Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-13
2003-11-11
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...
C514S291000, C546S090000, C546S153000
Reexamination Certificate
active
06645983
ABSTRACT:
The present invention relates to pharmaceutical compositions comprising 4-quinolones or compounds derived therefrom.
A cancer is a somatic gene disorder in which genetic dysfunctions are amplified as the tumor process progresses from the state of a precancerous lesion to that of a malignant transformation, the cancer tumor becoming metastatic and often resistant to cytotoxic drugs.
Despite considerable efforts conducted in all developed countries, in particular through experimental and clinical research programs, the death rate due to the various cancers (solid tumors and hematological neoplasias) remains unacceptably high. In many countries, the cancer death rate is the second largest, just after cardiovascular diseases.
In terms of newly diagnosed cancers, the distribution between solid tumors and hematological neoplasias (bone marrow, blood, lymphatic system) shows that 9 out of 10 cancers are solid tumors. Contrary to what is observed in hematological oncology (therapeutic success in 40 to 90% of blood cell cancers), 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 rate by cancer increased in the USA between 1973 and 1992.
Unfortunately, it is not sure that this tendency might be reversed solely by the appearance, alongside the established chemotherapeutic arsenal, of new antitumor drugs such as taxanes (paclitaxel and docetaxel) which interfere with the formation of microtubules (W. P. Mc Guire et al., Am. Intern. Med., 1989), topoisomerase I inhibitors derived from camptothecin (topotecan and irinotecan), vinorelbin (new alkaloid derived from periwinkle), gemcitabine (new cytotoxic antimetabolic agent), 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 drugs whose specific activity is now well established, for instance doxorubicin, cisplatin, vincristine, methotrexate and 5-fluorouracil.
The vast majority of the conventional chemotherapy treatments or of the treatments based on these new compounds consists in administering highly cytotoxic compounds either in monodrug therapy or in multidrug therapy. The therapeutic efficacy of these treatments is often limited by the intensity of the side effects, which makes it necessary to reduce the number of administrations and the duration of the treatments, whereas for certain solid tumors, therapeutic protocols by intensifying the dose improve the efficacy.
Another of the current difficulties 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 multidrug resistance genes or from the frequency of genetic mutations in certain types of tumor. Thus, cancer treatment requires new approaches, complementary to those currently used, and intended to combat more effectively the extension and heterogeneity of the tumor charge and the acquisition of “cytotoxic multidrug” resistance.
A first approach is that of preventing or treating “multidrug-resistant” (MDR) cancers by using substances that inhibit or bring about the reversibility of the MDR resistance possibly associated with the expression of the glycoprotein-P membrane transporter. Such an approach is described in U.S. Pat. No. 5,726,184. Other new approaches are already showing promise. This is the case for the induction of apoptosis, the inhibition of tumor angiogenesis and metastatic processes, not to mention gene therapy or immunotherapy.
The inventors have become interested in a different approach. The desired objective was to render the tumor cell population more sensitive to the reference anticancer treatments in order to achieve a twofold benefit:
1) to increase the cytotoxic activity and thus the efficacy of cytotoxic anticancer drugs, 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 antitumor efficacy.
It is this strategy that is at the origin of the discovery of compositions capable of inducing a highly significant increase in the cytotoxic activity of tested anticancer drugs. The inventors have become interested in a particular group of novel derivatives of the 3-aryl-4-quinolone family. These compositions have the capacity either of stimulating the recruitment of clonogenic cells in the tumor, 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. They have the advantage of having no intrinsic cytotoxicity, unlike, on the one hand, tyrosine kinase inhibitors of the essentially 7-chloro 3-aryl-4-quinolone family, described in WO 98/17662 and claimed in the treatment of benign or malignant tumors, and more specifically for treating psoriasis, neoplasias, in particular epithelial neoplasias, and also for treating leukemias and attacks of the immune system, and, on the other hand, 2-aryl-4-quinolone derivatives described in WO 94/02145 for their intrinsic antitumor properties.
X. Mingxia et al. (Bopuxue 1993; 927-929) have described the synthesis of 4-quinolone derivatives with estrogenic and antiosteoporotic properties. Y. L. Kanghou et al. (Zhogguo Haiyang Yaowu, 1989; 8: 2-9) have synthesized novel 4-quinolone derivatives described as antispasmodic and antiarrhythmic agents. M. Croissey et al. have proposed a synthetic process by thermal cyclization for the preparation of 2- and 4-quinolones (Heterocycle 1997, 45, 683-690), whereas Price et al. compare the infrared spectra of a series of 2- and 4-quinolone derivatives (Aust. J. Chem. 1959; 12: 589-600).
One 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 with activity on the proliferation of clonogenic cells in tumors, but that has no intrinsic antitumor activity (allowing a therapeutic use), which is chosen from the compounds of formulae:
in which:
R
1
is chosen from H, OH, C
1
-C
4
alkyl groups, C
2
-C
4
alkenyl groups, C
1
-C
4
alkoxy groups, phenyl groups or a phenyl group substituted 1 to 3 times with groups chosen from H, OH, a group —OCOR
7
, R
7
being a C
1
-C
4
alkyl group, a group —O—SO
2
—R′
7
, R′
7
being a C
1
-C
4
alkyl group or a CF
3
group, and a group —NR
16
R
17
, R
16
and R
17
being chosen, independently of each other, from hydrogen, C
1
-C
4
alkyl groups, C
2
-C
4
alkenyl groups, phenyl(C
1
-C
4
)alkyl groups, a phenyl(C
1
-C
4
)alkyl group substituted 1 to 3 times on the alkyl group with groups chosen from H, OH and C
1
-C
4
alkoxy, or a dimethylamino (C
1
-C
4
)alkyl group, or together forming, with the nitrogen atom, a 5- or 6-membered heterocycle optionally comprising one or more hetero atoms chosen from oxygen, nitrogen and sulfur, or a methylpiperazinyl group,
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 —OCOR
7
, and a group derived from a saccharide, at least one of the substituents 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 —OCO—R
7
, a phenyl(C
1
-C
4
)alkoxy group, a group —O—SO
2
—R′
7
, R′
7
being a C
1
-C
4
alkyl group or a CF
3
group, a benzylamino group and a group derived from a saccharide,
R
6
is chosen from H, a C
1
-C
4
alkyl group, a C
2
-C
4
alkenyl group, a group —CO—R
8
and a group —A—R
9
,
R
6a
is chosen from a C
1
-C
4
alkyl group, a C
2
-C
4
alkenyl group, a group —CO—R
8
and a group —A—R
9
,
R
8
being a C
1
-C
4
alkyl group,
A being a C
1
-C
4
alkylene group,
R
9
being chosen from 5- or
Darro Francis
Frydman Armand
Guillaumet Gerald
Joseph Benoît
Kiss Robert
Laboratoire L. Lafon
Seaman D. Margaret
Young & Thompson
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