Sulfamide and sulfamate inhibitors of hHint1
Embodiments provide, among things, compounds of the formula I: wherein Het, Y, R x , Z, X, R 1 -R 3 , R 6 , and R 7 are defined herein; and methods for using such compounds to reduce pain (e.g., neuronal pain), treat a mammal's addiction to nicotine or anti-pain drugs, and increase a mammal's sensitivity to drugs that bind MOR or NMDAR.
1. A compound of formula I:
wherein R 1 is guanine, 3-deazadenine or [6,7-imino(alkylene)] adenine, optionally substituted by 1, 2 or 3 U wherein each U is independently halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, hydroxy(C 1 -C 6 )alkyl, —(CH 2 ) 1-4 P(═O)(OR w ) 2 aryl, aryl(C 1 -C 6 )alkyl, or Nr x R y ;
R 2 , R 3 , R 6 and R 7 are each independently hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, —N(R z )C(═O)N(R aa )(R ab ), —N(R z )C(═O)OR ac , or NR ad R ae , provided that one of R 2 and R 6 is hydroxy, halo, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, trifluoromethyl, cyano, or Nr ad R ae ;
X is oxy, thio, or methylene;
Z is N(Rx) or O;
Y is (C 1 -C 9 )alkyl, that optionally contains 1-3 CH═CH moieties and/or 1-3 —O-, N(Rx) or —SO— moieties;
each R w is independently hydrogen or (C 1 -C 6 )alkyl;
R x , R y and Rz are each independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, phenethyl, or (C 1 -C 6 )alkanoyl; or R x and R y together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
R aa and R ab are each independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl; or R aa and R ab together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
R ac , R ad , and R ae are independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;
wherein any (C 1 -C 6 )alkyl of R 1 , R 2 , R 3 , R 6 , R 7 , R w , R x , R y , R z , R aa , R ab , R ac , R ad , and R ae is optionally substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, trifluoromethyl, azido, cyano, oxo (═O), (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S—(C 1 -C 6 )alkyl-, aryl, aryl(C 1 -C 6 )alkyl, or Het (C 1 -C 6 )alkyl, or NR aj R ak ; wherein each R aj and R ak is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, benzyl, or phenethyl;
wherein Het is (C 1 -C 6 ) alkyl or
Het-Y— is (C 1 -C 6 )alkyl substituted with a pyridyl, indolyl, isoindolyl, furyl, thienyl, pyrrolyl, benzofuranyl, benzothienyl, imidazolyl, thiazoyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholino ring, which ring is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, and amino;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein X is O.
3. The compound of claim 1 wherein Z is O or N(R x ).
4. The compound of claim 3 wherein Z is N(H).
5. The compound of claim 1 wherein R x is H.
6. The compound of claim 1 wherein Y is (C 1 -C 6 )alkyl.
7. The compound of claim 1 wherein Het is indolyl.
8. The compound of claim 1 where R 1 is adenine, guanine or 6,7-iminoalkenyl adenine.
9. A compound of the formula:
wherein R p is indole propanoyl and X is O; R p is butanoyl and X is O; R p is indole propanoyl and X is NH, or a pharmaceutically acceptable salt thereof.