Novel stiripentol derivatives and their uses

Abstract

The present invention provides a novel compound that can be used as a lactate dehydrogenase inhibitor and as an active ingredient of pharmaceuticals such as antiepileptic agents and anticancer agents, in particular, a novel compound having excellent metabolic stability. The novel compound is represented by formula (1). In formula (1), R represents an arbitrary substituent (for example, an aromatic or non-aromatic 3- to 14-membered monovalent substituent that may be unsubstituted or substituted, or monocyclic or polycyclic), and Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, and Ri each represent a hydrogen atom or an arbitrary substituent (for example, all Ra to Ri are hydrogen atoms, or Re, Rf, Rg, Rh, and Ri each are a hydrogen atom, and at least one among Ra, Rb, Rc, and Rd is an arbitrary substituent).

Description

[Technical field]

[0001] The present invention relates to a novel stiripentol derivative and use thereof, and more specifically to a novel stiripentol derivative and a lactate dehydrogenase inhibitor and a medicine (anti-epileptic drug, anti-cancer drug, etc.) containing the derivative as an active ingredient. [Background technology]

[0002] Epilepsy is a neurological disorder characterized by hyperexcitability of brain electrical activity. Therefore, existing anti-epileptic drugs have been designed to act on molecules (ion channels, synaptic receptors, etc.) that control brain electrical activity. However, these existing drugs are ineffective for approximately 30% of patients (Non-Patent Document 1).

[0003] Interestingly, a dietary therapy called "ketogenic diet therapy" is effective for this intractable epilepsy (Non-Patent Document 2). However, because strict dietary restrictions are imposed, there is a strong demand for "therapeutic drugs based on the mechanism of action of ketogenic diet therapy." In recent years, the metabolic enzyme "lactate dehydrogenase (LDH)" has been identified as the molecule responsible for the mechanism of action of this ketogenic diet (Non-Patent Document 3). In other words, "lactate dehydrogenase inhibitors" (sometimes referred to as "LDH inhibitors" in this specification) are expected to be new drugs with a completely different mechanism of action (electroregulatory molecules) from existing drugs.

[0004] To develop this new drug, first, the existing antiepileptic drug "stiripentol" (see formula (I) below) was reported to have an inhibitory effect on lactate dehydrogenase (Non-Patent Document 3). This stiripentol has been used clinically in recent years as a treatment for Dravet syndrome (pediatric epilepsy with a high mortality rate) (Non-Patent Document 4). However, the problem is that stiripentol is originally designed to act on the GABA system in the brain (Non-Patent Document 5), and its inhibitory effect on lactate dehydrogenase is weak. In other words, it is theoretically possible to develop a new drug by modifying the chemical structure of stiripentol and strengthening its inhibitory effect on lactate dehydrogenase.

[0005] [ka]

[0006] Based on this, many lactate dehydrogenase inhibitors modified from stiripentol have been reported (Patent Document 1). In this prior invention, a partial structure of stiripentol (isosafrole structure) was used as the mother nucleus, and many lactate dehydrogenase inhibitors were successfully identified. These stiripentol derivatives (see the following formula (II) as an example, R g (various substituents) has a much stronger lactate dehydrogenase inhibitory effect than stiripentol or isosafrole.

[0007] [ka]

[0008] In addition, lactate dehydrogenase is known as a "cancer drug discovery target molecule" (Non-Patent Documents 6, 7). Inhibiting lactate dehydrogenase has an anti-cancer effect via the "Warburg effect," an energy metabolism characteristic of cancer. Anti-cancer drugs based on the Warburg effect are expected to be effective against "intractable cancers" such as pancreatic cancer, and many lactate dehydrogenase inhibitors have been proposed (Non-Patent Documents 8-10). Stiripentol has also been reported to have an anti-cancer effect (Patent Document 2).

[0009] Furthermore, it has been recently reported that stiripentol is also effective against several diseases (calcium oxalate lithiasis, neuropathic pain) (Non-Patent Documents 11 and 12). [Prior art documents] [Patent documents]

[0010] [Patent Document 1] WO2016 / 129583(JP 6681072 B, US 10350192 B) [Patent Document 2] WO2014 / 115764 (JP 6194322 B)

Non-licensed literature

[0011] [Non-licensed document 1] Kwan and Brodie, N Engl J Med 342: 314-319, 2000 [Non-licensed document 2] Neal et al, Lancet Neurol 7: 500-506, 2008 [Non-licensed document 3] Sada et al, Science 347: 1362-1367, 2015

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed Document 8

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

[0012] Stiripentol has a unique structure as a lactate dehydrogenase inhibitor. Moreover, many stiripentol derivatives reported in a prior invention (Patent Document 1) have stronger lactate dehydrogenase inhibitory effects than stiripentol. These stiripentol derivatives are expected to be effective against a number of diseases, such as intractable epilepsy and intractable cancer, but there is a possibility that there is still room for further improvement in order to develop therapeutic drugs with excellent in vivo activity. For example, metabolic stability in blood is extremely important for orally administered therapeutic drugs. If the metabolic stability is low, the unchanged form will disappear quickly in the body even if taken, and sufficient medicinal effect cannot be obtained. If stiripentol derivatives with higher metabolic stability than conventional ones can be obtained, it is expected that the development of therapeutic drugs with better in vivo activity will progress significantly.

[0013] An object of the present invention is to provide a novel compound, particularly a novel compound having excellent metabolic stability, which can be used as a lactate dehydrogenase inhibitor or as an active ingredient of medicines such as antiepileptic drugs and anticancer drugs. [Means for solving the problem]

[0014] The present inventors focused on the stiripentol derivatives reported in the prior invention (Patent Document 1) that have been shown to have a strong lactate dehydrogenase inhibitory effect (compounds 1, 3-6, 9, and 11 in Patent Document 1, Figure 6. These are collectively represented in this specification as the following formula (III). R in formula (III) represents various substituents.) Among these, the stiripentol derivative having a biphenyl structure (compound 9 in Patent Document 1, Figure 6. These are represented in this specification as the following formula (IV)) has been reported to have the strongest lactate dehydrogenase inhibitory activity.

[0015] [ka]

[0016] The present inventors have found that among the stiripentol derivatives of the prior invention (Patent Document 1), preferred compounds represented by formula (III), for example, compounds in which the carbonyl group of the compound represented by formula (IV) is converted to a hydroxyl group, that is, compounds represented by the following formula (1A), and further compounds having a substituent R a ~R dIt has been found that the strong lactate dehydrogenase inhibitory activity is maintained for the compounds represented by the following formula (1B) into which is introduced, for example, various compounds such as compound No. 1 to compound No. 10 shown in the Examples (Table 1) (novel stiripentol derivatives according to the present invention). Furthermore, it has been found that, whereas the above stiripentol derivatives in the prior invention are easily metabolized in vivo and easily disappear from the blood, the novel stiripentol derivatives according to the present invention exhibit high metabolic stability in vivo, and that the novel stiripentol derivatives according to the present invention show a remarkable antiepileptic effect when orally administered (clinical administration route) to a model mouse of intractable epilepsy (temporal lobe epilepsy accompanied by hippocampal sclerosis) for which existing drugs are ineffective. The present invention was completed based on the fact that the above-mentioned compounds maintain strong lactate dehydrogenase inhibitory activity, have high metabolic stability, and have in vivo pharmacological effects, and that similar expectations can be expected for various compounds represented by the following formula (1) even when R in formula (1A) or formula (1B) is replaced with another cyclic structure or another substituent, or when a substituent is introduced at a site other than R, and that similar expectations can also be expected for compounds represented by formula (1') described below.

[0017] [ka]

[0018] That is, in one aspect, the present invention provides the following invention. [1] A compound represented by the following formula (1): [ka] In formula (1), R represents an arbitrary substituent, R a , R b , R c , R d , R e , R f , R g , R h and R iEach represents a hydrogen atom (unsubstituted) or an arbitrary substituent. [2] Item 2. The compound according to item 1, wherein R is a monovalent substituent of an aromatic or non-aromatic 3- to 14-membered ring, which may be unsubstituted or substituted, and may be monocyclic or polycyclic. [3] Item 3. The compound according to item 2, wherein R is an optionally substituted or unsubstituted phenyl group, pyridyl group, thienyl group, cyclopentenyl group, or cyclohexenyl group. [4] R e , R f , R g , R h and R i are all hydrogen atoms (unsubstituted). [5] R a , R b , R c and R d are all hydrogen atoms (unsubstituted). [6] R a , R b , R c and R d At least one of is an optional substituent. [7] A salt or solvate of the compound according to any one of items 1 to 6. [8] Item 8. A lactate dehydrogenase inhibitor comprising the compound, salt or solvate according to any one of items 1 to 7. [9] Item 8. A pharmaceutical comprising the compound, salt or solvate according to any one of items 1 to 7 as an active ingredient.

[10] Item 10. The pharmaceutical agent according to Item 9, which is an antiepileptic drug or an anticancer drug.

[0019] In addition, a person skilled in the art can convert the inventions relating to the above compounds, lactate dehydrogenase inhibitors, and medicines (e.g., antiepileptic drugs and anticancer drugs) into inventions of other categories based on the technical idea of ​​the present invention and the matters described in this specification. For example, in another aspect, the present invention provides inventions relating to "a compound, salt, or solvate according to any one of items 1 to 7 used for inhibiting lactate dehydrogenase (as a lactate dehydrogenase inhibitor) or used as an active ingredient of a medicine", "use of a compound, salt, or solvate according to any one of items 1 to 7 for inhibiting lactate dehydrogenase (as a lactate dehydrogenase inhibitor) or use as an active ingredient of a medicine", "a method for treating a disease (e.g., epilepsy, cancer) comprising administering an effective amount of a compound, salt, or solvate according to any one of items 1 to 7", and the like. Effect of the Invention

[0020] The present invention provides a novel compound having a strong lactate dehydrogenase inhibitory activity equivalent to that of the stiripentol derivative of the prior invention (Patent Document 1), and preferably a novel compound having improved metabolic stability. By using such a novel compound as an active ingredient, a more excellent antiepileptic drug, anticancer drug, and other medicines can be provided. [Brief description of the drawings]

[0021] [Figure 1] Inhibitory effect of compound No. 1 (a compound of formula (IV) as a prior art) and compound No. 2 (a compound of formula (3A-1) according to the present invention) on the enzyme activity of lactate dehydrogenase (LDH1, LDH5) (see Examples). A: Inhibitory activity of compound No. 1 (white circle) and compound No. 2 (black circle) on LDH5 (LDHA tetramer). B: Inhibitory activity of compound No. 1 (white circle) and compound No. 2 (black circle) on LDH1 (LDHB tetramer). The vertical axis of the graph is the inhibition rate, and 100% indicates that lactate dehydrogenase is completely inhibited (similar to Figures 2 to 5). [Diagram 2]Inhibitory effect of compound No. 3 (compound of formula (4A-1) according to the present invention) on the enzyme activity of lactate dehydrogenase (LDH1, LDH5) (see Examples). Black circles indicate inhibitory activity against LDH5 (LDHA tetramer), and white circles indicate inhibitory activity against LDH1 (LDHB tetramer). [Diagram 3] Inhibitory effect of compound No. 4 (compound of formula (3A-2) according to the present invention), compound No. 5 (compound of formula (3A-3) according to the present invention) and compound No. 6 (compound of formula (5A-1) according to the present invention) on the enzyme activity of lactate dehydrogenase (LDH5 = LDHA tetramer) (see Examples). [Figure 4] Inhibitory effect of compound No. 7 (compound of formula (6A-1) according to the present invention) and compound No. 8 (compound of formula (7A-1) according to the present invention) on the enzyme activity of lactate dehydrogenase (LDH5 = LDHA tetramer) (see Examples). [Diagram 5] Inhibitory effect of compound No. 9 (compound of formula (3B-1) according to the present invention) and compound No. 10 (compound of formula (3B-2) according to the present invention) on the enzyme activity of lactate dehydrogenase (LDH1, LDH5) (see Examples). Black circles represent inhibitory activity against LDH5 (LDHA tetramer), and white circles represent inhibitory activity against LDH1 (LDHB tetramer). [Figure 6] HPLC analysis of plasma components following oral administration of Compound No.1 to mice (see Examples). A: HPLC trace of plasma components following oral administration of vehicle. B: HPLC trace of plasma components following oral administration of Compound No.1 (50 mg / kg). Compound No.1 was administered orally using vehicle. C: HPLC trace of Compound No.1 as a standard substance. The HPLC retention time of the peak derived from Compound No.1 in plasma following oral administration (B, arrow) is slightly shifted from the peak of Compound No.1, the standard substance (C). [Figure 7]MS analysis of plasma components after oral administration of Compound No.1 to mice (see Examples). A: Extracted ion chromatogram (EIC) trace (m / z = 329.12 ± 0.1) of plasma components after oral administration of Vehicle (gray) or Compound No.1 (50 mg / kg, black). The exact mass of the protonated molecule of Compound No.1 is 329.12. B: EIC trace (m / z = 331.13 ± 0.1) of plasma components after oral administration of Vehicle (gray) or Compound No.1 (50 mg / kg, black). C: MS spectrum (upper row) after administration of vehicle, MS spectrum (middle row) after administration of Compound No.1, and their subtraction spectrum (lower row) at the EIC peak of plasma components (1.9-2.1 min). In the subtraction spectrum, a peak at m / z = 329.12 representing the unchanged substance is observed, but a much larger metabolite peak at m / z = 331.13 is also observed. [Figure 8] HPLC analysis of plasma components following oral administration of Compound No. 2 to mice (see Examples). A: HPLC trace of plasma components following oral administration of vehicle. B: HPLC trace of plasma components following oral administration of Compound No. 2 (50 mg / kg). Compound No. 2 was orally administered using vehicle. C: HPLC trace of Compound No. 2 as a standard substance. The HPLC retention time of the peak derived from Compound No. 2 in plasma following oral administration (B, arrow) is completely consistent with the peak of Compound No. 2, the standard substance (C). [Figure 9] HPLC analysis of plasma components following oral administration of Compound No. 4 to mice (see Examples). A: HPLC trace of plasma components following oral administration of Compound No. 4 (50 mg / kg). Compound No. 4 was administered orally using a vehicle. B: HPLC trace of Compound No. 4 as a standard substance. The HPLC retention time of the peak derived from Compound No. 4 in plasma following oral administration (A, arrow) is completely consistent with the peak of Compound No. 4, the standard substance (B). [Figure 10]HPLC analysis of plasma components following oral administration of Compound No. 9 to mice (see Examples). A: HPLC trace of plasma components following oral administration of Compound No. 9 (50 mg / kg). Compound No. 9 was administered orally using a vehicle. B: HPLC trace of Compound No. 9 as a standard substance. The HPLC retention time of the peak derived from Compound No. 9 in plasma following oral administration (A, arrow) is completely consistent with the peak of Compound No. 9, the standard substance (B). [Figure 11] Antiepileptic effect of Compound No. 2 on epileptic seizures in hippocampal sclerosis model mice (see Examples). A: Effect of vehicle on epileptic seizure waves. Hippocampal EEG before administration (Baseline) and 2.5 hours after administration (Vehicle) are shown. B: Effect of Compound No. 2 (150 mg / kg) on ​​epileptic seizure waves. Hippocampal EEG before administration (Baseline) and 2.5 hours after administration (Compound No. 2) are shown. C: Aggregated data on the effect of vehicle and Compound No. 2 on the number of spontaneous epileptic seizures. The number of epileptic seizures observed per hour was counted. Statistical analysis was performed using one-way repeated measures ANOVA and Dunnett's test to evaluate significant differences from the number of seizures before administration (Baseline) (*P < 0.05, **P < 0.01). D: Dose-dependency of the epileptic seizure suppression effect of Compound No. 2. The vertical axis of the graph shows the percentage change (%) from 1 hour before administration (Baseline) to 2-3 hours after administration. Statistical analysis was performed using one-way ANOVA and Dunnett's test to evaluate significant differences from the vehicle (0 mg / kg) (**P < 0.01). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] In this specification, "a compound represented by formula (N)" (N is 1 to 7, 1A to 7A, 1B to 7B, 1', 1'A, etc.) may be referred to as "compound (N)". In this specification, "a compound or a salt thereof, or a solvate thereof" may be referred to as "a compound, etc.", and "a compound represented by formula (N) or a salt thereof, or a solvate thereof" may be referred to as "compound (N), etc."

[0023] The "compound represented by formula (N)" or "compound (N)" may contain stereoisomers, i.e., enantiomers (mirror image isomers) and / or diastereomers (stereoisomers other than enantiomers). Diastereomers include, for example, cis-trans isomers in any cyclic structure contained in compound (N) and cis-trans isomers (E-Z isomers) in any double bond. In the present invention, as long as a predetermined action effect is exhibited, a mixture of stereoisomers (e.g., a racemate which is a mixture of enantiomers) may be used as compound (N), or a purified product in which the purity of a specific stereoisomer is increased, for example, a purified product having a purity of 90% or more, preferably a purity of 95% or more, more preferably a purity of 99% or more, and ideally consisting essentially of only the stereoisomer, may be used. Unless otherwise specified, for example, unless explicitly indicated by a dashed line-wedge symbol or the like in formula (N), or unless the name of the compound of formula (N) or the name of a substituent introduced into formula (N) is not indicated by RS, cis-trans, EZ, or the like, "compound (N)" in the specification can refer to all (any) stereoisomers.

[0024] -Compound- The compound of the present invention (novel stiripentol derivative) is a compound represented by the following formula (1), that is, compound (1).

[0025] [ka]

[0026] In formula (1), R represents an arbitrary substituent, R a , R b , R c , Rd , R e , R f , R g , R h and R i Each of R and R represents a hydrogen atom (unsubstituted) or an arbitrary substituent. a , R b , R c , R d , R e , R f , R g , R h and R i are not particularly limited as long as compound (1) has lactate dehydrogenase inhibitory activity and preferably has improved metabolic stability. a , R b , R c , R d , R e , R f , R g , R h and R i The type of substituent to be selected for (1) or whether to leave it unsubstituted can be appropriately determined while taking into consideration the desired lactate dehydrogenase inhibitory activity, metabolic stability, other properties (e.g., solubility in water), etc. A person skilled in the art can design and produce a compound (1) that exhibits the effects of the present invention and can be used to practice the present invention without excessive trial and error.

[0027] The "lactate dehydrogenase inhibitory activity" and "metabolic stability" and other properties can be measured and evaluated according to standard methods, for example, according to the methods described in the Examples below. Having "improved metabolic stability" means that the compound (1) of the present invention has higher metabolic stability than the conventional stiripentol derivative (a compound in which the hydroxy group in the compound (1) of the present invention is a carbonyl group) having the same substituent as that of the compound (1) of the present invention and described in Patent Document 1.

[0028] Specific examples of R include substituents belonging to the following Substituent Group 1, Substituent Group 2, or Substituent Group 3. Each substituent (particularly, a substituent containing a cyclic structure which may be further substituted, or a substituent containing a double bond) can refer to all (any) stereoisomers when stereoisomers exist, unless otherwise specified.

[0029] [Substituent group 1] [X] Halogen atom [O1] Hydroxy group [O2] Oxo group [S1] Sulfanyl group (thiol group) [S2] Sulfo group [N1] Amino group [N2] Imino group [N3] Nitro group [C1] Formyl group [C2] Carboxy group [C3] Thiocarboxy group [C4] Carbamoyl group [C5] Thiocarbamoyl group [C6] Cyano group

[0030] [Substituent group 2] [A1] Optionally substituted C 1-6 Alkyl group [A2]C 2-6 Alkenyl group [A3]C 2-6 Alkynyl group [A4]C 3-10 Cycloalkyl group [A5]C 3-10 Cycloalkenyl group [A6] Optionally substituted C 6-14 Aryl Group [A7]C 7-16 Aralkyl groups [H1] An optionally substituted 5- to 14-membered aromatic heterocyclic group [H2] Optionally substituted 3- to 14-membered non-aromatic heterocyclic group

[0031] [Substituent group 3] <-OR> [O11a] Optionally halogenated C 1-6 Alkoxy group [O11b]C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy) [O11c]C 7-16 Aralkyloxy groups (e.g., benzyloxy) [O11d] 5-14 membered aromatic heterocyclic oxy group (e.g. pyridyloxy) [O11e] 3-14 membered non-aromatic heterocyclic oxy group (e.g., morpholinyloxy, piperidinyloxy) <-O-CO-R> [O12a]C 1-6 Alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy) [O12b]C 6-14 Aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy) [O12c] 5-14 membered aromatic heterocyclic carbonyloxy group (e.g. nicotinoyloxy) [O12d] 3-14 membered non-aromatic heterocyclic carbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy) [O12e]C 1-6 Alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy) <-O-CO-NRR'> [O13a] Mono- or di-C 1-6 Alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy) [O13b]C 6-14 Aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy) <-O-SO2-R> [O14a] Optionally halogenated C 1-6 Alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy) [O14b]C1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy) <-SR> [S11] Optionally halogenated C 1-6 Alkylthio group <-SO2-R> [S21a] Optionally halogenated C 1-6 Alkylsulfonyl group [S21b]C 6-14 Arylsulfonyl group [S21c] 5-14 membered aromatic heterocyclic sulfonyl group (e.g. pyridylsulfonyl, thienylsulfonyl) <-SO-R> [S22a] Optionally halogenated C 1-6 Alkylsulfinyl group [S22b]C 6-14 Arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl) [S22c] 5-14 membered aromatic heterocyclic sulfinyl group (e.g. pyridylsulfinyl, thienylsulfinyl) <-NRR'> [N11a] Mono- or di-C 1-6 Alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino) [N11b] Mono- or di-C 6-14 Arylamino groups (e.g. phenylamino) [N11c] 5-14 membered aromatic heterocyclic amino group (e.g. pyridylamino) [N11d]C 7-16 Aralkylamino group (e.g., benzylamino) <-NH-C(O)H / -NH-C(O)R> [N12a] Formylamino group [N12b]C 1-6Alkyl-carbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino) [N12c](C 1-6 Alkyl)(C 1-6 Alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) [N12d]C 6-14 Aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino) [N12e]C 1-6 Alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino) [N12f]C 7-16 Aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino) <-NH-S(O)2R> [N13a]C 1-6 Alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) [N13b]C 1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonylamino group (e.g., phenylsulfonylamino, toluenesulfonylamino) <-C(O)R> [C11a] Optionally halogenated C 1-6 Alkyl-carbonyl group [C11b]C 6-14 Aryl-carbonyl group [C11c] 5-14 membered aromatic heterocyclic carbonyl group [C11d] 3-14 membered non-aromatic heterocyclic carbonyl group <-COO-R> [C21a]C 1-6 Alkoxy-carbonyl group [C21b]C 6-14 Aryloxy-carbonyl group (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl) [C21c]C 7-16Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl) <-CO-NRR'> [C41a] mono- or di-C 1-6 Alkyl-carbamoyl group [C41b]C 6-14 Aryl-carbamoyl groups (e.g., phenylcarbamoyl) [C41c] 5-14 membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl) [C41d] 3-14 membered non-aromatic heterocyclic carbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl)

[0032] The "halogen atom" in [X] etc. refers to, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0033] [A1] etc. 1-6 The term "alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. In one embodiment, the "C 1-6 The alkyl group is preferably a C 1-4 alkyl group”, more preferably “C 1-2 "Alkyl group."

[0034] [A1] etc. C 1-6 Examples of the substituent that the alkyl group may have include those belonging to Substituent Group 1, that is, groups such as halogen atoms, amino groups, and carboxy groups.

[0035] "C" has halogen atoms as a substituent, i.e., is "halogenated" 1-6The term "alkyl group" refers to a group in which one or more hydrogen atoms, for example, 1 to 7, preferably 1 to 5 hydrogen atoms in the alkyl group are substituted with halogen atoms. 1-6 It is also written as "haloalkyl group". 1-6 Examples of haloalkyl groups include trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.

[0036] [A2] etc. 2-6 The term "alkenyl group" refers to a linear or branched hydrocarbon group having one carbon-carbon double bond and 2 to 6 carbon atoms, and examples thereof include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl. In one embodiment, "C" in [A2] etc. 2-6 The alkenyl group is preferably 2-4 alkenyl group".

[0037] [A3] etc. 2-6 The term "alkynyl group" refers to a linear or branched hydrocarbon group having one carbon-carbon triple bond and 2 to 6 carbon atoms, and examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl. In one embodiment, "C" in [A3] etc. 2-6 The alkynyl group is preferably 2-4 alkynyl group".

[0038] [A4] etc. 3-10 The term "cycloalkyl group" refers to a monocyclic or polycyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl.

[0039] [A5] etc. 3-10 The term "cycloalkenyl group" refers to a monocyclic or polycyclic hydrocarbon group having one unsaturated bond and having 3 to 10 carbon atoms, and examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0040] [A6] etc. 6-14 The term "aryl group" refers to a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms (preferably 6 to 10 members), and examples thereof include phenyl, naphthyl (e.g., 1-naphthyl, 2-naphthyl), acenaphthylenyl, azulenyl, anthryl (e.g., 1-anthryl, 2-anthryl, 9-anthryl), and phenanthryl.

[0041] [A6] etc. C 6-14 Examples of the substituent that the aryl group may have include substituents belonging to Substituent Group 1, and those that do not have a cyclic structure among the substituents belonging to Substituent Group 2 or Substituent Group 3. For example, [A1] "optionally substituted C 1-6 (or C 1-4 Or C 1-2 ) alkyl group".

[0042] [A7] etc. 7-16 The term "aralkyl group" refers to an alkyl group to which an aryl group is bonded, and means that the total number of carbon atoms in the aryl group and the carbon atoms in the alkyl group is 7 to 16. 7-16The aralkyl group includes, for example, benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0043] The "5- to 14-membered aromatic heterocyclic group" in [H1] etc. refers to a monovalent group derived from a 5- to 14-membered aromatic heterocycle, that is, a 5- to 14-membered (preferably 5- to 10-membered) aromatic cyclic compound (which may be monocyclic or polycyclic (condensed ring)) containing at least one (preferably 1 to 4, more preferably 1 to 2) heteroatom selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom as a ring-constituting atom other than carbon atom. The position of the heteroatom (the position relative to the position where it is bonded to other moieties as a monovalent group) is arbitrary. Examples of the "5- to 14-membered aromatic heterocycle" include the following: 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazo 8- to 14-membered polycyclic (preferably bicyclic or tricyclic) aromatic heterocycles such as lopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0044] The "3- to 14-membered non-aromatic heterocyclic group" in [H2] etc. refers to a 3- to 14-membered non-aromatic heterocycle, i.e., a monovalent group derived from a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic cyclic compound (which may be monocyclic or polycyclic (condensed ring)) containing at least one (preferably 1-4, more preferably 1-2) heteroatom selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom other than carbon atom as a ring-constituting atom. The position of the heteroatom (the position relative to the position of bonding to other moieties as a monovalent group) is optional. Examples of the "3- to 14-membered non-aromatic heterocycle" include the following: 3-8 membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepanine, diazepane, azepine, azocane, diazocane, and oxepane; 9-14 membered polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline.

[0045] Examples of the substituents that may be possessed by the 5- to 14-membered aromatic heterocyclic group such as [H1] and the 3- to 14-membered non-aromatic heterocyclic group such as [H2] include, for example, the substituents listed in Substituent Group 1 and those that do not have a cyclic structure among the substituents belonging to Substituent Group 2 or Substituent Group 3, and as an example, the "optionally substituted C" of [A1] belonging to Substituent Group 2. 1-6 (or C 1-4 Or C 1-2 ) alkyl group".

[0046] [O11a] etc. 1-6 An alkoxy group has an oxygen atom with "C 1-6 "C" refers to a group to which an "alkyl group" is bonded, i.e., a linear or branched alkoxy group having 1 to 6 carbon atoms. 1-6 Examples of the "alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, and hexyloxy.

[0047] "C" in [O11b] 6-14 aryloxy group, [O11c] "C 7-16"Aralkyloxy group", "5- to 14-membered aromatic heterocyclic oxy group" in [O11d], and "3- to 14-membered non-aromatic heterocyclic oxy group" in [O11e] each have the above-mentioned C 6-14 Aryl group, C 7-16 It is a group in which an aralkyl group, a 5- to 14-membered aromatic heterocyclic group, or a 3- to 14-membered non-aromatic heterocyclic group is bonded.

[0048] [O12a] "C 1-6 Alkyl-carbonyloxy group, [O12b] "C 6-14 aryl-carbonyloxy group, [O12c] 5-14 membered aromatic heterocyclic carbonyloxy group, [O12d] 3-14 membered non-aromatic heterocyclic carbonyloxy group, [O12e] C 1-6 "Alkoxy-carbonyloxy group" refers to a carbonyloxy group having a C 1-6 Alkyl group, C 6-14 Aryl group, 5- to 14-membered aromatic heterocyclic group, 3- to 14-membered non-aromatic heterocyclic group, C 1-6 It is a group to which an alkoxy group is bonded.

[0049] [O13a] "Mono- or di-C 1-6 Alkyl-carbamoyloxy group, [O13b] C 6-14 "Aryl-carbamoyloxy group" refers to a carbamoyloxy group -O-CO-NH2, which is a C-aryl group as described above. 1-6 Alkyl group (1 or 2), C 6-14 It is a group to which an aryl group is attached as a substituent.

[0050] [O14a] "Optionally halogenated C 1-6 Alkyl sulfonyloxy group, [O14b] "C 1-6 C optionally substituted with an alkyl group 6-14 The "aryl-sulfonyloxy group" refers to a sulfonyloxy group -O-SO3H, optionally halogenated C-aryl group as described above. 1-6 Alkyl group, C 1-6 C optionally substituted with an alkyl group 6-14It is a group to which an aryl group is attached as a substituent.

[0051] [S11] "Optionally halogenated C 1-6 The "alkylthio group" is an optionally halogenated C alkylthio group as described above attached to a sulfur atom. 1-6 It is a group to which an alkyl group is attached.

[0052] [S21a] "Optionally halogenated C 1-6 Alkylsulfonyl group, [S21b] "C 6-14 The "arylsulfonyl group" and the "5- to 14-membered aromatic heterocyclic sulfonyl group" in [S21c] are each a sulfonyl group -S(=O)2- and an optionally halogenated C 1-6 Alkyl group, C 6-14 It is a group to which an aryl group or a 5- to 14-membered aromatic heterocyclic group is bonded.

[0053] [S22a] "Optionally halogenated C 1-6 Alkylsulfinyl group," [S22b] "C 6-14 The "arylsulfinyl group" and the "5- to 14-membered aromatic heterocyclic sulfinyl group" in [S22c] are each a sulfinyl group -S(=O)- and an optionally halogenated C 1-6 Alkyl group, C 6-14 It is a group in which an aryl group or a 5- to 14-membered aromatic heterocyclic group is bonded.

[0054] [N11a] "Mono- or di-C 1-6 Alkylamino group, [N11b] "C 6-14 "Arylamino group", "5-14 membered aromatic heterocyclic amino group" in [N11c], "C 7-16 "Aralkylamino group" refers to an amino group -NH2 with the above-mentioned C 1-6 Alkyl group (1 or 2), C 6-14 Aryl group, 5-14 membered aromatic heterocyclic group, C 7-16 It is a group to which an aralkyl group is bonded.

[0055] The formylamino group of [N12a] is a group in which a formyl group is bonded to an amino group. 1-6 Alkyl-carbonylamino group, [N12c] "(C 1-6 Alkyl)(C 1-6 Alkyl-carbonyl)amino group, [N12d] "C 6-14 Aryl-carbonylamino group, [N12e] "C 1-6 Alkoxy-carbonylamino group, [N12f] "C 7-16 "Aralkyloxy-carbonylamino group" refers to a carbonylamino group -NH-CO- and a C 1-6 Alkyl group, C 1-6 Alkyl groups and C 1-6 Alkyl-carbonyl group, C 6-14 Aryl group, C 1-6 Alkoxy group, C 7-16 It is a group to which an aralkyloxy group is bonded.

[0056] [N13a] "C 1-6 Alkylsulfonylamino group, [N13b] "C 1-6 C optionally substituted with an alkyl group 6-14 "Arylsulfonylamino group" refers to a sulfonylamino group -NH-SO2- and a C 1-6 Alkyl group, C 1-6 C optionally substituted with an alkyl group 6-14 It is a group to which an aryl group is bonded.

[0057] [C11a] "Optionally halogenated C 1-6 "Alkyl-carbonyl group," [C11b] 6-14 The "aryl-carbonyl group", the "5- to 14-membered aromatic heterocyclic carbonyl group" in [C11c], and the "3- to 14-membered non-aromatic heterocyclic carbonyl group" in [C11d] are each a carbonyl group -C(=O)- and an optionally halogenated C(=O) group as described above. 1-6 Alkyl group, C 6-14 It is a group in which an aryl group, a 5- to 14-membered aromatic heterocyclic group, or a 3- to 14-membered non-aromatic heterocyclic group is bonded.

[0058] [C21a] "C 1-6 Alkoxy-carbonyl group, [C21b] 6-14 Aryloxy-carbonyl group" and [C21c] "C 7-16 Each of the "aralkyloxy-carbonyl groups" is a carbonyl group -C(=O)-, optionally halogenated C(=O)- as described above. 1-6 Alkoxy group, C 6-14 Aryloxy group, C 7-16 It is a group to which an aralkyloxy group is bonded.

[0059] [C41a] "Mono- or di-C 1-6 Alkyl-carbamoyl group, [C41b] 6-14 "aryl-carbamoyl group", "5- to 14-membered aromatic heterocyclic carbamoyl group" in [C41c], and "3- to 14-membered non-aromatic heterocyclic carbamoyl group" in [C41d] are each a carbamoyl group -CO-NH2 and a C 1-6 Alkyl group (1 or 2), C 6-14 It is a group in which an aryl group, a 5- to 14-membered aromatic heterocyclic group, or a 3- to 14-membered non-aromatic heterocyclic group is bonded to a nitrogen atom as a substituent.

[0060] Preferred examples of R in the present invention include monovalent aromatic or non-aromatic 3- to 14-membered ring substituents that may be unsubstituted or substituted, and may be monocyclic or polycyclic, such as [A4]C 3-10 Cycloalkyl group, [A5]C 3-10 Cycloalkenyl group, [A6] optionally substituted C 6-14 Examples of the heterocyclic group include an aryl group, an optionally substituted 5- to 14-membered aromatic heterocyclic group [H1], and an optionally substituted 3- to 14-membered non-aromatic heterocyclic group [H2]. In such a preferred embodiment, the formula (1) can be represented as the following formula (2).

[0061] [ka]

[0062] In formula (2), ring A represents a monovalent aromatic or non-aromatic 3- to 14-membered ring substituent that may be unsubstituted or substituted, and may be monocyclic or polycyclic, such as [A4], [A5], [A6], [H1], and [H2] belonging to the above-mentioned substituent group 2. R' represents any substituent bonded to ring A, such as a substituent belonging to substituent group 1, or a substituent belonging to substituent group 2 or 3 that does not have a cyclic structure, such as [A1] "optionally substituted C" belonging to substituent group 2. 1-6 (or C 1-4 Or C 1-2 ) alkyl group" (i.e., those previously mentioned as further substituents which may be possessed by [A6], [H1], [H2], etc. in Substituent Group 2). n is the number of substituents possessed by Ring A, i.e., when Ring A is unsubstituted, n is 0, and when Ring A is substituted, n is any integer of 1 or more (preferably 1, 2 or 3). The binding site of R' in Ring A is arbitrary.

[0063] More preferred R (more preferred ring A) in the present invention includes unsubstituted or substituted, monocyclic or polycyclic, aromatic or non-aromatic 5- to 10-membered rings, particularly 5- or 6-membered rings, monovalent substituents, such as phenyl, pyridyl (e.g., 2-pyridyl), thienyl (e.g., 2-thienyl), cyclohexenyl (e.g., 1-cyclohexenyl), and cyclopentenyl (e.g., 1-cyclopentenyl), which may be substituted. Such preferred formulas (1) and (2) in the present invention can also be represented as the following formulas (3) to (7). R' and n in formulas (3) to (7) have the same meanings as those in formula (2).

[0064] [ka] [ka]

[0065] R in formula (1) a , R b , R c , Rd , R e , R f , R g , R h and R i may all be hydrogen atoms (unsubstituted), or at least one may be a substituent. For example, (i) R a , R b , R c and R d may all be hydrogen atoms (unsubstituted), or at least one of them may be a substituent. e and R f may be hydrogen atoms (unsubstituted), or at least one of them may be a substituent. g , R h and R i may all be hydrogen atoms (unsubstituted), or at least one may be a substituent. In formula (1), the above definitions of (i), (ii), and (iii) may be arbitrarily combined. In one aspect of the present invention, for example, R e and R f , and R in (iii) above g , R h and R i are all hydrogen atoms (unsubstituted), and R a , R b , R c and R d may all be hydrogen atoms (unsubstituted), or at least one may be a substituent.

[0066] R a , R b , R c , R d , R e , R f , R g , R h or R i When R is a substituent, specific examples of the respective substituents include the substituents belonging to the above-mentioned Substituent Group 1, Substituent Group 2, or Substituent Group 3. In one aspect of the present invention, R a , R b , R c , Rd , R e , R f , R g , R h or R i When is a substituent, each of the substituents is preferably a substituent belonging to Substituent Group 1 or a substituent belonging to Substituent Group 2 or Substituent Group 3 that does not have a cyclic structure.

[0067] In one aspect of the invention, R a , R b , R c , R d , R e , R f , R g , R h and R i are all preferably hydrogen atoms (unsubstituted). According to such an embodiment, the formulas (1) to (7) can also be represented as the following formulas (1A) to (7A).

[0068] [ka] [ka]

[0069] In one aspect of the invention, R e , R f , R g , R h and R i It is preferable that all of R are hydrogen atoms (unsubstituted). According to such an embodiment, formulas (1) to (7) can also be represented as the following formulas (1B) to (7B). a , R b , R c and R d Each of R may independently be a hydrogen atom (unsubstituted) or a substituent. a , R b , R c and R d When all of R are hydrogen atoms, they have the same meanings as those of the above formulas (1A) to (7A). a , R b , Rc and R d When at least one of R is a substituent, for example, R a and R b is a hydrogen atom (unsubstituted), R c and R d In the case where one or both of the formulae are substituents, they can be referred to as formulae (1B) to (7B) in the narrow sense, which do not overlap with the formulae (1A) to (7A) above.

[0070] [ka] [ka]

[0071] In one aspect of the present invention, the compound of the present invention is a compound represented by the following formula (1'), i.e., compound (1'). Compound (1') is a cis-trans isomer (E-Z form) at the double bond specified in the formula, relative to the compound represented by the above formula (1), i.e., compound (1). For convenience, compound (1') is called a cis form, and compound (1) is called a trans form. In this specification, the explanations regarding compound (1) and similar trans forms (i.e., compounds (2) to (7), formulas (1A) to (7A), and formulas (1B) to (7B)), such as the definitions of the substituents in the formulas, can also be applied to compound (1') and similar cis forms (i.e., cis compounds corresponding to the trans forms of compounds (2) to (7), formulas (1A) to (7A), and formulas (1B) to (7B), as an example, the compound represented by the following formula (1'A)). Furthermore, the descriptions in this specification regarding the embodiments, effects, and the like of the "compound (etc.) of the present invention" are applicable not only to trans-isomers such as compound (1) but also to cis-isomers such as compound (1').

[0072] [ka]

[0073] The compound of the present invention may be in the form of a salt. In addition, the compound of the present invention and its salt may be in the form of a solvate.

[0074] When the compound of the present invention has an acidic or basic group, it can be reacted with a base or an acid to obtain a "salt" of the compound of the present invention (basic salt or acid salt). When the salt of the compound of the present invention is used as an active ingredient of a medicine (in preparing a pharmaceutical composition), a pharma- ceutically acceptable salt is appropriate.

[0075] Examples of "basic salts" include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as magnesium salts and calcium salts; organic base salts such as N-methylmorpholine salts, triethylamine salts, tributylamine salts, diisopropylethylamine salts, dicyclohexylamine salts, N-methylpiperidine salts, pyridine salts, 4-pyrrolidinopyridine salts, and picoline salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate salts, and aspartate salts.

[0076] Examples of "acid salts" include hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; alkanesulfonate salts such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonate salts such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, and maleate; and amino acid salts such as chrysin salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.

[0077] A "solvate" of the compound of the present invention or its salt can be obtained by coordinating a solvent molecule to the compound of the present invention or its salt (for example, by mixing with a solvent and then crystallizing). Examples of the "solvate" include hydrates, ethanol solvates, and dimethylsulfoxide solvates.

[0078] The compound of the present invention (novel stiripentol derivative) can be synthesized by a person skilled in the art (for example, Tokyo Chemical Industry Co., Ltd. described in the Examples) using well-known conventional or known means (reaction method, reaction, conditions, steps, equipment, etc.), or can be obtained by entrusting synthesis to a person skilled in the art. Salts of the compound of the present invention and solvates of the compound of the present invention and its salts can also be obtained by well-known conventional or known means.

[0079] For more specific embodiments for synthesizing the compounds of the present invention, the disclosure of the Examples below can be referred to. It is possible to change the raw material compounds and adjust the reaction conditions according to the target compound. The outline of the synthesis scheme is as follows: (i) An organic halogen compound, such as 4-halogenated acetophenone or its derivative (R corresponding to the target compound) a ~R d (ii) cross-coupling the first intermediate with piperonal or a derivative thereof (R corresponding to the target compound) using a palladium catalyst (Suzuki-Miyaura cross-coupling reaction) to obtain a first intermediate; e ~R i (iii) reducing the carbonyl group of the second intermediate with a hydride reducing agent to a hydroxy group to obtain the target compound.

[0080] The synthesized compounds of the present invention can be isolated and purified by well-known conventional or known means, such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization, etc. The chemical structures of the compounds of the present invention can be identified using common instruments and analytical methods, such as 1H-NMR, 13C-NMR, HPLC, and high-resolution liquid chromatography mass spectrometry (LC-MS / MS).

[0081] The use of the compounds of the present invention is not particularly limited, but they can typically be used as lactate dehydrogenase (LDH) inhibitors as described below, or as active ingredients of pharmaceuticals such as antiepileptic drugs and anticancer drugs.

[0082] -Lactate dehydrogenase inhibitors- The lactate dehydrogenase (LDH) inhibitor of the present invention includes the compound, salt, or solvate of the present invention (the compound of the present invention, etc.). In other words, the compound of the present invention, etc. used under conditions (particularly in an amount) in which LDH inhibitory activity is observed in vitro or in vivo can be called the LDH inhibitor of the present invention.

[0083] Lactate dehydrogenase (LDH) is a protein with a molecular weight of approximately 140 kD that catalyzes the interconversion of lactate (L-lactate in the body) and pyruvate (at the same time, the interconversion of NADH and NAD occurs). LDH is a tetramer consisting of two types of subunits, LDHA (M) and LDHB (H), and there are five isozymes, LDH1 (four LDHBs), LDH2 (three LDHBs and one LDHA), LDH3 (two LDHBs and two LDHAs), LDH4 (one LDHB and three LDHAs), and LDH5 (four LDHAs), depending on the binding mode of these subunits. For example, in the brain, pyruvate is converted to L-lactate by LDH5 in astrocytes, while L-lactate taken up by neurons is converted to pyruvate by LDH1. In addition, in cancer cells, even when not in a hypoxic state, energy production is performed by converting pyruvate to lactate, and therefore the expression of LDH5 is significantly enhanced. The LDH inhibitor of the present invention can target any of the above isozymes. The LDH inhibitor of the present invention only needs to have an inhibitory activity against at least one of the above isozymes, and can have an inhibitory activity against at least one of LDH1 and LDH5, preferably both.

[0084] The LDH inhibitor of the present invention can be intended for human-derived LDH, or for LDH derived from other animals having LDH, such as non-human mammals such as mice, rats, guinea pigs, rabbits, goats, cats, dogs, pigs, monkeys, etc. Thus, the pharmaceutical of the present invention containing the LDH inhibitor of the present invention (the compound of the present invention, etc.) as an active ingredient can be intended for humans, or for animals other than humans.

[0085] -Medicine- The pharmaceutical of the present invention contains the compound of the present invention or the LDH inhibitor of the present invention as an active ingredient. The term "pharmaceutical" includes both those approved in accordance with the laws and regulations of each country (medicinal products) and those used in clinical trials before approval. Furthermore, "pharmaceutical" refers to those that are recognized to have a therapeutic or (recurrence) preventive effect (collectively referred to as "pharmaceutical effect" in this specification) against a specified disease, and the presence or absence of the pharmaceutical effect can be determined by appropriate criteria according to the disease and purpose.

[0086] The pharmaceutical of the present invention can be used for diseases in which the LDH inhibitory activity of the compound of the present invention exerts a medicinal effect, i.e., diseases in which inhibition of LDH exerts an effect of treating, improving, alleviating, preventing, etc., on the symptoms or diseased tissue of the disease. Representative examples of such diseases include epilepsy and cancer. That is, the pharmaceutical of the present invention is typically an antiepileptic drug and an anticancer drug. However, the pharmaceutical of the present invention is not limited to these, and can also be used for other diseases having the above-mentioned mechanism of action, such as calcium oxalate lithiasis and neuropathic pain, for which the efficacy of stiripentol has been reported.

[0087] The "epilepsy" targeted by the medicament of the present invention is not particularly limited. As an example, the medicament (antiepileptic drug) of the present invention is preferably targeted to refractory epilepsy for which no effective existing drug has been found, such as adult refractory epilepsy for which stiripentol is not effective (medial temporal lobe epilepsy associated with hippocampal sclerosis).

[0088] The "cancer" targeted by the pharmaceutical agent of the present invention is not particularly limited, and examples thereof include malignant lymphoma (Hodgkin's lymphoma, non-Hodgkin's lymphoma, etc.), gastric cancer, penile cancer, pharyngeal cancer (nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, etc.), vulvar cancer, pituitary adenoma, hepatocellular carcinoma, thymoma, mycosis fungoides, cancer of unknown primary site, myelodysplastic syndrome, uterine cancer (cervical cancer, uterine body cancer, uterine sarcoma, etc.), trophoblastic disease, esophageal cancer, renal pelvis cancer, ureteral cancer, glioma, and renal cell carcinoma. , pancreatic cancer, pancreatic endocrine tumor, testicular tumor, prostate cancer, colorectal cancer (appendicitis, colon cancer, rectal cancer, etc.), multiple myeloma, bile duct cancer, gallbladder cancer, vaginal cancer, mesothelioma, acoustic neuroma, soft tissue sarcoma, breast cancer, brain tumor, lung cancer, leukemia (acute myeloid leukemia, acute lymphocytic leukemia, adult T-cell leukemia lymphoma, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), skin cancer (malignant melanoma, etc.), bladder cancer, chronic myeloproliferative disease, ovarian cancer, ovarian germ cell tumor. As an example, the pharmaceutical agent (anticancer agent) of the present invention is preferably intended for intractable cancers such as pancreatic cancer, for which lactate dehydrogenase inhibition is effective.

[0089] The method of use and amount of the pharmaceutical of the present invention (e.g., route and site of administration, timing of administration, dosage per administration, number of administrations per day, and administration period) are not particularly limited, and an appropriate method of use and amount of administration can be determined through in vitro or in vivo tests, and taking into consideration the patient's age, sex, weight, pathological condition, concomitant medications, etc., so as to achieve the desired therapeutic effect.

[0090] The medicament of the present invention is generally prepared as a pharmaceutical composition containing an active ingredient (an effective amount of the compound of the present invention) and a pharma- ceutical acceptable additive. The pharmaceutical composition of the present invention can be prepared for oral administration as, for example, tablets, capsules, granules, powders, dry syrups, liquids (including syrups, liquids for external use, etc.), suppositories, ointments, creams, eye drops, nasal drops, patches, etc., or for parenteral administration as, for example, injections. The additives can be selected appropriately depending on the dosage form, and examples of the additives include excipients, bulking agents, diluents (solvents for injection, etc.), stabilizers, and preservatives. The pharmaceutical composition can be prepared according to the dosage form by using appropriate amounts of active ingredients and additives according to the dosage form, according to a method generally used in the art.

[0091] Hereinafter, more detailed embodiments of the compounds, LDH inhibitors and medicines of the present invention will be disclosed through examples, but the technical scope of the present invention is not limited to the specific embodiments disclosed as examples. Those skilled in the art can understand that the embodiments disclosed in the examples can be expanded or modified into various other embodiments based on the technical ideas of the present invention and the entire description of the present specification including drawings, so as to adapt to the intended use and action effect, or that the technical features of the prior art (known inventions) can be further combined or used in combination with the prior art (known inventions) as necessary. EXAMPLES

[0092] <Compound> Compounds No. 1 to No. 10 in the following examples respectively represent the compounds shown in the table below. Compound No. 1 (CAS: 42580-60-9) is a compound of the prior invention described in the above-mentioned Patent Document 1, and compounds No. 2 to No. 10 are novel compounds according to the present invention. Compounds No. 1 to No. 10 were all entrusted to Tokyo Chemical Industry Co., Ltd. for synthesis, and were obtained with the purity and form shown in the table below. Among the novel compounds, the synthesis methods of compounds No. 4 to No. 8 and No. 10 as representative examples are shown below. Note that the yields shown in those synthesis methods are all isolated yields.

[0093] [Table 1-1] [Table 1-2]

[0094] [Synthesis of compound No. 4] [ka]

[0095] (1) Synthesis of intermediate compound c4 A mixture of 4'-bromoacetophenone (compound a) (200 mg, 1.01 mmol), 4-fluorophenylboronic acid (compound b4) (141 mg, 1.01 mmol), Pd(dppf)Cl2·CH2Cl2 (82.1 mg, 0.101 mmol), K2CO3 (278 mg, 2.01 mmol), water (1.0 mL), and 1,4-dioxane (1.7 mL) was purged with nitrogen and stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature, 2 N hydrochloric acid (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was filtered off (filter aid: cellulose) and washed with ethyl acetate. Ethyl acetate (15 mL) was added to the filtrate, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel, methylene chloride / ethyl acetate) to obtain the first intermediate, compound c4 (207 mg, 0.966 mmol, yield 96%) as a pale pink solid.

[0096] (2) Synthesis of intermediate compound e4 A mixture of compound C4 (207 mg, 0.966 mmol), piperonal (compound D) (218 mg, 1.45 mmol), sodium hydroxide (46.4 mg, 1.16 mmol), water (0.1 mL), and methanol (4.8 mL) was stirred at 65° C. for 15 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and the solid was filtered off, washed with water and methanol, and dried under reduced pressure to obtain the second intermediate compound E4 (316 mg, 0.912 mmol, 94% yield) as a yellow solid.

[0097] (3) Synthesis of target compound No. 4 To a mixture of compound e4 (316 mg, 0.912 mmol), tetrahydrofuran (4.6 mL), and methanol (4.6 mL), NaBH4 (69.0 mg, 1.83 mmol) was added and stirred at room temperature for 1.5 hours. Ethyl acetate (15 mL) was added to the reaction solution, and the mixture was washed with water and saturated saline solution in that order. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was suspended in toluene (10 mL), heated to 60°C to dissolve, and then cooled to room temperature. The precipitated solid was filtered off, washed with toluene, and the filter cake was dried under reduced pressure to obtain the target compound No.4 (139 mg, 0.399 mmol, 44% yield) as a colorless solid.

[0098] [Synthesis of compound No. 5] [ka]

[0099] (1) Synthesis of intermediate compound c5 A mixture of 4'-bromoacetophenone (compound a) (200 mg, 1.01 mmol), 4-nitrophenylboronic acid (compound b5) (168 mg, 1.01 mmol), Pd(dppf)Cl2CH2Cl2 (82.1 mg, 0.101 mmol), K2CO3 (278 mg, 2.01 mmol), water (1.0 mL), and 1,4-dioxane (1.7 mL) was purged with nitrogen and stirred at 80 ° C for 2.5 hours. The reaction solution was cooled to room temperature, 2 N hydrochloric acid (10 mL) was added, stirred for 10 minutes, and the solid was filtered off (filter aid: cellulose), washed with ethyl acetate, and ethyl acetate (15 mL) was added to the filtrate, which was then washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel, methylene chloride / ethyl acetate) to obtain the first intermediate, compound c5 (187 mg, 0.775 mmol, yield 77%) as a pale yellow solid.

[0100] (2) Synthesis of intermediate compound e5 A mixture of compound e5 (187 mg, 0.775 mmol), piperonal (compound d) (175 mg, 1.16 mmol), sodium hydroxide (37.2 mg, 0.930 mmol), water (0.1 mL), and methanol (3.9 mL) was stirred at 65° C. for 13 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and the solid was filtered, washed with water and methanol, and the residue was dried under reduced pressure to obtain the second intermediate compound e5 (267 mg, 0.715 mmol, 92% yield) as a pale yellow solid.

[0101] (3) Synthesis of target compound No.5 To a mixture of compound e5 (267 mg, 0.715 mmol), tetrahydrofuran (3.6 mL), and methanol (3.6 mL), NaBH4 (54.1 mg, 1.43 mmol) was added and stirred at room temperature for 5 hours. Ethyl acetate (15 mL) was added to the reaction solution, and the mixture was washed with water and saturated saline solution in that order. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel, hexane / methylene chloride) to obtain the target compound No.5 (54.1 mg, 0.144 mmol, 20% yield) as a pale yellow solid.

[0102] [Synthesis of compound No.6] [ka]

[0103] (1) Synthesis of intermediate compound c6 A mixture of 4'-bromoacetophenone (compound a) (200 mg, 1.01 mmol), 2-thiophene pinacol boronic acid (compound b6) (211 mg, 1.01 mmol), Pd(dppf)Cl2·CH2Cl2 (82.1 mg, 0.101 mmol), K2CO3 (278 mg, 2.01 mmol), water (1.0 mL), and 1,4-dioxane (1.7 mL) was purged with nitrogen and stirred at 80°C for 1.5 hours. The reaction solution was cooled to room temperature, 2 N hydrochloric acid (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was filtered off (filter aid: cellulose) and washed with ethyl acetate. Ethyl acetate (15 mL) was added to the filtrate, and the mixture was washed with water and saturated saline in that order. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel, methylene chloride / ethyl acetate) to obtain the first intermediate, compound c6 (179 mg, 0.885 mmol, yield 88%) as a colorless solid.

[0104] (2) Synthesis of intermediate compound e6 A mixture of compound C6 (179 mg, 0.885 mmol), piperonal (compound D) (199 mg, 1.33 mmol), sodium hydroxide (42.5 mg, 1.06 mmol), water (0.1 mL), and methanol (4.4 mL) was stirred at 65° C. for 4.5 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and the solid was filtered, washed with water and methanol. The residue was dried under reduced pressure to obtain the second intermediate compound E6 (284 mg, 0.849 mmol, 96% yield) as a yellow solid.

[0105] (3) Synthesis of target compound No.6 To a mixture of compound e6 (284 mg, 0.849 mmol), tetrahydrofuran (4.3 mL), and methanol (4.3 mL), NaBH4 (64.3 mg, 1.70 mmol) was added and stirred at room temperature for 3 hours. Ethyl acetate (15 mL) was added to the reaction solution, and the mixture was washed with water and saturated saline solution in that order. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (amine silica gel, hexane / ethyl acetate) to obtain the target compound No.6 (263 mg, 0.782 mmol, yield 92%) as a pale yellow solid.

[0106] [Synthesis of compound No. 7] [ka]

[0107] (1) Synthesis of intermediate compound c7 A mixture of 4'-bromoacetophenone (compound a) (200 mg, 1.01 mmol), 1-cyclohexene pinacolboronate (compound b7) (209 mg, 1.01 mmol), Pd(dppf)Cl2·CH2Cl2 (82.1 mg, 0.101 mmol), K2CO3 (278 mg, 2.01 mmol), water (1.0 mL), and 1,4-dioxane (1.7 mL) was purged with nitrogen and stirred at 80°C for 1.5 hours. The reaction solution was cooled to room temperature, 2 N hydrochloric acid (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was filtered off (filter aid: cellulose) and washed with ethyl acetate. Ethyl acetate (15 mL) was added to the filtrate, and the mixture was washed with water and saturated saline in that order. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel, methylene chloride / ethyl acetate) to obtain the first intermediate, compound c7 (186 mg, 0.929 mmol, yield 92%) as a colorless solid.

[0108] (2) Synthesis of intermediate compound e7 A mixture of compound C7 (186 mg, 0.929 mmol), piperonal (compound D) (209 mg, 1.39 mmol), sodium hydroxide (44.6 mg, 1.11 mmol), water (0.1 mL), and methanol (4.6 mL) was stirred at 65° C. for 2.5 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and the solid was filtered, washed with water and methanol. The residue was dried under reduced pressure to obtain the second intermediate compound E7 (295 mg, 0.887 mmol, 96% yield) as a pale yellow solid.

[0109] (3) Synthesis of target compound No. 7 To a mixture of compound e7 (295 mg, 0.887 mmol), tetrahydrofuran (4.2 mL), and methanol (4.2 mL), NaBH4 (63.7 mg, 1.69 mmol) was added and stirred at room temperature for 1.5 hours. Ethyl acetate (15 mL) was added to the reaction solution, and the mixture was washed with water and saturated saline solution in that order. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (amine silica gel, hexane / ethyl acetate) to obtain the target compound No.7 (167 mg, 0.499 mmol, yield 59%) as a colorless solid.

[0110] [Synthesis of compound No.8] [ka]

[0111] (1) Synthesis of intermediate compound c8 A mixture of 4'-bromoacetophenone (compound a) (200 mg, 1.01 mmol), 1-cyclopentenylboronic acid (compound b8) (113 mg, 1.01 mmol), Pd(dppf)Cl2·CH2Cl2 (82.1 mg, 0.101 mmol), K2CO3 (278 mg, 2.01 mmol), water (1.0 mL), and 1,4-dioxane (1.7 mL) was purged with nitrogen and stirred at 80°C for 2.5 hours. The reaction solution was cooled to room temperature, 2 N hydrochloric acid (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was filtered off (filter aid: cellulose) and washed with ethyl acetate. Ethyl acetate (15 mL) was added to the filtrate, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel, methylene chloride / ethyl acetate) to obtain the first intermediate, compound C8 (162 mg, 0.870 mmol, yield 87%) as a colorless solid.

[0112] (2) Synthesis of intermediate compound e8 A mixture of compound C8 (162 mg, 0.870 mmol), piperonal (compound D) (196 mg, 1.31 mmol), sodium hydroxide (41.8 mg, 1.04 mmol), water (0.1 mL), and methanol (4.4 mL) was stirred at 65° C. for 13 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and the solid was filtered, washed with water and methanol. The residue was dried under reduced pressure to obtain the second intermediate compound E8 (256 mg, 0.804 mmol, 92% yield) as a yellow solid.

[0113] (3) Synthesis of target compound No.8 To a mixture of compound e8 (100 mg, 0.314 mmol), tetrahydrofuran (1.6 mL), and methanol (1.6 mL), NaBH4 (23.8 mg, 0.628 mmol) was added and stirred at room temperature for 1 hour. Ethyl acetate (15 mL) was added to the reaction solution, and the mixture was washed with water and saturated saline in that order. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel, hexane / methylene chloride), and the fraction containing the target product was concentrated. The resulting residue was purified by silica gel column chromatography (amine silica gel, hexane / ethyl acetate) to obtain the target compound No.8 (70.8 mg, 0.221 mmol, 70% yield) as a colorless solid.

[0114] [Synthesis of compound No. 10] [ka]

[0115] (1) Synthesis of intermediate compound c10 A mixture of 1-(4-bromo-2,6-difluorophenyl)ethanone (compound f) (12.5 g, 53.2 mmol), phenylboronic acid (compound b10) (6.48 g, 53.2 mmol), Pd(dppf)Cl2·CH2Cl2 (2.17 g, 2.66 mmol), K2CO3 (14.7 g, 106 mmol), water (53 mL), and 1,4-dioxane (89 mL) was purged with nitrogen and stirred at 80°C for 3 hours. The reaction solution was cooled to room temperature, 2 N hydrochloric acid (75 mL) was added, and the mixture was stirred for 30 minutes. The solid was filtered off (filter aid: cellulose) and washed with ethyl acetate. Ethyl acetate (50 mL) was added to the filtrate, and the mixture was washed successively with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane and filtered (filter aid: silica gel). The solution washed with dichloromethane was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel, hexane / methylene chloride) to obtain the first intermediate, compound C10 (11.48 g, 49.4 mmol, yield 93%) as a pink solid.

[0116] (2) Synthesis of intermediate compound e10 A mixture of compound C10 (11.48 g, 49.4 mmol), piperonal (compound D) (11.1 g, 74.2 mmol), sodium hydroxide (2.37 g, 59.3 mmol), water (4.9 mL), and methanol (247 mL) was stirred at 65° C. for 2 hours. The reaction solution was cooled to room temperature, water (100 mL) was added, and the solid was filtered off, washed with water and methanol, and dried under reduced pressure to obtain the second intermediate compound E10 (17.65 g, 48.4 mmol, 98% yield) as a yellow solid.

[0117] (3) Synthesis of target compound No. 10 A mixture of compound e10 (17.6 g, 48.2 mmol), cerium(III) chloride heptahydrate (21.5 g, 57.8 mmol), tetrahydrofuran (240 mL), and methanol (120 mL) was stirred at room temperature for 20 minutes, cooled in an ice bath, and NaBH4 (2.19 g, 57.8 mmol) was added and stirred at room temperature for 30 minutes. Ethyl acetate (250 mL) was added to the reaction solution, which was then washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Isopropyl alcohol (200 mL) was added to the resulting residue, and the solid was filtered off and washed with isopropyl alcohol. The filter cake was dried under reduced pressure to obtain the target compound No.10 (16.20 g, 44.2 mmol, 92% yield) as a colorless solid.

[0118] <Evaluation method> Evaluation of lactate dehydrogenase inhibitory activity (compounds No. 1 - 10, Figure 1-5): Lactate dehydrogenase produces lactate and NAD from pyruvate and NADH. In other words, if lactate dehydrogenase activity is high, NADH decreases, and if the enzyme activity is inhibited, NADH does not decrease. Therefore, to evaluate the enzyme activity of lactate dehydrogenase, an experiment was performed using an evaluation system consisting of an enzyme reaction (step 1) and a color reaction (step 2) (Patent Document 1, Non-Patent Document 9). In the enzyme reaction of step 1, sodium pyruvate (100 μM), NADH (100 μM), and lactate dehydrogenase (human LDH1 or LDH5) were added, and then inhibitors (compounds No. 1-10) of various concentrations were added, and the reaction was carried out for 60 minutes in 100 mM sodium phosphate buffer (pH 7.3, 37°C) (200 μL / well). At this stage, the background absorbance at 492 nm was measured with a plate reader (absorbance before the color reaction). Next, in the color reaction of step 2, to measure the amount of NADH remaining from the enzyme reaction of step 1, 100 μL / well of a color solution containing diaphorase (25 U / mL) and INT (5 mM) was added and reacted for 10 minutes. INT is converted to INT formazan by diaphorase in the presence of NADH, and its absorbance at 492 nm was measured with a plate reader (absorbance after the color reaction). In other words, if lactate dehydrogenase is inhibited, NADH remains, and it shows an absorbance at 492 nm. The value obtained by subtracting the absorbance before the color reaction from the absorbance after the color reaction was calculated as the "absorbance change value (ΔA)". Furthermore, the absorbance when the above reaction was performed in the absence of inhibitors was determined as the "0% control value," and the absorbance when the above reaction was performed in the absence of inhibitors and lactate dehydrogenase (LDH1, LDH5) was determined as the "100% control value." The inhibition rate (%) in Figure 1-5 was calculated as 100 x (ΔA in the presence of inhibitors - 0% control value) / (100% control value - 0% control value). Based on this formula, if lactate dehydrogenase is completely inhibited, it will show 100%, and if it is not inhibited, it will show 0%.

[0119] Pharmacokinetic evaluation by oral administration to mice (compounds No. 1, 2, 4, 9, Figure 6-10): In the pharmacokinetic study, 6-7 week old ICR mice were used in the experiment. Compounds No. 1, No. 2, No. 4, and No. 9 are all highly lipophilic, so they were orally administered using a vehicle containing an oily solvent triglyceride and a surfactant polyoxyethylene castor oil. Vehicle or each compound (50 mg / kg) was orally administered using a disposable blow probe, and after 30 min, the animals were decapitated to obtain blood. Sodium heparin (10 μg / mL) was added as an anticoagulant to the blood, which was then centrifuged for 15 min (1000 g, 4°C), and the supernatant was obtained as plasma. Next, ethyl acetate was added to the obtained plasma to extract the compounds, which were then air-dried with nitrogen gas and redissolved in acetonitrile to obtain the pretreated sample, which was then used for the following analyses (HPLC, MS). For HPLC analysis, a JASCO HPLC system was used to separate plasma components using a C18 reversed-phase column at a flow rate of 1.0 mL / min. Compound No. 1 was analyzed using a mobile phase consisting of 80% acetonitrile and 20% water, while compounds No. 2, No. 4, and No. 9 were analyzed using a mobile phase consisting of 70% acetonitrile and 30% water. Each compound was detected at 295 nm using a UV detector, and data was acquired and analyzed using the software ChromNAV (JASCO). To identify unchanged compounds in plasma components, the compounds themselves were also directly analyzed by HPLC as standard substances, and their retention times were compared. For MS analysis, an Agilent Technologies LC-MS / MS system (Agilent 1200 HPLC-Chip and 6520 Accurate-Mass Q-TOF) was used. The pretreated sample was adsorbed onto a C18 chip using a mobile phase consisting of 25% acetonitrile containing 0.1% formic acid and 75% water, and the plasma components were then separated using a mobile phase consisting of 60% acetonitrile containing 0.1% formic acid and 40% water.The MS spectra of the separated plasma components were detected using a mass spectrometer, and data were acquired and analyzed using the software MassHunter Qualitative Analysis (Agilent Technologies).

[0120] Drug efficacy evaluation using hippocampal sclerosis model mice (compound No. 2, Figure 11): The hippocampal sclerosis model mice used for the evaluation of antiepileptic activity were prepared according to previous literature (Non-Patent Documents 3, 13). First, 6-7 week-old ICR mice were anesthetized with a mixture of ketamine (100 mg / kg) and xylazine (40 mg / kg) and set in a brain stereotaxic apparatus. Next, the scalp was removed, and a U-shaped plastic frame required for in vivo EEG measurement was attached to the head. Furthermore, a small amount of kainic acid (0.8 nmol, 40 nL) was injected into the dorsal hippocampus (1.6 mm posterior to the bregma, 1.6 mm lateral to the center line, 1.4 mm from the brain surface) via a microglass electrode to induce epilepsy, and a metal electrode (diameter 200 μm) for measuring epilepsy EEG was embedded near the site of kainic acid injection. A reference electrode was placed in the cerebellum. Three weeks after surgery, spontaneous epileptic seizure waves emanating from the hippocampus were measured to evaluate the antiepileptic effect. The mouse head was fixed using a U-shaped frame, and hippocampal EEG was recorded through a 0.5-30 Hz analog filter and digitized at a sampling rate of 1 kHz using an AD converter. After measuring baseline EEG for 1 hour, vehicle or compound No. 2 was orally administered using a disposable probe, and EEG was recorded for another 3 hours. Epileptic seizure waves were analyzed using Igor Pro (WaveMetrics), and epileptic seizure waves lasting 8 seconds or more were counted. Statistical processing was performed using SigmaPlot (Systat Software).

[0121] <Result> First, the lactate dehydrogenase inhibitory activity of the new stiripentol derivative (compound No. 2) was examined and compared with that of the stiripentol derivative of the prior invention (Patent Document 1) (compound No. 1) (Figure 1). Lactate dehydrogenase is a tetrameric metabolic enzyme consisting of two subunits (LDHA, LDHB). Therefore, the inhibitory activity of stiripentol derivatives was examined for the LDHA tetramer (LDH5) and the LDHB tetramer (LDH1). First, when examining LDHA, compound No. 1 of the prior invention showed inhibitory activity up to a low concentration of 5 μM (Figure 1A, open circle, n = 3). This is almost consistent with the results of the prior invention (Patent Document 1). And this time, compound No. 2, in which the carbonyl group is replaced with a hydroxyl group, was also found to show inhibitory activity at the same concentration (Figure 1A, filled circle, n = 3). In addition, when LDHB was examined, both compounds showed similarly strong inhibitory activity (Fig. 1B, n = 3 for each). In other words, it was revealed that the novel stiripentol derivative (compound No. 2) discovered in this study also has strong lactate dehydrogenase inhibitory activity.

[0122] Compound No. 2 represented by formula (3A-1) is a new compound, and its lactate dehydrogenase inhibitory activity and usefulness as a medicine (active ingredient) have not been reported so far. Compounds represented by formula (1A), including compound No. 2 in which R is a phenyl group, and compounds in which R is any substituent group, have not been reported. Therefore, in order to verify whether compounds represented by formula (1A) other than compound No. 2 and compounds represented by formula (1B) in which a further substituent group is introduced also have lactate dehydrogenase inhibitory activity, compounds No. 3 to No. 10 represented by the specific structural formulas shown in Table 1, which are included in formula (1A) or formula (1B), were newly synthesized and enzyme activity was evaluated. As a result, it was revealed that all of compounds No. 3 to No. 10 have clear lactate dehydrogenase inhibitory activity, although their inhibitory activity may differ slightly from that of compound No. 2 (Figure 2-5, n = 3 for each). In other words, it was shown that various compounds represented by formula (1A) in which the carbonyl group of the compound represented by formula (III) of the prior invention is replaced with a hydroxyl group, and various compounds represented by formula (1B) in which a further substituent has been introduced, also function as lactate dehydrogenase inhibitors.

[0123] Next, the in vivo metabolic stability of the stiripentol derivative of the prior invention having a carbonyl group (compound No. 1) and the new stiripentol derivatives having a hydroxyl group (compounds No. 2, No. 4, and No. 9) was examined (Figures 6-10). First, compound No. 1 of the prior invention was orally administered to mice (50 mg / kg), and the plasma components 30 minutes later were analyzed by HPLC. Several peaks were observed that were not observed in vehicle-administered mice (Figures 6A and B). These were peaks derived from compound No. 1. Furthermore, by comparing with the HPLC peaks of the standard sample (Figure 6C), a peak with almost the same HPLC retention time, which is assumed to be the unchanged form of compound No. 1, was identified (Figure 6B, arrow).

[0124] However, the peak derived from Compound No.1 in this plasma (Figure 6B) was slightly different from the peak derived from Compound No.1 in the standard sample (Figure 6C), suggesting the possibility that metabolites were also present. We then analyzed the peak derived from Compound No.1 in this plasma (Figure 6B, arrow) by mass spectrometry using LC-MS (Figure 7). The molecular weight of Compound No.1 is 328.37, and the exact mass of the protonated molecule in positive mode is m / z = 329.12. When we examined the extracted ion chromatogram (EIC) of m / z = 329.12, we found that the EIC peak increased after oral administration of Compound No.1 (Figure 7A). In other words, the unchanged form of Compound No.1 was detected in the blood. However, when the MS spectrum of the peak was obtained from the plasma of vehicle-administered mice and compound No. 1-administered mice and the subtraction spectrum was calculated, an MS peak was observed at m / z = 329.12, but a larger MS peak was observed at m / z = 331.13 (Figure 7C). When the EIC of m / z = 331.13 was examined, it was found that the EIC peak observed in the plasma of compound No. 1-administered mice (Figure 7B) was clearly larger than the EIC peak at m / z = 329.12 (Figure 7A). In other words, it was revealed that compound No. 1 of the prior invention has low metabolic stability in vivo, and although it is observed in the blood after oral administration, the unchanged form disappears quickly.

[0125] Next, we orally administered compound No. 2, a novel stiripentol derivative, to mice (50 mg / kg) and analyzed the plasma components 30 min later by HPLC (Fig. 8). As a result, a large peak at 5.1 min and a small peak at 5.4 min were observed as HPLC peaks derived from compound No. 2 that were not observed in vehicle-administered mice (Fig. 8A, B). Next, when compared with the HPLC peak of the standard sample compound No. 2 (Fig. 8C), the retention time was completely consistent with the 5.1 min peak derived from compound No. 2 (Fig. 8B, arrow). In other words, it was revealed that compound No. 2, a novel stiripentol derivative, has high metabolic stability in vivo and maintains unchanged concentration in the blood even after oral administration. Compounds No. 4 and No. 9 were also analyzed by HPLC in the same manner as described above. As with the results for compound No. 2 above, the HPLC peak retention times of the plasma components and the standard sample were completely consistent, indicating that the compounds have high metabolic stability in vivo and that unchanged concentrations are maintained in the blood even after oral administration (Figures 9A and B, 10A and B).

[0126] Finally, the antiepileptic effect was evaluated as an in vivo pharmacological effect when the new stiripentol derivative, Compound No. 2, was orally administered (Figure 11). In a mouse model of "temporal lobe epilepsy with hippocampal sclerosis," known as a typical drug-resistant epilepsy in adults (Non-Patent Documents 3, 13), spontaneous epileptic seizures were observed (Figures 11A, B, Baseline). Therefore, oral administration of vehicle as a control did not change the epileptic seizures (Figure 11A, Vehicle), but oral administration of Compound No. 2 suppressed the epileptic seizures (Figure 11B, Compound No. 2). As tabulated data, the number of seizures did not change with the administration of vehicle, but a significant decrease in the number of seizures was observed from 1 hour after administration of Compound No. 2 (Figure 11C, n = 10 each). In addition, the dose-dependence of the compound was examined, and it was found that oral administration of 50 mg / kg significantly reduced the number of seizures (Fig. 11D, n = 20 for 0 mg / kg [vehicle], n = 11 for 50 mg / kg, n = 10 for 150 mg / kg, n = 9 for 300 mg / kg). These results indicate that oral administration of compound No. 2, a novel stiripentol derivative, can suppress epileptic seizures in an intractable epilepsy model.

[0127] It will be understood by those skilled in the art that the lactate dehydrogenase inhibitory activity, metabolic stability, usefulness as a medicine (active ingredient), and the like shown for compound No. 2 to compound No. 10 through the above examples can be understood to apply to all compounds represented by formulas (3A) to (7A) or formulas (3B) to (7B), including those having a substituent R' different from the above-mentioned specific compounds, to all compounds represented by formula (2A) or formula (2B), including those having ring A as R different from the above-mentioned specific compounds, further to all compounds represented by formula (1A) or formula (1B), including those having a substituent other than ring A as R, and finally to all compounds represented by formula (1A) or formula (1B), including those having R, R a ~R dIt can be understood that the same applies to all compounds represented by formula (1) in which a substituent other than the above may be introduced.

Claims

1. A compound represented by the following formula (1): 【Chemistry 1】 In formula (1), R represents a hydrogen atom (unsubstituted) or an aromatic or non-aromatic 5- or 6-membered monovalent substituent which may be substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an oxo group, a sulfanyl group, a sulfo group, an amino group, an imino group, a nitro group, a formyl group, a carboxy group, a thiocarboxy group, a carbamoyl group, a thiocarbamoyl group, and a cyano group; R a , R b , R c , R d , R e , R f , R g , R h and R i each represents a hydrogen atom (unsubstituted) or a halogen atom selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; compound.

2. 2. The compound of claim 1, wherein the aromatic or non-aromatic five- or six-membered ring is a phenyl group, a pyridyl group, a thienyl group, a cyclohexenyl group, or a cyclopentenyl group.

3. The R e , R f , R g , R h and R i The compound according to claim 1 or 2, wherein all of are hydrogen atoms (unsubstituted).

4. The R a , R b , R c and R d The compound according to claim 3 , wherein all of are hydrogen atoms (unsubstituted).

5. The R a , R b , R c and R d The compound according to claim 3, wherein at least one of is a halogen atom selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

6. A salt or solvate of the compound according to any one of claims 1 to 5.

7. A lactate dehydrogenase inhibitor comprising the compound according to any one of claims 1 to 6, a salt thereof, or a solvate thereof.

8. A pharmaceutical comprising the compound, salt or solvate thereof according to any one of claims 1 to 6 as an active ingredient.

9. The pharmaceutical composition according to claim 8 for use as an antiepileptic or anticancer agent.

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