Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-03-16
1998-03-17
Peselev, Elli
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514441, 540452, 540456, A61K 31395, C07D49116
Patent
active
057287104
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to rapamycin derivatives, pharmaceutical compositions comprising such derivatives, and methods of treatment of pathogenic fungi, methods of inducing immunosuppression and methods of treating carcinogenic tumors utilizing such rapamycin derivatives.
Rapamycin is a naturally occurring macrocyclic triene antibiotic which can be produced by culturing an organism in an aqueous nutrient medium. Its structure may be illustrated as follows: ##STR1##
At least one rapamycin-producing strain of Streptomyces hygroscopius was deposited with the Northern Utilization and Research Division, Agricultural Research Service, U.S. Department of Agriculture, Peoria, Ill., U.S.A. under accession number NRRL 5491. Rapamycin, and methods for its preparation by culturing NRRL 5491 are disclosed by U.S. Pat. No. 3,929,992, issued Dec. 30, 1975, the entire disclosure of which is hereby incorporated by reference.
SUMMARY OF THE INVENTION
This invention relates to novel rapamycin derivatives of the formula: ##STR2## wherein: X is selected from the group consisting of H, --OR.sup.10, --S(O) .sub.n R.sup.10, --NR.sup.10 R.sup.11, alkyl and aryl; R.sup.10, --NR.sup.10 R.sup.11, alkyl and aryl; and (H, H); (H,OH); --H, C.sub.1 -C.sub.4 alkyl, --C(.dbd.O )R.sup.7, --C(.dbd.O)OR.sup.7, --C(.dbd.O) NHR.sup.7, and --C(.dbd.S)OR.sup.7 ; formula A--C(R.sup.8) (R.sup.9)--O--B, where A is a bond to the oxygen bonded to the carbon at the 28-position and B is a bond to the carbon at the 30-position; alkyl; C.sub.3 -C.sub.6 cycloalkyl, aryl groups, and heterocyclic groups; H, C.sub.1 to C.sub.6 alkyl, or R.sup.8 and R.sup.9 taken together are .dbd.O ; of H, alkyl and aryl; pharmaceutically acceptable salts, hydrates or solvates thereof.
This invention also relates to a pharmaceutical composition comprising an effective amount of one or more compounds of Formula II and a pharmaceutically acceptable carrier or diluent.
This invention also relates to a method of inhibiting the growth of pathogenic fungi in a human or other animal in need thereof which comprises administering an effective, non-toxic amount of one or more compounds of Formula II to such human or other animal.
This invention also relates to a method of inducing immunosuppression in a human or other animal in need thereof which comprises administering an effective, non-toxic amount of one or more compounds of Formula II to such human or other animal.
In addition, this invention relates to a method of treating carcinogenic tumors in a human or other animal comprising administering an effective, non-toxic amount of one or more compounds of Formula II to such human or other animal.
Still further, this invention relates to a method of preparing compounds of Formula II comprising contacting a compound of the formula: ##STR3## with an acid selected from the group consisting of protic acids and Lewis acids, and with an appropriate nucleophile.
DETAILED DESCRIPTION OF THE INVENTION
When any substituent or variable (e.g., aryl, alkoxyl, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, etc.) occurs more than one time in the formula of any of the compounds of Formula II, such variable or substituent definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated. Combinations of substituents and/or variables in a constituent of the compounds of the invention are permissible only if such combinations result in a stable compound.
The parenthetical nomenclature used in the definition of substituents such as R.sup.1 (e.g., (H, OR.sup.6) is intended to reflect the substituents on both valences of the relevant atom. The invention is not limited to particular isomers and the order of moieties in the parentheses does not suggest a particular configuration.
As used herein, except where otherwise noted, the term "alkyl" is intended to include both branched-and straight-chain, cyclic, acyclic and polycyclic, saturated and unsaturated aliphatic hydrocarbon groups. Preferably, alkyl groups have from one to si
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patent: 5023263 (1991-06-01), Von Burg
patent: 5091389 (1992-02-01), Ondeyka et al.
patent: 5100883 (1992-03-01), Schiehser
patent: 5102876 (1992-04-01), Caufield
patent: 5434260 (1995-07-01), Skotnicki et al.
patent: 5441977 (1995-08-01), Ruwo et al.
Lentz Edward T.
Peselev Elli
SmithKline Beecham Corporation
Stercho Yuriy P.
Venetianer Stephen A.
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