Benzisoxazole Derivatives

• US 20080207690A1
• Filed: 02/15/2006
• Published: 08/28/2008
• Est. Priority Date: 02/25/2005
• Status: Active Grant

• Current Assignee: RaQualia Pharma Inc.
• Original Assignee: RaQualia Pharma Inc.
• Inventors: Uchida, Chikara, Waizumi, Nobuaki, Sakurada, Isao, Noguchi, Hirohide
• Granted Patent: US 8,816,090 B2
• Time in Patent Office: Days
• US Class Current: 514/321
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

This invention relates to compounds of the formula (I): wherein A, B, R¹, R⁴, m, and n are each as described herein or a pharmaceutically acceptable salt thereof, and compositions containing such compounds and the use of such compounds in the treatment of a condition mediated by 5-HT₄ receptor activity such as, but not limited to, gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central 10 nervous system disease, Alzheimer'"'"'s disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome.

Claims

1-11. -11. (canceled)

12. A compound of the formula (I):

13. The compound of claim 12, wherein:

A is selected from —

C(R²)(R³)—

or C₃-C₆ cycloalkylene;

R¹ is selected from carboxy or hydroxy;

R² and R³ are independently selected from halogen or C₁-C₄ alkyl;

or R² and R³ together with the atom to which they are attached, form unsubstituted C₃-C₆ cycloalkyl or unsubstituted C₃-C₆ heterocyclyl;

R⁴ is selected from trifluoroethyl, isobutyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentyl, tetrahydro-2H-pyran-4-yl, (1-hydroxycyclopentyl)methyl, 2-hydroxycyclopentyl, 2-methoxycyclopentyl, 2-oxocyclopentyl, 3-hydroxycyclopentyl, 2-hydroxycyclohexyl, 4-hydroxycyclohexyl, 4-(hydroxymethyl)cyclohexyl, [1-(hydroxymethyl)cyclobutyl]methyl, or [1-(hydroxymethyl)cyclopentyl]methyl;

m is 1 or 2; and

n is 1;

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 12, wherein:

A is —

C(R²)(R³)—

;

B is —

O—

;

R¹ is carboxy;

R² and R³ are independently selected from fluoro, methyl, or ethyl;

or R² and R³ together with the atom to which they are attached, form a ring selected from;

15. The compound of claim 12, which is selected from:

4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid;

1-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}cyclobutane-carboxylic acid;

2,2-dimethyl-3-[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]-propanoic acid;

trans-4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}-cyclohexanecarboxylic acid;

4-{2-[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]ethyl}tetrahydro-2H-pyran-4-carboxylic acid;

2,2-difluoro-3-[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]propanoic acid;

4-{[4-(2-{[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}ethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid;

4-[(4-{[(4-isobutoxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylic acid;

1-[(4-{[(4-isobutoxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidin-1-yl)methyl]cyclobutanecarboxylic acid;

4-[2-(4-{[(4-isobutoxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidin-1-yl)ethyl]tetrahydro-2H-pyran-4-carboxylic acid;

trans-4-[(4-{[(4-isobutoxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidin-1-yl)methyl]cyclohexanecarboxylic acid;

4-[(4-{[(4-isobutoxy-1,2-benzisoxazol-3-yl)amino]methyl}piperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylic acid;

4-{[4-({[4-(cyclobutylmethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid;

3-[4-({[4-(cyclobutylmethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]-2,2-dimethylpropanoic acid;

or

4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]amino}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid;

or

a pharmaceutically acceptable salt thereof.

16. The compound of claim 12, which is selected from:

4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid;

1-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}cyclobutane-carboxylic acid;

2,2-dimethyl-3-[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]-propanoic acid;

trans-4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}-cyclohexanecarboxylic acid

4-{2-[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]ethyl}tetrahydro-2H-pyran-4-carboxylic acid;

4-[(4-{[(4-isobutoxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylic acid;

1-[(4-{[(4-isobutoxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidin-1-yl)methyl]cyclobutanecarboxylic acid;

4-[2-(4-{[(4-isobutoxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidin-1-yl)ethyl]tetrahydro-2H-pyran-4-carboxylic acid;

trans-4-[(4-{[(4-isobutoxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidin-1-yl)methyl]cyclohexanecarboxylic acid;

4-[(4-{[(4-isobutoxy-1,2-benzisoxazol-3-yl)amino]methyl}piperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylic acid;

4-{[4-({[4-(cyclobutylmethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid;

3-[4-({[4-(cyclobutylmethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]-2,2-dimethylpropanoic acid;

or

4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]amino}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid;

or

a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising the compound of claim 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising the compound of claim 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising the compound of claim 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 17, further comprising a second pharmacologically active agent.

21. A method for the treatment of a condition mediated by 5-HT₄ receptor activity in a mammalian subject, including a human, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound or pharmaceutically acceptable salt of claim 12.

22. A method for the treatment of a condition mediated by 5-HT₄ receptor activity in a mammalian subject, including a human, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound or pharmaceutically acceptable salt of claim 13.

23. A method for the treatment of a condition mediated by 5-HT₄ receptor activity in a mammalian subject, including a human, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound or pharmaceutically acceptable salt of claim 14.

24. The method of claim 21, wherein said condition is selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer'"'"'s disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes, or apnea syndrome.