# US 8,541,441 B2 · Selective glycosidase inhibitors and uses thereof

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- Number: US 8,541,441 B2
- Document ID: US8541441B2
- Status: Granted
- Kind: B2
- Application number: 13/057,062
- Filed: 2009-07-31
- Published: 2012-04-19
- Granted: 2013-09-24
- Earliest claimed: 2008-08-01
- Assignees: Simon Fraser University
- Applicants: David Jaro Vocadlo; Ernest John McEachern; Keith Stubbs
- Inventors: David Jaro Vocadlo; Ernest John McEachern; Keith Stubbs
- Web page: https://patentgrep.com/patent/US8541441B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: 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
- A61P 27/14: Decongestants or antiallergics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C12Q 1/34: involving hydrolase
- G01N 2500/00: Screening for compounds of potential therapeutic value
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The invention provides compounds of Formula (I) 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.

## Claims

### Claim 1

A compound of Formula (I) or a pharmaceutically acceptable salt thereof or a prodrug of said compound or salt:
wherein each R1 is independently H or C(O)CH3; and
wherein R2 is NR8R9, wherein R8 is H or C1-10 alkyl, and R9 is CONR42.

### Claim 2 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, or a prodrug of said compound or salt, in combination with a pharmaceutically acceptable carrier.

### Claim 3

A compound or a pharmaceutically acceptable salt thereof or a prodrug of said compound or salt, selected from the group consisting of:
1-((1S,6S,7R,8R,8aR)- 1,7,8-trihydroxy-octahydroindolizin-6-yl)urea;
1-methyl-3-((1S,6S,7R,8R,8aR)-1,7,8-trihydroxy-octahydroindolizin-6-yl)urea;
1-ethyl-3-((1S,6S,7R,8R,8aR)-1,7,8-trihydroxy-octahydroindolizin-6-yl)urea;
1-propyl-3-((1S,6S,7R,8R,8aR)-1,7,8-trihydroxy-octahydroindolizin-6-yl)urea;
1-butyl-3-((1S,6S,7R,8R,8aR)-1,7,8-trihydroxy-octahydroindolizin-6-ylurea;
1-allyl-3-((1S,6S,7R,8R,8aR)-1,7,8-trihydroxy-octahydroindolizin-6-yl)urea;
1,1-dimethyl-3S,6S,7R,8R,8aR)- 1,7,8-trihydroxy-octahydro indolizin-6-yl)urea;
1-ethyl-1-methyl-3-((1S,6S,7R,8R,8aR)-1,7,8-trihydroxy-octahydroindolizin-6-yl)urea;
N-((1S,6S,7R,8R,8aR)-1,7,8-trihydroxy-octahydroindolizin-6-yl)pyrrolidine-1-carboxamide;
1,3-dimethyl-1-((1S,6S,7R,8R,8aR)-1,7,8-trihydroxy-octahydro indolizin-6-yl)urea; and
1,1,3-trimethyl-3-((1S,6S,7R,8R,8aR)-1,7,8-trihydroxy-octahydroindolizin-6-yl)urea.

### Claim 4 (depends on 3)

A pharmaceutical composition comprising the compound of claim 3, or a pharmaceutically acceptable salt thereof, or a prodrug of said compound or salt, in combination with a pharmaceutically acceptable carrier.