ATROPISOMERISM FOR INCREASED KINASE INHIBITOR SELECTIVITY

• US 20200131191A1
• Filed: 12/18/2019
• Published: 04/30/2020
• Est. Priority Date: 08/13/2015
• Status: Active Grant

• Current Assignee: San Diego State University (California State University System)
• Original Assignee: San Diego State University (SDSU) Research Foundation
• Inventors: GUSTAFSON, Jeffrey L., SMITH, Davis E., HECHT, David, MARQUEZ, Isaac, TOENJES, Sean
• Granted Patent: US 11,345,707 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• 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: A61K 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The invention provides a series of conformationally stable kinase inhibitors, and methods of using the kinase inhibitors. The effect of atropisomerism on kinase selectivity was assessed, finding improved selectivity compared to rapidly interconverting parent compounds.

Claims

1. A method of inhibiting the growth of cancer cells comprising administering to a mammal having cancer a therapeutically effective amount of an atropisomerically stable atropisomer of Formula I or an enantiomer or salt thereof:

2. The method of claim 1 wherein R¹ is methyl, cyclopentyl, tert-butyl, iso-pentyl, or phenyl, and R² is H or Me.

3. The method of claim 1 wherein X is chloro, bromo or methyl.

4. The method of claim 1 wherein Y is chloro, bromo or methyl.

5. The method of claim 1 wherein Y is chloro.

6. The method of claim 1 wherein the atropisomer of Formula I is (R)- or (S)-1f:

7. The method of claim 1 wherein the atropisomer is the (R)-atropisomer and the atropisomer is selective for RET kinase, YES kinase, or a combination thereof.

8. The method of claim 7 wherein the cancer cells cause Gastrointestinal Stromal Tumors (GIST), medullary thyroid cancer, ER-positive breast cancer, non-small cell lung cancer, melanoma, or rhabdomyosarcoma.

9. The method of claim 1 wherein the atropisomer is the (S)-atropisomer and the atropisomer is selective for SRC kinase, ABL kinase, YES kinase, or a combination thereof.

10. The method of claim 9 wherein the cancer cells cause breast cancer, colon cancer, prostate cancer, Chronic Myeloid Leukemia, melanoma, or rhabdomyosarcoma.

11. The method of claim 1 wherein the atropisomerically stable atropisomer of Formula I is an atropisomer of Formula X or an enantiomer or salt thereof:

12. The method of claim 11 wherein the atropisomer is the (R)-atropisomer and the atropisomer is selective for RET kinase, YES kinase, or a combination thereof.

13. The method of claim 12 wherein the cancer cells cause Gastrointestinal Stromal Tumors (GIST), medullary thyroid cancer, ER-positive breast cancer, non-small cell lung cancer, melanoma, or rhabdomyosarcoma.

14. The method of claim 11 wherein the atropisomer is the (S)-atropisomer and the atropisomer is selective for SRC kinase, ABL kinase, YES kinase, or a combination thereof.

15. The method of claim 14 wherein the cancer cells cause breast cancer, colon cancer, prostate cancer, Chronic Myeloid Leukemia, melanoma, or rhabdomyosarcoma.

16. The method of claim 11 wherein the atropisomer of Formula X is:

17. A method of inhibiting the growth of cancer cells comprising administering to a mammal having cancer a therapeutically effective amount of an atropisomerically stable atropisomer comprising Formula IA or an enantiomer or salt thereof:

18. The method of claim 17 wherein the atropisomerism rotational blocking moiety of the atropisomer forms a barrier to rotation of about 27 kcal/mol to about 30 kcal/mole, and the atropisomer has a half-life of about 8 days to about 8 years.

19. The method of claim 18 wherein the cancer cells cause breast cancer, colon cancer, Gastrointestinal Stromal Tumors (GIST), leukemia, lung cancer, melanoma, prostate cancer, rhabdomyosarcoma, or thyroid cancer.

20. A method to modulate the selectivity of a promiscuous kinase inhibitor that comprises a rotatable phenyl moiety comprising adding an atropisomerism rotational blocking moiety to the phenyl moiety of the inhibitor, thereby increasing or decreasing the selectivity of the kinase inhibitor for specific kinases.