JPS6357419B2 - - Google Patents
Info
- Publication number
- JPS6357419B2 JPS6357419B2 JP55118275A JP11827580A JPS6357419B2 JP S6357419 B2 JPS6357419 B2 JP S6357419B2 JP 55118275 A JP55118275 A JP 55118275A JP 11827580 A JP11827580 A JP 11827580A JP S6357419 B2 JPS6357419 B2 JP S6357419B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- acid
- dihydroxybenzamide
- ureido
- general formula
- 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
- 150000001875 compounds Chemical class 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000002425 furfuryl group Chemical group C(C1=CC=CO1)* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- -1 α-substituted ureidophenyl acetic acid Chemical class 0.000 description 21
- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 15
- 229960003424 phenylacetic acid Drugs 0.000 description 12
- 239000003279 phenylacetic acid Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- QCIDBNKTKNBPKM-UHFFFAOYSA-N dihydroxybenzamide Natural products NC(=O)C1=CC=CC(O)=C1O QCIDBNKTKNBPKM-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- OVFXWGLZXJTSFH-UHFFFAOYSA-N 3,4-dihydroxy-n-(3-hydroxypropyl)benzamide Chemical group OCCCNC(=O)C1=CC=C(O)C(O)=C1 OVFXWGLZXJTSFH-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000010531 catalytic reduction reaction Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 2
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 235000008206 alpha-amino acids Nutrition 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- RMIJYCIGXVCHAF-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]ethanol;n,n-diethylethanamine;n,n-dimethylformamide Chemical compound CN(C)C=O.CCN(CC)CC.OCCN(CCO)CCO RMIJYCIGXVCHAF-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- DBJUEJCZPKMDPA-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O DBJUEJCZPKMDPA-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000316 alkaline earth metal phosphate Inorganic materials 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- LULXBAGMGMJJRW-UHFFFAOYSA-N n,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)CC(=O)N[Si](C)(C)C LULXBAGMGMJJRW-UHFFFAOYSA-N 0.000 description 1
- RMBMIGGAJHKKEE-UHFFFAOYSA-N n-(furan-2-ylmethyl)-3,4-dihydroxybenzamide Chemical compound C1=C(O)C(O)=CC=C1C(=O)NCC1=CC=CO1 RMBMIGGAJHKKEE-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Furan Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は新規なα―置換ウレイドフエニル酢酸
誘導体、就中、下記一般式(1)
（式中R1は水素原子または水酸基を、ＸはC1
〜5の低級アルキル基を、そしてＹはＸの置換基
であり、基−OR2，−CN，COOR3，フルフリル
基またはフエニル基を意味する。R2は水素原子，
水酸基で置換されたC2〜4の低級アルキル基を、
R3はC1〜3の低級アルキル基を意味する。）で表
される化合物またはその塩に関する。
式(1)の定義中、低級アルキル基は直鎖または分
枝していてもよい飽和炭化水素基を基幹とするも
のである。Ｘが意味するところの低級アルキル基
における置換基Ｙの位置は、Ｙが基−OR2である
場合は２乃至５の炭素原子の何れにあつてもよ
く、またＹがそれ以外の基である場合は１乃至５
の炭素原子の何れにあつてもよい。
式(1)で表されるα―置換ウレイドフエニル酢酸
誘導体の塩は、例えばナトリウム・カリウム等の
アルカリ金属塩、カルシウム・バリウム等のアル
カリ土類金属塩、トリエチルアミン・Ｎ―メチル
ピペラジン・ピリジン等の三級有機塩基との塩で
ある。
式(1)で表されるα―置換ウレイドフエニル酢酸
誘導体は、不整炭素原子を有するため、その光学
異性体、すなわちＤ―，Ｌ―およびDL―体、更
には場合によりジアステレオマー（―Ｘ―Ｙに起
因する）が存在するが、これ等は何れも本発明の
範囲に含まれる。
式(1)で表される本発明の化合物は、次のように
して製造される。すなわち、一般式(2)
（式中R2は前記と同一）
で表されるα―アミノ酸またはその反応誘導体
と、一般式(3)
（式中Ｘは前記と同一。R4は保護された水酸
基を意味する。Y1はＹに相当する基であつて、
水酸基またはカルボキシル基が存在するときは、
それ（等）が保護されているものを意味する。Ｚ
はハロゲン原子を意味する。）で表されるＮ―ベ
ンゾイルカルバミン酸ハライド類とを反応させ、
次いで所望により生成物中に存在する保護基を除
去することを特徴とする方法である。
一般式(2)で表されるα―アミノ酸の反応性誘導
体とは、そのα―アミノ基が活性化された誘導体
であり、而してその活性化は、該アミノ基にトリ
メチルシリル基のごときシリル基を導入すること
により行われる。
一般式(3)で表されるＮ―ベンゾイルカルバミン
酸ハライド類において、R4およびY1が意味する
ところの保護基は、緩和な条件で容易に脱離する
ものであり、例えば、アセチル基，トリメチルシ
リル基，ｔ―ブチル基，メトキシメチル基等であ
る。
反応は、通常溶媒中で行われ、溶媒としては、
ジクロルメタン，１，２―ジクロルエタン，クロ
ロホルム，アセトニトリル，アセトン，テトラヒ
ドロフラン，酢酸エチル，ジオキサンのごとき不
活性有機溶媒が用いられる。また、これらのうち
親水性溶媒は、水と混合して使用することも可能
である。反応温度は、通常冷却ないし室温の範囲
で選ばれる。すなわち、−30℃〜35℃、好ましく
は−10℃〜20℃である。反応時間は、反応温度・
反応に供せられる化合物・溶媒等によつて異なる
が、数十分〜24時間、好ましくは30分〜５時間の
間で適宜選択される。
反応混合物からの目的物の単離は常法により行
うことができ、精製は再沈殿法或はクロマトグラ
フイー等の手段を適用して行うことができる。
一般式(1)において、R1および／またはＹが保
護基を含まない化合物を得る場合は、上記反応生
成物の保護基を除去する。R4，R1およびY1に含
まれる水酸基の保護基の除去は、アシル基の場合
は、無機または有機塩基による処理により行うこ
とができ、無機塩基の例として、水酸化ナトリウ
ム，水酸化カリウム等の水酸化アルカリ金属，水
酸化マグネシウム，水酸化カルシウム等の水酸化
アルカリ土類金属，炭酸ナトリウム，炭酸カリウ
ム等の炭酸アルカリ金属塩，炭酸マグネシウム，
炭酸カルシウム等の炭酸アルカリ土類金属塩，炭
酸水素ナトリウム，炭酸水素カリウム等の重炭酸
アルカリ金属塩，燐酸カルシウムのごとき燐酸ア
ルカリ土類金属塩，燐酸水素ジナトリウム，燐酸
水素ジカリウム等の燐酸水素アルカリ金属塩，ア
ンモニア等を挙げることができ、有機塩基の例と
して、アルカリ金属の酢酸塩，トリメチルアミ
ン，トリエチルアミン等のトリアルキルアミン，
ジエチルアミノエタノール，トリエタノールアミ
ン等のアルコールアミン等を挙げることができ
る。これ等塩基によるアシル基の除去は、水また
はアルコール性水酸基を有する有機溶媒（例え
ば、メタノール，エタノール，エタノールアミ
ン）或はそれ等の混合物を用いて行われる。好ま
しい例として、メタノール性アンモニア，トリエ
チルアミン―トリエタノールアミン―ジメチルホ
ルムアミド混合物を挙げることができる。
保護基がアラルキル基または置換アラルキル基
である場合は接触還元、例えばパラジウム―炭素
を用いた接触還元により除去を行うことができ
る。更に、ｔ―ブチル基，メトキシメチル基，フ
エナシル基，テトラヒドロピラニル基等およびシ
リル基は、塩基のごとき無機酸を用いて除去する
ことができる。
前記Y1に含まれるカルボキシル基の保護基の
除去は、ハロゲン化低級アルキル基の場合は金属
と酸、例えば亜鉛―酢酸による還元により、アラ
ルキル基および置換アラルキル基の場合は接触還
元、例えばパラジウム―炭素を用いた接触還元，
または酸、例えば蟻酸，トリフルオロ酢酸，ベン
ゼンスルホン酸，ｐ―トルエンスルホン酸，塩
酸，陽イオン交換樹脂の有機または無機酸による
処理により行うことができる。
一般式(1)で表される本発明の目的化合物の一つ
である光学活性体（Ｄ―またはＬ―異性体）およ
びそのジアステレオマー（−Ｘ−Ｙに帰因する）
の製造は、一般式(2)で表されるα―アミノ酸およ
び一般式(3)で表されるＮ―ベンゾイルカルバミン
酸ハライド類において所望の光学活性を有するも
のを選ぶことにより、行うことができる。上記光
学活性物質は、ラセミ体に通常の光学分割技術を
適用して得ることができる。
一般式(1)で表される化合物の塩は、常法によ
り、すなわち当該遊離酸の化合物を、当モル量の
所望の塩基で処理することにより製造することが
できる。
かくして得られる一般式(1)で表されるα―置換
ウレイドフエニル酢酸誘導体およびその塩は、優
れた抗菌活性を有するペニシリン誘導体の合成中
間体として有用である。すなわち、一般式(1)で表
される化合物を６―アミノペニシラン酸の６位ア
ミノ基に結合させ、次いで保護基が存在する場
合、それを除去することにより、一般式(4)
（式中、ＸおよびR1は前記と同一、Y2は前記
Ｙに相当する基であつて、水酸基またはカルボキ
シル基が存在するときは、それ（等）が保護され
ていないものを意味する。）で表されるペニシラ
ン誘導体を得ることができ、而してこれは、グラ
ム陽性菌および陰性菌に対し強い抗菌力を有し、
就中シユードモナス属菌に対しては生体内活性
（ED50）で比較したとき、従来既知化合物よりも
格段の抗菌活性を示す。
原料化合物として用いられる一般式(3)で表され
るＮ―ベンゾイルカルバミン酸ハライド類も新規
化合物であるが、一般式(5)
（式中、R4は前記と同一。）
で表される化合物またはその酸ハライドのごとき
反応性誘導体と、一般式(6)
H2N−Ｘ−Y1
（式中、ＸおよびY1は前記と同一。）
で表される化合物とを、常法により縮合させ、次
いで生成するアミド化合物にホスゲン，トリクロ
ロメチルクロロホルムメートのごときカルボニル
化剤を反応させることにより容易に製造すること
ができる。
以下に実施例を挙げて本発明の化合物の製法を
具体的に説明する。
実施例 １
(1) Ｎ―（３―ヒドロキシプロピル）―３，４―
ジヒドロキシベンズアミド5.0ｇとトリメチル
シリルクロライド12.9ｇとを含む乾燥ジクロル
メタン70mlの懸濁液にトリエチルアミン11.5ｇ
を含む乾燥ジクロルメタン溶液40mlを氷―水冷
却下に滴下する。混液を窒素雰囲気中40分間加
熱還流させ、次いで冷却下、−10〜−５℃でト
リクロロメチルクロロホルメート2.8mlを滴下
する。液温を徐々に上昇させ、０〜５℃で２時
間権拌した後、減圧下に過剰のホスゲンおよび
溶媒を留去する。残渣に冷却した乾燥ジクロル
メタン80mlを加え、不溶物を自然過により除
去し、後述の反応に供する。
(2) Ｄ（−）―フエニルグリシン4.7ｇをトリメチ
ルシリルクロライド7.8ｇとを含む乾燥ジクロ
ルメタン100mlの懸濁液に、トリエチルアミン
7.1ｇを５〜10℃で滴下する。次いでＮ，Ｏ―
ビス（トリメチルシリル）アセトアミド１mlを
同温度で滴下し、室温で１時間撹拌した後、上
記(1)で調製したジクロメタン溶液を５〜10℃で
撹拌下に滴下する。同温度で１時間撹拌し、次
いで減圧下に室温で蒸発乾固させた後、残渣に
酢酸エチル300mlと冷1N―塩酸100mlの混合液
を加え、有機層を分取する。該有機層を冷飽和
食塩水300mlで洗浄した後、冷飽和炭酸水素ナ
トリウム水溶液300mlで２回に分けて目的物を
抽出する。次いで該水層に酢酸エチル250mlを
加え、冷6N―塩酸でPH値を約1.5とし、これに
食塩を加えて水性層を飽和させた後、有機層を
分取する。分取した有機層を冷飽和食塩水100
mlで洗浄後、無水硫酸マグネシウムで乾燥さ
せ、減圧下に溶媒を留去する。残留物をアセト
ン―クロロホルムで結晶化させ、同溶媒系で再
結晶を行うと、Ｄ（−）―α―｛３―（３，４
―ジヒドロキシベンゾイル）―３―（３―ヒド
ロキシプロピル）―１―ウレイド｝フエニル酢
酸5.5ｇが白色結晶として得られた。
融点 139〜141℃（分解）
元素分析 C19H20N2O7・H2Oとして
Ｃ Ｈ Ｎ
計算値（％） 56.16 5.46 6.89
実測値（％） 56.30 5.40 6.87
Ｉ Ｒ νKBr nax（cm-1）：3540，3500，1690，1670，
1595，1520
NMR（DMSO―d6，60MHz）δ（ppm）：1.3〜2.0
（2H，ｍ），3.35（2H，ｔ，Ｊ＝６Hz），
3.73（2H，ｔ，Ｊ＝6.5Hz），5.22（1H，ｄ，
Ｊ＝７Hz），6.7〜7.5（8H，ｍ），9.19（1H，
ｄ，Ｊ＝７Hz）
塩化第二鉄呈色反応：陽性（暗緑色）
実施例 ２
実施例１(1)において、Ｎ―（３―ヒドロキシプ
ロピル）―３，４―ジヒドロキシベンズアミドの
代わりにＮ―（２―ヒドロキシエチル）―３，４
―ジヒドロキシベンズアミドを用い、以下同様の
処理をし、Ｄ（−）―α―｛３―（３，４―ジヒ
ドロキシベンゾイル）―３―（２―ヒドロキシエ
チル）―１―ウレイド｝フエニル酢酸を得た。
NMR（DMSO―d6，60MHz）δ（ppm）：3.1〜3.9
（4H，ｍ），5.25（1H，ｄ，Ｊ＝７Hz），6.7
〜7.6（8H，ｍ），9.26（1H，ｄ，Ｊ＝７Hz）
実施例 ３
実施例１(1)においてＮ―（３―ヒドロキシプロ
ピル）―３，４―ジヒドロキシベンズアミドの代
わりにＮ―（５―ヒドロキシペンチル）―３，４
―ジヒドロキシベンズアミドを用い、以下同様の
処理をし、Ｄ（−）―α―｛３―（３，４―ジヒ
ドロキシベンゾイル）―３―（５―ヒドロキシペ
ンチル）―１―ウレイド｝フエニル酢酸を得た。
NMR（DMSO―d6，60MHz）δ（ppm）：1.4（6H，
brs），3.1〜3.7（4H，ｍ），5.24（1H，ｄ，
Ｊ＝７Hz），6.7〜7.5（8H，ｍ），9.24（1H，
ｄ，Ｊ＝７Hz）
実施例 ４
実施例１(1)においてＮ―（３―ヒドロキシプロ
ピル）―３，４―ジヒドロキシベンズアミドの代
わりにＮ―｛２―（２―ヒドロキシエトキシ）エ
チル｝―３，４―ジヒドロキシベンズアミドを用
い以下同様の処理をし、Ｄ（−）―α―〔３―
（３，４―ジヒドロキシベンゾイル）―３―｛２
―（２―ヒドロキシエトキシ）エチル｝―１―ウ
レイド〕フエニル酢酸を得た。
NMR（DMSO―d6，60MHz）δ（ppm）：3.3〜4.1
（8H，ｍ），5.23（1H，ｄ，Ｊ＝７Hz），6.7
〜7.6（8H，ｍ），9.20（1H，ｄ，Ｊ＝７Hz）
実施例 ５
実施例１(1)においてＮ―（３―ヒドロキシプロ
ピル）―３，４―ジヒドロキシベンズアミドの代
わりにＮ―（２―メトキシエチル）―３，４―ジ
ヒドロキシベンズアミドを用い、且つトリメチル
シリルクロライド及びトリエチルアミンの量を１
モル当量分だけ減らして用い、以下同様の処理を
し、Ｄ（−）―α―｛３―（３，４―ジヒドロキ
シベンゾイル）―３―（２―メトキシエチル）―
１―ウレイド｝フエニル酢酸を得た。
NMR（DMSO―d6，60MHz）δ（ppm）：3.20
（3H，ｓ），3.4（2H，br），3.9（2H，br），
5.20（1H，ｄ，Ｊ＝７Hz），6.7〜7.6（8H，
ｍ），9.15（1H，ｄ，Ｊ＝７Hz）
実施例 ６
実施例１(1)においてＮ―（３―ヒドロキシプロ
ピル）―３，４―ジヒドロキシベンズアミドの代
りに、Ｎ―（２―シアノエチル）―３，４―ジヒ
ドロキシベンズアミドを用い、且つトリメチルシ
リルクロライド及びトリエチルアミンの量を１モ
ル当量分だけ減らして用い、以下同様の処理を
し、Ｄ（−）―α―｛３―（３，４―ジヒドロキ
シベンゾイル）―３―（２―シアノエチル）―１
―ウレイド｝フエニル酢酸を得た。
NMR（DMSO―d6，60MHz）δ（ppm）：2.8（2H，
br），4.0（2H，br），5.20（1H，ｄ，Ｊ＝７
Hz），6.7〜7.5（8H，ｍ），9.14（1H，ｄ，
Ｊ＝７Hz）
実施例 ７
実施例１(1)においてＮ―（３―ヒドロキシプロ
ピル）―３，４―ジヒドロキシベンズアミドの代
わりにＮ―エトキシカルボニルメチル―３，４―
ジヒドロキシベンズアミドを用い、且つ、トリメ
チルシリルクロライド及びトリエチルアミンの量
を１モル当量分だけ減らして用い、以下同様の処
理をし、Ｄ（−）―α―｛３―（３，４―ジヒド
ロキシベンゾイル）―３―エトキシカルボニルメ
チル―１―ウレイド｝フエニル酢酸を得た。
NMR（DMSO―d6，60MHz）δ（ppm）：1.0〜1.4
（3H，ｍ），3.8〜4.6（4H，ｍ），5.25（1H，
ｄ，Ｊ＝７Hz），6.7〜7.6（8H，ｍ），9.45
（1H，ｄ，Ｊ＝７Hz）
実施例 ８
実施例１(1)においてＮ―（３―ヒドロキシプロ
ピル）―３，４―ジヒドロキシベンズアミドの代
わりにＮ―ベンジル―３，４―ジヒドロベンズア
ミドを用い、且つトリメチルシリルクロライド及
びトリエチルアミンの量を１モル当量分だけ減ら
して用い、以下同様の処理をし、Ｄ（−）―α―
｛３―（３，４―ジヒドロキシベンゾイル）―３
―ベンジル―１―ウレイド｝フエニル酢酸を得
た。
NMR（DMSO―d6，60MHz）δ（ppm）：4.8〜5.1
（2H，brs），5.24（1H，ｄ，Ｊ＝７Hz），
6.7〜7.5（13H，ｍ），9.24（1H，ｄ，Ｊ＝
７Hz）
実施例 ９
実施例１(1)においてＮ―（３―ヒドロキシプロ
ピル）―３，４―ジヒドロキシベンズアミドの代
わりにＮ―フルフリル―３，４―ジヒドロキシベ
ンズアミドを用い、且つトリメチルシリルクロラ
イド及びトリエチルアミンの量を１モル当量分だ
け減らして用い、以下同様の処理をし、Ｄ（−）
―α―｛３―（３，４―ジヒドロキシベンゾイ
ル）―３―フルフリル―１―ウレイド｝フエニル
酢酸を得た。
NMR（DMSO―d6，60MHz）δ（ppm）：4.8〜5.1
（2H，brs），5.22（1H，ｄ，Ｊ＝７Hz），
6.2〜7.7（11H，ｍ），9.18（1H，ｄ，Ｊ＝
７Hz）
実施例 10
実施例１(2)においてＤ（−）―フエニルグリシ
ンの代りにＤ（−）―（４―ヒドロキシフエニル）
グリシンを用い、以下同様の処理して、Ｄ（−）
―α―｛３―（３，４―ジヒドロキシベンゾイ
ル）―３―（３―ヒドロキシプロピル）―１―ウ
レイド｝―α―（４―ヒドロキシフエニル）酢酸
を得た。
NMR（DMSO―d6，60MHz）δ（ppm）：1.3〜1.9
（2H，ｍ），3.34（2H，ｔ，Ｊ＝６Hz），
3.72（2H，ｔ，Ｊ＝6.5Hz），5.21（1H，ｄ，
Ｊ＝７Hz），6.5〜7.3（7H，ｍ），9.07（1H，
ｄ，Ｊ＝７Hz）
参考例 １
(1) 実施例(2)で得られたフエニル酢酸4.0ｇとト
リメチルシリルクロライド4.9ｇを含む乾燥ジ
クロルメタン50mlの懸濁液に、５〜10℃でトリ
エチルアミン4.2ｇを滴下後、15〜20℃で１時
間撹拌して上記フエニル酢酸のトリメチルシリ
ル化溶液を得、後述の反応に供する。
(2) トリクロロメチルクロロホルメート1.2ｇを
含む乾燥ジクロルメタン溶液30mlに、−20℃で
ジメチルホルムアミド0.8ｇを加え０〜５℃で
１時間撹拌した後、−30℃で上記(1)で調製した
ジクロルメタン溶液を加え、−10〜−15℃で1.5
時間撹拌する。次いでこれに６―アミノペニシ
ラン酸2.9ｇを含む乾燥ジクロルメタン50mlの
懸濁液にＮ，Ｏ―ビストリメチルシリルアセト
アミド5.5ｇを加えて溶解させた液を、−10〜−
15℃で滴下し、同温度で１時間撹拌する。
反応混合物を減圧下に室温で蒸発乾固させ、残
渣に酢酸エチル300mlと冷1N―塩酸100mlの混合
液を加え有機層を分取する。該有機層を冷飽和食
塩水300mlで洗浄し、次いで冷飽和炭酸水素ナト
リウム水溶液300mlで２回にわけて抽出する。分
離した水層を酢酸エチル100mlで洗浄し、これに
酢酸エチル250mlを加え、冷6N―塩酸でPH値を約
1.5とし、更に食塩を加えて水性層を飽和させた
後、有機層を分取する。該有機層を冷飽和食塩水
100mlで洗浄後、無水硫酸マグネシウムで乾燥さ
せ、減圧下に溶媒を留去する。残留物を活性炭素
（クロマトグラフ用）のカラムクロマトグラフイ
ーに付し、酢酸エチルで溶出させる。溶出液を集
め、液量が約30mlになるまで減圧濃縮し、次いで
これをｎ―ヘキサン300ml中に撹拌下に加えると、
６―〔Ｄ（−）―α―｛３―（３，４―ジヒドロ
キシベンゾイル）―３―（３―ヒドロキシプロピ
ル）―１―ウレイド｝―α―フエニルアセトアミ
ド〕ペニシラン酸（以下化合物Ａともいう）5.0
ｇが白色の粉末として得られる。
Ｉ Ｒ νKBr nax（cm-1）：3700〜2300，1775，1675，
1600，1515
NMR（DMSO―d6，60MHz）δ（ppm）：1.41
（3H，ｓ），1.55（3H，ｓ），1.4〜2.0（2H，
br），3.36（2H，ｔ，Ｊ＝６Hz），3.75（2H，
br），4.20（1H，ｓ），5.3〜5.8（3H，ｍ），
6.7〜7.5（8H，ｍ），9.12（1H，ｄ，Ｊ＝７
Hz），9.19（1H，ｄ，Ｊ＝７Hz）
Ｕ Ｖ λEtOH naxnm（ε）：209（3.1×104），225（
肩），
271（6.1×103），295（6.3×103）
塩化第二鉄呈色反応：陽性（暗緑色）
参考例 ２
参考例１(1)において、Ｄ（−）―α―｛３―
（３，４―ジヒドロキシベンゾイル）―３―（３
―ヒドロキシプロピル）―１―ウレイド｝フエニ
ル酢酸の代りに、実施例２で得られたＤ（−）―
α―｛３―（３，４―ジヒドロキシベンゾイル）
―３―（２―ヒドロキシエチル）―１―ウレイ
ド｝フエニル酢酸を用い、以下同様に処理すると
６―〔Ｄ（−）―α―｛３―（３，４―ジヒドロ
キシベンゾイル）―３―（２―ヒドロキシエチ
ル）―１―ウレイド｝―α―フエニルアセトアミ
ド〕ペニシラン酸（以下化合物Ｂともいう）が白
色の粉末として得られる。
Ｉ Ｒ νKBr nax（cm-1）：3700〜2200，1775，1675，
1600，1515
NMR（DRSO―d6，60NHz）δ（ppm）：1.42（3H，
ｓ），1.56（3H，ｓ），3.2〜4.0（4H，ｍ），
4.21（1H，ｓ），5.3〜5.8（3H，ｍ），6.7〜
7.6（8H，ｍ），9.10（1H，ｄ，Ｊ＝７Hz），
9.26（1H，ｄ，Ｊ＝７Hz）
Ｕ Ｖ λEtOH naxnm（ε）：208（2.8×104），221（
肩），
262（6.8×103），295（5.2×103）
塩化第二鉄呈色反応：陽性（暗緑色）
参考例 ３
化合物ＡおよびＢのED50
(1) 試験方法
５週令、体重21〜25ｇのddY系雄マウス５匹を
１グループとして用いた。被検菌株は、ブレイ
ン・ハート・インフユージヨン・アガー上、37℃
で一夜培養されたものを５％ムチン中に懸濁させ
て、マウスの腹腔内に投与された。試験化合物
は、種々の濃度に調製され、菌接種の１時間およ
び３時間後にマウスに皮下注射された。５日後、
各投与量におけるマウスの生存数から、ED50値
を算出した。
(2) 試験結果
【表】DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel α-substituted ureidophenyl acetic acid derivatives, particularly those having the following general formula (1). (In the formula, R 1 is a hydrogen atom or a hydroxyl group, and X is C 1
~ 5 lower alkyl group, and Y is a substituent of X, meaning a group -OR2 , -CN, COOR3 , furfuryl group or phenyl group. R 2 is a hydrogen atom,
A C2-4 lower alkyl group substituted with a hydroxyl group,
R3 means a C1-3 lower alkyl group. ) or a salt thereof. In the definition of formula (1), the lower alkyl group is based on a saturated hydrocarbon group which may be linear or branched. The position of the substituent Y in the lower alkyl group represented by 1 to 5 if
It can be any of the carbon atoms. The salt of the α-substituted ureidophenylacetic acid derivative represented by formula (1) is, for example, an alkali metal salt such as sodium or potassium, an alkaline earth metal salt such as calcium or barium, or a salt such as triethylamine, N-methylpiperazine, or pyridine. It is a salt with a class organic base. Since the α-substituted ureido phenyl acetic acid derivative represented by formula (1) has an asymmetric carbon atom, it can be used in its optical isomers, namely D-, L- and DL- forms, and in some cases diastereomers (-X- (attributable to Y), all of which are included within the scope of the present invention. The compound of the present invention represented by formula (1) is produced as follows. That is, general formula (2) (In the formula, R 2 is the same as above) (In the formula, X is the same as above. R 4 means a protected hydroxyl group. Y 1 is a group corresponding to Y,
When hydroxyl or carboxyl groups are present,
It (etc.) means something that is protected. Z
means a halogen atom. ) is reacted with N-benzoylcarbamic acid halides represented by
This method is characterized in that the protective groups present in the product are then optionally removed. The reactive derivative of the α-amino acid represented by the general formula (2) is a derivative in which the α-amino group is activated, and the activation is caused by a silyl group such as a trimethylsilyl group in the amino group. This is done by introducing a group. In the N-benzoylcarbamic acid halides represented by the general formula (3), the protecting groups represented by R 4 and Y 1 are easily removed under mild conditions, such as acetyl group, These include trimethylsilyl group, t-butyl group, methoxymethyl group, etc. The reaction is usually carried out in a solvent, and the solvent is
Inert organic solvents such as dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, acetone, tetrahydrofuran, ethyl acetate, and dioxane are used. Moreover, among these, hydrophilic solvents can also be used in combination with water. The reaction temperature is usually selected within the range of cooling to room temperature. That is, the temperature is -30°C to 35°C, preferably -10°C to 20°C. The reaction time depends on the reaction temperature and
Although it varies depending on the compound, solvent, etc. used in the reaction, the time period is appropriately selected between several tens of minutes and 24 hours, preferably between 30 minutes and 5 hours. Isolation of the target product from the reaction mixture can be carried out by conventional methods, and purification can be carried out by applying means such as reprecipitation or chromatography. In general formula (1), when obtaining a compound in which R 1 and/or Y do not contain a protecting group, the protecting group of the reaction product is removed. In the case of an acyl group, the protective group for the hydroxyl group contained in R 4 , R 1 and Y 1 can be removed by treatment with an inorganic or organic base. Examples of inorganic bases include sodium hydroxide, potassium hydroxide. Alkali metal hydroxides such as magnesium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, magnesium carbonate,
Alkaline earth metal carbonates such as calcium carbonate, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkaline earth metal phosphates such as calcium phosphate, alkali hydrogen phosphates such as disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc. Examples of organic bases include alkali metal acetates, trialkylamines such as trimethylamine and triethylamine,
Examples include alcohol amines such as diethylaminoethanol and triethanolamine. Removal of the acyl group with these bases is carried out using water or an organic solvent having an alcoholic hydroxyl group (eg, methanol, ethanol, ethanolamine), or a mixture thereof. Preferred examples include methanolic ammonia and a triethylamine-triethanolamine-dimethylformamide mixture. When the protecting group is an aralkyl group or a substituted aralkyl group, it can be removed by catalytic reduction, for example using palladium-carbon. Furthermore, t-butyl groups, methoxymethyl groups, phenacyl groups, tetrahydropyranyl groups, etc. and silyl groups can be removed using an inorganic acid such as a base. The protecting group of the carboxyl group contained in Y 1 is removed by reduction with a metal and an acid, such as zinc-acetic acid, in the case of a halogenated lower alkyl group, and by catalytic reduction, such as palladium-acetic acid, in the case of an aralkyl group and substituted aralkyl group. Catalytic reduction using carbon,
Alternatively, it can be carried out by treatment with an acid, such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, or a cation exchange resin with an organic or inorganic acid. An optically active substance (D- or L-isomer) which is one of the target compounds of the present invention represented by general formula (1) and its diastereomer (attributable to -X-Y)
can be produced by selecting α-amino acids represented by general formula (2) and N-benzoylcarbamic acid halides represented by general formula (3) that have the desired optical activity. . The above-mentioned optically active substance can be obtained by applying a conventional optical resolution technique to a racemate. The salt of the compound represented by the general formula (1) can be produced by a conventional method, that is, by treating the free acid compound with an equimolar amount of the desired base. The thus obtained α-substituted ureidophenyl acetic acid derivative represented by the general formula (1) and its salt are useful as intermediates for the synthesis of penicillin derivatives having excellent antibacterial activity. That is, by bonding the compound represented by general formula (1) to the 6-position amino group of 6-aminopenicillanic acid, and then removing the protective group if present, general formula (4) is obtained. (In the formula, X and R 1 are the same as above, Y 2 is a group corresponding to Y above, and when a hydroxyl group or a carboxyl group is present, it means that it (etc.) is not protected. ), which has strong antibacterial activity against Gram-positive and Gram-negative bacteria.
In particular, when compared in terms of in vivo activity (ED50) against Pseudomonas bacteria, it exhibits much more antibacterial activity than conventionally known compounds. N-benzoylcarbamic acid halides represented by general formula (3) used as raw material compounds are also new compounds, but general formula (5) (In the formula, R 4 is the same as above.) A compound represented by the formula (6) H 2 N-X-Y 1 (wherein, X and Y 1 are It can be easily produced by condensing the compound represented by (same as above) using a conventional method, and then reacting the resulting amide compound with a carbonylating agent such as phosgene or trichloromethyl chloroformate. The method for producing the compound of the present invention will be specifically explained below with reference to Examples. Example 1 (1) N-(3-hydroxypropyl)-3,4-
11.5 g of triethylamine in a suspension of 5.0 g of dihydroxybenzamide and 12.9 g of trimethylsilyl chloride in 70 ml of dry dichloromethane.
Add 40 ml of a dry dichloromethane solution containing the solution dropwise under ice-water cooling. The mixture is heated to reflux in a nitrogen atmosphere for 40 minutes, and then 2.8 ml of trichloromethyl chloroformate are added dropwise at -10 to -5°C while cooling. After gradually raising the liquid temperature and stirring at 0 to 5°C for 2 hours, excess phosgene and the solvent are distilled off under reduced pressure. 80 ml of cooled dry dichloromethane is added to the residue, insoluble materials are removed by natural filtration, and the mixture is subjected to the reaction described below. (2) Add triethylamine to a suspension of 4.7 g of D(-)-phenylglycine and 7.8 g of trimethylsilyl chloride in 100 ml of dry dichloromethane.
Add 7.1g dropwise at 5-10°C. Then N, O-
1 ml of bis(trimethylsilyl)acetamide is added dropwise at the same temperature, and after stirring at room temperature for 1 hour, the dichloromethane solution prepared in (1) above is added dropwise with stirring at 5-10°C. After stirring at the same temperature for 1 hour and then evaporating to dryness under reduced pressure at room temperature, a mixture of 300 ml of ethyl acetate and 100 ml of cold 1N hydrochloric acid was added to the residue, and the organic layer was separated. After washing the organic layer with 300 ml of cold saturated brine, the target product is extracted in two portions with 300 ml of cold saturated aqueous sodium bicarbonate solution. Next, 250 ml of ethyl acetate is added to the aqueous layer, the pH value is adjusted to about 1.5 with cold 6N hydrochloric acid, the aqueous layer is saturated by adding common salt, and the organic layer is separated. Collect the separated organic layer in cold saturated saline solution 100%
ml, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. When the residue is crystallized from acetone-chloroform and recrystallized from the same solvent system, D(-)-α-{3-(3,4
5.5 g of -dihydroxybenzoyl)-3-(3-hydroxypropyl)-1-ureido}phenylacetic acid was obtained as white crystals. Melting point 139-141℃ (decomposition) Elemental analysis C 19 H 20 N 2 O 7・H 2 O C H N Calculated value (%) 56.16 5.46 6.89 Actual value (%) 56.30 5.40 6.87 I R ν KBr nax (cm - 1 ): 3540, 3500, 1690, 1670,
1595, 1520 NMR (DMSO-d 6 , 60MHz) δ (ppm): 1.3-2.0
(2H, m), 3.35 (2H, t, J=6Hz),
3.73 (2H, t, J = 6.5Hz), 5.22 (1H, d,
J=7Hz), 6.7-7.5 (8H, m), 9.19 (1H,
d, J=7Hz) Ferric chloride color reaction: Positive (dark green) Example 2 In Example 1(1), N-(3-hydroxypropyl)-3,4-dihydroxybenzamide was replaced with N- (2-hydroxyethyl)-3,4
- Using dihydroxybenzamide, the same treatment was performed to obtain D(-)-α-{3-(3,4-dihydroxybenzoyl)-3-(2-hydroxyethyl)-1-ureido}phenylacetic acid. . NMR (DMSO-d 6 , 60MHz) δ (ppm): 3.1-3.9
(4H, m), 5.25 (1H, d, J=7Hz), 6.7
~7.6 (8H, m), 9.26 (1H, d, J = 7Hz) Example 3 In Example 1 (1), N-(5-hydroxypropyl)-3,4-dihydroxybenzamide was replaced with -Hydroxypentyl)-3,4
- Using dihydroxybenzamide, the same treatment was performed to obtain D(-)-α-{3-(3,4-dihydroxybenzoyl)-3-(5-hydroxypentyl)-1-ureido}phenylacetic acid. . NMR (DMSO-d 6 , 60MHz) δ (ppm): 1.4 (6H,
brs), 3.1-3.7 (4H, m), 5.24 (1H, d,
J=7Hz), 6.7-7.5 (8H, m), 9.24 (1H,
d, J = 7 Hz) Example 4 In Example 1 (1), N-{2-(2-hydroxyethoxy)ethyl}-3, instead of N-(3-hydroxypropyl)-3,4-dihydroxybenzamide The same treatment was performed using 4-dihydroxybenzamide to obtain D(-)-α-[3-
(3,4-dihydroxybenzoyl)-3-{2
-(2-hydroxyethoxy)ethyl}-1-ureido]phenylacetic acid was obtained. NMR (DMSO-d 6 , 60MHz) δ (ppm): 3.3-4.1
(8H, m), 5.23 (1H, d, J=7Hz), 6.7
~7.6 (8H, m), 9.20 (1H, d, J = 7Hz) Example 5 In Example 1 (1), N-(2-hydroxypropyl)-3,4-dihydroxybenzamide was replaced with -methoxyethyl)-3,4-dihydroxybenzamide, and the amount of trimethylsilyl chloride and triethylamine was 1
The molar equivalent is reduced and used, followed by the same treatment to obtain D(-)-α-{3-(3,4-dihydroxybenzoyl)-3-(2-methoxyethyl)-
1-Ureido}phenylacetic acid was obtained. NMR (DMSO-d 6 , 60MHz) δ (ppm): 3.20
(3H, s), 3.4 (2H, br), 3.9 (2H, br),
5.20 (1H, d, J = 7Hz), 6.7~7.6 (8H,
m), 9.15 (1H, d, J = 7Hz) Example 6 In Example 1 (1), N-(2-cyanoethyl)- was substituted for N-(3-hydroxypropyl)-3,4-dihydroxybenzamide. D(-)-α-{3-(3,4-dihydroxybenzoyl )-3-(2-cyanoethyl)-1
-ureido}phenylacetic acid was obtained. NMR (DMSO-d 6 , 60MHz) δ (ppm): 2.8 (2H,
br), 4.0 (2H, br), 5.20 (1H, d, J=7
Hz), 6.7-7.5 (8H, m), 9.14 (1H, d,
J=7Hz) Example 7 In Example 1(1), N-ethoxycarbonylmethyl-3,4- was used instead of N-(3-hydroxypropyl)-3,4-dihydroxybenzamide.
Using dihydroxybenzamide and reducing the amounts of trimethylsilyl chloride and triethylamine by 1 molar equivalent, the same treatment was performed to obtain D(-)-α-{3-(3,4-dihydroxybenzoyl)-3. -Ethoxycarbonylmethyl-1-ureido}phenylacetic acid was obtained. NMR (DMSO-d 6 , 60MHz) δ (ppm): 1.0-1.4
(3H, m), 3.8-4.6 (4H, m), 5.25 (1H,
d, J=7Hz), 6.7-7.6 (8H, m), 9.45
(1H, d, J = 7Hz) Example 8 Using N-benzyl-3,4-dihydrobenzamide instead of N-(3-hydroxypropyl)-3,4-dihydroxybenzamide in Example 1(1), In addition, by reducing the amounts of trimethylsilyl chloride and triethylamine by 1 molar equivalent and carrying out the same treatment, D(-)-α-
{3-(3,4-dihydroxybenzoyl)-3
-benzyl-1-ureido}phenylacetic acid was obtained. NMR (DMSO-d 6 , 60MHz) δ (ppm): 4.8-5.1
(2H, brs), 5.24 (1H, d, J=7Hz),
6.7-7.5 (13H, m), 9.24 (1H, d, J=
7Hz) Example 9 In Example 1(1), N-furfuryl-3,4-dihydroxybenzamide was used instead of N-(3-hydroxypropyl)-3,4-dihydroxybenzamide, and the amounts of trimethylsilyl chloride and triethylamine were Using a reduced amount of 1 molar equivalent, perform the same treatment to obtain D(-)
-α-{3-(3,4-dihydroxybenzoyl)-3-furfuryl-1-ureido}phenylacetic acid was obtained. NMR (DMSO-d 6 , 60MHz) δ (ppm): 4.8-5.1
(2H, brs), 5.22 (1H, d, J=7Hz),
6.2~7.7 (11H, m), 9.18 (1H, d, J=
7Hz) Example 10 In Example 1 (2), D(-)-(4-hydroxyphenyl) was used instead of D(-)-phenylglycine.
Using glycine and the same treatment below, D(-)
-α-{3-(3,4-dihydroxybenzoyl)-3-(3-hydroxypropyl)-1-ureido}-α-(4-hydroxyphenyl)acetic acid was obtained. NMR (DMSO-d 6 , 60MHz) δ (ppm): 1.3-1.9
(2H, m), 3.34 (2H, t, J=6Hz),
3.72 (2H, t, J = 6.5Hz), 5.21 (1H, d,
J=7Hz), 6.5-7.3 (7H, m), 9.07 (1H,
d, J = 7 Hz) Reference Example 1 (1) To a suspension of 50 ml of dry dichloromethane containing 4.0 g of phenyl acetic acid obtained in Example (2) and 4.9 g of trimethylsilyl chloride, 4.2 g of triethylamine was added at 5 to 10°C. After the dropwise addition, the solution was stirred at 15 to 20° C. for 1 hour to obtain the above trimethylsilylated solution of phenylacetic acid, which was then subjected to the reaction described below. (2) To 30 ml of a dry dichloromethane solution containing 1.2 g of trichloromethyl chloroformate, 0.8 g of dimethylformamide was added at -20°C, stirred at 0 to 5°C for 1 hour, and then heated to -30°C as prepared in (1) above. Add dichloromethane solution and heat at -10 to -15℃ for 1.5
Stir for an hour. Next, 5.5 g of N,O-bistrimethylsilylacetamide was added and dissolved in a suspension of 2.9 g of 6-aminopenicillanic acid in 50 ml of dry dichloromethane, and the solution was dissolved from -10 to -
Add dropwise at 15°C and stir at the same temperature for 1 hour. The reaction mixture is evaporated to dryness under reduced pressure at room temperature, a mixture of 300 ml of ethyl acetate and 100 ml of cold 1N hydrochloric acid is added to the residue, and the organic layer is separated. The organic layer is washed with 300 ml of cold saturated brine and then extracted in two portions with 300 ml of cold saturated aqueous sodium bicarbonate solution. The separated aqueous layer was washed with 100 ml of ethyl acetate, 250 ml of ethyl acetate was added thereto, and the pH value was adjusted to approx. with cold 6N hydrochloric acid.
1.5 and further add common salt to saturate the aqueous layer, then separate the organic layer. The organic layer was added to cold saturated saline solution.
After washing with 100 ml, it is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is subjected to column chromatography on activated carbon (for chromatography) and eluted with ethyl acetate. The eluate was collected and concentrated under reduced pressure until the volume was about 30 ml, and then added to 300 ml of n-hexane with stirring.
6-[D(-)-α-{3-(3,4-dihydroxybenzoyl)-3-(3-hydroxypropyl)-1-ureido}-α-phenylacetamide] penicillanic acid (hereinafter also referred to as compound A) )5.0
g is obtained as a white powder. I R ν KBr nax (cm -1 ): 3700-2300, 1775, 1675,
1600, 1515 NMR (DMSO-d 6 , 60MHz) δ (ppm): 1.41
(3H, s), 1.55 (3H, s), 1.4~2.0 (2H,
br), 3.36 (2H, t, J=6Hz), 3.75 (2H,
br), 4.20 (1H, s), 5.3-5.8 (3H, m),
6.7~7.5 (8H, m), 9.12 (1H, d, J=7
Hz), 9.19 (1H, d, J = 7Hz) UV λ EtOH nax nm (ε): 209 (3.1×10 4 ), 225 (
shoulder),
271 (6.1×10 3 ), 295 (6.3×10 3 ) Ferric chloride color reaction: Positive (dark green) Reference example 2 In reference example 1 (1), D(-)-α-{3-
(3,4-dihydroxybenzoyl)-3-(3
-Hydroxypropyl)-1-ureido}D(-)- obtained in Example 2 instead of phenyl acetic acid
α-{3-(3,4-dihydroxybenzoyl)
-3-(2-Hydroxyethyl)-1-ureido}phenylacetic acid is used in the same manner as below to obtain 6-[D(-)-α-{3-(3,4-dihydroxybenzoyl)-3-(2 -Hydroxyethyl)-1-ureido}-α-phenylacetamide]penicillanic acid (hereinafter also referred to as compound B) is obtained as a white powder. I R ν KBr nax (cm -1 ): 3700-2200, 1775, 1675,
1600, 1515 NMR (DRSO- d6 , 60NHz) δ (ppm): 1.42 (3H,
s), 1.56 (3H, s), 3.2~4.0 (4H, m),
4.21 (1H, s), 5.3~5.8 (3H, m), 6.7~
7.6 (8H, m), 9.10 (1H, d, J=7Hz),
9.26 (1H, d, J = 7Hz) UV λ EtOH nax nm (ε): 208 (2.8×10 4 ), 221 (
shoulder),
262 (6.8×10 3 ), 295 (5.2×10 3 ) Ferric chloride color reaction: Positive (dark green) Reference example 3 ED 50 of compounds A and B (1) Test method 5 weeks old, weight 21~ Five 25 g ddY male mice were used as one group. Test strains were grown on Brain Heart Infusion Agar at 37°C.
The cells cultured overnight were suspended in 5% mucin and administered intraperitoneally to mice. Test compounds were prepared at various concentrations and injected subcutaneously into mice 1 and 3 hours after inoculation. 5 days later,
The ED 50 value was calculated from the number of surviving mice at each dose. (2) Test results [Table]
Claims (1)
C1〜5の低級アルキル基を、そしてＹはＸの置換
基であり、基−OR2，−CN，−COOR3、フルフリ
ル基またはフエニル基を意味する。R2は水素原
子，水酸基で置換されたC2〜4の低級アルキル基
を、R3はC1〜3の低級アルキル基を意味する。）
で表される化合物またはその塩。[Claims] 1. General formula (In the formula, R 1 is a hydrogen atom or a hydroxyl group, and X is
a C1-5 lower alkyl group, and Y is a substituent of X, meaning a group -OR2 , -CN, -COOR3 , a furfuryl group or a phenyl group. R2 means a C2-4 lower alkyl group substituted with a hydrogen atom or a hydroxyl group, and R3 means a C1-3 lower alkyl group. )
A compound represented by or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55118275A JPS5742664A (en) | 1980-08-29 | 1980-08-29 | Alpha-substituted ureidophenylacetic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55118275A JPS5742664A (en) | 1980-08-29 | 1980-08-29 | Alpha-substituted ureidophenylacetic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5742664A JPS5742664A (en) | 1982-03-10 |
| JPS6357419B2 true JPS6357419B2 (en) | 1988-11-11 |
Family
ID=14732610
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP55118275A Granted JPS5742664A (en) | 1980-08-29 | 1980-08-29 | Alpha-substituted ureidophenylacetic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5742664A (en) |
-
1980
- 1980-08-29 JP JP55118275A patent/JPS5742664A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5742664A (en) | 1982-03-10 |
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