WO2011071048A1 - ヘテロアリールカルボン酸エステル誘導体 - Google Patents
ヘテロアリールカルボン酸エステル誘導体 Download PDFInfo
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- WO2011071048A1 WO2011071048A1 PCT/JP2010/071929 JP2010071929W WO2011071048A1 WO 2011071048 A1 WO2011071048 A1 WO 2011071048A1 JP 2010071929 W JP2010071929 W JP 2010071929W WO 2011071048 A1 WO2011071048 A1 WO 2011071048A1
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- Prior art keywords
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- substituent
- mmol
- acid
- pharmaceutically acceptable
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- 239000002253 acid Substances 0.000 title description 35
- 150000002148 esters Chemical class 0.000 title description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 283
- 150000003839 salts Chemical class 0.000 claims abstract description 70
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- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 125000001424 substituent group Chemical group 0.000 claims description 192
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 65
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 61
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 56
- 125000003277 amino group Chemical group 0.000 claims description 49
- 125000003545 alkoxy group Chemical group 0.000 claims description 44
- 125000005843 halogen group Chemical group 0.000 claims description 39
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 39
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 35
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 29
- 125000003342 alkenyl group Chemical group 0.000 claims description 28
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 28
- 125000002252 acyl group Chemical group 0.000 claims description 26
- 125000003282 alkyl amino group Chemical group 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 26
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- 108090000631 Trypsin Proteins 0.000 claims description 24
- 102000004142 Trypsin Human genes 0.000 claims description 24
- 125000000304 alkynyl group Chemical group 0.000 claims description 24
- 239000012588 trypsin Substances 0.000 claims description 24
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 23
- 125000002947 alkylene group Chemical group 0.000 claims description 23
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- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 21
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical class C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 19
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- 125000004442 acylamino group Chemical group 0.000 claims description 17
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- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 17
- 239000004480 active ingredient Substances 0.000 claims description 16
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 125000004423 acyloxy group Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
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- 125000004430 oxygen atom Chemical group O* 0.000 claims description 11
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- 208000002249 Diabetes Complications Diseases 0.000 claims description 10
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- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 235000020824 obesity Nutrition 0.000 claims description 9
- 125000004419 alkynylene group Chemical group 0.000 claims description 8
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 8
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- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 8
- 230000000069 prophylactic effect Effects 0.000 claims description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 8
- 125000005730 thiophenylene group Chemical group 0.000 claims description 8
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 7
- 206010022489 Insulin Resistance Diseases 0.000 claims description 7
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 6
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 6
- 229940122055 Serine protease inhibitor Drugs 0.000 claims description 5
- 101710102218 Serine protease inhibitor Proteins 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 5
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 5
- 125000005110 aryl thio group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
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- 239000003001 serine protease inhibitor Substances 0.000 claims description 5
- 125000004149 thio group Chemical group *S* 0.000 claims description 5
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- 229910052701 rubidium Inorganic materials 0.000 claims description 4
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- 150000002240 furans Chemical class 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 33
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 17
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- 230000002265 prevention Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 description 177
- 230000015572 biosynthetic process Effects 0.000 description 176
- -1 ester compound Chemical class 0.000 description 172
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 152
- 230000002829 reductive effect Effects 0.000 description 149
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 141
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 140
- 239000000243 solution Substances 0.000 description 126
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 103
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- 238000006243 chemical reaction Methods 0.000 description 89
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 88
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 69
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 59
- 238000004128 high performance liquid chromatography Methods 0.000 description 54
- 125000004432 carbon atom Chemical group C* 0.000 description 52
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 48
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 45
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 41
- 238000003756 stirring Methods 0.000 description 41
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 229960005261 aspartic acid Drugs 0.000 description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 33
- 238000010898 silica gel chromatography Methods 0.000 description 32
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 31
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
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- YGGXZTQSGNFKPJ-UHFFFAOYSA-N methyl 2-naphthalen-1-ylacetate Chemical compound C1=CC=C2C(CC(=O)OC)=CC=CC2=C1 YGGXZTQSGNFKPJ-UHFFFAOYSA-N 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
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- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
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- 239000001257 hydrogen Substances 0.000 description 21
- VHVJRSVTZPYXEH-UHFFFAOYSA-N [amino-(4-hydroxyphenyl)methylidene]azanium;chloride Chemical compound Cl.NC(=N)C1=CC=C(O)C=C1 VHVJRSVTZPYXEH-UHFFFAOYSA-N 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
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- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 12
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
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- GVLZIMQSYQDAHB-QRPNPIFTSA-N ditert-butyl (2s)-2-aminobutanedioate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C GVLZIMQSYQDAHB-QRPNPIFTSA-N 0.000 description 9
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- IWMVXSQQAIMBSS-BQYQJAHWSA-N 5-[(e)-2-methyl-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]thiophene-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)C(/C)=C/C1=CC=C(C(O)=O)S1 IWMVXSQQAIMBSS-BQYQJAHWSA-N 0.000 description 4
- ZQJWHFDKEWQHRF-UHFFFAOYSA-N 5-[5-(4-carbamimidoylphenoxy)carbonylfuran-2-yl]-4-methylpentanoic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.O1C(CC(CCC(O)=O)C)=CC=C1C(=O)OC1=CC=C(C(N)=N)C=C1 ZQJWHFDKEWQHRF-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
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- CTNGZOGOKKDHRI-UHFFFAOYSA-N [[3-[5-(4-carbamimidoylphenoxy)carbonylthiophen-2-yl]-2-methylpropanoyl]amino]methylphosphonic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.S1C(CC(C)C(=O)NCP(O)(O)=O)=CC=C1C(=O)OC1=CC=C(C(N)=N)C=C1 CTNGZOGOKKDHRI-UHFFFAOYSA-N 0.000 description 4
- PAAZCQANMCYGAW-UHFFFAOYSA-N acetic acid;2,2,2-trifluoroacetic acid Chemical compound CC(O)=O.OC(=O)C(F)(F)F PAAZCQANMCYGAW-UHFFFAOYSA-N 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
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Classifications
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- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
Definitions
- the present invention relates to a novel heteroarylcarboxylic acid ester derivative having serine protease (particularly trypsin and enteropeptidase) inhibitory activity, a pharmaceutical composition containing the same, and a therapeutic or prophylactic agent for diabetes.
- insulin secretion enhancers sulfonylureas
- glucose absorption inhibitors ⁇ -glucosidase inhibitors
- insulin resistance improvers biguanides, thiazolidine derivatives
- drugs that satisfy clinical needs such as being accompanied by side effects such as hypoglycemia, diarrhea, lactic acidosis, edema, and insufficient effects.
- Non-Patent Document 2 also describes a heteroarylcarboxylic acid ester having protease inhibitory activity represented by the following formula. However, only compounds having an unsubstituted heteroaryl moiety are disclosed, and no enteropeptidase inhibitory activity and blood glucose elevation inhibitory activity are described for these compounds.
- Patent Document 3 describes a compound represented by the following formula, which has a structure in which an aryl group substituted with a carboxyl group is directly bonded to a heteroaryl moiety, and the compound of the present invention is Completely different. Moreover, although the inhibitory activity with respect to the blood coagulation factor VIIa is disclosed in the said literature, the enteropeptidase inhibitory activity and the blood glucose rise inhibitory effect are not described at all.
- trypsin is one of the serine proteases in the gastrointestinal tract and is produced by decomposing inactive trypsinogen by enteropeptidase.
- trypsin is known to act on chymotrypsinogen, proelastase, procarboxyesterase, procolipase, proscrase isomaltase and the like to activate various digestive enzymes. Therefore, enteropeptidase and trypsin inhibitors reduce the digestibility of proteins, lipids and carbohydrates, and are considered effective for the treatment and prevention of obesity and hyperlipidemia.
- Patent Document 4 describes that a drug that inhibits both enteropeptidase and trypsin is interesting as a body fat reducing agent.
- Patent Document 5 reports compounds having inhibitory activity such as enteropeptidase, trypsin, plasmin, kallikrein and the like as anti-obesity agents.
- enteropeptidase trypsin
- plasmin plasmin
- kallikrein kallikrein
- a blood glucose elevation inhibitor having a serine protease inhibitory action which is a new diabetes treatment and prevention drug, is eagerly desired.
- An object of the present invention is to provide a heteroarylcarboxylic acid ester derivative which is a novel compound having a serine protease inhibitory action.
- the present invention also aims to provide serine protease (especially trypsin and enteropeptidase) inhibitors.
- Another object of the present invention is to provide an agent for suppressing blood sugar elevation and an agent for lowering blood glucose, and further provides a therapeutic or prophylactic agent for any of diabetes, obesity, hyperlipidemia, diabetic complications, and metabolic syndrome. The purpose is to do.
- the present inventors have intensively studied and thought that simultaneous inhibition of trypsin and enteropeptidase is particularly effective in suppressing blood sugar elevation.
- Various new heteroaryl carboxylic acid ester derivatives are synthesized, trypsin and enteropeptidase inhibitory activity is evaluated, and certain heteroaryl carboxylic acid ester derivatives are proteolytic enzyme inhibitors that inhibit both of them.
- the present invention has been completed. Furthermore, it has also been found that these representative compounds exhibit an effect of suppressing blood glucose elevation in a diabetic animal model.
- the present invention contains a heteroarylcarboxylic acid ester derivative represented by the following formula (I) and a pharmaceutically acceptable salt thereof (hereinafter sometimes simply referred to as “the compound of the present invention”).
- a pharmaceutical composition and a serine protease inhibitor comprising the same as an active ingredient are provided.
- R1, R2, R3 and R4 may be the same or different and each independently represents a hydrogen atom, a nitro group, a halogeno group, a cyano group, a hydroxyl group, a thiol group, an amino group, a guanidino group, a formyl group, or a lower alkyl.
- R6 and R7 may be the same or different, and each independently represents a hydrogen atom, a hydroxyl group, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, or a substituent.
- a lower alkynyl group which may have a lower alkoxyl group which may have a substituent, or R6 and R7 may be bonded to form a cyclic amino group which may have a substituent; .
- a cyclic amino group may be formed).
- R1, R2, R3 and R4 may be the same or different and each independently represents a hydrogen atom, a nitro group, a halogeno group, a cyano group, a hydroxyl group, a thiol group, an amino group, a guanidino group, a formyl group, or a lower alkyl.
- R6 and R7 may be the same or different and each independently represents a hydrogen atom, a hydroxyl group, a lower alkyl group which may have a substituent, or a lower alkenyl group which may have a substituent.
- a pharmaceutically acceptable salt thereof thereof.
- the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein in the general formula (I), R1, R2, R3 and R4 each independently represents a hydrogen atom, a nitro group or a halogeno group. To do.
- the present invention relates to a compound having a 5- to 10-membered aromatic ring containing 1 to 3 heteroatoms, and a pharmaceutically acceptable salt thereof, wherein HetAr may have a substituent in the general formula (I). Provide the resulting salt.
- Z1 and Z2 each independently represent CRa or a nitrogen atom
- Z3 represents an oxygen atom, a sulfur atom or NRb
- Ra and Rb may be the same or different and each independently represents a hydrogen atom, nitro group, halogeno group, cyano group, hydroxyl group, thiol group, amino group, guanidino group, formyl group, lower alkyl group, lower alkenyl group, lower group Alkynyl group, lower acyl group, carboxyl group, sulfo group, phosphono group, lower alkoxyl group, lower alkylthio group, lower alkylamino group, lower acyloxy group, lower acylamino group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, A lower alkylsulfonylamino group or a sulfamoyl group.
- the present invention is a group containing a heteroaromatic ring in which -HetAr- is represented by the group (III-1) or (III-2),
- Z1 and Z2 each independently represent CRa or a nitrogen atom
- Z3 represents an oxygen atom or a sulfur atom, or a pharmaceutically acceptable compound thereof Provide the resulting salt.
- the present invention represents a lower alkylene group which may have a substituent or a lower alkenylene group which may have a substituent, and the substituent includes a halogeno group, a hydroxyl group
- a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of a group, an amino group, a lower alkyl group, a lower alkoxyl group and a lower acyl group.
- the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein, in the general formula (I), Y represents a carbonyl group or a sulfonyl group.
- the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein, in the general formula (I), A represents —OR 5 (R 5 represents a hydrogen atom or a lower alkyl group).
- A is the following group (IV):
- R60 represents a carboxyl group, a sulfo group, a phosphono group, a lower alkoxycarbonyl group, or a hydroxyl group
- D represents a lower alkylene group which may have a substituent, a lower alkenylene group which may have a substituent or a lower alkynylene group which may have a substituent, and the substituent includes a nitro group, a halogeno group; Group, cyano group, hydroxyl group, thiol group, amino group, guanidino group, formyl group, lower acyl group, carboxyl group, sulfo group, phosphono group, lower alkoxyl group, lower alkylthio group, lower alkylamino group, lower acyloxy group, Lower acylamino group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, lower alkylsulfonyla
- A represents the group (IV)
- R60 represents a carboxyl group, a sulfo group, a lower alkoxycarbonyl group, or a hydroxyl group
- D represents a lower alkylene group which may have a substituent, and the substituent is a halogeno group, a hydroxyl group, a thiol group, an amino group, a guanidino group, a carboxyl group, a sulfo group, a lower alkoxyl group, or a lower alkylthio group.
- R70 represents a hydrogen atom, a hydroxyl group, a lower alkyl group which may have a substituent, or a lower alkoxyl group which may have a substituent, and R70 and D are bonded to each other to have a substituent. May form a cyclic amino group, A compound or pharmaceutically acceptable salt thereof is provided.
- R1, R2, R3, and R4 each independently represent a hydrogen atom, a nitro group, or a fluorine atom
- R1, R2, R3, and R4 each independently represent a hydrogen atom, a nitro group, or a fluorine atom
- HetAr represents furan, thiophene, or thiazole, which may have a substituent.
- the present invention also provides a gastrointestinal serine protease inhibitor containing the above heteroaryl carboxylic acid ester derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention also provides a dual inhibitor of trypsin and enteropeptidase containing the above heteroaryl carboxylic acid ester derivative, or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention also provides an antihyperglycemic agent or hypoglycemic agent comprising the above heteroarylcarboxylic acid ester derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention also provides a preventive or therapeutic agent for diabetes comprising the above heteroaryl carboxylic acid ester derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention also provides an insulin resistance ameliorating agent comprising the above heteroaryl carboxylic acid ester derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention also provides a prophylactic or therapeutic agent for obesity, hyperlipidemia, diabetic complications or metabolic syndrome, comprising the above heteroaryl carboxylic acid ester derivative or a pharmaceutically acceptable salt thereof as an active ingredient. provide.
- the present invention also provides a method for preventing or treating diabetes, which comprises administering an effective amount of the above heteroarylcarboxylic acid ester derivative or a pharmaceutically acceptable salt thereof.
- the present invention also provides a method for improving insulin resistance, which comprises administering an effective amount of the above heteroarylcarboxylic acid ester derivative or a pharmaceutically acceptable salt thereof.
- the present invention also relates to obesity, hyperlipidemia, diabetic complications or metabolic syndrome, characterized by administering an effective amount of the above heteroarylcarboxylic acid ester derivative, or a pharmaceutically acceptable salt thereof. Prophylactic or therapeutic methods are provided.
- the present invention also provides the use of the above heteroarylcarboxylic acid ester derivative or a pharmaceutically acceptable salt thereof for the prevention or treatment of diabetes.
- the present invention also provides the use of the above heteroarylcarboxylic acid ester derivative, or a pharmaceutically acceptable salt thereof, for improving insulin resistance.
- the present invention also provides the use of the above heteroarylcarboxylic acid ester derivative or a pharmaceutically acceptable salt thereof for the prevention or treatment of obesity, hyperlipidemia, diabetic complications or metabolic syndrome. To do.
- the compound of the present invention has a blood glucose elevation inhibitory effect, it can be suitably used as a therapeutic or prophylactic agent for diabetes.
- substituents examples include nitro group, halogeno group, cyano group, hydroxyl group, thiol group, amino group, guanidino group, formyl group, phenyl group, lower alkyl group, lower alkenyl group, lower alkynyl group, lower acyl group, Examples include carboxyl group, sulfo group, phosphono group, lower alkoxyl group, lower alkylthio group, lower alkylamino group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, lower alkylsulfonylamino group, and sulfamoyl group.
- arylsulfonylamino group which may have a substituent “cycloalkyl group which may have a substituent”, “aryl group which may have a substituent”, “substituent An aryloxy group which may have a substituent, an arylthio group which may have a substituent, an aralkyl group which may have a substituent, and an aralkyloxy group which may have a substituent.
- substituent in the “optional heterocyclic thio group” include a nitro group, a halogeno group, a cyano group, a hydroxyl group, a thiol group, an amino group, a guanidino group, a formyl group, a lower alkyl group, a lower alkenyl group, a lower group, and the like.
- Alkynyl group, lower acyl A carboxyl group, a sulfo group, a phosphono group, a lower alkoxyl group, lower alkylthio group, a lower alkylamino group, a lower alkoxycarbonyl group, a carbamoyl group, lower alkylcarbamoyl group, or the like lower alkylsulfonylamino group, and sulfamoyl group.
- the “heteroaromatic ring” is a 5- to 10-membered aromatic ring which may contain 1 to 3 heteroatoms such as nitrogen atom, oxygen atom, sulfur atom, etc.
- heteroatoms such as nitrogen atom, oxygen atom, sulfur atom, etc.
- monocycles include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine and pyrazine, etc.
- condensed aromatic rings examples include indole, isoindole, benzofuran, benzothiophene, indolizine, quinoline, isoquinoline, purine, 1H-indazole, quinazoline, cinnoline, quinoxaline, phthalazine, pteridine, benzoxazole, benzothiazole and benzimidazole.
- cyclic amino group refers to a saturated or unsaturated cyclic amino group having 2 to 7 carbon atoms, and includes one or more nitrogen atoms, oxygen atoms, sulfur atoms, etc. in the ring. Hetero atoms may be included. Examples include pyrrolidinyl group, pyrrolinyl group, piperidinyl group, morpholinyl group, piperazinyl group, thiomorpholinyl group, piperidinonyl group, piperazinonyl group and the like.
- the “lower alkyl group” refers to a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms.
- the “lower alkenyl group” refers to a linear or branched alkenyl group having 2 to 6 carbon atoms including each isomer. Examples thereof include a vinyl group, an allyl group, a propenyl group, a butenyl group, a pentenyl group, and a hexenyl group.
- the “lower alkynyl group” refers to a linear or branched alkynyl group having 2 to 6 carbon atoms including each isomer. Examples include ethynyl group, 1-propynyl group, 2-propynyl group, 2-butynyl group, 3-butynyl group, pentynyl group and the like.
- the “lower alkylene group” refers to a linear or branched or cyclic alkylene group having 1 to 6 carbon atoms, preferably a linear or branched chain.
- the “lower alkenylene group” refers to a linear or branched alkenylene group having 2 to 6 carbon atoms including each isomer. Examples include vinylene group, 1-propenylene group, 2-propenylene group, 2-butenylene group, 3-butenylene group, pentenylene group, hexenylene group, and —CH ⁇ C (CH 3 ) —.
- the “lower alkynylene group” refers to a linear or branched alkynylene group having 2 to 6 carbon atoms including each isomer. Examples include ethynylene group, 1-propynylene group, 2-propynylene group, 2-butynylene group, 3-butynylene group, pentynylene group and the like. Examples of the “halogeno group” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
- the “lower acyl group” refers to an acyl group having a linear, branched or cyclic alkyl or alkenyl group having 1 to 6 carbon atoms.
- acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, acryloyl group, methacryloyl group, crotonoyl group, isocrotonoyl group, cyclopropanoyl group, cyclobutanoyl group, cyclopenta A noyl group, a cyclohexanoyl group, etc. are mentioned.
- the “lower alkoxyl group” refers to an alkoxyl group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms.
- methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-pentyloxy group, n-hexyloxy group isopropoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, cyclopropyloxy Group, cyclobutyloxy group, cyclopentyloxy group and cyclohexyloxy group.
- the “lower alkylthio group” refers to an alkylthio group having a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms.
- the “lower alkylamino group” refers to an amino group that is mono- or disubstituted with the above-mentioned “lower alkyl group”. Examples thereof include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, and an ethylmethylamino group.
- the “lower acyloxy group” refers to a group in which an oxygen atom is bonded to carbon of the carbonyl moiety of the aforementioned “lower acyl group”.
- lower acylamino group refers to a group in which a nitrogen atom is bonded to carbon of the carbonyl moiety of the aforementioned “lower acyl group”.
- acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, acryloylamino, methacryloylamino, crotonoylamino and isotonyl examples include a crotonoylamin
- lower alkoxycarbonyl group refers to a carbonyl group having the above-mentioned “lower alkoxyl group”. Examples include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, and a tert-butoxycarbonyl group.
- lower alkylcarbamoyl group refers to a group in which the nitrogen atom of the aforementioned “lower alkylamino group” or “cyclic amino group” is bonded to the carbon atom of the carbonyl group.
- Examples thereof include N-methylcarbamoyl group, N-ethylcarbamoyl group, N, N-dimethylcarbamoyl group, 1-pyrrolidinylcarbonyl group, 1-piperidinylcarbonyl group and 4-morpholinylcarbonyl group.
- the “lower alkylsulfonylamino group” refers to a group in which a nitrogen atom is bonded to a sulfonyl group in which the aforementioned “lower alkyl group” is bonded to a sulfur atom.
- Examples thereof include a methylsulfonylamino group, an ethylsulfonylamino group, a propylsulfonylamino group, an isopropylsulfonylamino group, a butylsulfonylamino group, and an isobutylsulfonylamino group.
- arylsulfonylamino group refers to a group in which a nitrogen atom is bonded to a sulfur atom of a sulfonyl group substituted with an aryl group.
- a phenylsulfonylamino group, a naphthylsulfonylamino group, etc. are mentioned.
- Examples of the “aryl group” include aryl groups having 6 to 14 carbon atoms, such as a phenyl group and a naphthyl group.
- Heterocyclic group refers to a 5- to 14-membered monocyclic to tricyclic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms as ring atoms. . Any carbon atom which is a ring atom may be substituted with an oxo group, and a sulfur atom or a nitrogen atom may be oxidized to form an oxide. Further, it may be condensed with a benzene ring.
- phenylene group examples include 1,4-phenylene group, 1,3-phenylene group and the like.
- Thiophenylene group refers to divalent thiophene. Examples thereof include a thiophene-2,5-diyl group.
- the “serine protease” refers to a protease having a serine residue having a nucleophilic ability as a catalytic residue. Examples include trypsin, chymotrypsin, elastase, enteropeptidase, kallikrein, thrombin, factor Xa and tryptase. Moreover, in this specification, "serine protease inhibition” means reducing or eliminating the above-mentioned serine protease activity.
- Preferred examples include inhibition of serine protease activity in the digestive tract such as trypsin, enteropeptidase, chymotrypsin, and elastase, and particularly preferred is inhibition of trypsin and enteropeptidase activity.
- the serine protease inhibitor of the present invention is a dual inhibitor that simultaneously inhibits at least trypsin and enteropeptidase.
- diabetes refers to type I diabetes and type II diabetes, and type II diabetes is preferred.
- the heteroarylcarboxylic acid ester derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is preferably the following.
- R 1, R 2, R 3 and R 4 are each independently preferably a hydrogen atom, a nitro group, a halogeno group or the like, and further a hydrogen atom, a nitro group, a fluorine atom, a chlorine atom, a bromine atom, Are more preferable, and a hydrogen atom and a fluorine atom are particularly preferable.
- the group represented by HetAr is preferably a 5- to 10-membered aromatic ring containing 1 to 3 heteroatoms, which may have a substituent, such as furan, thiophene, oxazole, Examples include isoxazole, thiazole, isothiazole, benzofuran, benzothiophene, benzoxazole, and benzothiazole, and more preferably a 5-membered heteroaryl ring, and examples include furan, thiophene, oxazole, isoxazole, thiazole, and isothiazole. Particularly preferred are furan, thiophene and thiazole.
- the hetero atom include an oxygen atom, a sulfur atom, and a nitrogen atom.
- examples of the substituent include a nitro group, a halogeno group, a cyano group, a hydroxyl group, a thiol group, an amino group, a guanidino group, a formyl group, and a lower alkyl group.
- the group represented by HetAr is also preferably the following groups (III-1) and (III-2).
- Z1 and Z2 each independently represent CRa or a nitrogen atom
- Z3 represents an oxygen atom, a sulfur atom or NRb
- Ra and Rb may be the same or different and each independently represents a hydrogen atom, nitro group, halogeno group, cyano group, hydroxyl group, thiol group, amino group, guanidino group, formyl group, lower alkyl group, lower alkenyl group, lower group Alkynyl group, lower acyl group, carboxyl group, sulfo group, phosphono group, lower alkoxyl group, lower alkylthio group, lower alkylamino group, lower acyloxy group, lower acylamino group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, Selected from either a lower alkylsulfonylamino group or a sulfamoyl group It
- Z1 is preferably CH and a nitrogen atom, particularly preferably CH.
- Z2 is preferably CH.
- Z3 is preferably an oxygen atom or a sulfur atom.
- Ra and Rb are each independently a hydrogen atom, halogeno group, hydroxyl group, amino group, lower alkyl group, lower alkenyl group, lower alkynyl group, lower acyl Group, carboxyl group, sulfo group, phosphono group, lower alkoxyl group, lower alkylamino group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, lower alkylsulfonylamino group, sulfamoyl group and the like are preferable, hydrogen atom, halogeno group More preferred are a hydroxyl group, an amino group, a lower alkyl group, a lower alkyloxyl group, a lower alkylamino group, and the like.
- X is preferably a linear or branched lower alkylene group having 1 to 6 carbon atoms and a linear or branched lower alkenylene group having 2 to 4 carbon atoms, preferably having 1 to 5 carbon atoms.
- a linear or branched lower alkylene group is more preferred.
- X shows a phenylene group or a thiophenylene group, these show an unsubstituted phenylene group or an unsubstituted thiophenylene group.
- examples of the substituent include a nitro group, a halogeno group, a cyano group, a hydroxyl group, a thiol group, an amino group, a lower alkyl group, and a guanidino group.
- Y is preferably a carbonyl group.
- A is represented by —OR5, the following group (II), the following group (IV), —U—CH (R6 ′) R7 ′ and —NH—N (R6 ′′) R7 ′′.
- Preferred are the groups in general formula (I), A is preferably a group represented by —OR 5, the following group (II) and the following group (IV), and particularly preferably a group represented by the following group (IV).
- R5 is preferably a hydrogen atom.
- R6 and R7 are each independently preferably a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxyl group or the like, particularly preferably a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
- substituents include a nitro group, a halogeno group, a cyano group, a hydroxyl group, a thiol group, an amino group, a guanidino group, a formyl group, and a lower acyl.
- An heterocyclic group and an oxo group that may be used are preferable, and a hydroxyl group, a carboxyl group, a sulfo group, a lower alkoxycarbonyl group, and the like are particularly preferable.
- the number of substituents is preferably 1 to 3, more preferably 1 or 2.
- the cyclic amino group formed by combining R6 and R7 is preferably a pyrrolidinyl group, a piperidinyl group, or the like.
- examples of the substituent include a nitro group, a halogeno group, a cyano group, a hydroxyl group, a thiol group, an amino group, a guanidino group, and formyl.
- R60 is preferably a carboxyl group or a sulfo group, particularly preferably a carboxyl group.
- D is preferably a lower alkylene group which may have a substituent, and particularly preferably a lower alkylene group having 1 to 3 carbon atoms.
- the substituent when the group represented by D has a substituent, the substituent may have a halogeno group, a hydroxyl group, a carboxyl group, a sulfo group, a phosphono group, a lower alkoxycarbonyl group, or a substituent.
- a good aryl group, a heterocyclic group which may have a substituent, an oxo group and the like are preferable, and a hydroxyl group, a carboxyl group, a sulfo group and a lower alkoxycarbonyl group are particularly preferable.
- the number of substituents is preferably 1 to 3, more preferably 1 or 2, and still more preferably 1.
- the group represented by D is preferably unsubstituted.
- R70 is preferably a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 2 carbon atoms, or the like, particularly a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, or the like. preferable.
- examples of the substituent include a nitro group, a halogeno group, a cyano group, a hydroxyl group, a thiol group, an amino group, a guanidino group, a formyl group, a lower group.
- the cyclic amino group formed by combining R70 and D is preferably a pyrrolidinyl group, a piperidinyl group, or the like.
- examples of the substituent include a nitro group, a halogeno group, a cyano group, a hydroxyl group, a thiol group, an amino group, a guanidino group, and formyl.
- lower alkyl group lower alkenyl group, lower alkynyl group, lower acyl group, carboxyl group, sulfo group, phosphono group, lower alkoxyl group, lower alkylthio group, lower alkylamino group, lower alkoxycarbonyl group, carbamoyl group, lower alkyl group
- Examples thereof include a carbamoyl group, a lower alkylsulfonylamino group, a sulfamoyl group and an oxo group, and a hydroxyl group, a carboxyl group, a sulfo group, a phosphono group and a lower alkoxycarbonyl group are preferred.
- the number of substituents is preferably 1 to 3, more preferably 1 or 2, and still more preferably 1.
- R60 represents a carboxyl group
- D represents a lower alkylene group which may have a carboxyl group
- R70 represents a lower alkyl group or a hydrogen atom which may have a carboxyl group.
- Acid ester derivatives or pharmaceutically acceptable salts thereof are particularly preferred.
- a heteroarylcarboxylic ester derivative represented by any of the following formulas or a pharmaceutically acceptable salt thereof is preferred.
- a heteroarylcarboxylic acid ester derivative represented by any of the following formulas or a pharmaceutically acceptable salt thereof is also preferable.
- R1 represents a hydrogen atom, a nitro group, a halogeno group or a linear or branched alkoxyl group having 1 to 6 carbon atoms
- R3 represents a hydrogen atom or a halogeno group
- R2 and R4 represent a hydrogen atom
- HetAr represents furan, thiophene or thiazole, each of which may have 1 or 2 substituents selected from a linear or branched alkyl group having 1 to 6 carbon atoms
- X is (1) a linear or branched alkylene group having 1 to 6 carbon atoms which may have a carboxyl group, (2) a linear or branched alkenylene group having 2 to 6 carbon atoms, (3) represents a phenylene group or (4) a thiophenylene group
- Y represents a carbonyl group
- R6 is mono-substituted by an aryl group having 6 to 14 carbon atoms which may have a hydroxyl group, a hydroxyl group, a carboxyl group, a sulfo group, a phosphono group, or a linear or branched alkyl group having 1 to 6 carbon atoms.
- R7 is (1) a hydrogen atom, (2) straight or branched alkyl having 1 to 6 carbon atoms which may have 1 or 2 substituents selected from the group consisting of an aryl group having 6 to 14 carbon atoms, a hydroxyl group and a carboxyl group A group or (3) a linear or branched alkenyl group having 2 to 6 carbon atoms, R6 and R7 may combine to form a pyrrolidinyl group or piperidinyl group, each of which may have one or two substituents selected from the group consisting of a hydroxyl group and a carboxyl group.
- R1 represents a hydrogen atom, a nitro group, a halogeno group or a linear or branched alkoxyl group having 1 to 6 carbon atoms
- R3 represents a hydrogen atom or a halogeno group
- R2 and R4 represent a hydrogen atom
- HetAr represents furan, thiophene or thiazole, each of which may have 1 or 2 substituents selected from a linear or branched alkyl group having 1 to 6 carbon atoms
- X is (1) a linear or branched alkylene group having 1 to 6 carbon atoms which may have a carboxyl group, (2) a linear or branched alkenylene group having 2 to 6 carbon atoms, (3) represents a phenylene group or (4) a thiophenylene group
- Y represents a carbonyl group or a sulfonyl group
- A is —OR5 (R5 represents a hydrogen atom), the following group (II):
- R6 is mono-substituted by an aryl group having 6 to 14 carbon atoms which may have a hydroxyl group, a hydroxyl group, a carboxyl group, a sulfo group, a phosphono group, or a linear or branched alkyl group having 1 to 6 carbon atoms or A linear or branched alkyl group having 1 to 6 carbon atoms and having 1 or 2 substituents selected from the group consisting of a disubstituted amino group and a carbamoyl group
- R7 is (1) a hydrogen atom, (2) straight or branched alkyl having 1 to 6 carbon atoms which may have 1 or 2 substituents selected from the group consisting of an aryl group having 6 to 14 carbon atoms, a hydroxyl group and a carboxyl group A group or (3) a linear or branched alkenyl group having 2 to 6 carbon atoms, R6 and R7 may be bonded to each other to form a pyrrol
- R1 represents a hydrogen atom, a nitro group, a halogeno group or a linear or branched alkoxyl group having 1 to 6 carbon atoms
- R3 represents a hydrogen atom or a halogeno group
- R2 and R4 represent a hydrogen atom
- HetAr represents furan, thiophene or thiazole, each of which may have 1 or 2 substituents selected from a linear or branched alkyl group having 1 to 6 carbon atoms
- X is (1) a linear or branched alkylene group having 1 to 6 carbon atoms which may have a carboxyl group, (2) a linear or branched alkenylene group having 2 to 6 carbon atoms, (3) represents a phenylene group or (4) a thiophenylene group
- Y represents a carbonyl group or a sulfonyl group
- A is —OR5 (R5 represents a hydrogen atom) or the following group (IV):
- R60 represents a carboxyl group, a sulfo group, a phosphono group or a hydroxyl group
- D represents a linear or branched alkylene group having 1 to 6 carbon atoms which may have a substituent, and the substituent is an aryl group having 6 to 14 carbon atoms which may have a hydroxyl group, Selected from the group consisting of hydroxyl, carboxyl, sulfo and carbamoyl groups
- R70 is (1) a hydrogen atom, (2) straight or branched alkyl having 1 to 6 carbon atoms which may have 1 or 2 substituents selected from the group consisting of an aryl group having 6 to 14 carbon atoms, a hydroxyl group and a carboxyl group A group or (3) a linear or branched alkenyl group having 2 to 6 carbon atoms, R70 and D may be bonded to each other to form a pyrrolidinyl group or piperidinyl group which may have one or two substitu
- the serine protease inhibitory activity is preferably an activity that simultaneously inhibits trypsin and enteropeptidase.
- a pharmaceutically acceptable salt is preferred.
- pharmaceutically acceptable salts include ammonium salts, salts with alkali metals such as sodium and potassium, and alkaline earths such as calcium and magnesium for compounds having an acidic group such as a carboxyl group.
- examples include salts with other metals, aluminum salts, zinc salts, triethylamine, ethanolamine, morpholine, pyrrolidine, piperidine, piperazine, dicyclohexylamine, and other organic amines, and salts with basic amino acids such as arginine and lysine. Can do.
- salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid Tannic acid, butyric acid, hibenzic acid, pamoic acid, enanthic acid, decanoic acid, teocric acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, salt with organic carboxylic acid such as malic acid, methanesulfonic acid, benzenesulfonic acid, Mention may be made of salts with organic sulfonic acids such as p-toluenesulfonic acid.
- the compounds of the present invention also include optical isomers, stereoisomers, tautomers, rotational isomers, or mixtures thereof in any ratio.
- optical isomers can be obtained as a single product by a known synthesis method and separation method.
- optical isomers can be obtained by using optically active synthetic intermediates or optically resolving synthetic intermediates or final racemates according to a conventional method.
- the compounds of the present invention also include solvates thereof such as hydrates and alcohol adducts.
- the compounds of the present invention can also be converted into prodrugs.
- the prodrug in the present invention represents a compound that is converted in the body to produce the compound of the present invention.
- examples thereof include esters and amides.
- the active body contains a carboxyl group
- a group that can be converted into a carboxyl group by oxidative metabolism, such as hydroxy A methyl group etc. are mentioned.
- the active main body contains an amino group, its amide, carbamate and the like can be mentioned.
- the active main body contains a hydroxyl group, its ester, carbonate, carbamate and the like can be mentioned.
- the compound of the present invention is converted into a prodrug, it may be bound to an amino acid or a saccharide.
- the present invention includes metabolites of the compounds of the present invention.
- the metabolite of the compound of the present invention refers to a compound obtained by converting the compound of the present invention with a metabolic enzyme or the like in vivo.
- the compound of the present invention or a pharmaceutically acceptable salt thereof can be used as a pharmaceutical because it has an excellent inhibitory effect on blood glucose elevation in mammals such as cows, horses, dogs, mice and rats, including humans.
- a pharmaceutical composition mixed with a pharmaceutically acceptable carrier as it is or according to a method known per se oral is usually preferable, but parenteral (for example, intravenous, subcutaneous, intramuscular, suppository, enema, ointment, It can also be administered by routes such as patch, sublingual, eye drop, inhalation, etc.
- the dose to be used for the above purpose is determined by the intended therapeutic effect, administration method, treatment period, age, body weight, etc.
- the content of the compound of the present invention in the pharmaceutical composition is about 0.01% to 100% by weight of the whole composition.
- Examples of the pharmaceutically acceptable carrier in the pharmaceutical composition of the present invention include various organic or inorganic carrier substances conventionally used as a pharmaceutical material.
- excipients for example, excipients, lubricants, binders, disintegrants in solid preparations.
- Water-soluble polymers for example, basic inorganic salts; solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents, etc. in liquid preparations.
- additives such as ordinary preservatives, antioxidants, colorants, sweeteners, sour agents, foaming agents, and fragrances can be used.
- Examples of the dosage form of such a pharmaceutical composition include tablets, powders, pills, granules, capsules, suppositories, solutions, dragees, devoted drugs, syrups, suspensions, emulsions, lozenges, Sublingual, patch, orally disintegrating agent (tablet), inhalant, enema, ointment, patch, tape, ophthalmic preparation, manufactured according to conventional methods using ordinary formulation aids Can do.
- the pharmaceutical composition of the present invention can be produced by a method commonly used in the field of pharmaceutical technology, such as the method described in the Japanese Pharmacopoeia. Below, the specific manufacturing method of a formulation is explained in full detail.
- an excipient when the compound of the present invention is prepared as an oral preparation, an excipient, and further, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, etc.
- tablets, powders, pills, granules, capsules, suppositories, solutions, dragees, devoted drugs, syrups, and the like are used.
- Excipients include, for example, lactose, corn starch, sucrose, butter sugar, sorbit, crystalline cellulose, etc.
- binders include, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl Cellulose, hydroxypropyl starch, polyvinylpyrrolidone and the like are disintegrating agents such as starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextran, pectin and the like, and lubricants include, for example, Magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc.
- the compound of the present invention can be used as a therapeutic or preventive agent for diabetes, but can also be used in combination with other commonly used therapeutic agents for diabetics or therapeutic or preventive agents for diabetic complications.
- Commonly used therapeutic agents for diabetes and therapeutic or preventive agents for diabetic complications include, for example, insulin preparations, insulin derivatives, insulin-like agents, insulin secretagogues, insulin resistance improvers, biguanides, gluconeogenesis inhibitors, Glucagon-like peptide-1 receptor agonist, sugar absorption inhibitor, renal glucose reabsorption inhibitor, ⁇ 3 adrenergic receptor agonist, glucagon-like peptide-1 (7-37), glucagon-like peptide-1 (7-37) analog , Dipeptidyl peptidase IV inhibitor, aldose reductase inhibitor, terminal glycation product production inhibitor, glycogen synthase kinase-3 inhibitor, glycogen phosphorylase inhibitor, antihyperlipidemic agent, appetite suppressant, lipase inhibitor, One or more of antihypertensive agents, peripheral circulation improving agents, antioxidants, diabetic neuropathy therapeutic agents, etc. They include combinations or mixtures.
- the drugs used in combination with the compound of the present invention are mixed to form one agent, each is separately formulated, or a combination formulation (set, Kit, pack).
- a combination formulation set, Kit, pack
- the compound of the present invention is also useful when used in foods.
- the food composition containing the compound of the present invention is useful as a food for treating or preventing diabetes.
- Food in the present invention means food in general, but also includes foods for specified health use and functional foods for nutrition that are defined in the Health Functional Food System of the Consumer Affairs Agency in addition to general foods including so-called health foods. Yes, and dietary supplements are also included.
- the form of the food composition of the present invention is not particularly limited, and may be any form as long as it can be taken orally. Examples thereof include powders, granules, tablets, hard capsules, soft capsules, liquids (beverages, jelly beverages, etc.), candy, chocolate, etc., and all can be produced by methods known per se in the art.
- the content of the compound of the present invention in the food composition is appropriately determined so as to obtain an appropriate dose within the indicated range.
- the food composition of the present invention can use other food additives as required.
- Such food additives include fruit juice, dextrin, cyclic oligosaccharides, sugars (monosaccharides and polysaccharides such as fructose and glucose), acidulants, flavorings, matcha powder, etc. that improve and improve the texture.
- Emulsifiers collagen, whole milk powder, thickening polysaccharides and agar, vitamins, eggshell calcium, calcium pantothenate, other minerals, royal jelly, propolis, honey, dietary fiber, agaric, chitin, chitosan, flavonoids, carotenoids , Lutein, herbal medicine, chondroitin, various amino acids, and the like that are used as components of normal health foods.
- the manufacturing method of a typical compound is shown below among the heteroaryl carboxylic acid ester derivatives represented with general formula (I) which are the compounds of this invention.
- the heteroarylcarboxylic acid ester derivative (F) in which X in the general formula (I) is a lower alkylene group or a lower alkenylene group, A is —OR 5, and R 5 is a lower alkyl group is prepared as follows. Can do.
- Aldehyde (A) (wherein E 1 represents a protecting group such as a methyl group, ethyl group, tert-butyl group or benzyl group) and Wittig reagent (B) (wherein X ′ represents HetAr and X ′ in (C)) And a group that can be chemically converted to X) in the presence of a base such as sodium hydride in a solvent that does not adversely affect the reaction such as tetrahydrofuran.
- a base such as sodium hydride
- the alkenylene derivative (C) is converted into the carboxylic acid derivative (D) by deprotection such as hydrolysis using a base such as sodium hydroxide in a solvent that does not adversely affect the reaction such as tetrahydrofuran and methanol. Can be guided.
- a base such as sodium hydroxide
- the target heteroaryl carboxylic acid ester derivative (F) in which X represents a lower alkenylene group can be produced.
- X can be obtained by performing a treatment with a catalyst such as 10% palladium / carbon in a hydrogen atmosphere in a solvent that does not adversely affect the reaction, such as methanol, ethanol, or ethyl acetate.
- a heteroarylcarboxylic acid ester derivative (F) showing a lower alkylene group can be produced.
- a known method can be applied to the esterification reaction. Examples thereof include (1) a method using an acid halide and (2) a method using a condensing agent.
- the method using an acid halide is, for example, in the presence or absence of a catalyst such as N, N-dimethylformamide in a solvent that does not adversely affect the reaction, such as dichloromethane, or in the absence of a solvent.
- reaction is carried out using a condensing agent such as 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide (WSC) or 1,3-dicyclohexylcarbodiimide.
- a condensing agent such as 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide (WSC) or 1,3-dicyclohexylcarbodiimide.
- A is the group (II) in the general formula (I) is an amidation of the carboxylic acid, thiocarboxylic acid or sulfonic acid derivative (i) and the amine (J).
- the amidation reaction of the carboxylic acid and the thiocarboxylic acid derivative is performed by using the same reaction as the esterification reaction described above and using the corresponding amine instead of the alcohol.
- the amidation reaction of the sulfonic acid derivative is performed by using the corresponding amine in place of the alcohol, using the same reaction as that of the esterification reaction (1) using an acid halide.
- heteroarylcarboxylic ester derivative (K) in which A is the group (II) in the general formula (I) can also be produced as follows.
- Ester, thioester or sulfonic acid ester derivative (L) is hydrolyzed with a base such as sodium hydroxide, for example, hydrolyzed with an acid such as hydrochloric acid or trifluoroacetic acid, or treated with, for example, 10% palladium / carbon in a hydrogen atmosphere.
- Carboxylic acid, thiocarboxylic acid or sulfonic acid derivative (M) can be obtained by performing deprotection.
- the amide derivative (N) can be synthesized by amidating the carboxylic acid, thiocarboxylic acid or sulfonic acid derivative (M) with the amine (J).
- the amide derivative (N) can be converted to a carboxylic acid derivative (O) by hydrolysis with a base such as sodium hydroxide in a solvent that does not adversely affect the reaction such as tetrahydrofuran or methanol.
- a base such as sodium hydroxide
- the target heteroarylcarboxylic ester derivative (K) can be obtained by esterifying the acid derivative (O) and the amidinophenol derivative (E).
- heteroarylcarboxylic acid ester derivative (S) in which Y is a thiocarbonyl group and A is a group (II) in the general formula (I) can also be produced as follows.
- the thioamide derivative (Q) can be synthesized by reacting the amide derivative (P) with a Lawson reagent or the like in a solvent that does not adversely affect the reaction, such as toluene.
- the thioamide derivative (Q) can be converted to a carboxylic acid derivative (R) by hydrolysis using a base such as sodium hydroxide in a solvent that does not adversely affect the reaction such as tetrahydrofuran or methanol.
- the target heteroarylcarboxylic acid ester derivative (S) can be obtained by esterifying the carboxylic acid derivative (R) and the amidinophenol derivative (E).
- Example 1 Synthesis of 4 -amidino-2-nitrophenol hydrochloride (M-8) Concentrated sulfuric acid (2.5 mL) was added to 4-amidinophenol hydrochloride (1.0 g, 5.8 mmol) and dissolved. Concentrated nitric acid (0.38 mL) was added at ⁇ 15 ° C. The reaction solution was stirred for 1 hour while maintaining the temperature between ⁇ 15 ° C. and ⁇ 2 ° C., and then the reaction solution was slowly added to ice water. Sodium bicarbonate was slowly added to neutralize, and the precipitated orange solid was separated by filtration.
- Example 2 Synthesis of 4 -amidino-2-bromophenol trifluoroacetate (M-9) 4-Amidinophenol hydrochloride (1.0 g, 5.8 mmol) was dissolved in methanol (20 mL) and dissolved at -78 ° C. And a solution of bromine (0.30 mL, 5.8 mmol) in methanol (10 mL) was slowly added. The reaction mixture is gradually warmed to room temperature and stirred overnight, and then concentrated under reduced pressure, and the resulting residue is purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid). The title compound (0.24 g, 0.73 mmol, 13%) was obtained.
- Example 3 Synthesis of 4 -amidino-2-chlorophenol trifluoroacetate (M-10) 4-Amidinophenol hydrochloride (0.50 g, 2.9 mmol) was dissolved in N, N-dimethylformamide (25 mL). N-chlorosuccinimide (0.39 g, 2.9 mmol) was added and stirred overnight. The residue obtained by concentrating the reaction solution under reduced pressure was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (0.25 g, 0.88 mmol, 30%) Got.
- Example 4 Synthesis of 4-amidino-2-fluorophenol trifluoroacetate salt (M-11) 3-fluoro-4-hydroxybenzonitrile (3.0 g) in ethanol (3 mL) and 4N hydrochloric acid-dioxane (27 mL) And stirred at room temperature. After 18 hours, it was concentrated and dried with a vacuum pump. Subsequently, it melt
- Example 6 Synthesis of 2- (diethylphosphono) propanoic acid tert-butyl ester (M-13) 2-Bromo-propanoic acid tert-butyl ester (17.4 g, 83 mmol) and triethyl phosphite (14.5 g, 87 mmol) and stirred at 110 ° C. overnight. The reaction solution was dried under reduced pressure to obtain the title compound (23.9 g).
- Example 7 Synthesis of 2- (diethylphosphono) butanoic acid tert-butyl ester (M-14) Diethylphosphonoacetic acid tert-butyl ester (1.0 g, 4.0 mmol) was converted to N, N-dimethylformamide (1 4 mL) and 60% sodium hydride (0.17 g, 4.4 mmol) was added at 0 ° C. After stirring at room temperature for 30 minutes, the reaction mixture was cooled again to 0 ° C., ethyl iodide (0.33 mL, 4.1 mmol) was added, and the mixture was stirred overnight at room temperature.
- the reaction mixture is diluted with ethyl acetate, washed successively with 0.5N hydrochloric acid, water and saturated brine, and concentrated under reduced pressure.
- Example 8 Synthesis of 2- (diethylphosphono) pentanoic acid tert-butyl ester (M-15) Using propyl bromide instead of ethyl iodide, the title compound was obtained in the same manner as in the synthesis of M-14. (Yield 77%).
- Example 9 Synthesis of 1- (diethylphosphono) ethanesulfonic acid isopropyl ester (M-16) (Step 1) Synthesis of ethanesulfonic acid isopropyl ester solution of 2-propanol (2.4 mL, 32 mmol) in dichloromethane (50 mL) Were added triethylamine (3.5 mL, 25 mmol) and ethanesulfonyl chloride (2.0 mL, 21 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate.
- 2-propanol 2.4 mL, 32 mmol
- dichloromethane 50 mL
- triethylamine 3.5 mL, 25 mmol
- ethanesulfonyl chloride 2.0 mL, 21
- Step 2 Synthesis of 1- (diethylphosphono) ethanesulfonic acid isopropyl ester (M-16)
- M-16 A solution of ethanesulfonic acid isopropyl ester (1.0 g, 6.6 mmol) in tetrahydrofuran (15 mL) was cooled to -78 ° C.
- N-butyllithium (1.57M) (4.6 mL, 7.2 mmol) was added. After stirring at ⁇ 78 ° C. for 20 minutes, diethyl chlorophosphate (0.52 mL, 3.6 mmol) was added to the reaction mixture, and stirring was continued for another 30 minutes.
- Example 10 Synthesis of 5-[(1E) -2- (tert-butoxycarbonyl) -prop-1-en-1-yl] furan-2-carboxylic acid (M-1) (Step 1) Synthesis of (1E) -2- (tert-butoxycarbonyl) -prop-1-en-1-yl] furan-2-carboxylic acid methyl ester 5-formyl-2-furancarboxylic acid (5 g, 35.7 mmol) It melt
- a 1N aqueous hydrochloric acid solution (6.25 mL) was added and stirred for 10 minutes, and then the solvent was distilled off under reduced pressure. Ethyl acetate and 0.5N aqueous hydrochloric acid solution were added to the residue, the organic layer was extracted, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was collected, washed with saturated brine, dehydrated and dried over sodium sulfate, and the solvent in the filtrate was removed under reduced pressure to give the title compound.
- Step 2 Synthesis of 5- (2-tert-butoxycarbonylpropyl) furan-2-carboxylic acid (M-2) 5- (2-tert-butoxycarbonylpropyl) furan-2-carboxylic acid obtained in Step 1
- the acid methyl ester 1.0 g, 3.76 mmol
- tetrahydrofuran 4.5 mL
- methanol 3 mL
- 1N aqueous sodium hydroxide solution 4.5 mL
- the mixture was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, and washed successively with water and saturated brine.
- Example 12 Synthesis of 5-[(1E) -2- (tert-butoxycarbonyl) -prop-1-en-1-yl] thiophene-2-carboxylic acid (M-3) (Step 1) Synthesis of (1E) -2- (tert-butoxycarbonyl) -prop-1-en-1-yl] thiophene-2-carboxylic acid methyl ester M-12 (2.08 g, 7.8 mmol) in tetrahydrofuran (30 mL) 60% sodium hydride (0.37 g, 9.25 mmol) was added at 0 ° C., and the mixture was stirred for 30 minutes.
- Step 2 Synthesis of 5-[(1E) -2- (tert-butoxycarbonyl) -prop-1-en-1-yl] thiophene-2-carboxylic acid (M-3) 5 obtained in Step 1 -[(1E) -2- (tert-butoxycarbonyl) -prop-1-en-1-yl] thiophene-2-carboxylic acid methyl ester (1.18 g, 4.19 mmol) was dissolved in tetrahydrofuran (5 mL). 1N aqueous lithium hydroxide solution (4.6 mL) was added and stirred overnight. The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate.
- Example 13 Synthesis of 5- (2-tert-butoxycarbonylpropyl) thiophene-2-carboxylic acid (M-4) 5-[(1E) -2- (tert--) obtained in Step 1 of Example 12 The title compound was obtained in the same manner as in Example 11 using butoxycarbonyl) -prop-1-en-1-yl] thiophene-2-carboxylic acid methyl ester.
- Example 15 Synthesis of N- (3-triisopropylsilyloxypropyl) taurine isopropyl ester (M-7) (Step 1) Synthesis of vinylsulfonic acid isopropyl ester 2-chloroethylsulfonyl chloride (2 g, 12.3 mmol), Isopropanol (1 mL) and pyridine (2.7 mL) were dissolved in dichloromethane (20 mL) and stirred for 3 hours at room temperature. The reaction solution was washed successively with 1N hydrochloric acid and water, and the organic layer was dried over anhydrous magnesium sulfate. After filtering the desiccant, the solvent was distilled off to give the title compound (1.06 g).
- Step 2 Synthesis of N- (3-triisopropylsilyloxypropyl) taurine isopropyl ester (M-7) Vinylsulfonic acid isopropyl ester (0.3 g, 2.00 mmol) obtained in Step 1 and 3-triisopropyl Silyloxypropylamine (0.9 g, 3.89 mmol) was dissolved in methanol (10 mL) and stirred overnight at room temperature. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain the title compound (0.65 g).
- Example 16 Synthesis of (2E) -3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2-methylpropenyl acid trifluoroacetate (A-3) M-1 and 4-hydroxy Benzamidine hydrochloride (712 mg, 4.17 mmol) and WSC hydrochloride (869 mg, 4.53 mmol) were dissolved in pyridine (10 mL) and stirred at room temperature overnight. After the solvent was distilled off under reduced pressure, trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 15 minutes.
- Example 18 N- ⁇ (2E) -3- [5- (4-amidino-2-phenoxycarbonyl) furan-2-yl] -2-methylpropenoyl ⁇ -N- (3-hydroxypropyl) - ⁇ -Alanine Synthesis of trifluoroacetate (A-12) (Step 1) Synthesis of 3-triisopropylsilyloxypropylamine (M-6) 3-Hydroxypropylamine (100 ⁇ L, 1.31 mmol) in dichloromethane (4.4 mL) And triisopropylsilyl triflate (371 ⁇ L, 1.38 mmol) was added dropwise at room temperature.
- Step 2 Synthesis of N- (3-triisopropylsilyloxypropyl) - ⁇ -alanine tert-butyl ester (A-12)
- the crude product obtained in Step 1 was dissolved in toluene (3.0 mL).
- Acrylic acid tert-butyl ester (173 ⁇ L, 1.19 mmol) was added, and the mixture was stirred with heating under reflux for 6 hr.
- Step 3 N- ⁇ (2E) -3- [5- (4-amidino-2-phenoxycarbonyl) furan-2-yl] -2-methylpropenoyl ⁇ -N- (3-hydroxypropyl) - ⁇ -Synthesis of alanine trifluoroacetate (A-12)
- A-3 (87 mg, 0.20 mmol) was dissolved in thionyl chloride (500 ⁇ L) and stirred at 70 ° C.
- Example 19 Synthesis of N- ⁇ (2E) -3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2-methylpropenyl ⁇ -L-glutamic acid trifluoroacetate (A-13)
- A-3 49 mg, 0.11 mmol was dissolved in thionyl chloride (0.5 mL) and heated at 70 ° C. for 5 minutes. After distilling off thionyl chloride under reduced pressure, the resulting residue was dissolved in dichloromethane (0.35 mL), and glutamic acid di-tert-butyl ester hydrochloride (50.8 mg, 0.17 mmol) and pyridine (0.15 mL) And stirred at room temperature for 40 minutes.
- Step 2 Synthesis of 3- (5-hydroxycarbonylfuran-2-yl) -2-ethylpropionic acid tert-butyl ester
- the crude product obtained in Step 1 and 10% palladium / carbon (30 mg) were mixed with ethanol (30 mg). 3.0 mL) and stirred overnight at room temperature and normal pressure in a hydrogen atmosphere. Palladium / carbon was removed by Celite filtration, and the solvent was distilled off under reduced pressure to obtain a crude product of the title compound.
- Step 3 Synthesis of 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2-ethylpropionic acid trifluoroacetate (A-29)
- the crude product obtained in Step 2 and 4 -Hydroxybenzamidine hydrochloride (180 mg, 1.04 mmol) was dissolved in pyridine (3.0 mL) and WSC hydrochloride (217 mg, 1.13 mmol) was added at room temperature with stirring. After stirring at room temperature for 100 minutes, the solvent was distilled off under reduced pressure.
- Example 21 Synthesis of N- [5- (4-amidinophenoxycarbonyl) furan-2-ylacetic acid trifluoroacetate (A-32) (Step 1) Synthesis of 5-ethoxycarbonylfuran-2-ylacetic acid 5 -Chloromethyl-2-furancarboxylic acid ethyl ester (1.0 g, 5.3 mmol), potassium iodide (0.044 g, 0.27 mmol), chloro (1,5-cyclooctadiene) rhodium (I) dimer ( 0.26 g, 0.53 mmol) was dissolved in formic acid (25 mL) and stirred at 75 ° C. for 6 hours in a carbon monoxide atmosphere.
- Step 2 Synthesis of 5-ethoxycarbonylfuran-2-ylacetic acid tert-butyl ester 5-ethoxycarbonylfuran-2-ylacetic acid (0.61 g, 3.08 mmol) obtained in Step 1 was thionyl chloride (10 mL). ) And stirred at 70 ° C. for 1 hour. The solvent was distilled off under reduced pressure, tert-butanol (5 mL) and triethylamine (2 mL) were added, and the mixture was stirred for 30 min. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain the title compound (0.37 g).
- Step 3 Synthesis of 5-tert-butoxycarbonylmethyl-2-furancarboxylic acid 5-ethoxycarbonylfuran-2-ylacetic acid tert-butyl ester (0.37 g, 1.46 mmol) obtained in Step 2 was converted to tetrahydrofuran.
- Step 4 Synthesis of 5- (4-amidinophenoxycarbonyl) furan-2-ylacetic acid trifluoroacetate (A-32) 5-tert-butoxycarbonylmethyl-2-furancarboxylic acid obtained in Step 3 ( 80 mg, 0.24 mmol) and 4-hydroxybenzamidine hydrochloride (80 mg, 0.46 mmol) were dissolved in pyridine (5 mL), WSC hydrochloride (0.10 g, 0.52 mmol) was added and stirred overnight. . After the solvent was distilled off, trifluoroacetic acid (5 mL) was added and stirred for 30 minutes. Purification by high performance liquid chromatography and lyophilization gave the title compound.
- Example 22 N- ⁇ 3- [5- (4-Amidino-2-fluorophenoxycarbonyl) furan-2-yl] -2-methylpropanoyl ⁇ -N- (D) -aspartic acid trifluoroacetate ( Synthesis of A-35) A-33 (68 mg, 0.15 mmol) and (D) -aspartic acid dibenzyl ester 4-toluenesulfonate (96 mg, 0.20 mmol) were dissolved in pyridine (0.5 mL). WSC hydrochloride (44 mg, 0.23 mmol) was added and stirred overnight at room temperature.
- Step 2 Synthesis of 1- [5- (4-amidinophenoxycarbonyl) furan-2-yl] propane-2-sulfonic acid trifluoroacetate (A-36)
- 1- [5- (Benzyloxycarbonyl) furan-2-yl] propane-2-sulfonic acid isopropyl was stirred in 4N hydrochloric acid overnight, then purified by high performance liquid chromatography and lyophilized to give the title compound.
- Example 24 Synthesis of N- [5- (4-amidinophenoxycarbonyl) furan-2-ylacetyl]-(L) -aspartic acid trifluoroacetate (A-39)
- Example 21 As a by-product of step 3 The obtained 5-carboxymethyl-2-furancarboxylic acid (117 mg, 0.69 mmol) and L-aspartic acid ditert-butyl ester hydrochloride (193 mg, 0.68 mmol) were dissolved in dichloromethane (5 mL), and WSC hydrochloric acid Salt (158 mg, 0.82 mmol) and triethylamine (0.5 mL) were added and stirred overnight.
- Example 25 Synthesis of ( 2E) -3- [5- (4-amidinophenoxycarbonyl) thiophen-2-yl] -2-methylpropenoic acid trifluoroacetate (B-1) (Step 1) 3- [ Synthesis of 5- (4-amidinophenoxycarbonyl) thiophen-2-yl] -2-methylpropenoic acid tert-butyl ester 5- (2- (tert-butoxycarbonyl) -1-propenyl) -2-thiophenecarboxylic acid ( 0.51 g, 1.89 mmol) and 4-hydroxybenzamidine hydrochloride (0.33 g, 1.89 mmol) are dissolved in pyridine (10 mL), WSC hydrochloride (0.54 g, 2.8 mmol) is added, Stir overnight.
- Step 2 Synthesis of (2E) -3- [5- (4-amidinophenoxycarbonyl) thiophen-2-yl] -2-methylpropenoic acid trifluoroacetate (B-1) 3- [5- (4 -Amidinophenoxycarbonyl) thiophen-2-yl] -2-methylpropenoic acid tert-butyl ester (0.63 g) was added with trifluoroacetic acid (5 mL) and stirred for 30 minutes. The solvent was distilled off to obtain the title compound (0.62 g).
- Example 26 Synthesis of 3- [5- (4-amidinophenoxycarbonyl) thiophen-2-yl] -2-methylpropanoic acid trifluoroacetate (B-6) B-1 (50 mg, 0.11 mmol) It melt
- Example 27 N- ⁇ (2E) -3- [5- (4-amidinophenoxycarbonyl) thiophen-2-yl] -2-methylpropenoyl ⁇ -N-hydroxypropyltaurine trifluoroacetate (B-7 ) Synthesis B-1 (30 mg, 0.068 mmol) was suspended in thionyl chloride (4 mL) and stirred at 70 ° C. for 30 minutes. After the solvent was distilled off, dichloromethane (2 mL), M-7 (25 mg, 0.072 mmol) and pyridine (50 ⁇ L) were added and stirred for 30 minutes. After the solvent was distilled off, trifluoroacetic acid (3 mL) was added and stirred for 30 minutes.
- Example 28 N- ⁇ 3- [5- (4-amidino-2-nitrophenoxycarbonyl) thiophen-2-yl] -2-methylpropanoyl ⁇ -N- (3-hydroxypropyl) glycine hydrochloride (B -11) Synthesis (Step 1) N- ⁇ (1E) -3- [5- (methoxycarbonyl) thiophen-2-yl] -2-methylpropenoyl ⁇ -N- [3- (triisopropylsilyloxy) Synthesis of propyl] glycine tert-butyl ester 5-[(1E) -2- (tert-butoxycarbonyl) -2-methyl-prop-1-en-1-yl] thiophene-obtained in Step 1 of Example 12 Trifluoroacetic acid (5 mL) was added to 2-carboxylic acid methyl ester (600 mg, 2.13 mmol) and stirred at room temperature for 10 minutes, and then the reaction solution was concentrated under
- Example 30 Synthesis of ( 2E) -3- [4- (4-amidinophenoxycarbonyl) thiazol-2-yl] -2-methylpropenoic acid trifluoroacetate (C-1) (Step 1) 2-formyl Synthesis of -4-thiazolecarboxylic acid ethyl ester Bull. Chem. Soc. Jpn. , 58, 352 (1985), 2- (diethoxymethyl) -4-thiazolecarboxylic acid ethyl ester (2.90 g, 11.8 mmol) was dissolved in acetone (37.3 mL), and 1N aqueous hydrochloric acid solution ( 3.73 mL) was added and the mixture was heated and stirred at 60 ° C.
- Step 2 Synthesis of 3- [4- (ethoxycarboxyl) thiazol-2-yl] -2-methylpropenylic acid tert-butyl ester 60% sodium hydride (669 mg, 15.3 mmol) in tetrahydrofuran (38.0 mL) Was suspended at 0 ° C., a tetrahydrofuran solution (8 mL) in which M-13 (4.17 g, 15.7 mmol) was dissolved was added dropwise, and the mixture was warmed to room temperature.
- Step 2 After stirring for 30 minutes, the mixture was cooled again to 0 ° C., and a tetrahydrofuran solution (10 mL) in which the crude product (2.07 g) obtained in Step 1 was dissolved was added dropwise. Thereafter, the mixture was warmed to room temperature and stirred overnight at room temperature. After post-treatment by a conventional method, the target compound was extracted by column chromatography (10-15% ethyl acetate / hexane mixed solvent) to obtain the title compound (1.84 g, 6.19 mmol, 55% in 2 steps). It was.
- Step 2 Synthesis of 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2S-methylpropionic acid trifluoroacetate (A-41)
- Optically active S form obtained in Step 1 105 mg, 0.39 mmol
- ethanol 1.3 mL
- 1N aqueous lithium hydroxide solution (1 mol / L, 0.47 mL, 0.47 mmol) was added, and the mixture was stirred at room temperature for 4 hr.
- 1N Hydrochloric acid (0.47 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
- 0.5N Hydrochloric acid and ethyl acetate were added to the residue, and the organic layer was extracted. did.
- Example 32 Synthesis of 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2R-methylpropionic acid trifluoroacetate (A-42) Optical obtained in Step 1 of Example 31 An active R-form (130 mg, 0.48 mmol) is dissolved in ethanol (1.0 mL), 1N aqueous lithium hydroxide solution (1 mol / L, 0.73 mL, 0.73 mmol) is added, and the mixture is stirred at room temperature for 2 hours. Stir. 1N Hydrochloric acid (0.73 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
- Example 33 Synthesis of N- ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2S-methylpropionyl ⁇ -L-aspartic acid trifluoroacetate (A-43)
- A-41 31 mg, 0.072 mmol
- thionyl chloride 500 ⁇ L
- thionyl chloride 500 ⁇ L
- L-aspartic acid di-tert-butyl ester hydrochloride 30.4 mg, 0.11 mmol
- dichloromethane 350 ⁇ L
- pyridine 150 ⁇ L
- Example 34 Synthesis of N- ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2R-methylpropionyl ⁇ -L-aspartic acid trifluoroacetate (A-44)
- A-42 (30.8 mg, 0.072 mmol) was dissolved in thionyl chloride (500 ⁇ L) and stirred at 70 ° C. for 20 minutes. After thionyl chloride was distilled off under reduced pressure, the obtained residue and L-aspartic acid di-tert-butyl ester hydrochloride (30.3 mg, 0.11 mmol) were dissolved in dichloromethane (350 ⁇ L), and then pyridine (150 ⁇ L).
- Example 35 Synthesis of N- ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2S-methylpropionyl ⁇ -D-aspartic acid trifluoroacetate (A-45)
- A-41 31 mg, 0.072 mmol
- thionyl chloride 500 ⁇ L
- the resulting residue and D-aspartic acid dibenzyl ester tosylate 56.7 mg, 0.12 mmol
- dichloromethane 350 ⁇ L
- pyridine 150 ⁇ L
- Example 36 Synthesis of N- ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2R-methylpropionyl ⁇ -D-aspartic acid trifluoroacetate salt (A-46)
- A-42 (34.4 mg, 0.080 mmol) was dissolved in thionyl chloride (500 ⁇ L) and stirred at 70 ° C. for 20 minutes. After distilling off thionyl chloride under reduced pressure, the resulting residue and D-aspartic acid dibenzyl ester tosylate (58.2 mg, 0.12 mmol) were dissolved in dichloromethane (350 ⁇ L), and pyridine (150 ⁇ L) was added.
- Example 37 N- ⁇ 3- [5- (4-Amidino-2-fluorophenoxycarbonyl) thiophen-2-yl] -2R-methylpropionyl ⁇ -L-aspartic acid of trifluoroacetate (B-25) Synthesis (Step 1) Synthesis of (2R) -5- (2-tert-butoxycarbonylpropyl) thiophene-2-carboxylic acid 5- (2-tert-butoxycarbonylpropyl) thiophene obtained as an intermediate of Example 13 Optical resolution was carried out in the same manner as in Example 31 using -2-carboxylic acid methyl ester.
- Example 38 N- ⁇ 3- [5- (4-Amidino-2-fluorophenoxycarbonyl) thiophen-2-yl] -2R-isobutylpropionyl ⁇ -L-aspartic acid of trifluoroacetate (B-26) Synthesis (Step 1) Synthesis of 2- (diethylphosphono) -4-methylpentanoic acid tert-butyl ester (M-17) Synthesis was performed in the same manner as in Example 7 using isobutyl bromide instead of ethyl iodide. .
- Example 39 Synthesis of 5- ⁇ 2-methyl-2-[(2-phenylethyl) carbamoyl] ethyl ⁇ furan-2-carboxylic acid 4-amidinophenyl ester trifluoroacetate (A-47)
- A-6 50 mg, 0.12 mmol
- phenethylamine 17 mg, 0.14 mmol
- WSC hydrochloride 46 mg, 0.24 mmol
- pyridine 2 mL
- the residue was purified by high performance liquid chromatography to give the title compound (31 mg).
- Example 40 Synthesis of N- ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2-methylpropanoyl ⁇ nipecotic acid trifluoroacetate salt (A-52)
- A-6 (30 mg , 0.07 mmol), nipecotic acid tert-butyl ester (13 mg, 0.07 mmol) and WSC hydrochloride (63 mg, 0.33 mmol) were dissolved in pyridine (3 mL) and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, trifluoroacetic acid (3 mL) was added, and the mixture was stirred for 30 min at room temperature.
- Step 3 Synthesis of 5- (2-tert-butoxycarbonylethyl) furan-2-carboxylic acid (M-22) 5- (2-tert-butoxycarbonylethenyl) furan-2-carboxylic acid benzyl ester (0 .97 g, 2.80 mmol) was dissolved in methanol (50 mL), 10% palladium / carbon (0.1 g) was added, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. After completion of the reaction, palladium / carbon was removed by Celite filtration, and then the solvent was distilled off under reduced pressure to obtain the title compound (0.66 g).
- Step 4 Synthesis of N- ⁇ 3- [5- (4-amidino-2-methoxyphenoxycarbonyl) furan-2-yl] -propanoyl ⁇ -L-aspartic acid trifluoroacetate (A-53)
- Step 1 4-Amidino-2-methoxyphenol hydrochloride (63 mg, 0.31 mmol), M-22 (50 mg, 0.21 mmol) and WSC hydrochloride (80 mg, 0.42 mmol) obtained in 1 were dissolved in pyridine, After stirring for a period of time, the solvent was distilled off and the residue was purified by high performance liquid chromatography to obtain a white solid (39 mg).
- Step 3 Synthesis of N- ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -propanoyl ⁇ -N- (2-carboxyethyl) glycine trifluoroacetate (A-54) 2E) -3- [5- (Benzyloxycarbonyl) furan-2-yl] -2-propenoic acid (40 mg, 0.15 mmol) was suspended in thionyl chloride (4 mL) and stirred at 70 ° C. for 30 minutes.
- Trifluoroacetic acid (containing 5% water, 500 ⁇ L) was added to the residue obtained by concentrating the reaction solution under reduced pressure, and the mixture was stirred at room temperature for 35 minutes.
- the residue obtained by concentrating the reaction solution under reduced pressure was purified by high performance liquid chromatography (acetonitrile-water, each containing 0.1% trifluoroacetic acid, 5-35%) to purify the title compound (28.3 mg, 0.8%). 056 mmol, 74%).
- Example 44 Synthesis of N- ⁇ 3- [5- (4-amidino-2-fluorophenoxycarbonyl) thiophen-2-yl] propanoyl ⁇ -L-aspartic acid trifluoroacetate (B-32) (Step 1 ) ) Synthesis of 5- (2-tert-butoxycarbonylethyl) thiophene-2-carboxylic acid benzyl ester The title compound was synthesized in the same manner as in Example 12 using 5-formyl-2-thiophenecarboxylic acid benzyl ester.
- Step 2 Synthesis of 5- (2-tert-butoxycarbonylethyl) thiophene-2-carboxylic acid (M-23) The compound (0.5 g, 1.45 mmol) obtained in Step 1 was combined with methanol (5 mL).
- Example 45 Synthesis of N- ⁇ 3- [5- (4-amidino-2-fluorophenoxycarbonyl) thiophen-2-yl] propionyl ⁇ -N-allylglycine trifluoroacetate salt (B-38) 5- (4-Amidino-2-fluorophenoxycarbonyl) thiophen-2-yl] propanoic acid trifluoroacetate (38 mg, 0.084 mmol) was dissolved in thionyl chloride (500 ⁇ L) and stirred at room temperature for 20 minutes.
- the reaction mixture was concentrated under reduced pressure, 4N hydrochloric acid (0.5 mL) and dioxane (0.5 mL) were added to the resulting residue, and the mixture was stirred at 60 ° C. for 3 hr.
- the residue obtained by concentrating the reaction solution under reduced pressure was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (7.4 mg, 0.012 mmol, 56%).
- Example 47 Synthesis of N- ⁇ 3- [5- (4-amidinophenoxycarbonyl) thiophen-2-yl] -2-methylpropanoyl ⁇ aminomethylphosphonic acid trifluoroacetate (B-40) (Step 1) Synthesis of aminomethylphosphonic acid diethyl ester hydrochloride (M-19) Hydrazine monohydrate (0.89 mL, 18.4 mmol) was added to a solution of phthalimidomethylphosphonic acid diethyl ester (4.56 g, 15.3 mmol) in ethanol (55 mL). In addition, the mixture was heated to reflux for 5 hours.
- Example 48 Synthesis of 5- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -4-methylpentanoic acid trifluoroacetate (A-58) (Step 1) 5- (1-hydroxy- Synthesis of 2-methylprop-2-enyl) furan-2-carboxylic acid benzyl ester 5-Formyl-2-furancarboxylic acid benzyl ester (300 mg, 1.30 mmol) was dissolved in tetrahydrofuran (12 mL) at ⁇ 78 ° C. 2-Propenylmagnesium bromide (0.5 mol / L tetrahydrofuran solution, 2.6 mL, 1.3 mmol) was added and stirred for 15 minutes.
- Step 2 Synthesis of (E) -5- (4-ethoxycarbonyl-2-methylbut-1-enyl) furan-2-carboxylic acid benzyl ester
- (E) -5- (4-ethoxycarbonyl-2-methylbut-1-enyl) furan-2-carboxylic acid benzyl ester Compound (332 mg, 1.23 mmol) obtained in Step 1
- Triethyl acid (5.0 mL, 27 mmol) and propionic acid (0.020 mL, 0.27 mmol) were added, and the mixture was stirred at 138 ° C. overnight.
- Step 3 Synthesis of 5- (4-ethoxycarbonyl-2-methylbutyl) furan-2-carboxylic acid
- ethanol 3 mL
- palladium / carbon 15 mg
- the solvent was distilled off under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (75 mg, 0.30 mmol). 68%).
- Step 4 Synthesis of 5- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -4-methylpentanoic acid ethyl ester trifluoroacetate Compound obtained in Step 3 (75 mg, 0.30 mmol) 4-Amidinophenol hydrochloride (56 mg, 0.32 mmol) and WSC hydrochloride (68 mg, 0.35 mmol) were added with pyridine (1.5 mL) and stirred at room temperature overnight.
- Step 5 Synthesis of 5- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -4-methylpentanoic acid trifluoroacetate (A-58)
- the compound obtained in Step 4 (77 mg, 0 4N hydrochloric acid (1 mL) and 1,4-dioxane (1 mL) were added to .16 mmol), and the mixture was stirred at 60 ° C. for 5 hours.
- Example 49 Synthesis of N- ⁇ 5- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -4-methylpentanoyl ⁇ -L-aspartic acid trifluoroacetate (A-59)
- A- 58 (30 mg, 0.065 mmol), L-aspartic acid di-tert-butyl ester hydrochloride (17 mg, 0.059 mmol) and WSC hydrochloride (13 mg, 0.065 mmol) were added with pyridine (1 mL) at room temperature. Stir overnight. The reaction solution was concentrated under reduced pressure, trifluoroacetic acid (1 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 2 hours.
- Example 50 Synthesis of 5- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -4-carboxypentanoic acid trifluoroacetate (A-60)
- A-60 Step 1
- 5-formyl-2-furancarboxylic acid benzyl ester (0.2 g, 0.87 mmol), acrylic acid Tert-butyl ester (0.52 mL) and 1,4-diazabicyclo [2.2.2] octane (20 mg, 0.18 mmol) were mixed and stirred for 4 days.
- Example 51 Synthesis of N- ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2- (carboxyethyl) propanoyl ⁇ -L-aspartic acid trifluoroacetate (A-61) (Step 1) Synthesis of 5- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2- (2-ethoxycarbonyl) ethylpropanoic acid trifluoroacetate obtained in Step 3 of Example 50 5- [2- (tert-butoxycarbonyl) -5-ethoxy-5-oxopentyl] furan-2-carboxylic acid (82 mg, 0.19 mmol), 4-hydroxybenzamidine hydrochloride (65 mg, 0.33 mmol) and WSC hydrochloride (92 mg, 0.50 mmol) was dissolved in pyridine (3 mL) and stirred at room temperature overnight.
- reaction mixture was concentrated under reduced pressure, trifluoroacetic acid (2 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 30 min.
- the residue obtained by concentrating the reaction solution under reduced pressure was purified by high performance liquid chromatography to obtain the title compound (11 mg).
- Step 2 Synthesis of N- ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2- (carboxyethyl) propanoyl ⁇ -L-aspartic acid trifluoroacetate (A-61) 5- [5- (4-Amidinophenoxycarbonyl) furan-2-yl] -2- (2-ethoxycarbonyl) ethylpropanoic acid trifluoroacetate and 4-hydroxybenzamidine hydrochloride The title compound was synthesized in the same manner.
- the obtained crude fraction was dissolved in N, N-dimethylformamide (15 mL), palladium acetate (0.18 g, 0.78 mmol), triphenylphosphine (0.41 g, 1.55 mmol), triethylamine (2.2 mL). , 15.5 mmol) and water (0.7 mL, 38.8 mmol) were added, and the mixture was stirred overnight at 80 ° C. in a carbon monoxide atmosphere. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Step 3 Synthesis of 5-formyl-3-furancarboxylic acid ethyl ester 5-hydroxymethyl-3-furancarboxylic acid ethyl ester (0.34 g, 2.0 mmol) was dissolved in dichloromethane (20 mL), and manganese dioxide ( 1.4 g, 15.9 mmol) was added and stirred overnight. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the title compound (0.26 g).
- Step 5 Synthesis of N- ⁇ 3- [4- (4-amidinophenoxycarbonyl) furan-2-yl] -2-methylpropanoyl ⁇ -L-aspartic acid trifluoroacetate (A-62) 5- (2-tert-Butoxycarbonylpropyl) furan-3-carboxylic acid, 4-hydroxybenzamidine and L-aspartic acid di-tert-butyl ester
- A-62 2-(2-tert-Butoxycarbonylpropyl) furan-3-carboxylic acid, 4-hydroxybenzamidine and L-aspartic acid di-tert-butyl ester
- Example 53 Synthesis of 3- [4- (4-amidino-2-fluorophenoxycarbonyl) furan-2-yl] -2-methylpropanoic acid trifluoroacetate (A-63) M-1 and 4-hydroxy Using 5- (2-tert-butoxycarbonylpropyl) furan-3-carboxylic acid obtained in Step 4 of Example 52 and M-11 in place of benzamidine hydrochloride, the title was prepared in the same manner as in Example 16. The compound was obtained (yield 52%).
- Example 54 Synthesis of N- ⁇ 3- [2- (4-amidinophenoxycarbonyl) furan-4-yl] -2-methylpropanoyl ⁇ -L-aspartic acid trifluoroacetate salt (A-67) 1) Synthesis of 4-formyl-2-furancarboxylic acid benzyl ester 3-Furfural (0.96 g, 10 mmol) was dissolved in toluene (10 mL), and N, N′-dimethylethylenediamine (1.08 mL, 10.0 mmol) was dissolved. , P-toluenesulfonic acid monohydrate (10 mg, 0.11 mmol) was added, and the mixture was stirred at 105 ° C. overnight.
- the solvent was distilled off under reduced pressure and the layers were separated with ethyl acetate and 5% aqueous sodium hydrogen carbonate solution, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
- the obtained residue was dissolved in tetrahydrofuran (20 mL), 1.54N n-butyllithium / hexane solution (3 mL) was added dropwise at ⁇ 78 ° C., and the mixture was stirred for 1 hr. Dry ice was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours.
- N, N-dimethylformamide (10 mL), potassium carbonate (0.55 g, 4.0 mmol) and benzyl bromide (2.04 g, 11.9 mmol) were added, Stir at 60 ° C. overnight.
- 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- the obtained residue was purified by silica gel column chromatography to obtain the title compound (0.33 g).
- Step 3 Synthesis of N- ⁇ 3- [2- (4-amidinophenoxycarbonyl) furan-4-yl] -2-methylpropanoyl ⁇ -L-aspartic acid trifluoroacetate (A-67)
- the title compound was obtained in the same manner as in Step 5 of 52.
- Example 55 Synthesis of 3- [4- (4-amidino-2-fluorophenoxycarbonyl) thiophen-2-yl] -2-methylpropanoic acid trifluoroacetate (B-51) (Step 1) 5- ( Synthesis of 2-tert-butoxycarbonylpropyl) thiophene-3-carboxylic acid 3-furancarboxylic acid instead of ethyl ester 3-thiophenecarboxylic acid methyl ester, palladium / carbon instead of palladium hydroxide, sodium hydroxide The title compound was synthesized in the same manner as in Step 1 to Step 4 of Example 52 using lithium hydroxide.
- Step 2 Synthesis of 3- [4- (4-amidino-2-fluorophenoxycarbonyl) thiophen-2-yl] -2-methylpropanoic acid trifluoroacetate (B-51) M-1 and 4-amidino Using the compound obtained in Step 1 and M-11 instead of phenol hydrochloride, the title compound was obtained in the same manner as in Example 16 (yield 58%).
- Example 56 Synthesis of N- ⁇ 3- [4- (4-amidino-2-fluorophenoxycarbonyl) thiophen-2-yl] propanoyl ⁇ -L-aspartic acid trifluoroacetate (B-54) (Step 1 ) ) Synthesis of 5- (2-tert-butoxycarbonylethyl) thiophene-3-carboxylic acid Synthesis was performed in the same manner as in Step 1 of Example 55, using diethylphosphonoacetic acid tert-butyl ester instead of M-13.
- Example 57 Synthesis of N- ⁇ 4- [5- (4-amidinophenoxycarbonyl) furan-2-yl] benzoyl ⁇ -L-aspartic acid trifluoroacetate (A-68) 4-amidinophenol hydrochloride ( 50 mg, 0.29 mmol) was dissolved in pyridine (1.5 mL), 4- (5-chlorocarbonylfuran-2-yl) benzoic acid ethyl ester (81 mg, 0.29 mmol) was added, and the mixture was stirred overnight at room temperature. .
- Step 2 Synthesis of N- ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] benzoyl ⁇ -L-aspartic acid trifluoroacetate (A-71) B-6 and M-18 Instead of the compound obtained in Step 1 (100 mg, 0.41 mmol) and 4-amidinophenol hydrochloride (70 mg, 0.41 mmol) in the same manner as in Step 2 of Example 46.
- Example 59 Synthesis of O- ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2-methylpropionyl ⁇ -D-malic acid trifluoroacetate (A-72)
- A-6 (34.5 mg, 0.08 mmol) was dissolved in thionyl chloride (500 ⁇ L) and stirred at 70 ° C. for 15 minutes.
- D-malic acid dibenzyl ester 37.8 mg, 0.12 mmol
- dichloromethane 350 ⁇ L
- pyridine 150 ⁇ L
- reaction solution was concentrated under reduced pressure, water was added, and the solution was freeze-dried overnight. After freeze-drying, palladium / carbon (10 mg) and ethanol (1 mL) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through Celite to remove palladium / carbon, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to high performance liquid chromatography (acetonitrile-water, each containing 0.1% trifluoroacetic acid, 15-55% To give the title compound (14.4 mg, 0.026 mmol, 33%).
- Example 60 Synthesis of S- ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2-methylpropionyl ⁇ thiomalic acid trifluoroacetate (A-73) (Step 1) S- Synthesis of ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2-methylpropionyl ⁇ thiomalic acid diethyl ester trifluoroacetate A-6 (30 mg, 0.070 mmol) was thionyl chloride (500 ⁇ L ) And stirred at 60 ° C. for 10 minutes.
- Step 2 Synthesis of S- ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2-methylpropionyl ⁇ thiomalic acid trifluoroacetate (A-73) obtained in Step 1
- S- ⁇ 3- [5- (4-Amidinophenoxycarbonyl) furan-2-yl] -2-methylpropionyl ⁇ thiomalic acid diethyl ester trifluoroacetate (40 mg, 0.065 mmol) in 4N hydrochloric acid / dioxane solution: Water 3: 1 (500 ⁇ L) was added, and the mixture was stirred at 60 ° C. overnight.
- Example 61 Synthesis of (N'-carboxymethyl- ⁇ 3- [5- (4-amidinophenoxycarbonyl) furan-2-yl] -2-methylpropane ⁇ hydrazide) acetic acid trifluoroacetate (A-74) (Step 1) Synthesis of N, N-bis (tert-butoxycarbonylmethyl) -N′-benzyloxycarbonylhydrazine Benzyloxycarbonylhydrazine (3.0 g, 18 mmol), bromoacetic acid tert-butyl ester (7.9 mL, 54 mmol) ) And diisopropylethylamine (6.3 mL, 36 mmol) were dissolved in toluene (30 mL) and stirred at 75 ° C.
- Step 2 Synthesis of N, N-bis (tert-butoxycarbonylmethyl) hydrazine
- the compound obtained in Step 1 (5.8 g, 15 mmol) was dissolved in methanol (60 mL), and 10% palladium / carbon (M) was obtained. (3.0 g) was added and stirred overnight under a hydrogen atmosphere.
- the reaction solution was filtered through a filter cell, and the filtrate was concentrated.
- Trifluoroacetic acid (1 mL) was added to the residue obtained by concentrating the reaction solution under reduced pressure. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (13 mg, 0 0.023 mmol, 50%).
- Step 2 Synthesis of N- ⁇ 5- [5- (4-amidinophenoxycarbonyl) thiophen-2-yl] thiophen-2-ylcarbonyl ⁇ -L-aspartic acid trifluoroacetate (B-59) Step 1 To the compound obtained in step (0.20 g, 0.79 mmol), 4-amidinophenol hydrochloride (0.14 g, 0.79 mmol) and WSC hydrochloride (0.18 g, 0.94 mmol) in pyridine (10 mL) And stirred at room temperature overnight.
- Example 63 Synthesis of N- [5- (4-amidino-2-fluorophenoxycarbonyl) thiophen-2-ylacetyl] -L-aspartic acid trifluoroacetate (B-60)
- Step 1 5-tert- Synthesis of Butoxycarbonylmethyl-2-thiophenecarboxylic acid 5-Bromomethyl-2-thiophenecarboxylic acid methyl ester (2.6 g, 10.4 mmol) and chloro (1,5-cyclooctadiene) rhodium (I) dimer (0. 5 g, 1.02 mmol) was dissolved in formic acid (30 mL) and stirred overnight at 75 ° C. in a carbon monoxide atmosphere.
- Step 2 Synthesis of 5- (4-amidino-2-fluorophenoxycarbonyl) thiophen-2-ylacetic acid trifluoroacetate Compound obtained in Step 1 (29 mg, 0.12 mmol) and M-11 (34 mg, 0.18 mmol) was suspended in pyridine (3 mL), WSC hydrochloride (70 mg, 0.36 mmol) was added, and the mixture was stirred for 2 hours. The solvent was distilled off, trifluoroacetic acid (3 mL) was added, and the mixture was stirred for 15 minutes.
- Example 64 Synthesis of N- ⁇ 3- [5- (4-amidino-2-fluorophenoxycarbonyl) thiazol-2-yl] -methylpropionyl ⁇ -L-aspartic acid trifluoroacetate (C-4) Step 1) Synthesis of 5- (tert-butyldimethylsilyloxy) methylthiazole 5-hydroxymethylthiazole (5.0 g, 43 mmol), imidazole (7.4 g, 109 mmol) and diisopropylethylamine (14 g, 109 mmol) were added to N, N -Dissolved in dimethylformamide (50 mL), tert-butyldimethylsilyl chloride (13.1 g, 87 mmol) was added and stirred at room temperature for 20 hours.
- Step 2 Synthesis of 5- (tert-butyldimethylsilyloxy) methyl-2-formylthiazole
- the compound obtained in Step 1 (4.5 g, 20 mmol) was dissolved in tetrahydrofuran (30 mL) and 2.5 M n- A butyllithium / hexane solution (16 mL, 40 mmol) was added dropwise at ⁇ 78 ° C.
- the reaction mixture was stirred at ⁇ 78 ° C. for 35 minutes, N, N-dimethylformamide (4 mL) was added dropwise, and the mixture was stirred at ⁇ 30 ° C. for 1 hour.
- the solvent was distilled off under reduced pressure.
- Step 4 Synthesis of 5- [2- (tert-butoxycarbonyl) propyl] -2- (tert-butyldimethylsilyloxy) methylthiazole
- the compound obtained in Step 3 (0.5 g, 1.4 mmol) was treated with ethanol. (20 mL), palladium / carbon (0.1 g) was added, and the mixture was stirred at 50 ° C. for 20 hours under a hydrogen atmosphere (55 psi).
- Step 5 Synthesis of 5- [2- (tert-butoxycarbonyl) propyl] -2-formylmethylthiazole
- step A solution of compound 4 (0.30 g, 0.76 mmol) in tetrahydrofuran (2 mL) was added and stirred overnight at room temperature.
- the solvent was distilled off under reduced pressure, and the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure.
- Step 6 Synthesis of 5- [2- (tert-butoxycarbonyl) propyl] thiazole-2-carboxylic acid Compound (1.8 g, 7.0 mmol) of tert-butanol (27.1 mL) obtained in Step 5
- water 6.0 mL
- 2-methyl-2-butene 3. g, 52.9 mmol
- monosodium dihydrogen phosphate 3. g, 17.6 mmol
- sodium chlorite 3.2 g. 35.2 mmol
- Step 7 Synthesis of N- ⁇ 3- [5- (4-amidino-2-fluorophenoxycarbonyl) thiazol-2-yl] -methylpropionyl ⁇ -L-aspartic acid trifluoroacetate (C-4) Using the compound obtained in 6, the title compound was obtained in the same manner as in Example 37.
- Example 65 3- ⁇ 3- [4- (4-amidinophenoxycarbonyl) -1,3-thiazol-2-yl] -N- (carboxymethyl) propanamide ⁇ propanoic acid trifluoroacetate (C-5 (Step 1) Synthesis of 3- [4- (ethoxycarboxyl) thiazol-2-yl] propenylic acid tert-butyl ester Ethyl 2-formyl-4-thiazolecarboxylate obtained in Step 1 of Example 30 The title compound was obtained in the same manner as in Example 30 using ester and diethylphosphonoacetic acid tert-butyl ester.
- Step 2 2-[(1E) -2- ⁇ [2- (tert-butoxy) -2-oxoethyl] [3- (tert-butoxy) -3-oxopropyl] carbamoyl ⁇ eth-1-ene-1
- Step 2 2-[(1E) -2- ⁇ [2- (tert-butoxy) -2-oxoethyl] [3- (tert-butoxy) -3-oxopropyl] carbamoyl ⁇ eth-1-ene-1
- Step 3 2- (2- ⁇ [2- (tert-butoxy) -2-oxoethyl] [3- (tert-butoxy) -3-oxopropyl] carbamoyl ⁇ ethyl) -1,3-thiazole-4- Synthesis of Carboxylic Acid
- methanol 9 mL
- chloroform 1 mL
- palladium hydroxide 0.08 g
- hydrogen atmosphere was added at room temperature. Stir overnight.
- the reaction solution was filtered through Celite, and then the solvent was distilled off.
- Step 4 3- ⁇ 3- [4- (4-Amidinophenoxycarbonyl) -1,3-thiazol-2-yl] -N- (carboxymethyl) propanamide ⁇ propanoic acid trifluoroacetate (C-5).
- the title compound was obtained in the same manner as in Example 37 using the compound obtained in Step 3.
- Example 66 N- ⁇ 3- [5- (4-Amidino-2-fluorophenoxycarbonyl) -3-methylthiophen-2-yl] propanoyl ⁇ -L-aspartic acid of trifluoroacetate (B-61) Synthesis (Step 1) Synthesis of 1,3-dimethyl-2- (3-methylthiophen-2-yl) imidazolidine 2-Formyl-3-methylthiophene (3.0 g, 23.8 mmol) and N, N′- Dimethylethylenediamine (2.3 g, 26.2 mmol) was dissolved in toluene (80 mL) and stirred at 120 ° C. overnight.
- Step 3 Synthesis of (E) -3- (5-benzyloxycarbonyl-3-methylthiophen-2-yl) -2-propenoic acid tert-butyl ester Diethylphosphonoacetic acid tert-butyl ester (0.44 g, A solution of 1.74 mmol) in tetrahydrofuran (3 mL) was added dropwise to a suspension of 60% sodium hydride (0.055 g, 1.38 mmol) in tetrahydrofuran (15 mL) at 0 ° C. with stirring.
- Step 5 Synthesis of 3- [5- (4-amidino-2-fluorophenoxycarbonyl) -3-methylthiophen-2-yl] propanoic acid trifluoroacetate Compound obtained in Step 4 (1.02 g, 3.77 mmol), M-11 (1.08 g, 5.66 mmol) and WSC hydrochloride (1.45 g, 7.55 mmol) were dissolved in pyridine (10 ml) and stirred at room temperature overnight.
- Example 67 N- ⁇ 3- [5- (4-Amidino-2-fluorophenoxycarbonyl) thiophen-2-yl] propanoyl ⁇ -N-allyl-L-aspartic acid of trifluoroacetate (B-63) Synthesis (Step 1) Synthesis of N-allyl-L-aspartic acid di-tert-butyl ester hydrochloride L-aspartic acid di-tert-butyl ester hydrochloride (1.0 g, 3.5 mmol) in acetonitrile (7 ml) Dissolve, potassium carbonate (0.98 g, 7.1 mmol) and allyl bromide (0.29 mL, 3.4 mmol) were added and stirred at room temperature overnight.
- Example 68 N- ⁇ 3- [5- (4-amidino-2-fluorophenoxycarbonyl) thiophen-2-yl] -2,2-dimethylpropanoyl ⁇ -L-aspartic acid trifluoroacetate salt (B- 64) (Step 1) Synthesis of 5-chloromethylthiophene-2-carboxylic acid tert-butyl ester 5-formylthiophene-2-carboxylic acid (5.27 g, 33.7 mmol), di-tert-butyl dicarbonate (8.1 g, 37.1 mmol) and N, N-dimethylaminopyridine (0.41 g, 3.39 mmol) were dissolved in tert-butanol (120 mL) and dichloromethane (40 mL) and stirred overnight.
- the solvent was distilled off under reduced pressure, 0.5N aqueous hydrochloric acid solution was added to the residue, and the mixture was extracted with ethyl acetate.
- the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
- the obtained residue was dissolved in tetrahydrofuran (100 mL) and methanol (10 mL), sodium borohydride (1.28 g, 33.7 mmol) was added at 0 ° C., and the mixture was stirred for 3 hr.
- the solvent was distilled off under reduced pressure, 0.5N aqueous hydrochloric acid solution was added to the residue, and the mixture was extracted with ethyl acetate.
- the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
- the obtained residue was dissolved in dichloromethane (100 mL), methanesulfonyl chloride (2.87 mL, 37.1 mmol) and diisopropylethylamine (8.9 mL, 51.1 mmol) were added at 0 ° C., and the mixture was stirred for 2 days.
- the solvent was distilled off under reduced pressure, 0.5N aqueous hydrochloric acid solution was added to the residue, and the mixture was extracted with ethyl acetate.
- the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
- Step 3 Synthesis of N- [3- (5-carboxythiophen-2-yl) -2,2-dimethylpropanoyl] -L-aspartic acid dimethyl ester
- the crude product obtained in Step 2 was thionyl chloride ( 3.0 mL) and stirred at 60 ° C.
- Step 4 N- ⁇ 3- [5- (4-Amidino-2-fluorophenoxycarbonyl) thiophen-2-yl] -2,2-dimethylpropanoyl ⁇ -L-aspartic acid trifluoroacetate (B- 64) Synthesis of the compound obtained in Step 3 (56 mg, 0.15 mmol), M-11 (43.1 mg, 0.23 mmol) and WSC hydrochloride (57.8 mg, 0.30 mmol) in pyridine (500 ⁇ L) Dissolved and stirred at room temperature for 1 hour.
- Compound B-37 shown in Table 2 below was synthesized using M-20 in the same manner as in Example 18 above.
- M-1 to M- 23 and commercially available reagents were used in the same manner as in Examples 33 and 34 to synthesize each compound.
- Compound B-36 shown in Table 2 below was synthesized in the same manner as in Example 35 using M-1 to M-23 and commercially available reagents.
- Compounds B-27, B-28 and B-29 shown in Table 2 below were synthesized in the same manner as in Example 38 above using M-1 to M-23 and commercially available reagents. did.
- Example 39 For compounds A-48, A-49, A-50 and A-51 listed in Table 2 below, the same procedure as in Example 39 was performed using M-1 to M-23 and commercially available reagents. Each compound was synthesized. Compounds B-30, B-31 and B-34 shown in Table 2 below were synthesized in the same manner as in Example 40 above using M-1 to M-23 and commercially available reagents. did. Compound B-45 shown in Table 2 below was synthesized using M-1 to M-23 and commercially available reagents in the same manner as in Examples 44 and 46 above. Compound B-46 shown in Table 2 below was synthesized in the same manner as in Examples 44 and 47 using M-1 to M-23 and commercially available reagents.
- each compound was synthesized in the same manner as in Example 48 above using M-1 to M-23 and commercially available reagents.
- each compound was synthesized in the same manner as in Example 49 above using M-1 to M-23 and commercially available reagents.
- Compound B-55 shown in Table 2 below was synthesized by the same procedures as in Examples 55 and 56 using M-1 to M-23 and commercially available reagents.
- Compounds A-69, B-56 and B-57 shown in Table 2 below were synthesized in the same manner as in Example 57 above using M-1 to M-23 and commercially available reagents. did.
- Compound B-58 shown in Table 2 below was synthesized in the same manner as in Example 58 using M-1 to M-23 and commercially available reagents.
- Compounds B-62, B-65 and B-66 shown in Table 2 below were synthesized by the same procedure as in Example 33 using M-11, M-23 and commercially available reagents.
- Test Example 1 Measurement of trypsin inhibitory activity Using a 96-well plate (# 3915, Costar), 20 ⁇ M fluorescent enzyme substrate (Boc-Phe-) mixed with 25 ⁇ L of the test compound and 200 mM Tris-HCl buffer (pH 8.0) After mixing 50 ⁇ L of Ser-Arg-AMC), 25 ⁇ L of human trypsin (Sigma) was added. Using a fluorescence plate reader fmax (Molecular Devices), the reaction rate was measured from the change over time of the excitation wavelength of 355 nm and the fluorescence wavelength of 460 nm. From the test compound concentration, the reciprocal of the reaction rate, and the Km value of the enzyme substrate, the Ki value was calculated using a Dixon plot. The results are shown in Table 3.
- Test Example 2 Measurement of enteropeptidase inhibitory activity Using a 96-well plate (# 3915, Costar), 25 ⁇ L of a test compound, 25 ⁇ L of 400 mM Tris-HCl buffer (pH 8.0), and 0.5 mg / mL fluorescent enzyme substrate ( (Gly-Asp-Asp-Asp-Asp-Lys- ⁇ -Naphthylamide) 25 ⁇ L was mixed, and then recombinant human enteropeptidase (R & D Systems) 25 ⁇ L was added.
- fluorescent enzyme substrate (Gly-Asp-Asp-Asp-Asp-Asp-Lys- ⁇ -Naphthylamide) 25 ⁇ L was mixed, and then recombinant human enteropeptidase (R & D Systems) 25 ⁇ L was added.
- the reaction rate was measured from the change over time of an excitation wavelength of 320 nm and a fluorescence wavelength of 405 nm. From the test compound concentration, the reciprocal of the reaction rate, and the Km value of the enzyme substrate, the Ki value was calculated using a Dixon plot. The results are shown in Table 3.
- the compound of the present invention exhibits excellent enteropeptidase inhibitory activity and excellent trypsin inhibitory activity. Therefore, the compounds of the present invention having enteropeptidase and trypsin inhibitory activity decrease the digestibility of proteins, lipids and carbohydrates, and are shown to be effective in the treatment and prevention of obesity and hyperlipidemia. It was.
- Test Example 3 Evaluation of anti-diabetic action KK-A y / JCL mice (male, 5-7 weeks old, CLEA Japan, Inc.) known to spontaneously develop obesity type 2 diabetes were purchased for 1 week. After the preliminary breeding period, grouping was carried out so that there were 6 animals in each group using body weight and satiety blood glucose as indices. The animals were individually housed in polycarbonate cages and allowed to freely access water in water bottles. During the test period, the test compound (B-18 hydrochloride, B-20 hydrochloride, A-28 hydrochloride, B-23 hydrochloride, or B-32 hydrochloride) was added to the powdered feed CRF-1 (Oriental Yeast Co., Ltd.).
- CRF-1 Oriental Yeast Co., Ltd.
- the test compound showed a significant hypoglycemic effect. It has been shown that the compounds of the present invention having enteropeptidase inhibitory activity and trypsin inhibitory activity exhibit an antiglycemic activity or a hypoglycemic effect. In addition, the compound of the present invention exhibits an action to improve insulin resistance by exhibiting an inhibitory effect on blood sugar elevation or an action to lower blood sugar, and is also useful as an agent for preventing or treating obesity, diabetic complications or metabolic syndrome. It has been shown.
- the trypsin and enteropeptidase-inhibiting compound according to the present invention can be used as an active ingredient of a therapeutic or prophylactic agent for diabetes or diabetic complications.
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Priority Applications (10)
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JP2011545216A JP5482800B2 (ja) | 2009-12-07 | 2010-12-07 | ヘテロアリールカルボン酸エステル誘導体 |
EP10835968.8A EP2511271B1 (en) | 2009-12-07 | 2010-12-07 | Heteroarylcarboxylic acid ester derivative |
PL10835968T PL2511271T3 (pl) | 2009-12-07 | 2010-12-07 | Pochodna estru kwasu heteroarylokarboksylowego |
CN201080063274.5A CN102822154B (zh) | 2009-12-07 | 2010-12-07 | 杂芳基羧酸酯衍生物 |
DK10835968.8T DK2511271T3 (en) | 2009-12-07 | 2010-12-07 | HETEROARYL CARBOXYLIC ACID RESIDENT. |
ES10835968.8T ES2532201T3 (es) | 2009-12-07 | 2010-12-07 | Derivado de éster de ácido heteroarilcarboxílico |
US13/484,822 US8609715B2 (en) | 2009-12-07 | 2012-05-31 | Heteroarylcarboxylic acid ester derivative |
US14/089,040 US8877805B2 (en) | 2009-12-07 | 2013-11-25 | Heteroarylcarboxylic acid ester derivative |
US14/496,363 US9115107B2 (en) | 2009-12-07 | 2014-09-25 | Heteroarylcarboxylic acid ester derivative |
US14/799,130 US20150313889A1 (en) | 2009-12-07 | 2015-07-14 | Heteroarylcarboxylic acid ester derivative |
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WO2013039187A1 (ja) | 2011-09-15 | 2013-03-21 | アステラス製薬株式会社 | グアニジノ安息香酸化合物 |
WO2013187533A1 (en) * | 2012-06-14 | 2013-12-19 | Ajinomoto Co., Inc. | Heteroarylcarboxylic acid ester derivative |
WO2014142219A1 (ja) | 2013-03-13 | 2014-09-18 | アステラス製薬株式会社 | グアニジノ安息香酸エステル化合物 |
WO2015122187A1 (en) | 2014-02-13 | 2015-08-20 | Takeda Pharmaceutical Company Limited | Fused heterocyclic compound |
WO2015122188A1 (en) | 2014-02-13 | 2015-08-20 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
WO2015137407A1 (ja) * | 2014-03-11 | 2015-09-17 | 味の素株式会社 | ヘテロアリールカルボン酸エステル誘導体の製造方法、その製造中間体及び結晶 |
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DK2511271T3 (en) | 2015-03-23 |
CN102822154B (zh) | 2016-06-01 |
PL2511271T3 (pl) | 2015-06-30 |
US9115107B2 (en) | 2015-08-25 |
JPWO2011071048A1 (ja) | 2013-04-22 |
JP5482800B2 (ja) | 2014-05-07 |
ES2532201T3 (es) | 2015-03-25 |
US8609715B2 (en) | 2013-12-17 |
EP2511271A1 (en) | 2012-10-17 |
US8877805B2 (en) | 2014-11-04 |
EP2511271A4 (en) | 2013-05-15 |
US20140080790A1 (en) | 2014-03-20 |
US20150011511A1 (en) | 2015-01-08 |
CN102822154A (zh) | 2012-12-12 |
US20120283222A1 (en) | 2012-11-08 |
EP2511271B1 (en) | 2015-01-21 |
US20150313889A1 (en) | 2015-11-05 |
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