Taxol enhancer compounds

1. A compound represented by the following structural formula:

or a physiologically acceptable salt thereof, wherein:

Y″ is a covalent bond or —CH 2 —;

R 1 and R 2 are a substituted or unsubstituted phenyl group; and

R 3 and R 4 are a lower aliphatic group or a substituted lower aliphatic group.

2. The compound of claim 1 wherein R 1 and R 2 are the same and R 3 and R 4 are the same.

3. The compound of claim 2 wherein R 3 and R 4 are methyl.

4. The compound of claim 3 wherein Y″ is —CH 2 —.

5. A compound represented by the following structural formula:

or a physiologically acceptable salt thereof.

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula:

or a physiologically acceptable salt thereof, wherein:

Y″ is a covalent bond or —CH 2 —;

R 1 and R 2 are a substituted or unsubstituted phenyl group; and

R 3 and R 4 are a lower aliphatic group or a substituted lower aliphatic group.

7. The pharmaceutical composition of claim 6 wherein R 1 and R 2 are the same and R 3 and R 4 are the same.

8. The pharmaceutical composition of claim 7 wherein R 3 and R 4 are methyl.

9. The pharmaceutical composition of claim 8 wherein Y″ is —CH 2 —.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula:

or a physiologically acceptable salt thereof.

11. A method of treating a subject with cancer, said method comprising administering to the subject an effective amount of taxol or a taxol analog and an effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

Y″ is a covalent bond or —CH 2 —;

R 1 and R 2 are a substituted or unsubstituted phenyl group; and

R 3 and R 4 are a lower aliphatic group or a substituted lower aliphatic group.

12. The method of claim 11 wherein the taxol analog is represented by a structural formula selected from:

wherein:

R 10 is a lower alkyl group, a substituted lower alkyl group, a phenyl group, a substituted phenyl group, —SR 19 , —NHR 19 or —OR 19 ;

R 11 is a lower alkyl group, a substituted lower alkyl group, an aryl group or a substituted aryl group;

R 12 is —H, —OH, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, —O—C(O)-(lower alkyl), —O—C(O)-(substituted lower alkyl), —O—CH 2 —O-(lower alkyl) or S—CH 2 —O-(lower alkyl);

R 13 is —H, —CH 3 , or, taken together with R 14 , is —CH 2 —;

R 14 is —H, —OH, lower alkoxy, —O—C(O)-(lower alkyl), substituted lower alkoxy, —O—C(O)-(substituted lower alkyl), —O—CH 2 —O—P(O)(OH) 2 , —O—CH 2 —O-(lower alkyl), —O—CH 2 —S-(lower alkyl) or, taken together with R 20 , is a double bond;

R 15 —H, lower acyl, lower alkyl, substituted lower alkyl, alkoxymethyl, alkthiomethyl, —OC(O)—O(lower alkyl), —OC(O)—O(substituted lower alkyl), —OC(O)—NH(lower alkyl) or —OC(O)—NH(substituted lower alkyl);

R 16 is phenyl or substituted phenyl;

R 17 is —H, lower acyl, substituted lower acyl, lower alkyl, substituted, lower alkyl, (lower alkoxy)methyl or (lower alkyl)thiomethyl;

R 18 —H, —CH 3 or, taken together with R 17 and the carbon atoms to which R 17 and R 18 are bonded, is a five or six membered a non-aromatic heterocyclic ring;

R 19 is a lower alkyl group, a substituted lower alkyl group, a phenyl group, or a substituted phenyl group;

R 20 is —H or a halogen; and

R 21 is —H, lower alkyl, substituted lower alkyl, lower acyl or substituted lower acyl.

13. The method of claim 11 wherein:

R 10 is phenyl, tert-butoxy, —S—CH 2 —CH—(CH 3 ) 2 , —S—CH(CH 3 ) 3 , —S—(CH 2 ) 3 CH 3 , —O—CH(CH 3 ) 3 , —NH—CH(CH 3 ) 3 , —CH═C(CH 3 ) 2 or para-chlorophenyl;

R 11 is phenyl, (CH 3 ) 2 CHCH 2 —, -2-furanyl, cyclopropyl or para-toluyl;

R 12 is —H, —OH, CH 3 CO— or —(CH 2 ) 2 -N-morpholino;

R 13 is methyl, or, R 13 and R 14 , taken together, are —CH 2 —;

R 14 is —H, —CH 2 SCH 3 or —CH 2 —O—P(O)(OH) 2 ;

R 15 is CH 3 CO—;

R 16 is phenyl;

R 17 —H, or, R 17 and R 18 , taken together, are —O—CO—O—;

R 18 is —H;

R 20 is —H or —F; and

R 21 is —H, —C(O)—CHBr—(CH 2 ) 13 —CH 3 , —C(O)—(CH 2 ) 14 —CH 3 , —C(O)—CH 2 —CH(OH)—COOH, —C(O)—CH 2 —O—C(O)—CH 2 CH(NH 2 )—CONH 2 , —C(O)—CH 2 —O—CH 2 CH 2 OCH 3 or —C(O)—O—C(O)—H 2 CH 3 .

14. The method of claim 11 wherein the taxol analog is selected from:

15. The method of claim 11 wherein the taxol analog is the copolymer of N-(2-hydroxypropyl)methacrylamide, methacryloylglycine-2-hydroxypropylamide and [2aR[2α,4β,4β,6β,9α(2R,3S),11β,12α,12α,12α]]-6,12b-diacetoxy-9-[3-benzamido-2-(methacryloyl-glycyl-L-phenylalanyl-L-leucylglycyloxy)-3-phenylpropionyloxy]-12-benzoyloxy-4,11-dihydroxy-4a,8,13,13-tetramethyl-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benz[1,2-b]oxet-5-one.

16. The method of claim 11 wherein the subject is administered taxol or taxotere.

17. The method of claim 11 wherein R 1 and R 2 are the same and R 3 and R 4 are the same.

18. The method of claim 17 wherein R 3 and R 4 are methyl.

19. The method of claim 18 wherein Y″ is —CH 2 —.

20. A method of treating a subject with cancer, said method comprising administering to the subject an effective amount of taxol or a taxol analog and an effective amount of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

21. The method of claim 20 wherein the taxol analog is represented by a structural formula selected from:

R 10 is a lower alkyl group, a substituted lower alkyl group, a phenyl group, a substituted phenyl group, —SR 19 , —NHR 19 or —OR 19 ;

R 11 is a lower alkyl group, a substituted lower alkyl group, an aryl group or a substituted aryl group;

R 12 is —H, —OH, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, —O—C(O)-(lower alkyl), —O—C(O)-(substituted lower alkyl), —O—CH 2 —O-(lower alkyl) or —S—CH 2 —O-(lower alkyl);

R 13 is —H, —CH 3 , or, taken together with R 14 , is —CH 2 —;

R 14 is —H, —OH, lower alkoxy, —O—C(O)-(lower alkyl), substituted lower alkoxy, —O—C(O)-(substituted lower alkyl), —O—CH 2 —O—P(O)(OH) 2 , —O—CH 2 —O-(lower alkyl), —O—CH 2 —S-(lower alkyl) or, taken together with R 20 , is a double bond;

R 15 —H, lower acyl, lower alkyl, substituted lower alkyl, alkoxymethyl, alkthiomethyl, —OC(O)—O(lower alkyl), —OC(O)—O(substituted lower alkyl), —OC(O)—NH(lower alkyl) or —OC(O)—NH(substituted lower alkyl);

R 16 is phenyl or substituted phenyl;

R 17 is —H, lower acyl, substituted lower acyl, lower alkyl, substituted, lower alkyl, (lower alkoxy)methyl or (lower alkyl)thiomethyl;

R 18 —H, —CH 3 or, taken together with R 17 and the carbon atoms to which R 17 and R 18 are bonded, is a five or six membered a non-aromatic heterocyclic ring;

R 19 is a lower alkyl group, a substituted lower alkyl group, a phenyl group, or a substituted phenyl group;

R 20 is —H or a halogen; and

R 21 is —H, lower alkyl, substituted lower alkyl, lower acyl or substituted lower acyl.

22. The method of claim 21 wherein:

R 10 is phenyl, tert-butoxy, —S—CH 2 —CH—(CH 3 ) 2 , —S—CH(CH 3 ) 3 , —S—(CH 2 ) 3 CH 3 , —O—CH(CH 3 ) 3 , —NH—CH(CH 3 ) 3 , —CH═C(CH 3 ) 2 or para-chlorophenyl;

R 11 is phenyl, (CH 3 ) 2 CHCH 2 —, -2-furanyl, cyclopropyl or para-toluyl;

R 12 is —H, —OH, CH 3 CO— or —(CH 2 ) 2 -N-morpholino;

R 13 is methyl, or, R 13 and R 14 , taken together, are —CH 2 —;

R 14 is —H, —CH 2 SCH 3 or —CH 2 —O—P(O)(OH) 2 ;

R 15 is CH 3 CO—;

R 16 is phenyl;

R 17 —H, or, R 17 and R 18 , taken together, are —O—CO—O—;

R 18 is —H;

R 20 is —H or —F; and

R 21 is —H, —C(O)—CHBr—(CH 2 ) 13 —CH 3 , —C(O)—(CH 2 ) 14 —CH 3 , —C(O)—CH 2 —CH(OH)—COOH, —C(O)—CH 2 —O—C(O)—CH 2 CH(NH 2 )—CONH 2 , —C(O)—CH 2 —O—CH 2 CH 2 OCH 3 or —C(O)—O—C(O)—CH 2 CH 3 .

23. The method of claim 20 wherein the taxol analog is selected from:

24. The method of claim 20 wherein the subject is administered taxol or taxotere.