USRE41614EExpiredUtility
Synthetic analogs of ecteinascidin-743
Est. expirySep 30, 2018(expired)· nominal 20-yr term from priority
Inventors:Elias J. Corey
A61P 35/00C07D 491/22
75
PatentIndex Score
6
Cited by
48
References
51
Claims
Abstract
The present invention is directed to the synthesis and characterization of compounds having the formula: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, OH, OR′, SH, SR′, SOR′, SO 2 R′, NO 2 , NH 2 , NHR′, N(R′) 2 , NHC(═O)R′ NHC( ═O ) R′ , CN, halogen, ═O, C(═O)H, C(═O)R′, CO 2 H, CO 2 R′, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic; wherein each of the R′ groups is independently selected from the group consisting of H, OH, NH 2 , NO 2 , SH, CN, halogen, ═O, C(═O)H, C(═O)CH 3 , CO 2 H, CO 2 CH 3 , C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, aralkyl, and heteroaromatic; wherein each dotted circle represents one, two or three optional double bonds; wherein R 7 and R 8 may be are joined into a carbocyclic or heterocyclic ring system; and wherein X 1 and X 2 are each independently defined as above for R 1 -R 8 R 1 - R 6 and R 9 , and each further includes specific preferred groups as defined herein.
Claims
exact text as granted — not AI-modified1. Compounds having the formula:
wherein each of the groups X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is independently selected from the group consisting of H, OH, OR′, SR′, SOR′, SO 2 R′, NO 2 , NH 2 , NHR′, N(R′) 2 , NHC(O)R′ NHC( ═O ) R′ , CN, halogen, ═O, C(═O)H, C(═O)R′, CO 2 H, CO 2 R′, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic;
wherein each of the R′ groups is independently selected from the group consisting of H, OH, NH 2 , NO 2 , SH, CN, halogen, ═O, C(═O)H, C═O)CH 3 C( ═O ) CH 3 , CO 2 H, CO 2 CH 3 , C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, aryl, aralkyl, and heteroaromatic;
wherein each dotted circle represents one, two or three optional double bonds; and
wherein R 7 and R 8 may be are joined into a carbocyclic or heterocyclic ring system.
2. The compounds of claim 1 wherein X 1 and X 2 are independently selected from the group consisting of:
or the formula:
wherein Z is selected from the group consisting of:
where n=1, 2, 3 . . . 20
wherein each R group is independently selected from the group consisting of H, OH, SH, NH 2 , NO 2 , halogen, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -acyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl.
3. Compounds of the formula:
wherein each of the groups X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 9 is independently selected from the group consisting of H, OH, OR′, SH, SR′, SOR′, SO 2 R′, NO 2 , NH 2 , NHR′, N(R′) 2 , NHC(O)R′ NHC( ═O ) R′ , CN, halogen, ═O, C 1 -C 6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic;
wherein each of the R′ groups is independently selected from the group consisting of H, OH, NO 2 , NH 2 , SH, CN, halogen, ═O, C(═O)H, C(═O)CH 3 , CO 2 H, CO 2 CH 3 , C 1 -C 6 alkyl, phenyl, benzyl, and heteroaromatic; and
wherein each dotted circle represents one, two or three optional double bonds.
4. The compounds of claim 3 , wherein X 1 and X 2 are each independently selected from the group consisting of:
or the formula:
wherein Z is selected from the group consisting of:
wherein each R group is independently selected from the group consisting of H, OH, SH, NH 2 , NO 2 , halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -acyl, aryl or alky-laryl alkylaryl.
5. The compound of the formula:
and pharmaceutically acceptable salts and derivatives thereof, wherein:
R 1 is H, OH, SH or NH 2 ;
R 2 is H, OH, OCH 3 ;
R 3 is H, OH, SH, NH 2 or CH 3 ;
R 4 is H, OH, SH, NH 2 , OCH 3 , or halogen;
R 5 is H or C 1 -C 6 alkyl;
R 6 is CN, OH, SH, NH 2 , OR, SR, or O(C═O)R;
R 9 is C 1 -C 6 alkyl;
wherein X 1 is selected from the group consisting of:
where each R group, which may be the same or be different, is selected from the group consisting of H, OH, SH, NH 2 , NO 2 , halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -acyl, alyl aryl or alkylaryl.
6. The compound of claim 5 , wherein X 1 is:
7. The compound of claim 5 , wherein X 1 is:
8. The compound of claim 5 , wherein X 1 is:
9. The compound of claim 5 , wherein X 1 is:
10. The compound of claim 5 , wherein X 1 is:
11. The compound of claim 5 , wherein X 1 is:
12. The compound of claim 5 , wherein X 1 is:
13. The compound of claim 9 5 , wherein X 1 is:
14. The compound of claim 5 , wherein X 1 is:
15. The compound of claim 5 , wherein X 1 is:
16. The compound of claim 5 , wherein X 1 is:
17. The compound of claim 5 , wherein X 1 is:
18. The compound of claim 5 , wherein X 1 is:
19. Pharmaceutical compositions comprising an effective antitumor amount of a compound of the formula:
and pharmaceutically acceptable salts and derivatives thereof, wherein:
R 1 is H, OH, SH or NH 2 ;
R 2 is H, OH, OCH 3 ;
R 3 is H, OH, SH, NH 2 or CH 3 ;
R 4 is H, OH, SH, NH 2 , OCH 3 , or halogen;
R 5 is H or C 1 -C 6 alkyl;
R 6 is CN, OH, SH, NH 2 , OR, SR, or O(CO)R;
R 9 is C 1 -C 6 alkyl;
wherein X 1 is selected from the group consisting of:
and wherein each R group, which many be the same or be different, is selected from the group consisting of H, OH, SH, NH 2 , NO 2 , halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -acyl, aryl or alkylaryl.
20. The pharmaceutical composition of claim 19 , wherein X 1 is:
21. The pharmaceutical composition of claim 19 , wherein X 1 is:
22. The pharmaceutical composition of claim 19 , wherein X 1 is:
23. The pharmaceutical composition of claim 19 , wherein X 1 is:
24. The pharmaceutical composition of claim 19 , wherein X 1 is:
25. The pharmaceutical composition of claim 19 , wherein X 1 is:
26. The pharmaceutical composition of claim 19 , wherein X 1 is:
27. The pharmaceutical composition of claim 19 , wherein X 1 is:
28. The pharmaceutical composition of claim 19 , wherein X 1 is:
29. The pharmaceutical composition of claim 19 , wherein X 1 is:
30. The pharmaceutical composition of claim 19 , wherein X 1 is:
31. The pharmaceutical composition of claim 19 , wherein X 1 is:
32. The pharmaceutical composition of claim 19 , wherein X 1 is:
33. A method of treating tumors selected from the group consisting of lung cancer, colon cancer and prostate cancer in mammals comprising administering to a mammal in need of such treatment, an effective antitumor amount of a compound of the formula:
and pharmaceutically acceptable salts and derivatives thereof, wherein:
R 1 is H, OH, SH or NH 2 ;
R 2 is H, OH, OCH 3 ;
R 3 is H, OH, SH, NH 2 or CH 3 ;
R 4 is H, OH, SH, NH 2 , OCH 3 , or halogen;
R 5 is H or C 1 -C 6 alkyl;
R 6 is CN, OH, SH, NH 2 , OR, SR, or O(CO)R;
R 9 is C 1 -C 6 alkyl,
wherein X 1 is selected from the group consisting of:
and wherein each R group, which may be the same or be different, is selected from the group consisting of H, OH, SH, NH 2 , NO 2 , halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -acyl, aryl or alkylaryl.
34. The method of treatment of claim 33 , wherein X 1 is:
35. The method of treatment of claim 33 , wherein X 1 is:
36. The method of treatment of claim 33 , wherein X 1 is:
37. The method of treatment of claim 33 , wherein X 1 is:
38. The method of treatment of claim 33 , wherein X 1 is:
39. The method of treatment of claim 33 , wherein X 1 is:
40. The method of treatment of claim 33 , wherein X 1 is:
41. The method of treatment of claim 33 , wherein X 1 is:
42. The method of treatment of claim 33 , wherein X 1 is:
43. The method of treatment of claim 33 , wherein X 1 is:
44. The method of treatment of claim 33 , wherein X 1 is:
45. The method of treatment of claim 33 , wherein X 1 is:
46. The method of treatment of claim 33 , wherein X 1 is:
47. The compound of the formula:
and pharmaceutically acceptable salts and derivatives thereof, wherein:
R
1
is H, OH, SH or NH
2
;
R
2
is H, OH, OCH
3
;
R
3
is H, OH, SH, NH
2
or CH
3
;
R
4
is H, OH, SH, NH
2
, OCH
3
, or halogen;
R
5
is H or C
1
-C
6
alkyl;
R 6 is CN, OH, SH, NH 2 , OR, SR, or O ( C═O ) R;
R
9
is C
1
-C
6
alkyl;
wherein X
1
is selected from the group consisting of:
where each R group, which may be the same or be different, is selected from the group consisting of H, OH, SH, NH 2 , NO 2 , halogen, C 1 -C 6 - alkyl, C 1 -C 6 - alkoxy, C 1 -C 6 - acyl, aryl or alkylaryl.
48. Pharmaceutical compositions comprising an effective antitumor amount of a compound of the formula:
and pharmaceutically acceptable salts and derivatives thereof, wherein:
R
1
is H, OH, SH or NH
2
;
R
2
is H, OH, OCH
3
;
R
3
is H, OH, SH, NH
2
or CH
3
;
R
4
is H, OH, SH, NH
2
, OCH
3
, or halogen;
R
5
is H or C
1
-C
6
alkyl;
R 6 is CN, OH, SH, NH 2 , OR, SR, or O ( C═O ) R;
R
9
is C
1
-C
6
alkyl;
wherein X
1
is selected from the group consisting of:
and
wherein each R group, which many be the same or be different, is selected from the group consisting of H, OH, SH, NH 2 , NO 2 , halogen, C 1 -C 6 - alkyl, C 1 -C 6 - alkoxy, C 1 -C 6 - acyl, aryl or alkylaryl.
49. A method of treating tumors selected from the group consisting of lung cancer, colon cancer and prostate cancer in mammals comprising administering to a mammal in need of such treatment, an effective antitumor amount of a compound of the formula:
and pharmaceutically acceptable salts and derivatives thereof, wherein:
R
1
is H, OH, SH or NH
2
;
R
2
is H, OH, OCH
3
;
R
3
is H, OH, SH, NH
2
or CH
3
;
R
4
is H, OH, SH, NH
2
, OCH
3
, or halogen;
R
5
is H or C
1
-C
6
alkyl;
R 6 is CN, OH, SH, NH 2 , OR, SR, or O ( C═O ) R;
R
9
is C
1
-C
6
alkyl;
wherein X
1
is selected from the group consisting of:
and
wherein each R group, which may be the same or be different, is selected from the group consisting of H, OH, SH, NH 2 , NO 2 , halogen, C 1 -C 6 - alkyl, C 1 -C 6 - alkoxy, C 1 -C 6 - acyl, aryl or alkylaryl.
50. Pharmaceutical compositions comprising an effective antitumor amount of a compound of the formula:
and pharmaceutically acceptable salts and derivatives thereof, wherein:
X
1
is selected from the group consisting of:
and
wherein each R group, which many be the same or be different, is selected from the group consisting of H, OH, SH, NH 2 , NO 2 , halogen, C 1 -C 6 - alkyl, C 1 -C 6 - alkoxy, C 1 -C 6 - acyl, aryl or alkylaryl.
51. A method of treating tumors selected from the group consisting of lung cancer, colon cancer and prostate cancer in mammals comprising administering to a mammal in need of such treatment, an effective antitumor amount of a compound of the formula:
and pharmaceutically acceptable salts and derivatives thereof, wherein:
X
1
is selected from the group consisting of:
and
wherein each R group, which may be the same or be different, is selected from the group consisting of H, OH, SH, NH 2 , NO 2 , halogen, C 1 -C 6 - alkyl, C 1 -C 6 - alkoxy, C 1 -C 6 - acyl, aryl or alkylaryl.Join the waitlist — get patent alerts
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