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Organic compound

A technology of compounds and compositions, applied in organic chemistry, carbon-silicon compound conductors, organic active ingredients, etc., can solve problems such as limitations

Pending Publication Date: 2021-09-21
INTRA CELLULAR THERAPIES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the approved medical use of flutamine is limited due to side effects including perceptual disturbances, anxiety, dizziness, feelings of depersonalization and even psychosis (and it is a Table III drug that carries the risk of addiction and abuse)

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0193] Example 1: (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyridine Synthesis of [3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0194]

[0195] Sodium hydride (60% in mineral oil, 32 mg, 0.786 mmol) was added to (6bR, 10aS)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8 at 0°C 9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (0.1g, 0.262 mmol) in DMF (1 mL). The mixture was stirred at 0°C for 30 minutes, and iodomethane (19.6 μL, 0.315 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour, and water (4 mL) was added. The mixture was extracted with ethyl acetate (3×4ml) and washed over anhydrous Na 2 SO 4 The combined organic phases are dried. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography using a 0-100% mixed solvent in ethyl acetate [ethyl acetate / methanol / 7N NH 3 (10:1:0.1 v / v)] eluted. The title compound (110 g, 99% y...

Embodiment 2

[0196] Example 2: 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3′,4′:4,5]- Synthesis of pyrrolo[1,2,3-de]quinoxalin-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone

[0197]

[0198] (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3′,4′:4,5]-pyrrolo[1,2 , 3-de]quinoxaline (about 11.8g, about 50mmol), 4-chloro-4'-fluorobutyrophenone (15.0g, 74.8mmol), triethylamine (30mL, 214mmol) and potassium iodide (12.6g, 76 mmol) in dioxane (65 mL) and toluene (65 mL) was heated to reflux for 7 hours. After filtration and evaporation of the solvent, 200 ml of DCM were added. The DCM solution was washed with brine, dried (Na 2 SO 4 ) and concentrated to about 55ml. The concentrated solution was added dropwise to 600 ml of 0.5N HCl ether solution. The solid was filtered off, washed with ether, and dissolved in water. The resulting aqueous solution was basified with 2N NaOH and extracted with DCM. The DCM layers were combined, washed with brine (2×200 mL), dried (Na...

Embodiment 3

[0199] Example 3: (6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′, 4': Synthesis of 4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0200]

[0201] (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxa Lin-2(3H)-one (100 mg, 0.436 mmol), 1-(3-chloropropoxy)-4-fluorobenzene (100 μL, 0.65 mmol) and KI (144 mg, 0.87 mmol) in DMF (2 mL) The mixture was degassed with argon for 3 min, and DIPEA (150 μL, 0.87 mmol) was added. The resulting mixture was heated to 78°C and stirred at this temperature for 2 hours. The mixture was cooled to room temperature, then filtered. The filter cake was purified by silica gel column chromatography using methanol / 7N NH 3 A gradient of 0-100% ethyl acetate in a mixture in methanol (1:0.1 v / v) as eluent gave a partially purified product, which was further analyzed with a semi-preparative HPLC system using 0.1% formic acid Gradient purification of 0-60% acetonitrile in water over 16 minutes...

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Abstract

The invention relates to a particular substituted heterocycle fused gamma-carboline, in free, or pharmaceutically acceptable salt, and / or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving the 5-HT2A receptor, the serotonin transporter (SERT), and / or pathways involving the dopamine D1 and D2 receptor signaling system.

Description

[0001] Cross References to Related Applications [0002] This application is an International Application claiming priority and benefit from U.S. Provisional Application No. 62 / 780,804, filed December 17, 2018, which is hereby incorporated by reference in its entirety. [0003] field of invention [0004] The present invention relates to novel compounds, specifically substituted heterocyclic fused γ-carbolines, novel methods and uses related thereto, and pharmaceutical compositions thereof, such as methods of use in the treatment of diseases involving: 5 -HT2 A receptors, serotonin transporter (SERT), and / or pathways involving dopamine D1 and D2 receptor signaling systems, such as the following diseases or disorders: such as anxiety, psychosis, schizophrenia, sleep disorders, sexual dysfunction, paranoid Headaches, disorders associated with head pain, social phobia, gastrointestinal disorders such as gastrointestinal motility dysfunction and obesity; depression and mood disord...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): B32B5/00H01B1/04B82Y30/00
CPCB32B5/00B82Y5/00A61P25/18C07D471/16A61K31/4985A61P25/00A61P25/22A61P25/24A61K9/0019A61K9/1647
Inventor 李鹏张强R·戴维斯
Owner INTRA CELLULAR THERAPIES INC
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