Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reissue Patent
1999-07-23
2001-10-23
Kifle, Bruck (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C540S456000
Reissue Patent
active
RE037421
ABSTRACT:
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:
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:
wherein:
R
1
is selected from the group consisting of ═O (—OR
6
, H) and (H,H);
R
2
is selected from the group consisting of ═O (H,H), and (H, OH);
R
3
and R
6
are independently selected from the group consisting of —H, —C(═O)R
7
, —C(═O)OR
7
, —C(═O) NHR
7
, and —C(═S)OR
7
;
R
4
is selected from the group consisting of ═O and (H, OR
6
); or R
3
and R
4
can be taken together to form a bridge of the formula A-C(R
8
)(R
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;
R
5
is selected from the group consisting of —H and C
1
-C
4
alkyl;
R
7
is selected from the group consisting of C
1
-C
10
alkyl, C
3
-C
6
cycloalkyl, aryl groups, and heterocyclic groups;
R
8
and R
9
are independently selected from the group consisting of H, C
1
to C
6
alkyl, or R
8
and R
9
taken together are ═O;
provided that, when R
4
is ═O then R
2
is (H, OH);
and all 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 novel compounds of Formula II wherein R
4
is (H,OH) and R
1
, R
2
, R
3
, R
5
, R
6
, R
7
, R
8
, and R
9
are as described above, comprising contacting a compound of the formula
with a mixture of cerium trichloride and sodium cyanoborohydride.
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Carey et al., “Part B: Reactions and Synthesis”, (1983), Advanced Organic Chemistry, pp. 199-213.
Carey et al., “Reactions, Mechanisms, and Structure”, (1985), Advanced Organic Chemistry, pp. 691-699 and pp. 809-814.
Holt Dennis Alan
Luengo Juan Ignacio
Rozamus, Jr. Leonard Walter
Kifle Bruck
SmithKline Beecham Corporation
Stercho Yuriy P.
Venetianer Stephen
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