Tetrahydrobenzothiophene compound

Patent metadata

Field	Value
Publication number	US-9284295-B2
Application number	US-201414229146-A
Country	US
Kind code	B2
Filing date	Mar 28, 2014
Priority date	Apr 28, 2010
Publication date	Mar 15, 2016
Grant date	Mar 15, 2016

Abstract

The purpose is to provide a compound which has an intestinal phosphate transporter (NPT-IIb) inhibitory action and is useful as an active ingredient of an agent for treating and/or preventing hyperphosphatemia.
A tetrahydrobenzothiophene compound of the following formula (I) has NPT-IIb inhibitory action and can be used as an agent for treating and/or preventing hyperphosphatemia:

wherein, R 1 represents —O-lower alkyl, -lower alkylene-phenyl, or the like; R 2 and R 3 are the same as or different from each other and represent H, lower alkyl, cycloalkyl, aryl, heteroaryl or the like, or, R 2 and R 3 may be combined with a nitrogen atom to which they bind to form 5- to 7-membered saturated cyclic amino; R 4 's are the same as or different from each other and represent halogen, lower alkyl; and n represents 0 to 2.

First claim

The invention claimed is:

1. A compound of the formula (I) or a salt thereof:

wherein
R 1 represents —O-lower alkyl, -lower alkylene-phenyl, or -lower alkylene-pyridyl, in which phenyl or pyridyl may be substituted with carboxy or —CO—O-lower alkyl, —CO—O-lower alkenyl, —CO—O-lower alkynyl, —CO—O-lower alkylene-O-lower alkyl, —CO—O-lower alkylene-aryl, —CO—O-lower alkylene-O-aryl, —CO—NH 2 , —CO—NH-lower alkyl, —CO—N(lower alkyl) 2 , —CO—N(lower alkyl)-aryl, —CO—N(lower alkyl)-(lower alkylene-aryl), —CO—NH-lower alkylene-OH, —CO—NH-lower alkylene-CO 2 H, —CO—O-methyl, —CO—O-ethyl, or —COO-tert-butyl,
R 2 and R 3 are the same or different and each independently represents H, lower alkyl, cycloalkyl, aryl, heteroaryl, nitrogen-containing saturated hetero ring, -lower alkylene-aryl, or -lower alkylene-heteroaryl, in which lower alkyl, cycloalkyl, aryl, heteroaryl, and a nitrogen-containing saturated hetero ring may be substituted with halogen, -lower alkyl, pyridyl, carboxy, —CO—O-lower alkyl, —CO—O-lower alkenyl, —CO—O-lower alkynyl, —CO—O-lower alkylene-O-lower alkyl, —CO—O-lower alkylene-aryl, —CO—O-lower alkylene-O-aryl, —CO—NH, —CO—NH-lower alkyl, —CO—N(lower alkyl) 2 , —CO—N(lower alkyl)-aryl, —CO—N(lower alkyl)-lower alkylene-aryl), —CO—NH-lower alkylene-OH, —CO—NH-lower alkylene-CO 2 H, —CO—O-methyl, —CO—O-ethyl, —COO-tert-butyl, amino which may be substituted with one -lower alkyl, or the same or different two or more -lower alkyls, —O-lower alkyl, —[CH(—OH)] m —H or —OH, or
R 2 and R 3 may be combined with the nitrogen atom to which they bind to form 5- to 7-membered saturated cyclic amino, in which the 5- to 7-membered saturated cyclic amino may be substituted with halogen, —OH, oxo(═O), —O-lower alkyl, cyano, nitro, cycloalkyl, aryl, hetero ring, -lower alkylene-aryl, -lower alkylene-hetero ring, -lower alkyl which may be substituted with halogen, —OH, —O-lower alkyl, or cyano, carboxy, —CO—O-lower alkyl, —CO—O-lower alkenyl, —CO—O-lower alkynyl, —CO—O-lower alkylene-O-lower alkyl, —CO—O-lower alkyelen-aryl, —CO—O-lower alkylene-O-aryl, —CO—NH 2 , —CO—NH-lower alkyl, —CO—N(lower alkyl) 2 , —CO—N(lower alkyl)-aryl, —CO—N(lower alkyl)-(lower alkylene-aryl), —CO—NH-lower alkylene-OH, —CO—NH-lower alkylene-CO 2 H, —CO—O-methyl, —CO—O-ethyl, —COO-tert-butyl or —CO-lower alkyl,
R 4 's are the same as or different and each independently represents halogen, lower alkyl, —OH, —O-lower alkyl, —NO 2 , or a group represented by the formula (II):

wherein R 41 and R 42 are the same or different and each independently represents H or lower-alkyl which may be substituted with —OH, or R 41 and R 42 may be combined with the nitrogen atom to which they bind to form 5- to 7-membered saturated cyclic amino, and
m represents 1 to 5, and
n represents 0 to 2,
provided that N-(4-methoxyphenyl)-2-({3-[(4-methylpiperazin-1-yl)sulfonyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide is excluded.

2. The compound or a salt thereof according to claim 1 , wherein n is 0.

3. The compound or a salt thereof according to claim 2 , wherein R 1 is -lower alkylene-(phenyl substituted with carboxy or —CO—O-lower alkyl, —CO—O-lower alkenyl, —CO—O-lower alkynyl, —CO—O-lower alkylene-O-lower alkyl, —CO—O-lower alkylene-aryl, —CO—O-lower alkylene-O-aryl, —CO—NH 2 , —CO—NH-lower alkyl, —CO—N(lower alkyl)), —CO—N(lower alkyl)-aryl, —CO—N(lower alkyl)-(lower alkylene-aryl), —CO—NH-lower alkylene-OH, —CO—NH-lower alkylene-CO 2 H, —CO—O-methyl, —CO—O-ethyl, or —COO-tert-butyl).

4. The compound or a salt thereof according to claim 3 , wherein R 1 is -lower alkylene-(phenyl substituted with carboxy).

5. The compound or a salt thereof according to claim 4 , wherein R 2 is -lower alkyl, cycloalkyl, or phenyl, each of which is substituted with carboxy.

6. The compound or a salt thereof according to claim 5 , wherein R 3 is -lower alkyl or cycloalkyl.

7. The compound or a salt thereof according to claim 6 , wherein R 2 and R 3 are combined with the nitrogen atom to which they bind to form pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, or azepan-1-yl, each of which may be substituted with halogen, —OH, oxo(═O), —O—lower-alkyl, cyano, nitro, cycloalkyl, aryl, hetero ring, -lower alkylene-aryl, -lower alkylene-hetero ring, -lower alkyl which may be substituted with halogen, —OH, —O-lower alkyl, or cyano, carboxy, —CO—O-lower alkyl, —CO—O-lower -alkenyl, —CO—O-lower alkynyl, —CO—O-lower alkylene-O-lower alkyl, —CO—O-lower alkylene-aryl, —CO—O-lower alkylene-O-aryl, —CO—NH 2 , —CO—NH-lower alkyl, —CO—N(lower alkyl) 2 , —CO—N(lower alkyl)-aryl, —CO—N(lower alkyl)-(lower alkylene-aryl), —CO—NH-lower alkylene-OH, —CO—NH-lower alkylene-CO 3 H, —CO—O-methyl, —CO—O-ethyl, —COO-tert-butyl or —CO-lower alkyl.

8. The compound or a salt thereof according to claim 7 , wherein R 2 and R 3 are combined with the nitrogen atom to which they bind to form piperazin-1-yl which may be substituted with halogen, —OH, oxo(═O), —O-lower alkyl, cyano, nitro, cycloalkyl, aryl, hetero ring, -lower alkylene-aryl, -lower alkylene-hetero ring, -lower alkyl which may be substituted with halogen, —OH, —O-lower alkyl, or cyano, carboxy, —CO—O-lower alkyl, —CO—O-lower alkenyl, —CO—O-lower alkynyl, —CO—O-lower alkylene-O-lower alkyl, —CO—O-lower alkylene-aryl, —CO—O-lower alkylene-O-aryl, —CO—NH), —CO—NH-lower alkyl, —CO—N(lower alkyl) 2 , —CO—N(lower alkyl)-aryl, —CO—N(lower alkyl)-(lower alkylene-aryl), —CO—NH-lower alkylene-OH, —CO—NH-lower alkylene-CO 2 H, —CO—O-methyl, —CO—O-ethyl, —COO-tert-butyl or —CO-lower alkyl.

9. A pharmaceutical composition, comprising a compound or a salt thereof according to claim 1 , and a pharmaceutically acceptable excipient.

Assignees

• Astellas Pharma Inc

Inventors

• Hachiya Shunichiro
• Miura Masanori
• Imamura Yoshimasa
• Kaga Daisuke
• Sato Ippei
• Moritomo Hiroyuki
• Kato Koji
• Terai Kazuhiro
• Terada Yoh

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P3/12

  for electrolyte homeostasis · CPC title