SK1662002A3 - Ascididemin derivative, method for the preparation thereof and pharmaceutical composition containing the same - Google Patents

Abstract

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

Description

The invention relates to pharmaceutical compositions based on polyaromatic compounds, particularly useful as anticancer drugs.

BACKGROUND OF THE INVENTION

In 1999, cytotoxic drugs (chemotherapy) were used to reduce the size of cancerous tumors and capture the anticipated progression of the cancer process in a few cases with the intention of suppressing cancer cell accumulation and the risk of metastasis in combining previously established chemicals with other agents used only for a few decades. For example, 5-fluorouracil (5-FU), known 40 years ago to be the most active drug in colon and rectal cancers, can be replaced with specific topoisomerase inhibitors (irinotecan or topotecan) if the tumor is no longer at 5- FU sensitive. The treatment options known for the treatment of colon and rectal tumors have enriched oxaliplatin, a new donor instead of 5-FU or selective thymidylate synthetase inhibitors. This coexistence is not limited to the treatment of colon and rectal cancers, as breast, ovarian and lung cancer chemotherapy also now targets texane derivatives (paclitaxel, docetaxel). The need for more effective and better tolerated drugs to improve the survival and quality of life of patients is urgent because, taking only an example of colorectal tumors, it has been identified (SL 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 led to the death of patients. Knowledge of this situation has prompted the inventors to be interested in a family of polyaromatic compounds still little studied, identified in the algae of the Ascidies of the warm seas to develop original drug chemistry designed to isolate synthetic compounds having cytotoxic activity important for treatment.

The seas and oceans, which occupy more than 70% of the earth's surface, contain marine plants and fungi whose systematic progressive pharmacognostic studies show that these living organisms may contain complex alkaloids having interesting pharmacological properties.

For example, the fungi Cryptotheca crypta and Halichondria okadai have been the subject of in-depth studies since the discovery of the presence of cytarabine or halichondrin B in their cells. The same is true of the tunici family from the isolation of the aplidine of the Aplidium albicans tunic, which lives on the Balearic Islands (Spain). Alkaloids with tetrahydroisoquinoline structure were isolated from the algae Ecteinascidia turbinata. Among these, in-depth preclinical studies of ecteinascidin-743 (E. Igbicka et al., Symposium NCI-EORTC work 130, p. 34, 1998) also include clinical trials aimed at defining their therapeutic potential as an anticancer drug (A. Bowmann et al. , Symposium NCI-EORTC Work 452, p. 118, 1998; M. Villanova-Calero et al., Symposium NCI-EORTC Work 453, p. 118, 1998; MJX Hillebrand et al., Symposium NCI-EORTC Work 455, p. 119, 1998; E. Citkovic et al., NCI-EORTC Symposium, 456, pp. 119, 1998). New derivatives of pentacyclic algae have been the subject of pharmacochemical work (D. J. Hagan et al., J. Chem. Soc. Perkin Transf. 1, 2739-2746, 1997).

Another natural alkaloid of marine origin, ascididemin, was extracted from algae Didemnum sp. (J. Kobayashi et al., Tetrahedron Lett. 29, 1177-1188, 1988) and from the ascidia Cystodytes dellechiajei (I. Bonnard et al., Anti-cancer Drug Design 10, 333-346, 1995). Ascididemin has antiproliferative properties discovered in the mouse leukemia model (line P388 or L1210) described by F. Schmitz et al. (J. Org. Chem., 1991, 56, 804-808), B. Lindsay et al. (Bioorg. Med. Chem. Lett. 5: 739-742, 1995) and J. Kobayashi et al. (Tetrahedron Lett. 29, 1177-1180, 1988) and in the human leukemia model described by I. Bonnard et al. (Anti-cancer Drug Design 10: 333-346, 1995). The synthesis of ascididemin has been described by several authors F. Bracher et al. (Heterocycles 29, 2093-2095 (1989)), C.J. Moody et al. (Tetrahedron Lett. 48: 3589-3602, 1992) and G. Gellerman et al. (1994 Synthesis, pp. 239-241).

Also mentioned is 2-bromoleptoclinidone (according to the name SJ Bloor et al. (1987) isolated from the ascidium Leptoclinides sp. JJ Bloor et al. (J. Am. Chem. Soc. 109, 6134-6136, 1987) and synthesized by F Bracharoma et al (Heterocycles 29, 2093-2095, 1989), then ME Jungom et al (Heterocycles 39, 2, 767-778, 1994) 2-Bromoleptoclinidone shows cytotoxicity in the DE 50 leukemia cell model The cytotoxic properties were confirmed by F. Bracher (Pharmazie 52, 57-60, 1997), both in vitro on 60 tumor cell lines and in vivo in xenogreff models of human tumor cell lines (SW- 620 and HTC116, kidney tumor A498, and LOX melanoma (IM VI) implanted mice.

Of the other ascididemin derivatives such as 11-hydroxyascididemin, 11methoxyascididemin, 11-phenylascididemin and 11-nitrophenylascididemin, 1-nitroascididemin, 3-nitroascididemin and neocaliactin are described in the chemical plan (according to the numbering which is introduced by SJ et al.). skupina FJ Schmitze (J. Org. Chem. 56: 804-808, 1991) and Y. Kitahary et al. (Heterocycles 36: 943-946, 1993; Terahedron Lett. 53: 17029-17038, 1997); G.Germanerman et al. (Tetrahedron Lett. 34, 1827-1830, 1993), S. Nakahary et al. (Heterocycles 36: 1139-1144, 1993), I. Spector et al. (U.S. Patent No. 5,421,272, Jul. 11, 1995).

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition comprising an effective amount of a compound of Formula I or Ia

where it means

X is hydrogen, = NH or = N-OH,

R ¹ is hydrogen, halogen, nitro, and -NR ^with R ^9, wherein R ⁸ and R ⁹ is independently H or alkyl of 1 to 4 carbon atoms,

R ² is H or halogen,

R ³ is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, guanidino, -NR ^W R ¹¹ where R ¹⁰ and R ¹¹ are independently hydrogen, C 1 -C 4 alkyl to 4 carbon atoms, phenylalkyl having 1 to 4 carbon atoms in the alkyl group and _{(CH2) n-Y,} where Y is halogen, CN, -CH (O-Et) _2, C 1 -C 6 alkyl , -O- (CH ₂ ) ₂ N (CH ₃ ) ₂ , -N (CH ₃ ) ₂ and n = 1 to 3,

R ( ⁴⁾ is hydrogen, halogen, nitro or -NR ¹² R ¹³ , where R ¹² and R ^{13 are} each independently hydrogen or C 1 -C 4 alkyl;

R @ ⁵ , R @ ⁶ and R @ ⁷ independently of one another are hydrogen, halogen, C1 -C6 -alkyl, hydroxyl, C1 -C6 -alkoxy, C1 -C6 -alkoxyalkyl, an alkyl moiety, an alkylcarbonyloxyalkyl group having 1 to 4 carbon atoms in each alkyl moiety, -CHO, -COOH, -CN, -CO ² R ¹⁴ , -CONHR ¹⁴ , -CONR ¹⁴ R ¹⁵ , -NHCOR ^14, and -NR ¹⁴ R ¹⁵ , wherein R ¹⁴ and R ^{15 are} each independently hydrogen, C 1 -C 6 alkyl, phenyl-CO-CH 3, -CH ₂ -CH ₂ -N (CH ₃ ) ₂ , phenyl-CO-CH = CH -N (CH ₃ ) ₂ , morpholino, nitro, SO ₃ H,

-CH ₂ -N-COOR ¹⁶

_CH2 n -COOR ¹⁶

CH 2 -COOR ¹⁷

CH ₂ -Ar wherein R ¹⁶ and R ^{17 are} C 1 -C 6 alkyl and Ar is C 6 -C 14 aryl, except for compounds of formula I wherein X is also oxygen and

R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ is H, or

R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen and R ² is bromine, or

R ^1, R ^2, R ^3, R ^4, R ^6, R ⁷ = H, R ⁵ OH, and with the exception of the compounds of formula I in which at the same time X is O and R ^1, R ^2, R ^3, R ⁴ R ⁵ , R ⁶ , R ^{7 are} hydrogen, and addition salts of these compounds with pharmaceutically acceptable acids.

The present invention also provides pharmaceutical compositions comprising an effective amount of a compound of formula (I), wherein is

X is hydrogen, = NH or = N-OH,

R ¹ is hydrogen, halogen, nitro, and -NR ⁸ R ⁹ wherein R ⁸ and R ⁹ is independently H or alkyl of 1 to 4 carbon atoms,

R ² is H or halogen,

R ³ is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, guanidino, -NR ¹⁰ R ¹¹ where R ¹⁰ and R ¹¹ are independently hydrogen, C 1 -C 3 alkyl C 1 -C 4 -alkyl, C 1 -C 4 -phenylalkyl, (CH ₂ ) 2 -N (CH ₃ ) 2 and (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -N (CH ₃ ) ₂ ,

R ( ⁴⁾ is hydrogen, halogen, nitro or -NR ( ¹²⁾ R ( ¹³⁾ wherein R ( ¹²⁾ and R ( ¹³⁾ independently of one another are hydrogen or (C1-C4) -alkyl,

R ^5, R ⁶ and R ⁷ each independently hydrogen, halogen, alkyl having 1 to 6 carbon atoms, a group of a hydroxyl, C 1 -C 6 alkyl, -CHO, -COOH, -CN, -CO 2 R ¹⁴ , -CONHR ¹⁴ , -CONR ¹⁴ R ¹⁵ , -NHCOR ^14, and -NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ^{15 are} each independently hydrogen, C 1 -C 6 alkyl, -CH 2 -CH ₂ - N (CH ₃ ) ₂₁ -phenyl-CO-CH 3, -phenyl-CO-CH = CH-N (CH ₃ ) ₂ , morpholino, nitro, SO ₃ H,

-CH ₂ -N-COOR ¹⁶ -CH ₂ -N-COOR ¹⁶

CH ₂ -COOR ¹⁷ CH ₂ -Ar wherein R ¹⁶ and R ^{17 are} C 1 -C 6 alkyl and Ar is C 6 -C 14 aryl, except for compounds of formula I wherein X is also oxygen and

R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ is H, or

R ^1, R ^3, R ^4, R ^5, R ^6, R ⁷ = H, R ² Br, and the addition salts thereof with pharmaceutically acceptable acids.

In particular, the invention relates to pharmaceutical compositions comprising effective amounts of the compounds of formula (I), wherein:

X an oxygen atom,

R ^{@ 1} is hydrogen or amino,

R ² is H or halogen,

R ³ is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, guanidino, -NR ¹⁰ R ¹¹ where R ¹⁰ and R ¹¹ are independently hydrogen, methyl, phenylalkyl of 1 to 4 carbon atoms in the alkyl, (CH _{2) 2} N (CH _{3) 2,} (CH _{2) 2} -O- (CH _{2) 2} -N (CH _{3) 2,}

R ⁴ is H, halogen, nitro or amino,

R ⁵ , R ⁶ and R ^{7 are} hydrogen, with the exception of the compounds where R is

R ^1, R ^2, R ^3, R ^4, R ^5, R ⁶ and R ⁷ is H or

R ^1, R ^3, R ^4, R ^5, R ⁶ and R ⁷ is H and R ² Br, and the addition salts thereof with pharmaceutically acceptable acids.

The invention further relates, in particular, to pharmaceutical compositions comprising an effective amount of a compound of formula I, wherein it is

X an oxygen atom,

R ^{@ 1} is hydrogen or amino,

R ² is H or halogen,

R ³ is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, guanidino, -NR ¹⁰ R ¹¹ , where R ¹⁰ and R ^{11 are} each independently hydrogen, methyl, (C 1 -C 4) -phenylalkyl, (CH ₂ ) _n -Y, where Y is halogen, CN, -CH (O-Et) ₂ , (C 1 -C 6) alkoxy, -O- (CH ₂ ) ₂ -N (CH ₃ ) ₂ , -N (CH ₃ ) ₂ and n = 1 to 3,

R ( ⁴⁾ is hydrogen, halogen, nitro or amino,

R @ ⁵ is hydrogen, halogen or methoxy;

R ⁶ , R ^{7 are} hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyalkyl, both in the alkoxy moiety and in the alkyl moiety, and

-CH ₂ OCOCH ₃ , r

with the exception of the compounds where

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen or R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen and R ² is bromine, and compounds of formula Ia, wherein is

R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ is H, and the addition salts thereof with pharmaceutically acceptable acids.

The invention also relates to compounds of the formula I as defined above, with the exception of those compounds wherein X is O or R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen or R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen and R ² is bromine or

R ^1, R ^2, R ^4, R ^5, R ^6, R ⁷ = H, R ³ or OCH ₃

R ^1, R ^2, R ^3, R ^4, R ^6, R ⁷ = H, R ⁵ OH, or _OCH3, or

R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ = H, R ¹ NO2, and acid addition salts thereof with pharmaceutically acceptable acids.

In particular, the invention also relates to the compounds of the formula I as defined above, with the exception of those compounds wherein X is O and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} hydrogen and addition salts thereof. pharmaceutically acceptable acids.

By the term "pharmaceutically acceptable acid addition salts" is meant salts having the biological properties of the free bases without any unpleasant effects. These salts may in particular be salts with mineral acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, acidic metal salts such as disodium orthophosphate and monocal sulphate and organic acids.

In general, the compounds of the invention are prepared according to the general reaction scheme described for ascididemin by F. Bracher et al. (Heterocycles 29: 2093-2095 (1989)). According to this scheme, compounds are prepared by oxidative amination of 5,8-quinone substituted with substituted ortho-aminoacetophenone, followed by cyclization of the obtained diarylamine (compound of formula II) to the tetracyclic quinone intermediate (compound of formula III). The enamine formed by the reaction of a compound of formula III with dimethylformamide diethyl acetal leads to the final cyclization derivative:

Ascididemin (or 9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one), prepared as described by F. Bracher et al. (Heterocycles 29, 2093-2095 (1989)) is referred to herein as CRL 8274.

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

This is particularly the case when compounds of formula I where R ^{3 is} -NR ¹⁰ R ¹¹ and R ¹⁰ and / or R ^{11 are} not hydrogen can be prepared from a compound of formula I where R ^{3 is} NH ₂ .

Similarly, compounds of formula Ia can be obtained according to general scheme II. According to this scheme, compounds are prepared by condensing substituted chlorobenzoic acid and dimethoxyaniline to form a compound of formula IIIa. After transformation of the acidic group to the methyl ketone, cyclization and oxidation affords the tricyclic quinone as an intermediate (compound of formula IIIa). Diels Alder cyclization with 1-azadiene leads to the formation of a tetracyclic quinone (compound of formula IVa). Addition of dimethylformamide diethyl acetal to this quinone results in an enamine intermediate which is cyclized in the presence of ammonium chloride to give the final compound of formula Ia.

Scheme II

Hla 'IVa

Some compounds may be prepared directly from the isomers of ascididemin, called 9-H-quino [4,3,2] [1,7] phenanthrolin-9-one, or from a compound of formula Ia used as an intermediate.

This is particularly the case when compounds of formula I wherein R ^{3 is} -NR ¹⁰ R ¹¹ and R ¹⁰ and / or R ^{11 are} not hydrogen can be prepared from compounds of formula I where R ^{3 is} NH ₂ .

A - Preparation of intermediates of formula II (Scheme II)

A-1- Preparation of 6- (2-acetyl-4-methylphenylamino) quinoline-5,8-dione (intermediate A ^ (CRL 8322))

Add slowly a solution of quinoline-5,6-dione (0.215 g, 1.35 mmol) in 12 mL of ethanol to a solution of cerium chloride (1 g, 2.7 mmol) and 5-methyl-2-aminoacetophenone (0.402 g, 2). , 7 mmol) in 5 mL of ethanol. The reaction mixture (red) was stirred overnight at ambient temperature. It is hydrolyzed with 30 ml of a 10% aqueous acetic acid solution and extracted four times with chloroform. The organic phases are dried over magnesium sulphate and evaporated. The residue was purified by flash column chromatography on silica (dichloromethane / methanol 95: 5) to give 0.405 g of the desired tricyclic compound as a powder. (Yield 98%.)

RMN ¹ H (CDCl ₃ ): 2.42 (s, 3H), 2.77 (s, 3H), 6.86 (s, 1H), 7.38 (dd, 1H, J = 8 and 1) 7.6 Hz (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- Preparation of 6- (2-acetyl-4-chlorophenylamino) quinoline-5,8-dione (intermediate A ₂ )

Proceed as in A-1: the intermediate was obtained using quinoline-5,8-dione (0.188 g, 1.18 mmol), cerium chloride (0.88 g, 2.36 mmol) and 5-chloro-2-aminoacetophenone (0 , 4 g, 3.14 mmol), ethanol (10 + 4 mL) and acetic acid (25 mL) as 0.3 g of red powder. (Yield 78%.)

RMN 1 H (CDCl 3): 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).

RMN ¹³ C (CDCl ₃ ): 28.5; 107.36; 121.86; 126.69; 126.85; 127.49; 128.39; 132.10; 134.06; 134.75; 138.36; 143.29; 148.32; 155.22; 181,28; 182.63; 200.39.

A-3- Preparation of 6- (2-acetyl-4-benzylaminophenylamino) quinoline-5,8-dione (intermediate A ₃ )

Proceed as in A-1: the intermediate was obtained using 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) and acetic acid (35 mL) as 0.56 g of red powder. (Yield 91%.)

RMN ¹ H (CDCl 3): 2.54 (s, 3H), 4.38 (s, 2H), 6.70 (s, 1H), 6.83 (dd, 1H, J = 9.6 and 3.2 Hz), 7.08 (d, 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- Preparation of 6- (2-acetyl-5-bromophenylamino) quinoline-5,8-dione (intermediate A4) (CRL 8268)

The procedure is as described by F. Bracher (Liebigs Ann. Chem., P. 205-206, 1990).

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

Proceed as in A-1: the intermediate was obtained using 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) and acetic acid (50 mL) as 1.26 g of red powder. (Yield 84%.)

RMN ¹ H (CDCl ₃ ): 2.85 (s, 3H), 3.12 (s, 6H), 6.72 (s, 1H), 6.90 (dd, 1H, J = 2.8 and 9.2 Hz), 7.15 (d, 1H, J = 2.8 Hz), 7.49 (d, 1H, J = 9.2 Hz), 7.58 (dd, 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, 1 H).

A-6- Preparation of 6- (2-acetyl-4-methoxyphenylamino) quinoline-5,8-dione (Intermediate Αθ)

Proceed as in A-1: the intermediate was obtained using 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) and acetic acid (500 mL) as 4.25 g of red powder (Yield 60%).

RMN ¹ H (CDCl ₃ ): 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, 1 H).

A-7- Preparation of 4,6-bis (2-acetylanilino) quinoline-5,8-dione (intermediate A ₇ )

Proceed as in Example A-1: intermediate was obtained using 4-chloroquinoline-5,8-dione (3.5 g, 18 mmol), cerium chloride (13.5 g, 36.24 mmol), 2 aminoacetophenone (4.4 mL, 36 mmol), ethanol (160 + 70 mL) and acetic acid (400 mL), 2.32 g as a red powder. (Yield 30%).

RMN ¹ H (CDCl 3): 2.69 (s, 3H), 2.72 (s, 3H), 6.85 (s, 1H), 7.18 (ddd, 1H, J = 7.6 and 7) 6 and 0.8 Hz), 7.28 (m, 1H), 7.30 (d, 1H, J = 6.4 Hz), 7.54-7.59 (m, 3H), 7.63 (d, 1H, J = 7.6 Hz), 7.91 (dd, 1H, J = 1.6 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- Preparation of 6- (2-acetyl-4-bromophenylamino) -4-methoxyquinoline-5,8-dione (Intermediate Ae)

Proceed as in A-1: the intermediate was obtained using 4-methoxyquinoline-5,8-dione (1.57 g, 9.1 mmol), cerium chloride (3.1 g, 8.3 mmol) and 5-bromo-2. -aminoacetophenone (Leonard Boyd, J. Org. Chem. 11, 419-423, 1946) (1.95 g, 9.1 mmol), ethanol (200 mL) and acetic acid (180 mL) after purification by flash chromatography on a silica column (dichloromethane / methanol 95: 5) as an orange powder (1.22 g). (Yield 37%).

RMN ¹ H (CDCl 3): 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).

T

A-9- Preparation of 2-methoxy-6- (2-acetylphenylamino) quinoline-5,8-dione (intermediate A _g )

To a suspension of 2-methoxyquinoline-5,8-dione (0.54 g, 2.8 mmol) and cerium chloride (1.16 g, 4.7 mmol) in ethanol (100 mL) was added a solution of O-aminoacetophenone (0 , 41 g, 3.1 mmol) in ethanol (6 mL). The reaction mixture was stirred at ambient temperature for 40 hours. After concentration on a rotary evaporator, the crude obtained was purified by filtration on silica (chloroform / heptane 98: 2) to give the desired condensation product as a red powder (0.35 g). (Yield 38%).

(Melting point: 258 ° C).

¹ H RMN (CDCl 3): 2.67 (s, 3H); 4.15 (s. 3H); 6.79 (s, 1 H); 6.98 (d, 1H, J = 8.8Hz); 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 = 8.1 and 1.5 Hz); 8.31 (d, 1H, J = 8.8Hz).

¹³ C RMN (CDCl ₃ ): 28.51; 54.73; 106.02; 115.22; 120.78; 122.50; 123.11; 125.70; 132.34; 134.24; 137.18; 140.05; 143.30; 148.21; 167.75; 180.88; 183,05; 201.41.

-IR (CHCl3): 1668; 1644 cm ^-1 .

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

a) 3-Hydroxymethyl-5,8-dimethoxyquinoline

To a solution of ethyl 5,8-dimethoxyquinoline-3-carboxylate (180 mg, 0.689 mmol) in 60 mL of tetrahydrofuran was added dropwise 1M lithium aluminum hydride / ethyl ether (5 mL, 5 mmol) under nitrogen. The mixture was stirred at ambient temperature for 15 hours, after which it was poured into 15 ml of a 1N sodium hydroxide solution in 40 ml of water. After extraction with dichloromethane (3 x 100 ml), drying the organic phase over magnesium sulfate, the extract is concentrated on a rotary evaporator. The obtained product was purified by flash chromatography (dichloromethane / methanol 95: 5) to give the desired product as a brown powder (72 mg). (Yield 48%).

(Melting point: 150 ° C)

¹ H RMN (CDCl 3): 3.92 (s, 3H); 4.00 (s. 3H); 4.88 (s, 2 H); 6.72 (d, 1H, J = 8.4Hz); 6.88 (d, 1H, J = 8.4Hz); 8.47 (d, 1H, J = 2.2Hz); 8.87 (d, 1H, J = 2.2Hz).

¹³ C RMN (CDCl ₃ ): 55.76; 56.00; 63.09; 103.95; 106.70; 121.25; 128.62; 133.35; 139.80; 148.61; 149.21; 149.41.

IR (CDCl 3): 3607, 3417, 1622, 1605 cm ^-1 .

b) 3-Hydroxymethylquinoline-5,8-dione

A solution of 3-hydroxymethyl-5,8-dimethoxyquinoline (55 mg, 0.25 mmol) and cerito ammonium nitrate (550 mg, 1 mmol) in acetonitrile / water (3 mL / 1 mL) was stirred at ambient temperature for 40 minutes. After addition of 5 ml of water and 10 ml of saturated sodium bicarbonate solution, the reaction mixture is extracted with dichloromethane (6x30 ml) and the organic phases are dried over magnesium sulphate. Evaporation of the solvent on a rotary evaporator gave the desired quinone as a brown powder (11 mg). (Yield 22%). Mp 150 ° C.

¹ H NMR (CDCl 3): 4.95 (s, 2H); 7.06 (d, 1H, J = 10.2Hz); 7.15 (d, 1H, J = 10.2Hz); 8.43 (s, 1 H); 9.03 (s, 1 H).

¹³ C RMN (CDCl 3): 62.03; 128.86; 132.26; 138.00; 139.11; 141.33; 146.58; 153.10; 183.12; 184.54.

IR (CHCl 3): 3413; 1680; 1596 cm ¹ .

c) Preparation of 3-hydroxymethyl-6- (2-acetylphenylamino) quinoline-5,8-dione (intermediate A10)

To a suspension of 3-hydroxymethylquinoline-5,8-dione (0.22 g, 1.16 mmol) and cerium chloride (0.6 g, 2.43 mmol) in ethanol (40 mL) was added a solution of 2-aminoacetophenone (0 , 18 g, 1.33 mmol). The reaction mixture was stirred in the dark for three hours at ambient temperature. After concentration on a rotary evaporator, the obtained product was purified by filtration on silica (dichloromethane / methanol 98: 2) to give the condensation product as a violet powder (0.16 g). (Yield 42%). Mp 258 ° C.

¹ H RMN (DMSO-d ₆ ): 2.67 (s, 3H); 4.73 (d, 2H, J = 5.5Hz); 5.67 (t, 1H, J = 5.5Hz);

6.64 (s, 1 H); 7.30 (m, IH); 7.71 (m, 2 H); 8.12 (d, 1H, J = 8.0Hz); 8.35 (d, 1 H, J =

2.0 Hz); 8.93 (d, 1H, J = 2.0 Hz); 11.02 (s, 1H).

¹³ C RMN (CDCl ₃ ): 28.81; 60.08; 106.52; 120.96; 123.44; 126.14; 127.23; 131.52;

132.69; 134.43; 138.91; 141.75; 143,55; 146.62; 152.81; 181.62; 181.84; 202.02.

IR (CHCl 3): 3440, 1690, 1661, 1640 cm ^-1

B - Preparation of intermediates of formula III (Scheme II)

B-1- Preparation of 9,11-dimethyl-1,6-diazanphthacene-5,12-dione (intermediate B ^ (CRL 8324))

To a solution of tricyclic intermediate A1 (0.4 g, 1.3 mmol) in 12 mL of acetic acid was slowly added 1.9 mL of a solution of sulfuric acid in 9.6 mL of acetic acid. The reaction mixture is kept at reflux for 30 minutes, after which it is poured into a beaker containing crushed ice after cooling. The mixture was neutralized with ammonium hydroxide and extracted 4 times with dichloromethane. The organic phases are dried over magnesium sulphate and evaporated. The residue was purified by flash column chromatography on silica (dichloromethane / methanol 95: 5) to give 0.325 g of the desired tetracyclic compound. (Yield 86%).

RMN ¹ H (CDCl 3): 2.64 (s, 3H), 3.29 (s, 3H), 7.74 (dd, 1H, J = 7.6 and 4.8 Hz), 7.75 (s) 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- Preparation of 9-chloro-11-methyl-1,6-diazanaphthacene-5,12-dione (intermediate B ₂ )

Preparation is similar to paragraph B-1: tricyclic intermediate A ₂ (0.289 g, 0.88 mmol), sulfuric acid (1.3 mL) and acetic acid (8 + 6.5 mL) are used. Purification by flash chromatography (dichloromethane / methanol 95: 5) afforded 0.26 g of the tetracyclic intermediate. (Yield 95%).

RMN ¹ H (CDCl 3): 3.25 (s, 3H), 7.76 (dd, 1H, J = 8 and 4.8 Hz), 7.85 (dd, 1H, J = 8.8) and 2 Hz), 8.33 (dd, 1H, J = 2 Hz), 8.38 (d, 1H, J = 8.8), 8.71 (dd, 1H, J = 1.6 and 8 Hz) 9.15 (dd, 1H, J = 1.6 and 4.8 Hz).

B-3- Preparation of 9-benzylamino-11-methyl-1,6-diazanaphthacene-5,12-dione (intermediate B ₃ )

The preparation is similar to that in B-1: intermediate A ₃ (4 g, 10 mmol), sulfuric acid (15.1 mL) and acetic acid (92 + 75 mL) are used. After working up, 3.58 g of the tetracyclic intermediate is obtained. (Yield 98%).

RMN ¹ H (CDCl 3): 3.09 (s, 3H), 4.52 (d, 2H), 4.86 (t, 1H), 7.06 (d, 1H, J = 2.8 Hz) 7.29 (dd, 1H, J = 9.2 and 2.8 Hz), 7.3-7.43 (m, 5H), 7.71 (dd, 1H, J = 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- Preparation of 8-bromo-11-methyl-1,6-diazanaphthene-5,12-dione (intermediate B ₄ )

This intermediate was prepared as described by F. Bracher (Liebigs

Ann. Chem., P. 205-206 (1990).

B-5- Preparation of 9-dimethylamino-11-methyl-1,6-diazanaftacene-5,12-dione (intermediate Bs)

Preparation is similar to paragraph B-1: tricyclic intermediate A ₅ (0.76 g, 2.27 mmol), sulfuric acid (3.5 mL) and acetic acid (20 + 18 mL) are used. After working up, 0.67 g of the tetracyclic intermediate is obtained. (Yield 93%).

RMN ¹ H (CDCl 3): 3.17 (s, 3H), 3.21 (s, 6H), 7.04 (d, 1H, J = 3.2 Hz), 7.51 (dd, 1H, J = 3.2 and 9.2 Hz), 7.71 (dd, 1H, J = 8 and 4.4 Hz), 8.26 (d, 1H, J = 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- Preparation of 9-methoxy-11-methyl-1,6-diazanaftacene-5,12-dione (intermediate B ₆ )

Preparation is similar to paragraph B-1: tricyclic intermediate ββ (4.25 g, 13.18 mmol), sulfuric acid (20 mL) and acetic acid (110 + 100 mL) are used. The product obtained by flash chromatography (dichloromethane / methanol 100: 3) was washed with ethyl ether to give 2.9 g of the tetracyclic intermediate. (Yield 72%).

RMN ¹ H (CDCl ₃ ): 3.25 (s, 3H), 4.02 (s, 3H), 7.49 (d, 1H, J = 3.3 Hz), 7.56 (dd, 1H) J = 3.3 and 9.3 Hz), 7.74 (dd, 1H, J = 8.3 and 4.3 Hz), 8.34 (d, 1H, J = 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- Preparation of 4- (2-acetylanilino) -11-methyl-1,6-diazanaphthene-5,12-dione (intermediate B ₇ ) (CRL 8332)

The preparation is similar to paragraph B-1: will the tricyclic intermediate A be used?

(1 g, 2.35 mmol), sulfuric acid (3.5 mL), acetic acid (18 mL). The product obtained by flash chromatography (dichloromethane / methanol 100: 3) was washed with ethyl ether to give 0.6 g of the tetracyclic intermediate as an orange powder (Yield 63%).

RMN ¹ H (CDCl ₃ ): 2.59 (s, 3H), 3.25 (s, 3H), 7.29 (ddd, 1H, J = 7.2 and 7.2 and 1.2 Hz) 7.37 (d, 1H, J = 6Hz), 7.54 (ddd, 1H, J = 6.8 and 6.8 and 1.6Hz), 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).

B-8- Preparation of 4-methoxy-9-bromo-11-methyl-1,6-diazanaphthene-5,12-dione (Intermediate Be)

The preparation is similar to that in B-1: tricyclic intermediate A _a (1.22 g, 3.04 mmol), sulfuric acid (4.5 mL) and acetic acid (27 + 23 mL) are used. The product obtained by flash chromatography (dichloromethane / methanol 100: 3) was washed with ethyl ether to give 0.76 g of the tetracyclic intermediate as a yellow powder (Yield 65%).

RMN ¹ H (CDCl 3): 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) ).

B-9- Preparation of 2-methoxy-11-methyl-1,6-diazanaphthene-5,12-dione (Intermediate B ₉ )

A solution of 2-methoxy-6- (2-acetylphenylamino) quinoline-5,8-dione (0.34 g, 1.1 mmol), a mixture of acetic acid and sulfuric acid (25 mL / 2.7 mL) was kept at temperature 90 ° C. After cooling, the reaction mixture was poured into a mixture of water and ice (200 ml), then basified to pH 8 with potassium carbonate and extracted with chloroform (3x200 ml). The organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The obtained product was purified by filtration on silica (chloroform) to give the desired tetracyclic intermediate as a beige powder (0.23 g). (Yield 71%) (Melting point: 260 ° C)

^{@ 1} H NMR (CDCl3): 3.32 (s, 3H); 4.23 (s, 3H); 7.14 (d, 1H, J = 8.8Hz); 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 = 8.8Hz).

¹³ C RMN (CDCl 3): 16.63; 54.76; 117.29; 125.29; 125.50; 125.64; 129.62; 129.75; 132.37; 132.57; 138.12; 147.73; 148.63; 149.69; 152.28; 167.77; 181.10; 183.55.

IR (CDCl 3): 1683; 1599 cm ^-1

B-10- Preparation of 3-acetoxymethyl-11-methyl-1,6-diazanaphthene-5,12-dione (Intermediate B10)

A solution of 3-hydroxymethyl-6- (2-acetylphenylamino) quinoline-5,8-dione (Intermediate A ₁₀ ) (0.248 g, 0.77 mmol) in acetic / sulfuric acid (16 mL / 1.3 mL) was added held at 90 ° C for 2.5 hours. After cooling, the reaction mixture was poured into a mixture of water and ice (15 ml), then basified to pH 9 with sodium carbonate and extracted with dichloromethane (3x150 ml). The organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The product obtained was purified by filtration on silica (dichloromethane / methanol) to give the title compound as a brown powder (0.21 g). (Yield 85%).

¹ H NMR (CDCl ₃ ): 2.18 (s, 3H); 3.30 (s, 3H); 5.31 (s, 2 H); 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 = 2.2Hz); 9.09 (d, 1H, J = 2.2Hz).

¹³ C RMN (CDCl ₃ ): 16.06; 20.11; 62.06; 124.81; 124.91; 129.06; 129.18; 129.29; 131.70; 132.18; 134.06; 136,09; 146.86; 147.97; 149.01; 152.19; 154.30; 169.72; 180.96; 182,34.

IR (CDCl 3): 3420, 1746, 1692 cm ^-1 .

C - Preparation of intermediates of general formula IIIa (Scheme II)

1) Preparation 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), copper oxide (0.96 g) and potassium carbonate (10.4 g) in 120 ml of diglyme is kept under reflux overnight. After evaporation of the solvent, the reaction mixture was basified with 1N soda solution. Ether was added, the reaction mixture was filtered through a silica column and the ether phase was discarded. The aqueous phase is acidified with concentrated hydrochloric acid, then extracted with ethyl acetate. After drying over magnesium sulfate and evaporation of the solvent on a rotary evaporator, the product obtained is purified by filtration on silica (dichloromethane) to give the desired condensation product as a yellow powder (14.5 g). (Yield 89%).

(Melting point: 138 ° C)

RMN ¹ H RMN (CDCl 3): 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 = 9.2Hz); 7.04 (d, 1H, J = 2.9Hz); 7.3 and 7.4 (m, 2H); 9.35 (s broad, 1H).

¹³ C RMN (CDCl ₃ ): 55.76; 56.45; 107.30; 107.71; 112.00; 112.26; 114.70; 117.53; 130.78; 132.60; 134.09; 145.98; 147.71; 153.75; 172.95.

-IR (CHCl3): 3327; 1685 cm ^-1 .

2) Preparation of 2- (2,5-dimethoxyphenylamino) acetophenone (compound 5)

To a mixture of N- (2,5-dimethoxyphenylanthranilic acid (2 g, 73 mmol) in 14 mL of tetrahydrofuran was added 16 mL of methyl lithium (1.4 M / ethyl ether) at 0 ° C under nitrogen. The mixture was refluxed for two hours after which 100 mL of water was added and the mixture was extracted with ether (3 x 100 mL), dried over magnesium sulfate and the solvent was removed by rotary evaporation to give the desired derivative as a yellow solid powder (1.49). (yield 75%) (melting point: 79 ° C)

^{@ 1} 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 = 8.8Hz); 7.04 (d, 1H, J = 2.9Hz); 7.3 and 7.4 (m, 2H); 7.81 (dd, 1H, J = 1.5 and 8.0 Hz); 10.5 (s broad, 1H).

¹³ C RMN (CDCl 3): 48.15; 55.73; 56.36; 107.10; 107.72; 112.05; 114.80; 116.84; 120.09; 130.68; 132.42; 134.35; 145.98; 146.67; 153.62; 201.00.

IR (CDCl ₃ ): 3350; 1642 cm ^-1 .

3) Preparation of 1,4-dimethoxy-9-methylacridine (Compound 6)

A mixture of 2- (2,5-dimethoxyphenylamino) acetophenone (1.3 g, 48 mmol) and polyphosphoric acid (13 g, 133 mmol) was maintained at 100 ° C for one hour. After addition of 50 ml of water, the mixture was neutralized with 4M sodium carbonate solution and extracted with chloroform (3 x 100 ml). After drying over magnesium sulfate and evaporation of the solvent on a rotary evaporator, the product obtained is purified by filtration on silica (dichloromethane) to give the desired tricyclic derivative in quantitative form as an orange-brown solid. (Melting point: 136 ° C).

^{@ 1} H NMR (CDCl3): 3.36 (s, 3H); 3.96 (s, 3H); 4.09 (s, 3H); 6.68 (d, 1H, J = 8.0Hz); 6.89 (d, 1H, J = 8.4Hz); 7.54 (m, IH); 7.73 (m, IH); 8.32 (d, 1H, J = 8.4); 8.36 (d, 1H, J = 8.8Hz).

¹³ C RMN (CDCl ₃ ): 17.78; 55.66; 56.13; 102.43; 105.18; 120.25; 124.28; 125.62; 126.59; 129.44; 130.81; 142.45; 144.23; 147.21; 149.46; 151.45.

IR (CDCl ₃ ): 1685; 1661 cm ^-1 .

4) Preparation of 9-methylacridine-1,4-dione (compound 7)

A solution of 1,4-dimethoxy-9-methylacridine (20 mg, 0.079 mmol) and cerito ammonium nitrate (196 mg, 0.357 mmol) in dichloromethane / water (0.5 mL / 0.25 mL) was stirred at 0 for 20 min. C. After addition of 1.4 ml of water and 0.4 ml of saturated sodium bicarbonate solution, stirring is continued, followed by extraction with dichloromethane (3 x 3 ml). The organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The desired quinone was obtained as a brown powder (15 mg). (Yield 90%). (Melting point:> 260 ° C)

^{@ 1} H NMR (CDCl3): 3.22 (s, 3H); 7.09 (d, 1H, J = 10.3Hz); 7.18 (d, 1H, J = 10.3Hz); 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 = 8.5Hz).

¹³ C RMN (CDCl 3): 15.87; 124.40; 125.41; 126.30; 129.61; 132.32; 132.52; 137.88; 141.61; 147.05; 148.23; 151.23; 183.43; 186.69.

IR (CHCl3): 1701; 1661 cm ^-1 .

D - Preparation of intermediates of formula IVa (Scheme II)

D -1- Preparation of 6-methyl-1,11-diazanaphthacene-5,12-dione (Intermediate D1)

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) and 20 mL of dichloromethane was stirred at ambient temperature for 30 minutes under nitrogen. . After evaporation of the solvent, the reaction solution is purified by filtration on silica (dichloromethane) to give a not completely aromatic addition product. A suspension of this compound and 10% palladium on carbon (20 mg) in 4 ml of toluene was maintained at reflux for 30 minutes. After concentration, the obtained product was purified by flash chromatography on silica (dichloromethane / methanol 98: 2) to give the desired tetracyclic intermediate as a beige powder (23 mg). (Yield 13%).

^{@ 1} H NMR (CDCl3): 3.32 (s, 3H); 7.78-7.83 (m, 2 H); 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).

¹³ C RMN (CDCl 3): 16.67; 124.59; 125.44; 128.39; 129.76; 129.89; 132.25; 132.54; 132.88; 135.93; 148.00; 148.59; 148.73; 152.48; 155.31; 180,81; 184.37.

IR (CHCl ₃ ): 1703; 1663 cm ^-1 .

D-2 Preparation of 3-methoxy-6-methyl-1,11-diazanaphthacene-5,12-dione (Intermediate D ₂ )

3-Methoxy-6-methyl-1,11-diazanaphthacene-5,12-dione was prepared as described in D1 using a solution of 9-methylacridine-1,4-dione (compound 7) (200 mg, 0.896 mmol) 2- methoxy-2-propenaldimethylhydrazone (126 mg, 0.984 mmol) and acetic anhydride (1 mL) in 20 mL of dichloromethane.

The invention is illustrated in more detail by the following non-limiting examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

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

A solution of tetracyclic intermediate Bi (1 g, 3.47 mmol) and dimethylformamide diethyl acetal (2 mL, 10.41 mmol) in 7 mL of DMF was maintained at reflux for 1 h. After evaporation to dryness, ammonium chloride (2.77 g, 52 mmol) and 50 mL of ethanol were added. The reaction mixture was reheated and held at reflux for 30 minutes. After evaporation of the solvent, the product is taken up in water and extracted 4 times with dichloromethane. The organic phases are dried over magnesium sulphate and evaporated. Recrystallization from 125 ml of methanol gave 0.7 g of the desired product CRL 8323 as a mustard yellow solid. (Yield 67%). Mp = 200 ° C.

RMN ¹ H (CDCl 3): 2.69 (s, 3H), 7.65 (dd, 1H, = 8 and 4.8 Hz), 7.81 (dd, 1H, J = 8 and 1.2 Hz) ), 8.44 (d, 1H, J = 1.2Hz), 8.49 (d, 1H, J = 8Hz), 8.50 (d, 1H, J = 5.6Hz), 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).

RMN ¹³ C (CDCl ₃ ): 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-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8301)

Proceed as in Example 1 using tetracyclic intermediate Eb (0.25 g, 0.81 mmol), dimethylformamide diethyl acetal (1.5 mL, 8.75 mmol), dimethylformamide (4.5 mL). Ammonium chloride (2.95 g, 55 mmol) and ethanol (50 mL) were added. Purification by flash chromatography (dichloromethane / methanol 98: 2) afforded 60 mg of product CRL 8301 as a yellow solid. (Yield 23%). Melting point 200 ° C.

- RMN 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 = 5.6Hz), 8.55 (d, 1H, J = 8.8Hz), 8.63 (d, 1H, J = 2Hz), 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).

RMN ¹³ C (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).

Example 3

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

Proceed as in Example 1, using tetracyclic intermediate B ₃ (3.58 g, 9.45 mmol), dimethylformamide diethyl acetal (5.7 mL, 33.26 mmol) and dimethylformamide (19 mL). Ammonium chloride (2.95 g, 55 mmol) and ethanol (50 mL) were added. Purification by flash chromatography (dichloromethane / methanol 96: 4) gave 2 g of product CRL 8241 as a wine yeast powder. (Yield 55%). Mp 219 ° C.

- RMN ¹ H (CDCl ₃ ): 4.61 (d, 2H), 5.10 (t, 1H), 7.31 (dd, 1H, J = 8.8 Hz, J = 2.4 Hz),

I

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) 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).

Example 4

5- (Dimethylamino) -9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8325)

Proceed as in Example 1 using tetracyclic intermediate B5 (0.25 g, 0.79 mmol), dimethylformamide diethyl acetal (0.5 mL, 2.98 mmol) and dimethylformamide (5 mL). Ammonium chloride (1 g, 18.7 mmol) and ethanol (16 mL) were added. Purification by flash chromatography (dichloromethane / methanol 100: 5) gave 170 mg of CRL 8325 as a violet powder. (Yield 66%). Mp > 260 ° C.

RMN ¹ H (CDCl 3): 3.25 (s, 6H), 7.45 (dd, 1H, J = 9.2 Hz, J = 3 Hz), 7.57 (d, 1H, J = 3 Hz) ), 7.63 (dd, 1H, J = 4.4 and 8 Hz), 8.41 (d, 1H, J = 9.2 Hz), 8.43 (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-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8297)

The procedure is as in Example 1 with the use of the tetracyclic intermediate ₆ B (2 g, 6.57 mmol), dimethylformamide diethyl acetal (4 mL, 23.34 mmol) and DMF (14 mL). Ammonium chloride (8 g, 149.5 mmol) and ethanol (130 mL) were added. Purification by flash chromatography (dichloromethane / methanol 100: 5) afforded 170 mg of compound CRL 8297 as a greenish solid.

(Yield 66%). Mp > 260 ° C.

RMN ¹ H (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, 1 H, J =

5.2 Hz).

RMN ¹³ C (CDCl ₃ ): 30.93; 116.86; 118.41; 122.44; 125.56; 129.25; 134.96; 136.55; 137.13; 141,52; 143,67; 149.11; 149.77; 152.37; 155.38; 161.71; 181.93; 207.00.

MS (m / z): 313 (26); 312 (100); 285 (2); 284 (15); 269 (15); 242 (32.5).

Example 6

7-Nitro-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8289)

At 0 ° C, ascididemine (2 g, 7.06 mmol) was added portionwise to a mixture of 45 mL of sulfuric acid and 45 mL of nitric acid. The reaction mixture is kept at 130 ° C for two hours, after which it is poured after cooling into a flask containing 400 g of ice. After filtration, a yellow precipitate is obtained, which is washed several times with ether. The precipitate was added to a dichloromethane / ammonium hydroxide / water 600: 1: 300 mixture. The organic phase is separated and the aqueous phase is extracted 3 times with dichloromethane. After drying over magnesium sulfate, the organic phases are evaporated to give 1.62 g of compound CRL 8289 as a yellow solid. (Yield 70%). Mp 224 ° C.

RMN 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, 1 H, J = 5.2 Hz), 8.75 (dd, 1 H, J = 2 and 8 Hz), 8.89 (dd, 1 H, J =

1.2 and 8 Hz), 9.18 (dd, 1H, J = 4.4 and 2 Hz), 9.37 (d, 1H, J = 5.6 Hz).

RMN ¹³ C (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-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8344) t

A suspension of nitrated derivative CRL 8289 (0.4 g, 1.22 mmol) and iron (0.37 g,

6.59 mmol) in 10:10 acetic acid / water was maintained at reflux for one hour. Ethylenediaminetetraacetic acid (1.94 g, 6.59 mmol) was added, the reaction mixture basified with concentrated sodium hydroxide solution. Extract three times with dichloromethane. After drying over magnesium sulfate, the organic phases are evaporated to give 0.32 g of compound CRL 8344 as a blue solid. (Yield 88%). Mp > 260 ° C.

- RMN 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, 1H, J = 1.6 and 4.8 Hz), 9 21 (d, 1 H, J =

5.2 Hz).

RMN ¹³ C (CDCl ₃ ): 109.42; 112.71; 117.70; 118.43; 124.29; 125.64; 129.12; 132.63; 132.81; 135.53; 137.27; 141.68; 148.68; 148.89; 149.03; 151,96; 154.68; 180,71.

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

Example 8

5-Bromo-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8248)

To a solution of ascididemin (0.5 g, 1.77 mmol) in 20 mL acetic acid was added dropwise a solution of bromine (0.2 mL, 3.88 mmol) in 5 mL acetic acid. The reaction mixture is maintained at reflux (closed refrigerant) for 24 hours. After cooling, the reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted 4 times with dichloromethane. The organic phases are dried over magnesium sulphate and evaporated. Purification by flash column chromatography on silica (dichloromethane / methanol 96: 4) gave 0.548 g of compound CRL 8248 as a yellow solid. (Yield 86%). Mp 208 ° C.

RMN 1 H (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 = 8.8Hz), 8.49 (d, 1H, J = 6Hz), 8.79 (dd, 1H, J = 2 and 8Hz), 8.82 (d 1H, J = 2Hz), 9.18 (dd, 1H, J = 2Hz, J = 4.4Hz), 9.30 (d, 1H, J = 6Hz).

RMN ¹³ C (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-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8347)

To a solution of brominated ascididemin CRS 8248 (2.3 g, 6.33 mmol) in 460 mL of DMF was added sodium azide (2.34 g, 36.1 mmol). The reaction mixture was kept at reflux for four hours. After cooling, the reaction mixture was evaporated to dryness and the solid obtained was taken up in water. Extract 4x with dichloromethane. After drying over magnesium sulfate and evaporation of the solvent, the product was purified by flash column chromatography on silica (chloroform / methanol 90:10) to give 115 mg of CRL 8347 as a black powder.

(Yield 6%). Mp > 260 ° C.

RMN ¹ H (CDCl ₃ ): 7.43 (dd, 1H, J = 8.8 and 2.4 Hz), 7.74 (dd, 1H, J = 4.8 and 8 Hz), 7 81 (d, 1H, J = 2.4Hz), 8.48 (d, 1H, J = 6Hz), 8.50 (d, 1H, J = 8.8Hz), 8.90 (dd) 1 H, J = 2 and 8 Hz), 9.25 (dd, 1H, J = 2 and 4.8 Hz), 9.29 (d, 1H, J = 6 Hz). .

RMN ¹³ C (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).

Example 10

10-Methoxy-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8368)

The procedure is as described by Y. Kitahara et al. (Heterocycles 36, 943-946, 36: 943-946, 1993).

Example 11

10-Hydroxy-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8387)

The procedure is as described by Y. Kitahara et al. (Tetrahedron 53, pp. 17029-17038, 1997).

Example 12

9-H-Chino [4,3,2-de] [1,10] phenanthroline-9-imine (CRL 8290)

100 mg (0.353 mmol) of ascididemine are dissolved in a mixture containing 5 ml of ammonia and 2 ml of ethanol. The reaction mixture is maintained at reflux (closed refrigerant) for 72 hours. After evaporation of the solvent by rotary evaporation, the residue was purified by alumina flash chromatography (dichloromethane / methanol 99: 1) to give 87 mg of compound CRL 8290.

(Yield 87%). Mp > 260 ° C.

RMN 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); 8.40 (d, 1H, J = 8Hz); 8.43 (d, 1H, J = 6Hz); 8.64 (d, 1H, J = 8Hz); 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 = 6Hz); 12.48 (s, 1H).

Example 13

9-H-Chino [4,3,2-de] [1,10] phenanthroline-9-oxime (CRL 8292)

Dissolve 500 mg (1.77 mmol) of ascididemin and 500 mg of NH ₂ OH and 1/2 H ₂ SO ₄ in 1 mL of pyridine and 10 mL of ethanol. The reaction mixture is maintained at reflux for 48 hours. After evaporation of the solvent on a rotary evaporator, 20 ml of water are added and the reaction mixture is taken up in chloroform (3 x 20 ml). The organic phases are dried over magnesium sulphate and evaporated on a rotary evaporator. The residue was purified by flash column chromatography on alumina (dichloromethane / methanol 99: 1) to give 240 mg of oxime CRL 8292 as a yellow powder. (Yield 46%). Mp > 260 ° C.

RMN ¹ H (CDCl 3): 7.68 (dd, 1H, J = 4.4 and 8.4 Hz); 7.98 (ddd, 1H, J = 7.6 and 7.6 and 1.6 Hz); 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 = 6Hz); 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).

RMN ¹³ C (CDCl 3): 115.06; 116.14; 123.16; 123.29; 125.46; 128.33; 128.77; 129.54; 131.86; 132.16; 138.48; 140.94; 141.37; 145.82; 146.75; 151.27; 151.65; 151.80.

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

Example 14

10- (2-Acetylanilino-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8333)

The procedure is as in Example 1, using Intermediate B tetracyclic ₇ (0.4 g, 0.98 mmol), dimethylformamide diethyl acetal (0.6 mL, 3.43 mmol) and DMF (4 mL). Ammonium chloride (1.2 g, 22.4 mmol) and ethanol (20 mL) were added. Purification by flash chromatography (dichloromethane / methanol 100: 5) afforded 144 mg of compound CRL 8333 as a red-brown solid. (Yield 35%). Mp > 260 ° C.

RMN ¹ H (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 = 7.6Hz), 7.65 (broad S, 1H), 7.69 (d, 1H, J = 7.6Hz), 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 = 6Hz).

RMN ¹³ C (CDCl 3): 37.22; 45,05; 109.94; 113.94; 116.56; 117.38; 122.92; 123.34; 125.43; 125.90; 129.47; 130.27; 131.61; 132.94; 135.87; 137.17; 137.57; 145.87; 146.93; 149.81; 150.28; 153.30; 154.27; 154.54; 154.61; 183,73.

Example 15

10-Hydroxy-9-H 'chino [4,3,2-de] [1,10] phenanthrolin-9-one diiodide (CRL 8369)

Maintain 500 mg (1.597 mmol) of the compound of Example 10 (CRL 8368) and 40 mL of acetic acid in 100 mL of hydroiodic acid (57%) for 30 minutes at 100 ° C. After cooling, the reaction mixture was poured into 500 ml of ice water and neutralized with solid sodium bicarbonate. After several extractions with 5% methanol in chloroform (6 x 500 mL), the organic phases are dried over magnesium sulfate and concentrated on a rotary evaporator to give 0.36 g of CRL 8369 as a wine-colored powder. (Yield 41%). Mp > 260 ° C.

RMN 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 = 4Hz); 7.57 (d, 1H, J = 5.2Hz); 7.89 (d, 1H, J = 8Hz); 7.93 (dd, 1H, J = 7.6 and 7.6 Hz); 8.51 (d, 1H, J = 5.2Hz); 9.54 (s, 1 H); 12.62 (m broad, 1H); 14.42 (s, 1 H).

RMN ¹³ C RMN (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-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8373)

50 mg (0.09 mmol) of the compound of Example 15 (CRL 8369), dissolved in 4 ml of phosphorus oxychloride, was refluxed for two hours. After evaporation of the phosphorus oxychloride on a rotary evaporator, the reaction mixture is neutralized with a saturated sodium bicarbonate solution. After several extractions with a mixture of% methanol in chloroform (5x20 ml), the organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The residue was purified by flash column chromatography on silica (dichloromethane / methanol 95: 5) to give 20 mg of CRL 8373 as a yellow powder.

(Yield 77%). Mp > 260 ° C.

RMN ¹ H (CDCl 3): 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 = 5.6Hz); 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 = 5.6Hz); 9.30 (d, 1H, J = 5.6Hz).

- NMR ¹³ C NMR (CDCl): 117.60; 117.84; 123.31; 123.60; 126.69; 129.10; 131.17; 132.38; 133.47; 138.21; 146.24; 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

5-Bromo-10-methoxy-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8389)

The procedure is as in Example 1 with the use of the tetracyclic intermediate B ₈ (0.74 g, 1.93 mmol), dimethylformamide diethyl acetal (1.3 mL, 7.24 mmol) and DMF (15 ml). Ammonium chloride (1.96 g, 36.4 mmol) and ethanol (200 mL) were added. Purification by flash chromatography (dichloromethane / methanol 95: 5) afforded 210 mg of CRL 8389 as an orange powder (yield 42%), mp> 260 ° C.

RMN ¹ H (CDCl 3): 4.14 (s, 3H), 7.14 (d, 1H, J = 5.6 Hz), 8.05 (dd, 1H, J = 2 and 8.8 Hz) 8.43 (d, 1H, J = 6Hz), 8.44 (d, 1H, J = 8.8Hz); 8.76 (d, 1H, J = 2Hz), 8.95 (d, 1H, J = 6Hz), 9.27 (d, 1H, J = 5.6Hz).

RMN ¹³ C (CDCl 3): 57.12; 109.52; 117.00; 117.76; 119.46; 121.58; 124.81; 125.52; 134.72; 135.49; 137.00; 144.85; 146.51; 147.24; 147.92; 150.43; 156.21; 167,98; 180.57.

MS (m / z): 393 (100); 392 (61.7); 391 (99.2); 390 (17.4); 362 (9.2); 333 (9.8); 254 (34.5).

Example 18

5-Amino-11-methoxy-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8389)

A solution containing CRL 8389 (0.5 g, 1.3 mmol) and sodium azide (0.5 g,

7.7 mmol) in 20 ml of dimethylformamide is held at 90 ° C for 10 hours. After concentration, the residue was taken up in 1N potassium hydroxide solution (35 ml) and extracted with dichloromethane / methanol 95: 5 (4x200 ml). After drying, the product was purified by flash chromatography on silica (dichloromethane / methanol 80:20) to give CRL 8389 as a purple powder (65 mg). (Yield 15%). Mp > 260 ° C.

-RMN ¹ H (DMSO-d 6): 4.07 (s, 3H); 6.62 (s, 2 H); 7.36 (d, 1H, J = 8.8Hz); 7.41 (d, 1H, J = 5.9Hz); 7.74 (s, 1 H); 8.08 (d, 1H, J = 8.8Hz); 8.48 (d, 1H, J = 5.2Hz); 8.86 (d, 1H, J = 5.9Hz); 9.08 (d, 1H, J = 5.2Hz).

IR (KBr): 3420, 3196, 1636, 1616 cm < -1 >.

Example 19

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

A solution containing 5-amino-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (1 g,

3.35 mmol) and concentrated hydrochloric acid (0.56 mL) in 200 mL of methanol are stirred at ambient temperature for one hour. Ether (200 ml) was added and after precipitation of the salt, the reaction mixture was filtered to give compound CRL 8406 as a black powder. (Yield 90%).

RMN ¹ H (DMSO-d 6): 7.44 (dd, 1H, J = 8.8 and 2.2 Hz); 7.81 (d, 1H, J = 2.2Hz); 7.93 (dd, 1H, J = 5.6 and 5.9 Hz); 8.12 (d, 1H, J = 8.8Hz); 8.66 (d, 1H, J = 5.6Hz); 8.75 (d, 1H, J = 5.9Hz); 9.07 (d, 1H, J = 5.9Hz); 9.14 (d, 1H, J = 5.9Hz).

IR (KBr): 3404, 3287, 3170, 1691, 1676, 1649 cm ^-1 .

Example 20

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

A solution containing 5- (dimethylamino) -9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (1 g, 3.06 mmol) and concentrated hydrochloric acid (0.3 mL) ) in 120 ml of chloroform was stirred at ambient temperature for 45 minutes. After addition of 350 ml of ether and precipitation of the salt, the reaction mixture is filtered to give 0.97 g of the desired compound as a navy blue powder. (Yield 87%). Mp > 260 ° C.

Example 21

5- (Benzylamino) -9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one chlorohydrate (CRL 8416)

A solution containing 5- (benzylamino) -9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one ASC20 (0.94 g, 2.42 mmol) and concentrated hydrochloric acid (0 (2 ml) in 40 ml of chloroform was stirred at ambient temperature for 30 minutes. The solvent was evaporated, ether (150 ml) was added, and after precipitation of the salt, the reaction mixture was filtered to give 0.98 g of the desired compound CRL 8416 as a black powder. (Yield 95%). Mp > 260 ° C.

Example 22

5- (Dimethylamino-2-ethyl) amino-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8419)

To a mixture containing CRL 8347 (2.56 g, 8.59 mmol) and dimethylformamide diethyl acetal (7.9 mL, 43.3 mmol) was added 25 mL (166 mmol) of trifluoroacetic acid at 0 ° C. The reaction mixture was stirred for 5 minutes and sodium cyanoborohydride (8.2 g, 130 mmol) was added in portions. The reaction mixture was heated to 95 ° C by heating. After eighteen hours, the mixture was basified to pH 8 with saturated sodium bicarbonate solution (approximately 600 mL) and extracted with 95: 5 dichloromethane / methanol (3x800 mL). The organic phases are washed with water and dried over magnesium sulphate. After evaporation of the solvent, the product was purified by filtration on alumina (chloroform then chloroform / methanol 95: 5) to give 1.15 g of compound CRL 8419 as a black powder. (Yield 36%). Melting point: the product decomposes before melting. (Yield 70%).

- RMN ¹ H (CDCl ₃ ): 2.37 (s, 6H), 2.62 (t, 2H, J = 7.32 Hz), 3.70 (t, 2H, J = 7.32 Hz), T

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 (dcl, 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).

RMN ¹³ C (CDCl 3): 45.97; 50.31; 56.40; 101.05; 116.81; 118.48; 118.89; 125.22; 126.30; 129.35; 134.87; 135.97; 136.32; 138.91; 140.55; 148.25; 148.98; 149.69; 152.23; 154.82; 181.37.

IR (CHCl3): 1663 cm @ ^-1 .

MS (m / z): 369 (100); 354 (15); 236 (37).

Example 23

5- (Dimethylamino-2-ethyl) amino-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one chlorohydrate (CRL 8418)

To 1.2 g (3.25 mmol) of CRS 8419 dissolved in 60 ml of chloroform, add 265 μΙ (3.25 mmol) of concentrated hydrochloric acid. The reaction mixture was stirred at ambient temperature for two hours. The precipitate formed is filtered off and washed with ether. CRL 8418 (0.93 g) was obtained as a black powder. (Yield 70%).

RMN ¹ H (DMSO d ₆ ): 2.67 (s, 6H), 3.09 (m, 2H), 4.01 (m, 2H), 7.67 (dm, 1H, J = 9.2) Hz), 7.80 (dd, 1H, J = 8.0 and 4.5 Hz), 7.94 (m, 1H), 8.26 (d, 1H, J = 9.2 Hz), 8, 64 (d, 1H, J = 5.7 Hz), 9.09 (m, 1H), 9.12 (dd, 1H, J = 4.5 and 1.8 Hz), 9.14 (d, 1H) , J = 5.7 Hz).

Example 24

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

To a solution of 5-amino-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9'one (1g, 3.95 mmol) and chloroacetaldehyde (50% aqueous solution, 2.6 mL) , 16.8 mmol) in acetic acid (30 mL) was added in small portions at 0 ° C 10 mmol of sodium cyanoborohydride (0.63 g). The reaction mixture is kept under stirring at 0 ° C for five minutes, then at ambient temperature for 30 minutes. The reaction mixture was basified with saturated sodium bicarbonate solution, extracted with chloroform / methanol 95: 5. The organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The obtained product was purified by filtration on silica (chloroform finally chloroform / methanol 99: 1) to give two compounds: CRL 8422 and CRL 8423 (description in Example 25).

5-Bis (chloroethyl) amino-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8422) was obtained as a red powder (0.14 g). (10% yield). Mp 220 ° C.

IR (KBr) 1666; 1650 cm ^-1 .

RMN ¹ H (CDCl ₃ ): 3.83 (t, 4H, J = 7.0 Hz); 4.04 (t, 4H, J = 7.0 Hz); 7.47 (dd, 1H, J = 9.5 and 2.9 Hz); 7.66 (dd, 1H, J = 8.0 and 4.4 Hz); 7.70 (d, 1H, J = 2.9Hz); 8.42 (d, 1H, J = 5.6Hz); 8.50 (d, 1H, J = 9.5Hz); 8.81 (dd, 1H, J = 8.0 and 1.8 Hz); 9.16 (dd, 1H, J = 4.4 and 1.8 Hz); 9.23 (d, 1H, J = 5.6Hz).

RMN ¹³ C (CDCl 3): 40.16; 53.60; 101.70; 116.60; 118.37; 118.68; 125.39; 125.91; 129.25; 135.13; 136.12; 136.38; 139.42; 141.93; 148.24; 148.73; 149.34; 152.22; 155.08: 181.43.

Example 25

5- (2-Chloroethyl) amino-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8423)

The procedure was analogous to Example 24 to obtain 0.22 g of compound CRL

8423 in the form of a purple powder.

(Yield 18%). Melting point 196 ° C.

IR (KBr) 3413; 3275; 1654; 1617 cm ^-1 .

-RMN ¹ H (CDCl 3): 3.81 (t, 2H, J = 5.5 Hz); 3.88 (t, 2H, J = 5.5Hz); 5.01 (broad s, 1H); 7.34 (dd, 1H, J = 8.8 and 2.5 Hz); 7.60 (d, 1H, J = 2.5Hz); 7.65 (dd, 1H, J = 7.5 and

4.4 Hz); 8.41 (d, 1H, J = 5.8Hz); 8.43 (d, 1H, J = 8.8Hz); 8.82 (dd, 1H, J = 7.5 and 1.5 Hz); 9.15 (dd, 1H, J = 4.4 and 1.5 Hz); 9.21 (dd, 1H, J = 5.8 Hz).

- ¹³ C NMR (CDCl): 42.83; 45.01; 100.76; 116.81; 118.78; 120.85; 125.38; 126.35; 129.35; 135.04; 136.04; 136.43; 140.22; 141.56; 148.49 (2C); 149.41; 152.30; 155.07; 181.57.

Example 26

12-Methoxy-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8472)

To a suspension of 2-methoxy-11-methyl-1,6-diazanaphthacene-5,12-dione (intermediate

Bg) (0.23 g, 0.75 mmol) in dimethylformamide (7 mL) was added 0.54 mL (3 mmol) of dimethylformamide diethyl acetal under nitrogen. The reaction mixture was maintained at 120 ° C for one hour. After concentration in vacuo, ethanol (4.5 mL) and ammonium chloride (0.46 g) were added and the mixture was refluxed for 30 minutes. After concentration on a rotary evaporator, 30 mL of water was added, and the reaction mixture was extracted with chloroform (2 x 30 mL). The organic phases are dried over magnesium sulphate and evaporated. The obtained product was purified by flash chromatography on silica (chloroform) to give compound CRL 8472 as a brown powder (50 mg).

(Yield 21%). Mp > 260 ° C.

¹ H RMN (CDCl 3): 4.31 (s, 3H); 7.04 (d, 1H, J = 8.5Hz); 7.92 (ddd, 1H, J = 8.1, 7.0 and

1.5 Hz); 8.00 (ddd, 1H, J = 8.4, 7.0 and 1.5 Hz); 8.52 (d, 1H, J = 5.5Hz); 8.63 (dd, 1H, J = 8.1 and 1.5 Hz); 8.66 (d, 1H, J = 8.5Hz); 8.67 (dd, 1H, J = 8.4 and 1.5 Hz); 9.27 (d, 1H, J = 5.5Hz).

¹³ C RMN (CDCl 3): 54.69; 114.43; 116.75; 118.15; 122.92; 123.41; 124.51; 130.62; 131.81; 133.15; 137.86; 139.17; 145.80; 146.28; 149.59; 149.99; 152.24; 167.75; 181,04.

IR (CHCl3): 1671; 1588 cm ^-1 .

MS: m / z 313 (50); 312 (91); 284 (17); 283 (100); 254 (23); 193, 51.

Example 27

4-Bromo-5-amino-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8478)

To a suspension of CRL 8347 (0.2 g, 0.67 mmol) in acetic acid (8 mL) was added bromine (35 μΙ, 0.67 mmol). The reaction mixture was maintained at 50 ° C for six hours. After concentration, the reaction mixture was basified with 5N sodium hydroxide solution (20 mL) and extracted with 5% methanol in chloroform (400 mL). After drying over magnesium sulfate and evaporation of the solvent, CRL 8478 is obtained as a violet powder which is recrystallized from chloroform / pentane 20 ml / 15 ml (152 mg). (Yield 61%). Mp > 260 ° C.

1 H RMN (DMSO-d ₆ ): 7.07 (s broad, 2H); 7.61 (d, 1H, J = 8.8Hz); 7.77 (dd, 1H, J = 7.7 and 4.0 Hz); 8.18 (d, 1H, J = 8.8Hz); 8.61 (d, 1H, J = 7.7Hz); 9.10 (d, 1H, J = 4.0Hz); 9.14 (d, 1H, J = 5.9Hz); 9.91 (d, 1H, J = 5.9Hz).

IR (CHCl3): 3501; 3400; 1673 cm ^-1 .

MS: m / z 378 (42); 377 (100); 376 (48); 375 (27).

Example 28

11-Acetoxymethyl-9-H-quino [4,3,2-de] [1,1Q] phenanthrolin-9-one (CRL 8528)

To a suspension of 3-acetoxymethyl-11-methyl-1,1,6-diazanaphthacene-5,12-dione (intermediate Bi ₀ ) (0.11 g, 0.31 mmol) in dimethylformamide (4 mL) was added 0.27 mL (1.5 mmol) of dimethylformamide diethyl acetal under nitrogen. The reaction mixture was maintained at 120 ° C for one hour. After concentration in vacuo, ethanol (25 mL) and ammonium chloride (0.23 g) were added and the mixture was refluxed for 30 minutes. After concentration on a rotary evaporator, 30 mL of water was added and the reaction mixture was extracted with chloroform (2 x 30 mL). The organic phases are dried with magnesium sulfate. After evaporation of the solvent on a rotary evaporator and purification by flash chromatography on silica (chloroform), 65 mg of compound CRL 8528 is obtained.

(Yield 60%). Mp 206-210 ° C.

^{@ 1} H NMR (CDCl3): 2.19 (s, 3H); 5.32 (s, 2 H); 7.96 (ddd, 1H, J = 1, 1.8 and 8 Hz); 8.03 (ddd, 1H, J = 1, 1.8 and 8.4 Hz); 8.56 (d, 1H, J = 5.5Hz); 8.64 (dd, 1H, J = 1.1 and 8.4 Hz); 8.71 (dd, 1H, J = 1.1 and 8.0 Hz); 8.77 (d, 1H, J = 2.4Hz); 9.14 (d, 1H, J = 2.4Hz); 9.28 (d, 1H, J = 5.6Hz).

MS: m / z 355 (88); 313 (100); 296 (25); 267 (6).

Example 29

9-H-Chino [4,3,2-de] [1,10] phenanthrolin-9-one (CRL 8529)

To a suspension of 6-methyl-1,11-diazanaphthacene-5,12-dione (intermediate Di) (52 g, 0.875 mmol) was added dimethylformamide diethyl acetal (0.15 mL, 0.875 mmol) under nitrogen. The reaction mixture is kept at 120 ° C for 30 minutes. After concentration in vacuo, ethanol (60 mL) and ammonium chloride (0.34 g) were added and the mixture was refluxed for 30 minutes. After concentration on a rotary evaporator, 10 mL of water was added and the reaction mixture was extracted with dichloromethane (2 x 10 mL). The organic phases are dried over magnesium sulphate and concentrated. The crude product was purified by flash chromatography on silica (dichloromethane / methanol 99: 1) to give compound CRL 8529 as a yellow solid (6 mg). (Yield 11%).

¹ H RMN (CDCl 3): 7.78 (dd, 1H, J = 8.1 and 4.8 Hz); 7.97 (ddd, 1H, J = 8.0, 7.4 and 1.2 Hz); 8.04 (ddd, 1H, J = 8.0, 7.4 and 1.2 Hz); 8.51 (d, 1H, J = 5.9Hz); 8.69 (dd, 2H, J = 8.0 and 1.5 Hz); 9.08 (dd, 1H, J = 4.8 and 1.9 Hz); 9.13 (d, 1H, J = 5.9Hz); 9.27 (d, 1H, J = 1.9 and 8.1 Hz).

¹³ C RMN (CDCl 3): 115.15; 121.76; 122.28; 127.13; 127.16; 129.65; 130.82; 132.21; 132.60; 132.99; 136.88; 139,91; 144.85; 148.00; 148.03; 151.75; 151.84; 179.94.

MS: m / z 283 (54); 255 (100); 228 (10).

Example 30

5-Bromo-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8839)

Compound CRL 8839 was prepared as described in Example 8 using 9H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8529) (0.5 g, 1.77 mmol), 20 ml of acetic acid and bromine solution (0.2 ml, 3.88 mmol / 5 ml of acetic acid): the reaction mixture is refluxed for 24 hours.

Example 31

5-Amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8836)

Compound CRL 8836 was prepared as described in Example 9 using 5-bromo-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8839) (1.15 g, 18 mmol) 250 ml of dimethylformamide and sodium azide (1.2 g, 1.85 mmol): the reaction mixture was refluxed for four hours.

Example 32

5- (Dimethylamino-2-ethyl-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8840)

Compound CRL 8840 was prepared as described in Example 22 using 5-amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8836) (1.28 g, 4.3 mmol), dimethylformamide diacetal (4 mL, 21.9 mmol), trifluoroacetic acid (12.5 mL, 83 mmol) and sodium cyanoborohydride (4.1 g, 65 mmol): The reaction mixture was maintained at 90 ° C for 8 h C.

Example 33

5-Bis (chloroethylamino-2-ethyl) amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8841)

Compound CRL 8841 was prepared as described in Example 24 using 5-amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8836) (1g, 3.95) mmol), chloroacetaldehyde (2.6 mL, 16.8 mmol), acetic acid (30 mL) and sodium cyanoborohydride (0.63 g, 10 mmol); the reaction mixture is kept at ambient temperature for 30 minutes.

Example 34

5- (Chloroethylamino-2-ethyl) amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8842)

Compound CRL 8842 was prepared according to the procedure in the previous example, from 5-amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8836).

Example 35

4-Bromo-5-amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8843)

Compound CRL 8843 was prepared as described in Example 27 using

5-amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8836) (0.6 g, 2.01 mmol), 24 mL of acetic acid and bromine (35 μΙ, 0.67 mmol); the reaction mixture is kept at 50 ° C for six hours.

Example 36

7-Nitro-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8838)

Compound CRL 8838 was prepared as described in Example 6 using 9H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8529) (1 g, 3.53 mmol), 23 mL sulfuric acid and 23 ml of nitric acid; the reaction mixture was kept at 130 ° C for two hours.

Example 37

7-Amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8837)

Compound CRL 8837 was prepared as described in Example 7 using 7-nitro-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8838) (0.2 g, 0, 61 mmol), iron (0.19 g, 3.38 mmol) and a mixture of 10 mL acetic acid and water (50/50).

Example 38

12-Methoxy-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one (CRL 8844)

Compound CRL 8844 was prepared as described in Example 29 using 3-methoxy-6-methyl-1,11-diazanaphthacene-5,12-dione (intermediate D2) (0.76 g, 25 mmol) and diacetaldimethylformamide (2 mL, 11.67 mmol); the reaction mixture is kept at 120 ° C for 30 minutes; ammonium chloride (4.5 g) and 500 ml of ethanol are added; the reaction mixture is maintained at reflux for 30 minutes.

The results of the pharmacological studies show the cytotoxic properties of the compounds of formula I and Ia as well as the maximum tolerated dose. These data make it possible to appreciate the therapeutic interest in the claimed compounds.

1-Determination of the maximum tolerated dose (DMT)

The maximum tolerated dose is evaluated in 4-6 week old B6D2F1 / Jico mice. The compounds are administered intraperitoneally at increasing doses from 2.5 to 160 mg / kg. The DMT (expressed in mg / kg) is determined by monitoring the survival of the animals 14 days after the administration of a single dose of the test product. Weight gains of the animals over the test period are also monitored. If the dose of DMT is greater than 160 mg / kg, a 160 mg / kg dose is considered acceptable. The results of the maximum tolerated dose (DMT) determination are given in Table I.

Table I

Compound CRL DMT mg / kg

CRL 8274 (ascididemin)

CRL 8269 (2-bromleeeptoclinidone) 40 CRL8323 (Example 1) 20 CRL 8301 (Example 2) > 160 CRL 8241 (Example 3) > 160 CRL 8325 (Example 4) > 160 CRL 8297 (Example 5) > 160 CRL 8289 (Example 6) 20 CRL 8344 (Example 7) > 160 CRL 8248 (Example 8) > 160 CRL 8347 (Example 9) > 160 CRL 8292 (Example 13) > 160 CRL 8290 (Example 12) 80 CRL 8333 (Example 14) > 160 CRL 8368 (Example 10) > 160 CRL 8369 (Example 15) > 160 CRL 8373 (Example 16) > 160 CRL 8387 (Example 11) > 160 CRL 8389 (Example 17) > 160 CRL 8406 (Example 19) > 160 CRL 8407 (Example 20) > 160 CRL 8416 (Example 21) > 160 CRL 8419 (Example 22) 40 CRL 8418 (Example 23) 40 CRL 8422 (Example 24) > 160

CRL 8423 (Example 25)> 160

Most of the tested compounds of the ascididemin family or its isomers do not show direct toxicity (DMT> 160 mg / kg) and can be used in vivo at elevated tissue concentrations, i.e. at a higher dose.

2-Cytotoxic activity on tumor cell line in culture

The effect of compounds of formula I and Ia on cancer cells is evaluated by the MTT colorimetric assay. The principle of the MTT assay lies in the mitochondrial reduction by living cells of the metabolically active products of MTT [3 (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] yellow to the blue color product, formazan. The amount of formazan thus obtained is directly proportional to the number of viable cells present in the culture dishes. This amount of formazan is measured with a spectrophotometer.

Cell lines are maintained in a single-layer culture at 37 ° C in culture, stoppered vials containing MEM25MM HEPES (Minimum Essential Medium) medium. In this environment, adapted to grow the band of various mammalian cells diploid or primary, add:

- 5% of SVF (calf embryonic serum) purified at 56 ° C for one hour,

- 0,6 mg / ml L-glutamine,

- 200 IU ml / penicillin,

- 200 mg / ml streptomycin,

-0.1 mg / ml gentamicin.

12 human cancer cell lines were obtained from the American Type Culture Collection (ATCC, Rockville, MD USA). These are

- U-373MG (ATCC code: HTB-17) and U-87MG (ATCC code: HTB-14), which are 2 glioblastomas,

- SW1088 (ATCC code: HTB-12) which is an astrocytoma

- A549 (ATCC code: CCL-185) and A-427 (ATCC code: HTB-53, which are two small lung cancer cells,

- HCT-15 (ATCC code: CCL-225) and LoVo (ATCC code: CCL-229), which are 2 colorectal cancer cells,

- T-47D (ATCC code: HTB-133) and MCF7 (ATCC code: HTB-22), which are two breast cancer cells,

- J82 (ATCC code: HTB-1) and .T24 (ATCC code: HTB-4), which are 2 bladder cancer cells,

PC-3 (ATCC code: CRL-1435), which is a prostate cancer cell.

Test schedule: 100 μΙ of cell suspension containing 20000 to 50,000 (depending on the cell type used) cells / ml are inoculated in a 96-well flat-well titration plate for incubation at 37 ° C in a 5% carbon dioxide and 70% humidity environment. . After incubation for 24 hours, the culture medium is replaced with 100 μΙ of fresh medium containing either various test compounds at a concentration of 10 ^-5 to 10 ^-1 M or a solvent used to dissolve the test products (control). After 72 hours of incubation under the above conditions, the culture medium is replaced with 100 μΙ of a yellowish MTT solution dissolved to 1 mg / ml in RPMI 1640. The microplates are again incubated at 37 ° C for three hours, then centrifuged at 400 g for 10 minutes. The yellowish MTT solution is eliminated and the blue formazan crystals formed at the cell level are dissolved in 100 μΙ DMSO. The microplates are agitated for 5 minutes. The intensity of the blue color, resulting from the transformation of the NTT yellow product to blue formazan by still living cells, has been reported to be quantified spectrometrically by the DYNATECH IMMUNOASSAY SYSTEM at 570 nm and 630 nm long wavelengths corresponding to the wavelengths of maximum formazan absorbance and background noise. The integrated spectrometer logic calculates mean optical density values based on deviations from the standard (Dev. Std.) And mean error versus mean (ESM).

The cell growth inhibitory activity of the compounds of formulas I and Ia on various cell tumor lines is compared to the activity of the natural product ascididemin (CRL 8274). The set of compounds exhibited significant cell proliferation inhibitory activity of 12 human tumor lines: U-87MG, U-373MG, SW 1088, T24, J82, HCT-15, LoVo, MCF 7, T-47D, A549, A-427, and PC-3. with a 50% inhibitory concentration (IC ₅₀ ) of 10 ^-6 M to 10 ^-1 M, depending on the composition and tumor lines tested. By way of example, the following Table II shows the concentration values containing the obtained IC 50 on different cell lines.

Table II

Inhibitory concentrations give a concentration of 50% inhibition for compounds of formula I, II (x) or III (xx) for cell lines

Table II

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Lung I Cell Lines

In Table III, the results of the mean IC50 (in nM) (calculated from cytotoxic activity in the 12 tumor lines studied) and DMT / CI50 ratios (ratios are calculated with DMT and IC50 ratios expressed as dimensionless numbers).

Table III

Compound CRL IC ₅₀ (nM) MTD / IC50 DMT / ICsox CRL 8274 (ascididemin) 100 0,20 ' 1 CRL 8269 (2-bromleeeptoclinidone) 120 0.33 2 CRL 8323 (Example 1) 60 0.33 2 CRL 8301 (Example 2) 270 0.59 3 CRL 8241 (Example 3) 140 1.14 6 CRL 8325 (Example 4) 37 4.32 22 CRL 8297 (Example 5) 90 1.78 9 CRL 8289 (Example 6) 10 2.00 10 CRL 8344 (Example 7) 53 3.02 15 CRL 8248 (Example 8) 80 2.00 10 CRL 8347 (Example 9) 21 7.62 38 CRL 8368 (Example 10) 480 0.33 2 CRL 8389 (Example 17) 420 0.38 2 CRL 8406 (Example 19) 60 2.67 13 CRL 8407 (Example 20) 22 7.27 36 CRL 8416 (Example 21) 80 2.00 10 CRL 8419 (Example 22) 110 0.37 2 CRL 8418 (Example 23) 60 0.67 3.3

CRL 8422 (Example 24)

100 1.60 8.3

CRL 8423 (Example 25)

22.86 114 times the DMT / Cl50 ratio of the various compounds is determined against a reference ratio of 1 for ascididemin.

Test compounds show ICI ₅₀ (nM) values greater than or equal to ascididemin in cell tumor cell models. The exception is CRL 8289 (whose maximum tolerated dose is the same as ascididemin but its CI50 is ten times lower than that of ascididemin), the maximum tolerated doses of the compounds described, considered equivalent to 160 mg / kg, are slightly higher than ascididemin (20 mg / kg). kg). These results show that this new family of compounds does not present direct toxicity. As a result, the ratios of tolerance to the cytotoxic activity of the compounds in the examples according to the invention are slightly higher than with natural ascididemin. Thus, the compounds can be used as antitumor drugs for their cytotoxic properties at tissue concentrations higher than that of natural ascididemin. They are also characterized by improved therapeutic utility. CRL 8289, whose CI50 is 10 nM, also provides better therapeutic utility than ascididemin.

Due to their cytotoxic properties, the compounds of the formulas I and Ia described, optionally in the form of their salts or solvates, are pharmaceutically tolerable and can serve as active substances of medicaments.

The compounds of formula I and Ia are usually administered in dosage units determined by m ² of body surface area or by body weight in kg. Preferably, the dosage units are administered in the form of pharmaceutical compositions in which the active ingredient is mixed with several pharmaceutical excipients.

The compounds of formula I and Ia may be used according to the cancer pathology of the patient to be treated at doses of 0.05 to 350 mg / m ² body surface area, preferably at doses of 0.5 to 50 mg / m ² per day for treatment in its sharp phase depending from the cycles of each treatment. The compounds of formula I and Ia are preferably used in the treatment at doses of 0.05 to 25 mg / m ² / day, preferably 0.1 to 1.5 mg / m ² / day, depending on the number of courses of treatment. Doses may be associated with anticancer drugs used according to established intensive polychemical therapy protocols.

In the pharmacological compositions of the invention for oral or intravenous administration, the active compounds may be administered in a unitary dosage form, in admixture with conventional pharmaceutical carriers acceptable in the treatment of humans. The unit dosage form comprises oral forms such as tablets or gelatin capsules, implants and intravenous forms.

For parenteral administration (constant dose intravenous perfusion), a sterile aqueous suspension, saline isotonic sterile solutions or sterile and injectable solutions containing dispersing and / or solubilizing pharmaceutical compatible agents such as propylene glycol, polyethylene glycol, and β-cyclodextrin are used. Co-solvents such as alcohol such as ethanol, glycol such as polyethylene glycol or propylene glycol and surfactant hydrophilic agents such as Tween 80 may be used to prepare an injectable aqueous solution for intravenous administration over a period of 1 to 24 hours.

When preparing the composition in solid form, such as tablets, the active ingredient may optionally be comminuted, a plasticizer such as sodium laurysulfate and mixed with a pharmaceutical carrier such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or their analogs. The tablets may be supplemented with sucrose, various polymers, or other suitable agents, for example, to impart prolongation or delayed action, or to release a continuously determined amount of the active ingredient.

In the case of gelatin capsules, the active ingredient is mixed with a diluent, such as glycol or glycerol ester, to introduce the obtained mixture into soft or hard capsules.

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

The active ingredient may also be present in the form of a complex with a cyclodextrin, such as α-, β- or gamma-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.

Because of their cytotoxic activity, the compounds of formula I are used for the treatment of most solid tumors, in particular for the treatment of brain tumors, lung cancer, ovarian and bladder cancer, uterine cancer, colorectal cancer, prostate cancer and testicular cancer.

Industrial usability

The ascididemin derivative, its salts and solvates for the manufacture of pharmaceutical compositions for the treatment of most solid tumors, in particular brain, lung, ovarian, bladder, uterine, colorectal, prostate and testicular cancers.

T?

Claims (14)

CLAIMS 1. A pharmaceutical composition having cytotoxic properties for the treatment of cancer tumors and metastases thereof, comprising effective amounts of a compound of formula I or Ia, wherein: X is hydrogen, = NH or = N-OH, R ¹ is hydrogen, halogen, nitro, and -NR ⁸ R ⁹ wherein R ⁸ and R ⁹ is independently H or alkyl of 1 to 4 carbon atoms, R ² is H or halogen, R ³ is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, guanidino, -NR ¹⁰ R ¹¹ where R ¹⁰ and R ¹¹ are independently hydrogen, C 1 -C 3 alkyl to 4 carbon atoms, phenylalkyl having 1 to 4 carbon atoms in the alkyl group and _{(CH2) n-Y,} where Y is halogen, CN, -CH (O-Et) 2, C 1 -C 6 alkyl , -O- (CH ₂ ) 2 N (CH ₃ ) ₂ , -N (CH ₃ ) ₂ and n = 1 to 3 R ( ⁴⁾ is hydrogen, halogen, nitro or -NR ¹² R ¹³ , where R ¹² and R ^{13 are} each independently hydrogen or C 1 -C 4 alkyl; R ( ⁵⁾ , R ( ⁶⁾ and R ( ⁷⁾ independently of one another are hydrogen, halogen, C1-C6alkyl, hydroxyl, C1-C6alkoxy, C1-C6alkoxyalkyl and alkoxyalkyl an alkyl moiety, an alkylcarbonyloxyalkyl group having 1 to 4 carbon atoms in each alkyl moiety, a -CHO group, COOH, -CN, -CO ₂ R ¹⁴ , -CONHR ¹⁴ , -CONR ¹⁴ R ¹⁵ , -NHCOR ^14, and -NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ^{15 are} each independently hydrogen, C 1 -C 6 alkyl carbon atoms, phenyl-CO-CH 3, -CH ₂ -CH 2 -N (CH ₃ ) 2, phenylCO-CH = CH-N (CH ₃ ) 2, morpholino, nitro, SO ₃ H, -CH ₂ -N-COOR ¹⁶ -CH ₂ -N-COOR ¹⁶ CH 2 -COOR ¹⁷ CH ₂ -Ar, where R ¹⁶ and R ^{17 are} C 1 -C 6 alkyl and Ar is C 6 -C 14 aryl, except for compounds of formula I wherein X is O and R is both ^1, R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ is H, or R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen and R ² is bromine, or R ^{@ 1} , R ^{@ 2} , R ^{@ 3} , R ^{@ 4} , R @ ⁶ , R @ ^{7 are} hydrogen and R @ ^{5 is} OH, and with the exception of the compounds of formula I where X is O and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen, or a pharmaceutically acceptable acid addition salt thereof. Pharmaceutical composition according to claim 1, characterized in that it contains an effective amount of a compound of the formula I, wherein it is X is hydrogen, = NH or = N-OH, R ¹ is hydrogen, halogen, nitro, and -NR ⁸ R ⁹ wherein R ⁸ and R ^9, independently of one another are hydrogen or alkyl having 1 to 4 carbon atoms, R ² is H or halogen, R ³ is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, guanidino, -NR ¹⁰ R ¹¹ , where R ¹⁰ and R ¹¹ are independently hydrogen, alkyl; C 1 -C 4 -alkyl, C 1 -C 4 -phenylalkyl, (CH ₂ ) ₂ -N (CH ₃ ) ₂ and (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -N (CH 3) ₂ , R ( ⁴⁾ is hydrogen, halogen, nitro or -NR ¹² R ¹³ , where R ¹² and R ^{13 are} each independently hydrogen or C 1 -C 4 alkyl; R ^5, R ⁶ and R ⁷ each independently hydrogen, halogen, alkyl having 1 to 6 carbon atoms, hydroxyl, C 1 -C 6 alkyl, -CHO, -COOH, -CN, -CO 2 R ¹⁴ , -CONHR ¹⁴ , -CONR ¹⁴ R ¹⁵ , -NHCOR ^14, and -NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ^{15 are} each independently hydrogen, C 1 -C 6 alkyl, -CH 2 -CH ₂ N (CH ₃ ) ₂ , -phenyl-CO-CH ₃ , -phenyl-CO-CH = CH-N (CH ₃ ) ₂ , morpholino, nitro, SO ₃ H, -CH ₂ -N-COOR ¹⁶ -CH ₂ -N-COOR ¹⁶ I I CH ₂ -COOR ¹⁷ CH ₂ -Ar wherein R ¹⁶ and R ^{17 are} C 1 -C 6 alkyl and Ar is C 6 -C 14 aryl, with the exception of the compounds of formula I where X is oxygen and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ®, R ^{7 are} hydrogen, or R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen and R ² a bromine atom, or a pharmaceutically acceptable acid addition salt thereof. Pharmaceutical composition according to claim 2, characterized in that it contains an effective amount of a compound of the formula I, wherein it is X an oxygen atom, R ^{@ 1} is hydrogen or amino, R ² is H or halogen, R ³ is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 6 alkoxy, guanidino, -NR ¹⁰ R ¹¹ where R ¹⁰ and R ¹¹ are independently hydrogen, methyl, phenylalkyl of 1 to 4 carbon atoms in the alkyl, (CH _{2) 2} N (CH _{3) 2,} (CH ₂₎ 2 -O- (CH ₂₎ 2 -N (CH 3) 2, R ⁴ is H, halogen, nitro or amino, R ⁵ , R ® and R ^{7 are} hydrogen, with the exception of the compounds where it is R ^{@ 1} , R ^{@ 2} , R @ ³ , R @ ⁴ , R @ ⁵ , R @ ⁷ and R @ ^{7 are} hydrogen or R ^{@ 1} , R ^{@ 3} , R @ ⁴ , R @ ⁵ , R @ ⁷ and R @ ^{7 are} hydrogen and R @ ² is bromine, or the addition salts thereof with pharmaceutically acceptable acids. Pharmaceutical composition according to claim 2, characterized in that it contains an effective amount of a compound of the formulas I and Ia, wherein it is X an oxygen atom, R ^{@ 1} is hydrogen or amino, R ² is H or halogen, R ³ is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, guanidino, -NR ¹⁰ R ¹¹ , where R ¹⁰ and R ^{11 are} each independently hydrogen, methyl, phenylalkyl having 1 to 4 carbon atoms in the alkyl group, _(CH2) n-Y, where Y is halogen, CN, -CH (O-Et) _2, C 1 -C 6 alkyl, -O- (CH _{2) 2} -N (CH 3) _2, -N (CH 3) ₂ and n = 1 to 3, R ( ⁴⁾ is hydrogen, halogen, nitro or amino, R @ ⁵ is hydrogen, halogen or methoxy; R ⁶ , R ^{7 are} hydrogen, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyalkyl, in both the alkoxy and alkyl moieties, and -CH ₂ OCOCH 3, with the exception of compounds wherein R ¹ , R 7 ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ is H, or R ^1, R ^3, R ^4, R ^5, R ^6, R ⁷ = H, R ² Br, and the compounds of formula Ia, wherein R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ is H or an addition salt thereof with pharmaceutically acceptable acids. Pharmaceutical composition according to claim 4, characterized in that it contains an effective amount of a compound of the formulas I and Ia from the group consisting of: 5- (dimethylamino-9H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5- (benzylamino) -9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5-bromo-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 7-amino-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5-amino-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5-methyl-9H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 10-methoxy-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 5-methoxy-9-H-quino [4,3,2-de] [1, 10] phenanthroline-9-one, 7-nitro-9-H-quinoline [4 _l 3,2-de] [1,10] phenanthroline-9-one, 5-chloro-9-H-quinoline [4,3 , 2-d] [1,10] phenanthroline-9-one, 5-bromo-10-methoxy-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 5- (dimethylamino-2-ethyl) amino-9H-quino [4, 3 _l 2-de] [1,10] phenanthrolin-9-one, 5-bis (2-chloroethyl) amino-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5- (2-chloroethyl) amino-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, L-methoxy-G-H-quinolin-^ .S.ľ deKIJOjfenantrolín-g-one, 4-bromo-5-amino-9-H-quinoline _[4> 3,2-de] [1,10] phenanthroline-9-one, 11-acetoxymethyl-9-H-quino [4,3,2-de] [1,10] phenantolin-9-one, 5-Bromo-9H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, 5-amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, 5- (dimethylamino-2-ethyl) amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, 5-bis (chloroethylamino-2- ethyl) amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, 5- (chloroethylamino-2-ethyl) amino-9-H-quino [4,3, 2-d] [1,7] phenanthroline-9-one, 4-Bromo-5-amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, 7-nitro-9-H-quino [4,3,2-de ] [1,7] phenanthrolin-9-one, 7-amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, 12-methoxy-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, and their addition salts with pharmaceutically acceptable acids. Use of the compounds according to claims 1 to 5 for the production of anticancer drugs. The use according to claim 6 of compounds selected from the group consisting of 5- (dimethylamino-9H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 5- (benzylamino) -9-H-quino [4,3,2-de] [1] , 10] phenanthroline-9-one, 5-bromo-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 7-amino-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5-amino-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, S-methyl-quinolin-gH ^ .S ^ -dejtl.lOjfenantrolín-g-one, 10-methoxy-9-H-quino [4,3,2-de] [1,10jfenantrolín-9-one, 5-methoxy-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 7-nitro-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5-chloro-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5-bromo-10-methoxy-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5- (2-dimethylamino-ethyl) amino-9H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5-bis (2-chloroethyl) amino-9-H-quino [4,3,2-de] [1 _l 10] phenanthroline-9-one, 5- (2-chloroethyl) amino-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 12-methoxy-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 4-Bromo-5-amino-9-H'Chino [4,3,2-de] [1,10] phenanthrolin-9-one 11-acetoxymethyl-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 5-bromo-9H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, 5-amino-9-H-quino [4,3,2-de] [1,7] phenanthroline-9-one, 5- (dimethylamino-2-ethyl) amino-9-H-quino [4,3,2-de] [1,7] phenanthroline-9-one, 5-bis (chloroethylamino-2-ethyl) amino-9-H-quino [4,3,2-de] [1,7] phenanthroline-9-one 5- (chloroethylamino-2-ethyl) amino-9-H-quino [4,3,2-de] [1,7] phenanthroline-9-one, 4-bromo-5-amino-9-H-quino [4,3,2-de] [1,7] phenanthroline-9-one, 7-nitro-9-H-quino [4,3,2-de] [1,7] phenanthroline-9-one, 7-amino-9-H-quino [4,3,2-de] [1,7] phenanthroline-9-one, 12-methoxy-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, and pharmaceutically acceptable acid addition salts thereof. A compound of formula I or Ia (I) (Ia), wherein is X is hydrogen, = NH or = N-OH, R ¹ is hydrogen, halogen, nitro, and -NR ⁸ R ⁹ wherein R ⁸ and R ⁹ is independently H or alkyl of 1 to 4 carbon atoms, R ² is H or halogen, R ³ is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, guanidino, -NR ¹⁰ R ¹¹ where R ¹⁰ and R ¹¹ are independently hydrogen, C 1 -C 3 alkyl C 1 -C 4 -alkyl, C 1 -C 4 -phenylalkyl and (CH ₂ ) _n -Y. wherein Y is halogen, CN, -CH (O-Et) 2, (C 1 -C 6) alkoxy, -O- (CH ₂ ) 2 N (CH ₃ ) ₂ , -N (CH ₃ ) ₂ and n = 1 to 3 R ( ⁴⁾ is hydrogen, halogen, nitro or -NR ¹² R ¹³ , where R ¹² and R ^{13 are} each independently hydrogen or C 1 -C 4 alkyl; R ( ⁵⁾ , R ( ⁶⁾ and R ( ⁷⁾ independently of one another are hydrogen, halogen, C1-C6alkyl, hydroxyl, C1-C6alkoxy, C1-C6alkoxyalkyl and alkoxyalkyl an alkyl moiety, an alkylcarbonyloxyalkyl group having 1 to 4 carbon atoms in each alkyl moiety, a -CHO group, COOH, -CN, -CO ₂ R ¹⁴ , -CONHR ¹⁴ , -CONR ¹⁴ R ¹⁵ , -NHCOR ^14, and -NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ^{15 are} each independently hydrogen, C 1 -C 6 alkyl carbon atoms, phenylC _CH3, -ΟΗ ₂ -ΟΗ ₂ -Ν (ΟΗ _{3) 2,} phenyl-CH = CH-N (CH _{3) 2,} morpholino, nitro, SO ₃ H, I _CH2-N-CH2 COOR ¹⁶ n -COOR ¹⁶ CH ₂ -COOR ¹⁷ CH 2 -Ar, where R ¹⁶ and R ^{17 are} C 1 -C 6 alkyl and Ar is C 6 -C 14 aryl, except for compounds of formula I where X is oxygen and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen, or R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen and R ² is bromine, or R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen and R ^{3 is} OCH ₃ , or R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^{7 are} hydrogen and R ^{5 is} OH or OCH ₃ , or R ¹ NO ₂ group and R ^3, R ^4, R ^5, R ^6, R ⁷ is H, with the exception of the compounds of formula I in which simultaneously X is O and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen, and their addition salts with pharmaceutically acceptable acids. A compound according to claim 8 of the general formula I, wherein is X is hydrogen, = NH or = N-OH, R ¹ is hydrogen, halogen, nitro, and -NR ⁸ R ⁹ wherein R ⁸ and R ⁹ is independently H or alkyl of 1 to 4 carbon atoms, R ² is H or halogen, R ³ is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, guanidino, -NR ¹⁰ R ¹¹ where R ¹⁰ and R ¹¹ are independently hydrogen, C 1 -C 3 alkyl (C 4 -C 4) -phenyl-C 1 -C 4 -alkyl, (CH 2) 2 -N (CH ₃ ) 2 and (CH 2) 2 -O- (CH ₂ ) 2 -N (CH ₃ ) 2; F R ( ⁴⁾ is hydrogen, halogen, nitro or -NR ¹² R ¹³ , where R ¹² and R ^{13 are} each independently hydrogen or C 1 -C 4 alkyl; R ^5, R ⁶ and R ⁷ each independently hydrogen, halogen, alkyl having 1 to 6 carbon atoms, hydroxyl, C 1 -C 6 alkyl, -CHO, -COOH, -CN, -CO 2 R ¹⁴ . -CONHR ¹⁴ , -CONR ¹⁴ R ¹⁵ , -NHCOR ^14, and -NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ^{15 are} each independently hydrogen, C 1 -C 6 alkyl, -CH 2 -CH 2 -N ( CH ₃ ) 2, -phenyl-CO-CH 3, -phenyl-CO-CH = CH-N- (CH ₃ ) 2, morpholino, nitro, SO ₃ H, -CH ₂ -N-COOR ¹⁶ -CH 2 -N-COOR ¹⁶ I I CH 2 -COOR ¹⁷ CH ₂ -Ar, where R ¹⁶ and R ^{17 are} C 1 -C 6 alkyl and Ar is C 6 -C 14 aryl, with the exception of the compounds of formula I where X is oxygen and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen, or R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen and R ² is bromine, or R ^1, R ^3, R ^4, R ^5, R ^6, R ⁷ = H, R ³ methoxy, or R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen and R ^{5 is} OH or OCH ₃ , or R ¹ NO ₂ group and R ^3, R ^4, R ^5, R ^6, R ⁷ is H, or its addition salts with pharmaceutically acceptable acids. A compound according to claim 8 from the group consisting of 5- (dimethylamino) -9H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5- (benzylamino) -9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5-bromo-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 7-amino-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5-amino-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5-methyl-9H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5-chloro-9-H-quino [4,3,2-de] [1,10] phenanthroline-9-one, 5-Bromo-10-methoxy-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 5- (dimethylamino-2-ethyl) amino-9H-quino [4, 3,2-de] [1,10] phenanthrolin-9-one, 5-bis (2-chloroethyl) amino-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9- O, 5- (2-chloroethyl) amino-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 12-methoxy-9-H-quino [4,3, 2-de] [1,10] phenanthroline-9-one, 4-Bromo-5-amino-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 11-acetoxymethyl-9-H-quino [4,3,2-de] [1,10] phenanthrolin-9-one, 5-Bromo-9H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, 5-amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, 5- (dimethylamino-2-ethyl) amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, 5-bis (chloroethylamino-2- ethyl) amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, 5- (chloroethylamino-2-ethyl) amino-9-H-quino [4,3, 2-de] [1,7] phenanthrolin-9-one, 4-bromo-5-amino-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, 7- nitro-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, 7-amino-9-H-quino [4,3,2-de] [1,7] phenanthroline-9-one, 12-methoxy-9-H-quino [4,3,2-de] [1,7] phenanthrolin-9-one, and their addition salts with pharmaceutically acceptable acids. A process for the preparation of compounds of formula Ia, wherein is X is hydrogen, = NH or = N-OH, R ¹ is hydrogen, halogen, nitro, and -NR ⁸ R ⁹ wherein R ⁸ and R ⁹ is independently H or alkyl of 1 to 4 carbon atoms, R ² is H or halogen, R ³ is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, guanidino, -NR ¹⁰ R ¹¹ where R ¹⁰ and R ¹¹ are independently hydrogen, C 1 -C 3 alkyl to 4 carbon atoms, phenylalkyl having 1 to 4 carbon atoms in the alkyl group and _{(CH2) n-Y,} where Y is halogen, CN, -CH (O-Et) _2, C 1 -C 6 alkyl , -O- (CH ₂ ) ₂ N (CH ₃ ) ₂ , -N (CH ₃ ) ₂ and n = 1 to 3 R ( ⁴⁾ is hydrogen, halogen, nitro or -NR ¹² R ¹³ , where R ¹² and R ^{13 are} each independently hydrogen or C 1 -C 4 alkyl; R ( ⁵⁾ , R ( ⁶⁾ and R ( ⁷⁾ independently of one another are hydrogen, halogen, C1-C6alkyl, hydroxyl, C1-C6alkoxy, C1-C6alkoxyalkyl and alkoxyalkyl an alkyl moiety, an alkylcarbonyloxyalkyl group having 1 to 4 carbon atoms in each alkyl moiety, a -CHO group, COOH, -CN, -CO ₂ R ¹⁴ , -CONHR ¹⁴ , -CONR ¹⁴ R ¹⁵ , -NHCOR ^14, and -NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ^{15 are} each independently hydrogen, C 1 -C 6 alkyl carbon atoms, phenyl-CO-CH ₃ , -CH ₂ -CH ₂ -N (CH ₃ ) ₂ , phenylCO-CH = CH-N (CH ₃ ) ₂ , morpholino, nitro, SO ₃ H, _CH2-N-CH2 COOR ¹⁶ n -COOR ¹⁶ I ι CH ₂ -COOR ¹⁷ CH ₂ -Ar, wherein R ¹⁶ and R ^{17 are} C 1 -C 6 alkyl and Ar is C 6 -C 14 aryl, characterized in that: a) condenses the chlorobenzoic acid of the general formula R ¹ Cl , ^R2 ho ₂ c ^zX> Y iyi where each symbol has higher as defined above, with dimethoxyaniline of the general formula OMe ^ nh ₂ OMs wherein Me is methyl, to give a compound of formula (IIa) OMe wherein each symbol has the meaning given above b) cyclizing a compound of formula IIIa to give a compound of formula wherein each symbol is as defined above, c) the compound is converted to a quinone of the formula IIIa, wherein the symbols are as defined above, d) reacting the quinone of formula IIIa with an azadiene of formula R ⁶ R ⁵ , wherein each symbol is as defined above to give a compound of formula IVa (IVa), wherein each symbol is as defined above, e) reacting a compound of formula IVa with dimethylformamide diethyl acetal to give a compound of formula Ia, wherein the symbols are as defined above, f) optionally converting the compound of formula Ia to another compound of formula Ia. 12. A method of treating cancer cancer patients, comprising administering to said patient an effective amount of a compound of claim 1. 13. A process for the preparation of compounds of formula Ia, wherein is R ¹ is hydrogen, halogen, nitro, and -NR ⁸ R ⁹ wherein R ⁸ and R ⁹ is independently H or alkyl of 1 to 4 carbon atoms, R ² is H or halogen, R ³ is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, guanidino, -NR ¹⁰ R ¹¹ , where R ¹⁰ and R ¹¹ are independently hydrogen, alkyl; (C 1 -C 4) -phenylalkyl and (CH 2) n Y, where Y is halogen, CN, -CH (O-Et) 2, (C 1 -C 6) alkoxy, -O- (CH ₂ ) ₂ N (CH ₃ ) ₂ , -N (CH ₃ ) ₂ and n = 1 to 3 R ⁴ is hydrogen, halogen, nitro or -NR ¹² R ¹³ , where R ¹² and R ^{13 are} each independently hydrogen or C 1 -C 4 alkyl; R @ ⁵ , R @ ⁶ and R @ ⁷ independently of one another are hydrogen, halogen, C1 -C6 -alkyl, hydroxy, C1 -C6 -alkoxy, C1 -C6 -alkoxyalkyl and alkoxyalkyl; an alkyl moiety, an alkylcarbonyloxyalkyl group having 1 to 4 carbon atoms in each alkyl moiety, a -CHO group, COOH, -CN, -CO ₂ R ¹⁴ , -CONHR ¹⁴ , -CONR ¹⁴ R ¹⁵ , -NHCOR ^14, and -NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ^{15 are} each independently hydrogen, C 1 -C 6 alkyl carbon atoms, phenyl-CO-CH ₃ , -CH ₂ -CH ₂ -N (CH ₃ ) ₂ , phenylCO-CH = CH-N (CH ₃ ) ₂ , morpholino, nitro, SO ₃ H, -CH ₂ -N-COOR ¹⁶ -CH ₂ -N-COOR ¹⁶ I I CH ₂ -COOR ¹⁷ CH ₂ -Ar, where R ¹⁶ and R ^{17 are} C 1 -C 6 alkyl and Ar is C 6 -C 14 aryl, except for compounds of formula I where R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ is H, or R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen and R ² is bromine, or R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen and R ^{3 is} OCH ₃ , or R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^{7 are} hydrogen and R ^{5 is} OH or OCH ₃ , or R ¹ NO ₂ group and R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ is H, characterized in that the (a) reacting a hydroxyquinone of formula (I) as defined above with a compound of formula (I) as hereinbefore defined in the presence of cerium chloride heptahydrate and ethanol to obtain a compound of formula (II) wherein each symbol is as defined above . (b) converting a compound of formula (II) to a compound of formula (III) (H1) wherein each symbol is as defined above; c) reacting a compound of formula III with a compound of formula HC (OC ₂ H ₅ ) 2N (CH ₃ ) 2 in dimethylformamide at 120 ° C to give a compound of formula IV, wherein each symbol is as defined above, d) cyclizing the compound of formula IV in the presence of ammonium chloride and acetic acid to give a compound of formula I, (e) optionally converting the compound of formula I thus obtained into another compound of formula I. 14. A compound of the formula EMI3.0 wherein is R ¹ is hydrogen, halogen, nitro, and -NR ⁸ R ⁹ wherein R ⁸ and R ⁹ is independently H or alkyl of 1 to 4 carbon atoms, R @ ² is hydrogen or halogen; R ³ is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy, guanidino, -NR ¹⁰ R ¹¹ , where R ¹⁰ and R ¹¹ are independently hydrogen, alkyl; (C 1 -C 4) -phenylalkyl and (CH 2) n Y, where Y is halogen, CN, -CH (O-Et) 2, (C 1 -C 6) alkoxy, -O (CH 2) 2 N (CH ₃ ) ₂ , -N (CH ₃ ) ₂ and n = 1 to 3 R ( ⁴⁾ is hydrogen, halogen, nitro or -NR ¹² R ¹³ , where R ¹² and R ^{13 are} each independently hydrogen or C 1 -C 4 alkyl; R @ ⁵ , R @ ⁶ and R @ ⁷ independently of one another are hydrogen, halogen, C1 -C6 -alkyl, hydroxyl, C1 -C6 -alkoxy, C1 -C6 -alkoxyalkyl, such as also in the alkyl moiety, a (C 1 -C 4) alkylcarbonyloxyalkyl group in each alkyl moiety, -CHO, -COOH, -CN, -CO ² R ¹⁴ , -CONHR ¹⁴ , -CONR ¹⁴ R ¹⁵ , -NHCOR ^14, and -NR ¹⁴ R ^15, where R ¹⁴ and R ¹⁵ independently of one another, H, alkyl having 1 to 6 carbon atoms, phenyl-CO-CH 3, -CH 2 -CH 2 -N (CH ₃₎ 2, phenyl-COCH = CH-N (CH ₃ ) 2, morpholino, nitro, SO ₃ H, -CH ₂ -N-COOR ¹⁶ -CH 2 -N-COOR ¹⁶ I I CH 2 -COOR ¹⁷ CH ₂ -Ar, where R ¹⁶ and R ^{17 are} C 1 -C 6 alkyl and Ar is C 6 -C 14 aryl, except for compounds of formula I where R ^1, R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ is H, or R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen and R ² is bromine, or R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 are} hydrogen and R ^{3 is} OCH ₃ , or R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ^{7 are} hydrogen and R ^{5 is} OH or OCH ₃ , or R ¹ NO ₂ group and R ^2, R ^3, R ^4, R ^5, R ^6, R ⁷ are hydrogen.