Atropisomerism for increased kinase inhibitor selectivity

• US 10,550,124 B2
• Filed: 08/15/2016
• Issued: 02/04/2020
• 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 Foundation
• Inventors: Gustafson, Jeffrey L., Smith, Davis E., Hecht, David, Marquez, Isaac, Toenjes, Sean
• Primary Examiner(s): Pagano, Alexander R
• Application Number:
  US15/752,128
• Publication Number:
  US 20180230154A1
• Time in Patent Office: 1,268 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. An atropisomer comprising Formula IA:

11. The atropisomer of claim 1 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.

2. An atropisomer of Formula I:

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

4. The atropisomer of claim 2 wherein X is chloro, bromo, or methyl.

5. The atropisomer of claim 2 wherein Y is chloro.

6. The atropisomer of claim 2 wherein the atropisomer is an atropisomer of Formula X:

7. The atropisomer of claim 6 wherein X is chloro or bromo.

8. The atropisomer of claim 6 wherein the atropisomer is:

9. A pharmaceutical composition comprising the atropisomer of claim 2 in combination with a pharmaceutically acceptable diluent, carrier, or excipient.

12. The atropisomer of claim 2, wherein Y is chloro, bromo or methyl.

10. A conformationally stable atropisomer of Formula X: