Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active...
Patent
1995-04-05
1997-01-14
Kulkosky, Peter F.
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
514930, A61K 31785, A61K 31795
Patent
active
055936644
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the use of certain anionic oligomers which inhibit angiogenesis. These compounds can be used in the treatment of, for example, atherosclerosis, tumors, and metastasis.
Angiogenesis or neovascularization is the process by which new blood vessels originate as capillaries. This process is necessary in certain beneficial processes, such as wound healing and embryogenesis. Angiogenesis is also believed to be an essential prerequisite to certain deleterious effects, such as tumor growth and diabetic retinopathy. Nonvascularized tumors remain small in size, typically less than a few millimeters in diameter. The size of such tumors, both primary solid tumors and metastatic tumors, is limited by the ability of nutrients to diffuse into the tumor. Once vascularized however, tumors can grow rapidly and quickly become a clinical problem. Evidence suggests that tumors release a substance, termed tumor angiogenesis factor, which stimulates nearby endothelial cells to produce capillaries. Thus, if the ability of the tumor cell to release tumor angiogenesis factor could be suppressed or if the substance, once released could be rendered ineffectual, primary and metastatic tumor implantation or growth once implanted could be prevented and disease suppressed.
Other deleterious conditions are known to be associated with neovasularization, such as neovascular diseases of the eye, such as retrolental fibroplasia, diabetic retinopathy, and neovascular glaucoma. Such conditions, as well as tumors and tumor metastasis, could be treated by administration of an anti-angiogenesis agent. Heparin and heparin sulfate have been reported to be effective for these purposes.
Applicants have discovered that a class of synthetic oligomers are heparinmimetic in that this class of oligomers inhibits proliferative activity by means of anti-angiogenic activity. Such oligomers would thus be useful in the treatment of a variety of diseases and conditions associated with angiogenesis.
SUMMARY OF THE INVENTION
This invention relates to the use of anionic polyamide and polyurea oligomers of formulae 1a and 1b, respectively, ##STR1## wherein X and X.sup.3 each independently represent either a phenylene group of the formulae ##STR2## or a biphenylene group of the formula ##STR3## with the proviso that in a compound of formula la at least one of X and X.sup.3 must be a biphenylene moiety; ##STR4## m is an integer 0 or 1, with the proviso that in a compound of formula 1b when m is 0, R is a hydrogen atom; X.sup.3 ; group, or a phenyl group optionally substituted with 1 or 2 substituents selected from --SO.sub.3 R.sup.2, --CO.sub.2 R.sup.2, --PO.sub.3 (R.sup.2).sub.2, or --OPO.sub.3 R.sup.2 and optionally substituted with from 1 to 3 substituents selected from chloro, bromo, or C.sub.1 -C.sub.4 alkyl; (R.sup.2).sub.2, or --OPO.sub.3 R.sup.2 ; before; R--C(.dbd.O)--NH--X"--NH--; and R--C(.dbd.O)--, or RNH--C(.dbd.O)--X"--C(.dbd.O)--.
DETAILED DESCRIPTION OF THE INVENTION
The oligomers of the present invention are polyamides and polyureas having a number average molecular weight Mn of <10,000 comprising recurring units coupled by carbonyl linking moieties, said oligomer having anionic groups and predominantly linear geometry such that regular spacing between anionic groups exists in an aqueous medium. The oligomers are preferably linear in their backbone and also may be in their salt form. Particularly preferred salts are those that are pharmaceutically acceptable.
The term "pharmaceutically acceptable cation" means a cation acceptable for pharmaceutical use. Those cations that are not substantially toxic at the dosage administered to achieve the desired effect and do not independently possess significant pharmacological activity are included within the term "pharmaceutically acceptable cation". Illustratively, these salts include those of alkali metals, such as sodium and potassium; alkaline earth metals, such as calcium and magnesium; ammonium; light metals of Group IIIA including aluminum; and organic primary, secondary a
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Bitonti Alan J.
Wright Paul S.
Kulkosky Peter F.
Merrell Pharmaceuticals Inc.
Svoboda Craig G.
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