Prodrug salts

Inventors

Pelletier, Marc F. • Mcguirk, Paul Robert • Farr, George William • Zamboni, Robert • Colucci, John • Zaghdane, Helmi

Assignees

Aeromics Inc

Abstract

Provided are novel prodrug salts of selective aquaporin inhibitors, their use as pharmaceuticals, and pharmaceutical compositions comprising them, and novel processes for their synthesis and novel intermediates for use in their synthesis. Also provided is use of a compound for the prophylaxis, treatment, and control of aquaporin-mediated conditions. Aquaporin inhibitors, e.g., inhibitors of AQP4 and/or AQP2, may be of utility in the treatment or control of diseases of water imbalance, for example edema (particularly edema of the brain and spinal cord), hyponatremia, and excess fluid retention, as well as diseases such as epilepsy, retinal ischemia and other diseases of the eye, myocardial ischemia, myocardial ischemia/reperfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, and neuromyelitis optica, as well as migraines.

Core Innovation

The disclosure provides phosphorous-containing compounds, including compounds of Formula I and Formula II, prodrug salts, and related phosphate species such as 2-((3,5-bis(trifluoromethyl)phenyl)carbamoyl)-4-chlorophenyl dihydrogen phosphate. The embodiments define chemical structures that include cyclic polyol motifs and a bis(trifluoromethyl)-substituted chlorophenyl/benzamide linked to a phosphate/phosphonate center, with substituent options around the phosphate/phosphonate portion, including protecting-group-substituted phosphates.

The disclosure further provides selective aquaporin inhibitor prodrugs as novel salt forms of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, and also describes polymorphs, hydrates, solvates, complexes, isotopologues, isotopes, deuterium, and multiple salt forms. The therapeutic focus is on aquaporin-mediated water-imbalance and edema disorders, including AQP4-mediated cerebral edema, spinal cord edema, optic nerve edema, retinal edema, and pulmonary edema, and AQP2-mediated hyponatremia and water intoxication/excess fluid retention.

A core aspect is a process for synthesizing the compound by deprotecting with a deprotecting agent and isolating the synthesized product. The disclosure addresses a prior Pd(OH)2-on-carbon hydrogenation approach in which dechlorination produces a difficult-to-remove contaminant, and describes deprotection agents including tetra-n-butylammonium fluoride and CF3COOH (TFA), with deprotection reactions stirred at room temperature.

Claims Coverage

The consolidated claim set includes one independent process claim with dependent refinements. The inventive coverage centers on deprotecting with a deprotecting agent and isolating, with four specific inventive features tied to the deprotecting agent and reaction condition.

Across the independent process claim and its dependents, the claims cover a deprotection-and-isolation process further limited by a fluorine-containing deprotecting agent, including tetra-n-butylammonium fluoride or CF3COOH (TFA), and by stirring the deprotection reaction at room temperature.

Stated Advantages

Documented Applications