BICYCLIC PYRIDINE COMPOUND

• Main Authors: Akira KANAI, Yusuke INAGAKI, Masashi HIRAMOTO, Hajime TAKAMATSU, Akihiro ISHIHATA, Kentaro ENJO, Kenichi KAWAGUCHI
• Format: Patent
• Language: English; Spanish
• Published: 09.01.2020
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

The present invention addresses the problem of providing a pharmaceutical composition, particularly a compound suitable for the treatment of nocturia. Extensive and intensive studies have been made on compounds capable of inhibiting placental leucineaminopeptidase (P-LAP), in the anticipation that an antidiuretic activity associated with the maintenance of or increase in an endogenous AVP concentration can be exerted by inhibiting P-LAP, which is a metabolic enzyme for AVP, in the nighttime and the urination frequency in the nighttime can be decreased through the antidiuretic activity. As a result, it is found that a (2R)-3-amino-2-(bicyclic pyridylmethyl)-2-hydroxypropanoic acid derivative has a good P-LAP inhibition activity, and it is also found that, in an antidiuretic test using a drinking water-fed rat, the compound has a urine production inhibition activity associated with the increase in an endogenous AVP concentration which is resulted from the P-LAP inhibition by the compound. Thus, the present invention provides a compound which is expected to be used as a therapeutic agent for nocturia and of which the mechanism of action against nocturia is through the inhibition of P-LAP. El problema a resolver mediante la presente invención es proveer un compuesto adecuado para una composición farmacéutica, en especial una composición farmacéutica para tratar la nocturia. Los inventores han asumido que la inhibición de la actividad nocturna de la leucina aminopeptidasa placentaria (P-LAP), o sea aminopeptidasa que escinde AVP, mantendría y/o incrementaría un nivel endógeno de AVP para aumentar el efecto antidiurético, lo que contribuiría a un menor número de vaciamientos nocturnos, y han estudiado exhaustivamente los compuestos que inhiben a P-LAP. Como resultado, los inventores han hallado que los derivados del ácido (2R)-3-amino-2-(bi-cíclicopiridilmetil)-2-hidroxi-propanoico tienen una excelente actividad inhibitoria de P-LAP. Los inventores han evaluado efectos antidiuréticos en ratas administradas con agua y han hallado que los compuestos incrementan los niveles endógenos de AVP mediante la inhibición de P-LAP, y como consecuencia reducen la producción de orina. La presente invención por lo tanto provee compuestos que se espera que se usen como agentes para tratar la nocturia en base a la inhibición de P-LAP.