Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1997-04-23
2000-03-28
Dees, Jose G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
514825, 514903, 552508, 552530, 552533, C07J 1300, A61K 3156
Patent
active
060432365
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel compounds which are steroidal estrogens, to methods for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful for the treatment of inflammatory and immunologic disorders, especially for the treatment of autoimmune disorders. The compounds according to the present invention are especially preferred for the treatment of rheumatoid arthritis (RA) and multiple sclerosis (MS).
BACKGROUND AND PRIOR ART
Sex hormones have since long been known to ameliorate arthritic symptoms in chronic arthritis during pregnancy, see for example Hench P. S. "The ameliorating effect of pregnancy on chronic atrophic arthritis, fibrositis, and intermittent hydrathrosis", Mayo Clin. Proc., 13, 161-167, 1983. The use of oral contraceptives in patients with rheumatoid arthritis (RA) have proven to decrease the incidence of RA, see Wingrave S. J., Kay C. R. "Reduction in incidence of rheumatoid arthritis associated with oral contraceptives", Lancet, 569-571, 1978; and Vandenbroucke J. P. et al., "Oral contraceptives and rheumatoid arthritis: Further evidence for a preventive effect", Lancet 839-842, 1982.
In JP 268575/1990 estradiol derivatives are described, but the substituents in 17-position are completely different from the substituents in 17-position of the present application. The problem underlying the invention described in JP 268575/1990 is to find compounds against osteoporosis, said compounds having an excellent bone resorption inhibiting action without showing side effects such as risk for genital cancer etc. known in the art for estrogens.
The problem underlying the present invention is to develop novel steroidal estrogens with high anti-inflammatory and immunosuppressive effects, but with low "sex hormonal" activities. The steroidal estrogens known in the prior art, have the disadvantages that they influence genital and breast tissues, thereby conferring adverse effects such as endometrial and breast cancers if given in too high amounts.
The problem mentioned above has been solved by developing new steroidal estrogens according to the formula I, as will be described in the following.
SUMMARY OF THE INVENTION
The object of the present invention is to provide novel compounds, which are steroidal estrogens, and a method for their preparation.
Another object of the present invention is the use of the novel compounds for the treatment of inflammatory and immunologic diseases, especially for the treatment of autoimmune diseases.
Still another object of the invention is a pharmaceutical composition comprising a compound of the invention as active ingredient, optionally in the presence of a pharmaceutically acceptable carrier.
The novel compounds of the present invention are defined by the general formula I ##STR2## wherein A is hydrogen, C.sub.2 -C.sub.18 alkanoyl, (C.sub.6 aryl)carbonyl, C.sub.2 -C.sub.19 alkoxycarbonyl, (C.sub.6 aryloxycarbonyl, or a protecting group; C.sub.2 -C.sub.18 alkanoyl, (C.sub.6 aryl)carbonyl, C.sub.2 -C.sub.19 alkoxycarbonyl, (C.sub.6 aryloxy)carbonyl, or a protecting group; and
Within the scope of the invention are also pharmaceutically acceptable salts of the compounds of the formula I.
Preferred compounds of the invention are compounds of the formula I wherein C.sub.2 -C.sub.18 alkanoyl, (C.sub.6 aryl)carbonyl, C.sub.2 -C.sub.19 alkoxycarbonyl, (C.sub.6 aryloxy)carbonyl, or a protecting group;
Particularly preferred compounds of the invention are compounds according to the formula I wherein C.sub.2 -C.sub.19 alkanoyl or (C.sub.6 aryl)carbonyl;
Examples of protecting groups are benzyl, THP (tetrahydropyranyl), methoxymethyl, dimethylthexylsilyl, and tert-butyldimethylsilyl. A preferred protecting group is dimethylthexylsilyl.
The most preferred compound of the invention is 3,16.alpha.-dihydroxy-17-methylene-estra-1,3,5(10)triene.
The novel steroidal estrogens according to the invention are characterized by high anti-inflammatory and immunosuppressive effects, and
REFERENCES:
patent: 4977147 (1990-12-01), Jungblut et al.
patent: 5124321 (1992-06-01), Jungblut et al.
patent: 5371078 (1994-12-01), Clark et al.
Arnason et al., Effects of Estrogen, Progestin and Combined Estrogen-Progestin Oral Contraceptive Preparations on Experimental Allergic Encephalomyelitis, American Neurological Association Transactions, vol. 94, pp. 54-58, 1969.
Lichtenberger et al., New Synthetic Reactions. Catalytic vs. Stoichiometric Allylic Alkylation. Stereocontrolled Approach to Steroid Side Chain, Journal of the American Chemical Society, vol. 98, No. 2, Jan., 1996.
Vandenbroucke et al., Oral Contraceptives and Rheumatoid Arthritis: Further Evidence for a Preventive Effect, Lancet, pp. 839-842, Oct., 1982.
Walker et al., Influence of Natural and Synthetic Estrogens on the Course of Autoimmune Disease in the NZB/NZW Mouse, Arthritis and Rheumatism, vol. 16, No. 2, pp. 231-239, 1973.
Sally J. Wingave, Reduction in Incidence of Theumatoid Arthritis Associated with Oral Contraceptives, Lancet, pp. 569-571, Mar., 1978.
Trost et al., "Stereocontrolled approach to steroid side chain via organopalladium chemistry. Partial synthesis of 5alpha-cholestanone." J. Amer. Chem. Soc., vol. 100(11), pp. 3435-3443, 1978.
Trost et al., "New synthetic reactions. Catalytic vs. stoichiometric allylic alkylation. Stereocontrolled approach to steroid side chain." J. Amer. Chem. Soc., vol. 98(2), pp. 630-632, 1976.
Brattsand Ralph
Holmdahl Rikard
Jansson Liselotte
Loncar Marjana
Pettersson Lars
Astra Aktiebolag
Badio Barbara
Dees Jos,e G.
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