GLUT4 Selective Inhibitors for Cancer Therapy

• US 20190321345A1
• Filed: 12/28/2017
• Published: 10/24/2019
• Est. Priority Date: 12/28/2016
• Status: Abandoned Application

• Current Assignee: Emory University, Northwestern University, Washington University In St Louis
• Original Assignee: Emory University, Northwestern University, Washington University In St Louis
• Inventors: Shanmugam, Malathy, Schiltz, Gary, Mishra, Rama, Hruz, Paul
• Application Number:
  US16/475,062
• Publication Number:
  US 20190321345A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 31/4433 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4465 only substituted in position 4
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 213/16 containing only one pyridine ring
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

This disclosure relates to GLUT 4 inhibitors and uses as chemotherapy agents. In certain embodiments, this disclosure relates to methods of treating or preventing cancer comprising administering an effective amount of a GLUT 4 inhibitor disclosed herein to a subject in need thereof. In certain embodiments, the GLUT 4 inhibitor has Formula (I), prodrugs, derivatives, or salts thereof wherein the substituents are reported herein. In certain embodiments, the GLUT 4 inhibitor is N-(3-(4-fluorophenethoxy)benzyl)-2-(4-methoxyphenyl)-N-(pyridin-4-ylmethyl)acetamide or salts thereof.

Claims

1. A compound having Formula (I):

2. The compound of claim 1 wherein R¹ is alkoxy substituted with aryl, and wherein the aryl group is optionally substituted with a halogen.

3. The compound of claim 1 which is N-(3-(4-fluorophenethoxy)benzyl)-2-(4-methoxyphenyl)-N-(pyridin-4-ylmethyl)acetamide or salts thereof.

4. The compound of claim 1 wherein R¹ is alkoxy substituted with a heterocyclyl, and wherein the heterocyclyl group is optionally substituted with R¹¹.

5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

6. The pharmaceutical composition of claim 5 is in the form of a pill, tablet, capsule, or cream.

7. The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable excipient is saccharide or polysaccharide.

8. A method of treating or preventing cancer comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.

9. The method of claim 8, wherein the compound is administered in combination with a second chemotherapeutic agent.

10. The method of claim 9, wherein the second chemotherapeutic agent is venetoclax, melphalan, dexamethasone, or combinations thereof.

11. The method of claim 9, wherein the second chemotherapeutic agent is gefitinib, erlotinib, docetaxel, cis-platin, 5-fluorouracil, gemcitabine, tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin, vincristine, vinblastine, vindesine, vinorelbine taxol, taxotere, etoposide, teniposide, amsacrine, topotecan, camptothecin bortezomib anagrelide, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene fulvestrant, bicalutamide, flutamide, nilutamide, cyproterone, goserelin, leuprorelin, buserelin, megestrol anastrozole, letrozole, vorazole, exemestane, finasteride, marimastat, trastuzumab, cetuximab, dasatinib, imatinib, bevacizumab, combretastatin, thalidomide, and/or lenalidomide or combinations thereof.

12. The method of claim 1, wherein the cancer is selected from the group consisting of multiple myeloma, leukemia, cervical, ovarian, colon, breast, gastric, skin, ovarian, pancreatic, prostate, head, neck, renal, and lung cancer.