Chiral gamma malactam derivatives or pharmaceutically acceptable salts thereof and method for producing the same

Abstract

The present invention relates to a method for producing a chiral gamma malactam derivative or a pharmaceutically acceptable salt thereof using an organic chiral catalyst compound, and a composition containing the derivative or a pharmaceutically acceptable salt thereof for preventing, ameliorating, or treating muscular disorders, psychiatric disorders, or degenerative neurological disorders. The chiral gamma malactam derivative or a pharmaceutically acceptable salt thereof has MAO-B and MSTN inhibitory effects and targets D1-mClu5, and can be used to prevent, ameliorate, or treat muscular disorders such as sarcopenia, psychiatric disorders such as depression, and degenerative neurological disorders such as Parkinson's disease.

Description

[Technical Field]

[0001] The present invention relates to a chiral gamma malactam derivative or a pharmaceutically acceptable salt thereof, a method for producing the same, and a composition containing the derivative or a pharmaceutically acceptable salt thereof for preventing, ameliorating, or treating a muscular disorder, a mental disorder, or a degenerative neurological disorder. [Background technology]

[0002] Globally, more than 80% of people aged 65 or older suffer from one or more chronic diseases, and more than 68% suffer from two or more chronic diseases, including Parkinson's disease.

[0003] Parkinson's disease is a progressive degenerative neurological disorder characterized by symptoms such as slow movement, tremors when standing, muscle rigidity, a shuffling gait, and a stooped posture. Parkinson's disease is characterized by the specific death of dopaminergic brain cells in the substantia nigra of the brain. The causes of Parkinson's disease have been identified as reactive oxygen species (ROS), oxidative stress, abnormal protein structure formation, and mitochondrial damage, but the exact cause has yet to be elucidated.

[0004] Therefore, when treating Parkinson's disease, the treatment must be selected taking into consideration the patient's age, the severity of symptoms, and the side effects of the drug. It is known that dopamine agonists such as Mirapex and Requip, and MAO-B inhibitors are administered to treat early-stage Parkinson's disease, while dopamine agonists, MAO-B inhibitors, and COMT inhibitors are administered in combination with levodopa to treat later-stage Parkinson's disease with motor fluctuations.

[0005] Global pharmaceutical companies are developing drugs to treat Parkinson's disease, but most have dropped out at the clinical trial stage. Alternative approaches include attempts to regulate these receptors or transcription factors, but the results have yet to be very clear. Currently used anti-Parkinson's drugs have several fundamental limitations. These primarily involve simply supplementing the dopamine deficiency that is the main cause of Parkinson's symptoms (dopa therapy) or using dopamine agonists, which have significant side effects. Most drugs are not intended to be a cure, but rather merely slow the progression of symptoms.

[0006] The fundamental pathological phenomenon of Parkinson's disease is the death of neurons in the substantia nigra of the midbrain. Therefore, the most fundamental and complete treatment is to inhibit the death of dopamine neurons and normalize the dopamine production pathway (normalization of neurons). However, existing drugs persistently cause side effects such as dyskinesia and various forms of psychiatric disorders. As a result, they have limitations that prevent them from being a fundamental treatment for the dopamine nervous system.

[0007] In other words, conventionally, therapeutic agents for Parkinson's disease have been developed mainly based on the mechanisms of dopamine agonists and MAO-B inhibitors, but no research has been conducted on the occurrence of muscle atrophy induced by the movement disorders of Parkinson's disease, and currently there are almost no therapeutic agents with mechanisms to reverse such muscle atrophy, both in Japan and overseas.

[0008] There are approximately 6.3 million Parkinson's disease patients worldwide, with a market size of approximately 4 trillion won. In Korea, the number of patients exceeds 100,000, with an estimated market size of approximately 300 billion won. The incidence rate is particularly high among people aged 60 and over (approximately 1-2%), and the impact of this disease increases as society ages. It is a challenge that must be overcome in order to realize a healthier society.

[0009]

[0010] Meanwhile, lactams are highly bioactive pharmaceuticals and the main raw material for material chemistry, and are used as extremely important intermediates in medicine, materials, materials chemistry, synthetic chemistry, and more. For example, penicillin, the first beta-lactam discovered by humans, and Zetia, which has excellent efficacy in treating cardiovascular disease, levitiracetam, which has a gamma-lactam skeleton, is used in epilepsy, and azaspiren, known for its angiogenesis inhibitory properties, is used as a uterine cancer treatment. As such, lactams possess physiological activity and are widely used in actual medicines and are utilized as key raw materials in new drug development.

[0011] Lactams are core structural components of complex organic molecules and are basic skeletons widely used in pharmaceuticals, synthetic chemistry, materials, and more. However, research and development into the catalytic reactions required for the production of lactam compounds has stalled for some time. This is because carbonylnitrene, the key intermediate in the reaction to convert hydrocarbons into lactam compounds, is too cheap to decompose into by-products at room temperature. In other words, the Curtius rearrangement process has been the biggest obstacle to lactam production. Therefore, there is a strong demand for the development of new catalysts that can solve this problem.

[0012]

[0013] Under these circumstances, the present inventors have made intensive efforts to solve the problems of the prior art as described above, and as a result have found that when an organic chiral catalyst compound having a specific structure is used, a gamma lactam derivative or a pharmaceutically acceptable salt thereof can be produced in large quantities with high purity using a small amount of catalyst. They have also found that this can be used as a therapeutic agent that simultaneously inhibits neuronal death, provides neuroprotection, normalizes dopamine pathways, increases mobility, acts as an anticonvulsant, and increases muscle mass, thereby completing the present invention. Summary of the Invention [Problem to be solved by the invention]

[0014] An object of the present invention is to provide a chiral gamma malactam derivative or a pharmaceutically acceptable salt thereof.

[0015] Another object of the present invention is to provide a composition for preventing, ameliorating, or treating muscular disorders, mental disorders, or degenerative neurological disorders, which comprises the derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0016] A further object of the present invention is to provide a method for preparing said derivative or a pharmaceutically acceptable salt thereof.

[0017] However, the technical problems that the present invention aims to achieve are not limited to those mentioned above, and other problems not mentioned will be clearly understood by those of ordinary skill in the art from the following description. [Means for solving the problem]

[0018] To achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating muscular disorders, psychiatric disorders, or degenerative neurological disorders, comprising as an active ingredient at least one selected from the group consisting of a pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by the following formula 1a: a pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by the following formula 1b: a chiral gamma malactam derivative represented by the following formula 1c: or a pharmaceutically acceptable salt thereof; and combinations thereof. In this regard, the derivative or a pharmaceutically acceptable salt thereof includes its racemate, solvate, etc.

[0019] [Chemical formula 1a]

[0020] [ka]

[0021] [Formula 1b]

[0022] [ka]

[0023] [Chemical formula 1c]

[0024] [ka]

[0025] In one embodiment of the present invention, the pharmaceutically acceptable salt of the chiral gamma malactam derivative represented by the following [Chemical Formula 1c] may be any one or more selected from the group consisting of hydrochloride, bromide, sulfate, phosphate, nitrate, citrate, acetate, lactate, stannate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate, glutarate, adipate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt, and combinations thereof, but is not limited thereto. Preferably, it is hydrochloride, and more preferably, it may be a salt represented by the following [Chemical Formula 1d].

[0026] [Chemical formula 1d]

[0027] [ka]

[0028] In another embodiment of the present invention, the muscle disease may be any one or more selected from the group consisting of atony, muscular atrophy, muscular dystrophy, myasthenia, cachexia, rigid spinesyndrome, amyotrophic lateral sclerosis (Lou Gehrig's disease), Charcot-Marie-Tooth disease, sarcopenia, and combinations thereof, but is not limited to these.

[0029] In another embodiment of the present invention, the mental disorder may be at least one selected from the group consisting of depression, mania, bipolar disorder, schizophrenia, delirium, panic disorder, attention-deficit hyperactivity disorder (ADHD), cognitive disorder, anxiety disorder, post-traumatic stress disorder (PTSD), and combinations thereof, but is not limited thereto.

[0030] In another embodiment of the present invention, the degenerative neurological disease may be Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, spinocerebellar degeneration, spinocerebellar ataxia, Friedreich's ataxia, Machado-Joseph disease, dystonia, progressive supranuclear palsy, senile dementia, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, or the like. The condition may be, but is not limited to, any one or more selected from the group consisting of dementia, alcohol-related dementia, pre-senile dementia, temporal lobe epilepsy, multiple sclerosis, cerebral amyloid angiopathy, systemic amyloidosis, Tourette's disorder, stroke, and combinations thereof.

[0031] The present invention also provides one or more uses selected from the group consisting of a pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1a] above for the manufacture of a drug for the prevention or treatment of muscular diseases, psychiatric diseases, or degenerative neurological diseases; a pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1b] above; a chiral gamma malactam derivative represented by [Chemical Formula 1c] above or a pharmaceutically acceptable salt thereof; and combinations thereof.

[0032] Furthermore, the present invention can provide a method for preventing or treating a muscular disease, a mental disease, or a degenerative neurological disease, comprising administering to an individual any one or more selected from the group consisting of a pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1a]; a pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1b]; a chiral gamma malactam derivative represented by [Chemical Formula 1c] or a pharmaceutically acceptable salt thereof; and combinations thereof.

[0033] The present invention also provides a cosmetic composition for preventing or improving muscular disorders, mental disorders, or degenerative neurological disorders, comprising as an active ingredient at least one selected from the group consisting of: a cosmetically acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1a]; a cosmetically acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1b]; a chiral gamma malactam derivative represented by [Chemical Formula 1c] or a cosmetically acceptable salt thereof; and combinations thereof.

[0034] The present invention also provides a food composition for preventing or improving muscular diseases, mental diseases, or degenerative neurological diseases, comprising as an active ingredient at least one selected from the group consisting of a nutritively acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1a]; a nutritively acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1b]; a chiral gamma malactam derivative represented by [Chemical Formula 1c] or a nutritively acceptable salt thereof; and combinations thereof.

[0035]

[0036] The present invention also provides a method for producing a pharmaceutical composition for preventing or treating muscular disorders, psychiatric disorders, or degenerative neurological disorders, comprising, as an active ingredient, a pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1a], the method comprising the steps of:

[0037] (1) producing a compound represented by [Chemical Formula 4a] from a compound represented by [Chemical Formula 3a] using a catalyst compound represented by [Chemical Formula 2];

[0038] (2) producing a compound represented by [Chemical Formula 5a] from a compound represented by [Chemical Formula 4a];

[0039] (3) preparing a compound represented by [Chemical Formula 6a] from a compound represented by [Chemical Formula 5a]; and

[0040] (4) treating the compound represented by [Chemical Formula 6a] with sodium hydride (NaH), ethyl bromoacetate (BrCH2COOEt), and ammonia (NH3) to produce the compound represented by [Chemical Formula 1a];

[0041] [Chemical formula 1a]

[0042] [ka]

[0043] [Chemical formula 2]

[0044] [ka]

[0045] [Chemical formula 3a]

[0046] [ka]

[0047] [Chemical formula 4a]

[0048] [ka]

[0049] [Chemical formula 5a]

[0050] [ka]

[0051] [Chemical formula 6a]

[0052] [ka]

[0053] In Chemical Formula 2, R1 and R2 are the same or different and each represent one or more selected from the group consisting of hydrogen, a C1-C6 alkyl group, a halogen group, a cyano group, a nitro group, a trifluoromethyl group, an alkoxy group, a C3-C8 aryl group, and combinations thereof; R3 is a C3-C8 aryl group, and one or more hydrogen atoms of the aryl group are unsubstituted or substituted with one or more hydrogen atoms selected from the group consisting of a C1-C6 alkyl group, a halogen group, a cyano group, a nitro group, a trifluoromethyl group, an alkoxy group, and combinations thereof; and in Chemical Formula 5a, R4 may be hydrogen or a halogen group.

[0054] In one embodiment of the present invention, the catalyst compound represented by [Chemical Formula 2] may be at least one selected from the group consisting of catalyst compounds listed in Table 1 below and combinations thereof, but is not limited thereto.

[0055] [Table 1-1] [Table 1-2]

[0056]

[0057] In another embodiment of the present invention, the compound represented by [Chemical Formula 5a] may be, but is not limited to, one or more selected from the group consisting of compounds listed in Table 2 below and combinations thereof.

[0058] [Table 2]

[0059]

[0060] The present invention also provides a method for producing a pharmaceutical composition for preventing or treating muscular disorders, psychiatric disorders, or degenerative neurological disorders, comprising, as an active ingredient, a pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1b], the method comprising the steps of:

[0061] (1) producing a compound represented by [Chemical Formula 4b] from a compound represented by [Chemical Formula 3b] using a catalyst compound represented by [Chemical Formula 2];

[0062] (2) preparing a compound represented by [Chemical Formula 5b] from a compound represented by [Chemical Formula 4b];

[0063] (3) preparing a compound represented by [Chemical Formula 6b] from a compound represented by [Chemical Formula 5b]; and

[0064] (4) treating the compound represented by [Chemical Formula 6b] with sodium hydride (NaH), ethyl bromoacetate (BrCH2COOEt), and ammonia (NH3) to produce a compound represented by [Chemical Formula 1b];

[0065] [Chemical Formula 1b]

[0066]

change

[0067] [Chemical Formula 2]

[0068]

change

[0069] [Chemical Formula 3b]

[0070]

change

[0071] [Chemical Formula 4b]

[0072]

change

[0073] [Chemical Formula 5b]

[0074]

change

[0075] [Chemical Formula 6b]

[0076]

change

[0077] In Chemical Formula 2, R1 and R2 are the same or different and each represent one or more selected from the group consisting of hydrogen, a C1-C6 alkyl group, a halogen group, a cyano group, a nitro group, a trifluoromethyl group, an alkoxy group, a C3-C8 aryl group, and combinations thereof; R3 is a C3-C8 aryl group, and one or more hydrogen atoms of the aryl group are unsubstituted or substituted with one or more selected from the group consisting of a C1-C6 alkyl group, a halogen group, a cyano group, a nitro group, a trifluoromethyl group, an alkoxy group, and combinations thereof; and in Chemical Formula 5b, R4 may represent hydrogen or a halogen group, and R5 may represent a C1-C6 alkyl group or a benzyl group.

[0078] In one embodiment of the present invention, the catalyst compound represented by [Formula 2] may be at least one selected from the group consisting of the catalyst compounds listed in Table 1 and combinations thereof, but is not limited thereto.

[0079] In another embodiment of the present invention, the compound represented by [Chemical Formula 5b] may be, but is not limited to, one or more selected from the group consisting of compounds listed in Table 3 below and combinations thereof.

[0080] [Table 3-1] [Table 3-2]

[0081]

[0082]

[0083] The present invention also provides a method for producing a pharmaceutical composition for preventing or treating muscular disorders, psychiatric disorders, or degenerative neurological disorders, comprising, as an active ingredient, a pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1d], the method comprising the steps of:

[0084] (1) producing a compound represented by [Chemical Formula 4b] from a compound represented by [Chemical Formula 3b] using a catalyst compound represented by [Chemical Formula 2];

[0085] (2) preparing a compound represented by [Chemical Formula 5b] from a compound represented by [Chemical Formula 4b];

[0086] (3) preparing a compound represented by [Chemical Formula 6b] from a compound represented by [Chemical Formula 5b]; and

[0087] (4) treating the compound represented by [Chemical Formula 6b] with sodium hydride (NaH), ethyl bromoacetate (BrCH2COOEt), and hydrazine hydrate to produce a compound represented by [Chemical Formula 1d];

[0088] [Chemical formula 1d]

[0089] [ka]

[0090] [Chemical formula 2]

[0091] [ka]

[0092] [Chemical formula 3b]

[0093] [ka]

[0094] [Formula 4b]

[0095] [ka]

[0096] [Chemical formula 5b]

[0097] [ka]

[0098] [Chemical formula 6b]

[0099] [ka]

[0100] In Chemical Formula 2, R1 and R2 are the same or different and each represent one or more selected from the group consisting of hydrogen, a C1-C6 alkyl group, a halogen group, a cyano group, a nitro group, a trifluoromethyl group, an alkoxy group, a C3-C8 aryl group, and combinations thereof; R3 is a C3-C8 aryl group, and one or more hydrogen atoms of the aryl group are unsubstituted or substituted with one or more selected from the group consisting of a C1-C6 alkyl group, a halogen group, a cyano group, a nitro group, a trifluoromethyl group, an alkoxy group, and combinations thereof; and in Chemical Formula 5b, R4 may represent hydrogen or a halogen group, and R5 may represent a C1-C6 alkyl group or a benzyl group.

[0101] In one embodiment of the present invention, the catalyst compound represented by [Formula 2] may be at least one selected from the group consisting of the catalyst compounds listed in Table 1 and combinations thereof, but is not limited thereto.

[0102] In another embodiment of the present invention, the compound represented by [Formula 5b] may be one or more selected from the group consisting of the compounds listed in Table 3 and combinations thereof, but is not limited thereto.

[0103]

[0104] In the present invention, the term "substitution" refers to a reaction in which an atom or an atomic group contained in a molecule of a compound is replaced with another atom or an atomic group.

[0105] In the present invention, the term "alkyl group" refers to a group derived from a straight-chain, branched-chain, or cyclic saturated aliphatic hydrocarbon having a specific number of carbon atoms and a valence of at least 1. Examples of such alkyl groups may be, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0106] In the present invention, the term "aryl group" refers to an unsaturated aromatic ring compound having 6 to 20 carbon atoms and a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Examples of such aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0107] In the present invention, the term "alkoxy group" means an atomic group CnH2n+1O- formed by bonding an oxygen atom to an alkyl group. Examples of such alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy.

[0108] In the present invention, the term "halogen group" refers to an element belonging to Group 17 of the periodic table, which may be, but is not limited to, fluorine (F), chloride (Cl), bromine (Br), or iodine (I). [Effects of the Invention]

[0109] A chiral gamma lactam derivative or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention has MAO-B and MSTN inhibitory effects and targets D1-mClu5, and can be used to prevent, improve, or treat muscle disorders such as sarcopenia, mental disorders such as depression, and degenerative neurological disorders such as Parkinson's disease. In particular, the pharmaceutically acceptable salt can exhibit significantly superior efficacy in controlling Parkinson's disease compared to the derivative.

[0110] The method for preparing the derivative or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention is a chiral small molecule compound-based approach, which, unlike the conventional targets focused on dopamine agonists, can preemptively lead the paradigm of a new therapeutic drug for muscular diseases, psychiatric diseases, or degenerative neurological diseases.

[0111] The method for preparing the derivative or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention can produce a chiral gamma malactam derivative or a pharmaceutically acceptable salt thereof with high stereoselectivity using an appropriate amount of organic catalyst base. Furthermore, the chiral gamma malactam derivative can be discovered as a core biomaterial and a core material of the source of global biopharmaceuticals.

[0112] The effects of the chiral gamma lactam derivative or its pharmaceutically acceptable salt according to one embodiment of the present invention and its manufacturing method are not limited to those mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the following description. [Brief explanation of the drawings]

[0113] [Figure 1] 1 shows the results of calcium release from Ph-30 (Chemical Formula 1b), a pharmaceutically acceptable salt of a chiral gamma malactam derivative according to one embodiment of the present invention, as determined using a confocal laser scanning microscope (CLSM).

[0114] [Figure 2]This shows the results of confirming the calcium release rate of rasagiline as a control and (R)-phenylpiracetam as a comparative example.

[0115] [Figure 3] The calcium release rate of Ph-10 (Chemical Formula 1d), Ph-20 (Chemical Formula 1a), and Ph-30 (Chemical Formula 1b), which are pharmaceutically acceptable salts of chiral gamma lactam derivatives according to one embodiment of the present invention, was investigated.

[0116] [Figure 4] This shows the effects of Ph-10 (Chemical Formula 1d), Ph-20 (Chemical Formula 1a), and Ph-30 (Chemical Formula 1b), which are pharmaceutically acceptable salts of chiral gamma malactam derivatives according to one embodiment of the present invention, on GDF-8 / Myostatin expression levels (*p<0.05, **p<0.01, ***p<0.001).

[0117] [Figure 5] This shows the effect of Ph-10 (Chemical Formula 1d), Ph-20 (Chemical Formula 1a), and Ph-30 (Chemical Formula 1b), which are pharmaceutically acceptable salts of chiral gamma malactam derivatives according to one embodiment of the present invention, on the expression levels of SMAD2 (Figure 5(a)) and SMAD3 (Figure 5(b)) (*p<0.05. **p<0.01).

[0118] [Figure 6] Figure 6 shows the results of treating the SH-SY5Y human neuroblastoma cell line with pharmaceutically acceptable salts of chiral gamma lactam derivatives according to one embodiment of the present invention, Ph-10 (Chemical Formula 1d), Ph-20 (Chemical Formula 1a), and Ph-30 (Chemical Formula 1b). Figure 6(a) shows the expression levels of SYP, GAP-43, MAO-B, and iNOS, and Figure 6(b) shows the calcium release and superoxide anion production.

[0119] [Figure 7] 7 shows the results of an open field test (OFT) performed on mice treated with a pharmaceutically acceptable salt of a chiral gamma malactam derivative according to one embodiment of the present invention. Figure 7(a) shows the distance traveled when treated with various concentrations of Ph-30 (Chemical Formula 1b), and Figure 7(b) shows the distance traveled when treated with Ph-10 (Chemical Formula 1d), Ph-20 (Chemical Formula 1a), and Ph-30 (Chemical Formula 1b) (*p<0.05, **p<0.01, ***p<0.001).

[0120] [Figure 8] The figure shows the results of a forced swim test (FST) conducted on mice treated with Ph-10 (Chemical Formula 1d), Ph-20 (Chemical Formula 1a), and Ph-30 (Chemical Formula 1b), which are pharmaceutically acceptable salts of chiral gamma malactam derivatives according to one embodiment of the present invention (*p<0.05, **p<0.01, ***p<0.001).

[0121] [Figure 9] 9 shows the results of a rotarod test performed with pharmaceutically acceptable salts of chiral gamma lactam derivatives Ph-10 (Formula 1d), Ph-20 (Formula 1a), and Ph-30 (Formula 1b) according to one embodiment of the present invention. Figure 9(a) shows the time it took to fall from an accelerating rotarod (ARR), Figure 9(b) shows the muscle weight of the tibialis anterior (TA), and Figure 9(c) shows the muscle weight of the extensor digitorum longus (EDL) (*p<0.05, **p<0.01, ***p<0.001).

[0122] [Figure 10]The number of convulsive seizures was analyzed when treated with Ph-10 (Chemical Formula 1d), Ph-20 (Chemical Formula 1a), and Ph-30 (Chemical Formula 1b), which are pharmaceutically acceptable salts of chiral gamma lactam derivatives according to one embodiment of the present invention (**p<0.01).

[0123] [Figure 11] The figure shows the effect of Ph-10 (Chemical Formula 1d), Ph-20 (Chemical Formula 1a), and Ph-30 (Chemical Formula 1b), which are pharmaceutically acceptable salts of chiral gamma malactam derivatives according to one embodiment of the present invention, on the expression levels of GDF-8 / Myostatin in mouse serum (*p<0.05. **p<0.01). DETAILED DESCRIPTION OF THE INVENTION

[0124] The present inventors have solved the problems of the difficulty of synthesizing gamma lactam derivatives using chiral catalysts and the problem of using excessive amounts of chiral catalysts in the conventional synthesis of gamma lactam derivatives using chiral catalysts, and have solved the problem of mass production by shortening the reaction time.

[0125] Specifically, the inventors have synthesized a highly stereoselective unnatural gamma lactam derivative or a pharmaceutically acceptable salt thereof from a nitro compound using a bifunctional organic chiral catalyst compound with excellent stereoselectivity. Furthermore, the inventors have confirmed the MAO-B and MSTN inhibitory effects of the synthesized chiral gamma lactam derivative or a pharmaceutically acceptable salt thereof, as well as the preventive, ameliorative, or therapeutic effects of muscular disorders, psychiatric disorders, or degenerative neurological disorders through behavioral experiments and studies of changes in brain activity.

[0126] Based on the above results, the present invention provides a pharmaceutical composition for the prevention or treatment of muscular diseases, psychiatric diseases, or degenerative neurological diseases, comprising as an active ingredient a chiral gamma malactam derivative or a pharmaceutically acceptable salt thereof shown in Table 4 below.

[0127] [Table 4]

[0128]

[0129] The present invention can also provide use of a chiral gamma malactam derivative or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a muscular disease, a psychiatric disease, or a degenerative neurological disease.

[0130] The present invention also provides a method for preventing or treating a muscular disease, a psychiatric disease, or a degenerative neurological disease, comprising administering the chiral gamma malactam derivative or a pharmaceutically acceptable salt thereof to an individual.

[0131] In the present invention, the term "pharmaceutically acceptable salt" refers to a dosage form of a compound that does not cause significant irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutically acceptable salts can be obtained by reacting the compounds of the present invention with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, and phosphoric acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid; and organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, capric acid, isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and salicylic acid. The compounds of the present invention can also be obtained by reacting them with bases to form salts such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, and tris(hydroxymethyl)methylamine, and salts of amino acids such as arginine and lysine. In addition to pharmaceutically acceptable salts, the compounds may also include all salts, hydrates and solvates that can be prepared by conventional methods.

[0132] In the present invention, the term "prevention" means any action of suppressing or delaying the occurrence, spread or recurrence of geriatric diseases such as muscular diseases, depression, Parkinson's disease, etc. by administering the composition of the present invention, and "treatment" means any action of improving or beneficially changing the symptoms of the disease by administering the composition of the present invention.

[0133] In the present invention, the term "pharmaceutical composition" refers to a substance prepared for the purpose of preventing or treating the above-mentioned diseases, and can be formulated into various forms according to conventional methods for use, such as oral dosage forms such as acid tablets, granules, tablets, capsules, suspensions, emulsions, and syrups, and can also be formulated into external preparations, suppositories, and sterile injections.

[0134] In the present invention, "containing as an active ingredient" means that the ingredient is contained in an amount necessary or sufficient to achieve a desired biological effect. In practical application, the amount of the active ingredient can be determined taking into consideration the amount required to treat the target disease and not causing other toxicity, and can vary depending on various factors such as the disease or condition being treated, the form of the composition to be administered, the size of the subject, or the severity of the disease or condition. A person skilled in the art to which the present invention pertains can empirically determine the effective amount of each composition without undue experimentation.

[0135] Furthermore, the pharmaceutical composition of the present invention may further contain one or more pharmaceutically acceptable carriers in addition to the active ingredients described above, depending on the dosage form.

[0136] The pharmaceutically acceptable carrier may be physiological saline, sterile water, Ringer's solution, buffered physiological saline, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more of these components, and may further contain other common additives such as antioxidants, buffers, bacteriostatic agents, etc., as necessary. Diluents, dispersants, surfactants, binders, and lubricants may also be added to formulate the composition into injection forms such as aqueous solutions, suspensions, and emulsions, as well as pills, capsules, granules, or tablets. Furthermore, suitable formulations may be prepared according to the disease or ingredients using a suitable method in the art or the method disclosed in Remington's Pharmaceutical Sciences (Mack Publishing Company, Easton PA).

[0137] The compositions of the present invention can be administered orally or parenterally in a pharmaceutically effective amount depending on the intended method. The term "pharmaceutically effective amount" as used herein means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment, without causing any adverse effects. The effective dose level can be determined based on factors including the patient's health condition, severity, drug activity, sensitivity to the drug, administration method, administration time, administration route and excretion rate, treatment period, concomitant or concomitant drugs, and other factors well known in the medical field.

[0138] In the present invention, the term "individual" is not limited to any mammal, such as a domestic animal or a human, that requires prevention, treatment, and / or diagnosis of the disease, but is preferably a human.

[0139] The pharmaceutical composition of the present invention can be formulated into various forms for administration to an individual. A typical parenteral dosage form is an injectable dosage form, preferably an isotonic aqueous solution or suspension. Injectable dosage forms can be prepared according to techniques known in the art using appropriate dispersants or wetting agents and suspending agents. For example, each component can be dissolved in physiological saline or a buffer solution to form an injection formulation. Oral dosage forms include, for example, ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. These dosage forms may contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine) and lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, and may optionally further contain disintegrants, absorbents, colorants, flavorings and / or sweeteners such as starch, agar, alginic acid or its sodium salt, etc. The dosage forms may be manufactured by conventional mixing, granulating or coating methods.

[0140] Furthermore, the pharmaceutical composition of the present invention may further contain auxiliary substances such as preservatives, wetting agents, emulsifiers, salts for adjusting osmotic pressure or buffers, and other therapeutically useful substances, and can be formulated according to conventional methods.

[0141] The pharmaceutical composition according to the present invention can be administered via various routes including oral, transdermal, subcutaneous, intravenous or intramuscular, and the dosage of the active ingredient can be appropriately selected depending on various factors such as the administration route, the age, sex, weight and severity of the patient, etc. The composition of the present invention can also be administered in combination with a known compound that can enhance the desired effect.

[0142] The pharmaceutical composition of the present invention can be administered to humans or animals orally or parenterally, such as intravenously, subcutaneously, intranasally, or intraperitoneally. Oral administration also includes sublingual administration. Parenteral administration includes injections such as subcutaneous injection, intramuscular injection, and intravenous injection, as well as infusion methods.

[0143] Furthermore, the pharmaceutical composition of the present invention is not particularly limited in its dosage form, administration route, or administration method, as long as it exhibits the effects of the present invention. The pharmaceutical composition of the present invention may further contain known drugs in addition to the chiral gamma malactam derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and may be used in combination with other known treatments for the treatment of these diseases.

[0144]

[0145] The terms used in the examples are used for the purpose of explanation and should not be construed as limiting. A singular expression includes a plural expression unless the context clearly indicates otherwise. In this specification, the terms "comprise" or "have" are intended to specify the presence of a feature, number, step, operation, component, part, or combination thereof described in the specification, and should be understood not to preclude the possibility of the presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0146] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which the embodiments pertain. Terms as defined in commonly used dictionaries should be interpreted to have a meaning consistent with the meaning they have in the context of the relevant art, and should not be interpreted in an idealized or overly formal sense unless expressly defined in this application.

[0147] When describing components of the embodiments, terms such as first, second, A, B, (a), (b), etc. may be used. These terms are used to distinguish the component from other components, and do not limit the nature, order, or sequence of the components. When a component is described as being "coupled," "coupled," or "connected" to another component, it should be understood that the component may be directly coupled or connected to the other component, but that other components may also be "coupled," "coupled," or "connected" between the components. [Example]

[0148] Hereinafter, the embodiments will be described in detail with reference to the accompanying drawings. However, various modifications may be made to the embodiments, and the scope of the patent application is not limited or restricted by such embodiments. It should be understood that all modifications, equivalents, or alternatives to the embodiments are included in the scope of the patent application.

[0149] In addition, when describing the embodiments with reference to the accompanying drawings, the same reference numerals will be used to designate the same components regardless of the reference numerals in the drawings, and redundant descriptions thereof will be omitted. In describing the embodiments, if it is determined that a detailed description of related publicly known technology may unnecessarily obscure the gist of the embodiments, the detailed description thereof will be omitted.

[0150]

[0151] Since the present invention can be modified in various ways and can have various embodiments, specific embodiments will be illustrated in the drawings and described in detail below. However, this does not limit the present invention to the specific embodiments, but should be understood to include all modifications, equivalents, or alternatives within the spirit and technical scope of the present invention. In describing the present invention, if it is determined that a detailed description of related publicly known technology may obscure the gist of the present invention, the detailed description will be omitted.

[0152] Example 1. Preparation of organic chiral catalyst compounds of the present invention

[0153] A method for preparing an organic chiral catalyst compound, i.e., an arylated thiourea catalyst, according to one embodiment of the present invention is shown in Reaction Scheme 1 below.

[0154] [Reaction Scheme 1]

[0155] [ka]

[0156] To a suspension of (R,R)-1,2-diphenylethylenediamine (1.0 equiv.) in toluene (0.5 M) was added thiourea (0.95 equiv.) at 0 °C, and the mixture was stirred for 30 seconds. The product was concentrated in vacuo and purified by flash column chromatography on silica gel containing ethyl acetate (methanol / methylene chloride 1:20). To the thiourea-substituted DPEN (1.0 equiv.) in CHCl (0.1 M) was added an alkyl ketone (1.1 equiv.), and the mixture was stirred at room temperature for 1 hour. NaBH (2.0 equiv.) and ethanol were added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The product was filtered through a Celite filter, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO), and concentrated in vacuo. The product was purified by chromatography on a silica gel column (methanol / methylene chloride 1:20) to give the pure amide product (quantitative yield) as a brown foamy solid.

[0157] Specific examples of the organic chiral catalyst compounds are shown in Table 5 below.

[0158] [Table 5]

[0159]

[0160] (1) 1 - ((1R,2R)-2-(3,5-bis(trifluoromethyl)benzylamino)-1,2-diphenylethyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea (1a, Chemical formula 2-1)

[0161] 93% yield; [α] D 20 = +0.45 (c = 0.11, CH2Cl2); 1 1H NMR (500 MHz, DMSO-d6) δ 7.61 (br, 3H), 7.39~7.29 (m, 16H), 4.54 (s, 4H); 13 13C NMR (100 MHz, DMSO-d6) δ 171.58, 157.99, 142.12, 131.46, 134.14, 129.17, 127.28, 125.67, 122.96, 112.29, 89.59, 89.05, 84.78; IR (KBr) 3032.6, 2871.3, 1663.5, 1386.6, 1275.9, 1117.5, 930.2, 700.2 cm -1 ; HRMS (FAB + ) for C 32 H 23 F 12 N3S [M + H] + Calcd: 709.1421, Found: 709.1428

[0162] (2) 1 - [(1R,2R)-2-(Pentan-3-ylamino)-1,2-diphenylethyl]-3-(p-tolyl)thiourea (1b, Chemical formula 2-2)

[0163] 86% yield; [α] D 20 = +0.19 (c = 1.00, CH2Cl2); 1HNMR(300MHz, DMSO-d6) δ 9.76 (s, 1H), 7.89 (d, J = 7.0Hz, 1H), 7.32 - 7.18 (m, 14H), 5.44 (s, 1H), 4.08 (d, J = 5.1Hz, 1H), 2.29 (s, 2H), 2.02 (s, 1H), 1.39 (s, 1H), 1.20 - 1.06 (m, 4H), 0.68 (t, J = 7.5Hz, 3H), 0.41 (t, J = 7.1Hz, 3H); 13 CNMR(100MHz, DMSO-d6) δ 181.04, 141.83, 141.55, 136.71, 134.88, 130.03, 128.67, 128.51, 127.49, 127.40, 124.67, 64.28, 63.77, 55.84, 26.71, 24.02, 21.20, 10.94, 8.30; IR(KBr) 3180.2, 2958.4, 1948.8, 1510.1, 1240.1, 821.6, 700.1, 565.1 cm -1 ; HRMS(FAB + ) for C 27 H 34 N3S [M + H] + Calcd: 432.2473, Found: 432.6537, pattern 432.5, 345.3, 266.4, 176.3, 106.01

[0164] (3) 1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1R,2R)-2-(pentan-3-ylamino)-1,2-diphenylethyl]thiourea (1c, Chemical formula 2-3)

[0165] 90% yield; [α] D 20 = +0.31 (c = 0.11, CH2Cl2); 1 HNMR(300MHz, DMSO-d6) δ 10.5 (br, 1H), 8.30 (s, 2H), 7.74 (s, 1H), 7.40 - 7.19 (m, 10H), 5.57 (br, 1H), 4.18 (d, J = 4.9Hz, 1H), 2.09 (m, 1H), 1.​CNMR (100 MHz, DMSO-d6) δ 181.10, 142.49, 140.88, 130.96, 130.64, 128.70, 128.59, 128.56, 127.60, 125.22, 122.52, 122.19, 116.70, 64.34, 63.62, 56.48, 26.64, 23.90, 10.98, 8.54; IR (KBr) 3239.9, 2964.2, 1471.5, 1278.6, 1135.9, 885.2, 700.1 cm -1 ; HRMS (FAB + ) for C 28 H 30 F6N3S [M + H] + Calcd: 554.2065, Found: 554.2065

[0166] (4) 1-[(1R,2R)-2-(Pentan-3-ylamino)-1,2-diphenylethyl]-3-[4-(trifluoromethyl)phenyl]thiourea (1d, Chemical formula 2-4)

[0167] 88% yield; [α] D 20 = +45.5 (c = 0.02, CH2Cl2); 1 1H NMR (300 MHz, DMSO-d6) δ 10.2 (brs, 1H), 8.41 (brs, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.35~7.15 (m, 10H), 5.53 (brs, 1H), 4.13 (d, J = 5.5 Hz, 1H), 2.07 (m, 1H), 1.30~1.15 (m, 4H), 0.73 (t, J = 7.1 Hz, 3H), 0.49 (t, J = 6.9 Hz, 3H); 13 13C NMR (100 MHz, DMSO-d6) δ 180.91, 143.97, 141.18, 128.64, 128.52, 127.69, 127.48, 126.29, 122.-1 ; HRMS (FAB + ) for C 27 H 31 F3N3S [M + H] + Calcd: 486.2191, Found: 486.2190

[0168] (5) 1-[(1R,2R)-2-(Pentan-3-ylamino)-1,2-diphenylethyl]-3-(perfluorophenyl)thiourea (1e, Chemical formula 2-5)

[0169] 89% yield; [α] D 20 = +80.4 (c = 0.02, CH2Cl2); 1 1H NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.61 (s, 1H), 7.30~7.15 (m, 10H), 5.48 (brs, 1H), 4.13 (d, J = 6.1 Hz, 1H), 2.08 (m, 1H), 1.54 (br, 1H), 1.30~1.14 (m, 4H), 0.74 (t, J = 7.4 Hz, 3H), 0.55 (t, J = 6.3 Hz, 3H); 13 13C NMR (100 MHz, DMSO-d6) δ 183.63, 145.82, 143.43, 141.90, 140.77, 139.01, 138.84, 136.56, 129.39, 128.61, 128.43, 127.68, 127.60, 115.93, 64.77, 64.53, 56.37, 26.72, 24.16, 10.86, 8.58; IR (KBr) 3299.8, 2964.2, 1525.5, 1344.2, 1145.6, 991.3, 912.2, 700.1, 605.6 cm -1 ; HRMS (FAB + ) for C 26 H 27 F5N3S [M + H] + Calcd: 508.1846, Found: 508.1848

[0170] (6) 1-(4-Nitrophenyl)-3-[(1R,2R)-2-(pentan-3-ylamino)-1,2-diphenylethyl]thiourea (1f, Chemical Formula 2-6)

[0171] 89% yield; [α] D 20 = +37.7 (c = 0.02, CH2Cl2); 1 1H NMR (300 MHz, DMSO-d6) δ 10.5 (s, 1H), 8.16 (m, 2H), 7.90 (d, J = 9.1 Hz, 2H), 7.37~7.15 (m, 10H), 5.54 (brs, 1H), 4.16 (d, J = 5.5 Hz, 1H), 2.07 (m, 1H), 1.30~1.15 (m, 4H), 0.75 (t, J = 7.4 Hz, 3H), 0.50 (t, J = 7.4 Hz, 3H); 13 13C NMR (100 MHz, DMSO-d6) δ 180.51, 146.95, 142.46, 141.92, 140.92, 128.68, 128.56, 127.72, 125.16, 120.92, 64.35, 63.80, 56.35, 55.59, 26.70, 23.96, 11.03, 8.61; IR (KBr) 3330.5, 2960.2, 2599.6, 2456.4, 2345.0, 1951.6, 1743.3, 1496.5, 1346.1, 1110.8, 1072.2, 852.4, 700.0, 586.3 cm -1 ; HRMS (FAB + ) for C 26 H 31 N4O2S [M + H] + Calcd: 463.2168, Found: 463.2165

[0172] (7) 1-(4-Cyanophenyl)-3-[(1R,2R)-2-(pentan-3-ylamino)-1,2-diphenylethyl]thiourea (1g, Chemical Formula 2-7)

[0173] 69% yield; [α] D 20 = +55.5 (c = 0.02, CH2Cl2); 1HNMR (300 MHz, DMSO-d6) δ 10.3 (brs, 1H), 8.54 (brs, 1H), 7.84 - 7.72 (m, 4H), 7.35 - 7.17 (m, 10H), 5.54 (brs, 1H), 4.14 (d, J = 5.2 Hz, 1H), 2.07 (brs, 1H), 1.56 (brs, 1H), 1.21 (m, 4H), 0.74 (t, J = 7.4 Hz, 3H), 0.49 (t, J = 6.9 Hz, 3H); 13 CNMR (100 MHz, DMSO-d6) δ 180.62, 144.83, 141.92, 141.05, 133.40, 128.67, 128.33, 127.68, 127.64, 127.51, 121.76, 119.76, 105.41, 64.41, 63.72, 60.43, 56.33, 26.74, 23.98, 21.42, 14.74, 11.02, 8.56; IR (KBr) 3317.0, 2960.2, 2360.4, 2225.5, 1949.7, 1739.5, 1508.1, 1315.2, 1176.4, 1072.2, 837.0, 700.0, 545.8 cm -1 ; HRMS (FAB + ) for C 27 H 31 N4S [M + H] + Calcd: 443.2269, Found: 443.2271

[0174] (8) 1-(4-Fluorophenyl)-3-[(1R,2R)-2-(pentan-3-ylamino)-1,2-diphenylethyl]thiourea (1h, Chemical formula 2 - 8)

[0175] 84% yield; [α] D 20 = +17.9 (c = 0.02, CH2Cl2); 1HNMR (300 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.00 (d, J = 6.7 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.31 - 7.16 (m, 11H), 5.46 (brs, 1H), 4.09 (d, J = 5.22 Hz, 1H), 2.03 (brs, 1H), 1.44 (brs, 1H), 1.14 (m, 4H), 0.70 (t, J = 10.1, 3H), 0.44 (t, J = 7.0 Hz, 3H); 13 CNMR (100 MHz, DMSO-d6) δ 181.42, 161.03, 158.62, 141.90, 141.44, 135.97, 128.65, 128.51, 127.57, 127.42, 126.49, 116.13, 115.90, 64.39, 63.76, 56.03, 26.72, 24.02, 10.98, 8.39; IR (KBr) 3193.7, 2962.3, 1889.9, 1511.9, 1218.8, 848.6, 701.9, 555.42 cm -1 ; HRMS (FAB + ) for C 26 H 31 FN3S [M + H] + Calcd: 436.6172, Found: 436.2223. patern 436.5, 349.3, 266.4, 176.3, 106.1

[0176] (9) 1 - ((1R,2R)-2-(benzhydrylamino)-1,2-diphenylethyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea (1i, Chemical formula 2 - 9)

[0177] 95% yield; [α] D 20 = +0.39 (c = 0.16, CH2Cl2); 1 HNMR (400 MHz, DMSO-d6) δ 7.82 - 7.09 (m, 23H), 5.72 (s, 1H), 3.98 (s, 1H), 3.35 (s, 1H), 2.47 (br, 1H); 13CNMR (100 MHz, DMSO-d6) δ 181.06, 156.63, 153.35, 143.36, 142.03, 141.31, 138.68, 129.48, 129.34, 126.90, 125.59, 123.65, 122.55, 122.14, 70.83, 65.14, 55.50; IR (KBr) 3239.9, 2964.2, 1471.5, 1278.6, 1135.9, 885.2, 700.1 cm -1 ; HRMS (ESI + ) for C 28 H 30 F6N3S [M + H] + Calcd: 649.1986, Found: 649.1932

[0178] (10) 1-((1R,2R)-2-(benzhydrylamino)-1,2-diphenylethyl)-3-(4-(trifluoromethyl)phenyl)thiourea (1j, Chemical formula 2-10)

[0179] 89% yield; [α] D 20 = +124 (c 0.10, CH2Cl2); 1 HNMR (300 MHz, DMSO-d6) δ 9.44 (br, 1H), 7.77~7.10 (m, 26H), 4.90 (s, 1H), 4.82 (s, 2H), 1.92 (s, 1H); IR (KBr) 3679.5, 3352.2, 2985.3, 1402.4, 1265.9, 1065.7, 726.8 cm -1 ; HRMS (FAB + ) for C 35 H 30 F3N3S [M + H] + Calcd: 581.2113, Found: 581.2133

[0180] (11) 1-((1R,2R)-2-(3,5-dimethylbenzylamino)-1,2-diphenylethyl)-3-(3,5-dimethylphenyl)thiourea (1k, Chemical formula 2-11)

[0181] 89% yield;[α] D 20 =+112(c0.13, CH2Cl2); 1 HNMR (500MHz, DMSO-d6) δ7.38(t, 6H), 7.32(d, 2H), 7.27(d, 4H), 7.00(s, 4H), 4.54(s, 4H), 2.21(s, 12H), 1.25(br, 1H); 13 CNMR (100MHz, DMSO-d6) δ167.08, 157.71, 156.95, 143.07, 138.05, 131.22, 129.00, 128.93, 127.09, 127.03, 123.43, 118.64, 112.63, 70.28, 68.05, 67.38, 21.63; IR(KBr)3155.0, 2960.2, 2360.4, 1951.6, 1735.6, 1469.5, 1294.0, 1241.9, 1006.7, 837.0, 700.0, 572.8cm -1 ;HRMS(FAB + )forC 26 H 30 F2N3S[M+H] + Calcd:454.2129, Found:454.2133.

[0182]

[0183] Example 2. Preparation of (S)-phenylpiracetam hydrochloride (formula 1a)

[0184] A method for preparing (S)-phenylpiracetam hydrochloride (Chemical Formula 1a), a pharmaceutically acceptable salt of an (S)-chiral gamma lactam derivative according to one embodiment of the present invention, is shown in Reaction Scheme 2 below.

[0185] [Reaction Scheme 2]

[0186] [ka]

[0187] Using the organic chiral catalyst compound 1a prepared in Example 1, a Michael addition reaction was carried out with a nitroethyl ester in the presence of water as a solvent, and the reaction time and yield of the α,β-unsaturated ketone compound were confirmed. Specifically, an α,β-unsaturated ketone (1.0 equivalent), a nitroethyl ester (2.0 equivalents), and 0.1 to 0.001 mol% of the organic chiral catalyst compound 1a were added to water (0.4 mL), and the reaction mixture was stirred at room temperature (rt). The reaction conversion was then monitored by TLC. After completion of the reaction, sodium hydroxide (1.0 equivalent) and ethanol were added, and the mixture was stirred at room temperature for 12 hours. The mixture was then concentrated under reduced pressure to obtain the target product. The product was purified by chromatography on a silica gel column (hexane / ethylene acetate, 10:1).

[0188]

[0189] Example 2.1. (S)-4-Nitro-1,3-diphenyl-butan-1-one (3a, Formula 4a)

[0190] [ka]

[0191] [α] D 20 -18.5(c1.0, CHCl3); 1 HNMR (500MHz, CDCl3) δ7.91~7.92(m, 2H), 7.59~7.26(m, 8H), 4.85~4.81(dd, 1H), 4 .71~4.67(dd, 1H), 4.26~4.20(m, 1H), 3.51~3.46(dd, 1H), 3.45~3.40(dd, 1H)ppm; 13 CNMR (125MHz, CDCl3) δ196.87, 139.15, 136.39, 133.60, 129.09, 128.77, 128.04, 127.90, 127.48, 79.58, 41 .54, 39.30ppm; IR (KBr) 3058, 3029, 2920, 1687, 1544, 1440, 1367, 1268, 1224, 1084, 988, 764, 703, 623, 559cm -1;LRMS(ESI + )forC 16 H 15 NO3[M+Na] + Calcd:292.1, Found:292.1;HPLC[ChiralcelAD-H, hexane / 2-propanol=90 / 10, flowrate=1.0mL / min, λ=254nm, retentiontimes: (major)12.8min, (minor)17.4min]; R f( SiO2, EtOAc / n-hexane=1 / 5)=0.40

[0192]

[0193] Example 2.2. (S)-Fusyl-4-Tintotron derivative (Chemical Formula 5a)

[0194] (1) (S)-Phenyl4-nitro-3-phenylbutanoate (4a, Chemical Formula 5a-1)

[0195]

change

[0196] [α] D 20 +7.7(c1.0, CHCl3); 1 HNMR (500MHz, CDCl3) δ7.38~7.16(m, 8H), 6.87~6.85(m, 2H), 4.75~4.71(dd, J=11.6, 6.6Hz, 1H), 4.68~4.64(dd, J=11.6, 6.4Hz, 1H), 4.10~4.04(m, 1H), 3.04~3.0(dd, J=13.7, 4.6Hz, 1H), 2.99~2.94(dd, J=13.7, 5.6Hz, 1H)ppm; 13 CNMR (125MHz, CDCl3) δ169.33, 150.33, 137.96, 129.50, 129.22, 128.29, 127.55, 126.12, 121.39, 79.38, 40.38, 37.87ppm; LRMS (ESI + )forC 16 H15 NO4[M+Na] + Calcd:308.1、Found:308.1;R f( SiO2, EtOAc / n-hexane=1 / 5)=0.40

[0197] (2) (S)-Phenyl3-(4-chlorophenyl)-4-nitrobutanoate (4b, Chemical Formula 5a-2)

[0198]

change

[0199] [α] D 20 +20.8(c1.0,CH2Cl2); 1 HNMR (500MHz, CDCl3) δ7.35~7.22(m, 7H), 6.92~6.90(m, 2H), 4.79~4.75(dd, J=12.7, 7.3Hz, 1H), 4.71~4.67(dd, J =12.7, 7.9Hz, 1H), 4.11~4.06(m, 1H), 3.08~3.03(dd, J=14.7, 5.3Hz, 1H), 3.01~2.96(dd, J=14.7, 6.5Hz, 1H)ppm; 13 CNMR (125MHz, CDCl3) δ169.01, 150.17, 136.37, 134.23, 129.53, 129.43, 128.88, 126.20, 121.26, 79.08, 39.70, 37.67ppm; LRMS (ESI + )forC 16 H 14 ClNO4[M+Na] + Calcd:342.1、Found:342.1;R f( SiO2、EtOAc / n-hexane=1 / 5)=0.31

[0200]

[0201] Example 2.3. (S)-4-Phenylpyrrolidin-2-one (4c, chemical formula 6a)

[0202] [Chemical formula]

[0203] 1 HNMR (500 MHz, CDCl3) δ 7.37 - 7.33 (m, 2H), 7.29 - 7.27 (m, 2H), 7.26 - 7.25 (m, 1H), 5.92 (brs, 1H), 3.81 - 3.77 (m, 1H), 3.71 (q, J = 8.0 Hz, 1H), 3.45 - 3.41 (dd, J = 9.4, 2.0 Hz,​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​A solution of 4-phenyl-2-pyrrolidinone (1.0 equivalent) in 1,4-dioxane (30 ml) was added to a suspension of sodium hydride (1.1 equivalent) in 1,4-dioxane (30 ml). The mixture was heated at 90°C for 30 minutes and then cooled to room temperature. Ethyl bromoacetate (1.1 equivalent) was added, and the reaction mixture was refluxed at 120°C for 6 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 1:1 mixture of ethyl acetate and hexane to give N-ethoxycarbonylmethyl-4-phenyl-2-pyrrolidinone. A solution of N-ethoxycarbonylmethyl-4-phenyl-2-pyrrolidinone (250 mg, 1.01 mmol) in methanol (30 ml) was saturated with a gaseous ammonia stream for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using a 1:1 mixture of ethyl acetate and hexane and concentrated under reduced pressure. The concentrate was added to 6N HCl, stirred to dissolve, and concentrated again under reduced pressure to obtain N-carbamoylmethyl-4-phenyl-2-pyrrolidinone chloride (85%).

[0208] 1 HNMRspectrum (DMSO-d6), δ, ppm: 2.41dd (1H, 3-H), 2.72dd (1H, 3-H), 3.42m (1H, 5 -H), 3.59m(1H, 4-H), 3.79m(1H, 5-H), 4.00dd(2H, NCH2CO); 7.24-7.36m(5H, Ph). 13 CNMRspectrum (DMSO-d6), δC, ppm:37.01, 38.48, 44.04, 54.55, 127.16, 127.35, 129.08, 143.35, 170.64, 173.84pp; LRMS (ESI + )forC 10 H 14 ClNO2[M] + Calcd:254, Found:254;

[0209]

[0210] Example 3. Preparation of (R)-phenylpiracetam hydrochloride (Formula 1b)

[0211] A method for preparing (R)-phenylpiracetam hydrochloride (Chemical Formula 1b) and (R)-phenylpiracetam hydrazide hydrochloride (Chemical Formula 1d), which are pharmaceutically acceptable salts of (R)-chiral gamma lactam derivatives according to one embodiment of the present invention, is shown in Reaction Scheme 3 below.

[0212] [Reaction Scheme 3]

[0213] [ka]

[0214] a) Catalyst compound 1a (0.0001mol%), water, room temperature, 48 hours; b) Magnesium monoperoxyphthalate hexahydrate (MMPP), Li2CO3, MeOH, 0°C, 1 hour; c) NiCl2 6H2O / NaBH4, MeOH, room temperature, 6 hours; d) (1) NaOH, EtOH, room temperature, 0.5 hours; (2) Toluene, reflux, 0.5 hours.

[0215]

[0216] Example 3.1. (R)-Malonate Derivative (Formula 5b)

[0217] A method for producing the (R)-malonate derivative, which is an intermediate for producing the pharmaceutically acceptable salt of the (R)-chiral gamma malactam derivative, is shown in the following reaction scheme 4.

[0218] [Reaction Scheme 4]

[0219] [ka]

[0220]

[0221] The α,β-unsaturated nitro compound was mixed with trans-β-nitrostyrene (1.0 equiv.), malononitrile (2.0 equiv.), and malononitrile (2.0 equiv.) in the presence of malonitrile (2.0 equiv.) and the organic chiral catalyst compound 1a (0.001 mol%) prepared in Example 1, using water (0.4 mL) as the solvent. The reaction mixture was stirred at room temperature. The reaction conversion was monitored by TLC. Upon completion of the reaction, 6N HCl was added and heated at 65°C for 2 hours. After cooling to room temperature, dialkyl carbonate (1.5 equiv.) was added, and the solution was heated with stirring at 100°C for 3 hours. The homogeneous reaction mixture was then cooled to room temperature and poured into 10% aqueous NaHCO3 solution. Ethyl acetate (0.2 mL) was added to the reaction mixture. The solution was washed twice with water (2 × 1.0 mL), dried over magnesium sulfate, and concentrated to obtain the desired product. The product was then purified by chromatography on a silica gel column (hexane / methylene chloride 2:1).

[0222] Under an argon atmosphere, NaBH4 (10 equiv.) was added to a suspension of the obtained Michael addition reaction product (1.0 equiv., >99% ee) and NiCl2-6H2O (1.0 equiv.) in MeOH (8.0 mL) at 0 °C. After stirring the reaction mixture at room temperature for 7.5 h, the reaction mixture was quenched with NH4Cl and diluted with CHCl3. The organic layer was separated, filtered through MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel (solvent: MeOH / CHCl3 = 1:20) to obtain the desired product as a colorless powder.

[0223] (1)(R)-Dimethyl2-(2-nitro-1-phenylethyl)malonate(2a, chemical formula 5b-1)

[0224] [ka]

[0225] [α] D 20 =-1.98(c1.33, CH2Cl2); 1HNMR (300 MHz, CDCl3) δ 7.40 - 7.15 (m, 5H), 5.15 - 5.03 (m, 1H), 4.93 (dd, J = 4.5, 12.8 Hz, 1H), 4.88 - 4.76 (m, 2H), 4.20 (td, J = 4.5, 9.5 Hz, 1H), 3.76 (d, J = 9.5 Hz, 1H), 1.24 (d, J = 6.1 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 6.4 Hz, 3H) ppm; 13 CNMR (100 MHz, CDCl3) δ 167.1, 166.4, 136.3, 128.9, 128.3, 128.2, 77.9, 69.9, 69.5, 55.1, 42.9, 21.5, 21.4, 21.19, 21.17 ppm; IR (KBr) 3030, 2985, 1727, 1557 cm -1 ; HRMS (ESI) for C 13 H 16 N1O6 [M + H] + Calcd: 282.09721, Found: 282.09726; HPLC [Chiralcel AD - H, hexane / 2 - propanol = 95 / 5, 1.0 mL / min, λ = 254 nm, retention times: (major) 23.3 min, (minor) 38.0 min].

[0226] (2) (R) - Diethyl 2 - (2 - nitro - 1 - phenylethyl) malonate (2b, Chemical formula 5b - 2)

[0227]

Chem.

[0228] [α] D 20 = - 4.61 (c = 0.23, CH2Cl2); 11H NMR (300 MHz, CDCl3) δ 7.30 - 7.20 (m, 5H), 4.93 (dd, J = 4.6, 13.1 Hz, 1H), 4.86 (dd, J = 9.2, 13.1 Hz, 1H), 4.24 - 4.17 (m, 3H), 3.98 - 3.97 (q, 2H), 3.81 - 3.79 (d, 1H), 1.25 (t, 3H), 1.03 (t, 3H) ppm; 13 13C NMR (100 MHz, CDCl3) δ 167.4, 166.8, 136.2, 128.8, 128.2, 77.4, 77.0, 76.7, 62.1, 61.8, 54.9, 42.9, 13.9, 13.7 ppm; IR (KBr) 2989, 2938, 1731, 1557 cm -1 ; HRMS (ESI) for C 15 H 20 N1O6 [M + H] + Calcd: 310.12851, Found: 310.12936; HPLC [Chiralcel AD - H, hexane / ethanol = 90 / 10, 1.0 mL / min, λ = 254 nm, retention times: (major) 11.5 min, (minor) 15.3 min].

[0229] (3)(R)-Diisopropyl 2-(2-nitro-1-phenylethyl)malonate (2c, Chemical formula 5b - 3)

[0230]

Chem.

[0231] [α] D 20 = -1.24 (c 1.00, CH2Cl2); 1 1H NMR (300 MHz, CDCl3) δ 7.32 - 7.22 (m, 5H), 5.10 (dd, J = 5.0, 13.1 Hz, 1H), 4.91 - 4.979 (m, 3H), 4.21 - 4.19 (m, 1H), 1.25 (d, J = 2.0 Hz, 6H), 1.07 (dd, J = 2.0, 2.0 Hz, 6H) ppm; 1313C NMR (100 MHz, CDCl3) δ 167.27, 166.54, 136.47, 129.07, 128.34, 127.9, 78.15, 70.15, 69.75, 55.35, 43.14, 21.80, 21.67, 21.48 ppm; IR (KBr) 3029, 2956, 1737, 1558 cm -1 ; HRMS (ESI) for C 17 H 24 N1O6 [M + H] + Calcd: 338.15981 Found: 338.16336; HPLC [Chiralcel AD-H, hexane / 2-propanol = 95 / 5, 1.0 mL / min, λ = 254 nm, retention times: (major) 14.8 min, (minor) 34.4 min].

[0232] (4)(R)-Dipropyl 2-(2-nitro-1-phenylethyl)malonate (2d, Chemical formula 5b-4)

[0233]

Chem.

[0234] [α] D 20 = -1.73 (c 0.10, CH2Cl2); 1 1H NMR (300 MHz, CDCl3) δ 7.31~7.22 (m, 5H), 4.92~4.87 (t, J = 5.0, 9.5 Hz, 2H), 4.24 (m, 1H), 4.15~4.09 (m, 2H), 3.92~3.83 (dd, s, J = 6.6 9.7 Hz, 3H), 1.68~1.61 (m, 2H), 1.49~1.42 (m, 2H), 0.93~0.88 (t, J = 7.4, 7.4 Hz, 3H), 0.82~0.77 (t, J = 7.4, 7.4 Hz, 3H) ppm;<目标文本中未提及该标签对应的内容,保留原样 13CNMR (100 MHz, CDCl3) δ 167.79, 167.17, 136.46, 129.14, 128.52, 128.17, 77.85, 67.86, 67.65, 55.17, 43.16, 21.97, 21.81, 10.48 ppm; IR (KBr) 3029, 2956, 1737, 1558 cm -1 ; HRMS (ESI) for C 17 H 24 N1O6 [M + H] + Calcd: 338.15981 Found: 338.16336; HPLC [Chiralcel AD - H, hexane / 2 - propanol = 95 / 5, 1.0 mL / min, λ = 254 nm, retention times: (major) 18.4 min, (minor) 38.9 min].

[0235] (5)(R)-Benzyl - 2 - carbobenzyloxy - 4 - nitro - 3 - phenylbutyrate (2e, Chemical formula 5b - 5)

[0236]

Chem.

[0237] [α] D 20 = - 3.25 (c 0.10, CH2Cl2); 1 HNMR (400 MHz, CDCl3) δ 7.33 - 7.25 (m, 10H), 7.17 - 7.07 (m, 5H), 5.16 (d, 1H, J = 12.2 Hz), 5.18 (d, 1H, JAB = 12.2 Hz), 4.93 (S, 1H), 4.84 - 4.82 (m, 2H), 4.28~4.22 (q, 1H), 3.94 (d, 1H, 9.3 Hz); 13CNMR (100 MHz, CDCl3) δ 167.39, 166.78, 136.14, 134.85, 129.25, 128.90, 128.15, 77.63, 68.04, 67.86, 55.14, 43.16 ppm; IR (KBr) 3068, 3036, 2963, 1736, 1558, 1498, 1456, 1378, 1326, 1286, 1217, 1156, 1003, 975, 908, 562 cm-1 ; HRMS (EI) for C 25 H 23 N1O6 [M+H] + Calcd: 433.1525 Found: 433.1525; HPLC [Chiralcel AD-H, hexane / 2-propanol = 70 / 30, 1.0 mL / min, λ = 254 nm, retention times: (major) 26.0 min, (minor) 24.1 min].

[0238] (6)(R)-dibutyl 2-(2-nitro-1-phenylethyl)malonate (2f, chemical formula 5b-6)

[0239]

Chem.

[0240] [α] D 20 = -2.55 (c 0.10, CH2Cl2); 1 1H NMR (400 MHz, CDCl3) δ 7.31~7.22 (m, 5H), 4.92~4.87 (t, J = 5.0, 9.5 Hz, 2H), 4.24 (m, 1H), 4.15~4.09 (m, 2H), 3.92~3.83 (dd, s, J = 6.6 9.7 Hz, 3H), 1.68~1.61 (m, 2H), 1.49~1.42 (m, 2H), 0.93~0.88 (t, J = 7.4, 7.4 Hz, 3H), 0.82~0.77 (t, J = 7.4, 7.4 Hz, 3H) ppm; 13 13C NMR (100 MHz, CDCl3) δ 167.79, 167.17, 136.46, 129.14, 128.52, 128.17, 77.85, 67.86, 67.65, 55.17, 43.16, 21.97, 21.81, 10.48 ppm; HRMS (EI) for C 17 H 24 N1O6 [M+H] +Calcd: 338.15981, Found: 338.16336; HPLC [Chiralcel AD-H, hexane / 2-propanol = 95 / 5, 1.0 mL / min, λ = 254 nm, retention times: (major) 18.4 min, (minor) 38.9 min].

[0241] (7)(R)-Diethyl 2-[1-(4-bromophenyl)-2-nitroethyl]malonate (2 g, chemical formula 5b-7)

[0242] [Chem.]

[0243] [α] D 20 = -3.56 (c 2.33, CH2Cl2); 1 1H NMR (300 MHz, CDCl3) δ 7.44~7.42 (d, J = 8.5 Hz, 2H), 7.13~7.11 (d, J = 8.2 Hz, 2H), 4.88~4.81 (m, 2H), 4.22~4.16 (m, 3H), 4.04~3.97 (q, J = 7.1, 6.9 Hz, 2H), 3.78~3.75 (d, J = 9.4 Hz, 1H), 1.26~1.21 (t, J = 7.2, 7.1 Hz, 3H), 1.08~1.03 (t, J = 7.1, 7.1 Hz, 3H) ppm; 13 13C NMR (100 MHz, CDCl3) δ 167.42, 166.83, 135.52, 132.29, 130.00, 122.62, 77.55, 62.50, 62.26, 54.86, 42.60, 14.17, 13.99 ppm; IR (KBr) 2983, 2950, 1732, 1556, 1490, 1445 cm -1 HRMS (ESI) for C 15 H 19 N1O6Br [M + H] +Calcd: 388.03903 Found: 388.04495; HPLC [Chiralcel AD-H, hexane / ethanol = 95 / 5, 1.0 mL / min, λ = 254 nm, retention times: (major) 35.9 min, (minor) 44.4 min].

[0244] (8)(R)-diethyl 2-(1-(4-chlorophenyl)-2-nitroethyl)malonate (2h, Chemical formula 5b-8)

[0245]

Chem.

[0246] [α] D 20 = -0.24 (c 0.43, CH2Cl2); 1 1H NMR (300 MHz, CDCl3) δ 7.29~7.17 (dd, J = 20.6, 8.2 Hz, 4H), 4.88~4.81 (m, 2H), 4.23~4.16 (m, 3H), 4.04~3.97 (q, J = 7.1, 7.1 Hz, 2H), 3.78~3.75 (d, J = 9.3 Hz, 1H), 1.26~1.21 (t, J = 7.1, 7.2 Hz, 3H), 1.08~1.03 (t, J = 7.2, 6.8 Hz, 3H) ppm; 13 13C NMR (100 MHz, CDCl3) δ 167.44, 166.83, 134.98, 134.46, 129.69, 129.3, 77.63, 62.49, 62.23, 54.92, 42.55, 14.15, 13.97 ppm; IR (KBr) 2984, 1733, 155, 1478, 1445, 1371 cm -1 HRMS (ESI) for C 15 H 19 N1O6Cl [M + H] + Calcd: 344.08954 Found: 344.09119; HPLC [Chiralcel AD-H, hexane / ethanol = 90 / 10, 1.0 mL / min, λ = 254 nm, retention times: (major) 17.9 min, (minor) 24.1 min].

[0247]

[0248] Example 3.2. (R)-4-Phenylpyrrolidin-2-one (4d, chemical formula 6b)

[0249]

change

[0250] 1 HNMR (500MHz, CDCl3) δ7.37~7.33(m, 2H), 7.29~7.27(m, 2H), 7.26~7.25(m, 1H), 5.92(brs, 1H), 3.81~3.77(m, 1H), 3.71(q, J=8.0Hz, 1H), 3.45~3.41(dd, J=9.4, 2.0Hz, 1H), 2.77~2.72(dd, J=16.8, 8.7Hz, 1H), 2.54~2.49(dd, J=17.0, 8.5Hz, 1H)ppm; 13 CNMR (125MHz, CDCl3) δ177.93, 142.14, 128.88, 127.13, 126.79, 49.60, 40.31, 38.02ppm; LRMS (ESI + )forC 10 H 11 NO[M+H] + Calcd:162.1, Found:162.2;HPLC[ChiralcelAD-H, hexane / 2-propanol=90 / 10, flowrate=1.0mL / min, λ=254nm, retentiontimes: (minor)15.2min, (major)19.4min]; R f( SiO2, EtOAc) = 0.30

[0251]

[0252] Example 3.3(R)-2-(2-oxo-4-phenylpyrrolidin-1-yl)acetamidehydrochloride (5b, chemical formula 1b)

[0253] [ka]

[0254] N-carbamoylmethyl-4-phenyl-2-pyrrolidinone chloride (85%) was obtained by the same synthesis method as in Example 2.4.

[0255] 1 HNMRspectrum (DMSO-d6), δ, ppm: 2.41dd (1H, 3-H), 2.72dd (1H, 3-H), 3.42m (1H, 5 -H), 3.59m(1H, 4-H), 3.79m(1H, 5-H), 4.00dd(2H, NCH2CO); 7.24-7.36m(5H, Ph). 13 CNMRspectrum (DMSO-d6), δC, ppm:37.01, 38.48, 44.04, 54.55, 127.16, 127.35, 129.08, 143.35, 170.64, 173.84pp; LRMS (ESI + )forC 10 H 14 ClNO2[M] + Calcd:254, Found:254;

[0256]

[0257] Example 4. Preparation of (R)-phenylpiracetam hydrazide hydrochloride (Formula 1d)

[0258] [ka]

[0259] According to one embodiment of the present invention, the method for preparing (R)-phenylpiracetam hydrazide hydrochloride (Formula 1d), a pharmaceutically acceptable salt of an (R)-chiral gamma lactam derivative, is the same as in Reaction Scheme 3, and (R)-4-Phenylpyrrolidin-2-one (4d, Formula 6b) was obtained in the same manner as in Example 3.

[0260] A solution of 4-phenyl-2-pyrrolidinone (1.0 equivalent) in 1,4-dioxane (30 ml) was then added to a suspension of sodium hydride (1.1 equivalent) in 1,4-dioxane (30 ml). The mixture was heated at 90°C for 30 minutes and then cooled to room temperature. Ethyl bromoacetate (1.1 equivalent) was added, and the reaction mixture was refluxed at 120°C for 6 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 1:1 mixture of ethyl acetate and hexane to give N-ethoxycarbonylmethyl-4-phenyl-2-pyrrolidinone. A solution of N-ethoxycarbonylmethyl-4-phenyl-2-pyrrolidinone (250 mg, 1.01 mM) in methanol (30 ml) was saturated with a gaseous ammonia stream for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using a 1:1 mixture of ethyl acetate and hexane and concentrated under reduced pressure. The concentrate was dissolved in ethanol (30 ml) together with hydrazine hydrate (1.1 equivalents), stirred at room temperature for 1 hour, and then concentrated. The concentrate was added to 6N HCl, stirred and dissolved, and concentrated again under reduced pressure to obtain N-carbamoylmethyl-4-phenyl-2-pyrrolidinone hydrazine chloride (87%).

[0261] 1 HNMRspectrum(DMSO-d6), δ, ppm: 2.51dd(1H, 3-H), 2.70dd(1H, 3-H), 3.43m(1H, 5-H), 3.62m(1H, 4-H), 3 .77m(1H, 5-H), 3.87dd(2H, NCH2CO), 4.26br.s(2H, NH-NH2), 7.24-7.34m(5H, Ph), 9.19br.s(1H, CONH). 13 CNMRspectrum (DMSO-d6), δC, ppm:36.47, 37.99, 43.54, 54.07, 126.68, 126.90, 128.61, 142.88, 170.20, 173.30pp; LRMS (ESI + )forC 12 H 16 ClNO2[M+H] + Calcd:270, Found:270;

[0262]

[0263] Experimental Example 1. In vitro efficacy analysis of the chiral gamma lactam derivative or its pharmaceutically acceptable salt according to the present invention

[0264] The efficacy of the chiral gamma lactam derivatives of the present invention or their pharmaceutically acceptable salts in controlling muscle disorders, psychiatric disorders, and degenerative neurological disorders was analyzed using human kidney, skeletal muscle, and neuronal cell lines. Chirality control and derivatization confirmed their excellent calcium extrusion control effect, and cytotoxicity analysis confirmed their similarity to natural amino acids. Confirmation of the intracellular mode of action confirmed that the derivatives of the present invention or their pharmaceutically acceptable salts inhibit MAO-B as a D1-mGlu5 target and regulate calcium channels. Furthermore, regulation of myostatin-regulating factor (TNF-β), a marker of sarcopenia, and suppression of protein expression were confirmed.

[0265]

[0266] Experimental Example 1.1. Intracellular Ca using confocal laser scanning microscopy (CLSM) 2+ Concentration measurement

[0267] Intracellular Ca 2+ To detect calcium levels, human kidney epithelial cells (HEK293T cells) were seeded onto 35 mm diameter confocal dishes 24 hours before the experiment and cultured to 40–60% RI. The cells were loaded with 5 mM fluorescent radioactive calcium indicator Fluo-3-acetoxymethyl (Fluo-3-AM; Invitrogen) for 30 minutes at 37°C. 2+The concentration was measured using CLSM (Zeiss LSM 700 Meta; Zeiss, Oberkochen, Germany). After washing with medium, the culture plate was placed on a temperature-controlled microscope stage and observed at 200x magnification. The excitation and emission wavelengths for signal detection were 488 and 515 nm, respectively. Intracellular calcium intensity analysis was performed using Zen software (Carl Zeiss).

[0268] As a result, the intracellular calcium intensity was highest at 18 seconds and then gradually decreased as calcium was released (Figure 1). Compared to the control rasagiline and the comparative (R)-phenylpiracetam, the pharmaceutically acceptable salts of chiral gamma lactam derivatives according to one embodiment of the present invention, Ph-10 (Formula 1d), Ph-20 (Formula 1a), and Ph-30 (Formula 1b), exhibited significantly superior Ca2+ release performance (Figures 2 and 3). In particular, the (R)-type Ph-30 exhibited approximately two-fold higher performance than the (S)-type Ph-20, and when the hydrochloride salt was substituted, the calcium release performance was approximately 1.5-3-fold higher. This is likely due to the enhanced polarity and dipole moment of Ph-10, 20, and 30 compared to phenylpiracetam, which enhances the molecular polarity and promotes non-bonding interactions in the drug-receptor complex.

[0269]

[0270]

[0271] Experimental Example 1.2. Human skeletal myoblast (HSkM) differentiation induction test

[0272] For the human skeletal myoblast (HSkM) differentiation induction test, human skeletal myoblasts (3x10) were prepared in a 24-well plate. 5Cells (1000 x 1000 cells / well) were treated with the test substance and cultured for 48 hours in a 37°C CO2 incubator. After 24 and 48 hours of culture, the cell culture supernatant was collected in E-tubes and stored in a deep freezer. The supernatant was then thawed for ELISA analysis. ELISA analysis was performed according to the test method provided with the ELISA kit.

[0273] The results showed that compound Ph-30 had the greatest reduction in GDF-8 / myostatin levels, while compounds Ph-10 and 20 showed comparable or superior efficacy compared to the IGF-1 and (R)-phenylpiracetam (Ph-pira) treatment groups (Figure 4). Furthermore, compound Ph-30 was found to have the greatest reduction in SMAD2 and 3 levels, and compounds Ph-10 and 20 also showed efficacy compared to the (R)-phenylpiracetam treatment group (Figure 5).

[0274]

[0275] Experimental Example 1.3. Confirmation of mRNA expression changes associated with neuroinflammation and cell death

[0276] Human neuroblastoma SH-SY5Y cell line was treated with 2.5 mM MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to induce an inflammatory response, and the mRNA expression of SYP (synaptophysin), GAP-43 (growth-associated protein-43), MAO-B (monoamine oxidase-B), and iNOS (inducible nitric oxide synthase) was confirmed by real-time PCR.

[0277] As a result of examining SYP mRNA expression, mRNA expression was significantly increased when treated with the chiral gamma malactam derivative of the present invention or its pharmaceutically acceptable salt (Ph-10, 20, 30) compared to the group treated with MPTP alone. As a result of examining GAP-43 mRNA expression, mRNA expression was significantly increased in the group treated with Ph-10 compound compared to the group treated with MPTP alone. In the case of iNOS and MAO-B, mRNA expression was significantly decreased in the groups treated with Ph-10 and 30 compounds compared to the group treated with MPTP alone (Figure 6(a)). In particular, in the case of Ph-30 compound, the increased Ca after MPTP treatment was 2+ It was confirmed by fluorescence microscopy that the amount of HCl and superoxide anions was significantly reduced (Figure 6(b)).

[0278]

[0279] Experimental Example 2. In vivo efficacy analysis of the chiral gamma malactam derivative of the present invention or its pharmaceutically acceptable salt

[0280] Six-month-old normal mice were adapted for one week, trained for behavioral tests, and then randomly assigned to groups. To construct the MPTP mouse model of Parkinson's disease, mice were treated with the chiral gamma malactam derivative of the present invention or its pharmaceutically acceptable salt (dissolved in 0.9% saline, injected intraperitoneally (i.p.)) for three days, followed by MPTP (dissolved in 0.9% saline, i.p.) for five consecutive days. MPTP treatment damages the cerebellum, causing muscle hypotonia and impaired motor control. The control group received the same volume of saline i.p. Two days after the final injection, efficacy was confirmed through the open field test (OFT), forced swim test (FST), rotarod test, and pilocarpine-induced seizure assessment.

[0281] Furthermore, blood analysis confirmed a reduction in the amount of myostatin in the blood, a marker related to sarcopenia, and confirmed that there was no toxicity to liver function, kidney function, or myocardial function.The mechanism of action was confirmed through skeletal muscle tissue analysis, calcium content, mobility, and blood tests.

[0282]

[0283] Experimental Example 2.1. Open Field Test (OFT)

[0284] An open-field test was performed to measure general motor activity and behavioral anxiety. (1) First, 30 minutes before the open-field test, the chiral gamma malactam derivative of the present invention or its pharmaceutically acceptable salt and vehicle (saline, test drug) were intraperitoneally injected, and video recording was performed for 10 minutes. (2) The video analysis confirmed the absence of sedation, and the distance traveled was measured.

[0285] When treated with Ph-30 compound at concentrations of 5, 10, and 15 mg / kg, the distance traveled increased compared to the control group at all concentrations. Although there were differences in the total distance traveled by concentration, we used 10 mg / kg in subsequent experiments because too low a concentration may not be effective (Figure 7(a)).

[0286] An MPTP-only group was used as a negative control, and a selegiline-treated group was used as a positive control. Compared with the MPTP-only group, the Selegiline-treated group, and the (R)-phenylpiracetam (Ph-pira)-treated group, the chiral gamma lactam derivatives of the present invention or their pharmaceutically acceptable salts (Ph-10, 20, 30) showed an increased total distance traveled. In particular, the Ph-30-treated group showed a value approximately three times higher than the MPTP-only group (Figure 7(b)). This suggests that the derivatives of the present invention or their pharmaceutically acceptable salts increase motility and have an anti-anxiety effect.

[0287]

[0288] Experimental Example 2.2. Forced Swimming Test (FST)

[0289] A forced swimming test (FST) was performed to induce depressive behavior in mice. (1) First, a 2-L beaker was filled with water (25±1°C) to a depth of approximately 10 cm, and the mice were allowed to swim. After 6 minutes, they were returned to their cages. (2) The group with restraint stress was confined in a restraint tube for 90 minutes until 60 minutes before the forced swimming test. After that, the mice were allowed to swim as in (1) before being returned to their cages. (3) In this case, the chiral gamma malactam derivative of the present invention or a pharmaceutically acceptable salt thereof was intraperitoneally injected (saline, test drug) 30 minutes before the forced swimming test. The immobility time (4 minutes out of 6 minutes) was measured and compared between groups.

[0290] As a result, the MPTP-only treatment group showed an average immobility time that was approximately twice as long as the untreated control group (saline). Although the phenylpiracetam-treated group showed a decrease in immobility time compared to the MPTP-only treatment group, treatment with the chiral gamma malactam derivatives of the present invention or their pharmaceutically acceptable salts (Ph-10, 20, 30) showed even shorter immobility times. This difference was statistically significant, demonstrating that the chiral gamma malactam derivatives of the present invention or their pharmaceutically acceptable salts have antidepressant effects. In particular, the Ph-30 compound tended to show a shorter immobility time than the untreated control group, indicating its particularly excellent antidepressant effect (Figure 8).

[0291]

[0292] Experimental Example 2.3. Rotarod test

[0293] To assess lower limb walking and motor ability, a rotarod test was performed for five weeks. Mice were placed on a rotating rod and their latency to fall was measured to assess motor coordination and balance. MPTP was injected intraperitoneally into mice at a concentration of 30 mg / kg for five consecutive days. One week after MPTP injection, mice were administered the drug (15 mg / kg) intraperitoneally twice a week on a rotarod, a rotatable cylindrical rod 60 cm high with six compartments 7 cm in diameter and 15 cm apart. Mice were then placed on the rod, which rotated at speeds ranging from 5 rpm to 50 rpm (maximum speed), for 180 seconds, and their latency to fall was measured. Mice were thoroughly trained to ensure they adapted to the experimental period.

[0294] As a result, compared to the control group and the group treated with MPTP alone, treatment with the chiral gamma lactam derivatives of the present invention or their pharmaceutically acceptable salts (Ph-10, 20, 30) showed increased motility in all groups (Figure 9(a)). Furthermore, after 5 weeks, the muscle weights of the tibialis anterior (TA) and extensor digitorum longus (EDL) muscles both increased at a statistically significant level (Figures 9(b) and 9(c)). In particular, the Ph-30 compound showed approximately twice the efficacy of the Ph-20 compound, which is believed to be due to the difference in chirality.

[0295]

[0296] Experimental Example 2.4. Evaluation of Pilocarpine-Induced Seizures

[0297] To study changes in brain activity, a mouse model of pilocarpine-induced seizures was created. Pilocarpine is an agonist that binds to muscarinic cholinergic receptors in neurons, increasing cell activity, and is used to create a mesial temporal lobe epilepsy model.

[0298] Experiments were performed on surgically treated male C57BL / 6J mice under a constant environmental condition (24-25°C, 50-60% humidity, 12-hour light / dark cycle). To suppress side effects of pilocarpine, methylscopolamine bromide (1 mg / kg) was intraperitoneally injected 30 minutes before pilocarpine injection. The chiral gamma malactam derivative of the present invention or its pharmaceutically acceptable salt (15 mg) was intraperitoneally injected 25 minutes before pilocarpine injection. Pilocarpine (Sigma, Deisenhofen, Germany) was intraperitoneally injected at a single dose of 330 mg / kg, and behavioral and electrophysiological seizure patterns were monitored for 24 hours. After several convulsions, status epilepticus (SE, epilepsy overlap) developed.

[0299] Seizures were classified into five categories, and cases (4) and (5) were defined as convulsive seizures, and their frequency and duration were analyzed: (0) absence of convulsive behavior; (1) facial clonus; (2) head nodding; (3) forelimb clonus; (4) rearing (animal in a standing posture aided by the tail and the laterally spread hindlimbs showing increased tone); and (5) rearing and falling back.

[0300] As a result, as shown in Figure 10, the total number of convulsive seizures was significantly lower in the case of the Ph-30 compound compared to the control group, and the Ph-10 compound also showed similar effectiveness. The Ph-20 compound showed a higher number of convulsive seizures, but it was confirmed that the number of convulsive seizures was effectively reduced compared to the control group and the (R)-phenylpiracetam-treated group.

[0301]

[0302] Experimental Example 2.5. Confirmation of changes in sarcopenia-related marker expression

[0303] MPTP was injected intraperitoneally into mice at a concentration of 30 mg / kg for 5 consecutive days. One week after the MPTP injection, the chiral gamma malactam derivative of the present invention or its pharmaceutically acceptable salt (Ph-10, 20, 30) was intraperitoneally administered to the mice at 15 mg / kg twice a week for 5 weeks, and changes in the expression levels of GDF-8 / myostatin, a sarcopenia-related marker, in the mouse serum were observed.

[0304] The expression levels of GDF-8 / myostatin in mouse serum were statistically significantly lower for compounds Ph-10, 20, and 30 compared to the IGF-1-treated group and the (R)-phenylpiracetam-treated group. In mouse experiments, as in the cell experiments (Experimental Example 1.3), differences due to chirality were confirmed, with compound Ph-30 showing the lowest expression level (Figure 11). This suggests that the chiral gamma lactam derivatives of the present invention or pharmaceutically acceptable salts thereof can be used as therapeutic agents for muscle diseases such as sarcopenia.

[0305]

[0306]

[0307] Although the embodiments have been described above with limited drawings, those skilled in the art can apply various technical modifications and variations based on the above, for example, the described techniques may be performed in an order different from that described, and / or the components of the described systems, structures, devices, circuits, etc. may be combined or combined in a manner different from that described, or may be replaced or substituted by other components or equivalents, and still achieve suitable results.

[0308] Accordingly, other implementations, other embodiments, and equivalents of the claims are intended to be within the scope of the following claims.

Claims

1. A pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by the following chemical formula 1a: A pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by the following chemical formula 1b: A pharmaceutical composition for preventing or treating a muscular disease, a psychiatric disease, or a degenerative neurological disease, comprising, as an active ingredient, one or more selected from the group consisting of a chiral gamma malactam derivative represented by the following [Chemical Formula 1c] or a pharmaceutically acceptable salt thereof; and combinations thereof: [Chemical formula 1a] 【Chemical 1】 [Chemical formula 1b] 【Chemistry 2】 [Chemical formula 1c] 【Chemistry 3】

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of the chiral gamma lactam derivative represented by the following [Chemical Formula 1c] is a salt represented by the following [Chemical Formula 1d]: [Chemical formula 1d] 【Chemistry 4】

3. 2. The pharmaceutical composition according to claim 1, wherein the muscle disease is any one or more selected from the group consisting of atony, muscular atrophy, muscular dystrophy, myasthenia, cachexia, rigid spine syndrome, amyotrophic lateral sclerosis (Lou Gehrig's disease), Charcot-Marie-Tooth disease, sarcopenia, and combinations thereof.

4. 2. The pharmaceutical composition according to claim 1, wherein the psychiatric disorder is any one or more selected from the group consisting of depression, mania, bipolar disorder, schizophrenia, delirium, panic disorder, attention-deficit hyperactivity disorder (ADHD), cognitive disorder, anxiety disorder, post-traumatic stress disorder (PTSD), and combinations thereof.

5. The degenerative neurological diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, spinocerebellar degeneration, spinocerebellar ataxia, Friedreich's ataxia, Machado-Joseph disease, and others. disease, dystonia, progressive supranuclear palsy, senile dementia, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, alcohol-related dementia, presenile dementia, temporal lobe epilepsy, multiple sclerosis 2. The pharmaceutical composition of claim 1, wherein the amyloidosis is any one or more selected from the group consisting of cerebral amyloidosis, cerebral amyloid angiopathy, systemic amyloidosis, Tourette's disorder, stroke, and combinations thereof.

6. A method for producing a pharmaceutical composition for preventing or treating a muscular disease, a psychiatric disease, or a degenerative neurological disease, comprising, as an active ingredient, a pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1a], the method comprising the steps of: (1) preparing a compound represented by [Chemical Formula 4a] from a compound represented by [Chemical Formula 3a] using a catalyst compound represented by [Chemical Formula 2]; (2) preparing a compound represented by [Chemical Formula 5a] from a compound represented by [Chemical Formula 4a]; (3) preparing a compound represented by [Chemical Formula 6a] from a compound represented by [Chemical Formula 5a]; and (4) The compound represented by [Chemical Formula 6a] is reacted with sodium hydride (NaH), ethyl bromoacetate (BrCH ２ COOEt), and ammonia (NH ３ ) to prepare a compound represented by formula 1a; [Chemical formula 1a] 【Chemistry 5】 [Chemical formula 2] 【Chemistry 6】 [Chemical formula 3a] 【Chemistry 7】 [Chemical formula 4a] 【Chemistry 8】 [Chemical formula 5a] 【Chemistry 9】 [Chemical formula 6a] 【Chemistry 10】 In the above formula 2, R １ and R ２ are the same or different and are hydrogen, C １ -C ６ alkyl groups, halogen groups, cyano groups, nitro groups, trifluoromethyl groups, alkoxy groups, C ３ -C ８ and combinations thereof, and R ３ is C ３ -C ８ wherein one or more hydrogen atoms of the aryl group are unsubstituted or １ -C ６ and substituted with one or more selected from the group consisting of an alkyl group, a halogen group, a cyano group, a nitro group, a trifluoromethyl group, an alkoxy group, and combinations thereof; In the above formula 5a, R ４ is hydrogen or a halogen group.

7. The catalyst compound represented by [Chemical Formula 2] is at least one selected from the group consisting of catalyst compounds represented by the following [Chemical Formula 2-1] to [Chemical Formula 2-11] and combinations thereof: [Chemical formula 2-1] 【Chemistry 11】 [Chemical formula 2-2] 【Chemistry 12】 [Chemical formula 2-3] 【Chemistry 13】 [Chemical formula 2-4] 【Chemistry 14】 [Chemical formula 2-5] 【Chemistry 15】 [Chemical formula 2-6] 【Chemistry 16】 [Chemical formula 2-7] 【Chemistry 17】 [Chemical formula 2-8] 【Chemistry 18】 [Chemical formula 2-9] 【Chemistry 19】 [Chemical formula 2-10] 【Chemistry 20】 [Chemical formula 2-11] 【Chemical 21】

8. The method according to claim 6, wherein the compound represented by [Chemical Formula 5a] is at least one selected from the group consisting of compounds represented by the following [Chemical Formula 5a-1] and [Chemical Formula 5a-2] and combinations thereof: [Chemical formula 5a-1] 【Chemical 22】 [Chemical formula 5a-2] 【Chemical 23】

9. A method for producing a pharmaceutical composition for preventing or treating a muscular disease, a psychiatric disease, or a degenerative neurological disease, comprising, as an active ingredient, a pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1b], the method comprising the steps of: (1) preparing a compound represented by [Chemical Formula 4b] from a compound represented by [Chemical Formula 3b] using a catalyst compound represented by [Chemical Formula 2]; (2) preparing a compound represented by [Chemical Formula 5b] from a compound represented by [Chemical Formula 4b]; (3) preparing a compound represented by [Chemical Formula 6b] from a compound represented by [Chemical Formula 5b]; and (4) The compound represented by [Chemical Formula 6b] is reacted with sodium hydride (NaH), ethyl bromoacetate (BrCH ２ COOEt), and ammonia (NH ３ ) to prepare a compound represented by formula 1b; [Chemical formula 1b] 【Chemistry 24】 [Chemical formula 2] 【Chemistry 25】 [Chemical formula 3b] 【Chemical 26】 [Chemical formula 4b] 【Chemical 27】 [Chemical formula 5b] 【Chemical Formula 28】 [Chemical formula 6b] 【Chemical formula 29】 In the above formula 2, R １ and R2 are the same or different and each represents hydrogen, C １ -C ６ alkyl groups, halogen groups, cyano groups, nitro groups, trifluoromethyl groups, alkoxy groups, C ３ -C ８ and combinations thereof, and R ３ is C ３ -C ８ wherein one or more hydrogen atoms of the aryl group are unsubstituted or １ -C ６ and substituted with one or more selected from the group consisting of an alkyl group, a halogen group, a cyano group, a nitro group, a trifluoromethyl group, an alkoxy group, and combinations thereof; In the above formula 5b, R ４ is hydrogen or a halogen group, and R ５ is C １ -C ６ is an alkyl group or a benzyl group.

10. The method according to claim 9, wherein the compound represented by [Chemical Formula 5b] is at least one selected from the group consisting of compounds represented by the following [Chemical Formula 5b-1] to [Chemical Formula 5b-8] and combinations thereof: [Chemical formula 5b-1] 【Chemistry 30】 [Chemical formula 5b-2] 【Chemical 31】 [Chemical formula 5b-3] 【Chemical 32】 [Chemical formula 5b-4] 【Chemical 33】 [Chemical formula 5b-5] 【Chemical 34】 [Chemical formula 5b-6] 【Chemistry 35】 [Chemical formula 5b-7] 【Chemical 36】 [Chemical formula 5b-8] 【Chemical 37】

11. A method for producing a pharmaceutical composition for preventing or treating a muscular disease, a psychiatric disease, or a degenerative neurological disease, comprising, as an active ingredient, a pharmaceutically acceptable salt of a chiral gamma malactam derivative represented by [Chemical Formula 1d], the method comprising the steps of: (1) preparing a compound represented by [Chemical Formula 4b] from a compound represented by [Chemical Formula 3b] using a catalyst compound represented by [Chemical Formula 2]; (2) preparing a compound represented by [Chemical Formula 5b] from a compound represented by [Chemical Formula 4b]; (3) preparing a compound represented by [Chemical Formula 6b] from a compound represented by [Chemical Formula 5b]; and (4) The compound represented by [Chemical Formula 6b] is dissolved in sodium hydride (NaH), ethyl bromoacetate (BrCH ２ COOEt) and hydrazine hydrate to prepare a compound represented by [Chemical Formula 1d]; [Chemical formula 1d] 【Chemical 38】 [Chemical formula 2] 【Chemical Formula 39】 [Chemical formula 3b] 【Chemistry 40】 [Chemical formula 4b] 【Chemistry 41】 [Chemical formula 5b] 【Chemistry 42】 [Chemical formula 6b] 【Chemistry 43】 In the above formula 2, R １ and R ２ are the same or different and are hydrogen, C １ -C ６ alkyl groups, halogen groups, cyano groups, nitro groups, trifluoromethyl groups, alkoxy groups, C ３ -C ８ and combinations thereof, and R ３ is C ３ -C ８ wherein one or more hydrogen atoms of the aryl group are unsubstituted or １ -C ６ and substituted with one or more selected from the group consisting of an alkyl group, a halogen group, a cyano group, a nitro group, a trifluoromethyl group, an alkoxy group, and combinations thereof; In the above formula 5b, R ４ is hydrogen or a halogen group, and R ５ is C １ -C ６ is an alkyl group or a benzyl group.

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