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EP-3617208-B1 - HETEROCYCLIC COMPOUND

EP3617208B1EP 3617208 B1EP3617208 B1EP 3617208B1EP-3617208-B1

Inventors

  • KITAMURA SHUJI
  • IKEDA ZENICHI
  • IKOMA MINORU
  • WATANABE KOJI
  • HIROSE HIDEKI
  • YUKAWA TAKAFUMI
  • MORIMOTO SACHIE
  • NISHIZAWA NAOKI
  • ASAMI TAIJI

Dates

Publication Date
20260513
Application Date
20180426

Claims (6)

  1. A compound represented by formula (I): wherein Ring A is a benzene; R 1 is a hydrogen atom or a C 1-6 alkyl group; R 2 is a C 1-6 alkyl group; R 3 is a C 1-6 alkyl group; R 4 is a C 6-14 aryl group which is optionally substituted with one to five C 1-6 alkyl groups; R 5 is a C 1-6 alkyl group; R 6 is a hydrogen atom or a C 1-6 alkyl group; and R 7 is a hydrogen atom or a C 1-6 alkyl group which is optionally substituted with one to three substituents selected from the group consisting of (a) a carbamoyl group, (b) a carboxy group, (c) a hydroxy group, and (d) a phenyl group, or a salt thereof.
  2. The compound according to claim 1, wherein the compound is (5R) -N-((2R)-1-(((2S)-1-amino-1-oxopropan-2-yl)amino)-2-(4-ethylphenyl)-1-oxobutan-2-yl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof, or (5R) -N-(1-(((2S)-1-amino-1-oxopropan-2-yl)amino)-2-(4-ethylphenyl)-1-oxobutan-2-yl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof, or (5R) -N-(1-(((2S)-1-amino-1-oxobutan-2-yl)amino)-2-(4-ethylphenyl)-1-oxobutan-2-yl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof, or (5R) -N-(1-(((2S)-1-amino-3-methyl-1-oxobutan-2-yl)amino)-2-(4-ethylphenyl)-1-oxobutan-2-yl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof.
  3. A medicament comprising the compound or a salt thereof according to claim 1 or 2.
  4. A compound or a salt thereof according to claim 1 or 2 for use as a calcium-sensing receptor antagonist.
  5. A compound or a salt thereof according to claim 1 or 2 for use in preventing or treating heart failure.
  6. A compound or a salt thereof according to claim 1 or 2 for use in preventing or treating pulmonary hypertension.

Description

Technical Field The present invention relates to a heterocyclic compound having a calcium-sensing receptor antagonistic activity and being useful as an agent for preventing or treating heart failure, pulmonary hypertension, or the like. Background Art Heart failure is a disease characterized by a condition that cardiac output is decreased due to cardiomyocytes dysfunction and a condition resulting from a burden on the body caused by cardiac output maintenance mechanisms. The function of cardiomyocytes is contraction and relaxation, and the contraction and relaxation require Ca2+ ions. The contraction of cardiomyocytes is generated by the stage where the action potential is transmitted to the transverse tubule and the transverse tubular membrane is depolarized; the stage where Ca2+ ions inflow from a voltage-dependent L-type Ca2+ channel of the transverse tubule into the cell; and the stage where the flowed Ca2+ ions bind to Ca2+ release channels (ryanodine receptors or RYRs) of sarcoplasmic reticulum to release Ca2+ ions from the sarcoplasmic reticulum to cytoplasm; and the stage where Ca2+ ions released into cells bind to troponin C to induce contraction of cardiomyocytes. Furthermore, the relaxation of cardiomyocytes is generated by incorporation of Ca2+ ions into sarcoplasmic reticulum through Ca2+ release pumps (SERCA) which decrease cytoplasmic Ca2+ ions and deviate Ca2+ ions from troponin C. If an abnormality occurs in any of the stage above and Ca2+ ions are not released into the cytoplasm, cardiomyocytes cause dysfunction to develop heart failure. As the therapeutics for heart failure, for example, beta blockers, anti-aldosterone drugs, diuretics, digitalis, and cardiotonics are used in clinical settings to improve short-term symptoms and stabilize hemodynamics. However, these therapeutics are insufficient to improve the readmission rates or long-term prognosis. Thus, in recent years, new heart failure therapeutics which improve the readmission rates and long-term prognosis has been desired. Pulmonary hypertension is a disease having a very poor prognosis, in which pulmonary arterial pressure increases due to abnormal proliferation, remodeling, and contraction of cardiac muscle or pulmonary vascular tissues, and as the disease progresses, right heart failure occurs, leading to death. The main therapeutics used for pulmonary hypertension include endothelin receptor antagonists, phosphodiesterase 5 inhibitors, prostacyclin analogues, soluble guanylate cyclase (sGC) stimulators. These therapeutics improve some symptoms, but the prognosis remains poor. In recent years, it has been found that multiple molecules are involved in the pathogenesis of this disease. Since the effects of the current therapeutics alone are limited, the development of new therapeutics has been desired. Calcium-sensing receptors (CaSR) are G-protein coupled receptors (GPCR) which sense changes in extracellular calcium concentration, and are known to be associated with a variety of diseases. Patent Literature 1 discloses heterocyclic compounds or salts thereof represented by the formulae below. This literature also describes that these compounds or salts thereof have a calcium-sensing receptor (CaSR) control action (agonist activity or antagonist activity) and secretion control actions of parathyroid hormone (PTH) thereby. Patent Literature 2 discloses compounds or salts thereof represented by the formula below. This literature also describes that these compounds or salts thereof have a calcium-sensing receptor (CaSR) control action (agonist activity or antagonist activity) and secretion control actions of parathyroid hormone (PTH) thereby. For heart failure, Non Patent Literatures 1 and 2 describe that parathyroid hormone treatment improves cardiac function, while Non Patent Literature 3 describes that parathyroid hormone treatment deteriorates cardiac function. Thus, the relationship of parathyroid hormone treatment and cardiac function improvement has not yet been fully elucidated. Non Patent Literature 4 describes that CaSR inhibitor Calhex231 improves cardiac hypertrophy in aortic banding (TAC) models, but the effect after cardiac hypofunction is not elucidated. Non Patent Literature 5 describes the result of Calhex231 dosing and shows that the Calhex231 dosing after cardiac loading fails to improve cardiac hypofunction. Furthermore, Non Patent Literature 6 describes that CaSR antagonists nullify cardioprotective effects in ischemic preconditioning models. So, the relationship of CaSR inhibition and the improvement of cardiac hypofunction or survival rate has not yet been fully elucidated. For pulmonary hypertension, it has recently been reported that, in pulmonary arterial smooth muscle cells (PASMCs) isolated from pulmonary hypertension patients, CaSR is overexpressed, and the hyperactivity thereby causes, for example, abnormal proliferation of pulmonary vascular tissues. Furthermore, it has been reported that Compound NPS-2