Thioether conjugates

• US 5,622,929 A
• Filed: 01/23/1992
• Issued: 04/22/1997
• Est. Priority Date: 01/23/1992
• Status: Expired due to Fees

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Braslawsky, Gary R., Greenfield, Robert S., Trail, Pamela A., Willner, David, Hofstead, Sandra J., King, H. Dalton
• Primary Examiner(s): Peselev, Elli
• Application Number:
  US07/824,951
• Time in Patent Office: 1,916 Days
• Field of Search: 514/34, 514/249.8, 536/6.4, 536/22, 536/17.4, 536/17.6, 530/387.2, 530/322, 548/422, 540/478
• US Class Current: 424/85.2
• CPC Class Codes: A61K 47/6809 Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
• CPC Class Codes: A61K 47/6881 Cluster-antibody conjugates, i.e. the modifying agent consists of a plurality of antibodies covalently linked to each other or of different antigen-binding fragments covalently linked to each other
• CPC Class Codes: A61K 47/6883 Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy
• 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
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis

Abstract

Provided are drug/ligand compounds of Formula (I): ##STR1## in which D is a drug moiety;

n is an integer from 1 to 10;

p is an integer from 1 to 6;

Y is O or NH₂⁺ C1^- ;

z is 0 or 1;

q is about 1 to about 10;

X is a ligand; and,

A is a Michael Addition Adduct.

In a preferred embodiment, the ligand is an immunoglobulin, preferably a chimeric antibody or fragment thereof. Also provided are formulations comprising as an active ingredient a compound of Formula (I), intermediates useful for preparing the compounds of Formula (I), processes for preparing the compounds of Formula (I), and methods for using the compounds of the invention.

Claims

1. A compound of Formula (I):

##STR32## in which D is an anthracycline antibiotic;

n is an integer from 1 to 10;

p is an integer from 1 to 6;

Y is O or NH₂⁺ Cl^- ;

a is 0 or 1;

q is about 1 to about 10;

X is a ligand that specifically binds with a target cell population; and

A is a succinimido moiety;

wherein the anthracycline antibiotic is bound through the 13-keto position of the anthracycline.

7. A compound of claim 1 in which n is 5.

8. A compound of claim 1 in which X is an immunoglobulin selected from the group consisting of BR96, BR64, L6, a relaxed BR96, a relaxed BR64, a relaxed L6, a chimeric BR96, a chimeric BR64, a chimeric L6, a relaxed chimeric BR96, a relaxed chimeric BR64, a realxed chimeric L6;

and, fragments thereof.

9. A compound of claim 8 in which X is a chimeric BR96, a relaxed chimeric BR96;

or a fragment thereof.

10. A compound of claim 1 in which X is a ligand selected from the group consisting of bombesin, EGF, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TGF-α

, TGF-β

, VGF, insulin and insulin-like growth factors I and II.

11. A compound of claim 1 in which X is bombesin.

35. A compound of claim 1 in which X is bombesin.

2. An anthracycline antibiotic conjugate compound of Formula (Ia):

##STR33## in which R₁ is --CH₃, --CH₂ OH, --CH₂ OCO(CH₂)₃ CH₃ or --CH₂ OCOCH(C₂ H₅)₂ ;

R₃ is --OCH₃, --OH or hydrogen;

R₄ is --NH₂, --NHCOCF₃, 4-morpholinyl, 3-cyano-4-morpholinyl, 1-piperidinyl, 4-methoxy-1-piperidinyl, benzylamine, dibenzylamine, cyanomethyl amine or 1-cyano-2-methoxyethyl amine;

R₅ is --OH, --OTHP or hydrogen;

R₆ is --OH or hydrogen, provided that R₆ is not --OH when R₅ is --OH or --OTHP;

n is an integer from 1 to 10;

p is an integer from 1 to 6;

Y is O or NH₂⁺ Cl³¹ ;

z is 0 or 1;

q is about 1 to about 10; and

X is a ligand that specifically binds with a target cell population.

12. A compound of claim 2 in which Y is O, p is 2, and z is 1.

13. A compound of claim 2 in which Y=NH₂⁺ Cl^-, p is 3, and z is 1.

14. A compound of claim 2 in which z is 0.

15. A compound of claim 2 in which the anthracycline antibiotic moiety is selected from the group consisting of adriamycin, daunomycin, detorubicin, carminomycin, idarubicin, epirubicin, AD-32, 4-morpholinyl-adriamycin and 3'"'"'-deamino-3'"'"'-(3-cyano-4-morpholinyl)-deoxyrubicin.

16. A compound of claim 12 in which the anthracycline moiety is selected from the group consisting of adriamycin, daunomycin, detorubicin, carminomycin, idarubicin, epirubicin, AD-32, 4-morpholinyl-adriamycin and 3'"'"'-deamino-3'"'"'-(3-cyano-4-morpholinyl)-deoxyrubicin.

17. A compound of claim 13 in which the anthracycline moiety is selected from the group consisting of adriamycin, daunomycin, detorubicin, carminomycin, idarubicin, epirubicin, AD-32, 4-morpholinyl-adriamycin and 3'"'"'-deamino-3'"'"'-(3-cyano-4-morpholinyl)-deoxyrubicin.

18. A compound of claim 14 in which the anthracycline moiety is selected from the group consisting of adriamycin, daunomycin, detorubicin, carminomycin, idarubicin, epirubicin, AD-32, 4-morpholinyl-adriamycin and 3'"'"'-deamino-3'"'"'-(3-cyano-4-morpholinyl)-deoxyrubicin.

19. A compound of claim 15 in which the anthracycline moiety is adriamycin.

20. A compound of claim 16 in which the anthracycline moiety is adriamycin.

21. A compound of claim 17 in which the anthracycline moiety is adriamycin.

22. A compound of claim 18 in which the anthracycline moiety is adriamycin.

23. A compound of claim 19 in which X is an immunoglobulin selected from the group consisting of BR96, BR64, L6, a relaxed BR96, a relaxed BR64, a relaxed L6, a chimeric BR96, a chimeric BR64, a chimeric L6;

a relaxed chimeric BR96, a relaxed chimeric BR64, a relaxed chimeric L6; and

, fragments thereof.

24. A compound of claim 20 in which X is an immunoglobulin selected from the group consisting of BR96, BR64 and L6, a relaxed BR96, a relaxed BR64, a relaxed L6, a chimeric BR96, a chimeric BR64 and a chimeric L6, a relaxed chimeric BR96, a relaxed chimeric BR64, a relaxed chimeric L6;

and, fragments thereof.

25. A compound of claim 21 in which X is an immunoglobulin selected from the group consisting of BR96, BR64 and L6, a relaxed BR96, a relaxed BR64, a relaxed L6, a chimeric BR96, a chimeric BR64, a chimeric L6, a relaxed chimeric BR96, a relaxed chimeric BR64, a relaxed chimeric L6;

and, fragments thereof.

26. A compound of claim 22 in which X is an immunoglobulin selected from the group consisting of BR96, BR64 and L6, a relaxed BR96, a relaxed BR64, a relaxed L6, a chimeric BR96, a chimeric BR64, a chimeric L6, a relaxed chimeric BR96, a relaxed chimeric BR64, a relaxed chimeric L6;

and, fragments thereof.

27. A compound of claim 23 in which X is a chimeric BR96, a relaxed chimeric BR96;

or a fragment thereof.

28. A compound of claim 24 in which X is a chimeric BR96, a relaxed chimeric BR96;

or a fragment thereof.

29. A compound of claim 25 in which X is a chimeric BR96, a relaxed chimeric BR96;

or a fragment thereof.

30. A compound of claim 26 in which X is a chimeric BR96, a relaxed chimeric BR96;

or a fragment thereof.

31. A compound of claim 2 in which X is a ligand selected from the group consisting of bombesin, EGF, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TGF-α

, TGF-β

, VGF, insulin and insulin-like growth factors I and II.

32. A compound of claim 12 in which X is a ligand selected from the group consisting of bombesin, EGF, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TGF-α

, TGF-β

, VGF, insulin and insulin-like growth factors I and II.

33. A compound of claim 13 in which X is a ligand selected from the group consisting of bombesin, EGF, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TGF-α

, TGF-β

, VGF, insulin and insulin-like growth factors I and II.

34. A compound of claim 14 in which X is a ligand selected from the group consisting of bombesin, EGF, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TGF-α

, TGF-β

, VGF, insulin and insulin-like growth factors I and II.

36. A compound of claim 32 in which X is bombesin.

37. A compound of claim 33 in which X is bombesin.

38. A compound of claim 34 in which X is bombesin.

3. A compound of Formula (Ib):

##STR34## in which n is an integer from 1 to 10;

q is about 1 to about 10; and

X is a ligand that specifically binds with a target cell population.

39. A compound of claim 3 in which X is an immunoglobulin selected from the group consisting of BR96, BR64, L6, a relaxed BR96, a relaxed BR64, a relaxed L6, a chimeric BR96, a chimeric BR64, a chimeric L6, a relaxed chimeric BR96, a relaxed chimeric BR64, a relaxed chimeric L6 ;

and, fragments thereof.

40. A compound of claim 3 in which X is a chimeric BR96, a relaxed chimeric BR96, or a fragment thereof.

41. A compound of claim 3 in which X is a protein, or peptide ligand.

42. A compound of claim 41 in which X is selected from the group consisting of bombesin, EGF, transferrin, gastrin, gastrin-releasing peptide.

43. A compound of claim 42 in which X is bombesin.

4. A compound of Formula (Ic):

##STR35## in which q is about 4 to about 8; and

X is a ligand that specifically binds with a target cell population.

44. A compound of claim 4 in which X is an immunoglobulin, or a fragment thereof.

45. A compound of claim 4 in which X is an immunoglobulin selected from the group consisting of BR96, BR64, L6, a chimeric BR96, a chimeric BR64, a chimeric L6, a relaxed BR96, a relaxed BR64, a relaxed L6, a relaxed chimeric BR96, a relaxed chimeric BR64, a relaxed chimeric L6;

and, fragments thereof.

46. A compound of claim 45 in which X is a chimeric BR96, a relaxed chimeric BR96, or a fragment thereof.

47. A compound of claim 4 in which X is a protein, or peptide ligand.

48. A compound of claim 47 in which X is selected from the group consisting of bombesin, EGF, transferrin, gastrin, gastrin-releasing peptide.

49. A compound of claim 48 in which X is bombesin.

5. A formulation which comprises as an active ingredient a compound of Formula (Ia):

##STR36## in which R₁ is --CH₃, --CH₂ OH, --CH₂ OCO(CH₂)₃ CH₃ or --CH₂ OCOCH(C₂ H₅)₂ ;

R₃ is --OCH₃, --OH or hydrogen;

R₄ is --NH₂, --NHCOCF₃, 4-morpholinyl, 3-cyano-4-morpholinyl, 1-piperidinyl, 4-methoxy-1-piperidinyl, benzylamine, dibenzylamine, cyanomethyl amine or 1-cyano-2-methoxyethyl amine;

R₅ is --OH, --OTHP or hydrogen;

R₆ is --OH or hydrogen, provided that R₆ is not --OH when R₅ is --OH or --OTHP;

n is an integer from 1 to 10;

p is an integer from 1 to 6;

Y is O or NH₂⁺ Cl^- ;

z is 0 or 1;

q is about 1 to about 10; and

X is a ligand that specifically binds with a target cell population;

in a pharmaceutically acceptable amount associated with a pharmaceutically acceptable carrier, diluent or excipient therefor.

6. A formulation which comprises as an active ingredient a compound of Formula (Ib):

##STR37## in which n is an integer from 1 to 10;

q is about 1 to about 10; and

X is a ligand reactive with a selected target cell population;

in a pharmacutically acceptable amount associated with a pharmaceutically acceptable carrier, diluent or excipient therefor.

51. A formulation as claimed in claim 6 in which n is 5, X is a related chimeric BR96 antibody and q is about 4 to about 8.

50. A compound of Formula (Id):

##STR38## in which q is from about 4 to about 8 and Ig is a relaxed chimeric BR96 antibody, or a fragment thereof.

52. A formulation which comprises as an active ingredient a compound of Formula (Id):

##STR39## in which q is from about 4 to about 8 and Ig is a relaxed chimeric BR96 antibody, or a fragment thereof, associated with a pharmaceutically acceptable carrier, diluent or excipient therefor.