Compounds of the formulas L A n -Z-X—W w D and B Z-X—W w D wherein: D is a drug moiety; L is a ligand; B is a blocking group; A is an optional acyl unit; Z is an amino acid or a peptide; X is an aminobenzyl ether self-immolative spacer group; W is an optional second self-immolative group; n is an integer of 0 or 1; and w is an integer of 0 or 1, and compositions of said compounds with pharmaceutically acceptable carrier, diluent and/or excipient, and methods of delivery the drug D via the compounds.
1. A compound of the formula:
L A n -Z-X—W w D
wherein:
D is a drug moiety;
L is a ligand;
A is an optional acyl unit;
Z is an amino acid or a peptide;
X is an aminobenzyl ether self-immolative group;
W is an optional second self-immolative group;
n is an integer of 0 or 1;
w is an integer of 0 or 1; and
wherein X forms an ether linkage with W when w is 1 or with D 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;
A is an acyl unit where n is 0 or 1; and
L is a ligand.
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 O, 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;
A is an acyl unit and n is 0 or 1;
L is a ligand;
p is 1 or 2; and
each of R 1 , R 2 , R 3 and R 4 is independently selected from H and C 1 -C 5 alkyl.
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:
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; 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 2 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 drug 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 L is an immunoglobulin, or an antigen-binding fragment thereof.
20. A compound of claim 3 wherein L is an immunoglobulin, or an antigen-binding fragment thereof.
21. A compound of claim 19 wherein L is an mAb selected from the group consisting of BR96, L6, trastuzumab, rituximab, S2C6, AC10, and antigen-binding fragments thereof.
22. A compound of claim 20 wherein L is an mAb selected from the group consisting of BR96, L6, trastuzumab, rituximab, S2C6, AC10, and antigen-binding fragments thereof.
23. A compound of claim 2 wherein L is selected from the group consisting of bombesin, EGF, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TFG-α, TFG-β, VGF, insulin and insulin-like growth factors I and II, carbohydrates, lectins, and apoprotein from low-density lipoproteins.
24. A compound of claim 3 wherein L is selected from the group consisting of bombesin, EGF, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TFG-α, TFG-β, VGF, insulin and insulin-like growth factors I and II, carbohydrates, lectins, and apoprotein from low-density lipoproteins.
25. A compound of claim 2 wherein L is selected from the group consisting of poly(ethylene glycol); poly(propylene glycol); (hydroxypropyl)methacrylamide; chitins; dextrans; styrene-co-maleic acid/anhydride, polyglutamic acid and polylysine.
26. A compound of claim 3 wherein L is selected from the group consisting of poly(ethylene glycol); poly(propylene glycol); (hydroxypropyl)methacrylamide; chitins; dextrans; styrene-co-maleic acid/anhydride, polyglutamic acid and polylysine.
27. A compound of claim 2 wherein m is 0.
28. A compound of claim 3 wherein m is 0.
29. 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.
30. A compound of claim 3 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.
31. A compound of claim 2 wherein Z is a dipeptide or a tripeptide.
32. A compound of claim 3 wherein Z is a dipeptide or a tripeptide.
33. A compound of claim 2 wherein Z is valine-citrulline.
34. A compound of claim 3 wherein Z is valine-citrulline.
35. A compound of claim 2 wherein Z is phenylalanine-lysine.
36. A compound of claim 3 wherein Z is phenylalanine-lysine.
37. A compound of claim 2 wherein
situated at the para- position with respect to the —CH2— group.
38. A compound of claim 3 wherein
is situated at the para- position with respect to the —CH 2 — group.
39. A compound of claim 2 wherein n is 1.
40. A compound of claim 3 wherein n is 1.
41. A compound of claim 39 wherein A is
and q is 1-10.
42. A compound of claim 40 wherein A is
and q is 1-10.
43. A compound of claim 41 where q=5.
44. A compound of claim 42 where q=5.
45. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
46. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 2 and a pharmaceutically acceptable carrier, diluent or excipient.
47. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 3 and a pharmaceutically acceptable carrier, diluent or excipient.
48. The compound of claim 1 wherein:
D is
L is cAC10;
A is an optional acyl unit;
Z is -val-lys-;
X is
W is an optional second self-immolative group;
n is an integer of 0 or 1;
w is an integer of 0 or 1; and
MGB is a DNA minor groove binder.
49. The compound of claim 48 wherein
L is cAC10;
A is
and w is 0.
50. The compound of claim 49 having the formula
51. The compound of claim 48 wherein MGB is (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; or 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©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).