US 5,824,701 A · Taxane-based prodrugs

Abstract

Taxane-based compositions of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of aryls, substituted aryls, aralkyls, substituted aralkyls, alkyls and substituted alkyls; R.sub.2 is an aryl or substituted aryl, preferably phenyl; R.sub.3 is H, a C.sub.1-10 alkoxy, SiEt.sub.3 or ##STR2## Y is O or S; (n) is zero or a positive integer; X is oxygen, S, SO.sub.2 or NL, where L is selected from the group consisting of H, C.sub.1-8 alkyls, aryls and aralkyls; R.sub.4 is H or an aroyl of the formula: ##STR3## wherein Ar is an aromatic, substituted aromatic or heteroaromatic group; R.sub.5 is H, CH.sub.3 CO or a substituted acetic acid derivative; Z is H or OR.sub.6 where R.sub.6 is selected from the group consisting of H, C.sub.1-8 alkyls, C.sub.1-8 substituted alkyls, C.sub.1-8 aralkyls, substituted aryls, aralkyls, substituted aralkyls, C.sub.1-10 alkoxy, SiEt.sub.3, ##STR4## P is O or OH; R.sub.8 is one of H, S(CH.sub.3).sub.3, Si(C.sub.2 H.sub.5).sub.3, CH.sub.3 CO, or substituted acetic acid derivatives of the formula; ##STR5## where R.sub.10 is an alkyl, aryl, halogen, or hydrogen alkoxy or ##STR6## R.sub.9 is selected from the group consisting of substantially non-antigenic polymers, C.sub.1-12 alkyls, C.sub.1-12 substituted alkyls and bifunctional moieties such as alkyls or polymers containing a terminal group ##STR7## and one of R.sub.3, R.sub.6 and R.sub.8 is ##STR8## and methods of preparation and use of the compounds are also disclosed.

Claims28

Dependent claims

A taxane-based composition comprising a moiety of the formula:

##STR46## wherein:
R.sup.1 is selected from the group consisting of aryls, substituted aryls, aralkyls, substituted aralkyls, alkyls and substituted alkyls;
R.sup.2 is an aryl or substituted aryl;
R.sup.3 is H, a C.sub.1-10 alkoxy, SiEt.sub.3, or ##STR47## Y is O or S;
R.sup.4 is H or an aroyl of the formula ##STR48## where Ar is an aromatic, substituted aromatic or heteroaromatic group;
R.sup.5 is H, CH.sub.3 CO or a substituted acetic acid derivative;
Z is H or OR.sub.6 where R.sub.6 is selected from the group consisting of H, C.sub.1-8 alkyls, C.sub.1-8 substituted alkyls, C-.sub.1-8 alkoxy, C.sub.1-8 aralkyls, substituted aryls, aralkyls, substituted aralkyls, SiEt.sub.3, ##STR49## P is O or OH;
(n) is zero or a positive integer;
X is oxygen or NL, where L is selected from the group consisting of hydrogen, C.sub.1-8 alkyls, aryls and aralkyls;
and
R.sub.8 is H, Si(CH.sub.3).sub.3, Si(C.sub.2 H.sub.5).sub.3, CH.sub.3 CO, or a substituted acetic acid derivative of the formula:
##STR50## where R.sub.10 is an alkyl, aryl, halogen or hydrogen, or ##STR51## R.sub.9 is selected from the group consisting of substantially non-antigenic polymers substituted C.sub.1-12 alkyls, C.sub.1-12 alkyls, and bifunctional moieties containing a terminal group of the formula:
##STR52## and one of R.sub.3, R.sub.6 and R.sub.8 is ##STR53##

10 more elements

A method of preparing a taxane-based composition, comprising reacting a taxane of the formula:

##STR58## wherein:
R.sub.1 is selected from the group consisting of aryls, substituted aryls, aralkyls, substituted aralkyls, alkyls and substituted alkyls;
R.sub.2 is an aryl or substituted aryl;
R.sub.4 is H or an aroyl of the formula ##STR59## where Ar is an aromatic, substituted aromatic or heteroaromatic group;
R.sub.5 is H, CH.sub.3 CO or a substituted acetic acid derivative;
Z is H or OR.sub.6 where R.sub.6 is selected from the group consisting of H, C.sub.1-8 alkyls, C.sub.1-8 substituted alkyls, C-.sub.1-8 alkoxy, C.sub.1-8 aralkyls, substituted aryls, aralkyls, substituted aralkyls, SiEt.sub.3, ##STR60## P is O or OH;
(n) is zero or a positive integer;
X is oxygen or NL, where L is selected from the group consisting of hydrogen, C.sub.1-8 alkyls, aryls and aralkyls;
Y is O or S;
R.sub.8 is H, Si(CH.sub.3).sub.3, Si(C.sub.2 H.sub.5).sub.3, CH.sub.3 CO, or a substituted acetic acid derivative of the formula:
##STR61## where R.sub.10 is an alkyl, aryl, halogen or hydrogen, or ##STR62## R.sub.9 is selected from the group consisting of substantially non-antigenic polymers, substituted C.sub.1-12 alkyls, C.sub.1-12 alkyls, and bifunctional moieties containing a terminal group of the formula:
##STR63## with a reagent selected from the group consisting of ##STR64## wherein:
(n), X, Y, and R.sub.9 are as set forth above;
(m) is a positive integer;
R.sub.11 is a C.sub.1-4 alkyl, aryls, or other capping group;
and
Q is a group capable of being displaced by a nucleophilic reagent and is selected from the group consisting of OH, halides, N-hydroxysuccinimidyl, N-hydroxybenzotriazolyl, p-nitrophenoxy and imidazolyls;
whereby a composition is produced of the formula ##STR65## where R.sub.12 is ##STR66## when (III) is used and ##STR67## when (IV) is used.

15 more elements

Dependencies are inferred from the claim text.

Taxane-based prodrugs

Life of this patent

Taxane-based prodrugs

Life of this patent

Abstract

Claims28