Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-07-29
2001-04-17
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S042000
Reexamination Certificate
active
06218425
ABSTRACT:
TECHNICAL FIELD
The present invention relates to organic compounds having biological activity, to formulations containing the compounds and to medical methods of treatment. More particularly, the present invention concerns a class of hydroxy- and alkoxy-substituted B-nor-6-thiaequilenin compounds, to pharmaceutical compositions containing the compounds, and to a method for their use as selective estrogen receptor modulators in the treatment of estrogen-related disorders.
BACKGROUND OF THE INVENTION
Equilenin, I, is an estrogenic steroidal hormone isolated from the urine of pregnant mares.
(Position numbering and ring letter designations in formula 1 above are in accordance with traditional nomenclature for steroids.)
Replacement of benzene rings by heterocyclic rings in synthetic estrogenic steroidal hormones have been reported by a number of workers, and Collins, et al.,
J. Am. Chem. Soc.,
79: 1103-1107 (1957) reported the synthesis of 3-desoxy-B-nor-6-equilenin, 2, in which the 3-hydroxy group is missing and a thiophene ring replaces the benzene “B ring” of equilenin:
These compounds have been termed in the literature “B-nor-6-thiaequilenins” by virtue of the collapsing of ring B of equilenin by one carbon atom and the insertion of a sulfur atom.
Collins, et al. also reported the synthesis of the 13,14-dehydro compound, 3.
Crenshaw, et al.,
Tetrahedron Letters,
52:4495-4496 (1969) reported the corresponding alcohols derived from the reduction of the ketone functionality of B-nor-6-thiaequilenin, but reported that all of the compounds which they prepared were racemates at the ring fusion between the C and D rings.
BRIEF SUMMARY OF THE INVENTION
In its principle embodiment, the present invention provides class of the individual stereoisomers of 8-substituted B-nor-6-thiaequilenin compounds of the general formula
where R is hydrogen or straight or branched-chain alkyl of one to four carbon atoms.
The dotted line represents an optional double bond, and when the double bond is present, the parenthetical hydrogen atom is absent. The “squiggle” bonds represent that, in accordance with standard chemical notation, the atom or atoms so attached to the core molecular moiety lie in either possible stereochemical configuration.
The compounds are selective estrogen receptor modulators and, as such, are useful in the treatment of estrogen-related disorders including post-menopausal syndrome, osteoporosis, hyperlipidemia, estrogen-dependent breast cancer, uterine fibrosis, endometriosis, and restenosis.
In another embodiment, the present invention provides pharmaceutical compositions comprising an amount of a compound as defined above which is effective to treat conditions of estrogen-related disorders in combination with pharmaceutically acceptable carriers and excipients.
In yet another embodiment, the present invention provides a method of treating conditions of estrogen-related disorders which comprises administering to female in need of such treatment a therapeutically effective amount of a compound as defined above.
DETAILED DESCRIPTION
Throughout this specification and the appended claims, the naming convention for compounds of this invention employed is based on the numbering scheme:
and the designations beta (“&bgr;”) and alpha (“&agr;”) represent absolute configurations of the designated substituent either above or below the main plane of the fused ring system, respectively.
In the compounds of the present invention, when the optional double bond is present, the compounds possess the structural formula:
In this embodiment, the compounds possess chiral centers at positions 3 (hydroxyl substituent) and 3a (methyl substituent) and thus four stereoisomers are possible: 1) 3&agr;, 3a&agr;; 2) 3&agr;, 3a&bgr;; 3) 3&bgr;, 3a&agr;; and 4) 3&bgr;, 3a&bgr;.
When the double bond is absent, the compounds possess the structural formula.:
In this embodiment, the compounds possess chiral centers at positions 3 (hydroxyl substituent), 3a (methyl substituent) and 10a and thus eight stereoisomers are possible: 1) 3&agr;, 3a&agr;, 10a&agr;; 2) 3&agr;, 3a&agr;, 10a&bgr;; 3) 3&agr;, 3a&bgr;, 10a&agr;; 4) 3&agr;, 3a&bgr;, 10a&bgr;; 5) 3&bgr;, 3a&agr; 10a&agr;; 6) 3&bgr;, 3a&agr; 10a&bgr;; 7) 3&bgr;, 3a&bgr;, 10a&agr; and 8) 3&bgr;, 3a&bgr;, 10a&bgr;.
While the substituent designated “R” may be hydrogen or alkyl of one to four carbon atoms, the preferred values for R are hydrogen and methyl.
Compounds contemplated as falling within the scope of the present invention include, but are not limited to the following examples:
3&agr;-hydroxy-8-methoxy-3a&agr;-methyl-2,3,3a,4,5,10b&agr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&agr;-hydroxy-8-methoxy-3a&agr;-methyl-2,3,3a,4,5,10b&bgr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&agr;-hydroxy-8-methoxy-3a&bgr;-methyl-2,3,3a,4,5,10b&agr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&agr;-hydroxy-8-methoxy-3a&bgr;-methyl-2,3,3a,4,5,10b&bgr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&bgr;-hydroxy-8-methoxy-3a&agr;-methyl-2,3,3a,4,5,10b&agr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&bgr;-hydroxy-8-methoxy-3a&agr;-methyl-2,3,3a,4,5,10b&bgr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&bgr;-hydroxy-8-methoxy-3a&bgr;-methyl-2,3,3a,4,5,10b&agr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&bgr;-hydroxy-8-methoxy-3a&bgr;-methyl-2,3,3a,4,5,10b&bgr;-hexahydro-1H-[-benz[b]indeno[5,4-d]thiophene;
3&agr;,8-dihydroxy-3a&agr;-methyl-2,3,3a,4,5,10b&agr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&agr;,8-dihydroxy-3a&bgr;-methyl-2,3,3a,4,5,10b&bgr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&agr;,8-dihydroxy-3a&bgr;-methyl-2,3,3a,4,5,10b&agr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&agr;,8-Dihydroxy-3a&bgr;-methyl-2,3,4a,4,5,10b&bgr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&bgr;,8-dihydroxy-3a&agr;-methyl-2,3,3a,4,5,10b&agr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&bgr;,8-dihydroxy-3a&agr;-methyl-2,3,3a,4,5,10b&bgr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&bgr;,8-Dihydroxy-3a&bgr;-methyl-2,3,3a,4,5,10b&agr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&bgr;,8-dihydroxy-3a&bgr;-methyl-2,3,3a,4,5,10b&bgr;-hexahydro-1H-benz[b]indeno[5,4-d]thiophene;
3&agr;-Hydroxy-8-methoxy-3a&agr;-methyl-3,3a,4,5-tetrahydro-2H-benz[b]indeno[5,4-d]thiophene;
3&agr;-Hydroxy-8-methoxy-3a&bgr;-methyl-3,3a,4,5-tetrahydro-2H-benz[b]indeno[5,4-d]thiophene;
3&bgr;-Hydroxy-8-methoxy-3a&agr;-methyl-3,3a,4,5-tetrahydro-2H-benz[b]indeno[5,4-d]thiophene;
3&bgr;-Hydroxy-8-methoxy-3a&bgr;-methyl-3,3a,4,5-tetrahydro-2H-benz[b]indeno[5,4-d]thiophene;
3&agr;,8-Dihydroxy-3a&agr;-methyl-3,3a,4,5-tetrahydro-2H-benz[b]indeno[5,4-d]thiophene;
3&agr;,8-Diydroxy-3a&bgr;-methyl-3,3a,4,5-tetrahydro-2H-benz[b]indeno[5,4-d]thiophene;
3&bgr;,8-Dihydroxy-3a&agr;-methyl-3,3a,4,5-tetrahydro-2H-benz[b]indeno[5,4-d]thiophene; and
3&bgr;,8-Dihydroxy-3a&agr;-methyl-3,3a,4,5-tetrahydro-2H-benz[b]indeno[5,4-d]thiophene.
Synthesis of Compounds of the Invention
The general Reaction Schemes set out below describe the synthesis of the various individual stereoisomers of compounds contemplated as falling within the scope of the present invention. Specific examples for the preparation of compounds of the invention are detailed in Examples 1-11 below.
The synthesis of compounds in accordance with the present invention can be thought of as being divisible into two series based upon the stereochemistry of the 3a-methyl in structural formulae 4a and 4b above.
Compounds of the present invention where the configuration of the 3a-methyl group is beta are synthesized by the general reaction sequence depicted below in Reaction
Dodge Jeffrey Alan
Lugar, III Charles Willis
Eli Lilly and Company
Lambkin Deborah C.
Voy Gilbert T.
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