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Aryl sulfamide derivatives and methods of their use

A technology of heteroaryl and alkyl, applied in the field of arylsulfonamide derivatives

Inactive Publication Date: 2009-12-09
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these newer compounds are better tolerated than older tricyclic antidepressants, they are not free from side effects including sexual dysfunction, weight gain and nausea

Method used

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  • Aryl sulfamide derivatives and methods of their use
  • Aryl sulfamide derivatives and methods of their use
  • Aryl sulfamide derivatives and methods of their use

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0939] Example 1 : 3-[3-(4-chlorophenyl)-2,2-dioxo-2,1,3-benzothiadiazole-1(3H)-yl]-N-methylpropan-1-amine

[0940]

[0941] General procedure A for the synthesis of sulfonamides of structure I:

[0942] step 1 : Under a nitrogen atmosphere, anhydrous diglyme (10 mL) was added to a flask equipped with a dropping funnel and allowed to reflux vigorously. Dissolve N-(4-chloro-phenyl)-benzene-1,2-diamine (1.09g, 5.0mmol) and sulfonamide (0.58g, 6.0mmol) in 5mL diglyme and Put it in the dropping funnel. The mixture was added dropwise to the flask over 15 minutes, and then reflux was continued for another 15 minutes. The mixture was cooled to ambient temperature and diluted with ether, washed with water, 2N HCl, water, brine, dried over anhydrous magnesium sulfate and concentrated. The crude product was purified via Iscochromatography (Redisep, silica, 5-50% (ethyl acetate containing 2% formic acid) gradient in hexane) to obtain 1-(4 -Chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazol...

example 2

[0949] Example 2 : 3-[3-(4-chlorophenyl)-2,2-dioxo-2,1,3-benzothiadiazole-1(3H)-yl]propan-1-amine

[0950]

[0951] The 1-(3-bromo-propyl)-3-(4-chloro-phenyl)-1,3-dihydrobenzo[1,2,5]thiadiazole 2,2-dioxide (0.10 g, 0.25 mmol) was dissolved in 7N methylamine (20 mL) in methanol, heated to 60°C and stirred in a sealed flask for 16 hours. The mixture was cooled and concentrated in vacuo to give the crude product. The crude product was purified via chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 73 mg (87%) 3-[3-(4-chlorophenyl)-2,2-dioxo-2,1,3-benzene Thiadiazole-1(3H)-yl)prop-1-amine . The free base was dissolved in ether (2 mL) and treated with 1N hydrochloric acid (1 equivalent) in ether. The white precipitate was collected, dissolved in water, and lyophilized to obtain 56 mg 3-[3-(4-chlorophenyl)-2,2- Dioxo-2,1,3-benzothiadiazole-1(3H)-yl]prop-1-amine hydrochloride.

[0952] MS(ES)m / z 337.9;

[0953] HPLC purity: 100% at 210-370nm, 7.7 minutes...

example 3

[0954] Example 3 : N-{3-[3-(4-chlorophenyl)-2,2-dioxo-2,1,3-benzothiadiazole-1(3H)-yl]propyl}cyclopropylamine

[0955]

[0956] With general procedure A Step 3 In a similar way, 1-(3-bromo-propyl)-3-(4-chloro-phenyl)-1,3-dihydrobenzo[1,2,5]thiadiazole 2 is treated with cyclopropylamine, 2-Dioxide (0.10g, 0.25mmol), providing N-{3-[3-(4-chlorophenyl)-2,2-dioxo-2,1,3-benzothiadiazole- 1(3H)-yl]propyl}cyclopropylamine (87 mg).

[0957] MS(ES)m / z 378

[0958] HPLC purity: 100% at 210-370nm, 8.2 minutes; Stella RP18, 3.5u, 150×4.6mm column, 1.2mL / min, 85 / 15-5 / 95 (ammonium formate buffer, pH=3.5, Acetonitrile / MeOH) lasted 10 minutes and held for 4 minutes.

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Abstract

The present invention is directed to aryl sulfamide derivatives of formula (I): or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, which are monoamine reuptake inhibitors, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions, including, inter alia, vasomotor symptoms, sexual dysfunction, gastrointestinal disorders and genitourinary disorder, depression disorders, endogenous behavioral disorders, cognitive disorders, diabetic neuropathy, pain, and other diseases or disorders.

Description

Technical field [0001] The present invention relates to arylsulfonamide derivatives as monoamine reuptake inhibitors, compositions containing these derivatives, and their use in the prevention and treatment of vasomotor symptoms, depression, intrinsic behavioral disorders, and cognitive disorders , Sexual dysfunction or painful conditions, especially diseases or conditions with vasomotor symptoms. Background technique [0002] Vasomotor symptom (VMS) (called hot flashes and night sweats) is the most common symptom associated with menopause. After natural or surgically induced menopause, 60% to 80% of all women will This symptom appears. VMS may be an adaptive response of the central nervous system (CNS) to the decline of sex steroid hormones. So far, the most effective treatment for VMS is hormone-based therapy, including estrogen and / or some progesterone. Hormone therapy is extremely effective in reducing VMS, but it is not suitable for all women. [0003] VMS is caused by fluct...

Claims

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Application Information

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IPC IPC(8): C07D285/14C07D417/04C07D417/06
CPCC07D417/06C07D417/04C07D285/14A61P1/00A61P3/00A61P7/00A61P7/12A61P9/00A61P13/00A61P15/00A61P21/00A61P25/00A61P25/02A61P25/04A61P25/20A61P25/22A61P25/24A61P25/28A61P29/00
Inventor 凯西·卡梅伦·马科马斯斯蒂芬·托德·科恩马修·L·克劳利安德鲁·芬索美乔尔·亚当·戈德堡道格拉斯·约翰·詹金斯卡莱恩·永熙·金佩奇·埃林·马哈尼查尔斯·威廉·曼迈克尔·安东尼·马雷拉戴维·约翰·奥尼尔约瑟夫·P·萨巴图奇尤金·安东尼·特雷芬科尤金·约翰·特雷布斯基武安天理查德·佩奇·小伍德沃思张普文
Owner WYETH LLC
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