Calcium-sensing receptor-active compounds

A technology of compounds and stereoisomers, applied in the field of calcium-sensing receptor activating compounds, can solve problems such as women's influence, and achieve the effects of prolonging the half-life in vivo, prolonging the duration of curative effect in vivo, and high stability

Inactive Publication Date: 2013-11-13
LEO PHARMA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Menopausal women are highly susceptible and osteoporosis is increasingly a proven problem in older women for which there is currently no optimal treatment

Method used

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  • Calcium-sensing receptor-active compounds
  • Calcium-sensing receptor-active compounds
  • Calcium-sensing receptor-active compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0056] In an embodiment of the present invention, compound I is represented as Ia or Ib

[0057]

[0058] In an embodiment of the invention, R 3 stands for methyl.

[0059] In one embodiment, R 1 represents chlorine, fluorine, methoxy or ethoxy.

[0060] In one embodiment, R 2 represents chlorine, fluorine, methoxy or ethoxy.

[0061] In an embodiment of the invention, R 1 represents 4-fluoro, and R 2 represents 3-methoxy.

[0062] In one embodiment, R 1 represents chlorine, and R 2 represents hydrogen.

[0063] In an embodiment of the invention, R 4 stands for – C(O)NH 2 , C 1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, C 3-6 Cycloalkyl, C containing 1-3 heteroatoms selected from N and O 2-4 Heterocycloalkyl, C containing 1-3 heteroatoms selected from N and O 2-4 Heterocycloalkenyl, aminosulfonyl C 1-4 Alkyl, C 1-2 Alkylsulfonyl C 1-4 Alkyl, C 1-2 Alkylsulfonylamino C 1-3 Alkyl, C containing 1-3 heteroatoms selected fr...

Embodiment 1

[0247] Example 1: N-[2-[[4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]-amino] Cyclopentyl]benzoyl]amino]ethyl]-1H-1,2,4-triazole-3-carboxamide (Compound 101)

[0248] To a solution of Intermediate 4 (719 mg, 1.8 mmol) in dry DMF (12 mL) were added HOBt (276 mg, 2 mmol) and EDAC (517 mg, 2.7 mmol) and the mixture was stirred at room temperature for 4 hours. Then 1H-1,2,4-triazole-3-carboxylic acid (200 mg, 1.8 mmol) was added and stirring was continued at room temperature overnight. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (30% MeOH / DCM) to give the title compound in 78% yield.

[0249] 1 H NMR(300MHz,DMSO)δ8.70(br m,1H), 8.48(br m,1H), 8.41(s,1H), 7.76(d,J=8.2Hz,2H), 7.31(d,J= 8.2Hz,2H), 7.17(dd,J=8.6,1.6Hz,1H), 7.10(dd,J=11.5,8.3Hz,1H), 6.89(ddd,J=8.1,4.4,1.8Hz,1H), 3.84(s,3H), 3.78(q,J=6.6Hz,1H), 3.46(br m,4H), 3.04–2.85(m,2H), 2.15–1.54(m,6H), 1.43–1.19(m , 4H).

Embodiment 2

[0250] Example 2: N-[2-(2,3-Dihydroxypropionylamino)ethyl]-4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3- Methoxy-phenyl)ethyl]amino]cyclopentyl]benzamide (Compound 102)

[0251] Prepared from intermediate 4 and 2,3-dihydroxypropionic acid according to GP1.

[0252] 1H NMR(300MHz,DMSO)δ8.41-8.29(m,1H), 7.94-7.85(m,1H), 7.73(d,J=8.2Hz,2H), 7.30(d,J=8.3Hz,2H) , 7.20–7.14(m,1H), 7.10(dd,J=11.5,8.3Hz,1H), 6.93–6.84(m,1H), 5.48(d,J=5.4Hz,1H), 4.64(t,J =5.6Hz,1H), 3.92–3.71(m,5H), 3.64–3.16(m,6H), 3.03–2.84(m,2H), 2.17–2.00(m,1H), 2.00–1.51(m,4H) ), 1.43–1.28 (m, 1H), 1.24 (d, J=6.5Hz, 3H).

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Abstract

Compounds of general formula (I) their use as calcium receptor-active compounds for the prophylaxis, treatment or amelioration of physiological disorders or diseases associated with disturbances of CaSR activity, such as hyperparathyroidism, pharmaceutical compositions comprising said compounds, and methods of treating diseases with said compounds.

Description

technical field [0001] The present invention relates to novel calcium-sensing receptor activating compounds, use of said compounds in therapy, pharmaceutical compositions comprising said compounds, methods of treating diseases using said compounds, and use of said compounds in the manufacture of medicaments. Background technique [0002] Calcium-sensing receptors (CaSRs) are G-protein-coupled receptors (GPCRs) that signal by activating phospholipase C, increasing the levels of inositol 1,4,5-triphosphate and cytosolic calcium ions. CaSR belongs to a subfamily of the GPCR superfamily, which also includes receptors for glutamate, gamma-aminobutyric acid (GABA), pheromones, and flavor enhancers, all of which have very large extracellular domains. This domain is highly negatively charged and is capable of binding calcium and other positively charged molecules. CaSR is found in the parathyroid gland, and calcium-sensing receptors have also been identified in the brain, intestine...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/46C07C237/34C07C317/44C07C69/76C07D249/10A61K31/4196A61K31/166A61K31/10
CPCC07C317/44C07D249/10C07C229/46C07C2101/08C07C237/34C07C317/28C07C2601/08A61P1/00A61P1/12A61P1/14A61P13/12A61P19/08A61P19/10A61P25/00A61P25/28A61P3/02A61P3/14A61P35/00A61P43/00A61P5/00A61P5/18A61P7/00A61P7/06A61P9/00A61P9/14
Inventor K·曼森
Owner LEO PHARMA AS
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