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Crystal forms and methods of synthesis of (2r, 6r)-hydroxynorketamine and (2s, 6s)-hydroxynorketamine

A technology of methylketamine, methylketamine hydrochloride, applied in the crystal form of hydrochloride, recrystallizing 2R,6R-HNK hydrochloride, major depression, standard treatment selective 5-hydroxy, sexual biphasic Depression, as well as other areas of depression and focus, can address issues such as unresponsiveness

Active Publication Date: 2019-02-05
US DEPT OF HEALTH & HUMAN SERVICES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, some patients respond to the antidepressant effects of ketamine but not to SSRIs

Method used

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  • Crystal forms and methods of synthesis of (2r, 6r)-hydroxynorketamine and (2s, 6s)-hydroxynorketamine
  • Crystal forms and methods of synthesis of (2r, 6r)-hydroxynorketamine and (2s, 6s)-hydroxynorketamine
  • Crystal forms and methods of synthesis of (2r, 6r)-hydroxynorketamine and (2s, 6s)-hydroxynorketamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0157] Example 1. Chiral resolution of (S)-(+)-norketamine (14)

[0158]

[0159] Racemic norketamine (22.7 g, 101 mmol) (Cayman Chemicals, Ann Arbor, MI, USA, prepared as described by Hong, S.C. & Davisson, J.N., J.Pharm.Sci. (1982) 71:912-914) Dissolve in 1.1L ethanol. Then solid (D)-(R)-(+)-pyroglutamic acid (15.8 g, 0.5 equiv, 121 mmol) was added. The reaction was stirred and heated to reflux for 5 minutes. A white suspension formed while heating. Once the suspension reached reflux, it was allowed to cool to room temperature while stirring for 16 hours. The reaction was filtered and a white solid was collected. The resulting white solid was then resuspended in 0.9 L of ethanol, and the suspension was heated to reflux for 5 minutes. The suspension was allowed to cool to room temperature over 2 hours while stirring. The solid was collected by filtration, then suspended a third time in ethanol (0.8 L), heated to reflux for 5 minutes, then allowed to cool to room temp...

Embodiment 2

[0160] Example 2. Chiral resolution of (R)-(-)-norketamine (14A)

[0161]

[0162] (R)-(-)-norketamine (14A) was produced in a similar manner to (S)-(+)-norketamine (2), except using (L)-(S)-(-)-pyro Glutamic acid was used as a chiral resolution reagent instead of (D)-(R)-(+)-pyroglutamic acid. Chiral HPLC: 98% ee. (Chiralpak AD, 60% ethanol in hexane, 1 mL / min, rt: 6.8 min.) [α] D 20 : (-)-75°(c1.0, H 2 O, L-pyroglutamine salt).

Embodiment 3

[0163] Example 3. Synthesis of (S)-tert-butyl (1-(2-chlorophenyl)-2-oxocyclohexyl) carbamate (15)

[0164]

[0165] To a solution of (S)-(+)-norketamine (14) (1.85 g, 8.27 mmol) in toluene (100 mL) was added potassium carbonate (3.43 g, 24.8 mmol) and BOC-anhydride (2.71 g, 12.4 mmol). The reaction was heated to 80 °C and stirred for 16 hours. The reaction was then cooled, extracted with ethyl acetate and washed with water. The organic layer was extracted and the solvent was removed under vacuum to give crude product. Purification by silica gel chromatography (0% to 60% ethyl acetate in hexanes) gave the final product (15) as a white solid.

[0166] 1 H NMR (400MHz, CDCl 3 )δ7.83(d, J=8.0Hz, 1H), 7.42-7.28(m, 2H), 7.28-7.13(m, 1H), 6.59(s, 1H), 3.83(d, J=14.3Hz, 1H ), 2.45-2.36(m, 1H), 2.36-2.25(m, 1H), 2.04(ddq, J=11.5, 5.5, 3.0Hz, 1H), 1.89-1.56(m, 4H), 1.29(s, 9H ).

[0167] 13 C NMR (101MHz, CDCl 3 )δ 209.0, 153.4, 135.1, 133.7, 131.5, 130.9, 129.2, 126.2, 79....

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Abstract

The disclosure provides a method for synthesizing free base forms of (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-hydroxynorketamine. In an embodiment synthesis of (2R,6R)-hydroxynorketamine (HNK) includes preparation of (R)-norketamine via chiral resolution from racemic norketamine via a chiral resolution with L-pyroglutamic acid. The disclosure also provided crystal forms of the corresponding (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-hydroxynorketamine hydrochloride salts.

Description

[0001] Citations to related applications [0002] This application claims priority to, and all benefits derived therefrom, from U.S. Provisional Application No. 62 / 313,309, filed March 25, 2016, with the United States Patent and Trademark Office, the contents of which are hereby incorporated by reference in their entirety . [0003] Statement of Government Support [0004] This invention was made with Government support under Grant No. NH099345 awarded by the National Institutes of Health. The US Government has certain rights in this invention. Background technique [0005] Ketamine, a drug currently used in human anesthesia and veterinary medicine, has been shown in clinical studies to be effective in the treatment of a variety of conditions, including pain, treatment-resistant bipolar depression, major depressive disorder, and other depression and anxiety disorders related diseases. [0006] However, the routine use of this drug is subject to undesired central nervous sy...

Claims

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Application Information

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IPC IPC(8): C07C225/22A61K31/133
CPCC07C221/00C07C269/04C07C2601/14C07B2200/07C07C271/24C07C225/20C07C269/06C07C2601/16C07B2200/13
Inventor 克雷格·托马斯帕特里克·莫里斯卡洛斯·萨拉特鲁因·莫阿德尔托德·古尔德帕诺斯·萨诺斯
Owner US DEPT OF HEALTH & HUMAN SERVICES
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