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Novel triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors

a growth hormone secretagogue receptor and triazole technology, applied in the field of new triazole derivatives, can solve the problems of not providing any biological activity or medicinal use, not naming specific compounds, and failing to describe and demonstrate inhibitory and/or antagonistic activity of claimed compounds

Active Publication Date: 2007-09-06
ZENTARIS GMBH +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0344] Furthermore, the compounds of the invention, being of non-peptidic nature, are resistant to degradation by enzymes of the gastrointestinal tract. Hence, they offer the advantage to be given by oral route. They surprisingly display an improved metabolic stability and / or an improved bioavailability. Hence, again an advantageous dose reduction may be achievable which may cause less or even no side effects.

Problems solved by technology

However, neither of these patent families mentions ghrelin analogue ligands of the GHS receptor family nor modulation of these receptors nor GH secretagogue properties or the like.
However, they fail to provide any biological activity or any medicinal use nor do they name specific compounds.
However, although claiming in vivo GH release WO 00 / 54729 fails to actually prove such effect.
Furthermore, WO 00 / 54729 fails to describe and demonstrate inhibitory and / or antagonistic activity of claimed compounds.

Method used

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  • Novel triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors
  • Novel triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors
  • Novel triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors

Examples

Experimental program
Comparison scheme
Effect test

example 1

(R)—N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 1)

[0404] Compound 1 was obtained from Boc-(D)-Trp (10 mmoles), (2,4-dimethoxyphenyl)-methanamine, 3-(1H-indol-3-yl)propane hydrazide and Boc-2-amino-2-methylpropanoic acid according to the general synthetic schemes with a total yield after purification by HPLC of 35%.

[0405]1H NMR (400 MHz, 300° K, DMSO-d6):

[0406]δ 1.32 (3H, s, CH3 Aib), 1.36 (3H, s, CH3 Aib), 2.93 (2H, m, CH2—CH2-indole), 2.97 (2H, m, CH2—CH2-indole), 3.31 (1H, dd, J=14.5, J=6.1, 1H C2 βTrp), 3.38 (1H, dd, J=14.5, J=9.1, 1H C2 βTrp), 3.66 (3H, s, o-OCH3), 3.72 (3H, s, p-OCH3), 4.93 (1H, d, J=16.9, 1H C2 o,p-dimethoxybenzyl), 5.10 (1H, d, J=16.9, 1H C2 o,p-dimethoxybenzyl), 5.23 (1H, m, CαH Trp), 6.31 (1H, dd, J=8.5, J=1.7, H5 o,p-dimethoxybenzyl), 6.45 (1H, d, J=8.5, H6 o,p-dimethoxybenzyl), 6.59 (1H, d, J=1.7, H3 o,p-dimethoxybenzyl), 6.88 (1H, t, J=7.5, H5 Trp), 6.94 ...

example 2

(R)—N-(1-(5-benzyl-4-(naphthalen-1-ylmethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 4)

[0410] Compound 4 was obtained from Boc-(D)-Trp (10 mmoles), naphthalen-1-yl-methanamine, 2-phenylacetohydrazide and Boc-2-amino-2-methylpropanoic acid according to the general synthetic schemes with a total yield after purification by HPLC of 42%.

[0411]1H NMR (300 MHz, DMSO-d6, 300° K):

[0412]δ(ppm) 1.18 (3H, s, CH3 Aib), 1.24 (3H, s, CH3 Aib), 3.17 (1H, dd, J=14 Hz and 5 Hz, CH2 βTrp), 3.36 (1H, dd, J=14 and 9 Hz, CH2 βTrp), 4.05 (2H, m, CH2-benzyl), 4.90 (1H, m, CH αTrp), 5.65 (1H, d, J=18 Hz, CH2-naphtyl), 5.81 (1H, d, J=18 Hz, CH2-naphtyl), 6.12 (1H, d, Jo=7 Hz, H2 naphtyl), 6.38 (1H, t, Jo=7 Hz, H5 Trp), 6.47 (1H, d, Jo=8 Hz, H4 Trp), 6.85 (1H, t, Jo=8 Hz, H6 Trp), 7.03 (1H, d, Jm=2 Hz, H2 Trp), 7.05-7.12 (5H, m, CHar benzyl), 7.15 (1H, d, Jo=8 Hz, H7 Trp), 7.19 (1H, d, Jo=8 Hz, H3 naphtyl), 7.58 (2H, m, H6 and H7 naphtyl), 7.81 (1H, d, Jo=8 Hz,...

example 3

(R)—N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(naphthalen-1-ylmethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide (Compound 5)

[0416] Compound 5 was obtained from Boc-(D)-Trp (10 mmoles), naphthalen-1-yl-methanamine, 3-(1H-indol-3-yl)propane hydrazide and Boc-2-amino-2-methylpropanoic acid according to the general synthetic schemes with a total yield after purification by HPLC of 33%.

[0417]1H NMR (400 MHz, DMSO-d6, 300° K):

[0418]δ(ppm) 1.25 (3H, s, CH3 Aib), 1.28 (3H, s, CH3 Aib), 2.93 (2H, m, CH2—CH2-indole), 3.01 (2H, m, CH2—CH2-indole), 3.30 (1H, dd, 3J=14.3 and 5.8 Hz, CH2 βTrp), 3.40 (1H, dd, 3J=14.3 and 8.8 Hz, CH2 βTrp), 5.03 (1H, m, CH αTrp), 5.62 (1H, d, J=18.0 Hz, CH2-naphtyl), 5.76 (1H, J=18.0 Hz, CH2-naphtyl), 3.36 (1H, d, Jo=7.2 Hz, H2 naphtyl), 6.51 (1H, t, Jo=7.4 Hz, H5 Trp), 6.72 (1H, d, Jo=7.9 Hz, H4 Trp), 6.76 (1H, t, Jo=7.5 Hz, H5 indole), 6.92 (1H, t, Jo=7.5 Hz, H6 Trp), 7.0 (1H, t, Jo=7.5 Hz, H6 indole), 7.02 (1H, d, J=2.0 Hz, H2 indole...

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Abstract

The present invention provides novel triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors according to formula (I) that are useful in the treatment or prophylaxis of physiological and / or pathophysiological conditions in mammals, preferably humans, that are mediated by GHS receptors. The present invention further provides GHS receptor antagonists and agonists that can be used for modulation of these receptors and are useful for treating above conditions, in particular growth retardation, cachexia, short-, medium- and / or long term regulation of energy balance; short-, medium- and / or long term regulation (stimulation and / or inhibition) of food intake; adipogenesis, adiposity and / or obesity; body weight gain and / or reduction; diabetes, diabetes type I, diabetes type II, tumor cell proliferation; inflammation, inflammatory effects, gastric postoperative ileus, postoperative ileus and / or gastrectomy (ghrelin replacement therapy).

Description

REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. provisional application 60 / 707,941 filed Aug. 15, 2005, U.S. provisional application 60 / 787,543 filed Mar. 31, 2006, and European application 05017732.8 filed Aug. 16, 2005, all of which are incorporated herein by reference.TECHNICAL FIELD [0002] The invention relates to novel triazole derivatives that act as ghrelin analogue ligands of growth hormone secretagogue receptors. These compounds are useful in modulating growth hormone plasma levels in mammals as well as in the treatment and / or regulation of various physiological and pathophysiological conditions, such as growth retardation, obesity, food intake, energy balance, tumor cell proliferation, wound / burn healing, metabolic disorders and inflammation. BACKGROUND OF THE INVENTION [0003] Ghrelin, a 28 amino acid peptide with a unique octanoyl modification on Ser-3 (Kojima M et al., Nature 1999, 402: 656-660), was identified as an endogenous ligand fo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4439A61K31/4196
CPCA61K31/4196A61K31/4427A61K31/4439A61K31/4523A61K31/497A61K45/06C07D401/14C07D403/14C07D403/06A61K2300/00A61P1/02A61P1/04A61P1/14A61P1/16A61P11/00A61P11/02A61P13/12A61P15/00A61P15/08A61P15/14A61P17/00A61P17/02A61P17/14A61P19/08A61P19/10A61P21/00A61P21/06A61P25/00A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P27/02A61P27/16A61P29/00A61P3/00A61P3/04A61P31/18A61P35/00A61P3/06A61P37/00A61P37/04A61P37/06A61P43/00A61P5/00A61P5/06A61P5/08A61P5/38A61P5/50A61P7/04A61P7/08A61P9/02A61P9/04A61P9/10A61P9/12A61P3/10C07D498/08
Inventor PERRISSOUD, DANIELMARTINEZ, JEANMOULIN, ALINEFEHRENTZ, JEAN-ALAINBOEGLIN, DAMIENDEMANGE, LUC
Owner ZENTARIS GMBH
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