Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-16
2003-07-15
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S157000, C546S158000
Reexamination Certificate
active
06593342
ABSTRACT:
This application is a 371 of PCT/FR99/01716, filed Jul. 13, 1999.
The present invention relates to pharmaceutical compositions comprising 2-quinolones or derivative compounds.
A cancer is a disorder of the somatic genes in the course of which genetic dysfunctions are amplified as the tumoral process progresses from the state of precancerous lesion to that of malignant transformation, the cancer tumor becoming metastatic and often resistant to cytotoxic medicines.
Despite the very considerable efforts made in all the developed countries, in particular through experimental and clinical research programs, mortality due to various cancers (solid tumors and hematological neoplasties) remains unacceptably high. In many countries, cancer is the second most common cause of death, just after cardiovascular diseases.
In terms of newly diagnosed cancers, the distribution between solid tumors and hematological neoplasties (bone marrow, blood, lymphatic system) shows that 9 out of 10 cancers are solid tumors. In contrast with what is observed in hematological oncology (therapeutic successes in 40% to 90% of cancers of blood cells), only a small number of advanced or disseminated solid tumors respond to chemotherapy treatments alone. It is partly for this reason that the overall death by cancer grew in the USA between 1973 and 1992.
Unfortunately, it is not certain that this tendency may be reversed merely by the appearance, alongside the established chemotherapy arsenal, of new antitumor medicines such as taxanes (paclitaxel and docetaxel) which interfere with the formation of microtubules (W. P. McGuire et al., Am. Intern. Med., 1989), topoisomerase I inhibitors derived from camptothecin (topotecan and irinotecan), vinorelbine (novel alkaloid derived from periwinkle), gemcitabine (novel cytotoxic antimetabolite), raltitrexed (thymidylate synthetase inhibitor) and miltefosine (first representative of the alkyl-lysophospholipid family). These treatments are added, either as a first line treatment or as a second line treatment, to medicines whose specific activity is now well recognized, such as doxorubicin, cysplatin, vincristine, methotrexate and 5-fluorouracil.
One of the most difficult current problems in anticancer chemotherapy is due to the fact that many populations of malignant cells show considerable resistance to the established cytotoxic substances. Usually, this situation results from the existence of multi-drug-resistance genes or from the frequency of genetic mutations in certain types of tumors. Thus, the treatment of cancers requires novel approaches, complementary to those currently used, and designed to better combat the extension and heterogeneity of the tumor load and the acquisition of “cytotoxic multidrug” resistance.
Among these novel approaches, some are already promising. This is the case for the induction of apoptosis, the inhibition of tumor angiogenesis and of metastatic processes, not to mention gene therapy or immunotherapy.
The inventors have become interested in a different approach. The desired objective was to make the population of tumor cells more sensitive to the standard anticancer treatments in order to achieve a twofold benefit:
1) to increase the cytotoxic activity and thus the efficacy, and
2) to reduce the frequency and severity of certain side effects by means of reducing the dosage which might follow the induction of the increase in the antitumor efficacy.
It is this strategy which underlies the discovery of compositions capable of inducing a highly significant increase in the cytotoxic activity of tested anticancer medicines. These compositions have the capacity either of stimulating the recruitment of clonogenic cells in the tumor, thus making it more sensitive to the conventional treatment with cytotoxic agents, or of inhibiting the proliferation of clonogenic cells, thus contributing toward the regression of the tumor.
A subject of the present invention is thus the use, in the treatment of cancers with at least one antitumor agent chosen from cytotoxic agents, of a compound having activity on the proliferation of clonogenic cells in tumors, chosen from the compounds of formulae:
in which:
X is chosen from ═O, ═S and ═N—NH—R
7
, R
7
being a phenyl or pyridyl group,
R
1
, R
2
, R
3
and R
4
are chosen, independently of each other, from H, OH, a C
1
-C
4
alkyl group, a C
1
-C
4
alkoxy group, a group —OCO—R
8
, R
8
being a C
1
-C
4
alkyl group, and a group derived from a saccharide, at least one of the substituents R
1
, R
2
, R
3
or R
4
being other than H, and R
2
and R
3
together possibly forming a methylenedioxy group,
R
5
is a phenyl group or a phenyl group substituted 1 to 3 times with groups chosen from H, OH, a C
1
-C
4
alkoxy group, a group —OCOR
8
, a phenyl (C
1
-C
4
alkoxy) group, a group —O—SO
2
—R′
8
, R′
8
being a C
1
-C
4
alkyl group or a CF
3
group, and a group derived from a saccharide,
R
6
is chosen from H, a C
1
-C
4
alkyl group, a group —CO—R
9
and a group —A—R
10
,
R
6a
is chosen from a C
1
-C
4
alkyl group, a group —CO—R
9
and a group —A—R
10
,
R
9
being a C
1
-C
4
alkyl group,
A being a C
1
-C
4
alkylene group,
R
10
being chosen from 5- or 6-membered heterocyclic groups containing 1 to 4 hetero atoms chosen from oxygen, sulfur and nitrogen, the CN group, a group —COOR
11
, —CONR
12
R
13
, a group —NR
14
R
15
and a group —COR
16
, R
11
, R
12
, R
13
, R
14
, R
15
and R
16
being chosen independently from a hydrogen atom, a C
1
-C
4
alkyl group and a phenyl(C
1
-C
4
alkyl) group,
R
4
and R
6
together also possibly forming a —CO—CH
2
—CH
2
— group.
The cytotoxic agents may be used at their usual dose and, in this case, their efficacy is improved, or at lower doses given the increase in their antitumor efficacy.
In one preferred embodiment, the compound used is a compound of formula (I) in which:
R
1
is a C
1
-C
4
alkoxy group
R
2
is a hydrogen atom
R
3
is a C
1
-C
4
alkoxy group
R
4
is a hydrogen atom,
and in particular a compound of formula (I) in which:
R
5
is a 4-(C
1
-C
4
alkoxy)phenyl group,
and most particularly a compound of formula (I) in which:
R
1
is a methoxy group,
R
3
is a methoxy group, and
R
5
is a 4-methoxyphenyl group.
It has also been discovered that at least some of the compounds of formula (I) had antitumor activity themselves.
A subject of the present invention is also a composition having activity on the proliferation of clonogenic cells in tumors by interfering with the generation of clonogenic cells, either by stimulating proliferation and recruitment, or by inhibiting proliferation, and which comprises an effective amount of a compound of formulae:
in which:
X is chosen from ═O, ═S and ═N—NH—R
7
, R
7
being a phenyl or pyridyl group, R
1
, R
2
, R
3
and R
4
are chosen, independently of each other, from H, OH, a C
1
-C
4
alkyl group, a C
1
-C
4
alkoxy group, a group —OCO—R
8
, R
8
being a C
1
-C
4
alkyl group, and a group derived from a saccharide, at least one of the substituents R
1
, R
2
, R
3
or R
4
being other than H, and R
2
and R
3
together possibly forming a methylenedioxy group,
R
5
is a phenyl group or a phenyl group substituted 1 to 3 times with groups chosen from H, OH, a C
1
-C
4
alkoxy group, a group —OCOR
8
, a phenyl (C
1
-C
4
alkoxy) group, a group —O—SO
2
—R′
8
, R′
8
being a C
1
-C
4
alkyl group or a CF
3
group, and a group derived from a saccharide,
R
6
is chosen from H, a C
1
-C
4
alkyl group, a group —CO—R
9
and a group —A—R
10
,
R
6a
is chosen from a group —CO—R
9
and a group —A—R
10
,
R
9
being a C
1
-C
4
alkyl group,
A being a C
1
-C
4
alkylene group,
R
10
being chosen from 5- or 6-membered heterocyclic groups containing 1 to 4 hetero atoms chosen from oxygen, sulfur and nitrogen, the CN group, a group —COOR
11
, —CONR
12
R
13
, a group —NR
14
R
15
and a group —COR
16
,
R
11
, R
12
, R
13
, R
14
, R
15
and R
16
being chosen independently from a hydrogen atom, a C
1
-C
4
alkyl group and a phenyl(C
1
-C
4
alkyl) group,
R
4
and R
6
together also possib
Darro Francis
Frydman Armand
Guillaumet Gerald
Joseph Benoît
Kiss Robert
Jacobson & Holman PLLC
Laboratoire L. Lafon
Seaman D. Margaret
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