Prodrugs of the tyrosine kinase inhibitor for treating cancer
There are provided compounds of Formula I, and pharmaceutically acceptable salts and esters thereof, and pharmaceutical compositions thereof, useful for inhibition or modulation of the activity of tyrosine kinases and treatment of disease states or conditions mediated by tyrosine kinases, including cancers.
1 . A compound of Formula I, or a pharmaceutically acceptable salt or ester thereof:
where,
R 1 and R 2 are independently a hydrogen or a protecting group,
wherein the protecting group is R 4 W(R 5 R 6 C) m —, where m is an integer selected from 0 to 6; W is absent; R 5 and R 6 are independently a hydrogen or a lower alkyl group; and
(a) R 4 is
where X is oxygen (—O—), sulfur (—S—), nitrogen (—NH—), or a methylene (—CH 2 —) group; R 7 and R 8 are independently a hydrogen, a substituted or unsubstituted alkyl or cycloalkyl, an aryl or heteroaryl group without or with substitution, a PEG moiety, or an ester-forming group; or, the combination of R 7 and X is an aryl group with or without further substitution; or
(b) R 4 is
where R 7 is a PEG moiety and X is O, S, NH or —CH 2 —;
and
R 3 is absent or a protecting group selected from acyl group, carbonyl group, thiocarbonyl group, carbamoyl group, substituted or unsubstituted acetyl, substituted or unsubstituted aminoalkanoyl, substituted or unsubstituted α-aminoalkanoyl, an acyl group derived from a natural or an unnatural amino acid with or without substitution, an acyl group of a peptide residue, cycloalkane-carbonyl, heterocycloalkane-carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkoxycarbonyl, and heteroaryloxycarbonyl;
provided that the compound of Formula I is not axitinib.
2 . A compound of Formula II, or a pharmaceutically acceptable salt or ester thereof:
where,
R 1 and R 2 are independently a hydrogen or a protecting group,
wherein:
the protecting group is R 4 W(R 5 R 6 C) m —, where m is an integer selected from 0 to 6; W is oxygen (—O—), sulfur (—S—), nitrogen (—NH—), or absent; R 5 and R 6 are independently a hydrogen or a lower alkyl group; and
(a) R 4 is
where X is oxygen (—O—), sulfur (—S—), nitrogen (—NH—), or a methylene (—CH 2 —) group; R 7 and R 8 are independently a hydrogen, a substituted or unsubstituted alkyl or cycloalkyl, an aryl or heteroaryl group without or with substitution, a PEG moiety, or an ester-forming group; or, the combination of R 7 and X is an aryl group with or without further substitution;
provided that when R 4 is
and X is O, then R 7 and R 8 are not both hydrogen;
or
(b) R 4 is
where R 7 is a PEG moiety and X is O, S, NH or —CH 2 —;
provided that the compound of Formula II is not axitinib.
3 . The compound of claim 2 , wherein the PEG moiety is R 10 —(OCH 2 CH 2 ) n —, where n is 1 to 10, and R 10 is a hydrogen or a lower alkyl.
4 . The compound of claim 2 , wherein the ester-forming group is a lower alkyl or an aryl group.
5 . A compound of Formula III, or a pharmaceutically acceptable salt or ester thereof:
where,
R 3 is absent or a protecting group, wherein:
(a) the protecting group is selected from acyl group, carbonyl group, thiocarbonyl group, carbamoyl group, substituted or unsubstituted acetyl, substituted or unsubstituted aminoalkanoyl, substituted or unsubstituted a-aminoalkanoyl, an acyl group derived from a natural or an unnatural amino acid with or without substitution, an acyl group of a peptide residue, cycloalkane-carbonyl, heterocycloalkane-carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkoxycarbonyl, and heteroaryloxycarbonyl;
or
(b) the protecting group is R 4 W(R 5 R 6 C) m —, where m is an integer selected from 0 to 6; W is oxygen (—O—), sulfur (—S—), nitrogen (—NH—), or absent; R 5 and R 6 are independently a hydrogen or a lower alkyl group; and R 4 is
where X is oxygen (—O—), sulfur (—S—), nitrogen (—NH—), or a methylene (—CH 2 —) group; R 7 and R 8 are independently a hydrogen, a substituted or unsubstituted alkyl or cycloalkyl, an aryl or heteroaryl group without or with substitution, a PEG moiety, or an ester-forming group; or, the combination of R 7 and X is an alkyl or aryl group with or without further substitution;
Y ⊖ is a counterion;
provided that the compound of Formula III is not axitinib.
6 . The compound of claim 5 , wherein the PEG moiety is R 10 —(OCH 2 CH 2 ) n —, where n is 1 to 10, and R 10 is a hydrogen or a lower alkyl.
7 . The compound of claim 5 , wherein the ester forming group is a lower alkyl or an aryl group.
8 . A compound which is:
or a pharmaceutically-acceptable salt or ester thereof.
9 . The compound of claim 1 , wherein the compound is a prodrug of axitinib.
10 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
11 . A method for the inhibition or modulation of the activity of a tyrosine kinase in a subject, comprising administering to the subject an effective amount of the compound of claim 1 , such that the tyrosine kinase is inhibited or modulated in the subject.
12 . The method of claim 11 , wherein the subject suffers from a tumor or a cancer.
13 . The method of claim 12 , wherein the tumor or the cancer is a solid tumor.
14 . The method of claim 12 , wherein the tumor or the cancer is breast cancer, renal cell carcinoma, or thyroid cancer.
15 . The method of claim 11 , wherein the subject is a mammal.
16 . The method of claim 15 , wherein the mammal is a human.
17 . A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable carrier.
18 . A method for the inhibition or modulation of the activity of a tyrosine kinase in a subject, comprising administering to the subject an effective amount of the compound of claim 8 , such that the tyrosine kinase is inhibited or modulated in the subject.
19 . The method of claim 18 , wherein the subject suffers from a tumor or a cancer.
20 . The method of claim 18 , wherein the subject is a human.