Steroids with radical-attracting aromatic substituents, process

Details Steroids with radical-attracting aromatic substituents, process Steroids with radical-attracting aromatic substituents, process

1996-07-08

1999-06-22

Dees, Jose' G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

552610, 552626, 552630, A61K 3156, C07J 300

Patent

active

059143258

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The invention relates to novel steroids with radical-attracting aromatic substituents, processes for their production, and medications containing these compounds for the prophylaxis and therapy of radical-mediated cell damage.
From professional and patent literature it is known that reactive oxygen species (ROSs), free oxygen radicals and other radial forms play an important role in the occurrence of many kinds of cell damage, such as ischemic and traumatic organ injuries, and inflammatory and toxic processes.
A negative effect of ROSs, free oxygen radicals and other forms of radicals can also be found in brain and spinal column injuries, shock states, stroke, muscular dystrophy, emphysemas, adult respiratory distress syndrome (ARDS), asthma, aging processes, in tissue damage after myocardial infarction, damage from toxic processes and radiation, burns, and transplant-dictated immune reactions. Among other factors, lipid peroxidation and the oxidation of low-density lipoprotein (LDL) cholesterol, combined with irreversible membrane and endothelial damage are the starting point for such radical-mediated cell damage.
It is also known that lipophilic substances, such as lipophilic steroids, with radical-scavenging ("radical-trapping") properties can be suitable for prophylaxis and therapy of radical-mediated cell damage.
Unlike the known low-molecular phenolic antioxidants, these lipophilic steroids are transported with a certain selectivity into the region of the cell membrane or endothelium, where they can develop their efficacy.
The therapeutic utility is determined by the action spectrum of the respective substance.
International Patents WO 87/01716 and WO 91/11453, European Patents EP 0 389 368, EP 0 389 369, and EP 0 389 370, and French Patent FR 2 640 977, for instance, describe steroids with scavenger properties.
WO 87/01716, WO 91/11453 and EP 0 389 368/. . . 369/. . . 370 describe steroids which a the terminal carbon atom of the C.sub.17 side chain contain an amino group, which can be substituted or can be a component of a heterocyclic ring system.
In FR 2 640 977, a structural type is shown that has a substituted phenyl ring in the .beta. position on the C.sub.11 atom.
It is shown in J. Phys. Org. Chem. 3 (1990), 309-315 that estrogens, and especially catechol estrogens, can act as radical catchers. Estradiol, estrone, estriol and 2-hydroxyestradiol inhibit peroxidation in vitro and in vivo.


SUMMARY OF THE INVENTION

The object of the invention is to provide novel steroids with radical-attracting aromatic substituents and processes for their production.
A further object of the invention is to disclose medications that contain these compounds.
According to the invention, this object is attained in the novel steroids with radical-attracting aromatic substituents of general formula I and general formula II of the claims appended hereinbelow have been discovered.
The radical-attracting aromatic substituent Y can be represented as a component of a substituent of the following general formula: ##STR1## where A-E independently of one another represent H, alkyl, Oalkyl, Oacyl, OH or one of the substituents B, C, D=NR.sub.2, where R=alkyl, and each of the other four substituents are hydrogen.
The most highly preferred compounds of the steroids of the invention with radical-attracting aromatic substituents are e, .-androstan-3-one, 17-diol, 17-ol, -diol, -ol, 10)-triene-17-ol, riene-17-ol, iene-17-ol, (10)-triene-17-ol, 1,3,5(10)-triene-17-ol and
The invention further relates to a process for producing the steroids of general formulas I and II, which is characterized in that the insertion of the radical-attracting substituents into position 17 of the steroid skeleton is effected via the nucleophilic opening of a 17-spirooxirane or directly by alkylation of the 17-oxo group, and that the direct alkylation of the 17-oxo group is done via the conversion of corresponding metal organyls with cerium(III) salts. The methods of synthesis used in the production of the steroids of the in

REFERENCES:
patent: 3193564 (1965-07-01), Counsell et al.
patent: 5371078 (1994-12-01), Clark et al.
Inhibition of Peroxidations of Lipids and Membranes by Estrogens. Komur, E. Takahashi, Morita, Tsuchiya, Arakawa, Yamamoto & Niki (1990).
Eicosanoids, Lipid Peroxidation and Cancer. Nigam, McBrien & slater 1988.
Peters et al., "17-desoxy estrogen analogues", J. Med. Chem., vol. 32, pp. 1642-1652, 1989.

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