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Calcium-sensing receptor-active compounds

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

Inactive Publication Date: 2013-08-28
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 invention, compound I is represented as Ia or Ib

[0057]

[0058] In one embodiment of the present invention, Ar represents phenyl or naphthyl, optionally replaced by one or two, the same or different, selected from halogen or C 1-3 Alkoxy substituents are substituted.

[0059] In one embodiment of the invention, Ar represents phenyl, which is substituted by 1 or 2, the same or different, substituents selected from chlorine, fluorine or methoxy.

[0060] In one embodiment of the invention Ar represents 4-fluoro-3-methoxy or 3-chlorophenyl.

[0061] In one embodiment of the invention Ar represents naphthyl.

[0062] In one embodiment of the invention, R 1 stands for C 2-4 Alkenyl, hydroxyl C 2-4 Alkyl, hydroxyl C 2-4 Alkylamino C 2-4 Alkyl, C 1-3 Alkylsulfonylamino C 2-4 Alkyl, aminosulfonyl C 1-4 Alkyl, aminocarbonyl C 1-4 Alkyl or C containing 1-2 heteroatoms selected from N, O and S 2-5 Heterocycloalkyl.

[0063] In one embodim...

Embodiment 1

[0255] Example 1: 4-[2-[4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopenta Base] phenoxy] acetyl] piperazin-2-one (compound 101)

[0256] Following general procedure A, intermediate 1 was employed as the acid and piperazin-2-one was employed as the amine.

[0257] 1 H NMR (600MHz, DMSO) δ8.14 / 8.09 (s, 1H, rotamer), 7.16 (dd, J=8.6, 1.8Hz, 1H), 7.14–7.07 (m, 3H), 6.88 (ddd, J=8.1,4.3,1.9Hz,1H), 6.82(d,J=8.2Hz,2H), 4.80 / 4.78(s,2H, rotamer), 4.07 / 3.94(s,2H rotamer) , 3.82(s,3H), 3.75(q,J=6.5Hz,1H), 3.66–3.62 / 3.62–3.57(m,2H, rotamer), 3.29–3.25 / 3.20–3.15(m,2H, rotamers), 2.91–2.85(m,1H), 2.85–2.77(m,1H), 2.05–1.98(m,1H), 1.89–1.83(m,1H), 1.82–1.74(m,1H) , 1.65–1.52(m,2H), 1.32–1.24(m,1H), 1.23(d,J=6.6Hz,3H).

Embodiment 2

[0258] Example 2: 2-[4-[(1R,3S)-3-[[(1R)-1-(3-chlorophenyl)ethyl]amino]cyclopentyl]-phenoxy]-N -(4-piperidinyl)-acetamide (compound 102)

[0259] Following general procedure B, intermediate 6 was employed as the ketone and (R)-1-(3-chlorophenyl)ethanamine was employed as the amine. The BOC-protected intermediate was treated with HCl in methanol for 2 h, followed by evaporation of the solvent to obtain the target compound.

[0260] 1H NMR (600MHz, DMSO) δ7.97–7.87(m,1H, rotamer), 7.43–7.41(m,1H), 7.35–7.29(m,2H), 7.27–7.23(m,1H), 7.17–7.08(m,2H), 6.86–6.81(m,2H), 4.41–4.37(m,2H), 3.77(q,J=6.6Hz,1H), 3.71–3.63(m,1H), 2.94– 2.88(m,2H), 2.88–2.78(m,2H), 2.49–2.43(m,2H), 2.04–1.98(m,1H), 1.89–1.82(m,1H), 1.79–1.72(m,1H ), 1.67–1.53(m,4H), 1.37–1.24(m,3H), 1.23(d,J=6.6Hz,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, uses of the compounds in therapy, pharmaceutical compositions containing the compounds, methods of treating diseases with the compounds and uses of the compounds in the production of medicaments. Background technique [0002] Calcium-sensing receptors (CaSRs) are G-protein-coupled receptors (GPCRs) that signal through activation of phospholipase C to increase levels of inositol 1,4,5-triphosphate and cytosolic calcium. CaSRs belong 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 as well as other positively charged molecules. CaSRs are found in the parathyroid glands and have also been identified in the brain, gut, pituitary, thyroid, bone, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/74C07C235/10C07C237/22C07C311/46C07C59/90C07C69/734C07D211/58C07D295/185C07D295/194A61K31/4965A61K31/4409A61K31/18A61K31/165A61P3/14
CPCC07C217/74C07C235/10C07C237/22C07C311/46C07D211/58C07D295/185C07D295/194C07C2601/08C07D241/08C07D295/192A61P1/00A61P1/12A61P13/12A61P19/00A61P19/10A61P25/00A61P25/28A61P3/02A61P3/14A61P35/00A61P43/00A61P5/00A61P5/18A61P7/06A61P9/00C07C235/20C07C311/03
Inventor P·韦德索L·K·A·布莱尔
Owner LEO PHARMA AS
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