Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Crystalline forms of hydroxynorketamine

a technology of hydroxynorketamine and crystalline forms, which is applied in the directions of capsule delivery, organic active ingredients, organic chemistry, etc., can solve the problems of difficult processing into a pharmaceutical formulation, drawbacks of parenteral formulations, and challenges in developmen

Pending Publication Date: 2022-09-29
CYBIN UK LTD
View PDF0 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The acid addition salts provide high oral bioavailability and optimized systemic circulation, maximizing the pharmacological response of 2R,6R-hydroxynorketamine and 2S,6S-hydroxynorketamine, overcoming the stability and processing issues of the free base forms.

Problems solved by technology

However, parenteral formulations suffer drawbacks in the treatment of most depression sufferers, for whom treatment in an outpatient setting without the need of a medical professional would be preferable.
There are, however, challenges in the development of solid oral dosage forms of 2R,6R-hydroxynorketamine and 2S,6S-hydroxynorketamine.
For example, both compounds in the free base form readily form a viscous oil or gum under ambient conditions, are chemically unstable with a tendency to dimerise, and are particularly difficult to process into a pharmaceutical formulation unless in the liquid state.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Crystalline forms of hydroxynorketamine
  • Crystalline forms of hydroxynorketamine
  • Crystalline forms of hydroxynorketamine

Examples

Experimental program
Comparison scheme
Effect test

example 1

of 2R,6R-hydroxynorketamine hydrochloride

[0198](R)-N-Boc-norketamine (47)

[0199]Boc protection of norketamine was achieved with 95% yield by treating with Boc2O and triethylamine in THF at 70° C. for 16-18 hours.

[0200]1H-NMR (301 MHz, CHLOROFORM-D) δ 7.81 (d, J=6.9 Hz, 1H), 7.26 (d, J=48.2 Hz, 3H), 6.57 (s, 1H), 3.78-3.83 (m, 1H), 2.22-2.41 (m, 2H), 2.02-2.05 (m, 1H), 1.58-1.81 (m, 4H), 1.27 (s, 9H)

[0201]LCMS 20-70% MeCN: 0.1% formic acid / water; short acid methods , C18-CSA, 1.03 min m / z (+ve) 268.1 / 270.1 (loss of boc+H)

[0202](R)-N-Boc-norketamine-6-trimethylsilyl enol ether (48)

[0203]The trimethylsilyl enol ether of Boc protected R-norketamine was achieved with 99% yield by treating with strong base (lithium diisopropylamide (LDA)) in THF at −78° C., taking care to remove trace moisture from the reagents to avoid stalling the reaction.

[0204](2R, 6R)-N-Boc-6-hydroxynorketamine (49)

[0205]Alpha hydroxylation of the trimethyl silyl enol ether of R-norketamine was achieved with 92% yield...

example 2

of Crystalline forms of 2R,6R-hydroxynorketamine Salts

[0214]Methods of Analysis

[0215]X-ray Powder Diffraction (XRPD)—Transmission

[0216]XRPD analysis was carried out on a PANalytical X′pert pro, scanning the samples between 3 and 35° 2θ. The material was gently ground to release any agglomerates and loaded onto a multi-well plate with Kapton or Mylar polymer film to support the sample. The multi-well plate was then placed into the diffractometer and analysed using Cu K radiation (α1 λ=1.54060 Å; α2=1.54443 Å; β=1.39225 Å; α1:α2 ratio=0.5) running in transmission mode (step size 0.0130° 2θ) using 40 kV / 40 mA generator settings.

[0217]X-ray Powder Diffraction (XRPD)—Reflectance

[0218]XRPD analysis was carried out on a Philips X′pert Pro Multipurpose Diffractometer using a spinning stage with autosampler, scanning the samples between 3 and 35° 2θ. The material was loaded onto a circular sample holder and flattened using a glass slide. The sample holder was then loaded into position on the...

example 3

ric Analysis of Crystal Forms of 2R,6R-hydroxynorketamine

[0286]TG / DVA Analysis of 2R,6R-hydroxynorketamine hydrochloride

[0287]The TG / DTA Thermogram of the solids recovered from acetone is presented in FIG. 1A. TG / DTA shows that there is a sharp mass loss of 17.3 wt. % with an associated thermal event at 159° C. The sharp mass loss is attributed to loss of bound HCl which would be lost as a gas at that temperature, hence the sharp loss. The 17.3 wt. % loss calculates to 1 equivalent of HCl.

[0288]TG / DVA Analysis of 2R,6R-hydroxynorketamine difumarate

[0289]FIG. 1B presents the TG / DTA thermogram of the solid recovered from acetonitrile. The material degrades above 159° C. There were no thermal events in the DTA.

[0290]The 1H-NMR spectrum of the fumaric acid solid recovered from acetonitrile shows a singlet at 6.6 ppm with an integral of 4.2 protons gives 2 equivalents of fumaric acid per API. The presence of 2 equivalents of fumaric acid suggests the presence of a salt co-crystal.

[0291]T...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention provides novel, stable, processable and pharmaceutically acceptable salt forms of 2R,6R-hydrox-ynorketamineor 2S,6S-hydroxynorketamine with high aqueous solubility.

Description

FIELD OF THE INVENTION[0001]The present invention provides novel, stable, processable and pharmaceutically acceptable salt forms of 2R,6R-hydroxynorketamine or 2S,6S-hydroxynorketamine with high aqueous solubility.BACKGROUND OF THE INVENTION[0002]Ketamine derivatives, and in particular compounds derived from the ketamine metabolite 2R,6R-hydroxynorketamine and 2S,6S-hydroxynorketamine, show promise as antidepressant agents.[0003]Parenteral formulations of 2R,6R-hydroxynorketamine and 2S,6S-hydroxynorketamine are known from Zanos et al, Nature, (2016), 533, 481-486. However, parenteral formulations suffer drawbacks in the treatment of most depression sufferers, for whom treatment in an outpatient setting without the need of a medical professional would be preferable. The provision of solid oral dosage forms of 2R,6R-hydroxynorketamine and 2S,6S-hydroxynorketamine is therefore advantageous to parenteral dosage forms. There are, however, challenges in the development of solid oral dosa...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(United States)
IPC IPC(8): C07C225/20A61K9/20A61K9/48
CPCC07C225/20A61K9/2054A61K9/4825C07C2601/14C07B2200/13A61K31/135C07D201/00C07D207/28C07C215/44
Inventor PEARSON, DAVIDSHARP, LORRAINEARMSTRONG, ALANMYERSON, RICHARDHULL, JONATHANBLANEY, PAULRANDS, PETERLAYZELL, MARIEJOEL, ZELAH
Owner CYBIN UK LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com