Alkylsulphonamide quinolines

An alkyl and amide technology, applied in the field of quinoline derivatives, can solve problems such as limited evaluation

Inactive Publication Date: 2009-02-18
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

Method used

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  • Alkylsulphonamide quinolines
  • Alkylsulphonamide quinolines
  • Alkylsulphonamide quinolines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0179] Example 1. 3-[(methylsulfonyl)amino]-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-formyl Amines (1) (embodiment 1 relates to scheme 1)

[0180]

[0181] EDCl (289 mg, 1.5 mmol) was added to 3-[(methylsulfonyl)amino]-2-phenylquinoline-4-carboxylic acid (1c) (342 mg, 1.0 mmol), HOBT under nitrogen atmosphere at room temperature Hydrate (231 mg, 1.5 mmol), 4-methylmorpholine (276 μL, 1.5 mmol) in tetrahydrofuran (50 ml). Then (S)-1-phenylpropylamine (135 mg, 1.0 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. All solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and 10% aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography (eluting with 15-25% ethyl acetate / hexanes) to afford the title compound (70 mg, 15%) as a solid. 1 HNMR (300MHz, CDCl 3 )δ 0.94(t, 3H), 1.97(m, 2H), 3.44(s, 3H), 5.17(q, 1H), 5.47(m, 2H), 7.32(d, 2H),...

Embodiment 2

[0187] Example 2: 3-(methylsulfonylamino-methyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propane base)-amide (Example 2 and 3 relate to scheme 2)

[0188]

[0189] Under a nitrogen atmosphere, triethylamine (140 μL, 1.0 mmol) was added to 3-(aminomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-methanol Amide (2e) (197mg, 0.5mmol) in DCM (30ml). While cooling in an ice-water bath, methanesulfonyl chloride (39 μL, 0.51 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for an additional 2 hours. The mixture was washed with brine (10 mL), the organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by chromatography (eluting with 15-25% ethyl acetate / hexanes) to afford the title compound (79 mg, 42%) as a solid. 1 HNMR (300MHz, CDCl 3 )δ 0.94(t, 3H), 1.95(m, 2H), 2.99(s, 3H), 4.88(s, 2H), 5.25(q, 1H), 6.66(b, 2H), 7.30(d, 2H) , 7.34(d, 2H), 7.39(m, 1H), 7.78(m, ...

Embodiment 3

[0190] Example 3. 3-{[(ethylsulfonyl)amino]methyl}-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline -4-formamide

[0191]

[0192] Using a procedure similar to that described in Example 2, except using the component ethanesulfonyl chloride (48.6 μL, 0.51 mmol), the title compound was obtained as a white solid (90 mg, 38%). 1 HNMR (300MHz, CDCl 3 )δ 0.92(t, 3H), 1.32(t, 3H), 1.95(m, 2H), 3.04(q, 2H), 4.87(s, 2H), 5.17(q, 1H), 5.48(b, 2H) , 7.25(d, 2H), 7.34(d, 2H), 7.39(m, 1H), 7.78(m, 2H), 7.84(m, 2H), 8.08(m, 1H), 8.30(m, 2H), 8.17 (m, 2H). MSAPCI, m / z=488 (M+1). LCMS: 2.24 minutes.

[0193] The starting amine used in Examples 2 and 3, 3-(aminomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide, was prepared as follows:

[0194] 3-(Azidomethyl)-2-phenylquinoline-4-carboxylic acid methyl ester (2b)

[0195] Sodium azide (402 mg, 6.18 mmol) was added to 3-(bromomethyl)-2-phenylquinoline-4-carboxylic acid methyl ester (2a) (2000 mg, 5.618 mmol) in THF / DMF (...

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Abstract

The invention discloses compounds of Formula (1), pharmaceutically-acceptable salts, methods of making them, pharmaceutical compositions containing them and methods for their use. The compounds are neurokinin-3(NK-3) receptor antagonists and are used in the treatment of diseases such as depression, anxiety, schizophrenia, cognitive disorders, psychoses, obesity, inflammatory diseases, irritable bowel syndrome, inflammatory bowel disorder, emesis, preeclampsia, chronic obstructive pulmonary disease, disorders associated with excessive gonadotrophins and/or androgens including dysmenorrhea, benign prostatic hyperplasia, prostatic cancer and testicular cancer.

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 effects 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) recepto...

Claims

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Application Information

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IPC IPC(8): C07D215/52A61K31/47A61P25/18A61P25/22A61P25/24A61P25/28A61P3/04A61P35/00
Inventor 托马斯·辛普森詹姆斯·康杰弗里·艾伯特克里斯托巴尔·阿尔汉布拉杰拉德·凯瑟詹姆斯·伍兹李燕
Owner ASTRAZENECA AB
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