CN85101353A - 制备带有含氮脂环的吡啶-2-醚或吡啶-2-硫醚化合物的方法 - Google Patents
制备带有含氮脂环的吡啶-2-醚或吡啶-2-硫醚化合物的方法 Download PDFInfo
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- CN85101353A CN85101353A CN198585101353A CN85101353A CN85101353A CN 85101353 A CN85101353 A CN 85101353A CN 198585101353 A CN198585101353 A CN 198585101353A CN 85101353 A CN85101353 A CN 85101353A CN 85101353 A CN85101353 A CN 85101353A
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- Prior art keywords
- formula
- compound
- group
- alkyl
- pyridine
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims description 53
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 title abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 110
- -1 amine oxygen compound Chemical class 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 claims abstract description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000003814 drug Substances 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 239000005864 Sulphur Chemical group 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 239000001301 oxygen Substances 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- 238000007254 oxidation reaction Methods 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 230000003647 oxidation Effects 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- 150000001721 carbon Chemical group 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000003368 amide group Chemical group 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000001118 alkylidene group Chemical group 0.000 claims description 3
- XQJMXPAEFMWDOZ-UHFFFAOYSA-N 3exo-benzoyloxy-tropane Natural products CN1C(C2)CCC1CC2OC(=O)C1=CC=CC=C1 XQJMXPAEFMWDOZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005947 C1-C6 alkylsulfonyloxy group Chemical group 0.000 claims description 2
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 claims description 2
- QIZDQFOVGFDBKW-DHBOJHSNSA-N Pseudotropine Natural products OC1C[C@@H]2[N+](C)[C@H](C1)CC2 QIZDQFOVGFDBKW-DHBOJHSNSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- 125000005936 piperidyl group Chemical group 0.000 claims 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- 230000000202 analgesic effect Effects 0.000 abstract description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
- 238000006243 chemical reaction Methods 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- 239000002585 base Substances 0.000 description 23
- 235000019441 ethanol Nutrition 0.000 description 23
- 239000000203 mixture Substances 0.000 description 20
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 19
- 239000002253 acid Substances 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 239000003513 alkali Substances 0.000 description 17
- 239000003795 chemical substances by application Substances 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 235000011167 hydrochloric acid Nutrition 0.000 description 14
- 238000005984 hydrogenation reaction Methods 0.000 description 13
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229960001701 chloroform Drugs 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 11
- 229960000583 acetic acid Drugs 0.000 description 10
- 238000005917 acylation reaction Methods 0.000 description 10
- 238000013019 agitation Methods 0.000 description 10
- 230000029936 alkylation Effects 0.000 description 10
- 238000005804 alkylation reaction Methods 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- 230000037396 body weight Effects 0.000 description 9
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- 239000013543 active substance Substances 0.000 description 8
- 230000010933 acylation Effects 0.000 description 8
- 229910052783 alkali metal Inorganic materials 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 229910052728 basic metal Inorganic materials 0.000 description 7
- 150000003818 basic metals Chemical class 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- 229910000037 hydrogen sulfide Chemical class 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 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 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 238000001311 chemical methods and process Methods 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000010253 intravenous injection Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000002594 sorbent Substances 0.000 description 5
- WYSRTEVFLQJJDN-UHFFFAOYSA-N 2-chloro-1-oxidopyridin-1-ium Chemical compound [O-][N+]1=CC=CC=C1Cl WYSRTEVFLQJJDN-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000001340 alkali metals Chemical class 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 150000003512 tertiary amines Chemical class 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 3
- 150000008046 alkali metal hydrides Chemical class 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 150000001342 alkaline earth metals Chemical class 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 230000002152 alkylating effect Effects 0.000 description 3
- 150000001555 benzenes Chemical class 0.000 description 3
- 239000007844 bleaching agent Substances 0.000 description 3
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 150000002191 fatty alcohols Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 150000005826 halohydrocarbons Chemical class 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 150000004965 peroxy acids Chemical class 0.000 description 3
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000012286 potassium permanganate Substances 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- HZONRRHNQILCNO-UHFFFAOYSA-N 1-methyl-2h-pyridine Chemical compound CN1CC=CC=C1 HZONRRHNQILCNO-UHFFFAOYSA-N 0.000 description 2
- LTKMTXLIAZLQHS-UHFFFAOYSA-N 1-methylpyridine Chemical compound CN1C=CC=C=C1 LTKMTXLIAZLQHS-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 231100000111 LD50 Toxicity 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
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- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
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- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000039 preparative column chromatography Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
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- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
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- 239000012265 solid product Substances 0.000 description 1
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- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
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- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
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- 230000007704 transition Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- XLRPYZSEQKXZAA-OCAPTIKFSA-N tropane Chemical compound C1CC[C@H]2CC[C@@H]1N2C XLRPYZSEQKXZAA-OCAPTIKFSA-N 0.000 description 1
- 229930004006 tropane Natural products 0.000 description 1
- CYHOMWAPJJPNMW-JIGDXULJSA-N tropine Chemical compound C1[C@@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-JIGDXULJSA-N 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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- 239000003643 water by type Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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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
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D211/54—Sulfur atoms
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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
- C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
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- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
Abstract
发明公开相应于化学式I的,带有一个含氮脂环的新型吡啶-2-醚,或吡啶-2-硫醚,以及由此而制得的吡啶-N-氧化物(或)胺氧化合物及它们的适于药用的盐,及有上述化合物的制备方法。式I中符号的意义如说明书所述。这些化合物有特殊的止痛作用。
Description
从比利时专利No.630125人们知道了相应于下面通式的吡啶衍生物及其盐类。在这个式子中,R1与R2代表烷基,最好是那些连在环上的烷基,而这个环本身又含有一个杂原子,特别是氧。ALK代表至多为4个碳原子的直链或支链低级亚烷基,X代表硫、氧或亚胺基。Y(最好是在3-位上)可以代表卤素、烷基、三卤甲基或烷氧基,或者-CN、-COOR或-CONR3R4基团,R、R3及R4可以是相同的基团,也可以是不同的基团,它们代表氢或低级烷基。
从比利时专利№.650361人们也知道与上述化合物相应的和砜亚砜(上式中X代表SO或SO2)。
这些化合物具有止痛或消炎作用。
从欧洲专利申请No.21973人们还知道相应于下面通式的4-氨基-1-(2-吡啶基)-
啶类化合物及其可供药用的盐类。式中R代表氢,卤素,甲基,三氟甲基,低级烷氧基,三氟甲氧基,2,2,2-三氟乙氧基,低级烷硫基,三氟甲硫基,苯氧基,苯核上带有卤素、三氟甲基、低级烷基、低级烷氧基、低级烷硫基或氰基等取代基团的苯氧基,苯硫基或苯核上带有卤素、三氟甲基、低级烷基、低级烷氧基、低级烷硫基或氰基等取代基团的苯硫基。
这些化合物具有抑制食欲的作用。
在联邦德国专利申请公开说明书No.2230392中叙述了相应于下面通式的吡啶化合物,
式中:
X代表任意分枝和(或者)取代的烷基,任意分枝和(或者)取代的链烯基,任意取代的环烷基、芳烷基、芳基或杂环基团,或者,当Y不为氢时,X也可代表氢;
Y为氰基,氨基,亚硝基,硝基,任意分枝和(或者)取代的烷基,任意分枝和(或者)取代的链烯基,任意取代的环烷基或芳烷基,或为-COOR1,-OOR2,
,-SO2R2或
等基团,或者,当X不为氢时,Y也可为氢;
Z1特别代表-OR12或-SO2R12等基团;
Z2特别代表氯原子,溴原子,氰基,羟基或巯基;
R1和R2代表任意分枝和(或者)取代的烷基,或任意分枝和(或者)取代的链烯基,R2也可代表任意取代的环烷基、芳烷基、芳基或杂环基团;
R3和R4代表氢,任意分枝和(或者)取代的烷基,或任意取代的环烷基、芳烷基或芳基,并且烷基R3和R4也可以直接连在一起或通过一个杂原子相连;
R12代表任意分枝和(或者)取代的烷基,任意分枝和(或者)取代的链烯基,任意取代的环烷基、芳烷基或芳基。
这些化合物都是中间产物,特别是染料生产的中间产物。此外,还应该注意到这些化合物作为农药和用于药物方面的重要性。
本发明涉及权利要求书所规定的那些项目。
本发明的化合物在药理上都是有效用的。这些化合物特别具有确切的和高效的止痛作用。此外,还有降低血压的作用。
因此,本发明的一个目的是提供一些化合物,这些化合物具有良好的药理性质并可用作,例如,具有止痛作用的药物。
下述情形对本发明来说是重要的:
在本发明的化合物分子式
中,烷基、链烯基,链炔基,烷氧基,链烷酰胺基或链烷酰基可以是直链的或支链的。这也适用于烷基和烷氧基,如果它们是其它复合基团的组成部份(例如在-烷-或二烷-氨基,链烷酰胺基,烷氧碳酰胺基,烷氧羰基,链烷碳酰基及类似的基团中)。同样,在C1-C6的苯烷基中,如果烷基部分含有2至4个碳原子的话,它也可以是直链或支链的。卤素原子则是氯、溴或氟,特别是氯和氟。烷基和烷氧基本身,或作为其他复合基团的组成部分,特别是由1至4个碳原子组成的,以1个或2个碳原子的为好。链烯基或链炔基最好是含有3个或4个碳原子。链烷酰基或链烷酰胺基,特别是由2至4个碳原子组成的,以2至3个碳原子的为好。C1-C4的苯烷基中的烷基部分由1-3个碳原子组成,以1个或2个碳原子的为好。C3-C7的环烷基特别指由5至6个碳原子组成的,C5-C7的环烷稀基特别指由5至6个碳原子组成的。C2-C4的亚烷二氧基特别指由2至3个碳原子组成的。下面的基团:
特别是指5元,6元或7元环。
奎宁环以奎宁环基-(3)-基为好。托品烷则选托品烷基-(3)-基。
X为硫时比较好。
相应于分子式(Ⅰ)的一些特别重要的化合物是:X代表硫,R1或R2基团中有一个为氢,饱和的含氮环为
啶基,这个基团直接连在硫原子上,ALK=O个碳原子,也就是说ALK不存在,R3代表氢,含C3-C6的链烯基(直链或支链)或者含C1-C6的直链或支链的烷基,在烷基末端的碳原子上还可以有两个含C1至C4的烷氧基或一个含C2至C4的亚烷二氧基。在这个情况下,吡啶环最好是带有一个相应于上面所说的R1或R2取代基,这个取代基最好是连在吡啶环第6位上的卤原子(如氯)。
由相应于通式(Ⅱ)及(Ⅲ)
的化合物制备相应于分子式(Ⅰ)的化合物的过程是在溶剂或分散剂中于20-200℃下进行的,如在40-150℃下进行,则更好些,在50-120℃时则特别好。能用作溶剂或分散剂的化合物如下:较低级的脂肪醇(含1至6个碳原子),如丙醇、异丙醇、丁醇,较低级脂肪醚(乙醚、异丙醚),芳烃(苯、甲苯、二甲苯),环醚(二噁烷四氢呋喃),低级脂肪酸和低级脂肪醇所生成的酯,含C1-C4的脂肪酸的酰胺及N-烷基取代的酰胺(N,N-二甲基甲酰胺、N,N-二甲基乙酰胺),C1-C6的二烷基砜(二甲基砜、四亚甲基砜),含C1-C6的二烷基亚砜(二甲基亚砜),以及非质子传递溶剂,例如,N-甲基吡咯烷酮,四甲基脲,六甲基磷酸三酰胺,乙腈。上述溶剂中个别烷基含有,例如1至6个碳原子,特别是含有1至4个碳原子。
本制备过程适于在缩合剂中进行。这些缩合剂列举如下:无机缩合剂,如碱金属或碱土金属的氢氧化物,碱金属的氢化物,碱金属的胺化物,碱金属或碱土金属的碳酸盐,或者有机碱,例如吡啶,叔胺、
啶碱金属的醇化物,碱金属的醋酸盐,或者也可以是磷酸三乙酯。碱金属特别是钠或钾。本制备过程也可以在相转移的条件下进行(即加入一种或几种长链的胺,如苯甲基-三丁基铵卤化物,四丁基铵卤化物或苯甲基-三苯基磷氯化物。
相应的盐通常从含有羟基或巯基的原始反应物用上述所提到的碱金属首先制得,然后使其与第二种反应物作用。也可以采用相应于式(Ⅲ)原始反应物,这种化合物含有一个通常的氨基保护基团,以代替基团R3这个保护基团可以在反应完毕后通过溶剂分解作用或氢化作用而分离。按照说明规定的某些R3基团(例如苯甲基,烷氧羰基)甚至也可以代表这种保护基团。采用这些基团作保护基时当然就不必进行下一步的分离操作了。
如果式(Ⅲ)中的Y代表C1-C6的烷基磺酰氧基,那么这个基团的烷基部分含1至4个碳原子比较好(例如甲基磺酰氧基)。如果式(Ⅲ)中的Y代表芳基磺酰氧基,那么芳基最好是可以被C1-C4的烷基(尤其是甲基)任意取代的苯基或萘基(如对甲苯磺酰氧基)。
相应于式(Ⅱ)(式中Z代表SH)的原料制备:举例来说,这些化合物可以由相应于式(Ⅱ),式中Z代表卤素原子,即氟、氯、溴、碘的化合物与硫醇钠或硫醇钾在醇中(甲醇、乙醇、丙二醇)于20-150℃的温度下,或者甚至可以在水性介质中于100-150℃的温度下起反应而制得,或由这些化合物与硫脲在较低级的醇中(乙醇、异丙醇)于20-100℃的温度下起反应接着碱分解(例如在蒸汽浴上用碳酸钠水溶液)而制得。另一种可能的制备方法是将相应于式(Ⅱ)的化合物(式中X代表羟基)与五硫化二磷一起加热到50-200℃,例如68-160℃。这些反应也可模拟一些已知的方法进行。例如欧文·克林根伯格所著的《吡啶及基衍生物》一书中第四部分(1964)第348-351页(ERWIN KLINGENBERG,PYRIDINE AND ITS DPRIVATIVES,PART Ⅳ(1964),P.348-351或德国专利申请公告说明书№ 2 230 392,第9页(DE-OS2 230 392,P.9)中所述的方法。
相应于式(Ⅲ)的原料(式中Y代表羟基而且R3不是氢)可从相应于式(Ⅲ)(式中R3代表氢)的那些化合物制得。其方法是采用已知的方法或按本申请所给出的,在相应于式(Ⅰ)(式中R3代表氢)的化合物中引入基团R3的反应条件进行N-烷基化,N-酰化反应以及与适当的α-β-不饱和化合物加成,从而引入基团R3。相应于式(Ⅲ)(式中R3为氢)的那些化合物可由相应于式(Ⅲ)(式中R3为甲基(其他基团及符号如前所述))的化合物与氯甲酸乙酯反应随后分离乙酯基而制得(反应条件与本申请中所述的相应于式(Ⅰ)的化合物的类似反应相同)。
相应于式(Ⅲ)的原料(式中Y为卤素原子)可由相应于式(Ⅲ)(式中Y为羟基)的化合物与,例如,亚硫酰的卤化物(氯、溴、碘)或(烃基)磺酰氯在卤代烃(三氯甲烷)或芳烃(苯)中或者在吡啶中于20-150℃的温度时(在所用溶剂的沸点时更好)起反应而制得。相应于式(Ⅲ)(式中Y代表烷基磺酰氧基或芳基磺酰氧)的原料可由适当的羟基化合物(Y=OH)与C1-C6的烷基磺酰氯或相应的芳基磺酸或磺酰氯在通常用于这种反应的惰性溶剂中(苯、甲苯、二甲苯、氯仿、二氯甲烷、二氧杂环己烷)于20-150℃的温度下反应而制得。在有能与酸结合的物质(例如三乙胺之类的叔胺)存在时反应效果比较好。如果R3为氢,则N原子可用一个易于分离的保护基团来保护。
相应于式(Ⅲ)(式中Y为巯基)的原料可由相应于式(Ⅲ)的卤化物(Y为卤素)与碱金属的硫化物起反应而制得。这类反应可按C.费里(C.Ferri)所著的《有机合成反应》(Rcaktionen der organischen synthese)第205-209页(1978)中所述的条件或按德国专利申请公开说明书№.2 230 392中,例如第9页所述的条件进行。
相应于式(Ⅲ)的原料,如果具有如下结构:
(Y=OH,卤素,SH)
则可用下述例子的方法制得:
正如下面要叙述的一样,基团R3是通过烷基化或酰化作用引入到相应于式(Ⅲa)的化合物中的,式中R3为氢,基团CHY具有C=O的结构,所得到的化合物为下述形式:
然后将这个化合物与硫化氢反应,反应条件可参照《有机化学杂志》(J.org.chem.)1962年第27期641-643页所述条件,作者是H:巴雷拉和R.E.来尔(H.Barrera and R.E.LYIE)然后用硼氢化钠还原以生成式(Ⅲa)的化合物,式中Y代表SH。
然而,对于相应于式(Ⅲb)的化合物,可以采用已知的方法,比如用碱金属(Na、K、Li)的硼氢化物或复合金属氢化物(如氢化铝锂)把酮基还原成羟基(参阅霍本-魏尔的《有机化学方法》1981年第4/1d卷第271页及以下,Houben-Weyl:Methoden der Organishen Chemio,Vol4/ld,1981,27letseg)再采用常用的氯化试剂(如亚硫酰氯,硫酰氯)把羟基换成氯原子(参阅霍本-魏尔的《有机化学方法》1962年第5/3卷,第862-912页)作者及书名的德文同上)然后将所得的氯化物与镁作用从而生成相应的格氏化合物(式(Ⅲa)中,Y=Mgel)(参阅霍本-魏尔的《有机化学方法》1973年第13/2a卷,53-85页)再用硫或亚硫酰氯与这样的格氏化合物作用可进而制得硫醇化合物,式(Ⅲa)中Y代表SH(参阅霍本-魏尔的《有机化学方法》1955年第9卷第19页及E.E.里德的《二价硫的有机化学》,纽约化学出版公司出版,1958年第1卷,第37页,E.E.Reid organic Chemistry of Bivalent Sulfur Vol I,Chem Publ.Corp.New york,1958,page 37)。
如果愿意的话,可以再次采用通常的方法使R3基团(甲基或酰基)脱去。
相应于式(Ⅲa)(式中Y代表羟基,R3代表氢)的原料也可从相应的羟基吡啶用钠还原或催化一活化氢(在任意压力下,如达到100巴)在20-150℃时(溶剂C1-C6的醇类)还原制备。基团R3可按下述方法引入到这些化合物中。
采用下列反应可以把相应于式(Ⅰ)的化合物中的基团R1、R2和R3转变成别的基团:
1、通过烷基化或酰基化作用:
这两种反应是将基团R3引入到相应于式(Ⅰ)(式中R3代表氢)的化合物中的特别有效的方法,而且也是将氨基烷基化或酰基化的有效方法(例如,假定R1和(或)R2是氨基的话)。例如,烷基化的实现可以通过与相应于R′Hal,ArSO2OR′和SO2(OR′)2等式子的化合物进行反应,在这些式子中,Hal为卤素原子(尤其是指氯、溴、碘),Ar为芳基(如被一个或几个低级烷基任意取代的苯基或萘基),R′的定义与R3相同(但氢除外)。
下面列举这些化合物的例子:
对甲基苯磺酸-C1-C6-烷基酯,C1-C6-二烷基硫酸酯,C1-C6的卤代链烯烃,C3-C6的卤代链炔烃,C3-C7的卤代环烷烃,C3-C7的卤代环烯烃以及类似的化合物。上述化合物中烷基在各种情况下可以换成与R3定义一致的基团。如果R3为至少含有一个羟基(在2位上)的C1-C6的烷基,那就可用适当的C1-C6的氧化亚烷化合物来进行烷基化,而这样的化合物当然可以包含更多的与R3定义相应的取代基。烷基化和酰基化反应可以选择适当的条件进行,加入常用的酸结合试剂,如碱金属的氢氧化物,碱金属的碳酸盐,碱金属的碳酸氢盐,碱土金属的碳酸盐,碱金属的醋酸盐,叔胺(如三烷基胺,比如三乙胺),吡啶或者甚至碱金属的氢化物等,反应温度为0-200℃,40-140℃更好,反应应在惰性溶剂或悬浮剂中进行。可以采用的溶剂或分散剂列举如下:芳烃,如苯,甲苯,二甲苯;脂肪酮,如丙酮,甲乙酮;卤代烃,如三氯甲烷,四氯化碳,氯苯,二氯甲烷;脂肪醚,如丁醚;环醚化合物,如四氢呋喃,二 烷;亚 ,如二甲基亚 ;叔酰胺,如二甲基甲酰胺,N-甲基吡烷酮,六甲基磷酸三酰胺;脂肪醇,如甲醇,乙醇,异丙醇,正戊醇,叔丁醇;脂环烃,如环己烷以及类似的化合物。也可采用上述溶剂与水的混合物。反应通常在溶剂或分散剂的回流温度下进行。烷基化试剂通常需要过量。烷基化反应也可以在有季盐(尤其是卤化物的季盐)和碱金属的氢氧化物一起存在的条件下,在0-100℃的温度下(20-80℃更好),在非质子传递溶剂中,或者甚至在三氯甲烷或二氯甲烷中进行。可供使用的非质子传递溶剂的具体例子列举如下:叔酰胺(二甲基甲酰胺,N-甲基吡烷酮,六甲基磷酸三酰胺),二甲基亚,乙腈,二甲氧基乙烷,丙酮,四氢呋喃。在酰基化过程中已被一个C
-C6的环烷基或C
-C
的烷酯基任意取代了的C2-C6的烷酰基被引入到,比如,相应于式(Ⅰ)的那些化合物中,式中R
代表氢。反应是以已知的方法这样进行的,最好是用C1-C6的烷酯基卤化物(或其相应的酐)或C2-C6的烷酰卤(或相应的酐),其中烷酰基也可以取代有C
-C
的环烷基。反应温度为30-120℃比较好。烷基化和酰基化也可以任用他法,比如首先将需要进行烷基化或酰基化的化合物制成碱金属一化合物(如钠盐、钾盐或者甚至锂盐)其方法是使需要进行烷基化或酰基化的化合物和碱金属,碱金属的氢化物或碱金属的氨化物(特别是钠或钠的化合物)或丁基锂在惰性溶剂中,如在二 烷,二甲基甲酰胺,苯或甲苯中于0-150℃的温度下起反应,然后再加入烷基化试剂。
化学上其它常用的化学性质相当的试剂也可用来代替上述的烷基化及酰基化试剂(作为例子,可参阅路易·费萨及玛丽·费萨的《有机合成试剂》,纽约约翰威利父子公司出版,1967年第1卷第1303-4页及第2卷,471页,L.F.and Mary Fieser“Reagents for Organic Synfhcsis”,John Wiley and Sons,Inc New york,1967,Vol 1,pages 1303-4 and Vol 2,page 471)。
2.与双键相邻的碳原子上有C1-C6的链烷酰基,C1-C6的烷氧羰基或苯甲酰基的C3-C6的链烯基可以接到相应于式(Ⅰ)的化合物上,式中R3代表氢,这个反应可在溶剂中于20-150℃的温度下进行。适用的溶剂列举如下:C1-C6的链烷醇,饱和脂肪醚,芳烃(苯,甲苯,二甲苯)氯代脂肪烃(二氯甲烷,三氯甲烷,二氯乙烷)。
3.C1-C6的烷氧羰基可以引入到相当于式(Ⅰ),(式中R3代表甲基)的那些化合物中,其方法是使这些化合物与卤甲酸的C1-C6的烷基酯作用或先与碳酰氯随后与C1-C6的链烷醇反应。氯甲酸的C1-C6的烷基酯(如氯甲酸乙酯)比较常用。
这些反应可以在溶剂或分散剂中进行,也可以不在溶剂或分散剂中进行。反应温度为20-180℃,40-120℃更好。用于这些反应的溶剂列举如下:芳烃,(甲苯,二甲苯),氯代烃,如二氯甲烷或氯仿。
4.如果相应于式(Ⅰ)的化合物中的R3是C1-C6的烷氧羰基或C2-C6的链烷酰基(也可以带有环烷取代基,这些基团可以溶剂化裂解从而生成相当于式(Ⅰ)的化合物,此时式中R3代表氢。这些基团是用众所周知的方法从化合物中除去的,例如,可用酸(无机酸,如盐酸,硫酸,特别是浓度高的氢卤酸,如HBr/冰醋酸)或用碱类(碳酸钾,碳酸钠,碱水溶液,碱醇溶液,氨水)在10-150℃(20-100℃更好)的温度下进行皂化。如果R3代表S基,并且这个S基是一个可以用溶剂化分解的方法除去的保护基团(如三氟乙酰基,三苯甲基,对甲基苯磺酰基,甲酰基,叔丁酯基以及类似的基团),那么这个S基就可以用同样的方法除去。
如果R3是苯甲基,α-苯乙基或与S基一样,是另一个可通过加氢反应而除去的常用保护基,那么,这些基团就可以在常用的加氢催化剂,特别是催化剂,氧化铂或甚至瑞尼镍催化剂存在下,在溶剂或悬浮剂中,选择适当的高压,于20-100℃,特别是40-80℃的温度下,通过催化加氢作用而除去。可用作溶剂或悬浮剂的物质列举如下:水,较低级的脂肪醇,环醚,如二 烷或四氢呋喃,脂肪醚,二甲基甲酰胺等以及这些溶剂的混合液。可用加氢反应来除去的保护基团有:α-芳烷基,苯核上带有取代基的苯甲基,(对溴苯甲基或对硝基苯甲基),芳代烷酯基,如苄氧甲酰基,苄硫甲酰基。
肽合成中常用的保护基特别适于作为保护基S。关于这点可特别参考1961年纽约约翰·威利父子出版有限公司出版的杰西P·格林斯坦和米尔顿·威尼茨合著的《氨基酸化学》一书,第2卷883页以后。(Jesse P.Greenstein and Milton Winitz“Chemistry of Amino Acids”,N.Y,1961,John Wiley and Sons,Ine.Volume 2,for page 883 et seg)
5.如果基团R1与R
中有一个代表硝基,或者甚至两个都代表硝基,那么,这些硝基就可以被还原为相应的氨基。催化加氢反应则特别适用于这种还原作用。适用于加氢反应的催化剂有:瑞尼镍,贵金属催化剂,如钯,铂及其化合物,用不用载体都可以,如用载体,则可采用,硫酸钡,硫酸钙等。硝基的氢化反应最好是在20-80℃的温度下,5至50个表压下,在溶剂中,可在醇、二 烷、四氢呋喃中进行。反应开始前在要氢化的混合物中加入脱水剂,如无水硫酸钠或硫酸镁有利于被还原化合物的分离。然而,还原反应也可以按下述条件进行:用初生氢,如锌/盐酸,锡/盐酸,铁/盐酸或用硫化氢的盐类作还原剂在乙醇/水中于大约70℃至120℃下进行或用活化的铝作还原剂在含水的醚中于20-40℃的温度下进行,或者用氯化亚锡/盐酸作还原剂。
6.吡啶环上的活泼卤原子也可以被其他基团置换,例如被C1-C6的一烷基或二烷基氨基或任意被苯基或卤苯基或C1-C4的苯烷基取代了的氨基置换。这个置换反应可以在惰性溶剂或悬浮剂,如四氢呋喃、二 烷,低级链烷醇(乙醇,正丙醇),二甲基亚 或二甲基甲酰胺中进行,或者甚至可以在碱性反应组份过量的条件下进行,反应温度为50-200℃,80-130℃更好,反应时也可加入酸接受体,例如碳酸钾,碳酸钠,碳酸钙或非季铵化的叔胺,如二异丙基甲胺。吡啶环中3-,4-,或5-位置上的卤素原子如果由于存在吸电子基团,如硝基而变得活泼,那么这些卤素原子就容易发生这种置换反应。
相应于式(Ⅰ)的化合物可以转变为相应的胺一氧化物(例如氧化连有R8基的N原子)和(或者)吡啶-N-氧化物,其方法是,比如,可在惰性溶剂,如氯仿或其它氯代烃,苯,甲苯,丙酮,稀的醋酸或醋酸乙酯中用过氧化氢,常用的脂肪族或芳香族过酸(过氧醋酸,过氧苯甲酸,间(位)氯(代)过氧苯甲酸)或过氧化氢的其它单取代产物,如碱金属过氧化物或烷基过氧化物(如叔丁基过氧化物)进行氧化,反应温度为0-150℃,0-100℃更好。如果X代表S,那么,这个反应首先产生相应的亚 或 。然而,这些产物会进一步氧化生成胺氧化物。
用已知的方法通过氧化可以使相应于式(Ⅰ),式中X代表硫原子,的化合物转变为式中X代表SO或SO2基团的那些相应的化合物。过氧化氢,四氧化二氮,高锰酸钾,过酸(如过氧苯甲酸,单过氧邻苯二甲酸,过氧乙酸),硝酸,铬酸或其它众所周知的氧化剂都可以有效地用作氧化剂。这种氧化作用适于在水中或诸如醇、乙酸(冰醋酸),乙酸乙酯,苯,丙酮或氯仿等溶剂中进行。较低级的醇,如甲醇或甚至乙酸是特别合适的溶剂。用30%的过氧化氢,过酸,硝酸,亚硝气(二氧化氮)作氧化剂进行氧化,同时需要冷却,比如维持-20℃至+20℃的温度,所得到的主要产物一般是相应的亚 ,另外,还有少量的 。此外,从相应于式(Ⅰ),式中X代表S,的化合物也可制得相应的亚 ,其方法是用铬酸氧化(例如在乙酸溶液中在50-100℃的温度下),或用亚碘酰苯氧化或用溴处理(比如在卤代烃为三氯甲烷或四氯化碳中),反应时需要冷却,反应后接着用水或稀碱溶液将二溴代衍生物水解掉。关于反应条件及其它氧化剂,可参考霍本一魏尔的《有机化学方法》第9卷(1955)第211-218页(Houben,Weyl:Mefhoden der Organischen Chemie.Vol Ⅸ(1955)pages 211-218)。根据《有机化学杂志》,223期(1958),2028-2029页所述方法用二甲基亚 作氧化剂在高温下(150℃至180℃)也能把相应于式(Ⅰ)(式中X=S)的硫化物氧化。
用通常的分离方法,如用柱色谱法以硅胶为吸附剂可以把上述各种情况下所制得和亚分离开来。如果采用更强的氧化剂,如高锰酸钾在醋酸或硫酸的水溶液中于50-100℃的温度下进行氧化,则所得到相应的 产率相当大,或者是反应的主要产物。例如,相应于式(Ⅰ)(式中X代表S或SO)的化合物也可以用过氧化氢或过酸作氧化剂在较高的温度下,如80-120℃下进行氧化(反应在醋酸溶液中或在冰醋酸和醋酸酐中,在磷酸或通常用于该用途的其他任何惰性试剂存在下进行),也可用铬酸,采用阳极氧化法或者也可选用次氯酸钠溶液来氧化。(参考霍本-魏尔的《有机化学方法》第9卷(1955)227-231页,Houben-Weyl,Mefhoder der Organischen Chemie,Vol Ⅸ(1955)pages 227-231)。再一种可能的氧化方法是用有机氢化氧化物(例如烷基化过氧氢,象叔丁基化过氧氢)作氧化剂,在钒、钼或钛等化合物(例如上述金属的氧化物,象二氧化钼,五氧化二钒)的存在下,在有机溶剂中,如在芳烃(苯),链烷醇(乙醇)或脂肪酸与链烷醇所生成的酯(乙酸乙酯)中,在40-120℃的温度下(50-80℃更好)进行氧化,关于此法可参阅《应用化学》杂志,78卷,(1966)937页(Angewandte Chemie 78(1966),p937)。
相应于式(Ⅰ)的那些化合物中含有不对称碳原子并且通常以外消旋体的形式存在。用众所周知的方法,比如用具有旋光活性的酸可以把这些化合物析分成光活异构体。如果从一开始就选用有旋光活性的原料,则可得最终产物为相应的光活异构体或非对映异构体。
因此,当相应于式(Ⅰ)的化合物中存在一个不对称碳原子时本发明包括D型和L型以及DL型的混合物,在有两个或更多不对称碳原子时,还包括相应的非对映体。
相应于式(Ⅰ)的最终产物是以游离的形式得到还是以其盐的形式得到,这要取决于操作条件及所用的原料。用众所周知的方法,如用碱或离子交换剂可以把最终产物的盐类再一次转变成游离碱。用有机酸或无机酸,特别是那些适于形成治疗上可应用的盐的酸,与游离碱反应又可得到这些化合物的盐。比如,下面所列举的酸均可采用:氢卤酸,硫酸,磷酸,硝酸,高氯酸,脂肪族,脂环族,芳香族或杂环系列的有机一元、二元或三元羧酸以及磺酸。现举例如下:甲酸、乙酸、丙酸、丁二酸、羟基乙酸,乳酸,苹果酸,酒石酸,柠檬酸,抗坏血酸,马来酸,富马酸,羟基马来酸和丙酮酸;苯乙酸,苯甲酸,对氨基水杨酸,双羟萘酸,甲磺酸,乙磺酸,羟基乙磺酸,亚乙基二磺酸;卤代苯磺酸,甲基苯磺酸,萘磺酸或对氨基苯磺酸或者甚至8-氯代-萘碱。
这些化合物都适合用来制造药用制剂。药剂或药物可以包含一种或几种上述化合物。通常所用的药物载体及辅助剂都可用来制备药剂。这些药物可采用肠内投药,肠胃外投药(例如静脉注射,肌肉注射,皮下注射)或口服的方式施用。这些化合物可以调制成各种形式的药剂,如片剂、胶囊,丸剂,糖衣丸,栓剂或药膏等。液体制剂举例如下:油或水的溶液或其悬浮液(例如溶解或分散于芝麻油或橄榄油中),乳剂,可供注射的水或油的溶液或其悬浮液。此外,也可以制成粉针剂,安 中封装作为有效药物的本发明的化合物(Ⅰ),在使用之前将安 中的干药物溶解在水中,生理盐水中或生理盐水和,比如,二甲基亚 的混合液中。
有关药理或药物的资料如下:
本发明的化合物适用于制备药物复方和药物制剂。这些药物复方或药剂含有作为有效物质的一种或几种本发明的化合物,这些化合物也可以与其他药理上或药物上有效的物质掺合在一起,这些药物可用大家所熟知的方法来制备,制药时可采用众所周知的通常所使用的药物辅助剂及其他常用的载体和稀释剂。
例如,下列文献所推荐和详细说明的作为药物、化妆品及相关领域的辅助剂的那些物质都可以用作本发明的药物的载体和辅助剂:乌尔曼斯《技术化学大全》第4卷(1953),1-39页,(ullmanns Encyklopadie der technischen Chemie,Vol 4(1953)page 1 to 39);《药物科学杂志》第52卷(1963)918页及其以后(Journal of pharmaceutical Sciences,Vol,52(1963)pages 918 et seq);H.V.切茨一林登瓦尔德:药物,化妆品及其相关领域的辅助材料(H.V.Czetsch-Lindenwald,Hilfsstoffe fiir pharmazie kosmetik und angr enzende Gebiete);《药物工业杂志》第2卷(1961)72页以后(Pharm.Ind.Vol.2(1961)pages 72 to seq);H.P.菲德勒博士的药物、化妆品及其相关领域的辅助材料百科词典,1971年由符腾堡州奥伦多夫地区的坎托股份公司出版。(Dr.H.P.Fiedler,Lexilcon dcr Hilfsstoffe fur pharmagie,Kosmetik and angrenzende Gebiete Cantor KG.Aulendorf in wurtlem berg 1971)。
本发明的化合物采用常用的标准方法进行药物及盖仑制剂加工处理。举例来说,通过搅拌混合或均化作用(例如采用通常的混合设备)使有效物质和辅助剂或载体充分混合。这种操作一般在20-80℃的温度下进行,20-50℃较好,尤其在室温下进行更好。此外,还可参考下面的标准方法:祖克尔,富克斯及施派泽尔合著的《制药技术》,1978年由斯图加特的蒂梅出版公司出版(Sucker,Fuchs,sbeiscr:Pharmazeutische Technologie,Thieme-Verlag Stuttgart,1978。)
在电刺痛试验(Electropain test)(1),热板试验(Hot-plat-test)(2),甩尾试验(Tail-flick-test)(3)及哈夫纳试验(Haffner-test)(4)中均表明本发明的化合物具有良好的止痛作用。
在上述试验中,半数有效量(ED50)为2.8mg/小鼠体重,口服。
这样止痛效果可以和现有的有效药物布扑惹哪酚(Buprenorp-hine)相比。
在上述动物试验中最低有效止痛剂量为:
口服:1-1.5mg/每公斤体重,
静脉注射:0.1-0.15mg/每公斤体重。
根据上述动物试验,要达到这样的效果,一般的剂量范围如下:
口服:1-8mg/每公斤体重。
静脉注射:0.1-0.8mg/每公斤体重。
药物制剂中一般含本发明的有效成份0.1-10mg,最好是含0.5-3mg。
药剂可以调制成片剂,胶囊,凡剂,糖衣丸,栓剂,软膏,凝胶剂,乳膏(霜),粉剂,气雾剂等形式或液体形式。可以以液体形式应用的实例如下:油、醇或水的溶液、悬浮液及乳液。最好的应用形式是含有0.5至2mg的片剂或含有1-10%有效物质的溶液。
本发明有效成分的各个剂量为:
a)口服类型的,含药物0.1-20mg,最好是0.5-3mg,
b)非肠道类型用药(如静脉注射,肌内注射)为0.01-1mg,最好是0.05-0.5mg。
c)施用于直肠或阴道的药物为0.05-20mg,最好是0.05-5mg。
一(各种情况的剂量均指游离碱的用量)-
举例来说,建议每日服1-3片含有1-3mg有效物质的药片,分三次服用:如为静脉注射,则每日注射1安 ,内含有效物质0.1-0.5mg,体积为1-10ml,分1-3次注射。
口服时最大剂量每日不应超过3mg。
治疗狗和猫时,口服剂量一般为每公斤体重服用0.05至1mg。非肠道投药剂量每公斤体重约0.01至0.2mg。
对小鼠的试验表明,口服本发明的化合物引起急性中毒的剂量为每公斤体重70至110mg(或者说每公斤重80mg以上)。(急性中毒用半致死量LD50表示,即达到半数死亡时每公斤体重所用的毫克数mg/kg;试验方法依据米勒和泰恩特的文献:实验生物学和医学学会会报,57卷(1944)261页,Miller and Tainter:Proc.Soc.Exper.Bio.a Mcd.57(1944)261)。
这些药物不论其本身还是与其它有药理效果的物质一起的混合物都可用在人类医学、兽医学以及农学方面。
本发明的化合物是高效止痛药。
注(1)按照B·布莱克等人的方法:《实验医学》杂志9卷,146-150页(1963)(B Blake et al:Med.exp.9,pages 146-150(1963))。
注(2)按照詹森和贾格纽的方法:药物与药理学杂志9期381页(1957),(Janssen and Jageneau:J.pharm pharmacol 9 page 381(1957))。
注(3)按照达摩尔和史密斯的方法:药理学与实验治疗杂志,72卷,74页(1941),(D Amour and Smifh:J.of Pharmacol.and exp Therap,72,page 74(1941))。
(4)按照哈夫纳的方法:德国药物周刊,55期,731页(1929)(Haffner:Deutsche Medizimische Wechenschrift 55,page 731(1929))及比安奇和弗朗斯希尼的方法:英国药学与化学治疗杂志,9期,280页(1954),(Bianchi and France schim:Brit.J.Pharmacol.9,page 280(1954))。
实例1-21
用化合物(Ⅱ),Z代表卤素原子(氯),作原料合成表1中所列的例1至例21的化合物的一般方法步骤如下:
先将0.05克分子80%的氢化钠悬浮于大约30ml的前面所提到的无水溶剂中(参见表1)。然后在室温下一边搅拌一边滴加0.04克分子的相应于式(Ⅲ)(Y=OH)的对应的醇或者0.05克分子的相应于式(Ⅲ),式中y代表SH,的对应的硫醇(这些醇也可以事先溶于同样的溶剂中)。反应一开始就有氢生成。将混合物加热到50℃,如用硫醇则加热到60℃,此时0.05克分子的NaH就溶解在50ml的所用的溶剂中,在反应完成时,滴加(最好在室温下)0.05克分子的相应的氯代吡啶(也可以事先溶于同样的无水溶剂中),然后在回流温度下(如用硫醇,则温度为80-100℃)将反应混合物加热若干小时(3-6小时)。用水冷却后混合物被水解,所得的水溶液用乙醚或二氯甲烷萃取一次以上。溶剂用硫酸镁干燥后过滤,然后在真空下蒸掉。后处理可用下面三种方法进行:
A)用制备柱色谱法以硅胶为吸附剂来提纯残留物,提纯后也可以接着成盐,如用异丙醇的盐酸溶液来制成盐。
B)采用真空蒸馏提纯,随后也可以按上述A)中方法成盐。
C)如果最后所得到的残留物不是很不纯的话,那就不必再提纯而可以直接制成盐。通常将残留物溶于异丙醇中然后再与异丙醇的盐酸溶液混合。
结晶完全后,将盐滤出并用溶剂进行重结晶。
现将由此而制得的相应于下式的化合物列于表1中。
实例22
6-氯-2-〔(N-2-苯乙基)啶基-(4)-氧〕-吡啶
在室温下将1.3g 75%的氢化钠在搅拌的条件下分批加入到含有8.2g(0.04克分子)的N-(2-苯乙基)-4-羟基 啶和60ml无水的二甲基乙酰胺的溶液中。加完氢化钠后,再加入5.9g(0.04克分子)的2,6-二氯吡啶。将反应混合物加热到120-130℃,维持8小时。然后冷却到室温,再倒入到大约300ml的水中。将沉淀的结晶产物分离出来,放在浓度为2N的盐酸溶液中,搅拌大约1小时后,将产品抽滤分出,然后水洗、干燥,并在乙醇中重结晶。
该化合物的盐酸盐的熔点为253-254℃。
实例23
6-氯-2-〔啶基-(4)-硫〕吡啶
制备这个化合物的反应是在氩气中进行的。将0.27g80%的氢化钠(0.009克分子)悬浮于10ml二甲基乙酰胺中;用水将此混合物冷却,然后加入0.615g(0.004克分子)的固体4- 基- 啶盐酸盐并搅拌10分钟。再将含有0.588g(0.004克分子)2,6-二氯吡啶的5ml二甲基乙酰胺溶液滴加到此混合物中并在室温将反应混合物搅拌2.5小时。
反应混合物的后处理:一边冷却一边滴加25ml水,然后加入26ml二氯甲烷,将有机相分离出来,水相用二氯甲烷萃取两次,每次用15ml。将合并在一起的有机相用水洗两次,每次10ml,然后用硫酸钠干燥,干燥后的溶液在旋转式蒸发器中进行浓缩,残留物与10ml无水乙醇混合,然后再浓缩。将所得到的大约1.5ml的黄色液体用柱色谱法提纯,吸附剂可用60g硅胶(由达姆斯塔特的默克公司生产的Geduran Si 60,Merck,Darmstadt)。(料柱高度400mm,柱直径20mm)。被吸附的混合物用850ml氯仿,150ml乙醇和10ml浓氨水的混合液洗脱。
除去洗脱剂后所得到的产品用10ml乙醚稀释,并滴加等当量盐酸异丙醇溶液,加入晶种后将此混合物置于深度冷冻箱中放置若干小时。将结晶出来的6-氯代-2-〔啶基-(4)-硫〕-吡啶的盐酸盐抽吸过滤,用乙醚洗涤并用油泵抽真空在50℃温度下进行干燥。其盐酸盐的熔点为132-133℃。
4- 基 啶(盐酸盐)可用下述方法例如由1-甲基- 啶酮-(4)制得:
在搅拌情况下将大流量的硫化氢气体通入到含有1026g(9.066克分子)新蒸馏出来的1-甲基- 啶酮-(4)和1.5升的异丙醇的溶液中。反应混合物的温度维持在10-15℃之间。多余的硫化氢气体导入到商品纯的次氯酸钠溶液中,以便被吸收。通入硫化氢大约两个小时之后,反应产物就开始从溶液中结晶出来。再继续通硫化氢气体两小时。把以这种方法所制得的1-甲基- 啶-4-二(氢硫化)水合物抽吸过滤出来,洗涤两次,每次用300ml冷异丙醇,然后用乙醚再洗两次,每次用量为500ml。将所得到的化合物保存在放有五氧化二磷的干燥器中,干燥器要放在暗处,存放时间要短,要很快就进行下一步的加工处理。
将350g(9.23克分子)硼氢化钠粉末悬浮于2.5升异丙醇中,在搅拌情况下分批加入1396g(7.7克分子)1-甲基- 啶-4-二(氢硫化)-水合物。反应进行时放出热量:混合物用冰浴冷却,反应温度不应超过25℃。反应放出的硫化氢气体导入到商品纯的次氯酸钠溶液中以便被吸收。加完料后将冷却浴撤除,在室温下静置一夜。然后将反应混合物加热,徐徐升温,大约在60分钟内将温度升至80℃并在此温度下维持两个小时。在稍微抽点真空(100mmHg)的情况下,就能把异丙醇基本上由下降式冷凝器中蒸馏出来。
将浆糊状的残留物冷却至室温,然后用1.5升乙醚混合搅拌,得到易于搅拌的悬浮液。再慢慢滴加740ml冰水并再冷却。大约滴加一半冰水之后,反应并中的物料又变成难于搅拌的浆糊状。再继续加水又能使搅拌易于进行瓶使有机相和无机的硼氢化物残留物明显分层。调节搅拌速度,抽出醚相。残留物用新鲜乙醚搅拌洗涤三次,每次用量500ml。合并在一起的有机相用硫酸镁干燥。溶液经过滤后在减压下置于旋转式蒸发器中进行浓缩。浓缩后的残留物进行真空蒸馏。由于沸点低(在2毫米汞柱时为35-40℃),所以要将所得产物1-甲基-4- 基- 啶收集在用甲醇/干冰冷却剂冷却的容器中。
在15-20℃的温度下将59.6克(0.56克分子)氯甲酸乙酯在搅拌下滴加到含有65.5克(0.5克分子)1-甲基-4- 基- 啶和300ml丙酮的溶液中。产物1-甲基-4-乙氧羰基- 基- 啶的盐酸盐以结晶状沉淀出,待反应完毕后,通过抽吸过滤将沉淀物分离,然后用丙酮洗涤并进行干燥。用浓的氨水溶液加入到盐的水溶液中可使碱游离。
含碱的乙醚溶液用硫酸钠干燥后过滤并浓缩。所得产物用蒸馏方法提纯,在12mmHg下的沸点为128-130℃。
在搅拌下,用30分钟的时间将106.3克(0.88克分子)氯甲酸乙酯滴加到事先已经加热到90℃的含有100克(0.48克分子)1-甲基-4-乙氧羰基- 基- 啶和80ml甲苯的溶液中,然后将溶液加热到100-110℃,维持两小时。再加入40克氯甲酸乙酯后再将溶液加热三个小时。在室温下令其静置一夜,用玻璃纤维漏斗抽吸过滤。将所得溶液在旋转式蒸发器中进行浓缩,并将残留物蒸出,得到20克(理论产量的94%)1-乙氧羰基-4-乙氧羰基- 基- 啶,其沸点(在0.2mmHg下)为138-140℃。
把269.7克(1.032克分子)1-乙氧羰基-4-乙氧羰基- 基- 啶溶解在886ml(10.3克分子)浓盐酸和443ml冰醋酸的混合液中。在搅拌下于1小时内将混合液加热到回流温度。
反应60小时后,在旋转式蒸发器中将溶液浓缩。结晶残留物与异丙醇混合两次,每次用200ml,以便基本上除去残留的溶剂混合物。然后将所得混合物蒸出。由此所得到的4- 基- 啶盐酸盐在乙醇中进行重结晶。
该化合物的熔点为183-184℃(分解),产量为117.6克,母液处理后可再得27.5克,总产量约为理论产量的96%。
实例24
6-氯-2-〔N-甲基- 啶基-(4)-硫〕-吡啶-N-氧化物
将4.9克(0.03克分子)2.6-二氯-吡啶-N-氧化物滴加到含有4.5克(0.035克分子)N-甲基-4- 基- 啶的20ml乙醇溶液中。 啶化合物事先用11.9克(0.035克分子)20%的甲醇钠溶液制成其钠盐。
将反应混合物加热到50℃并维持此温度3小时。然后将反应混合物倒入到200ml左右的冰水中,结晶物质就会沉淀出来。将反应混合物抽吸过滤若干次,随后水洗、干燥并用乙醇重结晶,产品熔点为129-130℃。
原料2.6-二氯-吡啶-N-氧化物可用下面的方法制得。如,将含有16克(0.108克分子)2.6-二氯吡啶和17克35%的双氧水(相当于5.9克有效的H2O2,约为0.17克分子)以及25 250克三氟乙酸的溶液在水浴上加热8小时,溶液内温度约为75℃。然后将溶液倒入到1.5升水中,此时有少量结晶物析出,为未反应的2,6-二氯-吡啶。将沉淀物抽吸过滤出来后,用水泵减压在浴温为30至35℃将溶液基本浓缩。留下的液状残余物用500ml氯仿溶解在搅拌下加入足量的无水碳酸钾直到不再有气体生成而且水分亦被吸住。
在3C至35℃的溶温下进行过滤并在稍微的真空度下浓缩至干,可得到晶状残留物2,6-二氯-吡啶-N-氧化物,其熔点为137-138℃。
实例25
由式(Ⅱ)(式中Z代表SH或OH)的化合物和式(Ⅲ)(式中Y代表卤素)的化合物来制备:
将0.06克分子的相当于式(Ⅲ)(式中Y代表卤素)的化合物和0.06克分子的6-氯-2- 基-吡啶的钠盐在60ml正丙醇中的混合物在搅拌情况下于回流温度下加热若干小时(例如6小时),冷却后将不溶的残渣抽吸过滤掉。
将溶液浓缩,糖浆状残留物用异丙醇盐酸液酸化。用丙酮稀释后盐酸盐就结晶出来。分离结晶用丙酮洗涤后再水洗,最后用重结晶法进一步提纯。
用上面所述的方法从9.3克N-甲基-2-(2-氯乙基- 啶和9.6克2-硫钠基-6-氯-吡啶可制得相应于下式的2-〔N-甲基- 啶基-(2)-
该化合物盐酸盐的熔点为165-167℃,重结晶是在乙醇/乙醚混合液中进行的。表1中例13至16的那些化合物也是用这种方法制备的。
6-氯-2- 基-吡啶可用如下方法制得:
将103.1克(0.70克分子)的2,6-二氯吡啶和110.0克(2×0.70克分子)的硫化氢钠XH2O(71%)加入到700ml正丁醇中,在回流温度下总共加热10小时。在35℃抽吸过滤,滤液在60℃真空蒸发浓缩(残留物为170克)。残留物用1升乙醚混拌,令其静置一夜。将所形成的固体产物(钠盐)抽吸分离出来,用乙醚充分洗涤,然后于真空下在35℃干燥24小时。
实例24至26(见表2)叙述了通过烷基化或酰基化把基团R3引引入到相应于式(Ⅰ)(式中R3代表氢)的化合物中的方法。
实例24至43的化合物的一般制备过程如下:
将相应于式(Ⅰ)(式中R3代表氢)的胺与相应于分子式为HalR3的卤化物(卤化物过量10%至300%克分子)及碱在回流温度下一起加热(直到用薄层色谱分析法观察不到进一步的反应为止)。冷却后滤去沉淀物,并将溶液浓缩,混合物按通常所用的方法后处理成盐,在几个例子中还必须用色谱法以硅酸为吸附剂来提纯。
实例40与44中,没有测得化合物的熔点,因此用薄层色谱法所测得的Rf值来表示其特征。Rf值的测定方法及条件如下:
Rf值是在室温下在充满展开剂饱和蒸气的干燥器中测定的。固定相采用层厚为0.25毫米的硅胶(默克公司生产的成品硅胶板,型号为6F254)。试样用量约为100微克。展开剂采用95∶4∶1的氯仿、甲醇与25%的氨水的混合液。溶剂行程为14厘米。
鉴定方法采用:
1.紫外光,波长为254毫微米。
2.碘。
3.25%盐酸。
实例46
2-〔N-(2,3-二羟基-丙基)- 啶基-(4)-硫〕-6-氯-吡啶
将4.85克(0.0212克分子)2-( 啶基-(4)-硫)-6-氯-吡啶(游离碱)与1.4ml缩水甘油和40ml异丙醇一起加热5小时,温度达到沸点。将异丙醇溶液浓缩并与6ml异丙醇盐酸液混合。产物的盐酸盐会慢慢结晶出来,其熔点为115-121℃。
实例47
2-〔N-甲基- 啶基-(4)-氧〕-3-乙酰胺基-6-(4-氟-苯
在氮气流下将1.8ml乙酰氯加入到含有0.025克分子的2-〔N-甲基- 啶基-(4)-氧〕-3-氨基-6-(4-氟-苯甲胺基)-吡啶的加氢溶液中,而这种加氢溶液是由4.5克(0.025克分子)相应的3-硝基化合物在钯一碳催化剂的存在下,在温度为60℃,压力为5巴的条件下在125ml二 烷中进行氢化反应而得到的产物。将沉淀的盐酸盐抽吸过滤出来。按常用方法用氢氧化钠溶液将碱游离。产品的盐酸盐的熔点为188-190℃。
实例48
2-〔N-甲基- 啶基-(4)-氧〕-3-乙氧羰基胺基-6-(4-氟
在搅拌及氮气流下将4ml氯甲酸乙酯滴加到含有0.02克分子2-〔N-甲基- 啶基-(4)-氧〕-3-氨基-6-(4-氟-苯甲胺基)-吡啶的加氢溶液中,而这种加氢溶液是由7.2克(0.02克分子)相应的3-硝基化合物在钯-碳催化剂的存在下,在温度为60℃、压力为5巴的条件下,在125ml二 烷中进行加氢反应而得到的产物。在室温下将溶液搅拌半小时后进行浓缩,残留物用1∶1的汽油和乙醚的混合物搅拌。抽吸滤出结晶物质并在甲醇中进行重结晶。
该化合物盐酸盐的熔点为202-207℃。
用氢氧化钠溶液处理时可从其盐酸盐得到该化合物的游离碱。
该碱的熔点为168-169℃(未进行重结晶)。
实例49-55(表3)
这几个例子涉及用乙氧羰基取代相应于式(Ⅰ)(R3=CH3)的化合物中 啶环上的甲基以及尔后又将乙氧羰基除去的问题。
一般方法如下:
将0.09克分子相应于式(Ⅰ)(式中R3代表CH3)的化合物溶解在30ml甲苯中,然后在搅拌下用30分钟时间将此溶液滴加到事先已经加热到85℃的含有0.18克分子氯甲酸乙酯的30ml甲苯溶液中。滴加完后,在搅拌下将溶液在回流温度下再加热6小时,冷却后滤去固体部分并将滤液浓缩至干。所得到的N-乙酯基产物一般不用进一步提纯而以粗制品形式直接使用。将粗制品(相应于式(Ⅰ)的化合物,式中R3代表CO-OC2H5)溶解于80克浓盐酸和40ml冰醋酸的混合液中。在回流温度下将溶液加热15小时,然后浓缩至干,残留物用异丙醇搅拌混合并再次浓缩。固体残留物用重结晶提纯。所制得的相应于下式的化合物列于表3中。
实例56
(用乙氧羰基取代 啶环上的甲基然后再把乙氧羰基除去的例子)
6-氯-2-〔 啶基-(4)-硫〕-吡啶-N-氧化物
在搅拌下将3.5克2-〔1-甲基 啶-4-基〕-6-氯-吡啶-N-氧化物在20ml氯甲酸乙酯中的溶液加热回流。3小时后再加入20ml氯甲酸乙酯(此操作重复三次)。因此总加热时间为9小时。然后将溶液浓缩至干,固体残留物用乙醇进行重结晶。
这样制得的6-氯-2-〔N-乙酯- 啶基-(4)-硫〕-吡啶在151-152℃的温度下熔化。
在搅拌下将2.4克(0.0075克分子)上述乙酯化的化合物与7.6克浓盐酸(0.075克分子)和5ml冰醋酸一起加热回流16小时,然后将溶液浓缩,晶状残留物用25ml甲醇搅拌混合。然后再次浓缩至干。接着将残留物溶解在必要量的回流的甲醇中。加入硅藻土之后将溶液过滤,然后将溶液与乙醚混合直到开始发混为止。此时,6-氯-2-〔 啶基-(4)-硫〕-吡啶-N-氧化物的盐酸盐就会结晶出来。在冰浴中静置1小时后,将滤液抽滤除去,固体用丙酮洗涤并干燥。该化合物盐酸盐的熔点为232-233℃(分解)。
实例57
2〔N-甲基- 啶基-(4)-氧〕-3-硝基-6-(4-氟苯甲胺基-
将31克(0.114克分子)2-〔N-甲基- 啶基-(4)-氧〕-3-硝基-6-氯-吡啶,15.6克(0.125克分子)4-氟-苯甲胺,34.5ml(0.125克分子)三乙胺和70ml异丙醇的混合物共热回流7小时。将冷却后沉淀出来的三乙胺氯化物分离,并将母液在真空下浓缩。标题化合物以游离碱的形式结晶出来,将它抽吸过滤重干燥,熔点为90-94℃。
实例58
2-〔N-甲基- 啶基-(4)-氧〕-3-氨基-6-(4-氟-苯甲胺
将4.5克(0.0125克分子)2-〔N-甲基- 啶基-(4)-氧〕-3-硝基-6-(4-氟-苯甲胺基)-吡啶和0.6克附在活性碳上的钯(5%)悬浮于125ml二 烷中,并在温度为60℃压力为5巴的条件下在加氢设备中进行加氢反应5小时。除去催化剂后,将溶液与过量的异丙醇盐酸液混合。二盐酸盐沉淀后,抽吸滤出并在加有少量乙醚的乙醇中进行重结晶,其二盐酸盐的熔点为245至248℃。
实例59
2-〔N-甲基- 啶基-(4)-硫〕-6-氯-吡啶-亚 及-
将5克(0.018克分子)2-〔N-甲基- 啶基-(4)-硫〕-6-氯-吡啶-盐酸盐溶解于50ml甲醇中。用1N盐酸把PH值调到4后将溶液加热到50℃。在搅拌下滴加2.4克(约0.021克分子)30%的H2O2。然后将反应混合物加热到沸腾。大约2小时后,再滴加2.4克30%的H2O2。总的反应时间达16小时后,加入浓甲酸以便破坏多余的H2O2。在室温下将溶液浓缩并将糖浆状残留物溶解于少量水中。加入氢氧化钠的浓溶液使溶液呈碱性,游离碱用乙醚反复萃取分离。有机相经干燥后,将溶剂在真空下蒸出,晶状残留物以硅胶为吸附剂用柱色谱法提纯(洗脱液CHCl3/甲醇/氨为90∶9∶1)。
分离出两种物质:
1.400mg 熔点为123-124℃
2.2.3克亚 熔点为136-137℃
用下面的方法得到 的产率比较大:将3克(0.012克分子)2-〔N-甲基- 啶基-(4)-硫〕-6-氯-吡啶溶解在30ml冰醋酸中。在搅拌下于40℃下滴加含有3.5克(0.022克分子)高锰酸钾的50ml水溶液(用60分钟时间)。滴加完后将溶液加热2小时,维持60℃。将所生成的沉淀滤出,滤液浓缩至干。所得到的结晶残留物用乙醚搅拌并抽吸滤出。产物熔点为124-125℃。
药物制剂的实例
实例1:胶囊
将50克有效物质和350克微晶纤维素,590克乳糖和10克硬脂酸镁混合在一起。
每个固体的3号明胶胶囊填装100mg上述混合物。
每个胶囊含有5mg有效物质。
实例2:针剂
将10克有效物质与30.48克氯化钠一起溶解在3.8升注射用水中。用0.1N氢氧化钠溶液将所制得的溶液的PH值调到7.4并用注射用水加满至4升。以无菌操作方式用适当孔径的滤膜将溶液过滤。在无菌条件下将每个安 灌入2ml滤液。然后将安置于121℃蒸汽中消毒20分钟。
每支安 装2ml溶液,内含5mg有效物质。
Claims (8)
1、制备相应于下面分子式(Ⅰ)的化合物及其吡啶-N-氧化物和(或者)胺氧化
式中:R1与R2为相同或不同的基团,并且代表氢,卤素,三氟甲基,氰基,硝基,氨基,C1-C6的一烷基氨基,C1-C6的二烷基氨基,被苯基、一卤或二卤苯基或C1-C4的苯烷基取代的氨基,C1-C6的链烷酰胺基,C1-C6的烷氧碳酰胺基,被苯基任意取代的C1-C6的烷基;苯基,羟基,C1-C6的烷氧基,苯氧基,羧基,C1-C6的烷酯基或被一个或两个C1-C6的烷基取代的氨基甲酰基;基团R3代表氢,C1-C6的烷基,C3-C6的链烯基,C3-C6的链炔基,C3-C7的环烷基,C5-C7的环烯基,C1-C4的苯烷基,C1-C6的烷酯基,被C3-C6的环烷基取代的或被在同一碳原子上含有两个C1-C6的烷氧基或者一个C2-C4的亚烷二氧基的C1-C4的烷基取代的C2-C6的链烷酰基;或者式中:R3代表带有一个或两取代基的C1-C6的烷基,这些取代基可为C3-C7的环烷基,羟基,C1-C6的烷氧基,卤素原子,磺酸基(-SO3H),氨基,C1-C6的链烷基氨基,C1-C6的二烷基氨基,C1-C6的链烷羧基,C3-C7的环烷羰基,C1-C6的酯基或者苯甲酰基;X代表氧,硫,SO或SO2;Alk代表含有0至4个碳原子的亚烷基;n和m可以相同也可以不同,其值可为1至3,当Alk为至少含有一个碳原子的亚烷基时,n也可以是0,在这种情况下,m的值为2至6,并且基团
也可以是奎宁环基或托品烷基,该方法的特征在于:使相应于通式(Ⅱ)
(式中R1与R2的定义如前所述)
的化合物或其吡啶-N-氧化物与相应于通式(Ⅲ)的化合物起反应,
4、按照前述权利要求中任何一项要求所述的方法,其特征在于把所得到的化合物转变成其盐的形式。
6、制备药剂的方法,其特征在于,前述权利要求中的一项或几项所述的化合物与常用的药物载体或稀释剂一起加工制成药物制剂。
7、权利要求1至5中任何一项或几项所述的化合物的用途,其特征在于制药。
8、权利要求1至5中任何一项或几项所述的化合物的用途,其特征在于止痛。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DE3347276 | 1983-12-28 |
Publications (1)
Publication Number | Publication Date |
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CN85101353A true CN85101353A (zh) | 1986-10-15 |
Family
ID=6218282
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN198585101353A Pending CN85101353A (zh) | 1983-12-28 | 1985-04-01 | 制备带有含氮脂环的吡啶-2-醚或吡啶-2-硫醚化合物的方法 |
Country Status (20)
Country | Link |
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US (1) | US4643995A (zh) |
EP (1) | EP0149088B1 (zh) |
JP (1) | JPS60169476A (zh) |
KR (1) | KR870000354B1 (zh) |
CN (1) | CN85101353A (zh) |
AT (1) | ATE40131T1 (zh) |
AU (1) | AU566560B2 (zh) |
DD (1) | DD231354A5 (zh) |
DE (2) | DE3443968A1 (zh) |
DK (1) | DK613384A (zh) |
ES (1) | ES8607014A1 (zh) |
FI (1) | FI84062C (zh) |
GB (1) | GB2152048B (zh) |
GR (1) | GR82596B (zh) |
HU (1) | HU194209B (zh) |
IL (1) | IL73608A (zh) |
NO (1) | NO164237C (zh) |
PT (1) | PT79736B (zh) |
SU (1) | SU1417796A3 (zh) |
ZA (1) | ZA848275B (zh) |
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-
1984
- 1984-10-23 ZA ZA848275A patent/ZA848275B/xx unknown
- 1984-11-23 IL IL73608A patent/IL73608A/xx unknown
- 1984-12-01 EP EP84114607A patent/EP0149088B1/de not_active Expired
- 1984-12-01 DE DE19843443968 patent/DE3443968A1/de not_active Withdrawn
- 1984-12-01 DE DE8484114607T patent/DE3476205D1/de not_active Expired
- 1984-12-01 AT AT84114607T patent/ATE40131T1/de not_active IP Right Cessation
- 1984-12-17 US US06/682,773 patent/US4643995A/en not_active Expired - Fee Related
- 1984-12-20 GB GB08432162A patent/GB2152048B/en not_active Expired
- 1984-12-20 AU AU36996/84A patent/AU566560B2/en not_active Ceased
- 1984-12-20 DK DK613384A patent/DK613384A/da not_active Application Discontinuation
- 1984-12-21 PT PT79736A patent/PT79736B/pt not_active IP Right Cessation
- 1984-12-21 SU SU843826165A patent/SU1417796A3/ru active
- 1984-12-25 JP JP59272172A patent/JPS60169476A/ja active Pending
- 1984-12-27 NO NO845250A patent/NO164237C/no unknown
- 1984-12-27 ES ES539076A patent/ES8607014A1/es not_active Expired
- 1984-12-27 DD DD84271863A patent/DD231354A5/de unknown
- 1984-12-27 GR GR82596A patent/GR82596B/el unknown
- 1984-12-27 FI FI845126A patent/FI84062C/fi not_active IP Right Cessation
- 1984-12-28 HU HU844869A patent/HU194209B/hu not_active IP Right Cessation
- 1984-12-28 KR KR1019840008498A patent/KR870000354B1/ko not_active IP Right Cessation
-
1985
- 1985-04-01 CN CN198585101353A patent/CN85101353A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
ATE40131T1 (de) | 1989-02-15 |
GB2152048B (en) | 1987-11-11 |
NO164237C (no) | 1990-09-12 |
FI84062C (fi) | 1991-10-10 |
NO164237B (no) | 1990-06-05 |
FI84062B (fi) | 1991-06-28 |
DE3476205D1 (en) | 1989-02-23 |
DD231354A5 (de) | 1985-12-24 |
FI845126A0 (fi) | 1984-12-27 |
DK613384A (da) | 1985-06-29 |
DE3443968A1 (de) | 1985-10-31 |
ZA848275B (en) | 1985-08-28 |
GR82596B (en) | 1985-04-29 |
KR850004755A (ko) | 1985-07-27 |
KR870000354B1 (ko) | 1987-03-05 |
PT79736A (de) | 1985-01-01 |
PT79736B (de) | 1986-12-30 |
HUT36115A (en) | 1985-08-28 |
HU194209B (en) | 1988-01-28 |
IL73608A (en) | 1987-12-31 |
ES8607014A1 (es) | 1986-05-16 |
EP0149088A1 (de) | 1985-07-24 |
AU3699684A (en) | 1985-07-04 |
EP0149088B1 (de) | 1989-01-18 |
DK613384D0 (da) | 1984-12-20 |
JPS60169476A (ja) | 1985-09-02 |
SU1417796A3 (ru) | 1988-08-15 |
IL73608A0 (en) | 1985-02-28 |
NO845250L (no) | 1985-07-01 |
AU566560B2 (en) | 1987-10-22 |
GB8432162D0 (en) | 1985-01-30 |
ES539076A0 (es) | 1986-05-16 |
FI845126L (fi) | 1985-06-29 |
US4643995A (en) | 1987-02-17 |
GB2152048A (en) | 1985-07-31 |
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