Proteasome inhibitors and methods of using the same

• US 9,233,115 B2
• Filed: 07/24/2013
• Issued: 01/12/2016
• Est. Priority Date: 08/14/2003
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Bernardini, Raffaella, Bernareggi, Alberto, Cassara, Paolo G., Chatterjee, Sankar, D'Arasmo, Germano, De Munari, Sergio, Ferretti, Edmondo, Iqbal, Mohamed, Menta, Ernesto, Messina McLaughlin, Patricia A., Oliva, Ambrogio
• Primary Examiner(s): Hui, San-Ming
• Assistant Examiner(s): LEE, ANDREW P
• Application Number:
  US13/949,346
• Publication Number:
  US 20140088042A1
• Time in Patent Office: 902 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/12 for electrolyte homeostasis
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07F 5/025 : Boronic and borinic acid compounds

Abstract

The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.

Claims

1. A method for treating a cancer selected from the group consisting of skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, smooth muscle tissue, leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma comprising administering to a mammal having or predisposed to said cancer a therapeutically effective amount of a compound of Formula (I)

2. The method of claim 1, wherein X is R^AC(═

O)—

.

3. The method of claim 1, whereinX is R^AC(═

O)— and

R^A is aryl optionally substituted with 1-3 substituents selected from the group consisting of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, alkyl-OC(═

O)—

, alkyl-C(═

O)—

, alkyl-OC(═

O)NH—

, alkyl-C(═

O)NH—

, —

OH, —

CN, alkyl-S(═

O)—

, and alkyl-S(═

O)₂.

4. The method of claim 1, wherein the cancer is selected from the group consisting of skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, and smooth muscle tissue.

5. The method of claim 1, wherein the cancer is selected from the group consisting of leukemia, lymphoma, non-Hodgkin'"'"'s lymphoma, myeloma, and multiple myeloma.

6. The method of claim 1, wherein the cancer is multiple myeloma.

7. The method of claim 1, comprising administering the compound in combination with one or more antitumor or anticancer agents and/or radiotherapy.

8. The method of claim 1, wherein the cancer is leukemia.

9. The method of claim 1, wherein the cancer is non-Hodgkin'"'"'s lymphoma.

10. The method of claim 1, wherein the cancer is lymphoma.