IP Library › Granted Patent US 7,648,994

Granted Patent B2

US 7,648,994 · App. 12/044,817 · Granted Jan 19, 2010

Heterocyclic cyclopamine analogs and methods of use thereof

Assignee: Infinity Discovery, Inc.

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Quick Facts

Patent No.: US 7,648,994
App. No.: 12/044,817
Granted: Jan 19, 2010
Kind: B2

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Abstract

The present invention relates to steroidal alkaloids that can be used in the treatment of hedgehog pathway related disorders, particularly cancer.

Claims (103)

1. A compound of Formula 1a or 1b:

or a tautomer, or pharmaceutically acceptable salt thereof;

wherein;

R 1 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —SR 20 , —OR 20 , —C(O)R 20 , —CO 2 R 20 , —OC(O)R 20 , —C(O)N(R 20 )(R 20 ), —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 )(R 20 ), —[(W)—C(O)] p R 20 , —[(W)—C(O)O] p R 20 , —[(W)—OC(O)] p R 20 , —[(W)—SO 2 ] p R 20 , —[(W)—N(R 20 )SO 2 ] p R 20 , —[(W)—C(O)N(R 20 )] p R 20 , —[(W)—O] p R 20 , —[(W)—N(R 20 )] p R 20 , or —[(W)—S] p R 20 ;

each of R 2 , R 6 and R 9 is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, nitrile, alkoxyl, aryloxy, acyloxy, halide, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, alkylseleno, aralkylseleno, arylseleno, alkylthio, aralkylthio, or arylthio;

R 3 is H; or R 2 and R 3 taken together form a bond;

each of R 4 and R 5 independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, nitrile, aralkyl, alkoxyl, aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, alkylamino, arylamino, acylamino, aralkylamino, heteroaryl, or heteroaralkyl; or R 4 and R 5 taken together form ═O, ═S, ═N(R 20 ), ═N—OR 20 , or ═N(N(R 20 ) 2 );

each of R 7 and R 8 independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or aralkyl; or R 6 and R 7 taken together form a bond; or R 8 and R 9 taken together form a bond;

each of R 10 and R 11 independently is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, or aralkyl; or R 9 and R 10 taken together form a bond; or R 10 and R 11 taken together form a bond;

R 20 independently for each occurrence is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or —[C(R) 2 ] q —R 21 ; or any two occurrences of R 20 can be taken together to form a 4-8 membered optionally substituted ring which contains 0-3 heteroatoms selected from N, O, S, and P;

R 21 independently for each occurrence is H, cycloalkyl, aryl, heteroaryl, heterocyclyl; alkoxyl, aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, acylamino, amido, or carbonyl-containing group;

R 22 independently for each occurrence is H, halide, ester, amide, or nitrile;

R 23 independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, perhaloalkyl, halide, nitro, nitrile, ═O, —SR 20 , —OR 20 —N(R 20 )(R 20 ), —C(O)R 20 , —CO 2 R 20 , —OC(O)R 20 , —C(O)N(R 20 )(R 20 ), —N(R 20 )C(O)R 20 , —N(R 20 )C(O)N(R 20 )(R 20 ), —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 )(R 20 ), —N(R 20 )S(O) 2 R 20 , or —[C(R) 2 ] q —R 21 ;

R 24 independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, perhaloalkyl, halide, nitro, nitrile, —SR 20 , —OR 20 , —N(R 20 )(R 20 ), —C(O)R 20 , —CO 2 R 20 , —OC(O)R 20 , —C(O)N(R 20 )(R 20 ), —N(R 20 )C(O)R 20 , —N(R 20 )C(O)N(R 20 )(R 20 ), —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 )(R 20 ), —N(R 20 )S(O) 2 R 20 , or —[C(R 20 ) 2 ] q —R 21 ;

p is 0, 1, 2, 3, 4, 5, or 6;

q is 0, 1, 2, 3, 4, 5, or 6;

R independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;

-T 1 -T 2 -T 3 - is Y—B-A, B—Y-A, or A-B—Y;

each of A and B independently is N, S or C(R 23 );

W is a diradical;

X is a bond or —C(R 22 ) 2 —;

Y is —O—, —S—, or —N(R 24 )—;

and each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, whether alone or part of another group, is optionally substituted.

2. The compound of claim 1 , wherein R 6 , R 7 , R 8 , R 9 , R 10 , R 11 are each independently H or alkyl.

3. The compound of claim 1 , wherein R 2 and R 3 taken together form a bond.

4. The compound of claim 1 , wherein R 4 and R 5 are each H; or R 4 and R 5 taken together form ═O or ═S.

5. The compound of claim 1 , wherein Y is —O— or —N(R 24 )—.

6. The compound of claim 1 , wherein -T 1 -T 2 -T 3 - is A-B—Y, A is CR 23 , B is N and Y is NR 24 ; or -T 1 -T 2 -T 3 - is B—Y-A, A is N, B is CR 23 and Y is NR 24 .

7. A compound of formula 6a:

or a tautomer, or pharmaceutically acceptable salt thereof

wherein;

R 21 independently for each occurrence is H, cycloalkyl, aryl, heteroaryl, heterocycyl; alkoxyl, aryloxy, acyloxy, halide, sulfhydryl, alkylthio, arylthio, aralkylthio, hydroxyl, amino, acylamino, amido, or carbonyl-containing group;

R 22 independently for each occurrence is H, halide, ester, amide, or nitrile;

R 23 independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, perhaloalkyl, halide, nitro, nitrile, ═O, —SR 20 , —OR 20 —N(R 20 )(R 20 ), —C(O)R 20 , —CO 2 R 20 , —OC(O)R 20 , —C(O)N(R 20 )(R 20 ), —N(R 20 )C(O)R 20 ,—N(R 20 )C(O)N(R 20 )(R 20 ), —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 )(R 20 ), —N(R 20 )S(O) 2 R 20 , or —[C(R) 2 ] q —R 21 ;

p is 0, 1, 2, 3, 4, 5, or 6;

q is 0, 1, 2, 3, 4, 5, or 6;

R independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;

-T 1 -T 2 -T 3 - is Y—B-A, B—Y-A, or A-B—Y;

each of A and B independently is N, S or C(R 23 );

W is a diradical;

X is a bond or —C(R 22 ) 2 —;

Y is —O—, —S—, or —N(R 24 )—;

and each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, whether alone or part of another group, is optionally substituted.

8. The compound of claim 7 , wherein X is a bond or —CH 2 —.

9. The compound of claim 7 , wherein Y is —O— or —N(R 24 )—.

10. The compound of claim 7 , wherein -T 1 -T 2 -T 3 - is A-B—Y, A is CR 23 , B is N and Y is NR 24 ; or-T 1 -T 2 -T 3 - is B—Y-A, A is N, B is CR 23 and Y is NR 24 .

11. The compound of claim 10 , wherein R 24 is H, alkyl, or —S(O) 2 R 20 .

12. The compound of claim 7 , wherein R 1 is H, alkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, —OR 20 , —C(O)R 20 , —CO 2 R 20 , —C(O)N(R 20 )(R 20 ), —S(O) 2 R 20 , —S(O) 2 N(R 20 )(R 20 ), —[(W)—C(O)] p R 20 , —[(W)—C(O)O] p R 20 , —[(W)—OC(O)] p R 20 , —[(W)—SO 2 ] p R 20 , —[(W)—N(R 20 )SO 2 ] p R 20 , —[(W)—C(O)N(R 20 )] p R 20 , —[(W)—O] p R 20 , —[(W)—N(R 20 )] p R 20 , or —[(W)—S] p R 20 .

13. A compound of formula 11b:

or a tautomer, or pharmaceutically acceptable salt thereof

wherein;

R 22 independently for each occurrence is H, halide, ester, amide, or nitrile;

p is 0, 1, 2, 3, 4, 5, or 6;

q is 0, 1, 2, 3, 4, 5, or 6;

R independently for each occurrence is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;

-T 1 -T 2 -T 3 - is Y—B-A, B—Y-A, or A-B—Y;

each of A and B independently is N, S or C(R 23 );

W is a diradical;

X is a bond or —C(R 22 ) 2 —;

Y is —O—, —S—, or —N(R 24 )—;

and each alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, whether alone or part of another group, is optionally substituted.

14. The compound of claim 13 , wherein X is a bond or —CH 2 —.

15. The compound of claim 13 , wherein Y is —O— or —N(R 24 )—.

16. The compound of claim 13 , wherein -T 1 -T 2 -T 3 - is A-B—Y, A is CR 23 , B is N and Y is NR 24 ; or-T 1 -T 2 -T 3 - is B—Y-A , A is CR 23 and Y is NR 24 .

17. The compound of claim 16 , wherein R 24 is H, alkyl, or —S(O) 2 R 20 .

18. The compound of claim 13 , wherein R 1 is H, alkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, —OR 20 , —C(O)R 20 , —CO 2 R 20 , —C(O)N(R 20 )(R 20 ), —S(O) 2 R 20 , —S(O) 2 N(R 20 )(R 20 ), —[(W)—C(O)] p R 20 , —[(W)—C(O)O] p R 20 , —[(W)—OC(O)] p R 20 , —[(W)—SO 2 ] p R 20 , —[(W)—N(R 20 )SO 2 ] p R 20 , —[(W)—C(O)N(R 20 )] p R 20 , —[(W)—O] p R 20 , —[(W)—N(R 20 )] p R 20 , or —[(W)—S] p R 20 .

19. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound of claim 1 , or a tautomer or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

21. The compound of claim 1 , wherein X is a bond or —CH 2 —.

22. The compound of claim 1 , wherein X is —CH 2 —.

23. The compound of claim 1 , wherein R 4 and R 5 are each H.

24. The compound of claim 1 , wherein R 1 is H, alkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, —OR 20 , —C(O)R 20 , —CO 2 R 20 , —C(O)N(R 20 )(R 20 ), —S(O) 2 R 20 , —S(O) 2 N(R 20 )(R 20 ), —[(W)—C(O)] p R 20 , —[(W)—C(O)O] p R 20 , —[(W)—OC(O)] p R 20 , —[(W)—SO 2 ] p R 20 , [(W)—N(R 20 )SO 2 ] p R 20 , —[(W)—C(O)N(R 20 )] p R 20 , —[(W)—O] p R 20 , —[(W)—N(R 20 )] p R 20 , or —[(W)—S] p R 20 .

25. The compound of claim 1 , wherein R 1 is H, alkyl, hydroxyl, —C(O)R 20 , —CO 2 R 20 or —S(O) 2 R 20 .

26. The compound of claim 1 , wherein R 6 , R 8 , R 9 , R 10 , and R 11 are each H.

27. The compound of claim 1 , wherein Y is —N(R 24 )—.

28. The compound of claim 1 , wherein -T 1 -T 2 -T 3 - is B—Y-A, A is CR 23 , B is N and Y is NR 24 ; or -T 1 -T 2 -T 3 - is B—Y-A, A is N, B is CR 23 and Y is O; or -T 1 -T 2 -T 3 - is Y—B-A, A is N, B is CR 23 and Y is S.

29. The compound of claim 28 , wherein R 24 is H, alkyl, or —S(O) 2 R 20 .

30. The compound of claim 6 , wherein R 24 is H, alkyl, or —S(O) 2 R 20 .

31. The compound of claim 7 , wherein X is —CH 2 —.

32. The compound of claim 7 , wherein R 4 and R 5 are each H.

33. The compound of claim 7 , wherein R 1 is H, alkyl, hydroxyl, —C(O)R 20 , —CO 2 R 20 or —S(O) 2 R 20 .

34. The compound of claim 7 , wherein Y is —N(R 24 )—.

35. The compound of claim 7 , wherein -T 1 -T 2 -T 3 - is B—Y-A, A is CR 23 , B is N and Y is NR 24 ; or -T 1 -T 2 -T 3 - is B—Y-A, A is N, B is CR 23 and Y is O; or -T 1 -T 2 -T 3 - is Y—B-A, A is N, B is CR 23 and Y is S.

36. The compound of claim 35 , wherein R 24 is H, alkyl, or —S(O) 2 R 20 .

37. A pharmaceutical composition comprising a compound of claim 7 , or a tautomer or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

38. The compound of claim 13 , wherein X is —CH 2 —.

39. The compound of claim 13 , wherein R 4 and R 5 are each H.

40. The compound of claim 13 , wherein R 1 is H, alkyl, hydroxyl, —C(O)R 20 , —CO 2 R 20 or —S(O) 2 R 20 .

41. The compound of claim 13 , wherein Y is —N(R 24 )—.

42. The compound of claim 13 , wherein -T 1 -T 2 -T 3 - is B—Y-A, A is CR 23 , B is N and Y is NR 24 ; or -T 1 -T 2 -T 3 - is B—Y-A, A is N, B is CR 23 and Y is O; or -T 1 -T 2 -T 3 - is Y—B-A, A is N, B is CR 23 and Y is S.

43. The compound of claim 42 , wherein R 24 is H, alkyl, or —S(O) 2 R 20 .

44. A pharmaceutical composition comprising a compound of claim 13 , or a tautomer or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 8, 2020

From: INFINITY PHARMACEUTICALS, INC.

To: ROYALTY SECURITY, LLC

Reel/Frame 051519/0511 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 5, 2008

From: CASTRO, ALFREDO C.; GROGAN, MICHAEL J.; TREMBLAY, MARTIN

To: INFINITY DISCOVERY, INC.

Reel/Frame 021342/0688 →

Continuity (2)

Provisional Application 6089359500 · Mar 7, 2007

Related Publication 20080293755A1 · Nov 27, 2008