Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1995-04-20
1998-03-31
Dees, Jose G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
514172, 514176, 514182, A61K 3156, A61K 3158
Patent
active
057338990
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Squalamine, 5.alpha.-cholestane 24-sulfate, is an aminosterol that has been isolated from the dogfish shark, Squalus acanthias. See K. Moore, S. Wehrli, H. Roder, M. Rogers, J. Forrest, D. McCrimmon, and M. Zasloff, Proc. Nat. Acad. Sci. (USA), Vol. 90, February 1993, 1354-1358. See also U.S. Pat. No. 5,192,756 to Zasloff et al.
This water-soluble steroid exhibits potent bactericidal activity against both gram-positive and gram-negative bacteria. In addition, squalamine is antifungal and exhibits lytic activity against protozoa. The molecule was initially recovered as a natural product through extraction of several tissues of the dogfish shark, including the stomach, liver, gallbladder and spleen. Its structure was determined by fast atom bombardment mass spectroscopy and NMR spectroscopy (S. Wehrli et al., Steroids 58, 1993, 370-378). The chemical structure of squalamine is that of a cationic steroid characterized by a condensation of an anionic bile salt intermediate with spermidine. Squalamine represented the first example of a steroid to which spermidine is covalently coupled and a new class of antibiotics (K. Moore, S. Wehrli, H. Roder, M. Rogers, J. Forrest, D. McCrimmon, and M. Zasloff, Proc Nat. Acad. Sci. (USA), Vol. 90, February 1993, 1354-1358).
SUMMARY OF THE INVENTION
One aspect of the present invention relates to sterol antibiotics other than squalamine of the Formula I: ##STR2## wherein X and Y are each independently selected from a cationic hydrophilic side chain and an anionic hydrophilic side chain; and the steroid ring nucleus is saturated, unsaturated or partially saturated, and is optionally substituted with at least one group selected from --OH, --NH.sub.2, --SH, --F and alkyl.
Preferred compounds are of the Formula II: ##STR3## wherein each Z.sub.1 is independently selected from H and C.sub.1 -C.sub.4 alkyl; and Z.sub.2 and Z.sub.3 are each independently selected from OH, NH.sub.2 and SH.
Another aspect of this invention relates to compounds other than squalamine of the Formula III: ##STR4## wherein: the steroid ring nucleus is saturated or unsaturated; the steroid ring substituent Z.sub.5 is selected from .alpha.-H and .beta.-H; each of the steroid ring substituents Z.sub.7 is selected from --H, --OH, --SH, --F, --NH.sub.2, --(C.sub.1 -C.sub.3)-alkyl and --(C.sub.1 -C.sub.3)-alkoxy; one of the steroid ring substituents Z.sub.12 is --H and the other is selected from --H and --OH; X' is a polyamine side chain of the formula --X.sub.1 --(CH.sub.2).sub.p --X.sub.2 --(CH.sub.2)--N(R.sup.II)(R.sup.III) where one of X.sub.1 and X.sub.2 is --N(R.sup.V)(R.sup.V) and the other is independently selected from --N(R.sup.V)(R.sup.V), --O, --S and --CH.sub.2, with R.sup.IV and R.sup.V being independently selected from --H and --(C.sub.1 -C.sub.3)-alkyl, p and q are each independently an integer of from 0 to 5 but both p and q are not 0, and R.sup.II and R.sup.III are each independently selected from --H, --(C.sub.1 -C.sub.3)-alkyl and --(CH.sub.2).sub.r --N(R.sub.10)(R.sub.11) where r is an integer from 2 to 5 and R.sub.10 and R.sub.11 are each independently selected from --H and --(C.sub.1 -C.sub.3)-alkyl; R' is selected from --H and --(C.sub.1 -C.sub.3)-alkyl; and Y' is --(C.sub.1 -C.sub.10)-alkyl optionally substituted with one or more groups selected from --CO.sub.2 H, --OH, --NH--SO.sub.2 CF.sub.3, --SO.sub.3 H, --PO.sub.3 H.sub.2, --OSO.sub.3 H, --CF.sub.3, --F, ##STR5##
The invention also relates to pharmaceutical compositions containing such compounds and to their use as antimicrobials, antibiotics or disinfectants.
The invention further relates to the use of compositions containing squalamine or one of the compounds of the Formula I as antiangiogenic or cytotoxic agents. The invention therefore relates to the therapeutical use of such compositions to treat cancer.
Additionally, the invention relates to the use of compositions containing squalamine or one of the compounds of the Formula I as Na.sup.+ /K.sup.+ -ATPase inhibitors. The invention therefore relat
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Collins Delwood C.
Frye Leah L.
Kinney William A.
Moriarty Robert
Zasloff Michael A.
Badio Barbara
Dees Jos,e G.
Magainin Pharmaceuticals Inc.
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