Cytotoxic benzodiazepine derivatives

• US 8,765,740 B2
• Filed: 02/15/2012
• Issued: 07/01/2014
• Est. Priority Date: 02/15/2011
• Status: Active Grant

• Current Assignee: ImmunoGen Incorporated
• Original Assignee: ImmunoGen Incorporated
• Inventors: Li, Wei, Miller, Michael, Fishkin, Nathan, Chari, Ravi V. J.
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US13/397,195
• Publication Number:
  US 20120244171A1
• Time in Patent Office: 867 Days
• Field of Search: 514/219, 540/494
• US Class Current: 514/219
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/5517 condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/68035 the drug being a pyrrolobenzodiazepine
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6867 the tumour determinant being from a cell of a blood cancer
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepine compounds of formula (I)-(VII). The invention also provides conjugates of the benzodiazepine compounds linked to a cell-binding agent. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention.

Claims

1. A compound represented by the following formula:

2. The compound of claim 1, wherein the compound is represented by any one of the following formulas:

3. The compound of claim 2, wherein L′

is the linking group, and L″ and

L′

″

are —

H.

4. The compound of claim 3, wherein L′

is represented by the following formula;

—

W′

—

R^x—

V—

R^y-J,

wherein;

W′ and

V are the same or different, and are each independently absent, —

CR^eR^e′

—

, —

O—

, —

O—

C(═

O)—

, —

C(═

O)—

O—

, —

S—

, —

SO—

, —

SO₂—

, —

CH₂—

S—

, —

CH₂O—

, —

CH₂NR^e—

, —

O—

(C═

O)O—

, —

O—

(C═

O)N(R^e)—

, —

N(R^e)—

, —

N(R^e)—

C(═

O)—

, —

C(═

O)—

N(R^e)—

, —

N(R^e)—

C(═

O)O—

, —

N(C(═

O)R^e)C(═

O)—

, —

N(C(═

O)R^e)—

, —

(O—

CH₂—

CH₂)_n—

, —

SS—

, or —

C(═

O)—

, an amino acid, or a peptide having 2 to 8 amino acids;

R^x and R^y are the same or different, and are each independently absent or an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms, an aryl bearing 6 to 10 carbon atoms or a 3- to 8-membered hetereocyclic ring bearing 1 to 3 heteroatoms selected from the group consisting of O, N, and S;

R^e and R^e′

are the same or different, and are —

H, a linear, branched or cyclic alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms or —

(CH₂—

CH₂—

O)_n—

R^k, wherein R^k is a —

H, a linear, branched cyclic alkyl having 1 to 6 carbon atoms, optionally bearing —

NHR¹⁰¹ or —

NR¹⁰¹R¹⁰² group or a 5- or 6-membered nitrogen containing heterocycle, wherein R¹⁰¹ and R¹⁰² are each independently a linear, branched, or cyclic alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms;

n is an integer from 1 to 24;

J comprises the reactive group bonded thereto, and is selected from the group consisting of a maleimide, a haloacetamido, —

SH, —

SSR^d, —

CH₂SH, —

CH(Me)SH, —

C(Me)₂SH, —

NHR^c1, —

CH₂NHR^c1, —

NR^c1NH₂, —

COOH, and —

COE, wherein —

COE represents a reactive ester selected from the group consisting of N-hydroxysuccinimde ester, N-hydroxy sulfosuccinimide ester, nitrophenyl ester, dinitrophenyl ester, sulfo-tetrafluorophenyl ester, and pentafluorophenyl ester, and wherein R^c1 is —

H or an optionally substituted linear or branched alkyl having 1 to 4 carbon atoms, and,

R^d is phenyl, nitrophenyl, dinitrophenyl, carboxynitrophenyl, pyridyl or nitropyridyl.

5. The compound of claim 4, wherein J is —

SH, —

SSR^d, a maleimide, or a N-hydroxysuccinimide ester.

6. The compound of claim 4, wherein:

W′

is —

O—

, —

N(R^e)—

or —

N(R^e)—

C(═

O)—

;

R^e is —

H, -Me, or —

(CH₂—

CH₂—

O)_n-Me;

n is an integer from 2 to 6;

R^x is linear or branched alkyl bearing 1 to 6 carbon atoms;

V and R^y are absent; and

J is —

COE.

7. The compound of claim 6, wherein —

COE is N-hydroxysuccinimide ester.

8. The compound of claim 4, wherein L′

is represented by the following formula;

—

W′

—

[CR_1″

R_2″

]_a—

V-[Cy]_0-1-[CR_3″

R_4″

]_b—

COE,

wherein;

R_1″

, R_2″

, and R_3″

are each independently —

H or -Me;

R_4″

is —

H, -Me, —

SO₃H, or —

SO₃⁻

M⁺, wherein M⁺ is a pharmaceutically acceptable cation;

a is an integers from 0-2, b is an integer from 0-3; and

,

Cy is an optionally substituted 5-membered heterocyclic ring bearing an N heteroatom.

9. The compound of claim 4, wherein W′

is —

N(R^e)—

;

R^e is —

(CH₂—

CH₂—

O)_2-6—

R^k, wherein R^k is a —

H, a linear, branched cyclic alkyl having 1 to 6 carbon atoms; and

V is —

S—

or —

SS—

.

10. The compound of claim 4, wherein L′

is represented by the following formula;

—

NR^e—

[CR_1″

R_2″

]_a—

S—

[CR_3″

R_4″

]_b—

COE.

11. The compound to claim 4, which is:

12. The compound of claim 4, wherein L′

is represented by the following formula;

—

NR^e—

[CR_1″

R_2″

]_a—

S-Cy-[CR_3″

R_4″

]_b—

COE.

13. The compound of claim 4, which is:

14. The compound of claim 1, wherein the compound is represented by any one of the following formulas:

15. The compound of claim 14, wherein Z^s is represented by any one of the following formulas:

16. The compound of claim 14, wherein W′

is —

N(R^e)—

; and

R^e is —

(CH₂—

CH₂—

O)_n—

R^k, wherein R^k is a —

H, a linear, branched cyclic alkyl having 1 to 6 carbon atoms.

17. The compound of claim 16, wherein R^k is —

H or -Me, n is 4, and q is 2.

18. The compound of claim 17, wherein R^x is a linear or branched alkyl having 1 to 6 carbon atoms.

19. The compound of claim 17, wherein R^x is —

(CH₂)_p—

(CR^fR^g)—

, wherein R^f and R^g are each independently —

H or a linear or branched alkyl having 1 to 4 carbon atoms; and

p is 0, 1, 2 or 3.

20. The compound of claim 19, wherein R^f and R^g are the same or different, and are —

H or -Me; and

p is 1.

21. The compound of claim 14, wherein:

the double line between N and C represents a single bond or a double bond, provided that when it is a double bond X is absent and Y is —

H, and when it is a single bond, X is —

H;

Y is —

OH or —

SO₃M;

M is —

H or a pharmaceutically acceptable cation;

X′ and

Y′

are both —

H;

A and A′

are both —

O—

;

R₆ is —

OMe; and

R^x is a linear or branched alkyl having 1 to 6 carbon atoms.

22. The compound of claim 1, wherein the double line between N and C represents a double bond.

23. The compound of claim 1, wherein the double line between N and C represents a single bond, X is —

H, the linking group thereto, or an amine protecting group; and

Y is selected from the group consisting of —

H, —

OR, —

OCOR′

, —

SR, —

NR′

R,″

an optionally substituted 5- or 6-membered nitrogen-containing heterocycle, —

SO₃M, —

SO₂M and OSO₃M.

24. The compound of claim 23, wherein Y is —

H, —

SO₃M, —

OH, —

OMe, —

OEt or —

NHOH.

25. The compound of claim 11, wherein M is —

H, Na⁺ or K⁺.

26. The compound of claim 1, wherein:

the double line between N and C represents a double bond;

Y is —

H;

W is C═

O;

R₁, R₂, R₁′

, R₂′

, R₄ and R₄′

are —

H;

one of R₃, or R₃′

is optionally the linking group and the other is —

H;

R₆ is —

OMe;

Z and Z′

are —

CH₂;

X′

is —

H;

Y′

is —

H; and

A and A′

are —

O—

.

27. A conjugate comprising:

a compound and a cell binding agent (CBA), wherein the compound comprises a linking group which covalently links the compound to the CBA, and wherein said compound is represented by any one of the following formulas;

28. A pharmaceutical composition comprising the conjugate of claim 27 and a pharmaceutically acceptable carrier.

29. A method of treating a cancer in a mammal comprising administering to said mammal a therapeutically effective amount of a conjugate of claim 27 and, optionally, a chemotherapeutic agent, wherein the cancer is selected from the group consisting of leukemia, lymphoma, multiple myeloma, cervical cancer, non-small cell lung cancer, small-cell lung cancer, head and neck cancer and colon cancer.

30. The conjugate of claim 27, wherein the compound is represented by any one of the following formulas:

31. The conjugate of claim 30, wherein L′

is the linking group, and L″ and

L′

″

are —

H.

32. The conjugate of claim 31, wherein L′

is represented by the following formula;

—

W′

—

R^x—

V—

R^y-J,

wherein;

W′ and

V are the same or different, and are each independently absent, or selected from the group consisting of —

CR^eR^e′

—

, —

O—

, —

O—

C(═

O)—

, —

C(═

O)—

O—

, —

S—

, —

SO—

, —

SO₂—

, —

CH₂—

S—

, —

CH₂O—

, —

CH₂NR^e—

, —

O—

(C═

O)O—

, —

O—

(C═

O)N(R^e)—

, —

N(R^e)—

, —

N(R^e)—

C(═

O)—

, —

C(═

O)—

N(R^e)—

, —

N(R^e)—

C(═

O)O—

, —

N(C(═

O)R^e)C(═

O)—

, —

N(C(═

O)R^e)—

, —

(O—

CH₂—

CH₂)_n—

, —

SS—

, —

C(═

O)—

, an amino acid, and a peptide having 2 to 8 amino acids;

R^x and R^y are the same or different, and are each independently absent or an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms, an aryl bearing 6 to 10 carbon atoms or a 3- to 8-membered hetereocyclic ring bearing 1 to 3 heteroatoms selected from the group consisting of O, N and S;

R^e and R^e′

are the same or different, and are selected from —

H, a linear, branched or cyclic alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms or —

(CH₂—

CH₂—

O)_n—

R^k, wherein R^k is a —

H, a linear, branched cyclic alkyl having 1 to 6 carbon atoms, optionally bearing NHR¹⁰¹ or NR¹⁰¹R¹⁰² group or a 5- or 6-membered nitrogen containing heterocycle, wherein R¹⁰¹ and R¹⁰² are each independently a linear, branched, or cyclic alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms;

n is an integer from 1 to 24;

J comprises the reactive group bonded thereto, and is selected from the group consisting of a maleimide, a haloacetamido, —

SH, —

SSR^d, —

CH₂SH, —

CH(Me)SH, —

C(Me)₂SH, —

NHR^c1, —

CH₂NHR^c1, —

NR^c1NH₂, —

COOH, and —

COE, wherein —

COE represents a reactive ester selected from the group consisting of N-hydroxysuccinimde ester, N-hydroxy sulfosuccinimide ester, nitrophenyl ester, dinitrophenyl ester, sulfo-tetrafluorophenyl ester, and pentafluorophenyl ester, and wherein R^c1 is —

H or an optionally substituted linear or branched alkyl having 1 to 4 carbon atoms, and,

R^d is selected from the group consisting of phenyl, nitrophenyl, dinitrophenyl, carboxynitrophenyl, pyridyl and nitropyridyl.

33. The conjugate of claim 32, wherein J is —

SS—

, a succinimide, or —

C(═

O)—

.

34. The conjugate of claim 32, wherein:

W′

is —

O—

, —

N(R^e)—

or —

N(R^e)—

C(═

O)—

;

R^e is —

H, -Me, or —

(CH₂—

CH₂—

O)_n-Me;

n is an integer from 2 to 6;

R^x is linear or branched alkyl bearing 1 to 6 carbon atoms;

V and R^y are absent; and

J is —

C(═

O)—

.

35. The conjugate of claim 32, wherein L′

is represented by the following formula;

—

W′

—

[CR_1″

R_2″

]_a—

V-[Cy]_0-1-[CR_3″

R_4″

]_b—

C(═

O)—

,

wherein;

R_1″

, R_2″

, and R_3″

are each independently —

H or -Me;

R_4″

is —

H, -Me, —

SO₃H, or —

SO₃⁻

M⁺, wherein M⁺ is a pharmaceutically acceptable cation;

a is an integers from 0-2, b is an integer from 0-3; and

,

Cy is an optionally substituted 5-membered heterocyclic ring bearing an N heteroatom.

36. The conjugate of claim 32, wherein W′

is —

N(R^e)—

;

R^e is —

(CH₂—

CH₂—

O)_2-6—

R^k, wherein R^k is a —

H, a linear, branched cyclic alkyl having 1 to 6 carbon atoms; and

V is —

S—

or —

SS—

.

37. The conjugate of claim 32, wherein L′

is represented by the following formula;

—

NR^e—

[CR_1″

R_2″

]_a—

S—

[CR_3″

R_4″

]_b—

C(═

O)—

.

38. The conjugate of claim 32, which is:

39. The conjugate of claim 38, wherein the antibody is huMy9-6.

40. The conjugate of claim 32, wherein L′

is represented by the following formula;

—

NR^e—

[CR_1″

R_2″

]_a—

S-Cy-[CR_3″

R_4″

]_b—

C(═

O)—

.

41. The conjugate of claim 32, which is:

42. The conjugate of claim 27, wherein the compound is represented by any one of the following formulas:

43. The conjugate of claim 42, wherein Z^s is represented by any one of the following formulas:

44. The conjugate of claim 42, wherein W′

is —

N(R^e)—

; and

R^e is —

(CH₂—

CH₂—

O)_n—

R^k, wherein R^k is a —

H, a linear, branched cyclic alkyl having 1 to 6 carbon atoms.

45. The conjugate of claim 44, wherein R^k is —

H or -Me, n is 4, and q is 2.

46. The conjugate of claim 45, wherein R^x is a linear or branched alkyl having 1 to 6 carbon atoms.

47. The conjugate of claim 46, wherein R^x is —

(CH₂)_p—

(CR^fR^g)—

, wherein R^f and R^g are each independently —

H or a linear or branched alkyl having 1 to 4 carbon atoms; and

p is 0, 1, 2 or 3.

48. The conjugate of claim 47, wherein R^f and R^g are the same or different, and are —

H or -Me; and

p is 1.

49. The conjugate of claim 42, wherein:

the double line between N and C represents a single bond or a double bond, provided that when it is a double bond X is absent and Y is —

H, and when it is a single bond, X is —

H;

Y is —

OH or —

SO₃M;

M is —

H or a pharmaceutically acceptable cation;

X′ and

Y′

are both —

H;

A and A′

are both —

O—

;

R₆ is —

OMe; and

R^x is a linear or branched alkyl having 1 to 6 carbon atoms.

50. The conjugate of claim 27, wherein the double line between N and C represents a double bond.

51. The conjugate of claim 27, wherein the double line between N and C represents a single bond, X is —

H, the linking group, or an amine protecting group; and

Y is selected from the group consisting of —

H, —

OR, —

OCOR′

, —

SR, —

NR′

R,″

an optionally substituted 5- or 6-membered nitrogen-containing heterocycle, —

SO₃M, —

SO₂M and a sulfate —

OSO₃M.

52. The conjugate of claim 51, wherein Y is —

H, —

SO₃M, —

OH, —

OMe, —

OEt or —

NHOH.

53. The conjugate of claim 52, wherein M is —

H, Na⁺ or K⁺.

54. The conjugate of claim 27, wherein:

the double line between N and C represents a double bond;

Y is —

H;

W is C═

O;

R₁, R₂, R₁′

, R₂′

, R₄ and R₄′

are —

H;

one of R₃, or R₃′

is optionally the linking group and the other is —

H;

R₆ is —

OMe;

Z and Z′

are —

CH₂;

X′

is —

H;

Y′

is —

H; and

A and A′

are —

O—

.

55. The conjugate of claim 27, wherein the cell-binding agent is an antibody, a single chain antibody, an antibody fragment that specifically binds to the target cell, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment that specifically binds to a target cell, a chimeric antibody, a chimeric antibody fragment that specifically binds to the target cell, a domain antibody, a domain antibody fragment that specifically binds to the target cell, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, or a nutrient-transport molecule.

56. The conjugate of claim 55, wherein the antibody is a resurfaced antibody, a resurfaced single chain antibody, or a resurfaced antibody fragment, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment thereof, a humanized antibody, a humanized single chain antibody, or a humanized antibody fragment.