OXAZOLIDINONE CONTAINING DIMER COMPOUNDS, COMPOSITIONS AND METHODS TO MAKE AND USE
Dosage forms or pharmaceutical compositions comprise a compound having the structure of Formula IV: wherein n is a non-negative integer; wherein each Z is an oxazolidinone-containing moiety having antibiotic activity in vivo upon cleaving, wherein M is independently OR 1 or NR 1 R 2 ; wherein R 1 and R 2 are independently selected from the group consisting of H, an optionally-substituted hydrocarbyl residue or a pharmaceutically acceptable cation; wherein the compound in the dosage form or a pharmaceutical composition is present in an amount effective for treating or preventing an antibacterial infection in a mammalian subject. Methods of preparing and using these dosage forms or pharmaceutical compositions are also disclosed.
1 . A dosage form or a pharmaceutical composition comprising a therapeutically effective amount of compound having the structure of Formula IV:
wherein n is 0, 1 or 2;
wherein each Z is an oxazolidinone-containing moiety having antibiotic activity in vivo upon cleaving,
wherein M is independently OR 1 or NR 1 R 2 ;
wherein R 1 and R 2 are independently selected from the group consisting of H, an optionally-substituted hydrocarbyl residue that may contain one or more heteroatoms or a pharmaceutically acceptable cation.
2 . The dosage form or the pharmaceutical composition of claim 1 , wherein each Z is
wherein * is the point of attachment of Z to P;
wherein R 1 a and R 1 b are independently selected from H and F, provided that at least one of R 1 a and R 1 b is F, and
Het is an optionally-substituted five- or six-membered heterocycle comprising at least one N, O, or S atom.
3 . The dosage form or the pharmaceutical composition of claim 2 , wherein the compound has the structure
wherein M is OR 1 and R 1 is a pharmaceutically-acceptable cation.
4 . The dosage form or the pharmaceutical composition of claim 3
wherein R 1 is a nitrogen-containing cation.
5 . The dosage form or the pharmaceutical composition of claim 3
wherein R 1 is an imidazolium cation.
6 . The dosage form or the pharmaceutical composition of claim 3
wherein each Z is
7 . The dosage form or the pharmaceutical composition of claim 6 ,
wherein each Z is
8 . The dosage form or the pharmaceutical composition of claim 1 , wherein the dosage form or the pharmaceutical composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent or excipient.
9 . The dosage form or the pharmaceutical composition of claim 1 , wherein each Z has R stereochemistry.
10 . The dosage form or the pharmaceutical composition of claim 5 , wherein each Z is
11 . The dosage form or the pharmaceutical composition of claim 2 , which is
or pharmaceutically acceptable salt thereof.
12 . The dosage form or the pharmaceutical composition of claim 11 , wherein Het is tetrazolyl.
13 . A method of preparing the compound in the dosage form or pharmaceutical composition of claim 1 , comprising the step of treating a compound of the formula Z—H with a phosphorylating agent.
14 . A method of preparing the compound in the dosage form or pharmaceutical composition of claim 1 , comprising the step of treating with a dehydrating agent of the compound Z—P′, wherein P′ is a mono- or dihydrogen phosphate group.
15 . The method of claim 13 , wherein the phosphorylating agent is POCl 3 .
16 . A method of treating a bacterial infection comprising
administering the dosage form or the pharmaceutical composition of claim 1 to a subject in need thereof.
17 . A method of treating a bacterial infection comprising
administering the dosage form or the pharmaceutical composition of claim 12 to a subject in need thereof.