Glycosidase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9938299-B2
Application number	US-201314655222-A
Country	US
Kind code	B2
Filing date	Dec 20, 2013
Priority date	Dec 24, 2012
Publication date	Apr 10, 2018
Grant date	Apr 10, 2018

Abstract

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.

First claim

What is claimed:

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.

Assignees

• Merck Sharp & Dohme
• Alectos Therapeutics Inc

Inventors

• Selnick Harold G
• Liu Kun
• Mceachern Ernest J
• Kaul Ramesh
• Wei Zhongyong
• Wang Yaode
• Chang Jiang

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P11/02

  Nasal agents, e.g. decongestants · CPC title

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• B65D5/005

  Separate or attached stacking elements · CPC title

• B65D2571/00716

  tubular without end walls · CPC title