Therapeutic ureas

• US 6,635,764 B2
• Filed: 12/07/2000
• Issued: 10/21/2003
• Est. Priority Date: 12/07/1999
• Status: Expired due to Term

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Mammen, Mathai, Oare, David
• Primary Examiner(s): Baker, Maurie Garcia
• Application Number:
  US09/732,514
• Publication Number:
  US 20020049195A1
• Time in Patent Office: 1,048 Days
• Field of Search: 435/7.1, 435/7.2, 436/501, 546/184, 546/192, 546/195, 546/207, 546/208, 546/223, 546/224, 564/32, 564/48, 514/315, 514/317, 514/326, 514/329, 514/588, 514/596
• US Class Current: 546/224
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: 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
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 211/48 having an acyclic carbon atom attached in position 4
• CPC Class Codes: C07D 211/52 having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/08 : Bridged systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 471/14 : Ortho-condensed systems
• CPC Class Codes: C07D 495/08 : Bridged systems

Abstract

This invention relates to urea compounds that are muscarinic receptor antagonists and agonists, pharmaceutical compositions comprising such compounds, and methods of preparing these compounds.

Claims

1. A compound of formula (IVa):

wherein;

X is a group of formula;

2. The compound of claim 1 wherein L₂ is a group of the formula (d) and R⁴⁶ is alkyl or substituted alkyl;

R⁴⁷ is alkyl, substituted alkyl, or heterocycle;

or R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attached form heterocycle.

3. The compound of claim 1 wherein L₂ is a group of formula (d) wherein R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 5 substituents independently selected from the, group consisting of substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.

4. The compound of claim 1 wherein L₂ is a group of the formula (d) and R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring which ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.

5. The compound of claim 1 wherein L₂ has any one of the formula A1-A590 shown hereinabove.

6. The compound of claim 1 wherein L₂ is A234, A363, A364, A153, A28, A324, A329, A562, A87, or A239.

7. The compound of claim 1, wherein X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, or -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.

8. The compound of claim 1 wherein X is an alkylene group having from 3 to 20 carbon atoms;

wherein one or more carbon atoms in the alkylene group is optionally replaced with —

O—

; and

wherein the chain is optionally substituted on carbon with one or more hydroxyl.

9. The compound of claim 1 wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.

10. The compound of claim 1 wherein X has the formula:

wherein the phenyl ring is optionally substituted with 1, 2, or 3 fluoro groups.

11. The compound of claim 1 wherein X has one of the following formula:

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 11.

12. Compound number 1-643 as described in Table A, Table B, Table C, Table D, Table E, or Table F;

or a pharmaceutically acceptable salt thereof.