Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor and/or a JAK-2 Inhibitor

Patent metadata

Field	Value
Publication number	US-2017136014-A1
Application number	US-201515319740-A
Country	US
Kind code	A1
Filing date	Jun 17, 2015
Priority date	Jun 17, 2014
Publication date	May 18, 2017
Grant date	—

Abstract

Therapeutic combinations of a Janus kinase-2 (JAK-2) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, and/or a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms, are described. In some embodiments, the invention provides pharmaceutical compositions comprising combinations of (1) a PI3K-δ inhibitor and a BTK inhibitor, (2) a JAK-2 inhibitor and a BTK inhibitor, or (3) a JAK-2 inhibitor, PI3K-δ inhibitor, and BTK inhibitor, and methods of using the pharmaceutical compositions for treating a disease, in particular a cancer.

First claim

1 - 68 . (canceled)

69 . A method of treating a hyperproliferative disease, comprising co-administering, to a mammal in need thereof, therapeutically effective amounts of (1) a Janus kinase-2 (JAK-2) inhibitor, and (2) a Bruton's tyrosine kinase (BTK) inhibitor.

70 . The method of claim 69 , wherein the BTK inhibitor is selected from the group consisting of:

71 . The method of claim 69 , wherein the BTK inhibitor is selected from the group consisting of:

72 . The method of claim 69 , wherein the JAK-2 inhibitor is selected from the group consisting of:

73 . The method of claim 69 , further comprising the step of administering a therapeutically effective amount of an anti-CD20 antibody selected from the group consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, and ibritumomab.

74 . The method of claim 69 , further comprising the step of administering a phosphoinositide 3-kinase (PI3K) inhibitor.

75 . The method of claim 74 , wherein the PI3K inhibitor is a PI3K-δ inhibitor.

76 . The method of claim 74 , wherein the PI3K inhibitor is selected from the group consisting of:

77 . The method of claim 69 , wherein the hyperproliferative disease is a cancer, and the cancer is a B cell hematological malignancy, and wherein the B cell hematological malignancy is selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenström's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, and myelofibrosis.

78 . The method of claim 69 , wherein the hyperproliferative disease is a cancer, and wherein the cancer is a solid tumor cancer, and wherein the solid tumor cancer is selected from the group consisting of bladder cancer, non-small cell lung cancer, cervical cancer, anal cancer, pancreatic cancer, squamous cell carcinoma including head and neck cancer, renal cell carcinoma, melanoma, ovarian cancer, small cell lung cancer, glioblastoma, gastrointestinal stromal tumor, breast cancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer, oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney cancer, liver cancer, prostate cancer, esophageal cancer, testicular cancer, gynecological cancer, colon cancer, and brain cancer.

79 . A method of treating a cancer in a human comprising the step of co-administering (1) a therapeutically effective amount of a Janus kinase-2 (JAK-2) inhibitor, and (2) a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor, wherein the therapeutically effective amount is effective to inhibit signaling between a tumor cell of the cancer and at least one tumor microenvironment selected from the group consisting of macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts.

80 . The method of claim 79 , wherein the cancer is a solid tumor cancer selected from the group consisting of bladder cancer, non-small cell lung cancer, cervical cancer, anal cancer, pancreatic cancer, squamous cell carcinoma including head and neck cancer, renal cell carcinoma, melanoma, ovarian cancer, small cell lung cancer, glioblastoma, gastrointestinal stromal tumor, breast cancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer, oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney cancer, liver cancer, prostate cancer, esophageal cancer, testicular cancer, gynecological cancer, colon cancer, and brain cancer.

81 . The method of claim 79 , wherein the BTK inhibitor is selected from the group consisting of:

82 . The method of claim 79 , wherein the JAK-2 inhibitor is selected from the group consisting of:

83 . The method of claim 79 , further comprising the step of administering a therapeutically effective amount of a phosphoinositide 3-kinase (PI3K) inhibitor.

84 . The method of claim 83 , wherein the PI3K inhibitor is selected from the group consisting of:

85 . A pharmaceutical composition comprising (1) a Janus kinase-2 (JAK-2) inhibitor; and (2) a Bruton's tyrosine kinase (BTK) inhibitor present in an amount therapeutically effective to treat a hyperproliferative disease.

86 . The composition of claim 85 , wherein the BTK inhibitor is selected from the group consisting of:

87 . The composition of claim 85 , wherein the BTK inhibitor is selected from the group consisting of:

88 . The composition of claim 85 , wherein the JAK-2 inhibitor is selected from the group consisting of:

89 . The composition of claim 85 , further comprising a therapeutically effective amount of an anti-CD20 antibody selected from the group consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, and ibritumomab.

90 . The composition of claim 85 , further comprising a phosphoinositide 3-kinase (PI3K) inhibitor.

91 . The composition of claim 90 , wherein the PI3K inhibitor is a PI3K-δ inhibitor.

92 . The composition of claim 91 , wherein the PI3K-δ inhibitor is selected from the group consisting of:

93 . The composition of claim 85 , wherein the hyperproliferative disease is a cancer, and the cancer is a B cell hematological malignancy, and wherein the B cell hematological malignancy is selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenström's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, and myelofibrosis.

Assignees

• Acerta Pharma Bv

Inventors

• Hamdy Ahmed
• Rothbaum Wayne
• Izumi Raquel
• Lannutti Brian
• Covey Todd
• Ulrich roger
• Johnson Dave
• Barf Tjeerd
• Kaptein Allard

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title

• A61K31/4985 Primary

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title