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Heterocyclic phenylaminopropanol derivatives as modulators of the monoamine reuptake for the treatment of vasomotor symptoms (VMS)

A technology of methylamino and phenylpropane, which can be used in drug combinations, medical preparations containing active ingredients, diseases, etc., and can solve problems such as non-recommendation

Inactive Publication Date: 2007-05-09
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Also, hormone replacement therapy is generally not recommended for women or men who have or are at risk of hormone-sensitive cancers, such as breast or prostate cancer

Method used

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  • Heterocyclic phenylaminopropanol derivatives as modulators of the monoamine reuptake for the treatment of vasomotor symptoms (VMS)
  • Heterocyclic phenylaminopropanol derivatives as modulators of the monoamine reuptake for the treatment of vasomotor symptoms (VMS)
  • Heterocyclic phenylaminopropanol derivatives as modulators of the monoamine reuptake for the treatment of vasomotor symptoms (VMS)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0252] Example 1: (1RS, 2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-ol dihydrochloride Salt

[0253]

[0254] Step 1: A mixture of indole (2.34 g, 20 mmol) and crushed solid potassium hydroxide (1.12 g, 20 mmol) was stirred at room temperature under nitrogen for 30 minutes. A solution of trans-3-phenylglycidol (3.0 g, 20 mmol) in dimethylsulfoxide (1 mL) was then added and the mixture was stirred at 70°C for 2 hours until no epoxide remained. The mixture was then cooled and partitioned between water and dichloromethane. The organic layer was separated, washed several times with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 10%, 20%, 30% ethyl acetate / hexanes) to afford 1.92 g (36%) of (2RS, 3RS)-3-indole-1- yl-3-phenyl-propane-1,2-diol. 1 HNMR (DMSO): δ3.27 (m, 2H, CH 2 OH), δ4.45(m, 1H, CHOH), δ4.80(t, 1H, CHOH 2 OH), δ5.20 (d, 1H, CHO...

Embodiment 2

[0257] Example 2: (1RS, 2SR)-1-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-3-(methylamino)-1-phenylpropane- 2-alcohol dihydrochloride

[0258]

[0259] A mixture of 3,4-dihydro-2H-benzo[1,4]oxazine (2.027g, 15.00mmol) and trans-ethyl-3-phenyl glycidate (2.883g, 15.00mmol) was Stir at 135°C for 12 hours. After cooling, the viscous liquid was purified via Biotage Horizon (FLASH 40M, silica, 10%, 20%, 30% EtOAc / hexane) and recrystallized (slightly warmed chloroform / hexane / -20°C) to give 4.261 g (87%) ethyl (2RS, 3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-3-phenylpropionate , as a white solid. MS (ESI) m / z 328.0 ([M+H]+).

[0260] Ethyl (2RS, 3RS)-3-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-2-hydroxy-3-phenylpropionate (283mg, 0.864 mmol) and methylamine in ethanol (5 mL, 33%) was stirred at 70° C. in a sealed tube for 5 hours. After cooling, all volatiles were removed under reduced pressure. The resulting yellow solid was purified via Biotage Horizon (FLASH 12S, silica, ...

Embodiment 3

[0262] Example 3: (1S,2R)-1-(3-chlorophenyl)-1-(1H-indol-1-yl)-3-(methylamino)propan-2-ol hydrochloride

[0263]

[0264] Step 1: A suspension of sodium hydride (60% dispersion in mineral oil, 4.0 g, 100 mmol) in THF (600 mL) was added dropwise with diethylethoxycarbonylmethylphosphonate (20 mL, 100 mmol) at 23 °C deal with. After 1 hour, 3-chlorobenzaldehyde (9.3 mL, 82 mmol) was added. After an additional 1 hour, the reaction was quenched with water (20 mL) and concentrated in vacuo to remove tetrahydrofuran. The residue was dissolved in ethyl acetate (300 mL), washed with water (5 x 300 mL) and brine (1 x 300 mL), dried (magnesium sulfate) and concentrated in vacuo to give (2E)-3-(3-chlorobenzene base)-ethyl acrylate (18 g, quantitative) as a clear pale yellow oil. MS (ESI) m / z 210 ([M+H]+).

[0265] Step 2: (2E)-3-(3-Chlorophenyl)-ethyl acrylate (17.6 g, 82 mmol) was dissolved in anhydrous dichloromethane (300 mL), cooled to -78° C. Treat with isobutylaluminum hydr...

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Abstract

The present invention is directed to phenylaminopropanol 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 U.S. Application No. ______, filed March 28, 2005, which claims U.S. Application No. 60 / 557,831, filed March 30, 2004, and U.S. Application No. ______, filed May 11, 2004. 60 / 569,861, the entire disclosure of which is incorporated herein by reference. field of invention [0003] The present invention relates to phenylaminopropanol derivatives, compositions containing these derivatives and methods of their use for the prevention and treatment of conditions improved by monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual function Disorders, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndromes, nervous system disorders and combinations thereof, especially selected from the group consisting of: major depressive disorder, vasomotor symptoms, nervousness and impulsivity Conditions of urinary incontinence, fibromyalgia, pain, di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/36C07D241/42C07D279/16A61K31/538A61K31/498A61K31/5415A61P5/24A61P15/10
Inventor A·T·乌P·E·马哈伊S·T·科恩
Owner WYETH LLC
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