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Substituted arylamine compounds and uses as 5-HT6 moderator thereof

A compound and unsubstituted technology, applied in the field of serotonin receptor modulation, can solve problems such as abnormal electrocardiogram and weight gain

Inactive Publication Date: 2008-06-18
GALANEA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clozapine and olanzapine (ZYPREXA) were most likely to cause weight gain; ziprasidone (GEODON) did not appear to cause weight gain but could cause EKG abnormalities

Method used

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  • Substituted arylamine compounds and uses as 5-HT6 moderator thereof
  • Substituted arylamine compounds and uses as 5-HT6 moderator thereof
  • Substituted arylamine compounds and uses as 5-HT6 moderator thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0126] N-(3-chlorobenzyl)-2-nitro-5-(piperazin-1-yl)aniline hydrochloride :

[0127]

[0128] To a solution of tert-butyl 4-(3-(3-chlorobenzylamino)-4-nitrophenyl)piperazine-1-carboxylate (104 mg, 0.23 mmol) dissolved in anhydrous dichloromethane (1.0 mL) A saturated solution of HCl dissolved in diethyl ether (15 mL) was added. The reaction mixture was stirred for 4 hours. The solvent was evaporated and the precipitate was recrystallized from methanol (0.3 mL), dichloromethane (0.5 mL) and diethyl ether (5 mL). The product was collected by filtration and dried in vacuo to afford the title compound (35.0 mg, 39% yield after recrystallization). 1 HNMR (400MHz, CD 3 OD): δ8.07(d, 1H), 7.42(s, 1H), 7.33(m, 2H), 7.28(m, 1H), 6.40(d, 1H), 6.03(s, 1H), 4.61(s , 1H), 3.56 (m, 4H), 3.27 (m, 4H); MS (ESI) m / z: C 17 h 20 ClN 4 o 2 Calculated value: 347.13; Observed value: 347.5 (M + +1) [equivalent to free base].

[0129] tert-butyl 4-(3-(3-chlorobenzylamino)-4-nitrophenyl...

Embodiment 2

[0136] N-(3-chlorobenzyl)-4-nitro-3-(piperazin-1-yl)aniline hydrochloride :

[0137]

[0138] To a solution of N-(3-chlorobenzyl)-4-nitro-3-(piperazin-1-yl)aniline (77 mg, 0.17 mmol) in anhydrous dichloromethane (1.0 mL) was added HCl Saturated solution in diethyl ether (15 mL). The reaction mixture was stirred for 4 hours. The solvent was evaporated and the precipitate was recrystallized from methanol (0.3 mL), dichloromethane (0.5 mL) and diethyl ether (5 mL). The product was collected by filtration and dried in vacuo to afford the title compound (54 mg, 82% yield after recrystallization). 1 H NMR (400MHz, CD 3 OD): δ8.01(d, 1H), 7.37-7.27(m, 4H), 6.39(d, 1H), 6.25(s, 1H), 4.45(s, 2H), 3.36(m, 4H), 3.23 (m, 4H); MS (ESI) m / z: C 17 h 20 ClN 4 o 2 Calculated: 347.13; Observed: 347.4(M + +1) [equivalent to free base].

[0139] tert-butyl 4-(5-(3-chlorobenzylamino)-2-nitrophenyl)piperazine-1-carboxylate:

[0140]

[0141] At 80°C, 4-(5-fluoro-2-nitrophenyl)pip...

Embodiment 3

[0146] 1-(2-(1-(3,5-dimethoxyphenyl)ethylamino)-4-(piperazin-1-yl)phenyl)-2,2,2-trifluoroethane Ketone (ethanone) hydrochloride :

[0147]

[0148] To tert-butyl 4-(3-(1-(3,5-dimethoxyphenyl)ethylamino)-4-(2,2,2-trifluoroacetyl)-phenyl)piperazine-1-carboxylate To a solution of the ester (231 mg, 0.43 mmol) in dichloromethane (2.0 mL) and methanol (0.5 mL) was added a saturated solution of HCl in diethyl ether (20 mL). The reaction mixture was stirred for 3 hours. The solvent was removed by rotary evaporation to afford the title compound (198 mg, 97% yield). 1 H NMR (400MHz, CD 3 OD): δ7.62(m, 1H), 6.52(s, 2H), 6.36(m, 2H), 5.49(s, 1H), 4.66(m, 1H), 3.57(m, 2H), 3.50(m , 2H), 3.21 (m, 4H), 1.58 (d, 3H); MS (ESI) m / z: C 22 h 27 f 3 N 3 o 3 Calculated value: 438.2; Observed value: 439.5 (M + +1) [equivalent to free base].

[0149] tert-butyl 4-(3-(1-(3,5-dimethoxyphenyl)ethylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate:

[0150]

[0151] 1-...

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Abstract

The invention relates to 5-HT6 receptor antagonists. Novel arylamine compounds having the formula: (see formula I) and pharmaceutically acceptable salts and / or esters thereof, wherein - n is 0, 1, 2, 3, or 4; - A, when present is a lower alkyl group; - R1 is hydrogen or substituted or unsubstituted alkyl or aryl; - R2 is hydrogen; halo; nitro; cyano, lower alkoxy; carboxylate salt acid or alkyl ester thereof; a sulfone; haloalkyl or haloalkoxy; acetaldehyde; carboxamide; carbomyl; alkoxyaminocarbonyl; or substituted arylalkylamino; - R3 and R4 independently are hydrogen, substituted or unsubstituted alkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl, or, taken together, R3 and R4 form one substituted or unsubstituted aryl, alkylaryl, heteroaryl or alkylheteroaryl group; - B, when present, is lower alkyl; and - X and Y are independently C or N; and use of these compounds and their pharmaceutical compositions, e.g., in the treatment, modulation and / or prevention of physiological conditions associated with serotonin action, such as in treating obesity, and obesity-related disorders, e.g., cardiovascular disease, digestive disease, respiratory disease, cancer and type II diabetes; and psychological disorders such as schizophrenia, are disclosed.

Description

field of invention [0001] The present invention relates generally to serotonin (5-hydroxytryptamine, or 5-HT) receptor modulators, e.g., 5-HT 6 Field of antagonists, agonists, inverse agonists or partial agonists, and more particularly to novel substituted aromatic amine compounds, their synthesis and use and their pharmaceutical compositions, for example in the treatment of physiological or psychological conditions , regulation and / or prophylaxis. Background of the invention [0002] The serotonergic nervous system of the brain has been found to affect a variety of physiological functions, which manifest itself in disorders such as Alzheimer's disease, cognitive impairment, irritable bowel syndrome, malignancy, emesis, vomiting, prokinesia , gastroesophageal reflux disease, non-ulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorder, eating disorder, gastrointestinal const...

Claims

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Application Information

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IPC IPC(8): C07D295/12A61K31/495A61K31/496C07D243/08C07D311/68C07D317/62C07D319/18C07D333/66
Inventor O·贝克M·罗贝拉R·E·麦伦德兹A·沙拉丹杜L·伍X·Y·于D·S·迪哈诺阿S·R·舍鲁库Y·马兰特兹S·诺伊曼M·费克曼H·森德洛维特兹S·沙察穆A·萨哈P·欧巴驰
Owner GALANEA CORP
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