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WO2020059660A1 - Composé ayant une puissance d'activation d'enac - Google Patents

Composé ayant une puissance d'activation d'enac Download PDF

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Publication number
WO2020059660A1
WO2020059660A1 PCT/JP2019/036105 JP2019036105W WO2020059660A1 WO 2020059660 A1 WO2020059660 A1 WO 2020059660A1 JP 2019036105 W JP2019036105 W JP 2019036105W WO 2020059660 A1 WO2020059660 A1 WO 2020059660A1
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WIPO (PCT)
Prior art keywords
henac
αβγ
compound
amino
ethylbenzo
Prior art date
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Ceased
Application number
PCT/JP2019/036105
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English (en)
Japanese (ja)
Inventor
洋一 笠原
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Nissin Foods Holdings Co Ltd
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Nissin Foods Holdings Co Ltd
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Publication date
Priority claimed from JP2019165439A external-priority patent/JP7330828B2/ja
Application filed by Nissin Foods Holdings Co Ltd filed Critical Nissin Foods Holdings Co Ltd
Publication of WO2020059660A1 publication Critical patent/WO2020059660A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an activator of epithelial Na + channel hENaC ⁇ , a therapeutic agent for diseases and the like containing the same, and a salty taste enhancer.
  • Epithelial sodium channel ENaC is a non-voltage-dependent Na ion channel belonging to the ENaC / degenerin family (Non-Patent Document 1).
  • ENaC ⁇ is mainly expressed in the stomach, kidney and colon, and ENaC ⁇ is mainly expressed in nervous tissues such as cerebral cortex, cerebellum, hippocampus and testis (Non-patent Documents 2-4). In the tongue, ENaC ⁇ is expressed in the anterior part where the chorda tympani nerve projects, and is involved in low-concentration salty taste reception ( ⁇ 150 mM NaCl) (Non-Patent Document 5). Further, as one of the grounds for exhibiting the salty taste enhancing effect and the salty taste inhibiting effect, the phenomenon of activating or inhibiting humanENaC (hENaC) ⁇ is widely used (prior patent documents 1-5).
  • Non-Patent Documents 6, 7 Non-Patent Documents 6, 7
  • activators that activate hENaC ⁇ can be considered for the treatment of pseudoaldosteronism type 1 and neonatal respiratory distress syndrome.
  • Compound S3969 is known as a hENaCh ⁇ activator (activator), and is expected as a therapeutic agent for the above-mentioned diseases (Non-Patent Document 6).
  • the indole ring is considered to be one partial structure that activates hENaC, but there is no report on a partial structure capable of activating hENaC except for the indole ring.
  • hENaC ⁇ activators not only alleviate the genetic diseases associated with hENaC ⁇ , but also It is expected to modify salty taste reception and greatly improve taste.
  • the object of the present invention was to find a compound having an excellent hENaC ⁇ activating action.
  • Another object of the present invention is to provide a therapeutic agent for a disease or the like in the pharmaceutical field containing the compound and a salty taste enhancer in the food field.
  • the present inventors have conducted intensive studies and have found that 3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N-ethylbenzo [ ⁇ ] thiophene. It has been found that a compound having the same or similar structure as -2-carboxamide or a salt thereof has an activity of activating hENaC.
  • the first invention of the present application is: “3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N-ethylbenzo [ ⁇ ] thiophene represented by the following formula (1)
  • Activator of hENaC ⁇ comprising a compound having the same or similar structure as -2-carboxamide or a salt thereof as an active ingredient
  • the compound is a component derived from a food or a natural extract. That is, the second invention of the present application is: The hENaC ⁇ activator according to claim 1, wherein the compound is a component derived from a food or a natural extract.
  • the compound of the present application or a salt thereof can also be used as a therapeutic drug for diseases and the like. That is, the third invention of the present application: “A therapeutic agent for a disease or the like containing the hENaC ⁇ activator according to claim 1 or 2”. It is.
  • the compound of the present invention or a salt thereof can also be used as a salty taste enhancer. That is, the fourth invention of the present application “A salty taste enhancer containing the hENaC ⁇ activator according to claim 1 or 2”.
  • an activator of hENaC ⁇ is provided. Further, the 3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N-ethylbenzo [ ⁇ ] thiophen-2-carboxamide of the present invention
  • a therapeutic agent for a genetic disease caused by hENaC ⁇ is provided by containing an activator containing a compound having the same or similar structure as described above or a salt thereof as an active ingredient. Further, a salty taste enhancer is provided by activating hENaC ⁇ which is also a salty taste receptor.
  • FIG. 4 is a schematic view illustrating a method of Example 1 and Example 2. This is the result of Example 2, and using 3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N- using a membrane potential sensitive dye.
  • 3 shows hENaC ⁇ activity by ethylbenzo [ ⁇ ] thiophene-2-carboxamide and compounds (three kinds) having structures similar thereto. This is the result of Example 2, and using 3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N- using a membrane potential sensitive dye. 3 shows hENaC ⁇ activity by compounds (three kinds) having a structure similar to ethylbenzo [ ⁇ ] thiophene-2-carboxamide.
  • hENaC ⁇ refers to a human gene human ENaC ⁇ (or SCNN1a), human ENaC ⁇ (or SCNN1b), which is encoded by human ENaC ⁇ (or SCNN1g), forms ⁇ trimers on a biological membrane, Refers to a membrane protein that exhibits the properties of a sodium channel.
  • the activator is a compound that has an effect on the opening structure of the pores of the trimeric membrane protein composed of hENaC ⁇ and has the property of increasing the inflow efficiency of mainly sodium ions flowing through hENaC.
  • the 3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N-ethylbenzo [ ⁇ ] thiophen-2-carboxamide is as follows: Having a structure.
  • the compound has a benzothiophenone ring.
  • the present inventors have found that as a result of screening a large number of compounds, the present compounds have the ability to activate hENaC ⁇ . Furthermore, a compound having a structure similar to the compound was searched, and a plurality of compounds having the ability to activate hENaC ⁇ were found. The invention further contemplates salts of these compounds.
  • a compound having a similar structure to 2-carboxyamide indicates a compound showing a similarity of 60% or more in a similar search using ChemBioFinder Ultra 12.0 (manufactured by CambridgeSoft).
  • ChemBioFinder Ultra 12.0 a database management software for chemical structure information, can be used.
  • a compound library to be searched a compound library owned by a university, various research institutions, or the like can be used.
  • ChemBioFinder it is possible to combine structural key features such as Unity 2D Fingerprint, Similog key, and MaCCS key, and to convert the structural information of a compound into a descriptor using a modified unique structural key.
  • a Tanimoto similarity determination method having commutability was used (Non-Patent Document 8).
  • Q (query) and T (target) are expressed by the following formulas using Tanimoto coefficients:
  • Q (query) and T (target) shown here are respectively 3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N -Ethylbenzo [ ⁇ ] thiophen-2-carboxamide and 3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N-ethylbenzo [ ⁇ ]
  • Descriptors of compounds having a structure similar to thiophene-2-carboxamide are shown.
  • Components derived from foods and natural extracts Compound (3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2) capable of activating hENaC ⁇ of the present invention -Oxoethyl) -N-ethylbenzo [ ⁇ ] thiophene-2-carboxamide) can be obtained as an ingredient derived from foods and natural products.
  • the activator of hENaC ⁇ of the present invention can be used as a therapeutic agent for diseases and the like.
  • pseudohypoaldosteronism type I a disease in which re-absorption of sodium ions in the kidney is impaired, and in the lung, diseases such as pulmonary edema and neonatal respiratory syndrome caused by increasing intracellular sodium ions. It can be used (Non-Patent Document 7).
  • Salty taste enhancer The hENaC ⁇ activator of the present invention can be used as a salty taste enhancer. That is, the salty taste enhancer means to exert an action of strongly feeling the salty taste of salt.
  • the salty taste enhancer can be widely used for foods and drinks.
  • the salty taste enhancer of the present invention may be provided in the form of the above compound alone, or may be provided in the form of a solid composition or a liquid composition. When provided as a composition, additives that can be used in the production of foods and beverages, such as excipients, pigments, and flavors, may be contained as needed, as long as the salty taste enhancing effect is not hindered.
  • Example 1 3-Chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N-ethylbenzo [ ⁇ ] thiophene Using Cultured Cells Results of hENaC ⁇ activity by 2-carboxyamide.
  • Plasmid and expression protein experimental methods were performed according to JP-A-2017-217005. That is, in order to express human human ENaC ⁇ (hENaC ⁇ ) in HEK293T cells, a plasmid vector pEAK10 (EdgeBiosystem) having an EF1 ⁇ promoter was used.
  • Table 1 shows the accession numbers indicating the gene sequences of hENaC ⁇ and the inserted restriction enzyme sites.
  • Lipofectamine LTX Reagent with PLUS & Reagent was used as a gene transfer reagent.
  • the transfected cells are seeded on a 96-well plate (black wall, CellBIND surface; CORNING), and in a CO 2 incubator (37 ° C., 5% CO 2 ) for 24 to 72 hours, 10 ⁇ M amiloride (SIGMA) and 10% FBS (GIBCO) Were cultured in DMEM (Dulbecco's modified Eagle's medium SIGMA) containing
  • Cell-based assay using FlexStation 3 FlexStation 3 is a plate reader with a dispensing function. Using this, a ligand solution was administered to cells loaded with a membrane potential-sensitive dye, and the change over time in the fluorescence intensity was measured. The culture medium of the cells seeded in the 96-well plate was washed and replaced with an assay buffer solution before measurement.
  • composition of the assay buffer solution is 130 mM NaCl, 10 mM D glucose, 10 mM HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid), 5 mM KCl, 2 mM CaCl 2 , 1.2 mM MgCl 2 , The pH was adjusted to 7.4 using NaOH.
  • the assay was performed at 27 ° C., and the fluorescence (560 nm) of Membrane Potential Assay Kit blue (R8042 Molecular Devices) when excited at 530 nm was measured once every 2 seconds. Twenty seconds after the start of the measurement, a ligand solution prepared to a concentration twice as much as the buffer used for washing was administered to the cells, and a change in fluorescence intensity over time was measured for 120 seconds. The measurement results could be more stabilized by adding 2.5 mM probenecid to Membrane potential assay kit blue.
  • FIG. 2 shows a schematic diagram of the measurement results and a method of evaluating the activation ability. From the time course of fluorescence obtained by FlexStation 3, the value of the fluorescence intensity due to the effect of ligand addition at 100 seconds after administration of the ligand solution and the fluorescence intensity of the vehicle (assay buffer solution adjusted for ligand) at 100 seconds The value of delta relative fluorescence units ( ⁇ RFU) was calculated from the difference, and this was defined as the response value of the cell.
  • ⁇ RFU delta relative fluorescence units
  • Delta relative fluorescence units which is the difference between the fluorescence intensity value due to the effect of addition of -N-ethylbenzo [ ⁇ ] thiophene-2-carboxamide and the fluorescence intensity at 100 seconds with the vehicle (assay buffer solution in which the ligand was adjusted).
  • the large ( ⁇ RFU) value was obtained in a concentration-dependent manner, indicating that hENaC ⁇ has the activating ability.
  • the EC 50 of 3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N-ethylbenzo [ ⁇ ] thiophen-2-carboxamide is , 95.0 ⁇ 21.0 ⁇ M, and the maximum effect concentration (E max ) was 928 ⁇ 67.8 in ⁇ RFU value.
  • FIG. 1 shows the concentration of 3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N-ethylbenzo [ ⁇ ] thiophen-2-carboxamide. The response curve is shown.
  • ChemBioFinder ⁇ Ultra ⁇ 12.0 ⁇ a database management software for chemical structure information.
  • a compound library to be searched a compound library owned by the University of Tokyo Drug Discovery Organization was used. Definition of analogous compounds of 3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N-ethylbenzo [ ⁇ ] thiophen-2-carboxamide The method is described below.
  • Non-Patent Document 8 a Tanimoto similarity determination method having commutability was used.
  • Q (query) and T (target) are expressed by the following formulas using Tanimoto coefficients:
  • Q (query) and T (target) shown here are respectively 3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N -Ethylbenzo [ ⁇ ] thiophen-2-carboxamide and 3-chloro-N- (2-((1,1-dioxidetetrahydrothiophen-3-yl) amino) -2-oxoethyl) -N-ethylbenzo [ ⁇ ]
  • Descriptors of compounds having a structure similar to thiophene-2-carboxamide are shown.
  • FIG. 2 shows a schematic diagram of the evaluation method. This evaluation method is the same method as described in JP-A-2017-217005.

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Abstract

La présente invention traite le problème de la fourniture d'un nouvel agent d'activation de hENaC αβγ. La solution selon l'invention porte sur un agent d'activation de hENaC αβγ comprenant, en tant que composant efficace, un composé ou un sel de celui-ci ayant une structure identique ou similaire au 3-chloro-N-(2-((1,1-dioxydetétrahydrothiophéne-3-yl)amino)-2-oxoéthyl)-N-éthylbenzo[β]thiophène-2-carboxyamide, qui est représenté par la formule (1). L'utilisation de cet agent d'activation de hENaC αβγ participe au développement ultérieur de médicaments, à l'industrie alimentaire et aux sciences de la santé.
PCT/JP2019/036105 2018-09-20 2019-09-13 Composé ayant une puissance d'activation d'enac Ceased WO2020059660A1 (fr)

Applications Claiming Priority (4)

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JP2018176045 2018-09-20
JP2018-176045 2018-09-20
JP2019-165439 2019-09-11
JP2019165439A JP7330828B2 (ja) 2018-09-20 2019-09-11 ＥＮａＣ活性化能を有する化合物

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112898286A (zh) * 2021-01-28 2021-06-04 中国药科大学 苯并噻吩类化合物或其可药用的盐、异构体及其制备方法、药物组合物和用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07179430A (ja) * 1993-07-29 1995-07-18 American Cyanamid Co 三環式ベンズアゼピン・バソプレツシン拮抗薬
WO2009106980A2 (fr) * 2008-02-29 2009-09-03 Pfizer Inc. Dérivés d'indazole
JP2010523579A (ja) * 2007-04-02 2010-07-15 インスティテュート フォア ワンワールド ヘルス Ｃｆｔｒ阻害剤化合物およびそれらの使用
JP2014503473A (ja) * 2010-10-19 2014-02-13 エルセリクス セラピューティクス インコーポレイテッド 化学感覚受容体リガンドに基づく治療法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07179430A (ja) * 1993-07-29 1995-07-18 American Cyanamid Co 三環式ベンズアゼピン・バソプレツシン拮抗薬
JP2010523579A (ja) * 2007-04-02 2010-07-15 インスティテュート フォア ワンワールド ヘルス Ｃｆｔｒ阻害剤化合物およびそれらの使用
WO2009106980A2 (fr) * 2008-02-29 2009-09-03 Pfizer Inc. Dérivés d'indazole
JP2014503473A (ja) * 2010-10-19 2014-02-13 エルセリクス セラピューティクス インコーポレイテッド 化学感覚受容体リガンドに基づく治療法

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Screening of human ENaC activating agent by using chemical library", HUMAN ENAC, vol. 2019, 5 March 2019 (2019-03-05) *
CARPINO, L A ET AL.: "The 1,1-Dioxobenzo[b]thiophene-2-ylmethyloxycarbonyl (Bsmoc) amino-protecting group", JOURNAL OF ORGANIC CHEMISTRY, vol. 64, no. 12, 1999, pages 4324 - 4338, XP002203970, DOI: 10.1021/jo982140l *
DATABASE CHEMCATS REGISTRY [online] 11 January 2006 (2006-01-11), "CN : Cyclobutanecarboxamide, 1-(4-chlorophenyl)-N-ethyl-N- [2-oxo-2-[(tetrahydro-1, l-dioxido-3-thienyl)amino]ethyl]- ( CA INDEX NAME) SR: Chemical Library, Supplier: Enamine", retrieved from STN Database accession no. 871666-13-6 *
DATABASE CHEMCATS REGISTRY [online] 17 January 2006 (2006-01-17), "CN : Benzo[b]thiophene-2-carboxamide,3-chloro-N-ethyl-N- [2-oxo-2-[(tetrahydro-1, 1-dioxido-3-thienyl)amino]ethyl]- ( CA INDEX NAME) SR: Chemical Library, Supplier: Enamine", retrieved from STN Database accession no. 872024-60-7 *
DATABASE CHEMCATS REGISTRY [online] 22 August 2008 (2008-08-22), "CN : Benzo[b]thiophene-2-carboxamide, 3-chloro-N- [2-[(1,1-dimethylethyl)amino]-2-oxoethyl]-N-ethyl- ( CA INDEX NAME) SR: Chemical Library, Supplier: UkrOrgSynthesis", retrieved from STN Database accession no. 1042881-47-9 *
DATABASE CHEMCATS REGISTRY [online] 24 March 2006 (2006-03-24), "CN : Benzo[b]thiophene-2-carboxamide, N-ethyl-4-fluoro-N- [2-oxo-2-[(tetrahydro-1, 1-dioxido-3-thienyl)amino]ethyl]- ( CA INDEX NAME) SR: Chemical Library, Supplier: Enamine", retrieved from STN Database accession no. 877982-06-4 *
DATABASE CHEMCATS REGISTRY [online] 4 April 2006 (2006-04-04), "CN :Benzamide, N-ethyl-N-[2-oxo-2-[(tetrahydro-1, l-dioxido-3- thienyl)amino]ethyl]-2-(phenylmethyl)- ( CA INDEX NAME) SR: Chemical Library, Supplier: Enamine", retrieved from STN Database accession no. 879192-60-6 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112898286A (zh) * 2021-01-28 2021-06-04 中国药科大学 苯并噻吩类化合物或其可药用的盐、异构体及其制备方法、药物组合物和用途

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