(2,5-Dioxopyrrolidine-1-yl)(phenyl)acetamide derivatives and their use in the treatment of neurological disorders

Abstract

To provide compounds for use in the treatment or prevention of epileptic seizures or neuropathic pain or migraine.SOLUTION: The invention provides the compound of general formula (I) or pharmaceutically acceptable salts thereof. The invention also provides the use of compounds described by general formula (I) as active ingredients in pharmaceutical compositions for the treatment of epileptic seizures or neuropathic pain or migraine.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to (2,5-dioxopyrrolidine-1-yl)(phenyl)-acetamide derivatives and pharmaceutically acceptable salts thereof, which are suitable for the treatment of neurological disorders. The disclosed compounds exhibit broad protective activity in animal models of epileptic seizures and pain models, and thus can find applications in the treatment of neurological disorders, particularly epilepsy and neuropathic pain. Due to the broad therapeutic indications of antiepileptic drugs, these compounds may also be useful in the treatment of, for example, migraines, withdrawal syndromes, schizophrenia, schizoaffective disorder, personality and nutritional disorders, as well as anxiety and post-traumatic stress. [Background technology]

[0002] Epilepsy is one of the most common neurological disorders associated with excitability and neurotransmission disorders. It affects 1-2% of the human population and significantly reduces the quality of life and daily activity capacity of those affected (Nadkarni, S.; LaJoie, J.; Devinsky, O., Neurology 2005, 64, s2-s11). Due to its complex pathophysiology, epilepsy is a heterogeneous disorder characterized by the occurrence of various types of seizures (e.g., tonic-clonic, absence, partial, etc.) and marked drug resistance, reaching 30-40% of those diagnosed (Kwan, P.; Schachter, SC; Brodie, MJ, N.Engl.J.Med. 2011, 365, pp. 919-926). Neuropathic pain is another serious neurological disorder that presents therapeutic challenges. Current data show that only 50% of patients can achieve a 30–50% reduction in the sensation of neuropathic pain, while other patients cannot achieve improvement with any of the medications used (Butera, JA, J. Med. Chem. 2007, 11, pp. 2543–2546). Therefore, there is a very high need for novel AEDs that can control various types of epileptic seizures and, preferably, are effective for neuropathic pain. Many of the AEDs currently in use have a narrow range of therapeutic indications, so they are only applicable to specific types of epileptic seizures. These drugs include, among other things, modern AEDs such as levetiracetam and lacosamide. Studies conducted in recent years have shown that multi-target compounds, also known as multifunctional compounds, i.e., compounds with complex molecular mechanisms of action, may be particularly beneficial for treating diseases with complex pathological mechanisms (so-called multifactorial diseases). By combining different synergistic mechanisms, multi-target substances enable a comprehensive therapeutic process, making them more likely to exhibit higher therapeutic efficacy compared to substances that act on a single biological target (Bansal, Y.; Silakari, O., Eur. J. Med. Chem. 2014, 76, pp. 31-42).Another advantage of multi-functional drugs may be a reduction in the number of drugs taken, which can lead to fewer and weaker side effects, lower-risk drug interactions, and better physician-patient cooperation (adherence). It is also hypothesized that multi-target compounds may be useful in treating diseases characterized by high drug resistance (e.g., epilepsy) (Talevi, A., Front. Pharmacol. 2015, 6, p. 205). Multi-target substances are typically designed as hybrid or chimeric molecules that bind to structural fragments of a normal chemical skeleton that are involved in specific pharmacological effects (Morphy, R.; Rankovic, Z., J. Med. Chem. 2005, 48, pp. 6523-6543). In particular, there is active research into the development of multi-target compounds as candidates for novel drugs in the fields of cancer, neurodegenerative diseases, and inflammatory diseases.In particular, the concept of molecular hybridization has recently been proposed by the inventors as a method to enable the design and development of novel AEDs with a wide range of therapeutic applications (Abram, M.; Zagaja, M.; Mogilski, S.; Andres-Mach, M.; Latacz, G.; Bas, S.; Luszczki, JJ; Kiec-Kononowicz, K.; Kaminski, K., J. Med. Chem. 2017, 60, pp. 8565-8579; Kaminski, K.; Zagaja, M.; Rapacz, A.; Luszczki, JJ; Andres-Mach, M.; Abram, M.; Obniska, J., Bioorg. Med. Chem. 2016, 24, pp. 606-61). 8 pages; Kaminski, K.; Rapacz, A.; Filipek, B.; Obniska, J., Bioorg. Med. Chem. 2016, 24, 2938~2946 Page; Kaminski, K.; Zagaja, M.; Luszczki, JJ; Rapacz, A.; Andres-Mach, M.; Latacz, G.; Kiec-Konon owicz, K., J. Med. Chem. 2015, 58, pp. 5274-5286; Kaminski, K.; Rapacz, A.; Luszczki, JJ; Latacz, G.; Obniska, J.; Kiec-Kononowicz, K.; Filipek, B., Bioorg. Med. Chem. 2015, 23, pp. 2548-2561). [Overview of the project] [Problems that the invention aims to solve]

[0003] The anticonvulsant and / or analgesic activity of novel compounds is routinely evaluated in animal models (primarily mice and rats). From a clinical standpoint, particularly promising candidates for novel broad-spectrum AEDs effective for various types of human epileptic seizures are substances active in the maximal electroshock test (MES), the subcutaneous pentylenetetrazole seizure test (scPTZ), and the psychomotor 6Hz seizure model utilizing a 6Hz low-frequency current (at current intensities of 32mA and / or 44mA). Compounds exhibiting the aforementioned profiles in preclinical in vivo studies may be effective for human tonic-clonic seizures with or without secondary generalization, generalized absence seizures, myoclonic seizures, partial seizures, and drug-resistant epilepsy. The important added value of the above substances should be their activity in key animal tests / models that evaluate antinociceptive activity, namely, the formalin test, the capsaicin-induced pain model, and the oxaliplatin-induced neuropathic pain model.

[0004] The technical problem prior to the present invention is to provide chemical compounds, or pharmaceutically acceptable salts thereof, that are easily obtained, do not exhibit hepatotoxic effects, and can be used as active substances in pharmaceutical compositions for controlling various types of seizures (secondary generalization, generalized absence seizures, myoclonic seizures, partial seizures, and tonic-clonic seizures with or without drug-resistant epilepsy), and such compounds should also have analgesic activity in pain or migraine resulting from neurological disorders. [Means for solving the problem]

[0005] The first object of the present invention is general formula (I)

[0006] [ka] (In the formula, X is either N or C, k is a number equal to 0 or 1. A is - Phenyl substituent; - Phenyl substituents substituted with one, two, three, or four lateral substituents selected from the group consisting of halogen atoms, -SCF3, -CF3, -CHF2, -CN, -OCF3, -NO2, -OCH3, -OC2H5, and alkyl moieties having 1 to 4 carbon atoms in the carbon main chain, wherein the alkyl moiety has a linear or branched chain; - Phenyl substituents that are substituted with at least one aromatic or heteroaromatic substituent; - Benzhydryl substituent; - 1-naphthyl or 2-naphthyl substituent; - A benzothiophenyl substituent selected from the group consisting of 2-benzothiophenyl, 3-benzothiophenyl, 4-benzothiophenyl, or 5-benzothiophenyl substituents, preferably a 5-benzothiophenyl substituent; - A benzoisoxazole substituent selected from the group consisting of 3-benzoisoxazole, 4-benzoisoxazole, 5-benzoisoxazole, 6-benzoisoxazole, and 7-benzoisoxazole substituents, preferably a 5-benzoisoxazole substituent; - An alkyl moiety having 1 to 4 carbon atoms in a carbon main chain, having a linear, branched, or cyclic chain, and preferably substituted with at least one halogen atom. A substituent selected from the group consisting of; B is - Phenyl substituent; - A phenyl substituent substituted with one or two lateral substituents selected from the group consisting of halogen atoms, -SCF3, -CF3, -CHF2, -CN, -OCF3, -NO2, -OCH3, -OC2H5, and alkyl moieties having 1 to 4 carbon atoms in the carbon main chain, wherein the alkyl moiety has a linear or branched chain. Defined as; D is a substituent selected from the group consisting of H, amino (-NH2), an amino group substituted with one or two aliphatic substituents (particularly -CH3 and / or -C2H5), or an amino group that is part of a heterocycle. A compound having [the specified characteristic], or a pharmaceutically acceptable salt thereof.

[0007] The term "halogen," when used to describe compounds by general formula (I), includes fluorine, chlorine, bromine, and iodine. In another preferred embodiment of the present invention, the halogen atom is fluorine or chlorine.

[0008] Compounds having general formula (I) can exist in the form of optical isomers and mixtures thereof, as they have multiple chiral centers. Various proportions of the aforementioned optical isomers and mixtures thereof, including racemic mixtures, are within the scope of the present invention. Individual isomers can be obtained using appropriate isomer forms of the starting material (amino acid derivatives) or separated after preparing the final compound according to known separation methods.

[0009] Preferably, the compound of the present invention is of general formula (II)

[0010] [ka] (In the formula, X is either N or C, k is a number equal to 0 or 1. A is - Phenyl substituent; - Phenyl substituents substituted with one, two, three, or four lateral substituents selected from the group consisting of halogen atoms, -SCF3, -CF3, -CHF2, -CN, -OCF3, -NO2, -OCH3, -OC2H5, and alkyl moieties having 1 to 4 carbon atoms in the carbon main chain, wherein the alkyl moiety has a linear or branched chain; - Phenyl substituents that are substituted with at least one aromatic or heteroaromatic substituent; - Benzhydryl substituent; - 1-naphthyl or 2-naphthyl substituent; - A benzothiophenyl substituent selected from the group consisting of 2-benzothiophenyl, 3-benzothiophenyl, 4-benzothiophenyl, or 5-benzothiophenyl substituents, preferably a 5-benzothiophenyl substituent; - A benzoisoxazole substituent selected from the group consisting of 3-benzoisoxazole, 4-benzoisoxazole, 5-benzoisoxazole, 6-benzoisoxazole, and 7-benzoisoxazole substituents, preferably a 5-benzoisoxazole substituent; - An alkyl moiety having 1 to 4 carbon atoms in a carbon main chain, having a linear, branched, or cyclic chain, and preferably substituted with at least one halogen atom. A substituent selected from the group consisting of; B is - Phenyl substituent; - A phenyl substituent substituted with one or two lateral substituents selected from the group consisting of halogen atoms, -SCF3, -CF3, -CHF2, -CN, -OCF3, -NO2, -OCH3, -OC2H5, and alkyl moieties having 1 to 4 carbon atoms in the carbon main chain, wherein the alkyl moiety has a linear or branched chain. (is) A compound having [the specified characteristic], or a pharmaceutically acceptable salt thereof. Preferably, the halogen is a fluorine or chlorine atom.

[0011] Preferably, the alkyl portion in the carbon main chain contains 1 to 4 carbon atoms, and the alkyl portion has a linear or branched chain, and is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl substituents.

[0012] Compounds having general formula (II) possess a single chiral center and can therefore exist in the form of optical isomers and mixtures thereof. Various proportions of the aforementioned optical isomers and mixtures thereof, including racemic mixtures, are within the scope of the present invention. Individual isomers can be obtained using appropriate isomer forms of the starting material (amino acid derivatives) or separated after preparing the final compound according to known separation methods.

[0013] Preferably, k = 0.

[0014] Preferably, the X atom is a nitrogen atom.

[0015] Preferably, substituent A is selected from the group consisting of 5-benzothiophenyl, 2-naphthyl, and 5-benzoisoxazolyl substituents.

[0016] Preferably, A is selected from the group consisting of phenyl; phenyl substituted with at least one chlorine or -CF3, -CHF2, -OCF3, -CH3, -SCF3 or phenyl.

[0017] Preferably, substituent B is selected from the group consisting of phenyl or phenyl substituted with one or two halogen atoms.

[0018] Preferably, the compounds of the present invention are selected from the group consisting of: 1-(2-oxo-1-phenyl-2-(4-phenylpiperazine-1-yl)ethyl)pyrrolidine-2,5-dione, 1-(2-(4-(3-chlorophenyl)piperazin-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione, 1-(2-(4-(3,5-dichlorophenyl)piperazin-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione, 1-(2-oxo-1-phenyl-2-(4-(m-tolyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione, 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione, 1-(2-oxo-1-phenyl-2-(4-(4-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione, 1-(2-(4-(3,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione, 1-(2-oxo-1-phenyl-2-(4-(3-(difluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione, 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethoxy)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione, 1-(2-oxo-1-phenyl-2-(4-(4-(trifluoromethoxy)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione, 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl(sulfanyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione, 1-(2-(4-([1,1'-biphenyl]-3-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione, 1-(1-(4-fluorophenyl)-2-oxo-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione, 1-(2-(4-(naphtho-2-yl)piperazin-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione, 1-(2-(4-(benzo[b]thiophen-5-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione, 1-(2-(4-(1,2-benzoxazole-5-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione, 1-(2-(4-(3-chlorophenyl)piperidine-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione, 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperidine-1-yl)ethyl)pyrrolidine-2,5-dione, 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethoxy)phenyl)piperidine-1-yl)ethyl)pyrrolidine-2,5-dione.

[0019] Preferably, the compound of the present invention is a (R) enantiomer, and preferably selected from the following compounds: (R)-1-(2-(4-(3-chlorophenyl)piperazin-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione, (R)-1-(2-(4-(3,5-dichlorophenyl)piperazin-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione, (R)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione, (R)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethoxy)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione, (R)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl(sulfanyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione.

[0020] Preferably, the compound of the present invention is a water-soluble salt, particularly a hydrochloride salt, and is preferably selected from the following compounds: 3-(methylamino)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione hydrochloride, 3-(dimethylamino)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione hydrochloride, 3-(diethylamino)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione hydrochloride.

[0021] A second subject of the present invention is the compounds according to the present invention as defined above, used for the treatment or prevention of epileptic seizures, neuropathic pain, or migraines. In preferred embodiments, the compounds according to the present invention are used as active substances (one or more) contained in a pharmaceutical composition for the treatment or prevention of at least one of the above medical indications.

[0022] The compounds according to the present invention exhibit anticonvulsant and analgesic activity in a broad panel of animal models and can be found as active substances in various dosage forms for the treatment of epilepsy and neuropathic pain.

[0023] The compounds of formula (I) according to the present invention can be obtained using a multi-step synthesis procedure, which is illustrated in Figure 2A, where X, A, B, D, and k are as defined above. For the preparation of the compounds of formula (I), where D is a halogen, the procedure described for the compounds of formula (II) shown in Figure 2B is used. In the first step, an intermediate product with an amide structure is obtained as a result of a condensation reaction (i) between a suitable piperazine derivative and the corresponding tert-butoxycarbonyl (Boc) amino acid derivative, which is then deprotected (ii) to form an amine derivative. In the next step, the aforementioned amine derivative is subjected to a condensation reaction (iii) with maleic anhydride to obtain an unsaturated amide-acid derivative. This derivative is then subjected to a cyclization reaction (iv) to form the corresponding maleimide. In the next step (v), the maleimide derivative is subjected to an addition reaction with a suitable primary or secondary amine to obtain a compound having the general formula (I) according to the present invention.

[0024] The compound of formula (II) according to the present invention is of formula (III):

[0025] [ka] (In the formula, B and k are as defined with respect to formula (II)) It can be obtained starting from the compound of formula (III). The compound of formula (III) can be obtained in a two-step procedure using commercially available succinic anhydride and the corresponding amino acid derivative as a substrate. In the first step, an intermediate product of amide-acid structure (IV) is obtained as a result of a condensation reaction between succinic anhydride and a suitable amino acid derivative, and this is then cyclized to form the desired compound having formula (III). Alternatively, the compound described by formula (III) can be prepared by using a one-step thermocyclic condensation reaction between succinic anhydride or succinic acid and the corresponding amino acid.

[0026] The desired compounds of general formula (II) according to the present invention can be obtained by using an amidation reaction between the compound described in formula (III) and a suitable commercially available secondary aliphatic amine. This reaction can be carried out in the presence of a known coupling agent, including CDI, EDCI, DCC, etc. Alternatively, the compounds of formula (II) can be obtained by a reaction between the acid chloride obtained by the conversion of the carboxylic acid described in formula (II) and a corresponding commercially available secondary aliphatic amine. The compounds described in formula (II) according to the present invention can also be prepared in a reaction between a carboxylic acid and a corresponding aliphatic amine using an activator selected from BOP, HBTU, and HATU in the presence of an organic base, particularly triethylamine (TEA), N-methylmorpholine (NMM), or N,N-diisopropylethylamine (DIEA).

[0027] The synthesis procedure and reaction conditions, where X, A, B, and k are as defined above, are illustrated in Figure 2B.

[0028] The solutions according to the present invention have several advantages. Compounds disclosed in formula (I), preferably those of formula (II), are characterized by strong and broad anticonvulsant activity in various animal models of epilepsy, namely the maximal electroshock seizure test (MES), the subcutaneous pentylentrazole seizure test (scPTZ), and the 6 Hz seizure model (32 mA and / or 44 mA). Compounds exhibiting the aforementioned profiles in preclinical in vivo studies may be effective for various types of human epilepsy, including tonic-clonic seizures with or without secondary generalization, generalized seizures (absence), myoclonic seizures, partial seizures, and significant drug-resistant seizures. Another advantage of compounds of general formula (I), and especially those described in formula (II), is their strong analgesic activity in animal models used to assess antinociceptive activity, namely the formalin test, the capsaicin-induced pain model, and the oxaliplatin-induced neuropathic pain model. Therefore, compounds of formula (I), preferably of formula (II), may be useful in treating pain of both neurological and inflammatory origin, which is a unique feature among AEDs available for pharmacotherapy. Compounds of formula (I), preferably of formula (II), have a complex mechanism of molecular action, namely, they interact with voltage-gated sodium channels, calcium channels, and TRPV1 receptors. The beneficial antagonist effect observed in the case of TRPV1 receptors has not yet been demonstrated for known and therapeutically relevant AEDs. Importantly, while literature data suggests the possible involvement of TRPV1 in seizure induction (Naziroglu, M., Curr. Neuropharmacol. 2015, 13, pp. 239-247; Naziroglu, M.; Ovey, IS, Neuroscience 2015, 293, pp. 55-66), its role as a molecular target for substances with antinociceptive activity is well documented (Szallasi, A.; Cortright, DN; Blum, CA; Eid, SR, Nat. Rev. Drug. Discov. 2007, 6, pp. 357-372).Compounds according to formula (II) may also be potentially useful in the treatment of withdrawal syndrome, schizophrenia, schizoaffective disorder, personality and nutritional disorders, as well as anxiety and post-traumatic stress. Accordingly, the present invention provides compounds for use as drugs. Furthermore, the possibility of using TRPV1 receptor antagonists to treat various types of epileptic seizures is disclosed.

[0029] The compounds according to the present invention can be administered by various routes, including intra-intestinal, topical, or parenteral administration, by applying a pharmaceutically acceptable and effective amount of a pharmaceutical preparation suitable for a given route of administration, together with pharmaceutically acceptable diluents, carriers, and / or excipients known in the art, and containing at least one active compound according to formula (I), preferably formula (II). Methodologies for preparing such pharmaceutical formulations are known in the art. The therapeutic dose will vary depending on the substance, species, sex, age, disease entity being treated, route, and method of administration, which must be determined by experts in the art. The proposed doses of the compounds according to the present invention are 0.1 to about 1000 mg per day in single or divided doses. The compounds of the present invention may be administered to the patient either by themselves or in combination with one or more active components present in their own compositions, or some or all of the active components combined in a single composition and / or suitable pharmaceutical excipients. Suitable pharmaceutical excipients include conventional supporting substances necessary for the proper preparation of a given formulation, such as fillers, binders, disintegrants, lubricants, solvents, gel-forming agents, emulsifiers, stabilizers, dyes, and / or preservatives. The compounds of the present invention are formulated into dosage forms using generally known pharmaceutically appropriate preparation methods. The dosage forms may be, for example, tablets, capsules, granules, suppositories, emulsions, suspensions, or solutions. Depending on the method of administration and the Galenic form, the amount of active substance in the formulation may typically range from 0.01% (by weight) to 100% (by weight).

[0030] Embodiments of the present invention will be described below with reference to the drawings shown. [Brief explanation of the drawing]

[0031] [Figure 1] This figure shows the general formulas of compounds (I) and (II). [Figure 2A] This figure shows the synthesis of derivatives according to formula (I). [Figure 2B] This figure shows the synthesis of the derivative according to formula (II). [Figure 3] This graph shows the analgesic activity of compound 6 and valproic acid (VPA) in pain during phases I and II of the formalin test. Results are presented as limb licking time during phase I (0–5 minutes after formalin injection) and phase II (15–30 minutes after formalin injection) of the test, and values ​​represent the mean ± SEM for a group of 8–10 animals; statistically significant differences compared to the control (vehicle-Tween) group, statistical analysis: one-way ANOVA, Dunnett's post hoc test: *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. C: control group; VPA: valproic acid. [Figure 4] This graph shows the analgesic activity of compound 6 and valproic acid (VPA) in a capsaicin assay. Results are shown as the time spent licking the limb 0–5 minutes after capsaicin injection, and values ​​represent mean ± SEM; statistically significant differences compared to the control (vehicle-Tween) group. Statistical analysis: one-way ANOVA, Dunnett's post hoc test: *p<0.05, **p<0.01, ****p<0.0001. C: control group; VPA: valproic acid. [Figure 5]This graph shows the analgesic activity of compound 6 and valproic acid (VPA) in oxaliplatin-induced peripheral neuropathy. A: Effect of compound 6 on mechanical allodynia in the von Frey test. B: Effect of valproic acid (VPA) on mechanical allodynia in the von Frey test. C: Effect of compound 6 on thermal allodynia in the cold plate test. Results are presented as mean ± SEM of the latency of the onset of the foot-lifting pressure (von Frey test) or nociceptive cold plate response in groups of 8-10 animals; statistically significant difference compared to the control group (mice after OXPT administration and before administration of the test compound). Statistical analysis: one-way ANOVA, Dunnett's post hoc test: *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Veh: Vehicle (1% Tween80). [Figure 6] This graph shows the effect of compound 6 (at a concentration of 100 μM) on fast voltage-dependent sodium current. A: Traces of the maximum voltage-dependent sodium current in the control, in the presence of compound 6, and after washing out compound 6. B: Normalized mean current amplitude in the control, in the presence of compound 6 (*p<0.001, ANOVA with Tukey's test), and after washing out compound 6. I / Imax (on the vertical axis) means that the current was normalized to the control value. [Figure 7] This graph shows the UPLC analysis of the metabolism of compound 6 after incubation with HML. [Figure 8] This graph shows the effects of verapamil, Na3VO4, and compound 6 on baseline Pgp activity. Statistical significance was calculated using one-way ANOVA and Bonferroni method (**p<0.01, ***p<0.001, triple-tested compounds). [Figure 9]A: Graph showing the effects of the reference inhibitor ketoconazole (KE) and compound 6 on CYP3A4 activity. B: Graph showing the effects of the reference inhibitor quinidine (QD) and compound 6 on CYP2D6 activity. Statistical significance was calculated using one-way ANOVA and Bonferroni method (***p<0.001). [Figure 10] This graph shows the effects of the reference cell proliferation inhibitor doxorubicin (DX), the mitochondrial toxin CCCP (carbonyl cyanide m-chlorophenylhydrazone), and compound 6 on the cell viability of HepG2 strains after 72 hours of incubation. Statistical significance was calculated using one-way ANOVA and Bonferroni method (*p<0.05, ***p<0.001, compounds replicated four times). [Figure 11] This graph shows ATP levels in HepG2 cell lines after 3 hours of incubation. The compounds tested were doxorubicin (DX) and CCCP (carbonyl cyanide m-chlorophenylhydrazone). Statistical significance was calculated using one-way ANOVA and Bonferroni method (***p<0.001, compounds replicated 4 times). [Figure 12] This figure shows a general scheme for the synthesis of enantiomers of a compound using formula (II). [Figure 13] This graph shows the UPLC analysis of the metabolism of (R)-6 enantiomers after incubation with HML. [Figure 14] This figure shows a general scheme for the synthesis of water-soluble salts of compounds using formula (I). [Modes for carrying out the invention]

[0032] Analysis method: Proton magnetic resonance ( 1 ¹H NMR and carbon nuclear magnetic resonance ( 13The 3C NMR spectra were recorded using a Mercury-300 "Varian" spectrometer (Varian Inc., Palo Alto, CA, USA) operating at 300 MHz and 75 MHz, respectively, or a JEOL-500 spectrometer (JEOL USA, Inc., MA, USA) operating at 500 MHz and 126 MHz, respectively. Chemical shifts are given as δ (ppm) values ​​relative to TMSδ = 0 (1H) as an internal standard. J values ​​are expressed in Hertz (Hz). Deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-D6) were used as solvents. The following signal abbreviations are used in the spectral descriptions: s (single line), br s (broad single line), d (double line), dd (double line double line), ddd (double line double line double line), t (triple line), td (double line triple line), q (quadruple line), m (multiple lines). The UPLC / MS analysis system consisted of a Waters ACQUITY® UPLC® instrument (Waters Corporation, Milford, MA, USA) equipped with a Waters TQD mass spectrometer operating in electrospray ionization (ESI) mode. Chromatographic separation was performed using an Acquity UPLC BEH C18, 1.7 μm (2.1 × 100 mm) column with a VanGuard Acquity UPLC BEH C18, 1.7 μm (2.1 × 5 mm) column (Waters, Milford, CT, USA). The column was maintained at 40°C and eluted over 10 minutes at a flow rate of 0.3 mL / min with a gradient of eluent A from 95% to 0%. Eluent A: water / formic acid (0.1%, v / v); Eluent B: acetonitrile / formic acid (0.1%, v / v). Chromatograms were recorded using a Waters eλ PDA detector. The spectrum was analyzed at a sampling rate of 20 points / s in the range of 200–700 nm with a resolution of 1.2 nm. UPLC retention time (t R ) is shown in minutes. Thin-layer chromatography (TLC) is performed using a developing solvent system with the following composition, silica gel 60 F 254The tests were performed on coated aluminum sheets (Macherey-Nagel, Duren, Germany): DCM:MeOH (9:0.2;v / v), DCM:MeOH (9:0.3;v / v), DCM:MeOH (9:0.5;v / v), DCM:MeOH (9:1;v / v). Spot detection: UV light (λ=254nm). Melting point (mp) was determined using open capillary in a Buchi 353 instrument (Buchi Labortechnik, Flawil, Switzerland). Enantiomer purity was determined using chiral HPLC technique on Shimadzu Prominence and LC-2030C SD Plus instruments (Shimadzu Corporation, Kyoto, Japan) equipped with Amylose-C (250×4.6mm) chiral columns. The analysis was performed under the following conditions: column temperature: 20°C, eluent mixture: hexane / i-PrOH = 80 / 20 (v / v), flow rate: 1 mL / min, detection at wavelength λ = 206 nm. Enantiomer purity is expressed in %.

[0033] The preparation of the compounds of the present invention is shown in the following examples. The synthesis described in the following examples was not optimized in terms of yield, amount of reagents used, or final form of the resulting compound.

[0034] Abbreviations used: AcOEt: Ethyl acetate CDI: Carbonyldiimidazole DCC:N,N'-Dicyclohexylcarbodiimide DCM: Dichloromethane DMF: Dimethylformamide Et2O: Diethyl ether HCl: Hydrochloric acid HMDS: Hexamethyldisilazane MeOH: methanol NaCl: Sodium Chloride Na2SO4: Sodium sulfate ZnCl2: Zinc chloride [Examples]

[0035] Synthesis, Physicochemical, and Spectral Data of Intermediates (IV and III According to the Scheme of Figure 2B) Intermediate IV: 4-((Carboxy(phenyl)methyl)amino)-4-oxobutanoic acid Succinic anhydride (3.0 g, 30 mmol, 1 equivalent) was dissolved in 15 mL of glacial acetic acid, and then an equimolar amount of DL-phenylglycine (4.53 g) was added. The mixture was heated at 70 °C with stirring for 12 hours. After this time, acetic acid was distilled off to dryness. Intermediate IV was washed with Et2O and obtained as a solid.

[0036] White solid. Yield: 87% (6.55 g); m.p. 199.4 - 200.6 °C; TLC: R f = 0.25 (DCM:MeOH (9:1; v / v)); C 12 H 13 NO5 (251.24), Monoisotopic mass: 251.08. UPLC (100% purity): t R = 2.77 minutes. (M + H) + 252.1.

[0037] Intermediate III: 2-(2,5-Dioxopyrrolidin-1-yl)-2-phenylacetic acid ZnCl2 (2.73 g, 20 mmol, 1 equivalent) was added to a suspension of 4-((carboxy(phenyl)methyl)amino)-4-oxobutanoic acid (5.0 g, 20 mmol, 1 equivalent) (IV) in dry benzene (100 mL), and the mixture was heated to 80 °C. Then, a solution of HMDS (4.84 g, 6.25 mL, 30 mmol, 1.5 equivalents) in dry benzene (15 mL) was added dropwise over 30 minutes. The reaction mixture was stirred under reflux for about 24 hours and then concentrated under reduced pressure. After removal of the solvent, the oily residue was dissolved in DCM and extracted with 0.1 M HCl (3 × 50 mL), water (3 × 50 mL), and saturated NaCl solution (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness. 2-(2,5-Dioxopyrrolidin-1-yl)-2-phenylacetic acid was washed with Et2O and obtained as a solid material. Alternatively, 1,4-dioxane can be used instead of benzene in the above procedure.

[0038] White solid. Yield: 90% (4.20g); mp195.5~198.2℃; TLC: R f =0.45(DCM:MeOH(9:1;v / v));C 12 H 11 NO4 (233.22), monoisotopic mass: 233.07. UPLC (100% purity): t R = 3.41 minutes. (M+H) + 234.1. 1 H NMR (300 MHz, DMSO-D6) δ 2.73 (s, 4H), 5.76 (s, 1H), 7.26-7.35 (m, 3H), 7.36-7.45 (m, 2H), 13.22 (br s, 1H). [Examples]

[0039] 1-(2-oxo-1-phenyl-2-(4-phenylpiperazine-1-yl)ethyl)pyrrolidine-2,5-dione Carbonyl diimidazole (1.17 g, 7.2 mmol, 1.2 equivalents) was dissolved in 5 mL of dry DMF, and then added to a solution of 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) dissolved in 10 mL of anhydrous DMF. After stirring for 0.5 hours, a solution of 1-phenylpiperazine (0.97 g, 6 mmol, 1 equivalent) in 5 mL of anhydrous DMF was added dropwise. The reaction mixture was stirred at room temperature for 24 hours. After this time, the DMF was removed under reduced pressure. The crude product was purified by column chromatography using a mixture of DCM:MeOH (9:0.3; v / v) as the solvent system. The compound was washed with Et2O and obtained as a solid.

[0040] White solid. Yield: 84% (1.90g); mp156.7~157.4℃; TLC: R f =0.35(DCM:MeOH(9:0.3;v / v));C 22 H 23 N3O3 (377.44), monoisotope mass: 377.17. UPLC (100% purity): t R= 5.88 minutes. (M+H) + 378.1. 1 H NMR (300 MHz, CDCl3) δ 2.58-2.81 (m, 5H), 2.95-3.15 (m, 2H), 3.17-3.42 (m, 3H), 3.63-3.76 (m, 1H), 3.92-4.05 (m, 1H), 6.12 (s, 1H), 6.80-6.91 (m, 3H), 7.19-7.28 (m, 2H) 7.29-7.47 (m, 5H); 13 C NMR (75 MHz, CDCl3) δ 28.1, 42.4, 45.8, 48.9, 49.2, 56.8, 116.5, 116.6, 120.6, 128.6, 128.6, 128.9, 129.1, 129.2, 129.8, 129.9, 133.0, 150.7, 165.0, 176.3. [Examples]

[0041] 1-(2-(4-(3-chlorophenyl)piperazin-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 1-(3-chlorophenyl)piperazine (1.40 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.2; v / v) elution system.

[0042] White solid. Yield: 81% (2.00g); mp128.1~129℃; TLC: R f =0.51(DCM:MeOH(9:0.2;v / v));C 22 H 22 ClN3O3 (411.89), monoisotopic mass: 411.13. UPLC (100% purity): t R = 6.69 minutes, (M+H) + 412.1. 1H NMR (300 MHz, CDCl3) δ 2.58-2.73 (m, 4H), 3.00 (br s, 1H), 3.27-3.53 (m, 3H), 3.54- 3.86 (m, 2H), 4.17 (br s, 2H), 6.02 (s, 1H), 7.27-7.40 (m, 7H), 7.51-7.63 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 28.0, 40.0, 43.3, 53.3, 53.7, 56.5, 118.9, 120.8, 128.9, 129.1, 129.3, 129.6, 131.4, 132.1, 135.9, 143.8, 165.5, 176.7. [Examples]

[0043] 1-(2-(4-(3,5-dichlorophenyl)piperazin-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2: 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 1-(3,5-dichlorophenyl)piperazine (1.20 g, 6 mmol, 1 equivalent). The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) elution system.

[0044] White solid. Yield: 77% (2.06 g); mp163.8~165.2℃; TLC: R f =0.42(DCM:MeOH(9:0.2;v / v));C 22 H 21 Cl2N3O3 (446.33), monoisotopic mass: 446.10. UPLC (99% purity): t R = 7.59 minutes, (M+H) + 446.1. 1H NMR (500 MHz, CDCl3) δ 2.63-2.78 (m, 5H), 2.98-3.13 (m, 2H), 3.20-3.36 (m, 3H), 3.59-3.68 (m, 1H), 3.97-4.00 (m, 1H), 6.09 (s, 1H), 6.64 (d, J = 1.7 Hz, 2H), 6.80 (t, J = 1.7 Hz, 1H), 7.33-7.38 (m, 3H), 7.42 (d, J = 6.7 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 28.1, 42.2, 45.4, 48.0, 48.2, 56.9, 114.4, 119.8, 128.8, 129.1, 129.9, 132.9, 135.6, 152.1, 165.2, 176.4. [Examples]

[0045] 1-(2-oxo-1-phenyl-2-(4-(m-tolyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 1-(3-methylphenyl)piperazine (1.18 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) elution system.

[0046] White solid. Yield: 86% (2.02g); mp188.7~192.1℃; TLC: R f =0.45(DCM:MeOH(9:0.3;v / v));C 23 H 25 N3O3 (391.47), monoisotopic mass: 391.19. UPLC (98.9% purity): t R = 6.35 minutes, (M+H) + 392.2. 1H NMR (300 MHz, CDCl3) δ 2.36 (s, 3H), 2.57-2.78 (m, 5H), 2.91-3.54 (m, 3H), 3.63-4.55 (m, 4H), 6.06 (s, 1H), 7.22 (d, 1H, J = 7.5 Hz), 7.27-7.62 (m, 8H); 13 C NMR (75 MHz, CDCl3) δ 21.4, 28.1, 39.7, 43.0, 54.1, 54.6, 56.5, 117.9, 121.7, 128.9, 129.3, 129.7, 130.2, 130.8, 132.3, 141.0, 141.8, 165.4, 176.3. [Examples]

[0047] 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 1-[3-(trifluoromethyl)phenyl]piperazine (1.38 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.2; v / v) elution system.

[0048] White solid. Yield: 82% (2.19g); mp150.3~151.4℃; TLC: R f =0.34(DCM:MeOH(9:0.2;v / v));C 23 H 22 F3N3O3 (445.44), monoisotopic mass: 445.16. UPLC (100% purity): t R = 6.94 minutes, (M+H) + 446.2. 1H NMR (300 MHz, CDCl3) δ 2.60-2.86 (m, 5H), 3.00-3.20 (m, 2H), 3.23-3.44 (m, 3H), 3.62-3.76 (m, 1H), 3.93-4.06 (m, 1H), 6.12 (s, 1H), 6.94-7.04 (m, 2H), 7.09 (d, 1H, J = 7.7 Hz), 7.28-7.51 (m, 6H); 13 C NMR (75 MHz, CDCl3) δ 28.0, 42.2, 45.6, 48.4, 48.6, 56.8, 112.7 (q, J = 4.6 Hz), 116.7 (q, J = 4.6 Hz), 119.2, 123.4 (q, J = 271.8 Hz), 128.7, 128.9, 129.7, 129.8, 131.5 (q, J = 31.8 Hz), 132.9, 150.8, 165.1, 176.3. [Examples]

[0049] 1-(2-oxo-1-phenyl-2-(4-(4-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 1-[4-(trifluoromethyl)phenyl]piperazine (1.38 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) elution system.

[0050] White solid. Yield: 62% (1.66g); mp173.2~174.3℃; TLC: R f =0.49(DCM:MeOH(9:0.3;v / v));C 23 H 22 F3N3O3 (445.44), monoisotopic mass: 445.16. UPLC (100% purity): t R = 6.89 minutes, (M+H) +446.2. 1 H NMR (300 MHz, CDCl3) δ 2.61-2.85 (m, 5H), 3.04-3.43 (m, 5H), 3.63-3.77 (m, 1H), 3.91-4.05 (m, 1H), 6.12 (s, 1H), 6.83 (d, 2H, J = 8.6 Hz), 7.30-7.40 (m, 3H), 7.40-7.50 (m, 4H); 13 C NMR (75 MHz, CDCl3) δ 28.0, 42.1, 45.4, 47.6, 47.9, 56.8, 115.0, 124.5 (q, J = 270.6 Hz), 126.5 (q, J = 4.6 Hz), 128.7, 128.8, 128.9, 129.8, 132.8, 152.7, 165.1, 176.3. [Examples]

[0051] 1-(2-(4-(3,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 1-[3,5-bis(trifluoromethyl)phenyl]piperazine (1.18 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0052] White solid. Yield: 69% (2.12g); mp2 28.1~229.4℃; TLC: R f =0.47(DCM:MeOH(9:0.5;v / v));C 24 H 21 F6N3O3 (513.44), monoisotopic mass: 513.13. UPLC (100% purity): t R = 6.58 minutes, (M+H) + 514.1. 1H NMR (300 MHz, CDCl3) δ 2.52-2.75 (m, 4H), 2.82-3.07 (m, 4H), 3.12-3.86 (m, 4H), 6.11 (s, 1H), 6.97-7.05 (m, 3H), 7.22-7.61 (m, 5H). [Examples]

[0053] 1-(2-oxo-1-phenyl-2-(4-(3-(difluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 1-(3-difluoromethylphenyl)piperazine (1.27 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.2; v / v) elution system.

[0054] White solid. Yield: 83% (2.13g); mp156.4~157.6℃; TLC: R f =0.55(DCM:MeOH(9:0.2;v / v));C 23 H 23 F2N3O3 (427.45), monoisotopic mass: 427.17. UPLC (100% purity): t R = 6.36 minutes, (M+H) + 428.2. 1 H NMR (300 MHz, CDCl3) δ 2.58-2.78 (m, 5H), 3.02-3.18 (m, 2H), 3.24-3.46 (m, 3H), 3.62-4.08 (m, 2H), 6.12 (s, 1H), 6.44-7.62 (m, 1H), 6.94-7.04 (m, 2H), 7.28-7.51 (m, 7H). [Examples]

[0055] 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethoxy)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 1-[3-(trifluoromethoxy)phenyl]piperazine (1.48 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) elution system.

[0056] White solid. Yield: 89% (2.46g); mp100.3~101.6℃; TLC: R f =0.42(DCM:MeOH(9:0.3;v / v));C 23 H 22 F3N3O4 (461.44), monoisotopic mass: 461.16. UPLC (100% purity): t R = 7.15 minutes, (M+H) + 462.2. 1 H NMR (300 MHz, CDCl3) δ 2.63-2.79 (m, 5H), 3.00-3.16 (m, 2H), 3.22-3.39 (m, 3H), 3.93-4.05 (m, 1H), 3.63-3.75 (m, 1H), 6.12 (s, 1H), 6.62 (s, 1H), 6.66-6.78 (m, 2H), 7.16-7.28 (m, 1H), 7.32-7.48 (m, 5H); 13 C NMR (75 MHz, CDCl3) δ 28.0, 42.2, 45.5, 48.3, 48.5, 56.8, 108.8, 112.1, 114.2, 120.4 (q, J = 256.8 Hz), 128.7, 128.9, 129.8, 130.2, 132.8, 150.2, 151.9, 165.1, 176.3. [Examples]

[0057] 1-(2-oxo-1-phenyl-2-(4-(4-(trifluoromethoxy)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 1-[4-(trifluoromethoxy)phenyl]piperazine (1.48 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) elution system.

[0058] White solid. Yield: 83% (2.29g); mp102.3~103.5℃; TLC: R f =0.43(DCM:MeOH(9:0.3;v / v));C 23 H 22 F3N3O4 (461.44), monoisotopic mass: 461.16. UPLC (100% purity): t R = 7.17 minutes, (M+H) + 462.2. 1 H NMR (300 MHz, CDCl3) δ 2.61-2.73 (m, 5H), 2.98-3.13 (m, 2H), 3.20-3.37 (m, 3H), 3.91-4.08 (m, 1H), 3.63-3.75 (m, 1H), 6.13 (s, 1H), 6.60 (s, 1H), 6.63-6.79 (m, 2H), 7.14-7.28 (m, 1H), 7.29-7.51 (m, 5H). [Examples]

[0059] 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl(sulfanyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 1-[3-(trifluoromethylthio)phenyl]piperazine (1.57 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0060] White solid. Yield: 64% (1.83g); mp 97.8~99.2℃; TLC: R f =0.48(DCM:MeOH(9:0.5;v / v));C 23 H 22 F3N3O3S (477.50), monoisotopic mass: 478.13. UPLC (99% purity): t R = 7.55 minutes, (M+H) + 478.1. 1 H NMR (500 MHz, CDCl3) δ 2.64-2.78 (m, 5H), 3.01-3.07 (m, 1H), 3.09-3.15 (m, 1H), 3.24-3.32 (m, 2H), 3.34 (dd, J = 7.7, 3.2 Hz, 1H), 3.62-3.75 (m, 1H), 3.99 (ddd, J = 13.2, 5.7, 3.4 Hz, 1H), 6.11 (s, 1H), 6.92 (dd, J = 8.0, 2.3 Hz, 1H), 7.06 (s, 1H), 7.12 (d, J = 7.4 Hz, 1H), 7.24-7.29 (m, 1H), 7.33-7.38 (m, 3H), 7.43 (d, J = 6.8 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 28.1, 45.6, 48.4, 48.7, 56.9, 118.5, 123.7, 125.3, 127.8, 128.5, 129.4 (d, J = 141.2 Hz), 129.6 (d, J = 137.0 Hz), 130.9, 132.9, 151.4, 165.2, 176.4. [Examples]

[0061] 1-(2-(4-( [1,1'-Biphenyl]-3-yl)piperazin-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione The compound was prepared according to the procedure described in Example 2. 2-(2,5-Dioxopyrrolidin-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent), and 1-(biphen-3-yl)piperazine (1.43 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0062] White solid. Yield: 82% (2.23 g); m.p. 114.1~115.4 °C; TLC: R f = 0.4 (DCM:MeOH (9:0.5; v / v)); C 28 H 27 N3O3 (453.54), monoisotopic mass: 453.20. UPLC (100% purity): t R = 7.43 minutes, (M+H) + 454.2. 1 H NMR (300 MHz, CDCl3) δ 2.56 - 2.81 (m, 5H), 3.00 - 3.21 (m, 2H), 3.23 - 3.56 (m, 3H), 3.65 - 3.79 (m, 1H), 3.94 - 4.11 (m, 1H), 6.14 (s, 1H), 6.83 (dd, 1H, J = 8.1, 2.0 Hz), 7.00 - 7.17 (m, 2H), 7.27 - 7.62 (m, 11H); 13 C NMR (75 MHz, CDCl3) δ 28.1, 42.5, 45.8, 49.0, 49.2, 56.8, 115.4, 115.6, 119.7, 127.2, 127.4, 128.7, 128.8, 129.6, 129.9, 132.9, 141.4, 142.5, 151.1, 165.0, 176.4.

Example

[0063] 1-(1-(4-Fluorophenyl)-2-oxo-2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)pyrrolidine-2,5-dione The compound was prepared according to the procedure described in Example 2. 2-(2,5-Dioxopyrrolidin-1-yl)-2-(4-fluorophenyl)acetic acid (1.51 g, 6 mmol, 1 eq), and 1-[3-(trifluoromethoxy)phenyl]piperazine (1.38 g, 6 mmol, 1 eq) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0064] White solid. Yield: 73% (2.03 g); m.p. 88.8 - 90.7 °C; TLC: R f = 0.63 (DCM:MeOH (9:0.5; v / v)); C 23 H 21 F4N3O3 (463.43), monoisotopic mass: 463.15. UPLC (100% purity): t R = 7.05 minutes, (M+H) + 464.2. 1 H NMR (300 MHz, CDCl3) δ 2.61 - 2.89 (m, 5H), 3.02 - 3.46 (m, 5H), 3.67 - 3.80 (m, 1H), 3.88 - 4.04 (m, 1H), 6.09 (s, 1H), 6.94 - 7.27 (m, 6H), 7.29 - 7.40 (m, 2H). 13 C NMR (75 MHz, CDCl3) δ 28.0, 42.3, 45.6, 48.5, 48.6, 56.0, 112.7 (q, J = 3.4 Hz), 115.9, 116.2, 116.7 (q, J = 3.4 Hz), 117.0, 119.3, 124.1 (q, J = 272.9 Hz), 125.5 (d, J = 3.4 Hz), 129.7, 130.2, 130.3, 131.5 (q, J = 31.1 Hz), 135.1 (d, J = 6.9 Hz), 150.7, 160.9, 164.2, 164.5, 176.23. [Examples]

[0065] 1-(2-(4-(naphtho-2-yl)piperazin-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 1-(naphtho-2-yl)piperazine (1.27 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0066] White solid. Yield: 79% (2.02g); mp197.1~198.5℃; TLC: R f =0.71((DCM:MeOH(9:0.5;v / v));C 26 H 25 N3O3 (427.50), monoisotopic mass: 427.19. UPLC (100% purity): t R = 6.97 minutes (M+H) + 428.2. 1 H NMR (300 MHz, CDCl3) δ 2.58-2.87 (m, 5H), 3.03-3.25 (m, 2H), 3.29-3.60 (m, 3H), 3.69-3.89 (m, 1H), 3.96-4.17 (m, 1H), 6.12-6.18 (m, 1H), 7.00-7.24 (m, 2H), 7.28-7.54 (m, 7H), 7.61-7.80 (m, 3H). [Examples]

[0067] 1-(2-(4-(benzo[b]thiophen-5-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 1-(benzo[b]thiophen-5-yl)piperazine (1.30 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0068] White solid. Yield: 79% (2.05g); mp164.1~165.3℃; TLC: R f =0.66((DCM:MeOH(9:0.5;v / v));C 24 H 23 N3O3S (433.53), monoisotopic mass: 433.15. UPLC (100% purity): t R = 6.62 minutes, (M+H) + 434.1. 1 H NMR (300 MHz, CDCl3) δ 2.56-2.85 (m, 5H), 2.96-3.17 (m, 2H), 3.20-3.54 (m, 3H), 3.66-3.87 (m, 1H), 3.96-4.12 (m, 1H), 6.14 (s, 1H), 6.99 (dd, J = 8.7, 1.9 Hz, 1H), 7.15-7.25 (m, 1H), 7.30-7.55 (m, 7H), 7.72 (d, J = 8.8 Hz, 1H). [Examples]

[0069] 1-(2-(4-(1,2-benzoxazol-5-yl)piperazine-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 5-(piperazin-1-yl)benzo[d]isoxazole (1.22 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0070] White solid. Yield: 57% (1.43g); mp186.4~187.8℃; TLC: R f =0.58(DCM:MeOH(9:0.5;v / v));C 23 H 22 N4O4 (418.45), monoisotopic mass: 418.16. UPLC (98% purity): t R = 7.25 minutes, (M+H) + 419.1. 1 H NMR (300 MHz, CDCl3) δ 2.57-2.86 (m, 5H), 2.95-3.19 (m, 3H), 3.22-3.53 (m, 2H), 3.62-3.84 (m, 2H), 3.94-4.11 (m, 1H), 6.14 (s, 1H), 7.05-7.32 (m, 1H), 7.29-7.54 (m, 6H), 7.98 (d, J = 8.8 Hz, 1H). [Examples]

[0071] 1-(2-(4-(3-chlorophenyl)piperidine-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 4-(3-chlorophenyl)piperidine (1.17 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0072] White solid. Yield: 74% (1.83g); mp1 11.8~113.4℃; TLC: R f =0.43(DCM:MeOH(9:0.5;v / v));C 23 H 23 ClN2O3 (410.90), monoisotopic mass: 410.14. UPLC (100% purity): t R = 7.05 minutes, (M+H) + 411.1. 1 H NMR (300 MHz, CDCl3) δ 1.52-2.05 (m, 4H), 2.33-2.84 (m, 8H), 2.96-3.34 (m, 1H), 6.15 (s, 1H), 7.05-7.28 (m, 6H), 7.32-7.66 (m, 3H). [Examples]

[0073] 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperidine-1-yl)ethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 1-[3-(trifluoromethyl)phenyl]piperidine (1.37 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0074] White solid. Yield: 85% (2.26g); mp100.1~101.5℃; TLC: R f =0.45(DCM:MeOH(9:0.5;v / v));C 24 H 23 F3N2O3 (444.45), monoisotopic mass: 444.17. UPLC (100% purity): t R = 7.26 minutes, (M+H) + 445.1. 1H NMR (300 MHz, CDCl3) δ 1.49-2.00 (m, 3H), 2.54-2.83 (m, 8H), 2.94-3.77 (m, 2H), 6.14 (s, 1H), 7.09-7.60 (m, 9H). [Examples]

[0075] 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethoxy)phenyl)piperidine-1-yl)ethyl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-2-phenylacetic acid (1.40 g, 6 mmol, 1 equivalent) and 4-[3-(trifluoromethoxy)phenyl]piperidine (1.45 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0076] White solid. Yield: 79% (2.18g); mp1 12.1~113.2℃; TLC: R f =0.47(DCM:MeOH(9:0.5;v / v));C 24 H 23 F3N2O4 (460.45), monoisotopic mass: 460.16. UPLC (100% purity): t R = 7.12 minutes, (M+H) + 461.1. 1 H NMR (300 MHz, CDCl3) δ 1.38-2.15 (m, 3H), 2.49-2.92 (m, 8H), 2.99-3.85 (m, 2H), 6.15 (s, 1H), 7.11-7.64 (m, 9H). [Examples]

[0077] 1-(1-oxo-3-phenyl-1-(4-phenylpiperazine-1-yl)prop-2-yl)pyrrolidine-2,5-dione The compound was prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-3-phenylpropanoic acid (1.48 g, 6 mmol, 1 equivalent) and 1-phenylpiperazine (0.97 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0078] White solid. Yield: 87% (1.13g); mp1 21.7~123.2℃; TLC: R f =0.62(DCM:MeOH(9:0.5;v / v));C 23 H 25 N3O3 (391.47), monoisotopic mass: 392.19. UPLC (100% purity): t R = 6.22 minutes, (M+H) + 392.1. 1 H NMR (300 MHz, CDCl3) δ 2.49-2.61 (m, 4H), 3.08 (d, J = 16.4 Hz, 4H), 3.31-3.89 (m, 6H), 5.19 (dd, J = 10.3, 6.1 Hz, 1H), 6.83-6.96 (m, 3H), 7.13-7.33 (m, 7H). 13 C NMR (75 MHz, CDCl3) δ 27.8, 34.2, 42.5, 45.4, 49.3, 49.6, 52.9, 116.6, 120.7, 127.1, 128.6, 129.1, 129.3, 136.7, 150.7, 166.4, 176.5. [Examples]

[0079] 1-(1-(4-(3-chlorophenyl)piperazine-1-yl)-1-oxo-3-phenylpropane-2-yl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-3-phenylpropanoic acid (1.48 g, 6 mmol, 1 equivalent) and 1-(3-chlorophenyl)piperazine (1.40 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0080] White solid. Yield: 87% (1.23g); mp1 14.3~116.2℃; TLC: R f =0.80(DCM:MeOH(9:0.5;v / v));C 23 H 24 ClN3O3 (425.91), monoisotopic mass: 426.15. UPLC (100% purity): t R = 6.97 minutes, (M+H) + 426.1. 1 H NMR (300 MHz, CDCl3) δ 2.49-2.64 (m, 4H), 3.07 (d, J = 15.3 Hz, 4H), 3.30-3.86 (m, 6H), 5.17 (dd, J = 10.1, 6.2 Hz, 1H), 6.73 (ddd, J = 8.3, 2.2, 0.9 Hz, 1H), 6.79-6.88 (m, 2H), 7.06-7.35 (m, 6H). 13 C NMR (75 MHz, CDCl3) δ 27.8, 34.2, 42.2, 45.2, 48.7, 49.0, 52, 9, 114.4, 116.3, 120.2, 127.1, 128.6, 129.1, 130.2, 135.0, 136.6, 151.7, 166.4, 176.5. [Examples]

[0081] 1-(1-oxo-3-phenyl-1-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)propan-2-yl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-3-phenylpropanoic acid (1.48 g, 6 mmol, 1 equivalent) and 1-[3-(trifluoromethyl)phenyl]piperazine (1.38 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0082] White solid. Yield: 84% (1.59 g); mp1 26.1~127.2℃; TLC: R f =0.72(DCM:MeOH(9:0.5;v / v));C 24 H 24 F3N3O3 (459.47), monoisotopic mass: 460.18. UPLC (100% purity): t R = 7.22 minutes, (M+H) + 460.1.1H NMR (300 MHz, CDCl3) δ 2.50-2.64 (m, 4H) 3.12 (d, J = 14.8 Hz, 4H), 3.32-3.89 (m, 6H) 5.18 (dd, J = 9.9, 6.2 Hz, 1H), 6.94-7.42 (m, 9H). [Examples]

[0083] 1-(1-(4-([1,1'-biphenyl]-3-yl)piperazine-1-yl)-1-oxo-3-phenylpropane-2-yl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-3-phenylpropanoic acid (1.48 g, 6 mmol, 1 equivalent) and 1-(biphenyl-3)piperazine (1.43 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0084] White solid. Yield: 88% (1.46g); mp1 19.1~120.0℃; TLC: R f=0.77(DCM:MeOH(9:0.5;v / v));C 29 H 29 N3O3 (467.57), monoisotopic mass: 467.22. UPLC (100% purity): t R = 7.63 minutes, (M+H) + 468.2. 1 H NMR (300 MHz, CDCl3) δ 2.50-2.63 (m, 4H) 3.16 (d, J = 18.9 Hz, 4H), 3.32-3.91 (m, 6H), 5.20 (dd, J = 10.2, 6.0 Hz, 1H) 6.88 (dd, J = 8.1, 1.8 Hz, 1H), 7.06-7.38 (m, 9H), 7.39-7.48 (m, 2H), 7.51-7.62 (m, 2H). 13 C NMR (75 MHz, CDCl3) δ 27.8, 34.2, 42.5, 45.4, 49.4, 49.7, 53.0, 115.5, 115.7, 119.7, 127.1, 127.2, 127.4, 128.6, 128.7, 129.1, 129.6, 136.7, 141.4, 142.5, 151.1, 166.4, 176.5. [Examples]

[0085] 1-(1-oxo-3-phenyl-1-(4-(3-(trifluoromethoxy)phenyl)piperazine-1-yl)propan-2-yl)pyrrolidine-2,5-dione The compounds were prepared according to the procedure described in Example 2. 2-(2,5-dioxopyrrolidine-1-yl)-3-phenylpropanoic acid (1.48 g, 6 mmol, 1 equivalent) and 1-[3-(trifluoromethoxy)phenyl]piperazine (1.48 g, 6 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0086] White solid. Yield: 83% (1.32g); mp104.4~105.5℃; TLC: R f=0.71(DCM:MeOH(9:0.5;v / v));C 24 H 24 F3N3O4 (475.47), monoisotopic mass: 475.17. UPLC (100% purity): t R = 7.40 minutes, (M+H) + 476.1. 1 H NMR (300 MHz, CDCl3) δ 2.50-2.63 (m, 4H, 3.10 (d, J = 16.4 Hz, 4H), 3.31-3.86 (m, 6H), 5,18 (dd, J = 9.9, 6.2 Hz, 1H), 6.62-6.85 (m, 3H), 7.11-7.36 (m, 6H). [Examples]

[0087] Determination of in vivo anticonvulsant activity in mice Male Swiss albino mice (CD-1) weighing 18–26 g were used. All procedures were carried out in accordance with applicable Polish and international guidelines on animal testing ethics, after obtaining approval for the appropriate facility. The substance was administered intraperitoneally (ip) as a single injection of 10 ml / kg volume in a 1% aqueous solution of Tween 30 minutes prior to the given test. Screening was performed in groups of four mice. The mean effective dose (ED) in the given test was determined. 50 ), and toxic dose in rotorod tests (TD 50 This was estimated based on results obtained from 3-4 groups of animals consisting of 6 mice each. All tests were conducted according to procedures described in expert literature. [Examples]

[0088] Maximum electrical shock seizure test (MES) In the MES (Measuring Endoscopy) study, seizures were induced by a sustained electrical stimulus with a voltage of 500V and an intensity of 25mA for a duration of 0.2 seconds. The electrical stimulus was generated using an electric shock generator (Rodent shocker, Type 221, Hugo Sachs Elektronik, Germany) and delivered to the animals using electrodes placed in the auricle. The study was conducted 30 minutes after intraperitoneal administration of various doses of the compound. During the experiment, the number of animals that experienced seizure episodes in the form of tonic extension of the hind limbs was counted (Kaminski, K.; Rapacz, A.; Luszczki, JJ; Latacz, G.; Obniska, J.; Kiec-Kononowicz, K.; Filipek, B., Bioorg. Med. Chem. 2015, 23, pp. 2548-2561; Castel-Branco, MM; Alves, GL; Figueiredo, IV; Falcao, AC; Caramona, MM, Methods Find. Exp. Clin. Pharmacol. 2009, 31, pp. 101-106). [Examples]

[0089] Psychomotor seizure test (6Hz test) In the 6 Hz test, seizures were induced by electrical stimulation at 32 mA and / or 44 mA, and at a frequency of 6 pulses per second. Electrical pulses were generated using an electroshock generator (ECT Unit 57800; Ugo Basile, Gemonio, Italy) and delivered to the animals using ocular electrodes. Before starting the test, the surface of the eye was gently moistened with a local anesthetic solution (1% lidocaine solution). The test was performed 30 minutes after intraperitoneal administration of the compound at various doses. After delivering the electrical pulse for 3 seconds continuously, the animals were observed for 10 seconds. During this period, we observed restlessness or stun related to feeding, forelimb clonus, spasms of sensory hairs, and Straub's tail. These symptoms persisted throughout the observation period and indicate the occurrence of psychomotor seizures in mice. Mice that resumed normal functioning within 10 seconds after stimulation were considered protected (Barton, ME; Klein, BD; Wolf, HH; White, HS, Epilepsy Res. 2001, 47, pp. 217-227; Wojda, E.; Wlaz, A.; Patsalos, PN; Luszczki, JJ, Epilepsy Res. 2009, 86, pp. 163-174). [Examples]

[0090] Subcutaneous pentylenetetrazol seizure test (scPTZ) In the scPTZ trial, seizures were induced by subcutaneous administration of pentylenetetrazole (PTZ) at a dose of 100 mg / kg. This induced clonic seizures accompanied by loss of righting reflex. The test compound was administered 30 minutes prior to the experiment. After PTZ administration, animals were placed individually in clear containers and observed for 30 minutes for the onset of clonic seizures. During this period, the latency of the first onset of a clonic seizure, defined as generalized clonus lasting at least 3 seconds with loss of righting reflex and number of seizure episodes during the trial period, was observed and compared with the control group. The absence of clonic seizures during the observed period was interpreted as the ability of the compound to protect against PTZ-induced seizures (Ferreri, G.; Chimirri, A.; Russo, E.; Gitto, R.; Gareri, P.; De Sarro, A.; De Sarro, G., Pharmacol. Biochem. Behav. 2004, pp. 77, 85-94; Laczkowski, K.; Salat, K.; Misiura, K.; Podkowa, A.; Malikowska, N., J. Enzyme Inhib. Med. Chem. 2016, pp. 31, 1576-82). [Examples]

[0091] The effect of the rotorod test on motor coordination in mice. The effect of the tested compounds on motor coordination was evaluated using the rota rod test (equipment used: May Commat, RR 0711 Rota Rod, Turkey). Mice were trained the day before the actual experiment. They were individually placed on a 2 cm diameter rod rotating at 10 revolutions per minute (rpm). During each training session, the animals remained on the rod for 3 minutes. The experiment was conducted 30 minutes after administration of the compounds. Motor coordination was tested for 60 seconds at a rotating rod speed of 10 rpm. Motor impairment was defined as the inability to remain on the rotating rod for 1 minute. The average time spent on the rod was counted for each experimental group (Dunham, NW; Miya, TA; Edwards, LD, J. Am. Pharm. Assoc. 1957, pp. 46, 64-66; Laczkowski, K.; Salat, K.; Misiura, K.; Podkowa, A.; Malikowska, N., J. Enzyme Inhib. Med. Chem. 2016, pp. 31, pp. 1576-82). [Examples]

[0092] statistical analysis ED aligned with the corresponding 95% confidence interval 50 (Effective dose) and TD 50 The (toxic dose) values ​​were calculated based on the Litchfield and Wilcoxon methods (Litchfield, JT, Wilcoxon, F., 1949, A simplified method of evaluating dose-effect experiments. J. Pharmacol. Exp. Ther. 96, pp. 99-113). To perform a statistical evaluation of the results, one-way ANOVA analysis of variance and Dunnett's post hoc test (multiple comparison test) were used. Values ​​at significant levels of p < 0.05 were considered statistically significant. [Examples]

[0093] Results of the anticonvulsant activity test The compounds of the present invention exhibited broad anticonvulsant activity by effectively acting in MES tests, 6 Hz (32 mA and / or 44 mA), and scPTZ at a dose of 100 mg / kg. At 30 minutes, they protected 50–100% of the tested animals. The most potent protection was identified in compounds containing an electron-withdrawing substituent at position 3 of the aromatic ring connected to the piperazine moiety, preferably Cl, CF3, OCF3, SCF3, CHF2, or a phenyl substituent, where k is preferably 0. Table 1 shows pharmacological screening data for the selected substances.

[0094] [Table 1]

[0095] The above tests were carried out using a racemic mixture of the compounds according to the present invention.

[0096] Table 2 presents quantitative pharmacological data for the selected compound according to general formula (II), in particular the selected active compound: 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione (6), which protected 100% of mice during the screening test, including the MES test, 6Hz (32mA and 44mA) test, and scPTZ test (at 0.5 hours).

[0097] [Table 2]

[0098] The results obtained confirmed that the compounds of the present invention, particularly compound 6, exhibit a potent protective effect and a clearly superior protective index compared to the model AED-valproic acid. Valproic acid, in particular, is known to have a broad spectrum of therapeutic applications. [Examples]

[0099] Determination of antinociceptive activity in in vivo studies in mice The study was conducted using male white Swiss mice (CD-1) weighing 18–25 g. All procedures were carried out in accordance with Polish and international guidelines on animal testing ethics after obtaining appropriate facility authorization. Each test group consisted of 8–10 animals. The test substance and reference substance were administered intraperitoneally as a suspension in a 1% aqueous solution of Tween 30 minutes prior to the given test. All tests / models are referenced in expert literature: Formalin test (Beirith, A.; Santos, AR; Calixto, JB; Rodrigues, AL; Creczynski-Pasa, TB, Eur.J.Pharmacol. 1998, pp. 345, 233-245), Capsaicin-induced pain model (Mogilski, S.; Kubacka, M.; Redzicka, A.; Kazek, G.; Dudek, M.; Malinka, W.; Filipek, B., Pharmacol.Biochem.Behav. 2015, pp. 133, 99-110), Oxaliplatin-induced neuropathic pain model - von The test was performed according to the procedure described in Frey's test (Salat, K.; Cios, A.; Wyska, E.; Salat, R.; Mogilski, S.; Filipek, B.; Wieckowski, K.; Malawska, B., Pharmacol. Biochem. Behav. 2014, pp. 122, 173-181). [Examples]

[0100] Determination of analgesic activity in formalin testing Pain was induced by subpaw injection of 20 μL of 2.5% formalin solution into the right hind limb of mice. The animals were placed in a separate clear observation chamber for 30 minutes. The measurement was the total time spent licking or biting the formalin-injected limb. Nociceptive response time was calculated at the first 5 minutes after formalin injection (Phase 1 of the study: acute pain), and at time intervals of 15–20 minutes, 20–25 minutes, and 25–30 minutes after administration (Phase 2 of the study: inflammatory pain). Observed inhibition of the nociceptive response—a reduction in the time spent licking or biting the limb—was interpreted as the analgesic effect of the compound tested. Based on the results obtained, ED 50 The dose (the dose that reduces nociceptive response time by 50%) was calculated. The reference compound for this study was valproic acid, which was administered intraperitoneally at doses of 100 mg / kg, 150 mg / kg, and 200 mg / kg. Compound 6 was administered at doses of 10 mg / kg, 20 mg / kg, and 30 mg / kg.

[0101] Compound 6 exhibited different analgesic activity in both phases of the study. The mean nociceptive response time in the control group was 90.0 ± 4.97 seconds and 212.70 ± 10.16 seconds in phases 1 and 2 of the study, respectively. Compound 6 reduced nociceptive response time in phase 1 of the formalin test, corresponding to acute pain, at all doses tested, and statistically significant effects were observed at the two maximum doses. The ED of Compound 6 in phase 1 of the study... 50 The value was 28.50 mg / kg. In the Phase II trial corresponding to persistent inflammatory pain, compound 6 statistically significantly shortened the nociceptive response time at all doses used. Phase II ED for this compound 50 The value was 12.40 mg / kg (Figure 3).

[0102] Valproic acid (VPA) did not show analgesic activity in Phase 1 of the study at any of the doses tested. In Phase 2 of the VPA study, nociceptive response time was reduced at all doses used, and ED in this phase of the study 50 The value was 132.90 mg / kg (Figure 3). [Examples]

[0103] Determining the analgesic activity of capsaicin in a pain model This study evaluated the time mice spent licking and / or biting their hind limbs after being injected subpaw with 1.6 μg of capsaicin dissolved in a 20 μl mixture containing 0.9% saline and ethanol (5% of the final volume). Observations were made for 5 minutes after capsaicin administration. The test compound was administered intraperitoneally 30 minutes prior to capsaicin administration. Inhibition of nociceptive response—a reduction in the time spent licking or biting the limb—measuring the antinociceptive activity of the tested compound.

[0104] Valproic acid (VPA) was the reference compound in this study. VPA was administered intraperitoneally at doses of 100 mg / kg, 150 mg / kg, and 200 mg / kg. Compound 6 was administered at doses of 20 mg / kg, 30 mg / kg, and 40 mg / kg. The test compounds were administered as suspensions in 1.0% Tween 80 solution. The control group consisted of mice treated with vehicle alone (1% Tween 80 solution). The nociceptive response time in this group was 43.29 ± 3.21 seconds.

[0105] Compound 6 statistically significantly reduced nociceptive response time at 20 mg / kg and 30 mg / kg, and ED 50 The value was 17.9 mg / kg (Figure 4).

[0106] The reference compound (valproic acid) statistically significantly reduced the nociceptive response time to 25.00 ± 4.57 seconds only after administration of 200 mg / kg (corresponding to 42.25% analgesic activity) (Figure 4). [Examples]

[0107] A model of oxaliplatin-induced neuropathic pain - Determination of analgesic activity using the von Frey test. Oxaliplatin (OXPT) was dissolved in a 5% glucose solution and administered intraperitoneally to mice. A single dose of 10 mg / kg was used. Tactile and thermal (cold sensation) allodynia associated with oxaliplatin-induced neuropathy is characterized in two phases. The initial phase is acute and develops immediately after OXPT administration, while symptoms in the later (chronic) phase (associated with neuronal damage) develop several days later. Behavioral studies of OXPT-induced neuropathy in mice were performed 7 days after administration, i.e., during the later phase of neuropathy.

[0108] The effect of the tested compounds on tactile allodynia was determined by the von Frey test. To allow animals to adapt to the novel environment, they were individually placed in mesh-bottom cages 60 minutes before the start of the experiment. The pain threshold to mechanical stimulation was assessed using an Electronic Von Frey apparatus (Bioseb, France). Von Frey fibers were applied to the underside of the right limb of the mouse, increasing the pressure. The mechanical pressure that induced the limb retraction and subsequent nociceptive response upon crossing the pain threshold was recorded. Measurements were performed three times for each mouse with at least 30 seconds between measurements, and the results were averaged. The entire test was performed three times: before OXPT administration to determine the baseline pain threshold; before administration of the test compound 7 days after OXPT administration to assess the onset of neuropathy by setting a novel pain threshold; and 30 minutes after administration of the compound to determine the effect on developing neuropathy.

[0109] The effect of test compounds on thermal allodynia was evaluated using a cold plate test with specialized equipment: Cold / Hot Plate, Bioseb, France. Animals were placed individually on metal plates cooled to 2°C using a thermostat-equipped device. Observed nociceptive responses in the animals included licking and / or characteristic hind limb lifting or jumping. The observation time was set to 60 seconds to eliminate the potential risk of tissue damage and minimize animal discomfort. Measurements were performed three times, similar to the Von Frey test.

[0110] Compound 6 and valproic acid as a reference AED were administered intraperitoneally as a suspension in a 1% solution of Tween 80. Compound 6 was administered at doses of 10, 20, and 30 mg / kg. The reference compound (valproic acid) was administered at doses of 50, 100, and 150 mg / kg.

[0111] Injection of OXPT in mice induced the development of neuropathy, resulting in a significant and statistically substantial reduction in pain threshold, as measured by the von Frey method. The pain threshold in OXPT-administered mice decreased from 3.18±0.06–3.36±0.10 g in healthy mice to a range of 1.89±0.04–1.94±0.14 g. The results demonstrate a statistically significant analgesic effect of compound 6 tested. The mean pain threshold in the control group was 3.36±0.10 g, while after OXPT administration it decreased to 1.89±0.04 g (56.25% of the initial value). Administration of compound 6 at a dose of 10 mg / kg increased the pain threshold to 2.87±0.12 g (85.41% of the initial value), indicating an inhibitory effect on the development of mechanical allodynia even at low doses. Compound 6 at a dose of 20 mg / kg elevated the pain threshold up to 3.83 ± 0.13 g, which is 113.98% of the initial value. A dose of 30 mg / kg resulted in an elevation of the pain threshold up to 4.17 ± 0.17 g, which is 124.10% of the initial value. The results indicate that compound 6 is highly effective in suppressing the development of mechanical allodynia, a consequence of neuronal damage caused by the chemotherapeutic agent OXPT (Figure 5A).

[0112] The mean pain threshold in the control group relative to the reference compound (valproic acid, VPA) was 2.62 ± 0.06 g, which decreased to 1.78 ± 0.04 g after administration of OXPT. Administration of VPA at a dose of 150 mg / kg resulted in a maximum increase in the pain threshold of 3.97 ± 0.30 g, while doses of 100 mg / kg and 50 mg / kg body weight allowed for increases in the mean pain threshold to 3.18 ± 0.14 g and 2.75 ± 0.06 g, respectively (Figure 5B).

[0113] Compound 6 also significantly increased susceptibility to thermal allodynia in the cold plate test (Figure 5C). [Examples]

[0114] In vitro affinity and functionality testing Affinity and functionality studies performed in vitro on the most active compound 6 representing the compound by formula (II) showed that its mechanism of action is related to its effect on nerve conductivity via interactions with voltage-gated sodium channels (site 2) and calcium channels (dihydropyridine, diltiazem, and verapamil binding sites). A unique feature of compound 6 representing the compound by formula (II) according to the present invention is the inhibition of calcium current by blocking transient receptor potential vanilloid type 1 (TRPV1). This effect has not been disclosed for known AEDs. TRPV1 receptor antagonism can determine the antinociceptive effect of the compounds disclosed herein. The role of the TRPV1 receptor in the transmission of pain stimuli is well supported in expert literature (Szallasi, A.; Cortright, DN; Blum, CA; Eid, SR, Nat. Rev. Drug. Discov. 2007, 6, pp. 357-372). The compounds according to the present invention are characterized by a complex mechanism of action, which has not been described for known anticonvulsants. However, it should be emphasized that further in vitro studies may reveal additional molecular targets involved in the pharmacological action of the substance covered by these claims. The results of binding studies (sodium channels, calcium channels) and functional studies (TRPV1 receptor) for compound 6 are shown in Table 3.

[0115] [Table 3A] [Examples]

[0116] In vitro electrophysiological testing The experiment was conducted in accordance with institutional and international guidelines on the ethics of animal research. Three-week-old rats were anesthetized with ethyl chloride and decapitated. The brains were then removed and placed in ice-cold extracellular fluid. The methodology for sectioning and pre-incubation is described previously (Szulczyk, B.; Nurowska, E., Biochem. Biophys. Res. Commun. 2017, pp. 491, 291-295). Sections containing the prefrontal cortex were dispersed enzymatically and mechanically. Single prefrontal cortical pyramidal neurons were visualized using an inverted microscope (Nikon). Sodium currents were induced by rectangular depolarization stimuli. The potential between depolarization stimuli was maintained at -65 mV.

[0117] The intracellular fluid in the pipette contained CsF (110), NaCl (7), EGTA (3), HEPES-Cl (10), MgCl2 (2), and Na2ATP (4) (pH 7.4 and osmotic pressure 290 mOsm) (in mM).

[0118] The extracellular fluid used to wash the neurons contained NaCl (30), choline chloride (90), TEA-Cl (30), CaCl2 (2), MgCl2 (2), glucose (15), HEPES (10), LaCl3 (0.001), and CdCl2 (0.4) (pH 7.4) (in mM). Currents were recorded using an Axopatch 1D amplifier and analyzed using pClamp software (Axon Instruments and Molecular Devices, USA). Pipette tolerance was between 4 and 5 MΩ. After gigaseal formation, pipette capacitance was compensated by the amplifier.

[0119] After the patch membrane was destroyed by suction or electrical stimulation, the membrane capacitance was compensated. The access resistance was between 5 - 7 MΩ. 80% serial resistance compensation was used. The leakage current was subtracted from the recorded current. The recording was performed at room temperature. The voltage-dependent potassium current was blocked by TEA-Cl in the extracellular solution. The voltage-dependent calcium current was blocked by cadmium and lanthanum ions in the extracellular solution. The membrane potential of the neuron was maintained at -65 mV. Substance 6 was administered from the outside (to the whole bath).

[0120] The obtained results confirmed the inhibitory effect of compound 6 by rapidly activating and then rapidly inactivating voltage-dependent sodium channels in prefrontal cortical pyramidal neurons (the test was performed at a concentration of 100 μM). The maximum current was induced by a rectangular depolarizing stimulus lasting 20 milliseconds. The potential between depolarizing stimuli was maintained at -65 mV. Control recordings were performed for 2 minutes, the test substance was administered for 3 minutes, and the current after washout was recorded for 5 minutes. The recorded current was normalized to the value of the control current. Substance 6 blocked the maximum amplitude of the sodium current by up to 0.59 ± 0.08 compared to the control (1.0, p < 0.001). After washout, the current amplitude partially recovered to the control value (0.79 ± 0.07, n = 5). An example of the recording and averaged results of the sodium current is shown in Figure 6.

Example

[0121] Evaluation of ADMETox parameters in in vitro tests The ADME-Tox parameters of compound 6 were evaluated by in vitro methods using recombinant enzymes, human and mouse liver microsomes, and eukaryotic cell lines.

[0122] Metabolic stability. The metabolic stability of compound 6 was evaluated using human liver microsomes (HLM). The intrinsic clearance value CL intThis was calculated by monitoring the change in compound concentration per unit of time in the presence of microsomes, following the procedure proposed by Obach RS (Obach, RS, Drug Metab. Dispos. 1999, 27, pp. 1350-1359). Based on the obtained data, a very low clearance value for compound 6 after incubation with HLM was found, and CL int The metabolic rate reached 5.8 ml / min / kg, demonstrating the high stability predicted in the human body. UPLC analysis of compound 6's metabolism after incubation with HML revealed that it is metabolized into three metabolites M1-M3 (Figure 7). Based on UPLC / MS data, it was found that metabolite M1 is formed by dehydrogenation of the piperazine ring, M2 is formed by hydroxylation of the phenyl substituent linked to piperazine, while M3 is formed with high certainty as a result of the reduction of the ketone group in the imide fragment to a hydroxyl group, simultaneously with the hydroxylation of the lateral phenyl group (Figure 7).

[0123] Metabolic Stability Test - Methodology. Metabolic stability testing for compound 6 was performed using HLM (Promega, Madison, WI, USA). For this purpose, 10 μL of compound 6 at a concentration of 1000 μM was diluted in 132 μL of Tris-HCl buffer (100 mM, pH 7.4), and then 8 μL of appropriate microsomes were added. The reaction mixture was pre-incubated at 37°C for 5 minutes, after which 50 μL of NADPH Regeneration System supplied by Promega (Madison, WI, USA) was added. After mixing, the entire mixture was incubated at 37°C for 120 minutes. To complete the reaction, 200 μL of cold methanol was added to the tube and the mixture was centrifuged. The supernatant was subjected to ULC / MS analysis, including fragmentation analysis. Four mixtures of 6 and HLM were prepared and the internal clearance CL was determined. intThe reaction was determined. Each of these reactants was completed at different time points of 5, 15, 30, and 45 minutes by adding cold methanol containing a 50 μM internal standard. Then, following the guidelines of the literature (Obach, RS, Drug Metab. Dispos. 1999, 27, pp. 1350-1359), the regression equation was determined based on a plot of the relationship between the peak height from 6 and the height of the internal standard, and the reaction rate constant k was calculated. Then, the constant k was substituted into equation (1).

[0124]

number

[0125] Next, the calculated t 1 / 2 The values ​​were substituted into equation (2).

[0126]

number

[0127] Effects on Pgp activity. P-glycoprotein (Pgp) is an endogenous plasma membrane protein that acts as an ATP-dependent burst pump, actively removing xenobiotics and inducing drug-drug interactions. Pgp plays a crucial role in drug absorption in the gastrointestinal tract and across the blood-brain barrier. The effect of compound 6 on Pgp activity was tested using a commercially available bioluminescent Pgp-Glo® assay system (Promega, Madison, WI, USA). The test procedure was based on measuring the change in ATP levels consumed by a membrane containing recombinant Pgp protein in the presence of the test compound. Results are presented as a percentage of baseline activity and compared to reference compounds: selective Pgp inhibitor Na3VO4 and verapamil stimulant. Compound 6 showed a statistically significant (p<0.01) inhibitory effect on Pgp up to 38% of baseline activity at 100 μM, while no effect on Pgp activity was observed at 50 μM (Figure 8).

[0128] Effects on Pgp Activity - Methodology. The test was performed according to the protocol of the bioluminescent Pgp-Glo® assay system provided by Promega (Madison, WI, USA). The enzymatic reaction was performed on Nunc® MicroWell® 96-well white plates from Thermo Scientific (Waltham, MA, USA). Bioluminescence was measured using a PerkinElmer multispecific EnSpire plate reader (Waltham, MA, USA). After using the Na3VO4 Pgp inhibitor (which induced 100% inhibition), the signal increased relative to the control sample, indicating inhibition of ATP consumption by Pgp, or so-called base activity. The calculated difference in luminescence values ​​between the inhibitor-treated sample and the control sample was obtained as 100% Pgp base activity and was treated as a negative control in the test. The reference compounds Na3VO4 and verapamil were used at 100 μM and 200 μM, respectively, according to the manufacturer's instructions. Compound 6 was tested at concentrations of 50 and 100 μM, obtained after dilution of the concentrated stock solution (10 mM) in DMSO in the reaction buffer. The compound was incubated with a Pgp-containing membrane at 37°C for 40 minutes, and then bioluminescence was measured to determine the degree of ATP consumption by Pgp. Statistical significance was calculated using one-way ANOVA analysis of variance and the Bonferroni method with GraphPad Prism5. The compound was triple-tested.

[0129] Effect of compound 6 on cytochrome P-450 3A4 and 2D6 activity. Investigation of the literature (Socala, K.; Mogilski, S.; Pierog, M.; Nieoczym, D.; Abram, M.; Szulczyk, B.; Lubelska, A.; Latacz, G.; Doboszewska, U.; Wlaz, P.; Kaminski, K., ACS). The tests were conducted using commercially available luminescence testers, CYP3A4 P450-Glo® and CYP2D6 P450-Glo®, manufactured by Promega (Madison, WI, USA), based on the methodology described in Chem.Neurosci. 2018 (doi:10.1021 / acschemneuro.8b00476;Latacz,G.;Lubelska,A.;Jastrzebska-Wiesek,M.;Partyka,A.;Sobalo,A.;Olejarz,A.;Kucwaj-Brysz,K.;Satala,G.;Bojarski,AJ;Wesolowska,A.;Kiec-Kononowicz,K.;Handzlik,J., Chem.Biol.Drug.Des. 2017, 90, pp. 1295-1306). The CYP isoforms selected for testing are involved in the metabolism of approximately 40–50% of commercially available drugs, and their stimulation or inhibition determines most metabolic drug interactions. The results obtained show that compound 6 has no effect on CYP3A4 activity at a concentration of 10 μM (Figure 9A) and a very weak stimulating effect on CYP2D6 (Figure 9B). In summary, the results obtained indicate a low probability of potential metabolic interactions induced by compound 6.

[0130] In vitro hepatotoxicity evaluation. The tests were conducted using the Hepatocellular Carcinoma (HpG2) liver cancer cell line, which was used to evaluate the hepatotoxicity of the substances in vitro. The effects of compound 6 on HepG2 cell viability and proliferation were investigated using a classic MTS colorimetric assay from Promega (Madison, WI, USA). The compounds were tested at four concentrations within the range (0.1–100 μM). Doxorubicin was used as a reference cell proliferation inhibitor at a concentration of 1 μM. In addition, the mitochondrial toxin carbonyl cyanide m-chlorophenylhydrazone (CCCP) was also used as a reference at a concentration of 10 μM (Figure 10). Hepatotoxicity tests after 72 hours of incubation of HepG2 cells with compound 6 showed a statistically significant reduction (p<0.05) in cell viability only at the maximum concentration used in the tests, 100 μM (Figure 10). In addition, cell viability decreased to just 84% of that of the control, indicating a slight toxic effect of this compound on the HepG2 cell line. Additional tests were performed on the HepG2 cell line in the form of luminescence measurements of ATP levels in cells, after short 3-hour exposure to compound 6 at concentrations ranging from 1 to 100 μM, particularly due to the potential toxic effects of the xenobiotic. For this purpose, a commercial CellTiter-Glo Luminescent Cell Viability Assay from Promega (Madison, WI, USA) was used. The objective of the tests was to investigate the effect of the compound on mitochondrial respiration in hepatocellular carcinoma cells. The baseline was CCCP reference mitochondrial toxin at a concentration of 10 μM. Even at the maximum concentration of 100 μM used, compound 6 did not have a statistically significant effect on ATP levels in HepG2 cells. This indicates a very low risk of hepatotoxicity from compound 6 (Figure 11).

[0131] In vitro evaluation of hepatotoxicity - Methodology. The HepG2 hepatocellular carcinoma cell line (ATCC HB-8065) ​​was used in the study. The HepG2 cell line was incubated in Gibco (Carlsbad, CA, USA) Modified Eagle's Medium (MEM) culture medium supplemented with 2 mM glutamine and 10% FBS. Cells were incubated at 37°C in air containing 5% CO2. Cell viability was tested using CellTiter96® AQueous Non-Radioactive Cell Proliferation Assay (MTS) supplied by Promega (Madison, WI, USA). Prior to the study, cells were denatured at 1.5 × 10⁶ cells per well. 4 Cells were placed at individual cell concentrations in Thermo Scientific Nunc™ 96-well transparent culture plates (Waltham, MA, USA) and incubated for 24 hours. Then, a 10 mM stock solution of compound 6 was diluted in appropriate culture medium and added to the cells at a final concentration ranging from 0.1 to 100 μM (total well DMSO concentration was 1%). Reference compounds CCCP and DX were applied at final concentrations of 10 μM and 1 μM, respectively. After incubation for 72 hours at 37°C in air containing 5% CO2, the medium containing the compounds was removed, and fresh medium containing diluted MTS reagent was added. After further incubation of the plates for 2–3 hours, absorbance was measured at 490 nm using an EnSpire PerkinElmer (Waltham, MA, USA) reader. Statistical significance was calculated using one-way ANOVA and the Bonferroni method. The compounds were quadrupled.

[0132] ATP levels in HepG2 cells were tested using the CellTiter-Glo Luminescent Cell Viability Assay from Promega (Madison, WI, USA). Prior to testing, cells were seeded in white 96-well clear-bottom culture plates from Corning (Tewksbury, MA, USA), with 1.5 × 10⁶ cells per well. 4Cell concentrations were adjusted for luminescence measurement. The cells were then incubated at 37°C in air containing 5% CO2. Compound 6 was applied to plates in three final concentrations of 1, 10, and 100 μM, CCCP at 10 μM, and DX at 1 μM, in 100 μL volumes. The plates were incubated at 37°C for 3 hours in 5% CO2. After adding 100 μL of CellTiter-Glo Luminescent Cell Viability Assay to the culture, luminescence measurements were performed using an EnSpire PerkinElmer (Waltham, MA, USA) reader. Statistical significance was calculated using one-way ANOVA and Bonferroni analysis with GraphPad Prism5. All substances were quadrupled. [Examples]

[0133] Preparation of selected enantiomers of compounds according to the present invention The enantiomers of the compound according to formula (II) of the present invention can be obtained by applying a four-step procedure using commercially available tert-butoxycarbonyl (Boc) D- or L-amino acid derivatives (each in an R or S absolute configuration) as starting materials. The enantiomers are obtained for the selected compound described in formula (II), where k=0 and A and B have the same meanings as in the case of the racemic mixture of formula (II).

[0134] Figure 12 shows a general scheme for the synthesis of enantiomers of a compound using formula (II).

[0135] In the first step, a condensation reaction of a given piperazine derivative with the corresponding Boc-D- or Boc-L-amino acid derivative yields the intermediate product of formula (VII), followed by a deprotection reaction to form the amine derivative (VI). In the next step, compound (VI) is condensed with succinic anhydride to obtain an intermediate having an amide-acid structure (V), which is then cyclized to form compound R-(II) or S-(II). The asymmetric synthesis proceeds while maintaining the absolute configuration confirmed by crystallography.

[0136] Synthesis of the selected intermediates (VII, VI, and V according to FIG. 12), as well as examples of physicochemical and spectral data, are described below.

Example

[0137] tert-Butyl-(R)-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)carbamate (VII) Boc-D-phenylglycine (1.25 g, 5 mmol, 1 equivalent) was dissolved in 20 mL of DCM, and then DCC (1.55 g, 7.5 mmol, 1.5 equivalents) was added. Next, after 30 minutes, 1-(3-(trifluoromethyl)phenyl)piperazine (1.15 g, 5 mmol, 1 equivalent) dissolved in 5 mL of DCM was added. The reaction mixture was continuously stirred at room temperature for 4 hours. After this time, DCM was distilled off to dryness. Intermediate VII was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0138] Light oil. Yield: 78% (1.81 g); TLC: R f = 0.62 (DCM:MeOH (9:0.5; v / v)); C 24 H 28 F3N3O3 (463.50), monoisotopic mass: 463.21. UPLC (100% purity): t [[ID=二十一]] R [[ID=二十二]]= 8 minutes [[ID=二十三]] + [[ID=二十四]]464.2. [[ID=二十五]] [[ID=二十六]]

Example

[0139] [[ID=三十]] [[ID=三十一]](R)-2-Amino-2-phenyl-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethan-1-one (VI) [[ID=三十二]] 5 mL of TFA was added to tert-butyl-(R)-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl) carbamate solution (VII, 1.39 g, 3 mmol, 1 equivalent) in DCM (50 mL) and stirred for 2 hours. The reaction mixture was then neutralized with 25% NH4OH solution and extracted with DCM (3 × 50 mL). The organic layer was dehydrated with anhydrous Na2SO4 and evaporated to dryness. (R)-2-amino-2-phenyl-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethane-1-one was obtained as a yellow oil.

[0140] Yellow oil. Yield: 95% (1.03g);C 19 H 20 F3N3O (363.38), monoisotopic mass: 363.16. UPLC (purity > 99.9%): t R = 4.96 minutes. (M+H) + 364.1. [Examples]

[0141] (R)-4-oxo-4-((2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)amino)butanoic acid (V) Succinic anhydride (0.28 g, 2.8 mmol, 1 equivalent) was added to a solution of (R)-2-amino-2-phenyl-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethane-1-one (VI, 1.02 g, 2.8 mmol, 1 equivalent) in AcOEt (50 mL), and the mixture was stirred for 30 minutes. After this time, the solvent was removed by distillation to dryness. The compound was washed with Et2O and obtained in solid form.

[0142] White solid. Yield: 87% (1.13g); C 23 H 24 F3N3O4 (463.46), monoisotopic mass: 463.17. UPLC (purity > 99.9%): t R = 6.40 minutes. (M+H) + 464.2. [Examples]

[0143] (R)-1-(2-(4-(3-chlorophenyl)piperazin-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione((R)-3) ZnCl2 (0.27 g, 2.0 mmol, 1 equivalent) was added to a suspension of (R)-4-((2-(4-(3-chlorophenyl)piperazin-1-yl)-2-oxo-1-phenylethyl)amino)-4-oxobutanoic acid (V, 0.86 g, 2.0 mmol, 1 equivalent) in dry benzene (50 mL). The entire mixture was heated to 80°C, and then HMDS solution (0.48 g, 0.62 ml, 3.0 mmol, 1.5 equivalents) in dry benzene (5 mL) was added dropwise over 30 minutes. The reaction mixture was stirred under reflux for approximately 24 hours, and then concentrated under reduced pressure. After removing the solvent, the oily residue was dissolved in DCM and extracted with 0.1 M HCl (3 × 50 mL), water (3 × 50 mL), and saturated NaCl solution (3 × 50 mL). The organic layer was dehydrated with anhydrous Na2SO4 and then evaporated to dryness. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3;v / v) elution system. The compound was washed with Et2O and obtained as a solid.

[0144] White solid. Yield: 82%(0.67g);mp167.3~168.1℃;TLC:Rf=0.41(DCM:MeOH(9:0.3;v / v));C 22 H 22 ClN3O3 (411.89), monoisotopic mass: 411.13. UPLC (purity > 99.9%): t R = 6.70 minutes, (M+H) + 412.4. 1H NMR (500 MHz, CDCl3) δ 2.64-2.75 (m, 5H), 2.96-3.12 (m, 2H), 3.21-3.37 (m, 3H), 3.60-3.72 (m, 1H), 3.92-4.03 (m, 1H), 6.10 (s, 1H), 6.68 (dd, J = 8.0, 2.3 Hz, 1H), 6.77 (t, J = 2.0 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 7.32-7.37 (m, 3H), 7.42 (d, J = 6.8 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 28.1, 42.3, 45.6, 48.5, 48.8, 56.9, 114.5, 116.4, 120.3, 128.8, 129.0, 129.9, 130.2, 133.0, 135.1, 151.8, 165.1, 176.4.Enantiomeric purity >99%(t R (40.25 minutes). [Examples]

[0145] (R)-1-(2-(4-(3,5-dichlorophenyl)piperazin-1-yl)-2-oxo-1-phenylethyl)pyrrolidine-2,5-dione((R)-4) The compound was prepared according to the procedure described in Example 44. (R)-4-((2-(4-(3,5-dichlorophenyl)piperazin-1-yl)-2-oxo-1-phenylethyl)amino)-4-oxobutanoic acid (0.93 g, 2 mmol, 1 equivalent) was used as the starting material for the cyclization reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.2; v / v) elution system.

[0146] White solid. Yield: 79% (0.70g); mp174.3~175.5℃; TLC: R f =0.43(DCM:MeOH(9:0.2;v / v));C 22 H 21Cl2N3O3 (446.33), monoisotopic mass: 445.10. UPLC (purity >99.9%): t R = 7.59 minutes, (M+H) + 446.1. 1 H NMR (500 MHz, CDCl3) δ 2.64-2.74 (m, 5H,), 2.99-3.03 (m, 1H), 3.06-3.11 (m, 1H), 3.23-3.31 (m, 2H), 3.43-3.47 (m, 1H), 3.60-3.64 (m, 1H), 3.95-3.99 (m, 1H), 6.08 (s, 1H), 6.63 (d, J = 1.7 Hz, 2H), 6.79 (t, J = 1.4 Hz, 1H), 7.32-7.37 (m, 3H), 7.41 (d, J = 6.7 Hz, 2H). 13 C NMR (126 MHz, CDCl3) δ 28.1, 42.1, 45.4, 47.9, 48.2, 56.8, 114.3, 119.8, 128.8, 129.1, 129.9, 132.9, 135.6, 152.1, 165.2, 176.4.Enantiomeric purity >99%(t R (43.23 minutes). [Examples]

[0147] (R)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione((R)-6) The compound was prepared according to the procedure described in Example 44. (R)-4-oxo-4-((2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)amino)-butanoic acid (0.93 g, 2.0 mmol, 1 equivalent) was used as the starting material for the cyclization reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0148] White solid. Yield: 80% (0.71g); mp189.1~190.5℃; TLC: Rf =0.35(DCM:MeOH(9:0.5;v / v));C 23 H 22 F3N3O3 (445.44), monoisotopic mass: 445.16. UPLC (purity > 99.9%): t R = 6.93 minutes, (M+H) + 446.2. 1 H NMR (300 MHz, CDCl3) δ 2.52-2.85 (m, 5H), 2.99-3.19 (m, 2H), 3.22-3.45 (m, 3H), 3, 62-3.76 (m, 1H), 3.93-4.07 (m, 1H), 6.12 (s, 1H), 6.90-7.15 (m, 3H), 7.11 (d, 1H, J = 7.7 Hz), 7.28-7.55 (m, 6H); 13 C NMR (75 MHz, CDCl3) δ 28.0, 42.3, 45.5, 48.4, 48.6, 56.8, 112.7 (d, J = 3.4 Hz), 116.7 (d, J = 3.4 Hz), 119.2, 124.1 (q, J = 272.9 Hz), 128.7, 128.9, 129.7, 129.8, 130.9, 131.5 (q, J = 32.2 Hz), 132.8, 150.8, 165.1, 176.4.Enantiomeric purity >99%(t R (39.97 minutes). [Examples]

[0149] (S)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione((S)-6) The compound was prepared according to the procedure described in Example 44. (S)-4-oxo-4-((2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)amino)-butanoic acid (0.93 g, 2.0 mmol, 1 equivalent) was used as the substrate for the cyclization reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0150] White solid. Yield: 78% (0.69g); mp188.9~190.5℃; TLC: R f =0.36(DCM:MeOH(9:0.5;v / v));C 23 H 22 F3N3O3 (445.44), monoisotopic mass: 445.16. UPLC (purity > 99.9%): t R = 6.94 minutes, (M+H) + 446.2. 1 H NMR (300 MHz, CDCl3) δ 2.56-2.83 (m, 5H), 3.00-3.20 (m, 2H), 3.23-3.43 (m, 3H), 3.62-3.76 (m, 1H), 3.94-4.08 (m, 1H), 6.12 (s, 1H), 6.89-6.99 (m, 2H), 7.10 (d, 1H, J = 7.7 Hz), 7.28-7.53 (m, 6H); 13 C NMR (75 MHz, CDCl3) δ 28.0, 42.2, 45.5, 48.4, 48.6, 56.8, 112.7 (d, J = 4.6 Hz), 116.7 (d, J = 4.6 Hz), 124.1 (q, J = 272.9 Hz), 128.7, 129.0, 129.7, 129.8, 131.6 (q, J = 32.2 Hz), 132.8, 150.8, 165.1, 176.3.Enantiomeric purity >99%(t R (=26.21 minutes). [Examples]

[0151] (R)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethoxy)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione((R)-10) The compound was prepared according to the procedure described in Example 44. (R)-4-oxo-4-((2-oxo-1-phenyl-2-(4-(3-(trifluoromethoxy)phenyl)piperazine-1-yl)ethyl)amino)butanoic acid (0.96 g, 2.0 mmol, 1 equivalent) was used as the starting material for the cyclization reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0152] White solid. Yield: 77% (0.70g); mp168.2~169.1℃; TLC: R f =0.46(DCM:MeOH(9:0.5;v / v));C 23 H 22 F3N3O4 (461.44), monoisotopic mass: 461.16. UPLC (purity > 99.9%): t R = 7.18 minutes, (M+H) + 462.1. 1 H NMR (500 MHz, CDCl3) δ 2.60-2.78 (m, 5H), 2.98-3.16 (m, 2H), 3.23-3.38 (m, 3H), 3.63-3.72 (m, 1H), 3.98 (ddd, J = 12.89, 6.01, 2.86 Hz, 1H), 6.11 (s, 1H), 6.61 (s, 1H), 6.69-6.73 (m, 2H), 7.21 (t, J = 8.0 Hz, 1H), 7.32-7.38 (m, 3H), 7.42-7.44 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 28.1, 42.3, 45.6, 48.4, 48.6, 56.9, 108.9, 112.2, 114.3, 120.5 (q, J = 256.7 Hz), 129.4 (d, J = 143.7 Hz), 129.6 (d, J = 151.5 Hz), 132.9, 150.3, 152.0, 165.2, 176.4.Enantiomeric purity >99%(t R (35.08 minutes). [Examples]

[0153] (R)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl(sulfanyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione((R)-12) The compound was prepared according to the procedure described in Example 44. (R)-4-oxo-4-((2-oxo-1-phenyl-2-(4-(3-((trifluoromethyl)thio)phenyl)piperazine-1-yl)ethyl)amino)butanoic acid (0.99 g, 2.0 mmol, 1 equivalent) was used as the starting material for the cyclization reaction. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system.

[0154] White solid. Yield: 86% (0.82g); mp155.1~155.8℃; TLC: R f =0.48(DCM:MeOH(9:0.5;v / v));C 23 H 22 F3N3O3S (477.50), monoisotopic mass: 477.13. UPLC (purity > 99.9%): t R = 7.54 minutes, (M+H) + 478.1. 1 H NMR (500 MHz, CDCl3) δ 2.68-2.75 (m, 5H), 2.96-3.19 (m, 2H), 3.22-3.43 (m, 3H), 3.62-3.76 (m, 1H), 3.99 (ddd, J = 13.17, 5.73, 2.8 Hz, 1H), 6.11 (s, 1H), 6.91 (dd, J = 8.3, 2.6 Hz, 1H), 7.06 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.24-7.28 (m, 1H), 7.33-7.38 (m, 3H), 7.42-7.44 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 28.1, 42.3, 45.6, 48.4, 48.7, 56.9, 123.7, 125.3, 129.6 (q, J = 307, 8 Hz), 127.8, 129.4 (d, J = 142.4 Hz), 129.1, 130.1, 132.9, 151.4, 165.2, 176.4.Enantiomeric purity >99%(t R (34.82 minutes). [Examples]

[0155] The special properties of enantiomers. The effect of the stereochemistry of the compounds according to the present invention on these anticonvulsant activities was investigated. The anticonvulsant properties were evaluated according to the method described above, and the results are summarized in Tables 3 and 4.

[0156] [Table 3B]

[0157] [Table 4]

[0158] Based on the results obtained, it was unexpectedly discovered that the R enantiomer exhibited higher biological activity with the desired profile compared to the S enantiomer.

[0159] In particular, the following was found in the case of the R enantiomer: - Regarding racemic mixtures, weaker acute neurotoxicity in rotorod studies (see TD in Tables 2 and 4, respectively) 50 (See reference) - The anticonvulsant effect was unexpectedly found to be stereospecific. Enantiomers with the R configuration are characterized by stronger biological activity.

[0160] Metabolic stability. The metabolic stability of (R)-6 was evaluated according to the methodology described above. Based on the obtained data, a very low internal clearance value was found for compound (R)-6 after incubation with HLM, and CL int The clearance reached 2.4 mL / min / kg, demonstrating the high stability predicted in the human body. Furthermore, surprisingly, the determined clearance value was lower than that determined for the racemic mixture and compound 6 (CL). int =5.6), which indicates that the enantiomers are less sensitive to metabolic changes. In addition, UPLC analysis revealed that the (R)-6 enantiomer is preferably metabolized to two metabolites: the M1 metabolite formed by dehydrogenation of the piperazine ring, and the M2 metabolite formed by hydroxylation of the phenyl substituent linked to piperazine (Figure 13). In the case of the racemic mixture, a further M3 metabolite was observed, most likely obtained by hydroxylation of the lateral phenyl moiety and reduction of the keto group in the imide ring to hydroxyl (Figure 7). [Examples]

[0161] Preparation of water-soluble salts of compounds according to the present invention. The water-soluble salts of the compounds according to formula (I) of the present invention can be obtained by applying a six-step procedure using a commercially available tert-butoxycarbonyl (Boc) amino acid derivative as a starting material. The water-soluble salts are obtained for a selected compound described by formula (I), where k=0, D is a substituent selected from the group consisting of H, an amino group (-NH2), an amino group substituted with one or two aliphatic substituents (particularly -CH3 and / or -C2H5), or an amino group that is part of a heterocycle, and A and B have the same meanings as in the case of the compound described by formula (II).

[0162] A general scheme for the synthesis of a water-soluble salt of the compound represented by formula (I) according to the present invention is shown in Figure 14. For the preparation of the compound of formula (I) in which D is a halogen, the procedure described for the compound of formula (II) in Figure 2B is used, and the resulting compound is then converted to a water-soluble salt (preferably a hydrochloride salt) using a method described in the literature.

[0163] Steps i and ii are similar to the procedures described for the synthesis of enantiomers. The amine derivative (VI) is condensed with maleic anhydride to obtain a compound having an unsaturated amide-acid structure (VIII). Compound VIII is then cyclized to compound IX. In the next step, the compound of formula IX is subjected to an addition reaction with a suitable primary or secondary amine. The desired compound according to formula (I) is then converted to a water-soluble salt (preferably a hydrochloride salt) using a method described in the literature.

[0164] The synthesis of the selected intermediates (VIII, IX) and the final product shown in Figure 14, along with examples of physicochemical and spectral data, are described below. [Examples]

[0165] 4-Oxo-4-((2-Oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)amino)buta-2-enoic acid (VIII) Maleic anhydride (0.98 g, 10.0 mmol, 1 equivalent) was added to a solution of 2-amino-2-phenyl-1-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethane-1-one (4.61 g, 10.0 mmol, 1 equivalent) in AcOEt (50 mL), and the mixture was stirred for 30 minutes. After this time, the solvent was removed by distillation to dryness. The compound was washed with Et2O and obtained as a solid.

[0166] White solid. Yield: 85% (3.76g); C 23 H 22 F3N3O4 (461.44), monoisotopic mass: 461.16. UPLC (purity = 96%): t R= 6.94 minutes. (M+H) + 462.2. [Examples]

[0167] 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)-1H-pyrrole-2,5-dione(IX) ZnCl2 (1.36 g, 10.0 mmol, 1 equivalent) was added to a suspension of 4-oxo-4-((2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)amino)buta-2-enoic acid (4.40 g, 10.0 mmol, 1 equivalent) in dry benzene (100 mL), and the mixture was heated to 80°C. Then, a solution of HMDS (2.42 g, 3.14 mL, 15.0 mmol, 1.5 equivalents) in dry benzene (10 mL) was added dropwise over 30 minutes. The reaction mixture was stirred under reflux for approximately 24 hours, then cooled and concentrated under reduced pressure. After removing the solvent, the oily residue was dissolved in DCM and extracted with 0.1 M HCl (3 × 50 mL), water (3 × 50 mL), and saturated NaCl solution (3 × 50 mL). The organic layer was dehydrated with anhydrous Na₂SO₄ and then evaporated to dryness. The crude product was purified by column chromatography using a DCM:MeOH (9:0.3; v / v) mixture as the eluent. The compound was washed with Et₂O and obtained as a solid.

[0168] White solid. Yield: 79% (3.34g); C 23 H 22 F3N3O4 (443.43), monoisotopic mass: 443.15. UPLC (purity = 99%): t R = 7.45 minutes. (M+H) + 444.1. [Examples]

[0169] 3-(methylamino)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione hydrochloride A 2M methylamine solution in THF (0.07 g, 2.2 mmol, 1 equivalent) was added to a solution of 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)-1H-pyrrole-2,5-dione (0.98 g, 2.2 mmol, 1 equivalent) in dry benzene (50 mL). The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system. The compound was then converted to its hydrochloride salt by treatment with a 2M methanolic hydrochloric acid solution.

[0170] White solid. Yield: 87% (0.91g); mp161.2~163.4℃; C 24 H 25 F3N4O3 (474.48), monoisotopic mass: 474.19. UPLC (purity > 99.9%): t R = 5.53 minutes, (M+H) + 475.3. 1 H NMR (500 MHz, CDCl3) δ 2.76 (br s, 3H), 2.90 (br s, 1H), 3.22 (br s, 2H), 3.38-3.54 (m, 4H), 3.55-3.66 (m, 1H), 3.70 (br s, 1H), 3.84-4.23 (m, 2H), 4.53 (br s, 1H), 6.20 (br s, 1H), 7.18-7.24 (m, 3H), 7.29-7.51 (m, 5H), 7.71 (br s, 1H), 9.98 (br s, 1H). [Examples]

[0171] 3-(dimethylamino)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)-piperazine-1-yl)ethyl)pyrrolidine-2,5-dione hydrochloride The compound was prepared according to the procedure described in Example 54. 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)-1H-pyrrolo-2,5-dione (0.98 g, 2.2 mmol, 1 equivalent) and dimethylamine (0.10 g, 2.2 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system. The compound was converted to its hydrochloride salt by treatment with a 2 M methanolic hydrochloric acid solution.

[0172] White solid. Yield: 83% (0.90g); mp157.8~159.2℃; C 25 H 27 F3N4O3 (488.51), monoisotopic mass: 488.20. UPLC (purity > 99.9%): t R = 5.53 minutes, (M+H) + 489.3. 1 H NMR (500 MHz, CDCl3) δ 2.76 (d, J = 8.6 Hz, 1H), 2.93 (br s, 2H), 3.06-3.18 (m, 5H), 3.25-3.33 (m, 3H), 3.36-3.41 (m, 2H), 3.41-3.45 (m, 2H), 3.71 (br s, 1H), 3.94-3.98 (m, 1H), 6.14 (s, 1H), 7.01 (d, J = 7.4 Hz, 1H), 7.04 (br s, 1H), 7.12 (d, J = 7.4 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.39 (s, 5H), 13.02 (br s, 1H). 13C NMR (126 MHz, CDCl3) δ 31.4, 42.5 45.7, 48.7, 48.9, 57.7, 60.1, 65.9, 113.1, 117.5, 119, 3, 119.9, 119.7, 124.1 (d, J = 272.2 Hz) 129.1, 129.8, 129.9, 131.1, 131.7 (d, J = 32.0 Hz) 150.5, 164.4, 169.8, 171.7. [Examples]

[0173] 3-(diethylamino)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione hydrochloride The compound was prepared according to the procedure described in Example 54. 1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)-1H-pyrrolo-2,5-dione (0.98 g, 2.2 mmol, 1 equivalent) and diethylamine (0.16 g, 2.2 mmol, 1 equivalent) were used as starting materials. The crude product was purified by column chromatography using a DCM:MeOH (9:0.5; v / v) elution system. The compound was converted to its hydrochloride salt by treatment with a 2 M methanolic hydrochloric acid solution.

[0174] White solid. Yield: 88% (1.00g); mp142.2~143.1℃; TLC: R f =0.52(DCM:MeOH(9:0.5;v / v));C 27 H 31 F3N4O3 (516.57), monoisotopic mass: 516.23. UPLC (purity >99.9%): t R = 5.79 minutes, (M+H) + 517.2. 1H NMR (500 MHz, DMSO-d6) δ 1.17-1.27 (m, 6H), 2.79-2.89 (m, 1H), 3.05-3.36 (m, 9H), 3.54-3.78 (m, 3H), 4.79 (dd, J = 9.2, 5.7 Hz, 1H), 4.92 (dd, J = 9.2, 5.7 Hz, 1H), 6.20 (s, 1H), 7.04 (d, J = 7.4 Hz, 1H), 7.10 (s, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.31-7.37 (m, 5H), 12.88 (br s, 1H). [Examples]

[0175] Special properties of the water-soluble salt of the compound according to the present invention. The effect of improved water solubility (i.e., salts) of the compounds according to the present invention on these anticonvulsant activities was investigated. The anticonvulsant properties were evaluated according to the method described above, and the results are summarized in Tables 3 and 4.

[0176] [Table 5]

[0177] [Table 6]

[0178] Based on the results obtained, it was found that salts of the compounds according to the present invention clearly exhibit improved water solubility. This has a positive effect on their pharmacokinetics and / or pharmaceutically properties and is particularly advantageous in the case of intravenous administration of the compounds according to the present invention.

Claims

1. General formula (I) 【Chemistry 1】 (In the formula, X is either N or C, k is a number equal to 0 or 1. A is, - Phenyl group; - Halogen atom, -SCF ３ , -CF ３ ,-CHF ２ -CN, -OCF ３ , -NO ２ , -OCH ３ , -OC ２ H ５ , a phenyl group substituted with one, two, three, or four lateral groups selected from the group consisting of linear or branched alkyl groups having 1 to 4 carbon atoms in the carbon main chain; - A phenyl group substituted with at least one aromatic or heteroaromatic group; - 1-naphthyl or 2-naphthyl group; - A benzothiophenyl group selected from the group consisting of 2-benzothiophenyl, 3-benzothiophenyl, 4-benzothiophenyl, or 5-benzothiophenyl groups; - A benzoisoxazole group selected from the group consisting of 3-benzoisoxazole, 4-benzoisoxazole, 5-benzoisoxazole, 6-benzoisoxazole, and 7-benzoisoxazole groups; B is, - Phenyl group; - a halogen atom, -SCF ３ , -CF ３ , -CHF ２ , -CN, -OCF ３ , -NO ２ , -OCH ３ , -OC ２ H ５ a phenyl group substituted with one or two lateral groups selected from the group consisting of a linear or branched alkyl group having 1 to 4 carbon atoms in the carbon main chain And; D is H, amino(-NH) ２ ), and a group selected from the group consisting of an amino group substituted with one or two aliphatic groups. Compounds having [a certain property], or pharmaceutically acceptable salts thereof.

2. General formula (II) 【Chemistry 2】 (In the formula, X is either N or C, k is a number equal to 0 or 1. A is, - Phenyl group; - Halogen atom, -SCF ３ , -CF ３ ,-CHF ２ -CN, -OCF ３ , -NO ２ , -OCH ３ , -OC ２ H ５ , a phenyl group substituted with one, two, three, or four lateral groups selected from the group consisting of linear or branched alkyl groups having 1 to 4 carbon atoms in the carbon main chain; - A phenyl group substituted with at least one aromatic or heteroaromatic group; - 1-naphthyl or 2-naphthyl group; - A benzothiophenyl group selected from the group consisting of 2-benzothiophenyl, 3-benzothiophenyl, 4-benzothiophenyl, or 5-benzothiophenyl groups; - A benzoisoxazole group selected from the group consisting of 3-benzoisoxazole, 4-benzoisoxazole, 5-benzoisoxazole, 6-benzoisoxazole, and 7-benzoisoxazole groups; B is, - Phenyl group; - Halogen atom, -SCF ３ , -CF ３ ,-CHF ２ -CN, -OCF ３ , -NO ２ , -OCH ３ , -OC ２ H ５ A phenyl group that is substituted with one or two side groups selected from the group consisting of linear or branched alkyl groups having 1 to 4 carbon atoms in the carbon main chain. (is) The compound according to claim 1, characterized in that it is a compound of or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, characterized in that the halogen atom is a fluorine or chlorine atom.

4. The compound according to any one of claims 1 to 3, characterized in that the linear or branched alkyl group in the carbon main chain contains 1 to 4 carbon atoms, and the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.

5. The compound according to any one of claims 1 to 4, characterized in that k = 0.

6. The compound according to any one of claims 1 to 5, characterized in that X is nitrogen.

7. The compound according to any one of claims 1 to 6, characterized in that group A is selected from the group consisting of 5-benzothiophenyl, 2-naphthyl, and 5-benzoisoxazolyl groups.

8. Group A is phenyl; at least one chlorine atom or -CF ３ ,-CHF ２ , -OCF ３ ien-CH ３ , -SCF ３ The compound according to any one of claims 1 to 7, characterized in that it is selected from the group consisting of phenyl substituted with phenyl.

9. The compound according to any one of claims 1 to 8, characterized in that group B is selected from the group consisting of phenyl or phenyl substituted with one or two halogen atoms.

10. (R) The compound according to any one of claims 1 to 9, wherein the compound is an enantiomer.

11. A compound according to any one of claims 1 to 10, which is a water-soluble salt.

12. The compound according to claim 11, wherein the water-soluble salt is a hydrochloride salt.

13. The following compounds: 3-(methylamino)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione hydrochloride, 3-(dimethylamino)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione hydrochloride, 3-(diethylamino)-1-(2-oxo-1-phenyl-2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)pyrrolidine-2,5-dione hydrochloride The compound according to claim 11 or 12, characterized by being selected from among.

14. A pharmaceutical product for use in the treatment or prevention of epileptic seizures, neuropathic pain, or migraines, comprising as an active ingredient the compound described in any one of claims 1 to 13.

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