US 2018/0022755 A1 · BICYCLIC PYRIDINE COMPOUND

Abstract

The problem to be solved by the present invention is to provide a compound suitable for a pharmaceutical composition, specifically a pharmaceutically composition for treating nocturia. The inventors have assumed that inhibition of nocturnal activity of placental leucine aminopeptidase (P-LAP), i.e. aminopeptidase that cleaves AVP, would maintain and/or increase an endogenous AVP level to enhance the antidiuretic effect, which would contribute to a decreased number of nocturnal voids, and have extensively studied compounds which inhibit P-LAP. As a result, the inventors have found that (2R)-3-amino-2-(bi-cyclic pyridylmethyl)-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.

Claims18

Dependent claims

A compound represented by Formula (I) or a salt thereof:
wherein:
X is O or S;
a dotted line is a single bond or a double bond;
R1 is lower alkyl which optionally has one to four substituents selected from the Group G1, cycloalkyl which optionally has one to five substituents selected from the Group G2, or -lower alkylene-(cycloalkyl which optionally has one to five substituents selected from the Group G2);
R2 and R5 are the same or different from each other, and are H, lower alkyl or cycloalkyl;
R3 is -lower alkylene-X3-lower alkyl, -lower alkylene-X3-lower alkylene-(cycloalkyl which optionally has one to five substituents selected from the Group G2), -lower alkylene-(cycloalkyl which optionally has one to five substituents selected from the Group G2), or -lower alkylene-X3-(cycloalkyl which optionally has one to five substituents selected from the Group G2);
X3 is O or S(O)n, wherein n is 0, 1, or 2;
R4 is OH, NH2, or —O-lower alkyl and R6 is H;
or R4 and R6 are linked to each other to form, together with —C(═O)—C—O— to which they are attached, 2,2-di(lower alkyl)-4-oxo-1,3-dioxolane-5,5-diyl;
the Group G1 consists of halogen, OH, —O-lower alkyl, —S-lower alkyl, and —O-(lower halogenoalkyl);
and
the Group G2 consists of lower alkyl, halogen, lower halogenoalkyl, OH, —O-lower alkyl, —S-lower alkyl, and —O-lower halogenoalkyl.

10 more elements

Bicyclic pyridine compound

Life of this patent

Bicyclic pyridine compound

Life of this patent

Abstract

Claims18