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Highly selective serotonin and norepinephrine dual reuptake inhibitor and use thereof

A technology selected from, halogen, applied in the field of highly selective serotonin and norepinephrine dual reuptake inhibitors and their uses, which can solve the problems of high NE activity and moderate increase in diastolic blood pressure

Inactive Publication Date: 2008-07-16
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Another potential side effect of SNRIs is a modest increase in diastolic blood pressure at higher doses, and this side effect is associated with higher NE activity

Method used

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  • Highly selective serotonin and norepinephrine dual reuptake inhibitor and use thereof
  • Highly selective serotonin and norepinephrine dual reuptake inhibitor and use thereof
  • Highly selective serotonin and norepinephrine dual reuptake inhibitor and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0140] Example 1: Preparation of 1-[-2-dimethylamino-1-(4-phenol) ethyl]-cis-1,4-cyclohexanediol

[0141] with K 2 CO 3(35.6 g, 258.0 mmol) followed by benzyl bromide (28 mL, 238 mmol) in 4-(dimethylcarbamoylmethyl)phenol (35.6 g, 198.5 mmol). The mixture was stirred at room temperature for 4 days, then heated at 60 °C for 1 h. The mixture was concentrated to remove DMF, diluted with EtOAc and washed 3 times with water. Add anhydrous MgSO 4 , the mixture was filtered and concentrated to low volume. Hexane was added to precipitate the product. The solid was collected by filtration and dried to give 49 g, 92% yield of solid.

[0142]

[0143] A solution of 2N lithium diisopropylamide (LDA) (48.25 mL, 96.5 mmol) was cooled to -78 °C and diluted with 25 mL tetrahydrofuran (THF). To this was added dropwise a solution of 2-(4-benzyloxy-phenyl)-N,N-dimethyl-acetamide (20 g, 74.3 mmol) in 250 mL THF. The mixture was allowed to warm to 0°C, then cooled back to -78°C. A sol...

example 2

[0151] Example 2: Physical-chemical properties of 1-[-2-dimethylamino-1-(4-phenol)ethyl]-cis-1,4-cyclohexanediol

[0152] When prepared according to the method of Example 1, the characteristics of the title compound (free base) are as follows:

[0153] Purity 97.51% cis isomer, 1.91% trans isomer, 0.22% intermediate

[0154]

[0155] structural formula

[0156] Molecular formula C 16 h 25 NO 3

[0157] Molecular weight 279.379

[0158] Appearance White to off-white crystalline powder

[0159] Melting point (DSC start) about 193.3790°C

[0160] X-ray (powder diffraction) one polymorph

[0161] Hygroscopicity Non-hygroscopic (weight gain less than 2% at 26.30C / 90%RH, at %RH

[0162] No weight gain after lowering)

[0163] Solution Stability Compound in all aqueous solutions (pH 1.4-10.0) for at least 24 hours at room temperature

[0164] Stablize.

[0165] pH-Solubility Final pH 1.4 24.2mg / ml

[0166] Final...

example 3

[0169] Example 3: Salt Form of 1-[-2-Dimethylamino-1-(4-Phenol)ethyl]-cis-1,4-Cyclohexanediol

[0170] A. Succinate

[0171] 0.5008 g of 1-[-2-dimethylamino-1-(4-phenol)ethyl]-cis-1,4-cyclohexanediol was dissolved in 3 ml of acetone. The solution was heated to 60°C. 0.206 g of succinic acid (Sigma-Aldrich) was dissolved in 7 ml of acetone with 2 drops of water and heated to 70° C. in a water bath. The succinic acid solution was added dropwise to the 1-[-2-dimethylamino-1-(4-phenol)ethyl]-cis-1,4-cyclohexanediol solution with stirring at 70°C. Heating was continued at 65°C with the addition of a few drops of water to produce a single phase solution. Mixing was continued at 60°C for 10 minutes, then cooled to room temperature overnight. The precipitate formed at the bottom of the flask was dissolved in ethanol, and then the ethanol solution was evaporated under reduced pressure with a rotary evaporator to yield 0.4898 g of white powder.

[0172] 1 HNMR confirmed the struct...

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PUM

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Abstract

The present invention provides highly selective dual reuptake inhibitors of serotonin and norepinephrine. These compounds have a low side effect profile and are suitable for use in compositions and products for the treatment of various conditions including: depression, muscle fiber pain, anxiety, panic disorder, agoraphobia, post-traumatic stress disorder, Anxiety Disorder, Attention Deficit Disorder, Obsessive Compulsive Disorder, Social Anxiety Disorder, Generalized Anxiety Disorder, Autism, Schizophrenia, Obesity, Anorexia Nervosa, Bulimia, Gilles de la Tourette Syndrome , vasodilation flushing, cocaine and alcohol addiction, sexual dysfunction, borderline personality disorder, fibromyalgia syndrome, diabetic neuralgia, chronic fatigue syndrome, pain, visceral pain, Shy Drager syndrome syndrome), Raynaud's syndrome, Parkinson's Disease and epilepsy.

Description

technical field [0001] none Background technique [0002] As evidenced by recent developments in serotonin and noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine, neuroscience and womens health medicine The market is already trending toward dual serotonin and norepinephrine reuptake inhibitors (SNRIs) as first-line treatment for various conditions. This is in contrast to the traditional use of selective serotonin reuptake inhibitors (SSRIs). Although the side effect profiles of SSRTs and SNRIs are less severe than those of older tricyclic antidepressant compounds, some selective or other neuronal receptor binding to these SSNIs and SNRIs (muscarinic receptors , histamine receptors and α-adrenergic receptors, etc.) related adverse side effects. Binding to these receptors produces side effects such as dry mouth, drowsiness, appetite stimulation, and some cardiovascular risk factors. [0003] The higher norepinephrine (NE) activity of SNRIs is also...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/64A61K31/135
CPCC07B2200/13C07C215/64C07C217/52C07C2601/14A61P1/06A61P1/12A61P1/14A61P13/06A61P15/10A61P25/00A61P25/02A61P25/04A61P25/08A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P3/02A61P3/04A61P43/00A61P9/00A61P3/10A61K31/135
Inventor 赛义德·M·沙阿埃里克·C·埃恩施佩格理查德·W·桑德斯迈赫迪·B·福齐罗科·J·加兰特加思·T·怀特赛德
Owner WYETH LLC
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