CN1084736C - 取代的杂环羧酰胺酯,它们的制备及它们作为药物的用途 - Google Patents
取代的杂环羧酰胺酯,它们的制备及它们作为药物的用途 Download PDFInfo
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- CN1084736C CN1084736C CN94117622A CN94117622A CN1084736C CN 1084736 C CN1084736 C CN 1084736C CN 94117622 A CN94117622 A CN 94117622A CN 94117622 A CN94117622 A CN 94117622A CN 1084736 C CN1084736 C CN 1084736C
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- Prior art keywords
- alkyl
- radical
- carboxylic acid
- alkoxy
- amide
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000003814 drug Substances 0.000 title claims abstract description 15
- -1 heterocyclic carboxamide esters Chemical class 0.000 title claims description 427
- 150000001875 compounds Chemical class 0.000 claims abstract description 118
- 238000000034 method Methods 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 92
- 150000001408 amides Chemical class 0.000 claims description 87
- 229910052757 nitrogen Inorganic materials 0.000 claims description 59
- 239000001257 hydrogen Substances 0.000 claims description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 33
- MWHFMAMJIYHCLW-UHFFFAOYSA-N 3-phenylmethoxypyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=C1OCC1=CC=CC=C1 MWHFMAMJIYHCLW-UHFFFAOYSA-N 0.000 claims description 32
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical class OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 31
- 229910052760 oxygen Inorganic materials 0.000 claims description 29
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 25
- 239000000460 chlorine Substances 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 21
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical group 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 125000001153 fluoro group Chemical group F* 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000001931 aliphatic group Chemical group 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 229910052727 yttrium Inorganic materials 0.000 claims description 9
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000769 L-threonyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](O[H])(C([H])([H])[H])[H] 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 230000003176 fibrotic effect Effects 0.000 claims description 7
- 150000004702 methyl esters Chemical class 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 230000032050 esterification Effects 0.000 claims description 5
- 238000005886 esterification reaction Methods 0.000 claims description 5
- 125000004344 phenylpropyl group Chemical group 0.000 claims description 5
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 230000002440 hepatic effect Effects 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 3
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 3
- 238000007098 aminolysis reaction Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 13
- 125000003302 alkenyloxy group Chemical group 0.000 claims 4
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 1
- 150000003948 formamides Chemical class 0.000 claims 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
- 102000004079 Prolyl Hydroxylases Human genes 0.000 abstract description 13
- 108010043005 Prolyl Hydroxylases Proteins 0.000 abstract description 13
- 239000003112 inhibitor Substances 0.000 abstract description 7
- 230000036570 collagen biosynthesis Effects 0.000 abstract description 6
- 150000002148 esters Chemical class 0.000 abstract description 6
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 239000000651 prodrug Substances 0.000 abstract description 2
- 229940002612 prodrug Drugs 0.000 abstract description 2
- 150000003254 radicals Chemical class 0.000 description 316
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 73
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 239000000203 mixture Substances 0.000 description 60
- 239000000047 product Substances 0.000 description 58
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 49
- 239000000243 solution Substances 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 150000002431 hydrogen Chemical class 0.000 description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 25
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- 229910052717 sulfur Inorganic materials 0.000 description 21
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 20
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- GBCAVSYHPPARHX-UHFFFAOYSA-M n'-cyclohexyl-n-[2-(4-methylmorpholin-4-ium-4-yl)ethyl]methanediimine;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.C1CCCCC1N=C=NCC[N+]1(C)CCOCC1 GBCAVSYHPPARHX-UHFFFAOYSA-M 0.000 description 16
- 102000008186 Collagen Human genes 0.000 description 15
- 108010035532 Collagen Proteins 0.000 description 15
- 229920001436 collagen Polymers 0.000 description 15
- 238000001816 cooling Methods 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 14
- 125000003396 thiol group Chemical group [H]S* 0.000 description 14
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 13
- BRARRAHGNDUELT-UHFFFAOYSA-N 3-hydroxypicolinic acid Chemical compound OC(=O)C1=NC=CC=C1O BRARRAHGNDUELT-UHFFFAOYSA-N 0.000 description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 150000005690 diesters Chemical class 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 229960002429 proline Drugs 0.000 description 9
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 8
- 125000005116 aryl carbamoyl group Chemical group 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 210000004185 liver Anatomy 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000004471 Glycine Substances 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- 235000008206 alpha-amino acids Nutrition 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical class ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical class ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- MTLWOFJXBWULJS-UHFFFAOYSA-N 5-methoxy-6-methoxycarbonylpyridine-3-carboxylic acid Chemical compound COC(=O)C1=NC=C(C(O)=O)C=C1OC MTLWOFJXBWULJS-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
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- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 description 5
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 229960002591 hydroxyproline Drugs 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 238000010626 work up procedure Methods 0.000 description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 4
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N 1,3-di(propan-2-yl)urea Chemical compound CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- NGDNVOAEIVQRFH-UHFFFAOYSA-N 2-nonanol Chemical compound CCCCCCCC(C)O NGDNVOAEIVQRFH-UHFFFAOYSA-N 0.000 description 4
- MZTVBYJTDVINFE-UHFFFAOYSA-N 3-methoxypyridine-2,5-dicarboxylic acid Chemical compound COC1=CC(C(O)=O)=CN=C1C(O)=O MZTVBYJTDVINFE-UHFFFAOYSA-N 0.000 description 4
- RJXVAGCQRMBMCI-UHFFFAOYSA-N 3-methoxypyridine-2-carboxylic acid Chemical compound COC1=CC=CN=C1C(O)=O RJXVAGCQRMBMCI-UHFFFAOYSA-N 0.000 description 4
- TWXMQDRFBLSXFN-UHFFFAOYSA-N 4-chloro-3-methoxy-2-methyl-1-oxidopyridin-1-ium Chemical compound COC1=C(C)[N+]([O-])=CC=C1Cl TWXMQDRFBLSXFN-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 150000008575 L-amino acids Chemical class 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
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 4
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 4
- 125000004467 aryl imino group Chemical group 0.000 description 4
- 150000005840 aryl radicals Chemical class 0.000 description 4
- ONDMKQWGMAVUNZ-UHFFFAOYSA-N butyl 2-aminoacetate Chemical compound CCCCOC(=O)CN ONDMKQWGMAVUNZ-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- LNRLFKGMWKRKEJ-UHFFFAOYSA-N hexyl 2-aminoacetate Chemical compound CCCCCCOC(=O)CN LNRLFKGMWKRKEJ-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000002198 insoluble material Substances 0.000 description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000012286 potassium permanganate Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000005245 sintering Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 3
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 3
- NKAJKXQJZPJBFW-UHFFFAOYSA-N 3-[(4-fluorophenyl)methoxy]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=C1OCC1=CC=C(F)C=C1 NKAJKXQJZPJBFW-UHFFFAOYSA-N 0.000 description 3
- HRIXILRILGXVGH-UHFFFAOYSA-N 4-chloro-3-methoxypyridine-2-carboxylic acid Chemical compound COC1=C(Cl)C=CN=C1C(O)=O HRIXILRILGXVGH-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- NFWKVWVWBFBAOV-UHFFFAOYSA-N Dehydroabietic acid Natural products OC(=O)C1(C)CCCC2(C)C3=CC=C(C(C)C)C=C3CCC21 NFWKVWVWBFBAOV-UHFFFAOYSA-N 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000005277 alkyl imino group Chemical group 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000003435 aroyl group Chemical group 0.000 description 3
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 3
- 125000005199 aryl carbonyloxy group Chemical group 0.000 description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229950005499 carbon tetrachloride Drugs 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
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- KIWIECPQILTZMO-UHFFFAOYSA-N pentyl 2-[(3-phenylmethoxypyridine-2-carbonyl)amino]acetate Chemical compound CCCCCOC(=O)CNC(=O)C1=NC=CC=C1OCC1=CC=CC=C1 KIWIECPQILTZMO-UHFFFAOYSA-N 0.000 description 1
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- SATVIFGJTRRDQU-UHFFFAOYSA-N potassium hypochlorite Chemical compound [K+].Cl[O-] SATVIFGJTRRDQU-UHFFFAOYSA-N 0.000 description 1
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- SINQCIBMYNXTGS-UHFFFAOYSA-N propan-2-yl 2-[(3-methoxypyridine-2-carbonyl)amino]acetate Chemical compound COC1=CC=CN=C1C(=O)NCC(=O)OC(C)C SINQCIBMYNXTGS-UHFFFAOYSA-N 0.000 description 1
- NKXINMANTKMNCT-UHFFFAOYSA-N propan-2-yl 2-[(3-phenylmethoxypyridine-2-carbonyl)amino]acetate Chemical compound CC(C)OC(=O)CNC(=O)C1=NC=CC=C1OCC1=CC=CC=C1 NKXINMANTKMNCT-UHFFFAOYSA-N 0.000 description 1
- SLZJZJGPZQUKMO-UHFFFAOYSA-N propyl 2-[(3-methoxypyridine-2-carbonyl)amino]acetate Chemical compound CCCOC(=O)CNC(=O)C1=NC=CC=C1OC SLZJZJGPZQUKMO-UHFFFAOYSA-N 0.000 description 1
- KLNCQAUZLBLCFM-UHFFFAOYSA-N propyl 6-[(2-ethoxy-2-oxoethyl)carbamoyl]-5-methoxypyridine-3-carboxylate Chemical compound CCCOC(=O)C1=CN=C(C(=O)NCC(=O)OCC)C(OC)=C1 KLNCQAUZLBLCFM-UHFFFAOYSA-N 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000012262 resinous product Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- FDCZTCORTKPSAO-UHFFFAOYSA-N sodium;heptan-4-olate Chemical compound [Na+].CCCC([O-])CCC FDCZTCORTKPSAO-UHFFFAOYSA-N 0.000 description 1
- GRONZTPUWOOUFQ-UHFFFAOYSA-M sodium;methanol;hydroxide Chemical compound [OH-].[Na+].OC GRONZTPUWOOUFQ-UHFFFAOYSA-M 0.000 description 1
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- 210000004500 stellate cell Anatomy 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- OSWULUXZFOQIRU-UHFFFAOYSA-N tert-butyl 2-aminoacetate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)CN OSWULUXZFOQIRU-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
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- 239000003053 toxin Substances 0.000 description 1
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- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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- Organic Chemistry (AREA)
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- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Steroid Compounds (AREA)
- Quinoline Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及式I的化合物,涉及其制备方法及其作为药物的用途。这些化合物特别用作抑制胶原生物合成的脯氨酰羟化酯抑制剂的酯前药及纤维化抑制剂。
Description
本发明涉及取代的杂环羧酰胺酯,它们的制备,它们用于抑制胶原蛋白生物合成的用途及它们用作治疗纤维化疾病的药物。
抑制脯氨酸羟基化酶和赖氨酸羟基化酶的化合物通过其对胶原蛋白专一的羟基化反应的影响可选择性地抑制胶原蛋白的生物合成。在这些反应过程中,蛋白质结合的脯氨酸或赖氨酸可分别被脯氨酸羟基化酶或赖氨酸羟基化酶羟基化。如果该反应被抑制剂阻止的话,则会产生无功能的、亚羟基化的胶原蛋白分子,该分子仅有很少量能被细胞分泌到细胞外空间。进一步讲,该亚羟基化的胶原蛋白不能被加入到胶原蛋白基质中并且很容易被蛋白分解而降解。这些作用会导致细胞外寄存的胶原蛋白总量的减少。
因此脯氨酰羟基化酶抑制剂是适用于治疗这些疾病的物质,在这些疾病中胶原蛋白的寄存对于临床指标起着主要作用。这些疾病主要包括:
肺、肝和皮肤的纤维化(烧伤受伤和外科手术后的的硬皮病和结瘢)及动脉粥样硬化。
已知脯氨酸羟基化酶可被吡啶-2,4-二羧酸和吡啶2,5-二羧酸有效地抑制(K.Mazamaa等人,Eur,J.Biochem.138(1984)230-245)。但这些化合物作为抑制剂仅在细胞培养皿中以非常高的浓度才有活性(Tschank,G.等人,Biochem.J.238(1987)625-633)。
吡啶-2,4(5)-二羧酸酯的前药也是已知的并记载于相对老的德国申请P4233124.2,P4238506.7和P4209424,0。
作为脯氨酰-4-羟基化酶抑制剂的N-草酰甘氨酸记载于J.Med,Chem,1992,35,2652-2685(Cunliffe等人)和EP-A-0457 163。
羟基异喹啉羧酸甘氨酰胺和羟基肉啉羧酸甘氨酰胺记载于Biochem,Soc,Trans,1991,19,812-815(Franklin等人)中。3-苄氧吡啶-2-羧酸(苏氨酰甲基酯)酰胺,3-苄氧吡啶-2-羧酸(L-苏氨酰(Fmoc-phg)叔丁酯)酰胺,3-苄氧吡啶-2-羧酸(L-苏氨酰叔丁酯)酰胺和3-苄氧吡啶-2-羧酸(D-异苏氨酰甲酯)酰胺记载于Liebigs Ann.Chem,1986,1-20,(Kesster等人)中。
此外,3-苄氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺述于J.Org.Chem,31,636-638(1966)。
现已出人意料地发现在酰胺官能团邻位有醚取代基,硫醚取代基或氨基取代基的式I杂环羧酰胺对体内胶原蛋白的生物合成有强烈的抑制作用。
这些化合物是式I中B为羧基的式I羧酸的制药。
式I化合物在生命有机体(体内)和细胞培养皿中(体外)中裂开从而形成β为羧基的式I化合物或其盐。
一旦式I化合物被施用,由于在体内或体外会形成β为羧基的式I化合物或其盐,则在体内或体外就会看到它们对胶原蛋白生物合成的抑制作用。因此,这些化合物能抑制脯氨酰-4-羟基化酶从而抑制胶原蛋白的生物合成。
其中
Q为O,S,N R′或一个键
X为O或S,
Y为C-R3,或如R1和R2形成一个环,则Y为N或CR3,
m为0或1
A为C1-4亚烷基,其可被一或两个选自下面的基团取代:卤素、氰基,硝基,三氟甲基,C1-6烷基,C1-6羟烷基,C1-6烷氧基,-O-〔CH2〕x-CfH(2f+1-g)Halg,优选C1-8氟代烷氧基,C1-8氟代链烯氧基,C1-8氟代炔氧基,-OCF2Cl或-O-CF2-CHFCl,C1-6,C1-6烷巯基,C1-6烷基亚磺酰基,C1-6烷基磺酰基,C1-6烷羰基,C1-6烷氧羰基,氨基甲酰基,N-C1-4烷基氨基甲酰基,N,N-二(C1-4)烷基氨基甲酰基,C1-6烷羰氧基,C3-8环烷基,苯基,苄基,苯氧基,苄氧基,苯胺基,N-甲基苯胺基,苯基巯基,苯磺酰苯,苯亚磺酰基,氨磺酰基,N-C1-4烷基氨磺酰基或N,N-二C1-4烷基氨磺酰基,或其被取代的C6-C12芳氧基,C7-C11芳烷氧基,C6-C12芳基或C7-C11芳烷基取代,其中芳基被1,2,3,4或5个相同或不同的下面取代基取代:卤素,氰基,硝基,三氟甲基,C1-6烷基,C1-6烷氧基,-O-〔CH2〕x-CfH(2f+1-g)Halg,-OCF2Cl-CHFCl,C1-6烷基巯基,C1-6烷基亚磺酰基,C1-6烷基磺酰基,C1-6烷基羰基,C1-6烷氧羰基,氨基甲酰基,N-C1-4烷基氨基甲酰基,N,N-二C1-4烷基氨基甲酰基,C1-6烷基羰氧基,C3-8环烷基,氨磺酰基,N-C1-4烷基氨磺酰基或N,N-二C1-4烷基氨磺酰基,或其可被α-氨基酸的α-C原子上取代基R5取代,α-氨基酸可是天然L-氨基酸和它们的D-异构体;
B为-CO2,其中G为醇GOH基;
R1,R2和R3相同或不同,且为氢,羟基,卤素,氰基,三氟甲基,硝基,羧基,C1-20烷基,C3-8环烷基,C3-8环烷基-C1-12烷氧基,C3-8环烷氧基,C3-8环烷基-C1-12烷氧基,C3-8环烷氧基-C1-12烷氧基,C3-8环烷氧基-C1-12烷基,C3-8环烷基-C1-8烷基-C1-6烷氧基,C3-8环烷基-C1-8烷氧基-C1-6烷基,C3-8环烷氧基-C1-8烷氧基-C1-6烷基,C3-8环烷氧基-C1-8烷氧基-C1-8烷氧基,C6-12芳基,C7-16芳烷基,C7-12芳链烯基,C7-16芳炔基,C2-20链烯基,C2-20炔基,C1-20烷氧基,C2-20链烯氧基,C2-20炔氧基基,视黄氧氧,C1-12烷氧基-C1-12烷基,C1-12烷氧基-C1-12烷氧基,C1-12烷氧基0-C1-8烷氧基-C1-8烷基,C6-12芳氧基,C7-16芳烷氧基,C6-12芳氧基-C1-6烷氧基,C7-16芳烷氧基-C1-6烷氧基,C1-16羟烷基,C6-16芳氧基-C1-8烷基,C7-16芳烷氧基-C1-8烷基,C6-12芳氧基-C1-8烷氧基-C1-6烷基,C7-12芳烷氧基-C1-8烷氧基-C1-6烷基,C2-20链烯氧基-C1-6烷基,C2-20炔氧基-C1-6烷基,视黄氧基-C1-6烷基,-O-〔CH2〕x-CfH(2f+1-g)Fg,-OCF2Cl,OCF2-CHFCl,C1-20烷羰基,C3-8环烷基羰基,C6-12芳羰基,C7-16芳烷基羰基,肉啉酰基,C2-20链烯羰基,C2-20炔羰基,C1-20烷氧羰基,C1-12烷氧基-C1-12烷氧羰基,C6-12芳氧羰基,C7-16芳烷氧羰基,C3-8环烷氧羰基,C2-20链烯氧羰基,视黄氧羰基,C2-20炔氧羰基,C6-12芳氧基C1-6烷氧羰基,C7-16芳氧基C1-6烷氧羰基,C3-8环烷基-C1-6烷氧羰基,C3-8环烷氧基C1-6烷氧羰基,C1-2烷基羰氧基,C3-8环烷基羰氧基,C6-12芳羰氧基,C7-16芳烷基羰氧基,肉桂酰氧基,C2-12链烯羰氧基,C2-12炔羰氧基,C1-12烷氧羰氧基,C1-12烷氧基C1-12烷氧羰氧基,C6-12芳氧羰氧基,C7-16芳烷氧羰氧基,C3-8环烷氧羰氧基,C2-12链烯氧羰氧基,C2-12炔氧羰氧基,氨基甲酰基,N-C1-12烷基氨基甲酰基,N,N-二C1-12烷基氨基甲酰基,N-C3-8环烷基氨基甲酰基,N,N-二C3-8环烷基氨基甲酰基,N-C1-10烷基-N-C3-8环烷基氨基甲酰基,N-C3-8环烷基-C1-6烷基氨基甲酰基,N-C1-6烷基-N-C3-8环烷基-C1-6烷基氨基甲酰基,N-(+)-脱氢-枞酸基氨基甲酰基,N-C1-6烷基-N-(+)-脱氢枞酸氨基甲酰基,N-C6-12芳基氨基甲酰基,N-C7-16芳烷基氨基甲酰基,N-C1-10烷基-N-C6-16芳基氨基甲酰基,N-C1-10烷基-N-C7-16芳烷基氨基甲酰基,N-C1-18烷氧基-C1-10烷基氨基甲酰基,N-C6-16芳氧基-C1-10烷基氨基甲酰基,N-C7-16芳烷氧基C1-10烷基氨基甲酰基,N-C1-10烷基-N-C1-10烷氧基-C1-10烷基氨基甲酰基,N-C1-10烷基-N-(C6-16芳氧基-C1-10烷基)氨甲基酰基,N-C1-10烷基-N-(C7-12芳氧基-C1-10烷基)氨基甲酰基,或CON(CH2)h,其中CH2基团可被O,S,N-C1-8烷基亚氨基,N-C3-8环烷基亚氨基,N-C3-8环烷基-C1-4烷基亚氨基,N-C6-12芳亚氨基,N-C6-7芳烷亚氨基或N-C1-4烷氧基-C1-6烷基亚氨基取代,h为3-7,式II的氨基甲酰基
其中
Rx为α-氨基酸(其为L和D-氨基酸)的取代基,S为1,3,4或5,和T为OH,OR或NR*R**,其中R*,R**和R***可相同或不同,且为氢,C6-12芳基,C7-11芳烷基,C1-8烷基,C3-8环烷基,(+)脱氢枞酸基,C1-8烷氧基-C1-8烷基,C7-12芳烷氧-C1-8烷基,C6-12芳氧基-C1-8烷基,C1-10烷酰基,任意取代的C7-16芳烷酰基或任意取代的C6-12芳酰基,或R*和R**一起为-〔CH2〕h,其中CH2基团可被O,S,SO,SO2,N-酰氨基,N-C1-10烷氧羰基亚氨基,N-C1-8烷基亚氨基,N-C3-8环烷基亚氨基,N-C3-8环烷基-C1-4烷基亚氨基,N-C6-12芳基亚氨基,N-C7-16芳烷基亚氨基或N-C1-4烷氧基-C1-6烷基亚氨基取代,h为3-7。
氨基甲酰氧基,N-C1-12烷基氨基甲酰氧基,N,N-二C1-12烷基氨基甲酰氧基,N-C3-8环烷氨基甲酰氧基,N-C6-12芳基氨基甲酰氧基,N-C7-16芳烷基氨基甲酰氧基,N-C1-10烷基-N-C6-12芳基氨基甲酰氧基,N-C1-10烷基-N-C7-16芳烷基氨基甲酰氧基,N-C1-10烷基氨基甲酰氧基,N-C6-12芳氧基-C1-10烷基-氨基甲酰氧基,N-C7-16芳烷氧基-C1-10烷基-氨基甲酰氧基,N-C1-10烷基-N-C-1-10烷氧基-C1-10烷基-氨基甲酰氧基,N-C1-10烷基-N-C6-12-芳氧基-C1-10烷基氨基甲酰氧基,N-C1-10烷基-N-C7-16-芳烷氧基-C1-10烷基-氨基甲酰氧基,氨基,C1-12烷氨基,二C1-12烷氨基,C3-8环烷氨基,C3-12-链烯氨基,C3-12炔氨基,N-C6-12芳氨基,N-C7-11芳烷氨基,N-烷基-芳烷氨基,N-烷基-芳氨基,C1-12烷氧氨基,C1-12-烷氧-N-C1-10烷氨基C1-12烷酰氨基,C3-8环烷酰氨基,C6-12芳酰氨基-C1-8烷基,C7-16芳烷酰氨基C1-8烷基,氨基-C1-8烷基,N-C1-10烷氨基-C1-10烷基,N,N-二C1-10烷氨基-C1-10烷基,C3-8环烷氨基-C1-10烷基,C1-20烷基硫基,C1-20烷基亚磺酰基,C1-20烷基磺酰基,C-6-12芳基巯基,C6-12芳基亚磺酰基,C6-12芳基磺酰基,C7-16芳烷基巯基,C7-16芳烷基亚磺酰基,C-7-16芳烷基磺酰基,C1-12烷基巯基-C1-6烷基,C1-12烷基亚磺酰基-C1-6烷基,C1-12烷基磺酰基-C1-6烷基,C6-12芳基巯基-C1-6烷基,C6-12芳基亚磺酰基-C1-6烷基,C6-12芳基磺酰基-C1-6烷基,C7-16芳烷基巯基-C1-6烷基,C7-16芳烷基亚磺酰基-C1-6烷基,C7-16芳烷基磺酰基C1-6烷基,氨磺酰基,N-C1-10烷基氨磺酰基,N,N-二C1-10烷基氨磺酰基,C3-8环烷基氨磺酰基,N-C6-12芳基氨磺酰基,N-C7-16芳烷基氨磺酰基,N-C1-10烷基-N-C6-12-芳基氨磺酰基,N-C1-10烷基-N-C7-16芳烷基氨磺酰基,C1-10烷基亚磺酰氨基,N-C1-10烷基-C1-10烷基亚磺酰氨基,C7-16芳烷基亚磺酰氨基,或N-C1-10烷基-C7-16芳烷基亚磺酰氨基,其中含芳基的这些基团可在芳基上被1-5个选自下面的相同或不同的基团取代:羟基,卤素,氰基,三氟甲基,硝基,羧基,C1-6烷基,C3-8环烷基,C3-8环烷基-C1-12烷基,C3-8环烷氧基,C3-8环烷基-C1-12烷氧基,C3-8环烷氧基-C1-12烷基,C3-8环烷氧基-C1-12环氧基,C3-8环烷基-C1-8烷基-C1-6烷氧基,C3-8环烷基-C1-8烷氧基-C1-6烷基,C3-8环烷氧基-C1-8烷氧基-C1-6烷基,C-3-8环烷氧基-C1-8烷氧基-C1-8烷氧基,C6-12芳基,C7-16芳烷基,C2-16链烯基,C2-12炔基,C1-16烷氧基,C2-16链烯氧基,C1-12烷氧基-C1-12烷基,C1-12烷氧基-C1-12烷氧基,C1-12烷氧基-C1-8烷氧基-C1-8烷基,C6-12芳氧基,C7-16芳烷氧基,C6-12芳氧基-C1-6烷氧基,C7-16芳烷氧基-C1-6烷氧基,C1-8羟烷基,C6-16芳氧基-C1-8烷基,C7-16芳烷氧基-C1-8烷基,C6-12芳氧基-C1-8烷氧基-C1-6烷基,C7-12芳烷氧基-C1-8烷氧基-C1-6烷基,-O-〔CH2〕x-CfH(2f+1-g)Fg,-OCF2Cl,OCF2-CHFCl,C1-12烷羰基,C3-8环烷基羰基,C6-12芳羰基,C7-16芳烷基羰基,C1-12烷氧羰基,C1-12烷氧基-C1-12烷氧羰基,C6-12芳氧羰基,C7-16芳烷氧羰基,C3-8环烷氧羰基,C2-12链烯氧羰基,C2-12炔氧羰基,C6-12芳烷氧C1-6烷氧羰基,C7-16芳氧C1-6烷氧羰基,C3-8环烷基-C1-6烷氧羰基,C3-8环烷氧基C1-6烷氧羰基C1-12烷基羰氧基,C3-8环烷基羰氧基,C6-12芳羰氧基,C7-16芳烷基羰氧基,肉桂酰氧基,C2-12链烯羰氧基,C2-12炔羰氧基,C1-12烷氧羰氧基,C1-12烷氧基C1-12烷氧羰氧基,C6-12芳氧羰氧基,C7-16芳烷氧羰氧基,C3-8环烷氧羰氧基,C2-12链烯氧羰氧基,C2-12炔氧羰氧基,氨基甲酰基,N-C1-12烷基氨基甲酰基,N,N-二C1-12烷基氨基甲酰基,N-C3-8环烷基氨基甲酰基,N,N-二C3-8环烷基氨基甲酰基,N-C1-10烷基-N-C3-8环烷基氨基甲酰基,N-C3-8环烷基-C1-6烷基氨基甲酰基,N-C1-6烷基-N-C3-8环烷基-C1-6烷基氨基甲酰基,N-(+)-脱氢-枞酸基氨基甲酰基,N-C1-6烷基-N-(+)-脱氢枞酸氨基甲酰基,N-C6-12芳基氨基甲酰基,N-C7-16芳烷基氨基甲酰基,N-C1-10烷基-N-C6-16芳基氨基甲酰基,N-C1-10烷基-N-C7-16芳烷基氨基甲酰基,N-C1-6烷氧基-C1-10烷基氨基甲酰基,N-C6-16芳氧基-C1-10烷基氨基甲酰基,N-C7-16芳烷氧基C1-10烷基氨基甲酰基,N-C1-10烷基-N-C1-10烷氧基-C1-10烷基氨基甲酰基,N-C1-10烷基-N-(C6-12芳氧基-C1-10烷基)氨基甲酰基,N-C1-10烷基-N-(C7-16芳烷氧基-C1-10烷基)氨基甲酰基,或CON(CH2)h,其中CH2基团可被O,S,N-C1-8烷基亚氨基,N-C3-8环烷基亚氨基,N-C3-8环烷基-C1-4烷基亚氨基,N-C8-12芳亚氨基,N-C7-16芳烷亚氨基或N-C1-4烷氧基-C1-6烷基亚氨基取代,h为3-7,氨基甲酰氧基,N-C1-12烷基氨基甲酰氧基,N-N,二C1-12烷基氨基甲酰氧基,N-C3-8环烷基氨基甲酰氧基,N-C6-16芳基氨基甲酰氧基,N-C7-16芳烷基氨基甲酰氧基,N-C1-10烷基-N-C6-12芳基氨基甲酰氧基,N-C1-10烷基-N-C7-16芳烷基氨基甲酰氧基,N-C1-10烷基氨基甲酰氧基,N-C6-12芳氧基-C1-10烷基-氨基甲酰氧基,N-C7-16芳烷氧基-C1-10烷氧基-氨基甲酰氧基,N-C1-10烷基-N-C1-10烷氧基-C1-10烷基-氨基甲酰氧基,N-C1-10烷基-N-C6-12-芳氧基-C1-10烷基氨基甲酰氧基,N-C1-10烷基-N-C7-16-芳烷氧基-C1-10烷基-氨基甲酰氧基,氨基,C1-12烷氨基,二C1-12烷氨基,C3-8环烷氨基,C3-12-链烯氨基,C3-12炔氨基,N-C6-12芳氨基,N-C7-11芳烷氨基,N-烷基-芳烷氨基,N-烷基-芳氨基,C1-12烷氧氨基,C1-12-烷氧-N-C1-10烷氧基,C1-12烷酰氨基,C3-8环烷酰氨基,C6-12芳酰氨基,C7-16芳烷酰氨基,C1-12烷酰基-N-C1-10烷氨基,C3-8环烷酰基-N-C1-10烷氨基,C6-12芳酰基-N-C1-10-烷氨基,C7-11芳烷酰基-N-C1-10烷氨基,C1-12烷酰氨基-C1-8烷基,C3-8环烷酰氨基-C1-8烷基,C6-12芳酰氨基-C1-8烷基,C7-16芳烷酰氨基-C1-8烷基,氨基-C1-8烷基,N-C1-10烷氨基-C1-10烷基,N,N-二C1-10烷氨基-C1-10烷基,C3-8环烷氨基-C1-10烷基,C1-12烷基巯基,C1-12烷基亚磺酰基,C1-12烷基磺酰基,C6-16芳基巯基,C6-16芳基亚磺酰基,C6-16芳基磺酰基,C7-16芳烷基巯基,C7-16芳烷基亚磺酰基或C7-16芳烷基磺酰基,R1和R2或R2和R3形成链〔CH2〕o,其中该链的一或两个CH2基团是饱和的或是带C=C双键不饱和的,且可被O,S,SO,SO2或NR′任意取代,O为3,4或5,且R′为氢,C6-12芳基,C1-8烷基,C1-8烷氧基-C1-8烷基,C7-12芳烷氧基-C1-8烷基,C6-12芳氧基-C1-8烷基,C1-10链烷酰基,任意取代的C7-16芳烷酰基或任意取代的芳酰基,其中R1和R2或R2和R3与吡啶或哒嗪一起优选形成5,6,7,8-四氢异喹啉环,5,6,7,8-四氢喹啉环或5,6,7,8-四氢肉啉环,或R1和R2或R2和R3形成5-或6-员芳香碳环或杂环,其中基团R1和R2或R2和R3与吡啶或哒嗪一起优选形成下面的任意取代的杂环系统:
噻吩并吡啶,
呋喃并吡啶,
吡啶并吡啶,
嘧啶并吡啶,
咪唑并吡啶,
噻唑并吡啶,
恶唑并吡啶,
喹啉,异喹啉和肉啉,
其中喹啉,异喹啉或肉啉优选符合式Ia,Ib和Ic
取代基R11-R22在每种情况下互相独立,且具有R1,R2和R3的定义,
如Q为一个键,则R4为卤素,腈或三氟甲基,或如Q为O,S或NR′,则R4为支链或直链C1-20烷基,式〔CH2〕x-CfH(2f+1-g)Fg的未取代饱和氟烷基,C6-16芳基,C7-16芳烷基,杂芳基或杂芳烷基,其中这些基团可被选自下面的一或多个基团取代:
羟基,卤素,氰基,三氟甲基,硝基,羧基,C1-12烷基,C3-8环烷基,C3-8环烷基-C1-12烷基,C3-8环烷氧基,C3-8环烷基-C1-12烷氧基,C3-8环烷氧基-C1-12烷基,C3-8环烷氧基-C1-12烷氧基,C3-8环烷基-C1-8烷基-C1-6烷氧基,C3-8环烷基-C1-8烷氧基-C1-6烷基,C3-8环烷氧基-C1-8烷氧基-C1-6烷基,C3-8环烷氧基-C1-8烷氧基-C1-8烷氧基,C6-12芳基,C7-16芳烷基,C2-12链烯基,C2-12炔基,C1-12烷氧基,C1-12烷氧基-C1-12烷基,C1-12烷氧基-C1-12烷氧基,C1-12烷氧基-C1-8烷氧基-C1-8烷基,C6-12芳氧基,C7-16芳烷氧基,C6-12芳氧基-C1-6烷氧基,C7-16芳烷氧基-C1-6烷氧基,C1-8羟烷基,C6-16芳氧基-C1-8烷基,C7-16芳烷氧基-C1-8烷基,C6-12芳氧基-C1-8烷氧基-C1-6烷基,C7-12芳烷氧基-C1-8烷氧基-C1-6烷基,-O-〔CH2〕x-CfH(2f+1-g)Fg,-OCF2Cl,OCF2-CHFCl,C1-20烷羰基,C3-8环烷基羰基,C6-12芳羰基,C7-16芳烷基羰基,肉桂酰基,C2-12链烯羰基,C2-12炔羰基,C1-12烷氧羰基,C1-12烷氧基-C1-12烷氧羰基,C6-12芳氧羰羰C7-16芳烷氧羰基,C3-8环烷氧羰基,C2-12链烯氧羰基,C2-12炔氧羰基,C6-12芳氧C1-6烷氧羰基,C7-16芳烷氧C1-6烷氧羰基,C3-8环烷基-C1-6烷氧羰基,C3-8环烷氧基C1-6烷氧羰基,C1-12烷基羰氧基,C3-8环烷基羰氧基,C6-12芳羰氧基,C7-16芳烷基羰氧基,肉桂酰氧基,C2-12链烯羰氧基,C2-12炔羰氧基,C1-12烷氧羰氧基,C1-12烷氧基C1-12烷氧羰氧基,C6-12芳氧羰氧基,C7-16芳烷氧羰氧基,C3-8环烷氧羰氧基,C2-12链烯氧羰氧基,C2-12炔氧羰氧基,氨基甲酰基,N-C1-12烷基氨基甲酰基,N,N-二C1-12烷基氨基甲酰基,N-C3-8环烷基氨基甲酰基,N,N-二C3-8环烷基氨基甲酰基,N-C1-10烷基-N-C3-8环烷基氨基甲酰基,N-C3-8环烷基-C1-6烷基氨基甲酰基,N-C1-6烷基-N-C3-8环烷基-C1-6烷基氨基甲酰基,N-(+)-脱氢-枞酸基氨基甲酰基,N-C1-6烷基-N-(+)脱氢枞酸氨基甲酰基,N-C6-12芳基氨基甲酰基,N-C7-16芳烷基氨基甲酰基,N-C1-10烷基-N-C6-16芳基氨基甲酰基,N-C1-10烷基-N-C7-16芳烷基氨基甲酰基,N-C1-10烷氧基-C1-10烷基氨基甲酰基,N-C6-16芳氧基-C1-10烷基氨基甲酰基,N-C7-16芳烷氧基C1-10烷基氨基甲酰基,N-C1-10烷基-N-C1-10烷氧基-C1-10烷基氨基甲酰基,N-C1-10烷基-N-(C6-12芳氧基-C1-10烷基)氨基甲酰基,N-C1-10烷基-N-(C7-16芳烷氧基-C1-10烷基)氨基甲酰基,CON(CH2)h,其中CH2基团可被O,S,N-C1-8烷基亚氨基,N-C3-8环烷基亚氨基,N-C3-8环烷基-C1-4烷基亚氨基,N-C6-12芳亚氨基,N-C7-16芳烷基亚氨基或N-C1-4烷氧基-C1-6烷基亚氨基取代,h为3-7,或被式II的氨基甲酰基取代
其中Rx为α-氨基酸(其为L和D-氨基酸)的取代基,S为1,2,3,4或5,和T为OH,OR或NR*R**,其中R*,R**和R***可相同或不同,且为氢,C6-12芳基,C7-11芳烷基,C1-8烷基,C3-8环烷基,(+)脱氢枞酸基,C1-8烷氧基-C1-8烷基,C7-12芳烷氧-C1-8烷基,C6-12芳氧基-C1-8烷基,C1-10烷酰基,任意取代的C7-16芳烷酰基或任意取代的C6-12芳酰基,或R*和R**一起为-〔CH2〕h,其中CH2基团可被O,S,SO,SO2,N-酰氨基,N-C1-10烷氧羰基亚氨基,N-C1-8烷基亚氨基,N-C3-8环烷基亚氨基,N-C3-8环烷基-C1-4烷基亚氨基,N-C6-12芳基亚氨基,N-C7-16芳烷基亚氨基或N-C1-4烷氧基-C1-6烷基亚氨基取代,h为3-7,或被下列基团取代:氨基甲酰氧基,N-C1-12烷基氨基甲酰氧基,N,N-二C1-12烷基氨基甲酰氧基,N-C3-8环烷基氨基甲酰氧基,N-C6-12芳基氨基甲酰氧基,N-C7-16芳烷基氨基甲酰氧基,N-C1-10烷基-N-C6-12芳基氨基甲酰氧基,N-C1-10烷基-N-C7-16芳烷基氨基甲酰氧基,N-C1-10烷基氨基甲酰氧基,N-C6-12芳氧基-C1-10烷基-氨基甲酰氧基,N-C7-16芳烷氧基-C1-10烷基-氨基甲酰氧基,N-C1-10烷基-N-C1-10烷氧基-C1-10烷基-氨基甲酰氧基,N-C1-10烷基-N-C6-12-芳氧基-C1-10烷基氨基甲酰氧基,N-C1-10烷基-N-C7-16-芳烷氧基-C1-10烷基-氨基甲酰氧基,氨基,C1-12烷氨基,二C1-12烷氨基,C3-8环烷氨基,C3-12-链烯氨基,C3-12炔氨基,N-C6-12芳氨基,N-C7-11芳烷氨基,N-烷基-芳烷氨基,N-烷基-芳氨基,C1-12烷氧氨基,C1-12-烷氧基-N-C1-10烷氨基,C1-12烷酰氨基,C3-8环烷酰氨基,C6-12芳酰氨基,C7-16芳烷酰氨基,C1-12烷酰基-N-C1-10烷氨基,C3-8环烷酰基-N-C1-10烷基氨基,C6-12芳酰基-N-C1-10-烷氨基,C7-11芳烷酰基-N-C1-10烷氨基,C1-12烷酰氨基-C1-8烷基,C3-8环烷酰氨基-C1-8烷基,C6-12芳酰氨基-C1-8烷基,C7-16芳烷酰氨基-C1-8烷基,氨基-C1-8烷基,N-C1-10烷氨基-C1-10烷基,N,N-二C1-10烷氨基-C1-10烷基,C3-8环烷氨基-C1-10烷基,C1-12烷基巯基,C1-12烷基亚磺酰基,C1-12烷基磺酰基,C6-12芳基巯基,C6-12芳基亚磺酰基,C6-12芳基磺酰基,C7-16芳烷基巯基,C7-16基烷基亚磺酰基,C7-16芳烷基磺酰基,氨磺酰基,N-C1-10烷基氨磺酰基,N,N-二C1-10烷基氨磺酰基,C3-8环烷基氨磺酰基,N-C6-12芳基氨磺酰基,N-C7-16芳烷基氨磺酰基,N-C1-10烷基-N-C6-12-芳基氨磺酰基,N-C1-10烷基-N-C7-16芳烷基氨磺酰基,C1-10烷基亚磺酰氨基,N-C1-10烷基-C1-10烷基亚磺酰氨基,C7-16芳烷基亚磺酰氨基,或N-C1-10烷基-C7-16芳烷基亚磺酰氨基,其中含芳基的这些基团可在芳基上被1-5个选自下面的相同或不同基团取代:羟基,卤素,氰基,三氟甲基,硝基,羧基,C1-12烷基,C3-8环烷基,C3-8环烷基-C1-12烷基,C3-8环烷氧基,C3-8环烷基-C1-12烷氧基,C3-8环烷氧基-C1-12烷基,C3-8环烷氧基-C1-12烷氧基,C3-8环烷基-C1-8烷基-C1-6烷氧基,C3-8环烷基-C1-8烷氧基-C1-6烷基,C3-8环烷氧基-C1-8烷氧基-C1-6烷基,C3-8环烷氧基-C1-8烷氧基-C1-8烷氧基,C6-12芳基,C7-16芳烷基,C2-12链烯基,C2-12炔基,C1-12烷氧基,C1-12烷氧基-C1-12烷基,C1-12烷氧基-C1-12烷氧基,C1-12烷氧基-C1-8烷氧基-C1-8烷基,C6-12芳氧基,C7-16芳烷氧基,C6-12芳氧基-C1-6烷氧基,C7-16芳烷氧基-C1-6烷氧基,C1-8羟烷基,C6-16芳氧基-C1-8烷基,C7-16芳烷氧基-C1-8烷基,C6-12芳氧基-C1-8烷氧基-C1-6烷基,C7-12芳烷氧基-C1-8烷氧基-C1-6烷基,-O-〔CH2〕x-CfH(2f+1-g)Fg,-OCF2Cl,OCF2-CHFCl,C1-12烷羰基,C3-8环烷基羰基,C6-12芳羰基,C7-16芳烷基羰基,C1-12烷氧羰基,C1-12烷氧基-C1-12烷氧羰基,C6-12芳氧羰基,C7-16芳烷氧羰基,C3-8环烷氧羰基,C2-12链烯氧羰基,C2-12炔氧羰基,C6-12芳氧C1-6烷氧羰基,C7-16芳烷氧C1-6烷氧羰基,C3-8环烷基-C1-6烷氧羰基,C3-8环烷氧基C1-6烷氧羰基,C1-12烷基羰氧基,C3-8环烷基羰氧基,C6-12芳羰氧基,C7-16芳烷基羰氧基,肉桂酰氧基,C2-12链烯羰氧基,C2-12炔羰氧基,C1-12烷氧羰氧基,C1-12烷氧基C1-12烷氧羰氧基,C6-12芳氧羰氧基,C7-16芳烷氧羰氧基,C3-8环烷氧羰氧基,C2-12链烯氧羰氧基,C2-12炔氧羰氧基,氨基甲酰基,N-C1-12烷基氨基甲酰基,N,N-二C1-12烷基氨基甲酰基,N-C3-8环烷基氨基甲酰基,N,N-二C3-8环烷基氨基甲酰基,N-C1-10烷基-N-C3-8环烷基氨基甲酰基,N-C3-8环烷基-C1-6烷基氨基甲酰基,N-C1-6烷基-N-C3-8环烷基-C1-6烷基氨基甲酰基,N-(+)-脱氢-枞酸基氨基甲酰基,N-C1-6烷基-N-(+)-脱氢枞酸氨基甲酰基,N-C6-12芳基氨基甲酰基,N-C7-16芳烷基氨基甲酰基,N-C1-10烷基-N-C7-16芳烷基氨基甲酰基,N-C1-10烷氧基-C1-10烷基氨基甲酰基,N-C6-16芳氧基-C1-10烷基氨基甲酰基,N-C7-16芳烷氧基C1-10烷基氨基甲酰基,N-C1-10烷基-N-C1-10烷氧基-C1-10烷基氨基甲酰基,N-C1-10烷基-N-(C6-12芳氧基-C1-10烷基)氨基甲酰基,N-C1-10烷基-N-(C7-16芳烷氧基-C1-10烷基)氨基甲酰基,或CON(CH2)h,其中CH2基团可被O,S,N-C1-18烷基亚氨基,N-C3-8环烷基亚氨基,N-C3-8环烷基-C1-4烷基亚氨基,N-C6-12芳亚氨基,N-C7-16芳烷亚氨基或N-C1-4烷氧基-C1-6烷基亚氨基取代,h为3-7,氨基甲酰氧基,N-C1-12烷基氨基甲酰氧基,N,N-二C1-12烷基氨基甲酰氧基,N-C3-8环烷基氨基甲酰氧基,N-C6-16芳基氨基甲酰氧基,N-C7-16芳烷基氨基甲酰氧基,N-C1-10烷基-N-C6-12芳基氨基甲酰氧基,N-C1-10烷基-N-C7-16芳烷基氨基甲酰氧基,N-C1-10烷基氨基甲酰氧基,N-C6-12芳氧基-C1-10烷基-氨基甲酰氧基,N-C7-16芳烷氧基-C1-10烷基-氨基甲酰氧基,N-C1-10烷基-N-C1-10烷氧基-C1-10烷基-氨基甲酰氧基,N-C1-10烷基-N-C6-12-芳氧基-C1-10烷基氨基甲酰氧基,N-C1-10烷基-N-C7-16-芳烷氧基-C1-10烷基-氨基甲酰氧基,氨基,C1-12烷氨基,二C1-12烷氨基,C3-8环烷氨基,C3-12-链烯氨基,C3-12炔氨基,N-C6-12芳氨基,N-C7-11芳烷氨基,N-烷基-芳烷氨基,N-烷基-芳氨基,C1-12烷氧氨基,C1-12烷氧-N-C1-10烷氨基,C1-12烷酰氨基,C3-8环烷酰氨基,C6-12芳酰氨基,C7-16芳烷酰氨基,C1-12烷酰基-N-C1-10烷氨基,C3-8环烷酰基-N-C1-10烷氨基,C6-12芳酰基-N-C1-10-烷氨基,C7-11芳烷酰基-N-C1-10烷氨基,C1-12烷酰氨基-C1-8烷基,C3-8环烷酰氨基-C1-8烷基,C6-12芳酰氨基-C1-8烷基,C7-16芳烷酰氨基-C1-8烷基,氨基-C1-8烷基,N-C1-10烷氨基-C1-10烷基,N,N-二C1-10烷氨基-C1-10烷基,C3-8环烷氨基-C1-10烷基,C1-12烷基巯基,C1-12烷基亚磺酰基,C1-12烷基磺酰基,C6-16芳基巯基,C6-16芳基亚磺酰基,C6-16芳基磺酰基,C7-16芳烷基巯基,C7-16芳烷基亚磺酰基或C7-18芳烷基磺酰基,R4为R″,条件是Q为NR′,其中R′和R″可相同或不同,且为氢,C6-12芳基,C7-11芳烷基,C1-8烷基,C1-8烷氧基-C1-8烷基,C7-12芳烷氧基-C1-8烷基,C6-12芳氧基-C1-8烷基,C1-10链烷酰基,任意取代的C7-16芳烷酰基或任意取代的C6-12芳酰基,或R′和R″一起为-〔CH2〕h,其中CH2基团可被O,S,N-酰基亚氨基或N-C1-10烷氧羰基亚氨基取代,且f 为1-8,g 为0或1-(2f+1),x 为0-3h 为3-7本发明还包括式I化合物的药理活性盐,但3-苄氧吡啶-2-羧酸(L-苏氨酰甲酯)酰胺,3-苄氧吡啶-2-羧酸(L-苏氨酰(Fmoc-phg)叔丁酯)酰胺,3-苄氧吡啶-2-羧酸(L-苏氨酰叔丁酯)酰胺和3-苄氧吡啶-2-羧酸(D-异苏氨酸甲酯)酰胺除外。
芳基一般理解为芳香碳环和杂环系统。具体讲,其包括取代的苯基,取代的二苯基,取代的萘基,或含1,2或3个氮原子和/或氧原子和/或硫原子的未取代的5-和6-员芳香杂环,如吡啶衍生物,哒嗪衍生物,嘧啶衍生物,吡嗪衍生物,咪唑衍生物,三唑衍生物,噻吩衍生物,恶唑衍生物和噻唑省生物,及它们的苯并稠合衍生物。
本发明还包括式I化合物的盐。
在式I化合物的酸性基团(即B,R1,R2,R3和R4)上,尤其是R2上,可与碱性制剂一次、二次或三次成盐。所用碱性试剂为醇化物,氢氧化物,碳酸盐,碳酸氢盐,磷酸氢盐,碱和碱土元素、周期表III族和IV族元素及过渡金属元素的有机金属化合物,可被C1-8羟烷基,C1-4烷氧基-C1-8烷基,苯基,苄基或C1-8烷基任意取代1-3次的胺,可被羟基或C1-4烷基取代1-3次,如三羟甲基氨基甲烷缓冲液,2-氨基乙醇,3-氨基丙醇,羟胺,二甲基羟胺,2-甲氧乙基胺,3-乙氧丙基胺和碱性氨基酸及氨基衍生物,如氨基酸酯,组氨酸,精氨酸和赖氨基及它们的衍生物,及含有碱基团的药物,如(R)Amiloride,(R)Verapamil和β阻断剂。
本发明还涉及式I化合物加下面的化合物用作药物:3-苄氧吡啶-2-羧酸(苏氨酰甲基酯)酰胺,3-苄氧吡啶-2-羧酸(L-苏氨酰甲基酯)酰胺,3-苄氧吡啶-2-羧酸(L-苏氨酰(Fmoc-phg)叔丁酯)酰胺,3-苄氧吡啶-2-羧酸(L-苏氨酰叔丁酯)酰胺和3-苄氧吡啶-2-羧酸(D-异苏氨酰甲酯)酰胺。
以下式I化合物是非常有用的,其中
Q为O,S,NR′或一个键,
X为O,
Y为CR3,或如R1和R2形成一个环,则Y为N或CR3
m为0或1
G为醇GOH基团。
下面的式I化合物是非常重要的,其中,
Q为O,NR′式一个键,
X为O,和
G为醇GOH基团。
下面式I化合物也是非常重要的,其中Q为,S,X为O,G为醇GOH基团。
下面的式I化合物是特别重要的,
其中
Q为O,NR′或一个键
X为S
Y为C-R3,或如R1和R2形成一个环,则Y为N或CR4,
m为0或1
A为由卤素,氰基,三氟甲基,C1-6烷基,C1-6羟烷基,C1-6烷氧基或-O-〔CH2〕x-CfH(2f+1-g)Fg取代的C1-3亚烷基,或
A为-CHR5-,其中R5为α-氮基酸(尤指天然L-氨基酸和其D-异构体)的α-碳原子上取代基之-,
B这-CO2G,其中
G为醇GOH基团,其中G为支链或直链或环状的脂肪族C1-20烷基,或支链或直链或选择性环状的C2-20链烯基,视黄基,C2-20炔基或相应的C4-20链烯炔基(其中这些基团在每种情况下可含一或多个重键),或C6-16芳基,C7-16芳烷基或5-或6-员(优选含氮)杂芳基或5-或6-(优选含氮)杂芳烷基,其中上述基团可带有一或多个选自下面基团的取代基:
羟基,卤素,氰基,三氟甲基,硝基,羧基,C1-12烷基,C3-8环烷基,C5-8环链烯基,C6-12芳基,C7-16芳烷基,C2-12链烯基,C2-12炔基,C1-12烷氧基,C1-12烷氧基-C1-12烷基,C1-12烷氧基-C1-12烷氧基,C6-12芳氧基,C7-16芳烷氧基,C1-8羟烷基,-O-〔CH2〕x-CfH(2f+1-g)Fg,-OCF2Cl,OCF2-CHFCl,C1-12烷羰基,C3-8环烷基羰基,C6-12芳羰基,C7-16芳烷基羰基,肉桂酰基,C2-12链烯羰基,C2-12炔羰基,C1-12烷氧羰基,C1-12烷氧基-C1-12烷氧羰基,C6-12芳氧羰基,C7-16芳烷氧羰基,C3-8环烷氧羰基,C2-12链烯氧羰基,C2-12炔氧羰基,C1-12烷基羰氧基,C3-8环烷基羰氧基,C6-12芳羰氧基,C7-16芳烷基羰氧基,肉桂酰基,C2-12链烯羰氧基,C2-12炔羰氧基,C1-12烷氧羰氧基,C1-12烷氧基C1-12烷氧羰氧基,C6-12芳氧羰氧基,C7-16芳烷氧羰氧基,C3-8环烷氧羰氧基,C2-12链烯氧羰氧基,C2-12炔氧羰氧基,氨基甲酰基,N-C1-12烷基氨基甲酰基,N,N-二C1-12烷基氨基甲酰基,N-C3-8环烷基氨基甲酰基,N-C6-16芳基氨基甲酰基,N-C7-16芳烷式氨基甲酰基,N-C1-10烷基-N-C6-16芳基氨基甲酰基,N-C1-10烷基-N-C7-16芳烷基氨基甲酰基,N-C1-10烷氧基-C1-10烷基氨基甲酰基,N-C6-12芳氧基-C1-10烷基氨基甲酰基,N-C7-16芳烷氧基C1-10烷基氨基甲酰基,N-C1-10烷基-N-C1-10烷氧基-C1-10烷基氨基甲酰基,N-C1-10烷撕-N-(C6-16芳氧基-C1-10烷基)氨基甲酰基,N-C1-10烷基-N-(C7-16芳烷氧基-C1-10烷基)氨基甲酰基,氨基甲酰氧基,N-C1-12烷基氨基甲酰氧基,N,N-二C1-12烷基氨基甲酰氧基,N-C3-8环烷基氨基甲酰氧基,N-C6-12芳基氨基甲酰氧基,N-C7-16芳烷基氨基甲酰氧基,N-C1-10烷基-N-C6-12芳基氨基甲酰氧基,N-C1-10烷基-N-C7-16芳烷基氨基甲酰氧基,N-C1-10烷基氨基甲酰氧基,N-C6-12芳氧基-C1-10烷基-氨基甲酰氧基,N-C7-16芳烷氧基-C1-10烷基-氨基甲酰氧基,N-C1-10烷基-N-C1-10烷氧基-C1-10烷基-氨基甲酰氧基,N-C1-10烷基-N-C6-12-芳氧基-C1-10烷基氨基甲酰氧基,N-C1-10烷基-N-C7-16-芳烷氧基-C1-10烷基-氨基甲酰氧基,氨基,C1-12烷所基,二C1-12烷氨基,C3-8环烷氨基,C2-12-链烯氨基,C2-12炔氨基,N-C6-12芳氨基,N-C7-11芳烷氨基,N-烷基-芳烷氨基,N-烷基-芳氨基,C1-12烷氧氨基,C1-12-烷氧-N-C1-10烷氧基,C1-12烷酰氨基,C3-8环烷酰氨基,C6-12芳酰氨基,C7-16芳烷酰氨基,C1-12烷酰基-N-C1-10烷氨基,C3-8环烷酰基-N-C1-10烷氨基,C6-12芳酰基-N-C1-10-烷氨基,C7-11芳烷酰基-N-C1-10烷氨基,C1-12烷酰氨基-C1-8烷基,C3-8环烷酰氨基-C1-8烷基,C6-12芳酰氨基-C1-8烷基,C7-12芳烷酰氨基-C1-8烷基,氨基-C1-6烷基,N-C1-10烷氨基-C1-10烷基,N,N-二C1-10烷氨基-C1-10烷基,C3-8环烷氨基-C1-10烷基,C1-12烷基巯基,C1-12烷基亚磺酰基,C1-12烷基基酰基,C6-12芳基巯基,C6-12芳基亚磺酰基,C6-12芳基磺酰基,C7-16芳烷基巯基,C7-16芳烷基亚磺酰基,C7-16芳烷基磺酰基,氨磺酰基,N-C1-10烷基氨磺酰基,N,N-二C1-10烷基氨磺酰基,C3-8环烷基氨磺酰基,N-C6-12芳基氨磺酰基,N-C7-16芳烷基氨磺酰基,N-C1-10烷基-N-C6-12-芳基氨磺酰基,N-C1-10烷基-N-C7-16芳烷基氨磺酰基,C1-10烷基亚磺酰氨基,N-C1-10烷基-C1-10烷基亚磺酰氨基,C7-16芳烷基亚磺酰氨基,或N-C1-10烷基-C7-16芳烷基亚磺酰氨基,其中含芳基的这些基团可在芳基上被1-5个选自下面的相同或不同基团取代:羟基,卤素,氰基,三氟甲基,硝基,羧基,C1-12烷基,C3-8环烷基,C6-12芳基,C7-16芳烷基,C1-12烷氧基,C1-12烷氧基-C1-12烷基,C1-12烷氧基-C1-12烷氧基,C6-12芳氧基,C7-16芳烷氧基,C1-8羟烷基,C1-12烷羰基,C3-8环烷羰基,C6-12芳羰基,C7-16芳烷羰基,C1-12烷氧羰基,C1-12烷氧基-C1-12烷氧羰基,C6-12芳氧羰基,C7-16芳烷氧羰基,C3-8环烷氧羰基,C2-12链烯氧羰基,C2-12炔氧羰基,
(C1-C12)-烷基羰氧基,(C3-C8)-环烷基羰氧基,(C6-C12)-芳基羰氧基,(C7-C16)-芳烷基羰氧基,肉桂酰氧基,(C2-C12)-链烯基羰氧基,(C2-C12)-炔基羰氧基,(C1-C12)-烷氧羰氧基,(C1-C12)-烷氧-(C1-C12)-烷氧羰氧基,(C6-C12)-芳氧羰氧基,(C7-C16)-芳烷氧羰氧基,(C3-C8)-环烷氧羰氧基,(C2-C12)-链烯氧羰氧基,(C2-C12)-炔氧氧羰基,氨基甲酰基,N-(C1-C12)-烷基氨基甲酰基,N,N-二-(C1-C12)-烷基氨基甲酰基,N-(C3-C8)-环烷基氨基甲酰基,N-(C6-C12)-芳基氨基甲酰基,N-(C7-C16)-芳烷基氨基甲酰基,N-(C1-C10)-烷基-N-(C6-C12)-芳基氨基甲酰基,N-(C1-C10)-烷基-N-(C7-C16)-芳烷基氨基甲酰基,N-(C1-C10)-烷基-(C1-C10)烷基)-氨基甲酰基,N-(C6-C12)-芳氧基-(C1-C10)烷基)-氨基甲酰基,N-(C7-C16)-芳烷氧基-(C1-C10)烷基)-氨基甲酰基,N-(C1-C10)-烷基-N-(C1-C10)-烷氧基-(C1-C10)烷基)氨基甲酰基,N-(C1-C10)-烷基-N-((C6-C12)--芳氧基-(C1-C10)烷基)氨基甲酰基,N-(C1-C10)-烷基-N-((C7-C16)--芳烷氧基-(C1-C10)烷基)氨基甲酰基,氨基甲酰氧基,N-(C1-C12)-烷基氨基甲酰氧基,N,N-二-(C1-C12)-烷基氨基甲酰氧基,N-(C3-C8)-环烷基氨基甲酰氧基,N-(C6-C12)-芳基氨基甲酰氧基,N-(C7-C16)-芳烷基氨基甲酰氧基,N-(C1-C10)-烷基-N-(C6-C12)-芳基氨基甲酰氧基,N-(C1-C10)-烷基-N-(C7-C16)-芳烷基氨基甲酰氧基,N-((C1-C10)烷基)氨基甲酰氧基,N-((C6-C12)-芳氧基)-(C1-C10)烷基)氨基甲酰氧基,N-((C7-C16)-芳烷氧基-(C1-C10)烷基)氨基甲酰基,N-(C1-C10)-烷基-N-((C1-C10)-烷氧基)-(C1-C10)烷基)氨基甲酰氧基,N-(C1-C10)-烷基-N-((C6-C12)-芳氧基)-(C1-C10)烷基)氨基甲酰氧基,N-(C1-C10)-烷基-N-((C7-C16)-芳烷氧基)-(C1-C10)烷基)氨基甲酰氧基,氨基,(C1-C12)-烷基氨基,二-(C1-C12)-烷基氨基,(C3-C8)-环烷基氨基,(C3-C12)-链烯基氨基,(C3-C12)-炔基氨基,N-(C6-C12)-芳基氨基,N-(C7-C11)-芳烷基氨基,N-烷基-芳烷基氨基,N-烷基-芳基氨基,(C1-C12)-烷氧基氨基,(C1-C12)-烷氧基-N-(C1-C10)-烷基氨基,(C1-C12)-烷酰氨基,(C3-C8)-环烷酰氨基,(C6-C12)-芳酰氨基,(C7-C16)-芳烷酰氨基,(C1-C16)-烷酰-N-(C1-C10)-烷基氨基,(C3-C8)-环烷酰-N-(C1-C10)-烷基氨基,(C6-C12)-芳酰-N-(C1-C10)-烷基氨基,(C7-C11)-芳烷酰-N-(C1-C10)-烷基氨基,(C1-C12)-烷酰氨基-(C1-C8)-烷基,(C3-C8)-环烷酰氨基-(C1-C8)烷基,(C6-C12)-芳酰氨基-(C1-C8)烷基,(C7-C16)-芳烷酰氨基-(C1-C8)烷基,氨基-(C1-C10)-烷基,N-(C1-C10)烷基氨基-(C1-C10)-烷基,N,N-二(C1-C10)-烷基氨基-(C1-C10)-烷基,(C3-C8)-环烷基氨基-(C1-C10)-烷基,(C1-C12)-烷基巯基,(C1-C12)-烷基亚磺酰基,(C1-C12)-烷基磺酰基,(C6-C12)-芳基巯基,(C6-C12)-芳基亚磺酰基,(C6-C12)-芳基磺酰基,(C7-C16)-芳烷基巯基,(C7-C16)-芳烷基亚磺酰基或(C7-C16)-芳烷基磺酰基,
R2是氢,(C1-C20)-烷基,(C2-C20)-链烯基,(C2-C20)-炔基,(C2-C20)-链烯氧基,(C2-C20)-炔氧基,视黄基氧基,(C1-C20)-烷氧基-(C1-C3)-烷基,(C2-C20)-链烯氧基-(C1-C3)-烷基,视黄基氧基-(C1-C3)-烷基,(C2-C20)-炔氧基-(C1-C3)-烷基,(C1-C20)-烷氧基,卤素,氰基,三氟甲基,(C1-C8)-羟烷基,(C1-C10)-烷酰基,(C7-C12)-芳烷酰基,(C6-C12)-芳酰基,-O-〔CH2〕x-CfH(2f+1-g)Fg,NR′R″,(C1-C10)-烷基巯基,(C1-C10)-烷基亚磺酰基,(C1-C10)-烷基磺酰基,(C6-C12)-芳基巯基,(C6-C12)-芳基亚磺酰基,(C6-C12)-芳基磺酰基,(C7-C12)-芳烷基巯基,(C7-C12)-芳烷基亚磺酰基,(C7-C12)-芳烷基磺酰基,(C6-C12)-芳氧基,(C7-C16)-芳烷氧基,羧基,(C1-C20)-烷氧羰基,(C1-C12)-烷氧基-(C1-C12)-烷氧羰基,(C6-C12)-芳烷羰基,(C7-C16)-芳烷氧羰基,(C3-C8)-环烷氧羰基,(C2-C20)-链烯氧基羰基,视黄基氧基羰基,(C2-C20)-炔氧羰基,(C3-C8)-环烷基-(C1-C6)-烷氧羰基,(C3-C8)-环烷氧基-(C1-C6)-烷氧羰基,(C6-C12)-芳氧基-(C1-C6)-烷氧羰基,(C7-C16)-芳烷氧基-(C1-C6)-烷氧羰基,氨基甲酰基,N-(C1-C12)-烷基氨基甲酰基,N,N-二-(C1-C12)-烷氧氨基甲酰基,N-(C3-C8)-环烷基氨基甲酰基,N,N-二(C3-C8)-环烷基氨基甲酰基,N-(C1-C10)-烷基-N-(C3-C8)-环烷基氨基甲酰基,N-((C3-C8)-环烷基-(C1-C6)-烷基)氨基甲酰基,N-(C1-C6)-烷基-N-(C3-C8)-环烷基-(C1-C6)-烷基)氨基甲酰基,N-(+)-脱氢枞酸基氨基甲酰基,N-(C1-C6)-烷基-N-(+)-脱氢枞酸基氨基甲酰基,N-(C6-C12)芳基氨基甲酰基,N-(C7-C16)-芳烷基氨基甲酰基,N-(C1-C10)-烷基-(C6-C16)-芳基氨基甲酰基,N-(C1-C10)-烷基-N-(C7-C16)-芳烷基氨基甲酰基,N-((C1-C12)-烷氧基-(C1-C10)-烷基)氨基甲酰基,N-((C6-C16)-芳氧基-(C1-C10)-烷基)氨基甲酰基,N-((C7-C16)-芳烷氧基-(C1-C10)-烷基)氨基甲酰基,N-(C1-C10)-烷基-N-((C1-C10)-烷氧基-(C1-C10)-烷基)氨基甲酰基,N-(C1-C10)-烷基-N-((C6-C12)-芳氧基-(C1-C10)-烷基)氨基甲酰基,N-(C1-C10)-烷基-N-((C7-C16)-芳烷氧基-(C1-C10)-烷基)氨基甲酰基,CON(CH2)h,其中CH2基团可被O,S,N-(C1-C8)-烷基亚氨基,N-(C3-C8)-环烷基亚氨基,N-(C3-C8)-环烷基-(C1-C4)-烷基亚氨基,N-(C6-C12)-芳基亚氨基,N-(C7-C16)-芳基亚氨基或N-(C1-C4)-烷氧基-(C1-C6)烷基亚氨基取代,而h是3-7,在此芳基以R1和R3定义中的方式被取代,R1和R3是相同或不同的,为氢,卤素,(C1-C12)-烷基,(C1-C12)-烷氧基,-O-〔CH2〕x-CfH(2f+1-g)Halg,(C1-C12)-烷氧基-(C1-C12)-烷基,(C1-C8)-烷氧基-(C1-C12)-烷氧基,(C1-C12)-烷氧基-(C1-C8)-烷氧基-(C2-C6)-烷基,(C7-C11)-芳烷氧基,(C3-C8)-环烷基,(C3-C8)-环烷基-(C1-C8)-烷基,(C3-C8)-环烷氧基,(C3-C3)-环烷基-(C1-C8)-烷氧基,(C3-C8)-环烷氧基-(C1-C8)-烷基,(C3-C8)-环烷氧基-(C1-C8)-烷氧基,(C3-C8)-环烷基-(C1-C6)-烷基-(C1-C6)-烷氧基,(C3-C8)-环烷基-(C1-C6)-烷氧基-(C1-C6)-烷基,(C3-C8)-环烷氧基-(C1-C6)-烷氧基-(C1-C6)-烷基,NRYRZ,(C1-C8)-烷基巯基,(C1-C8)-烷基亚磺酰基或(C1-C8)-烷基磺酰基,(C6-C12)-芳基巯基,(C6-C12)-芳基亚磺酰基,(C6-C12)-芳基磺酰基,(C7-C12)-芳烷基巯基,(C7-C11)-芳烷基亚磺酰基,(C7-C11)-芳烷基磺酰基,取代的(C6-C12)-芳氧基-(C1-C6)-烷基,(C7-C11)-芳烷氧基-(C1-C6)-烷基,(C6-C12)-芳氧基-(C1-C6)-烷氧基-(C1-C6)-烷基,(C7-C11)-芳烷氧基-(C1-C6)-烷氧基-(C1-C6)-烷基,(C6-C12)-芳氧基,(C7-C11)-芳烷氧基,(C6-C12)-芳氧基-(C1-C6)-烷氧基或(C7-C11)-芳烷氧基(C1-C6)-烷氧基,在此芳基带有1,2,3,4或5个相同或不同的下列取代基:氢,卤素,氟基,硝基,三氟甲基,(C1-C16)-烷基,(C1-C16)-链烯基,(C2-C16)-羟烷基,(C1-C6)-烷氧基,(C1-C16)-链烯氧基,-O-〔CH2〕x-CfH(2f+1-g)Fg,-OCF2Cl,-O-CF2-CHFCl,(C1-C6)-烷基巯基,(C1-C6)-烷基亚磺酰基,(C1-C6)-烷基磺酰基,(C1-C6)-烷基羰基,(C1-C6)-烷氧羰基,氨基甲酰基,N-(C1-C4)-烷基氨基甲酰基,N,N-二-(C1-C4)-烷基氨基甲酰基,(C1-C4)-烷基羰氧基,(C3-C8)-环烷基氨基甲酰基,苯基,苄基,苯氧基,苄氧基,NRYRZ,苯基巯基,苯基磺酰基,苯基亚磺酰基,氨磺酰基,N-(C1-C4)-烷基氨磺酰基或N,N-二-(C1-C4)-烷基氨磺酰基,或选择性地带有至多3个上述相同或不同的取代基,芳烷氧基的两个相邻碳原子一起带有-〔CH2〕和/或-CH=CH-CH=CH-链,该链的CH2基团被O,S,SO,SO2或NR′选择性地取代,R1和R2或R2和R3形成〔CH2〕o链,而O是3,4或5,或与带有它们的吡啶或哒嗪一起形成噌啉环,喹啉环或异喹啉环,R4是氟,氯或溴(如果Q是一个键),或者或者如果Q是O或NR′,则是支链或直链(C1-C20)-烷基,该烷基可含有至多3个C-C重键,式〔CH2〕x-CfH (2f+1-g)Fg的未取代的饱和氟烷基,(C6-C16)-芳基或(C7-C16)芳烷基,在其烷基链中可含有至多2个C-C重键,或杂芳基或杂芳基烷基,在此这些基团被1个或多个下列基团取代:羟基,氟,氯,氰基,三氟甲基,羧基,(C1-C12)-烷基,(C3-C8)-环烷基,(C3-C8)-环烷基-(C1-C12)-烷基,(C3-C8)-环烷氧基,(C3-C8)-环烷氧基-(C1-C12)-烷氧基,(C3-C8)-环烷氧基-(C1-C12)-烷基,(C3-C8)-环烷氧基-(C1-C12)-烷氧基,(C3-C8)-环烷基-(C1-C8)-烷基-(C1-C6)-烷氧基,(C3-C8)-环烷氧基-(C1-C8)-烷氧基-(C1-C8)-烷氧基,(C6-C12)-芳基,(C7-C16)-芳烷基,(C2-C12)-链烯基,(C2-C12)-炔基,(C1-C12)-烷氧基,(C1-C12)-烷氧基-(C1-C12)-烷氧基,(C1-C12)-烷氧基-(C1-C8)-烷氧基-(C1-C8)-烷基,(C6-C12)-芳氧基,(C7-C16)-芳烷氧基,(C6-C12)-芳氧基-(C1-C6)-烷氧基,(C7-C16)-芳烷氧基-(C1-C6)-烷氧基,(C1-C8)-羟烷基,-O-〔CH2〕x-CfH(2f+1-g)Fg(C1-C12)-烷基羰基,(C3-C8)-烷环基羰基,(C6-C12)-芳基羰基,(C7-C16)-芳烷基羰基,(C1-C12)-烷氧羰基,(C1-C12)-烷氧基-(C1-C12)-烷氧羰基,(C6-C12)-芳氧羰基,(C7-C16)-芳烷氧羰基,(C3-C8)-环烷氧羰基,(C2-C12)-链烯氧羰基,(C2-C12)-炔氧羰基,(C3-C8)-环烷基-(C1-C6)-烷氧羰基,(C1-C12)-烷基羰氧基,(C3-C8)-环烷基羰氧基,(C6-C12)-芳基羰氧基,(C7-C16)-芳烷基羰氧基,氨基甲酰基,N-(C1-C12)-烷基氨基甲酰基,N,N-二-(C1-C12)-烷基氨基甲酰基,N-(C3-C8)-环烷基氨基甲酰基,N,N-二-(C3-C8)-环烷基氨基甲酰基,N-(C1-C10)-烷基-N-(C3-C8)-环烷基氨基甲酰基,N-((C3-C8)-环烷基-(C1-C6)-烷基)氨基甲酰基,N-(C1-C6)-烷基-N-((C3-C8)-环烷基(C1-C6)-烷基)氨基甲酰基,N-(+)-脱氢枞酸基氨基甲酰基,N-(C1-C6)烷基,-N-(+)-脱氢枞酸基氨基甲酰基,N-(C6-C12)-芳基氨基甲酰基,N-(C7-C16)-芳烷基氨基甲酰基,N-(C1-C10)-烷基-N-(C6-C16)-芳基氨基甲酰基,N-(C1-C10)-烷基-N-(C7-C16)-芳烷基氨基甲酰基,N-((C1-C10)-烷氧基-(C1-C10)-烷基)氨基甲酰基,N-((C6-C16)-芳氧基-(C1-C10)-烷基)氨基甲酰基,N-((C7-C16)-芳烷氧基-(C1-C10)-烷基)氨基甲酰基,CON(CH2)h,其中CH2基团可被O,N-(C1-C8)-烷基亚氨基,N-(C3-C8)-环烷基亚氨基,N-(C3-C8)-环烷基-(C1-C4)-烷基亚氨基,N-(C6-C12)-芳基亚氨基或N-(C7-C12)-芳烷基亚氨基取代,而h是3-6,在此含有芳基的基团在芳基上可被1-5个相同或不同的下列基团取代:羟基,氟,氯,氰基,三氟甲基,羧基,(C1-C12)-烷基,(C3-C8)-环烷基,(C1-C6)-烷氧基,(C3-C8)-环烷氧基,(C1-C12)-烷氧羰基,N-(C1-C6)-烷基氨基甲酰基,N,N-二-(C1-C6)-烷基氨基甲酰基或N-(C3-C8)-环烷基氨基甲酰基,R4是R″,条件是Q具有NR′的含意,而R′和R″是相同或不同的氢,(C1-C8)-烷基,或(C7-C11)-芳烷基,该基团可被氟,氯或(C1-C4)-烷氧基选择性地取代一次,RY和RZ是相同或不同的,为氢,(C6-C12)-芳基,(C1-C10)-烷基,(C3-C10)-环烷基,(C1-C8)-烷氧基-(C1-C8)-烷基,(C7-C12)-芳烷氧基-(C1-C8)-烷基,(C6-C12)-芳氧基-(C1-C8)-烷基,(C1-C10)-烷酰基,选择性取代的(C7-C16)-芳烷酰基或选择性地取代的(C6-C12)-芳酰基或RY和RZ一起为-〔CH2〕h-,其中CH2基团可被O,S,N-(C1-C4)-烷酰基亚氨基或N-(C1-C4)-烷氧羰基亚氨基取代f 为1-8,g 为0或1-(2f+1),h 为3-6,x 为0-3,n 为3或4。优选的式I化合物中,Q为O,NR′或一个键,X为O,Y为CR3或,如果R1和R2形成环,则为N或CR3,m为0,A是(C1-C3)-亚烷基,该基团可被卤素,氰基,三氟甲基,(C1-C6)-烷基,C1-C6)-羟烷基,C1-C6)-烷氧基或-O-〔CH2〕x-CfH(2f+1-g)Fg选择性地取一次或A是-CHR5-,在此R5是α-氨基酸,特别是天然L-氨基酸或其D-异构体的α-碳原子上的取代基之一,B是CO2G,在此G是支链或直链,或环状,脂族(C1-C20)-烷基,视黄基或支链或直链(C2-C20)-链烯基或(C2-C20)-炔基,这些基团均可含有1个或多个C-C重键,或(C6-C12)-芳基,(C7-C11)-芳烷基或杂芳基或杂芳烷基,上述基团可带有1或2个下列取代基:(C1-C8)-烷基,(C3-C8)-环烷基,氟,氯,羟基,(C1-C6)-烷氧基,(C1-C6)-烷氧基-(C1-C6)-烷氧基,(C6-C12)-芳氧基,(C7-C12)-芳烷氧基,(C1-C8)-烷氧羰基,(C3-C8)-环烷基羰基,(C6-C12)-芳基羰基,(C7-C12)-芳烷基羰基,(C1-C8)-烷氧羰基,(C1-C6)-烷氧基-(C1-C6)-烷氧羰基,(C6-C12)-芳氧羰基,(C7-C12)-芳烷氧羰基,(C3-C8)-环烷氧羰基,(C1-C20)-烷基羰氧基,(C3-C8)-环烷基羰氧基,(C6-C12)-芳基羰氧基,(C7-C12)-芳烷基羰氧基,(C1-C8)-烷氧基羰氧基,(C1-C6)-烷氧基-(C1-C6)-烷氧基羰氧基,(C6-C12)-芳氧基羰氧基,(C7-C12)-芳烷氧基羰氧基,(C3-C8)-环烷氧基羰氧基,氨基甲酰基,N-(C1-C8)-烷基氨基甲酰基,N,N-二-(C1-C8)-烷基氨基甲酰基,N-(C3-C8)-环烷基氨基甲酰基,N((C1-C6)-烷氧基-(C1-C6)烷基)氨基甲酰基,氨基,(C1-C6)-烷基氨基,二-(C1-C6)-烷基氨基,(C3-C8)-环烷基氨基,N-(C6-C12)-芳基氨基,N-(C7-C11)-芳烷基氨基,N-(C1-C5)-烷基-(C6-C12芳基氨基,(C1-C8)-烷酰氨基,(C3-C8)-环烷酰氨基,(C6-C12)-芳酰氨基,(C7-C12)-芳烷酰氨基,(C1-C8)-烷酰-N-(C1-C6)-烷基氨基,(C3-C8)-环烷酰-N-(C1-C6)-烷基氨基,(C6-C12)-芳酰基-N-(C1-C6)-烷基氨基或(C7-C11)-芳烷酰-N-(C1-C6)-烷基氨基,在此含有芳基的基团特别可被至多3个下列取代基取代:羟基,氟,氯,氰基,三氟甲基,(C1-C6)-烷基,(C3-C8)-环烷基,(C1-C8)-烷氧基,(C1-C6)-烷基羰基,(C3-C8)-环烷基羰基,(C1-C6)-烷氧羰基,(C3-C8)-环烷氧羰基,(C1-C6)-烷基羰氧基,(C3-C8)-环烷基羰氧基,(C1-C6)-烷氧羰氧基,(C3-C8)-环烷氧氨基甲酰氧基,氨基甲酰基,N-(C1-C6)-烷基氨基甲酰基,N,N-二-((C1-C6)-烷基氨基甲酰基,N-(C3-C8)-环烷基氨基甲酰基,N-((C1-C6)-烷氧基-(C1-C6)-烷基)氨基甲酰基,N-((C1-C6)-烷氧基-(C1-C6)-烷基)氨基甲酰基,氨基甲酰氧基,N-(C1-C6)-烷基氨基甲酰氧基,N,N-二-(C1-C6)-烷基氨基甲酰氧基,N-(C3-C8)-环烷基氨基甲酰氧基,(C1-C6)-烷酰氨基,(C3-C8)-环烷酰氨基,(C1-C6)-烷基巯基,(C1-C6)-烷基亚磺酰基,(C1-C6)-烷基磺酰基,R2是氢,(C1-C20)-烷基,(C2-C20)-链烯基,(C2-C20)-链烯氧基,(C2-C20)-炔氧基,视黄基氧基,(C1-C20)-烷氧基-(C1-C3)-烷基,(C2-C20)-链烯氧基-(C1-C3)-烷基,视黄基氧基-(C1-C3)-烷基,(C2-C20)-炔氧基-(C1-C3)-烷基,(C1-C20)-烷氧基,卤素,氰基,三氟甲基,(C1-C8)-羟烷基,(C1-C10)-烷酰基,(C7-C12)-芳烷酰基,(C6-C12)-芳酰基,-O-〔CH2〕x-CfH(2f+1-g)Fg,NR′R″,(C1-C10)-烷基巯基,(C1-C10)-烷基亚磺酰基,(C1-C10)-烷基磺酰基,(C6-C12)-芳基巯基,(C6-C12)-芳基亚磺酰基,(C6-C12)-芳基磺酰基,(C7-C12)-芳烷基巯基,(C7-C12)-芳烷基亚磺酰基,(C7-C12)-芳烷基磺酰基,(C6-C12)-芳氧基,(C7-C16)-芳烷氧基,羧基,(C1-C20)-烷氧羰基,(C1-C12)-烷氧基-(C1-C12)-烷氧羰基,(C6-C12)-芳氧羰基,(C7-C16)-芳烷氧羰基,(C3-C8)-环烷氧羰基,(C2-C20)-链烯氧基羰基,视黄基氧基羰基,(C2-C20)-炔氧羰基,(C3-C8)-环烷基-(C1-C6)-烷氧羰基,(C3-C8)-环烷氧基-(C1-C6)-烷氧羰基,(C6-C12)-芳氧基-(C1-C6)-烷氧羰基,(C7-C16)-芳烷氧基-(C1-C6)-烷氧羰基,氨基甲酰基,N-(C1-C12)-烷基氨基甲酰基,N,N-二(C1-C12)-烷基氨基甲酰基,N-(C3-C8)-环烷基氨基甲酰基,N,N-二环(C3-C8)-烷基氨基甲酰基,N-(C1-C10)-烷基-N-(C3-C8)-环烷基氨基甲酰基,N-((C3-C8)-环烷基-(C1-C6)-烷基)氨基甲酰基,N-(C1-C6)-烷基-N-((C3-C8)-环烷基-(C1-C6)-烷基)氨基甲酰基,N-(+)-脱氢枞酸基氨基甲酰基,N-(C1-C6)-烷基-N-(+)-脱氢枞酸基氨基甲酰基,N-(C6-C12)-芳基氨基甲酰基,N-(C7-C16)-芳烷基氨基甲酰基,N-(C1-C10)-烷基-N-(C6-C16)-芳基氨基甲酰基,N-(C1-C10)-烷基-N-(C7-C12)-芳烷基氨基甲酰基,N-(C1-C12)-烷氧基-((C1-C10)-烷基)氨基甲酰基,N-((C6-C16)-芳氧基-((C1-C10)-烷基)氨基甲酰基,N-((C7-C16)-芳烷氧基-(C1-C10)-烷基)氨基甲酰基,N-(C1-C10)-烷基-N-((C1-C10)-烷氧基-(C1-C10)-烷基)氨基甲酰基,N-(C1-C10)-烷基-N-((C6-C12)-芳氧基-((C1-C10)-烷基)氨基甲酰基,N-(C1-C10)-烷基-N-((C7-C16)-芳烷氧基-(C1-C10)-烷基)氨基甲酰基,或CON(CH2)h,其中CH2基团可被O,S,N-(C1-C8)-烷基亚氨基,N-(C3-C8)-环烷基亚氨基,N-(C3-C8)-环烷基-(C1-C4)-烷基亚氨基,N-(C6-C12)-芳基亚氨基,N-(C7-C16)-芳烷基亚氨基或N-(C1-C4)-烷氧基-(C1-C6)-烷基亚氨基取代,而h是3-6,在此芳基以R1和R3定义中的方式被取代,R1和R3是相同或不同的,为氢,卤素,(C1-C12)-烷基,(C1-C12)-烷氧基,-O-〔CH2〕x-CfH(2f+1-g)FgHalg,(C1-C12)-烷氧基-(C1-C12)-烷基,(C1-C8)-烷氧基-(C1-C12)-烷氧基,(C1-C12)-烷氧基-(C1-C8)-烷氧基-(C2-C6)-烷基,(C7-C11)-芳烷氧基,(C3-C8)-环烷基,(C3-C8)-环烷基-(C1-C8)-烷基,(C3-C8)-环烷氧基,(C3-C8)-环烷基-(C1-C8)-烷氧基,(C3-C8)-环烷氧基-(C1-C8)-烷基,(C3-C8)-环烷氧基-(C1-C8)-烷氧基,(C3-C8)-环烷基-(C1-C6)-烷基-(C1-C6)-烷氧基,(C3-C8)-环烷基-(C1-C6)-烷氧基-(C1-C6)-烷基,(C3-C8)-环烷氧基-(C1-C6)-烷氧基-(C1-C6)-烷基,NRYRZ,(C1-C8)-烷基巯基,(C1-C8)-烷基亚磺酰基或(C1-C8)-烷基磺酰基,(C6-C12)-芳基巯基,(C6-C12)-芳基亚磺酰基,(C6-C12)-芳基磺酰基,(C7-C12)-芳烷基巯基,(C7-C11)-芳烷基亚磺酰基,(C7-C11)-芳烷基磺酰基,取代的(C6-C12)-芳氧基-(C1-C6)-烷基,(C7-C11)-芳烷氧基-(C1-C6)-烷基,(C6-C12)-芳氧基-(C1-C6)-烷氧基-(C1-C6)-烷基,(C7-C11)-芳氧烷基-(C1-C6-)烷氧基-(C1-C6)烷基,(C6-C12)-芳氧基-(C1-C6)-烷氧基或(C7-C11)-芳烷氧基-(C1-C6)-烷氧基,在此芳基带有1,2,3,4或5个相同或不同的下列取代基:氢,卤素,氰基,硝基,三氟甲基,(C1-C12)-烷基,(C1-C12)-链烯基,(C1-C6)-羟烷基,(C1-C12)-烷氧基,(C1-C12)-链烯氧基,-O-〔CH2〕x-CfH(2f+1-g)Fg,-OCF2Cl,-O-CF2-CHFCl,(C1-C6)-烷基巯基,(C1-C6)-烷基亚磺酰基,(C1-C6)-烷基磺酰基,(C1-C6)-烷氧羰基,(C1-C6)-烷基羰基,氨基甲酰基,N-(C1-C4)-烷基氨基甲酰基,N,N-二-(C1-C4)-烷基氨基甲酰基,(C1-C6)-烷基羰氧基,(C3-C8)-环烷基氨基甲酰基,苯基,苄基,苯氧基,苄氧基,NRYRZ,苯基巯基,苯基磺酰基,苯基亚磺酰基,氨磺酰基,N-(C1-C4)-烷基氨磺酰基,或N,N-二-(C1-C4)-烷基氨磺酰基,或选择性地带有至多3个上述相同或不同的取代基,芳烷氧基的两个相邻碳原子一起带有-〔CH2〕和或-CH=CH-CH=CH-链,该链的CH2基团被O,S,SO,SO2或NRY选择性地取代,R1和R2或R2和R3可形成〔CH2〕o,而O是3,4或5,R4,当Q是一个键时,为氯或,如果Q是O或NR′,则为支链或直链-(C1-C10)-烷基,该基团可含有1或2个C-C重键,或式-〔CH2〕x-CfH(2f+1-g)Fg的未取代的氟烷基或(C1-C8)-烷氧基-(C1-C6)-烷基,(C1-C6)-烷氧基-(C1-C4)-烷氧基-(C1-C4)-烷基或Z的基团,〔CH2〕v-〔O〕w-〔CH2〕t-E (Z)在此E是式F的取代的苯基或(C3-C8)-环烷基,在此V是0,1,2,3,4,5或6,W是0或1,t是0,1,2或3,限制条件是若W为1,则V不等于0,R6,R7,R8,R9和R10是相同或不同的,为氢,卤素,氰基,硝基,三氟甲基,(C1-C6)-烷基,(C3-C8)-环烷基,(C1-C6)-烷氧基,-O-〔CH2〕x-CfH(2f+1-g)Fg,-OCF2Cl,-O-CF2-CHFCl,(C1-C6)-烷基巯基,(C1-C6)-羟烷基,(C1-C6)-烷氧基-(C1-C6)-烷氧基,(C1-C6)-烷氧基-(C1-C6)-烷基,(C1-C6)-烷基亚磺酰基,(C1-C6)-烷基磺酰基,(C1-C6)-烷基羰基,(C1-C8)-烷氧羰基,氨基甲酰基,N-(C1-C8)-烷基氨基甲酰基,N,N-二-(C1-C8)-烷基氨基甲酰基,(C7-C11)-芳烷基氨基甲酰基,该基团可被氟,氯,溴,三氟甲基或(C1-C6)-烷氧基选择性地取代,N-(C3-C8)-环烷基氨基甲酰基,N-(C3-C8)-环烷基-(C1-C4)-烷基氨基甲酰基,(C1-C6)-烷基羰氧基,苯基,苄基,苯氧基,苄氧基,NRYRZ,如氨基,苯胺基,N-甲基苯胺基,苯基巯基,苯基磺酰基,苯基亚磺酰基,氨磺酰基,N-(C1-C8)-烷基氨磺酰基或N,N-二-(C1-C8)-烷基氨磺酰基,或两个相邻的取代基一起构成-〔CH2〕n或-CH=CH-CH=CH-链,在此CH2基团可被O,S,SO,SO2或NRY选择性地取代,杂芳基可带有1,2或3个上述取代基,而环烷基可带有1个上述取代基,R4是R″,条件是Q具有NR′的含意,在此R′是氢或甲基,R″是苄基,如果R1和或/R3的含意为(C6-C12)-芳氧基,(C7-C11)-芳烷氧基,(C6-C12)-芳氧基-(C1-C6)-烷氧基,(C7-C11)-芳烷氧基-(C1-C6)-烷氧基或含有末端环烷基的相应基团,则该基团优选的是式D的基团OZ (D) 或如果R1和/或R3的含意为(C7-C11)-芳烷基,(C6-C12)-芳氧基-(C1-C6)-烷基,(C7-C11)-芳烷氧基-(C1-C6)-烷基或含有末端环烷基的相应基团,则该基团优选的是式Z的基团,RY和RZ是相同或不同的,为氢,(C6-C12)-芳基,(C1-C10)-烷基,(C3-C10)-环烷基,(C1-C8)-烷氧基-(C1-C8)-烷基,(C7-C12)-芳烷氧基-(C1-C8)-烷基,(C6-C12)-芳氧基-(C1-C8)-烷基,(C1-C10)-烷酰基,选择性取代的(C7-C16)-芳烷酰基或选择性取代的(C6-C12)-芳酰基,或RY和RZ一起为-〔CH2〕h-,其中CH2基团可被O,S,N-(C1-C4)-烷酰基亚氨基或N-(C1-C6)-烷氧羰基亚氨基取代f为1-8,g为0或1-(2f+1),h为3-6x为0-3,n为3或4。特别优选的式I化合物中,Q为O,X为O,Y为CR3,此外,若R1和R2形成环,则Y为N,m为0,A为-CHR5-,在此R5是α-氨基酸,特别是天然L-氨基酸或其D-异构体的α-碳原子上的取代基,B为CO2G,在此G为支链或直链,或环状,脂族(C1-C18)-烷基,(C3-C8)-环烷基-(C1-C8)-烷基,支链或直链(C2-C18)-链烯基,例如,香叶基或法呢基,或视黄基,或(C2-C18)-炔基,苯基,苄基,苯乙基,苯丙基或苯丁基,在此上述基团含有下列取代基:羟基,C1-C4)-烷氧基,酰氧基,C1-C6)-烷基羰氧基,(C3-C8)-环烷基羰氧基,苯甲酰氧基,(C7-C16)-苯基烷基羰氧基或(C3-C8)-环烷氧羰氧基,R2是氢,溴,氯,氰基,(C1-C18)-烷基,(C1-C8)-烷氧基,(C1-C18)-烷氧基甲基,(C2-C18)-链烯氧基甲基,(C2-C18)-炔氧基甲基,氨基甲酰基,N-(C1-C10)-烷基氨基甲酰基,N-((C1-C12)-烷氧基-(C1-C4)-烷基)氨基甲酰基,N,N-二-(C1-C8)-烷基氨基甲酰基,N-(C3-C8)-环烷基氨基甲酰基,N-(C6-C12)-苯基氨基甲酰基,N-(C7-C12)-苯基烷基氨基甲酰基,N-(C1-C6)-烷基-N-(C7-C12)-苯基烷基氨基甲酰基,N-((C1-C6)-烷氧基-(C1-C6)-烷基)氨基甲酰基,羧基,(C1-C20)-烷氧羰基,(C2-C20)-链烯氧羰基,视黄基氧基羰基,(C3-C8)-环烷氧羰基,(C3-C8)-环烷基-(C1-C6)-烷氧羰基,(C3-C8)-环烷氧基-(C1-C6)-烷氧羰基,苯基-(C1-C6)-烷氧羰基,苯氧基-(C1-C6)-烷氧羰基或苄氧基(C1-C6)-烷氧羰基,在此苯基以R1和R3定义中的方式被取代,下列基团之一R1和R3是氢,另一个是下列基团:氢,氟,氯,(C1-C8)-烷基,(C1-C10)烷氧基,(C5-C6)-环烷基-(C1-C6)-烷基,(C5-C6)-环烷氧基,(C5-C6)-环烷基-(C1-C6)-烷氧基,(C5-C6)-环烷氧基-(C1-C6)-烷基,(C5-C6)-环烷氧基-(C1-C6)-烷氧基,(C5-C6)-环烷基-(C1-C4)-烷基-(C1-C4)-烷氧基,(C5-C6)-环烷基-(C1-C4)-烷氧基-(C1-C2)-烷基,(C5-C6)-环烷氧基-(C1-C4)-烷氧基-(C1-C2)-烷基,-O-〔CH2〕x-CfH(2f+-g)Fg,(C1-C6)-烷氧基-(C1-C6)-烷基,(C1-C6)-烷氧基-(C1-C6)-烷氧基,(C1-C6)-烷氧基-(C1-C4)-烷氧基-(C1-C2)-烷基,取代的(C6-C12)-苯氧基,(C7-C11)-苯基烷氧基,(C6-C12)-苯氧基-(C1-C6)-烷氧基或(C7-C11)-苯基烷氧基-(C1-C6)-烷氧基,苯氧基-(C1-C4)-烷基,(C7-C11)-苯基烷氧基-(C1-C4)-烷基,苯氧基-(C1-C4)-烷氧基-(C1-C2)-烷基或(C7-C11)苯基烷氧基-(C1-C4)-烷氧基-(C1-C2)-烷基,在此芳基可被1,2或3个相同或不同的下列取代基取代:氟,氯,氰基,三氟甲基,(C1-C12)-烷基,(C2-C12)-链烯氧基,(C2-C12)-链烯氧基或(C1-C12)-烷氧基,R1和R2与带有它们的吡啶形成5,6,7,8-四氢异喹啉环,R4是支链或直链(C1-C10)-烷基,(C1-C4)-烷氧基-(C1-C4)-烷基或式Z的基团,-〔CH2〕v-〔O〕w-〔CH2〕t-E (Z)在此E是式F的取代的苯基或(C3-C8)-环烷基,在此V是0,1,2或3,W是0,t可以是0或1,并且其中R6,R7,R8,R9和R10是相同或不同的,为氢,氟,氯,氰基,三氟甲基,(C1-C6)-烷基,(C1-C6)-烷氧基,-O-〔CH2〕x-CfH(2f+1-g)Fg,N-(C1-C8)-烷基氨基甲酰基,N,N-二-(C1-C6)-烷基氨基甲酰基,N-(C3-C6)-环烷基氨基甲酰基,N(+)-脱氢枞酸基氨基羰基,或(C7-C11)-苯基烷基氨基甲酰基,该基团可被氟,氯,三氟甲基或(C1-C6)-烷氧基选择性地取代,或R6和R7或R7和R8与带有它们的苯环一起形成萘衍生物。如果R1和R3的含意为(C6-C12)-苯氧基,(C7-C11)-苯基烷氧基,(C6-C12)-苯氧基-(C1-C6)-烷氧基,(C7-C11)-苯基烷氧基-(C1-C6)-烷氧基,(C5-C6)--环烷氧基,(C5-C6)-环烷基-(C1-C6)-烷氧基,(C5-C6)-环烷氧基-(C1-C6)-烷氧基或(C5-C6)-环烷基-(C1-C4)-烷基-(C1-C4)-烷氧基,则该基团最好是式D的基团
OZ (D),或如果R1或R3的含意为苯基,苯氧基-(C1-C6)-烷基,(C7-C11)-苯基烷基,(C7-C11)-苯基烷氧基-(C1-C4)-烷基,(C5-C6)-环烷基,(C5-C6)-环烷基-(C1-C6)-烷基,(C5-C6)-环烷氧基-(C1-C4)-烷基,(C5-C6)-环烷基-(C1-C4)-烷氧基-(C1-C2)-烷基或(C5-C6)-环烷基-(C1-C4)-烷氧基-(C1-C2)-烷基,则该基团最好为式Z的基团,其中在这两种情况下,V是1,2,3或4,W是0,t是0,或V是1,2,3或4,W是1,t是0,或V是1,2,3或4,W是1,t是1,并且f是1-4,g是-或1-2(f+1)x是0或1。特别优选的式I化合物中,Q是O,X是O,Y是CR3,m是0,A是可被甲基取代的-CH2-基团,B是-CO2G,在此G为支链或直链,或环状,族(C1-C18)-烷基,(C3-C8)-环烷基-(C1-C4)-烷基或支链或直链(C2-C18)-链烯基在此上述基团可含有下列取代基:羟基,(C1-C4)-烷氧基,酰氧基,(C1-C6)-烷基羰氧基,(C3-C8)-环烷基羰氧基,苯甲酰氧基,(C7-C16)-苯基烷基羰氧基或(C3-C8)-环烷氧羰氧基,或G为苯基,苄基,苯乙基,苯丙基或苯丁基,R2是氢,(C1-C8)-烷氧基,(C1-C16)-烷氧基甲基,(C2-C16)-链烯氧基甲基,视黄基氧基甲基,N-(C1-C10)-烷基氨基甲酰基,N-((C1-C12)-烷氧基-((C1-C3)-烷基)氨基甲酰基,N,N-二-(C1-C8)-烷基氨基甲酰基,N-(C5-C6)-环烷基氨基甲酰基,N-苯基氨基甲酰基,N-苯基-(C1-C4)-烷基氨基甲酰基,羧基,(C1-C16)-烷氧羰基,(C2-C16)-链烯氧羰基,视黄基氧基羰基,(C5-C6)-环烷氧羰基,(C5-C6)-环烷基-(C1-C6)-烷氧羰基或苯基-(C1-C6)-烷氧羰基,在此苯基以R1和R3定义中的方式被取代,和下列基团之一R1或R3是氢,另一基团是下列基团:氢,(C1-C10)-烷氧基,(C5-C6)-环烷氧基,(C5-C6)-环烷基-(C1-C2)-烷氧基,-O-〔CH2〕x-CfH(2f+1-g)Fg,(C1-C4)-烷氧基-(C1-C4)-烷氧基,取代的(C6-C12)-苯氧基,(C7-C11)-苯基烷氧基,(C6-C12)-苯氧基-(C1-C4)-烷氧基或(C7-C11)-苯基烷氧基-(C1-C4)-烷氧基,在此芳基可被1,2或3个相同或不同的下列取代基取代:氟,氯,氰基,三氟甲基,(C1-C10)-烷基,(C1-C10)-烷氧基或(C2-C10)-链烯氧基,R4是支链或直链(C1-C8)-烷基或式Z的基团,-〔CH2〕v-〔O〕w-〔CH2〕t-E (Z)在此E是式F的取代的苯基或(C3-C8)-环烷基,在此V是0,1,2,或3,W是0,t可以是0或1,并且其中R6,R7,R8,R9和R10是相同或不同的,为氢,氟,氯,氰基,三氟甲基,(C1-C6)-烷基,(C1-C6)-烷氧基,-O-〔CH2〕x-CfH(2f+1-g)Fg,N-(C1-C8)-烷基氨基甲酰基,N,N-二(C1-C6)-烷基氨基甲酰基,N-(+)-脱氢枞酸基氨基羰基取代的苄基,而f为1-4,g为0或1-(2f+1),X为0或1。特别优选的式I化合物中,Q是O,X是O,Y是CR3,m是0,B是-CO2G,在此G是支链或直链脂族(C1-C16)-烷基,2-环己基乙基,(C1-C4)-烷氧基-(C1-C2)-烷基,支链或直链(C2-C10)-链烯基,苯基,苄基,苯乙基,苯丙基或苯丁基,A是-CH2-基团,R1是氢,(C1-C6)-烷氧基或-O-〔CH2〕x-CfH(2f+1-g)Fg,R2是氢,N-((C1-C10)-烷基氨基甲酰基,N-((C1-C10)-烷氧基-(C1-C3)-烷基)-氨基甲酰基,N,N-二-(C1-C8)-烷基氨基甲酰基,N-(C5-C6)-环烷基氨基甲酰基,N-苯基氨基甲酰基,N-苯基-(C1-C4)-烷基氨基甲酰基,羧基,(C1-C16)-烷氧羰基,(C2-C16)-链烯氧羰基,视黄基氧基羰基,(C5-C6)-环烷氧羰基,(C5-C6)-环烷基-(C1-C6)-烷氧羰基或苯基-(C1-C6)-烷氧羰基,在此芳基可被1或2个相同或不同的下列取代基取代:氟,氯,氰基,三氟甲基,(C1-C10)-烷基,(C2-C10)-烯氧基或(C1-C10)-烷氧基,R3是氢,(C1-C5)-烷氧基或(C5-C6)-环烷基-(C1-C2)-烷氧基,在此取代基R1和R3之一是氢,R4是支链或直链(C1-C6)-烷基,或2-苯乙基,或被1或2个下列基团取代的苄基:氟,氯,氰基,三氟甲基,(C1-C6)-烷基,(C1-C6)-烷氧基,-O-〔CH2〕x-CfH(2f+1-g)Fg,N-(C1-C8)-烷基氨基甲酰基,N,N-二-(C1-C6)-烷基氨基甲酰基,N-(C3-C6)-环烷基氨基甲酰基或N-(+)-脱氢枞酸基氨基甲酰基,而f是1-4,g是0或1-(2f+1),X是1。最优选的式I化合物中,Q是O,X是O,Y是CR3m是0,A是-CH2-基团,B是-CO2G,在此G是支链或直链脂族C1-C16)-烷基或苄基,R1是氢,R2是氢,N-C1-C10)-烷基氨基甲酰基,N-(C1-C12)-烷氧基-C1-C3)-烷基)氨基甲酰基,N-环己基氨基甲酰基,N-苯基氨基甲酰基,N-(苯基-C1-C2)-烷基)氨基甲酰基,在最后两种情况下,苯基可带有氟取代基,(C1-C10)-烷基取代基或(C1-C10)-烷基取代基,羧基,(C1-C16)-烷氧羰基,(C2-C16)-链烯氧羰基,视黄基氧基羰基,(C5-C6)-环烷氧羰基或苄氧羰基,R3是氢,(C1-C5)-烷氧基或2-(环己基)乙氧基,在此取代基R2和R3之一是氢,R4是支链或直链(C1-C4)-烷基或被氟,氯,三氟甲基,(C1-C4)-烷基或(C1-C3)-烷氧基取代一次的苄基。另一种最优选的式I化合物中,Q是S,x是O,Y是CR3,m是0,A是-CH2-基团,B是-CO2G,在此G是支链或直链脂族(C1-C16)-烷基或苄基,R1是氢,R2是氢,N-(C1-C10)-烷基氨基甲酰基,N-(C1-C12)-烷氧基-(C1-C3)-烷基)氨基甲酰基,N-环己基氨基甲酰基,N-苯基氨基甲酰基,N-(苯基-(C1-C2)-烷基)氨基甲酰基,在最后两种情况下,苯基可带有氟取代基,(C1-C10)-烷基取代基或(C1-C10)-烷氧基取代基,羧基,(C1-C10)-烷氧羰基,(C2-C16)-链烯氧羰基,视黄基氧羰基,(C5-C6)-环烷氧羰基或苄氧羰基,R3是氢,(C1-C5)-烷氧基或2-(环己基)乙氧基,在此取代基R2和R3之一是氢,R4是支链或直链(C1-C4)-烷基或被氟,氯,三氟甲基,(C1-C4)-烷基或(C1-C3)-烷氧基取代一次的苄基。另一种最优选的式I化合物中Q是S,x是O,Y是CR3,m是0,A是-CH2-基团,B是-CO2G,在此G是支链或直链脂族(C1-C16)-烷基或苄基,R1是氢,R2是羧基或(C1-C16)-烷氧羰基,R3是氢,R4是支链或直链(C1-C4)-烷基,另一种最优选的式I化合物中,Q是O,x是OY是CR3,在此R3是氢,m是0,A是-CH2-基团,B是-CO2G,在此G是支链或直链脂族(C1-C16)-烷基或苄基,R1和R2与带有它们的吡啶一起形成具有未取代的苯并部分的异喹啉环,R4是甲基。另一种最优选的式I化合物中,Q是O,x是OY是CR3,m是0,A是-CH2-基团,B是-CO2G,在此G是支链或直链脂族(C1-C16)-烷基或苄基,R1是氢,R2和R3与带有它们的吡啶一起形成具有未取代的苯并部分的喹啉环,R4是甲基。
本发明涉及式I化合物,以及其生理上可耐受盐在抑制胶原的生物合成的应用。
本发涉及式I化合物及其生理上的可耐受盐在抑制体内的脯氨酰-4-羟化酶的应用。
本发明涉及式I化合物及其生理上可耐受盐在生产抗纤维变性疾病的药物的应用。
本发明还涉及式I化合物及其生理上可耐受盐在生产抗肝脏、肺和皮肤的纤维性疾病的药物的应用。
最后,本发明涉及作为药物使用的式I化合物。
特别是,本发明涉及作为纤维化抑制剂使用的式I化合物。
本发明还涉及一种制备式I化合物的方法。
式I的化合物,其中A是取代的亚烷基部分,B是CO2G,Y是CR3,m是0或1,制备方法如下:
i1)使式II的吡啶-2-羧酸(R23为H)与式III的氨基酯反应,生成式I的酰胺酯或
i2)使式II的吡啶-2-羧酸酯(R23为(C1-C16)-烷基)在氨解条件下反应,生成式I的化合物;或
ii)用醇GOH酯化式IV的化合物;或
iii)用R4X使式V的化合物烷基化,并且,在适当的情况下,
iv)使式I的化合物(条件是Q为O或NR′)转化为它们的吡啶N-氧化物(式I′)。
R23是H或(C1-C16)-烷基,
x是离去基团,特别是:卤素,OSO2:Me或OSO2苯基。
肽化学中已知的羧基活化和缩合反应的方法是酰胺生成(反应i1)的适宜方法。
可以使用本领域的技术人员已知的物质如亚硫酰氯,草酰氯,新戊酰氯,氯甲酰酯衍生物,或N,N′-羧基二咪唑作为羧酸活化的试剂;可就地制备式II化合物的活化衍生物,然后使之与式III的酰胺衍生物反应。
一例适宜的缩合剂是N,N′-二环己基碳化二亚胺/N-羟基-1H-苯并三唑和N-乙基吗啉的结合体。
适宜的溶剂是二氯甲烷,四氯甲烷,乙酸丁酯,甲苯,四氢呋喃,二甲氧乙烷,1,4-二恶烷,乙腈,N,N-二甲基甲酰胺,N,N-二甲基乙酰胺,二甲亚砜,硝基甲烷和/或吡啶。
式I的化合物,其中R1和R3是氢,R2是羧基取代基,氨基甲酰基取代基或酯取代基,如方案1,2和3所述制备。
方案2说明了式II化合物的制备,其中R2是羧酸取代基,或其衍生物,R1和R3是氢。
式XI的3-取代的5-羧基吡啶-2-羧酸酯及其式XII的异构体可以从式VII的吡啶-1,5-二羧酸二酯制备。
式VII的吡啶-2,4-二羧酸酯的氧化述于J Chem.SocPerkin Trans 2,1978,34-38,和J Org.Chem.25(1960)565-568(M.L.Peterson)。
式VIII的吡啶N-氧化物用亚硫酰氯卤化(氯化)和3-氯吡啶-2,5-二羧酸二酯(式IX)与醇化物(Q是O或S)反应可按专利说明书CH 658 651(LONZA)中所述方法的类似方法进行,在此M是带有单电荷或带有双电荷的金属离子,较好的是周期表第一或第二主族的金属离子。
与已知的文献(CA:Vol 68,1968,68840h)类似,在水解条件下,由式xb的取代的吡啶-2,5-二羧酸二酯制备式XII的单酯。
由式Xb的二酯制备式XII化合物的另一种方法是使用Cu(II)盐的选择性水解(J Delarge,Phermaceutica Acta Helvetiae44,637-643,1969)。
使制得的式XII化合物与式III的氨基酯反应生成式IV的化合物(方案2)。
式XI的吡啶-2-羧酸酯-5-羧化物可在酯化条件下由式Xa的取代的吡啶-2,5-二羧酸制备(见CA:Vol 68,1968,68840h)。例如,适宜的条件是在硫酸存在下用甲醇进行酯化,选择反应时间是必要的,以便形成二酯产物的完全酯化,只在二级程度上发生,或以便可将二酯产物作为副产物分离除去。方案2
式XI的化合物可用胺或醇转化为式XIV的5-羧酸衍生物(方案3)。
EP-A-0 304 732,EP-A-0 321 385和EP-A-0 208452公开的2-羟基甲基吡啶可被用做制备4位上被(R1)取代的衍生物的中间体。VI II (R11·H)VIo/IIo:QR4·QMa(Ma·甲基)VIb/IIb:QR4·QBn(Bn·苄基)
如上述文献所述,用相似的方式得到式VIb的3-O-苄基衍生物。
在碱性含水介质中,式VIa和VIb的化合物与氧化剂,较好为KMnO4反应,形成式II的吡啶-2-羧酸衍生物。
取代的吡啶-2-羧酸的制备例如可见DE-A-353 046,3-(3-氯苯氧基)吡啶-2-羧酸和3-(3-甲基苯氧基)吡啶-2-羧酸的制备见J.Med.Chem.1975,18,pp.1-8,Villani et al.,3,5-二乙氧基吡啶-2-羧酸的制备见J.Med.Chem.1974,17,pp.172-181,French et al.,3-甲基硫代吡啶-2-羧酸和3-苄基硫代吡啶-2-羧酸制备见J.Med.Chem.1974,17,pp.1065-1071,Blank et al.,3-甲氧基吡啶-2,5-二羧酸的制备见CH-PS 658 651。
式I的新化合物具有有价值的药理性能,特别是抗纤维化活性。
可以采用四氯化碳诱发肝纤维化的模型测定抗纤维化效果。在此,用溶于橄榄油的CCl4每周两次处理大鼠(1ml/kg)。受试物质溶于适当溶剂每日口服或腹膜内给药,可一日两次。通过组织学确定肝纤维性变的程度,肝中胶原的比例通过测定羟基脯氨酸分析(如Kivirikko等人在Anal.Biochem.19,249 f.1967中所述)。可用放射免疫法测定血清中胶原片断和原胶原肽的方法测定生纤维活性,新化合物在浓度为1-100mg/kg时具有活性。
可通过放射免疫法测定血清中胶原型III的N端前肽或胶原型IV(7s胶原或型IV胶原NC1)的N端或C端交联区确定生纤维活性。
为此,测定了
a)未处理的大鼠(对照)
b)用过四氯化碳的大鼠(CCl4对照)
c)先用过CCl4,然后用新化合物的大鼠(这一试验方法述于“Rouiller,C.,Experimental toxic injury of the liver;in TheLiver,C.Rouiller,vol.2,5.335 to 476,New York,AcademicRress,1964”)。
新化合物在下述体系中也证实有活性。
体内抑制肝的脯氨酰-4-羟化酶:
这一模型用来表明在体内急剧抑制脯氨酰-4-羟化酶。在此,将受试物质或相应载体给予(腹膜内,静脉内或口服)雄性和雌性大鼠(健康的或诱发肝纤维化的),然后经腹膜内给予14C-L-脯氨酸(250μCi/kg体重)。接着再经腹膜内给予14C-L-脯氨酸(250uCi/kg体重),最后在戊巴比妥麻醉下处死动物,取出肝脏。通过用胃蛋白酶消化和硫酸铵分段沉淀纯化肝胶原(根据公开文献1和2)。纯化的肝胶原水解,采用离子交换色谱通过氨基酸分析测定14C-羟基脯氨酸和14C-脯氨酸含量。系数14C-羟基脯氨酸/〔14C-羟基脯氨酸+14C-脯氨酸〕的降低表明对脯氨酰-4-羟化酶的抑制。用2,2′-二吡啶作为参照物。(1:Chojkier,M.1986,Hepatocyte Collagen Production in Vivo in normalrats,J.Clin.Invest.78:333-339,2:Ogata I.,et al.1991,Minor contribution of hepatocytes to Collagen Production innormal and early fibrotic livers,Hepatology 14:361-367)。
细胞培养物中抑制脯氨酰-4-羟化酶:
使用下述细胞类型试验细胞培养物中脯氨酰-4-羟化酶的抑制剂:
正常人表皮成纤维细胞,(NHDF),小鼠肝上皮细胞(文献1)和大鼠肝脏的初级脂肪储藏细胞(文献2)。
在此,在抑制剂存在下对细胞进行培养。同时,在此期间新合成的胶原用4-3H-L-脯氨酸和14C-脯氨酸进行代谢标记。受试物质对胶原的羟基化的影响程度根据Chojkier等人的方法(文献3)测定。使用2,2′-二吡啶作为参照物。(1:Schrode,W.,Mecke,D.,Gebhard,R.1990,Induction of glutaminesynthetase in periportal hepatocytes by co-cultivation with aliver epithelial cell line,Eur.J.Cell.Biol.53:35-41;2:Blomhoff,R.,Berg T.1990,Isolation and Cultivation of ratliver stellate cells,Methods Enzymol.190:59-71;3:Chojkier,M.Peterkofsky,B.Bateman,J.1980,A new method fordetermining the extent of proline hydroxylation by measuringchanges in the ration of〔4-3H〕:〔14C〕Proline inCollagenase digests,Anal.Biochem.108:385-393)
式I的化合物可以含有该化合物和适当的药物赋形剂的药物制剂形式作为药物使用。例如,药物制剂可以是在混合物中含有所述化合物和适合于肠道、皮下和非肠道用药的药用有机或无机赋形剂如水、阿拉伯胶、明胶、乳糖、淀粉、硬脂酸镁、滑石、植物油、聚亚烷基二醇、凡士林等。
作为药物,所述化合物口服的剂量为0.1-25mg/kg/日,优选为1-5mg/kg/日;或非肠道的剂量为0.01-5mg/kg/日,优选为0.01-2.5mg/kg/日,最好为0.5-1.0mg/kg/日。在病状严重的情况下可以加大剂量。然而,在许多情况下更小的剂量也是有效的。上述数据针对约75kg体重的成人而言。
在下面的实施例中,将式I的新化合物指定为取代的杂环羧酸(氨基酸酯)酰胺,特别是吡啶-2-羧酸(甘氨酰酯)酰胺,这一指定方式应理解为例如表示取代的吡啶-2-羧酸N-((烷氧羰基)甲基)酰胺。另一个意义是将它们列为取代的N-(吡啶-2-羰基)甘氨酸。
实例1
3-甲氧基-4-(2,2,2-三氟乙氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
a)2-甲基-3-甲氧基-4-氯吡啶N-氧化物
在100ml磷酰氯中回流加热11.2g(80.5mmol)3-甲氧基-2-甲基-4(1H)-吡啶酮10小时。然后浓缩混合物,每2ml体积加入30ml甲苯,再次浓缩,残余物浸溶于150ml水,用K2CO3将pH调至11,然后用二氯甲烷萃取该混合物,有机相用水洗涤,干燥和脱除溶剂。
在标准条件下,使用溶于二氯甲烷的间氯过苯甲酸,自淡褐色油(9g)得到8g产物,m.p.88-89℃(石油醚)。
b)2-甲基-3-甲氧基-4-(2,2,2-三氟乙氧基)吡啶N-氧化物
于-20℃在氨气氛和搅拌下,将6.7g叔丁氧钾分批加到20ml三氟乙醇中。将混合物温热至0℃后,分批加入5.2g(30mmol)2-甲基-3-甲氧基-4-氯吡啶N-氧化物。混合物回流加热3小时,然后静置冷却至室温;再加入3.45g叔丁氧钾,混合物回流加热2小时。冷却后,将40ml水加到反应混合物中,然后用二氯甲烷萃取,萃取物用硫酸镁干燥,真空脱除溶剂。得到的油状产物用于下一步反应。
c)3-甲氧基-4-(2,2,2-三氟乙氧基)-2-羟甲基吡啶
于80℃和搅拌下将8g(33.8mmol)上述化合物溶于16ml冰乙酸中,加入24ml乙酸酐。反应混合物在110℃加热2小时,然后冷却至80℃;滴加40ml甲醇。真空浓缩该混合物,油状残余物加到75ml 2N甲醇NaOH中,混合物搅拌30分钟。经过活性炭处理,过滤,真空浓缩混合物;向残余物中加入50ml水,接着用二氯甲烷萃取;萃取物经干燥(MgSO4)和浓缩,用二异丙醚处理残余物。得到3.9g无色晶体形式的产物,m.p.107-108℃。
d)3-甲氧基-4-(2,2,2-三氟乙氧基)吡啶-2-羧酸
将0.8g(3.3mmol)上述醇溶于0.3g氢氧化钾和25ml水的溶液中,在100℃和搅拌下,分批加入1.6g高锰酸钾。脱色后,吸滤除去形成的二氧化锰,用热水洗涤两次,真空浓缩滤液至其1/3体积,用浓盐酸水溶液调节pH至1,真空浓缩;残余物用无水乙醇处理,滤除不溶物,自滤液中得到0.73g产物,m.p.157℃。
e)为制备标题化合物,将0.58g(2.3mmol)上述羧酸悬浮于100ml无水四氢呋喃,在20℃和搅拌下,加入322mg(2.3mmol)甘氨酸乙酯盐酸盐,0.64ml(5mmol)N-乙基吗啉,350mg(2.6mmol)1-羟基-1H-苯并三唑和537mg(2mmol)N,N′-二环己基碳化二亚胺,混合物在20℃搅拌48小时。滤除不溶物,真空浓缩滤液,残余物浸溶于乙酸乙酯并滤除不溶物;滤液与100ml饱和碳酸氢钠水溶液一起搅拌,干燥并真空浓缩有机相,用二异丙醚结晶残余物,得到0.45g无色晶体状产物,m.p.80-82℃。
实例2
4-氯-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
a)4-氯-2-羟甲基-3-甲氧基吡啶
将30g(173mmol)4-氯-3-甲氧基-2-甲基吡啶N-氧化物(参见实例1a)溶于100ml冰乙酸,然后在80℃搅拌下滴加150ml乙酸酐,混合物在110℃搅拌2小时。将混合物冷却至80℃,滴加200ml甲醇,加热沸腾混合物15分钟;冷却后,真空浓缩,将残余物浸溶于甲醇,使该混合物流入300ml 1.5N甲醇氢氧化钠溶液,在20℃搅拌30分钟,真空浓缩;残余物浸溶于水,用二氯甲烷萃取三次,干燥并浓缩有机相,用石油醚结晶残余物,得到23g产物,m.p.64-66℃。
b)4-氯-3-甲氧基吡啶-2-羧酸
将8.65g(50mmol)上述醇溶于0.8g氢氧化钾和60ml水的溶液中,在60℃搅拌下分批加入高锰酸钾(12g,75mmol)至无脱色现象发生。60℃静置1小时后,吸滤除去二氧化锰,用热水洗涤;真空浓缩滤液至200ml,冷却中用浓HCl将pH调至1。研磨后,冷却中结晶出产物。通过用石油醚处理可得到额外产物。总产率4.2g,m.p.116-117℃(气体产生法)。
c)为制备标题化合物,将4.7g(25mmol)上述羧酸悬浮于200ml无水二氯甲烷,然后在20℃和搅拌下先加入3.5g(25mnmol)甘氨酸乙酯盐酸盐,6.4ml(50mmol)N-乙基吗啉,3.8g(28mmol)1-羟基-(1H)-苯并三唑和5.15g(25mmol)N,N′-二环己基碳化二亚胺,混合物在20℃搅拌20小时。滤除不溶物,有机相与碳酸钠饱和水溶液一起震摇,干燥并真空浓缩,残余物用乙酸乙酯进行硅胶柱色谱层析,得到5.4g油状产物。
实例3
4-丁氧基-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例4
3,4-二甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例5
3-乙氧基-4-(3-甲氧基苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例6
4-己氧基-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例7
3-甲氧基-4-(3-甲基丁氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例8
4-(4-氯苄氧基)-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例9
3-甲氧基-4-(4-三氟甲基苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例10
3-甲氧基-4-(2,2,3,3,3-五氟丙氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例11
4-(2,2,3,3,4,4,4-七氟丁氧基)-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例12
4-(3-甲氧基苄氧基)-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例13
3-乙氧基-4-(2,2,2-三氟乙氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例14
4-丁氧基-3-乙氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例15
3-甲氧基-4-((2-苯氧乙基)氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例16
3-乙氧基-4-(苄氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例17
3,6-二甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
a)3,6-二甲氧基-2-甲基吡啶N-氧化物
将1.15g(50mmol)钠溶于100ml无水甲醇,然后在20℃搅拌下加入7.4g(40mmol)3-甲氧基-2-甲基-6-硝基吡啶N-氧化物。将混合物加热至回流3小时,冷却后,真空浓缩,残余物浸溶于水,用二氯甲烷萃取该混合物,有机相经干燥和浓缩,残余物用二异丙醚结晶,得到7g产物,m.p.63-65℃。
b)3,6-二甲氧基-2-羟甲基吡啶
与实例1c)相似,使7g(41.4mmol)上述化合物与冰乙酸/乙酸酐反应,使用1.5N甲醇氢氧化钠溶液水解得到的乙酸酯。得到5.6g油状产物,用于下步反应c)。
c)3,6-二甲氧基吡啶-2-羧酸
将5.6g(33mmol)上述化合物和2.4g氢氧化钾溶于150ml水,然后在60℃和搅拌下分批加入15g(100ml)高锰酸钾。吸滤除去形成的二氧化锰,用热水洗涤两次,合并的水相浓缩至100ml,冰冷下用浓盐酸将pH调至1,真空浓缩,用乙酸乙酯和乙醇处理残余物,从混合物中滤除不溶物,真空浓缩滤液,残余物用二乙醚结晶,得到4g产物,m.p.131-132℃(气体发生法)。
d)为制备标题化合物,将2.2g(12mmol)上述羧酸悬浮于300ml(无水二氯甲烷,然后在搅拌下加入1.68g(12mmol)甘氨酸乙酯盐酸盐,3.25ml(25mmol)N-乙基吗啉,1.62g(12mmol)1-羟基-1H-苯并三唑和5.2g(12mmol)N-环己基-N′-(2-吗啉代乙基)碳化二亚胺甲基对甲苯磺酸盐,混合物在20℃搅拌20小时,滤除少量的不溶物,滤液与水一起震摇一次,然后子饱和碳酸氢钠水溶液一起震摇一次,干燥并浓缩有机相,用二异丙醚结晶残余物,得到2g产物,m.p.93-95℃。
实例18
3,5-二乙氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例19
3-甲氧基-6-(3-甲基丁氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例20
3-苄氧基-4-(3-乙氧基丙氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例21
3-苄氧基-4-己氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例22
6-(2-丁氧乙氧基)-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例23
6-丁氧基-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例24
3-乙氧基-6-甲基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例25
6-苄氧基-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例26
3-苄氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例27
3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
m.p.141-142℃(气体发生法,自二乙醚)
该乙酯得自4-氯-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺(见实例2c)的催化氢化,前述化合物得自4-氯-3-甲氧基吡啶-2-羧酸(m.p.119-120℃,自4-氯-3-甲氧基-2-甲基吡啶N-氧化物与乙酸酐/冰乙酸的反应和随后的2-羟甲基吡啶衍生物的氧化)(见实例2a和2b)和甘氨酸乙酯盐酸盐。
实例28
3-乙氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例29
3-丙氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例30
3-丁氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
a)3-正丁氧基吡啶-2-羧酸
在20℃和搅拌下,将6g(150mmol)NaH(60%,矿物油中)分批加到9.8g(70mmol)3-羟基吡啶-2-羧酸于150ml N,N-二甲基乙酰胺的溶液中。30分钟后,滴加15ml(140mmol)丁基溴,混合物在95℃至125℃间加热2.5小时。冷却后,混合物经真空浓缩,用碳酸氢钠水溶液处理,用二氯甲烷萃取;干燥后,用乙酸乙酯在硅胶上进行色谱提纯。将所得13g产物引入250ml 1.5N甲醇氢氧化钠溶液,混合物在20℃搅拌30分钟,真空浓缩;残余物浸溶于250ml水,混合物用二氯甲烷萃取,用浓盐酸将水相调至pH1,真空浓缩,残余物用乙酸乙酯处理,然后用无水甲醇处理。所得溶液经浓缩,用丙酮结晶。得到9.3g产物(m.p.93-95℃),根据1H NMR,产物中仍含有约20%3-羟基吡啶-2-羧酸。
b)在20℃搅拌下,将2.8g(20mmol)甘氨酸乙酯盐酸盐,5.2ml(40mmol)N-乙基吗啉,2.7g(20mmol)1-羟基-1H-苯并三唑和3.0ml(20mmol)N,N′-二异丙基碳化二亚胺加到4g(20mmol)上述产物于200ml无水四氢呋喃和100ml无水乙腈的溶液中,混合物在20℃搅拌20小时。用碳酸氢钠溶液处理和脱除析出的二异丙基脲后,经硅胶色谱(乙酸乙酯/正庚烷1∶1,然后纯乙酸乙酯),得到3.5g油状产物,其中仍含有N,N′-二异丙基脲。
实例31
3-(4-氯苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
a)3-(4-氯苄氧基)吡啶-2-羧酸4-氯代苄酯
以与实例30a)相似的方式,在N,N-二甲基乙酰胺中用5.2g(约130mmol,60%)氢化钠和19.3g(120mmol)4-氯苄基氯烷基化8.4g(60mmol)3-羟基吡啶-2-羧酸(110℃,3小时)。直空浓缩和用碳酸氢钠溶液萃取后,残余物在硅胶上用庚烷/乙酸乙酯(1∶1)提纯,用二丙醚自适当的馏分结晶出14.8g产物,m.p.92-94℃。
b)3-(4-氯苄氧基)吡啶-2-羧酸
用200ml 1.5N甲醇氢氧化钠水解9.7g(25mmol)上述酯(20℃,20小时)。处理(浓缩,浸溶于水,二氯甲烷萃取和酸化)后,得到6.5g产物,m.p.144℃(水中,分解)。
c)为制备标题化合物,以与实例17d)相似的方式,使3.2g(12mmol)上述吡啶-2-羧酸与1.7g(12mmol)甘氨酸乙酯盐酸盐,1.62g(12mmol)1-羟基-(1H)-苯并三唑,3.3ml(25mmol)N-乙基吗啉和5.2g(12mmol)N-环己基-N′-(2-吗啉代乙基)碳化二亚胺甲基对甲苯磺酸盐反应。处理后,用二异丙醚结晶出3.0g产物,m.p.106-108℃。
实例32
3-(3-甲氧基苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
a)3-(3-甲氧基苄氧基)吡啶-2-羧酸3-甲氧基苄酯
以与实例38a)相似的方式,经硅胶色谱,自8.4g(60mmol)3-羟基吡啶-2-羧酸和3-甲氧基苄基氯得到10g无色油状产物,用于下一步反应。
b)3-(3-甲氧基苄氧基)吡啶-2-羧酸
10g上述酯在300ml 1.5N甲醇氢氧化钠中水解,得到7.5g产物,m.p.147℃(分解,含水盐酸中)。
c)为制备标题化合物,以与实例31c)相似的方式使3.2g(12mmol)上述羧酸反应。分离出3.6g油状粗产物,根据1HNMR谱,其中仍含有N-乙基吗啉。自该粗产物得到纯物质(自二异丙醚/乙酸乙酯),m.p.135-137℃。
实例33
3-(2-苯基乙氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
a)3-((2-苯基乙氧基)吡啶-2-羧酸
以与实例30a)相似的方式,在N,N′-二甲基乙酰胺中用NaH/2-苯乙基溴烷基化8.4g(60mmol)3-羟基吡啶-2-羧酸。柱色谱提纯后得到的10g油状产物以与实例30a)的方法用甲醇氢氧化氢溶液水解,得到3g产物(m.p.145℃(发泡法,丙酮中),根据1H NMR谱,仍含有约25%3-羟基吡啶甲酸。
b)为制备标题化合物,以与实例30b)相似的方式,使2.9g上述化合物与甘氨酸乙酯盐酸盐,N-乙基吗啉,1-羟基-1H-苯并三唑和N,N′-二环己基碳化二亚胺反应。处理后,用乙酸乙酯在硅胶上色谱提纯粗产物。开始洗脱出副产物3-羟基吡啶-2-羧酸(甘氨酰乙酯)酰胺,用石油醚自适当的馏分结晶出1.1g(m.p.86-88℃,紫外线下呈强荧光)。然后用二异丙醚自适当的馏分结晶产物,得到产物1.7g m.p.73-75℃。
实例34
3-(4-三氟甲基苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
m.p.107-109℃
实例35
3-(4-(2-丙基)苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺,无色油
实例36
3-(4-氟苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
m.p.97-99℃(自二异丙醚)
实例37
3-(4-(2-(4-甲氧苯基)乙基氨基)羰基)苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
m.p.141-143℃(自二乙醚/乙酸乙酯(9∶1))
以相似的方式制备下面实例38-64
实例38
3-(2,4-二氯苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例39
3-(3-氟苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例40
3-(3-氯苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例41
3-(3,4-二氯苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例42
3-(3-三氟甲氧基苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例43
3-(4-三氟甲氧基苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例44
3-(3-乙氧基苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例45
3-(4-氰基苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例46
3-((2-吡啶基甲基)氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺盐酸盐
实例47
3-((3-吡啶基甲基)氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺盐酸盐
实例48
3-((4-吡啶基甲基)氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺盐酸盐
实例49
3-(2-噻吩基甲基)氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例50
3-(3,5-二甲氧基苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例51
3-环己基氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例52
3-(3-苯基丙氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例53
3-(4-苯基丁氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例54
3-(((4-甲氧基-2-吡啶基)甲基)氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例55
3-(((4-乙氧基-2-吡啶基)甲基)氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例56
3-甲硫基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例57
3-苄硫基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例58
3-(3-氯苯氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例59
3-(3-甲氧基苯氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例60
3-苯氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例61
3-丁氧基吡啶-2-羧酸(L-丙氨酰乙酯)酰胺
实例62
3-丁氧基吡啶-2-羧酸(D-丙氨酰乙酯)酰胺
实例63
3-苯氧基吡啶-2-羧酸(β-丙氨酰乙酯)酰胺
实例64
3-(3-甲基丁氧基)吡啶-2-羧酸(L-亮氨酰乙酯)酰胺
实例65
4-甲氧基异喹啉-3-羧酸(甘氨酰甲酯)酰胺
a)1,2-二氢-4-羟基-1-氧代异喹啉-3-羧酸甲酯(如M.Suzuki et al.,Synthesis 1978,461所述制备)
b)1,2-二氢-4-甲氧基-1-氧代异喹啉-3-羧酸甲酯(自a),使用三甲基甲硅烷基叠氮甲烷于甲醇/乙腈中制备,m.p.177-179℃,(乙酸乙酯/庚烷))
c)1-氯-4-甲氧基异喹啉-3-羧酸甲酯(自b),使用磷酰氯制备,m.p.108℃(乙酸乙酯))
d)4-甲氧基异喹啉-3-羧酸甲酯(自c),使用H/Pd/C制备,m.p.129℃(甲基叔丁醚))
e)4-甲氧基异喹啉-3-羧酸(水解d制备),m.p.185-189℃(含水盐酸))
f)使用DCC,HOBT,THF和NEM,由上述化合物和甘氨酸甲酯盐酸盐制备出标题化合物,油状物质,1H NMR(CDCl3):δ=4.33(d,CH2-甘氨酸)。
从相应的异喹啉-3-羧酸或4,6,7,8-四氢衍生物以相似的方式分别得到实例66-76。
实例66
4-乙氧基异喹啉-3-羧酸(甘氨酰乙酯)酰胺
实例67
4-丙氧基异喹啉-3-羧酸(甘氨酰乙酯)酰胺
实例68
4-(3-甲基丁氧基)异喹啉-3-羧酸(甘氨酰乙酯)酰胺
实例69
4-甲氧基-5,6,7,8-四氢异喹啉-3-羧酸(甘氨酰乙酯)酰胺
实例70
4-(3-甲基丁氧基)-5,6,7,8-四氢异喹啉-3-羧酸(甘氨酰乙酯)酰胺
实例71
4-乙氧基-5,6,7,8-四氢异喹啉-3-羧酸(甘氨酰乙酯)酰胺
实例72
4-苄氧基-5,6,7,8-四氢异喹啉-3-羧酸(甘氨酰乙酯)酰胺
实例73
4-苄氧基异喹啉-3-羧酸(甘氨酰乙酯)酰胺
实例74
4-(3-甲氧苄氧基)-5,6,7,8-四氢异喹啉-3-羧酸(甘氨酰乙酯)酰胺
实例75
7-溴-甲氧基异喹啉-3-羧酸(甘氨酰乙酯)酰胺
实例76
7-甲氧基-4-甲氧基异喹啉-3-羧酸(甘氨酰乙酯)酰胺
实例77
3-甲氧基-6-((3-甲基丁氧基)甲基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例78
3-甲氧基-6-((环己基氧基)甲基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例79
3-甲氧基-6-苄氧基甲基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例80
5-羧基-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例81
5-甲氧羰基-3-甲氧基吡啶-2-羧酸(甘氨酰苯酯)酰胺
a)5-甲氧羰基吡啶-2-羧酸1-氧化物
将12g(60mmol)吡啶-2,5-二羧酸二甲酯悬浮于30ml冰乙酸,然后在20℃搅拌下加入13ml过氧化氢(35%)。搅拌下将混合物加热至100℃(内部温度),在50℃形成清辙溶液。在100℃搅拌90分钟后,使其冷却至20℃,吸滤除去结晶沉淀,用水洗涤,干燥后得到7.5g产物,m.p.160℃(分解)。
b)3-氯吡啶-2,5-二羧酸二甲酯
搅拌下将17ml亚硫酰氯,35ml无水氯仿和1.5ml N,N-二甲基甲酰胺加热至60℃,在此温度下分几份将7.5g上述产物加入。混合物在60℃继续搅拌60分钟,冷却后,真空除去溶剂和多余的试剂;将二氯甲烷加到残余物中,吸滤除去N,N-二甲基甲酰胺×HCl(复合物,然后用二氯甲烷洗涤,冷却下向母液中加入约15ml三乙胺和10ml甲醇,混合物搅拌30分钟。真空蒸发浓缩后,将残余物溶于50ml水中,混合物用二氯甲烷萃取三次,干燥并浓缩有机相,残余物用正庚烷和正庚烷/乙酸乙酯(3∶1)进行硅胶色谱纯化,用石油醚结晶出5.3g产物,m.p.36-38℃。
c)3-甲氧基吡啶-2,5-二羧酸
将53g(0.231mol)上述二酯溶于500ml甲醇,然后在20℃搅拌下加入150ml(0.81mol)甲醇钠溶液(30%甲醇溶液),此时将温度升至30℃。将混合物回流加热4.5小时,20℃下加入300ml水,混合物在35℃搅拌30分钟,真空蒸除多余的甲醇,冷却下用半浓缩含水盐酸将水相调至pH2。吸滤出无色晶体产物,得到49g,m.p.185℃(气体发生法);255℃(分解)。
d)3-甲氧基吡啶-2,5-二羧酸二甲酯
(参照实例90a))
e)5-甲氧羰基-3-甲氧基吡啶-2-羧酸
通过用稀释的甲醇氢氧化钠溶液(0.54g NaOH,13.5mmol)水解上述二酯,自3.4g(15mmol)上述二酯得到与单乙酯异构体混合的所述化合物(参照实例90a))。除1.8g未反应的二酯,得到1.8g单酯混合物,m.p.152℃。
f)在N-乙基吗啉,1-羟基-1H-苯并三唑和CMC存在下,以与实例90b)相似的方式用2.9g(8.6mmol)甘氨酸苄酯甲苯磺酸盐缩合1.8g上述混合物。处理后,用二氯甲烷(加至多为2%甲醇)对2.3g油状混合物进行硅胶色谱提纯,得到0.82g产物,m.p.108℃,分离出0.6g油状异构体。
实例82
5-(3-戊氧基)羰基-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例83
5-环己氧基羰基-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例84
5-(正丁基氨基羰基)-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例85
5-(2-甲基-2-丁基氨基羰基)-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例86
5-(环己基氨基羰基)-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
a)5-(环己基氨基羰基)-3-甲氧基吡啶-2-羧酸
以与实例90b)相似的方式,自5-羧基-3-甲氧基吡啶-2-羧酸和环己胺得到产物,m.p.155℃(80℃熔结,含水盐酸)。
b)以与实例90c)相似的方式,自上述化合物得到标题化合物,m.p.187-188℃(二乙醚)。
实例87
5-(环己基氨基羰基)-3-乙氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例88
5-((2-苯乙基)氨基羰基)-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例89
5-((+)-脱氢枞酸基氨基羰基)-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
a)5-((+)-脱氢枞酸基氨基羰基)-3-甲氧基吡啶-2-羧酸
以与实例90a)相似的方式,自5-羧基-3-甲氧基吡啶-2-羧酸甲酯和(+)-脱氢枞酸基胺得到树脂状产物。
b)以与实例90c)相似的方式,经水解,自上述化合物得到标题化合物,m.p.自150℃发泡(120℃熔结,二乙醚)。
实例90
5-((2-(4-氟苯基)乙基)氨基羰基)-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
a)5-羧基-3-甲氧基吡啶-2-羧酸甲酯
将10g(50.7mmol)3-甲氧基吡啶-2,5-二羧酸(实例81c))悬浮于150ml无水甲醇,然后加入2ml浓硫酸,混合物回流加热3小时。真空蒸除一半甲醇,将残余物引到400ml冰水中。吸滤出结晶残余物,用水洗涤。将残余物溶于150ml饱和碳酸氢钠水溶液,混合物用二氯甲烷(每次80ml)萃取两次,冷却下用半浓缩盐酸水溶液将碳酸氢盐相调至pH1,滤出沉淀产物,干燥,得到5g无色晶体物质,m.p.196-197℃。自二氯甲烷相得到1.7g二甲酯,m.p.53-55℃(石油醚)。
b)5-(((2-(4-氟苯基)乙基)氨基)羰基)-3-甲氧基吡啶-2-羧酸
将3.25-羧基-3-甲氧基吡啶-2-羧酸甲酯悬浮于300ml无水二氯甲烷,然后在20℃搅拌下先后加入2.0ml(15mmol)2-(4-氟苯基)-乙胺,1.95ml(15mmol)N-乙基吗啉,2.2g(16.5mmol)1-羟基-1H-苯并三唑和6.35g(15mmol)N-环己基-N′-(2-吗啉代乙基)碳化二亚胺甲基对甲苯磺酸盐(CMC),混合物搅拌24小时。滤除不溶物,有机相用碳酸氢钠水溶液,1N盐酸水溶液和水分别各萃取三次,干燥并浓缩有机相。得到3.7g甲酯(m.p.168-169℃),将其加到150ml1.5N甲醇NaOH中。30分钟后,浓缩混合物,将其溶于100ml水中,用含水浓盐酸将pH调至1,吸滤出结晶沉淀物,用水洗涤并干燥,得到3.4g产物,m.p.110℃(发泡法,75℃熔结)。
c)以与实例90a)相似的方式,使3.2g(10mmol)上述化合物与1.4g(10mmol)甘氨酸乙酯盐酸盐,N-乙基吗啉,1-羟基-1H-苯并三唑和CMC反应,相似处理后,用二异丙醚结晶出2.8g无色晶体产物,m.p.170-171℃。
实例91
5-((2-(4-甲氧基苯基)乙基)氨基羰基)-3-乙氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例92
5-氯-3-乙氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例93
5-氯-3-乙氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例94
5-环己氧基甲基-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例95
5-(3-甲基丁基)氧基甲基-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例96
5-苄氧基甲基-3-乙氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例97
3-((环己基)甲氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例98
3-((2-环己基)乙氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例99
3-((3-环己基)丙氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例100
3-(3-甲基丁氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例101
3-己氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例102
3-(4-乙基苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例103
3-(4-丙基苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例104
3-(4-丁基苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例105
3-(4-叔丁基苯甲酰氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例106
6-(3-甲氧苄氧基)-3-乙氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例107
3-(4-三氟甲基苄氧基)吡啶-2-羧酸(甘氨酰甲酯)酰胺
实例108
3-(4-(2-丙基)苄氧基)吡啶-2-羧酸(甘氨酰甲酯)酰胺
实例109
3-(3-氟苄氧基)吡啶-2-羧酸(甘氨酰甲酯)酰胺
实例110
3-(4-氟苄氧基)吡啶-2-羧酸(甘氨酰甲酯)酰胺
实例111
3-(2,4-二氯苄氧基)吡啶-2-羧酸(甘氨酰甲酯)酰胺
实例112
3-(4-(2,2,2-三氟乙氧基)苄氧基)吡啶-2-羧酸(甘氨酰甲酯)酰胺
实例113
3-(4-氯苄氧基)吡啶-2-羧酸(甘氨酰丁酯)酰胺
实例114
3-(3,4-二氯苄氧基)吡啶-2-羧酸(甘氨酰丁酯)酰胺
实例115
3-(3-三氟甲基苄氧基)吡啶-2-羧酸(甘氨酰丁酯)酰胺
实例116
3-(4-三氟甲基苄氧基)吡啶-2-羧酸(甘氨酰丁酯)酰胺
实例117
3-(4-(2-丙基)苄氧基)吡啶-2-羧酸(甘氨酰丁酯)酰胺
实例118
3-(4-氟苄氧基)吡啶-2-羧酸(甘氨酰丁酯)酰胺
实例119
3-(4-(2,2,2-三氟乙氧基)苄氧基)吡啶-2-羧酸(甘氨酰丁酯)酰胺
实例120
3-(4-(三氟甲基苄氧基)吡啶-2-羧酸(甘氨酰3-戊酯)酰胺
实例121
3-(4-(2-丙基)苄氧基)吡啶-2-羧酸(甘氨酰3-戊酯)酰胺
实例122
3-(3-氟苄氧基)吡啶-2-羧酸(甘氨酰2-乙基丁酯)酰胺
实例123
3-(4-氟苄氧基)吡啶-2-羧酸(甘氨酰2-乙基丁酯)酰胺
实例124
3-(4-(2,2,2-三氟乙氧基)苄氧基)吡啶-2-羧酸(甘氨酰3-甲基丁酯)酰胺
实例125
3-(三氟苄氧基)吡啶-2-羧酸(甘氨酰3-甲基丁酯)酰胺
实例126
3-(3-三氟甲基苄氧基)吡啶-2-羧酸(甘氨酰环己酯)酰胺
实例127
3-(4-三氟甲基苄氧基)吡啶-2-羧酸(甘氨酰苄酯)酰胺
实例128
3-(4-(2-丙基)苄氧基)吡啶-2-羧酸(甘氨酰苄酯)酰胺
实例129
3-(3-氟苄氧基)吡啶-2-羧酸(甘氨酰苄酯)酰胺
实例130
3-(4-氟苄氧基)吡啶-2-羧酸(甘氨酰苄酯)酰胺
实例131
3-(2,4-二氯苄氧基)吡啶-2-羧酸(甘氨酰苄酯)酰胺
实例132
3-(4-(2,2,2-三氟乙氧基)苄氧基)吡啶-2-羧酸(甘氨酰苄酯)酰胺
实例133
3-(氟苄氧基)吡啶-2-羧酸(甘氨酰己酯)酰胺
实例134
3-(4-氯苄氧基)吡啶-2-羧酸(甘氨酰丁酯)酰胺
实例135
3-(3-三氟甲基苄氧基)吡啶-2-羧酸(甘氨酰己酯)酰胺
实例136
3-(4-三氟甲基苄氧基)吡啶-2-羧酸(甘氨酰2-乙氧乙酯)酰胺
实例137
3-(4-(2-丙基)苄氧基)吡啶-2-羧酸(甘氨酰2-乙氧乙酯)酰胺
实例138
3-(4-氟苄氧基)吡啶-2-羧酸(甘氨酰2-丁氧乙酯)酰胺
实例139
3-(4-氟苄氧基)吡啶-2-羧酸(甘氨酰甲基环己酯)酰胺
实例140
3-(4-(2,2,2-三氟乙氧基)苄氧基)吡啶-2-羧酸(甘氨酰甲基环己酯)酰胺
实例141
3-(三氟苄氧基)吡啶-2-羧酸(甘氨酰2-丙酯)酰胺
实例142
3-(3,4-二氯苄氧基)吡啶-2-羧酸(甘氨酰2-丙酯)酰胺
实例143
3-(4-三氟甲基苄氧基)吡啶-2-羧酸(甘氨酰2-丙酯)酰胺
实例144
3-苄氧基吡啶-2-羧酸(甘氨酰苄酯)酰胺
实例145
3-苄氧基吡啶-2-羧酸(甘氨酰己酯)酰胺
实例146
3-甲氧基吡啶-2-羧酸N-((十六烷基氧基)羰基)甲基)酰胺盐酸盐
以与实例90b)和c)相似的方式将7.7ml(60mmol)N-乙基吗啉,4.5g(33mmol)1-羟基-1H-苯并三唑和12.8g(30mmol)N-环己基-N′-(2-吗啉代乙基)-碳化二亚胺甲基对甲苯磺酸盐(CMC)加到5.7g(30mmol)4-氯-3-甲氧基吡啶-2-羧酸和14.2g(30mmol)甘氨酸十六烷基酯甲苯磺酸盐(m.p.约90℃,用甲苯做水分离剂,自甘氨酸,1-十六烷醇和对甲苯磺酸制备)于300ml二氯甲烷的溶液中,混合物搅拌24小时。滤除不溶物,滤液与碳酸氢钠水溶液,水和含水盐酸一起振摇进行萃取,浓缩有机相,将残余物(14g)溶于500ml四氢呋喃/甲醇(1∶1),然后将Pd/C(10%)加到混合物中,用加氢罐进行氢化。吸氢完成后,吸滤出催化剂,浓缩滤液,用乙酸乙酯对残余物进行硅胶色谱提纯,浓缩适用的馏分,残余物用二乙醚结晶,得到2.1g无色标题化合物,m.p.63-65℃。
实例147
3-甲氧基吡啶-2-羧酸N-(((1-辛氧基)羰基)甲基)酰胺
2.5g(13mmol)3-甲氧基吡啶-2-羧酸盐酸盐(m.p.170℃分解,(乙酸乙酯)),5.5ml(45mmol)N-乙基吗啉,2g(15mmol)1-羟基-1H-苯并三唑,4.7g(13mmol)甘氨酸辛酯甲苯磺酸盐(用甲苯做水分离剂,自甘氨酸,辛醇和p-Tos OH制备)和6.3g(15mmol)CMC(参照实例146)在350ml无水二氯甲烷中搅拌48小时,以与实例146相似的方式处理后,用二氯甲烷(进行过程中加入至多2.5%甲醇)对粗产物进行硅胶柱色谱提纯,得到3.6g无色油状标题化合物,1H NMR(CDCl3):δ=4.26(d,CH2-甘氨酸)
实例148
3-甲氧基吡啶-2-羧酸N-(((1-己氧基)羰基)甲基酰胺
实例149
3-甲氧基吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
以与实例147相似的方法,用甘氨酸1-丁酯甲苯磺酸盐得到标题化合物,m.p.60-62℃(二氯甲烷)。
实例150
3-甲氧基吡啶-2-羧酸N-(((2-壬氧基)羰基)甲基)酰胺外消旋物
将2.5g(10mmol)3-甲氧基吡啶-2-羧酸N-(羧甲基)酰胺盐酸盐(m.p.157℃,气体发生法)悬浮于100ml无水四氢呋喃,然后加入1.6ml(12mmol)三乙胺,再于搅拌下滴加2.4g溶于少量四氢呋喃的新戊酰氯(温度升至35-40℃)。30分钟后,真空浓缩混合物,将微红色残余物浸溶于100ml无水四氢呋喃。向混合物中加入1.6ml三乙胺,接着在20℃加入30ml 2-壬醇钠的2-壬醇溶液(由30ml 2-壬醇和0.8g(20mmol)NaH制备)。1小时后,真空浓缩混合物,向残余物中加二氯甲烷,通过将混合物与2N氯化铵水溶液一起振摇进行萃取,干燥并真空浓缩有机相,用乙酸乙酯对残余物(9g)进行硅胶色谱提纯,得到1.1g无色油状标题化合物,1H NMR(DMSO):δ=3.95(d,CH2-甘氨酸)。
实例151
3-甲氧基吡啶-2-羧酸N-(((4-庚氧基)羰基)甲基)酰胺
如实例150所述处理2.5g(10mmol)3-甲氧基吡啶-2-羧酸N-(羧甲基)酰胺盐酸盐,然后在20℃加140ml 4-庚醇钠的庚醇溶液(自140ml 4-庚醇和0.6g(25mmol)钠于声波浴制备)。30分钟后,混合物在70-80℃加热1小时,冷却后真空浓缩。残余物浸溶于水,混合物用二氯甲烷萃取,真空浓缩有机相,在油泵上干燥。约15小时后结晶出粗产物,m.p.75-78℃。
实例152
3-苄氧基吡啶-2-羧酸N-(((1-辛氧基)羰基)甲基)酰胺
以与实例147相似的方式,用甘氨酸1-辛酯甲苯磺酸盐缩合1.1g(5mmol)3-苄氧基吡啶-2-羧酸。不用柱色谱,得到1.3g标题化合物,为淡褐色油,1H NMR(DMSO):δ=5.24(s,CH2-苄基)。
实例153
3-苄氧基吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
以与实例152相似的方法,使用甘氨酸1-丁酯甲苯磺酸盐,得到标题化合物。用饱和碳酸氢钠溶液,1N盐酸和水萃取有机相后,干燥并浓缩,用乙醚/石油醚结晶出产物,m.p.55-58℃。
实例154
5-(((3-(1-丁氧基)丙基)氨基)羰基)-3-甲氧基吡啶-2-羧酸N-((苄氧羰基)甲基)酰胺
a)5-(((3-(1-丁氧基)丙基)氨基羰基)-3-甲氧基吡啶-2-羧酸甲酯
在10℃和搅拌下,将溶于四氢呋喃的1.7g草酰氯(20mmol)以及两滴N,N-二甲基甲酰胺加到2.1g(10mmol)5-羧基-3-甲氧基吡啶-2-羧酸甲酯于100ml无水四氢呋喃的溶液中,反应混合物在10℃搅拌30分钟,在20℃搅拌1小时,然后浓缩,将残余物溶于二氯甲烷。在0℃向溶液中加入6.8ml(50mmol)三乙胺,然后加1.3g溶于二氯甲烷的3-丁氧基丙胺(1.5ml,10mmol)。30分钟后,使混合物升至室温,用水、碳酸氢钠溶液和含水1N盐酸萃取,干燥并浓缩有机相,用乙醚/石油醚(3∶1)使残余物结晶,得到2.3g产物,m.p.51-53℃。
b)用常规方法水解上述物质,在油泵上干燥后,使1.5g(5mmol)非晶5-(((3-(1-丁氧基)丙基)氨基)羰基)-3-甲氧基吡啶-2-羧酸与甘氨酸苄酯甲苯磺酸盐、N-乙基吗啉,1-羟基-(1H)-苯并三唑和CMC反应(如前所述)。用丙酮结晶出1.42g标题化合物,m.p.97-99℃。
实例155
5-(((3-(1-丁氧基)丙基)氨基)羰基)-3-甲氧基-吡啶-2-羧酸N-(((1-丁氧基)羰基)-甲基)酰胺
类似于上述实例,使用甘氨酸1-丁酯甲苯磺酸盐〔m.p.80-82℃(甲基)〕,获得标题化合物,m.p.115-117℃(二异丙醚)。
实例156
5-(((3-十二烷氧基)丙基)氨基)羰基)-3-甲氧基-吡啶-2-羧酸N-(((苯甲氧基)羰基)-甲基)酰胺
类似于实例154,使用3-十二烷氧基丙基胺,获得标题化合物,m.p.109-111℃(二异丙醚)。
实例157
5-(((2-甲氧基乙基)氨基)羰基)-3-甲氧基吡啶-2-羧酸N-((苯甲氧基羰基)甲基)酰胺
类似于实例154,使用2-甲氧基乙基胺,获得标题化合物。
a)5-(((2-甲氧基乙基)氨基)羰基)-3-甲氧基-吡啶-2-羧酸
m.p.160-161℃(有气体放出,乙酸乙酯)
b)用二异丙醚结晶标题化合物,m.p.129-131℃
类似于实例146-157,制备下列实施例。
实例158
3-甲氧基吡啶-2-羧酸N-(((2-丙氧基)羰基)甲基)酰胺
实例159
3-甲氧基吡啶-2-羧酸N-(((1-丙氧基)羰基)甲基)酰胺
实例160
3-甲氧基吡啶-2-羧酸N-(((1-戊氧基)羰基)甲基)酰胺
实例161
3-甲氧基吡啶-2-羧酸N-(((3-戊氧基)羰基)甲基)酰胺
实例162
3-甲氧基吡啶-2-羧酸N-(((1-癸氧基)羰基)甲基)酰胺
实例163
3-甲氧基吡啶-2-羧酸N-(((1-十二烷氧基)羰基)甲基)酰胺
实例164
3-甲氧基吡啶-2-羧酸N-(((1-香叶氧基)羰基)甲基)酰胺
实例165
3-苯甲氧基吡啶-2-羧酸N-(((2-丙氧基)羰基)甲基)酰胺
实例166
3-苯甲氧基吡啶-2-羧酸N-(((3-戊氧基)羰基)甲基)酰胺
实例167
3-苯甲氧基吡啶-2-羧酸N-(((1-戊氧基)羰基)甲基)酰胺
实例168
3-苯甲氧基吡啶-2-羧酸N-(((1-十二烷氧基)羰基)甲基)酰胺
实例169
3-苯甲氧基吡啶-2-羧酸N-(((1-香叶氧基)羰基)甲基)酰胺
实例170
5-(((3-(1-丁氧基)丙基)氨基)羰基)-3-甲氧基-吡啶-2-羧酸N-(((1-己氧基)羰基)甲基)酰胺
实例171
5-(((3-(1-丁氧基)丙基)氨基)羰基-3-甲氧基吡啶-2-羧酸N-(((己-3-烯-1-基氧基)羰基)甲基)酰胺
实例172
5-(((3-(1-丁氧基)丙基)氨基)羰基)-3-甲氧基吡啶-2-羧酸N-(((I-辛氧基)羰基)甲基)酰胺
实例173
5-(((3-(1-丁氧基)丙基)氨基)羰基)-3-甲氧基吡啶-2-羧酸N-(((1-癸氧基)羰基)甲基)酰胺
实例174
5-(((3-(1-丁氧基)丙基)氨基)羰基)-3-甲氧基吡啶-2-羧酸N-(((1-十二烷氧基)羰基)甲基)酰胺
实例175
5-(((3-(1-丁氧基)丙基)氨基)羰基)-3-甲氧基吡啶-2-羧酸N-(((3-甲基-1-丁氧基)羰基)甲基)酰胺
实例176
5-(((3-(1-丁氧基)丙基)氨基)羰基)-3-甲氧基吡啶-2-羧酸N-(((1-香叶氧基)羰基)甲基)酰胺
实例177
5-(((4-(1-丁氧基)苯基)氨基)羰基)-3-氯吡啶-2-羧酸N-((乙氧基羰基)甲基)酰胺
a)类似于实例90a),制备5-羧基-3-氯吡啶-2-羧酸甲酯,m.p.182-184℃(盐酸水溶液)。
b)使用草酰氯和4-(1-丁氧基)苯胺,由上述化合物获得5-(((4-(1-丁氧基)苯基)氨基)羰基)-3-氯吡啶-2-羧酸甲酯,m.p.121-123℃(二乙醚)
c)水解b)的产物,获得5-(((4-(1-丁氧基)苯基)氨基)羰基)-3-氯吡啶-2-羧酸,m.p.163-164℃(盐酸水溶液)。
d)类似于90b),通过与甘氨酸乙酯盐酸盐缩合(N-乙基吗啉,1-羟基-1H-苯并三唑和CMC),由上述物质获得标题化合物,m.p.177-179℃(乙醇)
实例178
3-(4-氯苯甲氧基)吡啶-2-羧酸N-(((乙氧基)羰基)甲基)酰胺1-氧化物
将0.7g(2mmol)实例31的标题化合物溶于二氯甲烷中并与1.41g 3-氯过苯甲酸反应,在20℃搅拌混合物1小时后,通过氨直到不再发生沉淀,然后过滤混合物,浓缩滤液并用二乙醚使油状残留物结晶,m.p.70-72℃。
实实179
5-甲氧基羰基-3-(2-甲基)-1-丙氧基)-吡啶-2-羧酸(甘氨酰苄酯)酰胺
a)3-(2-甲基-1-丙氧基)吡啶-2,5-二羧酸
类似于实例81c),将3.5g(146mmol)钠溶于350ml 2-甲基-1-丙醇(异丁醇)中,然后在20℃加入13.7g(55mmol)3-氯吡啶-2-羧酸乙酯5-羧酸甲酯(类似于实例81b)制得)并搅拌。然后在80℃搅拌混合物90分钟,冷却后真空浓缩;将残留物溶解于200ml 1N甲醇的NaOH中并在20℃搅拌该混合物。15分钟后,溶液变成混浊。加入水直到获得澄清溶液并搅拌1小时,然后真空浓缩;用盐酸水溶液酸化上述溶液,吸滤结晶产物,洗涤并干燥,获得10.6g二羧酸,m.p.192℃(分解)。
b)3-(2-甲基-1-丙氧基)吡啶-2,5-二羧酸二甲酯
在酯化条件下(甲醇/硫酸)和处理(用水洗涤和用乙酸乙酯萃取)后由上述二羧酸获得油状产物。
c)将溶于50ml甲醇中的0.48g(12mmol)NaOH加入于25ml甲醇中的3.2g(12mmol)上述二酯中,在65℃搅拌混合物90分钟。然后用稀盐酸水溶液酸化混合物,同时冷却,真空除甲醇。然后类于实例90b),在20℃将由此获得的2.5g(10mmol)单酯混合物与3.4g(10mmol)甘氨酸苄酯甲苯磺酸盐,1.4g(10mmol)1-羟基-1H-苯并三唑,2.6ml(20mmol)N-乙基吗啉和4.3g(10mmol)CMC一起在250nl二氯甲烷中搅拌24小时。
然后吸滤未溶解的物质,用碳酸氢钠水溶液,用稀释盐酸和用水萃取滤液;干燥和浓缩有机相,使用正庚烷/乙酸乙酯(1∶1)在硅胶上对残留物进行色谱分离。从合适的馏分中获得0.8g无色标题化合物,m.p.103-105℃。还获得1.1g异构树脂产物。
按类似方式制备实例108-228
实例180
5-乙氧基羰基-3-(2-甲基-1-丙氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例181
5-甲氧基羰基-3-(3-甲基-1-丁氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例182
5-乙氧羰基-3-乙氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例183
5-乙氧基羰基-3-(1-丙氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例184
5-乙氧基羰基-3-(2-丙氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例185
3-苄氧基-5-乙氧基羰基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例186
3-(4-氯苄氧基)-5-乙氧基羰基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例187
5-乙氧基羰基-3-(4-氟苄氧基)吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例188
5-乙氧基羰基-3-(4-(三氟甲基)苄氧基)吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例189
5-乙氧基羰基-3-(4-(三氟甲氧基)苄氧基)吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例190
5-乙氧基羰基-3-(4-(2-丙基)苄氧基)吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例191
3-(4-乙氧基苄氧基)-5-乙氧基羰基吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例192
5-乙氧基羰基-3-(3,4-二甲氧基苄氧基)吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例193
5-乙氧基羰基-3-(2-(4-氟苯基)乙氧基)吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例194
5-乙氧基羰基-3-(2,2,2-三氟乙氧基)吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例195
5-羧基-3-(3-甲基-1-丁氧基)吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例196
5-羧基-3-乙氧基吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例197
5-羧基-3-丙氧基吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例198
5-羧基-3-(2-丙氧基)吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例199
3-苄氧基-5-羧基吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例200
5-羧基-3-(4-氯苄氧基)吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例201
5-羧基-3-(4-氟苄氧基)吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例202
5-羧基-3-((4-三氟甲基)苄氧基)吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例203
5-羧基-3-((三氟甲氧基)苄氧基)吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例204
5-羧基-3-(4-(2-丙基)苄氧基)吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例205
5-羧基-3-(萘基-2-甲氧基)吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例206
5-羧基-3-(萘基-1-甲氧基)吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例207
5-(3-戊氧基)羰基-3-丙氧基吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例208
5-(3-戊氧基)羰基-3-(2-丙氧基)吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例209
3-苄氧基-5-(3-戊氧基)羰基吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例210
3-(4-氟苄氧基-5-(3-戊氧基)羰基吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例211
5-(4-庚氧基)羰基-3-甲氧基吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例212
3-苄氧基-5-(4-庚氧基)羰基吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例213
3-(4-氯苄氧基)-5-(4-庚氧基)羰基吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例214
3-(4-氟苄氧基)-5-(4-庚氧基)吡啶-2-羧酸(甘氨酰-1-己酯)酰胺
实例215
5-(4-庚氧基)羰基-3-(4-(2-丙基)苄氧基)-吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例216
3-苄氧基-5-((5-壬氧基)羰基)吡啶-2-羧酸(甘氨酸-1-己酯)酰胺
实例217
3-(4-氟苄氧基)-5-(5-壬氧基)羰基吡啶-2-羧酸(甘氨酰-1-己酯)酰胺
实例218
5-(5-壬氧基)羰基-3-(4-(2-丙基)苄氧基)吡啶-2-羧酯(甘氨酸-1-丁酯)酰胺
实例219
5-香叶氧基羰基-3-(2-甲基-1-丙氧基)吡啶-2-羧酸(甘氨酸-1-丁酯)酰胺
实例220
3-苄氧基-5-(香叶氧基羰基)吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例221
3-(4-氟苄氧基)-5-(香叶氧基羰基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例222
5-香叶氧基羰基-3-(3-甲氧基苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例223
3-苄氧基-5-(法呢氧基羰基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例224
5-法呢氧基羰基-3-(4-氟苄氧基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例225
3-甲氧基-5-(视黄氧基羰基)吡啶-2-羧酸(甘氨酸乙酯)酰胺
实例226
3-乙氧基-5-(视黄氧基羰基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例227
3-苄氧基-5-(视黄氧基羰基)吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例228
3-(4-氟苄氧基)-5-(视黄氧基羰基)吡啶-2-羧酸(甘氨酰1-丁酯)酰胺
实例229
5-(((4-正丁氧基苯基)氨基)羰基)-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
a)5-(((4-正丁氧基苯基)氨基)羰基)-3-甲氧基吡啶-2-羧酸甲酯。
类似于实例90b),将3.2g(15mmol)5-羧基-3-甲氧基吡啶-2-羧酸甲酯(见实例90a))与2.5g(15mmol)4-正丁氧基苯胺和该实例所述的反应试剂反应。用二乙醚结晶出3.9g产物,m.p.138-141℃。
b)5-(((4-正丁氧基苯基)氨基)羰基)-3-甲氧基-吡啶-2-羧酸
在20℃使用100ml 1.5N甲醇的氢氧化钠溶液水解3.2g上述酯,从盐酸水溶液中获得2.7g产物,m.p.128-130℃,120℃烧结。
c)5-(((4-正丁氧基苯基)氨基)羰基)-3-甲氧基吡啶-2-羧酸N-(乙氧基羰基甲基)酰胺
标题化合物按下述方式制备:
在20℃下,将2.7g(7.8mmol)上述吡啶-2-羧酸与1.1g(7.8mmol)甘氨酸乙酯盐酸盐、3.0ml(23.4mmol)N-乙基吗啉、1.2g(8.6mmol)1-羟基-(1H)-苯并三唑和3.3g(7.8mmol)CMC在500ml无水二氯甲烷中搅拌24小时,然后滤去不溶的物质,依次各用200ml水,碳酸氢钠水溶液,1N盐酸和水萃取有机相,用硫酸镁干燥并真空浓缩,用二乙醚对残留物进行结晶,获得2.4g产物,m.p.193-195℃。
实例230
5-(((4-(1-己氧基)苯基)氨基)羰基)-3-甲氧基吡啶-2-羧酸N-((乙氧基羰基)甲基)酰胺
a)由5-羧基-3-甲氧基吡啶-2-羧酸甲酯和4-己氧基苯胺制备5-(((4-正己氧基苯基)氨基)羰基)-3-甲氧基吡啶-2-羧酸甲酯,m.p.118-119℃(二乙醚)。
b)5-(((4-正己氧基苯基)氨基)羰基)-3-甲氧基吡啶-2-羧酸,160-162℃,在148℃烧结(盐酸水溶液/四氢呋喃)
c)类似于实例231c),由4.2g上述化合物获得标题化合物。用乙酸乙酯结晶出4.0g产物,m.p.157-159℃。
实例231
由5-(((4-正癸基苯基)氨基)羰基)-3-甲氧基吡啶-2-羧酸(m.p.160℃,分解;盐酸水溶液/THF)和甘氨酸乙酯盐酸盐制备5-(((4-正癸基苯基)氨基)羰基)-3-甲氧基吡啶-2-羧酸N-(乙氧基羰基甲基)酰胺,m.p.155-157℃(二异丙醚)。
类似于实例229至231,制备实例232至240。
实例232
5-(((4-乙氧基苯基)氨基)羰基)-3-甲氧基吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例233
5-(((4-乙氧基苯基)氨基)羰基)-3-苄氧基吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例234
5-(((4-正丁氧基苯基)氨基)羰基)-3-4-氟苄氧基)吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例235
5-(((4-正丁氧基苯基)氨基)羰基)-3-苄氧基吡啶-3-羧酸(甘氨酰-1-丁酯)酰胺
实例236
5-(((4-(1-己氧基)苯基)氨基)羰基)-3-甲氧基-吡啶-2-羧酸(甘氨酰-1-辛酯)酰胺
实例237
5-(((4-正癸氧基苯基)氨基)羰基)-3-甲氧基吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
实例238
5-(((4-香叶氧基苯基)氨基)羰基)-3-甲氧基)吡啶-2-羧酸N-((1-己氧基)羰基)甲基)酰胺
实例239
5-(((4-正辛氧基苯基)氨基)羰基)-3-甲氧基吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
实例240
5-(((4-正辛氧基苯基)氨基)羰基)-3-甲氧基吡啶-2-羧酸N-(((1-己氧基)羰基)甲基)酰胺
实例241
5-法呢氧基羰基-3-甲氧基吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例242
5-香叶氧基羰基-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例243
5-(法呢氧基甲基)-3-甲氧基吡啶-2-羧酸(甘氨酰乙酯)酰胺
实例244
5-(香叶氧基甲基)-3-甲氧基吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例245
5-视黄氧基甲基-3-甲氧基吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例246
5-视黄氧基甲基-3-(2-丙氧基)吡啶-2-羧酸(甘氨酰-1-丁酯)酰胺
实例247
5-(1-丁氧基甲基)-3-甲氧基吡啶-2-羧酸N-(((1-辛氧基)羰基)甲基)酰胺
实例248
5-(正己氧基甲基)-3-甲氧基吡啶-2-羧酸N-(((1-辛氧基)羰基)甲基)酰胺
实例249
5-(((正辛氧基甲基)-3-甲氧基吡啶-2-羧酸N-(((1-己氧基)羰基)甲基)酰胺
实例250
5-((1-己-3-烯基氧基)甲基)-3-甲氧基吡啶-2-羧酸N-(((1-辛氧基)羰基)甲基)酰胺
实例251
5-(正癸氧基甲基)-3-甲氧基吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
实例252
5-(正十二烷氧基甲基)-3-甲氧基吡啶-2-羧酸N-((1-丁氧基)羰基)甲基)酰胺
实例253
3-(4-((+)-脱氢枞酸基氨基)羰基)苄氧基)吡啶-2-羧酸N-((乙基羰基)甲基)酰胺
m.p.大约80℃(非晶形物质,出自乙酸乙酯)
实例254
N-(3-苄氧基吡啶基-2-羰基)丙氨酸乙酯外消旋物
1H NMR(CDCl3):δ=5.13(s,CH2)
实例255
N-(3-苄氧基吡啶基-2-羰基)-L-苯基丙氨酸叔丁酯
1H NMR(CDCl3):δ=5.12(s,CH2)
实例256
N-(3-苄氧基吡啶基-2-羰基)甘氨酸甲酯,m.p.81-82℃(乙酸乙酯)
实例257
5-((1-丁氧基)羰基)-3-甲氧基吡啶-2-羧酸N-(叔丁氧基羰基)甲基)酰胺
a)3-甲氧基吡啶-2,5-二羰基二(1-丁基)酯
将5.0g 3-甲氧基吡啶-2,5-二羧酸二甲酯(见实例90a))溶于100ml 1-丁醇,然后加入1.5ml浓硫酸,将混合物加热至沸2小时,顺带着蒸出部分溶剂。混合物冷却后,真空浓缩,将残留物溶于二氯甲烷中;用饱和碳酸氢钠水溶液萃取该溶液,干燥和浓缩有机相,得到6g油状粗产物。
b)双〔5-((1-丁氧基)羰基)-3-甲氧基吡啶-2-羧酸〕-Cu(II)配合物
将溶于10ml甲醇的6g(20mmol)上述油状产物加入到4.8g(20mmol)Cu(NO3)2·3H2O于100ml甲醇所形成的溶液中,加热混合物至沸4小时。然后将混合物冷却到0-5℃,吸抽结晶沉淀并用二乙醚洗涤。获得4.2g蓝-绿产物,m.p.267℃(分解)。
c)5-((1-丁氧基)羰基)-3-甲氧基吡啶-2-羧酸
将4g上述钢配合物悬浮于75ml 1,4-二恶烷中。通入H2S气,同时搅拌混合物,历时30分钟,通过硅藻土吸滤除去已沉淀的沉积物,然后用1,4-二恶烷洗涤(H2S的继续引入不导致任何进一步沉淀);真空浓缩滤液。用石油醚对残留物进行结晶,m.p.96-98℃。
d)通过使0.76g(3mmol)上述吡啶羧酸与0.52g(3mmol)甘氨酸叔丁酯盐酸盐,1.2ml(9mmol)N-乙基吗啉,0.45g(3.3mmol)1-羟基-1H-苯并三唑和1.3g(3nmol)CMC进行缩合,获得标题化合物。获得0.8g无色结晶产物,m.p.50-52℃(石油醚)。
实例258
5-((1-丁氧基)羰基)-3-甲氧基吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
通过与甘氨酸1-丁酯甲苯磺酸盐缩合由实例257c)所述的吡啶-2-羧酸制备标题化合物,m.p.80-81℃(石油醚)
实例259
5-((1-己氧基)羰基)-3-甲氧基吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
a)双〔5-((1-己氧基羰基)-3-甲氧基吡啶-2-羧酸〕-Cu(II)配合物
类似于实例257b),使6.6g(18mmol)3-甲氧基吡啶-2,5-二羧酸二(1-己基)酯(类似于实例257a),通过用1-己醇进行酸催化酯交换作用获得)反应,获得4.6g Cu(II)配合物,m.p.265℃(分解,用二乙醚洗涤)。
b)类似于实例257c),由上述Cu(II)配合物获得5-((1-己氧基)羰基)-3-甲氧基吡啶-2-羧酸,3.4g,m.p.108-110℃(石油醚)。
c)使用N-乙基吗啉,1-羟基-1H-苯并三唑和CMC,由0.71g(2.5mmol)上述酸和0.76g(2.5mmol)甘氨酸-1-丁酯甲苯磺酸盐获得标题化合物。分离出0.81g产物,m.p.53-55℃(石油醚)
按类似于实例257至260方法获得实例260-287。
实例260
5-((1-丁氧基)羰基)-3-甲氧基吡啶-2-羧酸N-((乙氧基羰基)甲基)酰胺
实例261
5-((1-己氧基)羰基)-3-甲氧基吡啶-2-羧酸N-((乙氧基羰基)甲基)酰胺
实例262
3-甲氧基-5-((1-戊氧基)羰基)吡啶-2-羧酸N-((乙氧基羰基)甲基)酰胺
实例263
5-((1-庚氧基)羰基)-3-甲氧基吡啶-2-羧酸N-((乙氧基羰基)甲基)酰胺
实例264
3-甲氧基-5-((1-辛氧基)羰基)吡啶-2-羧酸N-((乙氧基羰基)甲基)酰胺
实例265
5-(乙氧基羰基)-3-甲氧基吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
实例266
5-(乙氧基羰基)-3-甲氧基吡啶-2-羧酸N-((乙氧基)羰基)甲基)酰胺
实例267
3-甲氧基-5-((1-丙氧基)羰基)吡啶-2-羧酸N-((乙氧基羰基)甲基)酰胺
实例268
3-甲氧基-5-((1-戊氧基)羰基)吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
实例269
5-((1-庚氧基)羰基)-3-甲氧基吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
实例270
3-甲氧基-5-((1-辛氧基)羰基)吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
实例271
5-(乙氧基羰基)-3-甲氧基吡啶-2-羧酸N-(((1-己氧基)羰基)甲基)酰胺
实例272
5-((1-丁氧基羰基)-3-甲氧基吡啶-2-羧酸N-(((1-己氧基)羰基)甲基)酰胺
实例273
5-((1-己氧基羰基)-3-甲氧基哟啶-2-羧酸N-(((1-己氧基)羰基)甲基)酰胺
实例274
3-甲氧基-5-((1-戊氧基)羰基)吡啶-2-羧酸N-(((1-己氧基)羰基)甲基)酰胺
实例275
5-(((1-庚氧基)羰基)-3-甲氧基吡啶-2-羧酸N-(((1-己氧基)羰基)甲基)酰胺
实例276
3-甲氧基-5-((1-辛氧基)羰基)吡啶-2-羧酸N-(((1-己氧基)羰基)甲基)酰胺
实例277
5-((1-丁氧基)羰基)-3-甲氧基吡啶-2-羧酸N-(((1-辛氧基)羰基)甲基)酰胺
实例278
5-((1-己氧基)羰基)-3-甲氧基吡啶-2-羧酸N-(((1-辛氧基)羰基)甲基)酰胺
实例279
4-甲氧基-5-((1-戊氧基)羰基)吡啶-2-羧酸N-(((1-辛氧基)羰基)甲基)酰胺
实例280
5-((1-庚氧基)羰基)-3-甲氧基吡啶-2-羧酸N-(((1-辛氧基)羰基)甲基)酰胺
实例281
3-甲氧基-5-((1-辛氧基)羰基)吡啶-2-羰酸N-(((1-辛氧基)羰基)甲基)酰胺
实例282
5-(乙氧基羰基)-3-(2-丙氧基)吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
实例283
5-((1-丁氧基)羰基)-3-(2-丙氧基)吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
实例284
5-((1-己氧基)羰基)-3-(2-丙氧基)吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
实例285
5-((1-辛氧基)羰基)-3-(2-丙氧基)吡啶-2-羧酸N-(((1-丙氧基)羰基)甲基)酰胺
实例286
5-((1-辛氧基)羰基)-3-(2-丙氧基)吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
实例287
5-((1-辛氧基)羰基)-3-(2-丙氧基)吡啶-2-羧酸N-(((1-己氧基)羰基)甲基)酰胺
实例288
5-甲氧基羰基-3-(甲硫基)吡啶-2-羧酸N-(((1-丁氧基)羰基)甲基)酰胺
a)3-(甲硫基)吡啶-2,5-二羧酸
在20℃和搅拌下将4.6g(12mmol)3-氯吡啶-2,5-二羧酸二苄酯溶于二甲亚砜中,接着加入5.0g(70mmol)硫代甲醇钠,这期间温度升至80℃,在140℃下加热反应混合物1小时,然后冷却,接着往其中加入水。分离出油层并将浓盐酸(pH=1)加入水性DMSO相中,吸滤出沉淀产物,获得2.8g黄色结晶产物,m.p.223℃(分解)。
b)3-(甲硫基)吡啶-2,5-二羧酸二甲酯
将50ml 1,4-二恶烷,40ml四氢呋喃和0.5ml浓硫酸加入到2.8g上述化合物于150ml甲醇中形成的溶液中,加热混合物至回流2小时,这期间形成溶液。将溶液冷却后,真空浓缩,往残留物中加入100ml碳酸氢钠水溶液,用二氯甲烷萃取混合物,干燥和浓缩有机相,获得1.4g黄色结晶产物,m.p.103-105℃。
c)5-甲氧基羰基-3-(甲硫基)吡啶-2-羧酸-Cu(II)配合物
类似于实例257b),使1.3g上述3-(甲硫基)吡啶-2,5-二羧酸二甲酯反应。获得1.3g绿色/结晶产物,m.p.>330℃。
d)5-甲氧基羰基-3-(甲硫基)吡啶-2-羧酸
类似于实例257b),使1.3g上述化合物反应,获得0.72g产物,m.p.183-185℃。
e)通过使0.68g(3mmol)上述吡啶羧酸与0.91g(3mmol)甘氨酸-1-丁酯甲磺酸盐(1-羟基-(1H)-苯并三唑,N-乙基吗啉和CMC)缩合,获得标题化合物。得到0.57g浅黄色产物,m.p.47-49℃(石油醚)。
实例289
3-甲氧基喹啉-2-羧酸N-((甲氧基羰基)甲基)酰胺
a)由D.W.Bayne等人的J.Chem.Soc.Chem.Comm.1975,782得知2-乙酰基-3-羟基喹啉,m.p.106℃(盐酸水溶液)。
b)使用在丙酮中的碳酸钾/甲基碘由a)得到2-乙酰基-3-甲氧基喹啉;油状粗产物。
c)使用在水/二恶烷中的次氯酸钾获得3-甲氧基喹啉-2-羧酸,m.p.123℃(甲基·叔丁基醚)
d)使用DCC,HOBT,THF,NEM和甘氨酸甲酯盐酸盐,由c)获得标题化合物,
1H NMR(DMSO):δ=4.08(d,CH2-甘氨酸)
Claims (9)
1.通式(I)吡啶或其药理活性盐,
其中,
Q为O,
X为O,Y为CR3,
A为-CH2-基团,其可被甲基取代,
B为CO2G,
G为直链或支链或环状脂肪族C1-18烷基,C3-8环烷基-C1-4烷基,直链或支链C2-18链烯基,前述基团可被选自下面的取代基取代:羟基,C1-4烷氧基,酰氧基,C1-6烷基羰氧基,C3-8环烷基羰氧基,苯甲酰氧基,C7-16苯烷基羰氧基,C3-8环烷氧基羰氧基,或
G为苯基,苄基,苯乙基,苯丙基或苯丁基,
R2为氢,C1-8烷氧基,C1-16烷氧甲基,C2-16链烯氧甲基,视黄氧基甲基,N-C1-10烷基氨基甲酰基,N-(C1-12烷氧基-C1-3烷基)氨基甲酰基,N,N-二-C1-8烷基氨基甲酰基,N-C5-6环烷基氨基甲酰基,N-苯基氨基甲酰基,N-苯基-C1-4烷基氨基甲酰基,羧基,C1-16烷氧羰基,C2-16链烯氧羰基,视黄氧羰基,C5-6环烷氧羰基,C5-6环烷基-C1-6烷氧羰基,苯基C1-6烷氧羰基,其中苯基如对R1和R3所述的那样被取代,
R1或R3为氢且另一个为下列基团:氢,C1-10烷氧基,-O-〔CH2-〕x-CfH(2f+1-g)Fg,C1-4烷氧基-C1-4烷氧基,C6-12苯氧基,C7-11苯基烷氧基,C6-12苯氧基C1-4烷氧基或C7-11苯基烷氧基-C1-4烷氧基,其中芳基可被1,2或3个相同或不同的下面取代基取代:氟,氯,氰基,三氟甲基,C1-10烷基,C1-10烷氧基,C1-10链烯氧基,
R4为直链或支链C1-8烷基或式Z表示的基团:
-〔CH2〕v-〔O〕w-〔CH2〕t-E (Z),
其中v=0,1,2,3,w=0,t=0,1,且R6,R7,R8,R9和R10可相同或不同并代表氢,氟,氯,氰基,三氟甲基,C1-6烷基,C1 -6烷氧基,-O-〔CH2-〕x-CfH(2f+1-g)Fg,N-C1-6烷基氨基甲酰基,N,N-二-C1-6烷基氨基甲酰基,N-C3-6环烷基氨基甲酰基,N-(+)-脱氢枞酸基氨基羰基,f=1-4,g=0,1至(2f+1),X=0或1。
2.通式I的吡啶或其药理活性盐,其中,
Q为O,
X为O,
Y为CR3,
A为-CH2-基团,
B为CO2G,其中
G为直链或支链脂肪族C1-16烷基,2-环己基乙基,C1-4烷氧基C1-2烷基,直链或支链C2-10链烯基,苯基,苄基,苯乙基,苯丙基或苯丁基,
R1为氢,C1-6烷氧基,-O-〔CH2-〕x-CfH(2f+1-g)Fg,
R2为氢,N-C1-10烷基氨基甲酰基,N-(C1-12烷氧基C1-3烷基)氨基甲酰基,N,N-二-C1-8烷基氨基甲酰基,N-C5-6环烷基氨基甲酰基,N-苯基氨基甲酰基,N-苯基C1-2烷基氨基甲酰基,羧基,C1-16烷氧基羰基,C2-16链烯氧基羰基,视黄氧基羰基,C5-6环烷氧羰基,C5-6环烷基-C1-6烷氧羰基,苯基-C1-6烷氧羰基,其中苯基可被1或2个选自下面的取代基取代:氟,氯,氰基,三-氟甲基,C1-10烷基,C1-10烷氧基,C2-10链烯氧基,
R3为氢,C1-5烷氧基,C5-6环烷基-C1-2烷氧基,
其中取代基R1或R3之一为氢,
R4为直链或支链C1-6烷基或2-苯基乙基,或被1或2个下面取代基取代的苄基:氟、氯、氰基、三氟甲基、C1-6烷基、C1-6烷氧基、-O-〔CH2-〕x-CfH(2f+1-g)Fg,N-C1-8烷基氨基甲酰基,N,N-二-C1-6烷基氨基甲酰基,N-C3-6环烷基氨基甲酰基,N-(+)-脱氢枞酸基氨基羰基,f=1-4,g=0,1至(2f+1),X=1。
3.通式I的吡啶或其药理活性盐,其中
Q为O,
X为O,
Y为CR3,
A为-CH2-,
B为CO2G,
G为直链或支链脂肪族C1-16烷基或苄基,
R1为氢,
R2为氢,N-C1-10烷基氨基甲酰基,N-(C1-12烷氧基C1-3烷基)氨基甲酰基,N-环己基氨基甲酰基,N-苯基氨基甲酰基,N-(苯基C1-2烷基)氨基甲酰基,其中苯基可被氟、C1-10烷基或C1-10烷氧基取代,C1-16烷氧羰基,C2-16链烯氧羰基,视黄氧羰基,C5-6环烷氧羰基,苄氧羰基,
R3为氢,C1-5烷氧基,2-环己基乙氧基,其中取代基R2或R3之一为氢,
R4为直链或支链C1-4烷基或可被氟、氯、三氟甲基、C1-4烷基、C1-3烷氧基取代的苄基。
4.权利要求1-3任一项所要求的吡啶化合物或3-苄氧吡啶-2-甲酸-(C-苏氨酰甲酯)酰胺,3-苄氧吡啶-2-甲酸-(L-苏氨酰(Fmoc-Phg)叔丁酯)酰胺,3-苄氧吡啶-2-甲酸-(L-苏氨酰叔丁酯)酰胺或3-苄氧吡啶-2-甲酸-(D-别苏氨酰甲酯)酰胺用于制备抗纤维变性疾病的药物。
5.权利要求1-3任一项所要求的吡啶化合物或3-苄氧吡啶-2-甲酸-(C-苏氨酰甲酯)酰胺,3-苄氧吡啶-2-甲酸-(L-苏氨酰(Fmoc-Phg)叔丁酯)酰胺,3-苄氧吡啶-2-甲酸-(L-苏氨酰叔丁酯)酰胺或3-苄氧吡啶-2-甲酸-(D-别苏氨酰甲酯)酰胺用于制备抗肝纤维变性疾病的药物。
6.权利要求1-3任一项所要求的吡啶化合物或3-苄氧吡啶-2-甲酸-(C-苏氨酰甲酯)酰胺,3-苄氧吡淀-2-甲酸-(L-苏氨酰(Fmoc-Phg)叔丁酯)酰胺,3-苄氧吡啶-2-甲酸-(L-苏氨酰叔丁酯)酰胺或3-苄氧吡淀-2-甲酸-(D-别苏氨酰甲酯)酰胺用于制备抗肺纤维变性疾病的药物。
7.权利要求1-3任一项所要求的吡啶化合物或3-苄氧吡啶-2-甲酸-(C-苏氨酰甲酯)酰胺,3-苄氧吡啶-2-甲酸-(L-苏氨酰(Fmoc-Phg)叔丁酯)酰胺,3-苄氧吡啶-2-甲酸-(L-苏氨酰叔丁酯)酰胺或3-苄氧吡啶-2-甲酸-(D-别苏氨酰甲酯)酰胺用于制备抗皮肤纤维变性疾病的药物。
8.一种通过如下步骤制备根据权利要求1-3任一项所要求的式I吡啶化合物的方法,其中,A,B,Y,m如权利要求1~3任一项中定义,
i1)使R23=H的式II吡啶-2-甲酸与式III的氨基酯反应,形成式I的酰胺酯或
i2)使式II的吡啶-2-羧酸酯,其中R23=低级烷基,Q,R1,R2,R3,R4如权利要求1~3任一项中定义,在氨解条件下反应,形成式I的化合物,其中A,R1,R2,R3,R4,Q,G如权利要求1~3任一项中定义;
或
x为离去基团,SO2Me或OSO2苯基。
9.权利要求8的方法,其中在(iii)中,x为卤素。
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IL (1) | IL111455A0 (zh) |
NO (1) | NO302028B1 (zh) |
NZ (1) | NZ264822A (zh) |
PH (1) | PH31264A (zh) |
PL (1) | PL179687B1 (zh) |
RU (1) | RU2145959C1 (zh) |
TW (1) | TW330202B (zh) |
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JP6491093B2 (ja) | 2012-07-16 | 2019-03-27 | フィブロジェン インコーポレイテッド | プロリルヒドロキシラーゼ阻害剤の結晶形態 |
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RU2019134558A (ru) | 2013-06-13 | 2020-02-20 | Экебиа Терапьютикс, Инк. | Композиции и способы лечения анемии |
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CN106146395B (zh) * | 2015-03-27 | 2019-01-01 | 沈阳三生制药有限责任公司 | 3-羟基吡啶化合物、其制备方法及其制药用途 |
SG11201707994UA (en) | 2015-04-01 | 2017-10-30 | Akebia Therapeutics Inc | Compositions and methods for treating anemia |
CN112088155A (zh) | 2018-05-09 | 2020-12-15 | 阿克比治疗有限公司 | 用于制备2-[[5-(3-氯苯基)-3-羟基吡啶-2-羰基]氨基]乙酸的方法 |
CN113767089B (zh) * | 2019-04-26 | 2024-06-11 | 株式会社钟化 | 伐度司他中间体的制造方法 |
CN110305143B (zh) * | 2019-07-19 | 2021-03-09 | 济南新科医药科技有限公司 | 一种呋喃[2,3-c]并吡啶衍生物及其制备方法和用途 |
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- 1994-10-27 AT AT94117017T patent/ATE149485T1/de not_active IP Right Cessation
- 1994-10-28 PL PL94305647A patent/PL179687B1/pl unknown
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- 1994-10-31 NZ NZ264822A patent/NZ264822A/en unknown
- 1994-10-31 US US08/332,824 patent/US5658933A/en not_active Expired - Lifetime
- 1994-10-31 AU AU77566/94A patent/AU689135B2/en not_active Ceased
- 1994-11-01 CA CA002134865A patent/CA2134865A1/en not_active Abandoned
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- 1994-11-02 KR KR1019940028870A patent/KR950014069A/ko not_active Application Discontinuation
- 1994-12-05 TW TW083111258A patent/TW330202B/zh active
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1997
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1998
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Publication number | Publication date |
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RU94040163A (ru) | 1997-02-20 |
PL179687B1 (pl) | 2000-10-31 |
ATE149485T1 (de) | 1997-03-15 |
EP0650960B1 (de) | 1997-03-05 |
US5658933A (en) | 1997-08-19 |
PL305647A1 (en) | 1995-05-15 |
AU7756694A (en) | 1995-05-18 |
HK1006712A1 (en) | 1999-03-12 |
DK0650960T3 (da) | 1997-09-01 |
PH31264A (en) | 1998-06-18 |
DE59401923D1 (de) | 1997-04-10 |
CN1107144A (zh) | 1995-08-23 |
AU689135B2 (en) | 1998-03-26 |
KR950014069A (ko) | 1995-06-15 |
NO944161D0 (no) | 1994-11-01 |
NO944161L (no) | 1995-05-03 |
JPH07224039A (ja) | 1995-08-22 |
CZ287767B6 (en) | 2001-01-17 |
NZ264822A (en) | 1997-02-24 |
CA2134865A1 (en) | 1995-05-03 |
ES2101420T3 (es) | 1997-07-01 |
CZ268294A3 (en) | 1995-05-17 |
IL111455A0 (en) | 1994-12-29 |
EP0650960A1 (de) | 1995-05-03 |
NO302028B1 (no) | 1998-01-12 |
GR3023177T3 (en) | 1997-07-30 |
TW330202B (en) | 1998-04-21 |
RU2145959C1 (ru) | 2000-02-27 |
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