Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-02-02
2002-01-15
Padmanabhan, Sreeni (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S026000, C552S626000
Reexamination Certificate
active
06339079
ABSTRACT:
BACKGROUND OF THE INVENTION
a) Field of the Invention
The present invention is directed to gonane type and D-homogonane type steroids with a sulfatase-inhibiting and/or estrogenic activity for application in pharmacological research and in the pharmaceutical industry.
b) Description of the Related Art
Steroid-3-sulfamates with a sultamoyloxy group, alkyl group, cycloalkyl group or dialkylsulfamoyloxy group have long been known (DE 3376799, 1968, Schwarz, S.,
Pharmazie
30 (1975) 17-21). Due to their improved bioavailability and decreased metabolic degradation per hepatic passage, they are used as prodrugs for estrogens in substitution therapy, in the form of combination preparations for contraception, and as substances with scavenging properties.
In steroid sulfamates (DE 2,336,431), only 1,3-dialkylsulfamoyloxy-8&agr;-estratien-17-on as well as certain, possibly substituted, 3,11- and 3,17-disulfamoyloxy estratiens, which are used especially as hormonal contraceptives (WO 96/05216), are identified as likewise having an estrogenic activity. Recently, it was found by M. J. Reed, et al. [
Biochemistry
34 (1995) 11508-11514
; J. Steroid Biochem. Molec. Biol
. 57 (1996) 79-88] that a strong sulfatase-inhibiting activity is exerted by estradiol- and estrone-3-sulfamates. Sulfatase inhibitors can be used to treat estrogen-dependent tumors in that they prevent the release of estradiol or estrone from endogenic steroid conjugates, i.e., the corresponding sulfates. It was subsequently indicated that steroidal sulfatase inhibitors of the estradiol- or estrone-3-sulfamate type can be used only conditionally as sulfatase inhibitors for treating estrogen-dependent tumors. In in vivo experiments, these compounds show an increased estrogenic activity [Elger, W., et al.,
J. Ster. Biochem. Molec. Biol
. 55 (1995) 395-403] which is undesirable in this indication.
Nonsteroidal sulfatase inhibitors with a comparatively high sulfatase-inhibiting activity corresponding to estrone sulfamate have been reported on recently (Li P.-K. et al.,
J. Ster. Biochem. Molec. Biol
. 59 (1996) 41-48).
Complete suppression of estrogenic activity was not previously observed in the nonsteroidal and steroidal sulfatase inhibitors with constant or improved sulfatase-inhibiting activity.
OBJECT AND SUMMARY OF THE INVENTION
Therefore, there is a need for compounds which limit or prevent the availability of estrogens in hormone-dependent tumors, wherein there is an interest in sulfatase inhibitors having no estrogenic active component.
Further, it is known that the estrogenicity of estradiol can be varied through specific substitution in the D ring. Oral effectiveness can be decisively improved by substitution (alkylation or acetylation) of the proton residing geminal to the 17-hydroxy group. Substitution of the proton vicinal to the 17&bgr;-hydroxy group in the 16-position leads to reduced oral effectiveness. Substituting halogen or pseudohalogen leads to so-called braked, i.e., slightly or moderately effective, estrogens.
Further, since liver toxicity has been determined in long-term testing with 17-alkylated or acetylated estradiol derivatives, there is interest in highly effective estrogens with low toxicity in order to detach these compounds.
The object is met by providing new steroid sulfamoyloxy derivatives which are produced by suitable sulfamoylation reactions. It has been found that certain steroidal sulfamoyloxy compounds with more than one sulfamate grouping in the molecule, in particular those that are sulfamoylated at the characteristic positions for estrogenic activity, including substituents or side-chains (e.g., in the 7-position and/or 11-position) which can be found at the periphery of the steroid skeleton, show a clear increase in sulfatase activity with reduced estrogenic activity. In some cases, the estrogenicity can be reduced to such an extent that even antiestrogenic effects are observable.
According to the invention, it was found that compounds of the estradiol disulfamate and 16-halogen-estradiol disulfamate type have a greater sulfatase inhibition than any known compounds and, moreover, do not exhibit any estrogenicity. Due to the halogen substitution in the 16-position, the sulfatase-inhibiting activity is further increased compared with the unsubstituted compound.
Some monosulfamates, with the exception of the A-ring sulfamoyloxy compounds, show significant sulfatase activity with reduced estrogenicity. Synergistic effects are observed in the presence of two or more such pharmacophores in a molecule. In some cases, these effects lead to a multiplying of of the activity in comparison to the standard compounds, which was confirmed with respect to disulfamates and trisulfamates.
Due to the influencing of the estrogen biosynthesis, the direct sulfatase inhibition and other antiestrogenic effects, the availability of estrogens is limited or can be regulated, which can be utilized for the treatment of estrogen-dependent tumors and for diagnostics.
The direction of the pharmacological effect of the sulfamoyloxy compounds can be specifically changed depending on the substitution pattern, which makes it possible to use them as sulfatase inhibitors on the one hand and as estrogen components on the other hand. Surprisingly, in-vitro potential estrogen activities can be detected in some sulfamates by means of an estrogen transcription assay. In this test, 3,17-disulfamoyloxy compounds are found to be inactive.
The 16-substituted 3-monosulfamates which are the subject of this invention show an extraordinary therapeutic breadth. In addition to high sulfatase activity, these compounds are characterized by high estrogenicity. This is surprisingly high compared with the known highly effective estrone- or estradiol-3-sulfamates. According to the prior art, 16-halogen- or pseudohalogen-estradiols are less effective compared with estriol or estradiol. Estrogenicity is considerably increased by introducing the sulfamate group in the 3-position. Accordingly, 16&agr;-bromoestradiol-3-sulfamate applied orally in vivo is five times more effective than estriol and three times more effective than estradiol-3-sulfamate. Based on these findings, new orally effective estrogens are available for contraception and hormone replacement therapy on the one hand and for diagnostics in the application of radioactive species (PET) on the other hand.
In marked form, especially in the case of short-lived isotopes such as [
18
F], [
76
Br] or Tc, etc., the compounds according to the invention represent potential markers for diagnosing diseased tissue, including cancerous tissue, due to their target specificity relative to steroid sulfatase as well as estrogen receptors.
The compounds according to the invention are extremely effective sulfatase inhibitors which are suitable, by themselves or in combination with other active components, e.g., aromatase inhibitors or antiestrogens, for the treatment of diseases in relation to inhibition of sulfatases or estrogens, e.g., for treating hormone-dependent tumors.
Further, some of the steroidal sulfamoyloxy compounds in combination with a gestagen are also important means for contraception and for the treatment of climacteric complaints.
The compounds according to the invention having the general formula I, can be used as pharmaceuticals. Production of these preparations is carried out by galenic methods, known per se, by mixing with organic and/or inorganic inert carrier materials suitable for enteral, percutaneous or parenteral applications.
Suitable dosages can be determined routinely by determining bioequivalence relative to a known sulfatase inhibitor or a known estrogen. The dosage of the compounds according to the invention ranges from 0.001 to 200 mg per day.
BRIEF DESCRIPTION OF THE INVENTION
The sulfamoyloxy compounds according to the invention are steroids of the gonane type and D-homo-gonane type according to formula I,
wherein there is possibly an additional double bond between C atoms 9 and 11, 8 and 9, 8 and 14, 14 and 15, 15 and 1
Kasch Helmut
Roemer Johannes
Schumann Winfried
Steinbach Joerg
id pharma GmbH
Padmanabhan Sreeni
Reed Smith LLP
LandOfFree
Steroid sulfamates, method for the production and use thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Steroid sulfamates, method for the production and use thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Steroid sulfamates, method for the production and use thereof will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2817878