IP Library › Granted Patent US 6,936,714

Granted Patent B2

US 6,936,714 · App. 10/728,580 · Granted Aug 30, 2005

Compounds of the saframycin-ecteinascidin series, uses, and synthesis thereof

Assignee: The Trustees of Columbia University in the City of New York

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Patent No.: US 6,936,714
App. No.: 10/728,580
Granted: Aug 30, 2005
Kind: B2

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Abstract

Compounds of the saframycin-ecteinascidin series with cytotoxic properties having the following general formula, their uses and synthesis, are disclosed: wherein R 1 and R 4 is H, a C 1 to C 4 alkyl group, or an acyl group; wherein R 2 is an ether, ester, amide, or a phthalimide group; wherein R 3 is ═O, OH, an ether group, an acyl group such as OC(O)Me, OC(O)Bn and OC(O)Et, or a sulfide group; wherein R 5 is H, halogen, OH, an ether group, an acyl group, or an amide group; wherein R 6 is ═O, OH, OCH 3 , CN, or an acyloxy group; wherein R 7 , is ═O, OH, halogen, an ether group, or an acyl group; wherein R 8 and R 9 are independently H, CH 3 , OCH 3 , OC 2 H 5 , CF 3 , halogen such as Br and F, or R 8 and R 9 are joined together as a methylenedioxy group, or other five or six membered ring; wherein R 10 and R 11 are independently CH 3 , OCH 3 , OC 2 H 5 , SCH 3 , or SC 2 H 5 ; wherein R 12 is H, a C 1 to C 4 alkyl group, or an acyl group; and wherein the chiral center marked * has the R or the S configuration.

Claims (122)

1. A compound having the formula:

wherein R 1 and R 4 is H, a C 1 to C 4 alkyl group, C(O)(C 1 -C 4 alkyl) or additionally R 4 is benzyl;

wherein R 2 is H, OH, O(C 1 -C 4 alkyl), O-benzyl, OC(O)H, OC(O)(C 1 -C 4 alkyl), OC(O)benzyl, OSi(CH 1 ) 2 (t-butyl), or a phthalimide group;

wherein R 3 is ═O, OH, O(C 1 -C 4 alkyl), OC(O)(C 1 -C 2 alkyl), or OC(O)benzyl;

wherein R 5 is H, halogen, OH, or —OC (1-6) alkyl group;

wherein R 6 is ═O, OH, OC 3 , CN, OC(O)H, OC(O)(C 1 -C 4 alkyl), or OC(O)benzyl;

wherein R 7 , is H, ═O, OH, or halogen;

wherein R 8 and R 9 are independently H, CH 3 , OCH 3 , OC 2 H 5 , Br, P, or CF 3 ;

wherein R 10 and R 11 are independently CH 3 , OCH 3 , OC 2 H 5 , SCH 3 , or SC 2 H 5 ;

wherein R 12 is H, a C 1 to C 4 alkyl group, or C(O)(C 1 -C 4 alkyl); and

wherein the chiral center marked * has the R or the S configuration.

2. The compound of claim 1 , having the formula:

wherein R 1 and R 4 is H, a C 1 to C 4 alkyl group, C(O)(C 1 -C 4 alkyl) or additionally R 4 is benzyl;

wherein R 2 is H, OH, O(C 1 -C 4 alkyl), O-benzyl, OC(O)H, OC(O)(C 1 -C 4 alkyl), OC(O)benzyl, OSi(CH 3 ) 2 (t-butyl), or a phthalimide group;

wherein R 3 is ═O, OH, O(C 1 -C 4 alkyl), OC(O)(C 1 -C 2 alkyl), or OC(O)benzyl;

wherein R 5 is H, halogen, OH, or —OC (1-6) alkyl group;

wherein R 6 is ═O, OH, OCH 3 , CN, OC(O)H, OC(O)(C 1 -C 4 alkyl, or OC(O)benzyl;

wherein R 7 , is H, ═O, OH, or halogen;

wherein R 8 and R 9 are independently H, CH 3 , OCH 3 , OC 2 H 5 , Br, F, or CF 3 ; and

wherein the chiral center marked * has the R or the S configuration.

3. The compound of claim 2 , having the formula:

wherein R 1 and R 4 is H, a C 1 to C 4 alkyl group, C(O)(C 1 -C 4 alkyl) or additionally R 4 is benzyl;

wherein R 2 is H, OH, O(C 1 -C 4 alkyl), O-benzyl, OC(O)H, Osi(CH 3 ) 2 (t-butyl), or a phthalimide group;

wherein R 3 is ═O, OH, O(C 1 -C 4 alkyl), OC(O)(C 1 -C 2 alkyl), or OC(O)benzyl;

wherein R 5 is H, halogen, OH, or —OC (1-6) alkyl group;

wherein R 6 is ═O, OH, OCH 3 , CN, OC(O)H, OC(O)C 1 -C 4 alkyl), or OC(O)benzyl;

wherein R 7 , is H, ═O, OH, or halogen and

wherein the chiral center marked * has the R or the S configuration.

4. The compound of claim 3 , wherein R 1 is CH 3 , R 3 is ═O, R 4 is ═O, R 4 is CH 3 , R 5 is OCH 3 , R 6 is ═O, and R 7 is H.

5. The compound of claim 4 , wherein R 2 is OC(O)H.

6. The compound of claim 4 , wherein R 2 is H.

7. The compound of claim 4 , wherein R 2 is OH.

8. The compound of claim 4 , wherein R 2 is —O-benzyl.

9. The compound of claim 4 , wherein R 2 is OCOCH 3 .

10. The compound of claim 4 , wherein R 2 is —O-t-butyldimethylsilyl.

11. The compound of claim 4 , wherein R 2 is —O-Pivaloyl.

12. The compound of claim 3 , wherein R 1 is H, R 3 is ═O, R 4 is CH 3 , R 5 is OCH 3 , R 6 is ═O, and R 7 is H.

13. The compound of claim 12 , wherein R 2 is —O-pivaloyl.

14. The compound of claim 3 , wherein R 1 is H, R 3 is ═O, R 4 is benzyl, R 5 is OCH 3 , R 6 is ═O, and R 7 is H.

15. The compound of claim 3 , wherein R 1 is H, R 3 is ═O, R 4 is H, R 5 is OCH 3 , R 6 is ═O, and R 7 is H.

16. The compound of claim 3 , wherein R 1 is H, R 3 is ═O, R 4 is H, R 5 is H, R 6 is ═O, and R 7 is H.

17. The compound of claim 3 , wherein R 3 is ═O, R 4 is H, R 5 is halogen, R 6 is ═O, and R 7 is H.

18. A compound having the formula:

wherein R 1 and R 4 is H, a C 1 to C 4 alkyl group, C(O)(C 1 -C 4 alkyl) or additionally R 4 is benzyl;

wherein R 2 is H, OH, O(C 1 -C 4 alkyl), O-benzyl, OC(O)H, OC(O)(C 1 -C 4 alkyl), OC(O)benzyl, OSi (CH 3 ) 2 (t-butyl), or a phthalimide group;

wherein R 5 is H, halogen, OH, or O(C 1 -C 6 alkyl);

wherein R 6 is ═O, OH, OCH 3 , CN, OC(O)H, OC(O)(C 1 -C 4 alkyl), or OC(O)benzyl;

wherein R 7 , is H, ═O, OH, or halogen;

wherein R 8 and R 9 are independently H, CH 3 , OCH 3 , OC 2 H 5 , Br, F, or CF 3 ;

wherein R 10 and R 11 are independently CH 3 , OCH 3 , OC 2 H 5 , SCH 3 , or SC 2 H 5 ; and

wherein R 12 is H, a C 1 to C 4 alkyl group, or OC(O)benzyl.

19. The compound of claim 18 , having the formula:

wherein R 1 and R 4 is H, a C 1 to C 4 alkyl group, C(O)(C 1 -C 4 alkyl) or additionally R 4 is benzyl;

wherein R 2 is H, OH, O(C 1 -C 4 alkyl), O-benzyl, OC(O)H, OC(O)(C 1 -C 4 alkyl), OC(O)benzyl, OSi(CH 3 ) 2 (t-butyl), or a phthalimide group;

wherein R 5 , is H, halogen, OH, or O(C 1 -C 6 alkyl);

wherein R 6 is ═O, OH, OCH 3 , CN, OC(O)H, OC(O)(C 1 -C 4 alkyl), or OC(O)benzyl;

wherein R 7 , is H, ═O, OH, or halogen; and

wherein R 8 and R 9 are independently H, CH 3 , OCH 3 , OC 2 H 5 , Br, F, or CF 3 .

20. The compound of claim 19 , having the formula:

wherein R 1 and R 4 is H, a C 1 to C 4 alkyl group, C(O)(C 1 -C 4 alkyl) or additionally R 4 is benzyl;

wherein R 2 is H, OH, O(C 1 -C 4 alkyl), O-benzyl, OC(O)H, OC(O)(C 1 -C 4 alkyl), OC(O)benzyl, OSi(CH 3 ) 2 (t-butyl), or a phthalimide group;

wherein R 5 is H, halogen, OH, or O(C 1 -C 6 alkyl);

wherein R 6 is ═O, OH, OCH 3 , CN, OC(O)H, OC(O)(C 1 -C 4 alkyl), or OC(O)benzyl; and

wherein R 7 , is H, ═O, OH, or halogen.

21. The compound of claim 20 , wherein R 1 is CH 3 , R 4 is CH 3 , R 5 is OCH 3 , R 6 is ═O, and R 7 is H.

22. The compound of claim 21 , wherein R 2 is OC(O)H.

23. The compound of claim 21 , wherein R 2 is H.

24. The compound of claim 21 , wherein R 2 is OH.

25. The compound of claim 21 , wherein R 2 is —O-benzene.

26. The compound of claim 21 , wherein R 2 is OCOCH 3 .

27. The compound of claim 21 , wherein R 2 is —O-t-butyldimethylsilyl.

28. The compound of claim 21 , wherein R 2 is —O-Pivaloyl.

29. The compound of claim 20 , wherein R 1 is H, R 4 is CH 3 , R 5 is OCH 3 , R 6 is ═O, and R 7 is H.

30. The compound of claim 29 , wherein R 2 is —O-pivaloyl.

31. The compound of claim 20 , wherein R 1 is H, R 4 is benzyl, R 5 is OCH 3 , R 6 is ═O, and R 7 is H.

32. The compound of claim 20 , wherein R 1 is H, R 4 is H, R 5 is OCH 3 , R 6 is ═O, and R 7 is H.

33. The compound of claim 20 , wherein R 1 is H, R 4 is H, R 5 is H, R 6 is ═O, and R 7 is H.

34. The compound of claim 20 , wherein R 1 is H, R 4 is H, R 5 is halogen, R 6 is ═O, and R 7 is H.

35. A compound having the formula:

wherein R 1 and R 4 is H, a C 1 to C 4 alkyl group, C(O)(C 1 -C 4 alkyl) or additionally R 4 is benzyl;

wherein R 2 is H, OH, O(C 1 -C 4 alkyl), O-benzyl, OC(O)H, OC(O)(C 1 -C 4 alkyl), OC(O)benzyl, or OSi(CH 3 ) 2 (t-butyl);

wherein R 3 is ═O, OH, H, O(C 1 -C 4 alkyl), OC(O)(C 1 -C 2 alkyl), or OC(O)benzyl;

wherein R 5 is H, halogen, OH, or ═OC (2-6) alkyl group;

wherein R 6 is H, ═O, OH, OCH 3 , CN, OC(O)H, OC(O)(C 1 -C 4 alkyl), or OC(O)benzyl;

wherein R 7 , is H, ═O, OH, OCH 3 , or halogen;

wherein R 8 and R 9 are independently H, CR 3 , OCH 3 , OC 2 H 5 , Br, F, or CF 3 ;

wherein R 10 and R 11 are independently CH 3 , OCH 3 , OC 2 H 5 , SCH 3 , or SC 2 H 5 ;

wherein R 12 is H, a C 1 to C 4 alkyl group, or C(O)(C 1 -C 4 alkyl); and

wherein the chiral center marked * has the R or the S configuration.

36. The compound of claim 35 , having the formula:

wherein R 1 and is R 4 is H, a C 1 to C 4 alkyl group, C(O)(C 1 -C 4 alkyl) or additionlly R 4 is benzyl;

wherein R 2 is H, OH, O(C 1 -C 4 alkyl), O-benzyl, OC(O)H, OC(O)(C 1 -C 4 alkyl), OC(O)benzyl, or OSi (CH 3 ) 2 (t-butyl);

wherein R 3 is ═O, OH, H, O(C 1 -C 4 alkyl), OC(O)(C 1 -C 2 alkyl), or OC(O)benzyl;

wherein R 5 is H, halogen, OH, or —OC (2-6) alkyl group;

wherein R 6 is H, ═O, OH, OCH 3 , CN, OC(O)H, OC(O)(C 1 -C 4 alkyl), or OC(O)benzyl;

wherein R 7 is H, ═O, OH, OCH 3 , or halogen;

wherein R 8 and R 9 are independently H, CH 3 , OCH 3 , OC 2 H 5 , Br, F, or CF 3 ; and

wherein the chiral center marked * has the R or the S configuration.

37. The compound of claim 36 , having the formula:

wherein R 1 and R 4 is H, a C 1 to C 4 alkyl group, C(O)(C 1 -C 4 alkyl) or additionally R 4 is benzyl;

wherein R 2 is H, OH, O(C 1 -C 4 alkyl), O-benzyl, OC(O)H, OC(O)(C 1 -C 4 alkyl), OC(O)benzyl, or OSi(CH 3 ) 2 (t-butyl);

wherein R 3 is ═O, OH, H, O(C 1 -C 4 alkyl), OC(O)(C 1 -C 2 alkyl), or OC(O)benzyl;

wherein R 5 is H, halogen, OH, or —OC (2-6) alkyl group;

wherein R 6 is H, ═O, OH, OCH 3 , CN, OC(O)H, OC(O)(C 1 -C 4 alkyl, or OC(O)benzyl;

wherein R 7 , is H, ═O, OH, OCH 3 , or halogen; and

wherein the chiral center marked * has the R or the S configuration.

38. The compound of claim 37 , wherein R 1 is H, R 2 is OH, R 3 is H, R 4 is H, R 5 is H, R 6 is ═O, and R 7 is H.

39. The compound of claim 37 , wherein R 3 is H, R 4 is CH 3 , R 5 is OCH 3 , and R 7 is H.

40. The compound of claim 39 , wherein R 2 is OH.

41. The compound of claim 40 , wherein R 6 is H and R 1 is CH 3 .

42. The compound of claim 40 , wherein R 6 is ═O and R 1 is H.

43. A compound having the formula:

wherein R 1 and R 4 is H, a C 1 to C 4 alkyl group, C(O)(C 1 -C 4 alkyl) or additionally R 4 is benzyl;

wherein R 2 is H, OH, O(C 1 -C 4 alkyl), O-benzyl, OC(O)H, OC(O)(C 1 -C 4 alkyl), OC(O)benzyl, or OSi(CH 3 ) 2 (t-butyl);

wherein R 3 is H;

wherein R 5 is H, halogen, OH, or —OC (1-6) alkyl group;

wherein R 6 is H, ═O, OH, OCH 3 , CN, OC(O)H, OC(O)(C 1 -C 4 alkyl), or OC(O)benzyl;

wherein R 7 , is H, ═O, OH, OCH 3 , or halogen;

wherein R 8 and R 9 are independently H, CH 3 , OCH 3 , OC 2 H 5 , Br, F, or CF 3 ;

wherein R 10 and R 11 are independently CH 3 , OCH 3 , OC 2 H 5 , SCH 3 , or SC 2 H 5 ;

wherein R 12 is H, a C 1 to C 4 alkyl group, or C(O)(C 1 -C 4 alkyl); and

wherein the chiral center marked * has the R or the S configuration.

Assignments (2)

CONFIRMATORY LICENSE Recorded May 17, 2017

From: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK

To: NATIONAL INSTITUTES OF HEALTH - DIRECTOR DEITR

Reel/Frame 042408/0357 →

CONFIRMATORY LICENSE Recorded Dec 18, 2008

From: COLUMBIA UNIVERSITY NEW YORK MORNINGSIDE

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 021999/0258 →

Continuity (3)

Division 0976551500 · Jan 19, 2001

Provisional Application 6017707100 · Jan 19, 2000

Related Publication 20040127709A1 · Jul 1, 2004