O-alkylated rapamycin derivatives and their use, particularly as

Details O-alkylated rapamycin derivatives and their use, particularly as O-alkylated rapamycin derivatives and their use, particularly as

1995-04-07

1997-09-09

Bond, Robert T.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

540456, A61K 31395, C07D49816

Patent

active

056657722

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP93/02604, filed Sep. 24, 1993.
This invention comprises novel alkylated derivatives of rapamycin having pharmaceutical utility, especially as immunosuppressants.
Rapamycin is a known macrolide antibiotic produced by Streptomyces hygroscopicus, having the structure depicted in Formula A: ##STR1## 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. Rapamycin is an extremely 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 as well as its high toxicity. Moreover, rapamycin is highly insoluble, making it difficult to formulate stable galenic compositions.
It has now surprisingly been discovered that certain novel derivatives of rapamycin (the Novel Compounds) have an improved pharmacologic profile over rapamycin, exhibit greater stability and bioavailability, and allow for greater ease in producing galenic formulations. The Novel Compounds are alkylated derivatives of rapamycin having the structure of Formula I: ##STR2## wherein X is (H,H) or O; arylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, acyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, acylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl, and (R.sup.3).sub.3 Si where each R.sup.3 is independently selected from H, methyl, ethyl, isopropyl, t-butyl, and phenyl; wherein "alk-" or "alkyl" refers to C.sub.1-6 alkyl, branched or linear preferably C.sub.1-3 alkyl, in which the carbon chain may be optionally interrupted by an ether (--O--) linkage; and R.sup.1 is (R.sup.3).sub.3 Si or carbalkoxyalkyl, X and Y are not both O.
Preferred Novel Compounds include the following:
The Novel Compounds for immunosuppressive use are preferably the 40-O-substituted rapamycins where X and Y are both O, R.sup.2 is H, R.sup.4 is methyl, and R.sup.1 is other than H; most preferably where R.sup.1 is selected from hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkyl, and aminoalkyl; especially 40-O-(2-hydroxy)ethyl-rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-(2-acetaminoethyl)-rapamycin).
Preferably O-substitution at C40 or O,O-disubstitution at C28 and C40 is performed according to the following general process: Rapamycin (or dihydro or deoxorapamycin) is reacted with an organic radical attached to a leaving group (e.g., RX where R is the organic radical, e.g., an alkyl, allyl, or benzyl moiety, which is desired as the O-substituent, and X is the leaving group, e.g., CCl.sub.3 C(NH)O or CF.sub.3 SO.sub.3) under suitable reaction conditions, preferably acidic or neutral conditions, e.g., in the presence of an acid like trifluoromethanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid or their respective pyridinium or substituted pyridinium salts when X is CCl.sub.3 (NH)O or in the presence of a base like pyridine, a substituted pyridine, diisopropylethylamine or pentamethylpiperidine when X is CF.sub.3 SO.sub.3. O-substituents at C28 only are accomplished in the same manner, but with prior protection at C40. Further modifications are possible. For example, where the substituent is allyl, the isolated, monosubstituted double bond of the allyl moiety is highly amenable to further modification.
The 9-deoxorapamycin compounds are preferably produced by reducing a rapamycin using hydrogen sulfide, by reacting rapamycin with diphenyldiselenide and tributylphosphine or by other suitable reduction reaction.
The 26-dihydro-rapamycins are preferably produced by reducing rapamycins or 9-deoxorapamycins from keto to hydroxy at C26 by a mild reduction reaction, such as a borohydride reduction reaction.
The Novel Compounds are particularly useful for the following conditions: for the treatment of recipients of e.g. heart, lung, combined heart-l

REFERENCES:
patent: 5120842 (1992-06-01), Failli et al.
patent: 5151413 (1992-09-01), Caufield et al.
patent: 5258389 (1993-11-01), Goulet et al.

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