Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-10-14
2001-09-11
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S182000, C552S576000
Reexamination Certificate
active
06288051
ABSTRACT:
This invention relates to 7&agr;-(5-methylaminopentyl)-estratrienes of general formula I
in which
R
2
stands for a hydrogen or fluorine atom,
R
1
stands for a hydrogen atom, a methyl or ethinyl group,
n stands for 2, 3 or 4, and
x stands for 0, 1 or 2.
This invention especially relates to the estratrienes
7&agr;-{5-[N-Methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
17&agr;-methyl-7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino)]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
17&agr;-ethinyl-7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
7&agr;-{5-[N-methyl-N-2-(4,4,5,5,5-pentafluoropentanesulfonyl)-ethylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
2-fluoro-7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
2-fluoro-17&agr;-methyl-7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
2-fluoro-7&agr;-{5-[N-methyl-3-(4,4,5,5,5-pentafluoropentanesulfinyl)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
2-fluoro-17&agr;-methyl-7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
7&agr;-{5-[N-methyl-N-4-(4,4,5,5,5-pentafluoropentylthio)-butylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
7&agr;-{5-[N-methyl-N-4-(4,4,5,5,5-pentafluoropentanesulfinyl)-butylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
17&agr;-methyl-7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
17&agr;-methyl-7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
17&agr;-ethinyl-7&agr;-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17&bgr;-diol
The compounds of general formula I represent compounds with very strong antiestrogenic action.
Compounds with antiestrogenic properties, i.e., substances with inhibiting actions relative to estrogens, have already been described extensively.
As the compounds that come closest structurally to the compounds in question here of general formula I, the steroid derivatives that are described in EP-A 0 138 504 can be considered, and of the latter especially 7&agr;-[9-(4,4,5,5,5-pentafluoropentanesulfinyl)-nonyl]-estra-1,3,5(10)-triene-3,17&bgr;-diol (page 58, penultimate compound). This compound is currently under clinical development for hormone-dependent tumors (breast cancer) and represents the compound that is best known at this time, i.e., the one with the strongest antiestrogenic activity, of these steroid derivatives.
The compounds according to the invention are pure antiestrogens with stronger, several times better, antiestrogenic action than 7&agr;-[9-(4,4,5,5,5-pentafluoropentanesulfinyl)-nonyl]-estra-1,3,5(10)-triene-3,17&bgr;-diol. This holds true for several in vitro and in vivo criteria, but especially for oral action in vivo on rats.
Pharmaceutical compositions that contain sex steroid inhibitors and exhibit a steroidal skeleton, which exhibits a 7&agr;-side chain with the simultaneous presence of at least one other substituent, are the object of EP-A 0 367 576.
Other steroidal antiestrogens, which carry an 11&bgr;-phenyl radical, are described in EP-AS 0 384 842 and 0 629 635.
A considerable number of the most varied compounds—i.a., those of steroidal origin and those with a 2-phenylindole skeleton—which act as antiestrogens and/or suppress the estrogen biosynthesis, are disclosed in WO 93/10741.
The compounds of general formula I according to this application are distinguished in comparison to the already known steroid derivatives according to EP-A 0 138 504 by novel side chains on carbon atom 7 of the steroid skeleton. This structural modification results in especially greatly antiestrogenically active compounds.
The antiestrogenic action of the compounds according to the invention was determined in transactivation assays [Demirpence, E.; Duchesne M.-J.; Badia, E.; Gagne, D. and Pons, M.: MVLN Cells: A Bioluminescent MCF-7-Derived Cell Line to Study the Modulation of Estrogenic Activity; J. Steroid. Molec. Biol. Vol. 46, No. 3, 355-364 (1993) as well as Berry, M.; Metzeger D.; Chambon, P.: Role of the Two Activating Domains of the Estrogen Receptor in the Cell-type and Promoter-context Dependent Agonistic Activity of the Anti-estrogen 4-Hydroxytamoxifen; The EMBO Journal Vol. 9, 2811-2818 (1990)].
The antiproliferative activity of the new compounds in breast neoplasm cell lines is greater than that of 7&agr;-[9-4,4,5,5,5-pentafluoropentanesulfinyl)-nonyl]-estra-1,3,5(10)-triene-3,17&bgr;-diol.
The IC
50
values for the new compounds lie in the nanomolar range. In the HeLa cell line as well as the MVLN cell line, the following IC
50
values are produced for the compounds of Examples 1 to 6 as well as for reference compound 7&agr;-[9-(4,4,5,5,5-pentafluoropentanesulfinyl)-nonyl]-estra-1,3,5(10)-triene-3,17&bgr;-diol (execution of the test according to the above-indicated bibliographic references). The HeLa cells are transfixed with human estrogen receptor-expression vector (HEGO) and Vit-TK-CAT reporter genes, and the MVLN cells are transfixed with reporter gene Vit-TK-LUC:
IC
50
[nM]
Compound
HeLa cells
MVLN cells
Example 1
0.3
1.0
Example 2
0.2
0.6
Example 3
1.0
0.6
Example 4
0.16
1.3
Example 5
0.3
0.66
Example 6
0.1
1.0
Reference:
0.5
6.0
7&agr;-[9-(4,4,5,5,5-pentafluoro-
pentanesulfinyl)-nonyl]-estra-
1,3,5(10)-triene-3,17&bgr;-diol
The compounds have an inhibiting action on the growth of hormone-dependent tumor cells; they especially inhibit the growth of estrogen-dependent human breast neoplasm cells (MCF-7).
In-vivo tests also impressively confirm the superiority-of the compounds according to the invention compared to 7&agr;-[9-(4,4,5,5,5-pentafluoropentanesulfinyl)-nonyl]-estra-1,3,5(10)-triene-3,17&bgr;-diol. The tests described below were carried out:
1. Uterus growth test in infantile rats, s.c. and p.o. (test for antiestrogenic action)
2. Tumor tests of anti-tumor effect on hormone-dependent breast cancer)
2.1 MXT breast neoplasm in mice
2.2 DMBA*-induced breast cancer in rats
2.3 NNMU
+
-induced breast cancer in rats
*=dimethylbenzanthracene
+
=N-nitroso-N-methylurea
1. Uterus Growth Test in Infantile Rats (Antiestrogenic Action)
Principle of the Method
In rodents, the uterus reacts to the administration of estrogens with an increase in weight (both proliferation and water retention). This growth is to be inhibited in a dose-dependent-manner by simultaneous administration of compounds with an antiestrogenic action.
Execution of the Test
Animals:
Infantile female rats at a weight of 35-45 g at the beginning of the test, 5-6 animals per dose.
Formulation and Administration of the Substances:
Both for s.c. and for p.o. administration, the substances are dissolved in 1 part of ethanol (E) and made up with 9 parts of peanut oil (EÖ).
Test Batch
Young rats that have just been weaned from their mothers are delivered one day before the beginning of treatment for acclimatization and are immediately supplied with food—still in the animal cage. The treatment is then carried out once a day for 3 days in combination with 0.5 &mgr;g of estradiol benzoate (EB). EB is
Bittler Dieter
Bohlmann Rolf
Hegelehartung Christa
Heinrich Nikolaus
Kroll Jorg
Qazi Sabiha
Schering Aktiengesellschaft
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