p-amidobenzylethers in drug delivery agents

• US 7,553,816 B2
• Filed: 09/23/2002
• Issued: 06/30/2009
• 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., Jeffrey, Scott
• Primary Examiner(s): Gupta; Anish
• Application Number:
  US10/252,947
• Publication Number:
  US 20030130189A1
• Time in Patent Office: 2,472 Days
• Field of Search: None
• US Class Current: 514/1.1
• 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 formulas
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; 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:

LA_n-Z-X—

W_wD

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:

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:

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

38. A compound of claim 3 wherein

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

42. A compound of claim 40 wherein A is

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

49. The compound of claim 48 wherein

L is cAC10;

A is

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).