Compositions and methods for glucose transport inhibition

Patent metadata

Field	Value
Publication number	US-2016137585-A1
Application number	US-201514935902-A
Country	US
Kind code	A1
Filing date	Nov 9, 2015
Priority date	Mar 24, 2010
Publication date	May 19, 2016
Grant date	—

Abstract

Glucose deprivation is an attractive strategy in cancer research and treatment. Cancer cells upregulate glucose uptake and metabolism for maintaining accelerated growth and proliferation rates. Specifically blocking these processes is likely to provide new insights to the role of glucose transport and metabolism in tumorigenesis, as well as in apoptosis. As solid tumors outgrow the surrounding vasculature, they encounter microenvironments with a limited supply of nutrients leading to a glucose deprived environment in some regions of the tumor. Cancer cells living in the glucose deprived environment undergo changes to prevent glucose deprivation-induced apoptosis. Knowing how cancer cells evade apoptosis induction is also likely to yield valuable information and knowledge of how to overcome the resistance to apoptosis induction in cancer cells. Disclosed herein are novel anticancer compounds that inhibit basal glucose transport, resulting in tumor suppression and new methods for the study of glucose deprivation in animal cancer research.

First claim

1 .- 6 . (canceled)

7 . A compound of formula (II):

wherein, R 1 is selected from the group consisting of hydrogen, alkyl, benzyl, aryl, and heteroaryl;
wherein, R 2 is selected from the group consisting of hydrogen, alkyl, benzyl, aryl, and heteroaryl;
wherein, X is selected from the group consisting of hydrogen, halo, alkyl, benzyl, aryl, heteroaryl, amino, cyano, and alkoxy; and
wherein, Y is selected from the group consisting of hydrogen, halo, alkyl, benzyl, aryl, heteroaryl, amino, cyano, and alkoxy;
or, a salt thereof.

8 .- 13 . (canceled)

14 . A compound of formula (IV):

wherein R 1 is selected from the group consisting of hydrogen, halo, alkyl, benzyl, amino, nitro, cyano, and alkoxy;
wherein R 2 is selected from the group consisting of hydrogen, alkyl, benzyl, aryl, and heteroaryl;
wherein R 3 is selected from the group consisting of hydrogen, alkyl, benzyl, aryl, and heteroaryl;
or a salt thereof.

15 . The compound of claim 14 , wherein R 2 and R 3 are aryl.

16 . The compound of claim 15 ,
wherein R 2 and R 3 are independently selected from the group consisting of 2-nitro-5-hydroxyphenyl, 2-, 3-, and 4-hydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dihydroxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, and 3,4,5-trihydroxyphenyl, 2,3,4,5- and 2,3,4,6-tetrahydroxyphenyl, perhydroxyphenyl, 2-amino-5-hydroxyphenyl, 2-cyano-5-hydroxyphenyl, 2-fluoro-5-hydroxyphenyl, 2-chloro-5-hydroxyphenyl, 2-bromo-5-hydroxyphenyl, 2-carboxy-5-hydroxyphenyl, 2-keto-5-hydroxyphenyl, 2-alkoxy-5-hydroxyphenyl, and 2-alkyl-5-hydroxyphenyl.

17 .- 18 . (canceled)

19 . The compound of claim 16 , wherein
R 1 is chlorine; R 2 is 2-nitro-5-hydroxyphenyl; and R 3 is 2-nitro-5-hydroxyphenyl.

20 . A method of treating cancer, the method comprising:
administering to a subject in need of such treatment a therapeutically effective amount of a basal glucose transport inhibitor compound of formula (IV) or a pharmaceutically acceptable salt thereof:

wherein R 1 is selected from the group consisting of hydrogen, halo, alkyl, benzyl, amino, nitro, cyano, and alkoxy;
wherein R 2 is selected from the group consisting of hydrogen, alkyl, benzyl, aryl, and heteroaryl;
wherein R 3 is selected from the group consisting of hydrogen, alkyl, benzyl, aryl, and heteroaryl; and
whereby administration of said basal glucose transport inhibitor compound of formula (IV) or a pharmaceutically acceptable salt thereof to the subject treats said cancer by inhibiting basal glucose transport in said subject.

21 . The method of claim 20 , wherein the cancer comprises solid malignant tumors.

22 . The method of claim 20 , wherein the cancer upregulates basal glucose transport.

23 . The method of claim 20 , wherein the basal glucose transport inhibitor compound of formula (IV) or pharmaceutically acceptable salt thereof is administered by at least one of the following methods: oral, topical, intra-arterial, intrapleural, intrathecal, intraventricular, subcutaneous, intraperitoneal, intraveneous, intravesicular, and gliadel wafers.

24 . The method of claim 20 , wherein the subject is a human.

25 . The method of claim 20 , further comprising administering to the subject in need of such treatment a second cancer drug.

26 . The method of claim 25 , wherein the second cancer drug is selected from the group consisting of methotrexate, doxorubicin hydrochloride, fluorouracil, everolimus, imiquimod, aldesleukin, alemtuzumab, pemetrexed disodium, palonosetron hydrochloride, chlorambucil, aminolevulinic acid, anastrozole, aprepitant, exemestane, nelarabine, arsenic trioxide, ofatumumab, bevacizumab, azacitidine, bendamustine hydrochloride, bexarotene, bleomycin, bortezomib, cabazitaxel, irinotecan hydrochloride, capecitabine, carboplatin, daunorubicin hydrochloride, cetuximab, cisplatin, cyclophosphamide, clofarabine, ifosfamide, cytarabine, dacarbazine, decitabine, dasatinib, degarelix, denileukin difitox, denosumab, dexrazoxane hydrochloride, docetaxel, rasburicase, epirubicin hydrochloride, oxaliplatin, eltrombopaq olamine, eribulin mesylate, erlotinib hydrochloride, etoposide phosphate, raloxifene hydrochloride, toremifane, fulvestrant, letrozole, filgrastim, fludarabim phosphate, pralatrexate, gefitinib, gemcitabine hydrochloride, gemcitibine-cisplatin, gemtuzumab ozogamicin, imatinib mesylate, trastuzamab, topotecan hydrochloride, ibritumomab tiuxetan, romadepsin, ixabepilone, palifermin, lapatinib ditosylate, lenalidomide, leucovorin calcium, leuprolide acetate, liposomal procarbazine hydrochloride, temozolomide, plerixafor, acetidine, sorafenib tosylate, nilotinib, tamoxifen citrate, romiplostim, paclitaxel, pazopanib hydrochloride, pegaspargase, prednisone, procarbazine hydrochloride, proleukin, rituximab, romidepsin, Talc, sorafenic tosylate, sunitinib malate, thalidomide, temsirolimus, toremifene, trastuzumub, pantiumumab, vinblastine sulfate, vincristine, vorinostat, zoledronic acid, and any combination thereof.

27 . The compound of claim 16 , wherein
R 1 is chlorine; R 2 is 2-bromo-5-hydroxyphenyl; and R 3 is 2-bromo-5-hydroxyphenyl.

28 . The compound of claim 16 , wherein
R 1 is chlorine; R 2 is 2-methyl-5-hydroxyphenyl; and R 3 is 2-methyl-5-hydroxyphenyl.

29 . The compound of claim 16 , wherein
R 1 is chlorine; R 2 is 2-chloro-5-hydroxyphenyl; and R 3 is 2-chloro-5-hydroxyphenyl.

30 . The compound of claim 14 , wherein the compound is selected from any one of:

or a salt thereof.

31 . The method of claim 20 , wherein the basal glucose transport inhibitor compound of formula (IV) is selected from any one of:

or a pharmaceutically acceptable salt thereof.

Assignees

• Univ Ohio

Inventors

• Chen Xiaozhuo
• Bergmeier Stephen

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D231/12

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07C211/48

  N-alkylated amines · CPC title

• C07D319/20

  with substituents attached to the hetero ring · CPC title

• C07D311/16

  substituted in position 7 · CPC title