Organic compounds -- part of the class 532-570 series – Organic compounds – 9,10-seco-cyclopentanohydrophenanthrene ring system or...
Reexamination Certificate
2000-03-31
2002-04-30
Qazi, S. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
9,10-seco-cyclopentanohydrophenanthrene ring system or...
C514S167000
Reexamination Certificate
active
06380408
ABSTRACT:
The invention described and claimed herein was made in part under a grant from the National Institutes of Health. The U.S. Government has certain rights in the invention.
FIELD OF THE INVENTION
The present invention relates to novel analogs of the hormone 1&agr;,25 dihydroxy vitamin D
3
. Such analog materials exhibit a pharmacologically desirable combination of high antiproliferative and high transcriptional activity in vitro along with no or low calcemic activity in vivo.
BACKGROUND OF THE INVENTION
Because of its extraordinarily high potency in regulating diverse biochemical events vital to good health in humans, 1&agr;,25-dihydroxy vitamin D
3
, also known as calcitriol or 1,25D
3
, has stimulated the worldwide interest of medical researchers, molecular biologists, pharmacologists, medicinal and organic chemists, and researchers in the area of products for personal care and cancer prevention and/or treatment. This Material corresponds to the structure set forth in Formula I.
Numerous references can be cited as showing prior work with respect to vitamin D
3
analogues, calcitriol or the like. See, for example:
Vitamin D. Chemical, Biochemical and Clinical Update,
Proceedings of the Sixth Workshop on Vitamin D, Merano, Italy, March 1985; Norman, A. W., Schaefer, K., Grigoleit, H. G., Herrath, D. V. Eds.; W. de Gruyter; New York, 1985; Brommage, R., DeLucca, H. F.,
Endocrine Rev.
(1985) 6:491; Dickson, I.,
Nature
(1987) 325:18; Cancela, L., Theofon, G., Norman, A. W., in
Hormones and Their
Actions. Part I; Cooke, B. A., King, R. J. B., Van der Molen, H. J. Eds.; Elsevier, Holland, 1988; Tsoukas, D. C., Provvedini, D. M., Manolagas, S. C.,
Science,
(Washington, D.C.) (1984) 224:1438; Provvedini, D. M., Tsoukas, C. D., Deftoe, L. J., Manolagas, S. C.,
Science
(Washington, D.C.) (1983) 221:1181;
Vitamin D. Chemical Biochemical, and Clinical Endocrinology of Calcium Metabolism,
Proceedings of the Fifth Workshop on Vitamin D, Williamsburg, Va., February 1982, Norman, A. W., Schaefer, K., Herrath, D. V., Grigoleit, H. G., Eds., W. de Gruyter, New York, 1982, pp. 901-940; Calverley, M. J. in
Vitamin D: Molecular, Cellular, and Clinical Endocrinology,
Norman, A. W., Ed., de Gruyter; Berlin, 1988, p. 51; Calverley, M. J.,
Tetrahedron (
1987) 43:4609.
Vitamin D, A Pluripotent Steroid Hormone: Structural Studies, Molecular Endocrinology and Clinical Applications,
ed. Norman, Boullion and Thomasset, 1994, Walter de Gruyter, New York. Calverley and Binderup,
Bioorganic
&
Medicinal Chemistry Letters
(1993) 3:1845. U.S. Pat. Nos. 5,274,142; 5,389,622; 5,403,832 and 5,830,885 also describe and claim vitamin D
3
analogs. The entire contents of each reference and patent cited above and elsewhere in the present application are hereby incorporated by reference.
A major chemical challenge has been to design and synthesize analogs of 1&agr;,25-dihydroxy vitamin D
3
that retain potent antiproliferative and pro-differentiating activities but that lack hypercalcemic activity. Some synthetic analogs exhibiting such selective physiological activities, like 1&agr;, 25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol developed by Hoffman-La Roche, have been shown to possess very desirable pharmacological properties. Only a few 24-fluoro and 24,24-difluoro analogs of 1,25D
3
, having natural A-ring substituents and stereochemistry, have been synthesized. They have been shown, however, to be disappointingly similar to 1,25D
3
in terms of calcemic activity. Although their binding affinity to the vitamin D receptor (VDR) is similar to that of calcitriol, such materials do have longer plasma half-lives.
Given the foregoing, it is clear that there is a continuing need to identify additional synthetic analogs of the hormone 1&agr;,25-dihydroxy vitamin D
3
, which analogs selectively exhibit desirable pharmacological activities but do not exhibit hypercalcemic activity. Accordingly, it is an object of the present invention to provide novel 1,25D
3
analogs which are useful for a wide variety of beneficial medicinal and/or personal care product uses but which do not exhibit undesirably high levels of calcemic activity in vivo.
SUMMARY OF THE INVENTION
The present invention relates to novel sulfur-containing, and optionally fluorinated, unsaturated and/or oxa-containing analogs of 1&agr;,25-dihydroxy vitamin D
3
. Such analogs have the diastereoisomeric structural formulas set forth as Formulas II, III, IV, V, VI, VII, VIII, IX and X.
In Formulae II-X and other compounds of the invention, the hydroxyl substituents at Position 1 and at position 3 on the A-ring can be such that the analogs are either in the (−), i.e. (1&agr;, 3&bgr;) or the (+), i.e. (1&bgr;, 3&agr;) , diastereomeric configuration. The C—O bonds at these positions are occasionally indicated by wavy lines in structural formulae hereinbelow to indicate that alternative configurations are intended. Compounds with substituents in the (1&agr;, 3&bgr;) diastereomeric configuration are preferred according to the invention.
The present invention also includes materials which are similar to the compounds of Formulae II-X but which have 23-oxa-25-sulfone, 20-epi-22-oxasulfone; 16-ene-alkenyl sulfone; 16-ene-alkynyl sulfone; and 22E, 24E diene sulfone units. Compounds represented by Formulae XIV-XVII and XIX are among the preferred compounds of the invention:
Compounds of the invention can be represented by the general formulae XI-XIII and XVIII
wherein X is H
2
or F
2
and R is a branched or straight chain lower alkyl (1-6 carbons), an unsubstituted phenyl group or a phenyl group substituted with a lower alkyl or alkoxy group. Compounds wherein R is methyl, t-butyl, phenyl, and methoxyphenyl are especially preferred.
wherein X is H
2
or F
2
and R is a branched or straight chain lower alkyl (1-6 carbons), an unsubstituted phenyl group or a phenyl group substituted with a lower alkyl or alkoxy group. Compounds wherein R is methyl, t-butyl, phenyl, and methoxyphenyl are especially preferred.
wherein n is 1 or 2, and R is a branched or straight chain lower alkyl (1-6 carbons), an unsubstituted phenyl group or a phenyl group substituted with a lower alkyl or alkoxy group. Compounds wherein R is methyl, t-butyl, phenyl, and methoxyphenyl are especially preferred.
wherein R is a branched or straight chain lower alkyl (1-6 carbons), an unsubstituted phenyl group or a phenyl group substituted with a lower alkyl or alkoxy group. Compounds wherein R is methyl, t-butyl, phenyl, and methoxyphenyl are especially preferred.
REFERENCES:
patent: 4011250 (1977-03-01), Ishikawa et al.
patent: 4224231 (1980-09-01), DeLuca et al.
patent: 5190935 (1993-03-01), Binderup et al.
patent: 5260290 (1993-11-01), DeLuca et al.
patent: 5274142 (1993-12-01), Posner et al.
patent: 5376651 (1994-12-01), Binderup
patent: 5389622 (1995-02-01), Posner et al.
patent: 5401731 (1995-03-01), Calverley et al.
patent: 5401732 (1995-03-01), Calverley et al.
patent: 5403832 (1995-04-01), Posner et al.
patent: 5554599 (1996-09-01), Grue-Sorenson et al.
patent: 5830885 (1998-11-01), Posner
patent: 6043386 (2000-03-01), Posner et al.
Chodynski et al. (DN 127:190902, abstract of Steroids, (1997), 62(7), 546-553).
Crawford Kenneth R.
Han Gyoonhee
Lee Jae-Kyoo
Posner Gary H.
Wang Qiang
Arent Fox Kintner & Plotkin & Kahn, PLLC
Qazi S.
The Johns Hopkins University
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