Patent

1. A compound of the formula:

B Z-X—W w D

wherein:

D is a drug moiety;

B is a blocking group;

Z is an amino acid or a peptide residue;

X is an aminobenzyl ether self-immolative group;

W is an optional second self-immolative group;

w is an integer of 0 or 1;

wherein X—W forms an aminobenzyl ether when w is 1, and X-D forms an aminobenzyl ether when w is 0.

2. A compound of claim 1 , represented by the following formula:

wherein:

—O-D is a portion of a drug, where the drug has the formula HO-D;

J is a substituent group, and m is 0, 1, 2, 3 or 4;

is situated at an ortho- or para-position with respect to the —CH 2 — group;

Z-C(═O) is an amino acid or a peptide;

B is a hydrogen or a blocking group selected from a D-amino acid, and an N-terminus protecting group;

wherein —CH 2 —O-D forms an ether linkage.

3. A compound of claim 1 , represented by the following formula:

wherein:

T-D is a portion of a drug, where the drug has the formula HT-D;

T is 0, S, NH, or N(lower alkyl);

J is a substituent group, and m is 0, 1, 2, 3 or 4;

is situated at an ortho- or para-position with respect to the —CH 2 — group;

Z-C(═O) is an amino acid or a peptide;

p is 1 or 2; and

B is a hydrogen or a blocking group selected from a D-amino acid, and an N-terminus protecting group.

4. A compound of claim 2 wherein the O of —O-D is bonded to a carbon that forms an aromatic ring of D.

5. A compound of claim 4 wherein the drug is 1,2,9,9a-tetra-hydro-cyclo-propa[c]benz[e]indol-4-one (CBI) conjugated to a minor groove binder.

6. A compound of claim 4 wherein the drug is cyclopropapyrroloindole (CPI) conjugated to a minor groove binder.

7. A compound of claim 4 wherein the drug is 1,2,9,9a-tetra-hydro-cyclo-propa[c]pyrido[3,2-e]indol-4-one (CPyI) conjugated to a minor groove binder.

8. A compound of claim 4 wherein the drug is selected from: ((S)—N-[2-[[1-(chloromethyl)-1,6-dihydro-5-hydroxy-8-methylbenzo[1,2-b: 4,3-b′]dipyrrol-3(2-yl]carbonyl]-1H-indol-5-yl]-6-(diethylamino)-2-benzofurancarboxamide) (U-76,073); seco-adozelesin; bizelesin; 1,2,9,9a-tetra-hydro-cyclo-propa[c]benz[e]indol-4-one-trimethoxyindole (CBI-TMI); duocarmycin C2; duocarmycin B2; (Benzo(1,2-b:4,3-b′)dipyrrole-3(2H)-carboxamide, 7-((1,6-dihydro-4-hydroxy-5-methoxy-7-((4,5,8,8a-tetrahydro-7-methyl-4-oxocyclopropa(c)pyrrolo(3,2-e)indol-2(1H)-yl)carbonyl)benzo(1,2-b:4,3-b′)dipyrrol-3(2H)-yl)carbonyl)-1,6-dihydro-4-hydroxy-5-methoxy-, (7bR)—) (seco-CC-1065); pancratistatin; carminomycin; streptonigrin; zorubicin; elliptinium acetate; mitoxantrone; daunorubicin; phenol mustard; doxorubicin; etoposide, combretastatin A-4, and 7-ethyl-10-hydroxycamptothecin (SN-38).

9. A compound of claim 4 wherein the O of —O-D is bonded to an aliphatic carbon of D.

10. A compound of claim 9 in which the drug is auristatin E.

11. A compound of claim 2 wherein the H of H—O-D has a pKa of 16 or less.

12. A compound of claim 3 wherein T is NH or N(lower alkyl).

13. A compound of claim 3 wherein T is O or S.

14. A compound of claim 12 wherein the drug is selected from 5-amino-1,2,9,9a-tetra-hydro-cyclopropa[c]benz[e]indol-4-one (CBI) conjugated to a minor groove binder; 5-amino-cyclopropapyrroloindole (CPI) conjugated to a minor groove binder, and 5-amino-1,2,9,9a-tetra-hydro-cyclopropa[c]pyrido[3,2-e]indol-4-one (CPyI) conjugated to a minor groove binder.

15. A compound of claim 12 wherein the drug is an amino containing drug moiety selected from the group consisting of mitomycin-C, mitomycin-A, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, aminopterin, actinomycin, bleomycin, 9-amino camptothecin, N 8 -acetyl spermidine, 1-(2 chloroethyl)-1,2-dimethanesulfonyl hydrazide, tallysomycin, and derivatives thereof.

16. A compound of claim 13 wherein the drug is auristatin E.

17. A compound of claim 13 wherein the drug is a hydroxyl-containing moiety selected from the group consisting of: etoposide, camptothecin, taxol, esperamicin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyne-13-one, anguidine, doxorubicin, morpholino-doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, vincristine, vinblastine and derivatives thereof.

18. A compound of claim 13 wherein the drug is a sulfhydryl-containing moiety selected from the group consisting of esperamicin, 6-mercaptopurine, and derivatives thereof.

19. A compound of claim 2 wherein m is 0.

20. A compound of claim 3 wherein m is 0.

21. A compound of claim 2 wherein m is 1 and the substituent is an electron-withdrawing group selected from F, Cl, Br, CN, CF 3 , CONH 2 , CHO, CO 2 CH 3 , COCH 3 , NHCOCH 3 , NO 2 , and sulfonyl groups.

22. A compound of claim 2 wherein m is 1 and the substituent is an electron-withdrawing group selected from F, Cl, Br, CN, CF 3 , CONH 2 , CHO, CO 2 CH 3 , COCH 3 , NHCOCH 3 , NO 2 , and sulfonyl groups.

23. A compound of claim 2 wherein Z is a dipeptide or a tripeptide.

24. A compound of claim 3 wherein Z is a dipeptide or a tripeptide.

25. A compound of claim 2 wherein Z is valine-citrulline.

26. A compound of claim 3 wherein Z is valine-citrulline.

27. A compound of claim 2 wherein Z is phenylalanine-lysine.

28. A compound of claim 3 wherein Z is phenylalanine-lysine.

29. A compound of claim 2 wherein

is situated at the para-position with respect to the —CH 2 — group.

30. A compound of claim 3 wherein

is situated at the para-position with respect to the —CH 2 — group.

31. A compound of claim 2 wherein B is a carbobenzoxy protecting group.

32. A compound of claim 3 wherein B is a carbobenzoxy protecting group.

33. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

34. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier, diluent or excipient.

35. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier, diluent or excipient.

36. A compound of claim 1 wherein D is cytotoxic.

37. A compound of claim 2 wherein HO-D is cytotoxic.

38. A compound of claim 3 wherein HT-D is cytotoxic.