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4-phenyl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin

A phenyl and alkyl technology, applied in the direction of medical preparations containing active ingredients, metabolic diseases, preparations for in vivo tests, etc.

Inactive Publication Date: 2003-04-23
ALBANY MOLECULAR RESEARCH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, long-term administration of nomofensine  leading to fatal immune hemolytic anemia

Method used

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  • 4-phenyl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin
  • 4-phenyl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0416] The preparation of embodiment 12,7-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline

[0417]Step A: m-tolualdehyde (500 mg, 4.16 mmol), D-(methylaminomethyl ) A solution of benzyl alcohol (630mg, 4.16mmol) and acetic acid (0.5ml) was stirred in methanol (16ml). The reaction mixture was stirred for 5 minutes at 0°C and for two days at ambient temperature. The reaction mixture was adjusted to pH 12 with 2N sodium hydroxide, diluted with water and extracted with ether (3x). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give the desired intermediate (1.24 g): 1 HNMR (300MHz, CDCl 3 )δ7.08-7.35(m, 9H), 4.73-4.77(m, 1H), 3.71(d, J=13.0Hz, 1H), 3.50(d, J=13.0Hz, 1H), 2.46-2.67(m , 2H), 2.36(s, 3H), 2.32(s, 3H); CI MS m / z=256[C 17 h 21 NO+H] + .

[0418] Step B: The product from Step A (1.24g, 4.90mmol) was stirred in dichloromethane (208ml) and treated with concentrated sulfuric acid...

Embodiment 42

[0420] Example 42, Preparation of 7-dimethyl-4-(3-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline

[0421] Step A: m-Tolualdehyde (1.66g, 14.0mmol) was treated with methylamine (40% in water, 1.39ml, 18.0mmol) in methanol (20ml) at room temperature. The reaction was stirred for 20 minutes and treated with sodium borohydride (0.26 g, 7.0 mmol) in portions. The reaction was stirred for 1 hour and treated with 3'-fluoro-2-bromoacetophenone (3.0 g, 14.0 mmol), then stirred at room temperature for 45 minutes. Finally, the reaction was treated in portions with sodium borohydride (0.52 g, 14.0 mmol) and stirring was continued overnight. The reaction was diluted with water (100ml) and extracted with dichloromethane (3 x 100ml). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel, eluting with hexane / ethyl acetate (3 / 1 ), afforded the aminoalcohol (4.3 g) ...

Embodiment 62

[0424] Example 62, Preparation of 7-dimethyl-4-(4-fluoro-3-methylphenyl)-1,2,3,4-tetrahydroisoquinoline

[0425] Step A: m-Tolualdehyde (4.0 g, 33.0 mmol) was treated with methylamine (40% in water, 3.36 mL, 43.0 mmol) in methanol (40 mL) at room temperature. The reaction was stirred for 20 minutes and treated with sodium borohydride (0.64 g, 33.0 mmol) in portions. The reaction was stirred for 1 hour and treated with 4'-fluoro-3'-methyl-2-bromoacetophenone (7.69 g, 33.0 mmol), then stirred at room temperature for 45 minutes. Finally, the reaction was treated in portions with sodium borohydride (1.0 g, 33 mmol) and stirring was continued overnight. The reaction was diluted with water (100ml) and extracted with dichloromethane (3 x 100ml). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel, eluting with hexane / ethyl acetate (2 / 1), afforded...

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Abstract

Provided herein are compounds of formulae IA-IF. These compounds are tetrahydroisoquinolines of structure (A) wherein R<1>-R<8> for compounds of each of the formulae IA, IB, IC, ID, IE and IF are as described herein. Said compounds are particularly useful in the treatment of various neurological and psychiatric disorders, e.g., ADHD.

Description

field of invention [0001] The present invention relates to compounds, compositions, methods and the use of said compounds in combination therapy for the treatment of various neurological and psychiatric disorders. In particular, the present invention relates to compounds, compositions and methods wherein said compounds are novel 4-phenyl substituted tetrahydroisoquinoline derivatives. Background of the invention [0002] Serotonin, dopamine and norepinephrine are known to be important chemical messengers involved in the transmission of nerve impulses in the brain. These messengers are released and received at specific sites in the presynaptic cell to complete the transmission of impulses at specific sites in the postsynaptic cell. They are then terminated by metabolism or by uptake into presynaptic cells. Drugs that block the uptake of any of these chemical messengers by presynaptic bodies in the brain would be useful in alleviating diseases associated with reduced levels ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/137A61K31/198A61K31/438A61K31/472A61K31/495A61K45/00A61K51/00A61P3/04A61P25/00A61P25/02A61P25/16A61P25/22A61P25/24A61P25/28A61P39/02A61P43/00C07D217/04C07D217/14C07D217/16C07D217/24
CPCC07D217/04C07D217/16C07D217/14C07D217/24A61P3/04A61P25/00A61P25/02A61P25/16A61P25/22A61P25/24A61P25/28A61P39/02A61P43/00A61K31/472C07D217/22
Inventor J·P·贝克M·A·史密斯
Owner ALBANY MOLECULAR RESEARCH INC
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