5-HT.sub.4 agonists and antagonists

• US 6,117,882 A
• Filed: 06/23/1999
• Issued: 09/12/2000
• Est. Priority Date: 10/07/1997
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Schaus, John M., Thompson, Dennis C., Cohen, Marlene L.
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US09/338,707
• Time in Patent Office: 447 Days
• Field of Search: 514/304, 546/126
• US Class Current: 514/304
• 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 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 451/04 with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Abstract

Compounds of formula I: ##STR1## are used as antagonists and partial agonists for the serotonin receptor 5-HT₄ and provide therapeutic methods for treatment of disorders caused by or affected by dysfunction of the 5-HT₄ receptor.

Claims

1. A compound of formula I:

##STR7## wherein;

A-D is C═

N or N--C═

O;

n is 1, 2, 3, 4, or 5;

R is hydrogen, halo, C₁ -C₄ alkyl, hydroxy, C₁ -C₄ alkoxy, C₁ -C₄ alkylthio, cyano, trifluoromethyl, carboxamido, mono or di(C₁ -C₄ alkyl) carboxamido;

R¹ is hydrogen, C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, or substituted C₃ -C₆ cycloalkyl;

R² and R³ taken together form a bridge of 1 to 4 methylene units;

X is OR⁴ or NR⁴ R⁵ ;

R⁴ is hydrogen, C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, substituted C₃ -C₆ cycloalkyl, phenyl, substituted phenyl, (C₁ -C₆ alkyl)CO, benzoyl, substituted benzoyl, tricyclo[3.3.1.1³,7 ]decan-1-oyl, or S(O)₂ R⁶ ;

R⁵ is hydrogen or R⁴ and R⁵ together with the nitrogen to which they are attached form a 1-pyrrolidinyl, 1-piperazinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 2,3-dihydro-1-indolinyl, 4-morpholinyl, 1-piperidinyl, 1-hexamethyleneiminyl, or phthalimidyl ring;

R⁶ is C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, substituted C₃ -C₆ cycloalkyl, phenyl, or substituted phenyl;

or a pharmaceutically acceptable salt thereof provided that when A-D is C═

N and X is OR⁴, then R⁴ is phenyl substituted 1 to 3 times with a halogen.

2. A compound of claim 1 wherein n is 2 or 3, R is hydrogen, halo, C₁ -C₄ alkyl, hydroxy, C₁ -C₄ alkoxy, trifluoromethyl, and R¹ is C₁ -C₄ alkyl;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 wherein R² and R³ combine to form a bridge of 2 methylene units;

or a pharmaceutically acceptable salt thereof.

4. A compound of claim 3 wherein X is NR⁴ R⁵, R⁴ is SO₂ R⁶, R⁵ is hydrogen, and R⁶ is C₁ -C₆ alkyl, phenyl, or substituted phenyl;

or a pharmaceutically acceptable salt thereof.

5. A compound of claim 3 wherein X is NR⁴ R⁵, R⁴ is benzoyl, substituted benzoyl, or tricyclo[3.3.1³,7 ]decan-1-oyl, and R⁵ is hydrogen;

or a pharmaceutically acceptable salt thereof.

6. A compound of claim 3 wherein X is NR⁴ R⁵ and R⁴ and R⁵ together with the nitrogen to which they are attached form a 1-pyrrolidinyl, 1-piperazinyl, 4-morpholinyl, 1-piperidinyl, or phthalimidyl ring;

or a pharmaceutically acceptable salt thereof.

7. A compound of claim 3 which is N-(8-(3-(4-Fluorophenyl)propyl)-8-Azabicyclo[3.2.1]octan-8-yl)-2-oxo-3-isopropylbenzimidazole-1-carboxamide or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a compound of claim 1.

9. A method of providing treatment for anxiety, pain, depression, schizophrenia, memory disorders, dementia, irritable bowel syndrome, nausea, gastroesophageal reflux disease, dyspepsia, gastrointestinal motility disorders, constipation, atrial fibrilation, arrhythmias, tachycardia, urinary retention, urinary incontinence, or pain on urination, comprising adminstering to a subject in need of such treatment an effective amount of a compound selected from formula I or a pharmaceutically accepted salt of claim 1.

10. A method of claim 9 wherein the compound of formula I is a compound wherein n is 2 or 3, R is hydrogen, halo, C₁ -C₄ alkyl, hydroxy, C₁ -C₄ alkoxy, trifluoromethyl, and R¹ is C₁ -C₄ alkyl;

or a pharmaceutically acceptable salt thereof.

11. A method of claim 10 wherein the compound of formula I is a compound wherein R² and R³ combine to form a bridge of 2 methylene units;

or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the compound of formula I is:

N-(8-(3-(4-Fluorophenyl)propyl)-8-Azabicyclo[3.2.1]octan-8-yl)-2-oxo-3-isopropylbenzimidazole-1-carboxamide or a pharmaceutically acceptable salt thereof.