Heterocyclic sulfonamide inhibitors of beta amyloid production containing an azole
Compounds useful for lowering beta amyloid levels are provided. The compounds have the structure of formula Ia: wherein, R 1 is lower alkyl, substituted lower alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, or SO 2 R 5 ; R 5 is phenyl, substituted phenyl, heterocycle, substituted heterocycle, alkyl, or substituted alkyl; R 2 is lower alkyl, substituted lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, or cycloalkyl; R 3 is hydrogen, lower alkyl, or substituted lower alkyl; R 4 is phenyl, substituted phenyl, heterocycle, substituted heterocycle, thiophene, or substituted thiophene; R 6 is hydrogen, lower alkyl, substituted lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, or substituted cycloalkyl; W, X and Y are independently CR 7 or N; and R 7 is hydrogen, halogen, lower alkyl, or substituted lower alkyl.
1. A compound of formula (Ia) or a pharmaceutically acceptable salt thereof, of the structure:
wherein:
R 1 is selected from the group consisting of lower alkyl, substituted lower alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy, and SO 2 R 5 ;
R 5 is selected from the group consisting of phenyl, substituted phenyl, heterocycle, substituted heterocycle, alkyl, and substituted alkyl;
R 2 is selected from the group consisting of lower alkyl, substituted lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, and cycloalkyl;
R 3 is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl;
R 4 is selected from the group consisting of phenyl, substituted phenyl, heterocycle, substituted heterocycle, thiophene, and substituted thiophene;
R 6 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, CF 3 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, cycloalkyl, and substituted cycloalkyl;
W, X, and Y are selected from the group consisting of (i), (ii), and (iii):
(i) W is N, Y is CR 7 , and X is N;
(ii) W is CR 7 , Y is CR 7 , and X is N; and
(iii) W is CR 7 , Y is CR 7 , and X is CR 7 ;
R 7 is selected from the group consisting of hydrogen, halogen, lower alkyl, and substituted lower alkyl.
2. The compound according to claim 1 , wherein R 1 is substituted benzyl.
3. The compound according to claim 1 , wherein R 1 is substituted phenyl.
4. The compound according to claim 1 , wherein R 2 is lower alkyl.
5. The compound according to claim 2 , wherein R 3 is hydrogen.
6. The compound according to claim 2 , wherein R 4 is thiophene or substituted thiophene.
7. The compound according to claim 6 , wherein R 4 is 5-chloro-2-thiophene.
8. The compound according to claim 1 , wherein R 6 is H.
9. The compound according to claim 1 which is 5-Chloro-N-{2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butyl}thiophene-2-sulfonamide, 5-Chloro-N-(2-ethyl-1-{1-[4-(trifluoromethoxy)benzyl]-1H-1,2,4-triazol-5-yl}butyl)thiophene-2-sulfonamide, 5-Chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl]butyl}thiophene-2-sulfonamide, N-[1-(1-Benzyl-1H-1,2,4-triazol-5-yl)-2-ethylbutyl]-5-chlorothiophene-2-sulfonamide, N-[1-(1-Benzyl-1H-1,2,4-triazol5-yl)-2-methylpropyl]-5-chlorothiophene-2-sulfonamide, 5-Chloro-N-{2-methyl-1-[1-(4-methylbenzyl)-1H-1,2,4-triazol-5-yl]propyl}thiophene-2-sulfonamide, N-[1-(1-Benzyl-1H-1,2,4-triazol-5-yl)ethyl]-5-chlorothiophene-2-sulfonamide, 5-Chloro-N-{1-[1-(4-methylbenzyl)-1H-1,2,4-triazol-5-yl]ethyl}thiophene-2-sulfonamide, 5-Chloro-N-{2-ethyl-1-[1-(4-methylbenzyl)-1H-1,2,4-triazol-5-yl]butyl}thiophene-2-sulfonamide, N-[1-(1-Benzyl-1H-imidazol-2-yl)-2-ethylbutyl]-5-chlorothiophene-2-sulfonamide, 5-Chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1 H-imidazol-2-yl]butyl}thiophene-2-sulfonamide, 5-Chloro-N-{2-ethyl-1-[1-(4-hydroxybenzyl)-1-H-imidazol-2-yl]butyl}thiophene-2-sulfonamide, and N-[1-(1-Benzyl-1H-pyrrol-2-yl)-2-methylpropyl]-5-chlorothiophene-2-sulfonamide.