CN1047672A - 吡喃基氰基胍衍生物 - Google Patents
吡喃基氰基胍衍生物 Download PDFInfo
- Publication number
- CN1047672A CN1047672A CN90103959A CN90103959A CN1047672A CN 1047672 A CN1047672 A CN 1047672A CN 90103959 A CN90103959 A CN 90103959A CN 90103959 A CN90103959 A CN 90103959A CN 1047672 A CN1047672 A CN 1047672A
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- Prior art keywords
- alkyl
- cyano group
- dimethyl
- hydroxyl
- compound
- Prior art date
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- PSUZFEOOWHGNNG-UHFFFAOYSA-N 1-cyano-1-(2h-pyran-2-yl)guanidine Chemical class NC(=N)N(C#N)C1OC=CC=C1 PSUZFEOOWHGNNG-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 176
- 125000000217 alkyl group Chemical group 0.000 claims description 71
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 59
- -1 heterocyclic radical Chemical class 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 42
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- 229910052799 carbon Inorganic materials 0.000 claims description 35
- 150000001721 carbon Chemical group 0.000 claims description 28
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 25
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 24
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 23
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 18
- 150000001412 amines Chemical class 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 12
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- UEXCJVNBTNXOEH-UHFFFAOYSA-N phenyl acethylene Natural products C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 claims description 8
- 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 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 150000001718 carbodiimides Chemical class 0.000 claims description 4
- 150000004985 diamines Chemical class 0.000 claims description 4
- BRMYZIKAHFEUFJ-UHFFFAOYSA-L mercury diacetate Chemical compound CC(=O)O[Hg]OC(C)=O BRMYZIKAHFEUFJ-UHFFFAOYSA-L 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 238000012545 processing Methods 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002357 guanidines Chemical class 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 238000006317 isomerization reaction Methods 0.000 claims 1
- 235000019157 thiamine Nutrition 0.000 claims 1
- 150000003544 thiamines Chemical class 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 6
- 102000004257 Potassium Channel Human genes 0.000 abstract description 4
- 108020001213 potassium channel Proteins 0.000 abstract description 4
- 239000002327 cardiovascular agent Substances 0.000 abstract description 3
- 229940125692 cardiovascular agent Drugs 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 208000028867 ischemia Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 129
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 239000011541 reaction mixture Substances 0.000 description 46
- 239000000243 solution Substances 0.000 description 45
- 239000007787 solid Substances 0.000 description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- 238000005406 washing Methods 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 150000003839 salts Chemical class 0.000 description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 239000000725 suspension Substances 0.000 description 20
- 238000011097 chromatography purification Methods 0.000 description 19
- 238000001035 drying Methods 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 15
- 238000002425 crystallisation Methods 0.000 description 14
- 230000008025 crystallization Effects 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000000463 material Substances 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 229910052786 argon Inorganic materials 0.000 description 10
- 239000012141 concentrate Substances 0.000 description 10
- 239000000284 extract Substances 0.000 description 10
- 239000007789 gas Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 229960004756 ethanol Drugs 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- 230000002253 anti-ischaemic effect Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229940059260 amidate Drugs 0.000 description 4
- 150000001414 amino alcohols Chemical class 0.000 description 4
- 229960000935 dehydrated alcohol Drugs 0.000 description 4
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 208000023589 ischemic disease Diseases 0.000 description 3
- 229960002510 mandelic acid Drugs 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- ZJSQZQMVXKZAGW-UHFFFAOYSA-N 2H-benzotriazol-4-ol hydrate Chemical compound O.OC1=CC=CC2=C1N=NN2 ZJSQZQMVXKZAGW-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- 108010058207 Anistreplase Proteins 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 108010023197 Streptokinase Proteins 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000011505 plaster Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 229960005202 streptokinase Drugs 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical class O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- NVXFXLSOGLFXKQ-JMSVASOKSA-N (2s)-1-[(2r,4r)-5-ethoxy-2,4-dimethyl-5-oxopentanoyl]-2,3-dihydroindole-2-carboxylic acid Chemical compound C1=CC=C2N(C(=O)[C@H](C)C[C@@H](C)C(=O)OCC)[C@H](C(O)=O)CC2=C1 NVXFXLSOGLFXKQ-JMSVASOKSA-N 0.000 description 1
- BFNXYSZBURSNHS-UVJOBNTFSA-N (2s)-1-[(2s)-6-amino-2-[[(1s)-1-carboxy-3-phenylpropyl]amino]hexanoyl]pyrrolidine-2-carboxylic acid;6-chloro-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 BFNXYSZBURSNHS-UVJOBNTFSA-N 0.000 description 1
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 1
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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Abstract
公开了具有下式结构的新化合物。这些化合物具有钾通道激活活性,可用作,例如心血管药物,尤其是抗缺血药物。
式中
R1是或
Description
本发明涉及新的、具有钾通道激活活性因而可用作为例如心血管药物的化合物。
根据本发明,它公开了新的、具有钾通道激活活性因而可用作为例如心血管药物的化合物。这些化合物具有下述通式:
式中a、b、c都为碳原子,或a、b、c中的一个为氮原子或-NO-,而其它两个为碳原子;
R1为
R1为
R3和R4各独立地为氢、烷基或芳基烷基,或R3和R4与它们所连的碳原子一起形成5-7员碳环;
R5选自H、烷基、卤代烷基、链烯基、炔基、环烷基、芳基烷基、环烷基烷基、-CN、-NO2、-COR、-COOR、-CONHR、-CONR2、-CF3、S-烷基、-SO烷基、-SO2烷基、
卤素、氨基、取代的氨基、O-烷基、OCF3、OCH2CF3、-OCO烷基、-OCONR烷基、-NRCO烷基、NRCOO烷基、NRCONR2,其中在上述各基团中R可以是氢、烷基、芳基、芳基烷基、环烷基或环烷基烷基;
R6选自H、烷基、OH、O-烷基、氨基、取代的氨基、CN、NO2;
R7和R8分别独立地选自氢、烷基、链烯基、芳基、(杂环)烷基、杂环基、芳基烷基、环烷基、环烷基烷基、取代基包括烷氧基、烷硫基和取代的氨基的取代烷基,或R7和R8与它们所连的氮原子一起形成1-吡咯烷基、1-哌啶基、1-氮杂
基、4-吗啉基、4-硫代吗啉基、1-哌嗪基、4-烷基-1-哌嗪基或4-芳基烷基-1-哌嗪基,其中所形成的各基团可被烷基、烷氧基、烷硫基、卤素或三氟甲基取代;
R9和R10选自氢、烷基、链烯基、芳基、芳基烷基、环烷基或环烷基烷基;
n为1、2或3。
本发明在其最宽的方面涉及上述式Ⅰ氰基胍化合物、组合物和使用所述化合物的方法。式Ⅰ化合物,例如,可用作为心血管药剂。优选的化合物为具有3S,4R立体化学的那些化合物。
在对各种符号下定义中所用的术语“烷基”指最多含8个碳原子、最好含1-5个碳原子的直链或支链的饱和烃基。相似地,术语“烷氧基”和“烷硫基”指与氧或硫相连的这些烷基。
术语“链烯基”指具有2-8个碳原子、最好3-5个碳原子和一个双链的直链或支链烃基。术语“炔基”指具有2-8个碳原子、最好3-5个碳原子和一个叁键的直链或支链烃基。
术语“环烷基”指3-7个碳原子的碳环,最好为环丙基、环戊基和环己基。
术语“卤素”指氯、溴和氟。
术语“卤素取代的烷基”指其中的一个或多个氢原子已由氯、溴或氟取代了的上述那些烷基如三氟甲基(最好)、五氟乙基、2,2,2-三氯乙基、氯甲基、溴甲基等。
术语“芳基”指苯基、1-萘基、2-萘基或单取代的苯基、1-萘基、2-萘基,其中所述取代基是1-4个碳原子的烷基、1-4个碳原子的烷硫基、1-4个碳原子的烷氧基、卤素、硝基、氰基、羟基、氨基、其中的烷基含1-4个碳原子的-NH-烷基、其中的烷基含1-4个碳原子的-N(烷基)2,
(其中R11为氢、1-4个碳原子的烷基、1-4个碳原子的烷氧基、1-4个碳原子的烷硫基、卤素、羟基或CF3)、-O-CH2-环烷基、或-S-CH2-环烷基,以及二取代的苯基、1-萘基、2-萘基,其中所述取代基选自甲基、甲氧基、甲硫基、卤素、CF3、硝基、氨基和OCHF2。
较好的芳基包括未取代的苯基和单取代的苯基,其中的取代基为硝基、卤素、-CF3、烷基、氰基或甲氧基。
术语“杂环”指含1或2个O和S和/或1-4个氮原子的完全饱和或不饱和的五或六元环,如果环中的杂原子总数为4或少于4,杂环通过一个可利用的碳原子连接。较好的单杂环基包括2-和3-噻吩基、2-和3-呋喃基、2-,3-和4-吡啶基、以及咪唑基。“杂环”一词也包括含上述定义的O、S和N的五或六元环与苯环稠合的双环体系,该双环体系通过可利用的碳原子连接。较好的双环杂环基包括4-,5-,6-或7-吲哚基、4-,5-,6-或7-异吲哚基、5-,6-,7-或8-喹啉基、5-,6-,7-或8-异喹啉基、4-,5-,6-或7-苯并噻唑基、4-,5-,6-或7-苯并噁唑基、4-,5-,6-或7-苯并咪唑基、4-,5-,6-或7-苯并噁二唑基、以及4-,5-,6-或7-苯并呋喃基。
术语“杂环”还包括下述单环和双环体系,其中的一个可利用碳原子带有1-4个碳原子的低级烷基、1-4个碳原子的低级烷硫基、1-4个碳原子的低级烷氧基、卤素、硝基、酮、氰基、羟基、氨基、其中的烷基含1-4个碳原子的-NH-烷基,其中的烷基含1-4个碳原子的-N(烷基)2、CF3或OCHF2取代基,或者其中的两个或三个可利用碳原子带有选自甲基、甲氧基、甲硫基、卤素、CF3、硝基、羟基、氨基和OCHF2的取代基。
术语“取代的氨基”指式-NZ1Z2基团,其中Z1为氢、烷基、环烷基、芳基、芳基烷基、环烷基烷基,而Z2为烷基、环烷基、芳基、芳烷基、环烷基烷基,或者Z1和Z2与它们所连的氮原子一起表示1-吡咯烷基、1-哌啶基、1-氮杂
基、4-吗啉基、4-硫代吗啉基、1-哌嗪基、4-烷基-1-哌嗪基、4-芳基烷基-1-哌嗪基、4-二芳基烷基-1-哌嗪基、4-芳基烷基-1-哌嗪基、4-二芳基烷基-1-哌嗪基、由烷基、烷氧基、烷硫基、卤素、三氟甲基或羟基取代的1-吡咯烷基、1-哌啶基或1-氮杂
基。
R1为下式的化合物可以在有机溶剂如二甲基甲酰胺、四氢呋喃、乙腈或二氯甲烷中,在碳化二亚胺、最好是1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺或二环己基碳化二亚胺和一种酸源存在下,用式Ⅲ的胺处理式Ⅱ的硫脲来制备。
R8为氢的式Ⅱ硫脲可以在有机碱如三乙胺存在下将式Ⅳ的异硫氰酸酯与氰氨基单钠或氨基氰一起加热来制备。
Ⅳ R7N=C=S
其它的式Ⅱ硫脲可以按文献中所述的一般方法制备。例如下述文献中所述的方法:C.R.Rasmussen,F.J.Villani,Jr.,L.E.Weaner,B.E.Reynolds,A.R.Hood,L.R.Hecker,S.O.Nortey,A.Hanslin,M.J.Costanzo,E.T.Powell,A.J.Molinari,Synthesis,1988,P.456和V.V.Mozolis和S.P.Locubaitite,Russian Chemical Reviews,1973,42,587。
R2为羟基的式Ⅲ氨基醇可以按如下述文献中所述的方法制备:J.M.Evans,C.S.Fake,T.C.Hamilton,R.H.Poyser,E.A.Watts,J.Med.Chem.,1983,26,1582和J.Med.Chem.,1986,29,2194;R.W.Lang,P.F.Wenk,Helvetica Chemica Acta,1988,71,596;EP 0205292 A2(1986)以及WO 87/07607。
R2为氢的式Ⅲ胺可按一般方法从式Ⅴ的酮制备。
式Ⅴ的酮可以按例如下述文献中所公开的方法得到:P.Sebok和T.Timar,Heterocycles,1988,27,2595;P.Teixidor等人,Heterocycles,1988,27,2459;A.Benerji和N.C.Goomer,Tetrahedron Letters,1979,3685;G.Ariamala和K.K.Subramanian,Tetrahedron Letters,Vol.29,No.28,P.3487-3488(1988)。
R1为下式的式Ⅰ化合物也可以在有机溶剂中在碳化二亚胺如1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺或二环己基碳化二亚胺存在下,将式Ⅵ的硫脲与氰氨基单钠一起加热来制备。
式Ⅵ化合物可以按一般方法(即上述的Rasmussen和Mozolis方法)从式Ⅲ的氨基醇制备。
R1为下式的式Ⅰ化合物也可以在极性溶剂如异丙醇中,由式Ⅶ化合物与式Ⅷ的胺反应制备。
式Ⅶ化合物由式Ⅲ的胺与二苯基氰碳亚酰胺化物(diphenylcyanocarbonimidate)反应制备。
R1为下式的式Ⅰ化合物可在醇性溶剂如甲醇中,用乙酸汞处理式Ⅸ化合物来制备。
R1
式Ⅸ化合物用二甲基-N-氰基二硫代亚胺基碳酸酯处理式Ⅹ的二胺来制备。
R1为下式的式Ⅰ化合物也可以在醇性溶剂如2-丙醇中用二苯基氰碳亚酰胺化物处理式Ⅹ的二胺来制备。
R2为反式羟基的式Ⅹ化合物可在醇性溶剂如乙醇中用式Ⅻ的二胺处理环氧化物Ⅺ得到。
环氧化物Ⅺ的制备方法在上述Evans和Lang的文献中有叙述。
式Ⅹ化合物也可以在碱催化剂存在下由氨基醇Ⅲ与式ⅩⅢ的烷基化试剂反应,然后脱保护来制备。
式中P为保护基,X为离去基团如Cl、Br和I。式Ⅹ化合物还可以由式ⅩⅢ的酮或醛(即其中X为氧)和氨基醇Ⅲ按还原性胺化标准方法反应,然后脱除保护基P来制备。
R2为OCO烷基的本发明化合物可在碱催化剂如吡啶或三乙胺存在下用式ⅪⅤ酰氯对R2为OH的式Ⅰ醇进行酰化反应制备。
为了制备R2为H、OH的式Ⅰ化合物的单独的对映体,可在二环己基碳化二亚胺存在下,用手性非外消旋的扁桃酸处理化合物Ⅲ(R2=H、OH),从而把化合物Ⅲ(R2=H、OH)转化成式ⅩⅤ和ⅤⅥ的非对映异构的酰胺。
化合物ⅩⅤ和ⅩⅥ用结晶法或层析法分离。在拆分步骤中优先选用与所需的4R立体化学构型的苯并吡喃(如式ⅩⅤ所示)形成结晶非对映体的扁桃酸对映体。
然后,在二噁烷中,在硫酸存在下,通过加热使化合物ⅩⅤ和ⅩⅥ水解,得到式ⅩⅦ和ⅩⅧ的对映体。
然后,将对映体ⅩⅦ和ⅩⅧ转化成手性非外消旋的式Ⅰ化合物。
本发明化合物在苯并吡喃环的2-4位碳上具有不对称中心。任何一个R中也可以具有不对称碳。因此,式Ⅰ化合物可以非对映异构形式或其混合物形式存在。上述方法可以使用外消旋体、对映体或非对映体为起始原料。当制得非对映异构的产物时,它们可用常规的层析法或分析结晶法分离。
R9和/或R8为氢的本发明化合物可以下述各结构式表示的互变异构体的混合物存在。所得互变异构产物的量是相对的,该量因化合物而异。所有形式都包括在式Ⅰ的范围内。
式Ⅰ化合物和其可药用的盐可作为钾通道激活剂。因此,本发明化合物可用作抗心律失常药和抗局部缺血药,并用于治疗高血压。
业已发现,其中R7为芳基、芳基烷基、环烷基、(环烷基)烷基、杂环基或(杂环基)烷基的式Ⅰ化合物优先用作抗局部缺血药,即用于治疗缺血性疾病如心肌缺血、脑缺血、下肢缺血等。特别优选的是其中R7为芳基烷基,以及R8和R9各为氢的那些化合物。当把任何式Ⅰ化合物用作抗局部缺血药时,已发现这些优选的抗局部缺血药具有很小或没有血管舒张活性。这就意味着在治疗缺血性心脏病时,这些化合物很少引起冠状动脉血流改道、深度低血压和冠状灌注不足。
相似地,降低高血压用的最优选的式Ⅰ化合物是下述化合物,其中R7为氢或1-3个碳原子的烷基,R7和R8与它们所连的氮原子一起表示五或六元环如吡咯烷或哌啶,R9和R10各为氢,n为1或2。
因此,例如,通过服用含一种本发明化合物(或其组合物)的复方,可以减轻哺乳动物(如人)的缺血性疾病状况。减轻缺血性疾病的合适的日剂量为约0.001~10毫克/千克体重。优先为约0.1~25毫克/千克体重,可以把该剂量作为一次剂量,或最好分成2-4个份日剂量服用。该药物最好口服,但也可以通过非胃肠途径如皮下、肌内或静脉途径,或任何其它常规的给药途径如吸入或滴鼻剂或膏药(斑贴)给药。上述剂量也适用于其它心血管疾病(如高血压)和非心血管疾病。
由于本发明化合物具有钾通道激活活性,所以这些化合物也被用于治疗各种心血管疾病和任何与平滑肌收缩有关的疾病。例如,本发明的化合物可用于治疗充血性心力衰竭、外周血管疾病(如雷诺病)、肺动脉高血压,用作抗心绞痛药、抗纤颤药、血栓溶解药,并用来限制形成心肌梗塞。
此外,本发明的化合物可预期用于治疗各种中枢神经系统疾病(如帕金森神经机能障碍、作为抗震颤药、癫痫)、肾衰竭、尿失禁、作为抗腹泻药、治疗子痫前期、痛经和早产阵痛、以及促进毛发生长(如治疗男性秃发)和作为抗哮喘药。
本发明的化合物也可以与利尿药、血管紧张素转化酶抑制剂、血栓溶解药或钙通道阻断剂结合配制。利尿药的实例有氯噻嗪、双氢氯噻嗪、氟噻嗪、双氢氟噻嗪、苄氟噻嗪、甲氯噻嗪、三氯噻嗪、多噻嗪或苄噻嗪以及利尿酸,tricrynafen、氯噻酮、呋喃苯胺酸、musolimine、丁苯氧酸、氨苯喋啶、氨氯吡咪和螺旋内酯以及这些化合物的盐;血管紧张素转化酶抑制剂的实例有巯甲丙脯酸、zofenopril、fosinopril、enalapril、ceranopil、cilazopril、delapril、pentopril、quinapril、ramipril、lisinopril以及这些化合物的盐;由栓溶解药的实例有组织纤维蛋白溶酶原激活剂(tPA)、重组tPA、链激酶、尿激酶、原尿激酶、以及茴香酰化的纤维蛋白溶酶原链激酶激活剂复合物(APSAC,Eminase,Beecham Laboratories);钙通道阻断剂的实例有心痛定或硫氮
酮。作为固定剂量配制的话,这些结合产物可使用上述剂量范围内的本发明化合物和有利剂量范围内的其它有效的药剂。
式Ⅰ化合物及其组合物可如上述配制成复方如供口服给药的片剂、胶囊或驰剂,供非胃肠给药的无菌溶液或悬浮液,也可以经膏药(斑贴)或鼻吸入液给药。按可接受的药物学实践所要求的那样,把大约10-500毫克的式Ⅰ化合物与生理上可接受的赋形剂、载体、粘合剂、防腐剂、稳定剂、调味剂等配方成单位剂量形式,作为可接受的药用需要。这些组合物和制剂中的活性物质的量应能得到所指明范围的合适剂量。
优选的化合物为下述化合物,其中:
a为氮或-CR5;
b和c各为-CH-;
R1为
R2为羟基;
R3和R4各为烷基;
R5为吸电子基团;
R6为氢、烷基、O-烷基、氨基;
R7为氢、烷基、芳基或芳基烷基;
R8为氢;
R9为氢或烷基;
R10为氢;及
n为1或2。
最优选的化合物为下述化合物,其中:
a为氮或-CR5;
b和c各为-CH-;
R2为反式羟基;
R3和R4各为甲基;
R5为-CN或NO2;
R6为氢;
R7为甲基、乙基、苯基或苯甲基;
R8为氢;
R9为氢;
R10为氢;及
n为1。
优选用作为抗局部缺血药的优选的本发明化合物为
本发明的具体实施方案描述在下述实例中。
实例1
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-(1,1-二甲基丙基)胍
A.N-氰基-N′-(1,1-二甲基丙基)硫脲
在室温下于氰氨基单钠(0.64g,10mmol)在无水乙醇(30ml)中的悬浮液中慢慢加入1,1-二甲基丙基异硫氰酸酯(1.29g,10mmol)。加入期间发生放热反应,接近加完时,最初的多相混合物变成了均相溶液。在室温下搅拌2小时,然后在75℃加热1小时。将反应混合物冷至室温,滤出固体。浓缩滤液得到无色固状的标题A化合物(1.6g)。
B.(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-(1,1-二甲基丙基)胍
在室温和氩气下,于标题A化合物(0.94g,5.5mmol)和(反式)-4-氨基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈(按Evans等,J.Med.Chem.,1983,26,1582和J.Med.Chem.1986,29,2194制备)(1.0g,4.6mmol)在二甲基甲酰胺(5ml)中的溶液中加入1-(3-二甲基氨基丙基)-2-乙基碳化二亚胺盐酸盐(1.14g,5.9mmol)。将反应混合物在室温下搅拌2小时,然后在1N HCl和乙酸乙酯之间分配。分出有机层,水相用乙酸乙酯重新提取,合并的有机相用水、碳酸氢钠水溶液和盐水洗涤。用无水硫酸镁干燥后,浓缩滤液,残留物在硅胶上进行闪式层析(1∶1己烷/EtOAC)纯化。合并含所需产物的部分,浓缩后得到无色固体(620mg)。将该固体与异丙醚一起研制,得到了标题化合物,m.p.207-208℃。
C19H25N5O2计算值:C,64.20;H,7.09;N,19.71;
实验值:C,64.04;H,7.11;N,19.44。
实例2
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-乙基胍
A.N-氰基-N′-乙基硫脲
在室温和搅拌下,于氰氨基单钠(6.4g,100mmol)在无水乙醇(30ml)中的悬浮液中慢慢地加入异硫氰酸乙酯(9.0ml,100mmol)。加入期间发生放热反应,接近加完时,反应混合物变成了均相溶液。在室温下搅拌2小时,然后在75℃加热1小时。将反应混合物冷至室温,滤掉不溶物(700mg)。浓缩母液,所得固体与异丙醇一异丙醚一起研制,得到标题A化合物(11.2g),m.p.>240℃。
B.(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-乙基胍
在室温和氩气下,于标题A化合物(1.15g,8.9mmol)和(反式)-4-氨基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈(按照Evans等,J.Med.Chem.,1983,26,1582.和J.Med.Chem.,1986,29,2194制备)(1.5g,6.9mmol)在二甲基甲酰胺(5ml)中的溶液中加入1-(3-二甲基氨基丙基)-2-乙基碳化二亚胺盐酸盐(1.71g,8.9mmol)。将反应混合物在室温下搅拌2小时,然后在1N HCl和乙酸乙酯之间分配。分出有机相,水相用乙酸乙酯重新提取。合并的有机相用水、碳酸氢钠水溶液和盐水洗涤。经无水硫酸镁干燥后,蒸发溶剂,残留物在硅胶上进行闪式层析(25%丙酮在二氯甲烷中)纯化。合并含所需产物的部分,蒸发后得到无色固体(801mg)。该固体产物用乙腈-乙醚重结晶,得到标题化合物,m.p.185-188℃。
C16H19N5O2·0.2H2O
计算值:C,60.64;H,6.17;N,22.10;
实验值:C,60.63;H,6.16;N,22.25。
实例3
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍
A.N-氰基-N′-苯基硫脲
在室温和搅拌下,于氰氨基单钠(6.4g,100mmol)在无水乙醇(170ml)中的悬浮液中慢慢地加入异硫氰酸苯酯(12.5ml,104.5mmol)。在室温下搅拌1小时,然后在75℃加热4小时。将反应物冷至室温,滤出无色固体,用乙醇洗涤,得到标题A化合物(13.6g).m.p.>250℃。
B.(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍
在室温和氩气下,于标题A化合物(1.06g,5.96mmol)和(反式)-4-氨基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈(按照Evans等,J.Med.Chem,1983,26,1582和J.Med.Chem,1986,29,2194制备)(1.0g,4.59mmol)在二甲基甲酰胺(5ml)中的溶液中加入1-(3-二甲基氨基丙基)-2-乙基碳化二亚胺盐酸盐(1.17g,5.96mmol)。将反应混合物在室温下搅拌2小时,然后在1N HCl和乙酸乙酯之间分配。分出有机相,水相用乙酸乙酯重新提取,合并的有机相用水、碳酸氢钠水溶液和盐水洗涤。经无水硫酸镁干燥后,蒸发溶剂,无色残留物与乙醚一起研制后,得到标题化合物(1.3g).m.p.247-249℃(泡腾)。
C20H19N5O2计算值:C,66.46;H,5.30;N,19.38;
实验值:C,66.09;H,5.30;N,19.35。
实例4
(反式)-N″-氰基-N-(3,4-二氢-3-羟基-2,2-二甲基-6-硝基-2H-1-苯并吡喃-4-基)-N′-乙基胍
在室温和氩气下,于实例2标题A化合物(1.2g,9.4mmol)和(反式)-4-氨基-3,4-二氢-2,2-二甲基-6-硝基-2H-1-苯并吡喃(1.5g,6.3mmol)(按照Evans等,J.Med.Chem.,1983,26,1582和J.Med.Chem.,1986,29,2194制备)在二甲基甲酰胺(5ml)中的溶液中加入1-(3-二甲基氨基丙基)-2-乙基碳化二亚胺盐酸盐(2.1g,10.7mmol)。将反应混合物在室温下搅拌2小时,然后在1N HCl和乙酸乙酯之间分配。分出有机相,水相用乙酸乙酯重新提取,合并的有机相用水、碳酸氢钠水溶液和盐水洗涤。经无水硫酸镁干燥后,蒸发溶剂,残留物在硅胶上进行闪式层析(己烷/丙酮/6∶4)纯化,得到无色固体(500mg)。与异丙醚一起研制后,得到标题化合物,m.p.204-205℃。
C15H19N5O4·0.17H2O
计算值:C,53.55;H,5.79;N,20.82;
实验值:C,53.89;H,5.63;N,20.48。
实例5
(反式)-3,4-二氢-3-羟基-2,2-二甲基-4-〔2-(氰基亚氨基)-1-吡咯烷基〕-2H-1-苯并吡喃-6-腈
A.(反式)-4-〔(2-氨基乙基)氨基〕-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈
在室温下,于6-氰基-3,4-环氧-3,4-二氢-2,2-二甲基-2H-苯并吡喃(1.2g,5.97mmol)(按照Evans等,J.Med.Chem.,1983,26,1582和J.Med.Chem.,1986,29,2194制备)在乙醇(7.0ml)中的悬浮液中加入乙二胺(2.4ml,35.8mmol),并将反应混合物在室温下搅拌36小时。减压除去溶剂,残留物进一步用真空泵干燥,得到无色泡沫状的标题A化合物(1.74g,>100%),不经任何纯化,将该物质用于下一步反应中。
B.(反式)-3,4-二氢-3-羟基-2,2-二甲基-4-〔2-(氰基亚氨基)-1-吡咯烷基〕-2H-1-苯并吡喃-6-腈
在室温下,于标题A化合物(1.74g,5.97mmol)在乙醇中的溶液中慢慢地加入三乙胺(1.7ml,11.94mmol),然后加入N-氰基二硫代亚氨基碳酸二甲酯(1.16g,11.94mmol的90%)。将反应混合物在80℃加热3小时,然后冷至环境温度。蒸发溶剂后得到浅黄色泡沫(2.4g)。将该物质溶于甲醇(20ml)中,用乙酸汞(2.52g,7.77mmol)处理所得悬浮液,将反应混合物在室温下搅拌2小时,减压蒸发溶剂。残留物用水稀释,用5N NaOH碱化至pH~9.0,用5%氯仿甲醇溶液提取产物。将合并的有机提取液用盐水洗涤,得到了浓稠的乳浊液。将两相混合物滤过硅藻土垫,分出有机层,用硫酸镁干燥。蒸发溶剂,残留物在硅胶上进行闪式层析(5%甲醇在氯仿中)纯化,得到无色残留物。将该残留物与乙酸乙酯一起研制,得到所需产物(740mg)。浓缩母液,与乙酸乙酯一起研制,得到第二部分产物(370mg),共1.1g。将合并的产物用热乙酸乙酯重结晶,得到无色粉末状的标题化合物,m.p.254-255℃。
C16H17N5O2·0.42H2O
计算值:C,60.27;H,5.63;N,21.97;
实验值:C,60.40;H,5.30;N,21.84。
实例6
(反式)-N″-氰基-N-(3,4-二氢-3-羟基-2,2-二甲基-2H-吡喃并〔3,2-C〕吡啶-4-基)苯基胍
在室温和氩气下,于实例3标题A化合物(2.2g,12.5mmol)和(反式)-4-氨基-3,4-二氢-2,2-二甲基-2H-吡喃并〔3,2-C〕吡啶-3-醇(1.1g,5.7mmol)(按照EP 0205292 A2制备)在二甲基甲酰胺(5ml)中的溶液中加入1-(3-二甲氨基丙基)-2-乙基碳化二亚胺盐酸盐(2.2g,10.8mmol)。将反应混合物于室温下搅拌2小时,然后在水(pH~11)和乙酸乙酯之间分配。分出有机相,水相用乙酸乙酯重新提取,合并的有机相用水、碳酸氢钠水溶液和盐水洗涤。经无水硫酸镁干燥后,蒸发溶剂,残留物在硅胶上进行闪式层析(丙酮:二氯甲烷/1∶4)纯化,得到无色固体(470mg),经乙腈结晶,得到标题化合物,m.p.233-236℃。
C18H19N5O2计算值:C,64.08;H,5.67;N,20.76;
实验值:C,63.88;H,5.48;N,20.76。
实例7
(反式)-N′-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-1-吡咯烷-Carboximidamide
A.(反式)-4-〔〔(氰基亚氨基)苯氧基甲基〕氨基〕-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈
在室温下,于(反式)-4-氨基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈(按照Evans等,J.Med.Chem.,1983,26,1582和J.Med.Chem.,1986,29,2194制备)(5.0g,23mmol)在异丙醇(50ml)中的溶液中加入二苯基氰碳亚酰胺化物(5.5g,25mmol),将反应混合物于室温下搅拌16小时。蒸掉大部分异丙醇,残留物溶于乙酸乙酯中,所得溶液依次用10%柠檬酸、1N氢氧化钠溶液和盐水洗涤。经无水硫酸镁干燥后浓缩,残留物用氯仿-异丙醚结晶,得到标题A化合物(4.2g),为无色固体,m.p.186-188℃。
C20H18N4O3·0.6H2O
计算值:C,64.37;H,5.18;N,15.02;
实验值:C,64.64;H,4.86;N,14.75。
B.(反式)-N′-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-1-吡咯烷-carboximidamide
在室温下,于标题A化合物(0.8g,12.2mmol)在异醇(4ml)中的溶液中加入吡咯烷(0.5ml),并将反应混合物在室温下搅拌过夜。悬浮液用乙醚稀释,滤出无色固体,干燥,得到标题化合物(0.4g),m.p.263-264℃。
C18H21N5O2计算值:C,63.70;H,6.24;N,20.64;
实验值:C,63.45;H,6.29;N,20.88。
实例8
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-乙基-N-甲基胍
A.(反式)-N′-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N-甲基氨基甲酸苯酯
在室温下,于(反式)-3,4-二氢-3-羟基-2,2-二甲基-4-(甲氨基)-2H-1-苯并吡喃-6-腈(按照Evans等,J.Med.Chem.,1983,26,1582和J.Med.Chem.,1986,29,2194制备)(1.0g,4.3mmol)在异丙醇(4ml)中的溶液中加入二苯基氰碳亚酰胺化物(1.0g,4.3mmol),并将反应混合物于室温下搅拌16小时。蒸掉大部分异丙醇,残留物溶于乙酸乙酯中。将所得溶液依次用10%柠檬酸、1N氢氧化钠和盐水洗涤。经无水硫酸镁干燥后浓缩。残留物在硅胶上进行闪式层析(乙酸乙酯:己烷混合物/1∶1)纯化,得到标题A化合物。不经进一步纯化,将该化合物用于下一步反应中。
B.(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-乙基-N-甲基胍
在室温下,于标题A化合物(0.1g,0.27mmol)在异丙醇(1ml)和三乙胺(0.25ml)中的溶液中加入盐酸乙胺(0.1g,1.2mmol)。并将反应混合物在室温下搅拌过夜。蒸掉大部分溶剂,残留物溶于乙酸乙酯中。将该溶液依次用10%柠檬酸、碳酸氢钠水溶液和盐水洗涤,经无水硫酸镁干燥,蒸发溶剂,残留物与乙醚一起研制,得到无色固状的标题化合物,m.p.227-228℃。
实例9
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-〔2-(二甲氨基)乙基〕胍
在室温下,于实例7步骤A的化合物(0.8g,2.2mmol)在异丙醇(3ml)中的悬浮液中加入95%1,1-二甲基乙二胺(0.5g,5.7mmol)。将反应混合物在室温下搅拌20小时,然后真空下浓缩。残留物与异丙醚一起研制,得到白色固状的标题化合物(0.4g)。 m.p.172-173℃:1H NMR(CDCl3)δ7.6(s,1H),7.4(dd,J=2.0 & 9.0Hz,1H),6.9(d,J=9.0Hz,1H),6.6(s,1H),4.9(t,J=9.0Hz,2H),3.5(d,J=9.0Hz,1H),3.4(s,2H),2.5(m,2H),2.0(s,6H),1.5(s,3H),1.3(s,3H);13C NMR(CDCl3)δ163.4,156.8,133.1,132.5,122.8,118.8,118.7,118.0,103.9,80.4,76.2,69.1,60.8,51.8,44.6,41.7,26.4,18.5;IR(KBr)1126.9,1267.0,1431.4,1489.0,1577.0,1635.8,2173.3,3391.9,3407.6cm-1.
C18H24N6O2计算值:C,60.65;H,6.79;N,23.58;
实验值:C,60.53;H,6.75;N,23.62。
实例10
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-甲基胍
在室温下于实例7步骤A的化合物(1.0g,2.8mmol)在异丙醇(6ml)中的悬浮液中加入甲胺(40%甲醇溶液,1ml)。将反应混合物在室温下搅拌20小时,然后真空浓缩。得到的粗产物用异丙醇结晶,得到白色固状的标题化合物(0.4g),m.p.212-214℃:1H NMR(CDCl3/DMSO)δ7.5(s,1H),7.45(d,J=9.0Hz,1H),6.9(m,2H),6.8(d,J=8.0Hz,1H),5.55(br,1H),4.85(br,1H),3.7(m,1H),2.88(d,J=5.0Hz,3H),1.48(s,3H),1.24(s,3H);13C NMR(CDCl3/DMSO)160.5,155.5,131.6,131.3,123.7,117.9,117.3,116.9,102.2,79.4,76.6,70.9,27.6,25.6,17.7;IR(KBr)1267,1419,1489,1576,1608,2170,2225,2977,3338cm-1.
C15H17N5O2·0.3H2O
计算值:C,59.16;H,5.82;N,23.01;
实验值:C,59.16;H,5.57;N,23.01.
实例11
(反式)-4-〔(氰基亚氨基)〔〔4-(苯基甲基)-1-哌嗪基)甲基〕氨基〕-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈
在室温下于实例7步骤A的化合物(2.0g,5.5mmol)在异丙醇(5ml)中的悬浮液中加入4-苯甲基-1-哌嗪(1.0ml)。将反应混合物于室温下搅拌20小时,然后真空下浓缩。得到的粗产物在硅胶上用二氯甲烷/丙酮(7/3)洗脱进行闪式层析纯化,得到标题化合物(0.6g),用异丙醇-乙醚重结晶,得到所需产物(250mg),为白色固体,m.p.205-207℃。1H NMR(DMSO-d6)δ7.4(s,1H),7.3(d,J=8.0Hz,1H),7.2(d,J=8.0Hz,1H),7.0(s,6H),6.6(d,J=9.0Hz,1H),5.6(d,J=6.0Hz,1H),4.6(t,J=8.0 & 10.0Hz,1H),3.2(m,5H),2.2(m,5H),1.14(s,3H),0.88(s,3H);13C NMR(DMSO-d6)161.1,156.4,137.6,133.1,132.9,129.1,128.3,127.2,124.6,117.9,102.7,80.6,71.5,61.9,53.0,52.2,46.6,26.7,18.6;IR(KBr)1125,1490,1524,1577,1611,2170,2224,3429cm-1.
C25H28N6O2
计算值:C,67.54;H,6.35;N,18.91;
实验值:C,67.29;H,6.37;N,18.73.
实例12
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)胍
在室温下,于实例7步骤A的化合物(1.0g,2.8mmol)在异丙醇(6ml)中的悬浮液中加入氢氧化铵(1ml)。将反应混合物在室温下搅拌20小时,然后真空浓缩。所得粗产物用丙酮/乙酸乙酯结晶,得到白色固状的标题化合物(0.31g),m.p.250-251℃。
1H NMR(DMSO-d6)δ7.7(dd,J=2.0 & 7.0Hz,1H),7.5(s,1H),6.9(m,2H),7.0(d,J=9.0Hz,1H),5.8(br s,1H),4.8(br s,1H),3.6(m,1H),1.48(s,3H),1.25(s,3H);13C NMR(DMSO-d6)162.3,156.3,132.9,132.6,124.8,119.1,118.1,102.7,80.5,71.3,26.5,19.0;IR(KBr)1064,1268,1489.7,1555,1635,2183,2225,3432cm-1.
C14H15N5O2计算值:C,58.93;H,5.30;N,24.55;
实验值:C,58.74;H,5.32;N,24.23.
实例13
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-(甲基乙基)胍
在室温下,于实例7步骤A化合物(2.0g,5.5mmol)在异丙醇(5ml)中的悬浮液中加入异丙胺(1.5ml)。将反应混合物在室温下搅拌20小时后,真空下浓缩。所得粗产物在硅胶上用7/3二氯甲烷/丙醇洗脱进行闪式层析纯化,得到标题化合物(1.2g)。将该固体用异丙醇-异丙醚结晶,得到白色固状的所需产物,m.p.150-152℃。
1H NMR(DMSO-d6)δ7.6(dd,J=2.0 & 7.0Hz,1H),7.5(s,1H),7.2(d,J=9.0Hz,1H),7.0(d,J=9.0Hz,1H),6.8(d,J=8.0Hz,1H),5.9(d,J=5.0Hz,1H),4.8(t,J=9.0Hz,1H),3.9(m,1H),3.8(m,1H),1.47(s,3H),1.24(s,3H),1.2(d,J=3.0Hz,6H);13C NMR(DMSO-d6)159.5,156.3,132.7,132.4,125.2,119.1,118.0,117.8,102.7,80.5,71.1,51.5,43.4,26.7,22.6,22.4,18.7;IR(KBr)1268,1490,1587.8,2170,2226,2978,3419cm-1.
C17H21N5O2·0.1H2O
计算值:C,62.03;H,6.49;N,21.28;
实验值:C,61.75;H,6.66;N,21.86.
实例14
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-二甲基胍
在室温下,于实例7步骤A化合物(1.0g,2.8mmol)在异丙醇(6ml)中的悬浮液中加入二甲胺盐酸盐(0.33g,4.2mmol),然后加入粉状碳酸钾(0.57g,4.2mmol)。将反应混合物于室温下搅拌20小时,然后真空下浓缩。残留物溶于氯仿(150ml)中,用水洗涤,硫酸镁干燥,然后真空下浓缩。所得粗产物用二氯甲烷-乙醚结晶,得到标题化合物(0.44g),为白色固体。将该固体用乙腈-氯仿重结晶,得到无色固体,m.p.196-197℃。
1H NMR(DMSO-d6) δ7.7(s,1H),7.6(dd,J=3.0 & 8.0Hz,1H),7.2(d,J=9.0Hz,1H),6.9(d,J=9.0Hz,1H),5.8(d,J=6.0Hz,1H),4.9(t,J=9.0 & 10.0Hz,1H),3.6(dd,J=8.0 & 5.0Hz,1H),3.0(s,6H),1.42(s,3H),1.24(s,3H);13C NMR(DMSO-d6)159.3,154.9,131.5,130.8,123.4,116.1,101.4,78.9,70.3,51.5,25.2,17.0;IR(KBr)1143,1269,1398,1489,1527,1595,2168,2226,2935,2980,3433cm-1.
C16H19N5O2·0.5H2O
计算值:C,59.61;H,6.25;N,21.73;
实验值:C,59.44;H,5.95;N,22.03.
实例15
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基甲基胍
在室温下于实例7步骤A中的化合物(0.5g,1.4mmol)在异丙醇(3ml)中的悬浮液中加入苄胺(90%,0.5ml)。将反应混合物在室温下搅拌20小时,然后真空下浓缩。将残留物与另一批相同的物质合并,在硅胶上用己烷-乙酸乙酯(3∶7)洗脱进行闪式层析纯化,得到白色固体(0.8g)。该固体用乙腈-异丙醚结晶,得到无色固状的标题化合物。
m.p.188-189℃:1H NMR(CDCl3)δ7.7(m,1H),7.5(dd,J=2.0 & 9.0Hz,1H),7.4(m,6H),6.86(d,J=9.0Hz,1H),5.8(s,1H),4.8(m,1H),4.5(d,J=5.0Hz,2H),3.7(dd,J=6.0 & 4.0Hz,1H),1.41(s,3H),1.19(s,3H);13C NMR(CDCl3)158.7,154.5,136.8,130.7,126.5,125.2,125.0,123.0,116.0,101.0,78.6,42.6,24.8,16.9;IR(KBr)1267,1491,1579,1595,2175,2222,3433cm-1.
C21H21N5O2
计算值:C,67.18;H,5.64;N,18.66;
实验值:C,67.14;H,5.55;N,18.65.
实例16
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-〔2-〔(苯基甲基)甲基氨基〕乙基〕胍
在室温下于实例7步骤A的化合物(0.5g,1.4mmol)在异丙醇(3ml)中的悬浮液中加入N-甲基苄基乙基胺(0.5ml)。将反应混合物在室温下搅拌24小时。初始的多相混合物慢慢地变成了均相溶液。随着反应的进行,产物从反应混合物中沉淀出来。反应完成后,滤出固体,与乙醚一起研制,得到了无色固状的标题化合物(0.45g)。
m.p.184-185℃:1H NMR(CDCl3)δ9.4(s,1H),7.59(d,J=8.0Hz,1H),7.2(m,4H),6.96(s,2H),6.87(d,J=9.0Hz,1H),6.4(s,1H),4.9(m,2H),3.4(m,4H),2.6(m,2H),2.1(s,3H),1.49(s,3H),1.26(s,3H);13C NMR(CDCl3)205.2,160.7,155.6,131.6,128.0,127.4,126.2,123.5,118.0,117.3,117.1,102.4,79.4,61.3,55.6,40.5,25.7,17.74;IR(KBr)1126,1267,1489,1575,1608,2172,2224,2800,2976,3421cm-1.
C24H28N6O2
计算值:C,66.64;H,6.52;N,19.43;
实验值:C,66.40;H,6.52;N,19.99.
实例17
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-(2-甲氧基乙基)胍
在室温下于实例7步骤A的化合物(0.5g,1.4mmol)在异丙醇(3ml)中的悬浮液中加入2-甲氧基乙基胺(0.12g,1.7mmol,0.15ml)。将反应混合物在室温下搅拌20小时,然后真空下浓缩。残留物在硅胶上用乙酸乙酯洗脱进行闪式层析纯化,得到了标题化合物(0.3g),为白色固体,m.p.94-96℃。
1H NMR(CDCl3)δ7.5(s,1H),7.38(d,J=7.0Hz,1H),6.8(m,3H),4.86(s,1H),4.0(m,1H),3.5(m,4H),3.2(s,3H),1.9(s,1H),1.43(s,3H),1.19(s,3H);13C NMR(CDCl3)162.6,156.8,133.2,132.4,122.5,119.0,118.5,118.1,103.9,80.2,74.7,60.3,58.9,52.2,26.4,21.0,18.7,14.1;IR(KBr)1635,1693,3404cm-1.
C17H21N5O3·0.24H2O.
计算值:C,58.71;H,6.23;N,20.14;
实验值:C,58.81;H,6.38;N,20.04.
实例18
(3S-反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍
A.〔3R-〔3α,4β(S*)〕〕-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-α-羟基苯乙酰胺和
〔3S-〔3α,4β(R*)〕〕-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-α-羟基苯乙酰胺
在0℃下于(反式)-4-氨基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈(按照Evans等,J.Med.Chem.,1983,26,1582和J.Med.Chem.,1986,29,2194制备)(10.0g,45.9mmol)、S-(+)-扁桃酸(6.98g,45.9mmol)、羟基苯并三唑水合物(6.2g,45.9mmol)在二甲基甲酰胺(60ml)中的溶液中加入二环己基碳化二亚胺(9.5g,45.9mmol)。将反应混合物在室温下搅拌20小时,然后在冰浴中冷却。滤出沉淀的固体,真空下浓缩滤液。残留物溶于5%甲醇的氯仿溶液中,用1N氢氧化钠、1N盐酸、盐水洗涤,用无水硫酸镁干燥。除去干燥剂后。真空下除去溶剂。残留物用乙醇结晶,得到〔3R-〔3α,4β(S*)〕〕-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-α-羟基苯乙酰胺(6.0g),为白色固体。
m.p.238-240℃,[αD]25=+94.6°(C=1,MeOH):1H NMR(CDCl3)δ7.4(m,5H),7.26(t,J=1.0HZ,1H),6.97(d,J=9.0HZ,1H),6.83(d,J=9.0Hz,1H),5.16(s,1H),4.98(t,J=9.0HZ,1H,3.8(d,J=5.0Hz,1H),3.55(dd,J=4.0 & 5.0HZ,1H),1.45(s,3H),1.2(s,3H).
C20H20N2O4
计算值:C,68.17;H,5.72;N,7.95;
实验值:C,67.92;H,5.49;N,8.05.
将母液中的残留在硅胶上用己烷-乙酸乙酯(3∶7)洗脱进行闪式层析纯化,残留物用二氯甲烷-异丙醚结晶,得到〔3S-〔3α,4β(R*)〕〕-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-α-羟基苯乙酰胺(6.0g),为白色固体。
m.p.100-102℃(发泡);[αD]25=-26.1°(c=1,MeOH):1H NMR(DMSO-d6)δ8.45(d,J=8.0Hz,1H),7.5(m,4H),7.3(m,2H),7.0(s,1H),6.88(d,J=8.0Hz,1H),6.2(s,1H),5.57(d,J=5.0Hz,1H),5.0(s,1H),4.76(t,J=9.0Hz,1H),3.75(dd,J=5.0 & 5.0Hz,1H),1.40(S,3H),1.15(s,3H).
C20H20N2O4·0.25H2O
计算值:C,67.30;H,5.78;N,7.84;
实验值:C,67.54;H,5.95;N,7.44.
B.(3S-反式)-4-氨基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈
在室温下,于〔3S-〔3α,4β(R*)〕〕-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-α-羟基苯乙酰胺,标题A化合物(2.8g,7.9mmol)在二噁烷(30ml)中的溶液中加入硫酸(2.5g)在水(12ml)中的溶液,并将反应混合物加热回流24小时。真空下浓缩后,将残留物溶于乙酸乙酯(200ml)中。有机层用1N氢氧化钠(50ml)洗涤,然后用水(50ml)洗涤,经无水硫酸镁干燥,并真空浓缩,得到油状的标题B化合物(1.6g)。
1H NMR(CDCl3)δ7.74(s,1H),7.42(dd,J=2.0 & 6.0Hz,1H),6.82(d,J=8.0Hz,1H),3.65(d,J=10.0Hz,1H),3.36(d,J=10.0Hz,1H),1.53(s,3H),1.23(s,3H).
C.(3S-反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍
在室温和氩气下,于N-氰基-N′-苯基硫脲(1.7g,9.5mmol)和标题B化合物(1.6g,7.3mmol)在二甲基甲酰胺(7ml)中的溶液中加入1-(3-二甲氨基丙基)-2-乙基碳化二亚胺盐酸盐(1.8g,9.5mmol)。将反应混合物在室温下搅拌2小时,然后于1N盐酸盐和乙酸乙酯之间分配。分出有机相,水相用乙酸乙酯重新提取。合并的提取物用水、碳酸氢钠水溶液和盐水洗涤。经无水硫酸镁干燥后,蒸发溶剂,粗产物在硅胶上用乙酸乙酯/己烷混合物(7∶3)洗脱进行闪式层析纯化,得到无色固体(0.7g)。将该固体物与乙醚一起研制,得到了标题化合物(0.35g),m.p.214-216℃。
[αD]25=-34.8°(c=0.417,MeOH):1H NMR(DMSO-d6)d 9.28(s,1H),7.58(d,J=8.0Hz,3H),7.35(m,4H),7.15(m,1H),6.90(d,J=8.2Hz,1H),5.92(br s,1H),4.92(t,J=9.0Hz,1H),3.72(br d,J=5.9Hz,1H),1.41,1.18(s,3H each);13C NMR(DMSO-d6)159.2,156.3,137.5,132.6,132.5,129.0,124.8,124.7,123.6,119.0,117.8,117.0,102.6,80.4,70.9,51.9,26.6,18.6;IR(KBr)2226,2179,1609,1582,1491,1267cm-1.
C20H19N5O2·0.37H2O
计算值:C,65.26;H,5.40;N,19.02;
实验值:C,65.62;H,5.36;N,18.57.
实例19
(3R-反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍
A.(3R-反式)-4-氨基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈
在室温下,于〔3R-〔3α,4β(S*)〕〕-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-α-羟基苯乙酰胺,实例18部分A化合物(2.8g,7.9mmol)在二噁烷(30ml)中的溶液中加入浓硫酸(2.5g)和水(12ml),并将反应混合物加热回流24小时。真空浓缩后,将残留物与另一批相同的物质合并,溶于乙酸乙酯(400ml)中。所得溶液用1N氢氧化钠(50ml)洗涤,然后用水(50ml)洗涤,经无水硫酸镁干燥,于真空下浓缩,得到油状标题A化合物(3.7g)。
1H NMR(CDCl3)δ7.74(s,1H),7.42(dd,J=2.0 & 6.0Hz,1H),6.82(d,J=8.0Hz,1H),3.65(d,J=10.0Hz,1H),3.36(d,J=10.0Hz,1H),1.53(s,3H),1.23(s,3H).
B.(3R-反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍
在室温和氩气下,于N-氰基-N′-苯基硫脲(3.9g,21.9mmol)和标题A化合物(3.68g,16.9mmol)在二甲基甲酰胺(20ml)中的溶液中加入1-(3-二甲氨基丙基)-2-乙基碳化二亚胺盐酸盐(4.2g,21.9mmol)。将反应混合物在室温下搅拌2小时,然后在1N盐酸和乙酸乙酯之间分配。分出有机相,水相用乙酸乙酯重新提取。合并的提取液用水、碳酸氢钠水溶液和盐水洗涤。经无水硫酸镁干燥后,蒸发溶剂,粗产物与乙酸乙酯一起研制后,得到无色固体(3.5g)。粗产物在硅胶上用乙酸乙酯/己烷混合物(7∶3)洗脱进行闪式层析纯化,并将蒸发溶剂后所得固体与乙醚一起研制,得到了无色固状的标题化合物(1.8g),m.p.215-217℃。
[αD]25=+34.8°(c=0.417,MeOH):1H NMR(CDCl3/DMSO=d6)δ8.8(s,1H),7.6(s,1H),7.44(d,J=8.0Hz,1H),7.35(d,J=5.0Hz,4H),7.22(m,1H),6.85(d,J=8.8Hz,1H),6.7(br s,1H),5.0(t,J=9.0Hz,1H),3.72(br d,J=5.3Hz,1H),1.48,1.18(s,3H each);13C NMR(CDCl3/DMSO=d6)159.6,156.5,136.6,132.5,129.2,125.7,124.1,123.7,118.9,118.1,117.2,103.4,80.3,72.8,52.4,26.4,18.6;IR(KBr)2226,2179,1609,1582,1491,1267cm-1.
C20H19N5O2·0.45H2O
计算值:C,65.01;H,5.42;N,18.95;
实验值:C,65.18;H,5.47;N,18.51.
实例20是实例18的另一种方法,实例20的方法是优选的。此外,实例20的3S,4R对映体是本发明的优选化合物。
实例20
(3S-反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍
A.〔3S-〔3α,4β(S*)〕-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-α-羟基苯乙酰胺 和
〔3R-(3α,4β(R*)〕-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-α-羟基苯乙酰胺
在室温下于0℃的(反式)-4-氨基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈(按照Evans等,J.Med.Chem.,1983,26,1582和J.Med.Chem.,1986,29,2194制备)(1.64g,7.5mmol)、R-(-)-扁桃酸(1.14g,7.5mmol)、羟基苯并三唑水合物(1.0g,7.5mmol)在二甲基甲酰胺(15ml)中的溶液中加入二环己基碳化二亚胺(1.55g,7.5mmol)。将反应混合物在室温下搅拌20小时,然后在冰浴中冷却。滤出沉淀的固体,真空下浓缩滤液。残留物溶于5%甲醇的氯仿溶液中,用1N氢氧化钠、1N盐酸、盐水洗涤,用无水硫酸镁干燥。除去干燥剂后,真空下除去溶剂。残留物用乙醇结晶,得到〔3S-〔3α,4β(S*)〕〕-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-α-羟基苯乙酰胺(0.85g),为白色固体。
m.p.235-237℃:[αD]25=-94.9°(c=1,MeOH);1H NMR(DMSO-d6)δ8.45(d,J=8.0Hz,1H),7.5(m,4H),7.3(m,2H),7.0(s,1H),6.88(d,J=8.0Hz,1H),6.2(s,1H),5.57(d,J=5.0Hz,1H),5.0(s,1H),4.76(t,J=9.0Hz,1H),3.75(dd,J=5.0 & 5.0Hz,1H),1.40(s,3H),1.15(s,3H).
C20H20N2O4
计算值:C,68.17;H,5.72;N,7.95;
实验值:C,68.00;H,5.52;N,7.95.
将从母液中回收的残留物在硅胶上用己烷-乙酸乙酯(3∶7)洗脱进行闪式层析纯化,产物用二氯甲烷-异丙醚结晶,得到〔3R-〔3α,4β(R*)〕〕-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-α-羟基苯乙酰胺,为白色固体,m.p.100-102℃(发泡)。
[αD]25=+25.6°(c=1,MeOH):1H NMR(CDCl3)δ7.4(m,5H),7.26(t,J=1.0Hz,1H),6.97(d,J=9.0Hz,1H),6.83(d,J=9.0Hz,1H),5.16(s,1H),4.98(t,J=9.0Hz,1H),3.8(d,J=5.0Hz,1H),3.55(dd,J=4.0 & 5.0Hz,1H),1.45(s,3H),1.2(s,3H).
C20H20N2O4·0.25H2O
计算值:C,67.30;H,5.78;N,7.84;
实验值:C,67.17;H,5.87;N,7.44.B.(3S-反式)-4-氨基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈
在室温下,于〔3S-〔3α,4β(S*)〕〕-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-α-羟基苯乙酰胺,标题A化合物(6.09g,17.0mmol)在二噁烷(60ml)中的溶液中加入硫酸(6.0g)在水(30ml)中的溶液,并将反应混合物加热回流24小时。真空下浓缩后,将残留物溶于乙酸乙酯中。有机层用1N氢氧化钠洗涤,然后用水洗涤并用无水硫酸镁干燥。蒸发溶剂后,得到油状的标题B化合物。
1H NMR(CDCl3)δ7.74(s,1H),7.42(dd,J=2.0 & 6.0Hz,1H),6.82(d,J=8.0Hz,1H),3.65(d,J=10.0Hz,1H),3.36(d,J=10.0Hz,1H),1.53(s,3H),1.23(s,3H).
C.(3S-反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍
在室温和氩气下,于N-氰基-N′-苯基硫脲(2.11g,11.9mmol)和(3S-反式)-4-氨基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈(2.0g,9.1mmol),标题B化合物在二甲基甲酰胺(20ml)中的溶液中加入1-(3-二甲氨基丙基)-2-乙基碳化二亚胺盐酸盐(2.23g,11.9mmol)。将反应混合物在室温下搅拌2小时,然后于1N盐酸和乙酸乙酯之间分配。分出有机相,水相用乙酸乙酯重新提取。合并的有机提取物用水、碳酸氢钠水溶液和盐水洗涤。经无水硫酸镁干燥后,蒸发溶剂,粗产物在硅胶上用乙酸乙酯/己烷混合物(7∶3)洗脱进行闪式层析纯化,得到无色固体,与乙醚一起研制后,得到本标题化合物(0.35g)。
m.p.215-216℃:[α]25D=-33.5°(c=1,MeOH);1H NMR(DMSO-d6)δ9.28(s,1H),7.58(d,J=8.0Hz,3H),7.35(m,4H),7.15(m,1H),6.90(d,J=8.2Hz,1H),5.92(brs,1H),4.92(t,J=9.0Hz,1H),3.72(br d,J=5.9Hz,1H),1.41,1.18(s,各3H);13C NMR(DMSO-d6)159.2,156.3,137.5,132.6,132.5,129.0,124.8,124.7,123.6,119.0,117.8,117.0,102.6,80.4,70.9,51.9,26.6,18.6;IR(KBr)2226,2179,1609,1582,1491,1267cm-1.
C20H19N5O2·0.24H2O
计算值:C,65.26;H,5.40;N,19.02;
实验值:C,65.62;H,5.36;N,18.57。
HPLC:99.5%〔Chiracel OD柱/己烷(80%),异丙醇(20%),甲酸(0.1%)〕。
实例21
(反式)-4-〔2-(氰基亚氨基)四氢-1(2H)-嘧啶基〕-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈
A.(反式)-4-〔(3-氨基丙基)氨基〕-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈
在室温下,于6-氰基-3,4-环氧-3,4-二氢-2,2-二甲基-2H-苯并吡喃(按Evans等,J.Med.Chem.,1983,26,1582和J.Med.Chem.,1986,29,2194制备)(1.0g,5.0mmol)在乙醇(5.0ml)中的悬浮液中加入1,3-二氨基丙烷(2.4ml,32.4mmol),并将反应混合物在室温下搅拌36小时。减压除去溶剂,残留物用真空泵干燥5小时,得到无色泡沫状的标题A化合物(1.3g)。不进行纯化将该物质用于下一步反应中。
B.(反式)-4-〔2-(氰基亚氨基)四氢-1(2H)-嘧啶〕-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈
在室温和搅拌下,于标题A化合物(1.3g,4.7mmol)在乙醇(5ml)中的溶液中先后加入三乙胺(1.3ml,9.4mmol)和N-氰基二硫代亚胺基碳酸二甲酯(1.5g,9.4mmol的90%)。将反应温合物在80℃加热3小时,然后冷却至环境温度。蒸发溶剂后得到浅黄色泡沫体(1.5g)。将该物质溶于甲醇(20ml)中,用乙酸汞(2.0g,6.1mmol)处理所得悬浮液。将反应混合物在室温下搅拌2小时,并减压蒸发溶剂。残留物用水稀释后用2.5N氢氧化钠碱化至pH~9.0,并用10%甲醇氯仿提取产物三次。合并的提取液用盐水洗涤,得到稠乳液。将该两相混合物滤过硅藻土垫,分出有机层,用硫酸镁干燥。蒸发溶剂,残留物在硅胶上用含5%甲醇的氯仿洗脱进行闪式层析纯化,得到无色残留物,经异丙醚-乙酸乙酯结晶,得到白色粉状的标题化合物,m.p.152-153℃。
1H NMR(DMSO-d6)δ7.60(d,J=7.0Hz,1H),7.40(s,1H),7.0(d,J=9.0,1H),5.85(d,J=5.2Hz,1H),5.6(d,J=10.5Hz,1H),3.8(dd,J=5.0Hz,1H),3.2(m,4H),2.9(br d,1H),1.54,1.26(s,3H each);13C NMR(DMSO-d6)164.5,156.8,133.2,131.6,118.9,118.2,118.0,103.1,80.4,67.3,51.2,40.3,26.6,18.6;IR(KBr)1268.7,1316.8,1402.2,1489.5,1558.1,1580.4,2174.7,3421.3cm-1.
C17H19N5O2·0.42H2O
计算值:C,61.33;H,6.01;N,21.04;
实验值:C,61.31;H,6.02;N,21.06.
实例22
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-(4-吡啶基甲基)胍
在室温下,用4-(氨基甲基)吡啶(1.0ml)处理(反式)-4-〔〔(氰基亚氨基)苯氧基甲基〕氨基〕-3,4-二羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈(1.0g,2.76mmol),实例7部分A化合物在异丙醇(5ml)中的悬浮液。将反应混合物在室温下搅拌4小时,然后加热回流16小时,将反应混合物冷至室温,滤出固体沉淀。产物用乙酸乙酯重结晶,得到无色固状的标题化合物(0.76g),m.p.156-158℃,
1H NMR
m.p.226-228℃:1H NMR(DMSO-d6)δ8.55(s,1H),8.49(d,J=2.0Hz,2H),7.85(m,1H),7.75(d,J=8.0Hz,1H),7.59(d,J=8.0Hz,1H),7.40(m,3H),6.91(d,J=8.0Hz,1H),5.85(s,1H),4.82(m,1H),4.48(m,2H),3.74(m,1H),1.40(s,3H),1.17(s,3H);13C NMR 160.43,156.2,148.6,148.2,134.6,134.2,132.7,132.2,124.8,123.4,118.9,117.9,117.5,102,6,80.4,71.0,51.5,42.1,26.6,18.7;IR(KBr)1125.2,1490.1,1524.1,1577.8,1611.3,2170.4,2224.9,3429.7cm-1.
C20H20N6O2·0.2H2O
计算值:C,63.22;H,5.41;N,22.12;
实验值:C,63.42;H,5.17;N,21.92.
实例23
(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-(3-吡啶基甲基)胍
在室温下,用3-(氨基甲基)吡啶(1.0ml)处理(反式)-4-〔〔(氰基亚氨基)苯氧基甲基〕氨基〕-3,4-二羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈(1.0g,2.76mmol),实例7部分A化合物在异丙醇(5ml)中的悬浮液。将反应混合物于室温下搅拌4小时,然后加热回流16小时。真空下浓缩反应混合物,所得固体用乙酸乙酯结晶,得到无色固状的标题化合物(0.72g)。
(DMSO-d6)δ8.53(d,J=6.0Hz,2H),7.9(m,1H),7.59(dd,J=3.0 & 6.0Hz,1H),7.44(s,2H),7.31(d,J=6.0Hz,2H),6.91(d,J=9.0Hz,1H),5.9(s,1H),4.87(m,1H),4.48(t,J=2.0 & 6.0Hz,2H),3.7(m,1H),1.99(s,3H),1.18(s,3H);13C NMR(DMSO-d6)160.4,156.2,149.4,132.6,132.3,124.7,121.7,117.8,117.4,102.6,80.4,71.0,51.5,43.4,26.5,18.6;IR(KBr)1125.2,1490.2,1524.1,1577.8,1611.3,2170.4,2224.9,3429.7cm-1.
C20H20N6O2·0.17H2O
计算值:C,63.22;H,5.41;N,22.12;
实验值:C,63.08;H,5.32;N,22.38.
实例24
(反式)-N″-氰基-N-(6-乙炔基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍
A.1-((1,1-二甲基-2-丙炔基)氧基)-4-碘代苯
在室温下,将3-氯-3-甲基-1-丁炔(10.0g,97.9mmol)、4-碘代苯酚(15.0g,68.4mmol)、氢氧化钠(3.90g,97.5mmol)和四丁基铵硫酸氢盐(9.33g,27.5mmol)在二氯甲烷(50ml)和水(50ml)中的溶液搅拌19天。分离两层后,有机层先后用1N氢氧化钠和水洗涤,经硫酸镁干燥后,真空浓缩。将残留物溶于乙酸乙酯中,依次用1N盐酸、1N氢氧化钠、水、盐水洗涤,然后用无水硫酸镁干燥。除去干燥剂之后,真空下蒸除溶剂。粗产物在硅胶上用甲苯/己烷(1∶10)洗脱进行闪式层析纯化,得到油状标题化合物(5.78g,20.2mmol),产率30%。
1H NMR(CDCl3)δ7.56(d,J=8.7Hz,2H),6.98(d,J=8.8Hz,2H),2.56(s,1H),1.63(s,6H);13C NMR(CDCl3)δ155.4,137.8,123.5,86.0,85.6,74.3,72.6,29.5.
B.2,2-二甲基-6-碘-2H-1-苯并吡喃
将标题A化合物(3.91g,13.7mmol)在油浴中于170℃加热2小时。冷却后,粗产物在硅胶上用甲苯/己烷(1∶20)洗脱进行闪式层析纯化,得到油状标题化合物(3.26g,11.4mmol),产率83%,1HNMR
(CDCl3)δ7.34(dd,J1=1.8,J2=2.4Hz,1H),7.24(d,J=0.9Hz,1H),6.52(d,J=8.8Hz,1H),6.21(d,J=10.0Hz,1H),5.58(d,J=10.0Hz,1H),1.40(s,6H);13C NMR(CDCl3)δ152.8,137.5,134.7,131.6,123.6,121.1,118.6,82.4,76.4,27.9.
C.2,2-二甲基-6-(三甲基甲硅烷基)乙炔基)-2H-1-苯并吡喃
在氩气下和65℃油浴中,将标题B化合物(1.32g,4.61mmol)、三甲基((三甲基甲锡烷基)乙炔基)甲硅烷(1.60g,5.69mmol)、氯化锂(0.62g,14.6mmol)和四(三苯膦)钯(0.69g,0.60mmol)在二噁烷(16.5ml)中的溶液搅拌5小时。将反应混合物冷却到室温,真空浓缩后得到残留物,将该残留物与按相似方法制得的另一批2.42mmol的物质合并,将合并的物质用甲苯/己烷(1∶10)漂洗,真空下浓缩滤液。粗产物在硅胶上用甲苯/己烷(1∶10)洗脱进行闪式层析纯化,得到了油状标题C化合物(1.82g,7.00mmol),产率100%。
1H NMR(CDCl3)δ6.98(dd,J1=2.3,J2=8.2Hz,1H),6.87(d,J=1.8Hz,1H),6.44(d,J=8.2Hz,1H),6.02(d,J=9.4Hz,1H),5.38(d,J=10.0Hz,1H),1.20(s,6H),0.00(s,9H);13C NMR(CDCl3)δ153.4,133.0,131.2,130.0,121.6,121.0,116.3,115.2,105.2,92.1,76.7,28.1,0.1.
C10H20OSi
计算值:C,74.94;H,7.86;
实验值:C,75.19;H,7.61.
D.(顺式)-1a,7b-二氢-2,2-二甲基-6-((三甲基甲硅烷基)乙炔基)-2H-环氧乙烯基(C)-(1)-苯并吡喃
在0℃下于标题C化合物(1.37g,5.34mmol)和碳酸氢钠(2.33g,27.7mmol)在二氯甲烷(27ml)和水(27ml)中的溶液中加入3-氯过氧苯甲酸(1.51g,纯度80-85%,7.01mmol)。搅拌几分钟后,撤去冰浴,将反应混合物在室温下搅拌9小时。于反应混合物中加入二氯甲烷后,分出有机层,并依次用水、盐水洗涤,经硫酸镁干燥后于真空下浓缩。粗产物在硅胶上用己烷/乙酸乙酯(10∶1)洗脱进行闪式层析纯化,得到回收的起始原料(0.47g)和油状标题化合物(0.53g,1.95mmol),产率36%:
1H NMR(CDCl3)δ7.24(d,J=1.8Hz,1H),7.11(dd,J1=1.78,J2=2.3Hz,1H),6.49(d,J=8.2Hz,1H),3.62(d,J=4.1Hz,1H),3.25(d,J=4.1Hz,1H),1.34(s,3H),1.00(s,3H),0.00(s,9H);13C NMR(CDCl3)δ152.9,134.1,133.4,120.0,118.1,103.6,92.9,73.6,62.5,50.5,25.6,22.7,0.00.
E.(反式)-4-氨基-6-乙炔基-3,4-二氢-2H-1-苯并吡喃-3-醇
在室温下,将标题D化合物(0.53g,1.95mmol)在乙醇(15ml)和浓氨水(30ml)中的溶液搅拌4天。真空下除去溶剂,残留物在硅胶上用己烷/乙酸乙酯/甲醇(5∶5∶1)洗脱进行闪式层析纯化,得到部分纯化产物,该物质与乙醚一起研制后,得到白色固状的标题化合物(0.42g,1.93mmol),产率99%,
m.p.132-134℃:1H NMR(CDCl3)δ7.62(s,1H),7.38(dd,J1=1.2,J2=1.8Hz,1H),6.82(d,J=8.2,Hz,1H),3.73(d,J=10.0Hz,1H),3.45(d,J=9.4Hz,1H),3.10(s,1H),2.56(br s,3H),1.59(s,3H),1.30(s,3H);13C NMR(CDCl3)δ153.0,132.6,131.0,125.7,117.2,114.0,83.6,78.6,75.9,75.8,51.1,26.9,18.7.C13H15NO2·0.06H2O
计算值:C,71.52;H,6.98;N,6.42;
实验值:C,71.47;H,6.95;N,6.47.
F.(反式)-N″-氰基-N-(6-乙炔基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍
在室温下,于标题E化合物(0.150g,0.69mmol)和N-氰基-N′-苯基硫脲(0.180g,1.0mmol)在二甲基甲酰胺(5ml)中的溶液中加入1-(3-二甲氨基丙基)-2-乙基碳化二亚胺盐酸盐(0.200g,1.0mmol)。将反应混合物在室温下搅拌过夜,然后真空下除去溶剂,将残留物在水和乙酸乙酯之间分配。分出有机层,用硫酸钠干燥。真空下除去溶剂,残留物在硅胶上用己烷/乙酸乙酯/乙醇(30∶10∶5)洗脱进行闪式层析纯化,得到部分纯化产品。该物质与乙醚一起研制,得到标题化合物(0.12g,0.34mmol),产率49%。
m.p.220-222℃(dec);1H NMR(CDCl3)δ7.20-7.40(m,7H),6.70(d,J=8.2Hz,1H),5.00(d,J=10.0Hz,1H),3.67(d,J=9.4Hz,1H),3.34(s,1H),1.44(s,3H),1.24(s,3H);13C NMR(CDCl3)δ161.6,154.6,138.2,133.7,132.8,130.5,127.2,125.7,123.9,118.9,118.3,116.0,84.3,80.5,77.2,74.6,54.0,27.1,18.6.
C21H20N4O2·0.32H2O
计算值:C,68.89;H,5.68;N,15.31;
实验值:C,69.11;H,5.55;N,15.09.
实例25
(反式)-N″-氰基-N-(3,4-二氢-6-(苯基乙炔基)-2H-1-苯并吡喃-4-基)-N′-苯基胍
A.2,2-二甲基-6-(苯基乙炔基)-2H-1-苯并吡喃
在室温和氩气气氛下,于实例24标题B化合物(1.69g,5.91mmol)和苯基乙炔(2.0ml,18.1mmol)在二乙胺(30ml)中的溶液中加入氯化双(三苯膦)钯(Ⅱ)(0.40g,0.572mmol)和碘化铜(Ⅰ)(0.22g,1.41mmol)。在室温下搅拌1小时后,减压下浓缩反应混合物。将残留物溶于乙酸乙酯中,滤出不溶物。真空下浓缩滤液。将残留物重新溶于甲苯/己烷(1∶10)中,滤出不溶物。真空下浓缩滤液,粗产物在硅胶上用甲苯/己烷(1∶10)洗脱进行闪式层析纯化,得到了油状标题化合物(1.43g,5.49mmol),产率92%。
1H NMR(CDCl3)δ7.47-7.50(m,2H),7.24-7.31(m,4H),7.14(d,J=2.4Hz,1H),6.72(d,J=8.2Hz,1H),6.26(d,J=10.0Hz,1H),5.58(d,J=9.4Hz,1H),1.40(s,6H);13C NMR(CDCl3)δ153.2,132.5,131.3,131.2,129.5,128.2,127.8,123.6,121.6,121.1,116.4,115.2,89.4,87.8,76.7,28.0.
B.2,2-二甲基-6-(苯基乙炔基)-2H-环氧乙烯基(C)-(1)-苯并吡喃
在0℃下,于标题A化合物(1.14g,4.38mmol)和碳酸氢钠(1.86g,22.1mmol)在二氯甲烷(15ml)和水(15ml)中的溶液中加入3-氯过氧苯甲酸(1.21g,纯度80-85%,5.62mmol)。5分钟后,撤去冰浴,并将反应混合物在室温下搅拌8小时。用二氯甲烷稀释后分出有机层。依次用水和盐水洗涤,然后用硫酸镁干燥。真空下浓缩溶剂,残留物在硅胶上用己烷/乙酸乙酯(10∶1)洗脱进行闪式层析纯化,得到回收的起始原料(0.17g)和油状标题化合物(0.74g,2.68mmol),产率61%。
1H NMR(CDCl3)δ7.42-7.64(m,7H),6.90(d,J=8.8Hz,1H),3.99(d,J=4.7Hz,1H),3.60(d,J=4.7Hz,1H),1.69(s,3H),1.38(s,3H);13C NMR(CDCl3)δ152.8,133.7,132.9,131.4,128.3,128.0,123.4,120.2,118.2,115.9,88.9,88.3,73.6,62.5,50.6,48.2,22.7.
C.(反式)-4-氨基-3,4-二氢-2,2-二甲基-6-(苯基乙炔基)-2H-1-苯并吡喃-3-醇
将标题B化合物(0.71g,2.55mmol)在无水乙醇(20ml)和浓氨水(40ml)中的溶液搅拌7天,然后真空下除去溶剂,粗产物与己烷和异丙醚一起研制后,得到白色固状的标题化合物(0.64g,2.18mmol),产率86%,m.p.162-164℃;1HNMR
(CDCl3)δ7.36-7.67(m,7H),6.86(d,J=8.2Hz,1H),3.78(d,J=10.0Hz,1H),3.48(d,J=10.0Hz,1H),2.51(br s,3H),1.62(s,3H),1.32(s,3H);13C NMR(CDCl3)δ152.7,132.1,131.4,130.4,128.3,128.0,125.6,122.8,117.3,115.0,88.6,87.1,78.5,76.0,51.2,26.9,18.7.C19H19O2N·0.28H2O
计算值:C,76.46;H,6.61;N,4.69;
实经值:C,76.39;H,6.52;N,4.76.
D.(反式)-N″-氰基-N-(3,4-二氢-6-(苯基乙炔基)-2H-1-苯并吡喃-4-基)-N′-苯基胍
在室温下,于标题C化合物(0.64g,2.18mmol)和N-氰基-N′-苯基硫脲(0.56g,3.16mmol)在二甲基甲酰胺(16ml)中的溶液中加入1-(3-二甲氨基丙基)-2-乙基碳化二亚胺盐酸盐(0.60g,3.49mmol)。将反应混合物在室温下搅拌2天,然后真空下除去溶剂。残留物于乙酸乙酯和水之间分配。分出有机层,先后用水、盐水洗涤,经硫酸钠干燥后于真空下浓缩。将残留物在硅胶上用己烷/乙酸乙酯/乙醇(10∶10∶1)洗脱进行闪式层析纯化,得到部分纯化的物质。该物质与二异丙醚一起研制后,得到白色固状的标题化合物(0.46g,1.05mmol),产率48%,
m.p.175-177℃:1H NMR(DMSO-d6)δ9.42(s,1H),7.82(d,J=9.4Hz,1H),7.20-7.75(m,14H),6.88(d,J=9.4Hz,1H),5.59(br s,1H),5.02(dd,J1=8.8,J2=9.4Hz,1H),3.80(br d,J=9.4Hz,1H),1.50(s,3H),1.27(s,3H);13C NMR(DMSO-d6)δ159.5,153.2,138.0,132.2,131.6,131.3,129.3,129.0,128.0,124.9,124.1,123.7,122.9,117.4,114.3,89.7,88.3,79.9,71.6,52.5,27.1,18.8.
Claims (31)
1、一种制备具有下述通式的化合物及其立体化学异构体的方法,
式中a、b、c都为碳原子,或a、b、c中的一个为氮原子或-NO-,而其它两个为碳原子;
R1为
R2为氢、羟基、
R3和R4各独立地为氢、烷基或芳基烷基,或R3和R4与它们所连的碳原子一起形成5-7员碳环;
R5选自H、烷基、卤代烷基、链烯基、炔基、环烷基、芳基烷基、环烷基烷基、-CN、-NO2、-COR、-COOR、-CONHR、-CONR2、-CF3、S-烷基、-SO烷基、-SO2烷基、
卤素、氨基、取代的氨基、O-烷基、OCF3、OCH2CF3、-OCO烷基、-OCONR烷基、-NRCO烷基、NRCOO烷基、NRCONR2,其中在上述各基团中R可以是氢、烷基、芳基、芳基烷基、环烷基或环烷基烷基;
R6选自H、烷基、OH、O-烷基、氨基、取代的氨基、CN、NO2;
R7和R8分别独立地选自氢、烷基、链烯基、芳基、(杂环)烷基、杂环基、芳基烷基、环烷基、环烷基烷基、取代基包括烷氧基、烷硫基和取代的氨基的取代烷基,或R7和R8与它们所连的氮原子一起形成1-吡啶烷基、1-哌啶基、1-氮杂
基、4-吗啉基、4-硫代吗啉基、1-哌嗪基、4-烷基-1-哌嗪基或4-芳基烷基-1-哌嗪基,其中所形成的各基团可被烷基、烷氧基、烷硫基、卤素或三氟甲基取代;
R9和R10选自氢、烷基、链烯基、芳基、芳基烷基、环烷基或环烷基烷基;
n为1、2或3;
其特征在于:
(a)在有机溶剂中,在碳化二亚胺和酸源存在下,用式Ⅲ的胺处理式Ⅱ的硫脲,得到式Ⅰ中R1是下式的化合物;
(b)在有机溶剂中,在碳化二亚胺存在下,将式Ⅵ的硫胺与氰氨基单钠一起加热,制得式Ⅰ中R1是下式的化合物;
(c)在极性溶剂中,式Ⅶ化合物与式Ⅷ的胺反应,制得式Ⅰ中R1是下式的化合物;
(d)在醇性溶剂中,用乙酸汞处理式Ⅸ化合物,得到式Ⅰ中R1是下式的化合物;
(e)在醇性溶剂中,用二苯基氰碳亚酰胺处理式X的二胺,制得式Ⅰ中R1是下式的化合物;
如果需要,可制备其化学异构体。
3、根据权利要求1的方法,其中式Ⅰ化合物还可定义为:
a为氮或-CR5;
b和c各为-CH-;
R2为反式羟基;
R3和R4各为甲基;
R5为-CN或NO2;
R6为氢;
R7为氢、甲基、乙基、苯基或苯甲基;
R8为氢;
R9为氢;
R10为氢;及
n为1。
4、根据权利要求1的方法,其中化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-(1,1-二甲基丙基)胍。
5、根据权利要求1的方法,其中化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-乙基胍。
6、根据权利要求1的方法,其中化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍。
7、根据权利要求1的方法,其中化合物为(反式)-N″-氰基-N-(3,4-二氢-3-羟基-2,2-二甲基-6-硝基-2H-1-苯并吡喃-4-基)-N′-乙基胍。
8、根据权利要求1的方法,其中化合物为(反式)-3,4-二氢-3-羟基-2,2-二甲基-4-〔2-(氰基亚胺基)-1-吡咯烷基〕-2H-1-苯并吡喃-6-腈。
9、根据权利要求1的方法,其中化合物为(反式)-N″-氰基-N-(3,4-二氢-3-羟基-2,2-二甲基-2H-吡喃并〔3,2-C〕吡啶-4-基)苯基胍。
10、根据权利要求1的方法,其中化合物为(反式)-N′-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-1-吡咯烷-carboximidamide。
11、根据权利要求1的方法,其中化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-乙基-N-甲基胍。
12、根据权利要求1的方法,其中所述化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-〔2-(二甲氨基)乙基〕胍。
13、根据权利要求1的方法,其中化合物为(反式)-4-〔〔(氰基亚氨基)(1-吡咯烷基)-甲基〕氨基〕-3,4-二羟基-2,2-二甲基-1H-1-苯并吡喃-6-腈。
14、根据权利要求1的方法,其中所述化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-甲基胍。
15、根据权利要求1的方法,其中所述化合物为(反式)-4-〔(氰基亚氨基)〔〔4-(苯基甲基)-1-哌嗪基〕甲基〕氨基〕-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈。
16、根据权利要求1的方法,其中所述化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-胍。
17、根据权利要求1的方法,其中所述化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-(甲基乙基)胍。
18、根据权利要求1的方法,其中所述化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-二甲基胍。
19、根据权利要求1的方法,其中所述化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯甲基胍。
20、根据权利要求1的方法,其中所述化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-〔2-〔(苯甲基)甲基氨基〕乙基〕胍。
21、根据权利要求1的方法,其中所述化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-(2-甲氧基乙基)胍。
22、根据权利要求1的方法,其中所述化合物为(3S-反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍。
23、根据权利要求1的方法,其中所述化合物为(3R-反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍。
24、根据权利要求1的方法,其中所述化合物为(反式)-4-〔2-(氰基亚氨基)四氢-1(2H)-嘧啶基〕-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-6-腈。
25、根据权利要求1的方法,其中所述化合物具有下式结构:
26、根据权利要求1的方法,其中所述化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-(2-甲氧基乙基)胍。
27、根据权利要求1的方法,其中所述化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-(4-吡啶基甲基)胍。
28、根据权利要求1的方法,其中所述化合物为(反式)-N″-氰基-N-(6-氰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-(3-吡啶基甲基)胍。
29、根据权利要求1的方法,其中所述化合物为(反式)-N″-氰基-N-(6-乙炔基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基)-N′-苯基胍。
30、根据权利要求1的方法,其中所述化合物为(反式)-N″-氰基-N-(3,4-二氢-6-(苯基乙炔基)-2H-1-苯并吡喃-4-基)-N′-苯基胍。
31、根据权利要求1的方法,其中所述化合物具有下述结构:
式中a、b、c都为碳原子,或a、b、c中的一个为氮原子或-NO-,而其它两个为碳原子;
R1为
R2为氢、羟基或
R3和R4各独立地为氢、烷基或芳基烷基,或R3和R4与它们所连的碳原子一起形成5-7员碳环;
R5选自H、烷基、卤代烷基、链烯基、炔基、环烷基、芳基烷基、环烷基烷基、-CN、-NO2、-COR、-COOR、-CONHR、-CONR2、-CF3、S-烷基、-SO烷基、-SO2烷基、卤素、氨基、取代的氨基、O-烷基、-OCO烷基、-OCONR烷基、-NRCO烷基、NRCOO烷基、NRCONR2,其中在上述各基团中R可以是氢、烷基、芳基、芳基烷基、环烷基或环烷基烷基;
R6选自H、烷基、OH、O-烷基、氨基、取代的氨基、CN和NO2;
R7和R8分别独立地选自氢、烷基、链烯基、芳基、芳基烷基、环烷基和环烷基烷基,或R7和R8与它们所连的氮原子一起形成1-吡咯烷基、1-哌啶基、1-氮杂
基、4-吗啉基、4-硫代吗啉基、1-哌嗪基、4-烷基-1-哌嗪基或4-芳基烷基-1-哌嗪基,其中所形成的各基团可被烷基、烷氧基、烷硫基、卤素或三氟甲基取代;
R9和R10选自氢、烷基、链烯基、芳基、芳基烷基、环烷基或环烷基烷基;
n为1、2或3。
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US35923689A | 1989-05-31 | 1989-05-31 | |
US359,236 | 1989-05-31 | ||
US49306090A | 1990-03-13 | 1990-03-13 | |
US493,060 | 1990-03-13 |
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CN90103959A Pending CN1047672A (zh) | 1989-05-31 | 1990-05-31 | 吡喃基氰基胍衍生物 |
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EP (1) | EP0401010B1 (zh) |
JP (2) | JPH0327375A (zh) |
KR (1) | KR950006155B1 (zh) |
CN (1) | CN1047672A (zh) |
AT (1) | ATE141598T1 (zh) |
AU (1) | AU633082B2 (zh) |
CA (1) | CA2015296C (zh) |
DE (1) | DE69028143T2 (zh) |
DK (1) | DK0401010T3 (zh) |
EG (1) | EG19389A (zh) |
ES (1) | ES2090099T3 (zh) |
FI (1) | FI109120B (zh) |
GR (1) | GR3021702T3 (zh) |
HK (1) | HK16997A (zh) |
HU (1) | HU207857B (zh) |
IE (1) | IE901793A1 (zh) |
IL (1) | IL94326A (zh) |
NO (1) | NO174807B (zh) |
NZ (1) | NZ233845A (zh) |
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PT (1) | PT94210B (zh) |
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CN1854135B (zh) * | 2005-04-18 | 2013-06-12 | 李伟章 | 由氰基胍连接组成的杂环化合物及其医药应用 |
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DK657389A (da) * | 1988-12-23 | 1990-06-24 | Beecham Group Plc | Benzopyran-, tetrahydronaphthalen-, pyranopyridin- og indanderivater |
US5104890A (en) * | 1989-03-28 | 1992-04-14 | Fujisawa Pharmaceutical Company, Ltd. | Benzopyran derivatives and processes for preparation thereof |
US5140031A (en) * | 1989-05-31 | 1992-08-18 | E. R. Squibb & Sons, Inc. | Pyranyl cyanoguanidine derivatives |
CA2015296C (en) * | 1989-05-31 | 2001-08-07 | Karnail Atwal | Pyranyl cyanoguanidine derivatives |
FR2657872B2 (fr) * | 1989-11-06 | 1992-06-12 | Sanofi Sa | Derive d'amidino-4 chromanne, procede d'obtention et compositions pharmaceutiques le contenant. |
JP2825346B2 (ja) * | 1990-05-17 | 1998-11-18 | ユニオン キャンプ コーポレイション | リグノセルロース物質の環境上改良された漂白方法 |
AU651105B2 (en) * | 1990-06-18 | 1994-07-14 | E.R. Squibb & Sons, Inc. | Benzopyran derivatives and heterocyclic analogs thereof as antiischemic agents |
US5643921A (en) * | 1990-09-26 | 1997-07-01 | E.R. Squibb & Sons, Inc. | Cardiopulmonary bypass and organ transplant using a potassium channel activator |
CA2055376A1 (en) * | 1990-12-05 | 1992-06-06 | Gary J. Grover | Method of treating shock using a potassium channel activator |
DE4120322A1 (de) * | 1991-06-20 | 1992-12-24 | Bayer Ag | Aminomethyl-substituierte 2,3-dihydropyrano(2,3-b)pyridine, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln |
US5374643A (en) * | 1992-09-11 | 1994-12-20 | E. R. Squibb & Sons, Inc. | Aryl urea (thiourea) and cyanoguanidine derivatives |
IL109229A0 (en) * | 1993-05-11 | 1994-07-31 | Bristol Myers Squibb Co | Heterocyclic compounds and processes for the preparation of pyranyl cyanoguanidine derivatives using the same |
US5478734A (en) * | 1993-06-18 | 1995-12-26 | Bristol-Myers Squibb Company | Method of chiral epoxidation of benzopyran or pyranopyridine derivatives using microorganisms |
US5612323A (en) * | 1995-06-07 | 1997-03-18 | Bristol-Myers Squibb Company | Phosphinic ester substituted benzopyran derivatives |
US5629429A (en) * | 1995-06-07 | 1997-05-13 | Bristol-Myers Squibb Company | Process for preparing 4-arylamino-benzopyran and related compounds |
US5612370A (en) * | 1995-06-07 | 1997-03-18 | Bristol-Myers Squibb Company | Phenylglycine and phenylalaninen amido benzopyran derivatives |
US5869478A (en) * | 1995-06-07 | 1999-02-09 | Bristol-Myers Squibb Company | Sulfonamido substituted benzopyran derivatives |
BR0015227B1 (pt) * | 1999-10-21 | 2011-12-27 | derivados de benzopiranil guanidina, processo para a sua preparaÇço e composiÇÕes farmacÊuticas contendo os mesmos. | |
KR100429609B1 (ko) * | 1999-10-21 | 2004-05-03 | 동부한농화학 주식회사 | 벤조피라닐 구아니딘 유도체, 그의 제조방법 및 그를포함하는 약학적 조성물 |
WO2007022964A2 (de) | 2005-08-24 | 2007-03-01 | Abbott Gmbh & Co. Kg | Hetaryl substituierte guanidinverbindungen und ihre verwendung als bindungspartner für 5-ht5-rezeptoren |
CN102414163A (zh) * | 2009-04-23 | 2012-04-11 | 拜耳医药股份有限公司 | 用于f-18标记的pet示踪剂的新前体分子 |
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EP0205292B1 (en) * | 1985-06-08 | 1991-11-06 | Beecham Group Plc | Pyrano[3,2-c]pyridine derivatives, process and intermediates for their preparation and pharmaceutical compositions containing them |
GB8521857D0 (en) * | 1985-09-03 | 1985-10-09 | Beecham Group Plc | Active compounds |
JPH027217A (ja) * | 1988-04-30 | 1990-01-11 | Mitsubishi Electric Corp | 磁気記録再生装置 |
US4988723A (en) * | 1988-06-02 | 1991-01-29 | Fujisawa Pharmaceutical Co., Ltd. | Benzopyran derivatives and their use as anti-hypertensives |
DE3823533A1 (de) * | 1988-07-12 | 1990-02-08 | Beiersdorf Ag | Substituierte 4-heterocyclyl-2h-benzo(b)pyrane, verfahren und 4-hydroxy-3-brom-, 3,4-oxiranyl-3,4-dehydro-2h-benzo(b)pyrane als zwischenprodukte zu ihrer herstellung, sowie sie enthaltende pharmazeutsche praeparate |
DE68926729T2 (de) * | 1988-09-16 | 1997-02-13 | Beecham Group Plc | Benzopyranderivate mit einer blutdrucksenkenden Wirkung |
JPH02172984A (ja) * | 1988-12-23 | 1990-07-04 | Yamanouchi Pharmaceut Co Ltd | クロマン誘導体 |
US5104890A (en) * | 1989-03-28 | 1992-04-14 | Fujisawa Pharmaceutical Company, Ltd. | Benzopyran derivatives and processes for preparation thereof |
CA2015296C (en) * | 1989-05-31 | 2001-08-07 | Karnail Atwal | Pyranyl cyanoguanidine derivatives |
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- 1990-04-24 CA CA002015296A patent/CA2015296C/en not_active Expired - Lifetime
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- 1990-05-31 CN CN90103959A patent/CN1047672A/zh active Pending
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CN1854135B (zh) * | 2005-04-18 | 2013-06-12 | 李伟章 | 由氰基胍连接组成的杂环化合物及其医药应用 |
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