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1-(1h-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenyl propan-2-ol derivatives and related compounds as modulators of the norepinephrine(NE) and the serotonine(5-HT) activity and the monoamine reuptake

A compound, R11 technology, applied in the direction of drug combination, organic active ingredients, diseases, etc.

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

However, the use of such treatments is associated with a number of unwanted side effects resulting from the high doses necessary to relieve hot flashes as described herein and known in the related art

Method used

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  • 1-(1h-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenyl propan-2-ol derivatives and related compounds as modulators of the norepinephrine(NE) and the serotonine(5-HT) activity and the monoamine reuptake
  • 1-(1h-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenyl propan-2-ol derivatives and related compounds as modulators of the norepinephrine(NE) and the serotonine(5-HT) activity and the monoamine reuptake
  • 1-(1h-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenyl propan-2-ol derivatives and related compounds as modulators of the norepinephrine(NE) and the serotonine(5-HT) activity and the monoamine reuptake

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0693] Example 1: (1RS, 2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-ol dihydrochloride Salt

[0694]

[0695] 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 atmosphere 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 give 1.92 g (36%) of (2RS, 3RS)-3-indole-1- Base-3-phenyl-propane-1,2-diol as an oil. 1 HNMR (DMSO): δ3.27 (m, 2H, CH 2 OH), δ4.45(m, 1H, CHOH), δ4.80(t, 1H, CHOH 2...

Embodiment 2

[0698] Example 2: (1RS, 2SR)-1-(5-fluoro-1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropane-2- Alcohol dihydrochloride

[0699]

[0700] From 5-fluoroindole and trans-3-phenylglycidol, (2RS, 3RS)-3-(5-fluoro-indol-1-yl)-3 was prepared in a manner similar to Example 1 step 1 -Phenyl-propane-1,2-diol as an oil. MS (ESI) m / z 286 ([M+H] + ).

[0701] Prepare (2RS, 3RS)-Toluene-4-sulfonic acid 3-(5-fluoro-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester. MS (ESI) m / z 440 ([M+H] + ).

[0702] From (2RS, 3RS)-toluene-4-sulfonic acid 3-(5-fluoro-indol-1-yl)-2-hydroxyl-3-phenyl-propyl ester, according to steps similar to Example 1 step 3 Preparation of (1RS, 2SR)-1-(5-fluoro-1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropan-2-ol di Hydrochloride.

[0703] MS m / z 368 ([M+H] + ); HRMS: calculated value C 22 h 26 FN 3O +H+, 368.21327; Found (ESI, [M+H]+), 368.213.

Embodiment 3

[0704] Example 3: (1RS, 2SR)-1-(1H-indol-1-yl)-3-morpholin-4-yl-1-phenylpropan-2-ol hydrochloride

[0705]

[0706] From (2RS, 3RS)-toluene-4-sulfonic acid 2-hydroxy-3-indol-1-yl-3-phenylpropyl ester (Example 1, step 3) and morpholine, following a procedure analogous to Example Preparation of (1RS, 2SR)-1-(1H-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenylpropane-2-alcohol salt in step 3 salt.

[0707] MS (ESI) m / z 337 ([M+H] + ); HRMS: calculated value C 21 h 24 N 2 o 2 +H+, 337.19105; Found (ESI, [M+H]+), 337.1909.

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Abstract

The present invention is directed to phenylaminopropanol derivatives of formula (I): or a pharmaceutically acceptable salt thereof; wherein: the dotted line between Y and Z represents an optional double bond; the dotted line between the two R4 groups represents an optional heterocyclic ring of 4 to 6 ring atoms that may be formed between the two R4 groups, together with the nitrogen through which they are attached; Y is N, CR6, or C=O; Z is N, CR7, CR5, or C(R5)2; R2 is aryl substituted with 0-3 R1 or heteroaryl substituted with 0-3 R1; R3 is H or C1-C4 alkyl; n is an integer form 0 to 4; x is an integer from 1 to 2; and the other substituents are defined in the claims; 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 form 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 in turn claims U.S. Application No. 60 / 557,651, filed March 30, 2004, and U.S. Application No. 60 / 557,651, filed May 11, 2004. The benefit of Application No. 60 / 569,863, the entire disclosure of which is incorporated herein by reference. technical field [0003] The present invention relates to phenylaminopropanol derivatives, 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, especially those selected from the group consisting of major depressive disorder, vasomotor symptoms , tension and impulsive incontinence, fibromyal...

Claims

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Application Information

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IPC IPC(8): C07D209/08C07D209/30C07D209/42C07D265/36C07D241/42C07D235/06C07D471/04A61K31/4045A61P15/10
Inventor C·Y·基姆P·E·马哈伊E·J·特里布斯基张普文E·A·特雷芬克C·C·麦库马斯M·A·马雷拉R·D·科格伦G·D·赫弗伦S·T·科恩A·T·乌J·P·萨巴图奇叶飞
Owner WYETH LLC
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