Epothilone analogs

1. A compound represented by the following structure (formula (I)):

wherein n is 1 to 5; either R* is —OR 1 and R** is hydrogen, or R* and R** together form a further bond so that a double bond is present between the two carbon atoms carrying R* and R**; R 1 is a radical selected from the group consisting of hydrogen or methyl, or a protecting group; R 2 is a radical selected from the group consisting of hydrogen, methylene and methyl; R 3 is a radical selected from the group consisting of hydrogen, methylene and methyl; R 4 is a radical selected from the group consisting of hydrogen or methyl, or is a protecting group; R 5 is a radical selected from the group consisting of hydrogen, methyl, —CHO, —COOH, —CO 2 Me, —CO 2 (tert-butyl), —CO 2 (iso-propyl), —CO 2 (phenyl), —CO 2 (benzyl), —CONH(furfuryl), —CO 2 (N-benzo-(2R,3S)-3-phenylisoserine), —CON(methyl) 2 , —CON (ethyl) 2 , —CONH(benzyl), —CH═CH 2 , HC≡C—, and —CH 2 R 11 ; R 11 is a radical selected from the group consisting of —OH, —O-Trityl, —O—(C 1 –C 6 alkyl), —(C 1 –C 6 alkyl), —O-benzyl, —O-allyl, —O—COCH 3 , —O—COCH 2 Cl, —O—COCH 2 CH 3 , —O—COCF 3 , —O—COCH(CH 3 ) 2 , —O—CO—C(CH 3 ) 3 , —O—CO(cyclopropane), —OCO(cyclohexane), —O—COCH═CH 12 , —O—CO-Phenyl, —O-(2-furoyl), —O-(N-benzo-(2R,3S)-3-phenylisoserine), —O-cinnamoyl, —O-(acetyl-phenyl), —O-(2-thiophenesulfonyl), —S—(C 1 –C 6 alkyl), —SH, —S-Phenyl, —S-Benzyl, —S-furfuryl, —NH 2 , —N 3 , —NHCOCH 3 , —NHCOCH 2 Cl, —NHCOCH 2 CH 3 , —NHCOCF 3 , —NHCOCH(CH 3 ) 2 , —NHCO—C(CH 3 ) 3 , —NHCO(cyclopropane), —NHCO(cyclohexane), —NHCOCH═CH 2 , —NHCO-Phenyl, —NH(2-furoyl), —NH—(N-benzo-(2R,3S)-3-phenylisoserine), —NH-(cinnamoyl), —NH-(acetyl-phenyl), —NH-(2-thiophenesulfonyl), —F, —Cl, I, —CH 2 CO 2 H and methyl; R 6 is absent, methylene, or oxygen; R 8 is a radical selected from the group represented by the formulas:

wherein R 9 is a radical selected from the group consisting of hydrogen and methyl; R 10 is a radical selected from the group represented by the formulas:

wherein R x is acyl;

or a salt thereof where a salt-forming group is present;

where, in the above structures, “a” can be either absent or a single bond; “b” can be either a single or double bond; “c” can be either absent or a single bond; “d” can be either absent or a single bond, and the following provisos pertain:

a. if R 2 is methylene, then R 3 is methylene;

b. if R 2 and R 3 are both methylene, then “a” is a single bond;

c. if R 2 and R 3 are selected from the group consisting of hydrogen and methyl, then the single bond “a” is absent;

d. if n is 3, R 2 is methyl, R 3 is methyl, R 5 is selected from the group consisting of methyl and hydrogen, R 6 is oxygen, R 8 is represented by the formula:

wherein R 9 is hydrogen, and R 10 is represented by the formula

then R 1 and R 4 cannot both be simultaneously hydrogen or methyl or acetyl;

e. if R 6 is oxygen, then “c” and “d” are both a single bond and “b” is a single bond;

f. if R 6 is absent, then “c” and “d” are absent and “b” is a double bond; and

g. if “b” is a double bond then R 6 , “c”, and “d” are absent.

2. A compound of the formula I according to claim 1 , wherein n, a, b, c, d, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the meanings given in claim 1 , or a salt thereof where a salt-forming group is present, with the exception of a compound of the formula I

wherein

n is 3;

R 1 is hydrogen, methyl, acetyl, benzoyl, trialkyl silyl or benzyl;

R 2 is methyl;

R 3 is methyl;

R 4 is hydrogen, methyl, acetyl, benzoyl, trialkyl silyl or benzyl;

R 5 is hydrogen or methyl;

R 6 is O or

R 6 is absent and a is a double bond;

R 8 is a radical of the formula

wherein

R 9 is a radical selected from the group consisting of hydrogen and methyl; and

R 10 is a radical represented by the formula:

3. A compound according to claim 1 , represented by formula II,

wherein n is one to five,

R 1 is a radical selected from the group consisting of hydrogen, methyl or a protecting group,

R 4 is a radical selected from the group consisting of hydrogen, methyl or a protecting group,

R 5 is a radical selected from the group consisting of hydrogen, methyl, —CHO, —COOH, CO 2 Me, —CO 2 (tert-butyl), —CO 2 (iso-propyl), —CO 2 (phenyl), —CO 2 (benzyl), —CONH(furfuryl), CO 2 (N-benzo-(2R,3S)-3-phenylisoserine), —CON(methyl) 2 , —CON(ethyl) 2 , —CONH(benzyl, —CH 2 R 11 , —CH═CH 2 and; where R 11 is a radical selected from the group consisting of —OH, —O-Trityl, —O—(C 1 –C 6 alkyl), —O-benzyl, —O-allyl, —O—COCH 3 , —O—COCH 2 Cl, —O—COCH 2 CH 3 , —O—COCF 3 , —O—COCH(CH 3 ) 2 , —O—CO—C(CH 3 ) 3 , —O—CO(cycloprane), —OCO(cyclohexane), —O—COCH═CH 2 , —O—CO-phenyl, —O-(2-furoyl), —O—(N-benzo-(2R,3S)-3-phenylisoserine), —O-cinnamoyl, —O-(acetyl-phenyl), —O-(2-thiophenesulfonyl), —S—(C 1 –C 6 alkyl), —SH, —S-Phenyl, —S-Benzyl, —S-furfuryl, —NH 2 , —N 3 , —NHCOCH 3 , —NHCOCH 2 Cl, —NHCOCH 2 CH 3 , —NHCOCF 3 , —NHCOCH(CH 3 ) 2 , —NHCO—C(CH 3 ) 3 , —NHCO(cyclopropane), —NHCO(cyclohexane), —NHCOCH═CH 2 , —NHCO-phenyl, —NH(2-furoyl), —NH—(N-benzo-(2R,3S)-3-phenylisoserine), —NH-(cinnamoyl), —NH-(acetyl-phenyl), —NH-(2-thiophenesulfonyl), —F, —Cl, I, CH 2 CO 2 ,H, —(C 1 –C 6 alkyl) and methyl;

and R 10 is a radical selected from the group represented by the formulae:

wherein R x is acyl;

with the proviso that if R 5 is either methyl or hydrogen and R 10 is represented by the following formula:

then R 1 and R 4 cannot simultaneously be hydrogen or methyl or acetyl.

4. A compound of the formula II according to claim 3 , wherein the compound has the formula IIa

wherein n is 3 and R 1 , R 4 , R 5 and R 10 are as defined in claim 3 , or a salt thereof where a salt-forming group is present.

5. A compound according to claim 3 of the formula

wherein R 10 is as defined in claim 3 and R 5 is —CH 2 F, —CH 2 Cl, CH 2 OOCCH 3 , —CH 2 CH 3 or —CH═CH 2 .

6. A compound of the formula

wherein R 5 is —CH 2 F, —CH 2 Cl, CH 2 OOCCH3, —CH 2 CH 3 or —CH═CH 2 .

7. A compound according to claim 1 of the formula III,

wherein n preferably is one to five;

R 1 is a radical selected from the group consisting of hydrogen, methyl or a protecting group,

R 4 is a radical selected from the group consisting of hydrogen, methyl or a protecting group,

R 5 is a radical selected from the group consisting of hydrogen, methyl, —CHO, —COOH, CO 2 Me, —CO 2 (tert-butyl), —CO 2 (iso-propyl), —CO 2 (phenyl), —CO 2 (benzyl), —CONH(furfuryl), CO 2 (N-benzo-(2R,3S)-3-phenylisoserine), —CON(methyl) 2 , —CON(ethyl) 2 , —CONH(benzyl), and —CH 2 R 11 ,; or in a broader aspect also from —CH═CH 2 and; where R 11 is a radical selected from the group consisting of —OH, —O-Trityl, —O—(C 1 –C 6 alkyl), —O-benzyl, —O-allyl, —O—COCH 3 , —O—COCH 2 Cl, —O—COCH 2 CH 3 , —O—COCF 3 , —O—COCH(CH 3 ) 2 , —O—CO—C(CH 3 ) 3 , —O—CO(cycloprane), —OCO(cyclohexane), —O—COCH═CH 2 , —O—CO-phenyl, —O-(2-furoyl), —O—(N-benzo-(2R,3S)-3-phenylisoserine), —O-cinnamoyl, —O-(acetyl-phenyl), —O-(2-thiophenesulfonyl), —S—(C 1 –C 6 alkyl), —SH, —S-Phenyl, —S-Benzyl, —S-furfuryl, —NH 2 , —N 3 , —NHCOCH 3 , —NHCOCH 2 Cl, —NHCOCH 2 CH 3 , —NHCOCF 3 , —NHCOCH(CH 3 ) 2 , —NHCO—C(CH 3 ) 3 , —NHCO(cyclopropane), —NHCO(cyclohexane), —NHCOCH═CH 2 , —NHCO-phenyl, —NH(2-furoyl), —NH—(N-benzo-(2R,3S)-3-phenylisoserine), —NH-(cinnamoyl), —NH-(acetyl-phenyl), —NH-(2-thiophenesulfonyl), —F, —Cl, —I, CH 2 CO 2 ,H;

and from —(C 1 –C 6 alkyl) and methyl; and

and R 10 is a radical selected from the group represented by the formulae:

wherein R x is acyl;

with the proviso that if R 5 is either methyl or hydrogen and R 10 is represented by the following formula:

then R 1 and R 4 cannot simultaneously be hydrogen or methyl or acetyl;

or a salt thereof if a salt-froming group is present.

8. A compound of formula III according to claim 7 wherein R 5 is —CH 2 F, —CH 2 Cl, CH 2 OOCCH 3 , —CH 2 CH 3 or —CH═CH 2 the double bond with the wavered line is in cis form and the remaining moieties are as defined in claim 7 .

9. A compound according to claim 1 of the formula IV

wherein R 1 is a radical selected from the group consisting of hydrogen, methyl or a protecting group, R 4 is a radical selected from the group consisting of hydrogen, methyl or a protecting group, R 5 is a radical selected from the group consisting of hydrogen and methyl, R 10 is a radical selected from the group represented by the formulae:

wherein R x is acyl;

R 3 is a radical selected from hydrogen and methyl;

R 2 is hydrogen and methyl; and R 9 is hydrogen or methyl;

with the following provisos that

if R 3 and R 2 are hydrogen or methyl, then the single bond “a” is absent; and if R 5 is methyl or hydrogen and R 10 is represented by the formula

then R 1 and R 4 cannot simultaneously be hydrogen or methyl or acetyl;

or a salt thereof if a salt-froming group is present.

10. A compound according to claim 1 of the formula V

wherein

R 1 is a radical selected from the group consisting of hydrogen, methyl or a protecting group,

R 4 is a radical selected from the group consisting of hydrogen, methyl or a protecting group,

R 5 is a radical selected from the group consisting of hydrogen and methyl,

R 10 is a radical selected from the group represented by the formulae:

wherein R x is acyl;

R 3 is a radical selected from hydrogen, methylene or methyl;

R 2 is hydrogen, methylene or methyl; and R 9 is hydrogen or methyl;

with the following provisos that

if R 3 is methylene, then R 2 is methylene; if R 3 and R 2 are methylene, then R 3 and R 2 are chemically bonded to each other through a single bond “a”; if R 3 and R 2 are hydrogen or methyl, then the single bond “a” is absent; and if R 5 is methyl or hydrogen and R 10 is represented by the formula

then R 1 and R 4 cannot simultaneously be hydrogen or methyl or acetyl.

11. A compound according to claim 5 of the formula.