CN1297437A - 取代的n-[2-(吲哚-3-基)-乙基]-2-氧代-链烷酰胺 - Google Patents
取代的n-[2-(吲哚-3-基)-乙基]-2-氧代-链烷酰胺 Download PDFInfo
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- CN1297437A CN1297437A CN99805078A CN99805078A CN1297437A CN 1297437 A CN1297437 A CN 1297437A CN 99805078 A CN99805078 A CN 99805078A CN 99805078 A CN99805078 A CN 99805078A CN 1297437 A CN1297437 A CN 1297437A
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- Prior art keywords
- alkyl
- compound
- alkoxyl group
- halogen
- nitro
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- 150000001408 amides Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 23
- 150000002367 halogens Chemical class 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 20
- 239000001257 hydrogen Substances 0.000 claims abstract description 20
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 10
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 17
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 15
- -1 Hydrogen Chemical class 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 3
- 239000004599 antimicrobial Substances 0.000 claims description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
- 150000002475 indoles Chemical class 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 1
- 239000003242 anti bacterial agent Substances 0.000 abstract 1
- 241001465754 Metazoa Species 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229920001817 Agar Polymers 0.000 description 5
- 239000008272 agar Substances 0.000 description 5
- 230000000845 anti-microbial effect Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- CAAGZPJPCKMFBD-UHFFFAOYSA-N 2-(1-methyl-3-indolyl)ethanamine Chemical class C1=CC=C2N(C)C=C(CCN)C2=C1 CAAGZPJPCKMFBD-UHFFFAOYSA-N 0.000 description 4
- BKAJNAXTPSGJCU-UHFFFAOYSA-N 4-methyl-2-oxopentanoic acid Chemical compound CC(C)CC(=O)C(O)=O BKAJNAXTPSGJCU-UHFFFAOYSA-N 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000012752 auxiliary agent Substances 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
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- NIQUZFQMNMNAMD-NSHDSACASA-N (3s)-n-[2-(1h-indol-3-yl)ethyl]-3-methyl-2-oxopentanamide Chemical compound C1=CC=C2C(CCNC(=O)C(=O)[C@@H](C)CC)=CNC2=C1 NIQUZFQMNMNAMD-NSHDSACASA-N 0.000 description 3
- 239000001142 4-methyl-2-oxopentanoic acid Substances 0.000 description 3
- 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
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- NIQUZFQMNMNAMD-UHFFFAOYSA-N nematophin Natural products C1=CC=C2C(CCNC(=O)C(=O)C(C)CC)=CNC2=C1 NIQUZFQMNMNAMD-UHFFFAOYSA-N 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 2
- MVJLYXCJBPXRCY-UHFFFAOYSA-N 2-methylbutyl propanoate Chemical compound CCC(C)COC(=O)CC MVJLYXCJBPXRCY-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 241000606125 Bacteroides Species 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000000384 rearing effect Effects 0.000 description 2
- 210000000582 semen Anatomy 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical group CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- XTKOGHRUORLSMB-UHFFFAOYSA-N 2-(1-benzylindol-3-yl)ethanamine Chemical class C12=CC=CC=C2C(CCN)=CN1CC1=CC=CC=C1 XTKOGHRUORLSMB-UHFFFAOYSA-N 0.000 description 1
- QIEYQKPMBQAYNS-UHFFFAOYSA-N 2-(1-cyclopentylindol-3-yl)ethanamine Chemical class C12=CC=CC=C2C(CCN)=CN1C1CCCC1 QIEYQKPMBQAYNS-UHFFFAOYSA-N 0.000 description 1
- DAHZNRLDSGNWPR-UHFFFAOYSA-N 2-(1-ethylindol-3-yl)ethanamine Chemical class C1=CC=C2N(CC)C=C(CCN)C2=C1 DAHZNRLDSGNWPR-UHFFFAOYSA-N 0.000 description 1
- VTNTWBXHFCUYEF-UHFFFAOYSA-N 2-(1-phenylindol-3-yl)ethanamine Chemical class C12=CC=CC=C2C(CCN)=CN1C1=CC=CC=C1 VTNTWBXHFCUYEF-UHFFFAOYSA-N 0.000 description 1
- TYEYBOSBBBHJIV-UHFFFAOYSA-N 2-oxobutanoic acid Chemical compound CCC(=O)C(O)=O TYEYBOSBBBHJIV-UHFFFAOYSA-N 0.000 description 1
- KDVFRMMRZOCFLS-UHFFFAOYSA-N 2-oxopentanoic acid Chemical compound CCCC(=O)C(O)=O KDVFRMMRZOCFLS-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- GFDNSWDADUQLJC-UHFFFAOYSA-N 3-methyl-2-oxopentanoyl chloride Chemical compound CCC(C)C(=O)C(Cl)=O GFDNSWDADUQLJC-UHFFFAOYSA-N 0.000 description 1
- JVQYSWDUAOAHFM-UHFFFAOYSA-N 3-methyl-2-oxovaleric acid Chemical compound CCC(C)C(=O)C(O)=O JVQYSWDUAOAHFM-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 241000272814 Anser sp. Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000272201 Columbiformes Species 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 241000699798 Cricetulus Species 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 229920004449 Halon® Polymers 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
- 241000124008 Mammalia Species 0.000 description 1
- 241001508687 Mustela erminea Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000555745 Sciuridae Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 241000607735 Xenorhabdus nematophila Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000123 paper Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
本发明涉及:通式(Ⅰ)的新型N-[2-(吲哚-3-基)-乙基]-2-氧代—链烷酰胺,其中R1任选地代表支链C1~C8-烷基或C4~C8-环烷基,R2独立于R3地代表氢、C1~C4-烷基、C1~C4-烷氧基、C1~C4-烷硫基、苯基或卤素,R3代表氢、C1~C4-烷基或卤素,以及R4任选地代表支链C1~C6-烷基、C4~C6-环烷基;苯基,其上任选地取代上1~3个C1~C3-烷基、C1~C3-烷氧基、C1~C3-烷硫基、卤素、硝基或氨基;或者代表苄基,其上任选地取代上1~3个C1~C3-烷基、C1~C3-烷氧基、C1~C3-烷硫基、卤素、硝基或氨基,及其制备方法以及它们在抗菌组合物中的应用。
Description
本发明涉及一种新型取代的N-[2-(吲哚-3-基)-乙基]-2-氧代-链烷酰胺、其制备方法以及包含它们的抗菌组合物。
US-P5569668公开了一种N-[2-(1H-吲哚-3-基)-乙基]-2-氧代-链烷酰胺及其抗霉菌和抗菌性能,特别是抗葡萄球菌类的性能。特别强调了一种叫做nematophin的化合物,这是一种由Xenorhabdusnematophilus细菌产生的天然化合物。nematophin及其某些衍生物的作用和性质还公开在《Bioorganic&Medicinal ChemistryLetters(生物有机及药物化学文献),7(1997)1349~1352中。
日益增多的多抗药性细菌病原体使得探索新型抗菌活性物质成为一项紧迫的任务(《化学与工业》1997,131;Drug DiscoveryToday(最新药物发现)1997,47)。nematophin及其已知衍生物的抗菌活性仍不完全令人满意。
本发明提供
其中
R1代表任选地支链的C1~C8-烷基或C4~C8-环烷基,
R2独立于R3地代表氢、C1~C4-烷基、C1~C4-烷氧基、C1~C4-烷硫基、苯基或卤素,
R3代表氢、C1~C4-烷基或卤素,以及
R4代表任选支链的C1~C6-烷基、C4~C6-环烷基;苯基,其上任选地取代上1~3个C1~C3-烷基、C1~C3-烷氧基、C1~C3-烷硫基、卤素、硝基或氨基;或者代表苄基,其上任选地取代上1~3个C1~C3-烷基、C1~C3-烷氧基、C1~C3-烷硫基、卤素、硝基或氨基。
通式(Ⅰ)的化合物可以其外消旋物形式或以对映体意义上的纯化合物形式存在,以及以其可用作药物的水合物及酸加成盐的形式存在。
2.制备通式(Ⅰ)化合物的方法
其中
R1代表任选支链的C1~C8-烷基或C4~C8-环烷基,
R2独立于R3地代表氢、C1~C4-烷基、C1~C4-烷氧基、C1~C4-烷硫基、苯基或卤素,
R3代表氢、C1~C4-烷基或卤素,以及
R4代表任选支链的C1~C6-烷基、C4~C6-环烷基;苯基,其上任选地取代上1~3个C1~C3-烷基、C1~C3-烷氧基、C1~C3-烷硫基、卤素、硝基或氨基;或者代表苄基,其上任选地取代上1~3个C1~C3-烷基、C1~C3-烷氧基、C1~C3-烷硫基、卤素、硝基或氨基,
其中
R2、R3、R4如上所定义,
其中
Y代表OH或卤素,以及
R1如上所定义,
如果必要,存在一种酸结合剂并且如果必要存在一种稀释剂。
与同类结构的已知典型化合物相比,令人惊奇的是本发明的通式(Ⅰ)化合物具有高得多的抗菌活性。因此,它们适合作为人、畜药用抗菌活性化合物使用。
优选这样的通式(Ⅰ)化合物,其中
R1代表任选支链的C1~C6-烷基或C4~C6-环烷基,
R2独立于R3地代表氢、C1~C2-烷基、C1~C2-烷氧基、C1~C2-烷硫基、苯基、氟、氯或溴,
R3代表氢、C1~C2-烷基或氟或溴,以及
R4代表任选支链的C1~C4-烷基、C4~C6-环烷基;苯基,其上任选地取代上1~3个C1~C2-烷基、C1~C2-烷氧基、氟、氯、溴、硝基或氨基;或者代表苄基,其上任选地取代上1~3个C1~C2-烷基、C1~C2-烷氧基、氟、氯、溴、硝基或氨基,
以及它们的可用作药物的水合物以及酸加成盐。
尤其优选这样的通式(Ⅰ)化合物,其中
R1代表任选支链的C1~C6-烷基或C4~C6-环烷基,
R2独立于R3地代表氢、C1~C2-烷基、C1-C2-烷氧基、氟或氯,
R3代表氢、C1~C2-烷基、氟或氯,以及
R4代表任选支链的C1~C4-烷基、C4~C6-环烷基;苯基,其上任选地取代上1或2个C1~C2-烷基、C1~C2-烷氧基、氟、氯、硝基或氨基;或者代表苄基,其上任选地取代上1或2个C1~C2-烷基、C1~C2-烷氧基、氟、氯、硝基或氨基,
以及它们的可用作药物的水合物以及酸加成盐。
进一步尤其优选这样的通式(Ⅰ)化合物,其中
R1代表最多4个碳原子的支链烷基,
R2和R3代表氢,
R4代表C1~C4-烷基、苯基或苄基。
通式(Ⅱ)的化合物是已知的(例如,《药物化学杂志》37(1994),4307~4316)或者可由已知方法制备。可举出的通式(Ⅱ)化合物的例子是:
1-甲基-3-(2-氨乙基)-吲哚,
1-乙基-3-(2-氨乙基)-吲哚,
1-丙基-3-(2-氨乙基)-吲哚,
1-异丙基-3-(2-氨乙基)-吲哚,
1-环戊基-3-(2-氨乙基)-吲哚,
1-苯基-3-(2-氨乙基)-吲哚,
1-苄基-3-(2-氨乙基)-吲哚,
(4-氯苄基)-3-(2-氨乙基)-吲哚,
(2,6-二氯苄基)-3-(2-氨乙基)-吲哚。
通式(Ⅲ)的化合物同样也是已知的,而且它们当中的某些有市售供应。通式(Ⅲ)的化合物,而其中Y是卤素者,例如是氯的,可由通式(Ⅲ)中Y是OH的化合物按照已知的方法通过与卤化剂,例如与亚硫酰氯或草酰氯起反应来制备。可举出的化合物(Ⅲ),而其中Y是OH的例子是:
丙酮酸
2-氧代-丁酸,
2-氧代-戊酸,
2-氧代-4-甲基-戊酸,
2-氧代-3-甲基-戊酸,
环丁基-二羟乙酸,
环戊基-二羟乙酸,
环己基-二羟乙酸。
如果所用起始物料是通式(Ⅲ),而其中Y是氯的化合物,则通式(Ⅰ)的化合物可在惰性溶剂中在除酸剂存在下进行制备。合适的溶剂例如是卤化烃,如二氯甲烷、氯仿、四氯化碳;脂族或芳族烃,如甲苯;极性惰性溶剂,如二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜或环丁砜。也可使用这些溶剂的混合物。
合适的除酸剂是惯用的酸结合剂,如碱金属或碱土金属的碳酸盐、三甲胺、三乙胺、三丁胺、1,4-二氮杂双环[2.2.2]辛烷(DABCO)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)或者吡啶。
除酸剂的用量,以其中Y是氯的化合物(Ⅲ)的摩尔数量为基准,一般介于80~200mol%。优选采用110~150mol%的用量。
还可在大量过量的吡啶中进行反应,此时吡啶同时起到溶剂和除酸剂的作用。
通式(Ⅱ)与(Ⅲ)的化合物通常以近似等摩尔用量使用。
在该程序中,反应温度在-20~80℃之间变化。优选在-10℃~25℃之间进行。
反应可在大气压压力下,然而也可在提高的压力下进行。一般地,该反应在1bar~100bar,优选在1~10bar之间的压力下进行。
如果起始物料是通式(Ⅲ)的化合物,而其中Y是OH者,则该反应在隋性溶剂中,在通常用于生成酰胺键的助剂存在下进行。合适的溶剂是上面提到的溶剂,例如二氯甲烷、氯仿、二甲基甲酰胺或N-甲基吡咯烷酮。也可使用这些溶剂的混合物。
合适的助剂例如是N’-(3-二甲氨基丙基)-N-乙基碳化二亚胺(EDC)或二环己基碳化二亚胺(DCC)。
生成酰胺键的合适助剂例如是羟基苯并三唑,在有机碱存在下,例如三乙胺、三丁胺或N-甲基吗啉。通式(Ⅱ)和(Ⅲ)的起始物料以近似等摩尔数量使用。该助剂按照与通式(Ⅲ)化合物近似的等摩尔数量使用。
在该程序中,反应温度可在-20~80℃之间变化。反应优选在-10℃~25℃之间进行。
反应可在大气压压力下,然而也可在提高的压力下进行。一般地,该反应在1bar~100bar,优选在1~10bar之间的压力下进行。
反应结束后,生成的通式(Ⅰ)化合物按照有机化学惯用方法,例如通过结晶或色谱术,进行提纯。
本发明化合物的酸加成盐按照惯用方法制备,例如将该化合物溶解在充足量含水酸中,并利用水混溶性有机溶剂,如甲醇、乙醇、丙酮、乙腈,使盐沉淀出来。也可将等当量数量的本发明化合物与酸溶解在水中,然后蒸发至干,或者真空过滤出该沉淀的盐。
本发明的化合物具有强效抗菌作用并具有非常好的抗革兰氏阳性微生物,特别是葡萄球菌的作用。
由于具备这些有用的性质,它们可用作医疗及兽医中的化学治疗活性化合物,以及用于无机和有机材料的防腐物质,尤其是用于所有类型的有机材料,例如聚合物、润滑剂、染料、纤维、皮革、纸及木材,以及食品和水的防腐。
借助本发明化合物,革兰氏阳性细菌,尤其是葡萄球菌以及类似细菌的微生物将得到控制,并可预防、减轻和/或治疗由这些病原体导致的疾病。
即使对于那些认为对其他抗菌剂不太敏感的细菌类别,特别是耐药性金黄色葡萄球菌,本发明化合物仍旧表现出令人惊奇的活性增强。
本发明化合物对于细菌以及类似细菌的微生物具有特殊活性。因此,它们特别适合在人、兽医疗中,用于由这些病原体引起的局部及系统感染的预防及化学疗法。
该化合物还适合用来控制原生动物疾病(protozoonoses)以及蠕虫病。
本发明化合物可采取各种各样的药物制剂形式给药。可举出的优选药物制剂是片剂、包衣片剂、胶囊、丸剂、粒剂、栓剂、注射制剂以及可口服溶液、悬浮体以及乳液,乃至糊剂、软膏、凝胶、乳膏、洗剂、粉末以及喷雾剂。
该活性化合物优选地适合用来控制在生产性、配种、动物园、实验室以及实验用的动物及宠物的动物饲养以及动物繁殖过程中出现的各种细菌疾病。在这方面,它们具有对所有或者各个发展阶段以及对耐药性及一般敏感性菌株的抗菌活性。通过对各种细菌疾病或障碍的控制,死亡率以及减产(例如,肉、奶、羊毛、生皮、蛋、蜂蜜等的生产)应得到减轻,因此,由于采用此种活性化合物,可使得动物饲养的成本降低或变得更为简单。
生产以及配种用动物包括哺乳类,例如牛、马、绵羊、猪、山羊、骆驼、水牛、驴、兔子、黄占鹿、驯鹿;毛皮动物如貂、灰鼠、浣熊;禽类,如鸡、鹅、火鸡、鸭、鸽子以及各种各样家养或动物园饲养的鸟类。它们还包括生产或观赏鱼。
实验室及实验用动物包括小鼠、大鼠、豚鼠、金黄色仓鼠、狗和猫。
通常,为达到有效结果,约0.5~约50mg,优选1~20mg活性化合物/kg体重/日的给药量,已证明是有利的。
该活性化合物还可与动物的饲料和饮水一起喂入。
饲料和食物包含0.01~100ppm,优选0.5~50ppm活性化合物并混有合适的可食材料。
此种饲料或食物既可用于治疗也可用于预防的目的。
此种饲料或食物是通过包含0.5~30%,优选1~20wt%活性化合物的浓缩物或预混物与普通饲料中使用的可食用有机或无机载体混合物混合在一起配制的。可食用载体例如是玉米粉或者玉米及大豆粉或者无机盐,其中优选地包含少量可食用防扬灰油,例如玉米油或豆油。然后,如此获得的预混物可加入到整个饲料中并随即将其喂给动物。
曾通过连续稀释法在等敏感度试验琼脂(Oxoid)上测定过本发明化合物的最低抑菌浓度(MIC)。就每种试验物质而言,制备数个琼脂平面,在每个琼脂平面上滴加加倍稀释液,逐渐降低所包含的活性化合物浓度。该琼脂平面在多点孵化器(Denley)中进行孵化。采用病原体的过夜培养物进行接种,其中包含预先经过稀释以便使每个接种点包含约104个能形成菌落的颗粒。将接种后的琼脂平面置于37℃下孵化,约20 h后读取细菌生长数值。MIC值(μg/mL)指出最低活性化合物浓度,在该浓度时用肉眼无法观察到生长。
下表中给出某些本发明化合物的MIC值。下面给出由US5569608得知的化合物A或B,作为对照化合物。
活性化合物制备
在0℃并以冰冷却的情况下,0.9g 2-氧代-3-甲基-戊酰氯滴加到1g 1-甲基色胺溶于5mL吡啶的溶液中。让混合物暖至室温,然后搅拌过夜。随后,反应混合物与水混合并用乙醚萃取3次。该有机相随后相继用饱和氯化铵溶液、5%浓度氢氧化钠水溶液、水及饱和氯化钠溶液进行萃取,置于硫酸钠上干燥,最后在减压下浓缩。所获得的残留物在硅胶上进行色谱分离(二氯甲烷/甲醇,99∶1)。于是获得0.31g油状产物。
1H-NMR(400 MHz,CDCl3):δ=0,88(t,3H),1,09(d,3H),1,35-1,45(m,1H),1,57-
1,68(m,1H),1,95-2,05(m,1H),2,93-3,03(m,2H),3,55-3,63(m,2H),3,75(s,3H),
5,53(s,br,1H),6,87(s,1H),7,12(m,1H),7,25(m,1H),7,32(m,1H),7,6(m,1H)
ppm。
MS/EI(-70ev):m/e=286(M+,5%),157(32%),144(100%)。
在-30℃,1.34g 1-羟基-1H-苯并三唑水合物(HOBT)及1.68gN’-(3-二甲氨基丙基)-N-乙基碳化二亚胺盐酸盐EDC)加入到0.91g4-甲基-2-氧代-戊酸溶于40mL DMF的溶液中。将混合物搅拌半小时,然后在其中加入1.22g 1-甲基-色胺溶于5mL DMF的溶液。随后,加入三乙胺,以便使pH达到约9。混合物在0℃搅拌1h,然后任其暖至室温,继而在室温下搅拌过夜。反应混合物在减压下浓缩,残留物在乙酸乙酯中萃取。该溶液相继地用水、碳酸钠水溶液以及饱和氯化钠水溶液萃取,然后在硫酸钠上干燥,最后在减压下浓缩。残留物在硅胶上进行色谱分离(二氯甲烷/甲醇,99∶1)。于是获得1.34g粘稠油状物。1H-NMR(400 MHz,CDCl3):δ=0,94(d,J=6,6 Hz;6H),2,1-2,2(m;1H),2,79(d,J=6,8 Hz;2H),3,0(m;2H),3,58-3,63(m;2H),3,76(s;3H),6,89(s;1H),7,05(m,br;1H),7,1(m;1H),7,23(m;1H),7,3(m;1H),7,58(m;1H)ppm。
按照类似于实例2的程序,由0.91g 3-甲基-2-氧代-戊酸及1.43g1-异丙基色胺制取0.53g油状目标化合物。1H-NMR(400 MHz,CDCl3):δ=0,88(t,3H),1,1(d,3H),1,35-1,45(m,1H),1,52(d,6H),1,67-1,78(m,1H),3,02(m,2H),3,47-3,55(m,1H),3,63(m,2H),4,6-4,7(m,1H),7,03(s,br,1H),7,07(s,1H),7,12(m,1H),7,22(m,1H),7,37(m,1H),7,59(m,1H)ppm。
按照类似于实例2的程序,由0.91g 4-甲基-2-氧代-戊酸及1.43g1-异丙基色胺制取0.5g粘稠油状产物。1H-NMR(400 MHz,CDCl3):δ=0,94(d,6H),1,52(d,6H),2,1-2,2(m,1H),2,8(d,2H),3,0(m,2H),3,62(m,2H),4,6-4,7(m,1H),7,03(s,br,1H),7,07(s,1H),7,12(m,1H),7,22(m,1H),7,37(m,1H),7,58(m,1H)ppm。
按照类似于实例2的程序,由0.65g 4-甲基-2-氧代-戊酸及1.2g 1-苯基色胺制取0.53g产物。
1H-NMR(400 MHz,CDCl3):δ=0,94(d,J=6,6 Hz;6H),2,1-2,2(m;1H),2,80(d,
J=7 Hz;2H),3,04-3,1(m;2H),3,65-3,72(m,2H),7,12(m,br;1H),7,17-7,28(m;
3H),7,32-7,38(m;1H),7,47-7,55(m;4H),7,58(m;1H),7,67(m;1H)ppm。
实例6
按照类似于实例2的程序,由0.91g 3-甲基-2-氧代-戊酸及1.75g 1-苄基色胺制取1.43g油状产物。1H-NMR(400 MHz,CDCl3):δ=0,86(t,3H),1,08(d,3H),1,33-1,43(m,1H),1,65-1,75(m,1H),3,01(m,2H),3,45-3,55(m,1H),3,63(m,2H),5,29(s,2H),6,97(s,1H),7,05(s,br,1H),7,12(m,3H),7,18(m,1H),7,23-7,35(m,4H),7,62(m,1H)ppm。
实例7
按照类似于实例2的程序,由0.91g 4-甲基-2-氧代-戊酸及1.75g 1-苄基色胺制取1.08g产物。
熔点:82~3℃。1H-NMR(400 MHz,CDCl3):δ=0,93(d,6H),2,1-2,2(m,1H),2,79(d,2H),3,0(m,2H),3,62(m,2H),5,29(s,2H),6,96(s,1H),7,05(s,br,1H),7,12(m,3H),7,2(m,1H),7,25-7,35(m,4H),7,6(m,1H)ppm。
Claims (7)
其中
R1代表任选支链的C1~C8-烷基或C4~C8-环烷基,
R2独立于R3地代表氢、C1~C4-烷基、C1~C4-烷氧基、C1~C4-烷硫基、苯基或卤素,
R3代表氢、C1~C4-烷基或卤素,以及
R4代表任选支链的C1~C6-烷基、C4~C6-环烷基;苯基,其上任选地取代上1~3个C1~C3-烷基、C1~C3-烷氧基、C1~C3-烷硫基、卤素、硝基或氨基;或者代表苄基,其上任选地取代上1~3个C1~C3-烷基、C1~C3-烷氧基、C1~C3-烷硫基、卤素、硝基或氨基,
该化合物以其外消旋物形式或以对映体意义上的纯化合物形式存在,并且以其可用作药物的水合物及酸加成盐的形式存在。
2.制备通式(Ⅰ)化合物的方法
其中
R1代表任选支链的C1~C8-烷基或C4~C8-环烷基,
R2独立于R3地代表氢、C1~C4-烷基、C1~C4-烷氧基、C1~C4-烷硫基、苯基或卤素,
R3代表氢、C1~C4-烷基或卤素,以及
R4代表任选支链的C1~C6-烷基、C4~C6-环烷基;苯基,其上任选地取代上1~3个C1~C3-烷基、C1~C3-烷氧基、C1~C3-烷硫基、卤素、硝基或氨基;或者代表苄基,其上任选地取代上1~3个C1~C3-烷基、C1~C3-烷氧基、C1~C3-烷硫基、卤素、硝基或氨基,
其中
R2、R3、R4如上所定义,
其中
Y代表OH或卤素,
R1如上所定义,
如果必要存在一种酸结合剂并且如果必要存在一种稀释剂。
3.权利要求1的通式(Ⅰ)化合物,其中
R1代表任选支链的C1~C6-烷基或C4~C6-环烷基,
R2独立于R3地代表氢、C1~C2-烷基、C1~C2-烷氧基、C1~C2-烷硫基、苯基、氟、氯或溴,
R3代表氢、C1~C2-烷基、氟或溴,以及
R4代表任选支链的C1~C4-烷基、C4~C6-环烷基;苯基,其上任选地取代上1~3个C1~C2-烷基、C1~C2-烷氧基、氟、氯、溴、硝基或氨基;或者代表苄基,其上任选地取代上1~3个C1~C2-烷基、C1~C2-烷氧基、氟、氯、溴、硝基或氨基,
以及它们的可用作药物的水合物以及酸加成盐。
4.权利要求1的通式(Ⅰ)化合物,其中
R1代表任选支链的C1~C6-烷基或C4~C6-环烷基,
R2独立于R3地代表氢、C1~C2-烷基、C1~C2-烷氧基、氟、氯或溴,
R3代表氢、C1~C2-烷基、氟或氯,和
R4代表任选支链的C1~C4-烷基、C4~C6-环烷基;苯基,其上任选地取代上1或2个C1~C2-烷基、C1~C2-烷氧基、氟、氯、硝基或氨基;或者代表苄基,其上任选地取代上1或2个C1~C2-烷基、C1~C2-烷氧基、氟、氯、硝基或氨基,
以及它们的可用作药物的水合物以及酸加成盐。
5.含权利要求1的通式(Ⅰ)化合物的药物。
6.权利要求1的通式(Ⅰ)化合物在制药中的应用。
7.权利要求1的通式(Ⅰ)化合物在抗菌组合物中的应用。
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DE19816780.6 | 1998-04-16 | ||
DE19816780A DE19816780A1 (de) | 1998-04-16 | 1998-04-16 | Substituierte 2-Oxo-alkansäure-[2-(indol-3-yl)-ethyl]amide |
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CN1297437A true CN1297437A (zh) | 2001-05-30 |
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CN99805078A Pending CN1297437A (zh) | 1998-04-16 | 1999-04-03 | 取代的n-[2-(吲哚-3-基)-乙基]-2-氧代-链烷酰胺 |
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US (1) | US6255335B1 (zh) |
EP (1) | EP1071664A1 (zh) |
JP (1) | JP2002512226A (zh) |
KR (1) | KR20010052236A (zh) |
CN (1) | CN1297437A (zh) |
AU (1) | AU752273B2 (zh) |
BR (1) | BR9909692A (zh) |
CA (1) | CA2328875A1 (zh) |
DE (1) | DE19816780A1 (zh) |
HU (1) | HUP0102099A3 (zh) |
WO (1) | WO1999054301A1 (zh) |
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SE0102764D0 (sv) * | 2001-08-17 | 2001-08-17 | Astrazeneca Ab | Compounds |
GB0226930D0 (en) | 2002-11-19 | 2002-12-24 | Astrazeneca Ab | Chemical compounds |
KR20070007103A (ko) * | 2004-02-18 | 2007-01-12 | 아스트라제네카 아베 | 벤즈아미드 유도체 및 이의 글루코키나아제 활성화제로서의용도 |
JP2007523905A (ja) * | 2004-02-18 | 2007-08-23 | アストラゼネカ アクチボラグ | 化合物 |
TW200600086A (en) | 2004-06-05 | 2006-01-01 | Astrazeneca Ab | Chemical compound |
CA2581619A1 (en) * | 2004-10-16 | 2006-04-20 | Astrazeneca Ab | Process for making phenoxy benzamide compounds |
JP2008542247A (ja) * | 2005-05-24 | 2008-11-27 | アストラゼネカ アクチボラグ | グルコキナーゼモジュレーターとしての2−フェニル置換イミダゾール[4,5b]ピリジン/ピラジンおよびプリン誘導体 |
TW200714597A (en) * | 2005-05-27 | 2007-04-16 | Astrazeneca Ab | Chemical compounds |
US20080234273A1 (en) * | 2005-07-09 | 2008-09-25 | Mckerrecher Darren | Heteroaryl Benzamide Derivatives for Use as Glk Activators in the Treatment of Diabetes |
JP4651714B2 (ja) * | 2005-07-09 | 2011-03-16 | アストラゼネカ アクチボラグ | 糖尿病の治療においてglk活性化剤として使用するためのヘテロアリールベンズアミド誘導体 |
JP2009500442A (ja) * | 2005-07-09 | 2009-01-08 | アストラゼネカ アクチボラグ | 2型糖尿病を処置するためのグルコキナーゼのモジュレーターとしての2−ヘテロシクリルオキシベンゾイルアミノヘテロシクリル化合物 |
US9202182B2 (en) * | 2005-08-11 | 2015-12-01 | International Business Machines Corporation | Method and system for analyzing business architecture |
TW200738621A (en) * | 2005-11-28 | 2007-10-16 | Astrazeneca Ab | Chemical process |
TW200825063A (en) * | 2006-10-23 | 2008-06-16 | Astrazeneca Ab | Chemical compounds |
TW200825060A (en) * | 2006-10-26 | 2008-06-16 | Astrazeneca Ab | Chemical compounds |
UY30822A1 (es) * | 2006-12-21 | 2008-07-31 | Astrazeneca Ab | Fnueva forma cristalina de 3-{[5-azetidin-1-ylcabonyl)pyrazin-2-yl]oxy}-5-[1-methylethyloxy]-n-1h-pyrazol-3-ylbenzamida, composiciones conteniéndola, procesos de preparacion y aplicaciones |
BRPI0917589A2 (pt) | 2008-08-04 | 2015-11-17 | Astrazeneca Ab | composto, composição farmacêutica, uso de um composto, método para tratar doenças, processo, combinação farmacêutica, e, reação de metiloxirano-2-carboxilato (ix) com um álcool roh |
GB0902406D0 (en) * | 2009-02-13 | 2009-04-01 | Astrazeneca Ab | Crystalline polymorphic form |
GB0902434D0 (en) * | 2009-02-13 | 2009-04-01 | Astrazeneca Ab | Chemical process |
WO2010116176A1 (en) * | 2009-04-09 | 2010-10-14 | Astrazeneca Ab | Pyrazolo [4, 5-e] pyrimidine derivative and its use to treat diabetes and obesity |
WO2010116177A1 (en) | 2009-04-09 | 2010-10-14 | Astrazeneca Ab | A pyrazolo [4,5-e] pyrimidine derivative and its use to treat diabetes and obesity |
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US3217011A (en) | 1965-05-07 | 1965-11-09 | Sterling Drug Inc | 1-(indolyglyoxalyl)-piperidines |
US5569668A (en) | 1995-03-29 | 1996-10-29 | Webster; John M. | Indole derivatives with antibacterial and antimycotic properties |
-
1998
- 1998-04-16 DE DE19816780A patent/DE19816780A1/de not_active Withdrawn
-
1999
- 1999-03-03 US US09/673,155 patent/US6255335B1/en not_active Expired - Fee Related
- 1999-04-03 WO PCT/EP1999/002302 patent/WO1999054301A1/de not_active Application Discontinuation
- 1999-04-03 CN CN99805078A patent/CN1297437A/zh active Pending
- 1999-04-03 HU HU0102099A patent/HUP0102099A3/hu unknown
- 1999-04-03 KR KR1020007011057A patent/KR20010052236A/ko not_active Application Discontinuation
- 1999-04-03 JP JP2000544642A patent/JP2002512226A/ja active Pending
- 1999-04-03 CA CA002328875A patent/CA2328875A1/en not_active Abandoned
- 1999-04-03 EP EP99917958A patent/EP1071664A1/de not_active Withdrawn
- 1999-04-03 BR BR9909692-7A patent/BR9909692A/pt not_active IP Right Cessation
- 1999-04-03 AU AU36050/99A patent/AU752273B2/en not_active Ceased
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EP1071664A1 (de) | 2001-01-31 |
JP2002512226A (ja) | 2002-04-23 |
WO1999054301A1 (de) | 1999-10-28 |
AU752273B2 (en) | 2002-09-12 |
HUP0102099A3 (en) | 2001-12-28 |
US6255335B1 (en) | 2001-07-03 |
CA2328875A1 (en) | 1999-10-28 |
BR9909692A (pt) | 2000-12-19 |
DE19816780A1 (de) | 1999-10-21 |
AU3605099A (en) | 1999-11-08 |
HUP0102099A2 (hu) | 2001-11-28 |
KR20010052236A (ko) | 2001-06-25 |
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