Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-02-02
1999-07-27
Nazario-Gonzalez, Porfirio
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514501, 540145, 556148, A61K 31555, C07D48722
Patent
active
059290641
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND TO THE INVENTION
The present invention relates to amino acid complexes of cobalt (III) mesoporphyrin IX and cobalt (III) protoporphyrin IX useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are useful as antiobesity agents and can also be useful for treatment of cyanide poisoning, neonatal hyperbilirubinemia and cancer.
Cobalt porphyrins are known to have various endocrine activities including Kappas A., Proc. Natl. Acad. Sci. U.S.A., 1989;86:7653-7657; Galbraith R. A. and Krey L. C., Neuroendocrinology, 1989;49:641-648; Galbraith R. A., et al., Pharmacoloy, 1987;34:241-249; Galbraith R. A. and Jellinck P. H., Biochemical and Biophysical Research Communications, 1987;145(1):376-383; Drummond G. S., et al., Proc, Natl. Acad. Sci. U.S.A., 1982;79:2384-2388; Smith T. J., et al., Pharmacology, 1986;34(9):9-16)!.
Phototherapeutic porphyrin-type dimers are disclosed in U.S. Pat. No. 4,961,920. Various porphyrins are disclosed in U.S. Pat. No. 4,393,071 to be useful in treatment of tumors; in U.S. Pat. No. 4,619,923 to control tryptophan metabolism; in U.S. Pat. No. 4,657,902 to inhibit heme metabolism; and in U.S. Pat. No. 4,782,049 to treat psoriasis. Methods of suppressing the immune system with cobalt protoporpyrins are described in U.S. Pat. No. 4,948,792; International Published Patent Application WO 87/04927 and for weight loss in International Published Patent Application WO 90/09173. The adjustment of testosterone levels in rats by the administration of cobalt mesoporphyrin is disclosed by Galbraith R. A., et al., J. Steroid Biochem., 1989;32(3):421-427. Several related cobalt porphyrins are disclosed in U.S. Pat. No. 5,149,697 and U.S. Pat. No. 5,192,757 to be antiobesity agents.
The preparations of some amino acid ester complexes with cobalt (III) deuteroporphyrin dimethyl ester and with Co(III) tetraphenylporphyrin in nonpolar organic solvents are described by Gouedard M., et al., J. Chem. Res., 1978:36-37.
We have surprisingly and unexpectedly found that common amino acid salts in water will react with cobalt (II) mesoporphyrin IX and cobalt (II) protoporphyrin to produce water-soluble complexes of cobalt (III) mesoporphyrin IX and cobalt (III) protoporphyrin IX that are effective antiobesity agents. High water solubility allows therapeutically useful dose volumes when the compounds are administered by injection. Additionally, this reduces depot effect at the injection site and has the potential for providing greater initial potency with shorter duration of action.
SUMMARY OF THE INVENTION
Accordingly, the present invention is a compound of Formula I ##STR1## wherein R is ##STR2## or --CONH.sub.2, and ##STR3## R.sup.1 is --CH.sub.2 CH.sub.3 or --CH.dbd.CH.sub.2 ; and X is hydrogen or a pharmaceutically acceptable cation.
A further embodiment of the invention is a compound of Formula II ##STR4## wherein R is H, alkyl, ##STR5## --CO.sub.2 H, or --CONH.sub.2, and ##STR6## wherein n is as defined above; R.sup.1 is --CH.sub.2 CH.sub.3 or --CH.dbd.CH.sub.2 ; and
The compounds of Formula I and Formula II are useful as antiobesity agents and are useful for treating obesity. They are also useful for the treatment of cyanide poisoning, neonatal hyperbilirubinemia, and cancer.
A still further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of a compound of Formula I or Formula II in unit dosage form in the treatment methods mentioned above. Finally, the present invention is directed to methods for production of a compound of Formula I and Formula II.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is further described by the following nonlimiting examples which refer to the accompanying FIGS. 1 to 5, short particulars of which are given below.
FIG. 1. Effect of IM Injection of Example 1 on Weight Gain in Normal Rats
FIG. 2. Effect o
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Chemical Abstracts, vol. 78, No. 26, 1993 "Metal Ions and Hydrogen Peroxide, XXVII. Inhibition of the Catalase Activity of Cobalt (III)-Hematoporphyrin by Amino Acids, Adenine, and Related Ligands. Stability of the Inhibitor Adducts", Abstract No. 164749n, Waldmeier, P. et al.
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Inernal Medicine, 4th Edition, Editor-in-Chief Jay Stein, Chapters 71-72, pp. 699-715.
Goel Om P.
Johnson Stephen J.
Wise Lawrence D.
Nazario-Gonzalez Porfirio
Tinney Francis J.
Warner-Lambert & Company
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