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2-[bis(4-fluorophenyl)methyl]-2,7-diazaspiro[4.5]decan-10-one derivatives and related compounds as inhibitors of the human dopamine-active-transporter (dat) protein for the treatment of e.g. attention deficit disorder (add)

A kind of diazaspiro, the technology of compound, be used for treating such as attention deficit disorder (ADD) as human dopamine active transporter (DAT) protein inhibitor 2-[bis (4-fluorophenyl) methyl Base]-2,7-diazaspiro[4.5]decane-10-one derivatives and related compounds field

Inactive Publication Date: 2017-08-01
CHRONOS THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These pronounced secondary pharmacological activities may introduce undesired side effects to potentially therapeutically beneficial DAT inhibitors

Method used

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  • 2-[bis(4-fluorophenyl)methyl]-2,7-diazaspiro[4.5]decan-10-one derivatives and related compounds as inhibitors of the human dopamine-active-transporter (dat) protein for the treatment of e.g. attention deficit disorder (add)
  • 2-[bis(4-fluorophenyl)methyl]-2,7-diazaspiro[4.5]decan-10-one derivatives and related compounds as inhibitors of the human dopamine-active-transporter (dat) protein for the treatment of e.g. attention deficit disorder (add)
  • 2-[bis(4-fluorophenyl)methyl]-2,7-diazaspiro[4.5]decan-10-one derivatives and related compounds as inhibitors of the human dopamine-active-transporter (dat) protein for the treatment of e.g. attention deficit disorder (add)

Examples

Experimental program
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Effect test

preparation example Construction

[0306] It may be necessary to protect reactive functional groups (eg hydroxyl, amino, thio or carboxyl) in intermediates used in the preparation of compounds of the invention against their undesired participation in reactions leading to the formation of said compounds. Conventional protecting groups can be used, for example, those described by T.W. Greene and P.G.M. Wuts in "Protective groups in organic chemistry", John Wiley and Sons, 4th edition, 2006. For example, a common amino protecting group suitable for use herein is tert-butoxycarbonyl (Boc), which is readily removed by treatment with an acid such as trifluoroacetic acid or hydrochloric acid in an organic solvent such as dichloromethane. Alternatively, the amino protecting group may be benzyloxycarbonyl (Z) which is removable by hydrogenation with a palladium catalyst under a hydrogen atmosphere, or by a solution of a secondary organic amine such as diethylamine or piperidine in an organic solvent 9-Fluorenylmethoxyca...

Embodiment 1

[0551] Example 1: 2-[bis(4-fluorophenyl)methyl]-2,7-diazaspiro[4.5]decane-10-one (E1)

[0552]

[0553] TFA (1 mL) was added to tert-butyl 2-[bis(4-fluorophenyl)methyl]-10-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (p6, 350 mg , 0.767mmol) in a solution in 5mL DCM. The mixture was stirred for 1 h, then the solvent was removed under reduced pressure. The residue was loaded onto an SCX column, washed with MeOH and washed with 1M NH 3 Elution in MeOH gave 2-[bis(4-fluorophenyl)methyl]-2,7-diazaspiro[4.5]decane-10-one as a colorless oil (E1, 20 mg ,y=7%).

[0554]

Embodiment 2

[0555]Example 2: 2-[bis(4-fluorophenyl)methyl]-7-methyl-2,7-diazaspiro[4.5]decane-10-one (E2)

[0556]

[0557] To a solution of 2-[bis(4-fluorophenyl)methyl]-2,7-diazaspiro[4.5]decane-10-one (E1, 20 mg, 0.056 mmol) in DCM (1.5 mL) , a solution of 37% w / w formaldehyde in water (0.041 mL, 0.56 mmol) was added, and the mixture was stirred at room temperature for 15 min. Then add NaBH(OAc) 3 (17 mg, 0.084 mmol), and the mixture was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure and loaded onto an SCX column, washed with MeOH and washed with 1M NH 3 Solution in MeOH eluted.

[0558] After evaporation of the combined ammonia fractions, the residue was purified by FC on NH column (eluent: cHex to cHex / EtOAc 60 / 40) to give 2-[bis(4-fluorophenyl)formazol as a white foam yl]-7-methyl-2,7-diazaspiro[4.5]decane-10-one (E2, 13.6 mg, y=65%).

[0559]

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Abstract

The present invention provides compounds of formula (I) and in particular 2-[bis(4-fluorophenyl)methyl]-2,7- diazaspiro[4.5]decan-10-one derivatives and related compounds as inhibitors of human dopamine-active-transporter (DAT) protein for the treatment of sexual dysfunction, affective disorders, anxiety, depression, chronic fatigue, Tourette syndrome, Angelman syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), obesity, pain, obsessive-compulsive disorder, movement disorders, CNS disorders, sleep disorders, narcolepsy, conduct disorder, substance abuse (including smoking cessation), eating disorders, and impulse control disorders.

Description

[0001] The present invention relates to spirocyclic derivatives which are inhibitors of dopamine active transporter protein (DAT) and pharmaceutical compositions containing such derivatives as well as uses of such derivatives. Background technique [0002] The spirocyclic derivatives of the present invention are inhibitors of human dopamine active transporter protein (DAT) and have many therapeutic uses, especially in sexual dysfunction, affective disorder, anxiety, depression, chronic fatigue, hyperactive Tourette syndrome, Angelman syndrome, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), obesity, pain, obsessive-compulsive disorder, movement disorder, CNS disorder, sleep disorder, narcolepsy, conduct disorder, substance abuse (including smoking cessation), eating disorders, and impulse control disorders. [0003] Dopamine (DA) is a neurotransmitter with important roles in cognition, emotion, movement, arousal and reward-related functions. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/10C07D491/20C07D498/10C07D513/10A61K31/438A61K31/5386A61K31/547A61P15/00A61P25/18A61P25/22A61P25/24A61P25/14A61P25/28A61P3/04A61P25/04A61P25/20A61P25/30A61P25/34
CPCC07D471/10C07D491/20C07D498/10C07D513/10A61P3/04A61P15/00A61P15/10A61P25/00A61P25/02A61P25/04A61P25/14A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P25/34
Inventor T·塞梅拉罗L·塔尔西F·米凯利T·卢克S·克雷莫纳西
Owner CHRONOS THERAPEUTICS
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