Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-10-20
1998-12-08
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548188, 548194, 548200, 548201, 549408, 514456, A61K 31425, C07D27704
Patent
active
058469885
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US97/04387 filed Mar. 19, 1997 which claims priority from U.S. Provisional Application Serial No. 60/014,027 filed Mar. 25, 1996.
FIELD OF THE INVENTION
The present invention relates to pharmaceutical compounds useful in preventing tissue damage induced by oxidative stress. In particular, this invention relates to thiazolidine-4-carboxylic acid derivatives, possessing dual activity as antioxidants and cysteine prodrugs, which are useful as cytoprotective agents.
BACKGROUND OF THE INVENTION
Oxidative stress is known to contribute or lead to a variety of diseases. For a review of diseases and disease conditions associated with oxidative stress, see Drugs of the Future, vol. 13 (10), p. 973 (1988) and Molecular and Cellular Biochemistry, vol. 84, p. 199 (1988)
Glutathione plays an important role in protecting cellular systems from oxidative damage. Cysteine is an important amino acid and is the rate limiting substrate in the synthesis of glutathione. Cysteine when administered directly can be cytoxic. Prodrug forms of cysteine provide a cysteine delivery system which allows cysteine to be delivered at a rate that reduces cytoxicity and allows for the synthesis of glutathione. Cysteine prodrugs have been demonstrated to be effective in protecting cellular systems from various forms of stress. For these agents to be effective it is necessary for the prodrug to be cleaved either by enzymatic or non-enzymatic means. Once cysteine is released it must be converted into glutathione to demonstrate a therapeutic effect. References to the utility of thiazolidine-4-carboxylates as cysteine prodrugs include Cancer, Chemotherapy and Pharmacology, Vol. 28, p. 166 (1991) and Arch. Gerontology and Geriatrics, vol. 1, p. 299 (1982).
EP 0 373 002 A2 discloses the use of certain 2-substituted-thiazolidine-4-carboxylic acids as cysteine prodrugs in medicaments for delaying the onset of cataracts in mammals. None of the substituents defined by the reference imparts antioxidant or free radical scavenging properties to the reference 2-substituted-thiazolidine-4-carboxylic acid compounds.
U.S. Pat. No. 4,868,114 discloses a method of stimulating the biosynthesis of glutathione in mammalian cells by contacting the cells with an effective amount of certain L-cysteine prodrugs.
U.S. Pat. No. 4,952,596 discloses N-acyl derivatives of thiazolidine-4-carboxylic acid compounds which possess antipyretic, anti-inflammatory, mucolitic and analgesic activity in addition to activity in the treatment of ischemic pathologies and in pathologies caused by the overproduction of oxidant radicals.
Compounds which are not only capable of supplementing natural defenses against oxidative stress but also capable of protecting cellular systems against acute damage by active oxygen species are desirable.
SUMMARY OF THE INVENTION
The present invention provides compounds which are useful as cytoprotective agents. These compounds possess dual activity as antioxidants and cysteine prodrugs. The antioxidant properties of the compounds of the present invention protect the cellular system against acute damage by active oxygen species or free radicals, while the cysteine prodrug properties supplement the natural defense system by facilitating the synthesis of glutathione.
The present invention also relates to a method of providing cytoprotection to a patient in need thereof. The method comprises administering to such patient a cytoprotective amount of the dual activity compounds of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of the present invention combine two distinct biologically active moieties in a single chemical entity, and can be represented by the following structural formula ##STR1## wherein ##STR2##
n=0-12;
m=0-12;
X =nothing, NR.sup.1,O, or S(O).sub.n' ; provided that when X.dbd.NR.sup.1, O, or S(O).sub.n', then m>0 and n>0;
R.dbd.OH or a pharmaceutically acceptable salt thereof, C.sub.1 -C.sub.6 alkoxyl, amino, mono- or dialkylamino where the alkyl has from 1 to 4 c
REFERENCES:
patent: 4550022 (1985-10-01), Garabedian et al.
patent: 4868114 (1989-09-01), Nagasawa et al.
patent: 4952596 (1990-08-01), Della Bella et al.
patent: 5399573 (1995-03-01), Garner et al.
patent: 5424321 (1995-06-01), Hellberg et al.
patent: 5589464 (1996-12-01), Garner et al.
Bhuyan et al., "Antioxidant and Anticataractogenic Effects of Topical Captopril in Diquat-Induced Cataract in Rabbits," Free Radical Biology & Medicine, vol. 12, pp. 251-261 (1992).
Davison et al., "Active oxygen in neuromuscler disorders," Molecular and Cellular Biochemistry, vol. 84, pp. 199-216 (1988).
Nagasawa et al., "Prodrugs of L-Cysteine as Liver-Protective Agents," Journal of Medicinal Chemistry, vol. 25(5), pp. 489-491 (1982).
Nagasawa et al., "2-Substituted Thiazolidine-4-(r)-carboxylic Acids as Prodrugs of L-Cysteine Protection of Mice Against Acetaminophen Hepatotoxicity," J. Med. Chem., vol. 27, pp. 591-596 (1984).
Roberts et al., "L-Cysteine Prodrug Protects Against Cyclophosphamide Urotoxicity Without Compromising Therapeutic Activity," Cancer Chemother Pharmacol., vol. 28; pp. 166-170 (1991).
Roberts et al., "Prodrug of L-Cysteine as Protective Agents Against Acetaminophen-Induced Hepatotoxicity. 2-(Polyhydroxyalkyl)-and-2-(Polyacetoxyalkyl)thiazolidine-4(R)-carboxylic Acids," J. Med. Chem., vol. 30, pp. 1891-1896 (1987).
Santrucek et al., "Antioxidants--Potential Chemotherapeutic Agents, " Drugs of the Future, vol. 13(10), pp. 973-996 (1988).
Weber et al., "Thiazolidine-4-carboxylic acid, a physiologic sulfhydrul antioxidant with potential value in geriatric medicine," Arch. Gerontol. Geriatr., vol. 1, pp. 229-310 (1982).
Alcon Laboratories Inc.
Lutz Laura R. C.
Richter Johann
Ryan Patrick M.
LandOfFree
Thiazolidine-4-carboxylic acid derivatives as cytoprotective age does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Thiazolidine-4-carboxylic acid derivatives as cytoprotective age, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Thiazolidine-4-carboxylic acid derivatives as cytoprotective age will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-177577