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Quinoline 3-sulfonate esters as NK3 receptor modulators

A quinoline and precursor technology, applied in the field of quinoline derivatives, can solve problems such as limited evaluation

Inactive Publication Date: 2008-06-25
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] For each of the tachykinin receptors, non-peptide ligands have been developed, however, known non-peptide NK-3 receptor antagonists have many problems such as species selectivity, which limits their use in many suitable disease models. Possibility to evaluate these compounds in

Method used

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  • Quinoline 3-sulfonate esters as NK3 receptor modulators
  • Quinoline 3-sulfonate esters as NK3 receptor modulators
  • Quinoline 3-sulfonate esters as NK3 receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0141] 2-Phenyl-4-({[(1S)-1-phenylpropyl]amino}carbonyl)quinolin-3-yl methanesulfonate:

[0142]

[0143] at room temperature, at N 2 Add triethylamine (14 μL, 0.104 mmol) to 3-hydroxy-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (20 mg, 0.052 mmol) solution in dichloromethane (0.5 mL). The reaction mixture was cooled to 0 °C and methanesulfonyl chloride (5 μL, 0.062 mmol) was added. The reaction mixture was stirred at 0°C for 1 h, then diluted with dichloromethane, washed with aqueous citric acid (5%), NaHCO 3 saturated aqueous solution and brine. The organic layer was dried (Na 2 SO 4 ), filtration and concentration afforded the title compound (1) as a solid (19 mg, 79% yield). 1 H NMR (300MHz, CDCl 3 )δ0.98(t, J=7.5Hz, 3H), 1.91-2.00(m, 1H), 2.10-2.19(m, 1H), 2.48(s, 3H), 5.20(dt, J=8.0, 8.0Hz , 1H), 6.75(bd, J=8.0Hz, 1H), 7.30-7.44(m, 5H), 7.49-7.59(m, 4H), 7.76(dd, J=8.4, 8.4Hz, 1H), 7.81( d, J=8.4Hz, 1H), 7.87(d, J=7.8Hz, 2H), 8.16(d, J=8.4Hz, 1H)....

Embodiment 2-11

[0145] Examples 2-11 in the table below were prepared by using a method similar to that of Example 1, using the indicated sulfonyl chlorides to give the expected compounds.

[0146]

[0147]

[0148]

[0149]

[0150]

Embodiment 12

[0152] 2-(Dimethylamino)ethanesulfonic acid 2-phenyl-4-({[(1S)-1-phenylpropyl]amino}carbonyl)quinolin-3-yl ester:

[0153]

[0154] A solution of dimethylamine (1.0 mmol) in methanol (0.5 mL) was added to ethylenesulfonic acid 2-phenyl-4-({[(1S)-1-phenylpropyl]amino}carbonyl)quinoline-3- Ethyl ester (Example 10) (30 mg, 0.063 mmol). The reaction mixture was stirred for 4 hr at room temperature, concentrated, and passed directly through column chromatography (SiO 2 ) was purified using a gradient of 0-4% methanol in DCM. The title compound was isolated as a solid (18 mg, 56% yield). 1 H NMR (300MHz, CDCl 3 )δ0.97(t, J=7.3Hz, 3H), 1.89-1.99(m, 1H), 2.03-2.19(m, 1H), 2.08(s, 6H), 2.58-2.68(m, 3H), 2.78 -2.85(m, 1H), 5.19(dt, J=8.0, 8.0Hz, 1H), 6.79(bd, J=7.7Hz, 1H), 7.31-7.42(m, 5H), 7.46-7.56(m, 4H ), 7.71-7.79 (m, 2H), 7.84-7.87 (m, 2H), 8.14 (d, J=8.3Hz, 1H). MS ES+, m / z=518 (M+1).

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Abstract

Compounds of Formula I wherein R<1>, A, R<2>, R<3>, R<4>, R<5> n, m and q are as described in the specification, pharmaceutically-acceptable salts, methods of making, pharmaceutical compositions containing and methods for using the same.

Description

technical field [0001] The present invention relates to quinoline derivatives, pharmaceutical compositions comprising them and the use of these compounds in the treatment of central nervous system and peripheral diseases or disorders. The invention also relates to the use of these compounds in combination with one or more other CNS drugs to enhance the effect of the other CNS drugs. The compounds of the invention are also useful as probes for localization of cell surface receptors. Background technique [0002] Tachykinin receptors are the targets of a class of structurally related peptides including substance P (SP), neurokinin A (NKA) and neurokinin B (NKB). Tachykinins are synthesized in the central nervous system (CNS) as well as in peripheral tissues, and exert various biological activities in the CNS and peripheral tissues. Three tachykinin receptors are known, named neurokinin-1 (NK-1) receptor, neurokinin-2 (NK-2) receptor and neurokinin-3 (NK-3) receptor. NK-1 r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/52A61K31/47A61P11/06A61P25/00A61P25/18A61P25/22A61P25/24A61P25/28A61P3/04A61P35/00
CPCC07D215/52A61P1/04A61P1/08A61P11/00A61P11/06A61P13/06A61P15/08A61P25/00A61P25/08A61P25/18A61P25/22A61P25/24A61P25/28A61P29/00A61P3/04A61P35/00A61P43/00A61P5/00A61K31/47
Inventor 托马斯·R·辛普森詹姆斯·康杰弗里·S·艾伯特克里斯托巴尔·阿尔汉布拉杰勒德·M·凯瑟詹姆斯·伍兹李燕
Owner ASTRAZENECA AB
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