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Publication Number
US-11833143-B2
Publication Date
2023-12-05
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-(methylsulfony)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 disclosure provides crystalline forms of a named N—((S)-configured) HIV capsid inhibitor as a N,N,N-trimethylethanolammonium salt, including crystalline Forms IV, V, VI, and VII. The crystalline forms are defined and differentiated by characterization using XRPD data and DSC thermogram features, with some forms defined by reference to figures showing XRPD patterns or thermograms.
The disclosure also describes atropisomers labeled Isomer A and Isomer B of Compound 1 that can interconvert in solution. It states that the atropisomer content can be enriched by crystallization into different choline salt crystalline forms, and that the solid forms include unsolvated and solvated crystalline forms, with solvates exemplified by ethanol, tetrahydrofuran, and methyl tert-butyl ether.
The crystalline trimethylethanolammonium salt of Compound 1 is positioned as an HIV reverse-transcriptase-targeting agent used in combination regimens. The disclosure additionally includes pharmaceutical composition and kit formats with pharmaceutically acceptable excipients, and administration-route and packaging concepts associated with the crystalline form.
Claims Coverage
The claim set is directed to four specific crystalline forms (IV–VII) of the defined N,N,N-trimethylethanolammonium salt of the named HIV capsid inhibitor. Dependent claims further characterize the crystalline forms by XRPD and DSC criteria and extend the subject matter to pharmaceutical compositions and HIV treatment or prevention methods, including optional combination therapy.
Crystalline choline salt form selected from Forms IV to VII
A crystalline form of the named N—((S)-configured) HIV capsid inhibitor as a N,N,N-trimethylethanolammonium salt, selected from crystalline Form IV, crystalline Form V, crystalline Form VI, and crystalline Form VII.
XRPD-defined crystalline Form IV
A crystalline form (Form IV) having at least three XRPD peaks at specified 2-theta values (within ±0.2°) chosen from a listed set.
DSC-defined crystalline Form V
A crystalline form (Form V) characterized by a DSC thermogram with a melting onset of about 159°C.
Figure-referenced XRPD crystalline Form VI
A crystalline form (Form VI) defined by reference to an XRPD pattern substantially as shown in FIG. 14.
Pharmaceutical composition with a crystalline form and excipients
A pharmaceutical composition comprising a crystalline form referenced in claim 1 and at least one pharmaceutically acceptable excipient.
Method for treating or preventing HIV by administration
A method of treating or preventing an HIV infection in a human by administering a therapeutically effective amount of the crystalline form of the compound specified in claim 2.
Overall, the claim coverage centers on specific crystalline forms of the N,N,N-trimethylethanolammonium salt, differentiated by XRPD and DSC characterization, and extends to pharmaceutical compositions and HIV treatment or prevention by administration.
Stated Advantages
Improved potency and pharmacokinetic/stability profile for Compound 1 versus structurally close Compounds A and B.
Provides solid-form crystalline choline salt forms of the HIV capsid inhibitor, distinguished by XRPD and DSC characterization.
Supports enrichment of atropisomers (Isomer A or Isomer B) via crystallization into different choline salt crystalline forms.
Enables treating or preventing HIV infection in humans, including HIV prevention (PrEP/PEP) and treatment, including combination therapy.
Documented Applications
Antiviral use against HIV infection assessed in an MT4 HIV-1 assay, reported as EC50 and CC50 for Compound 1 versus Compounds A and B.
In vivo pharmacokinetic evaluation in rats, dogs, and cynomolgus monkeys for Compound 1.
Metabolic stability evaluation in human hepatocytes for Compound 1.
Pharmaceutical composition use including the crystalline form with pharmaceutically acceptable excipients.
Method of treating or preventing an HIV infection in a human by administering a therapeutically effective amount of the crystalline form.
Treating or preventing a Retroviridae viral infection, including HIV infection, by administering a therapeutically effective amount of the crystalline choline salt form.
HIV prevention, including PrEP and PEP, using administration of the crystalline form.
HIV treatment using the crystalline form, including combination therapy with 1–34 additional therapeutic agents from specified anti-HIV drug classes or specific listed agents.
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