FR2797445A1 - Ascidemin derivatives as cytotoxic agents, useful for the treatment of solid tumors - Google Patents

Abstract

A new composition contains ascidemin derivatives (I) and (II) as cytotoxic agents. A new composition contains ascidemin derivatives (I) and (II) or their acid addition salts as cytotoxic agents. X = O, =NH, or =N-OH; R1 = H, halo, NO2, -NR8R9; R8, R9 = H or 1-4C alkyl; R2 = H or halo; R3 = H, halo, 1-4C alkyl, 1-6C alkoxy, guanidino, -NR10R11 or -(CH2)n-Y; R10, R11 = H, 1-4C alkyl, or phenyl 1-4C alkyl; Y = CN, -CH(O-Et)2, 1-6C alkoxy, -O-(CH2)2-N-(CH3)2, or -N(CH3)2; n = 1-3; R4 = H, halo, NO2, -NR12R13; R12 and R13 = H or 1-4C alkyl; R5 - R7 = H, halo, 1-6C alkyl or alkoxy, OH, 1-6C alkoxy 1-6C alkyl, 1-4C alkyl carbonyl 1-4C alkyl, CHO, COOH, CN, -COOR14, -CONR14R15, -NHCOR14 or -NR14R15, -phenyl-COCH3, -phenyl-COCH=CH-N(CH3)2, morpholino, NO2, -SO3H, -CH2-N(CH2-COOR17)-COOR16 or -CH2-N(CH2-Ar)-COOR16; R14, R15 = H, 1-6C alkyl, -phenyl-COCH3, or -CH2-CH2-N(CH3)2; R16, R17 = 1-6C alkyl; Ar = 6-14C aryl; except for those compounds of formula (I) in which X = O and R1 - R7 = H or R1 and R3 - R7 = H, R2 = Br, and the compound of formula (Ia) in which X = O and R1 - R7 = H. Independent claims are also included for: (1) new compounds of formulae (I) and (II) or their acid addition salts, with the additional exclusion of compounds of formula (I) in which X = O and R1, R2, R4 - R7 = H and R3 = OCH3, or in which X = O and R1 - R3, R4 - R7 = H and R5 = OH or OCH3, or in which X = O and R1 = NO2 and R2 - R7 = H; and (2) the preparation of (Ia).

Description

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The present invention relates to pharmaceutical compositions based on polyaromatic compounds useful especially as antitumor drugs.

 In 1999, the cytotoxic treatments (chemotherapy) used to reduce the size of cancerous tumors, to contain the development of the tumoral process and even, in too few cases, to suppress the clusters of cancer cells and the risk of metastases, combine chemical substances of recent introduction with others that have been in use for a few decades. For example, 5-fluorouracil (5-FU), recognized for almost 40 years as one of the most active treatments for colorectal cancer, can be substituted for any of the specific topoisomerase 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 with the provision of oxaliplatin, new "donors" in situ 5-FU or selective inhibitors of thymidylate synthetase. This coexistence is not limited to the treatment of colorectal cancers since, also, the chemotherapy of breast, ovarian, and lung cancers is now largely based on the family of taxane derivatives (paclitaxel, docetaxel). The need for more effective and better tolerated treatments, thus improving the survival and quality of life of the patients is imperative since, always taking the example of colo-rectal tumors, it has been estimated (S. L. Parker, T.

Tong, S. Bolden et al., CA Cancer J. Clin., 1997) that, in the United States alone, more than 131,000 new cases were diagnosed in 1997, of which 54,000 were responsible for the deaths of patients. It is the knowledge of this situation that prompted the inventors to be interested in a family of polyaromatic compounds still poorly studied, identified in hot sea ascidians, to develop an original medicinal chemistry intended to select synthetic compounds derived from a chemical design / modulation work and endowed with a therapeutically significant cytotoxic activity.

 The seas and oceans, which cover more than 70% of the globe's surface, harbor marine plants and sponges whose progressive systematic pharmacognosic study shows that these living species may contain complex alkaloids with interesting pharmacological properties.

For example, Cryptotheca crypta and Halichondria okadai sponges are

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 since the discovery of the presence of cytarabine or halichondrin B in their cells. The same is true for the tunicate family, since the isolation of the aplidine from the tunicate Aplidium albicans, which lives in the Balearic Islands (Spain). Alkaloids with a tetrahydroisoquinolone structure were isolated from the ascidian Ecteinascidia turbinata. Of these, ecteinascidin-743 is the subject of extensive pre-clinical work (E. Igbicka et al., NCI-EORTC Symposium, 1998; 130 p. 34), as well as clinical trials to define its therapeutic potential as an anticancer drug (A. Bowman et al., NCI-EORTC symposium, 1998, 452 p.118, M. Villanova-Calero et al., NCI-EORTC Symposium, 1998, Abst 453 p.118, MJX Hillebrand et al., NCI-EORTC Symposium, 1998, 455 p.119, E. Citkovic et al., NCI-EORTC Symposium, 1998; 456 p.119). Novel pentacyclic acridine derivatives are also the subject of pharmaco-chemistry work (D.J.

Hagan et al., J. Chem. Soc., Perkin Transf., 1997; 1: 2739-2746).

 Another natural alkaloid of marine origin, ascididemine was extracted from the tunicate Didemnum sp. (J. Kobayashi et al., Tehahedron, lett., 1988; 29: 1177-80) and ascidian Cystodytes dellechiajei (Bonnard et al., Anti-cancer Drug design 1995; 333-46). Ascididemine has antiproliferative properties demonstrated on the murine leukemia model (P388 or L1210 lines) and described by F. Schmitz et al. (J. Org Chem 1991, 56: 804-8), B. Lindsay et al. (Bioorg Med Chem, Lett 1995, 5: 7392) and J. Kobayashi et al. (Tehahedron Lett 1988, 29: 1177-80) and the human leukemia model described by I. Bonnard et al. (Anti-Cancer Drug Design 1995; 333-46). Several synthetic routes of ascididemine have been reported by different authors: F. Bracher et al. (Heterocycles 1989; 29: 2093-95), C.J.

Moody et al. (Tetrahedron Lett 1992, 3589-602) and G. Gellerman et al.

(Synthesis 1994; 239-41).

 We can also mention 2-bromoleptoclinidone (according to the name of S. J. Bloor et al., 1987) and isolated from the ascidian Leptoclinides sp. by S. J. Bloor et al.

(J. Ann Chem Soc 1987, 6134-6) and synthesized by F. Bracher et al.

(Heterocycles 1989; 29: 2093-95) then by E.E. Jung et al. (Heterocycles 1994; 39; 2: 767-778). 2-bromoleptoclinidone exhibits cytotoxicity on the leukemia cell model with an ED 50 of 0.4 g / ml. Cytotoxic properties

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 were confirmed by F. Bracher (Pharmazie 1997; 57-60) both in vitro - out of sixty tumor cell lines in culture - and in vivo on xenograft models of human tumor cell lines (SW-620 colon tumors and HTC116, renal tumor A498 and melanoma LOX IM VI) implanted in mice.

 Other compounds derived from ascididemine such as 11-hydroxy ascididemine, 11-methoxy ascididemine, 11-phenyl and 11-nitrophenyl ascididemines, 1-nitro and 3-nitro ascididemines and neocalliactin have been described in the plan. chemical (as numbered by SJ Bloor et al., 1987) by different teams such as those of FJ Schmitz (J. Org Chem 1991, 804-8) and Y. Kitahara et al. (Heterocycles 1993, 36: 943-46, Tetrahedron Lett 1997, 53, 17029-38), G. Gellerman et al. (Tetrahedron Lett 1993, 34: 1827-30), S. Nakahara et al (Heterocycles 1993, 36: 1139-44), I. Spector et al.

(US Patent Number: 5,432,172, Jul. 11, 1995).

dans laquelle : - X est choisi parmi l'oxygène, le groupe =NH, le groupe =N-OH, The present invention relates to a pharmaceutical composition comprising an effective amount of a compound chosen from the compounds of the following general formula:

in which: X is chosen from oxygen, the group = NH, the group = N-OH,

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R16 et R17 étant choisis parmi les groupes alkyle en RC1-C6 et Ar étant un groupe aryle en C6-C14, à l'exclusion des composés dans lesquels X = 0, et ou bien R1, R2, R3, R4, R5, R6, R7 = H, ou bien R1, R3, R4, R5, R6, R7 = H et R2 = Br, R1 is chosen from hydrogen, halogens, nitro group and -NRgRg groups in which R8 and Rg are chosen independently of each other from hydrogen and (C1-C4) alkyl groups; R2 is chosen from hydrogen and halogen; R3 is chosen from hydrogen, halogens, (C1-C4) alkyl groups, (C1-C6) alkoxy groups, a guanidino group and -NR10R11 groups; in which R10 and R11 are independently selected from hydrogen, (C1-C4) alkyl, phenyl (C1-C4) alkyl, (CH2) 2-N (CH3) 2, and - (CH 2) 2 -O- (CH 2) 2 -N (CH 3) 2, - R 4 is chosen from hydrogen, halogens, nitro group and -NR 12 R 13 groups in which R 12 and R 13 are independently selected one of the other from hydrogen and (C1-C4) alkyl groups; - R5, R6 and R7 are chosen from: hydrogen, a halogen atom, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, -CHO, COOH, -CN, -CO2R14. -CONHR14, -CONR14R15, -NHCOR14 and -NR14R15 groups, wherein R14 and R15 are independently selected from hydrogen, (C1-C6) alkyl and -CH2-CH2-N ( CH3) 2, -phenyl-CO-CH3 or -phenyl-CO-CH = CH-N (CH3) 2, morpholino, nitro, SO3H, the groups:

Wherein R 16 and R 17 are selected from R 1 -C 6 alkyl and Ar is C 6 -C 14 aryl, with the exception of compounds where X = O, and either R 1, R 2, R 3, R 4, R 5, R 6 , R7 = H, or R1, R3, R4, R5, R6, R7 = H and R2 = Br,

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

 The present invention more particularly relates to a pharmaceutical composition comprising an effective amount of a compound chosen from compounds of formula # in which: - X represents oxygen, - R1 is chosen from hydrogen and the amino group, R2 is selected from hydrogen and halogen; R3 is selected from hydrogen, halogens, (C1-C4) alkyl groups, (C1-C4) alkoxy groups, guanidino group, -NR10R11-groups in which R10 and R11 are independently selected from hydrogen, methyl, phenyl (C1-C4) alkyl, - (CH2) 2-N (CH3) 2, - (CH2) 2 -0 - (CH2) 2-N (CH3) 2; - R4 is chosen from hydrogen, halogens and the nitro and amino group; - R5, R6, R7 represent a hydrogen, with the exception of compounds in which R1, R2, R3, R4, R5, R6, R7 = H, or R1, R3, R4, R5, R6, R7 = H and R2 = Br, and their addition salts of these compounds with pharmaceutically acceptable acids.

 "Pharmaceutically acceptable acid addition salts" means those salts which give the biological properties of the free bases without undesirable effects. These salts can be in particular those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acidic metal salts, such as disodium orthophosphate and monopotassium sulfate, and organic acids.

 In general, the compounds of formula # are obtained according to the general reaction scheme described by F. Bracher et al (Heterocycles 1989; 29:

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2093-95) for ascididemine. According to this scheme, the compounds are prepared by oxidative amination of a substituted 5,8-quinone with a substituted orthoaminoacetophenone, followed by cyclization of the resulting diaryl amine (compounds of formula II) to intermediate tetracyclic quinone (compounds of formula III) . The enamine formed by reacting the compound of formula III with dimethylformamide diethyl acetal leads to the final derivative by cyclization:

Ascididemine was prepared according to the method described by F. Bracher et al.

(Heterocycles 1989; 29: 2093-95) and is referred to herein as CRL 8274.

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 Some of the described compounds have been prepared directly from ascididemine or from a compound of formula I used as a synthetic intermediate.

A - Preparation of intermediates of formula II A-1 - Synthesis of 6- (2-acetyl-4-methyl-phenylamino) -quinoline-5,8-dione (intermediate A1) (CRL 8322)
A solution of quinoline-5,8-dione (0.215 g, 1.35 mmol) in 12 ml of ethanol is slowly added to a solution of cerium chloride (1 g, 2.7 mmol) and 5-methyl- 2 amino acetophenone (0.402 g, 2.7 mmol) in 5 ml of ethanol.

The reaction medium (red) is left stirring at room temperature overnight. It is hydrolyzed with 30 ml of a 10% aqueous acetic acid solution and extracted 4 times with chloroform. The organic phases are dried over MgSO 4 and then evaporated. The crude product obtained is purified by flash-chromatography on a silica column (CH 2 Cl 2 / MeOH 95: 5) to give 0.405 g of the expected tricyclic compound in the form of a powder: # Yield = 98% # 1 H NMR (CDCl 3): 2.42 (s, 3H), 2.77 (s, 3H), 6.86 (s, 1H), 7.38 (dd, 1H, J = 8 and 1.6 Hz), 7.52 (d, 1H). , J = 8 Hz), 7.61 (dd, 1H, J = 5.2 and 7.6 Hz), 7.74 (d, 1H, J = 1. 6 Hz), 8.46 (dd , 1H, J = 7.6 and 5.2 Hz), 9.02 (dd, 1H, J = 2 and 5.2 Hz), 11.18 (s, 1H).

A-2 - Synthesis of 6- (2-acetyl-4-chloro-phenylamino) -quinoline-5,8-dione (Intermediate A2)
Preparation according to the process described in Chapter A-1: quinoline-5,8-dione (0.188 g, 1.18 mmol), cerium chloride (0.88 g, 2.36 mmol), 5-chloro-2-aminoacetophenone ( 0.4 g, 3.14 mmol), ethanol (10 + 4 ml), acetic acid (25 ml). 0.3 g of red powder is obtained:

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 # Yield = 78% # 1H NMR (CDCl3): 2.65 (s, 3H), 6.84 (s, 1H), 7.52 (dd, 1H, J = 8.8 Hz), 7 , 57 (d, 1H, J = 8.8 Hz), 7.63 (dd, 1H, J = 8 and 4.4 Hz), 7.89 (d, 1H, J = 2.4 Hz ), 8.46 (dd, 1H, J = 0.8 and 8 Hz), 9.02 (dd, 1H, J = 2 and 5.2 Hz), 11.18 (s, 1H).

 # 13C NMR (CDCl3): 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-4-benzylamino-phenylamino) -quinoline-5,8-dione (Intermediate A3)
Preparation according to the process described in Chapter A-1: quinoline-5,8-dione (0.250 g, 1.57 mmol), cerium chloride (0.77 g, 3.14 mmol), 5-benzylamino-2-aminoacetophenone (0.603 g, 3.14 mmol), ethanol (15 + 7 mL), acetic acid (35 mL). 0.56 g of red powder is obtained: # Yield = 91%.

 . 1H NMR (CDCl3): 2.54 (s, 3H), 4.38 (s, 2H), 6.70 (s, 1H), 6.83 (dd, 1H, J = 9, and 3.2 Hz), 7.08 (d, 1H, J = 3.2 Hz), 7.30-7.37 (m, 5H), 7.43 (d, 1H, J = 9.6). Hz), 7.58 (dd, 1H, J = 7.6 and 4.8 Hz), 8.43 (dd, 1H, J = 7.6 and 2 Hz), 9.03 (dd, 1 H, J = 2 and 4.8 Hz), 10.67 (s, 1H).

A-4 - Synthesis of 6- (2-acetyl-5-bromo-phenylamino) -quinoline-5,8-dione (Intermediate A4) (CRL8268)
Preparation according to the method described by F. Bracher, Liebigs Ann. Chem. 1990,
205-206.

A-5 - Synthesis of 6- (2-acetyl-4-dimethylamino-phenylamino) -quinoline
5,8-dione (Intermediate A5)
Preparation according to the process described in Chapter A-1: quinoline-5,8-dione (0.36 g, 2.26 mmol), cerium chloride (1.67 g, 4.49 mmol), 5-dimethylamino- 2 aminoacetophenone (0.8 g, 4.49 mmol), ethanol (20 + 10 ml), acetic acid (50 ml). 1.26 g of red powder are obtained: Yield = 84%.

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 # 1H NMR (CDCl3): 2.85 (s, 3H), 3.12 (s, 6H), 6.72 (s, 1H), 6.90 (dd, 1H, J = 2.8 and 9.2 Hz), 7.15 (d, 1H, J = 2.8 Hz), 7.49 (d, 1H, J = 9.2 Hz), 7.58 (dd, 1H, J). = 8Hz 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), , 69 (s, 1H).

A-6 - Synthesis of 6- (2-acetyl-4-methoxy-phenylamino) -quinoline-5,8-dione (Intermediate A6)
Preparation according to the process described in Chapter A-1: quinoline-5,8-dione (3.51 g, 22.08 mmol), cerium chloride (16.4 g, 44.03 mmol), 5-methoxy 2-aminoacetophenone (7.29 g, 44.18 mmol), ethanol (200 + 90 mL), acetic acid (500 mL). 4.25 g of red powder are obtained:
Yield = 60%.

 . 1 H NMR (CDCl3): 2.65 (s, 3H), 3.87 (s, 3H), 6.76 (s, 1H), 7.12 (dd, 1H, J = 2.8 and 8). , 8 Hz), 7.42 (d, 1H, J = 2.8 Hz), 7.55 (d, 1H, J = 8.8 Hz), 7.61 (dd, 1H, J = 7.6 and 4.4 Hz), 8.45 (dd, 1H, J = 1.6 and 7.6 Hz), 9.01 (dd, 1H, J = 1.6 and 4.4 Hz ), 10.80 (s, 1H).

A-7 - Synthesis of 4- (2'-acetylanilino) -6- (2-acetylphenylamino) quinoline
5,8-dione (Intermediate A7)
Preparation according to the process described in Chapter A-1: 4-chloro-quinoline-5,8-dione (3.5 g, 18 mmol), cerium chloride (13.5 g, 36.24 mmol), 2 aminoacetophenone ( 4.4 ml, 36 mmol), ethanol (160 + 70 ml), acetic acid (400 ml). 2.32 g of red powder are obtained: # Yield = 30%.

 # 1H NMR (CDCl3): 2.69 (s, 3H), 2.72 (s, 3H), 6.85 (s, 1H), 7.18 (ddd, 1H, J = 7.6). and 7.6 and 0.8 Hz), 7.28 (m, 1H), 7.30 (d, 1H, J = 6.4 Hz), 7.54-7.59 (m, 3H). , 7.63 (d, 1H, J = 7.6 Hz), 7.91 (dd, 1H, J = 1.6 and 8.4 Hz), 7.94 (dd, 1H, J = 1.2 and 8.4 Hz), 8.47 (d, 1H, J = 6.4 Hz), 11.35 (s, 1H), 12.35 (s, 1H).

A-8 - Synthesis of 6- (2-acetyl-4-bromo-phenylamino) -3-methoxy-quinoline-5,8-dione (Intermediate A8)

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Preparation according to the process described in Chapter A-1: 3-methoxyquinoline-5,8-dione (1.57 g, 9.1 mmol), cerium chloride (3.1 g, 8.3 mmol), 5- 2-bromoaminoacetophenone (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 silica column (CH 2 Cl 2 / MeOH 95: 5) 1.22 g of orange powder: # Yield = 37%.

 # 1H NMR (CDCl3): 3.15 (s, 3H), 4.58 (s, 3H), 7.61 (d, 1H, J = 6Hz), 7.74 (s, 1H) , 7.99 (d, 1H, J = 8.8 Hz), 8.14 (dd, 1H, J = 8.8 and 2.4 Hz), 8.51 (d, 1H, J = 2.8 Hz), 9.32 (d, 1H, J = 6Hz), 11.68 (s, 1H).

B - Preparation of intermediate products of formula III B-1 - Synthesis of 9,11-dimethyl-1,6-diaza-naphtacene-5,12-dione (intermediate B1) (CRL 8324)
To an intermediate tricycle solution A1 (0.4 g, 1.3 mmol) in 12 ml of acetic acid, 1.9 ml of sulfuric acid dissolved in 9.6 ml of acetic acid are slowly added. The reaction medium is refluxed for 30 minutes and then poured, after cooling, into a beaker containing crushed ice. It is neutralized with NH 4 OH and then extracted 4 times with dichloromethane. The organic phases are dried over MgSO 4 and then evaporated. The crude product obtained is purified by flash-chromatography on a silica column (CH 2 Cl 2 / MeOH 95: 5) to give 0.325 g of the expected tetracycle compound.

 # Yield = 86% # 1 H NMR (CDCl3): 2.64 (s, 3H), 3.29 (s, 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 (d, 1H, J = 8, 4), 8.71 (dd, 1H, J = 2 and 7.6 Hz), 9.13 (dd, 1H, J = 2 and 4.8 Hz).

B-2 - Synthesis of 9-chloro-11-methyl-1,6-diaza-naphtacene-5,12-dione (Intermediate B2)

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Preparation according to the process described in Chapter B-1: Intermediate tricycle A2 (0.289 g, 0.88 mmol), sulfuric acid (1.3 ml), acetic acid (8 + 6.5 ml).

After purification by flash chromatography (95: 5 CH2Cl2 / MeOH), 0.26 g of tetracycle is obtained: # Yield: 95% # 1 H NMR (CDCl3): 3.25 (s, 3H), 7.76 ( dd, 1H, J = 8 and 4.8 Hz), 7.85 (dd, 1H, J = 8.8 and 2 Hz), 8.33 (dd, 1H, J = 2 Hz), 8 , 38 (d, 1H, J = 8.8), 8.71 (dd, 1H, J = 1. 6 and 8 Hz), 9.15 (dd, 1H, J = 1.6 and 4). , 8 Hz).

B-3 - Synthesis of 9-benzylamino-11-methyl-1,6-diaza-naphtacene-5,12-dione (Intermediate B3) Preparation according to the process described in Chapter B-1: A3 (4 g, 10 g) mmol), sulfuric acid (15.1 ml), acetic acid (92 + 75 ml). After treatment, 3.58 g of tetracycle is obtained.

 # Yield = 98% # 1H NMR (CDCl3): 3.09 (s, 3H), 4.52 (d, 2H), 4.86 (t, 1H), 7.06 (d, 1H, J = 2.8 Hz), 7.29 (dd, 1H, J = 9.2 and 2.8 Hz), 7.3-7.43 (m, 5H), 7.71 (dd, 1H). , J = 4.8 and 8 Hz), 8.20 (d, 1H, J = 9.8 Hz), 8.69 (dd, 1H, J = 1.6 and 8 Hz), 9.09 ( dd, 1H, J = 1.6 and 4.8 Hz).

B-4 - Synthesis of 8-bromo-11-methyl-1,6-diaza-naphtacene-5,12-dione (Intermediate B4)
Preparation according to the method described by F. Bracher, Liebigs Ann. Chem. 1990,
205-206.

B-5 - Synthesis of 9-dimethylamino-11-methyl-1,6-diaza-naphtacene-5,12-dione (Intermediate B5)
Preparation according to the process described in chapter B-1: intermediate tricycle A5 (0.76 g, 2.27 mmol), sulfuric acid (3.5 ml), acetic acid (20 + 18 ml).

After treatment, 0.67 g of tetracycle is obtained.

 # Yield = 93%

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 # 1H NMR (CDCl3): 3.17 (s, 3H), 3.21 (s, 6H), 7.04 (d, 1H, J = 3.2Hz), 7.51 (dd, 1H NMR (CDCl3):? H, J = 3.2 and 9.2 Hz), 7.71 (dd, 1H, J = 8 and 4.4 Hz), 8.26 (d, 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-11-methyl-1,6-diaza-naphtacene-5,12-dione (Intermediate B6)
Preparation according to the process described in chapter B-1: intermediate tricycle A6 (4.25 g, 13.18 mmol), sulfuric acid (20 ml), acetic acid (110 + 100 ml).

The product obtained by flash chromatography (CH 2 Cl 2 / MeOH 100: 3) is washed with ethyl ether to give 2.9 g of tetracycle.

 # Yield = 72% # 1H NMR (CDCl3): 3.25 (s, 3H), 4.02 (s, 3H), 7.49 (d, 1H, J = 3.3Hz), 7, 56 (dd, 1H, J = 3.3 and 9.3 Hz), 7.74 (dd, 1H, J = 8.3 and 4.3 Hz), 8.34 (d, 1H, J = 9.3 Hz), 8.71 (dd, 1H, J = 2.5 and 8.3 Hz) 9.12 (dd, 1H, J = 2.5 and 4.3 Hz).

B-7- Synthesis of 4- (2'-acetylanilino) -11-methyl-1,6-diaza-naphthalene
5,12-dione (Intermediate B7) (CRL 8332)
Preparation according to the process described in Chapter B-1: Intermediate tricycle A7 (1 g, 2.35 mmol), sulfuric acid (3.5 ml), acetic acid (18 ml). The product obtained by flash chromatography (CH 2 Cl 2 / MeOH 100: 3) is washed with ethyl ether to give 0.6 g of tetracycle in the form of an orange powder.

 # Yield = 63% # 1H NMR (CDCl3): 2.59 (s, 3H), 3.25 (s, 3H), 7.29 (ddd, 1H, J = 7.2 and 7.2, and 1.2 Hz), 7.37 (d, 1H, J = 6 Hz), 7.54 (ddd, 1H, J = 6.8 and 6.8 and 1.6 Hz), 7.59 ( d, 1H, J = 6.8 Hz), 7.74 (dd, 1H, J = 7.2 and 1.2 Hz), 7.76 (dd, 1H, J = 6.8 and 1 , 6 Hz), 7.87-7.918 (m, 2H), 8.34 (d, 1H, J = 8.4 Hz), 8.43 (d, 1H, J = 8.4 Hz), 8.54 (d, 1H, 6Hz), 12.5 (s, 1H).

B-8 Synthesis of 3-methoxy-9-bromo-11-methyl-1,6-diaza-naphthalene
5,12-dione (Intermediate B8)

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Preparation according to the process described in chapter B-1: intermediate tricycle A8 (1.22 g, 3.04 mmol), sulfuric acid (4.5 ml), acetic acid (27 + 23 ml). The product obtained by flash chromatography (CH 2 Cl 2 / MeOH 100: 3) is washed with ethyl ether to give 0.76 g of tetracycle in the form of a yellow powder.

 # Yield = 65% # 1H NMR (CDCl3): 3.21 (s, 3H), 4.10 (s, 3H), 7.18 (d, 1H, J = 6Hz), 7.96 ( dd, 1H, J = 8.8 and 2 Hz), 8.27 (d, 1H, J = 8.8 Hz), 8. 47 (d, 1H, J = 2 Hz), 8.89 (d, 1H, J = 6 Hz).

EXAMPLE 1
5-methyl-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8323)
A solution of intermediate tetracycle B1 (1 g, 3.47 mmol) and dimethylformamide diethyl acetal (2 ml, 10.41 mmol) in 7 ml of DMF is refluxed for 1 hour. After evaporation to dryness, ammomium chloride (2.77 g, 52 mmol) and 50 ml of ethanol are added. The reaction medium is again refluxed for 30 minutes. After evaporation of 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 pentacycle is obtained in the form of a mustard yellow solid.

 # Yield = 67% # Melting point = 200 C NMR 1 H (CDCl 3): 2.69 (s, 3H), 7.65 (dd, 1H, J = 8 and 4.8 Hz), 7, 81 (dd, 1H, J = 8 and 1.2 Hz), 8.44 (d, 1H, J = 1.2 Hz), 8.49 (d, 1H, J = 8 Hz), 8 , 50 (d, 1H, J = 5.6 Hz), 8.78 (dd, 1H, J = 2 and 8 Hz), 9.15 (dd, 1H, J = 4.8 and 2 Hz ), 9.24 (d, 1H, J = 5.6 Hz).

 # 13C NMR (CDCl3): 22.06; 116.54; 117.87; 122.15; 123.12; 125.24; 128.74; 132.58; 133.47; 136.25; 137.19; 141.63; 143.88; 144.79; 149.16; 149.31; 152.09; 155.15; 181.53.

 MS (m / z): 297 (17.6); 296 (34.3); 268 (25.4); 149 (50.3).

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EXAMPLE 2
5-chloro-9H-quino [4,3,2-de] [1,10] phenantrolin-9-one (CRL8301)
Preparation according to the process described in Example 1 from intermediate tetracycle B2 (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 (CH 2 Cl 2 / MeOH 98: 2), 60 mg of the expected pentacycle is obtained in the form of a yellow solid.

 # Yield = 23% # Melting point = 200 C NMR 1 H (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 (d, 1H, J = 5.6 Hz), 8.55 (d, 1H, J = 8.8 Hz), 8.63 (d, 1 H, J = 2 Hz), 8.79 (dd, 1H, J = 2 and 8.4 Hz), 9.18 (dd, 1H, J = 4.8 and 2 Hz), 9.30 (d, 1H, J = 5.6 Hz).

 . 13 C NMR (CDCl 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 (m / z): 319 (43); 317 (100); 291 (14.5); 290 (18); 289 (100).

5-(benzylamino)-9H-quino[4,3,2-de][1,10]phénanthrolin-9-one (CRL 8241)
Préparation selon le procédé décrit dans l'exemple 1 à partir du tétracycle intermédiaire B3 (3,58 g, 9,45 mmol) et le diméthylformamide diéthyl acétal (5,7 ml, 33,26 mmol) dans du DMF (19 ml). Chlorure d'ammomium (2,95 g, 55 mmol), éthanol (50 ml). Après purification par flash-chromatographie (CH2CI2/MeOH 96 : 4), on obtient 2 g du pentacycle attendu sous forme de poudre lie-de-vin. EXAMPLE 3

5- (benzylamino) -9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8241)
Preparation according to the process described in Example 1 from intermediate tetracycle B3 (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 (CH 2 Cl 2 / MeOH 96: 4), 2 g of the expected pentacycle is obtained in the form of a wine-wine powder.

 # Yield = 55% # Melting point = 219 C NMR 1H (CDCl3): 4.61 (d, 2H), 5.10 (t, 1H), 7.31 (dd, 1H, J = 8.8 Hz, J = 2.4 Hz), 7.452-7.327 (m, 5H), 7.55 (d, 1H, J = 2.4 Hz), 7.63 (dd, 1H, J = 4, 4 Hz, J =

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 8.4 Hz), 8.29 (d, 1H, J = 5.2 Hz), 8.36 (d, 1H, J = 8.8 Hz), 8.79 (dd, 1H, J). = 1.2 Hz, J = 8.4 Hz), 9.13 (dd, 1H, J = 4.4 and 1.2 Hz), 9.14 (d, 1H, J = 5.2 Hz) .

 #MS (m / z): 388 (7); 387 (100); 386 (85); 385 (25); 369 (99); 368 (44).

5-(diméthylamino)-9H-quino[4,3,2-de][1,10]phénanthrolin-9-one (CRL 8325)
Préparation selon le procédé décrit dans l'exemple 1 à partir du tétracycle intermédiaire B5 (0,25 g, 0,79 mmol) et le diméthylformamide diéthyl acétal (0,5 ml, 2,98 mmol) dans le DMF (5 ml). Chlorure d'ammomium (1 g, 18,7 mmol), éthanol (16 ml). Après purification par flash-chromatographie (CH2CI2/MeOH 100 : 5), on obtient 170 mg du pentacycle attendu sous forme d'une poudre violette. 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 from intermediate tetracycle B5 (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 (CH 2 Cl 2 / MeOH 100/5), 170 mg of the expected pentacycle is obtained in the form of a violet powder.

 # Yield = 66% # Melting point 260 C # 1 H NMR (CDCl3): 3.25 (s, 6H), 7.45 (dd, 1H, J = 9.2 Hz, J = 3Hz), 7 , 57 (d, 1H, J = 3Hz), 7.63 (dd, 1H, J = 4.4 and 8Hz), 8.41 (d, 1H, J = 9.2Hz), , 43 (d, 1H, J = 5.6 Hz), 8.81 (dd, 1H, J = 2 and 7.6 Hz), 9.13 (dd, 1H, J = 4.4 and 2 Hz ), 9.17 (d, 1H, J = 5.6 Hz).

 . 13 C NMR (CDCl3): 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 (m / z): 326 (34.5); 325 (100); 324 (100); 254 (15.5); 253 (13.4).

EXAMPLE 5 5-Methoxy-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8297)
Preparation according to the process described in Example 1 from intermediate tetracycle B6 (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 pentacycle is obtained in the form of a solid.

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 # Yield = 66% # Melting point> 260 ° C. 1 H NMR (CDCl 3): 4.10 (s, 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 (d, 1H, J = 2.4 Hz), 8.48 (d, 1H, J = 2.4 Hz), 8.54 (d, 1H, J). = 9.2 Hz), 8.80 (dd, 1H, J = 2.4 and 8 Hz), 9.16 (dd, 1H, J = 4.4 and 2.4 Hz), 9.25 (d, 1H, J = 5.2 Hz).

 . 13 C NMR (CDCl3): 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 (m / z): 313 (26); 312 (100); 285 (2); 284 (15); 269 (15); 242 (32.5).

7-nitro-9H-quino[4,3,2-de][1,10]phénanthrolin-9-one (CRL 8289)
A 0 C, on ajoute, par portions, de l'ascididémine (2 g, 7,06 mmol) à un mélange de 45 ml d'acide sulfurique et de 45 ml d'acide nitrique. Le milieu réactionnel est chauffé à 130 C pendant 2 heures puis versé après refroidissement dans un erlen contenant 400 g de glace. Après filtration, on obtient un précipité jaune que l'on rince plusieurs fois à l'éther. On le reprend ensuite dans un mélange CH2CI2/NH40H/H20 600 : 1 : 300. On récupère la phase organique et on extrait 3 fois la phase aqueuse au CH2CI2. Après séchage sur MgS04, les phases organiques sont évaporées pour donner 1,62 g de pentacycle attendu sous forme d'un solide jaune. EXAMPLE 6

7-nitro-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8289)
At 0 ° C., ascididemine (2 g, 7.06 mmol) is added in portions to a mixture of 45 ml of sulfuric acid and 45 ml of nitric acid. The reaction medium is heated at 130 ° C. for 2 hours and then poured after cooling into an Erlenmeyer 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 CH 2 Cl 2 / NH 4 OH / H 2 O 600: 1: 300 mixture. The organic phase is recovered and the aqueous phase is extracted 3 times with CH 2 Cl 2. After drying over MgSO4, the organic phases are evaporated to give 1.62 g of expected pentacycle as a yellow solid.

 # Yield = 70% # Melting point = 224 C NMR 1 H (CDCl 3): 7.69 (dd, 1H, J = 4.4 and 8 Hz), 8.04 (dd, 1H, J = 8 and 8 Hz), 8.28 (dd, 1H, J = 8 Hz), 8.56 (d, 1H, J = 5.2 Hz), 8.75 (dd, 1H, J = 2 and 8 Hz), 8.89 (dd, 1H, J = 1.2 and 8 Hz), 9.18 (dd, 1H, J = 4.4 and 2 Hz), 9.37 (d, 1) H, J = 5.6 Hz).

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 . 13 C NMR (CDCl 3): 79.20; 117.61; 118.39; 124.21; 124.89; 125.98; 127.54; 129.04; 130.14; 135.62; 136, 63; 148.17; 149.76; 149.94; 150.12; 151.66; 154.88; 180.56.

 #MS (m / z): 328 (18); 327 (100); 299 (22); 297 (9); 269 (10); 253 (24); 242 (11); 241 (33).

EXAMPLE 7 7-amino-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8344)
A suspension of nitrated derivative CRL 8289 (0.4 g, 1.22 mmol) and iron (0.37 g, 6.59 mmol) in a 10: 10 AcOH / H 2 O mixture is refluxed for 1 hour. EDTA (1.94 g, 6.59 mmol) is added, and then the reaction medium is made alkaline with concentrated sodium hydroxide solution. It is extracted 3 times with CH2Cl2. After drying over MgSO4, the organic phases are evaporated to give 0.32 g of expected amine as a blue solid.

 # Yield = 88% # Melting point> 260 C NMR 1 H (CDCl 3): 5.68 (s, 2H), 7.16 (d, 1H, J = 7.8 Hz), 7.66 ( dd, 1H, J = 7.6 and 4.8 Hz), 7.69 (dd, 1H, J = 7.8 and 7.8 Hz), 7.91 (d, 1H, J = 7). , 8 Hz), 8.46 (d, 1H, J = 5.2 Hz), 8.77 (dd, 1H, J = 1.6 and 7.6 Hz), 9.17 (dd, 1 H, J = 1.6 and 4.8 Hz), 9.21 (d, 1H, J = 5.2 Hz).

 . 13 C NMR (CDCl3): 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.

 MS (m / z): 298 (34.7); 297 (100); 269 (11); 268 (8).

EXAMPLE 8 5-bromo-9H-quino [4,3,2-de] [1,10] phenantrolin-9-one (CRL 8248)
To a solution of ascididemine (0.5 g, 1.77 mmol) in 20 ml of acetic acid is added dropwise a solution of bromine (0.2 ml, 3.88 mmol) in 5 ml of acetic acid. The reaction medium is brought to reflux (blocked refrigerant) 24

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 hours. After cooling, it is neutralized with a saturated solution of NaHCO 3 and extracted 4 times with CH 2 Cl 2. The organic phases are dried over MgSO 4 and then evaporated. The crude product obtained is purified by flash-chromatography on a silica column (CH 2 Cl 2 / MeOH 96: 4) to give 0.548 g of brominated derivative expected in the form of a yellow solid.

 # Yield = 86% # Melting point = 208 C # 1 H NMR (CDCl 3): 7.68 (dd, 1H, J = 4.4 and 8 Hz), 8.09 (dd, 1H, J = 8.8 Hz, J = 2 Hz), 8.48 (d, 1H, J = 8.8 Hz), 8.49 (d, 1H, J = 6Hz), 8.79 (dd, 1H). , J = 2 and 8 Hz), 8.82 (d, 1H, J = 2 Hz), 9.18 (dd, 1H, J = 2 Hz, J = 4.4 Hz), 9.30 ( d, 1H, J = 6 Hz).

 . 13 C NMR (CDCl 3): 116.76; 117.04; 118.26; 124.76; 125.81; 125.93; 129.05; 134.52; 135.43; 136.72; 137.01; 144.41; 146.24; 149.93; 150.12; 152.27; 155.67; 181.69.

 # MS (m / z): 363 (99); 362 (83); 361 (100); 360 (27); 255 (9); 254 (51).

EXAMPLE 9 5-amino-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8347)
To a brominated ascididemic solution: CRL 8248 (2.3 g, 6.33 mmol) in 460 ml of DMF was added sodium azide (2.34 g, 36.1 mmol). The reaction medium is refluxed for 4 hours. After cooling, evaporated to dryness and the solid obtained with water. It is extracted 4 times with CH2Cl2.

After drying over MgSO4 and evaporation of the solvent, the crude is purified by flash chromatography on a silica column (HCCl 3 / MeOH 90:10) to give 115 mg of expected product in the form of a black powder.

 # Yield = 6% # melting point> 260 C # 1 H NMR (CDCl3): 7.43 (dd, 1H, J = 8.8 and 2.4 Hz), 7.74 (dd, 1H, J = 4.8 and 8 Hz), 7.81 (d, 1H, J = 2.4 Hz), 8.48 (d, 1H, J = 6Hz), 8.50 (d, 1H, J = 8.8 Hz), 8.90 (dd, 1H, J = 2 and 8 Hz), 9.25 (dd, 1H, J = 2 and 4.8 Hz), 9.29 (d, 1H, J = 6Hz).

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 . 13 C 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 (m / z): 298 (32); 297 (100); 269 (4); 268 (0.5).

10-méthoxy-9H-quino(4,3,2-de][1,10]phénanthrolin-9-one (CRL 8368) Préparation selon la procédure décrite par Y. Kitahara et al., Heterocycles, 1993, 36, 943-946. EXAMPLE 10

10-methoxy-9H-quino (4,3,2-de) [1,10] phenanthrolin-9-one (CRL 8368) Preparation according to the procedure described by Y. Kitahara et al., Heterocycles, 1993, 36, 943 -946.

EXAMPLE 11: 10-Hydroxy-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8387)
Preparation according to the procedure described 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 ascididemine are dissolved in a solution containing 5 ml of ammonia and 2 ml of EtOH. The reaction medium is refluxed (chilled refrigerant) for 72 hours. After evaporation of the solvent on a rotary evaporator, the residue is purified by flash chromatography on alumina (99: 1 CH2Cl2 / MeOH) to give 87 mg of imine CRL 8290.

 # Yield = 87% # Melting point> 260 C NMR 1 H (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); (d, 1H, J = 8 Hz); 8.43 (d, 1H, J = 6Hz); 8.64

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 (d, 1H, J = 8 Hz); (dd, 1H, J = 8 and 2.5 Hz); (dd, 1H, J = 5 and 2.5 Hz); 9.22 (d, 1H, J = 6Hz), 12.48 (s, 1H).

EXAMPLE 13 9H-quino [4,3,2-de] [1,10] phenanthrolin-9-oxime (CRL 8292)
500 mg (1.77 mmol) of ascididemine and 500 mg of NH 2 OH, 1/2 H 2 SO 4 are dissolved in 1 ml of pyridine and 10 ml of EtOH. The reaction medium is refluxed for 48 hours. After evaporation of the solvent on a rotary evaporator, 20 ml of water are added, and the medium is extracted with HCC13 (3 times 20 ml).

The organic phases are dried over MgSO4 and then evaporated on a rotary evaporator. The residue is purified by flash chromatography on alumina (CH 2 Cl 2 / MeOH 99: 1) to give 240 mg of the CRL 8292 oxime as a yellow powder.

 * Yield = 46%. Melting point> 260 ° C. 1 H NMR (CDCl3): 7.68 (dd, 1H, J = 4.4 and 8.4 Hz); (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); (dd, 1H, J = 7.6 and 1.6 Hz); (d, 1H, J = 6 Hz); (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 = 6Hz).

 # 13C NMR (CDCl3): 115.06; 116.14; 123.16; 123.29; 125.46; 128.33; 128.77; 129.54; 131.86; 132.16; 138.48; 140.94; 141.37; 145.82; 146.75; 151.27; 151.65; 151.80.

 MS (m / z): 298 (64.5); 268 (100); 266 (21.9).

10-(2-acétylanilino)-9H-quino[4,3,2-cfe][1,10]phénanthrolin-9-one (CRL 8333)
Préparation selon le procédé décrit dans l'exemple 1 à partir du tétracycle intermédiaire B7 (0,4 g, 0,98 mmol) et du diméthylformamide diéthyl acétal (0,6 ml, 3,43 mmol) dans le DMF (4 ml). Chlorure d'ammomium (1,2 g, 22,4 mmol), EXAMPLE 14

10- (2-acetylanilino) -9H-quino [4,3,2-cfe] [1,10] phenanthrolin-9-one (CRL 8333)
Preparation according to the method described in Example 1 from intermediate tetracycle B7 (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),

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 ethanol (20 ml). After purification by flash chromatography (CH 2 Cl 2 / MeOH 100: 5), 144 mg of the expected pentacycle is obtained in the form of a red-brown solid.

 # Yield = 35% # Melting point> 260 C NMR 1H (CDCl3): 2.88 (s, 3H), 3.12 (s, 3H), 5.54 (d, 1H), 7, 13 (d, 1H, J = 6Hz), 7.30 (ddd, 1H, J = 7.6 and 7.6 and 1.2Hz), 7.45 (ddd, 1H, J = 7). , 6 and 7.6 and 1.2 Hz), 7.51 (d, 1H, J = 7.6 Hz), 7.65 (bs, 1H), 7.69 (d, 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 (d, 1H, J = 6 Hz), 8.51 (d, 1H, J = 6 Hz), 8.57 (dd, 1H, J = 7). , 6 and 1.2 Hz), 8.64 (dd, 1H, J = 7.6 and 1.2 Hz), 9.23 (d, 1H, J = 6 Hz).

 # 13C NMR (CDCl3): 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.

Diiodure de 10-hydroxy-9H-quino[4,3,2-de][1,10]phénanthrolin-9-one (CRL 8369)
500 mg (1,597 mmol) de composé de l'exemple 10 (CRL 8368) et 40 ml d'acide acétique dans 100ml d'acide iodhydrique (57 %) sont chauffés à 100 C pendant 30 min. Après refroidissement, le milieu réactionnel est versé dans 500 ml d'eau additionnée de glace puis neutralisé par NaHC03 (solide). Après plusieurs extractions par un mélange de 5 % de MeOH dans HCC13 (6 fois 500 ml), les phases organiques sont séchées sur MgS04 puis concentrées à l'évaporateur rotatif pour donner 0,36 g de sel sous forme de poudre lie-de-vin. EXAMPLE 15

10-hydroxy-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one diiodide (CRL 8369)
500 mg (1.597 mmol) of the compound of Example 10 (CRL 8368) and 40 ml of acetic acid in 100 ml of hydriodic acid (57%) are heated at 100 ° C. for 30 minutes. After cooling, the reaction medium is poured into 500 ml of water with ice and then neutralized with NaHCO3 (solid). After several extractions with a mixture of 5% MeOH in HCCl3 (6 times 500 ml), the organic phases are dried over MgSO4 and then concentrated on a rotary evaporator to give 0.36 g of salt in the form of a powder. wine.

 # Yield = 41% # Melting point> 260 C NMR 1 H (DMSO) 6.24 (d, 1H, J = 7.6 Hz); 6.86 (td, 1H, J = 8 and 4 Hz); 7.27 (d, 2H, J = 4 Hz); 7.57 (d, 1H, J = 5.2 Hz); 7.89 (d, 1H, J = 8Hz); 7.93 (dd, 1H, J = 7.6 and 7.6 Hz); 8.51 (d, 1H, J = 5.2 Hz); 9.54 (s, 1H); 12.62 (br m, 1H);

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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 salt of Example 15 (CRL 8369) dissolved in 4 ml of POCl3 are refluxed for 2 hours. After evaporation of the POCI 3 on a rotary evaporator, the reaction medium is neutralized with a saturated solution of NaHCO 3. After several extractions with a 5% MeOH mixture in HCCl3 (5 times 20 ml), the organic phases are dried over MgSO4 and then concentrated on a rotary evaporator. The residue obtained is purified by flash chromatography on a silica column (CH 2 Cl 2 / MeOH 95: 5) to give 20 mg of the expected derivative in the form of a yellow powder.

 # Yield = 77% # Melting point> 260 C NMR 1 H (CDCl 3) 7.67 (d, 1H, J = 5.6 Hz); (ddd, 1H, J = 8 and 8 and 0.8 Hz); 8.03 (ddd, 1H, J = 8 and 8 and 1.2 Hz); 8.57 (d, 1H, J = 5.6 Hz); (ddd, 1H, J = 8 and 1.2 Hz); 8.68 (ddd, 1H, J = 8 and 0.8 Hz); 8.97 (d, 1H, J = 5.6 Hz); (d, 1H, J = 5.6 Hz).

 # 13C NMR (CDCl3) 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 (m / z): 318 (9.6); 316 (70.2); 290 (29.6); 288 (100); 255 (23.4); 253 (26.8).

EXAMPLE 17

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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 from intermediate tricycle B8 (0.74 g, 1.93 mmol) and dimethylformamide diethyl acetal (1.3 ml, 7.24 mmol) in 15 ml of DMF. Ammonium chloride (1.96 g, 36.4 mmol), ethanol (200 ml). After purification by flash chromatography (CH 2 Cl 2 / MeOH 95: 5), 210 mg of the expected pentacycle is obtained in the form of an orange powder.

* Yield = 42%
Melting point> 260 ° C. 1 H NMR (CDCl3): 4.14 (s, 3H), 7.14 (d, 1H, J = 5.6 Hz), 8.05 (dd, 1H, J = 2 and 8.8 Hz). ), 8.43 (d, 1H, J = 6Hz), 8.44 (d, 1H, J = 8.8Hz), 8.76 (d, 1H, J = 2Hz), , 95 (d, 1H, J = 6Hz), 9.27 (d, 1H, J = 5.6Hz).

 # 13C NMR (CDCl3): 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 (m / z): 393 (100); 392 (61.7); 391 (99.2); 390 (17.4); 362 (9.2); 333 (9.8); 254 (34.5).

 The results of the pharmacological tests, presented below, demonstrate the cytotoxic properties of the compounds of formula I, as well as the maximum tolerated doses. These data make it possible to appreciate the therapeutic interest of the claimed compounds.

1- Determination of the maximum tolerated dose (MTD)
The evaluation of the maximum tolerated dose was performed in B6D2F1 / Jico mice aged 4-6 weeks. The compounds were administered intraperitoneally at increasing doses ranging from 2.5 to 160 mg / kg.

The value of the DMT (expressed in mg / kg) is determined from the observation of the survival rate of the animals over a period of 14 days after a

<Desc / Clms Page number 24>

 single administration of the product under consideration. The weight change 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 equated to 160 mg / kg by default.

The results of the estimation of the maximum tolerated dose (MTD) are summarized in Table 1 below:
BOARD

<Tb>
<tb> Compounds <SEP> CRL <SEP> DMT <SEP> (mg / kg)
<tb> CRL <SEP> 8274 <SEP> (Ascididemine) <SEP> 20
<tb> CRL <SEP> 8269 (2-bromoleptoclinidone) <SEP> 40
<tb> CRL <SEP> 8323 <SEP> (Example <SEP> 1) <SEP> 20
<tb> CRL <SEP> 8301 <SEP> (Example <SEP> 2) <SEP>> 160
<tb> CRL <SEP> 8241 <SEP> (Example <SEP> 3) <SEP>> 160
<tb> CRL <SEP> 8325 <SEP> (Example <SEP> 4) <SEP>> 160
<tb> CRL <SEP> 8297 <SEP> (Example <SEP> 5) <SEP>> 160
<tb> CRL <SEP> 8289 <SEP> (Example <SEP> 6) <SEP> 20
<tb> CRL <SEP> 8344 <SEP> (Example <SEP> 7) <SEP>> 160
<tb> CRL <SEP> 8248 <SEP> (Example <SEP> 8) <SEP>> 160
<tb> CRL <SEP> 8347 <SEP> (Example <SEP> 9) <SEP>> 160
<tb> CRL <SEP> 8292 <SEP> (Example <SEP> 13) <SEP>> 160
<tb> CRL <SEP> 8290 <SEP> (Example <SEP> 12) <SEP> 80
<tb> CRL <SEP> 8333 <SEP> (Example <SEP> 14) <SEP>> 160
<tb> CRL <SEP> 8368 <SEP> (Example <SEP> 10) <SEP>> 160
<tb> CRL <SEP> 8369 <SEP> (Example <SEP> 15) <SEP>> 160
<tb> CRL <SEP> 8373 <SEP> (Example <SEP> 16) <SEP>> 160
<Tb>

<Desc / Clms Page number 25>

<Tb>
<tb> CRL <SEP> 8387 <SEP> (Example <SEP> 11) <SEP>> 160
<tb> CRL <SEP> 8389 <SEP> (Example <SEP> 17) <SEP>> 160
<Tb>
The majority of the products described in the ascididemine family have no direct toxicity (MTD> 160 mg / kg) and can therefore be used in vivo at high tissue concentrations, and therefore at high dosages.

2- Cytotoxic activity on tumor cell lines in culture
The influence of the compounds of formula 1 on neoplastic cells was evaluated using the MTT colorimetric test. The principle of the MTT test is based on the mitochondrial reduction by the metabolically active living cells of the product yellow MTT (3- (4,5-dimethylthiazol-2-yl) -2,5 diphenyltetrazolium bromide) in a blue color product , formazan. The amount of formazan thus obtained is directly proportional to the amount of living cells present in the culture well (s). This amount of formazan is measured spectrophotometrically.

The cell lines are maintained in 37C monolayer culture in closed-cap culture dishes containing MM HEPES (Minimum Essential Medium) MEM base medium. This medium, adapted to the growth of a range of diploid or primary mammalian varied cells, is then added: - a quantity of 5% of FCS (fetal calf serum) decomplemented with
56 C for 1 hour, - 0.6 mg / ml of L-glutamine, - 200 IU / ml of penicillin,

<Desc / Clms Page number 26>

 - 200 mg / ml of streptomycin, - 0.1 mg / ml of gentamicin.

 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 (ATCC code: and U-87MG (ATCC code: which are two glioblastomas, - SW1088 (ATCC code: HTB-12) which is an astrocytoma, - A549 (ATCC code: and A -427 (ATCC code: HTB-53) which are two non-small-cell lung cancers, - HCT-15 (ATCC code: CCL-225) and LoVo (ATCC code: CCL-229) which are two cancers colorectal, - T-47D (ATCC code: and MCF7 (ATCC code: HTB-22) which are two breast cancers, - J82 (ATCC code: HTB-1) and T24 (ATCC code: which are two bladder cancers) , - PC-3 (ATCC code: CRL-1435) which is a prostate cancer.

 Experimentally: 100 μl of a cell suspension containing 20,000 to 50,000 (depending on the cell type used) cells / ml of culture medium are inoculated into 96-well multi-well plates with a flat bottom and are incubated at 37 C under an atmosphere comprising 5% CO 2 and 70% moisture. After 24 hours of incubation, the culture medium is replaced by 100 l of fresh medium containing either the various compounds to be tested at concentrations ranging from 10-5 to 10-10 M or the solvent used to apply solution of the products to be tested (control condition). After 72 hours of incubation under the above conditions, the culture medium is replaced by 100 l of a yellowish solution of MTT dissolved at a rate of 1 mg / ml in RPMI 1640. The microplates are incubated for 3 hours at room temperature. 37 C then centrifuged for 10 minutes

<Desc / Clms Page number 27>

 at 400 g. The yellow solution of MTT is removed and the blue formazan crystals formed at the cellular level are dissolved in 100 l of DMSO. The microplates are then stirred for 5 minutes. The intensity of the blue coloration thus resulting from the transformation of the yellow MTT product into blue formazan by the cells still alive at the end of the experiment is quantified by spectrophotometry using a device of DYNATECH IMMUNOASSAY SYSTEM type with wave of 570 nm and 630 nm respectively corresponding to the maximum absorbance wavelengths of formazan and the background noise. An integrated spectrophotometer software calculates the average optical density values as well as the standard deviation values (Dev.

Std. ) and standard error on the average (ESM).

 The cell growth inhibitory activity of compounds of formula # on the different tumor cell lines was compared with that of the natural product, ascididemine (CRL 8274). All the compounds exhibit a significant inhibitory activity of 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 (IC 50) which is between 10-6M and 10-10M, depending on the compounds and the tumor lines tested. For example, the values of the concentrations flanking the Cl50 obtained on the different cell lines are given in Table II:

<Desc / Clms Page number 28>

TABLE II

<tb> COMPOUNDS <SEP> CELL LINES <SEP>
<tb> CRL <SEP> U-87MG <SEP> U-373MG <SEP> SW1088 <SEP> T24 <SEP> J82 <SEP> HCT-15 <SEP> LoVo <SEP> MCF7 <SEP> T-47D <SEP > A549 <SEP> A-427 <SEP> PC-3
<Tb>

CRL8274 110-7@ 10 -81 (10- ,10-7) (10-6,10.7) 110.7,10-8) 110-6,10.7) 110-8,10.9) 110-6,10.7) (10.7,10.8) ilol '10-71 (ÎOIO"7] |10'7,10"*] IlOlO'9] CRL8289 110-8,10.9) 110-8,10.9] 110-8,10.9) 110-8,10.9) 110.7,10-8) I10"7,10"*] ))0'',10] 11 ol,iolj 110-6,10.7) 110-6,10.7) ilol@101, 110-6,10.7) CRL8248 |10107] )10,t0''] tl0,]0'] 110.7,10-8) [10-6,10.7) [10"7,10"*] 110110-11 {W7,W*] IIO"7,!"*] 110-6,10.7) [10\10] fl0'',10 CRL8241 I10"7,10J] IlO'lO"8] (10"*,10"7] 110",10-8] llol101, [ÎOIO"8] )10,ï0' [ÎOIO"1] 110-6,10.'] [10"7,10'8] )10,10' [10,10] CRL8297 110.',10-8] [10-",10'1 110'910-'] 110",10-8] l 10-7@101] |10'7,10""] IIOIO"7] ilo-7101, ilo-101, [ÎOIO"8] llol 1101, [1O'7,1OJ] CRL8301 (10"*,10"7l 110-6,10.') [10"*,107] 110.',10-8] 110-6,10.7] 110-',1011 [ÎOIO7] [ÎOIO'7] [ÎOIO7] [10,107] [1010] 110-6,10.') CRL8323 110-7 elo'l IIO',io .91 [10-6,10.'] [10-"1011 [10 -101] 110.7,10-8] 110-6,10.7] !10,10''j [10'7,10"*] 110.7,10-8] 110",10-8] [t0"7,10"*] CRL8325 110.',10 110.',10-8) llo,101, [10-',10) [t0"7,10"*l 110.7,10 (ÎOIO'7] flol@101, [ÎOIO"8] [10-7101, [10-8,10.'1 [ÎOIO"8] CRL8344 [10-"110'] [10"7,l0"*] [10.',10 110",10-8) [10,10'] [101 9le] [10.5,10-6] [10.7,10-8] [ÎO.IO7] [10",10-8] [101 910 Il [10-6,10.7] CRL8347 1 (10",10-8] (10-8,10.9] [10",10-8] [10"*40"'l (ÎOIO"8] ilo-l@101 [ÎOIO"6] [ÎOIO"8] [101 1 0] I10"",10"9l [10-8,10"] {10,10 CRL8368 [10"10'1 (10-6,10.') [10.5,10; [10-6,10.7] flo-l101, [10"*,107] [101101, [10-6,10.7) [10-10-11 [10-6,10.') 110-6,10.') [10-6,10.') CRL8369 [10'',10 (10.5,10; [lOlO"6] [10-6,10"] [lO'.tO"6! [10-6,10.7) [10-6,10.') Ile@10-71 [10-6,10.7) [10.5,10; [10-6,10.7) ilo-l@10 1] CRL8373 [10',10'1 [10'5,10"*] (10',10'1 [ÎOIO7] [101@10-71 110-6,10"] [101@10-71 [ÎOIO7] (101@10-11 110.5,10; [10,107] lio'liol CRL8387 [10"5,10"<i] [1O"S,1O" [10'',10 [ÎOIO"4] [10'',10] [ÎOIO"6] [10-6,10"] [10'',10] (ÎOIO"6] [ÎOIO"6] [101,10-,l lio-1 CRL8389 [lOlO7] ilol@10-11 110-6,10.') [ÎOIO'7] [ÎOIO"6] [ÎO.IO7] [ÎOIO7] [10-6,10.'] [101 110-1, flol@10-1, llol@101] ilol@10- "J CRL8268* [10-',10'1 {10''',10] >10.5 110.5,10-6] [10.5,10; [ÎOIO"6] [10,10] [M'',10] [10'',10] [10-6,10.'] [to'.lO"6] [ÎOIO"6] CRL8322* [10'5,10"*] 110.5,10-61 >10"5 >10'5 >10.5 [10--',io'l >1OS 110.5,10; [ÎOIO"6] [10-"10,1 [lû'.lO"6] >1OS CRL8324** 110.5,10-6] >10.5 >10"5 >10.5 >10'5 [10"5,10] [10,10] [1O'S,1O"*] IlO'jO"6] [1010] [ÎO'.IO"6] [10-Iliel Concentrations inhibitrices (M) encadrant la valeur de la concentration inhibitrice 50 % des composés de formule I, II (*) ou III (**) sur les lignées cellulaires

CRL8274 110-7 @ 10 -81 (10-, 10-7) (10-6,10.7) 110.7-10-8) 110-6.10.7) 110-8.10.9) 110-6.10.7) (10.7, 10.8) [10 -71] [10] [10]] [10]] [10]]]] [110] (8.10) 110-8.10.9) 110-8.10.9] 110-8.10.9) 110-8.10.9) 110.7, 10-8) I10 -7, 10-7), 10-10, 110-6, 70-7, 110-6, 10-7, 10-1, 110-6, 10-7). CRL8248 | 10107]) 10, t0 ''] tl0,] 0 '] 110.7,10-8) [10-6,10.7) [10 "7,10" *] 110110-11 {W7, W *] 10O7, ## STR1 ## 10- [10] [10] [10] [10] [10] [10] [10] [10] [10] [10] [10] [10] [10] [10-10] [10-10] [10,10] [10,10] [10,10] [10,10,10] [10,10] [10,10] 8] [10- ", 10'1 110'910- '] 110", 10-8] 10-7101, 7, 10 "-1010 7] ilo-7101, ilo-101 , [110] 110, 110 [1010] CRL8301 (10 ", 10-7, 110-6, 10), [10-7], 10-8, 10-8. 6,10,7] 110 - ', 1011 [10107] [1010] [10107] [10,107] [1010] 110-6,10.') CRL8323 110-7 elo'l IIO ', io .91 [10-] 6,10.] [10- "1011 [10 -101] 110.7,10-8] 110-6,10.7]! 10,10''j [10'7,10" *] 110,7,10-8] 110 ", 10-8] [t0" 7.10 "*] CRL8325 110, 10, 110, 10-8) Ilo, 101, [10-1, 10) [t0, 7.10, 110.7.10 (1010)], [10-10], [10-8, 10], 1 [10] 8 CRL8344 [10 -110] [10-7,10] * [10,1 ', 10,110, 10-8] [10,10'] [101 9le] [10,5,10 -6] [10.7,10-8] [1010] [10 ", 10-8] [101 910 II [10-6,10.7] CRL8347 1 (10", 10-8] (10-8.10.9) ] [10 ", 10-8] [10" * 40 "'(1010) 8] [101] [10] [10] [101] [10] [10] 10-8.10 "] {10.10 CRL8368 [10-10] (10-6.10.) [10.5.10; [10-6, 10.7] flo-1101, [10-7, 107] [101101, [10-6, 10.7] [10-10-11 [10-6, 10]], 110-6,10. ) [10-6,10.] CRL8369 [10 '', 10 (10.5,10; [10106] [10-6,10 "] [10-10,10] [10-6,10-7] [10-6.10.] Ile @ 10-71 [10-6,10.7) [10.5,10; [10-6, 10.7) [10 ', 10'] [10 '5, 10 "*] (10', 10 ', 10-10) 10-71 [10107] 10-110 [10,101] [10,107] 10,100 [10,107] [10,10] [10,107] 10,10,10] [10,10,10] [10,10] [10,10,10] [10,10,10] [10,10,10] [10,10,10] ## STR2 ## wherein R 1 is CRL 8389 [10O]] 10-1, 10-6, 10 ') [10] [10] [6] [10] [10] 7 [10 -6, 10. 101, 110-1, flol @ 10-1, 1110, 101, 10, 10, 10, 10, 110, 10, 10, 10, 10.5, 10.5, 10.5, 10.5, 10.5, 10.5, 10.5, 10.5, 10.5, 10.5 and 10.5. 10; [1010] [10, 10] [M ', 10] [10', 10] [10-6,10.] [To '. 10-6] [10 -6] CRL8322 * [10'5.10 "*] 110.5.10-61>10"5>10'5> 10.5 [10 -10,1OS 110.5,10] [10-10] [10-10] ## STR1 ## ] [1010] [10-10] [10-Il] inhibitory concentrations (M) flanking the value of the 50% inhibitory concentration of the compounds of formula I, II (*) or III (*) *) on cell lines

<Desc / Clms Page number 29>

Table III gives the results of the average Cl50 (in nM) (calculated from the cytotoxic activity on the 12 tumor lines studied) and the DMT / IC50 ratios (these ratios are calculated by making the ratio of the DMTs and Cl50 expressed as dimensionless numbers).

TABLE III

<Tb>
<tb> Compounds <SEP> CRL <SEP> IC <SEP> 50 <SEP> (nM) <SEP> DMT / IC50 <SEP> DMT / IC50 *
<tb> CRL <SEP> 8274 <SEP> (Ascididemine) <SEP> 100 <SEP> 0.20 <SEP> 1
<tb> CRL <SEP> 8269 <SEP> 120 <SEP> 0.33 <SEP> 2
<tb> (2-bromoleptoclinidone) <SEP> ~~~~~~ <SEP> ~~~~~~ <SEP> ~~~~~~~
<tb> CRL <SEP> 8289 <SEP> (Example <SEP> 6) <SEP> 10 <SEP> 2.00 <SEP> 10
<tb> CRL <SEP> 8248 <SEP> (Example <SEP> 8) <SEP> 80 <SEQ> 2.00 <SEP> 10
<tb> CRL <SEP> 8241 <SEP> (Example <SEP> 3) <SEP> 140 <SEP> 1.14 <SEP> 6
<tb> CRL <SEP> 8297 <SEP> (Example <SEP> 5) <SEP> 90 <SE> 1.78 <SEP> 9
<tb> CRL <SEP> 8325 <SEP> (Example <SEP> 4) <SEP> 37 <SEP> 4.32 <SEP> 22
<tb> CRL <SEP> 8344 <SEP> (Example <SEP> 7) <SEP> 53 <SEP> 3.02 <SEP> 15
<tb> CRL <SEP> 8347 <SEP> (Example <SEP> 9) <SEP> 21 <SEP> 7.62 <SEP> 38
<tb> CRL <SEP> 8323 <SEP> (Example <SEP> 1) <SEP> 60 <SEP> 0.33 <SEP> 2
<tb> CRL <SEP> 8301 <SEP> (Example <SEP> 2) <SEP> 270 <SEP> 0.59 <SEP> 3
<tb> CRL <SEP> 8389 <SEP> (Example <SEP> 17) <SEP> 420 <SEP> 0.38 <SEP> 2
<tb> CRL <SEP> 8368 <SEP> (Example <SEP> 10) <SEP> 480 <SEP> 0.33 <SEP> 2
<Tb>
*: the ratio DMT / IC50 of the different compounds was estimated by taking as a reference a ratio equal to 1 for ascididémine.

 The compounds described have, on tumor cell lines of IC 50 (nM) higher or equivalent to that of ascididemine.

With the exception of CRL 8289 (the maximum tolerated dose of which is equivalent to that of ascididemine but whose IC50 is ten times lower than that of

<Desc / Clms Page number 30>

 Ascididemine), the maximum tolerated doses of the compounds described, considered by default equivalent to 160 mg / kg, are significantly higher than that of ascididemine (20 mg / kg). These results suggest that this new family of compounds does not exhibit direct toxicity. As a result, the cytotoxic tolerance / activity ratios of the compounds exemplified in the present invention are significantly higher than that of natural ascididemine. These compounds can therefore be used as anti-tumor drugs for their cytotoxic properties at higher tissue concentrations than those induced by natural ascididemine. They are therefore characterized by better therapeutic maneuverability. CRL 8289 with a 10 nM Cl50 also has better therapeutic maneuverability than ascididemine.

Due to their cytotoxic properties, the compounds of formulas 1 as described or in the form of acceptable pharmaceutical salts or solvates, can be used as active ingredients of medicaments.

 Compounds of formulas # are generally administered in dosage units established either per m2 of body surface area or per kg of weight. The said dosage units are preferably formulated in pharmaceutical compositions in which the active ingredient is mixed with one or more pharmaceutical excipients.

 The compounds of formula # can be used according to the cancerous pathology of the subject to be treated at doses of between 0.05 and 350 mg / m 2 of body surface area, preferably at doses of 0.5 to 50 mg / m 2 / day for a curative treatment in its acute phase depending on the number of treatment cycles of each treatment. For maintenance treatment, the compounds of formulas # are advantageously used at doses of 0.05 to 25 mg / m 2 / day, preferably at doses of 0.1 to 1.5 mg / m 2 / day depending on the number of treatment cycles of the cure. They may be associated with the anti-tumor drugs used in the validated protocols of intensive multidrug therapy.

<Desc / Clms Page number 31>

 In the pharmaceutical compositions of the present invention for oral, intravenous administration, the active ingredients can be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers suitable for human therapy. Suitable unit dosage forms include oral forms such as tablets, optionally scored, or capsules, implants and intravenous forms of administration.

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

 Thus, to prepare an aqueous solution for intravenous injection and intended for an infusion carried out over 1 to 24 hours, a cosolvent can be used: an alcohol such as ethanol, a glycol such as polyethylene glycol or propylene glycol and a hydrophilic surfactant. such as the Tween 80.

 When a solid composition in the form of tablets is prepared, a wetting agent such as sodium lauryl sulphate may be added to the active ingredient, micronized or not, and the whole is mixed with a pharmaceutical vehicle such as silica or gelatin. starch, lactose, magnesium stearate, talc, gum arabic or the like. The sucrose tablets, various polymers or other suitable materials may be coated or treated in such a way that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.

 A preparation in capsules is obtained by mixing the active ingredient with a diluent such as a glycol or a glycerol ester and incorporating the mixture obtained into soft or hard gelatin capsules.

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

<Desc / Clms Page number 32>

 The active ingredient may also be presented as a complex with a cyclodextrin, for example α-, β- or γ-cyclodextrin, 2-hydroxypropyl-ss-cyclodextrin or methyl-β-cyclodextrin.

 The compounds of formulas 1 will be used in the treatment of most solid tumors because of their potent cytotoxic activities, in particular for treating brain tumors, lung cancers, ovarian and breast tumors, endometrium, colorectal cancer, prostate cancer and testicular tumors.

 The subject of the present invention is also compounds of formula # as defined above, with the exception of compounds in which R1, R2, R4, R5, R6, R7 = H and R3 = OCH3, or else R1, R2, R3. , R4, R6, R7 = H and R5 = OH or OCH3, or R1, = N02 and R2, R3, R4, R5, R6, R7 = H,

Claims (7)

 in which: X is chosen from oxygen, the group = NH, the group = N-OH, R1 is chosen from hydrogen, halogens, the nitro group and the groups -NRgRg in which R8 and Rg are independently selected from hydrogen and (C1-C4) alkyl; R2 is chosen from hydrogen and halogen; R3 is chosen from hydrogen, halogens, (C1-C4) alkyl groups, (C1-C6) alkoxy groups, a guanidino group and -NR10R11 groups; in which R10 and R11 are independently selected from hydrogen, (C1-C4) alkyl, phenyl (C1-C4) alkyl, (CH2) 2-N (CH3) 2, and - (CH 2) 2 -O- (CH 2) 2 -N (CH 3) 2, - R 4 is chosen from hydrogen, halogens, nitro group and -NR 12 R 13 groups in which R 12 and R 13 are independently selected one of the other from hydrogen and (C1-C4) alkyl groups; - R5, R6 and R7 are chosen from:

 1 - A pharmaceutical composition comprising an effective amount of a compound selected from compounds of formula # for treating, by virtue of their cytotoxic properties, cancerous tumors and their metastases: <Desc / Clms Page number 34>  R16 and R17 being selected from C1-C6 alkyl and Ar being C6-C14 aryl, excluding compounds wherein X = 0, and or R1, R2, R3, R4, R5, R6 , R7 = H, or R1, R3, R4, R5, R6, R7 = H and R2 = Br, and their addition salts of these compounds with pharmaceutically acceptable acids.

 hydrogen, a halogen atom, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, -CHO, COOH, -CN, -CO2R14, -CONHR14, -CONR14R15 groups -NHCOR14 and NR14R15, wherein R14 and R15 are independently selected from hydrogen, (C1-C6) alkyl and -CH2-CH2-N (CH3) 2, -phenyl-CO-CH3 or - phenyl-CO-CH = CH-N (CH3) 2, morpholino, nitro, SO3H, the groups:  2 - Pharmaceutical composition according to claim 1 comprising an effective amount of a compound selected from the compounds of formula 1 in which: - X represents oxygen, - R1 is chosen from hydrogen and the amino group, - R2 is chosen among hydrogen and halogens, R3 is chosen from hydrogen, halogens, (C1-C4) alkyl groups, (C1-C6) alkoxy groups, guanidino groups, -NR10R11 groups in which R10 and R11 are selected, independently of one another, from hydrogen, methyl, phenyl (C 1 -C 4) alkyl, - (CH 2) 2 -N (CH 3) 2, - (CH 2) 2 -O- (CH 2 ) 2-N (CH3) 2; - R4 is chosen from hydrogen, halogens and the nitro and amino group, - R5, R6, R7 represent a hydrogen, <Desc / Clms Page number 35>  excluding compounds in which R1, R2, R3, R4, R5, R6, R7 = H, or R1, R3, R4, R5, R6, R7 = H and R2 = Br, and their addition salts thereof. compounds with pharmaceutically acceptable acids. 3 - Composition according to claim 2 wherein 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] [1,10] phenanthrolin-9-one, 5-bromo-9H-quino [4,3,2-de] [1,10] phenantrolin-9 -one, 7-amino-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 5-amino-9H-quino [4,3,2-de] [1] 10] phenanthrolin-9-one, 5-methyl-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one,

 10-methoxy-9H-quino [4,3,2-de] [1,10] phenanthrofin-9-one, 5-methoxy-9H-quino [4,3,2-de] [1,10] phénanthrolin-9-one,

 7-nitro-9H quino [4,3,2-de] [1,10] phenanthrolin-9-one, 5-chloro-9H-quino [4,3,2-de] [1,10] phenantrolin 9-one, 5-bromo-10-methoxy-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, and their addition salts with pharmaceutically acceptable acids. 4 - Use of a compound as defined in claim 1 or claim 2 for the manufacture of an anticancer drug. 5 - Use according to claim 4 wherein 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] (1,10) phenanthrolin-9-one, 5-bromo-9H-quino [4,3,2-de] [1,1 O] phenantrolin-9-one, 7-amino-9H-quino [4] , 3,2-de] [1,10] phenanthrolin-9-one, 5-amino-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, <Desc / Clms Page number 36>  5-methyl-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 10-methoxy-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 5-methoxy-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 7-nitro-9H-quino [4,3,2-de ] [1,10] phenanthrolin-9-one, 5-chloro-9H-quino [4,3,2-de] [1,10] phenantrolin-9-one, 5-bromo-10-methoxy-9H- quino [4,3,2-de] [1,10] phenanthrolin-9-one, and their addition salts with pharmaceutically acceptable acids.

5 10 15 20 6 - Compounds of general formula #

 in which: X is chosen from oxygen, the group = NH, the group = N-OH, -R1 is chosen from hydrogen, halogens, nitro group and -NRgRg groups in which Rg and Rg are independently selected from hydrogen and (C1-C4) alkyl; R2 is chosen from hydrogen and halogen; R3 is chosen from hydrogen, halogens, (C1-C4) alkyl groups, (C1-C6) alkoxy groups, a guanidino group, and -NR10R11 groups; in which R10 and R11 are independently selected from hydrogen, (C1-C4) alkyl, phenyl (C1-C4) alkyl, (CH2) 2-N (CH3) 2, and - (CH 2) 2 -O- (CH 2) 2 -N (CH 3) 2, <Desc / Clms Page number 37>  R16 and R17 being selected from C1-C6 alkyl and Ar being C6-C14 aryl, excluding compounds wherein X = 0, and or R1, R2, R3, R4, R5, R6 , R7 = H, or R1, R3, R4, R5, R6, R7 = H and R2 = Br, or R1, R2, R4, R5, R6, R7 = H and R3 = OCH3, or R1, R2 R3, R4, R6, R7 = H and R5 = OH or OCH3, or R1 = NO2 and R2, R3, R4, R5, R6, R7 = H, and their addition salts with pharmaceutically acceptable acids.

 R4 is selected from hydrogen, halogens, nitro groups, and -NR12R13 groups wherein R12 and R13 are independently selected from hydrogen and (C1-C4) alkyl groups; R5, R6 and R7 are chosen from: hydrogen, a halogen atom, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, -CHO, COOH, -CN, -CO2R14, -CONHR14 groups; -CONR14R15, -NHCOR14 and -NR14R15 wherein R14 and R15 are independently selected from hydrogen, (C1-C6) alkyl and -CH2-CH2-N (CH3) 2, the groups -phenyl-CO-CH3 or -phenyl-CO-CH = CH-N (CH3) 2, morpholino, nitro, SO3H, the groups: 7 - Compounds according to claim 6 which are: 5- (dimethylamino) -9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one,

 5- (benzylamino) -9H-quino [4,3,2-d] [1,10Jphenanthrolin-9-one, 5-bromo-9H-quino [4,3,2-de] [1,10] phenantrolin 9-one, 7-amino-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 5-amino-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 5-methyl-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, <Desc / Clms Page number 38>  5-chloro-9H-quino [4,3,2-de] [1,10] phenantrolin-9-one, 5-bromo-10-methoxy-9H-quino [4,3,2-de] [1] , 10] phenanthrolin-9-one, and their addition salts with pharmaceutically acceptable acids.