CA2112561A1 - Benzodiazepine derivatives, compositions containing them and their use in therapy - Google Patents
Benzodiazepine derivatives, compositions containing them and their use in therapyInfo
- Publication number
- CA2112561A1 CA2112561A1 CA002112561A CA2112561A CA2112561A1 CA 2112561 A1 CA2112561 A1 CA 2112561A1 CA 002112561 A CA002112561 A CA 002112561A CA 2112561 A CA2112561 A CA 2112561A CA 2112561 A1 CA2112561 A1 CA 2112561A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- formula
- alkyl
- cck
- 6alkyl
- 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.)
- Abandoned
Links
- 238000002560 therapeutic procedure Methods 0.000 title claims abstract description 4
- 239000000203 mixture Substances 0.000 title abstract description 12
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 title 1
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 108010052343 Gastrins Proteins 0.000 claims abstract description 25
- 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 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 125000005843 halogen group Chemical group 0.000 claims abstract description 11
- 229940002612 prodrug Drugs 0.000 claims abstract description 11
- 239000000651 prodrug Substances 0.000 claims abstract description 11
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 14
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 6
- 102100021022 Gastrin Human genes 0.000 claims abstract 3
- 238000000034 method Methods 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 208000035475 disorder Diseases 0.000 claims description 13
- -1 N-methylimidazolyl Chemical group 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 208000019901 Anxiety disease Diseases 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 239000012948 isocyanate Substances 0.000 claims description 3
- 150000002513 isocyanates Chemical class 0.000 claims description 3
- 230000036407 pain Effects 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- GPCDGGKVBPVZCT-UHFFFAOYSA-N 1,1-difluorocyclopropane Chemical compound FC1(F)CC1 GPCDGGKVBPVZCT-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 239000005557 antagonist Substances 0.000 abstract description 15
- YYQGUWHFXVXQOO-GFCCVEGCSA-N 2-chloro-4-[[3-[(2R)-2-hydroxybutyl]-1-methyl-2-oxobenzimidazol-5-yl]amino]pyridine-3-carbonitrile Chemical compound ClC1=C(C#N)C(=CC=N1)NC1=CC2=C(N(C(N2C[C@@H](CC)O)=O)C)C=C1 YYQGUWHFXVXQOO-GFCCVEGCSA-N 0.000 abstract 1
- ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical compound O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 abstract 1
- 125000004430 oxygen atom Chemical group O* 0.000 abstract 1
- 125000004434 sulfur atom Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 101710089098 Cholecystokinins Proteins 0.000 description 30
- 102400000921 Gastrin Human genes 0.000 description 22
- 235000002639 sodium chloride Nutrition 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 238000010609 cell counting kit-8 assay Methods 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000027455 binding Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 229920002261 Corn starch Polymers 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 239000008120 corn starch Substances 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 108010089448 Cholecystokinin B Receptor Proteins 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 229940049706 benzodiazepine Drugs 0.000 description 6
- 150000001557 benzodiazepines Chemical class 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 102000052874 Gastrin receptors Human genes 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 238000000159 protein binding assay Methods 0.000 description 5
- 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 5
- 239000000725 suspension Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- LUBJCRLGQSPQNN-UHFFFAOYSA-N 1-Phenylurea Chemical compound NC(=O)NC1=CC=CC=C1 LUBJCRLGQSPQNN-UHFFFAOYSA-N 0.000 description 4
- 102000004859 Cholecystokinin Receptors Human genes 0.000 description 4
- 108090001085 Cholecystokinin Receptors Proteins 0.000 description 4
- 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 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 108010087230 Sincalide Proteins 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 208000019906 panic disease Diseases 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical class N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 206010027646 Miosis Diseases 0.000 description 3
- 108090000189 Neuropeptides Proteins 0.000 description 3
- 208000008469 Peptic Ulcer Diseases 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 230000036592 analgesia Effects 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 208000015114 central nervous system disease Diseases 0.000 description 3
- 239000003153 chemical reaction reagent Substances 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
- 239000003085 diluting agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 230000003547 miosis Effects 0.000 description 3
- 230000004899 motility Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- RGGLEJFUEMKQSH-UHFFFAOYSA-N 1,4-benzodiazepin-2-one Chemical compound O=C1C=NC=C2C=CC=CC2=N1 RGGLEJFUEMKQSH-UHFFFAOYSA-N 0.000 description 2
- CPPGZWWUPFWALU-UHFFFAOYSA-N 1-isocyanato-3-methylbenzene Chemical compound CC1=CC=CC(N=C=O)=C1 CPPGZWWUPFWALU-UHFFFAOYSA-N 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- JXCNUCFTHLGXDQ-UHFFFAOYSA-N 2h-tetrazol-2-ium;chloride Chemical compound Cl.C1=NN=NN1 JXCNUCFTHLGXDQ-UHFFFAOYSA-N 0.000 description 2
- ZJFFBXHGOXPKCP-UHFFFAOYSA-N 5-(3-nitrophenyl)-2h-tetrazole Chemical compound [O-][N+](=O)C1=CC=CC(C2=NNN=N2)=C1 ZJFFBXHGOXPKCP-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 108010001478 Bacitracin Proteins 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 2
- 241000557626 Corvus corax Species 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 206010013654 Drug abuse Diseases 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 102000003797 Neuropeptides Human genes 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- 101710162629 Trypsin inhibitor Proteins 0.000 description 2
- 229940122618 Trypsin inhibitor Drugs 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229960003071 bacitracin Drugs 0.000 description 2
- 229930184125 bacitracin Natural products 0.000 description 2
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000003754 cholecystokinin receptor blocking agent Substances 0.000 description 2
- 229960002303 citric acid monohydrate Drugs 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 230000003291 dopaminomimetic effect Effects 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 239000008387 emulsifying waxe Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 239000004090 neuroprotective agent Substances 0.000 description 2
- 239000002581 neurotoxin Substances 0.000 description 2
- 231100000618 neurotoxin Toxicity 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 230000000771 oncological effect Effects 0.000 description 2
- 229940127240 opiate Drugs 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000008058 pain sensation Effects 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 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
- 238000010992 reflux Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- 150000003536 tetrazoles Chemical group 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 230000001228 trophic effect Effects 0.000 description 2
- 239000002753 trypsin inhibitor Substances 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- KBQLILZTNFQUGU-UHFFFAOYSA-N (2-aminophenyl)-(1,3-thiazol-2-yl)methanone Chemical compound NC1=CC=CC=C1C(=O)C1=NC=CS1 KBQLILZTNFQUGU-UHFFFAOYSA-N 0.000 description 1
- CMIBUZBMZCBCAT-HZPDHXFCSA-N (2r,3r)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HZPDHXFCSA-N 0.000 description 1
- DYIOSHGVFJTOAR-JGWLITMVSA-N (2r,3r,4s,5r)-6-sulfanylhexane-1,2,3,4,5-pentol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CS DYIOSHGVFJTOAR-JGWLITMVSA-N 0.000 description 1
- CMIBUZBMZCBCAT-HOTGVXAUSA-N (2s,3s)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HOTGVXAUSA-N 0.000 description 1
- BTUGGGLMQBJCBN-UHFFFAOYSA-N 1-iodo-2-methylpropane Chemical compound CC(C)CI BTUGGGLMQBJCBN-UHFFFAOYSA-N 0.000 description 1
- NJBJFSMVZCWLEJ-UHFFFAOYSA-N 2-(propan-2-ylsulfanylamino)acetamide Chemical compound CC(C)SNCC(N)=O NJBJFSMVZCWLEJ-UHFFFAOYSA-N 0.000 description 1
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 1
- 125000005273 2-acetoxybenzoic acid group Chemical group 0.000 description 1
- GRWKNBPOGBTZMN-UHFFFAOYSA-N 2-benzyl-3-phenylpropane-1,2-diamine Chemical compound C=1C=CC=CC=1CC(N)(CN)CC1=CC=CC=C1 GRWKNBPOGBTZMN-UHFFFAOYSA-N 0.000 description 1
- UWIGBDRMNMPNHS-UHFFFAOYSA-N 3-(2h-tetrazol-5-yl)aniline;hydrochloride Chemical compound Cl.NC1=CC=CC(C=2NN=NN=2)=C1 UWIGBDRMNMPNHS-UHFFFAOYSA-N 0.000 description 1
- CHZPIKYQWANLJD-UHFFFAOYSA-N 3-amino-5-(1,3-thiazol-2-yl)-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC=CC=C2NC(=O)C(N)N=C1C1=NC=CS1 CHZPIKYQWANLJD-UHFFFAOYSA-N 0.000 description 1
- RUSAWEHOGCWOPG-UHFFFAOYSA-N 3-nitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC=CC(C#N)=C1 RUSAWEHOGCWOPG-UHFFFAOYSA-N 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
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- 206010002758 Anticipatory anxiety Diseases 0.000 description 1
- 244000186140 Asperula odorata Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 229940122623 CCK receptor antagonist Drugs 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 101800001982 Cholecystokinin Proteins 0.000 description 1
- 108010089335 Cholecystokinin A Receptor Proteins 0.000 description 1
- 102100034927 Cholecystokinin receptor type A Human genes 0.000 description 1
- 206010008748 Chorea Diseases 0.000 description 1
- 101800000414 Corticotropin Proteins 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 206010013647 Drowning Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-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
- 239000005977 Ethylene Substances 0.000 description 1
- 235000008526 Galium odoratum Nutrition 0.000 description 1
- 206010017807 Gastric mucosal hypertrophy Diseases 0.000 description 1
- 102100036016 Gastrin/cholecystokinin type B receptor Human genes 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 206010061459 Gastrointestinal ulcer Diseases 0.000 description 1
- 201000004311 Gilles de la Tourette syndrome Diseases 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 206010021143 Hypoxia 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 206010028923 Neonatal asphyxia Diseases 0.000 description 1
- 208000037212 Neonatal hypoxic and ischemic brain injury Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 102400000050 Oxytocin Human genes 0.000 description 1
- 101800000989 Oxytocin Proteins 0.000 description 1
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 208000016620 Tourette disease Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- 206010048010 Withdrawal syndrome Diseases 0.000 description 1
- 201000008629 Zollinger-Ellison syndrome Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000006350 alkyl thio alkyl group Chemical group 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 235000021229 appetite regulation Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000000749 benzodiazepine receptor blocking agent Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=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
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008129 cerebral palsy Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940107137 cholecystokinin Drugs 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
- 239000003743 cholecystokinin B receptor antagonist Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 208000012601 choreatic disease Diseases 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000001595 contractor effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 239000003629 gastrointestinal hormone Substances 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000011597 hartley guinea pig Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 125000006289 hydroxybenzyl group Chemical group 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 201000004614 iritis Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960002523 mercuric chloride Drugs 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 210000001259 mesencephalon Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000000631 nonopiate Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940099990 ogen Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000004533 oil dispersion Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 208000031237 olivopontocerebellar atrophy Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000001175 peptic effect Effects 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 208000033300 perinatal asphyxia Diseases 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000036186 satiety Effects 0.000 description 1
- 235000019627 satiety Nutrition 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000000862 serotonergic effect Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 235000011091 sodium acetates Nutrition 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 210000005070 sphincter Anatomy 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000002438 stress hormone Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Compounds of formula (I), and salts and prodrugs thereof, wherein one of W, X, Y or Z is N, another of W, X, Y or Z is N, O or S
atom or NR8, and the other two of W, X, Y and Z are N or CR8, and the dotted circle represents two double bonds; R1 represents optionally substituted C1-6 alkyl, or C3-7 cycloalkyl; R2 represents optionally substituted C1-6 alkyl, halo, CONR6R7, SO(C1-6alkyl), SO2(C1-4alkyl), CONHSO2R9, SO2NHCOR9, SONHR10, cyano, or B(OH)2; R3 represents H, C1-6 alkyl or halo; m is 0, 1 or 2; n is 0, 1, 2 or 3; are CCK and/or gastrin antagonists. They and compositions thereof are therefore useful in therapy.
atom or NR8, and the other two of W, X, Y and Z are N or CR8, and the dotted circle represents two double bonds; R1 represents optionally substituted C1-6 alkyl, or C3-7 cycloalkyl; R2 represents optionally substituted C1-6 alkyl, halo, CONR6R7, SO(C1-6alkyl), SO2(C1-4alkyl), CONHSO2R9, SO2NHCOR9, SONHR10, cyano, or B(OH)2; R3 represents H, C1-6 alkyl or halo; m is 0, 1 or 2; n is 0, 1, 2 or 3; are CCK and/or gastrin antagonists. They and compositions thereof are therefore useful in therapy.
Description
W093/02078 PCT/GB92/01~6 5 ~
. ~. , ,~
BENZODIAZEPINE DERIVATIVE~, COMPO8ITION~
CONTAINING THEM AND T~EIR ~8E IN ~E~APY
This invention relates to benzodiazepine compounds which are useful as antagonists of cholecystokinin and gastrin receptors.
Cholecystokinins (CCK) and gastrin are structurally related neuropeptides which exist in gastrointestinal ~
tissue and in the central nervous system (see, V. Mutt, ~ - -Gastrointestinal Hormones, G.B.J. Green, Ed., Raven Press, N.Y., p.l69 and G. Nission, ibid. p.l27).
Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form ~see, Mutt and Jorpes, Biochem. J. 125, 678 (1971)), its ;
carboxylterminal octapeptide, CCK-~ (also a naturally~
occurring neuropeptide and the minimum fully active ;~
sequence), and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14-amino acid forms, with the minimum active sequence being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH2, which is the common structural element shared by both CCK and gastrin. ~-CCKs are believed to be physiological satiety ~;
, hormones, thereby possibly playing an important role in appetite regulation (G. P. Smith, Eatina and Its Disorders, A. J~ Stunkard and E. Stellar, Eds, Raven Press, New York, 1984, p. 67), as well as stimulating -coIonic motility, gall bladder contraction, pancreatic enzyme secretion and inhibiting gastric emptying. They reportedly co-exist with dopamine in certain mid-brain neurons and thus may also play a role in the functioning of dopaminergic systems in the brain, in addition to serving as neurotransmitters in their own right (see A.
J. Prange çt al., "Peptides in the Central Nervous ,. '~
WO 93/02078 PCr/GB92/01366 System", Ann. Repts. ~ed. Chem 17, 31, 33 tl982] and references cited therein; J. A. Williams, Biomed Res. 3 107 ~1982~: and J.E. Morley, Life sci. 30, 479 tl982]).
The primary role of gastrin, on the other hand, ~
appears to be stimulation of the secretion of water and ~-electrolytes from the stomach and, as such, is involved ~;
in control of gastric acid and pepsin secretion. Other --~
physiological effects of gastrin then include increased ~-~
mucosal blood flow and increased antral motility. Rat studies have shown that gastrin has a positive trophic -effect on the gastric mucosa, as evidenced by increased -;--~
DNA, RNA and protein synthesis.
There are at least two subtypes of choiecystokinin receptors termed CCK-A and CCK-B (T.H. Moran et al., "Two - ~-brain cholecystokinin receptors: implications for - -behavioural actions", Brain Res., 362, 175-79 ~1986]).
Both subtypes are found both in the periphery and in the central nervous system.
CCK and gastrin receptor antagonists have been disclosed for preventing and treating CCK-related and/or gastrin related disorders of the gastrointestinal (GI) and central nervous (CNS) systems of animals, especially mammals, and more especially those of humans. Just as , there is some overlap in the biological activities of CCK
and gastrin, antagonists also tend to have affinity for both CCK-B receptors and gastrin receptors. Other antagonists have activity at the CCK-A subtype.
8elective CCK antagonists are themselves useful in treating CCK-related disorders of appetite regulatory systems of animals as well as in potentiating and prolonging opiate-mediated analgesia [see P. L. Faris et al., Science 226, 1215 (1984)], thus having utility in the treatment of pain. CCK-B and CCK-A antagonists have also been shown to have a direct analgesic effect [M.F.
..
W093/0207~ PCT/GB92/01366 '2~t2-.~61 :~
. ~. , ,~
BENZODIAZEPINE DERIVATIVE~, COMPO8ITION~
CONTAINING THEM AND T~EIR ~8E IN ~E~APY
This invention relates to benzodiazepine compounds which are useful as antagonists of cholecystokinin and gastrin receptors.
Cholecystokinins (CCK) and gastrin are structurally related neuropeptides which exist in gastrointestinal ~
tissue and in the central nervous system (see, V. Mutt, ~ - -Gastrointestinal Hormones, G.B.J. Green, Ed., Raven Press, N.Y., p.l69 and G. Nission, ibid. p.l27).
Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form ~see, Mutt and Jorpes, Biochem. J. 125, 678 (1971)), its ;
carboxylterminal octapeptide, CCK-~ (also a naturally~
occurring neuropeptide and the minimum fully active ;~
sequence), and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14-amino acid forms, with the minimum active sequence being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH2, which is the common structural element shared by both CCK and gastrin. ~-CCKs are believed to be physiological satiety ~;
, hormones, thereby possibly playing an important role in appetite regulation (G. P. Smith, Eatina and Its Disorders, A. J~ Stunkard and E. Stellar, Eds, Raven Press, New York, 1984, p. 67), as well as stimulating -coIonic motility, gall bladder contraction, pancreatic enzyme secretion and inhibiting gastric emptying. They reportedly co-exist with dopamine in certain mid-brain neurons and thus may also play a role in the functioning of dopaminergic systems in the brain, in addition to serving as neurotransmitters in their own right (see A.
J. Prange çt al., "Peptides in the Central Nervous ,. '~
WO 93/02078 PCr/GB92/01366 System", Ann. Repts. ~ed. Chem 17, 31, 33 tl982] and references cited therein; J. A. Williams, Biomed Res. 3 107 ~1982~: and J.E. Morley, Life sci. 30, 479 tl982]).
The primary role of gastrin, on the other hand, ~
appears to be stimulation of the secretion of water and ~-electrolytes from the stomach and, as such, is involved ~;
in control of gastric acid and pepsin secretion. Other --~
physiological effects of gastrin then include increased ~-~
mucosal blood flow and increased antral motility. Rat studies have shown that gastrin has a positive trophic -effect on the gastric mucosa, as evidenced by increased -;--~
DNA, RNA and protein synthesis.
There are at least two subtypes of choiecystokinin receptors termed CCK-A and CCK-B (T.H. Moran et al., "Two - ~-brain cholecystokinin receptors: implications for - -behavioural actions", Brain Res., 362, 175-79 ~1986]).
Both subtypes are found both in the periphery and in the central nervous system.
CCK and gastrin receptor antagonists have been disclosed for preventing and treating CCK-related and/or gastrin related disorders of the gastrointestinal (GI) and central nervous (CNS) systems of animals, especially mammals, and more especially those of humans. Just as , there is some overlap in the biological activities of CCK
and gastrin, antagonists also tend to have affinity for both CCK-B receptors and gastrin receptors. Other antagonists have activity at the CCK-A subtype.
8elective CCK antagonists are themselves useful in treating CCK-related disorders of appetite regulatory systems of animals as well as in potentiating and prolonging opiate-mediated analgesia [see P. L. Faris et al., Science 226, 1215 (1984)], thus having utility in the treatment of pain. CCK-B and CCK-A antagonists have also been shown to have a direct analgesic effect [M.F.
..
W093/0207~ PCT/GB92/01366 '2~t2-.~61 :~
O'Neill et al., Brain Re$earch, 534 2B7 (lsso)].
Selective CCK and gastrin antagonists are useful in the ~-~
modulation of behaviour mediated by dopaminergic and e serotonergic neuronal systems and thus have utility in -~
the treatment of schizophrenia and depression (Rasmussen -et. al., 1991, Eur. J. Pharmacol., 209, 135-138; Woodruff et. al., 1991, Neuro~e~tides, 19, 45-46; Cervo et. al., 1988, Eur. J. Pharmacol., 158, 53-59), as a palliative for gastrointestinal neoplasms, and in the treatment and prevention of gastrin-related disorders of the gastrointestinal system in humans and animals, such as peptic ulcers, Zollinger-Ellison syndrome, antral G cell hyperplasia and other conditions in which reduced gastrin - -activity is of therapeutic value, see e.g. U.S. Patent 4,820,834. Certain CCK antagonists are useful anxiolytic agents and can be used in the treatment of panic and anxiety disorders. -CCK has been reported to evoke the release of stress hormones such as adrenocorticotrophic hormone, ~-endorphin, vasopressin and oxytocin, CCX may function as a mediator of responses to stress and as part of the arousal system. CCK-A receptors are now known to be present in a number of areas of the CNS and may be , involved in modulating all of the above.
CCK may be involved in the regulation of stress and its relationship with drug abuse e.g. alleviation of the ~`
benzodiazepine withdrawal syndrome (Singh et. al., 1992, Br. J. Pharmacol., 105, 8-10) and neuroadaptive processes.
Since CCK and gastrin also have trophic effects on `
certain tumours [K. Okyama, Hokkaido J. Med. Sci., 206-216 (1985)], antagonists of CCK and gastrin are useful in treating these tumours [see, R.D. Beauchamp et al., Ann.
~E~-, 202, 203 (1985)].
W093/02078 PCT/GB92/01366 ~
~.: ' . -iiis6~ ' In the light of discussion in c. Xu et al., Peptides, ~, 1987, 769-772, CCK antagonists may also be `
effective in neuroprotection.
CCK receptor antagonists have been found to inhibit the contractile effects of CCK on iris sphincter and ciliary muscles of monkey and human eyes (Eur. J. -Pharmacol., 211(2), 183-187; A. Bill et al., Acta - -Physiol. Scand., 138, 479-485 tlg9o])~ thus having utility in inducing miosis for therapeutic purposes.
A class of benzodiazepine antagonist compounds has been reported which binds selectively to brain CCK (CCK-B
and CCK-A) and gastrin receptors tsee M. Bock et al.,J.
Med Chem., 32, 13-16 (1989)].
European patent application no. 0 167 919 discloses benzodiazepine CCX and gastrin antagonists substituted in ~
the 3-position by, inter alia, a phenyl urea and at the -5-position by an optionally substituted phenyl or pyridyl group.
British patent application no. 1,034,872 discloses -~
benzodiazepines substituted at the 3-position by an unsubstituted amino group or a substituted amino group containing up to eight carbon atoms, and at the 5- -~
position by a monocyclic aryl moiety. The only 5- -- -, substituents specifically disclosed are phenyl --(substituted or unsubstituted) and thienyl. There is no -~
disclosure of a phenyl urea substituent at C-3.
British patent no. 1,309,947 discloses benzodiazepines substituted at the 5-position by, inter alia, a heterocyclic group, and at the 3-position by H, alkyl, alkoxy, alkylthioalkyl, phenyl, benzyl or -~
hydroxybenzyl. The compounds are said to have - -tranquilizer, muscle relaxant, antispasmodic, anticonvulsant and hypnotic effects. There is no suggestion of the phenyl urea substituent of--the -~1125~1 ~
.. .: .:
- 5 - - ~:
compounds of t~e present invention. Nor is there any suggestion that the compounds are CCK or gastrin antagonists.
The present invention provides benzodiazepine compounds of formula (I):
~ ~ N
Z
',~ ' wherein: ~:
one of W, X, Y or Z represents a nitrogen atom, another of W, X, Y or Z is a nitrogen, oxygen or sulphur : -atom or a group NR8 where R8 is H or Cl_6alkyl, and the other two of W, X, Y and Z each independently represent ~-nitrogen atoms or groups CR8, and the dotted circle ' represents two double bonds;
Rl represents Cl_6 alkyl, C3_7 cycloalkyl, cyclopropylmethyl, (CH2)qimidazolyl, (CH2)qtetrazolyl, (CH2)qtriazolyl, (where q is l, 2 or 3), CH2Co2R5 (where R5 is Cl_4 alkyl) or a group CH2CoNR6R7 (where R6 ahd R7 each independently represents H or Cl_4alkyl, or R6 and R7 together form a chain (CH2)p where p is 4 or 5);
R2 represents Cl_6 alkyl, halo, (CH2)rtetrazolyl, optionally substituted in the tetrazole ring by Cl_4alkyl, (CH2)rimidazolyl, CoNR6R7, SO(Cl_6alkyl), SO2(Cl_6alkyl), CONHSO2R9, SO2NHCOR9, SONHRl0, cyano, -~?,ll2~1 B(H)2 or (CH2)rcO2H~ where r is zero, 1 or 2, R9 is C1_6alkyl, optionally substituted aryl, 2,2-difluorocyclopropane or trifluoromethyl, and R10 is a nitrogen containing heterocycle; ;~
R3 represents H, Cl_6 alkyl or halo;
m is 0, 1 or 2;
n is 0, 1, 2 or 3;
and salts or prodrugs thereof.
It will be appreciated that formul~ (I) is intended to embrace all possible isomers, including optical isomers, and mixtures thereof, including racemates.
The present invention includes within its scope -prodrugs of the compounds of formula ~ above. In general, such prodrugs will be functional deri~atives of -the compounds of formula I which are readily convertible -~
in vivo into the required compound of formula I.
Conventional procedures for the selection and preparation -~
of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bungaard, -Elsevier, 1985. -- -When Rl represents Cl_6alkyl, alkyl means --linear or branched chain alkyl. Examples of suitable -alkyl groups include methyl, ethyl, isopropyl and , isobutyl groups. -~-When Rl represents cycloalkyl, examples of ~-suitable cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl groups, preferably cyclopropyl.
Halo includes fluoro, chloro and bromo. -~
Preferably halo will be fluoro or chloro. ~;
Suitable examples of the substituent ~3~ J ~ J.~ t 9 1~
~112S61 ~, Z ' ';:.. -' X~Y
include imidazolyl, N-me~hylimidazolyl and thiaz~lyl, preferably thiazolyl.
In one subgroup of co~pounds of formula (I) represents Cl_6 alkyl, C3_7 cycloalkyl, cyclopropylmethyl, (CH2)qimidazolyl ~where q is 1, 2 or i -~
3), CH2Co2R5 (where R5 is cl_4 alkyl) or a group CH2CoNR6R7 ~where R6 and R7 eac~ indepen~n~ly represent~
a hyd~ogen atom or a Cl_4 alkyl group, or R6 and R7 ~ -together form a chain (CH2)p where p i~ 4 or 5~; R2 represents Cl_~ alkyl, halo, (CH2)stetrazolyl, (CH2)simidazolyl or ~ group (CR2)s~02H, where s is zero, 1 or 2; and m and n each represent 1.
Preferably Rl is C1_6alkyl, more p~e~erably methyl or iso-butyl~
When one substituent R2 is presen~, it will preferably be located at the 3- or 4-position of the phenyl ring, more preferably the 3-position. When ~wo substituents R2 are present, they will p~eferably he located at the 3- anq 4-positions.
5uitable values for R9 in~lude methyl, ethyl, i-p~opyl, t-butyl, phenyl and trifluoromethyl.
When R9 is optionally substituted a~yl, this will ..
preferably be optionally su~stituted phenyl. Suitable substituents include Cl_4alkyl, Cl_qalkoxy, ~alo an~ -trifluoromethyl. Pre~erre~ ~re ~ompounds wherein R9 ie unsubsti~uted aryl or aryl substituted by Cl_6alkyl, for ..... _ .. , ~ _ . .. ...
5 1;~, .; . ~
. ... ... . .
'~ 11 2 ~ 61 ~
- 8 - -~
example phenyl substituted by Cl_6alkyl in the ortho position.
When R9 is Cl_6alkyl, it will preferably represent -C1_4alkyl. Particularly preferred are methyl and iso- ;-propyl. -When R2 is SO2NHR10, suitable values of R10 include, for example, thiazole, thiadiazole and pyrazine. -~
Preferably R2 is tetrazolyl, methyl or COOH, more -~
preferably 5-tetrazolyl. ~ -Preferably m is 1.
Preferably n is zero.
Preferably q is 1.
Preferably r is zero.
One subgroup of compounds according to the invention - ~-~
is represented by formula (II)~
~ H H
Z '~
( I l ) ,: .. ;
wherein ~- -Z is a sulphur atom or a group NR18, where R18 is H
or methyl;
R20 is Cl_6alkyl; and -~
R21 is Cl_6alkyl, tetrazolyl or CO2H, preferably tetrazolyl.
Preferably the salts of the compounds of formula (I) are pharmaceutically acceptable, but non-pharmaceutically acceptable salts may be used for the preparation of pharmaceutically acceptable salts. The pharmaceutically 2112~61 ~:
acceptable salts of the compounds of formula (I) include the conventional non-toxic salts or the quaternary ammonium salts of the compounds from formula (I) formed, e.g., from inorganic or organic acids or bases. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulphuric, sulphamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, steric, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulphanilic, 2-acetoxy benzoic, fumaric, toluenesulphonic, methanesulphonic, ethane disulphonic, oxalic and isothionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compound of formula (I) which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with ~-stoichiometric amounts or with an excess of the desired ~;
salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
For example, an acid of formula (I) may be reacted , with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g. dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide.
The present invention also encompasses a ~~-pharmaceutical composition comprising a compound of formula (1), or a salt or prodrug thereof and a pharmaceutically acceptable carrier or diluent. ~ -w093/0207X pcT/GBs2/ol~6 2~
-- 1 0 ~
.... `.
The compounds of formula (I~ and their salts ;
and prodrugs, may be administered to animals, preferably -~
to mammalsr and most especially to a human subject either -~
alone or, preferably, in combination with ~- -S pharmaceutically acceptable carriers or diluents, - --optionally with known adjuvants, such as alum, in a pharmaceutical compostion, according to standard -pharmaceutical practice. The compounds can be administered orally, parenterally, including by ~
intravenous, intramuscular, intraperitoneal or - ~-subcutaneous administration, or topically.
For oral use of an antagonist of CCK, according to this in~ention, the selected compounds may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In . :
the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly addsd. For oral administration in capsule form, `;~
useful diluents include lactose and dried corn starch.
When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or , flavouring agents may be added.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic. ~,~
For topical administration, a compound of formula (I) may be formulated as, for example, a suspension, lotion, cream or ointment.
W093/02078 PCT/GB92/0l366 .
~112~61 For topical administration, pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or arylalkanols, vegetable oils, polyalkylene glycols, S petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic, pharmaceutically acceptable organic and inorganic carriers. The pharmaceutical prepara~ion may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents --and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium ~ ~-sulfosuccinate, monothioglycerol, thiosorbitol, , ethylenediamine tetraacetic acid, and the like.
The compounds of formula (I) antagonise CCK and/or gastrin and are useful for the treatment and prevention of disorders including central nervous system disorders wherein CCK and/or gastrin may be involved. Examples of such disease states include gastrointestinal diseases, including gastrointestinal ulcers, such as peptic and duodenal ulcers, irritable bowel syndrome, gastroesophagenal reflux disease or excess pancreatic or gastrin secretion, acute pancreatitis, or motility disorders; central nervous system disorders, including W093/02078 PCT/GB92/01366 -~
`, ,, . - , central nervous system disorders caused by CCK
interaction with dopamine, serotonin and other monoamine neurotransmitters, such as neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis or ~illes de la Tourette syndrome; depression; schizophrenia;
disorders of appetite regulatory systems; Zollinger- ~
Ellison syndrome, antral and cell hyperplasia, or pain. ~ -The compounds of formula (I) are particularly useful -in the treatment or prevention of neurological disorders involving anxiety disorders and panic disorders, wherein ;~
CCK and/or gastrin is involved. Examples of such disorders include panic disorders, anxiety disorders, panic syndrome, anticipatory anxiety, phobic anxiety, panic anxiety, chronic anxiety and endogenous anxiety.
The compounds of formula (I) are also useful for directly inducing analgesia, opiate or non-opiate mediated, as well as anesthesia or loss of the sensation of pain.
The compounds of formula (I) may further be useful for preventing or treating the withdrawal response produced by chronic treatment or abuse of drugs or alcohol. Such drugs include, but are not limited to benzodiazepines, cocaine, alcohol and nicotine.
, The compounds of formula (I) may further by useful ~ ~
in the treatment of stress and its relationship with drug - -abuse.
The compounds of formula (I) may further be useful in the treatment of oncologic disorders wherein CCK may -be involved. Examples of such oncologic disorders - ~-include small cell adenocarcinomas and primary tumours of the central nervous system glial and neuronal cells. - -Examples of such adenocarcinomas and tumours include, but are not limited to, tumours of the lower oesophagus, , ~ .
' ~.", W093/02078 PCT/~B92/01366 stomach, intestine, colon and lung, including small cell lung carcinoma.
The compounds of formula (I) may also be useful as neuroprotective agents, for example, in the treatment and/or prevention of neurodegenerative disorders arising as a consequence of such pathological conditions as stroke, hypoglycaemia, cerebral palsy, transient cerebral ischaemic attack, cerebral ischaemia during cardiac pulmonary surgery or cardiac arrest, perinatal asphyxia, epilepsy, ~untington's chorea, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, Olivo-ponto-cerebellar atrophy, anoxia such as from drowning, spinal cord and head injury, and poisoning by neurotoxins, including environmental neurotoxins.
T~e compounds of formula (I) may further be used to induce miosis for therapeutic purposes after certain types of examination and intraocular surgery. An example ~-of intraocular surgery would include cateract surgery ;~
with implantation of an artificial lens. The CCK ~ `
antagonist compounds of this invention can be used to prevent miosis occuring in association with iritis, ureitis and trauma.
The present invention therefore provides a compound -~
, of formula (I) or a salt or prodrug thereof for use in the preparation of a medicament. `-The present invention also provides a compound of formula (I) for use in therapy. `~
In a further or alternative embodiment the present invention provides a method for the treatment or prevention of a physiological disorder involvinq CCK
and/or gastrin which method comprises administration to a patient in need thereof of a CCK and/or gastrin antagonising amount of a compound of formula (I).
W093/02078 PCT/GB92/01366 ~
2 1 1 ~ ~ 6 1 - 14 - ~-~
When a compound according to formula (I) is used as an antagonist of CCK or gastrin in a human subject, the ~ -daily dosage will normally be determined by the prescibing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms. However, in most instances, an effective daily dosage wll be in the range from about 0.005mg/kg to about lOOmg/kg of body weight, and preferably, of from 0.05mg/kg to about 50mq/kg, such as from about 0.5mg/kg to about 2Omg/kg of body weight, administered in single or divided doses. In so~e cases, however, it may be necessary to use dosages outside these limits. For example, animal experiments have indicated that doses as low as lng may be effective.
In effective treatment of panic syndrome, panic disorder, anxiety disorder and the like, preferably about 0.05 mg/kg to about 0.5 mg/kg of CCK antagonist m~y be -administered orally (p.o.), administered in single or -divided doses per day (b.i.d.). Other routes of --~
administration are also suitable. ~-For directly inducing analgesia, anaesthesia or loss of pain sensation, the effective dosage preferably ranges , from about 100 ng/kg to about lmg/kg by intravenous administration. Oral administration is an alternative route, as well as others. ---In the treatment or irritable bowel syndrome, ~ -preferably about O.l to 1~ mg/kg of CCK antagonist is administered orally (p.o.), administered in single or divided doses per day (b.i.d.). Other routes of administration are also suitable.
The use of a gastrin antagonist as a tumour palliative for gastrointestinal neoplasma with gastrin receptors, as a modulator of central nervous activity, W093/0207~ PCT/GB92/01366 .~112561 treatment of Zollinger-Ellison syndro~e, or in the treatment of peptic ulcer disease, an effective dosage of preferably about O.l to about lO mg/kg administered one-to-four times daily is indicated.
For use as neuroprotective agents the effective dosage preferably ranges from about 0.5mg/kg to about 2Omg/kg.
Because these compounds antagonise the function of -CCK in animals, they may also be used as feed additives to increase the food intake of animals in daily dosage of preferably about 0.05mg/kg to about 50mg/kg of body weight.
The compounds of formula ~I) may be prepared by processes analogous to those described in European Patent :~
Specification No. 0167919. For example, a compound of ::
formula (I) may be prepared from an intermediate of :~
formula ~TII) R l ` ~ `
~ R~ NH2 W~z X`~~-'r ' wherein W, X, Y, Z, Rl, R3 and n are as defined for formula (I); by reaction with an isocyanate of formula (IV) W093/02078 PCT/~B92/01366 21t2561 .
~ N C O -( R2 )m~
( I V ) wherein R2 and m are as defined for formula (I). -~
The reaction is preferably conducted in a suitable organic solvent, such as an ether, for example, tetrahydrofuran, at room temperature.
The isocyanate of formula (IV) may be generated in - ~
situ from the corresponding amine by treatment with -triphosgene. ~ `
Intermediates of formula (III) may be prepared from ~ `
compounds of formula ~V) -- -(R~)~ ~ NHC
Z
( V ) wherein W, X, Y, Z, R3 and n are as defined for for~ula (I) and G is a protecting group; by reactio~ with a reagent suitable to introduce the group Rl, for example a halide of formula RlHal where Hal represents halo such as bromo or iodo, followed by deprotection.
The reaction is carried out in the presence of a base, such as an alkali metal hydride or an alkaline ~? I 1~
- 17 - :~
earth metal carbonate, for example sodium hydride or - .:
caesium carbonate. -; -Compounds of formula (v) may be prepared from ~ .
compounds of formula (VI) `~
H
( R ) n~
W~z '';'''-.''"'' X~ r ( V l ) ,~
wherein W, X, Y, Z, R3 and n are as defined for formula - -;
(I), by a reaction sequence comprising:
(i) reaction with a compound of formula (VII) s ~ ~oo~
NHC
(Vll) :~
wherein G is as defined above, in the presence of a base, such as a tertiary amine, for example triethylamine or N- :
methyl morpholine, and a coupling reagent. Any of the : coupling reagents commonly used in peptide synthesis are ~;
suitable, for example, 1,3-dicyclohexylcarbodiimide (DCC) -or isobutyl chloroformate.
(ii) Treatment with gaseous ammonia, preferably in the presence of a mercury containing catalyst, such as mercury(II) chloride. The reaction is conveniently effected in a suitable organic solvent, such as an ether, for example, tetrahydrofuran.
: ' W093~02078 PCT/GB92/01366 21~'~S61 (iii) Treatment with an organic acid, for example acetic or propionic acid, optionally in the presence of an ammonium salt, for example ammonium acetate.
Compounds of formula (VI) may be prepared aecording S to the procedures described in Journal of Heterocyclic Chemistry, 1975, 12, 49-57 and Journal of the Chemistry societY, Perkin Transactions I, 1989, 1139-1145.
Where the above-described process for the preparation of the compounds according to the invention lo gives rise to mixtures of stereoisomers these isomers may, if desired, be separated, suitably by conventional techniques such as preparative chromatography. ~ -~
The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-L-tartaric acid and/or (+)-di-p-toluoyl-D-tartaric acid followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, enantiomers of the novel compounds may be separated by HPLC using a chiral column.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Qraanic ChemistrY, ed. J.F.W. McOmie, Plenum Press, 1973;
and T.W. Greene and P.G.M. Wutts, Protective Groups in - 19 't1~.~61 organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a co~venient : : -subsequent stage using methods known from the art. :
The following examples are provided to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative of the scope thereof.
' '' ,',~ ~"
'' . '"' wo 93/02078 PCr/GB92/0l366 ~ ~ -h)J I 1 2 5 6120 -EXAMPLE 1: N-[3(R.S)-2.3-Dih~vdro-l-methYl-5-(1-methylimidazol-2-~vl)-2-oxo-1H-1,4-benzodiazepin-3-vll-N/-[3-, methylphenyl]urea Step 1: 1.3-Dihydro-3(R.S)-lbenzYlo~carbonylamino~5-(1- `
methvlimidazol-2-yl~2H-l,~benzodiazePin-2-one '' .- ':
To a stilTed, cooled (< 10C) solution of a-(isopropylthio)-Na-(benzyloxycarbonyl)glycine ( 1 .4g) in anhydrous dichloromethane (40ml), under a nitrogen atmosphere, was o added dropwise N-methylmorpholine (O.~g) followed by isobutylchloroformate (0.68g). The solution was stirred at 5C ~ -for 10 minutes then heated to reflu~. 2-Aminophenyl~
methylimidazol-2-yl)methanone (1.Og, J. Het. Chem. 1975, 12, 49-57) in anhydrous dichloromethane (lOml) waæ added dropwise and the resulting yellow solution heated at reflux for 1 hour then stirred at ambient temperature for 16 hours. The reaction mixture was washed ~vith lN citric acid, brine then dried (sodium sulphate) and evaporated to afford a yellow oil (2.1g). Rf= 0.1 in ethyl acetate/n-hexane (1:3) on silica (trace of . ~, .
20 amine, Rf- 0.2).
The crude (isopropylthio)glycinamide was dissolved in anhydrous tetrahydrofuran (lOOml) and the ice cooled solution was saturated with ammonia gas. Mercuric chloride (1.35g) .was added and the passage of ammonia continued for 3 hours. The 25 mixture was filtered and the filtrate concentrated. The residue was dissolved in glacial acetic acid (30ml), treated with ammonium acetate (1.4g) and the resulting mixture stirred at ..
W O 93/02078 P ~ /GB92/01366 `:-.
2S61 -~ ~
ambient temperature for 18 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (20ml) and lN
sodium hydroxide ~olution (25ml). The organic layer wa~
separated, dried (magnesium sulphate) then evaporated to give 5 a gummy solid (lg) which was purified by column chromatography on silica using ethyl acetate/petroleum ether (60-80) (1:1) to ethyl acetaWmethanol (9:1) as eluant. The title compound was obtained as a colourless solid (0.38g). lH NMR ~ ~
(250MHz, CDC13) ~ 3.95 (3H, s); 5.12 (2H, m); 5.18 (lH, d, J = ` -lo 8Hz); 6.65 (lH, d, J = 8Hz); 6.9 (lH, d, J = 8Hz); 7.0 (lH, s); 7.1-7.5 (8H, m); 7.55 (lH, d, J = 8Hz).
Step 2- 1.3-Dihydro-3(R.S~-(benzvloxvcarbonYlamino3-1-methyl-5-(1-methylimidazol-2-Y1~2H-1,4-benzodiazePin-2-one To a stirred solution of 1,3-dihydro-3(R,S)- ~-(benzylo~cycarbonylamino)-5-(1-methylimidazol-2-yl)-2H-1,4- -benzodiazepin-2-one (348mg) in anhydrous dimethylfonnamide (5ml), at ambient temperature, was added sodium hydride (40mg of a 5~;% oil dispersion). After 30 minutes iodomethane (142mg) was added and the mi~ture was stirred for 18 hours.
The solvent was evaporated then the residue was partitioned ; ~-between ethyl acetate and water. The organic layer was ~-separated and evaporated to give a gummy residue which was ~
purified by column chromatography o~ silica using ethyl ~ -acetate/petroleum ether (60-80) (2:1) to ethyl acetate/methanol ~ :
(95:5j to afford the title compound as a yellow powder (140mg).
Rf = 0.2 in ethyl acetate on silica plates. lH NMR (250MHz, - `
CDC13) ~ 3.43 (3H, s); 3.94 (3H, s); 5.05-5.20 (2H, m); 5.29 (lH, - -;
.
Selective CCK and gastrin antagonists are useful in the ~-~
modulation of behaviour mediated by dopaminergic and e serotonergic neuronal systems and thus have utility in -~
the treatment of schizophrenia and depression (Rasmussen -et. al., 1991, Eur. J. Pharmacol., 209, 135-138; Woodruff et. al., 1991, Neuro~e~tides, 19, 45-46; Cervo et. al., 1988, Eur. J. Pharmacol., 158, 53-59), as a palliative for gastrointestinal neoplasms, and in the treatment and prevention of gastrin-related disorders of the gastrointestinal system in humans and animals, such as peptic ulcers, Zollinger-Ellison syndrome, antral G cell hyperplasia and other conditions in which reduced gastrin - -activity is of therapeutic value, see e.g. U.S. Patent 4,820,834. Certain CCK antagonists are useful anxiolytic agents and can be used in the treatment of panic and anxiety disorders. -CCK has been reported to evoke the release of stress hormones such as adrenocorticotrophic hormone, ~-endorphin, vasopressin and oxytocin, CCX may function as a mediator of responses to stress and as part of the arousal system. CCK-A receptors are now known to be present in a number of areas of the CNS and may be , involved in modulating all of the above.
CCK may be involved in the regulation of stress and its relationship with drug abuse e.g. alleviation of the ~`
benzodiazepine withdrawal syndrome (Singh et. al., 1992, Br. J. Pharmacol., 105, 8-10) and neuroadaptive processes.
Since CCK and gastrin also have trophic effects on `
certain tumours [K. Okyama, Hokkaido J. Med. Sci., 206-216 (1985)], antagonists of CCK and gastrin are useful in treating these tumours [see, R.D. Beauchamp et al., Ann.
~E~-, 202, 203 (1985)].
W093/02078 PCT/GB92/01366 ~
~.: ' . -iiis6~ ' In the light of discussion in c. Xu et al., Peptides, ~, 1987, 769-772, CCK antagonists may also be `
effective in neuroprotection.
CCK receptor antagonists have been found to inhibit the contractile effects of CCK on iris sphincter and ciliary muscles of monkey and human eyes (Eur. J. -Pharmacol., 211(2), 183-187; A. Bill et al., Acta - -Physiol. Scand., 138, 479-485 tlg9o])~ thus having utility in inducing miosis for therapeutic purposes.
A class of benzodiazepine antagonist compounds has been reported which binds selectively to brain CCK (CCK-B
and CCK-A) and gastrin receptors tsee M. Bock et al.,J.
Med Chem., 32, 13-16 (1989)].
European patent application no. 0 167 919 discloses benzodiazepine CCX and gastrin antagonists substituted in ~
the 3-position by, inter alia, a phenyl urea and at the -5-position by an optionally substituted phenyl or pyridyl group.
British patent application no. 1,034,872 discloses -~
benzodiazepines substituted at the 3-position by an unsubstituted amino group or a substituted amino group containing up to eight carbon atoms, and at the 5- -~
position by a monocyclic aryl moiety. The only 5- -- -, substituents specifically disclosed are phenyl --(substituted or unsubstituted) and thienyl. There is no -~
disclosure of a phenyl urea substituent at C-3.
British patent no. 1,309,947 discloses benzodiazepines substituted at the 5-position by, inter alia, a heterocyclic group, and at the 3-position by H, alkyl, alkoxy, alkylthioalkyl, phenyl, benzyl or -~
hydroxybenzyl. The compounds are said to have - -tranquilizer, muscle relaxant, antispasmodic, anticonvulsant and hypnotic effects. There is no suggestion of the phenyl urea substituent of--the -~1125~1 ~
.. .: .:
- 5 - - ~:
compounds of t~e present invention. Nor is there any suggestion that the compounds are CCK or gastrin antagonists.
The present invention provides benzodiazepine compounds of formula (I):
~ ~ N
Z
',~ ' wherein: ~:
one of W, X, Y or Z represents a nitrogen atom, another of W, X, Y or Z is a nitrogen, oxygen or sulphur : -atom or a group NR8 where R8 is H or Cl_6alkyl, and the other two of W, X, Y and Z each independently represent ~-nitrogen atoms or groups CR8, and the dotted circle ' represents two double bonds;
Rl represents Cl_6 alkyl, C3_7 cycloalkyl, cyclopropylmethyl, (CH2)qimidazolyl, (CH2)qtetrazolyl, (CH2)qtriazolyl, (where q is l, 2 or 3), CH2Co2R5 (where R5 is Cl_4 alkyl) or a group CH2CoNR6R7 (where R6 ahd R7 each independently represents H or Cl_4alkyl, or R6 and R7 together form a chain (CH2)p where p is 4 or 5);
R2 represents Cl_6 alkyl, halo, (CH2)rtetrazolyl, optionally substituted in the tetrazole ring by Cl_4alkyl, (CH2)rimidazolyl, CoNR6R7, SO(Cl_6alkyl), SO2(Cl_6alkyl), CONHSO2R9, SO2NHCOR9, SONHRl0, cyano, -~?,ll2~1 B(H)2 or (CH2)rcO2H~ where r is zero, 1 or 2, R9 is C1_6alkyl, optionally substituted aryl, 2,2-difluorocyclopropane or trifluoromethyl, and R10 is a nitrogen containing heterocycle; ;~
R3 represents H, Cl_6 alkyl or halo;
m is 0, 1 or 2;
n is 0, 1, 2 or 3;
and salts or prodrugs thereof.
It will be appreciated that formul~ (I) is intended to embrace all possible isomers, including optical isomers, and mixtures thereof, including racemates.
The present invention includes within its scope -prodrugs of the compounds of formula ~ above. In general, such prodrugs will be functional deri~atives of -the compounds of formula I which are readily convertible -~
in vivo into the required compound of formula I.
Conventional procedures for the selection and preparation -~
of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bungaard, -Elsevier, 1985. -- -When Rl represents Cl_6alkyl, alkyl means --linear or branched chain alkyl. Examples of suitable -alkyl groups include methyl, ethyl, isopropyl and , isobutyl groups. -~-When Rl represents cycloalkyl, examples of ~-suitable cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl groups, preferably cyclopropyl.
Halo includes fluoro, chloro and bromo. -~
Preferably halo will be fluoro or chloro. ~;
Suitable examples of the substituent ~3~ J ~ J.~ t 9 1~
~112S61 ~, Z ' ';:.. -' X~Y
include imidazolyl, N-me~hylimidazolyl and thiaz~lyl, preferably thiazolyl.
In one subgroup of co~pounds of formula (I) represents Cl_6 alkyl, C3_7 cycloalkyl, cyclopropylmethyl, (CH2)qimidazolyl ~where q is 1, 2 or i -~
3), CH2Co2R5 (where R5 is cl_4 alkyl) or a group CH2CoNR6R7 ~where R6 and R7 eac~ indepen~n~ly represent~
a hyd~ogen atom or a Cl_4 alkyl group, or R6 and R7 ~ -together form a chain (CH2)p where p i~ 4 or 5~; R2 represents Cl_~ alkyl, halo, (CH2)stetrazolyl, (CH2)simidazolyl or ~ group (CR2)s~02H, where s is zero, 1 or 2; and m and n each represent 1.
Preferably Rl is C1_6alkyl, more p~e~erably methyl or iso-butyl~
When one substituent R2 is presen~, it will preferably be located at the 3- or 4-position of the phenyl ring, more preferably the 3-position. When ~wo substituents R2 are present, they will p~eferably he located at the 3- anq 4-positions.
5uitable values for R9 in~lude methyl, ethyl, i-p~opyl, t-butyl, phenyl and trifluoromethyl.
When R9 is optionally substituted a~yl, this will ..
preferably be optionally su~stituted phenyl. Suitable substituents include Cl_4alkyl, Cl_qalkoxy, ~alo an~ -trifluoromethyl. Pre~erre~ ~re ~ompounds wherein R9 ie unsubsti~uted aryl or aryl substituted by Cl_6alkyl, for ..... _ .. , ~ _ . .. ...
5 1;~, .; . ~
. ... ... . .
'~ 11 2 ~ 61 ~
- 8 - -~
example phenyl substituted by Cl_6alkyl in the ortho position.
When R9 is Cl_6alkyl, it will preferably represent -C1_4alkyl. Particularly preferred are methyl and iso- ;-propyl. -When R2 is SO2NHR10, suitable values of R10 include, for example, thiazole, thiadiazole and pyrazine. -~
Preferably R2 is tetrazolyl, methyl or COOH, more -~
preferably 5-tetrazolyl. ~ -Preferably m is 1.
Preferably n is zero.
Preferably q is 1.
Preferably r is zero.
One subgroup of compounds according to the invention - ~-~
is represented by formula (II)~
~ H H
Z '~
( I l ) ,: .. ;
wherein ~- -Z is a sulphur atom or a group NR18, where R18 is H
or methyl;
R20 is Cl_6alkyl; and -~
R21 is Cl_6alkyl, tetrazolyl or CO2H, preferably tetrazolyl.
Preferably the salts of the compounds of formula (I) are pharmaceutically acceptable, but non-pharmaceutically acceptable salts may be used for the preparation of pharmaceutically acceptable salts. The pharmaceutically 2112~61 ~:
acceptable salts of the compounds of formula (I) include the conventional non-toxic salts or the quaternary ammonium salts of the compounds from formula (I) formed, e.g., from inorganic or organic acids or bases. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulphuric, sulphamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, steric, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulphanilic, 2-acetoxy benzoic, fumaric, toluenesulphonic, methanesulphonic, ethane disulphonic, oxalic and isothionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compound of formula (I) which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with ~-stoichiometric amounts or with an excess of the desired ~;
salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
For example, an acid of formula (I) may be reacted , with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g. dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine, and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide.
The present invention also encompasses a ~~-pharmaceutical composition comprising a compound of formula (1), or a salt or prodrug thereof and a pharmaceutically acceptable carrier or diluent. ~ -w093/0207X pcT/GBs2/ol~6 2~
-- 1 0 ~
.... `.
The compounds of formula (I~ and their salts ;
and prodrugs, may be administered to animals, preferably -~
to mammalsr and most especially to a human subject either -~
alone or, preferably, in combination with ~- -S pharmaceutically acceptable carriers or diluents, - --optionally with known adjuvants, such as alum, in a pharmaceutical compostion, according to standard -pharmaceutical practice. The compounds can be administered orally, parenterally, including by ~
intravenous, intramuscular, intraperitoneal or - ~-subcutaneous administration, or topically.
For oral use of an antagonist of CCK, according to this in~ention, the selected compounds may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In . :
the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly addsd. For oral administration in capsule form, `;~
useful diluents include lactose and dried corn starch.
When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or , flavouring agents may be added.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic. ~,~
For topical administration, a compound of formula (I) may be formulated as, for example, a suspension, lotion, cream or ointment.
W093/02078 PCT/GB92/0l366 .
~112~61 For topical administration, pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or arylalkanols, vegetable oils, polyalkylene glycols, S petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic, pharmaceutically acceptable organic and inorganic carriers. The pharmaceutical prepara~ion may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents --and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium ~ ~-sulfosuccinate, monothioglycerol, thiosorbitol, , ethylenediamine tetraacetic acid, and the like.
The compounds of formula (I) antagonise CCK and/or gastrin and are useful for the treatment and prevention of disorders including central nervous system disorders wherein CCK and/or gastrin may be involved. Examples of such disease states include gastrointestinal diseases, including gastrointestinal ulcers, such as peptic and duodenal ulcers, irritable bowel syndrome, gastroesophagenal reflux disease or excess pancreatic or gastrin secretion, acute pancreatitis, or motility disorders; central nervous system disorders, including W093/02078 PCT/GB92/01366 -~
`, ,, . - , central nervous system disorders caused by CCK
interaction with dopamine, serotonin and other monoamine neurotransmitters, such as neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis or ~illes de la Tourette syndrome; depression; schizophrenia;
disorders of appetite regulatory systems; Zollinger- ~
Ellison syndrome, antral and cell hyperplasia, or pain. ~ -The compounds of formula (I) are particularly useful -in the treatment or prevention of neurological disorders involving anxiety disorders and panic disorders, wherein ;~
CCK and/or gastrin is involved. Examples of such disorders include panic disorders, anxiety disorders, panic syndrome, anticipatory anxiety, phobic anxiety, panic anxiety, chronic anxiety and endogenous anxiety.
The compounds of formula (I) are also useful for directly inducing analgesia, opiate or non-opiate mediated, as well as anesthesia or loss of the sensation of pain.
The compounds of formula (I) may further be useful for preventing or treating the withdrawal response produced by chronic treatment or abuse of drugs or alcohol. Such drugs include, but are not limited to benzodiazepines, cocaine, alcohol and nicotine.
, The compounds of formula (I) may further by useful ~ ~
in the treatment of stress and its relationship with drug - -abuse.
The compounds of formula (I) may further be useful in the treatment of oncologic disorders wherein CCK may -be involved. Examples of such oncologic disorders - ~-include small cell adenocarcinomas and primary tumours of the central nervous system glial and neuronal cells. - -Examples of such adenocarcinomas and tumours include, but are not limited to, tumours of the lower oesophagus, , ~ .
' ~.", W093/02078 PCT/~B92/01366 stomach, intestine, colon and lung, including small cell lung carcinoma.
The compounds of formula (I) may also be useful as neuroprotective agents, for example, in the treatment and/or prevention of neurodegenerative disorders arising as a consequence of such pathological conditions as stroke, hypoglycaemia, cerebral palsy, transient cerebral ischaemic attack, cerebral ischaemia during cardiac pulmonary surgery or cardiac arrest, perinatal asphyxia, epilepsy, ~untington's chorea, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, Olivo-ponto-cerebellar atrophy, anoxia such as from drowning, spinal cord and head injury, and poisoning by neurotoxins, including environmental neurotoxins.
T~e compounds of formula (I) may further be used to induce miosis for therapeutic purposes after certain types of examination and intraocular surgery. An example ~-of intraocular surgery would include cateract surgery ;~
with implantation of an artificial lens. The CCK ~ `
antagonist compounds of this invention can be used to prevent miosis occuring in association with iritis, ureitis and trauma.
The present invention therefore provides a compound -~
, of formula (I) or a salt or prodrug thereof for use in the preparation of a medicament. `-The present invention also provides a compound of formula (I) for use in therapy. `~
In a further or alternative embodiment the present invention provides a method for the treatment or prevention of a physiological disorder involvinq CCK
and/or gastrin which method comprises administration to a patient in need thereof of a CCK and/or gastrin antagonising amount of a compound of formula (I).
W093/02078 PCT/GB92/01366 ~
2 1 1 ~ ~ 6 1 - 14 - ~-~
When a compound according to formula (I) is used as an antagonist of CCK or gastrin in a human subject, the ~ -daily dosage will normally be determined by the prescibing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms. However, in most instances, an effective daily dosage wll be in the range from about 0.005mg/kg to about lOOmg/kg of body weight, and preferably, of from 0.05mg/kg to about 50mq/kg, such as from about 0.5mg/kg to about 2Omg/kg of body weight, administered in single or divided doses. In so~e cases, however, it may be necessary to use dosages outside these limits. For example, animal experiments have indicated that doses as low as lng may be effective.
In effective treatment of panic syndrome, panic disorder, anxiety disorder and the like, preferably about 0.05 mg/kg to about 0.5 mg/kg of CCK antagonist m~y be -administered orally (p.o.), administered in single or -divided doses per day (b.i.d.). Other routes of --~
administration are also suitable. ~-For directly inducing analgesia, anaesthesia or loss of pain sensation, the effective dosage preferably ranges , from about 100 ng/kg to about lmg/kg by intravenous administration. Oral administration is an alternative route, as well as others. ---In the treatment or irritable bowel syndrome, ~ -preferably about O.l to 1~ mg/kg of CCK antagonist is administered orally (p.o.), administered in single or divided doses per day (b.i.d.). Other routes of administration are also suitable.
The use of a gastrin antagonist as a tumour palliative for gastrointestinal neoplasma with gastrin receptors, as a modulator of central nervous activity, W093/0207~ PCT/GB92/01366 .~112561 treatment of Zollinger-Ellison syndro~e, or in the treatment of peptic ulcer disease, an effective dosage of preferably about O.l to about lO mg/kg administered one-to-four times daily is indicated.
For use as neuroprotective agents the effective dosage preferably ranges from about 0.5mg/kg to about 2Omg/kg.
Because these compounds antagonise the function of -CCK in animals, they may also be used as feed additives to increase the food intake of animals in daily dosage of preferably about 0.05mg/kg to about 50mg/kg of body weight.
The compounds of formula ~I) may be prepared by processes analogous to those described in European Patent :~
Specification No. 0167919. For example, a compound of ::
formula (I) may be prepared from an intermediate of :~
formula ~TII) R l ` ~ `
~ R~ NH2 W~z X`~~-'r ' wherein W, X, Y, Z, Rl, R3 and n are as defined for formula (I); by reaction with an isocyanate of formula (IV) W093/02078 PCT/~B92/01366 21t2561 .
~ N C O -( R2 )m~
( I V ) wherein R2 and m are as defined for formula (I). -~
The reaction is preferably conducted in a suitable organic solvent, such as an ether, for example, tetrahydrofuran, at room temperature.
The isocyanate of formula (IV) may be generated in - ~
situ from the corresponding amine by treatment with -triphosgene. ~ `
Intermediates of formula (III) may be prepared from ~ `
compounds of formula ~V) -- -(R~)~ ~ NHC
Z
( V ) wherein W, X, Y, Z, R3 and n are as defined for for~ula (I) and G is a protecting group; by reactio~ with a reagent suitable to introduce the group Rl, for example a halide of formula RlHal where Hal represents halo such as bromo or iodo, followed by deprotection.
The reaction is carried out in the presence of a base, such as an alkali metal hydride or an alkaline ~? I 1~
- 17 - :~
earth metal carbonate, for example sodium hydride or - .:
caesium carbonate. -; -Compounds of formula (v) may be prepared from ~ .
compounds of formula (VI) `~
H
( R ) n~
W~z '';'''-.''"'' X~ r ( V l ) ,~
wherein W, X, Y, Z, R3 and n are as defined for formula - -;
(I), by a reaction sequence comprising:
(i) reaction with a compound of formula (VII) s ~ ~oo~
NHC
(Vll) :~
wherein G is as defined above, in the presence of a base, such as a tertiary amine, for example triethylamine or N- :
methyl morpholine, and a coupling reagent. Any of the : coupling reagents commonly used in peptide synthesis are ~;
suitable, for example, 1,3-dicyclohexylcarbodiimide (DCC) -or isobutyl chloroformate.
(ii) Treatment with gaseous ammonia, preferably in the presence of a mercury containing catalyst, such as mercury(II) chloride. The reaction is conveniently effected in a suitable organic solvent, such as an ether, for example, tetrahydrofuran.
: ' W093~02078 PCT/GB92/01366 21~'~S61 (iii) Treatment with an organic acid, for example acetic or propionic acid, optionally in the presence of an ammonium salt, for example ammonium acetate.
Compounds of formula (VI) may be prepared aecording S to the procedures described in Journal of Heterocyclic Chemistry, 1975, 12, 49-57 and Journal of the Chemistry societY, Perkin Transactions I, 1989, 1139-1145.
Where the above-described process for the preparation of the compounds according to the invention lo gives rise to mixtures of stereoisomers these isomers may, if desired, be separated, suitably by conventional techniques such as preparative chromatography. ~ -~
The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-L-tartaric acid and/or (+)-di-p-toluoyl-D-tartaric acid followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, enantiomers of the novel compounds may be separated by HPLC using a chiral column.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Qraanic ChemistrY, ed. J.F.W. McOmie, Plenum Press, 1973;
and T.W. Greene and P.G.M. Wutts, Protective Groups in - 19 't1~.~61 organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a co~venient : : -subsequent stage using methods known from the art. :
The following examples are provided to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative of the scope thereof.
' '' ,',~ ~"
'' . '"' wo 93/02078 PCr/GB92/0l366 ~ ~ -h)J I 1 2 5 6120 -EXAMPLE 1: N-[3(R.S)-2.3-Dih~vdro-l-methYl-5-(1-methylimidazol-2-~vl)-2-oxo-1H-1,4-benzodiazepin-3-vll-N/-[3-, methylphenyl]urea Step 1: 1.3-Dihydro-3(R.S)-lbenzYlo~carbonylamino~5-(1- `
methvlimidazol-2-yl~2H-l,~benzodiazePin-2-one '' .- ':
To a stilTed, cooled (< 10C) solution of a-(isopropylthio)-Na-(benzyloxycarbonyl)glycine ( 1 .4g) in anhydrous dichloromethane (40ml), under a nitrogen atmosphere, was o added dropwise N-methylmorpholine (O.~g) followed by isobutylchloroformate (0.68g). The solution was stirred at 5C ~ -for 10 minutes then heated to reflu~. 2-Aminophenyl~
methylimidazol-2-yl)methanone (1.Og, J. Het. Chem. 1975, 12, 49-57) in anhydrous dichloromethane (lOml) waæ added dropwise and the resulting yellow solution heated at reflux for 1 hour then stirred at ambient temperature for 16 hours. The reaction mixture was washed ~vith lN citric acid, brine then dried (sodium sulphate) and evaporated to afford a yellow oil (2.1g). Rf= 0.1 in ethyl acetate/n-hexane (1:3) on silica (trace of . ~, .
20 amine, Rf- 0.2).
The crude (isopropylthio)glycinamide was dissolved in anhydrous tetrahydrofuran (lOOml) and the ice cooled solution was saturated with ammonia gas. Mercuric chloride (1.35g) .was added and the passage of ammonia continued for 3 hours. The 25 mixture was filtered and the filtrate concentrated. The residue was dissolved in glacial acetic acid (30ml), treated with ammonium acetate (1.4g) and the resulting mixture stirred at ..
W O 93/02078 P ~ /GB92/01366 `:-.
2S61 -~ ~
ambient temperature for 18 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (20ml) and lN
sodium hydroxide ~olution (25ml). The organic layer wa~
separated, dried (magnesium sulphate) then evaporated to give 5 a gummy solid (lg) which was purified by column chromatography on silica using ethyl acetate/petroleum ether (60-80) (1:1) to ethyl acetaWmethanol (9:1) as eluant. The title compound was obtained as a colourless solid (0.38g). lH NMR ~ ~
(250MHz, CDC13) ~ 3.95 (3H, s); 5.12 (2H, m); 5.18 (lH, d, J = ` -lo 8Hz); 6.65 (lH, d, J = 8Hz); 6.9 (lH, d, J = 8Hz); 7.0 (lH, s); 7.1-7.5 (8H, m); 7.55 (lH, d, J = 8Hz).
Step 2- 1.3-Dihydro-3(R.S~-(benzvloxvcarbonYlamino3-1-methyl-5-(1-methylimidazol-2-Y1~2H-1,4-benzodiazePin-2-one To a stirred solution of 1,3-dihydro-3(R,S)- ~-(benzylo~cycarbonylamino)-5-(1-methylimidazol-2-yl)-2H-1,4- -benzodiazepin-2-one (348mg) in anhydrous dimethylfonnamide (5ml), at ambient temperature, was added sodium hydride (40mg of a 5~;% oil dispersion). After 30 minutes iodomethane (142mg) was added and the mi~ture was stirred for 18 hours.
The solvent was evaporated then the residue was partitioned ; ~-between ethyl acetate and water. The organic layer was ~-separated and evaporated to give a gummy residue which was ~
purified by column chromatography o~ silica using ethyl ~ -acetate/petroleum ether (60-80) (2:1) to ethyl acetate/methanol ~ :
(95:5j to afford the title compound as a yellow powder (140mg).
Rf = 0.2 in ethyl acetate on silica plates. lH NMR (250MHz, - `
CDC13) ~ 3.43 (3H, s); 3.94 (3H, s); 5.05-5.20 (2H, m); 5.29 (lH, - -;
.
~112561 d, J = 8Hz); 6.71 (lH, d, J = 8Hz); 7.01 (lH, 8); 7.12 (lH, s); 7.25-7.70 (9H, m~.
Step 3: N-[3(R.S)-2.3-Dih~dro-1-methyl-5-(1-metbYlimidazol-2-vl)-2-oxo- lH- 1 .4-benzodiazePin-3-~vll-Nt-[3-meth~lPhenvl]urea To a solution of 1,3-dihydro-1-methyl-3~R,S)-~benzylo cycarbonylamino)-5-(1-methylimidazol-2-yl)-2H-1,4-benzodiazepin-2-one (O.llg) in methanol (30ml) was added 90%
formic acid (2ml~ and this mixture was added to a stirred o suspension of 10% palladium on carbon (0.2g) in methanol (lOml). The reactio~ mixture was stirred at ambient temperature for 30 minutes then filtered and the solvent evaporated. The residue was partitioned between ethyl acetate (20ml) and 109~ sodiu~n carbonate solution ~20ml). The organic phase was separated, dried (magIlesium sulphate) then evaporated to give 1,3-dihydro-3(R,S)-amino-l-methyl-5-(1-methylimidazol-2-yl~2H-1,4-benzodiazepin-2-one (50mg) whi~
was used without fi~rther purification.
A solution of this crude amine (50mg) in anhydrous tetraliydrofuran (3ml) was treated with m-tolylisocyanate (30mg). After 1 hour the resul~ng colourless precipitate was collected by filtration and washed with diethyl ether to a~ord the tit le compound (40mg) as a colourless solid of mp 222-223C.
lH NMR (360MHz, CDC13) ~ 2.30 (3H, s); 3.44 (3H, s); 3.98 (3H, s); 5.52 (lH, d, J = 8Hz); 6.85-7.70 (llH, m). (Found: C, 63.96;
H~ 5.54; N~ 20-41- C22H22N62--5H20 requires C, 64.22; H, 5.63; N, 20.43%).
- 23 - ~ 2 ~ 6 1 ~-EXAMPLE 2: N-r3(R,S)-2,3-Dihydro-1-(2-methylproPY1~2-oxo-5-(thiazol-2-yl)-lH-1,4-benzodiazepin-3-vll-N/-~3-methvlphenyllurea Step 1: 1.3-Dihydro-3(R.S)-(benzyloxycarbonYlamino)-5-(thiazol-2-Yl)-2H-1~4-benzodiazepin-2-one ..
The title compound (2.03g, 46%) was obtained from c~
(i~opropylthio)-Na-(benzyloxycarbonyl)glycine and 2-aminophenyl-(thiazol-2-yl)methanone (J. Het. Chem. 1975, ~, ~ ~-lo 49-57) as described in E~ample 1. mp 205C (dec.) (dichloromethane/n-hexane). Rf = 0.25 in ethyl acetaWpetroleum ether (60-80) (1:1) on silica plates; lH NM~
(360MHz, d6 DMSO) ~ 5.07 (2H, s); 5.17 (lH, d, J = 9Hz); 7.26-7.39 (7H, m); 7.64 (lH, dd, J1 = 7Hz, J2 = 8Hz); 7.88 (lH, d, J = -7Hz); 7.95-8.00 (2H, m); 8.50 (lH, d, J = 7Hz); 10.92 (lH, broad -~
s); MS, FAB+ ~ntz 393 for (M+H)+. (Found: C, 60.61; H, 4.15; N, 14-20- C20H16~43S- 0-2H20 requires C, 60.66; H, 4.17; N, - -14.15%).
Step 2: 1.3-Dihydro-3(R.S)-(benzYloxycarbonYlamino)-1-(2- -methYlpropYl~5~thiazol-2-Y1)-2H-1.4-benzodiazepin-2-one The title compound (500mg) was obtained firom 1,3-dihydr~
3(R,S)-(benzyloxycarbonylamino)-5-(thiazol-2-yl)-2H- 1,4- ~ -benzodiazepin-2-one and 1-iodo-2-methylpropane using a ~ -procedure similar to that described in Example 1. mp 115- - --117C. Rf = 0.45 in ethyl acetate/petroleum ether (60-80) (1~
on silica plates; lH NMR (360MHz, CDCl3) ~ 0.58 (3H, d, J =
7Hz); 0.71 (3H, d, J = 7Hz); 1.66-1.77 (lH, m); 3.43 (lH, dd, J1 =
6Hz, J2 = 14Hz); 4.29 (lH, dd, Jl = 9Hz, d2 = 14Hz); 5.09-5.18 WO 93/0207X PCr/GB92/01366 211~S61 (2H, m); 5.41 (lH, d, J = 8Hz); 6.67 (lH, d, J = 8Hz); 7.30-7.93 (llH, m).
Step 3: N-r3(R.S)-2.3-DihYdro-1-(2-methvlpropvl)-2-oxo-5-.
(thiazol-2-Yl)-1H-1,4-benzodiazePin-3-Yll-N/-r3 meth~lphenvllurea Crude 1,3-dihydro-3(1R,S)-amino-5-(thiazol-2-yl)-2H-1,4-benzodiazepin-2-one (22Gmg) was obtained from 1,3-dihydro-3(R,S)-(benzyloxycarbonylamino)-5-thiazol-2-yl)-2H-1,4-benzodiazepin-2-one as described in ExamPle 1, except that tlle o reaction time was 36 hours.
A solution of this crude amine (127mg) in anhydrous tetrahydrofuran (2ml) was treated with m-tolyl isocyanate (45.5mg). After 2 hours the solvent was evaporated and the -product purified by column chromatography (HPLC) on silica using ethyl acetate/petroleum ether (60-80) (1:1) as eluant to afford the title product (8mg). mp 222C (dec.). Rf = 0.35 in ethyl acetate/petroleum ether (60-80) (1:1) on silica plates; ~H
NMR (360MHz, CDCl3) ~ 0.59 (3H, d, J = 6Hz); 0.71 (3H, d, J =
6Hz); 1.69-1.78 (lH, m); 3.45 (lH, dd, J1 = 6Hz, J2 = 14Hz); 4.30 (lH, dd, J1 = 9Hz, J2 = 14Hz); 5.63 (lh, broad s); 6.74-7.92 (llH, m); MS, FAB+ m/z 448 for (M+H)+.
EXAMPLE 3: N-[3(R.S~2.3-DihYdro-1-(2-methYlProPYl)-2-oxo-5-(thiazol-2-vl)-lE-1,4-benzodiazepin-3-vll-N/-[3-(tetrazol-5-Yl)phenyllurea Step 1: 5-(3-NitrophenYl)tetrazole To a solution of 3-cyanonitrobenzene (20g) in 1-methyl-2-wo 93/02078 PCI/GB92/01366 ~`~112561 :
pyrrolidinone (200ml) was added triethylamine hydrochloride (27.9g) followed by sodium azide (26.4g). The mixture was heated at 160C for 1.5 hours, then cooled to ambient temperature, poured into ice water (1OOOml) and acidified using -5M HCl. The solid which precipitated from the mi2ture was ~ -~
filtered, washed with water and dried under vacuum at 50C to afford the title tetrazole (22.1g, 86%) as a beige powder. mp ~ ~ -154-156C. lH NMR (360MHz, CDCl3) ~ 7.59 (lH, dd, J = 8Hz);
8.19 (lH, d, J = 8Hz), 8.36 (lH, d, J = 8Hz); 8.86 (lH, s).
0 Step 2: 5-(3-Aminophenvl)tetrazolehydrochloride To a solution of 5-(3-nitrophenyl)tetrazole (22g) in ethanol ~ ~
(500ml) was added 10% palladium on carbon (1.5g, 7% (W/w)) in ~ ~-hydrochloric acid (23ml of a 5M solution). The mi2ture was hydrogenated at 40 psi for 10 minutes then the catalyst filtered ~ ~;
of f and washed with water. The solvents were evaporated in - ~ -vacuo and the brown solid azeotroped with toluene (4 x 100ml).
The resulting solid was triturated with hot ethanol to give 5-(3- -;
aminophenyl)tetrazole hydrochloride (16.3g) as a beige powder. ~ -mp 203-205C. lH NMR (360MHz, D20) o 7.63 (lH, d, J = 8Hz), -7.75 (lH, dd, J = 8Hz), 8.00 (2H, m).
SteP 3: N-[3(R,S)-2,3-DihYdro-1-(2-meth~rlpropvl)-2-oxo-5-(thiazol-2-yl)-lH-1,4-benzodiazepin-3-Yll-N/-~3-(tetrazol-5-yl)phenyllurea Triethylamine (193mg) was added to a stirred, cooled (0C) suspension of 5-(3-aminophenyl)tetrazole hydrochloride (188mg) in anhydrous tetrahydrofuran (2ml). Triphosgene (93mg) was 7112~61 added followed by a further quantity of triethylamine (96mg) ensuring the pH > 7. The reaction mixture was stirred at ambient temperature for 30 minutes. A solution of 1,3-dihydro-3(R,S)-amino-5-(thiazol-2-yl)-2H-1,4-benzodiazepin-2-one (254mg) m anhydrous tetIahydrofilran (lml) was added and the mixture s~rred for 2 hollrs. The reaction mi~cture was diluted with ethyl acetate (15ml) then acidified using 20% acetic acid.
The organic layer was separated and the aqueous re-extracted with ethyl acetate (15ml). The combined organics were washed lo with brine, dried (sodium sulphate) then filtered and e vaporated to dryness. The crude product was purified by column chromatography on silica using dichloromethane/methanoVacetic acid (95:5:0.5) to af~ord the title compound (12mg). mp 192C (dec.). Rf = 0.65 in ethyl acetate/acetic acid (50:1) on silica plates; lH NMR (360MHz, d~
DMSO) ~ 0.47 (3E~, d, J = 6Hz); 0.68 (3H, d, J = 6Hz); 1.50-1.62 (lH, m); 3.64 (lH, dd, Jl = 6Hz, J2 = 15 H z); 4.17 (lH, dd, Jl =
8Hz, J2 = 15Hz); 5.38 (lH, d, J = 8 H z); 7.44-8.18 (llH, m); 9.34 (lH, s); MS, FAB+ m/z 502 for (M+H)+. (Found: C, 55.71; H, 4.69; N, 24.15. C24H23NgO2S.H20 requires C, 55.48; H, 4.86; -N, 24.26%).
W093/02078 pcTJGs92/ol366 ~
~ 1 1 2 j 61 ':
EXAMPLE_4A Tablets containina 1-25mq of comnound Amount mg Compound of formula (I) l.o 2.0 25.0 Microcrystalline cellulose20.0 20.0 20.0 -~
Modified food corn starch 20.0 20.0 20.0 - -~ -Lactose 58.5 57.5 34.5 Magnesium Stearate 0.5 0.5 0.5 EXAMPLE 4B Tablets containinq 26-lOOmq of compound -Amount mg Compound of formula (I) 26.0 50.0 100.0 Microcrystalline cellulose80.0 80.0 80.0 ;~
Modified food corn starch 80.0 80.0 80.0 Lactose 213.5 189.5 139.5 ~agnesium Stearate 0.5 0.5 0.5 The compound of formula (I), cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting ~-granulation is then compressed into tablets containing l.Omg, 2.0mg, 25.0mg, 26.0mg, 50.0mg and lOOmg of the , active compound per tablet. --~
EXAMPLE 5 Parenteral in~ection Amount mg Compound of formula (I) 1 to lOOmg Citric Acid Monohydrate 0.75mg `
Sodium Phosphate 4.5mg Sodium Chloride 9mg -~
Water for injection to lml The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The W093/02078 PCT/GB92/01366 ~-compound of formula (I) is dissolved or suspended in the solution and made up to volume.
EXAMPLE 6 Topical formulation Amount ma Compound of formula (I) l-lOg Emulsifying Wax 30g Liquid paraffin 20g White Soft Paraffin to lOOg 10 The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The compound of formula (I) is added and stirring continued until dispersed. The -mixture is then cooled until solid.
BIOLOGICAL ACTIVITY
1. CCK Receptor Bindina fPancreas) CCK-8 sulphated was radiolabelled with 125I-Bolton Hunter reagent (2000 Ci/mmole). Receptor binding was performed according to Chang and Lotti (Proc. Natl. Acad.
Sci. 83, 4923-4926, 1986) with minor modifications.
Male Sprague-Dawley rats (150-200g) were sacrificed ~-, by decapitation. The whole pancreas was dissected free of fat tissue and was homogenized in 25 volumes of ice-cold 10 mM N-2-hydroxyethyl-piperazine-N'-2-ethane sulphonic acid (HEPES) buffer with 0.1% soya bean trypsin inhibitor (pH 7.4~at 25~C) with a Kinematica Polytron.
The homogenates were centrifuged at 47,800 g for 10 min.
Pellets were resuspended in 10 volumes of binding assay buffer (20mM (HEPES)), lmM ethylene glycol-bis-(~-aminoethylether-N,N'-tetraacetic acid) (EGTA), 5mM MgC12, 150 mM NaCl, bacitracin 0.25 mg/ml, soya bean trypsin inhibitor 0.1 mg/ml, and bovine serum albumin 2 mg/ml pH
W093/02078 PCT/GB92~01366 ~ 1 t 2 a 6 1 ~ ~.
, .
- 29 - `~
6.s at 25C) using a Teflon (trademark) homogenizer, 15 strokes at 500 rpm. The homogenate was further diluted ~-in binding assay buffer to qive a final concentration of ~-0.5 mg original wet weight/l ml buffer. For the binding assay, 50 ~1 of buffer (for total binding) or unlabelled CCK-8 sulphated to give a final concentration of 1 ~M
(for nonspecific binding) or the compounds of Formula I
(for determination of inhibition of 125I-CCK-8 binding) -~
and 50 ~1 of 500 pM 125I-CC~-8 (i.e. 50 pM final ~ --concentration) were added to 400 ~1 of the membrane suspensions in microfuge tubes. All assays were run in --duplicate. The reaction mixtures were incubated at 25~C
for 2 hours and the reaction terminated by rapid filtration (Brandell 24 well cell harvester) over Whatman GF/C filters, washing 3 x 4 mls with ice-cold 100 Mm ~-~
NaCl. The radioactivity on the filters was counted with a LKB gamma counter.
2. CCK Receptor Bindina tBrain) i~
CCK-8 sulphated was radiolabelled and the binding was performed according to the description for the pancreas method with minor modifications. --Male Hartley guinea pigs (300-500g) were sacrificed . by decapitation and the cortex was removed and homogenized in 25 mL ice-cold 0.32 M sucrose. The homogenates were centrifuged at 1000 g for 10 minutes and -the resulting supernatant was recentrifuged at 20,000 g - -for 20 minutes. The P2 pellet was resuspended in binding assay buffer (20mM HEPES, 5 mM MgC12, 0.25 mg/ml bacitracin, 1 mM EGTA pH 6.5 at 25 C), using a Teflon --(trademark) homogenizer (5 strokes at 500 rpm) to give a ;~
final concentration of 10 mg original wet weight/1.2 ml buffer. For the binding assay, 50 ~1 of buffer (for total binding) or unlabelled CCK-8 sulphated to give a ~-25'61 final concentration of 1 ~M ( for nonspecific binding) or the compounds of Formula I (for determination of inhibition of 125I-CCK-8 binding) and 50 ~1 of 500 pM
125I-CCK-8 (i.e. final concentration of 50 pM) were added to 400 ~1 of the membrane suspensions in microfuge tubes.
All assays were run in duplicate. The reaction mixtures were incubated at 25 C for 2 hours and then the reaction was terminated by rapid filtration (Brandell 24 well cell harvester) on Whatman GF/C filters with 3 x 5 ml washes of cold 100 mM NaCl. The radioactivity on the filters was counted with a LKB gamma counter.
In Vitro Results Effects of the Compounds of Formula I
~ I-CCK-8 rece~tor bindina -~
The preferred compounds of Formula I are those which produced dose-dependent inhibition of specific 125I-CCK-8 ~-binding as defined as the difference betweén total and non-specific (i.e. in the presence of 1 ~M CCK) binding.
Drug displacement studies were performed with at least 10 concentrations of compounds of Formula I and the ICsO values were determined by regression analysis IC50 refers to the concentration of the compound required to , inhibit 50% of specific binding of 125I-CCK-8.
The data in Table I were obtained for compounds of ~-~
Formula I.
-~
' ~'' "..
`''.`-`'','''~
- WO 93/02078 PCr/CB92/01366 ~!1 12 5 61 ,;..
TABLE I
CCK RECEPTOR BINDING RESULTS
IC5 o ( nM) , ~ ;
Compound 1~5I-CCK 125I-CCK
of Ex # Pancreas Brain 4~30 600 2 1300 78 ;~
3 1300 6.9 , ~, ,, ,"','~
. ~.
-' . ~, '', '.~- ..
'-`', '' '''` ~ "`'.
; ~' .
Step 3: N-[3(R.S)-2.3-Dih~dro-1-methyl-5-(1-metbYlimidazol-2-vl)-2-oxo- lH- 1 .4-benzodiazePin-3-~vll-Nt-[3-meth~lPhenvl]urea To a solution of 1,3-dihydro-1-methyl-3~R,S)-~benzylo cycarbonylamino)-5-(1-methylimidazol-2-yl)-2H-1,4-benzodiazepin-2-one (O.llg) in methanol (30ml) was added 90%
formic acid (2ml~ and this mixture was added to a stirred o suspension of 10% palladium on carbon (0.2g) in methanol (lOml). The reactio~ mixture was stirred at ambient temperature for 30 minutes then filtered and the solvent evaporated. The residue was partitioned between ethyl acetate (20ml) and 109~ sodiu~n carbonate solution ~20ml). The organic phase was separated, dried (magIlesium sulphate) then evaporated to give 1,3-dihydro-3(R,S)-amino-l-methyl-5-(1-methylimidazol-2-yl~2H-1,4-benzodiazepin-2-one (50mg) whi~
was used without fi~rther purification.
A solution of this crude amine (50mg) in anhydrous tetraliydrofuran (3ml) was treated with m-tolylisocyanate (30mg). After 1 hour the resul~ng colourless precipitate was collected by filtration and washed with diethyl ether to a~ord the tit le compound (40mg) as a colourless solid of mp 222-223C.
lH NMR (360MHz, CDC13) ~ 2.30 (3H, s); 3.44 (3H, s); 3.98 (3H, s); 5.52 (lH, d, J = 8Hz); 6.85-7.70 (llH, m). (Found: C, 63.96;
H~ 5.54; N~ 20-41- C22H22N62--5H20 requires C, 64.22; H, 5.63; N, 20.43%).
- 23 - ~ 2 ~ 6 1 ~-EXAMPLE 2: N-r3(R,S)-2,3-Dihydro-1-(2-methylproPY1~2-oxo-5-(thiazol-2-yl)-lH-1,4-benzodiazepin-3-vll-N/-~3-methvlphenyllurea Step 1: 1.3-Dihydro-3(R.S)-(benzyloxycarbonYlamino)-5-(thiazol-2-Yl)-2H-1~4-benzodiazepin-2-one ..
The title compound (2.03g, 46%) was obtained from c~
(i~opropylthio)-Na-(benzyloxycarbonyl)glycine and 2-aminophenyl-(thiazol-2-yl)methanone (J. Het. Chem. 1975, ~, ~ ~-lo 49-57) as described in E~ample 1. mp 205C (dec.) (dichloromethane/n-hexane). Rf = 0.25 in ethyl acetaWpetroleum ether (60-80) (1:1) on silica plates; lH NM~
(360MHz, d6 DMSO) ~ 5.07 (2H, s); 5.17 (lH, d, J = 9Hz); 7.26-7.39 (7H, m); 7.64 (lH, dd, J1 = 7Hz, J2 = 8Hz); 7.88 (lH, d, J = -7Hz); 7.95-8.00 (2H, m); 8.50 (lH, d, J = 7Hz); 10.92 (lH, broad -~
s); MS, FAB+ ~ntz 393 for (M+H)+. (Found: C, 60.61; H, 4.15; N, 14-20- C20H16~43S- 0-2H20 requires C, 60.66; H, 4.17; N, - -14.15%).
Step 2: 1.3-Dihydro-3(R.S)-(benzYloxycarbonYlamino)-1-(2- -methYlpropYl~5~thiazol-2-Y1)-2H-1.4-benzodiazepin-2-one The title compound (500mg) was obtained firom 1,3-dihydr~
3(R,S)-(benzyloxycarbonylamino)-5-(thiazol-2-yl)-2H- 1,4- ~ -benzodiazepin-2-one and 1-iodo-2-methylpropane using a ~ -procedure similar to that described in Example 1. mp 115- - --117C. Rf = 0.45 in ethyl acetate/petroleum ether (60-80) (1~
on silica plates; lH NMR (360MHz, CDCl3) ~ 0.58 (3H, d, J =
7Hz); 0.71 (3H, d, J = 7Hz); 1.66-1.77 (lH, m); 3.43 (lH, dd, J1 =
6Hz, J2 = 14Hz); 4.29 (lH, dd, Jl = 9Hz, d2 = 14Hz); 5.09-5.18 WO 93/0207X PCr/GB92/01366 211~S61 (2H, m); 5.41 (lH, d, J = 8Hz); 6.67 (lH, d, J = 8Hz); 7.30-7.93 (llH, m).
Step 3: N-r3(R.S)-2.3-DihYdro-1-(2-methvlpropvl)-2-oxo-5-.
(thiazol-2-Yl)-1H-1,4-benzodiazePin-3-Yll-N/-r3 meth~lphenvllurea Crude 1,3-dihydro-3(1R,S)-amino-5-(thiazol-2-yl)-2H-1,4-benzodiazepin-2-one (22Gmg) was obtained from 1,3-dihydro-3(R,S)-(benzyloxycarbonylamino)-5-thiazol-2-yl)-2H-1,4-benzodiazepin-2-one as described in ExamPle 1, except that tlle o reaction time was 36 hours.
A solution of this crude amine (127mg) in anhydrous tetrahydrofuran (2ml) was treated with m-tolyl isocyanate (45.5mg). After 2 hours the solvent was evaporated and the -product purified by column chromatography (HPLC) on silica using ethyl acetate/petroleum ether (60-80) (1:1) as eluant to afford the title product (8mg). mp 222C (dec.). Rf = 0.35 in ethyl acetate/petroleum ether (60-80) (1:1) on silica plates; ~H
NMR (360MHz, CDCl3) ~ 0.59 (3H, d, J = 6Hz); 0.71 (3H, d, J =
6Hz); 1.69-1.78 (lH, m); 3.45 (lH, dd, J1 = 6Hz, J2 = 14Hz); 4.30 (lH, dd, J1 = 9Hz, J2 = 14Hz); 5.63 (lh, broad s); 6.74-7.92 (llH, m); MS, FAB+ m/z 448 for (M+H)+.
EXAMPLE 3: N-[3(R.S~2.3-DihYdro-1-(2-methYlProPYl)-2-oxo-5-(thiazol-2-vl)-lE-1,4-benzodiazepin-3-vll-N/-[3-(tetrazol-5-Yl)phenyllurea Step 1: 5-(3-NitrophenYl)tetrazole To a solution of 3-cyanonitrobenzene (20g) in 1-methyl-2-wo 93/02078 PCI/GB92/01366 ~`~112561 :
pyrrolidinone (200ml) was added triethylamine hydrochloride (27.9g) followed by sodium azide (26.4g). The mixture was heated at 160C for 1.5 hours, then cooled to ambient temperature, poured into ice water (1OOOml) and acidified using -5M HCl. The solid which precipitated from the mi2ture was ~ -~
filtered, washed with water and dried under vacuum at 50C to afford the title tetrazole (22.1g, 86%) as a beige powder. mp ~ ~ -154-156C. lH NMR (360MHz, CDCl3) ~ 7.59 (lH, dd, J = 8Hz);
8.19 (lH, d, J = 8Hz), 8.36 (lH, d, J = 8Hz); 8.86 (lH, s).
0 Step 2: 5-(3-Aminophenvl)tetrazolehydrochloride To a solution of 5-(3-nitrophenyl)tetrazole (22g) in ethanol ~ ~
(500ml) was added 10% palladium on carbon (1.5g, 7% (W/w)) in ~ ~-hydrochloric acid (23ml of a 5M solution). The mi2ture was hydrogenated at 40 psi for 10 minutes then the catalyst filtered ~ ~;
of f and washed with water. The solvents were evaporated in - ~ -vacuo and the brown solid azeotroped with toluene (4 x 100ml).
The resulting solid was triturated with hot ethanol to give 5-(3- -;
aminophenyl)tetrazole hydrochloride (16.3g) as a beige powder. ~ -mp 203-205C. lH NMR (360MHz, D20) o 7.63 (lH, d, J = 8Hz), -7.75 (lH, dd, J = 8Hz), 8.00 (2H, m).
SteP 3: N-[3(R,S)-2,3-DihYdro-1-(2-meth~rlpropvl)-2-oxo-5-(thiazol-2-yl)-lH-1,4-benzodiazepin-3-Yll-N/-~3-(tetrazol-5-yl)phenyllurea Triethylamine (193mg) was added to a stirred, cooled (0C) suspension of 5-(3-aminophenyl)tetrazole hydrochloride (188mg) in anhydrous tetrahydrofuran (2ml). Triphosgene (93mg) was 7112~61 added followed by a further quantity of triethylamine (96mg) ensuring the pH > 7. The reaction mixture was stirred at ambient temperature for 30 minutes. A solution of 1,3-dihydro-3(R,S)-amino-5-(thiazol-2-yl)-2H-1,4-benzodiazepin-2-one (254mg) m anhydrous tetIahydrofilran (lml) was added and the mixture s~rred for 2 hollrs. The reaction mi~cture was diluted with ethyl acetate (15ml) then acidified using 20% acetic acid.
The organic layer was separated and the aqueous re-extracted with ethyl acetate (15ml). The combined organics were washed lo with brine, dried (sodium sulphate) then filtered and e vaporated to dryness. The crude product was purified by column chromatography on silica using dichloromethane/methanoVacetic acid (95:5:0.5) to af~ord the title compound (12mg). mp 192C (dec.). Rf = 0.65 in ethyl acetate/acetic acid (50:1) on silica plates; lH NMR (360MHz, d~
DMSO) ~ 0.47 (3E~, d, J = 6Hz); 0.68 (3H, d, J = 6Hz); 1.50-1.62 (lH, m); 3.64 (lH, dd, Jl = 6Hz, J2 = 15 H z); 4.17 (lH, dd, Jl =
8Hz, J2 = 15Hz); 5.38 (lH, d, J = 8 H z); 7.44-8.18 (llH, m); 9.34 (lH, s); MS, FAB+ m/z 502 for (M+H)+. (Found: C, 55.71; H, 4.69; N, 24.15. C24H23NgO2S.H20 requires C, 55.48; H, 4.86; -N, 24.26%).
W093/02078 pcTJGs92/ol366 ~
~ 1 1 2 j 61 ':
EXAMPLE_4A Tablets containina 1-25mq of comnound Amount mg Compound of formula (I) l.o 2.0 25.0 Microcrystalline cellulose20.0 20.0 20.0 -~
Modified food corn starch 20.0 20.0 20.0 - -~ -Lactose 58.5 57.5 34.5 Magnesium Stearate 0.5 0.5 0.5 EXAMPLE 4B Tablets containinq 26-lOOmq of compound -Amount mg Compound of formula (I) 26.0 50.0 100.0 Microcrystalline cellulose80.0 80.0 80.0 ;~
Modified food corn starch 80.0 80.0 80.0 Lactose 213.5 189.5 139.5 ~agnesium Stearate 0.5 0.5 0.5 The compound of formula (I), cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting ~-granulation is then compressed into tablets containing l.Omg, 2.0mg, 25.0mg, 26.0mg, 50.0mg and lOOmg of the , active compound per tablet. --~
EXAMPLE 5 Parenteral in~ection Amount mg Compound of formula (I) 1 to lOOmg Citric Acid Monohydrate 0.75mg `
Sodium Phosphate 4.5mg Sodium Chloride 9mg -~
Water for injection to lml The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The W093/02078 PCT/GB92/01366 ~-compound of formula (I) is dissolved or suspended in the solution and made up to volume.
EXAMPLE 6 Topical formulation Amount ma Compound of formula (I) l-lOg Emulsifying Wax 30g Liquid paraffin 20g White Soft Paraffin to lOOg 10 The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The compound of formula (I) is added and stirring continued until dispersed. The -mixture is then cooled until solid.
BIOLOGICAL ACTIVITY
1. CCK Receptor Bindina fPancreas) CCK-8 sulphated was radiolabelled with 125I-Bolton Hunter reagent (2000 Ci/mmole). Receptor binding was performed according to Chang and Lotti (Proc. Natl. Acad.
Sci. 83, 4923-4926, 1986) with minor modifications.
Male Sprague-Dawley rats (150-200g) were sacrificed ~-, by decapitation. The whole pancreas was dissected free of fat tissue and was homogenized in 25 volumes of ice-cold 10 mM N-2-hydroxyethyl-piperazine-N'-2-ethane sulphonic acid (HEPES) buffer with 0.1% soya bean trypsin inhibitor (pH 7.4~at 25~C) with a Kinematica Polytron.
The homogenates were centrifuged at 47,800 g for 10 min.
Pellets were resuspended in 10 volumes of binding assay buffer (20mM (HEPES)), lmM ethylene glycol-bis-(~-aminoethylether-N,N'-tetraacetic acid) (EGTA), 5mM MgC12, 150 mM NaCl, bacitracin 0.25 mg/ml, soya bean trypsin inhibitor 0.1 mg/ml, and bovine serum albumin 2 mg/ml pH
W093/02078 PCT/GB92~01366 ~ 1 t 2 a 6 1 ~ ~.
, .
- 29 - `~
6.s at 25C) using a Teflon (trademark) homogenizer, 15 strokes at 500 rpm. The homogenate was further diluted ~-in binding assay buffer to qive a final concentration of ~-0.5 mg original wet weight/l ml buffer. For the binding assay, 50 ~1 of buffer (for total binding) or unlabelled CCK-8 sulphated to give a final concentration of 1 ~M
(for nonspecific binding) or the compounds of Formula I
(for determination of inhibition of 125I-CCK-8 binding) -~
and 50 ~1 of 500 pM 125I-CC~-8 (i.e. 50 pM final ~ --concentration) were added to 400 ~1 of the membrane suspensions in microfuge tubes. All assays were run in --duplicate. The reaction mixtures were incubated at 25~C
for 2 hours and the reaction terminated by rapid filtration (Brandell 24 well cell harvester) over Whatman GF/C filters, washing 3 x 4 mls with ice-cold 100 Mm ~-~
NaCl. The radioactivity on the filters was counted with a LKB gamma counter.
2. CCK Receptor Bindina tBrain) i~
CCK-8 sulphated was radiolabelled and the binding was performed according to the description for the pancreas method with minor modifications. --Male Hartley guinea pigs (300-500g) were sacrificed . by decapitation and the cortex was removed and homogenized in 25 mL ice-cold 0.32 M sucrose. The homogenates were centrifuged at 1000 g for 10 minutes and -the resulting supernatant was recentrifuged at 20,000 g - -for 20 minutes. The P2 pellet was resuspended in binding assay buffer (20mM HEPES, 5 mM MgC12, 0.25 mg/ml bacitracin, 1 mM EGTA pH 6.5 at 25 C), using a Teflon --(trademark) homogenizer (5 strokes at 500 rpm) to give a ;~
final concentration of 10 mg original wet weight/1.2 ml buffer. For the binding assay, 50 ~1 of buffer (for total binding) or unlabelled CCK-8 sulphated to give a ~-25'61 final concentration of 1 ~M ( for nonspecific binding) or the compounds of Formula I (for determination of inhibition of 125I-CCK-8 binding) and 50 ~1 of 500 pM
125I-CCK-8 (i.e. final concentration of 50 pM) were added to 400 ~1 of the membrane suspensions in microfuge tubes.
All assays were run in duplicate. The reaction mixtures were incubated at 25 C for 2 hours and then the reaction was terminated by rapid filtration (Brandell 24 well cell harvester) on Whatman GF/C filters with 3 x 5 ml washes of cold 100 mM NaCl. The radioactivity on the filters was counted with a LKB gamma counter.
In Vitro Results Effects of the Compounds of Formula I
~ I-CCK-8 rece~tor bindina -~
The preferred compounds of Formula I are those which produced dose-dependent inhibition of specific 125I-CCK-8 ~-binding as defined as the difference betweén total and non-specific (i.e. in the presence of 1 ~M CCK) binding.
Drug displacement studies were performed with at least 10 concentrations of compounds of Formula I and the ICsO values were determined by regression analysis IC50 refers to the concentration of the compound required to , inhibit 50% of specific binding of 125I-CCK-8.
The data in Table I were obtained for compounds of ~-~
Formula I.
-~
' ~'' "..
`''.`-`'','''~
- WO 93/02078 PCr/CB92/01366 ~!1 12 5 61 ,;..
TABLE I
CCK RECEPTOR BINDING RESULTS
IC5 o ( nM) , ~ ;
Compound 1~5I-CCK 125I-CCK
of Ex # Pancreas Brain 4~30 600 2 1300 78 ;~
3 1300 6.9 , ~, ,, ,"','~
. ~.
-' . ~, '', '.~- ..
'-`', '' '''` ~ "`'.
; ~' .
Claims (13)
1. A compound of formula (I), or a salt or prodrug thereof:
(I) wherein:
one of W, X, Y or Z represents a nitrogen atom, another of W, X, Y or Z is a nitrogen, oxygen or sulphur atom or a group NR8 where R8 is H or C1-6alkyl, and the other two of W, X, Y and Z each independently represent nitrogen atoms or groups CR8, and the dotted circle represents two double bonds;
R1 represents C1-6 alkyl, C3-7 cycloalkyl, cyclopropylmethyl, (CH2)qimidazolyl, (CH2)qtetrazolyl, (CH2)qtriazolyl, (where q is 1, 2 or 3), CH2CO2R5 (where R5 is C1-4 alkyl) or a group CH2CONR6R7 (where R6 and R7 each independently represents H or C1-4alkyl, or R6 and R7 together form a chain (CH2)p where p is 4 or 5);
R represents C1-6 alkyl, halo, (CH2)rtetrazolyl, optionally substituted in the tetrazole ring by C1-4alkyl, (CH2)rimidazolyl, CONR6R7, SO(C1-6alkyl), SO2(C1-6alkyl), CONHSO2R9, SO2NHCOR9, SONHR10, cyano, B(OH)z or (CH2)rCO2H, where r is zero, 1 or 2, R9 is C1-6alkyl, optionally substituted aryl, 2,2-difluorocyclopropane or trifluoromethyl, and R10 is a nitrogen containing heterocycle;
R3 represents H, C1-6 alkyl or halo;
m is 0, 1 or 2;
n is 0, 1, 2 or 3.
(I) wherein:
one of W, X, Y or Z represents a nitrogen atom, another of W, X, Y or Z is a nitrogen, oxygen or sulphur atom or a group NR8 where R8 is H or C1-6alkyl, and the other two of W, X, Y and Z each independently represent nitrogen atoms or groups CR8, and the dotted circle represents two double bonds;
R1 represents C1-6 alkyl, C3-7 cycloalkyl, cyclopropylmethyl, (CH2)qimidazolyl, (CH2)qtetrazolyl, (CH2)qtriazolyl, (where q is 1, 2 or 3), CH2CO2R5 (where R5 is C1-4 alkyl) or a group CH2CONR6R7 (where R6 and R7 each independently represents H or C1-4alkyl, or R6 and R7 together form a chain (CH2)p where p is 4 or 5);
R represents C1-6 alkyl, halo, (CH2)rtetrazolyl, optionally substituted in the tetrazole ring by C1-4alkyl, (CH2)rimidazolyl, CONR6R7, SO(C1-6alkyl), SO2(C1-6alkyl), CONHSO2R9, SO2NHCOR9, SONHR10, cyano, B(OH)z or (CH2)rCO2H, where r is zero, 1 or 2, R9 is C1-6alkyl, optionally substituted aryl, 2,2-difluorocyclopropane or trifluoromethyl, and R10 is a nitrogen containing heterocycle;
R3 represents H, C1-6 alkyl or halo;
m is 0, 1 or 2;
n is 0, 1, 2 or 3.
2. A compound as claimed in claim 1 wherein represents C1-6 alkyl, C3-7 cycloalkyl, cyclopropylmethyl, (CH2)q-imidazolyl (where q is 1 or 2), CH2CO2R5 (where R5 is C1-4 alkyl) or a group CH2CONR6R7 (where R6 and R7 each independently represents a hydrogen atom or a C1-4 alkyl group, or R6 and R7 together form a chain (CH2)p where p is 4 or 5); and R2 represents C1-6 alkyl, halo, (CH2)r-tetrazolyl, (CH2)r-imidazolyl, or a group (CH2)rCO2H, where r is zero, 1 or 2; and m and n are both 1.
3. A compound as claimed in claim 1 or claim 2 wherein the substituent is imidazolyl, N-methylimidazolyl or thiazolyl.
4. A compound as claimed in any preceding claim wherein R2 is C1-6alkyl or COOH.
5. A compound as claimed in any one of claims 1 to 3 wherein R2 is tetrazolyl.
6. A compound as claimed in claim 1 selected from:
N-(3(R,S)-2,3-dihydro-1-methyl-5-(1-methylimidazol-2-yl)-2-oxo-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea;
N-(3(R,S)-2,3-dihydro-1-(2-methylpropyl)-2-oxo-5-(thiazol-2-yl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea;
N-(3(R,S)-2,3-dihydro-1-(2-methylpropyl)-2-oxo-5-(thiazol-2-yl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-(tetrazol-5-yl)phenyl)urea;
and pharmaceutically acceptable salts and prodrugs thereof.
N-(3(R,S)-2,3-dihydro-1-methyl-5-(1-methylimidazol-2-yl)-2-oxo-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea;
N-(3(R,S)-2,3-dihydro-1-(2-methylpropyl)-2-oxo-5-(thiazol-2-yl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea;
N-(3(R,S)-2,3-dihydro-1-(2-methylpropyl)-2-oxo-5-(thiazol-2-yl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-(tetrazol-5-yl)phenyl)urea;
and pharmaceutically acceptable salts and prodrugs thereof.
7. A compound as claimed in any preceding claim for use in therapy.
8. A process for the preparation of a compound as claimed in any one of claims 1 to 6 which process comprises reaction of an intermediate of formula (III) (III) wherein W, X, Y, Z, R1, R3 and n are as defined for formula (I), with an isocyanate of formula (IV) (IV) wherein R2 and m are as defined for formula (I).
9. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 6 in association with a pharmaceutically acceptable carrier.
10. A method for the treatment or prevention of a physiological disorder involving CCK and/or gastrin, which method comprises administration to a patient in need thereof of a CCK and/or gastrin reducing amount of a compound according to claim 1.
11. A method as claimed in claim 10 for the treatment or prevention of anxiety.
12. A method as claimed in claim 10 for the treatment or prevention of panic.
13. A method as claimed in claim 10 for the treatment of pain.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB919116113A GB9116113D0 (en) | 1991-07-25 | 1991-07-25 | Therapeutic agents |
GB9116113.3 | 1991-07-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2112561A1 true CA2112561A1 (en) | 1993-02-04 |
Family
ID=10698996
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002112561A Abandoned CA2112561A1 (en) | 1991-07-25 | 1992-07-23 | Benzodiazepine derivatives, compositions containing them and their use in therapy |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0595980A1 (en) |
JP (1) | JPH06509337A (en) |
CA (1) | CA2112561A1 (en) |
GB (1) | GB9116113D0 (en) |
WO (1) | WO1993002078A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2471611C2 (en) * | 2008-08-18 | 2013-01-10 | Дзе Жиллетт Компани | Combined device for shaving and trimming |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2282595A (en) * | 1993-08-25 | 1995-04-12 | Yamanouchi Pharma Co Ltd | Benzodiazepine derivatives |
US5438055A (en) * | 1993-11-22 | 1995-08-01 | Merck & Co., Inc. | Antiarrhythmic benzodiazepines |
US5426185A (en) * | 1993-11-22 | 1995-06-20 | Merck & Co., Inc. | Antiarrhythmic benzodiazepines |
US5428157A (en) * | 1993-11-22 | 1995-06-27 | Merck & Co., Inc. | 3-acylaminobenzodiazepines |
US5633251A (en) * | 1994-08-18 | 1997-05-27 | Merck & Co., Inc. | N-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1h-1,4-benzodiazepines |
SK282019B6 (en) * | 1994-08-18 | 2001-10-08 | Merck & Co., Inc. | 2,3-dihydro-1-(2,2,2-trifluoroethyl)-2-oxo-5-phenyl-1h-1,4- benzodiazepine derivatives, pharmaceutical preparation containing them and their use |
US5556969A (en) * | 1994-12-07 | 1996-09-17 | Merck Sharp & Dohme Ltd. | Benzodiazepine derivatives |
JPH11506760A (en) * | 1995-06-07 | 1999-06-15 | メルク エンド カンパニー インコーポレーテッド | Novel N- (2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl) -3-amide |
US5691331A (en) * | 1995-06-07 | 1997-11-25 | Merck & Co., Inc. | N-(2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3yl) -3- amides |
US5700797A (en) * | 1995-06-07 | 1997-12-23 | Merck & Co, Inc. | N-(2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl)-3-amides |
US5726171A (en) * | 1995-06-07 | 1998-03-10 | Merck & Co Inc | N-(1-alkyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo B! 1,4!diazepin-3yl)-acetamides |
US5631251A (en) * | 1995-06-07 | 1997-05-20 | Merck & Co., Inc. | 5-cyclopropyl-1,4 benzodiazepine-2-ones |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL39413A0 (en) * | 1971-05-13 | 1972-07-26 | Sparamedica Ag | Benzodiazepine derivatives,their preparation and pharmaceutical compositions containing them |
US4820834A (en) * | 1984-06-26 | 1989-04-11 | Merck & Co., Inc. | Benzodiazepine analogs |
-
1991
- 1991-07-25 GB GB919116113A patent/GB9116113D0/en active Pending
-
1992
- 1992-07-23 JP JP5502709A patent/JPH06509337A/en active Pending
- 1992-07-23 WO PCT/GB1992/001366 patent/WO1993002078A1/en not_active Application Discontinuation
- 1992-07-23 EP EP92916391A patent/EP0595980A1/en not_active Withdrawn
- 1992-07-23 CA CA002112561A patent/CA2112561A1/en not_active Abandoned
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2471611C2 (en) * | 2008-08-18 | 2013-01-10 | Дзе Жиллетт Компани | Combined device for shaving and trimming |
Also Published As
Publication number | Publication date |
---|---|
GB9116113D0 (en) | 1991-09-11 |
JPH06509337A (en) | 1994-10-20 |
EP0595980A1 (en) | 1994-05-11 |
WO1993002078A1 (en) | 1993-02-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5681833A (en) | Benzodiazepine derivatives | |
US5597915A (en) | Benzodiazepine derivatives, compositions containing them and their use in therapy | |
US5360802A (en) | Benzodiazepine derivatives, compositions containing them and their use in therapy | |
US5556969A (en) | Benzodiazepine derivatives | |
US5451582A (en) | Benzodiazepine derivatives, compositions containing them and their use in therapy | |
US5410049A (en) | Benzodiazepine derivatives, compositions containing them and their use in therapy | |
US5618812A (en) | Benzodiazepine derivatives | |
CA2068355A1 (en) | Benzodiazephine derivatives, compositions containing them and their use in therapy | |
US5478933A (en) | Benzodiazepine derivatives and their use as antagonists of cholecystokinin and/or gastrin receptors | |
US5302591A (en) | Benzodiazepine derivatives | |
US5220018A (en) | Cholecystokinin antagonists | |
US5521175A (en) | Benzodiazepine derivatives | |
CA2112561A1 (en) | Benzodiazepine derivatives, compositions containing them and their use in therapy | |
AU667690B2 (en) | Benzodiazepine derivatives and their use as antagonists of cholecystokinin and/or gastrin receptors | |
CA2066083C (en) | Benzodiazepine analogs as cholecystokinin antagonists | |
WO1994005673A1 (en) | Thienodiazepine derivatives as cholecystokinin and gastrin antagonists | |
US5696110A (en) | Benzodiazepine derivatives and their use as antagonists of cholecystokinin and/or gastrin receptors | |
GB2266528A (en) | Benzodiazepine derivatives | |
GB2271991A (en) | N-(2-oxo-1H-1,4-benzodiazepin-3-yl)-ureas |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Dead |