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Alkylnitrile quinolines, as NK-3 receptor ligands

A technology of alkyl and alkoxy, which is applied in the field of quinoline derivatives and can solve problems such as limited evaluation

Inactive Publication Date: 2008-09-17
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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  • Alkylnitrile quinolines, as NK-3 receptor ligands
  • Alkylnitrile quinolines, as NK-3 receptor ligands
  • Alkylnitrile quinolines, as NK-3 receptor ligands

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] Example 1: N-((S)-2-cyano-1-phenylethyl)-3-hydroxy-2-phenylquinoline-4-carboxamide

[0116]

[0117] This material was prepared as follows.

[0118] (a) Benzyl ((R)-2-hydroxy-1-phenyl-ethyl)-carbamate

[0119]

[0120] A solution of (R)-2-amino-2-phenyl-ethanol (3.0 g, 21.8 mmol) and triethylamine (4.5 mL, 32.8 mmol) was dissolved in dichloromethane (60 mL). Benzyl chloroformate (3.4 mL, 24 mmol) was added thereto, and the solution was stirred at room temperature overnight. The solution was then washed with pH 7 buffer and the organic layer was concentrated (MgSO 4 ), purification by flash chromatography on silica gel, eluting with a 1-5% methanol / dichloromethane gradient, afforded the product as a white solid (3.2 g).

[0121] (b) Toluene-4-sulfonic acid (R)-2-benzyloxycarbonylamino-2-phenyl-ethyl ester

[0122]

[0123] A solution of benzyl ((R)-2-hydroxy-1-phenyl-ethyl)-carbamate (1.0 g, 3.7 mmol) and triethylamine (771 μL, 5.5 mmol) was dissolved in dichl...

Embodiment 2

[0132] Example 2.3-amino-N-[(S)-2-cyano-1-1-phenylethyl]-2-(3-fluorophenyl)quinoline-4-methyl Amides (2)

[0133]

[0134] The compound of Example 2 was prepared according to the following scheme:

[0135]

[0136] at room temperature and N 2 , to 3-amino-2-(3-fluorophenyl)quinoline-4-carboxylic acid (56.4mg, 0.2mmol), HOBT hydrate (46.3mg, 0.3mmol), 4-methylmorpholine (55μl , 0.3 mmol) in tetrahydrofuran (11 ml), EDC (57.9 mg, 0.3 mmol) was added. Then (S)-3-amino-3-phenylpropionitrile (1d) (29.2 mg, 0.2 mmol) was added and the reaction mixture was stirred at room temperature for 3.0 h. All solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 10% aqueous sodium bicarbonate. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed eluting with 15-25% ethyl acetate / hexanes to afford the title compound (35 mg, 43%) as a solid. 1 H NMR (300MHz, CDCl 3 )δ3.05(d, 1...

Embodiment 3

[0137] Example 3. N-[(1S)-2-cyano-1-phenylethyl]-3-methyl-2-phenylquinoline-4-carboxamide (3)

[0138]

[0139] The compound of Example 3 was prepared according to the following scheme:

[0140]

[0141] According to the method described for N-[(1S)-2-cyano-1-phenylethyl]-3-hydroxyl-2-phenylquinoline-4-carboxamide (1), by making (S) -3-Amino-3-phenyl-propionitrile (1d) with 3-methyl-2-phenyl-quinoline-4-carboxylic acid (instead of 3-hydroxy-2-phenyl-quinoline-4-carboxy acid) to prepare the compound. 1 H NMR (300MHz, DMSO) δ9.67(d, J=8.6Hz, 1H), 8.05(d, J=8.4Hz, 1H), 7.77(s, 1H), 7.58-7.37(m, 14H), 5.61 (s, 1H), 3.20-3.01 (m, 2H), 2.16 (s, 3H).HRMS m / z392.1733, C 26 h 21 N 3 o 2 Calculated value: 392.1763.

[0142] Table 1

[0143]

[0144]

[0145]

[0146] biological test

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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), collectively referred to as "tachykinins". 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/52A61K31/47A61P11/00A61P25/00
CPCC07D215/52A61P1/00A61P1/08A61P3/04A61P5/24A61P5/26A61P11/00A61P13/08A61P15/00A61P25/00A61P25/18A61P25/22A61P25/24A61P25/28A61P29/00A61P35/00
Inventor 杰弗里·S·艾伯特克里斯托巴尔·阿尔哈姆布拉詹姆斯·康杰勒德·M·科瑟托马斯·R·辛普森詹姆斯·伍兹李艳
Owner ASTRAZENECA AB
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