# US 8,785,633 B2 · Guanidine-containing compounds useful as muscarinic receptor antagonists

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- Number: US 8,785,633 B2
- Document ID: US8785633B2
- Status: Granted
- Kind: B2
- Application number: 13/681,794
- Filed: 2012-11-20
- Published: 2013-10-10
- Granted: 2014-07-22
- Earliest claimed: 2007-09-07
- Assignees: Theravance Biopharma R&D IP, LLC
- Applicants: YuHua Ji; Craig Husfeld; YongQi Mu; Rick Lee; Li Li
- Inventors: YuHua Ji; Craig Husfeld; YongQi Mu; Rick Lee; Li Li
- Web page: https://patentgrep.com/patent/US8785633B2

## CPC

- C07D 333/24: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/12: Antidiarrhoeals
- A61P 9/06: Antiarrhythmics
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 11/08: Bronchodilators
- A61P 13/10: of the bladder
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 277/28: Radicals substituted by nitrogen atoms
- C07D 295/13: to an acyclic saturated chain
- C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 307/81: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 317/58: Radicals substituted by nitrogen atoms (nitro radicals C07D317/52)
- C07D 333/20: by nitrogen atoms (nitro, nitroso radicals C07D333/12)
- C07D 333/58: Radicals substituted by nitrogen atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides compounds of formula I: or a pharmaceutically acceptable salt thereof, wherein R1-3, R5-7, a, X, Y, Y′, Y″, and Z are as defined in the specification. These compounds are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes for preparing such compounds and methods of using such compounds to, for example, treat pulmonary disorders such as chronic obstructive pulmonary disease and asthma.

## Claims

### Claim 1

A process for preparing a compound selected from 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-furan-2-ylmethylpiperazine-1-carboxamidine and 4-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetyl)-N-thiophen-2-ylmethyl-piperazine-1-carboxamidine, or a pharmaceutically acceptable salt thereof, comprising:
(a) coupling compound (1) and compound (2) under amide bond-forming conditions and deprotecting the product to form compound (3):
where a is 0; R1 is cyclopentyl; R2 is phenyl; R3 is —OH; and P is an amino-protecting group;
(b) reacting compound (3) with compound (6) to form compound (7):
where X is a bond, Y is —CH2—, Y′ is —N—, Y″ is —CH2—, and R6 is H; and;
(c) reacting compound (7) and compound (8) to provide a compound of formula I:
where R7 is H, Z is —CH2-Q, and Q is furanyl or thiophenyl.