INHIBITORS OF CREATINE TRANSPORT AND USES THEREOF

• US 20190315680A1
• Filed: 04/19/2019
• Published: 10/17/2019
• Est. Priority Date: 04/30/2014
• Status: Active Grant

• Current Assignee: Inspirna Incorporated
• Original Assignee: Rgenix Inc.
• Inventors: Martinez, Eduardo J., Tavazoie, Sohail F.
• Granted Patent: US 10,717,704 B2
• Time in Patent Office: Days
• 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 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• 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 31/4168 having a nitrogen attached in position 2, e.g. clonidine
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/4427 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07C 257/14 having carbon atoms of amidino groups bound to acyclic carbon atoms
• CPC Class Codes: C07C 259/14 having carbon atoms of hydroxamidine groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 : with a four-membered ring
• CPC Class Codes: C07C 275/70 : Compounds containing any of the groups , e.g. isoureas
• CPC Class Codes: C07C 279/14 : being further substituted by carboxyl groups
• CPC Class Codes: C07C 279/16 : having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 279/26 : X and Y being nitrogen atoms, i.e. biguanides
• CPC Class Codes: C07C 279/36 : Substituted N-nitroguanidines
• CPC Class Codes: C07C 281/16 : Compounds containing any of the groups , e.g. aminoguanidine
• CPC Class Codes: C07C 281/18 : the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones
• CPC Class Codes: C07C 309/15 : the nitrogen atom of at least one of the amino groups being part of any of the groups , X being a hetero atom, Y being any atom
• CPC Class Codes: C07C 313/34 : either X or Y, but not both, being nitrogen atoms, e.g. N-sulfenylureas
• CPC Class Codes: C07D 205/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 205/08 : with one oxygen atom directly attached in position 2, e.g. beta-lactams
• CPC Class Codes: C07D 207/16 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 207/22 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/76 : to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/26 : Radicals substituted by carbon atoms having three bonds to hetero atoms
• CPC Class Codes: C07D 233/46 : with only hydrogen atoms attached to said nitrogen atoms
• CPC Class Codes: C07D 233/52 : with hetero atoms directly attached to said nitrogen atoms
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 233/88 : Nitrogen atoms, e.g. allantoin
• CPC Class Codes: C07D 239/06 : having one double bond between ring members or between a ring member and a non-ring member
• CPC Class Codes: C07D 239/14 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 249/14 : Nitrogen atoms
• CPC Class Codes: C07D 253/06 : 1,2,4-Triazines
• CPC Class Codes: C07D 257/08 : Six-membered rings
• CPC Class Codes: C07D 295/32 : acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07F 9/097 : Compounds containing the structure P(=O)-O-N
• CPC Class Codes: C07F 9/2458 : of aliphatic amines
• CPC Class Codes: C07F 9/3808 : Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4006 : Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/48 : Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof
• CPC Class Codes: C07F 9/568 : Four-membered rings
• CPC Class Codes: C07F 9/572 : Five-membered rings
• CPC Class Codes: C07F 9/6506 : having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07H 19/06 : Pyrimidine radicals

Abstract

This invention relates to compounds that inhibit creatine transport and/or creatine kinase, pharmaceutical compositions including such compounds, and methods of utilizing such compounds and compositions for the treatment of cancer.

Claims

1. A method for treating cancer, comprising administering to a subject in need thereof, a compound having the structure:

13. The method of claim 1, wherein said cancer is breast cancer, colon cancer, renal cell cancer, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, ovarian cancer, pancreatic cancer, esophageal cancer, prostate cancer, sarcoma, or melanoma.

14. The method of claim 1, wherein said cancer is gastrointestinal cancer.

15. The method of claim 14, wherein said gastrointestinal cancer is esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, gallbladder cancer, colorectal cancer, anal cancer, mucosa-associated lymphoid tissue cancer, gastrointestinal stromal tumors, a cancer of the biliary tree, or a gastrointestinal carcioid tumor.

16. The method of claim 1, wherein said cancer is a drug resistant cancer.

17. The method of claim 1 further comprising administering an additional antiproliferative agent.

18. The method of claim 17, wherein said additional antiproliferative agent is capecitabine, gemcitabine, fluorouracil, FOLFOX (5-FU, leucovorin, and Eloxatin), FOLFIRI (5-FU, leucovorin, and Camptosar), EOX (Epirubicin, Oxaliplatinum, and Xeloda), Taxotere, Erbitux, Zaltrap, Vectibix, Ramucirumab, Tivozanib, Stivarga, CRS-207, or a PD-1 or PDL-1 antibody.

2. A method of slowing the spread of a migrating cancer, comprising administering to a subject in need thereof, a compound having the structure:

3. The method of claim 2, wherein said method comprises the suppression of metastatic colonization of said migrating cancer in the liver.

4. The method of claim 2, wherein said migrating cancer is metastatic cancer.

5. The method of claim 4, wherein the metastatic cancer comprises cells exhibiting migration and/or invasion of migrating cells.

6. The method of claim 4, wherein said metastatic cancer comprises cells exhibiting endothelial recruitment and/or angiogenesis.

7. The method of claim 2, wherein said migrating cancer spreads via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces.

8. The method of claim 2, wherein said migrating cancer spreads via the lymphatic system.

9. The method of claim 2, wherein said migrating cancer spreads hematogenously.

10. The method of claim 2, wherein said migrating cancer is a cell migration cancer.

11. The method of claim 10, wherein said cell migration cancer is a non-metastatic cell migration cancer.

12. The method of claim 11, where said cell migration cancer is ovarian cancer, mesothelioma, or primary lung cancer.

19. A method of treating metastatic cancer in a subject in need thereof comprising:

(a) providing a subject identified to have, or to be at risk of having, metastatic cancer on the basis of the expression level of miR-483-5p and/or miR-551a is below a predetermined reference value or the expression level of CKB and/or SLC6a8 is above a predetermined reference value; and

(b) administering to said subject an effective amount of a compound having the structure;

20. A method for treating metastatic cancer in a subject in need thereof, comprising contacting creatine transport channel SLC6a8 with a compound having the structure: