JPH0533947B2 - - Google Patents
Info
- Publication number
- JPH0533947B2 JPH0533947B2 JP61113280A JP11328086A JPH0533947B2 JP H0533947 B2 JPH0533947 B2 JP H0533947B2 JP 61113280 A JP61113280 A JP 61113280A JP 11328086 A JP11328086 A JP 11328086A JP H0533947 B2 JPH0533947 B2 JP H0533947B2
- Authority
- JP
- Japan
- Prior art keywords
- isatin
- nmr
- diisopropylaminoethyl
- elemental analysis
- cdcl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical class C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- 150000001875 compounds Chemical class 0.000 description 42
- 238000000921 elemental analysis Methods 0.000 description 31
- 229910052739 hydrogen Inorganic materials 0.000 description 31
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- 238000002844 melting Methods 0.000 description 27
- 230000008018 melting Effects 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 19
- 239000002904 solvent Substances 0.000 description 18
- -1 2-(N-isopropylcyclohexylamino) Ethyl chloride hydrochloride N-isopropylcyclohexylamine Chemical compound 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 208000000718 duodenal ulcer Diseases 0.000 description 14
- 239000012156 elution solvent Substances 0.000 description 14
- 239000003814 drug Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 208000007107 Stomach Ulcer Diseases 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- IUSXYVRFJVAVOB-UHFFFAOYSA-N n-(2-chloroethyl)-n-propan-2-ylpropan-2-amine;hydron;chloride Chemical compound Cl.CC(C)N(C(C)C)CCCl IUSXYVRFJVAVOB-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 230000002496 gastric effect Effects 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 229940124597 therapeutic agent Drugs 0.000 description 8
- 208000025865 Ulcer Diseases 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- OWFDMTIOBATGBR-UHFFFAOYSA-N n-butyl-n-(2-chloroethyl)butan-1-amine;hydron;chloride Chemical compound Cl.CCCCN(CCCl)CCCC OWFDMTIOBATGBR-UHFFFAOYSA-N 0.000 description 7
- 231100000397 ulcer Toxicity 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 208000008469 Peptic Ulcer Diseases 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- VAJCSPZKMVQIAP-UHFFFAOYSA-N 5-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=C2NC(=O)C(=O)C2=C1 VAJCSPZKMVQIAP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- IOIOGEXCQPEOSV-UHFFFAOYSA-N 1-[2-[di(propan-2-yl)amino]ethyl]indole-2,3-dione Chemical compound C1=CC=C2N(CCN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 IOIOGEXCQPEOSV-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000767 anti-ulcer Effects 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- NJWWRCCRZLWGTQ-UHFFFAOYSA-N 1-[2-[di(propan-2-yl)amino]ethyl]-5-fluoroindole-2,3-dione Chemical compound FC1=CC=C2N(CCN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 NJWWRCCRZLWGTQ-UHFFFAOYSA-N 0.000 description 2
- OBRQJOPYHRMHAX-UHFFFAOYSA-N 1-[2-[di(propan-2-yl)amino]propyl]indole-2,3-dione Chemical compound C1=CC=C2N(CC(C)N(C(C)C)C(C)C)C(=O)C(=O)C2=C1 OBRQJOPYHRMHAX-UHFFFAOYSA-N 0.000 description 2
- VJQULJPYVAJZKN-UHFFFAOYSA-N 3-chloro-n,n-di(propan-2-yl)propan-1-amine;hydrochloride Chemical compound Cl.CC(C)N(C(C)C)CCCCl VJQULJPYVAJZKN-UHFFFAOYSA-N 0.000 description 2
- MBVCESWADCIXJN-UHFFFAOYSA-N 5-Bromoisatin Chemical compound BrC1=CC=C2NC(=O)C(=O)C2=C1 MBVCESWADCIXJN-UHFFFAOYSA-N 0.000 description 2
- XHDJYQWGFIBCEP-UHFFFAOYSA-N 5-Chloro-1H-indole-2,3-dione Chemical compound ClC1=CC=C2NC(=O)C(=O)C2=C1 XHDJYQWGFIBCEP-UHFFFAOYSA-N 0.000 description 2
- GKODDAXOSGGARJ-UHFFFAOYSA-N 5-Fluoroisatin Chemical compound FC1=CC=C2NC(=O)C(=O)C2=C1 GKODDAXOSGGARJ-UHFFFAOYSA-N 0.000 description 2
- DMHGXMPXHPOXBF-UHFFFAOYSA-N 5-Methoxyisatin Chemical compound COC1=CC=C2NC(=O)C(=O)C2=C1 DMHGXMPXHPOXBF-UHFFFAOYSA-N 0.000 description 2
- NPDJRIGMWAQKTQ-UHFFFAOYSA-N 7-bromo-5-methyl-1h-indole-2,3-dione Chemical compound BrC1=CC(C)=CC2=C1NC(=O)C2=O NPDJRIGMWAQKTQ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 206010042220 Stress ulcer Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940069428 antacid Drugs 0.000 description 2
- 239000003159 antacid agent Substances 0.000 description 2
- 230000002467 anti-pepsin effect Effects 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 230000000949 anxiolytic effect Effects 0.000 description 2
- 229940005530 anxiolytics Drugs 0.000 description 2
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 2
- 238000007654 immersion Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- BKMLLFWFPNUDNF-UHFFFAOYSA-N methyl 2,3-dioxo-1h-indole-7-carboxylate Chemical compound COC(=O)C1=CC=CC2=C1NC(=O)C2=O BKMLLFWFPNUDNF-UHFFFAOYSA-N 0.000 description 2
- LNVLCLWBIBORCX-UHFFFAOYSA-N n-(2,3-dioxo-1h-indol-5-yl)acetamide Chemical compound CC(=O)NC1=CC=C2NC(=O)C(=O)C2=C1 LNVLCLWBIBORCX-UHFFFAOYSA-N 0.000 description 2
- LYKHAUJOYOTMOW-UHFFFAOYSA-N n-(2-chloroethyl)-n-propan-2-ylcyclohexanamine;hydrochloride Chemical compound Cl.ClCCN(C(C)C)C1CCCCC1 LYKHAUJOYOTMOW-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000003204 tranquilizing agent Substances 0.000 description 2
- 230000002936 tranquilizing effect Effects 0.000 description 2
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 1
- SJALPCXFOSGNST-UHFFFAOYSA-N 1-(2-bromoethyl)indole-2,3-dione Chemical compound C1=CC=C2N(CCBr)C(=O)C(=O)C2=C1 SJALPCXFOSGNST-UHFFFAOYSA-N 0.000 description 1
- CKCTUTOUPKLMOE-UHFFFAOYSA-N 1-[1-[di(propan-2-yl)amino]propan-2-yl]indole-2,3-dione Chemical compound C1=CC=C2N(C(C)CN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 CKCTUTOUPKLMOE-UHFFFAOYSA-N 0.000 description 1
- IWMMBILXTRTTFE-UHFFFAOYSA-N 1-[2-[cyclohexyl(propan-2-yl)amino]ethyl]indole-2,3-dione Chemical compound O=C1C(=O)C2=CC=CC=C2N1CCN(C(C)C)C1CCCCC1 IWMMBILXTRTTFE-UHFFFAOYSA-N 0.000 description 1
- MYAPUDLDPIKVNK-UHFFFAOYSA-N 1-[2-[di(propan-2-yl)amino]ethyl]-5-methoxyindole-2,3-dione Chemical compound COC1=CC=C2N(CCN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 MYAPUDLDPIKVNK-UHFFFAOYSA-N 0.000 description 1
- NIAKTYVWEOJVEM-UHFFFAOYSA-N 1-[2-[di(propan-2-yl)amino]ethyl]-5-methylindole-2,3-dione Chemical compound CC1=CC=C2N(CCN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 NIAKTYVWEOJVEM-UHFFFAOYSA-N 0.000 description 1
- PWHIJVXEWLSCHU-UHFFFAOYSA-N 1-[2-[di(propan-2-yl)amino]ethyl]-7-methylindole-2,3-dione Chemical compound C1=CC(C)=C2N(CCN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 PWHIJVXEWLSCHU-UHFFFAOYSA-N 0.000 description 1
- UDVNIOJFSOLEIE-UHFFFAOYSA-N 1-[3-[di(propan-2-yl)amino]propyl]-5-methylindole-2,3-dione Chemical compound CC1=CC=C2N(CCCN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 UDVNIOJFSOLEIE-UHFFFAOYSA-N 0.000 description 1
- QEGAVARNEWSVEJ-UHFFFAOYSA-N 1-[3-[di(propan-2-yl)amino]propyl]indole-2,3-dione Chemical compound C1=CC=C2N(CCCN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 QEGAVARNEWSVEJ-UHFFFAOYSA-N 0.000 description 1
- VDEMCLUFYJGNTM-UHFFFAOYSA-N 2-[cyclohexyl(propan-2-yl)amino]ethanol Chemical compound OCCN(C(C)C)C1CCCCC1 VDEMCLUFYJGNTM-UHFFFAOYSA-N 0.000 description 1
- IDGDRZFXQRBZRR-UHFFFAOYSA-N 2-chloropropane;hydrochloride Chemical compound Cl.CC(C)Cl IDGDRZFXQRBZRR-UHFFFAOYSA-N 0.000 description 1
- DKAVQCARZCYRIS-UHFFFAOYSA-N 4-bromo-5-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=C2NC(=O)C(=O)C2=C1Br DKAVQCARZCYRIS-UHFFFAOYSA-N 0.000 description 1
- AWLGINQJAVUHTR-UHFFFAOYSA-N 5-amino-1-[2-[di(propan-2-yl)amino]ethyl]indole-2,3-dione Chemical compound NC1=CC=C2N(CCN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 AWLGINQJAVUHTR-UHFFFAOYSA-N 0.000 description 1
- CHLMVMWHBHBMPK-UHFFFAOYSA-N 5-bromo-1-[2-[di(propan-2-yl)amino]ethyl]indole-2,3-dione Chemical compound BrC1=CC=C2N(CCN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 CHLMVMWHBHBMPK-UHFFFAOYSA-N 0.000 description 1
- RNFNKGPPFPRMFJ-UHFFFAOYSA-N 5-chloro-1-[2-[di(propan-2-yl)amino]ethyl]indole-2,3-dione Chemical compound ClC1=CC=C2N(CCN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 RNFNKGPPFPRMFJ-UHFFFAOYSA-N 0.000 description 1
- TWCMLOSSMDTNAR-UHFFFAOYSA-N 6-chloro-1-[2-[di(propan-2-yl)amino]ethyl]indole-2,3-dione Chemical compound C1=C(Cl)C=C2N(CCN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 TWCMLOSSMDTNAR-UHFFFAOYSA-N 0.000 description 1
- RVXLBLSGEPQBIO-UHFFFAOYSA-N 6-chloro-1h-indole-2,3-dione Chemical compound ClC1=CC=C2C(=O)C(=O)NC2=C1 RVXLBLSGEPQBIO-UHFFFAOYSA-N 0.000 description 1
- AHQQISFKHQYNEL-UHFFFAOYSA-N 7-bromo-1-[2-[di(propan-2-yl)amino]ethyl]-5-methylindole-2,3-dione Chemical compound CC1=CC(Br)=C2N(CCN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 AHQQISFKHQYNEL-UHFFFAOYSA-N 0.000 description 1
- UEHZKEABUOAZSH-UHFFFAOYSA-N 7-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=CC2=C1NC(=O)C2=O UEHZKEABUOAZSH-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241001235534 Graphis <ascomycete fungus> Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- ZCJZIESLHUNJKW-UHFFFAOYSA-N [2-[cyclohexyl(propan-2-yl)amino]-2-oxoethyl] acetate Chemical compound CC(=O)OCC(=O)N(C(C)C)C1CCCCC1 ZCJZIESLHUNJKW-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000881 depressing effect Effects 0.000 description 1
- RBNPZEHAODHBPZ-UHFFFAOYSA-M dihydroxyaluminium Chemical compound O.O.NCC(=O)O[Al] RBNPZEHAODHBPZ-UHFFFAOYSA-M 0.000 description 1
- 125000006202 diisopropylaminoethyl group Chemical group [H]C([H])([H])C([H])(N(C([H])([H])C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GGQOPZKTDHXXON-UHFFFAOYSA-N hexane;methanol Chemical compound OC.CCCCCC GGQOPZKTDHXXON-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- AKAGAGZUNRXQDN-UHFFFAOYSA-N methyl 1-[2-[di(propan-2-yl)amino]ethyl]-2,3-dioxoindole-7-carboxylate Chemical compound COC(=O)C1=CC=CC2=C1N(CCN(C(C)C)C(C)C)C(=O)C2=O AKAGAGZUNRXQDN-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- OPNUBWBPOZDXDJ-UHFFFAOYSA-N n-(2-chloroethyl)-n-methylbutan-1-amine;hydrochloride Chemical compound Cl.CCCCN(C)CCCl OPNUBWBPOZDXDJ-UHFFFAOYSA-N 0.000 description 1
- HLHNBMAQONZOIF-UHFFFAOYSA-N n-[1-[2-[di(propan-2-yl)amino]ethyl]-2,3-dioxoindol-5-yl]acetamide Chemical compound CC(=O)NC1=CC=C2N(CCN(C(C)C)C(C)C)C(=O)C(=O)C2=C1 HLHNBMAQONZOIF-UHFFFAOYSA-N 0.000 description 1
- UURRECHSOADBEG-UHFFFAOYSA-N n-butyl-n-(3-chloropropyl)butan-1-amine;hydrochloride Chemical compound Cl.CCCCN(CCCC)CCCCl UURRECHSOADBEG-UHFFFAOYSA-N 0.000 description 1
- PDUSWJORWQPNRP-UHFFFAOYSA-N n-propan-2-ylacetamide Chemical compound CC(C)NC(C)=O PDUSWJORWQPNRP-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003349 semicarbazides Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
Landscapes
- Indole Compounds (AREA)
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明はストレス等により胃、十二指腸潰瘍の
治療剤として有用なイサチン=3−セミカルバゾ
ン誘導体の製造中間体に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to an intermediate for producing isatin=3-semicarbazone derivatives useful as therapeutic agents for gastric and duodenal ulcers caused by stress and the like.
従来より、胃、十二指腸潰瘍治療剤として、
(1) 胃酸あるいは胃内消化液を中和、失活させる
制酸剤、抗ペプシン剤
(2) 胃酸等の分泌に関与する化学伝達物質である
アセチルコリンやヒスタミンに拮抗して、胃酸
等の分泌を抑制する抗コリン剤、ヒスタミン
H2−受容体拮抗剤
(3) 損傷した胃粘膜を保護、修復する胃粘液分泌
促進剤、局所循環改善剤、組織修復剤
などの薬剤が数多く開発され使用されている。
Traditionally, drugs used to treat gastric and duodenal ulcers include (1) antacids and anti-pepsin agents that neutralize and deactivate gastric acid or digestive juices in the stomach, (2) acetylcholine, a chemical mediator involved in the secretion of gastric acid, etc. Histamine, an anticholinergic drug that suppresses the secretion of gastric acid, etc. by antagonizing histamine.
H 2 -Receptor Antagonist (3) Many drugs have been developed and used to protect and repair damaged gastric mucosa, such as gastric mucus secretion enhancers, local circulation improvers, and tissue repair agents.
また、最近生体内生理活性物質であるプロスタ
グランジン類の胃酸分泌抑制作用や細胞保護作用
などが注目され、潰瘍治療剤への応用が検討され
ている。 In addition, prostaglandins, which are physiologically active substances in vivo, have recently attracted attention for their gastric acid secretion suppressing effects and cell protective effects, and their application as ulcer therapeutic agents is being considered.
しかしながら、近年増加の傾向にあるストレス
による胃、十二指腸潰瘍に有効な潰瘍治療剤はほ
とんど開発されていない。 However, few ulcer therapeutic agents have been developed that are effective for stomach and duodenal ulcers caused by stress, which have been on the rise in recent years.
現在、胃、十二指腸潰瘍剤として用いられてい
るものは、主に制酸剤、抗ペプシン剤、抗コリン
剤、ヒスタミンH2−受容体拮抗剤などであるが、
これらはいずれも消化液の中和、失活あるいは分
泌抑制によつて潰瘍を治療しようとするものであ
る。
Currently, the drugs currently used as agents for gastric and duodenal ulcers include antacids, antipepsin agents, anticholinergic agents, and histamine H 2 -receptor antagonists.
All of these attempts to treat ulcers by neutralizing, inactivating, or suppressing secretion of digestive juices.
一方、臨床知見によれば、胃、十二指腸潰瘍患
者は、必ずしも過酸状態を呈しているとは言えず
むしろ低酸状態を示している例もかなり報告され
ている。 On the other hand, according to clinical findings, patients with gastric and duodenal ulcers are not necessarily in a hyperacid state, but rather have been reported to have a hypoacid state.
近年増加の傾向にあるストレスによる胃、十二
指腸潰瘍にはこのような症例が多いと言われてる
が、従来の消化性潰瘍治療剤の中にはこのような
ストレスによる胃、十二指腸潰瘍に有効なものは
ほとんどない。このため実際の治療においては通
常の潰瘍治療剤と抗不安剤あるいは精神安定剤等
を併用する方法がもつぱらとられている。しかし
ながら、これらの薬剤は中枢抑制作用が強く、催
眠、運動抑制等の副作用を発現することがしばし
ばであつた。 It is said that there are many cases of gastric and duodenal ulcers caused by stress, which have been on the rise in recent years, but some conventional peptic ulcer treatments are effective against stress-induced stomach and duodenal ulcers. There are almost no For this reason, in actual treatment, a method is commonly used in which ordinary ulcer treatment agents are used in combination with anxiolytics or tranquilizers. However, these drugs have a strong central depressing effect and often cause side effects such as hypnosis and motor inhibition.
本発明者らはストレスによる胃、十二指腸潰瘍
の治療に有効な化合物を見出すべく研究を重ねた
結果、イチサン=3−セミカルバゾン誘導体によ
つてその目的が達成できることを見出した。
The inventors of the present invention have conducted extensive research to find a compound effective in treating gastric and duodenal ulcers caused by stress, and have discovered that the purpose can be achieved with isisan=3-semicarbazone derivatives.
本発明はこのイチサン=3−セミカルバゾン誘
導体の製造中間体である、一般式
(式中のXは低級アルキル基、低級アルコキシ
基、アミノ基、アシルアミノ基またはアルコキシ
カルボニル基であり、nは1または2であり、Y
は炭素数2〜4の直鎖状または枝分かれ状のアル
キレン鎖であり、R1は炭素数3〜5の直鎖状ま
たは枝分かれ状のアルキル基または炭素数3〜6
のシクロアルキル基であり、R2は炭素数1〜5
の直鎖状または枝分かれ状のアルキル基である)
で表されるイサチン誘導体およびそれらの酸付加
塩を提供するものである。 The present invention is an intermediate for producing this isisane=3-semicarbazone derivative, which has the general formula (X in the formula is a lower alkyl group, lower alkoxy group, amino group, acylamino group, or alkoxycarbonyl group, n is 1 or 2, and Y
is a linear or branched alkylene chain having 2 to 4 carbon atoms, and R 1 is a linear or branched alkyl group having 3 to 5 carbon atoms or a linear or branched alkyl group having 3 to 6 carbon atoms.
is a cycloalkyl group, and R 2 has 1 to 5 carbon atoms.
straight-chain or branched alkyl group)
The present invention provides isatin derivatives represented by: and acid addition salts thereof.
本発明の一般式()で表されるイサチン誘導
体と、一般式
H2NNHCONHR3 ()
(式中のR3は水素原子、低級アルキル基、アリ
ール基、アラルキル基またはシクロアルキル基で
ある)で表されるセミカルバジド誘導体またはそ
の酸付加塩とを反応させることにより容易に消化
性潰瘍治療剤として有用な、一般式
(式中のX、Y、n、R1、R2およびR3は前記と
同じ意味をもつ)で表されるイチサン=3−セミ
カルバゾン誘導体に導くことができる。 The isatin derivative represented by the general formula () of the present invention and the general formula H 2 NNHCONHR 3 () (R 3 in the formula is a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group or a cycloalkyl group) The general formula is easily useful as a therapeutic agent for peptic ulcers by reacting with the semicarbazide derivative represented by the formula or its acid addition salt. (In the formula, X, Y, n, R 1 , R 2 and R 3 have the same meanings as above).
この一般式()のイチサン=3−セミカルバ
ゾン誘導体およびそれらの薬理学的に許容される
酸付加塩は、実験的潰瘍、例えばウイスター系雄
性ラツトを用いた水浸拘束ストレス潰瘍実験にお
いて優れた抗潰瘍作用を示し、ヒトを含む哺乳動
物の胃、十二指腸潰瘍治療剤として有用である。 Itisane=3-semicarbazone derivatives of the general formula () and their pharmacologically acceptable acid addition salts have shown excellent anti-ulcer properties in experimental ulcers, such as water immersion restraint stress ulcer experiments using male Wistar rats. It is useful as a therapeutic agent for gastric and duodenal ulcers in mammals including humans.
本発明の一般式()で表される化合物は新規
化合物であり、例えば、一般式
(式中のXおよびnは前記と同じ意味をもつ)で
表されるイサチン誘導体と、一般式
(式中のZは酸残基であり、R1、R2およびYは
前記と同じ意味をもつ)で表されるアミン誘導体
またはその酸付加塩とを水素化ナトリウム、炭酸
カリウムなどのような塩基の存在下に反応させる
か、または、一般式
(式中のn、X、YおよびZは前記と同じ意味を
もつ)で表されるイサチン誘導体とこれと等モル
ないし過剰モルの一般式
(式中のR1およびR2は前記と同じ意味をもつ)
で表されるアミン誘導体とをベンゼン、N,N−
ジメチルホルムアミドなどの不活性溶媒中で炭酸
カリウムなどの塩基の存在下または非存在下に反
応させることによつて製造することができる。 The compound represented by the general formula () of the present invention is a new compound, for example, the compound represented by the general formula (X and n in the formula have the same meanings as above) and an isatin derivative represented by the general formula (In the formula, Z is an acid residue, and R 1 , R 2 and Y have the same meanings as above) or an acid addition salt thereof, and the Reaction in the presence of a base or general formula (In the formula, n, X, Y and Z have the same meanings as above) and an equimolar or excess molar amount of the general formula (R 1 and R 2 in the formula have the same meanings as above)
amine derivative represented by benzene, N,N-
It can be produced by reaction in an inert solvent such as dimethylformamide in the presence or absence of a base such as potassium carbonate.
本製造方法で出発原料として用いられる一般式
()、()、()および()で表される化合
物は一部新規化合物であるが、市販品として、あ
るいは公知の方法またはそれに準じた方法に従つ
て製造することにより容易に入手することができ
る。 Although some of the compounds represented by the general formulas (), (), (), and () used as starting materials in this production method are new compounds, they are available as commercially available products or by known methods or similar methods. Therefore, it can be easily obtained by manufacturing.
本発明の製造方法を好適に実施するには、一般
式()の化合物と、これと等モルないしやや過
剰モルの一般式()の化合物またはその酸付加
塩とを不活性溶媒、例えばN,N−ジエチルホル
ムアミドまたはそのトルエンとの混合溶媒に溶解
もしくは懸濁し、氷冷下に必要量の水酸化ナトリ
ウムを加え、室温ないし加温下に1〜20時間反応
させ、常法に従つて処理して目的物を得る。 In order to suitably carry out the production method of the present invention, the compound of the general formula () and the compound of the general formula () or an acid addition salt thereof in an equimolar to slightly excess molar amount are mixed in an inert solvent, for example, N, Dissolve or suspend in N-diethylformamide or its mixed solvent with toluene, add the necessary amount of sodium hydroxide under ice cooling, react at room temperature or under heating for 1 to 20 hours, and treat according to a conventional method. to obtain the desired object.
また、本発明の一般式()の化合物の第二の
製造方法を好適に実施するには、前記一般式
()で表されるイサチン誘導体とこれと等モル
ないし過剰モルの前記一般式()で表されるア
ミン誘導体とを炭酸カリウムのような塩基および
ヨウ化ナトリウムの存在下または非存在下にベン
ゼン、N,N−ジメチルホルムアミドなどの不活
性溶媒中60〜120℃で1〜70時間反応させる。常
法により処理し、適当な方法により精製して目的
物を得る。 Further, in order to suitably carry out the second method for producing the compound of the general formula () of the present invention, the isatin derivative represented by the general formula () and an equimolar to excess molar amount of the isatin derivative represented by the general formula () An amine derivative represented by is reacted with an inert solvent such as benzene or N,N-dimethylformamide at 60 to 120°C for 1 to 70 hours in the presence or absence of a base such as potassium carbonate and sodium iodide. let The target product is obtained by processing in a conventional manner and purifying by an appropriate method.
本反応において核置換基Xがアミノ基である一
般式()または()の化合物を用いる場合、
反応に先だつて、アミノ基をアセチル基などで保
護した方がよい。保護基は反応後常法に従い除去
する。 When using a compound of general formula () or () in which the nuclear substituent X is an amino group in this reaction,
Prior to the reaction, it is better to protect the amino group with an acetyl group or the like. After the reaction, the protecting group is removed according to a conventional method.
本発明の一般式()の化合物から導かれる前
記一般式()で表される化合物が消化性潰瘍、
特にストレスによる胃、十二指腸潰瘍の治療剤と
して好ましいことは実験潰瘍に対する抗潰瘍作用
から確認される。例えば、ウイスター系雄性ラツ
トを用いた水浸拘束ストレス潰瘍実験において、
一般式()の化合物は、体重1Kg当たり100mg
の経口投与で約40%〜95%の抑制効果を示す。特
に(E)−1−(2−ジイソプロピルアミノエチル)
イチサン=3−セミカルバゾンは、体重1Kg当た
り10mgの経口投与でも50%程度の抑制効果を示
す。 The compound represented by the general formula () derived from the compound of the general formula () of the present invention can treat peptic ulcers,
Its suitability as a therapeutic agent for stress-induced gastric and duodenal ulcers is confirmed by its anti-ulcer effect on experimental ulcers. For example, in a water immersion restraint stress ulcer experiment using male Wistar rats,
The compound of general formula () is 100 mg per 1 kg of body weight.
Oral administration shows an inhibitory effect of about 40% to 95%. Especially (E)-1-(2-diisopropylaminoethyl)
Itisan=3-semicarbazone shows an inhibitory effect of about 50% even when administered orally at a dose of 10 mg/kg body weight.
また、一般式()で表される化合物が中枢作
用を有することは、本化合物がヒスタミンまたは
ペンタガストリン投与による胃酸分泌亢進に対し
てはほとんど抑制効果を示さず、2−デオキシ−
D−グルコース投与による胃酸分泌亢進に対して
は抑制効果を示すことから確認されるが、本化合
物は抗不安剤、精神安定剤に見られるような睡眠
延長および運動抑制作用はほとんど示さない。 Furthermore, the fact that the compound represented by the general formula (
Although this compound is confirmed to have a suppressive effect on increased gastric acid secretion caused by administration of D-glucose, this compound hardly exhibits the sleep prolonging and movement suppressing effects seen in anxiolytics and tranquilizers.
このように本発明の一般式()で表される化
合物から導かれるイチサン=3−セミカルバゾン
誘導体()は消化性潰瘍、特にストレス等によ
る胃、十二指腸潰瘍の治療剤として好適なもので
ある。 As described above, the isisane 3-semicarbazone derivative () derived from the compound represented by the general formula () of the present invention is suitable as a therapeutic agent for peptic ulcers, particularly gastric and duodenal ulcers caused by stress or the like.
本発明の一般式()の化合物からきわめて容
易に医薬品として有用なイチサン=3−セミカル
バゾン誘導体()を製造することができる。
Itisan=3-semicarbazone derivatives () useful as pharmaceuticals can be produced very easily from the compound of the general formula () of the present invention.
このイチサン=3−セミカルバゾン誘導体は動
物を用いた実験潰瘍において顕著な抗潰瘍作用を
示し、ヒトを含む哺乳動物の消化性潰瘍、特にス
トレス等による胃、十二指腸潰瘍の治療剤として
有用である。 This itisan=3-semicarbazone derivative exhibits a remarkable anti-ulcer effect in experimental ulcers using animals, and is useful as a therapeutic agent for peptic ulcers in mammals including humans, especially gastric and duodenal ulcers caused by stress, etc.
本発明の内容を以下の参考例および実施例によ
りさらに詳細に説明する。なお、各参考例および
実施例中の化合物の融点はすべて未補正である。
The content of the present invention will be explained in more detail with reference to the following reference examples and examples. Note that the melting points of the compounds in each Reference Example and Examples are all uncorrected.
参考例 1
7ブロモ−5−メチルイサチン
5−メチルイサチン8.0gを酢酸200mlにけんだ
くし、室温下にかき混ぜながら臭素3.3mlの酢酸
50ml溶液を滴下したのち、50℃で16時間反応させ
た。減圧下に溶媒を留去し、残留物をメタノール
−ヘキサンより再結晶し、融点176〜180℃の7−
ブロモ−5−メチルイサチン11.4gを得た。Reference example 1 7Bromo-5-methylisatin Suspend 8.0g of 5-methylisatin in 200ml of acetic acid and add 3.3ml of bromine and acetic acid while stirring at room temperature.
After dropping 50 ml of the solution, the mixture was reacted at 50°C for 16 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol-hexane to give 7-
11.4 g of bromo-5-methylisatin was obtained.
元素分析値:(C9H6BrNO2として)
C% H% N%
計算値 45.03 2.52 5.83
実測値 45.05 2.46 5.50
IR(KBr):νCO1730cm-1
NMR(d6−DMSO)
δ:2.27(3H、s)、7.35(1H、s)、7.64(1H、
s)、11.22(1H、s)
参考例 2
2−(N−イソプロピルシクロヘキシルアミノ)
エチルクロリド塩酸塩
N−イソプロピルシクロヘキシルアミン5.0g
およびトリエチルアミン4.3gを乾燥塩化メチレ
ン100mlに溶かし、氷冷下にかき混ぜながらアセ
トキシアセチルクロリド5.8gを滴下したのち、
室温で16時間かき混ぜた。反応液を炭酸水素ナト
リウム水溶液および水で洗つたのち、無水硫酸マ
グネシウムで乾燥した。減圧下に溶媒を留去し、
油状の2−アセトキシ−N−シクロヘキシル−N
−イソプロピルアセトアミド8.5gを得た。Elemental analysis value: (as C 9 H 6 BrNO 2 ) C% H% N% Calculated value 45.03 2.52 5.83 Actual value 45.05 2.46 5.50 IR (KBr): ν CO 1730cm -1 NMR (d 6 -DMSO) δ: 2.27 ( 3H, s), 7.35 (1H, s), 7.64 (1H,
s), 11.22 (1H, s) Reference example 2 2-(N-isopropylcyclohexylamino)
Ethyl chloride hydrochloride N-isopropylcyclohexylamine 5.0g
4.3 g of triethylamine were dissolved in 100 ml of dry methylene chloride, and 5.8 g of acetoxyacetyl chloride was added dropwise while stirring under ice cooling.
Stir at room temperature for 16 hours. The reaction solution was washed with an aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
Oily 2-acetoxy-N-cyclohexyl-N
- 8.5 g of isopropylacetamide was obtained.
IR(neat):νCO1735、1650cm-1
NMR(CDCl3)
δ:1.05(16H、m)、2.18(3H、s)、2.3〜2.5
(1H、m)、3.1〜3.15(1H、m)、4.67(2H、
s)
水素化リチウムアルミニウム4.1gをジエチル
エーテル500mlにけんだくし、氷冷下にかき混ぜ
ながら濃硫酸2.9mlを滴下したのち、1時間かき
混ぜた。この反応液に、2−アセトキシ−N−シ
クロヘキシル−N−イソプロピルアセトアミド
8.4gのジエチルエーテル150ml溶液を氷冷下にか
き混ぜながら滴下したのち、16時間加熱還流させ
た。冷後、氷冷下にかき混ぜながら、反応液に水
酸化ナトリウム水溶液および水を滴下し、無水硫
酸マグネシウムで乾燥したのち、不溶物をろ去し
た。減圧下に溶媒を留去し、油状の2−(N−イ
ソプロピルシクロヘキシルアミノ)エタノール
6.1gを得た。IR (neat): ν CO 1735, 1650 cm -1 NMR (CDCl 3 ) δ: 1.05 (16H, m), 2.18 (3H, s), 2.3-2.5
(1H, m), 3.1~3.15 (1H, m), 4.67 (2H,
s) 4.1 g of lithium aluminum hydride was suspended in 500 ml of diethyl ether, 2.9 ml of concentrated sulfuric acid was added dropwise while stirring under ice cooling, and the mixture was stirred for 1 hour. Add 2-acetoxy-N-cyclohexyl-N-isopropylacetamide to this reaction solution.
A solution of 8.4 g in 150 ml of diethyl ether was added dropwise while stirring under ice cooling, and the mixture was heated under reflux for 16 hours. After cooling, an aqueous sodium hydroxide solution and water were added dropwise to the reaction solution while stirring under ice cooling, and after drying over anhydrous magnesium sulfate, insoluble matter was filtered off. The solvent was distilled off under reduced pressure to obtain oily 2-(N-isopropylcyclohexylamino)ethanol.
6.1g was obtained.
IR(neat):νCO3375cm-1
NMR(CDCl3)
δ:1.03(6H、d、J=6.6Hz)、1.15〜1.85
(10H、m)、2.45〜2.6(1H、m)、2.68(2H、
t、J=5.5Hz)、3.07(1H、sept、J=6.6
Hz)、3.25(1H、br−s)、3.45(2H、t、J
=5.5Hz)
2−(N−イソプロピルシクロヘキシルアミノ)
エタノール6.0gを乾燥ベンゼン100mlに溶かし、
室温下にかき混ぜながら塩化チオニル3.2mlを滴
下後、4時間加熱還流させた。減圧下に溶媒を留
去し、残留物にジエチルエーテルを加え結晶化さ
せ、ろ取し、融点99〜103℃の2−(N−イソプロ
ピルシクロヘキシルアミノ)エチルクロリド塩酸
塩7.4gを得た。IR (neat): ν CO 3375cm -1 NMR (CDCl 3 ) δ: 1.03 (6H, d, J = 6.6Hz), 1.15 to 1.85
(10H, m), 2.45-2.6 (1H, m), 2.68 (2H,
t, J = 5.5Hz), 3.07 (1H, sept, J = 6.6
Hz), 3.25 (1H, br-s), 3.45 (2H, t, J
=5.5Hz) 2-(N-isopropylcyclohexylamino)
Dissolve 6.0g of ethanol in 100ml of dry benzene,
After adding 3.2 ml of thionyl chloride dropwise at room temperature with stirring, the mixture was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, and diethyl ether was added to the residue for crystallization, which was collected by filtration to obtain 7.4 g of 2-(N-isopropylcyclohexylamino)ethyl chloride hydrochloride having a melting point of 99-103°C.
元素分析値:(C11H23Cl2Nとして)
C% H% N%
計算値 55.00 9.65 5.83
実測値 54.82 10.00 5.73
NMR(CDCl3)
δ:1.15〜2.4(16H、m)、3.15〜3.3(3H、m)、
3.65〜3.85(1H、m)、4.05〜4.25(2H、m)、
11.90(1H、br−s)
実施例 1
1−(2−ジイソプロピルアミノエチル)イサ
チン
イサチン2.94gと2−ジイソプロピルアミノエ
チルクロリド塩酸塩4.00gを乾燥トルエン50mlと
乾燥N,N−ジメチルホルムアミド10mlの混液に
けんだくし、氷冷下にかき混ぜながら60%水素化
ナトリウム(油性)1.60gを加えたのち、室温で
30分さらに80℃で19時間反応させた。減圧下に溶
媒を留去し、残留物に水を加えベンゼンで抽出
し、水洗したのち無水硫酸マグネシウムで乾燥し
た。減圧下に溶媒を留去し、残留物をヘキサンよ
り再結晶し、融点60〜61℃の1−(2−ジイソプ
ロピルアミノエチル)イサチン4.62gを得た。Elemental analysis value: ( as C11H23Cl2N ) C% H% N % Calculated value 55.00 9.65 5.83 Actual value 54.82 10.00 5.73 NMR ( CDCl3 ) δ: 1.15-2.4 (16H, m), 3.15-3.3 ( 3H, m),
3.65-3.85 (1H, m), 4.05-4.25 (2H, m),
11.90 (1H, br-s) Example 1 1-(2-Diisopropylaminoethyl)isatin A mixture of 2.94 g of isatin and 4.00 g of 2-diisopropylaminoethyl chloride hydrochloride in 50 ml of dry toluene and 10 ml of dry N,N-dimethylformamide. Add 1.60 g of 60% sodium hydride (oil-based) to the Nikkendakushi while stirring under ice-cooling, and then stir at room temperature.
The reaction was continued for 30 minutes and then at 80°C for 19 hours. The solvent was distilled off under reduced pressure, water was added to the residue, extracted with benzene, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane to obtain 4.62 g of 1-(2-diisopropylaminoethyl)isatin having a melting point of 60 to 61°C.
元素分析値:(C16H22N2O2として)
C% H% N%
計算値 70.04 8.08 10.21
実測値 69.99 8.29 10.06
IR(KBr):νCO1725cm-1
NMR(CDCl3)
δ:0.98(12H、d、J=6.6Hz)、2.70(2H、
t、J=6.9Hz)、3.04(2H、sept、J=6.6
Hz)、3.69(2H、t、J=6.9Hz)、6.91(1H、
d、J=7.2Hz)、7.09(1H、t、J=7.2Hz)、
7.57(1H、t、J=7.2Hz)、7.59(1H、d、
J=7.2Hz)
実施例 2
1−(2−ジイソプロピルアミノエチル)イサ
チン
イサチン2.94g、2−ジイソプロピルアミノエ
チルクロリド塩酸塩4.20gおよび無水炭酸カリウ
ム3.17gをトルエン50mlにけんだくし、90℃で4
時間かき混ぜた。冷後反応液を水洗し、無水硫酸
マグネシウムで乾燥した。減圧下に溶媒を留去
し、残留物をヘキサンより再結晶し、1−(2−
ジイソプロピルアミノエチル)イサチン4.93gを
得た。このものの物性は実施例1で得られた化合
物の物性と同一であつた。Elemental analysis value: (as C 16 H 22 N 2 O 2 ) C% H% N% Calculated value 70.04 8.08 10.21 Actual value 69.99 8.29 10.06 IR (KBr): ν CO 1725cm -1 NMR (CDCl 3 ) δ: 0.98 ( 12H, d, J = 6.6Hz), 2.70 (2H,
t, J = 6.9Hz), 3.04 (2H, sept, J = 6.6
Hz), 3.69 (2H, t, J = 6.9Hz), 6.91 (1H,
d, J = 7.2Hz), 7.09 (1H, t, J = 7.2Hz),
7.57 (1H, t, J = 7.2Hz), 7.59 (1H, d,
J = 7.2 Hz) Example 2 1-(2-diisopropylaminoethyl) isatin 2.94 g of isatin, 4.20 g of 2-diisopropylaminoethyl chloride hydrochloride and 3.17 g of anhydrous potassium carbonate were suspended in 50 ml of toluene, and the
Stirred for an hour. After cooling, the reaction solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane to give 1-(2-
4.93 g of isatin (diisopropylaminoethyl) was obtained. The physical properties of this product were the same as those of the compound obtained in Example 1.
実施例 3
イサチンと3−ジイソプロピルアミノプロピル
クロリド塩酸塩を用い、実施例1とほぼ同様に反
応させ処理し、シリカゲルカラムクロマトグラフ
イー(溶出溶媒:クロロホルム/メタノール=
50/1)で精製後、ヘキサンより再結晶し、下記
の化合物を製造した。Example 3 Isatin and 3-diisopropylaminopropyl chloride hydrochloride were reacted and treated in substantially the same manner as in Example 1, and subjected to silica gel column chromatography (elution solvent: chloroform/methanol =
50/1) and then recrystallized from hexane to produce the following compound.
1−(3−ジイソピロピルアミノプロピル)イ
サチン
融点:49〜50℃
収率:72.9%
元素分析値:(C17H24N2O2として)
C% H% N%
計算値 70.80 8.39 9.71
実測値 70.98 8.35 9.41
IR(KBr):νCO1720cm-1
NMR(CDCl3)
δ:1.20(12H、d、J=6.6Hz)、1.79(2H、
quint、J=6.6Hz)、2.55(2H、t、J=6.6
Hz)、3.04(2H、sept、J=6.6Hz)、3.76(2H、
t、J=6.6Hz)、6.93(1H、d、J=7.7Hz)、
7.10(1H、t、J=7.7Hz)、7.58(1H、t、
J=7.7Hz)、7.60(1H、d、J=7.7Hz)
実施例 4
1−(2−ジイソプロピルアミノプロピル)イ
サチンおよび1−(2−ジイソプロピルアミノ
−1−メチルチル)イサチン
イサチン4.16gと2−ジイソプロピルアミノ−
1−メチルエチルクロリド塩酸塩6.06gを乾燥
N、N−ジエチルホルムアミド80mlに溶かし、氷
冷下にかき混ぜながら60%水素化ナトリウム(油
性)2.28gを加えたのち、室温で30分さらに90℃
で15時間反応させた。減圧下に溶媒を留去し、残
留物に水を加え酢酸エチルで抽出し、水洗したの
ち、無水硫酸マグネシウムで乾燥した。減圧下に
溶媒を留去し、残留物にヘキサンを加え結晶をろ
取したのち、ベンゼン−ヘキサンより再結晶し、
融点111〜112℃の1−(2−ジイソプロピルアミ
ノプロピル)イサチン4.48gを得た。 1-(3-diisopropylaminopropyl) isatin Melting point: 49-50℃ Yield: 72.9% Elemental analysis: (as C 17 H 24 N 2 O 2 ) C% H% N% Calculated value 70.80 8.39 9.71 Actual value 70.98 8.35 9.41 IR (KBr): ν CO 1720cm -1 NMR (CDCl 3 ) δ: 1.20 (12H, d, J = 6.6Hz), 1.79 (2H,
quint, J = 6.6Hz), 2.55 (2H, t, J = 6.6
Hz), 3.04 (2H, sept, J=6.6Hz), 3.76 (2H,
t, J = 6.6Hz), 6.93 (1H, d, J = 7.7Hz),
7.10 (1H, t, J=7.7Hz), 7.58 (1H, t,
J = 7.7Hz), 7.60 (1H, d, J = 7.7Hz) Example 4 1-(2-diisopropylaminopropyl)isatin and 1-(2-diisopropylamino-1-methylthyl)isatin 4.16 g of isatin and 2- Diisopropylamino
Dissolve 6.06 g of 1-methylethyl chloride hydrochloride in 80 ml of dry N,N-diethylformamide, add 2.28 g of 60% sodium hydride (oil-based) while stirring under ice cooling, and then incubate at room temperature for 30 minutes at 90°C.
The mixture was allowed to react for 15 hours. The solvent was distilled off under reduced pressure, water was added to the residue, extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the residue, the crystals were collected by filtration, and then recrystallized from benzene-hexane.
4.48 g of 1-(2-diisopropylaminopropyl)isatin having a melting point of 111-112°C was obtained.
元素分析値:(C17H24N2O2として)
C% H% N%
計算値 70.80 8.39 9.71
実測値 70.86 8.59 9.65
IR(KBr):νCO1720cm-1
NMR(CDCl3)
δ:0.89(6H、d、J=6.6Hz)、1.01(6H、d、
J=6.6Hz)、1.12(3H、d、J=6.6Hz)、3.16
(2H、sept、J=6.6Hz)、3.3〜3.45(1H、
m)、3.46(1H、dd、J=6.6and13.7Hz)、
3.71(1H、dd、J=7.7 and 13.7Hz)、6.87
(1H、d、J=7.7Hz)、7.09(1H、t、J=
7.7Hz)、7.55〜7.65(2H、m)
一方、前記ヘキサンろ液を濃縮し、残留物をシ
リカゲルカラムクロマトグラフイー(溶出溶媒:
クロロホルム)で精製後ヘキサンより再結晶し、
融点70〜71℃の1−(2−ジイソプロピルアミノ
−1−メチルエチル)イサチン0.83gを得た。Elemental analysis value: (as C 17 H 24 N 2 O 2 ) C% H% N% Calculated value 70.80 8.39 9.71 Actual value 70.86 8.59 9.65 IR (KBr): ν CO 1720cm -1 NMR (CDCl 3 ) δ: 0.89 ( 6H, d, J = 6.6Hz), 1.01 (6H, d,
J = 6.6Hz), 1.12 (3H, d, J = 6.6Hz), 3.16
(2H, sept, J=6.6Hz), 3.3~3.45 (1H,
m), 3.46 (1H, dd, J=6.6and13.7Hz),
3.71 (1H, dd, J=7.7 and 13.7Hz), 6.87
(1H, d, J = 7.7Hz), 7.09 (1H, t, J =
7.7Hz), 7.55-7.65 (2H, m) Meanwhile, the hexane filtrate was concentrated and the residue was subjected to silica gel column chromatography (elution solvent:
After purification with chloroform), recrystallized from hexane,
0.83 g of 1-(2-diisopropylamino-1-methylethyl)isatin having a melting point of 70-71°C was obtained.
元素分析値:(C17H24N2O2として)
C% H% N%
計算値 70.80 8.39 9.71
実測値 70.81 8.60 9.57
IR(KBr):νCO1730cm-1
NMR(CDCl3)
δ:0.82(6H、d、J=6.6Hz)、0.96(6H、d、
J=6.6Hz)、1.50(3H、d、J=7.2Hz)、2.68
(1H、dd、J=5.3and14.0Hz)、2.9〜3.05
(3H、m)、4.25〜4.45(1H、m)、6.98(1H、
d、J=7.7Hz)、7.06(1H、t、J=7.7Hz)、
7.53(1H、dt、J=1.1and7.7Hz)、7.58(1H、
dd、J=1.1and7.7Hz)
実施例 5
5−メチルイサチンと2−ジイソプロピルアミ
ノエチルクロリド塩酸塩を用い、実施例1とほぼ
同様にして下記の化合物を製造した。Elemental analysis value: (as C 17 H 24 N 2 O 2 ) C% H% N% Calculated value 70.80 8.39 9.71 Actual value 70.81 8.60 9.57 IR (KBr): ν CO 1730cm -1 NMR (CDCl 3 ) δ: 0.82 ( 6H, d, J = 6.6Hz), 0.96 (6H, d,
J = 6.6Hz), 1.50 (3H, d, J = 7.2Hz), 2.68
(1H, dd, J=5.3and14.0Hz), 2.9~3.05
(3H, m), 4.25-4.45 (1H, m), 6.98 (1H,
d, J = 7.7Hz), 7.06 (1H, t, J = 7.7Hz),
7.53 (1H, dt, J=1.1and7.7Hz), 7.58 (1H,
dd, J=1.1and7.7Hz) Example 5 The following compound was produced in substantially the same manner as in Example 1 using 5-methylisatin and 2-diisopropylaminoethyl chloride hydrochloride.
1−(2−ジイソプロピルアミノエチル)−5−メ
チルイサチン
融点:65〜67℃(ヘキサン)
収率:82.0%
元素分析値:(C17H24N2O2として)
C% H% N%
計算値 70.80 8.39 9.71
実測値 70.58 8.34 9.44
IR(KBr):νCO1720cm-1
NMR(CDCl3)
δ:0.97(12H、d、J=6.6Hz)、2.33(3H、
s)、2.68(2H、t、J=6.6Hz)、3.03(2H、
sept、J=6.6Hz)、3.67(2H、t、J=6.6
Hz)、6.80(1H、d、J=7、7Hz)、7.38
(1H、d、J=7.7Hz)、7.39(1H、s)
実施例 6
7−メチルイサチンと2−ジイソプロピルアミ
ノエチルクロリド塩酸塩を用い、実施例1とほぼ
同様にして下記の化合物を製造した。1-(2-diisopropylaminoethyl)-5-methylisatin Melting point: 65-67°C (hexane) Yield: 82.0% Elemental analysis: (as C 17 H 24 N 2 O 2 ) C% H% N% Calculated value 70.80 8.39 9.71 Actual value 70.58 8.34 9.44 IR (KBr): ν CO 1720cm -1 NMR (CDCl 3 ) δ: 0.97 (12H, d, J = 6.6Hz), 2.33 (3H,
s), 2.68 (2H, t, J=6.6Hz), 3.03 (2H,
sept, J = 6.6Hz), 3.67 (2H, t, J = 6.6
Hz), 6.80 (1H, d, J=7, 7Hz), 7.38
(1H, d, J=7.7Hz), 7.39 (1H, s) Example 6 The following compound was produced in substantially the same manner as in Example 1 using 7-methylisatin and 2-diisopropylaminoethyl chloride hydrochloride.
1−(2−ジイソプロピルアミノエチル)−7−メ
チルイサチン
融点:92〜93℃(ヘキサン)
収率:65.2%
元素分析値:(C17H24N2O2として)
C% H% N%
計算値 70.80 8.39 9.71
実測値 70.62 8.49 9.66
IR(KBr):νCO1720cm-1
NMR(CDCl3)
δ:0.93(12H、d、J=6.6Hz)、2.53(3H、
s)、2.68(2H、t、J=6.6Hz)、3.03(2H、
sept、J=6.6Hz)、3.96(2H、t、J=6.6
Hz)、6.99(1H、t.、J=7、1Hz)、7.33
(1H、d、J=7.1Hz)、7.47(1H、d、J=
7.1Hz)
実施例 7
1−(2−ジイソプロピルアミノエチル)−5−
フルオロイサチン
5−フルオロイサチン3.30gと2−ジイソプロ
ピルアミノエチルクロリド塩酸塩4.00gを乾燥
N、N−ジエチルホルムアミド75mlにけんだく
し、氷冷下にかき混ぜながら、60%水素化ナトリ
ウム(油性)1.60gを加えたのち、室温で30分さ
らに80℃で17時間反応させた。減圧下に溶媒を留
去し、残留物に水を加えベンゼンで抽出し、水洗
したのち無水硫酸マグネシウムで乾燥した。減圧
下に溶媒を留去し、残留物をヘキサン−石油ベン
ジンより再結晶し、融点100〜102℃の1−(2−
ジイソプロピルアミノエチル)−5−フルオロイ
サチン4.97gを得た。1-(2-diisopropylaminoethyl)-7-methylisatin Melting point: 92-93°C (hexane) Yield: 65.2% Elemental analysis: (as C 17 H 24 N 2 O 2 ) C% H% N% Calculated value 70.80 8.39 9.71 Actual value 70.62 8.49 9.66 IR (KBr): ν CO 1720cm -1 NMR (CDCl 3 ) δ: 0.93 (12H, d, J = 6.6Hz), 2.53 (3H,
s), 2.68 (2H, t, J=6.6Hz), 3.03 (2H,
sept, J = 6.6Hz), 3.96 (2H, t, J = 6.6
Hz), 6.99 (1H, t., J=7, 1Hz), 7.33
(1H, d, J = 7.1Hz), 7.47 (1H, d, J =
7.1Hz) Example 7 1-(2-diisopropylaminoethyl)-5-
Fluoroisatin 3.30 g of 5-fluoroisatin and 4.00 g of 2-diisopropylaminoethyl chloride hydrochloride were suspended in 75 ml of dry N,N-diethylformamide, and while stirring under ice-cooling, 60% sodium hydride (oil-based) was added. After adding 1.60 g, the mixture was reacted at room temperature for 30 minutes and then at 80°C for 17 hours. The solvent was distilled off under reduced pressure, water was added to the residue, extracted with benzene, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane-petroleum benzine to give 1-(2-
4.97 g of (diisopropylaminoethyl)-5-fluoroisatin was obtained.
元素分析値:(C16H21FN2O2として)
C% H% N%
計算値 65.73 7.24 9.58
実測値 65.64 7.52 9.59
IR(KBr):νCO1725cm-1
NMR(CDCl3)
δ:0.97(12H、d、J=6.6Hz)、2.70(2H、
t、J=6.6Hz)、3.03(2H、sept、J=6.6
Hz)、3.96(2H、t、J=6.6Hz)、6.85〜6.95
(1H、m)、7.25〜7.4(2H、m)
実施例 8
5−クロロイサチンと2−ジイソプロピルアミ
ノエチルクロリド塩酸塩を用い、実施例7とほぼ
同様にして下記の化合物を製造した。Elemental analysis value: (as C 16 H 21 FN 2 O 2 ) C% H% N% Calculated value 65.73 7.24 9.58 Actual value 65.64 7.52 9.59 IR (KBr): ν CO 1725cm -1 NMR (CDCl 3 ) δ: 0.97 ( 12H, d, J = 6.6Hz), 2.70 (2H,
t, J=6.6Hz), 3.03(2H, sept, J=6.6
Hz), 3.96 (2H, t, J = 6.6Hz), 6.85-6.95
(1H, m), 7.25-7.4 (2H, m) Example 8 The following compound was produced in substantially the same manner as in Example 7 using 5-chloroisatin and 2-diisopropylaminoethyl chloride hydrochloride.
5−クロロ−1−(2−ジイソプロピルアミノエ
チル)イサチン
融点:99〜101℃(ヘキサン)
収率:70.0%
元素分析値:(C16H21ClN2O2として)
C% H% N%
計算値 62.23 6.85 9.07
実測値 61.99 6.87 8.99
IR(KBr):νCO1730cm-1
NMR(CDCl3)
δ:0.96(12H、d、J=6.6Hz)、2.69(2H、
t、J=6.6Hz)、3.02(2H、sept、J=6.6
Hz)、3.69(2H、t、J=6.6Hz)、6.89(1H、
d、J=8.8Hz)、7.5〜7.6(2H、m)
実施例 9
6−クロロイサチンと2−ジイソプロピルアミ
ノエチルクロリド塩酸塩を用い、実施例1とほぼ
同様にして下記の化合物を製造した。5-Chloro-1-(2-diisopropylaminoethyl)isatin Melting point: 99-101°C (hexane) Yield: 70.0% Elemental analysis: (as C 16 H 21 ClN 2 O 2 ) C% H% N% Calculation Value 62.23 6.85 9.07 Actual value 61.99 6.87 8.99 IR (KBr): ν CO 1730cm -1 NMR (CDCl 3 ) δ: 0.96 (12H, d, J = 6.6Hz), 2.69 (2H,
t, J = 6.6Hz), 3.02 (2H, sept, J = 6.6
Hz), 3.69 (2H, t, J = 6.6Hz), 6.89 (1H,
d, J=8.8Hz), 7.5-7.6 (2H, m) Example 9 The following compound was produced in substantially the same manner as in Example 1 using 6-chloroisatin and 2-diisopropylaminoethyl chloride hydrochloride.
6−クロロ−1−(2−ジイソプロピルアミノ
エチル)イサチン
融点:78〜79℃(ヘキサン)
収率:86.2%
元素分析値:(C16H21N2O2として)
C% H% N%
計算値 62.23 6.85 9.07
実測値 61.98 6.97 9.00
IR(KBr):もνCO1730cm-1
NMR(CDCl3)
δ:0.96(12H、d、J=6.6Hz)、2.71(2H、
t、J=6.6Hz)、3.03(2H、sept、J=6.6
Hz)、3.68(2H、t、J=6.6Hz)、6.95(1H、
d、J=1.7Hz)、7.06(1H、dd、J=
1.7and8.2Hz)、7.52(1H、d、J=8.2Hz)
実施例 10
5−ブロモイサチンと2−ジイソプロピルアミ
ノエチルクロリド塩酸塩を用い、実施例7とほぼ
同様にして下記の化合物を製造した。6-Chloro-1-(2-diisopropylaminoethyl)isatin Melting point: 78-79°C (hexane) Yield: 86.2% Elemental analysis: (as C 16 H 21 N 2 O 2 ) C% H% N% Calculation Value 62.23 6.85 9.07 Actual value 61.98 6.97 9.00 IR (KBr): ν CO 1730cm -1 NMR (CDCl 3 ) δ: 0.96 (12H, d, J = 6.6Hz), 2.71 (2H,
t, J=6.6Hz), 3.03(2H, sept, J=6.6
Hz), 3.68 (2H, t, J=6.6Hz), 6.95 (1H,
d, J=1.7Hz), 7.06(1H, dd, J=
1.7 and 8.2 Hz), 7.52 (1H, d, J = 8.2 Hz) Example 10 The following compound was produced in substantially the same manner as in Example 7 using 5-bromoisatin and 2-diisopropylaminoethyl chloride hydrochloride.
5−ブロモ−1−(2−ジイソプロピルアミノエ
チル)イサチン
融点:91〜93℃(ヘキサン−石油ベンジン)
収率:82.9%
元素分析値:(C16H21BrN2O2・0.1C6H14(ヘキサ
ン)として)
C% H% N%
計算値 55.10 6.24 7.74
実測値 55.25 6.32 7.70
IR(KBr):νcp1725cm-1
NMR(CDCl3)
δ:0.96(12H、d、J=6.6Hz)、2.69(2H、
t、J=6.6Hz)、3.02(2H、sept、J=6.6
Hz)、3.68(2H、t、J=6.6Hz)、6.8〜6.85
(1H、m)、7.65〜7.7(2H、m)
実施例 11
5−アセトアミドイサチンと2−ジイソプロピ
ルアミノエチルクロリド塩酸塩を用い、実施例7
とほぼ同様にして下記の化合物を製造した。5-Bromo-1-(2-diisopropylaminoethyl)isatin Melting point: 91-93℃ (hexane-petroleum benzine) Yield: 82.9% Elemental analysis: (C 16 H 21 BrN 2 O 2・0.1C 6 H 14 (as hexane) C% H% N% Calculated value 55.10 6.24 7.74 Actual value 55.25 6.32 7.70 IR (KBr): ν cp 1725cm -1 NMR (CDCl 3 ) δ: 0.96 (12H, d, J = 6.6Hz), 2.69 (2H,
t, J = 6.6Hz), 3.02 (2H, sept, J = 6.6
Hz), 3.68 (2H, t, J = 6.6Hz), 6.8-6.85
(1H, m), 7.65-7.7 (2H, m) Example 11 Using 5-acetamidoisatin and 2-diisopropylaminoethyl chloride hydrochloride, Example 7
The following compounds were produced in substantially the same manner as above.
−トアミド−1−(2−ジイソプロピルアミ
ノエチル)イサチン
融点:187〜190℃(酢酸エチル−ヘキサン)
収率:77.0%
元素分析値:(C18H25N3O3として)
C% H% N%
計算値 65.24 7.60 12.68
実測値 65.07 7.61 12.38
IR(KBr):νNH3300cm-1
νCO1720、1660cm-1
NMR(d6−DMSO)
δ:0.88(12H、d、J=6.6Hz)、2.04(3H、
s)、2.62(2H、t、J=6.6Hz)、2.99(2H、
sept、J=6.6Hz)、3.62(2H、t、J=6.6
Hz)、7.10(1H、d、J=7.5Hz)、7.72(1H、
dd、J=2.2and7.5Hz)、7.84(1H、d、J=
2.2Hz)、10.05(1H、s)
実施例 12
5−アミノ−1−(2−ジイソプロピルアミノ
エチル)イサチン
5−アセトアミド−1−(2−ジイソプロピル
アミノエチル)イサチン2.07gを6規定塩酸150
mlに溶かし、1.5時間加熱還流させた。反応液を
減圧下に濃縮し、残留物に炭酸水素ナトリウム水
溶液を加えクロロホルムで抽出し、水洗したの
ち、無水硫酸マグネシウムで乾燥した。減圧下に
溶媒を留去し、残留物を酢酸エチルに溶かし、活
性炭素で処理したのち、減圧下に溶媒を留去い
た。残留結晶を酢酸エチル−ヘキサンより再結晶
し、融点166〜167℃の5−アミノ−1−(2−ジ
イソプロピルアミノエチル)イサチ1.45gを得
た。 -Toamide-1-(2-diisopropylaminoethyl)isatin Melting point: 187-190°C (ethyl acetate-hexane) Yield: 77.0% Elemental analysis: (as C 18 H 25 N 3 O 3 ) C% H% N % Calculated value 65.24 7.60 12.68 Actual value 65.07 7.61 12.38 IR (KBr): ν NH 3300cm -1 ν CO 1720, 1660cm -1 NMR (d 6 −DMSO) δ: 0.88 (12H, d, J = 6.6Hz), 2.04 (3H,
s), 2.62 (2H, t, J=6.6Hz), 2.99 (2H,
sept, J = 6.6Hz), 3.62 (2H, t, J = 6.6
Hz), 7.10 (1H, d, J = 7.5Hz), 7.72 (1H,
dd, J=2.2and7.5Hz), 7.84(1H, d, J=
2.2Hz), 10.05 (1H, s) Example 12 5-amino-1-(2-diisopropylaminoethyl)isatin 2.07g of 5-acetamido-1-(2-diisopropylaminoethyl)isatin was dissolved in 6N hydrochloric acid 150
ml and heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and an aqueous sodium bicarbonate solution was added to the residue, extracted with chloroform, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, treated with activated carbon, and then the solvent was distilled off under reduced pressure. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 1.45 g of 5-amino-1-(2-diisopropylaminoethyl)isachi having a melting point of 166-167°C.
元素分析値:(C16H23N3O2として)
C% H% N%
計算値 66.41 8.01 14.52
実測値 66.16 8.05 14.24
IR(KBr):νNH3420、3320cm-1
νCO1715cm-1
NMR(d6−DMSO)
δ:0.88(12H、d、J=6.6Hz)、2.59(2H、
t、J=6.6Hz)、2.98(2H、sept、J=6.6
Hz)、3.55(2H、t、J=6.6Hz)、5.13(2H、
s)、6.76(1H、d、J=2.2Hz)、6.84(1H、
d、J=8.2Hz)、6.89(1H、dd、J=
2.2and8.2Hz)
実施例 13
7−イサチンカルボン酸メチルと2−ジイソプ
ロピルアミノエチルクロリド塩酸塩を用い、実施
例7とほぼ同様にして下記の化合物を製造した。Elemental analysis value: (as C 16 H 23 N 3 O 2 ) C% H% N% Calculated value 66.41 8.01 14.52 Actual value 66.16 8.05 14.24 IR (KBr): ν NH 3420, 3320cm -1 ν CO 1715cm -1 NMR ( d 6 −DMSO) δ: 0.88 (12H, d, J = 6.6Hz), 2.59 (2H,
t, J = 6.6Hz), 2.98 (2H, sept, J = 6.6
Hz), 3.55 (2H, t, J = 6.6Hz), 5.13 (2H,
s), 6.76 (1H, d, J=2.2Hz), 6.84 (1H,
d, J=8.2Hz), 6.89(1H, dd, J=
2.2 and 8.2 Hz) Example 13 The following compound was produced in substantially the same manner as in Example 7 using methyl 7-isatincarboxylate and 2-diisopropylaminoethyl chloride hydrochloride.
1−(2−ジイソプロピルアミノエチル)−7−イ
サチンカルボン酸メチル
性状:油状
収率:94.6%
IR(neat):νCO1720cm-1
NMR(CDCl3)
δ:0.80(12H、d、J=6.6Hz)、2.51(2H、
t、J=6.6Hz)、2.95(2H、sept、J=6.6
Hz)、3.98(3H、s)、4.04(2H、t、J=6.6
Hz)、7.13(1H、t、J=7.7Hz)、7.72(1H、
dd、J=1.7and7.7Hz)、7.86(1H、dd、J=
1.7and7.7Hz)
実施例 14
1−(2−ジイソプロピルアミノエチル)−5−
メトキシイサチン
5−メトキシイサチン3.00gと2−ジイソプロ
ピルアミノエチルクロリド塩酸塩3.38gを乾燥
N、N−ジメチルホルムアミド50mlに溶かし、氷
冷下にかき混ぜながら60%水素化ナトリウム(油
性)1.36gを加えたのち、室温で1時間さらに80
℃で13時間反応させた。減圧下に溶媒を留去し、
残留物に水を加え酢酸エチルで抽出し、水洗した
のち、無水硫酸マグネシウムで乾燥した。減圧下
に溶媒を留去し、残留物をシリカゲルフラツシユ
カラムクロマトグラフイー(溶出溶媒:クロロホ
ルム)で精製後ヘキサンより再結晶し、融点81〜
82.5℃の1−(2−ジイソプロピルアミノエチル)
−5−メトキシイサチン3.33gを得た。Methyl 1-(2-diisopropylaminoethyl)-7-isatincarboxylate Properties: Oil Yield: 94.6% IR (neat): ν CO 1720cm -1 NMR (CDCl 3 ) δ: 0.80 (12H, d, J= 6.6Hz), 2.51(2H,
t, J = 6.6Hz), 2.95 (2H, sept, J = 6.6
Hz), 3.98 (3H, s), 4.04 (2H, t, J=6.6
Hz), 7.13 (1H, t, J = 7.7Hz), 7.72 (1H,
dd, J=1.7and7.7Hz), 7.86(1H, dd, J=
1.7and7.7Hz) Example 14 1-(2-diisopropylaminoethyl)-5-
Methoxyisatin Dissolve 3.00 g of 5-methoxyisatin and 3.38 g of 2-diisopropylaminoethyl chloride hydrochloride in 50 ml of dry N,N-dimethylformamide, and add 1.36 g of 60% sodium hydride (oil-based) while stirring under ice cooling. 80°C for another 1 hour at room temperature.
The reaction was carried out at ℃ for 13 hours. The solvent was distilled off under reduced pressure,
Water was added to the residue, extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (elution solvent: chloroform) and then recrystallized from hexane to give a melting point of 81~
1-(2-diisopropylaminoethyl) at 82.5℃
3.33 g of -5-methoxyisatin was obtained.
元素分析値:(C17H24N2O3として)
C% H% N%
計算値 67.08 7.95 9.20
実測値 67.35 8.11 9.19
IR(KBr):νCO1715cm-1
NMR(CDCl3)
δ:0.97(12H、d、J=6.6Hz)、2.68(2H、
t、J=6.6Hz)、3.03(2H、sept、J=6.6
Hz)、3.66(2H、t、J=6.6Hz)、3.80(3H、
s)、6.8〜6.9(1H、m)、7.1〜7.2(2H、m)
実施例 15
7−ブロモ−5−メチルイサチンと2−ジイソ
プロピルアミノエチルクロリド塩酸塩を用い、実
施例1とほぼ同様にして下記の化合物を製造し
た。Elemental analysis value: (as C 17 H 24 N 2 O 3 ) C% H% N% Calculated value 67.08 7.95 9.20 Actual value 67.35 8.11 9.19 IR (KBr): ν CO 1715cm -1 NMR (CDCl 3 ) δ: 0.97 ( 12H, d, J = 6.6Hz), 2.68 (2H,
t, J=6.6Hz), 3.03(2H, sept, J=6.6
Hz), 3.66 (2H, t, J=6.6Hz), 3.80 (3H,
s), 6.8-6.9 (1H, m), 7.1-7.2 (2H, m) Example 15 In almost the same manner as in Example 1 using 7-bromo-5-methylisatin and 2-diisopropylaminoethyl chloride hydrochloride. The following compounds were prepared.
7−ブロモ−1−(2−ジイソプロピルアミノ
エチル)−5−メチルイサチン
融点:94〜97℃(ヘキサン)
収率:13.1%
元素分析値:(C17H23BrN2O2として)
C% H% N%
計算値 55.59 6.31 7.63
実測値 55.35 6.29 7.53
IR(KBr):νCO1730cm-1
NMR(CDCl3)
δ:0.90(12H、d、J=6.6Hz)、2.30(3H、
s)、2.73(2H、t、J=6.6Hz)、3.03(2H、
sept、J=6.6Hz)、4.17(2H、t、J=6.6
Hz)、7.37(1H、d、J=1.1Hz)、7.52(1H、
d、J=1.1Hz)
実施例 16
5−メチルイサチンと3−ジイソプロピルアミ
ノプロピルクロリド塩酸塩を用い、実施例1とほ
ぼ同様にして下記の化合を製造した。7-bromo-1-(2-diisopropylaminoethyl)-5-methylisatin Melting point: 94-97°C (hexane) Yield: 13.1% Elemental analysis: (as C 17 H 23 BrN 2 O 2 )
C% H% N% Calculated value 55.59 6.31 7.63 Actual value 55.35 6.29 7.53 IR (KBr): ν CO 1730cm -1 NMR (CDCl 3 ) δ: 0.90 (12H, d, J = 6.6Hz), 2.30 (3H,
s), 2.73 (2H, t, J=6.6Hz), 3.03 (2H,
sept, J = 6.6Hz), 4.17 (2H, t, J = 6.6
Hz), 7.37 (1H, d, J = 1.1Hz), 7.52 (1H,
d, J=1.1Hz) Example 16 The following compound was produced in substantially the same manner as in Example 1 using 5-methylisatin and 3-diisopropylaminopropyl chloride hydrochloride.
1−(3−ジイソプロピルアミノプロピル)−5−
メチルイサチン
融点:87〜89℃(ヘキサン)
収率:53.3%
元素分析値:(C18H26N2O2として)
C% H% N%
計算値 71.49 8.67 9.26
実測値 71.61 8.86 9.24
IR(KBr):νCO1730cm-1
NMR(CDCl3)
δ:1.01(12H、d、J=6.6Hz)、1.7〜1.85
(2H、m)、2.33(3H、s)、2.45〜2.6(2H、
m)、2.95〜3.1(2H、m).3.73(2H、t、J
=7.1Hz)、6.81(1H、d、J=7.7Hz)、7.38
(1H、d、J=7.7Hz)、7.40(1H、s)
実施例 17
5−メトキシイサチンと2−ジブチルアミノエ
チルクロリド塩酸塩を用い、実施例7とほぼ同様
に反応させ処理後、シリカゲルフラツシユカラム
クロマドグラフイー(溶出溶媒:クロロホルム)
で精製し、下記の化合物を製造した。1-(3-diisopropylaminopropyl)-5-
Methylisatin Melting point: 87-89℃ (hexane) Yield: 53.3% Elemental analysis: (as C 18 H 26 N 2 O 2 ) C% H% N% Calculated value 71.49 8.67 9.26 Actual value 71.61 8.86 9.24 IR (KBr) :ν CO 1730cm -1 NMR (CDCl 3 ) δ: 1.01 (12H, d, J = 6.6Hz), 1.7 to 1.85
(2H, m), 2.33 (3H, s), 2.45~2.6 (2H,
m), 2.95-3.1 (2H, m). 3.73 (2H, t, J
= 7.1Hz), 6.81 (1H, d, J = 7.7Hz), 7.38
(1H, d, J = 7.7Hz), 7.40 (1H, s) Example 17 Using 5-methoxyisatin and 2-dibutylaminoethyl chloride hydrochloride, after treatment in almost the same manner as in Example 7, silica gel Flash column chromatography (elution solvent: chloroform)
The following compound was produced.
1−(2−ジブチルアミノエチル)−5−メトキシ
イサチン
融点:32〜34℃
収率:79.3%
元素分析値:(C19H28N2O3として)
C% H% N%
計算値 68.65 8.49 8.43
実測値 68.89 8.79 8.41
IR(KBr):νCO1715cm-1
NMR(CDCl3)
δ:0.86(6H、d、J=7.1Hz)、1.15〜1.45
(8H、m)、2.45(4H、t、J=7.1Hz)、2.68
(2H、t、J=6.6Hz)、3.75(2H、t、J=
6.6Hz).3.80(3H、s)、6.8〜6.9(1H、m)、
7.1〜7.2(2H、m)
実施例 18
5−フロオロイサチンと2−ジブチルアミノエ
チルクロリド塩酸塩を用い、実施例7とほぼ同様
に反応させ処理後、シリカゲルカラムクロマドグ
ラフイー(溶出溶媒:クロロホルム)で精製し、
下記の化合物を製造した。1-(2-dibutylaminoethyl)-5-methoxyisatin Melting point: 32-34°C Yield: 79.3% Elemental analysis: (as C 19 H 28 N 2 O 3 ) C% H% N% Calculated value 68.65 8.49 8.43 Actual value 68.89 8.79 8.41 IR (KBr): ν CO 1715cm -1 NMR (CDCl 3 ) δ: 0.86 (6H, d, J = 7.1Hz), 1.15 to 1.45
(8H, m), 2.45 (4H, t, J=7.1Hz), 2.68
(2H, t, J=6.6Hz), 3.75 (2H, t, J=
6.6Hz). 3.80 (3H, s), 6.8~6.9 (1H, m),
7.1-7.2 (2H, m) Example 18 Using 5-fluoroisatin and 2-dibutylaminoethyl chloride hydrochloride, react in almost the same manner as in Example 7, and then perform silica gel column chromatography (elution solvent: chloroform) Refined with
The following compounds were prepared.
1−(2−ジブチルアミノエチル)−5−フルオロ
イサチン
融点:52〜54℃
収率:61.0%
元素分析値:(C18H25FN2O2として)
C% H% N%
計算値 67.48 7.86 8.74
実測値 67.65 8.02 8.69
IR(KBr):νCO1730cm-1
NMR(CDCl3)
δ:0.85(6H、d、J=7.1Hz)、1.1〜1.4(8H、
m)、2.44(4H、t、J=7.1Hz)、2.69(2H、
t、J=6.6Hz)、3.78(2H、t、J=6.6Hz)、
6.58〜7.0(1H、m)、7.25〜7.4(2H、m)
実施例 19
5−クロロイサチンと2−ジブチルアミノエチ
ルエチルクロリド塩酸塩を用い、実施例7とほぼ
同様に反応させ処理後、シリカゲルカラムクロマ
トグラフイー(溶出溶媒:クロロホルム)で精製
し、下記の化合物を製造した。1-(2-dibutylaminoethyl)-5-fluoroisatin Melting point: 52-54℃ Yield: 61.0% Elemental analysis: (as C 18 H 25 FN 2 O 2 ) C% H% N% Calculated value 67.48 7.86 8.74 Actual value 67.65 8.02 8.69 IR (KBr): ν CO 1730cm -1 NMR (CDCl 3 ) δ: 0.85 (6H, d, J = 7.1Hz), 1.1 to 1.4 (8H,
m), 2.44 (4H, t, J=7.1Hz), 2.69 (2H,
t, J = 6.6Hz), 3.78 (2H, t, J = 6.6Hz),
6.58 to 7.0 (1H, m), 7.25 to 7.4 (2H, m) Example 19 Using 5-chloroisatin and 2-dibutylaminoethylethyl chloride hydrochloride, react in almost the same manner as in Example 7, and then apply it to a silica gel column. It was purified by chromatography (elution solvent: chloroform) to produce the following compound.
5−クロロ−1−(2−ジブチルアミノエチル)
イサチン
融点:35〜36℃
収率:51.5%
元素分析値:(C18H25ClN2O2として)
C% H% N%
計算値 64.18 7.48 8.32
実測値 64.31 7.69 8.55
IR(KBr):νCO1725cm-1
NMR(CDCl3)
δ:0.86(6H、d、J=7.1Hz)、1.1〜1.4(8H、
m)、2.44(4H、t、J=7.1Hz)、2.68(2H、
t、J=6.6Hz)、3.78(2H、t、J=6.6Hz)、
6.85〜7.95(1H、m)、7.5〜7.6(2H、m)
実施例 20
5−ブロモイサチンと2−ジブチルアミノエチ
ルクロリド塩酸塩を用い、実施例7とほぼ同様に
反応させ処理後、シリカゲルカラムクロマトグラ
フイー(溶出溶媒:クロロホルム)で精製し、下
記の化合物を製造した。5-chloro-1-(2-dibutylaminoethyl)
Isatin Melting point: 35-36℃ Yield: 51.5% Elemental analysis: (as C 18 H 25 ClN 2 O 2 ) C% H% N% Calculated value 64.18 7.48 8.32 Actual value 64.31 7.69 8.55 IR (KBr): ν CO 1725cm -1 NMR (CDCl 3 ) δ: 0.86 (6H, d, J = 7.1Hz), 1.1-1.4 (8H,
m), 2.44 (4H, t, J=7.1Hz), 2.68 (2H,
t, J = 6.6Hz), 3.78 (2H, t, J = 6.6Hz),
6.85 to 7.95 (1H, m), 7.5 to 7.6 (2H, m) Example 20 Using 5-bromoisatin and 2-dibutylaminoethyl chloride hydrochloride, react in almost the same manner as in Example 7, and then perform silica gel column chromatography. It was purified by graphie (elution solvent: chloroform) to produce the following compound.
5−ブロモ−1−(2−ジブチルアミノエチル)
イサチン
融点:38〜40℃
収率:46.9%
元素分析値:(C18H25BrN2O2として)
C% H% N%
計算値 56.70 6.61 7.35
実測値 56.38 6.85 7.59
IR(KBr):νCO1730cm-1
NMR(CDCl3)
δ:0.86(6H、d、J=7.1Hz)、1.1〜1.4(8H、
m)、2.44(4H、t、J=7.1Hz)、2.68(2H、
t、J=6.6Hz)、3.77(2H、t、J=6.6Hz)、
6.86(1H、d、J=8.8Hz)、7.65〜7.75(2H、
m)
実施例 21
5−アセトアミドイサチンと2−ジブチルアミ
ノエチルクロリド塩酸塩を用い、実施例7とほぼ
同様にして下記の化合物を製造した。5-Bromo-1-(2-dibutylaminoethyl)
Isatin Melting point: 38-40℃ Yield: 46.9% Elemental analysis value: (as C 18 H 25 BrN 2 O 2 ) C% H% N% Calculated value 56.70 6.61 7.35 Actual value 56.38 6.85 7.59 IR (KBr): ν CO 1730cm -1 NMR (CDCl 3 ) δ: 0.86 (6H, d, J = 7.1Hz), 1.1-1.4 (8H,
m), 2.44 (4H, t, J=7.1Hz), 2.68 (2H,
t, J = 6.6Hz), 3.77 (2H, t, J = 6.6Hz),
6.86 (1H, d, J = 8.8Hz), 7.65~7.75 (2H,
m) Example 21 The following compound was produced in substantially the same manner as in Example 7 using 5-acetamidoisatin and 2-dibutylaminoethyl chloride hydrochloride.
5−アセトアミド−1−(2−ジブチルアミノエ
チル)イサチン
融点:157〜159℃(酢酸エチル)
収率:63.3%
元素分析値:(C20H29N3O3として)
C% H% N%
計算値 66.83 8.13 11.69
実測値 66.56 8.00 11.51
IR(KBr):νNH3340cm-1
νCO1740、1710、1670cm-1
NMR(d6−DMSO)
δ:0.78(6H、t、J=7.1Hz)、1.05〜1.35
(8H、m)、2.04(3H、s)、2.37(4H、t、
J=7.1Hz)、2.60(2H、t、J=6.6Hz)、3.70
(2H、d、J=6.6Hz)、7.13(1H、d、J=
8.2Hz)、7.72(1H、dd、J=2.2and8.2Hz)、
7.84(1H、d、J=2.2Hz)、10.04(1H、s)
実施例 22
7−イサチンカルボン酸メチルと2−ジブチル
アミノエチルクロリド塩酸塩を用い、実施例7と
ほぼ同様に反応させ処理後、シリカゲルカラムク
ロマトグラフイー(溶出溶媒:クロロホルム)で
精製し、下記の化合物を製造した。5-acetamido-1-(2-dibutylaminoethyl)isatin Melting point: 157-159°C (ethyl acetate) Yield: 63.3% Elemental analysis: (as C 20 H 29 N 3 O 3 ) C% H% N% Calculated value 66.83 8.13 11.69 Actual value 66.56 8.00 11.51 IR (KBr): ν NH 3340cm -1 ν CO 1740, 1710, 1670cm -1 NMR (d 6 −DMSO) δ: 0.78 (6H, t, J = 7.1Hz), 1.05~1.35
(8H, m), 2.04 (3H, s), 2.37 (4H, t,
J=7.1Hz), 2.60 (2H, t, J=6.6Hz), 3.70
(2H, d, J = 6.6Hz), 7.13 (1H, d, J =
8.2Hz), 7.72 (1H, dd, J=2.2and8.2Hz),
7.84 (1H, d, J = 2.2Hz), 10.04 (1H, s) Example 22 Using methyl 7-isatincarboxylate and 2-dibutylaminoethyl chloride hydrochloride, react and treat in almost the same manner as in Example 7. Thereafter, the product was purified by silica gel column chromatography (elution solvent: chloroform) to produce the following compound.
1−(2−ジブチルアミノエチル)−7−イサチン
カルボン酸メチル
性状:油状
収率:91.7%
元素分析値:(C20H28N2O4・0.07CHCl3として)
C% H% N%
計算値 65.36 7.67 7.60
実測値 65.18 7.87 7.70
IR(neat):νCO1720cm-1
NMR(CDCl3)
δ:0.79(6H、t、J=7.1Hz)、1.0〜1.2(8H、
m)、2.30(4H、t、J=7.1Hz)、2.46(2H、
t、J=6.6Hz)、3.97(3H、s)、4.10(2H、
t、J=6.6Hz)、7.14(1H、t、J=7.7Hz)、
7.74(1H、dd、J=1.7and7.7Hz)、7.88(1H、
dd、J=1.7and7.7Hz)
実施例 23
イサチンと3−ジブチルアミノプロピルクロリ
ド塩酸塩を用い、実施例7とほぼ同様に反応させ
処理後、シリカゲルフラツシユカラムクロマトグ
ラフイー(溶出溶媒:クロロホルム/エタノール
=100/1)で精製し、下記の化合物を製造した。Methyl 1-(2-dibutylaminoethyl)-7-isatincarboxylate Properties: Oil Yield : 91.7% Elemental analysis: (as C20H28N2O4・0.07CHCl3 ) C% H% N% Calculated value 65.36 7.67 7.60 Actual value 65.18 7.87 7.70 IR (neat): ν CO 1720cm -1 NMR (CDCl 3 ) δ: 0.79 (6H, t, J = 7.1Hz), 1.0 to 1.2 (8H,
m), 2.30 (4H, t, J=7.1Hz), 2.46 (2H,
t, J=6.6Hz), 3.97 (3H, s), 4.10 (2H,
t, J = 6.6Hz), 7.14 (1H, t, J = 7.7Hz),
7.74 (1H, dd, J=1.7and7.7Hz), 7.88 (1H,
dd, J = 1.7 and 7.7 Hz) Example 23 Using isatin and 3-dibutylaminopropyl chloride hydrochloride, they were reacted in the same manner as in Example 7, and then subjected to silica gel flash column chromatography (elution solvent: chloroform/ The following compound was produced by purification using ethanol (100/1).
1−(3−ジブチルアミノプロピル)イサチン
性状:油状
収率:83.7%
元素分析値:(C19H28N2O2として)
C% H% N%
計算値 72.12 8.92 8.85
実測値 72.09 9.11 8.77
IR(neat):νCO1730cm-1
NMR(CDCl3)
δ:0.90(6H、t、J=7.1Hz)、1.2〜1.5(8H、
m)、1.83(2H、quint、J=7.1Hz)、2.39
(4H、t、7.1Hz)、2.49(2H、t、J=7.1
Hz)、3.77(2H、t、J=7.1Hz)、6.96(1H、
d、J=7.7Hz)、7.10(1H、t、J=7.7Hz)、
7.58(1H、t、J=7.7Hz)、7.60(1H、d、
J=7.7Hz)
実施例 24
イサチンと2−ジブチルアミノエチルクロリド
塩酸塩を用い、実施例1とほぼ同様に反応させ処
理し、シリカゲルフラツシユカラムクロマトグラ
フイー(溶出溶媒:クロロホルム/ムタノール=
100/1)で精製後、ヘキサンより再結晶し下記
の化合物を製造した。1-(3-dibutylaminopropyl)isatin Properties: Oil Yield: 83.7% Elemental analysis: (as C 19 H 28 N 2 O 2 ) C% H% N% Calculated value 72.12 8.92 8.85 Actual value 72.09 9.11 8.77 IR (neat): ν CO 1730cm -1 NMR (CDCl 3 ) δ: 0.90 (6H, t, J = 7.1Hz), 1.2-1.5 (8H,
m), 1.83 (2H, quint, J=7.1Hz), 2.39
(4H, t, 7.1Hz), 2.49 (2H, t, J=7.1
Hz), 3.77 (2H, t, J=7.1Hz), 6.96 (1H,
d, J = 7.7Hz), 7.10 (1H, t, J = 7.7Hz),
7.58 (1H, t, J = 7.7Hz), 7.60 (1H, d,
J = 7.7Hz) Example 24 Using isatin and 2-dibutylaminoethyl chloride hydrochloride, the reaction was carried out in almost the same manner as in Example 1, and silica gel flash column chromatography (elution solvent: chloroform/mtanol =
100/1) and recrystallized from hexane to produce the following compound.
1−(2−ジブチルアミノエチル)イサチン
融点:40〜42℃
収率:79.3%
元素分析値:(C18H26N2O2として)
C% H% N%
計算値 71.49 8.67 9.26
実測値 71.48 8.79 9.16
IR(KBr):νCO1720cm-1
NMR(CDCl3)
δ:0.86(6H、t、J=7.1Hz)、1.15〜1.45
(8H、m)、2.45(4H、t、J=7.1Hz)、2.69
(2H、t、J=6.6Hz)、3.78(2H、t、J=
6.6Hz)、6.93(1H、d、J=7.7Hz)、7.10
(1H、t、J=7.7Hz)、7.58(1H、t、J=
7.7Hz)、7.60(1H、d、J=7.7Hz)
実施例 25
5−メチルイサチンと2−ジブチルアミノエチ
ルクロリド塩酸塩を用い、実施例1とほぼ同様に
反応させ処理後、シリカゲルフラツシユカラムク
ロマトグラフイー(溶出溶媒:クロロホルク)で
精製し、下記の化合物を製造した。1-(2-dibutylaminoethyl)isatin Melting point: 40-42℃ Yield: 79.3% Elemental analysis: (as C 18 H 26 N 2 O 2 ) C% H% N% Calculated value 71.49 8.67 9.26 Actual value 71.48 8.79 9.16 IR (KBr): ν CO 1720cm -1 NMR (CDCl 3 ) δ: 0.86 (6H, t, J = 7.1Hz), 1.15 to 1.45
(8H, m), 2.45 (4H, t, J=7.1Hz), 2.69
(2H, t, J=6.6Hz), 3.78 (2H, t, J=
6.6Hz), 6.93 (1H, d, J = 7.7Hz), 7.10
(1H, t, J=7.7Hz), 7.58 (1H, t, J=
7.7Hz), 7.60 (1H, d, J = 7.7Hz) Example 25 Using 5-methylisatin and 2-dibutylaminoethyl chloride hydrochloride, the reaction was performed in substantially the same manner as in Example 1, and then subjected to silica gel flash column chromatography. Purification was performed using Graphi (elution solvent: chloroform) to produce the following compound.
1−(2−ジブチルアミノエチル)−5−メチルイ
サチン
融点:33〜35℃
収率:62.2%
元素分析値:(C19H28N2O2として)
C% H% N%
計算値 72.12 8.92 8.85
実測値 72.00 9.13 8.79
IR(KBr):νCO1720cm-1
NMR(CDCl3)
δ:0.86(6H、t、J=7.1Hz)、1.15〜1.45
(8H、m)、2.33(3H、s)、2.45(4H、t、
J=7.1Hz)、2.68(2H、t、J=6.6Hz)、3.76
(2H、t、J=6.6Hz)、6.82(1H、d、J=
7.7Hz)、7.38(1H、d、J=7.7Hz)、7.39
(1H、s)
実施例 26
5−アセトアミド−1−(2−ジブチルアミノ
エチル)イサチンを用い、実施例1とほぼ同様に
して下記の化合物を製造した。1-(2-dibutylaminoethyl)-5-methylisatin Melting point: 33-35°C Yield: 62.2% Elemental analysis: (as C 19 H 28 N 2 O 2 ) C% H% N% Calculated value 72.12 8.92 8.85 Actual value 72.00 9.13 8.79 IR (KBr): ν CO 1720cm -1 NMR (CDCl 3 ) δ: 0.86 (6H, t, J = 7.1Hz), 1.15 to 1.45
(8H, m), 2.33 (3H, s), 2.45 (4H, t,
J=7.1Hz), 2.68 (2H, t, J=6.6Hz), 3.76
(2H, t, J = 6.6Hz), 6.82 (1H, d, J =
7.7Hz), 7.38 (1H, d, J = 7.7Hz), 7.39
(1H, s) Example 26 The following compound was produced in substantially the same manner as in Example 1 using 5-acetamido-1-(2-dibutylaminoethyl)isatin.
5−アミノ−1−(2−ジブチルアミノエチル)
イサチン
融点:134〜135℃
収率:85.3%
元素分析値:(C18H27N3O2として)
C% H% N%
計算値 68.11 8.57 13.24
実測値 68.09 8.66 13.13
IR(KBr):νNH3450、3350cm-1
νCO1715cm-1
NMR(d6−DMSO)
δ:0.79(6H、t、J=7.1Hz)、1.05〜1.3(8H、
m)、2.36(4H、t、J=7.1Hz)、2.58(2H、
t、J=6.6Hz)、3.63(2H、t、J=6.6Hz)、
5.13(2H、s)、6.76(1H、s)、6.87(2H、
s)
実施例 27
イサチンと2−(N−メチルブチルアミノ)エ
チルクロリド塩酸塩を用い、実施例7とほぼ同様
に反応させ処理後、シリカゲルフラツシユカラム
クロマトグラフイー(溶出溶媒:クロロホルク)
で精製し、下記の化合物を製造した。5-amino-1-(2-dibutylaminoethyl)
Isatin Melting point: 134-135℃ Yield: 85.3% Elemental analysis: (as C 18 H 27 N 3 O 2 ) C% H% N% Calculated value 68.11 8.57 13.24 Actual value 68.09 8.66 13.13 IR (KBr): ν NH 3450, 3350cm -1 ν CO 1715cm -1 NMR ( d6 -DMSO) δ: 0.79 (6H, t, J = 7.1Hz), 1.05-1.3 (8H,
m), 2.36 (4H, t, J=7.1Hz), 2.58 (2H,
t, J = 6.6Hz), 3.63 (2H, t, J = 6.6Hz),
5.13 (2H, s), 6.76 (1H, s), 6.87 (2H,
s) Example 27 Isatin and 2-(N-methylbutylamino)ethyl chloride hydrochloride were reacted in substantially the same manner as in Example 7, followed by silica gel flash column chromatography (elution solvent: chloroform).
The following compound was produced.
1−〔2−(N−メチルブチルアミノ)エチル〕イ
サチン〕
性状:油状
収率:83.5%
元素分析値:(C15H20N2O2として)
C% H% N%
計算値 69.21 7.74 10.76
実測値 69.10 7.94 10.67
IR(neat):νCO1720cm-1
NMR(CDCl3)
δ:0.84(3H、t、J=7.1Hz)、1.15〜1.45
(4H、m)、2.30(3H、s)、2.38(2H、t、
J=7.1Hz)、2.64(2H、t、J=6.6Hz)、3.83
(2H、t、J=6.6Hz)、6.94(1H、d、J=
7.7Hz)、7.10(1H、t、J=7.7Hz)、7.10
(1H、t、J=7.7Hz)、7.58(1H、t、J=
7.7Hz)、7.60(1H、d、J=7.7Hz)
実施例 28
イサチンと2−(N−イソプロピルシクロヘキ
シルアミノ)エチルクロリド塩酸塩を用い、実施
例1とほぼ同様にして下記の化合物を製造した。1-[2-(N-methylbutylamino)ethyl]isatin] Properties: Oil Yield: 83.5% Elemental analysis: (as C 15 H 20 N 2 O 2 ) C% H% N% Calculated value 69.21 7.74 10.76 Actual value 69.10 7.94 10.67 IR (neat): ν CO 1720cm -1 NMR (CDCl 3 ) δ: 0.84 (3H, t, J = 7.1Hz), 1.15 to 1.45
(4H, m), 2.30 (3H, s), 2.38 (2H, t,
J = 7.1Hz), 2.64 (2H, t, J = 6.6Hz), 3.83
(2H, t, J = 6.6Hz), 6.94 (1H, d, J =
7.7Hz), 7.10 (1H, t, J = 7.7Hz), 7.10
(1H, t, J=7.7Hz), 7.58 (1H, t, J=
7.7Hz), 7.60 (1H, d, J = 7.7Hz) Example 28 The following compound was produced in substantially the same manner as in Example 1 using isatin and 2-(N-isopropylcyclohexylamino)ethyl chloride hydrochloride. .
1−〔2−(N−イソプロピルシクロヘキシルアミ
ノ)エチル〕イサチン
融点:103〜106℃(酢酸エチル−へキサン)
収率:75.5%
元素分析値:(C19H26N2O2として)
C% H% N%
計算値 72.58 8.33 8.91
実測値 72.37 8.48 8.99
IR(KBr):νCO1725cm-1
NMR(CDCl3)
δ:0.96(6H、d、J=6.6Hz)、1.0〜1.8(10H、
m)、2.45〜2.6(2H、m)、2.75(2H、t、J
=6.6Hz)、3.06(1H、sept、J=6.6Hz)、3.68
(2H、t、J=6.6Hz)、6.91(1H、d、J=
7.7Hz)、7.08(1H、t、J=7.7Hz)、7.57
(1H、t、J=7.7Hz)、7.58(1H、d、J=
7.7Hz)
実施例 29
1−(2−ジプロピルアミノエチル)イサチン
1−(2−ブロモエチル)イサチン2.50g、ジ
プロピルアミン1.37ml、無水炭酸カリウム1.38g
およびヨウ化ナトリウム1.50gを乾燥ベンゼン
100mlに加え、72時間加熱還流させた。冷後、反
応液を水洗したのち、無水硫酸マグネシウムで乾
燥し、減圧下に溶媒を留去した。残留物をシリカ
ゲルフラツシユカラムクロマトグラフイー(溶出
溶媒:クロロホルム)で精製し、融点30℃以下の
固体として1−(2−ジプロピルアミノエチル)
イサチン1.82gを得た。1-[2-(N-isopropylcyclohexylamino)ethyl]isatin Melting point: 103-106°C (ethyl acetate-hexane) Yield: 75.5% Elemental analysis: (as C 19 H 26 N 2 O 2 ) C% H% N% Calculated value 72.58 8.33 8.91 Actual value 72.37 8.48 8.99 IR (KBr): ν CO 1725cm -1 NMR (CDCl 3 ) δ: 0.96 (6H, d, J = 6.6Hz), 1.0 to 1.8 (10H,
m), 2.45-2.6 (2H, m), 2.75 (2H, t, J
= 6.6Hz), 3.06 (1H, sept, J = 6.6Hz), 3.68
(2H, t, J = 6.6Hz), 6.91 (1H, d, J =
7.7Hz), 7.08 (1H, t, J = 7.7Hz), 7.57
(1H, t, J = 7.7Hz), 7.58 (1H, d, J =
7.7Hz) Example 29 1-(2-dipropylaminoethyl) isatin 2.50 g of 1-(2-bromoethyl) isatin, 1.37 ml of dipropylamine, 1.38 g of anhydrous potassium carbonate
and 1.50 g of sodium iodide in dry benzene
The mixture was added to 100 ml and heated under reflux for 72 hours. After cooling, the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (elution solvent: chloroform) to obtain 1-(2-dipropylaminoethyl) as a solid with a melting point of 30°C or lower.
1.82 g of isatin was obtained.
元素分析値:(C16H22N2O2・0.2H2Oとして)
C% H% N%
計算値 69.14 8.12 10.08
実測値 69.26 8.23 9.91
IR(KBr):νCO1730cm-1
NMR(CDCl3)
δ:0.83(6H、t、J=7.1Hz)、1.40(4H、
sexn、J=7.1Hz)、2.43(4H、t、J=7.1
Hz)、2.70(2H、t、J=6.6Hz)、3.79(2H、
t、J=6.6Hz)、6.94(1H、d、J=7.7Hz)、
7.09(1H、t、J=7.7Hz)、7.58(1H、t、
J=7.7Hz)、7.59(1H、d、J=7.7Hz)
実施例 30
1−〔2−N−メチルシクロヘキシルアミノ)
エチル〕イサチン
1−(2−ブロモエチル)イサチン4.00gとN
−メチルシロヘキシルアミン3.58gを乾燥N、N
−ジエチルホルムアミド100mlに溶かし、95℃で
1時間かき混ぜた。減圧下に溶媒を留去し、残留
物を2規定塩酸50mlに溶かしたのち、酢酸エチル
で洗い、炭酸水素ナトリウム水溶液で中和後、酢
酸エチルで抽出した。酢酸エチル層を無水硫酸マ
グネシウムで乾燥し、減圧下に溶媒を留去した。
残留物をシリカゲルカラムクロマトグラフイー
(溶出溶媒:クロロホルム/メタノール=10/1)
で精製後、ベンゼン−ヘキサンより再結晶し、融
点58〜60℃の1−〔2−(N−メチルシクロヘキシ
ルアミノ)エチル〕イサチン2.44gを得た。Elemental analysis value: (as C 16 H 22 N 2 O 2・0.2H 2 O) C% H% N% Calculated value 69.14 8.12 10.08 Actual value 69.26 8.23 9.91 IR (KBr): ν CO 1730cm -1 NMR (CDCl 3 ) δ: 0.83 (6H, t, J=7.1Hz), 1.40 (4H,
sexn, J = 7.1Hz), 2.43 (4H, t, J = 7.1
Hz), 2.70 (2H, t, J = 6.6Hz), 3.79 (2H,
t, J = 6.6Hz), 6.94 (1H, d, J = 7.7Hz),
7.09 (1H, t, J = 7.7Hz), 7.58 (1H, t,
J=7.7Hz), 7.59 (1H, d, J=7.7Hz) Example 30 1-[2-N-methylcyclohexylamino)
Ethyl] isatin 1-(2-bromoethyl) isatin 4.00g and N
- Dry 3.58 g of methylsilohexylamine with N,N
-Dissolved in 100ml of diethylformamide and stirred at 95°C for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in 50 ml of 2N hydrochloric acid, washed with ethyl acetate, neutralized with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography (elution solvent: chloroform/methanol = 10/1)
After purification, the product was recrystallized from benzene-hexane to obtain 2.44 g of 1-[2-(N-methylcyclohexylamino)ethyl]isatin having a melting point of 58 to 60°C.
元素分析値:(C17H22N2O2として)
C% H% N%
計算値 71.30 7.74 9.78
実測値 71.17 7.79 9.65
IR(KBr):νCO1725cm-1
NMR(CDCl3)
δ:0.95〜1.3(5H、m)、1.5〜1.8(5H、m)、
2.25〜2.4(2H、m)、2.71(2H、t、J=6.6
Hz)、3.80(2H、t、J=6.6Hz)、6.95(1H、
d、J=7.1Hz)、7.09(1H、t、J=7.1Hz)、
7.57(1H、t、J=7.1Hz)、7.59(1H、d、
J=7.1Hz)Elemental analysis value: (as C 17 H 22 N 2 O 2 ) C% H% N% Calculated value 71.30 7.74 9.78 Actual value 71.17 7.79 9.65 IR (KBr): ν CO 1725 cm -1 NMR (CDCl 3 ) δ: 0.95 ~ 1.3 (5H, m), 1.5-1.8 (5H, m),
2.25-2.4 (2H, m), 2.71 (2H, t, J = 6.6
Hz), 3.80 (2H, t, J=6.6Hz), 6.95 (1H,
d, J = 7.1Hz), 7.09 (1H, t, J = 7.1Hz),
7.57 (1H, t, J = 7.1Hz), 7.59 (1H, d,
J=7.1Hz)
Claims (1)
基、アミノ基、アシルアミノ基またはアルコキシ
カルボニル基であり、nは1または2であり、Y
は炭素数2〜4の直鎖状または枝分かれ状のアル
キレン鎖であり、R1は炭素数3〜5の直鎖状ま
たは枝分かれ状のアルキル基または炭素数3〜6
のシクロアルキル基であり、R2は炭素数1〜5
の直鎖状または枝分かれ状のアルキル基である)
で表されるイサチン誘導体およびそれらの酸付加
塩。[Claims] 1. General formula (X in the formula is a lower alkyl group, lower alkoxy group, amino group, acylamino group, or alkoxycarbonyl group, n is 1 or 2, and Y
is a linear or branched alkylene chain having 2 to 4 carbon atoms, and R 1 is a linear or branched alkyl group having 3 to 5 carbon atoms or a linear or branched alkyl group having 3 to 6 carbon atoms.
is a cycloalkyl group, and R 2 has 1 to 5 carbon atoms.
straight-chain or branched alkyl group)
Isatin derivatives represented by and acid addition salts thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11328086A JPS62270559A (en) | 1986-05-16 | 1986-05-16 | Isatin derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11328086A JPS62270559A (en) | 1986-05-16 | 1986-05-16 | Isatin derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS62270559A JPS62270559A (en) | 1987-11-24 |
JPH0533947B2 true JPH0533947B2 (en) | 1993-05-20 |
Family
ID=14608176
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP11328086A Granted JPS62270559A (en) | 1986-05-16 | 1986-05-16 | Isatin derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS62270559A (en) |
-
1986
- 1986-05-16 JP JP11328086A patent/JPS62270559A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS62270559A (en) | 1987-11-24 |
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