TRIOXACARCINS, TRIOXACARCIN-ANTIBODY CONJUGATES, AND USES THEREOF

• US 20180221504A1
• Filed: 09/29/2017
• Published: 08/09/2018
• Est. Priority Date: 11/26/2012
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Myers, Andrew G., Smaltz, Daniel J., Schumacher, Andreas
• Granted Patent: US 10,639,381 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 47/6807 the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
• CPC Class Codes: A61K 47/6809 Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
• CPC Class Codes: A61K 47/6829 Bacterial toxins, e.g. diphteria toxins or Pseudomonas exotoxin A
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/18 against material from animals or humans

Abstract

Provided herein are trioxacarcin-antibody drug conjugates of Formula (A):

and pharmaceutically acceptable salts thereof, comprising at least one instance of the group -L¹-(A-L²)_a-B attached thereto, wherein a is an integer between 1 and 10, inclusive, L¹ is absent or is a linking group, A is a moiety formed from the reaction of two complimentary groups (X and Y), L² is absent or is another linking group, and B is an antibody or antibody fragment. Also provided are methods of preparing these antibody-drug conjugates, pharmaceutically acceptable compositions thereof, and methods of their use and treatment. Further provided are precursors to the trioxacarcin-antibody drug conjugates, novel trioxacarcins without an antibody conjugated thereto, pharmaceutical compositions thereof, and methods of their use and treatment.

Claims

1-36. -36. (canceled)

37. A compound of Formula (P-I):

39. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein L¹ is absent or is a linking group consisting of a combination of one or more groups of the formula:

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein L¹ is absent or is a linking group consisting of a combination of one or more groups of the formula:

41. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein X is

42. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (P-I-a):

43. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (P-I-b):

44. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (P-I-c):

45. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (P-I-d):

46. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (P-I-e):

47. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (P-I-f):

48. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen or —

OR^A1 and R² is hydrogen.

49. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² are joined to form ═

O.

50. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R³ is hydrogen.

51. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R³ is —

OR^C1.

52. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R¹, R², and R³ are each hydrogen.

53. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R⁴ is —

OR^D1.

54. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R⁵ is —

OR^E1.

55. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R⁶ is substituted or unsubstituted alkyl or —

OR^F1.

56. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R⁶ is substituted or unsubstituted alkyl.

57. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R⁸ is hydrogen, —

CH₂(OR^I1), —

CH(OR^I1)₂, or —

CH₂OC(═

O)R^I2.

58. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R⁸ is —

CH(OR^I1)₂.

38. (canceled)