Antidepressant compounds, pharmaceutical compositions, and methods for treating depression and other disorders

Abstract

In some embodiments, pharmaceutical compounds that may be useful in treating depression and / or related disorders are disclosed. In another embodiment, a pharmaceutical composition comprises a therapeutically effective amount of the compound and a pharmaceutically acceptable vehicle therefor. In yet another embodiment, a method for treating depression or other disorders comprises administering the pharmaceutical composition to an individual in need thereof.

Description

[Technical Field]

[0001] References to related applications This application claims priority under U.S. Patent Application No. 63 / 451,891, filed March 13, 2023, U.S. Patent Application No. 63 / 537,744, filed September 11, 2023, and U.S. Patent Application No. 63 / 605,144, filed December 1, 2023, under Section 119(e) of the U.S. Patent Act. The disclosures of these patent applications are incorporated herein by reference in their entirety. [Background technology]

[0002] Depression is one of the most severe medical disorders, with a lifetime prevalence of approximately 17%. It often develops in youth, can become chronic, and can negatively impact the prognosis of other medical conditions such as coronary artery disease, diabetes, and osteoporosis.

[0003] Depression is characterized by a depressed mood and a marked decrease in interest or pleasure in activities. Other symptoms include marked weight loss or gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, decreased self-esteem or excessive or inappropriate guilt, impaired thinking or concentration or indecisiveness, suicidal ideation, suicidal thoughts or attempts. A variety of physical symptoms may also occur. While a depressed mood is common, especially after a setback in life, a depressive disorder is diagnosed when symptoms reach a threshold and persist for at least two weeks. Depression varies in severity from mild to very severe. Most cases are episodic, but they can relapse or become chronic. Some people experience only a single episode and fully recover to premorbid functioning. However, more than 50% of people who experience a single major depressive episode for the first time will eventually develop another episode.

[0004] Depression is more common in women than in men. The point prevalence of unipolar depressive episodes is estimated to be 1.9% in men and 3.2% in women, and 5.8% of men and 9.5% of women will experience a depressive episode in a 12-month period. These prevalences vary across populations and may be higher in some groups. A World Health Organization study reported that depression is a leading global cause of years of life lived with disability and the fourth leading cause of disability-adjusted life-years. Disability-adjusted life-years refer to the reduction in an individual's productive life, adjusted for premature death.

[0005] The treatment of depression underwent a revolutionary advance about half a century ago with the accidental discovery of monoamine oxidase inhibitors and tricyclic antidepressants. Since then, the availability of numerous new drugs with better side effect profiles has greatly increased our ability to safely treat a significant proportion of patients. However, these new drugs are primarily those that simply increase or otherwise enhance the effects of existing drugs by exerting their main biochemical effects by increasing the intrasynaptic concentration of monoamines.

[0006] Unfortunately, current antidepressant medications take weeks to months to fully exert their effects, during which time patients continue to suffer from symptoms and remain at risk of self-harm and harm to their personal and professional lives. In fact, the several-week delay in the onset of action of conventional antidepressants is recognized as a significant limiting factor, particularly during the first nine days of antidepressant initiation, which can lead to considerable pathological conditions and a high risk of suicidal behavior. Therefore, pharmacological strategies that provide rapid onset and sustained antidepressant effects within hours to days would have a significant impact on public health.

[0007] Recently, the "initiation and adaptation" paradigm has been proposed to understand the delayed therapeutic effect of antidepressants. This paradigm assumes that the effect of acute drug administration is mediated through initial, direct target protein disturbance (e.g., inhibition of monoamine reuptake by binding to monoamine transporters), and that repeated administration causes this initial event to trigger sustained adaptive changes in key neural circuits over time, thereby resulting in a stable, long-term antidepressant effect. Thus, this paradigm assumes that the delayed therapeutic effect of existing pharmacological agents is due to the fact that they first act on proteins located much upstream of the target genes that ultimately contribute to the antidepressant effect. In this regard, the main systems that have been hypothesized to mediate the delayed adaptive effect of antidepressants are the neurotrophic signaling cascade and the glutamate system.

[0008] The effects of antidepressants on the neurotrophic signaling cascade have been discussed by many research groups. This application concerns the role of the glutamate system, particularly the NMDA system, in the action of antidepressants. NMDA receptor antagonists have antidepressant effects in many animal models of depression, including the application of unavoidable stressors, forced swimming, and immobility tests by tail suspension, in learned helplessness models of depression, and in animals treated with chronic mild stress. A single dose of the NMDA antagonist ketamine in male Wistar rats inhibits the induction of behavioral despair for up to 10 days post-administration. Furthermore, repeated administration of different classes of antidepressants within a timeframe consistent with delayed therapeutic effects leads to alterations in NMDA subunit mRNA expression and radioligand binding to these receptors in brain regions involved in the pathophysiology of depression.

[0009] Furthermore, multiple pieces of evidence suggest that dysfunction of the glutamatate system may play a significant role in the pathophysiology of depression. In particular, a recent study by Sanacora et al. showed that glutamate levels in the occipital cortex were significantly elevated in 29 drug-free patients with unipolar major depressive disorder compared to 28 age- and sex-matched healthy controls. Together, these data support the hypothesis of focal changes in glutamatate signaling in mood disorders. Finally, clinical trials have shown that the glutamatergic regulators lamotrigine and riluzole (both glutamate-releasing inhibitors) have antidepressant effects.

[0010] Ketamine is used to treat breakthrough pain (BTP) in patients with chronic pain. In such patients, the dose is increased by 10 mg every 90 seconds, with a total dose of 10–50 mg administered intranasally. The effect of this intranasal ketamine administration was a reduction in BTP in patients receiving intranasal ketamine compared to the placebo group. Side effects were very rare with this administration method.

[0011] Transdermal administration of ketamine is also used to treat refractory neuropathic pain. Results showed significant improvements in pain impairment, subjective physical function, and mental function in subjects receiving 75 mg of ketamine. Azevedo et al. reported the results of a randomized, double-blind, placebo-controlled trial using a transdermal delivery system of racemic ketamine after mild abdominal gynecological surgery with lidocaine epidural block. A controlled delivery transdermal patch containing either ketamine (25 mg / 24 hours) or placebo was applied at the end of surgery. The time to rescue analgesia was longer in the ketamine group (230 ± 112 minutes) than in the placebo group (94 ± 54 minutes).

[0012] While ketamine is not approved for use as an antidepressant, its enantiomer, esketamine, was developed as a nasal spray for the treatment of treatment-resistant depression and was approved for this label in the United States in March 2019. However, the effectiveness of esketamine has been limited, with only two out of five clinical trials showing significant efficacy against treatment-resistant depression. Despite evidence supporting the effectiveness of ketamine and esketamine in treating depression, there is no consensus on dosage, or efficacy and safety in long-term therapy. Ketamine has the potential for abuse because it can cause euphoria and dissociative hallucinogenic effects at high doses. Furthermore, ketamine has been associated with cognitive impairment, uremia, hepatotoxicity, and other complications in some individuals with long-term use. These undesirable effects may be limiting factors in the use of ketamine and esketamine for depression.

[0013] (R,S)-Ketamine is rapidly metabolized in vivo, producing a diverse range of metabolites, including 12 unique hydroxynorketamine (HNK) compounds. These HNKs are distinguished by hydroxylation of the cyclohexyl ring at positions 4, 5, or 6, and by their unique stereochemical structures at two stereocenters, and are generated from the metabolism of ketamine in vivo. See Non-Patent Document 1. [Prior art documents] [Non-patent literature]

[0014] [Non-Patent Document 1] Highland et al., “Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications,” Pharmacological Reviews, April 2021, 73 (2) 763-791 [Overview of the project] [Problems that the invention aims to solve]

[0015] There remains a need for improved therapies for the treatment of depression, neuropathic pain, and other disorders such as anxiety, asthma, and seizures. In particular, the development of compounds that circumvent some or all of the aforementioned drawbacks associated with currently available therapies, including ketamine, is desirable. [Means for solving the problem]

[0016] In one embodiment, this disclosure is given by formula (I): [ka] (In the formula, 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, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate esters, carboxylates, carboxyl, esters, hydroperoxy, peroxy, ethers, hemiacetals, hemiketals, acetals, ketals, orthoesters, methylenedioxy, orthocarbonate esters, carboxamides, amines, imines, amides, azides, azos, cyanates, nitrates, nitriles, isonitriles, nitrosoxy, nitro, pyridyl, thiol, sulfide, sulfinyl, sulfonyl, thiocyanate, carbonothioyl, phosphate, and heterocycle, and optionally, alkyl, alkenyl, alkynyl or acyl is halogen, -OH, alkyl, -O-alkyl, NR) A R B , is substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where R A and R B These are, independently, hydrogen and C 1~4 Selected from alkyl groups, aryl or heteroaryl groups may be used alone or as part of a substituent with halogens, -OH, alkyl, -O-alkyl, -COOH, or -C(O)-C 1~4Alkyl, -C(O)O-C 1~4 Alkyl, NR C R D is optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl and -SO2-alkyl, wherein R C and R D are each independently selected from hydrogen and C 1~4 alkyl,

Chemical formula

Chemical formula

[0017] In some embodiments, R1 in formula (I) is 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 Cl.

[0018] In some embodiments, R6 in formula (I) is hydrogen. In some embodiments, R7, R8 and / or R9 in formula (I) is OH.

[0019] In some embodiments, both

Chemical formula

[0020] In another aspect of the present disclosure, the compound is of formula (II): [ka] Alternatively, it may have a structure consisting of a pharmaceutically acceptable salt or ester thereof.

[0021] In some embodiments, R6 in formula (II) is hydrogen. In some embodiments, R7, R8 and / or R9 in formula (II) are OH groups. In some embodiments, both [ka] It is a single bond. In other embodiments, one [ka] It is a single bond, and the other is [ka] It is a double bond.

[0022] In another embodiment, this disclosure relates to formula (III): [ka] (In the formula, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10Each is independently selected from the group consisting of electron pairs, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate ester, carboxylate, carboxyl, ester, hydroperoxy, peroxy, ether, hemiacetal, hemiketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate ester, carboxamide, amine, imine, amide, azide, azo, cyanate, nitrate, nitrile, isonitrile, nitrosoxy, nitro, pyridyl, thiol, sulfide, sulfinyl, sulfonyl, thiocyanate, carbonothioyl, phosphate, and heterocycle, and optionally, alkyl, alkenyl, alkynyl or acyl is halogen, -OH, alkyl, -O-alkyl, NR A R B , is substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where R A and R B These are, independently, hydrogen and C 1~4 Selected from alkyl groups, aryl or heteroaryl groups may be used alone or as part of a substituent with halogens, -OH, alkyl, -O-alkyl, -COOH, or -C(O)-C 1~4 Alkyl, -C(O)OC 1~4 Alkyl, NR C R D It is optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, and -SO2-alkyl, where R C and R D These are, independently, hydrogen and C 1~4 The present invention relates to compounds having a structure (selected from alkyl) or pharmaceutically acceptable salts or esters thereof. In some embodiments, R8 in formula (III) is hydrogen.

[0023] In another embodiment, this disclosure relates to formula (IV): [ka] (In the formula, 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, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate esters, carboxylates, carboxyl, esters, hydroperoxy, peroxy, ethers, hemiacetals, hemiketals, acetals, ketals, orthoesters, methylenedioxy, orthocarbonate esters, carboxamides, amines, imines, amides, azides, azos, cyanates, nitrates, nitriles, isonitriles, nitrosoxy, nitro, pyridyl, thiol, sulfide, sulfinyl, sulfonyl, thiocyanate, carbonothioyl, phosphate, and heterocycle, and optionally, alkyl, alkenyl, alkynyl or acyl is halogen, -OH, alkyl, -O-alkyl, NR) A R B , is substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where R A and R B These are, independently, hydrogen and C 1~4 Selected from alkyl groups, aryl or heteroaryl groups may be used alone or as part of a substituent with halogens, -OH, alkyl, -O-alkyl, -COOH, or -C(O)-C 1~4 Alkyl, -C(O)OC 1~4 Alkyl, NR C R D It is optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, and -SO2-alkyl, where R C and R D These are, independently, hydrogen and C 1~4The present invention relates to compounds having a structure selected from alkyl groups (where at least one of R1, R2, R3, R4, and R5 is a halogen), or pharmaceutically acceptable salts or esters thereof.

[0024] 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 Cl.

[0025] In another embodiment, the compound is given by formula (V): [ka] (In the formula, 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 ester, carboxylate, carboxyl, ester, hydroperoxy, peroxy, ether, hemiacetal, hemiketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate ester, carboxamide, amine, imine, amide, azide, azo, cyanate, nitrate, nitrile, isonitrile, nitrosoxy, nitro, pyridyl, thiol, sulfide, sulfinyl, sulfonyl, thiocyanate, carbonothioyl, phosphate, and heterocycle, and optionally, alkyl, alkenyl, alkynyl or acyl is halogen, -OH, alkyl, -O-alkyl, NR) A R B , is substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where R A and R B These are, independently, hydrogen and C 1~4Selected from alkyl groups, aryl or heteroaryl groups may be used alone or as part of a substituent with halogens, -OH, alkyl, -O-alkyl, -COOH, or -C(O)-C 1~4 Alkyl, -C(O)OC 1~4 Alkyl, NR C R D It is optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, and -SO2-alkyl, where R C and R D These are, independently, hydrogen and C 1~4 Selected from alkyl groups, [ka] is a single bond or a double bond, but at least one [ka] The structure is a single bond, where 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.

[0026] In some embodiments, R1 and R2 are methyl groups.

[0027] In some embodiments, in formula (V), [ka] At least one of them is a double bond.

[0028] In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound having one of the structures shown above, and a pharmaceutically acceptable vehicle therefor.

[0029] In yet another embodiment, a method for treating depression, anxiety, asthma, or pain comprises administering a therapeutically effective amount of the above-mentioned pharmaceutical composition to an individual in need thereof.

[0030] In yet another embodiment, a method for inducing anesthesia or sedation includes administering a therapeutically effective amount of the above-mentioned pharmaceutical composition to an individual in need thereof. [Brief explanation of the drawing]

[0031] [Figure 1] The HPLC analysis of the product 2-(2-chlorophenyl)-2-(methylamino)cyclopentan-1-one hydrochloride is shown. [Figure 2] The mass spectrometry of the product, 2-(2-chlorophenyl)-2-(methylamino)cyclopentan-1-one hydrochloride, is shown. [Figure 3] The 1H-NMR analysis of the product 2-(2-chlorophenyl)-2-(methylamino)cyclopentan-1-one hydrochloride is shown. [Figure 4] The 13C-NMR analysis of the product 2-(2-chlorophenyl)-2-(methylamino)cyclopentan-1-one hydrochloride is shown. [Figure 5] The thermogravimetric analysis (TGA) of the product 2-(2-chlorophenyl)-2-(methylamino)cyclopentane-1-one hydrochloride is shown. [Figure 6] The results of the agonist mode of the GPCR biosensor assay for 2-(2-chlorophenyl)-2-(methylamino)cyclopentan-1-one are shown. [Figure 7] The results of the GPCR biosensor assay for 2-(2-chlorophenyl)-2-(methylamino)cyclopentan-1-one in antagonist mode are shown. [Modes for carrying out the invention]

[0032] This disclosure introduces a novel pharmaceutical compound. In one embodiment, this disclosure describes a compound of formula (I): [ka] (In the formula, 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, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate esters, carboxylates, carboxyl, esters, hydroperoxy, peroxy, ethers, hemiacetals, hemiketals, acetals, ketals, orthoesters, methylenedioxy, orthocarbonate esters, carboxamides, amines, imines, amides, azides, azos, cyanates, nitrates, nitriles, isonitriles, nitrosoxy, nitro, pyridyl, thiol, sulfide, sulfinyl, sulfonyl, thiocyanate, carbonothioyl, phosphate, and heterocycle, and optionally, alkyl, alkenyl, alkynyl or acyl is halogen, -OH, alkyl, -O-alkyl, NR) A R B , is substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where R A and R B These are, independently, hydrogen and C 1~4 Selected from alkyl groups, aryl or heteroaryl groups may be used alone or as part of a substituent with halogens, -OH, alkyl, -O-alkyl, -COOH, or -C(O)-C 1~4 Alkyl, -C(O)OC 1~4 Alkyl, NR C R D It is optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, and -SO2-alkyl, where R C and R D These are, independently, hydrogen and C 1~4 Selected from alkyl groups, [ka] is a single bond or a double bond, but at least one [ka] The present invention relates to compounds having the structure (where R1, R2, R3, R4, and R5 are single bonds, and at least one of them is a halogen, and X is C or N), or to pharmaceutically acceptable salts or esters thereof.

[0033] 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 Cl.

[0034] In some embodiments, R6 in formula (I) is methyl. In some embodiments, R6 in formula (I) is hydrogen. In some embodiments, R6 in formula (I) is ethyl. In some embodiments, R6 in formula (I) is C 1~4 It is alkyl.

[0035] In some embodiments, X in formula (I) is N. In some embodiments, X in formula (I) is C.

[0036] In some embodiments, both [ka] It is a single bond.

[0037] In another embodiment of this disclosure, the compound is of formula (II): [ka] Alternatively, it may have a structure consisting of a pharmaceutically acceptable salt or ester thereof.

[0038] In some embodiments, R6 in formula (II) is hydrogen. In some embodiments, R7, R8 and / or R9 in formula (II) are OH groups. In some embodiments, both [ka] It is a single bond. In other embodiments, one of them [ka] It is a single bond, and the other is [ka] It is a double bond.

[0039] In some embodiments, the compound is as follows: [ka] Alternatively, it may have a structure selected from the group consisting of pharmaceutically acceptable salts, esters, or ethers thereof.

[0040] In some embodiments, the compound is as follows: [ka] Alternatively, it may have a structure selected from the group consisting of pharmaceutically acceptable salts, esters, or ethers thereof.

[0041] In another embodiment, this disclosure relates to formula (III): [ka] (In the formula, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10Each is independently selected from the group consisting of electron pairs, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate ester, carboxylate, carboxyl, ester, hydroperoxy, peroxy, ether, hemiacetal, hemiketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate ester, carboxamide, amine, imine, amide, azide, azo, cyanate, nitrate, nitrile, isonitrile, nitrosoxy, nitro, pyridyl, thiol, sulfide, sulfinyl, sulfonyl, thiocyanate, carbonothioyl, phosphate, and heterocycle, and optionally, alkyl, alkenyl, alkynyl or acyl is halogen, -OH, alkyl, -O-alkyl, NR A R B , is substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where R A and R B These are, independently, hydrogen and C 1~4 Selected from alkyl groups, aryl or heteroaryl groups may be used alone or as part of a substituent with halogens, -OH, alkyl, -O-alkyl, -COOH, or -C(O)-C 1~4 Alkyl, -C(O)OC 1~4 Alkyl, NR C R D It is optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, and -SO2-alkyl, where R C and R D These are, independently, hydrogen and C 1~4 The present invention relates to compounds having a structure (selected from alkyl) or pharmaceutically acceptable salts or esters thereof. In some embodiments, R8 in formula (III) is hydrogen.

[0042] In some embodiments, the compounds disclosed herein are as follows: [ka] Alternatively, it may have a structure selected from the group consisting of pharmaceutically acceptable salts, esters, or ethers thereof.

[0043] In another embodiment, this disclosure relates to formula (IV): [ka] (In the formula, 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, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate esters, carboxylates, carboxyl, esters, hydroperoxy, peroxy, ethers, hemiacetals, hemiketals, acetals, ketals, orthoesters, methylenedioxy, orthocarbonate esters, carboxamides, amines, imines, amides, azides, azos, cyanates, nitrates, nitriles, isonitriles, nitrosoxy, nitro, pyridyl, thiol, sulfide, sulfinyl, sulfonyl, thiocyanate, carbonothioyl, phosphate, and heterocycle, and optionally, alkyl, alkenyl, alkynyl or acyl is halogen, -OH, alkyl, -O-alkyl, NR) A R B , is substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where R A and R B These are, independently, hydrogen and C 1~4 Selected from alkyl groups, aryl or heteroaryl groups may be used alone or as part of a substituent with halogens, -OH, alkyl, -O-alkyl, -COOH, or -C(O)-C 1~4 Alkyl, -C(O)OC 1~4Alkyl, NR C R D It is optionally substituted with one or more substituents independently selected from the group consisting of -S-alkyl, -SO-alkyl, and -SO2-alkyl, where R C and R D These are, independently, hydrogen and C 1~4 The present invention relates to compounds having a structure selected from alkyl groups (where at least one of R1, R2, R3, R4, and R5 is a halogen), or pharmaceutically acceptable salts or esters thereof.

[0044] 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 Cl.

[0045] In some embodiments, the compounds disclosed herein are as follows: [ka] Alternatively, it may have the structure of a pharmaceutically acceptable salt, ester, or ether thereof.

[0046] In another embodiment, the compound is given by formula (V): [ka] (Wherein, R1, R2, R3, R4, R5, R6, and R7 are each independently an electron pair, H, OH, a protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate ester, carboxylate, carboxyl, ester, hydroperoxy, peroxy, ether, hemialdehyde, hemiketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate ester, carboxamide, amine, imine, amide, azide, azo, cyanate, nitrate, nitrile, isonitrile, nitrosoxy, nitro, pyridyl, thiol, sulfide, sulfinyl, sulfonyl, thiocyanate, carbonothioyl, phosphate, and a heterocyclic ring, and optionally, the alkyl, alkenyl, alkynyl or acyl is halogen, -OH, alkyl, -O-alkyl, NR A R B , -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and a heterocyclic ring, and is substituted with one or more substituents independently selected from the group consisting of, where R A and R B are each independently hydrogen and C 1~4 alkyl, and the aryl or heteroaryl is optionally substituted, alone or as part of a substituent, with 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, where R C and R D are each independently hydrogen and C 1~4 alkyl,

Chemical formula

[0047] In some embodiments, R1 and R2 are methyl groups, respectively.

[0048] In some embodiments, in formula (V), [ka] At least one of them is a double bond.

[0049] In some embodiments, the compound is as follows: [ka] Alternatively, it may be a pharmaceutically acceptable salt or ester thereof.

[0050] In other aspects of this disclosure, the compound is as follows: [ka] [ka] [ka] [ka] Alternatively, it may have a structure selected from the group consisting of pharmaceutically acceptable salts, esters, or ethers thereof.

[0051] Compound synthesis In some cases, the compounds can be prepared by synthesis using the techniques described in C. Chen et al., “Enantioselective Syntheses of (S)-Ketamine and (S)-Norketamine,” Org. Lett. 2019, 21, 16, 6575-6578 (2019) (available at doi.org / 10.1021 / acs.orglett.9b02575). Appropriate modifications of reagents to obtain the structures described herein will be obvious to those skilled in the art. In some cases, the compounds can be synthesized based on the techniques described in Zhang et al., Org. Lett. 2017, 19, 1124. The above-mentioned literature describes a shortened synthesis of ketamine, obtaining a primary amine via direct nitration of a cyclic ketone followed by selective reduction of the nitro functional group, and then monomethylating it by reductive amination. In some cases, the compounds described herein can be synthesized based on the technique described in J. Highland et al., “Hydroxynorketamine Pharmacokinetics and Antidepressant Behavioral Effects of (2,6)- and (5R)-Methyl-(2R,6R)-hydroxynorketamines,” ACS Chem. Neurosci. 2022, 13, 4, 510-523. Yet another approach is described in Stevens et al., J. Org. Chem. 1965, 30, 2962. The above literature enables a shortened synthesis of ketamine via α-bromination of the starting material, followed by a one-step formation of an α-hydroxy and Schiff base intermediate, which is then rearranged to provide the desired product. Bromination of the α-position of the starting material 2-(2-chlorophenyl)cyclopentanone may be followed by substitution with methylhydroxylamine, and then reduction of the resulting intermediate. Alternatively, the bromination intermediate may be directly exposed to methylamine to provide the desired product.

[0052] In some embodiments, the compounds can be converted to pharmaceutically acceptable salts by applying techniques well known to those skilled in the art. For example, salts such as sodium salts and potassium salts can be prepared by treating the compound with a suitable sodium or potassium base, such as sodium hydroxide or potassium hydroxide, respectively. Esters and ethers of the compounds can be prepared, for example, as described in Advanced Organic Chemistry, 1992, 4th Edition, J. March, John Wiley & Sons, or J. Med. Chemistry, 1992, 35, 145-151.

[0053] Pharmaceutical composition and method of use The compounds described herein are particularly useful in the treatment of depression and may also be useful in the treatment of a variety of other disorders and symptoms, including anxiety, asthma, anesthesia / sedation, pain, and convulsions.

[0054] A pharmaceutical composition may contain a pharmaceutically acceptable carrier that facilitates the processing of an active ingredient into a pharmaceutically acceptable composition. As used herein, the term “pharmacologically acceptable carrier” is synonymous with “pharmacological carrier” and means any carrier that does not substantially impose long-term or permanent adverse effects upon administration, and includes terms such as “pharmacologically acceptable vehicle,” “stabilizer,” “diluent,” “additive,” “auxiliary,” or “excipient.” Such carriers can generally be mixed with the active ingredient or dilute or embed the active ingredient, and can be in solid, semi-solid, or liquid dosage forms. It is understood that the active ingredient is soluble in the desired carrier or diluent, or administered as a suspension. It is possible to use any of a variety of pharmaceutically acceptable carriers, including, but are not limited to, aqueous media such as water, saline, glycine, and hyaluronic acid; solid carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, and magnesium carbonate; solvents; dispersion media; coatings; antimicrobial and antifungal agents; isotonic and absorption retardants; or other inactive components. The selection of a pharmaceutically acceptable carrier may depend on the mode of administration. Unless a pharmaceutically acceptable carrier is incompatible with the active ingredient, its use in a pharmaceutically acceptable composition is assumed.Non-limiting specific examples of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed. 1999); REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional, 10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th edition 2003). These protocols are routine procedures, and modifications thereof are well within the bounds of expertise in the field and the teachings herein.

[0055] Compounds intended for administration to humans or other mammals should generally have very high purity. Purity refers to the ratio of the mass of the compound to the total sample mass after any purification steps. Typically, purity is at least about 95%, more commonly at least about 96%, about 97%, about 98%, or higher. For example, purity 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.

[0056] Compounds described herein that exist in the form of two or more optical isomers (enantiomers) may be provided as a racemic mixture or by separating one of the enantiomers. In the latter case, the purity described above may refer to the enantiomer purity.

[0057] The compositions described herein may be administered orally, nasally, topically, subcutaneously, intramuscularly, intravenously, or by other modes of administration. For example, an antidepressant may be formulated as a nasal spray as described in U.S. Patent No. 8,785,500B2. The disclosures of the above patent are incorporated herein by reference.

[0058] Pharmaceutical compositions may optionally contain, but are not limited to, other pharmaceutically acceptable components (or pharmaceutical components), including, but are not limited to, buffers, preservatives, isotonic agents, salts, antioxidants, osmotic regulators, physiological substances, pharmacological substances, bulking agents, emulsifiers, wetting agents, sweeteners, or flavorings. Pharmaceutical compositions disclosed herein may be prepared using various buffers and pH adjusting means, provided that the resulting preparations are pharmaceutically acceptable. Such buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, neutral buffered salines, phosphate-buffered salines, and borate buffers. It is understood that acids or bases may be used to adjust the pH of the composition as needed. 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, phenylmercury acetate, phenylmercury nitrate, stabilized oxychloro compounds, and chelating agents such as DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Useful isotonic agents in pharmaceutical compositions include, but are not limited to, salts such as sodium chloride and potassium chloride, mannitol or glycerin, and other pharmaceutically acceptable isotonic agents. Pharmaceutical compositions may be provided as salts and can be formed by many acids, including, but are not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, etc. Salts tend to be more soluble in aqueous or other protic solvents than their corresponding free base forms. It is understood that these substances and other substances known in the field of pharmaceuticals may be included in pharmaceutical compositions.

[0059] Examples of possible adjuvants and / or excipients include cremofol, poloxamer, benzalkonium chloride, sodium lauryl sulfate, dextrose, glycerin, magnesium stearate, polyethylene glycol, starch, dextrin, lactose, cellulose, sodium carboxymethylcellulose, talc, agar, mineral oil, animal oil, vegetable oil, organic and mineral waxes, paraffin, gel, propylene glycol, benzyl alcohol, dimethylacetamide, ethanol, polyglycol, tween 80, solutol HS 15, and water. The active ingredient may also be administered directly in an appropriate form, for example, in a capsule, without the use of a vehicle or diluent.

[0060] The pharmaceutical composition may contain a sufficient amount of the therapeutic compound to enable customary administration to an individual. A unit dose form 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 the therapeutic compound. In other embodiments, a unit dose form 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 the therapeutic compound. In yet another embodiment of this embodiment, the pharmaceutical compositions disclosed herein may include, for example, 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 of therapeutic compounds.In yet another embodiment of this embodiment, the pharmaceutical compositions disclosed herein include, 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, and about 100 mg. It may contain therapeutic compounds in amounts of approximately 250 mg, 100 mg to 500 mg, 100 mg to 750 mg, 100 mg to 1,000 mg, 100 mg to 1,500 mg, 200 mg to 500 mg, 200 mg to 750 mg, 200 mg to 1,000 mg, 200 mg to 1,500 mg, 5 mg to 1,500 mg, 5 mg to 1,000 mg, or 5 mg to 250 mg.

[0061] The pharmaceutical compositions described herein may contain pharmaceutically acceptable solvents. A solvent is a liquid, solid, or gas that dissolves other solids, liquids, or gases (solutes) to produce a solution. Useful solvents 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.

[0062] In specific cases, the appropriate method of administration and dosage range will vary depending on the type of treatment and the respective symptoms or disease state, and can be optimized by those skilled in the art using well-known techniques. In most cases, the daily dose of the active ingredient in a patient is 0.0005 mg to 15 mg / kg, and more commonly, 0.001 mg to 7.5 mg / kg. Administration can be a single dose or cumulative (sequential) dose, which can be easily determined by those skilled in the art. For example, treatment of a bacterial infection may involve a single dose of the effective dose of the pharmaceutical composition disclosed herein. Alternatively, treatment may involve multiple doses of the effective dose of the pharmaceutical composition administered over a period of time, such as once daily, twice daily, three times daily, once every few days, or once a week. The timing of administration can be modified on an individual basis, depending on factors such as the severity of the individual's symptoms. For example, the effective dose of the pharmaceutical composition disclosed herein may be administered to an individual once daily indefinitely, or until the individual no longer requires treatment. Those skilled in the art will understand that an individual's symptoms can be monitored during the course of treatment, and that the effective amount of the pharmaceutical composition disclosed herein administered can be adjusted accordingly.

[0063] The pharmaceutical composition may contain any conventional, non-toxic, pharmaceutically acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation may be adjusted with an acceptable pharmaceutical or food-grade acid, base, or buffer to improve the stability of the formulated composition or its delivery form.

[0064] Liquid dosage forms for oral administration include acceptable pharmaceutical or food-grade emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl sulfoxide (DMSO), dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavorings, and fragrances.

[0065] Solid dosage forms for oral administration include capsules, tablets, lozenges, pills, powders, and granules. In such solid dosage forms, the active ingredient is at least one inert, acceptable pharmaceutical or food-grade excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silica acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, potato... or it may be mixed with tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders, e.g., paraffin; f) absorption enhancers, e.g., quaternary ammonium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) absorbents, e.g., kaolin and bentonite clay; i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and j) sweeteners, flavors, fragrances, and mixtures thereof. In the case of capsules, lozenges, tablets, and pills, the dosage form may also include buffers.

[0066] Solid dosage forms such as tablets, capsules, pills, and granules can be prepared by coatings and shells, such as enteric coatings and other coatings known in pharmaceutical formulation technology. These may optionally contain opacifying agents and may be composed to release only the active ingredient, or preferentially the active ingredient, at a specific site in the intestinal tract, or in an optionally delayed or prolonged manner. Examples of usable embedding compositions include polymers and waxes. Sustained-release tablet formulations are also described in U.S. Patent No. 5,942,244.

[0067] The composition may contain the compounds disclosed herein alone or in combination with other therapeutic compounds. Therapeutic compounds are compounds that provide pharmacological activity or other direct effects in the diagnosis, treatment, alleviation, therapy, or prevention of disease, or that affect the structure or any function of the human or animal body. Therapeutic compounds disclosed herein may be used in the form of pharmaceutically acceptable salts, solvates, or solvates of salts, e.g., hydrochloride salts. Furthermore, therapeutic compounds disclosed herein may be provided as racemates or as individual enantiomers containing R- or S-enantiomers. Thus, therapeutic compounds disclosed herein may include only the R-enantiomer, only the S-enantiomer, or a combination of the R-enantiomer and the S-enantiomer. In some embodiments, the therapeutic compounds may have anti-inflammatory activity, such as nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are a large group of therapeutic compounds that have analgesic, anti-inflammatory, and antipyretic properties. NSAIDs reduce inflammation by inhibiting cyclooxygenase.NSAIDs, but not limited to them, include aceclofenac, acemetacin, actarito, alcofenac, aluminoprofen, amfenac, alloxypyrine, aminophenazone, anthraphenine, aspirin, azapropazon, benolilate, benoxaprofen, benzydamine, butibufen, celecoxib, chlortenoxacin, choline salicylate, clometacin, dexketoprofen, diclofenac, diflunisal, emorphazon, epirizole, etodolac, etricoxib, feclobuzon, felbinac, fenbufen, fenclofenac, flurbiprofen, graphenine, and salicylic acid. This includes hydroxyethyl ethyl hydroxylate, ibuprofen, indomethacin, indoprofen, ketoprofen, ketrolac, lactylphenetidine, loxoprofen, lumiracoxib, mefenamic acid, meloxicam, metamisole, methiadic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxamethacin, phenacetin, pipebzone, pranoprofen, propifenazone, procazone, brotidic acid, lofecoxib, salicylamide, sarsalate, sulfinduct, suprofen, tiaramide, tinoridine, tolfenamic acid, valdecoxib, and zomepirac.

[0068] NSAIDs can be classified based on their chemical structure or mechanism of action. Non-exclusive examples of NSAIDs include salicylate derivative NSAIDs, p-aminophenol derivative NSAIDs, propionic acid derivative NSAIDs, acetic acid derivative NSAIDs, enolic acid derivative NSAIDs, phenamic acid derivative NSAIDs, non-selective cyclooxygenase (COX) inhibitors, selective cyclooxygenase-1 (COX-1) inhibitors, and selective cyclooxygenase-2 (COX-2) inhibitors. An NSAID may be a profen. Suitable examples of salicylate derivative NSAIDs include, but are not limited to, acetylsalicylic acid (aspirin), diflunisal, and salsalate. Suitable examples of p-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, aluminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and suprofen. Examples of suitable acetate derivative NSAIDs include, but are not limited to, aceclofenac, acemetacin, actarito, alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indomethacin, ketorolac, methiadic acid, mofezolac, nabumetone, naproxen, oxamethacin, 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 phenamic acid derivative NSAIDs include, but are not limited to, fluphenamic acid, mefenamic acid, meclophenamic acid, and tolphenamic acid. Examples of suitable selective COX-2 inhibitors include, but are not limited to, celecoxib, etoricoxib, firocoxib, lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib.

[0069] Certain elements of any of the embodiments described above can be combined with or replaced with elements of other embodiments. Furthermore, while the advantages associated with specific embodiments of this disclosure are described in relation to those embodiments, other embodiments may also exhibit such advantages, and not all embodiments necessarily need to exhibit such advantages in order to be included within the scope of this disclosure. [Examples]

[0070] Example 1 This example illustrates the synthesis of 2-(2-chlorophenyl)-2-(methylamino)cyclopentane-1-one hydrochloride. [ka]

[0071] This synthesis, based on Zhang et al (Org. Lett. 2017, 19, 1124), involved obtaining a primary amine by direct nitration of a cyclic ketone followed by selective reduction of the nitro functional group, and then converting it to a hydrochloride salt by monomethylation via reductive amination. [ka]

[0072] Nitration of 2-(2-chlorophenyl)cyclopentan-1-one (Int-1-1) Cerium ammonium nitrate (CAN) was completely dried in a vacuum oven (100°C, 60 mbar). CAN (71 g, 130 mmol, 2 equivalents), a degassed ketone solution in DCE (150 mL) (12 g, 62 mmol, 1 equivalent), and Cu(OAc)2 (2.25 g, 12 mmol, 0.2 equivalents) were loaded into a 350 mL pressure vessel. The reaction mixture was stirred under an argon atmosphere at 90°C for 18 hours. The reaction mixture was poured into DCM (250 mL) and the solution was stirred for 30 minutes. The reaction mixture was filtered through a Celite pad. The filtrate was washed with a water / saturated NaHCO3 (50 / 50) mixture to separate the phases, and the aqueous phase was extracted with DCM (100 mL). The combined organic phase was washed with water (100 mL) and saline solution (2 × 100 mL), dried over MgSO4, filtered, and evaporated. The resulting product was used in the next step without purification (13.9 g).

[0073] Nitroketone reduction (Int-1-2) Crude nitroketone 1-1 (13.9 g) from the previous step was dissolved in AcOH (200 mL) in a 1 L flask, and the flask was placed in a water bath at room temperature. Four doses of zinc powder (4 × 4 g) were added to the reaction mixture every 15 minutes, and after 2 hours, an additional dose of zinc powder (4 g) was added to the reaction mixture. The reaction mixture was quenched when the starting material (nitroketone 1-1, [M+H]+=257) and intermediate (nitrosoketone, [M+H]+=226) were completely consumed. The reaction mixture was filtered through a Celite pad and evaporated. Water (500 mL) and ELISA (100 mL) were added to the resulting residue, and the mixture was stirred and separated. The aqueous phase was washed with ELISA (100 mL), and the combined organic phase I was washed with water (50 mL). The combined aqueous phase was neutralized with solid NaHCO3 (20 g) and extracted with DCM (3 × 150 mL) (organic phase II), yielding a large amount of stable emulsion. Organic phase II was dried over MgSO4, filtered, and evaporated (2.9 g of product). LC-MS revealed that organic phase I contained a large amount of the desired product; therefore, organic phase I was evaporated and dissolved in a mixture of DCM (100 mL), water (250 mL), and 37% fHCl (5 mL). The aqueous phase was separated, neutralized with solid NaHCO3 (20 g), and extracted with DCM (3 × 150 mL). The organic phase was separated, dried over MgSO4, filtered, and evaporated (1.3 g of product). Total mass 4.2 g (yield 33% (step 1 + step 2)).

[0074] Monomethylation of aminoketones (M209) Formaldehyde (154 mg, 0.7 equivalents, 0.4 mL of 37% w / w aqueous solution) was added to a solution of aminoketone 1-2 (1.45 g, 7 mmol, 1 equivalent) in MeOH (20 mL). In a separate vial, a solution of NaCNBH3 (0.37 g, 5.9 mmol, 0.85 equivalents) in MeOH (15 mL) was prepared. AcOH (0.4 mL, 7 mmol, 1 equivalent) was added to this stirred mixture, and after 1.5 minutes, the formaldehyde / aminoketone solution from the previous step was added at room temperature. After 6 minutes, the reaction was quenched with water (25 mL). The solution was partially evaporated and dissolved in Et2O (200 mL) and water (50 mL) for water-Et2O purification. The weight of the crude mixture was 1.2 g (77%). The batch was combined with other similar batches and purified by reverse-phase column chromatography. The ACN phase was evaporated, and the product was extracted with DCM and EtOAC. The organic phases were combined, dried over Na2SO4, and then evaporated. An off-white solid was obtained (approximately 0.8 g, HPLC purity 99%). The provisional yield for the entire process was approximately 8%.

[0075] Formation of M209·HCl Previously isolated M209 was dissolved in EtOH (5-7 mL), HCl (3 mL) from the EtOH was added, the solution was stirred for 5 minutes, and evaporated to obtain a yellow oily substance. Next, crystallization was carried out with CHCl3 / heptane, and the turbid solution was evaporated to dryness to obtain an off-white solid. This solid was dried under high vacuum (0.8 g, HPLC purity 99.4%). Figure 1 shows the results of the HPLC analysis. Figure 2 shows the results of the mass spectrometry analysis. Figures 3 and 4 show, respectively. 1 H-NMR and 13 The results of the 1C-NMR analysis are shown. Figure 5 shows the results of the thermogravimetric analysis (TGA).

[0076] Example 2 This example demonstrates the evaluation of 2-(2-chlorophenyl)-2-(methylamino)cyclopentan-1-one in a DiscoverX-developed cell line panel for stable expression of untagged GPCRs that signal via cAMP. The Hit Hunter® cAMP assay is a homogeneous, non-imaging assay format that uses a DiscoverX-developed technique called Enzyme Fragment Complementation (EFC) with β-galactosidase (β-Gal) as a functional reporter to monitor GPCR activation via Gi and Gs secondary messenger signaling.

[0077] The enzyme is divided into two complementary parts: the enzyme receptor EA and the enzyme donor ED. ED is fused to cAMP and, in the assay, competes with cAMP produced by cells to bind to cAMP-specific antibodies. Active β-Gal is formed when exogenous EA is complemented by any unbound EDcAMP. The active enzyme then converts a chemiluminescent substrate, generating an output signal detectable by a standard microplate reader.

[0078] Calcium No Wash PLUS The assay monitors GPCR activation via Gq secondary messenger signaling in living cells in a non-imaging assay format. Calcium mobilization in the PathHunter® cell line or other cell lines stably expressing Gq-binding GPCRs is monitored using intracellularly loaded calcium-sensitive dyes. Activation of GPCRs by the compound triggers the release of calcium from intracellular stores, resulting in an increase in dye fluorescence, which is measured in real time.

[0079] Handling of cells 1. The cAMP Hunter cell line was augmented from frozen stocks following standard procedures. 2. Cells were seeded in a total volume of 20 μL in a 384-well white-walled microplate and incubated at 37°C for an appropriate time before testing. 3. cAMP modulation was determined using the DiscoverX HitHunter cAMP XS+ assay.

[0080] Gs Agonist Format 1. To determine the agonist, cells were incubated with the sample to induce a response. 2. The culture medium was aspirated from the cells and replaced with 15 μL of 2:1 HBSS / 10 mM Hepes:cAMP XS+Ab reagent. 3. An intermediate dilution of the sample stock was performed to generate a 4-fold sample in the assay buffer. 5 μL of the 4.4x sample was added to the cells and incubated at 37°C or room temperature for 30 or 60 minutes. The vehicle concentration was 1%.

[0081] Gi Agonist Format 1. To determine the agonist, cells were incubated with the sample in the presence of EC80 forskolin to induce a response. 2. The culture medium was aspirated from the cells and replaced with 15 μL of 2:1 HBSS / 10 mM Hepes:cAMP XS+Ab reagent. 3. The sample stock was intermediate-diluted, and a 4-fold sample was prepared in an assay buffer containing 4x EC80 false colorin. 5 μL of the 4.4x sample was added to the cells and incubated at 37°C or room temperature for 30 or 60 minutes. The final assay vehicle concentration was 1%.

[0082] Allosteric Modulation Format 1. For allosteric determination, cells were pre-incubated with the sample and then agonist-induced at EC20 concentration. 2. The culture medium was aspirated from the cells and replaced with 10 μL of 1:1 HBSS / 10 mM Hepes:cAMP XS+Ab reagent. 3. The sample stock was intermediate-diluted, and a 4-fold sample was prepared in the assay buffer. 5 μL of the 4.4-fold compound was added to the cells and incubated at room temperature or 37°C for 30 minutes. 5 μL of 5.4x EC20 agonist was added to the cells and incubated at room temperature or 37°C for 30 or 60 minutes. For Gi-conjugated GPCRs, EC80 forskolin was added.

[0083] Inverse agonist format (Gi only) 1. To determine the reverse agonist, cells were pre-incubated with the sample in the presence of EC20 forskolin. 2. The culture medium was aspirated from the cells and replaced with 15 μL of 2:1 HBSS / 10 mM Hepes:cAMP XS+Ab reagent. 3. The sample stock was intermediate-diluted, and a 4-fold sample was prepared in an assay buffer containing 4x EC20 false colorin. 5 μL of the 4.4x sample was added to the cells and incubated at 37°C or room temperature for 30 or 60 minutes. The final assay vehicle concentration was 1%.

[0084] Antagonist format 1. To determine the antagonist, cells were pre-incubated with the sample, and then agonist challenge was performed at an EC80 concentration. 2. The culture medium was aspirated from the cells and replaced with 10 μL of 1:1 HBSS / Hepes:cAMP XS+Ab reagent. 5 μL of the 3.4x compound was added to the cells and incubated at 37°C or room temperature for 30 minutes. 5 μL of 4.4x EC80 agonist was added to the cells and incubated at 37°C or room temperature for 30 or 60 minutes. For Gi-conjugated GPCRs, EC80 forskolin was included.

[0085] Signal detection 1. After appropriate compound incubation, the reagents were incubated with 20 μL of cAMP XS+ED / CL lysis cocktail for 1 hour, and then incubated with 20 μL of cAMP XS+EA reagent at room temperature for 3 hours to generate the assay signal. 2. After signal generation, the microplate was read using a PerkinElmer Envision™ instrument to detect the chemiluminescence signal.

[0086] Data Analysis 1. Compound activity was analyzed using the CBIS data analysis suite (ChemInnovation, CA). 2. In the case of a Gs agonist mode assay, the activity rate is calculated using the following formula: % activity = 100% × (average RLU of test sample - average RLU of vehicle control) / (average RLU of MAX control - average RLU of vehicle control). 3. For Gs-positive allosteric mode assays, the modulation rate is calculated using the following formula: % Modulation = 100% × (Average RLU of test sample - Average RLU of EC20 control) / (Average RLU of MAX control - Average RLU of EC20 control). 4. For Gs antagonist or negative allosteric mode assays, the inhibition rate is calculated using the following formula: % inhibition = 100% × (1 - (mean RLU of test sample - mean RLU of vehicle control) / (mean RLU of EC80 control - mean RLU of vehicle control)). 5. In the Gi agonist mode assay, the activity rate is calculated using the following formula: % activity = 100% × (1 - (average RLU of test sample - average RLU of MAX control) / (average RLU of vehicle control - average RLU of MAX control)). 6. For Gi-positive allosteric mode assays, the modulation rate is calculated using the following formula: %Modulation = 100% × (1 - (Average RLU of test sample - Average RLU of MAX control) / (Average RLU of EC20 control - Average RLU of MAX control)). 7. In the case of the Gi reverse agonist mode assay, the activity rate is calculated using the following formula: % Reverse agonist activity = 100% × ((Average RLU-EC20 of test samples, average RLU of forskolin) / (Average RLU of forskolin-positive controls, average RLU of forskolin-positive controls)) 8. For Gi antagonist or negative allosteric mode assays, the inhibition rate is calculated using the following formula: % inhibition = 100% × (mean RLU-EC80 of the test sample, mean RLU of the control group) / (mean RLU-EC80 of the forskolin-positive control group, mean RLU of the control group).

[0087] The results of the data analysis are summarized in the table below.

[0088] [Table 1]

[0089] Figures 6 and 7 show the results of the agonist and antagonist assays, respectively. For the agonist assay, the data were normalized to the maximum and minimum responses observed in the presence of the control ligand and vehicle. [Industrial applicability]

[0090] Although the present invention has been described based on specific embodiments, those skilled in the art will understand that there are numerous variations and combinations of the above systems and techniques that fall within the spirit and scope of the invention as revealed in the appended claims.

Claims

1. Equation (I): 【Chemistry 1】 (wherein, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , and R ９ are each independently an electron pair, H, halogen, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, phenyl, carbonate ester, carboxylate, carboxyl, ester, hydroperoxy, peroxy, ether, hemialdehyde, hemiketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate ester, carboxamide, amine, imine, amide, azide, azo, cyanate, nitrate, nitrile, isonitrile, nitrosooxy, nitro, pyridyl, thiol, sulfide, sulfinyl, sulfonyl, thiocyanate, carbonothioyl, phosphate, and a heterocyclic ring, and optionally, the alkyl, alkenyl, alkynyl or acyl is a halogen, -OH, alkyl, -O-alkyl, NR Ａ R Ｂ , -S-alkyl, -SO-alkyl, -SO ２ -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and a heterocyclic ring, and is substituted with one or more substituents independently selected from the group consisting of, wherein R Ａ and R Ｂ are each independently hydrogen and C １～４ alkyl, and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, -COOH, -(C)O-C １～４ alkyl, -(C)OO-C １～４ alkyl, NR Ｃ R Ｄ , -S-alkyl, -SO-alkyl and -SO<, and R ２ Ｃ and R Ｄ These are, independently, hydrogen and C １～４ Selected from alkyl groups, 【Chemistry 2】 is a single bond or a double bond, provided that at least one 【Transformation 3】 This is a single bond, and here, R １ , R ２ , R ３ , R ４ , and R ５ A compound having the structure (where at least one of is a halogen and X is C or N), or a pharmaceutically acceptable salt or ester thereof.

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

3. R １ The compound according to claim 2, wherein is Cl.

4. R ６ The compound according to claim 1, wherein is methyl.

5. R ６ C １～４ The compound according to claim 1, wherein it is alkyl.

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

7. Both 【Chemistry 4】 The compound according to any one of claims 1 to 6, wherein the bond is a single bond.

8. The aforementioned compound is of formula (II): 【Transformation 5】 The compound according to claim 1, or having a structure comprising a pharmaceutically acceptable salt or ester thereof.

9. A compound according to any one of claims 1 to 7, wherein X is N.

10. below: 【Transformation 6】 The compound according to claim 1, or having a structure selected from the group consisting of pharmaceutically acceptable salts, esters, or ethers thereof.

11. below: 【Transformation 7】 The compound according to claim 1, or having a structure selected from the group consisting of pharmaceutically acceptable salts, esters, or ethers thereof.

12. below: 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 The compound according to claim 1, or having a structure selected from the group consisting of pharmaceutically acceptable salts, esters, or ethers thereof.

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

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable vehicle therefor.

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

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

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