Macrocyclic compounds useful as inhibitors of kinases and HSP90
View Patent ↗Disclosed are macrocyclic compounds of formulae I-V, which are analogs of the pochonin resorcylic acid lactones, and processes for the preparation of the compounds. The compounds disclosed are useful as inhibitors of kinases and Heat Shock Protein 90 (HSP 90). Also disclosed are pharmaceutical compositions comprising an effective kinase-inhibiting amount or an effective HSP90-inhibiting amount of the compounds and methods for the treatment of disorders that are mediated by kinases and HSP90.
1. A compound of formula 1, tautomers thereof, or a pharmaceutically acceptable salt, solvate, or ester thereof:
wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are independently hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, alkenyl, alkynyl, alkylaryl, aralkyl, aryl, heteroalkyl, alkylheteroaryl, heterocyclyl, heteroaryl, OH, OR, NH 2 , N(R) 2 , SR, S(O)R, S(O) 2 R, —SO 2 N(R) 2 , —N(R)SO 2 R, —N(CO)R, —N(CO)N(R) 2 , —N(CO)OR, —O(CO)R, —(CO)R, —(CO)OR, —(CO)N(R) 2 , —O(CO)OR, or —O(CO)N(R) 2 , wherein each R can be the same or different;
when B 1 and B 2 together are —CH 2 —CH 2 —, then A 1 and A 2 together are —CH 2 —CH 2 —, or —CH═CH—; or when B 1 and B 2 together represent a covalent bond, then A 1 and A 2 together are —CH 2 —CH 2 —, —CH═CH—, —CH(OH)—CH(OH)—, —CH(OH)—CH(halogen)- , —CH(halogen)-CH(OH)—, 1,2-cyclopropadiyl;
X 1 is hydrogen, halogen, OH, OR, NH 2 , N(R) 2 , NH—OR, SR, S(O)R, S(O) 2 R, —NH—O—(CH 2 ) n —CO 2 —R, —NH—O—(CH 2 ) n —CON(R) 2 ; or X 1 together with X 2 or X 3 represents a covalent bond, wherein each R can be the same or different;
X 2 and X 3 are both hydrogen, or one of X 2 and X 3 is hydrogen and the other together with X 1 represents a covalent bond;
X 4 and X 5 together are ═N—OR, ═N—O—(CH 2 ) n COOR, ═N—O—(CH 2 ) n CON(R) 2 , =N—N(R) 2 , ═N—N—SOR or ═N—N—SO 2 R; or one of X 4 and X 5 is hydrogen and the other is OH, OR, O(CO)R, O(CO)OR, O(CO)N(R) 2 , —(CH 2 ) n C(O)OR, or —(CH 2 )C(O)N(R) 2 , and n is 0, 1, 2, or 3; or one of X 4 and X 5 together with X 6 represents a covalent bond and the other of X 4 and X 5 is OH, OR, O(CO)R, O(CO)OR, —N(R) 2 or O(CO)N(R) 2 , wherein each R can be the same or different;
X 6 is hydrogen or X 6 together with one of X 4 and X 5 represents a covalent bond; and
R is hydrogen, alkyl, acyl, aryl, alkaryl, arylalkyl including benzyl, heteroalkyl, heteroaryl, heterocyclyl, a protecting group; or two R on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclic or heteroaryl ring; and
n is 0, 1, 2 or 3.
2. The compound of claim 1 , wherein the compound has the structure of formula II:
wherein, R 7 is ═N—OR, ═N—O—(CH 2 ) n COOR, ═N—O—(CH 2 ) n CON(R) 2 , ═N—N(R) 2 , ═N—N—SOR or ═N—N—SO 2 R; and wherein each R can be the same or different.
3. The compound of claim 2 , wherein R 1 is H, halogen or heterocyclyl.
4. The compound of claim 2 , wherein R 5 is hydrogen, alkyl, aryl, heteroaryl or arylalkyl.
5. The compound of claim 2 , wherein A 1 and A 2 together are —CH═CH—.
6. The compound of claim 2 , wherein A 1 and A 2 together are —CH(OH)—CH(OH)—, —CH(OH)—CH(halogen)- or —CH(halogen)- CH(OH)—.
7. The compound of claim 2 , wherein:
R 1 is H, Cl or heterocyclyl;
R 2 and R 4 are independently OH or OR;
R 5 is hydrogen, alkyl, aryl or aralkyl;
A 1 and A 2 together are —CH═CH— or —C(OH)—C(OH)—;
X 1 is hydrogen, halogen or NH—OR; and
R 7 is ═N—OR, ═N—O—(CH 2 ) n COOR, ═N—O—(CH 2 ) n CON(R) 2 , ═N—N(R) 2 , ═N—N—SOR, ═N—N—SO 2 R.
8. The compound of claim 2 , wherein:
R 1 is H, Cl or heterocyclyl;
R 2 and R 4 are independently OH or OR;
R 5 is hydrogen, alkyl, aryl or aralkyl;
A 1 and A 2 together are 1,2-oxirane;
X 1 is hydrogen, halogen or NH—OR; and
R 7 is ═N—OR, ═N—O—(CH 2 ) n COOR, ═N—O—(CH 2 ) n CON(R) 2 , ═N—N(R) 2 , ═N—N—SOR, ═N—N—SO 2 R.
9. The compound of claim 2 , wherein:
R 1 is H, Cl or heterocyclyl;
R 2 and R 4 are independently OH or OR;
R 5 is hydrogen, alkyl, aryl or aralkyl;
A 1 and A 2 together are —CH═CH— or —C(OH)—C(OH)—;
X 1 together with X 2 represent a bond; and
R 7 is ═N—OR, ═N—O—(CH 2 ) n COOR, ═N—O—(CH 2 ) n CON(R) 2 , ═N—N(R) 2 , ═N—N—SOR, ═N—N—SO 2 R.
10. The compound of claim 2 , wherein:
R 1 is Cl or heterocyclyl;
R 2 and R 4 are independently OH or OR;
R 5 is hydrogen, alkyl, aryl or aralkyl;
A 1 and A 2 together are 1,2-oxirane;
X 1 together with X 2 represent a bond; and
R 7 is ═N—OR, ═N—O—(CH 2 ) n COOR, ═N—O—(CH 2 ) n CON(R) 2 , ═N—N(R) 2 , ═N—N—SOR, ═N—N—SO 2 R.
11. The compound of claim 9 , wherein:
R 1 is H or Cl;
R 5 is hydrogen, methyl, propyl, isopropyl or phenyl; and
R 7 is ═N—OR, ═N—O—(CH 2 ) n COOR, or ═N—O—(CH 2 ) n CON(R) 2 .
12. The compound of claim 11 , wherein R 1 is Cl and R 5 is hydrogen.
13. The compound of claim 11 , wherein R 7 is ═N—O—(CH 2 ) n COOR, or ═N—O—(CH 2 ) n CON(R) 2 ; and n is 1.
14. The compound of claim 11 , wherein R 5 is hydrogen and R 7 is ═N—O—(CH 2 ) n COOR, or ═N—O—(CH 2 ) n CON(R) 2 .
15. The compound of claim 11 , wherein R 5 is hydrogen and R 7 is ═N—OR.
16. The compound of claim 7 , wherein R 7 is ═N—OR, ═N—O—(CH 2 ) n COOR, or ═N—O—(CH 2 ) n CON(R) 2 .
17. The compound of claim 10 , wherein R 7 is ═N—OR, ═N—O—(CH 2 ) n COOR, or ═N—O—(CH 2 ) n CON(R) 2 .
18. The compound of claim 1 , wherein the compound has the formula IV:
wherein R 6 is hydrogen, or N(R) 2 .
19. The compound of claim 18 , wherein R 1 is H, halogen or heterocyclyl.
20. The compound of claim 18 , wherein R 5 is hydrogen, alkyl, aryl, heteroaryl or arylalkyl.
21. The compound of claim 18 , wherein A 1 and A 2 together are —CH═CH—.
22. The compound of claim 1 , wherein the compound has the formula V:
wherein R 6 is (CH 2 ) n C(O)OR, or —(CH 2 ) n C(O)N(R) 2 ; and
n is 0, 1, 2 or 3.
23. The compound of claim 22 , wherein R 6 is —CH 2 C(O)N(Me)OMe.
24. The compound of claim 22 , wherein R 1 is H, halogen or heterocyclyl.
25. The compound of claim 22 , wherein R 5 is hydrogen, alkyl, aryl, heteroaryl or arylalkyl.
26. The compound of claim 22 , wherein A 1 and A 2 together are —CH═CH—.
27. The compound of claim 22 , wherein A 1 and A 2 together are —CH(OH)—CH(OH)—, —CH(OH)—CH(halogen)- or —CH(halogen)-CH(OH)—.
28. The compound of claim 22 , wherein A 1 and A 2 together are 1,2-oxirane.
29. The compound of claim 1 , wherein the compound is selected from the group consisting of
30. A pharmaceutical composition comprising an effective kinase-inhibiting amount of a compound of any of claim 1 , 2 , 18 , 22 or 29 in combination with a pharmaceutically acceptable carrier.
31. A pharmaceutical composition comprising an effective HSP 90-inhibiting amount of a compound of any of claim 1 , 2 , 18 , 22 or 29 in combination with a pharmaceutically acceptable carrier.
32. The composition of claim 31 , wherein the composition comprises particles that are less than about 2 microns average particle size.
33. The composition of claim 31 , wherein the composition is incorporated into a biodegradable or non-biodegradable polymer.
34. The composition of claim 31 , further comprising an additive.
35. The composition of claim 34 , wherein the additive is selected from an anti-oxidant, a buffer, a bacteriostat, a liquid carrier, a solute, a suspending agent, a thickening agent, a flavoring agent, a gelatin, glycerin, a binder, a lubricant, an inert diluent, a preservative, a surface active agent, a dispersing agent, a biodegradable polymer, or any combination thereof.
36. The composition of claim 31 , wherein the carrier is suitable for oral, parenteral, inhalation, topical, or intradermal administration.