Benzamide derivatives

• US 9,221,790 B2
• Filed: 04/18/2011
• Issued: 12/29/2015
• Est. Priority Date: 04/23/2010
• Status: Active Grant

• Current Assignee: Dong-A Pharm Company Limited
• Original Assignee: Dong-A Pharm Company Limited
• Inventors: Kim, Soon-Hoe, Im, Weon-Bin, Choi, Sung-Hak, Choi, Sun-Ho, Sohn, Ju-Hee, Sung, Hyun-Jung, Kim, Mi-Yeon, Cho, Kang-Hun, Sohn, Tae-Kyoung
• Primary Examiner(s): Reese, Heidi
• Application Number:
  US13/641,867
• Publication Number:
  US 20130085160A1
• Time in Patent Office: 1,716 Days
• Field of Search: None
• US Class Current: 1/1
• 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 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention provides a novel benzamide derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a 5-HT₄ receptor agonist containing the same as an active ingredient. Benzamide derivatives of the present invention have a superior affinity for 5-HT₄ receptors, a capability to reduce a gastric emptying time and a low toxicity, and consequently are therapeutically effective for the treatment of a variety of diseases associated with 5-HT₄ receptors.

Claims

1. A compound of Formula 1:

2. The compound of claim 1, wherein:

m is an integer of 1 to 5; and

Q is either;

(i) a heteroaromatic ring that is selected from the group consisting of triazole, tetrazole, indole, imidazole and pyrrole and substituted by 0, 1, 2 or 3 substituents selected from among C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy and halogen;

or

(ii) a phenyl substituted by 1, 2 or 3 substituents selected from among C₁-C₄ alkyl, hydroxy and fluoro.

4. A method for preparing a compound of Formula 1 of claim 1, comprising:

reacting a compound of Formula 2;

5. The method of claim 4, wherein the base is selected from among potassium carbonate, potassium iodide, triethylamine, diisopropylethylamine and mixtures thereof.

8. The method of claim 4, wherein the compound of Formula 2 or the pharmaceutically acceptable salt thereof is prepared by:

(1) reacting a compound of Formula 4;

9. The method of claim 8, wherein the amine protecting group-introducing reagent of Step (1) is di-t-butyl dicarbonate or ethyl chloroformate in the presence of a tertiary amine base.

10. The method of claim 8, wherein the C₁-C₄ alkyl sulfonyl halide of Step (2) is methane sulfonyl chloride, methane sulfonyl bromide or methane sulfonyl fluoride.

11. The method of claim 8, wherein the reducing agent of Step (4) is triphenylphosphine or lithium aluminum hydride.

12. The method of claim 8, wherein the amide bond formation-inducing reagent of Step (5) is N-(3-dimethyl-aminopropyl)-N′

-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole in the presence of a base, ethyl chloroformate in the presence of a base, or carbodiimidazole in the absence of a base.

13. The method of claim 8, wherein the base or acid of Step (6) is selected from among hydrochloric acid, trifluoroacetic acid and potassium hydroxide.

14. A 5-HT4 receptor agonist, comprising a compound of Formula of claim 1:

15. The agonist of claim 14, wherein:

m is an integer of 1 to 5; and

Q is either;

(i) a heteroaromatic ring that is selected from the group consisting of triazole, tetrazole, indole, imidazole and pyrrole and substituted by 0, 1, 2 or 3 substituents selected from among C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy and halogen;

or

(ii) a phenyl substituted by 1, 2 or 3 substituents selected from among C₁-C₄ alkyl, hydroxy and fluoro.

17. A composition, comprising the agonist of any one of claims 14 to 16.

18. A method for the treatment or alleviation of a disease due to attenuated efficacy of a 5-HT4 receptor, comprising administering a 5-HT4 receptor agonist containing a compound of Formula 1 of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient to a mammal in need of 5-HT4 receptor agonistic effects, wherein the disease is selected from among gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, nausea, emesis, migraine, cardiovascular disorder, cardiac failure, cardiac arrhythmia, and apnea syndrome.

19. The compound of claim 1, wherein Q is a heteroaromatic ring that is selected from among triazole, tetrazole, indole, imidazole and pyrrole.

20. The agonist of claim 14, wherein Q is a heteroaromatic ring that is selected from among triazole, tetrazole, indole, imidazole and pyrrole.

21. The method of claim 18, wherein the mammal is a human.

3. A compound selected from among the following compounds:

N-((1-(3-(1,2,4-triazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(3-(tetrazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(3-(indol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(3-(2-methylimidazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(5-(indol-1-yl)pentyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(5-(1,2,3-triazol-1-yl)pentyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(3-(1,2,3-triazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(3-(1,2,3-triazol-2-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-((1-methylindol-3-yl)methyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(imidazol-2-ylmethyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-((1-methylpyrrol-2-yl)methyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(4-hydroxybenzyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(2-(indol-3-yl)ethyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(3-(tetrazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide hydrochloride,

N-((1-(5-(1,2,3-triazol-1-yl)pentyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide hydrochloride,

N-((1-(3-(1,2,3-triazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide hydrochloride,

N-((1-((1-methylindol-3-yl)methyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide hydrochloride,

N-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide hydrochloride,

N-((1-(4-hydroxybenzyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide hydrochloride, and

a pharmaceutically acceptable salt thereof.

6. A method for preparing a compound of Formula 1:

7. The method of claim 6, wherein the reducing agent is sodium cyanoborohydride and acetic acid, or sodium borohydride.

16. A 5-HT4 receptor agonist, comprising a compound selected from among the following compounds:

N-((1-(3-(1,2,4-triazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(3-(tetrazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(3-(indol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(3-(2-methylimidazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(5-(indol-1-yl)pentyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(5-(1,2,3-triazol-1-yl)pentyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(3-(1,2,3-triazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(3-(1,2,3-triazol-2-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1((1-methylindol-3-yl)methyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(imidazol-2-ylmethyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-((1-methylpyrrol-2-yl)methyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(4-hydroxybenzyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(2-(indol-3-yl)ethyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide,

N-((1-(3-(tetrazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide hydrochloride,

N-((1-(5-(1,2,3-triazol-1-yl)pentyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide hydrochloride,

N-((1-(3-(1,2,3-triazol-1-yl)propyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide hydrochloride,

N-((1((1-methylindol-3-yl)methyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide hydrochloride,

N-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide hydrochloride,

N-((1-(4-hydroxybenzyl)piperidin-4-yl)methyl)-4-amino-5-chloro-2-methoxybenzamide hydrochloride,

and a pharmaceutically acceptable salt thereof.