AU779932B2 - 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/FR00/02312 Ascididemin derivatives and therapeutic uses thereof The present invention relates to pharmaceutical compositions based on polyaromatic compounds that are 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 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 which has been known for nearly 40 years as one of the 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 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 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 patients, is imperative since, taking once again the example of colorectal tumors, it has been estimated 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 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 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 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 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 isolated from the ascidian Ecteinascidia turbinata.

Among these, ecteinascidin-743 has been the subject of extensive preclinical studies Igbicka et al., NCI-EORTC symposium, 1998; Abst. 130 p. 34), and also clinical trials intended to define its therapeutic potential as an anticancer drug 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., NCI-EORTC symposium, 1998; Abst. 456 p. 119) Novel pentacyclic acridine derivatives have also been the subject of pharmacochemical studies Hagan et al., J. Chem. Soc., Perkin Transf., 1997; 1: 2739-2746).

Another natural alkaloid of marine origin, ascididemin, has been extracted from the tunicate Didemnum sp.

Kobayashi et al., Tetrahedron, lett. 1988; 29: 1177-80) and from the ascidian Cystodytes dellechiajei Bonnard et al., Anti-cancer Drug design 1995; 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. Org. Chem. 1991; 56: 804-8), B. Lindsay et al.

(Bioorg. Med. Chem. Lett. 1995; 5: 739-42) and J. Kobayashi et al. (Tetrahedron lett. 1988; 29: 1177and on the model of human leukemia described by I. Bonnard et al. (Anti-cancer Drug design 1995; 333-46). Several routes for synthesizing ascididemin 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).

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. Ann. Chem. Soc. 1987; 109: 6134-6) and synthesized by F. Bracher et al.

(H6t6rocycles 1989; 29: 2093-95) and then by M.E. Jung et al. (Heterocycles 1994; 39; 2: 767-778).

2-Bromoleptoclinidone shows cytotoxicity on the cellular model of leukemia with an EDso of 0.4 pg/ml.

The cytotoxic properties were confirmed by F. Bracher (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.

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 chemically described (according to the numbering by S.J. Bloor et al. 1987) by various teams such as those of F.J. Schmitz 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 4 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).

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 N R2 R7 N 2 t R R3

\R

3 N RK/ N R Formula I Formula la in which: X is chosen from oxygen, an =NH group and an =N-OH group, RI is chosen from hydrogen, halogens, a nitro group and groups -NR 8 R9 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,

R

3 is chosen from hydrogen, halogens, (Ci-C 4 alkyl groups, (C1-C6) alkoxy groups, a guanidino group, groups -NR 1 oR 11 in which Rio and Rn are chosen, independently of each other, from hydrogen, (Ci-C 4 alkyl groups, (Ci-C4) phenylalkyl groups and groups

-(CH

2 )n-Y with Y being chosen from halogens and CN, -CH(O-Et)2, (Ci-C6) alkoxy, -0-(CH 2 2

-N(CH

3 )2 and -N(CH 3 )2 groups and n 1 to 3, R4 is chosen from hydrogen, halogens, nitro groups and groups -NR 1 2

R

1 3 in which R 12 and R 13 are 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,

C

1

-C

6 alkyl, hydroxyl, C1-C6 alkoxy, (C 1

-C

6 alkoxy (C 1

-C

6 alkyl, (C 1

-C

4 alkylcarbonyloxy (Ci-C4) alkyl, -CHO, -COOH, -CN, -C0 2

R

1 4

-CONHR

14 and -CONR 4

R

5 groups,

-NHCOR

14 and -NR 4

R

1 5 in which R 14 and R 15 are chosen, independently of each other, from hydrogen and (CI-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 morpholino, nitro or SO 3 H groups, groups: -CH2-N-COOR 6 -CH2- N- COOR 16 I I CH2- COOR 17 CH2-Ar

R

1 6 and R 17 being chosen from C-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, and, either: Ri, 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 with the exclusion of the compound formula la containing the combination X O and RI, R 2

R

3

R

4

R

5

R

6

R

7

H,

and the addition salts of these compounds with pharmaceutically acceptable acids.

The present invention relates more particularly to 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, 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, 6 independently of each other, from hydrogen and (CI-C4) alkyl groups,

R

2 is chosen from hydrogen and halogens,

R

3 is chosen from hydrogen, halogens, (C 1

-C

4 alkyl groups, (Ci-C6) alkoxy groups, a guanidino group, groups -NRIoRI1 in which R 1 0 and R 11 are chosen, independently of each other, from hydrogen, (CI-C4) alkyl groups, (Ci-C4) phenylalkyl, -(CH 2 2

-N(CH

3 2 and

-(CH

2 2

-O-(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 are chosen, independently of each other, from hydrogen and (Ci-C4) alkyl groups,

R

5

R

6 and R 7 are chosen from: hydrogen or a halogen atom, Ci-C6 alkyl, hydroxyl, Ci-C6 alkoxy, -CHO, COOH, -CN, -C0 2

R

1 4

-CONHR

14 and -CONRi 4

R

1 5 groups,

NHCOR

1 4 and -NR 4

R

1 5 groups in which R14 and R 15 are chosen, independently of each other, from hydrogen and (Ci-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 S03H groups, groups: -C2 N COOR 6 -CH2-N-COOR 16 CH2- COOR 17 CH2-Ar

R

1 6 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 O, and, either RI, 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 with pharmaceutically acceptable acids.

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, RI is chosen from hydrogen and an amino group,

R

2 is chosen from hydrogen and halogens,

R

3 is chosen from hydrogen, halogens, (C 1

-C

4 alkyl groups, (C 1

-C

6 alkoxy groups, a guanidino group, groups -NRioR 11 in which Ro 1 and R 11 are chosen, independently of each other, from hydrogen, methyl groups, (Ci-C 4 phenylalkyl, (CH 2 2 -N (CH 3 2, (CH 2 (CH2) 2

-N(CH

3 2 groups,

R

4 is chosen from hydrogen, halogens and nitro and amino groups,

R

5

R

6 and R7 represent a hydrogen, with the exclusion of the compounds in which R 1

R

2 R3 R 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 with 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 compound chosen from the compounds of formulae I and Ia in which: 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, (Ci-C4) alkyl groups, (Ci-C6) alkoxy groups, a guanidino group, groups -NRioR 11 in which R 0 o and R 1 are chosen, independently of each other, from hydrogen, methyl groups, (Ci-C4) phenylalkyl groups and groups -(CH 2 )n-Y with Y being chosen from halogens and groups CN, -CH(O- Et) 2 (Cl-C6) alkoxy, -0-(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 is chosen from a hydrogen, a halogen and a methoxy group,

R

6 and R 7 are chosen from hydrogen and CI-C6 alkoxy, (C-C 6 )alkoxy(Ci-C 6 )alkyl and -CH 2

OCOCH

3 groups, with the exclusion of the compounds of formula I in which RI, R 2

R

3

R

4

R

5

R

6 R7 H or RI, R 3

R

4

R

5

R

6

R

7 H and R 2 Br, and of the compound of formula Ia in which RI, R 2

R

3

R

4 Rs, 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 compounds of formula I as defined above, with the exclusion of the compounds in which X O, and either RI, R 2

R

3

R

4 Rs, R 6

R

7

H,

or RI, R 3

R

4

R

5

R

6

R

7 H and R 2 Br, or RI, R 2

R

4

R

5 R6, R 7 H and R 3

OCH

3 or RI, 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 R6, R 7

H,

and the addition salts of these compounds with pharmaceutically acceptable acids.

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 RI, R 2

R

3

R

4

R

5

R

6

R

7

H,

and the addition salts of these compounds with pharmaceutically acceptable acids.

The expression "addition salts with pharmaceutically acceptable acids" denotes salts which give the biological properties of the free bases, without having 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 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, 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 final derivative by cyclization: Scheme I

K

5 0 0 H R H 2 N R 2 R 2 1 O C 2 HOH 0 I CeC13,7H20

R

7 R 3 R7

R

3 O CH o C CH 3 R FonmJla II RS O

R,

RR

2 H250.conc OH HC2H5)2N(CH 3 2 reflux DMF, 120°C Formula III 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 number CRL 8274.

Certain compounds may be prepared directly from ascididemin or from a compound of formula I used as a synthetic intermediate.

Thus, in particular, the compounds of formula I in which R 3 is a group -NRIoR 11 where Rio 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.

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 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 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.

11 Scheme II O M e N H l R O M e H R

R

+H

CU

2 +1

N~HO

2 C

R

3 Ho 2 C R3 OMe R 4 OMe R 4 Formula ila OMe H R, OMe

R

LiOH 3 42

CH

3 00C 3R *OMe R4Oe4

N

R

R

5 0R 4 5 4 Formula Ilia For-mula Iva 0 R* R7~,

R

2 DIMFEA, NHCl 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.

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.

Thus, in particular, the compounds of formula Ia in which R3 is a group -NR!oR 11 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.

S A Preparation of the intermediate products of formula II (Scheme I) A-1 Synthesis of 6-( 2 -acetyl-4-methylphenylamino)quinoline-5,8-dione (Intermediate (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-aminoacetophenone (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 ml of aqueous 10% acetic acid solution and extracted 4 times with chloroform. The organic phases are dried over MgS0 4 and then evaporated. The crude product obtained is purified by flash chromatography on a column of silica (95/5 CH 2 C12/MeOH) to give 0.405 g of the expected tricyclic compound in the form of a powder: Yield 98% 'H NMR (CDC1 3 2.42 3H), 2.77 3H), 6.86 1H), 7.38 (dd, 1H, J 8 and 1.6 Hz), 7.52 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 1H).

A-2 Synthesis of 6-(2-acetyl-4chlorophenylamino)quinoline-5,8-dione (Intermediate A 2 Preparation according to the process described in chapter A-i: quinoline-5,8-dione (0.188 g, 1.18 mmol), cerium chloride (0.88 g, 2.36 mmol), 5-chloro-2aminoacetophenone (0.4 g, 3.14 mmol), ethanol 4 ml), acetic acid (25 ml). 0.3 g of a red powder is obtained: Yield 78% 1H NMR (CDCI 3 2.65 3H), 6.84 1H), 7.52 (dd, 1H, J 8.8 Hz), 7.57 1H, J 8.8 Hz), 7.63 (dd, 1H, J 8 and 4.4 Hz), 7.89 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 1H).

1C NMR (CDC1 3 28.5; 107.36; 121.86; 126.69; 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-4benzylaminophenylamino)quinoline-5,8-dione (Intermediate A 3 Preparation according to the process described in chapter A-i: quinoline-5,8-dione (0.250 g, 1.57 mmol), cerium chloride (0.77 g, 3.14 mmol), 5-benzylamino-2aminoacetophenone (0.603 g, 3.14 mmol), ethanol (15 7 ml), acetic acid (35 ml). 0.56 g of a red powder is obtained: Yield 91% H NMR (CDCI3): 2.54 3H), 4.38 2H), 6.70 1H), 6.83 (dd, 1H, J 9.6 and 3.2 Hz), 7.08 (d, 1H, J 3.2 Hz), 7.30-7.37 5H), 7.43 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 1H).

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

A

4 (CRL 8268) Preparation according to the process described by F. Bracher, Liebigs Ann. Chem. 1990, 205-206.

Synthesis of 6-(2-acetyl-4dimethylaminophenylamino)quinoline-5,8-dione (Intermediate As) Preparation according to the process described in chapter A-i: quinoline-5,8-dione (0.36 g, 2.26 mmol), cerium chloride (1.67 g, 4.49 mmol), 5-dimethylamino-2aminoacetophenone (0.8 g, 4.49 mmol), ethanol 10 ml), acetic acid (50 ml). 1.26 g of a red powder are obtained: Yield 84% H NMR (CDCl 3 2.85 3H), 3.12 6H), 6.72 1H), 6.90 (dd, 1H, J 2.8 and 9.2 Hz), 7.15 (d, 1H, J 2.8 Hz), 7.49 1H, J 9.2 Hz), 7.58 (dd, IH, 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-4methoxyphenylamino)quinoline-5,8-dione (Intermediate A 6 Preparation according to the process described in chapter A-i: quinoline-5,8-dione (3.51 g, 22.08 mmol), cerium chloride (16.4 g, 44.03 mmol), 5-methoxy-2aminoacetophenone (7.29 g, 44.18 mmol), ethanol (200 90 ml), acetic acid (500 ml). 4.25 g of a red powder are obtained: Yield H NMR (CDC13): 2.65 3H), 3.87 3H), 6.76 1H), 7.12 (dd, 1H, J 2.8 and 8.8 Hz), 7.42 (d, 1H, J 2.8 Hz), 7.55 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 A7,) Preparation according to the process described in chapter A-i: 4-chloroquinoline-5,8-dione (3.5 g, 18 mmol), cerium chloride (13.5 g, 36.24 mmol),2aminoacetophenone (4.4 ml, 36 mmol), ethanol (160 70 ml) acetic acid (400 ml). 2.32 g of a red powder are obtained: e Yield 0 1 NMR (CDCl 3 2 .69 3H) 2. 72 3H) 6. 1H) 7. 18 (ddd, 1H, J 6 and 7. 6 and 0. 8 Hz) 7.28 (in, 1H), 7.30 1H, J 6.4 Hz), 7.54-7.59 (in, 3H), 7.63 1H, J 7.6 Hz), 7.91 (dd, 1H, J 1.6 and 8.4 Hz), 7.94 (dd, 1H, J 1.2 and 8.4 Hz), 8.47 1H, J 6.4 Hz), 11.35 1H), 12.35 1H).

A-8 Synthesis of 6-(2-acetyl-4-bromophenylamino)-4- 8-dione (IntermediateA) PreparaLioi according to the process described in chapter A-i: 4-methoxyquinoline-5,8-dione (1.57 g, 9.1 inmol), cerium chloride (3.1 g, 8.3 inmol), 2-aminoacetophenone (Leonard, Boyd, J. Org. Chem. 1946; 11, 419-423) (1.95 g, 9.1 mmol), ethanol (200 ml), 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: 9 Yield 37% 0 1H NMR (CDCl 3 3. 15 3H) 4. 58 3H) 7. 61 1H, J 6 Hz), 7. 74 1H) 7. 99 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 1H, J 6 Hz), 11.68 1H).

A-9 Synthesis of 2-methoxy-6-(2acetyiphenylamino) quinoline-5, 8-dione (Intermediate A 9 A solution of o-aminoacetophenone (0.41 g, 3.1 mxnol) in ethanol (6 ml) is added to a suspension of 2-methoxyquinoline-5,8-dione (0.54 g, 2.8 minol) and cerium 16 chloride (1.16 g, 4.7 mmol) in ethanol (100 ml). The reaction medium is stirred at room temperature for hours. After concentration on a rotary evaporator, the crude product obtained is purified by filtration on silica (98/2 CHC1 3 /heptane) to give the expected codensation product in the form of a red powder (0.35 g).

Yield 38% Melting point 258°C H NMR (CDC1 3 2.67 3H), 4.15 3H), 6.79 1H), 6.98 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 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 1H, J 8.8 Hz).

1C NMR (CDC1 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 Synthesis of 3-hydroxymethyl-6-(2acetylphenylamino)quinoline-5,8-dione (Intermediate A 1 0 a) 3-Hydroxymethyl-5,8-dimethoxyquinoline A solution of 1M LiAlH 4 /Et 2 0 (5 ml, 5 mmol) is added dropwise and under nitrogen to a solution of ethyl 5,8dimethoxyquinoline-3-carboxylate (180 mg, 0.689 mmol) in 60 ml of THF. The mixture is stirred at room temperature for 15 hours and then poured into 15 ml of 1N NaOH and 40 ml of water. After extraction with CH 2 C12 (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 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 0

C

17 1 H NMR (CDC 3 3.92 3H) 4.00 3H), 4.88 2H), 6.72 1H, J 8.4 Hz), 6.88 1H, J 8.4 Hz), 8.47 1H, J 2.2 Hz), 8.87 1H, J 2.2 Hz) 13C NMR (CDC1 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 (CDCI 3 3607, 3417, 1622, 1605 cm b) 3-Hydroxymethyl-5,8-dimethoxyquinoline A solution of 3-hydroxymethyl-5,8-dimethoxyquinoline mg, 0.25 mmol) and cerium ammonium nitrate (550 mg, 1 mmol) in a CH 3

CN/H

2 0 mixture (3 ml/l ml) is stirred at room temperature for 40 minutes. After addition of 5 ml of H20 and 10 ml of saturated NaHCO 3 solution, the medium is extracted with CH 2 C12 (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 (11 mg): Yield 22% Melting point 150°C 1H NMR (CDCl 3 4.95 2H), 7.06 1H, J 10.2 Hz), 7.15 1H, J 10.2 Hz), 8.43 1H), 9.03 1H).

3C NMR (CDCl 3 62.03, 128.86, 132.26, 138.00, 139.11, 141.33, 146.58, 153.10, 183.12, 184.54.

IR (CHC13): 3413, 1680, 1596 cm 1 c) Synthesis of 3-hydroxymethyl-6-(2-acetylphenylamino)quinoline-5,8-dione (Intermediate A 1 0 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 (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 C1 2 /MeOH) to give the expected 18 condensation product in the form of a violet powder (0.16 g): Yield 42% Melting point 258 0

C

IH NMR (DMSO-d) 2.67 3H), 4.73 2H, J Hz), 5.67 1H, J 5.5 Hz), 6.64 1H), 7.30 1H), 7.71 2H), 8.12 1H, J 8.0 Hz), 8.35 1H, J 2.0 Hz), 8.93 1H, J 2.0 Hz), 11.02 1H).

1C NMR (CDC13): 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.

IR (CHC1 3 3440, 1690, 1661, 1640 cm 1 B Preparation of the intermediate products of formula III (Scheme II) B-1 Synthesis of 9,11-dimethyl-1,6-diazanaphthacene- 5,12-dione (Intermediate Bi) (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 Ai (0.4 g, 1.3 mmol) in 12 ml of acetic acid. The reaction medium is refluxed for 30 minutes and, after cooling, is then poured into a beaker containing crushed ice. The mixture is neutralized with and then extracted 4 times with dichloromethane.

The organic phases are dried over MgS0 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 0.325 g of the expected tetracyclic compound.

Yield 86% H NMR (CDC13): 2.64 3H), 3.29 3H), 7.74 (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 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-1,6diazanaphthacene-5,12-dione (Intermediate B 2 Preparation according to the process described in chapter B-1: tricyclic intermediate A 2 (0.289 g, 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 1 H NMR (CDC1 3 3.25 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 1H, J 8.71 (dd, 1H, J 1.6 and 8 Hz), 9.15 (dd, 1H, J 1.6 and 4.8 Hz).

B-3 Synthesis of 9-benzylamino-ll-methyl-1,6diazanaphthacene-5,12-dione (Intermediate B 3 Preparation according to the process described in chapter B-l: tricyclic intermediate A 3 (4 g, 10 mmol), sulfuric acid (15.1 ml), acetic acid (92 75 ml).

After work-up, 3.58 g of tetracycle are obtained.

Yield 98% 1 H NMR (CDC1 3 3.09 3H), 4.52 2H), 4.86 1H), 7.06 1H, J 2.8 Hz), 7.29 (dd, 1H, J 9.2 and 2.8 Hz), 7.3-7.43 5H), 7.71 (dd, 1H, J 4.8 and 8 Hz), 8.20 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-1l-methyl-l,6diazanaphthacene-5,12-dione (Intermediate B 4 Preparation according to the process described by F. Bracher, Liebigs Ann. Chem. 1990, 205-206.

Synthesis of 9-dimethylamino-ll-methyl-1,6diazanaphthacene-5,12-dione (Intermediate Bs) Preparation according to the process described in chapter B-1: intermediate tricycle As (0.76 g, 2.27 mmol), sulfuric acid (3.5 ml), acetic acid 18 ml). After work-up, 0.67 g of tetracycle is obtained.

20 Yield 93% 'H NMR (CDCl 3 3.17 3H), 3.21 6H), 7.04 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 1H, J 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-ll-methyl-1,6diazanaphthacene-5,12-dione (Intermediate Be) Preparation according to the process described in chapter B-1: intermediate tricycle As (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 C1 2 /MeOH) is washed with ethyl ether to give 2.9 g of tetracycle.

Yield 72% H NMR (CDCl 3 3.25 3H), 4.02 3H), 7.49 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 1H, J 9.3 Hz), 8.71 (dd, IH, 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-1,6diazanaphthacene-5,12-dione (Intermediate B 7 (CRL 8332) Preparation according to the process described in chapter B-l: 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

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% 'H NMR (CDCl 3 2.59 3H), 3.25 3H), 7.29 (ddd, 1H, J 7.2 and 7.2 and 1.2 Hz), 7.37 1H, J 6 Hz), 7.54 (ddd, 1H, J 6.8 and 6.8 and 1.6 Hz), 7.59 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 2H), 8.34 1H, J 8.4 Hz), 8.43 1H, J 8.4 Hz), 8.54 1H, 6 Hz), 12.5 1H).

21 B-8 Synthesis of 4-methoxy-9-bromo-ll-methyl-1,6diazanaphthacene-5,12-dione (Intermediate B 8 Preparation according to the process described in chapter B-l: intermediate tricycle As (1.22 g, 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.

Yield H NMR (CDC1 3 3.21 3H), 4.10 3H), 7.18 1H, J 6 Hz), 7.96 (dd, 1H, J 8.8 and 2 Hz), 8.27 1H, J 8.8 Hz), 8.47 1H, J 2 Hz), 8.89 1H, J 6 Hz).

B-9 Synthesis of 2-methoxy-ll-methyl-1,6diazanaphthacene-5,12-dione (Intermediate Bs) A solution of 2-methoxy-6-(2acetylphenylamino)quinoline-5,8-dione (0.34 g, 1.1 mmol) in an acetic acid/sulfuric acid mixture 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

CO

3 and extracted with CHC1 3 (3 x 200 ml). The organic phases are dried over MgS0 4 and then concentrated on a rotary evaporator. The crude product obtained is purified by filtration on silica (CHC1 3 to give the expected tetracycle in the form of a beige-colored powder (0.23 g): Yield 71% Melting point 2600C H NMR (CDC1 3 3.32 3H), 4.23 3H), 7.14 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 (dd, 1H, J 8.6 and 1.2 Hz), 8.46 (dd, 1H, J 8.4 and 1.2 Hz), 8.58 1H, J 8.8 Hz).

13C NMR (CDC1 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 IR %CHCl 3 1683, 1599 cm 1 Synthesis of 3-acetoxymethyl-ll-methyl-1,6diazanaphthacene-5,12-dione (Intermediate B 10 A solution of 3-hydroxymethyl-6-(2-acetylphenylamino)quinoline-5,8-dione (Intermediate Ao 1 (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 minutes. After cooling, the reaction medium is poured into a water/ice mixture (15 ml) and then basified to pH 9 with Na 2 C0 3 The medium is then extracted with CH 2 C1 2 (3 x 150 ml). The organic phases are dried over MgS0 4 and then concentrated on a rotary evaporator. The crude product obtained is purified by 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 Melting point 210°C 1 H NMR (CDCl 3 2.18 3H), 3.30 3H), 5.31 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 1H, J 2.2 Hz), 9.09 1H, J 2.2 Hz).

1C NMR (CDCI 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.

IR (CHC1 3 3420, 1746, 1692 cm 1 C Preparation of the intermediate products of formula IIIa (Scheme II) 1) Synthesis of acid (Compound 4) A mixture of 2-chlorobenzoic acid (9.2 g, 60 mmol), dimethoxyaniline (10 g, 65 mmol), copper (0.96 Cu 2 0 (0.96 g) and K2C03 (10.4 g) in 120 ml of diglyme is 23 refluxed overnight. After evaporating off the solvent, the reaction medium is basified with IN sodium hydroxide. Ether is added and the medium is then filtered through silica and the ether phase is removed.

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 C12) to give the expected condensation product in the form of a yellow powder (14.5 g).

Yield 89% Melting point 138°C H NMR (CDC13): 3.77 3H), 3.85 3H), 6.57 (dd, 1H, J 8.8 and 2.9 Hz), 6.77 (ddd, 1H, J 1.9 and 7.5 Hz), 6.87 1H, J 9.2 Hz), 7.04 1H, J 2.9 Hz), 7.3 to 7.4 2H), 9.35 (broad s, 1H) 13C NMR (CDC1 3 55.76, 56.45, 107.30, 107.71, 112.00, 112.26, 114.70, 117.53, 130.78, 132.60, 134.09, 145.98, 147.71, 153.75, 172.95 IR (CHC1 3 3327, 1685 cm 1 2) Synthesis of 2-(2,5-dimethoxyphenylamino)acetophenone (Compound 16 ml of MeLi (1.4 M/Et 2 0) are added at 0°C 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 with ether (3 x 100 ml). After drying over MgS0 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 Melting point 79°C 'H NMR (CDC1 3 2.64 3H), 3.76 3H), 3.84 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 1H, J 8.8 Hz), 7.04 24 1H, J 2.9 Hz), 7.3 to 7.4 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, 134.35, 145.98, 146.67, 153.62, 201.00 IR (CHC1 3 3350, 1642 cm 3) Synthesis of 1,4-dimethoxy-9-methylacridine (Compound 6) 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 CHCl 3 (3 x 100 ml). After drying over MgS0 4 and evaporating off the solvent, the crude product obtained is purified by filtration through silica (CH 2 C12) to give the expected tricyclic derivative quantitatively in the form of a brown-orange solid.

Melting point 136°C H NMR (CDCl 3 3.36 3H), 3.96 3H), 4.09 3H), 6.68 1H, J 8.0 Hz), 6.89 1H, J 8.4 Hz), 7.54 1H), 7.73 1H), 8.32 1H, J 8.36 1H, J 8.8 Hz) 1C 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 (CHC 3 1685, 1661 cm 1 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

H

2 0 and 0.4 ml of saturated NaHC03 solution, the medium is left stirring and is then extracted with CH 2 C1 2 (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 Melting point 260°C H NMR (CDC1 3 3.22 3H), 7.09 1H, J 10.3 Hz), 7.18 1H, J 10.3 Hz), 7.78 (dd, 1H, J and 8.5 Hz), 7.91 (dd, 1H, 8.5 and 8.5 Hz), 8.32 1H, J 8.43 1H, J 8.5 Hz).

13C NMR (CDCI 3 15.87, 124.40, 125.41, 126.30, 129.61, 132.32, 132.52, 137.88, 141.61, 147.05, 148.23, 151.23, 183.43, 186.69 IR (CHC 3 1701, 1661 cm 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) 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 C12 is stirred under N 2 at room temperature for minutes. After concentrating the solvent, the medium is 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 mg) in 4 ml of toluene is refluxed for 30 minutes.

After concentrating, the crude product obtained is 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% H NMR (CDCl 3 3.32 3H), 7.78-7.83 2H), 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 "C NMR (CDC1 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 IR (CHC1 3 1703, 1663 cm D-2 Syntheasis of 3-methoxy-6-methyl-1,11diazanaphthacene-5,12-dione (Intermediate D 2 3-Methoxy-6-methyl-l,11-diazanaphthacene-5,12-dione is prepared according to the procedure described in D-l, starting with a solution of 9-methylacridine-l,4-dione (Compound 7) (200 mg, 0.896 mmol),2-methoxy-2-propenaldimethylhydrazone (126 mg, 0.984 mmol) and acetic anhydride (1 ml) in 20 ml of CH 2 C12.

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 (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 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.

Yield 67% Melting point 200°C 1 H NMR (CDCl 3 2.69 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 1H, J 8 Hz), 8.50 1H, J 5.6 Hz), 8.78 (dd, 1H, J 2 and 8 Hz), 9.15 (dd, 1H, J 4.8 and 2 Hz), 9.24 1H, J 5.6 Hz) 13C 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 MS 297 296 268 (25.4), 149 (50.3) EXAMPLE 2 5-Chloro-9H-quino[4,3,2-de][1,10]phenanthrolin-9-one (CRL 8301) Preparation according to the process described in 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), 60 mg of the expected compound CRL 8301 are obtained in the form of a yellow solid.

Yield 23% Melting point 200 0

C

H NMR (CDCl 3 7.68 (dd, 1H, J 8.4 and 4.8 Hz), 7.94 (dd, 1H, J 8.8 and 2 Hz), 8.46 1H, J 5.6 Hz), 8.55 1H, J 8.8 Hz), 8.63 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 1H, J 5.6 Hz) "C NMR (CDC1 3 117.07, 118.46, 122.98, 124.82, 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 MS 319 317 (100), 291 290 289 (100).

EXAMPLE 3 -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 (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 Melting point 219°C 'H NMR (CDC1 3 4.61 2H), 5.10 1H), 7.31 (dd, 1H, J 8.8 Hz, J 2.4 Hz), 7.452-7.327 7.55 1H, J 2.4 Hz), 7.63 (dd, 1H, J 4.4 Hz, J 8.4 Hz), 8.29 1H, J 5.2 Hz), 8.36 1H, J 8.8 Hz), 8.79 (dd, 1H, J 1.2 Hz, J 8.4 Hz), 9.13 (dd, 1H, J 4.4 and 1.2 Hz), 9.14 1H, J 5.2 Hz) MS 388 387 (100), 386 385 369 368 (44) EXAMPLE 4 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 (0.25 g, 0.79 mmol) and dimethylformamide diethyl 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 C12/MeOH), 170 mg of the expected compound CRL 8325 are obtained in the form of a violet powder.

Yield 66% Melting point 260°C H NMR (CDCl 3 3.25 6H), 7.45 (dd, 1H, J 9.2 Hz, J 3 Hz), 7.57 1H, J 3 Hz), 7.63 (dd, 1H, J 4.4 and 8 Hz), 8.41 1H, J 9.2 Hz), 8.43 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 1H, J 5.6 Hz) 13C NMR (CDC 3 40.45, 100.84, 116.81, 118.69, 118.99, 125.19, 126.10, 129.46, 134.62, 136.03, 136.30, 139.00, 140.69, 148.16, 149.15, 151.53, 152.47, 154.83, 181.65 MS 326 325 (100), 324 (100), 254 253 (13.4).

29 EXAMPLE 5-Methoxy-9H-quino[4,3,2-de][1,10]phenanthrolin-9-one (CRL 8297) Preparation according to the process described in 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 the expected compound CRL 8297 are obtained in the form of a greenish solid.

Yield 66% Melting point 260 0

C

H NMR (CDCl 3 4.10 3H), 7.62 (dd, 1H, J 9.2 Hz, J 2.4 Hz), 7.66 (dd, 1H, J 4.4 and 8 Hz), 7.96 1H, J 2.4 Hz), 8.48 1H, J 2.4 Hz), 8.54 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 1H, J 5.2 Hz) 3C NMR (CDC1 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 MS 313 312 (100), 285 284 269 242 (32.5).

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 mixture of 45 ml of sulfuric acid and 45 ml of nitric acid at 0°C. The reaction medium is heated at 130°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 rinsed several times with ether. It is then taken up in a 600/1/300 CH 2 C1 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 Melting point 224°C IH 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 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 1H, J 5.6 Hz) 3C NMR (CDC1 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 328 327 (100) 299 297 269 253 242 241 (33).

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, 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 over MgS0 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 260°C 'H NMR (CDC1 3 5.68 2H), 7.16 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 1H, J 7.8 Hz), 8.46 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 1H, J 5.2 Hz).

13C NMR (CDC 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 MS 298 297 (100), 269 268 EXAMPLE 8 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.

The reaction medium is refluxed (stoppered condensor) for 24 hours. After cooling, the mixture is neutralized with saturated NaHC0 3 solution and extracted 4 times with CH 2 C12. The organic phases are dried over MgSO 4 and then evaporated. The crude product obtained is purified 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 0

C

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 1H, J 8.8 Hz), 8.49 1H, J 6 Hz), 8.79 (dd, 1H, J 2 and 8 Hz), 8.82 1H, J 2 Hz), 9.18 (dd, 1H, J 2 Hz, J 4.4 Hz), 9.30 1H, J 6 Hz) 13C NMR (CDC13) 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 363 362 361 (100), 360 255 254 (51).

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 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 C12. 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 powder.

Yield 6% Melting point 260°C H 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 1H, J 2.4 Hz), 8.48 1H, J 6 Hz), 8.50 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 1H, J 6 Hz) 3C NMR (DMSO): 102.26, 117.13, 118.54, 121.62, 123.20, 125.34, 126.11, 129.18, 133.80, 134.83, 135.47, 138.42, 147.65, 148.29, 151.63, 152.39, 154.32, 180.35 MS 298 297 (100), 269 268 EXAMPLE 10-Methoxy-9H-quino[4,3,2-de] [,10]phenanthrolin-9-one (CRL 8368) Preparation according to the procedure described by Y. Kitahara et al., Heterocycles, 1993, 36, 943-946.

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.

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 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 '3y flash chromatography on alumina (99/1 CH 2 C12/MeOH) to give 87 mg of compound CRL 8290.

Yield 87% Melting point 260°C H 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 1H, J 8 Hz), 8.43 1H, J 6 Hz), 8.64 1H, J 8 Hz), 9.04 (dd, 1H, J 8 and Hz), 9.08 (dd, 1H, J 5 and 2.5 Hz), 9.22 1H, J 6 Hz), 12.48 1H) EXAMPLE 13 9H-Quino[4,3,2-de][1,10]phenanthrolin-9-oxime (CRL 8292) 500 mg (1.77 mmol) of ascididemin and 500 mg of NH 2 0H, 1/2 H 2 S0 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 extracted with HCCl 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 powder.

Yield 46% Melting point 260°C H NMR (CDC1 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), 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 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) C NMR (CDC 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 298 268 (100), 266 (21.9) 34 'XAMPLE 14 10-(2-Acetylanilino)-9H-quino[4,3,2-de] 9-one (CRL 8333) 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 by flash chromatography (100/5 CH 2 C1 2 /MeOH), 144 mg of the expected compound CRL 8333 are obtained in the form of a brown-red solid.

Yield Melting point 260°C IH NMR (CDC1 3 2.88 3H), 3.12 3H), 5.54 1H), 7.13 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 1H, J 7.6 Hz), 7.65 (broad s, 1H), 7.69 1H, J 7.6 Hz), 7.88 (ddd, 1H, J 7.6 and 7.6 and 1.2 Hz), 7.96 (ddd, 1H, J 7.6 and 7.6 and 1.2 Hz), 8.48 1H, J 6 Hz), 8.51 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 1H, J 6 Hz) 1C NMR (CDC1 3 37.22, 45.05, 109.94, 113.94, 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 EXAMPLE 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 (CRL 8368) and 40 ml of acetic acid in 100 ml of hydriodic acid are heated at 100 0 C for 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 HCC13 (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 powder.

Yield 41% Melting point 260°C H NMR (DMSO) 6.24 1H, J 7.6 Hz), 6.86 (td, 1H, J 8 and 4 Hz), 7.27 2H, J 4 Hz), 7.57 1H, J 5.2 Hz), 7.89 1H, J 8 Hz), 7.93 (dd, 1H, J 7.6 and 7.6 Hz), 8.51 1H, J 5.2 Hz), 9.54 1H), 12.62 (broad m, 1H), 14.42 1H) 13C NMR (DMSO): 107.81, 109.87, 114.24, 115.36, 116.31, 117.33, 120.11, 120.97, 124.14, 127.63, 132.18, 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) 50 mg (0.09 mmol) of the salt of Example 15 (CRL 8369) dissolved in 4 ml of POC1 3 are refluxed for 2 hours.

After evaporating off the POC13 on a rotary evaporator, the reaction medium is neutralized with saturated NaHCO 3 solution. After several extractions with a 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 CH2C1 2 /MeOH) to give 20 mg of the expected compound CRL 8373 in the form of a yellow powder.

Yield 77% Melting point 260°C H NMR (CDC1 3 7.67 1H, J 5.6 Hz), 7.95 (ddd, 1H, J 8 and 8 and 0.8 Hz), 8.03 (ddd, 1H, J 8 and 8 and 1.2 Hz), 8.57 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 1H, J 5.6 Hz), 9.30 1H, J 5.6 Hz) 36 S13C 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 MS 318 316 290 288 (100), 255 253 (26.8).

EXAMPLE 17 5-Bromo-10-methoxy-9H-quino [4,3,2-de] [1,10]phenanthrolin- 9-one (CRL 8389) Preparation according to the process described in Example 1, starting with the intermediate tetracycle Be (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 CH 2 Cl 2 /MeOH), 210 mg of the expected compound CRL 8389 are obtained in the form of an orange powder.

Yield 42% Melting point 260°C IH NMR (CDC 3 4.14 3H), 7.14 1H, J 5.6 Hz), 8.05 (dd, 1H, J 2 and 8.8 Hz), 8.43 (d, 1H, J 6 Hz), 8.44 1H, J 8.8 Hz), 8.76 1H, *J 2 Hz), 8.95 1H, J 6 Hz), 9.27 1H, 25 J 5.6 Hz) "C NMR (CDC1 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 MS 393 (100), 392 391 390 362 333 254 (34.5) EXAMPLE 18 5-Amino-10-methoxy-9H-quino[4,3,2-de][1,10]phenanthrolin- 9-one 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 for 10 hours. After concentrating, the residue is 37 taken up in IN KOH (35 ml) and then extracted with 95/5

CH

2 C0 2 /MeOH (4 x 200 ml). After drying over MgS0 4 and concentrating on a rotary evaporator, the crude product obtained is purified by flash chromatography on silica (80/20 CH 2 C1 2 /MeOH) to give the expected compound CRL 8389 in the form of a violet powder (65 mg).

Yield Melting point 260°C H NMR (DMSO-d 6 4.07 3H), 6.62 2H), 7.36 1H, J 8.8 Hz), 7.41 1H, J 5.9 Hz), 7.74 1H), 8.08 1H, J 8.8 Hz), 8.48 1H, J 5.2 Hz), 8.86 1H, J 5.9 Hz), 9.08 1H, J 5.2 Hz) IR (KBr): 3420, 3196, 1636, 1616 cm 1 EXAMPLE 19 5-Amino-9H-quino[4,3,2-de] [1,10]phenanthrolin-9-one hydrochloride (CRL 8406) A solution of 5-amino-9H-quino[4,3,2-de] [1,10]phenanthrolin-9-one (1 g, 3.35 mmol) and concentrated HC1 (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 is filtered to recover the expected compound CRL 8406 in the form of a black powder (1 g).

Yield H NMR (DMSO-d 6 7.44 (dd, 1H, J 8.8 and 2.2 Hz), 7.81 1H, J 2.2 Hz), 7.93 (dd, 1H, J 5.6 and 5.9 Hz), 8.12 1H, J 8.8 Hz), 8.66 (d, 1H, J 5.6 Hz), 8.75 1H, J 5.9 Hz), 9.07 1H, J 5.9 Hz), 9.14 1H, J 5.9 Hz) IR (KBr): 3404, 3287, 3170, 1691, 1676, 1649 cm 1 EXAMPLE 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 HC1 (0.3 ml) in 120 ml of CHC1 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 in the form of a navy blue powder (0.97 g).

Yield 87% Melting point 2600C EXAMPLE 21 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 HC1 (0.2 ml) in 40 ml of CHC1 3 is stirred 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).

Yield Melting point 260°C EXAMPLE 22 5-(Dimethylamino-2-ethyl)amino-9H-quino[4,3,2-de]- [1,10]phenanthrolin-9-one (CRL 8419) 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 sodium cyanoborohydride (8.2 g, 130 mmol) is then added portionwise. The reaction medium is then heated and maintained at 95°C. 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 (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 'H NMR (CDCl 3 2.37 6H), 2.62 2H, J 7.32 Hz), 3.70 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 1H, J 3 Hz), 8.35 1H, J 9.2 Hz), 8.38 1H, J 5.7 Hz), 8.79 (dd, 1H, J 8.0 and 1.8 Hz), 9.12 (dd, 1H, J 4.5 and 1.8 Hz), 9.15 1H, J 5.7 Hz) 13C NMR (CDCI3): 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, 152.23, 154.82, 181.37 IR (CHCl 3 1663 cm MS 369 (100), 354 236 (37) EXAMPLE 23 5- (Dimethylamino-2-ethyl) amino-9H-quino 4,3,2de][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 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.

Yield 'H NMR (DMSO-d 6 2.67 6H), 3.09 2H), 4.01 2H), 7.67 (dm, 1H, J 9.2 Hz), 7.80 (dd, 1H, J 8,0 and 4.5 Hz), 7.94 1H), 8.26 1H, J 9.2 Hz), 8.64 1H, J 5.7 Hz), 9.09 1H), 9.12 (dd, 1H, J 4.5 and 1.8 Hz), 9.14 1H, J 5.7 Hz).

EXAMPLE 24 5-Bis(2-chloroethyl)amino-9H-quino[4,3,2-de][1,10]phenanthrolin-9-one (CRL 8422) 40 mmol of sodium cyanoborohydride NaBH3CN (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) in acetic acid (30 ml), at 0°C. The reaction medium is stirred at 0 0 C 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 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 (CHC1 3 and then 99/1 CHC1 3 /MeOH) to give two compounds: CRL 8422 and CRL 8423 (described in Example 5-Bis(chloroethyl)amino-9H-quino[4,3,2-de][1,10]phenanthrolin-9-one (CRL 8422) was obtained in the form of a pink powder (0.14 g): Yield Melting point 220°C IR (KBr): 1666, 1650 cm H NMR (CDC1 3 3.83 4H, J 7.0 Hz), 4.04 4H, J 7.0 Hz), 7.47 (dd, 1H, J 9.5 and 2.9 Hz), 7.66 (dd, 1H, J 8.0 and 4.4 Hz), 7.70 1H, J 2.9 Hz), 8.42 1H, J 5.6 Hz), 8.50 1H, J 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 1H, J 5.6 Hz) 13C NMR (CDC 3 40.16, 53.60, 101.70, 116.60, 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 5- (2-chloroethyl)amino-9H-quino[4,3,2de] [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°C IR (KBr): 3413, 3275, 1654, 1617 cm H NMR (CDC1 3 3.81 2H, J 5.5 Hz), 3.88 2H, J 5.5 Hz), 5.01 (broad s, 1H), 7.34 (dd, 1H, J 8.8 and 2.5 Hz), 7.60 1H, J 2.5 Hz), 7.65 (dd, 1H, J 7.5 and 4.4 Hz), 8.41 1H, J 5.8 Hz), 8.43 1H, J 8.8 Hz), 8.82 (dd, 1H, J 7.5 and Hz), 9.15 (dd, 1H, J 4.4 and 1.5 Hz), 9.21 (dd, 1H, J 5.8 Hz) "C NMR (CDC 3 42.83, 45.01, 100.76, 116.81, 118.78, 120.85, 125.38, 126.35, 129.35, 135.04, 136.04, 136.43, 140.22, 141.56, 148.49 149.41, 152.30, 155.07, 181.57.

EXAMPLE 26 12-Methoxy-9-H-quino[4,3,2-de] [1,10]phenanthrolin-9-one (CRL 8472) 0.54 ml (3 mmol) of dimethylformamide diethyl acetal is added to a suspension of 2-methoxy-11-methyl-1,6diazanaphthacene-5,12-dione (Intermediate B 9 (0.23 g, 0.75 mmol) in DMF (7 ml) under N 2 The reaction medium is heated at 1200C for 1 hour. After concentrating under vacuum, ethanol (45 ml) and NH 4 C1 (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 CHCl 3 (2 x 30 ml). The organic phases are dried over MgS0 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).

Yield 21% Melting point 260°C H NMR (CDC1 3 4.31 3H), 7.04 1H, J 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 1H, J 42 Hz), 8.63 (dd, 1H, J 8.1 and 1.5 Hz), 8.66 (d, il, J 8.5 Hz), 8.67 (dd, 1H, J 8.4 and 1.5 Hz), 9.27 1H, J 5.5 Hz) 13C NMR (CDC 3 54.69, 114.43, 116.75, 118.15, 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 MS 313 312 284 283 (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) Bromine (35 pi, 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 0 C for 6 hours. After concentrating, the medium is basified with sodium hydroxide (20 ml) and then extracted with a 5% MeOH/CHC1 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 CHC13/pentane mixture (152 mg).

Yield 61% Melting point 2600C 1 H NMR (DMSO-d 6 7.07 (broad s, 2H), 7.61 1H, J 8.8 Hz), 7.77 (dd, 1H, J 7.7 and 4.0 Hz), 8.18 1H, J 8.8 Hz), 8.61 1H, J 7.7 Hz), 9.10 1H, J 4.0 Hz), 9.14 1H, J 5.9 Hz), 9.91 1H, J 5.9 Hz) IR (CHC1 3 3501, 3400, 1673 cm 1 MS 378 377 (100), 376 375 (27) EXAMPLE 28 11-Acetoxymethyl-9-H-quino[4,3,2de][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-ll-methyl-l,6diazanaphthacene-5,12-dione (Intermediate B 10 (0.11 g, 0.31 mmol) in DMF (4 ml) under N 2 The reaction medium is heated at 120 0 C for 1 hour. After concentrating under vacuum, ethanol (25 ml) and NH 4 C1 (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 CHC13 (2 x 30 ml). The organic phases are dried over MgS0 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.

Yield Melting point 206-210°C H NMR (CDCl 3 2.19 3H), 5.32 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 1H, J 5.5 Hz), 8.64 (dd, 1H, J 1.1 and 8.4 Hz), 8.71 (dd, 1H, J 1.1 and Hz), 8.77 1H, J 2.4 Hz), 9.14 1H, J 2.4 Hz), 9.28 1H, J 5.5 Hz) MS 355 313 (100), 296 267 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-l,11diazanaphthacene-5,12-dione (Intermediate Di) (52 mg, 0.875 ml) under N 2 The reaction medium is heated at 120 0 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 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 CH 2 C1 2 /MeOH) to 44 give the expected compound CRL 8529 in the form of a yellow solid (6 mg).

Yield 11% H NMR (CDCl 3 7.78 (dd, 1H, J 8.1 and 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 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 1H, J 5.9 Hz), 9.27 1H, J 1.9 and 8.1 Hz) "C 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 283 255 (100) 228 EXAMPLE 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-Hquino[4,3,2-de][1,7]phenanthrolin-9-one (CRL 8529) 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.

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 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 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 mrnol); dimethylformamide diacetal (4 ml, 21.9 minol); trifluoroacetic acid (12.5 ml, 83 mmol); sodium cyanoborohydride (4.1 g, 65 mmol); 900C for 8 hours.

EXAMPLE 33 (chloroethylamino-2-ethyl)amirio-9-H-quino[4 ,3,2de] [1,7]phenanthrolin-9-one (CRL 8841) Compound CRL 8841 is prepared according to the procedure described in Example 24, starting with 5-amino-9-H-quinoll4,3,2-de] f1,7]phenanthrolin-9-one (CRL 8836) (1 g, 3.95 mmol); chioroacetaldehyde (2.6 ml, 16.8 mmol); acetic acid (30 ml); sodium cyanoborohydride 63 g, 10 mmol) 30 minutes at room temperature.

EXAMPLE 34 (Chloroethylamino-2-ethyl) amino-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9-one (CRL 8842) 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 4-Bromo-5-amirio-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[14, 3,2-de] [l,7]phenanthrolin-9-one (CRL 8836) (0.6 g, 2.01 mmol); 24 ml of acetic acid; bromine (35 il, 0.67 mmol); 5000 for 6 hours.

EXAMPLE 36 7-Nitro-9-H-quino[4 ,3,2-de] [1,7]phenanthrolin-9-one (CRL 8838) Compound CRL 8838 is prepared according to the procedure described in Example 6, starting with 9-Hquino[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; 130 0 C for 2 hours.

EXAMPLE 37 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 7nitro-9-H-quino[4,3,2-de][1, 7 ]phenanthrolin-9-one (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 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-l,11-diazanaphthacene-5,12-dione (Intermediate D 2 (0.76 g, 25 mmol); dimethylformamide diacetal (2 ml, 11.67 mmol); 120 0 C for 30 minutes;

NH

4 C1 (4.5 500 ml of ethanol; refluxed for minutes.

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.

1 Determination of the maximum tolerated dose (MTD) The evaluation of the maximum tolerated dose was performed on 4- to 6-week-old B6D2Fl/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 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: 48 TABLE I Compounds CRL MTD (mg/kg) CRL 8274 (Ascididemin) CRL 8269 (2-bromoleptoclinidone) CRL 8323 (Example 1) CRL 8301 (Example 2) 160 CRL 8241 (Example 3) 160 CRL 8325 (Example 4) 160 CRL 8297 (Example 5) 160 CRL 8289 (Example 6) CRL 8344 (Example 7) 160 CRL 8248 (Example 8) 160 CRL 8347 (Example 9) 160 CRL 8292 (Example 13) 160 CRL 8290 (Example 12) 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) CRL 8418 (Example 23) CRL 8422 (Example 24) 160 CRL 8423 (Example 25) 160 The majority of the products described in the family of 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 colorimetric test. The principle of the MTT test is based on the mitochondrial reduction by metabolically active live cells of the yellow product MTT dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) into a blue product, formazan. The amount of formazan 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 37 0 C 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: with an amount of 5% FCS (Fetal Calf Serum) decomplemented at 56 0 C for 1 hour, with 0.6 mg/ml of L-glutamine, with 200 IU/ml of penicillin, 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, 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 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: 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.

Experimentally: 100 pil of a cell suspension containing 000 to 50 000 (depending on the cell type used) cells/mL of culture medium are inoculated in flatbottomed 96-well multi-well plates and are incubated at 37°C under an atmosphere comprising 5% CO2 and humidity. After incubating for 24 hours, the culture medium is replaced with 100 p1 of fresh medium containing either the various test compounds at concentrations ranging from 10 5 to 10-10 M or the 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 p1l of a yellowish solution of MTT dissolved at a rate of 1 mg/mL in RPMI 1640. The microplates are reincubated for 3 hours at 37°C 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 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 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 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- 373MG, SW 1088, T24, J82, HCT-15, LoVo, MCF7, T-47D, A549, A-427 and PC-3 with a 50% inhibitory concentration (ICso) which is between 10-6M and 10- 0

M,

depending on the compounds and the tumor lines tested.

By way of example, the values of the concentrations flanking the IC50 values which are obtained on the various cell lines are given in Table II: 52 TABLE II COMPOUNDS CELL LINES, CRL U-87MG U-373MGI SWIMS T24 I£82 ticr-is I ivO MCV7 IT-471) A549 IA-4427 IPC*3 CR18S289 110.10-'I lI0'.I0*' 1101,10"I i10.I5.'i 1b0'.i0'l 110",10"1 110,I0',1"1 110',10"1 il0',l0_'l 110",10"1 110',10'1I CRL189 1101.101 110',I0'1 II0'.IB'I 110".5-1 110-1.10I 110'.10 0".I 0-72O1 104.201 120'.10.'I flO'.10-1I 1101,10-11 II0t',*' CRL329 110'.10"I ilo'.2o'I Iloi0'11 Ito '1o' Ia'. 110'.10'I i.O'I I I"O',ID iI0" 0lf'0'I 110'.iO'i 110'.l011 I20'1.10 CRI.8241 111,.l'I I 'l Iloio'. 10'l oo'l .1 1,0.,Io 1.10 2 1100.11 110 ',10-I11 0.210'i l10i 12 I0I'I CRL.S297 110-.10 '1 110'. ,10' 1 4.10'1 111'.11 110'.1041 110'.l0' I 110' 1'I 120 iwo l~o-'to'I iio',,o 1 i1'',9 CR1.8344 110',10-'l l1e0' I 110. j1,10 20-11 i1ol.io i 110.1,104 11'.10' I 220'l'I 110"10.)1 110'.10.) II0*'Iot'i il0',I0'I CR1J8323 110".10'11 110". 101 110',10'1It11'.10'I Im0.)d 110-1,10'1 Il0'.Io0'I 1lW1.10'1 II0'Ilo'l 220"' 110'1 Io.Io'i 10' I11 CR1J36 110-.',11 111)",1'1 1101101 It811 ID'I ,1-1 120411011 110 oI 0 1 lio1011 110,10.11 110'.101 II0'.10-1 1101,10.9 CR1337341 110",10'I 110",10'1 I10O',10'1 Ito-'.10'I 1104.2011 f.01 1 1 110-1.1011 11O0_'I 10'lI II'1D 10'.10'1 II0-',10* II0'202 CR183.17 110.01181.01 ioo.io'l1111 110'.1011 ji,'.I0 i iIto'.I0' 1101,10'I 110 aO'l IGl'.l0'I 110"1.)' II0'.W0'l liot'w CRIJ3S96 110' '.10 1 i210I'l :io',io'i ilo',,0' 1101,l0 1 110"'10.)' "0I 1101,10-11 II0'.I0 'I 110',0' I0.) 1 l04.10)I CRI.8369 110-11011I to ,joll 10.1 I*W1 220. 1011 1101,10 I 10104-1 110.1.2041 11'j10'I j11.l 10'.1 It0-,,20' CR1331273 I101,1 .I0I 1.I0'1 130'' I1t0'I 110.10' 112'. I 0'I >0.1 0.I ,0"1 i1io' l 110.,Is'i ItoI0 .0'1 >0' CRL8324 110.10'1 11>'101 >20-1o' >2r"01 >0'01 I10'.010 01 I'l10'.2O' II0'.OIii''i101041 119"101','181 I0'I CRI.3322 110.1,1041l 110'.10"I t120.'.iO'I Il0'.21 110',10' 110',10' 110',10I 110.10"1120 1104.10'I110.o'12042 1104,1011 1 4 1 i'4'i 1 3CR.8343 110".10,1 >0tojg4 2 >2 10I 110lo I 110,11011I0-1,I011 110 .10 '11-,041 010 41 1.14 Inhibitory concentrations flanking the value of the inhibitory concentration of the compounds of formula I, or on the cell lines 53 Table III gives the results of the average IC 50 values (in nM) (calculated from the cytotoxic activity on the 12 tumor lines studied) and the MTD/IC 50 ratios (these ratios are calculated by forming the ratio of the MTD values and the ICso values expressed as numbers without units).

TABLE III Compounds CRL IC 50 (nM) MTD/IC 50 MTD/ICs 0 CRL 8274 CRL 8274 100 0.20 1 (Ascididemin) CRL 8269 CRL 8269 120 0.33 2 (2-bromoleptoclinidone) CRL 8289 (Example 6) 10 2.00 CRL 8248 (Example 8) 80 2.00 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 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 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 the ratio MTD/IC 50 for the estimated by taking as reference ascididemin.

various compounds was a ratio equal to 1 for The compounds described show, on the tumor cell line models, IC 50 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 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 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 ascididemin. They are thus characterized by better therapeutic manageability. CRL 8289, whose IC50 value is nM, also shows better therapeutic manageability than ascididemin.

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.

The compounds of formulae I and Ia are generally administered in dosage units established either per m 2 of body surface or per kg of weight. Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed 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 body surface, preferably at doses from 0.5 to 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 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 administration, mixed with conventional pharmaceutical supports that are suitable for human therapy. The suitable unit forms of administration comprise oralroute forms such as tablets, which may be splittable, or gel capsules, implants and intravenous administration forms.

For a parenteral administration (intravenous infusion at a constant flow rate), sterile aqueous suspensions, sterile isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or solubilizing agents, for example propylene glycol, polyethylene glycol or a cyclodextrin, are used.

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 as Tween 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 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.

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.

The active principle may also be formulated in the form of microcapsules or microspheres, optionally with one or more supports or additives.

The active principle may also be presented in the form of a complex with a cyclodextrin, for example 0- or y-cyclodextrin,2-hydroxypropyl-(-cyclodextrin or methyl-P-cyclodextrin.

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 testicular tumors.

P %OPERVk\70124-00 spc do-23/1 104 -56a- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

*.o *°oo **o*o

Claims (12)

1. A pharmaceutical composition comprising an effective amount of a compound chosen from the compounds of general formulae I and Ia below for treating, by virtue of their cytotoxic properties, cancerous tumors and their metastases: R X R, X R, R6 N R2 R7 N N F N R R R *R5 R, N, R4 Formula I Formula la in which: X is chosen from oxygen, an =NH group and an =N-OH 10 group, 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, 15 R 3 is chosen from halogens, (Cl-C4) alkyl groups, (CI-C6) alkoxy groups, a guanidino group, groups -NRioR 11 in which Rio and R 11 are chosen, independently of each other, from hydrogen, (C1-C4) alkyl groups, (C1-C4) phenylalkyl groups and groups -(CH 2 )n-Y with Y being chosen from halogens and CN, CH (O-Et)2, (C0-C6) alkoxy, (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 R 13 in which R 12 and R 13 are chosen, independently of each other, from hydrogen and (Cl-C4) alkyl groups, Rs, R 6 and R 7 are chosen from: P \OPER k\70124-00 sp doc-23] 1/4 -58- hydrogen or a halogen atom, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, (Ci- C 6 alkoxy (Ci-C 6 alkyl, (C1-C4) alkylcarbonyloxy- (Ci- C4)alkyl, -CHO, -COOH, -CH, -C0 2 R 1 4 -CONHR 14 and -CONRi 4 R 1 5 groups, -NHCOR 14 and -NR 1 4 R 15 in which R 14 and R 15 are chosen, independently of each other, from hydrogen and (CI-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, morpholino, nitro or SO 3 H groups, "groups: -CH 2 N -COOR 16 -CH 2 N -COOR16 S* CH 2 COOR 1 7 CH 2 Ar R 16 and R 17 being chosen from C 1 -C 6 alkyl groups and Ar being a C6-C 1 4 aryl group, 15 and the addition salts of these compounds with pharmaceutically acceptable acids.

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, 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 (C 1 -C 4 alkyl groups, R 2 is chosen from hydrogen and halogens, R 3 is chosen from halogens, (Ci-C4) alkyl groups, (C1-C6) alkoxy groups, a guanidino group, groups -NRioR 11 in which Rio and R 11 are chosen, independently of each other, from P \OPERPxk\70124-00 spe doc-23/1 l4 -59- hydrogen, (C 1 -C 4 alkyl groups, (C 1 -C 4 phenylalkyl, -(CH 2 2 N(CH 3 and -(CH 2 )2-O-(CH 2 2 -N(CH 3 )2 groups, R 4 is chosen from hydrogen, halogens, nitro groups and groups -NR 12 R 13 in which R 12 and R 13 are chosen, independently of each other, from hydrogen and (C1-C4) alkyl groups, R 5 R 6 and R 7 are chosen from: hydrogen or a halogen atom, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, -CHO, -COOH, -CN, -C0 2 R 1 4 -CONHR 14 and -CONR 4 R 1 5 groups, -NHCOR 14 and -NR 1 4 R 1 5 groups in which R 14 and R 15 are chosen, independently of each other, from hydrogen and (Ci-C6) S" 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, e 15 groups: -CH 2 N -COOR16 -CH 2 N -COOR 16 CH 2 COOR17 CH2 Ar R 16 and R 17 being chosen from Cl-C6 alkyl groups and Ar being a C6-C14 aryl group, and the addition salts of these compounds with pharmaceutically acceptable acids.

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: 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 halogens, (Ci-C4) alkyl groups, (CI-C6) alkoxy groups, a guanidino group, groups -NRIoR 1 1 in which Rio P \OPER\Pxk\70 24-00 spe do-23/1 I4 and R 11 are chosen, independently of each other, from hydrogen, methyl groups, (C 1 -C 4 phenylalkyl, -(CH 2 2 -N(CH 3 )2, -(CH 2 )2-O-(CH 2 2 -N(CH 3 )2 groups, R 4 is chosen from hydrogen, halogens and nitro and amino groups, R 5 R 6 and R7 represent a hydrogen, and the addition salts of these compounds with pharmaceutically acceptable acids.

4. The pharmaceutical composition as claimed in claim 1, comprising an effective amount of a compound chosen from the compounds of formulae I and la in which: X represents oxygen, RI is chosen from hydrogen and an amino group, R 2 is chosen from hydrogen and halogens, i- R 3 is chosen from halogens, (Ci-C 4 alkyl groups, (Ci-C 6 alkoxy groups, a guanidino group, groups -NRioR 11 in which R 10 D and R 11 are chosen, independently of each other, from hydrogen, methyl groups, (C 1 -C 4 phenylalkyl groups and 20 groups -(CH 2 )nY 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, 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, R 6 and R 7 are chosen from hydrogen and Ci-C 6 alkoxy, (Cl- C 6 )alkoxy(Cl-C 6 )alkyl and -CH 2 0COCH 3 groups, and the addition salts of these compounds with pharmaceutically acceptable acids. P \OPE.R\P-kk7OI 24.00 sp 8oc.2311I 1A4 -61 The composition as claimed in claim 4, in which the compounds are chosen from:

5-(dimethylamino)-9H-quino[4,3,2-de} [1,10]phenanthrolin-9- one, 5-(benzylamino)-9H-quino[4,3,2-de] [1,lO]phenanthrolin-9-one, 5-bromo-9H-quino[4,3,2-de] [l,1O)phenanthrolin-9-one, 5-amino-9H-quino[4,3,2-de] [1,1O]phenanthrolin-9-one, 5-methyl-9H-quino[4,3,2-de] [l,10]phenanthrolin-9-one, 5-methoxy-9H-quino[4,3,2-de] [1,10]phenanthrolin-9-one, 5-chloro-9H-quinoll4,3,2-del [1,l0]phenanthrolin-9-one, 5-bromo-1O-methoxy-9H-quino[4,3,2-de] [1,1O]phenanthrolin-9- one, (dimethylamino-2-ethyl) amino-9H-quino [4,3,2- :4 de] 1O]phenanthrolin-9-one, 5-bis (2-choroethy].) amino-,9H--t1ui r- r A i r i J phenanthrolin-9-one, 4***5-(2-chloroethyl)amino-9H-quino[4,3,2-de)(l,1O1- phenanthrolin-9-one, 4 4-bromo-5-amino-9-H-quino[4,3,2-de] [1,1O]phenanthrolin-9- one, 5-bromo-9-H-quino[4,3,2-de] (l,7]phenanthrolin-9-one, 5-amino-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9-one, (demethylamino-2-ethyl) amino-9-H-quino [4,3,2- de] [l,7]phenanthrolin-9-one, 5-bis(chloroethylamino-2-ethyl)amino-9-H-quino-[4,3,2- de] [1,7]phenanthrolin-9-one, (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] [l,7]phenanthrolin-9-one, and the addition salts thereof with pharmaceutically acceptable acids. P %OPERN\ 1,7O12--0 sp dM-2 II IN~ 62

6. The use of a compound as defined in one of claims 1 to for the manufacture of an anticancer drug.

7. The use as claimed in claim 6, in which the compounds are chosen from: 5-(dimethylamino)-9H-quino[4,3,2-de] [1,l0]phenanthrolin-9- one, 5-(benzylamino)-9H-quino[4,3,2-de] [l,1O]phenanthrolin-9-one, 5-bromo-9H-quino[4,3,2-de] [l,lO]phenanthrolin-9-one, 5-amino-9H-quino[4,3,2-de] [l,1O)phenanthrolin-9-one, 5-methyl-9H-quino[4,3,2-de] [1,lO]phenanthrolin-9-one, 5-methoxy--9H-quino[4,3,2-de] [l,lO]phenanthrolin-9-one, 5-chloro-9H-quino[4,3,2-de] [l,10]phenanthrolin-9-one, 5-bromo-1O-methoxy-9H-quino[4,3,2-de] [l,lO]phenanthrolin-9- one, 5-(dimethylamino-2-ethyl)amino-9H-quino[4,3,2-de][1~,10]phen- anthrolin-9-one, 5-bis(2-chloroethyl)amino-9H-quino[4,3,2-de] [l,l0]phenan- throlin- 9-one, 5-(2-chloroethyl)amino-9H-quino[4,3,2-de] (l,lO]phenan- throlin- 9-one, 4-bromo-5-amino-9-H-quino[4,3,2-de] [l,l0]phenanthrolin-9- one, 5-bromo-9-H-quino[4,3,2-de] [l,7]phenanthrolin-9-one, 5-amino-9-H-quinol4,3,2-de] [1,7]phenanthrolin-9-one, 5-(dimethylamino-2-ethyl)amino-9-H-quino[4,3,2-de] phenanthrol in-9-one, (chloroethylamino-2-ethyl) amino-9-H-quino[4, 3,2- de] [l,7]phenanthrolin-9-one, 5-(chloroethylamino-2-ethyl)amino-9-H-quino[4,3,2-de] phenanthrolin-9-one, 4-bromo-5-amino-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9-one, P %OPER\PL\701244)00 doc.23/li O -63- and the addition salts thereof with pharmaceutically acceptable acids.

8. Compounds of general formulae I and Ia Re N R 2 R7) N R, R7 N R3 R3 N R RR5 NI R 4 Formula I Formula la in which: X is chosen from oxygen, an =NH group and an =N-OH group, S- Ri is chosen from hydrogen, halogens, a nitro group and groups -NReR 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, R 3 is chosen from halogens (Ci-C4) alkyl groups, a guanidino group, groups -NRloR 11 in which R 10 and R 11 are 15 chosen, independently of each other, from hydrogen, (Ci-C4) S**o alkyl groups, (CI-C4) phenylalkyl groups and groups -(CH 2 )n-Y with Y being chosen from halogens and CN, -CH(O-Et) 2 (CI-C6) alkoxy, -0-(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 13 in which R 12 and R 13 are chosen, independently of each other, from hydrogen and (CI-C4) alkyl groups, R 5 R 6 and R 7 are chosen from: hydrogen or a halogen atom, CI-C6 alkyl, hydroxyl, Ci-C6 alkoxy, (Cz- C6)alkoxy(Ci-C6)alkyl, (C1-C6) alkylcarbonyloxy (Ci- P WOERTWd7O240 W~ 311 V4 64 C 4 )alkyl, -CHO, -COOH, -CN, -C0 2 R 1 4 -CONHR1 4 and -C0NR 14 R 15 groups, -NHCOR 14 and -NR 14 R 1 5 in which R 14 and R 1 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 (CR 3 2, morpholino, nitro or S0 3 H groups, groups: -CH 2 N -C00R 16 -CH 2 N -C00R 16 OH 2 C00R 17 CH 2 Ar 000 10 R 1 6 and R 1 7 being chosen from C 1 -C 6 alkyl groups and Ar being a C 6 -C 1 4 aryl group, *and the addition salts of these compounds with 'fgee pharmaceutically acceptable acrids. 0 00 0: o* %6 0 0000 P %OPERU\P 7012400 Sp do.-2311 I/O4

9. Compounds as claimed in claim 8, of formula I in which: X is chosen from oxygen, an =NH group and an =N-OH group, R is chosen from hydrogen, halogens, a nitro group and groups -NReR 9 in which R 8 and R9 are chosen, independently of each other, from hydrogen and (C1-C 4 alkyl groups, R 2 is chosen from hydrogen and halogens, R 3 is chosen from halogens, (C1-C4) alkyl groups, a guanidino group, groups -NRioR 11 in which Rio and R 11 are chosen, independently of each other, from hydrogen, (Ci-C4) alkyl groups, (C 1 -C 4 phenylalkyl, -(CH 2 2 -N(CH 3 and -(CH 2 )2--(CH 2 2 -N(CH 3 2 groups, R 4 is chosen from hydrogen, halogens, nitro groups and groups -NR 1 2 R 13 in which R 12 and R 13 are chosen, independently 15 of each other, from hydrogen and (CI-C4) alkyl groups, o«oo o o P %0PERVP~k\7OI24.00 Spe dMc.2311 t104 66 R 5 R 6 and R7 are chosen f rom: hydrogen or a halogen atom, C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, -CR0, -COON, -CN, -C0 2 R 1 4 -CONHR 14 and -C0NR 14 RI 5 groups, -NHCOR 14 and -NR 14 R 15 in which R 14 and R 1 5 are chosen, independently of each other, from hydrogen and (C 1 -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 and S0 3 H groups, groups: P %OPER WO0240 d.2311 M4 -67- CH 2 -N-C0R 1 6 -R N-C0R 1 6 CH 2 -C00R 17 CH 2 -Ar R 16 and R 17 being chosen from 0 1 -C 6 alkyl groups and Ar being a C 6 -C 14 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 R7 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 R 3 R 4 R 6 R 7 =H and R 5 OH or OCH3, or R, NO 2 and R 2 R 3 R 4 R 5 R 6 R 7 =H, and the addition salts thereof with pharmaceutically acceptable acids. Compounds which are: (direthylamino)-9H-quino--4,3,2-de] l0]phenanthrolin-9- one, 5- (benzylamino)-9H-quino[4,3,2-de] [l,10]phenanthrolin-9-one, 5-bromo-9H-quino[4,3,2-de] [l,10]phenanthrolin-9-one, 7-amino-9H-quino[4,3,2-de] [l,10]phenanthrolin-9-one, 5-amino-9H-quino[4,3,2-de] [l,l0]phenanthrolin-9-one, 5-methyl-9H-quino[4,3,2-de] 10]phenanthrolin-9-one, 5-chloro-9H-quino[4,3,2-de] 10]phenanthrolin-9-one, 5-bromo-10-methoxy-9H-quino[4,3,2-de] l0]phenanthrolin-9- one, 5-(dimethyloamino-2-ethyl)amino-9H-quino[4,3,2- de] l0]phenan-throlin-9-one, 5-bis-(2-chloroethyl)amino-9H-quinot4,3,2-de] phenanthrol in- 9-one, (2-chloroethyl)amino-9H-quino(4,3,2-de] [1,10] phenanthrol in- 9-one,

12-methoxy-9-H-quino[4,3,2-de] 10]phenanthrolin-9-one, 4-bromo-5-amino-9-H-quino(4, 3, 2-de] 10]phenanthrolin-9-one, 68 11-acetoxymethyl-9-H-quino[4,3,2-de] [1,l1iphenanthrolin- 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, (dimethylamino-2 -ethyl) amino- 9-H-quino[(4, 3,2-de] phenanthrolin-9-one, s (chloroethylamino-2 -ethyl) amino- 9-H-quino C4, 3, 2-de] 7]phenanthrolin-9-one, (chloroethylamino-2 -ethyl) amino- 9-H-quino 3, 2-de] phenanthrolin-9-one, 4-bromo-5-amino-9-H-quino[4,3,2-deI [1,7]phenanthrolin-9- one, 7-nitro-9-H-quino[4,3,2-de] [1,7]phenanthrolin-9-one, 7 -amino- 9-H-quino 3,2-de] C 1, 7 ]phenanth-rolin-9-one, 12-methoxy-9-H-quinojj4,3,2-de] [1,7]phenanthrolin-9-one, and the addition salts thereof with pharmaceutically acceptable acids. 1.A process for preparing a compound of formula Ia, 'n wijl-'c. X is chosen from oxygen, an =NH group and an =N-OH group, R, 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 (Cl-C 4 alkyl groups, R 2 is chosen from hydrogen and halogens, R 3 is chosen from hydrogen, halogens, (Cl-C 4 alkyl groups, (Cl-C 6 alkoxy groups, a guanidino, group, groups -NR 1 0 R 11 in which R 10 and R 11 are chosen, independently of each other, from hydrogen, (Cl-C 4 alkyl groups, (Cl-C 4 phenylalkyl groups and groups -(CH 2 )n-Y with Y being chosen from halogens and CN, -CH(O-Et) 2 (Cl-C 6 alkoxy, (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 RI 3 in which R 12 and R 1 3 AMENDED SHEET 69 are chosen, independently of each other, from hydrogen and (C1-0 4 alkyl groups, -R 5 R 6 and R 7 are chosen f rom: hydrogen or a halogen atom, 01-06 alkyl, hydroxyl, 01-06 alkoxy, (01-06) alkoxy (Cl-C 6 alkyl, (C 1 -0 4 alkylcarbonyloxy- (C 1 -0 4 alkyl, -CHO, -COOH, -ON, -C0 2 R 14 -OONH-R 14 and -C0NR 14 R, 5 groups, -NHCOR 14 and -NR 14 R 15 in which R 14 and R 15 are chosen, independently of each other, from hydrogen and (0 1 -C 6 alkyl, -phenyl-CO- OH 3 and -CH 2 -CH 2 -N (OH 3 2 groups, -phenyl-CO-CH 3 or -phenyl-O-H=OH- N(0H 3 2 morpholino, nitro or S0 3 H groups, groups: -C12 -N -00R 1 6 ,-CH2 -N-C0R 16 CH 2 -COOR 17 CF Ar R 16 and R 17 being chosen from 01-06 alkyl groups and Ar being a 06-014 aryl group, which consists in: a condensing a chlorobenzoic acid of formula: GI R H0 2 C R with a dimethoxyaniline of formula: AMENDED SHEET 70 OMe .NH 2 OMe to give a compound of formula IIa: b cyclizing the compound of formula IIa to give a compound of formula: SOMe RI c converting the compound into a quinone of formula IIIa: AMENDED SHEET 71 0 R4 d reacting the quinone of formula IIIa with an azadiene of formula: to give a compound of formula IVa: e reacting the compound of the formula IVa with dimethylformamide diethyl acetal to give the compound of formula Ia, f and, optionally, converting the compound thus obtained into another compound of formula Ia. AMENDED SHEET 72 12. A process for treating patients having a cancer tumor, which consists in administering an effective amount of a compound as defined in claim 1.

13. A process for preparing compounds of general formula I, of formula: R 5 O R, R6 N 2 R7 X6 R4 R3 N R4 in which: R is chosen from hydrogen, halogens, a nitro group and groups -NRsR9 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, (Ci-C 4 alkyl groups, (Ci-C 6 alkoxy groups, a guanidino group, groups -NRioR 1 in which Rio 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 from halogens and CN, -CH(O-Et) 2 (Cl-C 6 alkoxy, -O-(CH 2 2 -N(CH 3 2 groups and -N(CH 3 2 and n 1 to 3, R 4 is chosen from hydrogen, halogens, nitro groups and groups -NR 1 2 R 1 3 in which R 12 and R 13 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, AMENDED SHEET 73 Cl-C 6 alkyl, hydroxyl, C 1 -C 6 alkoxy, (C 1 -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 14 and -C0NR 14 R 1 5 groups, -NHCOR 14 and -NR 14 R 15 in which R 1 4 and R 15 are chosen, independently of each other, from hydrogen and (C1-C 6 alkyl, -phenyl-CO- CH 3 and -CH 2 -CH 2 -N (OH 3 2 groups, -phenyl-CO-CH 3 or -phenyl-CO-CH=CH- N(CH 3 2 morpholino, nitro or S0 3 H groups, groups: -CH 2 N -C0R 1 6 -CH 2 -N-COOR 16 CK2 -COOR 1 7 Urt-Ar R 1 6 and R 17 being chosen from Cl-C 6 alkyl groups and Ar being a C 6 -C 1 4 aryl group, with the exclusion of the compounds of formula I in which either R. 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 RI, R 2 R 3 R 4 R 6 R7, 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, which consists a) in reacting a hydroquinone of formula R 5 0 R 6 Rj'N 0 with a compound of formula AMENDED SHEET 74 in the presence of CeC1 3 7H 2 0 and ethanol to give a compound of formula II R 5 0 H Ri R 6 N R N I R R7 #R O CH3 R4 b) in converting the compound of formula II into a compound of formula III 'R 5 0 Ri R6; N -R2 R7R3 O CH3 R4 c) in reacting the compound of the formula III with HC(OC 2 H 5 2 N(CH 3 2 in DMF at 120 C to form a compound of formula IV AMENDED SHEET 75 d) in cyclizing the compound of formula IV to a compound of formula I in the presence of NH 4 C1 and AcOH, e) optionally converting the compound of formula I thus obtained into another compound of formula I.

14. A compound of formula R 5 O R R 6 N R 2 R, R3 0 R 4 N(CH 3 2 o *in which: 15 R 1 is chosen from hydrogen, halogens, a nitro group and groups -NRaR 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, 20 R 3 is chosen from hydrogen, halogens, (Cl-C 4 alkyl groups, (Ci-C 6 alkoxy groups, a guanidino group, groups -NRIOR 11 in which R1i and Ru 1 are chosen, independently of each other, from hydrogen, (CI-C 4 alkyl groups, (Cz-C 4 phenylalkyl groups and groups -(CH 2 )n-Y with Y being chosen from halogens and CN, -CH(O-Et) 2 (CI-C 6 alkoxy, 0-(CH 2 2 -N(CH3)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 13 in which R12 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: 76 hydrogen or a halogen atom, C 1 -C 6 alkyl, hydroxyl, Cj-C 6 alkoxy, (Cl-C 6 alkoxy (Cl-C 6 alkyl, (C 1 -C 4 alkylcarbonyloxy- (Cl-C 4 alkyl, -CHO, -COOH, -CN, -C0 2 R 1 4 -CONHR 14 and -C0NR 14 R, 5 groups, -NHCOR 14 and -NR 14 R, 5 in which R 1 4 and R 1 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 S0 3 H groups, groups: -CF2-N-CORj6 -CH!2-N-COOR 16 I I CH-CO0R 17 CF -Ar R 1 6 and R 1 7 being chosen from Cl-C 6 alkyl groups and Ar being a C 6 -C 1 4 aryl group, with the exclusion of compounds i~n which either R 1 R 2 R 3 R 4 R 5 R 6 R 7 H, or RI, R 3 R 4 ,r R 5 R 6 R= 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 R 3 R 4 R 6 R 7 H and R 5 OH or OCR 3 or R, NO 2 and R 2 R 3 R 4 R 5 R 6 R 7 H, and the addition salts of these compounds with pharmaceutically acceptable acids. AMENDED SHEET