SHEDDASE INHIBITORS COMBINED WITH CD30-BINDING IMMUNOTHERAPEUTICS FOR THE TREATMENT OF CD30 POSITIVE DISEASES

• US 20070280943A1
• Filed: 06/04/2007
• Published: 12/06/2007
• Est. Priority Date: 06/05/2006
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Original Assignee: Incyte Corporation
• Inventors: Friedman, Steven M., Scherle, Peggy A., Vaddi, Krishna, Newton, Robert C.
• Granted Patent: US 7,910,108 B2
• Time in Patent Office: Days
• US Class Current: 424/144.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95

Abstract

The present invention is directed to pharmaceutical methods for the treatment of CD30 positive diseases, such as Hodgkin'"'"'s disease, by administration of a combination of at least one sheddase inhibitor and at least one anti-CD30 immunotherapeutic.

Claims

1. A method of treating a disease in a patient, comprising administering to said patient:

i) an antibody or antibody-conjugate which binds CD30; and

ii) a compound of Formula I;

2. The method of claim 1 wherein A is C(O)NHOH.

3. The method of claim 1 wherein X is (CR_dR_f)_jNR_b or (CH₂)_j.

4. The method of claim 1 wherein X is (CR_dR_f)_jNR_b.

5. The method of claim 1 wherein X is CH₂NR_b, CH₂CH₂, or CH₂.

6. The method of claim 1 wherein X is CH₂NR_b.

7. The method of claim 1 wherein Y is (CR_dR_f)_jNR_b or (CH₂)_j.

8. The method of claim 1 wherein Y is (CH₂)_j.

9. The method of claim 1 wherein Y is CH₂NR_b, CH₂CH₂, or CH₂.

10. The method of claim 1 wherein Y is CH₂.

11. The method of claim 1 wherein B is (CH₂)_n.

12. The method of claim 1 wherein B is CH₂.

13. The method of claim 1 wherein G is (CH₂)_n.

14. The method of claim 1 wherein G is CH₂.

15. The method of claim 1 wherein M is CO.

16. The method of claim 1 wherein U is absent or NR_b.

17. The method of claim 1 wherein U is absent.

18. The method of claim 1 wherein U′

is absent, C_1-10 alkylene substituted with 0 to 5 R_a, O, C═

O, or O—

(C_1-10 alkylene).

19. The method of claim 1 wherein U′

is absent or C_1-10 alkylene substituted with 0 to 5 R_a.

20. The method of claim 1 wherein U′

is absent.

21. The method of claim 1 wherein V is C_3-13 carbocyclyl substituted with 0-5 R_e or heterocyclyl substituted with 0-5 R_e.

22. The method of claim 1 wherein V is heterocyclyl substituted with 0-5 R_e.

23. The method of claim 1 wherein V is piperazin-1,4-diyl, piperidin-1,3-diyl, piperidin-1,4-diyl, 3,6-dihydropyridin-1,4(2H)-diyl, azetidin-1,4-yl, pyrrolidin-1,3-diyl, 2,5-dihydro-1H-pyrrol-1,3-diyl, 2,3,4,7-tetrahydro-1H-azepin-1,5-diyl, azepan-1,4-diyl, or 2,3-dihydro-1H-indol-1,5-diyl.

24. The method of claim 1 wherein V is piperazin-1,4-diyl.

25. The method of claim 1 wherein V′

is C_1-8 alkyl, C_3-13 carbocyclyl substituted with 0-5 R_e or heterocyclyl substituted with 0-5 R_e.

26. The method of claim 1 wherein V′

is C_3-13 carbocyclyl substituted with 0-5 R_e or heterocyclyl substituted with 0-5 R_e.

27. The method of claim 1 wherein V′

is heterocyclyl substituted with 0-5 R_e.

28. The method of claim 1 wherein V′

is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 5-(trifluoromethyl)pyridin-2-yl, 3-(trifluoromethyl)pyridin-2-yl, 4,7,-dihydrothieno[2,3-c]pyridine-6(5H)-yl, 3,4-dihydroisoquinolin-2-(1H)-yl, 2,3-dihydro-1H-indol-1-yl, 4-phenyl-1,3-thiazol-2-yl, 4-tert-butyl-1,3-thiazol-2-yl, 2-thienyl, 3-thienyl, dibenzo[b,d]furan-4-yl, 1-methyl-1H-benzimidazol-6-yl, 1-ethyl-1H-benzimidazol-6-yl, 1,3-benzothiazol-6-yl, 1,4,5,6-tetrahydrobenzo[f]isoquinolin-3(2H)-yl, 2,3-dihydrobenzofuran-5-yl, 3,3-dimethyl-2,3-dihydrobenzofuran-5-yl, pyrazin-2-yl, 1,3,4,9-tetrahydro-2H-β

-carbolin-2-yl, 9-methyl-1,3,4,9-tetrahydro-2H-β

-carbolin-2-yl, 3,4,10,10a-tetrahydropyrazino[1,2-a]-indol-2(1H)-yl, quinolin-2-yl, quinolin-4-yl, 2-methyl-quinolin-4-yl, 3,3a,8,8a-tetrahydroindeno[1,2-c]pyrrol-2(1H)-yl, piperidin-1-yl, 1,4,4a,5,6,10b-hexahydrobenzo[f]isoquinolin-3-(2H)-yl, 1,3,3a,4,5,9b-hexahydro-2H-benzo[e]isoindol-2-yl, 1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinolin-3-yl, 1-methyl-1H-indazol-5-yl, or 1,3-dihydro-1′

H-spiro[indene-2,4′

-piperdin]-1′

-yl.

29. The method of claim 1 wherein V′

is C_3-13 carbocyclyl substituted with 0-5 R_e.

30. The method of claim 1 wherein V′

is phenyl, cyclohexyl, 2-naphthyl, or 5,6,7,8-tetrahydronaphthalen-2-yl.

31. The method of claim 1 wherein V′

is phenyl substituted with 0-5 R_e.

32. The method of claim 1 wherein V′

is phenyl.

33. The method of claim 1 wherein R_b is H, T, C_1-6 alkylene-T, C(O)O(CR_b′

R_c′

)_r-T, C(O)(CR_b′

R_c′

)_r-T, or S(O)_p(CR_b′

R_c′

)_r-T.

34. The method of claim 1 wherein R_b is C(O)O(CR_b′

R_c′

)_r-T.

35. The method of claim 1 wherein R_b is C(O)OCH₃.

36. The method of claim 1 wherein R₁ is H.

37. The method of claim 1 wherein R₂ is H.

38. The method of claim 1 wherein:

A is C(O)NHOH;

B and G are independently selected from (CH₂)_n, (CH₂)_nC(O), (CH₂)_nC(S), (CR_dR_f)_nNR₈, (CR_dR_f)_nO(CR_dR_f)_r, (CR_dR_f)_nS(CR_dR_f)_r, OC(O)NR₈, O, NR₈, S(O)_m, S, C(O)NR₈(CR_dR_f)_n and C(O)(CR_dR_f)_n;

X and Y are independently selected from absent, (CH₂)_j, C_1-10 alkylene substituted with 0 to 3 R_a, NR_b, or (CR_dR_f)_jNR_b;

M is CO;

U is absent, C_1-10 alkylene substituted with 0 to 5 R_a, or NR_b;

V is absent, C_3-13 carbocyclyl substituted with 0-5 R_e or heterocyclyl substituted with 0-5 R_e;

U′

is absent, C_1-10 alkylene substituted with 0 to 5 R_a, O, NR_bS(O)_m, C═

O, NR_bC(O), NR_bC(O)O, NR_bC(O)NR_b, C(O)O, O—

(C₁-C₁₀ alkylene) or NR_bS(O)NR_b;

V′

is H, C_1-8 alkyl, NR_bR_c, C_3-13 carbocyclyl substituted with 0-5 R_e or heterocyclyl substituted with 0-5 R_e;

R_e is H, T, C_1-8 alkylene-T, (CR_b′

R_c′

)_r—

O—

(CR_b′

R_c′

)_r-T, OH, Cl, F, Br, I, CN, NO₂, NR^IR^II, COR^III, OR^IV, CONR^IR^II, C_1-8 haloalkyl, C_3-13 carbocyclyl, or heterocyclyl;

R_b and R_c are independently selected from H, C(O)O(CR_b′

R_c′

)_r-T and S(O)_p(CR_b′

R_c′

)_r-T;

R_d and R_f are independently selected from H and C_1-6 alkyl;

R₁ and R₂ are independently selected from H and C_1-6 alkyl; and

R₄′ and

R₅′

are independently selected from H, C(O)NR_a′

(CR_c′

R_b′

)_r-T, C(O)O(CR_b′

R_c′

)_r-T and S(O)_p(CR_b′

R_c′

)_r-T.

39. The method of claim 1 wherein:

A is C(O)NHOH;

B and G are independently selected from (CH₂)_n, (CH₂)_nC(O), (CR_dR_f)_nNR₈, O, NR₈, S(O)_m, S, C(O)NR₈(CR_dR_f)_n and C(O)(CR_dR_f)_n;

X and Y are independently selected from absent, (CH₂)_j, CH₂NR_b or CH₂CH₂NR_b;

M is CO;

U is absent or NR_b;

V is heterocyclyl substituted with 0-5 R_e;

U′

is absent, C_1-10 alkylene substituted with 0 to 5 R_a, or O;

V′

is NR_bR_c, C_3-13 carbocyclyl substituted with 0-5 R_e or heterocyclyl substituted with 0-5 R_e;

R_e is H, T, OH, Cl, F, CN, or C_1-8 haloalkyl;

R_b is H, C(O)NR_a′

(CR_c′

R_b′

)_r-T, C(O)O(CR_b′

R_c′

)_r-T, C(O)(CR_b′

R_c′

)_r-T, S(O)_p(CR_b′

R_c′

)_r-T, (CR_c′

R_b′

)_r—

O—

(CR_c′

R_b′

)_r-T, C(NR_a′

R_a′

)(═

N—

CN) or C(NR_a′

R_a′

)(═

CHNO₂);

R_c is H, T, C_1-6 alkylene-T, C_2-8 alkenylene-T or C_2-6 alkynylene-T;

R_d and R_f are independently selected from H and C_1-6 alkyl;

R_a′

is H or C_1-6 alkyl;

R_b′ and

R_c′

are independently selected from H, C_1-6 alkyl, OH, Cl, F, Br, I, CN, NO₂, NR^IR^II, OR^IV and C_1-8 haloalkyl;

R₁ and R₂ are each H;

R₄′ and

R₅′

are each H;

j is 1 or 2;

n is 0, 1, 2, 3 or 4; and

r is 0, 1 or 2.

40. The method of claim 1 wherein:

A is C(O)NHOH;

B and G are each (CH₂)_n;

X and Y are independently selected from absent, (CH₂)_j, CH₂NR_b or NR_bCH₂CH₂;

M is CO;

U is absent;

V is heterocyclyl substituted with 0-5 R_e;

U′

is absent, C_1-10 alkylene substituted with 0 to 5 R_a, or O;

V′

is H, C_1-8 alkyl, NR_bR_c, C_3-13 carbocyclyl substituted with 0-5 R_e or heterocyclyl substituted with 0-5 R_e;

R_b is H, C(O)NR_a′

(CR_c′

R_b′

)_r-T, C(O)O(CR_b′

R_c′

)_r-T, C(O)(CR_b′

R_c′

)_r-T, C(NR_a′

R_a′

)(═

N—

CN) or C(NR_a′

R_a′

)(═

CHNO₂);

R_c is H, T, C_1-6 alkylene-T, C_2-8 alkenylene-T or C_2-6 alkynylene-T;

R_a′

is H or C_1-6 alkyl;

R_b′ and

R_c′

are each, independently, H, C_1-6 alkyl, OH, Cl, F, Br, I, CN, NO₂, NR^IR^II, OR^IV or C_1-8 haloalkyl;

R₁ and R₂ are each H;

R₄′ and

R₅′

are each H;

j is 1 or 2;

n is 0, 1, 2, 3 or 4; and

r is 0, 1 or 2.

41. The method of claim 1 wherein:

A is C(O)NHOH;

B and G are each CH₂;

X is CH₂NR_b;

Y is CH₂;

M is CO;

U and U′

are each absent;

V is piperazin-1,4-diyl;

V′

is phenyl;

R_b is C(O)O(CR_b′

R_c′

)_r-T;

R_b′

, R_c′

, R₁, R₂, R₄′

, R₅′ and

T are each H; and

r is 1.

42. The method of claim 1 where said compound of Formula I is methyl (6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate or pharmaceutically acceptable salt thereof.

43. The method of claim 1 wherein said disease is characterized by expression of CD30.

44. The method of claim 1 wherein said disease is characterized by shedding of CD30.

45. The method of claim 1 wherein said disease is cancer.

46. The method of claim 45 wherein said disease is CD30 positive lymphoma.

47. The method of claim 45 wherein said disease is Hodgkin'"'"'s disease (HD), Burkitt'"'"'s lymphoma, anaplastic large-cell lymphoma (ALCL), cutaneous T-cell lymphoma, nodular small cleaved-cell lymphoma, lymphocytic lymphoma, peripheral T-cell lymphomas, Lennert'"'"'s lymphoma, immunoblastic lymphoma, T-cell leukemia, adult T-cell leukemia (ATL), and entroblastic/centrocytic follicular lymphoma.

48. The method of claim 45 wherein said disease is Hodgkin'"'"'s disease (HD), anaplastic large-cell lymphoma (ALCL), or adult T-cell leukemia (ATL).

49. The method of claim 1 wherein an antibody which binds CD30 is administered.

50. The method of claim 49 wherein said antibody is a monoclonal antibody.

51. The method of claim 49 wherein said antibody is a human, humanized, or chimeric antibody.

52. The method of claim 49 wherein said antibody is 17G1, 2H9, or 5F11.

53. The method of claim 1 wherein an antibody-conjugate which binds CD30 is administered.

54. The method of claim 53 wherein said antibody-conjugate is an anti-CD30 antibody conjugated with a cytotoxin or radiotoxin.

55. The method of claim 54 wherein said antibody-conjugate is a monoclonal anti-CD30 antibody conjugated with a cytotoxin or radiotoxin.

56. The method of claim 55 wherein said antibody-conjugate is a human, humanized, or chimeric anti-CD30 antibody conjugated with a cytotoxin or radiotoxin.

57. The method of claim 1 wherein said administering is carried out such that the physiological effects of both said compound of Formula I and said antibody or antibody conjugate overlap in said patient.

58. A method of treating a disease in a patient, wherein said disease is characterized by expression of CD30 and CD30 shedding, comprising administering to said patient:

i) an antibody or antibody-conjugate which binds CD30; and

ii) methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate or pharmaceutically acceptable salt thereof,

wherein the amount of said antibody or antibody-conjugate and the amount of said compound or pharmaceutically acceptable salt thereof together provide a therapeutically effective amount.

59. A method of treating cancer in a patient, comprising administering to said patient:

i) an antibody or antibody-conjugate which binds CD30; and

ii) methyl(6S,7S)-7-[(hydroxyamino)carbonyl]-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-5-carboxylate or pharmaceutically acceptable salt thereof,

wherein the amount of said antibody or antibody-conjugate and the amount of said compound or pharmaceutically acceptable salt thereof together provide a therapeutically effective amount.

60. A composition comprising:

i) an antibody or antibody-conjugate that binds CD30;

ii) a pharmaceutically acceptable carrier; and

iii) a compound of Formula I;