Glycosidase inhibitors and uses thereof
View Patent ↗The invention provides compounds with enhanced permeability for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, accumulation or deficiency of O-GlcNAc.
1. A compound of Formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are each independently hydrogen, C1-6alkyl, C2-6alkenyl or C2-6alkynyl wherein the alkyl, alkenyl or alkynyl are optionally substituted with one up to the maximum number of substituents with one or more of fluoro, —OH, or methyl;
R 3 and R 4 are each independently hydrogen, or C1-6acyl;
W is
(1) —(CH 2 ) m —C(R 5 R 6 )—* wherein m is 1-3, R 5 and R 6 are each independently hydrogen, C1-3alkyl, —OH, halo, or —CF 3 , and the * represents the point of attachment to the tetrahydropyran ring;
(2) —(CH 2 ) n —CH═C(R 7 )—* wherein n is 0-3, R 7 is hydrogen or —CF 3 , and the * represents the point of attachment to the tetrahydropyran ring;
(3) —(CH 2 ) p —S(O) 2 —CH 2 —* wherein p is 0-1, and the * represents the point of attachment to the tetrahydropyran ring; or
(4) —(CH 2 ) q —S—CH 2 —* wherein q is 0-1 and the * represents the point of attachment to the tetrahydropyran ring; and
X is
(1)
wherein R 8 is hydrogen or C1-3alkoxy,
(2) —C(O)—O—R 9 wherein R 9 is hydrogen, C1-3alkyl, C2-3alkenyl or C2-3alkynyl; or
(3) —C(O)—NR 10 R 11 wherein R 10 and R 11 are each independently hydrogen, C1-3alkyl, C2-3alkenyl or C2-3alkynyl;
with the proviso that if W is —(CH 2 ) m —C(R 5 R 6 )—*, then X is (2) —C(O)—O—R 9 , or (3) —C(O)—NR 10 R 11 .
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each hydrogen or methyl.
3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are hydrogen.
4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is —(CH 2 ) m —C(R 5 R 6 )—* wherein m is 1-3, R 5 and R 6 are each independently hydrogen, C1-3alkyl, —OH, halo, or —CF 3 , and the * represents the point of attachment to the tetrahydropyran ring.
5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is —(CH 2 ) n —CH═C(R 7 )—* wherein n is 0-3, R 7 is hydrogen or —CF 3 , and the * represents the point of attachment to the tetrahydropyran ring.
6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein W is —(CH 2 ) p —S(O) 2 —CH 2 —*, wherein p is 0-1 and the * represents the point of attachment to the tetrahydropyran ring, or W is —(CH 2 ) q —S—CH 2 —*, wherein q is 0-1 and the * represents the point of attachment to the tetrahydropyran ring.
7. The compound according to claim 1 wherein X is:
wherein R 8 is hydrogen or C1-3alkoxy.
8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein X is —C(O)—O—R 9 wherein R 9 is hydrogen or C1-3alkyl.
9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein X is —C(O)—NR 10 R 11 wherein R 10 and R 11 are each independently hydrogen or C1-3alkyl.
10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
R 1 is hydrogen and R 2 is methyl, or R 1 is methyl and R 2 is hydrogen, or R 1 and R 2 are both methyl;
R 3 and R 4 are hydrogen;
W is —(CH 2 ) m —C(R 5 R 6 )—* wherein m is 1-2, R 5 and R 6 are each independently hydrogen, —OH, fluoro, or —CF 3 , and the * represents the point of attachment to the tetrahydropyran ring; and
X is —C(O)—O—R 9 wherein R 9 is hydrogen or C1-3alkyl.
11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
R 1 is hydrogen and R 2 is methyl, or R 1 is methyl and R 2 is hydrogen, or R 1 and R 2 are both methyl;
R 3 and R 4 are hydrogen;
W is (CH 2 ) m —C(R 5 R 6 )—* wherein m is 1-3, R 5 and R 6 are each independently hydrogen, —OH, fluoro, or —CF 3 , and the * represents the point of attachment to the tetrahydropyran ring; and
X is —C(O)—NR 10 R 11 wherein R 10 and R 11 are each independently hydrogen or C1-3alkyl.
12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
R 1 is hydrogen and R 2 is methyl, or R 1 is methyl and R 2 is hydrogen, or R 1 and R 2 are both methyl;
W is —(CH 2 ) n —CH═C(R 7 )—* wherein n is 0-1, R 7 is hydrogen or —CF 3 , and the * represents the point of attachment to the tetrahydropyran ring; and
X is
(1)
wherein R 8 is hydrogen or C1-3alkoxy, or
(2) —C(O)—O—R 9 wherein R 9 is hydrogen or C1-3alkyl.
13. A compound which is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. A method for treating a disease or disorder selected from the group consisting of consisting of Alzheimer's disease, Amyotrophic lateral sclerosis, glaucoma, schizophrenia, Huntington's disease, Parkinson's disease, Schizophrenia, Mild Cognitive Impairment (MCI) and Neuropathy, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.