JPS63250374A - (2-(1,3-benzodixol-5-yl)ethyl)thio derivative - Google Patents
(2-(1,3-benzodixol-5-yl)ethyl)thio derivativeInfo
- Publication number
- JPS63250374A JPS63250374A JP62082258A JP8225887A JPS63250374A JP S63250374 A JPS63250374 A JP S63250374A JP 62082258 A JP62082258 A JP 62082258A JP 8225887 A JP8225887 A JP 8225887A JP S63250374 A JPS63250374 A JP S63250374A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- lower alkyl
- group
- magnetic resonance
- 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.)
- Granted
Links
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- -1 [2-(1,3-benzodioxole-5- yl)ethyl]thio Chemical class 0.000 claims description 33
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 80
- 208000019423 liver disease Diseases 0.000 abstract description 14
- 238000002360 preparation method Methods 0.000 abstract description 8
- 125000002252 acyl group Chemical group 0.000 abstract description 4
- IMEQHZBNJVZGIB-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)ethanethiol Chemical compound SCCC1=CC=C2OCOC2=C1 IMEQHZBNJVZGIB-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract description 2
- 150000002367 halogens Chemical class 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 34
- 238000004949 mass spectrometry Methods 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- 238000004519 manufacturing process Methods 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000002585 base Substances 0.000 description 24
- 239000002904 solvent Substances 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 238000002844 melting Methods 0.000 description 17
- 230000008018 melting Effects 0.000 description 17
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 238000010992 reflux Methods 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 239000013076 target substance Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 5
- 101150041968 CDC13 gene Proteins 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 5
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- XMXCRJLWEKHZAV-UHFFFAOYSA-N 5-ethynyl-1,3-benzodioxole Chemical compound C#CC1=CC=C2OCOC2=C1 XMXCRJLWEKHZAV-UHFFFAOYSA-N 0.000 description 3
- 239000004378 Glycyrrhizin Substances 0.000 description 3
- 206010067125 Liver injury Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 3
- 229960004949 glycyrrhizic acid Drugs 0.000 description 3
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 3
- 235000019410 glycyrrhizin Nutrition 0.000 description 3
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 231100000234 hepatic damage Toxicity 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000008818 liver damage Effects 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 206010023126 Jaundice Diseases 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- DIYWRNLYKJKHAM-MDOVXXIYSA-N (-)-cubebin Chemical compound C1=C2OCOC2=CC(C[C@@H]2[C@@H](CC=3C=C4OCOC4=CC=3)CO[C@@H]2O)=C1 DIYWRNLYKJKHAM-MDOVXXIYSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は医薬として優れた作用を有する〔2−(1,3
−ベンゾジオキソール−5−イル)エチルコチオ誘導体
及びその薬理学的に許容できる塩に関する。Detailed Description of the Invention [Industrial Field of Application] The present invention has excellent effects as a medicine [2-(1,3
-benzodioxol-5-yl)ethylcothio derivatives and pharmacologically acceptable salts thereof.
肝疾患はその病因、病像、病態生理が一様でなく、不明
な点が多く、従って肝疾患治療薬の開発は極めて困難性
が高いのが現状である。The etiology, pathological features, and pathophysiology of liver diseases are not uniform, and there are many unknown points. Therefore, it is currently extremely difficult to develop therapeutic agents for liver diseases.
現在、この肝疾患の治療及び予防に広く使用され、臨床
上評価されている代表的な薬剤としては、グリチルリチ
ン製剤を挙げることができる。しかしながら、グリチル
リチン製剤は、肝臓障害、肝硬変、肝炎、外科手術後の
肝臓保護などに有効であるとされているが、その薬効は
それ程強いものではなく、ステロイド様副作用があると
いう問題点もある。更にグリチルリチン製剤は静注製剤
であるが、経口では無効であるという欠点がある。Glycyrrhizin preparations are currently widely used and clinically evaluated for the treatment and prevention of liver diseases. However, although glycyrrhizin preparations are said to be effective in treating liver disorders, cirrhosis, hepatitis, and liver protection after surgery, their medicinal efficacy is not very strong, and they also have the problem of steroid-like side effects. Furthermore, although glycyrrhizin preparations are intravenous preparations, they have the disadvantage of being ineffective when administered orally.
このような状況から安全性が高く、経口で有効な優れた
薬剤の開発が渇望されている。Under these circumstances, there is a strong desire to develop excellent drugs that are highly safe and effective orally.
このような実情に鑑み、本発明者等は新しい肝疾患治療
剤を開発するべく、探索研究に着手した。In view of these circumstances, the present inventors undertook exploratory research in order to develop a new therapeutic agent for liver diseases.
本発明者等は、民間で使用されている植物を素材とし、
長期間にわたって研究を重ねた結果、ペティペリア・ア
リアセア(Petivelia alliaceaL、
)及びシンナモマム・ポレクタム(Cinnamomu
rnporrectum(Roxb、)Kosterm
、)よりそれぞれ下記の化学構造式で示される2−〔(
フェニルメチル)トリチオ〕エタノール(A)及びクベ
ビン(B)が肝疾患治療剤として有効な活性化合物であ
ることを見出した。The present inventors used plants used in the private sector as materials,
As a result of long-term research, Petivelia alliacea (Petivelia alliacea L,
) and Cinnamomum pollectum (Cinnamomu
rnporrectum (Roxb,) Kosterm
, ), each of which is represented by the chemical structural formula below is 2-[(
It has been found that phenylmethyl)trithio]ethanol (A) and cubebin (B) are active compounds effective as therapeutic agents for liver diseases.
〇−(’)12−5−5−3−C)1.[”H2DH(
A)その後本発明者等は、これらの化合物を基本化合物
とし、種々の化合物を合成し、その薬理活性について鋭
意研究を重ねた結果、下記の一般式(1)で表されるベ
ンゾジオキソール誘導体又はその薬理学的に許容できる
塩がより安全性が高く、より優れた肝疾患治療剤として
有効な化合物であることを見出し、本発明を完成した。〇-(')12-5-5-3-C)1. [”H2DH(
A) Thereafter, the present inventors synthesized various compounds using these compounds as basic compounds, and as a result of intensive research on their pharmacological activities, the benzodioxole represented by the following general formula (1) The present invention was completed based on the discovery that derivatives or pharmacologically acceptable salts thereof are safer and more effective compounds as therapeutic agents for liver diseases.
肝疾患の治療を目的として、次の2件の特許出願が公開
されているが、本発明のベンゾジオキソール誘導体とは
化学構造上異なるものである。The following two patent applications have been published for the purpose of treating liver diseases, but these are chemically structurally different from the benzodioxole derivative of the present invention.
即ち、特開昭62−29522号公報に開示されている
化合物は、ベンゾジオキソールのフェニル環に飽和アル
キル基が結合している化合物であり、殆どが公知化合物
である。That is, the compounds disclosed in JP-A-62-29522 are compounds in which a saturated alkyl group is bonded to the phenyl ring of benzodioxole, and most of them are known compounds.
更に特開昭62−39583号公報には、(1゜3−ベ
ンゾジオキソール−5−イル)メチルチオ誘導体が開示
されているが、Sに結合しているのはピリジン、ピリミ
ジン、チアジアゾールなどの複素環であり、本発明化合
物とは構造を著しく異にする。Furthermore, JP-A No. 62-39583 discloses (1゜3-benzodioxol-5-yl)methylthio derivatives, but the S-bond is pyridine, pyrimidine, thiadiazole, etc. It is a heterocyclic ring and has a significantly different structure from the compound of the present invention.
本発明は上述の如く、植物成分から本発明者等自身が見
出した化合物(A)及び(B)からヒントを得て、後記
する本発明化合物(1)に至ったちのであり、前記2件
の公開公報に見られる発明とはその発想を異にしており
、それに伴って前記2件の特許出願とは化学構造を異に
しているものである。As mentioned above, the present invention was inspired by the compounds (A) and (B) that the present inventors themselves discovered from plant ingredients, and arrived at the present compound (1), which will be described later. The idea is different from the invention found in the published gazette, and accordingly, the chemical structure is different from the two patent applications mentioned above.
本発明の目的化合物は、次の一般式(I)で示される[
2−(1,3−ベンゾジオキソール−5−イル)エチル
コチオ誘導体又はその薬理学的に許容できる塩である。The target compound of the present invention is represented by the following general formula (I) [
It is a 2-(1,3-benzodioxol-5-yl)ethyl cothio derivative or a pharmacologically acceptable salt thereof.
示される基、又は式−8−で示される基を意味する。or a group represented by formula -8-.
Rは
■ 水素原子、又は低級アルキル基、
■ 式−(CH2) 、、−COOR’ (式中nは1
〜5の整数を意味し、R1は水素原子又は低級アルキル
基を意味する)で示される基、
■ 式−(CH2) 、−OR” (式中nは1〜5の
整数を意味し、R2は水素原子、低級アルキル基、又は
アシル基を意味する)で示される基、
整数を意味し、Rs、 R4は同−又は相異なる水素原
子、低級アルキル基又はカルボキシメチル基を意味する
)で示される基、
数を意味し、R6,Rliは同−又は相異なる水素原子
又は低級アルキル基を意味する)で示される基、
H2
■ 式−(CH2)、−CH−CDOR’ (式中n
は1〜5の整数を意味し、R1は水素原子又は低級アル
キル基を意味する)で示される基、
■ 上記■において、炭素数n個からなるアルキレン鎮
において、1つ又はそれ以上の炭素原子に、水素原子の
代わりに低級アルキル基又は式 −COOR’ (式中
R8は水素原子又は低級アルキル基を意味する)で示さ
れる基が結合している基、
■ 上記■において、炭素数n個からなるアルキレン鎖
において、1つ又はそれ以上の炭素原子に、水素原子の
代わりに水酸基が結合している基、
又は
5の整数を意味し、mは3〜4の整数を意味する)で示
される基を意味する。R is ■ a hydrogen atom or a lower alkyl group, ■ the formula -(CH2) , -COOR' (in the formula, n is 1
a group represented by the formula -(CH2), -OR" (wherein n means an integer of 1 to 5, R1 means a hydrogen atom or a lower alkyl group), means a hydrogen atom, a lower alkyl group, or an acyl group), an integer; Rs, R4 means the same or different hydrogen atoms, a lower alkyl group, or a carboxymethyl group); group represented by the formula -(CH2), -CH-CDOR' (wherein n represents the same or different hydrogen atoms or lower alkyl groups);
means an integer of 1 to 5, and R1 means a hydrogen atom or a lower alkyl group); (1) In the above (2), in the alkylene group consisting of n carbon atoms, one or more carbon atoms; , a group in which a lower alkyl group or a group represented by the formula -COOR' (in the formula, R8 means a hydrogen atom or a lower alkyl group) is bonded instead of a hydrogen atom; In the alkylene chain consisting of, a hydroxyl group is bonded to one or more carbon atoms instead of a hydrogen atom, or an integer of 5, m is an integer of 3 to 4) means a group that
但し、上記の定義において、Xが式−8−で示される基
であり、かつRが低級アルキル基である場合は、その低
級アルキル基はメチル基である場合は除くものとする。However, in the above definition, when X is a group represented by formula -8- and R is a lower alkyl group, cases where the lower alkyl group is a methyl group are excluded.
〕
本発明化合物(1)における上記の定義において、R1
,R2t R3,R4,R5,Rli、 R7及びR8
にみられる低級アルキル基とは、炭素数1〜6の直鎮も
しくは分枝状のアルキル基、例えばメチル、エチノペn
−プロピノ吠n−プチノペイソブロビノペイソブチル、
1−メチルプロピル、tert−ブチル、n−ペンチル
、1−エチルプロピル、イソアミル、n−ヘキシルなど
を意味するが、最も好ましい例は、メチル基、エチル基
である。] In the above definition of the compound (1) of the present invention, R1
, R2t R3, R4, R5, Rli, R7 and R8
The lower alkyl group found in
- propinobutyl,
It means 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl, etc., and the most preferred examples are methyl group and ethyl group.
R2の定義にみられるアシル基とは、脂肪族飽和カルボ
ン酸、脂肪族不飽和カルボン酸、炭素環式カルボン酸又
は複素環式カルボン酸のような有機酸の残基が挙げられ
るが、具体的には、例えばホルミル、アセチル、プロピ
オニル、ブチリル、イソブチリル、バレリ/L=、イソ
バレリノペピバロイルなどの低級アルカノイル基、ベン
ゾイル、トルオイル、ナフトイルなどのアロイル基、フ
ロイル、ニコチノイノベイソニコチノイルなどのヘテロ
アロイル基などを挙げることができる。The acyl group seen in the definition of R2 includes residues of organic acids such as aliphatic saturated carboxylic acids, aliphatic unsaturated carboxylic acids, carbocyclic carboxylic acids, and heterocyclic carboxylic acids. For example, lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl/L=, isovalerinopepivaloyl, aroyl groups such as benzoyl, toluoyl, naphthoyl, furoyl, nicotinoinobeisonicotinoyl, etc. Examples include a heteroaroyl group.
薬理学的に許容できる塩とは、慣用の無毒性塩類であり
、例えばナトリウム塩、カリウム塩などのアルカリ金属
塩、カルシウム塩、マグネシウム塩のようなアルカリ土
類金属塩、トリメチルアミン塩、トリエチルアミン塩、
ピリジン塩、ピコリン塩、ジシクロヘキシルアミン塩、
N、N″−ジベンジルエチレンジアミン塩などの有機ア
ミン塩、アンモニウム塩などを、更に置換基によっては
、例えば塩酸塩、臭化水素酸塩、硫酸塩、燐酸塩などの
無機酸塩、例えば酢酸塩、マレイン酸塩、酒石酸塩、メ
タンスルホン酸塩、ベンゼンスルホン酸塩、トルエンス
ルホン酸塩などの有機酸塩、又は例えばアルギニン、ア
スパラギン酸、グルタミン酸などのアミノ酸との塩など
を挙げることができる。また、化合物によっては水和物
を形成してもよい。Pharmacologically acceptable salts are conventional non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, trimethylamine salts, triethylamine salts,
Pyridine salt, picoline salt, dicyclohexylamine salt,
Organic amine salts such as N,N''-dibenzylethylenediamine salts, ammonium salts, etc., and inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, phosphates, etc., such as acetates, depending on the substituent. , organic acid salts such as maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, or salts with amino acids such as arginine, aspartic acid, and glutamic acid. , some compounds may form hydrates.
な右、本発明化合物は置換基の種類によっては不斉炭素
を有し、光学異性体が存在しろるが、これらは本発明の
範囲に属することはいうまでもない。Furthermore, the compounds of the present invention may have asymmetric carbon atoms depending on the type of substituents and optical isomers may exist, but it goes without saying that these belong to the scope of the present invention.
製造方法
本発明化合物の製造方法は種々考えられるが、代表的な
方法について述べれば以下の通りである。Manufacturing method Various methods can be considered for manufacturing the compound of the present invention, but typical methods are described below.
製造方法A
〔一般式(I)において、Xが式−8−で示される基で
ある場合〕
+
l5−R(I[I)
1 塩基
〔式(n)〜(TV)において、Hal はハロゲン原
子を意味し、Rは前記と同様の意味を有する。〕即ち、
一般式(n)で表される5−(2−ハロゲノエチル)−
1,3−ベンゾジオキソールと、一般式(III)で表
されるチオールとを反応させて、目的物質の一つである
化合物(rV)を得ることができる。Production method A [In general formula (I), when X is a group represented by formula -8-] + l5-R(I[I) 1 base [In formulas (n) to (TV), Hal is a halogen means an atom, and R has the same meaning as above. ] That is,
5-(2-halogenoethyl)- represented by general formula (n)
Compound (rV), which is one of the target substances, can be obtained by reacting 1,3-benzodioxole with a thiol represented by general formula (III).
この反応は無溶媒或いは、例えばベンゼン、エタノール
、キシレン、テトラヒドロフラン、クロロホルム、四塩
化炭素、N、N−ジメチルホルムアミドなどの中から選
ばれた反応に関与しない有機溶媒中で、常法により氷冷
下又は室温〜加熱下で数時間反応を行う。この場合、炭
酸水素ナトリウム、炭酸カリウム、炭酸ナトリウム、水
酸化す) IJウムの如き無機塩基類或いはトリエチル
アミン、ピリジン、ピリミジン、NlN−ジエチルアニ
リンのような有機塩基類を脱ハロゲン化水素剤として使
用することにより反応は容易に進行する。This reaction is carried out without a solvent or in an organic solvent that does not participate in the reaction, such as benzene, ethanol, xylene, tetrahydrofuran, chloroform, carbon tetrachloride, N,N-dimethylformamide, etc., by a conventional method under ice cooling. Alternatively, the reaction is carried out at room temperature or under heating for several hours. In this case, inorganic bases such as sodium bicarbonate, potassium carbonate, sodium carbonate, hydroxide or organic bases such as triethylamine, pyridine, pyrimidine, NlN-diethylaniline are used as dehydrohalogenating agents. This allows the reaction to proceed easily.
製造方法B
〔一般式(I)において、Xが式−8−で示される基で
ある場合〕
+
Hal −R(VI)
↓ 塩基
〔式(V)、(VI)及び(IV)において、Halは
ハロゲン原子を意味し、Rは前記と同様の意味を有する
。〕
即ち、2−(1,3−ベンゾジオキソール−5−イル)
エタンチオール(V)と一般式(VI)で示されるハロ
ゲン化物とを、製造方法Aと同様な条件で反応を行い目
的物質の一つである化合物(I’V)を得ることができ
る。この場合も、製造方法Aで示した塩基を用いること
が好ましい結果を与える。なお、製造方法A、 Bにお
いて、ハロゲン原子とは臭素、塩素、ヨウ素などを挙げ
ることができるが、通常は臭素、塩素を用いる。Production method B [In general formula (I), when X is a group represented by formula -8-] + Hal -R(VI) ↓ Base [In formulas (V), (VI) and (IV), Hal means a halogen atom, and R has the same meaning as above. ] That is, 2-(1,3-benzodioxol-5-yl)
Compound (I'V), which is one of the target substances, can be obtained by reacting ethanethiol (V) and a halide represented by general formula (VI) under the same conditions as in production method A. In this case as well, using the base shown in Production Method A gives preferable results. In production methods A and B, examples of the halogen atom include bromine, chlorine, and iodine, but bromine and chlorine are usually used.
製造方法C
〔一般式(I)において、Xが式−8−で示される基で
ある場合〕
+
R9−CH=CH−R10(■)
ll
〔式(■)及び(■)にふいて R9は低級アルキルを
示し、R10は低級アルキルオキシ力ルボニノペN、
N’−ビス低級アルキルアミノカルボニAt、カルバモ
イルを示す〕
即ち、チオール(V)と一般式(■)で表される不飽和
化合物とを無溶媒下、又は例えばベンゼン、ジクロロメ
タン、テトラヒドロフラン、N、N−ジメチルホルムア
ミド、エタノールなどから選択された溶媒中で氷冷下又
は室温〜加熱還流下で常法により反応を行い、目的物質
の一つである化合物(■)を得ることができる。反応の
進行が遅い場合は、例えばピペリジン、トリエチルアミ
ン、ナトリウムメチラート、トリトンB、硫黄、硫酸な
どを触媒として加えることもできる。Production method C [In the general formula (I), when X is a group represented by the formula -8-] + R9-CH=CH-R10 (■) ll [Wipe the formulas (■) and (■) R9 represents lower alkyl, R10 is lower alkyloxy,
N'-bis-lower alkylaminocarbonyl At, represents carbamoyl] That is, the thiol (V) and the unsaturated compound represented by the general formula (■) are mixed in the absence of a solvent, or for example in benzene, dichloromethane, tetrahydrofuran, N, Compound (■), which is one of the target substances, can be obtained by carrying out the reaction in a solvent selected from N-dimethylformamide, ethanol, etc. under ice cooling or under heating at room temperature to reflux in a conventional manner. If the reaction progresses slowly, for example, piperidine, triethylamine, sodium methylate, Triton B, sulfur, sulfuric acid, etc. can be added as a catalyst.
上記方法で得られた化合物(■)は、一般式(I)にお
いてXが式−8−で示され、Rが式−CH−CH2−R
Ioで表される化合物であり、本発明化合物の目的物の
一つである。In the compound (■) obtained by the above method, in the general formula (I), X is represented by the formula -8-, and R is the formula -CH-CH2-R
It is a compound represented by Io, and is one of the target compounds of the present invention.
製造方法D
〔一般式(I)において、Xが式−3−で示される基で
ある場合〕
+
Its−R(III)
(式中Rは前記の意味を有する)
即ち、5−エチニル−1,3−ベンゾジオキソール(I
X)と、一般式(III)で表されるチオールとを無溶
媒下、又は例えばテトラヒドロフランなどから選択され
た溶媒中で、水冷下又は室温〜加熱還流下で常法により
反応せしめて目的物質の一つである化合物(IV)を得
ることができる。反応の進行が遅い場合は、例えば過酸
化ベンゾイルなどの過酸化物、アゾビスイソブチロニト
リルなどのような触媒を加えることもできる。Production method D [In general formula (I), when X is a group represented by formula -3-] + Its-R (III) (in the formula, R has the above-mentioned meaning), that is, 5-ethynyl-1 ,3-benzodioxole (I
X) and a thiol represented by the general formula (III) are reacted in a conventional manner in the absence of a solvent or in a solvent selected from tetrahydrofuran, etc., under cooling with water or under heating at room temperature to reflux to obtain the target substance. One compound (IV) can be obtained. If the reaction progresses slowly, a catalyst such as a peroxide such as benzoyl peroxide or azobisisobutyronitrile may be added.
製造方法E
↑
〔一般式〇)において、Xが式−8−で示される基であ
る場合〕
酸化
(式中Rは前記の意味を有する)
本反応は、例えば前記の方法によって得られた目的化合
物の一つである化合物(EV)を酸化して、目的化合物
の一つである化合物(X)を得るものである。具体的に
は化合物(rV)を、例エバベンゼン、トルエン、キシ
レンなどのような芳香族炭化水素類、ジクロロメタン、
クロロホルム、四塩化炭素などのハロゲン化炭化水素類
、水、メタノール、エタノールなどのアルコール類、更
には酢酸エチル、アセトン、酢酸などから選択された溶
媒に溶解し、ドライアイス−アルコール又は氷水による
冷却下、等モルの例えば過酸化水素、過酢酸、m−クロ
ロ過安息香酸、次亜塩素酸ナトリウムのような酸化剤を
加えて常法により反応させて目的化合物の一つであるス
ルホキシド化合物(X)を得ることができる。Production method E ↑ [In the general formula 〇), when X is a group represented by the formula -8-] Oxidation (in the formula, R has the above-mentioned meaning) This reaction is for example Compound (EV), which is one of the compounds, is oxidized to obtain compound (X), which is one of the target compounds. Specifically, the compound (rV) is mixed with aromatic hydrocarbons such as evabenzene, toluene, xylene, etc., dichloromethane,
Dissolve in a solvent selected from halogenated hydrocarbons such as chloroform and carbon tetrachloride, water, alcohols such as methanol and ethanol, and furthermore ethyl acetate, acetone, and acetic acid, and cool with dry ice-alcohol or ice water. , an equimolar amount of an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, or sodium hypochlorite is added and reacted by a conventional method to obtain a sulfoxide compound (X), which is one of the target compounds. can be obtained.
製造方法F
〔一般式(I)において、Xが式−8−で示される基で
ある場合〕
酸化
(式中Rは前記の意味を有する)
本反応は、例えば前記の方法によって得られた目的化合
物の一つである化合物(IV)を酸化して、目的化合物
の一つである化合物(XI>を得るものである。具体的
には化合物(IV)を、例エバベンゼン、トルエン、キ
シレンなどのような芳香族炭化水素類、ジクロロメタン
、クロロホルム、四塩化炭素などのハロゲン化炭化水素
類、水、メタノール、エタノールなどのアルコール類、
更には酢酸エチル、アセトン、酢酸などから選択された
溶媒に溶解し、水冷下又は室温で2当量以上の例えば過
酸化水素、過酢酸、m−クロロ過安息香酸、次亜塩素酸
ナトリウム、m−過ヨウ素酸ナトリウムなどのような酸
化剤を加え、反応させて、目的化合物の一つであるスル
ホン化合物(X[)を得ることができる。Production method F [In general formula (I), when X is a group represented by formula -8-] Oxidation (in the formula, R has the above-mentioned meaning) Compound (IV), which is one of the compounds, is oxidized to obtain compound (XI>, which is one of the target compounds. Specifically, compound (IV) is oxidized with a compound such as evabenzene, toluene, xylene, etc. Aromatic hydrocarbons such as dichloromethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, water, alcohols such as methanol and ethanol,
Furthermore, it is dissolved in a solvent selected from ethyl acetate, acetone, acetic acid, etc., and 2 equivalents or more of hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium hypochlorite, m- By adding an oxidizing agent such as sodium periodate and causing a reaction, a sulfone compound (X[), which is one of the target compounds, can be obtained.
また別の製造方法として、例えば製造方法Eの方法によ
って得られたスルホキシド化合物(X)をクロロホルム
などの溶媒に溶解し、m−クロロ過安息香酸の如き酸化
剤を加え、反応させて得ることもできる。As another production method, for example, the sulfoxide compound (X) obtained by the method of production method E may be dissolved in a solvent such as chloroform, and an oxidizing agent such as m-chloroperbenzoic acid may be added and reacted. can.
製造方法G
〔一般式(I)において、Xが式−8−で示される基で
ある場合〕
(式中nは1〜5の整数を意味し、R11は低級アルキ
ル基、アリール基、又はヘテロアリール基を意味する。Production method G [In general formula (I), when X is a group represented by formula -8-] (In the formula, n means an integer of 1 to 5, and R11 is a lower alkyl group, an aryl group, or a hetero group) means an aryl group.
)
即ち、一般式(XI)で表される〔2−(1,3−ペン
ツジオキソ−ルー5−イル)エチルコチオ誘導体を、例
えば無溶媒又はベンゼン、ジクロロメタン、クロロホル
ム、テトラヒドロフラン、N、N−ジメチルホルムアミ
ド等に溶解し、脱ハロゲン化水素剤として、例えばピリ
ジン、トリエチルアミン、N、N−ジメチルアニリン、
炭酸す) IJウムなどの塩基を用い、これに一般式(
X[I)で表される酸ハロゲン化物を加え反応を行い、
目的化合物の一つである化合物(J)を得る。この場合
、ピリジンを溶媒兼脱ハロゲン化水素剤として用いるこ
とも可能である。反応は水冷却下又は加熱還流下で行う
。) That is, the [2-(1,3-penzdioxol-5-yl)ethylcothio derivative represented by the general formula (XI)] can be prepared, for example, without a solvent or with benzene, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, etc. as a dehydrohalogenating agent, such as pyridine, triethylamine, N,N-dimethylaniline,
Using a base such as IJium carbonate), the general formula (
Add an acid halide represented by X[I) to carry out a reaction,
Compound (J), one of the target compounds, is obtained. In this case, it is also possible to use pyridine as a solvent and a dehydrohalogenating agent. The reaction is carried out under water cooling or heating under reflux.
製造方法H
〔一般式(I)において、Xが式−8−で示される基で
ある場合〕
+
H,N−CH2−C0OH(XV)
(式中nは1〜5の整数を意味する)
即ち、例えば製造方法A、 B又はDによって製造され
た[:2−(1,3−ベンゾジオキソール−5−イル)
エチルコチオ誘導体(XIJ)を、例エバベンゼン、ク
ロロホルム、ジメチルホルムアミドなどの溶媒に溶解し
た後、例えば塩化チオニル、蓚酸クロリド、オキシ塩化
リン、五塩化リンなどを加え、氷冷下又は室温〜加熱還
流下で反応させて化合物(店)の酸塩化物を得て、これ
にグリシン(XV)の例えば炭酸水素ナトリウム水溶液
、炭酸ナトリウム水溶液又は水酸化す) IJウム水溶
液を氷水冷却撹拌下注ぎ、反応させて目的物質の一つで
あるグリシンアミド(■)を得ることができる。Production method H [In general formula (I), when X is a group represented by formula -8-] + H,N-CH2-C0OH (XV) (in the formula, n means an integer of 1 to 5) That is, for example, [:2-(1,3-benzodioxol-5-yl) produced by production method A, B or D]
After dissolving the ethyl cothio derivative (XIJ) in a solvent such as evabenzene, chloroform, or dimethylformamide, for example, thionyl chloride, oxalic acid chloride, phosphorus oxychloride, phosphorus pentachloride, etc. are added, and the mixture is heated under ice cooling or from room temperature to reflux. The acid chloride of the compound is obtained by reaction, and an aqueous solution of glycine (XV), such as an aqueous sodium bicarbonate solution, an aqueous sodium carbonate solution, or an aqueous solution of hydroxide, is poured into this while cooling with ice water and stirring, and the reaction is carried out to obtain the desired product. One of the substances, glycinamide (■), can be obtained.
上記方法で得られた化合物(■)は一般式(I)におい
て、Xが式−8−で示され、R2が式−(C11,)
、、−CONHCH,CD叶で表される化合物であり、
本発明化合物の目的物の一つである。In the compound (■) obtained by the above method, in the general formula (I), X is represented by the formula -8-, and R2 is the formula -(C11,)
,, -CONHCH, is a compound represented by CD leaf,
This is one of the objects of the compound of the present invention.
製造方法I
〔一般式(I)において、Xが式−8−で示される基で
ある場合〕
H2N−C−NH,(XVII)
アルカリ加水分解
(式中(n)及び(罵)においてHal はハロゲン原
子を意味する。)
即ち、一般式(If)で表される5−(2−ハロゲノエ
チル)−1,3−ベンゾジオキソールと式(罵)で表さ
れるチオ尿素とを例えばメタノール、エタノールなどの
溶媒に溶解した後、室温〜加熱還流下で反応させてチウ
ロニウム塩(罵)を得て、これを例えば水、メタノール
、エタノール、含水メタノール、含水エタノールなどか
ら適宜選択された溶媒中で、例えば水酸化ナトリウム、
水酸化カリウムなどの塩基存在下、室温〜加熱還流下に
て加水分解して目的物質の一つである2−(1,3−ベ
ンゾジオキソール−5−イル)エタンチオール(V)を
得ることができる。なお、ハロゲン原子とは臭素、塩素
、ヨウ素などを挙げることができるが、通常は臭素、塩
素を用いる。Production method I [In general formula (I), when X is a group represented by formula -8-] H2N-C-NH, (XVII) Alkaline hydrolysis (in (n) and (expletive) in the formula, Hal is ) That is, 5-(2-halogenoethyl)-1,3-benzodioxole represented by general formula (If) and thiourea represented by formula , dissolved in a solvent such as ethanol, and reacted at room temperature to reflux under heating to obtain a thiuronium salt, which is then dissolved in a solvent appropriately selected from water, methanol, ethanol, aqueous methanol, aqueous ethanol, etc. For example, sodium hydroxide,
Hydrolysis in the presence of a base such as potassium hydroxide at room temperature to heating reflux yields 2-(1,3-benzodioxol-5-yl)ethanethiol (V), which is one of the target substances. be able to. Note that halogen atoms include bromine, chlorine, iodine, etc., but bromine and chlorine are usually used.
製造方法J
〔一般式(I)において、Xが式−8−で示される基で
ある場合〕
(式中nは1〜5の整数を意味し、R’、 R’は同−
又は相異なる水素原子、低級アルキル基を意味する。)
即ち、例えば製造方法A、 B又はDによって製造され
た一般式(XM)で示されるカルボン酸又はその反応性
誘導体を一般式(m)で示されるアミノ化合物に反応さ
せてアミド化することにより目的化合物の一つである化
合物(XX)を得ることができる。Manufacturing method J [In the general formula (I), when X is a group represented by the formula -8-] (In the formula, n means an integer of 1 to 5, and R' and R' are the same -
or different hydrogen atoms or lower alkyl groups. ) That is, for example, by reacting a carboxylic acid represented by general formula (XM) or a reactive derivative thereof produced by manufacturing method A, B or D with an amino compound represented by general formula (m) to amidate it. Compound (XX), one of the target compounds, can be obtained.
化合物(店)の反応性誘導体としては、酸クロ・ライド
、酸ブロマイドの如き酸ハライド;酸アジド; N−ヒ
ドロキシベンゾトリアゾールやN−ヒドロキシスクシン
イミドなどとの活性エステル;対称型酸無水物;アルキ
ル炭酸やp −トルエンスルホン酸などとの混合酸無水
物等が挙げられる。Reactive derivatives of compounds include acid halides such as acid chlorides and acid bromides; acid azides; active esters with N-hydroxybenzotriazole and N-hydroxysuccinimide; symmetrical acid anhydrides; alkyl carbonates. and mixed acid anhydrides with p-toluenesulfonic acid and the like.
化合物(罵)として遊離のカルボン酸を用いるときは、
ジシクロへキシルカルボジイミドや1.1′−カルボニ
ルジイミダゾール等の縮合剤の存在下に反応させるのが
好ましい。When using a free carboxylic acid as a compound (expletive),
The reaction is preferably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole.
反応は、化合物(XM)又はその反応性誘導体と化合物
(m)をほぼ等モルあるいは一方をやや過剰モルで用い
、反応に不活性な有機溶媒、例えばピリジン、テトラヒ
ドロフラン、ジオキサン、エーテル、ベンゼン、トルエ
ン、キシレン、メチレンクロリド、ジクロルエタン、ク
ロロホルム、ジメチルホルムアミド、酢酸エチノペアセ
トニトリル等の溶媒中で行われる。The reaction is carried out using Compound (XM) or its reactive derivative and Compound (m) in approximately equimolar amounts or in a slightly excess molar amount of one of them, and an organic solvent inert to the reaction, such as pyridine, tetrahydrofuran, dioxane, ether, benzene, toluene. , xylene, methylene chloride, dichloroethane, chloroform, dimethylformamide, acetic acid ethynopeacetonitrile, etc.
反応性誘導体の種類によっては、反応に際し、トリエチ
ルアミン、ピリジン、ピコリン、ルチジン、N、N−ジ
メチルアニリンや炭酸カリウム、水酸化ナトリウム等の
塩基を添加するのが反応を円滑に進行させる上で有利な
場合がある。Depending on the type of reactive derivative, it may be advantageous to add a base such as triethylamine, pyridine, picoline, lutidine, N,N-dimethylaniline, potassium carbonate, or sodium hydroxide during the reaction to make the reaction proceed smoothly. There are cases.
反応温度は、反応性誘導体の種類によって異なり特に限
定されない。The reaction temperature varies depending on the type of reactive derivative and is not particularly limited.
なお、本発明の目的物質の一つである目的物質(I)の
薬理学的に許容できる塩を製造する際は、例えば一般式
(I)において、Rが式−(CH,) 、−CD叶であ
る場合のカルボン酸化合物ミノ酸化合物、又はRが−(
CH,) 、、−CONHCI12COOHである場合
のグリシンアミド化合物(XW)に炭酸水素ナトリウム
、炭酸水素カリウムなどの炭酸水素アルカリ、炭酸ナト
リウム、炭酸カリウムなどの炭酸アルカリ、水酸化ナト
リウム、水酸化カリウムなどの水酸化アルカリなどを作
用させて前述のナトリウム塩、カリウム塩などの薬理学
的に許容できる塩を製造することができる。In addition, when producing a pharmacologically acceptable salt of target substance (I), which is one of the target substances of the present invention, for example, in general formula (I), R is of the formula -(CH,), -CD A carboxylic acid compound, a amino acid compound when R is -(
CH, ) ,, -CONHCI12COOH, the glycinamide compound (XW) is treated with alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali carbonates such as sodium carbonate and potassium carbonate, sodium hydroxide, potassium hydroxide, etc. Pharmacologically acceptable salts such as the aforementioned sodium salts and potassium salts can be produced by the action of alkali hydroxide and the like.
次に本発明化合物の効果を詳細に説明するため薬理実験
例を示す。Next, pharmacological experimental examples will be shown to explain in detail the effects of the compounds of the present invention.
1、実験方法
体重180g前後のフィシ+ −(Fischer系)
(F344)雄性ラットにD−ガラクトサミン400m
g/kg皮下投与1時間後に各試験化合物の0.5%メ
チルセルロース液(100mg/kg)を経口投与した
。D−ガラクトサミンは生理食塩水で溶解希釈し、次い
でl0N−水酸化カリウム水溶液でpH7,0に調整し
、最終濃度を200mg/−とした。1. Experimental method Fischer + - (Fischer type) weighing around 180g
(F344) D-galactosamine 400m for male rats
One hour after the subcutaneous administration of 0.5% methylcellulose (100 mg/kg) of each test compound was orally administered. D-galactosamine was dissolved and diluted with physiological saline, and then adjusted to pH 7.0 with 10N aqueous potassium hydroxide solution to give a final concentration of 200 mg/-.
D−ガラクトサミン投与48時間後にラット尾部より採
血し、全血の血液凝固時間をヘパブラスチンテスト(H
PT)により測定すると共に、血漿中のGPT活性を酵
素法により測定した。Blood was collected from the tail of the rat 48 hours after administration of D-galactosamine, and the blood clotting time of the whole blood was measured using the hepablastin test (H
PT), and GPT activity in plasma was also measured by an enzymatic method.
各試験化合物のD−ガラクトサミンによる肝障害の抑制
率を表1に示した。Table 1 shows the inhibition rate of liver damage caused by D-galactosamine for each test compound.
2、試験化合物及び結果
表 1 (その5)
表1において抑制率の欄の*印は50mg/kg経口投
与の場合の数値を示す。2. Test compound and results table 1 (Part 5) In Table 1, the * mark in the inhibition rate column indicates the value in the case of oral administration of 50 mg/kg.
1、実験方法
0.5%メチルセルロース溶液(100mg/kg)に
懸濁した試験化合物を、体重180g前後のフィシャー
(Fischer)系雄性ラットに経口投与し、1時間
後に四塩化炭素0.57F+7!/kgを腹腔的投与し
た。四塩化炭素はオリーブ油で希釈し、最終濃度を0.
25m1/Wtlとした。1. Experimental method A test compound suspended in a 0.5% methylcellulose solution (100 mg/kg) was orally administered to male Fischer rats weighing approximately 180 g, and 1 hour later, carbon tetrachloride 0.57F + 7! /kg was administered intraperitoneally. Carbon tetrachloride was diluted with olive oil to a final concentration of 0.
It was set as 25 m1/Wtl.
四塩化炭素投与24時間後にラット尾部より採血し、血
漿中のGPT活性を酵素法により測定した。各試験化合
物の四塩化炭素による肝障害の抑制率を表2に示した。Blood was collected from the tail of the rat 24 hours after carbon tetrachloride administration, and GPT activity in the plasma was measured by an enzymatic method. Table 2 shows the inhibition rate of liver damage caused by carbon tetrachloride for each test compound.
表 2
体重30g前後の7遷令ddY系雄性マウスを使用し、
表1に示した本発明化合物を4日間経口投与(投与量8
00mg/kg) した場合、いずれの化合物も死亡例
が見られなかった。Table 2 Using 7-year-old ddY male mice weighing around 30 g,
The compounds of the present invention shown in Table 1 were orally administered for 4 days (dose 8
00 mg/kg), no cases of death were observed for any of the compounds.
実験例1.2から本発明化合物は、D−ガラクトサミン
及び四塩化炭素による肝障害を著しく抑制することが明
らかであり、肝疾患治療剤として有用である。From Experimental Example 1.2, it is clear that the compound of the present invention significantly inhibits liver damage caused by D-galactosamine and carbon tetrachloride, and is useful as a therapeutic agent for liver diseases.
従って本発明化合物は、ヒトを含む動物の種々の肝障害
の治療・予防薬として有用であり、具体的には、例えば
慢性肝炎、急性肝炎、薬物中毒性肝障害、ウィルス性肝
炎、アルコール性肝炎、黄痘、更にはそれらの終末像で
ある肝硬変の治療或いは予防に使用することができる。Therefore, the compounds of the present invention are useful as therapeutic and preventive agents for various liver disorders in animals including humans, and specifically, for example, chronic hepatitis, acute hepatitis, drug-induced liver disorders, viral hepatitis, and alcoholic hepatitis. It can be used for the treatment or prevention of jaundice, jaundice, and even liver cirrhosis, which is the final stage thereof.
更に本発明化合物は実験例3で明らかな如く、毒性が極
めて低く、安全性が高い。従って、本発明化合物は疾患
の性質上、長期間の連続投与が余儀なくされる場合が多
いが、この意味でも本発明は価値が高い。Furthermore, as is clear from Experimental Example 3, the compound of the present invention has extremely low toxicity and high safety. Therefore, due to the nature of the disease, the compound of the present invention often requires continuous administration over a long period of time, and the present invention is also of high value in this sense.
本発明化合物を肝疾患治療・予防剤として投与する場合
、散剤、顆粒剤、カプセル剤、シロップ剤などとして経
口的に投与してもよいし、また坐剤、注射剤、外用剤、
点滴剤として非経口的に投与してもよい。投与量は症状
の程度、年令、肝疾患の種類などにより著しく異なるが
、通常成人1日当たり約0.1mg〜1000mg、好
ましくは2mg〜500mg 、更に好ましくは5〜1
00mgを1日1〜数回にわけて投与する。When administering the compound of the present invention as a treatment or prevention agent for liver diseases, it may be administered orally in the form of powders, granules, capsules, syrups, etc., or suppositories, injections, external preparations, etc.
It may also be administered parenterally as a drop. The dosage varies significantly depending on the severity of symptoms, age, type of liver disease, etc., but is usually about 0.1 mg to 1000 mg, preferably 2 mg to 500 mg, more preferably 5 to 1 mg per day for adults.
Administer 00mg in divided doses once or several times a day.
製剤化の際は通常の製剤担体を用い、常法により製造す
る。When formulating the drug, it is produced by a conventional method using a conventional pharmaceutical carrier.
すなわち、経口用固形製剤を調製する場合は、生薬に賦
形剤、更に必要に応じて結合剤、崩壊剤、滑沢剤、着色
剤、矯味矯臭剤などを加えた後、常法により錠剤、被覆
錠剤、顆粒剤、散剤、カプセル剤などとする。That is, when preparing a solid preparation for oral use, after adding excipients to the crude drug, and further adding binders, disintegrants, lubricants, coloring agents, flavoring agents, etc. as necessary, tablets, Form into coated tablets, granules, powders, capsules, etc.
賦形剤としては、例えば乳糖、コーンスターチ、白糖、
ブドウ糖、ソルビット、結晶セルロース、二酸化ケイ素
などが、結合剤としては、例えばポリビニルアルコール
、ポリビニルエーテル、エチルセルロース、メチルセル
ロース、アラビアゴム、トラガント、ゼラチン、シェラ
ツク、ヒドロキシプロピルセルロース、ヒドロキシプロ
ピルメチルセルロース、クエン酸カルシウム、デキスト
リン、ペクチン等が、滑沢剤としては、例えばステアリ
ン酸マグネシウム、タルク、ポリエチレングリコーノペ
シリカ、硬化植物油等が、着色剤としては医薬品に添加
することが許可されているものが、矯味矯臭剤としては
、ココア末、ハツカ脳、芳香酸、ハツカ油、電脳、桂皮
末等が用いられる。これらの錠剤、頚粒剤には糖衣、ゼ
ラチン衣、その他必要により適宜コーティングすること
は勿論差し支えない。Examples of excipients include lactose, cornstarch, white sugar,
Glucose, sorbitol, crystalline cellulose, silicon dioxide, etc., and binders include, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, calcium citrate, dextrin. , pectin, etc., as lubricants, such as magnesium stearate, talc, polyethylene glycone pessilica, hydrogenated vegetable oil, etc., as coloring agents, those permitted to be added to pharmaceuticals, as flavoring agents. For example, cocoa powder, peppermint, aromatic acid, peppermint oil, dennou, cinnamon powder, etc. are used. Of course, these tablets and granules may be coated with sugar coating, gelatin coating, or other coatings as appropriate.
注射剤を調製する場合には、生薬に必要によりpH調整
剤、緩衝剤、安定化剤、可溶化剤などを添加し、常法に
より皮下、筋肉内、静脈内用注射剤とする。When preparing injections, pH adjusters, buffers, stabilizers, solubilizers, etc. are added to the herbal medicine as necessary, and the preparations are made into subcutaneous, intramuscular, or intravenous injections using conventional methods.
次に本発明の実施例を掲げるが、本発明がこれらに限定
されることがないことは云うまでもない。Examples of the present invention will be listed next, but it goes without saying that the present invention is not limited to these.
実施例1 (化合物1)
タンチオール
5−(2−ブロモエチル)−1,3−ベンゾジオキソー
ル750gをエタノール1j2に溶解し、チオ尿素31
2gを加え、沸騰水浴上で2時間加熱還流した。反応液
を冷却後、水酸化ナトリウム300gを水11に溶解し
た液を加え、45分間沸騰水浴上で加熱還流した。冷却
後、水31を加え、酢酸エチル51で抽出し、これを希
塩酸で洗浄した。次いで洗液がほぼ中性となるまで水洗
し、無水硫酸ナトリウムで乾燥後、40℃で溶媒を留去
し、帯黄色油状物質的570gが得られた。これを約3
kgのシリカゲルを用いてカラムクロマトグラフィー(
ヘキサン:ベンゼン=2 : 1) ヲ行い精製すると
、標記化合物310gが無色油状物として得られた。Example 1 (Compound 1) 750 g of tanthiol 5-(2-bromoethyl)-1,3-benzodioxole was dissolved in ethanol 1j2, and thiourea 31
2 g was added, and the mixture was heated under reflux on a boiling water bath for 2 hours. After cooling the reaction solution, a solution prepared by dissolving 300 g of sodium hydroxide in 11 parts of water was added, and the mixture was heated under reflux on a boiling water bath for 45 minutes. After cooling, 31 parts of water was added, extracted with 51 parts of ethyl acetate, and this was washed with dilute hydrochloric acid. Next, the mixture was washed with water until the washing liquid became almost neutral, dried over anhydrous sodium sulfate, and the solvent was distilled off at 40°C to obtain 570 g of a yellowish oily substance. This is about 3
Column chromatography using kg of silica gel (
Purification was carried out using hexane:benzene=2:1) to obtain 310 g of the title compound as a colorless oil.
・核磁気共鳴スペクトル(90MHz、 CDCl5)
δ;1.36(m、1)1)、 2.6〜2.9
(m、4H)、 5.87(s、2H)。・Nuclear magnetic resonance spectrum (90MHz, CDCl5)
δ; 1.36 (m, 1) 1), 2.6 to 2.9
(m, 4H), 5.87 (s, 2H).
6、50〜6.74 (m、 3H)
L−システィン・HCI・H2O406gを水11とエ
タノール500−に懸濁し、これに水酸化ナトリウム3
70gを水1.51に溶解した液を加えた。6,50-6.74 (m, 3H) Suspend 406 g of L-cysteine/HCI/H2O in 11 parts of water and 500 parts of ethanol, and add 3 parts of sodium hydroxide to this.
A solution prepared by dissolving 70 g in 1.5 ml of water was added.
コレに5−エチニル−1,3−ベンゾジオキソール52
7gを加え、更にエタノール500mj!を加え加熱還
流下2.5時間反応させた。エタノールを減圧留去し、
濾過、濾液を酢酸酸性とし、生じた無色結晶を濾取し、
3Ilの水から再結し、無色針状晶の2−アミノ−3−
C(2−(1,3−ベンゾジオキソール−5−イル)エ
チル)チオ〕プロピオン酸250gを得た。This is 5-ethynyl-1,3-benzodioxole 52
Add 7g and add 500mj of ethanol! was added and reacted under heating under reflux for 2.5 hours. Distill the ethanol under reduced pressure,
Filtration, making the filtrate acidic with acetic acid, and collecting the colorless crystals produced by filtration.
Recrystallization from 3Il of water gives colorless needle-like crystals of 2-amino-3-
250 g of C(2-(1,3-benzodioxol-5-yl)ethyl)thio]propionic acid were obtained.
上記結晶を水酸化ナトリウム37gを水11に溶解した
液に加え溶解し、濾過後濾液を約半量に濃縮し、エタノ
ール1.51を加え、再結晶すると、標記化合物100
gが無色結晶として得られた。The above crystals were dissolved in a solution of 37 g of sodium hydroxide dissolved in 11 parts of water, and after filtration, the filtrate was concentrated to about half its volume, and 1.51 parts of ethanol was added to recrystallize, yielding the title compound 100.
g was obtained as colorless crystals.
・融点;170〜172℃
・核磁気共鳴スペクトル(400MHz、 DMSO−
ds)δ;2、64〜2.74(m、 5H)、 2.
91 (dd、 J=12.8Hz、 3.7Hz、I
H)、 3.0Hm、LH)、 3J(m、2H)、
5.95(s。・Melting point: 170-172℃ ・Nuclear magnetic resonance spectrum (400MHz, DMSO-
ds) δ; 2, 64-2.74 (m, 5H), 2.
91 (dd, J=12.8Hz, 3.7Hz, I
H), 3.0Hm, LH), 3J (m, 2H),
5.95 (s.
2H)、 6.68(dd、J=8.1Hz、1.8H
z、LH)、 6.79(d。2H), 6.68(dd, J=8.1Hz, 1.8H
z, LH), 6.79 (d.
J=8.1Hz、 18)、 6.83(d、 J=1
.8Hz、 1)1)・質量分析(FAR) m/z
;314(M’″+Na)、 292(M″−+1)
・元素分析;
分子式:C+28+4NO43NaとしてHN
理論値(%) 49.48 4.84 4.81実
測値(%’) 49.58 4.91 4.91エチ
ル)チオ〕酢酸 ナトリウム塩
2−(1,3−ベンゾジオキソール−5−イル)エタン
チオール100gと、ブロム酢酸75.1gを11のエ
タノールに溶解し、これに44gの水酸化ナトリウムを
125m1の水に溶解したものを加え、更にエタノール
21を加えた後、加熱還流下3時間反応させた。反応液
を減圧下濃縮し、2.51の水を加え、IN−水酸化ナ
トリウム液でアルカリ性とした後、81(2ix4)の
クロロホルムで洗浄後、35%塩酸で酸性とした後、酢
酸エチルで抽出し、水洗4回、硫酸ナトリウム乾燥し、
減圧下溶媒を留去すると、((2−(1,3−ベンゾジ
オキソール−5−イル)エチル)チオ〕酢酸121gが
帯黄色油状物として得られた。J=8.1Hz, 18), 6.83(d, J=1
.. 8Hz, 1)1)・Mass spectrometry (FAR) m/z
;314 (M'''+Na), 292 (M''-+1)
・Elemental analysis; Molecular formula: C+28+4NO43Na as HN Theoretical value (%) 49.48 4.84 4.81 Actual value (%') 49.58 4.91 4.91 Ethyl)thio]acetic acid sodium salt 2-(1, 100 g of 3-benzodioxol-5-yl)ethanethiol and 75.1 g of bromoacetic acid were dissolved in 11 ml of ethanol, to which was added 44 g of sodium hydroxide dissolved in 125 ml of water, and then 21 g of ethanol was added. After adding, the mixture was reacted under heating under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, 2.51 of water was added, made alkaline with IN-sodium hydroxide solution, washed with 81 (2ix4) of chloroform, acidified with 35% hydrochloric acid, and then made with ethyl acetate. Extract, wash with water 4 times, dry with sodium sulfate,
The solvent was distilled off under reduced pressure to obtain 121 g of ((2-(1,3-benzodioxol-5-yl)ethyl)thio]acetic acid as a yellowish oil.
・核磁気共鳴スペクトル(90MHz、 CDCl5)
δ;2.80(s、4H)、 3.20(s、2
H)、 5.85(s、2H)。・Nuclear magnetic resonance spectrum (90MHz, CDCl5)
δ; 2.80 (s, 4H), 3.20 (s, 2
H), 5.85 (s, 2H).
6.44〜6.74(m、3H)、 10.24(bs
、IH)・質量分析(Bl) m/z ;240(M”
)、 135(Base)水酸化す) IJウム20.
27gを200mf!の水に溶解し、上記油状物質に加
え、溶解し、希エタノールより再結晶すると、標記化合
物102.5gが無色結晶として得られた。6.44-6.74 (m, 3H), 10.24 (bs
, IH)・Mass spectrometry (Bl) m/z; 240 (M”
), 135 (Base) hydroxide) IJum20.
27g at 200mf! of water, added to the above oily substance, dissolved and recrystallized from dilute ethanol to obtain 102.5 g of the title compound as colorless crystals.
・融点;224〜226℃
・核磁気共鳴スペクトル(400MHz、 DMSO−
ds)δ;2.69(m、48)、 2.95(s、2
H)、 5.95(s、2H)。・Melting point: 224-226℃ ・Nuclear magnetic resonance spectrum (400MHz, DMSO-
ds) δ; 2.69 (m, 48), 2.95 (s, 2
H), 5.95 (s, 2H).
6、66(dd、 J=7.7Hz、 1.5Hz、
LH)、 6.79(d、 J=7.7Hz、 1)1
)、 6.81(d、 J=1.5Hz、 IH)・質
量分析(FAB) m/z ;285(M”+Na)
、 263(M”+1)・元素分析;
分子式:C++H++O*SNaとしてH
理論値(%>、 50,38 4.23実測値(%
) 50,27 4.312−(1,3−ベンゾジ
オキソール−5−イル)エタンチオール5gと、アクリ
ルアミド4gとをエタノール100m1i!に溶解し、
加熱還流下200時間反応せた。反応液を氷冷し、エタ
ノール100−を加え、析出した結晶を濾取すると、標
記化合物4.2gが無色針状晶として得られた。6, 66 (dd, J=7.7Hz, 1.5Hz,
LH), 6.79(d, J=7.7Hz, 1)1
), 6.81 (d, J=1.5Hz, IH)・Mass spectrometry (FAB) m/z; 285 (M”+Na)
, 263 (M''+1)・Elemental analysis; Molecular formula: C++H++O*SNaH Theoretical value (%>, 50,38 4.23 Actual value (%
) 50,27 4.31 5 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 4 g of acrylamide were mixed in 100 ml of ethanol! dissolved in
The reaction was carried out under heating under reflux for 200 hours. The reaction solution was ice-cooled, 100% of ethanol was added, and the precipitated crystals were collected by filtration to obtain 4.2 g of the title compound as colorless needle-like crystals.
・融点:103〜104℃
・核磁気共鳴スペクトル(90MHz、 C1)C13
) δ;2.50(m、2H)、 2.89(s、4
H)、 2.73〜2.93(m。・Melting point: 103-104℃ ・Nuclear magnetic resonance spectrum (90MHz, C1) C13
) δ; 2.50 (m, 2H), 2.89 (s, 4
H), 2.73-2.93 (m.
211)、 5.6(br、s、2N)、 5.9Hs
、2H)、 6.68(m。211), 5.6 (br, s, 2N), 5.9Hs
, 2H), 6.68 (m.
3H)
・質量分析(EI) m/z ;253(M”)、 1
49.136(Base)5−エチニル−1,3−ベン
ゾジオキソール6gにチオグリコール酸エチル3.24
gを加え、室温で14時間撹拌した。反応液をシリカゲ
ルカラムクロマトグラフィー(ベンゼン:酢酸エチル=
40:1)にて精製すると、標記化合物5gが無色油状
物として得られた。3H) ・Mass spectrometry (EI) m/z; 253 (M”), 1
49.136 (Base) 6 g of 5-ethynyl-1,3-benzodioxole to 3.24 ethyl thioglycolate
g and stirred at room temperature for 14 hours. The reaction solution was subjected to silica gel column chromatography (benzene: ethyl acetate =
40:1) to give 5 g of the title compound as a colorless oil.
・核磁気共鳴スペクトル(90MHz、 CDCl、)
δ;1.27(t、J=7Hz、3H)、 2.8
0(s、4H)、 3.18(s。・Nuclear magnetic resonance spectrum (90MHz, CDCl,)
δ; 1.27 (t, J=7Hz, 3H), 2.8
0 (s, 4H), 3.18 (s.
2H)、 4.15(q、J=7Hz、2H)、 5.
86(s、2H)、 6.62(m、3H)
・質量分析(Bl) m/z ;268(M”)、 1
49(Base)5−(2−(メチルチオ)エチル)
−1,3−ベンゾジオキソール3gを100艷のクロロ
ホルムに溶解し、ドライアイス−アルコールで冷却下撹
拌しながら等モルのm−クロロ過安息香酸を加え、1時
間反応させた後、300mfのクロロホルムと300−
の水を加え、水層がアルカリ性となるまで炭酸ナトリウ
ムを加え、分液し、りロロホルム層を2回水洗後、硫酸
ナトリウム乾燥し、減圧下溶媒を留去した。得られた油
状物をシリカゲルカラムクロマトグラフィー(クロロホ
ルム:メタノール=20:1)にて精製すると、標記化
合物1.6gが無色油状物として得られた。2H), 4.15 (q, J=7Hz, 2H), 5.
86 (s, 2H), 6.62 (m, 3H) ・Mass spectrometry (Bl) m/z; 268 (M”), 1
49(Base)5-(2-(methylthio)ethyl)
- Dissolve 3 g of 1,3-benzodioxole in 100 mf of chloroform, add equimolar amount of m-chloroperbenzoic acid while stirring under cooling with dry ice-alcohol, and react for 1 hour. Chloroform and 300-
of water was added thereto, and sodium carbonate was added until the aqueous layer became alkaline. The layers were separated. The lyloform layer was washed twice with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained oil was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 1.6 g of the title compound as a colorless oil.
・核磁気共鳴スペクトル(90MH2,CDC13)
δ;2.55(s、3H)、 2.74〜3.12(
m、4H)、 5.87(s。・Nuclear magnetic resonance spectrum (90MH2, CDC13)
δ; 2.55 (s, 3H), 2.74-3.12 (
m, 4H), 5.87 (s.
2H)、 6.64(m、3H)
・質量分析(81) m/z ; 212(M″″)、
196.148(Base)3−ベンゾジオキソール
5− (2−(メチルチオ)エチル) −1,3−ベン
ゾジオキソール3.5gを100Wdlのクロロホルム
に溶解し、氷水冷却下8.88のm−クロロ過安息香酸
を加え、2時間反応させた後、300rnlのクロロホ
ルムと300rrtlの水を加え、水層がアルカリ性と
なるまで炭酸ナトリウムを加え分液し、クロロホルム層
を2回水洗後、硫酸ナトリウム乾燥し、減圧下溶媒を留
去し酢酸エチル−イソプロピルエーテルより再結晶する
と、標記化合物3gが無色針状晶として得られた。2H), 6.64 (m, 3H) ・Mass spectrometry (81) m/z; 212 (M″″),
196.148 (Base) 3-Benzodioxole 3.5 g of 5-(2-(methylthio)ethyl)-1,3-benzodioxole was dissolved in 100 Wdl of chloroform, and 8.88 m - After adding chloroperbenzoic acid and reacting for 2 hours, add 300rnl of chloroform and 300rrtl of water, add sodium carbonate until the aqueous layer becomes alkaline, separate the layers, wash the chloroform layer twice with water, and then add sodium sulfate. The residue was dried, the solvent was distilled off under reduced pressure, and recrystallized from ethyl acetate-isopropyl ether to obtain 3 g of the title compound as colorless needles.
・核磁気共鳴スペクトル(90MH2,CDC13)
δ;2.80(S、3H)、 2.93〜3.36(
m、4H)、 5.88(s。・Nuclear magnetic resonance spectrum (90MH2, CDC13)
δ; 2.80 (S, 3H), 2.93 to 3.36 (
m, 4H), 5.88 (s.
2H)、 6.65(m、3)f)
・質量分析(fI) rnlz ;228(M’)、
148(Base)−5−イル)エチル)チオ〕エチル
実施例2に準じて合成した〔(2−(1,3−ベンゾジ
オキソール−5−イル)エチル)チオ〕エタノール4g
を20m1のピリジンに溶解し、ベンゼン50Wtlを
加え、撹拌しながら4.7gのニコチン酸塩化物塩酸塩
4.7gを加え、沸騰水浴上で2時間加熱後、氷水中に
反応液を注ぎ、水100 rnlと炭酸水素す) IJ
ウムを加えて弱アルカリ性とした後、酢酸エチルを加え
抽出し、酢酸エチル層を4回水洗し、硫酸ナトリウムで
乾燥し、溶媒を留去し、シリカゲルカラムクロマトグラ
フィー(ベンゼン:酢酸エチル=3 : 1)にて精製
すると、標記化合物2gが無色油状物として得られた。2H), 6.65 (m, 3) f) ・Mass spectrometry (fI) rnlz; 228 (M'),
148(Base)-5-yl)ethyl)thio]ethyl 4 g of [(2-(1,3-benzodioxol-5-yl)ethyl)thio]ethanol synthesized according to Example 2
was dissolved in 20 ml of pyridine, 50 Wtl of benzene was added thereto, 4.7 g of nicotinic acid chloride hydrochloride was added with stirring, and after heating on a boiling water bath for 2 hours, the reaction solution was poured into ice water and water was added. 100 rnl and hydrogen carbonate) IJ
After making it weakly alkaline by adding aluminum, extract it by adding ethyl acetate. The ethyl acetate layer was washed with water four times, dried with sodium sulfate, the solvent was distilled off, and the mixture was subjected to silica gel column chromatography (benzene: ethyl acetate = 3: After purification in step 1), 2 g of the title compound was obtained as a colorless oil.
・核磁気共鳴スペクトル(90Mtlz、 CDCl5
) δ:2.80(s、4H)、 2.85(t、J
=7Hz、2tl)、 4.44(t、J=7Hz、2
H)、 5.86(s、28)、 6.61(m、3H
)、 7.31(m、LH)、 8.20(m、LH)
、 8.69(m、1tl)、 9.13(m。・Nuclear magnetic resonance spectrum (90Mtlz, CDCl5
) δ: 2.80 (s, 4H), 2.85 (t, J
=7Hz, 2tl), 4.44(t, J=7Hz, 2
H), 5.86 (s, 28), 6.61 (m, 3H
), 7.31 (m, LH), 8.20 (m, LH)
, 8.69 (m, 1tl), 9.13 (m.
1ll)
・質量分析(BI) m/z ;33HM”、Ba5e
)、 148ミノ酢酸
実施例2で合成したC(2−(1,3−ベンゾジオキソ
ール−5−イル)エチル)チオ〕酢酸5.3gをベンゼ
ン20−に溶解し、塩化チオニル6.43F!11を加
え、加熱還流下2時間反応させた。1ll) ・Mass spectrometry (BI) m/z; 33HM”, Ba5e
), 148minoacetic acid 5.3 g of C(2-(1,3-benzodioxol-5-yl)ethyl)thio]acetic acid synthesized in Example 2 was dissolved in benzene 20-, and thionyl chloride 6.43F ! 11 was added thereto, and the mixture was allowed to react under heating and reflux for 2 hours.
反応液を減圧下溶媒を留去した。1.6gの水酸化ナト
リウムを10−の水に溶解した液に3gのグリシンを加
え、氷水冷却下、撹拌しながら上記反応物を加え、約1
0℃で15分間撹拌後、室温で2時間反応させた。水を
加え、濃塩酸で酸性とし、生じた沈澱を濾取し、水洗後
希エタノールより再結を繰り返すと、標記化合物3gが
無色針状晶として得られた。The solvent of the reaction solution was distilled off under reduced pressure. 3 g of glycine was added to a solution of 1.6 g of sodium hydroxide dissolved in 10-g of water, and the above reaction product was added with stirring while cooling with ice water.
After stirring at 0° C. for 15 minutes, the mixture was allowed to react at room temperature for 2 hours. Water was added, acidified with concentrated hydrochloric acid, and the resulting precipitate was collected by filtration, washed with water, and then repeatedly recrystallized from dilute ethanol to obtain 3 g of the title compound as colorless needle-like crystals.
・融点;121.5〜122.5℃
・核磁気共鳴スペクトル(90MHz、 CDCl 、
−CD300) δ;2.84(s、4H)、 3.
26(s、2H)、 3.99(s、2H)。・Melting point: 121.5-122.5℃ ・Nuclear magnetic resonance spectrum (90MHz, CDCl,
-CD300) δ; 2.84 (s, 4H), 3.
26 (s, 2H), 3.99 (s, 2H).
5.92(s、2)1)、 6.7Hm、3tl)、
7.54(s、LH)・質量分析(El) m/z ;
297(Ml、 149(Base)、 148以下の
実施例1O〜27は、下記の一般式(I′)において、
Rが以下に記載した基である場合の化合物をそれぞれ示
す。5.92 (s, 2) 1), 6.7Hm, 3tl),
7.54 (s, LH)・Mass spectrometry (El) m/z;
297 (Ml, 149 (Base), 148 Examples 1O to 27 below have the following general formula (I'),
Compounds in which R is a group described below are shown below.
尚、製造方法の欄はAが実施例2と同様の方法、Bが実
施例3と同様の方法、Cが実施例4と同様の方法、Dが
実施例5と同様の方法、Eが実施例9と同様の方法で製
造したことを示す。In addition, in the manufacturing method column, A is the same method as Example 2, B is the same method as Example 3, C is the same method as Example 4, D is the same method as Example 5, and E is the same method as Example 5. This shows that it was produced in the same manner as Example 9.
・核磁気共鳴スペクトル(90MH2,(:DCl、)
δ;0.98(t、J=7Hz、3H)、 1.4
〜1.8(m、2)1)、 2.51(t、J=7Hz
、2H)、 2.75(s、4H)、 5.91(s、
2H)。・Nuclear magnetic resonance spectrum (90MH2, (:DCl,)
δ; 0.98 (t, J=7Hz, 3H), 1.4
~1.8 (m, 2) 1), 2.51 (t, J=7Hz
, 2H), 2.75 (s, 4H), 5.91 (s,
2H).
6、7 (m、 3H)
・質量分析(旧) m/z ;224(M”)、 14
8.135.77(Base′実施例11 (化合物3
)
R= −CI−+2cH2[IH<製造方法B)・核磁
気共鳴スペクトル(90MH2,CDCl、) δ;
2、72 (t、 J=6Hz、 2H) 、 2.7
8 (s、 4H) 、 3.72 (Q、 J=6H
z、2)1)、 5.92(s、2H)、 6.6〜6
.8(m、3H)・質量分析(FD) m/z ;22
6(M”ン・元素分析;
分子式’C11H1403Sとして
CHS
理論値(%) 58.39 6.24 14.17実
測値(%) 58.61 6.22 13.83・核
磁気共鳴スペクトル<90MHz、 CDCl5)
δ;1.59(m、LH)、 1.85(m、2H)、
2.66(t、J=7Hz。6, 7 (m, 3H) ・Mass spectrometry (old) m/z; 224 (M”), 14
8.135.77 (Base'Example 11 (Compound 3
) R= -CI-+2cH2[IH<Production method B)/Nuclear magnetic resonance spectrum (90MH2, CDCl,) δ;
2,72 (t, J=6Hz, 2H), 2.7
8 (s, 4H), 3.72 (Q, J=6H
z, 2) 1), 5.92 (s, 2H), 6.6-6
.. 8 (m, 3H)・Mass spectrometry (FD) m/z; 22
6 (M” elemental analysis; CHS as molecular formula 'C11H1403S) Theoretical value (%) 58.39 6.24 14.17 Actual value (%) 58.61 6.22 13.83 Nuclear magnetic resonance spectrum <90MHz, CDCl5)
δ; 1.59 (m, LH), 1.85 (m, 2H),
2.66 (t, J=7Hz.
2H)、 2.78(s、4H)、 3.76(m、2
H)、 5.93(s、3H)。2H), 2.78 (s, 4H), 3.76 (m, 2
H), 5.93 (s, 3H).
6、70 (m、 3H)
・質量分析(BI) m/Z ;240(M”)、 1
48(Base)、 135実施例13(化合物5)
R=−C’)1.−C’H−[’H2DH、(製造方法
A)lu
・核磁気共鳴スペクトル(9QMHz、CDCP>
a :2.02(t、J=6Hz、LH)、 2.6〜
2.9(m、3H)、 2.80(s、4H)、 3
.4〜3.9(m、3H)、 5.94(s、2H)
。6,70 (m, 3H) ・Mass spectrometry (BI) m/Z; 240 (M”), 1
48 (Base), 135 Example 13 (Compound 5) R=-C')1. -C'H-['H2DH, (Production method A) lu Nuclear magnetic resonance spectrum (9QMHz, CDCP>
a: 2.02 (t, J=6Hz, LH), 2.6~
2.9 (m, 3H), 2.80 (s, 4H), 3
.. 4-3.9 (m, 3H), 5.94 (s, 2H)
.
6、 TO(m、 3)1)
・質量分析(BI) m/z ;
256(M”)、 149. 135. 91. 7
7、 65(Base)・核磁気共鳴スペクトル(90
MHz、 CDCl5) δ;2.68(t、J=7
Hz、2H)、 2.76(s、4H)、 3.33(
s。6, TO (m, 3) 1) ・Mass spectrometry (BI) m/z; 256 (M”), 149. 135. 91. 7
7, 65 (Base)・Nuclear magnetic resonance spectrum (90
MHz, CDCl5) δ; 2.68 (t, J=7
Hz, 2H), 2.76 (s, 4H), 3.33 (
s.
3H)、 3.52(t、J=7Hz、2H)、 5.
87(s、2H)、 6.62(m、 3)I)
・質量分析([!I) m/z ;
240 (M”) 、 148.135.77 (Ba
se)・核磁気共鳴スペクトル(90MHz、 CDC
l5) δ;1.5〜2.2(m、4H)、 2.4
6(m、2H)、 2.79(s、4H)。3H), 3.52 (t, J=7Hz, 2H), 5.
87 (s, 2H), 6.62 (m, 3) I) ・Mass spectrometry ([!I) m/z; 240 (M”), 148.135.77 (Ba
se)・Nuclear magnetic resonance spectrum (90MHz, CDC
l5) δ; 1.5-2.2 (m, 4H), 2.4
6 (m, 2H), 2.79 (s, 4H).
2.6〜3.1(+n、3H)、 5.91(s、2)
1)、 6.68(m、3H)・質量分析(El) m
/z ;266(M”)、 149(Base)実施例
16 (化合物9)
B、 D、)
・融点; 63. O〜64.0℃
・核磁気共鳴スペクトル(90MH2,CDCl 3)
δ;2.77(+y+、4)1)、 2.50〜2
.90(m、41()、 5.91(s。2.6-3.1 (+n, 3H), 5.91 (s, 2)
1), 6.68 (m, 3H)・Mass spectrometry (El) m
/z; 266 (M”), 149 (Base) Example 16 (Compound 9) B, D,) ・Melting point; 63. O ~ 64.0°C ・Nuclear magnetic resonance spectrum (90MH2, CDCl 3)
δ; 2.77 (+y+, 4) 1), 2.50-2
.. 90 (m, 41 (), 5.91 (s.
2H)、 6.67(m、3H)、 8.0(br、5
lH)・質量分析(81) m/z :254(M+、
Ba5e)、 148.135R=−CH2CH2CO
ONa (製造方法A、 B、 D)・融点;187
〜189℃
・核磁気共鳴X ヘクト/’ (400MHz、 d4
−DMSO)δ;2.11(+n、2H)、 2.62
〜2.74(m、6)1)、 5.95(s。2H), 6.67 (m, 3H), 8.0 (br, 5
lH)・Mass spectrometry (81) m/z: 254 (M+,
Ba5e), 148.135R=-CH2CH2CO
ONa (Manufacturing method A, B, D) Melting point: 187
~189℃ ・Nuclear magnetic resonance X hect/' (400MHz, d4
-DMSO) δ; 2.11 (+n, 2H), 2.62
~2.74 (m, 6) 1), 5.95 (s.
2N)、 6.68(dd、J=7.7Hz、1.5H
z、IH)、 6.79(d、 J=7.7Hz、 1
8)、 6.82 (d、 J=1.5Hz、 IH)
・質量分析(FAR) m/z ;299(M”+N
a)、 277(M”+1)・元素分析;
分子式: C+2Hts04SNaとしてCH
理論値(%’) 52.17 4.74実測値(%
’) 52.15 4.80実施例17 (化合物
10)
・核磁気共鳴スペクトル(90MH2,020) δ
:1.90(m、2H)、 2.30(t、J=7Hz
、2H)、 2.59(t、J=7Hz、2H)、 2
.85(s、4H)、 5.94(s、2H)、 6.
80(m、3H)
・質量分析(FAB) m/z ;313(M”+N
a)、 29HM”+1)・核磁気共鳴スペクトル(9
0MHz、 CDCl5) δ:1.69(m、4H
)、 2.46(m、4H)、 2.74(s、4[(
)。2N), 6.68(dd, J=7.7Hz, 1.5H
z, IH), 6.79(d, J=7.7Hz, 1
8), 6.82 (d, J=1.5Hz, IH)
・Mass spectrometry (FAR) m/z; 299 (M”+N
a), 277 (M''+1)・Elemental analysis; Molecular formula: CH as C+2Hts04SNa Theoretical value (%') 52.17 4.74 Actual value (%
') 52.15 4.80 Example 17 (Compound 10) Nuclear magnetic resonance spectrum (90MH2,020) δ
: 1.90 (m, 2H), 2.30 (t, J=7Hz
, 2H), 2.59 (t, J=7Hz, 2H), 2
.. 85 (s, 4H), 5.94 (s, 2H), 6.
80 (m, 3H) ・Mass spectrometry (FAB) m/z; 313 (M”+N
a), 29HM”+1)・Nuclear magnetic resonance spectrum (9
0MHz, CDCl5) δ:1.69(m, 4H
), 2.46(m, 4H), 2.74(s, 4[(
).
5.87(s、3H)、 6.61(m、3H)、 7
.20(br、1tl)・質量分析(Na塩)(FAB
) m/z ;327(M”+Na)、 305(M”
+1)・融点;248〜251℃
・核磁気共鳴スペクトル(90MH2,020) δ
;1.16〜1.70(m、6H)、 2.17(m、
2H)、 2.45(m。5.87 (s, 3H), 6.61 (m, 3H), 7
.. 20 (br, 1tl)・Mass spectrometry (Na salt) (FAB
) m/z; 327 (M"+Na), 305 (M"
+1)・Melting point; 248-251℃・Nuclear magnetic resonance spectrum (90MH2,020) δ
; 1.16-1.70 (m, 6H), 2.17 (m,
2H), 2.45 (m.
2H)、 2.66(s、4H)、 5.82(s、2
H)、 6.66(m、3H)・質量分析(FAB)
m/z ;341(M”+Na)、 319(M”+
1)実施例20 (化合物13)
R=−C)l−CH2COOH(フリ一体)(製造方法
B)CH3
・核磁気共鳴スペクトル(90MHz、 CDCl、)
δ;1.35(d、J=7Hz、3H)、 2.5
7(m、2H)、 2.76(s。2H), 2.66(s, 4H), 5.82(s, 2
H), 6.66 (m, 3H)・Mass spectrometry (FAB)
m/z; 341 (M”+Na), 319 (M”+
1) Example 20 (Compound 13) R=-C)l-CH2COOH (Fri-integrated) (Production method B) CH3 Nuclear magnetic resonance spectrum (90MHz, CDCl,)
δ; 1.35 (d, J=7Hz, 3H), 2.5
7 (m, 2H), 2.76 (s.
4ft)、 3.18(m、LH)、 5.86(s、
2H)、 6.62(m、3H)。4ft), 3.18(m, LH), 5.86(s,
2H), 6.62 (m, 3H).
7、2 (br、 LH)
R= −CH−CH2COONa (製造方法B)C
H3
・融点;126〜128.5℃
・核磁気共鳴スペクトル(400MHz、 DMSO−
da)δ;L、 18 (d、 J=6.6)1z、
3H) 、 1.88 (dd、 J=14.1Hz。7, 2 (br, LH) R= -CH-CH2COONa (Manufacturing method B)C
H3 ・Melting point; 126-128.5℃ ・Nuclear magnetic resonance spectrum (400MHz, DMSO-
da) δ; L, 18 (d, J=6.6)1z,
3H), 1.88 (dd, J=14.1Hz.
9、9Hz、 IH)、 2.20(dd、 J=14
.7Hz、 4.4Hz、 LH)。9,9Hz, IH), 2.20(dd, J=14
.. 7Hz, 4.4Hz, LH).
2.69(m、4H)、 3.14(m、LH)、 5
.95(s、2H)。2.69 (m, 4H), 3.14 (m, LH), 5
.. 95 (s, 2H).
6、68 (dd、 J=8.0tlz、 1.8Hz
、 LH)、 6.79 (d、 J=8.0Hz、
11()、 6.82(d、 J=1.8tlz、 I
H)・質量分析(PAB) m/z ;313(M”
+Na)、 291(M”+1>・元素分析;
分子式:C13旧5LSNa−%l、(lとするとCH
理論値(%) 51,39 5.47実測値(%)
51.22 5.52実施例21 (化合物14
)
R=−CH−CH2COOH(製造方法D)・融点;1
39〜140℃
・核磁気共鳴スペクトル(90MHz、 DMSO−d
、) δ;2、77 (br、 s、 4H) 、
3.28 (br、 s、 2H) 、 3.50 (
m。6, 68 (dd, J=8.0tlz, 1.8Hz
, LH), 6.79 (d, J=8.0Hz,
11(), 6.82(d, J=1.8tlz, I
H)・Mass spectrometry (PAB) m/z; 313 (M”
+Na), 291 (M”+1>・Elemental analysis; Molecular formula: C13 former 5LSNa-%l, (where L is CH Theoretical value (%) 51,39 5.47 Actual value (%)
51.22 5.52 Example 21 (Compound 14
) R=-CH-CH2COOH (manufacturing method D), melting point; 1
39-140℃ ・Nuclear magnetic resonance spectrum (90MHz, DMSO-d
,) δ;2,77 (br, s, 4H),
3.28 (br, s, 2H), 3.50 (
m.
LH)、 5゜88(s、2H)、 6.69(m、3
)1)・質量分析(BI) m/z ;298(M”)
、 280.148(Base)実施例22 (化合物
15)
R=−CH−COOH(製造方法D)
CH。LH), 5°88 (s, 2H), 6.69 (m, 3
)1)・Mass spectrometry (BI) m/z; 298 (M”)
, 280.148 (Base) Example 22 (Compound 15) R=-CH-COOH (Production Method D) CH.
・核磁気共鳴スペクトル(90MH2,020) δ
;1.40(d、J=7Hz、38)、 2.86(s
、4H)、 3.43(q、J=7Hz、IH)、 5
.93(s、2H)、 6.80(m、3H)・質量分
析(FAB) m/z ;299(M”+Na)、
277(M”+1)実施例23(化合物16)
R=−CH2CONl12(製造方法B)・融点; 9
3.5〜94.5℃
・核磁気共鳴スペクトル(90Mllz、 CDCl、
) δ;2.78(s、4H)、 3.18(s、2
8)、 5.6〜6.9(br、s。・Nuclear magnetic resonance spectrum (90MH2,020) δ
; 1.40 (d, J=7Hz, 38), 2.86 (s
, 4H), 3.43 (q, J=7Hz, IH), 5
.. 93 (s, 2H), 6.80 (m, 3H)・Mass spectrometry (FAB) m/z; 299 (M”+Na),
277 (M”+1) Example 23 (Compound 16) R=-CH2CONl12 (Production method B) Melting point; 9
3.5-94.5℃ ・Nuclear magnetic resonance spectrum (90Mllz, CDCl,
) δ; 2.78 (s, 4H), 3.18 (s, 2
8), 5.6-6.9 (br, s.
2H)、 5.86°(s、2H)、 6.6Hm、3
tl)・質量分析(81) m/z ;229(M=)
、 148(Base)・元素分析:
分子式: C+ 1H1303NsとしてCHN
S
理論値(%)55.21 5゜48 5.85 13.
40実測値(%) 55.38 5.42 5.82
13.34Q核磁気共鳴スペクトル(90MHz、
CDCl、) δ;1.17(q、J=7Hz、6H
)、 2.86(s、2H)、 3.28(s。2H), 5.86°(s, 2H), 6.6Hm, 3
tl)・Mass spectrometry (81) m/z; 229 (M=)
, 148 (Base)・Elemental analysis: Molecular formula: CHN as C+ 1H1303Ns
S Theoretical value (%) 55.21 5゜48 5.85 13.
40 Actual value (%) 55.38 5.42 5.82
13.34Q nuclear magnetic resonance spectrum (90MHz,
CDCl, ) δ; 1.17 (q, J = 7Hz, 6H
), 2.86 (s, 2H), 3.28 (s.
2)1)、 3.37(Q、J=7H2,2H)、 3
.39((1,J=7H2,2H)。2) 1), 3.37 (Q, J = 7H2, 2H), 3
.. 39 ((1, J = 7H2, 2H).
5.92(s、2H)、 6.72(m、3H)・質量
分析(BI) m/z ;295(M”)、 148(
Base)・核磁気共鳴スペクトル(90MH2,CD
Cl、) δ:2.44〜2.85(m、4H)、
2.75(s、4H)、 2.92(s。5.92 (s, 2H), 6.72 (m, 3H)・Mass spectrometry (BI) m/z; 295 (M”), 148 (
Base)・Nuclear magnetic resonance spectrum (90MH2, CD
Cl,) δ: 2.44-2.85 (m, 4H),
2.75 (s, 4H), 2.92 (s.
3H)、 2.96(s、3H)、 5.84(s、2
H)、 6.6Hm、3H)・質量分析(BI) m/
z ;28HM”)、 149(Base)・融点;1
46〜148℃
−核磁気共鳴スペクトル(90MHz、 CDC13)
δ;2.79(s、6H)、 2.84(s、4H
)、 3.06(m、4H)。3H), 2.96(s, 3H), 5.84(s, 2
H), 6.6Hm, 3H)・Mass spectrometry (BI) m/
z; 28HM"), 149 (Base), melting point; 1
46-148℃ - Nuclear magnetic resonance spectrum (90MHz, CDC13)
δ; 2.79 (s, 6H), 2.84 (s, 4H
), 3.06 (m, 4H).
5.94(s、2H)、 6.72(m、3H)・質量
分析(81) m/z ;
253(M”)、 149.135.105.91(B
ase)・融点;152〜153℃
・核磁気共鳴スペクトル(90MHz、 CDCl3−
CD30D) δ;2.53(m、2H)、 2.
73〜2.92(m、6H)、 3.94(s。5.94 (s, 2H), 6.72 (m, 3H)・Mass spectrometry (81) m/z; 253 (M”), 149.135.105.91 (B
ase)・Melting point; 152-153℃・Nuclear magnetic resonance spectrum (90MHz, CDCl3-
CD30D) δ; 2.53 (m, 2H), 2.
73-2.92 (m, 6H), 3.94 (s.
2H)、 5.90(s、2H)、 6.69(m
、3H)、 7.58(s、LH)・質量分析(81
) m/z ;311(M”)、 149(Base)
、 148以下の実施例28は、下記の一般式(I”)
において、Rが以下に記載した基である場合の化合物を
それぞれ示す。2H), 5.90 (s, 2H), 6.69 (m
, 3H), 7.58(s, LH)・Mass spectrometry (81
) m/z; 311 (M”), 149 (Base)
, 148 Example 28 below has the following general formula (I'')
In the following, compounds in which R is a group described below are shown.
尚、本化合物は実施例6と同様の方法で製造した。Note that this compound was produced in the same manner as in Example 6.
・融点;107〜108℃
・核磁気共鳴スペクトル(90MH2,CDC13)
δ;2.8〜3.3(m、7H)、 4.18(m、
2H)、 5.94(s、2H)。・Melting point: 107-108℃ ・Nuclear magnetic resonance spectrum (90MH2, CDC13)
δ; 2.8 to 3.3 (m, 7H), 4.18 (m,
2H), 5.94 (s, 2H).
6、72 (m、 3H)
・質量分析(FAB) m/z ;243(M”+1
)以下の実施例29〜32は下記の一般式(I″)にお
いて、Rが以下に記載した基である場合の化合物をそれ
ぞれ示す。6,72 (m, 3H) ・Mass spectrometry (FAB) m/z; 243 (M”+1
) The following Examples 29 to 32 show compounds in which R is a group described below in the following general formula (I''), respectively.
尚、これらの化合物は実施例7と同様の方法で製造した
。Note that these compounds were produced in the same manner as in Example 7.
R=CH2CH20H
・融点;78〜80℃
・核磁気共鳴スペクトル(90MH2,CDC13)
δ;2.37(t、J=6Hz、IH)、 2.9〜
3.5(m、6H)、 4.12(m、2H)、 5.
95(s、2H)、 6.72(m、3H)・質量分析
(BI) m/z ;258(M”)、 149.11
9(Base)・融点; 144.5〜145℃
・核磁気共鳴スペクトル(90MHz、 DMSO−d
s−CDCl3)3.04(m、2H)、 3.52(
m、2H)、 4.07(s、2H)、 5.3(br
、IH)、 5.95(s、2H)、 6.86(
m、3H)・質量分析(81) m/z ;272(M
″″)、 148 (Base)・融点; 176、5
〜177、5℃
・核磁気共鳴スペクトル(90MHz、 DMSO−d
s) δ;2、60〜3.10 (m、 4)1)、
3.24〜3.50 (m、 4H)。R=CH2CH20H ・Melting point: 78-80℃ ・Nuclear magnetic resonance spectrum (90MH2, CDC13)
δ; 2.37 (t, J=6Hz, IH), 2.9~
3.5 (m, 6H), 4.12 (m, 2H), 5.
95 (s, 2H), 6.72 (m, 3H)・Mass spectrometry (BI) m/z; 258 (M”), 149.11
9 (Base)・Melting point; 144.5~145℃・Nuclear magnetic resonance spectrum (90MHz, DMSO-d
s-CDCl3) 3.04 (m, 2H), 3.52 (
m, 2H), 4.07 (s, 2H), 5.3 (br
, IH), 5.95 (s, 2H), 6.86 (
m, 3H)・Mass spectrometry (81) m/z; 272 (M
″″), 148 (Base)・Melting point; 176, 5
~177,5℃ ・Nuclear magnetic resonance spectrum (90MHz, DMSO-d
s) δ; 2, 60-3.10 (m, 4) 1),
3.24-3.50 (m, 4H).
5.98(s、2H)、 6.81(+n、2H)、
6.92(m、1)1)。5.98 (s, 2H), 6.81 (+n, 2H),
6.92 (m, 1) 1).
12、3 (br、 IH)
・質量分析(Bl) m/z ; 286 (M”、
Ba5e)・融点; 153.5〜155.5℃
・核磁気共鳴スペクトル(90MHz、 DMSO−d
6) δ;1.95(m、2H)、 2.40(t、
J=7Hz、2H)、 2.80〜3.46(m、6H
)、 5.96(s、2H)、 6.80(m、LH)
。12,3 (br, IH) ・Mass spectrometry (Bl) m/z; 286 (M”,
Ba5e)・Melting point; 153.5-155.5℃・Nuclear magnetic resonance spectrum (90MHz, DMSO-d
6) δ; 1.95 (m, 2H), 2.40 (t,
J=7Hz, 2H), 2.80-3.46(m, 6H
), 5.96 (s, 2H), 6.80 (m, LH)
.
6、91 (m、 LH) 、 12.5 (br、
11()・質量分析(81) m/z ;300(Ma
、 149(Base)、 148δ;6,91 (m, LH), 12.5 (br,
11 ()・Mass spectrometry (81) m/z; 300 (Ma
, 149(Base), 148δ;
Claims (1)
基、又は式−S−で示される基を意味する。 Rは [1]水素原子、又は低級アルキル基、 [2]式−(CH_2)_n−COOR^1(式中nは
1〜5の整数を意味し、R^1は水素原子又は低級アル
キル基を意味する)で示される基、 [3]式−(CH_2)_n−OR^2(式中nは1〜
5の整数を意味し、R^2は水素原子、低級アルキル基
、又はアシル基を意味する)で示される基、 [4]式▲数式、化学式、表等があります▼(式中nは
1〜5の整数を意味し、R^3、R^4は同一又は相異
なる水素原子、低級アルキル基又はカルボキシメチル基
を意味する)で示される基、 [5]式▲数式、化学式、表等があります▼(式中nは
1〜5の整数を意味し、R^5、R^6は同一又は相異
なる水素原子又は低級アルキル基を意味する)で示され
る基、 [6]式▲数式、化学式、表等があります▼(式中nは
1〜5の整数を意味し、R^7は水素原子又は低級アル
キル基を意味する)で示される基、 [7]上記[2]において、炭素数n個からなるアルキ
レン鎖において、1つ又はそれ以上の炭素原子に、水素
原子の代わりに低級アルキル基又は式−COOR^8(
式中R^8は水素原子又は低級アルキル基を意味する)
で示される基が結合している基、 [8]上記[3]において、炭素数n個からなるアルキ
レン鎖において、1つ又はそれ以上の炭素原子に、水素
原子の代わりに水酸基が結合している基、 又は [9]式▲数式、化学式、表等があります▼(式中nは
1〜5の整数を意味し、mは3〜4の整数を意味する)
で示される基を意味する。 但し、上記の定義において、Xが式−S−で示される基
であり、かつRが低級アルキル基である場合は、その低
級アルキル基はメチル基である場合は除くものとする。 〕 で表される〔2−(1,3−ベンゾジオキソール−5−
イル)エチル〕チオ誘導体及びその薬理学的に許容でき
る塩。[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, X is a group represented by the formula -S-, a group represented by the formula -S-, or a group represented by the formula -S-] means. R is [1] a hydrogen atom or a lower alkyl group, [2] the formula -(CH_2)_n-COOR^1 (in the formula, n means an integer from 1 to 5, and R^1 is a hydrogen atom or a lower alkyl group) ), [3] a group represented by the formula -(CH_2)_n-OR^2 (where n is 1 to
[4] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, n is 1) [5] Formula ▲ Numerical formula, chemical formula, table, etc. There is a group represented by ▼ (in the formula, n means an integer from 1 to 5, and R^5 and R^6 mean the same or different hydrogen atoms or lower alkyl groups), [6] Formula ▲ Numerical formula , chemical formulas, tables, etc. ▼ (in the formula, n means an integer from 1 to 5, and R^7 means a hydrogen atom or a lower alkyl group), [7] In [2] above, In an alkylene chain consisting of n carbon atoms, one or more carbon atoms have a lower alkyl group or the formula -COOR^8(
In the formula, R^8 means a hydrogen atom or a lower alkyl group)
[8] In [3] above, a group in which a hydroxyl group is bonded to one or more carbon atoms in place of a hydrogen atom in the alkylene chain consisting of n carbon atoms; or [9] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, n means an integer from 1 to 5, m means an integer from 3 to 4)
means a group represented by However, in the above definition, when X is a group represented by the formula -S- and R is a lower alkyl group, cases where the lower alkyl group is a methyl group are excluded. ] [2-(1,3-benzodioxole-5-
yl)ethyl]thio derivatives and their pharmacologically acceptable salts.
Priority Applications (19)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62082258A JP2535528B2 (en) | 1987-04-03 | 1987-04-03 | [2- (1,3-benzodioxo-l-5-yl) ethyl] thio derivative |
PH36545A PH26101A (en) | 1987-03-04 | 1988-02-23 | Benzodioxole derivatives |
FI880905A FI880905A (en) | 1987-03-04 | 1988-02-26 | BENSODIOXOLDERIVAT. |
AT88103164T ATE82750T1 (en) | 1987-03-04 | 1988-03-02 | BENZODIOXOL DERIVATIVES, COMPOSITIONS CONTAINING THEM AND THEIR USE IN THE MANUFACTURE OF MEDICATIONS. |
EP88103164A EP0281098B1 (en) | 1987-03-04 | 1988-03-02 | Benzodioxole derivatives, compositions comprising the same, and the use of the same for the manufacture of medicaments |
NZ223725A NZ223725A (en) | 1987-03-04 | 1988-03-02 | Benzodioxole derivatives and pharmaceutical compositions |
DE8888103164T DE3876114T2 (en) | 1987-03-04 | 1988-03-02 | BENZODIOXOL DERIVATIVES, THE COMPOSITIONS CONTAINING THEM AND THE USE THEREOF FOR THE PRODUCTION OF MEDICATIONS. |
CA000560311A CA1311241C (en) | 1987-03-04 | 1988-03-02 | Benzodioxol derivatives |
NO880922A NO880922L (en) | 1987-03-04 | 1988-03-02 | PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE BENZODIOX OLD DERIVATIVES. |
ES88103164T ES2052622T3 (en) | 1987-03-04 | 1988-03-02 | DERIVATIVES OF BENZODIOXOL, COMPOUNDS THAT INCLUDE THEM AND THEIR USE OF THEM FOR THE MANUFACTURE OF MEDICINES. |
DK114388A DK114388A (en) | 1987-03-04 | 1988-03-03 | BENZODIOXOL DERIVATIVES |
HU881039A HU201046B (en) | 1987-03-04 | 1988-03-03 | Process for production of new derivatives of benzodioxol and medical compositions containing them |
CN198888101155A CN88101155A (en) | 1987-03-04 | 1988-03-04 | The preparation of benzo benzodioxole derivatives and application thereof |
AU12764/88A AU600800B2 (en) | 1987-03-04 | 1988-03-04 | Benzodioxol derivatives |
KR1019880002264A KR910005428B1 (en) | 1987-03-04 | 1988-03-04 | Benzodioxol perivatives |
US07/517,444 US5110956A (en) | 1987-03-04 | 1990-04-23 | Benzodioxale derivatives |
US07/832,220 US5292901A (en) | 1987-03-04 | 1992-02-06 | Benzodioxole derivatives |
GR920402452T GR3006337T3 (en) | 1987-03-04 | 1992-11-26 | |
US08/166,019 US5475024A (en) | 1987-03-04 | 1993-10-14 | Benzodioxole derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62082258A JP2535528B2 (en) | 1987-04-03 | 1987-04-03 | [2- (1,3-benzodioxo-l-5-yl) ethyl] thio derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS63250374A true JPS63250374A (en) | 1988-10-18 |
JP2535528B2 JP2535528B2 (en) | 1996-09-18 |
Family
ID=13769425
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP62082258A Expired - Lifetime JP2535528B2 (en) | 1987-03-04 | 1987-04-03 | [2- (1,3-benzodioxo-l-5-yl) ethyl] thio derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP2535528B2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63270675A (en) * | 1987-04-28 | 1988-11-08 | Eisai Co Ltd | Benzodioxole derivative |
-
1987
- 1987-04-03 JP JP62082258A patent/JP2535528B2/en not_active Expired - Lifetime
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63270675A (en) * | 1987-04-28 | 1988-11-08 | Eisai Co Ltd | Benzodioxole derivative |
Also Published As
Publication number | Publication date |
---|---|
JP2535528B2 (en) | 1996-09-18 |
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