MARIBAVIR ISOMERS, COMPOSITIONS, METHODS OF MAKING AND METHODS OF USING

Abstract

The invention relates to novel compositions and methods of using maribavir which enhance its effectiveness in medical therapy, as well as to maribavir isomers and methods of use thereof for counteracting the potentially adverse effects of maribavir isomerization in vivo in the event it occurs.

Claims

1. A method for treatment or prophylaxis of a herpes viral infection in a patient in need thereof comprising administering to said patient the compound 5,6-dichloro-2-(isopropylamino)-1-(-L-ribofuranosyl)-1H-benzimidazole, or an isomer of said compound, in an amount effective to counteract molecular conversion of said compound occurring in vivo, and thereby providing an anti-virally effective amount of said compound to said patient.

2. A method according to claim 1, wherein said amount is greater than 200 mg per day.

3. A method according to claim 2, wherein the amount administered is up to 6400 mg per day.

4. A method according to claim 1, wherein said herpes viral infection is cytomegalovirus.

5. A method according to claim 4, wherein said patient is a stem cell transplant recipient, a liver transplant recipient, or kidney transplant recipient.

6. A method according to claim 1, wherein said compound is administered to said patient under fasted conditions.

7. The method of claim 1 wherein said compound is administered as a composition comprising a therapeutically acceptable adjuvant, excipient or carrier medium.

8. The method of claim 7 wherein said composition is an immediate release formulation, a delayed release formulation, a controlled release formulation or an intravenous formulation.

9. The method of claim 1, wherein said compound is administered in combination with at least one of an antacid which is effective for neutralizing acid that catalyzes isomerization of maribavir, an antibiotic having activity against a microorganism that mediates isomerization of maribavir and an antagonist that inhibits metabolism that induces isomerization of maribavir, said isomerization producing a decrease in the therapeutic efficacy of said compound.

10. A method for the treatment or prophylaxis of herpes viral infection in a patient in need thereof comprising administering to said patient one or more maribavir isomers.

11. The method according to claim 10, wherein the prodrug of the maribavir isomers is administered to said patient.

12. The method according to claim 11, wherein the prodrug is isomerized in vivo to produce one or more maribavir isomers.

13. The method according to claim 1, wherein said compound comprises a pyranosyl analog of maribavir.

14. The method according to claim 7, wherein said composition comprises a pyranosyl isomer of maribavir.

15. A method for determining the therapeutic efficacy of the compound 5,6-dichloro-2-(isopropylamino)-1-(-L-riboffiranosyl)-1H-benzimidazole, or an isomer of said compound in the blood plasma of a patient administered said compound, comprising measuring the concentration of a therapeutically effective form of said compound in a blood plasma sample from said patient and comparing said measured concentration with the concentration(s) of at least one of a lesser therapeutically effective form of said compound or an isomer or analog thereof in same patient sample.

16. The method according to claim 15, wherein said measurement and comparison is performed on patient samples during and within 12 hours of terminating treatment.

17. The method according to claim 15, wherein said measurement(s) and comparison(s) determine the treatment protocol of said patient.

18. The method according to claim 17, wherein said treatment protocol is the dosage amount of said compound administered to said patient, the dosage regimen for administration of said compound to said patient, the discontinuation of administration of said compound to said patient, or the initiation of other therapeutic intervention for said patient.

19. A method of increasing the bioavailability of maribavir to a patient receiving maribavir therapy comprising administering to said patient an oral dose comprising about 200 mg to 800 mg of maribavir under fasted conditions, whereby said administration results in an increase of the maximum plasma concentration and the extent of absorption of maribavir relative to the plasma concentration and the extent of absorption for the corresponding administration of maribavir under fed conditions.

20. A method of informing a patient receiving maribavir therapy that dosing of maribavir under fasted conditions results in an increase of the maximum plasma concentration as compared to the administration of maribavir under fed conditions, comprising providing to said patient a container of maribavir doses, said container being associated with prescription information that advises the patient that administration of a maribavir dose under fasted conditions results in said increase.

21. A method of more effectively and safely using maribavir therapy comprising providing information and guidance in maribavir product packaging and promotional materials regarding the nature of in vivo isomerization of maribavir and related guidance on dosing and use of maribavir so as to mitigate any potential undesired effects from said in vivo maribavir isomerization.

22. A method of making one or more maribavir isomers comprising the step of administering maribavir to a mammal, wherein said administration results in the in vivo isomerization of maribavir to one or more maribavir isomers.

23. The method according to claim 22, wherein the said mammal is human that has a herpes virus infection.

24. A composition for the treatment or prophylaxis of herpes viral infection comprising the compound 5,6-dichloro-2-(isopropylamino)-1-(-L-ribofuranosyl)-1H-benzimidazole and at least one of an antacid which is effective for neutralizing acid that catalyzes isomerization of maribavir, an antibiotic having activity against a microorganism that mediates isomerization of maribavir and an antagonist that inhibits metabolism that induces isomerization of maribavir, said isomerization producing a decrease in the therapeutic efficacy of said compound.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] FIG. 1 shows chemical structures of maribavir and maribavir configurational stereoisomers that have the same configuration at the furanoysl anomer carbon.

[0034] FIG. 2 shows chemical structures of maribavir configurational stereoisomers that have the opposite configuration at the furanosyl anomer carbon.

[0035] FIG. 3 shows chemical structures of maribavir pyranosyl constitutional isomers)

[0036] A number of patent and non-patent documents are cited in the foregoing specification in order to describe the state of the art to which this invention pertains. The entire disclosure of each of these citations is incorporated by reference herein.

[0037] While certain of the preferred embodiments of the present invention have been described and specifically exemplified above, it is not intended that the invention be limited to such embodiments. Various modifications may be made thereto without departing from the scope and spirit of the present invention, as set forth in the following claims. Furthermore, the transitional terms comprising, consisting essentially of and consisting of define the scope of the appended claims, in original and amended form, with respect to what unrecited additional claim elements or steps, if any, are excluded from the scope of the claims. The term comprising is intended to be inclusive or open-ended and does not exclude additional, unrecited elements, methods step or materials. The phrase consisting of excludes any element, step or material other than those specified in the claim, and, in the latter instance, impurities ordinarily associated with the specified materials. The phrase consisting essentially of limits the scope of a claim to the specified elements, steps or materials and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. All compositions or formulations identified herein can, in alternate embodiments, be more specifically defined by any of the transitional phases comprising, consisting essentially of and consisting of.