Epothilone derivatives and their synthesis and use
The invention relates to epothilone analog represented by the formula I wherein (i) R 2 is absent or oxygen; “a” can be either a single or double bond; “b” can be either absent or a single bond; and “c” can be either absent or a single bond, with the proviso that if R 2 is oxygen then “b” and “c” are both a single bond and “a” is a single bond; if R 2 is absent then “b” and “c” are absent and “a” is a double bond; and if “a” is a double bond, then R 2 , “b” and “c” are absent; R 3 is a radical selected from the group consisting of hydrogen; lower alkyl; —CH═CH 2 ; —C≡CH; —CH 2 F; —CH 2 Cl; —CH 2 —OH; —CH 2 —O—(C 1 -C 6 -alkyl); and —CH 2 —S—(C 1 -C 6 -alkyl); R 4 and R 5 are independently selected from hydrogen, methyl or a protecting group; and R 1 is as defined in the specification, or a salt of a compound of the formula I where a salt-forming group is present. A further aspect of the invention is related to the synthesis of epothilone E. These compounds have inter alia microtubuli depolymerisation inhibiting activity and are e.g. useful against proliferative diseases.
1. A compound represented by the following structure:
wherein
the waved bond indicates that bond “a” is present either in the cis or in the trans form;
(i) R 3 is a radical selected from the group consisting of hydrogen; lower alkyl (C 1 -C 6 );
—CH═CH 2 ; —C≡CH; —CH 2 F; —CH 2 Cl; —CH 2 —OH; —CH 2 —O—(C 1 -C 6 alkyl); and —CH 2 —S—(C 1 -C 6 alkyl);
R 4 and R 5 are independently selected from the group consisting of hydrogen, methyl, and a hydroxyl protecting group; and
R 1 is a radical selected from the following structures:
(ii) and, if R 3 is —CH═CH 2 ; C≡CH; —CH 2 F; —CH 2 Cl; —CH 2 —OH;
—CH 2 —O—(C 1 -C 6 alkyl); and —CH 2 —S—(C 1 -C 6 alkyl); and the other symbols except R 1 have the same meanings given above, R 1 can also be a radical selected from the following structures:
(iii)and, if R 3 is —CH═CH 2 ; C≡CH; —CH 2 F; —CH 2 Cl; —CH 2 —OH;
—CH 2 —O—(C 1 -C 6 alkyl); and —CH 2 —S—(C 1 -C 6 alkyl); and the other symbols except R 1 have the same meanings given above under (i), R 1 can also be a moiety of the formula
or a salt thereof where one or more salt-forming groups are present.
2. A compound of the formula I according to claim 1 wherein:
(i) R 3 is a radical selected from the group consisting of hydrogen; lower alkyl (C 1 -C 6 );
—CH═CH 2 ; C≡CH; —CH 2 F; —CH 2 Cl; —CH 2 —OH; —CH 2 —O—(C 1 -C 6 alkyl); and —CH 2 —S—(C 1 -C 6 alkyl);
R 4 and R 5 are independently selected from the group consisting of hydrogen, methyl, and a protecting group; and
R 1 is a radical selected from the following structures:
or a salt thereof where one or more salt-forming groups are present.
3. A compound of the formula I according to claim 1 wherein:
(i) R 3 is a radical selected from the group consisting of hydrogen; lower alkyl (C 1 -C 6 );
—CH═CH 2 ; C≡CH; —CH 2 F; —CH 2 Cl; —CH 2 —OH; —CH 2 —O—(C 1 -C 6 alkyl); and —CH 2 —S—(C 1 -C 6 alkyl);
R 4 and R 5 are independently selected from the group consisting of hydrogen, methyl, and a protecting group; and
R 1 is a radical selected from the following structure:
or a salt thereof where one or more salt-forming groups are present.
4. A compound according to claim 1 , selected from the group consisting of a compound of the following formulae:
or a salt thereof where one or more salt-forming groups are present.
5. A compound represented by the following structure:
wherein:
A is selected from the group consisting of methoxy, methylthio and ethenyl; and
D is selected from the group consisting of fluoro, and hydroxy.