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Benzothiadiazolyphenylalkylamine derivatives for use in the treatment of conditions ameliorated by monoamine reuptake

An alkyl, phenyl technology, applied in sexual diseases, drug combinations, nervous system diseases, etc., can solve problems such as unsuitability for women

Inactive Publication Date: 2008-10-01
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although hormone therapy is very effective in reducing VMS, it is not suitable for all women

Method used

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  • Benzothiadiazolyphenylalkylamine derivatives for use in the treatment of conditions ameliorated by monoamine reuptake
  • Benzothiadiazolyphenylalkylamine derivatives for use in the treatment of conditions ameliorated by monoamine reuptake
  • Benzothiadiazolyphenylalkylamine derivatives for use in the treatment of conditions ameliorated by monoamine reuptake

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0304] Example 1: (3R)-3-[3-(4-Chlorophenyl)-2,2-dioxide-2,1,3-benzothiadiazol-1(3H)-yl]-N-methyl-3 -Phenyl propan-1-amine

[0305]

[0306] 1-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide

[0307]

[0308] Anhydrous diglyme (10 mL) was added to the flask and allowed to reflux vigorously (oil bath, maintained at 190° C.) under a nitrogen atmosphere. N-(4-Chloro-phenyl)-benzene-1,2-diamine (1.09 g, 5.0 mmol) and sulfonamide (0.58 g, 6 mmol) were dissolved in diglyme (5 mL) over 15 minutes ) was added dropwise to the refluxing solution. The mixture was refluxed for another 15 minutes, and then cooled and diluted with ether, washed with 2N HCl, water and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was dissolved in ether and passed through a plug of silica gel to give 1-(3-bromopropyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxid...

example 2

[0318] Example 2: (3R)-3-(3-chloro-5-fluorophenyl)-3-(3-isopropyl-2,2-dioxide-2,1,3-benzothiadiazole-1(3H) - base)-N-methylpropan-1-amine hydrochloride

[0319]

[0320] step 1 : A reaction flask (500 mL) containing zinc chloride (6.98 g, 51.2 mmol) was dried by heating under vacuum using a heat gun. After cooling to room temperature, a solution of 3-chloro-5-fluorophenylmagnesium bromide (0.5M in anhydrous THF, 100 mL, 50.0 mmol) was added to the reaction flask via cannula, and the mixture was stirred until all the zinc chloride The solids all dissolved and a viscous bright yellow solution formed (ca. 1 h). A warm water bath (40°C) can be applied to accomplish this. Anhydrous tetrahydrofuran (100 mL) was added followed by tetrakis(triphenylphosphine)palladium (2.89 g, 2.50 mmol, 0.05 equiv). After cooling to 0°C, 3-chloropropionyl chloride (5.05 mL, 52.5 mmol, 1.05 equiv) was added dropwise, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was...

example 3

[0334] Example 3: (3R)-3-(3-chloro-5-fluorophenyl)-N-methyl-3-(3-methyl-2,2-dioxide-2,1,3-benzothiadiazole -1(3H)-yl)propan-1-amine hydrochloride

[0335]

[0336] In a manner similar to Example 2, step 4, from N-methyl-1,2-phenylenediamine prepared as a white solid 1-Methyl -1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide . MS(ES) m / z 183.1 ([M-H] - ).

[0337] In a manner similar to Example 2, step 5, from 1-methyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and (1S)-3-chloro- 1-(3-Chloro-5-fluorophenyl)propan-1-ol (Example 2 step 2) was prepared as a viscous colorless liquid 1-[(1R)-3-chloro-1-(3-chloro-5-fluorophenyl)propyl]-3-methyl-1,3-dihydro-2,1,3-benzothiadi Azole 2,2-dioxide .

[0338] In a manner similar to Example 2, Step 6, from 1-[(1R)-3-chloro-1-(3-chloro-5-fluorophenyl)propyl]-3-methyl-1,3-dihydro -2,1,3-Benzothiadiazole 2,2-dioxide prepared as white powder (3R)-3-(3-chloro-5-fluorophenyl)-N-methyl -3-(3-Methyl-2,2-dioxide-2,1,3-benzothia...

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Abstract

The present invention is directed to benzothiadiazolylphenylalkylamine derivatives of formula (I) or a pharmaceutically acceptable salt thereof, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions ameliorated by monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disorders, and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Application Serial No. 60 / 721,693, filed September 29, 2005, the entire disclosure of which is incorporated herein by reference. technical field [0003] The present invention relates to benzothiadiazolylphenylalkylamine derivatives, compositions containing said derivatives and methods for their use in the prevention and treatment of conditions ameliorated by monoamine reuptake, wherein said conditions include vasodilation VMS, sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, neurological disorders, and combinations thereof, especially those selected from the group consisting of: Severe Depression, vasomotor symptoms, stress and urge incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations thereof. Background technique [0004] Vasomotor symptoms (VMS), known as hot flashes and night sweats, are the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D285/14A61K31/428
CPCC07D285/14A61P1/00A61P13/00A61P13/10A61P15/00A61P15/08A61P15/10A61P15/12A61P25/00A61P25/20A61P25/22A61P25/24A61P29/00A61P43/00A61P9/00A61K31/428
Inventor 凯西·卡梅伦·马科马斯张普文尤金·约翰·特雷布斯基尤金·安东尼·特雷芬科武安天
Owner WYETH LLC
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