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The use of (2r, 6r)-hydroxynorketamine, (s)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (r,s)- ketamine in the treatment of depression and neuropathic pain

A hydroxyl, compound technology for (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydrogenated and hydroxylated metabolites of (R,S)-ketamine Areas of application in the treatment of depression and neuropathic pain

Inactive Publication Date: 2015-03-04
UNITED STATES OF AMERICA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, ketamine treatment is associated with serious side effects due to the drug's narcotic effects and potential for abuse

Method used

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  • The use of (2r, 6r)-hydroxynorketamine, (s)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (r,s)- ketamine in the treatment of depression and neuropathic pain
  • The use of (2r, 6r)-hydroxynorketamine, (s)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (r,s)- ketamine in the treatment of depression and neuropathic pain
  • The use of (2r, 6r)-hydroxynorketamine, (s)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (r,s)- ketamine in the treatment of depression and neuropathic pain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0155] Example 1. Synthesis of lysine conjugates of norketamine

[0156]

Embodiment 26

[0157] Synthesis of the ester conjugate of embodiment 2.6-hydroxynorketamine

[0158]

Embodiment 3

[0159] Example 3. Synthesis of (+,-)-(2S,6R / 2R,6S)-6-hydroxynorketamine

[0160]

[0161] Synthesis of (+,-)-(Z+E)-6-bromonorketamine. A 50 mL sample of racemic (+,-)-norketamine (free base) (10.0 g, 35.8 mmol) in glacial acetic acid was treated with bromopyridine (16.4 g, 51.3 mmol). The resulting mixture was heated at 130 °C for 1 h using a microwave. The solvent was removed in vacuo and the crude was dissolved in CHCl 3 , with saturated NaHCO 3 Washed, dried in vacuum (Na 2 SO 4 ) and evaporated, leaving 12.4 g of a crude mixture of diastereoisomers (Z+E, 3:1). Using silica gel chromatography with CH varying in concentration from (99.9 / 0 / 0.1) to (98.9 / 1 / 0.1) 2 Cl 2 / MeOH / Et 3 N eluted to afford the pure isolated isomers, (+,-)-(E)-6-bromonorketamine (1.22 g) (9% yield) and (+,-)-(Z) - 6-bromonorketamine (6.6 g) (49% yield).

[0162] Analytical data for (+,-)-(E)-6-bromonorketamine: 1 H NMR: (300MHz, CDCl 3 ):δ7.60(m,1H),7.20-7.10(m,3H),5.17(dd,1H,J=12.0Hz,J=6...

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Abstract

The disclosure provides pharmaceutical preparations containing (2R,6R)-hydroxynorketamine, or (R)- or (S)-dehydronorketamine, or other stereoisomeric dehydro or hydroxylated ketamine metabolite. (2R,6R)-hydroxynorketamine The disclosure also provides novel ketamine metabolite prodrugs. The disclosure provides methods of treating, bipolar depression, major depressive disorder, neuropathic and chronic pain, including complex regional pain disorder (CRPS) by administering a purified ketamine metabolite or a ketamine metabolite prodrug directly to patients in need of such treatment.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial No. 61 / 547,336, filed October 14, 2011, the entire contents of which are hereby incorporated by reference. [0003] Statement of Government Support [0004] The subject matter of the present disclosure was funded by an in-house research program of the National Institute of Aging and the Nation Institute of Mental Health. The US Government has certain rights in this application. technical field [0005] The present disclosure demonstrates that the active agent is responsible for the therapeutic response to ketamine in patients primarily due to (2R,6R)-hydroxynorketamine and (S)-dehydronorketamine (ketamine metabolites). The present disclosure provides pharmaceutical formulations comprising ketamine metabolites and prodrugs of ketamine metabolites. The present disclosure also provides novel ketamine prodrugs. The present disclosure provides me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C225/20C07C237/02C07D295/155C07D295/145A61P25/04A61P25/28A61P25/00A61K31/133A61K31/122
CPCC07C229/48C07D295/15C07B2200/07C07C225/20C07D295/155C07C2101/14C07D295/108C07C237/04C07D295/112C07C237/20C07C2101/16C07C2601/14C07C2601/16A61K31/137A61K31/165A61K31/222A61K31/24A61K31/265A61K31/4453A61K31/5375A61P21/02A61P25/00A61P25/04A61P25/18A61P25/24A61P25/28A61P29/00A61K31/135A61K45/06
Inventor 欧文·W·魏纳鲁因·莫阿德尔米歇尔·伯尼尔卡洛斯·A·萨拉特马克·C·托尔曼迈克尔·E·戈德堡玛丽·J·坦加
Owner UNITED STATES OF AMERICA
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