Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-09-27
2003-12-30
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S182000, C514S825000, C540S072000, C552S558000, C552S617000
Reexamination Certificate
active
06670347
ABSTRACT:
This invention relates to new 19-nor-17&agr;-pregna-1,3,5(10)-trien-17&bgr;-ols with a 21,16&agr;-lactone ring, process for their production and pharmaceutical preparations that contain these compounds, as well as 17&agr;-cyanomethylated estra-1,3,5(10)-trienes, which produce intermediate products on the way to the 19-nor-17&agr;-pregna-1,3,5(10)-trien-17&bgr;-ols.
The 19-nor-17&agr;-pregna-1,3,5(10)-trien-17&bgr;-ols with a 21,16&agr;-lactone ring produce novel selective estrogens that in contrast to standard estrogens, such as estradiol, show a preference for one of the two known estrogen receptors, estrogen receptor alpha (ER&agr;; Kuiper et al. (1996), Proc. Natl. Acad. Sci. 93:5925-5930; Mosselman, Dijkema (1996) Febs Letters 392:49-53 (and EP-A-0 798 378); Tremblay et al. (1997), Molecular Endocrinology 11:353-365). Since the two estrogen receptors, ER&agr; and ER&bgr;, have a different organ distribution (Kuiper et al. (1996), Endocrinology 138:863-870), the ER&agr; tracing of selective estrogens represents an important technical step forward. With these new estrogens, a more selective therapy of estrogen-deficiency-induced diseases with low estrogen action on organs that do not express ER&agr; is possible.
Estrogens exert their physiological action on a receptor protein, estrogen receptor (ER). In this case, this is a nuclear-position transcription factor that can be activated by ligands. Until a few years ago, it was assumed that estrogens exert their action on a single receptor. Recently, ER&bgr; was discovered as a second subtype of the estrogen receptor (Kuiper et al. (1996), Proc. Natl. Acad. Sci. 93:5925-5930; Mosselman, Dijkema (1996) Febs Letters 392:49-53; Tremblay et al. (1997), Molecular Endocrinology 11:353-365). The expression pattern of ERG was distinguished from that of the ERA (Kuiper et al. (1996), Endocrinology 138:863-870). Thus, relative to ER&agr;, ER&bgr; predominates in the rat prostates, while ER&agr; predominates in the rat uterus. In the brain, areas were identified in which in each case only one of the two ER-subtypes is expressed (Shugrue et al. (1996), Steroids 61:678-681), Li et al. (1997), Neuroendocrinology 66:63-67). In bones (Kuiper et al. (1998), Frontiers in Neuroendocrinology 19:253-286) and blood vessels, both ER&agr; and ER&bgr; are expressed (Iafrati et al. (1997) Nature Med. 3:545-48).
Because of the different tissue distribution, it was possible to achieve a selective estrogen action by subtype-specifice ligands. Substances with preference for ER&bgr; compared to ER&agr; in the in-vitro receptor binding test were described by Kuiper et al. (Kuiper et al. (1996), Endocrinology 138:863-870). In addition, ER&bgr;-selective estrogens were described in separate patent applications (DE 199 06 159, DE 199 17 930 and DE 199 54 105), as well as in a patent application of Sumitomo Chemicals Co. [JP 11292872; JP 1998-90296]. Patents by Katzenellenbogen et al. (WO 00/19994; PCT/US99/22747) and Loozen et al. (PCT/EP99/09053; WO 00/31112) describe subtype-specific estrogen receptor ligands, i.a., ER&agr;-selective compounds.
This invention is based on the surprising finding that 19-nor-17&agr;-pregna-1,3,5(10)-trienes with a 21,16&agr;-lactone ring have a higher binding affinity to ER&agr;.
This invention consequently relates to 19-nor-17&agr;-pregna-1,3,5(10)-trienes with a 21,16&agr;-lactone ring of general formula (II)
in which the dotted lines in rings B, C and D optionally mean one or two double bonds, and R
1
, R
2
, R
7
to R
9
, R
11
, R
13
to R
15
and R
18
, independently of one another, have the following meanings:
R
1
means a halogen atom, a hydroxyl, methyl, trifluoromethyl, methoxy or ethoxy group or a hydrogen atom,
R
2
means a halogen atom, hydroxyl group, straight-chain or branched-chain, saturated or unsaturated alkoxy group with 1 to 6 carbon atoms or a hydrogen atom,
R
7
means an &agr;- or &bgr;-position halogen atom, an &agr;- or &bgr;-position, straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms, straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom,
R
8
means an &agr;- or &bgr;-position hydrogen atom, an &agr;- or &bgr;-position, straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms or an &agr;- or &bgr;-position cyano group,
R
9
means an &agr;- or &bgr;-position hydrogen atom, an &agr;- or &bgr;-position methyl, ethyl, trifluoromethyl or pentafluoroethyl group,
R
11
means an &agr;- or &bgr;-position nitrooxy group, an &agr;- or &bgr;-position hydroxyl- or mercapto group, an &agr;- or &bgr;-position halogen atom, an &agr;- or &bgr;-position chloromethyl group, an &agr;- or &bgr;-position, straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 17 carbon atoms, an &agr;- or &bgr;-position, straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms, an optionally substituted, &agr;- or &bgr;-position aryl or heteroaryl radical or hydrogen atom,
R
13
means a methyl or ethyl group,
R
14
means an &agr;- or &bgr;-position, straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms or an &agr;- or &bgr;-position hydrogen atom,
R
15
means an &agr;- or &bgr;-position, straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms or an &agr;- or &bgr;-position hydrogen atom,
R
14
and R
15
together mean a 14&bgr;,15&bgr;-methylene group that is optionally substituted with one or two halogen atoms, and
R
18
means a hydrogen atom, methyl, C
2-6
acyl or tri(C
1-4
alkyl)silyl group or a group R
19
SO
2
, whereby R
19
means a group R
20
R
21
N, whereby R
20
and R
21
, independently of one another, represent a hydrogen atom, a C
1-5
alkyl radical, a group C(O)R
22
, in which R
22
can contain a straight-chain or branched hydrocarbon radical with up to 12 carbon atoms, which in addition can contain up to three double bonds, a C
3-7
cycloalkyl radical, an aryl radical or a combination of these structural features, or together with the N-atom means a polymethylenimino radical with 4- to 6 C-atoms or a morpholino radical, whereby the 3,17&bgr;-dihydroxy-2-methoxy-19-nor-17&agr;-pregna-1,3,5(10)-triene-21,16&agr;-lactone is excluded.
The substances that are described in this invention produce ER&agr;-selective estrogens, which relative to the above-mentioned compounds are distinguished by a novel structural type and a specific profile of action.
The 3,17&bgr;-dihydroxy-2-methoxy-19-nor-17&agr;-pregna-1,3,5(10)-triene-21,16&agr;-lactone excluded per disclaimer was found in metabolite studies of 17&agr;-cyanomethyl-3-methoxy-estra-1,3,5(10)-trien-17&bgr;-ol (G. Hobe, R. Schön, W. Schade, Steroids 36 (1980) 131).
According to the invention, 19-nor-17&agr;-pregna-1,3,5(10)-trienes with a 21,16&agr;-lactone ring of general formula (IIa)
in which R
1
, R
2
, R
7
to R
9
, R
11
, R
13
to R
15
and R
18
have the above-indicated meaning, whereby among the latter, 19-nor-17&agr;-pregna-1,3,5(10)-trienes are preferred, in which R
1
, R
2
, R
7
, R
8
, R
11
and R
13
to R
15
mean a hydrogen atom, R
9
means a C
1-4
alkyl group and R
18
means a hydrogen atom or a methyl group, in which R
1
, R
2
, R
7
, R
8
, R
9
and R
13
to R
15
mean a hydrogen atom, R
11
means a C
1-6
alkyl group, C
1-6
alkoxy group, vinyl group or phenyl group, and R
18
means a hydrogen atom or a methyl group, or in which R
1
, R
2
, R
8
, R
9
, R
11
and R
13
to R
15
mean a hydrogen atom, R
7
means a C
1-4
alkyl group, C
1-4
alkoxy group, vinyl group or phenyl group, and R
18
means a hydrogen atom or a methyl group, are preferred.
Examples of
Elger Walter
Fritzemeier Karl-Heinrich
Kollenkirchen Uwe
Kosemund Dirk
Müller Gerd
Badio Barbara P.
Millen White Zelano & Branigan P.C.
Schering AG
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