WO2022025242A1 - 新規スチリペントール誘導体およびその用途 - Google Patents

新規スチリペントール誘導体およびその用途 Download PDF

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WO2022025242A1
WO2022025242A1 PCT/JP2021/028307 JP2021028307W WO2022025242A1 WO 2022025242 A1 WO2022025242 A1 WO 2022025242A1 JP 2021028307 W JP2021028307 W JP 2021028307W WO 2022025242 A1 WO2022025242 A1 WO 2022025242A1
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compound
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substituent
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French (fr)
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剛 井上
渚 佐田
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Okayama University NUC
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Okayama University NUC
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Priority to JP2022539600A priority patent/JP7650521B2/ja
Priority to US18/018,792 priority patent/US12516043B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a novel stiripentol derivative and its use, more specifically, a novel stiripentol derivative and a lactate dehydrogenase inhibitor and a drug (antiepileptic agent, anticancer agent, etc.) containing the derivative as an active ingredient.
  • Epilepsy is a neurological disorder characterized by hyperexcitability of electrical brain activity. Therefore, existing epilepsy treatments have been designed to act on molecules that control electrical activity in the brain (ion channels, synaptic receptors, etc.). However, these existing drugs are not effective for about 30% of patients (Non-Patent Document 1).
  • Non-Patent Document 2 a diet called “ketogenic diet” is effective for this intractable epilepsy.
  • “therapeutic agents based on the mechanism of action of the ketogenic diet” are sought after.
  • a metabolic enzyme “lactate dehydrogenase” (LDH) has been clarified as a molecule responsible for the mechanism of action of this ketone diet (Non-Patent Document 3). That is, “lactate dehydrogenase inhibitor” (sometimes referred to as “LDH inhibitor” in the present specification) is expected as a new drug completely different from the mechanism of action (electrically controlled molecule) of existing drugs.
  • Non-Patent Document 3 the inhibitory effect of lactate dehydrogenase was first reported on the existing antiepileptic drug "stiripentol" (see formula (I) below) (Non-Patent Document 3).
  • This stiripentol has been clinically used in recent years as a therapeutic agent for Dravet syndrome (pediatric epilepsy with a high mortality rate) (Non-Patent Document 4).
  • stiripentol is originally designed to act on the GABA system in the brain (Non-Patent Document 5), and the inhibitory effect of lactate dehydrogenase is weak. That is, it is theoretically possible to develop a new drug by modifying the chemical structure of stiripentol and enhancing the lactate dehydrogenase inhibitory action.
  • lactate dehydrogenase is also known as a "cancer drug discovery target molecule" (Non-Patent Documents 6 and 7).
  • a cancer drug discovery target molecule lactate dehydrogenase
  • an anticancer effect is obtained through the "Warburg effect", which is an energy metabolism (Cancer metabolism) characteristic of cancer. Since anticancer drugs based on the Warburg effect are expected to be effective for "refractory cancer” such as pancreatic cancer, many lactate dehydrogenase inhibitors have been proposed so far (Non-Patent Document 8-- 10).
  • the anticancer effect of stiripentol has also been reported (Patent Document 2).
  • Non-Patent Documents 11 and 12 More recently, it has been reported that stiripentol is also effective for multiple diseases (calcium oxalate stone disease, neuropathic pain) (Non-Patent Documents 11 and 12).
  • Stiripentol has a unique structure as a lactate dehydrogenase inhibitor. Moreover, many stiripentol derivatives reported in the previous invention (Patent Document 1) have a stronger lactate dehydrogenase inhibitory action than stiripentol. These stiripentol derivatives are expected to be effective for multiple diseases such as intractable epilepsy and intractable cancer, but there is still room for further improvement in order to develop therapeutic agents with excellent in vivo activity. There may be. For example, in orally administered therapeutic agents, metabolic stability in blood is extremely important. If the metabolic stability is low, the unchanged drug disappears quickly in the body even if it is taken, so that a sufficient medicinal effect cannot be obtained. If a stiripentol derivative with higher metabolic stability than before can be obtained, it is expected that the development of an excellent therapeutic agent with in vivo activity will be greatly promoted.
  • An object of the present invention is to provide a novel compound that can be used as a lactate dehydrogenase inhibitor and as an active ingredient of a drug such as an antiepileptic agent and an anticancer agent, particularly a novel compound having excellent metabolic stability. do.
  • Patent Document 1 Among the stiripentol derivatives reported in the previous invention (Patent Document 1), the present inventors have shown a strong lactate dehydrogenase inhibitory action (Patent Document 1, Compounds 1 and 3- in FIG. 6). 6, 9, 11. In the present specification, the following formula (III) is comprehensively expressed. R in the formula (III) represents various substituents). Among them, the strongest lactate dehydrogenase inhibitory activity has been reported in the stiripentol derivative having a biphenyl structure (Compound 9 of Patent Document 1, FIG. 6; represented by the following formula (IV) in the present specification).
  • Patent Document 1 Among the stiripentol derivatives of the previous invention (Patent Document 1), the present inventors have converted a preferable compound represented by the formula (III), for example, a compound in which the carbonyl group of the compound represented by the formula (IV) is converted into a hydroxy group. That is, the compound represented by the following formula (1A) and the compound represented by the following formula (1B) into which the substituents R a to R d have been introduced, for example, the compound No. 1 shown in Example (Table 1). It was found that strong lactate dehydrogenase inhibitory activity is maintained even for various compounds such as Compound No. 10 (the novel stiripentol derivative according to the present invention).
  • a preferable compound represented by the formula (III) for example, a compound in which the carbonyl group of the compound represented by the formula (IV) is converted into a hydroxy group. That is, the compound represented by the following formula (1A) and the compound represented by the following formula (1B) into which the substituents R a to
  • the novel stiripentol derivative according to the present invention exhibits high metabolic stability in vivo and already exists. It was also found that oral administration (clinical administration route) of the novel stiripentol derivative according to the present invention to a model mouse of intractable epilepsy (temporal lobar epilepsy with hippocampal sclerosis) for which the drug does not work shows a remarkable antiepileptic effect. rice field.
  • R in the formula (1A) or the formula (1B) can be used as another cyclic structure.
  • substituents When the substituent is replaced with another substituent or when the substituent is introduced at a site other than R, that is, various compounds represented by the following formula (1) can be similarly expected, and further, the formula described later.
  • the present invention has been completed based on the possibility that the compound represented by (1') can also be expected.
  • a compound represented by the following formula (1) R represents an arbitrary substituent, and R a , R b , R c , R d , R e , R f , R g , R h , and R i are hydrogen atoms (unsubstituted), respectively. Or represents any substituent.
  • R represents an aromatic or non-aromatic 3- to 14-membered monovalent substituent which may be unsubstituted or substituted, monocyclic or polycyclic. The compound described.
  • Item 2 Item 1 wherein R is an aromatic or non-aromatic 3- to 14-membered monovalent substituent which may be unsubstituted or substituted, monocyclic or polycyclic. The compound described.
  • the invention is any of items 1-7, "used to inhibit lactate dehydrogenase (as a lactate dehydrogenase inhibitor) or used as an active ingredient in a pharmaceutical. (Lactate dehydrogenase) for inhibiting lactate dehydrogenase of the compound, salt or admixture according to any one of Items 1 to 7 and the compound, salt or admixture according to item (1).
  • the present invention provides a novel compound having a strong lactate dehydrogenase inhibitory activity, which is equivalent to the stiripentol derivative of the previous invention (Patent Document 1), preferably a novel compound having further improved metabolic stability.
  • novel compounds as active ingredients provides better antiepileptic agents, anticancer agents and other pharmaceuticals.
  • HPLC analysis of plasma components by oral administration of compound No. 1 to mice see Examples.
  • Compound No. 1 was orally administered using a vehicle.
  • MS analysis of plasma components by oral administration of compound No. 1 to mice see Examples.
  • A: Extraction ion chromatogram (EIC) trace of plasma components (m / z 329.12 ⁇ 0.1) for oral administration of Vehicle (gray) or compound No.
  • HPLC analysis of plasma components by oral administration of compound No. 2 to mice see Examples.
  • Compound No. 2 was orally administered using a vehicle.
  • HPLC analysis of plasma components by oral administration of compound No. 4 to mice see Examples.
  • Compound No. 4 was orally administered using a vehicle.
  • B HPLC trace of compound No. 4 as a standard substance.
  • the HPLC retention time of the compound No. 4 derived peak (A, arrow) in plasma by oral administration is completely in agreement with the compound No. 4 peak (B) which is a standard substance.
  • HPLC analysis of plasma components by oral administration of compound No. 9 to mice (see Examples).
  • A HPLC trace of plasma components for compound No. 9 oral administration (50 mg / kg).
  • Compound No. 9 was orally administered using a vehicle.
  • B HPLC trace of compound No. 9 as a standard substance.
  • the HPLC retention time of the compound No. 9-derived peak (A, arrow) in plasma by oral administration is completely in agreement with the compound No. 9 peak (B) which is a standard substance.
  • A The 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 seizure waves. Hippocampal EEG before administration (Baseline) and 2.5 hours after administration (Compound No. 2) are shown.
  • C Aggregated data on the effects of vehicle and compound No. 2 on the number of spontaneous epileptic seizures. It counts the number of epileptic seizures observed per hour.
  • compound represented by the formula (N) (N is 1 to 7, 1A to 7A, 1B to 7B, 1', 1'A, etc.) is referred to as “compound (N)".
  • compound or salt thereof or solvate thereof may be referred to as “compound or the like”
  • compound represented by the formula (N) or salt thereof or solvate thereof may be referred to as “compound or solvate thereof”. It may be described as “compound (N), etc.”
  • the “compound represented by the formula (N)” contains a stereoisomer, that is, an enantiomer (mirror isomer) and / or a diastereomer (a stereoisomer other than the mirror isomer).
  • a stereoisomer that is, an enantiomer (mirror isomer) and / or a diastereomer (a stereoisomer other than the mirror isomer).
  • Diastereomers also include, for example, cis-trans isomers in any cyclic structure contained in compound (N) and cis-trans isomers (E-form-Z) in any double bond.
  • a mixture of stereoisomers (for example, a racemic mixture of enantiomers) may be used as the compound (N) as long as a predetermined action and effect are exhibited, or the purity of a specific stereoisomer may be determined.
  • An enhanced purified product 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 substantially only the stereoisomer thereof may be used.
  • the compound of the present invention (new stiripentol derivative) is a compound represented by the following formula (1), that is, the compound (1).
  • R represents an arbitrary substituent
  • R a , R b , R c , R d , R e , R f , R g , R h , and R i are hydrogen atoms (unsubstituted), respectively. Or represents any substituent.
  • compound (1) has lactate dehydrogenase inhibitory activity and is preferably further improved. It is not particularly limited as long as it has the required metabolic stability.
  • R What substituents should be selected as R, and what substituents should be selected as R a , R b , R c , R d , Re , R f , R g , R h and R i . Whether it is substituted or not can be appropriately determined in consideration of the target lactate dehydrogenase inhibitory activity, metabolic stability, other properties (for example, solubility in water) and the like.
  • a person skilled in the art can design and manufacture a compound (1) that exhibits the effects of the present invention and can be used for carrying out the present invention without requiring undue trial and error.
  • lactate dehydrogenase inhibitory activity "metabolic stability", and other properties can be measured and evaluated according to a conventional method, for example, according to the method shown in the examples below.
  • improved metabolic stability means that the compound (1) of the present invention has the same substituent as the conventional stiripentol derivative described in Patent Document 1 (compound (1) of the present invention). It means that the metabolic stability is higher than that of the compound in which the hydroxy group in the above is a carbonyl group).
  • R include substituents belonging to the following substituent group 1, substituent group 2, or substituent group 3.
  • Each substituent is all (arbitrary) unless otherwise specified in the presence of a stereoisomer. It can refer to a stereoisomer.
  • [Substituent group 2] [A1] May be 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 group [H1] optionally substituted 5--14 member aromatic heterocyclic group [H2] substituted May be a 3- to 14-membered non-aromatic heterocyclic group
  • halogen atom in [X] and the like refers to, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the "C 1-6 alkyl group” in [A1] and the like refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl and butyl. , Isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl Can be mentioned.
  • the "C 1-6 alkyl group” in [A1] and the like is preferably a "C 1-4 alkyl group", more preferably a "C 1-2 alkyl group”.
  • Examples of the substituent that the C 1-6 alkyl group such as [A1] may have include those belonging to the substituent group 1, that is, a halogen atom, an amino group, a carboxy group and the like.
  • a "Halogenated""C 1-6 alkyl group” that has a halogen atom as a substituent is one or more hydrogen atoms in the alkyl group, such as 1-7, preferably 1-5 hydrogens. It means a group in which an atom is substituted with a halogen atom, and is sometimes referred to as "C 1-6 haloalkyl group".
  • Examples of the C 1-6 haloalkyl group include trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and penta.
  • Fluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6,6,6 -Trifluorohexyl can be mentioned.
  • the "C 2-6 alkenyl group” in [A2] and the like refers to a linear or branched hydrocarbon group having one carbon-carbon double bond and having 2 to 6 carbon atoms, for example. , 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, 5-hexenyl.
  • the "C 2-6 alkenyl group" in [A2] and the like is preferably a "C 2-4 alkenyl group”.
  • the "C 2-6 alkynyl group” in [A3] and the like refers to a linear or branched hydrocarbon group having one carbon-carbon triple bond and having 2 to 6 carbon atoms, for example. 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, Examples thereof include 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.
  • the "C 2-6 alkynyl group" in [A3] and the like is preferably a "C 2-4 alkynyl group".
  • C 3-10 cycloalkyl group in [A4] and the like refers to a monocyclic or polycyclic saturated hydrocarbon group having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. , Cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, adamantyl.
  • C 3-10 cycloalkenyl group in [A5] and the like refers to a monocyclic or polycyclic hydrocarbon group having one unsaturated bond and having 3 to 10 carbon atoms, for example, cyclo. Examples thereof include propenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • C 6-14 aryl group in [A6] and the like refers to a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms (preferably 6 to 10 members), for example.
  • Phenyl, naphthyl eg 1-naphthyl, 2-naphthyl
  • acenaphtylenyl azurenyl
  • anthryl eg 1-anthryl, 2-anthryl, 9-anthryl
  • phenanthryl can be mentioned.
  • Examples of the substituent that the C 6-14 aryl group such as [A6] may have include a substituent belonging to the substituent group 1 and a substituent belonging to the substituent group 2 or the substituent group 3.
  • substituent group 1 a substituent belonging to the substituent group 1
  • substituent group 2 a substituent belonging to the substituent group 3.
  • substituent group 3 Those having no cyclic structure, for example, [A1] "C 1-6 (or C 1-4 or C 1-2 ) alkyl group which may be substituted" belonging to the substituent group 2 can be mentioned.
  • C7-16 aralkyl group in [A7] and the like refers to an alkyl group to which an aryl group is bonded, and means that the total number of carbon atoms of the aryl group and the number of carbon atoms of the alkyl group is 7 to 16. do.
  • Examples of the "C 7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl and phenylpropyl.
  • the "5- to 14-membered aromatic heterocyclic group" in [H1] and the like is selected from a group consisting of a 5- to 14-membered aromatic heterocycle, that is, a group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • a 5- to 14-membered (preferably 5 to 10-membered) aromatic cyclic (even monocyclic) containing at least one (preferably 1-4, more preferably 1-2) heteroatoms. refers to a monovalent group derived from a compound (which may be a polycyclic (condensed ring)).
  • the position of the heteroatom is arbitrary.
  • Examples of the "5- to 14-membered aromatic heterocycle” include: Thiadiazole, furan, pyrrol, imidazole, pyrazole, thiazole, isothiazole, oxazole, isooxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1, 5- or 6-membered monocyclic aromatic heterocycles such as 2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine; Benzothiophene, benzofuran, benzoimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazolepyridine, thienopyridine, flopyr
  • the "3-14-membered non-aromatic heterocyclic group" in [H2] and the like is composed of a 3- to 14-membered non-aromatic heterocycle, that is, a group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • the position of the heteroatom (the position relative to the position bonded to another site as a monovalent group) is arbitrary.
  • Examples of the "3-14 member non-aromatic heterocycle” include: Aziridine, oxylan, thiirane, azetidine, oxetane, thietan, tetrahydrothiophene, tetrahydrofuran, pyrrolin, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazolin, thiazolidine, tetrahydroisothiazole, tetrahydroxazole, tetrahydroisoxazole, piperidine.
  • Examples of the substituents that the 5- to 14-membered aromatic heterocyclic group such as [H1] and the 3- to 14-membered non-aromatic heterocyclic group such as [H2] may have are included in the substituent group 1.
  • the above-mentioned substituents, substituents belonging to the substituent group 2 or the substituent group 3 which do not have a cyclic structure, for example, "may be substituted" of [A1] belonging to the substituent group 2 "C 1-6 (or C 1-4 or C 1-2 ) alkyl group" can be mentioned.
  • the "C 1-6 alkoxy group” in [O11a] and the like is a group in which a “C 1-6 alkyl group” is bonded to an oxygen atom, that is, a linear or branched alkoxy group having 1 to 6 carbon atoms. Point to.
  • Examples of the "C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy and hexyloxy. ..
  • the "3 to 14-membered non-aromatic heterocyclic oxy group” has a C 6-14 aryl group, a C 7-16 aralkyl group, and a 5 to 14-membered aromatic heterocyclic group, 3 to 14, as described above, respectively. It is a group to which a member non-aromatic heterocyclic group is bonded.
  • the "mono- or di-C 1-6 alkyl-carbamoyloxy group" of [O13a] and the "C 6-14 aryl-carbamoyloxy group” of [O13b] are respectively carbamoyloxy group-O-CO-NH 2 . , C 1-6 alkyl group (1 or 2) as described above, C 6-14 aryl group bonded as a substituent.
  • Halogenated C 1-6 alkylthio group in [S11] is a group in which a halogenated C 1-6 alkyl group as described above is bonded to a sulfur atom.
  • the "C 7-16 aralkylamino group” of [N11d] is an amino group -NH 2 , a C 1-6 alkyl group (1 or 2) as described above, a C 6-14 aryl group, 5 to, respectively. It is a group to which a 14-membered aromatic heterocyclic group and a C 7-16 aralkyl group are bonded.
  • the formylamino group of [N12a] is a group in which a formyl group is bonded to an amino group.
  • [N12b] "C 1-6 alkyl-carbonylamino group”
  • [N12c] "(C 1-6 alkyl) (C 1-6 alkyl-carbonyl) amino group”
  • [N12d] "C 6-14 ""Aryl-carbonylaminogroup”
  • C 7-16 aralkyloxy-carbonylamino group are carbonylamino group-NH-CO-, respectively.
  • C 1-6 alkyl sulfonylamino group of [N13a] and the "C 6-14 aryl sulfonyl amino group optionally substituted with a C 1-6 alkyl group” of [N13b] are sulfonylamino groups-NH, respectively.
  • -SO 2 - is a group to which a C 6-14 aryl group optionally substituted with a C 1-6 alkyl group or a C 1-6 alkyl group as described above is bonded.
  • [C11a] "C 1-6 alkyl-carbonyl group which may be halogenated”
  • [C11b] "C 6-14 aryl-carbonyl group”
  • [C11c] "5-14 member aromatic heterocycle”
  • Preferred R in the present invention is, for example, an aromatic or non-aromatic 3- to 14-membered monovalent substituent which may be unsubstituted or substituted, monocyclic or polycyclic.
  • R an aromatic or non-aromatic 3- to 14-membered monovalent substituent which may be unsubstituted or substituted, monocyclic or polycyclic.
  • Examples thereof include a 5- to 14-membered aromatic heterocyclic group which may be substituted, and a 3- to 14-membered non-aromatic heterocyclic group which may be substituted [H2].
  • the formula (1) can be expressed as the following formula (2).
  • ring A may be unsubstituted or substituted, and may be monocyclic or polycyclic, and is an aromatic or non-aromatic 3- to 14-membered monovalent substituent.
  • it represents [A4], [A5], [A6], [H1], [H2], etc., which belong to the above-mentioned substituent group 2.
  • R' represents an arbitrary substituent attached to the ring A, for example, a substituent belonging to the substituent group 1 or a substituent belonging to the substituent group 2 or the substituent group 3 which does not have a cyclic structure.
  • [A1] may be substituted C 1-6 (or C 1-4 or C 1-2 ) alkyl group" belonging to the substituent group 2 (that is, [A6], [A6] of the substituent group 2 As a further substituent that H1], [H2] and the like may have, the above-mentioned ones) can be mentioned.
  • n is the number of substituents that ring A has, i.e. n is 0 if ring A is unsubstituted, and any integer greater than or equal to 1 if ring A is substituted (preferably 1, 2 or 3). Represents.
  • the binding site for R'in ring A is arbitrary.
  • the more preferred R (more preferred ring A) in the present invention is an aromatic or non-aromatic 5- to 10-membered ring, which may be unsubstituted or substituted, monocyclic or polycyclic, and the like.
  • a monovalent substituent on a 5- or 6-membered ring such as a phenyl group, a pyridyl group (eg, 2-pyridyl group), a thienyl group (eg, 2-thienyl group), a cyclohexenyl group (eg, which may be substituted).
  • 1-Cyclohexenyl group), cyclopentenyl group for example, 1-cyclopentenyl group
  • Such preferable formulas (1) and (2) in the present invention can also be expressed as the following formulas (3) to (7).
  • R'and n in equations (3) to (7) are synonymous with those in equation (2).
  • R a , R b , R c , R d , R e , R f , R g , R h and R i in the formula (1) may be hydrogen atoms (unsubstituted), or at least.
  • One may be a substituent.
  • R a , R b , R c and R d may all be hydrogen atoms (unsubstituted), or at least one may be a substituent.
  • Both Re and R f may be hydrogen atoms (unsubstituted), or at least one may be a substituent.
  • R g , R h and R i may all be hydrogen atoms (unsubstituted), or at least one may be a substituent.
  • the provisions of (i), (ii) and (iii) above can be arbitrarily combined.
  • Re and R f of the above (ii) and R g , R h and Ri of the above ( iii ) are all hydrogen atoms (unsubstituted), and the above ( i ).
  • R a , R b , R c and R d may all be hydrogen atoms (unsubstituted) or at least one may be a substituent.
  • R a , R b , R c , R d , R e , R f , R g , R h or R i substituents
  • specific examples of the respective substituents include the above-mentioned Substituent Group 1, Substituent. Examples thereof include substituents belonging to the group 2 or the substituent group 3.
  • the respective substituents are a group of substituents. Substituents belonging to Substituent Group 1 and Substituents belonging to Substituent Group 2 or Substituent Group 3 that do not have a cyclic structure are preferable.
  • R a , R b , R c , R d , Re e , R f , R g , R h and R i are all hydrogen atoms (unsubstituted).
  • the formulas (1) to (7) can also be expressed as the following formulas (1A) to (7A).
  • Re , R f , R g , R h and Ri are all hydrogen atoms (unsubstituted).
  • the formulas (1) to (7) can also be expressed as the following formulas (1B) to (7B).
  • R a , R b , R c and R d may be independent hydrogen atoms (unsubstituted) or substituents.
  • all of R a , R b , R c and R d are hydrogen atoms, it has the same meaning as the above formulas (1A) to (7A).
  • R a , R b , R c and R d are a substituent, for example, R a and R b are hydrogen atoms (unsubstituted) and one or both of R c and R d are substituents.
  • R a and R b are hydrogen atoms (unsubstituted) and one or both of R c and R d are substituents.
  • the compound of the present invention is a compound represented by the following formula (1'), that is, a compound (1').
  • the compound (1') is a compound represented by the above formula (1), that is, the compound (1) is a cis-trans isomer (E-form-Z-form) in the double bond specified in the formula.
  • E-form-Z-form a cis-trans isomer
  • trans form a compound represented by the following formula (1')
  • the description of compound (1) and similar trans-forms that is, compounds (2) to (7), formulas (1A) to (7A) and formulas (1B) to (7B)), for example, in the formula.
  • the definition of the substituent of the above is defined as that of the compound (1') and a similar cis compound (that is, the trans compounds (2) to (7), formulas (1A) to (7A) and formulas (1B) to (. 7B)
  • the cis compound corresponding to each, for example, the compound represented by the following formula (1'A)) can also be applied.
  • the description regarding the embodiment, action and effect, etc. of the "compound (etc.)" of the present invention in the present specification refers not only to a trans form such as compound (1) but also to a cis form such as compound (1'). Can also be applied.
  • the compound of the present invention may be in the form of a salt. Further, the compound of the present invention and a salt thereof may be in the form of a solvate.
  • a “salt" (basic salt or acidic salt) of the compound of the present invention can be obtained by reacting with a base or an acid, respectively.
  • a salt of a compound of the invention is used as an active ingredient in a pharmaceutical (in the preparation of a pharmaceutical composition), a pharmaceutically acceptable salt is appropriate.
  • Examples of the "basic salt” include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as magnesium salt and calcium salt; N-methylmorpholin salt, triethylamine salt and tributylamine.
  • Organic basic salts such as salts, diisopropylethylamine salts, dicyclohexylamine salts, N-methylpiperidin salts, pyridine salts, 4-pyrrolidinohilysin salts, picolin salts; glycine salts, lysine salts, arginine salts, ornithine salts, glutamates.
  • Amino acid salts such as asparagitate.
  • Acid salts include, for example, hydrohalogenates such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrates, perchlorates, sulfates, phosphates.
  • Inorganic acid salts such as salts; alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate; aryl sulfonates such as benzene sulfonate, p-toluene sulfonate;
  • Organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate; chrysin, lysine, arginine, ornithine. Examples include amino acid salts such as salts, glutamates and asparagitates.
  • solvate By coordinating a molecule of a solvent to the compound of the present invention or a salt thereof (for example, by crystallization after mixing with a solvent), a “solvate” of the compound of the present invention or a salt thereof can be obtained.
  • the “solvate” include hydrates, ethanol solvates, and dimethyl sulfoxide solvates.
  • the compound of the present invention (new stiripentol derivative) can be prepared by a person skilled in the art (for example, Tokyo Chemical Industry Co., Ltd. described in Examples) using a well-known conventional or known means (reaction method, reaction, condition, process, apparatus, etc.). It can be synthesized by a person skilled in the art, or can be obtained by contract synthesis with a person skilled in the art.
  • the salt of the compound of the present invention and the solvate of the compound of the present invention and the salt thereof can also be obtained by a well-known conventional method or a known means.
  • the disclosure of Examples described later can be referred to, and the compound as a raw material is changed or the reaction conditions are adjusted according to the target compound. It is possible to do it.
  • the outline of the synthesis scheme is as follows: (i) Organic halogen compounds such as 4-halogenated acetophenone or derivatives thereof (such as those having Ra to R d corresponding to the target compound) and organic boron compounds.
  • RB (OH) 2 R corresponds to the formula (1), etc.
  • a palladium catalyst Sudzuki-Miyaura cross-coupling reaction
  • the synthesized compound of the present invention and the like can be isolated and purified by a well-known conventional or known means such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like. Further, the chemical structure of the compound or the like of the present invention is identified by using general instruments and analytical methods such as 1H-NMR, 13C-NMR, HPLC, and a high-resolution liquid chromatograph mass spectrometer (LC-MS / MS). can do.
  • general instruments and analytical methods such as 1H-NMR, 13C-NMR, HPLC, and a high-resolution liquid chromatograph mass spectrometer (LC-MS / MS).
  • LDH lactate dehydrogenase
  • the lactate dehydrogenase (LDH) inhibitor of the present invention comprises the compound, salt or solvate of the present invention (compound of the present invention, etc.).
  • the compound of the present invention or the like used under conditions (particularly in an amount) in which LDH inhibitory activity is observed in vitro or in vivo can be referred to as the LDH inhibitor of the present invention.
  • Lactate dehydrogenase is a protein with a molecular weight of about 140 kD that catalyzes the interconversion of lactic acid (L-lactic acid in vivo) and pyruvate (at that time, the interconversion of NADH and NAD also occurs at the same time).
  • LDH is a tetramer consisting of two types of subunits, LDHA (M) and LDHB (H), and LDH1 (4 LDHB) and LDH2 (3 LDHB and 1) depending on the binding mode of these subunits.
  • LDH5 converts pyruvate to L-lactic acid in astrocytes (stellar cells), while the conversion of L-lactic acid to pyruvate taken up by neurons (nerve cells) is LDH1. It is done by. Further, in cancer cells, energy is produced by conversion of pyruvic acid to lactic acid even if it is not in a hypoxic state, and therefore the expression of LDH5 is remarkably enhanced.
  • the LDH inhibitor of the present invention can be targeted at any of the above isozymes.
  • the LDH inhibitor of the present invention may have inhibitory activity against at least one of the above isozymes, for example, it may have inhibitory activity against at least one of LDH1 and LDH5, preferably both. can.
  • the LDH inhibitor of the present invention can target LDH derived from humans, and other animals having LDH, such as mice, rats, guinea pigs, rabbits, goats, cats, dogs, pigs, and monkeys, other than humans. LDH derived from mammals can also be targeted. Therefore, the drug of the present invention containing the LDH inhibitor of the present invention (compound of the present invention, etc.) as an active ingredient can be targeted at humans or animals other than humans.
  • the medicine of the present invention contains the compound of the present invention or the LDH inhibitor of the present invention as an active ingredient.
  • pharmaceutical includes both those approved in accordance with the laws and regulations of each country (pharmaceutical products) and those used in clinical trials before approval.
  • pharmaceutical refers to those having a therapeutic or (recurrence) preventive effect (collectively referred to as “medicinal effect” in the present specification) for a predetermined disease, and the medicinal effect thereof. Presence or absence can be determined by appropriate criteria according to the disease and purpose.
  • the medicine of the present invention has an effect of treating, improving, alleviating, preventing, etc. on a disease in which the LDH inhibitory activity of the compound of the present invention exerts a medicinal effect, that is, by inhibiting LDH on the symptom or lesion tissue of the disease.
  • the drug of the present invention is not limited to these, and other diseases having the above-mentioned mechanism of action, such as calcium oxalate stone disease and neuropathic pain for which a medicinal effect due to stiripentol has been reported, are included. It is also possible to target various diseases.
  • the "epilepsy” targeted by the drug of the present invention is not particularly limited.
  • the drug of the present invention is an intractable epilepsy for which no effective existing drug has been found, such as adult intractable epilepsy (medial temporal lobe epilepsy associated with hippocampal sclerosis) for which stiripentol is not effective. It is preferable to target.
  • the "cancer” targeted by the drug of the present invention is not particularly limited, and is, for example, malignant lymphoma (hodgkin lymphoma, non-hodgkin lymphoma, etc.), gastric cancer, penis cancer, pharyngeal cancer (nasopharyngeal cancer, etc.).
  • the method and amount of the drug of the present invention are not particularly limited, and are in vitro or. Appropriate usage and dosage can be set to achieve the desired therapeutic effect through in vivo studies and also in consideration of the patient's age, gender, weight, pathology, concomitant medications, etc. ..
  • the pharmaceutical product 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 pharmaceutically acceptable additive.
  • the pharmaceutical composition of the present invention is used for oral administration, for example, tablets, capsules, granules, powders, dry syrups, liquids (including syrups, external liquids, etc.), suppositories, ointments, creams, eye drops, etc. It can be prepared as a nasal drop, a patch, or the like, or it can be prepared for parenteral administration, for example, as an injection.
  • Appropriate additives can be selected depending on the dosage form, and examples thereof include excipients, bulking agents, diluents (solvents for injection, etc.), stabilizers, and preservatives.
  • Pharmaceutical compositions can be prepared in appropriate amounts of active ingredients and additives, depending on the dosage form, according to methods commonly used in the art.
  • Compounds No. 1 to No. 10 in the following examples represent the compounds shown in the table below, respectively.
  • 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. All of Compounds No. 1 to No. 10 were obtained by commissioning Tokyo Chemical Industry Co., Ltd. for the purity and shape shown in the table below. Among the new compounds, the methods for synthesizing compounds No. 4 to No. 8 and No. 10 as typical examples are shown below. The yields shown in these synthetic methods are all isolated yields.
  • the reaction solution was cooled to room temperature, 2 N hydrochloric acid (10 mL) was added, the mixture was stirred for 10 minutes, the solid was filtered off (filtration 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 brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained 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%) was obtained as a pale pink solid.
  • reaction solution was cooled to room temperature, 2 N hydrochloric acid (75 mL) was added, the mixture was stirred for 30 minutes, the solid was filtered off (filtration 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 brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained residue is dissolved in dichloromethane, filtered (filtration aid: silica gel), the solution washed with dichloromethane is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography (silica gel, hexane / methylene chloride). Purification gave the first intermediate compound c10 (11.48 g, 49.4 mmol, yield 93%) as a pink solid.
  • Lactate dehydrogenase produces lactate and NAD from pyruvate and NADH. That is, if the lactate dehydrogenase activity is high, NADH decreases, and if the enzyme activity is inhibited, NADH does not decrease. Therefore, in order to evaluate the enzymatic activity of lactate dehydrogenase, an experiment was conducted using an evaluation system (Patent Document 1, Non-Patent Document 9) consisting of an enzymatic reaction (step 1) and a color development reaction (step 2).
  • step 1 sodium pyruvate (100 ⁇ M), NADH (100 ⁇ M), lactate dehydrogenase (human LDH1 or LDH5) are added, and an inhibitor of each concentration (Compound No. 1-10) is added.
  • the reaction was carried out under 100 mM sodium phosphate buffer (pH 7.3, 37 ° C.) for 60 minutes (200 ⁇ L / well).
  • the background absorbance at 492 nm was first measured with a plate reader (absorbance before the color reaction).
  • step 2 in order to measure the amount of NADH remaining in the enzymatic reaction of step 1, 100 ⁇ L / well of a color-developing solution in which diaphorase (25 U / mL) and INT (5 mM) were dissolved was added. It was allowed to react for 10 minutes. INT was changed to INT formazan by diaphorase in the presence of NADH, and the absorbance at 492 nm was measured with a plate reader (absorbance after color reaction). In other words, if lactate dehydrogenase is inhibited, NADH remains, indicating absorption at 492 nm.
  • the value obtained by subtracting the absorbance before the color development reaction from the absorbance after the color development reaction was calculated as the "absorbance change value ( ⁇ A)". Furthermore, the absorbance when the above reaction was carried out in the absence of an inhibitor was "0% control value”, and the above reaction was carried out in the absence of lactate dehydrogenase (LDH1, LDH5) in the absence of an inhibitor. Absorbance was calculated as "100% control value", and the inhibition rate (%) in Fig. 1-5 was 100 x ( ⁇ A-0% control value in the presence of inhibitor) / (100% control value-0% control value). Calculated as. Based on this equation, 100% is shown if lactate dehydrogenase is completely inhibited, and 0% if it is not.
  • mice Compound No. 1, 2, 4, 9, Fig. 6-10: In the pharmacokinetic test, 6-7 week old ICR mice were used in the experiment. Since compounds No. 1, No. 2, No. 4, and No. 9 are all highly lipophilic, 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 sonde, and blood was obtained by decapitation after 30 min. Heparin sodium (10 ⁇ g / mL) was added to blood as an anticoagulant and centrifuged (1000 g, 4 ° C) for 15 min, and the supernatant was obtained as plasma.
  • Each compound was detected at 295 nm using a UV detector, and data was acquired and analyzed using software ChromNAV (JASCO Corporation).
  • the compound itself was directly analyzed by HPLC as a standard substance, and its retention times were compared.
  • an LC-MS / MS system (Agilent 1200 HPLC-Chip and 6520 Accurate-Mass Q-TOF) manufactured by Agilent Technologies was used.
  • the pretreated sample is adsorbed on a C18 chip using a mobile phase consisting of 25% acetonitrile containing 0.1% formic acid and 75% water, and then a mobile phase consisting of 60% acetonitrile containing 0.1% formic acid and 40% water.
  • Plasma components were separated using.
  • the MS spectrum of the separated plasma component was detected using a mass spectrometer, and the data was acquired and analyzed using the software MassHunter Qualitative Analysis (Agilent Technologies).
  • Hippocampal sclerosis model mice used for antiepileptic effect evaluation were prepared according to past documents (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 localization device. Next, the scalp was removed, and a U-shaped plastic frame necessary for in vivo EEG measurement was attached to the head.
  • kainic acid 0.8 nmol, 40 nL
  • a metal electrode (diameter 200 ⁇ m) for measuring epileptic EEG was embedded near the kainic acid injection site.
  • the reference electrode was placed in the cerebellum.
  • the mouse head was fixed via a U-shaped frame, the hippocampus brain waves were recorded via an analog filter of 0.5-30 Hz, and digitized at a sampling rate of 1 kHz by an AD converter.
  • vehicle or compound No. 2 was orally administered using a disposable sonde, and recorded for another 3 hours.
  • Epileptic seizure waves were analyzed using Igor Pro (WaveMetrics), and epileptic seizure waves lasting 8 seconds or longer were counted.
  • Statistical processing was performed using SigmaPlot (Systat Software).
  • Lactate dehydrogenase inhibitory activity of the novel stiripentol derivative was investigated and compared with the stiripentol derivative (Compound No. 1) of the previous invention (Patent Document 1) (FIG. 1).
  • Lactate dehydrogenase is a tetrameric metabolic enzyme consisting of two subunits (LDHA, LDHB). Therefore, the inhibitory activity of the stiripentol derivative was investigated for the LDHA tetramer (LDH5) and the LDHB tetramer (LDH1).
  • LDH5 LDHA tetramer
  • LH1 LDHB tetramer
  • Patent Document 1 This is almost in agreement with the result of the previous invention (Patent Document 1).
  • Compound No. 2 represented by this formula (3A-1) is a novel compound, and its lactate dehydrogenase inhibitory action and usefulness as a pharmaceutical (active ingredient) have not been reported so far.
  • the compound represented by the formula (1A) has not been reported not only in the compound No. 2 in which R is a phenyl group, but also in the compound in which R is any substituent. Therefore, in order to verify whether the compound represented by the formula (1A) other than the compound No. 2 and the compound represented by the formula (1B) into which a substituent is further introduced also have a lactate dehydrogenase inhibitory action.

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CN118045081A (zh) * 2024-02-05 2024-05-17 中山大学孙逸仙纪念医院 司替戊醇在制备抗肿瘤药物中的应用
WO2025229111A1 (en) 2024-05-01 2025-11-06 Basf Se Pyrimidinone derivatives as pesticidal compounds
WO2026037853A1 (en) 2024-08-14 2026-02-19 Basf Se Benzoxazole derivatives as pesticidal compounds
WO2026041702A1 (en) 2024-08-21 2026-02-26 Basf Se Benzoxazole derivatives as pesticidal compounds

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116930368A (zh) * 2023-07-27 2023-10-24 石家庄四药有限公司 一种司替戊醇异构体的检测方法
CN116930368B (zh) * 2023-07-27 2024-03-29 石家庄四药有限公司 一种司替戊醇异构体的检测方法
CN118045081A (zh) * 2024-02-05 2024-05-17 中山大学孙逸仙纪念医院 司替戊醇在制备抗肿瘤药物中的应用
WO2025229111A1 (en) 2024-05-01 2025-11-06 Basf Se Pyrimidinone derivatives as pesticidal compounds
WO2026037853A1 (en) 2024-08-14 2026-02-19 Basf Se Benzoxazole derivatives as pesticidal compounds
WO2026041702A1 (en) 2024-08-21 2026-02-26 Basf Se Benzoxazole derivatives as pesticidal compounds

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