ZA200200840B - Ascididemin derivatives and their therapeutic applications. - Google Patents

Description

. i ~

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

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 (5-FU), 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 sclective 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 bhetter tolerated, thus improving the survival and the quality of life of the patients, 1s imperative since, taking once again the example of colorectal tumors, it has been estimated (S.L.. Parker, T. Tong, S. Bolden et al., CA Cancer

J. Clin., 1997) that in the United States alone, more than 131 000 new cases were diagnosed in 1997, 54 000 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

. 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 (E. 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 (A. Bowman et al.,

NCI-EORTC symposium, 1998; Abst. 452 p.- 118;

M. Villanova-Calero et al., NCI-EORTC symposium, 1998;

Abst. 453 p. 118; M.J.X. Hillebrand et al., NCI-EORTC symposium, 1998; Abst. 455 p. 119; E. Citkovic et al.,

NCI-EORTC symposium, 1998; Abst. 456 p. 119). Novel pentacyclic acridine derivatives have also been the subject of pharmacochemical studies (D.J. Hagan et al.,

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

Another natural alkaloid of marine origin, ascididemin, has been extracted from the tunicate Didemnum sp. (J. Kobayashi et al., Tetrahedron, lett. 1988; 29: 1177-80) and from the ascidian Cystodytes dellechiajei (I. Bonnard et al., Anti-cancer Drug design 1995; 10:

333-46). Ascididemin possesses antiproliferative properties demonstrated on the model of mouse leukemia (lines P388 or L1210) and described by F. Schmitz et al. (J. Org. Chem. 1991; 56: 804-8), B. Lindsay et al. (Bioorg. Med. Chem. Lett. 1995; 5: 739-42) and

J. Kobayashi et al. (Tetrahedron lett. 1988; 29: 1177- 80) and on the model of human leukemia described by

I. Bonnard et al. (Anti-cancer Drug design 1995; 10: 333-46). Several routes for synthesizing ascididemin 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. (J. Ann. Chem. Soc. 1987; 109: 6134-6) and synthesized by F. Bracher et al. (Hétérocycles 1989; 29: 2093-95) and then by M.E. Jung et al. (Hétérocycles 1994; 39; 2: 767-778). 2-Bromoleptoclinidone shows cytotoxicity on the cellular model of leukemia with an EDs; of 0.4 ug/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 HTClle, renal tumor A498 and melanoma

LOX IM VI) implanted inlo mice.

Other compounds derived from ascididemin, such as 11-hydroxy ascididemin, ll-methoxy ascididemin, ll-phenyl and 1ll-nitrophenyl ascididemin, 1l-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 (J. Org. Chem. 1991; 56: 804-8) and

Y. Kitahara et al. (Heterocycles 1993; 36: 943-46;

Tetrahedron Lett. 1997; 53, 17029-38), G. Gellerman et al. (Tetrahedron lett. 1993; 34: 1827-30), S. Nakahara et al (Heterocycles 1993; 36: 1139-44), I. Spector et al. (US Patent Number: 5,432,172, Jul. 11, 1995).

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:

Rs . Ry X R, = AN Fe = AN k ~ | P - »

R Rs RE Rs

NZ Re No 2 Re

Formula i Formula la 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 -NRgRg in which Rg and Rg are chosen, independently of each other, from hydrogen and (Ci-C4) alkyl groups, - R; is chosen from hydrogen and halogens, - R3 is chosen from hydrogen, halogens, (Ci—C4) alkyl groups, (Ci-Cs) alkoxy groups, a guanidino group, groups -NR;gR11 in which Rig and Rj; are chosen, independently of each other, from hydrogen, {C1—-Cy) alkyl groups, (C;—-C4) phenylalkyl groups and groups ~ (CH) p-Y with Y being chosen from halogens and CN, -CH(O-Et)2, (C1-Cg¢) alkoxy, -0-(CH;),-N(CHs3)2 and -N(CHs): groups and n = 1 to 3, - Ry is chosen from hydrogen, halogens, nitro groups and groups -NR;;R;3 in which Rj; and Riz are chosen, independently of each other, from hydrogen and (C1-C4) alkyl groups,

: C5 - Rs, Rg and Ry are chosen from: hydrogen or a halogen atom,

C1-Ce¢ alkyl, hydroxyl, C;-C¢ alkoxy, (C;-Cg)- alkoxy (Ci-Cg¢) alkyl, (C1-Cy) alkylcarbonyloxy (Ci-Cy) alkyl, -CHO, -COOH, -CN, -COzRis, -CONHR;s and -CONRisR;5 groups, -NHCOR;4 and -NRj4R;s in which Rjy and Ris are chosen, independently of each other, from hydrogen and (C;-Cg) alkyl, -phenyl-CO-CH; and -CH,-CH;-N(CH3), groups, ~phenyl-CO-CH; or —phenyl-CO-CH=CH-N (CH3) 5, morpholino, nitro or SOsH groups, groups: “OF =N-COORyg g -CH; = N— COORyg ,

CH,- COORy7 Ch, —Ar

Ris and Rj7; being chosen from C;-C¢ alkyl groups and Ar being a C¢-Cy;4 aryl group, with the exclusion of the compounds of formula I containing the combination:

X = 0, and, either: Ri, Rz, Rs, Ry, Rs, Rg, Ry = H, or : Ry, Rs, Rsy Rs, Rg, Ry = H and R; = Br, and with the exclusion of the compound formula Ia containing the combination X = O and R;, R», Riz, Rs, Rs,

R¢, Ry = 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, - R; 1s chosen from hydrogen, halogens, a nitro group and groups -NRgRg in which Rg and Ry are chosen, independently of each other, from hydrogen and (C;-Cy) alkyl groups,

< - 6 - independently of each other, from hydrogen and (C;-Cy) alkyl groups, - R, is chosen from hydrogen and halogens, - R; is chosen from hydrogen, halogens, (C;—Cy4) alkyl groups, (C;-Cs) alkoxy groups, a guanidino group, groups -NRjoR;; in which Ryo and R31 are chosen, |. independently of each other, from hydrogen, (C;-C,) alkyl groups, (C1-C4) phenylalkyl, -(CH;),-N(CH3),;, and = (CH) 2-0~ (CH2) 2-N (CH3) 2 groups, - Ry is chosen from hydrogen, halogens, nitro groups and groups -NRj;2R;3 in which Rj; and Riz are chosen, independently of each other, from hydrogen and (C;-C4) alkyl groups, - Rs, Rg and Ry; are chosen from: hydrogen or a halogen atom,

Ci-C¢ alkyl, hydroxyl, C;-C¢ alkoxy, -CHO, -

COOH, ~CN, -COz2Ri14, ~CONHR;s and -CONRisRi5 groups, -

NHCOR3;4 and -NRj4Ri5 groups in which Rjs and Ris are chosen, independently of each other, from hydrogen and (C1-C¢) alkyl and -CH,-CH,-N(CHs3): groups, -phenyl~CO-CH; or -phenyl-CO~CH=CH-N(CH3),, morpholino, nitro or SO3H groups, groups: -CH, -N —~COORyg , -CH,— i COR,

CH, - COOR7 CH, —Ar

Ri;¢ and Rj; being chosen from C;-Cs alkyl groups and Ar being a C¢-C;4 aryl group, with the exclusion of the compounds in which X = O, and, either : Ri, Rs, Rs, Ry, Rs, R¢, Ry = H, or : Ri, Rs,

Rs; Rs, Rg, R; = H and R, = 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 effective amount of a compound chosen from the compounds of formula I in which: v - X represents oxygen, = R; 1s chosen from hydrogen and an amino group, - R; is chosen from hydrogen and halogens, - R3 is chosen from hydrogen, halogens, (C;-Cy) alkyl groups, (C1-C¢) alkoxy groups, a guanidino group, groups -NRjpR;; in which Ryo and Rj; are chosen, independently of each other, from hydrogen, methyl groups, (C;-C4) phenylalkyl, -(CHy),-N(CH3),, (CHjy),-0- (CHz) 2-N(CH3) 2 groups, - Ry 1s chosen from hydrogen, halogens and nitro and amino groups, - Rs, Re¢ and Ry; represent a hydrogen, with the exclusion of the compounds in which Ry,

R2, Rs, Rs, Rs, R¢, Ry = H, or Ry, Rs, Rg, Rs, Rg, Ry =H and R, = 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, - R; is chosen from hydrogen and an amino group, ~ R> is chosen from hydrogen and halogens, - Rs; is chosen from hydrogen, halogens, (C1-Cy) alkyl groups, (C;-Cg) alkoxy groups, a guanidino group, groups -NRjpRi;; in which Ry; and Ry; are chosen, independently of each other, from hydrogen, methyl groups, (C1-C4) phenylalkyl groups and groups -(CHy),-Y with Y being chosen from halogens and groups CN, -CH(O-

Et)2, (C1-Cs) alkoxy, -0-(CH;),-N(CH3), and -N(CHs3), and n=1 to 3,

‘ ~ 8 - - Ry; 1s chosen from hydrogen, halogens, and nitro and. amino groups, - Rs is chosen from a hydrogen, a halogen and a methoxy group, - R¢ and Ry; are chosen from hydrogen and C;-Ce alkoxy, (C1-Ce¢)alkoxy(Ci-Cs)alkyl and -CH,OCOCH; groups, with the exclusion of the compounds of formula I in which R;, R;, R3, Rs, Rs, Rg, Ry = H or Ri, Rs, Rs, Rs,

Rg, Ry = H and R, = Br, and of the compound of formula

Ia in which R;, Rz, Rs, Rs, Rs, Rg, R7 = 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, R2, Rs, Rs, Rs, Rg, Ry; = H, or Ri, R3, Rs, Rs, Rg, Ry = H and R, = Br, or Ri, R2, Ry, Rs, Rg, Ry = H and R3 = OCHs, or Ri, R2y R3, Rs, Rg, R; = H and Rs = OH or OCHs, or Ry; = NO; and Ry, Rs, Ry, Rg, Ry = 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 = O and R;, Rj, Rj,

Rsr Rs, Rg, Ry = H, and the addition salls 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

Rk - 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

ITI with dimethylformamide diethyl acetal gives the final derivative by cyclization:

Scheme I

Rs O Ry Rs 0 H R;

Re HN R; Re Ry z CeCl3,7H20 Z : ceasrag 17 ) Q CyHsOH N :

RS R3 Ry Ry

Oo O

Hs Re CH, Re

Formula 1]

Re pp N Ry

H,S0,conc./AcOH | | = HAOGHI NCH, —————————p- reflux x Z DMF, 120°C a . lo) CH; R,

Formula: it} : Rs O R Rs O R,

Re Ry NHAC Rg R “2 | AN AcOH = AN :

EEEe— a = a xX Z

O

7 Ry = Re

N(CH), Formula

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; is a group -NRjoRi;, where Ry; and/or Rj; are other than hydrogen, may be obtained from a compound of formula I in which R3 is an -NH; 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 l-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.

Scheme II

OMe co Ru OMe Ri

NH, Ry . R, + Cug -

HO,C Rs HO,C Rs

OMe Ry OMe Ra

Formula ITa

OMe H Ti OMe R4 2 R

LICH, = H+ = 2 — | —

CHoc” TT "Rs YY Rs

OMe Ra OMe Ry

SN

R N O Ry 0 R, 7 R R R i AN 2 he 2

NF

REN | Rs Rg Rs

Rs 0 Rg Rs O R4

Formula IIIa Formula IVa 0 Ry

R; R,

DMFDEA, NH, Cl A oN —_— xy ION

Rg Rs;

Rs NA Ry

Formula Ia

AMENDED SHEET

} 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.

AMENDED SHEET

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- chlorophenylamino)quinoline-5,8-dione (Intermediate A)

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 gq, 3.14 mmol), ethanol (10 + 4 ml), acetic acid (25 ml). 0.3 g of a red powder is obtained: e Yield = 78% e '"H 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 (4d, 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). e C NMR (CDCl): 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- benzylaminophenylamino)quinoline-~5,8-dione (Intermediate As)

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), b5-benzylamino-2- aminoacetophenone (0.603 g, 3.14 mmol), ethanol (15 + 7 ml), acetic acid (35 ml). 0.56 g of a red powder is obtained: e Yield = 91% e 'H NMR (CDCls): 2.54 (s, 3H), 4.38 (s, 2H), 6.70 (s, 1H), 6.83 (dd, 1H, J = 9.6 and 3.2 Hz), 7.08 (d, 1H, J = 3.2 Hz), 7.30-7.37 (m, 5H), 7.43 (d, 1H, J = 9.6 Hz), 7.58 (dd, 1H, J = 7.6 and 4.8 Hz), 8.43 (dd, 1H, J = 7.6 and 2 Hz), 9.03 (dd, 1H, J = 2 and 4.8 Hz), 10.67 (s, 1H).

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

A;) (CRL 8268)

Preparation according to the process described by

F. Bracher, Liebigs Ann. Chem. 1990, 205-206.

A-5 - Synthesis of 6-(2-acetyl-4- dimethylaminophenylamino)quinoline-5,8~dione (Intermediate As)

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 qg, 4.49 mmol), ethanol (20 + 10 ml), acetic acid (50 ml). 1.26 g of a red powder are obtained: e Yield = 84% e 'H 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, 14, J = 2.8 Hz), 7.49 (4, 1H, J = 9.2 Hz), 7.58 (44, 1H, J = 8 Hz and 4.4 Hz), 8.43 (dd, 1H, J = 1.6 and 8 Hz), 9.00 (dd, 1H, J = 1.6 and 4.4 Hz), 10.69 (s, 1H).

A-6 — Synthesis of 6-(2-acetyl-4- methoxyphenylamino) quinoline-5,8-dione (Intermediate Ag)

Preparation according to the process described in chapter A-1: quinoline-5,8-dione (3.51 g, 22.08 mmol), cerium chloride (16.4 gq, 44.03 mmol), S5-methoxy-2- aminoacetophenone (7.29 gq, 44.18 mmol), ethanol (200 + 90 ml), acetic acid (500 ml). 4.25 g of a red powder are obtained: e Yield = 60% e 'H NMR (CDCls): 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 (4, 14, 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 4,6-bis(2-acetylanilino)quinoline- 5,8~-dione (Intermediate A;)

Preparation according to the process described in chapter A-1: 4-chloroquinoline-5, 8-dione (3.5 gq, 18 mmol), cerium chloride (13.5 g, 36.24 mmol), 2-~ aminoacetophenone (4.4 ml, 36 mmol), ethanol (160 + 70 ml), acetic acid (400 ml). 2.32 g of a red powder are obtained: e Yield = 30% e 'H 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-bromophenylamino)-4- methoxyquinoline-5,8-dione (Intermediate Ag)

Preparation according to the process described in chapter A-1: 4-methoxyquinoline-5, 8-dione (1.57 g, 9.1 mmol), cerium chloride (3.1 g, 8.3 mmol), 5-bromo- 2-aminoacetophenone (Leonard, Boyd, J. Org. Chem. 1946; 11, 419-423) (1.95 g, 9.1 mmol), ethanol (200 ml), acetic acid (180 ml). After purification by flash chromatography on a column of silica (95/5 CH,Cl,/MeOH), 1.22 g of an orange powder are obtained: e Yield = 37% » 'H NMR (CDCls): 3.15 (s, 3H), 4.58 (s, 3H), 7.61 (d, 14, J = 6 Hz), 7.74 (s, 1H), 7.99 (4, 1H, J = 8.8 Hz), 8.14 (dd, 1H, J = 8.8 and 2.4 Hz), 8.51 (d, 1H, 0 = 2.8 Hz), 9.32 (d, 1H, J = 6 Hz), 11.68 (s, 1H).

A-9 - Synthesis of 2-methoxy-6-(2- acetylphenylamino)quinoline-5,8-dione (Intermediate A,)

A solution of o-aminoacetophenone (0.41 g, 3.1 mmol) in ethanol (6 ml) is added to a suspension of 2-methoxy- quinoline-5,8-dione (0.54 gq, 2.8 mmol) and cerium chloride (1.16 g, 4.7 mmol) in ethanol (100 ml). The reaction medium is stirred at room temperature for 40 hours. After concentration on a rotary evaporator, the crude product obtained is purified by filtration on silica (98/2 CHClsz/heptane) to give the expected codensation product in the form of a red powder (0.35 qg). ® Yield = 38% e Melting point = 258°C e 'H NMR (CDCl3): 2.67 (s, 3H), 4.15 (s, 3H), 6.79 (s, 1H), 6.98 (d4, 1H, J = 8.8 Hz), 7.18 (ddd, 1H, J = 8.1, 8.4 and 1.5 Hz), 7.56 (dd, 1H, J = 8.4 and 1.5 Hz), 7.61 (ddd, 1H, J = 8.1 and 8.4 and 1.1 Hz), 7.94 (dd, 1H, J = 8.1 and 1.5 Hz), 8.31 (d, 1H, J = 8.8 Hz). e °C NMR (CDCl3): 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. e IR (CHCl3): 1668, 1644 cm

A-10 ~- Synthesis of 3-hydroxymethyl-6-(2- acetylphenylamino)quinoline~5, 8-dione (Intermediate Aq) a) - 3-Hydroxymethyl-5,8-dimethoxyquinoline

A solution of 1M LiAlH4/Et,0 (5 ml, 5 mmol) is added dropwise and under nitrogen to a solution of ethyl 5, 8- dimethoxyquinoline-3-carboxylate (180 mg, 0.689 mmol) in 60 ml of THF. The mixture is stirred at room temperature for 15 hours and then poured into 15 ml of

IN NaOH and 40 ml of water. After extraction with CH,Cl, (3 x 100 ml) and then drying of the organic phase over

MgSQy, the extract is concentrated on a rotary evaporator. The crude product obtained is purified by flash chromatography (95/5 CH;Cl,/MeOH) to give the expected product in the form of a brown powder (72 mg): e Yield = 48% e Melting point = 150°C a _ 17 —_— e 'H NMR (CDCl3): 3.92 (s, 3H), 4.00 (s, 3H), 4.88 (s, 2H), 6.72 (d, 1H, J = 8.4 Hz), 6.88 (d, 1H, J = 8.4 Hz), 8.47 (d, 1H, J = 2.2 Hz), 8.87 (d, 1H, J = 2.2 Hz) e YC NMR (CDCl3;): 55.76, 56.00, 63.09, 103.95, 106.70, 121.25, 128.62, 133.35, 139.80, 148.61, 149.21, 149.41. e IR (CDCl): 3607, 3417, 1622, 1605 cm’. b) - 3-Hydroxymethyl-5,8-dimethoxyquinoline

A solution of 3-hydroxymethyl-5,8-dimethoxyquinoline (35 mg, 0.25 mmol) and cerium ammonium nitrate (550 mg, 1 mmol) in a CH3CN/H,O0 mixture (3 ml/1 ml) is stirred at room temperature for 40 minutes. After addition of 5 ml of HO and 10 ml of saturated NaHCO3 solution, the medium 1s extracted with CHyCl, (6 x 30 ml) and the organic phases are dried over MgSO;. After evaporating off the solvent on a rotary evaporator, the expected quincne is obtained in the form of a brown powder (11 mg): e Yield = 22% e Melting point = 150°C e 'H NMR (CDCl3): 4.95 (s, 2H), 7.06 (d, 1H, J = 10.2 Hz), 7.15 (d, 1H, J = 10.2 Hz), 8.43 (s, 1H), 9.03 (s, 1H). e ’C NMR (CDClj3): 62.03, 128.86, 132.26, 138.00, 139.11, 141.33, 146.58, 153.10, 183.12, 184.54. e IR (CHCls): 3413, 1680, 1596 cm™. ¢) — Synthesis of 3-hydroxymethyl-6-(2-acetylphenyl- amino)quinoline-5,8~dione (Intermediate A;j)

A solution of 2-aminocacetophencne (0.18 g, 1.33 mmol) is added to a suspension of 3-hydroxymethylquinoline- 5,8-dione (0.22 gq, 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,C1l,/MeOH) to give the expected condensation product in the form of a violet powder (0.16 qg): e Yield = 42% e Melting point = 258°C e 'H NMR (DMSO-d¢): 2.67 (s, 3H), 4.73 (d, 2H, J = 5.5 Hz), 5.67 (t, 1H, J = 5.5 Hz), 6.64 (s, 1H), 7.30 (m, 1H), 7.71 (m, 2H), 8.12 (d, 1H, J = 8.0 Hz), 8.35 (d, 1H, J = 2.0 Hz), 8.93 (d, 1H, J = 2.0 Hz), 11.02 (s, 1H). e C NMR (CDCls): 28.81, 60.08, 106.52, 120.96, 123.44, 126.14, 127.23, 131.52, 132.69, 134.43, 138.91 141.75, 143.55, 146.62, 152.81, 181.62, 181.84, 202.02. e IR (CHCl): 3440, 1690, 1661, 1640 cm™.

B — Preparation of the intermediate products of formula

III (Scheme II)

B-1 - Synthesis of 9,1ll-dimethyl-1,6-diazanaphthacene- 5,12-dione (Intermediate B;) (CRL 8324) 1.9 m1 of sulfuric acid dissolved in 9.6 ml of acetic acid are added slowly to a solution of tricyclic intermediate A; (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

NH,OH and then extracted 4 times with dichloromethane.

The organic phases are dried over MgSO, and then evaporated. The crude product obtained is purified by flash chromatography on a column of silica (95/5

CH;Cl,/MeQH) to give 0.325 g of the expected tetracyclic compound. e Yield = 86% e '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).

: - 19 = : B-2 - Synthesis of 9-chloro-1ll-methyl-1,6- diazanaphthacene-5,12-dione (Intermediate B;)

Preparation according to the process described in chapter B-1: tricyclic intermediate A, (0.289 gq, 0.88 mmol), sulfuric acid (1.3 ml), acetic acid (8 + 6.5 ml). After purification by flash chromatography (95/5 CH,;Cl,/MeOH), 0.26 g of tetracycle is obtained: e Yield = 95% e '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, 14, 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-l1ll-methyl-1,6- diazanaphthacene-5,12-dione (Intermediate Bj)

Preparation according to the process described in chapter B-1: tricyclic intermediate As (4 g, 10 mmol), sulfuric acid (15.1 ml), acetic acid (92 + 75 ml).

After work-up, 3.58 g of tetracycle are obtained. e Yield = 98% e 'H NMR (CDCl3): 3.09 (s, 3H), 4.52 (d, 2H), 4.86 (¢, 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-l1ll-methyl-1,6- diazanaphthacene-5,12-dione (Intermediate Bj)

Preparation according to the process described by

F. Bracher, Liebigs Ann. Chem. 1990, 205-206.

B-5 - Synthesis of 9-dimethylamino-ll-methyl-1,6- diazanaphthacene-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 (20 + 18 ml). After work-up, 0.67 g of tetracycle is obtained.

® Yield = 93% e 'H NMR (CDCl3): 3.17 (s, 3H), 3.21 (s, 6H), 7.04 (d, 1H, J = 3.2 Hz), 7.51 (dd, 1H, J = 3.2 and 9.2 Hz), 7.71 (dd, 1H, J = 8 and 4.4 Hz), 8.26 (d, 1H, J = 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-1ll-methyl-1,6- diazanaphthacene-5,12-dione (Intermediate Bg)

Preparation according to the process described in chapter B-1: intermediate tricycle Ag (4.25 gq, 13.18 mmol), sulfuric acid (20 ml), acetic acid (110 + 100 ml). The product obtained by flash chromatography (100/3 CH,Cl,/MeOH) is washed with ethyl ether to give 2.9 g of tetracycle. ® Yield = 72% e 'H NMR (CDCl3): 3.25 (s, 3H), 4.02 (s, 3H), 7.49 (d, 1H, J = 3.3 Hz), 7.56 (dd, 1H, J = 3.3 and 9.3 Hz), 7.74 (dd, 1H, J = 8.3 and 4.3 Hz), 8.34 (d, 1H, J = 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)-l1l-methyl-1,6- diazanaphthacene-5,12-dione (Intermediate B;) (CRL 8332)

Preparation according to the process described in chapter B-1: intermediate tricycle A; (1 g, 2.35 mmol), sulfuric acid (3.5 ml), acetic acid (18 ml). The product obtained by flash chromatography (100/3

CHzCl;/MeOH) is washed with ethyl ether to give 0.6 g of tetracycle in the form of an orange powder. e Yield = 63% e 'H NMR (CDCls): 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, 6 Hz), 12.5 (s, 1H).

j - 21 -

B-8 - Synthesis of 4-methoxy-9-bromo-1ll-methyl-1,6- : diazanaphthacene-5,12-dione (Intermediate Bg) :

Preparation according to the process described in chapter B-1: intermediate tricycle Ag (1.22 gq, 3.04 mmol), sulfuric acid (4.5 ml), acetic acid (27 + 23 ml). The product obtained by flash chromatography (100/3 CHyCl,/MeCH) is washed with ethyl ether to give 0.76 g of tetracycle in the form of a yellow powder. e Yield = 65% e 'H NMR (CDCl3): 3.21 (s, 3H), 4.10 (s, 3H), 7.18 (d, 1H, J = 6 Hz), 7.96 (dd, 1H, J = 8.8 and 2 Hz), 8.27 (4, 1H, J = 8.8 Hz), 8.47 (d, 1H, J = 2 Hz), 8.89 (d, 1H, J = 6 Hz).

B-9 - Synthesis of 2-methoxy-1l-methyl-1,6- diazanaphthacene-5,12-dione (Intermediate By)

A solution of 2-methoxy-6- (2- acetylphenylamino) quinoline-5, 8—-dione (0.34 gq, 1.1 mmol) in an acetic acid/sulfuric acid mixture (25 mol/2.7 ml) is heated at 90°C 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,CO3 and extracted with CHCl; (3 x 200 ml). The organic phases are dried over MgSO; and then concentrated on a rotary evaporator. The crude product obtained is purified by filtration on silica (CHCli) to give the expected tetracycle in the form of a beige-colored powder (0.23 g): e Yield = 71% e Melting point = 260°C e 'H NMR (CDCl3): 3.32 (s, 3H), 4.23 (s, 3H), 7.14 (d, 1H, J = 8.8 Hz), 7.79 (ddd, 1H, J = 8.6, 8.4 and 1.2 Hz), 7.91 (ddd, 1H, J = 8.4, 8.6 and 1.2 Hz), 8.38 (dd, 1H, J = 8.6 and 1.2 Hz), 8.46 (dd, 1H, J = 8.4 and 1.2 Hz), 8.58 (d, 1H, J = 8.8 Hz). e °C NMR (CDClj3): 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.

e IR (CHCl3): 1683, 1599 cm’! x

B-10 - Synthesis of 3-acetoxymethyl-ll-methyl-1,6- diazanaphthacene-5,12-dione (Intermediate Bg)

A solution of 3-hydroxymethyl-6-(2-acetylphenylamino)- quinoline-5, 8-dione (Intermediate Aig), (0.248 gq, 0.77 mmol) in an acetic acid/sulfuric acid mixture (16 ml/1.3 ml) is heated at 90°C for 2 hours 30 minutes. After cooling, the reaction medium is poured into a water/ice mixture (15 ml) and then basified to pH 9 with NayCO3. The medium is then extracted with CHCl, (3 x 150 ml). The organic phases are dried over MgSO; and then concentrated on a rotary evaporator. The crude product obtained is purified by filtration through silica (98/2 CH,Cl,/MeOH) to give the expected compound in the form of a brown powder (0.21 g). e Yield = 85% e Melting point = 210°C e 'H NMR (CDCl): 2.18 (s, 3H), 3.30 (s, 3H), 5.31 (s, 2H), 7.78 (ddd, 1H, J = 1.1, 6.8 and 8.1 Hz), 7.92 (ddd, 1H, J = 1.1, 6.8 and 8.1 Hz), 8.37 (dd, 1H, J = 8.1 and 1.1 Hz), 8.43 (dd, 1H, J = 8.1 and 1.1 Hz), 8.66 (d, 1H, J = 2.2 Hz), 9.09 (d, 1H, J = 2.2 Hz). e ’C NMR (CDCl3): 16.06, 20.11, 62.06, 124.81, 124.91, 129.06, 129.18, 129.29, 131.70, 132.18, 134.06, 136.09, 146.86, 147.97, 149.01, 152.19, 154.30, 169.72, 180.96, 182.34. e IR (CHClj3): 3420, 1746, 1692 cm™

C — Preparation of the intermediate products of formula

IIIa (Scheme II) 1) Synthesis of N-(2,5-dimethoxyphenyl)anthranilic acid (Compound 4)

A mixture of 2-chlorobenzoic acid (9.2 g, 60 mmol), dimethoxyaniline (10 g, 65 mmol), copper (0.96 g), Cuy0 (0.96 g) and K;CO3 (10.4 g) in 120 ml of diglyme is refluxed overnight. After evaporating off the solvent, the reaction medium is Dbasified 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 HCl and then extracted with ethyl acetate. After drying over MgSO, and evaporating off the solvent on a rotary evaporator, the crude product obtained is purified by filtration through silica (CH,Cl,) to give the expected condensation product in the form of a yellow powder (14.5 qg). e Yield = 89% e Melting point = 138°C e 'H NMR (CDCl3): 3.77 (s, 3H), 3.85 (s, 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 (d, 1H, J = 9.2 Hz), 7.04 (d, 1H, J = 2.9 Hz), 7.3 to 7.4 (m, 2H), 9.35 (broad s, 1H) e C NMR (CDCl3): 55.76, 56.45, 107.30, 107.71, 112.00, 112.26, 114.70, 117.53, 130.78, 132.60, 134.009, 145.98, 147.71, 153.75, 172.95 e IR (CHCl): 3327, 1685 cm™ 2) Synthesis of 2-(2,5-dimethoxyphenylamino) aceto- phenone (Compound 5) 16 ml of MeLi (1.4 M/Et,0) are added at 0°C and under N, 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 MgSO4, the solvent 1s evaporated off on a rotary evaporator to give the expected derivative in the form of a yellow solid (1.49 q). e Yield = 75% e Melting point = 79°C e 'H NMR (CDCl3): 2.64 (s, 3H), 3.76 (s, 3H), 3.84 (s, 3H), 6.55 (dd, 1H, J = 8.8 and 2.9 Hz), 6.73 (dd, 1H, J = 1.4 and 7.5 Hz), 6.85 (d, 1H, J = 8.8 Hz), 7.04

(d, 1H, J = 2.9 Hz), 7.3 to 7.4 (m, 2H), 7.81 (dd, 1H,

J =1.5 and 8.0 Hz), 10.5 (broad s, 1H). e 3C NMR (CDCl3): 48.15, 55.73, 56.36, 107.10, 107.72, 112.05, 114.80, 116.84, 120.09, 130.68, 132.42,

S 134.35, 145.98, 146.67, 153.62, 201.00 e IR (CHCl;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 gq, 133 mmol) is heated at 100°C for 1 hour. After addition of 50 ml of water, the mixture is neutralized with 4M sodium hydroxide and then extracted with CHCl; (3 x 100 ml). After drying over MgSO, and evaporating off the solvent, the crude product obtained is purified by filtration through silica (CH;Cl;) to give the expected tricyclic derivative quantitatively in the form of a brown-orange solid. e Melting point = 136°C e 'H NMR (CDCl3): 3.36 (s, 3H), 3.96 (s, 3H), 4.09 (s, 3H), 6.68 (d, 1H, J = 8.0 Hz), 6.89 (d, 1H, J = 8.4 Hz), 7.54 (m, 1H), 7.73 (m, 1H), 8.32 (d, 1H, J = 8.4), 8.36 (d, 1H, J = 8.8 Hz) e YC 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 e IR (CHCl;): 1685, 1661 cm™ 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 CHCl,/H,0 mixture (0.5 ml/0.25 ml) is stirred at 0°C for 20 minutes. After adding 1.4 ml of

HyO0 and 0.4 ml of saturated NaHCO3 solution, the medium is left stirring and is then extracted with CHyCl, (3 x 3 ml). The organic phases are dried over MgSQ,.

After evaporating off the solvent on a rotary evaporator, the expected quinone is obtained in the form of a brown powder (15 mg). e Yield = 90% e Melting point = > 260°C e 'H NMR (CDCl3): 3.22 (s, 3H), 7.09 (d, 1H, J = 10.3 Hz), 7.18 (d, 1H, J = 10.3 Hz), 7.78 (dd, 1H, J = 8.5 and 8.5 Hz), 7.91 (dd, 1H, 8.5 and 8.5 Hz), 8.32 (d, 1H, J = 8.5), 8.43 (d, 1H, J = 8.5 Hz). e >C NMR (CDCl3): 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 e IR (CHCl3): 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 D;)

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

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

After concentrating, the crude product obtained is purified by flash chromatography on silica (98/2

CH,C1,/MeOH) to give the expected tetracycle in the form of a beige-colored powder (23 mg). e Yield = 13% e 'H NMR (CDCls): 3.32 (s, 3H), 7.78-7.83 (m, 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)

e 3C NMR (CDCl3): 16.67, 124.59, 125.44, 128.39, 129.76, 129.89, 132.25, 132.54, 132.88, 135.93, 148.00, 148.59, 148.73, 152.48, 155.31, 180.81, 184.37 e IR (CHCl3): 1703, 1663 cm"

D-2 - Syntheasis of 3-methoxy-6-methyl-1,11- diazanaphthacene-5,12~dione (Intermediate D)) 3-Methoxy-6-methyl-1, 11-diazanaphthacene-5, 12-dione is prepared according to the procedure described in D-1, starting with a solution of 9-methylacridine-1,4-dione (Compound 7) (200 mg, 0.896 mmol) ,2-methoxy-2-propenal- dimethylhydrazone (126 mg, 0.984 mmol) and acetic anhydride (1 ml) in 20 ml of CHyCl,.

EXAMPLE 1 5-Methyl-9H-quino([4,3,2~-de] [1,10] phenanthrolin-9-one (CRL 8323)

A solution of the intermediate tetracycle B; (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; 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. oe Yield = 67% e Melting point = 200°C e 'H NMR (CDCl): 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, 14, 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) e 3c NMR (CDCls): 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)

EXAMPLE 2 5-Chloro-9H-quino[4,3,2-de]l [1,10] phenanthrolin-9-one (CRL 8301)

Preparation according to the process described in

Example 1, starting with the intermediate tetracycle B, (0.25 gq, 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,Cl,/MeOH), 60 mg of the expected compound CRL 8301 are obtained in the form of a yellow solid. e Yield = 23% e Melting point = 200°C e 'H NMR (CDCl3): 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, 1H, J = 2 Hz), 8.79 (dd, 1H, J = 2 and 8.4 Hz), 9.18 (dd, 1H, J = 4.8 and 2 Hz), 9.30 (d, 1H, J = 5.6 Hz) e °C NMR (CDCl3): 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 e MS (m/z): 319 (43), 317 (100), 291 (14.5), 290 (18), 289 (100).

EXAMPLE 3 5- (Benzylamino)-9H-quino[4,3,2-de] [1,10]lphenanthrolin-9-one (CRL 8241)

Preparation according to the process described in

Example 1, starting with the intermediate tetracycle Bj; (3.58 gq, 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,Cl,/MeOH),

2 g of the expected compound CRL 8241 are obtained in the form of a wine-colored powder. e Yield = 55% e Melting point = 219°C e 'H NMR (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 = 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) e MS (m/z): 388 (7), 387 (100), 386 (85), 385 (25), 369 (99), 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 Bs (0.25 gq, 0.79 mmol) and dimethyl formamide diethyl acetal (0.5 ml, 2.98 mmol) in DMF (5 ml). Ammonium chloride (1 gq, 18.7 mmol), ethanol (16 ml). After purification by flash chromatography (100/5

CH,C1l,/MeOH), 170 mg of the expected compound CRL 8325 are obtained in the form of a violet powder. e Yield = 66% e Melting point = > 260°C e 'H NMR (CDCl3): 3.25 (s, 6H), 7.45 (dd, 1H, J = 9.2 Hz, J = 3 Hz), 7.57 (d, 1H, J = 3 Hz), 7.63 (dd, 1H, J = 4.4 and 8 Hz), 8.41 (d, 1H, J = 9.2 Hz), 8.43 (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 (4, 1H, J = 5.6 Hz) e °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 e 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, starting with the intermediate tetracycle Bs (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 CHyCl,/MeOH), 170 mg of the expected compound CRL 8297 are obtained in the form of a greenish solid. e Yield = 66% e Melting point = > 260°C e 'H NMR (CDCl3): 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) e 13C NMR (CDCls): 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 e MS (m/z): 313 (26), 312 (100), 285 (2), 284 (15), 269 (15), 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,Cl,/NH,OH/H,0 mixture. The organic phase is recovered and the aqueous phase is extracted 3 times with CH,Cl,. After drying over MgSO,, the organic phases

Are evaporated to give 1.62 g of the expected compound

CRL 8289 in the form of a yellow solid. ® Yield = 70% ¢ Melting point = 224°C e 'H NMR (CDCls): 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 (d4, 1H, J = 5.6 Hz) e °C NMR (CDCls): 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. e 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]l [1,10] phenanthrolin-9-one (CRL 8344)

A suspension of the nitro derivative CRL 8289 (0.4 gq, 1.22 mmol) and iron (0.37 g, 6.59 mmol) in a 10/10

AcOH/H;0 mixture is refluxed for 1 hour. EDTA (1.94 gq, 6.59 mmol) is added and the reaction medium is then basified with concentrated sodium hydroxide. The mixture is extracted 3 times with CH,Cl,. After drying over MgSO4, the organic phases are evaporated to give 0.32 g of the expected compound CRL 8344 in the form of a blue solid. e Yield = 88% e Melting point = > 260°C e 'H NMR (CDCl3): 5.68 (s, 2H), 7.16 (d, 1H, J = 7.8 Hz), 7.66 (dd, 1H, J = 7.6 and 4.8 Hz), 7.69 (dd, 1H, J = 7.8 and 7.8 Hz), 7.91 (d, 1H, J = 7.8 Hz), 8.46 (d, 1H, J = 5.2 Hz), 8.77 (dd, 1H, J = 1.6 and 7.6 Hz), 9.17 (dd, 1H, J = 1.6 and 4.8 Hz), 9.21 (d, 1H, J = 5.2 Hz). « Cc 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

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

EXAMPLE 8 i; 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 NaHCO; solution and extracted 4 times with CH,Cl,. The organic phases are dried over MgSO, and then evaporated. The crude product obtained is purified by flash chromatography on a column of silica (96/4

CH,Cl,/MeQOH) to give 0.548 g of the expected compound

CRL 8248 in the form of a yellow solid. e Yield = 86% e Melting point = 208°C e 'H NMR (CDCl): 7.68 (dd, 1H, J = 4.4 and 8 Hz), 8.09 (dd, 1H, J = 8.8 Hz, J = 2 Hz), 8.48 (d, 1H, J = 8.8 Hz), 8.49 (d, 1H, J = 6 Hz), 8.79 (dd, 1H, J = 2 and 8 Hz), 8.82 (d, 1H, J = 2 Hz), 9.18 (dd, 1H, J = 2 Hz, J = 4.4 Hz), 9.30 (d, 1H, J = 6 Hz) e 3c NMR (CDCl3): 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 e 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)

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 1s extracted 4 times with CH,Cl,. After

. drying over MgSO, and evaporating off the solvent, the crude product is purified by flash chromatography on a column of silica (90/10 HCCl3/MeOH) to give 115 mg of the expected compound CRL 8347 in the form of a black powder. ® Yield = 6% Co e Melting point = > 260°C e '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 = 6 Hz), 8.50 (d, 1H, J = 8.8 Hz), 8.90 (dd, 1H, J = 2 and 8 Hz), 9.25 (dd, 1H,

J = 2 and 4.8 Hz), 9.29 (d, 1H, J = 6 Hz) e °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 e MS (m/z): 298 (32), 297 (100), 269 (4), 268 (0.5)

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 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 by flash chromatography on alumina (99/1 CH,Cl,/MeOH) to give 87 mg of compound CRL 8290. : e Yield = 87% ¢ Melting point = > 260°C e 'H NMR (CDCl3): 7.61 (dd, 1H, J = 5 and 8 Hz), 7.86 (dd, 1H, J = 8 and 8 Hz), 7.97 (dd, 1H, J = 8 and 8 Hz), 8.40 (d, 1H, J = 8 Hz), 8.43 (d, 1H, J = 6 Hz), 8.64 (d, 1H, J = 8 Hz), 9.04 (dd, 1H, J = 8 and 2.5 Hz), 9.08 (dd, 1H, J = 5 and 2.5 Hz), 9.22 (d, 1H,

J = 6 Hz), 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 ascididemin and 500 mg of NH,OH, 1/2 Hp;SO; 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 x 20 ml). The organic phases are dried over MgSO; and then evaporated on a rotary evaporator. The residue is purified by flash chromatography on alumina (99/1 CHyCl,/MeOH) to give 240 mg of the oxime CRL 8292 in the form of a yellow powder. e Yield = 46% e Melting point = > 260°C e 'H NMR (CDCl3): 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 (d, 1H, J = 6 Hz), 8.75 (dd, 1H, J = 7.6 and 1.6 Hz), 9.00 (dd, 1H, J = 8.4 and 1.2 Hz), 9.12 (dd, 1H, J = 4.4 and 1.2 Hz), 9.41 (d, 1H, J = 6 Hz) e ’C NMR (CDCl): 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 e MS (m/z): 298 (64.5), 268 (100), 266 (21.9)

ag -

TXAMPLE 14 3 10- (2-Acetylanilino) ~9H-quino[4,3,2~de] [1,10]lphenanthrolin- 9~-one (CRL 8333)

Preparation according to the process described in

Example 1, starting with the intermediate tetracycle By (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,Cl,/MeOH), 144 mg of the expected compound CRL 8333 are obtained in the form of a brown-red solid. e Yield = 35% e Melting point = > 260°C e 'H NMR (CDCl;3): 2.88 (s, 3H), 3.12 (s, 3H), 5.54 (d, 1H), 7.13 (d, 1H, J = 6 Hz), 7.30 (ddd, 1H, J = 7.6 and 7.6 and 1.2 Hz), 7.45 {(ddd, 1H, J = 7.6 and 7.6 and 1.2 Hz), 7.51 (d, 1H, J = 7.6 Hz), 7.65 (broad s, 1H), 7.69 (d, 1H, J = 7.6 Hz), 7.88 (ddd, 1H, J = 7.6 and 7.6 and 1.2 Hz), 7.96 (ddd, 1H, J = 7.6 and 7.6 and 1.2 Hz), 8.48 (4d, 1H, J = 6 Hz), 8.51 (4, 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 (4, 1H, J = 6 Hz) e °C NMR (CDCls3): 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 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 and ice is added, followed by neutralization with NaHCO; (solid). After several

: extractions with a mixture of 5% MeOH in HCCli (6 times 500 ml), the organic phases are dried over MgSO, and then concentrated on a rotary evaporator to give 0.36 g of compound CRL 8369 in the form of a wine-colored powder. e Yield = 41% e Melting point = > 260°C e 'H NMR (DMSO): 6.24 (d, 1H, J = 7.6 Hz), 6.86 (td, 1H, J = 8 and 4 Hz), 7.27 (d, 2H, J = 4 Hz), 7.57 (d, 1H, J = 5.2 Hz), 7.89 (d, 1H, J = 8 Hz), 7.93 (dd, lH, J = 7.6 and 7.6 Hz), 8.51 (d, 1H, J = 5.2 Hz), 9.54 (s, 1H), 12.62 (broad m, 1H), 14.42 (s, 1H) e °C 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 POCls; are refluxed for 2 hours.

After evaporating off the POCl; on a rotary evaporator, the reaction medium is neutralized with saturated

NaHCO; solution. After several extractions with a mixture of 5% MeOH in HCCly; (5 times 20 ml), the organic phases are dried over MgSO, and then concentrated on a rotary evaporator. The residue obtained is purified by flash chromatography on a column of silica (95/5 CH;Cl,/MeOH) to give 20 mg of the expected compound CRL 8373 in the form of a yellow powder. e Yield = 77% e Melting point = > 260°C e 'H NMR (CDCl3): 7.67 (d, 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 (d, 1H, J = 5.6 Hz), 8.61 (ddd, 1H, J = 8 and 1.2 Hz), 8.68 (ddd, 1H, J = 8 and 0.8 Hz), 8.97 (d, 1H, J = 5.6 Hz), 9.30 (d, 1H, J = 5.6 Hz)

e “C 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 e MS (m/z): 318 (9.6), 316 (70.2), 290 (29.6), 288 (100), 255 (23.4), 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 Bg (0.74 gq, 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 (95/5 CH,Cl./MeOH), 210 mg of the expected compound CRL 8389 are obtained in the form of an orange powder. e Yield = 42% e Melting point = > 260°C e 'H NMR (CDCls): 4.14 (s, 3H), 7.14 (d, 1H,

J = 5.6 Hz), 8.05 (dd, 1H, J = 2 and 8.8 Hz), 8.43 (dg, 1H, J = 6 Hz), 8.44 (d, 1H, J = 8.8 Hz), 8.76 (d, 1H,

J = 2 Hz), 8.95 (d, 1H, J = 6 Hz), 9.27 (d, 1H,

J = 5.6 Hz) e 3C 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 e MS (m/z): 393 (100), 392 (61.7), 391 (99.2), 390 (17.4), 362 (9.2), 333 (9.8), 254 (34.5).

EXAMPLE 18 5-Amino-ll-methoxy-9H-quino[4,3,2-de] [1,10] phenanthrolin~ 9-one (CRL 8389)

A solution of compound CRL 8389 (0.5 g, 1.3 mmol) and

NaN; (0.5 g, 7.7 mmol) in 20 ml of DMF is heated at 90°C for 10 hours. After concentrating, the residue is taken up in 1IN KOH (35 ml) and then extracted with 95/5

CH2C1l,/MeOH (4 x 200 ml). After drying over MgSO, and concentrating on a rotary evaporator, the crude product obtained is purified by flash chromatography on silica (80/20 CH,Cl,/MeOH) to give the expected compound

CRL 8389 in the form of a violet powder (65 mg). e Yield = 15% e Melting point = > 260°C e 'H NMR (DMSO-dg¢)): 4.07 (s, 3H), 6.62 (s, 2H), 7.36 (d4, 1H, J = 8.8 Hz), 7.41 (4d, 1H, J = 5.9 Hz), 7.74 (s, 1H), 8.08 (d, 1H, J = 8.8 Hz), 8.48 (d, 1H, J = 5.2 Hz), 8.86 (d, 1H, J = 5.9 Hz), 9.08 (d, 1H, J = 5.2 Hz) e IR (KBr): 3420, 3196, 1636, 1616 cm

EXAMPLE 19 5-Amino-~9H-quino[4,3,2-de] [1,10] phenanthrolin-9-one hydrochloride (CRL 8406)

A solution of b5-amino-9H-quinol[4,3,2-de][1l,10]phenan- throlin-9-one (1 g, 3.35 mmol) and concentrated HCl (0.56 ml) in 200 ml of methanol is heated at room temperature for 1 hour. 200 ml of ether are added and, after leaving the salt to precipitate out, the medium 1s filtered to recover the expected compound CRL 8406 in the form of a black powder (1 g). e Yield = 90% e 'H NMR (DMSO-dg): 7.44 (dd, 1H, J = 8.8 and 2.2 Hz), 7.81 (d, 1H, J = 2.2 Hz), 7.93 (dd, 18H,

J = 5.6 and 5.9 Hz), 8.12 (d, 1H, J = 8.8 Hz), 8.66 (d, 1H, J = 5.6 Hz), 8.75 (d, 1H, J = 5.9 Hz), 9.07 (d, 1H,

J = 5.9 Hz), 9.14 (d, 1H, J = 5.9 Hz) e IR (KBr): 3404, 3287, 3170, 1691, 1676, 1649 cm

EXAMPLE 20 5- (Dimethylamino) -9H-quino[4,3,2-de] [1,10] phenanthrolin- 9-one hydrochloride (CRL 8407)

A solution of 5-(dimethylamino) -9H-quino[4, 3,2-de] - [1,10]phenanthrolin-9-one (1 g, 3.06 mmol) and concentrated HCl (0.3 ml) in 120 ml of CHCl; 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). e Yield = 87% e Melting point = > 260°C

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-del[1,10]- phenanthrolin-9-one ASC20 (0.94 qg, 2.42 mmol) and concentrated HCl (0.2 ml) in 40 ml of CHCl; 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). e Yield = 95% e Melting point = > 260°C

EXAMPLE 22 5- (Dimethylamino-2-ethyl)amino-9H-quino[4, 3,2-de] - [1,10]phenanthrolin-9-one (CRL 8419) 25 ml (166 mmol) of trifluoroacetic acid are added to a mixture of compound CRL 8347 (2.56 g, 8.59 mmol) and dimethyl formamide 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; 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,. After evaporating off the solvent on a rotary evaporator, the crude product obtained is purified by filtration through alumina (CHCl; and then 95 CHCl3/MeOH) to give 1.15 g of the expected compound CRL 8419 in the form of a black powder. ® Yield = 36% ® Melting point: decomposes before melting e 'H NMR (CDCl3): 2.37 (s, 6H), 2.62 (t, 2H,

J = 7.32 Hz), 3.70 (t, 2H, J = 7.32 Hz), 7.39 (dd, 1H,

J = 9.2 and 3 Hz), 7.62 (dd, 1H, J = 8.0 and 4.5 Hz), 7.66 (d, 1H, J = 3 Hz), 8.35 (d, 1H, J = 9.2 Hz), 8.38 (d, 1H, J = 5.7 Hz), 8.79 (dd, 1H, J = 8.0 and 1.8 Hz), 9.12 (dd, 1H, J = 4.5 and 1.8 Hz), 9.15 (d, 1H,

J = 5.7 Hz) e C NMR (CDCl3): 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 e IR (CHCl3): 1663 cm’ e MS (m/z): 369 (100), 354 (15), 236 (37)

EXAMPLE 23 5-(Dimethylamino-2-ethyl) amino-9H-quino[4,3,2- de] [1,10] phenanthrolin-9-one hydrochloride (CRL 8418) 265 pul (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. e Yield = 70% e 'H NMR (DMSO-dg): 2.67 (s, 6H), 3.09 (m, 2H), 4.01 (m, 2H), 7.67 (dm, 1H, J = 9.2 Hz), 7.80 (dd, 1H,

J = 8,0 and 4.5 Hz), 7.94 (m, 1H), 8.26 (d, 1H, J = 9.2 Hz), 8.64 (d, 1H, J = 5.7 Hz), 9.09 (m, 1H), 9.12 (dd, 1H, J = 4.5 and 1.8 Hz), 9.14 (d, 1H, J = 5.7 Hz). 35 .

EXAMPLE 24 5-Bis (2-chloroethyl)amino-9H-quino[4,3,2~-de] [1,10] - phenanthrolin-9-one (CRL 8422)

Claims (1)

1. Co - 57 - CLAIMS Ce .-

   1. A pharmaceutical composition comprising an effective amount of a compound chosen from the oo Co compounds of general formulae I and Ia below for R treating, by virtue of their cytotoxic properties, cancerous tumors and their metastases: oo Rg 9) Fy x Ry “ Ny K No EN NC ry AN = ’, y x | | = = , ANPZ R, © Ry N= R, Formula } Formula la 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 -NRgRgy in which Rs and Rg are chosen, independently of each other, from hydrogen and (C;-C4) alkyl groups, - R; is chosen from hydrogen and halogens, - R; 1s chosen from halogens, i (C1-C4) alkyl groups, (C1-Cs) alkoxy groups, a guanidino group, groups -NRygR;; in which Rio and Ry, are chosen, independently of each other, from hydrogen, (C;-Cq) alkyl groups, (C;-C4) phenylalkyl groups and groups =(CHz)p-Y with Y being chosen from halogens and Cu, -CH({O-Et),;, (C;-Cp) alkoxy, —0-(CH;) 2-N(CH;); and -N(CH3)2; groups and n = 1 to 3, - Ri 1s chosen from hydrogen, halogens, nitro groups and groups -NRy;R;3 in which Riz and Ri; E are chosen, independently of each other, from hydrogen and (C;-Cy4) alkyl groups, - Rs, Rs and R; are chosen from: hydrogen or a halogen atom, : AMENDED SHEET g Amended Sheet — 2004-01-09 oo

   C;-Cs alkyl, hydroxyl, C,-Cs alkoxy, (C1-Cs) alkoxy (C,-Cq) alkyl, (C1-C4) alkylcarbonyloxy- (C1-Cq) alkyl, -CHO, -COOH, -CN, -CO3R.,, -CONHR 14 and -CONR14R;¢ groups, ~-NHCOR 4 and -NR14R;5 in which Ris and Rys are chosen, independently of each other, from hydrogen and (C1-Cs) alkyl, -phenyl-CO- CH; and -CHz-CH,-N(CH,) , groups, -phenyl-CO-CH; or ~phenyl-CO-CH=CH- N(CH;),, morpholino, nitro or SO;H groups, groups: : -CHs —-N —COOR5 ' -CH, - N= COOR45 , . CH; -COORy~ CH, —Ar Ris and R;; being chosen from Ci-Cs alkyl groups and Ar being a C¢-Ciq aryl group, and the addition salts of these compounds with pharmaceutically acceptable acids.

   2. A pharmaceutical composition comprising an effective amount of =a compaund chosen from the compounds of formula I in which: - X 1s chosen from oxygen, an =NH group and an =N-QH group, - RR; 1s chosen from hydrogen, halogens, a nitro group and groups -NR3Rs; in which RB; and Rg AMENDED SHEET : Amended Sheet — 2004-01-09 are chosen, independently -.of. each .other;, from - hydrogen and (C,-C,) alkyl groups,

   - R; is chosen from hydrogen and halogens, - R, is chosen from halogens, (Ci=Cq) alkyl groups, (Ci;-Cg) alkoxy groups, a guanidino group, groups ~NRyoR11 -in which Ry and Ri . are chosen, independently of each other, from hydrogen, (C1-Cq) alkyl groups, (Ci=C4) phenyl- alkyl, =~ (CH) ,-N(CH3),;, and = (CHz) 2-0~ (CH;) 2-N (CHj) » groups, - Ry 1s chosen from hydrogen, halogens, nitro groups and groups -NRi2Ri3 in which Ri; and Ry; are chosen, independently of each other, from hydrogen and (C,;-C,) alkyl groups, : - Rs, Rg and Ry; are chosen from: hydrogen or a halogen atom, Ci—Cs alkyl, hydroxyl, C1-Cs alkoxy, -CHO, -COOH, -cCN, —COz2R14, -CONHRy;4; and —~CONR¢R;5 groups, -NHCORi;4 and -NRy4R;s groups in which Ry4 and Ris are chosen, independently of each other, from hydrogen and (C1-Cs) alkyl and —CH-CHy-N (CH;3) » groups, -phenyl-CO-CH; or ~phenyl-CO-CH=CH- N(CH3);, morpholino, nitro or SO3H groups, groups: “CH —=N -COORys , -CH;— N= COORys, Cr -COQRy7 CH — Ar Ris and Ry; being chosen from C1~C¢ alkyl groups and Ar being a C;-C;q4 aryl group, dnd the addition salts of these compounds with pharmaceutically acceptable acids.

   AMENDED SHEET Amended Sheet — 2004-01-09

   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, ~- R, is chosen from hydrogen and an amino group, to. - R; is chosen from hydrogen and halogens, - R, is chosen from halogens, i (c,-Cq) alkyl groups, (C,-Cg) alkoxy groups, @ guanidino group, groups -NRjoR;1 in which Rig and Ri are chosen, independently of each other, from hydrogen, methyl ~~ groups, (C1-Cq) phenylalkyl, _(CHy) 2-N (CHa) 2, — (CHa) 2-0 (CHa) 2=N (CHa) z groups, : - Ry, is chosen from hydrogen, halogens and nitro and amino groups; - R;, Rg and Ry represent a hydrogen, i 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 Ia in which: - X represents oxygen, - R; is chosen from hydrogen and an amino group, - R, is chosen from hydrogen and halogens, - R, is chosen from halogens, (C,—C4) alkyl groups, (C;-Cs) alkoxy groups, a guanidino group, groups -NRygR11 in which Rie and Ry are chosen, independently anf each other, from hydrogen, methyl groups, (C;-C4) phenylalkyvl groups and groups ~(CHz)a"Y with Y being chosen from halogens and groups CN, -CH(O-Et)2, [(C1-Cs) alkoxy, -0- (CHy) 2-N (CHj) 2 and -N(CH3), and n = 1 to 3, AMENDED SHEET Amended Sheet — 2004-01-09 a - Ry 1s chosen from hydrogen, ---halogens, --- and nitro and amino groups, ~ - Rs is chosen from a hydrogen, a halogen . and a methoxy group, : - Re and Ry; are chosen from hydrogen and C1-Cq alkoxy, (C1-Ce) alkoxy (Ci-Cq) alkyl and + —CH,0CQCH; groups, : : and the addition salts of these compounds with pharmaceutically acceptable acids.

   5. The composition as claimed in claim 4, in which the compounds are chosen from: 3 (dimethylamino) -9H-quino (4,3, 2-de] [1,10] phenan- throlin-9-one, > (benzylamino) ~SH-quino (4, 3, 2~de] [1,10] phenan- throlin-9-one, >Tbromo-Sf-quino(4,3,2-de] [1,10] phenanthrolin-9- one, . J-amino-98-quino(4,3,2-de] [1,10] phenanthrolin-g- one, S-methyl-9H-quino(4,3,2-de] [1,10] phenanthrolin-g- one, Tmethoxy-9H-quino(4,3,2-de] [1,10] phenanthrolin-g- one, 3-chloro-9%-quino(4,3,2-de] [1,10] phenanthrolin-g- one, : AMENDED SHEET Amended Sheet — 2004-01-09

   : - 62 ~- S-bromo~10-methoxy-9H-quino(4,3,2-de].[1,10]phenan-- throlin-9-one, 5-(dimethylamino-2-ethyl)amino-9H-quino(4, 3, 2-de] - (1,10]phenanthrolin-9-one, 5-bis(2-chloroethyl)amino-9H-quino(4, 3,2-de] - (1,10) phenanthrolin-9-one, - 5-(2-chloroethyl)amino-9H-quino(4,3,2-de] [1,10]- phenanthrolin-9-one, 4-bromo-5-amino-9-H-quino[4,3,2-de] [1,10] phenan- throlin-9-one, : S-bromo-8-H-quino(4,3,2-del (1, 7]phenanthrolin-9- one, 3 . S-amino-9-H-quino(4,3,2-de] (1, 7] phenanthrolin-9- one, 5S-(dimethylamino-2-ethyl)amino-9-H-quino (4,3, 2- de] {1,7]phenanthrolin-S-one, a. 5-bis (chloroethylamino-2-ethyl) amino-9-H-quino- (4,3,2-de] (1, 7]phenanthrolin-9-one, 3-(chloroethylamino-2-ethyl)amino-9-H-quina(4,3,2- de] [1,7]phenanthrolin-9-one, 4-bromo-S-amino-9-H-quino(4,3,2-de] (1, 7]phenan- throlin-S-one, and the addition salts thereof with pharmaceutically acceptable acids.

   8. The use of a compound as defined in one of claims 1 to 5, for the manufacture of an anticancer drug. AMENDED SHEET Amended Sheet — 2004-01-09

   7. The use as claimed in claim 6, in- which--the- compounds are chosen from: S-(dimethylamino)-SH-quino(4,3,2-de] [1,10] phenan- throlin-9-one, ’ 5-(benzylamino) -9H-quino(4,3,2-de] (1, 10] phenan- throlin-%-one, . -

   ~. 5-bromo-9H-quino(4,3,2-de] [1,10]phenanthrolin-9-. one, S5-amino-9H~quino (4, 3,2-de] [1,10]phenanthrolin-9- one, oo S-methyl-9H-quino(4,3,2~-de](1,10]phenanthrolin-9- one, S-methoxy-9Hd-quino (4, 3,2-de] (1,10]phenanthrolin-9- one, * S-chloro-9d-quino(4,3,2-de] [1,10] phenanthrolin-9- one, S-bromo-1l0-methoxy—-9H-quino(4,3,2-de] [1,10] phenan- throlin-9%-one, S-(dimethylamino-2-ethyl)amino-%H-quino (4, 3,2-de]- (1,10]phenanthrolin-9-one, ~ 5-bis (2-chloroethyl)amino-9H-quino(4, 3,2-de}- ~ [1,10]phenanthrolin-9-one, 5-(2-chloroethyl)amino-SH-quino([4,3,2-de] [1,10]- phenanthrolin-%-one, 4-bromo-5-amino~9-H~quino (4, 3,2~de] [1,10] phenan- throlin-%-one, S-bromo-S-H-quino (4,3, 2-de] (1, 7]phenanthrolin-9- one, AMENDED SHEET Amended Sheet — 2004-01-09

   S-amino-9-H-quino(4,3,2-de] (1, 7]phenanthrolin-9=... .. one, : 5-(dimethylamino-2-ethyl)amino~9-H-quino(4, 3, 2- de] [1,7] phenanthrolin-9-one, - S-bis(chloroethylamino-2-ethyl)amino~9-H-quino- (4,3,2-de] [1,7]phenanthrolin-9%-one, 5-(chloroethylamino-2-ethyl)amino-9-H-quino[4, 3, 2- de] [1,7]phenanthrolin-9-one, oo B 4-bromo-5-amino-9-H-quino(4,3,2-de] [1,7] phenan- throlin-9%-one, : and the addition salts thereof with pharmaceutically acceptable acids.

   8. Compounds of general formulae I and Ia Rg x Rr, X R, = Nao Ng Na a RE Ra RS Co [= Na A Rr, No = R, Farmula | Formula ja in which: - X is chosen from oxygen, an =NH group and an =N-0H group, - R; is chosen from hydrogen, halogens, a nitro group and groups -NRgRy in which Rg and Rg are chosen, independently of each other, from hydrogen and (C;-C4) alkyl groups, - R; is chosen from hydrogen and halogens, - R, 1s chosen from halogens,

   (C.-C4) alkyl groups, (C1-Cs) alkoxy groups, a AMENDED SHEET Amended Sheet — 2004-01-09 guanidino group, groups -NRjoRi1 in which Ryg-and Rix are chosen, .independently of each other, from" hydrogen, (Cy-Cq) alkyl groups, (C:;-C4) phenylalkyl groups and groups =-(CHz),-Y with Y being chosen from halogens and CN, -CH(O-Et),, (C,~Cg) alkoxy, - O- (CH) 2-N(CH3), and -N(CH3); groups and n = 1 to 3,

   - R, is chosen from hydrogen, “halogens, nitro groups and groups -NRj;R13 in which Rj; and Ris are chosen, independently of each other, from hydrogen and (Ci-Cq) alkyl groups,

   - Rs, Rg and Ry; are chosen from: hydrogen or a halogen atom, C;-Cs alkyl, hydroxyl, C1-Cs alkoxy,

   (C1-Cg) alkoxy (C1 -Cg) alkyl, (Ci=Cq)alkylcarbonyloxy- (C;—-Cq)alkyl, -CHO, -COQH, -CN, -CO;R;q, -CONHRi,4 and -CONRi;4R;s groups, ~NHCOR; 4 and -NRj;4R;s in which Ry4 and Ri; are chosen, independently of each other, from hydrogen and {(C;-Cgs) alkyl, -phenyl-CO- CH; and -CH,~CH,-N(CH3),; groups,

   -phenyl-CO-CH; or -phenyl-CO-CH=CH- N(CH3),, morpholino, nitro or SO3H groups,

   groups:

   -Cip ~N-CO0Ry; -CH — N= COORs, CH,- COOR, 7 Crp —pr

   Rig and Ry7 being chosen from C,-Cs alkyl groups and Ar being a C3-Ci4 aryl group,

   AMENDED SHE=ET

   Amended Sheet — 2004-01-09

   - 66 ~ N and the addition salts of these. . compounds with pharmaceutically acceptable acids.

   9S. 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, 1s chosen from hydrogen, halogens, a nitro group and groups -NRgRg in which Rg and Rg are chosen, independently of each other, from hydrogen and (C;-Cs) alkyl groups, : - R; is chosen from hydrogen and halogens, - R, is chosen from halogens, (C1-C4) alkyl groups, (C1-Cq) alkoxy groups, a guanidino group, groups =NRioR11 in which Ry and Ry; . are chosen, independently of each other, from hydrogen, (C1—-Cyq) alkyl groups, (C1~Cyq) phenylalkyl, = (CHz) 2—N (CH3) 2, and —(CHz) 2-0- (CHa) 2~N(CH3), groups, ~ Rg is chosen from hydrogen, halogens, nitro groups and groups -NRi2R13 in which Ry; and Rj; are chosen, independently of each other, from hydrogen and (C;-Cs) alkyl groups, - Rs, Rg and Rs are chosen from: hydrogen or a halogen atom, C1-Cs alkyl, hydroxyl, C;-Cq alkoxy, -CHO, -COOH, —CN, -COzRy4, -CONHR;4 and —CONR4R; 5 ) groups, -NHCOR;4 and -NRyi4Ris in which Ry, and Ris are chosen, independently of each other, from hydrogen and (C1-Cs) alkyl and ~CH,-ClI;-N (CH3) » groups, -phenyl-CO-CH; or -phenyl-CO-CH=CH- N(CH3),, morpholino, nitro or SO3H groups, - groups: . : AMENDED SHEET 3 Amended Sheet — 2004-01-09

   -CH, N -COORis "W -CH, ~N=COCRys, CH;-COORy7 CH Ar Rig and Ry; being chosen from C;-Cg alkyl groups and Ar being a C¢~Cyq aryl group, Lo and the addition salts _ thereof with Pharmaceutically acceptable acids.

   10. Compounds as claimed in claim 8, which are: 5-(dimethylamino) ~-9#-quino (4,3, 2-de] [1,10] phenanthrolin- 9-one, >= (benzylamine) -9H-quino(4,3,2-de] [1,10] phenanthrolin-9- one, S-bromo-94-quino(4,3,2-de] (1,10) phenanthrolin-9-one, S-amino-S#-quino(4,3,2-de] (1, 10] phenanthrolin-9-one, -methyl-94-quino(4,3,2 de] [1,10] phenanthrolin-9-one, S-chloro-SH-quino(4,3,2-de] [1,10] phenanthrolin-S-one, S-bromo-10-methoxy-9H-quino(4,3,2-de] [1,10] phenanthrolin- S-one, ] 5-(dimethylamino-2-ethyl) aminolSa-quino(4, 3, 2-de) [1,10] - phenanthrolin-9-~one, 3-bls(2-chloroethyl) amino-94-quino (4,3, 2-d=] (1, 10] phenan- throlin-9-one, 5-(2-chloroethyl) amina-94-quino (4,3, 2-de] [1,10] phenan- throlin-9-one, “7bromo-S-amine-9-#-quino(4,3,2-de] [1,10] phenantarolin-g - one, AMENDED SHEET Amended Sheet — 2004-01-09

   S-bromo-9-H-quino(4,3,2-de] (1, 7]phenanthrolin-9-one, S-amino-9-H-quino(4,3,2-de] (1, 7]phenanthrolin-9-cne, : 5-(dimethylamino-2-ethyl)amino-9-H-quino (4,3, 2-de] ~ (1, 7]phenanthrolin-9-one, - >~bis(chloroechylanino-2-ethyl)amino-9-H-quino(4, 3, 2-del- [1,7]phenanthrolin-9-one, 5-(chloroethylamino-2-ethyl)amino-9-H-quino (4,3, 2-de] - (1,7) phenanthrolin-9-one, 4-bromo-5-amino-9-H-quino[4,3,2-del [1,7] phenanthrolin-9- : one, - and the addition ‘salts thereof with Pharmaceutically acceptable acids.

   11. A process for preparing a compound of formula Ia, in which: - X is chosen from oxygen, an =NH group and an =N-OH group, - Ry; is chosen from hydrogen, halogens, a nitro group and groups -NRgRs in which R; and Rg are chosen, independently of each other, from hydrogen and (C;-C4) alkyl groups, - R; is chosen from hydrogen and halogens, - R; is chosen from halogens, (Ci=Cq) alkyl groups, (Ci-Ce¢) alkoxy groups, a guanidino group, groups -NRyjoRy; in which Ry and Rui are chosen, independently of each other, from hydrogen, (C;-C,) alkyl groups, (c,-cC,) phenylalkyl groups and groups = (CHz).~Y with Y being chosen from halogens and CN, -CH(O-Et),, (C1~Cj5) alkoxy, ~0~-(CH;) ;~N(CH;); and -N{CH3), groups and n = 1 to 3, - Ry 1s chosen from hydrogen, halogens, nitro groups and groups -NRi3R;; in which Ry; and Ris AMENDED SHEET Amended Sheet — 2004-01-09 are chosen, independently of each other, from hydrogen and (C;-C4) alkyl groups, - Rs, Rg and Ry; are chosen from: hydrogen or a halogen atom, C1-C¢ alkyl, hydroxyl, C;-Cg alkoxy, : (C:1—-Cs)alkoxy (C1~-Cg) alkyl, (C1-Cy) alkylcarbonyloxy- (Ci-Cq) alkyl, -CHO, -COOH, =-CN, =COpR;s, ~-CONHRi4 and ~CONRj4R1s groups, -NHCORi4 and =-NRi4R;s in which Ris and R;s5 are chosen, independently of each other, from hydrogen and (C;-Cg) alkyl, -phenyl-CO- CH3 and -~CH,~CH,-N (CH3)2 groups, -phenyl-CO-CH; or -phenyl-CO-CH=CH- N(CHz)»>, morpholino, nitro or SO3H groups, groups:

   "CF ~N COR ) “CH — N= COCR , CH; -COORy7 CHa —Ar Rie and Rj; being chosen from C;-Cg alkyl groups and Ar being a Cg-Ciy aryl group, which consists in: a —- condensing a chlorobenzoic acid of formula: Ry : Gl Ry HOC Rs with a dimethoxyaniline of formula: ) AMENDED SHEET

   I - 70 - OMe NH, OMe to give a compound of formula Ila: OMe Ry H : g Ra HOC Rs CMe Ry b - cyclizing the compound of formula IIa to give a compound of formula: ‘OMe R, . \ Ry IAN = Rs OMe :

   Cc — converting the compound into a quinone of formula IIIa: AMENDED SHEET

   Co. - 71 - ® R N Re ~N - pr” ~~ Ra 0 Ry d - reacting the quinone of formula IIIa with an azadiene of formula: N,

   N . Ry — NN 5 to give a compound of formula IVa: R ’ N | N Ry = ~ NN = Rs | | Rs R, © CH; R € - reacting the compound of the formula IVa with dimethylformamide diethyl acetal to give the compound of formula Ia, N f - and, optionally, converting the compound thus obtained into another compound of formula Ia. AMENDED SHEET

   12.. A process for preparing compounds of general formula I, of formula: - Rs 7 R,

   R N Ra 6 Rn YY x ~~ Rj R4 ] N_~ Ra in which:

   - R; is chosen from hydrogen, halogens, a nitro group and groups -NRgRs in which Rg and Rg are chosen, independently of each other, from hydrogen and (Cy;-C4) alkyl groups,

   = R, is chosen from hydrogen and halogens,

   - R, 1s chosen from halogens,

   (C;-Cq) alkyl groups, (C1-Cg) alkoxy groups, a guanidino group, groups -NRijgRi; in which Rye and Ry; are chosen, independently of each other, from hydrogen, (C;-C4) alkyl groups, (C;-C4) phenylalkyl .groups and groups -(CHz)a~Y with Y being chosen from halogens and CN, -CH(O-Et),, (C;-Cg) alkoxy, —-0-(CH;)3-N(CH3); groups and -N(CH;); and n =1 to 3,

   - Ry is chosen from hydrogen, halogens, nitro groups and groups -NRizR13 in which Riz and Rij ars chosen, independently of each other, from hydrogen and (C;-Cyq) alkyl groups,

   ~ Rs, Rs; and Ry are chosen from:

   hvdrogen or a halogen atom, AMENDED SHEET Amended Sheet — 2004-01-09

   C1~Cg alkyl, hydroxyl, C;-Cs alkoxy, (C1~Cq) alkoxy (C1~Cg) alkyl, .(C1=Cy) alkylcarbonyloxy- (Ci-C4) alkyl, =-CHO, -COOH, -CN, -COzR14, -—CONHRiq4 and —CONR14R 5 groups, -NHCOR;s and ~NR14R;5 in which Rie and Ris are chosen, independently of each other, from hydrogen and (C1~Cg). alkyl, -phenyl-CO- CH; and ~CHp-CH;-N.(CHai) 2 groups, -phenyl~CO~CH; or —phenyl-CO-CH=CH- : N(CHj3);, morpholino, nitro or SO3H groups, groups: ~-CH, ~N —COORyg + -CHp N= COOR5 CH,-COORy7 CH; —Ar Rig and Ry7 being chosen from C;-Cq alkyl groups and Ar being a Cg-Cy4 aryl group, with the exclusion of the compounds of formula I in which R,, R,, R,, Ry, R,, R, = H and R, = OCH,, = . which consists a) in reacting a hydroquinone of formula R: O Rs Co

   { . | pt Sn @) with a compound of formula AMENDED SHEET Amended Sheet — 2004-01-09

   R, oo CL HaN R2 © Ra CH, Rs - in the presence of CeCl;, 7H0 and ethanol to give a compound of formula II + Rg a | N R, © cp, b) in converting the compound of formula II into a compound of formula III RE

   ‘Rs. Oo ' i Re N Ra L 7 . R7 | 3 ] O CHi R. in the presence of concentrated H,80, in refluxing AcCH c) in reacting the compound of the formula III with HC (OCzHs)N(CHs3)z in DMF at 120°C to form a compound of formula IV Rs O Ry Re N R, Rs Rs o Rr, © N(CH3), AMENDED SHEET ~~ Amended Sheet — 2004-01-09 d) in cyclizing the compound of formula IV to a compound of formula I ‘in the presence of ~ NH4Cl and AcOH, : © &) optionally converting the compound of formula I thus obtained into another compound of - | : formula II.

   13. A compound of formula Rs O 'R, R @) Ry N(CHa3), in which: - Ri 1s chosen from hydrogen, halogens, a nitro group and groups -NRgRg in which R; and Rg are chosen, independently of each other, from hydrogen and (C;-Cy) alkyl groups, - R; 1s chosen from hydrogen and halogens, . So C= R, is chosen from halogens, (Ci-C4) alkyl groups, (C1-Cs) alkoxy groups, a - ‘quanidino group, groups -NRygRi1 in which R;; and Riz are chosen, independently of each other, from hydrogen, (C{-C,) alkyl groups, (C,;-C4) phenylalkyl groups and groups -~(CHz),~Y with Y being chosen from halogens and CN, . -CH(O-Et)2, (C:-Cq) alkoxy, - O-(CHz)2-N(CH;),; and -N(CHj3), groups and n = 1 to 3, = = Ry 1s chosen from hydrogen, halogens, . nitro groups and groups ~NR12R;3 in which Rj; and Ry; are cnosen, independently of each other, from hydrogen and (C.-C) alkyl groups, : - Rs, Rs and Ry are chosen from: ’ AMENDED SHEET Amended Sheet —- 2004-01-09

   : = 76 - hydrogen or a halogen atom, - : ~ C1-Cg alkyl, hydroxyl, Ci-Cs alkoxy, : (C1~Cs) alkoxy (C,~Cg) alkyl, (C1~Cyq) alkylcarbonyloxy- (C1-Cq) alkyl, -CHO, -COOH, -CN, ~CO2Ry4, ~—CONHRy4 3 and -CONRy;4R;s groups, ~NHCOR1y and -NRy4R;s in which Ri¢ and Ris are chosen, independently of each : - other, from hydrogen and (C1=Cq) alkyl, ~phenyl-CO- Co

   ©. CH; and -CH;-CH,=N (CHy), groups, | _ -phenyl-CO~CH; or ~phenyl-CO-CH=CH- N(CHi);, morpholino, nitro or SO3H groups, groups: -ChH, “N -COORy5 , -CHy — N= COOR4g , CH; -COQRyy; CHa —Ar Ris and Ry; being chosen from Ci1-Cs alkyl groups and Ar being a C4-Cyq4 aryl group, - with the exclusion of compounds in which R;, R,, R,, Rs, Re, R, = H and R, = OCH, and the addition salts of these compounds with pharmaceutically acceptable acids. : Amended Sheet — 2004-01-09