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Novel neurokinin 1 receptor antagonist compounds ii

A compound and solvate technology, applied in the field of the new neurokinin 1 receptor antagonist compound II, can solve the problem of reducing systemic effects in the central nervous system

Inactive Publication Date: 2016-05-11
LEO PHARMA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Because many currently available antipruritic treatments have side effects that may limit their use, and because many skin disorders are preferentially treated with topical agents, especially when the disorder is of mild to moderate severity, there is a continuing need to develop the neurokinin 1 receptor ( NK1R) antagonists that are effective in treating pruritus when applied topically, but have reduced systemic effects on the central nervous system

Method used

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  • Novel neurokinin 1 receptor antagonist compounds ii
  • Novel neurokinin 1 receptor antagonist compounds ii
  • Novel neurokinin 1 receptor antagonist compounds ii

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0095] In one embodiment the present invention relates to a compound of general formula A(i) or a pharmaceutically acceptable salt or solvate thereof

[0096]

[0097] where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and Y as shown above,

[0098] The condition is that when both X and Y are CH, R 4 Not 2-methylphenyl.

[0099] In one embodiment the present invention relates to a compound of general formula A(ii) or a pharmaceutically acceptable salt or solvate thereof

[0100]

[0101] where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and Y as shown above,

[0102] The condition is that when both X and Y are CH, R 4 Not 2-methylphenyl.

[0103] In one embodiment the invention relates to compounds of general formula A, wherein R 1 and R 2 Indicates (C 1-4 ) Haloalkyl.

[0104] In one embodiment the invention relates to compounds of general formula A, wherein R 1 Indicates (C 1-4 ) haloalkyl and R 2 Indicates (C 1-4 )alkyl.

[0105] In one embodiment the inve...

Embodiment

[0420] Proton magnetic resonance (NMR) spectra were recorded on a Bruker instrument on a 400 MHz spectrometer at 25°C. Chemical shifts are reported in ppm (δ) using the residual solvent line as internal standard. Peak diversity is indicated as follows: s, singlet; d, doublet; dd, double doublet; t, triplet; dt, double triplet; q, quartet; quin, quintet; m, Multiplet; brs, broad singlet.

[0421] Total ion current (TIC) and DADUV chromatographic traces along with peak-related MS and UV spectra were also collected on a SHIMADZUL LCMS2020 system equipped with an LCMS2020 mass spectrometer operating in positive and / or negative electrospray ionization modes. [LC / MS / ESI(+ / -): analysis was performed using ChromolithSpeedRODC18 column (50x4.6mm, 2μm particle size), column temperature 35°C, mobile phase: A=CH3CN / H2O / FA=10 / 90 / 0.05 and B =CH3CN / H2O / FA=90 / 10 / 0.05, flow rate: 3.0mL / min, gradient: t=0.8min20%B, t=3.5min95%B, t=4.3min95%B, t=4.4min20%B.

[0422] Use the SHIMADZU6A system ...

Embodiment 3

[1119] Example 3: Compound 3

[1120] N-(3,5-bis(trifluoromethyl)benzyl)-1-(2,4-dimethylphenyl)-N-methyl-6-oxohexahydropyrrolo [1,2-a]pyrazine-2(1H)-carboxamide (mixture of trans isomers)

[1121]

[1122] To a solution of triphosgene (65 mg, 0.22 mmol) in EtOAc (10 mL) was added Intermediate 3 (mixture of trans, 120 mg, 0.49 mmol), DMAP (4 mg, 0.035 mmol) and TEA (209 μL, 1.5 mmol) at 0 °C ) in EtOAc (2 mL). The mixture was stirred at room temperature for 1.5 h before the addition of 1-(3,5-bis(trifluoromethyl)phenyl)-N-methylmethanamine (251 mg, 0.98 mmol) and TEA ( 107mg, 1.05mmol). The reaction was stirred at 45 °C for 48 h and washed with saturated NH 4 The Cl(aq) solution was quenched. The resulting mixture was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine, washed with anhydrous Na 2 SO 4 Dry and concentrate in high vacuum. The residue was purified by Prep-HPLC to give the title compound 3 (10 mg, 4%). 1 HNMR (600MHz...

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Abstract

The invention relates novel NK1 receptor antagonists represented in formula A, wherein R1 and R2 independently are selected from the group consisting of (C1-4)alkyl, (C1-4)haloalkyl, (C1-4)alkoxy, CD3 or halogen; R3 is selected from the group consisting of hydrogen, (C1-4)alkyl, (C1-4)haloalkyl and (C1-4)hydroxyalkyl; R4 is selected from the group consisting of phenyl, 5-membered heteroaryl and 6-membered heteroaryl; R5 and R6 are independently selected from the group consisting of hydrogen, (C1-4)alkyl, (C1-4)hydroxyalkyl and (C1-4)haloalkyl and X and Y are independently selected from the group consisting of CH and N. The invention furthermore relates to intermediates for the preparation of said compounds, to their use in therapy, and to pharmaceutical compositions comprising said compounds.

Description

field of invention [0001] The present invention relates to novel heterocyclic compounds that are neurokinin 1 receptor antagonists, intermediates for the preparation of said compounds, their use in therapy such as the prevention or treatment of pruritic skin diseases or disorders, and compounds comprising said compounds pharmaceutical composition. Background of the invention [0002] Pruritus is a common symptom of skin disorders as well as a sign of underlying systemic pathology. Itching is an unpleasant sensation in the skin that provokes the desire to scratch and can be acute (of short duration), as in response to an insect bite, or chronic (lasting more than 6 weeks), as in many inflammatory skin disease. It is well known that patients with inflammatory skin diseases perceive itching as severely impairing their quality of life. [0003] Pruritus is mediated via free nerve endings of unmyelinated C-type nerve fibers in the epidermis. They have been found to express ne...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4985A61P17/04
Inventor H·布拉德J·费尔丁周鼎蔡振伟M·D·瑟伦森
Owner LEO PHARMA AS
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