NO173014B - Analogifremgangsmaate for fremstilling av terapeutisk aktive benzodiazepinderivater - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive benzodiazepinderivater Download PDFInfo
- Publication number
- NO173014B NO173014B NO892799A NO892799A NO173014B NO 173014 B NO173014 B NO 173014B NO 892799 A NO892799 A NO 892799A NO 892799 A NO892799 A NO 892799A NO 173014 B NO173014 B NO 173014B
- Authority
- NO
- Norway
- Prior art keywords
- benzodiazepine
- dihydro
- phenyl
- mixture
- indolylcarbonylamino
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 230000001225 therapeutic effect Effects 0.000 title claims 2
- 150000001557 benzodiazepines Chemical class 0.000 title description 6
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 150000002367 halogens Chemical class 0.000 claims abstract description 14
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 3
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 11
- 125000006239 protecting group Chemical group 0.000 abstract description 10
- 125000001424 substituent group Chemical group 0.000 abstract description 5
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 125000001589 carboacyl group Chemical group 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 15
- 125000003118 aryl group Chemical group 0.000 abstract 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 2
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 125000004193 piperazinyl group Chemical group 0.000 abstract 1
- 125000004076 pyridyl group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 162
- 239000000203 mixture Substances 0.000 description 135
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 83
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 68
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 59
- 238000001819 mass spectrum Methods 0.000 description 47
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 46
- 238000003756 stirring Methods 0.000 description 45
- 238000000354 decomposition reaction Methods 0.000 description 42
- -1 alkali metal salt Chemical class 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 34
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 23
- 235000019341 magnesium sulphate Nutrition 0.000 description 23
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 19
- 238000001914 filtration Methods 0.000 description 19
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- 239000002244 precipitate Substances 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
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- 239000000284 extract Substances 0.000 description 13
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- 239000000706 filtrate Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 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 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 8
- 101800001982 Cholecystokinin Proteins 0.000 description 7
- 102100025841 Cholecystokinin Human genes 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 229940107137 cholecystokinin Drugs 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 6
- ARBKMZHZDXQRIB-PSXMRANNSA-N (3r)-3-amino-5-(2-fluorophenyl)-1-[(1-tritylimidazol-4-yl)methyl]-3h-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(N(CC=1N=CN(C=1)C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C11)=O)N)=C1C1=CC=CC=C1F ARBKMZHZDXQRIB-PSXMRANNSA-N 0.000 description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
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- VIBOPBRXBCVTRE-UHFFFAOYSA-N 3-amino-1-[2-(oxan-2-yloxy)ethyl]-5-phenyl-3h-1,4-benzodiazepin-2-one Chemical compound C12=CC=CC=C2N(CCOC2OCCCC2)C(=O)C(N)N=C1C1=CC=CC=C1 VIBOPBRXBCVTRE-UHFFFAOYSA-N 0.000 description 4
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- WFXSAKKWAMGTIW-UHFFFAOYSA-N [2-acetyloxy-4-[[3-(1h-indole-2-carbonylamino)-2-oxo-5-phenyl-3h-1,4-benzodiazepin-1-yl]methyl]phenyl] acetate Chemical compound C1=C(OC(C)=O)C(OC(=O)C)=CC=C1CN1C(=O)C(NC(=O)C=2NC3=CC=CC=C3C=2)N=C(C=2C=CC=CC=2)C2=CC=CC=C21 WFXSAKKWAMGTIW-UHFFFAOYSA-N 0.000 description 4
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- VIHQHUBDFZNRLQ-UHFFFAOYSA-N n-[1-[2-(2-hydroxyethylamino)ethyl]-2-oxo-5-phenyl-3h-1,4-benzodiazepin-3-yl]-1h-indole-2-carboxamide Chemical compound N=1C(NC(=O)C=2NC3=CC=CC=C3C=2)C(=O)N(CCNCCO)C2=CC=CC=C2C=1C1=CC=CC=C1 VIHQHUBDFZNRLQ-UHFFFAOYSA-N 0.000 description 1
- LYILNYVKNPLYCN-UHFFFAOYSA-N n-[1-[2-(4-methylpiperazin-1-yl)ethyl]-2-oxo-5-phenyl-3h-1,4-benzodiazepin-3-yl]-1h-indole-2-carboxamide Chemical compound C1CN(C)CCN1CCN1C(=O)C(NC(=O)C=2NC3=CC=CC=C3C=2)N=C(C=2C=CC=CC=2)C2=CC=CC=C21 LYILNYVKNPLYCN-UHFFFAOYSA-N 0.000 description 1
- DXSOCMVWGSXXMU-UHFFFAOYSA-N n-[1-[2-[2-(1,3-dioxoisoindol-2-yl)ethoxy]ethyl]-2-oxo-5-phenyl-3h-1,4-benzodiazepin-3-yl]-1h-indole-2-carboxamide Chemical compound C=1C2=CC=CC=C2NC=1C(=O)NC(C(N(CCOCCN1C(C2=CC=CC=C2C1=O)=O)C1=CC=CC=C11)=O)N=C1C1=CC=CC=C1 DXSOCMVWGSXXMU-UHFFFAOYSA-N 0.000 description 1
- CZXADHQDCPRXBH-UHFFFAOYSA-N n-[1-[2-[2-(4-methylpiperazin-1-yl)ethoxy]ethyl]-2-oxo-5-phenyl-3h-1,4-benzodiazepin-3-yl]-1h-indole-2-carboxamide Chemical compound C1CN(C)CCN1CCOCCN1C(=O)C(NC(=O)C=2NC3=CC=CC=C3C=2)N=C(C=2C=CC=CC=2)C2=CC=CC=C21 CZXADHQDCPRXBH-UHFFFAOYSA-N 0.000 description 1
- AOJPLEGMCCQGAQ-UHFFFAOYSA-N n-[2-oxo-1-[(3-oxo-1,2-oxazol-5-yl)methyl]-5-phenyl-3h-1,4-benzodiazepin-3-yl]-1h-indole-2-carboxamide Chemical compound C=1C2=CC=CC=C2NC=1C(=O)NC(C(N(CC=1ONC(=O)C=1)C1=CC=CC=C11)=O)N=C1C1=CC=CC=C1 AOJPLEGMCCQGAQ-UHFFFAOYSA-N 0.000 description 1
- QBLADHNBJHHYLZ-UHFFFAOYSA-N n-[2-oxo-5-phenyl-1-(2-phenylmethoxyethyl)-3h-1,4-benzodiazepin-3-yl]-1h-indole-2-carboxamide Chemical compound C=1C2=CC=CC=C2NC=1C(=O)NC(C(N(CCOCC=1C=CC=CC=1)C1=CC=CC=C11)=O)N=C1C1=CC=CC=C1 QBLADHNBJHHYLZ-UHFFFAOYSA-N 0.000 description 1
- JSISGRMOWBHMSY-UHFFFAOYSA-N n-[2-oxo-5-phenyl-1-(2-propan-2-yloxyethyl)-3h-1,4-benzodiazepin-3-yl]-1h-indole-2-carboxamide Chemical compound N=1C(NC(=O)C=2NC3=CC=CC=C3C=2)C(=O)N(CCOC(C)C)C2=CC=CC=C2C=1C1=CC=CC=C1 JSISGRMOWBHMSY-UHFFFAOYSA-N 0.000 description 1
- GKKBWVAUKFBICU-UHFFFAOYSA-N n-[2-oxo-5-phenyl-1-(2-pyridin-4-ylsulfanylethyl)-3h-1,4-benzodiazepin-3-yl]-1h-indole-2-carboxamide Chemical compound C=1C2=CC=CC=C2NC=1C(=O)NC(C(N(CCSC=1C=CN=CC=1)C1=CC=CC=C11)=O)N=C1C1=CC=CC=C1 GKKBWVAUKFBICU-UHFFFAOYSA-N 0.000 description 1
- AHENAJCRUWXBDL-UHFFFAOYSA-N n-[5-(2-fluorophenyl)-1-(2-hydroxyethyl)-2-oxo-3h-1,4-benzodiazepin-3-yl]-1h-indole-2-carboxamide Chemical compound N=1C(NC(=O)C=2NC3=CC=CC=C3C=2)C(=O)N(CCO)C2=CC=CC=C2C=1C1=CC=CC=C1F AHENAJCRUWXBDL-UHFFFAOYSA-N 0.000 description 1
- BMPQBYSFDGYVTN-UHFFFAOYSA-N n-[5-(2-fluorophenyl)-1-(2-methoxyethyl)-2-oxo-3h-1,4-benzodiazepin-3-yl]-1h-indole-2-carboxamide Chemical compound N=1C(NC(=O)C=2NC3=CC=CC=C3C=2)C(=O)N(CCOC)C2=CC=CC=C2C=1C1=CC=CC=C1F BMPQBYSFDGYVTN-UHFFFAOYSA-N 0.000 description 1
- JVHPKYBRJQNPAT-UHFFFAOYSA-N n-cyclohexyl-2,2-diphenylethenimine Chemical compound C1CCCCC1N=C=C(C=1C=CC=CC=1)C1=CC=CC=C1 JVHPKYBRJQNPAT-UHFFFAOYSA-N 0.000 description 1
- LWFWUJCJKPUZLV-UHFFFAOYSA-N n-trimethylsilylacetamide Chemical compound CC(=O)N[Si](C)(C)C LWFWUJCJKPUZLV-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 150000003222 pyridines 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
- 230000036186 satiety Effects 0.000 description 1
- 235000019627 satiety Nutrition 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 210000005070 sphincter Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- HQQWJMHWSCQSQO-ZCYQVOJMSA-N tert-butyl n-[(2s)-1-oxo-1-[[(3r)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]amino]-3-phenylpropan-2-yl]carbamate Chemical compound C([C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1C(NC2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C1=CC=CC=C1 HQQWJMHWSCQSQO-ZCYQVOJMSA-N 0.000 description 1
- HQQWJMHWSCQSQO-UKILVPOCSA-N tert-butyl n-[(2s)-1-oxo-1-[[(3s)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]amino]-3-phenylpropan-2-yl]carbamate Chemical compound C([C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1C(NC2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C1=CC=CC=C1 HQQWJMHWSCQSQO-UKILVPOCSA-N 0.000 description 1
- 125000005934 tert-pentyloxycarbonyl group Chemical group 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000003871 white petrolatum 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Otolaryngology (AREA)
- Hospice & Palliative Care (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Child & Adolescent Psychology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Den foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av hittil ukjente benzodiazepinderivater og farmasøytisk akseptable salter derav.
Oppfinnelsen angår særlig fremstilling av hittil ukjente benzodiazepinderivater og farmasøytisk akseptable salter derav, som er cholecystokinin-(CCK)-antagonister og derfor kan anvendes som terapeutiske midler mot emesis, pankreatitt, metthets- og appetittkontroll, smertekontroll, insulinoma, gastroparesis, akutt obstruktiv cholecystitt, irritabel tarmsykdom, pankreaskarcinom, etc.
Benzodiazepinderivatene fremstilt ifølge oppfinnelsen kan angis med følgende formel (I):
hvor
R<1> tetrazolyl eller OH,
R<2> er fenyl, som kan bære én eller flere halogen-substituenter,
R<3> er hydrogen eller halogen,
RA er hydrogen, halogen eller lavere alkoksy, og
A er lavere alkylen.
Forbindelsene med formel (I) som fremstilles ifølge foreliggende oppfinnelse, kjennetegnes ved substituenten -A-R<1 >hvor A og R<1> hver er som angitt ovenfor, i 1-stilling i benzodiazepin-kjernen. I US 4,628,084 og EP 167,919, er det beskrevet lignende forbindelser, men de inneholder imidlertid ikke en slik subsituent i 1-stilling i benzodiazepin-kjernen. Det vil fremgå av resultatene vist i det nedenfor beskrevne sammenligningsforsøk at forbindelsene fremstilt ifølge oppfinnelsen utmerker seg klart overfor den kjente forbindelse med hensyn til CCK antagonisme.
Ifølge den foreliggende oppfinnelse kan de hittil ukjente benzodiazepinderivater (I) fremstilles ved de fremgangsmåter som er illustrert i følgende skjema.
i hvilke formler R1, R<2>, R<3>, R* og A hver har den ovenfor angitte betydning, og
X er halogen.
Utgangsforbindelsen (IV) er hittil ukjent og kan fremstilles ved følgende fremgangsmåter:
i hvilke formler R1, R<2>, R<3>, A og X hver har den ovenfor angitte betydning, Y er en syrerest, og R<17> er en beskyttet aminogruppe.
Egnede farmasøytisk akseptable salter av den omhandlede forbindelse (I) er vanlige ikke-toksiske salter og omfatter et metallsalt så som et alkalimetallsalt (f.eks. natriumsalt, kaliumsalt, etc.) og et jordalkalimetallsalt (f.eks. kalsiumsalt, magnesiumsalt, etc), et ammoniumsalt, et salt med en organisk base (f.eks. trimetylaminsalt, trietylaminsalt, pyridinsalt, pikolinsalt, dicykloheksylaminsalt, N,N'-dibenzyletylendiaminsalt, etc), et salt med en organisk syre (f.eks. acetat, maleat, tartrat, metansulfonat, benzensulfonat, formiat, toluensulfonat, trifluoracetat, etc), et salt med en uorganisk syre (f.eks. hydroklorid, hydrobromid, sulfat, fosfat, etc), et salt med en aminosyre (f.eks. arginin, asparaginsyre, glutaminsyre, etc.) og lignende.
I ovenstående og etterfølgende beskrivelse er egnede eksempler og illustrasjoner av de forskjellige definisjoner som den foreliggende oppfinnelse omfatter, forklart nærmere som følger.
Uttrykket "lavere" betegner 1-6 karbonatomer, hvis ikke annet er angitt.
Egnet "halogen" kan f.eks. være klor, brom, fluor og jod.
Fremgangsmåtene for fremstilling av den omhandlede forbindelse (I) forklares detaljert i det følgende.
FREMGANGSMÅTE 1
Forbindelsen (I) eller et salt derav kan fremstilles ved omsetning av forbindelsen (II) eller et salt derav med forbindelsen (III) eller et salt derav.
Egnede salter av forbindelsene (II) og (III) kan være de salter som er eksemplifisert for forbindelsen (I).
Denne reaksjon utføres vanligvis i nærvær av en base.
En egnet base kan f.eks. være en uorganisk base så som et alkalimetallhydrid (f.eks. natriumhydrid, etc), et alkali-metallhydroksyd (f.eks. natriumhydroksyd, kaliumhydroksyd, etc), et jordalkalimetallhydroksyd (f.eks. magnesium-hydroksyd, kalsiumhydroksyd, etc), et alkalimetallkarbonat (f.eks. natriumkarbonat, kaliumkarbonat, etc), et jordalkali-metallkarbonat (f.eks. magnesiumkarbonat, kalsiumkarbonat, etc), et alkalimetallhydrogenkarbonat (f.eks. natriumhydrogenkarbonat, kaliumhydrogenkarbonat, etc), et alkali-metallacetat (f.eks. natriumacetat, kaliumacetat, etc), et jordalkalimetallfosfat (f.eks. magnesiumfosfat, kalsiumfosfat, etc), et alkalimetallhydrogenfosfat (f.eks. dinatrium-hydrogenfosfat, dikaliumhydrogenfosfat, etc.) eller lignende, og en organisk base så som trialkylamin (f.eks. trimetylamin, trietylamin, etc), pikolin, N-metylpyrrolidin, N-metylmorfolin eller lignende.
Denne reaksjon utføres vanligvis i et oppløsningsmiddel så som alkohol (f.eks. metanol, etanol, etc), benzen, N,N-dimetylformamid, tetrahydrofuran, dietyleter eller et hvilket som helst annet oppløsningsmiddel som ikke har noen skadelig innvirkning på reaksjonen.
Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis ved omgivelsestemperatur eller under moderat eller kraftig oppvarmning.
FREMGANGSMÅTE 2
Forbindelsen (I) eller et salt derav kan fremstilles ved omsetning av forbindelsen (IV) eller et reaktivt derivat derav ved aminogruppen eller et salt derav med forbindelsen (V) eller et reaktivt derivat derav ved karboksygruppen eller et salt derav.
Et egnet reaktivt derivat ved aminogruppen av forbindelsen (IV) kan f.eks. være imino av Schiffs basetype eller dens tautomere isomer av enamintype dannet ved omsetning av forbindelsen (IV) med en karbonylforbindelse så som aldehyd, keton eller lignende; et silylderivat dannet ved omsetning av forbindelsen (IV) med en silylforbindelse så som N,0-bis(trimetylsilyl)acetamid, N-trimetylsilylacetamid eller lignende; et derivat dannet ved omsetning av forbindelsen (IV) med fosfortriklorid eller fosgen og lignende.
Egnede salter av forbindelsene (IV) og (V) kan være de samme som er eksemplifisert for forbindelsen (I).
Et egnet reaktivt derivat ved karboksygruppen av forbindelsen (V) kan f.eks. være et syrehalogenid, et syreanhydrid, et aktivert amid, en aktivert ester og lignende. Et egnet eksempel kan være et syreklorid, et syreazid; et blandet syreanhydrid med en syre så som substituert fosforsyre (f.eks. dialkylfosforsyre, fenylfosforsyre, difenylfosforsyre, dibenzylfosforsyre, halogenert fosforsyre, etc), dialkylfosforsyrling, svovelsyrling, tiosvovelsyre, alkansul-fonsyre (f.eks. metansulfonsyre, etansulfonsyre, etc), svovelsyre, alkylkarbonsyre, alifatisk karboksylsyre (f.eks. pivalinsyre, pentansyre, isopentansyre, 2-etylsmørsyre eller trikloreddiksyre, etc.) eller aromatisk karboksylsyre (f.eks. benzoesyre, etc); et symmetrisk syreanhydrid; et aktivert amid med imidazol, 4-substituert imidazol, dimetylpyrazol, triazol eller tetrazol; eller en aktivert ester (f.eks. cyanometylester, metoksymetylester, dimetyliminometyl-[ (CH3) 2N=CH-]-ester, vinylester, propargylester, p-nitrofenyl-ester, 2,4-dinitrofenylester, triklorfenylester, pentaklorfenylester, mesylfenylester, fenylazofenylester, fenyltioester, p-nitrofenyltioester, p-kresyltioester, karboksymetyltioester, pyranylester, pyridylester, piperidyl-ester, 8-kinolyltioester, etc) eller en ester med en N-hydroksyforbindelse (f.eks. N,N-dimetylhydroksylamin, 1-hydroksy-2-(1H)-pyridon, N-hydroksysuccinimid, N-hydroksybenzotriazol, N-hydroksyftalimid, l-hydroksy-6-klor-lH-benzotriazol, etc.) og lignende. Disse reaktive derivater kan eventuelt velges avhengig av typen av forbindelsen (V) som skal anvendes.
Reaksjonen utføres vanligvis i et konvensjonelt oppløsnings-middel så som vann, aceton, dioksan, acetonitril, kloroform, metylenklorid, etylenklorid, tetrahydrofuran, etylacetat, N,N-dimetylformamid, pyridin eller et hvilket som helst annet oppløsningsmiddel som ikke har ugunstig virkning på reaksjonen. Disse vanlige oppløsningsmidler kan også anvendes i blanding med vann.
Når forbindelsen (V) anvendes i fri syreform eller en saltform derav i reaksjonen, utføres reaksjonen fortrinnsvis i nærvær av et vanlig kondenseringsmiddel så som N,N'-dicykloheksylkarbodiimid; N-cykloheksyl-N'-morfolinoetylkarbodiimid; N-cykloheksyl-N'-(4-dietylaminocykloheksyl)karbodiimid; N,N'-dietylkarbodiimid, N,N'-diisopropylkarbodiimid; N-etyl-N'-(3-dimetylaminopropyl)karbodiimid; N,N-karbonylbis-(2-metylim-idazol) ; pentametylenketen-N-cykloheksylimin; difenylketen-N-cykloheksylimin; etoksyacetylen; 1-alkoksy-l-kloretylen; trialkylfosfitt; etylpolyfosfat; isopropylpolyfosfat; fosforoksyklorid (fosforylklorid); fosfortriklorid; tionyl-klorid; oksalylklorid; trifenylfosfin; 2-etyl-7-hydroksybenz-isoksazoliumsalt; 2-etyl-5-(m-sulfofenyl)isoksazolium-hydroksyd-intramolekylært salt; 1-(p-klorbenzensulfonyloksy)-6-klor-lH-benzotriazol; det såkalte Vilsmeier-reagens som fremstilles ved omsetning av N,N-dimetylformamid med tionyl-klorid, fosgen, fosforoksyklorid, etc; eller lignende.
Reaksjonen kan også utføres i nærvær av en uorganisk eller organisk base så som et alkalimetallhydrogenkarbonat, tri-(lavere)alkylamin, pyridin, N-(lavere)alkylmorfolin, N,N-di(lavere)alkylbenzylamin eller lignende. Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis under betingelser fra avkjøling til kraftig oppvarmning.
Fremgangsmåte for fremstilling av utgangsforbindelsen (IV) forklares i det følgende.
FREMGANGSMÅTE A-I
Forbindelsen (VIII) eller et salt derav kan fremstilles ved omsetning av forbindelsen (VI) eller et salt derav med forbindelsen (VII) eller et salt derav. Reaksjonsmåten og be-tingelsene kan være de samme som beskrevet under fremstilling 1 nedenfor.
FREMGANGSMÅTE A-2
Forbindelsen (IX) eller et salt derav kan fremstilles ved omsetning av forbindelsen (VIII) eller et salt derav med forbindelsen (III) eller et salt derav. Denne reaksjon utføres ved i det vesentlige den samme fremgangsmåte som fremgangsmåte 1, og det henvises derfor til den reaksjonsmåte og de betingelser som er nevnt under fremgangsmåte 1.
FREMGANGSMÅTE A-3
Forbindelsen (IV) eller et salt derav kan fremstilles ved å underkaste forbindelsen (IX) eller et salt derav en reaksjon for å fjerne aminobeskyttelsesgruppen.
Egnede salter av forbindelsen (IX) kan være de samme som er eksemplifisert for forbindelsen (I).
Elimineringsreaksjonen utføres ifølge en vanlig fremgangsmåte så som hydrolyse; reduksjon; Edmans metode (fenylisotiocyanat-metoden); eller lignende. Hydrolysen kan f.eks. være en fremgangsmåte under anvendelse av en syre eller base eller hydrazin og lignende. Disse fremgangsmåter kan velges avhengig av typen av beskyttelsesgruppene som skal fjernes.
Blant disse fremgangsmåter er hydrolyse under anvendelse av en syre én av de almindeligste og mest foretrukne fremgangsmåter for eliminering av beskyttelsesgrupper så som substituert eller usubstituert alkoksykarbonyl, f.eks. tert-pentyloksykarbonyl, lavere alkanoyl (f.eks. formyl, acetyl, etc), cykloalkoksykarbonyl, substituert eller usubstituert aralkoksykarbonyl, aralkyl (f.eks. trityl), substituert fenyl-tio, substituert aralkyliden, substituert alkyliden, substituert cykloalkyliden eller lignende.
En egnet syre omfatter en organisk eller uorganisk syre så som maursyre, trifluoreddiksyre, benzensulfonsyre, p-toluensulfon-syre, saltsyre og lignende, og den mest egnede syre er en syre som lett kan fjernes fra reaksjonsblandingen på vanlig måte så som ved destillasjon under redusert trykk, f.eks. maursyre, trifluoreddiksyre, saltsyre, etc. Syrene kan velges ifølge typen av beskyttelsesgruppen som skal fjernes.
Elimineringsreaksjonen under anvendelse av trifluoreddiksyre kan utføres i nærvær av anisol. Hydrolysen under anvendelse av hydrazin anvendes vanligvis til eliminering av en amino-beskyttelsesgruppe av ftaloyl- eller succinyltypen.
Fjernelsen under anvendelse av base anvendes til eliminering av en acylgruppe så som trifluoracetyl. En egnet base kan f.eks. være en uorganisk base og en organisk base.
Den reduktive fjernelse anvendes vanligvis til eliminering av beskyttelsesgrupper, f.eks. halogenalkoksykarbonyl (f.eks. trikloretoksykarbonyl, etc), substituert eller usubstituert aralkoksykarbonyl (f.eks. benzyloksykarbonyl, etc), 2-pyridylmetoksykarbonyl, etc. En egnet reduksjon kan f.eks. være reduksjon med et alkalimetallborhydrid (f.eks. natrium-borhydrid, etc), reduksjon med en kombinasjon av et metall (f.eks. tinn, sink, jern, etc.) eller det omtalte metall sammen med en metallsaltforbindelse (f.eks. kromklorid, kromacetat, etc.) og en organisk eller uorganisk syre (f.eks. eddiksyre, propionsyre, saltsyre, etc); og katalytisk reduksjon. Egnede katalysatorer omfatter vanlige katalysatorer, f.eks. Raney-nikkel, platinaoksyd, palladiumkull og lignende.
Blant beskyttelsesgruppene kan acylgruppen vanligvis elimineres ved hydrolyse. Særlig halogensubstituerte alkoksykarbonyl- og 8-kinolyloksykarbonylgrupper elimineres vanligvis ved behandling med et tungmetall så som kobber, sink eller lignende.
Reaksjonen utføres vanligvis i et konvensjonelt oppløsnings-middel så som vann, kloroform, metylenklorid, alkohol (f.eks. metanol, etanol, etc), tetrahydrofuran eller et hvilket som helst annet oppløsningsmiddel som ikke har noen skadelig innvirkning på reaksjonen.
Reaksjonstemperaturen er ikke kritisk og kan hensiktsmessig velges avhengig av typen av aminobeskyttelsesgruppen og elimineringsmetoden som nevnt ovenfor, og reaksjonen utføres vanligvis under milde betingelser så som under avkjøling eller ved lett forhøyet temperatur. Blant beskyttelsesgruppene kan acylgruppen avledet av en a-aminosyre elimineres ved Edmans metode.
Den omhandlede forbindelse (I) og farmasøytisk akseptable salter derav er CCK-antagonister og derfor nyttige som terapeutiske midler mot emesis, pankreatitt, etc. Til påvisning av anvendeligheten av den omhandlede forbindelse (I) er CCK-antagonisme av to representative forbindelse og en kjent forbindelse vist i det følgende.
CCK- receptorantagonisme i isolert fundus- ringmuskel fra marsvinmave
[I] Testforbindelser:
(1) (3RS)-l,3-Dihydro-l-(2-hydroksyetyl)-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on [fremstilt ifølge
oppfinnelsen]
(2) (3RS)-l,3-Dihydro-l-(5-tetrazolylmetyl)-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on [fremstilt ifølge
oppfinnelsen]
(a) (3RS)-1,3-Dihydro-l-metyl-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on
(ifølge US 4.628.084 og EP 016.719)
[II] Testmetode:
En strimmel av ringmuskelen suspendert i 25 ml organbad inneholdende Krebs hydrogenkarbonatoppløsning (NaCl 118 mM,
KC1 4,8 mM, KH2P04 1,2 mM, MgSO,, 1,2 mM, CaCl2 2,5 mM, NaHC03 25 mM, glukose 11 mM og bovint serumalbumin 0,1%) ble holdt ved 37°C og gasset med 95% 02 og 5% C02.
Strimmelen ble anbragt under en initial spenning på 0,5 g og ekvilibrert i 60 minutter, idet badvolumet ble utskiftet hvert 15. minutt. Isometrisk kontraksjon ble målt under anvendelse av en trykktransducer. CCK-8 (3,2 x 10"<7>M) ble satt til bad-oppløsningen, og kontraktilkraften ble målt. Efter utvaskning av CCK-8 ble testforbindelsene (1 x 10~<5>M) tilsatt. 5 minutter senere ble CCK-8 tilsatt, og kontraktilkraften ble målt. CCK-antagonisme ble beregnet ved å sammenligne den kontraktilkraft, som ble fremkalt av CCK i fravær eller nærvær av testforbindelsene.
[III] Testresultat:
Den omhandlede forbindelse (I) eller farmasøytisk akseptable salter derav kan vanligvis administreres til pattedyr, herunder mennesker, i form av et vanlig farmasøytisk preparat så som en kapsel, en mikrokapsel, en tablett, en granule, et pulver, en pastill, en sirup, en aerosol, en inhalasjon, en oppløsning, en injeksjon, en suspensjon, en emulsjon eller lignende.
Det farmasøytiske preparat inneholdende en forbindelse fremstilt ifølge oppfinnelsen kan inneholde forskjellige organiske eller uorganiske bærematerialer som vanligvis anvendes til farmasøytiske formål, så som hjelpestoffer (f.eks. saccharose, stivelse, mannitol, sorbitol, laktose, glukose, cellulose, talkum, kalsiumfosfat, kalsiumkarbonat, etc), bindemidler (cellulose, metylcellulose, hydroksypropylcellulose, polypropylpyrrolidon, gelatin, gummi arabicum, polyetylenglykol, saccharose, stivelse, etc), sprengmidler (f.eks. stivelse, karboksymetylcellulose, kalsiumsalt av karboksymetylcellulose, hydroksypropylstivelse, natriumglykolstivelse, natriumhydrogenkarbonat, kalsiumfosfat, kalsiumcitrat, etc.)/ glidemidler (f.eks. magnesiumstearat, talkum, natriumlaurylsulfat, etc), smaksgivende midler (f.eks. sitronsyre, mentol, glycin, appelsinpulvere, etc), konserveringsmidler (f.eks. natriumbenzoat, natriumhydro-gensulfitt, metylparaben, propylparaben, etc), stabilisatorer (f.eks. sitronsyre, natriumcitrat, eddiksyre etc), suspenderingsmidler (f.eks. metylcellulose, polyvinylpyrrolidon, aluminiumstearat, etc), dispergerings-midler, vandige fortynningsmidler (f.eks. vann), basiske voks-arter (f.eks. kakaosmør, polyetylenglykol, hvit vaselin, etc.) .
Den virksomme bestanddel kan vanligvis administreres i en enhetsdose på 0,01 mg/kg til 50 mg/kg 1-4 ganger om dagen. Imidlertid kan ovenstående dose økes eller minskes avhengig av pasientens alder, vekt eller tilstand eller administrerings-metoden.
Oppfinnelsen belyses nærmere i følgende fremstillinger og eksempler.
FREMSTILLING 1
En blanding av (3RS)-1,3-dihydro-3-acetoksy-5-fenyl-2H-l,4-benzodiazepin-2-on (11,75 g), kaliumftalimid (11,1 g), natriumjodid (60 g) og N,N-dimety1formamid (80 ml) ble omrørt i 45 minutter ved 90-95°C. Reaksjonsblandingen ble hellet i kaldt vann (1 liter). Bunnfallene ble oppsamlet ved filtrering, vasket med vann og omkrystallisert fra etanol, hvilket ga (3RS)-1,3-dihydro-5-fenyl-3-ftalimido-2H-l,4-benzodiazepin-2-on (8,32 g).
IR (Nujol): 3500, 3370, 3230, 1780, 1720, 1695, 1610, 1575 cm"<1 >NMR (DMS0-d6, <S): 5,73 (1H, s) , 7,30-7,70 (9H, m) , 7,97 (4H, m), 11,90 (1H, bred s)
FREMSTILLING 2
En blanding av (3RS)-1,3-dihydro-5-fenyl-3-ftalimido-2H-l,4-benzodiazepin-2-on (8,2 g), hydrazinhydrat (1,08 g) og tetrahydrofuran (160 ml) ble omrørt i 1,0 time ved romtemperatur og oppvarmet under tilbakeløpskjøling i 1,5 time. Efter fra-filtrering av bunnfallene ble filtratet inndampet til et lite volum, og et tilsvarende volum diisopropyleter ble tilsatt. Bunnfallene ble oppsamlet ved filtrering, hvilket ga (3RS)-1.3- dihydro-3-amino-5-fenyl-2H-l,4-benzodiazepin-2-on (3,64 g).
IR (Nujol): 3360, 3290, 2700, 1670, 1600, 1570, 1480 cm"<1>
NMR (DMS0-d6, 6): 4,30 (1H, s), 5,0 (2H, bred s), 7,20-7,60
(9H, m)
FREMSTILLING 3
Til en oppløsning av (3RS)-1,3-dihydro-5-fenyl-3-ftalimido-2H-1.4- benzodiazepin-2-on (1,90 g) i N,N-dimetylformamid (30 ml) ble det gradvis satt natriumhydrid (62% suspensjon i mineralolje; 0,20 g) under omrøring og under avkjøling i et isbad (<3°C). Blandingen ble omrørt i 10 minutter under de samme betingelser. Til den resulterende blanding ble det på én gang satt 2-[(tetrahydropyran-2-yl)oksy]etylbromid (1,60 g). Blandingen ble omrørt ved omgivelsestemperatur i én time og ved 45°C i 4,5 timer og fikk stå natten over. Den resulterende reaksjonsblanding ble hellet i vann og ekstrahert to ganger med etylacetat. Ekstrakten ble vasket med vann og tørret over magnesiumsulfat. Fjernelse av oppløsningsmidlet ga et lysegult pulver som ble vasket med en blanding av etylacetat og dietyleter og oppsamlet ved filtrering, hvilket ga en blanding (1,48
g) av (3RS)-1,3-dihydro-5-fenyl-3-ftalimido-l-{2-((RS)-2-tetrahydropyranyloksy)etylJ-2H-1,4-benzodiazepin-2-on og
(3RS)-1,3-dihydro-5-fenyl-3-ftalimido-l-{2-((SR)-2-
tetrahydropyranyloksy)etyl}-2H-1,4-benzodiazepin-2-on.
IR (Nujol): 1770, 1714, 1670, 1600, 1375, 1130, 1014, 710 cm"<1 >NMR (CDC13, 5) : 1,3-1,9 (6H, bred), 3,4-4,7 (7H, m), 6,00 (1H, s), 7,3-8,1 (13H, m)
FREMSTILLING 4
Til en oppløsning av en blanding (0,51 g) av (3RS)-1,3-dihydro-5-fenyl-3-ftalimido-l-{2-((RS)-2-tetrahydropyranyloksy)etyl}-2H-l,4-benzodiazepin-2-on og (3RS)-1,3-dihydro-5-fenyl-3-ftalimido-l-{2-((SR)-2-tetrahydropyranyloksy)etyl}-2H-l,4-benzodiazepin-2-on i kloroform (10 ml) ble satt hydrazinhydrat (55 mg) ved omgivelsestemperatur under omrøring. Blandingen ble omrørt i 1,5 time under de samme betingelser og oppvarmet under tilbakeløpskjøling i 1,5 time. Efter avkjøling ble det resulterende bunnfall frafiltrert, og filtratet ble inndampet til tørrhet. Residuet ble oppløst i en liten mengde etanol, og dietyleter ble tilsatt. Et hvitt pulver ble frafiltrert igjen, og filtratet ble inndampet, hvilket ga en rå blanding (0,43 g) av (3RS)-1,3-dihydro-5-fenyl-3-amino-l-{2-((RS)-2-tetrahy-dropyranyloksy)etyl}-2H-l,4-benzodiazepin-2-on og (3RS)-1,3-dihydro-5-fenyl-3-amino-l-{2-((SR)-2-tetrahydropyranyloksy)etyl}-2H-l,4-benzodiazepin-2-on.
IR (Nujol): 3340, 1680, 1660, 1600, 780, 760, 695 cm"<1>
EKSEMPEL 1
Til en oppløsning av (3RS)-1,3-dihydro-3-(2-indolylkarbonyl-amino)-5-fenyl-2H-l,4-benzodiazepin-2-on (1,18 g) i N,N-dimetylformamid (30 ml) ble satt natriumhydrid (62% suspensjon i mineralolje; 0,26 g) under omrøring og avkjøling ved 0°C i et issaltbad under en nitrogenstrøm. Efter omrøring av blandingen i 40 minutter under de samme betingelser ble det tilsatt 5-klormetyltetrazol (0,39 g). Den resulterende blanding ble omrørt ved omgivelsestemperatur i 66 timer. Reaksjonsblandingen ble hellet i en mettet vandig oppløsning av riatriumhydrogenkarbonat, og den vandige oppløsning ble vasket med etylacetat. Efter fjernelse av en liten mengde uoppløselig materiale ved filtrering ble den fraskilte vandige fase syrnet med fortynnet saltsyre.
Den syrnede vandige blanding ble ekstrahert to ganger med etylacetat, og ekstrakten ble vasket med vann og tørret over magnesiumsulfat. Fjernelse av oppløsningsmidlet ga en orange olje (1,27 g) som ble kromatografert på silikagel med en blanding av kloroform og metanol (10:1) som elueringsmiddel, hvilket ga det ønskede rene produkt av (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-1-(5-tetrazolylmetyl)-2H-1,4-benzodiazepin-2-on (0,5 g), smp. 190-195°C (spaltning).
IR (Nujol): 3350 (skulder), 3250, 1680, 1635, 1600, 740, 695 cm"1
NMR (DMS0-d6, 6) : 5,42 (2H, ABq), 5,70 (1H, d, J=8,0Hz), 6,9-8,0 (15H, m), 9,44 (1H, d, J=8,0Hz), 11,6 (1H, bred s) Massespektrum: m/e = 447 (M<+>)
EKSEMPEL 2
Til en blanding av indol-2-karboksylsyre (0,19 g), N-hydroksybenzotriazol (0,16 g) og N,N'-dicykloheksylkarbodiimid (0,24 g) i kloroform (10 ml) ble satt en blanding (0,43 g) av (3RS)-1,3-dihydro-5-fenyl-3-amino-l-{2-((RS)-2-tetrahydropyranyloksy)etyl)-2H-1,4-benzodiazepin-2-on og (3RS)-1,3-dihydro-5-fenyl-3-amino-l-{2-((SR)-2-tetra-hydropyranyloksy)etyl}-2H-1,4-benzodiazepin-2-on ved omgivelsestemperatur under omrøring. Blandingen ble omrørt i 2 timer under de samme betingelser. Det resulterende bunnfall ble frafiltrert. Det samlede filtrat og vaskefaser ble inndampet under redusert trykk, og den gjenværende olje (1,20 g) ble underkastet kolonnekromatografi på silikagel med en blanding av kloroform og etylacetat (10:1) som elueringsmiddel, hvilket ga en blanding (hvitt pulver, 0.45 g) av (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-l-{2-((RS)-2-tetrahydropyranyloksy)etyl}-2H-l,4-benzodiazepin-2-on og (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-l-{2-((SR)-2-tetrahydropyranyloksy)etyl}-2H-1,4-benzodiazepin-2-on.
IR (Nujol): 3340, 3280, 1680, 1630, 1610 (skulder)/ 750, 700 cm"1
NMR (CDC13, <S) : 1,0-2,0 (6H, m) , 3,1-4,7 (7H, m) , 5,82 (1H, d, J=8Hz), 7,0-7,9 (14H, m), 8,13 (1H, d, J=8Hz), 9,62 (1H, bred)
EKSEMPEL 3
Til en suspensjon av en blanding (0,42 g) av (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-l-{2-((RS)-2-tetrahydropyranyloksy)etyl}-2H-l,4-benzodiazepin-2-on og (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-l-{2-((SR)-2-tetrahydropyranyloksy)etyl}-2H-l,4-benzodiazepin-2-on i aceton (10 ml) ble satt 6N saltsyre (0,4 ml) under omrøring ved omgivelsestemperatur. Efter omrøring av den klare gule oppløsning i 45 minutter ble det tilsatt ytterligere 6N saltsyre (0,4 ml) og vann (1 ml). Blandingen ble omrørt i 0,5 time ved omgivelsestemperatur. Nøytralisering med en vandig oppløsning av natriumhydrogenkarbonat og fjernelse av aceton ga gule bunnfall som ble oppsamlet ved filtrering, vasket med vann og tørret. Råproduktet ble renset ved kolonnekromatografi på silikagel med en blanding av kloroform og etylacetat (5:1) som elueringsmiddel, hvilket ga ren (3RS)-1,3-dihydro-l-(2-hydroksyetyl)-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (0,28 g) som et amorft stoff. Dette ble triturert i dietyleter, hvilket ga et lysegult pulver, smp. 170-175°C (spaltning).
IR (Nujol): 3400 (skulder), 3260, 1675 (skulder), 1630, 1595, 740, 690 cm"<1>
NMR (CDCI3, 6) : 2,32 (1H, bred), 3,65-4,4 (4H, m) , 5,74 (1H, d, J=8Hz), 7,05-7,7 (14H, m), 8,02 (1H, d, J=8Hz), 9,45 (1H, bred s)
Massespektrum: m/e = 438 (M<*>)
FREMSTILLING 5
(1) Til en oppløsning av en blanding (1,0 g) av (3R)-1,3-dihydro-5-fenyl-3-[((2S)-2-tert-butoksykarbonylamino-3-fenyl-propanoyl)amino]-2H-1,4-benzodiazepin-2-on og (3S)-1,3-dihydro-5-fenyl-3-[((2S)-2-tert-butoksykarbonylamino-3-fenylpropanoyl)amino]-2H-1,4-benzodiazepin-2-on i N,N-dimetylformamid (5 ml) ble satt natriumhydrid (77,4 mg, 62% suspensjon i mineralolje) under omrøring og avkjøling i et isbad (ca. 3°C). Blandingen ble omrørt i 40 minutter under samme betingelser. Til den resulterende blanding ble det på én gang satt 2-acetoksyetylbromid (0,37 g) under omrøring og avkjøling. Blandingen ble omrørt i 1,5 time under isavkjøling og i 2 timer ved omgivelsestemperatur. Reaksjonsblandingen ble hellet i vann og ekstrahert to ganger med etylacetat. Ekstrakterne ble samlet, vasket med saltvann og tørret over magnesiumsulfat. Fjernelse av oppløsningsmidlet ved avdampning ga en olje (1,29 g) som ble underkastet kolonnekromatografi på silikagel med en blanding av kloroform og etylacetat (10:1) som elueringsmiddel. Fraksjonene inneholdende den ønskede forbindelse ble samlet og inndampet, hvilket ga en farveløs oljeaktig blanding (0,84 g) av (3R)-1-(2-acetoksyetyl)-1,3-dihydro-5-fenyl-3-[((2S)-2-tert-butoksykarbonylamino-3-fenylpropanoyl)amino]-2H-1,4-benzodiazepin-2-on og (3S)-l-(2-acetoksyetyl)-l,3-dihydro-5-^fenyl-3-[ ((2S) -2-tert-butoksykarbonylamino-3-fenylpropanoyl)amino]-2H-1,4-benzodiazepin-2-on.
IR (væske): 3400 (skulder), 3300, 1730, 1700 (skulder), 1690, 1660, 1600, 745, 695 cm"<1>
NMR (CDCI3, S) : 1,40 (9H, s), 1,62 (3H, s), 3,0-3,3 (2H, m) , 3,9-4,2 (3H, m) , 4,4-4,8 (2H, m) , 5,06 (1H, bred d), 5,51 & 5,53 (1H, d & d), 7,2-7,85 (14H, m)
Følgende forbindelse ble fremstilt på lignende måte som beskrevet i fremstilling 5(1): (2) En blanding av (3R)-1-(2-acetoksyetyl)-1,3-dihydro-5-(2-fluorfenyl)-3-[((2S)-2-tert-butoksykarbonylamino-3-fenyl-propanoyl)amino]-2H-1,4-benzodiazepin-2-on og (3S)-l-(2-acetoksyetyl)-1,3-dihydro-5-(2-fluorfenyl)-3-[((2S)-2-tert-butoksykarbonylamino-3-fenylpropanoyl)amino]-2H-1,4-benzodiazepin-2-on
IR (væske): 3400 (skulder), 3320, 1730, 1700 (skulder), 1690, 1662, 1485, 1440, 1380, 1365, 1230, 1161, 1048, 750, 695 cm"<1 >NMR (CDCI3, 6): 1,40 (9H, s), 1,79 (3H, s), 3,0-3,3 (2H, m) , 3,8-4,8 (5H, m), 5,07 (1H, bred d, J=7,4Hz), 5,53, 5,55 (1H, dd, J=8Hz), 6,95-7,9 (14H, m)
FREMSTILLING 6
I en oppløsning av en blanding (0,7 g) av (3R)-1-(2-acetoksy-etyl) -1, 3-dihydro-5-fenyl-3-[ ((2S)-2-tert-butoksykarbonylamino-3-fenylpropanoyl)amino]-2H-1,4-benzodiazepin-2-on og (3S)-1-(2-acetoksyetyl)-1,3-dihydro-5-fenyl-3-[((2S)-2-tert-butoksykarbonylamino-3-fenylpro-panoyl)amino]-2H-1,4-benzodiazepin-2-on i etylacetat (20 ml) ble det innført hydrogenkloridgass under avkjøling i et isbad under omrøring. Efter metning av oppløsningen med hydrogen-klorid ble blandingen omrørt i 30 minutter ved den samme temperatur og i 1 time ved omgivelsestemperatur. Efter fjernelse av hydrogenkloridet ved bobling av tørret nitrogen-gass ble blandingen inndampet under redusert trykk. Til residuet ble det satt vann, og blandingen ble nøytralisert med en mettet vandig oppløsning av natriumhydrogenkarbonat. Blandingen ble ekstrahert to ganger med etylacetat, og ekstrakten ble vasket med vann og tørret over magnesiumsulfat. Fjernelse av oppløsningsmidlet ga en blanding (0,57 g) av (3R)-1-(2-acetoksyetyl)-3-[((2S)-2-amino-3-fenylpropanoyl)-amino]-1,3-dihydro-5-fenyl-2H-l,4-benzodiazepin-2-on og (3S)-1-(2-acetoksyetyl)-3-[((2S)-2-amino-3-fenylpropanoyl)amino]-1.3- dihydro-5-fenyl-2H-l,4-benzodiazepin-2-on.
FREMSTILLING 7
En blanding (12,2 g) av (3R)-1-(2-acetoksyetyl)-3-[((2S)-2-amino-3-fenylpropanoyl)amino]-1,3-dihydro-5-fenyl-2H-l,4-benzodiazepin-2-on (3R-isomer) og (3S)-1-(2-acetoksyetyl)-3-[((2S)-2-amino-3-fenylpropanoyl)amino]-1,3-dihydro-5-fenyl-2H-1.4- benzodiazepin-2-on (3S-isomer) ble underkastet kolonnekro-matograf i på silikagel (0,074-0,037 mm; 230-400 mesh) med en blanding av kloroform og metanol (20:1) som elueringsmiddel. Fraksjonene inneholdende den ønskede forbindelse ble samlet og inndampet til tørrhet, hvilket ga ren 3S-isomer (3,32 g) som en olje. Fra de andre fraksjoner ble det oppnådd en oljeaktig blanding (8,50 g) av 3S-isomer og 3R-isomer. Den oljeaktige blanding ble påny kromatografert på silikagel (0,074-0,037 mm; 2 3 0-4 00 mesh) med en blanding av kloroform og metanol (15:1) som elueringsmiddel, hvilket ga en oljeaktig ren 3S-isomer (1,30 g) og en oljeaktig ren 3R-isomer (4,01 g).
NMR (CDC13 + D20, S) 270 MHz:
3S- isomer
1,648 (3H, s), 2,817 (1H, dd, J=14,0Hz, 10,8Hz), 3,336 (1H, dd, J=14Hz, 6,5Hz), 3,704 (1H, dd, J=10,8Hz, 6,5Hz), 3,927 (1H, dt, J=15,lHz, 6,5Hz), 4,07-4,20 (2H, m), 4,660 (1H, oktet, J=13,6HZ, 7,6Hz, 7,6Hz), 5,578 (1H, s), 7,19-7,64 (14H, m)
3R- isomer
1,642 (3H, s), 2,696 (1H, dd, J=14,0Hz, 10,8Hz), 3,349 (1H, dd, J=14,0Hz, 6,5Hz), 3,729 (1H, dd, J=10,8Hz, 6,5Hz), 3,927 (1H, dt, J=15,lHz, 6,5Hz), 4,09-4,17 (2H, m), 4,690 (1H, oktet, J=13,6Hz, 7,6Hz, 7,6Hz), 5,571 (1H, s), 7,21-7,63 (14H, m)
FREMSTILLING 8
Følgende forbindelser ble fremstilt på lignende måte som beskrevet i fremstilling 6 og 7: (3S)-l-(2-Acetoksyetyl)-3-[((2S)-2-amino-3-fenylpropanoyl) amino] -1, 3-dihydro-5- (2-fluorfenyl) -2H-1, 4-benzodiazepin-2-on, smp. 168-170°C
IR (Nujol): 3410, 3360, 3325 (skulder), 1742, 1680 (skulder), 1667, 1610 (skulder), 1600, 1480, 1448, 1240, 1108, 1045, 810, 781, 730, 699 cm"<1>
NMR (CDC13, 6) : 1,81 (3H, s), 1,85 (2H, s), 2,84 (1H, dd, J=10,5Hz, 13,5Hz), 3,33 (1H, dd, J=13,5Hz, 4Hz), 3,69-4,25 (4H, m), 4,5-4,8 (1H, m), 5,60 (1H, d, J=8Hz), 6,95-7,9 (13H, m), 9,01 (1H, d, J=9Hz)
(3R)-l-(2-Acetoksyetyl)-3-[((2S)-2-amino-3-fenylpropanoyl) amino] -1, 3-dihydro-5- (2-f luorfenyl) -2H-1, 4-benzodiazepin-2-on
IR (film): 3400 (skulder), 3360, 1738, 1685 (skulder), 1668, 1605, 1510 (skulder), 1495, 1450, 1380, 1328, 1240, 1220, 1108, 1045, 820, 750, 700 cm"<1>
NMR (CDC13, 8) : 1,80 (3H, s), 1,87 (2H, s), 2,73 (1H, dd, J=13,5Hz, 10,5Hz), 3,39 (1H, dd, J=13,5Hz, 4Hz), 3,7-4,25 (4H, m), 4,5-4,8 (1H, m), 5,61 (1H, d, J=8Hz), 6,95-7,9 (13H, m), 9,04 (1H, d, J=8Hz)
FREMSTILLING 9
(1) En oppløsning av (3S)-1-(2-acetoksyetyl)-3-[((2S)-2-amino-3-fenylpropanoyl)amino]-1,3-dihydro-5-fenyl-2H-l,4-benzodiazepin-2-on (4,65 g) og fenylisotiocyanat (1,43 g) i metylenklorid (100 ml) ble oppvarmet på et dampbad under omrøring. Efter fjernelse av oppløsningsmidlet ble metylenklorid (100 ml) satt til residuet. Den ovenfor beskrevne fremgangsmåte ble gjentatt tre ganger. Derefter ble metylen-kloridet fjernet fullstendig under redusert trykk, hvilket ga et oljeaktig mellomprodukt (tiourinstoffderivat). Til oljen ble det satt trifluoreddiksyre (80 ml), og blandingen ble oppvarmet på et vannbad innstilt til 52°C under omrøring i 20 minutter. Oppløsningsmidlet ble fjernet under redusert trykk, og residuet ble behandlet to ganger med henholdsvis metylenklorid og dietyleter, hvilket ga en viskøs rød olje som ble underkastet kolonnekromatografi på silikagel med en blanding av kloroform og metanol (15:1) som elueringsmiddel. Fraksjonerne inneholdende den ønskede forbindelse ble samlet og inndampet, hvilket ga en orange olje (2,24 g). Oljen ble oppløst i etylacetat og vasket med en liten mengde av en vandig oppløsning av natriumhydrogenkarbonat. Den organiske fase ble skilt fra og tørret over magnesiumsulfat. Fjernelse av oppløsningsmidlet ga (3S)-1-(2-acetoksyetyl)-3-amino-l,3-dihydro-5-fenyl-2H-l,4-benzodiazepin-2-on (1,35 g).
IR (film): 3370, 3300, 1725, 1665, 1600 cm"<1>
NMR (CDC13, <5) : 1,66 (3H, s), 2,90 (2H, bred s), 3,8-4,8 (5H, m) , 7,1-7,8 (9H, m)
[a]V'S = -111,73° (0,00260 g/ml, CHC13)
Følgende forbindelser ble fremstilt på lignende måte som beskrevet i fremstilling 9(1): (2) (3R)-1-(2-Acetoksyetyl)-3-amino-l,3-dihydro-5-fenyl-2H-1,4-benzodiazepin-2-on
IR (film): 3370, 3300, 1725, 1665, 1600 cm"<1>
NMR (CDC13, 6) : 1,66 (3H, s), 2,89 (2H, bred s), 3,8-4,8 (5H, m), 7,1-7,8 (9H, m)
[a]<2>D6,8 = 123,63° (0,00312 g/ml, CHC13)
(3) (3S)-l-(2-Acetoksyetyl)-3-amino-l,3-dihydro-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on
IR (film): 3450 (skulder), 3380, 3325 (skulder), 1738, 1680, 1660 (skulder), 1605, 1580, 1490, 1455, 1375, 1332, 1230, 1110, 1050, 820, 760, 745 cm"<1>
NMR (CDC13, 6): 1,81 (3H, s) , 3,8-4,8 (6H, m) , 6,95-7,9 (9H, m)
[a]V = -57,68° (3,10 mg/ml, CH2C12)
(4) (3R)-1-(2-Acetoksyetyl)-3-amino-l,3-dihydro-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on
IR (film): 3450 (skulder), 3350, 3325 (skulder), 1736, 1690 (skulder), 1673, 1650 (skulder), 1600, 1580, 1482, 1450, 1370, 1328, 1222, 1105, 1000, 815, 750 cm"<1>
NMR (CDC13, 6) : 1,80 (3H, s) , 3,8-4,8 (6H, m) , 6,95-7,9 (9H, m)
[a]2D<5> = 50,52° (3,18 mg/ml, CH2C12)
EKSEMPEL 4
(1) Til en oppløsning av (3S)-1-(2-acetoksyetyl)-3-amino-l,3-dihydro-5-fenyl-2H-l,4-benzodiazepin-2-on (1,35 g) i N,N-dimetylformamid (25 ml) ble satt indol-2-karboksylsyre (0,64 g), N-hydroksybenzotriazol (0,54 g) og
N,N'-dicykloheksylkarbodiimid (0,83 g) under omrøring ved omgivelsestemperatur. Blandingen ble omrørt i 2 timer ved den samme temperatur og fikk stå natten over. De resulterende bunnfall ble frafiltrert, og filtratet og vaskefåsene ble samlet. Oppløsningsmidlet (N,N-dimetylformamid) ble avdampet under redusert trykk. Residuet ble tilsatt vann, og blandingen ble ekstrahert med etylacetat. Ekstrakten ble vasket to ganger med saltvann og tørret over magnesiumsulfat. Fjernelse av oppløsningsmidlet ga en olje (3,05 g) som ble underkastet kolonnekromatografi på silikagel med en blanding av kloroform og metanol (15:1) som elueringsmiddel. Fraksjonene inneholdende det ønskede produkt ble samlet og inndampet under redusert trykk, hvilket ga (3S)-l-(2-acetoksyetyl)-3-(2-indolylkarbonylamino)-1,3-dihydro-5-fenyl-2H-l,4-benzodiazepin-2-on (1,90 g).
IR (Nujol): 3325, 3260, 1735, 1680, 1630, 1600, 1230, 745, 697 cm"1
NMR (CDC13, S): 1,65 (3H, s), 3,8-4,3 (3H, m), 4,55-4,9 (1H, m), 5,84 (1H, d, J=8,25Hz), 7,0-7,8 (14H, m), 8,14 (1H, d, J=8,25Hz), 9,98 (1H, bred s)
Massespektrum: m/e = 481 (M<+>)
[a]2D<6,>8 = -51,27° (0,00340 g/ml, CHC13)
Følgende forbindelser ble fremstilt på lignende måte som beskrevet i eksempel 4(1): (2) (3R)-1-(2-Acetoksyetyl)-3-(2-indolylkarbonylamino)-1,3-dihydro-5-fenyl-2H-l,4-benzodiazepin-2-on
IR (Nujol) : 3325, 3260, 1735, 1680, 1630, 1600, 1230, 745, 697 cm"<1>
NMR (CDCI3, 6): 1,65 (3H, s), 3,8-4,3 (3H, m), 4,55-4,9 (1H, m), 5,84 (1H, d, J=8,25Hz) 7,0-7,8 (14H, m), 8,14 (1H, d, J=8,25Hz), 10,06 (1H, bred s)
Massespektrum: m/e = 481 (M+)
[a]<2>D<6,8> = 58,90° (0,00300 g/ml, CHC13)
(3) (3S)-l-(2-Acetoksyetyl)-3-(2-indolylkarbonylamino)-1,3-dihydro-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on, smp. 183-187°C (spaltning)
IR (Nujol): 3350 (skulder), 3275, 1733, 1687, 1640, 1610 (skulder), 1539, 1455, 1380, 1260, 1235, 821, 775, 750 cm"<1>
NMR (CDCI3, 8) : 1,80 (3H, s), 3,8-4,25 (3H, m) , 4,45-4,85 (1H, m), 5,84 (1H, d, J=8Hz), 6,9-7,9 (13H, m) , 8,15 (1H, d, J=8Hz), 10,11 (1H, bred s)
Massespektrum: m/e = 498 (M<+>)
(4) (3R)-1-(2-Acetoksyetyl)-3-(2-indolylkarbonylamino)-1,3-dihydro-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on, smp. 185-189°C (spaltning)
IR (Nujol): 3325 (skulder), 3260, 1726, 1682, 1635, 1610 (skulder), 1535, 1448, 1372, 1255, 1226, 820, 770, 745 cm"<1 >NMR (CDCI3, 8) : 1,81 (3H, s), 3,8-4,3 (3H, m), 4,55-4,85 (1H, m), 5,84 (1H, d, J=8Hz), 6,9-7,85 (13H, m), 8,14 (1H, d, J=8Hz), 10,00 (1H, bred s)
Massespektrum: m/e = 498 (M<*>)
EKSEMPEL 5
(1) En blanding av (3S)-1-(2-acetoksyetyl)-3-(2-indolylkarbonylamino)-1,3-dihydro-5-fenyl-2H-l,4-benzodiazepin-2-on (1,80 g) og kaliumkarbonat (0,30 g) i 85% vandig etanol (30 ml) ble oppvarmet ved 65-70°C i 1 time under omrøring. Efter avkjøling ble etanol fjernet under redusert trykk, og residuet ble tilsatt vann. Den vandige blanding ble syrnet med fortynnet saltsyre og ekstrahert med etylacetat. Ekstrakten ble vasket med saltvann og tørret over magnesiumsulfat. Fjernelse av oppløsningsmidlet ga et lysegult amorft pulver som ble kromatografert på silikagel med en blanding av kloroform og etylacetat (3:1) som elueringsmiddel. Fraksjonene inneholdende det ønskede produkt ble samlet og inndampet, hvilket ga (3S)-1-(2-hydroksyetyl)-3-(2-indolylkarbonylamino)-1,3-dihydro-5-fenyl-2H-l,4-benzodiazepin-2-on (1,47 g) som et farveløst amorft pulver.
IR (Nujol): 3400 (skulder), 3260, 1680, 1635, 1600, 745, 695 cm"1
NMR (CDCI3, 6) : 2,7 (1H, bred s), 3,65-4,3 (4H, m) , 5,79 (1H, d, J=8Hz), 7,0-7,9 (14H, m) , 8,17 (IH, d, J=8Hz), 10,15 (1H, bred s).
Massespektrum: m/e = 438 (M<*>)
[a]2D6,8 = -59,04° (0,00352 g/ml, CHC13)
Følgende forbindelser ble fremstilt på lignende måte som beskrevet i eksempel 5(1): (2) (3R)-1-(2-Hydroksyetyl)-3-(2-indolylkarbonylamino)-1,3-dihydro-5-fenyl-2H-l,4-benzodiazepin-2-on
IR (Nujol): 3400 (skulder), 3260, 1680, 1635, 1600, 740, 695 cm"1
NMR (CDCI3, 8) : 2,83 (1H, bred s), 3,55-4,3 (4H, m), 5,78 (1H, d, J=8Hz), 6,9-7,8 (14H, m), 8,18 (1H, d, J=8Hz), 10,28 (1H, bred s)
Massespektrum: m/e = 438 (M<+>)
[a]2D6,<8> = 69,16° (0,00360 g/ml, CHC13)
(3) (3S)-1-(2-Hydroksyetyl)-3-(2-indolylkarbonylamino)-1,3-dihydro-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on, smp. 190-195°C (spaltning)
IR (Nujol): 3400 (skulder), 3270, 1680 (skulder), 1640, 1610 (skulder), 1535, 1485, 1450, 1379, 1330, 1220, 818, 770 (skulder) , 748 cm"<1>
NMR (CDCI3, 8) : 2,17 (1H, s) , 3,7-4,55 (4H, m) , 5,79 (1H, d, J=8Hz), 6,9-7,85 (13H, m), 8,12 (1H, d, J=8Hz), 9,81 (1H, bred s)
Massespektrum: m/e = 456 (M<+>)
[a]<2>D<5><=><->1,20° (3,32 mg/ml, CHC13)
(4) (3R)-1-(2-Hydroksyetyl)-3-(2-indolylkarbonylamino)-1,3-dihydro-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on, smp. 190-195°C (spaltning)
IR (Nujol): 3400 (skulder), 3270, 1680 (skulder), 1639, 1610 (skulder), 1533, 1484, 1450, 1378, 1330, 1220, 818, 770 (skulder) , 745 cm"<1>
NMR (CDC13, 6): 1,91 (1H, s), 3,7-4,55 (4H, m), 5,79 (1H, d, J=8Hz), 6,9-7,85 (13H, m), 8,08 (1H, d, J=8Hz), 9,61 (1H, bred s)
Massespektrum: m/e = 456 (M<+>)
[a]V = 0/99° (3,26 mg/ml, CHC13)
EKSEMPEL 6
(1) Til en oppløsning av (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (394 mg) i N,N-dimetylformamid (4 ml) ble satt natriumhydrid (62% suspensjon i mineralolje, 44 mg) under omrøring ved 0°C i et isbad. Blandingen ble omrørt i 1,0 time ved 0 til -5°C. 2-Metoksyetylklorid (142 mg) ble tilsatt. Blandingen ble omrørt i 6,0 timer ved 60-70°C og avkjølt. Til den avkjølte reaksjonsblanding ble tilsatt eddiksyre (0,5 ml), etylacetat (40 ml) og vann (40 ml) under omrøring. Den organiske fase ble skilt fra, vasket med en vandig oppløsning av natriumhydrogenkarbonat og vann, tørret over magnesiumsulfat og inndampet. Residuet ble kromatografert på silikagel med kloroform som elueringsmiddel, hvilket ga det rene produkt av (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-l-(2-metoksyetyl)-2H-1,4-benzodiazepin-2-on (110 mg), smp. 180-185°C (spaltning).
IR (Nujol): 3440, 3275, 1685, 1630, 1600, 1540, 1490 cm"<1>
NMR (CDCI3, 6) : 3,13 (3H, s), 3,45-3,65 (2H, m), 3,80-4,50 (2H, m), 5,80 (1H, d, J=8Hz), 7,0-7,80 (14H, m), 8,15 (1H, d, J=8HZ), 9,75 (1H, s)
Følgende forbindelse ble fremstilt på lignende måte som beskrevet i eksempel 6(1): (2) (3 RS)-1-AcetyImety1-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on
IR (Nujol): 3325, 3250, 1720, 1680, 1630, 1530, 1448, 1375, 740, 695 cm"<1>
NMR (DMS0-d6, 6) : 2,16 (3H, s), 4,71 (2H, s), 5,90 (1H, d, J=7,5Hz), 7,0-7,75 (14H, m), 8,09 (1H, d, J=7,5Hz), 10,01 (1H, bred s)
Massespektrum: m/e = 450 (M<*>)
EKSEMPEL 7
(3 RS)-1,3-Dihydro-1-(2-hydroksyetyl)-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (0,30
g) ble oppløst i en blanding av vannfritt dimetylsulfoksyd (1 ml) og benzen (1 ml) inneholdende pyridin (0,056 ml) og
trifluoreddiksyre (0,028 ml). Efter tilsetning av dicykloheksylkarbodiimid (0,42 g) ble blandingen omrørt natten over ved romtemperatur. Vann ble tilsatt, og det uoppløselige dicykloheksylurinstoff ble fjernet ved filtrering. Filtratet ble ekstrahert to ganger med etylacetat, og den organiske fase ble vasket med henholdsvis vann, vandig natriumhydrogenkarbonat og vann. Ekstrakten ble tørret over magnesiumsulfat og inndampet, hvilket ga en amorf olje (0,53 g) som ble underkastet kolonnekromatografi på silikagel med en blanding av kloroform og etylacetat (5:1) som elueringsmiddel.
Fraksjonene inneholdende de ønskede materialer ble samlet og inndampet, hvilket ga hvitt pulver som ble renset ved vask med diisopropyleter, hvilket ga ren (3RS)-1,3-dihydro-l-formyl-metyl-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (0,20 g), smp. 168°C (spaltning).
IR (Nujol): 3400 (skulder), 3270, 1725, 1680, 1635, 1600, 1445, 1375, 745, 695 cm"<1>
NMR (CDC13, 6) : 4,68 (2H, s), 5,90 (1H, d, J=7,5Hz), 7,0-7,75 (14H, m), 8,07 (1H, d, J=7,5Hz), 9,66 (1H, s), 10,05 (1H, bred s)
Massespektrum: m/e = 43 6 (M<*>)
EKSEMPEL 8
Til en oppløsning av (3RS)-1,3-dihydro-l-formylmetyl-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (0,44
g) i kloroform (10 ml) ble satt
metoksykarbonylmetylentrifenylfosforan (0,37 g). Blandingen
ble omrørt ved romtemperatur i 2 timer. Reaksjonsblandingen ble konsentrert, hvilket ga en restolje som ble underkastet kolonnekromatografi på silikagel med en blanding av kloroform og etylacetat (10:1) som elueringsmiddel.
(3RS) -1, 3-dihydro-l-[(Z)-3-metoksykarbonyl-2-propenyl]-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (64,6 mg) ble oppnådd fra førstnevnte fraksjoner.
IR (Nujol): 3340, 3250, 1718, 1700, 1665, 1637, 1598, 1536, 1450, 1375, 805, 740, 690 cm"<1>
NMR (CDC13, S) z 3,74 (3H, s), 5,24 (2H, dd, J=6Hz, 1,5Hz), 5,86 (1H, d, J=8Hz), 5,90 (1H, dt, J=12,7Hz, 1,5Hz), 6,21 (1H, dt, J=12,7Hz, 6Hz), 7,1-7,8 (14H, m), 8,13 (1H, d, J=8Hz), 9,98
(1H, bred s)
(3RS) -1,3-dihydro-l-[(E)-3-metoksykarbonyl-2-propenyl]-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (291,1 mg) ble oppnådd fra de sistnevnte fraksjoner.
IR (Nujol): 3340, 3270, 1711, 1685, 1635, 1600, 1535, 1450, 1375, 830, 772, 740, 700 cm"<1>
NMR (CDC13, 6): 3,64 (3H, s), 4,7-4,82 (2H, m), 5,87 (1H, d, J=7,5Hz), 5,88 (1H, dt, J=16,5Hz, 1,5Hz), 6,94 (1H, dt, J=16,5Hz, 4,5Hz), 7,1-7,8 (14H, m) , 8,11 (1H, d, J=7,5Hz), 9,92 (1H, bred s)
EKSEMPEL 9
En blanding av (3RS) -1-acetyliaetyl-l, 3-dihydro-3-(2-indolyl-karbonylamino)-5-f enyl-2H-l, 4-benzodiazepin-2-on (0,30 g) og hydrazinhydrat (36,0 mg) i tetrahydrofuran (5 ml) ble tilbake-løpskjølt i 15 timer og konsentrert, hvilket ga et amorft materiale (0,30 g).
Dette materiale (0,30 g) ble krornatografert på silikagel med en blanding av kloroform og metanol (30:1). Efter at oppløsningsmidlet var fjernet fra fraksjonene inneholdende den omhandlede forbindelse, ble residuet pulverisert i diisopropyleter, hvilket ga (3RS)-1-(2-hydrazonopropyl)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (hvitt pulver, 178 mg), smp. 187°C (spaltning).
IR (Nujol): 3400 (skulder), 3250, 1680, 1630, 1600, 1528, 1450, 1374, 800, 760, 740, 690 cm"<1>
NMR (CDC13, 6) : 1,53 (3H, s) , 4,75 (2H, ABq), 5,90 (2H, bred s), 5,87 (1H, d, J=7,5Hz), 7,0-7,75 (14H, m), 8,16 (1H, d, J=7,5Hz), 9,67 (1H, bred s)
Massespektrum: m/e = 464 (M<+>)
EKSEMPEL 10
En blanding av (3RS)-1-acetylmetyl-l,3-dihydro-3-(2-indolyl-karbonylamino) -5-fenyl-2H-l,4-benzodiazepin-2-on (0,42 g), hydroksylamin-hydroklorid (62,5 mg) i etanol (20 ml) ble omrørt ved romtemperatur i 40 timer. Blandingen ble inndampet til tørrhet, og residuet ble underkastet kolonnekromatografi på silikagel med en blanding av kloroform og metanol (40:1) som elueringsmiddel. Fraksjonene inneholdende det ønskede produkt ble samlet og inndampet, hvilket ga en lysegrønn olje som ble pulverisert i diisopropyleter, hvilket ga (3RS)-l-(2-hydroksyiminopropyl)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (177 mg), smp. 187°C (spaltning).
IR (Nujol): 3400 (skulder), 3250, 1680 (skulder), 1635, 1600, 1532, 1450, 1375, 802, 765, 740, 695 cm"<1>
NMR (CDC13, 6) : 1,63 (3H, s), 4,75 (2H, ABq), 5,00 (1H, bred s), 5,87 (1H, d, J=7,5Hz), 7,1-7,8 (14H, m), 8,19 (1H, d, J=7,5Hz), 10,03 (1H, bred s)
Massespektrum: m/e = 465 (M<*>)
EKSEMPEL 11
Til en blanding av (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (800 mg), l-trityl-4-klormetylimidazolhydroklorid (790 mg) og N,N-dimetylformamid (16 ml) ble satt natriumhydrid (62 % suspensjon i mineralolje, 168 mg) under omrøring og avkjøling ved 0°C i et isbad. Blandingen ble omrørt i 30 minutter ved 0-5°C og oppvarmet ved 70-80"C i 3,0 timer. Til den avkjølte reaksjonsblanding ble det satt eddiksyre (2,0 ml) og 6N saltsyre (5 ml). Blandingen ble omrørt i 1,0 time ved 60°C. Den avkjølte reaksjonsblanding ble hellet i en blanding av etylacetat (100 ml) og vann (100 ml) under omrøring. Den organiske fase ble skilt fra, vasket tre ganger med vann, tørret over magnesiumsulfat og inndampet. Residuet ble kromatografert på silikagel med en blanding av kloroform og metanol (20:1) som elueringsmiddel, hvilket ga (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-1-(4-imidazolylmetyl)-5-fenyl-2H-l,4-benzodiazepin-2-on (306,0 mg), smp. 195-200°C (spaltning).
IR (Nujol): 3250, 1680, 1635, 1600, 1530 cm"<1>
NMR (CDCI3, <5) : 4,93 (2H, s) , 5,75, (1H, d, J=8Hz) , 6,78 (1H, s), 7,0-7,85 (15H, m), 8,35 (1H, d, J=8Hz), 10,35 (1H, bred s) Massespektrum: m/e = 474 (M<+>)
Følgende forbindelser ble fremstilt på lignende måte som
beskrevet i eksempel 11(1):
(2) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(4-imidazolylmetyl)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on, smp. 2 05-210°C (spaltning)
NMR (CDC13, 5): 4,85, 5,10 (2H, ABq, J=15Hz), 5,80 (1H, d, J=8Hz), 6,80-7,83 (15H, m), 8,10 (1H, d, J=8Hz), 10,10 (1H, bred s)
Massespektrum: m/e = 492 (M1")
(3) (3RS)-l,3-Dihydro-3-(2-indolylkarbonylamino)-l-[(5-metyl-imidazol-4-yl)metyl]-5-fenyl-2H-l,4-benzodiazepin-2-on, smp.
205-210°C (spaltning)
NMR (DMSO-d6, 8) : 1,96 (3H, s), 4,80, 5,15 (2H, ABq, J=15Hz), 5,55 (1H, d, J=8Hz), 6,90-8,15 (15H, m) , 9,33 (1H, d, J=8Hz), 11,58 (2H, bred s)
Massespektrum: m/e = 488 (M<1>")
(4) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(2-imidazolylmetyl)-5-fenyl-2H-l,4-benzodiazepin-2-on, smp.
175-180°C (spaltning)
NMR (DMSO-d6, 8) : 5,10 (2H, s), 5,65 (1H, d, J=8Hz), 6,60-8,10 (16H, m), 9,36 (1H, d, J=8Hz), 11,65 (1H, bred s), 11,90 (1H, bred s)
Massespektrum: m/e = 474 (M<+>)
(5) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(3-pyrazolylmetyl)-5-fenyl-2H-l,4-benzodiazepin-2-on, smp.
255-260°C (spaltning)
NMR (DMSO-d6, 8) : 5,03, 5,30 (2H, ABq, J=15Hz), 5,65 (1H, d, J=8Hz), 5,85 (1H, bred s), 6,90-7,90 (15H, m), 9,43 (1H, d, J=8Hz), 11,60 (1H, bred s), 12,55 (1H, bred s), Massespektrum: m/e = 474 (M<+>) (6) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-l-[(1,2,4-triazol-3-yl)metyl]-5-fenyl-2H-l,4-benzodiazepin-2-on, smp.
205-210°C (spaltning)
NMR (DMSO-d6, 6) : 5,10, 5,35 (2H, ABq, J=15Hz), 5,66 (1H, d, J=8Hz), 6,90-7,93 (15H, m), 8,23 (1H, bred s), 9,40 (1H, d, J=8Hz), 11,65 (1H, bred s)
Massespektrum: m/e = 475 (M<+>)
(7) (3RS)-l,3-Dihydro-3-(2-indolylkarbonylamino)-l-[2-(4-imidazolyl)etyl]-5-fenyl-2H-l,4-benzodiazepin-2-on, smp.
185-190°C (spaltning)
NMR (DMSO-d6, 6) : 2,63 (2H, t, J=7Hz), 3,85-4,20 (1H, m), 4,20-4,75 (1H, m), 5,55 (1H, d, J=8Hz), 6,60 (1H, s), 6,93-7,85 (15H, m), 9,43 (1H, d, J=8Hz), 11,65 (1H, bred s) Massespektrum: m/e = 488 (M<*>)
EKSEMPEL 12
Følgende forbindelse ble fremstilt på lignende måte som beskrevet i eksempel 5(1): (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(2-hydroksyetyl)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on
IR (Nujol): 3240, 1670, 1630, 1530 cm"<1>
NMR (DMSC~d6, 6) : 3,30-3,90 (2H, m), 3,90-4,40 (1H, m), 4,70-5,0 (1H, m), 5,70 (1H, d, J=8Hz), 6,90-8,0 (13H, m), 9,50 (1H, d, J=8Hz), 11,50 (1H, bred s)
Massespektrum: m/e = 456 (M1")
EKSEMPEL 13
Følgende forbindelser ble fremstilt på lignende måte som beskrevet i eksempel 6(1): (1) (3RS)-l-(2-Acetoksyetyl)-1,3-dihydro-5-(2-fluorfenyl) -3-(2-indolylkarbonylamino)-2H-1,4-benzodiazepin-2-on
NMR (CDC13, 6) : 1,80 (3H, s) , 3,80-4,90 (4H, m), 5,85 (1H, d, J=8Hz), 6,80-7,95 (13H, m), 8,10 (1H, d, J=8Hz), 9,90 (1H, bred s)
(2) (3RS)-l-(2-Acetoksyetyl)-1,3-dihydro-3-(2-indolylkarbonyl-amino) -5-fenyl-2H-l,4-benzodiazepin-2-on
IR (Nujol): 3250, 1730, 1680, 1600, 1530 cm"<1>
NMR (CDCI3, 6) : 7,65 (3H, s), 4,05-5,0 (4H, m), 5,87 (1H, d, J=8Hz), 7,0-7,85 (14H, m), 8,15 (1H, d, J=8Hz), 10,15 (1H, bred s)
(3) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(2-iso-propoksyetyl)-5-fenyl-2H-l,4-benzodiazepin-2-on, smp. 190-193°C
NMR (CDCI3, 5): 0,98 (6H, d, J=6Hz), 3,20-3,70 (3H, m), 3,80-4,40 (2H, m), 5,75 (1H, d, J=8Hz), 7,0-7,80 (14H, m), 8,05 (1H, d, J=8Hz), 9,66 (1H, bred s)
Massespektrum: m/e = 480 (M<+>)
(4) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(3-metoksy-propyl)-5-fenyl-2H-l,4-benzodiazepin-2-on, smp. 170-175°C
(spaltning)
NMR (CDCI3, 6) : 1,60-1,90 (2H, m) , 3,13 (3H, s) , 3,05-3,35 (2H, m), 3,40-4,0 (1H, m), 4,25-4,65 (1H, m), 5,73 (1H, d, J=8Hz), 7,0-7,75 (14H, m), 8,06 (1H, d, J=8Hz), 9,60 (1H, bred s) Massespektrum: m/e = 466 (M<*>)
(5) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(2-tienyl-metyl)-5-fenyl-2H-l,4-benzodiazepin-2-on, smp. 165-170°C
(spaltning)
NMR (CDCI3, 5) : 5,0, 5,67 (2H, ABq, J=15Hz), 5,80 (1H, d, J=8Hz), 6,70-7,80 (17H, m) , 8,10 (1H, d, J=8Hz), 9,80 (1H, bred s)
Massespektrum: m/e = 490 (M<+>)
(6) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-l-furfuryl-5-fenyl-2H-l,4-benzodiazepin-2-on, smp. 150-155°C (spaltning)
NMR (CDCI3, 5): 4,96, 5,33 (2H, ABq, J=15Hz), 5,83 (1H, d, J=8Hz), 6,20 (2H, s), 6,95-7,75 (15H, m), 8,10 (1H, d, J=8Hz), 9,90 (1H, bred s)
Massespektrum: m/e = 474 (M<1->)
(7) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(2-etoksy-etyl)-5-fenyl-2H-l,4-benzodiazepin-2-on, smp. 205-210°C
(spaltning)
NMR (CDCI3, 6) : 0,96 (3H, t, J=7Hz), 3,35 (2H, q, J=7Hz), 3,50-3,75 (2H, m), 3,80-4,20 (1H, m), 4,20-4,55 (1H, m), 5,80 (1H, d, J=8Hz), 7,05-7,80 (14H, m), 8,10 (1H, d, J=8Hz), 9,90 (1H, bred s)
(8) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(2-metoksy-etyl) -5- (2-f luorfenyl) -2H-1, 4-benzodiazepin-2-on, smp. 230-235°C (spaltning)
NMR (CDCI3, 6): 3,20 (3H, s), 3,40-3,75 (2H, m), 3,80-4,16 (1H, m), 4,20-4,55 (1H, m), 5,76 (1H, d, J=8Hz), 6,90-7,80 (13H, m), 8,10 (1H, d, J=8Hz), 9,95 (1H, bred s)
Massespektrum: m/e = 470 (M<*>)
(9) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-l-[(2-acet-amidotiazol-4-yl)metyl]-5-fenyl-2H-l,4-benzodiazepin-2-on, smp. 175-180°C (spaltning)
NMR (CDCI3, <5): 1,93 (3H, s), 4,83, 5,30 (2H, ABq, J=15Hz), 5,85 (1H, d, J=8Hz), 6,53 (1H, s), 6,90-7,70 (14H, m), 8,25
(1H, d, J=8Hz), 9,56 (1H, s), 10,0 (1H, s)
(10) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(2-brometyl)-5-fenyl-2H-l,4-benzodiazepin-2-on
NMR (CDC13, 6) : 3,30-3,70 (2H, m) , 3,85-4,40 (1H, m), 4,60-5,20 (1H, m), 5,83 (1H, d, J=8Hz), 7,0-7,90 (14H, m), 8,15 (1H, d, J=8Hz), 10,05 (1H, s)
(11) (3RS)-1,3-Dihydro-l-[[2-(2-tetrahydropyranyl)-3-okso-2,3-dihydroisoksazol-5-yl]metyl]-3-(2-indolylkarbonylamino)-5-fenyl-1,4-benzodiazepin-2-on
IR (Nujol): 3260, 1700, 1682, 1630 cm"<1>
NMR (CDCI3, <S): 1,3-2 (6H, m) , 3,5-4,2 (2H, m) , 4,8-5,6 (4H, ABq), 5,89 (1H, d, J=8Hz), 7,1-7,9 (14H, m), 8,04 (1H, d, J=8Hz), 9,7 (1H, bred s) (12) (3RS) -1, 3-Dihydro-3- [ (5-klorindol-2-yl) karbonyl amino]-5-fenyl-1-(2-metoksyetyl)-2H-1,4-benzodiazepin-2-on, smp.
>260°C.
IR (Nujol): 3350 (skulder), 3290, 1668, 1630, 1596, 1530, 1445, 1374, 1324, 1240, 1215, 1110, 910, 759, 690 cm"<1>
NMR (CDCI3, 8) : 3,10 (3H, s), 3,45-3,75 (2H, m), 3,80-4,53 (2H, m), 5,77 (1H, d, J=8,0Hz), 6,9-7,7 (13H, m), 8,12 (1H, d, J=8,0Hz), 10,26 (1H, bred s)
Massespektrum: m/e = 487 (M<+>)
(13) (3RS) -1, 3-Dihydro-3-[ (5-metoksyindol-2-yl) karbonylamino]-5-fenyl-1-(2-metoksyetyl)-2H-1,4-benzodiazepin-2-on, smp. 221-222°C
IR (Nujol): 3400 (skulder), 3250, 1673, 1630, 1596, 1530, 1447, 1375, 1322, 1235, 1115, 1024, 842, 802, 762, 694 cm"<1 >NMR (CDCI3, S) : 3,11 (3H, s) , 3,45-3,75 (2H, m) , 3,82 (3H, s) , 3,80-4,55 (2H, m), 5,78 (1H, d, J=8,0Hz), 6,75-7,7 (13H, m),
8,04 (1H, d, J=8,0Hz), 9,90 (1H, bred s)
Massespektrum: m/e = 482 (M<*>)
(14) (3RS)-1-(3-Brompropyl)-3-(2-indolylkarbonylamino)-5-fenyl-1,3-dihydro-2H-l,4-benzodiazepin-2-on
IR (Nujol): 3400 (skulder), 3250, 1675, 1633, 1600, 1530, 1445, 1375, 1242, 800, 742, 692 cm"<1>
NMR (CDC13, <S) : 1,8-2,3 (2H, m) , 2,95-3,4 (2H, m) , 3,8-4,75 (1H, dt, J=13,8Hz, 6,6Hz)f 4,35-4,65 (1H, dt, J=13,8Hz, 6,6Hz), 5,77 (1H, d, J=8Hz), 7,0-7,7 (14H, m), 8,15 (1H, d, J=8Hz), 9,97 (1H, bred s)
EKSEMPEL 14
En blanding av (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-1-[(2-acetamidotiazol-4-yl)metyl]-5-fenyl-2H-l,4-benzodiazepin-2-on, metanol (13 ml), tetrahydrofuran (8 ml) og konsentrert saltsyre (0,8 ml) ble omrørt i 7,0 timer ved 70"C, avkjølt og innstilt til pH 7,0 med en 5% vandig oppløsning av natriumhydrogenkarbonat. Blandingen ble tilsatt vann (100 ml) og etylacetat (100 ml) under avkjøling. Den adskilte organiske fase ble vasket med vann, tørret over magnesiumsulfat og inndampet. Residuet ble kromatografert på silikagel med en blanding av etylacetat og kloroform (2:1) som elueringsmiddel, hvilket ga (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-l-[(2-aminotiazol-4-yl)metyl]-5-fenyl-2H-l,4-benzodiazepin-2-on, smp. 200-205°C (spaltning).
NMR (DMS0-d6, <5) : 4,80, 5,06 (2H, ABq, J=15Hz), 5,60 (1H, d, J=8Hz), 6,06 (1H, s), 6,75 (2H, bred s), 6,90-7,95 (14H, m), 9,40 (1H, d, J=8Hz), 11,65 (1H, s)
Massespektrum: m/e = 506 (M<+>)
EKSEMPEL 15
(1) En blanding av (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-1-[(E)-3-metoksykarbonyl-2-propenyl]-5-fenyl-2H-l,4-benzodiazepin-2-on (0,47 g), tetrahydrofuran (15 ml), metanol (7,5 ml) og IN vandig natriumhydroksyd (1 ml) ble omrørt i 1,0 time ved romtemperatur og avkjølt. Til den avkjølte reaksjonsblanding ble satt vann (100 ml) og etylacetat (100 ml), og blandingen ble innstilt til pH 4,0 med 6N saltsyre under omrøring. Den organiske fase ble skilt fra, vasket med vann, tørret over magnesiumsulfat og inndampet. Residuet ble kromatografert på silikagel med en blanding av kloroform og metanol (1:1) som elueringsmiddel, hvilket ga (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-l-[(E)-3-karboksy-2-propenyl]-5-fenyl-2H-l,4-benzodiazepin-2-on (80 mg), smp. 175-180°C (spaltning).
NMR (DMSO-d6, 8) : 3,13 (2H, d, J=7,5Hz), 5,20-5,66 (1H, m), 5,66 (1H, d, J=8Hz), 6,90-7,90 (15H, m) , 9,55 (1H, d, J=8Hz), 11,58 (1H, bred s)
Massespektrum: m/e = 478 (M<+>)
Følgende forbindelse ble fremstilt på lignende måte som beskrevet i eksempel 15(1): (2) (3RS)-l,3-Dihydro-3-(2-indolylkarbonylamino)-l-[ (Z)-3-karboksy-2-propenyl]-5-fenyl-2H-l,4-benzodiazepin-2-on, smp.
230-235°C (spaltning)
NMR (DMSO-d6, 8) : 5,12 (2H, d, J=4,5Hz), 5,68 (1H, d, J=8Hz), 5,75-6,30 (1H, m), 6,95-7,90 (15H, m), 9,55 (1H, d, J=8Hz) Massespektrum: m/e = 478 (M<*>)
EKSEMPEL 16
En blanding av (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-1-(2-brometyl)-5-fenyl-2H-l,4-benzodiazepin-2-on (0,3 g) og 1-metylpiperazin (3,0 ml) ble omrørt i 4,0 timer ved romtemperatur, og diisopropyleter (20 ml) ble tilsatt. De resulterende bunnfall ble oppsamlet ved filtrering og oppløst i fortynnet saltsyre. Oppløsningen ble innstilt til pH 7 med en vandig oppløsning av natriumhydrogenkarbonat, og de resulterende bunnfall ble oppsamlet ved filtrering, hvilket ga (3RS)-1,3-dihydro-3-(2-indolylkarbonylamino)-1-[2-(4-metyl-1-piperazinyl)etyl]-5-fenyl-2H-l,4-benzodiazepin-2-on (0,20 g), smp. 135-140°C (spaltning).
IR (Nujol): 3230, 1670, 1635, 1600, 1530 cm"<1>
NMR (CDC13, 6) : 2,0-2,70 (13H, m), 3,60-4,10 (1H, m), 4,30-4,90 (1H, m), 5,83 (1H, d, J=8HZ), 7,0-7,90 (14H, m), 8,20 (1H, d, J=8Hz), 10,10 (1H, bred s)
EKSEMPEL 17
En blanding av (3RS)-l-formylmetyl-3-(2-indolylkarbonylamino)-5-fenyl-l,3-dihydro-2H-l,4-benzodiazepin-2-on (0,5 g) og metoksyamin-hydroklorid (144,1 mg) i etanol (5 ml) ble omrørt i 3 timer ved romtemperatur. Efter fjernelse av oppløsnings-midlet ble residuet tilsatt etylacetat og en fortynnet vandig oppløsning av natriumhydrogenkarbonat. Den organiske fase ble vasket to ganger med vann og tørret over magnesiumsulfat. Fjernelse av oppløsningsmidlet ga et amorft materiale (0,56 g) som ble underkastet kolonnekromatografi på silikagel under eluering med en blanding av kloroform og etylacetat (10:1). Fraksjonene inneholdende det ønskede produkt ble samlet og inndampet, hvilket ga et glassaktig materiale som ble omrørt i diisopropyleter natten over, hvilket ga (3RS)-l-(2-metoksyiminoetyl) -3-(2-indolylkarbonylamino)-5-fenyl-l,3-dihydro-2H-l,4-benzodiazepin-2-on (1:1-blanding av E- og Z-isomerer, 0,34 g) som et hvitt pulver, smp. 169-174°C.
IR (Nujol): 3400 (skulder), 3300, 1690, 1640, 1600, 1535, 1490, 1450, 1379, 1040, 850, 820, 772, 747, 699 cm"<1>
NMR (CDCI3, 5): 3,72 og 3,87 (3H, hver s), 4,6-4,7 og 4,75-4,85 (2H, hver dd, J=5,4Hz, 3Hz), 5,80 (1H, d, J=8Hz), 6,62 og 7,05 (1H, hver t, J=5,4Hz), 7,07-7,7 (14H, m) , 8,03 (1H, d, J=8Hz), 9,78 (1H, bred s)
Massespektrum: m/e = 465 (M<+>)
EKSEMPEL 18
Til en suspensjon av (3RS)-1,3-dihydro-l-[[2-(2-tetrahydro-pyranyl) -3-okso-2,3-dihydroisoksazol-5-yl]metyl]-3-(2-indolyl-karbonylamino) -5-fenyl-l, 4-benzodiazepin-2-on (212,9 mg) i metanol (4 ml) ble satt 2N saltsyre under omrøring ved romtemperatur, Tetrahydrofuran (1 ml) ble tilsatt for å få en klar oppløsning som ble omrørt ved den samme temperatur i 3 0 minutter. Reaksjonsblandingen ble inndampet til tørrhet, hvilket ga et gult pulver som ble vasket med eter under omrøring natten over, oppsamlet ved filtrering og tørret, hvilket ga (3RS)-1,3-dihydro-l-[(3-hydroksyisoksazol-5-yl)metyl]-3-(2-indolylkarbonylamino)-5-fenyl-l,4-benzodiazepin-2-on (149,1 mg) som et gult pulver, smp. 207°C (spaltning).
NMR (DMSO-dé, 6) : 5,24 (2H, ABq, J=15Hz, 25,5Hz), 5,67 (1H, d, J=8Hz), 5,70 (1H, s), 7,0-7,85 (14H, m), 9,52 (1H, d, J=8Hz), 11,61 (1H, bred s)
Massespektrum: m/e = 491 (MT1")
EKSEMPEL 19
Følgende forbindelser ble fremstilt på lignende måte som beskrevet i eksempel 6(1): (1) (3RS)-1-[2-(2-Kloretoksy)etyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on NMR (CDCI3, 5): 3,20-4,60 (8H, m), 5,80 (1H, d, J=8Hz), 7,0-7,80 (14H, m) , 8,15 (1H, d, J=8Hz), 10,20 (1H, bred s) (2) (3RS)-1-(2-Vinyloksyetyl)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on, smp.
210-215°C (spaltning)
NMR (CDCI3, 6) : 3,75-4,0 (4H, m), 4,0-4,20 (1H, m), 4,30-4,65 (1H, m) , 5,76 (1H, d, J=8Hz), 6,05-6,35 (1H, m), 7,0-7,75 (14H, m), 8,03 (1H, d, J=8Hz), 9,53 (1H, bred s) Massespektrum: m/e = 464 (M<*>) (3) (3RS)-l-(2-Benzyloksyetyl)-l,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on, smp.
195-200°C (spaltning)
NMR (CDCI3, <S): 3,55-3,80 (2H, m) , 3,80-4,20 (1H, m) , 4,20-4,55 (1H, m), 4,30 (2H, s), 5,75 (1H, d, J=8Hz), 6,96-7,80 (14H,
m) , 8,06 (1H, d, J=8Hz), 9,85 (1H, bred s)
(4) (3RS)-1-(3,4-Dimetoksybenzyl)-1,3-dihydro-3-(2-indolyl-karbonylamino) -5-fenyl-2H-l,4-benzodiazepin-2-on, smp.
220-225°C (spaltning)
IR (Nujol): 3300, 3200, 1680, 1635, 1590, 1525, 1505 cm"<1>
NMR (CDCI3, 6) : 3,40 (3H, s), 3,75 (3H, s), 4,70, 5,75 (2H, ABq, J=15Hz), 5,90 (1H, d, J=8Hz), 6,45-6,65 (3H, m), 7,10-7,80 (14H, m), 8,20 (1H, d, J=8Hz), 9,98 (1H, bred s) (5) . (3RS)-1-(3,4-Diacetoksybenzyl)-1,3-dihydro-3-(2-indolyl-karbonylamino) -5-fenyl-2H-l,4-benzodiazepin-2-on (6) (3RS)-1-Benzyl-l,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on, smp. 145-150°C (spaltning)
IR (Nujol): 3250, 1680, 1635, 1600, 1530 cm"<1>
NMR (CDCI3, 6) : 4,88, 5,68 (2H, ABq, J=15Hz), 5,93 (1H, d,
J=5Hz), 7,0-7,80 (19H, m), 8,25 (1H, d, J=8Hz), 10,08 (1H, bred s)
Massespektrum: m/e = 484 (M<*>)
(7) (3RS)-l-(2-Ftalimidoetyl)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on
IR (Nujol): 3400, 3250, 1770, 1712, 1678, 1646 cm"<1>
NMR (DMS0-d6, 6) : 3,6-4,8 (4H, m), 5,60 (1H, d, J=8Hz), 7,0-8,0 (18H, m), 9,50 (1H, d, J=8Hz), 11,45 (1H, bred s) (8) (3RS)-1-(2-Metyltioetyl)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on, smp.
149-156°C
IR (Nujol): 3380 (skulder), 3270, 1672, 1635, 1595, 1530, 1445, 1375, 1320, 740, 690 cm"<1>
NMR (CDC13, <5) : 1,98 (3H, s), 2,63 (2H, t, J=7,5Hz), 3,88 (1H, dt, J=13,5Hz, 7,5Hz)f 4,63 (1H, dt, J=13,5Hz, 7,5Hz), 5,80
(1H, d, J=8,4Hz), 7,0-7,8 (14H, m), 8,11 (1H, d, J=8,4Hz), 9,93 (1H, bred s)
Massespektrum: m/e = 469 (M<+>)
EKSEMPEL 20
En blanding av (3RS)-1-(3,4-diacetoksybenzyl)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (287 mg), metanol (5 ml), tetrahydrofuran (5 ml), vann (1 ml) og IN vandig kaliumkarbonat (5 ml) ble omrørt i 1,0 time ved 0-5°C og derefter innstilt til pH 1-2 med 6N saltsyre. Etylacetat (50 ml) og vann (50 ml) ble satt til blandingen under omrøring. Den adskilte organiske fase ble vasket med vann, tørret over magnesiumsulfat og inndampet. Residuet ble kromatografert på silikagel med en blanding av kloroform og etylacetat (4:1) som elueringsmiddel, hvilket ga (3RS)-1-(3,4-dihydroksybenzyl)-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-
benzodiazepin-2-on (155 mg), smp. 165-170"C (spaltning).
NMR (CDCl3-DMSO-d6, 6) : 4,75, 5,35 (2H, ABq, J=15Hz) , 5,75 (1H, d, J=8HZ) , 6,20-6,60 (3H, m) , 6,90-7,70 (14H, m) , 8,35 (2H, bred s), 8,96 (lH,d, J=8Hz), 11,46 (1H, bred s) Massespektrum: m/e = 516 (M<+>)
EKSEMPEL 21
Til en oppløsning av karbontetraklorid (792,1 mg) i metylenklorid (20 ml) ble det satt trifenylfosfin (2,70 g) under omrøring ved romtemperatur. Til den resulterende blanding ble det satt (3RS)-1-formylmetyl-l,3-dihydro-3-(2-indolylkarbonyl-amino) -5-f enyl-2H-l, 4-benzodiazepin-2-on (0,90 g). Blandingen ble omrørt i 6 timer under omrøring ved romtemperatur. Metylenklorid ble fjernet fra reaksjonsblandingen ved avdampning. Vann ble satt til residuet. Blandingen ble syrnet med fortynnet saltsyre og ekstrahert to ganger med etylacetat. Ekstrakten ble tørret over magnesiumsulfat og inndampet, hvilket ga en rød olje som ble underkastet kolonnekromatografi på silikagel med en blanding av kloroform og etylacetat (20:1) som elueringsmiddel. Fraksjonene inneholdende den ønskede forbindelse ble samlet og inndampet til tørrhet, hvilket ga et glassaktig materiale (0,20 g) som ble pulverisert i diisopropyleter, hvilket ga (3RS)-1-(3,3-diklor-2-propenyl)-1, 3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (138,8 mg) som et gult pulver, smp. 149-152°C (spaltning).
IR (Nujol): 3400 (skulder), 3550, 1680, 1640, 1535, 1450, 1378, 742, 694 cm"<1>
NMR (CDC13, 6) : 4,53 (1H, dd, J=15Hz, 7,2Hz), 4,77 (1H, dd, J=15Hz, 7,2Hz), 5,93 (1H, dd, J=7,2Hz, 7,8Hz), 5,77 (1H, d, J=7,8HZ), 7,0-7,7 (14H, m) , 7,99 (1H, d, J=7,8Hz), 9,67 (1H, bred s)
Massespektrum: m/e = 503 (M<+>)
EKSEMPEL 22
Følgende forbindelse ble fremstilt på lignende måte som beskrevet i eksempel 16: (3RS)-l-[2-(2-hydroksyetylamino)etyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on, smp.
125-130°C (spaltning)
IR (Nujol): 3250, 1680, 1630, 1600, 1535 cm"<1>
NMR (CDC13, . 6) : 2,45-2,85 (4H, m) , 3,30-3,50 (2H, m) , 3,50-3,90 (1H, m) , 4,20-4,60 (1H, m), 5,80 (1H, d, J=8Hz), 7,0-7,80
(14H, m), 8,25 (1H, d, J=8Hz), 10,20 (1H, bred s)
EKSEMPEL 2 3
En blanding av (3RS)-1-[2-(2-kloretoksy)etyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (700 mg), kaliumftalimid (610 mg) og N,N-dimetylformamid (5 ml) ble omrørt i 7 timer ved 80-90°C. Reaksjonsblandingen ble hellet i kaldt vann (100 ml) og ekstrahert med etylacetat. Ekstrakten ble vasket med vann, tørret over magnesiumsulfat og inndampet, hvilket ga (3RS)-1-[2-(2-ftalimidoetoksy)etyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (0,9 g).
EKSEMPEL 24
En blanding av (3RS)-1-[2-(2-kloretoksy)etyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (500 mg) og 1-metylpiperazin (5,0 ml) ble omrørt ved 70°C i 5,0 timer. Derefter ble diisopropyleter (30 ml) satt til reaksjonsblandingen. Efter at det resulterende bunnfall var frafiltrert, ble filtratet inndampet. Residuet ble vasket med vann og tørret, hvilket ga (3RS)-1-[2-[2-(4-metyl-l-piperazinyl)etoksy]etyl]-l,3-dihydro-3-(2-indolylkarbo-nylamino) -5-f enyl-2H-l, 4-benzodiazepin-2-on (0,43 g), smp. 100-105°C (spaltning).
IR (Nujol): 3250, 1690, 1635, 1600, 1540 cm"<1>
NMR (CDC13, 5) : 2,15-2,60 (13H, m), 3,35-4,50 (6H, m), 5,80 (1H, d, J=8Hz), 7,0-7,85 (14H, m), 8,15 (1H, d, J=8Hz), 10,10
(1H, bred s)
Massespektrum: m/e = 564 (M1")
EKSEMPEL 25
(1) En blanding av (3RS)-1-(2-ftalimidoetyl)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (1,04 g) og hydrazinhydrat (130 mg) i N,N-dimetylformamid (10 ml) ble oppvarmet ved 70°C under omrøring i 3 timer, ytterligere hydrazinhydrat (130 mg) ble tilsatt. Den resulterende blanding ble oppvarmet ved 80°C i 12,5 timer. Blandingen ble hellet i vann og ekstrahert med etylacetat. Ekstrakten ble vasket med vann og tørret. Oppløsningsmidlet ble fjernet ved avdampning under redusert trykk, hvilket ga en viskøs olje (1,03 g) som ble renset ved kolonnekromatografi på silikagel med en blanding av kloroform og metanol (50:1) som elueringsmiddel. Fraksjonene inneholdende det ønskede produkt ble samlet og inndampet, hvilket ga (3RS)-1-(2-aminoetyl)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (0,76 g) som en amorf olje som ble pulverisert i eter ved omrøring natten over, hvilket ga et krystallinsk pulver (456,2 mg).
IR (Nujol): 3260, 1690, 1660, 1620 cm"<1>
NMR (CDCI3, 6) : 3,3-3,8 (3H, ro), 4,0-4,4 (1H, m), 5,83 (1H, d, J=8Hz), 6,12 (2H, bred t), 7,1-7,9 (14H, m), 8,20 (1H, d, J=8Hz), 9,85 (1H, bred s)
Følgende forbindelse ble fremstilt på lignende måte som beskrevet i eksempel 25(1): (2) (3RS)-1-[2-(2-Aminoetoksy) etyl]-1, 3-dihydro-3-(2-indolyl-karbonylamino) -5-fenyl-2H-l,4-benzodiazepin-2-on, smp.
130-135°C (spaltning)
IR (Nujol): 3250, 1680, 1640, 1600, 1540 cm"<1>
NMR (CDC13, 6) : 2,30-2,80 (2H, m) , 3,0-4,0 (5H, m) , 4,30-4,70 (1H, m), 5,80 (1H, s), 7,0-7,80 (14H, m)
Massespektrum: m/e = 481 (M<*>)
EKSEMPEL 2 6
En blanding av en blanding (0,66 g) av (3R) -1-[2-((2R)-2-tert-butoksykarbonylamino-2-benzhydryloksykarbonyletyltio) etyl] - 1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on og (3S)-1-[2-((2R)-2-tert-butoksykarbonylamino-2-benzhydryloksykarbonyletyltio) etyl ] - 1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on, anisol (0,6 ml), trifluoreddiksyre (1,5 ml) og diklormetan (15 ml) ble omrørt i 3,0 timer ved romtemperatur. Efter fjernelse av oppløsningsmidlet ble residuet blandet med etylacetat (50 ml) og vann (50 ml) . Blandingen ble innstilt til pH 6-7 med en 5% vandig oppløsning av natriumhydrogenkarbonat under omrøring. Den organiske fase ble skilt fra og konsentrert. Det resulterende bunnfall ble oppsamlet ved filtrering, vasket med vann og tørret, hvilket ga en blanding (0,20 g) av (3R)-1-[2-((2R)-2-amino-2-karboksyetyltio)etyl]-1,3-dihydro-3-(2-indolylkarbonylamino) - 5-fenyl-2H-l,4-benzodiazepin-2-on og (3S)-1-[2-((2R)-2-amino-2-karboksyetyltio)etyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on, smp. 190-195°C (spaltning).
NMR (CD3OD + DC1, 6) : 2,60-3,10 (4H, m) , 4,0-4,40 (2H, m) , 4,60-5,0 (1H, m) , 5,96, (1H, s), 6,65-8,15 (14H, m) Massespektrum: m/e = 541 (M<*>)
EKSEMPEL 27
En blanding av (3RS)-1-[N-(etoksykarbonylmetyl)karbamoylmetyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (350 mg), tetrahydrofuran (10 ml) og IN vandig natriumhydroksyd (0,65 ml) ble omrørt i 4,0 timer ved romtemperatur, og defefter ble tilsatt vann (50 ml) og etylacetat (50 ml). Blandingen ble innstilt til pH 1-2 med IN saltsyre under omrøring. Den adskilte organiske fase ble vasket med vann, tørret over magnesiumsulfat og inndampet. Residuet ble krystallisert med tetrahydrofuran, hvilket ga (3RS)-1-[N-(karboksymetyl)karbamoylmetyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (204 mg), smp. 170-175°C (spaltning).
NMR (DMSO-d6, 8) : 3,77 (2H, d, J=5Hz) , 4,65 (2H, s) , 5,73 (1H, d, J=8HZ), 6,90-7,80 (14H, m), 8,50 (1H, tri, J=5Hz), 9,45 (1H, d, J=8Hz), 11,65 (1H, bred s)
EKSEMPEL 28
(1) Til en blanding av (3RS)-1-karboksymetyl-l,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (452 mg), 1-hydroksybenzotriazol (135 mg) og N,N-dimetylformamid (5 ml) ble satt N,N'-dicykloheksylkarbodiimid (206 mg) ved 5°C under omrøring. Blandingen ble omrørt i 1,0 time ved romtemperatur, og glycinamid-hydroklorid (74 mg) og trietylamin (120 mg) ble satt til reaksjonsblandingen ved 5°C. Blandingen ble omrørt i 3,0 timer ved romtemperatur. Bunnfallene ble frafiltrert, og filtratet ble hellet i en blanding av etylacetat og vann. De resulterende bunnfall ble oppsamlet ved filtrering, hvilket ga (3RS)-1-[N-(karbamoylmetyl)karba-moylmetyl ]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-1,4-benzodiazepin-2-on (180 mg).
IR (Nujol): 3270, 1680, 1665, 1630, 1600, 1540 cm"<1>
NMR (DMSO-d6, 5): 3,65 (2H, d, J=5Hz), 4,65 (2H, s), 5,73 (1H, d, J=8HZ), 6,90-7,80 (14H, m), 8,40 (1H, tri, J=5Hz), 9,48 (1H, d, J=8Hz), 11,65 (1H, s)
Massespektrum: m/e = 508 (M1")
Følgende forbindelser ble fremstilt på lignende måte som beskrevet i eksempel 28(1): (2) (3RS)-1-[N-(Etoksykarbonylmety1)karbamoylmetyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (3) En blanding av (3R)-1-[N-((IS)-l-karbamoyl-2-fenyletyl)karbamoylmetyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on og (3S)-1-[N-((IS)-l-karbamoyl-2-fenyletyl)karbamoylmetyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on, smp. 165-170°C (spaltning)
IR (Nujol): 3230, 1680, 1650, 1600, 1525 cm"<1>
NMR (DMSO-d6, 6): 2,65-3,20 (2H, m), 4,30-4,90 (3H, m), 5,67 (1H, d, J=8Hz), 7,0-7,80 (19H, m), 8,25-8,50 (1H, m), 9,37-9,57 (1H, m), 11,65 (1H, bred s)
Massespektrum: m/e = 598 (M<+>)
EKSEMPEL 29
Til en suspensjon av (3RS)-1-karboksymetyl-l,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (1,53
g) i metylenklorid (30 ml) ble satt oksalylklorid (1,29 g) under omrøring og avkjøling i et isbad. Blandingen ble omrørt i 3,5 timer ved romtemperatur. Oppløsningsmidlet og det over-skytende oksalylklorid ble fjernet under redusert trykk, og residuet ble triturert i eter, hvilket ga et syreklorid som et orange pulver som ble oppsamlet ved filtrering, vasket med eter og tørret under redusert trykk. Pulveret (0,5 g) ble satt til en oppløsning av cyanoamin (0,17 g) og trietylamin (0,42 g) i metylenklorid (20 ml) under omrøring ved romtemperatur. Blandingen ble omrørt i 2 timer ved den samme temperatur.
Reaksjonsblandingen ble tilsatt metylenklorid (50 ml), og blandingen ble vasket med fortynnet saltsyre og vann. Efter tørring over magnesiumsulfat ble den organiske fase inndampet under redusert trykk. Residuet ble underkastet kolonnekromato-graf i på silikagel med en blanding av etylacetat, n-heksan og eddiksyre (2:1:0,1) som elueringsmiddel, hvilket ga det ønskede produkt som ble omrørt i eter, hvilket ga (3RS)-1-[N-(cyano) karbamoylmetyl] -1, 3-dihydro-3- (2-indolylkarbonylamino) - 5-fenyl-2H-l,4-benzodiazepin-2-on som et lysorange pulver (0,14 g), smp. 255-260°C (spaltning).
IR (Nujol): 2170, 1680, 1640, 1600, 1540, 1460, 1380, 1305, 745 cm"<1>
NMR (DMSO-d6, 6) : 4,77 (2H, s), 5,75 (1H, d, J=8Hz), 7,0-7,9 (14H, m), 9,52 (1H, d, J=8Hz), 11,50 (1H, bred s)
EKSEMPEL 3 0
Til en oppløsning av (3RS)-1-(3-brompropyl)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (0,52
g) i N,N-dimetylformamid (3 ml) ble satt metanolisk natrium-metantiolat fremstilt fra 30% metanolisk metantiol (0,48 g) og
IM metanolisk natriumhydroksyd (3,0 ml). Blandingen ble omrørt i 6 timer og fikk stå i 37 timer.
Reaksjonsblandingen ble hellet i vann inneholdende flere dråper eddiksyre under omrøring og ekstrahert to ganger med etylacetat, og ekstraktene ble samlet, vasket tre ganger med vann og tørret over magnesiumsulfat. Oppløsningsmidlet ble avdampet til tørrhet, hvilket ga en gul olje (0,59 g) som ble underkastet kolonnekromatografi på silikagel med en blanding av kloroform og etylacetat (20:1) som elueringsmiddel, hvilket ga et glassaktig materiale (330 mg). Dette materiale ble omrørt i diisopropyleter natten over, hvilket ga (3RS)-l-(3-metyltiopropyl)-1,3-dihydro-3-(2-indolylkarbonylamino) -5-fenyl-2H-l,4-benzodiazepin-2-on (248,1 mg) som et hvitt pulver, smp. 216-221°C.
IR (Nujol): 3430, 3260, 1673, 1638, 1600, 1532, 1450, 1375, 1270, 800, 778, 739, 695 cm"<1>
NMR (CDC13, 8) : 1,7-2,0 (2H, m), 1,9 (3H, s), 2,25-2,45 (2H, m), 3,7-4,0 (1H, dt, J=13,8Hz, 6,6Hz), 4,4-4,7 (1H, dt, J=13,8Hz, 6,6Hz), 5,83 (1H, d, J=7,8Hz), 7,1-7,8 (14H, m), 8,17 (1H, d, J=7,8Hz), 10,01 (1H, bred s)
Massespektrum: m/e = 482 (M<1>")
EKSEMPEL 31
(1) En blanding av (3RS)-1-(2-brometyl)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (501 mg), trietylamin (0,12 g), 4-merkaptopyridin (0,133 g) og N,N-dimetylformamid (6 ml) ble omrørt natten over ved romtemperatur. Reaksjonsblandingen ble hellet i en blanding av vann og etylacetat. Den organiske fase ble skilt fra, vasket tre ganger med vann, tørret over magnesiumsulfat og inndampet. Residuet ble kromatografert på silikagel med etylacetat som elueringsmiddel, hvilket ga (3RS)-1-[2-(4-pyridyltio)etyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l, 4-benzodiazepin-2-on (0,19 g), smp. 150-155°C (spaltning).
IR (Nujol): 3230, 1680, 1630, 1600, 1570, 1530 cm"<1>
NMR (CDCI3, 8) : 3,0-3,30 (2H, m), 3,70-4,10 (1H, m), 4,40-4,80 (1H, m), 5,80 (1H, d, J=8Hz), 7,0-7,80 (16H, m), 8,10 (1H, d, J=8Hz), 8,25-8,45 (2H, m), 10,05 (1H, bred s)
Massespektrum: m/e = 531 (M<+>)
Følgende forbindelse ble fremstilt på lignende måte som beskrevet i eksempel 31(1): (2) En blanding av (3R)-l-[2-((2R)-2-tert-butoksykarbonylamino-2-benzhydryloksykarbonyletyltio)etyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on og (3S)-1-[2-((2R)-2-tert-butoksykarbonylamino-2-benzhydryloksykarbonyletyltio)etyl]-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on
NMR (CDC13, 6): 1,40 (9H, s), 2,20-3,10 (4H, m), 3,50-4,0 (1H, m), 4,20-4,70 (2H, m), 5,15-5,45 (1H, m), 5,80 (1H, d, J=8Hz), 6,90 (1H, s), 7,10-7,85 (24H, m), 8,15 (1H, d, J=8Hz), 9,75
(1H, bred s)
EKSEMPEL 32
Til en oppløsning av (3RS)-1-(2-aminoetyl)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (434 mg) og trietylamin (222 mg) i metylenklorid (4 ml) ble det dråpevis satt acetylklorid (172,8 mg) under avkjøling i et isbad og omrøring. Blandingen ble omrørt i 4 timer under de samme betingelser. Efter at oppløsningsmidlet var fjernet ved avdampning under redusert trykk, ble vann satt til residuet. Blandingen ble ekstrahert med etylacetat. Ekstrakten ble vasket med en vandig natriumhydrogenkarbonatoppløsning og vann og derefter tørret over magnesiumsulfat. Oppløsningsmidlet ble fjernet ved avdampning, hvilket ga en brun olje (672,2 mg) som ble kromatografert på silikagel med en blanding av kloroform og metanol (30:1) som elueringsmiddel. Fraksjonene inneholdende det ønskede produkt ble samlet og inndampet, hvilket ga et amorft produkt som ble pulverisert i eter ved omrøring natten over. Det krystallinske pulver ble oppsamlet ved filtrering og vasket med eter, hvilket ga (3RS)-l-(2-acetylaminoetyl)-1,3-dihydro-3-(2-indolylkarbonylamino)-5-fenyl-2H-l,4-benzodiazepin-2-on (327,1 mg), smp. 167-175°C (spaltning).
IR (Nujol): 3250, 1690, 1672, 1635 cm"<1>
NMR (DMSO-d6, 6) : 2,25 (3H, s), 3,6-4,4 (4H, m), 5,59 (1H, d, J=8Hz), 6,9-7,9 (14H, m), 9,48 (1H, d, J=8Hz), 11,48 (1H, bred s)
Massespektrum: m/e = 479 (M<1>")
FREMSTILLING 10
Til en suspensjon av (3RS)-1,3-dihydro-5-(2-fluorfenyl)-3-ftalimido-2H-l,4-benzodiazepin-2-on (1,0 g) og l-trityl-4-klormetylimidazolhydroklorid (1,28 g) i N,N-dimetylformamid (25 ml) ble det gradvis satt natriumhydrid (40% suspensjon i mineralolje, 0,3 6 g) under omrøring og avkjøling i et isbad, og blandingen ble omrørt ved den samme temperatur i 1 time og derefter ved omgivelsestemperatur i 17 timer. Efter tilsetning av eddiksyre (0,5 ml) ble reaksjonsblandingen hellet i vann (100 ml). Blandingen ble innstilt til pH 7 med vandig natriumhydrogenkarbonat under omrøring. De resulterende bunnfall ble oppsamlet ved filtrering, vasket med vann og tørret under redusert trykk og oppvarmning, hvilket ga et gult pulver (2,22 g). Pulveret ble renset ved kolonnekromatografi på silikagel med en blanding av kloroform og etylacetat (20:1) som elueringsmiddel, hvilket ga (3RS)-1,3-dihydro-5-(2-fluorfenyl)-3-ftalimido-1-(l-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on (1,38 g).
NMR (DMS0-d6, <5) : 5,08 (2H, ABq) , 5,75 (1H, s) , 6,7-7,7 (29H, m)
FREMSTILLING 11
Til en suspensjon av (3RS)-1,3-dihydro-5-(2-fluorfenyl)-3-ftalimido-1-(l-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on (19,96 g) i tetrahydrofuran (200 ml) ble satt en oppløsning av hydrazinhydrat (1,38 g) i metanol (10 ml). Blandingen ble omrørt ved omgivelsestemperatur i 0,5 time, og derefter ble den resulterende klare oppløsning tilbakeløpskjølt i 2 timer under omrøring. Reaksjonsblandingen ble avkjølt i et isbad, og bunnfallene ble frafiltrert. Filtratet og vaskefaser ble inndampet under redusert trykk. Residuet ble oppløst i kloroform, og blandingen ble filtrert. Filtratet ble inndampet, hvilket ga en olje (19,3 0 g), som ble kromatografert på silikagel med en blanding av kloroform og metanol (30:1) som elueringsmiddel, hvilket ga (3RS)-1,3-dihydro-5-(2-fluorfenyl)-3-amino-l-(l-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on (9,97 g).
NMR (CDC13, 8) : 2,42 (2H, bred s), 4,49 (1H, s), 5,06 (2H, s), 6,8-8,0 (25H, m)
FREMSTILLING 12
(1) Til en oppløsning av (3RS)-1,3-dihydro-5-(2-fluorfenyl)-3-amino-1-(l-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on (591,7 mg) i etylacetat (2 ml) ble satt en oppløsning av (S)-(+)-mandelsyre (129,3 mg) i etylacetat (4 ml) under omrøring ved omgivelsestemperatur. Den utfelite gel ble oppløst ved tilsetning av metanol (0,2 ml). Til den klare oppløsning ble det satt etylacetat (4 ml) og diisopropyleter (3 dråper). Blandingen ble omrørt i 2 timer og fikk stå natten over. De resulterende bunnfall ble oppsamlet ved filtrering, vasket med etylacetat og diisopropyleter og tørret, hvilket ga et hvitt pulver (202,2 mg) som ble omkrystallisert fra etylacetat, hvilket ga (S)-(+)-mandelsyresalt av (3S)-1,3-dihydro-5-(2-fluorfenyl)-3-amino-l-(l-trityl-4-imidazolyl)metyl-2H-l,4-
benzodiazepin-2-on som krystaller,
[a]V = -33,33" (C=0,846, CH3OH)
Dessuten ble en blanding av (3R)-1,3-dihydro-5-(2-fluorfenyl)-3-amino-l-(l-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on og (3S)-l,3-dihydro-5-(2-fluorfenyl)-3-amino-l-(l-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on oppnådd fra
filtratet.
(2) (S)-(+)-Mandelsyresalt av (3S)-1,3-dihydro-5-(2-fluorfenyl)-3-amino-l-(l-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on som var oppnådd som beskrevet i fremstilling 12(1), ble suspendert i en blanding av vann og etylacetat. Den resulterende blanding ble innstilt til pH 7-8 med en vandig oppløsning av natriumhydrogenkarbonat under omrøring. Den organiske fase ble skilt fra, vasket med vann og inndampet til tørrhet, hvilket ga (3S)-1,3-dihydro-5-(2-fluorfenyl)-3-amino-l-(l-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on (181,4 mg).
[a]V = -35,34° (C=0,846, CH3OH)
FREMSTILLING 13
(1) En blanding ([a]D = +14,4°) (1,57 g) av (3R)-1,3-dihydro-5-(2-fluorfenyl)-3-amino-l-(l-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on og (3S)-1,3-dihydro-5-(2-fluorfenyl)-3-amino-1-(l-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on som var oppnådd som beskrevet i fremstilling 12(1), ble oppløst i en blanding av etylacetat (5,3 ml) og metanol (0,5 ml). Til oppløsningen ble det satt en oppløsning av (R)-(-)-mandelsyre (342,7 mg) i etylacetat (20 ml) under omrøring ved omgivelsestemperatur. Til blandingen ble satt diisopropyleter (0,5 ml), og den resulterende blanding ble omrørt i 2 timer og fikk stå natten over. Bunnfallene ble oppsamlet ved filtrering, vasket med etylacetat og diisopropyleter og tørret, hvilket ga (R)-(-)-mandelsyresalt av (3R)-1,3-dihydro-5-(2-fluorfenyl)-3-amino-1-(l-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on (hvitt pulver, 685,6 mg).
[a]<2>D<*>~ +33,60° (C=0,848, CH30H)
(2) (3R)-1,3-Dihydro-5-(2-fluorfenyl)-3-amino-l-(l-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on ble fremstilt ved behandling av (R)-(-)-mandelsyresalt av (3R)-1,3-dihydro-5-(2-fluorfenyl)-3-amino-l-(l-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on på lignende måte som beskrevet i fremstilling 12(2).
[a]2D2 = <+>37,91° (C=0,844, CH30H)
EKSEMPEL 3 3
Følgende forbindelser ble fremstilt på lignende måte som beskrevet i eksempel 6(1): (1) (3S)-1,3-Dihydro-1-(l-trityl-4-imidazolyl)metyl-3-(2-indolylkarbonylamino)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on
NMR (CDC13, 6) 1 5,085 (2H, ABq), 5,76 (1H, d, J=7,9Hz), 6,8-8,0 (30H, m), 8,10 (1H, d, J=7,9Hz), 9,81 (1H, s)
(2) (3R)-1,3-Dihydro-l-(l-trityl-4-imidazolyl)metyl-3-(2-indolylkarbonylamino)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on
NMR (DMSO-d6, <5) : 5,11 (2H, ABq), 5,64 (1H, d, J=8,0Hz), 6,7-8,0 (30H, m), 9,55 (1H, d, J=8,0Hz), 11,66 (1H, s) (3) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(4-imidazolylmetyl)-5-fenyl-2H-l,4-benzodiazepin-2-on IR (Nujol): 3250, 1680, 1635, 1600, 1530 cm"<1 >(4) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino) -1-(4-imidazolylmetyl)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on NMR (CDC13, 8) : 4,85, 5,10 (2H, ABq, J=15Hz), 5,80 (1H, d, J=8Hz), 6,80-7,83 (15H, m), 8,10 (1H, d, J=8Hz), 10,10 (1H, bred s)
(5) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-l-[(5-metyl-imidazol-4-yl)metyl]-5-fenyl-2H-l,4-benzodiazepin-2-on
NMR (DMSC~d6, 8) : 1,96 (3H, s), 4,80, 5,15 (2H, ABq, J=15Hz), 5,55 (1H, d, J=8Hz), 6,90-8,15 (15H, m), 9,33 (1H, d, J=8Hz), 11,58 (2H, bred s)
(6) (3S)-l,3-Dihydro-l-(4-imidazolylmetyl)-3-(2-indolylkarbonylamino)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on
NMR (DMSC~d6, 8) : 5,04 (2H, ABq), 5,63 (1H, d, J=7,9Hz), 6,9-8.2 (15H, m), 9,58 (1H, d, J=7,9Hz), 11,65 (1H, s), 11,92 (1H, s)
(7) (3R)-1,3-Dihydro-l-(4-imidazolylmetyl)-3-(2-indolylkarbonylamino)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on
NMR (DMSO-d6, 8) : 5,04 (2H, ABq), 5,62 (1H, d, J=7,9Hz), 6,9-8.3 (15H, m), 9,58 (1H, d, J=7,9Hz), 11,66 (1H, s), 11,93 (1H, s)
(8) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(2-imidazolylmetyl)-5-fenyl-2H-l,4-benzodiazepin-2-on
NMR (DMSO-d6, 6) : 5,10 (2H, s), 5,65 (1H, d, J=8Hz), 6,60-8,10 (16H, m) , 9,36 (1H, d, J=8Hz), 11,65 (1H, bred s), 11,90 (1H, bred s)
(9) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(3-pyrazolylmetyl)-5-fenyl-2H-l,4-benzodiazepin-2-on
NMR (DMS0-d6, 6): 5,03, 5,30 (2H, ABq, J=15Hz), 5,65 (1H, d, J=8Hz), 5,85 (1H, bred s), 6,90-7,90 (15H, m), 9,43 (1H, d, J=8Hz), 11,60 (1H, bred s), 12,55 (1H, bred s)
(10) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-[(1,2 , 4-triazol-3-yl)metyl]-5-fenyl-2H-l,4-benzodiazepin-2-on
NMR (DMSO-d6, 6) : 5,10, 5,35 (2H, ABq, J=15Hz), 5,66 (1H, d, J=8Hz), 6,90-7,93 (15H, m), 8,23 (1H, bred s), 9,40 (1H, d, J=8Hz), 11,65 (1H, bred s)
(11) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-l-[2-(4-imidazolyl)etyl]-5-fenyl-2H-l,4-benzodiazepin-2-on
NMR (DMS0-d6, S): 2,63 (2H, t, J=7Hz), 3,85-4,20 (1H, m), 4,20-4,75 (1H, m), 5,55 (1H, d, J=8Hz), 6,60 (1H, s), 6,93-7,85 (15H, m), 9,43 (1H, d, J=8Hz), 11,65 (1H, bred s)
(12) (3S)-1,3-Dihydro-l-(4-imidazolylmetyl)-3-(2-indolylkarbonylamino)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on-hydroklorid
NMR (DMSO-d6, 6) : 5,33 (2H, ABq), 5,69 (1H, d, J=7,6Hz), 7,0-8,0 (15H, m), 9,05 (1H, s), 9,60 (1H, d, J=7,6Hz), 11,74 (1H, s), 14,73 (1H, bred s)
EKSEMPEL 34
En blanding av (3S)-1,3-dihydro-5-(2-fluorfenyl)-3-amino-l-(1-trityl-4-imidazolyl)metyl-2H-l,4-benzodiazepin-2-on (0,79 g), indol-2-karboksylsyre (0,22 g), N-hydroksybenzotriazol (0,18
g) og N,N'-dicykloheksylkarbodiimid (0,28 g) i N,N-dimetylformamid (8 ml) ble omrørt ved omgivelsestemperatur
natten over og filtrert. Filtratet og vaskefaser ble fortynnet med etylacetat. Blandingen ble vasket med en vandig oppløsning av natriumhydrogenkarbonat. Den adskilte organiske fase ble vasket med vann og tørret over magnesiumsulfat. Oppløsnings-midlet ble fjernet under redusert trykk, hvilket ga en viskøs olje (1,12 g), som ble kromatografert på silikagel med en blanding av kloroform og metanol (30:1) som elueringsmiddel, hvilket ga (3S)-1,3-dihydro-l-(l-trityl-4-imidazolyl)metyl-3-(2-indolylkarbonylamino)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on (amorft stoff, 0,97 g).
[<*]<2>D<3> ~ "32,47° (C=0,85, CH3OH)
NMR (CDC13, 8) : 5,085 (2H, ABq), 5,76 (1H, d, J=7,9Hz), 6,8-8,0 (30H, m), 8,10 (1H, d, J=7,9Hz), 9,81 (1H, s)
EKSEMPEL 35
Til en oppløsning av (3R)-1,3-dihydro-l-(l-trityl-4-imidazolyl)metyl-3-amino-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on (0,81 g), indol-2-karboksylsyre (0,23 g), N-hydroksybenzotriazol (0,19 g) i N,N-dimetylformamid (8 ml) ble satt l-etyl-3-(3-dimetylaminopropyl)karbodiimid-hydroklorid (0,27 g) og trietylamin (0,14 g) under omrøring ved omgivelsestemperatur. Blandingen ble omrørt i 4 timer ved omgivelsestemperatur. Reaksjonsblandingen ble tilsatt etylacetat og vann under omrøring. Blandingen ble innstilt til pH 8 med vandig natriumhydrogenkarbonat. Den organiske fase ble skilt fra, og den vandige fase ble ekstrahert med etylacetat. Den adskilte organiske fase og ekstrakten ble samlet, vasket to ganger med vann og tørret over magnesiumsulfat. Oppløsningsmidlet ble fjernet under redusert trykk, hvilket ga (3R) -1,3-dihydro-l-(l-trityl-4-imidazolyl)metyl-3-(2-indolylkarbonylamino) -5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on (1,0 g).
[o]2D2 = +41,58° (C=0,856, CH3OH)
NMR (DMSO-d6, 6) : 5,11 (2H, ABq), 5,64 (1H, d, J=8,0Hz), 6,7-8,0 (30H, m), 9,55 (1H, d, J=8,0Hz), 11,66 (1H, s)
EKSEMPEL 3 6
Til en oppløsning av (3S)-1,3-dihydro-l-(l-trityl-4-imidazolyl)metyl-3- (2-indolylkarbonylamino) -5- (2-f luorfenyl) - 2H-l,4-benzodiazepin-2-on (1,0 g) i N,N-dimetylformamid (10 ml) ble satt 6N saltsyre (7 ml) under omrøring og avkjøling i et isbad. Blandingen ble oppvarmet til 50°C og omrørt i 2 timer. Efter avkjøling til romtemperatur ble det til reaksjonsblandingen satt vann og etylacetat under omrøring. Blandingen ble innstilt til pH 8 med en vandig oppløsning av natriumhydrogenkarbonat. Den adskilte organiske fase ble vasket med vann og tørret. Fjernelse av oppløsningsmidlet ga en viskøs olje (1,20 g) , som ble kromatografert på silikagel med en blanding av kloroform og metanol (20:1) som elueringsmiddel, hvilket ga (3S)-1,3-dihydro-l-(4-imidazolylmetyl) -3- (2-indolylkarbonylamino) -5- (2-f luorfenyl) - 2H-1,4-benzodiazepin-2-on (601,5 mg) som et gult krystallinsk pulver.
[a]<2>D° = +24,68° (C=0,64, CHC13)
NMR (DMSO-d6, 5) : 5,04 (2H, ABq), 5,63 (1H, d, J=7,9Hz), 6,9-8,2 (15H, m), 9,58 (1H, d, J=7,9Hz), 11,65 (1H, s), 11,92 (1H, s)
EKSEMPEL 37
Følgende forbindelse ble fremstilt på lignende måte som beskrevet i eksempel 36: (3R)-1,3-Dihydro-l-(4-imidazolylmetyl)-3-(2-indolylkarbonyl-amino) -5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on
[o]<2>D<5><=><->26,40" (C=0,64, CHC13)
NMR (DMSO-d6, 6"): 5,04 (2H, ABq), 5,62 (1H, d, J=7,9Hz), 6,9-8,3 (15H, m), 9,58 (1H, d, J=7,9Hz), 11,66 (1H, s) , 11,93 (1H, s)
EKSEMPEL 38
Til en oppløsning av (3S)-1,3-dihydro-l-(4-imidazolylmetyl)-3-(2-indolylkarbonylamino)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on (215,1 mg) i metanol (5 ml) ble satt en 6N hydrogenkloridoppløsning i eter (0,1 ml) under avkjøling. Den klare gule oppløsning ble inndampet til tørrhet under redusert trykk. Residuet ble triturert i eter, hvilket ga et gult pulver, som ble oppsamlet ved filtrering og vasket to ganger med eter, hvilket ga (3S)-1,3-dihydro-l-(4-imidazolylmetyl)-3-(2-indolylkarbonylamino)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on-hydroklorid (197,1 mg), smp. 214-218°C (spaltning).
[a]V = -35,94° (C=0,612, CH30H)
NMR (DMS0-d6, 5): 5,33 (2H, ABq), 5,69 (1H, d, J=7,6Hz), 7,0-8,0 (15H, m), 9,05 (1H, s), 9,60 (1H, d, J=7,6Hz), 11,74 (1H, s), 14,73 (1H, bred s)
EKSEMPEL 39
Til en oppløsning av (3S)-1,3-dihydro-l-(4-imidazolylmetyl)-3-(2-indolylkarbonylamino)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on (246 mg) i metanol (10 ml) ble satt L-(+)-vinsyre (75,0 mg) ved romtemperatur. Efter omrøring i flere minutter ble blandingen konsentrert til 2 ml. Det resulterende lysegule pulver ble oppsamlet ved filtrering, vasket to ganger med diisopropyleter og tørret, hvilket ga (3S)-1,3-dihydro-l-(4-imidazolylmetyl)-3-(2-indolylkarbonylamino)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on-L-(+)-tartrat (235,3 mg), smp. 170-175°C (spaltning).
NMR (DMSO-d6, 6) : 4,31 (2H, s) , 5,07 (2H, s) , 5,63 (1H, d, J=7,7Hz), 6,9-8,1 (15H, m), 9,58 (1H, d, J=7,7Hz), 11,65 (1H, s)
EKSEMPEL 4 0
Følgende forbindelse ble fremstilt ved omsetning av (3S)-1,3-dihydro-1-(4-imidazolylmetyl)-3-(2-indolylkarbonylamino)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on med metansulfonsyre på lignende måte som beskrevet i eksempel 38 og 39: (3S)-1,3-Dihydro-l-(4-imidazolylmetyl)-3-(2-indolylkarbonyl-amino) -5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on-metansulfonat, smp. 136-139°C (spaltning)
[a]V = -31,32° (C=0,632, CH3OH)
NMR (DMSO-d6, 6) : 2,39 (3H), 5,33 (2H, ABq) , 5,69 (1H, d, J=7,7Hz), 7,0-7,8 (15H, m), 8,99 (1H, s), 9,58 (1H, d, J=7,7Hz), 11,68 (1H, s), 14,26 (1H, bred)
EKSEMPEL 41
Følgende forbindelser ble fremstilt på lignende måte som beskrevet i eksempel 4(1): (1) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-l-(4-imidazolylmetyl)-5-fenyl-2H-l,4-benzodiazepin-2-on IR (Nujol): 3250, 1680, 1635, 1600, 1530 cm"<1>
(2) (3RS) -1, 3-Dihydro-3-(2-indolylkarbonylamino)-l-(4-imidazolylmetyl)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on
NMR (CDC13, 6) : 4,85, 5,10 (2H, ABq, J=15Hz), 5,80 (1H, d, J=8Hz), 6,80-7,83 (15H, m), 8,10 (1H, d, J=8Hz), 10,10 (1H, bred s)
(3) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-l-[(5-metyl-imidazol-4-yl)metyl]-5-fenyl-2H-l,4-benzodiazepin-2-on
NMR (DMSO-d6, 6) : 1,96 (3H, s), 4,80, 5,15 (2H, ABq, J=15Hz), 5,55 (1H, d, J=8Hz), 6,90-8,15 (15H, m), 9,33 (1H, d, J=8Hz), 11,58 (2H, bred s)
(4) (3 S)-1,3-Dihydro-1-(4-imidaz olylmety1)-3-(2-indolylkarbonylamino)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on
NMR (DMSO-d6, 5): 5,04 (2H, ABq), 5,63 (1H, d, J=7,9Hz), 6,9-8.2 (15H, m), 9,58 (1H, d, J=7,9Hz), 11,65 (1H, s), 11,92 (1H, s)
(5) (3R)-1,3-Dihydro-l-(4-imidazolylmetyl)-3-(2-indolylkarbonylamino)-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on
NMR (DMSO-d6, <S) : 5,04 (2H, ABq), 5,62 (1H, d, J=7,9Hz), 6,9-8.3 (15H, m), 9,58 (1H, d, J=7,9Hz), 11,66 (1H, s), 11,93 (1H, s)
(6) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(2-imidazolylmetyl)-5-fenyl-2H-l,4-benzodiazepin-2-on
NMR (DMSO-d6, <S) : 5,10 (2H, s), 5,65 (1H, d, J=8Hz), 6,60-8,10 (16H, m), 9,36 (1H, d, J=8Hz), 11,65 (1H, bred s), 11,90 (1H, bred s)
(7) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-1-(3-pyrazolylmetyl)-5-fenyl-2H-l,4-benzodiazepin-2-on
NMR (DMSO-d6, <S) : 5,03, 5,30 (2H, ABq, J=15Hz), 5,65 (1H, d, J=8Hz), 5,85 (1H, bred s), 6,90-7,90 (15H, m), 9,43 (1H, d, J=8Hz), 11,60 (1H, bred s), 12,55 (1H, bred s)
(8) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-l-[(1,2,4-triazol-3-yl)metyl]-5-fenyl-2H-l,4-benzodiazepin-2-on
NMR (DMS0-d6, 5): 5,10, 5,35 (2H, ABq, J=15Hz), 5,66 (1H, d, J=8Hz), 6,90-7,93 (15H, m), 8,23 (1H, bred s), 9,40 (1H, d, J=8Hz), 11,65 (1H, bred s)
(9) (3RS)-1,3-Dihydro-3-(2-indolylkarbonylamino)-l-[2-(4-imidazolyl)etyl]-5-fenyl-2H-l,4-benzodiazepin-2-on
NMR (DMSO-d6, <S) : 2,63 (2H, t, J=7Hz), 3,85-4,20 (1H, m), 4,20-4,75 (1H, m), 5,55 (1H, d, J=8Hz), 6,60 (1H, s), 6,93-7,85 (15H, m), 9,43 (1H, d, J=8Hz), 11,65 (1H, bred s)
(10) (3S)-1,3-Dihydro-l-(4-imidazolylmetyl)-3-(2-indolylkarbonylamino)-5- (2-fluorfenyl)-2H-1,4-benzodiazepin-2-on-hydroklorid
NMR (DMSO-d6, 6) : 5,33 (2H, ABq), 5,69 (1H, d, J=7,6Hz), 7,0-8,0 (15H, m), 9,05 (1H, s), 9,60 (1H, d, J=7,6Hz), 11,74 (1H, s), 14,73 (1H, bred s)
Claims (1)
- Analogifremgangsmåte for fremstilling av en terapeutiskaktiv forbindelse med den generelle formel (I)hvorR<1> tetrazolyl eller -0H,R<2> er fenyl, som kan bære én eller flere halogen-substituenter,R<3> er hydrogen eller halogen,RA er hydrogen, halogen eller lavere alkoksy, og A er lavere alkylen,eller et farmasøytisk akseptabelt salt derav, karakterisert ved at (1) en forbindelse med den generelle formel (II)hvor R<2>, R3 og RA hver har den ovenfor angitte betydning, eller et salt derav, omsettes med en forbindelse med den generelle formel (III)hvor R<1> og A hver har den ovenfor angitte betydning, og X er halogen, eller et salt derav, for å danne en forbindelse med den generelle formel (I) hvor R<1>, R<2>, R<3>, R* og A hver har den ovenfor angitte betydning, eller et salt derav, eller (2) en forbindelse med den generelle formel (IV) hvor R<1>, R<2>, R3 og A hver har den ovenfor angitte betydning, eller et reaktivt derivat derav ved aminogruppen eller et salt derav, omsettes med en forbindelse med den generelle formel (V) hvor RA har den ovenfor angitte betydning, eller et reaktivt derivat derav ved karboksygruppen eller et salt derav, for å danne en forbindelse med den generelle formel (I) hvor R1, R<2>, R3, RA og A hver har den ovenfor angitte betydning, eller et salt derav,og eventuelt omdannes en oppnådd forbindelse med formel (I) eller et salt derav til et farmasøytisk akseptabelt salt derav.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB888816207A GB8816207D0 (en) | 1988-07-07 | 1988-07-07 | Benzodiazepine derivatives |
GB888820560A GB8820560D0 (en) | 1988-08-31 | 1988-08-31 | Benzodiazepine derivatives |
GB888823660A GB8823660D0 (en) | 1988-10-07 | 1988-10-07 | Benzodiazepine derivatives |
Publications (4)
Publication Number | Publication Date |
---|---|
NO892799D0 NO892799D0 (no) | 1989-07-06 |
NO892799L NO892799L (no) | 1990-01-08 |
NO173014B true NO173014B (no) | 1993-07-05 |
NO173014C NO173014C (no) | 1993-10-13 |
Family
ID=27263983
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO892799A NO173014C (no) | 1988-07-07 | 1989-07-06 | Analogifremgangsmaate for fremstilling av terapeutisk aktive benzodiazepinderivater |
Country Status (17)
Country | Link |
---|---|
US (1) | US4970207A (no) |
EP (1) | EP0349949B1 (no) |
JP (2) | JP2536160B2 (no) |
KR (1) | KR900001688A (no) |
CN (1) | CN1041941A (no) |
AT (1) | ATE147403T1 (no) |
AU (1) | AU3785989A (no) |
CA (1) | CA1334589C (no) |
DE (1) | DE68927620T2 (no) |
DK (1) | DK336589A (no) |
ES (1) | ES2095833T3 (no) |
FI (1) | FI95699C (no) |
GR (1) | GR3022239T3 (no) |
HU (1) | HUT50331A (no) |
IL (1) | IL90830A (no) |
NO (1) | NO173014C (no) |
PT (1) | PT91092B (no) |
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-
1989
- 1989-06-29 US US07/373,171 patent/US4970207A/en not_active Expired - Lifetime
- 1989-06-30 IL IL9083089A patent/IL90830A/en not_active IP Right Cessation
- 1989-07-01 ES ES89112084T patent/ES2095833T3/es not_active Expired - Lifetime
- 1989-07-01 DE DE68927620T patent/DE68927620T2/de not_active Expired - Fee Related
- 1989-07-01 AT AT89112084T patent/ATE147403T1/de not_active IP Right Cessation
- 1989-07-01 EP EP89112084A patent/EP0349949B1/en not_active Expired - Lifetime
- 1989-07-03 FI FI893226A patent/FI95699C/fi not_active IP Right Cessation
- 1989-07-05 JP JP1176636A patent/JP2536160B2/ja not_active Expired - Lifetime
- 1989-07-05 AU AU37859/89A patent/AU3785989A/en not_active Abandoned
- 1989-07-06 HU HU893435A patent/HUT50331A/hu unknown
- 1989-07-06 CN CN89104788A patent/CN1041941A/zh active Pending
- 1989-07-06 NO NO892799A patent/NO173014C/no unknown
- 1989-07-06 DK DK336589A patent/DK336589A/da not_active Application Discontinuation
- 1989-07-06 KR KR1019890009654A patent/KR900001688A/ko not_active Application Discontinuation
- 1989-07-06 CA CA000604941A patent/CA1334589C/en not_active Expired - Fee Related
- 1989-07-07 PT PT91092A patent/PT91092B/pt not_active IP Right Cessation
-
1994
- 1994-03-08 JP JP6037275A patent/JPH07224060A/ja active Pending
-
1997
- 1997-01-09 GR GR960403582T patent/GR3022239T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
JPH0256481A (ja) | 1990-02-26 |
FI893226A (fi) | 1990-01-08 |
CA1334589C (en) | 1995-02-28 |
IL90830A (en) | 1995-06-29 |
NO892799L (no) | 1990-01-08 |
EP0349949B1 (en) | 1997-01-08 |
DK336589A (da) | 1990-01-08 |
NO173014C (no) | 1993-10-13 |
PT91092B (pt) | 1995-05-04 |
EP0349949A3 (en) | 1991-09-04 |
AU3785989A (en) | 1990-01-11 |
HUT50331A (en) | 1990-01-29 |
ATE147403T1 (de) | 1997-01-15 |
DK336589D0 (da) | 1989-07-06 |
FI893226A0 (fi) | 1989-07-03 |
FI95699B (fi) | 1995-11-30 |
US4970207A (en) | 1990-11-13 |
DE68927620T2 (de) | 1997-04-24 |
GR3022239T3 (en) | 1997-04-30 |
JPH07224060A (ja) | 1995-08-22 |
DE68927620D1 (de) | 1997-02-20 |
CN1041941A (zh) | 1990-05-09 |
EP0349949A2 (en) | 1990-01-10 |
FI95699C (fi) | 1996-03-11 |
KR900001688A (ko) | 1990-02-27 |
JP2536160B2 (ja) | 1996-09-18 |
IL90830A0 (en) | 1990-01-18 |
ES2095833T3 (es) | 1997-03-01 |
NO892799D0 (no) | 1989-07-06 |
PT91092A (pt) | 1990-02-08 |
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