Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-09-06
2003-06-24
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S182000, C540S113000, C552S510000
Reexamination Certificate
active
06583130
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to new estra-1,3,5(10)-trien-3-yl sulfamates having a C
2
-C
5
alkyl, alkenyl or alkynyl residue in C
13
position and an acyl, oxycarbonyl, aminocarbonyl, sulfonyl, or aminosulfonyl residue on the nitrogen atom of the sulfamate group. The invention is also directed to methods of producing the compounds according to the invention, and to pharmaceutical compositions containing these compounds. The compounds of the invention were found to be steroid sulfatase inhibitors, which exhibit no estrogenic effect.
In the human organism, estrogens are predominantly synthesized and secreted by the ovaries. Accordingly, the estradiol, estrone and estrone sulfate blood levels are subject to fluctuations in sexually mature women during the cycle. During human pregnancy, substantially higher amounts of estrogen are secreted by the placenta compared to the ovary. In addition to these estrogen sources, peripheral estrogen sources play a role in the human organism which, above all, gain importance in those cases where ovarian estrogen secretion has ceased or has not been established yet. As has been demonstrated, these estrogen sources are of major physiological importance in males as well.
Various tissues possess an enzymatic equipment (Purohit A. et al., Regulation of aromatase and sulphatase in breast tumor cells, 150 (1996), p. 65) that causes conversion of adrenal steroids to estrone and estradiol in tissue. Their effect proceeds in an autocrine or paracrine fashion at the site of biosynthesis, and significant estrogen levels do not necessarily have to appear in the blood. Another mechanism by which biologically relevant amounts of estrogen are formed in the tissue is hydrolytic cleavage of estrogen conjugates, particularly estrone sulfate. In this context, the production of estrone in the endometrium and in breast tissue and the tumors proceeding from such tissue is of special pathological importance, because tumor growth can be stimulated in this way. In breast carcinoma, it has been found that the amount of estrogen generated by sulfatase activity (cleavage of estrone sulfate) exceeds that via aromatase by a factor of 50-300 fold (Pasqualini J. R. et al., Estrone sulfatase versus estrone sulfotransferase in human breast cancer: potential clinical applications. J. Steroid Biochem. and Mol. Biol. 69 (1999) 287-292). Similar findings have been gathered by other groups as well. In breast tissue, 10 times more estrone is produced from androstenedione via sulfatase than via aromatase.
Accordingly, the fact can be regarded as proven that sulfatase inhibitors are capable of inhibiting the growth of estrogen-dependent tumors with high efficiency, because they massively reduce the estrogen concentration in the tumor tissue itself.
Under therapeutic aspects, sulfatase inhibitors are therefore the subject of intensified search, which themselves are non-estrogenic and do not yield estrogenic products as a result of hydrolysis. Thus, for example, Purohit A. et al., J. Steroid Biochem. Molec. Biol., Vol. 64, No. 5-6, pp. 269-275 (1998), describe 2-methoxyestrone 3-O-sulfamate to be a potent sulfatase inhibitor that does not exhibit any estrogenic effect on the uterine growth in ovariectomized rats. Estrone 3-O-sulfamates as sulfatase inhibitors have also been described in WO 93/05064. The estrone 3-O-sulfamate with an unsubstituted nitrogen is a strong sulfatase inhibitor (cf., Horwarth et al. in J. Med. Chem. 1994, 37, pp. 219-221, particularly FIG. 3 on page 220). However, this substance also exhibits a strong estrogenic effect, as described by Elger W. et al. in J. Steroid Biochem. Mol. Biol. 55 (1995), pp. 395-403. Other estrone 3-O-sulfamates as sulfatase inhibitors have been disclosed in WO 99/33858. These compounds have no essential estrogenic activity.
Bioorg. & Med. Chem. Lett. 7, 24, 3075-3080 (1997), describes N-acetylestrone 3-O-sulfamate as sulfatase inhibitor. However, this compound has a strong estrogenic effect, exceeding ethynylestradiol with respect to its systemic oral efficacy (cf., WO 97/14712).
Likewise, the DE 197 12 488 A1 describes steroid sulfamates which inhibit steroid sulfatase. The estrogenic effect of these compounds is low or absent. Certain steroid sulfamoyloxy compounds having more than one sulfamate group in their molecules, particularly those which are sulfamoylated in positions characteristic for an estrogenic effect, including substituents or side chains (e.g., in 7 and/or 11 position) which may be located at the periphery of the steroid skeleton, have been described to exhibit a significant increase in sulfatase activity with reduced estrogenic effect. Thus, 3,17-disulfamoyloxy derivatives in particular show good sulfatase activity. According to DE 197 12 488 A1, monosulfamates likewise have good sulfatase inhibition with low estrogenicity, with the exception of A ring sulfamates. As mentioned above, A ring sulfamates are known from WO 97/14712 to be compounds having a distinctly strong estrogenic effect.
SUMMARY OF THE INVENTION
It was the object of the present invention to provide additional steroid sulfatase inhibitors which themselves do not exhibit any estrogenic effect and will not yield any estrogenic products as a result of hydrolysis
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Surprisingly, it was found that new C
13
-substituted estra-1,3,5(10)-trien-3-yl sulfamates of general formula I, their physiologically tolerable salts or eaters,
wherein
R
1
represents COR
3
, COOR
4
, CONR
5
R
6
, SO
2
R
4
, SO
2
NR
5
R
6
,
R
2
represents hydrogen, C
1
-C
10
alkyl, C
1
-C
10
alkoxyalkyl, C
3
-C
10
cycloalkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, aryl, aryl (C
1
-C
3
)alkyl, or C
1
-C
3
alkylaryl, COR
3
; COOR
4
; CONR
5
R
6
; SO
2
R
4
; SO
2
NR
5
R
6
,
R
3
represents H or R
4
,
R
4
represents C
1
-C
17
alkyl, C
1
-C
17
haloalkyl, C
2
-C
17
alkenyl, C
2
-C
17
alkynyl, C
3
-C
10
cycloalkyl, aryl, aryl(C
1
-C
3
)alkyl, C
1
-C
3
alkylaryl,
R
5
, R
6
independently represent hydrogen, C
1
-C
5
alkyl, C
1
-C
5
haloalkyl, aryl, aryl(C
1
-C
3
)alkyl, C
1
-C
3
alkylaryl, or, together with the nitrogen atom to which they are bound, form a polymethyleneimino residue having 2-6 C atoms or a morpholino residue,
R
7
, R
9
independently represent H, OH, halogen, C
1
-C
5
alkoxy or C
1
-C
5
haloalkoxy,
R
8
represents H, OH, C
1
-C
5
alkyl, C
1
-C
5
haloalkyl, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, or halogen,
R
10
, R
11
represent hydrogen, or R
10
and R
11
together represent a CH
2
group,
R
12
, R
13
, R
14
independently represent H, OH, C
1
-C
5
alkoxy, or C
1
-C
5
haloalkoxy, or
R
12
represents halogen, or
R
13
and R
14
together represent oxygen, or together represent a ═CXY group wherein X and Y independently represent hydrogen, halogen or a C
1
-C
5
alkyl group, or
R
13
, R
14
independently represent C
1
-C
5
alkyl, C
2
-C
5
alkenyl, or C
2
-C
5
alkynyl,
R
15
represents C
2
-C
5
alkyl, C
2
-C
5
alkenyl or C
2
-C
5
alkynyl,
R
8
, R
9
, R
10
, R
12
, R
13
, R
15
independently are in &agr; or &bgr; position, and
up to 2 additional double bonds may be present in rings B and C, inhibit the activity of steroid sulfatase (EC 3.1.6.2) with extreme efficiency and do not exhibit any estrogenic effect.
In the meaning of the invention, physiologically tolerable salts are alkali or alkaline earth salts, particularly sodium, potassium or ammonium salts.
Conventional, physiologically tolerable inorganic or organic acids which may be esterified with the free hydroxy groups of the compounds of general formula I are e.g. phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid, and benzoic acid.
In the meaning of the invention, alkyl represents a branched or unbranched hydrocarbon chain. Accordingly, halozalkyl represents a mono- or polyhalogen-substituted, branched or unbranched hydrocarbon chain. Alkenyl represents a branched or unbranched hydrocarbon chain having at least one double bond. Alkynyl
Elger Walter
Kosemund Dirk
Michel Thomas
Müller Gerd
Peters Olaf
McKane Joseph K.
Norris & McLaughlin & Marcus
Schering AG
Small Andrea D.
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