Anti-depression compound, pharmaceutical composition and method for treating depression and other diseases

Abstract

In some aspects, the disclosure relates to pharmaceutical compounds useful in the treatment of depression and / or related diseases. In another aspect, a pharmaceutical composition comprises a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier thereof. In yet another aspect, a method of treating depression or various other diseases comprises administering the pharmaceutical composition to an individual in need thereof.

Description

[0001] Cross-references to related applications

[0002] This application claims priority under 35 USC §119(e) to U.S. Application No. 63 / 451,891, filed March 13, 2023; U.S. Application No. 63 / 537,744, filed September 11, 2023; and U.S. Application No. 63 / 605,144, filed December 1, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Depression is one of the most common causes of disability among all medical conditions, with a lifetime prevalence of approximately 17%. It often appears early in life, may have a chronic course, and can negatively impact the prognosis of other medical conditions such as coronary artery disease, diabetes, and osteoporosis.

[0004] Depression is characterized by depressed mood and a significant loss of interest in or pleasure from activities. Other symptoms include significant weight loss or gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, impaired or indecisive thinking or concentration, recurrent thoughts of death, suicidal ideation, or suicide attempts. Various physical symptoms may also be present. While depressive mood is common, especially after experiencing life's setbacks, a depressive disorder is only diagnosed when symptoms reach a certain threshold and persist for at least two weeks. The severity of depression can range from mild to severe. It is often episodic, but can also relapse or become chronic. Some people experience only one episode and fully recover to their pre-disordered functional level. However, more than 50% of those with an initial single major depressive episode will eventually experience another episode.

[0005] Depression is more common in women than men. The estimated point prevalence of unipolar depressive episodes is 1.9% in men and 3.2% in women; and over a 12-month period, 5.8% of men and 9.5% of women will experience a depressive episode. These prevalence figures vary by population and may be higher in some groups. A World Health Organization study reported that depression is the leading cause of Years Lived with Disability (YLD) globally and the fourth leading cause of Disability-Adjusted Life-Years (DALY). Disability-adjusted life years refer to the reduction in an individual's healthy lifespan and are an indicator that comprehensively considers premature mortality.

[0006] About half a century ago, the accidental discovery of monoamine oxidase inhibitors and tricyclic antidepressants revolutionized the treatment of depression. Since then, a host of new drugs with fewer side effects have emerged, greatly improving our ability to safely treat large numbers of patients. However, most of these new drugs exert their main biochemical effects by increasing intrasynaptic monoamine levels, thereby enhancing or strengthening the effects of existing medications.

[0007] Unfortunately, existing antidepressants take weeks to months to fully take effect, during which time patients continue to suffer from symptoms and still face the risk of self-harm and impairment in their personal and professional lives. In fact, the weeks-long lag in the onset of action of traditional antidepressants is widely recognized as a major limitation, especially in the first nine days of starting treatment, leading to significant morbidity and a high risk of suicidal behavior. Therefore, a drug treatment strategy that can take effect rapidly within hours or days and maintain its effectiveness would have a significant impact on public health.

[0008] Recently, a "priming and adaptation" paradigm has been proposed to explain the delayed onset of action in antidepressant therapy. This paradigm posits that the effect of acute administration is mediated by initial perturbations of direct target proteins (such as binding to monoamine transporters to inhibit monoamine reuptake); however, with repeated administration, the same initial event leads to persistent adaptive changes in key neural networks over time, resulting in a stable, long-term antidepressant effect. Therefore, this paradigm suggests that the delayed onset of action of existing drug therapies is due to their initial action on proteins located upstream of the target genes that ultimately mediate the antidepressant effect. In this context, the main systems considered to mediate the delayed adaptive effect of antidepressants are neurotrophic signaling pathways and the glutamatergic system.

[0009] Several research teams have explored the effects of antidepressants on neurotrophic signaling pathways. The context of this application relates to the role of the glutamatergic system (particularly the NMDA system) in the action of antidepressants. NMDA receptor antagonists have demonstrated antidepressant effects in various animal models of depression, including inescapable stressor application, forced swimming and tail-suspended immobility tests, learned helplessness depression models, and animals subjected to chronic mild stress programs. In male Wistar rats, a single administration of the NMDA antagonist ketamine interfered with the induction of behavioral hopelessness, with effects lasting up to 10 days. Furthermore, repeated administration of different classes of antidepressants within a timeframe consistent with their delayed therapeutic effects induced changes in NMDA subunit mRNA expression and the binding of radioligands to these receptors in brain regions associated with the pathophysiology of depression.

[0010] Multiple pieces of evidence also suggest that glutamatergic system dysfunction may play an important role in the pathophysiology of depression. Notably, a recent study by Sanacora et al. showed that in 29 medication-naïve subjects with unipolar major depressive disorder, occipital cortex glutamate levels were significantly elevated compared to 28 age- and sex-matched healthy controls. These data collectively support the hypothesis of regional alterations in glutamatergic signaling in mood disorders. Finally, in clinical trials, glutamatergic modulators lamotrigine and riluzole (both glutamate release inhibitors) have been shown to possess antidepressant properties.

[0011] Ketamine has been used to treat breakthrough pain (BTP) in patients with chronic pain. In these patients, 10-50 mg of ketamine is administered intranasally, with a dose increment of 10 mg every 90 seconds. This intranasal administration resulted in lower levels of breakthrough pain in patients receiving ketamine compared to the placebo group. Side effects from this administration method are minimal.

[0012] Transdermal administration of ketamine has also been used to treat refractory neuropathic pain. Results showed that subjects receiving a 75 mg dose experienced significant improvements in pain-related disability and subjective psychological well-being. Azevedo et al. reported the results of a randomized, double-blind, placebo-controlled trial in which racemic ketamine was administered via a transdermal delivery system following lidocaine epidural block during minor abdominal gynecological surgery. At the end of the surgery, controlled-release transdermal patches containing either ketamine (25 mg / 24 hours) or placebo were applied. The rescue analgesia time in the ketamine group (230 ± 112 minutes) was longer than that in the placebo group (94 ± 54 minutes).

[0013] Ketamine is not approved for use as an antidepressant, but its enantiomer, ethacrylone, was developed as a nasal spray for the treatment of treatment-resistant depression and was approved in the United States for this indication in March 2019. However, ethacrylone has limited efficacy, with only two out of five clinical trials showing significant efficacy against treatment-resistant depression. Despite evidence supporting the efficacy of ketamine and ethacrylone in treating depression, consensus remains lacking regarding dosing regimens and the long-term effects and safety of treatment. Ketamine can produce euphoria and dissociative hallucinations at higher doses, thus posing a potential for abuse. Furthermore, long-term ketamine use has been associated with cognitive deficits, urinary tract toxicity, hepatotoxicity, and other complications in some individuals. These adverse effects may limit the use of ketamine and ethacrylone in the treatment of depression.

[0014] (R,S)-ketamine is rapidly metabolized in vivo to form a series of metabolites, including 12 unique hydroxynorketamines (HNKs). These metabolites are distinguished by their unique stereochemical structures, which are derived from the metabolism of ketamine in vivo, through hydroxylation at positions 4, 5, or 6 on the cyclohexane ring and two stereocenters. See Highland et al., “Hydroxynorketamine: Pharmacology and Potential Therapeutic Uses,” Pharmacology Reviews, April 2021, 73(2):763-791.

[0015] There is still a need to improve treatments for depression, neuropathic pain, and other conditions such as anxiety, asthma, and seizures. In particular, there is a need to develop compounds that can avoid some or all of the aforementioned drawbacks of currently available treatments, including ketamine. Summary of the Invention

[0016] In one respect, this disclosure relates to a compound having the structure of formula (I):

[0017]

[0018] R1, R2, R3, R4, R5, R6, R7, R8, and R9 are each independently selected from the group consisting of: electron pairs, H, halogens, OH, protected hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, acyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, phenyl groups, carbonate groups, carboxyl groups, esters, hydroperoxy groups, peroxy groups, ethers, hemiacetals, hemiketals, acetals, ketals, orthoesters, methylenedioxy groups, orthocarbonates, carboxamides, amines, imines, amides, azides, azo groups, cyanates, nitrates, nitriles, isonitriles, nitrites, nitro groups, pyridyl groups, thiols, thioethers, sulfinyl groups, sulfonyl groups, thiocyanates, thiocarbonyl groups, phosphate groups, and heterocyclic groups.

[0019] Optionally, the alkyl, alkenyl, alkynyl, or acyl group is substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NR. A R B —S-alkyl, —SO-alkyl, —SO2-alkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein R A and R B Each is independently selected from hydrogen and C. 1-4 alkyl;

[0020] The aryl or heteroaryl group, whether present alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C. 1-4 Alkyl, —C(O)O—C 1-4 Alkyl, NRc R D —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R C and R D Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein

[0021] It can be a single bond or a double bond, and must satisfy at least one condition. It is a single bond; wherein at least one of R1, R2, R3, R4 and R5 is a halogen; and X is C or N; or a pharmaceutically acceptable salt or ester thereof.

[0022] In some embodiments, R1 in formula (I) is a halogen. In some embodiments, the halogen is selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen is chlorine (Cl).

[0023] In some embodiments, R6 in formula (I) is hydrogen. In some embodiments, R7, R8 and / or R9 in formula (I) are OH.

[0024] In some implementations, two All are single bonds. In some embodiments, X in formula (I) is carbon (C). In some embodiments, X in formula (I) is nitrogen (N).

[0025] In another aspect of this disclosure, a compound has the structure shown in formula (II):

[0026]

[0027] Or its pharmaceutically acceptable salts or esters.

[0028] In some embodiments, R6 in formula (II) is hydrogen. In some embodiments, R7, R8, and / or R9 in formula (II) are OH. In some embodiments, both... All are single bonds. In other embodiments, one One is a single key, the other It is a double bond.

[0029] On the other hand, this disclosure relates to compounds having the structure of formula (III):

[0030]

[0031] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10Each group is independently selected from the group consisting of: electron pairs, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate, carboxylate, carboxyl, ester, hydroperoxy, peroxy, ether, hemiacetal, hemiketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate, carboxamide, amine, imine, amide, azido, azo, cyanate, nitrate, nitrile, isonitrile, nitrite, nitro, pyridyl, thiol, thioether, sulfinyl, sulfonyl, thiocyanate, thiocarbonyl, phosphate, and heterocyclic groups; optionally, wherein the alkyl, alkenyl, alkynyl, or acyl group is substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NR A R B —S-alkyl, —SO-alkyl, —SO2-alkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein R A and R B Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein the aryl or heteroaryl group, whether alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1-4 Alkyl, —C(O)O—C 1-4 Alkyl, NR C R D —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R C and R D Each is independently selected from hydrogen and C. 1-4 Alkyl group; or a pharmaceutically acceptable salt or ester thereof. In some embodiments, R8 in formula (III) is hydrogen.

[0032] On the other hand, this disclosure relates to compounds having the structure of formula (IV):

[0033]

[0034] R1, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from the group consisting of: electron pairs, H, halogens, OH, protected hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, acyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, phenyl groups, carbonates, carboxyl groups, esters, hydroperoxy groups, peroxy groups, ethers, hemiacetals, hemiketals, acetals, ketals, orthoesters, methylenedioxy groups, orthocarbonates, carboxamides, amines, imines, amides, azides, azo groups, cyanates, nitrates, nitriles, isonitriles, nitrites, nitro groups, pyridyl groups, thiols, thioethers, sulfinyl groups, sulfonyl groups, thiocyanates, thiocarbonyl groups, phosphate groups, and heterocyclic groups; optionally, the alkyl, alkenyl, alkynyl, or acyl groups are substituted by one or more substituents independently selected from the group consisting of: halogens, -OH, alkyl, -O-alkyl, NR A R B —S-alkyl, —SO-alkyl, —SO2-alkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein R A and R B Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein the aryl or heteroaryl group, whether alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1-4 Alkyl, —C(O)O—C 1-4 Alkyl, NR C R D —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R C and R D Each is independently selected from hydrogen and C. 1-4 Alkyl group; wherein at least one of R1, R2, R3, R4 and R5 is a halogen; or a pharmaceutically acceptable salt or ester thereof.

[0035] In some embodiments, R1 in formula (IV) is a halogen. In some embodiments, the halogen is selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen is chlorine (Cl).

[0036] On the other hand, a compound has the structure shown in formula (V):

[0037]

[0038] R1, R2, R3, R4, R5, R6, and R7 are each independently selected from the group consisting of: electron pairs, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate, carboxyl, carboxyl, ester, hydroperoxy, peroxy, ether, hemiacetal, hemiketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate, carboxamide, amine, imine, amide, azido, azo, cyanate, nitrate, nitrile, isonitrile, nitrite, nitro, pyridyl, thiol, thioether, sulfinyl, sulfonyl, thiocyanate, thiocarbonyl, phosphate, and heterocyclic groups; optionally, wherein the alkyl, alkenyl, alkynyl, or acyl group is substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NR A R B —S-alkyl, —SO-alkyl, —SO2-alkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein R A and R B Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein the aryl or heteroaryl group, whether alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1-4 Alkyl, —C(O)O—C 1-4 Alkyl, NR C R D —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R C and R D Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein

[0039] It can be a single bond or a double bond, and must satisfy at least one condition. It is a single bond; wherein at least one of R1, R2, R3, R4 and R5 is a halogen; and wherein X is carbon (C) or nitrogen (N); or a pharmaceutically acceptable salt or ester thereof.

[0040] In some embodiments, R1 and R2 are each methyl groups.

[0041] In some implementations, at least one of the formulas (V) It is a double bond.

[0042] On the other hand, a pharmaceutical composition comprises a therapeutically effective amount of a compound having any of the above-described structural formulas, and a pharmaceutically acceptable carrier thereof.

[0043] In another aspect, a method of treating depression, anxiety, asthma, or pain includes administering a therapeutically effective amount of the pharmaceutical composition to an individual in need.

[0044] In another aspect, a method of inducing anesthesia or sedation includes administering a therapeutically effective amount of the pharmaceutical composition to an individual in need. Attached Figure Description

[0045] Figure 1 The HPLC analysis results of the product 2-(2-chlorophenyl)-2-(methylamino)cyclopentane-1-one hydrochloride are shown.

[0046] Figure 2 The mass spectrometry results of the product 2-(2-chlorophenyl)-2-(methylamino)cyclopentane-1-one hydrochloride are shown.

[0047] Figure 3 The 1H-NMR analysis results of the product 2-(2-chlorophenyl)-2-(methylamino)cyclopentane-1-one hydrochloride are shown.

[0048] Figure 4 The 13C-NMR analysis results of the product 2-(2-chlorophenyl)-2-(methylamino)cyclopentane-1-one hydrochloride are shown.

[0049] Figure 5 Thermogravimetric analysis (TGA) results of the product 2-(2-chlorophenyl)-2-(methylamino)cyclopentane-1-one hydrochloride are shown.

[0050] Figure 6 Results of agonist mode detection using the GPCR biosensor of 2-(2-chlorophenyl)-2-(methylamino)cyclopentan-1-one are shown.

[0051] Figure 7 Results of antagonist mode detection using the GPCR biosensor of 2-(2-chlorophenyl)-2-(methylamino)cyclopentan-1-one are shown. Detailed Implementation

[0052] This disclosure describes novel pharmaceutical compounds. In one aspect, this disclosure relates to compounds having the structure of formula (I):

[0053]

[0054] R1, R2, R3, R4, R5, R6, R7, R8, and R9 are each independently selected from the group consisting of: electron pairs, H, halogens, OH, protected hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, acyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, phenyl groups, carbonate groups, carboxyl groups, esters, hydroperoxy groups, peroxy groups, ethers, hemiacetals, hemiketals, acetals, ketals, orthoesters, methylenedioxy groups, orthocarbonates, carboxamides, amines, imines, amides, azido groups, azo groups, cyanates, nitrates, nitriles, isonitriles, nitrites, nitro groups, pyridyl groups, thiols, thioethers, sulfinyl groups, sulfonyl groups, thiocyanates, thiocarbonyl groups, phosphate groups, and heterocyclic groups; optionally, the alkyl, alkenyl, alkynyl, or acyl groups are substituted by one or more substituents independently selected from the group consisting of: halogens, -OH, alkyl, -O-alkyl, NR A R B —S-alkyl, —SO-alkyl, —SO2-alkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein R A and R B Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein the aryl or heteroaryl group, whether alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1-4 Alkyl, —C(O)O—C 1-4 Alkyl, NR C R D —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R C and R D Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein

[0055] It can be a single bond or a double bond, and must satisfy at least one condition. It is a single bond; wherein at least one of R1, R2, R3, R4 and R5 is a halogen; and wherein X is carbon (C) or nitrogen (N); or a pharmaceutically acceptable salt or ester thereof.

[0056] In some embodiments, R1 in formula (I) is a halogen. In some embodiments, the halogen is selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen is chlorine (Cl).

[0057] In some embodiments, R6 in formula (I) is a methyl group. In some embodiments, R6 in formula (I) is hydrogen. In some embodiments, R6 in formula (I) is an ethyl group. In some embodiments, R6 in formula (I) is C6. 1-4 alkyl.

[0058] In some embodiments, X in formula (I) is nitrogen (N). In some embodiments, X in formula (I) is carbon (C).

[0059] In some implementations, two All are single keys.

[0060] In another aspect of this disclosure, a compound has the structure shown in formula (II):

[0061]

[0062] Or its pharmaceutically acceptable salts or esters.

[0063] In some embodiments, R6 in formula (II) is hydrogen. In some embodiments, R7, R8, and / or R9 in formula (II) are OH. In some embodiments, both... All are single bonds. In other embodiments, one One is a single key, the other It is a double bond.

[0064] In some embodiments, a compound has a structure selected from the group consisting of:

[0065]

[0066] as well as Or its pharmaceutically acceptable salt, ester or ether.

[0067] In some embodiments, a compound has a structure selected from the group consisting of:

[0068]

[0069] Or its pharmaceutically acceptable salt, ester or ether.

[0070] On the other hand, this disclosure relates to compounds having the structure of formula (III):

[0071]

[0072] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10Each group is independently selected from the group consisting of: electron pairs, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate, carboxyl, carboxyl, ester, hydroperoxy, peroxy, ether, hemiacetal, hemiketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate, carboxamide, amine, imine, amide, azido, azo, cyanate, nitrate, nitrile, isonitrile, nitrite, nitro, pyridyl, thiol, thioether, sulfinyl, sulfonyl, thiocyanate, thiocarbonyl, phosphate, and heterocyclic groups; optionally, wherein the alkyl, alkenyl, alkynyl, or acyl group is substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NR A R B —S-alkyl, —SO-alkyl, —SO2-alkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein R A and R B Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein the aryl or heteroaryl group, whether alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1-4 Alkyl, —C(O)O—C 1-4 Alkyl, NR C R D —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R C and R D Each is independently selected from hydrogen and C. 1-4 Alkyl group; or a pharmaceutically acceptable salt or ester thereof. In some embodiments, R8 in formula (III) is hydrogen.

[0073] In some embodiments, the compounds disclosed herein have the following structures:

[0074]

[0075] Or its pharmaceutically acceptable salt, ester or ether.

[0076] On the other hand, this disclosure relates to compounds having the structure of formula (IV):

[0077]

[0078] R1, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from the group consisting of: electron pairs, H, halogens, OH, protected hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, acyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, phenyl groups, carbonate groups, carboxyl groups, esters, hydroperoxy groups, peroxy groups, ethers, hemiacetals, hemiketals, acetals, ketals, orthoesters, methylenedioxy groups, orthocarbonates, carboxamides, amines, imines, amides, azides, azo groups, cyanates, nitrates, nitriles, isonitriles, nitrites, nitro groups, pyridyl groups, thiols, thioethers, sulfinyl groups, sulfonyl groups, thiocyanates, thiocarbonyl groups, phosphate groups, and heterocyclic groups; optionally, the alkyl, alkenyl, alkynyl, or acyl groups are substituted by one or more substituents independently selected from the group consisting of: halogens, -OH, alkyl, -O-alkyl, NR A R B —S-alkyl, —SO-alkyl, —SO2-alkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein R A and R B Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein the aryl or heteroaryl group, whether alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1-4 Alkyl, —C(O)O—C 1-4 Alkyl, NR C R D —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R C and R D Each is independently selected from hydrogen and C. 1-4 Alkyl group; wherein at least one of R1, R2, R3, R4 and R5 is a halogen; or a pharmaceutically acceptable salt or ester thereof.

[0079] In some embodiments, R1 in formula (IV) is a halogen. In some embodiments, the halogen is selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen is chlorine (Cl).

[0080] In some embodiments, the compounds disclosed herein have the following structures:

[0081]

[0082] Or its pharmaceutically acceptable salt, ester or ether.

[0083] On the other hand, the compound has the structure shown in formula (V):

[0084]

[0085] R1, R2, R3, R4, R5, R6, and R7 are each independently selected from the group consisting of: electron pairs, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate, carboxyl, carboxyl, ester, hydroperoxy, peroxy, ether, hemiacetal, hemiketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate, carboxamide, amine, imine, amide, azido, azo, cyanate, nitrate, nitrile, isonitrile, nitrite, nitro, pyridyl, thiol, thioether, sulfinyl, sulfonyl, thiocyanate, thiocarbonyl, phosphate, and heterocyclic groups; optionally, wherein the alkyl, alkenyl, alkynyl, or acyl group is substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NR A R B —S-alkyl, —SO-alkyl, —SO2-alkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein R A and R B Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein the aryl or heteroaryl group, whether alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1-4 Alkyl, —C(O)O—C 1-4 Alkyl, NR C R D —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R C and R D Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein

[0086] It can be a single bond or a double bond, and must satisfy at least one condition. It is a single bond; wherein at least one of R1, R2, R3, R4 and R5 is a halogen; and wherein X is carbon (C) or nitrogen (N); or a pharmaceutically acceptable salt or ester thereof.

[0087] In some embodiments, R1 and R2 are each methyl groups.

[0088] In some implementations, at least one of the formulas (V) It is a double bond.

[0089] In some embodiments, the compound is

[0090]

[0091] Or its pharmaceutically acceptable salts or esters.

[0092] In other aspects of this disclosure, a compound has a structure selected from the group consisting of:

[0093]

[0094]

[0095]

[0096]

[0097] as well as

[0098] Or its pharmaceutically acceptable salt, ester or ether.

[0099] Compound Synthesis

[0100] In some instances, the enantioselective synthesis of (S)-Ketamine and (S)-Norketamine described in C. Chen et al., Organic Letters, Vol. 21, No. 16, 2019, pp. 6575-6578 (available at doi.org / 10.1021 / acs.orglett.9b02575), can be used, with appropriate modifications to the reagents, to obtain the structures described herein, which will be apparent to those skilled in the art. In some instances, compounds can be synthesized based on the technique described by Zhang et al., Organic Letters, Vol. 19, No. 1124, 2017, which achieves a concise synthesis of ketamine through direct nitration of a cyclic ketone, followed by selective reduction of the nitro functional group to obtain a primary amine, and then monomethylation via reductive amination. In some instances, the compounds described herein can be synthesized based on the technique described by J. Highland et al., "Hydroxynorketamine Pharmacokinetics and Antidepressant Behavioral Effects of (2,6)-and (5R)-Methyl-(2R,6R)-hydroxynorketamines," 2022, Vol. 13, No. 4, pp. 510-523. Another method, as described by Stevens et al., 1965, Vol. 30, p. 2962, achieves a concise synthesis of ketamine through α-bromination of the starting material, followed by a one-step formation of an α-hydroxy and Schiff base intermediate, and rearrangement to obtain the target product. The starting material 2-(2-chlorophenyl)cyclopentanone, after α-bromination at the α-position, can undergo a substitution reaction with methylhydroxylamine, followed by reduction of the resulting intermediate. Alternatively, the brominated intermediate can react directly with methylamine to yield the target product.

[0101] In some respects, the compound can be converted into a pharmaceutically acceptable salt using techniques well known to those skilled in the art. For example, sodium and potassium salts can be prepared, respectively, by treating the compound with a suitable sodium or potassium base (such as sodium hydroxide or potassium hydroxide). Esters and ethers of the compound can be prepared according to methods described in publications such as *Advanced Organic Chemistry* (J. March, 4th edition, 1992, John Wiley & Sons) or *J. Med. Chemistry* (1992, Vol. 35, pp. 145-151).

[0102] Pharmaceutical Compositions and Methods of Use

[0103] The compounds described in this article are particularly suitable for the treatment of depression, and may also be used to treat a variety of other conditions and indications, including anxiety, asthma, anesthesia / sedation, pain, and seizures.

[0104] Pharmaceutical compositions may contain pharmaceutically acceptable carriers that facilitate the formulation of the active ingredient into a pharmaceutically acceptable composition. As used herein, the term "pharmaceutically acceptable carrier" is synonymous with "pharmacologically acceptable carrier" and refers to any carrier that, after administration, will not substantially produce long-term or permanent harmful effects, including terms such as "pharmaceutically acceptable excipient," "stabilizer," "diluent," "additive," "excipient," or "adjuvant." Such carriers are typically mixed with or used to dilute or encapsulate the active compound and can be in solid, semi-solid, or liquid dosage forms. The active ingredient is soluble in the desired carrier or diluent or delivered in suspension. A wide variety of pharmaceutically acceptable carriers can be used, including but not limited to aqueous media (such as water, physiological saline, glycine, hyaluronic acid, etc.); solid carriers (such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc.); solvents; dispersion media; coating materials; antibacterial and antifungal agents; isotonic and absorption-delaying agents; or any other inactive ingredient. The choice of pharmaceutically acceptable carrier depends on the route of administration. Any pharmaceutically acceptable carrier that is incompatible with the active ingredient is considered for use in a pharmaceutically acceptable composition. Non-limiting examples of specific uses of such drug carriers can be found in *Pharmaceutical Dosage Forms and Drug Delivery Systems* (edited by Howard C. Ansel et al., Lippincott Williams & Wilkins, 7th edition, 1999); *Remington: The Science and Practice of Pharmaceuticals* (edited by Alfonso R. Gennaro, Lippincott Williams & Wilkins, 20th edition, 2000); *Goodman & Gilman's The Pharmacological Basis of Therapeutics* (edited by Joel G. Hardman et al., McGraw-Hill Professional, 10th edition, 2001); and *Handbook of Pharmaceutical Excipients* (Raymond). C. Rowe et al., American Association of Pharmacists (APhA) Publications, 4th Edition, 2003. These protocols are standard procedures, and any modifications are within the capabilities of those skilled in the art and can be learned from the teachings herein.

[0105] Compounds intended for use in humans or other mammals should generally have extremely high purity. Purity refers to the ratio of the compound's mass to the total mass of the sample after any purification steps. Typically, the purity level is at least about 95%, and more commonly at least about 96%, about 97%, about 98%, or higher. For example, purity levels can be about 98.5%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher.

[0106] The compounds described herein exist in multiple optical isomers (enantiomers) and can be provided as racemic mixtures or obtained by separating one of the enantiomers. In the latter case, the purity mentioned above refers to enantiomer purity.

[0107] The compositions described herein may be administered orally, nasally, topically, subcutaneously, intramuscularly, intravenously, or otherwise. For example, antidepressants may be formulated as nasal sprays, as described in U.S. Patent 8,785,500B2, the contents of which are incorporated herein by reference.

[0108] The pharmaceutical compositions may optionally contain other pharmaceutically acceptable components (or pharmaceutical components), including but not limited to buffers, preservatives, osmolarity regulators, salts, antioxidants, osmolality regulators, physiological substances, pharmacological substances, fillers, emulsifiers, wetting agents, sweeteners, or flavoring agents. Various buffers and pH adjustment methods may be used to prepare the pharmaceutical compositions disclosed herein, provided the resulting formulation is pharmaceutically acceptable. Such buffers include, but are not limited to, acetate buffer, citrate buffer, phosphate buffer, neutral buffered saline, phosphate buffered saline, and borate buffer. The pH of the composition may be adjusted as needed using acids or bases. Pharmaceutically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Useful preservatives include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, stable oxychloride compositions, and chelating agents such as DTPA or DTPA-diamide, calcium DTPA, and CaNaDTPA-diamide. Osmoregulators that can be used in pharmaceutical compositions include, but are not limited to, salts (such as sodium chloride, potassium chloride), mannitol or glycerol, and other pharmaceutically acceptable osmoregulators. Pharmaceutical compositions may be provided in salt form and can form with a variety of acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, etc. Salts are often more soluble in water or other protic solvents than their corresponding free base forms. These, along with other substances known in the field of pharmacology, may be included in pharmaceutical compositions.

[0109] Examples of adjuvants and / or excipients that may be mentioned include: cremofer, poloxamer, benzalkonium chloride, sodium lauryl sulfate, glucose, glycerin, magnesium stearate, polyethylene glycol, starch, dextrin, lactose, cellulose, sodium carboxymethyl cellulose, talc, agar, mineral oil, animal oil, vegetable oil, organic and mineral waxes, paraffin, gels, propylene glycol, benzyl alcohol, dimethylacetamide, ethanol, polyethylene glycol, Tween 80, Solutol HS15, and water. The active substance may also be administered directly in a suitable form, such as in capsules, without the use of a carrier or diluent.

[0110] The pharmaceutical composition may contain sufficient amounts of a therapeutic compound to allow for routine administration to an individual. Unit dosage forms may contain, for example, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a therapeutic compound. In other aspects, unit dosage forms may contain, for example, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of a therapeutic compound. In other aspects of this embodiment, the pharmaceutical compositions disclosed herein may comprise, for example, a therapeutic compound of about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg to about 1,500 mg. In other aspects of this embodiment, the pharmaceutical composition disclosed herein may contain, for example, about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about Therapeutic compounds of 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,000 mg, or about 5 mg to about 250 mg.

[0111] The pharmaceutical compositions described herein may contain pharmaceutically acceptable solvents. A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gas (solute) to form a solution. Solvents that can be used in pharmaceutical compositions include, but are not limited to, pharmaceutically acceptable polar aprotic solvents, pharmaceutically acceptable polar protic solvents, and pharmaceutically acceptable nonpolar solvents. Pharmaceutically acceptable polar aprotic solvents include, but are not limited to, dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile (MeCN), and dimethyl sulfoxide (DMSO). Pharmaceutically acceptable polar protic solvents include, but are not limited to, acetic acid, formic acid, ethanol, n-butanol, 1-butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol, n-propanol, isopropanol, 1,2-propanediol, methanol, glycerol, and water. Pharmaceutically acceptable nonpolar solvents include, but are not limited to, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, N-methylpyrrolidone (NMP), and diethyl ether.

[0112] The administration method and dosage range applicable to a particular situation depend on the species to be treated and the state of the corresponding condition or disease, and can be optimized using techniques known in the art. In most cases, the daily dose of the active compound in a patient is from 0.0005 mg to 15 mg per kilogram, more commonly from 0.001 mg to 7.5 mg per kilogram. Administration can be a single dose or a cumulative dose (continuous administration), which can be readily determined by those skilled in the art. For example, treatment of bacterial infections may include a single administration of an effective dose of the pharmaceutical composition disclosed herein. Alternatively, treatment may include multiple administrations of an effective dose of the pharmaceutical composition over a period of time, such as once daily, twice daily, three times daily, every few days, or weekly. The timing of administration varies from person to person, depending on factors such as the severity of individual symptoms. For example, an effective dose of the pharmaceutical composition disclosed herein may be administered to an individual once daily indefinitely until the individual no longer requires treatment. Those skilled in the art will recognize that individual conditions can be monitored throughout treatment, and the effective dosage of the pharmaceutical composition disclosed herein can be adjusted accordingly.

[0113] Pharmaceutical compositions may contain any conventional, non-toxic, pharmaceutically acceptable carriers, adjuvants, or mediators. In some cases, the pH of the formulation may be adjusted with acceptable pharmaceutical or food-grade acids, bases, or buffers to enhance the stability of the formulation composition or its delivery form.

[0114] Liquid dosage forms for oral administration include acceptable pharmaceutical or food-grade emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethyl sulfoxide (DMSO), dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0115] Solid dosage forms for oral administration include capsules, tablets, lozenges, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, acceptable pharmaceutical or food-grade excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or spreaders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof; and j) sweeteners, flavoring agents, aroma agents, and mixtures thereof. For capsules, lozenges, tablets and pills, the dosage forms may also contain buffers.

[0116] Solid dosage forms such as tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulations. They may optionally contain light-blocking agents, and their composition may be designed to release the active ingredient only in or preferentially in a segment of the intestine, or optionally in a delayed or extended manner. Examples of usable encapsulation compositions include polymeric substances and waxes. Extended-release tablet formulations are also described in U.S. Patent No. 5,942,244.

[0117] The composition may comprise the compounds disclosed herein, alone or in combination with other therapeutic compounds. A therapeutic compound is a compound that provides pharmacological activity or other direct effects in the diagnosis, cure, relief, treatment, or prevention of disease, or affects the structure or any function of a human or animal body. The therapeutic compounds disclosed herein may be used in the form of pharmaceutically acceptable salts, solvates, or solvates of salts; for example, hydrochloride is a pharmaceutically acceptable salt. Furthermore, the therapeutic compounds disclosed herein may be provided in racemate form or as a single enantiomer, including R-enantiomers or S-enantiomers. Thus, the therapeutic compound may comprise only the R-enantiomer, only the S-enantiomer, or both the R-enantiomer and the S-enantiomer. In some aspects, the therapeutic compound may have anti-inflammatory activity, such as a non-steroidal anti-inflammatory drug (NSAID). NSAIDs are a large class of therapeutic compounds with analgesic, anti-inflammatory, and antipyretic properties, reducing inflammation by inhibiting cyclooxygenase activity. NSAIDs include, but are not limited to: aceclofenac, acemetacin, actarit, alcofenac, alminoprofen, amfenac, aloxiprin, aminophenazone, antraphenine, aspirin, azapropazone, benorilate, benzoxaprofen, benzyldamine, butibufen, celecoxib, chlorthenoxazine, and choline.salicylate, clometacin, dexketoprofen, diclofenac, diflunisal, emorfazone, epirizoole, etodolac, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxyethylsalicylic acid salicylate, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, lactylphenetidin, loxoprofen, lumiracoxib, mefenamic acid, meloxicam, metamizole, metiazinic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid The following are listed: oxametacin, phenacetin, pipebuzone, pranoprofen, propyphenazone, proquazone, protizinic acid, rofecoxib, salicylamide, salsalate, sulindac, suprafen, tiaramide, tinoridine, tolfenamic acid, valdecoxib, and zomepirac.

[0118] NSAIDs can be classified according to their chemical structure or mechanism of action. Non-limiting examples of NSAIDs include: salicylic acid derivative NSAIDs, para-aminophenol derivative NSAIDs, propionic acid derivative NSAIDs, acetic acid derivative NSAIDs, enolic acid derivative NSAIDs, fenamic acid derivative NSAIDs, non-selective cyclooxygenase (COX) inhibitors, selective cyclooxygenase-1 (COX-1) inhibitors, and selective cyclooxygenase-2 (COX-2) inhibitors. NSAIDs may be propionic acid derivatives. Suitable examples of salicylic acid derivative NSAIDs include, but are not limited to: acetylsalicylic acid (aspirin), diflunisal, and salsalate. Suitable examples of para-aminophenol derivative NSAIDs include, but are not limited to: paracetamol and phenacetin. Examples of suitable propionic acid derivative NSAIDs include, but are not limited to: aminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and suprafen. Examples of suitable acetic acid derivative NSAIDs include, but are not limited to: aceclofenac, acemetacin, actarit, alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indometacin, ketorolac, metiazinic acid, mofezolac, nabumetone, naproxen, oxametacin, sulindac, and zomepirac.Examples of suitable enolic acid (oxicam) derivative NSAIDs include, but are not limited to: droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, and tenoxicam. Examples of suitable fenamic acid derivative NSAIDs include, but are not limited to: flufenamic acid, mefenamic acid, meclofenamic acid, and tolfenamic acid. Examples of suitable selective COX-2 inhibitors include, but are not limited to: celecoxib, etoricoxib, firocoxib, lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib.

[0119] Specific elements of any of the foregoing embodiments may be combined or substituted with elements of other embodiments. Furthermore, while certain advantages of embodiments of this disclosure have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments must exhibit such advantages to fall within the scope of this disclosure.

[0120] Example 1

[0121] This example illustrates the synthesis of 2-(2-chlorophenyl)-2-(methylamino)cyclopentan-1-one hydrochloride.

[0122]

[0123] This synthetic method is based on the work of Zhang et al. (Org. Lett. 2017, 19, 1124), and involves the direct nitration of cyclic ketones, followed by selective reduction of the nitro functional group to obtain a primary amine, which is then monomethylated by reductive amination and converted into a hydrochloride salt.

[0124]

[0125] Nitration of 2-(2-chlorophenyl)cyclopentan-1-one (Int-1-1)

[0126] Cerium ammonium nitrate (CAN) was thoroughly dried in a vacuum oven (100°C, 60 mbar). CAN (71 g, 130 mmol, 2 eq), a degassed solution (150 mL) of the ketone compound (12 g, 62 mmol, 1 eq) in dichloroethane (DCE), and copper acetate (Cu(OAc)₂, 12 mmol, 0.2 eq) were added to a 350 mL pressure vessel. The reaction mixture was stirred at 90°C for 18 hours under an argon atmosphere. The reaction mixture was then poured into dichloromethane (DCM) (250 mL) and stirred for 30 minutes. The reaction mixture was filtered through a Celite pad. The filtrate was washed with a 50 / 50 mixture of water and saturated NaHCO₃, separated, and the aqueous phase was extracted with dichloromethane (100 mL). The combined organic phases were washed with water (100 mL) and brine (2 x 100 mL), dried over magnesium sulfate (MgSO4), filtered, and concentrated. The resulting product (13.9 g) was used directly in the next reaction without purification.

[0127] Reduction of nitroketones (Int-1-2)

[0128] The crude nitroketone 1-1 (13.9 g) obtained in the previous step was dissolved in acetic acid (200 mL) and placed in a 1 L flask. The flask was then placed in a water bath at room temperature. Zinc powder (4 x 4 g) was added to the reaction mixture in four batches, one batch every 15 minutes, with a final batch of zinc powder (4 g) added after 2 hours. When the starting material (nitroketone 1-1, [M+H])... + =257) and intermediates (nitrosoketone, [M+H) +=226) When completely consumed, the reaction was quenched. The reaction mixture was filtered through a Celite pad and concentrated. Water (500 mL) and ethyl acetate (EtOAc, Ethyl acetate) (100 mL) were added to the resulting residue, and the mixture was stirred and separated. The aqueous phase was washed with ethyl acetate (100 mL), and the combined organic phase I (organic fraction I) was washed with water (50 mL). The combined aqueous phases were neutralized with solid sodium bicarbonate (NaHCO3) (20 g) and extracted with dichloromethane (3 x 150 mL) (organic phase II), producing a large amount of stable emulsion. Organic phase II was dried over magnesium sulfate, filtered, and concentrated (to give 2.9 g of product). According to LC-MS analysis, organic phase I contained a large amount of the target product, so organic phase I was concentrated and dissolved in a mixture of dichloromethane (100 mL), water (250 mL), and 37% hydrochloric acid (5 mL). The aqueous phase was separated, neutralized with solid sodium bicarbonate (20 g), and extracted with dichloromethane (3 x 150 mL). After separation of the organic phase, it was dried with magnesium sulfate, filtered, and concentrated (to obtain 1.3 g of product). Total mass 4.2 g (overall yield 33% (step 1 + step 2)).

[0129] Monomethylation of aminoketone (M209)

[0130] Formaldehyde (154 mg, 0.7 eq, 0.4 mL 37% w / w aqueous solution) was added to a methanol (MeOH, Methanol) solution (20 mL) of aminoketone 1-2 (1.45 g, 7 mmol, 1 eq). Sodium cyanoborohydride (NaCNBH3, Sodium cyanoborohydride) (0.37 g, 5.9 mmol, 0.85 eq) was dissolved in methanol (15 mL) in another vial. Acetic acid (0.4 mL, 7 mmol, 1 eq) was added to the stirred mixture, and the formaldehyde / aminoketone solution prepared in the previous step was added at room temperature after 1.5 minutes. The reaction was quenched with water (25 mL) after 6 minutes. The solution was partially concentrated and dissolved in diethyl ether (Et2O, Diethyl ether) (200 mL) and water (50 mL) for water-ether post-treatment. The crude mixture weighed 1.2 g (77%). This batch was combined with other similar batches and purified by reversed-phase column chromatography. The acetonitrile (ACN) fraction was concentrated, and the product was extracted with dichloromethane and ethyl acetate. The combined organic phases were dried over sodium sulfate (Na₂SO₄) and concentrated to give an off-white solid (approximately 0.8 g, HPLC purity 99%). The overall yield for all processes was approximately 8%.

[0131] Formation of M209·HCl of M209·HCl)

[0132] The previously separated M209 was dissolved in ethanol (5-7 mL), and HCl (3 mL) was added to the ethanol. After stirring for 5 minutes, the mixture was concentrated to obtain a yellow oily substance. Subsequently, it was crystallized with chloroform (CHCl3, Chloroform) / heptane. The turbid solution was concentrated to dryness to obtain an off-white solid, which was then dried under high vacuum (0.8 g, HPLC purity 99.4%). Figure 1 (FIG.1) shows the results of HPLC (High Performance Liquid Chromatography) analysis. Figure 2 (FIG.2) shows the results of the mass spectrometry analysis. Figure 3 (FIG.3) and Figure 4 (FIG.4) shows 1H-NMR (Proton Nuclear Magnetic Resonance) and... 13 C-NMR (Carbon-13 Nuclear Magnetic Resonance) analysis results. Figure 5 (FIG.5) shows the results of thermogravimetric analysis (TGA).

[0133] Example 2

[0134] This embodiment describes a method for evaluating 2-(2-chlorophenyl)-2-(methylamino)cyclopentan-1-one in a set of cell lines developed by DiscoverX that stably express non-tagged GPCRs (G protein-coupled receptors) signaling via cAMP (cyclic adenosine monophosphate). cAMP detection (Hit) cAMP assays utilize a technology developed by DiscoverX—Enzyme Fragment Complementation (EFC)—which uses β-galactosidase as a functional reporter gene to monitor GPCR activation via Gi and Gs second messenger signals in a homogeneous, non-imaging assay format.

[0135] The enzyme is cleaved into two complementary parts: EA (Enzyme Acceptor) and ED (Enzyme Donor). ED fuses with cAMP and competes with cell-produced cAMP for binding to cAMP-specific antibodies during detection. Exogenous EA complements any unbound ED-cAMP (EDcAMP) to form active β-Gal. The active enzyme then converts the chemiluminescent substrate, generating an output signal detectable on a standard microplate reader.

[0136] The Calcium No WashPLUS assay, in a live-cell, non-imaging assay format, monitors GPCR activation via the Gq second messenger signal. It utilizes a calcium-sensitive dye loaded into the cells for monitoring. Calcium mobilization in cell lines or other cell lines that stably express Gq-coupled GPCRs. Activation of the GPCR by the compound leads to the release of calcium ions from intracellular calcium stores, causing an increase in dye fluorescence intensity; this process can be measured in real time.

[0137] Cell Handling

[0138] 1. The cAMP Hunter cell line was expanded from the cryopreservation bank according to standard procedures.

[0139] 2. Seed cells in a total seeding volume of 20 μL into white-walled 384-well microplates and incubate at 37°C for an appropriate time before testing.

[0140] 3. cAMP regulation was determined using the DiscoverX HitHunter cAMP XS+ assay.

[0141] Gs Agonist Format

[0142] 1. For agonist assays, cells are co-incubated with the sample to induce a reaction.

[0143] 2. Remove the culture medium from the cells and replace it with 15 μL of 2:1 HBSS / 10 mM Hepes:cAMP XS+Ab reagent.

[0144] 3. Perform intermediate dilution of the sample stock solution to generate 4X samples in the detection buffer.

[0145] 4. Add 5 μL of 4X sample to the cells and incubate at 37°C or room temperature for 30 days or longer.

[0146] 60 minutes. Final carrier concentration: 1%.

[0147] Gi Agonist Format

[0148] 1. For agonist assays, cells were co-incubated with the sample in the presence of EC80 forskolin to induce a reaction.

[0149] 2. Remove the culture medium from the cells and replace it with 15 μL of 2:1 HBSS / 10 mM Hepes:cAMP XS+Ab reagent.

[0150] 3. Perform intermediate dilution of the sample stock solution to generate 4X sample in detection buffer containing 4X EC80 laryngin.

[0151] 4. Add 5 μL of 4X sample to the cells and incubate at 37°C or room temperature for 30 or 60 minutes. The final detection vector concentration is 1%.

[0152] Allosteric Modulation Format

[0153] 1. For allosteric effect assays, cells are pre-incubated with the sample and then induced with an agonist at an EC20 concentration.

[0154] 2. Remove the culture medium from the cells and replace it with 10 μL of 1:1 HBSS / 10 mM Hepes:cAMP XS+Ab reagent.

[0155] 3. Perform intermediate dilution of the sample stock solution to generate 4X samples in the detection buffer.

[0156] 4. Add 5 μL of 4X compound to the cells and incubate at room temperature or 37°C for 30 minutes.

[0157] 5. Add 5 μL of 4X EC20 agonist to the cells and incubate at room temperature or 37°C for 30 or 60 minutes. For Gi-coupled GPCRs, the system contains EC80 pharyngein.

[0158] Inverse Agonist Format (Gi only)

[0159] 1. For the inverse agonist assay, cells were pre-incubated with the sample in the presence of EC20 concentration of tuftin.

[0160] 2. Aspirate the culture medium from the cells and use 15 μL of 2:1 HBSS / 10 mM Hepes solution.

[0161] cAMP XS+Ab reagent replacement.

[0162] 3. Perform intermediate dilution of the sample stock solution to generate 4X sample in detection buffer containing 4X EC20 laryngin.

[0163] 4. Add 5 μL of 4X sample to the cells and incubate at 37°C or room temperature for 30 or 60 minutes. The final detection vector concentration is 1%.

[0164] Antagonist model Format)

[0165] 1. For antagonist assays, cells are pre-incubated with the sample and then challenged with an EC80 concentration of agonist.

[0166] 2. Remove the culture medium from the cells and replace it with 10 μL of 1:1 HBSS / Hepes:cAMP XS+Ab reagent.

[0167] 3. Add 5 μL of 4X compound to the cells and incubate at 37°C or room temperature for 30 minutes.

[0168] 4. Add 5 μL of 4X EC80 agonist to the cells and incubate at 37°C or room temperature.

[0169] 30 or 60 minutes. For Gi-conjugated GPCRs, the system contains EC80 laryngin.

[0170] Signal Detection

[0171] 1. After the compound incubation is complete, add 20 μL of cAMP XS + ED / CL lysis mixture and incubate for 1 hour. Then add 20 μL of cAMP XS + EA reagent and incubate for 3 hours at room temperature to generate a detection signal.

[0172] 2. After the signal is generated, use PerkinElmer Envision. TM The instrument reads the microplate and performs chemiluminescence signal detection.

[0173] Data Analysis

[0174] 1. Use the CBIS data analysis suite (ChemInnovation, CA) to analyze compound activity.

[0175] 2. For Gs agonist mode assays, percentage activity is calculated using the following formula:

[0176] %Activity = 100% × (Average RLU of test samples - Average RLU of vector control) / (Maximum average RLU of control - Average RLU of vector control)

[0177] 3. For Gs positive allosteric mode detection, the percentage adjustment is calculated using the following formula:

[0178] %Modulation = 100% × (Test sample average RLU - EC20 control average RLU) / (Maximum control average RLU - EC20 control average RLU)

[0179] 4. For Gs antagonist or negative allosteric mode detection, the percentage inhibition is calculated using the following formula:

[0180] %Inhibition = 100% × (1 - (average RLU of test samples - average RLU of vector control) / (average RLU of EC80 control - average RLU of vector control))

[0181] 5. For Gi agonist mode assays, percentage activity is calculated using the following formula:

[0182] %Activity = 100% × (1 - (average RLU of test samples - average RLU of maximum control) / (average RLU of vector control - average RLU of maximum control))

[0183] 6. For Gi positive allosteric mode detection, the percentage adjustment is calculated using the following formula:

[0184] %Modulation = 100% × (1 - (average RLU of test samples - average RLU of maximum control) / (average RLU of EC20 control - average RLU of maximum control))

[0185] 7. For Gi reverse agonist mode detection, the percentage reverse agonist activity is calculated using the following formula:

[0186] %Inverse Agonist Activity = 100% × ((Mean RLU of test samples - Mean RLU of EC20 control) / (Mean RLU of positive control - Mean RLU of EC20 control))

[0187] 8. For Gi antagonist or negative allosteric mode detection, the percentage inhibition is calculated using the following formula:

[0188] %Inhibition = 100% × (mean RLU of test samples - mean RLU of EC80 control) / (mean RLU of trichomonas positive control - mean RLU of EC80 control)

[0189] The data analysis results are summarized in the table below:

[0190]

[0191] Figure 6 and Figure 7 Results for agonist and antagonist assays are shown separately. For agonist assays, data were normalized to the maximum and minimum responses observed in the presence of control ligands and carriers.

[0192] Although the invention has been described with reference to specific embodiments, those skilled in the art will understand that numerous variations and substitutions of the above systems and techniques fall within the spirit and scope of the invention as set forth in the appended claims.

Claims

1. A compound having the structure of formula (I): R1, R2, R3, R4, R5, R6, R7, R8, and R9 are each independently selected from the group consisting of: electron pairs, H, halogens, OH, protected hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, acyl groups, aryl groups, heteroaryl groups, cycloalkyl groups, phenyl groups, carbonate groups, carboxyl groups, esters, hydroperoxy groups, peroxy groups, ethers, hemiacetals, hemiketals, acetals, ketals, orthoesters, methylenedioxy groups, orthocarbonates, carboxamides, amines, imines, amides, azides, azo groups, cyanates, nitrates, nitriles, isonitriles, nitrites, nitro groups, pyridyl groups, thiols, thioethers, sulfinyl groups, sulfonyl groups, thiocyanates, thiocarbonyl groups, phosphate groups, and heterocyclic groups. Optionally, the alkyl, alkenyl, alkynyl, or acyl group is substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NR. A R B —S-alkyl, —SO-alkyl, —SO2-alkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein R A and R B Each is independently selected from hydrogen and C. 1-4 alkyl; The aryl or heteroaryl group, whether present alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C. 1-4 Alkyl, —C(O)O—C 1-4 Alkyl, NR c R D —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R C and R D Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein It can be a single bond or a double bond, and must satisfy at least one condition. It is a single bond; wherein at least one of R1, R2, R3, R4 and R5 is a halogen; and X is C or N; or a pharmaceutically acceptable salt or ester thereof.

2. The compound according to claim 1, wherein R1 is selected from the group consisting of fluorine F, chlorine Cl, bromine Br and iodine I.

3. The compound according to claim 2, wherein R1 is Cl.

4. The compound according to claim 1, wherein R6 is methyl.

5. The compound according to claim 1, wherein R6 is C. 1-4 alkyl.

6. The compound according to claim 1, wherein R6 is hydrogen.

7. The compound according to any one of claims 1 to 6, wherein two of them All are single keys.

8. The compound according to claim 1, characterized in that, The compound has the structure shown in formula (II): Or its pharmaceutically acceptable salts or esters.

9. The compound according to any one of claims 1 to 7, characterized in that, X is N.

10. The compound according to claim 1, characterized in that, The structure is selected from the group consisting of: Or its pharmaceutically acceptable salt, ester or ether.

11. The compound according to claim 1, characterized in that, The structure is selected from the group consisting of: Or its pharmaceutically acceptable salt, ester or ether.

12. The compound according to claim 1, characterized in that, The structure is selected from the group consisting of: Or its pharmaceutically acceptable salt, ester or ether.

13. The compound according to claim 1, wherein it is 2-(2-chlorophenyl)-2-(methylamino)cyclopentane-1-one hydrochloride.

14. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 13, and a pharmaceutically acceptable carrier thereof.

15. A method of treating depression, anxiety, asthma, or pain, comprising administering the pharmaceutical composition according to claim 14 to an individual in need.

16. A method of inducing anesthesia or sedation, comprising administering to an individual in need the pharmaceutical composition according to claim 14.

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