Adenosine 2 receptor antagonists

Inventors

Anand, Neel K. • Aurrecoechea, Natalia • Brockway, Anthony James • Cai, Haiying • Cheng, Lin • Deng, Bo-Liang • O'Mahony, Donogh John Roger • Ren, Zhongxu • Zhang, Wen

Assignees

Nektar Therapeutics

Abstract

The instant disclosure provides novel adenosine receptor antagonist compounds, compositions, methods of making and methods of using. In a further aspect, a method of treating a subject in need thereof, comprising administering a therapeutically effective amount of any one or more of the compounds described herein. In some embodiments, the subject has cancer and the method is a method of treating cancer.

Core Innovation

The invention relates to adenosine A2A receptor (A2AR) selective antagonist compounds defined by a chemical formula in which multiple substituents are selected from H and D, including R1 selected from —CH3 and —CD3, R2 selected from H, F, Cl, —CF3, —OCH3, and —OCD3, and R3 selected from hydrogen, —CH3, —CD3, and —CF3. R4 and R5 are each selected from H and D or combine with intervening atoms to form a 5-membered ring, while X1, X2, and X3 are independently selected from —N— and —CH— and Y is selected from —CH— and —N—.

The compounds are characterized as adenosine A2A receptor (A2AR) selective antagonists and include deuterated variants, fluorinated and methoxy variants, pharmaceutically acceptable salts, hydrates, and solvates. A key described structural change is replacing a tetrahydrofuran in earlier A2AR antagonists with an oxazole, and the disclosure also refers to related scaffold variants and analog preparations, including substituted piperazine linked to a 1,2,4-triazolo[1,5-c]pyrimidine-5,7-diamine core with an oxazole substituent, linker/methoxyethoxy phenyl substituents, and N-methylation.

The document further describes formation of related compound structures and metabolite profiling using hepatocytes and liver microsomes with metabolite forms identified as M1–M5. It also reports analytical characterization including 1H NMR and MS (EI) with molecular ions (MH+), and references intermediate and final compounds, including compounds 6–10 and 19.

Claims Coverage

The provided independent claims include three main categories: a structurally defined adenosine A2A receptor (A2AR) selective antagonist compound, a composition comprising the compound and a pharmaceutically acceptable excipient, and a method of treating cancer by administering a therapeutically effective amount of the compound. The coverage is driven by multiple inventive structure constraints (R/R1–R5, X1–X3, and Y) and the A2AR selective antagonist and treatment context.

Across the independent claims, the core coverage centers on A2AR selective antagonist compounds defined by a structured formula with explicit selection rules for deuterated substituents and fluorinated or methoxy substituents. This structural definition is extended to compositions that include a pharmaceutically acceptable excipient and to a method claim for treating cancer using a therapeutically effective amount of the defined A2AR selective antagonist.

Stated Advantages

Documented Applications