Pyridine derivative

Patent metadata

Field	Value
Publication number	US-10975091-B2
Application number	US-201916544245-A
Country	US
Kind code	B2
Filing date	Aug 19, 2019
Priority date	May 28, 2014
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

Abstract

As a result, the inventors have found that (2R)-3-amino-2-{[4-(substituted pyridine)-2-yl]methyl}-2-hydroxy-propanoic acid derivatives have excellent P-LAP inhibitory activity. The inventors have evaluated antidiuretic effects in water-loaded rats and have found that the compounds increase endogenous AVP levels by inhibiting P-LAP and consequently reduce urine production. The present invention therefore provides compounds expected to be used as an agent for treating nocturia based on P-LAP inhibition.

First claim

The invention claimed is:

1. A method of treating nocturia comprising administering to a subject an effective amount of a compound represented by Formula (I) or a salt thereof:

wherein, X is O, S or NR 4 ;
R 4 is H, lower alkyl which optionally has one to five substituents selected from the Group G 1 , C 3-12 cycloalkyl which optionally has one to five substituents selected from the Group G 2 , -(lower alkylene)-(C 3-12 cycloalkyl which optionally has one to five substituents selected from the Group G 2 ), —C(O)-(lower alkyl which optionally has one to five substituents selected from the Group G 1 ), —C(O)—(C 3-12 cycloalkyl which optionally has one to five substituents selected from the Group G 2 ), or —C(O)-(lower alkylene)-(C 3-12 cycloalkyl which optionally has one to five substituents selected from the Group G 2 ), or R 4 forms together with neighboring —NR 1 , as —NR 1 R 4 , a 4- to 8-membered nitrogen-containing saturated heterocyclic group, wherein the nitrogen-containing saturated heterocyclic group may be condensed with a benzene ring and optionally has one to five substituents selected from the Group G 4 ;
R 1 is H, C 1-10 alkyl which optionally has one to five substituents selected from the Group G 1 , -(lower alkylene)-X 11 -(lower alkyl which optionally has one to five substituents selected from the Group G 1 ), R 11 , -(lower alkylene)-R 11 , -(lower alkylene)-X 11 —R 11 , or -(lower alkylene)-X 11 -(lower alkylene)-R 11 ;
R 2 's are the same or different from each other, and are H, lower alkyl which optionally has one to five substituents selected from the Group G 1 , halogen, OH, SH, —O-(lower alkyl), —O-(lower alkylene)-aryl, —O-aryl, —S-(lower alkyl), —S-(lower alkylene)-aryl, —S-aryl, —O-(lower halogenoalkyl), —C(O)-(lower alkyl), —S(O) 2 -(lower alkyl), —S(O)-(lower alkyl), NO 2 , —NH 2 , —NH-(lower alkyl), —N(lower alkyl) 2 , —NH-aryl, —N(lower alkyl)-aryl, —C(O)OH, —C(O)O-(lower alkyl), —CHO, —C(O)NH 2 , —C(O)NH-(lower alkyl), —C(O)N(lower alkyl) 2 , CN, -(lower alkylene)-X 21 -(lower alkyl which optionally has one to five substituents selected from the Group G 1 ), C 3-12 cycloalkyl which optionally has one to five substituents selected from the Group G 2 , C 3-12 cycloalkenyl which optionally has one to five substituents selected from the Group G 2 and which may be condensed with a benzene ring optionally having one to four substituents selected from the Group G 3 , aryl which optionally has one to five substituents selected from the Group G 5 , -(lower alkylene)-R 21 , -(lower alkylene)-X 21 —R 21 , or -(lower alkylene)-X 21 -(lower alkylene)-R 21 ;
R 3 is R 32 , -(lower alkylene)-X 31 —R 32 , -(lower alkenylene)-X 31 —R 32 , R 31 , -(lower alkylene)-R 31 , -(lower alkylene)-X 31 —R 31 , -(lower alkylene)-X 31 -(lower alkylene)-R 31 , -(lower alkenylene)-R 31 , -(lower alkynylene)-R 31 or —CH=(saturated monocyclic heterocycle);
X 11 , X 21 and X 31 are the same or different from each other, and are O or S(O), wherein n is 0, 1, or 2;
R 11 , R 21 , and R 31 are the same or different from each other, and are C 3-12 cycloalkyl which optionally has one to five substituents selected from the Group G 2 , C 3-12 cycloalkenyl which optionally has one to five substituents selected from the Group G 2 and which may be condensed with a benzene ring optionally having one to four substituents selected from the Group G 3 , aryl which optionally has one to five substituents selected from the Group G 5 , or mono- or bi-cyclic heterocyclic group which optionally has one to five substituents selected from the Group G 5 ;
R 32 is C 1-10 alkyl which optionally has one to five substituents selected from the Group G 1 , lower alkenyl which optionally has one to five substituents selected from the Group G 1 , or lower alkynyl which optionally has one to five substituents selected from the Group G 1 ;
R P is H or an ester group and R 6 is H; or R P and R 6 are linked to each other to form, together with —O—C(═O)—C—O— to which they are attached, 2,2-di(lower alkyl)-4-oxo-1,3-dioxolane-5,5-diyl;
if R 3 is C 1-10 alkyl which is optionally substituted by one to five halogens, —X—R 1 is optionally linked to any one of R 2 's attached to a pyridine ring to which —X—R 1 is also attached, to constitute a group represented by any one of formulae —X b —(CH 2 ) m —Y—, —X b —CH═CH—, —X b —CH═N—, and —X b —N═CH—, and form a heterocycle condensed with the pyridine ring, wherein m is an integer of 1 to 3, X b is O, S or NH, Y is CH 2 , O, S or NH, and the heterocycle optionally has one to four substituents selected from the group consisting of: C 3-12 cycloalkyl which optionally has one to five substituents selected from the Group G 2 ; -(lower alkylene)-(C 3-12 cycloalkyl which optionally has one to five substituents selected from the Group G 2 ); and the substituents defined in the Group G 3 ; in replacement of one or more H atoms attached to the ring atom(s) of the heterocycle;
—X—R 1 is optionally linked to R 3 to form a group represented by formula —X—(C 5-15 carbon chain)-, wherein the C 5-15 carbon chain optionally has one to two O or S atoms in replacement of C atom(s), optionally has one to five unsaturated bonds, and optionally has one to five substituents selected from the Group G 4 ;
Group G 1 consists of halogen, OH, SH, —O-(lower alkyl), —O-(lower alkylene)-aryl, —O-aryl, —S-(lower alkyl), —S-(lower alkylene)-aryl, —S-aryl, —O-(lower halogenoalkyl), —C(O)-(lower alkyl), —C(O)-aryl, —S(O) 2 -(lower alkyl), —S(O)-(lower alkyl), NO 2 , —NH 2 , —NH-(lower alkyl), —N(lower alkyl) 2 , —NH-aryl, —N(lower alkyl)-aryl, —C(O)OH, —C(O)O-(lower alkyl), —CHO, —C(O)NH 2 , —C(O)NH-(lower alkyl), —C(O)N(lower alkyl) 2 , —C(O)NH-aryl, and CN;
Groups G 2 and G 4 consist of the substituents in the Group G 1 , lower alkyl which optionally has one to five substituents selected from the Group G 1 , —O—(C 2-3 alkylene)-O—, and —O—(C 3-4 alkylene)-;
Group G 3 consists of the substituents in the Group G 1 and lower alkyl which optionally has one to five substituents selected from the Group G 1 ; and
Group G 5 consists of: i) the substituents in the Group G 1 ; ii) lower alkyl, lower alkenyl and lower alkynyl, each of which optionally has one to five substituents selected from the Group G 1 ; iii) -(lower alkylene)-O-(lower alkyl, lower alkenyl or lower alkynyl, which optionally has one to five substituents selected from the Group G 1 ); iv) C 3-12 cycloalkyl, and C 3-12 cycloalkenyl which may be condensed with a benzene ring optionally having one to four substituents selected from the Group G 3 , the C 3-12 cycloalkyl and the C 3-12 cycloalkenyl optionally have one to five substituents selected from the Group G 2 ; v) aryl which optionally has one to five substituents selected from the Group G 3 ; vi) mono- or bi-cyclic heterocyclic group which optionally has one to five substituents selected from the Group G 3 ; vii) -(lower alkylene)-R G ; viii) -(lower alkylene)-O—R G ; ix) —C(O)—R G ; x) —C(O)—O—R G ; xi) —C(O)—O-(lower alkylene)-R G ; and xii) —S(O) 2 —R G , wherein R G 's are the same or different from each other, and are C 3-12 cycloalkyl which optionally has one to five substituents selected from the Group G 2 , C 3-12 cycloalkenyl which optionally has one to five substituents selected from the Group G 2 and which may be condensed with a benzene ring optionally having one to four substituents selected from the Group G 3 , aryl which optionally has one to five substituents selected from the Group G 3 , or a mono- or bi-cyclic heterocyclic group which optionally has one to five substituents selected from the Group G 3 .

Assignees

• Astellas Pharma Inc
• Kotobuki Pharmaceutical Co Ltd

Inventors

• Kawaguchi Kenichi
• Ishihata Akihiro
• Inagaki Yusuke
• Tsuchiya Kazuyuki
• Hanadate Tadaatsu
• Kanai Akira
• Kaizawa Hiroyuki
• Kazami Junichi
• Morikawa Hiroshi
• Hiramoto Masashi
• Enjo Kentaro
• Takamatsu Hajime

Classifications

• C07D491/04

  Ortho-condensed systems · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title