EP-4735464-A1 - SOLID FORMS OF A NUCLEOSIDE REVERSE TRANSCRIPTASE TRANSLOCATION INHIBITOR

Abstract

The present disclosure relates to crystalline and solvate forms of a nucleoside reverse transcriptase translocation inhibitor (NRTTI), and pharmaceutical compositions thereof, which are useful in the treatment and prevention of a Retroviridae viral infection including an infection caused by the HIV virus.

Inventors

• SHI, BING

Assignees

• GILEAD SCIENCES, INC.

Dates

Publication Date

20260506

Application Date

20240626

Claims (1)

1. 1478-US-NP/WO-PCT NON-PROVISIONAL/ PCT WHAT IS CLAIMED IS: 1. A crystalline form of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-((2- phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate, which is selected from crystalline Form II, crystalline Form III, crystalline Form IV, and crystalline Form V. 2. The crystalline form of claim 1, which is crystalline Form II. 3. The crystalline form of claim 2, wherein the crystalline Form II has at least three XRPD peaks, in terms of 2-theta ± 0.2°, selected from 5.5°, 9.3°, 10.8°, 14.9°, 18.5°, 19.3°, 23.8°, 24.3°, and 28.4°. 4. The crystalline form of claim 2, wherein the crystalline Form II is characterized by an XRPD pattern substantially as shown in FIG.2. 5. The crystalline form of any one of claims 2 to 4, wherein the crystalline Form II is characterized by a DSC thermogram having an endothermic transition at about 93 °C. 6. The crystalline form of any one of claims 2 to 4, wherein the crystalline Form II is characterized by a DSC thermogram substantially as shown in FIG.3. 7. The crystalline form of claim 1, which is crystalline Form III. 8. The crystalline form of claim 7, wherein the crystalline Form III has at least three XRPD peaks, in terms of 2-theta ± 0.2°, selected from 7.8°, 11.6°, 13.0°, 14.2°, 16.8°, 21.8°.25.8°, 26.1°, and 28.0°. 9. The crystalline form of claim 7, wherein the crystalline Form III is characterized by an XRPD pattern substantially as shown in FIG.8. 10. The crystalline form of any one of claims 7 to 9, wherein the crystalline Form III is characterized by a DSC thermogram having an endothermic transition at about 125°C. 1478-US-NP/WO-PCT NON-PROVISIONAL/ PCT 11. The crystalline form of any one of claims 7 to 9, wherein the crystalline Form III is characterized by a DSC thermogram substantially as shown in FIG.9. 12. The crystalline form of claim 1, which is crystalline Form IV. 13. The crystalline form of claim 12, wherein the crystalline Form IV has at least three XRPD peaks, in terms of 2-theta ± 0.2°, selected from 8.4°, 12.2°, 12.8°, 14.8°, 15.9°, 18.0°, 24.4°, 24.8°, and 25.8°. 14. The crystalline form of claim 12, wherein the crystalline Form IV is characterized by an XRPD pattern substantially as shown in FIG.13. 15. The crystalline form of any one of claims 12 to 14, wherein the crystalline Form IV is characterized by a DSC thermogram having an endothermic transition at about 114 °C. 16. The crystalline form of any one of claims 12 to 14, wherein the crystalline Form IV is characterized by a DSC thermogram substantially as shown in FIG.14. 17. The crystalline form of claim 1, which is crystalline Form V. 18. The crystalline form of claim 17, wherein the crystalline Form V has at least three XRPD peaks, in terms of 2-theta ± 0.2°, selected from 5.4°, 9.0°, 11.2°, 15.1°, 15.4°, 18.0°, 19.6°, 20.9°, and 22.3°. 19. The crystalline form of claim 17, wherein the crystalline Form V is characterized by an XRPD pattern substantially as shown in FIG.18. 20. The crystalline form of any one of claims 17 to 19, wherein the crystalline Form V is characterized by a DSC thermogram having a melting onset of about 156 °C. 21. The crystalline form of any one of claims 17 to 19, wherein the crystalline Form V is characterized by a DSC thermogram substantially as shown in FIG.19. 1478-US-NP/WO-PCT NON-PROVISIONAL/ PCT 22. A solvate form of (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-((2- phenylacetoxy)methyl)tetrahydrofuran-3-yl 2-phenylacetate. 23. The solvate form of claim 22, which is selected from, an acetone solvate form, a methyl ethyl ketone solvate form, a dichloromethane solvate form, a tetrahydrofuran solvate form, a toluene solvate form, a n-butyl acetate solvate form, a methyl acetate solvate form, a xylene solvate form, a heptane solvate form, a 1-butanol solvate form, a p-dioxane solvate form, a DMAc solvate form, an ethyl acetate solvate form, and a dimethylacetamide solvate form. 24. The solvate form of claim 22 or 23, which is an acetonitrile solvate form. 25. The solvate form of claim 22 or 23, which is an acetone solvate form. 26. The solvate form of claim 25, which is acetone solvate, form I. 27. The solvate form of claim 25, which is acetone solvate, form II. 28. The solvate form of claim 22 or 23, which is a methyl ethyl ketone solvate form. 29. The solvate form of claim 22 or 23, which is a dichloromethane solvate form. 30. The solvate form of claim 22 or 23, which is a tetrahydrofuran solvate form. 31. The solvate form of claim 22 or 23, which is a toluene solvate form. 32. The solvate form of claim 22 or 23, which is a DMAc solvate form. 33. The solvate form of claim 22 or 23, which is a n-butyl acetate solvate form. 34. The solvate form of claim 22 or 23, which is a methyl acetate solvate form. 35. The solvate form of claim 22 or 23, which is a xylene solvate form. 1478-US-NP/WO-PCT NON-PROVISIONAL/ PCT 36. The solvate form of claim 22 or 23, which is a heptane solvate form. 37. The solvate form of claim 22 or 23, which is a 1-butanol solvate form. 38. The solvate form of claim 22 or 23, which is a chloroform solvate form. 39. The solvate form of claim 22 or 23, which is a p-dioxane solvate form. 40. The solvate form of claim 22 or 23, which is a N-methyl-2-pyrrolidone solvate form. 41. The solvate form of claim 22 or 23, which is an ethyl acetate solvate form. 42. The solvate form of claim 22 or 23, which is an dimethylacetamide solvate form. 43. A pharmaceutical composition comprising the crystalline, co-crystalline or salt form of any one of claims 1 to 21, or the solvate form of any one of claims 22 to 42, and at least one pharmaceutically acceptable excipient. 44. A method of treating or preventing a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of the crystalline, co-crystalline, or salt form of any one of claims 1 to 21, or the solvate form of any one of claims 22 to 42, to a subject in need thereof. 45. The crystalline, co-crystalline, or salt form of any one of claims 1 to 21, or the solvate form of any one of claims 22 to 42, for use in therapy. 46. The crystalline, co-crystalline, or salt form of any one of claims 1 to 21, or the solvate form of any one of claims 22 to 42, for use in a method of treating or preventing a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of said crystalline, co-crystalline, salt or solvate form to a subject in need thereof.

Description

1478-US-NP/WO-PCT NON-PROVISIONAL/ PCT Solid Forms CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No.63/523,505, filed on June 27, 2023, which is hereby incorporated by reference in its entirety. TECHNICAL FIELD The present disclosure relates to crystalline and solvate forms of a nucleoside reverse transcriptase translocation inhibitor (NRTTI), and pharmaceutical compositions thereof, for use in the treatment or prevention of a Retroviridae viral infection including an infection caused by the HIV virus. BACKGROUND Positive-single stranded RNA viruses comprising the Retroviridae family include those of the subfamily Orthoretrovirinae and genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Spumavirus, and Lentivirus, which cause many human and animal diseases. Among the Lentivirus, HIV-1 infection in humans leads to depletion of T helper cells and immune dysfunction, producing immunodeficiency and vulnerability to opportunistic infections. One approach to treating HIV-1 infection is by administering NRTTIs. NRTTIs inhibit HIV-1 reverse transcriptase and, because reverse transcriptase function is essential for viral replication and production of viral proteins, NRTTIs can be effective against HIV-1 infection. Curr Opin HIV AIDS.2018 July; 13(4): 294–299. HIV treatments, however, have historically lead to the emergence of HIV strains that are resistant to current therapies. Expert Opin Emerg Drugs.2018 June; 23(2): 149–157. Therefore, there is an ongoing need to discover new antiretroviral agents and to develop methods for their preparation and purification as well as prepare improved pharmaceutical formulations of the same. The solid forms of NRTTIs disclosed herein help meet these and other needs. SUMMARY 1478-US-NP/WO-PCT NON-PROVISIONAL/ PCT The present disclosure provides, inter alia, a crystalline form of (2R,3S,5R)-5-(6-amino- 2-fluoro-9H-purin-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2- phenylacetate, which is selected from crystalline Form II, crystalline Form III, crystalline Form IV, and crystalline Form V. The present disclosure further provides a solvate form of (2R,3S,5R)-5-(6-amino-2- fluoro-9H-purin-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl 2- phenylacetate. The present disclosure further provides a pharmaceutical composition comprising a crystalline or solvate form disclosed herein, and at least one pharmaceutically acceptable excipient. The present disclosure further provides a method of treating or preventing a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of a crystalline or solvate form disclosed herein, to a subject in need thereof. The present disclosure further provides a crystalline or solvate form disclosed herein, for use in therapy. The present disclosure further provides a crystalline or solvate form disclosed herein, for use in a method of treating or preventing a human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of the a crystalline or solvate form to a subject in need thereof. DESCRIPTION OF DRAWINGS FIG.1 shows a representative X-Ray powder diffraction (XRPD) pattern of Compound 1, acetone solvate 1. FIG.2 shows a representative XRPD pattern of Compound 1, crystalline Form II. FIG.3 shows a representative differential scanning calorimetry (DSC) thermogram of Compound 1, crystalline Form II. FIG.4 shows a representative thermogravimetric analysis (TGA) thermogram of Compound 1, crystalline Form II. FIG.5 shows a representative dynamic vapor sorption (DVS) analysis of Compound 1, crystalline Form II. FIG.6 shows representative XRPD patterns of Compound 1, solvate forms. From top to bottom: DCM solvate, acetone solvate 2, methyl ethyl ketone solvate, ethyl acetate solvate, 1478-US-NP/WO-PCT NON-PROVISIONAL/ PCT methyl acetate solvate, n-butyl acetate solvate, tetrahydrofuran solvate, 1-butanol solvate, p- dioxane solvate, and heptane solvate. FIG.7 shows the asymmetric unit of Compound 1, crystalline Form III. FIG.8 shows a representative XRPD pattern of Compound 1, crystalline Form III. FIG.9 shows a representative DSC thermogram of Compound 1, crystalline Form III. FIG.10 shows a representative TGA thermogram of Compound 1, crystalline Form III. FIG.11 shows a representative DVS analysis of Compound 1, crystalline Form III. FIG.12 shows a representative XRPD pattern of Compound 1, toluene solvate. FIG.13 shows a representative XRPD pattern of Compound 1, crystalline Form IV. FIG.14 shows a representative DSC thermogram of Compound 1, crystalline Form IV. FIG.15 shows a representative TGA thermogram of Compound 1, crystalline Form IV. FIG.16 shows a representative DVS analysis of Compound 1, crystalline Form IV. FIG.17 shows a representative XRPD patterns of Compound 1, xylene solvate (top) and