Phenanthroline-7-one derivatives and their therapeutic uses

Details Phenanthroline-7-one derivatives and their therapeutic uses Phenanthroline-7-one derivatives and their therapeutic uses

2002-02-13

2004-10-26

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S287000, C546S064000, C546S081000, C544S125000, C544S126000

Reexamination Certificate

active

06809096

ABSTRACT:

The present invention relates to pharmaceutical compositions based on polyaromatic compounds of use in particular as antitumour medicaments.
In 1999, cytotoxic treatments (chemotherapy) used to reduce the size of cancerous tumours, to suppress the development of the tumour process or indeed even, in still too few cases, to eliminate clumps of cancer cells and the risk of metastases, combine chemical substances which have been recently introduced with to others which have been used for several decades. For example, 5-fluorouracil (5-FU), recognized for nearly 40 years as one of the most active treatments for colorectal cancer, can be replaced by one or other of the specific inhibitors of topoisomerase I (irinotecan or topotecan) when the tumour is no longer sensitive to 5-FU. More generally, the therapeutic arsenal available for treating colorectal tumours will also be enriched with the availability of oxaliplatin, novel in situ “donors” of 5-FU or selective inhibitors of thymidylate synthetase. This coexistence is not limited to the treatment of colorectal cancers since, in addition, the chemotherapy of breast, ovarian and lung cancers now makes wide use of the family of taxane derivatives (paclitaxel, docetaxel). The need for more effective and better tolerated treatments, thus improving the survival and the quality of life of the patients, is imperative since, still taking the example of colorectal tumours, it has been estimated (S. L. Parker, T. Tong, S. Bolden et al., CA Cancer J. Clin., 1997) that, in the United States alone, over 131 000 new cases were diagnosed in 1997, 54 000 of which were responsible for the death of the patient. It is the awareness of this situation which has prompted the inventors to focus their attention on a family of polyaromatic compounds which have not yet been studied to any great extent, identified in the Ascidia of warm seas, in order to develop a novel medicinal chemistry intended to select synthetic compounds resulting from chemical design/modulation research which possess a significant cytotoxic activity at the therapeutic level.
The seas and oceans which cover more than 70% of the surface of the planet harbour marine plants and sponges, which living species, under gradual systematic pharmacognosic, have been shown to be able to contain complex alkaloids exhibiting advantageous pharmacological properties. For example, the sponges
Cryptotheca crypta
and
Halichondria okadai
have formed the subject of in-depth studies since the discovery of the presence, in their cells, of cytarabine or of halichondrin B. It is the same for the tunicates, since the isolation of aplidine from the tunicate
Aplidium albicans
, which lives in the Balearic Islands (Spain). Alkaloids with a tetrahydroisoquinolone structure have been isolated from the ascidian
Ecteinascidia turbinata
. Among these, ecteinascidin-743 has formed the subject of in-depth preclinical studies (E. Igbicka et al., NCI-EORTC symposium, 1998; Abst. 130, p. 34) and of clinical trials intended to define its therapeutic potential as anticancer medicament (A. Bowman et al., NCI-EORTC symposium, 1998; Abst. 452, p. 118; M. Villanova-Calero et al., NCI-EORTC symposium, 1998; Abst. 453, p. 118; M. J. X. Hillebrand et al., NCI-EORTC symposium; 1998; Abst. 455, p. 119; E. Citkovic et al., NCI-EORTC symposium, 1998; Abst. 456, p. 119). Novel pentacyclic acridine derivatives have also formed the subject of pharmacochemical studies (D. J. Hagan et al., J. Chem. Soc., Perkin Transf., 1997; 1: 2739-2746).
Other natural alkaloid of marine origin, ascididemin, has been extracted from the tunicate Didemnum sp. (J. Kobayashi et al., Tetrahedron Lett., 1988; 29: 1177-80) and from the ascidian
Cystodytes dellechiajei
(I. Bonnard et al., Anti-cancer Drug Design, 1995; 10: 333-46). Ascididemin has antiproliferative properties demonstrated on the model of murine leukaemia (P388 or L1210 lines) and described by F. J. Schmitz et al. (J. Org. Chem. 1991; 56: 804-8), B. Lindsay et al. (Bioorg. Med. Chem. Lett., 1995; 5: 739-42) and J. Kobayashi et al. (Tetrahedron Lett., 1988; 29: 1177-80), and on the model of human leukaemia as described by I. Bonnard et al. (Anti-cancer Drug Design, 1995; 10: 333-46). Mention may also be made of 2-bromoleptoclinidone, isolated from the ascidian Leptoclinides sp. by S. J. Bloor et al. (J. Am. Chem. Soc., 1987; 109: 6134-6) and synthesized by F. Bracher et al. (Heterocycles, 1989; 29: 2093-95) and then by M. E. Jung et al. (Heterocycles, 1994; 39; 2: 767-778). 2-Bromoleptoclinidone exhibits cytotoxicity with respect to the leukaemia cell model with an ED
50
of 0.4 &mgr;g/ml. The cytotoxic properties were confirmed by F. Bracher (Pharmazie, 1997; 52: 57-60), both in vitro, on sixty tumour cell lines in culture, and in vivo, on models of xenografts of human tumour cell lines (colon tumours SW-620 and HTC116, renal tumour A498 and melanoma LOX IM VI) implanted in mice.
Other compounds derived from ascididemin, such as 11-hydroxyascididemin, 11-methoxyascididemin, 11-phenylascididemin, 11-nitrophenylascididemin, 1-nitroascididemin, 3-nitroascididemin and neocalliactine, have been described chemically by various groups, such as those of F. J. Schmitz (J. Org. Chem., 1991; 56: 804-8) and Y. Kitahara et al. (Heterocycles, 1993; 36: 943-46; Tetrahedron Lett., 1997; 53, 17029-38), G. Gellerman et al. (Tetrahedron Lett., 1993; 34: 1827-30), S. Nakahara et al., (Heterocycles, 1993; 36: 1139-44) and I. Spector et al. (U.S. Pat. No. 5,432,172).
Meridine is another natural alkaloid extracted from the ascidian
Amphicarpa meridiana
or from the marine sponge Corticum sp. Meridine was isolated by F. J. Schmitz et al. (J. Org. Chem., 1991; 56: 804-808) and then described for its antiproliferative properties on a model of murine leukaemia (P388) and its antifungal properties in U.S. Pat. No. 5,182,287 (Gunawardana et al. of 23 Jan. 1993). Its cytotoxic properties on two human cell lines, colon cancer cells (HT-29) and lung carcinoma cells (A549), were reported by R. E. Longley et al. (J. of Nat. Products, 1993; 56: 915-920).
Mention may also be made, among these compounds, of cystodamine, a pentacyclic alkaloid isolated from the ascidian
Cystodytes dellechiajei
by N. Bontemps et al. (Tetrahedron Lett., 1994; 35: 7023-7026), which exhibits cytotoxic activity with respect to human leukaemia lymphoblasts.
A subject-matter of the present invention is compounds of general formula I and Ia
in which:
R
1
, R
2
, R
3
, R
4
and R
5
are selected from hydrogen, halogens, C
1
-C
6
alkyl groups, hydroxyl, —CHO, —OR
8
, —COOH, —CN, —CO
2
R
8
, —CONHR
8
, —CONR
8
R
9
, —NH
2
, —NHR
8
, —N(R
8
)
2
, —NH—CH
2
—CH
2
—N(CH
3
)
2
, —NH—CH
2
—CH
2
—Cl, —NHCOR
8
, morpholino, nitro, SO
3
H,
R
8
and R
9
being selected from C
1
-C
6
alkyl groups and phenyl(C
1
-C
4
)alkyl groups and Ar being a C
6
-C
14
aryl group,
R
6
is selected from hydrogen, halogens, C
1
-C
6
alkyl or —(CH
2
)
n
R
10
groups with R
10
being selected from halogens or —OH, (C
1
-C
6
)alkoxy or —O—CO—(C
1
-C
6
)alkyl groups and n between 1 and 6, —CN, —CO
2
Et or —COR
11
groups with R
11
being selected from C
1
-C
6
and phenyl(C
1
-C
4
)alkyl groups, and —NR
12
R
13
groups with R
12
and R
13
selected, independently of one another, from hydrogen or C
1
-C
6
alkyl, phenyl(C
1
-C
4
)alkyl or —(CH
2
)
n
R
14
groups with R
14
being selected from halogens or (C
1
-C
6
)alkoxy and —N(CH
3
)
2
groups and n between 1 and 6,
R—R
7
is selected from hydrogen, groups of type (C
1
-C
6
)alkyl, phenyl(C
1
-C
4
)alkyl, —NR
15
R
16
with R
15
and R
16
selected, independently of one another, from hydrogen, groups of type C
1
-C
6
alkyl and phenyl(C
1
-C
4
)alkyl and —(CH
2
)
n
R
17
, with R
17
selected from hydrogen, halogens or —OH or (C
1
-C
6
)alkoxy groups and n between 1 and 6,
and the addition salts of these compounds with pharmaceutically acceptable acids.
A specific group of compounds of the formula I and/or Ia is those in which:
R
1
, R
2
, R
3
, R
4
and R
5
are selected from hydrogen, halogens, C
1
-C
6
alkyl groups, hydrox

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