Rapamycin derivatives

Details Rapamycin derivatives Rapamycin derivatives

1997-12-08

1999-11-16

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

540456, C07D49818, A61K 31435, A61K 31695, C07F 718

Patent

active

059858907

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to rapamycin derivatives, a process for their production, their use as a pharmaceutical and pharmaceutical compositions containing them.
Rapamycin is a known macrolide antibiotic produced by Streptomyces hygoscopicus, having the structure depicted in Formula A: ##STR2## See, e.g., McAlpine, J. B., et al., J. Antibiotics (1991) 44: 688; Schreiber, S. L., et al., J. Am. Chem. Soc. (1991) 113: 7433; U.S. Pat. No. 3,929,992. (There have been various numbering schemes proposed for rapamycin. To avoid confusion, when specific rapamycin derivatives are named herein, the names are given with reference to rapamycin using the numbering scheme of formula A.) Rapamycin is a potent immunosuppressant and has also been shown to have antitumor and antifungal activity. Its utility as a pharmaceutical, however, is restricted by its very low and variable bioavailability. Moreover, rapamycin is insoluble and lacks stability, making it difficult to formulate stable galenic compositions.
Numerous derivatives of rapamycin air, known. Certain 40-O-substituted rapamycins are described in, e.g., in U.S. Pat. No. 5,258,389 and WO 94/09010 (O-alkyl rapamycins); WO 92/05179 (carboxylic acid esters), U.S. Pat. No. 5,118,677 (amide esters), U.S. Pat. No. 5,118,678 (carbamates), U.S. Pat. No. 5,100,883 (fluorinated esters), U.S. Pat. No. 5,151,413 (acetals), and U.S. Pat. No. 5,120,842 (silyl ethers).
It has now surprisingly been discovered that certain novel derivatives of rapamycin have an improved pharmacologic profile over rapamycin, and exhibit greater stability. According to the invention, their, is provided a compound of Formula I ##STR3## wherein R.sub.1 is alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, benzyl, alkoxybenzyl or chlorobenzyl, ##STR4## wherein R.sub.3 is selected from H, alkyl, alkenyl, alkynyl, aryl, thioalkyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl and alkylsilyl; alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl, thioalkyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylarninoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl and carbalkoxyalkyl; aryloxy, amino, alkylamino, a residue of an amino acid, or N,N-disubstituted-amino wherein the substituents (a) are selected from alkyl, aryl or arylalkyl or (b) form a heterocyclic structure; R.sub.8 NCH--, wherein R.sub.8 is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy or arylsulfonylamino; --O--CH--O--; or substituted dioxymethylyne; from C.sub.1-4 alkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl or aryl; and optionally interrupted by an oxy linkage; and "ar" or "aryl" refers to a monocyclic, optionally heterocyclic, optionally substituted, C.sub.4-14 aromatic substituent, formula II, then R.sub.3 is other than H.
Any "alk" moiety or "alkyl" mentioned above may be branched, linear or cyclic; preferably it is a C.sub.1-6 aliphatic substituent optionally interrupted by an oxy linkage, more preferably uninterrupted by oxy.
Examples of "ar" moiety or "aryl" mentioned above and optionally substituted may include e.g. phenyl, benzyl, tolyl, pyridyl and the like.
When R.sub.1 is chlorobenzyl or alkoxybenzyl, the substituent is preferably in ortho.
When R.sub.7 CO-- is N,N-disubstituted-carbamoyl, it may be e.g. N-methyl-N-(2-pyridin-2-yl-ethyl)-carbamoyl, (4-methyl-piperazin-1-yl)-carbonyl or (morpholin-4yl)-carbonyl.
When R.sub.5 is substituted dioxymethylyne, it ma

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