p-Amidobenzylethers in drug delivery agents

• US 7,091,186 B2
• Filed: 09/24/2001
• Issued: 08/15/2006
• Est. Priority Date: 09/24/2001
• Status: Expired due to Term

• Current Assignee: Seagen Inc. (Pfizer Inc.)
• Original Assignee: Seattle Genetics Incorporated (Pfizer Inc.)
• Inventors: Toki, Brian E., Senter, Peter D.
• Primary Examiner(s): Lukton, David
• Application Number:
  US09/963,103
• Publication Number:
  US 20030096743A1
• Time in Patent Office: 1,786 Days
• Field of Search: 530/330, 530/331, 514/18, 514/19, 514/717
• US Class Current: 514/1.3
• CPC Class Codes: A61K 47/6889 Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment

Abstract

Compounds of the formulae
LA_n-Z-X—W_wD and BZ-X—W_wD
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 residue; 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.

Claims

1. A compound of the formula:

BZ-X—

W_wD

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:

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

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, N⁸-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, CF₃, CONH₂, CHO, CO₂CH₃, COCH₃, NHCOCH₃, NO₂, 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, CF₃, CONH₂, CHO, CO₂CH₃, COCH₃, NHCOCH₃, NO₂, 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

30. A compound of claim 3 wherein

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.