Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-11-30
1995-07-11
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
540456, A61K 31395, C07D4916, C07D49116
Patent
active
054321832
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to the use of rapamycin prodrugs as immunosuppressant agents, e.g. for use in a human host in the treatment of autoimmune diseases and/or prevention of organ transplant rejections, intermediates formed in the preparation of the prodrugs as well as the prodrugs themselves.
In 1983, the United States Food and Drug Administration licensed cyclosporin A, an anti-rejection drug that revolutionized the field of organ transplant surgery. The drug acts by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein. Although cyclosporin A is effective in fighting transplantation rejection, it suffers drawbacks in causing kidney failure, liver damage, and ulcers which in many cases can be very severe. Newer, safer drugs exhibiting less side effects are constantly being searched for.
Rapamycin has been found to be useful as an antifungal agent, U.S. Pat. No. 3,929,992, as well as capable of inhibition of the immune response, Martel, et al., Can. J, Physiol. Pharmacol., 55, 48-51 (1977).
SUMMARY OF THE INVENTION
The present invention relates to a method for suppressing the immune system, for example, in treating autoimmune disease or preventing or ameliorating organ or tissue transplant rejection comprising administering to a mammal in need of such treatment an effective immunosuppressive amount of a compound of the formula ##STR2## wherein R.sup.1 and R.sup.2 are independently selected from hydrogen, and a group of the formula ##STR3## wherein m is 1-6, R.sup.3 and R.sup.4 are each hydrogen; branch or straight C.sub.1 to C.sub.8 alkyl; cyclic C.sub.3 to C.sub.4 alkyl; phenyl; benzyl; or R.sup.3 and R.sup.4 taken together with the nitrogen to which they are attached form a saturated heterocyclic ring having four or five carbon atoms, with the proviso that R.sup.1 and R.sup.2 can not both be hydrogen. In a preferred embodiment of the present invention, at least one of R.sup.1 and R.sup.2 is a group of the formula II more, even preferred, R.sub.3 and R.sub.4 are C.sub.1 to C.sub.8 alkyl.
The present invention also relates to intermediates for forming prodrugs of rapamycin of formula I wherein R.sub.1 or R.sub.2 are each independently ##STR4## X is a suitable leaving group, and m is 1 to 6. Preferred leaving groups include, Br, Cl, I, --OSO.sub.2 CH.sub.3, and p-toluenesulfonate.
The present invention also relates to prodrugs of rapamycin of formula I wherein R.sup.2 is hydrogen and R.sup.1 is ##STR5## wherein n is 1 to 6; R.sup.3 and R.sup.4 are each independently hydrogen; branch or straight C.sub.1 to C.sub.8 alkyl; cyclic C.sub.3 to C.sub.8 alkyl; phenyl; benzyl; or R.sup.3 and R.sup.4 taken together with the nitrogen to which they are attached to form a saturated heterocyclic ring having four or five carbons atoms, or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions including the prodrugs.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula I are rapamycin prodrugs. Rapamycin and certain prodrugs thereof are described in U.S. Pat. Nos. 3,929,992; 3,993,749; 4,316,885; and 4,650,803, the disclosure of which is hereby incorporated herein by reference.
The prodrug compounds of the present invention are produced by first forming the alkanoate ester of rapamycin. This is accomplished by reacting rapamycin, the compound of formula I where R.sub.1 and R.sub.2 are both hydrogen, with an acylating agent of the formula YCO(CH.sub.2).sub.m X (V) where m is as defined above, in the presence of an alkylamine base and a non-polar solvent. For the acylating agent of formula V, Y is, for example, halogen, N.sub.3, --O--COCH.sub.2 --X, ##STR6## and X is a suitable leaving group such as, for example, halogen, ##STR7## Preferably the acylating agent is where X and Y are each a bromine atom. Suitable amine bases include the following bases: ##STR8## wherein R.sup.7 =C.sub.1 to C.sub.4 alkyl, C.sub.5 -C.sub.6 cycloalkyl
Mono- and dialkylamine bases will rea
REFERENCES:
patent: 4650803 (1987-03-01), Stella et al.
patent: 5200411 (1993-04-01), Edmunds et al.
J. Am. Chem. Soc., vol. 91, pp. 1409-1411 (1991) Fretz et al.
Tetrahedron Letters, vol. 33 pp. 2295-2298 (1992) Curran et al.
Canadian J. Physiology and Pharmacology vol. 55 (1977) pp. 48-51.
Bond Robert T.
Fuller Jr. Grover F.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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