Discodermolide analogues and methods of their use
View Patent ↗6- and 7-substituted coumarin and related 6- and 7-substituted 1H-quinolin-2-one compounds, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the 7-substituted coumarin and related 7-substituted 1H-quinolin-2-one compounds mimic or exceed the high level of pharmacological activity of discodermolide. In other embodiments, their preparation involves more readily available materials, higher yield processes and/or simpler synthetic sequences. In yet other embodiments, the compounds of the invention represent structurally simpler, therapeutically active analogues of discodermolide than heretofore known and may be useful as microtubule stabilizers and, inter alia, for treating and/or preventing cancer and other diseases, disorders, and/or conditions mediated by the stabilization of microtubules.
1. A compound of formula I or Ia:
wherein:
represents the presence of a single bond or double bond;
R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 11 are each independently H or C 1-10 alkyl;
R 4 and R 9 are each independently H or acid labile protecting group;
R 5 is C 2-6 monoalkenyl or C 4-6 alkadienyl;
R 10 is H, C(═O)NR 13 R 14 , or oxidatively labile hydroxyl protecting group;
Q is —O—;
Z is —CH— or —CH 2 —, provided that when represents a double bond, then Z is —CH—;
R 12 is H, alkyl, or acid labile amino protecting group;
R 13 and R 14 are each independently H, C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR c , C(═O)R b , S(O) p R b , (CH 2 ) r C 3-12 carbocycle, or (CH 2 ) r heterocycle having 5 to 12 ring atoms; or R 13 and R 14 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle containing 0-3 additional heteroatoms selected from O, S, and N;
R b and R c are each independently H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, or (CH 2 ) r phenyl;
p is 1 or 2; and
each r is independently 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.
2. The compound or its pharmaceutically acceptable salt of claim 1 having formula I.
3. The compound or its pharmaceutically acceptable salt of claim 2 , wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 11 are each independently H or C 1-3 alkyl.
4. The compound or its pharmaceutically acceptable salt of claim 2 , wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , and R 11 are each independently H or methyl.
5. The compound or its pharmaceutically acceptable salt of claim 2 , wherein at least one of R 4 and R 9 is H.
6. The compound or its pharmaceutically acceptable salt of claim 5 , wherein R 4 and R 9 are each H.
7. The compound or its pharmaceutically acceptable salt of claim 2 , wherein R 5 is C 2-4 -monoalkenyl or 1,3-butadien-1-yl.
8. The compound or its pharmaceutically acceptable salt of claim 2 , wherein R 5 is
9. The compound or its pharmaceutically acceptable salt of claim 2 , wherein R 10 is —C(═O)NR 13 R 14 or oxidatively labile hydroxyl protecting group.
10. The compound or its pharmaceutically acceptable salt of claim 2 or, wherein R 10 is —C(═O)NR 13 R 14 .
11. The compound or its pharmaceutically acceptable salt of claim 1 , wherein represents the presence of a carbon-carbon double bond.
12. The compound or its pharmaceutically acceptable salt of claim 10 , wherein at least one of R 13 and R 14 is H.
13. The compound or its pharmaceutically acceptable salt of claim 10 , wherein R 13 and R 14 are each H.
14. The compound or its pharmaceutically acceptable salt of claim 4 , wherein R 4 and R 9 are each H.
15. The compound or its pharmaceutically acceptable salt of claim 1 , having the structure:
16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
17. A method for stabilizing microtubules, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to claim 15 or a pharmaceutically acceptable salt thereof.
19. A method for stabilizing microtubules, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 15 or a pharmaceutically acceptable salt thereof.