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Publication Number
US-11266638-B2
Publication Date
2022-03-08
Expiration Date
Abstract
The present disclosure relates to choline salts, and crystalline forms thereof, of a compound which is N—((S-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3- (trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, which is useful in the treatment and prevention of a Retroviridae viral infection including an infection caused by the HIV virus.
Core Innovation
The invention relates to a choline (N,N,N-trimethylethanolammonium) salt of an HIV capsid inhibitor, referred to as Compound 1, for treating or preventing HIV infection and Retroviridae infections. The disclosure describes the salt and crystalline solid forms of the choline salt as pharmaceutical forms for administration to a subject in need thereof.
The disclosure includes crystalline and solvated solid forms of the choline salt, including crystalline Form I through crystalline Form VII, as well as ethanol, tetrahydrofuran, and methyl tert-butyl ether solvates. The crystalline solids are characterized by XRPD peak sets and DSC melting-onset temperatures, and the compound material is also characterized by MS and NMR.
Broad therapeutic use is described for treating or preventing HIV infection, including prophylactic use such as PrEP and post-exposure use such as PEP, and use in combination therapy with other anti-HIV drugs. The document also describes re-equilibration behavior between atropisomers Isomer A and Isomer B and processes to enrich one atropisomer salt relative to the other under specified solvents.
Claims Coverage
The independent claims cover administering a therapeutically effective amount of a specific pharmaceutically acceptable N,N,N-trimethylethanolammonium salt of an HIV capsid inhibitor, or a crystalline form of that salt, for treating or preventing HIV infection. Dependent coverage adds combination therapy and specific crystalline form constraints, including XRPD and DSC characterization features.
Treating or preventing HIV infection by administering a choline acetamide salt or crystalline form
A method of treating or preventing human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of a pharmaceutically acceptable N,N,N-trimethylethanolammonium salt of a specified acetamide compound, or the crystalline form of the salt, to a subject in need thereof.
Combination therapy with additional therapeutic agents
The method further includes administering the stated salt or crystalline form together with additional therapeutic agents.
Additional therapeutic agents selected from an enumerated set of HIV and immune/host-targeting agents
The additional therapeutic agents are chosen from HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, other HIV-related targets, immune and host-targeting therapies, and pharmacokinetic enhancers.
Crystalline Form I
The method is performed using a crystalline form identified as crystalline Form I.
Crystalline Form I defined by XRPD peak constraint
Crystalline Form I is required to exhibit at least three XRPD peaks (2-theta ± 0.2°) chosen from a listed set of peak positions.
Crystalline Form II defined by DSC melting-onset constraint
The crystalline Form II has a DSC thermogram with a melting onset of about 147°C.
Overall, the claim coverage centers on administering the specified N,N,N-trimethylethanolammonium (choline) salt of Compound 1 for treating or preventing HIV infection, with dependent refinements for combination therapy and for specific crystalline forms defined by XRPD and DSC constraints.
Stated Advantages
Antiviral activity is supported by an antiviral assay in MT4 cells with EC50 determination and comparative advantages vs related compounds.
Improved potency relative to Compounds A and B.
Improved pharmacokinetic and stability profile relative to Compounds A and B.
Documented Applications
Treating or preventing HIV infection in a subject in need thereof using the N,N,N-trimethylethanolammonium (choline) salt of Compound 1 or its crystalline form.
HIV combination therapy using the choline salt or crystalline form together with additional therapeutic agents selected from specified HIV/immune/host-targeting therapies and pharmacokinetic enhancers.
Treating a human immunodeficiency virus (HIV) infection.
Preventing a human immunodeficiency virus (HIV) infection.
Prophylaxis use in the form of PrEP (pre-exposure prophylaxis).
Post-exposure use in the form of PEP (post-exposure prophylaxis).
Use in combination therapy with other anti-HIV drug classes.
Antiviral evaluation using an Example A antiviral assay in MT4 cells with EC50/CC50 comparisons versus Compounds A and B.
Cytotoxicity comparisons using an Example B cytotoxicity assay versus Compounds A and B.
In vivo pharmacokinetic analysis using Example C pharmacokinetic analysis in Sprague-Dawley rats, beagle dogs, and cynomologous monkeys, including CL/Vss/t1/2 and AUC/Cmax.
Metabolic stability evaluation using Example D metabolic stability in human liver hepatocytes with predicted human hepatic clearance.
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