 chlorophenylamino)quinoline-5,8-dione (Intermediate A 2 ) Preparation according to the process described in chapter A-1: quinoline-5,8-dione (0.188 g, 1.18 mmol), cerium chloride (0.88 g, 2.36 mmol), 5-chloro-2 10 aminoacetophenone (0.4 g, 3.14 mmol), ethanol (10 + 4 ml), acetic acid (25 ml). 0.3 g of a red powder is obtained: * Yield = 78% 1 H NMR (CDCl 3 ): 2.65 (s, 3H), 6.84 (s, 1H), 7.52 15 (dd, 1H, J = 8.8 Hz), 7.57 (d, 1H, J = 8.8 Hz), 7.63 (dd, 1H, J = 8 and 4.4 Hz), 7.89 (d, 1H, J = 2.4 Hz), 8.46 (dd, 1H, J = 0.8 and 8 Hz), 9.02 (dd, 1H, J = 2 and 5.2 Hz), 11.18 (s, 1H). * 13 C NMR (CDCl 3 ): 28.5; 107.36; 121.86; 126.69; 20 126.85; 127.49; 128.39; 132.10; 134.06; 134.75; 138.36; 143.29; 148.32; 155.22; 181.28; 182.63; 200.39. A-3 - Synthesis of 6-(2-acetyl-4 benzylaminophenylamino)quinoline-5,8-dione 25 (Intermediate

A

3 ) Preparation according to the process described in chapter A-1: quinoline-5,8-dione (0.250 g, 1.57 mmol), cerium chloride (0.77 g, 3.14 mmol), 5-benzylamino-2 aminoacetophenone (0.603 g, 3.14 mmol), ethanol 30 (15 + 7 ml), acetic acid (35 ml). 0.56 g of a red powder is obtained: " Yield = 91% e 1 H NMR (CDCl 3 ): 2.54 (s, 3H), 4.38 (s, 2H), 6.70 (s, 1H), 6.83 (dd, 1H, J = 9.6 and 3.2 Hz), 7.08 (d, 35 1H, J = 3.2 Hz), 7.30-7.37 (m, 5H), 7.43 (d, 1H, J = 9.6 Hz), 7.58 (dd, 1H, J = 7.6 and 4.8 Hz), 8.43 (dd, 1H, J = 7.6 and 2 Hz), 9.03 (dd, 1H, J = 2 and 4.8 Hz), 10.67 (s, 1H).

- 14 A-4 - Synthesis of 6-(2-acetyl-5 bromophenylamino) quinoline-5 , 8-dione (Intermediate

A

4 ) (CRL 8268) Preparation according to the process described by 5 F. Bracher, Liebigs Ann. Chem. 1990, 205-206. A-5 - Synthesis of 6-(2-acetyl-4 dimethylaminophenylamino)quinoline-5,8-dione (Intermediate As) 10 Preparation according to the process described in chapter A-1: quinoline-5,8-dione (0.36 g, 2.26 mmol), cerium chloride (1.67 g, 4.49 mmol), 5-dimethylamino-2 aminoacetophenone (0.8 g, 4.49 mmol), ethanol (20 + 10 ml), acetic acid (50 ml). 1.26 g of a red 15 powder are obtained: " Yield = 84% e 1H NMR (CDCl 3 ): 2.85 (s, 3H), 3.12 (s, 6H), 6.72 (s, 1H), 6.90 (dd, 1H, J = 2.8 and 9.2 Hz), 7.15 (d, 1H, J = 2.8 Hz), 7.49 (d, 1H, J = 9.2 Hz), 7.58 (dd, 20 1H, J = 8 Hz and 4.4 Hz), 8.43 (dd, 1H, J = 1.6 and 8 Hz), 9.00 (dd, 1H, J = 1.6 and 4.4 Hz), 10.69 (s, 1H). A-6 - Synthesis of 6-(2-acetyl-4 25 methoxyphenylamino) quinoline-5, 8-dione (Intermediate A) Preparation according to the process described in chapter A-1: quinoline-5,8-dione (3.51 g, 22.08 mmol), cerium chloride (16.4 g, 44.03 mmol), 5-methoxy-2 30 aminoacetophenone (7.29 g, 44.18 mmol), ethanol (200 + 90 ml), acetic acid (500 ml). 4.25 g of a red powder are obtained: e Yield = 60% e 1H NMR (CDCl 3 ): 2.65 (s, 3H), 3.87 (s, 3H), 6.76 35 (s, 1H), 7.12 (dd, 1H, J = 2.8 and 8.8 Hz), 7.42 (d, 1H, J = 2.8 Hz), 7.55 (d, 1H, J = 8.8 Hz), 7.61 (dd, 1H, J = 7.6 and 4.4 Hz), 8.45 (dd, 1H, J = 1.6 and 7.6 Hz), 9.01 (dd, 1H, J = 1.6 and 4.4 Hz), 10.80 (s, 1H).

- 15 A-7 - Synthesis of 4,6-bis(2-acetylanilino)quinoline 5,8-dione (Intermediate A 7 ) Preparation according to the process described in 5 chapter A-1: 4-chloroquinoline-5,8-dione (3.5 g, 18 mmol), cerium chloride (13.5 g, 36.24 mmol),2 aminoacetophenone (4.4 ml, 36 mmol), ethanol (160 + 70 ml), acetic acid (400 ml). 2.32 g of a red powder are obtained: 10 * Yield = 30% e 1H NMR (CDCl 3 ): 2.69 (s, 3H), 2.72 (s, 3H), 6.85 (s, 1H), 7.18 (ddd, 1H, J = 7.6 and 7.6 and 0.8 Hz), 7.28 (m, 1H), 7.30 (d, 1H, J = 6.4 Hz), 7.54-7.59 (m, 3H), 7.63 (d, 1H, J = 7.6 Hz), 7.91 (dd, 1H, J = 1.6 15 and 8.4 Hz), 7.94 (dd, 1H, J = 1.2 and 8.4 Hz), 8.47 (d, 1H, J = 6.4 Hz), 11.35 (s, 1H), 12.35 (s, 1H). A-8 - Synthesis of 6-(2-acetyl-4-bromophenylamino)-4 methoxyquinoline-5,8-dione (Intermediate A 8 ) 20 Preparation according to the process described in chapter A-1: 4-methoxyquinoline-5,8-dione (1.57 g, 9.1 mmol), cerium chloride (3.1 g, 8.3 mmol), 5-bromo 2-aminoacetophenone (Leonard, Boyd, J. Org. Chem. 1946; 11, 419-423) (1.95 g, 9.1 mmol), ethanol (200 ml), 25 acetic acid (180 ml). After purification by flash chromatography on a column of silica (95/5 CH 2 Cl 2 /MeOH), 1.22 g of an orange powder are obtained: " Yield = 37% e 1H NMR (CDCl 3 ): 3.15 (s, 3H), 4.58 (s, 3H), 7.61 30 (d, 1H, J = 6 Hz), 7.74 (s, 1H), 7.99 (d, 1H, J = 8.8 Hz), 8.14 (dd, 1H, J = 8.8 and 2.4 Hz), 8.51 (d, 1H, J = 2.8 Hz), 9.32 (d, 1H, J = 6 Hz), 11.68 (s, 1H). A-9 - Synthesis of 2-methoxy-6-(2 35 acetylphenylamino)quinoline-5,8-dione (Intermediate A) A solution of o-aminoacetophenone (0.41 g, 3.1 mmol) in ethanol (6 ml) is added to a suspension of 2-methoxy quinoline-5,8-dione (0.54 g, 2.8 mmol) and cerium - 16 chloride (1.16 g, 4.7 mmol) in ethanol (100 ml). The reaction medium is stirred at room temperature for 40 hours. After concentration on a rotary evaporator, the crude product obtained is purified by filtration on 5 silica (98/2 CHCl 3 /heptane) to give the expected codensation product in the form of a red powder (0.35 g). " Yield = 38% " Melting point = 258 0 C 10 e 1H NMR (CDCl 3 ): 2.67 (s, 3H), 4.15 (s, 3H), 6.79 (s, 1H), 6.98 (d, 1H, J = 8.8 Hz), 7.18 (ddd, 1H, J = 8.1, 8.4 and 1.5 Hz), 7.56 (dd, 1H, J = 8.4 and 1.5 Hz), 7.61 (ddd, 1H, J = 8.1 and 8.4 and 1.1 Hz), 7.94 (dd, 1H, J = 8.1 and 1.5 Hz), 8.31 (d, 1H, J = 15 8.8 Hz). e 1C NMR (CDCl 3 ) 28.51, 54.73, 106.02, 115.22, 120.78, 122.50, 123.11, 125.70, 132.34, 134.24, 137.18, 140.05, 143.30, 148.21, 167.75, 180.88, 183.05, 201.41. * IR (CHC1 3 ): 1668, 1644 cm~ 1 20 A-10 - Synthesis of 3-hydroxymethyl-6-(2 acetylphenylamino)quinoline-5,8-dione (Intermediate A 10 ) 25 a) - 3-Hydroxymethyl-5,8-dimethoxyquinoline A solution of 1M LiAlH 4 /Et 2 O (5 ml, 5 mmol) is added dropwise and under nitrogen to a solution of ethyl 5,8 dimethoxyquinoline-3-carboxylate (180 mg, 0.689 mmol) in 60 ml of THF. The mixture is stirred at room 30 temperature for 15 hours and then poured into 15 ml of 1N NaOH and 40 ml of water. After extraction with CH 2 Cl 2 (3 x 100 ml) and then drying of the organic phase over MgSO 4 , the extract is concentrated on a rotary evaporator. The crude product obtained is purified by 35 flash chromatography (95/5 CH 2 Cl 2 /MeOH) to give the expected product in the form of a brown powder (72 mg): " Yield = 48% " Melting point = 150*C - 17 e 'H NMR (CDC1 3 ): 3.92 (s, 3H), 4.00 (s, 3H), 4.88 (s, 2H), 6.72 (d, 1H, J = 8.4 Hz), 6.88 (d, 1H, J = 8.4 Hz), 8.47 (d, 1H, J = 2.2 Hz), 8.87 (d, 1H, J = 2.2 Hz) 5 13C NMR (CDCl 3 ): 55.76, 56.00, 63.09, 103.95, 106.70, 121.25, 128.62, 133.35, 139.80, 148.61, 149.21, 149.41. * IR (CDCl 3 ): 3607, 3417, 1622, 1605 cm'. 10 b) - 3-Hydroxymethyl-5,8-dimethoxyquinoline A solution of 3-hydroxymethyl-5, 8 -dimethoxyquinoline (55 mg, 0.25 mmol) and cerium ammonium nitrate (550 mg, 1 mmol) in a CH 3

CN/H

2 0 mixture (3 ml/i ml) is stirred at room temperature for 40 minutes. After addition of 5 ml 15 of H 2 0 and 10 ml of saturated NaHCO 3 solution, the medium is extracted with CH 2 C1 2 (6 x 30 ml) and the organic phases are dried over MgSO 3 . After evaporating off the solvent on a rotary evaporator, the expected quinone is obtained in the form of a brown powder 20 (11 mg): " Yield = 22% " Melting point = 150*C e 1H NMR (CDCl 3 ): 4.95 (s, 2H), 7.06 (d, 1H, J = 10.2 Hz), 7.15 (d, 1H, J = 10.2 Hz), 8.43 (s, 1H), 9.03 25 (s, 1H). S13C NMR (CDCl 3 ) : 62.03, 128.86, 132.26, 138.00, 139.11, 141.33, 146.58, 153.10, 183.12, 184.54. * IR (CHC1 3 ): 3413, 1680, 1596 cm. 30 c) - Synthesis of 3 -hydroxymethyl-6-(2-acetylphenyl amino)quinoline-5,8-dione (Intermediate

A

10 ) A solution of 2 -aminoacetophenone (0.18 g, 1.33 mmol) is added to a suspension of 3 -hydroxymethylquinoline 5,8-dione (0.22 g, 1.16 mmol) and cerium chloride 35 (0.6 g, 2.43 mmol) in ethanol (40 ml). The reaction medium is stirred at room temperature in darkness for 3 hours. After concentrating on a rotary evaporator, the crude product obtained is purified by filtration on silica (98/2 CH 2 Cl 2 /MeOH) to give the expected - 18 condensation product in the form of a violet powder (0.16 g): " Yield = 42% " Melting point = 2580C 5 e 'H NMR (DMSO-d 6 ): 2.67 (s, 3H), 4.73 (d, 2H, J = 5.5 Hz), 5.67 (t, 1H, J = 5.5 Hz), 6.64 (s, 1H), 7.30 (m, 1H), 7.71 (m, 2H), 8.12 (d, 1H, J = 8.0 Hz), 8.35 (d, 1H, J = 2.0 Hz), 8.93 (d, 1H, J = 2.0 Hz), 11.02 (s, 1H). 10 * 13C NMR (CDC1 3 ): 28.81, 60.08, 106.52, 120.96, 123.44, 126.14, 127.23, 131.52, 132.69, 134.43, 138.91 141.75, 143.55, 146.62, 152.81, 181.62, 181.84, 202.02. e IR (CHC1 3 ): 3440, 1690, 1661, 1640 cm~. 15 B - Preparation of the intermediate products of formula III (Scheme II) B-1 - Synthesis of 9,11-dimethyl-1,6-diazanaphthacene 20 5,12-dione (Intermediate B 1 ) (CRL 8324) 1.9 ml of sulfuric acid dissolved in 9.6 ml of acetic acid are added slowly to a solution of tricyclic intermediate A 1 (0. 4 g, 1. 3 mmol) in 12 ml of acetic acid. The reaction medium is refluxed for 30 minutes 25 and, after cooling, is then poured into a beaker containing crushed ice. The mixture is neutralized with

NH

4 0H and then extracted 4 times with dichloromethane. The organic phases are dried over MgSO 4 and then evaporated. The crude product obtained is purified by 30 flash chromatography on a column of silica (95/5

CH

2 Cl 2 /MeOH) to give 0.325 g of the expected tetracyclic compound. e Yield = 86% e 1H NMR (CDC1 3 ): 2.64 (s, 3H), 3.29 (s, 3H), 7.74 35 (dd, 1H, J = 7.6 and 4.8 Hz), 7.75 (dd, 1H, J = 8.4 and 1.6 Hz), 8.12 (dd, J = 1.6 Hz), 8.33 (d, 1H, J = 8.4), 8.71 (dd, 1H, J = 2 and 7.6 Hz), 9.13 (dd, 1H, J = 2 and 4.8 Hz).

- 19 B-2 - Synthesis of 9-chloro-11-methyl-1,6 diazanaphthacene-5,12-dione (Intermediate B 2 ) Preparation according to the process described in chapter B-1: tricyclic intermediate A 2 (0.289 g, 5 0.88 mmol), sulfuric acid (1.3 ml), acetic acid (8 + 6.5 ml). After purification by flash chromatography (95/5 CH 2 Cl 2 /MeOH), 0.26 g of tetracycle is obtained: * Yield = 95% 10 e 'H NMR (CDCl 3 ): 3.25 (s, 3H), 7.76 (dd, 1H, J = 8 and 4.8 Hz), 7.85 (dd, 1H, J = 8.8 and 2 Hz), 8.33 (dd, 1H, J = 2 Hz), 8.38 (d, 1H, J = 8.8), 8.71 (dd, 1H, J = 1.6 and 8 Hz), 9.15 (dd, 1H, J = 1.6 and 4.8 Hz). 15 B-3 - Synthesis of 9-benzylamino-11-methyl-1,6 diazanaphthacene-5,12-dione (Intermediate B 3 ) Preparation according to the process described in chapter B-1: tricyclic intermediate A 3 (4 g, 10 mmol), sulfuric acid (15.1 ml), acetic acid (92 + 75 ml). 20 After work-up, 3.58 g of tetracycle are obtained. e Yield = 98% * 1H NMR (CDCl 3 ): 3.09 (s, 3H), 4.52 (d, 2H), 4.86 (t, 1H), 7.06 (d, 1H, J = 2.8 Hz), 7.29 (dd, 1H, J = 9.2 and 2.8 Hz), 7.3-7.43 (m, 5H), 7.71 (dd, 1H, J = 25 4.8 and 8 Hz), 8.20 (d, 1H, J = 9.8 Hz), 8.69 (dd, 1H, J = 1.6 and 8 Hz), 9.09 (dd, 1H, J = 1.6 and 4.8 Hz). B-4 - Synthesis of 8-bromo-11-methyl-1,6 diazanaphthacene-5,12-dione (Intermediate B 4 ) 30 Preparation according to the process described by F. Bracher, Liebigs Ann. Chem. 1990, 205-206. B-5 - Synthesis of 9-dimethylamino-11-methyl-1,6 diazanaphthacene-5,12-dione (Intermediate B) 35 Preparation according to the process described in chapter B-1: intermediate tricycle A 5 (0.76 g, 2.27 mmol), sulfuric acid (3.5 ml), acetic acid (20 + 18 ml). After work-up, 0.67 g of tetracycle is obtained.

- 20 " Yield = 93% e 1H NMR (CDCl 3 ): 3.17 (s, 3H), 3.21 (s, 6H), 7.04 (d, 1H, J = 3.2 Hz), 7.51 (dd, 1H, J = 3.2 and 9.2 Hz), 7.71 (dd, 1H, J = 8 and 4.4 Hz), 8.26 (d, 1H, J 5 9.2 Hz), 8.7 (dd, 1H, J = 1.6 and 8 Hz) 9.09 (dd, 1H, J = 1.6 and 4.4 Hz). B-6 - Synthesis of 9-methoxy-11-methyl-1,6 diazanaphthacene-5,12-dione (Intermediate B) 10 Preparation according to the process described in chapter B-1: intermediate tricycle

A

6 (4.25 g, 13.18 mmol), sulfuric acid (20 ml), acetic acid (110 + 100 ml) . The product obtained by flash chromatography (100/3 CH 2 Cl 2 /MeOH) is washed with ethyl 15 ether to give 2.9 g of tetracycle. " Yield = 72% * 1 H NMR (CDCl 3 ): 3.25 (s, 3H), 4.02 (s, 3H), 7.49 (d, 1H, J = 3.3 Hz), 7.56 (dd, 1H, J = 3.3 and 9.3 Hz), 7.74 (dd, 1H, J = 8.3 and 4.3 Hz), 8.34 (d, 1H, J = 20 9.3 Hz), 8.71 (dd, 1H, J = 2.5 and 8.3 Hz), 9.12 (dd, 1H, J = 2.5 and 4.3 Hz). B-7 - Synthesis of 4

-(

2 -acetylanilino)-11-methyl-1,6 diazanaphthacene-5,12-dione (Intermediate B) 25 (CRL 8332) Preparation according to the process described in chapter B-1: intermediate tricycle A 7 (1 g, 2.35 mmol), sulfuric acid (3.5 ml), acetic acid (18 ml). The product obtained by flash chromatography (100/3 30 CH 2 Cl 2 /MeOH) is washed with ethyl ether to give 0.6 g of tetracycle in the form of an orange powder. " Yield = 63% e 1H NMR (CDC1 3 ): 2.59 (s, 3H), 3.25 (s, 3H), 7.29 (ddd, 1H, J = 7.2 and 7.2 and 1.2 Hz), 7.37 (d, 1H, J = 35 6 Hz), 7.54 (ddd, 1H, J = 6.8 and 6.8 and 1.6 Hz), 7.59 (d, 1H, J = 6.8 Hz), 7.74 (dd, 1H, J = 7.2 and 1.2 Hz), 7.76 (dd, 1H, J = 6.8 and 1.6 Hz), 7.87-7.918 (m, 2H), 8.34 (d, 1H, J = 8.4 Hz), 8.43 (d, 1H, J = 8.4 Hz), 8.54 (d, 1H, 6 Hz), 12.5 (s, 1H).

- 21 B-8 - Synthesis of 4 -methoxy-9-bromo-11-methyl-1,6 diazanaphthacene-5,12-dione (Intermediate

B

8 ) Preparation according to the process described in chapter B-1: intermediate tricycle

A

8 (1.22 g, 5 3.04 mmol), sulfuric acid (4.5 ml), acetic acid (27 + 23 ml). The product obtained by flash chromatography (100/3 CH 2 Cl 2 /MeOH) is washed with ethyl ether to give 0.76 g of tetracycle in the form of a yellow powder. 10 * Yield = 65% e 1H NMR (CDCl 3 ) : 3.21 (s, 3H), 4.10 (s, 3H), 7.18 (d, 1H, J = 6 Hz), 7.96 (dd, 1H, J = 8.8 and 2 Hz), 8.27 (d, 1H, J = 8.8 Hz), 8.47 (d, 1H, J = 2 Hz), 8.89 (d, 1H, J = 6 Hz). 15 B-9 - Synthesis of 2-methoxy-11-methyl-1,6 diazanaphthacene-5,12-dione (Intermediate

B

9 ) A solution of 2-methoxy-6- (2 acetylphenylamino) quinoline-5, 8-dione (0.34 g, 20 1.1 mmol) in an acetic acid/sulfuric acid mixture (25 mol/2.7 ml) is heated at 900C for 45 minutes. After cooling, the reaction medium is poured into a water/ice mixture (200 ml) and then basified to pH 8 with K 2 C0 3 and extracted with CHCl 3 (3 x 200 ml) . The organic 25 phases are dried over MgSO 4 and then concentrated on a rotary evaporator. The crude product obtained is purified by filtration on silica (CHCl 3 ) to give the expected tetracycle in the form of a beige-colored powder (0.23 g): 30 * Yield = 71% e Melting point = 2600C e 1H NMR (CDCl 3 ): 3.32 (s, 3H), 4.23 (s, 3H), 7.14 (d, 1H, J = 8.8 Hz), 7.79 (ddd, 1H, J = 8.6, 8.4 and 1.2 Hz), 7.91 (ddd, 1H, J = 8.4, 8.6 and 1.2 Hz), 8.38 35 (dd, 1H, J = 8.6 and 1.2 Hz), 8.46 (dd, 1H, J = 8.4 and 1.2 Hz), 8.58 (d, 1H, J = 8.8 Hz). 13 C NMR (CDCl 3 ): 16.63, 54.76, 117.29, 125.29, 125.50, 125.64, 129.62, 129.75, 132.37, 132.57, 138.12, 147.73, 148.63, 149.69, 152.28, 167.77, 181.10, 183.55.

- 22 e IR CHC1 3 ) : 1683, 1599 cm- 1 B-10 - Synthesis of 3 -acetoxymethyl-11-methyl-1,6 diazanaphthacene-5,12-dione (Intermediate

B

10 ) 5 A solution of 3 -hydroxymethyl-6- (2-acetylphenylamino) quinoline-5,8-dione (Intermediate

A

10 ), (0.248 g, 0.77 mmol) in an acetic acid/sulfuric acid mixture (16 ml/1.3 ml) is heated at 900C for 2 hours 30 minutes. After cooling, the reaction medium is 10 poured into a water/ice mixture (15 ml) and then basified to pH 9 with Na 2

CO

3 . The medium is then extracted with CH 2 C1 2 (3 x 150 ml) . The organic phases are dried over MgSO 4 and then concentrated on a rotary evaporator. The crude product obtained is purified by 15 filtration through silica (98/2 CH 2 Cl 2 /MeOH) to give the expected compound in the form of a brown powder (0.21 g). " Yield = 85% e Melting point = 2100C 20 e 1 H NMR (CDCl 3 ): 2.18 (s, 3H), 3.30 (s, 3H), 5.31 (s, 2H), 7.78 (ddd, 1H, J = 1.1, 6.8 and 8.1 Hz), 7.92 (ddd, 1H, J = 1.1, 6.8 and 8.1 Hz), 8.37 (dd, 1H, J = 8.1 and 1.1 Hz), 8.43 (dd, 1H, J = 8.1 and 1.1 Hz), 8.66 (d, 1H, J = 2.2 Hz), 9.09 (d, 1H, J = 2.2 Hz). 25 e 1C NMR (CDCl 3 ): 16.06, 20.11, 62.06, 124.81, 124.91, 129.06, 129.18, 129.29, 131.70, 132.18, 134.06, 136.09, 146.86, 147.97, 149.01, 152.19, 154.30, 169.72, 180.96, 182.34. e IR (CHC1 3 ) : 3420, 1746, 1692 cm 1 30 C - Preparation of the intermediate products of formula IIIa (Scheme II) 35 1) Synthesis of N-( 2

,

5 -dimethoxyphenyl)anthranilic acid (Compound 4) A mixture of 2-chlorobenzoic acid (9.2 g, 60 mmol), dimethoxyaniline (10 g, 65 mmol), copper (0.96 g), Cu 2 0 (0.96 g) and K2CO3 (10.4 g) in 120 ml of diglyme is - 23 refluxed overnight. After evaporating off the solvent, the reaction medium is basified with 1N sodium hydroxide. Ether is added and the medium is then filtered through silica and the ether phase is removed. 5 The aqueous phase is acidified with concentrated HC1 and then extracted with ethyl acetate. After drying over MgSO 4 and evaporating off the solvent on a rotary evaporator, the crude product obtained is purified by filtration through silica (CH 2 Cl 2 ) to give the expected 10 condensation product in the form of a yellow powder (14.5 g). " Yield = 89% " Melting point = 1380C " H NMR (CDCl 3 ): 3.77 (s, 3H), 3.85 (s, 3H), 6.57 15 (dd, 1H, J = 8.8 and 2.9 Hz), 6.77 (ddd, 1H, J = 1.9 and 7.5 Hz), 6.87 (d, 1H, J = 9.2 Hz), 7.04 (d, 1H, J = 2.9 Hz), 7.3 to 7.4 (m, 2H), 9.35 (broad s, 1H) * 1C NMR (CDCl 3 ) : 55.76, 56.45, 107.30, 107.71, 112.00, 112.26, 114.70, 117.53, 130.78, 132.60, 134.09, 20 145.98, 147.71, 153.75, 172.95 * IR (CHCl 3 ): 3327, 1685 cm 1 2) Synthesis of 2- (2, 5-dimethoxyphenylamino) aceto phenone (Compound 5) 25 16 ml of MeLi (1.4 M/Et 2 0) are added at 00C and under N 2 to a mixture of N-( 2 ,5-dimethoxyphenyl)anthranilic acid (2 g, 73 mmol) in 14 ml of THF. After raising the temperature, the medium is refluxed for 2 hours, 100 ml of water are then added and the mixture is extracted 30 with ether (3 x 100 ml) . After drying over MgSO 4 , the solvent is evaporated off on a rotary evaporator to give the expected derivative in the form of a yellow solid (1.49 g). " Yield = 75% 35 9 Melting point = 79*C e 1 H NMR (CDCl 3 ): 2.64 (s, 3H), 3.76 (s, 3H), 3.84 (s, 3H), 6.55 (dd, 1H, J = 8.8 and 2.9 Hz), 6.73 (dd, 1H, J = 1.4 and 7.5 Hz), 6.85 (d, 1H, J = 8.8 Hz), 7.04 - 24 (d, 1H, J = 2.9 Hz), 7.3 to 7.4 (m, 2H), 7.81 (dd, 1H, J = 1.5 and 8.0 Hz), 10.5 (broad s, 1H). * 1C NMR (CDC1 3 ): 48.15, 55.73, 56.36, 107.10, 107.72, 112.05, 114.80, 116.84, 120.09, 130.68, 132.42, 5 134.35, 145.98, 146.67, 153.62, 201.00 * IR (CHC1 3 ): 3350, 1642 cm-1 3) Synthesis of 1, 4-dimethoxy-9-methylacridine (Compound 6) 10 A mixture of 2-(2,5-dimethoxyphenylamino)acetophenone (1.3 g, 48 mmol) and polyphosphoric acid (13 g, 133 mmol) is heated at 1000C for 1 hour. After addition of 50 ml of water, the mixture is neutralized with 4M sodium hydroxide and then extracted with CHC1 3 15 (3 x 100 ml). After drying over MgSO 4 and evaporating off the solvent, the crude product obtained is purified by filtration through silica (CH 2 Cl 2 ) to give the expected tricyclic derivative quantitatively in the form of a brown-orange solid. 20 9 Melting point = 136*C e 1 H NMR (CDCl 3 ): 3.36 (s, 3H), 3.96 (s, 3H), 4.09 (s, 3H), 6.68 (d, 1H, J = 8.0 Hz), 6.89 (d, 1H, J = 8.4 Hz), 7.54 (m, 1H), 7.73 (m, 1H), 8.32 (d, 1H, J = 8.4), 8.36 (d, 1H, J = 8.8 Hz) 25 13C NMR (CDCl 3 ): 17.78, 55.66, 56.13, 102.43, 105.18, 120.25, 124.28, 125.62, 126.59, 129.44, 130.81, 142.45, 144.23, 147.21, 149.46, 151.45 * IR (CHC1 3 ): 1685, 1661 cm 1 30 4) Synthesis of 9-methylacridine-1,4-dione (Compound 7) A solution of 1,4-dimethoxy-9-methylacridine (20 mg, 0.079 mmol) and cerium ammonium nitrate (196 mg, 0.357 mmol) in a CH 2 C1 2

/H

2 0 mixture (0.5 ml/0.25 ml) is stirred at 0*C for 20 minutes. After adding 1.4 ml of 35 H 2 0 and 0.4 ml of saturated NaHCO 3 solution, the medium is left stirring and is then extracted with CH 2 C12 (3 x 3 ml). The organic phases are dried over MgSO 4 . After evaporating off the solvent on a rotary - 25 evaporator, the expected quinone is obtained in the form of a brown powder (15 mg). " Yield = 90% " Melting point = > 260*C 5 e 1H NMR (CDCl 3 ): 3.22 (s, 3H), 7.09 (d, 1H, J = 10.3 Hz), 7.18 (d, 1H, J = 10.3 Hz), 7.78 (dd, 1H, J = 8.5 and 8.5 Hz), 7.91 (dd, 1H, 8.5 and 8.5 Hz), 8.32 (d, 1H, J = 8.5), 8.43 (d, 1H, J = 8.5 Hz). e 1C NMR (CDCl 3 ) 15.87, 124.40, 125.41, 126.30, 10 129.61, 132.32, 132.52, 137.88, 141.61, 147.05, 148.23, 151.23, 183.43, 186.69 o IR (CHC1 3 ): 1701, 1661 cm~ 1 15 D - Preparation of the intermediate products of formula IVa (Scheme II) D-1 - Synthesis of 6-methyl-1,11-diazanaphthacene 5,12-dione (Intermediate DI) 20 A solution of 9-methylacridine-1,4-dione (200 mg, 0.896 mmol), acrolein-N,N-dimethylhydrazone (96 mg, 0.984 mmol) and acetic anhydride (1 ml) in 20 ml of

CH

2 Cl 2 is stirred under N 2 at room temperature for 30 minutes. After concentrating the solvent, the medium is 25 purified by filtration through silica (CH 2 C1 2 ) to recover the addition product that is not completely aromatic. A suspension of this compound and of 10% Pd/C (20 mg) in 4 ml of toluene is refluxed for 30 minutes. After concentrating, the crude product obtained is 30 purified by flash chromatography on silica (98/2

CH

2 Cl 2 /MeOH) to give the expected tetracycle in the form of a beige-colored powder (23 mg). " Yield = 13% e 1H NMR (CDCl 3 ): 3.32 (s, 3H), 7.78-7.83 (m, 2H), 35 7.95 (ddd, 1H, J = 8.4, 7.7 and 1.5 Hz), 8.39 (dd, 1H, J =8.8 and 1.5 Hz), 8.51 (dd, 1H, J = 7.7 and 1.5 Hz), 8.68 (dd, 1H, J = 8.1 and 1.9 Hz), 9.16 (dd, 1H, J = 4.8 and 1.9 Hz) - 26 1 C NMR (CDCl 3 ) : 16.67, 124.59, 125.44, 128.39, 129.76, 129.89, 132.25, 132.54, 132.88, 135.93, 148.00, 148.59, 148.73, 152.48, 155.31, 180.81, 184.37 e IR (CHCl 3 ): 1703, 1663 cm 1 5 D-2 - Syntheasis of 3-methoxy-6-methyl-1,11 diazanaphthacene-5,12-dione (Intermediate D 2 ) 3-Methoxy-6-methyl-1,11-diazanaphthacene-5,12-dione is prepared according to the procedure described in D-1, 10 starting with a solution of 9-methylacridine-1,4-dione (Compound 7) (200 mg, 0.896 mmol),2-methoxy-2-propenal dimethylhydrazone (126 mg, 0.984 mmol) and acetic anhydride (1 ml) in 20 ml of CH 2 Cl 2 15 EXAMPLE 1 5-Methyl-9H-quino[4,3,2-de] [1,10]phenanthrolin-9-one (CRL 8323) A solution of the intermediate tetracycle Bi (1 g, 3.47 mmol) and of dimethylformamide diethyl acetal 20 (2 ml, 10.41 mmol) in 7 ml of DMF is refluxed for 1 hour. After evaporating to dryness, ammonium chloride (2.77 g, 52 mmol) and 50 ml of ethanol are added. The reaction medium is refluxed again for 30 minutes. After evaporating off the solvent, the crude product is taken 25 up in water and extracted 4 times with dichloromethane. The organic phases are dried over MgSO 4 and then evaporated. After recrystallization from 125 ml of methanol, 0.7 g of the expected compound CRL 8323 is obtained in the form of a mustard-yellow solid. 30 o Yield = 67% e Melting point = 200*C e 1 H NMR (CDCl 3 ): 2.69 (s, 3H), 7.65 (dd, 1H, J = 8 and 4.8 Hz), 7.81 (dd, 1H, J = 8 and 1.2 Hz), 8.44 (d, 1H, J = 1.2 Hz), 8.49 (d, 1H, J = 8 Hz), 8.50 (d, 1H, J 35 = 5.6 Hz), 8.78 (dd, 1H, J = 2 and 8 Hz), 9.15 (dd, 1H, J = 4.8 and 2 Hz), 9.24 (d, 1H, J = 5.6 Hz) e 1C NMR (CDCl 3 ) : 22.06, 116.54, 117.87, 122.15, 123.12, 125.24, 128.74, 132.58, 133.47, 136.25, 137.19, - 27 141.63, 143.88, 144.79, 149.16, 149.31, 152.09, 155.15, 181.53 9 MS (m/z): 297 (17.6), 296 (34.3), 268 (25.4), 149 (50.3) 5 EXAMPLE 2 5-Chloro-9H-quino [4,3,2-de] [1,10]phenanthrolin-9-one (CRL 8301) Preparation according to the process described in 10 Example 1, starting with the intermediate tetracycle B 2 (0.25 g, 0.81 mmol) and dimethylformamide diethyl acetal (1.5 ml, 8.75 mmol) in DMF (4.5 ml) . Ammonium chloride (2.95 g, 55 mmol), ethanol (50 ml). After purification by flash chromatography (98/2 CH 2 Cl 2 /MeOH), 15 60 mg of the expected compound CRL 8301 are obtained in the form of a yellow solid. * Yield = 23% " Melting point = 200*C e 1 H NMR (CDCl 3 ): 7.68 (dd, 1H, J = 8.4 and 20 4.8 Hz), 7.94 (dd, 1H, J = 8.8 and 2 Hz), 8.46 (d, 1H, J = 5.6 Hz), 8.55 (d, 1H, J = 8.8 Hz), 8.63 (d, 1H, J = 2 Hz), 8.79 (dd, 1H, J = 2 and 8.4 Hz), 9.18 (dd, 1H, J = 4.8 and 2 Hz), 9.30 (d, 1H, J = 5.6 Hz) e 1C NMR (CDCl 3 ) : 117.07, 118.46, 122.98, 124.82, 25 126.12, 129.34, 133.02, 134.81, 137.00, 137.42, 137.79, 144.45, 146.35, 150.24, 150.45, 152.55, 156.02, 181.9 e MS (m/z): 319 (43), 317 (100), 291 (14.5), 290 (18), 289 (100) 30 EXAMPLE 3 5- (Benzylamino) -9H-quino[4 ,3,2-de] [1,10]phenanthrolin-9-one (CRL 8241) Preparation according to the process described in Example 1, starting with the intermediate tetracycle B 3 35 (3.58 g, 9.45 mmol) and dimethylformamide diethyl acetal (5.7 ml, 33.26 mmol) in DMF (19 ml) . Ammonium chloride (2.95 g, 55 mmol), ethanol (50 ml). After purification by flash chromatography (96/4 CH 2 Cl 2 /MeOH), - 28 2 g of the expected compound CRL 8241 are obtained in the form of a wine-colored powder. " Yield = 55% " Melting point = 2190C 5 0 1H NMR (CDCl 3 ): 4.61 (d, 2H), 5.10 (t, 1H), 7.31 (dd, 1H, J = 8.8 Hz, J = 2.4 Hz), 7.452-7.327 (m, 5H), 7.55 (d, 1H, J = 2.4 Hz), 7.63 (dd, 1H, J = 4.4 Hz, J = 8.4 Hz), 8.29 (d, 1H, J = 5.2 Hz), 8.36 (d, 1H, J = 8.8 Hz), 8.79 (dd, 1H, J = 1.2 Hz, J = 8.4 Hz), 9.13 10 (dd, 1H, J = 4.4 and 1.2 Hz), 9.14 (d, 1H, J = 5.2 Hz) * MS (m/z): 388 (7), 387 (100), 386 (85), 385 (25), 369 (99), 368 (44) EXAMPLE 4 15 5- (Dimethylamino) -9H-quino[4 ,3,2-de] [1,10]phenanthrolin-9-one (CRL 8325) Preparation according to the process described in Example 1, starting with the intermediate tetracycle

B

5 (0.25 g, 0.79 mmol) and dimethylformamide diethyl 20 acetal (0.5 ml, 2.98 mmol) in DMF (5 ml). Ammonium chloride (1 g, 18.7 mmol), ethanol (16 ml). After purification by flash chromatography (100/5

CH

2 Cl 2 /MeOH) , 170 mg of the expected compound CRL 8325 are obtained in the form of a violet powder. 25 e Yield = 66% e Melting point = > 260*C " 1 H NMR (CDCl 3 ): 3.25 (s, 6H), 7.45 (dd, 1H, J = 9.2 Hz, J = 3 Hz), 7.57 (d, 1H, J = 3 Hz), 7.63 (dd, 1H, J = 4.4 and 8 Hz), 8.41 (d, 1H, J = 9.2 Hz), 8.43 30 (d, 1H, J = 5.6 Hz), 8.81 (dd, 1H, J = 2 and 7.6 Hz), 9.13 (dd, 1H, J = 4.4 and 2 Hz), 9.17 (d, 1H, J 5.6 Hz) e 1C NMR (CDCl 3 ): 40.45, 100.84, 116.81, 118.69, 118.99, 125.19, 126.10, 129.46, 134.62, 136.03, 136.30, 35 139.00, 140.69, 148.16, 149.15, 151.53, 152.47, 154.83, 181.65 * MS (m/z): 326 (34.5), 325 (100), 324 (100), 254 (15.5), 253 (13.4).

- 29 EXAMPLE 5 5-Methoxy-9H-quino[4 ,3,2-de] [1,10]phenanthrolin-9-one (CRL 8297) Preparation according to the process described in 5 Example 1, starting with the intermediate tetracycle B 6 (2 g, 6.57 mmol) and dimethylformamide diethyl acetal (4 ml, 23.34 mmol) in DMF (14 ml) . Ammonium chloride (8 g, 149.5 mmol), ethanol (130 ml). After purification by flash chromatography (100/5 CH 2 Cl 2 /MeOH), 170 mg of 10 the expected compound CRL 8297 are obtained in the form of a greenish solid. " Yield = 66% " Melting point = > 260 0 C * 1H NMR (CDC 3 ): 4.10 (s, 3H), 7.62 (dd, 1H, J = 15 9.2 Hz, J = 2.4 Hz), 7.66 (dd, 1H, J = 4.4 and 8 Hz), 7.96 (d, 1H, J = 2.4 Hz), 8.48 (d, 1H, J = 2.4 Hz), 8.54 (d, 1H, J = 9.2 Hz), 8.80 (dd, 1H, J = 2.4 and 8 Hz), 9.16 (dd, 1H, J = 4.4 and 2.4 Hz), 9.25 (d, 1H, J = 5.2 Hz) 20 e 1C NMR (CDCl 3 ): 30.93, 116.86, 118.41, 122.44, 125.56, 129.25, 134.96, 136.55, 137.13, 141.52, 143.67, 149.11, 149.77, 152.37, 155.38, 161.71, 181.93, 207.00 9 MS (m/z) : 313 (26), 312 (100), 285 (2), 284 (15), 269 (15), 242 (32.5). 25 EXAMPLE 6 7-Nitro-9H-quino[4,3,2-de] [1,10]phenanthrolin-9-one (CRL 8289) Ascididemin (2 g, 7.06 mmol) is added portionwise to a 30 mixture of 45 ml of sulfuric acid and 45 ml of nitric acid at 00C. The reaction medium is heated at 130 0 C for 2 hours and, after cooling, is then poured into a conical flask containing 400 g of ice. After filtration, a yellow precipitate is obtained, which is 35 rinsed several times with ether. It is then taken up in a 600/1/300 CH 2 Cl 2

/NH

4 0H/H 2 0 mixture. The organic phase is recovered and the aqueous phase is extracted 3 times with CH 2 C1 2 . After drying over MgSO 4 , the organic phases - 30 are evaporated to give 1.62 g of the expected compound CRL 8289 in the form of a yellow solid. " Yield = 70% e Melting point = 2240C 5 1H NMR (CDCl 3 ): 7.69 (dd, 1H, J = 4.4 and 8 Hz), 8.04 (dd, 1H, J = 8 and 8 Hz), 8.28 (dd, 1H, J = 8 Hz), 8.56 (d, 1H, J = 5.2 Hz), 8.75 (dd, 1H, J = 2 and 8 Hz), 8.89 (dd, 1H, J = 1.2 and 8 Hz), 9.18 (dd, 1H, J = 4.4 and 2 Hz), 9.37 (d, 1H, J = 5.6 Hz) 10 e 13C NMR (CDCl 3 ) : 79.20, 117.61, 118.39, 124.21, 124.89, 125.98, 127.54, 129.04, 130.14, 135.62, 136.63, 148.17, 149.76, 149.94, 150.12, 151.66, 154.88, 180.56. * MS (m/z): 328 (18), 327 (100). 299 (22), 297 (9), 269 (10), 253 (24), 242 (11), 241 (33). 15 EXAMPLE 7 7-Amino-9H-quino[4 ,3,2-de] [1,10]phenanthrolin-9-one (CRL 8344) A suspension of the nitro derivative CRL 8289 (0.4 g, 20 1.22 mmol) and iron (0.37 g, 6.59 mmol) in a 10/10 AcOH/H 2 0 mixture is refluxed for 1 hour. EDTA (1.94 g, 6.59 mmol) is added and the reaction medium is then basified with concentrated sodium hydroxide. The mixture is extracted 3 times with CH 2 C1 2 . After drying 25 over MgSO 4 , the organic phases are evaporated to give 0.32 g of the expected compound CRL 8344 in the form of a blue solid. " Yield = 88% * Melting point = > 2600C 30 0 1 H NMR (CDCl 3 ): 5.68 (s, 2H), 7.16 (d, 1H, J = 7.8 Hz), 7.66 (dd, 1H, J = 7.6 and 4.8 Hz), 7.69 (dd, 1H, J = 7.8 and 7.8 Hz), 7.91 (d, 1H, J = 7.8 Hz), 8.46 (d, 1H, J = 5.2 Hz), 8.77 (dd, 1H, J = 1.6 and 7.6 Hz), 9.17 (dd, 1H, J = 1.6 and 4.8 Hz), 9.21 (d, 1H, J = 35 5.2 Hz). e 1C NMR (CDCl 3 ): 109.42, 112.71, 117.70, 118.43, 124.29, 125.64, 129.12, 132.63, 132.81, 135.53, 137.27, 141.68, 148.68, 148.89, 149.03, 151.96, 154.68, 180.71 - 31 e MS (m/z): 298 (34.7), 297 (100), 269 (11), 268 (8). EXAMPLE 8 5 5-Bromo-9H-quino[4 ,3,2-de] [1,10]phenanthrolin-9-one (CRL 8248) A solution of bromine (0.2 ml, 3.88 mmol) in 5 ml of acetic acid is added dropwise to a solution of ascididemin (0.5 g, 1.77 mmol) in 20 ml of acetic acid. 10 The reaction medium is refluxed (stoppered condensor) for 24 hours. After cooling, the mixture is neutralized with saturated NaHCO 3 solution and extracted 4 times with CH 2 C1 2 . The organic phases are dried over MgSO 4 and then evaporated. The crude product obtained is purified 15 by flash chromatography on a column of silica (96/4

CH

2 Cl 2 /MeOH) to give 0.548 g of the expected compound CRL 8248 in the form of a yellow solid. " Yield = 86% " Melting point = 208*C 20 e 1H NMR (CDCl 3 ): 7.68 (dd, 1H, J = 4.4 and 8 Hz), 8.09 (dd, 1H, J = 8.8 Hz, J = 2 Hz), 8.48 (d, 1H, J = 8.8 Hz), 8.49 (d, 1H, J = 6 Hz), 8.79 (dd, 1H, J = 2 and 8 Hz), 8.82 (d, 1H, J = 2 Hz), 9.18 (dd, 1H, J = 2 Hz, J = 4.4 Hz), 9.30 (d, 1H, J = 6 Hz) 25 e 1C NMR (CDCl 3 ) : 116.76, 117.04, 118.26, 124.76, 125.81, 125.93, 129.05, 134.52, 135.43, 136.72, 137.01, 144.41, 146.24, 149.93, 150.12, 152.27, 155.67, 181.69 * MS (m/z): 363 (99), 362 (83), 361 (100), 360 (27), 255 (9), 254 (51). 30 EXAMPLE 9 5-Amino-9H-quino [4, 3,2-de] [1,10 ]phenanthrolin-9-one (CRL 8347) Sodium azide (2.34 g, 36.1 mmol) is added to a solution 35 of bromo ascididemin: CRL 8248 (2.3 g, 6.33 mmol) in 460 ml of DMF. The reaction medium is refluxed for 4 hours. After cooling, the mixture is evaporated to dryness and the solid obtained is taken up in water. This mixture is extracted 4 times with CH 2 Cl 2 . After - 32 drying over MgSO 4 and evaporating off the solvent, the crude product is purified by flash chromatography on a column of silica (90/10 HCCl 3 /MeOH) to give 115 mg of the expected compound CRL 8347 in the form of a black 5 powder. " Yield = 6% " Melting point = > 2600C e 1H NMR (CDCl 3 ): 7.43 (dd, 1H, J = 8.8 and 2.4 Hz), 7.74 (dd, 1H, J = 4.8 and 8 Hz), 7.81 (d, 1H, 10 J = 2.4 Hz), 8.48 (d, 1H, J = 6 Hz), 8.50 (d, 1H, J = 8.8 Hz), 8.90 (dd, 1H, J = 2 and 8 Hz), 9.25 (dd, 1H, J = 2 and 4.8 Hz), 9.29 (d, 1H, J = 6 Hz) * 1C NMR (DMSO) : 102.26, 117.13, 118.54, 121.62, 123.20, 125.34, 126.11, 129.18, 133.80, 134.83, 135.47, 15 138.42, 147.65, 148.29, 151.63, 152.39, 154.32, 180.35 e MS (m/z): 298 (32), 297 (100), 269 (4), 268 (0.5) EXAMPLE 10 20 10-Methoxy-9H-quino[4 ,3,2-de] [1,10]phenanthrolin-9-one (CRL 8368) Preparation according to the procedure described by Y. Kitahara et al., Heterocycles, 1993, 36, 943-946. 25 EXAMPLE 11 10-Hydroxy-9H-quino [4,3,2-de] [1,10]phenanthrolin-9-one (CRL 8387) Preparation according to the procedure described by Y. Kitahara et al., Tetrahedron, 1997, 53, 17029-17038. 30 EXAMPLE 12 9H-Quino[4 ,3,2-de] [1,10]phenanthrolin-9-imine (CRL 8290) 100 mg (0.353 mmol) of ascididemin are dissolved in a 35 solution containing 5 ml of aqueous ammonia and 2 ml of EtOH. The reaction medium is refluxed (stoppered condensor) for 72 hours. After evaporating off the solvent on a rotary evaporator, the residue is purified - 33 Dy flash chromatography on alumina (99/1 CH 2 C1 2 /MeOH) to give 87 mg of compound CRL 8290. e Yield = 87% * Melting point = > 260*C 5 e 1H NMR (CDCl 3 ): 7.61 (dd, 1H, J = 5 and 8 Hz), 7.86 (dd, 1H, J = 8 and 8 Hz), 7.97 (dd, 1H, J = 8 and 8 Hz), 8.40 (d, 1H, J = 8 Hz), 8.43 (d, 1H, J = 6 Hz), 8.64 (d, 1H, J = 8 Hz), 9.04 (dd, 1H, J = 8 and 2.5 Hz), 9.08 (dd, 1H, J = 5 and 2.5 Hz), 9.22 (d, 1H, 10 J = 6 Hz), 12.48 (s, 1H) EXAMPLE 13 9H-Quino [4,3,2-de] [1, 10]phenanthrolin-9-oxime (CRL 8292) 15 500 mg (1.77 mmol) of ascididemin and 500 mg of NH 2 OH, 1/2 H 2

SO

4 are dissolved in 1 ml of pyridine and 10 ml of EtOH. The reaction medium is refluxed for 48 hours. After evaporating off the solvent on a rotary evaporator, 20 ml of water are added and the medium is 20 extracted with HCC1 3 (3 x 20 ml). The organic phases are dried over MgSO 4 and then evaporated on a rotary evaporator. The residue is purified by flash chromatography on alumina (99/1 CH 2 Cl 2 /MeOH) to give 240 mg of the oxime CRL 8292 in the form of a yellow 25 powder. " Yield = 46% " Melting point = > 260"C " 1H NMR (CDCl 3 ): 7.68 (dd, 1H, J = 4.4 and 8.4 Hz), 7.98 (ddd, 1H, J = 7.6 and 7.6 and 1.6 Hz), 30 8.07 (ddd, 1H, J = 7.6 and 7.6 and 1.6 Hz), 8.30 (dd, 1H, J = 7.6 and 1.6 Hz), 8.56 (d, 1H, J = 6 Hz), 8.75 (dd, 1H, J = 7.6 and 1.6 Hz), 9.00 (dd, 1H, J = 8.4 and 1.2 Hz), 9.12 (dd, 1H, J = 4.4 and 1.2 Hz), 9.41 (d, 1H, J = 6 Hz) 35 13C NMR (CDCl 3 ): 115.06, 116.14, 123.16, 123.29, 125.46, 128.33, 128.77, 129.54, 131.86, 132.16, 138.48, 140.94, 141.37, 145.82, 146.75, 151.27, 151.65, 151.80 * MS (m/z): 298 (64.5), 268 (100), 266 (21.9) - 34 EXAMPLE 14 10- (2-Acetylanilino) -9H-quino[4,3,2-de] [1,10]phenanthrolin 9-one (CRL 8333) 5 Preparation according to the process described in Example 1, starting with the intermediate tetracycle B 7 (0.4 g, 0.98 mmol) and dimethylformamide diethyl acetal (0.6 ml, 3.43 mmol) in DMF (4 ml) . Ammonium chloride (1.2 g, 22.4 mmol), ethanol (20 ml). After purification 10 by flash chromatography (100/5 CH 2 Cl 2 /MeOH), 144 mg of the expected compound CRL 8333 are obtained in the form of a brown-red solid. e Yield = 35% " Melting point = > 2600C 15 e 1H NMR (CDCl 3 ): 2.88 (s, 3H), 3.12 (s, 3H), 5.54 (d, 1H), 7.13 (d, 1H, J = 6 Hz), 7.30 (ddd, 1H, J = 7.6 and 7.6 and 1.2 Hz), 7.45 (ddd, 1H, J = 7.6 and 7.6 and 1.2 Hz), 7.51 (d, 1H, J = 7.6 Hz), 7.65 (broad s, 1H), 7.69 (d, 1H, J = 7.6 Hz), 7.88 (ddd, 1H, J = 7.6 and 20 7.6 and 1.2 Hz), 7.96 (ddd, 1H, J = 7.6 and 7.6 and 1.2 Hz), 8.48 (d, 1H, J = 6 Hz), 8.51 (d, 1H, J = 6 Hz), 8.57 (dd, 1H, J = 7.6 and 1.2 Hz), 8.64 (dd, 1H, J = 7.6 and 1.2 Hz), 9.23 (d, 1H, J = 6 Hz) S13C NMR (CDCl 3 ): 37.22, 45.05, 109.94, 113.94, 25 116.56, 117.38, 122.92, 123.34, 125.43, 125.90, 129.47, 130.27, 131.61, 132.94, 135.87, 137.17, 137.57, 145.87, 146.93, 149.81, 150.28, 153.30, 154.27, 154.54, 154.61, 183.73 30 EXAMPLE 15 10-Hydroxy-9H-quino [4 ,3,2-de] [1,10]phenanthrolin-9-one diiodide (CRL 8369) 500 mg (1.597 mmol) of the compound of Example 10 35 (CRL 8368) and 40 ml of acetic acid in 100 ml of hydriodic acid (57%) are heated at 1000C for 30 minutes. After cooling, the reaction medium is poured into 500 ml of water and ice is added, followed by neutralization with NaHCO 3 (solid). After several - 35 extractions with a mixture of 5% MeOH in HCC1 3 (6 times 500 ml), the organic phases are dried over MgSO 4 and then concentrated on a rotary evaporator to give 0.36 g of compound CRL 8369 in the form of a wine-colored 5 powder. " Yield = 41% " Melting point = > 260"C e 1H NMR (DMSO): 6.24 (d, 1H, J = 7.6 Hz), 6.86 (td, 1H, J = 8 and 4 Hz), 7.27 (d, 2H, J = 4 Hz), 7.57 10 (d, 1H, J = 5.2 Hz), 7.89 (d, 1H, J = 8 Hz), 7.93 (dd, 1H, J = 7.6 and 7.6 Hz), 8.51 (d, 1H, J = 5.2 Hz), 9.54 (s, 1H), 12.62 (broad m, 1H), 14.42 (s, 1H) e 1C NMR (DMSO): 107.81, 109.87, 114.24, 115.36, 116.31, 117.33, 120.11, 120.97, 124.14, 127.63, 132.18, 15 132.81, 134.89, 139.24, 139.35, 141.15, 148.72, 181.29 EXAMPLE 16 10-Chloro-9H-quino[4,3,2-de] [1,10]phenanthrolin-9-one (CRL 8373) 20 50 mg (0.09 mmol) of the salt of Example 15 (CRL 8369) dissolved in 4 ml of POCl 3 are refluxed for 2 hours. After evaporating off the POCl 3 on a rotary evaporator, the reaction medium is neutralized with saturated NaHCO 3 solution. After several extractions with a 25 mixture of 5% MeOH in HCC1 3 (5 times 20 ml), the organic phases are dried over MgSO 4 and then concentrated on a rotary evaporator. The residue obtained is purified by flash chromatography on a column of silica (95/5 CH 2 Cl 2 /MeOH) to give 20 mg of the 30 expected compound CRL 8373 in the form of a yellow powder. o Yield = 77% o Melting point = > 260*C e 1H NMR (CDCl 3 ): 7.67 (d, 1H, J = 5.6 Hz), 7.95 35 (ddd, 1H, J = 8 and 8 and 0.8 Hz), 8.03 (ddd, 1H, J = 8 and 8 and 1.2 Hz), 8.57 (d, 1H, J = 5.6 Hz), 8.61 (ddd, 1H, J = 8 and 1.2 Hz), 8.68 (ddd, 1H, J = 8 and 0.8 Hz), 8.97 (d, 1H, J = 5.6 Hz), 9.30 (d, 1H, J = 5.6 Hz) - 36 13 C NMR (CDC1 3 ) : 117.60, 117.84, 123.31, 123.60, 126.69, 129.10, 131.17, 132.38, 133.47, 138.21, 146.24, 146.51, 147.26, 149.40, 150.32, 154.30, 154.94, 180.47 o MS (m/z): 318 (9.6), 316 (70.2), 290 (29.6), 288 5 (100), 255 (23.4), 253 (26.8). EXAMPLE 17 5 -Bromo-10-methoxy-9H-quino[4,3,2-de] [1,10]phenanthrolin 9-one 10 (CRL 8389) Preparation according to the process described in Example 1, starting with the intermediate tetracycle

B

8 (0.74 g, 1.93 mmol) and dimethylformamide diethyl acetal (1.3 ml, 7.24 mmol) in 15 ml of DMF. Ammonium 15 chloride (1.96 g, 36.4 mmol), ethanol (200 ml). After purification by flash chromatography (95/5 CH2Cl 2 /MeOH), 210 mg of the expected compound CRL 8389 are obtained in the form of an orange powder. e Yield = 42% 20 * Melting point = > 260*C e 1 H NMR (CDCl 3 ): 4.14 (s, 3H), 7.14 (d, 1H, J = 5.6 Hz), 8.05 (dd, 1H, J = 2 and 8.8 Hz), 8.43 (d, 1H, J = 6 Hz), 8.44 (d, 1H, J = 8.8 Hz), 8.76 (d, 1H, J = 2 Hz), 8.95 (d, 1H, J = 6 Hz), 9.27 (d, 1H, 25 J = 5.6 Hz) S 13C NMR (CDCl 3 ) : 57.12, 109.52, 117.00, 117.76, 119.46, 121.58, 124.81, 125.52, 134.72, 135.49, 137.00, 144.85, 146.51, 147.24, 147.92, 150.43, 156.21, 167.98, 180.57 30 e MS (m/z): 393 (100), 392 (61.7), 391 (99.2), 390 (17.4), 362 (9.2), 333 (9.8), 254 (34.5). EXAMPLE 18 5 -Amino-11-methoxy-9H-quino [4,3,2-de] [1,10 ]phenanthrolin 35 9-one (CRL 8389) A solution of compound CRL 8389 (0.5 g, 1.3 mmol) and NaN 3 (0.5 g, 7.7 mmol) in 20 ml of DMF is heated at 900C for 10 hours. After concentrating, the residue is - 37 taken up in 1N KOH (35 ml) and then extracted with 95/5

CH

2 Cl 2 /MeOH (4 x 200 ml). After drying over MgSO 4 and concentrating on a rotary evaporator, the crude product obtained is purified by flash chromatography on silica 5 (80/20 CH 2 Cl 2 /MeOH) to give the expected compound CRL 8389 in the form of a violet powder (65 mg). " Yield = 15% " Melting point = > 260 0 C * 1H NMR (DMSO-d 6 ) ) : 4.07 (s, 3H) , 6. 62 (s, 2H) , 10 7.36 (d, 1H, J = 8.8 Hz), 7.41 (d, 1H, J = 5.9 Hz), 7.74 (s, 1H), 8.08 (d, 1H, J = 8.8 Hz), 8.48 (d, 1H, J = 5.2 Hz), 8.86 (d, 1H, J = 5.9 Hz), 9.08 (d, 1H, J = 5.2 Hz) e IR (KBr): 3420, 3196, 1636, 1616 cm~ 1 15 EXAMPLE 19 5-Amino-9H-quino[4,3,2-de] [1,10]phenanthrolin-9-one hydrochloride (CRL 8406) 20 A solution of 5-amino-9H-quino[4,3,2-de] [1,10]phenan throlin-9-one (1 g, 3.35 mmol) and concentrated HCl (0.56 ml) in 200 ml of methanol is heated at room temperature for 1 hour. 200 ml of ether are added and, after leaving the salt to precipitate out, the medium 25 is filtered to recover the expected compound CRL 8406 in the form of a black powder (1 g). " Yield = 90% " 1 H NMR (DMSO-d 6 ): 7.44 (dd, 1H, J = 8.8 and 2.2 Hz), 7.81 (d, 1H, J = 2.2 Hz), 7.93 (dd, 1H, 30 J = 5.6 and 5.9 Hz), 8.12 (d, 1H, J = 8.8 Hz), 8.66 (d, 1H, J = 5.6 Hz), 8.75 (d, 1H, J = 5.9 Hz), 9.07 (d, 1H, J = 5.9 Hz), 9.14 (d, 1H, J = 5.9 Hz) e IR (KBr): 3404, 3287, 3170, 1691, 1676, 1649 cm 1 35 EXAMPLE 20 5- (Dimethylamino) -9H-quino [4,3 ,2-de] [1,10] phenanthrolin 9-one hydrochloride (CRL 8407) A solution of 5-(dimethylamino)-9H-quino[4,3,2-de] [1,10]phenanthrolin-9-one (1 g, 3.06 mmol) and - 38 concentrated HCl (0.3 ml) in 120 ml of CHCl 3 is stirred at room temperature for 45 minutes. After addition of 350 ml of ether, followed by precipitation of the salt, the medium is filtered to recover the expected product 5 in the form of a navy blue powder (0.97 g) e Yield = 87% e Melting point = > 260*C EXAMPLE 21 10 5- (Benzylamino) -9H-quino[4 ,3,2-de] [1,10]phenanthrolin 9-one hydrochloride (CRL 8416) A solution of 5-(benzylamino)-9H-quino[4,3,2-de] [1,10] phenanthrolin-9-one ASC20 (0.94 g, 2.42 mmol) and concentrated HCl (0.2 ml) in 40 ml of CHCl 3 is stirred 15 at room temperature for 30 minutes. The solvent is evaporated off and 150 ml of ether are added and, after leaving the salt to precipitate out, the medium is filtered to recover the expected compound CRL 8416 in the form of a black powder (0.98 g). 20 e Yield = 95% e Melting point = > 260*C EXAMPLE 22 5- (Dimethylamino-2-ethyl) amino-9H-quino [4,3 ,2-de] 25 [1,10]phenanthrolin-9-one (CRL 8419) 25 ml (166 mmol) of trifluoroacetic acid are added to a mixture of compound CRL 8347 (2.56 g, 8.59 mmol) and dimethylformamide diethyl acetal (7.9 ml, 43.3 mmol) at 0*C. The reaction medium is stirred for 5 minutes and 30 sodium cyanoborohydride (8.2 g, 130 mmol) is then added portionwise. The reaction medium is then heated and maintained at 950C. After 18 hours, the mixture is basified to pH 8 with saturated NaHCO 3 solution (about 600 ml) and then extracted with 95/5 CHCl 3 /MeOH 35 (3 x 800 ml) . The organic phases are washed with water and then dried over MgSO 4 . After evaporating off the solvent on a rotary evaporator, the crude product obtained is purified by filtration through alumina (CHC1 3 and then 95 CHCl 3 /MeOH) to give 1.15 g of the - 39 expected compound CRL 8419 in the form of a black powder. " Yield = 36% " Melting point: decomposes before melting 5 * 1H NMR (CDCl 3 ): 2.37 (s, 6H), 2.62 (t, 2H, J = 7.32 Hz), 3.70 (t, 2H, J = 7.32 Hz), 7.39 (dd, 1H, J = 9.2 and 3 Hz), 7.62 (dd, 1H, J = 8.0 and 4.5 Hz), 7.66 (d, 1H, J = 3 Hz), 8.35 (d, 1H, J = 9.2 Hz), 8.38 (d, 1H, J = 5.7 Hz), 8.79 (dd, 1H, J = 8.0 and 1.8 Hz), 10 9.12 (dd, 1H, J = 4.5 and 1.8 Hz), 9.15 (d, 1H, J = 5.7 Hz) S 13C NMR (CDCl 3 ): 45.97, 50.31, 56.40, 101.05, 116.81, 118.48, 118.89, 125.22, 126.30, 129.35, 134.87, 135.97, 136.32, 138.91, 140.55, 148.25, 148.98, 149.69, 15 152.23, 154.82, 181.37 " IR (CHCl 3 ) : 1663 cm " MS (m/z): 369 (100), 354 (15), 236 (37) EXAMPLE 23 20 5- (Dimethylamino-2-ethyl)amino-9H-quino[4,3,2 de] [1,10]phenanthrolin-9-one hydrochloride (CRL 8418) 265 pl (3.25 mmol) of concentrated hydrochloric acid are added to 1.2 g (3.25 mmol) of compound CRL 8419 dissolved in 60 ml of chloroform. The reaction medium 25 is stirred for 2 hours at room temperature. The precipitate formed is filtered off and then washed with ether. Compound CRL 8418 (0.93 g) is obtained in the form of a black powder. e Yield = 70% 30 1 H NMR (DMSO-d 6 ): 2.67 (s, 6H), 3.09 (m, 2H), 4.01 (m, 2H), 7.67 (dm, 1H, J = 9.2 Hz), 7.80 (dd, 1H, J = 8,0 and 4.5 Hz), 7.94 (m, 1H), 8.26 (d, 1H, J = 9.2 Hz), 8.64 (d, 1H, J = 5.7 Hz), 9.09 (m, 1H), 9.12 (dd, 1H, J = 4.5 and 1.8 Hz), 9.14 (d, 1H, J = 5.7 Hz). 35 EXAMPLE 24 5-Bis(2-chloroethyl)aamino-9H-quino[4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8422) - 40 10 mmol of sodium cyanoborohydride NaBH 3 CN (0.63 g) are added portionwise to a solution of 5-amino-9H-quino [4,3,2-de] [1,10]phenanthrolin-9-one (1 g, 3.95 mmol) and chloroacetaldehyde (50% aqueous, 2.6 ml, 16.8 mmol) 5 in acetic acid (30 ml), at 00C. The reaction medium is stirred at 00C for 5 minutes and then at room temperature for 30 minutes. Next, the medium is basified with saturated sodium hydrogen carbonate NaHCO 3 solution and then extracted with a 95/5 10 CHCl 3 /MeOH mixture. The organic phases are dried over magnesium sulfate MgSO 4 and concentrated on a rotary evaporator. The crude product obtained is purified by filtration through silica (CHCl 3 and then 99/1 CHCl 3 /MeOH) to give two compounds: CRL 8422 and 15 CRL 8423 (described in Example 25). 5-Bis(chloroethyl)amino-9H-quino[4,3,2-de][1,10]phenan throlin-9-one (CRL 8422) was obtained in the form of a pink powder (0.14 g): 20 e Yield = 10% " Melting point = 2200C " IR (KBr) : 1666, 1650 cm * 1H NMR (CDCl 3 ): 3.83 (t, 4H, J = 7.0 Hz), 4.04 (t, 4H, J = 7.0 Hz), 7.47 (dd, 1H, J = 9.5 and 2.9 Hz), 25 7.66 (dd, 1H, J = 8.0 and 4.4 Hz), 7.70 (d, 1H, J = 2.9 Hz), 8.42 (d, 1H, J = 5.6 Hz), 8.50 (d, 1H, J = 9.5 Hz), 8.81 (dd, 1H, J = 8.0 and 1.8 Hz), 9.16 (dd, 1H, J = 4.4 and 1.8 Hz), 9.23 (d, 1H, J = 5.6 Hz) S 13C NMR (CDCl 3 ): 40.16, 53.60, 101.70, 116.60, 30 118.37, 118.68, 125.39, 125.91, 129.25, 135.13, 136.12, 136.38, 139.42, 141.93, 148.24, 148.73, 149.34, 152.22, 155.08, 181.43. EXAMPLE 25 35 5- (2-chloroethyl) amino-9H-quino [4,3,2 de] [1,10]phenanthrolin-9-one (CRL 8423) According to the process described in Example 24, 0.22 g of compound CRL 8423 are obtained in the form of - 41 a violet powder. The characteristics of compound CRL 8423 are as follows: " Yield = 18% " Melting point = 196 0 C 5 e IR (KBr): 3413, 3275, 1654, 1617 cm~ 1 e 1H NMR (CDCl 3 ): 3.81 (t, 2H, J = 5.5 Hz), 3.88 (t, 2H, J = 5.5 Hz), 5.01 (broad s, 1H), 7.34 (dd, 1H, J = 8.8 and 2.5 Hz), 7.60 (d, 1H, J = 2.5 Hz), 7.65 (dd, 1H, J = 7.5 and 4.4 Hz), 8.41 (d, 1H, J = 5.8 Hz), 10 8.43 (d, 1H, J = 8.8 Hz), 8.82 (dd, 1H, J = 7.5 and 1.5 Hz), 9.15 (dd, 1H, J = 4.4 and 1.5 Hz), 9.21 (dd, 1H, J = 5.8 Hz) 1 * C NMR (CDCl 3 ) : 42.83, 45.01, 100.76, 116.81, 118.78, 120.85, 125.38, 126.35, 129.35, 135.04, 136.04, 15 136.43, 140.22, 141.56, 148.49 (2C), 149.41, 152.30, 155.07, 181.57. EXAMPLE 26 12-Methoxy-9-H-quino [4,3,2-de] [1, 10]phenanthrolin-9-one 20 (CRL 8472) 0.54 ml (3 mmol) of dimethylformamide diethyl acetal is added to a suspension of 2-methoxy-11-methyl-1,6 diazanaphthacene-5,12-dione (Intermediate B 9 ) (0.23 g, 0.75 mmol) in DMF (7 ml) under N 2 . The reaction medium 25 is heated at 1200C for 1 hour. After concentrating under vacuum, ethanol (45 ml) and NH 4 Cl (0.46 g) are added and the mixture is then refluxed for 30 minutes. After concentrating on a rotary evaporator, 30 ml of water are added and the medium is then extracted with 30 CHC1 3 (2 x 30 ml). The organic phases are dried over MgSO 4 and concentrated. The crude product obtained is purified by flash chromatography on silica (CHCl 3 ) to give the expected compound CRL 8472 in the form of a brown powder (50 mg). 35 e Yield = 21% e Melting point = > 260*C e 1 H NMR (CDCl 3 ): 4.31 (s, 3H), 7.04 (d, 1H, J = 8.5 Hz), 7.92 (ddd, 1H, J = 8.1, 7.0 and 1.5 Hz), 8.00 (ddd, 1H, J = 8.4, 7.0 and 1.5 Hz), 8.52 (d, 1H, J = - 42 5.5 Hz), 8.63 (dd, 1H, J = 8.1 and 1.5 Hz), 8.66 (d, I, J = 8.5 Hz), 8.67 (dd, 1H, J = 8.4 and 1.5 Hz), 9.27 (d, 1H, J = 5.5 Hz) C * 1C NMR (CDCl 3 ) : 54.69, 114.43, 116.75, 118.15, 5 122.92, 123.41, 124.51, 130.62, 131.81, 133.15, 137.86, 139.17, 145.80, 146.28, 149.59, 149.99, 152.24, 167.75, 181.04 " IR (CHC1 3 ) :1671, 1588 cm 1 " MS (m/z): 313 (50), 312 (91), 284 (17), 283 10 (100), 254 (23), 193 (51). EXAMPLE 27 4 -Bromo-5-amino-9-H-quino [4,3, 2-de] [1,10]phenanthrolin 9-one (CRL 8478) 15 Bromine (35 pl, 0.67 mmol) is added to a suspension of compound CRL 8347 (0.2 g, 0.67 mmol) in acetic acid (8 ml) . The reaction medium is heated at 50*C for 6 hours. After concentrating, the medium is basified with 5N sodium hydroxide (20 ml) and then extracted with a 20 5% MeOH/CHCl 3 mixture (400 ml) . After drying over MgSO 4 and evaporating off the solvent, compound CRL 8478 is obtained in the form of a violet powder which is recrystallized from a 20 ml/15 ml CHCl3/pentane mixture (152 mg). 25 * Yield = 61% e Melting point = > 260*C " 1H NMR (DMSO-d 6 ): 7.07 (broad s, 2H), 7.61 (d, 1H, J = 8.8 Hz), 7.77 (dd, 1H, J = 7.7 and 4.0 Hz), 8.18 (d, 1H, J = 8.8 Hz), 8.61 (d, 1H, J = 7.7 Hz), 30 9.10 (d, 1H, J = 4.0 Hz), 9.14 (d, 1H, J = 5.9 Hz), 9.91 (d, 1H, J = 5.9 Hz) e IR (CHCl 3 ): 3501, 3400, 1673 cm 1 e MS (m/z) : 378 (42), 377 (100), 376 (48), 375 (27) 35 EXAMPLE 28 11-Acetoxymethyl-9-H-quino[4,3,2 de] [1, 10]phenanthrolin-9-one (CRL 8528) - 43 Dimethylformamide diethyl acetal (0.27 ml, 1.5 mmol) is added to a suspension of 3 -acetoxymethyl-11-methyl-1, 6 diazanaphthacene-5,12-dione (Intermediate

B

1 0 ) (0.11 g, 0.31 mmol) in DMF (4 ml) under N 2 . The reaction medium 5 is heated at 1200C for 1 hour. After concentrating under vacuum, ethanol (25 ml) and NH 4 Cl (0.23 g) are added and the mixture is then refluxed for 30 minutes. After concentrating on a rotary evaporator, 30 ml of water are added and the medium is then extracted with 10 CHCl 3 (2 x 30 ml). The organic phases are dried over MgSO 4 . After evaporating off the solvent on a rotary evaporator and purification by flash chromatography on silica (CHC1 3 ) , 65 mg of compound CRL 8528 are obtained. 15 * Yield = 60% e Melting point = 206-210*C e 1H NMR (CDCl 3 ): 2.19 (s, 3H), 5.32 (s, 2H), 7.96 (ddd, 1H, J = 1, 1.8 and 8 Hz), 8.03 (ddd, 1H, J = 1, 1.8 and 8.4 Hz), 8.56 (d, 1H, J = 5.5 Hz), 8.64 20 (dd, 1H, J = 1.1 and 8.4 Hz), 8.71 (dd, 1H, J = 1.1 and 8.0 Hz), 8.77 (d, 1H, J = 2.4 Hz), 9.14 (d, 1H, J = 2.4 Hz), 9.28 (d, 1H, J = 5.5 Hz) e MS (m/z): 355 (88), 313 (100), 296 (25), 267 (7). 25 EXAMPLE 29 9-H-Quino[4,3,2-de] [1, 7 ]phenanthrolin-9-one (CRL 8529) Dimethylformamide diethyl acetal (0.15 ml, 0.875 mmol) is added to a suspension of 6-methyl-1,11 30 diazanaphthacene-5,12-dione (Intermediate Dj) (52 mg, 0.875 ml) under N 2 . The reaction medium is heated at 120*C for 30 minutes. After concentrating under vacuum, ethanol (60 ml) and NH 4 Cl (0.34 g) are added and the mixture is refluxed for 30 minutes. After concentrating 35 on a rotary evaporator, 10 ml of water are added and the medium is then extracted with CH 2 C1 2 (2 x 10 ml) . The organic phases are dried over MgSO 4 and concentrated. The crude product obtained is purified by flash chromatography on silica (99/1 CH2Cl 2 /MeOH) to - 44 give the expected compound CRL 8529 in the form of a yellow solid (6 mg). e Yield = 11% e 1H NMR (CDCl 3 ): 7.78 (dd, 1H, J = 8.1 and 5 4.8 Hz), 7.97 (ddd, 1H, J = 8.0, 7.4 and 1.2 Hz), 8.04 (ddd, 1H, J = 8.0, 7.4 and 1.2 Hz), 8.51 (d, 1H, J = 5.9 Hz), 8.69 (dd, 2H, J = 8.0 and 1.5 Hz), 9.08 (dd, 1H, J = 4.8 and 1.9 Hz), 9.13 (d, 1H, J = 5.9 Hz), 9.27 (d, 1H, J = 1.9 and 8.1 Hz) 10 e 1C NMR (CDC 3 ) : 115.15, 121.76, 122.28, 127.13, 127.16, 129.65, 130.82, 132.21, 132.60, 132.99, 136.88, 139.91, 144.85, 148.00, 148.03, 151.75, 151.84, 179.94 * MS (m/z): 283 (54), 255 (100) 228 (10). 15 EXAMPLE 30 5 -Bromo-9-H-quino[4,3,2-de] [1, 7 ]phenanthrolin-9-one (CRL 8839) Compound CRL 8839 is prepared according to the procedure described in Example 8, starting with 9-H 20 quino[4,3,2-de] [1, 7 ]phenanthrolin-9-one (CRL 8529) (0.5 g, 1.77 mmol); 20 ml of acetic acid; bromine solution (0.2 ml, 3.88 mmol/5 ml of acetic acid); reflux for 24 hours. 25 EXAMPLE 31 5-Amino-9-H-quino [4,3,2-de] [1, 7 ]phenanthrolin-9-one (CRL 8836) Compound CRL 8836 is prepared according to the procedure described in Example 9, starting with 5 30 bromo-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9-one (CRL 8839) (1.15 g, 18 mmol) ; 250 ml of DMF; sodium azide (1.2 g, 1.85 mmol); reflux for 4 hours. EXAMPLE 32 35 5-(Dimethylamino-2-ethyl)amino-9-H-quino[4,3,2-de] [1, 7 ]phenanthrolin-9-one (CRL 8840) Compound CRL 8840 is prepared according to the procedure described in Example 22, starting with 5-amino-9-H-quino[4,3,2-de] [1, 7 ]phenanthrolin-9-one - 45 (CRL 8836) (1.28 g, 4.3 mmol); dimethylformamide diacetal (4 ml, 21.9 mmol); trifluoroacetic acid (12.5 ml, 83 mmol); sodium cyanoborohydride (4.1 g, 65 mmol); 90 0 C for 8 hours. 5 EXAMPLE 33 5-Bis (chloroethylamino-2-ethyl) amino-9-H-quino [4,3,2 de] [1,7]phenanthrolin-9-one (CRL 8841) Compound CRL 8841 is prepared according to the 10 procedure described in Example 24, starting with 5-amino-9-H-quino[4,3,2-de][1,7]phenanthrolin-9-one (CRL 8836) (1 g, 3.95 mmol); chloroacetaldehyde (2.6 ml, 16.8 mmol); acetic acid (30 ml); sodium cyanoborohydride (0. 63 g, 10 mmol) ; 30 minutes at room 15 temperature. EXAMPLE 34 5- (Chloroethylamino-2-ethyl) amino-9-H-quino [4,3, 2-de] [1,7]phenanthrolin-9-one (CRL 8842) 20 Compound CRL 8842 is also obtained during the procedure described in the above example from 5-amino-9-H-quino [4,3,2-de][1,7]phenanthrolin-9-one (CRL 8836). EXAMPLE 35 25 4-Bromo-5-amino-9-H-quino [4,3,2-de] [1,7]phenanthrolin 9-one (CRL 8843) Compound CRL 8843 is prepared according to the procedure described in Example 27, starting with 5-amino-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9-one 30 (CRL 8836) (0.6 g, 2.01 mmol); 24 ml of acetic acid; bromine (35 pl, 0.67 mmol); 50 0 C for 6 hours. EXAMPLE 36 7-Nitro-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9-one 35 (CRL 8838) Compound CRL 8838 is prepared according to the procedure described in Example 6, starting with 9-H quino[4,3,2-de][1,7]phenanthrolin-9-one (CRL 8529) - 46 (1 g, 3.53 mmol); 23 ml of sulfuric acid and 23 ml of nitric acid; 1300C for 2 hours. EXAMPLE 37 5 7 -Amino-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9-one (CRL 8837) Compound CRL 8837 is prepared according to the procedure described in Example 7, starting with 7 nitro-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9-one 10 (CRL 8838) (0.2 g, 0.61 mmol); iron (0.19 g, 3.38 mmol), 10 ml of acetic acid/water mixture (50/50). EXAMPLE 38 15 12-Methoxy-9-H-quino [4 ,3,2-de] [1, 7 ]phenanthrolin-9-one (CRL 8844) Compound CRL 8844 is prepared according to the procedure described in Example 29, starting with 3-methoxy-6-methyl-1,11-diazanaphthacene-5,12-dione 20 (Intermediate

D

2 ) (0.76 g, 25 mmol); dimethylformamide diacetal (2 ml, 11.67 mmol); 120*C for 30 minutes;

NH

4 Cl (4.5 g); 500 ml of ethanol; refluxed for 30 minutes. 25 The results of the pharmacological tests, presented below, demonstrate the cytotoxic qualities of the compounds of formulae I and Ia, and also the maximum tolerated doses. These data enable the therapeutic value of the claimed compounds to be assessed. 30 1 - Determination of the maximum tolerated dose (MTD) The evaluation of the maximum tolerated dose was 35 performed on 4- to 6-week-old B6D2F1/Jico mice. The compounds were administered intraperitoneally at increasing doses ranging from 2.5 to 160 mg/kg. The value of the MTD (expressed in mg/kg) is determined from the observation of the survival rate of the - 47 animals over a 14-day period after a single administration of the products under consideration. The change in the weight of the animals is also monitored during this period. When the value of the MTD is 5 greater than 160 mg/kg, the value of the MTD is considered as 160 mg/kg by default. The results of the estimation of the maximum tolerated dose (MTD) are collated in Table I below: 10 - 48 TABLE I Compounds CRL MTD (mg/kg) CRL 8274 (Ascididemin) 20 CRL 8269 (2-bromoleptoclinidone) 40 CRL 8323 (Example 1) 20 CRL 8301 (Example 2) > 160 CRL 8241 (Example 3) > 160 CRL 8325 (Example 4) > 160 CRL 8297 (Example 5) > 160 CRL 8289 (Example 6) 20 CRL 8344 (Example 7) > 160 CRL 8248 (Example 8) > 160 CRL 8347 (Example 9) > 160 CRL 8292 (Example 13) > 160 CRL 8290 (Example 12) 80 CRL 8333 (Example 14) > 160 CRL 8368 (Example 10) > 160 CRL 8369 (Example 15) > 160 CRL 8373 (Example 16) > 160 CRL 8387 (Example 11) > 160 CRL 8389 (Example 17) > 160 CRL 8406 (Example 19) > 160 CRL 8407 (Example 20) > 160 CRL 8416 (Example 21) > 160 CRL 8419 (Example 22) 40 CRL 8418 (Example 23) 40 CRL 8422 (Example 24) > 160 CRL 8423 (Example 25) > 160 The majority of the products described in the family of 5 ascididemin or of its isomer do not show any direct toxicity (MTD > 160 mg/kg) and may thus be used in vivo at high tissue concentrations, and thus at high doses.

- 49 2 - Cytotoxic activity on tumor cell lines in culture The influence of the compounds of formulae I and Ia on neoplastic cells was evaluated using the MTT 5 colorimetric test. The principle of the MTT test is based on the mitochondrial reduction by metabolically active live cells of the yellow product MTT (3-(4,5 dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide) into a blue product, formazan. The amount of formazan 10 thus obtained is directly proportional to the amount of live cells present in the culture well(s). This amount of formazan is measured by spectrophotometry. The cell lines are maintained as a monolayer culture at 15 370C in closed culture dishes containing MEM 25 MM HEPES base medium (minimum essential medium). This medium, adapted to the growth of a varied range of mammalian diploid or primary cells, is then supplemented: 20 - with an amount of 5% FCS (Fetal Calf Serum) decomplemented at 560C for 1 hour, - with 0.6 mg/ml of L-glutamine, - with 200 IU/ml of penicillin, 25 - with 200 mg/ml of streptomycin, - with 0.1 mg/ml of gentamycin. The 12 human cancer cell lines used were obtained from the American Type Culture Collection (ATCC, Rockville, 30 MD, USA). These 12 cell lines are: - U-373MG (code ATCC: HTB-17) and U-87MG (code ATCC: HTB-14) which are two glioblastomas, - SW1088 (code ATCC: HTB-12) which is an 35 astrocytoma, - A549 (code ATCC: CCL-185) and A-427 (code ATCC: HTB-53) which are two non-small-cell lung cancers, - 50 - HCT-15 (code ATCC: CCL-225) and LoVo (code ATCC: CCL-229) which are two colorectal cancers, - T-47D (code ATCC: HTB-133) and MCF7 (code ATCC: 5 HTB-22) which are two breast cancers, - J82 (code ATCC: HTB-1) and T24 (code ATCC: HTB 4) which are two bladder cancers, - PC-3 (code ATCC: CRL-1435) which is a prostate cancer. 10 Experimentally: 100 pil of a cell suspension containing 20 000 to 50 000 (depending on the cell type used) cells/mL of culture medium are inoculated in flat bottomed 96-well multi-well plates and are incubated at 15 370C under an atmosphere comprising 5% Co 2 and 70% humidity. After incubating for 24 hours, the culture medium is replaced with 100 ptl of fresh medium containing either the various test compounds at concentrations ranging from 10~5 to 10~10 M or the 20 solvent used to dissolve the test products (control condition) . After incubating for 72 hours under the above conditions, the culture medium is replaced with 100 ptl of a yellowish solution of MTT dissolved at a rate of 1 mg/mL in RPMI 1640. The microplates are 25 reincubated for 3 hours at 370C and then centrifuged for 10 minutes at 400 g. The yellowish solution of MTT is removed and the blue formazan crystals formed at the cellular level are dissolved in 100 pl of DMSO. The microplates are then agitated for 5 minutes. The 30 intensity of the resulting blue coloration, and thus of the conversion of the yellow MTT product into blue formazan by the cells that are still alive at the end of the experiment is quantified by spectrophotometry using a Dynatech Immunoassay System machine at 35 wavelengths of 570 nm and 630 nm corresponding, respectively, to the maximum absorption wavelengths of formazan and to the background noise. Software built into the spectrophotometer calculates the average - 51 optical density values and also the standard deviation (Std. Dev.) and standard error of mean (SEM) values. The inhibitory activity on the cell growth of the 5 compounds of formulae I and Ia on the different tumor cell lines was compared with that of the natural product ascididemin (CRL 8274). All of the compounds show significant inhibitory activity on the cell proliferation of the 12 human tumor lines: U-87MG, U 10 373MG, SW 1088, T24, J82, HCT-15, LoVo, MCF7, T-47D, A549, A-427 and PC-3 with a 50% inhibitory concentration (IC50) which is between 10 6 M and 10' 0 M, depending on the compounds and the tumor lines tested. By way of example, the values of the concentrations 15 flanking the IC50 values which are obtained on the various cell lines are given in Table II: - 52 TABLE II COMPOUNDS CELL LINES, CRL U4I7MG U-373MtG SWIS Og IT4 £82 rIS lo- o i~.Imcr7 T-47D IA549 A-427 I 'C-3 CR18274 1101,0110,01 1l1' o1,10-11 iioo.io'i ii110-1,1tl1, 0I iio1,o'i i'o-.io.' 1101,1011 11o0-,o, 1~',' iio 11o~ 11o 7 j 0-11 1 10o-'l CRL8189 110',110"I l10l.I0'I 11" 0111-.9 10o01 ''1-1 1,10-1 ['I'I ho',oiIw','I to'.oII o'-' 11o',to'i 110119-11 1101 ' l10,10 11o'l' CR18248 ii0',10t 1, l0lwl jlw0'.I1O 1-'I 91 1101,1-71 1 Wio.i . 0-'.1o-Il . -1 110-1,1.11' 110-1,19-1 i'1 o 1,7 11o',I' lIo 1 .:w'; C11,2411 1101,1I I 110.,101, liio,Ir'I 110-1,1Io11 11fl 4 ,1D'I11 0' ' I to,',1,1 141.io 1-7io.I II,0I 110. 7t, 10-11 110"1.11~ iz01o 4 ,o CRL8297 110-,10'81 i10',10-8 110',10"1 110 '.o11 iioI04i ii0.1.1011 i101,wliw I i0 10 11w ji~ i, g IW.O' ',l *'l 110 1 8 1l C1813011 110'I10"111111 110-6,1o-11 110-1,101 11O ~, o i jI ' I 0 -1 1 110.1,1w.1 11 w, I W1 i'o'100.'i Ileo'.1o'i 1101,Io v o' CR18323 110-1,101, Io*',Io *i 11o.610-7 1t- 11o'.04 Iie lo11-,10,11 Iloio.'OI11 I1FT0I 1101,101,10. olO' 0'i 7O,101 119*.10-11 CR138325 flIO,104I (,~i ' 10',10"1I jl01,I0'j 101 II I10.1,101, 1101,IT 7 1 iioI',iriy 1101,oIl 11v 71s 1 1 10 ,o ' t ol 1,,10 CR18344 I~o I W , 110 ,10 ' io1'1 Ito -1,o0', 11o 4 .r' 0-11 11 vr',i0Iolj 1Ii 7 ,IWII 1101,10-11 1I0.',10*'i ;io,,o-'i I ~o CR-837 io0"9o01 JII',1o'l 110-'10.'I 101,10-11 119-110-11 tt01ol8 l 110-1,101, 110-101, 110'.,10-11 110,10-i11 ~ 1100 '.le 7I CR1.83871 0, I ' II 01.OiI0,10-7 1-1 I 10 5 .8 4 io' 11,161O.j o" II9',I) ii'.0 110 -I '. 10 1 ji 0,io 1I04'.10-11 IIotl. 101' In-) CRI1832' 111 ,10 110-'.10'1 11'10' 1 >4I 10-' >1011 1101,1-11ll>o o '.'o 110 11011 1 O'i- it 0'1i', I1I81'7.tO' ,I 1 1 CRL,83243 1100-61r' 110 >o' >1 10'1 1'1' 1,0' Iie 10', 1W.I ItI'I I1t'i0'11 'Io'io1 jig"ol',15'I w It 10'I1ii061~ CRI.828 110',0'1 110-,1061 110',10'1 v1F1.io9'1 1tI,0'i 119.'.10.', 110110-71 110'...Q7I 110,10*', II0*'.10I1 1101,10-11l vs ,:o CRI.8423 10,10-) 1110,1f) I110',100'1 1 *" helo-110-l'1 I10.',10'I II40*,DIo.71 ~ 1104,10-i 11@1.1 .1110 4 i 0. 9,10 o I o i Inhibitor06110y.11 >I' l,14 concentration (M) 1106 flanking105.0 Ithe .ll v lue1101 of-1106 the4, 50I nhibitory concentration oM) fakn the compund ofth formula I, II(*) or III(**) on the cell lines - 53 'able III gives the results of the average IC50 values (in nM) (calculated from the cytotoxic activity on the 12 tumor lines studied) and the MTD/IC 5 0 ratios (these ratios are calculated by forming the ratio of the MTD 5 values and the IC5o values expressed as numbers without units) TABLE III Compounds CRL IC50 (nM) MTD/IC 5 0

MTD/IC

5 0 * CRL 8274 (Ascididemin) 100 0.20 1 CRL 8269

(

2 -bromoleptoclinidone) 120 0.33 2 CRL 8289 (Example 6) 10 2.00 10 CRL 8248 (Example 8) 80 2.00 10 CRL 8241 (Example 3) 140 1.14 6 CRL 8297 (Example 5) 90 1.78 9 CRL 8325 (Example 4) 37 4.32 22 CRL 8344 (Example 7) 53 3.02 15 CRL 8347 (Example 9) 21 7.62 38 CRL 8323 (Example 1) 60 0.33 2 CRL 8301 (Example 2) 270 0.59 3 CRL 8389 (Example 17) 420 0.38 2 CRL 8368 (Example 10) 480 0.33 2 CRL 8406 (Example 19) 60 2.67 13 CRL 8407 (Example 20) 22 7.27 36 CRL 8416 (Example 21) 80 2.00 10 CRL 8418 (Example 23) 110 0.37 2 CRL 8419 (Example 22) 60 0.67 3.3 CRL 8422 (Example 24) 100 1.60 8.3 CRL 8423 (Example 25) 7 22.86 114 10 *: the ratio MTD/IC 5 0 for the various compounds was estimated by taking as reference a ratio equal to 1 for ascididemin. The compounds described show, on the tumor cell line 15 models, IC50 values (nM) which are greater than or equivalent to that of ascididemin. With the exception - 54 of CRL 8289 (whose maximum tolerated dose is equivalent to that of ascididemin, but whose IC50 value is ten times lower than that of ascididemin), the maximum tolerated doses of the compounds described, considered 5 by default as equivalent to 160 mg/kg, are markedly higher than those of ascididemin (20 mg/kg). These results suggest that this novel family of compounds have no direct toxicity. Consequently, the tolerance/cytotoxic activity ratios of the compounds 10 illustrated in the present invention are markedly higher than that of the natural ascididemin. These compounds may thus be used as antitumor drugs, for their cytotoxic properties, at tissue concentrations that are higher than those induced with the natural 15 ascididemin. They are thus characterized by better therapeutic manageability. CRL 8289, whose IC50 value is 10 nM, also shows better therapeutic manageability than ascididemin. 20 By virtue of their cytotoxic properties, the compounds of formulae I and Ia as described, or in the form of acceptable pharmaceutical salts or solvates, may be used as active principles of drugs. 25 The compounds of formulae I and Ia are generally administered in dosage units established either per M2 of body surface or per kg of weight. Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed 30 with one (or more) pharmaceutical excipient(s). The compounds of formulae I and Ia may be used, according to the cancer pathology of the individual to be treated, at doses of between 0.05 and 350 mg/m 2 of 35 body surface, preferably at doses from 0.5 to 50 mg/m 2 /day for a curative treatment in the acute phase as a function of the number of treatment cycles of each cure. For maintenance treatment, the compounds of formulae I and Ia will advantageously be used at - 55 doses from 0.05 to 25 mg/m 2 /day and preferably at doses from 0.1 to 1.5 mg/m 2 /day depending on the number of treatment cycles of the cure. They may be combined with antitumor drugs used in validated intensive multidrug 5 therapy protocols. In the pharmaceutical compositions of the present invention for oral or intravenous administration, the active principles may be administered in unit forms of 10 administration, mixed with conventional pharmaceutical supports that are suitable for human therapy. The suitable unit forms of administration comprise oral route forms such as tablets, which may be splittable, or gel capsules, implants and intravenous 15 administration forms. For a parenteral administration (intravenous infusion at a constant flow rate), sterile aqueous suspensions, sterile isotonic saline solutions or sterile and 20 injectable solutions which contain pharmacologically compatible dispersants and/or solubilizing agents, for example propylene glycol, polyethylene glycol or a cyclodextrin, are used. 25 Thus, to prepare an aqueous solution for intravenous injection intended for an infusion performed over 1 to 24 h, it is possible to use a co-solvent: an alcohol such as ethanol, a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such 30 as Tween 80. When a solid composition in the form of tablets is prepared, a wetting agent such as sodium lauryl sulfate may be added to the micronized or unmicronized active 35 principle, and the whole is mixed with a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets may be coated with sucrose, with various polymers or with other suitable materials, or - 56 alternatively they may be treated such that they have sustained or delayed activity and such that they continuously release a predetermined amount of active principle. 5 A preparation as gel capsules is obtained by mixing the active principle with a diluent such as a glycol or a glycerol ester and by incorporating the mixture obtained into soft or hard gel capsules. 10 The active principle may also be formulated in the form of microcapsules or microspheres, optionally with one or more supports or additives. 15 The active principle may also be presented in the form of a complex with a cyclodextrin, for example a-, P- or y-cyclodextrin,2-hydroxypropyl-$-cyclodextrin or methyl-p-cyclodextrin. 20 The compounds of formulae I and Ia will be used in the treatment of most solid tumors on account of their powerful cytotoxic activities, in particular for treating cerebral tumors, lung cancers, ovarian and breast tumors, colorectal cancers, prostate cancers and 25 testicular tumors.

Claims (5)

1. A pharmaceutical composition comprising an effective amount of a compound chosen from the 5 compounds of general formulae I and Ia below for treating, by virtue of their cytotoxic properties, cancerous tumors and their metastases: X Rs R1 X R1 N R2 R7 N R2 N FR4N Formula I Formula la 10 in which: - X is chosen from oxygen, an =NH group and an =N-OH group, - Ri is chosen from hydrogen, halogens, a 15 nitro group and groups -NR 8 R 9 in which R 8 and R 9 are chosen, independently of each other, from hydrogen and (C 1 -C 4 ) alkyl groups, - R 2 is chosen from hydrogen and halogens, - R 3 is chosen from hydrogen, halogens, 20 (C 1 -C 4 ) alkyl groups, (C1-C 6 ) alkoxy groups, a guanidino group, groups -NRioR 1 1 in which Rio and R 11 are chosen, independently of each other, from hydrogen, (CI-C 4 ) alkyl groups, (Ci-C 4 ) phenylalkyl groups and groups -(CH 2 )n-Y with Y being chosen 25 from halogens and CN, -CH(O-Et) 2 , (C 1 -C 6 ) alkoxy, -O-(CH 2 ) 2 -N(CH 3 ) 2 and -N(CH 3 ) 2 groups and n = 1 to 3, - R 4 is chosen from hydrogen, halogens, nitro groups and groups -NR 1 2 RI 3 in which R 1 2 and R 1 3 30 are chosen, independently of each other, from )ydrogen and (Ci-C 4 ) alkyl groups, - R 5 , R 6 and R 7 are chosen from: - 58 hydrogen or a halogen atom, Ci-C6 alkyl, hydroxyl, Cl-C6 alkoxy, (C1-C6) alkoxy (Ci-C 6 ) alkyl, (C1-C 4 ) alkylcarbonyloxy (C 1 -C 4 ) alkyl, -CHO, -COOH, -CN, -C0 2 R 1 4 , -CONHR 1 4 5 and -CONR 1 4 R 1 5 groups, -NHCOR 14 and -NR 14 R 1 5 in which R 1 4 and R 1 5 are chosen, independently of each other, from hydrogen and (Ci-C 6 ) alkyl, -phenyl-CO CH 3 and -CH 2 -CH 2 -N(CH 3 ) 2 groups, -phenyl-CO-CH 3 or -phenyl-CO-CH=CH 10 N(CH 3 ) 2 , morpholino, nitro or SO 3 H groups, groups: -CH2-N-COOR 1 6 -CH2-N-COOR1 6 , Cr- COOR 17 CH2-Ar 15 RiE and R 1 7 being chosen from Ci-C 6 alkyl groups and Ar being a C 6 -C 1 4 aryl group, with the exclusion of the compounds of formula I containing the combination: X = 0, 20 and, either : R 1 , R 2 , R 3 , R 4 , R 5 , R6, R7 = H, or R 1 , R 3 , R 4 , R 5 , R6, R 7 = H and R2 = Br, and with the exclusion of the compound formula Ia 25 containing the combination X = 0 and R 1 , R 2 , R 3 , R 4 , R 5 , R6, R 7 = H, and the addition salts of these compounds with pharmaceutically acceptable acids. 30 2. A pharmaceutical composition comprising an effective amount of a compound chosen from the compounds of formula I in which: - X is chosen from oxygen, an =NH group and an =N-OH group, 35 - R, is chosen from hydrogen, halogens, a nitro group and groups -NR 8 R 9 in which R 8 and R9 - 59 are chosen, independently of each other, from hydrogen and (C 1 -C 4 ) alkyl groups, - R 2 is chosen from hydrogen and halogens, - R 3 is chosen from hydrogen, halogens, 5 (Ci-C 4 ) alkyl groups, (C 1 -C 6 ) alkoxy groups, a guanidino group, groups -NRioRii in which R 10 and R 11 are chosen, independently of each other, from hydrogen, (C 1 -C 4 ) alkyl groups, (Ci-C 4 ) phenylalkyl, -(CH 2 ) 2 -N(CH 3 ) 2 , and -(CH 2 ) 2 -0-(CH 2 ) 2 10 N(CH 3 ) 2 groups, - R 4 is chosen from hydrogen, halogens, nitro groups and groups -NR 1 2 R 1 3 in which R 1 2 and R 1 3 are chosen, independently of each other, from hydrogen and (Ci-C 4 ) alkyl groups, 15 - R 5 , R 6 and R 7 are chosen from: hydrogen or a halogen atom, Ci-C 6 alkyl, hydroxyl, Ci-C 6 alkoxy, -CHO, -COOH, -CN, -C0 2 R 1 4 , -CONHR 14 and -CONR 1 4 R 15 groups, -NHCOR 1 4 and -NR 1 4 R 15 groups in which R 14 and 20 R 1 5 are chosen, independently of each other, from hydrogen and (Ci-C 6 ) alkyl and -CH 2 -CH 2 -N(CH 3 ) 2 groups, -phenyl-CO-CH 3 or -phenyl-CO-CH=CH N(CH 3 ) 2 , morpholino, nitro or SO 3 H groups, 25 groups: -CH2-N-COOR 1 6 -CH 2 -N C0OR 1 6 , CH2COOR 17 CH-Ar R 16 and R 17 being chosen from Ci-C 6 alkyl groups and 30 Ar being a C 6 -C 1 4 aryl group, with the exclusion of the compounds in which X = 0, and, either: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 = H, or: RI R 3 , R 4 , R 5 , R 6 , R 7 = H and R 2 = Br, and the addition salts of these compounds 35 with pharmaceutically acceptable acids. - 60 3. The pharmaceutical composition as claimed in claim 2, comprising an effective amount of a compound chosen from the compounds of formula I in which: 5 - X represents oxygen, - Ri is chosen from hydrogen and an amino group, - R 2 is chosen from hydrogen and halogens, - R 3 is chosen from hydrogen, halogens, 10 (Ci-C 4 ) alkyl groups, (C 1 -C 6 ) alkoxy groups, a guanidino group, groups -NRioRii in which R 10 and R 11 are chosen, independently of each other, from hydrogen, methyl groups, (Ci-C 4 ) phenylalkyl, -(CH 2 ) 2 -N(CH 3 ) 2 , -(CH2) 2 -0-(CH 2 ) 2 -N(CH 3 ) 2 groups, 15 - R 4 is chosen from hydrogen, halogens and nitro and amino groups, - R 5 , R 6 and R 7 represent a hydrogen, with the exclusion of the compounds in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 = H, or R 1 , R 3 , R 4 , R 5 , R 6 , 20 R7 = H and R 2 = Br, and the addition salts of these compounds with pharmaceutically acceptable acids.

4. The pharmaceutical composition as claimed in 25 claim 1, comprising an effective amount of a compound chosen from the compounds of formulae I and Ia in which: - X represents oxygen, - R, is chosen from hydrogen and an amino 30 group, - R 2 is chosen from hydrogen and halogens, - R 3 is chosen from hydrogen, halogens, (Ci-C 4 ) alkyl groups, (C 1 -C 6 ) alkoxy groups, a guanidino group, groups -NRioRii in which R 10 and R 11 35 are chosen, independently of each other, from hydrogen, methyl groups, (C 1 -C 4 ) phenylalkyl groups and groups -(CH 2 )n-Y with Y being chosen from halogens and GROUPS CN, -CH(O-Et) 2 , (C 1 -C 6 ) alkoxy, -0- (CH 2 ) 2 -N(CH 3 ) 2 and -N(CH 3 ) 2 and n = 1 to 3, - 61 R 4 is chosen from hydrogen, halogens, and nitro and amino groups, - R 5 is chosen from a hydrogen, a halogen and a methoxy group, 5 - R 6 and R 7 are chosen from hydrogen and C1-C6 alkoxy, (C 1 -C 6 ) alkoxy(C1-C 6 )alkyl and -CH 2 0COCH 3 groups, with the exclusion of the compounds of formula I in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 = H or 10 R 1 , R 3 , R 4 , R 5 , R 6 , R 7 = H and R 2 = Br, and of the compound of formula Ia in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 = H, and the addition salts of these compounds with pharmaceutically acceptable acids. 15

5. The composition as claimed in claim 4, in which the compounds are chosen from: 5-(dimethylamino)-9H-quino[4,3,2-de][1,10]phenan throlin-9-one, 20 5-(benzylamino)-9H-quino[4,3,2-de][1,10]phenan throlin-9-one, 5-bromo-9H-quino[4,3,2-de][1,10]phenanthrolin-9-one, 7 -amino-9H-quino[4,3,2-de][1,10]phenanthrolin-9-one, 5-amino-9H-quino[4,3,2-de][1,10]phenanthrolin-9-one, 25 5-methyl-9H-quino[4,3,2-de][1,10]phenanthrolin-9 one,

10-methoxy-9H-quino[4,3,2-de][1,10]phenanthrolin-9 one, 5-methoxy-9H-quino[4,3,2-de][1,10]phenanthrolin-9 30 one, 7 -nitro-9H-quino[4,3,2-de][1,10]phenanthrolin-9-one, 5-chloro-9H-quino[4,3,2-de][1,10]phenanthrolin-9 one, 5-bromo-10-methoxy-9H-quino[4,3,2-de][1,10]phenan 35 throlin-9-one, 5-$igethylamino-2-ethyl)amino-9H-quino[4 3, 2-de] [1,10]phenanthrolin-9-one, 5-bis( 2 -chloroethyl)amino-9H-quino[4,3,2-de][1,10] phenanthrolin-9-one, - 62 5-( 2 -chloroethyl)amino-9H-quino[4,3,2-de] [1,10] phenanthrolin-9-one,

12-methoxy-9-H-quino[4,3,2-de] [1,10]phenanthrolin 9-one, 5 4 -bromo-5-amino-9-H-quino[4,3,2-de] [1,10]phenan throlin-9-one, 11-acetoxymethyl-9-H-quino[4,3,2-de] [1,10]phenan throlin-9-one, 5-bromo-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9 10 one, 5-amino-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9 one, 5- (dimethylamino-2-ethyl) amino-9-H-quino [4,3,2 de][1,7]phenanthrolin-9-one, 15 5-bis (chloroethylamino-2-ethyl)amino-9-H-quino [4,3,2-de][1,7]phenanthrolin-9-one, 5- (chloroethylamino-2-ethyl) amino-9-H-quino [4,3,2 de][1,7]phenanthrolin-9-one, 4-bromo-5-amino-9-H-quino [4, 3,2 20 de][1, 7 ]phenanthrolin-9-one, 7 -nitro-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9 one, 7-amino-9-H-quino[4,3,2-de] [1,7l]phenanthrolin-9 one, 25 1 2 -methoxy-9-H-quino[4,3,2-de] [1,7]phenanthrolin 9-one, and the addition salts of these compounds with pharmaceutically acceptable acids. 30 6. The use of a compound as defined in one of claims 1 to 5, for the manufacture of an anticancer drug. 7. The use as claimed in claim 6, in which the compounds are chosen from: 35 5-(dimethylamino)-9H-quino[4,3,2-de] [1,10]phenan throlin-9-one, 5-(benzylamino)-9H-quino[4,3,2-de] [1,10]phenan throlin-9-one, 5-bromo-9H-quino[4,3,2-de] [1,10]phenanthrolin-9-one, - 63 7-amino-9H-quino[4,3,2-de] [1,10]phenanthrolin-9-one, 5-amino-9H-quino[4,3,2-de][1,10Jphenanthrolin-9-one, 5-methyl-9H-quino[4,3,2-de] [1,10]phenanthrolin-9 one, 5 10-methoxy-9H-quino[4,3,2-de] [1,10]phenanthrolin 9-one, 5-methoxy-9H-quino[4,3,2-de] [1,10]phenanthrolin-9 one, 7-nitro-9H-quino[4,3,2-de] [1,10]phenanthrolin-9-one, 10 5-chloro-9H-quino[4,3,2-de] [1,10]phenanthrolin-9 one, 5-bromo-10-methoxy-9H-quino[4,3,2-de] [1,10]phenan throlin-9-one, 5- (dimethylamino-2-ethyl)amino-9H-quino [4,3, 2-de] 15 [1,10]phenanthrolin-9-one, 5-bis (2-chloroethyl) amino-9H-quino [4,3, 2-de] [1,10]phenanthrolin-9-one, 5-( 2 -chloroethyl)amino-9H-quino[4,3,2-de] [1,10] phenanthrolin-9-one, 20 12-methoxy-9-H-quino[4,3,2-de] [1,10]phenanthrolin 9-one, 4 -bromo-5-amino-9-H-quino[4,3,2-de] [1, 10]phenan throlin-9-one, 11-acetoxymethyl-9-H-quino[4,3,2-de] [1,10]phenan 25 throlin-9-one, 5-bromo-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9 one, 5-amino-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9 one, 30 5-(dimethylamino-2-ethyl)amino-9-H-quino[4,3,2 de][1,7]phenanthrolin-9-one, 5-bis (chloroethylamino-2-ethyl) amino-9-H-quino [4,3,2-de] [1,7]phenanthrolin-9-one, 5- (chloroethylamino-2-ethyl) amino-9-H-quino [4,3,2 35 de][1,7]phenanthrolin-9-one, 4 -bromo-5-amino-9-H-quino[4,3,2-de] [1,7]phenan throlin-9-one, 7-nitro-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9 one , - 64 7-amino-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9 one, 12-methoxy-9-H-quino[4,3,2-de] [l,7]phenanthrolin 9-one, 5 and the addition salts of these compounds with pharmaceutically acceptable acids. 8. Compounds of general formulae I and Ia x R5 R1 X R NN,_ 2 R7N R2 R7 R3 R3 R N ZR4N Formula I Formula la 10 in which: - X is chosen from oxygen, an =NH group and an =N-OH group, 15 - Ri is chosen from hydrogen, halogens, a nitro group and groups -NR 8 R 9 in which R 8 and R 9 are chosen, independently of each other, from hydrogen and (Ci-C 4 ) alkyl groups, - R 2 is chosen from hydrogen and halogens, 20 - R 3 is chosen from hydrogen, halogens, (Ci-C 4 ) alkyl groups, (C 1 -C 6 ) alkoxy groups, a guanidino group, groups -NRioRii in which R 10 and R 11 are chosen, independently of each other, from hydrogen, (C 1 -C 4 ) alkyl groups, (C 1 -C 4 ) phenylalkyl 25 groups and groups -(CH 2 )n-Y with Y being chosen from halogens and groups CN, -CH(O-Et) 2 , (C 1 -C 6 ) alkoxy, -O-(CH 2 ) 2 -N(CH 3 ) 2 and -N(CH 3 ) 2 and n = 41 to 3, - R 4 is chosen from hydrogen, halogens, 30 nitro groups and groups -NR 12 R 13 in which R 1 2 and R 1 3 are chosen, independently of each other, from hydrogen and (Ci-C 4 ) alkyl groups, - R 5 , R 6 and R 7 are chosen from: - 65 hydrogen or a halogen atom, - 66 Ci-C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl, (C1-C 4 ) alkylcarbonyloxy (C 1 C 4 ) alkyl, -CHO, -COOH, -CN, -C0 2 R 14 , -CONHR 1 4 and CONR 1 4 Ri 5 groups, -NHCOR 1 4 and -NR 1 4 Ri 5 in which R 1 4 and R 15 5 are chosen, independently of each other, from hydrogen and (C 1 -C 6 ) alkyl, -phenyl-CO-CH 3 and -CH 2 -CH 2 -N(CH 3 ) 2 groups, -phenyl-CO-CH 3 or -phenyl-CO-CH=CH N(CH 3 ) 2 , morpholino, nitro or SO 3 H groups, 10 groups: -CH2-N-COOR 16 -CH2-N- COOR 1 6 , CH2- COOR 17 CH2-Ar R 1 6 and R 1 7 being chosen from C 1 -C 6 alkyl groups and 15 Ar being a C 6 -C 1 4 aryl group, with the exclusion of the compounds of formula I in which X = 0, and, either R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 = H, or R 1 , R 3 , R 4 , R 5 , R 6 , R 7 = H and R 2 = Br, or R 1 , R 2 , R 4 , R 5 , R 6 , R 7 = H and R 3 = OCH 3 , or R 1 , R 2 , 20 R 3 , R 4 , R 6 , R 7 = H and R 5 = OH or OCH 3 , or R, = NO 2 and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 = H, and with the exclusion of the compound formula Ia in which X = 0 and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 = H, and the addition salts of these compounds 25 with pharmaceutically acceptable acids. 9. Compounds as claimed in claim 8, of formula I in which: - X is chosen from oxygen, an =NH group 30 and an =N-OH group, - R 1 is chosen from hydrogen, halogens, a nitro group and groups -NR 8 R 9 in which R 8 and R 9 are chosen, independently of each other, from hydrogen and (C 1 -C 4 ) alkyl groups, 35 - R 2 is chosen from hydrogen and halogens, - 67 - R 3 is chosen from hydrogen, halogens, (C 1 -C 4 ) alkyl groups, (C 1 -C 6 ) alkoxy groups, a guanidino group, groups -NRioRii in which R 10 and R 11 are chosen, independently of each other, from 5 hydrogen, (Ci-C 4 ) alkyl groups, (Ci-C 4 ) phenylalkyl, -(CH 2 ) 2 -N(CH 3 ) 2 , and -(CH 2 ) 2 -0-(CH 2 ) 2 N(CH 3 ) 2 groups, - R 4 is chosen from hydrogen, halogens, nitro groups and groups -NR 1 2 R 1 3 in which R 1 2 and R 1 3 10 are chosen, independently of each other, from hydrogen and (Ci-C 4 ) alkyl groups, - R 5 , RE and R 7 are chosen from: hydrogen or a halogen atom, Ci-C6 alkyl, hydroxyl, C 1 -C 6 alkoxy, 15 -CHO, -COOH, -CN, -C0 2 R 1 4 , -CONHR 14 and -CONR 14 R 15 groups, -NHCOR1 4 and -NR 14 R 15 in which R 14 and R 15 are chosen, independently of each other, from hydrogen and (C1-C6) alkyl and -CH 2 -CH 2 -N(CH 3 ) 2 groups, 20 -phenyl-CO-CH 3 or -phenyl-CO-CH=CH N(CH 3 ) 2 , morpholino, nitro or SO 3 H groups, groups: -CH 2 - N - COOR 1 , -CH 2 - N- COOR 16 , CrCOOR 1 7 CH2-Ar 25 R16 and R 1 7 being chosen from CI-C6 alkyl groups and Ar being a C6-C 1 4 aryl group, with the exclusion of the compounds in which X = 0, and, either R 1 , R 2 , R 3 , R 4 , R 5 , R6, R 7 = H, 30 or R 1 , R 3 , R 4 , R 5 , R6, R 7 = H and R 2 = Br, or R 1 , R 2 , R 4 , R 5 , R6, R 7 = H and R 3 = OCH 3 , or R 1 , R 2 , R 3 , R 4 , R6 R 7 = H and R 5 = OH or OCH 3 , or R, = NO 2 and R 2 , R 3 , R, R 5 , RE, R 7 = H, and the addition salts of these compounds with 35 pharmaceutically acceptable acids. - 68 10. Compounds as claimed in claim 8, which are: 5-(dimethylamino)-9H-quino[4,3,2-de][1,10]phenan throlin-9-one, 5-(benzylamino)-9H-quino[4,3,2-de][1,10]phenan 5 throlin-9-one, 5-bromo-9H-quino[4,3,2-de][1,10]phenanthrolin-9-one, 7-amino-9H-quino[4,3,2-de][1,10]phenanthrolin-9-one, 5-amino-9H-quino[4,3,2-de][1,10]phenanthrolin-9-one, 5-methyl-9H-quino[4,3,2-de][1,10]phenanthrolin-9 10 one, 5-chloro-9H-quino[4,3,2-de][1,10]phenanthrolin-9 one, 5-bromo-10-methoxy-9H-quino[4,3,2-de][1,10]phenan throlin-9-one, 15 5-(dimethylamino-2-ethyl)amino-9H-quino[4,3,2-de] [1,10]phenanthrolin-9-one, 5-bis(2-chloroethyl)amino-9H-quino[4,3,2-de] [1,10]phenanthrolin-9-one, 5-(2-chloroethyl)amino-9H-quino[4,3,2-de][1,10] 20 phenanthrolin-9-one, 12-methoxy-9-H-quino[4,3,2-de][1,10]phenanthrolin 9-one, 4-bromo-5-amino-9-H-quino[4,3,2-de][1,10]phenan throlin-9-one, 25 11-acetoxymethyl-9-H-quino[4,3,2-de][1,10]phenan throlin-9-one, 5-bromo-9-H-quino[4,3,2-de][1,7]phenanthrolin-9 one, 5-amino-9-H-quino[4,3,2-de][1,7]phenanthrolin-9 30 one, 5-(dimethylamino-2-ethyl)amino-9-H-quino[4,3,2 de][1,7]phenanthrolin-9-one, 5-bis(chloroethylamino-2-ethyl)amino-9-H-quino [4,3,2-de][1,7]phenanthrolin-9-one, 35 5-(chloroethylamino-2-ethyl)amino-9-H-quino[4,3,2 de][1,7]phenanthrolin-9-one, 4 -bromo-5-amino-9-H-quino[4,3,2-de][1,7]phenan throlin-9-one, - 69 7 -nitro-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9 one, 7 -amino-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9 one, 5 1 2 -methoxy-9-H-quino[4,3,2-d] [1,7]phenanthrolin 9-one, and the addition salts of these compounds with pharmaceutically acceptable acids. 10 11. A process for preparing a compound of formula Ia, in which: - X is chosen from oxygen, an =NH group and an =N-OH group, - R 1 is chosen from hydrogen, halogens, a 15 nitro group and groups -NR 8 R 9 in which R 8 and R 9 are chosen, independently of each other, from hydrogen and (Ci-C 4 ) alkyl groups, - R 2 is chosen from hydrogen and halogens, - R 3 is chosen from hydrogen, halogens, 20 (Ci-C 4 ) alkyl groups, (Ci-C 6 ) alkoxy groups, a guanidino group, groups -NRioRii in which R 10 and R 11 are chosen, independently of each other, from hydrogen, (C 1 -C 4 ) alkyl groups, (Ci-C 4 ) phenylalkyl groups and groups -(CH 2 )n-Y with Y being chosen 25 from halogens and groups CN, -CH(O-Et) 2 , (C 1 -C 6 ) alkoxy, -O-(CH 2 ) 2 -N(CH 3 ) 2 and -N(CH 3 ) 2 and n = 1 to 3, - R 4 is chosen from hydrogen, halogens, nitro groups and groups -NR 12 R 13 in which R 12 and R 13 30 are chosen, independently of each other, from hydrogen and (CI-C 4 ) alkyl groups, - R 5 , R 6 and R 7 are chosen from: hydrogen or a halogen atom, Ci-C 6 alkyl, hydroxyl, C1-C 6 alkoxy, 35 (Ci-C 6 ) alkoxy (Ci-C 6 ) alkyl, (C 1 -C 4 ) alkylcarbonyloxy (C1-C 4 ) alkyl, -CHO, -COOH, -CN, -C0 2 R 1 4 , -CONHR 1 4 and -CONR 1 4 Ri 5 groups, -NHCOR 1 4 and -NR 14 R 1 5 in which R 1 4 and R 1 5 are chosen, independently of each - 70 other, from hydrogen and (C 1 -C 6 ) alkyl, -phenyl-CO CH 3 and -CH 2 -CH 2 -N(CH 3 ) 2 groups, -phenyl-CO-CH 3 or -phenyl-CO-CH=CH N(CH 3 ) 2 , morpholino, nitro or SO 3 H groups, 5 groups: -CH 2 -N-COOR 1 6 -CH2-N-COOR 1 6 , CH 2 -COOR 17 CH 1 2-Ar R1 6 and R 1 7 being chosen from C 1 -C 6 alkyl groups and 10 Ar being a C 6 -C1 4 aryl group, which consists in: a - condensing a chlorobenzoic acid of formula: R1 C1 R2 HO 2 C R 3 15 with a dimethoxyaniline of formula: OMe NH 2 OMe - 71 to give a compound of formula IIa: OMe R1 H N R2 HO 2 C R3 Me 5 b - cyclizing the compound of formula IIa to give a compound of formula: OMe R, R3 OWe 10 c - converting the compound into a quinone of formula IIIa: O R1 N R2 R3 15 d - reacting the quinone of formula IIIa with an azadiene of formula: - 72 R 7 N to give a compound of formula IVa: O R1 R7 N R2 R3 5R5 O R4 5 e - reacting the compound of the formula IVa with dimethylformamide diethyl acetal to give the compound of formula Ia, 10 f - and, optionally, converting the compound thus obtained into another compound of formula Ta. 12. A process for treating patients having a cancer 15 tumor, which consists in administering an effective amount of a compound as defined in claim 1.