Heterocyclic sulfonamide inhibitors of beta amyloid production
View Patent ↗Compounds of Formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , T, W, X, Y and Z are as defined herein are provided, together with pharmaceutically acceptable salt, hydrates and/or prodrugs thereof. Methods of using these compounds for inhibiting beta amyloid production and for treatment of Alzheimer's Disease and Down's syndrome are described
1. A compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:
wherein:
R 1 , R 2 , R 3 , and R 5 are independently hydrogen or CH 3 ;
R 4 is selected from the group consisting of alkyl, substituted alkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkylOH, substituted alkylOH, alkylOBn, substituted alkylOBn, alkylpyridyl, substituted alkylpyridyl, piperdinyl, substituted piperidinyl, tetrahydrothiopyran, substituted tetrahydrothiopyran, 2-indane, substituted 2-indane, phenyl, substituted phenyl, benzyl, substituted benzyl and alkylNHR 7 ;
R 7 is alkyl;
or R 3 and R 4 may be joined to form a monocyclic ring structure;
R 6 is selected from the group consisting of hydrogen and halogen;
T is
W, Y and Z are independently selected from the group consisting of C and CR 10 ;
R 10 is selected from the group consisting of hydrogen and halogen, with the proviso that at least one of W, Y and Z must be C;
X is selected from the group consisting of O, S, and SO 2 ;
provided that when the compound contains one or more chiral centers, at least the α-amino alcohol chiral center must be of S-stereochemistry.
2. The compound according to claim 1 , wherein:
R 1 , R 2 , R 3 , and R 5 are hydrogen;
R 4 is selected from the group consisting of alkyl and substituted alkyl;
X is selected from the group consisting of O and S.
3. The compound according to claim 1 , wherein:
R 1 , R 2 , and R 5 are H;
R 3 and R 4 are joined to form the monocyclic ring structure;
X is selected from the group consisting of O and S.
4. The compound according to claim 1 , wherein:
R 1 , R 2 , R 3 , and R 5 are hydrogen;
R 4 is selected from the group consisting of butyl, substituted butyl, propyl, pentyl, and substituted pentyl.
5. The compound according to claim 1 , wherein:
R 1 and R 2 are CH 3 ;
R 3 and R 5 are hydrogen;
R 4 is selected from the group consisting of butyl, substituted butyl, pentyl, and substituted pentyl;
W, Y and Z are independently selected from the group consisting of C and CR 10 ;
with the proviso that at least one of W, Y, and Z must be C.
6. A prodrug or hydrate of a compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:
wherein:
T is
R 1 , R 2 , and R 5 are hydrogen;
R 4 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylOH, substituted alkylOH, alkylOBn, substituted alkylOBn, alkylpyridyl, substituted alkylpyridyl, piperidinyl, substituted piperidinyl, tetrahydrothiopyran, substituted tetrahydrothiopyran, 2-indane, substituted 2-indane, phenyl, substituted phenyl, benzyl, substituted benzyl, and alkylNHR 7 ;
R 7 is alkyl;
R 3 is H or R 3 and R 4 may be joined to form a monocyclic ring structure;
R 6 is selected from the group consisting of hydrogen and halogen;
W, Y and Z are independently selected from the group consisting of C and CR 10 ;
R 10 is selected from the group consisting of hydrogen and halogen, with the proviso that at least one of W, Y and Z must be C;
X is selected from the group consisting of O, S, and SO 2 ;
provided that when the compound contains one or more chiral centers, at least the α-amino alcohol chiral center must be of S-stereochemistry.
7. The prodrug according to claim 6 , wherein the prodrug is an ester or carbamate thereof.