JPS6254423B2 - - Google Patents
Info
- Publication number
- JPS6254423B2 JPS6254423B2 JP10617080A JP10617080A JPS6254423B2 JP S6254423 B2 JPS6254423 B2 JP S6254423B2 JP 10617080 A JP10617080 A JP 10617080A JP 10617080 A JP10617080 A JP 10617080A JP S6254423 B2 JPS6254423 B2 JP S6254423B2
- Authority
- JP
- Japan
- Prior art keywords
- acetyl
- general formula
- formula
- alkyl
- liver
- 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
Links
- -1 amino compound Chemical class 0.000 claims description 21
- 125000002947 alkylene group Chemical group 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 229960004308 acetylcysteine Drugs 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000012345 acetylating agent Substances 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 30
- 239000003814 drug Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 230000017074 necrotic cell death Effects 0.000 description 19
- 230000000694 effects Effects 0.000 description 17
- 238000012360 testing method Methods 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 14
- 206010067125 Liver injury Diseases 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 13
- 208000019423 liver disease Diseases 0.000 description 13
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 12
- 208000006454 hepatitis Diseases 0.000 description 11
- 210000004185 liver Anatomy 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 235000018417 cysteine Nutrition 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 229960002433 cysteine Drugs 0.000 description 9
- 231100000234 hepatic damage Toxicity 0.000 description 9
- 230000008818 liver damage Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 229940124597 therapeutic agent Drugs 0.000 description 9
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 8
- 210000002966 serum Anatomy 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 7
- 210000003494 hepatocyte Anatomy 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 108030000917 Glutamine-pyruvate transaminases Proteins 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 231100000283 hepatitis Toxicity 0.000 description 6
- 239000002904 solvent Substances 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
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- YTGJWQPHMWSCST-UHFFFAOYSA-N Tiopronin Chemical compound CC(S)C(=O)NCC(O)=O YTGJWQPHMWSCST-UHFFFAOYSA-N 0.000 description 5
- 108010058907 Tiopronin Proteins 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
- 210000000941 bile Anatomy 0.000 description 5
- 208000019425 cirrhosis of liver Diseases 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229960005489 paracetamol Drugs 0.000 description 5
- RYGLCORNOFFGTB-YFKPBYRVSA-N (2r)-2-acetamido-3-methylsulfanylpropanoic acid Chemical compound CSC[C@@H](C(O)=O)NC(C)=O RYGLCORNOFFGTB-YFKPBYRVSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 208000004930 Fatty Liver Diseases 0.000 description 4
- 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 4
- 206010019708 Hepatic steatosis Diseases 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- IDIDJDIHTAOVLG-UHFFFAOYSA-N S-methyl-L-cysteine Natural products CSCC(N)C(O)=O IDIDJDIHTAOVLG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 231100000354 acute hepatitis Toxicity 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 238000001784 detoxification Methods 0.000 description 4
- 208000010706 fatty liver disease Diseases 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000003908 liver function Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 231100000240 steatosis hepatitis Toxicity 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- 229940028870 thiola Drugs 0.000 description 4
- MGYFMGITJVIKQQ-ZETCQYMHSA-N (2r)-2-acetamido-n-ethyl-3-methylsulfanylpropanamide Chemical compound CCNC(=O)[C@H](CSC)NC(C)=O MGYFMGITJVIKQQ-ZETCQYMHSA-N 0.000 description 3
- LCTORNIWLGOBPB-SVZMEOIVSA-N (3r,4s,5r,6r)-2-amino-6-(hydroxymethyl)oxane-2,3,4,5-tetrol Chemical compound NC1(O)O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O LCTORNIWLGOBPB-SVZMEOIVSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- IDIDJDIHTAOVLG-VKHMYHEASA-N S-methylcysteine Chemical compound CSC[C@H](N)C(O)=O IDIDJDIHTAOVLG-VKHMYHEASA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 108090000340 Transaminases Proteins 0.000 description 3
- 102000003929 Transaminases Human genes 0.000 description 3
- 239000003613 bile acid Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000023852 carbohydrate metabolic process Effects 0.000 description 3
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000002440 hepatic effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 210000005229 liver cell Anatomy 0.000 description 3
- 210000004738 parenchymal cell Anatomy 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 230000008929 regeneration Effects 0.000 description 3
- 238000011069 regeneration method Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- JAMFLIAUDKUJQJ-QMMMGPOBSA-N (2r)-2-acetamido-n-ethyl-3-ethylsulfanylpropanamide Chemical compound CCNC(=O)[C@@H](NC(C)=O)CSCC JAMFLIAUDKUJQJ-QMMMGPOBSA-N 0.000 description 2
- 206010008635 Cholestasis Diseases 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- 229920002527 Glycogen Polymers 0.000 description 2
- 206010019728 Hepatitis alcoholic Diseases 0.000 description 2
- 206010019799 Hepatitis viral Diseases 0.000 description 2
- 206010023126 Jaundice Diseases 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- HSCJRCZFDFQWRP-JZMIEXBBSA-N UDP-alpha-D-glucose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 HSCJRCZFDFQWRP-JZMIEXBBSA-N 0.000 description 2
- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 208000002353 alcoholic hepatitis Diseases 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 230000001989 choleretic effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 150000001945 cysteines Chemical class 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229940096919 glycogen Drugs 0.000 description 2
- 231100000304 hepatotoxicity Toxicity 0.000 description 2
- 230000003902 lesion Effects 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
- 239000012528 membrane Substances 0.000 description 2
- PVZMIVQODTYDBQ-LURJTMIESA-N methyl (2r)-2-acetamido-3-methylsulfanylpropanoate Chemical compound COC(=O)[C@H](CSC)NC(C)=O PVZMIVQODTYDBQ-LURJTMIESA-N 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 201000001862 viral hepatitis Diseases 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- AGIHDBZUEQVVRU-VIFPVBQESA-N (2r)-2-acetamido-3-ethylsulfanyl-n-propylpropanamide Chemical compound CCCNC(=O)[C@@H](NC(C)=O)CSCC AGIHDBZUEQVVRU-VIFPVBQESA-N 0.000 description 1
- BSVHABSINROVJJ-LURJTMIESA-N (2r)-2-acetamido-3-ethylsulfanylpropanoic acid Chemical compound CCSC[C@@H](C(O)=O)NC(C)=O BSVHABSINROVJJ-LURJTMIESA-N 0.000 description 1
- VZPQRBPLWDEMKS-QMMMGPOBSA-N (2r)-2-acetamido-3-methylsulfanyl-n-propylpropanamide Chemical compound CCCNC(=O)[C@H](CSC)NC(C)=O VZPQRBPLWDEMKS-QMMMGPOBSA-N 0.000 description 1
- JDENUHFQFBZFOO-LURJTMIESA-N (2r)-2-acetamido-n-methyl-3-methylsulfanylpropanamide Chemical compound CNC(=O)[C@H](CSC)NC(C)=O JDENUHFQFBZFOO-LURJTMIESA-N 0.000 description 1
- XMYSIDGHENUGDE-LURJTMIESA-N (2r)-n-acetyl-2-amino-3-ethylsulfanylpropanamide Chemical compound CCSC[C@H](N)C(=O)NC(C)=O XMYSIDGHENUGDE-LURJTMIESA-N 0.000 description 1
- XSROMVUWIVCEAU-YFKPBYRVSA-N (2r)-n-acetyl-2-amino-3-methylsulfanylpropanamide Chemical compound CSC[C@H](N)C(=O)NC(C)=O XSROMVUWIVCEAU-YFKPBYRVSA-N 0.000 description 1
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IGIJSFNBEUBMGB-UHFFFAOYSA-N 4-(cyclohexyliminomethylideneamino)-n,n-diethylcyclohexan-1-amine Chemical compound C1CC(N(CC)CC)CCC1N=C=NC1CCCCC1 IGIJSFNBEUBMGB-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- HSCJRCZFDFQWRP-UHFFFAOYSA-N Uridindiphosphoglukose Natural products OC1C(O)C(O)C(CO)OC1OP(O)(=O)OP(O)(=O)OCC1C(O)C(O)C(N2C(NC(=O)C=C2)=O)O1 HSCJRCZFDFQWRP-UHFFFAOYSA-N 0.000 description 1
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- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 231100000439 acute liver injury Toxicity 0.000 description 1
- 231100000570 acute poisoning Toxicity 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- NRDQFWXVTPZZAZ-UHFFFAOYSA-N butyl carbonochloridate Chemical compound CCCCOC(Cl)=O NRDQFWXVTPZZAZ-UHFFFAOYSA-N 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 235000019994 cava Nutrition 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
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- 238000006482 condensation reaction Methods 0.000 description 1
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- 235000005822 corn Nutrition 0.000 description 1
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- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
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Description
本発明はS−アルキル−N−アセチルシステイ
ンアミド類およびそれらの製法に関するものであ
る。詳しくは本発明は肝臓疾患治療薬として有用
な新規なS−アルキル−N−アセチル−システイ
ンアミド類およびそれらの製法に関するものであ
る。
肝臓では種々の化学反応が生化学的に営まれて
いる。例えば、解毒作用、糖質代謝、蛋白質代
謝、脂質代謝、胆汁の生成と分泌、ホルモンの調
節、血液凝固作用物質プロトロンビンの生成、肝
細胞の再生、各種生体構成要素(脂肪、グリコゲ
ン、蛋白質、ビタミンなど)の貯蔵などである。
このように精密で均衡のとれた機能を有する肝
臓は自己修復能力が大きく、機能障害を起した場
合、自然治癒が期待できる臓器ではあるが、アル
コール、栄養不良、ウイルス、薬物、毒物、胆管
閉塞、肝循環系の障害など種々の因子によつて急
性的に又は慢性的に障害を受けることがあり、そ
れは脂肪肝、薬物中毒性肝臓疾患、アルコール肝
炎、ウイルス肝炎、うつ血性肝炎、胆汁うつ滞に
よる肝障害、黄疸、それらの終末像としての肝硬
変などの病気として現われる。
これらの肝疾患への移行が生じた場合、薬剤投
与による肝実質細胞の修復の促進、肝細胞の損傷
の軽減を計ることにより、その機能障害からの回
復を早めることができる。
本発明者らはS−アルキル−N−アセチル−シ
ステインアミド類が、その目的に有効であること
を見い出し、本発明に到達した。
すなわち本発明の要旨は、
(1) 一般式
(式中、R1はメチル基またはエチル基を表
わし、R2およびR3は水素原子または炭素数1
〜4の低級アルキル基を表わすか、R2とR3が
一緒になつてアルキレン鎖もしくはヘテロ原子
を含むアルキレン鎖を表わし、窒素原子と共に
環を形成していてもよい。)
で示されるS−アルキル−N−アセチル−シス
テインアミド類,
(2) 一般式()
〔式中、R1は一般式()におけると同義
とし、R4はメチル基またはエチル基を表わ
す。〕
で示されるS−アルキル−N−アセチル−シス
テインアルキルエステル類と、一般式()
〔式中、R2およびR3は一般式()におけ
ると同義とする。〕
で示されるアミノ化合物とを反応させることを
特徴とする前記一般式()で示されるS−ア
ルキル−N−アセチル−システインアミド類の
製法,
(3) 一般式()
〔式中、R1は一般式()におけると同義
とする。〕
で示されるS−アルキル−N−アセチル−シス
テイン類またはそれらの反応性誘導体と、前記
一般式()で示されるアミノ化合物とを反応
させることを特徴とする前記一般式()で示
されるS−アルキル−N−アセチル−システイ
ンアミド類の製法,
(4) 一般式()
〔式中、R1,R2およびR3は一般式()に
おけると同義とする。〕
で示されるS−アルキル−システインアミド類
と、アセチル化剤とを反応させることを特徴と
する前記一般式()で示されるS−アルキル
−N−アセチル−システインアミド類の製法に
存する。
以下に本発明を詳細に説明する。
本発明に係わる化合物は前記一般式()で示
されるS−アルキル−N−アセチル−システイン
アミド類である。
一般式()において、R1はメチル基または
エチル基を表わす。R2およびR3は、水素原子ま
たはメチル、エチル、n−プロピル、n−ブチル
等の炭素数1〜4の低級アルキル基を表わすか
R2とR3が一緒になつてテトラメチレン、ペンタ
メチレン等のアルキレン鎖、2−チア−テトルメ
チレン、3−アザ−ペンタメチレン、3−オキサ
−ペンタメチレン等の硫黄原子、窒素原子、酸素
原子等のヘテロ原子を含むアルキレン鎖を表わ
す。R1,R2およびR3は同一でも、また相互に異
つていてもよい。
一般式()で示されるS−アルキル−N−ア
セチル−システインアミド類としては、例えばS
−メチル−N−アセチル−システインアミド、S
−メチル−N−アセチル−システインメチルアミ
ド、S−メチル−N−アセチル−システインエチ
ルアミド、S−メチル−N−アセチル−システイ
ンプロピルアミド、S−メチル−N−アセチル−
システインブチルアミド、N−(S−メチル−N
−アセチル−システイニル)−ピロリジン、N−
(S−メチル−N−アセチル−システイニル)チ
アゾリジン、S−エチル−N−アセチル−システ
インアミド、S−エチル−N−アセチル−システ
インメチルアミド、S−エチル−N−アセチル−
システインエチルアミド、S−エチル−N−アセ
チル−システインプロピルアミド、S−エチル−
N−アセチル−システインブチルアミド、N−
(S−エチル−N−アセチル−システイニル)−ピ
ロリジンおよびN−(S−エチル−N−アセチル
−システイニル)−チアゾリジンが挙げられる。
これらの化合物にはD,LおよびDL体が存在す
るが通常はL体又はDL体が用いられる。
本発明者らは、上記一般式()で表わされる
化合物が肝細胞を賦括し、肝臓が有する糖質代
謝、解毒(例えばアルコール解毒)作用、胆汁も
しくは胆汁酸の生成並びに分泌(利胆作用)、肝
細胞の再生などの機能を賦括させる作用を有する
ことを見い出した。
又本発明者らは上記一般式()で表わされる
化合物が既に障害を受けている肝に作用して当該
障害を軽減又は除去する薬理作用を有することを
見い出した。
更に本発明者らは上記一般式()で表わされ
る化合物が肝機能をある種の障害又は負担から保
護する薬理作用を有することを見い出した。
中毒性肝障害、肝炎あるいは脂肪肝は種々の原
因によつて発症するが、主な病変は肝細胞壊死、
間葉系の反応あるいは脂肪の貯留である。
壊死の特徴はその原因によつて異なり、小葉中
心性、小葉周辺性及び小葉散在性壊死に分けるこ
とができる。
これらの病変は実験室的には次の様な薬物を被
験動物に投与することによつて病態モデルを作る
ことができる。
小葉中心性壊死は四塩化炭素、チオアセトアミ
ド、クロロホルム、ブロモベンゼンによつて引き
起すことができる。
小葉周辺性壊死はアリルアルコールによつて引
き起すことができる。
間葉系反応を伴つた小葉散在性壊死はD−ガラ
クト−スアミンによつて引き起すことができる。
又脂肪肝の病態モデルは四塩化炭素、エチオニ
ンによつて作ることができる。
これら急性、亜急性あるいは慢性の肝臓障害は
終末像としての肝硬変となることが知られて居
り、例えば実験室的には被験動物への四塩化炭素
の長期間反復投与によつて肝硬変の病態モデルを
作ることができる。
本発明の化合物は実験動物肝炎の作成時に細胞
膜の安定化、ラジカル消去効果、抗酸化効果によ
る生体内チオール化合物の保護、チオール化合物
として様々の肝臓内酵素の賦括化を通して肝臓障
害に対する有効な効果を有することが判明した。
たとえば
小葉中心性壊死を伴う、肝障害の治療(予
防、軽減を含む以下同じ)作用
小葉周辺性壊死を伴う、肝障害の治療作用
小葉散在性壊死に間葉系反応を伴う肝炎の治
療作用
脂肪肝の治療作用
肝硬変の治療作用
中毒性肝障害の治療作用
うつ血肝の治療作用
胆汁及び胆汁酸の分泌促進作用(利胆作用)
血中アルコール濃度の低下作用
異常に高められた血中糖濃度の低下作用
金属塩(セレニウム塩、カドミウム塩)によ
る中毒症状の軽減作用
等の効果が認められる。
このように本発明の化合物は急性肝炎、慢性肝
炎等の肝疾患、薬物中毒で肝の実質細胞の数又は
機能が減少した際のその再生又は新生を促進さ
せ、本来の肝臓の機能を回復させる目的の肝機能
回復剤あるいは肝機能刺戟剤となり、人間および
動物の肝疾患治療剤として有用である。
すなわち、本発明によれば、一般式()で表
わされる化合物は、脂肪肝、アルコール性肝炎、
肝炎、中毒性肝障害、うつ血肝、胆汁うつ滞性肝
障害、あるいはそれらの終末像である肝硬変の治
療剤として使用することができる。
本発明の化合物は組織病理学的所見によれば肝
臓の小葉中心性壊死、小葉周辺性壊死並びに間葉
系反応を伴つた小葉散在性壊死に起因する肝障害
の治療作用を有する。したがつてこのような壊死
を伴う人間や動物の肝臓疾患治療剤として有用で
ある。
本発明の化合物は肝細胞を賦括し肝臓におけ
る、胆汁及び胆汁酸の分泌、糖質代謝、アルコー
ルなどの肝毒性物質の解毒などの機能を賦括させ
る作用を有するので、人間や動物の利胆剤あるい
は黄疸治療剤として有用である。
本発明化合物を肝疾患治療剤として使用するに
は、目的とする薬効を得るに都合のよい形で使用
する。本発明化合物は、そのままの状態で肝疾患
治療剤として使用しうるし、また製薬上の慣習に
従つて、製薬的に許容し得る希釈剤と組成するこ
とも、さらに他の薬理作用物質と組成することも
可能である。
本発明化合物を含む医薬(以下「本発明医薬」
という。)は、投薬量単位形に組成された状態で
も提供されうる。
本発明医薬は経口的に、また非経口的に適用さ
れうる。経口的投与は、舌下投与を含む。
本発明医薬が提供される形態としては、経口投
与用には例えば散剤、顆粒、錠剤、糖衣錠、ピ
ル、カプセル、液剤等、非経口投与用には例えば
座剤、懸濁液、液剤、乳剤、アンプルおよび注射
液等が挙げられる。勿論これらを組み合わせた形
態でも提供しうる。
本発明医薬において、本発明化合物は一般に
0.01〜100重量%含まれる。
本発明化合物と組成しうる希釈剤は、固体、半
固体および液体のいずれでもよく、例えば賦形
剤、増量剤、結合剤、湿潤化剤、崩解剤、界面活
性剤、滑沢剤、分散剤、緩衝剤、矯味剤、矯臭
剤、色素、香料、保存剤、溶解補助剤、溶剤被覆
剤、糖衣剤およびカプセル等が挙げられる。勿論
これらの希釈剤を二種以上併用することもでき
る。希釈剤としては、例えば水:ゼラチン:乳
糖、グルコース等の糖類:とうもろこし、小麦、
米、アロウルート澱粉等の澱粉類:ステアリン酸
等の脂肪酸:ステアリン酸カルシウム、ステアリ
ン酸マグネシウム等の脂肪酸塩:タルク:植物
油:ステアリルアルコール、ベンジルアルコー
ル、ポリアルキレングリコール等のアルコール:
ガム:石油、ミネラル油等の油;生理食塩水;デ
キストロースまたは類似の糖類溶液等が挙げられ
る。
本発明医薬は、常法により製造することができ
る。例えば、本発明化合物を希釈剤と混合して顆
粒とし、次いでその組成物を希釈剤と混合して錠
剤としたり、同様にして顆粒化粉末包装も行いう
る。これらのカプセル、錠剤、顆粒、粉末は一般
的に5〜100重量%、好ましくは25〜100重量%の
本発明化合物を含む。
経口投与の液剤の場合、0.5〜10重量%の本発
明化合物を含む懸濁液またはシロツプがよい。
非経口投与剤は通常無菌とし、また必要に応じ
て血液と等張とする。
注射用の適当な溶剤としては、滅菌水、塩酸リ
ドカイン溶液(筋肉内注射用)、生理食塩水、ぶ
どう糖、静脈内注射用液体、電解質溶液(静脈内
注射および点滴用)等が挙げられる。これらの注
射液の場合には、通常0.5〜20重量%、好ましく
は1〜10重量%の本発明化合物を含むようにする
ことがよい。
本発明医薬の投与量は対象の種(ヒトである
か、動物であるか)、年令、性別、体重、感受性
差、投与方法、投与の時期・間隔、病状の程度、
体調、医薬製剤の性質・調剤・種類、有効成分の
種類などを考慮して、医師により決定される。
動物を対象として有効結果を得るためには、活
性成分として、経口的投与の場合、体重1Kg当り
1日に0.1〜500mg、好ましくは1〜100mg、非経
口投与の場合、0.01〜250mg、好ましくは0.1〜25
mgの範囲が有利である。
人間を対象とする場合の有効結果を得るための
薬量は、動物での有効薬量から感受性差並びに安
全性などを考慮して、例えば次の薬量範囲が有利
である。経口的投与の場合体重1Kg1日当り0.1
〜250mg、好ましくは0.5〜50mg非経口的投与の場
合、体重1Kg1日当り0.01〜100mg好ましくは0.1
〜25mg。
勿論、前述の条件次第では上記の最小量より少
ない量であつても十分のこともあり、また上記の
最大量を超えて投与する必要の生ずることもあ
る。
なお、大量投与の場合、1日数回に分けて投与
するのが好ましい。
本発明に係わる化合物は、例えば前記した様な
方法で製造することができる。
まず第一にS−アルキル−N−アセチル−シス
テインアミド類はS−アルキル−N−アセチル−
N−システインアルキルエステルとアミノ化合物
とを反応させることにより製造し得る。
一般式()で示されるS−アルキル−N−ア
セチル−システインアルキルエステル類と一般式
()で示されるアミノ化合物との反応の際、通
常はアミノ化合物を過剰に用いる。反応は通常メ
タノール、エタノール等の有機溶媒中、又は無溶
媒で、室温又は冷却下行われる。
又、S−アルキル−N−アセチル−システイン
アミド類は、S−アルキル−N−アセチル−N−
システイン類とアミノ化合物の縮合反応によつて
製造することができる。一般式()で示される
S−アルキル−N−アセチルシステイン類と一般
式()で示されるアミノ化合物とを反応させる
際には、通常、脱水縮合剤を用いる。脱水縮合剤
としては通常N,N′−ジシクロヘキシルカルボ
ジイミド、1−シクロヘキシル−3−(4−ジエ
チルアミノシクロヘキシル)カルボジイミド、1
−エチル−3−(3−ジエチルアミノプロピル)
カルボジイミドなどを用いることができる。反応
は通常ジクロルメタン、クロロホルム等の有機溶
媒中で、室温又は冷却下に行われる。一般式
()で示されるS−アルキル−N−アセチル−
システイン類と一般式()で示されるアミノ化
合物と脱水縮合剤とのモル比は通常ほゞ1:1:
1である。
さらに、また、S−アルキル−N−アセチル−
システインアミド類は上記一般式()で示され
るS−アルキル−N−アセチル−システイン類の
反応性誘導体と一般式()で示されるアミノ化
合物とを反応させることにより製造することもで
きる。
S−アルキル−N−アセチル−システイン類の
反応性誘導体としてはたとえばアルキル炭酸混合
無水物等の混合酸無水物、酸クロリド等があげら
れる。これら反応性誘導体は必ずしも単離精製さ
れる必要はなく、反応混合物のままアミノ化合物
との反応に使用することができる。
一般式()で示されるS−アルキル−N−ア
セチル−システイン類の反応性誘導体と一般式
()で示されるアミノ化合物との反応の際、通
常はアミノ化合物を少過剰用いる。
反応は通常トリエチルアミン、ジメチルアニリ
ン等の塩基の存在下、アセトン、テトラヒドロフ
ラン、ジオキサン、ジメチルホルムアミド、クロ
ロホルム、ジクロルメタン、ヘキサメチルホスホ
ルアミド等の有機溶媒、これらの混合溶媒又はこ
れら有機溶媒と水との混合溶媒中、室温又は冷却
下行われる。
さらにまたS−アルキル−N−アセチル−シス
テインアミド類は一般式()で示されるS−ア
ルキルシステインアミド類もしくはそれらの塩と
酢酸もしくはその反応性誘導体などのアセチル化
剤とを縮合させることによつて製造することがで
きる。
S−アルキルシステインアミド類と酢酸を反応
させる場合には前記したように通常N,N′−ジ
シクロヘキシルカルボジイミドなどの脱水縮合剤
を用いることができる。
またS−アルキルシステインアミド類の塩(た
とえば塩酸塩)を原料として使用する時はトリエ
チルアミン、ジメチルアニリン等の塩基の存在下
に反応を行うのが普通である。
又酢酸の反応性誘導体としては、無水酢酸、酢
酸クロリド、アルキル炭酸混合無水物などを用い
ることができる。反応はS−アルキル−N−アセ
チル−システイン類の反応性誘導体とアミノ化合
物の反応の際に述べたと同様にして行なうことが
できる。
以上述べたように種々の合成経路を通して目的
とするS−アルキル−N−アセチル−システイン
アミド類を製造することができるが、上記反応後
は有機化学の常法にしたがつて、有機溶媒抽出、
洗浄、溶媒留去、過再結晶などの操作を行なつ
て、目的物を精製することができる。
以下に実施例を挙げて本発明を更に詳細に説明
するが、本発明はその要旨を超えない限り以下の
実施例により限定を受けるものではない。
実施例 1
L−システイン−塩酸塩175.64g(1.0mole)
を氷冷した2規定の水酸化ナトリウム水溶液の1
(2mole)に粉末で加え均一溶液とした。
メチルアルコール2を加え氷冷し、ヨウ化メ
チル70ml(1.10mole)を滴下した。白色結晶析出
後、数時間撹拌し、室温で一晩放置する。5%塩
酸水溶液でPH6.5とし、氷冷後過し、60%メチ
ルアルコール水溶液で洗浄した。収量62.9g。
液を減圧下濃縮し、回収した。69.7g。
S−メチル−L−システインが収量132.6g
(収率98%)で得られた。
S−メチル−L−システイン119.6g
(0.89mole)を1規定水酸化ナトリウム水溶液
1.87(1.87mole)にとかし、氷冷した。無水酢
酸92.6ml(0.98mole)を滴下し、室温で2.0時間
撹拌した。6規定の塩酸水溶液でPH1.0とし、酢
酸エチルの1で5回抽出し、無水硫酸マグネシ
ウムで乾燥後、減圧濃縮すると、オイル状のS−
メチル−N−アセチル−L−システイン126.4g
が得られた。(収率80.6%)。水層再抽出により、
5.17g(3.3%)回収。
メチルアルコール600mlを−10℃に冷却し、塩
化チオニル180ml(2.54mole)をゆつくり滴下す
る。−10℃で20分撹拌後、S−メチル−N−アセ
チル−L−システイン131.6gr(0.74mole)を−
10℃で滴下し、室温で数時間撹拌後、一晩放置し
た。メチルアルコールを減圧留去し、残留物をク
ロロホルム1と水1にとかす。粉末炭酸水素
ナトリウムを加え、中性とし分液した。水層をク
ロロホルムの1で2回抽出し、クロロホルム層
を5%炭酸水素ナトリウム600mlで2回、飽和塩
化ナトリウム水溶液600mlで2回洗浄し、無水硫
酸マグネシウムで乾燥後、減圧濃縮した。オイル
状のS−メチル−N−アセチル−L−システイン
メチルエステルが130.5g(収率92.8%)得られ
た。
S−メチル−N−アセチル−L−システインメ
チルエステル130.5g(0.69mole)をメチルアル
コール650mlに溶解し、氷冷する。アンモニアガ
スをふき込み、飽和させる。室温で三日間放置
後、減圧濃縮する。白色結晶が析出した。結晶を
エチルエーテルで洗浄し、減圧乾燥するとS−メ
チル−N−アセチル−L−システインアミドが
96.5g(収率79%)得られた。
m.p 120.4〜123℃
〔α〕D=−36.6゜ 1%メチルアルコール溶液
IR(cm-1)KBr 3350,3250,1680,1640,
1550,1410,1370,1295,1180,
1120,965,645,610,520,510
NMR(100MHz)ppm
DMSO−d6 1.97(S,3H,
The present invention relates to S-alkyl-N-acetylcysteinamides and methods for producing them. Specifically, the present invention relates to novel S-alkyl-N-acetyl-cysteinamides useful as therapeutic agents for liver diseases and methods for producing them. Various biochemical reactions take place in the liver. For example, detoxification, carbohydrate metabolism, protein metabolism, lipid metabolism, production and secretion of bile, regulation of hormones, production of blood coagulation agent prothrombin, regeneration of liver cells, various biological components (fat, glycogen, protein, vitamin etc.). The liver, which has such precise and balanced functions, has a great ability to self-repair, and if dysfunction occurs, it is an organ that can be expected to recover naturally. It can be acutely or chronically impaired due to various factors such as disorders of the hepatic circulatory system, including fatty liver, drug-induced liver disease, alcoholic hepatitis, viral hepatitis, depressive hepatitis, and cholestasis. It manifests as diseases such as liver damage, jaundice, and liver cirrhosis as the final stage of these diseases. When transition to these liver diseases occurs, recovery from the dysfunction can be accelerated by promoting the repair of hepatic parenchymal cells and reducing damage to hepatocytes by administering drugs. The present inventors have discovered that S-alkyl-N-acetyl-cysteinamides are effective for this purpose, and have arrived at the present invention. In other words, the gist of the present invention is (1) General formula (In the formula, R 1 represents a methyl group or an ethyl group, and R 2 and R 3 represent a hydrogen atom or a carbon number of 1
-4 lower alkyl group, or R 2 and R 3 together may represent an alkylene chain or an alkylene chain containing a hetero atom, and may form a ring together with the nitrogen atom. ) S-alkyl-N-acetyl-cysteinamides represented by (2) General formula () [In the formula, R 1 has the same meaning as in the general formula (), and R 4 represents a methyl group or an ethyl group. ] S-alkyl-N-acetyl-cysteine alkyl esters represented by the general formula () [In the formula, R 2 and R 3 have the same meanings as in the general formula (). ] A method for producing S-alkyl-N-acetyl-cysteinamides represented by the general formula (), characterized by reacting with an amino compound represented by the general formula (), (3) a method for producing S-alkyl-N-acetyl-cysteinamides represented by the general formula () [In the formula, R 1 has the same meaning as in the general formula (). ] S-alkyl-N-acetyl-cysteines represented by the above formula () or their reactive derivatives are reacted with an amino compound represented by the general formula () above. -Production method of alkyl-N-acetyl-cysteinamides, (4) General formula () [In the formula, R 1 , R 2 and R 3 have the same meanings as in the general formula (). ] A method for producing S-alkyl-N-acetyl-cysteinamides represented by the general formula (), characterized by reacting the S-alkyl-cysteinamides represented by the following with an acetylating agent. The present invention will be explained in detail below. The compounds according to the present invention are S-alkyl-N-acetyl-cysteinamides represented by the general formula (). In the general formula (), R 1 represents a methyl group or an ethyl group. R 2 and R 3 represent a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, etc.
R 2 and R 3 together form alkylene chains such as tetramethylene and pentamethylene, sulfur atoms, nitrogen atoms, and oxygen atoms such as 2-thia-tetrumethylene, 3-aza-pentamethylene, 3-oxa-pentamethylene, etc. represents an alkylene chain containing a heteroatom such as R 1 , R 2 and R 3 may be the same or different from each other. Examples of the S-alkyl-N-acetyl-cysteinamides represented by the general formula () include S
-Methyl-N-acetyl-cysteinamide, S
-Methyl-N-acetyl-cysteine methylamide, S-methyl-N-acetyl-cysteine ethylamide, S-methyl-N-acetyl-cysteine propylamide, S-methyl-N-acetyl-
Cysteine butyramide, N-(S-methyl-N
-acetyl-cysteinyl)-pyrrolidine, N-
(S-Methyl-N-acetyl-cysteinyl)thiazolidine, S-ethyl-N-acetyl-cysteinamide, S-ethyl-N-acetyl-cysteinemethylamide, S-ethyl-N-acetyl-
Cysteine ethylamide, S-ethyl-N-acetyl-cysteine propylamide, S-ethyl-
N-acetyl-cysteine butyramide, N-
Mention may be made of (S-ethyl-N-acetyl-cysteinyl)-pyrrolidine and N-(S-ethyl-N-acetyl-cysteinyl)-thiazolidine.
These compounds exist in D, L and DL forms, but usually the L form or the DL form is used. The present inventors have demonstrated that the compound represented by the above general formula () binds hepatocytes and has a carbohydrate metabolism, detoxification (e.g. alcohol detoxification) effect, bile or bile acid production and secretion (choleretic effect). ) was found to have the effect of stimulating functions such as liver cell regeneration. The present inventors have also discovered that the compound represented by the above general formula () has a pharmacological action that acts on the liver that has already suffered from damage and reduces or eliminates the damage. Furthermore, the present inventors have discovered that the compound represented by the above general formula () has a pharmacological action that protects liver function from certain disorders or burdens. Toxic liver disease, hepatitis, or fatty liver develops due to various causes, but the main lesions are hepatocyte necrosis,
It is a mesenchymal response or fat storage. The characteristics of necrosis vary depending on its cause and can be divided into centrilobular, perilobular, and disseminated necrosis. In the laboratory, pathological models of these lesions can be created by administering the following drugs to test animals. Centrilobular necrosis can be induced by carbon tetrachloride, thioacetamide, chloroform, and bromobenzene. Perilobular necrosis can be caused by allyl alcohol. Lobular disseminated necrosis with mesenchymal reactions can be induced by D-galactosamine. Furthermore, a pathological model of fatty liver can be created using carbon tetrachloride and ethionine. It is known that these acute, subacute, or chronic liver disorders can lead to liver cirrhosis as a final outcome.For example, in the laboratory, a pathological model of liver cirrhosis is created by repeatedly administering carbon tetrachloride to test animals over a long period of time. can be made. The compound of the present invention has an effective effect on liver damage by stabilizing cell membranes, radical scavenging effect, protection of in-vivo thiol compounds by antioxidant effect, and enrichment of various liver enzymes as a thiol compound when creating hepatitis in experimental animals. It was found that the For example, the therapeutic effect (including prevention and alleviation) of liver damage accompanied by centrilobular necrosis; the therapeutic action of liver damage accompanied by perilobular necrosis; the therapeutic action of hepatitis accompanied by mesenchymal reactions in disseminated lobular necrosis; fat Therapeutic effect on the liver Therapeutic effect on liver cirrhosis Therapeutic effect on toxic liver disorder Therapeutic effect on depressed liver The effect on promoting the secretion of bile and bile acids (choleretic effect) The effect on lowering blood alcohol concentration Abnormally elevated blood sugar concentration Metal salts (selenium salts, cadmium salts) have been shown to be effective in reducing poisoning symptoms. As described above, the compound of the present invention promotes the regeneration or new generation of liver parenchymal cells when the number or function of hepatic parenchymal cells decreases due to liver diseases such as acute hepatitis or chronic hepatitis, or drug addiction, thereby restoring the original liver function. It serves as a liver function restoring agent or liver function stimulant, and is useful as a therapeutic agent for liver diseases in humans and animals. That is, according to the present invention, the compound represented by the general formula () can be used to treat fatty liver, alcoholic hepatitis,
It can be used as a therapeutic agent for hepatitis, toxic liver disease, hemorrhagic liver disease, cholestatic liver disease, or liver cirrhosis, which is the final stage thereof. According to histopathological findings, the compounds of the present invention have a therapeutic effect on liver disorders caused by centrilobular necrosis, perilobular necrosis, and scattered lobular necrosis accompanied by mesenchymal reactions. Therefore, it is useful as a therapeutic agent for liver diseases in humans and animals that are accompanied by such necrosis. The compounds of the present invention have the effect of stimulating hepatocytes and stimulating functions in the liver, such as secretion of bile and bile acids, carbohydrate metabolism, and detoxification of hepatotoxic substances such as alcohol, and are therefore useful for humans and animals. It is useful as a bile agent or as a treatment for jaundice. When using the compound of the present invention as a therapeutic agent for liver diseases, it is used in a form convenient for obtaining the desired medicinal effect. The compounds of the present invention can be used as they are as agents for treating liver diseases, or they can be formulated with pharmaceutically acceptable diluents or with other pharmacologically active substances in accordance with pharmaceutical practice. It is also possible. A drug containing the compound of the present invention (hereinafter referred to as "the drug of the present invention")
That's what it means. ) may also be provided in dosage unit form. The medicament of the present invention can be applied orally or parenterally. Oral administration includes sublingual administration. The pharmaceuticals of the present invention may be provided in a form for oral administration, such as powders, granules, tablets, sugar-coated tablets, pills, capsules, and liquid preparations, and for parenteral administration, such as suppositories, suspensions, solutions, emulsions, etc. Examples include ampoules and injection solutions. Of course, a combination of these can also be provided. In the pharmaceutical of the present invention, the compound of the present invention is generally
Contains 0.01-100% by weight. Diluents that can be combined with the compounds of the invention may be solid, semi-solid or liquid, such as excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, etc. agent, buffering agent, flavoring agent, flavoring agent, dye, fragrance, preservative, solubilizing agent, solvent coating agent, sugar coating agent, capsule, etc. Of course, two or more of these diluents can also be used in combination. Examples of diluents include water: gelatin: sugars such as lactose and glucose: corn, wheat,
Starches such as rice and arrowroot starch: Fatty acids such as stearic acid: Fatty acid salts such as calcium stearate and magnesium stearate: Talc: Vegetable oils: Alcohols such as stearyl alcohol, benzyl alcohol, and polyalkylene glycol:
Gums: Oils such as petroleum and mineral oils; physiological saline; dextrose or similar sugar solutions, and the like. The medicament of the present invention can be manufactured by conventional methods. For example, the compound of the present invention may be mixed with a diluent to form granules, and then the composition may be mixed with a diluent to form tablets, or granulated powder packaging may be performed in the same manner. These capsules, tablets, granules and powders generally contain from 5 to 100% by weight, preferably from 25 to 100% by weight of the compound of the invention. In the case of liquid preparations for oral administration, suspensions or syrups containing 0.5 to 10% by weight of the compound of the present invention are preferred. Parenterally administered preparations are usually sterile and, if necessary, isotonic with blood. Suitable solvents for injection include sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, dextrose, intravenous fluids, electrolyte solutions (for intravenous injection and infusion), and the like. These injection solutions usually contain 0.5 to 20% by weight, preferably 1 to 10% by weight of the compound of the present invention. The dosage of the pharmaceutical of the present invention depends on the target species (human or animal), age, sex, body weight, sensitivity difference, administration method, administration timing/interval, degree of disease state,
It will be decided by your doctor, taking into consideration your physical condition, the nature, preparation, and type of pharmaceutical preparation, and the type of active ingredient. In order to obtain effective results in animals, the active ingredient should be 0.1 to 500 mg per kg of body weight per day for oral administration, preferably 1 to 100 mg, and 0.01 to 250 mg per day for parenteral administration. 0.1~25
mg range is advantageous. Regarding the dosage for obtaining effective results in humans, the following dosage range is advantageous, for example, taking into account the effective dosage in animals, sensitivity differences, safety, and the like. For oral administration: 0.1 per kg body weight per day
~250mg, preferably 0.5-50mg For parenteral administration, 0.01-100mg per kg body weight per day, preferably 0.1
~25mg. Of course, depending on the conditions mentioned above, it may be sufficient to use an amount less than the above-mentioned minimum amount, and it may also be necessary to administer more than the above-mentioned maximum amount. In addition, in the case of large-dose administration, it is preferable to divide the administration into several times a day. The compound according to the present invention can be produced, for example, by the method described above. First of all, S-alkyl-N-acetyl-cysteinamides are S-alkyl-N-acetyl-
It can be produced by reacting an N-cysteine alkyl ester with an amino compound. When reacting the S-alkyl-N-acetyl-cysteine alkyl ester represented by the general formula () with the amino compound represented by the general formula (), the amino compound is usually used in excess. The reaction is usually carried out in an organic solvent such as methanol or ethanol, or without a solvent, at room temperature or under cooling. Further, S-alkyl-N-acetyl-cysteinamides are S-alkyl-N-acetyl-N-
It can be produced by a condensation reaction of cysteines and amino compounds. When reacting the S-alkyl-N-acetyl cysteines represented by the general formula () with the amino compound represented by the general formula (), a dehydration condensation agent is usually used. The dehydration condensation agent is usually N,N'-dicyclohexylcarbodiimide, 1-cyclohexyl-3-(4-diethylaminocyclohexyl)carbodiimide, 1
-ethyl-3-(3-diethylaminopropyl)
Carbodiimide and the like can be used. The reaction is usually carried out in an organic solvent such as dichloromethane or chloroform at room temperature or under cooling. S-alkyl-N-acetyl- represented by the general formula ()
The molar ratio of cysteines, the amino compound represented by the general formula (), and the dehydration condensation agent is usually approximately 1:1:
It is 1. Furthermore, S-alkyl-N-acetyl-
Cysteinamides can also be produced by reacting a reactive derivative of S-alkyl-N-acetyl-cysteine represented by the above general formula () with an amino compound represented by the general formula (). Examples of reactive derivatives of S-alkyl-N-acetyl-cysteines include mixed acid anhydrides such as alkyl carbonic acid mixed anhydrides, acid chlorides, and the like. These reactive derivatives do not necessarily need to be isolated and purified, and can be used as a reaction mixture in the reaction with the amino compound. When reacting the reactive derivative of S-alkyl-N-acetyl-cysteine represented by the general formula () with the amino compound represented by the general formula (), the amino compound is usually used in slight excess. The reaction is usually carried out in the presence of a base such as triethylamine or dimethylaniline, using an organic solvent such as acetone, tetrahydrofuran, dioxane, dimethylformamide, chloroform, dichloromethane, hexamethylphosphoramide, a mixed solvent thereof, or a mixture of these organic solvents and water. It is carried out in a solvent at room temperature or under cooling. Furthermore, S-alkyl-N-acetyl-cysteinamides can be obtained by condensing S-alkylcysteinamides represented by the general formula () or their salts with an acetylating agent such as acetic acid or a reactive derivative thereof. It can be manufactured by When S-alkylcysteinamides and acetic acid are reacted, a dehydration condensation agent such as N,N'-dicyclohexylcarbodiimide can usually be used as described above. Further, when a salt of S-alkyl cysteinamide (for example, hydrochloride) is used as a raw material, the reaction is usually carried out in the presence of a base such as triethylamine or dimethylaniline. Further, as the reactive derivative of acetic acid, acetic anhydride, acetic chloride, alkyl carbonic acid mixed anhydride, etc. can be used. The reaction can be carried out in the same manner as described for the reaction of reactive derivatives of S-alkyl-N-acetyl-cysteines with amino compounds. As mentioned above, the desired S-alkyl-N-acetyl-cysteinamides can be produced through various synthetic routes, but after the above reaction, organic solvent extraction,
The target product can be purified by operations such as washing, solvent distillation, and over-recrystallization. The present invention will be described in more detail with reference to Examples below, but the present invention is not limited by the Examples unless it exceeds the gist thereof. Example 1 L-cysteine hydrochloride 175.64g (1.0mole)
1 of a 2N aqueous solution of sodium hydroxide cooled on ice
(2 mole) was added as a powder to make a homogeneous solution. Methyl alcohol 2 was added, cooled on ice, and 70 ml (1.10 mole) of methyl iodide was added dropwise. After precipitation of white crystals, stir for several hours and leave at room temperature overnight. The pH was adjusted to 6.5 with a 5% aqueous hydrochloric acid solution, cooled on ice, filtered, and washed with a 60% aqueous methyl alcohol solution. Yield: 62.9g.
The liquid was concentrated under reduced pressure and collected. 69.7g. Yield of S-methyl-L-cysteine: 132.6g
(yield 98%). S-methyl-L-cysteine 119.6g
(0.89mole) in 1N aqueous sodium hydroxide solution
It was dissolved to 1.87 (1.87 mole) and cooled on ice. 92.6 ml (0.98 mole) of acetic anhydride was added dropwise, and the mixture was stirred at room temperature for 2.0 hours. Adjust the pH to 1.0 with a 6N aqueous solution of hydrochloric acid, extract 5 times with ethyl acetate, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain an oily S-
Methyl-N-acetyl-L-cysteine 126.4g
was gotten. (Yield 80.6%). By re-extracting the aqueous layer,
5.17g (3.3%) recovered. Cool 600 ml of methyl alcohol to -10°C, and slowly add 180 ml (2.54 mole) of thionyl chloride dropwise. After stirring at -10℃ for 20 minutes, 131.6gr (0.74mole) of S-methyl-N-acetyl-L-cysteine was added to -
The mixture was added dropwise at 10°C, stirred at room temperature for several hours, and then left overnight. The methyl alcohol was distilled off under reduced pressure, and the residue was dissolved in 1 part chloroform and 1 part water. Powdered sodium hydrogen carbonate was added to neutralize the mixture and separate the layers. The aqueous layer was extracted twice with 1 portion of chloroform, and the chloroform layer was washed twice with 600 ml of 5% sodium bicarbonate and twice with 600 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 130.5 g (yield 92.8%) of oily S-methyl-N-acetyl-L-cysteine methyl ester was obtained. 130.5 g (0.69 mole) of S-methyl-N-acetyl-L-cysteine methyl ester is dissolved in 650 ml of methyl alcohol and cooled on ice. Blow in ammonia gas to saturate. After standing at room temperature for three days, concentrate under reduced pressure. White crystals precipitated. When the crystals are washed with ethyl ether and dried under reduced pressure, S-methyl-N-acetyl-L-cysteinamide is obtained.
96.5g (yield 79%) was obtained. mp 120.4 - 123℃ [α] D = -36.6゜ 1% methyl alcohol solution IR (cm -1 ) KBr 3350, 3250, 1680, 1640,
1550, 1410, 1370, 1295, 1180,
1120, 965, 645, 610, 520, 510 NMR (100MHz) ppm DMSO−d 6 1.97 (S, 3H,
【式】), 2.07(S,3H,CH 3S−), 2.70(m,2H,[Formula]), 2.07 (S, 3H, C H 3 S-), 2.70 (m, 2H,
【式】), 4.39(q,1H,【formula】), 4.39(q, 1H,
【式】),
7.10と7.48(S×2,2H,
[Formula]), 7.10 and 7.48 (S×2, 2H,
【式】 8.0(d,1H,【formula】 8.0(d, 1H,
【式】)
実施例 2
実施例1の「L−システイン−塩酸塩」をDL
−システイン−塩酸塩にかえたほかは、実施例−
1と全く同様にして、S−メチル−DL−システ
インを、ついでS−メチル−N−アセチル−DL
−システインを、ついでS−メチル−N−アセチ
ル−DL−システインメチルエステルを、つい
で、S−メチル−N−アセチル−DL−システイ
ンアミドを合成した。
m.p 139.3〜141.7℃
IR(cm-1)KBr 3250,3210,1700,1679,
1620,1540,1420,1375,1300,
660,630,610
NMR(100MHz)ppm
DMSO−d6 1.84(S,3H,[Formula]) Example 2 DL “L-cysteine-hydrochloride” of Example 1
- Example except that cysteine hydrochloride was used -
In exactly the same manner as in 1, S-methyl-DL-cysteine was then added to S-methyl-N-acetyl-DL.
-cysteine, then S-methyl-N-acetyl-DL-cysteine methyl ester, and then S-methyl-N-acetyl-DL-cysteinamide were synthesized. mp 139.3~141.7℃ IR (cm -1 ) KBr 3250, 3210, 1700, 1679,
1620, 1540, 1420, 1375, 1300,
660, 630, 610 NMR (100MHz) ppm DMSO−d 6 1.84 (S, 3H,
【式】)
2.04(S,3H,CH 3S−),
2.7(m,2H,−SCH 2CH),
4.38(q,1H,−SCH2CH),
7.07と7.44(S×2,2H,
[Formula]) 2.04 (S, 3H, CH 3 S-), 2.7 (m, 2H, -SC H 2 CH), 4.38 (q, 1H, -SCH 2 CH ), 7.07 and 7.44 (S x 2 ,2H,
【式】) 8.0(d,1H,【formula】) 8.0(d, 1H,
【式】)
実施例 3
実施例1の「S−メチル−L−システイン」を
S−エチル−L−システインにかえたほかは、実
施例1と全く同様にして、S−エチル−N−アセ
チル−L−システインアミドを合成した。
m.p 120〜(分解)
IR(cm-1)KBr 3360,1680,1620,1540,1410
NMR(100MHz)ppm
DMSO−d6 1.17(t,3H,CH3CH2S−),
1.86(S,3H,[Formula]) Example 3 S-ethyl-N-acetyl -L-cysteinamide was synthesized. mp 120 ~ (decomposition) IR (cm -1 ) KBr 3360, 1680, 1620, 1540, 1410 NMR (100MHz) ppm DMSO−d 6 1.17 (t, 3H, CH 3 CH 2 S−), 1.86 (S, 3H ,
【式】), 2.5(m,2H,CH3CH 2S−), 2.7(m,2H,[Formula]), 2.5 (m, 2H, CH 3 C H 2 S-), 2.7 (m, 2H,
【式】), 4.34(q,1H,【formula】), 4.34(q, 1H,
【式】),
7.1と7.5(S×2,2H,
[Formula]), 7.1 and 7.5 (S×2, 2H,
【式】), 8.10(d,1H,【formula】), 8.10(d, 1H,
【式】)
実施例 4
S−メチル−L−システイン(13.5g,
100mmole)を1規定の水酸化ナトリウム水溶液
210mlにとかし、氷冷する。無水酢酸(10.4ml,
110mmole)を滴下した。室温で2.0時間後、6規
定の塩酸でPH1.0とし、酢酸エチルで抽出し、無
水硫酸マグネシウムで乾燥後、減圧濃縮すると、
オイル状のS−メチル−N−アセチル−L−シス
テインの15.9gが得られた。収率89.6M%
S−メチル−N−アセチル−L−システイン
(3.54g,20mmole)をテトラヒドロフラン25ml
に溶解し、これにトリエチルアミン2.8ml
(20mmole)を加えた。−15℃に冷却して、クロル
ギ酸ブチル2.7ml(20mmole)を滴下し、この温
度で20分間撹拌した。−40℃に冷却後70%エチル
アミン水溶液3.0ml(46.6mmole)を一度に加
え、氷冷下3時間撹拌した。酢酸エチル100mlで
3回抽出し、5%炭酸水素ナトリウム水溶液(30
ml×2)、飽和食塩水(30ml×2)で洗浄し、無
水硫酸マグネシウムで乾燥後、減圧濃縮すると、
結晶が析出したので、エチルエーテルで洗浄し、
S−メチル−N−アセチル−L−システインエチ
ルアミド2.20gを得た。収率53.8%
m.p 104.5〜105.3℃
IR(cm-1)KBr 3300,3240,3050,1645,
1580,1550,1380,1265,1150,
770,700,600
NMR(100MHz)ppm
DMSO−d6 1.03(t,3H,−NHCH2CH3),
1.94(S,3H,[Formula]) Example 4 S-methyl-L-cysteine (13.5g,
100 mmole) in 1N sodium hydroxide aqueous solution
Dissolve to 210ml and chill on ice. Acetic anhydride (10.4ml,
110 mmole) was added dropwise. After 2.0 hours at room temperature, the pH was adjusted to 1.0 with 6N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
15.9 g of oily S-methyl-N-acetyl-L-cysteine was obtained. Yield 89.6 M % S-methyl-N-acetyl-L-cysteine (3.54 g, 20 mmole) was dissolved in 25 ml of tetrahydrofuran.
Dissolve 2.8 ml of triethylamine in this
(20 mmole) was added. After cooling to −15° C., 2.7 ml (20 mmole) of butyl chloroformate was added dropwise, and the mixture was stirred at this temperature for 20 minutes. After cooling to -40°C, 3.0 ml (46.6 mmole) of a 70% aqueous ethylamine solution was added at once, and the mixture was stirred for 3 hours under ice cooling. Extract 3 times with 100 ml of ethyl acetate, and add 5% aqueous sodium hydrogen carbonate solution (30 ml).
ml x 2), washed with saturated saline (30 ml x 2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
Crystals were precipitated, so they were washed with ethyl ether and
2.20 g of S-methyl-N-acetyl-L-cysteine ethylamide was obtained. Yield 53.8% mp 104.5-105.3℃ IR (cm -1 ) KBr 3300, 3240, 3050, 1645,
1580, 1550, 1380, 1265, 1150,
770, 700, 600 NMR (100MHz) ppm DMSO-d 6 1.03 (t, 3H, -NHCH 2 CH 3 ), 1.94 (S, 3H,
【式】), 2.04(S,3H,CH 3S−), 2.66(m,2H,[Formula]), 2.04 (S, 3H, C H 3 S-), 2.66 (m, 2H,
【式】),
3.08(qui,2H,NHCH 2CH3),
4.38(q,1H,
[Formula]), 3.08 (qui, 2H, NHC H 2 CH 3 ), 4.38 (q, 1H,
【式】)
8.04(ブロード、2H,
[Formula]) 8.04 (Broad, 2H,
【式】)
実施例 5
実施例4の「70%エチルアミン水溶液」をチア
ゾリジンにかえたほかは実施例4と全く同様にし
て、N−(N−アセチル−S−メチル−L−シス
テイニル)チアゾリジンを合成した。
実施例 6
実施例4の「S−メチル−N−アセチル−L−
システイン」をS−エチル−N−アセチル−L−
システインにかえたほかは実施例4と全く同様に
して、S−エチル−N−アセチル−L−システイ
ンエチルアミドを合成した。
実施例 7
実施例4の「S−メチル−N−アセチル−L−
システイン」をS−エチル−N−アセチル−L−
システインにかえ、「70%エチルアミン水溶液」
をn−ブチルアミンにかえたほかは、実施例4と
全く同様にして、S−エチル−N−アセチル−L
−システインブチルアミドを合成した。
実施例 8
実施例4の「S−メチル−N−アセチル−L−
システイン」をS−エチル−N−アセチル−L−
システインにかえ、「70%エチルアミン水溶液」
をピロリジンにかえたほかは、実施例4と全く同
様にして、N−(N−アセチル−S−メチル−L
−システイニル)ピロリジンを合成した。実施例
5〜8の結果を表1に示す。[Formula]) Example 5 N-(N-acetyl-S-methyl-L-cysteinyl)thiazolidine was prepared in exactly the same manner as in Example 4 except that "70% ethylamine aqueous solution" in Example 4 was replaced with thiazolidine. Synthesized. Example 6 "S-Methyl-N-acetyl-L-" of Example 4
"Cysteine" is S-ethyl-N-acetyl-L-
S-ethyl-N-acetyl-L-cysteine ethylamide was synthesized in exactly the same manner as in Example 4 except that cysteine was used. Example 7 "S-Methyl-N-acetyl-L-" of Example 4
"Cysteine" is S-ethyl-N-acetyl-L-
Instead of cysteine, "70% ethylamine aqueous solution"
S-ethyl-N-acetyl-L
-Cysteine butyramide was synthesized. Example 8 "S-Methyl-N-acetyl-L-" of Example 4
"Cysteine" is S-ethyl-N-acetyl-L-
Instead of cysteine, "70% ethylamine aqueous solution"
N-(N-acetyl-S-methyl-L
-cysteinyl)pyrrolidine was synthesized. The results of Examples 5 to 8 are shown in Table 1.
【表】
試験例 1
小葉中心性壊死を伴う急性肝障害に対する作用
(四塩化炭素1回投与における肝炎モデル)
投与された四塩化炭素は肝臓ミクロゾームの薬
物代謝酵素によつて代謝を受けトリクロルラジカ
ルを生じる。このラジカルは肝細胞膜、ミトコン
ドリア膜あるいはミクロゾームの膜に障害を与え
肝細胞本来の機能を失なわせ小葉中心性壊死を引
き起こす。肝細胞のこの様な障害時には酵素の遊
出が起こり、種々の酵素活性が血清中に出現す
る。そのため障害の指標として血清トランスアミ
ナーゼの活性を測定するのは適当な方法である。
血清トランスアミナーゼにはGOT(グルタミン
−オキザロ酢酸トランスアミナーゼ)、GPT(グ
ルタミン−ピルビン酸トランスアミナーゼ)があ
るが両酵素活性共に測定した。
試験方法
ラツト(体重100g前後、ウイスター雄)に供
試化合物を31,62,125mg/Kgの割合で経口投与
し、その3時間後に四塩化炭素を0.25ml/Kg(オ
リーブ油で4倍に稀釈したもの)で復腔内に投与
し更に24時間後に屠殺し復大静脈より採血後、遠
沈によつて血清を得、血清GOT,GPTを測定し
活性を国際単位法に従つて表現した。結果を表1
に示した。[Table] Test example 1 Effect on acute liver injury accompanied by centrilobular necrosis (hepatitis model with single administration of carbon tetrachloride) The administered carbon tetrachloride is metabolized by drug-metabolizing enzymes in liver microsomes and converted into trichlor radicals. arise. These radicals damage hepatocyte membranes, mitochondrial membranes, or microsomal membranes, causing loss of the original functions of hepatocytes and causing centrilobular necrosis. When hepatocytes are damaged in this way, enzymes are extravasated and various enzyme activities appear in the serum. Therefore, it is an appropriate method to measure serum transaminase activity as an indicator of the disorder.
Serum transaminases include GOT (glutamine-oxaloacetate transaminase) and GPT (glutamine-pyruvate transaminase), and both enzyme activities were measured. Test method The test compound was orally administered to rats (body weight around 100 g, male Wistar) at a rate of 31, 62, and 125 mg/Kg, and 3 hours later, carbon tetrachloride was administered at 0.25 ml/Kg (diluted 4 times with olive oil). After 24 hours, the animals were sacrificed and blood was collected from the retrovena cava. Serum was obtained by centrifugation, serum GOT and GPT were measured, and the activity was expressed according to the International Units method. Table 1 shows the results.
It was shown to.
【表】
供試化合物S−メチル−N−アセチル−L−シ
ステインアミドは対照薬チオラ(αメルカプトプ
ロピオニルグリシン)の薬効を上回るものであ
り、従つてこの供試化合物は小葉中心性壊死を伴
う人間や動物の肝障害の治療剤として有用であ
る。
試験例 2
間葉系反応と小葉散在性壊死を伴う急性肝炎に
対する作用(D−ガラクト−スアミン1回投与
モデル試験)
D−ガラクト−スアミンの大量投与によつて本
来肝臓内で合成されるべきUDPグルコース(ウ
リジンジフオスフエイト−グルコース)がD−ガ
ラクト−スアミンによつて競合阻害を受けてその
量が減少する。このためUDPグルコースを経る
グリコーゲンの合成、グルクロニド合成が抑制さ
れて肝細胞の機能障害を発症すると考えられてい
る。病態組織像は人間におけるウイルス性肝炎に
似た間葉系反応を伴つた散在性の壊死を引き起こ
す。
試験方法
供試化合物S−メチル−N−アセチル−L−シ
ステインアミド及びチオラをそれぞれ31,62,
125mg/Kgと125,250,500mg/Kgでラツト(体重
200g前後、ウイスター雄)に経口投与し、その
3時間後にD−ガラクトースアミンを400mg/Kg
で復腔内に投与し更に24時間後に屠殺し腹部大静
脈より採血後遠沈によつて血清を集め血清
GOT,GPTを測定し活性を国際単位法に従つて
表現した。結果を表2に示した。[Table] The efficacy of the test compound S-methyl-N-acetyl-L-cysteinamide exceeds that of the control drug Thiola (α-mercaptopropionylglycine), and therefore this test compound is effective in humans with centrilobular necrosis. It is useful as a therapeutic agent for liver disorders in animals. Test Example 2 Effect on acute hepatitis accompanied by mesenchymal reaction and lobular disseminated necrosis (D-galactosamine single-dose model test) UDP that should originally be synthesized in the liver by large doses of D-galactosamine Glucose (uridine diphosphate-glucose) is competitively inhibited by D-galactosamine and its amount is reduced. Therefore, it is thought that glycogen synthesis and glucuronide synthesis via UDP glucose are suppressed, leading to the development of liver cell dysfunction. The histology causes diffuse necrosis with a mesenchymal reaction similar to viral hepatitis in humans. Test method Test compounds S-methyl-N-acetyl-L-cysteinamide and thiola were tested at 31, 62,
Rats (body weight
Orally administered to a male Wistar (approximately 200g), and 3 hours later, 400mg/Kg of D-galactoseamine was administered.
After 24 hours, the blood was collected from the abdominal vena cava, and the serum was collected by centrifugation.
GOT and GPT were measured and the activity was expressed according to the international unit method. The results are shown in Table 2.
【表】
供試化合物S−メチル−N−アセチル−L−シ
ステインアミドは対照として用いた市販の肝臓薬
チオラの薬効を上回るものであり、従つてこの化
合物は間葉系反応と散在性壊死を伴う人間や動物
の肝障害の治療薬として有用であると期待され
る。
試験例 3
アセトアミノフエン急性肝障害に対する肝保護
作用
解熱剤として一般に人間に使用されているアセ
トアミノフエンは、投与量過剰によつて急性の肝
障害を引き起こすために臨床的な問題となつてい
る。この原因としてアセトアミノフエンの代謝産
物の毒性や肝臓中の還元型グルタチオンの減少が
説明されている。
アセトアミノフエンはマウスにおいても同様の
肝障害を引き起こすことが明らかにされており、
この実験モデルで肝障害予防、治療効果の高い薬
物は人間においても有効でありアセトアミノフエ
ンの急性中毒あるいは他の薬物による急性肝障害
の予防、治療に有効である。
試験方法
マウス(体重20g前後、ddy雄)に供試化合物
を50〜400mg/Kgの割合で経口投与しその2時間
30分後に生理食塩水中に溶かしたアセトアミノフ
エン500mg/Kgを腹腔に投与し24時間後に死亡し
たマウスの数を数えた。又生存マウスは屠殺後採
血しGPTの活性を測定し、活性は国際単位法に
よつて表現した。結果は表3に示した。[Table] The efficacy of the test compound S-methyl-N-acetyl-L-cysteinamide exceeds that of the commercially available liver drug Thiola, which was used as a control. It is expected to be useful as a therapeutic agent for associated liver damage in humans and animals. Test Example 3 Hepatoprotective effect of acetaminophen against acute liver damage Acetaminophen, which is generally used in humans as an antipyretic agent, has become a clinical problem because it causes acute liver damage when administered in excess. This is explained by the toxicity of acetaminophene metabolites and the decrease in reduced glutathione in the liver. Acetaminophen has been shown to cause similar liver damage in mice.
Drugs that are highly effective in preventing and treating liver damage in this experimental model are also effective in humans and are effective in preventing and treating acute poisoning of acetaminophen or acute liver damage caused by other drugs. Test method: The test compound was orally administered to mice (body weight around 20 g, ddy male) at a rate of 50 to 400 mg/Kg for 2 hours.
Thirty minutes later, 500 mg/Kg of acetaminophen dissolved in physiological saline was administered intraperitoneally, and the number of dead mice was counted 24 hours later. In addition, blood was collected from surviving mice after sacrifice, and GPT activity was measured, and the activity was expressed using the international unit method. The results are shown in Table 3.
【表】【table】
【表】
供試化合物S−メチル−N−アセチル−L−シ
ステインアミドは対照薬システインとほぼ同様あ
るいは強い薬効を示しチオラ、グルタチオンより
も明らかに強い薬効を示し、従つてこの供試化合
物S−メチル−N−アセチル−L−システインア
ミドはアセトアミノフエンの過剰投与時の肝障害
時にあるいは他の薬物による肝障害時の解毒、治
療剤として有用である。
試験例 4
D−ガラクト−スアミン急性肝炎に対する効果
試験法
供試化合物S−エチル−N−アセチル−システ
インエチルアミド、S−メチル−N−アセチル−
システインエチルアミドをそれぞれ125mg/Kgラ
ツト(体重200g前後、ウイスター雄)に経口投
与しその3時間後にD−ガラクトースアミンを
400mg/Kgで腹腔内に投与し更に24時間後に屠殺
し腹部大静脈より採血後遠沈によつて血清を集め
血清GOT,GPT値を測定し活性を国際単位法に
従つて表現した。結果を表4に示した。[Table] The test compound S-methyl-N-acetyl-L-cysteinamide has almost the same or stronger medicinal efficacy as the control drug cysteine, and clearly has a stronger medicinal efficacy than thiola and glutathione. Methyl-N-acetyl-L-cysteinamide is useful as a detoxifying and therapeutic agent for liver damage caused by excessive administration of acetaminophene or liver damage caused by other drugs. Test example 4 D-galactosamine effect test method on acute hepatitis Test compound S-ethyl-N-acetyl-cysteine ethylamide, S-methyl-N-acetyl-
Cysteine ethylamide was orally administered at 125 mg/kg to rats (wistar male, weighing around 200 g), and 3 hours later, D-galactoseamine was administered.
The animals were administered intraperitoneally at 400 mg/Kg, sacrificed 24 hours later, blood was collected from the abdominal vena cava, serum was collected by centrifugation, serum GOT and GPT values were measured, and the activity was expressed according to the International Unit Method. The results are shown in Table 4.
【表】
供試化合物はいずれもD−ガラクトースアミン
急性肝炎を有意に抑制するものであり、従つてこ
れらの化合物は間葉系反応と散在性壊死を伴う人
間や動物の肝障害の治療薬として有用であると期
待される。[Table] All of the test compounds significantly inhibit D-galactoseamine acute hepatitis, and therefore, these compounds can be used as therapeutic agents for liver disorders associated with mesenchymal reactions and diffuse necrosis in humans and animals. Expected to be useful.
Claims (1)
し、R2及びR3は水素原子または炭素数1〜4の
低級アルキル基を表わすか、R2とR3が一緒にな
つてアルキレン鎖もしくはヘテロ原子を含むアル
キレン鎖を表わし、窒素原子と共に環を形成して
いてもよい。) で示されるS−アルキル−N−アセチル−システ
インアミド類。 2 一般式() (式中、R1およびR4はメチル基またはエチル
基を表わす。) で示されるS−アルキル−N−アセチル−システ
インアルキルエステル類と、一般式() (式中、R2およびR3は水素原子または炭素数
1〜4の低級アルキル基を表わすか、R2とR3が
一緒になつてアルキレン鎖もしくはヘテロ原子を
含むアルキレン鎖を表わし、窒素原子と共に環を
形成していてもよい。) で示されるアミノ化合物とを反応させることを特
徴とする一般式() 〔式中、R1,R2およびR3は、一般式()ま
たは()におけると同義とする。〕 で示されるS−アルキル−N−アセチル−システ
インアミド類の製法。 3 一般式() (式中、R1はメチル基またはエチル基を表わ
す。) で示されるS−アルキル−N−アセチル−システ
イン類またはそれらの反応性誘導体と、一般式
() (式中、R2およびR3は水素原子または炭素数
1〜4の低級アルキル基を表わすか、R2とR3が
一緒になつてアルキレン鎖もしくはヘテロ原子を
含むアルキレン鎖を表わし、窒素原子と共に環を
形成していてもよい。) で示されるアミノ化合物とを反応させることを特
徴とする一般式() 〔式中、R1,R2およびR3は、一般式()ま
たは()におけると同義とする。〕 で示されるS−アルキル−N−アセチル−システ
インアミド類の製法。 4 一般式() (式中、R1はメチル基またはエチル基を表わ
し、R2およびR3は水素原子または炭素数1〜4
の低級アルキル基を表わすか、R2とR3が一緒に
なつてアルキレン鎖もしくはヘテロ原子を含むア
ルキレン鎖を表わし、窒素原子と共に環を形成し
ていてもよい。) で示されるS−アルキル−システインアミド類
と、アセチル化剤とを反応させることを特徴とす
る一般式() 〔式中、R1,R2およびR3は、一般式()に
おけると同義とする。〕 で示されるS−アルキル−N−アセチル−システ
インアミド類の製法。[Claims] 1 General formula () (In the formula, R 1 represents a methyl group or an ethyl group, R 2 and R 3 represent a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, or R 2 and R 3 together represent an alkylene chain or S-alkyl-N-acetyl-cysteinamides, which represent an alkylene chain containing a heteroatom and may form a ring together with a nitrogen atom. 2 General formula () (In the formula, R 1 and R 4 represent a methyl group or an ethyl group.) S-alkyl-N-acetyl-cysteine alkyl esters represented by the general formula () (In the formula, R 2 and R 3 represent a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, or R 2 and R 3 together represent an alkylene chain or an alkylene chain containing a heteroatom, and a nitrogen atom may form a ring with the general formula () characterized by reacting with an amino compound represented by [In the formula, R 1 , R 2 and R 3 have the same meanings as in the general formula () or (). ] A method for producing S-alkyl-N-acetyl-cysteinamides. 3 General formula () (In the formula, R 1 represents a methyl group or an ethyl group.) S-alkyl-N-acetyl-cysteines or their reactive derivatives represented by the general formula () (In the formula, R 2 and R 3 represent a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, or R 2 and R 3 together represent an alkylene chain or an alkylene chain containing a heteroatom, and a nitrogen atom may form a ring with the general formula () characterized by reacting with an amino compound represented by [In the formula, R 1 , R 2 and R 3 have the same meanings as in the general formula () or (). ] A method for producing S-alkyl-N-acetyl-cysteinamides. 4 General formula () (In the formula, R 1 represents a methyl group or an ethyl group, R 2 and R 3 are a hydrogen atom or a carbon number of 1 to 4
represents a lower alkyl group, or R 2 and R 3 together represent an alkylene chain or an alkylene chain containing a heteroatom, and may form a ring with the nitrogen atom. General formula () characterized by reacting an S-alkyl-cysteinamide represented by ) with an acetylating agent [In the formula, R 1 , R 2 and R 3 have the same meanings as in the general formula (). ] A method for producing S-alkyl-N-acetyl-cysteinamides.
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10617080A JPS5731656A (en) | 1980-08-01 | 1980-08-01 | S-alkyl-n-acetyl-cysteinamide and its preparation |
EP81901205A EP0051682B1 (en) | 1980-05-13 | 1981-05-11 | Cysteine derivatives and process for their preparation |
DE8181901205T DE3165832D1 (en) | 1980-05-13 | 1981-05-11 | Cysteine derivatives and process for their preparation |
PCT/JP1981/000107 WO1981003330A1 (en) | 1980-05-13 | 1981-05-11 | Cysteine derivative and production thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10617080A JPS5731656A (en) | 1980-08-01 | 1980-08-01 | S-alkyl-n-acetyl-cysteinamide and its preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5731656A JPS5731656A (en) | 1982-02-20 |
JPS6254423B2 true JPS6254423B2 (en) | 1987-11-14 |
Family
ID=14426781
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP10617080A Granted JPS5731656A (en) | 1980-05-13 | 1980-08-01 | S-alkyl-n-acetyl-cysteinamide and its preparation |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5731656A (en) |
-
1980
- 1980-08-01 JP JP10617080A patent/JPS5731656A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS5731656A (en) | 1982-02-20 |
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