CN1120845A - 具有cck和/或胃泌素拮抗活性的1,5-苯并二氮杂䓬衍生物 - Google Patents
具有cck和/或胃泌素拮抗活性的1,5-苯并二氮杂䓬衍生物 Download PDFInfo
- Publication number
- CN1120845A CN1120845A CN94191771A CN94191771A CN1120845A CN 1120845 A CN1120845 A CN 1120845A CN 94191771 A CN94191771 A CN 94191771A CN 94191771 A CN94191771 A CN 94191771A CN 1120845 A CN1120845 A CN 1120845A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- compound
- formula
- group
- cck
- 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.)
- Pending
Links
- 108010052343 Gastrins Proteins 0.000 title claims description 18
- AOXOCDRNSPFDPE-UKEONUMOSA-N chembl413654 Chemical compound C([C@H](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](C)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@@H](N)CCC(O)=O)C1=CC=C(O)C=C1 AOXOCDRNSPFDPE-UKEONUMOSA-N 0.000 title claims description 18
- 102100021022 Gastrin Human genes 0.000 title claims 3
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical class N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 title description 2
- 230000003042 antagnostic effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 147
- -1 CO2R6 Chemical group 0.000 claims abstract description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 150000001412 amines Chemical class 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- CDODDZJCEADUQQ-UHFFFAOYSA-N 3,3-dimethylpiperidine Chemical compound CC1(C)CCCNC1 CDODDZJCEADUQQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 claims description 5
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- SDGKUVSVPIIUCF-UHFFFAOYSA-N 2,6-dimethylpiperidine Chemical compound CC1CCCC(C)N1 SDGKUVSVPIIUCF-UHFFFAOYSA-N 0.000 claims description 3
- IECMOFZIMWVOAS-UHFFFAOYSA-N 4,4-dimethylpiperidine Chemical compound CC1(C)CCNCC1 IECMOFZIMWVOAS-UHFFFAOYSA-N 0.000 claims description 3
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 claims description 3
- CAZDSXIGMKEKAW-UHFFFAOYSA-N 2,5-dimethyl-1-pyrrolidin-1-ylpyrrolidine Chemical compound CC1CCC(C)N1N1CCCC1 CAZDSXIGMKEKAW-UHFFFAOYSA-N 0.000 claims 1
- 125000002883 imidazolyl group Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000003831 tetrazolyl group Chemical group 0.000 abstract 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- 239000000203 mixture Substances 0.000 description 56
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 35
- 238000004809 thin layer chromatography Methods 0.000 description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 101800001982 Cholecystokinin Proteins 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 102100025841 Cholecystokinin Human genes 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 229940107137 cholecystokinin Drugs 0.000 description 16
- 239000003480 eluent Substances 0.000 description 16
- 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 16
- 102400000921 Gastrin Human genes 0.000 description 15
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 15
- 239000007788 liquid Substances 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 14
- 239000000470 constituent Substances 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 14
- 239000012299 nitrogen atmosphere Substances 0.000 description 14
- 230000008020 evaporation Effects 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 238000000605 extraction Methods 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 235000019359 magnesium stearate Nutrition 0.000 description 9
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229920000881 Modified starch Polymers 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 230000002496 gastric effect Effects 0.000 description 5
- 150000005826 halohydrocarbons Chemical class 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 150000003141 primary amines Chemical class 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229960001866 silicon dioxide Drugs 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 102000004859 Cholecystokinin Receptors Human genes 0.000 description 3
- 108090001085 Cholecystokinin Receptors 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 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
- ZEBFPAXSQXIPNF-UHFFFAOYSA-N 2,5-dimethylpyrrolidine Chemical compound CC1CCC(C)N1 ZEBFPAXSQXIPNF-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 108010089335 Cholecystokinin A Receptor Proteins 0.000 description 2
- 108010089448 Cholecystokinin B Receptor Proteins 0.000 description 2
- 102100034927 Cholecystokinin receptor type A Human genes 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-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
- 206010065713 Gastric Fistula Diseases 0.000 description 2
- 102100036016 Gastrin/cholecystokinin type B receptor Human genes 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 102100039813 Inactive tyrosine-protein kinase 7 Human genes 0.000 description 2
- 108090000189 Neuropeptides Proteins 0.000 description 2
- 108010079943 Pentagastrin Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 108010012944 Tetragastrin Proteins 0.000 description 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- ZCLYCHVAVBUHHI-UHFFFAOYSA-N benzyl 2-(3-aminophenyl)acetate Chemical compound NC1=CC=CC(CC(=O)OCC=2C=CC=CC=2)=C1 ZCLYCHVAVBUHHI-UHFFFAOYSA-N 0.000 description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 239000003754 cholecystokinin receptor blocking agent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical group 0.000 description 2
- 239000008141 laxative Substances 0.000 description 2
- 230000002475 laxative effect Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 229960000444 pentagastrin Drugs 0.000 description 2
- ANRIQLNBZQLTFV-DZUOILHNSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- SXYFKXOFMCIXQW-UHFFFAOYSA-N propanedioyl dichloride Chemical compound ClC(=O)CC(Cl)=O SXYFKXOFMCIXQW-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- RGYLYUZOGHTBRF-BIHRQFPBSA-N tetragastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)CCSC)C(N)=O)C1=CC=CC=C1 RGYLYUZOGHTBRF-BIHRQFPBSA-N 0.000 description 2
- HRMRLUUZPLAPAS-UHFFFAOYSA-N (3-nitrophenyl) acetate Chemical compound CC(=O)OC1=CC=CC([N+]([O-])=O)=C1 HRMRLUUZPLAPAS-UHFFFAOYSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical class OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 1-chloro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- AFPHTEQTJZKQAQ-UHFFFAOYSA-N 3-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1 AFPHTEQTJZKQAQ-UHFFFAOYSA-N 0.000 description 1
- QJNLUNBGDFUULX-UHFFFAOYSA-N 4-n,4-n'-dimethyl-3h-pyridine-4,4-diamine Chemical compound CNC1(NC)CC=NC=C1 QJNLUNBGDFUULX-UHFFFAOYSA-N 0.000 description 1
- 208000008811 Agoraphobia Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose 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
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010012335 Dependence Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 206010016275 Fear Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 206010061968 Gastric neoplasm Diseases 0.000 description 1
- 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 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000867725 Mucilago Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 206010061882 Oesophageal neoplasm Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 1
- 206010034912 Phobia Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 201000008629 Zollinger-Ellison syndrome Diseases 0.000 description 1
- MIOPJNTWMNEORI-MHPPCMCBSA-N [(4r)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-MHPPCMCBSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- RJQMPUQTLOZERR-UHFFFAOYSA-N benzyl 2-(3-nitrophenyl)acetate Chemical compound [O-][N+](=O)C1=CC=CC(CC(=O)OCC=2C=CC=CC=2)=C1 RJQMPUQTLOZERR-UHFFFAOYSA-N 0.000 description 1
- YQEQHIZMMDWDOV-UHFFFAOYSA-N benzyl 3-aminobenzoate Chemical compound NC1=CC=CC(C(=O)OCC=2C=CC=CC=2)=C1 YQEQHIZMMDWDOV-UHFFFAOYSA-N 0.000 description 1
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 206010007776 catatonia Diseases 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- QFLBZJPOIZFFJQ-UHFFFAOYSA-N cholecystokinin 33 Chemical compound C=1NC2=CC=CC=C2C=1CC(C(=O)NC(CCSC)C(=O)NC(CC(O)=O)C(=O)NC(CC=1C=CC=CC=1)C(N)=O)NC(=O)CNC(=O)C(CCSC)NC(=O)C(C=1C=CC(OS(O)(=O)=O)=CC=1)NC(=O)C(CC(O)=O)NC(=O)C(CCCNC(N)=N)NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(C(C)CC)NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(CO)NC(=O)C1N(CCC1)C(=O)C(CC(O)=O)NC(=O)C(CC(C)C)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(CC(N)=O)NC(=O)C(CCCCN)NC(=O)C(NC(=O)C(NC(=O)C(CO)NC(=O)C(CCSC)NC(=O)C(CCCNC(N)=N)NC(=O)CNC(=O)C(CO)NC(=O)C1N(CCC1)C(=O)C(C)NC(=O)C(N)CCCCN)C(C)CC)C(C)C)CC1=CNC=N1 QFLBZJPOIZFFJQ-UHFFFAOYSA-N 0.000 description 1
- 239000003766 cholecystokinin A receptor antagonist Substances 0.000 description 1
- 239000003743 cholecystokinin B receptor antagonist Substances 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- 229910000071 diazene Inorganic materials 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000003629 gastrointestinal hormone Substances 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 description 1
- 125000005908 glyceryl ester group Chemical group 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-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
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- AXWDMVVFIGPIKT-UHFFFAOYSA-N n-(2-fluorophenyl)-2-nitroaniline Chemical compound [O-][N+](=O)C1=CC=CC=C1NC1=CC=CC=C1F AXWDMVVFIGPIKT-UHFFFAOYSA-N 0.000 description 1
- NENZSHGMDIEWOH-UHFFFAOYSA-N n-cyclohexyl-2-nitroaniline Chemical compound [O-][N+](=O)C1=CC=CC=C1NC1CCCCC1 NENZSHGMDIEWOH-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 208000025402 neoplasm of esophagus Diseases 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 230000000631 nonopiate Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 230000037324 pain perception Effects 0.000 description 1
- 230000001175 peptic effect Effects 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000003478 temporal lobe Anatomy 0.000 description 1
- YGIRNXMYJLWFLH-UHFFFAOYSA-N tert-butyl 3-aminobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC(N)=C1 YGIRNXMYJLWFLH-UHFFFAOYSA-N 0.000 description 1
- LYDRKKWPKKEMNZ-UHFFFAOYSA-N tert-butyl benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1 LYDRKKWPKKEMNZ-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Crystallography & Structural Chemistry (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
通式(I)化合物及其生理上可接受的盐,它们的制备方法以及它们作为胃泌素和CCK拮抗剂在医药方面的应用,其中基团NR<sub>1</sub>R<sub>2</sub>代表可以由1或2个甲基取代的五~七元饱和的杂环;R<sub>3</sub>为C<sub>1-6</sub>烷基、C<sub>3-6</sub>环烷基或由1或2个卤原子任意取代的苯基;R<sub>4</sub>为苯基或由1或2个选自以下基团取代的苯基:卤素、C<sub>1-4</sub>烷基、三氟甲基、三氟甲氧基或(CH<sub>2</sub>)nR<sub>5</sub>,这里n为零或1;R<sub>5</sub>代表C<sub>1-4</sub>烷氧基、羟基、硝基、氰基、CO<sub>2</sub>R<sub>6</sub>、S(O)pCH<sub>3</sub>、NR<sub>7</sub>R<sub>8</sub>、CONR<sub>7</sub>R<sub>8</sub>、SO<sub>2</sub>NR<sub>7</sub>CO(C<sub>1-4</sub>烷基)、四唑基、甲酰氨基四唑基或3-三氟甲基1,2,4-***基;R<sub>6</sub>为氢、C<sub>1-4</sub>烷基或苄基;R<sub>7</sub>为氢或C<sub>1-4</sub>烷基;R<sub>8</sub>为氢、C<sub>1</sub>烷基、SO<sub>2</sub>CH<sub>3</sub>或SO<sub>2</sub>CF<sub>3</sub>;X代表氢、C<sub>1-4</sub>烷基或卤素;m为零、1或2,并且p为零、1或2。
Description
本发明涉及新的1,5-苯并二氮杂衍生物、它们的制备方法、含有它们的药用组合物以及它们在医药方面的应用。
缩胆囊素(CCK)和胃泌素是存在于胃肠组织和中枢神经***的结构上有关的肽。缩胆囊素包括CCK-33,为以其独特分离形式的33个氨基酸的神经肽,其羧基末端8肽CCK-8也是天然产生的神经肽,以及39-和12-氨基酸形式。胃泌素以34-、17-和14氨基酸形式出现,并且最小活性序列是C-末端4肽、Trp-Met-Asp-Phe-NH2(CCK-4),它是CCK和胃泌素共有的通用结构单元。
CCK和胃泌素是神经和末稍***中的胃肠激素与神经递质,并且通过与分布在全身不同部位的特殊受体结合而发挥它们各自的生物作用。
至少有2个称为CCK-A和CCK-B的缩胆囊素受体亚型,它们均在末稍和中枢神经***中被发现。人们发现,CCK和胃泌素受体拮抗剂具有预防和治疗动物(尤其是人)的胃肠***和中枢神经***与CCK和或胃泌素有关的疾病。
美国专利号4,988,692叙述了一组作为缩胆囊素拮抗剂的3-酰氨基1-烷基-5-苯基1,5-苯并二氮杂类衍生物。此外,该专利说明书还报告,该类化合物对CCK-A受体比对CCK-B受体具有明显大的亲合性。
我们现已发现一组新的3-脲基1,5-苯并二氯杂类化合物,它们是胃泌素和/或CCK有效的和特定的拮抗剂,尤其是在CCK-B受体上拮抗胃泌素和/或CCK。
因此,本发明提供了下列通式(I)化合物及其生理上可以接受的盐,其中基团NR1R2代表可以由1或2个甲基取代的五~七元饱和的杂环:
R3为C1-6烷基、C3-6环烷基或由1或2个卤原子任意取代的苯基:
R4为苯基或由1或2个选自以下基团取代的苯基:卤素、C1-4烷基、三氟甲基、三氟甲氧基或(CH2)nR3,这里n为零或1:
R5代表C1-4烷氧基、羟基、硝基、氰基、CO2R6、S(O)pCH3、NR7R8、CONR7R8、SO2NR7CO(C1-4烷基)、四唑基、甲酰氨基四唑基或3-三氟甲基1,2,4-***基:
R6为氢、C1-4烷基或苄基;
R7为氢或C1-4烷基;
R8为氢、C1-4烷基、SO2CH3或SO2CF3;
X代表氢、C1-4烷基或卤素:
m代表零、1或2,并且
p为零、1或2。
本发明的化合物具有至少一个不对称碳原子,因此本发明的化合物包括对映体和它们的混合物,包括外消旋体。
这里应用的术语烷基是指直链和支链的烷基。例如C1-6烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基或己基。
术语卤素包括氟、氯、溴或碘。
当R3代表四唑基、甲酰氨基四唑基或3-三氟甲基1,2,4-***基时,那么这些基团是经过其中的碳原子与分子的其余部分连接,并且本发明包括它们所有的互变异构体和C1-4烷基-N-取代的衍生物。所述基团的实例包括(1H)四唑-5-基、甲酰氨基-1H-四唑-5-基、2-甲基四唑-5-基和(3-三氟甲基)-1,2,4-***-5-基。
基团NR1R2是经过其氮原子连接在分子的其余部分,该基团的实例包括吡咯烷子基、哌啶子基、六亚甲亚氨基、2,5-二甲基吡咯烷子基、3,3-二甲基哌啶子基、2,6-二甲基哌啶子基、或4,4-二甲基哌啶子基。
如果R3代表由卤素任意取代的苯基,那么R3的实例包括由氟任意取代的苯基,例如苯基或2-氟苯基或4-氟苯基。
如果R3代表C3-6环烷基,那么R3的实例包括环丙基、环戊基或环己基。
如果R3代表C1-6烷基,那么R3的实例包括甲基、乙基、丙基、丁基、3-甲基丁基或3,3-二甲基丁基。
合适的R4基团的实例包括由卤素(如氟)、烷基(如甲基)、烷氧基(如甲氧基)、硝基、氰基、硫甲基、甲酰氨基、羧基、二甲氨基、氰甲基、1H-四唑-5-基、羧甲基或N-甲磺酰氨基任意取代的苯基。
本发明优选的一类化合物是其中基团NR1R2代表吡咯烷子基、哌啶子基、3,3-二甲基哌啶子基、4,4-二甲基哌啶子基、2,6-二甲基哌啶子基或2,5-二甲基吡咯烷子基。在该类化合物中,基团NR1R2通常为吡咯烷子基、哌啶子基或3,3-二甲基哌啶子基。
基团X通常为卤素,例如溴、氟或氟或尤其是氢。
更优选的一类式(I)化合物是其中R3为苯基、2-氟苯基或环己基,尤其是2-氟苯基或环己基。
另一类优选的式(I)化合物是其中R4为苯基或由甲基取代的苯基,例如3-甲基苯基或3,5-二甲基苯基、3-二甲氨基苯基,由氟取代的苯基,例如4-氟苯基,由甲氧基取代的苯基,例如3-甲氧基苯基或4-甲氧基苯基,以及3-硝基苯基,3-氰甲基苯基,3-甲酰氨基苯基,3-羧基苯基,3-羧甲基苯基或3-(1H)-四唑-5-基苯基。
本发明化合物特别优选的基团是其中NR1R2代表吡咯烷子基、哌啶子基或3,3-二甲基哌啶子基,R3代表2-氟苯基或环己基,并且X代表氢原子。在所述基团内,特别优选的化合物包括其中R4为苯基、4-氟苯基、3-二甲氨基苯基、3-羧基苯基、3-羧甲基苯基或3-(1H)-四唑-5-基-苯基。
本发明特别优选的化合物是:
1-[1-环己基-2,4-二氧-5-(2-氧-2-吡咯烷-1-基-乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-3-(4-氟苯基)脲及其对映体。
本发明更优选的化合物包括下述化合物及其对映体:
3-{3-[1-环己基-2,4-二氧-5-(2-氧-2-吡咯烷-1-基-乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-脲基}-苯甲酸;
3-{3-[1-(2-氟苯基)-2,4-二氧-5-(2-氧-2-吡咯烷-1-基-乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-脲基}苯基)-乙酸;
3-{3-[1-(2-(3,3-二甲基-哌啶-1-基)-2-氧-乙基]-5-(2-氟-苯基)-2,4-二氧-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-脲基}-苯甲酸。
式(I)化合物的生理上可接受的盐包括常用的盐,例如由药学上可接受的无机酸或有机酸生成的盐以及季铵生成的酸加成盐。合适的盐的实例包括盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、高氯酸盐、富马酸盐、乙酸盐、丙酸盐、琥珀酸盐、羟基乙酸盐、甲酸盐、乳酸盐、马来酸盐、酒石酸盐、柠檬酸盐、双羟萘酸盐、丙二酸盐、羟基马来酸盐、苯基乙酸盐、谷氨酸盐、苯甲酸盐、水杨酸盐、富马酸盐、甲苯磺酸盐、甲磺酸盐、萘-2-磺酸盐、苯磺酸盐等。其他的酸例如草酸,虽然其本身不是药学上可接受的,但在制备本发明化合物及它们的药学上可接受的盐中可以用于制备草酸盐作为中间体应用。
下面提到的本发明化合物包括式(I)的化合物和它们的药学上可接受的盐以及溶剂化物。
本发明化合物可调节哺乳动物中胃泌素和/或CCK的作用。尤其是本发明化合物是胃泌素和/或CCK的拮抗剂。
已表明本发明的化合物是CCK受体,尤其是CCK-B受体的拮抗剂,例如已经证明,在CCK-A拮抗剂存在下,在分离的豚鼠回肠纵向肌肉-肠肌层丛中,本发明化合物具有抑制CCK-4收缩作用的能力。
分离的豚鼠回肠纵向肌肉-肠肌层丛的制备和应用已由K-HBuchheit等(Nauyn-Schmeideberg′s Arch.Pharmacol.,(1985),329,p36-41)和V.L.Lucaites等(J.Pharmacol.Exp.Ther.,(1991)256,695-703)叙述。
与对CCK-A受体相比,本发明化合物对CCK-B受体还具有较大的亲合性。这可以应用由Fornos等(J.Pharmacol.Exp.Ther.,261,1056-1063,1992)所述的CCK受体结合试验测得。
另外,本发明化合物对CCK-A和CCK-B受体的结合亲合性可以用人CCK-B受体转染的海拉细胞膜或由人CCK-A受体转染的COS-M6细胞膜测定。
本发明化合物是胃泌素的拮抗剂,这可以应用J.J.Reeves和R.Stables(Br.J.Pharmac.,1985,86,p.677-684)所述方法,由分离的大鼠胃粘膜通过它们抑制五肽胃泌素刺激酸分泌作用的能力来证明。
应用Hedges和Parsons(Journal of Physiology,1977,267,181-194)所述方法,可以表明本发明化合物还具有抑制有意识的胃瘘管大鼠的五肽胃泌素刺激的酸分泌作用。
因此,本发明化合物可用于治疗和/或预防哺乳动物(尤其是人)的疾病,其中减轻胃泌素或CCK的作用具有治疗的好处。所以本发明化合物可用于治疗胃肠疾病,尤其是其中降低胃酸性是有益的疾病。所述疾病包括消化性胃溃疡、消化性食管炎和佐林格-埃利森综合征。本发明化合物还可用于治疗胃肠疾病,例如过敏性肠综合征、过量的胰腺分泌、急性胰腺炎、能动性疾病、窦的G细胞增生、胃基底粘膜增生或胃肠道瘤。本发明化合物也可用于治疗涉及CCK和/或胃泌素的中枢神经***疾病。例如焦虑(包括惊恐症、广场恐怖症、社交恐怖症、初级恐怖症、强迫观念与行为疾病、外伤后紧张症和一般的焦虑疾病)、抑郁症、迟发的运动障碍、帕金森氏病或精神病。它们还可以用于治疗对药物的依赖或滥用物质以及脱瘾、图雷特病或食欲调节***的机能障碍,以及治疗较低食管肿瘤、胃肿瘤、肠肿瘤和结肠肿瘤。本发明化合物也可用于直接地诱发止痛或提高***制剂或非***制剂介导的止痛,以及麻醉或失去疼痛感觉。
因此,本发明提供了用于治疗(尤其是作为人用药物)的式(I)化合物或其药学上可接受的盐或溶剂化物。
另一方面,本发明提供了应用式(I)化合物或其药学上可接受的盐或溶剂化物作为制备治疗上述疾病(其中减轻胃泌素和/或CCK的作用在治疗上是有益的)的药物。
再一方面,本发明提供了治疗哺乳动物(包括人)疾病的方法,尤其是治疗其中减轻胃泌素和/或CCK的作用在治疗上是有益的疾病,该方法包括给患者服用有效剂量的式(I)化合物或其药学上可接受的盐或溶剂化物。
熟悉本技术领域的专业人员明白,这里提到的治疗应延伸至预防以及已确诊疾病或综合征的治疗。
此外,还应明白,用于治疗的本发明化合物的用量随需治疗的疾病的性质、患者的年龄和情况而改变,并且最终由主治医师或兽医自行决定。然而,一般来讲成人治疗应用的剂量通常在1~2000mg/天范围,例如10~500mg/天。
所需剂量通常以单次剂量或以合适间隔(例如每天2、3、4或更多次)服用的均分剂量给药。
具有拮抗动物中CCK作用的本发明化合物也可以作为饲料添加剂应用,以便增加动物的食物摄入,每天的剂量为1mg/kg~10mg/kg。
虽然本发明化合物用于治疗可以作为原料药服用,但是最好使其作为有效成分以药用配方给药。
因此,本发明进一步提供了含有式(I)化合物或其药学上可接受的盐和一种或多种药学上可接受的载体以及任意的其他治疗和/或预防成分的药用配方。所述载体必须是“可接受的”,即与配方中的其他成分可配伍并且对服用者没有危害。
本发明的组合物包括下述剂型,尤其可以配制成口服、口腔含化剂、非经胃肠道给药、植入剂或直肠给药的剂型。优选口服给药剂型。
口服给药的片剂和胶囊剂可以含有常用的赋形剂如粘合剂,例如糖浆、***胶、明胶、山梨糖醇、西黄蓍胶、淀粉胶浆或聚乙烯吡咯烷酮;填充剂例如乳糖、白糖、微晶纤维素、玉米淀粉、磷酸钙或山梨糖醇;润滑剂例如硬脂酸镁、硬脂酸、滑石、聚乙二醇或硅胶;崩解剂例如土豆淀粉或淀粉羟基乙酸钠;湿润剂例如十二烷基硫酸钠。片剂可以按照本技术领域熟知的方法进行包衣。口服液体制剂可以是例如水混悬液剂或油混悬液剂、溶液乳剂、糖浆剂或酏剂,或者可以为干燥的产品,在应用之前将其与水或其他合适的媒液进行配制。所述液体制剂可以含有常用的添加剂如混悬剂,例如山梨糖醇糖浆、甲基纤维素、葡萄糖/白糖糖浆、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化的食用脂肪;乳化剂例如卵磷脂、山梨糖醇酐单油酸酯或***胶;非水媒液(包括可食用的油)例如杏仁油、精馏椰子油、油质酯、丙二醇或乙醇;防腐剂例如对羟基苯甲酸甲酯或丙酯、抗坏血酸。所述组合物还可以配制成栓剂,该栓剂例如含有常用的栓剂基质如可可脂或其他的甘油酯。
作为口腔含化剂给药,该组合物可以为按通常方式配制的片剂形式或锭剂形式。
本发明的组合物可以配制成注射或连续输注的非经胃肠给药的形式。注射剂型可以单位剂量形式置于安瓿中,或以加有另外防腐剂的多倍剂量形式置于容器中。非经胃肠道给药组合物可以为在油质或水媒液中的混悬液剂、溶液剂或乳剂,并且可以含有辅助剂例如混悬剂、稳定剂和/或分散剂。另外有效成分可以为粉剂形式,在应用之前将其与合适的媒液(例如无菌、无热原的水)进行配制。
本发明的组合物还可以配制成缓释型制剂。该长效制剂可以通过植入(例如植于皮下或肌内)或通过肌内注射给药。例如本发明的化合物可以与合适的多聚材料或疏水材料(例如在可接受的油中配制成乳剂)或离子交换树脂进行配制,或作为微溶的衍生物(例如作为微溶的盐)。
本发明组合物可以含有0.1~99%有效成分,作为片剂和胶囊剂通常含有30~95%有效成分,作为液体制剂通常含有3~50%有效成分。
通式(I)化合物及其盐可以按下面所述通常法进行制备。在下面的叙述中,除非另有说明,否则基团R1~R8和X同式(I)化合物中的定义。
按照通常法A,式(I)化合物可以通过胺(式II,其中R1、R2、R3、X和m同式(I)中的定义)与化合物R4Y(其中R4Y为异氰酸酯(式III)、氨基甲酰氯(式IV)、1-酰基咪唑(式V)或任意取代的苯基氨基甲酸酯(式VI),这里Ra为任意的苯氧基)反应制备, CICONHR4
R4CONHR4
(VI)
上述反应通常在合适的溶剂如卤代烃(例如二氯甲烷)、醚(例如四氢呋喃)或腈(例如乙腈)或它们的混合溶剂存在下,于0°~80℃温度进行。
异氰酸酯(式III)可以买到,或者通过胺H2N-R4与光气或三光气于合适溶剂如二氯甲烷中反应制得。氨基甲酰氯(式IV)也可以通过胺H2NR4与光气或三光气于合适溶剂如二氯甲烷中反应制得。1-酰基咪唑(式VI)可以通过胺H2N-R4与羰基二咪唑于合适溶剂(如二氯甲烷、***、四氢呋喃)中,在0~80℃温度(通常在室温)反应制得。任意取代的苯基氨基甲酸酯(式VI)可以通过胺H2N-R4与合适的氯代甲酸酯RaCOCl于碱(如吡啶、三乙胺)存在下,在合适的溶剂(如二氯甲烷)和0~50℃温度反应制得。
此外,按照通常法B,式(I)化合物可以通过中间体式(VII)与胺(式VIII)任意地于碱如叔胺(例如三乙胺)存在下进行反应制备,其中Y为基团-NCO、-NHCOCl或NHCORa,这里Ra为任意取代的苯氧基或1-咪唑基,
H2N-R4 (VIII)
上述反应通常在合适的溶剂如卤代烃(例如二氯甲烷)或醚(例如四氢呋喃)或酰胺(例如N,N-二甲基甲酰胺)中任意地于室温~溶剂的回流温度进行。
式(VII)化合物通常可以在原处由式(II)胺制得。
对于方法B,当Y为基团NHCORa,并且Ra为任意取代的苯氧基,那么与伯胺(式VIII)的反应最好在碱如叔胺(例如三乙胺)存在下进行。
对于方法B,当Y为异氰酸酯基团-N=C=O,那么与伯胺(式VIII)的反应最好在非质子传递溶剂如卤代烃(例如二氯甲烷)中进行。通常在加入伯胺(式VIII)之前,先使所述异氰酸酯在原处生成。
其中Ra为任意取代的苯氧基的式(VII)化合物可以通过伯胺(II)与相应的任意取代的苯基氯代甲酸酯于碱如吡啶存在下制备。该反应可以在溶剂如卤代烃(例如二氯甲烷)中于0~50℃温度进行。
其中Ra为1-咪唑基团的式(VII)化合物可以通过式(II)化合物与羰基二咪唑于合适的溶剂如卤代烃(例如二氯甲烷)或醚(例如四氢呋喃)存在下,在0°~80℃(通常在室温)进行反应制得。
其中Y为异氰酸酯基-N=C=O或氨基甲酰氯-NHCOCl的式(VII)化合物可以通过伯胺(II)与光气(COCl2)或三光气于合适的溶剂(如二氯甲烷)中反应制得。
按照通法C,式(I)化合物还可以通过式(IX)化合物与卤化物R2R1NCOCH2Z(其中Z为离去基团,例如溴、氯或碘)反应制备。
该反应通常按下法进行:将式(IX)化合物用强碱如氢化钠于极性非质子传递溶剂(如N,N-二甲基甲酰胺)中进行处理,接着与烷基化剂R1R2NCOCH2Z反应。
式(II)化合物可以通过还原式(X)化合物制得,其中W为CH-N3或C=N-NHPh。
其中W为CH-N3的式(X)化合物通过在合适的催化剂(如钯碳或钯-碳酸钙,或氧化铂(IV))存在下进行氢化,可以还原为式(II)化合物。该反应通常在溶剂如链烷醇(例如乙醇)、酯(例如乙酸乙酯)或乙酸存在下进行。
其中W为C=N-NHPh的式(X)化合物通过与锌和乙酸反应可以还原为式(II)化合物,该反应可以在0~50℃温度进行。
其中W为CHN3的式(X)化合物可以从其中W为CH2的式(X)化合物按下法制备:用强碱如氢化钠或叔丁醇钾进行处理,接着用三-异丙基苯磺酰基叠氮化物进行处理。该反应通常在溶剂如醚(例如四氢呋喃)中于-78~20℃温度进行。
其中W为C=NNHPh的式(X)化合物可以通过邻-苯二胺(XI)与二酰氯(XII)于合适的溶剂如醚(例如四氢呋喃)中反应制得,
其中W为CH2的式(X)化合物可以通过式(XI)化合物与二酰氯(XIII)反应制得,
式(XI)化合物或者是已知化合物,或者可以按类似的方法制备。因此,例如式(XI)化合物可以通过胺(XIV)的烷基化制得。
因此,使胺(XIV)与化合物R1R2NCOCH2Z(其中Z为氯或溴)任意地在碘化钠存在下,于溶剂如N,N-二甲基甲酰胺中进行反应。
一般来讲,式(III)、(IV)、(V)和(VI)的化合物或者为已知化合物,或者可以按类似于制备已知化合物的方法进行制备,
按照方法(D),式(I)化合物可以由式(XV)化合物(其中Rb为氢)进行制备,其方法是使式(XV)化合物的活性衍生物与胺R1R2NH进行反应。该反应通常是用酸在二亚胺如二环己基碳二亚胺和羟基苯并***存在下于溶剂如二氯甲烷中进行,或者在2-乙氧基-1-乙氧基羰基-1,2-二氢喹啉存在下于溶剂如二甲氧基乙烷中进行。
其中Rb为氢的式(XV)化合物可以通过使其中Rb为叔丁基的相应的式(XV)化合物水解,例如与三氟乙酸反应制得。其中Rb为叔丁基的式(XV)化合物可以通过相应的式(IX)化合物与卤代酯Z-CH2CO2Rb(其中Z为卤素)进行烷基化作用制得。另外,其中Rb为叔丁基的式(XV)化合物可以用上述制备式(I)化合物的通法A和B制备,但需由合适的N取代的苯并二氮杂衍生物开始。
按照方法(E),应用一般的技术,可以将式(I)化合物转变成另一式(I)化合物。
因此,其中R4为由羧基或羧甲基取代的苯基的式(I)化合物可以通过下法制备:将其中R4为由烷氧基羰基或烷氧基羰基甲基取代的苯基的相应式(I)化合物进行水解。
应用上述从相应的邻苯二胺(XI)制备式(I)化合物的通法,式(IX)化合物可以由二胺(式XIV)制备,其中伯氨基团是以对甲氧基苄基衍生物被保护,然后用普通方法脱去N-保护基对甲氧基苄基。
式(I)化合物含有至少一个不对称碳原子,即与取代的脲基连接的二氮杂环的碳原子。应用一般的方法例如手性高效液相色谱法(HPLC),通过拆开外消旋化合物可以得到式(I)化合物特定的对映体。另外,应用上述从胺(II)制备式(I)化合物的任一方法,从相应胺式(II)的对映体可以制备所需的对映体。该胺(II)的对映体可以从外消旋胺(II)应用一般的方法例如与具有适当旋光活性的酸(如R-樟脑磺酸)形成盐的方法制备,或者用制备性手性高效液相色谱法制备。
下面叙述实施例,以便更充分地理解本发明。
在中间体和实施例中,除非另有说明,否则熔点(mp)是在Gallenkamp熔点仪上进行测定并且未经校正。所有的温度是指摄氏度。柱层析在硅胶上进行。T.L.C是指在硅胶板上进行薄层层析。干燥是指溶液经无水硫酸钠干燥。在实施例中还应用以下缩写:EA=乙酸乙酯,DMF=N,N-二甲基甲酰胺,THF=四氢呋喃,DE=***,DCM=二氯甲烷,MeOH=甲醇,AcOH=乙酸,ee对映体过量,RT=保留时间。中间体1环己基-(2-硝基-苯基)-胺
在氮气氛下,将2-氯硝基苯(20g)、碳酸钾(35g)和碘化铜(I)(1.21g)在环己胺(43.6ml)中的混合物于150℃加热18小时。该混合物冷却至室温并使其吸附在硅胶上。经层析,用己烷-EA(98∶2)作为洗脱剂,得到标题化合物(22.94g),为橙色固体。薄层层析(98∶2己烷-EA)Rf0.38。中间体2N-环己基-苯-1,2-二胺
将中间体1(10g)在乙酸乙酯(400ml)中的溶液用10%钯碳(1g)于23℃和1个大气压下氢化4小时。通过hyflo过滤除去催化剂,蒸发滤液得到标题化合物(8.5g),为橙色油状物。薄层层析(9∶1己烷-EA)Rf0.36。中间体32-(2-环己氨基-苯基氨基)-1-吡咯烷-1-基-乙酮
在氮气氛下,将中间体2(8.5g)、2-氧-2-(吡咯烷-1-基)乙基溴(9.4g)和碳酸钾(18.5g)在无水DMF(250ml)中的混合物于23℃搅拌18小时。该混合物倒入水(600ml)中并用乙酸乙酯(3×300ml)萃取。合并的萃取液依次用水(3×300ml)和饱和盐水(200ml)洗涤,干燥并蒸发,得到棕色油状物。经层析,用己烷-EA(1∶1)作为洗脱剂,得到标题化合物(9.8g),为淡黄色固体,m.p.108~110℃。薄层层析(1∶1己烷-EA)Rf0.42。中间体4
1-环己基-5-(2-氧-2-吡咯烷-1-基-乙基)-3-(苯基-亚肼基)-1,5-二氢苯并[b][1,4]二氮杂-2,4-二酮
在氮气氛下,将中间体3(9.8g)和2-(苯基-亚肼基)-丙二酰基二氯化物(8.36g)在无水THF(75ml)中的溶液等速地加到冷却至-10℃的无水THF(75ml)中。加完后使混合物温热至室温并搅拌3小时。蒸除溶剂,得到粗品标题化合物(19.5g),为黄色的泡沫状物。薄层层析(DE)Rf0.23中间体53-氨基-1-环己基-5-(2-氧-2-吡咯烷-1-基-乙基)-1,5-二氢苯并[b][1,4]二氮杂-2,4-二酮
在搅拌下向锌粉(15g)的冰乙酸混悬液中滴加中间体4(19g)在冰乙酸(200ml)中的溶液。该混合物于23℃搅拌1.5小时,随后通过Hyflo过滤除去锌粉,蒸发滤液得到红色油状物。该油状物在水(200ml)和乙酸乙酯(75ml)之间分配。水相用固体Na2CO3调节至pH9并用乙酸乙酯(4×100ml)萃取。合并的有机萃取液经干燥和蒸发得到棕色油状物,经层析,用DCM-MeOH(95∶5)作为洗脱剂,得到标题化合物,为桃红色的泡沫状物。薄层层析(95∶5 DCM-MeOH )Rf0.26中间体63-{3-[1-环己基-2,4-二氧-5-(2-氧-2-吡咯烷-1-基-乙基)-2,3,4,5-四氢-1 H-苯并[b][1,4]二氮杂-3-基]-脲基}-苯甲酸苄基酯
于0℃在氮气氛下,向3-氨基-苯甲酸苄基酯(177mg)的无水THF(10ml)溶液中依次加入三乙胺(108μl)和三光气(77mg)。再加入三乙胺(108μl)并于0℃连续搅拌30分钟。加入中间体5(250mg)在无水THF(10ml)中的溶液并于23℃连续搅拌18小时。然后混合物在2N盐酸(50ml)和乙酸乙酯(50ml)间分配。将干燥的有机萃取液蒸发,残余物经层析,用EA-己烷(2∶1)作为洗脱剂,得到标题化合物(320mg),为淡黄色固体。薄层层析(2∶1EA-己烷)Rf0.17。红外(氯仿溶液)3384;2939:1690;1658;1423cm-1。中间体73-硝基-苯甲酸叔丁基酯
3-硝基苯甲酸(1.4g)在无水甲苯(10ml)中的溶液与1,1-二叔丁氧基-N,N-二甲基甲胺(10ml)处理。将混合物加热回流18小时,然后冷却、用乙酸乙酯稀释并依次用水、8%碳酸氢钠溶液和饱和盐水洗涤。将干燥的有机相蒸发得到标题化合物(1.02g),为黄色油状物。薄层层析(97∶3 DCM-MeOH)Rf0.66。中间体83-氨基-苯甲酸叔丁基酯
以10%钯碳(200mg)为催化剂将中间体7(1g)在乙醇(20ml)中的溶液于23℃和1个大气压下进行氢化。2小时后混合物通过Hyflo过滤并蒸发滤液。残余物经层析,用DCM-MeOH(97∶3)作为洗脱剂,得到标题化合物(727mg),为无色油状物。薄层层析(97∶3 DCM-MeOH)Rf0.35。中间体9(3-硝基-苯基)-乙酸苄基酯
3-硝基苯基乙酸(5g)、苄醇(2.9ml)和4,4-二甲氨基吡啶(300mg)在无水二氯甲烷(50ml)中的溶液用1-(3-二甲氨基丙基)-3-乙基碳二亚胺(7.4g)处理。所得的黄色混合物于23℃搅拌3天,然后在真空下除去溶剂。残余物在水(100ml)和乙酸乙酯(100ml)间分配,有机相用水(2×100ml)和饱和盐水(100ml)洗涤,然后干燥和蒸发。残余物经层析,用己烷-EA(4∶1)作为洗脱剂,再用异己烷-DCM(1∶1)作为洗脱剂,得到标题化合物(2.05g),为淡黄色油状物。薄层层析(4∶1己烷-EA)Rf0.35。中间体10(3-氨基-苯基)-乙酸苄基酯
以5%铂碳(200mg)作为催化剂将中间体9(2.05g)在乙酸乙酯(100ml)中的溶液于23℃和1个大气压下进行氢化。90分钟后混合物通过hyflo过滤并蒸发滤液,得到标题化合物(1.77g),为淡黄色油状物。薄层层析(DCM)Rf0.35。中间体11(2-氟-苯基)-(2-硝基-苯基)-胺
在氮气氛下将2-氟苯胺(5.0g)、碳酸钾(2.5g)和碘化铜(I)(414mg)在2-氟硝基苯(16.9ml)中的混合物加热至180℃并保持18小时。经冷却的混合物倒入水(300ml)中,并用乙酸乙酯(2×250ml)萃取,合并的萃取液用饱和盐水洗涤并蒸发。残余的棕色油状物先与乙醇水然后与甲苯一起共沸。残余物经层析,用己烷-DE(100∶0~95∶5 )洗脱,得到标题化合物(3.25g),为嫩橙色固体,m.p.58-9℃。薄层层析(95∶5己烷-DE)Rf0.45。中间体12N-(2-氟-苯基)-苯-1,2-二胺
以5%铂碳(2g)为催化剂将中间体11(15.6g)在乙酸乙酯(400ml)中的溶液于23℃和1个大气压下进行氢化。1小时后该混合物通过hyflo过滤并蒸发滤液,得到标题化合物(13.45g),为黄色固体。薄层层析(9∶1己烷-DE)Rf0.25。中间体132-[2-(2-氟-苯基氨基)-苯基氨基]-1-吡咯烷-1-基-乙酮
于23℃在氮气氛下,向中间体12(13.45g)、碳酸钾(27.5g)和无水DMF(100ml)的混合物中滴加2-氧-2-(吡咯烷-1-基)乙基溴(12.8g)在无水DMF(60ml)中的溶液。该混合物于60℃搅拌4小时,然后倒入2N碳酸钠溶液(500ml)中并用乙酸乙酯(400ml)萃取。有机萃取液依次用水(2×250ml)和饱和盐水(250ml)萃取,干燥并蒸发。残余物经层析,用己烷-DE(50∶50~0∶100)作为洗脱剂,得到标题化合物(14.12g),为淡棕色固体。薄层层析(DE)Rf0.53。中间体141-(2-氟-苯基)-5-(2-氧-2-吡咯烷-1-基-乙基)-3-(苯基-亚肼基)-1,5-二氢-苯并[b][1,4]二氮杂-2,4-二酮
在氮气氛下向冷却至-10℃的无水THF(100ml)中同时并以相等速度滴加中间体13(14.12g)和2-(苯基-亚肼基)-丙二酰基二氯化物(11.04g)的无水THF(100ml)溶液。加完后将混合物温热至室温并搅拌3.5小时。蒸发除去溶剂得到粗品标题化合物(23g),为黄色泡沫状物。薄层层析(EA)Rf0.5。中间体153-氨基-1-(2-氟-苯基)-5-(2-氧-2-吡咯烷-1-基-乙基)-1,5-二氢苯并[b][1,4]二氮杂-2,4-二酮
在搅拌下向冷水浴冷却的锌粉(22.2g)的冰乙酸(100ml)混悬液中滴加中间体14(23g)在冰乙酸(200ml)中的溶液。该混合物于23℃搅拌2.5小时,然后通过hyflo过滤除去锌粉并蒸发滤液。残余物在水(150ml)和乙酸乙酯(100ml)间分配,水相用固体Na2CO3碱化。分离两层,水相再用乙酸乙酯萃取。然后将合并的有机萃取液用饱和盐水洗涤,干燥并蒸发。残余物经层析,先用EA-MeOH(100∶0~95∶5)作为洗脱剂,随后用DCM-MeOH(80∶20)作为洗脱剂,得到标题化合物(11.07g),为淡黄色的粉末。薄层层析(95∶5 DCM-MeOH)Rf0.23。中间体1 6(3-{3-[1-(2-氟-苯基)-2,4-二氧-5-(2-氧-2-吡咯烷-1-基-乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-脲基}-苯基)-乙酸苄基酯
在氮气氛和搅拌下,向光气的甲苯(60ml)溶液中滴加中间体15(3g)在无水二氯甲烷(40ml)中的溶液。所得的混合物于23℃搅拌4小时,然后将氮气成泡吹过混合物的氨溶液18小时。蒸发混合物,残余物于60℃在真空下干燥3小时,得到中间体异氰酸酯(3.3g),为米色固体,应用该固体无需进一步特征证明。于23℃在氮气氛下向搅拌的(3-氨基-苯基)-乙酸苄基酯(241mg)的无水二氯甲烷(2ml)溶液中滴加上述异氰酸酯(400mg)的无水二氯甲烷(3ml)溶液。60分钟后在真空下除去溶剂,残余物与***一起研磨。滤出固体并干燥,得到标题化合物(263mg),为灰白色固体,m.p.104-6℃。薄层层析(EA)Rf0.54。中间体172-溴-1-(3,3-二甲基-哌啶-1-基)-乙酮
向冰冷却的溴乙酰溴(7.7ml)的无水二氯甲烷(100ml)溶液中滴加3,3-二甲基哌啶(10g)和三乙胺(12.3ml)在无水二氯甲烷(50ml)中的混合物。该混合物于23℃搅拌18小时,然后再冷至0℃。加入冰水(200ml)并分离两层。水层再用二氯甲烷(2×200ml)萃取,然后将合并的萃取液依次用2N CHl(200ml)和饱和盐水(200ml)洗涤,干燥并蒸发,得到标题化合物(17.28g),为棕色油状物。薄层层析(DE)Rf0.49。中间体1 81-(3,3-二甲基-哌啶-1-基)-2-[2-(2-氟-苯基氨基)-苯基氨基]乙酮
中间体12(3g)和碳酸钾(6.15g)在无水DMF(10ml)中的混合物用2-溴-1-(3,3-二甲基-哌啶-1-基)-乙酮(3.5g)的无水DMF(10ml)溶液处理,并于23℃在氮气氛下搅拌3天。将混合物倒入水中并用乙酸乙酯萃取。合并的萃取液依次用水和饱和盐水洗涤,干燥并蒸发,得到棕色油状物。该油状物经层析,用DCM-MeOH(100∶0~97∶3)作为洗脱剂,得到标题化合物(3.17g),为淡棕色泡沫状物。薄层层析(DCM)Rf0.23。中间体191-[2-(3,3-二甲基-哌啶-1-基)-2-氧-乙基]-5-(2-氟-苯基)-3-(苯基-亚肼基)-1,5-二氢-苯并[b][1,4]二氮杂-2,4-二酮
在氮气氛下向冷却至-10℃的无水THF(50ml)中以相等的速度加入中间体18(3.08g)和2-(苯基-亚肼基)-丙二酰基二氯化物(2.12g)在无水THF(100ml)中的溶液。加完后将混合物温热至室温并搅拌2小时,蒸发除去溶剂,得到粗品标题化合物(5.25g),为黄色的泡沫状物。薄层层析(95∶5 DCM-MeOH)Rf0.68。中间体203-氨基-1-[2-(3,3-二甲基-哌啶-1-基)-2-氧-乙基]-5-(2-氟-苯基)-1,5-二氢-苯并[b][1,4]二氮杂-2,4-二酮
在搅拌下向冷水浴冷却的锌粉(4.47g)的冰乙酸(50ml)混悬液中滴加中间体19(5.15g)在冰乙酸(75ml)中的溶液。混合物于23℃搅拌6小时,然后通过hyflo过滤除去锌粉并蒸发滤液。残余物在水和乙酸乙酯间分配,水相用固体Na2CO3碱化。有机萃取液用饱和盐水洗涤,干燥并蒸发。残余物经层析,用DCM-MeOH(95∶5)作为洗脱剂,得到标题化合物(2.38g),为淡棕色固体。薄层层析(95∶5 DCM-MeOH)Rf0.18。中间体213-{3-[1-[2-(3,3-二甲基-哌啶-1-基)-2-氧-乙基]-5-(2-氟-苯基)-2,4-二氧-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-脲基}-苯甲酸叔丁基酯
于0℃在氮气氛下,向3-氨基-苯甲酸叔丁基酯(423mg)的无水THF(10ml)溶液中依次加入三乙胺(0.31ml)和三光气(217mg)。再加入三乙胺(0.31ml)并于0℃继续搅拌30分钟。加入中间体20(800mg)在无水THF(10ml)中的溶液并于23℃继续搅拌18小时。然后该混合物在磷酸缓冲液(pH6.5)和二氯甲烷间分配。合并的有机萃取液用饱和盐水洗涤,干燥并蒸发,残余物经层析,用DCM-MeOH(97∶3)作为洗脱剂,得到淡绿色固体,该固体与DE-己烷(1∶1)一起研磨,得到标题化合物(1.07g),为白色固体,m.p.170℃。薄层层析(97∶3 DCM-MeOH)Rf0.15。实施例11-[1-环己基-2,4-二氧-5-(2-氧-2-吡咯烷-1-基-乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-3-(4-氟-苯基)脲
于23℃在氮气氛下,向中间体5(2g)的无水二氯甲烷(50ml)溶液中加入4-氟苯基异氰酸酯(650μl)。将所得的混合物搅拌1小时,然后使其吸附到硅胶上并层析,用EA-MeOH(100∶0~95∶5)作为洗脱剂,得到标题化合物(1.92g),为白色固体,m p.181-3℃。薄层层析(EA)Rf0.42。
用手性HPLC将实施例1化合物(1.7g)分离成它的2个对映体(异构体1和异构体2)。
柱:Chiralcel外径25cm×20mm内径
洗脱剂:己烷-EtOH(70∶30)
流速:20ml分-1
检测:紫外@254nm异构体1,(452mg)为白色固体,RT8.6分。HPLC>99.5%ee薄层层析(EA)Rf0.42红外(氯仿溶液)3622;3091;2938;2895;2403;1657;1515;1425;1189;1047;929cm-1异构体2,(488mg)为白色固体,RT15.1分。HPLC 98.8%ee薄层层析(EA)Rf0.42红外(KBr法):3366;2935;1695;1657;1558;1510;1422;1206;833;763cm-1实施例23-{3-[1-环己基-2,4-二氧-5-(2-氧-2-吡咯烷-1-基-乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-脲基}-苯甲酸
用10%钯碳(25mg)为催化剂将中间体6(248mg)在乙酸乙酯(10ml)和THF(5ml)中的溶液于23℃在1个大气压下氢化过夜。再加入催化剂(25mg)并继续氢化2小时,然后混合物通过hyflo过滤并蒸发滤液,得到标题化合物(216mg),为白色固体,m.p.275-6℃。薄层层析(100∶2 EA-AcOH)Rf0.25红外(KBr法)3369;2935;1700;1659;1557;1499;1431;1233;760cm-1实施例3(3-{3-[1-(2-氟-苯基)-2,4-二氧-5-(2-氧-2-吡咯烷-1-基-乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-脲基}-苯基)-乙酸
用10%钯碳(10mg)为催化剂将中间体16(177mg)在THF(10ml)中的溶液于23℃在1个大气压下进行氢化。90分钟后混合物通过hyflo过滤并蒸发滤液,得到标题化合物(67mg),为白色固体,m.p.197-9℃。薄层层析(EA)Rf0.17红外(KBr法)3331;1708;1651;1562;1499;1454;1403;1238;761cm-1实施例43-{3-[1-[2-(3,3-二甲基-哌啶-1-基)-2-氧-乙基]-5-(2-氟-苯基)-2,4-二氧-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-脲基}-苯甲酸
中间体21(400mg)在二氯甲烷(20ml)中的溶液用三氟乙酸(2ml)处理并于23℃在氮气氛下搅拌1小时。混合物在真空下浓缩。残余物经层析,用DCM-MeOH(95∶5)作为洗脱剂,得到标题化合物(344mg),为白色固体,m.p.225℃(分解)。薄层层析(95∶5 DCM-MeOH)Rf0.26
用上述通法A、B,C和D还可以制备以下化合物。表1实施例号 X R5 mp 方法5 H 3,5-diCH3 254-50 A6 H 4-OCH3 180-20 A7 H 3-F 188-900 A8 H 3-NO2 173-50 A9 H 3-CH2CN 210-20 A10 H H 216-80 A11 H 3-CONH2 275-70 A12 H 3-N(CH3)2 251-30 A13 Br 4-F *Rf0.3 D*T.l.c.环己烷∶EA∶AcOH 1∶1∶0.04表2实施例号 R3 R5 mp 方法14 Ph 3-tetrazolyl 2430 A15 Ph 3-CH3 234-60 A16 Ph 3-CONHSO2CH3 199-2000 B17 2-F-Ph 4-F 155-70 A18 2F-Ph 3-CH3 195-70 A19 2F-Ph 3-CO2H -225-70 B表3实施例号 NR1R2 mp 方法20
2400 A21
1700 A22
2600 A23
220-50dec C24
255-80 D药剂学实施例片剂
a.有效成分 50mg
干燥的乳糖(USP) 163mg
微晶纤维素(NF) 69mg
预胶凝化的淀粉(Ph.Eur.) 15mg
硬脂酸镁(USP) 3mg
片重 300mg
将有效成分、微晶纤维素、乳糖和预胶凝化的淀粉通过500微米筛,并在合适的混合容器中混合。硬脂酸镁通过250微米筛,并与上述有效成分混合物混合。混合物用合适的冲头压片。
b.有效成分 50mg
乳糖-水合物(USP) 120mg
预胶凝化的淀粉(Ph.Eur.) 20mg
交联聚乙烯吡咯烷酮(NF) 8mg
硬脂酸镁(USP) 2mg
片重 200mg
将有效成分、乳糖和预胶凝化的淀粉混合,并用水制颗粒。将湿颗粒干燥并磨细。硬脂酸镁和交联聚乙烯吡咯烷酮通过250微米筛,并与上述颗粒混合。用合适的压片冲头将得到的混合物压片。胶囊剂
a.有效成分 50mg
预胶凝化的淀粉(Ph.Eur.) 148mg
硬脂酸镁(USP) 2mg
装填物料重 200mg
将有效成分和预胶凝化的淀粉通过500微米筛,混合,并与润滑剂硬脂酸镁(通过250微米筛)混合。将混合物装入合适大小的硬明胶胶囊中。
b.有效成分 50mg
乳糖-水合物(USP) 223mg
聚乙烯吡咯烷酮(USP) 12mg
交联聚乙烯吡咯烷酮(NF) 12mg
硬脂酸镁 3mg
装填物料重 300mg
将有效成分和乳糖混合,并用聚乙烯吡咯烷酮溶液制颗粒。将湿颗粒干燥并磨细。硬脂酸镁和交联聚乙烯吡咯烷酮通过250微米筛,并与上述颗粒混合。将得到的混合物装入合适大小的硬明胶胶囊中。CCK-B受体结合亲合性
使用海拉细胞膜对CCK-B受体结合作用进行研究,该细胞膜是已经用人CCK-B受体恒定转染的,而这种人CCK-B受体则是从颞叶皮层cDNA库克隆产生的。CCK-B结合亲合性测定
在不同浓度的待测化合物(1pM~1μM)存在的情况下,将己被转染的海拉细胞膜与30pM[125I]BH-sCCK-8共同温育。所有实验的测定体积为250μl。用细胞收集器(Brandel M-24R型),通过快速过滤在GF/C玻璃纤维滤纸(Whatman,UK)上收集细胞膜,并用在4℃保存的HEPESWash缓冲液洗涤3次。用伽玛计数器(MiniGamma counter,LKB,Wallac,Finland)以77%的计数效率,测定捕获在各个滤纸片上的放射活性,计数测定时间为60秒。以不加待测化合物的样品作对照同时进行试验。
以计算机辅助非线性回归分析程序(ALLFIT progammes DeLaan等,1978)对数据进行分析。用Cheng & Prussof方程式(Ki=IC50/(1+[L]/KD))将待测化合物的IC50值转换成Ki值(Cheng andPrussof,1973)。用本发明具有代表性的化合物在本测定中所得到的实验结果列于下表中,结果以pKi值表示。CCK-A受体结合亲合性
用已经被人胆囊CCK-A受体cDNA暂时性转染的COS-M6细胞膜对CCK-A受体的结合作用进行研究。
用基于Seed and Araffo.Proc.Natl,Acad,Sci.USA 84,33651987法的二甲氨基乙基-葡萄糖法,将克隆暂时性地转染到生长达80%融合的COS-M6细胞中。然后用常规的方法分离出所需要的被转染的细胞膜。
应用上述对CCK-B受体的测定程序,测定本发明化合物对CCK-A受体的亲合性,但是在这些实验中,待测化合物的浓度范围是10pM~10μM。CCK-B结合研究
实施例号 pKi
1 8.5
1(异构体1) 8.5
1(异构体2) 8.1
2 8.7
3 8.4
4 8.8
7 8.3
8 8.6
10 8.4
12 9.0
14 8.5
15 8.8
20 8.7
本发明化合物在治疗有效剂量下实质上是无毒的。因此,当将实施例1(异构体1)化合物以剂量0.3和1mg/kg静脉注射给予胃瘘管大鼠时,没有观察到不适当的副作用,并且在该剂量下,胃酸分泌作用明显地被抑制。
Claims (14)
R3为C1-6烷基、C3-6环烷基或由1或2个卤原子任意取代的苯基:
R4为苯基或由1或2个选自以下基团取代的苯基:卤素、C1-4烷基、三氟甲基、三氟甲氧基或(CH2)nR5,这里n为零或1:
R5代表C1-4烷氧基、羟基、硝基、氰基、CO2R6、S(O)pCH3、NR7R8、CONR7R8、SO2NR7CO(C1-4烷基)、四唑基、甲酰氨基四唑基或3-三氟甲基1,2,4-***基:
R6为氢、C1-4烷基或苄基;
R7为氢或C1-4烷基:
R8为氢、C1-4烷基、SO2CH3或SO2CF3;
X代表氢、C1-4烷基或卤素:
m为零、1或2,并且
p为零、1或2。
2.权利要求1所述的化合物,其中NR1R2代表吡咯烷子基、2,5-二甲基吡咯烷子基、哌啶子基、3,3-二甲基哌啶子基、4,4-二甲基哌啶子基或2,6-二甲基哌啶子基。
3.权利要求1或2所述的化合物,其中NR1R2代表吡咯烷子基。
4.权利要求1~3中任何一项所述的化合物,其中R3代表苯基、2-氟苯基或环己基。
5.权利要求1~4中任何一项所述的化合物,其中R3代表环己基。
6.权利要求1~5中任何一项所述的化合物,其中R4代表苯基、3-甲基苯基、3,5-二甲基苯基、3-二甲氨基苯基、4-氟苯基、3-甲氧基苯基、4-甲氧基苯基、3-硝基苯基、3-氰基甲基苯基、3-甲酰氨基苯基、3-羧基苯基、3-羧甲基苯基或3-(1H)-四唑-5-基-苯基。
7.权利要求1~6中任何一项所述的化合物,其中R4代表苯基、4-氟苯基、3-二甲氨基苯基、3-羧基苯基、3-羧甲基苯基或3-(1H)-四唑-5-基-苯基。
8.1-[1-环己基-2,4-二氧-5-(2-氧-2-比咯烷-1-基-乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-3-(4-氟-苯基)脲及其对映体。
9.选自以下的化合物及它们的对映体:
3-{3-[1-环己基-2,4-二氧-5-(2-氧-2-比咯烷-1-基-乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-脲基}-苯甲酸;
3-{3-[1-(2-氟-苯基)-2,4-二氧-5-(2-氧-2-吡咯烷-1-基-乙基)-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-脲基}-苯基)-乙酸;
3-{3-[1-[2-(3,3-二甲基-哌啶-1-基)-2-氧-乙基]-5-(2-氟-苯基)-2,4-二氧-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-脲基}-苯甲酸。
10.用于治疗的权利要求1~9中任何一项所述的化合物。
11.应用权利要求1~9中任何一项所述化合物制备的治疗疾病的药物,在这里减轻胃泌素和/或CCK的作用具有治疗的效果。
12.含有权利要求1~9中任何一项所述化合物以及一种或多种生物上可接受的载体或赋形剂的药用组合物。
13.治疗哺乳动物(包括人)疾病的方法,在这里减轻胃泌素和/或CCK的作用具有治疗的效果,该方法包括服用有效剂量的权利要求1~9中任何一项所述的化合物。
14.制备权利要求1所述化合物的方法,该方法包括:
(a)使式(II)化合物与选自异氰酸酯(III)、氨基甲酰氯(IV)、1-酰基咪唑(V)或苯基氨基甲酸酯(VI)(其中Ra为任意取代的苯氧基)的化合物R4Y反应,其中R1、R2、R3和X同式(I)化合物中的定义,CICONHR4(IV)
R4CONHR4
(VI)R4同式(II)中的定义,
(b)使式(VII)化合物与胺R4NH2(式VIII)(这里R4同式(I)中的定义)反应,其中R1、R2、R3、X和m同式(I)中的定义,
Y系选自NCO、NHCOCl或NHCORa,这里Ra为任意取代的苯氧基或咪唑基,
Rb代表氢,
并且如果需要或要求,可以在分离成其主体异构体之前或之后,将式(I)化合物转变成另一式(I)化合物。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9307833.5 | 1993-04-15 | ||
GB939307833A GB9307833D0 (en) | 1993-04-15 | 1993-04-15 | Modulators of cholecystokinin and gastrin |
GB9406037A GB9406037D0 (en) | 1994-03-29 | 1994-03-29 | 1,5 Benzodiazepine derivatives |
GB9406037.3 | 1994-03-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1120845A true CN1120845A (zh) | 1996-04-17 |
Family
ID=26302765
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN94191771A Pending CN1120845A (zh) | 1993-04-15 | 1994-04-13 | 具有cck和/或胃泌素拮抗活性的1,5-苯并二氮杂䓬衍生物 |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0694040A1 (zh) |
JP (1) | JPH08508743A (zh) |
CN (1) | CN1120845A (zh) |
AU (1) | AU688316B2 (zh) |
CA (1) | CA2158972A1 (zh) |
CZ (1) | CZ267695A3 (zh) |
FI (1) | FI954852A (zh) |
HU (1) | HUT74091A (zh) |
NO (1) | NO954091L (zh) |
NZ (1) | NZ265271A (zh) |
OA (1) | OA10236A (zh) |
PL (1) | PL311083A1 (zh) |
SK (1) | SK125495A3 (zh) |
WO (1) | WO1994024151A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1130351C (zh) * | 1996-12-10 | 2003-12-10 | 泽里新药工业株式会社 | 1,5-苯并二氮杂䓬衍生物 |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69430068T2 (de) * | 1993-12-28 | 2002-08-14 | Shionogi & Co | Benzodiazepinderivate |
US6444849B1 (en) | 1997-06-25 | 2002-09-03 | Mitsubishi Chemical Corporation | Amide derivatives |
JP2000026434A (ja) | 1998-06-05 | 2000-01-25 | Zeria Pharmaceut Co Ltd | 新規1,5−ベンゾジアゼピン誘導体 |
EP1142868A4 (en) * | 1998-12-22 | 2004-09-29 | Mitsubishi Chem Corp | amide derivatives |
GB201414116D0 (en) | 2014-08-08 | 2014-09-24 | Trio Medicines Ltd | Benzodiazepine derivatives |
GB201513979D0 (en) | 2015-08-07 | 2015-09-23 | Trio Medicines Ltd | Synthesis of benzodiazepine derivatives |
WO2021071837A1 (en) | 2019-10-07 | 2021-04-15 | Kallyope, Inc. | Gpr119 agonists |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2641280B1 (fr) * | 1988-12-29 | 1994-01-21 | Roussel Uclaf | Nouveaux derives de la 2,4-dioxo 2,3,4,5-tetrahydro 1h-1,5-benzodiazepine, leur procede de preparation et leur application comme medicaments |
FR2659653B1 (fr) * | 1990-03-13 | 1992-05-22 | Rhone Poulenc Sante | Derives de l'uree, leur preparation et les medicaments les contenant. |
US5206234A (en) * | 1990-10-22 | 1993-04-27 | Merck & Co., Inc. | Benzolactam analogs as antagonists of cck |
GB9201180D0 (en) * | 1992-01-21 | 1992-03-11 | Glaxo Group Ltd | Chemical compounds |
-
1994
- 1994-04-13 AU AU65675/94A patent/AU688316B2/en not_active Ceased
- 1994-04-13 NZ NZ265271A patent/NZ265271A/en unknown
- 1994-04-13 CN CN94191771A patent/CN1120845A/zh active Pending
- 1994-04-13 CA CA002158972A patent/CA2158972A1/en not_active Abandoned
- 1994-04-13 JP JP6522733A patent/JPH08508743A/ja active Pending
- 1994-04-13 HU HU9502977A patent/HUT74091A/hu unknown
- 1994-04-13 PL PL94311083A patent/PL311083A1/xx unknown
- 1994-04-13 CZ CZ952676A patent/CZ267695A3/cs unknown
- 1994-04-13 EP EP94913579A patent/EP0694040A1/en not_active Withdrawn
- 1994-04-13 WO PCT/EP1994/001130 patent/WO1994024151A1/en not_active Application Discontinuation
- 1994-04-13 SK SK1254-95A patent/SK125495A3/sk unknown
-
1995
- 1995-10-12 FI FI954852A patent/FI954852A/fi unknown
- 1995-10-13 NO NO954091A patent/NO954091L/no unknown
- 1995-10-21 OA OA60721A patent/OA10236A/en unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1130351C (zh) * | 1996-12-10 | 2003-12-10 | 泽里新药工业株式会社 | 1,5-苯并二氮杂䓬衍生物 |
Also Published As
Publication number | Publication date |
---|---|
OA10236A (en) | 1997-10-07 |
FI954852A0 (fi) | 1995-10-12 |
NZ265271A (en) | 1997-06-24 |
AU6567594A (en) | 1994-11-08 |
SK125495A3 (en) | 1996-06-05 |
CA2158972A1 (en) | 1994-10-27 |
NO954091D0 (no) | 1995-10-13 |
CZ267695A3 (en) | 1996-04-17 |
WO1994024151A1 (en) | 1994-10-27 |
NO954091L (no) | 1995-12-13 |
JPH08508743A (ja) | 1996-09-17 |
AU688316B2 (en) | 1998-03-12 |
HUT74091A (en) | 1996-11-28 |
HU9502977D0 (en) | 1995-12-28 |
EP0694040A1 (en) | 1996-01-31 |
PL311083A1 (en) | 1996-02-05 |
FI954852A (fi) | 1995-10-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AP462A (en) | 1,5 Benzodiazepine derivatives. | |
CA2620280C (en) | Novel triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors | |
CN1534023A (zh) | 作为多巴胺-d3配位体的杂环化合物 | |
TWI603967B (zh) | 具有增進之受體活性及生物有效性性質之新穎***衍生物在用作生長激素促泌素受體之腦腸肽拮抗劑上之用途 | |
JP2571899B2 (ja) | ベンゾジアゼピン誘導体、それを含有する組成物、及び治療に於ける使用 | |
AU640277B2 (en) | Tetrahydropyridoindoles as cholecystokinin and gastrin antagonists | |
EA018046B1 (ru) | Сульфониламидные производные в качестве антагонистов брадикининовых рецепторов, их получение и фармацевтическая композиция, их содержащая | |
JPH05255279A (ja) | コレシストキニン拮抗薬 | |
CN1399631A (zh) | 新的乙内酰脲、乙内酰硫脲、嘧啶二酮和硫代嘧啶酮衍生物,制备方法和作为药物的用途 | |
CN1050835C (zh) | 1,5-苯并二氮杂衍生物、其制备方法及其药物用途 | |
CN1120845A (zh) | 具有cck和/或胃泌素拮抗活性的1,5-苯并二氮杂䓬衍生物 | |
CN1340044A (zh) | 莫维诺林衍生物 | |
JPH0680649A (ja) | コレシストキニン拮抗剤 | |
CN1167698C (zh) | 用作神经激肽受体拮抗剂的n-***基甲基哌嗪衍生物 | |
CN1059722A (zh) | 3-芳基-4(3h)喹唑酮类肠促胰酶肽拮抗剂及其药物制剂 | |
CN1247584C (zh) | 1-[烷基]、1-[(杂芳基)烷基]和1-[(芳基)烷基]-7-吡啶基-咪唑并[1,2-a]嘧啶-5(1H)-酮衍生物 | |
CN1100724A (zh) | 5-酰胺基-1,2,4-噻二唑及其制备和药物组合物 | |
CN1449386A (zh) | 作为血管升压素拮抗剂的非肽取代的螺苯并氮杂䓬 | |
JPH0680650A (ja) | コレシストキニン拮抗薬 | |
CN1123792A (zh) | 氧代吡啶基喹喔啉衍生物 | |
CN1468233A (zh) | 新颖的氨基***酮化合物、它们的制备方法和含有它们的药物组合物 | |
CN1267297A (zh) | 用作法呢基蛋白转移酶抑制剂的苯并(5.6)环庚并吡啶环脲和内酰胺 | |
JPH0624990A (ja) | ベンゾジアゼピン類似体 | |
CN1161345C (zh) | 作为cck-a受体激动剂的1,5-苯并二氮杂�衍生物 | |
JPH08509236A (ja) | ガストリンまたはcck拮抗剤として有用な3‐フェニルウレイド‐1,5‐ベンゾジアゼピン‐ジオン |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C01 | Deemed withdrawal of patent application (patent law 1993) | ||
WD01 | Invention patent application deemed withdrawn after publication |