Prodrug salts
Inventors
Pelletier, Marc F. • Mcguirk, Paul Robert • Farr, George William • Zamboni, Robert • Colucci, John • Zaghdane, Helmi
Assignees
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Publication Number
US-11071744-B2
Publication Date
2021-07-27
Expiration Date
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 patent describes a process for synthesizing a compound of Formula IV, where R1 through R5 are independently H, halogen, C1-4-alkyl, C1-4-haloalkyl, or cyano. The process proceeds by reacting a compound of Formula VII with a compound of Formula VIII to provide a compound of Formula V, followed by reacting the compound of Formula V with a compound of Formula VI to provide a compound of Formula III.
The disclosed route includes Formula III bearing a substituent defined by R35 and R36 as —(CH2CH2)n—Si(R37)3, where each R37 is independently C1-6-alkyl and n is 0 or 1. After formation of the compound of Formula III, the process deprotects the compound of Formula III to produce the compound of Formula IV.
The patent also describes prodrug salts of selective aquaporin inhibitors comprising compounds of Formula I and compounds of Formula II, including an anionic/prodrug counterion Q+ linked to a phosphorus center via O− or OH forms. It addresses pharmaceutical formulation limitations, including solubility, and includes therapy applications targeting aquaporins, including AQP4 and AQP2, for water-balance-related conditions.
Claims Coverage
The consolidated claim coverage includes two independent process features: one directed to a multi-step synthesis chain from Formula VII and Formula VIII to Formula V, to Formula III via Formula VI, and then deprotection to produce Formula IV; and another directed to conversion of Formula VII to Formula IX using phosphorus/sulfur-containing reagents in a nonpolar solvent. The inventive features center on the defined reaction sequences and the specified substituent framework for the intermediates and final structures.
Multi-step conversion to deprotected formula IV
A process for synthesizing a compound of Formula IV by reacting a compound of Formula VII with a compound of Formula VIII to provide a compound of Formula V, reacting the compound of Formula V with a compound of Formula VI to provide a compound of Formula III, and deprotecting the compound of Formula III to produce the compound of Formula IV.
Silicon-containing protected intermediate defined by R35 and R36
The process includes forming a compound of Formula III where R35 and R36 are independently —(CH2CH2)n—Si(R37)3, where each R37 is independently C1-6-alkyl and n is 0 or 1, before deprotecting to yield the compound of Formula IV.
Alternative conversion from Formula VII to Formula IX using P/S reagents in nonpolar solvent
The process further converts a compound of Formula VII to a compound of Formula IX by reacting with phosphorus/sulfur-containing reagents selected from PCl3, PCl5, and SOCl2 in a nonpolar solvent.
Overall, the claims cover a defined intermediate-building sequence to reach a silicon-containing protected Formula III and then deprotect to produce Formula IV, with additional coverage for converting Formula VII to Formula IX using PCl3, PCl5, or SOCl2 in a nonpolar solvent.
Stated Advantages
Solubility is improved for pharmaceutical use, including IV administration.
Selective inhibition of aquaporin-mediated water-imbalance conditions including conditions involving AQP4 and/or AQP2.
Documented Applications
Prophylaxis, treatment, and control of aquaporin-mediated water-imbalance conditions, including cerebral edema, spinal cord edema, optic nerve edema, retinal edema, pulmonary edema, hyponatremia, and excess fluid retention.
Treatment/control assertions for broader associated diseases including epilepsy, retinal ischemia, myocardial ischemia/infarction, congestive heart failure, sepsis, neuromyelitis optica, migraines, and glioblastoma.
Therapeutic methods for AQP4 (Method A) and edema using AQP4-inhibitor prodrug salts (Method B), including onset assertions and references to edema models/diseases such as stroke/trauma/glioma/meningitis/hypoxia/microgravity/radiation.
Therapy applications using Method A–G targeting aquaporins (AQP4 and AQP2) for conditions including cerebral/spinal edema, cytotoxic cerebral edema, hyponatremia, fluid retention, hyponatremia/SIADH, and other enumerated water-balance-related diseases and disorders.
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