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-10258636-B2
Publication Date
2019-04-16
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 document describes a process for synthesizing compounds of Formula IV by deprotecting a corresponding compound of Formula III. The substitution patterns are defined for R1-R5 in Formula IV and for R30-R34 and R35/R36 in Formula III, including options for H, halogen, C1-4-alkyl, C1-4-haloalkyl, or cyano, and a Si-containing protecting group of the form —(CH2CH2)n—Si(R37)3 where each R37 is C1-6-alkyl and n is 0 or 1.
The deprotection transforms the Si-protected structure of Formula III into the corresponding deprotected Formula IV compound. The document also describes a process for synthesizing a compound of Formula III by reacting a compound of Formula V with a compound of Formula VI, using the same classes of substituents for R30-R34 and for R35/R36 in Formula III.
The disclosure relates to exemplary compounds defined by Formula II, including embodiments 2.23-2.26, illustrated with phosphate/phosphorane-containing arylamide derivatives bearing halogen substituents such as Cl and substituents such as trifluoromethyl (CF3). The document further includes specific exemplary chemical structures, including an arylamide example described as N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide.
The disclosure further expands to pharmaceutical composition and therapeutic-use embodiments for aquaporin-mediated diseases, primarily aquaporin-4 (AQP4) and also aquaporin-2 (AQP2). These therapeutic-use embodiments include edema-related conditions, hyponatremia, fluid retention, and related aquaporin-mediated conditions.
Claims Coverage
Four independent claims are identified across the input items. Two claims focus on synthetic processes involving deprotection and reacting intermediates, and two claims focus on compound and therapeutic-use subject matter.
Deprotecting a Formula III compound to synthesize a Formula IV compound
A process for synthesizing a compound of Formula IV, where R1, R2, R3, R4, and R5 are independently H, halogen, C1-4-alkyl, C1-4-haloalkyl, or cyano, and the process comprises deprotecting a compound of Formula III wherein R30, R31, R32, R33, and R34 are independently H, halogen, C1-4-alkyl, C1-4-haloalkyl, or cyano, and R35 and R36 are independently —(CH2CH2)n—Si(R37)3 with each R37 independently C1-6-alkyl and n is 0 or 1.
Reacting a Formula V compound with a Formula VI compound to synthesize a Formula III compound
A process for synthesizing a compound of Formula III, comprising reacting a compound of Formula V with a compound of Formula VI wherein R30, R31, R32, R33, and R34 are independently H, halogen, C1-4-alkyl, C1-4-haloalkyl, or cyano, and R35 and R36 are independently —(CH2CH2)n—Si(R37)3 with each R37 independently C1-6-alkyl and n is 0 or 1.
Formula II compounds
Exemplary compounds defined by Formula II, including embodiments 2.23-2.26, illustrated with phosphate/phosphorane-containing arylamide derivatives bearing halogen substituents such as Cl and substituents such as trifluoromethyl (CF3).
Aquaporin-mediated disease treatment
Pharmaceutical composition and therapeutic-use embodiments for aquaporin-mediated diseases, primarily aquaporin-4 (AQP4) and also aquaporin-2 (AQP2), including edema-related conditions, hyponatremia, and fluid retention.
Overall, the independent claims cover deprotection from Formula III to Formula IV, reacting Formula V with Formula VI to obtain Formula III, exemplary Formula II compounds, and aquaporin-mediated disease treatment.
Stated Advantages
Improved survival in the MCA occlusion stroke model.
Reduced cerebral edema and reduced intracranial pressure (ICP) in the MCA occlusion stroke model.
AQP2/AQP4 inhibition is demonstrated in an aquaporin-mediated cell volume change assay.
Specificity against other aquaporins is reported.
Radioligand binding evidence is reported for direct interaction with AQP4b.
Documented Applications
Aquaporin inhibition applications, including AQP2/AQP4 inhibition as assessed by an aquaporin-mediated cell volume change assay, with specificity against other aquaporins.
Use in a mouse water-toxicity model to assess in vivo outcomes.
Use in a mouse MCA occlusion stroke model, including assessment of survival and cerebral edema/ICP (including MRI-described cerebral edema).
Aquaporin-mediated disease treatment using pharmaceutical compositions associated with aquaporin-4 (AQP4) and aquaporin-2 (AQP2), including edema-related conditions expressly including cerebral edema, spinal cord edema, optic nerve edema, retinal edema, and pulmonary edema.
Therapeutic-use embodiments for hyponatremia and fluid retention as aquaporin-mediated conditions.
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