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Calcium-sensing receptor-active compounds

A kind of technology of compound and stereoisomer, applied in the field of preparation of medicament

Inactive Publication Date: 2013-07-31
LEO PHARMA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This new therapeutic approach for the treatment of osteoporosis appears to be very beneficial, although the use of the PTH hormone is associated with important problems such as the route of injection, but also the appearance of tumors recently observed in human clinical trials.

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

[0061] In one embodiment of the invention, compound I represents Ia or Ib

[0062]

[0063] In one embodiment of the invention Ar represents phenyl optionally substituted by one or more identical or different substituents independently selected from chlorine, fluorine or C 1-3 alkoxy.

[0064] In one embodiment of the invention Ar represents phenyl substituted by one or two identical or different substituents independently selected from chlorine, fluorine or methoxy.

[0065] In one embodiment of the invention Ar represents 4-fluoro-3-methoxyphenyl, 3-chlorophenyl or 3-ethoxyphenyl.

[0066] In one embodiment of the invention, Ar represents C comprising 1-3 heteroatoms selected from O 2-5 Heterocycloalkylphenyl.

[0067] In one embodiment of the invention, R 1 means C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, hydroxyl C 2-4 Alkyl, amino C 2-4 Alkyl, hydroxyl C 2-4 Alkylamino C 2-4 Alkyl, C 1-2 Alkylsulfonylamino C 2-4 Alkyl, aminosulfonyl C 1-4 Alkyl, aminocarb...

Embodiment 1

[0279] Example 1: 4-[2-[4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]-amino]- ring Pentyl]phenyl]acetyl]piperazin-2-one; formic acid (compound 101)

[0280] Following general procedure B, intermediate 3 was used as the acid and piperazin-2-one as the amine.

[0281] 1 H NMR (300MHz, DMSO) δ8.25(s, 1H), 8.09 / 8.01(s, 1H, rotamer), 7.26(dd, J=8.5, 1.8Hz, 1H), 7.20-7.07(m, 5H), 6.96(ddd, J=8.2, 4.4, 1.9Hz, 1H), 4.08-3.89(m, 3H), 3.84(s, 3H), 3.73-3.55(m, 4H), 3.18-2.97(m, 3H), 2.96-2.80(m, 1H), 2.20-2.05(m, 1H), 1.97-1.60(m, 4H), 1.53-1.38(m, 1H), 1.35(d, J=6.6Hz, 3H) .

Embodiment 2

[0282] Example 2: 2-[4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]-cyclopentyl] Phenyl]-N-[2-(methylsulfonylamino)ethyl]acetamide; Formic acid (compound 102)

[0283] Following general procedure B, intermediate 3 was used as the acid and N-(2-aminoethyl)methanesulfonamide hydrochloride as the amine.

[0284] 1 H NMR (600MHz, DMSO) δ8.31(s, 1H), 8.13(t, J=5.8Hz, 1H), 7.30(dd, J=8.4, 1.8Hz, 1H), 7.20-7.12(m, 5H) , 7.09(t, J=5.4Hz, 1H), 6.99(ddd, J=8.2, 4.2, 2.0Hz, 1H), 4.03(q, J=6.6Hz, 1H), 3.84(s, 3H), 3.36( s, 2H), 3.15(dd, J=12.7, 6.4Hz, 2H), 3.12-3.06(m, 1H), 2.98(dd, J=12.1, 6.3Hz, 2H), 2.92-2.84(m, 1H) , 2.87(s, 3H), 2.17-2.10(m, 1H), 1.94-1.84(m, 2H), 1.81-1.73(m, 1H), 1.72-1.64(m, 1H), 1.50(td, J= 11.9, 9.4 Hz, 1H), 1.39 (d, J = 6.7 Hz, 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

field of invention [0001] The present invention relates to novel calcium sensing receptor active compounds, said compounds for use in therapy, pharmaceutical compositions comprising said compounds, methods of treating diseases with said compounds and the use of said compounds in the preparation of medicaments. Background of the invention [0002] Calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals through activation of phospholipase C to increase inositol 1,4,5-trisphosphate and cytosolic calcium levels. CaSR belongs to subfamily C of the GPCR superfamily, which also includes glutamate receptors, γ-aminobutyric acid (GABA) receptors, pheromone receptors, and odorant receptors, all of which have very large extracellular domains . This domain is highly negatively charged and is involved in the binding of calcium to other positively charged molecules. CaSR is found in the parathyroid glands, but has also been identified in the brain, gut, pitu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/46C07C235/10C07C311/05C07C311/46C07C69/738C07D205/04C07D317/58C07D295/185A61K31/4965A61K31/4409A61K31/18A61K31/165A61P3/14
CPCC07D205/04C07D211/58C07D243/08C07C229/46C07C2101/08C07C235/10C07D317/58C07C311/05C07C311/46C07C237/20C07D241/08C07D295/192C07C317/28A61P1/00A61P1/12A61P1/14A61P3/02A61P3/14A61P5/00A61P5/18A61P7/06A61P9/00A61P9/14A61P13/12A61P19/08A61P19/10A61P25/00A61P25/28A61P35/00A61P43/00C07C2601/08
Inventor P·韦德索L·K·A·布莱尔
Owner LEO PHARMA AS
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