83777-65-5

Upstream product

• 6740-88-1 ketamine 
• 2079878-75-2 2-(2-chlorophenyl)-2-nitrocyclohexan-1-one 
• 17465-36-0 2'-chloro-2,3,4,5-tetrahydro-1,1'-biphenyl 
• 100477-72-3 (+)-Ketamine 
• 100477-72-3 (S)-ketamine 
• 6740-86-9 (1-Bromocyclopentyl)(2-chlorophenyl)methanone 
• 6740-85-8 (2-chlorophenyl)(cyclopentyl)methanone 
• 873-32-5 2-Chlorobenzonitrile 
• 79499-58-4 1-<(2-Chlorophenyl)iminomethyl>cyclopentanol hydrochloride 
• 79499-57-3 (±)-1-((2-chlorophenyl)(imino)methyl)cyclopentan-1-ol 
• 91393-49-6 2-amino-2-(2-chlorophenyl)cyclohexan-1-one 
• 286-20-4 cyclohexane-1,2-epoxide 
• 694-80-4 2-bromo-1-chlorobenzene 
• 35211-10-0 norketamine 

Downstream Products

• 91003-15-5 3-(o-Chlorophenyl)-2-hydroxycyclohex-2-enone 
• 79499-61-9 2-Bromo-6-amino-6-(2-chlorophenyl)cyclohexanone 
• 1430202-69-9 (2R,6R)-(+)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone hydrochloride 
• 83777-64-4 (R)-Norketamine 
• 1430202-70-2 (2S,6S)-(+)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone hydrochloride 
• 100477-72-3 (S)-ketamine 
• 1430202-46-2 C₁₈H₂₆ClN₃O₂ 

Relevant academic research and scientific papers

NMDA receptor antagonist and use thereof

The present invention relates to an NMDA receptor antagonist and use thereof. The NMDA receptor antagonist is a compound as shown in the formula I, and pharmaceutically acceptable salts, enantiomers, diastereoisomers, tautomers, solvates, isotope substitutes, polymorphic substances, prodrugs or metabolites thereof, and in the formula, ring A, ring B and R2 are as described in the specification. The invention also provides pharmaceutical compositions containing the compounds, and applications of the compounds in preparation of drugs for treating or preventing NMDA receptor mediated diseases.

Family of Structurally Related Bioconjugates Yields Antibodies with Differential Selectivity against Ketamine and 6-Hydroxynorketamine

The dissociative-hypnotic compound ketamine is being used in an increasingly wide range of therapeutic contexts, including anesthesia, adjunctive analgesia, treatment-resistant depression, but it also continues to be a notable substance of abuse. No specific antidotes exist for ketamine intoxication or overdose. Immunopharmacotherapy has demonstrated the ability to offer overdose protection through production of highly specific antibodies that prevent psychoactive drug penetration across the blood-brain barrier, although antiketamine antibodies have not yet been assessed or optimized for use in this approach. Moreover, generation of specific antibodies also provides an opportunity to address the role of 6-hydroxynorketamine metabolites in ketamine's rapid-acting antidepressant effect through selective restriction of metabolite access to the central nervous system. Hapten design is a critical element for tuning immune recognition of small molecules, as it affects the presentation of the target antigen and thus the quality and selectivity of the response. Here, we report the synthesis and optimization of carrier protein and conjugation conditions for an initial hapten, norketamine-N-COOH (NK-N-COOH), to optimize vaccination conditions and assess the functional consequences of such vaccination on ketamine-induced behavioral alterations occurring at dissociative-like (50 mg/kg) doses. Iterating from this initial approach, two additional haptens, ketamine-N-COOH (KET-N-COOH) and 6-hydroxynorketamine-N-COOH (HNK-N-COOH), were synthesized to target either ketamine or 6-hydroxynorketamine with greater selectivity. The ability of these haptens to generate antiketamine, antinorketamine, and anti-6-hydroxynorketamine immune responses in mice was then assessed using enzyme-linked immunosorbent assay (ELISA) and competitive surface plasmon resonance (SPR) methods. All three haptens provoked immune responses in vivo, although the KET-N-COOH and 6-HNK-N-COOH haptens yielded antibodies with 5- to 10-fold improvements in affinity for ketamine and/or 6-hydroxynorketamine, as compared to NK-N-COOH. Regarding selectivity, vaccines bearing a KET-N-COOH hapten yielded an antibody response with approximately equivalent Kd values against ketamine (86.4 ± 3.2 nM) and 6-hydroxynorketamine (74.1 ± 7.8 nM) and a 90-fold weaker Kd against norketamine. Contrastingly, 6-HNK-N-COOH generated the highest affinity and most selective antibody profile, with a 38.3 ± 4.7 nM IC50 against 6-hydroxynorketamine; Kd values for ketamine and norketamine were 33- to 105-fold weaker, at 1290 ± 281.5 and 3971 ± 2175 nM, respectively. Overall, these findings support the use of rational hapten design to generate antibodies capable of distinguishing between structurally related, yet mechanistically distinct, compounds arising from the same precursor molecule. As applied to the production of the first-reported anti-6-hydroxynorketamine antibodies to date, this approach demonstrates a promising path forward for identifying the individual and combinatorial roles of ketamine and its metabolites in supporting rewarding effects and/or rapid-acting antidepressant activity.

SYNTHETIC METHODS OF PREPARING ESKETAMINE

The present invention is directed to methods for the asymmetric synthesis of esketamine. The present invention is further directed to key intermediates in the asymmetric esketamine synthesis. In one embodiment, the invention is an asymmetric synthesis of esketamine comprising the conversion of (S)-2'-chloro-2-methoxy-3,4,5,6-5 tetrahydro-[1,1'-biphenyl]-3-yl carbamate to (S)-2'-chloro-1-isocyanato-6-methoxy- 1,2,3,4-tetrahydro-1,1'-biphenyl.

Preparation method of ketamine and synthesis method of intermediate compound

The invention discloses an intermediate compound II for synthesizing ketamine, and the chemical structural formula of the intermediate compound II is disclosed in the invention. The compound II is directly synthesized by one-step reaction of a compound under the action of iodobenzene acetate and azidotrimethylsilane; and ketamine is synthesized from the compound II through two steps: 1) reducing azide into amino; and 2) carrying out aminomethylation reaction. Compared with the prior art, the HPLC purity of the product can reach 97% or above, meanwhile, the ketamine prepared through the methodis high in industrialization degree, the quality of the product is greatly improved, intermediate impurities do not exist, the process route is easy to operate, the cost is low, and conditions are mild.

Delivery Of Esketamine For The Treatment Of Depression

The present invention provides devices and methods for treating depression in a patient, comprising administering to the patient in need of the treatment a therapeutically effective amount of esketamine. In some embodiments, the depression is major depressive disorder or treatment resistant depression. In other embodiments, the therapeutically effective amount is clinically proven safe and/or effective. Also provided are methods to mitigate the risk or misuse or abuse of esketamine, instructions for use of the esketamine product, and methods for selling a drug product containing esketamine.

Halogen Substitution Influences Ketamine Metabolism by Cytochrome P450 2B6: In Vitro and Computational Approaches

Ketamine is analgesic at anesthetic and subanesthetic doses, and it has been used recently to treat depression. Biotransformation mediates ketamine effects, influencing both systemic elimination and bioactivation. CYP2B6 is the major catalyst of hepatic ketamine N-demethylation and metabolism at clinically relevant concentrations. Numerous CYP2B6 substrates contain halogens. CYP2B6 readily forms halogen-protein (particularly Cl-π) bonds, which influence substrate selectivity and active site orientation. Ketamine is chlorinated, but little is known about the metabolism of halogenated analogs. This investigation evaluated halogen substitution effects on CYP2B6-catalyzed ketamine analogs N-demethylation in vitro and modeled interactions with CYP2B6 using various computational approaches. Ortho phenyl ring halogen substituent changes caused substantial (18-fold) differences in Km, on the order of Br (bromoketamine, 10 μM) max varied minimally (83-103 pmol/min/pmol CYP). Thus, apparent substrate binding affinity was the major consequence of halogen substitution and the major determinant of N-demethylation. Docking poses of ketamine and analogs were similar, sharing a π-stack with F297. Libdock scores were deschloroketamine m model generated with Assay Central had a ROC of 0.86. The probability of activity at 15 μM for ketamine and analogs was predicted with this model. Deschloroketamine scores corresponded to the experimental Km, but the model was unable to predict activity with fluoroketamine. The binding pocket of CYP2B6 also suggested a hydrophobic component to substrate docking, on the basis of a strong linear correlation (R2 = 0.92) between lipophilicity (AlogP) and metabolism (log Km) of ketamine and analogs. This property may be the simplest design criteria to use when considering similar compounds and CYP2B6 affinity.

Enantioselective Syntheses of (S)-Ketamine and (S)-Norketamine

An efficient asymmetric synthesis of (S)-ketamine (esketamine) based on catalytic enantioselective transfer hydrogenation of cyclic enone and [3,3]-sigmatropic rearrangement of allylic cyanate to isocyanate is described. The catalytic asymmetric route afforded esketamine (99.9% ee) in 50% overall yield over four steps and forms the basis for the future development of the drug substance. Furthermore, the route was applicable to the synthesis of (S)-norketamine via simple hydrolysis of isocyanate penultimate.

Expedient preparation of active pharmaceutical ingredient ketamine under sustainable continuous flow conditions

A robust three-step continuous flow procedure is presented for the efficient and sustainable preparation of active pharmaceutical ingredient ketamine. The procedure relies on the main assets of continuous flow processing, starts from commercially available chemicals, utilizes low toxicity reagents and a FDA class 3 solvent under intensified conditions. The procedure features a unique hydroxylation step with molecular oxygen, a fast imination relying on triisopropyl borate and a thermolysis employing Montmorillonite K10 as a heterogeneous catalyst, all three steps being performed in ethanol. The three individual steps can be run independently or can be concatenated, thus providing a compact yet efficient setup for the production of ketamine. The scalability of the critical hydroxylation step was assessed in a commercial pilot continuous flow reactor. The process can also be adapted for the preparation of ketamine analogs. A thorough computational study on the backbone rearrangement of the cyclopentylphenylketone scaffold under thermal stress rationalizes the experimental selectivity and the various experimental observations reported herein.

A Method for the Catalytic Enantioselective Synthesis of Chiral α-Azido and α-Amino Ketones from Racemic α-Bromo Ketones, and Its Generalization to the Formation of Bonds to C, O, and S

A new and practical method has been developed for the transformation of racemic α-bromo ketones to chiral α-azido and α-amino ketones with high enantioselectivity using phase transfer, ion-pair mediated reactions with a recoverable chiral quaternary salt (10 mol %) as catalyst in fluorobenzene-water. The process has been generalized to a variety of other attachments including of C, O, S, and NHR.

PROCESS FOR SYNTHESIS AND PURIFICATION OF (2R,6R)-HYDROXYNORKETAMINE

A process for the preparation of (2R,6R)-hydroxynorketamine is provided. The process requires no chromatography purification and affords the (2R,6R)-hydroxynorketamine in eight steps with a 26% overall yield and greater than 97% purity.