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Organic compounds

A technology of compound and composition, applied in the direction of organic chemistry, organic chemical method, heterocyclic compound isotope introduction, etc., can solve problems that have not been fully elucidated

Pending Publication Date: 2020-12-15
INTRA CELLULAR THERAPIES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The family of enzymes that catalyze ketone reduction is large and varied, and the mechanism has not been fully elucidated

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0219] 1-(4-fluorophenyl)-4-((6bR,10aS)-1,1,2,2-tetradeutero-3-methyl-2,3,6b,7,10,10a-hexahydro -1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one p-toluenesulfonate

[0220]

[0221] Step 1: Addition of degassed 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylic acid (4aS, 9bR)- Ethyl ester (1.60 g, 8.0 mmol), 2-chloro-2,2-dideutero-N-methylacetamide (1.74 g, 16 mmol) and KI (2.68 g, 16 mmol) in dioxane (28 mL) Diisopropylethylamine (2.8 mL, 16 mmol) was added to the mixture. The reaction mixture was then heated to 104 °C for 20 h with vigorous stirring. The solvent was removed in vacuo, the residue was suspended in dichloromethane (50 mL) and extracted with water (20 mL). Separate the organic phase with K 2 CO 3 Dry and concentrate to a residue. The product was purified by column chromatography using a 0-100% mixed solvent gradient in ethyl acetate [ethyl acetate / methanol (10:1 v / v)] to give 6-bromo-5-(1,1-bis Deutero-2-(methyla...

Embodiment 2

[0227] Example 2: Determination of maternal and metabolite levels in mice

[0228] The compound of Example 1 and the compound of formula Q were co-administered in mice (n=3), and the levels of these two compounds were studied. Synthesis of compounds of formula Q can be found in WO 2008 / 112280. Plasma and brain levels were determined at 0.25, 0.5, 1, 2 and 4 hours after single oral dose administration of test compounds. The mean values ​​of the maximum concentration, time to maximum concentration and area under the curve (AUC) of the two compounds were determined. The results are summarized in Table 1 below.

[0229]

[0230] Both plasma and blood concentrations of the compound of Example 1 were found to be higher than those of the compound of formula Q, resulting in higher Cmax values ​​and higher AUC values. This indicates that the tetradeuterated compound of Example 1 has reduced metabolic clearance compared to its non-deuterated counterpart, the compound of Formula Q....

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Abstract

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

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 62 / 647,482, filed March 23, 2018, the contents of which are hereby incorporated by reference in their entirety. [0003] field of invention [0004] The present invention relates to specific deuterated heterocyclic fused γ-carboline compounds as described herein in free form, pharmaceutically acceptable salt form and / or in substantially pure form, pharmaceutical compositions thereof and methods for treating diseases involving: 5-HT 2A receptor, serotonin transporter (SERT), and / or involved in dopamine D 1 / D 2 pathways of receptor signaling systems, for example diseases or disorders such as: anxiety, psychosis, schizophrenia, sleep disorders, sexual disorders, migraines, conditions associated with head pain, social phobia, gastrointestinal disorders such as gastric Gut motility dysfunction and obesity; depression and mood disorders associated with psy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4985
CPCA61K31/4985A61K45/06C07D471/16A61K2300/00A61K9/0019C07B2200/05C07B59/002C07D471/04
Inventor 李鹏R·戴维斯
Owner INTRA CELLULAR THERAPIES INC
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