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.-24. (canceled)

25. 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.

26. A method according to claim 25, wherein said amount is greater than 200 mg per day.

27. A method according to claim 26, wherein the amount administered is up to 6400 mg per day.

28. A method according to claim 25, wherein said herpes viral infection is cytomegalovirus.

29. A method according to claim 28, wherein said patient is a stem cell transplant recipient, a liver transplant recipient, or kidney transplant recipient.

30. A method according to claim 25, wherein said compound is administered to said patient under fasted conditions.

31. The method of claim 25, wherein said compound is administered as a composition comprising a therapeutically acceptable adjuvant, excipient or carrier medium.

32. The method of claim 31, wherein said composition is an immediate release formulation, a delayed release formulation, a controlled release formulation or an intravenous formulation.

33. The method of claim 25, 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.

34. 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.

35. 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.

36. 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.

37. The method according to claim 36, wherein the said mammal is human that has a herpes virus infection.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0023] The following table contains list of useful dosing protocols that may be used to improve the efficacy and safety for treating a patient with maribavir.

TABLE-US-00001 Fasting Maribavir conditions Route of dosing (before/after administration and Protocol Dosing amount dosing) dosage form. 01 3200 mg/2 ? day None Oral-tablet-immediate release 02 3200 mg/2 ? day None IV 03 1600 mg/2 ? day None Oral-tablet-w/antacids 04 1600 mg/1 ? day None Oral-tablet-w/antibiotics 05 800 mg/3 ? day None Oral-tablet-delayed release 06 800 mg/2 ? day None Oral-tablet-immediate release 07 800 mg/1 ? day None IV 08 400 mg/4 ? day None Oral-tablet-w/antacids 09 400 mg/3 ? day None Oral-tablet-w/antibiotics 10 400 mg/2 ? day None Oral-tablet-delayed release 11 400 mg/1 ? day None Oral-tablet-immediate release 12 3200 mg/2 ? day 12 hrs/3 hrs IV 13 3200 mg/2 ? day 12 hrs/3 hrs Oral-tablet-w/antacids 14 1600 mg/2 ? day 12 hrs/3 hrs Oral-tablet-w/antibiotics 15 1600 mg/1 ? day 12 hrs/3 hrs Oral-tablet-delayed release 16 800 mg/3 ? day 12 hrs/3 hrs Oral-tablet-immediate release 17 800 mg/2 ? day 12 hrs/3 hrs IV 18 800 mg/1 ? day 12 hrs/3 hrs Oral-tablet-w/antacids 19 400 mg/4 ? day 12 hrs/3 hrs Oral-tablet-w/antibiotics 20 400 mg/3 ? day 12 hrs/3 hrs Oral-tablet-delayed release 21 400 mg/2 ? day 12 hrs/3 hrs Oral-tablet-immediate release 22 400 mg/1 ? day 12 hrs/3 hrs Oral-tablet-immediate release 23 3200 mg/2 ? day 6 hrs/2 hrs Oral-tablet-immediate release 24 3200 mg/2 ? day 6 hrs/2 hrs IV 25 1600 mg/2 ? day 6 hrs/2 hrs Oral-tablet-w/antacids 26 1600 mg/1 ? day 6 hrs/2 hrs Oral-tablet-w/antibiotics 27 800 mg/3 ? day 6 hrs/2 hrs Oral-tablet-delayed release 28 800 mg/2 ? day 6 hrs/2 hrs Oral-tablet-immediate release 29 800 mg/1 ? day 6 hrs/2 hrs IV 30 400 mg/4 ? day 6 hrs/2 hrs Oral-tablet-w/antacids 31 400 mg/3 ? day 6 hrs/2 hrs Oral-tablet-w/antibiotics 32 400 mg/2 ? day 6 hrs/2 hrs Oral-tablet-delayed release 33 400 mg/1 ? day 6 hrs/2 hrs Oral-tablet-immediate release 34 3200 mg/2 ? day 3 hrs/1 hr IV 35 3200 mg/2 ? day 3 hrs/1 hr Oral-tablet-w/antacids 36 1600 mg/2 ? day 3 hrs/1 hr Oral-tablet-w/antibiotics 37 1600 mg/1 ? day 3 hrs/1 hr Oral-tablet-delayed release 38 800 mg/3 ? day 3 hrs/1 hr Oral-tablet-immediate release 39 800 mg/2 ? day 3 hrs/1 hr IV 40 800 mg/1 ? day 3 hrs/1 hr Oral-tablet-w/antacids 41 400 mg/4 ? day 3 hrs/1 hr Oral-tablet-w/antibiotics 42 400 mg/3 ? day 3 hrs/1 hr Oral-tablet-delayed release 43 400 mg/2 ? day 3 hrs/1 hr Oral-tablet-immediate release 44 400 mg/1 ? day 3 hrs/1 hr Oral-tablet-immediate release

[0024] In carrying out the method of the invention, it is preferably to determine the presence and/or concentration of maribavir isomers, especially isomers of diminished therapeutic efficacy in patient blood plasma samples as part of the method.

[0025] As used herein, the terms fasted conditions, fasting conditions and without food are defined to mean, in general, the condition of not having consumed food during the period between from at least about 3 to 12 hours prior to the administration of maribavir to at least about 1 to 3 hours after the administration of maribavir. Other narrower fasted conditions are also contemplated herein and described below.

[0026] The term with food is defined to mean, in general, the condition of having consumed food prior to, during and/or after the administration of maribavir that is consistent with the relevant intended definition of fasted conditions (which may be narrow or broad depending on the circumstances). Preferably, the food is a solid food sufficient bulk and fat content that it is not rapidly dissolved and absorbed in the stomach. More preferably, the food is a meal, such as breakfast, lunch or dinner.

[0027] The term isomers means compounds that have the same molecular formula but a different molecular structure.

[0028] The term constitutional isomers is defined to mean isomers that have the same molecular formula but a different molecular structure wherein the molecular structures of the isomers have different connectivity of the constituent atoms.

[0029] The term configurational stereoisomers is defined to mean isomers that have the same connectivity but differ in the molecular structure in the way the atoms and groups of atoms are oriented in space.

[0030] The term immediate release is defined to mean release of drug from drug formulation by dissolution is less than 60 minutes or is otherwise release from the drug formulation in less than 60 minutes.

[0031] The term IV is defined to mean intravenous.

[0032] The chemical structure of maribavir and some maribavir isomers are shown below. The instant invention contemplates novel formulations, dosage levels and methods of use of maribavir, the maribavir isomers MFI-01 to MFI-015 (configurational stereoisomers), as well as the maribavir isomers MPI-01 to MPI-016 (constitutional isomers). The invention also contemplates the corresponding acyclic constitutional isomers wherein the sugar moiety is an open chain and attached to the benzimidazole.

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.