Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-08-18
1997-06-10
Cook, Rebecca
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540108, 552506, 552507, 552521, 552524, 552540, 552542, 552544, 552548, 552550, 552551, 552552, 552554, 552557, 552559, 552582, 552583, 552584, 552599, 552600, C07J 1700, C07J 5300, C07J 4100
Patent
active
056376910
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Squalamine, 3.beta.-(N-[3-aminopropyl]-1,4-butanediamine)-7.alpha.,24.zeta.-dihydroxy- 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 asteroid 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. Aced. 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. The invention also relates to pharmaceutical compositions containing such compounds and their use as antimicrobials or antibiotics. The invention further relates to the use of such compounds as disinfectants or anti-infectives.
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 H, 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).sub.q --N(R.sup.II)(R.sup.III), where one of X.sub.1 and X.sub.2 is --N(R.sup.IV) and the other is independently selected from --N(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##
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention is directed to steroid compounds other than squalamine of the Formula I: ##STR6## wherein X and Y are each independently selected from a cationic hydrophilic side chain and an anionic hydrophilic side chain; and the steroid ring nucle
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Frye Leah L.
Kinney William A.
Moriarty Robert
Zasloff Michael A.
Cook Rebecca
Magainin Pharmaceuticals Inc.
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