JP2003327532A - Peptidase inhibitor - Google Patents
Peptidase inhibitorInfo
- Publication number
- JP2003327532A JP2003327532A JP2002135969A JP2002135969A JP2003327532A JP 2003327532 A JP2003327532 A JP 2003327532A JP 2002135969 A JP2002135969 A JP 2002135969A JP 2002135969 A JP2002135969 A JP 2002135969A JP 2003327532 A JP2003327532 A JP 2003327532A
- Authority
- JP
- Japan
- Prior art keywords
- group
- carbon atoms
- optionally substituted
- mmol
- examples
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 229940122344 Peptidase inhibitor Drugs 0.000 title claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 65
- 125000005843 halogen group Chemical group 0.000 claims abstract description 38
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 29
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 28
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 19
- 229940002612 prodrug Drugs 0.000 claims abstract description 9
- 239000000651 prodrug Substances 0.000 claims abstract description 9
- 150000002430 hydrocarbons Chemical group 0.000 claims description 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 claims description 16
- 230000003449 preventive effect Effects 0.000 claims description 14
- 229940126585 therapeutic drug Drugs 0.000 claims description 14
- 239000004215 Carbon black (E152) Substances 0.000 claims description 12
- 229930195733 hydrocarbon Natural products 0.000 claims description 12
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 10
- 102000035195 Peptidases Human genes 0.000 claims description 8
- 108091005804 Peptidases Proteins 0.000 claims description 8
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 8
- 208000002249 Diabetes Complications Diseases 0.000 claims description 7
- 206010012655 Diabetic complications Diseases 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 7
- 235000019833 protease Nutrition 0.000 claims description 7
- 208000008589 Obesity Diseases 0.000 claims description 4
- 235000020824 obesity Nutrition 0.000 claims description 4
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 121
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 20
- 230000002265 prevention Effects 0.000 abstract description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 3
- -1 aminocarbamoyl group Chemical group 0.000 description 238
- 125000004432 carbon atom Chemical group C* 0.000 description 166
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 109
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 65
- 239000000243 solution Substances 0.000 description 64
- 239000000203 mixture Substances 0.000 description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 238000005160 1H NMR spectroscopy Methods 0.000 description 47
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 40
- 229940079593 drug Drugs 0.000 description 39
- 239000013078 crystal Substances 0.000 description 37
- 125000000217 alkyl group Chemical group 0.000 description 36
- 230000002829 reductive effect Effects 0.000 description 35
- 235000002639 sodium chloride Nutrition 0.000 description 34
- 238000002844 melting Methods 0.000 description 33
- 230000008018 melting Effects 0.000 description 33
- 238000000921 elemental analysis Methods 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
- 125000001424 substituent group Chemical group 0.000 description 30
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 29
- 239000000460 chlorine Substances 0.000 description 29
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 27
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 27
- 229910052794 bromium Inorganic materials 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 27
- 229910052801 chlorine Inorganic materials 0.000 description 27
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 26
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 26
- 239000011737 fluorine Substances 0.000 description 26
- 229910052731 fluorine Inorganic materials 0.000 description 26
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 25
- 238000000034 method Methods 0.000 description 25
- 239000012044 organic layer Substances 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 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 description 24
- 239000008103 glucose Substances 0.000 description 24
- 238000010898 silica gel chromatography Methods 0.000 description 24
- 239000003795 chemical substances by application Substances 0.000 description 23
- 125000002252 acyl group Chemical group 0.000 description 21
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 description 20
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 19
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 125000003710 aryl alkyl group Chemical group 0.000 description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 18
- 125000003277 amino group Chemical group 0.000 description 17
- 125000000753 cycloalkyl group Chemical group 0.000 description 17
- 125000003118 aryl group Chemical group 0.000 description 16
- 238000001816 cooling Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 14
- 229940124597 therapeutic agent Drugs 0.000 description 14
- 125000003545 alkoxy group Chemical group 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 230000003287 optical effect Effects 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 206010056997 Impaired fasting glucose Diseases 0.000 description 11
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 206010006895 Cachexia Diseases 0.000 description 10
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- 125000004093 cyano group Chemical group *C#N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 229940123208 Biguanide Drugs 0.000 description 9
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 9
- 229940122199 Insulin secretagogue Drugs 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- 125000000392 cycloalkenyl group Chemical group 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- AFBBKYQYNPNMAT-UHFFFAOYSA-N 1h-1,2,4-triazol-1-ium-3-thiolate Chemical compound SC=1N=CNN=1 AFBBKYQYNPNMAT-UHFFFAOYSA-N 0.000 description 8
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 8
- 102100040918 Pro-glucagon Human genes 0.000 description 8
- 229940100389 Sulfonylurea Drugs 0.000 description 8
- 238000002835 absorbance Methods 0.000 description 8
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 238000007410 oral glucose tolerance test Methods 0.000 description 8
- 239000008177 pharmaceutical agent Substances 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 125000004434 sulfur atom Chemical group 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004877 Insulin Human genes 0.000 description 7
- 108090001061 Insulin Proteins 0.000 description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 7
- 239000001768 carboxy methyl cellulose Substances 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 229940125396 insulin Drugs 0.000 description 7
- 125000006717 (C3-C10) cycloalkenyl group Chemical group 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 6
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 6
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 6
- 229940122355 Insulin sensitizer Drugs 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 229930006000 Sucrose Natural products 0.000 description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 6
- 125000005018 aryl alkenyl group Chemical group 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 125000001485 cycloalkadienyl group Chemical group 0.000 description 6
- 238000009501 film coating Methods 0.000 description 6
- 239000007888 film coating Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 235000010355 mannitol Nutrition 0.000 description 6
- 239000005720 sucrose Substances 0.000 description 6
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 5
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 5
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 5
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 125000005236 alkanoylamino group Chemical group 0.000 description 5
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 5
- 150000001721 carbon Chemical class 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 235000013305 food Nutrition 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- OFCCYDUUBNUJIB-UHFFFAOYSA-N n,n-diethylcarbamoyl chloride Chemical compound CCN(CC)C(Cl)=O OFCCYDUUBNUJIB-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- 244000215068 Acacia senegal Species 0.000 description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 229920000084 Gum arabic Polymers 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 239000004373 Pullulan Substances 0.000 description 4
- 229920001218 Pullulan Polymers 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 235000010489 acacia gum Nutrition 0.000 description 4
- 239000000205 acacia gum Substances 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 125000003302 alkenyloxy group Chemical group 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 239000003524 antilipemic agent Substances 0.000 description 4
- 125000005110 aryl thio group Chemical group 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 150000004283 biguanides Chemical class 0.000 description 4
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 4
- 229940105329 carboxymethylcellulose Drugs 0.000 description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 4
- 238000010575 fractional recrystallization Methods 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 125000005946 imidazo[1,2-a]pyridyl group Chemical group 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 235000019423 pullulan Nutrition 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 4
- 125000004149 thio group Chemical group *S* 0.000 description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 239000004375 Dextrin Substances 0.000 description 3
- 229920001353 Dextrin Polymers 0.000 description 3
- 206010012735 Diarrhoea Diseases 0.000 description 3
- 102100020751 Dipeptidyl peptidase 2 Human genes 0.000 description 3
- 102100020750 Dipeptidyl peptidase 3 Human genes 0.000 description 3
- 108010058940 Glutamyl Aminopeptidase Proteins 0.000 description 3
- 102000006485 Glutamyl Aminopeptidase Human genes 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 102100040411 Tripeptidyl-peptidase 2 Human genes 0.000 description 3
- 108030005913 Xaa-Pro dipeptidyl-peptidases Proteins 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000000883 anti-obesity agent Substances 0.000 description 3
- 229940030600 antihypertensive agent Drugs 0.000 description 3
- 239000002220 antihypertensive agent Substances 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940125710 antiobesity agent Drugs 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 3
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 235000019425 dextrin Nutrition 0.000 description 3
- 108090000212 dipeptidyl peptidase II Proteins 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 230000002363 herbicidal effect Effects 0.000 description 3
- 239000004009 herbicide Substances 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000001771 impaired effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 3
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 3
- JJYKJUXBWFATTE-UHFFFAOYSA-N mosher's acid Chemical compound COC(C(O)=O)(C(F)(F)F)C1=CC=CC=C1 JJYKJUXBWFATTE-UHFFFAOYSA-N 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 230000008929 regeneration Effects 0.000 description 3
- 238000011069 regeneration method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 229960002920 sorbitol Drugs 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 108010039189 tripeptidyl-peptidase 2 Proteins 0.000 description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 2
- WAAPEIZFCHNLKK-UFBFGSQYSA-N (2s,4s)-6-fluoro-2',5'-dioxospiro[2,3-dihydrochromene-4,4'-imidazolidine]-2-carboxamide Chemical compound C([C@H](OC1=CC=C(F)C=C11)C(=O)N)[C@@]21NC(=O)NC2=O WAAPEIZFCHNLKK-UFBFGSQYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- OSKSVLBJJXQUPI-UHFFFAOYSA-N 2h-triazole-4-carboxamide Chemical class NC(=O)C1=CNN=N1 OSKSVLBJJXQUPI-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 102100022749 Aminopeptidase N Human genes 0.000 description 2
- 102000004400 Aminopeptidases Human genes 0.000 description 2
- 108090000915 Aminopeptidases Proteins 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108010066768 Bacterial leucyl aminopeptidase Proteins 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 2
- 108010071840 Cytosol nonspecific dipeptidase Proteins 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 102100029921 Dipeptidyl peptidase 1 Human genes 0.000 description 2
- 108030006877 Dipeptidyl-dipeptidases Proteins 0.000 description 2
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 108700036514 EC 3.4.14.1 Proteins 0.000 description 2
- 208000010228 Erectile Dysfunction Diseases 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 108030005223 Glu-Glu dipeptidases Proteins 0.000 description 2
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 description 2
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 101710151321 Melanostatin Proteins 0.000 description 2
- 108030004763 Met-Xaa dipeptidases Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 108090000192 Methionyl aminopeptidases Proteins 0.000 description 2
- 102000034452 Methionyl aminopeptidases Human genes 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- 102400000064 Neuropeptide Y Human genes 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- VRAHPESAMYMDQI-UHFFFAOYSA-N Nicomol Chemical compound C1CCC(COC(=O)C=2C=NC=CC=2)(COC(=O)C=2C=NC=CC=2)C(O)C1(COC(=O)C=1C=NC=CC=1)COC(=O)C1=CC=CN=C1 VRAHPESAMYMDQI-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 2
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 2
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 108010070926 Tripeptide aminopeptidase Proteins 0.000 description 2
- 108010039203 Tripeptidyl-Peptidase 1 Proteins 0.000 description 2
- 102100034197 Tripeptidyl-peptidase 1 Human genes 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 206010046543 Urinary incontinence Diseases 0.000 description 2
- 102100026867 Xaa-Arg dipeptidase Human genes 0.000 description 2
- 108030005286 Xaa-Arg dipeptidases Proteins 0.000 description 2
- 108030004686 Xaa-Pro aminopeptidases Proteins 0.000 description 2
- 108030000960 Xaa-Trp aminopeptidases Proteins 0.000 description 2
- 108030005284 Xaa-methyl-His dipeptidases Proteins 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000012042 active reagent Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 description 2
- 229960002535 alfacalcidol Drugs 0.000 description 2
- 125000005108 alkenylthio group Chemical group 0.000 description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 2
- 125000005133 alkynyloxy group Chemical group 0.000 description 2
- 125000005109 alkynylthio group Chemical group 0.000 description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 229940125682 antidementia agent Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229960004926 chlorobutanol Drugs 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 2
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 2
- 108010065327 clostridial aminopeptidase Proteins 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000002285 corn oil Substances 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 239000002385 cottonseed oil Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 2
- 125000005366 cycloalkylthio group Chemical group 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 108090000283 dipeptidyl peptidase III Proteins 0.000 description 2
- RLIRIVMEKVNVQX-UHFFFAOYSA-L disodium;(2-cycloheptyl-1-phosphonatoethyl)-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound [Na+].[Na+].OP([O-])(=O)C(P(O)([O-])=O)CC1CCCCCC1 RLIRIVMEKVNVQX-UHFFFAOYSA-L 0.000 description 2
- FUZBPOHHSBDTJQ-CFOQQKEYSA-L disodium;5-[(2r)-2-[[(2r)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate Chemical compound [Na+].[Na+].C1([C@@H](O)CN[C@@H](CC=2C=C3OC(OC3=CC=2)(C([O-])=O)C([O-])=O)C)=CC=CC(Cl)=C1 FUZBPOHHSBDTJQ-CFOQQKEYSA-L 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- SSQPWTVBQMWLSZ-AAQCHOMXSA-N ethyl (5Z,8Z,11Z,14Z,17Z)-icosapentaenoate Chemical compound CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC SSQPWTVBQMWLSZ-AAQCHOMXSA-N 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 description 2
- 230000004153 glucose metabolism Effects 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 2
- 201000008980 hyperinsulinism Diseases 0.000 description 2
- 229960002600 icosapent ethyl Drugs 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 210000001596 intra-abdominal fat Anatomy 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 229960002900 methylcellulose Drugs 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 2
- HWMFFWCDLWDYGX-UHFFFAOYSA-N n-(4-aminophenyl)furan-2-carboxamide Chemical compound C1=CC(N)=CC=C1NC(=O)C1=CC=CO1 HWMFFWCDLWDYGX-UHFFFAOYSA-N 0.000 description 2
- XWLVOJZVWRCRMD-OFNKIYASSA-N n-[5-[(1r)-2-[[(1r)-1-[4-(difluoromethoxy)phenyl]-2-phenylethyl]amino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide Chemical compound C1=C(O)C(NS(=O)(=O)C)=CC([C@@H](O)CN[C@H](CC=2C=CC=CC=2)C=2C=CC(OC(F)F)=CC=2)=C1 XWLVOJZVWRCRMD-OFNKIYASSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229960000698 nateglinide Drugs 0.000 description 2
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 229950001071 nicomol Drugs 0.000 description 2
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 2
- 239000002664 nootropic agent Substances 0.000 description 2
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229960005434 oxybutynin Drugs 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000000813 peptide hormone Substances 0.000 description 2
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 230000000291 postprandial effect Effects 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108010017378 prolyl aminopeptidase Proteins 0.000 description 2
- 229960001187 propiverine hydrochloride Drugs 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 102220240796 rs553605556 Human genes 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229960004025 sodium salicylate Drugs 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 238000009495 sugar coating Methods 0.000 description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- DBGIVFWFUFKIQN-VIFPVBQESA-N (+)-Fenfluramine Chemical compound CCN[C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-VIFPVBQESA-N 0.000 description 1
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 description 1
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- VLPIATFUUWWMKC-SNVBAGLBSA-N (2r)-1-(2,6-dimethylphenoxy)propan-2-amine Chemical compound C[C@@H](N)COC1=C(C)C=CC=C1C VLPIATFUUWWMKC-SNVBAGLBSA-N 0.000 description 1
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 1
- YKXCWZVUWWQSAV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O YKXCWZVUWWQSAV-BTVCFUMJSA-N 0.000 description 1
- ZXEIEKDGPVTZLD-NDEPHWFRSA-N (2s)-2-dodecylsulfanyl-n-(4-hydroxy-2,3,5-trimethylphenyl)-2-phenylacetamide Chemical compound O=C([C@@H](SCCCCCCCCCCCC)C=1C=CC=CC=1)NC1=CC(C)=C(O)C(C)=C1C ZXEIEKDGPVTZLD-NDEPHWFRSA-N 0.000 description 1
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 1
- VMDKRSNUUUUARH-MQDBWYGVSA-N (3s)-4-[[(2s)-1-[[(2s)-2-[[(2s)-3-(1h-indol-3-yl)-2-[[2-[[(2s)-2-[[2-(4-sulfooxyphenyl)acetyl]amino]hexanoyl]amino]acetyl]amino]propanoyl]amino]hexanoyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(methylamino)-4-oxobutanoic acid Chemical compound N([C@@H](CCCC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCC)C(=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC)C(=O)CC1=CC=C(OS(O)(=O)=O)C=C1 VMDKRSNUUUUARH-MQDBWYGVSA-N 0.000 description 1
- BMHZAHGTGIZZCT-LJQANCHMSA-N (4r)-2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4,3'-pyrrolidine]-1,2',3,5'-tetrone Chemical compound C1([C@]2(C(NC(=O)C2)=O)C2=O)=CC(F)=CC=C1C(=O)N2CC1=CC=C(Br)C=C1F BMHZAHGTGIZZCT-LJQANCHMSA-N 0.000 description 1
- ULVDFHLHKNJICZ-JVCXMKTPSA-N (4z)-4-[[4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl]methoxyimino]-4-phenylbutanoic acid Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1COC(C=C1)=CC=C1CO\N=C(\CCC(O)=O)C1=CC=CC=C1 ULVDFHLHKNJICZ-JVCXMKTPSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 1
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 1
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 description 1
- 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 1
- 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 description 1
- KMXPHBJUGYLXDM-UHFFFAOYSA-N 1-(7-hydroxy-6,6-dimethyl-7,8-dihydropyrano[2,3-f][2,1,3]benzoxadiazol-8-yl)piperidin-2-one Chemical compound OC1C(C)(C)OC2=CC3=NON=C3C=C2C1N1CCCCC1=O KMXPHBJUGYLXDM-UHFFFAOYSA-N 0.000 description 1
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- 125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- 125000005955 1H-indazolyl group Chemical group 0.000 description 1
- 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- CILPHQCEVYJUDN-VWYCJHECSA-N 2-[(1s,2s,5r)-5-methyl-2-propan-2-ylcyclohexyl]oxyacetic acid Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1OCC(O)=O CILPHQCEVYJUDN-VWYCJHECSA-N 0.000 description 1
- NSVFSAJIGAJDMR-UHFFFAOYSA-N 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate Chemical compound CC=1NC(C)=C(C(=O)OCCN(CC=2C=CC=CC=2)C=2C=CC=CC=2)C(C=2C=C(C=CC=2)[N+]([O-])=O)C=1P1(=O)OCC(C)(C)CO1 NSVFSAJIGAJDMR-UHFFFAOYSA-N 0.000 description 1
- YGZFYDFBHIDIBH-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]icosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCC(CO)N(CCO)CCO YGZFYDFBHIDIBH-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- ROJNYKZWTOHRNU-UHFFFAOYSA-N 2-chloro-4,5-difluoro-n-[[2-methoxy-5-(methylcarbamoylamino)phenyl]carbamoyl]benzamide Chemical compound CNC(=O)NC1=CC=C(OC)C(NC(=O)NC(=O)C=2C(=CC(F)=C(F)C=2)Cl)=C1 ROJNYKZWTOHRNU-UHFFFAOYSA-N 0.000 description 1
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 description 1
- ULQQGOGMQRGFFR-UHFFFAOYSA-N 2-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC=C1Cl ULQQGOGMQRGFFR-UHFFFAOYSA-N 0.000 description 1
- JCCBZCMSYUSCFM-UHFFFAOYSA-N 2-chlorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1Cl JCCBZCMSYUSCFM-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- YFNOTMRKVGZZNF-UHFFFAOYSA-N 2-piperidin-1-ium-4-ylacetate Chemical compound OC(=O)CC1CCNCC1 YFNOTMRKVGZZNF-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- BCSVCWVQNOXFGL-UHFFFAOYSA-N 3,4-dihydro-4-oxo-3-((5-trifluoromethyl-2-benzothiazolyl)methyl)-1-phthalazine acetic acid Chemical compound O=C1C2=CC=CC=C2C(CC(=O)O)=NN1CC1=NC2=CC(C(F)(F)F)=CC=C2S1 BCSVCWVQNOXFGL-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- AEDQNOLIADXSBB-UHFFFAOYSA-N 3-(dodecylazaniumyl)propanoate Chemical compound CCCCCCCCCCCCNCCC(O)=O AEDQNOLIADXSBB-UHFFFAOYSA-N 0.000 description 1
- OCIGTFOKXKNOBY-UHFFFAOYSA-N 3-[(3-chloroimidazo[1,2-a]pyridin-2-yl)methylsulfonyl]-N,N-diethyl-1,2,4-triazole-1-carboxamide Chemical compound CCN(CC)C(=O)N1C=NC(S(=O)(=O)CC2=C(N3C=CC=CC3=N2)Cl)=N1 OCIGTFOKXKNOBY-UHFFFAOYSA-N 0.000 description 1
- YKMUTVOCLPDFMQ-UHFFFAOYSA-N 3-[(3-chloroimidazo[1,2-a]pyridin-2-yl)methylsulfonyl]-n,n-dimethyl-1,2,4-triazole-1-carboxamide Chemical compound CN(C)C(=O)N1C=NC(S(=O)(=O)CC2=C(N3C=CC=CC3=N2)Cl)=N1 YKMUTVOCLPDFMQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UZKXVFBKGNVTFE-UHFFFAOYSA-N 4-(4-chlorophenyl)-2-(2-methylimidazol-1-yl)-5-[3-(2-methylphenoxy)propyl]-1,3-oxazole Chemical compound CC1=NC=CN1C(O1)=NC(C=2C=CC(Cl)=CC=2)=C1CCCOC1=CC=CC=C1C UZKXVFBKGNVTFE-UHFFFAOYSA-N 0.000 description 1
- QBQLYIISSRXYKL-UHFFFAOYSA-N 4-[[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]methyl]-1,2-oxazolidine-3,5-dione Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1CCOC(C=C1)=CC=C1CC1C(=O)NOC1=O QBQLYIISSRXYKL-UHFFFAOYSA-N 0.000 description 1
- JUHPDXOIGLHXTC-UHFFFAOYSA-N 4-fluoro-2-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1C(F)(F)F JUHPDXOIGLHXTC-UHFFFAOYSA-N 0.000 description 1
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- JTSFIVQMXUDGAB-UHFFFAOYSA-N 4-thiomorpholin-4-ylmorpholine Chemical compound C1COCCN1N1CCSCC1 JTSFIVQMXUDGAB-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- NFFXEUUOMTXWCX-UHFFFAOYSA-N 5-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-2-methoxy-n-[[4-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound C1=C(C(=O)NCC=2C=CC(=CC=2)C(F)(F)F)C(OC)=CC=C1CC1SC(=O)NC1=O NFFXEUUOMTXWCX-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- BKYKPTRYDKTTJY-UHFFFAOYSA-N 6-chloro-3-(cyclopentylmethyl)-1,1-dioxo-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1CCCC1 BKYKPTRYDKTTJY-UHFFFAOYSA-N 0.000 description 1
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000004611 Abdominal Obesity Diseases 0.000 description 1
- 206010000060 Abdominal distension Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- JBMKAUGHUNFTOL-UHFFFAOYSA-N Aldoclor Chemical class C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O JBMKAUGHUNFTOL-UHFFFAOYSA-N 0.000 description 1
- 102100032126 Aminopeptidase B Human genes 0.000 description 1
- 101710082401 Aminopeptidase Ey Proteins 0.000 description 1
- 108030000961 Aminopeptidase Y Proteins 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- 201000005670 Anovulation Diseases 0.000 description 1
- 206010002659 Anovulatory cycle Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 102100033261 Aspartyl aminopeptidase Human genes 0.000 description 1
- 108030000937 Aspartyl aminopeptidases Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- PTQXTEKSNBVPQJ-UHFFFAOYSA-N Avasimibe Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1CC(=O)NS(=O)(=O)OC1=C(C(C)C)C=CC=C1C(C)C PTQXTEKSNBVPQJ-UHFFFAOYSA-N 0.000 description 1
- 108700001281 BIM 51077 Proteins 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 102100031006 Beta-Ala-His dipeptidase Human genes 0.000 description 1
- 108030004753 Beta-Ala-His dipeptidases Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 1
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- 239000002081 C09CA05 - Tasosartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 1
- 125000005974 C6-C14 arylcarbonyl group Chemical group 0.000 description 1
- 108010049990 CD13 Antigens Proteins 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102000001327 Chemokine CCL5 Human genes 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 101800001982 Cholecystokinin Proteins 0.000 description 1
- 102100025841 Cholecystokinin Human genes 0.000 description 1
- 229940127328 Cholesterol Synthesis Inhibitors Drugs 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- LHWOLQLMCJDKGX-UHFFFAOYSA-N ClN1C(CCC1=O)=O.CN(C=O)C Chemical compound ClN1C(CCC1=O)=O.CN(C=O)C LHWOLQLMCJDKGX-UHFFFAOYSA-N 0.000 description 1
- BMOVQUBVGICXQN-UHFFFAOYSA-N Clinofibrate Chemical compound C1=CC(OC(C)(CC)C(O)=O)=CC=C1C1(C=2C=CC(OC(C)(CC)C(O)=O)=CC=2)CCCCC1 BMOVQUBVGICXQN-UHFFFAOYSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- YVIXXPCJZAUQHJ-YGRLFVJLSA-N Cp-114271 Chemical compound C([C@@H](C)NC[C@H](O)C=1N=C(SC=1)C(F)(F)F)C1=CC=C(OCC(O)=O)C=C1 YVIXXPCJZAUQHJ-YGRLFVJLSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 108091000069 Cystinyl Aminopeptidase Proteins 0.000 description 1
- 102000030900 Cystinyl aminopeptidase Human genes 0.000 description 1
- 108030000958 Cytosol alanyl aminopeptidases Proteins 0.000 description 1
- 102100034560 Cytosol aminopeptidase Human genes 0.000 description 1
- 102100031007 Cytosolic non-specific dipeptidase Human genes 0.000 description 1
- 108030000936 D-stereospecific aminopeptidases Proteins 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010012665 Diabetic gangrene Diseases 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 102100029857 Dipeptidase 3 Human genes 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- 108700033902 EC 3.4.11.22 Proteins 0.000 description 1
- 239000004129 EU approved improving agent Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- VXLCNTLWWUDBSO-UHFFFAOYSA-N Ethiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)NC(CC)NC2=C1 VXLCNTLWWUDBSO-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229920003148 Eudragit® E polymer Polymers 0.000 description 1
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 1
- 229920003136 Eudragit® L polymer Polymers 0.000 description 1
- 229920003153 Eudragit® NE polymer Polymers 0.000 description 1
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 1
- 229920003137 Eudragit® S polymer Polymers 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102100023374 Forkhead box protein M1 Human genes 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 1
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- 229940121931 Gluconeogenesis inhibitor Drugs 0.000 description 1
- 102000003638 Glucose-6-Phosphatase Human genes 0.000 description 1
- 108010086800 Glucose-6-Phosphatase Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- NMWQEPCLNXHPDX-UHFFFAOYSA-N Glybuzole Chemical compound S1C(C(C)(C)C)=NN=C1NS(=O)(=O)C1=CC=CC=C1 NMWQEPCLNXHPDX-UHFFFAOYSA-N 0.000 description 1
- HNSCCNJWTJUGNQ-UHFFFAOYSA-N Glyclopyramide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)NC(=O)NN1CCCC1 HNSCCNJWTJUGNQ-UHFFFAOYSA-N 0.000 description 1
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 206010020112 Hirsutism Diseases 0.000 description 1
- 101000931862 Homo sapiens Dipeptidyl peptidase 3 Proteins 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- 101000907578 Homo sapiens Forkhead box protein M1 Proteins 0.000 description 1
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 1
- 101000841267 Homo sapiens Long chain 3-hydroxyacyl-CoA dehydrogenase Proteins 0.000 description 1
- 101000879758 Homo sapiens Sjoegren syndrome nuclear autoantigen 1 Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000031773 Insulin resistance syndrome Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- SFBODOKJTYAUCM-UHFFFAOYSA-N Ipriflavone Chemical compound C=1C(OC(C)C)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 SFBODOKJTYAUCM-UHFFFAOYSA-N 0.000 description 1
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 108010004098 Leucyl aminopeptidase Proteins 0.000 description 1
- 102000002704 Leucyl aminopeptidase Human genes 0.000 description 1
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 1
- 108010019598 Liraglutide Proteins 0.000 description 1
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 1
- 102100029107 Long chain 3-hydroxyacyl-CoA dehydrogenase Human genes 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- ZPXSCAKFGYXMGA-UHFFFAOYSA-N Mazindol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 ZPXSCAKFGYXMGA-UHFFFAOYSA-N 0.000 description 1
- 108030004467 Membrane alanyl aminopeptidases Proteins 0.000 description 1
- 108030004769 Membrane dipeptidases Proteins 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CESYKOGBSMNBPD-UHFFFAOYSA-N Methyclothiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CCl)NC2=C1 CESYKOGBSMNBPD-UHFFFAOYSA-N 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- JTVPZMFULRWINT-UHFFFAOYSA-N N-[2-(diethylamino)ethyl]-2-methoxy-5-methylsulfonylbenzamide Chemical compound CCN(CC)CCNC(=O)C1=CC(S(C)(=O)=O)=CC=C1OC JTVPZMFULRWINT-UHFFFAOYSA-N 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 102000003797 Neuropeptides Human genes 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- KUEUWHJGRZKESU-UHFFFAOYSA-N Niceritrol Chemical compound C=1C=CN=CC=1C(=O)OCC(COC(=O)C=1C=NC=CC=1)(COC(=O)C=1C=NC=CC=1)COC(=O)C1=CC=CN=C1 KUEUWHJGRZKESU-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108010066503 Non-stereospecific dipeptidase Proteins 0.000 description 1
- 102000004140 Oncostatin M Human genes 0.000 description 1
- 108090000630 Oncostatin M Proteins 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010049088 Osteopenia Diseases 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 229940123973 Oxygen scavenger Drugs 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- CZYWHNTUXNGDGR-UHFFFAOYSA-L Pamidronate disodium Chemical compound O.O.O.O.O.[Na+].[Na+].NCCC(O)(P(O)([O-])=O)P(O)([O-])=O CZYWHNTUXNGDGR-UHFFFAOYSA-L 0.000 description 1
- 102000019280 Pancreatic lipases Human genes 0.000 description 1
- 108050006759 Pancreatic lipases Proteins 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- GHUUBYQTCDQWRA-UHFFFAOYSA-N Pioglitazone hydrochloride Chemical compound Cl.N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 GHUUBYQTCDQWRA-UHFFFAOYSA-N 0.000 description 1
- UJEWTUDSLQGTOA-UHFFFAOYSA-N Piretanide Chemical compound C=1C=CC=CC=1OC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1N1CCCC1 UJEWTUDSLQGTOA-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010036018 Pollakiuria Diseases 0.000 description 1
- CYLWJCABXYDINA-UHFFFAOYSA-N Polythiazide Polymers ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CSCC(F)(F)F)NC2=C1 CYLWJCABXYDINA-UHFFFAOYSA-N 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229940127315 Potassium Channel Openers Drugs 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- 102100033192 Puromycin-sensitive aminopeptidase Human genes 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 229920002305 Schizophyllan Polymers 0.000 description 1
- 101000733770 Schizosaccharomyces pombe (strain 972 / ATCC 24843) Aminopeptidase 1 Proteins 0.000 description 1
- 206010040026 Sensory disturbance Diseases 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- JLRNKCZRCMIVKA-UHFFFAOYSA-N Simfibrate Chemical compound C=1C=C(Cl)C=CC=1OC(C)(C)C(=O)OCCCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 JLRNKCZRCMIVKA-UHFFFAOYSA-N 0.000 description 1
- 102100037330 Sjoegren syndrome nuclear autoantigen 1 Human genes 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 102100022831 Somatoliberin Human genes 0.000 description 1
- 101710142969 Somatoliberin Proteins 0.000 description 1
- 102100038803 Somatotropin Human genes 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 1
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 108090000361 Transferred entry: 3.4.13.18 and 3.4.13.20 Proteins 0.000 description 1
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 1
- 108030000963 Tryptophanyl aminopeptidases Proteins 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 description 1
- 102100038364 Xaa-Pro aminopeptidase 2 Human genes 0.000 description 1
- 102100039662 Xaa-Pro dipeptidase Human genes 0.000 description 1
- 208000005946 Xerostomia Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- WCQRWCFGZARAMR-UHFFFAOYSA-N [F].[F] Chemical compound [F].[F] WCQRWCFGZARAMR-UHFFFAOYSA-N 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000004054 acenaphthylenyl group Chemical group C1(=CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- 229960001466 acetohexamide Drugs 0.000 description 1
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 201000009840 acute diarrhea Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000003288 aldose reductase inhibitor Substances 0.000 description 1
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- DCSBSVSZJRSITC-UHFFFAOYSA-M alendronate sodium trihydrate Chemical compound O.O.O.[Na+].NCCCC(O)(P(O)(O)=O)P(O)([O-])=O DCSBSVSZJRSITC-UHFFFAOYSA-M 0.000 description 1
- 229960004343 alendronic acid Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000006323 alkenyl amino group Chemical group 0.000 description 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 1
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
- 125000005336 allyloxy group Chemical group 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229960003318 alteplase Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 108090000449 aminopeptidase B Proteins 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 231100000552 anovulation Toxicity 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 229940064004 antiseptic throat preparations Drugs 0.000 description 1
- 239000004019 antithrombin Substances 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000005116 aryl carbamoyl group Chemical group 0.000 description 1
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 229950010046 avasimibe Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- IIOPLILENRZKRV-UHFFFAOYSA-N azosemide Chemical compound C=1C=CSC=1CNC=1C=C(Cl)C(S(=O)(=O)N)=CC=1C1=NN=N[N]1 IIOPLILENRZKRV-UHFFFAOYSA-N 0.000 description 1
- 229960004988 azosemide Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- QQFYLZXBFWWJHR-UHFFFAOYSA-M benzyl(triethyl)phosphanium;bromide Chemical compound [Br-].CC[P+](CC)(CC)CC1=CC=CC=C1 QQFYLZXBFWWJHR-UHFFFAOYSA-M 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229960002890 beraprost Drugs 0.000 description 1
- YTCZZXIRLARSET-VJRSQJMHSA-M beraprost sodium Chemical compound [Na+].O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC([O-])=O YTCZZXIRLARSET-VJRSQJMHSA-M 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- 229960000516 bezafibrate Drugs 0.000 description 1
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 1
- 208000024330 bloating Diseases 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 1
- 229960004111 buformin Drugs 0.000 description 1
- XSEUMFJMFFMCIU-UHFFFAOYSA-N buformin Chemical compound CCCC\N=C(/N)N=C(N)N XSEUMFJMFFMCIU-UHFFFAOYSA-N 0.000 description 1
- 229960004064 bumetanide Drugs 0.000 description 1
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960003773 calcitonin (salmon synthetic) Drugs 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 239000011612 calcitriol Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- OYPRJOBELJOOCE-RNFDNDRNSA-N calcium-44 Chemical compound [44Ca] OYPRJOBELJOOCE-RNFDNDRNSA-N 0.000 description 1
- GDDSFMMICZTVCA-UHFFFAOYSA-L calcium;2-carboxyphenolate;3,7-dimethylpurine-2,6-dione Chemical compound [Ca+2].OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O.CN1C(=O)NC(=O)C2=C1N=CN2C GDDSFMMICZTVCA-UHFFFAOYSA-L 0.000 description 1
- 229960004349 candesartan cilexetil Drugs 0.000 description 1
- LEMUFSYUPGXXCM-JNEQYSBXSA-N caninsulin Chemical compound [Zn].C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC3N=CN=C3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1C=NC=N1 LEMUFSYUPGXXCM-JNEQYSBXSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 229960005110 cerivastatin Drugs 0.000 description 1
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229930002875 chlorophyll Natural products 0.000 description 1
- 235000019804 chlorophyll Nutrition 0.000 description 1
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 229960001523 chlortalidone Drugs 0.000 description 1
- 229940107137 cholecystokinin Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000019902 chronic diarrheal disease Diseases 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 229960004588 cilostazol Drugs 0.000 description 1
- RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229950003072 clinofibrate Drugs 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 201000010897 colon adenocarcinoma Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 1
- 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229960003206 cyclopenthiazide Drugs 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 229940018872 dalteparin sodium Drugs 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- 235000019258 dehydroacetic acid Nutrition 0.000 description 1
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 1
- JEQRBTDTEKWZBW-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1=C(O)OC(C)=CC1=O JEQRBTDTEKWZBW-UHFFFAOYSA-N 0.000 description 1
- 229960005227 delapril Drugs 0.000 description 1
- WOUOLAUOZXOLJQ-MBSDFSHPSA-N delapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 WOUOLAUOZXOLJQ-MBSDFSHPSA-N 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960004597 dexfenfluramine Drugs 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 229960004242 dronabinol Drugs 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229950005925 eflucimibe Drugs 0.000 description 1
- 229950003102 efonidipine Drugs 0.000 description 1
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 1
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 1
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 1
- 229950000269 emiglitate Drugs 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 description 1
- 229950010170 epalrestat Drugs 0.000 description 1
- CHNUOJQWGUIOLD-UHFFFAOYSA-N epalrestate Natural products C=1C=CC=CC=1C=C(C)C=C1SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-UHFFFAOYSA-N 0.000 description 1
- 229960004563 eprosartan Drugs 0.000 description 1
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 description 1
- 229960001348 estriol Drugs 0.000 description 1
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 1
- 229960003199 etacrynic acid Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229950007164 ethiazide Drugs 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- NWWORXYTJRPSMC-QKPAOTATSA-N ethyl 4-[2-[(2r,3r,4r,5s)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl]ethoxy]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1OCCN1[C@H](CO)[C@@H](O)[C@H](O)[C@@H](O)C1 NWWORXYTJRPSMC-QKPAOTATSA-N 0.000 description 1
- WDCDAAMJNUHOIY-UHFFFAOYSA-N ethyl acetate;2-propan-2-yloxypropane Chemical compound CCOC(C)=O.CC(C)OC(C)C WDCDAAMJNUHOIY-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- FSXVSUSRJXIJHB-UHFFFAOYSA-M ethyl prop-2-enoate;methyl 2-methylprop-2-enoate;trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium;chloride Chemical compound [Cl-].CCOC(=O)C=C.COC(=O)C(C)=C.CC(=C)C(=O)OCC[N+](C)(C)C FSXVSUSRJXIJHB-UHFFFAOYSA-M 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000005290 ethynyloxy group Chemical group C(#C)O* 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- ZZCHHVUQYRMYLW-HKBQPEDESA-N farglitazar Chemical compound N([C@@H](CC1=CC=C(C=C1)OCCC=1N=C(OC=1C)C=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 ZZCHHVUQYRMYLW-HKBQPEDESA-N 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 229960001582 fenfluramine Drugs 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 229950007256 fidarestat Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960003064 flavoxate hydrochloride Drugs 0.000 description 1
- XOEVKNFZUQEERE-UHFFFAOYSA-N flavoxate hydrochloride Chemical compound Cl.C1=CC=C2C(=O)C(C)=C(C=3C=CC=CC=3)OC2=C1C(=O)OCCN1CCCCC1 XOEVKNFZUQEERE-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960003765 fluvastatin Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 1
- FODTZLFLDFKIQH-FSVGXZBPSA-N gamma-Oryzanol (TN) Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)O[C@@H]2C([C@@H]3CC[C@H]4[C@]5(C)CC[C@@H]([C@@]5(C)CC[C@@]54C[C@@]53CC2)[C@H](C)CCC=C(C)C)(C)C)=C1 FODTZLFLDFKIQH-FSVGXZBPSA-N 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 208000004104 gestational diabetes Diseases 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 229960000346 gliclazide Drugs 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- WPNGPBPCQMDAAD-WRFZDFFOSA-N glp-1 (9-36) amide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@@H](N)CCC(O)=O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 WPNGPBPCQMDAAD-WRFZDFFOSA-N 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 108700005418 glucagon-like peptide-1 (9-36)-amide Proteins 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 229950005232 glybuzole Drugs 0.000 description 1
- 229950002888 glyclopyramide Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229940095529 heparin calcium Drugs 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- MOTRZVVGCFFABN-UHFFFAOYSA-N hexane;2-propan-2-yloxypropane Chemical compound CCCCCC.CC(C)OC(C)C MOTRZVVGCFFABN-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 229960003313 hydroflumethiazide Drugs 0.000 description 1
- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 201000010066 hyperandrogenism Diseases 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000002434 immunopotentiative effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 229950006971 incadronic acid Drugs 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 229960004569 indapamide Drugs 0.000 description 1
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 description 1
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 229960005431 ipriflavone Drugs 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960002479 isosorbide Drugs 0.000 description 1
- 208000006443 lactic acidosis Diseases 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 230000008604 lipoprotein metabolism Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 229940083747 low-ceiling diuretics xanthine derivative Drugs 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- ANEBWFXPVPTEET-UHFFFAOYSA-N manidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ANEBWFXPVPTEET-UHFFFAOYSA-N 0.000 description 1
- 229960003963 manidipine Drugs 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960000299 mazindol Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WVJKHCGMRZGIJH-UHFFFAOYSA-N methanetriamine Chemical compound NC(N)N WVJKHCGMRZGIJH-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000006626 methoxycarbonylamino group Chemical group 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 229960003404 mexiletine Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 229950002259 minalrestat Drugs 0.000 description 1
- 229960003365 mitiglinide Drugs 0.000 description 1
- WPGGHFDDFPHPOB-BBWFWOEESA-N mitiglinide Chemical compound C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)O)C1=CC=CC=C1 WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 108010075698 monteplase Proteins 0.000 description 1
- 229950005805 monteplase Drugs 0.000 description 1
- XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- BSOQXXWZTUDTEL-ZUYCGGNHSA-N muramyl dipeptide Chemical class OC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O BSOQXXWZTUDTEL-ZUYCGGNHSA-N 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- RSAFAYLZKCYUQW-UHFFFAOYSA-N n,n-di(propan-2-yl)carbamoyl chloride Chemical compound CC(C)N(C(C)C)C(Cl)=O RSAFAYLZKCYUQW-UHFFFAOYSA-N 0.000 description 1
- DKQGOINODKCOTC-UHFFFAOYSA-N n,n-diethyl-3-(imidazo[1,2-a]pyridin-2-ylmethylsulfonyl)-1,2,4-triazole-1-carboxamide Chemical compound CCN(CC)C(=O)N1C=NC(S(=O)(=O)CC=2N=C3C=CC=CN3C=2)=N1 DKQGOINODKCOTC-UHFFFAOYSA-N 0.000 description 1
- JFCHSQDLLFJHOA-UHFFFAOYSA-N n,n-dimethylsulfamoyl chloride Chemical compound CN(C)S(Cl)(=O)=O JFCHSQDLLFJHOA-UHFFFAOYSA-N 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000005029 naphthylthio group Chemical group C1(=CC=CC2=CC=CC=C12)S* 0.000 description 1
- 229950002774 nateplase Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000009925 nephrosclerosis Diseases 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 230000032064 neurotrophin production Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- 229960000827 niceritrol Drugs 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229960003978 pamidronic acid Drugs 0.000 description 1
- 108010085108 pamiteplase Proteins 0.000 description 1
- 229950003603 pamiteplase Drugs 0.000 description 1
- 229940116369 pancreatic lipase Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229940068065 phytosterols Drugs 0.000 description 1
- 229960002827 pioglitazone hydrochloride Drugs 0.000 description 1
- BIFDXOOJPDHKJH-UHFFFAOYSA-N piperidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCCC1 BIFDXOOJPDHKJH-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229960001085 piretanide Drugs 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 108010001062 polysaccharide-K Proteins 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229960005483 polythiazide Drugs 0.000 description 1
- 229920000046 polythiazide Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 229960003611 pramlintide Drugs 0.000 description 1
- 108010029667 pramlintide Proteins 0.000 description 1
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 150000003145 progesterone derivatives Chemical class 0.000 description 1
- 108010066823 proline dipeptidase Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- XACWJIQLDLUFSR-UHFFFAOYSA-N pyrrolidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCC1 XACWJIQLDLUFSR-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 108010068072 salmon calcitonin Proteins 0.000 description 1
- 229950005789 sarpogrelate Drugs 0.000 description 1
- FFYNAVGJSYHHFO-UHFFFAOYSA-N sarpogrelate Chemical compound COC1=CC=CC(CCC=2C(=CC=CC=2)OCC(CN(C)C)OC(=O)CCC(O)=O)=C1 FFYNAVGJSYHHFO-UHFFFAOYSA-N 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960002639 sildenafil citrate Drugs 0.000 description 1
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 description 1
- 229960004058 simfibrate Drugs 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- WSRBRQQGWDWSON-UHFFFAOYSA-M sodium;3,7-dimethylpurine-2,6-dione;2-hydroxybenzoate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O.CN1C(=O)NC(=O)C2=C1N=CN2C WSRBRQQGWDWSON-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960000651 tasosartan Drugs 0.000 description 1
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 1
- WRGVLTAWMNZWGT-VQSPYGJZSA-N taspoglutide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NC(C)(C)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)C(C)(C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 WRGVLTAWMNZWGT-VQSPYGJZSA-N 0.000 description 1
- 229950007151 taspoglutide Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 229960005344 tiapride Drugs 0.000 description 1
- 229960002961 ticlopidine hydrochloride Drugs 0.000 description 1
- MTKNGOHFNXIVOS-UHFFFAOYSA-N ticlopidine hydrochloride Chemical compound [H+].[Cl-].ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 MTKNGOHFNXIVOS-UHFFFAOYSA-N 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- UXHMGTYELGTNSJ-UHFFFAOYSA-N triazole-1-carboxamide Chemical compound NC(=O)N1C=CN=N1 UXHMGTYELGTNSJ-UHFFFAOYSA-N 0.000 description 1
- 229960004813 trichlormethiazide Drugs 0.000 description 1
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 125000005454 tryptophanyl group Chemical group 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- WQEVDHBJGNOKKO-UHFFFAOYSA-K vanadic acid Chemical compound O[V](O)(O)=O WQEVDHBJGNOKKO-UHFFFAOYSA-K 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960000883 warfarin potassium Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- SXONDGSPUVNZLO-UHFFFAOYSA-N zenarestat Chemical compound O=C1N(CC(=O)O)C2=CC(Cl)=CC=C2C(=O)N1CC1=CC=C(Br)C=C1F SXONDGSPUVNZLO-UHFFFAOYSA-N 0.000 description 1
- 229950006343 zenarestat Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229950005346 zopolrestat Drugs 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明は、糖尿病の予防また
は治療薬などとして有用な医薬およびペプチダーゼ阻害
剤に関する。TECHNICAL FIELD The present invention relates to a drug and a peptidase inhibitor useful as a preventive or therapeutic drug for diabetes and the like.
【0002】[0002]
【従来の技術】ペプチダーゼは様々な疾患に関連してい
ることが知られている。例えば、ペプチダーゼの1種で
あるジペプチジルペプチダーゼ−IV(以下、DPP−
IVと略記することがある)は、N末端から2番目にプロ
リン(あるいはアラニン)を含むペプチドに特異的に結合
し、そのプロリン(あるいはアラニン)のC末端側を切断
してジペプチドを産生するセリンプロテアーゼである。
また、DPP−IVはCD26と同一分子であることも
示されており、免疫系にも関係があることが報告されて
いる。哺乳類におけるDPP−IVの役割は完全には明
らかになっていないが、神経ペプチドの代謝、T細胞の
活性化、ガン細胞の内皮細胞への接着やHIVの細胞内
への侵入等において重要な役割を演じていると考えられ
ている。特に糖代謝の面では、DPP−IVはインクレ
チンであるGLP−1(glucagon-likepeptide-1)あるい
はGIP(Gastric inhibitory peptide/Glucose-depend
ent insulinotoropic peptide)の不活性化に一役買って
いる。GLP−1に関して更に言えば、血漿中の半減期
が1−2分と短い上、DPP−IVによる分解産物である
GLP−1(9−36)amideがGLP−1受容体に
対してアンタゴニストとして働くなど、DPP−IVに
分解されることによりその生理活性が著しく損なわれる
事が知られている。そしてDPP−IV活性を阻害する
ことによりGLP-1の分解を抑制すれば、グルコース
濃度依存的にインスリン分泌を促進するなどGLP−1
の有する生理活性が増強される事も知られている。これ
らの事実からDPP−IV阻害作用を有する化合物は、
I型及びII型糖尿病などにおいて認められる耐糖能異
常、食後高血糖、空腹時高血糖やそれに伴う肥満・糖尿
病性合併症などに効果を示すことが期待される。現在使
用されている糖尿病の治療薬としては、スルホニルウレ
ア剤、ビグアナイド剤およびα−グルコシダーゼ阻害剤
などが用いられている。しかし、スルホニルウレア剤は
強力な血糖低下作用を有するが、しばしば重篤な低血糖
を引き起こし、使用上の注意が必要である。ビグアナイ
ド剤は、副作用として比較的重篤な乳酸アシドーシスを
引き起こしやすい。また、α−グルコシダーゼ阻害剤は
消化管における糖質の消化・吸収を遅延させ食後の血糖
上昇を抑制するが、膨満感あるいは下痢などの副作用が
問題となっている(JOSLIN’S DIABETES MELLITUS 13Th
Edition 521-522)。2. Description of the Related Art Peptidases are known to be associated with various diseases. For example, one type of peptidase, dipeptidyl peptidase-IV (hereinafter referred to as DPP-
IV is sometimes abbreviated) is a serine that specifically binds to a peptide containing proline (or alanine) at the second position from the N-terminal and cleaves the C-terminal side of the proline (or alanine) to produce a dipeptide. It is a protease.
DPP-IV has also been shown to be the same molecule as CD26, and has been reported to be related to the immune system. Although the role of DPP-IV in mammals has not been completely clarified, it plays an important role in neuropeptide metabolism, T cell activation, adhesion of cancer cells to endothelial cells, and invasion of HIV into cells. Is believed to be playing. Particularly in terms of glucose metabolism, DPP-IV is an incretin such as GLP-1 (glucagon-like peptide-1) or GIP (Gastric inhibitory peptide / Glucose-depend).
It plays a role in the inactivation of ent insulinotoropic peptide). Speaking of GLP-1, further, the plasma half-life is as short as 1-2 minutes, and the degradation product of DPP-IV, GLP-1 (9-36) amide, acts as an antagonist to the GLP-1 receptor. It is known that its bioactivity is remarkably impaired by being decomposed into DPP-IV such as working. If GLP-1 degradation is suppressed by inhibiting DPP-IV activity, GLP-1 is promoted in a glucose concentration-dependent manner such as promoting insulin secretion.
It is also known that the physiological activity possessed by is enhanced. From these facts, a compound having a DPP-IV inhibitory action is
It is expected to show effects on glucose intolerance, postprandial hyperglycemia, fasting hyperglycemia, and associated obesity / diabetic complications, which are observed in type I and type II diabetes. As therapeutic agents for diabetes currently used, sulfonylurea agents, biguanides, α-glucosidase inhibitors and the like are used. However, although sulfonylureas have a strong hypoglycemic effect, they often cause severe hypoglycemia and require caution in use. As a side effect, biguanides are likely to cause relatively severe lactic acidosis. In addition, α-glucosidase inhibitors suppress digestion and absorption of carbohydrates in the digestive tract and suppress postprandial blood glucose elevation, but side effects such as bloating and diarrhea are a problem (JOSLIN'S DIABETES MELLITUS 13Th.
Edition 521-522).
【0003】一方、カルバモイルトリアゾール誘導体と
しては下記の化合物が報告されている。特開平9−14318
1には、式On the other hand, the following compounds have been reported as carbamoyltriazole derivatives. JP 9-14318
1 is the expression
【化3】
[式中、Qは置換基を有していてもよい橋頭に窒素原子
を有する縮合複素環基を、WはOまたはSを、R1および
R2はそれぞれ水素原子または置換されていてもよい炭化
水素基を、R1およびR2は隣接する窒素原子と共に置換さ
れていてもよい含窒素複素環基を形成してもよく、R3は
水素原子、ハロゲン原子、または置換されていてもよい
炭化水素基を、mは0または1を、nは0〜2の整数をそれ
ぞれ示す]で表される化合物またはその塩が除草剤、殺
虫剤、殺菌剤などの農薬として有用であることが記載さ
れている。特開平59−39880には、式[Chemical 3] [In the formula, Q is a condensed heterocyclic group having a nitrogen atom at the bridgehead which may have a substituent, W is O or S, R 1 and
R 2 is each a hydrogen atom or an optionally substituted hydrocarbon group, R 1 and R 2 may form an optionally substituted nitrogen-containing heterocyclic group, and R 3 is A hydrogen atom, a halogen atom, or an optionally substituted hydrocarbon group, m is 0 or 1, and n is an integer of 0 to 2] or a salt thereof is a herbicide or an insecticide. , It is described to be useful as an agricultural chemical such as a fungicide. Japanese Patent Laid-Open No. 59-39880 discloses that
【化4】
[式中、nは0、1または2、R1とR2は低級アルキル基ま
たはR1とR2とで環をなす低級アルキレン基、Xはハロゲ
ン原子または低級アルキル基、R3は水素原子または低級
アルキル基を表す。ただし、R3が水素原子のとき、mは
1、2または3を表し、R3が低級アルキル基のとき、mは
0、1、2または3を表す]で表される化合物が除草剤とし
て有用であることが記載されている。USP4280831には、
式[Chemical 4] [Wherein n is 0, 1 or 2, R 1 and R 2 are lower alkyl groups or a lower alkylene group forming a ring of R 1 and R 2 , X is a halogen atom or a lower alkyl group, and R 3 is a hydrogen atom. Alternatively, it represents a lower alkyl group. However, when R 3 is a hydrogen atom, m is
Represents 1, 2, or 3, and when R 3 is a lower alkyl group, m is
Representing 0, 1, 2 or 3] is useful as a herbicide. USP4280831 has
formula
【化5】
で表される化合物が除草剤として有用であることが記載
されている。しかしながら、これらのカルバモイルトリ
アゾール誘導体が医薬またはペプチダーゼ阻害剤として
有用であるとの報告はない。[Chemical 5] It is described that the compound represented by is useful as a herbicide. However, there is no report that these carbamoyltriazole derivatives are useful as a drug or a peptidase inhibitor.
【0004】[0004]
【発明が解決しようとする課題】糖尿病の予防または治
療薬などとして有用であり、かつ薬効、作用時間、特異
性、低毒性等の点で優れた性質を有する医薬およびペプ
チダーゼ阻害剤の開発が望まれている。[Problems to be Solved by the Invention] It is desired to develop a drug and a peptidase inhibitor which are useful as a preventive or therapeutic drug for diabetes and have excellent properties such as drug efficacy, action time, specificity and low toxicity. It is rare.
【0005】[0005]
【課題を解決するための手段】本発明者らは、1位にア
ミノカルバモイル基を有する1,2,4−トリアゾール
が、3位で硫黄原子と結合している点に化学構造上の特
徴を有する、式Means for Solving the Problems The present inventors have found that 1,2,4-triazole having an aminocarbamoyl group at the 1-position is bonded to a sulfur atom at the 3-position and is characterized by its chemical structure. Having an expression
【化6】
[式中、Aは置換されていてもよい複素環基または置換
されていてもよい炭化水素基を、nは0〜2の整数を示
し、R1およびR2は同一または異なって、水素原子また
は置換されていてもよい炭化水素基を示すか、またはR
1およびR2が、隣接する窒素原子とともに、置換され
ていてもよい含窒素複素環を形成し、R3は水素原子、
ハロゲン原子または置換されていてもよい炭化水素基を
示す]で表される化合物[以下、化合物(I)と略記す
ることもある]またはその塩が優れたペプチダーゼ阻害
作用を有し、糖尿病の予防または治療薬などとして有用
であることを初めて見出した。この知見に基づいて、本
発明者は、鋭意研究を行い、本発明を完成するに至っ
た。すなわち、本発明は
1)化合物(I)もしくはその塩またはそのプロドラッ
グを含有してなる医薬;
2)糖尿病の予防または治療薬である前記1)記載の医
薬;
3)糖尿病性合併症の予防または治療薬である前記1)
記載の医薬;
4)耐糖能不全の予防または治療薬である前記1)記載
の医薬;
5)肥満の予防または治療薬である前記1)記載の医
薬;
6)化合物(I)もしくはその塩またはそのプロドラッ
グを含有してなるペプチダーゼ阻害剤;
7)ペプチダーゼがジペプチジルペプチダーゼ−IVで
ある前記6)記載の阻害剤;などに関する。[Chemical 6] [In the formula, A represents an optionally substituted heterocyclic group or an optionally substituted hydrocarbon group, n represents an integer of 0 to 2, R 1 and R 2 are the same or different, and a hydrogen atom Or represents an optionally substituted hydrocarbon group, or R
1 and R 2 together with an adjacent nitrogen atom form an optionally substituted nitrogen-containing heterocycle, R 3 is a hydrogen atom,
A compound represented by a halogen atom or a hydrocarbon group which may be substituted] [hereinafter, sometimes abbreviated as compound (I)] or a salt thereof has an excellent peptidase inhibitory action and prevents diabetes. For the first time, it was found to be useful as a therapeutic drug. Based on this finding, the present inventor has conducted earnest research and completed the present invention. That is, the present invention provides 1) a drug comprising compound (I) or a salt thereof or a prodrug thereof; 2) the drug according to 1) above, which is a preventive or therapeutic drug for diabetes; 3) prevention of diabetic complications. Or 1) which is a therapeutic drug
The pharmaceutical according to 1), which is a preventive or therapeutic drug for impaired glucose tolerance; 5) the pharmaceutical according to 1), which is a preventive or therapeutic drug for obesity; 6) Compound (I) or a salt thereof; A peptidase inhibitor comprising the prodrug thereof; 7) the inhibitor according to 6) above, wherein the peptidase is dipeptidyl peptidase-IV;
【0006】以下、式(I)中の各記号の定義について
詳述する。Aで示される「置換されていてもよい複素環
基」における「複素環基」としては、例えば環構成原子
として炭素原子以外に酸素原子、硫黄原子および窒素原
子から選ばれるヘテロ原子を1ないし4個含有する、5
〜7員の単環式複素環基または縮合複素環基が挙げられ
る。該縮合複素環基としては、例えばこれら5〜7員の
単環式複素環基と、1ないし2個の窒素原子を含む6員
環、ベンゼン環または1個の硫黄原子を含む5員環とが
縮合した基等が挙げられる。「複素環基」の具体例とし
ては、テトラヒドロフリル、ピロリジニル、ピペリジニ
ル、モルホリニル、チオモルホリニル、ピペラジニル、
ヘキサメチレンイミニル、オキサゾリジニル、チアゾリ
ジニル、イミダゾリジニル、2−オキソイミダゾリジニ
ル、2,4−ジオキソイミダゾリジニル、2,4−ジオ
キソオキサゾリジニル、2,4−ジオキソチアゾリジニ
ル、1,3−ジオキソイソインドリルなどの非芳香族複
素環基;およびフリル、チエニル、ピリジル、ピリミジ
ニル、ピリダジニル、ピラジニル、ピロリル、イミダゾ
リル、1−ピラゾリル、3−ピラゾリル、ピラゾリル、
イソオキサゾリル、イソチアゾリル、チアゾリル、オキ
サゾリル、1,2,4−オキサジアゾリル、1,3,4−オ
キサジアゾリル、1,2,4−トリアゾリル、1,2,3−
トリアゾリル、テトラゾリル、キノリル、キナゾリル、
キノキサリル、ベンゾフリル、ベンゾチエニル、ベンゾ
オキサゾリル、ベンゾチアゾリル、ベンズイミダゾリ
ル、インドリル、1H−インダゾリル、1H−ピロロ
[2,3−b]ピラジニル、1H−イミダゾ[4,5−
b]ピリジニル、1H−イミダゾ[4,5−c]ピリジ
ニル、イミダゾ[1,2−a]ピリジル、イミダゾ
[1,2−a]ピリミジニル、イミダゾ[1,2−b]
ピリダジニルなどの芳香族複素環基が挙げられる。The definition of each symbol in the formula (I) will be described in detail below. The "heterocyclic group" in the "optionally substituted heterocyclic group" represented by A is, for example, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom other than carbon atoms as ring-constituting atoms. Contains 5
To 7-membered monocyclic heterocyclic groups or condensed heterocyclic groups. Examples of the fused heterocyclic group include a 5- to 7-membered monocyclic heterocyclic group, a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or a 5-membered ring containing 1 sulfur atom. And the like. Specific examples of the "heterocyclic group" include tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,
Hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, 2-oxoimidazolidinyl, 2,4-dioxoimidazolidinyl, 2,4-dioxooxazolidinyl, 2,4-dioxothiazolidinyl, A non-aromatic heterocyclic group such as 1,3-dioxoisoindolyl; and furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, 1-pyrazolyl, 3-pyrazolyl, pyrazolyl,
Isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-
Triazolyl, tetrazolyl, quinolyl, quinazolyl,
Quinoxalyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl, 1H-indazolyl, 1H-pyrrolo [2,3-b] pyrazinyl, 1H-imidazo [4,5-
b] pyridinyl, 1H-imidazo [4,5-c] pyridinyl, imidazo [1,2-a] pyridyl, imidazo [1,2-a] pyrimidinyl, imidazo [1,2-b]
Examples include aromatic heterocyclic groups such as pyridazinyl.
【0007】該「複素環基」は、置換可能な位置に1な
いし3個の置換基を有していてもよい。このような置換
基としては、例えば「ハロゲン原子」、「ニトロ基」、
「シアノ基」、「C1-3アルキレンジオキシ基」、「置
換されていてもよい炭素数1〜10のアルキル基」、
「置換されていてもよい炭素数2〜10のアルケニル
基」、「置換されていてもよい炭素数2〜10のアルキ
ニル基」、「置換されていてもよい炭素数3〜10のシ
クロアルキル基」、「置換されていてもよい炭素数3〜
10のシクロアルケニル基」、「置換されていてもよい
炭素数4〜10のシクロアルカジエニル基」、「置換さ
れていてもよい炭素数6〜14のアリール基」、「置換
されていてもよい炭素数7〜13のアラルキル基」、
「置換されていてもよい炭素数8〜13のアリールアル
ケニル基」、「置換されていてもよい非芳香族複素環
基」、「置換されていてもよい芳香族複素環基」、「ア
シル基」、「置換されていてもよいアミノ基」、「置換
されていてもよいヒドロキシ基」、「置換されていても
よいチオール基」、「アミジノ基」などが挙げられる。The "heterocyclic group" may have 1 to 3 substituents at substitutable positions. Such substituents include, for example, "halogen atom", "nitro group",
"Cyano group", "C 1-3 alkylenedioxy group", "optionally substituted alkyl group having 1 to 10 carbon atoms",
"Alkenyl group having 2 to 10 carbon atoms which may be substituted", "Alkynyl group having 2 to 10 carbon atoms which may be substituted", "Cycloalkyl group having 3 to 10 carbon atoms which may be substituted" , "C3-C which may be substituted"
10 cycloalkenyl group "," optionally substituted cycloalkadienyl group having 4 to 10 carbon atoms "," optionally substituted aryl group having 6 to 14 carbon atoms "," optionally substituted " A good aralkyl group having 7 to 13 carbon atoms ",
"Aryl alkenyl group having 8 to 13 carbon atoms which may be substituted", "non-aromatic heterocyclic group which may be substituted", "aromatic heterocyclic group which may be substituted", "acyl group" , "Optionally substituted amino group", "optionally substituted hydroxy group", "optionally substituted thiol group", "amidino group" and the like.
【0008】ここで、「ハロゲン原子」としては、例え
ばフッ素、塩素、臭素、ヨウ素などが挙げられ、なかで
もフッ素、塩素、臭素が好ましい。「C1-3アルキレン
ジオキシ基」としては、例えばメチレンジオキシ、エチ
レンジオキシなどが挙げられる。「置換されていてもよ
い炭素数1〜10のアルキル基」における「炭素数1〜
10のアルキル基」としては、例えばメチル、エチル、
プロピル、イソプロピル、ブチル、イソブチル、sec.-
ブチル、t.-ブチル、ペンチル、イソペンチル、ネオペ
ンチル、1−エチルプロピル、ヘキシル、イソヘキシ
ル、1,1−ジメチルブチル、2,2−ジメチルブチ
ル、3,3−ジメチルブチル、2−エチルブチル、ヘプ
チル、オクチル、ノニル、デシルなどが挙げられる。
「置換されていてもよい炭素数2〜10のアルケニル
基」における「炭素数2〜10のアルケニル基」として
は、例えばエテニル、1−プロペニル、2−プロペニ
ル、2−メチル−1−プロペニル、1−ブテニル、2−
ブテニル、3−ブテニル、3−メチル−2−ブテニル、
1−ペンテニル、2−ペンテニル、3−ペンテニル、4
−ペンテニル、4−メチル−3−ペンテニル、1−ヘキ
セニル、3−ヘキセニル、5−ヘキセニル、1−ヘプテ
ニル、1−オクテニルなどが挙げられる。「置換されて
いてもよい炭素数2〜10のアルキニル基」における
「炭素数2〜10のアルキニル基」としては、例えばエ
チニル、1−プロピニル、2−プロピニル、1−ブチニ
ル、2−ブチニル、3−ブチニル、1−ペンチニル、2
−ペンチニル、3−ペンチニル、4−ペンチニル、1−
ヘキシニル、2−ヘキシニル、3−ヘキシニル、4−ヘ
キシニル、5−ヘキシニル、1−ヘプチニル、1−オク
チニルなどが挙げられる。Here, examples of the "halogen atom" include fluorine, chlorine, bromine, iodine and the like, among which fluorine, chlorine and bromine are preferable. Examples of the “C 1-3 alkylenedioxy group” include methylenedioxy, ethylenedioxy and the like. "C1-C10 alkyl" in the "optionally substituted C1-C10 alkyl group"
As the “10 alkyl group”, for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec.-
Butyl, t.-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl , Nonyl, decyl and the like.
Examples of the "alkenyl group having 2 to 10 carbon atoms" in the "alkenyl group having 2 to 10 carbon atoms which may be substituted" include, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1 -Butenyl, 2-
Butenyl, 3-butenyl, 3-methyl-2-butenyl,
1-pentenyl, 2-pentenyl, 3-pentenyl, 4
-Pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like can be mentioned. Examples of the "alkynyl group having 2 to 10 carbon atoms" in the "optionally substituted C 2 to 10 alkynyl group" include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3 -Butynyl, 1-pentynyl, 2
-Pentynyl, 3-pentynyl, 4-pentynyl, 1-
Hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like can be mentioned.
【0009】前記「炭素数1〜10のアルキル基」、
「炭素数2〜10のアルケニル基」および「炭素数2〜
10のアルキニル基」は、置換可能な位置に1ないし3
個の置換基を有していてもよい。このような置換基とし
ては、例えば炭素数3〜10のシクロアルキル基;芳香
族複素環基(例、チエニル、フリル、ピリジル、オキサ
ゾリル、チアゾリル、イミダゾ[1,2−a]ピリジ
ル、イミダゾ[1,2−a]ピリミジニル、イミダゾ
[1,2−b]ピリダジニルなど);非芳香族複素環基
(例、テトラヒドロフリル、モルホリノ、チオモルホリ
ノ、ピペリジノ、ピロリジニル、ピペラジニルなど);
炭素数1〜4のアルキル基あるいは炭素数2〜8のアシ
ル基(例、アルカノイル基、アルコキシカルボニル基な
ど)でモノあるいはジ置換されていてもよいアミノ基;
炭素数1〜8のアルキルスルホニルアミノ基;アミジノ
基;炭素数2〜8のアシル基(例、アルカノイル基、ア
ルコキシカルボニル基など);炭素数1〜8のアルキル
スルホニル基;炭素数1〜4のアルキル基でモノあるい
はジ置換されていてもよいカルバモイル基;炭素数1〜
4のアルキル基でモノあるいはジ置換されていてもよい
スルファモイル基;カルボキシル基;ヒドロキシ基;1
〜3個のハロゲン原子(例、フッ素、塩素、臭素、ヨウ
素など)で置換されていてもよい炭素数1〜6のアルコ
キシ基;1〜3個のハロゲン原子(例、フッ素、塩素、
臭素、ヨウ素など)で置換されていてもよい炭素数2〜
5のアルケニルオキシ基;炭素数3〜7のシクロアルキ
ルオキシ基;炭素数7〜13のアラルキルオキシ基;炭
素数6〜14のアリールオキシ基(例、フェニルオキ
シ、ナフチルオキシなど);チオール基;1〜3個のハ
ロゲン原子(例、フッ素、塩素、臭素、ヨウ素など)で
置換されていてもよい炭素数1〜6のアルキルチオ基;
炭素数7〜13のアラルキルチオ基;炭素数6〜14の
アリールチオ基(例、フェニルチオ、ナフチルチオな
ど);スルホ基;シアノ基;アジド基;ニトロ基;ニト
ロソ基;ハロゲン原子(例、フッ素、塩素、臭素、ヨウ
素)などが挙げられる。The above "alkyl group having 1 to 10 carbon atoms",
"C2-C10 alkenyl group" and "C2-C2
10 alkynyl groups "are 1 to 3 at substitutable positions.
May have one substituent. Examples of such a substituent include a cycloalkyl group having 3 to 10 carbon atoms; an aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, imidazo [1,2-a] pyridyl, imidazo [1 , 2-a] pyrimidinyl, imidazo [1,2-b] pyridazinyl, etc.); non-aromatic heterocyclic groups (eg, tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl, etc.);
An amino group which may be mono- or di-substituted by an alkyl group having 1 to 4 carbon atoms or an acyl group having 2 to 8 carbon atoms (eg, alkanoyl group, alkoxycarbonyl group, etc.);
An alkylsulfonylamino group having 1 to 8 carbon atoms; an amidino group; an acyl group having 2 to 8 carbon atoms (eg, an alkanoyl group, an alkoxycarbonyl group, etc.); an alkylsulfonyl group having 1 to 8 carbon atoms; Carbamoyl group which may be mono- or di-substituted by an alkyl group; carbon number 1 to
A sulfamoyl group which may be mono- or di-substituted with an alkyl group of 4; a carboxyl group; a hydroxy group; 1
To alkoxy groups having 1 to 6 carbon atoms which may be substituted with 3 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.); 1 to 3 halogen atoms (eg, fluorine, chlorine,
2 to 2 carbon atoms which may be substituted with bromine, iodine, etc.)
An alkenyloxy group having 5 carbon atoms; a cycloalkyloxy group having 3 to 7 carbon atoms; an aralkyloxy group having 7 to 13 carbon atoms; an aryloxy group having 6 to 14 carbon atoms (eg, phenyloxy, naphthyloxy, etc.); An alkylthio group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.);
Aralkylthio group having 7 to 13 carbon atoms; arylthio group having 6 to 14 carbon atoms (eg, phenylthio, naphthylthio, etc.); sulfo group; cyano group; azido group; nitro group; nitroso group; halogen atom (eg, fluorine, chlorine , Bromine, iodine) and the like.
【0010】「置換されていてもよい炭素数3〜10の
シクロアルキル基」における「炭素数3〜10のシクロ
アルキル基」としては、例えばシクロプロピル、シクロ
ブチル、シクロペンチル、シクロヘキシル、シクロヘプ
チル、シクロオクチル、ビシクロ[2.2.1]ヘプチ
ル、ビシクロ[2.2.2]オクチル、ビシクロ[3.
2.1]オクチル、ビシクロ[3.2.2]ノニル、ビ
シクロ[3.3.1]ノニル、ビシクロ[4.2.1]
ノニル、ビシクロ[4.3.1]デシルなどが挙げられ
る。「置換されていてもよい炭素数3〜10のシクロア
ルケニル基」における「炭素数3〜10のシクロアルケ
ニル基」としては、例えば2−シクロペンテン−1−イ
ル、3−シクロペンテン−1−イル、2−シクロヘキセ
ン−1−イル、3−シクロヘキセン−1−イルなどが挙
げられる。「置換されていてもよい炭素数4〜10のシ
クロアルカジエニル基」における「炭素数4〜10のシ
クロアルカジエニル基」としては、例えば2,4−シク
ロペンタジエン−1−イル、2,4−シクロヘキサジエ
ン−1−イル、2,5−シクロヘキサジエン−1−イル
などが挙げられる。「置換されていてもよい炭素数6〜
14のアリール基」における「炭素数6〜14のアリー
ル基」としては、例えばフェニル、ナフチル、アントリ
ル、フェナントリル、アセナフチレニル、ビフェニリル
などが挙げられる。なかでもフェニル、1−ナフチル、
2−ナフチルなどが好ましい。「置換されていてもよい
炭素数7〜13のアラルキル基」における「炭素数7〜
13のアラルキル基」としては、例えばベンジル、フェ
ネチル、ナフチルメチルなどが挙げられる。「置換され
ていてもよい炭素数8〜13のアリールアルケニル基」
における「炭素数8〜13のアリールアルケニル基」と
しては、例えばスチリルなどが挙げられる。The "cycloalkyl group having 3 to 10 carbon atoms" in the "optionally substituted cycloalkyl group having 3 to 10 carbon atoms" is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. , Bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.
2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1]
Nonyl, bicyclo [4.3.1] decyl and the like can be mentioned. Examples of the "cycloalkenyl group having 3 to 10 carbon atoms" in the "optionally substituted cycloalkenyl group having 3 to 10 carbon atoms" include, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2 -Cyclohexen-1-yl, 3-cyclohexen-1-yl and the like can be mentioned. Examples of the "cycloalkadienyl group having 4 to 10 carbon atoms" in the "optionally substituted cycloalkadienyl group having 4 to 10 carbon atoms" include, for example, 2,4-cyclopentadien-1-yl, 2, 4-cyclohexadiene-1-yl, 2,5-cyclohexadiene-1-yl and the like can be mentioned. "6 to 6 carbon atoms which may be substituted
Examples of the “aryl group having 6 to 14 carbon atoms” in the “14 aryl group” include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Among them, phenyl, 1-naphthyl,
2-naphthyl and the like are preferable. "C7-C7" in "aralkyl group which may be substituted and has a carbon number of 7-13"
Examples of the “13 aralkyl group” include benzyl, phenethyl, naphthylmethyl and the like. "Arylalkenyl group having 8 to 13 carbon atoms which may be substituted"
Examples of the "arylalkenyl group having 8 to 13 carbon atoms" in include styryl and the like.
【0011】「置換されていてもよい非芳香族複素環
基」における「非芳香族複素環基」としては、例えば環
構成原子として炭素原子以外に酸素原子、硫黄原子およ
び窒素原子から選ばれるヘテロ原子を1ないし4個含有
する5〜7員の単環式非芳香族複素環基または縮合非芳
香族複素環基が挙げられる。該非芳香族縮合複素環基と
しては、例えばこれら5〜7員の単環式非芳香族複素環
基と、1ないし2個の窒素原子を含む6員環、ベンゼン
環または1個の硫黄原子を含む5員環とが縮合した基等
が挙げられる。非芳香族複素環基の好適な例としては、
テトラヒドロフリル、1−ピロリジニル、ピペリジノ、
モルホリノ、チオモルホリノ、1−ピペラジニル、ヘキ
サメチレンイミン−1−イル、オキサゾリジン−3−イ
ル、チアゾリジン−3−イル、イミダゾリジン−3−イ
ル、2−オキソイミダゾリジン−1−イル、2,4−ジ
オキソイミダゾリジン−3−イル、2,4−ジオキソオ
キサゾリジン−3−イル、2,4−ジオキソチアゾリジ
ン−3−イル、1,3−ジオキソイソインドール−2−
イル、5-オキソオキサジアゾール−3−イル、5-オキ
ソチアジアゾール−3−イルなどが挙げられる。The "non-aromatic heterocyclic group" in the "optionally substituted non-aromatic heterocyclic group" is, for example, a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to carbon atoms as ring-constituting atoms. A 5- to 7-membered monocyclic non-aromatic heterocyclic group or condensed non-aromatic heterocyclic group containing 1 to 4 atoms can be mentioned. Examples of the non-aromatic condensed heterocyclic group include a 5-membered to 7-membered monocyclic non-aromatic heterocyclic group, a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or 1 sulfur atom. And a group condensed with a 5-membered ring. Suitable examples of the non-aromatic heterocyclic group include:
Tetrahydrofuryl, 1-pyrrolidinyl, piperidino,
Morpholino, thiomorpholino, 1-piperazinyl, hexamethyleneimine-1-yl, oxazolidin-3-yl, thiazolidin-3-yl, imidazolidin-3-yl, 2-oxoimidazolidin-1-yl, 2,4- Dioxoimidazolidin-3-yl, 2,4-dioxooxazolidin-3-yl, 2,4-dioxothiazolidin-3-yl, 1,3-dioxoisoindole-2-
And 5-oxooxadiazol-3-yl, 5-oxothiadiazol-3-yl and the like.
【0012】「置換されていてもよい芳香族複素環基」
における「芳香族複素環基」としては、例えば環構成原
子として炭素原子以外に酸素原子、硫黄原子および窒素
原子から選ばれるヘテロ原子を1ないし4個含有する5
〜7員の単環式芳香族複素環基または縮合芳香族複素環
基が挙げられる。該縮合芳香族複素環基としては、例え
ばこれら5〜7員の単環式芳香族複素環基と、1ないし
2個の窒素原子を含む6員環、ベンゼン環または1個の
硫黄原子を含む5員環とが縮合した基等が挙げられる。
芳香族複素環基の好適な例としては、2−フリル、3−
フリル、2−チエニル、3−チエニル、2−ピリジル、
3−ピリジル、4−ピリジル、2−ピリミジニル、4−
ピリミジニル、5−ピリミジニル、6−ピリミジニル、
3−ピリダジニル、4−ピリダジニル、2−ピラジニ
ル、1−ピロリル、2−ピロリル、3−ピロリル、1−
イミダゾリル、2−イミダゾリル、4−イミダゾリル、
5−イミダゾリル、1−ピラゾリル、3−ピラゾリル、
4−ピラゾリル、イソオキサゾリル、イソチアゾリル、
2−チアゾリル、4−チアゾリル、5−チアゾリル、2
−オキサゾリル、4−オキサゾリル、5−オキサゾリ
ル、1,2,4−オキサジアゾール−5−イル、1,3,4
−オキサジアゾール−2−イル、1,3,4−チアジアゾ
ール−2−イル、1,2,4−トリアゾール−1−イル、
1,2,4−トリアゾール−3−イル、1,2,3−トリア
ゾール−1−イル、1,2,3−トリアゾール−2−イ
ル、1,2,3−トリアゾール−4−イル、テトラゾール
−1−イル、テトラゾール−5−イル、2−キノリル、
3−キノリル、4−キノリル、2−キナゾリル、4−キ
ナゾリル、2−キノキサリル、2−ベンゾフリル、3−
ベンゾフリル、2−ベンゾチエニル、3−ベンゾチエニ
ル、2−ベンゾオキサゾリル、2−ベンゾチアゾリル、
ベンズイミダゾール−1−イル、ベンズイミダゾール−
2−イル、インドール−1−イル、インドール−3−イ
ル、1H−インダゾール−3−イル、1H−ピロロ
[2,3−b]ピラジン−2−イル、1H−ピロロ[2,
3−b]ピリジン−6−イル、1H−イミダゾ[4,5
−b]ピリジン−2−イル、1H−イミダゾ[4,5−
c]ピリジン−2−イル、1H−イミダゾ[4,5−
b]ピラジン−2−イル、イミダゾ[1,2−a]ピリ
ジル、イミダゾ[1,2−a]ピリミジニル、イミダゾ
[1,2−b]ピリダジニルなどが挙げられる。“Aromatic heterocyclic group which may be substituted”
The "aromatic heterocyclic group" in includes, for example, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atoms as ring members 5
To 7-membered monocyclic aromatic heterocyclic groups or condensed aromatic heterocyclic groups. The fused aromatic heterocyclic group includes, for example, a 5- to 7-membered monocyclic aromatic heterocyclic group, a 6-membered ring containing 1 to 2 nitrogen atoms, a benzene ring or 1 sulfur atom. Examples thereof include a group condensed with a 5-membered ring.
Preferred examples of the aromatic heterocyclic group include 2-furyl and 3-
Furyl, 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-
Pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl,
3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-
Imidazolyl, 2-imidazolyl, 4-imidazolyl,
5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl,
4-pyrazolyl, isoxazolyl, isothiazolyl,
2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2
-Oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl, 1,3,4
-Oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-triazol-1-yl,
1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, tetrazole- 1-yl, tetrazol-5-yl, 2-quinolyl,
3-quinolyl, 4-quinolyl, 2-quinazolyl, 4-quinazolyl, 2-quinoxalyl, 2-benzofuryl, 3-
Benzofuryl, 2-benzothienyl, 3-benzothienyl, 2-benzoxazolyl, 2-benzothiazolyl,
Benzimidazol-1-yl, benzimidazole-
2-yl, indol-1-yl, indol-3-yl, 1H-indazol-3-yl, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,
3-b] Pyridin-6-yl, 1H-imidazo [4,5]
-B] Pyridin-2-yl, 1H-imidazo [4,5-
c] Pyridin-2-yl, 1H-imidazo [4,5-
b] pyrazin-2-yl, imidazo [1,2-a] pyridyl, imidazo [1,2-a] pyrimidinyl, imidazo [1,2-b] pyridazinyl and the like.
【0013】前記「置換されていてもよい炭素数3〜1
0のシクロアルキル基」、「置換されていてもよい炭素
数3〜10のシクロアルケニル基」、「置換されていて
もよい炭素数4〜10のシクロアルカジエニル基」、
「置換されていてもよい炭素数6〜14のアリール
基」、「置換されていてもよい炭素数7〜13のアラル
キル基」、「置換されていてもよい炭素数8〜13のア
リールアルケニル基」、「置換されていてもよい非芳香
族複素環基」および「置換されていてもよい芳香族複素
環基」における置換基としては、例えば1〜3個のハロ
ゲン原子(例、フッ素、塩素、臭素、ヨウ素など)で置
換されていてもよい炭素数1〜6のアルキル基;1〜3
個のハロゲン原子(例、フッ素、塩素、臭素、ヨウ素な
ど)で置換されていてもよい炭素数2〜6のアルケニル
基;炭素数3〜10のシクロアルキル基;炭素数6〜1
4のアリール基(例、フェニル、ナフチルなど);芳香
族複素環基(例、チエニル、フリル、ピリジル、オキサ
ゾリル、チアゾリル、イミダゾ[1,2−a])ピリジ
ル、イミダゾ[1,2−a]ピリミジニル、イミダゾ
[1,2−b]ピリダジニルなど);非芳香族複素環基
(例、テトラヒドロフリル、モルホリノ、チオモルホリ
ノ、ピペリジノ、ピロリジニル、ピペラジニルなど);
炭素数7〜13のアラルキル基;炭素数1〜4のアルキ
ル基あるいは炭素数1〜15(好ましくは炭素数2〜
8)のアシル基(例、アルカノイル基など)でモノある
いはジ置換されていてもよいアミノ基(例、アミノ、モ
ノ−またはジ−C 2-10アルカノイルアミノ、C1-10アル
コキシ−カルボニルアミノ、カルバモイルアミノ、モノ
−またはジ−C1-10アルキル−カルバモイルアミノ、C
6-14アリール−カルボニルアミノ、C3-10シクロアルキ
ル−カルボニルアミノ、C7-13アラルキルオキシ−カル
ボニルアミノ、モノ−またはジ−C1-10アルキルスルホ
ニルアミノ、C6-14アリールスルホニルアミノ、C1-6
アルコキシ−カルバモイルアミノなど);アミジノ基;
炭素数2〜8のアシル基(例、アルカノイル基など);
炭素数1〜4のアルキル基でモノあるいはジ置換されて
いてもよいカルバモイル基;炭素数1〜4のアルキル基
でモノあるいはジ置換されていてもよいスルファモイル
基;カルボキシル基;炭素数2〜8のアルコキシカルボ
ニル基;ヒドロキシ基;1〜3個のハロゲン原子(例、
フッ素、塩素、臭素、ヨウ素など)で置換されていても
よい炭素数1〜6のアルコキシ基;1〜3個のハロゲン
原子(例、フッ素、塩素、臭素、ヨウ素など)で置換さ
れていてもよい炭素数2〜5のアルケニルオキシ基;炭
素数3〜7のシクロアルキルオキシ基;炭素数7〜13
のアラルキルオキシ基;炭素数6〜14のアリールオキ
シ基(例、フェニルオキシ、ナフチルオキシなど);チ
オール基;1〜3個のハロゲン原子(例、フッ素、塩
素、臭素、ヨウ素など)で置換されていてもよい炭素数
1〜6のアルキルチオ基;炭素数7〜13のアラルキル
チオ基;炭素数6〜14のアリールチオ基(例、フェニ
ルチオ、ナフチルチオなど);スルホ基;シアノ基;ア
ジド基;ニトロ基;ニトロソ基;ハロゲン原子(例、フ
ッ素、塩素、臭素、ヨウ素)などが挙げられる。置換基
の数は、例えば1〜3個である。The above-mentioned "C3 to C1 which may be substituted"
0 cycloalkyl group "," optionally substituted carbon "
Number 3-10 cycloalkenyl group "," substituted
A cycloalkadienyl group having 4 to 10 carbon atoms,
“Aryl having 6 to 14 carbon atoms which may be substituted
Group "," aralkyl which may be substituted and has 7 to 13 carbon atoms
Kill group "," optionally substituted C8-C13
Lille alkenyl group "," non-aromatic optionally substituted "
Group heterocyclic group ”and“ optionally substituted aromatic heterocycle ”
Examples of the substituent in the “ring group” include 1 to 3 halo.
Place at a gen atom (eg, fluorine, chlorine, bromine, iodine, etc.)
1-3 optionally substituted alkyl groups having 1 to 6 carbon atoms;
Individual halogen atoms (eg fluorine, chlorine, bromine, iodine
C2-6 alkenyl optionally substituted with
Group: C3-C10 cycloalkyl group; C6-C1
4 aryl groups (eg, phenyl, naphthyl, etc.); aromatic
Group heterocyclic groups (eg thienyl, furyl, pyridyl, oxa
Zolyl, thiazolyl, imidazo [1,2-a]) pyridy
Le, imidazo [1,2-a] pyrimidinyl, imidazo
[1,2-b] pyridazinyl etc.); non-aromatic heterocyclic group
(Eg, tetrahydrofuryl, morpholino, thiomorpholin
No, piperidino, pyrrolidinyl, piperazinyl, etc.);
Aralkyl group having 7 to 13 carbon atoms; Alky group having 1 to 4 carbon atoms
Group or 1 to 15 carbon atoms (preferably 2 to 2 carbon atoms)
8) Acyl group (eg, alkanoyl group, etc.) is mono
Or an optionally disubstituted amino group (eg, amino,
No or di-C 2-10Alkanoylamino, C1-10Al
Coxy-carbonylamino, carbamoylamino, mono
-Or di-C1-10Alkyl-carbamoylamino, C
6-14Aryl-carbonylamino, C3-10Cycloalk
L-carbonylamino, C7-13Aralkyl Oxy-Cal
Bonylamino, mono- or di-C1-10Alkyl sulfo
Nylamino, C6-14Arylsulfonylamino, C1-6
Alkoxy-carbamoylamino etc.); amidino group;
An acyl group having 2 to 8 carbon atoms (eg, alkanoyl group, etc.);
Mono- or di-substituted with an alkyl group having 1 to 4 carbon atoms
Carbamoyl group which may be present; alkyl group having 1 to 4 carbon atoms
Sulfamoyl optionally mono- or di-substituted with
Group; carboxyl group; alkoxycarbo having 2 to 8 carbon atoms
Nyl group; Hydroxy group; 1-3 halogen atoms (eg,
Even if it is substituted with fluorine, chlorine, bromine, iodine, etc.)
Good alkoxy group having 1 to 6 carbon atoms; 1 to 3 halogens
Substituted with atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
Optionally substituted alkenyloxy group having 2 to 5 carbon atoms; charcoal
Cycloalkyloxy group having a prime number of 3 to 7; carbon number of 7 to 13
Aralkyloxy group; aryloxy having 6 to 14 carbon atoms
Si group (eg, phenyloxy, naphthyloxy, etc.);
All group; 1-3 halogen atoms (eg, fluorine, salt
Number of carbon atoms that may be substituted with hydrogen, bromine, iodine, etc.)
1-6 alkylthio groups; aralkyl having 7-13 carbon atoms
Thio group; arylthio group having 6 to 14 carbon atoms (eg, phenyl group)
Ruthio, naphthylthio, etc.); sulfo group; cyano group;
Zido group; nitro group; nitroso group; halogen atom (eg, fluorine
Fluorine, chlorine, bromine, iodine) and the like. Substituent
Is 1 to 3, for example.
【0014】「アシル基」としては、例えば式: −C
OR4,−CO−OR4,−SO2R4,−SOR4,−P
O3R4R5,−CO−NR4aR5a,−CS−NR4aR5a
[式中、R4およびR5は、同一または異なって、水素
原子、置換されていてもよい炭化水素基または置換され
ていてもよい複素環基を示す。R4aおよびR5aは、同一
または異なって、水素原子、置換されていてもよい炭化
水素基または置換されていてもよい複素環基を示すか、
またはR4aおよびR5aが、隣接する窒素原子とともに、
置換されていてもよい含窒素複素環を形成する]で表さ
れる基などが挙げられる。R4、R5、R4aまたはR5aで
示される「置換されていてもよい炭化水素基」として
は、Aで示される「置換されていてもよい複素環基」に
おける置換基として例示した「置換されていてもよい炭
素数1〜10のアルキル基」、「置換されていてもよい
炭素数2〜10のアルケニル基」、「置換されていても
よい炭素数2〜10のアルキニル基」、「置換されてい
てもよい炭素数3〜10のシクロアルキル基」、「置換
されていてもよい炭素数3〜10のシクロアルケニル
基」、「置換されていてもよい炭素数4〜10のシクロ
アルカジエニル基」、「置換されていてもよい炭素数6
〜14のアリール基」、「置換されていてもよい炭素数
7〜13のアラルキル基」、「置換されていてもよい炭
素数8〜13のアリールアルケニル基」などが挙げられ
る。Examples of the "acyl group" include those represented by the formula: -C
OR 4 , -CO-OR 4 , -SO 2 R 4 , -SOR 4 , -P
O 3 R 4 R 5 , -CO-NR 4a R 5a , -CS-NR 4a R 5a
[In the formula, R 4 and R 5 are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. R 4a and R 5a are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
Or R 4a and R 5a , together with the adjacent nitrogen atom,
Forming an optionally substituted nitrogen-containing heterocycle] and the like. The "optionally substituted hydrocarbon group" represented by R 4 , R 5 , R 4a or R 5a is exemplified as the substituent in the "optionally substituted heterocyclic group" represented by A. An optionally substituted alkyl group having 1 to 10 carbon atoms, an "optionally substituted alkenyl group having 2 to 10 carbon atoms", an "optionally substituted alkynyl group having 2 to 10 carbon atoms", "A cycloalkyl group having 3 to 10 carbon atoms which may be substituted", "a cycloalkenyl group having 3 to 10 carbon atoms which may be substituted", "a cycloalkyl group having 4 to 10 carbon atoms which may be substituted""Alkadienylgroup","optionally substituted carbon number 6"
To 14 aryl groups "," optionally substituted C7 to C13 aralkyl groups "," optionally substituted C8 to C13 arylalkenyl groups "and the like.
【0015】R4、R5、R4aまたはR5aで示される「置
換されていてもよい複素環基」としては、Aで示される
「置換されていてもよい複素環基」における置換基とし
て例示した「置換されていてもよい非芳香族複素環基」
および「置換されていてもよい芳香族複素環基」が挙げ
られる。R4aおよびR5aが隣接する窒素原子とともに形
成する「置換されていてもよい含窒素複素環」における
「含窒素複素環」としては、例えば環構成原子として炭
素原子以外に少なくとも1個の窒素原子を含み、さらに
酸素原子、硫黄原子および窒素原子から選ばれるヘテロ
原子を1ないし2個含有していてもよい5〜7員の含窒
素複素環が挙げられる。該含窒素複素環の好適な例とし
ては、ピロリジン、イミダゾリジン、ピラゾリジン、ピ
ペリジン、ピペラジン、モルホリン、チオモルホリン、
ヘキサメチレンイミン、ピロール、ピラゾール、オキサ
ゾリジン、チアゾリジン、イミダゾール、1,2,3−トリ
アゾール、テトラゾール、インドールなどが挙げられ
る。該含窒素複素環は、置換可能な位置に1〜2個の置
換基を有していてもよい。このような置換基としては、
ヒドロキシ基、1〜3個のハロゲン原子(例、フッ素、
塩素、臭素、ヨウ素など)で置換されていてもよいC
1-6アルキル基、C7-1 3アラルキル基(例、ベンジル、
ジフェニルメチルなど)などが挙げられる。The "optionally substituted heterocyclic group" represented by R 4 , R 5 , R 4a or R 5a is a substituent in the "optionally substituted heterocyclic group" represented by A. Examples of "optionally substituted non-aromatic heterocyclic group"
And “optionally substituted aromatic heterocyclic group”. Examples of the “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R 4a and R 5a together with the adjacent nitrogen atom include, for example, at least one nitrogen atom other than carbon atom as a ring-constituting atom. And a 5- to 7-membered nitrogen-containing heterocycle which may further contain 1 or 2 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom. Preferable examples of the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine,
Hexamethyleneimine, pyrrole, pyrazole, oxazolidine, thiazolidine, imidazole, 1,2,3-triazole, tetrazole, indole and the like can be mentioned. The nitrogen-containing heterocycle may have 1 to 2 substituents at substitutable positions. As such a substituent,
Hydroxy group, 1 to 3 halogen atoms (eg, fluorine,
C optionally substituted with chlorine, bromine, iodine, etc.)
1-6 alkyl group, C 7-1 3 aralkyl group (eg, benzyl,
Such as diphenylmethyl).
【0016】「アシル基」の好適な例としては、ホルミ
ル;カルボキシル;カルバモイル;C1-6アルキル−カ
ルボニル(例、アセチル、イソブタノイル、イソペンタ
ノイルなど);C1-6アルコキシ−カルボニル(例、メト
キシカルボニル、エトキシカルボニル、プロポキシカル
ボニル、tert−ブトキシカルボニルなど);C6-14アリ
ール−カルボニル(例、ベンゾイル、1−ナフトイル、2
−ナフトイルなど);C6-14アリールオキシ−カルボニ
ル(例、フェニルオキシカルボニル、ナフチルオキシカ
ルボニルなど);C7-13アラルキルオキシ−カルボニル
(例、ベンジルオキシカルボニル、フェネチルオキシカ
ルボニルなど);モノ−またはジ−(ハロゲン原子およ
びC1-6アルコキシ−カルボニルから選ばれる1ないし
3個の置換基を有していてもよいC1-6アルキル)−カ
ルバモイル(例、メチルカルバモイル、エチルカルバモ
イル、ジメチルカルバモイル、ジエチルカルバモイル、
エチルメチルカルバモイル、プロピルカルバモイル、ト
リフルオロエチルカルバモイルなど);C6-14アリール
−カルバモイル(例、フェニルカルバモイルなど);C
3-10シクロアルキル−カルバモイル(例、シクロプロピ
ルカルバモイルなど);C7-13アラルキル−カルバモイ
ル(例、ベンジルカルバモイルなど);C1-6アルキル
スルホニル(例、メチルスルホニルなど);C6-14アリ
ールスルホニル(例、フェニルスルホニルなど);ヒド
ロキシで置換されていてもよい含窒素複素環−カルボニ
ル(例、ピロリジニルカルボニル、ピペリジノカルボニ
ルなど);C1-6アルキルスルフィニル(例、メチルス
ルフィニルなど);C1-6アルコキシ−カルバモイル
(例、メトキシカルバモイル);アミノカルバモイル;ヒ
ドロキシカルバモイル;チオカルバモイルなどが挙げら
れる。Preferable examples of "acyl group" include formyl; carboxyl; carbamoyl; C 1-6 alkyl-carbonyl (eg, acetyl, isobutanoyl, isopentanoyl etc.); C 1-6 alkoxy-carbonyl (eg, Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.); C 6-14 aryl-carbonyl (eg, benzoyl, 1-naphthoyl, 2
-Naphthoyl, etc.); C 6-14 aryloxy-carbonyl (eg, phenyloxycarbonyl, naphthyloxycarbonyl, etc.); C 7-13 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.); mono- or di - (halogen atoms and C 1-6 alkoxy - 1 to 3 substituents substituted C 1-6 alkyl selected from carbonyl) - carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, Diethylcarbamoyl,
Ethylmethylcarbamoyl, propylcarbamoyl, trifluoroethylcarbamoyl, etc.); C 6-14 aryl-carbamoyl (eg, phenylcarbamoyl, etc.); C
3-10 cycloalkyl-carbamoyl (eg cyclopropylcarbamoyl); C 7-13 aralkyl-carbamoyl (eg benzylcarbamoyl); C 1-6 alkylsulfonyl (eg methylsulfonyl); C 6-14 aryl Sulfonyl (eg, phenylsulfonyl, etc.); Nitrogen-containing heterocycle optionally substituted with hydroxy-carbonyl (eg, pyrrolidinylcarbonyl, piperidinocarbonyl, etc.); C 1-6 alkylsulfinyl (eg, methylsulfinyl, etc.) ); C 1-6 alkoxy-carbamoyl
(Eg, methoxycarbamoyl); aminocarbamoyl; hydroxycarbamoyl; thiocarbamoyl and the like.
【0017】「置換されていてもよいアミノ基」として
は、例えば炭素数1〜10のアルキル基、炭素数2〜1
0のアルケニル基、炭素数3〜10のシクロアルキル
基、炭素数3〜10のシクロアルケニル基、炭素数6〜
14のアリール基およびアシル基から選ばれる1または
2個の置換基で置換されていてもよいアミノ基が挙げら
れる。ここで、「炭素数1〜10のアルキル基」、「炭
素数2〜10のアルケニル基」、「炭素数3〜10のシ
クロアルキル基」、「炭素数3〜10のシクロアルケニ
ル基」、「炭素数6〜14のアリール基」および「アシ
ル基」としては、Aで示される「置換されていてもよい
複素環基」における置換基において例示したものが挙げ
られる。置換されたアミノ基の好適な例としては、モノ
−またはジ−C1-10アルキルアミノ(例、メチルアミ
ノ、ジメチルアミノ、エチルアミノ、ジエチルアミノ、
プロピルアミノ、ジブチルアミノ);モノ−またはジ−
C2-10アルケニルアミノ(例、ジアリルアミノ);モノ
−またはジ−C3-10シクロアルキルアミノ(例、シクロ
ヘキシルアミノ);モノ−またはジ−C2-10アルカノイ
ルアミノ(例、アセチルアミノ、プロピオニルアミノ、
ブタノイルアミノ、イソブタノイルアミノ、イソペンタ
ノイルアミノ);C6-14アリール−カルボニルアミノ
(例、ベンゾイルアミノ);C6-14アリールアミノ
(例、フェニルアミノ);カルバモイルアミノ;モノ−
またはジ−C1-10アルキル−カルバモイルアミノ(例、
メチルカルバモイルアミノ、ジメチルカルバモイルアミ
ノ);C1-10アルコキシ−カルボニルアミノ(例、メト
キシカルボニルアミノ);C7-13アラルキルオキシ−カ
ルボニルアミノ(例、ベンジルオキシカルボニルアミ
ノ);C3-10シクロアルキル−カルボニルアミノ(例、
シクロペンチルカルボニルアミノ、シクロヘキシルカル
ボニルアミノ);モノ−またはジ−C1-10アルキルスル
ホニルアミノ(例、メチルスルホニルアミノ、ジメチル
スルホニルアミノ);C6-14アリールスルホニルアミノ
(例、フェニルスルホニルアミノ);C1-6アルコキシ
−カルバモイルアミノ(例、メトキシカルバモイルアミ
ノ)等が挙げられる。The "optionally substituted amino group" is, for example, an alkyl group having 1 to 10 carbon atoms or 2-1 to 2 carbon atoms.
0 alkenyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-
Examples thereof include an amino group which may be substituted with 1 or 2 substituents selected from 14 aryl groups and acyl groups. Here, "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms", "cycloalkyl group having 3 to 10 carbon atoms", "cycloalkenyl group having 3 to 10 carbon atoms", " Examples of the "aryl group having 6 to 14 carbon atoms" and the "acyl group" include those exemplified as the substituent of the "optionally substituted heterocyclic group" for A. Suitable examples of the substituted amino group include mono- or di-C 1-10 alkylamino (eg, methylamino, dimethylamino, ethylamino, diethylamino,
Propylamino, dibutylamino); mono- or di-
C 2-10 alkenylamino (eg, diallylamino); mono- or di-C 3-10 cycloalkylamino (eg, cyclohexylamino); mono- or di-C 2-10 alkanoylamino (eg, acetylamino, propionyl amino,
Butanoylamino, isobutanoylamino, isopentanoylamino); C 6-14 aryl-carbonylamino (eg, benzoylamino); C 6-14 arylamino (eg, phenylamino); carbamoylamino; mono-
Or di-C 1-10 alkyl-carbamoylamino (eg,
Methylcarbamoylamino, dimethylcarbamoylamino); C 1-10 alkoxy-carbonylamino (eg, methoxycarbonylamino); C 7-13 aralkyloxy-carbonylamino (eg, benzyloxycarbonylamino); C 3-10 cycloalkyl- Carbonylamino (eg,
Cyclopentylcarbonylamino, cyclohexylcarbonylamino); mono- or di-C 1-10 alkylsulfonylamino (eg, methylsulfonylamino, dimethylsulfonylamino); C 6-14 arylsulfonylamino (eg, phenylsulfonylamino); C 1 -6 alkoxy-carbamoylamino (eg, methoxycarbamoylamino) and the like.
【0018】「置換されていてもよいヒドロキシ基」と
しては、例えばそれぞれ置換されていてもよい「炭素数
1〜10のアルキル基」、「炭素数2〜10のアルケニ
ル基」、「炭素数2〜10のアルキニル基」、「炭素数
3〜10のシクロアルキル基」、「炭素数3〜10のシ
クロアルケニル基」、「炭素数6〜14のアリール基」
または「炭素数7〜13のアラルキル基」で置換されて
いてもよいヒドロキシ基が挙げられる。ここで、「炭素
数1〜10のアルキル基」、「炭素数2〜10のアルケ
ニル基」、「炭素数2〜10のアルキニル基」、「炭素
数3〜10のシクロアルキル基」、「炭素数3〜10の
シクロアルケニル基」、「炭素数6〜14のアリール
基」および「炭素数7〜13のアラルキル基」として
は、前記Aで示される「置換されていてもよい複素環
基」における置換基において例示したものが挙げられ
る。これら「炭素数1〜10のアルキル基」、「炭素数
2〜10のアルケニル基」、「炭素数2〜10のアルキ
ニル基」、「炭素数3〜10のシクロアルキル基」、
「炭素数3〜10のシクロアルケニル基」、「炭素数6
〜14のアリール基」および「炭素数7〜13のアラル
キル基」は、それぞれ置換可能な位置に1ないし3個の
置換基を有していてもよい。このような置換基として
は、例えばハロゲン原子(例、フッ素、塩素、臭素、ヨ
ウ素など)、炭素数1〜3のアルコキシ基、炭素数2〜
5のアルコキシカルボニル基、炭素数2〜5のアルカノ
イル基、シアノ基、カルバモイル基、ヒドロキシ基、炭
素数3〜10のシクロアルキル基、カルボキシル基、ア
ミノ基、炭素数2〜5のアルカノイルアミノ基等が挙げ
られる。The "optionally substituted hydroxy group" is, for example, an optionally substituted "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms" or "2 carbon atoms". -10 alkynyl group "," C3-10 cycloalkyl group "," C3-10 cycloalkenyl group "," C6-14 aryl group "
Alternatively, a hydroxy group that may be substituted with a "C7-C13 aralkyl group" is exemplified. Here, "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms", "alkynyl group having 2 to 10 carbon atoms", "cycloalkyl group having 3 to 10 carbon atoms", "carbon The “cycloalkenyl group having 3 to 10 carbon atoms”, the “aryl group having 6 to 14 carbon atoms” and the “aralkyl group having 7 to 13 carbon atoms” are “an optionally substituted heterocyclic group” represented by the above A. Those exemplified as the substituents in are mentioned. These "alkyl group having 1 to 10 carbon atoms", "alkenyl group having 2 to 10 carbon atoms", "alkynyl group having 2 to 10 carbon atoms", "cycloalkyl group having 3 to 10 carbon atoms",
"C3-C10 cycloalkenyl group", "C6
The "to 14 aryl group" and the "C7 to C13 aralkyl group" may each have 1 to 3 substituents at substitutable positions. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an alkoxy group having 1 to 3 carbon atoms, and 2 to 2 carbon atoms.
5 alkoxycarbonyl group, alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoyl group, hydroxy group, cycloalkyl group having 3 to 10 carbon atoms, carboxyl group, amino group, alkanoylamino group having 2 to 5 carbon atoms, etc. Is mentioned.
【0019】置換されたヒドロキシ基は、好ましくは、
ハロゲン原子(例、フッ素、塩素、臭素、ヨウ素な
ど)、炭素数1〜3のアルコキシ基、炭素数2〜5のア
ルコキシカルボニル基、炭素数2〜5のアルカノイル
基、シアノ基、カルバモイル基、ヒドロキシ基、カルボ
キシル基、アミノ基、炭素数2〜5のアルカノイルアミ
ノ基および炭素数3〜10のシクロアルキル基から選ば
れる1ないし3個の置換基をそれぞれ有していてもよ
い、「炭素数1〜10のアルコキシ基」、「炭素数2〜
10のアルケニルオキシ基」、「炭素数2〜10のアル
キニルオキシ基」、「炭素数3〜10のシクロアルキル
オキシ基」、「炭素数3〜10のシクロアルケニルオキ
シ基」、「炭素数6〜14のアリールオキシ基」、「炭
素数7〜13のアラルキルオキシ基」等である。ここ
で、「炭素数1〜10のアルコキシ基」としては、例え
ばメトキシ、エトキシ、プロポキシ、イソプロポキシ、
ブトキシ、イソブトキシ、sec.−ブトキシ、t.−ブトキ
シ、ペンチルオキシ、イソペンチルオキシ、ネオペンチ
ルオキシ、ヘキシルオキシ、ヘプチルオキシ、ノニルオ
キシなどが挙げられる。「炭素数2〜10のアルケニル
オキシ基」としては、例えばアリル(allyl)オキシ、
クロチルオキシ、2−ペンテニルオキシ、3−ヘキセニ
ルオキシなどが挙げられる。「炭素数2〜10のアルキ
ニルオキシ基」としては、例えばエチニルオキシ、プロ
ピニルオキシ、ペンチニルオキシなどが挙げられる。
「炭素数3〜10のシクロアルキルオキシ基」として
は、例えばシクロブトキシ、シクロペンチルオキシ、シ
クロヘキシルオキシなどが挙げられる。「炭素数3〜1
0のシクロアルケニルオキシ基」としては、例えば2−
シクロペンテニルオキシ、2−シクロヘキセニルオキシ
などが挙げられる。「炭素数6〜14のアリールオキシ
基」としては、例えばフェノキシ、ナフチルオキシ等が
挙げられる。「炭素数7〜13のアラルキルオキシ基」
としては、例えばベンジルオキシ、フェネチルオキシ、
ナフチルメチルオキシ等が挙げられる。The substituted hydroxy group is preferably
Halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), alkoxy group having 1 to 3 carbon atoms, alkoxycarbonyl group having 2 to 5 carbon atoms, alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoyl group, hydroxy A group, a carboxyl group, an amino group, an alkanoylamino group having 2 to 5 carbon atoms and a cycloalkyl group having 3 to 10 carbon atoms, each of which may have 1 to 3 substituents. -10 alkoxy group "," 2 to 2 carbon atoms
"10 alkenyloxy group", "C2-C10 alkynyloxy group", "C3-C10 cycloalkyloxy group", "C3-C10 cycloalkenyloxy group", "C6-C6" 14 aryloxy groups "," C7-C13 aralkyloxy groups "and the like. Here, examples of the “alkoxy group having 1 to 10 carbon atoms” include methoxy, ethoxy, propoxy, isopropoxy,
Examples include butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy and the like. Examples of the “alkenyloxy group having 2 to 10 carbon atoms” include allyloxy,
Examples include crotyloxy, 2-pentenyloxy, 3-hexenyloxy and the like. Examples of the "alkynyloxy group having 2 to 10 carbon atoms" include ethynyloxy, propynyloxy, pentynyloxy and the like.
Examples of the "cycloalkyloxy group having 3 to 10 carbon atoms" include cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. "C1-C3
“A cycloalkenyloxy group of 0” is, for example, 2-
Examples include cyclopentenyloxy and 2-cyclohexenyloxy. Examples of the "aryloxy group having 6 to 14 carbon atoms" include phenoxy, naphthyloxy and the like. "Aralkyloxy group having 7 to 13 carbon atoms"
As, for example, benzyloxy, phenethyloxy,
Naphthylmethyloxy and the like can be mentioned.
【0020】置換されたヒドロキシ基は、さらに好まし
くは、ハロゲン原子(例、フッ素、塩素、臭素、ヨウ素
など)、炭素数1〜3のアルコキシ基、炭素数2〜5の
アルコキシカルボニル基、炭素数2〜5のアルカノイル
基、シアノ基、カルバモイル基、ヒドロキシ基、カルボ
キシル基、アミノ基、炭素数2〜5のアルカノイルアミ
ノ基および炭素数3〜10のシクロアルキル基から選ば
れる1ないし3個の置換基をそれぞれ有していてもよ
い、「炭素数1〜10のアルコキシ基」、「炭素数3〜
10のシクロアルキルオキシ基」または「炭素数7〜1
3のアラルキルオキシ基」である。The substituted hydroxy group is more preferably a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, and a carbon number. 1 to 3 substituents selected from 2 to 5 alkanoyl group, cyano group, carbamoyl group, hydroxy group, carboxyl group, amino group, alkanoylamino group having 2 to 5 carbon atoms and cycloalkyl group having 3 to 10 carbon atoms "Alkoxy group having 1 to 10 carbon atoms" which may have a group, "C3 to 3 carbon atoms"
10 cycloalkyloxy groups "or" 7 to 1 carbon atoms
3 aralkyloxy groups ".
【0021】「置換されていてもよいチオール基」とし
ては、例えばそれぞれ置換されていてもよい「炭素数1
〜10のアルキル基」、「炭素数2〜10のアルケニル
基」、「炭素数2〜10のアルキニル基」、「炭素数3
〜10のシクロアルキル基」、「炭素数3〜10のシク
ロアルケニル基」、「炭素数6〜14のアリール基」ま
たは「炭素数7〜13のアラルキル基」で置換されてい
てもよいチオール基が挙げられる。ここで、「炭素数1
〜10のアルキル基」、「炭素数2〜10のアルケニル
基」、「炭素数2〜10のアルキニル基」、「炭素数3
〜10のシクロアルキル基」、「炭素数3〜10のシク
ロアルケニル基」、「炭素数6〜14のアリール基」お
よび「炭素数7〜13のアラルキル基」としては、前記
Aで示される「置換されていてもよい複素環基」におけ
る置換基において例示したものが挙げられる。これら
「炭素数1〜10のアルキル基」、「炭素数2〜10の
アルケニル基」、「炭素数2〜10のアルキニル基」、
「炭素数3〜10のシクロアルキル基」、「炭素数3〜
10のシクロアルケニル基」、「炭素数6〜14のアリ
ール基」および「炭素数7〜13のアラルキル基」は、
それぞれ置換可能な位置に1ないし3個の置換基を有し
ていてもよい。このような置換基としては、例えばハロ
ゲン原子(例、フッ素、塩素、臭素、ヨウ素など)、炭
素数1〜3のアルコキシ基、炭素数2〜5のアルコキシ
カルボニル基、炭素数2〜5のアルカノイル基、シアノ
基、カルバモイル基、ヒドロキシ基、炭素数3〜10の
シクロアルキル基、カルボキシル基、アミノ基、炭素数
2〜5のアルカノイルアミノ基等が挙げられる。The "optionally substituted thiol group" is, for example, optionally substituted "1 carbon atom".
-10 alkyl group "," C2-10 alkenyl group "," C2-10 alkynyl group "," C3 "
-10 cycloalkyl group "," C3-10 cycloalkenyl group "," C6-14 aryl group "or" C7-13 aralkyl group ", which may be substituted with a thiol group. Is mentioned. Here, "1 carbon number
-10 alkyl group "," C2-10 alkenyl group "," C2-10 alkynyl group "," C3 "
"Cycloalkyl group having 10 to 10", "cycloalkenyl group having 3 to 10 carbon atoms", "aryl group having 6 to 14 carbon atoms" and "aralkyl group having 7 to 13 carbon atoms" are represented by A above. What was illustrated in the substituent in "the heterocyclic group which may be substituted" is mentioned. These "C1-C10 alkyl group", "C2-C10 alkenyl group", "C2-C10 alkynyl group",
"C3-C10 cycloalkyl group", "C3-C3
"10 cycloalkenyl group", "aryl group having 6 to 14 carbon atoms" and "aralkyl group having 7 to 13 carbon atoms" include
Each may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an alkoxy group having 1 to 3 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, and an alkanoyl group having 2 to 5 carbon atoms. Examples thereof include groups, cyano groups, carbamoyl groups, hydroxy groups, cycloalkyl groups having 3 to 10 carbon atoms, carboxyl groups, amino groups, and alkanoylamino groups having 2 to 5 carbon atoms.
【0022】置換されたチオール基は、好ましくは、ハ
ロゲン原子(例、フッ素、塩素、臭素、ヨウ素など)、
炭素数1〜3のアルコキシ基、炭素数2〜5のアルコキ
シカルボニル基、炭素数2〜5のアルカノイル基、シア
ノ基、カルバモイル基、ヒドロキシ基、カルボキシル
基、アミノ基、炭素数2〜5のアルカノイルアミノ基お
よび炭素数3〜10のシクロアルキル基から選ばれる1
ないし3個の置換基をそれぞれ有していてもよい、「炭
素数1〜10のアルキルチオ基」、「炭素数2〜10の
アルケニルチオ基」、「炭素数2〜10のアルキニルチ
オ基」、「炭素数3〜10のシクロアルキルチオ基」、
「炭素数3〜10のシクロアルケニルチオ基」、「炭素
数6〜14のアリールチオ基」、「炭素数7〜13のア
ラルキルチオ基」等が挙げられる。「炭素数1〜10の
アルキルチオ基」としては、例えばメチルチオ、エチル
チオ、プロピルチオ、イソプロピルチオ、ブチルチオ、
イソブチルチオ、sec.−ブチルチオ、t.−ブチルチオ、
ペンチルチオ、イソペンチルチオ、ネオペンチルチオ、
ヘキシルチオ、ヘプチルチオ、ノニルチオ等が挙げられ
る。「炭素数2〜10のアルケニルチオ基」としては、
例えばアリル(allyl)チオ、クロチルチオ、2−ペン
テニルチオ、3−ヘキセニルチオなどが挙げられる。
「炭素数2〜10のアルキニルチオ基」としては、例え
ばエチニルチオ、プロピニルチオ、ペンチニルチオなど
が挙げられる。「炭素数3〜10のシクロアルキルチオ
基」としては、例えばシクロブチルチオ、シクロペンチ
ルチオ、シクロヘキシルチオ等が挙げられる。「炭素数
3〜10のシクロアルケニルチオ基」としては、例えば
2−シクロペンテニルチオ、2−シクロヘキセニルチオ
などが挙げられる。「炭素数6〜14のアリールチオ
基」としては、例えばフェニルチオ、ナフチルチオ等が
挙げられる。「炭素数7〜13のアラルキルチオ基」と
しては、例えばベンジルチオ、フェネチルチオ、ナフチ
ルメチルチオ等が挙げられる。The substituted thiol group is preferably a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.),
Alkoxy group having 1 to 3 carbon atoms, alkoxycarbonyl group having 2 to 5 carbon atoms, alkanoyl group having 2 to 5 carbon atoms, cyano group, carbamoyl group, hydroxy group, carboxyl group, amino group, alkanoyl group having 2 to 5 carbon atoms 1 selected from an amino group and a cycloalkyl group having 3 to 10 carbon atoms
To, "alkylthio group having 1 to 10 carbon atoms", "alkenylthio group having 2 to 10 carbon atoms", "alkynylthio group having 2 to 10 carbon atoms", each of which may have 3 to 3 substituents. "A cycloalkylthio group having 3 to 10 carbon atoms",
Examples thereof include a “cycloalkenylthio group having 3 to 10 carbon atoms”, a “arylthio group having 6 to 14 carbon atoms”, and an “aralkylthio group having 7 to 13 carbon atoms”. Examples of the “alkylthio group having 1 to 10 carbon atoms” include methylthio, ethylthio, propylthio, isopropylthio, butylthio,
Isobutylthio, sec.-butylthio, t.-butylthio,
Pentylthio, isopentylthio, neopentylthio,
Hexylthio, heptylthio, nonylthio and the like can be mentioned. As the "alkenylthio group having 2 to 10 carbon atoms",
Examples include allylthio, crotylthio, 2-pentenylthio, 3-hexenylthio and the like.
Examples of the "alkynylthio group having 2 to 10 carbon atoms" include ethynylthio, propynylthio, pentynylthio and the like. Examples of the "cycloalkylthio group having 3 to 10 carbon atoms" include cyclobutylthio, cyclopentylthio, cyclohexylthio and the like. Examples of the "cycloalkenylthio group having 3 to 10 carbon atoms" include 2-cyclopentenylthio, 2-cyclohexenylthio and the like. Examples of the “arylthio group having 6 to 14 carbon atoms” include phenylthio, naphthylthio and the like. Examples of the "aralkylthio group having 7 to 13 carbon atoms" include benzylthio, phenethylthio, naphthylmethylthio and the like.
【0023】Aで示される「置換されていてもよい複素
環基」は、式The "optionally substituted heterocyclic group" represented by A has the formula
【化7】
[式中、Aa環は置換されていてもよい5−10員芳香
環を、R1aは置換されていてもよい炭化水素基または
置換されていてもよい複素環基を、Lは2価の炭化水素
基を示す]で示される基でないことが好ましい。[Chemical 7] [In the formula, Aa ring is an optionally substituted 5-10 membered aromatic ring, R 1a is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and L is a divalent group. A hydrocarbon group] is preferred.
【0024】Aで示される「置換されていてもよい炭化
水素基」における「炭化水素基」としては、例えば前記
Aで示される「置換されていてもよい複素環基」におけ
る置換基において例示した「炭素数1〜10のアルキル
基」、「炭素数2〜10のアルケニル基」、「炭素数2
〜10のアルキニル基」、「炭素数3〜10のシクロア
ルキル基」、「炭素数3〜10のシクロアルケニル
基」、「炭素数4〜10のシクロアルカジエニル基」、
「炭素数6〜14のアリール基」、「炭素数7〜13の
アラルキル基」、「炭素数8〜13のアリールアルケニ
ル基」などが挙げられる。該「炭化水素基」は、置換可
能な位置に1ないし3個の置換基を有していてもよい。
このような置換基としては、例えば前記Aで示される
「置換されていてもよい複素環基」における置換基とし
て例示した「ハロゲン原子」、「ニトロ基」、「シアノ
基」、「C1-3アルキレンジオキシ基」、「置換されて
いてもよい非芳香族複素環基」、「置換されていてもよ
い芳香族複素環基」、「アシル基」、「置換されていて
もよいアミノ基」、「置換されていてもよいヒドロキシ
基」、「置換されていてもよいチオール基」、「アミジ
ノ基」などが挙げられる。The "hydrocarbon group" in the "optionally substituted hydrocarbon group" represented by A is exemplified by the substituents in the "optionally substituted heterocyclic group" represented by A above. "Alkyl group having 1 to 10 carbon atoms", "Alkenyl group having 2 to 10 carbon atoms", "2 carbon atoms"
-10 alkynyl group "," C3-10 cycloalkyl group "," C3-10 cycloalkenyl group "," C4-10 cycloalkadienyl group ",
Examples thereof include "aryl group having 6 to 14 carbon atoms", "aralkyl group having 7 to 13 carbon atoms", "arylalkenyl group having 8 to 13 carbon atoms" and the like. The "hydrocarbon group" may have 1 to 3 substituents at substitutable positions.
Examples of such a substituent include, for example, the "halogen atom", "nitro group", "cyano group", "C 1- 3 alkylenedioxy group "," optionally substituted non-aromatic heterocyclic group "," optionally substituted aromatic heterocyclic group "," acyl group "," optionally substituted amino group " , "Optionally substituted hydroxy group", "optionally substituted thiol group", "amidino group" and the like.
【0025】Aは、好ましくは置換されていてもよい炭
化水素基であり、さらに好ましくは「置換されていても
よい芳香族複素環基」で置換されていてもよい炭化水素
基である。Aの好適な具体例としては、例えば
1)「1〜3個のハロゲン原子(好ましくはフッ素、塩
素、臭素など)で置換されていてもよい芳香族複素環基
(好ましくはイミダゾ[1,2−a]ピリジル、イミダ
ゾ[1,2−a]ピリミジニル、イミダゾ[1,2−
b]ピリダジニルなど)」で置換されていてもよい「炭
素数1〜6のアルキル基(好ましくはメチル、エチルな
ど)」;
2)炭素数1〜6のアルキル基(好ましくはメチル、エ
チルなど)、炭素数1〜6のアルコキシ基(好ましくは
メトキシ、エトキシなど)から選ばれる1ないし3個の
置換基で置換されていてもよい「炭素数7〜13のアラ
ルキル基(好ましくはベンジルなど)」などが挙げられ
る。A is preferably a hydrocarbon group which may be substituted, and more preferably a hydrocarbon group which may be substituted with "an aromatic heterocyclic group which may be substituted". Preferable specific examples of A include, for example, 1) "an aromatic heterocyclic group optionally substituted with 1 to 3 halogen atoms (preferably fluorine, chlorine, bromine, etc.) (preferably imidazo [1,2] -A] pyridyl, imidazo [1,2-a] pyrimidinyl, imidazo [1,2-
b] pyridazinyl etc.) ", which may be substituted with" alkyl group having 1 to 6 carbon atoms (preferably methyl, ethyl etc.) "; 2) alkyl group having 1 to 6 carbon atoms (preferably methyl, ethyl etc.) An "aralkyl group having 7 to 13 carbon atoms (preferably benzyl etc.) which may be substituted with 1 to 3 substituents selected from an alkoxy group having 1 to 6 carbon atoms (preferably methoxy, ethoxy etc.)" And so on.
【0026】nは0〜2の整数を示すが、好ましくは1
または2であり、さらに好ましくは2である。N represents an integer of 0 to 2, preferably 1
Or 2, and more preferably 2.
【0027】R1およびR2で示される「置換されてい
てもよい炭化水素基」としては、前記Aとして例示した
「置換されていてもよい炭化水素基」が挙げられる。R
1およびR2で示される「置換されていてもよい炭化水
素基」は、好ましくはハロゲン原子、シアノ基、置換さ
れていてもよいヒドロキシ基、アシル基および置換され
ていてもよいアミノ基から選ばれる置換基を有していて
もよい炭素数1〜6のアルキル基であり、さらに好まし
くはアミノ基で置換されていてもよい炭素数1〜6のア
ルキル基(例、メチル、エチル、2−アミノエチル、プ
ロピル、イソプロピル)である。とりわけ、メチル、エ
チル、プロピル、イソプロピルなどの炭素数1〜6のア
ルキル基が好ましい。R1およびR2が隣接する窒素原
子とともに形成する「置換されていてもよい含窒素複素
環」としては、前記R4aおよびR5aが隣接する窒素原子
とともに形成する「置換されていてもよい含窒素複素
環」と同様のものが挙げられる。「置換されていてもよ
い含窒素複素環」は、好ましくは、1〜3個のハロゲン
原子(例、フッ素、塩素、臭素、ヨウ素など)で置換さ
れていてもよいC1-6アルキル基で置換されていてもよ
い5ないし7員の含窒素複素環(例、ピロリジン、ピペ
リジン、モルホリン、チオモルホリン、ピペラジン、チ
アゾリジン)などである。なかでも、ピロリジン、ピペ
リジン、モルホリン、4−メチルピペラジン、チアゾリ
ジンなどが好ましい。R3で示される「ハロゲン原子」
としては、フッ素、塩素、臭素、ヨウ素などが挙げられ
る。なかでも、塩素が好ましい。R3で示される「置換
されていてもよい炭化水素基」としては、Aで示される
「置換されていてもよい複素環基」における置換基とし
て例示した「置換されていてもよい炭素数1〜10のア
ルキル基」、「置換されていてもよい炭素数2〜10の
アルケニル基」、「置換されていてもよい炭素数2〜1
0のアルキニル基」、「置換されていてもよい炭素数3
〜10のシクロアルキル基」、「置換されていてもよい
炭素数3〜10のシクロアルケニル基」、「置換されて
いてもよい炭素数4〜10のシクロアルカジエニル
基」、「置換されていてもよい炭素数6〜14のアリー
ル基」、「置換されていてもよい炭素数7〜13のアラ
ルキル基」、「置換されていてもよい炭素数8〜13の
アリールアルケニル基」などが挙げられる。R3で示さ
れる「置換されていてもよい炭化水素基」は、好ましく
は、1〜3個のハロゲン原子(例、フッ素、塩素、臭
素、ヨウ素など)で置換されていてもよい炭素数1〜1
0のアルキル基であり、さらに好ましくは1〜3個のハ
ロゲン原子(例、フッ素、塩素、臭素、ヨウ素など)で
置換されていてもよい炭素数1〜6のアルキル基であ
る。R3は、好ましくは、水素原子、ハロゲン原子、ま
たは1〜3個のハロゲン原子(例、フッ素、塩素、臭
素、ヨウ素など)で置換されていてもよい炭素数1〜6
のアルキル基(例、メチル、エチル、プロピル、イソプ
ロピルなど)であり、さらに好ましくは水素原子であ
る。Examples of the “optionally substituted hydrocarbon group” represented by R 1 and R 2 include the “optionally substituted hydrocarbon group” exemplified as A above. R
The “optionally substituted hydrocarbon group” represented by 1 and R 2 is preferably selected from a halogen atom, a cyano group, an optionally substituted hydroxy group, an acyl group and an optionally substituted amino group. Is an alkyl group having 1 to 6 carbon atoms which may have a substituent, more preferably an alkyl group having 1 to 6 carbon atoms which may be substituted with an amino group (eg, methyl, ethyl, 2- Aminoethyl, propyl, isopropyl). Especially, an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl and isopropyl is preferable. The “optionally substituted nitrogen-containing heterocycle” formed by R 1 and R 2 together with the adjacent nitrogen atom is “an optionally substituted nitrogen-containing heterocycle formed by R 4a and R 5a together with the adjacent nitrogen atom. The same thing as a "nitrogen heterocycle" is mentioned. The "optionally substituted nitrogen-containing heterocycle" is preferably a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). And an optionally substituted 5- to 7-membered nitrogen-containing heterocycle (eg, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, thiazolidine) and the like. Of these, pyrrolidine, piperidine, morpholine, 4-methylpiperazine, thiazolidine and the like are preferable. "Halogen atom" represented by R 3
Examples thereof include fluorine, chlorine, bromine and iodine. Of these, chlorine is preferred. The “optionally substituted hydrocarbon group” represented by R 3 is the “optionally substituted carbon number 1” exemplified as the substituent of the “optionally substituted heterocyclic group” represented by A. -10 alkyl group "," optionally substituted C2-C10 alkenyl group "," optionally substituted C2-1 "
0 alkynyl group "," optionally substituted 3 carbon atoms "
-10 cycloalkyl group "," optionally substituted C3-10 cycloalkenyl group "," optionally substituted C4-10 cycloalkadienyl group "," substituted " An optionally substituted aryl group having 6 to 14 carbon atoms, an "optionally substituted aralkyl group having 7 to 13 carbon atoms", an "optionally substituted arylalkenyl group having 8 to 13 carbon atoms" and the like. To be The "optionally substituted hydrocarbon group" for R 3 is preferably 1 to 3 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). ~ 1
An alkyl group having 0 to 6 carbon atoms, and more preferably an alkyl group having 1 to 6 carbon atoms, which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). R 3 is preferably a hydrogen atom, a halogen atom, or 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.).
Is an alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.), and more preferably a hydrogen atom.
【0028】化合物(I)の好適な例としては、以下の
化合物が挙げられる。
化合物(I−1)
Aが「1〜3個のハロゲン原子(好ましくはフッ素、塩
素、臭素など)で置換されていてもよい芳香族複素環基
(好ましくはイミダゾ[1,2−a]ピリジル、イミダ
ゾ[1,2−a]ピリミジニル、イミダゾ[1,2−
b]ピリダジニルなど)」で置換されていてもよい「炭
素数1〜6のアルキル基(好ましくはメチル、エチルな
ど)」;R1およびR2が、同一または異なって、炭素
数1〜6のアルキル基(例、メチル、エチル、プロピ
ル、イソプロピル);あるいはR1およびR2が、隣接
する窒素原子とともに、C1-6アルキル基で置換されて
いてもよい5ないし7員の含窒素複素環(例、ピロリジ
ン、ピペリジン、モルホリン、4−メチルピペラジン、
チアゾリジンなど)を形成し;R3が、水素原子、ハロ
ゲン原子、または1〜3個のハロゲン原子(例、フッ
素、塩素、臭素、ヨウ素など)で置換されていてもよい
炭素数1〜6のアルキル基(例、メチル、エチル、プロ
ピル、イソプロピルなど);である化合物。
化合物(I−2)
Aが炭素数1〜6のアルキル基(好ましくはメチル、エ
チルなど)、炭素数1〜6のアルコキシ基(好ましくは
メトキシ、エトキシなど)から選ばれる1ないし3個の
置換基で置換されていてもよい「炭素数7〜13のアラ
ルキル基(好ましくはベンジルなど)」;R1およびR
2が、同一または異なって、炭素数1〜6のアルキル基
(例、メチル、エチル、プロピル、イソプロピル);あ
るいはR1およびR2が、隣接する窒素原子とともに、
C1-6アルキル基で置換されていてもよい5ないし7員の
含窒素複素環(例、ピロリジン、ピペリジン、モルホリ
ン、4−メチルピペラジン、チアゾリジンなど)を形成
し;R3が、水素原子、ハロゲン原子、または1〜3個
のハロゲン原子(例、フッ素、塩素、臭素、ヨウ素な
ど)で置換されていてもよい炭素数1〜6のアルキル基
(例、メチル、エチル、プロピル、イソプロピルな
ど);である化合物。Preferred examples of the compound (I) include the following compounds. Compound (I-1) A is an aromatic heterocyclic group (preferably imidazo [1,2-a] pyridyl which may be substituted with 1 to 3 halogen atoms (preferably fluorine, chlorine, bromine, etc.). , Imidazo [1,2-a] pyrimidinyl, imidazo [1,2-
b] pyridazinyl etc.) ”, which may be substituted with“ alkyl group having 1 to 6 carbon atoms (preferably methyl, ethyl etc.) ”; R 1 and R 2 are the same or different and have 1 to 6 carbon atoms. An alkyl group (eg, methyl, ethyl, propyl, isopropyl); or a 5- to 7-membered nitrogen-containing heterocycle in which R 1 and R 2 together with the adjacent nitrogen atom may be substituted with a C 1-6 alkyl group. (Eg, pyrrolidine, piperidine, morpholine, 4-methylpiperazine,
Thiazolidine, etc.); R 3 is a hydrogen atom, a halogen atom, or 1 to 3 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) An alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.); Compound (I-2) A is 1 to 3 substituents selected from an alkyl group having 1 to 6 carbon atoms (preferably methyl, ethyl and the like) and an alkoxy group having 1 to 6 carbon atoms (preferably methoxy, ethoxy and the like). “Aralkyl group having 7 to 13 carbon atoms (preferably benzyl etc.)” which may be substituted with a group; R 1 and R
2 is the same or different, and is an alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, isopropyl); or R 1 and R 2 together with the adjacent nitrogen atom
Forming a 5- to 7-membered nitrogen-containing heterocyclic ring which may be substituted with a C 1-6 alkyl group (eg, pyrrolidine, piperidine, morpholine, 4-methylpiperazine, thiazolidine, etc.); R 3 is a hydrogen atom; A halogen atom or an alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (eg, methyl, ethyl, propyl, isopropyl, etc.) A compound which is
【0029】化合物(I)の塩としては、薬理学的に許
容される塩が好ましく、このような塩としては、例えば
無機塩基との塩、有機塩基との塩、無機酸との塩、有機
酸との塩、塩基性または酸性アミノ酸との塩などが挙げ
られる。無機塩基との塩の好適な例としては、ナトリウ
ム塩、カリウム塩などのアルカリ金属塩;カルシウム
塩、マグネシウム塩などのアルカリ土類金属塩;アルミ
ニウム塩;アンモニウム塩などが挙げられる。有機塩基
との塩の好適な例としては、トリメチルアミン、トリエ
チルアミン、ピリジン、ピコリン、エタノールアミン、
ジエタノールアミン、トリエタノールアミン、ジシクロ
ヘキシルアミン、N,N−ジベンジルエチレンジアミン
などとの塩が挙げられる。無機酸との塩の好適な例とし
ては、塩酸、臭化水素酸、硝酸、硫酸、リン酸などとの
塩が挙げられる。有機酸との塩の好適な例としては、ギ
酸、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒
石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メ
タンスルホン酸、ベンゼンスルホン酸、p−トルエンス
ルホン酸などとの塩が挙げられる。塩基性アミノ酸との
塩の好適な例としては、アルギニン、リジン、オルニチ
ンなどとの塩が挙げられる。酸性アミノ酸との塩の好適
な例としては、アスパラギン酸、グルタミン酸などとの
塩が挙げられる。上記した塩の中でもナトリウム塩、カ
リウム塩、塩酸塩などが好ましい。The salt of compound (I) is preferably a pharmacologically acceptable salt. Examples of such a salt include salts with inorganic bases, salts with organic bases, salts with inorganic acids, organic salts, and the like. Examples thereof include salts with acids and salts with basic or acidic amino acids. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt. Suitable examples of salts with organic bases include trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
Examples thereof include salts with diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like. Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. Among the above-mentioned salts, sodium salt, potassium salt, hydrochloride and the like are preferable.
【0030】化合物(I)のプロドラッグは、生体内に
おける生理条件下で酵素や胃酸等による反応により化合
物(I)に変換する化合物、すなわち酵素的に酸化、還
元、加水分解等を起こして化合物(I)に変化する化合
物、胃酸等により加水分解などを起こして化合物(I)
に変化する化合物である。化合物(I)のプロドラッグ
としては、化合物(I)のアミノ基がアシル化、アルキ
ル化、りん酸化された化合物(例、化合物(I)のアミ
ノ基がエイコサノイル化、アラニル化、ペンチルアミノ
カルボニル化、(5−メチル−2−オキソ−1,3−ジ
オキソレン−4−イル)メトキシカルボニル化、テトラ
ヒドロフラニル化、ピロリジルメチル化、ピバロイルオ
キシメチル化、tert−ブチル化された化合物な
ど);化合物(I)の水酸基がアシル化、アルキル化、
りん酸化、ほう酸化された化合物(例、化合物(I)の
水酸基がアセチル化、パルミトイル化、プロパノイル
化、ピバロイル化、サクシニル化、フマリル化、アラニ
ル化、ジメチルアミノメチルカルボニル化された化合物
など);化合物(I)のカルボキシル基がエステル化、
アミド化された化合物(例、化合物(I)のカルボキシ
ル基がエチルエステル化、フェニルエステル化、カルボ
キシメチルエステル化、ジメチルアミノメチルエステル
化、ピバロイルオキシメチルエステル化、エトキシカル
ボニルオキシエチルエステル化、フタリジルエステル
化、(5−メチル−2−オキソ−1,3−ジオキソレン
−4−イル)メチルエステル化、シクロヘキシルオキシ
カルボニルエチルエステル化、メチルアミド化された化
合物など)等が挙げられる。これらの化合物は自体公知
の方法によって化合物(I)から製造することができ
る。また、化合物(I)のプロドラッグは、広川書店1
990年刊「医薬品の開発」第7巻分子設計163頁か
ら198頁に記載されているような、生理的条件で化合
物(I)に変化するものであってもよい。また、化合物
(I)は、同位元素(例、3H, 14C, 35S,125Iなど)な
どで標識されていてもよい。さらに、化合物(I)は、
無水物であっても、水和物であってもよい。The prodrug of compound (I) is a compound which is converted into compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound which undergoes enzymatic oxidation, reduction or hydrolysis. Compound (I) which changes to (I) and undergoes hydrolysis by gastric acid etc.
It is a compound that changes to. As a prodrug of compound (I), a compound in which the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated compounds, etc.); The hydroxyl group of compound (I) is acylated, alkylated,
Phosphorylated or borated compounds (eg, compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); The carboxyl group of compound (I) is esterified,
Amidated compound (eg, carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds and the like) and the like. These compounds can be produced from compound (I) by a method known per se. In addition, the prodrug of compound (I) is available from Hirokawa Shoten 1
It may be a compound (I) which is changed under physiological conditions as described in “Development of Pharmaceuticals”, Vol. 7, Molecular Design, pages 163 to 198, 1990. The compound (I) may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 I, etc.) and the like. Further, the compound (I) is
It may be an anhydride or a hydrate.
【0031】本発明の医薬およびペプチダーゼ阻害剤
は、毒性が低く、哺乳動物(例、ヒト、マウス、ラッ
ト、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタ、サル等)
に対して、後述する各種疾患の予防または治療薬、また
は診断薬として用いることができる。また、本発明の医
薬およびペプチダーゼ阻害剤は、化合物(I)もしくは
その塩またはそのプロドラッグ(以下、単に化合物
(I)と略記することがある)そのものであってもよい
し、化合物(I)と薬理学的に許容し得る担体などとを
混合して得られる組成物であってもよい。ここにおい
て、薬理学的に許容される担体としては、製剤素材とし
て慣用の各種有機あるいは無機担体物質が用いられ、固
形製剤における賦形剤、滑沢剤、結合剤、崩壊剤;液状
製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、
緩衝剤、無痛化剤などとして配合される。また必要に応
じて、防腐剤、抗酸化剤、着色剤、甘味剤などの製剤添
加物を用いることもできる。賦形剤の好適な例として
は、乳糖、白糖、D−マンニトール、D−ソルビトー
ル、デンプン、α化デンプン、デキストリン、結晶セル
ロース、低置換度ヒドロキシプロピルセルロース、カル
ボキシメチルセルロースナトリウム、アラビアゴム、デ
キストリン、プルラン、軽質無水ケイ酸、合成ケイ酸ア
ルミニウム、メタケイ酸アルミン酸マグネシウムなどが
挙げられる。滑沢剤の好適な例としては、ステアリン酸
マグネシウム、ステアリン酸カルシウム、タルク、コロ
イドシリカなどが挙げられる。結合剤の好適な例として
は、α化デンプン、ショ糖、ゼラチン、アラビアゴム、
メチルセルロース、カルボキシメチルセルロース、カル
ボキシメチルセルロースナトリウム、結晶セルロース、
白糖、D−マンニトール、トレハロース、デキストリ
ン、プルラン、ヒドロキシプロピルセルロース、ヒドロ
キシプロピルメチルセルロース、ポリビニルピロリドン
などが挙げられる。崩壊剤の好適な例としては、乳糖、
白糖、デンプン、カルボキシメチルセルロース、カルボ
キシメチルセルロースカルシウム、クロスカルメロース
ナトリウム、カルボキシメチルスターチナトリウム、軽
質無水ケイ酸、低置換度ヒドロキシプロピルセルロース
などが挙げられる。The pharmaceutical agent and peptidase inhibitor of the present invention have low toxicity and are mammals (eg, human, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc.).
On the other hand, it can be used as a preventive or therapeutic agent for various diseases described below, or as a diagnostic agent. The pharmaceutical agent and peptidase inhibitor of the present invention may be compound (I) or a salt thereof or a prodrug thereof (hereinafter, may be simply referred to as compound (I)) itself, or compound (I). It may be a composition obtained by mixing the above with a pharmacologically acceptable carrier. Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances conventionally used as a formulation material are used, and an excipient, a lubricant, a binder, a disintegrant in a solid formulation; a solvent in a liquid formulation , Solubilizing agents, suspending agents, tonicity agents,
It is used as a buffer and soothing agent. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used. Suitable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, dextrin, pullulan. , Light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic,
Methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose,
Examples thereof include sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Suitable examples of the disintegrant include lactose,
Examples thereof include sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.
【0032】溶剤の好適な例としては、注射用水、生理
的食塩水、リンゲル液、アルコール、プロピレングリコ
ール、ポリエチレングリコール、ゴマ油、トウモロコシ
油、オリーブ油、綿実油などが挙げられる。溶解補助剤
の好適な例としては、ポリエチレングリコール、プロピ
レングリコール、D−マンニトール、トレハロース、安
息香酸ベンジル、エタノール、トリスアミノメタン、コ
レステロール、トリエタノールアミン、炭酸ナトリウ
ム、クエン酸ナトリウム、サリチル酸ナトリウム、酢酸
ナトリウムなどが挙げられる。懸濁化剤の好適な例とし
ては、ステアリルトリエタノールアミン、ラウリル硫酸
ナトリウム、ラウリルアミノプロピオン酸、レシチン、
塩化ベンザルコニウム、塩化ベンゼトニウム、モノステ
アリン酸グリセリンなどの界面活性剤;例えばポリビニ
ルアルコール、ポリビニルピロリドン、カルボキシメチ
ルセルロースナトリウム、メチルセルロース、ヒドロキ
シメチルセルロース、ヒドロキシエチルセルロース、ヒ
ドロキシプロピルセルロースなどの親水性高分子;ポリ
ソルベート類、ポリオキシエチレン硬化ヒマシ油などが
挙げられる。等張化剤の好適な例としては、塩化ナトリ
ウム、グリセリン、D−マンニトール、D−ソルビトー
ル、ブドウ糖などが挙げられる。緩衝剤の好適な例とし
ては、リン酸塩、酢酸塩、炭酸塩、クエン酸塩などの緩
衝液などが挙げられる。無痛化剤の好適な例としては、
ベンジルアルコールなどが挙げられる。防腐剤の好適な
例としては、パラオキシ安息香酸エステル類、クロロブ
タノール、ベンジルアルコール、フェネチルアルコー
ル、デヒドロ酢酸、ソルビン酸などが挙げられる。抗酸
化剤の好適な例としては、亜硫酸塩、アスコルビン酸塩
などが挙げられる。着色剤の好適な例としては、水溶性
食用タール色素(例、食用赤色2号および3号、食用黄
色4号および5号、食用青色1号および2号などの食用
色素)、水不溶性レーキ色素(例、前記水溶性食用ター
ル色素のアルミニウム塩など)、天然色素(例、β−カ
ロチン、クロロフィル、ベンガラなど)などが挙げられ
る。甘味剤の好適な例としては、サッカリンナトリウ
ム、グリチルリチン酸二カリウム、アスパルテーム、ス
テビアなどが挙げられる。Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. And so on. Suitable examples of the suspending agent, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin,
Surfactants such as benzalkonium chloride, benzethonium chloride and glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, Examples include polyoxyethylene hydrogenated castor oil and the like. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like. Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Preferable examples of soothing agents include
Examples thereof include benzyl alcohol. Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite, ascorbate and the like. Suitable examples of colorants include water-soluble food tar dyes (eg, food red Nos. 2 and 3, food yellows No. 4 and 5, food blue Nos. 1 and 2, etc.), water-insoluble lake dyes. (Eg, aluminum salts of the water-soluble food tar pigments), natural pigments (eg, β-carotene, chlorophyll, red iron oxide, etc.) and the like. Preferable examples of the sweetener include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia and the like.
【0033】本発明の医薬およびペプチダーゼ阻害剤の
剤形としては、例えば錠剤(舌下錠、口腔内崩壊錠を含
む)、カプセル剤(ソフトカプセル、マイクロカプセル
を含む)、散剤、顆粒剤、トローチ剤、シロップ剤等の
経口剤;および注射剤(例、皮下注射剤,静脈内注射
剤,筋肉内注射剤,腹腔内注射剤、点滴剤等)、外用剤
(例、経皮製剤,軟膏剤等)、坐剤(例、直腸坐剤,膣
坐剤等)、ペレット、経鼻剤、経肺剤(吸入剤)、点眼
剤等の非経口剤が挙げられる。これらの製剤は、速放性
製剤または徐放性製剤などの放出制御製剤(例、徐放性
マイクロカプセルなど)であってもよい。本発明の医薬
およびペプチダーゼ阻害剤は、製剤技術分野において慣
用の方法、例えば日本薬局方に記載の方法等により製造
することができる。以下に、経口剤および非経口剤の製
造法について詳述する。例えば、経口剤は、有効成分
に、賦形剤(例、乳糖,白糖,デンプン,D−マンニト
ールなど)、崩壊剤(例、カルボキシメチルセルロース
カルシウムなど)、結合剤(例、α化デンプン,アラビ
アゴム,カルボキシメチルセルロース,ヒドロキシプロ
ピルセルロース,ポリビニルピロリドンなど)または滑
沢剤(例、タルク,ステアリン酸マグネシウム,ポリエ
チレングリコール6000など)などを添加して圧縮成
形し、次いで必要により、味のマスキング、腸溶性ある
いは持続性を目的として、コーティング基剤を用いて自
体公知の方法でコーティングすることにより製造され
る。該コーティング基剤としては、例えば糖衣基剤、水
溶性フィルムコーティング基剤、腸溶性フィルムコーテ
ィング基剤、徐放性フィルムコーティング基剤などが挙
げられる。糖衣基剤としては、白糖が用いられ、さら
に、タルク、沈降炭酸カルシウム、ゼラチン、アラビア
ゴム、プルラン、カルナバロウなどから選ばれる1種ま
たは2種以上を併用してもよい。水溶性フィルムコーテ
ィング基剤としては、例えばヒドロキシプロピルセルロ
ース、ヒドロキシプロピルメチルセルロース、ヒドロキ
シエチルセルロース、メチルヒドロキシエチルセルロー
スなどのセルロース系高分子;ポリビニルアセタールジ
エチルアミノアセテート、アミノアルキルメタアクリレ
ートコポリマーE〔オイドラギットE(商品名)、ロー
ムファルマ社〕、ポリビニルピロリドンなどの合成高分
子;プルランなどの多糖類などが挙げられる。腸溶性フ
ィルムコーティング基剤としては、例えばヒドロキシプ
ロピルメチルセルロース フタレート、ヒドロキシプロ
ピルメチルセルロース アセテートサクシネート、カル
ボキシメチルエチルセルロース、酢酸フタル酸セルロー
スなどのセルロース系高分子;メタアクリル酸コポリマ
ーL〔オイドラギットL(商品名)、ロームファルマ
社〕、メタアクリル酸コポリマーLD〔オイドラギット
L−30D55(商品名)、ロームファルマ社〕、メタ
アクリル酸コポリマーS〔オイドラギットS(商品
名)、ロームファルマ社〕などのアクリル酸系高分子;
セラックなどの天然物などが挙げられる。徐放性フィル
ムコーティング基剤としては、例えばエチルセルロース
などのセルロース系高分子;アミノアルキルメタアクリ
レートコポリマーRS〔オイドラギットRS(商品
名)、ロームファルマ社〕、アクリル酸エチル・メタア
クリル酸メチル共重合体懸濁液〔オイドラギットNE
(商品名)、ロームファルマ社〕などのアクリル酸系高
分子などが挙げられる。上記したコーティング基剤は、
その2種以上を適宜の割合で混合して用いてもよい。ま
た、コーティングの際に、例えば酸化チタン、三二酸化
鉄等のような遮光剤を用いてもよい。Examples of dosage forms of the medicine and peptidase inhibitor of the present invention include tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), powders, granules, and troches. , Oral preparations such as syrup; and injections (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip, etc.), external preparations (eg, transdermal preparation, ointment, etc.) ), Suppositories (eg, rectal suppositories, vaginal suppositories, etc.), pellets, nasal agents, pulmonary agents (inhalants), parenteral agents such as eye drops. These preparations may be controlled-release preparations (eg, sustained-release microcapsules, etc.) such as immediate-release preparations or sustained-release preparations. The pharmaceutical agent and peptidase inhibitor of the present invention can be produced by a method conventionally used in the field of formulation technology, such as the method described in the Japanese Pharmacopoeia. Below, the manufacturing method of an oral agent and a parenteral agent is explained in full detail. For example, oral agents include active ingredients such as excipients (eg, lactose, sucrose, starch, D-mannitol, etc.), disintegrants (eg, carboxymethylcellulose calcium, etc.), binders (eg, pregelatinized starch, gum arabic). , Carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) are added and compression-molded, and then, if necessary, taste masking, enteric coating or For the purpose of sustainability, it is produced by coating with a coating base in a manner known per se. Examples of the coating base include sugar coating bases, water-soluble film coating bases, enteric film coating bases, sustained-release film coating bases and the like. As the sugar coating base, sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination. Examples of the water-soluble film coating base include cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name), ROHM Pharma Co.], synthetic polymers such as polyvinylpyrrolidone; and polysaccharides such as pullulan. Examples of enteric film coating bases include cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name), Acrylic polymers such as Rohm Pharma Co., Ltd., methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma Co.], methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co.];
Examples include natural products such as shellac. Examples of the sustained-release film coating base include cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Rohm Pharma Co.], ethyl acrylate / methyl methacrylate copolymer suspension. Suspended liquid [Eudragit NE
(Trade name), ROHM Pharma Co., Ltd., and the like. The coating base described above,
You may mix and use 2 or more types in an appropriate ratio. Further, at the time of coating, a light shielding agent such as titanium oxide, iron sesquioxide, etc. may be used.
【0034】注射剤は、有効成分を分散剤(例、ポリソ
ルベート80,ポリオキシエチレン硬化ヒマシ油60,
ポリエチレングリコール,カルボキシメチルセルロー
ス,アルギン酸ナトリウムなど)、保存剤(例、メチル
パラベン,プロピルパラベン,ベンジルアルコール,ク
ロロブタノール,フェノールなど)、等張化剤(例、塩
化ナトリウム,グリセリン,D−マンニトール,D−ソ
ルビトール,ブドウ糖など)などと共に水性溶剤(例、
蒸留水,生理的食塩水,リンゲル液等)あるいは油性溶
剤(例、オリーブ油,ゴマ油,綿実油,トウモロコシ油
などの植物油、プロピレングリコール等)などに溶解、
懸濁あるいは乳化することにより製造される。この際、
所望により溶解補助剤(例、サリチル酸ナトリウム,酢
酸ナトリウム等)、安定剤(例、ヒト血清アルブミン
等)、無痛化剤(例、ベンジルアルコール等)等の添加
物を用いてもよい。For injection, the active ingredient is a dispersant (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60,
Polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), preservative (eg, methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol, etc.), tonicity agent (eg, sodium chloride, glycerin, D-mannitol, D-sorbitol) , Glucose, etc., along with an aqueous solvent (eg,
Dissolved in distilled water, physiological saline, Ringer's solution, etc.) or oily solvent (eg olive oil, sesame oil, cottonseed oil, vegetable oil such as corn oil, propylene glycol, etc.),
It is produced by suspending or emulsifying. On this occasion,
If desired, additives such as solubilizing agents (eg, sodium salicylate, sodium acetate, etc.), stabilizers (eg, human serum albumin, etc.), soothing agents (eg, benzyl alcohol, etc.) may be used.
【0035】本発明の医薬およびペプチダーゼ阻害剤
は、優れたペプチダーゼ阻害作用を有し、ペプチドホル
モン、サイトカイン、神経伝達物質等の生理活性物質の
ペプチダーゼによる分解を抑制することができる。該ペ
プチドホルモンとしては、例えばグルカゴン様ペプチド
−1(GLP−1)、グルカゴン様ペプチド−2(GLP
−2)、GIP、成長ホルモン放出ホルモン(GHR
H)等が挙げられる。サイトカインとしてはランテス
(RANTES)等が挙げられる。神経伝達物質として
はニューロペプチドY(neuropeptide Y)等が挙げら
れる。The medicament and peptidase inhibitor of the present invention have an excellent peptidase inhibitory action and can suppress the degradation of physiologically active substances such as peptide hormones, cytokines and neurotransmitters by peptidases. Examples of the peptide hormone include glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP).
-2), GIP, growth hormone releasing hormone (GHR
H) and the like. Examples of cytokines include RANTES. Neuropeptide Y (neuropeptide Y) etc. are mentioned as a neurotransmitter.
【0036】ペプチダーゼとしては、例えば生化学国際
連合命名委員会(IUBMB)が分類するところの、 E
C 3.4.11.1(Leucyl aminopeptidase), EC 3.4.11.2(Mem
brane alanine aminopeptidase), EC 3.4.11.3(Cystiny
l aminopeptidase), EC 3.4.11.4(Tripeptide aminopep
tidase), EC 3.4.11.5(Prolyl aminopeptidase), EC3.
4.11.6(Aminopeptidase B), EC 3.4.11.7(Glutamyl ami
nopeptidase), EC 3.4.11.9(Xaa-Pro aminopeptidase),
EC 3.4.11.10(Bacterial leucyl aminopeptidase), EC
3.4.11.13(Clostridial aminopeptidase), EC 3.4.11.
14(Cytosol alanyl aminopeptidase), EC 3.4.11.15(Ly
syl aminopeptidase), EC 3.4.11.16(Xaa-Trp aminopep
tidase), EC 3.4.11.17(Tryptophanyl aminopeptidas
e), EC 3.4.11.18(Methionyl aminopeptidase), EC 3.
4.11.19(D-stereospecific aminopeptidase), EC 3.4.1
1.20(Aminopeptidase Ey), EC 3.4.11.21(Aspartyl ami
nopeptidase), EC 3.4.11.22(Aminopeptidase I), EC
3.4.13.3(Xaa-His dipeptidase), EC 3.4.13.4(Xaa-Arg
dipeptidase), EC 3.4.13.5(Xaa-methyl-His dipeptid
ase), EC 3.4.13.7(Glu-Glu dipeptidase), EC 3.4.13.
9(Xaa-Pro dipeptidase), EC 3.4.13.12(Met-Xaa dipep
tidase), EC 3.4.13.17(Non-stereospecific dipeptida
se), EC 3.4.13.18(Cytosol nonspecific dipeptidas
e), EC 3.4.13.19(Membrane dipeptidase), EC 3.4.13.
20(Beta-Ala-His dipeptidase), EC 3.4.14.1(Dipeptid
yl-peptidase I), EC 3.4.14.2(Dipeptidyl-peptidase
II), EC 3.4.14.4(Dipeptidyl-peptidase III), EC 3.
4.14.5(Dipeptidyl-peptidase IV), EC3.4.14.6(Dipept
idyl-dipeptidase), EC 3.4.14.9(Tripeptidyl-peptida
se I),EC 3.4.14.10(Tripeptidyl-peptidase II), EC
3.4.14.11(Xaa-Pro dipeptidyl-peptidase)等が挙げら
れる。これらのなかでも、EC 3.4.14.1, EC 3.4.14.2,
EC 3.4.14.4, EC 3.4.14.5,EC 3.4.14.6, EC 3.4.14.9,
EC 3.4.14.10, EC 3.4.14.11が好ましく、とりわけEC
3.4.14.5が好ましい。Examples of peptidases include, for example, E
C 3.4.11.1 (Leucyl aminopeptidase), EC 3.4.11.2 (Mem
brane alanine aminopeptidase), EC 3.4.11.3 (Cystiny
l aminopeptidase), EC 3.4.11.4 (Tripeptide aminopep
tidase), EC 3.4.11.5 (Prolyl aminopeptidase), EC3.
4.11.6 (Aminopeptidase B), EC 3.4.11.7 (Glutamyl ami
nopeptidase), EC 3.4.11.9 (Xaa-Pro aminopeptidase),
EC 3.4.11.10 (Bacterial leucyl aminopeptidase), EC
3.4.11.13 (Clostridial aminopeptidase), EC 3.4.11.
14 (Cytosol alanyl aminopeptidase), EC 3.4.11.15 (Ly
syl aminopeptidase), EC 3.4.11.16 (Xaa-Trp aminopep
tidase), EC 3.4.11.17 (Tryptophanyl aminopeptidas
e), EC 3.4.11.18 (Methionyl aminopeptidase), EC 3.
4.11.19 (D-stereospecific aminopeptidase), EC 3.4.1
1.20 (Aminopeptidase Ey), EC 3.4.11.21 (Aspartyl ami
nopeptidase), EC 3.4.11.22 (Aminopeptidase I), EC
3.4.13.3 (Xaa-His dipeptidase), EC 3.4.13.4 (Xaa-Arg
dipeptidase), EC 3.4.13.5 (Xaa-methyl-His dipeptid
ase), EC 3.4.13.7 (Glu-Glu dipeptidase), EC 3.4.13.
9 (Xaa-Pro dipeptidase), EC 3.4.13.12 (Met-Xaa dipep
tidase), EC 3.4.13.17 (Non-stereospecific dipeptida
se), EC 3.4.13.18 (Cytosol nonspecific dipeptidas
e), EC 3.4.13.19 (Membrane dipeptidase), EC 3.4.13.
20 (Beta-Ala-His dipeptidase), EC 3.4.14.1 (Dipeptid
yl-peptidase I), EC 3.4.14.2 (Dipeptidyl-peptidase
II), EC 3.4.14.4 (Dipeptidyl-peptidase III), EC 3.
4.14.5 (Dipeptidyl-peptidase IV), EC3.4.14.6 (Dipept
idyl-dipeptidase), EC 3.4.14.9 (Tripeptidyl-peptida
se I), EC 3.4.14.10 (Tripeptidyl-peptidase II), EC
3.4.14.11 (Xaa-Pro dipeptidyl-peptidase) and the like. Among these, EC 3.4.14.1, EC 3.4.14.2,
EC 3.4.14.4, EC 3.4.14.5, EC 3.4.14.6, EC 3.4.14.9,
EC 3.4.14.10, EC 3.4.14.11 are preferred, especially EC
3.4.14.5 is preferred.
【0037】本発明の医薬およびペプチダーゼ阻害剤
は、糖尿病(例、1型糖尿病、2型糖尿病、妊娠糖尿病
等)の予防・治療薬;高脂血症(例、高トリグリセリド
血症、高コレステロール血症、低HDL血症、食後高脂
血症等)の予防・治療薬;動脈硬化の予防・治療薬;耐
糖能不全[IGT(Impaired Glucose Tolerance)]
の予防・治療薬;インスリン分泌促進剤;および耐糖能
不全から糖尿病への移行抑制剤として用いることができ
る。糖尿病の判定基準については、1999年に日本糖
尿病学会から新たな判定基準が報告されている。この報
告によれば、糖尿病とは、空腹時血糖値(静脈血漿にお
けるグルコース濃度)が126mg/dl以上、75g
経口ブドウ糖負荷試験(75gOGTT)2時間値(静
脈血漿におけるグルコース濃度)が200mg/dl以
上、随時血糖値(静脈血漿におけるグルコース濃度)が
200mg/dl以上のいずれかを示す状態である。ま
た、上記糖尿病に該当せず、かつ、「空腹時血糖値(静
脈血漿におけるグルコース濃度)が110mg/dl未
満または75g経口ブドウ糖負荷試験(75gOGT
T)2時間値(静脈血漿におけるグルコース濃度)が1
40mg/dl未満を示す状態」(正常型)でない状態
を、「境界型」と呼ぶ。また、糖尿病の判定基準につい
ては、1997年にADA(米国糖尿病学会)から、1
998年にWHOから、新たな判定基準が報告されてい
る。これらの報告によれば、糖尿病とは、空腹時血糖値
(静脈血漿におけるグルコース濃度)が126mg/d
l以上であり、かつ、75g経口ブドウ糖負荷試験2時
間値(静脈血漿におけるグルコース濃度)が200mg
/dl以上を示す状態である。The drug and peptidase inhibitor of the present invention are prophylactic / therapeutic agents for diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.); hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia)・ Low HDL, postprandial hyperlipidemia, etc.) preventive / therapeutic agent; arteriosclerosis preventive / therapeutic agent; impaired glucose tolerance [IGT (Impaired Glucose Tolerance)]
It can be used as a prophylactic / therapeutic agent for insulin, an insulin secretagogue, and an inhibitor of transition from impaired glucose tolerance to diabetes. Regarding the criteria for diabetes, a new criteria was reported by the Japan Diabetes Society in 1999. According to this report, diabetes means a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, 75 g.
Oral glucose tolerance test (75 g OGTT) 2-hour value (glucose concentration in venous plasma) is 200 mg / dl or more, and occasionally blood glucose level (glucose concentration in venous plasma) is 200 mg / dl or more. In addition, it does not correspond to the above-mentioned diabetes mellitus and "the fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dl or 75 g oral glucose tolerance test (75 g OGT
T) 2 hour value (glucose concentration in venous plasma) is 1
A state that is not “a state showing less than 40 mg / dl” (normal type) is called “boundary type”. Regarding the criteria for diabetes, from ADA (American Diabetes Association) in 1997, 1
WHO reported new criteria in 998. According to these reports, diabetes has a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / d.
1 or more, and 75 g oral glucose tolerance test 2-hour value (glucose concentration in venous plasma) is 200 mg
/ Dl or more.
【0038】また、上記報告によれば、耐糖能不全と
は、空腹時血糖値(静脈血漿におけるグルコース濃度)
が126mg/dl未満であり、かつ、75g経口ブド
ウ糖負荷試験2時間値(静脈血漿におけるグルコース濃
度)が140mg/dl以上200mg/dl未満を示
す状態である。さらに、ADAの報告によれば、空腹時
血糖値(静脈血漿におけるグルコース濃度)が110m
g/dl以上126mg/dl未満の状態をIFG(Im
paired Fasting Glucose)と呼ぶ。一方、WHOの報
告によれば、該IFG(Impaired Fasting Glucose)
のうち、75g経口ブドウ糖負荷試験2時間値(静脈血
漿におけるグルコース濃度)が140mg/dl未満で
ある状態をIFG(Impaired Fasting Glycemia)と
呼ぶ。本発明の医薬およびペプチダーゼ阻害剤は、上記
した新たな判定基準により決定される糖尿病、境界型、
耐糖能異常、IFG(Impaired Fasting Glucose)お
よびIFG(Impaired Fasting Glycemia)の予防・
治療薬としても用いられる。さらに、本発明の医薬およ
びペプチダーゼ阻害剤は、境界型、耐糖能異常、IFG
(Impaired Fasting Glucose)またはIFG(Impair
ed Fasting Glycemia)から糖尿病への進展を防止す
ることもできる。Further, according to the above report, impaired glucose tolerance means fasting blood glucose level (glucose concentration in venous plasma).
Is less than 126 mg / dl, and the 2-hour 75 g oral glucose tolerance test value (glucose concentration in venous plasma) is 140 mg / dl or more and less than 200 mg / dl. Furthermore, the ADA reported that the fasting blood glucose level (glucose concentration in venous plasma) was 110 m.
The state of g / dl or more and less than 126 mg / dl is IFG (Im
Called paired Fasting Glucose). On the other hand, according to the WHO report, the IFG (Impaired Fasting Glucose)
Among them, the state in which the 75-g oral glucose tolerance test 2-hour value (glucose concentration in venous plasma) is less than 140 mg / dl is called IFG (Impaired Fasting Glycemia). The drug and peptidase inhibitor of the present invention include diabetes, borderline type, which is determined by the above new criteria.
Prevention of glucose intolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia)
Also used as a therapeutic drug. Furthermore, the pharmaceutical agent and peptidase inhibitor of the present invention are characterized by borderline type, impaired glucose tolerance, IFG.
(Impaired Fasting Glucose) or IFG (Impaired Fasting Glucose)
It is also possible to prevent the progression from ed fasting glycemia to diabetes.
【0039】本発明の医薬およびペプチダーゼ阻害剤
は、例えば糖尿病性合併症[例、神経障害、腎症、網膜
症、白内障、大血管障害、骨減少症、糖尿病性高浸透圧
昏睡、感染症(呼吸器感染症、尿路感染症、消化器感染
症、皮膚軟部組織感染症、下肢感染症等)、糖尿病性壊
疽、口腔乾燥症、聴覚の低下、脳血管障害、末梢血行障
害等]、肥満、骨粗鬆症、悪液質(例、癌性悪液質、結
核性悪液質、糖尿病性悪液質、血液疾患性悪液質、内分
泌疾患性悪液質、感染症性悪液質または後天性免疫不全
症候群による悪液質)、脂肪肝、高血圧、多嚢胞性卵巣
症候群、腎臓疾患(例、糖尿病性ネフロパシー、糸球体
腎炎、糸球体硬化症、ネフローゼ症候群、高血圧性腎硬
化症、末期腎臓疾患等)、筋ジストロフィー、心筋梗
塞、狭心症、脳血管障害(例、脳梗塞、脳卒中)、イン
スリン抵抗性症候群、シンドロームX、高インスリン血
症、高インスリン血症における知覚障害、腫瘍(例、白
血病、乳癌、前立腺癌、皮膚癌等)、過敏性腸症候群、
急性または慢性下痢、炎症性疾患(例、慢性関節リウマ
チ、変形性脊椎炎、変形性関節炎、腰痛、痛風、手術外
傷後の炎症、腫脹の緩解、神経痛、咽喉頭炎、膀胱炎、
肝炎(非アルコール性脂肪性肝炎を含む)、肺炎、膵
炎、炎症性大腸疾患、潰瘍性大腸炎、胃粘膜損傷(アス
ピリンにより引き起こされた胃粘膜損傷を含む)等)、
内臓肥満症候群などの予防・治療薬としても用いること
ができる。本発明の医薬およびペプチダーゼ阻害剤は、
内臓脂肪の減少、内臓脂肪蓄積の抑制、糖代謝改善、脂
質代謝改善、酸化LDL産生抑制、リポタンパク代謝改
善、冠動脈代謝改善、心血管合併症の予防・治療、心不
全合併症の予防・治療、血中レムナント低下、無排卵症
の予防・治療、多毛症の予防・治療、高アンドロゲン血
症の予防・治療、膵(β細胞)機能改善、膵(β細胞)
再生、膵(β細胞)再生促進などにも用いられる。本発
明の医薬およびペプチダーゼ阻害剤は、上記した各種疾
患(例、心筋梗塞などの心血管イベント)の2次予防お
よび進展抑制にも用いられる。The drug and peptidase inhibitor of the present invention can be used, for example, for diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infectious disease ( Respiratory infections, urinary tract infections, digestive infections, skin and soft tissue infections, lower limb infections, etc.), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorders, peripheral blood circulation disorders, etc.], obesity , Osteoporosis, cachexia (eg, cancer cachexia, tuberculous cachexia, diabetic cachexia, hematological cachexia, endocrine cachexia, infectious cachexia or cachexia due to acquired immunodeficiency syndrome) Quality), fatty liver, hypertension, polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end stage renal disease, etc.), muscular dystrophy, myocardium Infarction, angina, cerebrovascular disorder (Eg, cerebral infarction, stroke), insulin resistance syndrome, syndrome X, hyperinsulinemia, sensory disturbance in hyperinsulinemia, tumor (eg, leukemia, breast cancer, prostate cancer, skin cancer, etc.), irritable bowel syndrome ,
Acute or chronic diarrhea, inflammatory diseases (eg, rheumatoid arthritis, degenerative spondylitis, osteoarthritis, low back pain, gout, inflammation after surgical trauma, swelling remission, neuralgia, pharyngitis, cystitis,
Hepatitis (including non-alcoholic steatohepatitis), pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis, gastric mucosal damage (including gastric mucosal damage caused by aspirin), etc.),
It can also be used as a prophylactic / therapeutic agent for visceral obesity syndrome and the like. The pharmaceutical agent and peptidase inhibitor of the present invention are
Reduction of visceral fat, suppression of visceral fat accumulation, improvement of glucose metabolism, improvement of lipid metabolism, suppression of oxidized LDL production, improvement of lipoprotein metabolism, improvement of coronary artery metabolism, prevention / treatment of cardiovascular complications, prevention / treatment of heart failure complications, Blood remnant reduction, anovulation prevention / treatment, hirsutism prevention / treatment, hyperandrogenemia prevention / treatment, pancreatic (β cell) function improvement, pancreas (β cell)
It is also used for regeneration and promotion of pancreatic (β cell) regeneration. The medicament and peptidase inhibitor of the present invention are also used for secondary prevention and suppression of progression of the above-mentioned various diseases (eg, cardiovascular events such as myocardial infarction).
【0040】本発明の医薬およびペプチダーゼ阻害剤
は、高血糖の患者(例えば、空腹時血糖値が126mg
/dl以上または75g経口ブドウ糖負荷試験(75g
OGTT)2時間値が140mg/dl以上である患者
など)において、選択的にインスリン分泌促進作用を発
揮する、グルコース依存性インスリン分泌促進剤であ
る。したがって、本発明の医薬およびペプチダーゼ阻害
剤は、インスリンの弊害である血管合併症や低血糖誘発
などの危険性の低い、安全な糖尿病の予防または治療薬
として有用である。The medicine and peptidase inhibitor of the present invention are used for hyperglycemic patients (for example, a fasting blood glucose level is 126 mg).
/ Dl or more or 75g Oral glucose tolerance test (75g
OGTT) A glucose-dependent insulin secretagogue that selectively exerts an insulin secretagogue action in patients with a 2-hour value of 140 mg / dl or more). Therefore, the pharmaceutical agent and peptidase inhibitor of the present invention are useful as a safe preventive or therapeutic drug for diabetes with low risk of vascular complications and hypoglycemia induction, which are harmful effects of insulin.
【0041】本発明の医薬およびペプチダーゼ阻害剤の
投与量は、投与対象、投与ルート、対象疾患、症状など
によっても異なるが、例えば成人の糖尿病患者に経口投
与する場合、有効成分である化合物(I)を通常1回量
として約0.01〜100mg/kg体重、好ましくは
0.05〜30mg/kg体重、さらに好ましくは0.
1〜10mg/kg体重であり、この量を1日1回〜3
回投与するのが望ましい。The doses of the drug of the present invention and the peptidase inhibitor vary depending on the administration subject, administration route, target disease, condition and the like, but when administered orally to an adult diabetic patient, for example, the compound (I ) Is generally used as a single dose of about 0.01 to 100 mg / kg body weight, preferably 0.05 to 30 mg / kg body weight, and more preferably 0.1.
1 to 10 mg / kg body weight, and this amount once to 3 times a day
It is desirable to administer a single dose.
【0042】本発明の医薬およびペプチダーゼ阻害剤
は、糖尿病治療剤、糖尿病性合併症治療剤、抗高脂血症
剤、降圧剤、抗肥満剤、利尿剤、化学療法剤、免疫療法
剤、抗血栓剤、骨粗鬆症治療剤、抗痴呆剤、勃起不全改
善剤、尿失禁・頻尿治療剤などの薬剤(以下、併用薬剤
と略記する)と組み合わせて用いることができる。この
際、本発明の医薬もしくはペプチダーゼ阻害剤と併用薬
剤との投与時期は限定されず、これらを投与対象に対
し、同時に投与してもよいし、時間差をおいて投与して
もよい。併用薬剤の投与量は、臨床上用いられている用
量を基準として適宜選択することができる。また、本発
明の医薬もしくはペプチダーゼ阻害剤と併用薬剤との配
合比は、投与対象、投与ルート、対象疾患、症状、組み
合わせなどにより適宜選択することができる。例えば投
与対象がヒトである場合、本発明の医薬およびペプチダ
ーゼ阻害剤の有効成分である化合物(I)1重量部に対
し、併用薬剤を0.01〜100重量部用いればよい。The pharmaceutical agent and peptidase inhibitor of the present invention are used as antidiabetic agents, therapeutic agents for diabetic complications, antihyperlipidemic agents, antihypertensive agents, antiobesity agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, anti-hyperlipidemic agents. It can be used in combination with a drug such as a thrombotic agent, a therapeutic agent for osteoporosis, an anti-dementia agent, an erectile dysfunction improving agent, and a therapeutic agent for urinary incontinence and pollakiuria (hereinafter abbreviated as a concomitant drug). At this time, the administration timing of the drug of the present invention or the peptidase inhibitor and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or at a staggered time. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the drug of the present invention or the peptidase inhibitor and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound (I) which is an active ingredient of the drug of the present invention and the peptidase inhibitor.
【0043】なお、糖尿病治療剤としては、インスリン
製剤(例、ウシ、ブタの膵臓から抽出された動物インス
リン製剤;大腸菌、イーストを用い、遺伝子工学的に合
成したヒトインスリン製剤;インスリン亜鉛;プロタミ
ンインスリン亜鉛;インスリンのフラグメントまたは誘
導体(例、INS−1等)など)、インスリン抵抗性改
善剤(例、塩酸ピオグリタゾン、(マレイン酸)ロシグ
リタゾン、GI−262570、JTT−501、MC
C−555、YM−440、KRP−297、CS−0
11、FK−614、WO99/58510に記載の化
合物(例えば(E)−4−[4−(5−メチル−2−フ
ェニル−4−オキサゾリルメトキシ)ベンジルオキシイ
ミノ]−4−フェニル酪酸)等)、α−グルコシダーゼ
阻害剤(例、ボグリボース、アカルボース、ミグリトー
ル、エミグリテート等)、ビグアナイド剤(例、フェン
ホルミン、メトホルミン、ブホルミン等)、インスリン
分泌促進剤[スルホニルウレア剤(例、トルブタミド、
グリベンクラミド、グリクラジド、クロルプロパミド、
トラザミド、アセトヘキサミド、グリクロピラミド、グ
リメピリド、グリピザイド、グリブゾール等)、レパグ
リニド、セナグリニド、ナテグリニド、ミチグリニドま
たはそのカルシウム塩水和物]、GLP−1受容体アゴ
ニスト[例、GLP−1、NN−2211、AC−2993(ex
endin−4)、BIM−51077、Aib(8,35)hGLP
−1(7,37)NH2等]、アミリンアゴニスト(例、プラ
ムリンチド等)、フォスフォチロシンフォスファターゼ
阻害剤(例、バナジン酸等)、ジペプチジルペプチダー
ゼIV阻害剤(例、NVP−DPP−278、PT−1
00、P32/98、LAF−237等)、β3アゴニス
ト(例、CL−316243、SR−58611−A、
UL−TG−307、SB−226552,AJ−96
77、BMS−196085、AZ40140等)、糖
新生阻害剤(例、グリコーゲンホスホリラーゼ阻害剤、
グルコース−6−ホスファターゼ阻害剤、グルカゴン拮
抗剤等)、SGLT(sodium-glucose cotransporte
r)阻害剤(例、T−1095等)等が挙げられる。As a therapeutic agent for diabetes, an insulin preparation (eg, animal insulin preparation extracted from bovine or porcine pancreas; human insulin preparation genetically synthesized using Escherichia coli or yeast; insulin zinc; protamine insulin) Zinc; insulin fragment or derivative (eg, INS-1 etc.), insulin sensitizer (eg, pioglitazone hydrochloride, (maleic acid) rosiglitazone, GI-262570, JTT-501, MC
C-555, YM-440, KRP-297, CS-0
11, FK-614, the compound described in WO99 / 58510 (for example, (E) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid). Etc.), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), insulin secretagogues [sulfonylureas (eg, tolbutamide, etc.)
Glibenclamide, gliclazide, chlorpropamide,
Trazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole, etc.), repaglinide, senaglinide, nateglinide, mitiglinide or its calcium salt hydrate], GLP-1 receptor agonist [eg, GLP-1, NN-2211, AC-3992 (ex
endin-4), BIM-51077, Aib (8,35) hGLP
-1 (7,37) NH 2 etc.], amylin agonist (eg pramlintide etc.), phosphotyrosine phosphatase inhibitor (eg vanadic acid etc.), dipeptidyl peptidase IV inhibitor (eg NVP-DPP-278, PT-1
00, P32 / 98, LAF-237, etc.), β3 agonist (eg CL-316243, SR-58611-A,
UL-TG-307, SB-226552, AJ-96
77, BMS-196085, AZ40140, etc.), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor,
Glucose-6-phosphatase inhibitor, glucagon antagonist, etc., SGLT (sodium-glucose cotransporte)
r) Inhibitors (eg, T-1095 etc.) and the like can be mentioned.
【0044】糖尿病性合併症治療剤としては、アルドー
ス還元酵素阻害剤(例、トルレスタット、エパルレスタ
ット、ゼナレスタット、ゾポルレスタット、ミナルレス
タット、フィダレスタット、SNK−860、CT−1
12等)、神経栄養因子およびその増加薬(例、NG
F、NT−3、BDNF、WO01/14372に記載
のニューロトロフィン産生・分泌促進剤(例えば4−
(4−クロロフェニル)−2−(2−メチル−1−イミ
ダゾリル)−5−[3−(2−メチルフェノキシ)プロ
ピル]オキサゾールなど)等)、神経再生促進薬(例、
Y−128等)、PKC阻害剤(例、LY−33353
1等)、AGE阻害剤(例、ALT946、ピマゲジ
ン、ピラトキサチン、N−フェナシルチアゾリウム ブ
ロマイド(ALT766)、EXO−226等)、活性
酸素消去薬(例、チオクト酸等)、脳血管拡張剤(例、
チアプリド、メキシレチン等)が挙げられる。抗高脂血
症剤としては、コレステロール合成阻害剤であるスタチ
ン系化合物(例、セリバスタチン、プラバスタチン、シ
ンバスタチン、ロバスタチン、アトルバスタチン、フル
バスタチン、イタバスタチンまたはそれらの塩(例、ナ
トリウム塩)等)、スクアレン合成酵素阻害剤(例、W
O97/10224に記載の化合物、例えばN−[[(3
R,5S)-1-(3-アセトキシ-2,2-ジメチルプロピル)-7-クロ
ロ-5-(2,3-ジメトキシフェニル)-2-オキソ-1,2,3,5-テ
トラヒドロ-4,1-ベンゾオキサゼピン-3-イル]アセチ
ル]ピペリジン-4-酢酸など)あるいはトリグリセリド
低下作用を有するフィブラート系化合物(例、ベザフィ
ブラート、クロフィブラート、シムフィブラート、クリ
ノフィブラート等)、ACAT阻害剤(例、アバシマイ
ブ(Avasimibe)、エフルシマイブ(Eflucimibe)な
ど)、陰イオン交換樹脂(例、コレスチラミンなど)、
プロブコール、ニコチン酸系薬剤(例、ニコモール(nic
omol)、ニセリトロール(niceritrol)など)、イコサペ
ント酸エチル、植物ステロール(例、ソイステロール(s
oysterol)、ガンマオリザノール(γ−oryzanol)など)
等が挙げられる。降圧剤としては、アンジオテンシン変
換酵素阻害剤(例、カプトプリル、エナラプリル、デラ
プリル等)あるいはアンジオテンシンII拮抗剤(例、カ
ンデサルタン シレキセチル、ロサルタン、エプロサル
タン、バルサンタン、テルミサルタン、イルベサルタ
ン、タソサルタン等)、カルシウム拮抗剤(例、マニジ
ピン、ニフェジピン、アムロジピン、エホニジピン、ニ
カルジピン等)、カリウムチャンネル開口薬(例、レブ
クロマカリム、L-27152、AL 0671、NIP-121など)、ク
ロニジン等が挙げられる。抗肥満剤としては、例えば中
枢性抗肥満薬(例、デキスフェンフルラミン、フェンフ
ルラミン、フェンテルミン、シブトラミン、アンフェプ
ラモン、デキサンフェタミン、マジンドール、フェニル
プロパノールアミン、クロベンゾレックス等)、膵リパ
ーゼ阻害薬(例、オルリスタット等)、β3アゴニスト
(例、CL−316243、SR−58611−A、U
L−TG−307、SB−226552,AJ−967
7、BMS−196085、AZ40140等)、ペプ
チド性食欲抑制薬(例、レプチン、CNTF(毛様体神
経栄養因子)等)、コレシストキニンアゴニスト(例、
リンチトリプト、FPL−15849等)等が挙げられ
る。Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, trrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CT-1).
12, etc.), neurotrophic factors and their increasing drugs (eg, NG)
F, NT-3, BDNF, the neurotrophin production / secretion promoter described in WO01 / 14372 (for example, 4-
(4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2-methylphenoxy) propyl] oxazole, etc.), a nerve regeneration promoter (eg,
Y-128), PKC inhibitor (eg, LY-33353)
1), AGE inhibitors (eg, ALT946, pimagegedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), EXO-226, etc.), active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (Eg,
Tiapride, mexiletine, etc.). Antihyperlipidemic agents include statin compounds that are cholesterol synthesis inhibitors (eg, cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or salts thereof (eg, sodium salt)), squalene Synthetic enzyme inhibitors (eg W
O97 / 10224, for example, N-[[(3
R, 5S) -1- (3-Acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4 , 1-Benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid, etc.) or a fibrate compound having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.), ACAT inhibitor ( Eg, Avasimibe, Eflucimibe, etc.), anion exchange resin (eg, cholestyramine, etc.),
Probucol, nicotinic acid drugs (eg, nicomol (nic
omol), niceritrol, etc.), ethyl icosapentate, phytosterols (eg, soysterols
oysterol), gamma-oryzanol, etc.)
Etc. Antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.) or angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan, tasosartan, etc.), calcium antagonists (eg Examples include manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc.), potassium channel openers (eg, levocromakalim, L-27152, AL 0671, NIP-121, etc.), clonidine and the like. Examples of the anti-obesity agent include central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampfepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex, etc.), pancreatic lipase inhibition Drug (eg, orlistat, etc.), β3 agonist (eg, CL-316243, SR-58611-A, U
L-TG-307, SB-226552, AJ-967
7, BMS-196085, AZ40140, etc.), peptide appetite suppressants (eg, leptin, CNTF (ciliary nerve trophic factor) etc.), cholecystokinin agonists (eg,
Lynchtripto, FPL-15849, etc.) and the like.
【0045】利尿剤としては、例えばキサンチン誘導体
(例、サリチル酸ナトリウムテオブロミン、サリチル酸
カルシウムテオブロミン等)、チアジド系製剤(例、エ
チアジド、シクロペンチアジド、トリクロルメチアジ
ド、ヒドロクロロチアジド、ヒドロフルメチアジド、ベ
ンチルヒドロクロロチアジド、ペンフルチジド、ポリチ
アジド、メチクロチアジド等)、抗アルドステロン製剤
(例、スピロノラクトン、トリアムテレン等)、炭酸脱
水酵素阻害剤(例、アセタゾラミド等)、クロルベンゼ
ンスルホンアミド系製剤(例、クロルタリドン、メフル
シド、インダパミド等)、アゾセミド、イソソルビド、
エタクリン酸、ピレタニド、ブメタニド、フロセミド等
が挙げられる。化学療法剤としては、例えばアルキル化
剤(例、サイクロフォスファミド、イフォスファミド
等)、代謝拮抗剤(例、メソトレキセート、5−フルオ
ロウラシル等)、抗癌性抗生物質(例、マイトマイシ
ン、アドリアマイシン等)、植物由来抗癌剤(例、ビン
クリスチン、ビンデシン、タキソール等)、シスプラチ
ン、カルボプラチン、エトポキシドなどが挙げられる。
なかでも5−フルオロウラシル誘導体であるフルツロン
あるいはネオフルツロンなどが好ましい。免疫療法剤と
しては、例えば微生物または細菌成分(例、ムラミルジ
ペプチド誘導体、ピシバニール等)、免疫増強活性のあ
る多糖類(例、レンチナン、シゾフィラン、クレスチン
等)、遺伝子工学的手法で得られるサイトカイン(例、
インターフェロン、インターロイキン(IL)等)、コ
ロニー刺激因子(例、顆粒球コロニー刺激因子、エリス
ロポエチン等)などが挙げられ、中でもIL−1、IL
−2、IL−12などが好ましい。Examples of the diuretics include xanthine derivatives (eg, sodium theobromine salicylate, calcium theobromine salicylate, etc.), thiazide type preparations (eg, ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, ventilhydrochlorothiazide, Penfluthizide, polythiazide, meticlotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), Azosemide, isosorbide,
Ethacrynic acid, piretanide, bumetanide, furosemide and the like can be mentioned. Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), Examples include plant-derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etopoxide and the like.
Among them, 5-fluorouracil derivative such as furtulon or neofurtulon is preferable. Immunotherapeutic agents include, for example, microbial or bacterial components (eg, muramyl dipeptide derivative, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques ( Example,
Interferon, interleukin (IL, etc.), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin, etc.) and the like, among which IL-1, IL
-2, IL-12 and the like are preferable.
【0046】抗血栓剤としては、例えばヘパリン(例、
ヘパリンナトリウム、ヘパリンカルシウム、ダルテパリ
ンナトリウム(dalteparin sodium)など)、ワルファリ
ン(例、ワルファリンカリウムなど)、抗トロンビン薬
(例、アルガトロバン(aragatroban)など)、血栓溶解
薬(例、ウロキナーゼ(urokinase)、チソキナーゼ(tiso
kinase)、アルテプラーゼ(alteplase)、ナテプラーゼ(n
ateplase)、モンテプラーゼ(monteplase)、パミテプラ
ーゼ(pamiteplase)など)、血小板凝集抑制薬(例、塩
酸チクロピジン(ticlopidine hydrochloride)、シロス
タゾール(cilostazol)、イコサペント酸エチル、ベラプ
ロストナトリウム(beraprost sodium)、塩酸サルポグレ
ラート(sarpogrelate hydrochloride)など)などが挙げ
られる。骨粗鬆症治療剤としては、例えばアルファカル
シドール(alfacalcidol)、カルシトリオール(calcit
riol)、エルカルトニン(elcaltonin)、サケカルシト
ニン(calcitonin salmon)、エストリオール(estrio
l)、イプリフラボン(ipriflavone)、パミドロン酸二
ナトリウム(pamidronate disodium)、アレンドロン
酸ナトリウム水和物(alendronate sodium hydrat
e)、インカドロン酸二ナトリウム(incadronate diso
dium)等が挙げられる。抗痴呆剤としては、例えばタク
リン(tacrine)、ドネペジル(donepezil)、リバスチ
グミン(rivastigmine)、ガランタミン(galantamin
e)等が挙げられる。勃起不全改善剤としては、例えば
アポモルフィン(apomorphine)、クエン酸シルデナフ
ィル(sildenafil citrate)等が挙げられる。尿失禁
・頻尿治療剤としては、例えば塩酸フラボキサート(fl
avoxate hydrochloride)、塩酸オキシブチニン(oxyb
utynin hydrochloride)、塩酸プロピベリン(propive
rine hydrochloride)等が挙げられる。Examples of antithrombotic agents include heparin (eg,
Heparin sodium, heparin calcium, dalteparin sodium, etc.), warfarin (eg, warfarin potassium, etc.), antithrombin drug (eg, aragatroban, etc.), thrombolytic drug (eg, urokinase, thisokinase) (tiso
kinase), alteplase, nateplase (n
ateplase), monteplase, pamiteplase, etc.), platelet aggregation inhibitors (eg, ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) ) Etc.) and the like. Examples of therapeutic agents for osteoporosis include alfacalcidol (alfacalcidol) and calcitriol (calcit).
riol, elcaltonin, salmon calcitonin salmon, estriol
l), ipriflavone, pamidronate disodium, alendronate sodium hydrat
e), disodium incadronate (incadronate diso
dium) and the like. Examples of anti-dementia agents include tacrine, donepezil, rivastigmine, and galantamin.
e) and the like. Examples of the erectile dysfunction improving agent include apomorphine, sildenafil citrate and the like. Examples of therapeutic agents for urinary incontinence and frequent urination include flavoxate hydrochloride (fl
avoxate hydrochloride), oxybutynin hydrochloride (oxyb
utynin hydrochloride), propiverine hydrochloride (propive
rine hydrochloride) and the like.
【0047】さらに、動物モデルや臨床で悪液質改善作
用が認められている薬剤、すなわち、シクロオキシゲナ
ーゼ阻害剤(例、インドメタシン等)〔キャンサー・リ
サーチ(Cancer Research)、第49巻、5935〜5
939頁、1989年〕、プロゲステロン誘導体(例、
メゲステロールアセテート)〔ジャーナル・オブ・クリ
ニカル・オンコロジー(Journal of Clinical Oncolog
y)、第12巻、213〜225頁、1994年〕、糖
質ステロイド(例、デキサメサゾン等)、メトクロプラ
ミド系薬剤、テトラヒドロカンナビノール系薬剤(文献
はいずれも上記と同様)、脂肪代謝改善剤(例、エイコ
サペンタエン酸等)〔ブリティシュ・ジャーナル・オブ
・キャンサー(British Journal of Cancer)、第68
巻、314〜318頁、1993年〕、成長ホルモン、
IGF−1、あるいは悪液質を誘導する因子であるTN
F−α、LIF、IL−6、オンコスタチンMに対する
抗体なども本発明の医薬もしくはペプチダーゼ阻害剤と
併用することができる。Furthermore, drugs which have been found to have cachexia-improving effects in animal models and clinical practice, namely, cyclooxygenase inhibitors (eg, indomethacin, etc.) [Cancer Research, Vol. 49, 5935-5]
939, 1989], progesterone derivatives (eg,
Megesterol Acetate [Journal of Clinical Oncolog
y), Vol. 12, pp. 213-225, 1994], glucosteroids (eg, dexamethasone, etc.), metoclopramide drugs, tetrahydrocannabinol drugs (both documents are the same as above), fat metabolism improving agents ( (Eg, eicosapentaenoic acid) [British Journal of Cancer, No. 68
Vol., 314-318, 1993], growth hormone,
IGF-1, or TN, a factor that induces cachexia
Antibodies against F-α, LIF, IL-6, oncostatin M and the like can also be used in combination with the pharmaceutical agent or peptidase inhibitor of the present invention.
【0048】併用薬剤は、好ましくはインスリン製剤、
インスリン抵抗性改善剤、α−グルコシダーゼ阻害剤、
ビグアナイド剤、インスリン分泌促進剤(好ましくはス
ルホニルウレア剤)などである。上記併用薬剤は、2種
以上を適宜の割合で組み合わせて用いてもよい。2種以
上の併用薬剤を用いる場合の好ましい組み合わせとして
は、例えば以下のものが挙げられる。
1)インスリン分泌促進剤(好ましくはスルホニルウレ
ア剤)およびα−グルコシダーゼ阻害剤;
2)インスリン分泌促進剤(好ましくはスルホニルウレ
ア剤)およびビグアナイド剤;
3)インスリン分泌促進剤(好ましくはスルホニルウレ
ア剤)、ビグアナイド剤およびα−グルコシダーゼ阻害
剤;
4)インスリン抵抗性改善剤およびα−グルコシダーゼ
阻害剤;
5)インスリン抵抗性改善剤およびビグアナイド剤;
6)インスリン抵抗性改善剤、ビグアナイド剤およびα
−グルコシダーゼ阻害剤。
本発明の医薬およびペプチダーゼ阻害剤が併用薬剤と組
み合せて使用される場合には、お互いの剤の量は、それ
らの剤の反対効果を考えて安全な範囲内で低減できる。
特に、インスリン抵抗性改善剤、インスリン分泌促進剤
(好ましくはスルホニルウレア剤)およびビグアナイド
剤は通常の投与量よりも低減できる。したがって、これ
らの剤により引き起こされるであろう反対効果は安全に
防止できる。それに加えて、糖尿病性合併症剤、抗高脂
血症剤、降圧剤の投与量は低減でき、その結果これらの
剤により引き起こされるであろう反対効果は効果的に防
止できる。The concomitant drug is preferably an insulin preparation,
Insulin sensitizer, α-glucosidase inhibitor,
Examples thereof include biguanides, insulin secretagogues (preferably sulfonylureas), and the like. The concomitant drug may be used in combination of two or more kinds at an appropriate ratio. Preferred combinations when using two or more concomitant drugs include, for example, the following. 1) Insulin secretagogue (preferably sulfonylurea agent) and α-glucosidase inhibitor; 2) Insulin secretagogue (preferably sulfonylurea agent) and biguanide agent; 3) Insulin secretagogue (preferably sulfonylurea agent), biguanide agent And α-glucosidase inhibitor; 4) Insulin sensitizer and α-glucosidase inhibitor; 5) Insulin sensitizer and biguanide; 6) Insulin sensitizer, biguanide and α
-Glucosidase inhibitors. When the drug of the present invention and the peptidase inhibitor are used in combination with a concomitant drug, the amount of each drug can be reduced within a safe range in consideration of the opposite effects of the drugs.
In particular, the insulin sensitizer, insulin secretagogue (preferably sulfonylurea drug) and biguanide drug can be reduced in doses lower than usual doses. Therefore, the adverse effects that would be caused by these agents can be safely prevented. In addition, the doses of diabetic complications, antihyperlipidemic agents and antihypertensive agents can be reduced, so that the adverse effects that may be caused by these agents can be effectively prevented.
【0049】化合物(I)は、自体公知の方法、例えば
特開平9−143181、特開平59−39880、USP4280831などに
記載された方法、あるいはこれに準ずる方法にしたがっ
て製造することができる。Compound (I) can be produced according to a method known per se, for example, the method described in JP-A-9-143181, JP-A-59-39880, USP4280831, or the like, or a method analogous thereto.
【0050】化合物(I)が、光学異性体、立体異性
体、位置異性体、回転異性体を含有する場合には、これ
らも化合物(I)として含有されるとともに、自体公知
の合成手法、分離手法によりそれぞれを単品として得る
ことができる。例えば、化合物(I)に光学異性体が存
在する場合には、該化合物から分割された光学異性体も
化合物(I)に包含される。光学異性体は自体公知の方
法により製造することができる。具体的には、光学活性
な合成中間体を用いる、または、最終物のラセミ体を常
法に従って光学分割することにより光学異性体を得る。
光学分割法としては、自体公知の方法、例えば、分別再
結晶法、キラルカラム法、ジアステレオマー法等が用い
られる。
1)分別再結晶法
ラセミ体と光学活性な化合物(例えば、(+)−マンデ
ル酸、(−)−マンデル酸、(+)−酒石酸、(−)−
酒石酸、(+)−1−フェネチルアミン、(−)−1−
フェネチルアミン、シンコニン、(−)−シンコニジ
ン、ブルシンなど)と塩を形成させ、これを分別再結晶
法によって分離し、所望により、中和工程を経てフリー
の光学異性体を得る方法。When the compound (I) contains an optical isomer, a stereoisomer, a positional isomer, and a rotational isomer, these are also contained as the compound (I), and the synthetic method and the separation known per se. Each can be obtained as a single item by the method. For example, when the compound (I) has an optical isomer, the optical isomer resolved from the compound is also included in the compound (I). The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the racemate of the final product according to a conventional method.
As the optical resolution method, a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method or the like is used. 1) Fractional recrystallization method racemate and optically active compound (for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-
Tartaric acid, (+)-1-phenethylamine, (-)-1-
Phenethylamine, cinchonine, (−)-cinchonidine, brucine, etc.) to form a salt, and this is separated by a fractional recrystallization method, and if desired, a free optical isomer is obtained through a neutralization step.
【0051】2)キラルカラム法
ラセミ体またはその塩を光学異性体分離用カラム(キラ
ルカラム)にかけて分離する方法。例えば液体クロマト
グラフィーの場合、ENANTIO−OVM(トーソー
社製)あるいは、ダイセル社製 CHIRALシリーズ
などのキラルカラムに光学異性体の混合物を添加し、
水、種々の緩衝液(例、リン酸緩衝液)、有機溶媒
(例、エタノール、メタノール、イソプロパノール、ア
セトニトリル、トリフルオロ酢酸、ジエチルアミンな
ど)を単独あるいは混合した溶液として展開させること
により、光学異性体を分離する。また、例えばガスクロ
マトグラフィーの場合、CP−Chirasil−De
X CB(ジーエルサイエンス社製)などのキラルカラ
ムを使用して分離する。
3)ジアステレオマー法
ラセミ体の混合物を光学活性な試薬と化学反応によって
ジアステレオマーの混合物とし、これを通常の分離手段
(例えば、分別再結晶、クロマトグラフィー法等)など
を経て単一物質とした後、加水分解反応などの化学的な
処理により光学活性な試薬部位を切り離すことにより光
学異性体を得る方法。例えば、化合物(I)が分子内に
ヒドロキシまたは1,2級アミノを有する場合、該化合
物と光学活性な有機酸(例えば、MTPA〔α−メトキ
シ−α−(トリフルオロメチル)フェニル酢酸〕、
(−)−メントキシ酢酸等)などとを縮合反応に付すこ
とにより、それぞれエステル体またはアミド体のジアス
テレオマーが得られる。一方、化合物(I)がカルボン
酸基を有する場合、該化合物と光学活性アミンまたはア
ルコール試薬とを縮合反応に付すことにより、それぞれ
アミド体またはエステル体のジアステレオマーが得られ
る。分離されたジアステレオマーは、酸加水分解あるい
は塩基性加水分解反応に付すことにより、元の化合物の
光学異性体に変換される。2) Chiral column method A method in which a racemate or a salt thereof is applied to a column for separating optical isomers (chiral column) for separation. For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series manufactured by Daicel Corporation,
Optical isomers by developing water, various buffers (eg, phosphate buffer), organic solvents (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) as single or mixed solutions To separate. In the case of gas chromatography, for example, CP-Chirasil-De
Separation is performed using a chiral column such as XCB (manufactured by GL Sciences Inc.). 3) Diastereomer method A mixture of racemates is converted into a mixture of diastereomers by a chemical reaction with an optically active reagent, and this mixture is subjected to usual separation means (eg, fractional recrystallization, chromatography method, etc.) to obtain a single substance. Then, a method of obtaining an optical isomer by cleaving the optically active reagent site by a chemical treatment such as a hydrolysis reaction. For example, when the compound (I) has hydroxy or 1,2 amino in the molecule, the compound and an optically active organic acid (for example, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid],
(−)-Menthoxyacetic acid and the like) and the like are subjected to a condensation reaction to obtain an ester or amide diastereomer, respectively. On the other hand, when the compound (I) has a carboxylic acid group, the compound and the optically active amine or alcohol reagent are subjected to a condensation reaction to obtain an amide or ester diastereomer, respectively. The separated diastereomer is converted into an optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis reaction.
【0052】[0052]
【発明の実施の形態】本発明は、以下の参考例、実施
例、実験例および製剤例によって、さらに詳しく説明さ
れるが、これらの例は本発明を限定するものではなく、
また本発明の範囲を逸脱しない範囲で変化させてもよ
い。なお、参考例および実施例中の略号は次の意味を有
する。
s:シングレット、 d:ダブレット、 t:トリプレ
ット、 q:クァルテット、 dd:ダブレットダブレ
ット、 dt:ダブレットトリプレット、 ddd:ダ
ブレットダブレットダブレット、 td:トリプレット
ダブレット、m:マルチプレット、 brs:幅広いシ
ングレット、 brt:幅広いトリプレット、 br
q:幅広いクァルテット、 tt:トリプレットトリプ
レット、J:カップリング定数、 室温:10〜30
℃、 %:重量%BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be explained in more detail by the following Reference Examples, Examples, Experimental Examples and Formulation Examples, but these Examples do not limit the present invention.
It may be changed without departing from the scope of the present invention. The abbreviations in Reference Examples and Examples have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dd: doublet doublet, dt: doublet triplet, ddd: doublet doublet, td: triplet doublet, m: multiplet, brs: wide singlet, brt: wide singlet. Triplet, br
q: wide quartet, tt: triplet triplet, J: coupling constant, room temperature: 10-30
℃,%:% by weight
【0053】[0053]
【実施例】参考例1
2-[(1H-1,2,4-トリアゾール-3-イルチオ)メチル]イミダ
ゾ[1,2-a]ピリミジン2-クロロメチルイミダゾ[1,2-a]ピ
リミジン(1289 mg, 7.7 mmol)、3-メルカプト-1,2,4-ト
リアゾール(778 mg, 7.7 mmol)及び炭酸カリウム(1063
mg, 7.7 mmol)のアセトニトリル(20 ml)溶液を70℃で4
時間撹拌した。反応液を室温に戻した後、水(100 ml)を
加え、生じた結晶を濾取した。水(20 ml×2)、アセトニ
トリル(10 ml)及びジエチルエーテル(10 ml)で順次洗浄
後、乾燥すると表題化合物(893mg, 収率50 %)を白色結
晶として得た。1
H-NMR (DMSO-d6) δ: 4.49 (2H, s), 7.03 (1H, dd,
J = 6.6, 4.4Hz), 7.80(1H, s), 8.44 (1H, s), 8.50
(1H, dd, J = 4.4, 2.2Hz), 8.91 (1H, dd, J =6.6, 2.
2Hz).
参考例2
6-クロロ-2-[(1H-1,2,4-トリアゾール-3-イルチオ)メチ
ル]イミダゾ[1,2-b]ピリダジン
6-クロロ-2-クロロメチルイミダゾ[1,2-a]ピリダジン(2
02 mg, 1 mmol)、3-メルカプト-1,2,4-トリアゾール(10
1 mg, 1 mmol)及び炭酸カリウム(137 mg, 1 mmol)のN,N
-ジメチルホルムアミド(2 ml)溶液を室温で1時間撹拌し
た。反応液に水(20 ml)を加え、塩化メチレン(20 ml)で
抽出し、有機層を飽和食塩水(20 ml)で洗浄、無水硫酸
ナトリウムで乾燥後、減圧濃縮した。得られた残留物を
ジイソプロピルエーテルで結晶化すると、表題化合物(1
86 mg, 収率 70%)を白色結晶として得た。1
H-NMR (DMSO-d6) δ: 4.50 (2H, s), 7.36 (1H, d,
J = 9.6Hz), 8.16 (1H,d, J = 9.6Hz), 8.18 (1H, s),
8.46 (1H, s).Examples Reference Example 1 2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-a] pyrimidine 2-chloromethylimidazo [1,2-a] pyrimidine ( 1289 mg, 7.7 mmol), 3-mercapto-1,2,4-triazole (778 mg, 7.7 mmol) and potassium carbonate (1063
4 mg of a solution of (mg, 7.7 mmol) in acetonitrile (20 ml) at 70 ° C.
Stir for hours. The reaction solution was returned to room temperature, water (100 ml) was added, and the generated crystals were collected by filtration. It was washed with water (20 ml × 2), acetonitrile (10 ml) and diethyl ether (10 ml) successively and dried to obtain the title compound (893 mg, yield 50%) as white crystals. 1 H-NMR (DMSO-d 6 ) δ: 4.49 (2H, s), 7.03 (1H, dd,
J = 6.6, 4.4Hz), 7.80 (1H, s), 8.44 (1H, s), 8.50
(1H, dd, J = 4.4, 2.2Hz), 8.91 (1H, dd, J = 6.6, 2.
Reference example 2 6-chloro-2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-b] pyridazine 6-chloro-2-chloromethylimidazo [1 , 2-a] pyridazine (2
02 mg, 1 mmol), 3-mercapto-1,2,4-triazole (10
1 mg, 1 mmol) and potassium carbonate (137 mg, 1 mmol) N, N
-The dimethylformamide (2 ml) solution was stirred at room temperature for 1 hour. Water (20 ml) was added to the reaction solution, extraction was performed with methylene chloride (20 ml), the organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (1
86 mg, yield 70%) was obtained as white crystals. 1 H-NMR (DMSO-d 6 ) δ: 4.50 (2H, s), 7.36 (1H, d,
J = 9.6Hz), 8.16 (1H, d, J = 9.6Hz), 8.18 (1H, s),
8.46 (1H, s).
【0054】参考例3
2-[(1H-1,2,4-トリアゾール-3-イルチオ)メチル]イミダ
ゾ[1,2-b]ピリダジン
2-クロロメチルイミダゾ[1,2-a]ピリダジン(700 mg, 4.
2 mmol)、3-メルカプト-1,2,4-トリアゾール(422 mg,
4.2 mmol)及び炭酸カリウム(577 mg, 4.2 mmol)のN,N-
ジメチルホルムアミド(4 ml)溶液を室温で18時間撹拌し
た。反応液に水(100 ml)を加え、生じた結晶を濾取し
た。水(20 ml×2)、ジエチルエーテル(10 ml)で順次洗
浄後、乾燥すると表題化合物(381 mg, 収率39 %)を白色
結晶として得た。1
H-NMR (DMSO-d6) δ: 4.50 (2H, s), 7.21 (1H, dd,
J = 9.2, 4.4Hz), 8.06(1H, dd, J = 9.2, 1.4Hz), 8.
13 (1H, s), 8.45 (1H, s), 8.47 (1H, dd, J =4.4, 1.
4Hz).
参考例4
2-[(1H-1,2,4-トリアゾール-3-イルチオ)メチル]イミダ
ゾ[1,2-a]ピリジン
2-クロロメチルイミダゾ[1,2-a]ピリミジン(15.5 g, 93
mmol)、3-メルカプト-1,2,4-トリアゾール(9.41 g, 93
mmol)及び炭酸カリウム(12.9 g, 93 mmol)のアセトニ
トリル(150 ml)溶液を70℃で4時間撹拌した。反応液を
室温に戻した後、水(500 ml)を加え、生じた結晶を濾取
した。水(200 ml)、アセトニトリル(100ml)及びジエチ
ルエーテル(50 ml)で順次洗浄後、乾燥すると表題化合
物(16.2 g, 収率75 %)を白色結晶として得た。1
H-NMR (DMSO-d6) δ: 4.47 (2H, s), 6.86 (1H, td,
J = 6.6, 1.0Hz), 7.21(1H, ddd, J = 9.2, 6.6, 1.0H
z), 7.49 (1H, dd, J = 9.2, 1.0Hz), 7.83 (1H, s),
8.44 (1H, s), 8.48 (1H, dt, J = 6.6, 1.0).Reference Example 3 2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-b] pyridazine 2-chloromethylimidazo [1,2-a] pyridazine (700 mg, 4.
2 mmol), 3-mercapto-1,2,4-triazole (422 mg,
4.2 mmol) and potassium carbonate (577 mg, 4.2 mmol) in N, N-
The dimethylformamide (4 ml) solution was stirred at room temperature for 18 hours. Water (100 ml) was added to the reaction solution, and the generated crystals were collected by filtration. It was washed with water (20 ml × 2) and diethyl ether (10 ml) successively and dried to obtain the title compound (381 mg, yield 39%) as white crystals. 1 H-NMR (DMSO-d 6 ) δ: 4.50 (2H, s), 7.21 (1H, dd,
J = 9.2, 4.4Hz), 8.06 (1H, dd, J = 9.2, 1.4Hz), 8.
13 (1H, s), 8.45 (1H, s), 8.47 (1H, dd, J = 4.4, 1.
Reference Example 4 2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-a] pyridine 2-chloromethylimidazo [1,2-a] pyrimidine (15.5 g, 93
mmol), 3-mercapto-1,2,4-triazole (9.41 g, 93
mmol) and potassium carbonate (12.9 g, 93 mmol) in acetonitrile (150 ml) were stirred at 70 ° C. for 4 hours. The reaction solution was returned to room temperature, water (500 ml) was added, and the generated crystals were collected by filtration. It was washed with water (200 ml), acetonitrile (100 ml) and diethyl ether (50 ml) successively and dried to obtain the title compound (16.2 g, yield 75%) as white crystals. 1 H-NMR (DMSO-d 6 ) δ: 4.47 (2H, s), 6.86 (1H, td,
J = 6.6, 1.0Hz), 7.21 (1H, ddd, J = 9.2, 6.6, 1.0H
z), 7.49 (1H, dd, J = 9.2, 1.0Hz), 7.83 (1H, s),
8.44 (1H, s), 8.48 (1H, dt, J = 6.6, 1.0).
【0055】参考例5
2-[(1H-1,2,4-トリアゾール-3-イルスルホニル)メチル]
イミダゾ[1,2-a]ピリジン
2-[(1H-1,2,4-トリアゾール-3-イルチオ)メチル]イミダ
ゾ[1,2-a]ピリジン(16.2 g, 70 mmol)のメタノール(100
ml)-水(170 ml)溶液に氷冷下濃硫酸(2.2 ml)及びオキ
ソン(64.5 g, 105 mmol)を加え、室温で5時間撹拌し
た。反応液に氷冷下、1N 水酸化ナトリウム水溶液を加
えpH8にし、析出した結晶を濾取した。水(200 ml)、ア
セトニトリル(100 ml)及びジエチルエーテル(50 ml)で
順次洗浄後、乾燥すると表題化合物(21.4 g, 収率100
%)を白色結晶として得た。1
H-NMR (DMSO-d6) δ: 4.91 (2H, s), 6.89 (1H, td,
J = 6.6, 1.0Hz), 7.23(1H, ddd, J = 9.2, 6.6, 1.
0), 7.47 (1H, dd, J = 9.2, 1.0Hz), 7.87 (1H,s), 8.
54 (1H, dt, 6.6, 1.0Hz), 8.90 (1H, s).
参考例6
2-[(1H-1,2,4-トリアゾール-3-イルスルフィニル)メチ
ル]イミダゾ[1,2-a]ピリジン
2-[(1H-1,2,4-トリアゾール-3-イルチオ)メチル]イミダ
ゾ[1,2-a]ピリジン(500 mg, 2.2 mmol)のメタノール(3
ml)-水(5 ml)溶液に氷冷下濃硫酸(0.073 ml)及びオキソ
ン(797 mg, 1.3 mmol)を加え、室温で5時間撹拌した。
反応液に氷冷下、1N 水酸化ナトリウム水溶液を加えpH
8にし、析出した結晶を濾取した。水(5ml)、エタノール
(5 ml)及びジイソプロピルエーテル(5 ml)で順次洗浄
後、乾燥すると表題化合物(104 mg, 収率20 %)を薄黄色
結晶として得た。1
H-NMR (DMSO-d6) δ: 4.64 (2H, s), 6.88 (1H, td,
J = 6.6, 1.0Hz), 7.23(1H, ddd, J = 9.2, 6.6, 1.0H
z), 7.51 (1H, dd, J = 9.2, 1.0,Hz), 7.80 (1H, s),
8.50 (1H, dt, J = 6.6, 1.0Hz), 8.87 (1H, s).Reference Example 5 2-[(1H-1,2,4-triazol-3-ylsulfonyl) methyl]
Imidazo [1,2-a] pyridine 2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-a] pyridine (16.2 g, 70 mmol) in methanol (100
ml) -water (170 ml) solution, concentrated sulfuric acid (2.2 ml) and oxone (64.5 g, 105 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was adjusted to pH 8 with 1N aqueous sodium hydroxide solution under ice cooling, and the precipitated crystals were collected by filtration. It was washed with water (200 ml), acetonitrile (100 ml) and diethyl ether (50 ml) successively and dried to give the title compound (21.4 g, yield 100
%) As white crystals. 1 H-NMR (DMSO-d 6 ) δ: 4.91 (2H, s), 6.89 (1H, td,
J = 6.6, 1.0Hz), 7.23 (1H, ddd, J = 9.2, 6.6, 1.
0), 7.47 (1H, dd, J = 9.2, 1.0Hz), 7.87 (1H, s), 8.
54 (1H, dt, 6.6, 1.0Hz), 8.90 (1H, s). Reference Example 6 2-[(1H-1,2,4-triazol-3-ylsulfinyl) methyl] imidazo [1,2-a] ] Pyridine 2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-a] pyridine (500 mg, 2.2 mmol) in methanol (3
Concentrated sulfuric acid (0.073 ml) and oxone (797 mg, 1.3 mmol) were added to a (ml) -water (5 ml) solution under ice cooling, and the mixture was stirred at room temperature for 5 hours.
To the reaction mixture was added 1N sodium hydroxide aqueous solution under ice cooling to adjust the pH.
Then, the precipitated crystals were collected by filtration. Water (5 ml), ethanol
(5 ml) and diisopropyl ether (5 ml) were washed successively, and dried to obtain the title compound (104 mg, yield 20%) as pale yellow crystals. 1 H-NMR (DMSO-d 6 ) δ: 4.64 (2H, s), 6.88 (1H, td,
J = 6.6, 1.0Hz), 7.23 (1H, ddd, J = 9.2, 6.6, 1.0H
z), 7.51 (1H, dd, J = 9.2, 1.0, Hz), 7.80 (1H, s),
8.50 (1H, dt, J = 6.6, 1.0Hz), 8.87 (1H, s).
【0056】参考例7
N,N-ジエチル-3-[(イミダゾ[1,2-a]ピリジン-2-イルメ
チル)スルフィニル]-1H-1,2,4-トリアゾール-1-カルボ
キサミド
2-[(1H-1,2,4-トリアゾール-3-イルスルフィニル)メチ
ル]イミダゾ[1,2-a]ピリジン(80 mg, 0.324 mmol)及び
炭酸カリウム(54 mg, 0.39 mmol)のジメチルスルホキシ
ド(1mol)溶液にジエチルカルバモイルクロリド(0.049 m
l, 3.9 mmol)を加え、室温で18時間撹拌した。反応液に
水(10 ml)を加え、塩化メチレン(10 ml)で抽出した。有
機層を飽和食塩水で(20 ml)洗浄し、無水硫酸ナトリウ
ムで乾燥後、減圧濃縮した。得られた残留物をフラッシ
ュシリカゲルクロマトグラフィー(酢酸エチル:メタノ
ール=10/1, v/v)で精製し、ジイソプロピルエーテル-
ヘキサン(1/1,5 ml)で結晶化すると、表題化合物(77 m
g, 収率69%)を白色結晶として得た。
融点 174.6-175.6℃1
H-NMR (CDCl3) δ: 1.10-1.30 (6H, m), 3.40-3.70
(4H, m), 4.74 (2H, s),6.90 (1H, td, J = 6.7, 1.2H
z), 7.32 (1H, ddd, J = 9.0, 6.7, 1.2Hz), 7.62 (1
H, dt, J = 9.0, 1.2Hz), 7.70 (1H, s), 8.13 (1H, d
t, J = 6.7, 1.2Hz), 8.93 (1H, s).
IR (KBr): 1709, 1433, 1275, 1059 cm-1.
元素分析値 C15H18N6O2S・0.5H2Oとして
計算値(%): C, 50.69; H, 5.39; N, 23.65.
実測値(%): C, 50.92; H, 5.33; N, 23.88.
参考例8
N,N-ジエチル-3-[(イミダゾ[1,2-a]ピリジン-2-イルメ
チル)スルホニル]-1H-1,2,4-トリアゾール-1-カルボキ
サミド
2-[(1H-1,2,4-トリアゾール-3-イルスルホニル)メチル]
イミダゾ[1,2-a]ピリジン(1420 mg, 4.71 mmol)及び炭
酸カリウム(780 mg, 5.6 mmol)のジメチルスルホキシド
(10 mol)溶液にジエチルカルバモイルクロリド(0.659 m
l, 5.2 mmol)を加え、室温で20時間撹拌した。反応液に
水(30 ml)を加え、塩化メチレン(20 ml× 2)で抽出し
た。有機層を飽和食塩水で(20 ml)洗浄し、無水硫酸ナ
トリウムで乾燥後、減圧濃縮した。得られた残留物をジ
イソプロピルエーテルから結晶化すると、表題化合物(1
592 mg, 収率93%)を白色結晶として得た。1
H-NMR (CDCl3) δ: 1.00-1.40 (6H, m), 3.50 (4H,
q, J = 7.0Hz), 4.89 (2H, s), 6.81 (1H, td, J = 6.
6, 1.2Hz), 7.17 (1H, ddd, J = 9.0, 6.6, 1.2Hz),
7.48 (1H, dd, J = 9.0, 1.2Hz), 7.78 (1H, s), 8.09
(1H, dt, J = 6.6, 1.2Hz), 8.86 (1H, s).Reference Example 7 N, N-diethyl-3-[(imidazo [1,2-a] pyridin-2-ylmethyl) sulfinyl] -1H-1,2,4-triazole-1-carboxamide 2-[( 1H-1,2,4-triazol-3-ylsulfinyl) methyl] imidazo [1,2-a] pyridine (80 mg, 0.324 mmol) and potassium carbonate (54 mg, 0.39 mmol) in dimethyl sulfoxide (1 mol) Diethylcarbamoyl chloride (0.049 m
(1, 3.9 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Water (10 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (10 ml). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography (ethyl acetate: methanol = 10/1, v / v), and diisopropyl ether-
Crystallization from hexane (1 / 1,5 ml) gave the title compound (77 m
g, yield 69%) was obtained as white crystals. Melting point 174.6-175.6 ° C 1 H-NMR (CDCl 3 ) δ: 1.10-1.30 (6H, m), 3.40-3.70
(4H, m), 4.74 (2H, s), 6.90 (1H, td, J = 6.7, 1.2H
z), 7.32 (1H, ddd, J = 9.0, 6.7, 1.2Hz), 7.62 (1
H, dt, J = 9.0, 1.2Hz), 7.70 (1H, s), 8.13 (1H, d
t, J = 6.7, 1.2Hz), 8.93 (1H, s). IR (KBr): 1709, 1433, 1275, 1059 cm -1 . Elemental analysis C 15 H 18 N 6 O 2 S ・ 0.5H 2 O Calculated as (%): C, 50.69; H, 5.39; N, 23.65. Measured value (%): C, 50.92; H, 5.33; N, 23.88. Reference Example 8 N, N-diethyl-3-[( Imidazo [1,2-a] pyridin-2-ylmethyl) sulfonyl] -1H-1,2,4-triazol-1-carboxamide 2-[(1H-1,2,4-triazol-3-ylsulfonyl) methyl ]
Imidazo [1,2-a] pyridine (1420 mg, 4.71 mmol) and potassium carbonate (780 mg, 5.6 mmol) in dimethyl sulfoxide
(10 mol) solution in diethylcarbamoyl chloride (0.659 m
(1, 5.2 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Water (30 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (20 ml × 2). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (1
(592 mg, yield 93%) was obtained as white crystals. 1 H-NMR (CDCl 3 ) δ: 1.00-1.40 (6H, m), 3.50 (4H,
q, J = 7.0Hz), 4.89 (2H, s), 6.81 (1H, td, J = 6.
6, 1.2Hz), 7.17 (1H, ddd, J = 9.0, 6.6, 1.2Hz),
7.48 (1H, dd, J = 9.0, 1.2Hz), 7.78 (1H, s), 8.09
(1H, dt, J = 6.6, 1.2Hz), 8.86 (1H, s).
【0057】参考例9
3-{[(3-クロロイミダゾ[1,2-a]ピリジン-2-イル)メチ
ル]スルホニル}-N,N-ジエチル-1H-1,2,4-トリアゾール-
1-カルボキサミド
N,N-ジエチル-3-[(イミダゾ[1,2-a]ピリジン-2-イルメ
チル)スルホニル]-1H-1,2,4-トリアゾール-1-カルボキ
サミド(500 mg, 1.4 mmol)のN,N-ジメチルホルムアミド
(6 ml)溶液に氷冷下、N-クロロコハク酸イミド(98%含
量, 314 mg, 2.4 mmol)を加え、室温で15時間撹拌し
た。反応液に水(20 ml)を加え、塩化メチレン(20 ml ×
2)で抽出し、有機層を飽和食塩水(20 ml)で洗浄後、無
水硫酸ナトリウムで乾燥した。溶媒を減圧濃縮し、残留
物をフラッシュシリカゲルクロマトグラフィー(酢酸エ
チル:ヘキサン=5/1→酢酸エチル, v/v)で精製し、ジ
イソプロピルエーテルで結晶化すると、表題化合物(180
mg, 収率32%)を白色結晶として得た。1
H-NMR (CDCl3) δ: 1.21 (6H, br), 3.5 (4H, q, J
= 7.0Hz), 4.89 (2H, s), 6.96 (1H, td, J = 6.8,
1.1Hz), 7.24 (1H, ddd, J = 9.2, 6.8, 1.3Hz),7.49
(1H, dd, J = 9.2, 1.1Hz), 8.04 (1H, dt, J = 6.8,
1.1Hz), 8.89 (1H, s).
参考例10
N,N-ジエチル-3-[(メシチリルメチル)チオ]-1H-1,2,4-
トリアゾール-1-カルボキサミド
3-[(メシチルメチル)チオ]-1H-1,2,4-トリアゾール(500
mg, 2.14 mmol)及び炭酸カリウム(355 mg, 2.57 mmol)
のジメチルスルホキシド(5 ml)溶液にジエチルカルバモ
イルクロリド (0.326 ml, 2.57 mmol)を加え、室温で2
日間撹拌した。反応液に水(20 ml)を加え、塩化メチレ
ン(10ml)で抽出した。有機層を飽和食塩水で(30 ml)洗
浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得
られた残留物をフラッシュシリカゲルクロマトグラフィ
ー(酢酸エチル:ヘキサン=1/1, v/v)で精製し、ジイソ
プロピルエーテル-ヘキサンで結晶化すると、表題化合
物(514 mg, 収率72%)を白色結晶として得た。
融点 84.0-85.5℃1
H-NMR (CDCl3) δ: 1.31 (6H, t, J = 7.0Hz), 2.27
(3H, s), 2.41 (6H, s), 3.62 (4H, brq, J = 7.0Hz),
4.43 (2H, s), 6.87 (2H, s), 8.78 (1H, s).IR (KB
r): 2970, 1698, 1472, 1429, 1269, 1254 cm-1.
元素分析値 C17H24N4OSとして
計算値(%): C, 61.41; H, 7.28; N, 16.85.
実測値(%): C, 61.39; H, 7.17; N, 16.92.Reference Example 9 3-{[(3-chloroimidazo [1,2-a] pyridin-2-yl) methyl] sulfonyl} -N, N-diethyl-1H-1,2,4-triazole-
1-Carboxamide N, N-diethyl-3-[(imidazo [1,2-a] pyridin-2-ylmethyl) sulfonyl] -1H-1,2,4-triazole-1-carboxamide (500 mg, 1.4 mmol) N, N-dimethylformamide
N-chlorosuccinimide (98% content, 314 mg, 2.4 mmol) was added to the (6 ml) solution under ice cooling, and the mixture was stirred at room temperature for 15 hr. Water (20 ml) was added to the reaction mixture, and methylene chloride (20 ml ×
After extraction with 2), the organic layer was washed with saturated saline (20 ml) and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, the residue was purified by flash silica gel chromatography (ethyl acetate: hexane = 5/1 → ethyl acetate, v / v), and crystallized from diisopropyl ether to give the title compound (180
mg, yield 32%) was obtained as white crystals. 1 H-NMR (CDCl 3 ) δ: 1.21 (6H, br), 3.5 (4H, q, J
= 7.0Hz), 4.89 (2H, s), 6.96 (1H, td, J = 6.8,
1.1Hz), 7.24 (1H, ddd, J = 9.2, 6.8, 1.3Hz), 7.49
(1H, dd, J = 9.2, 1.1Hz), 8.04 (1H, dt, J = 6.8,
1.1Hz), 8.89 (1H, s). Reference Example 10 N, N-diethyl-3-[(mesitylylmethyl) thio] -1H-1,2,4-
Triazole-1-carboxamide 3-[(mesitylmethyl) thio] -1H-1,2,4-triazole (500
mg, 2.14 mmol) and potassium carbonate (355 mg, 2.57 mmol)
Diethyl carbamoyl chloride (0.326 ml, 2.57 mmol) was added to a solution of dimethylsulfoxide (5 ml) in water at room temperature.
It was stirred for a day. Water (20 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (10 ml). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography (ethyl acetate: hexane = 1/1, v / v) and crystallized from diisopropyl ether-hexane to give the title compound (514 mg, yield 72%) as white. Obtained as crystals. Melting point 84.0-85.5 ° C 1 H-NMR (CDCl 3 ) δ: 1.31 (6H, t, J = 7.0Hz), 2.27
(3H, s), 2.41 (6H, s), 3.62 (4H, brq, J = 7.0Hz),
4.43 (2H, s), 6.87 (2H, s), 8.78 (1H, s) .IR (KB
r): 2970, 1698, 1472, 1429, 1269, 1254 cm -1 . Elemental analysis value C 17 H 24 N 4 Calculated as OS (%): C, 61.41; H, 7.28; N, 16.85. %): C, 61.39; H, 7.17; N, 16.92.
【0058】参考例11
N,N-ジエチル-3-[(メシチルメチル)スルホニル]-1H-1,
2,4-トリアゾール-1-カルボキサミド
N,N-ジエチル-3-[(メシチリルメチル)チオ]-1H-1,2,4-
トリアゾール-1-カルボキサミド(333 mg, 1 mmol)のメ
タノール(16 ml)-水(4 ml)溶液に濃硫酸(0.034 ml)及び
オキソン(922 mg, 1.5 mmol)を加え、室温で20時間撹拌
した。反応液に氷冷下、1N 水酸化ナトリウム水溶液を
加えpH8にし、塩化メチレン(10 ml×2)で抽出した。有
機層を飽和食塩水で(20 ml)洗浄し、無水硫酸ナトリウ
ムで乾燥後、減圧濃縮した。残留物をフラッシュシリカ
ゲルクロマトグラフィー(酢酸エチル:ヘキサン=2/1,
v/v)に付し、第一溶出分を減圧濃縮し、ジイソプロピル
エーテルより結晶化すると表題化合物(152 mg, 収率42
%)を白色結晶として得た。融点 132.1-132.4℃1
H-NMR (CDCl3) δ: 1.30 (6H, t, J = 7.0Hz), 2.27
(3H, s), 2.41 (6H, s), 3.50-3.70 (4H, m), 4.80 (2
H, s), 6.92 (2H, s), 8.92 (1H, s).
IR (KBr): 1717, 1435, 1333, 1429, 1269, 1254 cm-1.
元素分析値 C17H24N4O3Sとして
計算値(%): C, 56.02; H, 6.64; N, 15.37.
実測値(%): C, 56.10; H, 7.51; N, 15.86.
参考例12
N,N-ジエチル-3-[(メシチルメチル)スルフィニル]-1H-
1,2,4-トリアゾール-1-カルボキサミド
参考例11で行ったフラッシュシリカゲルカラムクロマト
グラフィーにおける第二溶出分を減圧濃縮し、ジイソプ
ロピルエーテルより結晶化すると表題化合物(70 mg, 収
率20%)を白色結晶として得た。
融点 117.3-118.6℃1
H-NMR (CDCl3) δ: 1.27 (6H, brt, J = 6.6Hz), 2.
26 (3H, s), 2.35 (6H,s), 3.55 (4H, brq, J = 6.6H
z), 4.42 (1H, d, J = 13.2Hz), 4.77 (1H, d, J= 13.2
Hz), 6.89 (2H, s), 8.93 (1H, s).
IR (KBr): 1709, 1474, 1431, 1273, 1073 cm-1.
元素分析値 C17H24N4O2Sとして
計算値(%): C, 58.59; H, 6.94; N, 16.08.
実測値(%): C, 58.61; H, 7.24; N, 16.32.Reference Example 11 N, N-diethyl-3-[(mesitylmethyl) sulfonyl] -1H-1,
2,4-triazole-1-carboxamide N, N-diethyl-3-[(mesitylylmethyl) thio] -1H-1,2,4-
To a solution of triazole-1-carboxamide (333 mg, 1 mmol) in methanol (16 ml) -water (4 ml) was added concentrated sulfuric acid (0.034 ml) and oxone (922 mg, 1.5 mmol), and the mixture was stirred at room temperature for 20 hours. . The reaction solution was adjusted to pH 8 with 1N aqueous sodium hydroxide solution under ice cooling, and extracted with methylene chloride (10 ml × 2). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography (ethyl acetate: hexane = 2/1,
v / v), the first eluate was concentrated under reduced pressure and crystallized from diisopropyl ether to give the title compound (152 mg, yield 42
%) As white crystals. Melting point 132.1-132.4 ° C 1 H-NMR (CDCl 3 ) δ: 1.30 (6H, t, J = 7.0Hz), 2.27
(3H, s), 2.41 (6H, s), 3.50-3.70 (4H, m), 4.80 (2
H, s), 6.92 (2H, s), 8.92 (1H, s). IR (KBr): 1717, 1435, 1333, 1429, 1269, 1254 cm -1 . Elemental analysis C 17 H 24 N 4 O 3 Calculated value for S (%): C, 56.02; H, 6.64; N, 15.37. Measured value (%): C, 56.10; H, 7.51; N, 15.86. Reference Example 12 N, N-diethyl-3- [ (Mesitylmethyl) sulfinyl] -1H-
1,2,4-triazole-1-carboxamide The second eluate in flash silica gel column chromatography performed in Reference Example 11 was concentrated under reduced pressure and crystallized from diisopropyl ether to give the title compound (70 mg, yield 20%). Obtained as white crystals. Melting point 117.3-118.6 ° C 1 H-NMR (CDCl 3 ) δ: 1.27 (6H, brt, J = 6.6Hz), 2.
26 (3H, s), 2.35 (6H, s), 3.55 (4H, brq, J = 6.6H
z), 4.42 (1H, d, J = 13.2Hz), 4.77 (1H, d, J = 13.2)
Hz), 6.89 (2H, s), 8.93 (1H, s). IR (KBr): 1709, 1474, 1431, 1273, 1073 cm -1 . Elemental analysis value Calculated as C 17 H 24 N 4 O 2 S (%): C, 58.59; H, 6.94; N, 16.08. Actual value (%): C, 58.61; H, 7.24; N, 16.32.
【0059】実施例1
3-[(イミダゾ[1,2-a]ピリジン-2-イルメチル)スルホニ
ル]-N,N-ジメチル-1H-1,2,4-トリアゾール-1-カルボキ
サミド
2-[(1H-1,2,4-トリアゾール-3-イルスルホニル)メチル]
イミダゾ[1,2-a]ピリジン(527 mg, 2 mmol)及び炭酸カ
リウム(332 mg, 2.4 mmol)のジメチルスルホキシド(5 m
ol)溶液にジメチルカルバモイルクロリド(0.295 ml, 3.
2 mmol)を加え、室温で2時間撹拌した。反応液に水(20
ml)を加え、塩化メチレン(20 ml × 2)で抽出した。有
機層を飽和食塩水で(20 ml)洗浄し、無水硫酸ナトリウ
ムで乾燥後、減圧濃縮した。得られた残留物をジイソプ
ロピルエーテルから結晶化すると、表題化合物(565 mg,
収率85%)を白色結晶として得た。
融点 1991-202.4℃1
H-NMR (DMSO-d6) δ: 2.92 (3H, brs), 3.05 (3H, b
rs), 5.00 (2H, s), 6.90 (1H, td, J = 7.0, 1.0Hz),
7.22 (1H, ddd, J = 9.2, 7.0, 1.0Hz), 7.41 (1H, dd,
J = 9.2, 1.0Hz), 7.94 (1H, s), 8.54 (1H, td, J
= 7.0, 1.0Hz), 9.35 (1H, s).
元素分析値 C13H14N6O3Sとして
計算値(%): C, 46.70; H, 4.22; N, 25.14.
実測値(%): C, 46.58; H, 4.08; N, 24.85.
実施例2
3-[(イミダゾ[1,2-a]ピリジン-2-イルメチル)スルホニ
ル]-N,N-ジイソプロピル-1H-1,2,4-トリアゾール-1-カ
ルボキサミド
2-[(1H-1,2,4-トリアゾール-3-イルスルホニル)メチル]
イミダゾ[1,2-a]ピリジン(526.6 mg, 2 mmol)及び炭酸
カリウム(443 mg, 3.2 mmol)のジメチルスルホキシド(5
ml)溶液にジイソプロピルカルバモイルクロリド (589
mg, 3.6 mmol)を加え、室温で4日間撹拌した。反応液に
水(20 ml)を加え、塩化メチレン(30ml× 2)で抽出し
た。有機層を水(20 ml)、飽和食塩水で(20 ml)洗浄し、
無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた
残留物をフラッシュシリカゲルクロマトグラフィー(酢
酸エチル)で精製し、ジイソプロピルエーテルから結晶
化すると、表題化合物(348 mg, 収率45%)を白色結晶と
して得た。
融点 195.0-195.6℃1
H-NMR (CDCl3) δ: 1.12-1.60 (12H, m), 3.70-4.20
(2H, m), 4.90 (2H, s), 6.81 (1H, td, J = 7.0, 1.
0Hz), 7.17 (1H, ddd, J = 10.0, 7.0, 1.0Hz),7.48
(1H, dd, J = 10.0, 1.0Hz), 7.78 (1H, s), 8.09 (1
H, dt, J = 7.0,1.0Hz), 8.75 (1H, s).
IR (KBr): 1717, 1360, 1335, 1306 cm−1.
元素分析値 C17H22ClN6O3Sとして
計算値(%): C, 52.29; H, 5.68; N, 21.52.
実測値(%): C, 52.34; H, 5.50; N, 21.34.Example 1 3-[(imidazo [1,2-a] pyridin-2-ylmethyl) sulfonyl] -N, N-dimethyl-1H-1,2,4-triazole-1-carboxamide 2-[( 1H-1,2,4-triazol-3-ylsulfonyl) methyl]
Imidazo [1,2-a] pyridine (527 mg, 2 mmol) and potassium carbonate (332 mg, 2.4 mmol) in dimethyl sulfoxide (5 m
ol) solution in dimethylcarbamoyl chloride (0.295 ml, 3.
(2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (20
ml) was added, and the mixture was extracted with methylene chloride (20 ml × 2). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (565 mg,
Yield 85%) was obtained as white crystals. Melting point 1991-202.4 ° C 1 H-NMR (DMSO-d 6 ) δ: 2.92 (3H, brs), 3.05 (3H, b
rs), 5.00 (2H, s), 6.90 (1H, td, J = 7.0, 1.0Hz),
7.22 (1H, ddd, J = 9.2, 7.0, 1.0Hz), 7.41 (1H, dd,
J = 9.2, 1.0Hz), 7.94 (1H, s), 8.54 (1H, td, J
= 7.0, 1.0Hz), 9.35 (1H, s). Elemental analysis value Calculated as C 13 H 14 N 6 O 3 S (%): C, 46.70; H, 4.22; N, 25.14. Measured value (%) : C, 46.58; H, 4.08; N, 24.85. Example 2 3-[(imidazo [1,2-a] pyridin-2-ylmethyl) sulfonyl] -N, N-diisopropyl-1H-1,2,4 -Triazole-1-carboxamide 2-[(1H-1,2,4-triazol-3-ylsulfonyl) methyl]
Imidazo [1,2-a] pyridine (526.6 mg, 2 mmol) and potassium carbonate (443 mg, 3.2 mmol) in dimethyl sulfoxide (5
(ml) solution with diisopropylcarbamoyl chloride (589
(mg, 3.6 mmol) was added, and the mixture was stirred at room temperature for 4 days. Water (20 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (30 ml × 2). The organic layer was washed with water (20 ml) and saturated saline (20 ml),
The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography (ethyl acetate) and crystallized from diisopropyl ether to give the title compound (348 mg, yield 45%) as white crystals. Melting point 195.0-195.6 ° C 1 H-NMR (CDCl 3 ) δ: 1.12-1.60 (12H, m), 3.70-4.20
(2H, m), 4.90 (2H, s), 6.81 (1H, td, J = 7.0, 1.
0Hz), 7.17 (1H, ddd, J = 10.0, 7.0, 1.0Hz), 7.48
(1H, dd, J = 10.0, 1.0Hz), 7.78 (1H, s), 8.09 (1
H, dt, J = 7.0,1.0Hz), 8.75 (1H, s). IR (KBr): 1717, 1360, 1335, 1306 cm −1 . Elemental analysis value Calculated as C 17 H 22 ClN 6 O 3 S (%): C, 52.29; H, 5.68; N, 21.52. Actual value (%): C, 52.34; H, 5.50; N, 21.34.
【0060】実施例3
3-{[(3-クロロイミダゾ[1,2-a]ピリジン-2-イル)メチ
ル]スルホニル}-N,N-ジメチル-1H-1,2,4-トリアゾール-
1-カルボキサミド
3-[(イミダゾ[1,2-a]ピリジン-2-イルメチル)スルホニ
ル]-N,N-ジメチル-1H-1,2,4-トリアゾール-1-カルボキ
サミド(334 mg, 1 mmol)のN,N-ジメチルホルムアミド(5
ml)溶液に氷冷下N-クロロコハク酸イミド(98%含量, 23
1 mg, 1.7 mmol)を加え、室温で15時間撹拌した。反応
液に水(20 ml)を加え、塩化メチレン(20 ml × 2)で抽
出し、有機層を飽和食塩水(20 ml)で洗浄後、無水硫酸
ナトリウムで乾燥した。溶媒を減圧濃縮し、残留物をフ
ラッシュシリカゲルクロマトグラフィー(酢酸エチル:
ヘキサン=5/1→酢酸エチル→酢酸エチル:メタノール
=10/1,v/v)で精製し、ジイソプロピルエーテルで結晶
化すると、表題化合物(130 mg,収率35%)を白色結晶とし
て得た。
融点 174.7-175.6℃1
H-NMR (CDCl3) δ: 3.17 (3H, brs), 3.21 (3H, br
s), 4.90 (2H, s), 6.96(1H, td, J = 7.0, 1.0Hz),
7.24 (1H, ddd, J = 9.2, 7.0, 1.0Hz), 7.48 (1H, d
t, J = 9.2, 1.0Hz), 8.03 (1H, dt, J = 7.0, 1.0H
z), 8.88 (1H, s).
元素分析値 C13H13ClN6O3Sとして
計算値(%): C, 42.34; H, 3.55; N, 22.36.
実測値(%): C, 42.37; H, 3.53; N, 22.36.
実施例4
3-{[(3-クロロイミダゾ[1,2-a]ピリジン-2-イル)メチ
ル]スルホニル}-N,N-ジイソプロピル-1H-1,2,4-トリア
ゾール-1-カルボキサミド
3-[(イミダゾ[1,2-a]ピリジン-2-イルメチル)スルホニ
ル]-N,N-ジイソプロピル-1H-1,2,4-トリアゾール-1-カ
ルボキサミド(200 mg, 0.512 mmol)のN,N-ジメチルホル
ムアミド(2.5 ml)溶液に氷冷下、N-クロロコハク酸イミ
ド(98%含量, 105 mg, 0.768 mmol)を加え、室温で20時
間撹拌した。反応液に塩化メチレン(20 ml)を加え、水
(20 ml)、飽和食塩水(20 ml)で洗浄後、無水硫酸ナトリ
ウムで乾燥した。溶媒を減圧濃縮し、得られた残留物に
塩化メチレンを加え、結晶化すると表題化合物(54 mg,
収率20%)を白色結晶として得た。濾液をフラッシュシリ
カゲルクロマトグラフィー(酢酸エチル:ヘキサン=3/2
→酢酸エチル, v/v)で精製し、ジイソプロピルエーテル
で結晶化すると表題化合物(29 mg, 収率13%)を得た。融
点 231.8-133.9℃1
H-NMR (CDCl3) δ: 1.00-1.50 (12H, m), 3.80-4.20
(2H, m), 4.90 (2H, s), 6.96 (1H, td, J = 7.0, 1.
0Hz), 7.24 (1H, ddd, J = 9.2, 7.0, 1.0Hz),7.50 (1
H, dd, J = 9.2, 1.0Hz), 8.03 (1H, dt, J = 7.0,
1.0Hz), 8.78 (1H, s).
IR (KBr): 1717, 1350, 1306, 1148 cm−1.
元素分析値 C17H21ClN6O3Sとして
計算値(%): C, 48.05; H, 4.98; N, 19.78.
実測値(%): C, 48.00; H, 4.94; N, 19.17.Example 3 3-{[(3-chloroimidazo [1,2-a] pyridin-2-yl) methyl] sulfonyl} -N, N-dimethyl-1H-1,2,4-triazole-
1-Carboxamide 3-[(imidazo [1,2-a] pyridin-2-ylmethyl) sulfonyl] -N, N-dimethyl-1H-1,2,4-triazole-1-carboxamide (334 mg, 1 mmol) N, N-dimethylformamide (5
N-chlorosuccinimide (98% content, 23%
1 mg, 1.7 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Water (20 ml) was added to the reaction solution, extraction was performed with methylene chloride (20 ml × 2), the organic layer was washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was subjected to flash silica gel chromatography (ethyl acetate:
Hexane = 5/1-> ethyl acetate-> ethyl acetate: methanol = 10/1, v / v) and purified by diisopropyl ether to give the title compound (130 mg, yield 35%) as white crystals. . Melting point 174.7-175.6 ° C 1 H-NMR (CDCl 3 ) δ: 3.17 (3H, brs), 3.21 (3H, br
s), 4.90 (2H, s), 6.96 (1H, td, J = 7.0, 1.0Hz),
7.24 (1H, ddd, J = 9.2, 7.0, 1.0Hz), 7.48 (1H, d
t, J = 9.2, 1.0Hz), 8.03 (1H, dt, J = 7.0, 1.0H
z), 8.88 (1H, s). Elemental analysis value Calculated as C 13 H 13 ClN 6 O 3 S (%): C, 42.34; H, 3.55; N, 22.36. Measured value (%): C, 42.37 H, 3.53; N, 22.36. Example 4 3-{[(3-chloroimidazo [1,2-a] pyridin-2-yl) methyl] sulfonyl} -N, N-diisopropyl-1H-1,2 , 4-Triazole-1-carboxamide 3-[(imidazo [1,2-a] pyridin-2-ylmethyl) sulfonyl] -N, N-diisopropyl-1H-1,2,4-triazole-1-carboxamide (200 N, N-Dimethylformamide (2.5 ml) solution of (mg, 0.512 mmol) was added with N-chlorosuccinimide (98% content, 105 mg, 0.768 mmol) under ice cooling, and the mixture was stirred at room temperature for 20 hours. Add methylene chloride (20 ml) to the reaction mixture and add water.
(20 ml) and saturated brine (20 ml), and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, methylene chloride was added to the obtained residue, and crystallization was performed to give the title compound (54 mg,
Yield 20%) was obtained as white crystals. The filtrate was subjected to flash silica gel chromatography (ethyl acetate: hexane = 3/2
→ Purified with ethyl acetate, v / v) and crystallized with diisopropyl ether to give the title compound (29 mg, yield 13%). Melting point 231.8-133.9 ° C 1 H-NMR (CDCl 3 ) δ: 1.00-1.50 (12H, m), 3.80-4.20
(2H, m), 4.90 (2H, s), 6.96 (1H, td, J = 7.0, 1.
0Hz), 7.24 (1H, ddd, J = 9.2, 7.0, 1.0Hz), 7.50 (1
H, dd, J = 9.2, 1.0Hz), 8.03 (1H, dt, J = 7.0,
1.0Hz), 8.78 (1H, s) .IR (KBr): 1717, 1350, 1306, 1148 cm −1 . Elemental analysis value C 17 H 21 ClN 6 O 3 S Calculated value (%): C, 48.05; H, 4.98; N, 19.78. Found (%): C, 48.00; H, 4.94; N, 19.17.
【0061】実施例5
3-[(イミダゾ[1,2-a]ピリミジン-2-イルメチル)チオ]-
N,N-ジメチル-1H-1,2,4-トリアゾール-1-カルボキサミ
ド
2-[(1H-1,2,4-トリアゾール-3-イルチオ)メチル]イミダ
ゾ[1,2-a]ピリミジン(465 mg, 2 mmol)及び炭酸カリウ
ム(332 mg, 2.4 mmol)のジメチルスルホキシド(5 ml)溶
液にジメチルカルバモイルクロリド (0.258 ml, 2.8 mm
ol)を加え、室温で2日間撹拌した。反応液に水(20 ml)
を加え、塩化メチレン(10ml)で抽出した。有機層を飽和
食塩水で(30 ml)洗浄し、無水硫酸ナトリウムで乾燥
後、減圧濃縮した。得られた残留物をジイソプロピルエ
ーテルで結晶化すると、表題化合物(469 mg, 収率77%)
を白黄色結晶として得た。
融点 149.9-150.3℃1
H-NMR (CDCl3) δ: 3.20 (6H, brs), 4.60 (2H, d,
J = 0.8Hz), 6.85 (1H,dd, J = 6.0, 4.0Hz), 7.55 (1
H, s), 8.35 (1H, dd, J = 6.6, 2.2Hz), 8.52 (1H, d
d, J = 4.0, 2.2Hz), 8.73 (1H, s).
IR (KBr): 1701, 1507, 1483, 1402, 1240 cm−1.
元素分析値 C12H13N7OSとして
計算値(%): C, 47.51; H, 4.32; N, 32.32.
実測値(%): C, 47.13; H, 4.38; N, 31.98.
実施例6
3-[(イミダゾ[1,2-a]ピリミジン-2-イルメチル)スルホ
ニル]-N,N-ジメチル-1H-1,2,4-トリアゾール-1-カルボ
キサミド
3-[(イミダゾ[1,2-a]ピリミジン-2-イルメチル)チオ]-
N,N-ジメチル-1H-1,2,4-トリアゾール-1-カルボキサミ
ド(400 mg, 1.32 mmol)のメタノール(5 ml)-水(10 ml)
溶液に濃硫酸(0.045 ml)及びオキソン(1217 mg, 1.98 m
mol)を加え、室温で12時間撹拌した。反応液に水(10 m
l)を加え、塩化メチレン(20 ml×2)で抽出した。有機層
を飽和食塩水で(10 ml)洗浄し、無水硫酸ナトリウムで
乾燥後、減圧濃縮した。残留物をフラッシュシリカゲル
クロマトグラフィー(酢酸エチル:メタノール=10/1→2
/1, v/v)に付し、ジイソプロピルエーテルで結晶化する
と表題化合物(111 mg, 収率25%)を白色結晶として得
た。融点 215.6-217.1℃1
H-NMR (DMSO-d6) δ: 2.95 (3H, brs), 3.05 (3H, b
rs), 5.06 (2H, s), 7.07 (1H, dd, J = 6.6, 4.0Hz),
7.95 (1H, s), 8.52 (1H, dd, J = 4.0, 2.0Hz),8.98
(1H, dd, J = 6.6, 2.2Hz), 9.36 (1H, s).
元素分析値 C12H13N7O3Sとして
計算値(%): C, 42.98; H, 3.91; N, 29.24.
実測値(%): C, 42.81; H, 3.62; N, 19.14.Example 5 3-[(imidazo [1,2-a] pyrimidin-2-ylmethyl) thio]-
N, N-Dimethyl-1H-1,2,4-triazole-1-carboxamide 2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-a] pyrimidine (465 mg, 2 mmol) and potassium carbonate (332 mg, 2.4 mmol) in dimethylsulfoxide (5 ml) solution, dimethylcarbamoyl chloride (0.258 ml, 2.8 mm)
ol) was added and the mixture was stirred at room temperature for 2 days. Water (20 ml) in the reaction mixture
Was added and extracted with methylene chloride (10 ml). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (469 mg, yield 77%).
Was obtained as white-yellow crystals. Melting point 149.9-150.3 ° C 1 H-NMR (CDCl 3 ) δ: 3.20 (6H, brs), 4.60 (2H, d,
J = 0.8Hz), 6.85 (1H, dd, J = 6.0, 4.0Hz), 7.55 (1
H, s), 8.35 (1H, dd, J = 6.6, 2.2Hz), 8.52 (1H, d
d, J = 4.0, 2.2Hz), 8.73 (1H, s) .IR (KBr): 1701, 1507, 1483, 1402, 1240 cm −1 . Elemental analysis value Calculated as C 12 H 13 N 7 OS (% ): C, 47.51; H, 4.32; N, 32.32. Actual value (%): C, 47.13; H, 4.38; N, 31.98. Example 6 3-[(imidazo [1,2-a] pyrimidine-2 -Ylmethyl) sulfonyl] -N, N-dimethyl-1H-1,2,4-triazole-1-carboxamide 3-[(imidazo [1,2-a] pyrimidin-2-ylmethyl) thio]-
N, N-Dimethyl-1H-1,2,4-triazole-1-carboxamide (400 mg, 1.32 mmol) in methanol (5 ml) -water (10 ml)
Concentrated sulfuric acid (0.045 ml) and oxone (1217 mg, 1.98 m) were added to the solution.
mol) was added and the mixture was stirred at room temperature for 12 hours. Water (10 m
l) was added, and the mixture was extracted with methylene chloride (20 ml × 2). The organic layer was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography (ethyl acetate: methanol = 10/1 → 2
(1/1, v / v) and crystallized from diisopropyl ether to give the title compound (111 mg, yield 25%) as white crystals. Melting point 215.6-217.1 ° C 1 H-NMR (DMSO-d 6 ) δ: 2.95 (3H, brs), 3.05 (3H, b
rs), 5.06 (2H, s), 7.07 (1H, dd, J = 6.6, 4.0Hz),
7.95 (1H, s), 8.52 (1H, dd, J = 4.0, 2.0Hz), 8.98
(1H, dd, J = 6.6, 2.2Hz), 9.36 (1H, s). Elemental analysis calculated as C 12 H 13 N 7 O 3 S (%): C, 42.98; H, 3.91; N, 29.24 Actual value (%): C, 42.81; H, 3.62; N, 19.14.
【0062】実施例7
N,N-ジエチル-3-[(イミダゾ[1,2-a]ピリミジン-2-イル
メチル)チオ]-1H-1,2,4-トリアゾール-1-カルボキサミ
ド
2-[(1H-1,2,4-トリアゾール-3-イルチオ)メチル]イミダ
ゾ[1,2-a]ピリミジン(232 mg, 1 mmol)及び炭酸カリウ
ム(166 mg, 1.2 mmol)のジメチルスルホキシド(2.5 ml)
溶液にジエチルカルバモイルクロリド (0.18 ml, 1.4 m
mol)を加え、室温で2日間撹拌した。反応液に水(20 ml)
を加え、塩化メチレン(20ml×2)で抽出した。有機層を
飽和食塩水で(30 ml)洗浄し、無水硫酸ナトリウムで乾
燥後、減圧濃縮した。得られた残留物をジイソプロピル
エーテルで結晶化すると、表題化合物(268 mg, 収率81
%)を白黄色結晶として得た。
融点 134.1-134.2℃1
H-NMR (CDCl3) δ: 1.23 (6H, t, J = 7.0Hz), 3.40
-3.70 (4H, m), 4.60 (2H, s), 6.85 (1H, dd, J = 6.
6, 4.0Hz), 7.56 (1H, s), 8.35 (1H, dd, J = 6.6, 2.
2Hz), 8.53 (1H, dd, J = 4.0, 2.2Hz), 8.76 (1H, s).
IR (KBr): 1698,1507,1431,1271,1254 cm-1.
元素分析値 C14H17N7OSとして
計算値(%): C, 50.74; H, 5.17; N, 29.59.
実測値(%): C, 50.28; H, 5.08; N, 29.26.
実施例8
N,N-ジエチル-3-[(イミダゾ[1,2-a]ピリミジン-2-イル
メチル)スルフィニル]-1H-1,2,4-トリアゾール-1-カル
ボキサミド
N,N-ジエチル-3-[(イミダゾ[1,2-a]ピリミジン-2-イル
メチル)チオ]-1H-1,2,4-トリアゾール-1-カルボキサミ
ド(100 mg, 0.3 mmol)の塩化メチレン(10 ml)溶液にm-
クロロ過安息香酸(216 mg, 0.87 mmol)を加え、室温で2
4時間撹拌した。反応液に飽和重曹液(20 ml)を加え、塩
化メチレン(20 ml)で抽出した。有機層を飽和食塩水(20
ml)で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を
減圧濃縮し、得られた残留物をフラッシュシリカゲルク
ロマトグラフィー(酢酸エチル:メタノール=10/1, v/
v)で精製すると、表題化合物(11 mg, 収率10%)を白色結
晶として得た。
融点 182.3-182.7℃1
H-NMR (CDCl3) δ: 1.26 (6H, t, J = 6.6Hz), 3.40
-3.70 (4H, m), 4.72 (2H, s), 6.89 (1H, dd, J = 6.
6, 4.0Hz), 7.66 (1H, s), 8.39 (1H, dd, J = 6.6, 1.
8Hz), 8.56 (1H, dd, J = 4.0, 1.8Hz), 8.91 (1H, s).
IR (KBr): 1705, 1507, 1435, 1275, 1059cm-1.Example 7 N, N-diethyl-3-[(imidazo [1,2-a] pyrimidin-2-ylmethyl) thio] -1H-1,2,4-triazole-1-carboxamide 2-[( 1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-a] pyrimidine (232 mg, 1 mmol) and potassium carbonate (166 mg, 1.2 mmol) in dimethyl sulfoxide (2.5 ml)
Diethylcarbamoyl chloride (0.18 ml, 1.4 m
mol) was added and the mixture was stirred at room temperature for 2 days. Water (20 ml) in the reaction mixture
Was added and extracted with methylene chloride (20 ml × 2). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (268 mg, yield 81
%) As white yellow crystals. Melting point 134.1-134.2 ℃ 1 H-NMR (CDCl 3 ) δ: 1.23 (6H, t, J = 7.0Hz), 3.40
-3.70 (4H, m), 4.60 (2H, s), 6.85 (1H, dd, J = 6.
6, 4.0Hz), 7.56 (1H, s), 8.35 (1H, dd, J = 6.6, 2.
2Hz), 8.53 (1H, dd, J = 4.0, 2.2Hz), 8.76 (1H, s) .IR (KBr): 1698,1507,1431,1271,1254 cm -1 Elemental analysis C 14 H 17 N 7 Calculated as OS (%): C, 50.74; H, 5.17; N, 29.59. Measured value (%): C, 50.28; H, 5.08; N, 29.26.Example 8 N, N-diethyl-3- [(Imidazo [1,2-a] pyrimidin-2-ylmethyl) sulfinyl] -1H-1,2,4-triazole-1-carboxamide N, N-diethyl-3-[(imidazo [1,2-a] Pyrimidin-2-ylmethyl) thio] -1H-1,2,4-triazole-1-carboxamide (100 mg, 0.3 mmol) in methylene chloride (10 ml) in m-
Add chloroperbenzoic acid (216 mg, 0.87 mmol) and add 2 at room temperature.
It was stirred for 4 hours. A saturated sodium bicarbonate solution (20 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (20 ml). The organic layer was saturated brine (20
(ml) and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography (ethyl acetate: methanol = 10/1, v /
Purification by v) gave the title compound (11 mg, yield 10%) as white crystals. Melting point 182.3-182.7 ° C 1 H-NMR (CDCl 3 ) δ: 1.26 (6H, t, J = 6.6Hz), 3.40
-3.70 (4H, m), 4.72 (2H, s), 6.89 (1H, dd, J = 6.
6, 4.0Hz), 7.66 (1H, s), 8.39 (1H, dd, J = 6.6, 1.
8Hz), 8.56 (1H, dd, J = 4.0, 1.8Hz), 8.91 (1H, s) .IR (KBr): 1705, 1507, 1435, 1275, 1059cm -1 .
【0063】実施例9
N,N-ジエチル-3-[(イミダゾ[1,2-a]ピリミジン-2-イル
メチル)スルホニル]-1H-1,2,4-トリアゾール-1-カルボ
キサミド
N,N-ジエチル-3-[(イミダゾ[1,2-a]ピリミジン-2-イル
メチル)チオ]-1H-1,2,4-トリアゾール-1-カルボキサミ
ド(465 mg, 2 mmol)のメタノール(10 ml)-水(20ml)溶液
に氷冷下濃硫酸(0.068 ml)及びオキソン(1.844 g, 3 mm
ol)を加え、室温で5時間撹拌した。反応液に氷冷下、1N
水酸化ナトリウム水溶液を加えpH8にし、塩化メチレ
ン(30 ml×2)で抽出した。有機層を飽和食塩水で(30 m
l)洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し
た。得られた残留物をジイソプロピルエーテルで結晶化
すると、表題化合物(289 mg, 収率40%)を白色結晶とし
て得た。
融点 209.2-210.6℃1
H-NMR (CDCl3) δ: 1.10-1.40 (6H, m), 3.40-3.60
(4H, m), 4.93 (2H, s),6.90 (1H, dd, J = 6.9, 4.2H
z), 7.81 (1H, s), 8.43 (1H, dd, J = 6.9, 1.2Hz),
8.53 (1H, dd, J = 4.2, 1.2Hz), 8.84 (1H, s).
IR (KBr): 1707, 1508, 1433, 1325, 1267, 1144 c
m−1.
元素分析値 C14H17N7O3Sとして
計算値(%): C, 46.27; H, 4.72; N, 26.98.
実測値(%): C, 46.14; H, 4.59; N, 26.80.
実施例10
3-{[(3-クロロイミダゾ[1,2-a]ピリミジン-2-イル)メチ
ル]スルホニル}-N,N-ジエチル-1H-1,2,4-トリアゾール-
1-カルボキサミド
N,N-ジエチル-3-[(イミダゾ[1,2-a]ピリミジン-2-イル
メチル)スルホニル]-1H-1,2,4-トリアゾール-1-カルボ
キサミド(100 mg, 0.401 mmol)のN,N-ジメチルホルムア
ミド(1 ml)溶液に氷冷下、N-クロロコハク酸イミド(98%
含量, 56 mg, 0.413 mmol)を加え、室温で23時間撹拌し
た。反応液に水(10 ml) を加え、塩化メチレン(10 ml)
で抽出した。有機層を飽和食塩水(10 ml)で洗浄後、無
水硫酸ナトリウムで乾燥した。溶媒を減圧濃縮し、得ら
れた残留物をフラッシュシリカゲルクロマトグラフィー
(塩化メチレン:メタノール=20/1, v/v)で精製し、ジ
イソプロピルエーテル-酢酸エチルで結晶化すると表題
化合物(74 mg, 収率67%)を白色結晶として得た。
融点 195.6-196.0℃1
H-NMR (CDCl3) δ: 1.10-1.40 (6H, m), 3.40-3.70
(4H, m), 4.92 (2H, s),7.04 (1H, dd, J = 6.0, 4.0H
z), 8.37 (1H, dd, J = 6.6, 2.0Hz), 8.58 (1H,dd, J
= 4.0, 2.0Hz), 8.87 (1H, s).
IR (KBr): 1717, 1501, 1437, 1346, 1146 cm-1.
元素分析値 C14H16ClN7O3Sとして
計算値(%): C, 42.27; H, 4.05; N, 24.64.
実測値(%): C, 42.00; H, 3.81; N, 24.62.Example 9 N, N-Diethyl-3-[(imidazo [1,2-a] pyrimidin-2-ylmethyl) sulfonyl] -1H-1,2,4-triazole-1-carboxamide N, N- Diethyl-3-[(imidazo [1,2-a] pyrimidin-2-ylmethyl) thio] -1H-1,2,4-triazole-1-carboxamide (465 mg, 2 mmol) in methanol (10 ml)- Concentrated sulfuric acid (0.068 ml) and oxone (1.844 g, 3 mm) in water (20 ml) under ice cooling.
ol) was added and the mixture was stirred at room temperature for 5 hours. 1N to the reaction mixture under ice cooling
The pH was adjusted to 8 by adding an aqueous sodium hydroxide solution, and the mixture was extracted with methylene chloride (30 ml × 2). The organic layer was saturated with brine (30 m
l) Washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (289 mg, yield 40%) as white crystals. Melting point 209.2-210.6 ° C 1 H-NMR (CDCl 3 ) δ: 1.10-1.40 (6H, m), 3.40-3.60
(4H, m), 4.93 (2H, s), 6.90 (1H, dd, J = 6.9, 4.2H
z), 7.81 (1H, s), 8.43 (1H, dd, J = 6.9, 1.2Hz),
8.53 (1H, dd, J = 4.2, 1.2Hz), 8.84 (1H, s). IR (KBr): 1707, 1508, 1433, 1325, 1267, 1144 c
m −1 . Elemental analysis value Calculated as C 14 H 17 N 7 O 3 S (%): C, 46.27; H, 4.72; N, 26.98. Measured value (%): C, 46.14; H, 4.59; N , 26.80. Example 10 3-{[(3-chloroimidazo [1,2-a] pyrimidin-2-yl) methyl] sulfonyl} -N, N-diethyl-1H-1,2,4-triazole-
1-Carboxamide N, N-diethyl-3-[(imidazo [1,2-a] pyrimidin-2-ylmethyl) sulfonyl] -1H-1,2,4-triazole-1-carboxamide (100 mg, 0.401 mmol) Solution of N-N-dimethylformamide (1 ml) in N-chlorosuccinimide (98%
Content, 56 mg, 0.413 mmol) were added, and the mixture was stirred at room temperature for 23 hours. Water (10 ml) was added to the reaction mixture, and methylene chloride (10 ml) was added.
It was extracted with. The organic layer was washed with saturated saline (10 ml) and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was subjected to flash silica gel chromatography.
It was purified by (methylene chloride: methanol = 20/1, v / v) and crystallized from diisopropyl ether-ethyl acetate to give the title compound (74 mg, yield 67%) as white crystals. Melting point 195.6-196.0 ° C 1 H-NMR (CDCl 3 ) δ: 1.10-1.40 (6H, m), 3.40-3.70
(4H, m), 4.92 (2H, s), 7.04 (1H, dd, J = 6.0, 4.0H
z), 8.37 (1H, dd, J = 6.6, 2.0Hz), 8.58 (1H, dd, J
= 4.0, 2.0Hz), 8.87 (1H, s) .IR (KBr): 1717, 1501, 1437, 1346, 1146 cm -1 . Elemental analysis value calculated as C 14 H 16 ClN 7 O 3 S (%) : C, 42.27; H, 4.05; N, 24.64. Actual value (%): C, 42.00; H, 3.81; N, 24.62.
【0064】実施例11
N,N-ジエチル-3-[(イミダゾ[1,2-b]ピリダジン-2-イル
メチル)チオ]-1H-1,2,4-トリアゾール-1-カルボキサミ
ド
2-[(1H-1,2,4-トリアゾール-3-イルチオ)メチル]イミダ
ゾ[1,2-b]ピリダジン(331 mg, 1.43 mmol)及び炭酸カリ
ウム(237 mg, 1.7 mmol)のジメチルスルホキシド(2.5 m
l)溶液にジエチルカルバモイルクロリド (0.218 ml, 1.
7 mmol)を加え、室温で15時間撹拌した。反応液に水(20
ml)を加え、塩化メチレン(20ml)で抽出した。有機層を
飽和食塩水で(30 ml)洗浄し、無水硫酸ナトリウムで乾
燥後、減圧濃縮した。得られた残留物をフラッシュシリ
カゲルクロマトグラフィー(酢酸エチル:ヘキサン=10/
1→酢酸エチル, v/v)に付し、ジイソプロピルエーテル
で結晶化すると、表題化合物(383 mg, 収率81%)を白黄
色結晶として得た。
融点 122.5-122.8℃1
H-NMR (CDCl3) δ: 1.25 (6H, t, J = 7.2Hz), 3.40
-3.70 (4H, m), 4.59 (2H, s), 7.02 (1H, dd, J = 9.
0, 4.5Hz), 7.44 (1H, dd, J = 4.5, 1.8Hz), 7.97 (1
H, s), 8.27 (1H, dd, J = 4.5, 1.8Hz), 8.77 (1H,
s).
IR (KBr): 1698,1530, 1476, 1431, 1333, 1273, 1236
cm-1.
元素分析値 C14H17N7OSとして
計算値(%): C, 50.71, 5.17, 29.59.
実測値(%): C, 50.77, 5.24, 29.62.
実施例12
N,N-ジエチル-3-[(イミダゾ[1,2-b]ピリダジン-2-イル
メチル)スルホニル]-1H-1,2,4-トリアゾール-1-カルボ
キサミド
N,N-ジエチル-3-[(イミダゾ[1,2-b]ピリダジン-2-イル
メチル)チオ]-1H-1,2,4-トリアゾール-1-カルボキサミ
ド(200 mg, 0.604 mmol)のメタノール(8 ml)-水(5 ml)
溶液に濃硫酸(0.02 ml)及びオキソン(557 mg, 0.91 mmo
l)を加え、室温で15時間撹拌した。反応液に氷冷下、1N
水酸化ナトリウム水溶液を加えpH8にし、塩化メチレ
ン(20 ml×2)で抽出した。有機層を飽和食塩水で(20 m
l)洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し
た。残留物をフラッシュシリカゲルクロマトグラフィー
(酢酸エチル→酢酸エチル:メタノール=10/1, v/v)に
付し、ジイソプロピルエーテルで結晶化すると表題化合
物(148 mg, 収率67%)を白色結晶として得た。
融点 133.5-134.8℃1
H-NMR (CDCl3) δ: 1.10-1.40 (6H, m), 3.40-3.60
(4H, m), 4.94 (2H, s),7.05 (1H, dd, J = 9.0, 4.5H
z), 7.85 (1H, dd, J = 9.0, 1.5Hz), 8.12 (1H,s), 8.
82 (1H, dd, J = 4.5, 1.5Hz), 8.89 (1H, s).
IR (KBr): 1713, 14535, 1337, 1265 cm−1.
元素分析値 C14H17N7O3Sとして
計算値(%): C, 46,27; H, 4.72; N, 26.98.
実測値(%): C, 46.26; H, 4.68; N, 26.90.Example 11 N, N-diethyl-3-[(imidazo [1,2-b] pyridazin-2-ylmethyl) thio] -1H-1,2,4-triazole-1-carboxamide 2-[( 1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-b] pyridazine (331 mg, 1.43 mmol) and potassium carbonate (237 mg, 1.7 mmol) in dimethyl sulfoxide (2.5 m
l) Diethylcarbamoyl chloride (0.218 ml, 1.
(7 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Water (20
ml) was added and the mixture was extracted with methylene chloride (20 ml). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to flash silica gel chromatography (ethyl acetate: hexane = 10 /
It was subjected to 1 → ethyl acetate, v / v) and crystallized from diisopropyl ether to give the title compound (383 mg, yield 81%) as white-yellow crystals. Melting point 122.5-122.8 ° C 1 H-NMR (CDCl 3 ) δ: 1.25 (6H, t, J = 7.2Hz), 3.40
-3.70 (4H, m), 4.59 (2H, s), 7.02 (1H, dd, J = 9.
0, 4.5Hz), 7.44 (1H, dd, J = 4.5, 1.8Hz), 7.97 (1
H, s), 8.27 (1H, dd, J = 4.5, 1.8Hz), 8.77 (1H,
s) .IR (KBr): 1698,1530, 1476, 1431, 1333, 1273, 1236
cm -1 . Elemental analysis value C 14 H 17 N 7 Calculated value as OS (%): C, 50.71, 5.17, 29.59. Measured value (%): C, 50.77, 5.24, 29.62. Example 12 N, N- Diethyl-3-[(imidazo [1,2-b] pyridazin-2-ylmethyl) sulfonyl] -1H-1,2,4-triazole-1-carboxamide N, N-diethyl-3-[(imidazo [1, 2-b] Pyridazin-2-ylmethyl) thio] -1H-1,2,4-triazole-1-carboxamide (200 mg, 0.604 mmol) in methanol (8 ml) -water (5 ml)
Add concentrated sulfuric acid (0.02 ml) and oxone (557 mg, 0.91 mmo) to the solution.
l) was added and the mixture was stirred at room temperature for 15 hours. 1N to the reaction mixture under ice cooling
The pH was adjusted to 8 by adding an aqueous sodium hydroxide solution, and the mixture was extracted with methylene chloride (20 ml × 2). The organic layer was saturated with brine (20 m
l) Washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Flash silica gel chromatography of the residue
It was then subjected to (ethyl acetate → ethyl acetate: methanol = 10/1, v / v) and crystallized from diisopropyl ether to give the title compound (148 mg, yield 67%) as white crystals. Melting point 133.5-134.8 ° C 1 H-NMR (CDCl 3 ) δ: 1.10-1.40 (6H, m), 3.40-3.60
(4H, m), 4.94 (2H, s), 7.05 (1H, dd, J = 9.0, 4.5H
z), 7.85 (1H, dd, J = 9.0, 1.5Hz), 8.12 (1H, s), 8.
82 (1H, dd, J = 4.5, 1.5Hz), 8.89 (1H, s) .IR (KBr): 1713, 14535, 1337, 1265 cm -1 . Elemental analysis value C 14 H 17 N 7 O 3 S Calculated (%): C, 46,27; H, 4.72; N, 26.98. Measured (%): C, 46.26; H, 4.68; N, 26.90.
【0065】実施例13
3-{[(6-クロロイミダゾ[1,2-b]ピリダジン-2-イル)メチ
ル]チオ}-N,N-ジエチル-1H-1,2,4-トリアゾール-1-カル
ボキサミド
6-クロロ-2-[(1H-1,2,4-トリアゾール-3-イルチオ)メチ
ル]イミダゾ[1,2-b]ピリダジン(500 mg, 1.87 mmol)及
び炭酸カリウム(310 mg, 2.2 mmol)のジメチルスルホキ
シド(5 mol)溶液にジエチルカルバモイルクロリド (0.3
32 ml, 2.62 mmol)を加え、室温で3時間撹拌した。反応
液に水(20 ml)を加え、塩化メチレン(20ml×2)で抽出し
た。有機層を飽和食塩水で(30 ml)洗浄し、無水硫酸ナ
トリウムで乾燥後、減圧濃縮した。得られた残留物をジ
イソプロピルエーテルで結晶化すると、表題化合物(591
mg, 収率86%)を白黄色結晶として得た。
融点 104.0-105.0℃1
H-NMR (CDCl3) δ: 1.25 (6H, t, J = 7.0Hz), 3.5
7 (4H, q, J = 7.0Hz),4.56 (2H, s), 7.03 (1H, d, J
= 9.6Hz), 7.84 (1H, d, J = 9.6Hz), 7.92 (1H, s),
8.76 (1H, s).
IR (KBr): 1698, 1520, 1431, 1271, 1254, 1098 cm
−1.
元素分析値 C14H16ClN7OSとして
計算値(%): C, 45.96; H, 4.41; N, 26.80.
実測値(%): C, 45.88; H, 4.28; N, 26.73.
実施例14
3-{[(6-クロロイミダゾ[1,2-b]ピリダジン-2-イル)メチ
ル]スルホニル}-N,N-ジエチル-1H-1,2,4-トリアゾール-
1-カルボキサミド
3-{[(6-クロロイミダゾ[1,2-b]ピリダジン-2-イル)メチ
ル]チオ}-N,N-ジエチル-1H-1,2,4-トリアゾール-1-カル
ボキサミド(200 mg, 0.55 mmol)のメタノール(10 ml)-
水(8 ml)溶液に濃硫酸(0.018 ml)及びオキソン(504 mg,
0.82 mmol)を加え、室温で5時間撹拌した。反応液に氷
冷下、1N 水酸化ナトリウム水溶液を加えpH8にし、析
出した粉末を濾取した。得られた粉末をフラッシュシリ
カゲルクロマトグラフィー(酢酸エチル→酢酸エチル:
メタノール=10/1, v/v)に付し、第一溶出分を減圧濃縮
し、ジイソプロピルエーテルより結晶化すると表題化合
物(111 mg, 収率51%)を白色結晶として得た。
融点 169.0-169.5℃1
H-NMR (CDCl3) δ: 1.10-1.40 (6H, m), 3.40-3.7
0 (4H, m), 4.92 (2H, s), 7.07 (1H, d, J = 9.4Hz),
8.81 (1H, d, J = 9.4Hz), 8.06 (1H, s), 8.89(1H,
s).
IR (KBr): 1713, 1522, 1345, 1294, 1265, 1146, 1096
cm−1.
元素分析値 C14H16ClN7O3Sとして
計算値(%): C, 42.27; H, 4.05; N, 24.64.
実測値(%): C, 42.29; H, 4.01; N, 24.71.
実施例15
3-{[(6-クロロイミダゾ[1,2-b]ピリダジン-2-イル)メチ
ル]スルフィニル}-N,N-ジエチル-1H-1,2,4-トリアゾー
ル-1-カルボキサミド
実施例14で行ったフラッシュシリカゲルカラムクロマト
グラフィーにおける第二溶出分を減圧濃縮し、ジイソプ
ロピルエーテルより結晶化すると表題化合物(20 mg, 収
率10%)を白色結晶として得た。
融点 160.2-164.8℃1
H-NMR (CDCl3) δ: 1.25 (6H, t, J = 7.0Hz), 3.4
0-3.70 (4H, m), 4.73 (2H, d, J = 2.2Hz), 7.07 (1H,
d, J = 9.0Hz), 7.83 (1H, d, J = 9.0Hz), 7.94 (1H,
s), 8.94 (1H, s).
IR (KBr): 1707, 1522, 1433, 1292, 1275, 1098 cm-1.Example 13 3-{[(6-chloroimidazo [1,2-b] pyridazin-2-yl) methyl] thio} -N, N-diethyl-1H-1,2,4-triazole-1 -Carboxamide 6-chloro-2-[(1H-1,2,4-triazol-3-ylthio) methyl] imidazo [1,2-b] pyridazine (500 mg, 1.87 mmol) and potassium carbonate (310 mg, 2.2 Dimethylsulfamoyl chloride (0.3 mmol) in dimethyl sulfoxide (5 mol) solution
(32 ml, 2.62 mmol) was added and the mixture was stirred at room temperature for 3 hours. Water (20 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (20 ml × 2). The organic layer was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (591
mg, yield 86%) was obtained as white yellow crystals. Melting point 104.0-105.0 ° C 1 H-NMR (CDCl 3 ) δ: 1.25 (6H, t, J = 7.0Hz), 3.5
7 (4H, q, J = 7.0Hz), 4.56 (2H, s), 7.03 (1H, d, J
= 9.6Hz), 7.84 (1H, d, J = 9.6Hz), 7.92 (1H, s),
8.76 (1H, s) .IR (KBr): 1698, 1520, 1431, 1271, 1254, 1098 cm
-1 . Elemental analysis value C 14 H 16 ClN 7 Calculated value as OS (%): C, 45.96; H, 4.41; N, 26.80. Measured value (%): C, 45.88; H, 4.28; N, 26.73. Example 14 3-{[(6-chloroimidazo [1,2-b] pyridazin-2-yl) methyl] sulfonyl} -N, N-diethyl-1H-1,2,4-triazole-
1-carboxamide 3-{[(6-chloroimidazo [1,2-b] pyridazin-2-yl) methyl] thio} -N, N-diethyl-1H-1,2,4-triazole-1-carboxamide ( 200 mg, 0.55 mmol) in methanol (10 ml)-
Concentrated sulfuric acid (0.018 ml) and oxone (504 mg, in a water (8 ml) solution.
0.82 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was adjusted to pH 8 with 1N aqueous sodium hydroxide solution under ice cooling, and the precipitated powder was collected by filtration. The obtained powder is subjected to flash silica gel chromatography (ethyl acetate → ethyl acetate:
Methanol = 10/1, v / v), the first eluate was concentrated under reduced pressure and crystallized from diisopropyl ether to give the title compound (111 mg, yield 51%) as white crystals. Melting point 169.0-169.5 ° C 1 H-NMR (CDCl 3 ) δ: 1.10-1.40 (6H, m), 3.40-3.7
0 (4H, m), 4.92 (2H, s), 7.07 (1H, d, J = 9.4Hz),
8.81 (1H, d, J = 9.4Hz), 8.06 (1H, s), 8.89 (1H,
s) .IR (KBr): 1713, 1522, 1345, 1294, 1265, 1146, 1096
cm −1 . Elemental analysis value Calculated as C 14 H 16 ClN 7 O 3 S (%): C, 42.27; H, 4.05; N, 24.64. Measured value (%): C, 42.29; H, 4.01; N , 24.71. Example 15 3-{[(6-chloroimidazo [1,2-b] pyridazin-2-yl) methyl] sulfinyl} -N, N-diethyl-1H-1,2,4-triazole-1 -Carboxamide The second eluate in the flash silica gel column chromatography performed in Example 14 was concentrated under reduced pressure and crystallized from diisopropyl ether to give the title compound (20 mg, yield 10%) as white crystals. Melting point 160.2-164.8 ° C 1 H-NMR (CDCl 3 ) δ: 1.25 (6H, t, J = 7.0Hz), 3.4
0-3.70 (4H, m), 4.73 (2H, d, J = 2.2Hz), 7.07 (1H,
d, J = 9.0Hz), 7.83 (1H, d, J = 9.0Hz), 7.94 (1H,
s), 8.94 (1H, s) .IR (KBr): 1707, 1522, 1433, 1292, 1275, 1098 cm -1 .
【0066】実施例16
3-{[(3-クロロイミダゾ[1,2-b]ピリダジン-2-イル)メチ
ル]スルホニル}-N,N-ジエチル-1H-1,2,4-トリアゾール-
1-カルボキサミド
N,N-ジエチル-3-[(イミダゾ[1,2-b]ピリダジン-2-イル
メチル)スルホニル]-1H-1,2,4-トリアゾール-1-カルボ
キサミド(64 mg, 0.177 mmol)のN,N-ジメチルホルムア
ミド(1 ml)溶液に氷冷下、N-クロロコハク酸イミド(98%
含量, 58 mg, 0.425 mmol)を加え、室温で30時間撹拌し
た。反応液に水(10 ml) を加え、塩化メチレン(10 ml)
で抽出した。有機層を飽和食塩水(10 ml)で洗浄後、無
水硫酸ナトリウムで乾燥した。溶媒を減圧濃縮し、得ら
れた残留物をフラッシュシリカゲルクロマトグラフィー
(酢酸エチル:ヘキサン=1/1→酢酸エチル, v/v)で精製
すると、表題化合物(3.8 mg, 収率5%)を得た。1
H-NMR (CDCl3) δ: 1.12-1.35 (6H, m), 3.40-3.70
(4H, m), 4.94 (2H, s),7.12 (1H, dd, J = 9.6, 4.4H
z), 7.89 (1H, dd, J = 9.6, 1.4Hz), 8.46 (1H,dd, J
= 4.4, 1.4Hz), 8.91 (1H, s).
IR (KBr): 1715, 1435, 1337, 1265, 1208, 1152 c
m−1.
実施例17
2-({[1-(1-ピロリジニルカルボニル)-1H-1,2,4-トリア
ゾール-3-イル]スルホニル}メチル)イミダゾ[1,2-a]ピ
リジン
2-[(1H-1,2,4-トリアゾール-3-イルスルホニル)メチル]
イミダゾ[1,2-a]ピリジン(412 mg, 1.57 mmol)及び炭酸
カリウム(260 mg, 1.9 mmol)のジメチルスルホキシド(5
ml)溶液に1-ピロリジニルカルボニルクロリド (0.277
ml, 2.5 mmol)を加え、室温で2日間撹拌した。反応液に
水(30 ml)を加え、塩化メチレン(25ml× 2)で抽出し
た。有機層を飽和食塩水で(20 ml)洗浄し、無水硫酸ナ
トリウムで乾燥後、減圧濃縮した。得られた残留物をジ
イソプロピルエーテルから結晶化すると、表題化合物(4
85 mg, 収率86%)を白色結晶として得た。
融点 181.9-184.7℃1
H-NMR (CDCl3) δ: 1.82-1.99 (4H, m), 3.62-3.69
(2H, m), 3.74 (2H, m),4.90 (2H, s), 6.81 (1H, td,
J = 7.0, 1.0Hz), 7.17 (1H, ddd, J = 9.0,7.0, 1.0
Hz), 7.48 (1H, dd, J = 9.0, 1.0Hz), 7.77 (1H, s),
8.09 (1H, dt,J = 7.0, 1.0Hz), 8.95 (1H, s).
元素分析値 C15H16N6O3Sとして
計算値(%): C, 49.99; H, 4.47; N, 23.32.
実測値(%): C, 49.71; H, 4.25; N, 23.14.Example 16 3-{[(3-chloroimidazo [1,2-b] pyridazin-2-yl) methyl] sulfonyl} -N, N-diethyl-1H-1,2,4-triazole-
1-Carboxamide N, N-diethyl-3-[(imidazo [1,2-b] pyridazin-2-ylmethyl) sulfonyl] -1H-1,2,4-triazole-1-carboxamide (64 mg, 0.177 mmol) Solution of N-N-dimethylformamide (1 ml) in N-chlorosuccinimide (98%
Content, 58 mg, 0.425 mmol) were added, and the mixture was stirred at room temperature for 30 hours. Water (10 ml) was added to the reaction mixture, and methylene chloride (10 ml) was added.
It was extracted with. The organic layer was washed with saturated saline (10 ml) and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was subjected to flash silica gel chromatography.
Purification with (ethyl acetate: hexane = 1/1 → ethyl acetate, v / v) gave the title compound (3.8 mg, yield 5%). 1 H-NMR (CDCl 3 ) δ: 1.12-1.35 (6H, m), 3.40-3.70
(4H, m), 4.94 (2H, s), 7.12 (1H, dd, J = 9.6, 4.4H
z), 7.89 (1H, dd, J = 9.6, 1.4Hz), 8.46 (1H, dd, J
= 4.4, 1.4Hz), 8.91 (1H, s). IR (KBr): 1715, 1435, 1337, 1265, 1208, 1152 c
m −1 .Example 17 2-({[1- (1-pyrrolidinylcarbonyl) -1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] pyridine 2-[(1H-1,2,4-triazol-3-ylsulfonyl) methyl]
Imidazo [1,2-a] pyridine (412 mg, 1.57 mmol) and potassium carbonate (260 mg, 1.9 mmol) in dimethyl sulfoxide (5
1-pyrrolidinyl carbonyl chloride (0.277
(ml, 2.5 mmol) was added, and the mixture was stirred at room temperature for 2 days. Water (30 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (25 ml × 2). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (4
85 mg, yield 86%) was obtained as white crystals. Melting point 181.9-184.7 ° C 1 H-NMR (CDCl 3 ) δ: 1.82-1.99 (4H, m), 3.62-3.69
(2H, m), 3.74 (2H, m), 4.90 (2H, s), 6.81 (1H, td,
J = 7.0, 1.0Hz), 7.17 (1H, ddd, J = 9.0,7.0, 1.0
Hz), 7.48 (1H, dd, J = 9.0, 1.0Hz), 7.77 (1H, s),
8.09 (1H, dt, J = 7.0, 1.0Hz), 8.95 (1H, s) Elemental analysis C 15 H 16 N 6 O 3 Calculated S (%):. C, 49.99; H, 4.47; N, 23.32. Found (%): C, 49.71; H, 4.25; N, 23.14.
【0067】実施例18
2-({[1-(1-ピペリジニルカルボニル)-1H-1,2,4-トリア
ゾール-3-イル]スルホニル}メチル)イミダゾ[1,2-a]ピ
リジン
2-[(1H-1,2,4-トリアゾール-3-イルスルホニル)メチル]
イミダゾ[1,2-a]ピリジン(526.6 mg, 2 mmol)及び炭酸
カリウム(332 mg, 2.4 mmol)のジメチルスルホキシド(5
mol)溶液にピペリジニルカルボニルクロリド (0.35 m
l, 3.6 mmol)を加え、室温で2日間撹拌した。反応液に
水(30 ml)を加え、塩化メチレン(20ml)で抽出した。有
機層を水(30 ml)、飽和食塩水で(30 ml)洗浄し、無水硫
酸ナトリウムで乾燥後、減圧濃縮した。得られた残留物
をフラッシュシリカゲルクロマトグラフィー(酢酸エチ
ル/ヘキサン=5/1→酢酸エチル)で精製し、ジイソプロピ
ルエーテルから結晶化すると、表題化合物(426 mg, 収
率57%)を白色結晶として得た。
融点 154.0-154.6℃1
H-NMR (CDCl3) δ: 1.40-1.80 (6H, m), 3.60-3.70
(4H, m), 4.90 (2H, s),6.80 (1H, td, J = 7.0, 1.0H
z), 7.17 (1H, ddd, J = 9.2, 7.0, 1.0Hz), 7.47 (1
H, dt, J = 9.2, 1.0Hz), 7.76 (1H, s), 8.08 (1H, d
t, J = 7.0, 1.0Hz), 8.81 (1H, s).
IR (KBr): 1717, 1441, 1335, 1250, 1236, 1146 c
m−1.
元素分析値 C16H18N6O3Sとして
計算値(%): C, 51.33; H, 4.85; N, 22.45.
実測値(%): C, 51.34; H, 4.91; N, 22.28.
実施例19
3-クロロ-2-(ジクロロ{[1-(1-ピペリジニルカルボニル)
-1H-1,2,4-トリアゾール-3-イル]スルホニル}メチル)イ
ミダゾ[1,2-a]ピリジン
2-({[1-(1-ピペリジニルカルボニル)-1H-1,2,4-トリア
ゾール-3-イル]スルホニル}メチル)イミダゾ[1,2-a]ピ
リジン(200 mg, 0.534 mmol)のN,N-ジメチルホルムアミ
ド(2.5 ml)溶液に氷冷下、N-クロロコハク酸イミド(98%
含量, 306 mg,2.25 mmol)を加え、室温で48時間撹拌し
た。反応液に水(20 ml) を加え、塩化メチレン(20 ml×
2)で抽出した。有機層を飽和食塩水(20 ml)で洗浄後、
無水硫酸ナトリウムで乾燥した。溶媒を減圧濃縮し、得
られた残留物をフラッシュシリカゲルクロマトグラフィ
ー(酢酸エチル:ヘキサン=2/3→酢酸エチル, v/v)で精
製し、ジイソプロピルエーテルで結晶化すると表題化合
物(93 mg, 収率37%)を得た。
融点 187.6-190.0℃1
H-NMR (CDCl3) δ: 1.50-1.80 (6H, m), 3.60-3.80
(4H, m), 7.05 (1H, td,J = 7.0, 1.0Hz), 7.37 (1H,
ddd, J = 9.2, 7.0, 1.0Hz), 7.59 (1H, dt, J= 9.2,
1.0Hz), 8.16 (1H, dt, J = 7.0, 1.0Hz), 8.77 (1H,
s).
IR (KBr): 1721, 1437, 1366, 1244, 1155 cm−1.
元素分析値 C16H15Cl3N6O3Sとして
計算値(%): C, 40.22; H, 3.16; N, 17.59.
実測値(%): C, 40.13; H, 3.14; N, 17.29.Example 18 2-({[1- (1-piperidinylcarbonyl) -1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] pyridine 2 -[(1H-1,2,4-triazol-3-ylsulfonyl) methyl]
Imidazo [1,2-a] pyridine (526.6 mg, 2 mmol) and potassium carbonate (332 mg, 2.4 mmol) in dimethyl sulfoxide (5
mol) solution to piperidinyl carbonyl chloride (0.35 m
(1, 3.6 mmol) was added, and the mixture was stirred at room temperature for 2 days. Water (30 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (20 ml). The organic layer was washed with water (30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography (ethyl acetate / hexane = 5/1 → ethyl acetate) and crystallized from diisopropyl ether to give the title compound (426 mg, yield 57%) as white crystals. It was Melting point 154.0-154.6 ° C 1 H-NMR (CDCl 3 ) δ: 1.40-1.80 (6H, m), 3.60-3.70
(4H, m), 4.90 (2H, s), 6.80 (1H, td, J = 7.0, 1.0H
z), 7.17 (1H, ddd, J = 9.2, 7.0, 1.0Hz), 7.47 (1
H, dt, J = 9.2, 1.0Hz), 7.76 (1H, s), 8.08 (1H, d
t, J = 7.0, 1.0Hz), 8.81 (1H, s). IR (KBr): 1717, 1441, 1335, 1250, 1236, 1146 c
m −1 . Elemental analysis value Calculated value as C 16 H 18 N 6 O 3 S (%): C, 51.33; H, 4.85; N, 22.45. Measured value (%): C, 51.34; H, 4.91; N 22.28.Example 19 3-chloro-2- (dichloro {[1- (1-piperidinylcarbonyl))
-1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] pyridine 2-({[1- (1-piperidinylcarbonyl) -1H-1,2, 4-Triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] pyridine (200 mg, 0.534 mmol) in N, N-dimethylformamide (2.5 ml) under ice cooling under N-chlorosuccinimide (98%
Content, 306 mg, 2.25 mmol) were added, and the mixture was stirred at room temperature for 48 hours. Water (20 ml) was added to the reaction solution, and methylene chloride (20 ml ×
Extracted in 2). After washing the organic layer with saturated saline (20 ml),
It was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by flash silica gel chromatography (ethyl acetate: hexane = 2/3 → ethyl acetate, v / v) and crystallized from diisopropyl ether to give the title compound (93 mg, yield Rate 37%). Melting point 187.6-190.0 ° C 1 H-NMR (CDCl 3 ) δ: 1.50-1.80 (6H, m), 3.60-3.80
(4H, m), 7.05 (1H, td, J = 7.0, 1.0Hz), 7.37 (1H,
ddd, J = 9.2, 7.0, 1.0Hz), 7.59 (1H, dt, J = 9.2,
1.0Hz), 8.16 (1H, dt, J = 7.0, 1.0Hz), 8.77 (1H,
IR (KBr): 1721, 1437, 1366, 1244, 1155 cm −1 . Elemental analysis value calculated as C 16 H 15 Cl 3 N 6 O 3 S (%): C, 40.22; H, 3.16; N, 17.59. Found (%): C, 40.13; H, 3.14; N, 17.29.
【0068】実施例20
2-({[1-(4-モルホリニルカルボニル)-1H-1,2,4-トリア
ゾール-3-イル]スルホニル}メチル)イミダゾ[1,2-a]ピ
リジン
2-[(1H-1,2,4-トリアゾール-3-イルスルホニル)メチル]
イミダゾ[1,2-a]ピリジン(526.6 mg, 2 mmol)及び炭酸
カリウム(332 mg, 2.4 mmol)のジメチルスルホキシド(3
mol)溶液に4-モルホリニルカルボニルクロリド (0.327
ml, 2.8 mmol)を加え、室温で17時間撹拌した。反応液
に水(20 ml)を加え、塩化メチレン(30ml× 2)で抽出し
た。有機層を飽和食塩水で(20 ml)洗浄し、無水硫酸ナ
トリウムで乾燥後、減圧濃縮した。得られた残留物をジ
イソプロピルエーテルから結晶化すると、表題化合物(6
33 mg, 収率84%)を白色結晶として得た。
融点 204.1-205.0℃1
H-NMR (CDCl3) δ: 3.60-3.90 (8H, m), 4.89 (2H,
s), 6.82 (1H, td, J =6.6, 1.2Hz), 7.18 (1H, ddd,
J = 9.0, 6.6, 1.2Hz), 7.45 (1H, dd, J = 9.0, 1.2
Hz), 7.78 (1H, s), 8.09 (1H, dt, J = 6.6, 1.2Hz),
8.86 (1H, s).
元素分析値 C15H16N6O4Sとして
計算値(%): C, 47.87; H, 4.28; N, 22.33.
実測値(%): C, 47.81; H, 4.72; N, 22.10.
実施例21
3-クロロ-2-({[1-(1-ピロリジニルカルボニル)-1H-1,2,
4-トリアゾール-3-イル]スルホニル}メチル)イミダゾ
[1,2-a]ピリジン
2-({[1-(1-ピロリジニルカルボニル)-1H-1,2,4-トリア
ゾール-3-イル]スルホニル}メチル)イミダゾ[1,2-a]ピ
リジン(360 mg, 1 mmol)のN,N-ジメチルホルムアミド(5
ml)溶液に氷冷下、N-クロロコハク酸イミド(98%含量,
204 mg, 1.5 mmol)を加え、室温で24時間撹拌した。反
応液に水(20 ml)を加え、塩化メチレン(20 ml×2)で抽
出し、飽和食塩水(20 ml)で洗浄後、無水硫酸ナトリウ
ムで乾燥した。溶媒を減圧濃縮し、残留物をフラッシュ
シリカゲルクロマトグラフィー(酢酸エチル:ヘキサン
=5/1→酢酸エチル→酢酸エチル:メタノール=10/1, v
/v)で精製し、ジイソプロピルエーテルで結晶化する
と、表題化合物(78 mg, 収率20%)を白色結晶として得
た。
融点 195.9-197.3℃1
H-NMR (CDCl3) δ: 1.80-1.97 (4H, m), 3.64-3.71
(2H, m), 3.79-3.86 (2H, m), 4.90 (2H, s), 6.96(1H,
td, J = 6.6, 1.0Hz), 7.25 (1H, ddd, J = 9.2, 6.
6, 1.0Hz), 7.50 (1H, dt, J = 9.2, 1.0Hz), 8.04 (1
H, dt, J = 6.6,1.0Hz), 8.98 (1H, s).
元素分析値 C15H15ClN6O3Sとして
計算値(%): C, 45.63; H, 3.83; N, 21.28.
実測値(%): C, 45.77; H, 3.80; N, 20.73.Example 20 2-({[1- (4-morpholinylcarbonyl) -1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] pyridine 2 -[(1H-1,2,4-triazol-3-ylsulfonyl) methyl]
Imidazo [1,2-a] pyridine (526.6 mg, 2 mmol) and potassium carbonate (332 mg, 2.4 mmol) in dimethyl sulfoxide (3
mol) solution with 4-morpholinyl carbonyl chloride (0.327
(ml, 2.8 mmol) was added, and the mixture was stirred at room temperature for 17 hours. Water (20 ml) was added to the reaction solution, and the mixture was extracted with methylene chloride (30 ml × 2). The organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from diisopropyl ether to give the title compound (6
33 mg, yield 84%) was obtained as white crystals. Melting point 204.1-205.0 ° C 1 H-NMR (CDCl 3 ) δ: 3.60-3.90 (8H, m), 4.89 (2H,
s), 6.82 (1H, td, J = 6.6, 1.2Hz), 7.18 (1H, ddd,
J = 9.0, 6.6, 1.2Hz), 7.45 (1H, dd, J = 9.0, 1.2
Hz), 7.78 (1H, s), 8.09 (1H, dt, J = 6.6, 1.2Hz),
8.86 (1H, s). Elemental analysis value Calculated as C 15 H 16 N 6 O 4 S (%): C, 47.87; H, 4.28; N, 22.33. Actual value (%): C, 47.81; H, 4.72; N, 22.10.Example 21 3-chloro-2-({[1- (1-pyrrolidinylcarbonyl) -1H-1,2,
4-triazol-3-yl] sulfonyl} methyl) imidazo
[1,2-a] Pyridine 2-({[1- (1-pyrrolidinylcarbonyl) -1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] Pyridine (360 mg, 1 mmol) in N, N-dimethylformamide (5
(ml) solution under ice cooling, N-chlorosuccinimide (98% content,
(204 mg, 1.5 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Water (20 ml) was added to the reaction solution, extracted with methylene chloride (20 ml × 2), washed with saturated saline solution (20 ml), and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was subjected to flash silica gel chromatography (ethyl acetate: hexane = 5/1 → ethyl acetate → ethyl acetate: methanol = 10/1, v
/ v) and crystallized from diisopropyl ether to give the title compound (78 mg, yield 20%) as white crystals. Melting point 195.9-197.3 ° C 1 H-NMR (CDCl 3 ) δ: 1.80-1.97 (4H, m), 3.64-3.71
(2H, m), 3.79-3.86 (2H, m), 4.90 (2H, s), 6.96 (1H,
td, J = 6.6, 1.0Hz), 7.25 (1H, ddd, J = 9.2, 6.
6, 1.0Hz), 7.50 (1H, dt, J = 9.2, 1.0Hz), 8.04 (1
. H, dt, J = 6.6,1.0Hz ), 8.98 (1H, s) Elemental analysis C 15 H 15 ClN 6 O 3 Calculated S (%): C, 45.63 ; H, 3.83; N, 21.28. Found (%): C, 45.77; H, 3.80; N, 20.73.
【0069】実施例22
3-クロロ-2-({[1-(4-モルホリニルカルボニル)-1H-1,2,
4-トリアゾール-3-イル]スルホニル}メチル)イミダゾ
[1,2-a]ピリジン
2-({[1-(4-モルホリニルカルボニル)-1H-1,2,4-トリア
ゾール-3-イル]スルホニル}メチル)イミダゾ[1,2-a]ピ
リジン(200 mg, 0.53 mmol)のN,N-ジメチルホルムアミ
ド(4 ml)溶液に氷冷下、N-クロロコハク酸イミド(98%含
量, 80 mg, 0.59mmol)を加え、室温で20時間撹拌した。
更にN-クロロコハク酸イミド(98%含量, 36 mg, 0.27 mm
ol)を加え、55℃で3時間撹拌した。反応液に水(20 ml)
を加え、塩化メチレン(20 ml)で抽出し、飽和食塩水(20
ml)で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を
減圧濃縮し、残留物をフラッシュシリカゲルクロマトグ
ラフィー(酢酸エチル→酢酸エチル:メタノール=10/1,
v/v)で精製し、ジイソプロピルエーテルで結晶化する
と、表題化合物(59 mg, 収率27%)を白色結晶として得
た。
融点 160.3-161.2℃1
H-NMR (CDCl3) δ: 3.60-4.00 (8H, m), 4.90 (2H,
s), 6.97 (1H, td, J =7.0, 1.0Hz), 7.25 (1H, ddd,
J = 9.0, 7.0, 1.0Hz), 7.46 (1H, dt, J = 9.0, 1.0
Hz), 8.03 (1H, dt, J = 7.0, 1.0Hz), 8.91 (1H, s).
元素分析値 C15H15ClN6O4Sとして
計算値(%): C, 43.85; H, 3.68; N, 20.46.
実測値(%): C, 43.29; H, 3.58; N, 20.37
実施例23
3-クロロ-2-({[1-(1-ピペリジニルカルボニル)-1H-1,2,
4-トリアゾール-3-イル]スルホニル}メチル)イミダゾ
[1,2-a]ピリジン
2-({[1-(1-ピペリジニルカルボニル)-1H-1,2,4-トリア
ゾール-3-イル]スルホニル}メチル)イミダゾ[1,2-a]ピ
リジン(150 mg, 0.401 mmol)のN,N-ジメチルホルムアミ
ド(1.5 ml)溶液に氷冷下、N-クロロコハク酸イミド(98%
含量, 64 mg, 0.48 mmol)を加え、室温で20時間撹拌し
た。N-クロロコハク酸イミド(98%含量, 16 mg, 0.12 mm
ol)をさらに加え、室温で2時間撹拌した。反応液に水(2
0 ml) を加え、塩化メチレン(20 ml)で抽出した。有機
層を飽和食塩水(20 ml)で洗浄後、無水硫酸ナトリウム
で乾燥した。溶媒を減圧濃縮し、得られた残留物をフラ
ッシュシリカゲルクロマトグラフィー(酢酸エチル:ヘ
キサン=10/1, v/v)で精製し、ジイソプロピルエーテル
で結晶化すると表題化合物(52 mg, 収率32%)を得た。
融点 151.2-151.3℃1
H-NMR (CDCl3) δ: 1.40-1.80 (6H, m), 3.60-3.80
(4H, m), 4.90 (2H, s),6.96 (1H, td, J = 6.8, 1.0H
z), 7.13 (1H, ddd, J = 9.2, 6.8, 1.0Hz), 7.49 (1
H, dt, J = 9.2, 1.0Hz), 8.03 (1H, dt, J = 6.8,
1.0Hz), 8.84 (1H,s).
IR (KBr): 1717, 1439, 1341, 1250, 1236, 1146 c
m−1.
元素分析値 C16H17ClN6O3Sとして
計算値(%): C, 47.00; H, 4.19; N, 20.55.
実測値(%): C, 46.84; H, 4.41; N, 20.19.Example 22 3-chloro-2-({[1- (4-morpholinylcarbonyl) -1H-1,2,
4-triazol-3-yl] sulfonyl} methyl) imidazo
[1,2-a] Pyridine 2-({[1- (4-morpholinylcarbonyl) -1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] N-chlorosuccinimide (98% content, 80 mg, 0.59 mmol) was added to a solution of pyridine (200 mg, 0.53 mmol) in N, N-dimethylformamide (4 ml) under ice cooling, and the mixture was stirred at room temperature for 20 hours. .
Further N-chlorosuccinimide (98% content, 36 mg, 0.27 mm
ol) was added and the mixture was stirred at 55 ° C. for 3 hours. Water (20 ml) in the reaction mixture
Was added, extracted with methylene chloride (20 ml), and saturated saline (20 ml).
(ml) and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was subjected to flash silica gel chromatography (ethyl acetate → ethyl acetate: methanol = 10/1,
The product was purified by v / v) and crystallized from diisopropyl ether to give the title compound (59 mg, yield 27%) as white crystals. Melting point 160.3-161.2 ° C 1 H-NMR (CDCl 3 ) δ: 3.60-4.00 (8H, m), 4.90 (2H,
s), 6.97 (1H, td, J = 7.0, 1.0Hz), 7.25 (1H, ddd,
J = 9.0, 7.0, 1.0Hz), 7.46 (1H, dt, J = 9.0, 1.0
Hz), 8.03 (1H, dt, J = 7.0, 1.0Hz), 8.91 (1H, s). Elemental analysis calculated as C 15 H 15 ClN 6 O 4 S (%): C, 43.85; H, 3.68 N, 20.46.Actual value (%): C, 43.29; H, 3.58; N, 20.37 Example 23 3-chloro-2-({[1- (1-piperidinylcarbonyl) -1H-1,2 ,
4-triazol-3-yl] sulfonyl} methyl) imidazo
[1,2-a] Pyridine 2-({[1- (1-piperidinylcarbonyl) -1H-1,2,4-triazol-3-yl] sulfonyl} methyl) imidazo [1,2-a] N-chlorosuccinimide (98%) was added to a solution of pyridine (150 mg, 0.401 mmol) in N, N-dimethylformamide (1.5 ml) under ice cooling.
Content, 64 mg, 0.48 mmol) was added, and the mixture was stirred at room temperature for 20 hours. N-chlorosuccinimide (98% content, 16 mg, 0.12 mm
ol) was further added, and the mixture was stirred at room temperature for 2 hours. Water (2
0 ml) was added, and the mixture was extracted with methylene chloride (20 ml). The organic layer was washed with saturated saline (20 ml) and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by flash silica gel chromatography (ethyl acetate: hexane = 10/1, v / v) and crystallized from diisopropyl ether to give the title compound (52 mg, yield 32%) ) Got. Melting point 151.2-151.3 ° C 1 H-NMR (CDCl 3 ) δ: 1.40-1.80 (6H, m), 3.60-3.80
(4H, m), 4.90 (2H, s), 6.96 (1H, td, J = 6.8, 1.0H
z), 7.13 (1H, ddd, J = 9.2, 6.8, 1.0Hz), 7.49 (1
H, dt, J = 9.2, 1.0Hz), 8.03 (1H, dt, J = 6.8,
1.0Hz), 8.84 (1H, s) .IR (KBr): 1717, 1439, 1341, 1250, 1236, 1146 c
m −1 . Elemental analysis value Calculated as C 16 H 17 ClN 6 O 3 S (%): C, 47.00; H, 4.19; N, 20.55. Actual value (%): C, 46.84; H, 4.41; N , 20.19.
【0070】実施例24
3-[(2-メトキシベンジル)チオ]-N,N-ジメチル-1H-1,2,4
-トリアゾール-1-カルボキサミド
2-メトキシベンジルクロリド(0.39 g, 2.5 mmol)、3-メ
ルカプト-1,2,4-トリアゾール(0.25 g, 2.5 mmol)及び
炭酸カリウム(0.35 g, 2.5 mmol)のN,N-ジメチルホルム
アミド(4 ml)溶液を室温で1時間撹拌した。反応液に、
ジメチルカルバモイルクロリド(0.34 ml, 3.75 mmol)を
加え、室温で更に1時間撹拌した。反応液に水(10 mL)を
加え、塩化メチレン(2 mL)で抽出した。有機層を分離
し、シリカゲルクロマトグラフィー(酢酸エチル:ヘキ
サン=3/1→1/3, v/v)で精製し、ジイソプロピルエーテ
ル/酢酸エチルで結晶化すると表題化合物(497 mg, 収率
68%)を得た。
融点 80.6-81.3℃1
H-NMR (CDCl3) δ: 3.22 (6H, s), 3.87 (3H, s),
4.41 (2H, s), 6.80-6.90(2H, m), 7.20-7.30 (1H, m),
7.35-7.40 (1H, m), 8.73 (1H, s).
元素分析値 C13H16N4O2Sとして
計算値(%): C, 53.41; H, 5.52; N, 19.16.
実測値(%): C, 53.42; H, 5.41; N, 19.07.
実施例25
3-[(2-メトキシベンジル)スルホニル]-N,N-ジメチル-1H
-1,2,4-トリアゾール-1-カルボキサミド
3-[(2-メトキシベンジル)チオ]-N,N-ジメチル-1H-1,2,4
-トリアゾール-1-カルボキサミド(0.38 g, 1.3 mmol)の
塩化メチレン(3.5 mL)溶液に、氷冷下、m-クロロ過安息
香酸(0.51 g, 2.1 mmol)を添加し、室温で2時間撹拌し
た。反応液を飽和重曹水(4 mL)で洗浄した後、シリカゲ
ルクロマトグラフィー(酢酸エチル:ヘキサン=1/1, v/
v→酢酸エチル)で精製し、第一溶出分を減圧濃縮し、ジ
イソプロピルエーテル/酢酸エチルで結晶化すると表題
化合物(263 mg, 収率63%)を得た。
融点 134.1-135.6℃1
H-NMR (CDCl3) δ: 3.17 (6H, s), 3.68 (3H, s),
4.74 (2H, s), 6.80-6.85(1H, m), 6.90-7.00 (2H, m),
7.25-7.40 (1H, m), 8.86 (1H, s).
元素分析値 C13H16N4O4Sとして
計算値(%): C, 48.14; H, 4.97; N, 17.27.
実測値(%): C, 48.18; H, 5.15; N, 16.89.
実施例26
3-[(2-メトキシベンジル)スルフィニル]-N,N-ジメチル-
1H-1,2,4-トリアゾール-1-カルボキサミド
実施例25で行ったフラッシュシリカゲルカラムクロマト
グラフィーにおける第二溶出分を濃縮することで表題化
合物(105 mg, 22%)を油状物として得た。1
H-NMR (CDCl3) δ: 3.17 (3H, brs), 3.19 (3H, br
s), 3.83 (3H, m), 4.52(1H, d, J = 12.0 Hz), 4.67
(1H, d, J = 12.0 Hz), 6.80-6.90 (2H, m), 7.05(1H,
dd, J = 1.8, 7.5 Hz), 7.25-7.35 (1H, m), 8.90 (1H,
s).Example 24 3-[(2-Methoxybenzyl) thio] -N, N-dimethyl-1H-1,2,4
-Triazole-1-carboxamide 2-methoxybenzyl chloride (0.39 g, 2.5 mmol), 3-mercapto-1,2,4-triazole (0.25 g, 2.5 mmol) and potassium carbonate (0.35 g, 2.5 mmol) in N, The N-dimethylformamide (4 ml) solution was stirred at room temperature for 1 hour. In the reaction solution,
Dimethylcarbamoyl chloride (0.34 ml, 3.75 mmol) was added, and the mixture was further stirred at room temperature for 1 hr. Water (10 mL) was added to the reaction solution, and the mixture was extracted with methylene chloride (2 mL). The organic layer was separated, purified by silica gel chromatography (ethyl acetate: hexane = 3/1 → 1/3, v / v), and crystallized from diisopropyl ether / ethyl acetate to give the title compound (497 mg, yield
68%). Melting point 80.6-81.3 ° C 1 H-NMR (CDCl 3 ) δ: 3.22 (6H, s), 3.87 (3H, s),
4.41 (2H, s), 6.80-6.90 (2H, m), 7.20-7.30 (1H, m),
7.35-7.40 (1H, m), 8.73 (1H, s). Elemental analysis calculated as C 13 H 16 N 4 O 2 S (%): C, 53.41; H, 5.52; N, 19.16. %): C, 53.42; H, 5.41; N, 19.07. Example 25 3-[(2-Methoxybenzyl) sulfonyl] -N, N-dimethyl-1H
-1,2,4-triazole-1-carboxamide 3-[(2-methoxybenzyl) thio] -N, N-dimethyl-1H-1,2,4
To a solution of -triazole-1-carboxamide (0.38 g, 1.3 mmol) in methylene chloride (3.5 mL) was added m-chloroperbenzoic acid (0.51 g, 2.1 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. . The reaction solution was washed with saturated aqueous sodium hydrogen carbonate (4 mL) and then subjected to silica gel chromatography (ethyl acetate: hexane = 1/1, v /
(v → ethyl acetate), the first eluate was concentrated under reduced pressure, and crystallized from diisopropyl ether / ethyl acetate to give the title compound (263 mg, yield 63%). Melting point 134.1-135.6 ° C 1 H-NMR (CDCl 3 ) δ: 3.17 (6H, s), 3.68 (3H, s),
4.74 (2H, s), 6.80-6.85 (1H, m), 6.90-7.00 (2H, m),
7.25-7.40 (1H, m), 8.86 (1H, s). Elemental analysis value Calculated as C 13 H 16 N 4 O 4 S (%): C, 48.14; H, 4.97; N, 17.27. %): C, 48.18; H, 5.15; N, 16.89. Example 26 3-[(2-methoxybenzyl) sulfinyl] -N, N-dimethyl-
1H-1,2,4-triazole-1-carboxamide The second eluate in the flash silica gel column chromatography performed in Example 25 was concentrated to give the title compound (105 mg, 22%) as an oil. 1 H-NMR (CDCl 3 ) δ: 3.17 (3H, brs), 3.19 (3H, br
s), 3.83 (3H, m), 4.52 (1H, d, J = 12.0 Hz), 4.67
(1H, d, J = 12.0 Hz), 6.80-6.90 (2H, m), 7.05 (1H,
dd, J = 1.8, 7.5 Hz), 7.25-7.35 (1H, m), 8.90 (1H,
s).
【0071】実施例27
3-[(3-メトキシベンジル)チオ]-N,N-ジメチル-1H-1,2,4
-トリアゾール-1-カルボキサミド
3-メトキシベンジルクロリド(0.39 g, 2.5 mmol)、 3-
メルカプト-1,2,4-トリアゾール(0.25 g, 2.5 mmol)、
炭酸カリウム(0.35 g, 2.5 mmol)及びジメチルカルバモ
イルクロリド(0.34 ml, 3.75 mmol) から実施例23と同
様の方法で、表題化合物(641 mg, 収率88%)を得た。
融点 64.6-66.3℃1
H-NMR (CDCl3) δ: 3.16 (6H, s), 3.67 (3H, s),
4.73 (2H, s), 6.81 (1H,dm, J = 8.1 Hz), 6.92 (1H,
dt, J = 1.2, 8.1 Hz), 7.25-7.35 (2H, m), 8.73 (1H,
s).
実施例28
3-[(3-メトキシベンジル)スルホニル]-N,N-ジメチル-1H
-1,2,4-トリアゾール-1-カルボキサミド
3-[(3-メトキシベンジル)チオ]-N,N-ジメチル-1H-1,2,4
-トリアゾール-1-カルボキサミド(0.48 g, 1.6 mmol)及
びm-クロロ過安息香酸(0.65 g, 2.6 mmol)から、実施例
25と同様の方法で、表題化合物(241 mg, 収率45%)を油
状物として得た。1
H-NMR (CDCl3) δ: 3.15 (6H, s), 3.77 (3H, s),
4.61 (2H, s), 6.80-6.90(3H, m), 7.15-7.25 (1H, m),
8.87 (1H, s).
元素分析値 C13H16N4O4Sとして
計算値(%): C, 48.14; H, 4.97; N, 17.27.
実測値(%): C, 47.77; H, 4.86; N, 17.07.Example 27 3-[(3-Methoxybenzyl) thio] -N, N-dimethyl-1H-1,2,4
-Triazole-1-carboxamide 3-methoxybenzyl chloride (0.39 g, 2.5 mmol), 3-
Mercapto-1,2,4-triazole (0.25 g, 2.5 mmol),
The title compound (641 mg, yield 88%) was obtained from potassium carbonate (0.35 g, 2.5 mmol) and dimethylcarbamoyl chloride (0.34 ml, 3.75 mmol) in the same manner as in Example 23. Melting point 64.6-66.3 ° C 1 H-NMR (CDCl 3 ) δ: 3.16 (6H, s), 3.67 (3H, s),
4.73 (2H, s), 6.81 (1H, dm, J = 8.1 Hz), 6.92 (1H,
dt, J = 1.2, 8.1 Hz), 7.25-7.35 (2H, m), 8.73 (1H,
s). Example 28 3-[(3-Methoxybenzyl) sulfonyl] -N, N-dimethyl-1H
-1,2,4-triazole-1-carboxamide 3-[(3-methoxybenzyl) thio] -N, N-dimethyl-1H-1,2,4
-Triazole-1-carboxamide (0.48 g, 1.6 mmol) and m-chloroperbenzoic acid (0.65 g, 2.6 mmol)
By a method similar to 25, the title compound (241 mg, yield 45%) was obtained as an oil. 1 H-NMR (CDCl 3 ) δ: 3.15 (6H, s), 3.77 (3H, s),
4.61 (2H, s), 6.80-6.90 (3H, m), 7.15-7.25 (1H, m),
8.87 (1H, s). Elemental analysis calculated as C 13 H 16 N 4 O 4 S (%): C, 48.14; H, 4.97; N, 17.27. Actual measurement (%): C, 47.77; H, 4.86; N, 17.07.
【0072】実施例29
3-[(3-メトキシベンジル)スルフィニル]-N,N-ジメチル-
1H-1,2,4-トリアゾール-1-カルボキサミド
実施例26と同様の方法で表題化合物(227 mg, 45%)を油
状物として得た。1
H-NMR (CDCl3) δ: 3.15 (6H, s), 3.76 (3H, s),
4.41 (1H, d, J = 12.9 Hz), 4.52 (1H, d, J = 12.9 H
z), 6.70-6.85 (2H, m), 7.05-7.25 (2H, m), 8.90 (1
H, s).
実施例30
3-[(4-メトキシベンジル)チオ]-N,N-ジメチル-1H-1,2,4
-トリアゾール-1-カルボキサミド
4-メトキシベンジルクロリド(0.39 g, 2.5 mmol)、 3-
メルカプト-1,2,4-トリアゾール(0.25 g, 2.5 mmol)、
炭酸カリウム(0.35 g, 2.5 mmol)及びジメチルカルバモ
イルクロリド(0.34 ml, 3.75 mmol) から実施例23と同
様の方法で、表題化合物(622 mg, 収率85%)を得た。
融点 95.0-96.0℃1
H-NMR (CDCl3) δ: 3.21 (6H, s), 3.79 (3H, s),
4.33 (2H, s), 6.80-6.90(2H, m), 7.25-7.35 (2H, m),
8.73 (1H, s).
元素分析値 C13H16N4O2Sとして
計算値(%): C, 53.41; H, 5.52; N, 19.16.
実測値(%): C, 53.43; H, 5.48; N, 18.88.Example 29 3-[(3-Methoxybenzyl) sulfinyl] -N, N-dimethyl-
1H-1,2,4-triazole-1-carboxamide The title compound (227 mg, 45%) was obtained as an oil by a method similar to that in Example 26. 1 H-NMR (CDCl 3 ) δ: 3.15 (6H, s), 3.76 (3H, s),
4.41 (1H, d, J = 12.9 Hz), 4.52 (1H, d, J = 12.9 H
z), 6.70-6.85 (2H, m), 7.05-7.25 (2H, m), 8.90 (1
H, s). Example 30 3-[(4-Methoxybenzyl) thio] -N, N-dimethyl-1H-1,2,4
-Triazole-1-carboxamide 4-methoxybenzyl chloride (0.39 g, 2.5 mmol), 3-
Mercapto-1,2,4-triazole (0.25 g, 2.5 mmol),
The title compound (622 mg, yield 85%) was obtained from potassium carbonate (0.35 g, 2.5 mmol) and dimethylcarbamoyl chloride (0.34 ml, 3.75 mmol) in the same manner as in Example 23. Melting point 95.0-96.0 ° C 1 H-NMR (CDCl 3 ) δ: 3.21 (6H, s), 3.79 (3H, s),
4.33 (2H, s), 6.80-6.90 (2H, m), 7.25-7.35 (2H, m),
8.73 (1H, s). Elemental analysis value Calculated value as C 13 H 16 N 4 O 2 S (%): C, 53.41; H, 5.52; N, 19.16. Actual value (%): C, 53.43; H, 5.48; N, 18.88.
【0073】実施例31
3-[(4-メトキシベンジル)スルホニル]-N,N-ジメチル-1H
-1,2,4-トリアゾール-1-カルボキサミド
3-[(4-メトキシベンジル)チオ]-N,N-ジメチル-1H-1,2,4
-トリアゾール-1-カルボキサミド(0.47 g, 1.6 mmol)及
びm-クロロ過安息香酸(0.64 g, 2.6 mmol)から、実施例
25と同様の方法で、表題化合物(241 mg, 収率45%)を得
た。
融点 121.5-121.6℃1
H-NMR (CDCl3) δ: 3.16 (6H, s), 3.78 (3H, s),
4.58 (2H, s), 6.83 (2H,dd, J = 2.1, 6.6 Hz), 7.20
(2H, dd, J = 2.1, 6.6 Hz), 8.87 (1H, s).
元素分析値 C13H16N4O4Sとして
計算値(%): C, 48.14; H, 4.97; N, 17.27.
実測値(%): C, 48.19; H, 4.96; N, 17.20.
実施例32
3-[(4-メトキシベンジル)スルフィニル]-N,N-ジメチル-
1H-1,2,4-トリアゾール-1-カルボキサミド
実施例26と同様の方法で表題化合物(211 mg, 42%)を油
状物として得た。1
H-NMR (CDCl3) δ: 3.15 (6H, s), 3.77 (3H, s),
4.35-4.55 (2H, m), 6.70-6.90 (2H, m), 7.05-7.25 (2
H, m), 8.89 (1H, s).Example 31 3-[(4-Methoxybenzyl) sulfonyl] -N, N-dimethyl-1H
-1,2,4-triazole-1-carboxamide 3-[(4-methoxybenzyl) thio] -N, N-dimethyl-1H-1,2,4
-Triazole-1-carboxamide (0.47 g, 1.6 mmol) and m-chloroperbenzoic acid (0.64 g, 2.6 mmol)
The title compound (241 mg, yield 45%) was obtained by a method similar to that of 25. Melting point 121.5-121.6 ° C 1 H-NMR (CDCl 3 ) δ: 3.16 (6H, s), 3.78 (3H, s),
4.58 (2H, s), 6.83 (2H, dd, J = 2.1, 6.6 Hz), 7.20
(2H, dd, J = 2.1, 6.6 Hz), 8.87 (1H, s). Elemental analysis calculated as C 13 H 16 N 4 O 4 S (%): C, 48.14; H, 4.97; N, 17.27 Actual value (%): C, 48.19; H, 4.96; N, 17.20. Example 32 3-[(4-methoxybenzyl) sulfinyl] -N, N-dimethyl-
1H-1,2,4-triazole-1-carboxamide The title compound (211 mg, 42%) was obtained as an oil by the same method as in Example 26. 1 H-NMR (CDCl 3 ) δ: 3.15 (6H, s), 3.77 (3H, s),
4.35-4.55 (2H, m), 6.70-6.90 (2H, m), 7.05-7.25 (2
H, m), 8.89 (1H, s).
【0074】実施例33
N,N-ジメチル-3-[(2-オキソ-2-フェニルエチル)チオ]-1
H-1,2,4-トリアゾール-1-カルボキサミド
2-ブロモアセトフェノン(0.50 g, 2.5 mmol)、 3-メル
カプト-1,2,4-トリアゾール(0.25 g, 2.5 mmol)、炭酸
カリウム(0.35 g, 2.5 mmol)及びジメチルカルバモイル
クロリド(0.34 ml, 3.75 mmol) から実施例23と同様の
方法で、表題化合物(554 mg, 収率76%)を得た。
融点 91.7-92.2℃1
H-NMR (CDCl3) δ: 3.14 (6H, s), 4.68 (2H, s),
7.45-7.55 (2H, m), 7.60-7.65 (1H, m), 8.00-8.05 (2
H, m), 8.70 (1H, s).
元素分析値 C13H14N4O2Sとして
計算値(%): C, 53.78; H, 4.86; N, 19.30.
実測値(%): C, 53.94; H, 4.97; N, 19.22.
実施例34
N,N-ジメチル-3-[(2-オキソ-2-フェニルエチル)スルホ
ニル]-1H-1,2,4-トリアゾール-1-カルボキサミド
N,N-ジメチル-3-[(2-オキソ-2-フェニルエチル)チオ]-1
H-1,2,4-トリアゾール-1-カルボキサミド(0.41 g, 1.4
mmol)及びm-クロロ過安息香酸(0.55 g, 2.3 mmol)か
ら、実施例25と同様の方法で、表題化合物(212 mg, 収
率47%)を油状物として得た。1
H-NMR (CDCl3) δ: 3.19 (3H, brs), 3.30 (3H, br
s), 5.04 (2H, s), 7.45-7.55 (2H, m), 7.60-7.70 (1
H, m), 7.90-8.00 (2H, m), 8.89 (1H, s).
元素分析値 C13H14N4O4Sとして
計算値(%): C, 48.44; H, 4.38; N, 17.38.
実測値(%): C, 48.31; H, 4.41; N, 17.19.Example 33 N, N-Dimethyl-3-[(2-oxo-2-phenylethyl) thio] -1
H-1,2,4-triazole-1-carboxamide 2-bromoacetophenone (0.50 g, 2.5 mmol), 3-mercapto-1,2,4-triazole (0.25 g, 2.5 mmol), potassium carbonate (0.35 g, The title compound (554 mg, yield 76%) was obtained by the same method as in Example 23 from 2.5 mmol) and dimethylcarbamoyl chloride (0.34 ml, 3.75 mmol). Melting point 91.7-92.2 ° C 1 H-NMR (CDCl 3 ) δ: 3.14 (6H, s), 4.68 (2H, s),
7.45-7.55 (2H, m), 7.60-7.65 (1H, m), 8.00-8.05 (2
H, m), 8.70 (1H, s). Elemental analysis value Calculated as C 13 H 14 N 4 O 2 S (%): C, 53.78; H, 4.86; N, 19.30. Measured value (%): C , 53.94; H, 4.97; N, 19.22. Example 34 N, N-Dimethyl-3-[(2-oxo-2-phenylethyl) sulfonyl] -1H-1,2,4-triazole-1-carboxamide N , N-Dimethyl-3-[(2-oxo-2-phenylethyl) thio] -1
H-1,2,4-triazole-1-carboxamide (0.41 g, 1.4
mmol) and m-chloroperbenzoic acid (0.55 g, 2.3 mmol) and in the same manner as in Example 25, the title compound (212 mg, yield 47%) was obtained as an oil. 1 H-NMR (CDCl 3 ) δ: 3.19 (3H, brs), 3.30 (3H, br
s), 5.04 (2H, s), 7.45-7.55 (2H, m), 7.60-7.70 (1
H, m), 7.90-8.00 (2H, m), 8.89 (1H, s). Elemental analysis calculated as C 13 H 14 N 4 O 4 S (%): C, 48.44; H, 4.38; N, 17.38. Found (%): C, 48.31; H, 4.41; N, 17.19.
【0075】実施例35
N,N-ジメチル-3-[(2-オキソ-2-フェニルエチル)スルフ
ィニル]-1H-1,2,4-トリアゾール-1-カルボキサミド
実施例26と同様の方法で得た油状物をジイソプロピルエ
ーテル/酢酸エチルで結晶化すると表題化合物(211 mg,
42%)を得た。
融点 129.6-132.0℃1
H-NMR (CDCl3) δ: 3.18 (3H, brs), 3.31 (3H, br
s), 4.92 (1H, d, J = 15.3 Hz), 5.11 (1H, d, J = 1
5.3 Hz), 7.45-7.55 (2H, m), 7.60-7.70 (1H, m),7.90
-8.00 (2H, m), 8.87 (1H, s).
元素分析値 C13H14N4O3Sとして
計算値(%): C, 50.97; H, 4.61; N, 18.29.
実測値(%): C, 51.02; H, 4.61; N, 18.22.Example 35 N, N-Dimethyl-3-[(2-oxo-2-phenylethyl) sulfinyl] -1H-1,2,4-triazole-1-carboxamide Obtained by a method similar to that in Example 26. The oily product was crystallized from diisopropyl ether / ethyl acetate to give the title compound (211 mg,
42%). Melting point 129.6-132.0 ° C 1 H-NMR (CDCl 3 ) δ: 3.18 (3H, brs), 3.31 (3H, br
s), 4.92 (1H, d, J = 15.3 Hz), 5.11 (1H, d, J = 1
5.3 Hz), 7.45-7.55 (2H, m), 7.60-7.70 (1H, m), 7.90
-8.00 (2H, m), 8.87 (1H, s). Elemental analysis value Calculated as C 13 H 14 N 4 O 3 S (%): C, 50.97; H, 4.61; N, 18.29. Measured value (% ): C, 51.02; H, 4.61; N, 18.22.
【0076】実験例1
1)ジペプチジルペプチダーゼIV粗酵素溶液の調製
ヒト結腸腺癌由来細胞株Caco−2細胞膜に存在する
ジペプチジルペプチダーゼIVの酵素活性については、
すでにチャン(Yong S. Chung)らによっ
て報告(カンサー リサーチ(Cancer Rese
rch)、45巻、2976−2982頁、1985
年)されている。ジペプチジルペプチダーゼIV粗酵素
溶液をCaco−2(ATCC HTB−37)の培養
細胞より調製した。Caco−2細胞は、10%FBS
(牛胎児血清、ギブコ(GIBCO)社製)を含有する
D−MEM培地(日水製)で培養した。細胞抽出液は、
培地を除いて集めた細胞を0.5%Triton X−
100を含む20mMリン酸緩衝液(pH7.5)に浸
し、氷浴中30分抽出し、1500gで30分遠心した
上清を分離して調製した。細胞抽出液22mlを20m
Mトリス−塩酸緩衝液(pH7.5)で調製したセファ
デックスG−200(600ml、ファルマシア社製)
に付し、同緩衝液で展開溶出した。10mlずつ分画
し、酵素活性を調べ、190ml〜280mlの画分
(90ml)を集めた。同緩衝液260mlを加えて希
釈し、粗酵素溶液(14mU/ml、350ml)とし
た。但し、ジペプチジルペプチダーゼIV酵素活性1U
は、グリシル・プロリル−p−ニトロアニリドから1分
間あたり、1μmolのp−ニトロアニリンを生成する
酵素量とする。
2)Caco−2由来のジペプチジルペプチダーゼIV
阻害活性の測定
反応は、ナガツらの方法(アナリティカル・バイオケミ
ストリー(Analytical Biochemis
try)、74巻、466−467頁、1976年)に
準じて、96穴平底プレートを用いて37℃で実施し
た。水25μl、1Mトリス−塩酸緩衝液(pH7.
5)10μl、1mMグリシル・プロリル−p−ニトロ
アニリド(Gly−Pro−p−NA;バッケム社製)
水溶液50μlに試験化合物のN,N−ジメチルホルム
アミド溶液5μlを添加し、混合溶液を調製した。次い
で前記1)で得られたCaco−2由来のジペプチジル
ペプチダーゼIV粗酵素溶液10μlを上記混合溶液に
加え、37℃で酵素反応を開始した。0時間および3時
間後の吸光度をマイクロプレートリーダー(マルチスキ
ャン バイクロマティック;ラボシステムズ社製)を用
いて波長405nmで測定し、吸光度の増加(△OD
s)を求めた。同時に、試験化合物を含まない反応液に
おける吸光度の増加(△ODc )、試験化合物および
酵素を含まない反応液における吸光度の増加(△OD
b)を求め、ジペプチジルペプチダーゼIV酵素活性の
阻害率を計算式:
{1−[(△ODs−△ODb)/(△ODc−△OD
b)]}×100
により求めた。試験化合物群のジペプチジルペプチダー
ゼIV阻害活性は、IC50値(μM)で表し、[表
1]に示した。
[表1]
試験化合物 IC50値 (実施例番号) (μM) 3 1.0
このように、化合物(I)は、優れたジペプチジルペプ
チダーゼIV酵素活性を有するため、糖尿病の予防また
は治療薬などとして有用である。Experimental Example 1 1) Preparation of dipeptidyl peptidase IV crude enzyme solution Regarding the enzymatic activity of dipeptidyl peptidase IV present in the human colon adenocarcinoma cell line Caco-2 cell membrane,
Already reported by Yong S. Chung et al. (Cancer Research
rch), 45, 2976-2982, 1985.
Years). A crude dipeptidyl peptidase IV enzyme solution was prepared from cultured cells of Caco-2 (ATCC HTB-37). Caco-2 cells are 10% FBS
The cells were cultured in a D-MEM medium (manufactured by Nissui) containing (fetal bovine serum, manufactured by Gibco). The cell extract is
The cells collected after removing the medium were treated with 0.5% Triton X-
It was prepared by immersing in 20 mM phosphate buffer (pH 7.5) containing 100, extracting for 30 minutes in an ice bath, and centrifuging at 1500 g for 30 minutes, and separating the supernatant. 20 ml of cell extract 22 ml
Sephadex G-200 (600 ml, Pharmacia) prepared with M Tris-HCl buffer (pH 7.5)
The sample was developed and eluted with the same buffer solution. Fractions of 10 ml each were examined for enzyme activity, and 190 ml to 280 ml fractions (90 ml) were collected. The same buffer solution (260 ml) was added to dilute to give a crude enzyme solution (14 mU / ml, 350 ml). However, 1 U of dipeptidyl peptidase IV enzyme activity
Is the amount of enzyme that produces 1 μmol of p-nitroaniline from glycyl prolyl-p-nitroanilide per minute. 2) Caco-2 derived dipeptidyl peptidase IV
The assay reaction of the inhibitory activity is carried out by the method of Nagatu et al. (Analytical Biochemistry).
try), Vol. 74, 466-467, 1976) using a 96-well flat bottom plate at 37 ° C. 25 μl water, 1M Tris-HCl buffer (pH 7.
5) 10 μl, 1 mM glycyl prolyl-p-nitroanilide (Gly-Pro-p-NA; manufactured by Backchem)
A mixed solution was prepared by adding 5 μl of an N, N-dimethylformamide solution of the test compound to 50 μl of the aqueous solution. Then, 10 μl of the Caco-2-derived dipeptidyl peptidase IV crude enzyme solution obtained in 1) was added to the above mixed solution, and the enzyme reaction was started at 37 ° C. The absorbance after 0 hours and 3 hours was measured at a wavelength of 405 nm using a microplate reader (multiscan bichromatic; manufactured by Lab Systems) to increase the absorbance (ΔOD
s) was calculated. At the same time, an increase in absorbance in the reaction solution containing no test compound (ΔODc) and an increase in absorbance in the reaction solution containing no test compound (ΔOD)
b) is calculated, and the inhibition rate of dipeptidyl peptidase IV enzyme activity is calculated by the formula: {1-[(ΔODs-ΔODb) / (ΔODc-ΔOD
b)]} × 100. The dipeptidyl peptidase IV inhibitory activity of the test compound group was expressed as an IC 50 value (μM) and is shown in [Table 1]. [Table 1] Test compound IC 50 value (Example No.) (μM) 3 1.0 As described above, compound (I) has excellent dipeptidyl peptidase IV enzyme activity, and is therefore useful as a drug for preventing or treating diabetes. .
【0077】実験例2
ラット血漿中のジペプチジルペプチダーゼIV阻害活性
の測定
反応はレイモンド(Raymond)らの方法(ダイア
ビーティーズ(Diabetes)、47巻、1253
−1258頁、1998年)に準じて96穴平底プレー
トを用いて30℃で実施した。水69μl、1Mトリス
−塩酸緩衝液(pH7.5)10μl、1mMGly−
Pro−p−NA水溶液100μlに、試験化合物の
N,N−ジメチルホルムアミド溶液1μlを添加し、混
合溶液を調製した。次いでSDラット血液より常法で調
製した血漿20μlを上記混合溶液に加え、30℃で酵
素反応を開始した。0時間および1時間後の吸光度をマ
イクロプレートリーダーを用いて波長405nmで測定
し、吸光度の増加(△ODs)を求めた。同時に、試験
化合物を含まない反応液における吸光度の増加(△OD
c )、試験化合物および酵素を含まない反応液におけ
る吸光度の増加(△ODb)を求め、ジペプチジルペプ
チダーゼIV酵素活性の阻害率を計算式:
{1−[(△ODs−△ODb)/(△ODc−△OD
b)]}×100
により求めた。試験化合物群のジペプチジルペプチダー
ゼIV阻害活性は、IC50値(μM)で表し、[表
2]に示した。
[表2]
試験化合物 IC50値 (実施例番号) (μM) 3 2.4
このように、化合物(I)は、優れたジペプチジルペプ
チダーゼIV酵素活性を有するため、糖尿病の予防また
は治療薬などとして有用である。Experimental Example 2 Measurement of dipeptidyl peptidase IV inhibitory activity in rat plasma was carried out by the method of Raymond et al. (Diabetes, Vol. 47, 1253).
-1258, 1998) using a 96-well flat bottom plate at 30 ° C. 69 μl water, 1 M Tris-HCl buffer (pH 7.5) 10 μl, 1 mM Gly-
A mixed solution was prepared by adding 1 μl of an N, N-dimethylformamide solution of a test compound to 100 μl of a Pro-p-NA aqueous solution. Next, 20 μl of plasma prepared from SD rat blood by a conventional method was added to the above mixed solution, and the enzyme reaction was started at 30 ° C. The absorbance after 0 hour and 1 hour was measured at a wavelength of 405 nm using a microplate reader to determine the increase in absorbance (ΔODs). At the same time, the increase in absorbance in the reaction solution containing no test compound (ΔOD
c), the increase in absorbance (ΔODb) in the reaction solution containing no test compound or enzyme is calculated, and the inhibition rate of dipeptidyl peptidase IV enzyme activity is calculated by the formula: {1-[(ΔODs-ΔODb) / (Δ ODc- △ OD
b)]} × 100. The dipeptidyl peptidase IV inhibitory activity of the test compound group was expressed as an IC 50 value (μM) and is shown in [Table 2]. [Table 2] Test compound IC 50 value (Example No.) (μM) 3 2.4 As described above, since compound (I) has excellent dipeptidyl peptidase IV enzyme activity, it is useful as a drug for preventing or treating diabetes. .
【0078】
製剤例1(カプセルの製造)
1)実施例3の化合物 30 mg
2)微粉末セルロース 10 mg
3)乳糖 19 mg
4)ステアリン酸マグネシウム 1 mg
計 60 mg
1)、2)、3)および4)を混合して、ゼラチンカプ
セルに充填する。
製剤例2(錠剤の製造)
1)実施例3の化合物 30 g
2)乳糖 50 g
3)トウモロコシデンプン 15 g
4)カルボキシメチルセルロースカルシウム 44 g
5)ステアリン酸マグネシウム 1 g
1000錠 計 140 g
1)、2)、3)の全量および30gの4)を水で練合
し、真空乾燥後、整粒を行う。この整粒末に14gの
4)および1gの5)を混合し、打錠機により打錠す
る。このようにして、1錠あたり実施例3の化合物30
mgを含有する錠剤1000錠を得る。Formulation Example 1 (Production of Capsule) 1) Compound of Example 3 30 mg 2) Finely powdered cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Total 60 mg 1), 2), 3) And 4) are mixed and filled into a gelatin capsule. Formulation Example 2 (Production of tablets) 1) Compound of Example 3 30 g 2) Lactose 50 g 3) Corn starch 15 g 4) Carboxymethylcellulose calcium 44 g 5) Magnesium stearate 1 g 1000 tablets Total 140 g 1), The whole amount of 2) and 3) and 30 g of 4) are kneaded with water, dried in vacuum, and then sized. 14 g of 4) and 1 g of 5) are mixed with this sized powder, and the mixture is compressed with a tableting machine. Thus, 1 tablet of compound 30 of Example 3
1000 tablets containing mg are obtained.
【0079】[0079]
【発明の効果】本発明の医薬およびペプチダーゼ阻害剤
は、糖尿病の予防または治療薬などとして有用であり、
かつ薬効、作用時間、特異性、低毒性等の点で優れた性
質を有する。INDUSTRIAL APPLICABILITY The drug and peptidase inhibitor of the present invention are useful as a preventive or therapeutic drug for diabetes,
In addition, it has excellent properties such as drug efficacy, action time, specificity, and low toxicity.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 FI テーマコート゛(参考) A61P 3/04 A61P 3/04 3/10 3/10 43/00 111 43/00 111 C07D 249/12 513 C07D 249/12 513 471/04 108 471/04 108A 487/04 144 487/04 144 Fターム(参考) 4C050 AA01 BB05 CC08 EE03 FF02 GG01 GG02 HH04 4C065 AA03 BB06 CC01 DD02 EE02 HH01 JJ01 KK07 LL01 PP09 4C086 AA01 AA02 BC60 CB05 MA01 MA04 NA14 NA15 ZA70 ZC20 ZC35 ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 7 Identification code FI theme code (reference) A61P 3/04 A61P 3/04 3/10 3/10 43/00 111 43/00 111 C07D 249/12 513 C07D 249/12 513 471/04 108 108 471/04 108A 487/04 144 487/04 144 F Term (reference) 4C050 AA01 BB05 CC08 EE03 FF02 GG01 GG02 HH04 4C065 AA03 BB06 CC01 DD02 EE02 HH01 JJ01 CKK0LL02 PP01 409 CB05 MA01 MA04 NA14 NA15 ZA70 ZC20 ZC35
Claims (7)
されていてもよい炭化水素基を、nは0〜2の整数を示
し、R1およびR2は同一または異なって、水素原子また
は置換されていてもよい炭化水素基を示すか、またはR
1およびR2が、隣接する窒素原子とともに、置換され
ていてもよい含窒素複素環を形成し、R3は水素原子、
ハロゲン原子または置換されていてもよい炭化水素基を
示す]で表される化合物もしくはその塩またはそのプロ
ドラッグを含有してなる医薬。1. The formula: [In the formula, A represents an optionally substituted heterocyclic group or an optionally substituted hydrocarbon group, n represents an integer of 0 to 2, R 1 and R 2 are the same or different, and a hydrogen atom Or represents an optionally substituted hydrocarbon group, or R
1 and R 2 together with an adjacent nitrogen atom form an optionally substituted nitrogen-containing heterocycle, R 3 is a hydrogen atom,
Which represents a halogen atom or an optionally substituted hydrocarbon group] or a salt thereof or a prodrug thereof.
記載の医薬。2. A preventive or therapeutic drug for diabetes.
The described medicine.
請求項1記載の医薬。3. The medicine according to claim 1, which is a preventive or therapeutic drug for diabetic complications.
項1記載の医薬。4. The medicine according to claim 1, which is a preventive or therapeutic drug for impaired glucose tolerance.
載の医薬。5. The medicine according to claim 1, which is a preventive or therapeutic drug for obesity.
されていてもよい炭化水素基を、nは0〜2の整数を示
し、R1およびR2は同一または異なって、水素原子また
は置換されていてもよい炭化水素基を示すか、またはR
1およびR2が、隣接する窒素原子とともに、置換され
ていてもよい含窒素複素環を形成し、R3は水素原子、
ハロゲン原子または置換されていてもよい炭化水素基を
示す]で表される化合物もしくはその塩またはそのプロ
ドラッグを含有してなるペプチダーゼ阻害剤。6. The formula: [In the formula, A represents an optionally substituted heterocyclic group or an optionally substituted hydrocarbon group, n represents an integer of 0 to 2, R 1 and R 2 are the same or different, and a hydrogen atom Or represents an optionally substituted hydrocarbon group, or R
1 and R 2 together with an adjacent nitrogen atom form an optionally substituted nitrogen-containing heterocycle, R 3 is a hydrogen atom,
Which represents a halogen atom or an optionally substituted hydrocarbon group] or a salt thereof or a prodrug thereof, and a peptidase inhibitor.
−IVである請求項6記載の阻害剤。7. The inhibitor according to claim 6, wherein the peptidase is dipeptidyl peptidase-IV.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002135969A JP2003327532A (en) | 2002-05-10 | 2002-05-10 | Peptidase inhibitor |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002135969A JP2003327532A (en) | 2002-05-10 | 2002-05-10 | Peptidase inhibitor |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2003327532A true JP2003327532A (en) | 2003-11-19 |
Family
ID=29698150
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2002135969A Withdrawn JP2003327532A (en) | 2002-05-10 | 2002-05-10 | Peptidase inhibitor |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP2003327532A (en) |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005067976A2 (en) * | 2004-01-20 | 2005-07-28 | Novartis Ag | Direct compression formulation and process |
EP2116235A1 (en) | 2005-01-10 | 2009-11-11 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
US7816364B2 (en) | 2006-04-11 | 2010-10-19 | Arena Pharmaceuticals, Inc. | GRP119 receptor agonists in methods of increasing bone mass and of treating osteoporosis and other conditions characterized by low bone mass, and combination therapy relating thereto |
US7833730B2 (en) | 2006-04-11 | 2010-11-16 | Arena Pharmaceuticals, Inc. | Methods of using GPR119 to identify compounds useful for increasing bone mass in an individual |
US7838254B2 (en) | 2008-04-07 | 2010-11-23 | Arena Pharmaceuticals, Inc. | Methods of using GPR119 to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY |
WO2011005929A1 (en) | 2009-07-09 | 2011-01-13 | Arena Pharmaceuticals, Inc. | Piperidine derivative and its use for the treatment of diabets and obesity |
WO2010074588A3 (en) * | 2008-12-24 | 2011-05-19 | BIAL - PORTELA & Cª, S.A. | Pharmaceutical compounds |
WO2011127051A1 (en) | 2010-04-06 | 2011-10-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
CN101618216B (en) * | 2004-01-20 | 2012-01-04 | 诺瓦提斯公司 | Direct compression formulation and process |
WO2012040279A1 (en) | 2010-09-22 | 2012-03-29 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012135570A1 (en) | 2011-04-01 | 2012-10-04 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145361A1 (en) | 2011-04-19 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145603A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145604A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
US10555929B2 (en) | 2015-03-09 | 2020-02-11 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
US11253508B2 (en) | 2017-04-03 | 2022-02-22 | Coherus Biosciences, Inc. | PPARy agonist for treatment of progressive supranuclear palsy |
-
2002
- 2002-05-10 JP JP2002135969A patent/JP2003327532A/en not_active Withdrawn
Cited By (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2165703A3 (en) * | 2004-01-20 | 2012-03-28 | Novartis Pharma AG | Direct compression formulation and process |
WO2005067976A3 (en) * | 2004-01-20 | 2006-11-16 | Novartis Ag | Direct compression formulation and process |
JP2007518760A (en) * | 2004-01-20 | 2007-07-12 | ノバルティス アクチエンゲゼルシャフト | Direct compression formulations and methods |
AU2005205055B2 (en) * | 2004-01-20 | 2009-06-11 | Novartis Ag | Direct compression formulation and process |
EP3738585A1 (en) * | 2004-01-20 | 2020-11-18 | Novartis Ag | Direct compression formulation and process |
CN101618216B (en) * | 2004-01-20 | 2012-01-04 | 诺瓦提斯公司 | Direct compression formulation and process |
EP3366283A1 (en) * | 2004-01-20 | 2018-08-29 | Novartis AG | Direct compression formulation and process |
EP3023095A1 (en) * | 2004-01-20 | 2016-05-25 | Novartis AG | Direct compression formulation and process |
EP3023095B1 (en) | 2004-01-20 | 2018-05-16 | Novartis AG | Direct compression formulation and process |
JP2012176968A (en) * | 2004-01-20 | 2012-09-13 | Novartis Ag | Direct compression formulation and process |
WO2005067976A2 (en) * | 2004-01-20 | 2005-07-28 | Novartis Ag | Direct compression formulation and process |
RU2766487C2 (en) * | 2004-01-20 | 2022-03-15 | Новартис Аг | Composition and method for direct pressing |
EP3366283B1 (en) | 2004-01-20 | 2021-09-01 | Novartis AG | Direct compression formulation and process |
US7803754B2 (en) | 2005-01-10 | 2010-09-28 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
US8198232B2 (en) | 2005-01-10 | 2012-06-12 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
US8022034B2 (en) | 2005-01-10 | 2011-09-20 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
US8003597B2 (en) | 2005-01-10 | 2011-08-23 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
US7803753B2 (en) | 2005-01-10 | 2010-09-28 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
US8030270B2 (en) | 2005-01-10 | 2011-10-04 | Arena Pharmaceuticals, Inc. | Methods for identifying GLP-1 secretagogues |
EP2116235A1 (en) | 2005-01-10 | 2009-11-11 | Arena Pharmaceuticals, Inc. | Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level |
US8017574B2 (en) | 2006-04-11 | 2011-09-13 | Arena Pharmaceuticals, Inc. | Methods of preparing pharmaceutical compositions comprising GPR119 agonists having the effect of glucose-dependent insulinotropic peptide secretagogues |
US8101626B2 (en) | 2006-04-11 | 2012-01-24 | Arena Pharmaceuticals, Inc. | GPR119 receptor agonists in methods of increasing bone mass and of treating osteoporosis and other conditions characterized by low bone mass, and combination therapy relating thereto |
US8026074B2 (en) | 2006-04-11 | 2011-09-27 | Arena Pharmaceuticals, Inc. | Methods of using GPR119 to identify compounds useful for increasing bone mass in an individual |
US8026212B2 (en) | 2006-04-11 | 2011-09-27 | Arena Pharmaceuticals, Inc. | Methods of preparing pharmaceutical compositions comprising GPR119 agonists having the effect of glucose-dependent insulinotropic peptide secretatgogues |
EP2253311A2 (en) | 2006-04-11 | 2010-11-24 | Arena Pharmaceuticals, Inc. | Use of GPR119 receptor agonists for increasing bone mass and for treating osteoporosis, as well as combination therapy relating thereto |
US7833730B2 (en) | 2006-04-11 | 2010-11-16 | Arena Pharmaceuticals, Inc. | Methods of using GPR119 to identify compounds useful for increasing bone mass in an individual |
US7816364B2 (en) | 2006-04-11 | 2010-10-19 | Arena Pharmaceuticals, Inc. | GRP119 receptor agonists in methods of increasing bone mass and of treating osteoporosis and other conditions characterized by low bone mass, and combination therapy relating thereto |
US8580526B2 (en) | 2006-04-11 | 2013-11-12 | Arena Pharmaceuticals, Inc. | Methods of using GPR119 receptor to identify compounds which stimulate glucose-dependent insulinotropic peptide secretion |
US8486646B2 (en) | 2008-04-07 | 2013-07-16 | Arena Pharmaceuticals, Inc. | Methods of using a G protein-coupled receptor to identify peptide YY (PYY) secretagogues |
US7838254B2 (en) | 2008-04-07 | 2010-11-23 | Arena Pharmaceuticals, Inc. | Methods of using GPR119 to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY |
US8883714B2 (en) | 2008-04-07 | 2014-11-11 | Arena Pharmaceuticals, Inc. | Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues |
JP2012513990A (en) * | 2008-12-24 | 2012-06-21 | バイアル ポルテラ アンド シーエイ エス エイ | Medicine |
WO2010074588A3 (en) * | 2008-12-24 | 2011-05-19 | BIAL - PORTELA & Cª, S.A. | Pharmaceutical compounds |
AU2009330821B2 (en) * | 2008-12-24 | 2015-06-11 | Bial - Portela & Ca, S.A. | Pharmaceutical compounds |
RU2553451C2 (en) * | 2008-12-24 | 2015-06-20 | Биал-Портела Энд Ка, С.А. | Pharmaceutical compounds |
WO2011005929A1 (en) | 2009-07-09 | 2011-01-13 | Arena Pharmaceuticals, Inc. | Piperidine derivative and its use for the treatment of diabets and obesity |
WO2011127051A1 (en) | 2010-04-06 | 2011-10-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
EP3323818A1 (en) | 2010-09-22 | 2018-05-23 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012040279A1 (en) | 2010-09-22 | 2012-03-29 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012135570A1 (en) | 2011-04-01 | 2012-10-04 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145361A1 (en) | 2011-04-19 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145603A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012145604A1 (en) | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2012170702A1 (en) | 2011-06-08 | 2012-12-13 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2013055910A1 (en) | 2011-10-12 | 2013-04-18 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
WO2014074668A1 (en) | 2012-11-08 | 2014-05-15 | Arena Pharmaceuticals, Inc. | Modulators of gpr119 and the treatment of disorders related thereto |
US10555929B2 (en) | 2015-03-09 | 2020-02-11 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
US10772865B2 (en) | 2015-03-09 | 2020-09-15 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
US11400072B2 (en) | 2015-03-09 | 2022-08-02 | Coherus Biosciences, Inc. | Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy |
US11253508B2 (en) | 2017-04-03 | 2022-02-22 | Coherus Biosciences, Inc. | PPARy agonist for treatment of progressive supranuclear palsy |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2003327532A (en) | Peptidase inhibitor | |
RU2159613C2 (en) | Substituted n-(indole-2-carbonyl)-beta-alanylamides and their derivatives, method of treating glycogenphosphorylazo-dependent diseases, method for preventing ischemic myocardium damages, and pharmaceutical compositions | |
US20090088419A1 (en) | Pyridyl acetic acid compounds | |
TW200523252A (en) | Pyridine compounds | |
JP2001226350A (en) | Nitrogen-containing 5-membered heterocyclic compound | |
EA017114B1 (en) | N-(pyrazole-3-yl)benzamide derivatives as glucokinase activators | |
US20060199795A1 (en) | Receptor agonists | |
CN101646653A (en) | Fused ring compounds as partial agonists of ppar-gamma | |
CN102834393A (en) | Apoptosis signal-regulating kinase 1 inhibitors | |
EA015169B1 (en) | Use of dipeptidyl peptidase inhibitors | |
KR20010032304A (en) | Combination of an aldose reductase inhibitor and a glycogen phosphorylase inhibitor | |
JP4542757B2 (en) | Fused heterocyclic compounds | |
JP2003238566A (en) | Condensed heterocyclic compound | |
JP2007530479A (en) | Novel pyrrolidine-3,4-dicarboxamide derivatives | |
US6455532B1 (en) | Pyrazinone thrombin inhibitors | |
WO2003000257A1 (en) | TGF-ß SUPERFAMILY PRODUCTION/SECRETION PROMOTER | |
JP2003081832A (en) | Function regulator for retinoid relative receptor | |
US6521625B2 (en) | Pyrazinone thrombin inhibitors | |
EP1604983A1 (en) | Receptor antagonist | |
JP4422949B2 (en) | TGF-β superfamily production / secretion promoter | |
US7026324B2 (en) | Thrombin inhibitors | |
JP2002212171A (en) | Isoxazole derivative | |
JP4473698B2 (en) | Pyridine compounds | |
JP2003261545A (en) | Neurotrophic factor production/secretion accelerator | |
CN105829303B (en) | Condensed heterocyclic compouds as ion channel modulators |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A300 | Application deemed to be withdrawn because no request for examination was validly filed |
Free format text: JAPANESE INTERMEDIATE CODE: A300 Effective date: 20050802 |