Prodrug salts
View Patent ↗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.
1. A process for synthesizing a compound of Formula IV
wherein:
R 1 , R 2 , R 3 , R 4 , and R 5 are independently H, halogen, C 1-4 -alkyl, C 1-4 -haloalkyl, or cyano, wherein the process comprises deprotecting a compound of Formula III
wherein:
R 30 , R 31 , R 32 , R 33 , and R 34 are independently H, halogen, C 1-4 -alkyl, C 1-4 -haloalkyl, or cyano; and
R 35 and R 36 are independently —(CH 2 CH 2 ) n —Si(R 37 ) 3 , wherein each R 37 is independently C 1-6 -alkyl and n is 0 or 1.
2. The process of claim 1 , wherein the compound of Formula III is
3. The process of claim 2 , wherein the compound of Formula III is deprotected with a deprotecting agent comprising F.
4. The process of claim 3 , wherein the deprotecting agent is tetra-n-butylammonium fluoride.
5. The process of claim 2 , wherein the compound of Formula III is deprotected with a deprotecting agent that is an acid.
6. The process of claim 5 , wherein the acid is CF 3 COOH (TFA).
7. A process for synthesizing a compound of Formula III
wherein the process comprises reacting a compound of Formula V
with a compound of Formula VI
wherein:
R 30 , R 31 , R 32 , R 33 , and R 34 are independently H, halogen, C 1-4 -alkyl, C 1-4 -haloalkyl, or cyano; and
R 35 and R 36 are independently —(CH 2 CH 2 ) n —Si(R 37 ) 3 , wherein each R 37 is independently C 1-6 -alkyl and n is 0 or 1.
8. The process of claim 7 , wherein the compound of Formula VI is
9. The process of claim 8 , wherein the compound of Formula V is
10. The process of claim 9 , wherein the reaction occurs in the presence of a base.
11. The process of claim 10 , wherein the base is a trialkylamine.
12. The process of claim 11 , wherein the base is N,N-diisopropylethylamine.
13. The process of claim 9 , wherein the reaction occurs in the presence of a catalyst.
14. The process of claim 13 , wherein the catalyst is 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).
15. The process of claim 9 , wherein the reaction occurs in CH 3 CN and CCl 4 .