Morphic forms of hexadecyloxypropyl-phosphonate esters and methods of synthesis thereof
View Patent ↗The disclosure describes methods of synthesis of phosphonate ester compounds. The methods according to the disclosure allow for large-scale preparation of phosphonate ester compounds having high purity and stability. Also disclosed are morphic forms of phosphonate ester compounds.
1. A method of treating a viral infection in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of morphic Form II of phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl) ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester, wherein the morphic Form II is characterized by an X-ray diffraction pattern that lacks prominent peaks at about 12.6 and at about 15.6 degrees 2θ.
2. The method of claim 1 , wherein the morphic Form II is characterized by an X-ray diffraction pattern including prominent peaks at about 2.81 and about 5.63 degrees 2θ.
3. The method of claim 1 , wherein the morphic Form II is characterized by an X-ray diffraction pattern with three or more peaks expressed in degrees 2θ (±0.2) selected from 2.81, 5.63, 19.00, 19.57, and 24.70.
4. The method of claim 1 , wherein the subject is an immunodeficient subject.
5. The method of claim 1 , wherein the morphic Form II is administered orally.
6. The method of claim 5 , wherein the morphic Form II is administered in the form of a tablet or capsule.
7. The method of claim 1 , wherein the morphic Form II is administered at a dose of about 200 mg once a week.
8. The method of claim 1 , wherein the morphic Form II has a purity of at least 91%.
9. The method of claim 1 , wherein the viral infection is cytomegalovirus infection.
10. The method of claim 1 , wherein the viral infection is BK virus infection.
11. The method of claim 1 , wherein the subject is a pre-organ or pre-tissue transplantation subject.
12. The method of claim 1 , wherein the subject is a post-organ or post-tissue transplantation subject.
13. The method of claim 1 , wherein the viral infection is resistant to valganciclovir hydrochloride or ganciclovir.
14. The method of claim 1 , wherein the subject exhibits side effects to valganciclovir hydrochloride or ganciclovir.
15. The method of claim 1 , wherein the subject is a stem cell transplant patient and there is a risk for bone marrow toxicity from ganciclovir in the subject.
16. A method of preventing a viral infection in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of morphic Form II of phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl) ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester, wherein the morphic Form II is characterized by an X-ray diffraction pattern that lacks prominent peaks at about 12.6 and at about 15.6 degrees 2θ.
17. The method of claim 16 , wherein the morphic Form II is characterized by an X-ray diffraction pattern including prominent peaks at about 2.81 and about 5.63 degrees 2θ.
18. The method of claim 16 , wherein the morphic Form II is characterized by an X-ray diffraction pattern with three or more peaks expressed in degrees 2θ (±0.2) selected from 2.81, 5.63, 19.00, 19.57, 22.76, and 24.70.
19. The method of claim 16 , wherein the subject is an immunodeficient subject.
20. The method of claim 16 , wherein the morphic Form II is administered orally.