Prodrug salts
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 reacting a compound of Formula VII and a compound of Formula VIII
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 to provide a compound of Formula V
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, followed by reacting the compound of Formula V with a compound of Formula VI
wherein R 35 and R 36 are independently —(CH 2 CH 2 ) n —Si(R 37 ) 3 and each R 37 is independently C 1-6 -alkyl and n is 0 or 1 to provide 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, R 35 and R 36 are independently —(CH 2 CH 2 ) n —Si(R 37 ) 3 , and each R 37 is independently C 1-6 -alkyl and n is 0 or 1, followed by deprotecting the compound of Formula III to produce the compound of Formula IV.
2. The process of claim 1 , wherein the process further comprises converting the compound of Formula VII to a compound of Formula IX
wherein R 30 is H, halogen, C 1-4 -alkyl, C 1-4 -haloalkyl, or cyano.
3. The process of claim 2 , wherein the compound of Formula IX is formed by reaction with a compound comprising P or S.
4. The process of claim 3 , wherein the compound of Formula IX is formed by reaction with PCl 3 , PCl 5 , or SOCl 2 .
5. The process of claim 4 , wherein the reaction occurs in a nonpolar solvent.
6. The process of claim 5 , wherein the nonpolar solvent is toluene.
7. The process of claim 2 , wherein R 30 , R 32 , and R 34 are independently halogen or C 1-4 -haloalkyl and R 31 and R 33 are H.
8. The process of claim 2 , wherein R 30 , R 32 , and R 34 are independently F, Cl, Br, or —CF 3 and R 31 and R 33 are H.
9. The process of claim 2 , wherein R 30 is halogen, R 31 and R 33 are H, and R 32 and R 34 are independently C 1-4 -haloalkyl.
10. The process of claim 9 , wherein R 30 is Cl and R 32 and R 34 are —CF 3 .
11. The process of claim 2 , wherein each R 37 is independently C 1-4 -alkyl.
12. The process of claim 2 , wherein R 35 and R 36 are the same.
13. The process of claim 2 , wherein n is 1.
14. The process of claim 10 , wherein R 35 and R 36 are —CH 2 —CH 2 —Si(CH 3 ) 3 .
15. The process of claim 14 , wherein the compound of Formula V is
16. The process of claim 15 , wherein the compound of Formula VI is
17. The process of claim 16 , wherein the compound of Formula III is
18. The process of claim 17 , wherein the compound of Formula III is deprotected with a deprotecting agent comprising F.
19. The process of claim 18 , wherein the deprotecting agent is CF 3 COOH.
20. The process of claim 19 , wherein the compound of Formula IV is