Synthesis and formulations of salts of isophosphoramide mustard and analogs thereof

An oral formulation of the compound of formula (E):

• wherein the formulation comprises a lubricant, a diluent, a disintegrant, and the compound wherein
• X and Y independently represent leaving groups;
• and
• A+ is an ammonium cation, and
• wherein two or more of the lubricant, diluent, and disintegrant may be a single component.

A method for preparing a compound of formula (B):

• comprising treating a compound of formula (A):
• with an alcohol R1—OH under condensation conditions, wherein, as valence and stability permit,
• X1 independently for each occurrence, is selected from Cl, I, and Br,
• R1 is benzyl optionally substituted with one or more substituents selected from halogen, —R2, —OR2 and —NR22 wherein R2 is selected in each occurrence from H and lower alkyl.

A method for preparing a compound of formula (C):

• comprising treating a compound of formula (B):
• with amines XCH2CH2NH2 and YCH2CH2NH2 or salts thereof under condensation conditions, wherein, as valence and stability permit,
• X and Y independently represent leaving groups which may be the same or different;
• and
• R1 is benzyl optionally substituted with one or more substituents selected from halogen, —R2, —OR2 and —NR22 wherein R2 is selected in each occurrence from H and lower alkyl.

A method for preparing a compound of formula (C):

• comprising
• a. treating a compound of formula (A):
• with an alcohol R1—OH under condensation conditions to generate a compound of formula (B):
• and
• b. treating a compound of formula (B) with amines XCH2CH2NH2 and YCH2CH2NH2 or a salt thereof under condensation conditions, wherein, independently for each occurrence and as valence and stability permit,
• X and Y independently represent leaving groups;
• X1 independently for each occurrence, is selected from Cl, I, and Br,
• R1 is benzyl optionally substituted with one or more substituents selected from halogen, —R2, —OR2 and —NR22 wherein R2 is selected in each occurrence from H and lower alkyl.

A method for preparing a compound of formula (D):

• comprising treating a compound of formula (C):
• with a reducing agent under hydrogenolysis conditions, wherein as valence and stability permit,
• X and Y independently represent leaving groups;
• and
• R1 is benzyl optionally substituted with one or more substituents selected from halogen, —R2, —OR2 and —NR22 wherein R2 is selected in each occurrence from H and lower alkyl.

A method for preparing a compound of formula (E):

• comprising treating a compound of formula (D):
• with a base such as tris(hydroxymethyl)methylamine under salt-forming conditions, wherein as valence and stability permit,
• X and Y independently represent leaving groups;
• and
• A+ represents an ammonium cation.

A method of treating a condition characterized by abnormal cell growth and/or differentiation, comprising orally administering a composition comprising a lubricant, a diluent, a disintegrant, and a compound of formula (E):

• wherein
• X and Y independently represent leaving groups;
• and
• A+ is an ammonium cation,
• wherein two or more of the lubricant, diluent, and disintegrant may be a single component.