WO2021166899A1 - Gastric protease inhibitor-containing drug for combination use with incretin mimetic - Google Patents

Gastric protease inhibitor-containing drug for combination use with incretin mimetic Download PDF

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WO2021166899A1
WO2021166899A1 PCT/JP2021/005680 JP2021005680W WO2021166899A1 WO 2021166899 A1 WO2021166899 A1 WO 2021166899A1 JP 2021005680 W JP2021005680 W JP 2021005680W WO 2021166899 A1 WO2021166899 A1 WO 2021166899A1
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group
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伊藤　幸治
智子 神田
哲男 川口
奈良　太
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宇部興産株式会社
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Definitions

  • the present invention relates to a drug containing a gastrointestinal protease inhibitor for use in combination with an incretin-like substance, and its use.
  • Gastrointestinal protease is a protease secreted in the tube through which food passes from the oral cavity to the anus, and is mainly responsible for digesting food. Food-derived proteins are degraded by gastrointestinal proteases and eventually become amino acids or peptides that are absorbed into the body. Its major protease is trypsin. Enteropeptidase is a serine protease that is secreted by duodenal mucosal cells and converts trypsinogen, which is secreted from the pancreas by diet, into trypsin.
  • trypsin acts on protease precursors such as chymotrypsinogen, procarboxypeptidase, proelastase, and procolipase to activate various enzymes. Therefore, a compound that inhibits enteropeptidase and / or trypsin is expected to have an action of suppressing protein decomposition and absorption, an action of suppressing lipid absorption, and an action of lowering the digestive ability of sugar, and obesity. It is considered to be useful as a therapeutic drug for illness and an antidiabetic drug.
  • Various compounds are known as enteropeptidase inhibitors and / or trypsin inhibitors (see, for example, Patent Documents 1 to 6).
  • Incretin is a general term for gastrointestinal hormones that mainly act on the ⁇ cells of the islets of Langerhans in the pancreas to promote insulin secretion.
  • GLP-1 glucagon-like peptide-1
  • GLP-1 receptor agonists are mainly used as therapeutic agents for diabetes because they lower blood glucose levels by promoting insulin secretion from pancreatic Langerhans islet ⁇ cells.
  • Various compounds are known as GLP-1 receptor agonists (see, for example, Patent Documents 7-8 and Non-Patent Document 1).
  • the present invention is a drug containing a gastrointestinal protease inhibitor for use in combination with an incretin-like substance having excellent preventive, alleviating, and / or therapeutic effects on diseases such as obesity and diabetes, and uses thereof.
  • the challenge is to provide.
  • the present inventors have found a drug containing a gastrointestinal protease inhibitor for use in combination with an incretin-like substance. We have found that it is useful for the prevention, alleviation, and / or treatment of diseases such as obesity and diabetes, and completed the present invention.
  • the present invention provides: [1] A drug containing a gastrointestinal protease inhibitor for use in combination with an incretin-like substance (hereinafter, also referred to as "this drug"). [2] The agent according to [1], wherein the gastrointestinal protease inhibitor is an enteropeptidase inhibitor and / or a trypsin inhibitor. [3] The agent according to [1], wherein the gastrointestinal protease inhibitor is an enteropeptidase inhibitor.
  • G 2 and G 3 are, 1 each independently selected hydrogen atom, or a 1-5 -COOR 3 phenyl group which may be substituted with groups and independently from the group consisting of -COOR 3 group ⁇ be five may be substituted with a substituent C 1 -C 6 alkyl group;
  • G 4 are hydrogen, C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy -C 1 -C 4 alkyl group;
  • R 3 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group;
  • L 1 and L 2 may be independently substituted with 1 to 5 —COOR 4 groups and may be substituted with 1 to 5 C 1 ⁇ C 6 alkyl groups C 1 ⁇ .
  • C 1 -C 6 alkylene group C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group
  • R 4 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group
  • Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and; m is an integer from 1 to 6; n is an integer from 2 to 12]
  • the agent according to any one of [2] to [4], which is a compound represented by (1) or a pharmaceutically acceptable salt thereof.
  • Enteropeptidase inhibitors are (2S, 13S) -3,12-bis (10-guanidine-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl ) -6,9-Dioxa-3,12-Diazatetradecane-1,2,13,14-Tetracarboxylic acid; (2S, 2'S) -2,2'-((oxybis (ethane-2,1-diyl))) Bis ((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandyl)) disuccinic acid; (2S, 16S) -3,15-bis (10-guanidine-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4]
  • the enteropeptidase inhibitor is (2S, 2'S) -2,2'-((oxybis (ethane-2,1-diyl)) bis ((10-guanidino-13-oxo-6,7,8,13-)
  • the GLP-1 receptor agonist is one or more GLP-1 receptor agonists selected from the group consisting of semaglutide, liraglutide, duraglutide, exenatide, lixisenatide, albiglutide, and efpeglenatide. ..
  • the GLP-1 receptor agonist is one or more GLP-1 receptor agonists selected from the group consisting of semaglutide, liraglutide, and duraglutide.
  • the agent according to [8], wherein the GLP-1 receptor agonist is semaglutide.
  • the GLP-1 receptor agonist is liraglutide.
  • This drug has excellent preventive, alleviating, and / or therapeutic effects on diseases such as obesity and diabetes.
  • diseases such as obesity and diabetes.
  • it exhibits a very strong weight-reducing effect equivalent to that of obesity surgery such as Roux-en-Y Gastric Bypass (RYGB) and obesity treatment devices such as end barrier.
  • RYGB Roux-en-Y Gastric Bypass
  • FIG. 1 is a graph showing body weight fluctuation (%) from the 0th day to the 21st day in Test Example 1.
  • FIG. 2 is a graph comparing the amount of FGF-21 in blood in Test Example 2.
  • FIG. 3 is a graph comparing the amount of insulin in blood in Test Example 2.
  • FIG. 4 is a graph comparing the amount of HbA1c in blood in Test Example 2.
  • FIG. 5 is a graph showing the body weight fluctuation (%) from the 0th day to the 21st day in Test Example 3.
  • FIG. 6 is a graph comparing the amount of FGF-21 in blood in Test Example 4.
  • FIG. 7 is a graph comparing the amount of insulin in blood in Test Example 4.
  • FIG. 8 is a graph comparing the amount of HbA1c in blood in Test Example 4.
  • FIG. 9 is a graph showing the body weight fluctuation (%) from the 0th day to the 21st day in Test Example 5.
  • the "drug” described in the present specification is used in combination with an incretin-like substance, and its form is not limited as long as it contains a gastrointestinal protease inhibitor.
  • the drug may be in the form of a mixture in which a gastrointestinal protease inhibitor and an incretin-like substance are formulated in one composition, or a drug containing a gastrointestinal protease inhibitor, which is separately formulated. It may be administered separately from the drug containing the incretin-like substance. If the gastrointestinal protease inhibitor and the incretin-like substance are formulated in separate compositions, they may be used in the form of a kit containing them.
  • gastrointestinal protease inhibitor described in the present specification is particularly limited as long as it is a substance having an activity of inhibiting a protease secreted from the gastrointestinal tract such as the oral cavity, esophagus, stomach, small intestine, and large intestine. is not it.
  • examples of the gastrointestinal protease inhibitor include enteropeptidase inhibitors and / or trypsin inhibitors, and enteropeptidase inhibitors are preferable.
  • enteropeptidase inhibitor and trypsin inhibitor are not particularly limited as long as they are substances having enterelopeptidase inhibitory activity and trypsin inhibitory activity, respectively.
  • enteropeptidase inhibitor and / or trypsin inhibitor include compound (I) or a pharmaceutically acceptable salt thereof, a compound of group A or a pharmaceutically acceptable salt thereof, and compound (II) or a pharmaceutically acceptable salt thereof.
  • acceptable salts preferably compound (I) or a pharmaceutically acceptable salt thereof.
  • the "incretin-like substance” described in the present specification includes incretins and substances having the same activity as incretins.
  • the incretin-like substance include a GLP-1 receptor agonist and a glucose-dependent insulinotropic polypeptide (GIP), and a GLP-1 receptor agonist is preferable.
  • GLP-1 receptor agonists include semaglutide, liraglutide, dulaglutide, exenatide, lixisenatide, lixisenatide, albiglutide, albiglutide, albiglutide, and albiglutide.
  • the "incretin-like substance” may have both an incretin-like action and a glucagon-like action, and the glucagon-like action may be a glucagon antagonistic action.
  • halogen atom described in the present specification means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • a fluorine atom and a chlorine atom are preferable.
  • the "C 1 -C 4 alkyl group” described herein means a straight or branched saturated hydrocarbon group having 1 to 4 carbon atoms.
  • the C 1 -C 4 alkyl group e.g., methyl group, ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, and a tert- butyl group and the like.
  • Methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl groups are preferred.
  • the "C 1 -C 6 alkyl group” described herein means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
  • the C 1 -C 6 alkyl group in addition to the radicals included within the "C 1 -C 4 alkyl group", for example, n- pentyl group, and isopentyl group, n- hexyl, and isohexyl group and the like .
  • Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, n-pentyl group, and n-hexyl group are preferable.
  • C 1- C 4 alkyl group and the "C 1- C 6 alkyl group” are, for example, a C 1- C 3 alkyl group (ie, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group). , preferably a methyl group, an ethyl group, and n- propyl group), and C 1 -C 2 alkyl group (i.e. methyl and ethyl, and the like, preferably a methyl group) or the like.
  • a C 1- C 3 alkyl group ie, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.
  • C 1 -C 2 alkyl group i.e. methyl and ethyl, and the like, preferably a methyl group
  • the "C 1 -C 4 alkylene group” described herein refers to a divalent group obtained by removing one arbitrary hydrogen atom of the above "C 1 -C 4 alkyl group”.
  • the C 1 -C 4 alkylene group include a methylene group, an ethylene group, methylmethylene group, trimethylene group, ethyl methylene group, dimethylmethylene group, and tetramethylene group and the like. Methylene groups, ethylene groups, methylmethylene groups, trimethylene groups, and tetramethylene groups are preferable.
  • the "C 1 -C 6 alkylene group” described herein refers to a divalent group obtained by removing one arbitrary hydrogen atom of the above "C 1 -C 6 alkyl group”.
  • the C 1 -C 6 alkylene group in addition to the radicals included within the "C 1 -C 4 alkylene group", for example, a pentamethylene group and a hexamethylene group and the like. Methylene groups, ethylene groups, methylmethylene groups, trimethylene groups, tetramethylene groups, pentamethylene groups, and hexamethylene groups are preferable. Further preferable forms of the "C 1- C 4 alkylene group” and the "C 1- C 6 alkylene group” include a C 1- C 2 alkylene group (that is, a methylene group and an ethylene group, preferably a methylene group) and the like. Be done.
  • -(CH 2 ) m- (C 6- C 12 allylene)-(CH 2 ) m- (m is an integer of 1 to 6) is preferably-(CH 2 ) m -biphenylene- (CH 2 ).
  • m- (m is an integer of 1 to 6), more preferably-(CH 2 ) m -([1,1'-biphenyl] -3,3'-diyl)-(CH 2 ) m- (m) Is an integer from 1 to 6).
  • the "phenylene group” described in the present specification means a divalent group obtained by removing an arbitrary hydrogen atom of a phenyl group.
  • the phenylene group include an o-phenylene group, an m-phenylene group, and a p-phenylene group.
  • the "biphenylene group” described in the present specification means a divalent group in which two phenylene groups are linked by a single bond.
  • Examples of the biphenylene group include [1,1'-biphenyl] -2,2'-diyl group, [1,1'-biphenyl] -3,3'-diyl group, and [1,1'-biphenyl]. -4,4'-diyl group and the like are mentioned, and [1,1'-biphenyl] -3,3'-diyl group is preferable.
  • aryl group means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 (C 6 to C 12 ) ring-constituting carbon atoms, for example, C 6 to C 11. ..
  • a monocyclic aryl group such as a phenyl group; a ring-constituting carbon number of 9 to 12 (C 9 to C 12 ) which may be partially saturated such as a naphthyl group, a tetrahydronaphthyl group, an indenyl group, and an indanyl group. of, for example, it includes a bicyclic aryl group having C 9 ⁇ C 11.
  • a phenyl group and a naphthyl group are preferable, and a phenyl group is more preferable.
  • Arylene group or "C 6 -C 12 arylene group” described herein, refers to a divalent group obtained by removing one arbitrary hydrogen atom of the above “aryl group.”
  • heteroaryl group is a 5- to 11-membered monocyclic or bicyclic fragrance containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms. It means a group heterocyclic group, for example, pyrrolyl group, furyl group, thienyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isooxazolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridadinyl group.
  • Examples thereof include an 8- to 11-membered bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a
  • heteroarylene group described in the present specification means a divalent group from which any one hydrogen atom of the above “heteroaryl group” has been removed.
  • the "C 1 -C 4 alkoxy group” described herein, refers to a monovalent group in which the C 1 -C 4 alkyl group is bonded to oxy group.
  • the C 1 -C 4 alkoxy group include a methoxy group, an ethoxy group, n- propoxy group, isopropoxy group, n- butoxy group, isobutoxy group, sec- butoxy group, and a tert- butoxy group. Methoxy group, ethoxy group, and n-propoxy group are preferable.
  • C 1 -C 4 alkoxy -C 1 -C 4 alkyl group described herein means a group wherein the C 1 -C 4 alkyl group is substituted by C 1 -C 4 alkoxy group.
  • Examples of the C 1- C 4 alkoxy-C 1- C 4 alkyl group include a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, an ethoxyethyl group, an n-propoxymethyl group, an isopropoxymethyl group, and an n-butoxymethyl group. Groups, isobutoxymethyl groups, sec-butoxymethyl groups, tert-butoxymethyl groups and the like can be mentioned.
  • a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, and an ethoxyethyl group are preferable.
  • C 1 -C 4 alkylene group means a bivalent radical wherein C 1 -C 4 alkylene group is bonded to oxy group.
  • the C 1 -C 4 alkyleneoxy group for example, methylene group, ethylene group, methylmethylene group, trimethylene group, ethyl methylene group, a dimethylmethylene group, and tetramethylene group, and the like .
  • Ethyleneoxy groups, trimethyleneoxy groups, and tetramethyleneoxy groups are preferred.
  • C 7 -C 12 aralkyl group means a group wherein the C 1 -C 6 alkyl group substituted with an aryl group.
  • Examples of the C 7- C 12 aralkyl group include a benzyl group and a phenethyl group. A benzyl group is preferred.
  • the "any one hydrogen atom” in the "residue excluding any one hydrogen atom or hydroxy group” described in the present specification is any one hydrogen atom bonded to a carbon atom, a nitrogen atom, or an oxygen atom.
  • the "any one hydroxy group” in the “residue excluding any one hydrogen atom or hydroxy group” described in the present specification may be a hydroxy group or is a hydroxy group present in a carboxy group. You may.
  • a drug containing a gastrointestinal protease inhibitor for use in combination with an incretin-like substance ie, this drug.
  • Aspect 2 The agent according to aspect 1, wherein the gastrointestinal protease inhibitor is an enteropeptidase inhibitor and / or a trypsin inhibitor.
  • Aspect 3 The drug according to aspect 1, wherein the gastrointestinal protease inhibitor is an enteropeptidase inhibitor.
  • G 2 and G 3 are, 1 each independently selected hydrogen atom, or a 1-5 -COOR 3 phenyl group which may be substituted with groups and independently from the group consisting of -COOR 3 group ⁇ be five may be substituted with a substituent C 1 -C 6 alkyl group;
  • G 4 are hydrogen, C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy -C 1 -C 4 alkyl group;
  • R 3 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group;
  • L 1 and L 2 may be independently substituted with 1 to 5 —COOR 4 groups and may be substituted with 1 to 5 C 1 ⁇ C 6 alkyl groups C 1 ⁇ .
  • a 1 and A 2 are residues obtained by removing any one hydrogen atom or hydroxy group from the compound represented by the general formula (II), respectively.
  • Aspect 6 Any one hydrogen atom or a residue obtained by removing any one hydrogen atom or hydroxy group from the compound represented by the general formula (II) is present in any one hydrogen atom in X or Y of the compound represented by the general formula (II).
  • the drug according to aspect 4 or 5 which is a residue excluding a hydroxy group.
  • Compound (I) or a pharmaceutically acceptable salt thereof is the following general formula (III):
  • G 11 and G 12 are independently hydrogen atoms, or -COOR 2 ;
  • R 2 is 1-5 optionally substituted by an aryl group C 1 -C 4 alkyl group;
  • C 1 -C 6 alkylene group C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group
  • R 4 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group
  • Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and; m is an integer from 1 to 6; n is an integer from 2 to 12]
  • the present drug according to Aspect 4 which is a compound represented by the above or a pharmaceutically acceptable salt thereof.
  • C 1 -C 4 alkyl group "-COO- (C 1 -C 4 alkyl group)" in R 1 is methyl group, ethyl group, n- propyl group, an isopropyl group, n- butyl
  • R 1 is a hydrogen atom or a tert-butoxycarbonyl group, preferably a hydrogen atom.
  • W 1 is a single bond, or a C 1 -C 2 alkylene group, preferably a single bond, the agent according to any one of embodiments 9-11.
  • W 2 is a single bond, or a C 1 -C 2 alkylene group, preferably a single bond, the agent according to any one of embodiments 9-12.
  • G 11 and R 2 of "-COOR 2 group" in the G 12, 1 to 3 is C 1 optionally -C 4 alkyl group substituted with a phenyl group, preferably 1 a number of optionally substituted C 1 -C 4 alkyl group with a phenyl group, more preferably a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, tert- butyl group, or benzyl
  • the present drug according to any one of aspects 9 to 15, which is a group.
  • G 11 is a hydrogen atom, a tert-butoxycarbonyl group, or a benzyloxycarbonyl group, preferably a hydrogen atom or a benzyloxycarbonyl group, and more preferably a hydrogen atom.
  • the present drug according to any one of 16 to 16.
  • G 12 is a hydrogen atom, a tert-butoxycarbonyl group, or a benzyloxycarbonyl group, preferably a hydrogen atom or a benzyloxycarbonyl group, and more preferably a hydrogen atom.
  • the drug according to any one of 17 to 17.
  • Y 1 is, -NG 21 - a is, the agent according to any one of embodiments 9-18.
  • Y 2 is, -NG 22 - a is, the agent according to any one of embodiments 9-19.
  • the “phenyl group optionally substituted with 1 to 5 ⁇ COOR 3 groups” in G 21 , G 31 , G 22 and G 32 is the 2- (COOR 3 ) -phenyl group,
  • R 3 of "-COOR 3 groups" in G 21 , G 31 , G 22 and G 32 independently has a hydrogen atom, a methyl group, an ethyl group, an n-propyl group and an isopropyl group. , N-Butyl group, tert-butyl group, or benzyl group, preferably hydrogen atom, benzyl group, or tert-butyl group, more preferably hydrogen atom, or tert-butyl group, still more preferably.
  • G 21 is hydrogen atom, or one to three -COOR 3 group in an optionally substituted C 1 -C 3 alkyl group, preferably one to three carboxy groups in a substituted C 1 -C 3 alkyl group, the agent according to any one of embodiments 9-22.
  • G 31 is hydrogen atom, or one to three -COOR 3 group in an optionally substituted C 1 -C 3 alkyl group, preferably a hydrogen atom, aspects 9 The present drug according to any one of ⁇ 23.
  • G 22 is hydrogen atom, or one to three -COOR 3 group in an optionally substituted C 1 -C 3 alkyl group, preferably one to three carboxy groups in a substituted C 1 -C 3 alkyl group, the agent according to any one of embodiments 9-24.
  • G 32 is hydrogen atom, or one to three -COOR 3 group in an optionally substituted C 1 -C 3 alkyl group, preferably a hydrogen atom, aspects 9 The present drug according to any one of 25 to 25.
  • L 11, L 12, L 21, and R 4 "-COOR 4 group" in the L 22 are each independently a hydrogen atom, a methyl group, an ethyl group, n- propyl group, isopropyl A group, an n-butyl group, a tert-butyl group, or a benzyl group, preferably a hydrogen atom, a tert-butyl group, or a benzyl group, more preferably a hydrogen atom or a tert-butyl group, and further preferably.
  • the drug according to any one of aspects 9 to 26, wherein is a hydrogen atom.
  • L 11 is a C 1 -C 2 alkylene group, preferably a methylene group, the agent according to any one of embodiments 9-27.
  • L 12 is a C 1- C 2 alkylene group, preferably a methylene group.
  • L 21 is a C 1 -C 2 alkylene group, preferably a methylene group, the agent according to any one of embodiments 9-29.
  • L 22 is a C 1 -C 2 alkylene group, preferably a methylene group, the agent according to any one of embodiments 9-30.
  • Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and, preferably - (CH 2 -CH 2 -O )
  • the present drug according to any one of aspects 9 to 34, which is m- CH 2- CH 2-.
  • G 11 and G 12 are independently hydrogen atoms or -COOR 2 ;
  • R 2 is located at 1-5 which may be substituted by an aryl group C 1 -C 4 alkyl group;
  • C 1 may be substituted with a substituent -C 6 alkyl group which is selected;
  • R 3 are each independently a hydrogen atom, or a 1-5 aryl group optionally substituted C 1 -C 4 alkyl group;
  • L 11 , L 21 , L 12 and L 22 are each independently substituted with 1 to 5 C 1- C 6 alkyl groups, which may be substituted with 1 to 5 -COOR 4 groups.
  • C 1 -C 6 alkylene group which may be C 1 -C 6 alkylene group, C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group;
  • R 4 is a hydrogen atom, respectively;
  • Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and;
  • m is an integer from 1 to 6;
  • Each R 1 is a hydrogen atom; W 1 and W 2 are each independently a single bond, or a C 1 -C 4 alkylene group;
  • G 11 and G 12 are hydrogen atoms, respectively;
  • C 1 may be substituted with a substituent -C 6 alkyl group which is selected;
  • R 3 is a hydrogen atom, respectively;
  • L 11 , L 21 , L 12 and L 22 are each independently substituted with 1 to 5 C 1- C 6 alkyl groups, which may be substituted with 1 to 5 -COOR 4 groups.
  • C 1 -C 6 alkylene group which may be C 1 -C 6 alkylene group, C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group;
  • R 4 is a hydrogen atom, respectively;
  • Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and;
  • m is an integer from 1 to 6;
  • Each R 1 is independently a hydrogen atom, or tert-butoxycarbonyl group; W 1 and W 2 are each independently a single bond, or a C 1 -C 2 alkylene group;
  • G 11 and G 12 are hydrogen atoms, respectively;
  • Each R 1 is a hydrogen atom; W 1 and W 2 are each independently a single bond, or a C 1 -C 2 alkylene group;
  • G 11 and G 12 are hydrogen atoms, respectively;
  • Each R 1 is a hydrogen atom; W 1 and W 2 are each independently a single bond, or a C 1 -C 2 alkylene group;
  • G 11 and G 12 are hydrogen atoms, respectively;
  • a 1 and A 2 are residues obtained by independently removing any one hydrogen atom or hydroxy group from any one molecule selected from the following molecular group. ..
  • Compound (I) or a pharmaceutically acceptable salt thereof is (2S, 2'S) -2,2'-((oxybis (ethane-2,1-diyl))) bis ((10-guanidino-13-oxo). -6,7,8,13-Tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandyl)) disuccinic acid (hereinafter, also referred to as compound A), the book according to aspect 4. Drug.
  • Compound (II) or a pharmaceutically acceptable salt thereof is the following general formula (II') or the following general formula (II''): [In the formula, the symbols have the same meaning as above]
  • the present drug according to any one of aspects 4 to 49, which is a compound represented by (1) or a pharmaceutically acceptable salt thereof.
  • C 7- C 12 substituted with 1-5 substituents independently selected from the group consisting of C 6 alkylene group, hydroxy group and carboxy group C 1- C 6 substituted with aralkyl group alkylene group, C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group; L 3 is a phenylene moiety 1-3 optionally substituted by -COOR 4 group of C 1 -C 4 alkylene - be a phenylene group; R 4 are each independently a hydrogen atom, a benzyl group, or tert- butyl; R 5 and R 6 are each independently a hydrogen atom, a halogen atom, C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy group, the agent according to embodiment 50.
  • the present drug according to any one of aspects 50 to 52.
  • R 4 are each independently hydrogen atom, or a 1-5 aryl-substituted C 1 optionally -C 4 alkyl group with a group]
  • the drug according to any one of aspects 4 to 49 or 57, which is a compound represented by (1) or a pharmaceutically acceptable salt thereof.
  • R 4 are each independently a hydrogen atom, a benzyl group, or a tert- butyl group, the agent according to embodiment 58.
  • Each R 1 is a hydrogen atom; W is, be a C 1 -C 2 alkylene group; X is -NG-SO 2- ; G is a hydrogen atom; Y is -NG 2 G 4 ; G 2 is a C-1- C 3 alkyl group substituted with 1 to 3 substituents independently selected from the group consisting of a phenyl group substituted with 1 carboxy group and a carboxy group;
  • the enteropeptidase inhibitor is N-(((3S) -6-((4-carbamimideamidebenzoyl) oxy) -2,3-dihydro-1-benzofuran-3-yl) acetyl) -L-aspartic acid.
  • the drug according to aspect 63 which is a pharmaceutically acceptable salt thereof (hereinafter, also referred to as compound B).
  • the agent according to aspect 66, wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists comprising semaglutide.
  • the GLP-1 receptor agonist is semaglutide.
  • the GLP-1 receptor agonist is one or more GLP-1 receptor agonists comprising liraglutide.
  • the GLP-1 receptor agonist is liraglutide.
  • the GLP-1 receptor agonist is one or more GLP-1 receptor agonists comprising duraglutide.
  • the GLP-1 receptor agonist is one or more GLP-1 receptor agonists comprising albiglutide.
  • the GLP-1 receptor agonist is albiglutide.
  • the GLP-1 receptor agonist is one or more GLP-1 receptor agonists comprising efpeglenatide.
  • the GLP-1 receptor agonist is efpeglenatide.
  • the gastrointestinal protease inhibitor is compound A and the incretin-like substance is one or more GLP-1 receptor agonists selected from the group consisting of semaglutide, liraglutide, duraglutide, exenatide, lixisenatide, albiglutide, and efpeglenatide. , The present drug according to the first aspect.
  • the agent for preventing, alleviating, and / or treating a disease associated with gastrointestinal protease and / or incretin.
  • Diseases involving gastrointestinal protease and / or insulin are obesity, pathophysiology or disease associated with obesity, diabetes (type 1, type 2, etc.), diabetic complications (nephropathy, retinopathy, neuropathy, etc.), kidney Diseases, cardiovascular diseases (coronary artery disease, cerebral infarction, peripheral arterial disease, etc.), bone / joint diseases, psoriatic arthritis, metabolic syndrome, hyperlipidemia, arteriosclerosis, hypertension, hyperuricemia, fatty liver ( Non-alcoholic steatosis (including NASH)), liver disease (including biliary tract disorder), pancreatic disorder, cystic fibrosis, insulin resistance syndrome, hyperinsulinemia, glucose tolerance disorder, muscular dystrophy, muscle atrophic lateral sclerosis choose from ALS, cerebral infarction, Parkinson's disease
  • Aspect 95 wherein the disease involving the gastrointestinal protease and / or incretin is one or more diseases selected from obesity, diabetes, diabetic complications (nephropathy, retinopathy, neuropathy, etc.), and NASH. This drug described in.
  • Aspect 98 The agent according to aspect 95, wherein the disease involving gastrointestinal protease and / or incretin is one or more diseases selected from obesity and diabetes.
  • Aspect 99 The drug according to aspect 95, wherein the disease involving gastrointestinal protease and / or incretin is obesity.
  • Aspect 100 The drug according to any one of aspects 1 to 99 for increasing FGF-21.
  • Aspect 101 The drug according to any one of aspects 1 to 100 for preventing, alleviating, and / or treating a disease whose symptoms are improved by an increase in FGF-21.
  • Aspect 102 The present drug according to any one of aspects 1 to 101 for lowering insulin.
  • Aspect 103 The present drug according to any one of aspects 1 to 102 for preventing, alleviating, and / or treating a disease in which symptoms are improved by a decrease in insulin.
  • Aspect 104 The present drug according to any one of aspects 1 to 103 for lowering HbA1c.
  • the gastrointestinal protease inhibitor and incretin-like substance in the present invention may be commercially available ones or may be produced according to a known method.
  • compound (I), compound (II), or compound (III), or a pharmaceutically acceptable salt thereof is the method described in WO2019 / 088270 or the like, or a combination of the method and a known method. It can be manufactured by the above method.
  • the compound of Group A is described in, for example, International Publication No. 2015/122187, International Publication No. 2015/122188, International Publication No. 2014/142219, or International Publication No. 2013/187533. Can be manufactured at. Further, as the incretin-like substance, a commercially available substance can be used.
  • the compound (I), the compound (II), or the compound (III) in the present invention, or the compound of the group A can exist in the form of a tautomer or a mixture thereof.
  • the compounds (I), compounds (II), or compounds (III), or compounds of group A in the present invention may be present in the form of stereoisomers such as enantiomers, diastereomers, or mixtures thereof.
  • Compound (I), compound (II), or compound (III), or compound of group A in the present invention comprises tautomers, mixtures of stereoisomers, or pure or substantially pure isomers, respectively. do.
  • compound (I), compound (II), or compound (III), or a compound of group A in the present invention is obtained in the form of diastereomers or enantiomers, these can be obtained by methods commonly used in the art, such as chromatography. And can be separated by a fractional crystallization method or the like.
  • Pharmaceutically acceptable salts of compound (I), compound (II), or compound (III), or compounds of group A include alkali metal salts such as lithium, sodium, and potassium; Group 2 metal salts; salts with aluminum or zinc; ammonia, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris (hydroxymethyl) aminomethane, N-methyl-glucosamine, triethanolamine, and Salts with amines such as dehydroabiethylamine; salts with inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitrate, and phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, Salts with organic acids such as malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methane
  • the pharmaceutically acceptable salts of compound (I), compound (II), or compound (III), or compounds of group A include their intramolecular salts, hydrates, and solvates.
  • pharmaceutically acceptable generally means that it is not harmful to the recipient and that the ingredients are compatible with each other when preparing the pharmaceutical composition. Means that it is useful not only for human medicinal use but also for veterinary use.
  • the gastrointestinal protease inhibitor and incretin-like substance in the present invention may be administered as they are, or may be administered as a pharmaceutical composition mixed with a pharmaceutically acceptable carrier.
  • the gastrointestinal protease inhibitor and the incretin-like substance in the present invention can be administered orally or parenterally, respectively.
  • the gastrointestinal protease inhibitor and incretin-like substance of the present invention are contained in one composition.
  • the gastrointestinal protease inhibitor and the incretin-like substance in the present invention are formulated into separate compositions. In this case, the gastrointestinal protease inhibitor and the incretin-like substance may be administered simultaneously or separately.
  • the gastrointestinal protease inhibitor and the incretin-like substance When the gastrointestinal protease inhibitor and the incretin-like substance are administered separately, they may be administered continuously, or at intervals of time, for example, 30 minutes to 1 hour, 1 to 6 hours, etc. It may be administered at intervals of 6 to 12 hours, 12 to 24 hours, or 1 to 7 days. Furthermore, when the gastrointestinal protease inhibitor and the incretin-like substance are administered separately, the gastrointestinal protease inhibitor may be administered first, or the incretin-like substance may be administered first.
  • the present invention may be in the form of a kit containing a composition containing a gastrointestinal protease inhibitor and a composition containing an incretin-like substance.
  • the pharmaceutically acceptable carrier may be a carrier commonly used in the art, such as diluents, binders (syrup, gum arabic, gelatin, sorbitol, tragacant, and polyvinylpyrrolidone, etc.), excipients (lactose, sho).
  • diluents such as diluents, binders (syrup, gum arabic, gelatin, sorbitol, tragacant, and polyvinylpyrrolidone, etc.), excipients (lactose, sho).
  • compositions include a suspending agent (methyl cellulose, etc.) and a buffer solution (citrate buffer solution, etc.).
  • the dosage form of the composition is not particularly limited, and it can be used as a conventional pharmaceutical preparation such as tablets, granules, capsules, powders, injections, inhalants, and suppositories.
  • the dosage forms of the compositions may be the same or different from each other.
  • the gastrointestinal protease inhibitor is formulated into tablets, granules, capsules, powders, etc. and orally administered
  • the incretin-like substance is formulated into injections, etc. and administered parenterally, for example. It is administered subcutaneously.
  • the gastrointestinal protease inhibitor and incretin-like substance in the present invention are formulated into an appropriate dosage form and then administered to a patient, for example, a human or an animal, preferably a human.
  • the dose (that is, effective amount) and frequency of administration of the gastrointestinal protease inhibitor and the incretin-like substance in the present invention are the severity of the disease, the age, weight, sex of the patient, the type of drug, the dosage form, the route of administration, etc. It can be changed as appropriate depending on the conditions of.
  • the gastrointestinal protease inhibitor and the incretin-like substance respectively, parenterally, for example, subcutaneously, intravenously, intraperitoneally, intramuscularly, intrarectally, etc. .001-100 mg / kg body weight, preferably about 0.01-50 mg / kg body weight, particularly preferably about 0.02-10 mg / kg body weight, and orally about 1-1000 mg / kg body weight, preferably about.
  • the number of administrations may be once or multiple times per day, for example, 1 to 3 times, 1 to 2 times, or once per day, or every few days, for example, once every two days, once every three days. Once every 4 days, once every 5 days, once every 6 days, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month May be.
  • the gastrointestinal protease inhibitor is about 1 to 1000 mg / kg body weight, preferably about 10 to 500 mg, per administration of 1 to 3 times, 1 to 2 times, or 1 time per day.
  • Parenteral administration eg, subcutaneously, at a dose of about 0.001 to 100 mg / kg body weight, preferably about 0.01 to 50 mg / kg body weight, particularly preferably about 0.02 to 10 mg / kg body weight per single dose.
  • the period of administration of the gastrointestinal protease inhibitor and the incretin-like substance in the present invention varies depending on conditions such as the severity of the disease, the age, weight, sex of the patient, the type of drug, the dosage form, and the route of administration. Often, for example, it can be 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, or 1 year or more.
  • the drug has excellent prophylactic, alleviating, and / or therapeutic effects on diseases associated with gastrointestinal proteases and / or incretins.
  • diseases include, for example, obesity, pathological conditions or diseases associated with obesity, diabetes (type 1, type 2, etc.), diabetic complications (nephropathy, retinopathy, neuropathy, etc.), kidney disease, cardiovascular disease.
  • COPD chronic obstructive pulmonary disease
  • the agent prevents, alleviates, and / or prevents obesity, diabetes, diabetic complications (nephropathy, retinopathy, neuropathy, etc.), and one or more diseases selected from NASH. Used for treatment.
  • the agent is used for the prevention, alleviation, and / or treatment of one or more diseases selected from obesity and diabetes.
  • the drug is used for the prevention, alleviation, and / or treatment of obesity.
  • this drug has an FGF-21 increasing action, an insulin lowering action, and an HbA1c lowering action. Therefore, this drug is also effective in the prevention, alleviation, and / or treatment of diseases in which symptoms are improved by an increase in FGF-21, a decrease in insulin, and / or a decrease in HbA1c.
  • diseases whose symptoms are improved by increasing FGF-21 include obesity, diabetes, NASH and the like.
  • diseases in which symptoms are improved by a decrease in insulin include obesity and diabetes.
  • diseases whose symptoms are improved by lowering HbA1c include obesity, diabetes, NASH and the like.
  • One embodiment of the invention relates to the use of gastrointestinal protease inhibitors in the manufacture of agents for use in combination with incretin-like substances.
  • the agent is used for the prevention, alleviation, and / or treatment of diseases involving gastrointestinal proteases and / or incretins.
  • the agent prevents, alleviates, one or more diseases selected from obesity, diabetes, diabetic complications (nephropathy, retinopathy, neuropathy, etc.), and NASH. And / or used to treat.
  • the agent is used to prevent, alleviate, and / or treat one or more diseases selected from obesity and diabetes.
  • the agent is used to prevent, alleviate, and / or treat obesity.
  • One embodiment of the invention relates to the use of a combination of gastrointestinal protease inhibitors and incretin-like substances to prevent, alleviate, and / or treat a disease. Another embodiment of the invention relates to the use of a combination of gastrointestinal protease inhibitors and incretin-like substances to prevent, alleviate, and / or treat diseases involving gastrointestinal proteases and / or incretins. Another embodiment of the invention prevents, alleviates, and / or treats obesity, diabetes, diabetic complications (nephropathy, retinopathy, neuropathy, etc.), and one or more diseases selected from NASH. With respect to the use of a combination of gastrointestinal protease inhibitors and incretin-like substances to do so.
  • Another embodiment of the invention relates to the use of a combination of gastrointestinal protease inhibitors and incretin-like substances to prevent, alleviate, and / or treat one or more diseases selected from obesity and diabetes.
  • Another embodiment of the invention relates to the use of a combination of gastrointestinal protease inhibitors and incretin-like substances to prevent, alleviate, and / or treat obesity.
  • One embodiment of the invention relates to a combination of gastrointestinal protease inhibitors and incretin-like substances for use in the prevention, alleviation, and / or treatment of disease.
  • Another embodiment of the invention relates to a combination of gastrointestinal protease inhibitors and incretin-like substances for use in the prevention, alleviation, and / or treatment of diseases involving gastrointestinal proteases and / or incretins.
  • Another embodiment of the invention is the prevention, alleviation, and / or treatment of obesity, diabetes, diabetic complications (nephropathy, retinopathy, neuropathy, etc.), and one or more diseases selected from NASH.
  • Another embodiment of the invention relates to a combination of gastrointestinal protease inhibitors and incretin-like substances for use in the prevention, alleviation, and / or treatment of one or more diseases selected from obesity and diabetes.
  • Another embodiment of the invention relates to a combination of gastrointestinal protease inhibitors and incretin-like substances for use in the prevention, alleviation, and / or treatment of obesity.
  • One embodiment of the present invention relates to a method for preventing, alleviating, and / or treating a disease, which comprises administering to a patient an effective amount of a combination of a gastrointestinal protease inhibitor and an incretin-like substance.
  • Another embodiment of the present invention comprises administering to a patient an effective amount of a combination of a gastrointestinal protease inhibitor and an incretin-like substance to prevent a disease in which symptoms are ameliorated by enteropeptidase inhibition and / or trypsin inhibition.
  • Another embodiment of the present invention comprises administering to a patient an effective amount of a combination of a gastrointestinal protease inhibitor and an incretin-like substance for obesity, diabetes, diabetic complications (nephropathy, retinopathy, nerves). Disorders, etc.), and methods of preventing, alleviating, and / or treating one or more diseases selected from NASH.
  • Another embodiment of the invention is the prevention and alleviation of one or more diseases selected from obesity and diabetes, comprising administering to a patient an effective amount of a combination of a gastrointestinal protease inhibitor and an incretin-like substance. And / or the treatment method.
  • Another embodiment of the present invention relates to a method for preventing, alleviating, and / or treating obesity, which comprises administering to a patient an effective amount of a combination of a gastrointestinal protease inhibitor and an incretin-like substance.
  • the gastrointestinal protease inhibitor and incretin-like substance are administered to the patient separately in the above method.
  • compound A is the compound described in Example 26- (b) of International Publication No. 2019/088270
  • compound B is described in Example 1 of International Publication No. 2015/122187.
  • Example 1 Weight loss test using DIO mice (test method) Diet-induced ability (DIO) mice (D12492 diet, male, 27 weeks old) were divided into 4 groups (7 animals / group). Vehicles, Compound A, and / or semaglutide were administered for 21 days according to the combination in Table 1. The administration start date is set to day 0, and a 0.5% methylcellulose (MC) solution or a 0.5% MC suspension containing compound A (25 mg / kg) is orally administered once a day from day 0 to 20 mM. A 20 mM citrate buffer containing citrate buffer or semaglutide (10 nmol / kg) was subcutaneously administered once every 3 days (days 0, 3, 6, 9, 12, 15 and 18). Semaglutide was purchased from Adipo Gene.
  • the mean value and standard error (mean ⁇ SE) of the body weight fluctuation (%) from the 0th day to the 21st day are shown in FIG. Table 2 shows the average body weight and standard error of each group on the 0th and 21st days.
  • the group to which this drug was administered that is, the group to which compound A and semaglutide were administered in combination, showed an excellent weight-reducing effect as compared with the group to which compound A was administered alone and the group to which semaglutide was administered alone.
  • This effect is a very strong effect comparable to Roux-en-Y Gastric Bypass (RYGB), and is an effect that cannot be achieved by existing anti-obesity drugs.
  • Test Example 2 Measurement of bioactive substances in blood (test method)
  • blood was collected from the abdominal vena cava of each mouse under isoflurane inhalation anesthesia about 16 hours after the end of administration on the 20th day.
  • the collected blood was placed in a blood collection tube containing a protein stabilizer, and then 30 ⁇ L was separated and each was ice-cooled.
  • Plasma was separated by centrifuging the blood collection tube at 4 ° C. and 1300 g for 10 minutes. Plasma and previously collected whole blood were cryopreserved at about ⁇ 20 ° C. until use.
  • Example 3 Weight loss test using DIO mice (test method) Diet-induced ability (DIO) mice (D12492 diet, male, 27 weeks old) were divided into 4 groups (4-5 animals / group). Vehicles, Compound A, and / or liraglutide were administered for 21 days according to the combination in Table 3. The administration start date is set to the 0th day, and a 0.5% methylcellulose (MC) solution or a 0.5% MC suspension containing compound A (25 mg / kg) is orally administered once a day from the 0th day, and the compound is administered. Except for the A administration group, 20 mM citrate buffer or 20 mM citrate buffer containing liraglutide (0.2 mg / kg) was subcutaneously administered once a day. Liraglutide was purchased from Adipo Gene.
  • the mean value and standard error (mean ⁇ SE) of the body weight fluctuation (%) from the 0th day to the 21st day are shown in FIG. Table 4 shows the average body weight and standard error of each group on the 0th day and the 21st day.
  • the group to which this drug was administered that is, the group to which compound A and liraglutide were administered in combination, showed an excellent weight-reducing effect as compared with the group to which compound A was administered alone and the group to which liraglutide was administered alone.
  • This effect is a very strong effect comparable to Roux-en-Y Gastric Bypass (RYGB), and is an effect that cannot be achieved by existing anti-obesity drugs.
  • Test Example 4 Measurement of bioactive substances in blood (test method)
  • blood was collected from the abdominal vena cava of each mouse under isoflurane inhalation anesthesia about 16 hours after the end of administration on the 20th day (the last day of continuous administration until the 27th day for the compound A administration group). ..
  • the collected blood was placed in a blood collection tube containing a protein stabilizer, and then 30 ⁇ L was separated and each was ice-cooled. Plasma was separated by centrifuging the blood collection tube at 4 ° C. and 1300 g for 10 minutes. Plasma and previously collected whole blood were cryopreserved at about ⁇ 20 ° C. until use.
  • ⁇ Test Example 5 Weight loss test using DIO mice (test method) Similar to Test Example 1, vehicle, compound A, compound B, and / or semaglutide were administered for 21 days according to the combination in Table 5.
  • the administration start date is the 0th day, and 0.5 containing 0.5% methylcellulose (MC) solution, compound A (12.5 mg / kg (half the amount of Test Example 1)), or compound B (50 mg / kg).
  • % MC suspension is orally administered once daily from day 0, and 20 mM citrate buffer or 20 mM citrate buffer containing semaglutide (10 nmol / kg) is administered once every 3 days (0, 3, 6, (Days 9, 12, 15 and 18) Subcutaneous administration was performed.
  • FIG. 9 shows the mean value and standard error (mean ⁇ SE) of the body weight fluctuation (%) from the 0th day to the 21st day.
  • Table 6 shows the average body weight and standard error of each group on the 0th and 21st days.
  • the group to which this drug was administered that is, the group to which compound A or compound B was administered in combination with semaglutide, was superior in body weight to the group to which compound A or compound B was administered alone and the group to which semaglutide was administered alone. It showed a lowering effect.
  • Test Example 6 Measurement of bioactive substances in blood (test method) In Test Example 5, fibroblast growth factor-21 (FGF-21), insulin, and HbA1c were measured in the same manner as in Test Example 1.
  • FGF-21 fibroblast growth factor-21
  • insulin insulin
  • HbA1c HbA1c
  • the drug of the present invention has excellent preventive, alleviating, and / or therapeutic effects on diseases such as obesity and diabetes, it can be used for prevention, alleviation, and / or treatment of the diseases.

Abstract

The present invention provides a drug having excellent preventive, alleviating, and/or therapeutic effects against disease such as obesity and diabetes. Specifically, the present invention provides a gastric protease inhibitor-containing drug for combination use with an incretin mimetic.

Description

インクレチン様物質と組み合わせて使用するための消化管プロテアーゼ阻害剤を含む薬剤Drugs containing gastrointestinal protease inhibitors for use in combination with incretin-like substances
　本発明は、インクレチン様物質と組み合わせて使用するための消化管プロテアーゼ阻害剤を含む薬剤、ならびにその用途に関する。 The present invention relates to a drug containing a gastrointestinal protease inhibitor for use in combination with an incretin-like substance, and its use.
　消化管プロテアーゼは、口腔から肛門に至るまでの食物が通る管において分泌されるプロテアーゼであり、主として食物を消化する働きを担っている。食物由来の蛋白質は消化管プロテアーゼにより分解され、最終的にアミノ酸あるいはペプチドとなり体内へ吸収される。その主要なプロテアーゼはトリプシンである。エンテロペプチダーゼは十二指腸粘膜細胞から分泌され、食事により膵臓から分泌されるトリプシノーゲンをトリプシンへと変換するセリンプロテアーゼである。またトリプシンはキモトリプシノーゲン、プロカルボキシペプチダーゼ、プロエラスターゼ、及びプロコリパーゼ等のプロテアーゼ前駆体に作用して種々の酵素を活性化することも知られている。従って、エンテロペプチダーゼ及び／又はトリプシンを阻害する化合物は、蛋白質の分解と吸収を抑制する作用や脂質の吸収を抑制する作用、及び糖質の消化能力を低下させる作用を有することが期待され、肥満症治療薬や抗糖尿病薬として有用であると考えられる。エンテロペプチダーゼ阻害剤及び／又はトリプシン阻害剤として、様々な化合物が知られている（例えば、特許文献１～６参照）。 Gastrointestinal protease is a protease secreted in the tube through which food passes from the oral cavity to the anus, and is mainly responsible for digesting food. Food-derived proteins are degraded by gastrointestinal proteases and eventually become amino acids or peptides that are absorbed into the body. Its major protease is trypsin. Enteropeptidase is a serine protease that is secreted by duodenal mucosal cells and converts trypsinogen, which is secreted from the pancreas by diet, into trypsin. It is also known that trypsin acts on protease precursors such as chymotrypsinogen, procarboxypeptidase, proelastase, and procolipase to activate various enzymes. Therefore, a compound that inhibits enteropeptidase and / or trypsin is expected to have an action of suppressing protein decomposition and absorption, an action of suppressing lipid absorption, and an action of lowering the digestive ability of sugar, and obesity. It is considered to be useful as a therapeutic drug for illness and an antidiabetic drug. Various compounds are known as enteropeptidase inhibitors and / or trypsin inhibitors (see, for example, Patent Documents 1 to 6).
　インクレチンは主として膵臓のランゲルハンス島β細胞に作用してインスリン分泌を促進する消化管ホルモンの総称である。インクレチンとして、例えばグルカゴン様ペプチド－１（ｇｌｕｃａｇｏｎ－ｌｉｋｅ　ｐｅｐｔｉｄｅ－１：以下「ＧＬＰ－１」と称する）が知られており、消化管粘膜上皮から分泌され、膵臓のランゲルハンス島β細胞に作用してインスリンを分泌させることにより血糖値を下げる作用を示す。ＧＬＰ－１受容体作動薬は膵臓ランゲルハンス島β細胞からのインスリン分泌を促進することにより血糖値を下げるため、主として糖尿病の治療薬として用いられている。ＧＬＰ－１受容体作動薬として、様々な化合物が知られている（例えば、特許文献７～８及び非特許文献１参照）。 Incretin is a general term for gastrointestinal hormones that mainly act on the β cells of the islets of Langerhans in the pancreas to promote insulin secretion. As an incretin, for example, glucagon-like peptide-1 (hereinafter referred to as "GLP-1") is known, which is secreted from the gastrointestinal mucosal epithelium and acts on the islet β-cells of the pancreas. It has the effect of lowering the blood glucose level by secreting insulin. GLP-1 receptor agonists are mainly used as therapeutic agents for diabetes because they lower blood glucose levels by promoting insulin secretion from pancreatic Langerhans islet β cells. Various compounds are known as GLP-1 receptor agonists (see, for example, Patent Documents 7-8 and Non-Patent Document 1).
　これまでに、消化管プロテアーゼ阻害剤とインクレチン様物質の併用に関する示唆はある（例えば、特許文献２、３、５、６及び８参照）。しかしながら、消化管プロテアーゼ阻害剤とインクレチン様物質を実際に組み合わせた例はこれまでに知られておらず、肥満症や糖尿病等の消化管プロテアーゼ及び／又はインクレチンが関与する疾患に対する該組み合わせの効果についての報告もない。 So far, there have been suggestions regarding the combined use of gastrointestinal protease inhibitors and incretin-like substances (see, for example, Patent Documents 2, 3, 5, 6 and 8). However, no actual combination of a gastrointestinal protease inhibitor and an incretin-like substance has been known so far, and the combination for diseases involving gastrointestinal protease and / or incretin such as obesity and diabetes. There is no report on the effect.
国際公開第２０１９／０８８２７０号公報International Publication No. 2019/088270 国際公開第２０１５／１２２１８７号公報International Publication No. 2015/122187 国際公開第２０１５／１２２１８８号公報International Publication No. 2015/122188 国際公開第２０１４／１４２２１９号公報International Publication No. 2014/142219 国際公開第２０１３／１８７５３３号公報International Publication No. 2013/187533 国際公開第２０１２／１６９５７９号公報International Publication No. 2012/169597 国際公開第２００６／０９７５３７号公報International Publication No. 2006/07537 特開２０１８－１１５２０４号公報JP-A-2018-115204
　本発明は、肥満症や糖尿病等の疾患に対して優れた予防、緩和、及び／又は治療効果を有するインクレチン様物質と組み合わせて使用するための消化管プロテアーゼ阻害剤を含む薬剤、ならびにその用途を提供することを課題とする。 The present invention is a drug containing a gastrointestinal protease inhibitor for use in combination with an incretin-like substance having excellent preventive, alleviating, and / or therapeutic effects on diseases such as obesity and diabetes, and uses thereof. The challenge is to provide.
　本発明者らは、肥満症や糖尿病等の疾患に対する優れた治療効果を有する薬剤について鋭意研究を重ねた結果、インクレチン様物質と組み合わせて使用するための消化管プロテアーゼ阻害剤を含む薬剤が、肥満症や糖尿病等の疾患の予防、緩和、及び／又は治療に有用であることを見出し、本発明を完成させた。 As a result of intensive research on a drug having an excellent therapeutic effect on diseases such as obesity and diabetes, the present inventors have found a drug containing a gastrointestinal protease inhibitor for use in combination with an incretin-like substance. We have found that it is useful for the prevention, alleviation, and / or treatment of diseases such as obesity and diabetes, and completed the present invention.
　本発明は、以下を提供する。
［１］
　インクレチン様物質と組み合わせて使用するための、消化管プロテアーゼ阻害剤を含む薬剤（以下、「本薬剤」とも称する）。
［２］
　消化管プロテアーゼ阻害剤がエンテロペプチダーゼ阻害剤及び／又はトリプシン阻害剤である、［１］に記載の薬剤。
［３］
　消化管プロテアーゼ阻害剤がエンテロペプチダーゼ阻害剤である、［１］に記載の薬剤。
［４］
　エンテロペプチダーゼ阻害剤が
（ａ）下記一般式（Ｉ）：
Figure JPOXMLDOC01-appb-C000008
 ［式中、Ａ１及びＡ２は、それぞれ独立して、以下の群Ａ：
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000012
 から選択される化合物、又は下記一般式（ＩＩ）：
Figure JPOXMLDOC01-appb-C000013
 ［式中、
　環Ｂ及び環Ｃは、それぞれ独立して、アリール基、又はヘテロアリール基であり；
　各Ｒ１は、それぞれ独立して、水素原子、又は－ＣＯＯ－（Ｃ１－Ｃ４アルキル基）であり；
　Ｗは、単結合、又はＣ１－Ｃ４アルキレン基であり；
　Ｘは、－Ｃ（＝Ｏ）－、－Ｏ－Ｃ（＝Ｏ）－、又は－ＮＧ－ＳＯ２－であり；
　Ｇは水素原子、Ｃ１－Ｃ４アルキル基、又は－ＣＯＯＲ２であり；
　Ｒ２は、１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｙは、－ＮＧ２Ｇ４、－ＮＧ２－Ｌ１－ＣＯＯＨ、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＨ２、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－ＣＯＯＨ、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－ＣＯＯＨ、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－Ｃ（＝Ｏ）－ＮＨ２、－ＮＧ２－Ｌ３－ＯＨ、又は－ＮＧ２－（ＣＨ２－ＣＨ２－Ｏ）ｑ－ＣＨ２－ＣＨ２－ＣＯＯＨであり；
　ｑは、１～６の整数であり；
　Ｇ２及びＧ３は、それぞれ独立して、水素原子、又は１～５個の－ＣＯＯＲ３基で置換されていてもよいフェニル基及び－ＣＯＯＲ３基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ６アルキル基であり；
　Ｇ４は、水素原子、Ｃ１－Ｃ４アルキル基、又はＣ１－Ｃ４アルコキシ―Ｃ１－Ｃ４アルキル基であり；
　Ｒ３は、それぞれ独立して、水素原子、又は１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｌ１及びＬ２は、それぞれ独立して、１～５個の－ＣＯＯＲ４基で置換されていてもよい１～５個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、ヒドロキシ基及びカルボキシ基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ７－Ｃ１２アラルキル基で置換されたＣ１－Ｃ６アルキレン基、Ｃ１－Ｃ４アルキレン－フェニレン基、又はフェニレン－Ｃ１－Ｃ４アルキレン基であり；
　Ｌ３は、フェニレン部分が１～３個の－ＣＯＯＲ４基で置換されていてもよいＣ１－Ｃ４アルキレン－フェニレン基であり；
　Ｒ４は、それぞれ独立して水素原子、又はアリール基及びトリメチルシリル基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｒ５及びＲ６は、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１－Ｃ４アルキル基、Ｃ１－Ｃ４アルコキシ基、カルボキシ基、又は－Ｃ（＝Ｏ）－ＮＧ２Ｇ４であり；
　ｓ及びｔは、それぞれ独立して、１～４の整数であり；
　複数のＲ５及び／又は複数のＲ６は、それぞれ同一であっても異なっていてもよく；
　又は、Ｒ５のいずれか１つ及びＲ６のいずれか１つは互いに結合して、Ｃ１－Ｃ４アルキレンオキシ基を形成してもよい］
で表される化合物からいずれか１つの水素原子又はヒドロキシ基を除いた残基を示し；
　Ｚは、単結合、アリーレン、ヘテロアリーレン、又はＣ２－Ｃ３０アルキレン基（ただし、該アルキレン基の鎖中の１つ以上のメチレン基は、－Ｃ（＝Ｏ）－、－ＮＲ７－、－Ｏ－、－ＳｉＲ８Ｒ９－、－ＳＯｒ－、アリーレン、及びヘテロアリーレンからなる群から独立して選択される基と置き換わっていてもよく、Ｒ７は水素原子、又はＣ１－Ｃ４アルキル基であり、Ｒ８及びＲ９は、それぞれ独立して、Ｃ１－Ｃ４アルキル基であり、ｒは、０～２の整数である）である］
で表される化合物又はその薬学上許容される塩；
（ｂ）群Ａの化合物又はその薬学上許容される塩；並びに
（ｃ）一般式（ＩＩ）で表される化合物又はその薬学上許容される塩
からなる群から選択される１つ以上の化合物又はその薬学上許容される塩である、［２］又は［３］に記載の薬剤。
［５］
　エンテロペプチダーゼ阻害剤が下記一般式（ＩＩＩ）：
Figure JPOXMLDOC01-appb-C000014
 ［式中、
　各Ｒ１は、それぞれ独立して、水素原子、又は－ＣＯＯ－（Ｃ１－Ｃ４アルキル基）であり；
　Ｗ１及びＷ２は、それぞれ独立して、単結合、又はＣ１－Ｃ４アルキレン基であり；
　Ｘ１は、－Ｃ（＝Ｏ）－、又は－ＮＧ１１－ＳＯ２－であり；
　Ｘ２は、－Ｃ（＝Ｏ）－、又は－ＳＯ２－ＮＧ１２－であり；
　Ｇ１１及びＧ１２は、それぞれ独立して、水素原子、又は－ＣＯＯＲ２であり；
　Ｒ２は、１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｙ１は、－ＮＧ２１－、－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＨ－、又は－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＧ３１－Ｌ２１－Ｃ（＝Ｏ）－ＮＨ－であり；
　Ｙ２は、－ＮＧ２２－、－ＮＨ－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－、又は－ＮＨ－Ｃ（＝Ｏ）－Ｌ２２－ＮＧ３２－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－であり；
　Ｇ２１、Ｇ３１、Ｇ２２、及びＧ３２は、それぞれ独立して、水素原子、又は１～５個の－ＣＯＯＲ３基で置換されていてもよいフェニル基及び－ＣＯＯＲ３基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ６アルキル基であり；
　Ｒ３は、それぞれ独立して、水素原子、又は１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｌ１１、Ｌ２１、Ｌ１２、及びＬ２２は、それぞれ独立して、１～５個の－ＣＯＯＲ４基で置換されていてもよい１～５個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、Ｃ１－Ｃ４アルキレン－フェニレン基、又はフェニレン－Ｃ１－Ｃ４アルキレン基であり；
　Ｒ４は、それぞれ独立して、水素原子、又は１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｚは、－（ＣＨ２－ＣＨ２－Ｏ）ｍ－ＣＨ２－ＣＨ２－、又は－（ＣＨ２）ｎ－であり；
　ｍは、１～６の整数であり；
　ｎは、２～１２の整数である］
で表される化合物又はその薬学上許容される塩である、［２］～［４］のいずれか１つに記載の薬剤。
［６］
　エンテロペプチダーゼ阻害剤が
　（２Ｓ，１３Ｓ）－３，１２－ビス（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）－６，９－ジオキサ－３，１２－ジアザテトラデカン－１，２，１３，１４－テトラカルボン酸；
　（２Ｓ，２’Ｓ）－２，２’－（（オキシビス（エタン－２，１－ジイル））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸；
　（２Ｓ，１６Ｓ）－３，１５－ビス（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）－６，９，１２－トリオキサ－３，１５－ジアザヘプタデカン－１，２，１６，１７－テトラカルボン酸；
　（２Ｓ，２’Ｓ）－２，２’－（（［１，１’－ビフェニル］－３，３’－ジイルビス（メチレン））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸；及び
　（２Ｓ，２’Ｓ）－２，２’－（（（（（オキシビス（エタン－２，１－ジイル））ビス（オキシ））ビス（３－カルボキシ－５，１－フェニレン））ビス（メチレン））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸
からなる群から選択される化合物又はその薬学上許容される塩である、［２］～［５］のいずれか１つに記載の薬剤。
［７］
　エンテロペプチダーゼ阻害剤が（２Ｓ，２’Ｓ）－２，２’－（（オキシビス（エタン－２，１－ジイル））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸である、［２］～［６］のいずれか１つに記載の薬剤。
［８］
　インクレチン様物質がＧＬＰ－１受容体作動薬である、［１］～［７］のいずれか１つに記載の薬剤。
［９］
　ＧＬＰ－１受容体作動薬がセマグルチド、リラグルチド、デュラグルチド、エキセナチド、リキシセナチド、アルビグルチド、及びエフペグレナチドからなる群から選択される１つ以上のＧＬＰ－１受容体作動薬である、［８］に記載の薬剤。
［１０］
　ＧＬＰ－１受容体作動薬がセマグルチド、リラグルチド、及びデュラグルチドからなる群から選択される１つ以上のＧＬＰ－１受容体作動薬である、［８］に記載の薬剤。
［１１］
　ＧＬＰ－１受容体作動薬がセマグルチドである、［８］に記載の薬剤。
［１２］
　ＧＬＰ－１受容体作動薬がリラグルチドである、［８］に記載の薬剤。
［１３］
　消化管プロテアーゼ及び／又はインクレチンが関与する疾患を予防、緩和、及び／又は治療するための、［１］～［１２］のいずれか１つに記載の薬剤。
［１４］
　消化管プロテアーゼ及び／又はインクレチンが関与する疾患が肥満症及び糖尿病から選択される１つ以上の疾患である、［１３］に記載の薬剤。
［１５］
　消化管プロテアーゼ阻害剤とインクレチン様物質が別々の組成物に製剤化されている、［１］～［１４］のいずれか１つに記載の薬剤。 The present invention provides:
[1]
A drug containing a gastrointestinal protease inhibitor for use in combination with an incretin-like substance (hereinafter, also referred to as "this drug").
[2]
The agent according to [1], wherein the gastrointestinal protease inhibitor is an enteropeptidase inhibitor and / or a trypsin inhibitor.
[3]
The agent according to [1], wherein the gastrointestinal protease inhibitor is an enteropeptidase inhibitor.
[4]
The enteropeptidase inhibitor is (a) the following general formula (I):
Figure JPOXMLDOC01-appb-C000008
 [In the formula, A 1 and A 2 are independent of each other, and the following group A:
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000012
 Compounds selected from, or the following general formula (II):
Figure JPOXMLDOC01-appb-C000013
 [During the ceremony,
Rings B and C are independently aryl groups or heteroaryl groups;
Each R 1 is independently a hydrogen atom, or -COO- (C 1 -C 4 alkyl group);
W is a single bond, or a C 1 -C 4 alkylene group;
X is -C (= O)-, -OC (= O)-, or -NG-SO 2- ;
G is hydrogen, C 1 -C 4 alkyl group, or a -COOR 2;
R 2 is 1-5 optionally substituted by an aryl group C 1 -C 4 alkyl group;
Y is -NG 2 G 4 , -NG 2- L 1- COOH, -NG 2- L 1- C (= O) -NH 2 , -NG 2- L 1- C (= O) -NG 3- L 2- COOH, -NG 2- L 1- C (= O) -NG 3- L 2- C (= O) -NG 3- L 2- COOH, -NG 2- L 1- C (= O) -NG 3- L 2- C (= O) -NH 2 , -NG 2- L 3- OH, or -NG 2- (CH 2- CH 2- O) q -CH 2- CH 2- COOH. ;
q is an integer from 1 to 6;
G 2 and G 3 are, 1 each independently selected hydrogen atom, or a 1-5 -COOR 3 phenyl group which may be substituted with groups and independently from the group consisting of -COOR 3 group ~ be five may be substituted with a substituent C 1 -C 6 alkyl group;
G 4 are hydrogen, C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy -C 1 -C 4 alkyl group;
R 3 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group;
L 1 and L 2 may be independently substituted with 1 to 5 —COOR 4 groups and may be substituted with 1 to 5 C 1 − C 6 alkyl groups C 1 −. C 7- C 12 substituted with 1-5 substituents independently selected from the group consisting of C 6 alkylene group, hydroxy group and carboxy group C 1- C 6 substituted with aralkyl group alkylene group, C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group;
L 3 is a phenylene moiety 1-3 optionally substituted by -COOR 4 group of C 1 -C 4 alkylene - be a phenylene group;
R 4 are each independently a hydrogen atom, or an aryl group and 1 to 5 may be substituted with a substituent C 1 -C 4 alkyl groups independently selected from the group consisting of trimethylsilyl group ;
R 5 and R 6 are each independently a hydrogen atom, a halogen atom, C 1 -C 4 alkyl group, C 1 -C 4 alkoxy group, a carboxy group, or -C (= O) -NG 2 G 4 can be;
s and t are independently integers from 1 to 4;
A plurality of R 5 and / or R 6, which may be each independently identical or different;
Or any one of any one and R 6 in R 5, taken together, may form a C 1 -C 4 alkylene group]
Indicates a residue obtained by removing any one hydrogen atom or hydroxy group from the compound represented by;
Z is a single bond, arylene, heteroarylene, or C 2 -C 30 alkylene group (wherein one or more methylene groups in the chain of the alkylene group, -C (= O) -, - NR 7 -, -O -, - SiR 8 R 9 -, - SO r -, arylene, and may be replaced by groups independently selected from the group consisting heteroarylene, R 7 is a hydrogen atom, or a C 1 -C an alkyl group, R 8 and R 9 are each independently a C 1 -C 4 alkyl group, r is an a) an integer of 0-2]
The compound represented by or a pharmaceutically acceptable salt thereof;
One or more compounds selected from the group consisting of (b) a compound of group A or a pharmaceutically acceptable salt thereof; and (c) a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof. Or the agent according to [2] or [3], which is a pharmaceutically acceptable salt thereof.
[5]
The enteropeptidase inhibitor is the following general formula (III):
Figure JPOXMLDOC01-appb-C000014
 [During the ceremony,
Each R 1 is independently a hydrogen atom, or -COO- (C 1 -C 4 alkyl group);
W 1 and W 2 are each independently a single bond, or a C 1 -C 4 alkylene group;
X 1 is -C (= O)-or-NG 11 -SO 2- ;
X 2 is, -C (= O) -, or -SO 2 -NG 12 - a and;
G 11 and G 12 are independently hydrogen atoms, or -COOR 2 ;
R 2 is 1-5 optionally substituted by an aryl group C 1 -C 4 alkyl group;
Y 1 is, -NG 21 -, - NG 21 -L 11 -C (= O) -NH-, or -NG 21 -L 11 -C (= O ) -NG 31 -L 21 -C (= O) -NH-;
Y 2 is, -NG 22 -, - NH- C (= O) -L 12 -NG 22 -, or -NH-C (= O) -L 22 -NG 32 -C (= O) -L 12 - NG 22- and;
G 21, G 31, G 22 , and G 32 is a independently a hydrogen atom, or 1 to the group of five -COOR 3 phenyl group and -COOR 3 groups optionally substituted by group independently is 1 to 5 C 1 may be substituted with a substituent -C 6 alkyl group which is selected;
R 3 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group;
L 11 , L 21 , L 12 and L 22 are each independently substituted with 1 to 5 C 1- C 6 alkyl groups, which may be substituted with 1 to 5 -COOR 4 groups. which may be C 1 -C 6 alkylene group, C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group;
R 4 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group;
Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and;
m is an integer from 1 to 6;
n is an integer from 2 to 12]
The agent according to any one of [2] to [4], which is a compound represented by (1) or a pharmaceutically acceptable salt thereof.
[6]
Enteropeptidase inhibitors are (2S, 13S) -3,12-bis (10-guanidine-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl ) -6,9-Dioxa-3,12-Diazatetradecane-1,2,13,14-Tetracarboxylic acid;
(2S, 2'S) -2,2'-((oxybis (ethane-2,1-diyl))) Bis ((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandyl)) disuccinic acid;
(2S, 16S) -3,15-bis (10-guanidine-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) -6,9 , 12-Trioxa-3,15-diazaheptadecane-1,2,16,17-tetracarboxylic acid;
(2S, 2'S) -2,2'-(([1,1'-biphenyl] -3,3'-diylbis (methylene))) Bis ((10-guanidino-13-oxo-6,7,8) , 13-Tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandyl)) disuccinic acid; and (2S, 2'S) -2,2'-(((((oxybis (ethane) ethane) -2,1-diyl)) bis (oxy)) bis (3-carboxy-5,1-phenylene)) bis (methylene)) bis ((10-guanidino-13-oxo-6,7,8,13-) Tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandyl)) A compound selected from the group consisting of disuccinic acid or a pharmaceutically acceptable salt thereof, [2] to [5]. The agent according to any one of the above.
[7]
The enteropeptidase inhibitor is (2S, 2'S) -2,2'-((oxybis (ethane-2,1-diyl)) bis ((10-guanidino-13-oxo-6,7,8,13-) The agent according to any one of [2] to [6], which is tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandiyl)) disuccinic acid.
[8]
The agent according to any one of [1] to [7], wherein the incretin-like substance is a GLP-1 receptor agonist.
[9]
The agent according to [8], wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists selected from the group consisting of semaglutide, liraglutide, duraglutide, exenatide, lixisenatide, albiglutide, and efpeglenatide. ..
[10]
The agent according to [8], wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists selected from the group consisting of semaglutide, liraglutide, and duraglutide.
[11]
The agent according to [8], wherein the GLP-1 receptor agonist is semaglutide.
[12]
The agent according to [8], wherein the GLP-1 receptor agonist is liraglutide.
[13]
The agent according to any one of [1] to [12] for preventing, alleviating, and / or treating a disease associated with gastrointestinal protease and / or incretin.
[14]
The agent according to [13], wherein the disease involving gastrointestinal protease and / or incretin is one or more diseases selected from obesity and diabetes.
[15]
The agent according to any one of [1] to [14], wherein the gastrointestinal protease inhibitor and the incretin-like substance are formulated in separate compositions.
　本薬剤は、肥満症や糖尿病等の疾患に対して優れた予防、緩和、及び／又は治療効果を有する。特に、肥満症に対しては、ルーワイ胃バイパス術（Ｒｏｕｘ－ｅｎ－Ｙ　Ｇａｓｔｒｉｃ　Ｂｙｐａｓｓ；ＲＹＧＢ）等の肥満手術及びエンドバリア等の肥満治療用デバイスと同等の非常に強い体重低下効果を示す。 This drug has excellent preventive, alleviating, and / or therapeutic effects on diseases such as obesity and diabetes. In particular, for obesity, it exhibits a very strong weight-reducing effect equivalent to that of obesity surgery such as Roux-en-Y Gastric Bypass (RYGB) and obesity treatment devices such as end barrier.
図１は、試験例１における０日目から２１日間の体重変動（％）を示すグラフである。FIG. 1 is a graph showing body weight fluctuation (%) from the 0th day to the 21st day in Test Example 1. 図２は、試験例２における血中ＦＧＦ－２１量を比較したグラフである。FIG. 2 is a graph comparing the amount of FGF-21 in blood in Test Example 2. 図３は、試験例２における血中インスリン量を比較したグラフである。FIG. 3 is a graph comparing the amount of insulin in blood in Test Example 2. 図４は、試験例２における血中ＨｂＡ１ｃ量を比較したグラフである。FIG. 4 is a graph comparing the amount of HbA1c in blood in Test Example 2. 図５は、試験例３における０日目から２１日間の体重変動（％）を示すグラフである。FIG. 5 is a graph showing the body weight fluctuation (%) from the 0th day to the 21st day in Test Example 3. 図６は、試験例４における血中ＦＧＦ－２１量を比較したグラフである。FIG. 6 is a graph comparing the amount of FGF-21 in blood in Test Example 4. 図７は、試験例４における血中インスリン量を比較したグラフである。FIG. 7 is a graph comparing the amount of insulin in blood in Test Example 4. 図８は、試験例４における血中ＨｂＡ１ｃ量を比較したグラフである。FIG. 8 is a graph comparing the amount of HbA1c in blood in Test Example 4. 図９は、試験例５における０日目から２１日間の体重変動（％）を示すグラフである。FIG. 9 is a graph showing the body weight fluctuation (%) from the 0th day to the 21st day in Test Example 5.
　本発明の態様及び実施態様について、以下に説明する。なお、本明細書中、「一般式（Ｉ）で表される化合物」等を便宜上、それぞれ「化合物（Ｉ）」等ともいう。以下に定義又は例示される各種の置換基は、任意に選択して組み合わせることができる。又、以下に定義される各態様及び実施態様を任意に選択して組み合わせた態様及び実施態様も本発明に包含される。 The embodiments and embodiments of the present invention will be described below. In the present specification, "compound represented by the general formula (I)" and the like are also referred to as "compound (I)" and the like for convenience. The various substituents defined or exemplified below can be arbitrarily selected and combined. The present invention also includes aspects and embodiments in which the embodiments and embodiments defined below are arbitrarily selected and combined.
　本明細書において用いる各用語の定義は以下の通りである。 The definitions of each term used in this specification are as follows.
　本明細書に記載の「薬剤」は、インクレチン様物質と組み合わせて使用され、消化管プロテアーゼ阻害剤を含むものであればその形態は限定されない。例えば該薬剤は消化管プロテアーゼ阻害剤とインクレチン様物質が１つの組成物に製剤化された合剤の形態であってもよく、又消化管プロテアーゼ阻害剤を含む薬剤であって、別に製剤化されたインクレチン様物質を含む薬剤と別々に投与される形態であってもよい。消化管プロテアーゼ阻害剤とインクレチン様物質が別々の組成物に製剤化されている場合、それらを含むキットの形態として使用してもよい。 The "drug" described in the present specification is used in combination with an incretin-like substance, and its form is not limited as long as it contains a gastrointestinal protease inhibitor. For example, the drug may be in the form of a mixture in which a gastrointestinal protease inhibitor and an incretin-like substance are formulated in one composition, or a drug containing a gastrointestinal protease inhibitor, which is separately formulated. It may be administered separately from the drug containing the incretin-like substance. If the gastrointestinal protease inhibitor and the incretin-like substance are formulated in separate compositions, they may be used in the form of a kit containing them.
　本明細書に記載の「消化管プロテアーゼ阻害剤」は、口腔、食道、胃、小腸、及び大腸等の消化管から分泌されるプロテアーゼを阻害する活性を有する物質であれば、特に限定されるものではない。消化管プロテアーゼ阻害剤としては、例えば、エンテロペプチダーゼ阻害剤及び／又はトリプシン阻害剤が挙げられ、エンテロペプチダーゼ阻害剤が好ましい。 The "gastrointestinal protease inhibitor" described in the present specification is particularly limited as long as it is a substance having an activity of inhibiting a protease secreted from the gastrointestinal tract such as the oral cavity, esophagus, stomach, small intestine, and large intestine. is not it. Examples of the gastrointestinal protease inhibitor include enteropeptidase inhibitors and / or trypsin inhibitors, and enteropeptidase inhibitors are preferable.
　本明細書に記載の「エンテロペプチダーゼ阻害剤」及び「トリプシン阻害剤」は、それぞれエンテロペプチダーゼ阻害活性及びトリプシン阻害活性を有する物質であれば、特に限定されるものではない。エンテロペプチダーゼ阻害剤及び／又はトリプシン阻害剤としては、例えば、化合物（Ｉ）又はその薬学上許容される塩、群Ａの化合物又はその薬学上許容される塩、及び化合物（ＩＩ）又はその薬学上許容される塩が挙げられ、化合物（Ｉ）又はその薬学上許容される塩が好ましい。 The "enteropeptidase inhibitor" and "trypsin inhibitor" described in the present specification are not particularly limited as long as they are substances having enterelopeptidase inhibitory activity and trypsin inhibitory activity, respectively. Examples of the enteropeptidase inhibitor and / or trypsin inhibitor include compound (I) or a pharmaceutically acceptable salt thereof, a compound of group A or a pharmaceutically acceptable salt thereof, and compound (II) or a pharmaceutically acceptable salt thereof. Examples include acceptable salts, preferably compound (I) or a pharmaceutically acceptable salt thereof.
　本明細書に記載の「インクレチン様物質」は、インクレチン及びインクレチンと同様の活性を有する物質を包含する。インクレチン様物質としては、例えば、ＧＬＰ－１受容体作動薬及びグルコース依存性インスリン分泌刺激ポリペプチド（ｇｌｕｃｏｓｅ－ｄｅｐｅｎｄｅｎｔ　ｉｎｓｕｌｉｎｏｔｒｏｐｉｃ　ｐｏｌｙｐｅｐｔｉｄｅ：ＧＩＰ）が挙げられ、ＧＬＰ－１受容体作動薬が好ましい。ＧＬＰ－１受容体作動薬としては、例えばセマグルチド（ｓｅｍａｇｌｕｔｉｄｅ）、リラグルチド（ｌｉｒａｇｌｕｔｉｄｅ）、デュラグルチド（ｄｕｌａｇｌｕｔｉｄｅ）、エキセナチド（ｅｘｅｎａｔｉｄｅ）、リキシセナチド（ｌｉｘｉｓｅｎａｔｉｄｅ）、アルビグルチド（ａｌｂｉｇｌｕｔｉｄｅ）、及びエフペグレナチド（ｅｆｐｅｇｌｅｎａｔｉｄｅ）が挙げられる。また「インクレチン様物質」としてはインクレチン様作用とグルカゴン様作用の両方を合わせ持つものでもよく、グルカゴン様作用についてはグルカゴン拮抗作用でも良い。 The "incretin-like substance" described in the present specification includes incretins and substances having the same activity as incretins. Examples of the incretin-like substance include a GLP-1 receptor agonist and a glucose-dependent insulinotropic polypeptide (GIP), and a GLP-1 receptor agonist is preferable. Examples of GLP-1 receptor agonists include semaglutide, liraglutide, dulaglutide, exenatide, lixisenatide, lixisenatide, albiglutide, albiglutide, albiglutide, and albiglutide. Further, the "incretin-like substance" may have both an incretin-like action and a glucagon-like action, and the glucagon-like action may be a glucagon antagonistic action.
　本明細書記載の「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、又はヨウ素原子を意味する。ハロゲン原子としては、フッ素原子及び塩素原子が好ましい。 The "halogen atom" described in the present specification means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. As the halogen atom, a fluorine atom and a chlorine atom are preferable.
　本明細書記載の「Ｃ１－Ｃ４アルキル基」とは、炭素数１～４の直鎖状、又は分岐状の飽和炭化水素基を意味する。Ｃ１－Ｃ４アルキル基としては、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、及びｔｅｒｔ－ブチル基等が挙げられる。メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、及びｔｅｒｔ－ブチル基が好ましい。
　また、本明細書記載の「Ｃ１－Ｃ６アルキル基」とは、炭素数１～６の直鎖状、又は分岐状の飽和炭化水素基を意味する。Ｃ１－Ｃ６アルキル基としては、上記「Ｃ１－Ｃ４アルキル基」に包含される基に加え、例えば、ｎ－ペンチル基、イソペンチル基、ｎ－ヘキシル基、及びイソヘキシル基等が挙げられる。メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、及びｎ－ヘキシル基が好ましい。
　「Ｃ１－Ｃ４アルキル基」及び「Ｃ１－Ｃ６アルキル基」のさらに好ましい形態としては、例えばＣ１－Ｃ３アルキル基（すなわちメチル基、エチル基、ｎ－プロピル基、及びイソプロピル基、好ましくはメチル基、エチル基、及びｎ－プロピル基）、並びにＣ１－Ｃ２アルキル基（すなわちメチル基、及びエチル基、好ましくはメチル基）等が挙げられる。 The "C 1 -C 4 alkyl group" described herein means a straight or branched saturated hydrocarbon group having 1 to 4 carbon atoms. The C 1 -C 4 alkyl group, e.g., methyl group, ethyl group, n- propyl group, an isopropyl group, n- butyl group, isobutyl group, sec- butyl group, and a tert- butyl group and the like. Methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl groups are preferred.
The "C 1 -C 6 alkyl group" described herein means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. The C 1 -C 6 alkyl group, in addition to the radicals included within the "C 1 -C 4 alkyl group", for example, n- pentyl group, and isopentyl group, n- hexyl, and isohexyl group and the like .. Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, n-pentyl group, and n-hexyl group are preferable.
More preferred forms of the "C 1- C 4 alkyl group" and the "C 1- C 6 alkyl group" are, for example, a C 1- C 3 alkyl group (ie, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group). , preferably a methyl group, an ethyl group, and n- propyl group), and C 1 -C 2 alkyl group (i.e. methyl and ethyl, and the like, preferably a methyl group) or the like.
　本明細書記載の「Ｃ１－Ｃ４アルキレン基」とは、上記「Ｃ１－Ｃ４アルキル基」の任意の水素原子１個を除去した二価基を意味する。Ｃ１－Ｃ４アルキレン基としては、例えば、メチレン基、エチレン基、メチルメチレン基、トリメチレン基、エチルメチレン基、ジメチルメチレン基、及びテトラメチレン基等が挙げられる。メチレン基、エチレン基、メチルメチレン基、トリメチレン基、及びテトラメチレン基が好ましい。
　本明細書記載の「Ｃ１－Ｃ６アルキレン基」とは、上記「Ｃ１－Ｃ６アルキル基」の任意の水素原子１個を除去した二価基を意味する。Ｃ１－Ｃ６アルキレン基としては、上記「Ｃ１－Ｃ４アルキレン基」に包含される基に加え、例えば、ペンタメチレン基及びヘキサメチレン基等が挙げられる。メチレン基、エチレン基、メチルメチレン基、トリメチレン基、テトラメチレン基、ペンタメチレン基、及びヘキサメチレン基が好ましい。
　「Ｃ１－Ｃ４アルキレン基」及び「Ｃ１－Ｃ６アルキレン基」のさらに好ましい形態としては、Ｃ１－Ｃ２アルキレン基（すなわちメチレン基、及びエチレン基、好ましくはメチレン基）等が挙げられる。 The "C 1 -C 4 alkylene group" described herein, refers to a divalent group obtained by removing one arbitrary hydrogen atom of the above "C 1 -C 4 alkyl group". The C 1 -C 4 alkylene group include a methylene group, an ethylene group, methylmethylene group, trimethylene group, ethyl methylene group, dimethylmethylene group, and tetramethylene group and the like. Methylene groups, ethylene groups, methylmethylene groups, trimethylene groups, and tetramethylene groups are preferable.
The "C 1 -C 6 alkylene group" described herein, refers to a divalent group obtained by removing one arbitrary hydrogen atom of the above "C 1 -C 6 alkyl group". The C 1 -C 6 alkylene group, in addition to the radicals included within the "C 1 -C 4 alkylene group", for example, a pentamethylene group and a hexamethylene group and the like. Methylene groups, ethylene groups, methylmethylene groups, trimethylene groups, tetramethylene groups, pentamethylene groups, and hexamethylene groups are preferable.
Further preferable forms of the "C 1- C 4 alkylene group" and the "C 1- C 6 alkylene group" include a C 1- C 2 alkylene group (that is, a methylene group and an ethylene group, preferably a methylene group) and the like. Be done.
　本明細書記載の「Ｃ２－Ｃ３０アルキレン基（ただし、該アルキレン基の鎖中の１つ以上のメチレン基は、－Ｃ（＝Ｏ）－、－ＮＲ７－、－Ｏ－、－ＳｉＲ８Ｒ９－、－ＳＯｒ－、アリーレン、及びヘテロアリーレンからなる群から独立して選択される基と置き換わっていてもよく、Ｒ７は水素原子、又はＣ１－Ｃ４アルキル基であり、Ｒ８及びＲ９は、それぞれ独立して、Ｃ１－Ｃ４アルキル基であり、ｒは、０～２の整数である）」とは、炭素数２～３０の直鎖状、又は分岐状の飽和炭化水素基の任意の水素原子１個を除去した二価基において、鎖中の１つ以上のメチレン基が－Ｃ（＝Ｏ）－、－ＮＲ７－、－Ｏ－、－ＳｉＲ８Ｒ９－、－ＳＯｒ－、アリーレン、及びヘテロアリーレンからなる群から独立して選択される基と置き換わっていてもよい基を意味し、例えば－（ＣＨ２－ＣＨ２－Ｃ（＝Ｏ））Ｍ－ＣＨ２－ＣＨ２－（Ｍは１～９の整数である）、－（ＣＨ２－ＣＨ２－ＮＲ７）Ｍ－ＣＨ２－ＣＨ２－（Ｍは１～９の整数である）、－（ＣＨ２－ＣＨ２－Ｏ）Ｍ－ＣＨ２－ＣＨ２－（Ｍは１～９の整数である）、－（ＣＨ２－ＣＨ２－ＳｉＲ８Ｒ９）Ｍ－ＣＨ２－ＣＨ２－（Ｍは１～９の整数である）、－（ＣＨ２－ＣＨ２－ＳＯｒ）Ｍ－ＣＨ２－ＣＨ２－（Ｍは１～９の整数である）、－（ＣＨ２－ＣＨ２－アリーレン）Ｍ－ＣＨ２－ＣＨ２－（Ｍは１～９の整数である）、－（ＣＨ２－ＣＨ２－ヘテロアリーレン）Ｍ－ＣＨ２－ＣＨ２－（Ｍは１～９の整数である）、－（ＣＨ２）Ｎ－（Ｎは２～３０の整数である）等が挙げられる。－（ＣＨ２－ＣＨ２－Ｏ）ｍ－ＣＨ２－ＣＨ２－（ｍは１～６の整数である）、－（ＣＨ２－Ｏ－ＣＨ２）ｍ－（ｍは１～６の整数である）、－（ＣＨ２）ｍ－（Ｃ６－Ｃ１２アリーレン）－（ＣＨ２）ｍ－（ｍは１～６の整数である）及び－（ＣＨ２）ｎ－（ｎは２～１２の整数である）が好ましい。－（ＣＨ２）ｍ－（Ｃ６－Ｃ１２アリーレン）－（ＣＨ２）ｍ－（ｍは１～６の整数である）は、好ましくは－（ＣＨ２）ｍ－ビフェニレン－（ＣＨ２）ｍ－（ｍは１～６の整数である）、より好ましくは－（ＣＨ２）ｍ－（［１，１’－ビフェニル］－３，３’―ジイル）－（ＣＨ２）ｍ－（ｍは１～６の整数である）である。 "C 2 -C 30 alkylene group described herein (provided that one or more methylene groups in the chain of the alkylene group, -C (= O) -, - NR 7 -, - O -, - SiR 8 R 9 -, - SO r -, arylene, and may be replaced by groups independently selected from the group consisting heteroarylene, R 7 is a hydrogen atom, or a C 1 -C 4 alkyl group, R 8 and R 9 are each independently a C 1 -C 4 alkyl groups, r is 0 to a is) "is the integer 2, 2-30 straight, or branched in optional divalent group obtained by removing one hydrogen atom of a saturated hydrocarbon group, one or more methylene groups in the chain -C (= O) -, - NR 7 -, - O -, - SiR 8 R 9 -, - SO r - , means arylene, and substituted group be replaced by groups independently selected from the group consisting heteroarylene, for example - (CH 2 -CH 2 -C ( = O) ) M- CH 2- CH 2- (M is an integer of 1 to 9),-(CH 2- CH 2- NR 7 ) M- CH 2- CH 2- (M is an integer of 1 to 9) ),-(CH 2- CH 2- O) M- CH 2- CH 2- (M is an integer of 1 to 9),-(CH 2- CH 2- SiR 8 R 9 ) M- CH 2- CH 2- (M is an integer from 1 to 9),-(CH 2- CH 2- SO r ) M- CH 2- CH 2- (M is an integer from 1 to 9),-(CH 2) -CH 2 - arylene) M -CH 2 -CH 2 - ( M is an integer of 1 ~ 9), - (CH 2 -CH 2 - heteroarylene) M -CH 2 -CH 2 - ( M 1 to (It is an integer of 9),-(CH 2 ) N- (N is an integer of 2 to 30), and the like. - (CH 2 -CH 2 -O) m -CH 2 -CH 2 - ( where m is an integer of 1 ~ 6), - (CH 2 -O-CH 2) m - (m is an integer from 1 to 6 ),-(CH 2 ) m- (C 6- C 12 allele)-(CH 2 ) m- (m is an integer of 1 to 6) and- (CH 2 ) n- (n is 2 to It is an integer of 12). -(CH 2 ) m- (C 6- C 12 allylene)-(CH 2 ) m- (m is an integer of 1 to 6) is preferably-(CH 2 ) m -biphenylene- (CH 2 ). m- (m is an integer of 1 to 6), more preferably-(CH 2 ) m -([1,1'-biphenyl] -3,3'-diyl)-(CH 2 ) m- (m) Is an integer from 1 to 6).
　本明細書記載の「フェニレン基」とは、フェニル基の任意の水素原子１個を除去した二価基を意味する。フェニレン基としては、ｏ－フェニレン基、ｍ－フェニレン基、及びｐ－フェニレン基が挙げられる。本明細書記載の「ビフェニレン基」とは、２個のフェニレン基が単結合で連結した二価基を意味する。ビフェニレン基としては、例えば、［１，１’－ビフェニル］－２，２’―ジイル基、［１，１’－ビフェニル］－３，３’―ジイル基、及び［１，１’－ビフェニル］－４，４’―ジイル基等が挙げられ、好ましくは、［１，１’－ビフェニル］－３，３’―ジイル基である。 The "phenylene group" described in the present specification means a divalent group obtained by removing an arbitrary hydrogen atom of a phenyl group. Examples of the phenylene group include an o-phenylene group, an m-phenylene group, and a p-phenylene group. The "biphenylene group" described in the present specification means a divalent group in which two phenylene groups are linked by a single bond. Examples of the biphenylene group include [1,1'-biphenyl] -2,2'-diyl group, [1,1'-biphenyl] -3,3'-diyl group, and [1,1'-biphenyl]. -4,4'-diyl group and the like are mentioned, and [1,1'-biphenyl] -3,3'-diyl group is preferable.
　本明細書記載の「アリール基」とは、環構成炭素数６～１２（Ｃ６～Ｃ１２）、例えばＣ６～Ｃ１１の単環式又は二環式の芳香族炭化水素基を意味する。例えば、フェニル基等の単環式のアリール基；ナフチル基、テトラヒドロナフチル基、インデニル基、及びインダニル基等の一部飽和されていてもよい環構成炭素数９～１２（Ｃ９～Ｃ１２）の、例えばＣ９～Ｃ１１の二環式のアリール基が挙げられる。アリール基としては、フェニル基及びナフチル基が好ましく、フェニル基がより好ましい。 As used herein, the term "aryl group" means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 (C 6 to C 12 ) ring-constituting carbon atoms, for example, C 6 to C 11. .. For example, a monocyclic aryl group such as a phenyl group; a ring-constituting carbon number of 9 to 12 (C 9 to C 12 ) which may be partially saturated such as a naphthyl group, a tetrahydronaphthyl group, an indenyl group, and an indanyl group. of, for example, it includes a bicyclic aryl group having C 9 ~ C 11. As the aryl group, a phenyl group and a naphthyl group are preferable, and a phenyl group is more preferable.
　本明細書記載の「アリーレン基」又は「Ｃ６－Ｃ１２アリーレン基」とは、上記「アリール基」の任意の水素原子１個を除去した二価基を意味する。 "Arylene group" or "C 6 -C 12 arylene group" described herein, refers to a divalent group obtained by removing one arbitrary hydrogen atom of the above "aryl group."
　本明細書記載の「ヘテロアリール基」とは、炭素原子以外に酸素原子、硫黄原子及び窒素原子から選ばれるヘテロ原子を１～４個含む５～１１員の単環式又は二環式の芳香族複素環基を意味し、例えば、ピロリル基、フリル基、チエニル基、ピラゾリル基、イミダゾリル基、オキサゾリル基、イソオキサゾリル基、チアゾリル基、イソチアゾリル基、チアジアゾリル基、ピリジル基、ピラジニル基、ピリミジニル基、ピリダジニル基、トリアジニル基等の炭素原子以外に酸素原子、硫黄原子及び窒素原子から選ばれるヘテロ原子を１～４個含む５～６員の単環式のヘテロアリール基；インドリル基、インドリニル基、イソインドリニル基、インダゾリル基、テトラヒドロインダゾリル基、ベンゾフラニル基、ジヒドロベンゾフラニル基、ジヒドロイソベンゾフラニル基、ベンゾチオフェニル基、ジヒドロベンゾチオフェニル基、ジヒドロイソベンゾチオフェニル基、ベンゾオキサゾリル基、ジヒドロベンゾオキサゾリル基、ベンゾチアゾリル基、ジヒドロベンゾチアゾリル基、キノリル基、テトラヒドロキノリル基、イソキノリル基、テトラヒドロイソキノリル基、ナフチリジニル基、テトラヒドロナフチリジニル基、キノキサリニル基、テトラヒドロキノキサリニル基、キナゾリニル基等の炭素原子以外に酸素原子、硫黄原子及び窒素原子から選ばれるヘテロ原子を１～４個含む８～１１員の二環式のヘテロアリール基が挙げられる。ピロリル基、フリル基、チエニル基、ピラゾリル基、イミダゾリル基、オキサゾリル基、イソオキサゾリル基、チアゾリル基、イソチアゾリル基、チアジアゾリル基、ピリジル基、ピラジニル基、ピリミジニル基、ピリダジニル基、及びトリアジニル基が好ましく、ピロリル基、フリル基、及びチエニル基がより好ましい。 The "heteroaryl group" described herein is a 5- to 11-membered monocyclic or bicyclic fragrance containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms. It means a group heterocyclic group, for example, pyrrolyl group, furyl group, thienyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isooxazolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridadinyl group. A 5- to 6-membered monocyclic heteroaryl group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom such as a group and a triazineyl group; an indrill group, an indolinyl group and an isoindrinyl group. , Indazolyl group, tetrahydroindazolyl group, benzofuranyl group, dihydrobenzofuranyl group, dihydroisobenzofuranyl group, benzothiophenyl group, dihydrobenzothiophenyl group, dihydroisobenzothiophenyl group, benzoxazolyl group, Dihydrobenzoxazolyl group, benzothiazolyl group, dihydrobenzothiazolyl group, quinolyl group, tetrahydroquinolyl group, isoquinolyl group, tetrahydroisoquinolyl group, naphthyldinyl group, tetrahydronaphthyldinyl group, quinoxalinyl group, tetrahydroquinoxari Examples thereof include an 8- to 11-membered bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom such as an nyl group and a quinazolinyl group. Pyrrolyl group, furyl group, thienyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isooxazolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, and triazinyl group are preferable. , Frill group, and thienyl group are more preferred.
　本明細書記載の「ヘテロアリーレン基」とは、上記「ヘテロアリール基」の任意の水素原子１個を除去した二価基を意味する。 The "heteroarylene group" described in the present specification means a divalent group from which any one hydrogen atom of the above "heteroaryl group" has been removed.
　本明細書記載の「Ｃ１－Ｃ４アルコキシ基」とは、前記Ｃ１－Ｃ４アルキル基がオキシ基と結合した一価基を意味する。Ｃ１－Ｃ４アルコキシ基としては、例えば、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、及びｔｅｒｔ－ブトキシ基等が挙げられる。メトキシ基、エトキシ基、及びｎ－プロポキシ基が好ましい。 The "C 1 -C 4 alkoxy group" described herein, refers to a monovalent group in which the C 1 -C 4 alkyl group is bonded to oxy group. The C 1 -C 4 alkoxy group include a methoxy group, an ethoxy group, n- propoxy group, isopropoxy group, n- butoxy group, isobutoxy group, sec- butoxy group, and a tert- butoxy group. Methoxy group, ethoxy group, and n-propoxy group are preferable.
　本明細書記載の「Ｃ１－Ｃ４アルコキシ―Ｃ１－Ｃ４アルキル基」とは、前記Ｃ１－Ｃ４アルキル基がＣ１－Ｃ４アルコキシ基で置換された基を意味する。Ｃ１－Ｃ４アルコキシ―Ｃ１－Ｃ４アルキル基としては、例えば、メトキシメチル基、メトキシエチル基、エトキシメチル基、エトキシエチル基、ｎ－プロポキシメチル基、イソプロポキシメチル基、ｎ－ブトキシメチル基、イソブトキシメチル基、ｓｅｃ－ブトキシメチル基、及びｔｅｒｔ－ブトキシメチル基等が挙げられる。メトキシメチル基、メトキシエチル基、エトキシメチル基、及びエトキシエチル基が好ましい。 The "C 1 -C 4 alkoxy -C 1 -C 4 alkyl group" described herein means a group wherein the C 1 -C 4 alkyl group is substituted by C 1 -C 4 alkoxy group. Examples of the C 1- C 4 alkoxy-C 1- C 4 alkyl group include a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, an ethoxyethyl group, an n-propoxymethyl group, an isopropoxymethyl group, and an n-butoxymethyl group. Groups, isobutoxymethyl groups, sec-butoxymethyl groups, tert-butoxymethyl groups and the like can be mentioned. A methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, and an ethoxyethyl group are preferable.
　本明細書記載の「Ｃ１－Ｃ４アルキレンオキシ基」とは、前記Ｃ１－Ｃ４アルキレン基がオキシ基と結合した二価基を意味する。Ｃ１－Ｃ４アルキレンオキシ基としては、例えば、メチレンオキシ基、エチレンオキシ基、メチルメチレンオキシ基、トリメチレンオキシ基、エチルメチレンオキシ基、ジメチルメチレンオキシ基、及びテトラメチレンオキシ基等が挙げられる。エチレンオキシ基、トリメチレンオキシ基、及びテトラメチレンオキシ基が好ましい。 The "C 1 -C 4 alkylene group" described herein means a bivalent radical wherein C 1 -C 4 alkylene group is bonded to oxy group. The C 1 -C 4 alkyleneoxy group, for example, methylene group, ethylene group, methylmethylene group, trimethylene group, ethyl methylene group, a dimethylmethylene group, and tetramethylene group, and the like .. Ethyleneoxy groups, trimethyleneoxy groups, and tetramethyleneoxy groups are preferred.
　本明細書記載の「Ｃ７－Ｃ１２アラルキル基」とは、前記Ｃ１－Ｃ６アルキル基が前記アリール基で置換された基を意味する。Ｃ７－Ｃ１２アラルキル基としては、例えばベンジル基及びフェネチル基等が挙げられる。ベンジル基が好ましい。 The "C 7 -C 12 aralkyl group" described herein means a group wherein the C 1 -C 6 alkyl group substituted with an aryl group. Examples of the C 7- C 12 aralkyl group include a benzyl group and a phenethyl group. A benzyl group is preferred.
　本明細書記載の「いずれか１つの水素原子又はヒドロキシ基を除いた残基」における「いずれか１つの水素原子」は、炭素原子、窒素原子、又は酸素原子に結合したいずれか１つの水素原子を意味する。
　本明細書記載の「いずれか１つの水素原子又はヒドロキシ基を除いた残基」における「いずれか１つのヒドロキシ基」は、ヒドロキシ基であってもよく、又はカルボキシ基に存在するヒドロキシ基であってもよい。 The "any one hydrogen atom" in the "residue excluding any one hydrogen atom or hydroxy group" described in the present specification is any one hydrogen atom bonded to a carbon atom, a nitrogen atom, or an oxygen atom. Means.
The "any one hydroxy group" in the "residue excluding any one hydrogen atom or hydroxy group" described in the present specification may be a hydroxy group or is a hydroxy group present in a carboxy group. You may.
　以下に、本発明の態様を記載する。なお、以下の各態様を任意に選択して組み合わせた態様も本発明に包含される。 Hereinafter, aspects of the present invention will be described. The present invention also includes aspects in which the following aspects are arbitrarily selected and combined.
［態様１］
　インクレチン様物質と組み合わせて使用するための、消化管プロテアーゼ阻害剤を含む薬剤（すなわち、本薬剤）。
［態様２］
　消化管プロテアーゼ阻害剤がエンテロペプチダーゼ阻害剤及び／又はトリプシン阻害剤である、態様１に記載の本薬剤。
［態様３］
　消化管プロテアーゼ阻害剤がエンテロペプチダーゼ阻害剤である、態様１に記載の本薬剤。 [Aspect 1]
A drug containing a gastrointestinal protease inhibitor for use in combination with an incretin-like substance (ie, this drug).
[Aspect 2]
The agent according to aspect 1, wherein the gastrointestinal protease inhibitor is an enteropeptidase inhibitor and / or a trypsin inhibitor.
[Aspect 3]
The drug according to aspect 1, wherein the gastrointestinal protease inhibitor is an enteropeptidase inhibitor.
［態様４］
　エンテロペプチダーゼ阻害剤が
（ａ）下記一般式（Ｉ）：
Figure JPOXMLDOC01-appb-C000015
 ［式中、Ａ１及びＡ２は、それぞれ独立して、以下の群Ａ：
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000019
 から選択される化合物、又は下記一般式（ＩＩ）：
Figure JPOXMLDOC01-appb-C000020
 ［式中、
　環Ｂ及び環Ｃは、それぞれ独立して、アリール基、又はヘテロアリール基であり；
　各Ｒ１は、それぞれ独立して、水素原子、又は－ＣＯＯ－（Ｃ１－Ｃ４アルキル基）であり；
　Ｗは、単結合、又はＣ１－Ｃ４アルキレン基であり；
　Ｘは、－Ｃ（＝Ｏ）－、－Ｏ－Ｃ（＝Ｏ）－、又は－ＮＧ－ＳＯ２－であり；
　Ｇは水素原子、Ｃ１－Ｃ４アルキル基、又は－ＣＯＯＲ２であり；
　Ｒ２は、１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｙは、－ＮＧ２Ｇ４、－ＮＧ２－Ｌ１－ＣＯＯＨ、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＨ２、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－ＣＯＯＨ、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－ＣＯＯＨ、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－Ｃ（＝Ｏ）－ＮＨ２、－ＮＧ２－Ｌ３－ＯＨ、又は－ＮＧ２－（ＣＨ２－ＣＨ２－Ｏ）ｑ－ＣＨ２－ＣＨ２－ＣＯＯＨであり；
　ｑは、１～６の整数であり；
　Ｇ２及びＧ３は、それぞれ独立して、水素原子、又は１～５個の－ＣＯＯＲ３基で置換されていてもよいフェニル基及び－ＣＯＯＲ３基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ６アルキル基であり；
　Ｇ４は、水素原子、Ｃ１－Ｃ４アルキル基、又はＣ１－Ｃ４アルコキシ―Ｃ１－Ｃ４アルキル基であり；
　Ｒ３は、それぞれ独立して、水素原子、又は１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｌ１及びＬ２は、それぞれ独立して、１～５個の－ＣＯＯＲ４基で置換されていてもよい１～５個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、ヒドロキシ基及びカルボキシ基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ７－Ｃ１２アラルキル基で置換されたＣ１－Ｃ６アルキレン基、Ｃ１－Ｃ４アルキレン－フェニレン基、又はフェニレン－Ｃ１－Ｃ４アルキレン基であり；
　Ｌ３は、フェニレン部分が１～３個の－ＣＯＯＲ４基で置換されていてもよいＣ１－Ｃ４アルキレン－フェニレン基であり；
　Ｒ４は、それぞれ独立して水素原子、又はアリール基及びトリメチルシリル基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｒ５及びＲ６は、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１－Ｃ４アルキル基、Ｃ１－Ｃ４アルコキシ基、カルボキシ基、又は－Ｃ（＝Ｏ）－ＮＧ２Ｇ４であり；
　ｓ及びｔは、それぞれ独立して、１～４の整数であり；
　複数のＲ５及び／又は複数のＲ６は、それぞれ同一であっても異なっていてもよく；
　又は、Ｒ５のいずれか１つ及びＲ６のいずれか１つは互いに結合して、Ｃ１－Ｃ４アルキレンオキシ基を形成してもよい］
で表される化合物からいずれか１つの水素原子又はヒドロキシ基を除いた残基を示し；
　Ｚは、単結合、アリーレン、ヘテロアリーレン、又はＣ２－Ｃ３０アルキレン基（ただし、該アルキレン基の鎖中の１つ以上のメチレン基は、－Ｃ（＝Ｏ）－、－ＮＲ７－、－Ｏ－、－ＳｉＲ８Ｒ９－、－ＳＯｒ－、アリーレン、及びヘテロアリーレンからなる群から独立して選択される基と置き換わっていてもよく、Ｒ７は水素原子、又はＣ１－Ｃ４アルキル基であり、Ｒ８及びＲ９は、それぞれ独立して、Ｃ１－Ｃ４アルキル基であり、ｒは、０～２の整数である）である］
で表される化合物又はその薬学上許容される塩；
（ｂ）群Ａの化合物又はその薬学上許容される塩；並びに
（ｃ）一般式（ＩＩ）で表される化合物又はその薬学上許容される塩
からなる群から選択される１つ以上の化合物又はその薬学上許容される塩である、態様２又は３に記載の本薬剤。 [Aspect 4]
The enteropeptidase inhibitor is (a) the following general formula (I):
Figure JPOXMLDOC01-appb-C000015
 [In the formula, A 1 and A 2 are independent of each other, and the following group A:
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000019
 Compounds selected from, or the following general formula (II):
Figure JPOXMLDOC01-appb-C000020
 [During the ceremony,
Rings B and C are independently aryl groups or heteroaryl groups;
Each R 1 is independently a hydrogen atom, or -COO- (C 1 -C 4 alkyl group);
W is a single bond, or a C 1 -C 4 alkylene group;
X is -C (= O)-, -OC (= O)-, or -NG-SO 2- ;
G is hydrogen, C 1 -C 4 alkyl group, or a -COOR 2;
R 2 is 1-5 optionally substituted by an aryl group C 1 -C 4 alkyl group;
Y is -NG 2 G 4 , -NG 2- L 1- COOH, -NG 2- L 1- C (= O) -NH 2 , -NG 2- L 1- C (= O) -NG 3- L 2- COOH, -NG 2- L 1- C (= O) -NG 3- L 2- C (= O) -NG 3- L 2- COOH, -NG 2- L 1- C (= O) -NG 3- L 2- C (= O) -NH 2 , -NG 2- L 3- OH, or -NG 2- (CH 2- CH 2- O) q -CH 2- CH 2- COOH. ;
q is an integer from 1 to 6;
G 2 and G 3 are, 1 each independently selected hydrogen atom, or a 1-5 -COOR 3 phenyl group which may be substituted with groups and independently from the group consisting of -COOR 3 group ~ be five may be substituted with a substituent C 1 -C 6 alkyl group;
G 4 are hydrogen, C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy -C 1 -C 4 alkyl group;
R 3 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group;
L 1 and L 2 may be independently substituted with 1 to 5 —COOR 4 groups and may be substituted with 1 to 5 C 1 − C 6 alkyl groups C 1 −. C 7- C 12 substituted with 1-5 substituents independently selected from the group consisting of C 6 alkylene group, hydroxy group and carboxy group C 1- C 6 substituted with aralkyl group alkylene group, C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group;
L 3 is a phenylene moiety 1-3 optionally substituted by -COOR 4 group of C 1 -C 4 alkylene - be a phenylene group;
R 4 are each independently a hydrogen atom, or an aryl group and 1 to 5 may be substituted with a substituent C 1 -C 4 alkyl groups independently selected from the group consisting of trimethylsilyl group ;
R 5 and R 6 are each independently a hydrogen atom, a halogen atom, C 1 -C 4 alkyl group, C 1 -C 4 alkoxy group, a carboxy group, or -C (= O) -NG 2 G 4 can be;
s and t are independently integers from 1 to 4;
A plurality of R 5 and / or R 6, which may be each independently identical or different;
Or any one of any one and R 6 in R 5, taken together, may form a C 1 -C 4 alkylene group]
Indicates a residue obtained by removing any one hydrogen atom or hydroxy group from the compound represented by;
Z is a single bond, arylene, heteroarylene, or C 2 -C 30 alkylene group (wherein one or more methylene groups in the chain of the alkylene group, -C (= O) -, - NR 7 -, -O -, - SiR 8 R 9 -, - SO r -, arylene, and may be replaced by groups independently selected from the group consisting heteroarylene, R 7 is a hydrogen atom, or a C 1 -C an alkyl group, R 8 and R 9 are each independently a C 1 -C 4 alkyl group, r is an a) an integer of 0-2]
The compound represented by or a pharmaceutically acceptable salt thereof;
One or more compounds selected from the group consisting of (b) a compound of group A or a pharmaceutically acceptable salt thereof; and (c) a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof. Or the drug according to aspect 2 or 3, which is a pharmaceutically acceptable salt thereof.
［態様５］
　Ａ１及びＡ２が、それぞれ独立して、一般式（ＩＩ）で表される化合物からいずれか１つの水素原子又はヒドロキシ基を除いた残基である、態様４に記載の本薬剤。
［態様６］
　一般式（ＩＩ）で表される化合物からいずれか１つの水素原子又はヒドロキシ基を除いた残基が、一般式（ＩＩ）で表される化合物のＸ又はＹに存在するいずれか１つの水素原子又はヒドロキシ基を除いた残基である、態様４又は５に記載の本薬剤。
［態様７］
　いずれか１つの水素原子が、いずれか１つの窒素原子又は酸素原子と結合した水素原子、好ましくはいずれか１つの窒素原子と結合した水素原子である、態様４～６のいずれか１つに記載の本薬剤。
［態様８］
　いずれか１つのヒドロキシ基が、いずれか１つのヒドロキシ基又はカルボキシ基に存在するヒドロキシ基、好ましくはいずれか１つのカルボキシ基に存在するヒドロキシ基である、態様４～７のいずれか１つに記載の本薬剤。 [Aspect 5]
The drug according to aspect 4, wherein A 1 and A 2 are residues obtained by removing any one hydrogen atom or hydroxy group from the compound represented by the general formula (II), respectively.
[Aspect 6]
Any one hydrogen atom or a residue obtained by removing any one hydrogen atom or hydroxy group from the compound represented by the general formula (II) is present in any one hydrogen atom in X or Y of the compound represented by the general formula (II). Alternatively, the drug according to aspect 4 or 5, which is a residue excluding a hydroxy group.
[Aspect 7]
The invention according to any one of aspects 4 to 6, wherein any one hydrogen atom is a hydrogen atom bonded to any one nitrogen atom or oxygen atom, preferably a hydrogen atom bonded to any one nitrogen atom. This drug.
[Aspect 8]
The hydroxy group according to any one of aspects 4 to 7, wherein the hydroxy group is a hydroxy group present in any one hydroxy group or carboxy group, preferably a hydroxy group present in any one carboxy group. This drug.
［態様９］
　化合物（Ｉ）又はその薬学上許容される塩が下記一般式（ＩＩＩ）：
Figure JPOXMLDOC01-appb-C000021
 ［式中、
　各Ｒ１は、それぞれ独立して、水素原子、又は－ＣＯＯ－（Ｃ１－Ｃ４アルキル基）であり；
　Ｗ１及びＷ２は、それぞれ独立して、単結合、又はＣ１－Ｃ４アルキレン基であり；
　Ｘ１は、－Ｃ（＝Ｏ）－、又は－ＮＧ１１－ＳＯ２－であり；
　Ｘ２は、－Ｃ（＝Ｏ）－、又は－ＳＯ２－ＮＧ１２－であり；
　Ｇ１１及びＧ１２は、それぞれ独立して、水素原子、又は－ＣＯＯＲ２であり；
　Ｒ２は、１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｙ１は、－ＮＧ２１－、－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＨ－、又は－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＧ３１－Ｌ２１－Ｃ（＝Ｏ）－ＮＨ－であり；
　Ｙ２は、－ＮＧ２２－、－ＮＨ－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－、又は－ＮＨ－Ｃ（＝Ｏ）－Ｌ２２－ＮＧ３２－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－であり；
　Ｇ２１、Ｇ３１、Ｇ２２、及びＧ３２は、それぞれ独立して、水素原子、又は１～５個の－ＣＯＯＲ３基で置換されていてもよいフェニル基及び－ＣＯＯＲ３基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ６アルキル基であり；
　Ｒ３は、それぞれ独立して、水素原子、又は１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｌ１１、Ｌ２１、Ｌ１２、及びＬ２２は、それぞれ独立して、１～５個の－ＣＯＯＲ４基で置換されていてもよい１～５個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、Ｃ１－Ｃ４アルキレン－フェニレン基、又はフェニレン－Ｃ１－Ｃ４アルキレン基であり；
　Ｒ４は、それぞれ独立して、水素原子、又は１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｚは、－（ＣＨ２－ＣＨ２－Ｏ）ｍ－ＣＨ２－ＣＨ２－、又は－（ＣＨ２）ｎ－であり；
　ｍは、１～６の整数であり；
　ｎは、２～１２の整数である］
で表される化合物又はその薬学上許容される塩である、態様４に記載の本薬剤。 [Aspect 9]
Compound (I) or a pharmaceutically acceptable salt thereof is the following general formula (III):
Figure JPOXMLDOC01-appb-C000021
 [During the ceremony,
Each R 1 is independently a hydrogen atom, or -COO- (C 1 -C 4 alkyl group);
W 1 and W 2 are each independently a single bond, or a C 1 -C 4 alkylene group;
X 1 is -C (= O)-or-NG 11 -SO 2- ;
X 2 is, -C (= O) -, or -SO 2 -NG 12 - a and;
G 11 and G 12 are independently hydrogen atoms, or -COOR 2 ;
R 2 is 1-5 optionally substituted by an aryl group C 1 -C 4 alkyl group;
Y 1 is, -NG 21 -, - NG 21 -L 11 -C (= O) -NH-, or -NG 21 -L 11 -C (= O ) -NG 31 -L 21 -C (= O) -NH-;
Y 2 is, -NG 22 -, - NH- C (= O) -L 12 -NG 22 -, or -NH-C (= O) -L 22 -NG 32 -C (= O) -L 12 - NG 22- and;
G 21, G 31, G 22 , and G 32 is a independently a hydrogen atom, or 1 to the group of five -COOR 3 phenyl group and -COOR 3 groups optionally substituted by group independently is 1 to 5 C 1 may be substituted with a substituent -C 6 alkyl group which is selected;
R 3 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group;
L 11 , L 21 , L 12 and L 22 are each independently substituted with 1 to 5 C 1- C 6 alkyl groups, which may be substituted with 1 to 5 -COOR 4 groups. which may be C 1 -C 6 alkylene group, C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group;
R 4 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group;
Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and;
m is an integer from 1 to 6;
n is an integer from 2 to 12]
The present drug according to Aspect 4, which is a compound represented by the above or a pharmaceutically acceptable salt thereof.
［態様１０］
　化合物（ＩＩＩ）において、Ｒ１における「－ＣＯＯ－（Ｃ１－Ｃ４アルキル基）」のＣ１－Ｃ４アルキル基が、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、又はｔｅｒｔ－ブチル基である、態様９に記載の本薬剤。
［態様１１］
　化合物（ＩＩＩ）において、Ｒ１が、水素原子又はｔｅｒｔ－ブトキシカルボニル基であり、好ましくは水素原子である、態様９又は１０に記載の本薬剤。
［態様１２］
　化合物（ＩＩＩ）において、Ｗ１が、単結合、又はＣ１－Ｃ２アルキレン基であり、好ましくは単結合である、態様９～１１のいずれか１つに記載の本薬剤。
［態様１３］
　化合物（ＩＩＩ）において、Ｗ２が、単結合、又はＣ１－Ｃ２アルキレン基であり、好ましくは単結合である、態様９～１２のいずれか１つに記載の本薬剤。
［態様１４］
　化合物（ＩＩＩ）において、Ｘ１が、－Ｃ（＝Ｏ）－又は－ＮＧ１１－ＳＯ２－であり、好ましくは－Ｃ（＝Ｏ）－である、態様９～１３のいずれか１つに記載の本薬剤。
［態様１５］
　化合物（ＩＩＩ）において、Ｘ２が、－Ｃ（＝Ｏ）－又は－ＳＯ２－ＮＧ１２－であり、好ましくは－Ｃ（＝Ｏ）－である、態様９～１４のいずれか１つに記載の本薬剤。 [Aspect 10]
In the compound (III), C 1 -C 4 alkyl group "-COO- (C 1 -C 4 alkyl group)" in R 1 is methyl group, ethyl group, n- propyl group, an isopropyl group, n- butyl The drug according to aspect 9, which is a group or a tert-butyl group.
[Aspect 11]
The drug according to aspect 9 or 10, wherein in compound (III), R 1 is a hydrogen atom or a tert-butoxycarbonyl group, preferably a hydrogen atom.
[Aspect 12]
In the compound (III), W 1 is a single bond, or a C 1 -C 2 alkylene group, preferably a single bond, the agent according to any one of embodiments 9-11.
[Aspect 13]
In the compound (III), W 2 is a single bond, or a C 1 -C 2 alkylene group, preferably a single bond, the agent according to any one of embodiments 9-12.
[Aspect 14]
In compound (III), X 1 is any one of aspects 9 to 13, wherein X 1 is -C (= O)-or -NG 11- SO 2-, preferably -C (= O)-. The listed drug.
[Aspect 15]
In the compound (III), X 2 is, -C (= O) - or -SO 2 -NG 12 - a and, preferably is -C (= O) - in a, any one of embodiments 9-14 The listed drug.
［態様１６］
　化合物（ＩＩＩ）において、Ｇ１１及びＧ１２における「－ＣＯＯＲ２基」のＲ２が、１～３個のフェニル基で置換されていてもよいＣ１－Ｃ４アルキル基であり、好ましくは１個のフェニル基で置換されていてもよいＣ１－Ｃ４アルキル基であり、より好ましくはメチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、ｔｅｒｔ－ブチル基、又はベンジル基である、態様９～１５のいずれか１つに記載の本薬剤。
［態様１７］
　化合物（ＩＩＩ）において、Ｇ１１が、水素原子、ｔｅｒｔ－ブトキシカルボニル基、又はベンジルオキシカルボニル基であり、好ましくは水素原子、又はベンジルオキシカルボニル基であり、より好ましくは水素原子である、態様９～１６のいずれか１つに記載の本薬剤。
［態様１８］
　化合物（ＩＩＩ）において、Ｇ１２が、水素原子、ｔｅｒｔ－ブトキシカルボニル基、又はベンジルオキシカルボニル基であり、好ましくは水素原子、又はベンジルオキシカルボニル基であり、より好ましくは水素原子である、態様９～１７のいずれか１つに記載の本薬剤。 [Aspect 16]
In the compound (III), G 11 and R 2 of "-COOR 2 group" in the G 12, 1 to 3 is C 1 optionally -C 4 alkyl group substituted with a phenyl group, preferably 1 a number of optionally substituted C 1 -C 4 alkyl group with a phenyl group, more preferably a methyl group, an ethyl group, n- propyl group, an isopropyl group, n- butyl group, tert- butyl group, or benzyl The present drug according to any one of aspects 9 to 15, which is a group.
[Aspect 17]
In compound (III), G 11 is a hydrogen atom, a tert-butoxycarbonyl group, or a benzyloxycarbonyl group, preferably a hydrogen atom or a benzyloxycarbonyl group, and more preferably a hydrogen atom. The present drug according to any one of 16 to 16.
[Aspect 18]
In compound (III), G 12 is a hydrogen atom, a tert-butoxycarbonyl group, or a benzyloxycarbonyl group, preferably a hydrogen atom or a benzyloxycarbonyl group, and more preferably a hydrogen atom. The drug according to any one of 17 to 17.
［態様１９］
　化合物（ＩＩＩ）において、Ｙ１が、－ＮＧ２１－である、態様９～１８のいずれか１つに記載の本薬剤。
［態様２０］
　化合物（ＩＩＩ）において、Ｙ２が、－ＮＧ２２－である、態様９～１９のいずれか１つに記載の本薬剤。 [Aspect 19]
In the compound (III), Y 1 is, -NG 21 - a is, the agent according to any one of embodiments 9-18.
[Aspect 20]
In the compound (III), Y 2 is, -NG 22 - a is, the agent according to any one of embodiments 9-19.
［態様２１］
　化合物（ＩＩＩ）において、Ｇ２１、Ｇ３１、Ｇ２２及びＧ３２における「１～５個の－ＣＯＯＲ３基で置換されていてもよいフェニル基」が、２－（ＣＯＯＲ３）－フェニル基、３－（ＣＯＯＲ３）－フェニル基、又は４－（ＣＯＯＲ３）－フェニル基である、態様９～２０のいずれか１つに記載の本薬剤。 [Aspect 21]
In compound (III), the “phenyl group optionally substituted with 1 to 5 −COOR 3 groups” in G 21 , G 31 , G 22 and G 32 is the 2- (COOR 3 ) -phenyl group, The drug according to any one of aspects 9 to 20, which is a 3- (COOR 3 ) -phenyl group or a 4- (COOR 3) -phenyl group.
［態様２２］
　化合物（ＩＩＩ）において、Ｇ２１、Ｇ３１、Ｇ２２及びＧ３２における「－ＣＯＯＲ３基」のＲ３が、それぞれ独立して、水素原子、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、ｔｅｒｔ－ブチル基、又はベンジル基であり、好ましくは水素原子、ベンジル基、又はｔｅｒｔ－ブチル基であり、より好ましくは水素原子、又はｔｅｒｔ－ブチル基であり、さらに好ましくは水素原子である、態様９～２１のいずれか１つに記載の本薬剤。 [Aspect 22]
In compound (III), R 3 of "-COOR 3 groups" in G 21 , G 31 , G 22 and G 32 independently has a hydrogen atom, a methyl group, an ethyl group, an n-propyl group and an isopropyl group. , N-Butyl group, tert-butyl group, or benzyl group, preferably hydrogen atom, benzyl group, or tert-butyl group, more preferably hydrogen atom, or tert-butyl group, still more preferably. The drug according to any one of aspects 9 to 21, which is a hydrogen atom.
［態様２３］
　化合物（ＩＩＩ）において、Ｇ２１が、水素原子、又は１～３個の－ＣＯＯＲ３基で置換されていてもよいＣ１－Ｃ３アルキル基であり、好ましくは、１～３個のカルボキシ基で置換されたＣ１－Ｃ３アルキル基である、態様９～２２のいずれか１つに記載の本薬剤。
［態様２４］
　化合物（ＩＩＩ）において、Ｇ３１が、水素原子、又は１～３個の－ＣＯＯＲ３基で置換されていてもよいＣ１－Ｃ３アルキル基であり、好ましくは、水素原子である、態様９～２３のいずれか１つに記載の本薬剤。
［態様２５］
　化合物（ＩＩＩ）において、Ｇ２２が、水素原子、又は１～３個の－ＣＯＯＲ３基で置換されていてもよいＣ１－Ｃ３アルキル基であり、好ましくは、１～３個のカルボキシ基で置換されたＣ１－Ｃ３アルキル基である、態様９～２４のいずれか１つに記載の本薬剤。
［態様２６］
　化合物（ＩＩＩ）において、Ｇ３２が、水素原子、又は１～３個の－ＣＯＯＲ３基で置換されていてもよいＣ１－Ｃ３アルキル基であり、好ましくは、水素原子である、態様９～２５のいずれか１つに記載の本薬剤。 [Aspect 23]
In the compound (III), G 21 is hydrogen atom, or one to three -COOR 3 group in an optionally substituted C 1 -C 3 alkyl group, preferably one to three carboxy groups in a substituted C 1 -C 3 alkyl group, the agent according to any one of embodiments 9-22.
[Aspect 24]
In the compound (III), G 31 is hydrogen atom, or one to three -COOR 3 group in an optionally substituted C 1 -C 3 alkyl group, preferably a hydrogen atom, aspects 9 The present drug according to any one of ~ 23.
[Aspect 25]
In the compound (III), G 22 is hydrogen atom, or one to three -COOR 3 group in an optionally substituted C 1 -C 3 alkyl group, preferably one to three carboxy groups in a substituted C 1 -C 3 alkyl group, the agent according to any one of embodiments 9-24.
[Aspect 26]
In the compound (III), G 32 is hydrogen atom, or one to three -COOR 3 group in an optionally substituted C 1 -C 3 alkyl group, preferably a hydrogen atom, aspects 9 The present drug according to any one of 25 to 25.
［態様２７］
　化合物（ＩＩＩ）において、Ｌ１１、Ｌ１２、Ｌ２１、及びＬ２２における「－ＣＯＯＲ４基」のＲ４が、それぞれ独立して、水素原子、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、ｔｅｒｔ－ブチル基、又はベンジル基であり、好ましくは水素原子、ｔｅｒｔ－ブチル基、又はベンジル基であり、より好ましくは水素原子、又はｔｅｒｔ－ブチル基であり、さらに好ましくは水素原子である態様９～２６のいずれか１つに記載の本薬剤。
［態様２８］
　化合物（ＩＩＩ）において、Ｌ１１が、Ｃ１－Ｃ２アルキレン基であり、好ましくはメチレン基である、態様９～２７のいずれか１つに記載の本薬剤。
［態様２９］
　化合物（ＩＩＩ）において、Ｌ１２が、Ｃ１－Ｃ２アルキレン基であり、好ましくはメチレン基である、態様９～２８のいずれか１つに記載の本薬剤。
［態様３０］
　化合物（ＩＩＩ）において、Ｌ２１が、Ｃ１－Ｃ２アルキレン基であり、好ましくはメチレン基である、態様９～２９のいずれか１つに記載の本薬剤。
［態様３１］
　化合物（ＩＩＩ）において、Ｌ２２が、Ｃ１－Ｃ２アルキレン基であり、好ましくはメチレン基である、態様９～３０のいずれか１つに記載の本薬剤。 [Aspect 27]
In the compound (III), L 11, L 12, L 21, and R 4 "-COOR 4 group" in the L 22 are each independently a hydrogen atom, a methyl group, an ethyl group, n- propyl group, isopropyl A group, an n-butyl group, a tert-butyl group, or a benzyl group, preferably a hydrogen atom, a tert-butyl group, or a benzyl group, more preferably a hydrogen atom or a tert-butyl group, and further preferably. The drug according to any one of aspects 9 to 26, wherein is a hydrogen atom.
[Aspect 28]
In the compound (III), L 11 is a C 1 -C 2 alkylene group, preferably a methylene group, the agent according to any one of embodiments 9-27.
[Aspect 29]
The drug according to any one of aspects 9 to 28, wherein in compound (III), L 12 is a C 1- C 2 alkylene group, preferably a methylene group.
[Aspect 30]
In the compound (III), L 21 is a C 1 -C 2 alkylene group, preferably a methylene group, the agent according to any one of embodiments 9-29.
[Aspect 31]
In the compound (III), L 22 is a C 1 -C 2 alkylene group, preferably a methylene group, the agent according to any one of embodiments 9-30.
［態様３２］
　化合物（ＩＩＩ）において、Ｒ１、Ｒ３、Ｒ４、Ｇ１１、及びＧ１２の少なくとも１つが水素原子である、態様９～３１のいずれか１つに記載の本薬剤。
［態様３３］
　化合物（ＩＩＩ）において、Ｒ１及びＲ４の少なくとも１つが水素原子である、態様９～３２のいずれか１つに記載の本薬剤。
［態様３４］
　化合物（ＩＩＩ）において、Ｒ１、Ｒ３、Ｒ４、Ｇ１１、及びＧ１２がいずれも水素原子である、態様９～３３のいずれか１つに記載の本薬剤。 [Aspect 32]
The agent according to any one of aspects 9 to 31, wherein in compound (III), at least one of R 1 , R 3 , R 4 , G 11 and G 12 is a hydrogen atom.
[Aspect 33]
The drug according to any one of aspects 9 to 32, wherein in compound (III), at least one of R 1 and R 4 is a hydrogen atom.
[Aspect 34]
The drug according to any one of aspects 9 to 33, wherein in compound (III), R 1 , R 3 , R 4 , G 11 and G 12 are all hydrogen atoms.
［態様３５］
　化合物（ＩＩＩ）において、Ｚが、－（ＣＨ２－ＣＨ２－Ｏ）ｍ－ＣＨ２－ＣＨ２－、又は－（ＣＨ２）ｎ－であり、好ましくは－（ＣＨ２－ＣＨ２－Ｏ）ｍ－ＣＨ２－ＣＨ２－である、態様９～３４のいずれか１つに記載の本薬剤。 [Aspect 35]
In the compound (III), Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and, preferably - (CH 2 -CH 2 -O ) The present drug according to any one of aspects 9 to 34, which is m- CH 2- CH 2-.
［態様３６］
　化合物（ＩＩＩ）において、ｍが１～６の整数であり、ｎが２～１２の整数であり、好ましくはｍが１～４の整数であり、ｎが２～６の整数である、態様９～３５のいずれか１つに記載の本薬剤。 [Aspect 36]
In compound (III), aspect 9 in which m is an integer of 1 to 6, n is an integer of 2 to 12, preferably m is an integer of 1 to 4, and n is an integer of 2 to 6. The present drug according to any one of ~ 35.
［態様３７］
　化合物（ＩＩＩ）において、
　各Ｒ１が、それぞれ水素原子であり；
　Ｗ１及びＷ２が、それぞれ独立して、単結合、又はＣ１－Ｃ４アルキレン基であり；
　Ｘ１が、－Ｃ（＝Ｏ）－、又は－ＮＧ１１－ＳＯ２－であり；
　Ｘ２が、－Ｃ（＝Ｏ）－、又は－ＳＯ２－ＮＧ１２－であり；
　Ｇ１１及びＧ１２が、それぞれ独立して、水素原子、又は－ＣＯＯＲ２であり；
　Ｒ２が、１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｙ１が、－ＮＧ２１－、－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＨ－、又は－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＧ３１－Ｌ２１－Ｃ（＝Ｏ）－ＮＨ－であり；
　Ｙ２が、－ＮＧ２２－、－ＮＨ－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－、又は－ＮＨ－Ｃ（＝Ｏ）－Ｌ２２－ＮＧ３２－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－であり；
　Ｇ２１、Ｇ３１、Ｇ２２、及びＧ３２が、それぞれ独立して、水素原子、又は１～５個の－ＣＯＯＲ３基で置換されていてもよいフェニル基及び－ＣＯＯＲ３基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ６アルキル基であり；
　Ｒ３が、それぞれ独立して、水素原子、又は１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｌ１１、Ｌ２１、Ｌ１２、及びＬ２２が、それぞれ独立して、１～５個の－ＣＯＯＲ４基で置換されていてもよい１～５個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、Ｃ１－Ｃ４アルキレン－フェニレン基、又はフェニレン－Ｃ１－Ｃ４アルキレン基であり；
　Ｒ４が、それぞれ水素原子であり；
　Ｚが、－（ＣＨ２－ＣＨ２－Ｏ）ｍ－ＣＨ２－ＣＨ２－、又は－（ＣＨ２）ｎ－であり；
　ｍが、１～６の整数であり；
　ｎが、２～１２の整数である、態様９に記載の本薬剤。 [Aspect 37]
In compound (III)
Each R 1 is a hydrogen atom;
W 1 and W 2 are each independently a single bond, or a C 1 -C 4 alkylene group;
X 1 is -C (= O)-or-NG 11 -SO 2- ;
X 2 is, -C (= O) -, or -SO 2 -NG 12 - a and;
G 11 and G 12 are independently hydrogen atoms or -COOR 2 ;
R 2 is located at 1-5 which may be substituted by an aryl group C 1 -C 4 alkyl group;
Y 1 is, -NG 21 -, - NG 21 -L 11 -C (= O) -NH-, or -NG 21 -L 11 -C (= O ) -NG 31 -L 21 -C (= O) -NH-;
Y 2 is, -NG 22 -, - NH- C (= O) -L 12 -NG 22 -, or -NH-C (= O) -L 22 -NG 32 -C (= O) -L 12 - NG 22- and;
From the group consisting of phenyl groups and -COOR 3 groups in which G 21 , G 31 , G 22 and G 32 are each independently substituted with a hydrogen atom or 1 to 5 -COOR 3 groups. independently is 1 to 5 C 1 may be substituted with a substituent -C 6 alkyl group which is selected;
R 3 are each independently a hydrogen atom, or a 1-5 aryl group optionally substituted C 1 -C 4 alkyl group;
L 11 , L 21 , L 12 and L 22 are each independently substituted with 1 to 5 C 1- C 6 alkyl groups, which may be substituted with 1 to 5 -COOR 4 groups. which may be C 1 -C 6 alkylene group, C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group;
R 4 is a hydrogen atom, respectively;
Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and;
m is an integer from 1 to 6;
The drug according to aspect 9, wherein n is an integer of 2 to 12.
［態様３８］
　化合物（ＩＩＩ）において、
　各Ｒ１が、それぞれ水素原子であり；
　Ｗ１及びＷ２が、それぞれ独立して、単結合、又はＣ１－Ｃ４アルキレン基であり；
　Ｘ１が、－Ｃ（＝Ｏ）－、又は－ＮＧ１１－ＳＯ２－であり；
　Ｘ２が、－Ｃ（＝Ｏ）－、又は－ＳＯ２－ＮＧ１２－であり；
　Ｇ１１及びＧ１２が、それぞれ水素原子であり；
　Ｙ１が、－ＮＧ２１－、－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＨ－、又は－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＧ３１－Ｌ２１－Ｃ（＝Ｏ）－ＮＨ－であり；
　Ｙ２が、－ＮＧ２２－、－ＮＨ－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－、又は－ＮＨ－Ｃ（＝Ｏ）－Ｌ２２－ＮＧ３２－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－であり；
　Ｇ２１、Ｇ３１、Ｇ２２、及びＧ３２が、それぞれ独立して、水素原子、又は１～５個の－ＣＯＯＲ３基で置換されていてもよいフェニル基及び－ＣＯＯＲ３基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ６アルキル基であり；
　Ｒ３が、それぞれ水素原子であり；
　Ｌ１１、Ｌ２１、Ｌ１２、及びＬ２２が、それぞれ独立して、１～５個の－ＣＯＯＲ４基で置換されていてもよい１～５個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、Ｃ１－Ｃ４アルキレン－フェニレン基、又はフェニレン－Ｃ１－Ｃ４アルキレン基であり；
　Ｒ４が、それぞれ水素原子であり；
　Ｚが、－（ＣＨ２－ＣＨ２－Ｏ）ｍ－ＣＨ２－ＣＨ２－、又は－（ＣＨ２）ｎ－であり；
　ｍが、１～６の整数であり；
　ｎが、２～１２の整数である、態様９に記載の本薬剤。 [Aspect 38]
In compound (III)
Each R 1 is a hydrogen atom;
W 1 and W 2 are each independently a single bond, or a C 1 -C 4 alkylene group;
X 1 is -C (= O)-or-NG 11 -SO 2- ;
X 2 is, -C (= O) -, or -SO 2 -NG 12 - a and;
G 11 and G 12 are hydrogen atoms, respectively;
Y 1 is, -NG 21 -, - NG 21 -L 11 -C (= O) -NH-, or -NG 21 -L 11 -C (= O ) -NG 31 -L 21 -C (= O) -NH-;
Y 2 is, -NG 22 -, - NH- C (= O) -L 12 -NG 22 -, or -NH-C (= O) -L 22 -NG 32 -C (= O) -L 12 - NG 22- and;
From the group consisting of phenyl groups and -COOR 3 groups in which G 21 , G 31 , G 22 and G 32 are each independently substituted with a hydrogen atom or 1 to 5 -COOR 3 groups. independently is 1 to 5 C 1 may be substituted with a substituent -C 6 alkyl group which is selected;
R 3 is a hydrogen atom, respectively;
L 11 , L 21 , L 12 and L 22 are each independently substituted with 1 to 5 C 1- C 6 alkyl groups, which may be substituted with 1 to 5 -COOR 4 groups. which may be C 1 -C 6 alkylene group, C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group;
R 4 is a hydrogen atom, respectively;
Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and;
m is an integer from 1 to 6;
The drug according to aspect 9, wherein n is an integer of 2 to 12.
［態様３９］
　化合物（ＩＩＩ）において、
　各Ｒ１が、それぞれ独立して、水素原子、又はｔｅｒｔ－ブトキシカルボニル基であり；
　Ｗ１及びＷ２が、それぞれ独立して、単結合、又はＣ１－Ｃ２アルキレン基であり；
　Ｘ１が、－Ｃ（＝Ｏ）－、又は－ＮＧ１１－ＳＯ２－であり；
　Ｘ２が、－Ｃ（＝Ｏ）－、又は－ＳＯ２－ＮＧ１２－であり；
　Ｇ１１及びＧ１２が、それぞれ水素原子であり；
　Ｙ１が、－ＮＧ２１－、－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＨ－、又は－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＧ３１－Ｌ２１－Ｃ（＝Ｏ）－ＮＨ－であり；
　Ｙ２は、－ＮＧ２２－、－ＮＨ－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－、又は－ＮＨ－Ｃ（＝Ｏ）－Ｌ２２－ＮＧ３２－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－であり；
　Ｇ２１、Ｇ３１、Ｇ２２、及びＧ３２が、それぞれ独立して、水素原子、又は１～３個の－ＣＯＯＲ３基で置換されていてもよいＣ１－Ｃ３アルキル基であり；
　Ｒ３が、それぞれ独立して、水素原子、又はｔｅｒｔ－ブチル基であり；
　Ｌ１１、Ｌ２１、Ｌ１２、及びＬ２２が、それぞれ独立して、Ｃ１－Ｃ２アルキレン基であり；
　Ｚが、－（ＣＨ２－ＣＨ２－Ｏ）ｍ－ＣＨ２－ＣＨ２－、又は－（ＣＨ２）ｎ－であり；
　ｍが、１～６の整数であり；
　ｎが、２～１２の整数である、態様９に記載の本薬剤。 [Aspect 39]
In compound (III)
Each R 1 is independently a hydrogen atom, or tert-butoxycarbonyl group;
W 1 and W 2 are each independently a single bond, or a C 1 -C 2 alkylene group;
X 1 is -C (= O)-or-NG 11 -SO 2- ;
X 2 is, -C (= O) -, or -SO 2 -NG 12 - a and;
G 11 and G 12 are hydrogen atoms, respectively;
Y 1 is, -NG 21 -, - NG 21 -L 11 -C (= O) -NH-, or -NG 21 -L 11 -C (= O ) -NG 31 -L 21 -C (= O) -NH-;
Y 2 is, -NG 22 -, - NH- C (= O) -L 12 -NG 22 -, or -NH-C (= O) -L 22 -NG 32 -C (= O) -L 12 - NG 22- and;
G 21 , G 31 , G 22 and G 32 are C 1- C 3 alkyl groups, which may be independently substituted with hydrogen atoms or 1 to 3 -COOR 3 groups, respectively;
Each R 3 is independently a hydrogen atom or a tert-butyl group;
L 11, L 21, L 12 , and L 22 are each independently a C 1 -C 2 alkylene group;
Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and;
m is an integer from 1 to 6;
The drug according to aspect 9, wherein n is an integer of 2 to 12.
［態様４０］
　化合物（ＩＩＩ）において、
　各Ｒ１が、それぞれ水素原子であり；
　Ｗ１及びＷ２が、それぞれ独立して、単結合、又はＣ１－Ｃ２アルキレン基であり；
　Ｘ１が、－Ｃ（＝Ｏ）－、又は－ＮＧ１１－ＳＯ２－であり；
　Ｘ２が、－Ｃ（＝Ｏ）－、又は－ＳＯ２－ＮＧ１２－であり；
　Ｇ１１及びＧ１２が、それぞれ水素原子であり；
　Ｙ１が、－ＮＧ２１－、－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＨ－、又は－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＧ３１－Ｌ２１－Ｃ（＝Ｏ）－ＮＨ－であり；
　Ｙ２は、－ＮＧ２２－、－ＮＨ－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－、又は－ＮＨ－Ｃ（＝Ｏ）－Ｌ２２－ＮＧ３２－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－であり；
　Ｇ２１、Ｇ３１、Ｇ２２、及びＧ３２が、それぞれ独立して、水素原子、又は１～３個の－ＣＯＯＲ３基で置換されていてもよいＣ１－Ｃ３アルキル基であり；
　Ｒ３が、それぞれ独立して、水素原子、又はｔｅｒｔ－ブチル基であり；
　Ｌ１１、Ｌ２１、Ｌ１２、及びＬ２２が、それぞれ独立して、Ｃ１－Ｃ２アルキレン基であり；
　Ｚが、－（ＣＨ２－ＣＨ２－Ｏ）ｍ－ＣＨ２－ＣＨ２－、又は－（ＣＨ２）ｎ－であり；
　ｍが、１～６の整数であり；
　ｎが、２～１２の整数である、態様９に記載の本薬剤。 [Aspect 40]
In compound (III)
Each R 1 is a hydrogen atom;
W 1 and W 2 are each independently a single bond, or a C 1 -C 2 alkylene group;
X 1 is -C (= O)-or-NG 11 -SO 2- ;
X 2 is, -C (= O) -, or -SO 2 -NG 12 - a and;
G 11 and G 12 are hydrogen atoms, respectively;
Y 1 is, -NG 21 -, - NG 21 -L 11 -C (= O) -NH-, or -NG 21 -L 11 -C (= O ) -NG 31 -L 21 -C (= O) -NH-;
Y 2 is, -NG 22 -, - NH- C (= O) -L 12 -NG 22 -, or -NH-C (= O) -L 22 -NG 32 -C (= O) -L 12 - NG 22- and;
G 21 , G 31 , G 22 and G 32 are C 1- C 3 alkyl groups, which may be independently substituted with hydrogen atoms or 1 to 3 -COOR 3 groups, respectively;
Each R 3 is independently a hydrogen atom or a tert-butyl group;
L 11, L 21, L 12 , and L 22 are each independently a C 1 -C 2 alkylene group;
Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and;
m is an integer from 1 to 6;
The drug according to aspect 9, wherein n is an integer of 2 to 12.
［態様４１］
　化合物（ＩＩＩ）において、
　各Ｒ１が、それぞれ水素原子であり；
　Ｗ１及びＷ２が、それぞれ独立して、単結合、又はＣ１－Ｃ２アルキレン基であり；
　Ｘ１が、－Ｃ（＝Ｏ）－、又は－ＮＧ１１－ＳＯ２－であり；
　Ｘ２が、－Ｃ（＝Ｏ）－、又は－ＳＯ２－ＮＧ１２－であり；
　Ｇ１１及びＧ１２が、それぞれ水素原子であり；
　Ｙ１が、－ＮＧ２１－、－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＨ－、又は－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＧ３１－Ｌ２１－Ｃ（＝Ｏ）－ＮＨ－であり；
　Ｙ２は、－ＮＧ２２－、－ＮＨ－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－、又は－ＮＨ－Ｃ（＝Ｏ）－Ｌ２２－ＮＧ３２－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－であり；
　Ｇ２１及びＧ２２が、それぞれ独立して、水素原子、又は１～３個の－ＣＯＯＲ３基で置換されていてもよいＣ１－Ｃ３アルキル基であり；
　Ｇ３１及びＧ３２が、それぞれ水素原子であり；
　Ｒ３が、それぞれ水素原子であり；
　Ｌ１１、Ｌ２１、Ｌ１２、及びＬ２２が、それぞれ独立して、Ｃ１－Ｃ２アルキレン基であり；
　Ｚが、－（ＣＨ２－ＣＨ２－Ｏ）ｍ－ＣＨ２－ＣＨ２－、又は－（ＣＨ２）ｎ－であり；
　ｍが、１～６の整数であり；
　ｎが、２～１２の整数である、態様９に記載の本薬剤。 [Aspect 41]
In compound (III)
Each R 1 is a hydrogen atom;
W 1 and W 2 are each independently a single bond, or a C 1 -C 2 alkylene group;
X 1 is -C (= O)-or-NG 11 -SO 2- ;
X 2 is, -C (= O) -, or -SO 2 -NG 12 - a and;
G 11 and G 12 are hydrogen atoms, respectively;
Y 1 is, -NG 21 -, - NG 21 -L 11 -C (= O) -NH-, or -NG 21 -L 11 -C (= O ) -NG 31 -L 21 -C (= O) -NH-;
Y 2 is, -NG 22 -, - NH- C (= O) -L 12 -NG 22 -, or -NH-C (= O) -L 22 -NG 32 -C (= O) -L 12 - NG 22- and;
G 21 and G 22 are C 1- C 3 alkyl groups, which may be independently substituted with hydrogen atoms or 1 to 3 -COOR 3 groups, respectively;
G 31 and G 32 are hydrogen atoms, respectively;
R 3 is a hydrogen atom, respectively;
L 11, L 21, L 12 , and L 22 are each independently a C 1 -C 2 alkylene group;
Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and;
m is an integer from 1 to 6;
The drug according to aspect 9, wherein n is an integer of 2 to 12.
［態様４２］
　化合物（ＩＩＩ）において、
　各Ｒ１が、それぞれ水素原子であり；
　Ｗ１及びＷ２が、それぞれ単結合であり；
　Ｘ１が、－Ｃ（＝Ｏ）－であり；
　Ｘ２が、－Ｃ（＝Ｏ）－であり；
　Ｙ１が、－ＮＧ２１－であり；
　Ｙ２が、－ＮＧ２２－であり；
　Ｇ２１及びＧ２２が、それぞれ独立して、１～３個のカルボキシ基で置換されたＣ１－Ｃ３アルキル基であり；
　Ｚが、－（ＣＨ２－ＣＨ２－Ｏ）ｍ－ＣＨ２－ＣＨ２－であり；
　ｍが、１～６の整数である、態様９に記載の本薬剤。 [Aspect 42]
In compound (III)
Each R 1 is a hydrogen atom;
W 1 and W 2 are single bonds, respectively;
X 1 is -C (= O)-;
X 2 is -C (= O)-;
Y 1 is, -NG 21 - a and;
Y 2 is, -NG 22 - a and;
G 21 and G 22 are each independently a one to three C 1 -C 3 alkyl group substituted by a carboxy group;
Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 - and is;
The present drug according to aspect 9, wherein m is an integer of 1 to 6.
［態様４３］
　Ａ１及びＡ２が、それぞれ独立して、以下の分子群から選択されるいずれか１つの分子からいずれか１つの水素原子又はヒドロキシ基を除いた残基である、態様４に記載の本薬剤。
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000027
 [Aspect 43]
The drug according to aspect 4, wherein A 1 and A 2 are residues obtained by independently removing any one hydrogen atom or hydroxy group from any one molecule selected from the following molecular group. ..
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000027
［態様４４］
　Ａ１及びＡ２が、それぞれ独立して、以下の群から選択される基である、態様４に記載の本薬剤。
Figure JPOXMLDOC01-appb-C000028
 ［式中、記号
Figure JPOXMLDOC01-appb-C000029
 はＺとの結合点を示す。］ [Aspect 44]
The drug according to aspect 4, wherein A 1 and A 2 are independent groups selected from the following groups.
Figure JPOXMLDOC01-appb-C000028
 [Symbols in formulas
Figure JPOXMLDOC01-appb-C000029
 Indicates the connection point with Z. ]
［態様４５］
　化合物（Ｉ）又はその薬学上許容される塩が、
　（２Ｓ，２’Ｓ）－２，２’－（（オキシビス（エタン－２，１－ジイル））ビス（（Ｎ－（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）スルファモイル）アザンジイル））二コハク酸；
　（２Ｓ，１３Ｓ）－３，１２－ビス（Ｎ－（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）スルファモイル）－６，９－ジオキサ－３，１２－ジアザテトラデカン－１，２，１３，１４－テトラカルボン酸；
　（２Ｓ，１６Ｓ）－３，１５－ビス（Ｎ－（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）スルファモイル）－６，９，１２－トリオキサ－３，１５－ジアザヘプタデカン－１，２，１６，１７－テトラカルボン酸；
　（２Ｓ，１９Ｓ）－３，１８－ビス（Ｎ－（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）スルファモイル）－６，９，１２，１５－テトラオキサ－３，１８－ジアザイコサン－１，２，１９，２０－テトラカルボン酸；
　（２Ｓ，２２Ｓ）－３，２１－ビス（Ｎ－（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）スルファモイル）－６，９，１２，１５，１８－ペンタオキサ－３，２１－ジアザトリコサン－１，２，２２，２３－テトラカルボン酸；
　（２Ｓ，２５Ｓ）－３，２４－ビス（Ｎ－（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）スルファモイル）－６，９，１２，１５，１８，２１－ヘキサオキサ－３，２４－ジアザヘキサコサン－１，２，２５，２６－テトラカルボン酸；
　（２Ｓ，２’Ｓ）－２，２’－（プロパン－１，３－ジイルビス（（Ｎ－（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）スルファモイル）アザンジイル））二コハク酸；
　（２Ｓ，２’Ｓ）－２，２’－（ブタン－１，４－ジイルビス（（Ｎ－（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）スルファモイル）アザンジイル））二コハク酸；
　（２Ｓ，２’Ｓ）－２，２’－（ペンタン－１，５－ジイルビス（（Ｎ－（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）スルファモイル）アザンジイル））二コハク酸：
　３，１８－ビス（（（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）オキシ）カルボニル）－６，９，１２，１５－テトラオキサ－３，１８－ジアザイコサン－１，２，１９，２０－テトラカルボン酸；
　２，２’－（１，２０－ビス（４－（（４－グアニジノベンゾイル）オキシ）フェニル）－３，１８－ジオキソ－２，１９－ジオキサ－４，１７－ジアザイコサン－４，１７－ジイル）二コハク酸；
　（３Ｓ，６Ｓ，２５Ｓ，２８Ｓ）－６，２５－ビス（カルボキシメチル）－３，２８－ビス（（（（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）オキシ）カルボニル）アミノ）－４，７，２４，２７－テトラオキソ－１１，１４，１７，２０－テトラオキサ－５，８，２３，２６－テトラアザトリアコンタン－１，３０－二酸；
　（３Ｓ，６Ｓ，２３Ｓ，２６Ｓ）－６，２３－ビス（カルボキシメチル）－３，２６－ビス（（（（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）オキシ）カルボニル）アミノ）－４，７，２２，２５－テトラオキソ－５，８，２１，２４－テトラアザオクタコサン－１，２８－二酸；
　（３Ｓ，２２Ｓ）－３，２２－ビス（２－（（３－カルボキシベンジル）（（（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）オキシ）カルボニル）アミノ）アセトアミド）－４，２１－ジオキソ－８，１１，１４，１７－テトラオキサ－５，２０－ジアザテトラコサン－１，２４－二酸；
　（４Ｓ，７Ｓ，２６Ｓ，２９Ｓ）－４，７，２６，２９－テトラキス（カルボキシメチル）－３，３０－ビス（（（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）オキシ）カルボニル）－５，８，２５，２８－テトラオキソ－１２，１５，１８，２１－テトラオキサ－３，６，９，２４，２７，３０－ヘキサアザドトリアコンタン－１，３２－二酸；
　（３Ｓ，２２Ｓ）－３，２２－ビス（（３－カルボキシベンジル）（（（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）オキシ）カルボニル）アミノ）－４，２１－ジオキソ－８，１１，１４，１７－テトラオキサ－５，２０－ジアザテトラコサン－１，２４－二酸；
　（２Ｓ，２’Ｓ）－２，２’－（（（（５，８，１１，１４－テトラオキサ－２，１７－ジアザオクタデカン－１，１８－ジオイル）ビス（３，１－フェニレン））ビス（メチレン））ビス（（（（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）オキシ）カルボニル）アザンジイル））二コハク酸；
　（２Ｓ，２’Ｓ）－２，２’－（（（（５，８，１１，１４－テトラオキサ－２，１７－ジアザオクタデカン－１，１８－ジオイル）ビス（３，１－フェニレン））ビス（メチレン））ビス（（Ｎ－（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）スルファモイル）アザンジイル））二コハク酸；
　３，１２－ビス（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）－６，９－ジオキサ－３，１２－ジアザテトラデカン－１，２，１３，１４－テトラカルボン酸；
　（２Ｓ，１３Ｓ）－３，１２－ビス（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）－６，９－ジオキサ－３，１２－ジアザテトラデカン－１，２，１３，１４－テトラカルボン酸；
　（２Ｒ，１３Ｒ）－３，１２－ビス（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）－６，９－ジオキサ－３，１２－ジアザテトラデカン－１，２，１３，１４－テトラカルボン酸；
　（２Ｓ，１３Ｓ）－３，１２－ビス（Ｎ－（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）－Ｎ－メチルスルファモイル）－６，９－ジオキサ－３，１２－ジアザテトラデカン－１，２，１３，１４－テトラカルボン酸；
　３，３’－（（（エタン－１，２－ジイルビス（オキシ））ビス（エタン－２，１－ジイル））ビス（（Ｎ－（４－（（４－グアニジノベンゾイル）オキシ）ベンジル）スルファモイル）アザンジイル））ジペンタン二酸；
　（２Ｓ，２’Ｓ）－２，２’－（（１，１２－ビス（４－（（４－グアニジノベンゾイル）オキシ）フェニル）－５，８－ジオキサ－２，１１－ジアザドデカンジスルホニル）ビス（アザンジイル））二コハク酸；
　（２Ｓ，１３Ｓ）－３，１２－ビス（Ｎ－（３－（（４－グアニジノベンゾイル）オキシ）ベンジル）スルファモイル）－６，９－ジオキサ－３，１２－ジアザテトラデカン－１，２，１３，１４－テトラカルボン酸；
　（２Ｓ，２’Ｓ）－２，２’－（（オキシビス（エタン－２，１－ジイル））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸；
　（２Ｓ，１６Ｓ）－３，１５－ビス（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）－６，９，１２－トリオキサ－３，１５－ジアザヘプタデカン－１，２，１６，１７－テトラカルボン酸；
　（２Ｓ，２’Ｓ）－２，２’－（（［１，１’－ビフェニル］－３，３’－ジイルビス（メチレン））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸；
　（２Ｓ，２’Ｓ）－２，２’－（（（（（オキシビス（エタン－２，１－ジイル））ビス（オキシ））ビス（３－カルボキシ－５，１－フェニレン））ビス（メチレン））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸；
及び
　（２Ｓ，２’Ｓ）－２，２’－（（オキシビス（エタン－２，１－ジイル））ビス（（３－（（４－グアニジノベンゾイル）オキシ）ベンゾイル）アザンジイル））二コハク酸
からなる群から選択される化合物又はその薬学上許容される塩である、態様４に記載の本薬剤。 [Aspect 45]
Compound (I) or a pharmaceutically acceptable salt thereof
(2S, 2'S) -2,2'-((oxybis (ethane-2,1-diyl)) bis ((N-(4-((4-guanidinobenzoyl) oxy) benzyl) sulfamoyl) azandiyl)) Benzyl acid;
(2S, 13S) -3,12-bis (N- (4-((4-guanidinobenzoyl) oxy) benzyl) sulfamoyl) -6,9-dioxa-3,12-diazatetradecane-1,2,13 , 14-Tetracarboxylic acid;
(2S, 16S) -3,15-bis (N- (4-((4-guanidinobenzoyl) oxy) benzyl) sulfamoyl) -6,9,12-trioxa-3,15-diazaheptadecane-1, 2,16,17-tetracarboxylic acid;
(2S, 19S) -3,18-bis (N- (4-((4-guanidinobenzoyl) oxy) benzyl) sulfamoyl) -6,9,12,15-tetraoxa-3,18-diazycosan-1,2 , 19, 20-tetracarboxylic acid;
(2S, 22S) -3,21-bis (N- (4-((4-guanidinobenzoyl) oxy) benzyl) sulfamoyl) -6,9,12,15,18-pentaoxa-3,21-diazatricosan-1 , 2,22,23-tetracarboxylic acid;
(2S, 25S) -3,24-bis (N- (4-((4-guanidinobenzoyl) oxy) benzyl) sulfamoyl) -6,9,12,15,18,21-hexaoxa-3,24-dia Zahexacosane-1,2,25,26-tetracarboxylic acid;
(2S, 2'S) -2,2'-(Propane-1,3-diylbis ((N- (4-((4-guanidinobenzoyl) oxy) benzyl) sulfamoyl) azandiyl)) disuccinic acid;
(2S, 2'S) -2,2'-(butane-1,4-diylbis ((N- (4-((4-guanidinobenzoyl) oxy) benzyl) sulfamoyl) azandiyl)) disuccinic acid;
(2S, 2'S) -2,2'-(pentane-1,5-diylbis ((N- (4-((4-guanidinobenzoyl) oxy) benzyl) sulfamoyl) azandiyl)) disuccinic acid:
3,18-bis (((4-((4-guanidinobenzoyl) oxy) benzyl) oxy) carbonyl) -6,9,12,15-tetraoxa-3,18-diazycosan-1,2,19,20- Tetracarboxylic acid;
2,2'-(1,20-bis (4-((4-guanidinobenzoyl) oxy) phenyl) -3,18-dioxo-2,19-dioxa-4,17-diazycosan-4,17-diyl) Disuccinic acid;
(3S, 6S, 25S, 28S) -6,25-bis (carboxymethyl) -3,28-bis ((((4-((4-guanidinobenzoyl) oxy) benzyl) oxy) carbonyl) amino) -4 , 7,24,27-Tetraoxo-11,14,17,20-Tetraoxa-5,8,23,26-Tetraazatriacontane-1,30-dioic acid;
(3S, 6S, 23S, 26S) -6,23-bis (carboxymethyl) -3,26-bis ((((4-((4-guanidinobenzoyl) oxy) benzyl) oxy) carbonyl) amino) -4 , 7,22,25-Tetraoxo-5,8,21,24-Tetraazaoctacosane-1,28-diacid;
(3S, 22S) -3,22-bis (2-((3-carboxybenzyl) (((4-((4-guanidinobenzoyl) oxy) benzyl) oxy) carbonyl) amino) acetamide) -4,21- Dioxo-8,11,14,17-tetraoxa-5,20-diazatetracosan-1,24-diacid;
(4S, 7S, 26S, 29S) -4,7,26,29-Tetrakis (carboxymethyl) -3,30-bis (((4-((4-guanidinobenzoyl) oxy) benzyl) oxy) carbonyl)- 5,8,25,28-Tetraoxo-12,15,18,21-Tetraoxa-3,6,9,24,27,30-Hexaazadotriacontane-1,32-diacid;
(3S, 22S) -3,22-bis ((3-carboxybenzyl) (((4-((4-guanidinobenzoyl) oxy) benzyl) oxy) carbonyl) amino) -4,21-dioxo-8,11 , 14,17-Tetraoxa-5,20-diazatetracosan-1,24-diacid;
(2S, 2'S) -2,2'-((((5,8,11,14-tetraoxa-2,17-diazaoctadecane-1,18-dioil) bis (3,1-phenylene))) Bis (methylene)) Bis ((((4-((4-guanidinobenzoyl) oxy) benzyl) oxy) carbonyl) azandyl)) disuccinic acid;
(2S, 2'S) -2,2'-(((((5,8,11,14-tetraoxa-2,17-diazaoctadecane-1,18-dioil) bis (3,1-phenylene)))) Bis (methylene)) Bis ((N- (4-((4-guanidinobenzoyl) oxy) benzyl) sulfamoyl) azandiyl)) disuccinic acid;
3,12-bis (10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) -6,9-dioxa-3,12 -Diazatetradecane-1,2,13,14-tetracarboxylic acid;
(2S, 13S) -3,12-bis (10-guanidine-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) -6,9 -Dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid;
(2R, 13R) -3,12-bis (10-guanidine-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) -6,9 -Dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid;
(2S, 13S) -3,12-bis (N- (4-((4-guanidinobenzoyl) oxy) benzyl) -N-methylsulfamoyl) -6,9-dioxa-3,12-diazatetradecane -1,2,13,14-tetracarboxylic acid;
3,3'-(((ethane-1,2-diylbis (oxy)) bis (ethane-2,1-diyl)) bis ((N- (4-((4-guanidinobenzoyl) oxy) benzyl) sulfamoyl) ) Azandiyl)) Dipentanedioic acid;
(2S, 2'S) -2,2'-((1,12-bis (4-((4-guanidinobenzoyl) oxy) phenyl) -5,8-dioxa-2,11-diazadodecanedisulfonyl) ) Bis (Azandiyl)) Disuccinic acid;
(2S, 13S) -3,12-bis (N- (3-((4-guanidinobenzoyl) oxy) benzyl) sulfamoyl) -6,9-dioxa-3,12-diazatetradecane-1,2,13 , 14-Tetracarboxylic acid;
(2S, 2'S) -2,2'-((oxybis (ethane-2,1-diyl))) Bis ((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandyl)) disuccinic acid;
(2S, 16S) -3,15-bis (10-guanidine-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) -6,9 , 12-Trioxa-3,15-diazaheptadecane-1,2,16,17-tetracarboxylic acid;
(2S, 2'S) -2,2'-(([1,1'-biphenyl] -3,3'-diylbis (methylene))) Bis ((10-guanidino-13-oxo-6,7,8) , 13-Tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandyl)) disuccinic acid;
(2S, 2'S) -2,2'-(((((Oxybis (ethane-2,1-diyl)) bis (oxy)) bis (3-carboxy-5,1-phenylene)) bis (methylene) )) Bis ((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandyl)) disuccinic acid;
And (2S, 2'S) -2,2'-((oxybis (ethane-2,1-diyl)) bis ((3-((4-guanidinobenzoyl) oxy) benzoyl) azandiyl)) from disuccinic acid The present drug according to the fourth aspect, which is a compound selected from the above group or a pharmaceutically acceptable salt thereof.
［態様４６］
　化合物（Ｉ）又はその薬学上許容される塩が、
　（２Ｓ，１３Ｓ）－３，１２－ビス（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）－６，９－ジオキサ－３，１２－ジアザテトラデカン－１，２，１３，１４－テトラカルボン酸；
　（２Ｓ，２’Ｓ）－２，２’－（（オキシビス（エタン－２，１－ジイル））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸；
　（２Ｓ，１６Ｓ）－３，１５－ビス（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）－６，９，１２－トリオキサ－３，１５－ジアザヘプタデカン－１，２，１６，１７－テトラカルボン酸；
　（２Ｓ，２’Ｓ）－２，２’－（（［１，１’－ビフェニル］－３，３’－ジイルビス（メチレン））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸；及び
　（２Ｓ，２’Ｓ）－２，２’－（（（（（オキシビス（エタン－２，１－ジイル））ビス（オキシ））ビス（３－カルボキシ－５，１－フェニレン））ビス（メチレン））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸
からなる群から選択される化合物又はその薬学上許容される塩である、態様４に記載の本薬剤。 [Aspect 46]
Compound (I) or a pharmaceutically acceptable salt thereof
(2S, 13S) -3,12-bis (10-guanidine-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) -6,9 -Dioxa-3,12-diazatetradecane-1,2,13,14-tetracarboxylic acid;
(2S, 2'S) -2,2'-((oxybis (ethane-2,1-diyl))) Bis ((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandyl)) disuccinic acid;
(2S, 16S) -3,15-bis (10-guanidine-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) -6,9 , 12-Trioxa-3,15-diazaheptadecane-1,2,16,17-tetracarboxylic acid;
(2S, 2'S) -2,2'-(([1,1'-biphenyl] -3,3'-diylbis (methylene))) Bis ((10-guanidino-13-oxo-6,7,8) , 13-Tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandyl)) disuccinic acid; and (2S, 2'S) -2,2'-(((((oxybis (ethane) ethane) -2,1-diyl)) bis (oxy)) bis (3-carboxy-5,1-phenylene)) bis (methylene)) bis ((10-guanidino-13-oxo-6,7,8,13-) Tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandiyl)) A compound selected from the group consisting of disuccinic acid or a pharmaceutically acceptable salt thereof, which is the present drug according to aspect 4. ..
［態様４７］
　化合物（Ｉ）又はその薬学上許容される塩が、（２Ｓ，２’Ｓ）－２，２’－（（オキシビス（エタン－２，１－ジイル））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸（以下、化合物Ａとも称する）である、態様４に記載の本薬剤。
Figure JPOXMLDOC01-appb-C000030
 [Aspect 47]
Compound (I) or a pharmaceutically acceptable salt thereof is (2S, 2'S) -2,2'-((oxybis (ethane-2,1-diyl))) bis ((10-guanidino-13-oxo). -6,7,8,13-Tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandyl)) disuccinic acid (hereinafter, also referred to as compound A), the book according to aspect 4. Drug.
Figure JPOXMLDOC01-appb-C000030
［態様４８］
　化合物（ＩＩ）又はその薬学上許容される塩が下式：
Figure JPOXMLDOC01-appb-C000031
 ［式中、記号は前記と同一意味を有する］
で表される化合物又はその薬学上許容される塩である、態様４～４７のいずれか１つに記載の本薬剤。 [Aspect 48]
Compound (II) or a pharmaceutically acceptable salt thereof is described by the following formula:
Figure JPOXMLDOC01-appb-C000031
 [In the formula, the symbols have the same meaning as above]
The present drug according to any one of aspects 4 to 47, which is a compound represented by (1) or a pharmaceutically acceptable salt thereof.
［態様４９］
　化合物（ＩＩ）又はその薬学上許容される塩が下式：
Figure JPOXMLDOC01-appb-C000032
 ［式中、記号は前記と同一意味を有する］
で表される化合物又はその薬学上許容される塩である、態様４～４８のいずれか１つに記載の本薬剤。 [Aspect 49]
Compound (II) or a pharmaceutically acceptable salt thereof is described by the following formula:
Figure JPOXMLDOC01-appb-C000032
 [In the formula, the symbols have the same meaning as above]
The present drug according to any one of aspects 4 to 48, which is a compound represented by (1) or a pharmaceutically acceptable salt thereof.
［態様５０］
　化合物（ＩＩ）又はその薬学上許容される塩が下記一般式（ＩＩ’）又は下記一般式（ＩＩ’’）：
Figure JPOXMLDOC01-appb-C000033
 ［式中、記号は前記と同一意味を有する］
で表される化合物又はその薬学上許容される塩である、態様４～４９のいずれか１つに記載の本薬剤。 [Aspect 50]
Compound (II) or a pharmaceutically acceptable salt thereof is the following general formula (II') or the following general formula (II''):
Figure JPOXMLDOC01-appb-C000033
 [In the formula, the symbols have the same meaning as above]
The present drug according to any one of aspects 4 to 49, which is a compound represented by (1) or a pharmaceutically acceptable salt thereof.
［態様５１］
　化合物（ＩＩ’）において、
　各Ｒ１が、それぞれ独立して、水素原子、又はｔｅｒｔ－ブトキシカルボニル基であり；
　Ｗが、単結合、又はＣ１－Ｃ４アルキレン基であり；
　Ｘが、－Ｃ（＝Ｏ）－、－Ｏ－Ｃ（＝Ｏ）－、又は－ＮＧ－ＳＯ２－であり；
　Ｇが、水素原子、Ｃ１－Ｃ４アルキル基、又は－ＣＯＯＲ２であり；
　Ｒ２が、１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｙが、－ＮＧ２Ｇ４、－ＮＧ２－Ｌ１－ＣＯＯＨ、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－ＣＯＯＨ、－ＮＧ２－Ｌ３－ＯＨ、又は－ＮＧ２－（ＣＨ２－ＣＨ２－Ｏ）ｑ－ＣＨ２－ＣＨ２－ＣＯＯＨであり；
　ｑが、１～６の整数であり；
　Ｇ２及びＧ３が、それぞれ独立して、水素原子、又は１～５個の－ＣＯＯＲ３基で置換されていてもよいフェニル基及び－ＣＯＯＲ３基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ６アルキル基であり；
　Ｇ４が、水素原子、Ｃ１－Ｃ４アルキル基、又はＣ１－Ｃ４アルコキシ―Ｃ１－Ｃ４アルキル基であり；
　Ｒ３が、それぞれ独立して、水素原子、ベンジル基、又はｔｅｒｔ－ブチル基であり；
　Ｌ１及びＬ２が、それぞれ独立して、１～５個の－ＣＯＯＲ４基で置換されていてもよい１～５個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、ヒドロキシ基及びカルボキシ基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ７－Ｃ１２アラルキル基で置換されたＣ１－Ｃ６アルキレン基、Ｃ１－Ｃ４アルキレン－フェニレン基、又はフェニレン－Ｃ１－Ｃ４アルキレン基であり；
　Ｌ３が、フェニレン部分が１～３個の－ＣＯＯＲ４基で置換されていてもよいＣ１－Ｃ４アルキレン－フェニレン基であり；
　Ｒ４が、それぞれ独立して、水素原子、ベンジル基、又はｔｅｒｔ－ブチル基であり；
　Ｒ５及びＲ６が、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１－Ｃ４アルキル基、又はＣ１－Ｃ４アルコキシ基である、態様５０に記載の本薬剤。 [Aspect 51]
In compound (II')
Each R 1 is independently a hydrogen atom, or tert-butoxycarbonyl group;
W is a single bond, or a C 1 -C 4 alkylene group;
X is -C (= O)-, -OC (= O)-, or -NG-SO 2- ;
G is a hydrogen atom, C 1 -C 4 alkyl group, or a -COOR 2;
R 2 is located at 1-5 which may be substituted by an aryl group C 1 -C 4 alkyl group;
Y is -NG 2 G 4 , -NG 2- L 1- COOH, -NG 2- L 1- C (= O) -NG 3- L 2- COOH, -NG 2- L 3- OH, or- NG 2- (CH 2- CH 2- O) q- CH 2- CH 2- COOH;
q is an integer from 1 to 6;
G 2 and G 3 are each independently selected from hydrogen atom, or a 1-5 -COOR 3 phenyl group which may be substituted with groups and independently from the group consisting of -COOR 3 group 1 ~ be five may be substituted with a substituent C 1 -C 6 alkyl group;
G 4 is hydrogen atom, C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy -C 1 -C 4 alkyl group;
R 3 is independently a hydrogen atom, a benzyl group, or a tert-butyl group;
L 1 and L 2 may be independently substituted with 1 to 5 —COOR 4 groups and may be substituted with 1 to 5 C 1 − C 6 alkyl groups C 1 −. C 7- C 12 substituted with 1-5 substituents independently selected from the group consisting of C 6 alkylene group, hydroxy group and carboxy group C 1- C 6 substituted with aralkyl group alkylene group, C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group;
L 3 is a phenylene moiety 1-3 optionally substituted by -COOR 4 group of C 1 -C 4 alkylene - be a phenylene group;
R 4 are each independently a hydrogen atom, a benzyl group, or tert- butyl;
R 5 and R 6 are each independently a hydrogen atom, a halogen atom, C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy group, the agent according to embodiment 50.
［態様５２］
　化合物（ＩＩ’）において、
　各Ｒ１が、それぞれ水素原子であり；
　Ｗが、Ｃ１－Ｃ４アルキレン基であり；
　Ｘが、－Ｏ－Ｃ（＝Ｏ）－、又は－ＮＧ－ＳＯ２－であり；
　Ｇが、水素原子であり；
　Ｙが、－ＮＧ２Ｇ４、－ＮＧ２－Ｌ１－ＣＯＯＨ、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－ＣＯＯＨ、又は－ＮＧ２－（ＣＨ２－ＣＨ２－Ｏ）ｑ－ＣＨ２－ＣＨ２－ＣＯＯＨであり；
　ｑが、１～６の整数であり；
　Ｇ２が、水素原子、又は１～３個のカルボキシ基で置換されたＣ１－Ｃ３アルキル基であり；
　Ｇ３が、水素原子であり；
　Ｇ４が、水素原子、Ｃ１－Ｃ２アルキル基、又はＣ１－Ｃ２アルコキシ―Ｃ１－Ｃ２アルキル基であり；
　Ｌ１及びＬ２が、それぞれ独立して、１～２個の－ＣＯＯＲ４基で置換されていてもよい１～２個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、又はＣ１－Ｃ４アルキレン－フェニレン基であり；
　Ｌ３が、フェニレン部分が１個の－ＣＯＯＲ４基で置換されていてもよいメチレンフェニレン基であり；
　Ｒ４が、水素原子であり；
　Ｒ５及びＲ６が、それぞれ独立して、水素原子、フッ素原子、塩素原子、メチル基、又はメトキシ基である、態様５０に記載の本薬剤。 [Aspect 52]
In compound (II')
Each R 1 is a hydrogen atom;
W is a C 1 -C 4 alkylene group;
X is -OC (= O)-or-NG-SO 2- ;
G is a hydrogen atom;
Y is -NG 2 G 4 , -NG 2- L 1- COOH, -NG 2- L 1- C (= O) -NG 3- L 2- COOH, or -NG 2- (CH 2- CH 2) -O) q- CH 2- CH 2- COOH;
q is an integer from 1 to 6;
G 2 is hydrogen atom, or one to three C 1 -C 3 alkyl group substituted by a carboxy group;
G 3 is a hydrogen atom;
G 4 is a hydrogen atom, a C 1- C 2 alkyl group, or a C 1- C 2 alkoxy-C 1- C 2 alkyl group;
L 1 and L 2 may be independently substituted with 1 or 2 −COOR 4 groups or 1 or 2 C 1-2 C 6 alkyl groups, respectively C 1 − C 6 alkylene group or C 1- C 4 alkylene-phenylene group;
L 3 is a methylene phenylene group in which the phenylene moiety may be substituted with one -COOR 4 group;
R 4 is a hydrogen atom;
The drug according to aspect 50, wherein R 5 and R 6 are independently hydrogen atoms, fluorine atoms, chlorine atoms, methyl groups, or methoxy groups, respectively.
［態様５３］
　化合物（ＩＩ’’）において、
　各Ｒ１が、それぞれ独立して、水素原子、又はｔｅｒｔ－ブトキシカルボニル基であり；
　Ｗが、単結合、又はＣ１－Ｃ４アルキレン基であり；
　Ｘが、－Ｃ（＝Ｏ）－、－Ｏ－Ｃ（＝Ｏ）－、又は－ＮＧ－ＳＯ２－であり；
　Ｇが、水素原子、Ｃ１－Ｃ４アルキル基、又は－ＣＯＯＲ２であり；
　Ｒ２が、１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｙが、－ＮＧ２Ｇ４、－ＮＧ２－Ｌ１－ＣＯＯＨ、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－ＣＯＯＨ、－ＮＧ２－Ｌ３－ＯＨ、又は－ＮＧ２－（ＣＨ２－ＣＨ２－Ｏ）ｑ－ＣＨ２－ＣＨ２－ＣＯＯＨであり；
　ｑが、１～６の整数であり；
　Ｇ２及びＧ３が、それぞれ独立して、水素原子、又は１～５個の－ＣＯＯＲ３基で置換されていてもよいフェニル基及び－ＣＯＯＲ３基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ６アルキル基であり；
　Ｇ４が、水素原子、Ｃ１－Ｃ４アルキル基、又はＣ１－Ｃ４アルコキシ―Ｃ１－Ｃ４アルキル基であり；
　Ｒ３が、それぞれ独立して、水素原子、ベンジル基、又はｔｅｒｔ－ブチル基であり；
　Ｌ１及びＬ２が、それぞれ独立して、１～５個の－ＣＯＯＲ４基で置換されていてもよい１～５個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、ヒドロキシ基及びカルボキシ基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ７－Ｃ１２アラルキル基で置換されたＣ１－Ｃ６アルキレン基、Ｃ１－Ｃ４アルキレン－フェニレン基、又はフェニレン－Ｃ１－Ｃ４アルキレン基であり；
　Ｌ３が、フェニレン部分が１～３個の－ＣＯＯＲ４基で置換されていてもよいＣ１－Ｃ４アルキレン－フェニレン基であり；
　Ｒ４が、それぞれ独立して、水素原子、ベンジル基、又はｔｅｒｔ－ブチル基であり；
　Ｒ５及びＲ６が、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１－Ｃ４アルキル基、Ｃ１－Ｃ４アルコキシ基、カルボキシ基、又は－Ｃ（＝Ｏ）－ＮＧ２Ｇ４である、態様５０～５２のいずれか１つに記載の本薬剤。 [Aspect 53]
In compound (II'')
Each R 1 is independently a hydrogen atom, or tert-butoxycarbonyl group;
W is a single bond, or a C 1 -C 4 alkylene group;
X is -C (= O)-, -OC (= O)-, or -NG-SO 2- ;
G is a hydrogen atom, C 1 -C 4 alkyl group, or a -COOR 2;
R 2 is located at 1-5 which may be substituted by an aryl group C 1 -C 4 alkyl group;
Y is -NG 2 G 4 , -NG 2- L 1- COOH, -NG 2- L 1- C (= O) -NG 3- L 2- COOH, -NG 2- L 3- OH, or- NG 2- (CH 2- CH 2- O) q- CH 2- CH 2- COOH;
q is an integer from 1 to 6;
G 2 and G 3 are each independently selected from hydrogen atom, or a 1-5 -COOR 3 phenyl group which may be substituted with groups and independently from the group consisting of -COOR 3 group 1 ~ be five may be substituted with a substituent C 1 -C 6 alkyl group;
G 4 is hydrogen atom, C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy -C 1 -C 4 alkyl group;
R 3 is independently a hydrogen atom, a benzyl group, or a tert-butyl group;
L 1 and L 2 may be independently substituted with 1 to 5 —COOR 4 groups and may be substituted with 1 to 5 C 1 − C 6 alkyl groups C 1 −. C 7- C 12 substituted with 1-5 substituents independently selected from the group consisting of C 6 alkylene group, hydroxy group and carboxy group C 1- C 6 substituted with aralkyl group alkylene group, C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group;
L 3 is a phenylene moiety 1-3 optionally substituted by -COOR 4 group of C 1 -C 4 alkylene - be a phenylene group;
R 4 are each independently a hydrogen atom, a benzyl group, or tert- butyl;
R 5 and R 6 are each independently a hydrogen atom, a halogen atom, C 1 -C 4 alkyl group, C 1 -C 4 alkoxy group, a carboxy group, or -C (= O) -NG 2 G 4 The present drug according to any one of aspects 50 to 52.
［態様５４］
　化合物（ＩＩ’’）において、
　各Ｒ１が、それぞれ水素原子であり；
　Ｗが、Ｃ１－Ｃ４アルキレン基であり；
　Ｘが、－Ｏ－Ｃ（＝Ｏ）－、又は－ＮＧ－ＳＯ２－であり；
　Ｇが、水素原子であり；
　Ｙが、－ＮＧ２Ｇ４、－ＮＧ２－Ｌ１－ＣＯＯＨ、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－ＣＯＯＨ、又は－ＮＧ２－（ＣＨ２－ＣＨ２－Ｏ）ｑ－ＣＨ２－ＣＨ２－ＣＯＯＨであり；
　ｑが、１～６の整数であり；
　Ｇ２が、水素原子、又は１～３個のカルボキシ基で置換されたＣ１－Ｃ３アルキル基であり；
　Ｇ３が、水素原子であり；
　Ｇ４が、水素原子、Ｃ１－Ｃ２アルキル基、又はＣ１－Ｃ２アルコキシ―Ｃ１－Ｃ２アルキル基であり；
　Ｌ１及びＬ２が、それぞれ独立して、１～２個の－ＣＯＯＲ４基で置換されていてもよい１～２個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、又はＣ１－Ｃ４アルキレン－フェニレン基であり；
　Ｌ３が、フェニレン部分が１個の－ＣＯＯＲ４基で置換されていてもよいメチレンフェニレン基であり；
　Ｒ４が、水素原子であり；
　Ｒ５及びＲ６が、それぞれ独立して、水素原子、フッ素原子、塩素原子、メチル基、メトキシ基、カルボキシ基、又は－Ｃ（＝Ｏ）－ＮＧ２Ｇ４である、態様５０～５２のいずれか１つに記載の本薬剤。 [Aspect 54]
In compound (II'')
Each R 1 is a hydrogen atom;
W is a C 1 -C 4 alkylene group;
X is -OC (= O)-or-NG-SO 2- ;
G is a hydrogen atom;
Y is -NG 2 G 4 , -NG 2- L 1- COOH, -NG 2- L 1- C (= O) -NG 3- L 2- COOH, or -NG 2- (CH 2- CH 2) -O) q- CH 2- CH 2- COOH;
q is an integer from 1 to 6;
G 2 is hydrogen atom, or one to three C 1 -C 3 alkyl group substituted by a carboxy group;
G 3 is a hydrogen atom;
G 4 is a hydrogen atom, a C 1- C 2 alkyl group, or a C 1- C 2 alkoxy-C 1- C 2 alkyl group;
L 1 and L 2 may be independently substituted with 1 or 2 −COOR 4 groups or 1 or 2 C 1-2 C 6 alkyl groups, respectively C 1 − C 6 alkylene group or C 1- C 4 alkylene-phenylene group;
L 3 is a methylene phenylene group in which the phenylene moiety may be substituted with one -COOR 4 group;
R 4 is a hydrogen atom;
Aspects 50-52, wherein R 5 and R 6 are independently hydrogen atoms, fluorine atoms, chlorine atoms, methyl groups, methoxy groups, carboxy groups, or -C (= O) -NG 2 G 4 respectively. The drug according to any one.
［態様５５］
　化合物（ＩＩ）又はその薬学上許容される塩が化合物（ＩＩ’）又はその薬学上許容される塩である、態様５０～５４のいずれか１つに記載の本薬剤。 [Aspect 55]
The drug according to any one of aspects 50 to 54, wherein the compound (II) or a pharmaceutically acceptable salt thereof is the compound (II') or a pharmaceutically acceptable salt thereof.
［態様５６］
　化合物（ＩＩ）又はその薬学上許容される塩が化合物（ＩＩ’’）又はその薬学上許容される塩である、態様５０～５４のいずれか１つに記載の本薬剤。 [Aspect 56]
The drug according to any one of aspects 50 to 54, wherein the compound (II) or a pharmaceutically acceptable salt thereof is the compound (II ″) or a pharmaceutically acceptable salt thereof.
［態様５７］
　化合物（ＩＩ）又はその薬学上許容される塩が下式：
Figure JPOXMLDOC01-appb-C000034
 ［式中、記号は前記と同一意味を有する］
で表される化合物又はその薬学上許容される塩である、態様４～４９のいずれか１つに記載の本薬剤。 [Aspect 57]
Compound (II) or a pharmaceutically acceptable salt thereof is described by the following formula:
Figure JPOXMLDOC01-appb-C000034
 [In the formula, the symbols have the same meaning as above]
The present drug according to any one of aspects 4 to 49, which is a compound represented by (1) or a pharmaceutically acceptable salt thereof.
［態様５８］
　化合物（ＩＩ）又はその薬学上許容される塩が下記一般式（ＩＩ’’’）：
Figure JPOXMLDOC01-appb-C000035
 ［式中、
　各Ｒ１は、それぞれ独立して、水素原子、又は－ＣＯＯ－（Ｃ１－Ｃ４アルキル基）であり；
　Ｗは、単結合、又はＣ１－Ｃ４アルキレン基であり；
　Ｘは、－Ｏ－Ｃ（＝Ｏ）－、又は－ＮＧ－ＳＯ２－であり；
　Ｇは、水素原子、又は－ＣＯＯＲ２であり；
　Ｒ２は、１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｙは、－ＮＧ２Ｇ４、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＨ２、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－Ｃ（＝Ｏ）－ＮＨ２、又は－ＮＧ２－（ＣＨ２－ＣＨ２－Ｏ）ｑ－ＣＨ２－ＣＨ２－ＣＯＯＨであり；
　ｑは、１～６の整数であり；
　Ｇ２及びＧ３は、それぞれ独立して、水素原子、又は１～５個の－ＣＯＯＲ３基で置換されていてもよいフェニル基及び－ＣＯＯＲ３基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ６アルキル基であり；
　Ｇ４は、水素原子、Ｃ１－Ｃ４アルキル基、又はＣ１－Ｃ４アルコキシ―Ｃ１－Ｃ４アルキル基であり；
　Ｒ３は、それぞれ独立して、水素原子、又は１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｌ１及びＬ２は、それぞれ独立して、１～５個の－ＣＯＯＲ４基で置換されていてもよい１～５個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、Ｃ１－Ｃ４アルキレン－フェニレン基、又はフェニレン－Ｃ１－Ｃ４アルキレン基であり；
　Ｒ４は、それぞれ独立して、水素原子、又は１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基である］
で表される化合物又はその薬学上許容される塩である、態様４～４９又は５７のいずれか１つに記載の本薬剤。 [Aspect 58]
Compound (II) or a pharmaceutically acceptable salt thereof is the following general formula (II'''):
Figure JPOXMLDOC01-appb-C000035
 [During the ceremony,
Each R 1 is independently a hydrogen atom, or -COO- (C 1 -C 4 alkyl group);
W is a single bond, or a C 1 -C 4 alkylene group;
X is -OC (= O)-or-NG-SO 2- ;
G is a hydrogen atom, or -COOR 2 ;
R 2 is 1-5 optionally substituted by an aryl group C 1 -C 4 alkyl group;
Y is -NG 2 G 4 , -NG 2- L 1- C (= O) -NH 2 , -NG 2- L 1- C (= O) -NG 3- L 2- C (= O)- NH 2- , or -NG 2- (CH 2- CH 2- O) q- CH 2- CH 2- COOH;
q is an integer from 1 to 6;
G 2 and G 3 are, 1 each independently selected hydrogen atom, or a 1-5 -COOR 3 phenyl group which may be substituted with groups and independently from the group consisting of -COOR 3 group ~ be five may be substituted with a substituent C 1 -C 6 alkyl group;
G 4 are hydrogen, C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy -C 1 -C 4 alkyl group;
R 3 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group;
L 1 and L 2 may be independently substituted with 1 to 5 -COOR 4 groups and may be substituted with 1 to 5 C 1- C 6 alkyl groups C 1-. C 6 alkylene group, C 1- C 4 alkylene-phenylene group, or phenylene-C 1- C 4 alkylene group;
R 4 are each independently hydrogen atom, or a 1-5 aryl-substituted C 1 optionally -C 4 alkyl group with a group]
The drug according to any one of aspects 4 to 49 or 57, which is a compound represented by (1) or a pharmaceutically acceptable salt thereof.
［態様５９］
　化合物（ＩＩ’’’）において、
　各Ｒ１が、それぞれ独立して、水素原子、又はｔｅｒｔ－ブトキシカルボニル基であり；
　Ｗが、Ｃ１－Ｃ４アルキレン基であり；
　Ｘが、－Ｏ－Ｃ（＝Ｏ）－、又は－ＮＧ－ＳＯ２－であり；
　Ｇが、水素原子、又は－ＣＯＯＲ２であり；
　Ｒ２が、１～３個のフェニル基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
　Ｙが、－ＮＧ２Ｇ４、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＨ２、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－Ｃ（＝Ｏ）－ＮＨ２、又は－ＮＧ２－（ＣＨ２－ＣＨ２－Ｏ）ｑ－ＣＨ２－ＣＨ２－ＣＯＯＨであり；
　ｑが、１～６の整数であり；
　Ｇ２及びＧ３が、それぞれ独立して、水素原子、又は１～３個の－ＣＯＯＲ３基で置換されていてもよいフェニル基及び－ＣＯＯＲ３基からなる群から独立して選択される１～３個の置換基で置換されていてもよいＣ１－Ｃ６アルキル基であり；
　Ｇ４が、水素原子、Ｃ１－Ｃ２アルキル基、又はＣ１－Ｃ２アルコキシ―Ｃ１－Ｃ２アルキル基であり；
　Ｒ３が、それぞれ独立して、水素原子、ベンジル基、又はｔｅｒｔ－ブチル基であり；
　Ｌ１及びＬ２が、それぞれ独立して、１～５個の－ＣＯＯＲ４基で置換されていてもよい１～５個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、Ｃ１－Ｃ４アルキレン－フェニレン基、又はフェニレン－Ｃ１－Ｃ４アルキレン基であり；
　Ｒ４が、それぞれ独立して、水素原子、ベンジル基、又はｔｅｒｔ－ブチル基である、態様５８に記載の本薬剤。 [Aspect 59]
In compound (II''')
Each R 1 is independently a hydrogen atom, or tert-butoxycarbonyl group;
W is a C 1 -C 4 alkylene group;
X is -OC (= O)-or-NG-SO 2- ;
G is a hydrogen atom, or -COOR 2 ;
R 2 is located at one to three optionally substituted with a phenyl group C 1 -C 4 alkyl group;
Y is -NG 2 G 4 , -NG 2- L 1- C (= O) -NH 2 , -NG 2- L 1- C (= O) -NG 3- L 2- C (= O)- NH 2- , or -NG 2- (CH 2- CH 2- O) q- CH 2- CH 2- COOH;
q is an integer from 1 to 6;
G 2 and G 3 are each independently selected from hydrogen atom, or a 1-3 -COOR 3 phenyl group which may be substituted with groups and independently from the group consisting of -COOR 3 group 1 ~ be three optionally substituted with a substituent C 1 -C 6 alkyl group;
G 4 is a hydrogen atom, a C 1- C 2 alkyl group, or a C 1- C 2 alkoxy-C 1- C 2 alkyl group;
R 3 is independently a hydrogen atom, a benzyl group, or a tert-butyl group;
L 1 and L 2 may be independently substituted with 1 to 5 —COOR 4 groups and may be substituted with 1 to 5 C 1 − C 6 alkyl groups C 1 −. A C 6 alkylene group, a C 1- C 4 alkylene-phenylene group, or a phenylene-C 1- C 4 alkylene group;
R 4 are each independently a hydrogen atom, a benzyl group, or a tert- butyl group, the agent according to embodiment 58.
［態様６０］
　化合物（ＩＩ’’’）において、
　各Ｒ１が、それぞれ水素原子であり；
　Ｗが、Ｃ１－Ｃ２アルキレン基であり；
　Ｘが、－ＮＧ－ＳＯ２－であり；
　Ｇが、水素原子であり；
　Ｙが、－ＮＧ２Ｇ４であり；
　Ｇ２が、１個のカルボキシ基で置換されたフェニル基及びカルボキシ基からなる群から独立して選択される１～３個の置換基で置換されたＣ１－Ｃ３アルキル基であり；
　Ｇ４が、水素原子、Ｃ１－Ｃ２アルキル基、又はＣ１－Ｃ２アルコキシ―Ｃ１－Ｃ２アルキル基である、態様５８に記載の本薬剤。 [Aspect 60]
In compound (II''')
Each R 1 is a hydrogen atom;
W is, be a C 1 -C 2 alkylene group;
X is -NG-SO 2- ;
G is a hydrogen atom;
Y is -NG 2 G 4 ;
G 2 is a C-1- C 3 alkyl group substituted with 1 to 3 substituents independently selected from the group consisting of a phenyl group substituted with 1 carboxy group and a carboxy group;
The agent according to aspect 58, wherein G 4 is a hydrogen atom, a C 1- C 2 alkyl group, or a C 1- C 2 alkoxy-C 1- C 2 alkyl group.
［態様６１］
　エンテロペプチダーゼ阻害剤が化合物（Ｉ）又はその薬学上許容される塩から選択される１つ以上のエンテロペプチダーゼ阻害剤である、態様４～６０のいずれか１つに記載の本薬剤。 [Aspect 61]
The agent according to any one of aspects 4 to 60, wherein the enteropeptidase inhibitor is one or more enterelopeptidase inhibitors selected from compound (I) or a pharmaceutically acceptable salt thereof.
［態様６２］
　エンテロペプチダーゼ阻害剤が化合物（ＩＩＩ）又はその薬学上許容される塩から選択される１つ以上のエンテロペプチダーゼ阻害剤である、態様９～６１のいずれか１つに記載の本薬剤。 [Aspect 62]
The agent according to any one of aspects 9 to 61, wherein the enteropeptidase inhibitor is one or more enterelopeptidase inhibitors selected from compound (III) or a pharmaceutically acceptable salt thereof.
［態様６３］
　エンテロペプチダーゼ阻害剤が群Ａの化合物又はその薬学上許容される塩から選択される１つ以上のエンテロペプチダーゼ阻害剤である、態様４～６０のいずれか１つに記載の本薬剤。 [Aspect 63]
The agent according to any one of aspects 4 to 60, wherein the enteropeptidase inhibitor is one or more enterelopeptidase inhibitors selected from the compounds of group A or pharmaceutically acceptable salts thereof.
［態様６４］
　エンテロペプチダーゼ阻害剤が、Ｎ－（（（３Ｓ）－６－（（４－カルバムイミドアミドベンゾイル）オキシ）－２，３－ジヒドロ－１－ベンゾフラン－３－イル）アセチル）－Ｌ－アスパラギン酸又はその薬学上許容される塩（以下、化合物Ｂとも称する）である、態様６３に記載の本薬剤。 [Aspect 64]
The enteropeptidase inhibitor is N-(((3S) -6-((4-carbamimideamidebenzoyl) oxy) -2,3-dihydro-1-benzofuran-3-yl) acetyl) -L-aspartic acid. Or the drug according to aspect 63, which is a pharmaceutically acceptable salt thereof (hereinafter, also referred to as compound B).
［態様６５］
　エンテロペプチダーゼ阻害剤が化合物（ＩＩ）又はその薬学上許容される塩から選択される１つ以上のエンテロペプチダーゼ阻害剤である、態様４～６０のいずれか１つに記載の本薬剤。 [Aspect 65]
The agent according to any one of aspects 4 to 60, wherein the enteropeptidase inhibitor is one or more enterelopeptidase inhibitors selected from compound (II) or a pharmaceutically acceptable salt thereof.
［態様６６］
　インクレチン様物質がＧＬＰ－１受容体作動薬である、態様１～６５のいずれか１つに記載の本薬剤。
［態様６７］
　ＧＬＰ－１受容体作動薬がセマグルチド、リラグルチド、デュラグルチド、エキセナチド、リキシセナチド、アルビグルチド、及びエフペグレナチドからなる群から選択される１つ以上のＧＬＰ－１受容体作動薬である、態様６６に記載の本薬剤。
［態様６８］
　ＧＬＰ－１受容体作動薬がセマグルチド、リラグルチド、及びデュラグルチドからなる群から選択される１つ以上のＧＬＰ－１受容体作動薬である、態様６６に記載の本薬剤。
［態様６９］
　ＧＬＰ－１受容体作動薬がセマグルチド及びリラグルチドからなる群から選択される１つ以上のＧＬＰ－１受容体作動薬である、態様６６に記載の本薬剤。
［態様７０］
　ＧＬＰ－１受容体作動薬がセマグルチドを含む１つ以上のＧＬＰ－１受容体作動薬である、態様６６に記載の本薬剤。
［態様７１］
　ＧＬＰ－１受容体作動薬がセマグルチドである、態様６６に記載の本薬剤。
［態様７２］
　ＧＬＰ－１受容体作動薬がリラグルチドを含む１つ以上のＧＬＰ－１受容体作動薬である、態様６６に記載の本薬剤。
［態様７３］
　ＧＬＰ－１受容体作動薬がリラグルチドである、態様６６に記載の本薬剤。
［態様７４］
　ＧＬＰ－１受容体作動薬がデュラグルチドを含む１つ以上のＧＬＰ－１受容体作動薬である、態様６６に記載の本薬剤。
［態様７５］
　ＧＬＰ－１受容体作動薬がデュラグルチドである、態様６６に記載の本薬剤。
［態様７６］
　ＧＬＰ－１受容体作動薬がエキセナチドを含む１つ以上のＧＬＰ－１受容体作動薬である、態様６６に記載の本薬剤。
［態様７７］
　ＧＬＰ－１受容体作動薬がエキセナチドである、態様６６に記載の本薬剤。
［態様７８］
　ＧＬＰ－１受容体作動薬がリキシセナチドを含む１つ以上のＧＬＰ－１受容体作動薬である、態様６６に記載の本薬剤。
［態様７９］
　ＧＬＰ－１受容体作動薬がリキシセナチドである、態様６６に記載の本薬剤。
［態様８０］
　ＧＬＰ－１受容体作動薬がアルビグルチドを含む１つ以上のＧＬＰ－１受容体作動薬である、態様６６に記載の本薬剤。
［態様８１］
　ＧＬＰ－１受容体作動薬がアルビグルチドである、態様６６に記載の本薬剤。
［態様８２］
　ＧＬＰ－１受容体作動薬がエフペグレナチドを含む１つ以上のＧＬＰ－１受容体作動薬である、態様６６に記載の本薬剤。
［態様８３］
　ＧＬＰ－１受容体作動薬がエフペグレナチドである、態様６６に記載の本薬剤。 [Aspect 66]
The drug according to any one of aspects 1 to 65, wherein the incretin-like substance is a GLP-1 receptor agonist.
[Aspect 67]
16. ..
[Aspect 68]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists selected from the group consisting of semaglutide, liraglutide, and duraglutide.
[Aspect 69]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists selected from the group consisting of semaglutide and liraglutide.
[Aspect 70]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists comprising semaglutide.
[Aspect 71]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is semaglutide.
[Aspect 72]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists comprising liraglutide.
[Aspect 73]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is liraglutide.
[Aspect 74]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists comprising duraglutide.
[Aspect 75]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is duraglutide.
[Aspect 76]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists comprising exenatide.
[Aspect 77]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is exenatide.
[Aspect 78]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists comprising lixisenatide.
[Aspect 79]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is lixisenatide.
[Aspect 80]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists comprising albiglutide.
[Aspect 81]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is albiglutide.
[Aspect 82]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists comprising efpeglenatide.
[Aspect 83]
The agent according to aspect 66, wherein the GLP-1 receptor agonist is efpeglenatide.
［態様８４］
　消化管プロテアーゼ阻害剤が化合物Ａであり、インクレチン様物質がＧＬＰ－１受容体作動薬である、態様１に記載の本薬剤。
［態様８５］
　消化管プロテアーゼ阻害剤が化合物Ａであり、インクレチン様物質がセマグルチド、リラグルチド、デュラグルチド、エキセナチド、リキシセナチド、アルビグルチド、及びエフペグレナチドからなる群から選択される１つ以上のＧＬＰ－１受容体作動薬である、態様１に記載の本薬剤。
［態様８６］
　消化管プロテアーゼ阻害剤が化合物Ａであり、インクレチン様物質がセマグルチド、リラグルチド、及びデュラグルチドからなる群から選択される１つ以上のＧＬＰ－１受容体作動薬である、態様１に記載の本薬剤。
［態様８７］
　消化管プロテアーゼ阻害剤が化合物Ａであり、インクレチン様物質がセマグルチド及びリラグルチドからなる群から選択される１つ以上のＧＬＰ－１受容体作動薬である、態様１に記載の本薬剤。
［態様８８］
　消化管プロテアーゼ阻害剤が化合物Ａであり、インクレチン様物質がセマグルチドである、態様１に記載の本薬剤。
［態様８９］
　消化管プロテアーゼ阻害剤が化合物Ａであり、インクレチン様物質がリラグルチドである、態様１に記載の本薬剤。
［態様９０］
　消化管プロテアーゼ阻害剤が化合物Ａであり、インクレチン様物質がデュラグルチドである、態様１に記載の本薬剤。
［態様９１］
　消化管プロテアーゼ阻害剤が化合物Ａであり、インクレチン様物質がエキセナチドである、態様１に記載の本薬剤。
［態様９２］
　消化管プロテアーゼ阻害剤が化合物Ａであり、インクレチン様物質がリキシセナチドである、態様１に記載の本薬剤。
［態様９３］
　消化管プロテアーゼ阻害剤が化合物Ａであり、インクレチン様物質がアルビグルチドである、態様１に記載の本薬剤。
［態様９４］
　消化管プロテアーゼ阻害剤が化合物Ａであり、インクレチン様物質がエフペグレナチドである、態様１に記載の本薬剤。 [Aspect 84]
The drug according to aspect 1, wherein the gastrointestinal protease inhibitor is compound A and the incretin-like substance is a GLP-1 receptor agonist.
[Aspect 85]
The gastrointestinal protease inhibitor is compound A and the incretin-like substance is one or more GLP-1 receptor agonists selected from the group consisting of semaglutide, liraglutide, duraglutide, exenatide, lixisenatide, albiglutide, and efpeglenatide. , The present drug according to the first aspect.
[Aspect 86]
The agent according to aspect 1, wherein the gastrointestinal protease inhibitor is compound A and the incretin-like substance is one or more GLP-1 receptor agonists selected from the group consisting of semaglutide, liraglutide, and duraglutide. ..
[Aspect 87]
The agent according to aspect 1, wherein the gastrointestinal protease inhibitor is compound A and the incretin-like substance is one or more GLP-1 receptor agonists selected from the group consisting of semaglutide and liraglutide.
[Aspect 88]
The drug according to aspect 1, wherein the gastrointestinal protease inhibitor is compound A and the incretin-like substance is semaglutide.
[Aspect 89]
The drug according to aspect 1, wherein the gastrointestinal protease inhibitor is compound A and the incretin-like substance is liraglutide.
[Aspect 90]
The drug according to aspect 1, wherein the gastrointestinal protease inhibitor is compound A and the incretin-like substance is duraglutide.
[Aspect 91]
The drug according to aspect 1, wherein the gastrointestinal protease inhibitor is compound A and the incretin-like substance is exenatide.
[Aspect 92]
The drug according to aspect 1, wherein the gastrointestinal protease inhibitor is compound A and the incretin-like substance is lixisenatide.
[Aspect 93]
The drug according to aspect 1, wherein the gastrointestinal protease inhibitor is compound A and the incretin-like substance is albiglutide.
[Aspect 94]
The drug according to aspect 1, wherein the gastrointestinal protease inhibitor is compound A and the incretin-like substance is efpeglenatide.
［態様９５］
　消化管プロテアーゼ及び／又はインクレチンが関与する疾患を予防、緩和、及び／又は治療するための、態様１～９４のいずれか１つに記載の本薬剤。
［態様９６］
　消化管プロテアーゼ及び／又はインクレチンが関与する疾患が肥満症、肥満に伴う病態又は疾患、糖尿病（一型、二型等）、糖尿病性合併症（腎症、網膜症、神経障害等）、腎臓疾患、心血管疾患（冠動脈疾患、脳梗塞、末梢動脈疾患等）、骨・関節疾患、乾癬性関節炎、メタボリックシンドローム、高脂血症、動脈硬化症、高血圧症、高尿酸血症、脂肪肝（非アルコール性脂肪肝炎（ＮＡＳＨ）を含む）、肝臓疾患（胆道障害含む）、膵臓障害、嚢胞性線維症、インスリン抵抗性症候群、高インスリン血症、耐糖能障害、筋ジストロフィー、筋萎縮性側索硬化症（ＡＬＳ）、脳梗塞、パーキンソン病、アルツハイマー病、睡眠時無呼吸症、摂食障害、急性又は慢性下痢、炎症性疾患、慢性閉塞性肺疾患（ＣＯＰＤ）、骨粗鬆症、及び種々の癌から選択される１つ以上の疾患である、態様９５に記載の本薬剤。
［態様９７］
　消化管プロテアーゼ及び／又はインクレチンが関与する疾患が肥満症、糖尿病、糖尿病性合併症（腎症、網膜症、神経障害等）、及びＮＡＳＨから選択される１つ以上の疾患である、態様９５に記載の本薬剤。
［態様９８］
　消化管プロテアーゼ及び／又はインクレチンが関与する疾患が肥満症及び糖尿病から選択される１つ以上の疾患である、態様９５に記載の本薬剤。
［態様９９］
　消化管プロテアーゼ及び／又はインクレチンが関与する疾患が肥満症である、態様９５に記載の本薬剤。 [Aspect 95]
The agent according to any one of aspects 1 to 94, for preventing, alleviating, and / or treating a disease associated with gastrointestinal protease and / or incretin.
[Aspect 96]
Diseases involving gastrointestinal protease and / or insulin are obesity, pathophysiology or disease associated with obesity, diabetes (type 1, type 2, etc.), diabetic complications (nephropathy, retinopathy, neuropathy, etc.), kidney Diseases, cardiovascular diseases (coronary artery disease, cerebral infarction, peripheral arterial disease, etc.), bone / joint diseases, psoriatic arthritis, metabolic syndrome, hyperlipidemia, arteriosclerosis, hypertension, hyperuricemia, fatty liver ( Non-alcoholic steatosis (including NASH)), liver disease (including biliary tract disorder), pancreatic disorder, cystic fibrosis, insulin resistance syndrome, hyperinsulinemia, glucose tolerance disorder, muscular dystrophy, muscle atrophic lateral sclerosis Choose from ALS, cerebral infarction, Parkinson's disease, Alzheimer's disease, sleep apnea, feeding disorders, acute or chronic diarrhea, inflammatory disease, chronic obstructive pulmonary disease (COPD), osteoporosis, and various cancers The present drug according to aspect 95, which is one or more diseases to be treated.
[Aspect 97]
Aspect 95, wherein the disease involving the gastrointestinal protease and / or incretin is one or more diseases selected from obesity, diabetes, diabetic complications (nephropathy, retinopathy, neuropathy, etc.), and NASH. This drug described in.
[Aspect 98]
The agent according to aspect 95, wherein the disease involving gastrointestinal protease and / or incretin is one or more diseases selected from obesity and diabetes.
[Aspect 99]
The drug according to aspect 95, wherein the disease involving gastrointestinal protease and / or incretin is obesity.
［態様１００］
　ＦＧＦ－２１を増加させるための、態様１～９９のいずれか１つに記載の本薬剤。
［態様１０１］
　ＦＧＦ－２１の増加によって症状が改善する疾患を予防、緩和、及び／又は治療するための、態様１～１００のいずれか１つに記載の本薬剤。
［態様１０２］
　インスリンを低下させるための、態様１～１０１のいずれか１つに記載の本薬剤。
［態様１０３］
　インスリンの低下によって症状が改善する疾患を予防、緩和、及び／又は治療するための、態様１～１０２のいずれか１つに記載の本薬剤。
［態様１０４］
　ＨｂＡ１ｃを低下させるための、態様１～１０３のいずれか１つに記載の本薬剤。
［態様１０５］
　ＨｂＡ１ｃの低下によって症状が改善する疾患を予防、緩和、及び／又は治療するための、態様１～１０４のいずれか１つに記載の本薬剤。
［態様１０６］
　消化管プロテアーゼ阻害剤とインクレチン様物質が別々の組成物に製剤化されている、態様１～１０５のいずれか１つに記載の本薬剤。 [Aspect 100]
The drug according to any one of aspects 1 to 99 for increasing FGF-21.
[Aspect 101]
The drug according to any one of aspects 1 to 100 for preventing, alleviating, and / or treating a disease whose symptoms are improved by an increase in FGF-21.
[Aspect 102]
The present drug according to any one of aspects 1 to 101 for lowering insulin.
[Aspect 103]
The present drug according to any one of aspects 1 to 102 for preventing, alleviating, and / or treating a disease in which symptoms are improved by a decrease in insulin.
[Aspect 104]
The present drug according to any one of aspects 1 to 103 for lowering HbA1c.
[Aspect 105]
The drug according to any one of aspects 1 to 104 for preventing, alleviating, and / or treating a disease in which symptoms are improved by lowering HbA1c.
[Aspect 106]
The drug according to any one of aspects 1 to 105, wherein the gastrointestinal protease inhibitor and the incretin-like substance are formulated in separate compositions.
　本発明における消化管プロテアーゼ阻害剤及びインクレチン様物質は、市販されているものを用いてもよく、又は公知の方法に従って製造してもよい。例えば、化合物（Ｉ）、化合物（ＩＩ）、若しくは化合物（ＩＩＩ）、又はその薬学上許容される塩は、国際公開第２０１９／０８８２７０号公報等に記載の方法または当該方法と公知の方法を組み合わせた方法で製造することができる。又、群Ａの化合物は、例えば国際公開第２０１５／１２２１８７号公報、国際公開第２０１５／１２２１８８号公報、国際公開第２０１４／１４２２１９号公報、又は、国際公開第２０１３／１８７５３３号公報に記載の方法で製造することができる。さらに、インクレチン様物質は、市販されているものを用いることができる。 The gastrointestinal protease inhibitor and incretin-like substance in the present invention may be commercially available ones or may be produced according to a known method. For example, compound (I), compound (II), or compound (III), or a pharmaceutically acceptable salt thereof, is the method described in WO2019 / 088270 or the like, or a combination of the method and a known method. It can be manufactured by the above method. The compound of Group A is described in, for example, International Publication No. 2015/122187, International Publication No. 2015/122188, International Publication No. 2014/142219, or International Publication No. 2013/187533. Can be manufactured at. Further, as the incretin-like substance, a commercially available substance can be used.
　本発明における化合物（Ｉ）、化合物（ＩＩ）、若しくは化合物（ＩＩＩ）、又は群Ａの化合物は、互変異性体の形態又はこれらの混合物で存在し得る。本発明における化合物（Ｉ）、化合物（ＩＩ）、若しくは化合物（ＩＩＩ）、又は群Ａの化合物は、エナンチオマー、又はジアステレオマー等の立体異性体の形態又はこれらの混合物で存在し得る。本発明における化合物（Ｉ）、化合物（ＩＩ）、若しくは化合物（ＩＩＩ）、又は群Ａの化合物は、互変異性体や立体異性体の混合物又はそれぞれ純粋な若しくは実質的に純粋な異性体を包含する。 The compound (I), the compound (II), or the compound (III) in the present invention, or the compound of the group A can exist in the form of a tautomer or a mixture thereof. The compounds (I), compounds (II), or compounds (III), or compounds of group A in the present invention may be present in the form of stereoisomers such as enantiomers, diastereomers, or mixtures thereof. Compound (I), compound (II), or compound (III), or compound of group A in the present invention comprises tautomers, mixtures of stereoisomers, or pure or substantially pure isomers, respectively. do.
　本発明における化合物（Ｉ）、化合物（ＩＩ）、若しくは化合物（ＩＩＩ）、又は群Ａの化合物がジアステレオマーまたはエナンチオマーの形態で得られる場合、これらを当該技術分野で慣用の方法、例えばクロマトグラフィーおよび分別結晶法等で分離することができる。 When compound (I), compound (II), or compound (III), or a compound of group A in the present invention is obtained in the form of diastereomers or enantiomers, these can be obtained by methods commonly used in the art, such as chromatography. And can be separated by a fractional crystallization method or the like.
　本発明における化合物（Ｉ）、化合物（ＩＩ）、若しくは化合物（ＩＩＩ）、又は群Ａの化合物は、同位元素（例えば、２Ｈ、３Ｈ、１３Ｃ、１４Ｃ、１５Ｎ、１８Ｆ、３２Ｐ、３５Ｓ、１２５Ｉ等）等で標識された化合物及び重水素変換体を包含する。 Compounds in the present invention (I), the compound (II), or a compound (III), or compound of Group A, isotopes (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 F, 32 Includes compounds labeled with P, 35 S, 125 I, etc.) and deuterium converters.
　化合物（Ｉ）、化合物（ＩＩ）、若しくは化合物（ＩＩＩ）、又は群Ａの化合物の薬学上許容される塩としては、リチウム、ナトリウム、及びカリウム等のアルカリ金属塩；マグネシウム、及びカルシウム等の第２族金属塩；アルミニウム又は亜鉛との塩；アンモニア、コリン、ジエタノールアミン、リジン、エチレンジアミン、ｔｅｒｔ－ブチルアミン、ｔｅｒｔ－オクチルアミン、トリス（ヒドロキシメチル）アミノメタン、Ｎ－メチル－グルコサミン、トリエタノールアミン、及びデヒドロアビエチルアミン等のアミンとの塩；塩化水素、臭化水素、ヨウ化水素、硫酸、硝酸、及びリン酸等の無機酸との塩；ギ酸、酢酸、トリフルオロ酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマール酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、及びベンゼンスルホン酸等の有機酸との塩；又はアスパラギン酸、グルタミン酸等の酸性アミノ酸との塩が挙げられる。 Pharmaceutically acceptable salts of compound (I), compound (II), or compound (III), or compounds of group A include alkali metal salts such as lithium, sodium, and potassium; Group 2 metal salts; salts with aluminum or zinc; ammonia, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris (hydroxymethyl) aminomethane, N-methyl-glucosamine, triethanolamine, and Salts with amines such as dehydroabiethylamine; salts with inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitrate, and phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, Salts with organic acids such as malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, and benzenesulfonic acid; Examples include salts with amino acids.
　さらに、化合物（Ｉ）、化合物（ＩＩ）、若しくは化合物（ＩＩＩ）、又は群Ａの化合物の薬学上許容される塩には、それらの分子内塩、水和物、溶媒和物を包含する。 Furthermore, the pharmaceutically acceptable salts of compound (I), compound (II), or compound (III), or compounds of group A include their intramolecular salts, hydrates, and solvates.
　本明細書において、「薬学上許容される」とは、一般的に、投与を受ける者に対して有害性がないものであり、医薬組成物を調製する際に成分が互いに適合性があることを意味し、ヒトの医薬としての使用だけではなく獣医学での使用にも有用なものを含む。 As used herein, "pharmaceutically acceptable" generally means that it is not harmful to the recipient and that the ingredients are compatible with each other when preparing the pharmaceutical composition. Means that it is useful not only for human medicinal use but also for veterinary use.
　本発明における消化管プロテアーゼ阻害剤とインクレチン様物質は、各有効成分をそのまま投与してもよく、又は薬学上許容される担体と混合した医薬組成物として投与してもよい。また、本発明における消化管プロテアーゼ阻害剤とインクレチン様物質は、それぞれ経口的にも非経口的にも投与することができる。
　１つの実施態様では、本発明における消化管プロテアーゼ阻害剤とインクレチン様物質は、１つの組成物中に含まれている。
　別の実施態様では、本発明における消化管プロテアーゼ阻害剤とインクレチン様物質は、別々の組成物に製剤化されていている。この場合、消化管プロテアーゼ阻害剤とインクレチン様物質は同時に投与されてもよく、又は別々に投与されてもよい。また、消化管プロテアーゼ阻害剤とインクレチン様物質が別々に投与される場合、これらを連続して投与してもよく、又は時間間隔をおいて、例えば３０分～１時間、１～６時間、６～１２時間、１２～２４時間、若しくは１～７日間の間隔をおいて投与してもよい。さらに、消化管プロテアーゼ阻害剤とインクレチン様物質が別々に投与される場合、消化管プロテアーゼ阻害剤を先に投与してもよく、又はインクレチン様物質を先に投与してもよい。
　本発明は、消化管プロテアーゼ阻害剤を含む組成物とインクレチン様物質を含む組成物を含むキットの形態であってもよい。 The gastrointestinal protease inhibitor and incretin-like substance in the present invention may be administered as they are, or may be administered as a pharmaceutical composition mixed with a pharmaceutically acceptable carrier. In addition, the gastrointestinal protease inhibitor and the incretin-like substance in the present invention can be administered orally or parenterally, respectively.
In one embodiment, the gastrointestinal protease inhibitor and incretin-like substance of the present invention are contained in one composition.
In another embodiment, the gastrointestinal protease inhibitor and the incretin-like substance in the present invention are formulated into separate compositions. In this case, the gastrointestinal protease inhibitor and the incretin-like substance may be administered simultaneously or separately. When the gastrointestinal protease inhibitor and the incretin-like substance are administered separately, they may be administered continuously, or at intervals of time, for example, 30 minutes to 1 hour, 1 to 6 hours, etc. It may be administered at intervals of 6 to 12 hours, 12 to 24 hours, or 1 to 7 days. Furthermore, when the gastrointestinal protease inhibitor and the incretin-like substance are administered separately, the gastrointestinal protease inhibitor may be administered first, or the incretin-like substance may be administered first.
The present invention may be in the form of a kit containing a composition containing a gastrointestinal protease inhibitor and a composition containing an incretin-like substance.
　薬学上許容される担体としては、当該技術分野で慣用の担体でよく、例えば希釈剤、結合剤（シロップ、アラビアゴム、ゼラチン、ソルビット、トラガカント、及びポリビニルピロリドン等）、賦形剤（乳糖、ショ糖、コーンスターチ、リン酸カリウム、ソルビット、及びグリシン等）、滑沢剤（ステアリン酸マグネシウム、タルク、ポリエチレングリコール、及びシリカ等）、崩壊剤（バレイショデンプン等）、湿潤剤（ラウリル硫酸ナトリウム等）、懸濁化剤（メチルセルロース等）、並びに緩衝液（クエン酸緩衝液等）等が挙げられる。また、組成物の剤形は特に限定されるものではなく、錠剤、顆粒剤、カプセル剤、散剤、注射剤、吸入剤、又は坐剤等の慣用の医薬製剤として用いることができる。
　本発明における消化管プロテアーゼ阻害剤とインクレチン様物質が別々の組成物として製剤化されていている場合、各組成物の剤型は同一であっても互いに異なっていてもよい。１つの実施態様では、消化管プロテアーゼ阻害剤が錠剤、顆粒剤、カプセル剤、又は散剤等に製剤化されて経口投与され、インクレチン様物質が注射剤等に製剤化されて非経口投与、例えば皮下投与される。 The pharmaceutically acceptable carrier may be a carrier commonly used in the art, such as diluents, binders (syrup, gum arabic, gelatin, sorbitol, tragacant, and polyvinylpyrrolidone, etc.), excipients (lactose, sho). Sugars, corn starch, potassium phosphate, sorbitol, glycine, etc.), lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (potassium starch, etc.), wetting agents (sodium lauryl sulfate, etc.), Examples thereof include a suspending agent (methyl cellulose, etc.) and a buffer solution (citrate buffer solution, etc.). The dosage form of the composition is not particularly limited, and it can be used as a conventional pharmaceutical preparation such as tablets, granules, capsules, powders, injections, inhalants, and suppositories.
When the gastrointestinal protease inhibitor and the incretin-like substance in the present invention are formulated as separate compositions, the dosage forms of the compositions may be the same or different from each other. In one embodiment, the gastrointestinal protease inhibitor is formulated into tablets, granules, capsules, powders, etc. and orally administered, and the incretin-like substance is formulated into injections, etc. and administered parenterally, for example. It is administered subcutaneously.
　本発明における消化管プロテアーゼ阻害剤とインクレチン様物質は、適切な剤形に製剤化された後、患者、例えばヒトまたは動物、好ましくはヒトに投与される。 The gastrointestinal protease inhibitor and incretin-like substance in the present invention are formulated into an appropriate dosage form and then administered to a patient, for example, a human or an animal, preferably a human.
　本発明における消化管プロテアーゼ阻害剤とインクレチン様物質の投与量（すなわち有効量）および投与回数は、疾患の重篤度、患者の年齢、体重、性別、薬物の種類、剤形、投与経路等の条件によって適宜変化しうる。ヒトに投与する場合、消化管プロテアーゼ阻害剤とインクレチン様物質はそれぞれ、例えば非経口的には皮下、静脈内、腹腔内、筋肉内、又は直腸内等に、１回の投与当たり、約０．００１～１００ｍｇ／ｋｇ体重、好ましくは約０．０１～５０ｍｇ／ｋｇ体重、特に好ましくは約０．０２～１０ｍｇ／ｋｇ体重、又、経口的には約１～１０００ｍｇ／ｋｇ体重、好ましくは約１０～５００ｍｇ／ｋｇ体重、特に好ましくは約２０～１００ｍｇ／ｋｇ体重投与される。又、投与回数は、１日当たり１回または複数回、例えば１日当たり１～３回、１～２回、又は１回であってよく、あるいは数日毎、例えば２日に１回、３日に１回、４日に１回、５日に１回、６日に１回、１週間に１回、２週間に１回、３週間に１回、４週間に１回、又は１カ月に１回であってよい。
　１つの実施態様では、消化管プロテアーゼ阻害剤が１日当たり１～３回、１～２回、又は１回の頻度で１回の投与当たり、約１～１０００ｍｇ／ｋｇ体重、好ましくは約１０～５００ｍｇ／ｋｇ体重、特に好ましくは約２０～１００ｍｇ／ｋｇ体重の用量で経口投与され、インクレチン様物質が１日１回、又は数日毎、例えば２日に１回、３日に１回、４日に１回、５日に１回、６日に１回、１週間に１回、２週間に１回、３週間に１回、４週間に１回、若しくは１カ月に１回の頻度で、１回の投与当たり、約０．００１～１００ｍｇ／ｋｇ体重、好ましくは約０．０１～５０ｍｇ／ｋｇ体重、特に好ましくは約０．０２～１０ｍｇ／ｋｇ体重の用量で、非経口投与、例えば皮下、静脈内、腹腔内、筋肉内、または直腸内投与される。 The dose (that is, effective amount) and frequency of administration of the gastrointestinal protease inhibitor and the incretin-like substance in the present invention are the severity of the disease, the age, weight, sex of the patient, the type of drug, the dosage form, the route of administration, etc. It can be changed as appropriate depending on the conditions of. When administered to humans, the gastrointestinal protease inhibitor and the incretin-like substance, respectively, parenterally, for example, subcutaneously, intravenously, intraperitoneally, intramuscularly, intrarectally, etc. .001-100 mg / kg body weight, preferably about 0.01-50 mg / kg body weight, particularly preferably about 0.02-10 mg / kg body weight, and orally about 1-1000 mg / kg body weight, preferably about. It is administered at a body weight of 10 to 500 mg / kg, particularly preferably about 20 to 100 mg / kg body weight. The number of administrations may be once or multiple times per day, for example, 1 to 3 times, 1 to 2 times, or once per day, or every few days, for example, once every two days, once every three days. Once every 4 days, once every 5 days, once every 6 days, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month May be.
In one embodiment, the gastrointestinal protease inhibitor is about 1 to 1000 mg / kg body weight, preferably about 10 to 500 mg, per administration of 1 to 3 times, 1 to 2 times, or 1 time per day. Orally administered at a dose of / kg body weight, particularly preferably about 20-100 mg / kg body weight, with incretin-like substances once daily or every few days, eg, once every two days, once every three days, four days. Once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month. Parenteral administration, eg, subcutaneously, at a dose of about 0.001 to 100 mg / kg body weight, preferably about 0.01 to 50 mg / kg body weight, particularly preferably about 0.02 to 10 mg / kg body weight per single dose. , Intravenously, intraperitoneally, intramuscularly, or intrarectally.
　本発明における消化管プロテアーゼ阻害剤とインクレチン様物質を投与する期間は、疾患の重篤度、患者の年齢、体重、性別、薬物の種類、剤形、投与経路等の条件によって適宜変化してよく、例えば１週間、２週間、３週間、４週間、１カ月、２カ月、３カ月、４カ月、６カ月、９カ月、又は１年以上等とすることができる。 The period of administration of the gastrointestinal protease inhibitor and the incretin-like substance in the present invention varies depending on conditions such as the severity of the disease, the age, weight, sex of the patient, the type of drug, the dosage form, and the route of administration. Often, for example, it can be 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, or 1 year or more.
　本薬剤は、消化管プロテアーゼ及び／又はインクレチンが関与する疾患に対して、優れた予防、緩和、及び／又は治療効果を有する。そのような疾患としては、例えば、肥満症、肥満に伴う病態又は疾患、糖尿病（一型、二型等）、糖尿病性合併症（腎症、網膜症、神経障害等）、腎臓疾患、心血管疾患（冠動脈疾患、脳梗塞、末梢動脈疾患等）、骨・関節疾患、乾癬性関節炎、メタボリックシンドローム、高脂血症、動脈硬化症、高血圧症、高尿酸血症、脂肪肝（非アルコール性脂肪肝炎（ＮＡＳＨ）を含む）、肝臓疾患（胆道障害含む）、膵臓障害、嚢胞性線維症、インスリン抵抗性症候群、高インスリン血症、耐糖能障害、筋ジストロフィー、筋萎縮性側索硬化症（ＡＬＳ）、脳梗塞、パーキンソン病、アルツハイマー病、睡眠時無呼吸症、摂食障害、急性又は慢性下痢、炎症性疾患、慢性閉塞性肺疾患（ＣＯＰＤ）、骨粗鬆症、及び種々の癌等を挙げることができる。
　１つの実施態様では、本薬剤は、肥満症、糖尿病、糖尿病性合併症（腎症、網膜症、神経障害等）、及びＮＡＳＨから選択される１つ以上の疾患の予防、緩和、及び／又は治療に用いられる。
　別の実施態様では、本薬剤は、肥満症及び糖尿病から選択される１つ以上の疾患の予防、緩和、及び／又は治療に用いられる。
　別の実施態様では、本薬剤は、肥満症の予防、緩和、及び／又は治療に用いられる。 The drug has excellent prophylactic, alleviating, and / or therapeutic effects on diseases associated with gastrointestinal proteases and / or incretins. Such diseases include, for example, obesity, pathological conditions or diseases associated with obesity, diabetes (type 1, type 2, etc.), diabetic complications (nephropathy, retinopathy, neuropathy, etc.), kidney disease, cardiovascular disease. Diseases (coronary artery disease, cerebral infarction, peripheral arterial disease, etc.), bone / joint disease, psoriatic arthritis, metabolic syndrome, hyperlipidemia, arteriosclerosis, hypertension, hyperuricemia, fatty liver (non-alcoholic fat) Hepatitis (including NASH)), liver disease (including biliary tract disorder), pancreatic disorder, cystic fibrosis, insulin resistance syndrome, hyperinsulinemia, glucose tolerance disorder, muscular dystrophy, muscular atrophic lateral sclerosis (ALS) , Cerebral infarction, Parkinson's disease, Alzheimer's disease, sleep apnea, feeding disorder, acute or chronic diarrhea, inflammatory disease, chronic obstructive pulmonary disease (COPD), osteoporosis, and various cancers. ..
In one embodiment, the agent prevents, alleviates, and / or prevents obesity, diabetes, diabetic complications (nephropathy, retinopathy, neuropathy, etc.), and one or more diseases selected from NASH. Used for treatment.
In another embodiment, the agent is used for the prevention, alleviation, and / or treatment of one or more diseases selected from obesity and diabetes.
In another embodiment, the drug is used for the prevention, alleviation, and / or treatment of obesity.
　さらに本薬剤は、ＦＧＦ－２１増加作用、インスリン低下作用、及びＨｂＡ１ｃ低下作用を有する。従って、本薬剤は、ＦＧＦ－２１の増加、インスリンの低下、及び／又はＨｂＡ１ｃの低下によって症状が改善する疾患の予防、緩和、及び／又は治療にも有効である。ＦＧＦ－２１の増加によって症状が改善する疾患としては、例えば肥満症、糖尿病、及びＮＡＳＨ等を挙げることができる。インスリンの低下によって症状が改善する疾患としては、例えば肥満症及び糖尿病等を挙げることができる。ＨｂＡ１ｃの低下によって症状が改善する疾患としては、例えば肥満症、糖尿病、及びＮＡＳＨ等を挙げることができる。 Furthermore, this drug has an FGF-21 increasing action, an insulin lowering action, and an HbA1c lowering action. Therefore, this drug is also effective in the prevention, alleviation, and / or treatment of diseases in which symptoms are improved by an increase in FGF-21, a decrease in insulin, and / or a decrease in HbA1c. Examples of diseases whose symptoms are improved by increasing FGF-21 include obesity, diabetes, NASH and the like. Examples of diseases in which symptoms are improved by a decrease in insulin include obesity and diabetes. Examples of diseases whose symptoms are improved by lowering HbA1c include obesity, diabetes, NASH and the like.
　本発明の１つの実施態様は、インクレチン様物質と組み合わせて使用するための薬剤の製造における消化管プロテアーゼ阻害剤の使用に関する。
　本発明の別の実施態様では、前記薬剤は、消化管プロテアーゼ及び／又はインクレチンが関与する疾患の予防、緩和、及び／又は治療に用いられる。
　本発明の別の実施態様では、前記薬剤は、肥満症、糖尿病、糖尿病性合併症（腎症、網膜症、神経障害等）、及びＮＡＳＨから選択される１つ以上の疾患を予防、緩和、及び／又は治療するために用いられる。
　本発明の別の実施態様では、前記薬剤は、肥満症及び糖尿病から選択される１つ以上の疾患を予防、緩和、及び／又は治療するために用いられる。
　本発明の別の実施態様では、前記薬剤は、肥満症を予防、緩和、及び／又は治療するために用いられる。 One embodiment of the invention relates to the use of gastrointestinal protease inhibitors in the manufacture of agents for use in combination with incretin-like substances.
In another embodiment of the invention, the agent is used for the prevention, alleviation, and / or treatment of diseases involving gastrointestinal proteases and / or incretins.
In another embodiment of the invention, the agent prevents, alleviates, one or more diseases selected from obesity, diabetes, diabetic complications (nephropathy, retinopathy, neuropathy, etc.), and NASH. And / or used to treat.
In another embodiment of the invention, the agent is used to prevent, alleviate, and / or treat one or more diseases selected from obesity and diabetes.
In another embodiment of the invention, the agent is used to prevent, alleviate, and / or treat obesity.
　本発明の１つの実施態様は、疾患を予防、緩和、及び／又は治療するための消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせの使用に関する。
　本発明の別の実施態様は、消化管プロテアーゼ及び／又はインクレチンが関与する疾患を予防、緩和、及び／又は治療するための消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせの使用に関する。
　本発明の別の実施態様は、肥満症、糖尿病、糖尿病性合併症（腎症、網膜症、神経障害等）、及びＮＡＳＨから選択される１つ以上の疾患を予防、緩和、及び／又は治療するための消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせの使用に関する。
　本発明の別の実施態様は、肥満症及び糖尿病から選択される１つ以上の疾患を予防、緩和、及び／又は治療するための消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせの使用に関する。
　本発明の別の実施態様は、肥満症を予防、緩和、及び／又は治療するための消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせの使用に関する。 One embodiment of the invention relates to the use of a combination of gastrointestinal protease inhibitors and incretin-like substances to prevent, alleviate, and / or treat a disease.
Another embodiment of the invention relates to the use of a combination of gastrointestinal protease inhibitors and incretin-like substances to prevent, alleviate, and / or treat diseases involving gastrointestinal proteases and / or incretins.
Another embodiment of the invention prevents, alleviates, and / or treats obesity, diabetes, diabetic complications (nephropathy, retinopathy, neuropathy, etc.), and one or more diseases selected from NASH. With respect to the use of a combination of gastrointestinal protease inhibitors and incretin-like substances to do so.
Another embodiment of the invention relates to the use of a combination of gastrointestinal protease inhibitors and incretin-like substances to prevent, alleviate, and / or treat one or more diseases selected from obesity and diabetes.
Another embodiment of the invention relates to the use of a combination of gastrointestinal protease inhibitors and incretin-like substances to prevent, alleviate, and / or treat obesity.
　本発明の１つの実施態様は、疾患の予防、緩和、及び／又は治療に使用するための消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせに関する。
　本発明の別の実施態様は、消化管プロテアーゼ及び／又はインクレチンが関与する疾患の予防、緩和、及び／又は治療に使用するための消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせに関する。
　本発明の別の実施態様は、肥満症、糖尿病、糖尿病性合併症（腎症、網膜症、神経障害等）、及びＮＡＳＨから選択される１つ以上の疾患の予防、緩和、及び／又は治療に使用するための消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせに関する。
　本発明の別の実施態様は、肥満症及び糖尿病から選択される１つ以上の疾患の予防、緩和、及び／又は治療に使用するための消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせに関する。
　本発明の別の実施態様は、肥満症の予防、緩和、及び／又は治療に使用するための消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせに関する。 One embodiment of the invention relates to a combination of gastrointestinal protease inhibitors and incretin-like substances for use in the prevention, alleviation, and / or treatment of disease.
Another embodiment of the invention relates to a combination of gastrointestinal protease inhibitors and incretin-like substances for use in the prevention, alleviation, and / or treatment of diseases involving gastrointestinal proteases and / or incretins.
Another embodiment of the invention is the prevention, alleviation, and / or treatment of obesity, diabetes, diabetic complications (nephropathy, retinopathy, neuropathy, etc.), and one or more diseases selected from NASH. With respect to a combination of gastrointestinal protease inhibitors and incretin-like substances for use in.
Another embodiment of the invention relates to a combination of gastrointestinal protease inhibitors and incretin-like substances for use in the prevention, alleviation, and / or treatment of one or more diseases selected from obesity and diabetes.
Another embodiment of the invention relates to a combination of gastrointestinal protease inhibitors and incretin-like substances for use in the prevention, alleviation, and / or treatment of obesity.
　本発明の１つの実施態様は、消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせの有効量を患者に投与することを含む、疾患の予防、緩和、及び／又は治療方法に関する。
　本発明の別の実施態様は、消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせの有効量を患者に投与することを含む、エンテロペプチダーゼ阻害及び／又はトリプシン阻害によって症状が改善する疾患の予防、緩和、及び／又は治療方法に関する。
　本発明の別の実施態様は、消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせの有効量を患者に投与することを含む、肥満症、糖尿病、糖尿病性合併症（腎症、網膜症、神経障害等）、及びＮＡＳＨから選択される１つ以上の疾患の予防、緩和、及び／又は治療方法に関する。
　本発明の別の実施態様は、消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせの有効量を患者に投与することを含む、肥満症及び糖尿病から選択される１つ以上の疾患の予防、緩和、及び／又は治療方法に関する。
　本発明の別の実施態様は、消化管プロテアーゼ阻害剤及びインクレチン様物質の組み合わせの有効量を患者に投与することを含む、肥満症の予防、緩和、及び／又は治療方法に関する。
　本発明の特定の実施態様では、上記方法において消化管プロテアーゼ阻害剤とインクレチン様物質は別々に患者に投与される。 One embodiment of the present invention relates to a method for preventing, alleviating, and / or treating a disease, which comprises administering to a patient an effective amount of a combination of a gastrointestinal protease inhibitor and an incretin-like substance.
Another embodiment of the present invention comprises administering to a patient an effective amount of a combination of a gastrointestinal protease inhibitor and an incretin-like substance to prevent a disease in which symptoms are ameliorated by enteropeptidase inhibition and / or trypsin inhibition. Concerning palliative and / or treatment methods.
Another embodiment of the present invention comprises administering to a patient an effective amount of a combination of a gastrointestinal protease inhibitor and an incretin-like substance for obesity, diabetes, diabetic complications (nephropathy, retinopathy, nerves). Disorders, etc.), and methods of preventing, alleviating, and / or treating one or more diseases selected from NASH.
Another embodiment of the invention is the prevention and alleviation of one or more diseases selected from obesity and diabetes, comprising administering to a patient an effective amount of a combination of a gastrointestinal protease inhibitor and an incretin-like substance. And / or the treatment method.
Another embodiment of the present invention relates to a method for preventing, alleviating, and / or treating obesity, which comprises administering to a patient an effective amount of a combination of a gastrointestinal protease inhibitor and an incretin-like substance.
In certain embodiments of the invention, the gastrointestinal protease inhibitor and incretin-like substance are administered to the patient separately in the above method.
　以下に、試験例を示して本発明を更に詳細に説明するが、これらの例示は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。なお、以下の試験例において、化合物Ａは国際公開第２０１９／０８８２７０号公報の実施例２６－（ｂ）に記載の化合物、化合物Ｂは国際公開第２０１５／１２２１８７号公報の実施例１に記載の化合物であり、それぞれ当該実施例に記載の方法または当該方法と公知の方法を組み合わせた方法で製造した。 Hereinafter, the present invention will be described in more detail with reference to test examples, but these examples are for better understanding of the present invention and do not limit the scope of the present invention. In the following test examples, compound A is the compound described in Example 26- (b) of International Publication No. 2019/088270, and compound B is described in Example 1 of International Publication No. 2015/122187. These compounds were produced by the methods described in the examples or a combination of the methods and known methods.
＜試験例１＞ＤＩＯマウスを用いた体重低下試験
（試験方法）
　Ｄｉｅｔ－ｉｎｄｕｃｅｄ　ｏｂｅｓｉｔｙ（ＤＩＯ）マウス（Ｄ１２４９２食、雄性、２７週齢）を４群に分けた（７匹／群）。表１の組み合わせに従って、ビヒクル、化合物Ａ、及び／又はセマグルチドを２１日間投与した。投与開始日を０日目とし、０．５％メチルセルロース（ＭＣ）溶液又は化合物Ａ（２５ｍｇ／ｋｇ）を含む０．５％ＭＣ懸濁液を０日目から１日１回経口投与し、２０ｍＭクエン酸緩衝液又はセマグルチド（１０ｎｍｏｌ／ｋｇ）を含む２０ｍＭクエン酸緩衝液を３日に１回（０、３、６、９、１２、１５及び１８日目）皮下投与した。なお、セマグルチドはＡｄｉｐｏ　Ｇｅｎｅから購入した。
Figure JPOXMLDOC01-appb-T000036
 <Test Example 1> Weight loss test using DIO mice (test method)
Diet-induced ability (DIO) mice (D12492 diet, male, 27 weeks old) were divided into 4 groups (7 animals / group). Vehicles, Compound A, and / or semaglutide were administered for 21 days according to the combination in Table 1. The administration start date is set to day 0, and a 0.5% methylcellulose (MC) solution or a 0.5% MC suspension containing compound A (25 mg / kg) is orally administered once a day from day 0 to 20 mM. A 20 mM citrate buffer containing citrate buffer or semaglutide (10 nmol / kg) was subcutaneously administered once every 3 days ( days 0, 3, 6, 9, 12, 15 and 18). Semaglutide was purchased from Adipo Gene.
Figure JPOXMLDOC01-appb-T000036
　０日目から２１日間の体重変動（％）の平均値と標準誤差（ｍｅａｎ±ＳＥ）を図１に示す。また０日目と２１日目の各群の平均体重と標準誤差を表２に示す。
Figure JPOXMLDOC01-appb-T000037
 The mean value and standard error (mean ± SE) of the body weight fluctuation (%) from the 0th day to the 21st day are shown in FIG. Table 2 shows the average body weight and standard error of each group on the 0th and 21st days.
Figure JPOXMLDOC01-appb-T000037
（結果）
　本薬剤を投与した群、すなわち化合物Ａとセマグルチドを組み合わせて投与した群は、化合物Ａを単独で投与した群及びセマグルチドを単独で投与した群と比較して、優れた体重低下効果を示した。当該効果は、ルーワイ胃バイパス術（Ｒｏｕｘ－ｅｎ－Ｙ　Ｇａｓｔｒｉｃ　Ｂｙｐａｓｓ；ＲＹＧＢ）に匹敵する非常に強い効果であり、既存の抗肥満薬では達成できていない効果である。 (result)
The group to which this drug was administered, that is, the group to which compound A and semaglutide were administered in combination, showed an excellent weight-reducing effect as compared with the group to which compound A was administered alone and the group to which semaglutide was administered alone. This effect is a very strong effect comparable to Roux-en-Y Gastric Bypass (RYGB), and is an effect that cannot be achieved by existing anti-obesity drugs.
＜試験例２＞血中生理活性物質の測定
（試験方法）
　試験例１において、２０日目の投与終了から約１６時間後にイソフルラン吸入麻酔下にて各マウスの腹部大静脈より採血した。採血した血液を蛋白安定化剤入り採血管に入れた後、３０μＬを分取し、それぞれを氷冷した。採血管を４℃、１３００ｇで１０分間遠心し、血漿を分離した。血漿および先に分取した全血は、使用時まで約－２０℃にて凍結保存した。血漿を溶解し、ＥＬＩＳＡ法（使用キット；Ｍｏｕｓｅ／Ｒａｔ　ＦＧＦ－２１　Ｑｕａｎｔｉｋｉｎｅ　ＥＬＩＳＡ　ｋｉｔ：Ｒ＆Ｄ社製）により線維芽細胞増殖因子（ｆｉｂｒｏｂｌａｓｔ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）－２１（ＦＧＦ－２１）を定量した（図２）。また同様に血漿を溶解し、タンパク質多項目同時解析装置マルチプレックスアッセイシステム（ＭＩＬＬＩＰＬＥＸ　ＭＡＰ　Ｍｏｕｓｅ　Ｍｅｔａｂｏｌｉｃ　Ｈｏｒｍｏｎｅ　Ｍａｇｎｅｔｉｃ　Ｂｅａｄ　Ｐａｎｅｌ：Ｍｉｌｌｉｐｏｒｅ社製）を用いてインスリンを定量した（図３）。さらに全血を用いて、酵素法（オリエンタル酵母工業株式会社）によりＨｂＡ１ｃを測定した（図４）。 <Test Example 2> Measurement of bioactive substances in blood (test method)
In Test Example 1, blood was collected from the abdominal vena cava of each mouse under isoflurane inhalation anesthesia about 16 hours after the end of administration on the 20th day. The collected blood was placed in a blood collection tube containing a protein stabilizer, and then 30 μL was separated and each was ice-cooled. Plasma was separated by centrifuging the blood collection tube at 4 ° C. and 1300 g for 10 minutes. Plasma and previously collected whole blood were cryopreserved at about −20 ° C. until use. Plasma was lysed and fibroblast growth factor-21 (FGF-21) was quantified by the ELISA method (use kit; Mouse / Rat FGF-21 Quantikine ELISA kit: manufactured by R & D) (Fig. 2). .. Similarly, plasma was lysed, and insulin was quantified using a protein multi-item simultaneous analyzer multiplex assay system (MILLIPLEX MAP Mouse Metabolic Hormone Magnetic Bed Panel: manufactured by Millipore) (Fig. 3). Further, using whole blood, HbA1c was measured by an enzymatic method (Oriental Yeast Co., Ltd.) (Fig. 4).
（結果）
　本薬剤を投与した群、すなわち化合物Ａとセマグルチドを組み合わせて投与した群は、化合物Ａを単独で投与した群及びセマグルチドを単独で投与した群と比較して、優れたＦＧＦ－２１増加作用、高インスリン異常値の低下作用、及びＨｂＡ１ｃ低下作用を示した。従って、本薬剤は、ＦＧＦ－２１の増加、インスリンの低下、及び／又はＨｂＡ１ｃの低下によって症状が改善する疾患の予防、緩和、及び／又は治療にも有効である。 (result)
The group to which this drug was administered, that is, the group to which compound A and semaglutide were administered in combination, had an excellent FGF-21 increasing effect and higher effect than the group to which compound A was administered alone and the group to which semaglutide was administered alone. It showed a lowering effect on abnormal insulin levels and a lowering effect on HbA1c. Therefore, this drug is also effective in the prevention, alleviation, and / or treatment of diseases in which symptoms are improved by an increase in FGF-21, a decrease in insulin, and / or a decrease in HbA1c.
＜試験例３＞ＤＩＯマウスを用いた体重低下試験
（試験方法）
　Ｄｉｅｔ－ｉｎｄｕｃｅｄ　ｏｂｅｓｉｔｙ（ＤＩＯ）マウス（Ｄ１２４９２食、雄性、２７週齢）を４群に分けた（４～５匹／群）。表３の組み合わせに従って、ビヒクル、化合物Ａ、及び／又はリラグルチドを２１日間投与した。投与開始日を０日目とし、０．５％メチルセルロース（ＭＣ）溶液又は化合物Ａ（２５ｍｇ／ｋｇ）を含む０．５％ＭＣ懸濁液を０日目から１日１回経口投与し、化合物Ａ投与群以外は２０ｍＭクエン酸緩衝液又はリラグルチド（０．２ｍｇ／ｋｇ）を含む２０ｍＭクエン酸緩衝液を１日１回皮下投与した。なお、リラグルチドはＡｄｉｐｏ　Ｇｅｎｅから購入した。
Figure JPOXMLDOC01-appb-T000038
 <Test Example 3> Weight loss test using DIO mice (test method)
Diet-induced ability (DIO) mice (D12492 diet, male, 27 weeks old) were divided into 4 groups (4-5 animals / group). Vehicles, Compound A, and / or liraglutide were administered for 21 days according to the combination in Table 3. The administration start date is set to the 0th day, and a 0.5% methylcellulose (MC) solution or a 0.5% MC suspension containing compound A (25 mg / kg) is orally administered once a day from the 0th day, and the compound is administered. Except for the A administration group, 20 mM citrate buffer or 20 mM citrate buffer containing liraglutide (0.2 mg / kg) was subcutaneously administered once a day. Liraglutide was purchased from Adipo Gene.
Figure JPOXMLDOC01-appb-T000038
　０日目から２１日間の体重変動（％）の平均値と標準誤差（ｍｅａｎ±ＳＥ）を図５に示す。また０日目と２１日目の各群の平均体重と標準誤差を表４に示す。
Figure JPOXMLDOC01-appb-T000039
 The mean value and standard error (mean ± SE) of the body weight fluctuation (%) from the 0th day to the 21st day are shown in FIG. Table 4 shows the average body weight and standard error of each group on the 0th day and the 21st day.
Figure JPOXMLDOC01-appb-T000039
（結果）
　本薬剤を投与した群、すなわち化合物Ａとリラグルチドを組み合わせて投与した群は、化合物Ａを単独で投与した群及びリラグルチドを単独で投与した群と比較して、優れた体重低下効果を示した。当該効果は、ルーワイ胃バイパス術（Ｒｏｕｘ－ｅｎ－Ｙ　Ｇａｓｔｒｉｃ　Ｂｙｐａｓｓ；ＲＹＧＢ）に匹敵する非常に強い効果であり、既存の抗肥満薬では達成できていない効果である。 (result)
The group to which this drug was administered, that is, the group to which compound A and liraglutide were administered in combination, showed an excellent weight-reducing effect as compared with the group to which compound A was administered alone and the group to which liraglutide was administered alone. This effect is a very strong effect comparable to Roux-en-Y Gastric Bypass (RYGB), and is an effect that cannot be achieved by existing anti-obesity drugs.
＜試験例４＞血中生理活性物質の測定
（試験方法）
　試験例３において、２０日目（化合物Ａ投与群については２７日目まで継続して投与した最終日）の投与終了から約１６時間後にイソフルラン吸入麻酔下にて各マウスの腹部大静脈より採血した。採血した血液を蛋白安定化剤入り採血管に入れた後、３０μＬを分取し、それぞれを氷冷した。採血管を４℃、１３００ｇで１０分間遠心し、血漿を分離した。血漿および先に分取した全血は、使用時まで約－２０℃にて凍結保存した。血漿を溶解し、ＥＬＩＳＡ法（使用キット；Ｍｏｕｓｅ／Ｒａｔ　ＦＧＦ－２１　Ｑｕａｎｔｉｋｉｎｅ　ＥＬＩＳＡ　ｋｉｔ：Ｒ＆Ｄ社製）によりＦＧＦ－２１を定量した（図６）。また同様に血漿を溶解し、タンパク質多項目同時解析装置マルチプレックスアッセイシステム（ＭＩＬＬＩＰＬＥＸ　Ｍｏｕｓｅ　Ｍｅｔａｂｏｌｉｃ　Ｈｏｒｍｏｎｅ　Ｅｘｐａｎｄｅｄ　Ｐａｎｅｌ：Ｍｉｌｌｉｐｏｒｅ社製）を用いてインスリンを定量した（図７）。さらに全血を用いて、酵素法（オリエンタル酵母工業株式会社）によりＨｂＡ１ｃを測定した（図８）。 <Test Example 4> Measurement of bioactive substances in blood (test method)
In Test Example 3, blood was collected from the abdominal vena cava of each mouse under isoflurane inhalation anesthesia about 16 hours after the end of administration on the 20th day (the last day of continuous administration until the 27th day for the compound A administration group). .. The collected blood was placed in a blood collection tube containing a protein stabilizer, and then 30 μL was separated and each was ice-cooled. Plasma was separated by centrifuging the blood collection tube at 4 ° C. and 1300 g for 10 minutes. Plasma and previously collected whole blood were cryopreserved at about −20 ° C. until use. Plasma was lysed and FGF-21 was quantified by the ELISA method (use kit; Mouse / Rat FGF-21 Quantikine ELISA kit: manufactured by R & D) (Fig. 6). Similarly, plasma was lysed, and insulin was quantified using a protein multi-item simultaneous analyzer multiplex assay system (MILLIPLEX Mouse Metabolic Hormone Expanded Panel: manufactured by Millipore) (FIG. 7). Further, using whole blood, HbA1c was measured by an enzymatic method (Oriental Yeast Co., Ltd.) (Fig. 8).
（結果）
　本薬剤を投与した群、すなわち化合物Ａとリラグルチドを組み合わせて投与した群は、化合物Ａを単独で投与した群及びリラグルチドを単独で投与した群と比較して、優れたＦＧＦ－２１増加作用、高インスリン異常値の低下作用、及びＨｂＡ１ｃ低下作用を示した。従って、本薬剤は、ＦＧＦ－２１の増加、インスリンの低下、及び／又はＨｂＡ１ｃの低下によって症状が改善する疾患の予防、緩和、及び／又は治療にも有効である。 (result)
The group to which this drug was administered, that is, the group to which compound A and liraglutide were administered in combination, had an excellent FGF-21 increasing effect and higher effect than the group to which compound A was administered alone and the group to which liraglutide was administered alone. It showed a lowering effect on insulin abnormal values and a lowering effect on HbA1c. Therefore, this drug is also effective in the prevention, alleviation, and / or treatment of diseases in which symptoms are improved by an increase in FGF-21, a decrease in insulin, and / or a decrease in HbA1c.
＜試験例５＞ＤＩＯマウスを用いた体重低下試験
（試験方法）
　試験例１と同様に、表５の組み合わせに従って、ビヒクル、化合物Ａ、化合物Ｂ、及び／又はセマグルチドを２１日間投与した。投与開始日を０日目とし、０．５％メチルセルロース（ＭＣ）溶液、化合物Ａ（１２．５ｍｇ／ｋｇ（試験例１の半分量））、又は化合物Ｂ（５０ｍｇ／ｋｇ）を含む０．５％ＭＣ懸濁液を０日目から１日１回経口投与し、２０ｍＭクエン酸緩衝液又はセマグルチド（１０ｎｍｏｌ／ｋｇ）を含む２０ｍＭクエン酸緩衝液を３日に１回（０、３、６、９、１２、１５及び１８日目）皮下投与した。
Figure JPOXMLDOC01-appb-T000040
 <Test Example 5> Weight loss test using DIO mice (test method)
Similar to Test Example 1, vehicle, compound A, compound B, and / or semaglutide were administered for 21 days according to the combination in Table 5. The administration start date is the 0th day, and 0.5 containing 0.5% methylcellulose (MC) solution, compound A (12.5 mg / kg (half the amount of Test Example 1)), or compound B (50 mg / kg). % MC suspension is orally administered once daily from day 0, and 20 mM citrate buffer or 20 mM citrate buffer containing semaglutide (10 nmol / kg) is administered once every 3 days (0, 3, 6, (Days 9, 12, 15 and 18) Subcutaneous administration was performed.
Figure JPOXMLDOC01-appb-T000040
　０日目から２１日間の体重変動（％）の平均値と標準誤差（ｍｅａｎ±ＳＥ）を図９に示す。また０日目と２１日目の各群の平均体重と標準誤差を表６に示す。
Figure JPOXMLDOC01-appb-T000041
 FIG. 9 shows the mean value and standard error (mean ± SE) of the body weight fluctuation (%) from the 0th day to the 21st day. Table 6 shows the average body weight and standard error of each group on the 0th and 21st days.
Figure JPOXMLDOC01-appb-T000041
（結果）
　本薬剤を投与した群、すなわち化合物Ａ又は化合物Ｂとセマグルチドを組み合わせて投与した群は、化合物Ａ又は化合物Ｂを単独で投与した群及びセマグルチドを単独で投与した群と比較して、優れた体重低下効果を示した。 (result)
The group to which this drug was administered, that is, the group to which compound A or compound B was administered in combination with semaglutide, was superior in body weight to the group to which compound A or compound B was administered alone and the group to which semaglutide was administered alone. It showed a lowering effect.
＜試験例６＞血中生理活性物質の測定
（試験方法）
　試験例５において、試験例１と同様にして、線維芽細胞増殖因子（ｆｉｂｒｏｂｌａｓｔ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）－２１（ＦＧＦ－２１）、インスリン、ＨｂＡ１ｃを測定した。 <Test Example 6> Measurement of bioactive substances in blood (test method)
In Test Example 5, fibroblast growth factor-21 (FGF-21), insulin, and HbA1c were measured in the same manner as in Test Example 1.
（結果）
　本薬剤を投与した群、すなわち化合物Ａ又は化合物Ｂとセマグルチドを組み合わせて投与した群は、ＦＧＦ－２１増加作用、高インスリン異常値の低下作用、及びＨｂＡ１ｃ低下作用において、試験例２と同様な傾向を示した。従って、本薬剤は、ＦＧＦ－２１の増加、インスリンの低下、及び／又はＨｂＡ１ｃの低下によって症状が改善する疾患の予防、緩和、及び／又は治療にも有効である。 (result)
The group to which this drug was administered, that is, the group to which compound A or compound B was administered in combination with semaglutide, had the same tendency as in Test Example 2 in the FGF-21 increasing action, the hyperinsulin abnormal value lowering action, and the HbA1c lowering action. showed that. Therefore, this drug is also effective in the prevention, alleviation, and / or treatment of diseases in which symptoms are improved by an increase in FGF-21, a decrease in insulin, and / or a decrease in HbA1c.
　上記試験例１～６により、異なるエンテロペプチダーゼ阻害剤及び／又はトリプシン阻害剤と、異なるＧＬＰ－１受容体作動薬の組み合わせにおいても、同様な結果又は同様な傾向が示された。 According to Test Examples 1 to 6 above, similar results or similar tendencies were shown in the combination of different enteropeptidase inhibitors and / or trypsin inhibitors and different GLP-1 receptor agonists.
　本発明の薬剤は、肥満症や糖尿病等の疾患に対して優れた予防、緩和、及び／又は治療効果を有するため、該疾患の予防、緩和、及び／又は治療に使用することができる。 Since the drug of the present invention has excellent preventive, alleviating, and / or therapeutic effects on diseases such as obesity and diabetes, it can be used for prevention, alleviation, and / or treatment of the diseases.

Claims (15)

  1. 　インクレチン様物質と組み合わせて使用するための、消化管プロテアーゼ阻害剤を含む薬剤。 A drug containing a gastrointestinal protease inhibitor for use in combination with an incretin-like substance.
  2. 　消化管プロテアーゼ阻害剤がエンテロペプチダーゼ阻害剤及び／又はトリプシン阻害剤である、請求項１に記載の薬剤。 The agent according to claim 1, wherein the gastrointestinal protease inhibitor is an enteropeptidase inhibitor and / or a trypsin inhibitor.
  3. 　消化管プロテアーゼ阻害剤がエンテロペプチダーゼ阻害剤である、請求項１に記載の薬剤。 The agent according to claim 1, wherein the gastrointestinal protease inhibitor is an enteropeptidase inhibitor.
  4. 　エンテロペプチダーゼ阻害剤が
    （ａ）下記一般式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
     ［式中、Ａ１及びＡ２は、それぞれ独立して、以下の群Ａ：
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
     から選択される化合物、又は下記一般式（ＩＩ）
    Figure JPOXMLDOC01-appb-C000006
     ［式中、
    　環Ｂ及び環Ｃは、それぞれ独立して、アリール基、又はヘテロアリール基であり；
    　各Ｒ１は、それぞれ独立して、水素原子、又は－ＣＯＯ－（Ｃ１－Ｃ４アルキル基）であり；
    　Ｗは、単結合、又はＣ１－Ｃ４アルキレン基であり；
    　Ｘは、－Ｃ（＝Ｏ）－、－Ｏ－Ｃ（＝Ｏ）－、又は－ＮＧ－ＳＯ２－であり；
    　Ｇは水素原子、Ｃ１－Ｃ４アルキル基、又は－ＣＯＯＲ２であり；
    　Ｒ２は、１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
    　Ｙは、－ＮＧ２Ｇ４、－ＮＧ２－Ｌ１－ＣＯＯＨ、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＨ２、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－ＣＯＯＨ、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－ＣＯＯＨ、－ＮＧ２－Ｌ１－Ｃ（＝Ｏ）－ＮＧ３－Ｌ２－Ｃ（＝Ｏ）－ＮＨ２、－ＮＧ２－Ｌ３－ＯＨ、又は－ＮＧ２－（ＣＨ２－ＣＨ２－Ｏ）ｑ－ＣＨ２－ＣＨ２－ＣＯＯＨであり；
    　ｑは、１～６の整数であり；
    　Ｇ２及びＧ３は、それぞれ独立して、水素原子、又は１～５個の－ＣＯＯＲ３基で置換されていてもよいフェニル基及び－ＣＯＯＲ３基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ６アルキル基であり；
    　Ｇ４は、水素原子、Ｃ１－Ｃ４アルキル基、又はＣ１－Ｃ４アルコキシ―Ｃ１－Ｃ４アルキル基であり；
    　Ｒ３は、それぞれ独立して、水素原子、又は１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
    　Ｌ１及びＬ２は、それぞれ独立して、１～５個の－ＣＯＯＲ４基で置換されていてもよい１～５個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、ヒドロキシ基及びカルボキシ基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ７－Ｃ１２アラルキル基で置換されたＣ１－Ｃ６アルキレン基、Ｃ１－Ｃ４アルキレン－フェニレン基、又はフェニレン－Ｃ１－Ｃ４アルキレン基であり；
    　Ｌ３は、フェニレン部分が１～３個の－ＣＯＯＲ４基で置換されていてもよいＣ１－Ｃ４アルキレン－フェニレン基であり；
    　Ｒ４は、それぞれ独立して水素原子、又はアリール基及びトリメチルシリル基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
    　Ｒ５及びＲ６は、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１－Ｃ４アルキル基、Ｃ１－Ｃ４アルコキシ基、カルボキシ基、又は－Ｃ（＝Ｏ）－ＮＧ２Ｇ４であり；
    　ｓ及びｔは、それぞれ独立して、１～４の整数であり；
    　複数のＲ５及び／又は複数のＲ６は、それぞれ同一であっても異なっていてもよく；
    　又は、Ｒ５のいずれか１つ及びＲ６のいずれか１つは互いに結合して、Ｃ１－Ｃ４アルキレンオキシ基を形成してもよい］
    で表される化合物からいずれか１つの水素原子又はヒドロキシ基を除いた残基を示し；
    　Ｚは、単結合、アリーレン、ヘテロアリーレン、又はＣ２－Ｃ３０アルキレン基（ただし、該アルキレン基の鎖中の１つ以上のメチレン基は、－Ｃ（＝Ｏ）－、－ＮＲ７－、－Ｏ－、－ＳｉＲ８Ｒ９－、－ＳＯｒ－、アリーレン、及びヘテロアリーレンからなる群から独立して選択される基と置き換わっていてもよく、Ｒ７は水素原子、又はＣ１－Ｃ４アルキル基であり、Ｒ８及びＲ９は、それぞれ独立して、Ｃ１－Ｃ４アルキル基であり、ｒは、０～２の整数である）である］
    で表される化合物又はその薬学上許容される塩；
    （ｂ）群Ａの化合物又はその薬学上許容される塩；並びに
    （ｃ）一般式（ＩＩ）で表される化合物又はその薬学上許容される塩
    からなる群から選択される１つ以上の化合物又はその薬学上許容される塩である、請求項２又は３に記載の薬剤。     The enteropeptidase inhibitor is (a) the following general formula (I):
    Figure JPOXMLDOC01-appb-C000001
     [In the formula, A 1 and A 2 are independent of each other, and the following group A:
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
     Compounds selected from, or the following general formula (II)
    Figure JPOXMLDOC01-appb-C000006
     [During the ceremony,
    Rings B and C are independently aryl groups or heteroaryl groups;
    Each R 1 is independently a hydrogen atom, or -COO- (C 1 -C 4 alkyl group);
    W is a single bond, or a C 1 -C 4 alkylene group;
    X is -C (= O)-, -OC (= O)-, or -NG-SO 2- ;
    G is hydrogen, C 1 -C 4 alkyl group, or a -COOR 2;
    R 2 is 1-5 optionally substituted by an aryl group C 1 -C 4 alkyl group;
    Y is -NG 2 G 4 , -NG 2- L 1- COOH, -NG 2- L 1- C (= O) -NH 2 , -NG 2- L 1- C (= O) -NG 3- L 2- COOH, -NG 2- L 1- C (= O) -NG 3- L 2- C (= O) -NG 3- L 2- COOH, -NG 2- L 1- C (= O) -NG 3- L 2- C (= O) -NH 2 , -NG 2- L 3- OH, or -NG 2- (CH 2- CH 2- O) q -CH 2- CH 2- COOH. ;
    q is an integer from 1 to 6;
    G 2 and G 3 are, 1 each independently selected hydrogen atom, or a 1-5 -COOR 3 phenyl group which may be substituted with groups and independently from the group consisting of -COOR 3 group ~ be five may be substituted with a substituent C 1 -C 6 alkyl group;
    G 4 are hydrogen, C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy -C 1 -C 4 alkyl group;
    R 3 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group;
    L 1 and L 2 may be independently substituted with 1 to 5 —COOR 4 groups and may be substituted with 1 to 5 C 1 − C 6 alkyl groups C 1 −. C 7- C 12 substituted with 1-5 substituents independently selected from the group consisting of C 6 alkylene group, hydroxy group and carboxy group C 1- C 6 substituted with aralkyl group alkylene group, C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group;
    L 3 is a phenylene moiety 1-3 optionally substituted by -COOR 4 group of C 1 -C 4 alkylene - be a phenylene group;
    R 4 are each independently a hydrogen atom, or an aryl group and 1 to 5 may be substituted with a substituent C 1 -C 4 alkyl groups independently selected from the group consisting of trimethylsilyl group ;
    R 5 and R 6 are each independently a hydrogen atom, a halogen atom, C 1 -C 4 alkyl group, C 1 -C 4 alkoxy group, a carboxy group, or -C (= O) -NG 2 G 4 can be;
    s and t are independently integers from 1 to 4;
    A plurality of R 5 and / or R 6, which may be each independently identical or different;
    Or any one of any one and R 6 in R 5, taken together, may form a C 1 -C 4 alkylene group]
    Indicates a residue obtained by removing any one hydrogen atom or hydroxy group from the compound represented by;
    Z is a single bond, arylene, heteroarylene, or C 2 -C 30 alkylene group (wherein one or more methylene groups in the chain of the alkylene group, -C (= O) -, - NR 7 -, -O -, - SiR 8 R 9 -, - SO r -, arylene, and may be replaced by groups independently selected from the group consisting heteroarylene, R 7 is a hydrogen atom, or a C 1 -C an alkyl group, R 8 and R 9 are each independently a C 1 -C 4 alkyl group, r is an a) an integer of 0-2]
    The compound represented by or a pharmaceutically acceptable salt thereof;
    One or more compounds selected from the group consisting of (b) a compound of group A or a pharmaceutically acceptable salt thereof; and (c) a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof. The agent according to claim 2 or 3, which is a pharmaceutically acceptable salt thereof.
  5. 　エンテロペプチダーゼ阻害剤が下記一般式（ＩＩＩ）：
    Figure JPOXMLDOC01-appb-C000007
     ［式中、
    　各Ｒ１は、それぞれ独立して、水素原子、又は－ＣＯＯ－（Ｃ１－Ｃ４アルキル基）であり；
    　Ｗ１及びＷ２は、それぞれ独立して、単結合、又はＣ１－Ｃ４アルキレン基であり；
    　Ｘ１は、－Ｃ（＝Ｏ）－、又は－ＮＧ１１－ＳＯ２－であり；
    　Ｘ２は、－Ｃ（＝Ｏ）－、又は－ＳＯ２－ＮＧ１２－であり；
    　Ｇ１１及びＧ１２は、それぞれ独立して、水素原子、又は－ＣＯＯＲ２であり；
    　Ｒ２は、１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
    　Ｙ１は、－ＮＧ２１－、－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＨ－、又は－ＮＧ２１－Ｌ１１－Ｃ（＝Ｏ）－ＮＧ３１－Ｌ２１－Ｃ（＝Ｏ）－ＮＨ－であり；
    　Ｙ２は、－ＮＧ２２－、－ＮＨ－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－、又は－ＮＨ－Ｃ（＝Ｏ）－Ｌ２２－ＮＧ３２－Ｃ（＝Ｏ）－Ｌ１２－ＮＧ２２－であり；
    　Ｇ２１、Ｇ３１、Ｇ２２、及びＧ３２は、それぞれ独立して、水素原子、又は１～５個の－ＣＯＯＲ３基で置換されていてもよいフェニル基及び－ＣＯＯＲ３基からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－Ｃ６アルキル基であり；
    　Ｒ３は、それぞれ独立して、水素原子、又は１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
    　Ｌ１１、Ｌ２１、Ｌ１２、及びＬ２２は、それぞれ独立して、１～５個の－ＣＯＯＲ４基で置換されていてもよい１～５個のＣ１－Ｃ６アルキル基で置換されていてもよいＣ１－Ｃ６アルキレン基、Ｃ１－Ｃ４アルキレン－フェニレン基、又はフェニレン－Ｃ１－Ｃ４アルキレン基であり；
    　Ｒ４は、それぞれ独立して、水素原子、又は１～５個のアリール基で置換されていてもよいＣ１－Ｃ４アルキル基であり；
    　Ｚは、－（ＣＨ２－ＣＨ２－Ｏ）ｍ－ＣＨ２－ＣＨ２－、又は－（ＣＨ２）ｎ－であり；
    　ｍは、１～６の整数であり；
    　ｎは、２～１２の整数である］
    で表される化合物又はその薬学上許容される塩である、請求項２～４のいずれか１項に記載の薬剤。     The enteropeptidase inhibitor is the following general formula (III):
    Figure JPOXMLDOC01-appb-C000007
     [During the ceremony,
    Each R 1 is independently a hydrogen atom, or -COO- (C 1 -C 4 alkyl group);
    W 1 and W 2 are each independently a single bond, or a C 1 -C 4 alkylene group;
    X 1 is -C (= O)-or-NG 11 -SO 2- ;
    X 2 is, -C (= O) -, or -SO 2 -NG 12 - a and;
    G 11 and G 12 are independently hydrogen atoms, or -COOR 2 ;
    R 2 is 1-5 optionally substituted by an aryl group C 1 -C 4 alkyl group;
    Y 1 is, -NG 21 -, - NG 21 -L 11 -C (= O) -NH-, or -NG 21 -L 11 -C (= O ) -NG 31 -L 21 -C (= O) -NH-;
    Y 2 is, -NG 22 -, - NH- C (= O) -L 12 -NG 22 -, or -NH-C (= O) -L 22 -NG 32 -C (= O) -L 12 - NG 22- and;
    G 21, G 31, G 22 , and G 32 is a independently a hydrogen atom, or 1 to the group of five -COOR 3 phenyl group and -COOR 3 groups optionally substituted by group independently is 1 to 5 C 1 may be substituted with a substituent -C 6 alkyl group which is selected;
    R 3 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group;
    L 11 , L 21 , L 12 and L 22 are each independently substituted with 1 to 5 C 1- C 6 alkyl groups, which may be substituted with 1 to 5 -COOR 4 groups. which may be C 1 -C 6 alkylene group, C 1 -C 4 alkylene - be a phenylene group or a phenylene -C 1 -C 4 alkylene group;
    R 4 is independently hydrogen atom, or 1 to be a five aryl group optionally substituted C 1 -C 4 alkyl group;
    Z is, - (CH 2 -CH 2 -O ) m -CH 2 -CH 2 -, or - (CH 2) n -, and;
    m is an integer from 1 to 6;
    n is an integer from 2 to 12]
    The agent according to any one of claims 2 to 4, which is a compound represented by the above or a pharmaceutically acceptable salt thereof.
  6. 　エンテロペプチダーゼ阻害剤が
    　（２Ｓ，１３Ｓ）－３，１２－ビス（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）－６，９－ジオキサ－３，１２－ジアザテトラデカン－１，２，１３，１４－テトラカルボン酸；
    　（２Ｓ，２’Ｓ）－２，２’－（（オキシビス（エタン－２，１－ジイル））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸；
    　（２Ｓ，１６Ｓ）－３，１５－ビス（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）－６，９，１２－トリオキサ－３，１５－ジアザヘプタデカン－１，２，１６，１７－テトラカルボン酸；
    　（２Ｓ，２’Ｓ）－２，２’－（（［１，１’－ビフェニル］－３，３’－ジイルビス（メチレン））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸；及び
    　（２Ｓ，２’Ｓ）－２，２’－（（（（（オキシビス（エタン－２，１－ジイル））ビス（オキシ））ビス（３－カルボキシ－５，１－フェニレン））ビス（メチレン））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸
    からなる群から選択される化合物又はその薬学上許容される塩である、請求項２～５のいずれか１項に記載の薬剤。     Enteropeptidase inhibitors are (2S, 13S) -3,12-bis (10-guanidine-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl ) -6,9-Dioxa-3,12-Diazatetradecane-1,2,13,14-Tetracarboxylic acid;
    (2S, 2'S) -2,2'-((oxybis (ethane-2,1-diyl))) Bis ((10-guanidino-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandyl)) disuccinic acid;
    (2S, 16S) -3,15-bis (10-guanidine-13-oxo-6,7,8,13-tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) -6,9 , 12-Trioxa-3,15-diazaheptadecane-1,2,16,17-tetracarboxylic acid;
    (2S, 2'S) -2,2'-(([1,1'-biphenyl] -3,3'-diylbis (methylene))) Bis ((10-guanidino-13-oxo-6,7,8) , 13-Tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandyl)) disuccinic acid; and (2S, 2'S) -2,2'-(((((oxybis (ethane) ethane) -2,1-diyl)) bis (oxy)) bis (3-carboxy-5,1-phenylene)) bis (methylene)) bis ((10-guanidino-13-oxo-6,7,8,13-) Tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandiyl)) A compound selected from the group consisting of disuccinic acid or a pharmaceutically acceptable salt thereof, any of claims 2 to 5. Or the drug according to item 1.
  7. 　エンテロペプチダーゼ阻害剤が（２Ｓ，２’Ｓ）－２，２’－（（オキシビス（エタン－２，１－ジイル））ビス（（１０－グアニジノ－１３－オキソ－６，７，８，１３－テトラヒドロジベンゾ［ｂ，ｆ］［１，４］ジオキセシン－４－カルボニル）アザンジイル））二コハク酸である、請求項２～６のいずれか１項に記載の薬剤。 Enteropeptidase inhibitors are (2S, 2'S) -2,2'-((oxybis (ethane-2,1-diyl))) bis ((10-guanidino-13-oxo-6,7,8,13-) The agent according to any one of claims 2 to 6, which is tetrahydrodibenzo [b, f] [1,4] dioxesin-4-carbonyl) azandiyl)) disuccinic acid.
  8. 　インクレチン様物質がＧＬＰ－１受容体作動薬である、請求項１～７のいずれか１項に記載の薬剤。 The drug according to any one of claims 1 to 7, wherein the incretin-like substance is a GLP-1 receptor agonist.
  9. 　ＧＬＰ－１受容体作動薬がセマグルチド、リラグルチド、デュラグルチド、エキセナチド、リキシセナチド、アルビグルチド、及びエフペグレナチドからなる群から選択される１つ以上のＧＬＰ－１受容体作動薬である、請求項８に記載の薬剤。 The agent according to claim 8, wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists selected from the group consisting of semaglutide, liraglutide, duraglutide, exenatide, lixisenatide, albiglutide, and efpeglenatide. ..
  10. 　ＧＬＰ－１受容体作動薬がセマグルチド、リラグルチド、及びデュラグルチドからなる群から選択される１つ以上のＧＬＰ－１受容体作動薬である、請求項８に記載の薬剤。 The agent according to claim 8, wherein the GLP-1 receptor agonist is one or more GLP-1 receptor agonists selected from the group consisting of semaglutide, liraglutide, and duraglutide.
  11. 　ＧＬＰ－１受容体作動薬がセマグルチドである、請求項８に記載の薬剤。 The agent according to claim 8, wherein the GLP-1 receptor agonist is semaglutide.
  12. 　ＧＬＰ－１受容体作動薬がリラグルチドである、請求項８に記載の薬剤。 The agent according to claim 8, wherein the GLP-1 receptor agonist is liraglutide.
  13. 　消化管プロテアーゼ及び／又はインクレチンが関与する疾患を予防、緩和、及び／又は治療するための、請求項１～１２のいずれか１項に記載の薬剤。 The agent according to any one of claims 1 to 12, for preventing, alleviating, and / or treating a disease associated with gastrointestinal protease and / or incretin.
  14. 　消化管プロテアーゼ及び／又はインクレチンが関与する疾患が肥満症及び糖尿病から選択される１つ以上の疾患である、請求項１３に記載の薬剤。 The agent according to claim 13, wherein the disease involving gastrointestinal protease and / or incretin is one or more diseases selected from obesity and diabetes.
  15. 　消化管プロテアーゼ阻害剤とインクレチン様物質が別々の組成物に製剤化されている、請求項１～１４のいずれか１項に記載の薬剤。 The agent according to any one of claims 1 to 14, wherein the gastrointestinal protease inhibitor and the incretin-like substance are formulated in separate compositions.
PCT/JP2021/005680 2020-02-17 2021-02-16 Gastric protease inhibitor-containing drug for combination use with incretin mimetic WO2021166899A1 (en)

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Citations (6)

* Cited by examiner, † Cited by third party
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JP2009530395A (en) * 2006-03-21 2009-08-27 アミリン・ファーマシューティカルズ，インコーポレイテッド Peptide-peptidase inhibitors and uses thereof
JP2011519915A (en) * 2008-05-05 2011-07-14 オラムド エルティーディー． Methods and compositions for oral administration of exenatide
WO2013187533A1 (en) * 2012-06-14 2013-12-19 Ajinomoto Co., Inc. Heteroarylcarboxylic acid ester derivative
JP2017505823A (en) * 2014-02-13 2017-02-23 武田薬品工業株式会社 Heterocyclic compounds
JP2017506627A (en) * 2014-02-13 2017-03-09 武田薬品工業株式会社 Fused heterocyclic compounds
WO2019088270A1 (en) * 2017-11-02 2019-05-09 宇部興産株式会社 Double-headed protease inhibitor

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009530395A (en) * 2006-03-21 2009-08-27 アミリン・ファーマシューティカルズ，インコーポレイテッド Peptide-peptidase inhibitors and uses thereof
JP2011519915A (en) * 2008-05-05 2011-07-14 オラムド エルティーディー． Methods and compositions for oral administration of exenatide
WO2013187533A1 (en) * 2012-06-14 2013-12-19 Ajinomoto Co., Inc. Heteroarylcarboxylic acid ester derivative
JP2017505823A (en) * 2014-02-13 2017-02-23 武田薬品工業株式会社 Heterocyclic compounds
JP2017506627A (en) * 2014-02-13 2017-03-09 武田薬品工業株式会社 Fused heterocyclic compounds
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