CN1048546A - 作为血管张肽ii对抗药物的取代咪唑并稠合6元杂环 - Google Patents
作为血管张肽ii对抗药物的取代咪唑并稠合6元杂环 Download PDFInfo
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- CN1048546A CN1048546A CN90103234A CN90103234A CN1048546A CN 1048546 A CN1048546 A CN 1048546A CN 90103234 A CN90103234 A CN 90103234A CN 90103234 A CN90103234 A CN 90103234A CN 1048546 A CN1048546 A CN 1048546A
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- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 31
- 239000003814 drug Substances 0.000 title abstract description 17
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 title abstract description 12
- 229950006323 angiotensin ii Drugs 0.000 title abstract description 11
- 102000005862 Angiotensin II Human genes 0.000 title abstract description 8
- 101800000733 Angiotensin-2 Proteins 0.000 title abstract description 8
- 230000008485 antagonism Effects 0.000 title abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 21
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 270
- 238000000034 method Methods 0.000 claims description 216
- -1 sulphinyl Chemical group 0.000 claims description 138
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 103
- 238000002360 preparation method Methods 0.000 claims description 97
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 92
- 239000000203 mixture Substances 0.000 claims description 92
- 239000000460 chlorine Substances 0.000 claims description 86
- 238000006243 chemical reaction Methods 0.000 claims description 69
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 58
- 150000003839 salts Chemical class 0.000 claims description 55
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 45
- 229910052801 chlorine Inorganic materials 0.000 claims description 45
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 239000002904 solvent Substances 0.000 claims description 40
- 239000002253 acid Substances 0.000 claims description 39
- 239000011541 reaction mixture Substances 0.000 claims description 37
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 31
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 30
- 229910052794 bromium Inorganic materials 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- 229910052731 fluorine Inorganic materials 0.000 claims description 28
- 229910052740 iodine Inorganic materials 0.000 claims description 28
- 239000002585 base Substances 0.000 claims description 26
- 238000000605 extraction Methods 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 238000010438 heat treatment Methods 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 23
- 230000004044 response Effects 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- 230000000903 blocking effect Effects 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 13
- 150000002460 imidazoles Chemical class 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 229910052763 palladium Inorganic materials 0.000 claims description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 7
- 238000004587 chromatography analysis Methods 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 229930195733 hydrocarbon Natural products 0.000 claims description 6
- 150000002430 hydrocarbons Chemical class 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 150000004703 alkoxides Chemical class 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 21
- 239000008096 xylene Substances 0.000 claims 11
- 239000003377 acid catalyst Substances 0.000 claims 10
- 235000013877 carbamide Nutrition 0.000 claims 9
- 150000003672 ureas Chemical class 0.000 claims 9
- 230000003213 activating effect Effects 0.000 claims 6
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims 6
- 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 claims 6
- 239000004215 Carbon black (E152) Substances 0.000 claims 5
- 229910019142 PO4 Inorganic materials 0.000 claims 5
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 5
- 239000010452 phosphate Substances 0.000 claims 5
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 5
- 239000002841 Lewis acid Substances 0.000 claims 4
- 150000001298 alcohols Chemical class 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 4
- 150000007517 lewis acids Chemical class 0.000 claims 4
- 150000003512 tertiary amines Chemical class 0.000 claims 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims 2
- 150000008046 alkali metal hydrides Chemical class 0.000 claims 2
- 229940037003 alum Drugs 0.000 claims 2
- 239000004411 aluminium Substances 0.000 claims 2
- 229910052782 aluminium Inorganic materials 0.000 claims 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 2
- 229910052796 boron Inorganic materials 0.000 claims 2
- 150000001718 carbodiimides Chemical class 0.000 claims 2
- 229910052742 iron Inorganic materials 0.000 claims 2
- UGKDIUIOSMUOAW-UHFFFAOYSA-N iron nickel Chemical compound [Fe].[Ni] UGKDIUIOSMUOAW-UHFFFAOYSA-N 0.000 claims 2
- SORXVYYPMXPIFD-UHFFFAOYSA-N iron palladium Chemical compound [Fe].[Pd] SORXVYYPMXPIFD-UHFFFAOYSA-N 0.000 claims 2
- BSIDXUHWUKTRQL-UHFFFAOYSA-N nickel palladium Chemical compound [Ni].[Pd] BSIDXUHWUKTRQL-UHFFFAOYSA-N 0.000 claims 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims 2
- 239000002798 polar solvent Substances 0.000 claims 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims 2
- 239000010936 titanium Substances 0.000 claims 2
- 229910052719 titanium Inorganic materials 0.000 claims 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims 2
- 229910052723 transition metal Inorganic materials 0.000 claims 2
- 150000003624 transition metals Chemical class 0.000 claims 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims 2
- 229910052770 Uranium Inorganic materials 0.000 claims 1
- 229940125904 compound 1 Drugs 0.000 claims 1
- 229940125782 compound 2 Drugs 0.000 claims 1
- 229940126214 compound 3 Drugs 0.000 claims 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims 1
- 229910052737 gold Inorganic materials 0.000 claims 1
- 239000010931 gold Substances 0.000 claims 1
- 239000002516 radical scavenger Substances 0.000 claims 1
- 206010020772 Hypertension Diseases 0.000 abstract description 8
- 206010007559 Cardiac failure congestive Diseases 0.000 abstract description 5
- 206010019280 Heart failures Diseases 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 175
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 154
- 238000005160 1H NMR spectroscopy Methods 0.000 description 114
- FZESPVBONPPRAW-UHFFFAOYSA-N 2-methyl-1h-imidazo[4,5-b]pyridine Chemical compound C1=CC=C2NC(C)=NC2=N1 FZESPVBONPPRAW-UHFFFAOYSA-N 0.000 description 96
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 95
- 235000019439 ethyl acetate Nutrition 0.000 description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
- 239000000047 product Substances 0.000 description 67
- 239000000243 solution Substances 0.000 description 66
- 239000007787 solid Substances 0.000 description 55
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 54
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
- 238000003756 stirring Methods 0.000 description 47
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 46
- 238000005481 NMR spectroscopy Methods 0.000 description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 44
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
- 239000000741 silica gel Substances 0.000 description 37
- 229910002027 silica gel Inorganic materials 0.000 description 37
- KMEBCRWKZZSRRT-UHFFFAOYSA-N 2-methyl-7h-purine Chemical compound CC1=NC=C2NC=NC2=N1 KMEBCRWKZZSRRT-UHFFFAOYSA-N 0.000 description 36
- 229960001866 silicon dioxide Drugs 0.000 description 36
- 238000003818 flash chromatography Methods 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 229910004298 SiO 2 Inorganic materials 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 31
- 239000003480 eluent Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 238000001704 evaporation Methods 0.000 description 22
- 230000008020 evaporation Effects 0.000 description 22
- 229910000104 sodium hydride Inorganic materials 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 19
- 229940124530 sulfonamide Drugs 0.000 description 19
- 238000005406 washing Methods 0.000 description 19
- 239000012141 concentrate Substances 0.000 description 18
- 235000008504 concentrate Nutrition 0.000 description 18
- 239000012043 crude product Substances 0.000 description 18
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 15
- 125000003831 tetrazolyl group Chemical group 0.000 description 15
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 14
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 13
- 239000002243 precursor Substances 0.000 description 13
- 238000001291 vacuum drying Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- XXCZQJUMJUIIOX-UHFFFAOYSA-N 2-methyl-3-[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]imidazo[4,5-b]pyridine Chemical compound N1N=NN=C1C1=C(C=CC=C1)C1=CC=C(C=C1)N1C(=NC=2C1=NC=CC=2)C XXCZQJUMJUIIOX-UHFFFAOYSA-N 0.000 description 11
- 238000013019 agitation Methods 0.000 description 11
- 150000004985 diamines Chemical class 0.000 description 11
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 11
- 229910004373 HOAc Inorganic materials 0.000 description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 10
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 10
- 239000000284 extract Substances 0.000 description 10
- 238000010265 fast atom bombardment Methods 0.000 description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 239000002775 capsule Substances 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 229960004756 ethanol Drugs 0.000 description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 8
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 235000010290 biphenyl Nutrition 0.000 description 8
- 239000004305 biphenyl Substances 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 229960001701 chloroform Drugs 0.000 description 8
- 239000006185 dispersion Substances 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 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 8
- SLLDUURXGMDOCY-UHFFFAOYSA-N 2-butyl-1h-imidazole Chemical compound CCCCC1=NC=CN1 SLLDUURXGMDOCY-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 7
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- 238000004364 calculation method Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 238000006386 neutralization reaction Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
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- 229960002317 succinimide Drugs 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- HCSPFVZWTIJQSD-UHFFFAOYSA-N tert-butyl 2-[4-[(2,2-dibutyl-1H-imidazo[4,5-c]pyridin-3-yl)methyl]phenyl]benzoate Chemical compound C(CCC)C1(NC2=C(C=NC=C2)N1CC1=CC=C(C=C1)C1=C(C=CC=C1)C(=O)OC(C)(C)C)CCCC HCSPFVZWTIJQSD-UHFFFAOYSA-N 0.000 description 1
- DKOWOQYYXGDSMO-UHFFFAOYSA-N tert-butyl 2-iodobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1I DKOWOQYYXGDSMO-UHFFFAOYSA-N 0.000 description 1
- WUBVEMGCQRSBBT-UHFFFAOYSA-N tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)C(F)(F)F)=CC1 WUBVEMGCQRSBBT-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 150000004897 thiazines Chemical class 0.000 description 1
- 125000005323 thioketone group Chemical group 0.000 description 1
- 150000007944 thiolates Chemical class 0.000 description 1
- AGHANLSBXUWXTB-UHFFFAOYSA-N tienilic acid Chemical compound ClC1=C(Cl)C(OCC(=O)O)=CC=C1C(=O)C1=CC=CS1 AGHANLSBXUWXTB-UHFFFAOYSA-N 0.000 description 1
- 229960000356 tienilic acid Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- BYQADQLDVPAGSR-UHFFFAOYSA-N toluene;hydrobromide Chemical compound Br.CC1=CC=CC=C1 BYQADQLDVPAGSR-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
- 229960004813 trichlormethiazide Drugs 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- HALWUDBBYKMYPW-STOWLHSFSA-M trimethaphan camsylate Chemical compound C1C[C@@]2(CS([O-])(=O)=O)C(=O)C[C@@H]1C2(C)C.C12C[S+]3CCCC3C2N(CC=2C=CC=CC=2)C(=O)N1CC1=CC=CC=C1 HALWUDBBYKMYPW-STOWLHSFSA-M 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- MHNHYTDAOYJUEZ-UHFFFAOYSA-N triphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 MHNHYTDAOYJUEZ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
- 239000006200 vaporizer Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- NSYUKKYYVFVMST-LETVYOFWSA-L zofenopril calcium Chemical compound [Ca+2].C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C([O-])=O)SC(=O)C1=CC=CC=C1.C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C([O-])=O)SC(=O)C1=CC=CC=C1 NSYUKKYYVFVMST-LETVYOFWSA-L 0.000 description 1
- 229960001988 zofenopril calcium Drugs 0.000 description 1
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
取代咪唑并稠合6元杂环如下图所示
其中A,B,C或D分别是碳原子或氮原子,是血
管紧张肽II对抗药物,用于治疗高血压和充血性心力
衰竭。
Description
本申请是申请号358,971,申请日1989年5月30日,未决申请的部份继续。
本发明涉及结构式Ⅰ的新化合物,该化合物为血管紧张肽Ⅱ对抗药物,在治疗高血压、充血性心力衰竭和内眼压升高方面是有用的。
本发明也涉及该新化合物的制备方法,包含一个或多个该化合物作为活性成份的药物制剂,以及治疗高血压、充血性心力衰竭和内眼压升高的方法。
血管紧张肽原酶-血管紧张肽系统(RAS)在正常血压的调节中起着核心作用,并且被认为在高血压和充血性心力衰竭的发展和维持中起着决定性作用。血管紧张肽Ⅱ(AⅡ)是一种主要产生于血液中的八肽荷尔蒙,它产生于位于肺、肾和许多其它器官的血管的血管紧张肽转化酶(ACE)使血管紧张肽Ⅰ分裂的期间,它还是RAS的最终产物。AⅡ是一种强有力的动脉血管收缩药物,通过与存在于细胞膜上的特殊受体相互作用而起作用。控制RAS可能的方式之一是血管紧张肽Ⅱ受体拮抗作用。众所周知,AⅡ的几种肽类似物因完全阻断这些受体而抑制这一荷尔蒙的效果,但它们的实验和临床应用由于部分促效药的活性和口服药物吸收不足而受到限制。[M Antonaccio Clin.Exp.Hypertens.A4.27-46(1982);D.H.P.Streeten andG.H.Anderson,Jr.-Handbook of Hypertension,Clinical Pharmacology of Antihypertensive Drugs,ed.A.E.Doyle,Vol.5,pp.246-271,Elservier Science.Publisher,Amsterdam,The Netherlands,1984]。
最近,几种非肽化合物已经被称作AⅡ对抗药物。这些化合物的说明已在下述文献中公开,U.S.-4,207,324;4,340,598;4,576,958;4,582,847;和4,880,804;欧洲专利申请028,834;245,637;253,310;和291,969;和文章A.T.Chiu,et al[Eur.J.Pharm.Exp Therap,157,13-21(1988)]和P.C.Wong,et al[J.Pham Exp.Therap,247,1-7(1988)]上述美国专利和欧洲专利申请028,834和253,310和上述两篇文章均公开了取代咪唑化合物,该化合物通常通过一个低烷基桥被键合在一个取代苯基上。欧洲专利申请245,637公开了4,5,6,7-四氢-2H-咪唑并[4,5-C]-吡啶-6-羧酸衍生物及其类似物作为抗高血压剂。
上述美国专利、欧洲申请和文章中所公开的化合物不具有本发明化合物的杂双环结构。
本发明涉及下面式Ⅰ所示取代咪唑并稠合6元杂环,该化合物为血管紧张肽Ⅱ对抗药物,在治疗高血压、充血性心力衰竭、和内眼压升高方面具有实用价值。
其中:R1是:
(a)-CO2R4,
(b)-SO3R5,
(c)-NHSO2CF3,
(d)-PO(OR5)2,
(e)-SO2-NH-R9,
(f)-CONHOR5,
(g)
(h)-SO2NH-杂芳基,
(i)-CH2SO2NH-杂芳基,
(j)-SO2NHCO-R23,
(k)-CH2SO2NHCO-R23,
(l)-CONH-SO2R23,
(m)-CH2CONH-SO2R23,
(n)-NHSO2NHCO-R23,
(o)-NHCONHSO2-R23,
(p)-SO2NHCONR23,
其中杂芳基是未被取代的、单取代的、或双取代的5或6元芳环,该环可以任意含有1-3个杂原子,杂原子选自O、N或S,其中的取代基选自以下基团:-OH,-SH,-C1-C4-烷基,-C1-C4-烷氧基,卤原子(Cl、Br、F、I)、-NO2,-CO2H,-CO2-C1-C4-烷基,-NH2,-NH(C1-C4-烷基)和-N(C1-C4-烷基)2;
R2a和R2b分别是H,卤原子(Cl、Br、I、F),-NO2,-NH2,C1-C4-烷基氨基,二(C1-C4烷基)氨基,-SO2NHR9,CF3,C1-C4-烷基,或C1-C4-烷氧基;
R3a是
(a)H,
(b)卤原子(Cl、Br、I、F)
(C)C1-C6-烷基,
(d)C1-C6-烷氧基,
(e)C1-C6-烷氧基烷基;
R3b是
(a)H,
(b)卤原子(Cl、Br、I、F)
(c)NO2,
(d)C1-C6-烷基,
(e)C1-C6-酸基,
(f)C1-C6-环烷基,
(g)C1-C6-烷氧基,
(h)-NHSO2R4,
(i)羟基C1-C4-烷基,
(j)芳基C1-C4-烷基,
(k)C1-C4烷硫基,
(l)C1-C4烷基亚磺酰基,
(m)C1-C4烷基磺酰基,
(n)NH2,
(o)C1-C4烷基氨基,
(p)C1-C4二烷基氨基,
(q)氟代C1-C4烷基,
(r)-SO2-NHR9,
(s)芳基或
(t)呋喃基;
其中芳基是任意被一个或两个取代基的苯基和萘基,这些取代基选自以下基团:卤原子(Cl,Br,I,F),C1-C4-烷基,C1-C4-烷氧基,NO2,CF3,C1-C4-烷硫基,OH,NH2,NH(C1-C4-烷基),N(C1-C4-烷基)2,CO2H,和CO2-C1-C4烷基;
R4是H,直链或支链C1-C6烷基,芳基或-CH2-芳基,该芳基如上述定义:
R4a是C1-C6-烷基,芳基或-CH2-芳基,该芳基如上述定义:
E是一个单键,-NR13(CH2)s-,-S(O)x-(CH2)s-,在此x为0-2,s为0-5,-CH(OH)-,-O-,-CO-;
R6是(a)芳基,如上述定义,是任意被1或2个取代基取代的,这些取代基选自以下基团:卤原子(Cl,Br,I,F),-O-C1-C4-烷基,C1-C4-烷基,-NO2,-CF3,-SO2NR9R10,-S-C1-C4-烷基,-OH,-NH2,C3-C7-环烷基,C3-C10-链烯基;
(b)直链或支链C1-C9-烷基,C2-C6-链烯基,或C2-C6-炔基,且可分别被取代基任意取代,这些取代基选自以下基团:如上述定义的芳基,C3-C7-环烷基,卤原子(Cl,Br,I,F),-OH,-NH2,-NH(C1-C4-烷基),-CF2CF3,-N(C1-C4-烷基)2,-NH-SO2R4,-COOR4,-CF3,-CF2CH3,-SO2NHR9;
(c)未被取代、单取代或双取代芳香5或6元环,该环含有一或两个N、O、S原子,并且其中的取代基选自以下基团:-OH,-SH,C1-C4-烷基,C1-C4-烷氧基,-CF3,卤原子(Cl、Br、I、F),或NO2;
(d)全氟代-C1-C4-烷基;
(e)任意被C1-C4-烷基或CF3单或双取代的C3-C7-环烷基;
R9是H,C1-C5-烷基,芳基或-CH2-芳基在此芳基如上述定义;
R10是H,C1-C4-烷基;
R11是H,C1-C6-烷基,C2-C4-链烯基,C1-C4-烷氧基-C1-C4-烷基,或
R12是-CN,-NO2或-CO2R4;
R13是H,-CO(C1-C4-烷基),C1-C6-烷基,烯丙基,C1-C6-环烷基,苯基或苄基;
R14是H,C1-C6-烷基,C1-C8-全氟代烷基,C3-C6-环烷基,苯基或苄基;
R15是H,C1-C6-烷基;
R16是H,C1-C6-烷基,C3-C6-环烷基,苯基或苄基;
R17是-NR9R10,-OR10,-NHCONH2,-NHCSNH2,
R18和R19分别是C1-C4-烷基或一起形成-(CH2)q-,在此q为2或3;
R20是H,-NO2,-NH2,-OH或-OCH3;
R23是(a)如上述定义的芳基,
(b)如上述定义的杂芳基,
(c)C3-C4-环烷基,
(d)任意被取代基取代的C1-C4-烷基,这些取代基选自以下基团:如上述定义的芳基,如上述定义的杂芳基,-OH,-SH,-C1-C4烷基,-O(C1-C4-烷基),-S(C1-C4-烷基),-CF3,卤原子(Cl,Br,F, I),-NO2,-CO2H,-CO2-C1-C4-烷基,-NH2,-NH(C1-C4-烷基),-NHCOR4a,-N(C1-C4-烷基)2,-PO3H,-PO(OH)(C1-C4-烷基),-PO(OH)(芳基),或-PO(OH)(O-C1-C4-烷基),
(c)全氟代-C1-C4-烷基;
X不存在或者是
(a)一个碳-碳单键,
(b)-CO-,
(c)-O-,
(d)-S-,
(h)-OCH2-,
(i)-CH2O-
(j)-SCH2-,
(k)-CH2S-,
(l)-NHC(R9)(R10),
(m)-NR9SO2-,
(n)-SO2NR9-,
(o)-C(R9)(R10)NH-,
(p)-CH=CH-,
(q)-CF=CF-,
(r)-CH=CF-,
(s)-CF=CH-,
(t)-CH2CH2-,
(u)-CF2CF2-,
Z是O,NR13或S;
-A-B-C-D-代表连接在咪唑上的饱和的或不饱和的6元杂环的组成原子,该杂环含有1-3个氮原子,并且包括下述结构:
R7基团可以相同或不同并且代表:
(a)氢,
(b)C1-C6直链或支链烷基,或C2-C6链烯基,或炔基,且分别未被取代或被以下基团取代:
ⅰ)-OH,
ⅱ)C1-C4-烷氧基,
ⅲ)-CO2R4,
ⅳ)-OCOR4,
ⅷ)-N(R4)2,
ⅸ)如上述定义的芳基,
ⅹ)如下述(p)中定义的杂环,
ⅹⅰ)-S(O)xR23,
ⅹⅱ)四唑-5-基,
ⅹⅲ)-CONHSO2R23,
ⅹⅳ)-SO2NH-杂芳基,
ⅹⅴ)-SO2NHCOR23,
ⅹⅸ)-PO(OR4)2,
ⅹⅹ)-PO(OR4)R9,
c)卤原子,如氯、溴或碘,
d)全氟代-C1-C4-烷基,
e)-OH,
f)-NH2,
i)-OR23,
j)-CO2R4,
k)-CON(R4)2,
l)-NH-C3-C7-环烷基,
m)C3-C7-环烷基,
n)如上述定义的芳基,
o)5或6元饱和的或不饱和的杂环,该环最多含有三个杂原子,杂原子包括O,N或S,其中S可以亚砜或砜的形式存在,并且该杂环可任意被1个或两个取代基所取代,这些取代基选自以下基团:卤原子(Cl,Br,F,I),C1-C4-烷基,C1-C4-烷氧基,C1-C4-S(O)x-,在此x如上述定义,CF3,NO2,OH,CO2H,CO2-C1-C4-烷基,或N(R4)2;
p)-CN,
r)-SO2N(R4)2,
s)四唑-5-基,
t)-CONHSO2R23,
u)-PO(OR4)2,
v)-NHSO2CF3,
w)-SO2NH-杂芳基,
x)-SO2NHCOR23,
y)-S(O)x-R23,
z)
aa)-PO(OR4)R9,
bb)-NHSO2R23,
cc)-NHSO2NHR23,
dd)-NHSO2NHCOR23,
ee)-NHCONHSO2R23,
ff)-N(R4)CO2R23,
hh)-CO-芳基,
R8基团可以相同或不同并且代表:
a)氢,
b)未被取代或被羟基,C1-C4-烷氧基,-N(R4)2,-CO2R4或C3-C5-环烷基所取代的C1-C6-烷基或链烯基,
c)C3-C5-环烷基;
R8a是R8或C1-C4酰基,
R9a基团可以相同或不同并且代表:
a)氢,
b)未被取代或被
ⅰ)羟基
ⅱ)-CO2R4,
ⅲ)-CONHR4,或
ⅳ)-CON(R4)2所取代的C1-C6烷基及其药物上可接受的盐。
本发明新化合物的一个实例是式Ⅰ化合物的一类,其中:
R1是
(e)-SO2NH-杂芳基,
(f)-CH2SO2NH-杂芳基,
(g)-SO2NHCOR23,
(h)-CH2SO2NHCOR23,
(i)-CONHSO2R23,
(j)-CH2CONHSO2R23,
(k)-NHSO2NHCOR23,or
(l)-NHCONHSO2R23,
(m)-SO2NHCONHR23,
其中杂芳基如上述第一次定义;
x是一个单键,
R2a和R2b分别是:
a)C1-C4烷基,
b)卤素,
c)氢;
R3a和R3b分别是
a)C1-C6-烷基,
b)卤素,或
c)C1-C6-烷氧基,
d)氢;
R4是H,或C1-C4-烷基;
E是一个单键或-S-;
R6是一个支链或直链C1-C6-烷基,C3-C7-环烷基,C2-C6-链烯基或C2-C6炔基,且分别为未被取代或被C1-C4烷硫基,C1-C4-烷氧基,CF3、CF2CF3或CF2CH3所取代;
并且A-B-C-D代表:
其中:R7基团可以相同或不同并且代表:
a)氢,
b)未被取代或被下述基团取代的C1-C4-烷基;
ⅰ)-OH,
ⅱ)-CO2R4,
ⅲ)-NH2,
ⅳ)(C1-C4烷基)氨基,
ⅴ)二(C1-C4-烷基)氨基,
c)卤原子
d)-CF3,
e)-OH,
f)-N(R4)2,
g)-C1-C4-烷氧基,
h)-CO2R4,
i)-CONH2,
j)-C3-C7-环烷基,
k)芳基,
l)如上述定义的杂环基,
m)-CF3,
n)四唑-5-基,
o)-CONHSO2R23;
R8基团可以相同或不同并且代表:
a)氢,
b)未被取代或被-OH或-CO2R4所取代的C1-C4-烷基;
R8a代表:
a)氢,
b)C1-C4烷基,或
c)(C1-C4-烷基)CO-;
R9a可以相同或不同并且代表;
a)氢,
b)C1-C4-烷基。
本发明另一个实例是式Ⅰ化合物的一组,其中:R1是:
a)-CO2R4,
b)-SO2NH-杂芳基,
c)-CH2SO2NH-杂芳基,
d)-SO2NHCOR23,
e)-CH2SO2NHCOR23,
f)-CONHSO2R23,
g)-CH2CONHSO2R23,
h)-NHSO2NHCOR23,
i)-NHCONHSO2R23,
j)-SO2NHCONHR23,
其中杂芳基如上述第一次定义;
R2a和R2b分别是:
a)C1-C4-烷基,或
b)氯,
c)氢;
R3a和R3b分别是:
a)C1-C4-烷基,
b)氯,或
c)C1-C4-烷氧基,
d)氢;
E是一个单键或-S-;
R6是(a)支链或直链C1-C6烷基,C2-C6-链烯基或C2-C6-炔基,且分别为未被取代或被C1-C4-烷硫基,C1-C4-烷氧基,CF3,CF2CF3或CF2CH3所取代;
b)C3-C7-环烷基,
c)全氟代-C1-C4-烷基;
A-B-C-D-代表:
其中:
R7基团可以相同或不同并且代表:
a)氢,
b)未被取代或被-OH或-CO2R4所取代的C1-C4-烷基,
c)卤原子,
d)-OH,
e)-N(R4)2,
f)-C1-C4-烷氧基,或
g)-CO2R4,
h)芳基,
i)如上述定义的杂环基,
j)-CF3,
k)四唑-5-基;
R8基团可以相同或不同并且代表:
a)H,
b)未被取代或被-OH或-CO2R4所取代的C1-C4烷基。
这个实例中的一组是式Ⅰ中的这些化合物,其中:R1是:
a)-CO2R4
b)
c)-NHSO2CF3,
d)-SO2NH-杂芳基,
e)-CH2SO2NH-杂芳基,
f)-SO2NHCOR23,
g)-CH2SO2NHCOR23,
h)-CONHSO2R23,
i)-CH2CONHSO2R23;
E是一个单键;
A-B-C-D代表:
下述化合物作为这组的实例:
(1)2-丁基-3-(2′-羧基联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(2)3-(2′-羧基联苯-4-基)甲基-2-丙基-3H-咪唑并[4,5-b]吡啶;
(3)3-(2′-羧基联苯-4-基)甲基-2-乙基-3H-咪唑并[4,5-b]吡啶;
(4)3-(2′-羧基联苯-4-基)甲基-2-异丙基-3H-咪唑并[4,5-b]吡啶;
(5)3-(2′-羧基联苯-4-基)甲基-2-环丙基-3H-咪唑并[4,5-b]吡啶;
(6)3-(2′-羧基联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并[4,5-b]吡啶;
(7)3-(2′-羧基联苯-4-基)甲基-7-乙基-2-丙基-3H-咪唑并[4,5-b]吡啶;
(8)3-(2′-羧基联苯-4-基)甲基-2-乙基-7-甲基-3H-咪唑并[4,5-b]吡啶;
(9)3-(2′-羧基联苯-4-基)甲基-2,7-二乙基-3H-咪唑并[4,5-b]吡啶;
(10)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-丙基-3H-咪唑并[4,5-b]吡啶;
(11)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-乙基-3H-咪唑并[4,5-b]吡啶;
(12)3-(2′-羧基联苯-4-基)甲基-2-环丙基-5,7-二甲基-3H-咪唑并[4,5-b]吡啶;
(13)3-(2′-羧基联苯-4-基)甲基-5-乙基-7-甲基-2-丙基-3H-咪唑并[4,5-b]吡啶;
(14)3-(2′-羧基联苯-4-基)甲基-2,5-二乙基-7-甲基-3H-咪唑并[4,5-b]吡啶;
(15)3-(2′-羧基联苯-4-基)甲基-2-乙基-7-甲基-5-甲基氨基-3H-咪唑并[4,5-b]吡啶;
(16)5-氨基-3-(2′-羧基联苯-4-基)甲基-2-乙基-7-甲基-3H-咪唑并[4,5-b]吡啶;
(17)3-(2′-羧基联苯-4-基)甲基-2-乙基-5-甲基氨基-7-三氟甲基-3H-咪唑并[4,5-b]吡啶;
(18)3-(2′-羧基联苯-4-基)甲基-2-乙基-5-甲基-7-甲基氨基-3H-咪唑并[4,5-b]吡啶;
(19)3-(2′-羧基联苯-4-基)甲基-7-二甲基氨基-2-乙基-5-甲基-3H-咪唑并[4,5-b]吡啶;
(20)3-(2′-羧基联苯-4-基)甲基-2-乙基-5-甲基-7-苯基氨基-3H-咪唑并[4,5-b]吡啶;
(21)3-(2′-羧基联苯-4-基)甲基-2-乙基-5-甲基-7-(吗啉-4-基)-3H-咪唑并[4,5-b]吡啶;
(22)3-(2′-羧基联苯-4-基)甲基-2-乙基-7-甲基-5-(吗啉-4-基)-3H-咪唑并[4,5-b]吡啶;
(23)3-(2′-羧基联苯-4-基)甲基-2-乙基-7-甲氧基-5-甲基-3H-咪唑并[4,5-b]吡啶;
(24)3-(2′-羧基联苯-4-基)甲基-2-乙基-5-羟甲基-7-甲基-3H-咪唑并[4,5-b]吡啶;
(25)5-羧基-3-(2′-羧基联苯-4-基)甲基-2-乙基-7-甲基-3H-咪唑并[4,5-b]吡啶;
(26)5-甲酯基-3-(2′-羧基联苯-4-基)-甲基-2-乙基-7-甲基-3H-咪唑并[4,5-b]吡啶;
(27)3-(2′-羧基联苯-4-基)甲基-2-乙基-7-甲基-5-苯基-3H-咪唑并〔4,5-b〕吡啶;
(28)3-(2′-羧基联苯-4-基)甲基-5-(2-氯)-苯基-2-乙基-7-甲基-3H-咪唑并[4,5-b]吡啶;
(29)3-(2′-羧基联苯-4-基)甲基-5-(4-氯)-苯基-2-乙基-7-甲基-3H-咪唑并[4,5-b]吡啶;
(30)3-(2′-羧基联苯-4-基)甲基-2-乙基-7-甲基-5-(2-三氟甲基)苯基-3H-咪唑并[4,5-b]吡啶;
(31)6氨基-3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-乙基-3H-咪唑并[4,5-b]吡啶;
(32)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-乙基-6-乙基氨基-3H-咪唑并[4,5-b]吡啶;
(33)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-乙基-6-氟-3H-咪唑并[4,5-b]吡啶;
(34)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-(2,2,2,-三氟)乙基-3H-咪唑并[4,5-b]吡啶;
(35)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-五氟乙基-3H-咪唑并[4,5-b]吡啶;
(36)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-(3,3,3,-三氟)丙基-3H-咪唑并[4,5-b]吡啶;
(37)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-(4,4,4-三氟)丁基-3H-咪唑并[4,5-b]吡啶;
(38)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-(2,2-二氟)丙基-3H-咪唑并[4,5-b]吡啶;
(39)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-(反-2-丁烯基)-3H-咪唑并[4,5-b]吡啶;
(40)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-(反-1-丙烯基)-3H-咪唑并[4,5-b]吡啶;
(41)2-烯丙基-3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-3H-咪唑并[4,5-b]吡啶;
(42)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-(2-丙炔基)-3H-咪唑并[4,5-b]吡啶;
(43)2-(2-丁炔基)-3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-3H-咪唑并[4,5-b]吡啶;
(44)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-(4,4,4-三氟-2-丁炔基)-3H-咪唑并[4,5-b]吡啶;
(45)3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-(2,2,2,-三氟)乙氧基-3H-咪唑并[4,5-b]吡啶;
(46)2-丁基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(47)2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(48)2-乙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(49)2-异丙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(50)2-环丙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(51)2-丁基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(52)7-甲基-2-(3-甲基)丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(53)2-甲氧基甲基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(54)7-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(55)7-乙基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(56)2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(57)2,7-二乙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(58)2-丁基-5,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(59)5,7-二甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(60)5,7-二甲基-2-乙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(61)2-环丙基-5,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(62)5-乙基-7-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(63)2,5-二乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(64)2,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(65)7-甲基-2-戊基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(66)7-甲基-2-壬基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(67)2-乙基-7-甲基-5-甲基氨基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(68)5-氨基-7-甲基-2-乙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(69)5-氨基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(70)2-乙基-5-甲基氨基-7-三氟甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(71)2-乙基-5-甲基-7-甲基氨基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(72)7-二甲基氨基-2-乙基-5-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(73)2-乙基-5-甲基-7-苯基氨基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(74)2-乙基-5-甲基-7-(吗啉-4-基)-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(75)2-乙基-7-甲基-5-(吗啉-4-基)-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(76)5-氨基-2-乙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-7-三氟甲基-3H-咪唑并[4,5-b]吡啶;
(77)2-乙基-7-甲氧基-5-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(78)2-乙基-5-羟甲基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(79)5-羧基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(80)5-甲酯基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(81)2-乙基-7-甲基-5-苯基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(82)5-(2-氯)苯基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(83)5-(4-氯)苯基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(84)2-乙基-7-甲基-5-(2-三氟甲基)苯基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(85)6-氨基-5,7-二甲基-2-乙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(86)5,7-二甲基-2-乙基-6-乙基氨基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(87)5,7-二甲基-2-乙基-6-氟-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(88)5,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-2-(2,2,2,-三氟)乙基-3H-咪唑并[4,5-b]吡啶;
(89)5,7-二甲基-2-五氧乙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(90)5,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-2-(3,3,3,-三氟)丙基-3H-咪唑并[4,5-b]吡啶;
(91)5,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-2-(4,4,4,-三氟)丁基-3H-咪唑并[4,5-b]吡啶;
(92)5,7-二甲基-2-(2,2,-二氟)丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(93)5,7-二甲基-2-(反-2-丁烯基)-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(94)5,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)-2-(反-1-丙烯基)-3H-咪唑并[4,5-b]吡啶;
(95)2-烯丙基-5,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(96)5,7-二甲基-2-(2-丙炔基)-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(97)2-(2-丁炔基)-5,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)-3H-咪唑并[4,5-b]吡啶;
(98)5,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-2-(4,4,4-三氟-2-丁炔基)-3H-咪唑并[4,5-b]吡啶;
(99)5,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-2-(2,2,2-三氟乙氧基)-3H-咪唑并[4,5-b]吡啶;
(100)5,7-二甲基-2-乙基-3-(2′-(N-(苯基-磺酰基)甲酰氨基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(101)5,7-二甲基-2-乙基-3-(2′-(N-(2-溴苯基-磺酰基)甲酰氨基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(102)3-(2′-(N-(4-氯苯基磺酰基)甲酰氨基)联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并[4,5-b]吡啶;
(103)3-(2′-(N-甲基磺酰基甲酰氨基)联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并[4,5-b]吡啶;
(104)5,7-二甲基-2-乙基-3-(2′-(N-甲基磺酰基)甲酰氨基联苯-4-基)甲基-3H-咪唑并[4,5-b)吡啶;
(105)5,7-二甲基-2-乙基-3-(2′-(N-三氟甲基磺酰基)甲酰氨基联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(106)3-(2′-(N-(2-氨基乙基)磺酰基)甲酰氨基联苯-4-基)甲基-5,7-二甲基-2-乙基-3H-咪唑并[4,5-b]吡啶;
(107)5,7-二甲基-2-乙基-3-(2′-(N-吗啉-4-基)磺酰基)甲酰氨基联苯-4-基)-甲基-3H-咪唑并[4,5-b]吡啶;
(108)5,7-二甲基-(2′-(N-(N,N-二甲基氨基)磺酰基)甲酰氨基联苯-4-基)甲基-2-乙基-3H-咪唑并[4,5-b]吡啶;
(109)3-(2′-(N-环戊基磺酰基)甲酰氨基联苯-4-基)甲基-5,7-二甲基-2-乙基-3H-咪唑并[4,5-b]吡啶;
(110)5,7-二甲基-2-乙基-3-(2′-(N-嘧啶-2-基)亚磺酰氨基联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(111)5,7-二甲基-3-(2′-(N-4,6-二甲基嘧啶-2-基)亚磺酰氨基)联苯-4-基)甲基-2-乙基-3H-咪唑并[4,5-b]吡啶;
(112)5,7-二甲基-2-乙基-3-(2′-(N-(三嗪-2-基)-亚磺酰氨基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(113)5,7-二甲基-2-乙基-3-(2′-(N-(噁唑-2-基)亚磺酰氨基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(114)3-(2′-(N-乙酰基)亚磺酰氨基联苯-4-基)甲基-5,7-二甲基-2-乙基-3H-咪唑并[4,5-b]吡啶;
(115)3-(2′-(N-苯甲酰基)亚磺酰氨基联苯-4-基)-甲基-5,7-二甲基-2-乙基-3H-咪唑并[4,5-b]吡啶;
(116)5,7-二甲基-2-乙基-3-(2′-(N-(4-硝基)-苯甲酰基)亚磺酰氧基联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(117)3-(2′-(N-(4-氯)苯甲酰基)亚磺酰氨基联苯-4-基)甲基-5,7-二甲基-2-乙基-3H-咪唑并[4,5-b]吡啶;
(118)5,7-二甲基-2-乙基-3-(2′-(N-(吗啉-4-基)羰基)亚磺酰氨基联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(119)5,7-二甲基-2-乙基-3-(2′-(N-(哌嗪-1-基)羰基)亚磺酰氨基联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(120)5,7-二甲基-2-乙基-3-(2′-(N-(三氟甲基)羰基)亚磺酰氨基联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(121)3-(2′-(N-(2-羧基乙基)羰基)亚磺酰氨基联苯-4-基)甲基-5,7-二甲基-2-乙基-3H-咪唑并[4,5-b]吡啶;
(122)5,7-二甲基-3-(2′-(N-(2-2氧基乙基)-羰基)亚磺酰氨基联苯-4-基)甲基-2-乙基-3H-咪唑并[4,5-b]吡啶;
(123)5,7-二甲基-2-乙基-3-(2′-N-(苯基-磺酰基)甲酰氨基甲基)联苯-4-基)甲基-3H-咪唑并[4,5-b]吡啶;
(124)5,7-二甲基-3-(2′-N-(4,6-二甲基嘧啶-2-基)磺氨基甲基)联苯-4-基)-甲基-2-乙基-3H-咪唑并〔4,5-b〕吡啶;
(125)7-甲基-3-(2′-(N-苯基磺酰基)甲酰氨基联苯-4-基)甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶;
(126)3-(2′-((N-乙酰基)-亚磺酰氨基甲基)联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶;
(127)7-甲基-2-丙基-3-((2′-三氟甲烷亚磺酰氨基)联苯-4-基)甲基-3H-咪唑并吡啶;
(128)5,7-二甲基-2-乙基-3-((2′-三氟甲烷亚磺酰氨基)联苯-4-基)甲基-3H-咪唑并吡啶;
(129)4,7-二甲基-2-乙基-3-(2′-(四唑5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶-5-酮;
(130)2-乙基-5-羟基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶;
(131)7-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶钠盐;
(132)7-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶钾盐;
(133)5,7-二甲基-2-乙基-3-(4′-氯-2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶;
(134)5,7-二甲基-2-乙基-3-(4′-氟-2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶;
(135)5,7-二甲基-2-乙基-3-(4′-氨基-2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶;
(136)5,7-二甲基-2-乙基-3-(5′-氟-2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶;
(137)3-(2′-羧基-6′-氯联苯-4-基)甲基-5,7-二甲基-2-乙基-3H-咪唑并〔4,5-b〕吡啶;
(138)3-(2′-羧基-3′-氟联苯-4-基)甲基-2-乙基-7-甲基-3H-咪唑并〔4,5-b〕吡啶;
(139)5,7-二甲基-2-乙基-3-(4′-硝基-2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶;
(140)5,7-二甲基-2-乙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶钠盐;
(141)5,7-二甲基-2-乙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶钾盐;
(142)9-(2′-羧基联苯-4-基)甲基-6-氯-8-丙基嘌呤;
(143)9-(2′-羧基联苯-4-基)甲基-6-甲基-8-丙基嘌呤;
(144)9-(2′-羧基联苯-4-基)甲基-6-甲基-8-乙基嘌呤;
(145)9-(2′-羧基联苯-4-基)甲基-4,6-二甲基-8-丙基嘌呤;
(146)9-(2′-羧基联苯-4-基)甲基-4,6-二甲基-8-乙基嘌呤;
(147)9-(2′-羧基联苯-4-基)甲基-4-二甲基氨基-6-甲基-8-乙基嘌呤;
(148)9-(2′-羧基联苯-4-基)甲基-4-甲基氨基-6-甲基-8-乙基嘌呤;
(149)9-(2′-羧基联苯-4-基)甲基-4-(吗啉-4-基)-6-甲基-8-乙基嘌呤;
(150)9-(2′-羧基联苯-4-基)甲基-4-乙基氨基-6-甲基-8-乙基嘌呤;
(151)9-(2′-羧基联苯-4-基)甲基-4-丙基氨基-6-甲基-8-乙基嘌呤;
(152)9-(2′-羧基联苯-4-基)甲基-4-甲基氨基-6-三氟甲基-8-乙基嘌呤;
(153)9-(2′-羧基联苯-4-基)甲基-4,6-二甲基-8-(2,2,2,-三氟)乙基嘌呤;
(154)9-(2′-羧基联苯-4-基)甲基-4,6-二甲基-8-(3,3,3-三氟)丙基嘌呤;
(155)9-(2′-羧基联苯-4-基)甲基-4,6-二甲基-8-(2,2-二氟)丙基嘌呤;
(156)8-丁基-9-(2′-羧基联苯-4-基)甲基-6-氯嘌呤;
(157)8-丁基-9-(2′-羧基联苯-4-基)甲基-6-羟基嘌呤;
(158)4-羧基-9-(2′-羧基联苯-4-基)-甲基-6-甲基-8-乙基嘌呤;
(159)4-甲酯基-9-(2′-羧基联苯-4-基)-甲基-6-甲基-8-乙基嘌呤;
(160)9-(2′-羧基联苯-4-基)甲基-8-乙基-4-羟甲基-6-甲基嘌呤;
(161)6-氯-8-丙基-9-(2′-(四唑-5基)联苯-4-基)甲基嘌呤;
(162)6-甲基-8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(163)8-乙基-6-甲基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(164)4,6-二甲基-8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(165)4,6-二甲基-8-乙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(166)6-甲基-2-甲基氨基-8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(167)4-二甲基氨基-8-乙基-6-甲基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(168)8-乙基-6-甲基-4-甲基氨基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(169)8-乙基-6-甲基-4-(吗啉-4-基)-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(170)8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(171)8-丁基-6-氯-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(172)8-丁基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(173)2-氯-6-甲基-8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(174)6-甲基-2-(吗啉-4-基)-8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(175)8-乙基-4-乙基氨基-6-甲基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(176)8-乙基-6-甲基-4-丙基氨基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(177)8-乙基-4-甲基氨基-6-三氟甲基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(178)4,6-二甲基-8-(2,2,2-三氟)乙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(179)4,6-二甲基-8-(3,3,3-三氟)丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(180)8-(2,2-二氟)丙基-4,6-二甲基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(181)4-羧基-8-乙基-6-甲基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(182)4-甲酯基-8-乙基-6-甲基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;
(183)8-乙基-4-羧甲基-6-甲基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤;和
(184)8-丁基-1,3-二甲基-7-(2′-(四唑-5-基)联苯-4-基)甲基-1,2,3,6-四氢-2,6-二氧嘌呤。
式Ⅰ化合物可以用下面所描述的反应和技术进行合成。反应在适合于所用试剂和材料的溶剂中进行并且适合于有效的转换。对于在有机合成方面的专业人员来说这一点是可以理解的,即在杂环上和所用反应中的官能度应该符合所进行的化学转移。根据所采用的反应和技术,最佳产率可通过改变合成步骤的顺序或使用保护基然后除去。
在反应过程中所用的缩写
试剂
NBS N-溴琥珀酰亚胺
AIBN 偶氮(双)异丁腈
DDO 二氯氰醌
Ac2O 乙酐
TEA 三乙胺
DMAP 4-二甲基氨基吡啶
PPh3三苯基膦
TFA 三氟乙酸
TMS-Cl 三甲基氯硅烷
Im 咪唑
AcSK 硫代乙酸钾
p-TsOH P-甲苯磺酸
溶剂
Et2O 乙醚
DMF 二甲基甲酰胺
HoAc(AcOH) 乙酸
EtoAc(EtAc) 乙酸乙酯
Hex 己烷
THF 四氢呋喃
DMSO 二甲亚砜
MeOH 甲醇
iPrOH 异丙醇
DBU 1.8-二氮杂双环-〔5.4.0〕
十一碳-7-烯
Me3SnCl 三甲基氯化锡
其它
rt 室温
TBDMS t-丁基二甲基硅烷
OTf OSO2CF3
OTs OSO2-(4-甲基)苯基
OMs OSO2CH3
Ph 苯基
FAB-MS(FABMS) 快原子轰击质谱
NOE 核极化效应
SiO2硅胶
trityl 三苯基甲基
如图1所示,式Ⅰ化合物可以通过直接进行杂环(1)(杂环的制备在反应图3-6中说明)的碱金属盐的烷基取代反应来制备,使用适当受保护的卤化苄基、甲苯磺酸盐(OTs)或甲磺酰盐(OMs)衍生物(2)。该盐的制备最好是在无水二甲基甲酰胺(DMF)中用MH(其中M是锂,钠或钾),或用金属醇盐如甲醇、乙醇或叔丁醇的钠盐或钾盐,在适当的醇如甲醇、乙醇或叔丁醇溶剂中处理。该烷基取代反应一般通过将杂环金属盐溶解在双极非质子传递溶剂如DMF或二甲亚砜(DMSO)中,并且将其在20℃至溶剂回流温度与烷基化试剂反应1-24小时。
反应程序1
这里Q=卤素(I,Br,Cl),-O-甲苯磺酰基,-O-甲磺酰基。
如果取代基和/或六元环中杂原子的位置不是对称存在,那么咪唑氮的烷基化通常产生N1和N3烷基化的两种区域异构体(regioisomers)的混合产物。该同分异构体Ⅰ和Ⅰa具有不同的物化和生物学性质并在大多数情况下可用常规的分离技术如层析法(快速层析,中压液相层析,高效液相层析)和/或结晶法分离和纯化。对用常规方法分离同分异构体困难的情况,可将混合物转化成适当的用上述分离方法能够分离的衍生物。可用核极化效应(NOE),1H-13C联合NMR实验或X-射线结晶学进行异构体结构确定。
当六员杂环中有可烷基化的基团时,可用适当的保护基保护。
取代的苄基卤(2)及其它更好的烷基化试剂(反应程序2中8a,8b和8c)可按欧洲专利申请253,310和291,969及其中引述的参考文献中所述方法制备。此外用Ni(O)和Pd(O)催化的交叉偶合反应[E.Negishi,T.Takahashi,和A.O.King,有机合成,66,67(1987)]制备二苯基前体7a,7b的优选方法列于反应程序2。如反应程序2所示,4-溴甲苯(3)与t-BuLi反应,再加入ZnCl2溶液产生有机锌化合物(5)。化合物(5)再在Ni(PPh3)Cl2催化剂存在下与6a或6b偶合生成所需要的联苯基化合物7a或7b。同样,1-溴-2-硝基苯(6c)在Pd(PPh3)4催化剂[由Cl2Pd(PPh3)2与(i-Bu)2AlH(2倍量)反应制得]存在下与有机锌化合物5偶合得到联苯基化合物7c。这些前体化合物7a,7b和7c再按照欧洲专利申请253,310和291,969所描述的方法分别转化为卤甲基联苯基衍生物8a,8b和8c。
当第二个苯环上有另一个取代基(R2不是氢)时,优选的用Pd(O)催化的交叉偶合反应[J.K.Stille,Angew.Chem.Int.Ed.Engl.,25,508(1986)]制备联苯基前体化合物7d和7e的方法列于反应程序2a。如反应程序2a所示,对-三甲基锡基甲苯(5a)在回流甲苯中,在5mole% Pd(PPh3)4存在下与6d或6e偶合生成所需的联苯基化合物7d和7e。表1说明了这个反应程序在合成上的应用。化合物7d(R2=NO2)和7e(R2=NO2)可通过催化氢化,重氮化及与氯化铜(Ⅰ)反应分别转化为它们的氯化物。联苯基氟化物不能由直接偶合到氟芳基溴化物上,可由7d(R2=NO2)和7e(R2=NO2)通过还原,形成四氟硼酸重氮盐再经分解制备。这些前体化合物7d(R2=NO2或F或Cl)和7e(R2=NO2或F或Cl)再按欧洲专利申请253,310和292,969所述方法分别转化成卤甲基联苯衍生物8d和8e。
类型(1)的杂环可由文献[J.A.Montgomery和J.A.Secrist Ⅲ,“Comprehensive Heterocyclic Chemistry,”Vol.5,A.R.Katritsky和C.W.Rees Eds.,Pergamon Press 1984;pp567-597和631-656和它引用的参考文献]所描述的任一标准方法制备,如反应程序3所示,最广泛应用的起始原料是六员杂环连二胺(9)。稠合的咪唑(10)可通过(9)与一种合适的羧酸,腈,咪唑酸酯或原酸酯缩合制备,该反应可在一种适当的与起始原料及试剂相溶的溶剂中进行,如多磷酸,乙醇,甲醇,烃类,也可不用溶剂。如果需要,再加入催化量的酸。用氧化剂如Cu(Ⅱ),硝基苯或2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)氧化由二胺(9)与一适当醛反应生成的亚胺也可制得杂环化合物(10)。氨基酰胺(11,W=H)或二酰胺(11,W=R6CO)可通过加热或在一种溶剂如二甲苯中在酸性或中性条件下加热转化为稠合的咪唑(10)。
如反应程序4所示,类型(12和13)的杂环可通过二胺(9)与试剂如尿素,光气,氰酸钾,氯代甲酸烷基酯,碳酸二烷基酯或二硫化碳在碱如氢氧化钾或碳酯钾存在下反应制得。氨基酸(14)或(15)可通过适当衍生物如酰基叠氮化物,羟基酰胺或N-卤代酰胺的Curtius或Hoffman重排转化为(13),类型16,(E=硫或氧)的二环化合物可由12在中性或碱性条件下与卤代烷,甲磺酸烷基酯,甲苯磺酸烷基酯,三烷基氧鎓盐或与一适当的重氮烷反应制得。类型16:(E=氧或硫)化合物可通过醇盐或烷基硫醇盐与氯代中间体的置换反应制得。
类型9的二胺可用许多方法制得,如二酰胺或氨基酰胺的水解,二硝基、氨基硝基、肼基或叠氮基的还原,杂芳基的卤素、烷氧基、硫、烷硫基、羟基或烷基磺酰基被氨或胺取代或者酰基叠氮化物、酰胺或酸的重排(Curtius,Hofman或Schmidt重排)。[A.S.Tomcufcik,L.N.Starker in“Heterocyclic Compounds,Pyridine and it′s Derivatives”Pt 3,E.Klingsberg Ed.,Wiley Interscience,1962,pp 59-62,及其参考文献;T.Nakagome in“Heterocyclic Compounds,Pyridazines”Vol.28,R.N.Castle,Ed.,Wiley Interseience,1973,pp597-601,及其引用的参考文献;“Heterocyclic Compounds,The Pyrimidines”Vol.16,D.J.Brown Ed.,Wiley Interscience 1985,pp299-325;E.Schipper和A.R.Day J.Am.Chem.Soc.(1952)74,350;“Comprehensive Heterocyclic Chemistry,”Vol.5,A.R.Katritsky和C.W.Rees Eds.,Pergamon Press 1984;pp567-597和631-656及其引用的参考文献]。
当类型10或16的杂环不易由其相应的二胺化合物制得,或这些二胺化合物不易制得时,可采用另一途径,该途径是将六员杂环与一适当取代咪唑稠合。这两条反应途径在反应程序5中加以说明。例如,咪唑并[4,5-d][1,2,3]三嗪(18)优先选用氨基酰氨基咪唑(17)与亚硝酸钠在酸水溶液中反应来制备。前体化合物咪唑(17)可通过降解一适当取代黄嘌呤制得,或者用一适当的咪唑酸酯与氨基氰基乙酰胺缩合制得。咪唑并〔4,5-b〕哒嗪(20)可由咪唑二羧酸酯(19)与肼反应制得。氧化(20)得到哒嗪二酮(21)。(20)或(21)中的氧可转化为其它功能团如卤素或硫酮,它们本身可做为合成更复杂系统的前体化合物[“Comprehensive Heterocyclic chemistry,”Vol.5,A.R.Katritsky和C.W.Rees Eds.,Pergamon Press 1984;pp567-597和631-656及其引用的参考文献]。
W=H或R6CO
α:不同的试剂和反应条件:
R6C≡N,PPA
R6C(OCH3)3,甲苯,H+,△
R6CHO,C2H5OH,Cu(OCOCH3)2。
此外,如反应程序6所示,氨基咪唑酯和酰胺是制备嘌呤的通用的中间体。这个程序也说明在烷基化试剂2与一合适的取代咪唑反应形成22或24之后6-员杂环的合成。
杂环的还原形式可通过催化还原制备,或者由一合适的咪唑前体合成。例如,组氨酸及其衍生物与甲醛反应得到部分饱和的咪唑并(4,5-c)吡啶[参看Neuberger,A.Biochem.J.,(1944),38,309]。
R1是-CONHSO2R23(其中R23=烷基,芳基或杂芳基)的通式Ⅰ化合物可由相应的羧酸衍生物(Ⅰ)按程序7制得。羧酸(Ⅰ)可按程序1所述方法制得,它可与回流的亚硫酰氯或更好地与草酰氯及催化量的二甲基甲酰胺在低温下反应转化成其相应的酰氯[A.W.Burgstahler,L.O.Weigel,和C.G.Shaefer-Synthesis,767,(1976)]。酰氯再与R23SO2NH2的碱金属盐反应制得所需要的酰基磺酰胺26。或者,这些酰基磺酰胺也可由羧酸用N,N-二苯基氨基甲酸酐中间体制得[F.J.Brown等-European Patent Application,Ep 199543;K.L.Shepard和W.Halczenko-J.Het.Chem.,16,321(1979)]。优选羧酸化合物转化成酰基咪唑中间体,它进一步与一适当的芳基或烷基氨磺酰胺和二氮杂二环十一烷(DBU)反应得到所需要的酰基磺酰胺26[J.T.Drummond和G.Johnson-Tetra.Lett.,29,1653(1988)]。
程序7
*另一种方法:
a)(ⅰ)SOCl2,回流
(ⅱ)R23SO2NH-M+(其中M是Na或Li)
b)(ⅰ)(COCl)2-DMF,-20℃
(ⅱ)R23SO2NH-M+
c)(ⅰ)N(N,N-二苯基氨基甲酰基)吡啶鎓
氯化物/NaOH水溶液
(ⅱ)R23SO2NH-M+。
R1是-SO2NHCOR23的通式Ⅰ的化合物可按程序8所示制备。硝基化合物7c(按程序2所示制备)可被还原为相应的氨基化合物并转化成芳香重氮氯化物,它进一步与二氧化硫在铜(Ⅱ)盐存在下形成相应的芳基磺酰氯27[H.Meerwein,G.Dittmer,R.Gollner,K.Hafner,F.Mensch和O.Steifort-chem.Ber.,90,841(1957);A.J.Prinsen和H.Cerfontain,Recueil,84,24(1965);E.E.Gilbert,Synthesis,3(1969)及其引用的参考文献]。磺酰氯可和氨在水溶液或惰性有机溶剂中反应[F.H.Bergheim和W.Baker,J.Amer.Chem.Soc.,66,(1944),1459],或与碳酸铵干粉反应[E.H.Huntress和J.S.Autenrieth,J.Amer.Chem.Soc.,63,(1941),3446;E.H.Huntress和F.H.Carten,J.Amer.Chem.Soc.,62,(1940),511]形成磺酰胺28。苄基溴30可由程序8指出的那样由磺酰胺28制得,它再进一步与一适当的杂环化合物的碱金属盐反应制得关键的磺酰胺31。磺酰胺31也可由芳基磺酰氯36制得,芳香磺酰氯可用程序9所示方法由芳基胺35制得。用适当的酰氯(或酰基咪唑或其它酰化剂)酰化31可以得到所需要的酰基磺酰胺32。
a.ⅰ)H2/pd-c,ⅱ)NaNO2-HCl,ⅲ)SO2,AcOH,CuCl2
b.NH3或(NH4)2CO3
c.(C6H5)3CCl,Et3N,CH2Cl2,25℃.
d.N-溴代琥珀酰亚胺
e.R23COCl或R23CO-Im或其它酰化剂。
R1是-SO2NHR23(其中R23是杂芳基)的化合物可由芳基磺酰氯36如程序9所示与杂芳胺反应制得,磺酰氯36是合成这组化合物的优选中间体,芳香磺酰氯也可由芳香磺酸钠盐与PCl5或POCl3反应制得[C.M.Suter,The Organic Chemistry of Sulfur,John Wiley & Sons,459,(1944)]。芳香磺酸前体可通过芳香环与氯磺酸的氯磺化反应制得[E.H.Huntress和F.H.Carten,J.Amer.Chem.Soc.,62,511(1940)]。
a.ⅰ)t-BuLi/乙醚,-78℃ ⅱ)Me3SnCl
b.ⅰ)NaNO2/HCl ⅱ)SO2,CuCl2
C.Pd(PPh3)4,甲苯或(PPh3)2PdCl2,DMF,90℃
a.t-BuMe2Si-Cl/咪唑,DMF
b.t-BuLi,-78℃,Me3SnCl
C.四丁基铵氟化物
d.CBr4/Ph3P。
a.ⅰ)EtOCOCl/Et3N,THF,0℃ ⅱ),NaBH4ⅲ)CCl4或CBr4/PPh3
b.AcSK
c.SO2Cl2
d.Cl2,AcOH,H2O或,ⅰ)SO2Cl2ⅱ)氧化
二芳基磺酰胺28a和29可选择地由适当的芳基有机锡前体通过钯(O)催化交叉偶合制得[J.K.Stille,Pure Appl.Chem.,57,1771(1985);T.R.Baiely,Tetra Lett.,27,4407(1986);D.A.Widdowson和Y.Z.Zhang,Tetrahedron,42,2111(1986)],如程序10所示。有机锡化合物39[S.M.Moerlein,J.Organometallic Chem.,319,29(1987)],可由芳香前体化合物38制得,它可在Pd(PPh3)4或(PPh3)2PdCl2催化下与芳香磺酰胺41和42偶合分别得到二芳香基磺酰胺28a和29。同样,苄基溴化物30可选择地在Pd(O)催化下由适当的有机锡前体化合物45通过交叉偶合反应制得,如程序11所示。
R1是-CH2SO2NHCOR23和-CH2SO2NHR23的化合物可如程序12所示方法制备。关键性的前体化合物芳基甲磺酰氯52可由芳基甲基氯化镁(51)(由相应的苄基氯(48)制得)与硫酰氯反应制得[S.N.Bhattacharya,C.Eaborn和D.P.M.Walton,J.Chem.Soc.C,1265(1968)],也可由芳甲基硫代乙酸酯(50)(由苄基溴化物49制得)与氯气在痕量水存在下经氧化制得[Bagnay和Dransch,chem.Ber.,93,784(1960)]。此外,芳基甲基硫代乙酸酯(50)可以在乙酸酐存在下被硫酰氯氧化成芳基甲基亚磺酰氯[S.Thea和G.Cevasco,Tetra.Lett.,28,5193(1987)],它可进一步被适当的氧化剂氧化成磺酰氯52。磺酰氯52与适当的胺反应得到化合物53和54。
R1是-NHSO2NHR23的化合物可通过适当的一级胺与硫酰胺56反应制得[S.D.McDermott和W.J.Spillane,synthesis,192(1983)],如程序13所示。化合物56可由用无水三氟乙酸处理后的N-叔-丁基硫酰胺55制得[J.d.Catt和W.L.Matier,J.Org.Chem.,39,566(1974)],而55可由芳香胺35与叔丁基氨磺酰氯反应制得[W.L.Matier,W.T.Comer和D.Deitchman,J.Med.chem.,15,538(1972)]。
R1是-NHSO2CF3的通式Ⅰ阻断剂可用程序9和14提供方法制备。7c(由程序2所述方法制得)被N-溴代琥珀酰亚胺溴化得到4-溴甲基-2′-硝基联苯(33)。这个溴化物被用于在无水DMF中烷基化适当的杂环化合物的钠盐得到34。34用Pd/C催化剂催化还原得到相应的氨基衍生物35,它再用三氟甲基磺酸酐处理得到磺酰胺58。
R1=-cH2SO2NHCOR23的通式Ⅰ阻断剂可按程序15提供方法制得。用叔丁基锂再用氯化锌处理2-溴甲苯(59),再在双(三苯基磷)镍(Ⅱ)氯化物催化下偶合所得金属锌化合物和4-溴苯甲酸甲酯(60),用N-溴代琥珀酰亚胺溴化所得联苯(61),得到溴化物62。用硫脲处理溴化物得到盐63,它再用氯气处理得到磺酰氯64。用叔丁基胺处理64得到磺酰胺65,它再用氢化铝锂处理转化为醇66。用甲磺酰氯处理66得到磺酰酯,再将其在丙酮中用碘化钠处理得到相应的碘化物67。用碘化物67烷基化适当的杂环化合物钠盐得到磺酰胺68。用三氟乙酸处理68得到磺酰胺类似物69,它再进一步用乙酸酐和吡啶处理得到所需要的酰基磺酰胺70。
咪唑并〔4,5-b〕吡啶环上6-位的卤化可用Br2或N-溴代琥珀酰亚胺完成。7位上的卤化可通过相应的咪唑并吡啶-4-氧化物(咪唑并吡啶与过酸如m-氯代过苯甲酸反应制得)与POCl3反应完成。当7位上不是氢时,可用POCl3处理使4(N)-氧化物前体在5位上卤化。氯化物可在溶剂如HOAc中用HBr或HI处理分别转化为溴化物或碘化物。
用亲核试剂如氰化物,胺,烷氧基铜,三烷基亚磷酸盐和硫醇盐取代相应位置的卤素可使2-烷基-咪唑并〔4,5-b〕吡啶的5,6或7位被取代。卤素尤其是溴或碘的取代也可通过与一偶合物如烷基锡卤化物,芳基锡卤化物或单烷基芳基亚磷酸盐在一合适的金属催化剂如镍,钯,钌或铂存在下反应得到。对于那些由于酸性质子而显示钝性或复杂的反应,可用苄基或其它的芳基甲基保护咪唑并吡啶的1,3或4位。
在芳基和杂环的环上可进行官能团的转化以得到所需要的类似物,这种转化对本领域技术的人员是清楚的。例如,酯与胺在加热下可转化为酰胺并且杂环中的酰胺氮(假如有的话)可在矸如氢化钠存在下在DMF中用一适当的烷基卤烷基化。贯穿这些合成的官能基的保护应选择以适应随后的反应条件。最后这些保护基都要被除去以产生所需要的最佳活性的通式Ⅰ化合物。例如,羧基R1通常以其叔丁基酯加以保护,该酯在最后一步用三氟乙酸处理除去。用乙酸水溶液在室温下过夜是除去三苯甲基保护基以释放R1为四唑基的优选方法。
本发明化合物可与各种无机和有机酸及碱形成盐,这也属于本发明的范围。这些盐包括铵盐,碱金属盐如钠盐,钾盐,碱土金属盐如钙盐和镁盐;与有机碱形成的盐如二环己基胺盐,N-甲基-D葡萄糖胺盐,与氨基酸如精氨酸赖氨酸形成的盐等。有机和无机酸盐也能制得,如HCl,HBr,H2SO4,H3PO4,甲磺酸,甲苯磺酸,马来酸,富马酸,樟脑磺酸盐。优先选用无毒的生理上可接受的盐,虽然例如在分离和纯化产品时其它盐也是有用的。
盐可用常规方法制成,如产物的游离酸或游离碱与等量或过量的适当碱或酸在一种该盐不溶的溶剂或介质中反应制得,或者以水作溶剂,其后在真空下将其除去,或者进行冷冻干燥,或者在一种适当的离子交换树脂上,将现有的盐的阳离子交换成另一种阳离子。
血管紧张肽Ⅱ(AⅡ)是一种有效的动脉血管收缩药,它通过与位于细胞膜上的特殊受体相互作用而发挥作用。本发明所述的化合物作为AⅡ在受体上的竞争性拮抗剂。为了鉴定AⅡ拮抗剂并确定它们的体外效能,建立下列两种配位体-受体结合试验。
用兔主动脉膜制备液进行受体结合试验
三个冷冻的兔主动脉(从Pel-Freeze Biologicals得到)悬浮于5mM Tris-0.25M蔗糖的pH7.4的缓冲液中(50ml),搅匀,然后离心。混合物用干酪包布过滤且将上清液在4℃下以20,000rpm离心30分钟。得到的沉降物重新悬浮于30ml含0.2%牛血清清旦白和0.2mg/ml Bacitration的50mM Tris-5mM MgCl2缓冲液中,悬浮液可用于100个分析管。用于筛选的试样制成一式两份。往膜制备液中(0.25ml)加入含或不含试验样品的125I-Sar1Ile8-血管紧张肽Ⅱ(从New England Nuclear得到)(10μl,20,000cpm),混合物在37℃下培养90分钟,然后用冰冷却的pH7.4的50mM Tris-0.9%NaCl(4ml)稀释,并用一玻璃纤维漏斗过漏(GF/B Whatman,直径2.4″),将滤器浸在闪烁液(10ml)中,并用Packard 2660 Tricarb液体闪烁计数器测定其放射性。提供了有效的AⅡ拮抗剂的抑制浓度(IC50)(能将所有特殊结合的125I-Sar1Ile8血管紧张肽Ⅱ置换50%),并以此衡量AⅡ的拮抗剂的效力。
用牛肾上腺皮质制备液进行受体试验
选用牛肾上腺皮质作为AⅡ受体源。称重的组织(100个分析管需0.1g)悬浮于Tris-HCl(50mM),P7.7的缓冲液中并搅匀。均匀物在20,000rpm下离心15分钟,弃去上清液且将沉降物重新悬浮于缓冲液[Na2HPO4(10mM)-NaCl(120mM)-EDTA二钠(5mM),其中含苯基甲烷磺酰氟(PMSF)(0.1mM)]中。(为了筛选化合物,通常采用平行的两个试验管进行试验)。住膜制备液(0.5ml)中加入含或不含试验样品的3H-血管紧张肽Ⅱ(50mM)(10μl)。混合物在37℃下培养1小时,混合物再用Tris缓冲液(4ml)稀释并用一玻璃纤维滤器(GF/B,whatman,直径2.4″)过滤,将滤器浸在闪烁液(10ml)中,用Packard 2660 Triscarb液体闪烁计数器测定放射性。提供了有效的AⅡ拮抗剂的抑制浓度(IC50)(能将全部特殊结合物的3H-血管紧张肽Ⅱ置换50%),并以此衡量这种AⅡ拮抗剂的效力。
本发明所述的化合物的抗高血压作用用下述方法说明。
雄性Charles River sprague-Dawley鼠(300-375g)用甲己炔巴比妥(Brevital;50mg/kg,腹腔注射)麻醉并用PE205管作气管插入。将一不锈钢质骨髓棒(1.5mm粗,150mm长)插入右眼窝并深入脊柱,立即将大鼠置于一个Harvard Rodent通风器中(速度为每分钟打击60次,体积为每100克体重1.1cc)。结扎右颈动脉,切断左右迷走神经,用PE50管做右颈动脉插管以给药。用静热力控制的加热垫(它接受来自直肠温度电极的输入)使体温保持37℃。注射阿托品(1mg/kg,静脉注射),15分钟后注射心得安(1mg/kg,静脉注射)30分钟后每隔30分钟静脉注射一次血管紧张肽Ⅱ或其它激动剂并在药物或媒介物注射前后记录舒张血压的增加。
用上述方法,可评价本发明的有代表性的化合物并发现显示的活性至少是IC50<50μM,由此说明并确定了本发明化合物作为有效的AⅡ拮抗剂的应用价值。
本发明化合物对治疗高血压是有用的。它们在治疗急性或慢性充血性心力衰竭方面也很有价值。它们可望在治疗二期醛甾酮过多症,一期和二期肺醛甾酮过多症,一期和二期肺高血压,肾衰如糖脲病性肾病,肾小球性肾炎,硬皮病,血管小球硬化,一期肾病旦白脲,末期肾病,肾移植治疗及类似疾病,肾血管高血压,左室机能障碍,糖尿病性视网膜病及在治疗血管紊乱如偏头痛,Raynaud氏病,鲁米那高破坏症(luminal hyperclasia)和减小粥样硬化过程等方面是有用的。本发明化合物用于治疗上述及类似的紊乱方面的疾病对本领域技术人员来说是明显的。
本发明化合物也可用于治疗高眼内压并能提高视网膜血液流动并可根据治疗的需要给病人以典型的药学剂型用药,如片剂,胶囊,注射剂等以及用于局部眼内使用的剂型如溶液,膏剂,嵌入形式,凝胶等。用于治疗眼内压的药物剂型一般含重量约0.1%到15%,尤其是0.5%到2%重量的本发明化合物。
在治疗高血压及上述临床疾病时,可用本发明化合物的组合物,如用于口服给药的片剂,胶囊或酏剂;用于肠道给药的栓剂,腹腔或肌肉给药的无菌溶液或悬浮液等,应根据治疗的需要给患者(动物或人)服用能达到最佳药效剂量的本发明的化合物。虽然由于病因,病的严重程度,病人的体重,服药后患者特殊的饮食,同时服用的药物及其它本领域技术人员所知的因素,不同病人之间服药的剂量不同,但剂量范围通常约为每人每天1到1000mg,单独或复合给药。优选的剂量范围约为每人每天2.5到250mg;更为优选的是约每人每天5到150mg。
本发明化合物可与其它抗高血压剂和/或利尿剂和/或血管紧张肽素转化酶抑制剂和/或钙通道阻断剂联合使用。例如,本发明化合物可与如下的化合物联合服用:氨氯吡脒,氨酰心安,苄氟噻嗪,氯噻酮,氯噻嗪,氯压定,醋酸绿藜安和绿藜安鞣酸盐,去甲蛇根碱,氯甲苯噻嗪,硫酸胍乙啶,盐酸肼苯哒嗪,双氢氯噻嗪,甲苯喹唑酮,甲氧乙心安酒石酸盐,甲基氯噻嗪,甲基多巴,盐酸甲基多巴,长压定,盐酸优降宁,多噻嗪,哌唑嗪,萘心安,蛇根萝芙木,利血胺,利血平,硝普钠,安体舒通,噻吗心安马来酸盐,三氯噻嗪,咪噻芬,苄噻嗪,喹乙唑酮,氯噻苯氧酸,三氨喋呤,乙酰唑胺,氨茶矸,环噻嗪,利尿酸,速尿,汞乙氧茶矸普鲁卡因,利尿酸钠,巯甲丙脯酸,delapril hydrochloride,enalapril,enalaprilat,fosinopril sodium,lisinopril,pentopril,quinapril.hydrochloride ramapril,壬肽抗压素,zofenopril calcium,二氟苯水扬酸,硫氮 酮,非洛地平,硝吡胺甲酯,硝苯吡啶,硝基吡双酯,硝苯吡酯,硝吡丁甲酯,硝吡乙甲酯及它们的混合和联合使用。
一般来说,对于联合用药当它们做为统一体单独给药时,每个人日服剂量的范围可以从最小临床用量的五分之一到最大剂量。
为了进一步说明这种联合用药,临床有效的每天2.5-250毫克范围的本发明血管紧张肽Ⅱ拮抗剂中的一个化合物可有效地在每天0.5-250毫克范围内与下列化合物在每天指定的剂量范围内结合:双氢氯噻嗪(15-200mg),氯噻嗪(125-2000mg),利尿酸(15-200mg),氨氯吡脒(5-20mg),速尿(5-80mg),萘心安(20-480mg),噻吗心安马来酸盐(5-60mg),甲基多巴(65-2000mg),非洛地平(5-60mg),硝基吡啶(5-60mg)和硝吡乙甲酯(5-60mg)。另外,双氢氯噻嗪(15-200mg)加氨氯吡脒(5-20mg)加本发明的血管紧张肽Ⅱ拮抗剂(3-200mg);或双氢氯噻嗪(15-200mg)加噻吗心安马来酸盐(5-60mg)加一种本发明血管紧张肽Ⅱ拮抗剂(0.5-250mg);或双氢氯噻嗪(15-200mg)与硝基吡啶(5-60mg)加一种本发明的血管紧张肽Ⅱ拮抗剂(0.5-250mg),以上所述的三种药的联合可有效地控制高血压患者的血压。自然,这些剂量范围可作为一个整体进行调节,根据需要允许将日服剂量分成几份,如上所述,剂量可根据疾病的病因和严重程度,病人体重,特殊饮食和其它因素变化。
典型地,这些联合给药方式可配制成如下讨论的药物组合物。
约1到100mg的式Ⅰ化合物或式Ⅰ化合物的混合物或生理上可接受的盐与一生理上可接受的媒介物,载体,赋形剂,粘合剂,防腐剂,稳定剂,调味剂等用所述的可接受的药学上的方法做成一个单位剂型。这些组合物或制剂中的活性物质的量以在指定范围内的合适剂量为宜。
能在片剂,胶囊等中结合的佐剂说明如下:粘合剂如黄蓍树胶,阿拉伯胶,玉米淀粉或明胶,赋形剂如微晶纤维素;崩解剂如玉米淀粉,予成胶淀粉,藻酸等;润滑剂如硬脂酸镁;甜化剂如蔗糖,乳糖或糖精;调味剂如薄荷,冬青油或樱桃油。当单剂量剂型是胶囊时,它除了上述类型物质外还含有一种液体载体如脂肪油。各种其它材料也可作为外皮或用于限定剂量单元的物理形状。如片剂可用虫胶,糖或二者同时包裹。糖浆或酏剂可含有活性化合物,作为加甜剂的蔗糖,作为防腐剂的甲基和丙基对羟基苯甲酸酯,一种染料和调味剂如樱桃或桔子汁。
用于注射的无菌组合物可按常规的药学方法通过将活性物质溶解或悬浮于媒介物如注射用水,天然植物油如芝麻油,椰子油,花生油,棉籽油等或合成的脂肪媒介如油酸乙酯等中形成。可根据需要加入缓冲剂,防腐剂抗氧化剂等。
下列实施例进一步说明了通式Ⅰ化合物及其药物组合物的制备方法,但并不能认为在其后的权利要求书所述的本发明仅限于这些实施例。
实施例1
2-叔丁氧羰基-4′-溴甲基-联苯的制备
步骤1:2-叔丁氧羰基-4′-甲基联苯
在-78℃下,用滴液漏斗将戊烷中的t-BuLi(1.7M)(210ml)慢慢加入到对一溴甲苯(30g)的干乙醚(150ml)溶液中,约加1.5小时。移去冷浴再在室温下继续搅拌混合物2小时。将反应瓶内容物再慢慢在室温下加入(用一套管)一种事先混合好的ZnCl2的乙醚(180ml)和THF(360ml)溶液(1M)中。混合物在该温度下搅拌2小时并将所得浆状物加入到(用一套管)2-叔丁氧羰基碘苯(35.6g)和NiCl2(Ph3P)2(2.1g)的干THF(360ml)溶注但。在室温下搅拌过夜后(18小时),将混合物在搅拌下慢慢倾入冰冷却的0.5NHCl(1500ml)中。分离出有机层,水溶液相用乙醚(3×300ml)萃取。合并有机层并用水,盐水洗涤随后用MgSO4干燥。除去溶剂得到油状粗品(32g)。在硅胶柱上快速层析纯化,用乙酸乙酯/己烷(1∶12)洗脱得到油状标题化合物(24g,76%)。NMR(CDCl3)δ1.24(s,9H),2.42(s,3H),7.2-7.8(m,8H);FAB-MS:m/e 269(M+H)。
步骤2:2-叔丁氧羰基-4′-溴甲基联苯
标题化合物可由2-叔丁氧羰基-4′-甲基联苯(从步骤1得到)按照欧洲专利申请EP0,253,310所述的方法制得。
实施例2
N-三苯甲基-5-(4′-溴甲基-联苯-2-基)四唑的制备
步骤1:2-氰基-4′-甲基联苯
在-78℃下,用滴液漏斗将t-BuLi的戊烷溶液(1.7M)(210ml)在1.5小时内慢慢加入到对-溴甲苯(30g)的干乙醚溶液(150ml)中。移去冷浴并将混合物在室温下继续搅拌2小时。在室温下将烧瓶内容物慢慢加入到(用一套管)事先混合好的ZnCl2的乙醚(180ml)和干THF(360ml)的溶液(1M)中。混合物在室温下搅拌2小时,将所得浆状物加入到(用一套管)2-溴苄腈(21.3g)和NiCl2(Ph3P)2(2.1g)的干THF(300ml)溶液中。在室温下搅拌过夜(18小时)后,混合物在搅拌下慢慢倾入冰冷的0.5NHCl(1500ml)中。分出有机层,水相用乙醚(3×300ml)萃取。合并的有机层用水,盐水洗涤再用MgSO4干燥。除去溶剂得到半固体状粗品(34g)。在硅胶柱上快速层析纯化,用乙酸乙酯/己烷(1∶12)洗脱,得到所需要的腈是低熔点固体(28g,88%)。NMR(CDCl3)δ2.42(s,3H),7.2-7.8(m,8H);FAB-MS:m/e 194(M+H)
步骤2:三甲基甲锡烷基叠氮化物
剧烈搅拌下将三甲基锡氯化物(20g)的二恶烷(10ml)溶液分三份加入到浓的NaN3(40g)的水(100ml)溶液中。立该有沉淀形成。在室温下搅拌过夜后过滤混合物。残余物用水洗,吸滤及在真空下用P2O5干燥。得18.7g产品(81%),mp.132-136℃。
步骤3:N-三苯基甲基-5-(4′-溴甲基-联苯-2-基)四唑
标题化合物可由2-氰基-4′-甲基联苯(步骤1)起始,按欧洲专利申请EP0,291,969方法制得。
实施例3
2-丁基-3-[(2′-羧基联苯-4-基)甲基]-3H-咪唑并〔4,5-b〕吡啶
步骤1:2-丁基咪唑并〔4,5-b〕吡啶的制备
在搅拌下将戊酸(5.50ml,50.4mmol),2,3-二氨基吡啶(5.0g,45.8mmol)和多磷酸(50g)的混合物加热至100℃5个小时。矸化(NH4OH),萃取(EtOAc,4×20ml),干燥(K2CO3),浓缩得到7.61g(95%)无定形褐色的标题的化合物。由1H-NMR和tlc(未重结晶mp约80℃)鉴定是纯的。
步骤2:2-丁基-3-[(2′-羧基联苯-4-基)甲基]-3H-咪唑并〔4,5-b〕吡啶
A部分
将2-丁基咪唑并〔4,5-b〕吡啶(504mg,2.88mmol)在室温下加入到搅拌的NaH(104mg,80%分散体,3.45mmol)的干二甲基甲酰胺(8ml)悬浮液中。30分钟后,一次性加入叔丁基-4′-溴甲基联苯基-2-羧酸酯(1.0g,2.88mmol)。15小时后,用水(0.5ml)除去过量的NaH,在40-50℃下真空蒸去大部分的DMF。将如此规模的两次反应产物合并以便于以后的纯化。用EtOAc(5×20ml)从盐水(5ml)中萃取,干燥(K2CO3),浓缩并纯化(快速层析SiO2,100%EtOAc)得到925mg(36%)稠油状的2-丁基-3-[(2′-叔丁氧羰基)联苯-4-基)甲基]咪唑并〔4,5-b〕吡啶:Rf=0.7(SiO2,100% EtOAc);
1H-NMR(250MHz,CDCl3)δ:8.36(dd,1H,J=4.8,1.4Hz),8.01(dd,1H,J=7.9,1.4Hz),7.76(dd,1H,J=7.6,1.9Hz.),7.52-7.36(m,2H),7.28-7.18(m,6H),5.58(s,2H),2.85(t,2H,J=7.6Hz),1.92-1.81(m,2H),1.52-1.48(m,2H),1.19(s,9H),0.95(t,3H,J=7.3Hz)。
B部分
在室温下往上述叔丁基酯(820mg,1.85mmol)的二氯甲烷(30ml)中加入三氟乙酸(4ml)。18小时后,蒸发此溶液(除去苯)并层析(Sephadex-LH-20,MeOH)得到680mg(95%)白色固体的标题化合物:mp181-183℃(EtOAc);1H-NMR(250MHz,CDCl3)δ:8.35(dd,1H,J=4.8,1.1Hz),8.05(dd,1H,J=8,1.3Hz),7.91(d,1H,J=7.3Hz),7.54-7.08(m,8H),5.48(s,2H),2.67(t,2H,J=7.5Hz),1.57-1.42(m,2H),1.21-1.07(m,2H),0.65(t,3H,J=7.3Hz)。
实施例4
2-丁基-1-(2′-羧基联苯-4-基)甲基-1H-咪唑并〔4,5-b〕吡啶
A部分
异构体2-丁基-1-(2′-叔丁氧羰基-联苯-4-基)甲基-1H-咪唑并〔4,5-b〕吡啶可由实施例3,A部分得到。产量:(153mg,6%)Rf=0.15(SiO2,100% EtOAc)(2次淋洗);1H-NMR(250MHz,CDCl3)δ8.50(dd,1H,J=5,1.2Hz),7.78(dd,1H,J=8.5,1.5Hz),7.54-7.35(m,3H),7.39-7.22(m,3H),7.12-7.02(m,2H),5.39(s,2H),2.92(t,2H,J=8Hz),1.97-1.84(m,2H),1.53-1.38(m,2H),1.20(s,9H),0.93(t,3H,J=7Hz)。第三个异构体,4-(2′-羧基联苯-4-基)甲基-2-丁基-4H-咪唑并〔4,5-b〕吡啶(414mg)可从实施例3,A部分得到并由MS,1H-NMR和NOE鉴定。
B部分
标题化合物可按实施例3,B部分的方法制得。产量85mg(85%),无定形固体(mp.>260℃)。
实施例5
2-丁基-3-(2′-羧基联苯-4-基)甲基-3H-咪唑并〔4,5-C〕吡啶
步骤1:2-丁基咪唑并〔4,5-c〕吡啶的制备
标题化合物可按照由3,4-二氨基吡啶起始制备2-丁基咪唑并〔4,5-b〕吡啶所描述的方法制得。产量:3.69g(92%),稠油状:1H-NMR(300MHz,CDCl3)δ8.93(S,1H),8.35(d,1H,J=6Hz),7.48(d,1H,J=6Hz),3.01(t,2H,J=7Hz),1.92-1.82(m,2H),1.48-1.30(m,2H),0.86(t,3H,J=7Hz)。
步骤2:2-丁基-3-(2′-羧基联苯-4-基)甲基-3H-咪唑并〔4,5-c〕吡啶
A部分
2-丁基-3-[(2′-叔丁氧羰基联苯-4-基)甲基]-2-丁基-3H-咪唑并〔4,5-c〕吡啶可按实施例1,A部分描述的方法由2-丁基咪唑并〔4,5-c〕吡啶(220mg,1.25mmol),叔丁基-4′-溴甲基联苯基-2-羧酸酯(414mg,1.19mmol)和NaH(1.88mmol)制得。产量:25mg(5%)稠油状;Rf:0.45(SiO2Tlc,1% MeOH/EtOAc);1H NMR(250MHz,CDCl3)δ8.66(s,1H),8.42(d,1H,J=5.6Hz),7.78(dd,1H,J=7.5,1.4Hz),7.66(d,1H,J=5.5Hz),7.52-7.35(m,2H),7.31-7.24(m,3H),7.10(d,2H,J=8Hz),5.46(s,2H),2.92(t,2H,J=7.5Hz),1.97-1.80(m,2H),1.55-1.39(m,2H),1.21(s,9H),0.96(t,3H,J=7.3Hz)。
B部分
标题化合物可按实施例1,B部分所述方法制得。产量:24mg(104%),油状。1H NMR(300MHz,CD3OD)δ9.28(s,1H),8.52(d,1H,J=5.3Hz),8.13(d,1H,5.5Hz),7.82(d,1H,J=7.5Hz),7.56(t,1H,7.5Hz),7.46(t,1H,7.5Hz),7.40-7.32(m,3H),7.24(d,2H,J=7Hz),5.73(s,2H),3.05(t,2H,J=7Hz),1.92-1.78(m,2H),1.54-1.40(m,2H),0.95(t,3H,J=7Hz)。
实施例6
1-(2′-羧基联苯-4-基)甲基-2-丁基-1H-咪唑并〔4,5-c〕吡啶
A部分
异构体1-(2′-叔丁氧羰基-联苯-4-基)甲基-2-丁基-1H-咪唑并〔4,5-b〕吡啶可由实施例5,A部分得到。产量:32mg,稠油状;Rf=0.40(siO2tlc,1% MeOH/EtOAc);1H NMR(250MHz,CDCl3)δ9.07(s,1H,8.35(d,1H,J=5.6Hz),7.77(dd,1H,J=7.5,1.3Hz),7.51-7.35(m,2H),7.33-7.22(m,3H),7.18(d,1H,J=5.6Hz),7.06(d,2H,J=8Hz),5.39(s,2H),2.90(t,2H,J=7.5Hz),1.93-1.80(m,2H),1.53-1.37(m,2H),1.22(s,9H),0.96(t,3H,J=7.2Hz)。异构体5-(2′-叔丁氧羰基联苯-4-基)甲基-2-丁基-5H-咪唑并〔4,5-b〕吡啶(154mg)也可由实施例5,A部分得到,并由MS,1H NMR和NOE鉴定。
B部分
标题化合物可按照实施例3,B部分描述的方法制得。产量:28mg,油状。1H NMR(300MHz,CD3OD)δ9.21(s,1H),8.54(d,1H,J=6Hz),8.31(d,1H,J=6Hz),7.82(d,1H,J=7Hz),7.55(t,1H,J=7Hz),7.44(t,1H,J=7Hz),7.38-7.31(m,3H),7.23(d,2H,J=8Hz),5.74(s,2H),3.08(t,2H,J=7.5Hz),1.82-1.78(m,2H),1.53-1.42(m,2H),.0.95(t,3H,J=7.6Hz)。
实施例7
2-丁基-3-[2′-(四唑-5-基)联苯-4基]甲基-3H-咪唑并〔4,5-b〕吡啶
A部分
将2-丁基咪唑并〔4,5-b〕吡啶(495mg,2.83mmol)在室温下一次加入到搅拌的NaH(102mg,80%分散体,3.39mmol)的干二甲基甲酰胺(6ml)的悬浮液中。20分钟后,混合物冷至0℃并一次加入N-三苯基甲基-5-(4′-溴甲基联苯-2-基)-四唑(1.50g,2.70mmol)。所得黑色混合物热至室温并搅拌15小时。用水(1ml)除去过量的NaH并在40-50℃真空下除去大部分的DMF。从盐水(60ml)中用EtOAc(4×20ml)萃取,干燥(K2CO3)并浓缩得到一稠的黑色油状物。快速层析提纯(SiO2,溶剂梯度:80% EtOAc/己烷,100% EtOAc)得到417mg(23%)的2-丁基-3-(2′-(N-三苯基甲基-四唑-5-基)联苯-4-基)甲基-1H-咪唑并〔4,5-b〕-吡啶,稠油状:Rf=0.75(SiO2,100% EtOAc),1H NMR(300MHz,CDCl3)δ8.35(1H,dd,J=6.1Hz),8.05(1H,dd,J=9,1Hz),7.92(1H,dd,J=9,1.5Hz),7.51-7.42(3H,m),7.36-7.20(11H,M),7.07(2H,d,7Hz),6.96-6.89(7H,m),5.40(2H,s),2.73(2H,t,J=7.5Hz),.1.84-1.70(2H,m),1.41-1.30(2H,m),0.88(3H,t,J=7.5Hz)。
B部分
将水(4ml)在室温下加入到上面搅拌着的三苯甲基保护的四唑(140mg,0.215mmol)冰醋酸(4ml)溶液中。混合物热至80℃2小时,然后在室温下搅拌15小时。真空(35℃)下除去溶剂,将残余物层析(SiO2,80∶20∶1 CH2Cl2-MeOH-NH4OH)得到66mg(75%)灰白色无定形固体的标题化合物:1H NMR(300MHz,CD3OD)δ8.33(1H,dd,J=4.5,1.5Hz),8.00(1H,dd,J=8,1.5Hz),7.56(2H,明显的tm,J=8Hz),7.47(2H,明显的tm,J=8Hz),7.32(1H,dd,J=4.5,8Hz),7.07(明显单峰,4H),5.55(2H,S),2.86(2H,t,J=8Hz),1.75-1.63(2H,m),1.45-1.32(2H,m),0.91(3H,t,7.5Hz)。
实施例8
2-丙基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕-吡啶的制备
步骤1:2-丙基咪唑并〔4,5-b〕吡啶的制备
标题化合物可按照所述的由3,4-二氨基吡啶和丁酸起始制备2-丁基咪唑并〔4,5-b〕吡啶的方法制备。产量:6.60g(89%),无定形固体。
步骤2:
2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶的制备
A部分
2-丙基-3-(2′-(N-三苯基甲基四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶可按实施例7,A部分描述的方法由2-丙基咪唑并〔4,5-b〕吡啶(19mg,0.118mmol),N-三苯基甲基-5-(4′-溴-甲基联苯-2-基)四唑(60mg,0.108mmol)和NaH(0.236mmol)制得。产量:18mg(26%)稠油状;Rf:0.75(siO2tlc,100% EtOAc);1H NMR(300MHz,CDCl3)δ8.27(dd,1H,J=6,1Hz),8.01(dd,1H,J=9,1Hz),7.85(dd,1H,J=9,1.5Hz),7.50-7.42(m,2H),7.38-7.22(m,11H),7.08(d,2H,J=7Hz),6.98-6.88(m,7H),5.40(s,2H),2.66(t,2H,J=7.5Hz),1.80-1.65(m,2H),0.93(t,3H,J=6Hz)。
B部分
按照实施例7,B部分的方法可制备标题化合物。产量:10mg(95%),无定形固体。1H NMR(300MHz,CD3OD)δ8.33(d,1H,J=5Hz),7.99(d,1H,J=8Hz),7.58(t,2H,J=7.5Hz),7.48(t,2H,J=7.5Hz),.7.33(dd,1H,J=5.8Hz),7.06(明显单峰,4H),5.56(s,2H),2.84(t,2H,J=8Hz),1.83-1.68(m,2H),0.98(t,3H,J=6Hz)。
实施例9
甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-7-3H-咪唑并〔4,5-b〕吡啶
步骤1:7-甲基-2-丙基咪唑并〔4,5-b〕吡啶的制备
将丁酸(6.57ml,71.9mmol),2,3-二氨基-4-甲基吡啶(8.05g,65.4mmol)(Lappin,G.R.,Slezak,F.B.J.Am.Chem.Soc.(1950)72,7806-7)和多磷酸(50g)的混合物加热至100℃,并搅拌反应3小时。反应由NH4OH中和的等分试样的tlc控制。碱化(NH4OH),萃取(CH2Cl2,4×50ml),干燥(K2CO3),纯化(用100g SiO2过滤,EtOAc洗脱)并浓缩得到10.0g(95%)褐色无定形被1H NMR和tlc鉴定为纯的固体标题化合物:mp110-112℃(未重结晶);1H NMR(300MHz,CDCl3)δ8.13(d,1H,J=5Hz),7.01(d,1H,J=5Hz),3.01(t,2H,J=7.8Hz),2.67(s,3H),2.07-1.93(m,2H),1.06(t,3H,J=7.5Hz)。
步骤2:7-甲基-2-丙基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
A部分
3-[2′-(N-三苯基甲基四唑-5-基)联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶可按实施例7A部分描述的方法由2-丙基-7-甲基咪唑并〔4,5-b〕吡啶(991mg,5.66mmol),N-三苯基甲基-5-(4′-溴甲基联苯-2-基)四唑(3.0g,5.39mmol)和NaH(6.47mmol)制得。产量1.11g,(32%),稠油状;Rf:0.80(SiO2,tlc,1∶1 EtOAc-己烷);1H NMR(300MHz,CDCl3)δ8.20(d,1H,J=5Hz),7.89(d,1H,J=8Hz),7.51-7.39(m,2H),7.38-7.20(m,10H),7.10-7.03(m,3H),6.95-6.88(m,8H),5.49(s,2H),2.78-2.68(m,2H),2.69(s,3H),1.83-1.60(m,2H),.0.91(t,3H,J=5.5Hz)。
B部分
标题化合物可按照实施例7,B部分描述的方法由1.01g上面制备的化合物制得。产量:583(92%),无定形固体。mp:195-197℃(EtOAc);
1H NMR(300MHz,CD3OD)δ8.16(d,1H,J=5Hz),7.60-7.38(m,4H),7.12(d,1H,J=5Hz),7.09(明显单峰,4H),5.52(S,2h),2.83(t,2H,J=5HZ),2.64(S,3H),1.79-1.60(m,2H),0.95(t,3H,J=5.5Hz)。C24H23N7.0.25H2O分析计算值:C,69.63;H,5.72;N,23.68。
实验值:C,69.75;H,5.58;N,23.69。
钠盐和钾盐可由产物与等量的NaOH或KOH结合制得并可将所得盐从指定溶剂中重结晶出来。
7-甲基-2-丙基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶钠盐
mp:>250℃(EtOAc);1H NMR(300MHz,CD3OD)δ8.17(d,1H,J=5Hz),7.53-7.37(m,4H),7.20(d,1H,J=5Hz),7.08(d,2H,J=8.3Hz),7.00(d,2H,J=8.3Hz),5.51(s,2H),2.84(t,2H,J=7.5Hz),2.65(s,3H),1.79-1.62(m,2H),0.96(t,3H,J=7.5Hz)。
7-甲基-2-丙基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶钾盐
mp:>250℃(丙酮/己烷);1H NMR(300MHz,CD3OD)δ8.17(d,1H,J=5Hz),7.52-7.37(m,4H),7.13(d,1H,J=5Hz),7.08(d,2H,J-8.3Hz),6.99(d,2H,J=8.3Hz),5.51(s,2H),2.84(t,2H,J=7.5Hz),2.65(s,3H),1.79-1.62(m,2H),0.96(t,3H,J=7.5Hz)。
实施例10
2-丁基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶的制备
步骤1:6-溴-2-丁基-7-甲基-咪唑并〔4,5-b〕吡啶的制备
标题化合物可按照由5-溴-2,3-二氨基-4-甲基吡啶制2-丁基咪唑并〔4,5-b〕吡啶的方法制得。产量:2.54g(95%)无定形固体。1H NMR(250MHz,CDCl3)δ8.45(s,1H),3.05(t,2H,J=7Hz),2.73(s,3H),2.02-1.87(m,2H),1.61-1.45(m,2H),1.02(t,3H,J=7Hz)。
步骤2:2-丁基-7-甲基咪唑并〔4,5-b〕吡啶的制备
在一冷的(-78℃)搅拌的6-溴-2-丁基-7-甲基咪唑并〔4,5-b〕吡啶(98mg,0.366mmol)的THF(4ml)溶液中加入叔丁基锂(1.7M的戊烷溶液0.86ml,1.46mmol)。15分钟后,加入MeOH(0.5ml)和盐水,混合物热至室温并用EtOAc萃取(4×10ml)。干燥(K2CO3),浓缩并纯化(SiO2,100% EtOAc)得到60mg(87%)油状标题化合物:1H NMR(300MHz,CDCl3)δ8.18(d,1H,J=5Hz),7.08(d,1H,J=5Hz),3.05(t,2H,J=7.6Hz),2.72(s,3H),2.03-1.89(m,2H),1.62-1.43(m,2H),0.96(t,3H,J=7.8Hz)。
步骤3:2-丁基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶的制备
A部分
2-丁基-7-甲基-3-(2′-(N-三苯基甲基四唑-5-基-)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶可按实施例7,A部分描述的方法由2-丁基-7-甲基咪唑并〔4,5-b〕吡啶(28mg,0.148mmol),N-三苯基甲基-5-(4′-溴甲基联苯-2-基)-四唑(62mg,0.135mmol)和NaH(0.296mmol)制得。产量:16mg(16%)稠油状;Rf:0.80(SiO2tlc,90% EtOAc/己烷);1H NMR(300MHz,CDCl3)δ8.22(d,1H,J=5Hz),7.92(d,1H,J=8Hz),7.54-7.41(m,2H),7.38-7.20(m,10H),7.11-7.04(m,3H),6.97-6.88(m,8H),5.40(s,2H),2.76-2.68(m,2H),2.71(s,3H),1.74-1.63(m,2H),1.42-1.30(m,2H),0.91(t,3H,J=5.5Hz)。
B部分
标题化合物可按照实施例7,B部分描述的方法制备。产量:8.5mg(89%)无定形固体。1H NMR(300MHz,CD3OD)δ8.17(d,1H,J=5Hz),7.59-7.42(m,4H),7.15(d,1H,J=5Hz),7.10-7.01(m,4H),5.52(s,2H),2.86(t,2H,J=8Hz),2.66(s,3H),1.71-1.59(m,2H),1.45-1.30(m,2H),0.90(t,3H,J=7Hz)。
实施例11
8-丁基-1,3-二甲基-7-(2′-(四唑-5-基)联苯-4-基)甲基-1,2,3,6-四氢-2,6-二氧嘌呤
步骤1:8-丁基-1,3-二甲基-1,2,3,6-四氢-2,6-二氧嘌呤的制备
在置于50ml园底烧瓶中的3.00g(17.6mmol)5,6-二氨基-1,3-二甲基尿嘧啶水合物(Aldrich)中加入2.31ml(2.17g,21.2mmol,1.2eq)的戊酸和足够的多磷酸使得烧瓶约半满。粘性混合物在间歇搅拌下在50-60℃加热14小时。
混合物冷却,用30ml蒸馏水稀释并缓慢加入浓氢氧化铵(约20ml)调pH至8-9。形成褐色沉淀并过滤除去。滤液用氯仿萃取(5X)并且将萃取物与褐色沉淀合并,干燥(MgSO4),过滤并在真空下除去溶剂。灰黄色残余物在硅胶上层析,用乙酸乙酯洗脱。这样,得到2.16g(9.14mmol,52%)绒毛状白色固体的标题化合物,NMR(300MHz,DMSO-d6):0.89(t,3H),1.30(m,2H),1.66(m,2H),2.68(t,2H),3.23(s,3H),3.42(s,3H)。FAB-MS:237(M+H,100%)。
步骤2:8-丁基-1,3-二甲基-7-(2′-(四唑-5-基)联苯-4-基)甲基-1,2,3,6-四氢-2,6-二氧嘌呤
在室温下将20mg60%氢化钠油分散体(12mg NaH,0.50mmol,1.2)加入到100mg(0.42mmol)由步骤1制得的嘌呤的2ml干燥DMF溶液中。15分钟后,加入226mg(0.41mmol,0.96eq)N-三苯基-甲基-5-(4′-溴甲基联苯-2-基)四唑的1ml干DMF溶液且将混合物在室温下搅拌16小时。
将反应混合物加入到30ml乙酸乙酯中并用5%柠檬酸水溶液(2X),饱和的碳酸氢钠水溶液(1X)和盐水(1X)洗涤。分出有机层,干燥(MgSO4),过滤并在真空下除去溶剂。残余物在硅胶柱上通过中压液相层析纯化,用乙酸乙酯/己烷(2∶1)洗脱,得到246mg(0.35mmol,82%)白色的三苯甲基中间体。NMR(300MHz,CDCl3)δ0.87(t,3H),1.30(m,2H),1.61(m,2H),2.57(t,2H),3.37(s,3H),3.58(s,3H),5.43(s,2H),6.8-7.8(几个多重峰,23H)。FAB-MS:712(M+H,1%),471(M-三苯甲基,7%),243(三苯甲基,100%)。
用2ml 50%乙酸水溶液在室温下并剧烈搅拌下处理上述中间体(50mg,0.07mmol)16小时。将所有挥发物在真空下除去,残余物用反相HPLC在C18柱上纯化,用甲醇/0.1%三氟乙酸水溶液(线性梯度:85%甲醇经10分钟增为95%甲醇)洗脱。这样,得到17mg(0.04mmol,57%)无色玻璃状标题化合物。NMR(300MHz,DMSO-d6):0.81(t,3H),1.26(m,2H),1.50(m,2H),2.66(t,2H),3.23(s,3H),3.42(s,3H),5.58(s,2H),7.07(d,2H),7.13(d,2H),7.5-7.7(m,4H)。FAB-MS:471(M+H,100%)。
实施例12
9-(2′-羧基联苯-4-基)甲基-6-氯-8-丙基嘌呤的制备
步骤1:6-氯-4,5-二氨基嘧啶
在5-氨基-4,6-二氯-嘧啶(2.0g,12.2mmol)的异丙醇(20ml)的冷溶液中加入液氨(5ml),将混合物移入一个密封管中。管子在130℃下加热3小时然后冷至室温。沉淀出的产物滤出并真空干燥。产量2.0g(定量的)。
步骤2:6-氯-8-丙基嘌呤
将三甲基原丁酸酯(0.5ml,3mmol)和对-甲苯磺酸(0.03g)加入到4,5-二氨基-6-氯嘧啶(0.289g,2mmol)的2-甲氧基乙醇(10ml)溶液中,混合物回流18小时并真空浓缩。残余物分配在水和乙酸乙酯中。有机相用盐水洗涤并干燥(MgSO4)。蒸出溶剂后所得粗品用硅胶快速柱层析纯化,用乙酸乙酯/己烷(1∶1)洗脱。将含纯品的组份收集起来并真空浓缩,再于室温下搁置过夜。将结晶出的产品过滤并干燥。产量0.17g(43%);NMR(CDCl3):δ1.05(t,J=9Hz,3H),2.0(q,2H),3.1(q,2H),8.74(s,1H);FAB
质谱:m/e 197和199。(M+H)
C8H9Cl分析计算值:
C,48.86;H,4.61;N,28.50。
实验值:C,49.06;H,4.76;N,28.30。
步骤3:6-氯-8-丙基-9-(2′-叔-丁氧羰基-联苯-4-基)甲基嘌呤
在NaH(0.20g)的干DMF(3ml)悬浮液中加入6-氯-8-丙基-嘌呤(0.06g,0.3mmol),混合物在40℃搅拌20分钟。室温下加入叔丁基-4-溴甲基联苯-2′-羧酸酯(0.11g,0.31mmol)并在40℃下继续搅拌3小时。烧瓶内容物倾入冰水(100ml)中并用乙酸乙酯萃取。分出有机相并用MgSO4干燥。在减压下除去溶剂得到粗品。再在硅胶上通过快速层析纯化,用乙酸乙酯-己烷(1∶1)洗脱。得到似玻璃状的纯的固体标题化合物(0.073g,53%)。NMR(CDCl3):δ1.04(t,J=9Hz,3H),1.213(s,9H),1.91(m,2H),2.89(t,2H),5.52(s,2H),7.15-7.52(m,7H),7.79(dd,J1=8Hz和J2=2Hz,1H),8.72(s,1H);FAB-MS:m/e463和465(M+H)。
步骤4:6-氯-8-丙基-9-(2′-羧基联苯-4-基)-甲基嘌呤
在上面的叔-丁基酯(0.070g,0.15mmol)的二氯甲烷溶液(3ml)中,加入无水三氟乙酸(2ml)和茴香醚(0.02ml)。室温下搅拌3小时,将混合物蒸发至干。粗品在硅胶上用快速层析纯化并用氯仿-甲醇-NH4OH(40∶10∶1)洗脱。产量0.034g(56%)。NMR(CD3OD):δ0.99(t,J=9Hz,3H),1.78(m,2H),2.94(t,2H),5.624(s,2H),7.20-7.58(m,7H),7.79(d,J1=8Hz,1H),8.72(s,1H);FAB-MS:m/e 407和409(M+H)。
C22H19N4O2Cl.0.25H2O分析计算值:
C,64.23;H,4.77;N,13.62。
实验值:C,64.09;H,4.86;N,13.27。
实施例13
8-丁基-9-[(2′-羧基联苯-4-基)甲基]-6-氯嘌呤的制备
步骤1:8-丁基-6-氯嘌呤
将6-氯-4,5-二氨基嘧啶(0.289g,2mmol)(从实施例12步骤1得到),三甲基原戊酸酯(0.52ml,3mmol)和P-TsOH(0.04g)的2-甲氧基乙醇(10ml)的混合物回流24小时。将产物游离并如实施例12步骤2所述纯化,得到晶状的标题化合物(0.113g,23%,NMR(CDCl3):δ0.997(t,J=9Hz,3H),1.484(m,2H),1.925(m,2H),3.075(m,2H),7.27(s,1H)和8.723(s,1H)。FAB-MS:m/e 211和213(M+H)。
C9H11N4Cl分析计算值:
C,51.31;H,5.26;N,26.60。
实验值:C,51.34;H,5.30;N,26.46。
步骤2:8-丁基-6-氯-9-(2′-叔-丁氧羰基联苯-4基)甲基嘌呤
标题化合物可按实施例12步骤3描述的方法用叔丁基-4-溴甲基联苯-2′-羧酸酯(0.104g,0.3mmol)烷基化6-氯-8-丁基嘌呤(0.063g,0.3mmol)制得。粗品经快速层析纯化,用乙酸乙酯-己烷(1∶1)洗脱后,得到泡沫状产品(0.085g,60%)。NMR(CDCl3):δ0.946(t,J=9Hz,3H),1.26(s,9H),1.464(m,2H),1.86(m,2H),2.91(m,2H),5.51(s,2H),7.16-7.51(m,7H),7.78(m,1H)和8.723(s,1H)。FAB-MS:m/e 477和479(M+H)。
步骤3:8-丁基-6-氯-9-(2′-羧基联苯-4-基)甲基嘌呤
按照实施例12步骤4描述的方法将叔丁基酯(0.080g)脱保护。从甲醇-乙醚中结晶得到纯品。产量0.030g(42%)。NMR(CD3OD):δ0.91(t,J=9Hz,3H),1.41(m,2H),1.76(m,2H),2.98(m,2H),5.63(s,2H),7.2-7.6(m,7H),7.8(d,J=8Hz,2H),8.715(s,1H)。FAB-MS:m/e 421和423(M+H)。
C23H21N4O2Cl.0.2H2O分析计算值:
C,65.07;H,5.08;N,13.20。
实验值:C,65.23;H,5.44;N,12.80。
实施例14
8-丁基-9-(2′-羧基联苯-4-基)甲基-6-羟基嘌呤的制备
在实施例13步骤3中,标题化合物作为较少的(10%)反应付产品分离出来。化合物假定是嘌呤的6-氯官能团与水进行亲核性取代反应得到的。其结构鉴定:NMR(CD3OD)δ0.886(m,3H),1.35(m,2H),1.64(m,2H),2.79(m,2H),5.50(s,2H),7.2-7.6(m,7H),7.79(m,2H),8.051(s,1H)质谱分析。FAB-MS:m/e 403(M+H) C23H22N4O3分析计算值:
C,68.66;H,5.47;N,13.93。
实验值:C,68.32;H,5.52;N,14.07。
实施例15
6-氯-8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤的制备
步骤1:6-氯-8-丙基-9-(2′-(N-三苯甲基-四唑-5-基)联苯-4基)-甲基嘌呤
在室温下,将6-氯-8-丙基嘌呤(0.044g,0.25mmol)加入到搅拌着的NaH(0.016g,于油中,60%的分散体0.4mmol)的干燥二甲基甲酰胺(1.5ml)悬浮液中。20分钟后,将混合物冷至0℃并加入N-三苯甲基-5-(4′-溴甲基联苯-2-基)四唑(0.139g,0.25mmol)。将所得混合物热至室温并在40℃下搅拌3小时。反应冷却下来,将烧瓶内容物倾入冰水(50ml)中并用乙酸乙酯萃取(3×15ml)。合并的有机相用盐水洗涤然后用无水Na2SO4干燥。除去溶剂得到泡沫状粗产品,在硅胶上用快速层析提纯用乙酸乙酯/己烷(1∶3)洗脱。产量0.07g(泡沫状)。NMR(CDCl3):δ0.96(t,J=8Hz,3H),1.806(m,2H),2.75(m,2H),5.35(s,2H),6.85-7.54(m,22H),7.85(m,1H),8.72(s,1H)。FAB-MS:m/e 674和676(M+H)。
步骤2:6-氯-8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤
将上面所得的三苯甲基保护的化合物(0.065g)溶于50%乙酸水溶液(2ml)中,混合物在50℃下加热15小时。真空除去溶剂,残余物硅胶上用快速层析纯化,用氯仿-甲醇-NH4OH(40∶10∶1)洗脱得到玻璃状固体的所需纯产物(0.016g)。NMR(CD3OD):δ0.98(t,J=8Hz,3H),1.754(m,2H),2.89(m,2H),5.57(s,2H),7.135(q,4H),7.5-7.7(m,5H),8.70(s,1H)。FAB-MS:m/e 431和433(M+H)。C22H19N8Cl分析计算值:
C,61.27;H,4.41;N,25.99。
实验值:C,61.47;H,4.78;N,26.32。
实施例16
5,7-二甲基-2-乙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶的制备
步骤1:2-氨基-4,6-二甲基-3-硝基吡啶
2-氨基-4,6-二甲基吡啶(10.0g,81.8mmol)分次加入到在0℃下搅拌(机械)着的65ml H2SO4(浓,d=1.84)中。加完后,将混合物热至室温直至混合物变均匀。溶液再冷至-10℃并以使内部反应温度不高于-9℃的速度加入一事先冷却的(0℃)浓HNO3(11.5ml,=1.40)和H2SO4(8.2ml,d=1.84)的混合物。十分钟后加完,将冷却(-10℃)的混合物倾入到400g碎冰上。冷却(冰浴)的同时加入浓NH4OH使所得浆状物中和(到pH5.5)。过滤分出固体,并在室温下干燥得到13.3g白色固体的2-硝氨基-4,6-二甲基吡啶。
在75ml冷至-5℃(冰-盐浴)的搅拌着的浓H2SO4中,以保持内部温度低于-3℃的速度分次加入4,6-二甲基-2-硝氨基吡啶(13.2g,79mmol)。将混合物热至0℃直至成为均相(30分钟),此时tlc(SiO2,1∶1 EtOAc/己烷,用NH4OH中和后取一部分)显示重排己完成。将混合物倒在400g碎冰上并加入浓NH4OH调pH至5.5。所得黄色浆状物冷至0℃,过滤,冷水(50ml)洗涤并在室温下干燥得到10.32g标题化合物和5-硝基异构体(55∶45)的混合物(1H NMR测定)。该混合物直接用于步骤2。
步骤2:5,7-二甲基-2-乙基咪唑并〔4,5-b〕吡啶
往8.44g55∶45的2-氨基-3-硝基-4,6-二甲基吡啶和2-氨基-4,6-二甲基-5-硝基吡啶在甲醇(1.2L)中的混合物中加入10%Pd/c(2.4g)。反应容器抽真空再在1atm下通入H2并剧烈搅拌18小时。过滤(硅藻土)并浓缩得到6.65g黑色固体状的2,3-二氨基-4,6-二甲基吡啶和2,5-二氨基-4,6-二甲基-吡啶的混合物。在5.40g(39.4mmol)的该混合物中加入丙酸(8.80ml,118mmol),再加入多磷酸(100ml)。将该搅拌的混合物热至90℃3个小时,然后至100℃1小时。反应完成后,将温热混合物倾于300g冰中并用NH4OH使之矸化。萃取混合物(CH2Cl2,4×50ml),干燥(K2CO3)并浓缩得到标题化合物和4,6-二甲基-2,5-二(丙酰胺基)吡啶混合物。纯化(siO2,5% MeOH/EtOAc)慢洗脱得到1.66g标题化合物。1H NMR(CD3OD,300MHz)δ6.95(s,1H),2.92(q,2H,J=7.8Hz),2.54(明显的s,6H),1.40(t,3H,J=7.8Hz)。
步骤3:5,7-二甲基-2-乙基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
A部分
按照实施例7,A部分描述的方法5,7-二甲基-2-乙基-3-(2′-(N-三苯基甲基四唑-5-基)联苯-4基)甲基-3H-咪唑并〔4,5-b〕吡啶可由5,7-二甲基-2-乙基咪唑并〔4,5-b〕吡啶(1.51g,8.62mmol),N-三苯甲基-5-(4′-溴甲基联苯-2-基)四唑(5.29g,9.48mmol)和NaH(17.2mmol)制得。产量:4.25g,白色固体:1H NMR(300MHz,CDCl3)δ7.86(dd,1H,J=7,2Hz),7.50-7.41(m,2H),7.36-7.21(m,10H),7.05(d,2H,J=4.5Hz),6.95-6.89(m,7H),6.86(d,2H,J=4.5Hz),5.35(s,2H),2.67(q,2H,J=7.5Hz),2.65(s,3H),2.58(s,3H),1.25(t,3H,J=7.5Hz)。
B部分
在室温下在搅拌的三苯甲基保护的四唑(4.13g,6.33mmol)的CH2Cl2溶液(40ml)中加入85%甲酸(60ml)。45分钟后,将混合物浓缩,残余物层析纯化(SiO2,85∶13.5∶1.5 CHCl3-MeOH-NH4OH),再从30ml MeOH中结晶得到2.18g(84%)固体:mp156-158℃。1H NMR(300MHz,CD3OD)δ7.68-7.61(m,2H),7.57-7.50(m,2H),7.07(明显的单峰,4H),7.04(s,1H),5.55(s,2H),2.85(q,2H,J=7.5Hz),2.61(s,3H),2.58(5,3H),1.25(t,3H,J=7.5Hz)。
分析,C24H23N7.0.25H2O计算值:C,69.63;H,5.72;N,23.68。
实验值:C,69.91;H,5.73;N,23.60。
当从10%水-甲醇中结晶时得到另一种晶形(一水合物,mp186℃)。
如实施例9所述制得钠或钾盐。
实施例17
5,7-二甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶的制备
标题化合物可如实施例16描述方法用丁酸代替步骤2中丙酸制得。FAB-MS,M++H=424;1H NMR(300MHz,CD3OD)δ7.67-7.60(m,2H),7.56-7.49(m,2H),7.07(明显单峰,4H),7.04(s,1H),5.55(s,2H),2.81(t,2H,J=7.8Hz),2.60(s,3H,2.58(s,3H),1.73-1.60(m,2H),0.95(t,3H,J=7.5Hz)。
实施例18
2-丁基-5,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶的制备
标题化合物可按实施例16描述方法用戊酸代替步骤2中丙酸制得。FAB MS,M++1=438;1H NMR(300MHz,CD3OD)δ7.67-7.60(m,2H),7.56-7.49(m,2H),7.07(明显单峰,4H),7.04(s,1H),5.55(s,2H),2.81(t,2H,J=7.8Hz),2.60(s,3H),2.58(s,3H),1.73-1.60(m,2H),0.95(t,3H,J=7.5Hz)。
实施例19
3-(2′-羧基联苯-4-基)甲基-5,7-二甲基-2-乙基-3H-咪唑并〔4,5-b〕吡啶的制备
A部分
按实施例3、A部分描述的方法3-(2′-叔-丁氧羰基联苯-4-基)甲基-5,7-二甲基-2-乙基-3H-咪唑并〔4,5-b〕吡啶可由5,7-二甲基-2-乙基咪唑并〔4,5-c〕吡啶(50mg,0.28mmol),叔-丁基-4′-溴甲基联苯-2-羧酸酯(109mg,0.314mmol)和NaH(0.417mmol)制得。产量:层析后得96mg稠状油(SiO2,50% EtOAc/己烷);FAB-MS,M++1=442。
B部分
按实施例3,B部分描述方法制得标题化合物。产量:80mg;FAB MS:M++1=386;1H NMR(300MHz,CD3OD)δ7.71(dd,1H,J=7.2,1.2Hz),7.52-7.30(m,5H),7.15(d,2H,J=8.4Hz),7.04(s,1H),5.60(s,2H),2.88(q,2H,J=7.5Hz),2.62(s,3H),2.59(s,3H),1.31(t,3H,J=7.5Hz)。
实施例20
5-氨基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶的制备
步骤1:5-丁酰氨基-2-丙基咪唑并〔4,5-b〕吡啶
在latm H2下将2,6-二氨基-3-硝基吡啶(878mg 5.7mmol)和Pd-C(10%,100mg)在甲醇(100ml)中的混合物搅拌16小时。将混合物(包括对空气敏感的三胺)过滤,蒸发并往烧瓶中加入多磷酸(15ml)和丁酸(1.05ml,11.5mmol)。将混合物热至80℃5小时,冷至室温后用水稀释并用浓NH4OH中和。萃取后(CH2Cl2)得到345mg5-(丁酰氨基)-2-丙基咪唑并〔4,5-b〕吡啶:1H NMR(300MHz,CDCl3)δ7.94(d,1H,J=8.5Hz),7.65(d,1H,J=8.5Hz),2.96(t,2H,J=7.5Hz),2.30(t,2H,J=7Hz),1.98-1.84(m,2H),1.68-1.55(m,2H),0.99(t,3H,J=7.5Hz),0.80(t,3H,J=7.0Hz)。
步骤2:5-氨基-2-丙基咪唑并〔4,5-b〕吡啶
5-丁酰氨基-2-丙基-咪唑并〔4,5-b〕吡啶(250mg,1.07mmol),MeOH(20ml)和浓HCl水溶液(2ml)的混合物热至45℃16小时。浓缩并用NaHCO3中和得到150mg琥珀状标题化合物。1H-NMR(300MHz,CD3OD)δ7.57(d,1H,J=8.5Hz),6.46(d,1H,J=8.5Hz),2.76(t,2H,J=7.5Hz),1.85-1.70(m,2H),0.93(t,3H,J=7.5Hz)。
步骤3:5-氨基-2-丙基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
A部分:
5-氨基-2-丙基-3-(2′-(N-三苯甲甲基-四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶是根据例7A部分描述的方法制得,原料5-氨基-2-丙基-咪唑并〔4,5-b〕吡啶(130mg,0.80mmol),N-三苯基甲基-5-(4′-溴代甲基联苯-2-基)-四唑(445mg,0.800mmol),和氢化钠(2.4mmol),生成产物185mg(作为玻璃态固体)。
B部分:
将A部分所述的三苯甲基四唑盐(80mg,0.122mmol)浓盐酸(1ml)的混合物在甲醇(10ml)中,室温搅拌16小时。浓缩并纯化(SiO2,80∶19∶1 CH2Cl2∶MeOH∶NH4OH)得到50mg标题化合物的白色固体。FABMS M++1=411;1H NMR(300MHz,CD3OD)δ7.67(d,1H,J=8.7Hz),7.61-7.55(m,2H),7.51-7.43(m,2H),7.07表观单峰 4H),6.58(d,1H,J=8.7Hz),5.42(s,2H),2.76(t,2H,J=7.5Hz),1.73-1.60(d,2H),0.93(t,3H,J=7.2Hz)。
实例21
2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶的制备
步骤1:2-乙基-7-甲基-咪唑并〔4,5-b〕吡啶
将丙酸(0.89ml,12mmols),2,3-二氨基-4-甲基吡啶(1,23g,10mmol)和多磷酸(40g)的混合物加热到100℃并反应6小时。反应完后,根据例9中步骤1所述的方法纯化粗产物,得到褐色固体的所欲化合物(1.46g,90%)。1H NMR(300MHz,CDCl3):8.14(d,1H,J=5Hz),7.01(d,1H,J=5Hz),3.02(q,2H,J=7.8Hz),2.69(s,3H),1.45(t,3H,J=7.8Hz)。
步骤2:2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
A部分:
根据实例7中A部分所述的方法,由2-乙基-7-甲基-咪唑并〔4,5-b〕吡啶(0.5g,3.11mmol),N-三苯基甲基-5-(4′-溴代甲基联苯基-2-基)-四唑(1.82g,3.26mmol)和氢化钠(3.12mmol)反应制得2-乙基-7-甲基-3-(2′-(N-三苯基甲基-四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶。粗产物(1.9g,泡沫体)经淋洗剂为乙酸乙酯-正己烷(1∶1.5)的硅胶柱进行快速层析纯化,得到白色固体所欲产物0.95g,47.5%)。1H NMR(300MHz,CDCl3):8.2(d,1H,J=5Hz),7.9(d,1H,J=8Hz),6.80-7.55(m,23H),5.4(s,2H),2.58-2.85(m,5H),1.25(t,3H,J=7.8Hz)。
B部分:
根据实例7中B部分所述的方法由上面化合物(0.42g)制备标题化合物。产率:0.26g(99%)。最后该化合物在甲醇-乙醚中结晶,得到白色晶体产物(0.24g)。
mp:192-193℃
1H NMR(300MHz,CD3OD):
8.2(d,1H,J=5Hz),7.4-7.62(m,4H),6.96-7.45(m,5H),5.52(s,2H),2.88(q,2H,J=7.8Hz),2.65(s,3H),1.27(t,3H,J=7.8Hz)。
元素分析(C23H21N7.0.5H2O)
C H N
计算值 68.32 5.45 24.26
实测值 68.59 5.73 24.12
实例22
2,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)-甲基-3H-咪唑并〔4,5-b〕吡啶
步骤1:2,7-二甲基-咪唑并〔4,5-b〕吡啶
标题化合物由2,3-二氨基-4-甲基吡啶(0.246g,2mmol)和乙酸(0.15ml)根据实例9中步骤1所用的方法制得。粗产物用硅胶柱进行快速层析纯化,淋洗剂为EtOAc-MeOH(9∶1),得到纯产物(0.25g,85%),产物为浅棕色固体。
1H NMR(300MHz,CDCl3):8.14(d,1H,J=5Hz),7.01(d,1H,J=5Hz),2.73(s,3H),2.62(s,3H)。
步骤2:2,7-二甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物由上步化合物根据实例5中A部分和B部分所述的方法制得。得到的理想纯产物为白色无定性粉末。
1H NMR(300MHz,CD3OD):8.12(d,1H,J=5Hz),7.45-7.65(m,4H),6.96-7.4(m,5H),5.52(s,2H),2.65(s,3H),2.52(s,3H)。
元素分析(C22H19N7.H2O):
C H N
计算值 77.19 5.26 24.56
实测值 76.91 5.73 24.33
实例23
7-甲基-2-戊基-3-(2′-(四唑-5-基)联苯-4-基)-甲基-3H-咪唑并〔4,5-b〕吡啶
步骤1:7-甲基-2-戊基-咪唑并〔4,5-b〕吡啶
标题化合物由2,3-二氨基-4-甲基吡啶(0.246g,2mmol)和己酸(0.25ml,2mmols)根据实例9中步骤1所用方法制得。粗产物用硅胶柱进行快速层析纯化,淋洗剂为EtOAc-MeOH(9∶1),得到纯产物(0.28g,69%),产物为褐色固体。
1H NMR(300MHz CDCl3):8.17(d,1H,J=5Hz),7.05(d,1H,J=5Hz),3.03(t,2H,J=7.8Hz),2.70(s,3H),1.32-2.1(m,6H),0.92(t,3H,J=7.8Hz),(t,3H,J=7.8HZ)
步骤2:7-甲基-2-戊基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物由上步产物根据实例7中A部分和B部分所用的方法制备。得到的纯净的理想产物为白色无定性粉末(Rf 0.45,CHCl3-MeOH-NH4OH 40∶10∶1)。
1H NMR(300MHz,CD3OD):8.20(d,1H,J=5Hz),7.48-7.80(m,4H),7.01-7.3(m,5H),5.72(s,2H),2.84(t,2H,J=7.8Hz),2.65(s,3H),1.68(m,2H),1.32(m,4H),0.9(t,3H,J=7.8Hz)。FAB-Ms:m/e 438(M+H)。
实施例24
7-甲基-2-壬基-3-(2′-(四唑-5-基)联苯-4-基)-甲基-3H-咪唑并〔4,5-b〕吡啶
步骤1:7-甲基-2-壬基-咪唑并〔4,5-b〕吡啶
标题化合物由2,3-二氨基-4-甲基吡啶(0.246g,2mmol)和癸酸(0.35g,2mmol)根据实例9中步骤1所用的方法制备。粗产物用硅胶柱进行快速层析纯化,淋洗剂为EtOAc-MeOH(20∶1),得到纯净产物(0.38g,72%),产物为褐色固体。
1H NMR(300MHz,CDCl3):8.16(d,1H,J=5Hz),7.05(d,1H,J=5Hz),3.03(t,2H,J=7.8Hz),2.69(s,3H),1.25-2.0(m,14H),0.90(t,3H,J=7.8Hz)。
步骤2:7-甲基-2-壬基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物由上步产物按实例7中A部分和B部分所用方法制备。得到的纯净理想产物为奶油色无定形粉未(在CHCl3-MeOH-NH4OH 40∶10∶1中,Rf为0.5)。
1H NMR(300MHz,CD3OD):8.20(d,1H,J=5Hz),7.48-7.70(m,4H),7.08-7.3(m,5H),5.58(s,2H),2.84(t,2H,J=7.8Hz),2.64(s,3H),1.68(m,2H),1.1-1.4(m,12H),0.89(t,3H,J=7.8Hz)。
FAB-MS:m/e 494(M+H)。
实施例25
2-异丙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)-甲基-3H-咪唑并〔4,5-b〕吡啶
步骤1:2-异丙基-7-甲基-咪唑并〔4,5-b〕吡啶
标题化合物由2,3-二氨基-4-甲基吡啶(0.246g,2mmol)和异丁酸(0.19ml,2mmol)按实例9中步骤1所述方法制备。粗产物用硅胶柱进行快速层析纯化,淋洗剂为EtOAc-MeOH(20∶1),得到纯净产物(0.25g,72%),产物为褐色固体。
1H NMR(300MHz,CDCl3):8.21(d,1H,J=5Hz),7.05(d,1H,J=5Hz),3.40(m,1H),2.71(s,3H),1.55(d,6H,J=7Hz).FAB-MS:m/e 176(M+H).
步骤2:2-异丙基-7-甲基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物由上步产物按实例7中A部分和B部分所述方法制得。得到的纯净理想产物为奶油色无定形粉末(在CHcl3-MeOH-NH4OH 40∶10∶1中,Rf为0.45)。
1H NMR(300MHz,CD3OD):8.20(d,1H,J=5Hz),7.50-7.70(m,4H),7.08-7.2(m,5H),5.6(s,2H),3.3(m,1H),2.68(s,3H),1.3(d,6H,J=7Hz)。FAB-MS:m/e 410(M+H)。
实例26
7-甲基-2-(3-甲基)丙基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
步骤1:7-甲基-2-(3-甲基)丙基-咪唑并〔4,5-b〕吡啶
标题化合物由2,3-二氨基-4-甲基吡啶(0.246g,2mmol)和3-甲基-丁酸(0.22ml,2mmol)按实例9中步骤1所述方法制备。粗产物用硅胶柱进行快速层析纯化,淋洗剂为EtOAc-MeOH(20∶1),得到纯净化合物(0.30g,78%),产物为褐色固体。
1H NMR(300MHz,CDCl3):8.20(d,1H,J=5Hz),7.05(d,1H,J=5Hz),2.90(d,2H,J=7Hz),2.70(s,3H),2.32(m,1H),1.11(d,6H,J=7Hz).FAB-MS:m/e 190(M+H).
步骤2:7-甲基-2-(3-甲基)丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物由上步产物按实例7中A部分和B部分所述方法制备。得到的纯净理想产物为奶油色无定形粉末。
1H NMR(300MHz,CD3OD):8.20(d,1H,J=5Hz),7.50-7.70(m,4H),7.08-7.2(m,5H),5.6(s,2H),2.75(d,2H,J=7Hz),2.68(s,3H),2.1(m,1H),0.92(d,6H,J=7Hz).FAB-MS:m/e 424(M+H).
实例27
制备2-环丙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)-甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物按实例9的方法,用环丙烷羧酸代替实例9步骤1中的丁酸制备。
1H NMR(300MHz,CD3OD):8.14(d,1H,J=5Hz),7.50-7.70(m,4H),7.08-7.2(m,5H),5.64(s,2H),2.61(s,3H),2.12(m,1H),1.11(m,4H).FAB-MS:m/e 408(M+H).
实例28
制备2-甲氧基甲基-7-甲基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
步骤1:2-甲氧基甲基-7-甲基-咪唑并〔4,5-b〕吡啶
将2,3-二氨基-4-甲基吡啶(0.1g,0.81mmol)和甲氧基乙酸(0.16ml,2mmol)的混合物在封管中加热到165℃反应24小时。然后使反应冷下来,用NH4OH中和。粗产物溶解于甲醇(2ml)中,加入硅胶(10g)。将干燥好的硅胶装到硅胶快速柱中,然后淋洗,先用EtOAc,再用含2%甲醇的EtOAc。得到的纯净理想产物为奶油色固体(0.067g,47%)。
1H-NMR(CDCl3):8.27(d,1H,J=5Hz),7.07(d,1H,J=5Hz),4.86(s,2H),3.57(s,3H),2.7(s,3H).FAB-MS:m/e 178(M+H).
步骤2:2-甲氧基甲基-7-甲基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物由步骤1的产物按实例9中步骤2所述方法制备。
1H NMR(300MHz,CD3OD):8.26(d,1H,J=5Hz),7.50-7.71(m,4H),7.05-7.26(m,5H),5.61(s,2H),4.64(s,2H),3.32(s,3H),2.67(s,3H).FAB-MS:m/e 412(M+H).
实例29
制备8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤
将6-氯-8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤0.030g)溶于乙醇(2ml)中,在Pd-C(10%(0.01g)存在下,通氢气搅拌24小时。然后滤去催化剂,将滤液蒸发至干,得到纯净理想产物,产物为玻璃态固体(0.020g)。
NMR(CD3OD):δ1.0(t,3H,J=7.4Hz),1.8(m,2H),2.88(t,2H,J=7.4Hz),5.56(s,2H),7.1-7.34(m,5H),7.45-7.7(m,4H),8.90(s,1H),8.98(s,1H).FAB-MS:m/e 397(M+H).
元素分析(C22H20N8):
C H N
计算值 66.00 5.00 28.00
实测值 65.57 5.34 27.67
例30
制备8-丁基-6-氯-9-(2′-(四唑-5-基)联苯-4-基)甲基-嘌呤
标题化合物由8-丁基-6-氯代嘌呤按照实例15中所述方法制备。
NMR(CD3OD):δ0.92(t,J=8Hz,3H),1.42(m,2H),1.75(m,2H),2.92(m,2H),5.58(s,2H),7.14(m,4H),7.5-7.7(m,5H),8.72(s,1H).FAB-MS:m/e 445 and 447(M+H).
元素分析(C23H21N8Cl):
C H N
计算值 62.09 4.72 25.20
实测值 61.79 4.95 25.32
实例31
制备8-丁基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤
标题化合物由8-丁基-6-氯-9-(2′-(四唑-5-基)-联苯-4-基)甲基-嘌呤按实例29所述方法制备。
NMR(CD3OD):δ0.99(t,3H,J=7.4Hz),1.30(m,2H),1.78(m,2H),2.88(t,2H,J=7.4Hz),5.55(s,2H),7.1-7.3(m,5H),7.45-7.63(m,4H),8.90(s,1H),8.98(s,1H),FAB-MS:m/e 411(M+H).
元素分析(C23H22N8)
C H N
计算值 67.32 5.37 27.32
实测值 67.76 5.54 27.67
实例32
制备2-氯-6-甲基-8-丙基-9-(2′-(四唑-5-基)-联苯-4-基)甲基嘌呤
步骤1:2-氯-6-甲基-8-丙基嘌呤
将2-氯-4,5-二氨基-6-甲基嘧啶(0.80g,5.04mmol),原丁酸三甲基酯(1.2ml,7.6mmol)和p-TsOH(0.08g)在2-甲氧基乙醇(24ml)的混合物在油浴中140℃加热反应24小时。按实例12中步骤2所述方法分离产物,并且快速层析纯化,淋洗剂为乙酸乙酯-己烷(1∶1),得到晶体标题化合物(0.5g,47%)。
NMR(CDCl3):δ1.03(t,J=8Hz,3H),1.9(q,2H),2.82(s,3H),3.0(t,J=8Hz,2H).FAB-MS:m/e 211 and 213(M+H).
元素分析(C9H11N4Cl)
C H N
计算值 51.31 5.26 26.60
实测值 51.43 5.50 26.81
步骤2:2-氯-6-甲基-8-丙基-9-(2′-(四唑-5-基)-联苯-4-基)甲基嘌呤
标题化合物由2-氯-6-甲基-8-丙基嘌呤(来自步骤1)按实例15中所述方法制备。
NMR(CD3OD):δ0.97(t,J=8Hz,3H),1.73(q,2H),2.77(s,3H),2.82(t,J=8Hz,2H),5.52(s,2H),7.1-7.3(m,4H),7.5-7.75(m,5H).FAB-MS:m/e 445 and 447(M+H).
元素分析(C23H21N8Cl)
C H N
计算值 62.09 4.72 25.20
实测值 61.79 4.95 25.32
实例33
制备2-二甲基氨基-6-甲基-8-丙基-9-(2′-(四唑-5-基)-联苯-4-基)甲基嘌呤
步骤1:2-二甲基氨基-6-甲基-8-丙基嘌呤
在0℃下,向2-氯-6-甲基-8-丙基嘌呤(来自例32步骤1)(0.1g,0.47mmol)的乙醇(2ml)溶液中加入缩合的二甲胺(1ml)。该混合物然后放在一钢弹中,在110℃加热7小时。待反应冷下来后,将反应混合物在真空下浓缩。得到的残余物分配于三氯甲烷和水中,分离有机相,并用MgSO4干燥。蒸去溶剂后得到的粗产物用硅胶柱进行快速层析纯化,淋洗剂为含5%甲醇的CHCl3,得到标题化合物,产物为无定形固体(0.065g,64%)。
NMR(CDCl3):δ1.01(t,J=8Hz,3H),1.8(q,J=8Hz,2H),2.65(s,3H),2.8(t,J=8Hz,2H),3.2(s,6H).FAB-MS:m/e 220(M+H).
步骤2:2-二甲基氨基-6-甲基-8-丙基-9-(2′-(四唑-5-基)-联苯-4-基)甲基嘌呤
标题化合物由2-甲基氨基-6-甲基-8-丙基-嘌呤(来自步骤1)按实例15中所用方法制备。
NMR(CD3OD):δ0.95(t,J=8Hz,3H),1.66(q,J=8Hz,2H),2.61(s,3H),2.75(t,J=8Hz,2H),3.2(s,6H),5.36(s,2H),7.07-7.23(m,4H),7.5-7.7(m,5H).FAB-MS:m/e 454(M+H)and 476(M+Na).
实例34
制备6-甲基-2-甲基氨基-8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤
步骤1:6-甲基-2-甲基氨基-8-丙基嘌呤
在-20℃下,向2-氯-6-甲基-8-丙基嘌呤(来自实例32步骤1)(0.1g,0.47mmol)的乙醇(2ml)中,加入缩合甲胺(1ml)。然后将混合物置于钢弹中,在110℃加热7小时。待反应冷下来后,真空浓缩反应混合物。得到的残余物分配于三氯甲烷和水中,分离有机层,并用硫酸镁干燥。去溶剂后得到的粗产物用硅胶柱进行快速层析纯化,淋洗剂为含5%甲醇的三氯甲烷,得到标题化合物,产物为无定形固体(0.115g,定量)。
NMR(CDCl3):δ1.03(t,J=8Hz,3H),1.8(q,J=8Hz,2H),2.64(s,3H),2.8(t,J=8Hz,2H),3.0(d,J=5Hz,3H),5.1(br s,1H).FAB-MS:m/e 206(M+H).
步骤2:6-甲基-2-甲基氨基-8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤
标题化合物由6-甲基-2-甲基氨基-8-丙基嘌呤(来自步骤1)按实例15中所述的方法制得。
NMR(CD3OD):δ0.90(t,J=8Hz,3H),1.62(q,J=8Hz,2H),2.5(s,3H),2.65(t,J=8Hz,2H),2.88(s,3H),5.26(s,2H),7.02(s,4H),7.3-7.5(m,5H).FAB-MS:m/e 440(M+H).
实例35
制备6-甲基-2-(吗啉-4-基)-8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤
步骤1:6-甲基-2-(吗啉-4-基)-8-丙基嘌呤
将2-氯-6-甲基-8-丙基嘌呤(来自实例32步骤1)(0.1g,0.47mmol)的吗啉(2ml)溶液置于钢弹中,并且将混合物在122℃加热18小时。待反应冷下来后,真空浓缩反应混合物。得到的剩余物溶于三氯甲烷(2ml)中,用硅胶柱进行快速层析纯化,淋洗剂为含5%MeOH的CHCl3,得到标题化合物,产物为无定形固体(0.1g,87%)。
NMR(CDCl3):δ1.03(t,J=8Hz,3H),1.8(q,J=8Hz,2H),2.65(s,3H),2.82(t,J=8Hz,2H),3.8(s,8H).FAB-MS:m/e 262(M+H).
步骤2:6-甲基-2-(吗啉-4-基)-8-丙基-9-(2′-(四唑-5-基)联苯-4-基)甲基嘌呤
标题化合物由6-甲基-2-(N-吗啉代)-8-丙基嘌呤(来自步骤1)按实例15所用方法制得。
NMR(CD3OD):δ0.90(t,J=8Hz,3H),1.62(q,J=8Hz,2H),2.54(s,3H),2.68(t,J=8Hz,2H),3.7(m,8H),5.29(s,2H),7.05(m,4H),7.4-7.6(m,5H).FAB-MS:m/e 496(M+H).
实例36
制备3-(2′-羧基联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶
7-甲基-2-丙基咪唑并〔4,5-b〕吡啶(在实例9中所述)用2-叔-丁氧羰基-4′-溴代甲基联苯烷基化,得到的被保护的衍生物按实例3中步骤2所用方法脱保护。
NMR(CDCl3):δ0.93(t,J=7.5Hz,3H),1.69(q,2H),2.63(s,3H),2.78(t,J=7.5Hz,2H),5.49(s,3H),7.04-7.5(m,8H),7.8(d,J=2.4Hz,1H),8.14(d,J=5Hz,1H).
FAB-MS:m/e 386(M+H).
实例37
制备7-甲基-3-(2′-(N-(苯磺酰)甲酰胺基-联苯-4-基)甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶
向含有3-(2′-羧基联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶(0.1g,0.26mmol)的干燥THF(5ml)悬浮液中加入1,1′-羰基二咪唑(0.042g,0.26mmol),将混合物回流3小时,然后冷至室温。再加入苯磺酰胺(0.05g,0.33mmol)和DBU(0.49ml,0.33mmol),并且将反应混合物在40℃搅拌7小时。待反应冷却后,真空浓缩。得到的剩余物溶于水(5ml)中,并用10%的NaH2PO4水溶液酸化至pH5,然后用EtOAc(3×20ml)萃取。合并有机相,并用硫酸镁干燥,真空浓缩得到粗产物。然后用硅胶柱进行快速层析纯化,淋洗剂为含2%MeOH的EtOAc,得到的理想产物为白色非晶形固体(0.087g,64%)。
NMR(CDCl3):δ1.0(t,J=7.5Hz,3H),1.8(q,2H),2.7(s,3H),2.78(t,J=7.5Hz,2H),5.50(s,3H),6.8-7.8(m,14H),8.2(d,J=5Hz,1H).
FAB-MS:m/e 525(M+H).
实例38
制备3-(2′-(N-(4-氯)苯磺酰基-甲酰胺基)联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶
标题化合物由3-(2′-羧基联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶和对-氯苯磺酰胺按实例37中所述方法合成。
NMR(CD3OD):δ0.99(t,J=7.5Hz,3H),1.76(m,2H),2.69(s,3H),2.87(t,J=7.5Hz,2H),5.60(s,3H),6.95(d,J=8Hz,2H),7.1-7.8(m,11H),8.25(d,J=5Hz,1H).FAB-MS:m/e 559 and 561(M+H).
元素分析(C30H27N4O3ClS)
C H N
计算值 64.46 4.83 10.03
实测值 64.78 5.07 10.26
实例39
制备3-(2′-(甲基磺酰基甲酰胺基)联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶
向含有3-(2′-羧基联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶(0.1g,0.26mmol)的干燥THF(5ml)的悬浮液中,加入1,1′-羰基二咪唑(0.042g,0.26mmol),将混合物回流3小时,然后冷至室温。加入甲磺酰胺的钠盐溶液[由甲磺酰胺(0.036g,0.39mmol)和NaH(0.39mmol)在DMF(1.5ml)中,于40℃下反应制得],并且将混合物在40℃搅拌8小时。待反应冷却后,真空浓缩。得到的剩余物溶于水(5ml)中,用10%的NaH2PO4水溶液酸化至pH5,并用EtOAc(3×20ml)萃取。合并有机相,用MgSO4干燥,并真空浓缩。得到粗产物,并用硅胶柱进行快速层析纯化,淋洗剂为含2% MeOH的EtOAc,得到白色非晶体固体理想产物(0.05g,42%)。
NMR(CD3OD):δ0.99(t,J=7.5Hz,3H),1.77(m,2H),2.67(s,3H),2.90(t,J=7.5Hz,2H),2.98(s,3H),5.62(s,3H),7.14-7.27(m,3H),7.37-7.6(m,6H),8.2(d,J=5Hz,1H).FAB-MS:m/e 463(M+H).
实例40
制备2-环丙基-5,7-二甲基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物按实例16所述方法,用环丙烷羧酸代替步骤2中的丙酸反应制得。
1H NMR(CD3OD;300MHz):δ1.08(m,4H),2.06(m,1H),2.55(s,3H),2.56(s,3H),5.63(s,2H),6.99(s,1H),7.10(m,4H),7.49-7.63(m,4H).FAB-MS:m/e 422(M+H).
制备7-甲基-2-丙基-3-(2′-三氟甲基亚磺酰氨基联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
实例41
步骤1:4-甲基-2′-硝基联苯
将装有机械搅拌,250ml恒压滴液漏斗并在顶部有氮气入口管和一个隔膜的1升三口(24/40)圆底烧瓶加热干燥,冷却,然后在氮气气氛中加入29.07g(0.17mol)对-溴甲苯的100ml无水四氢呋喃。搅拌溶液并冷至-78℃,在30分内,通过滴液漏斗加入200ml(0.34mol)1.7M的叔-丁基锂的戊烷溶液。加完之后,移去冷浴;将反应混合物继续搅拌30分钟,并允许加热到室温。再在10分钟内,用滴液漏斗向反应混合物中加入170ml(0.17mol)的1.0M氯化锌的乙醚溶液。把装有机械搅拌器,氮气导管和隔膜的另一1升三口(24/40)圆底烧瓶加热烘干,冷却,然后通氮气并加入4.04g(6.0mmol)二-(三苯基膦)钯化氯(Ⅱ)和50ml无水的四氢呋喃。开始搅拌并通过注射器向该悬浮液中加入8.0ml的1.5M氢化二异丁基铝(12mmol)的甲苯溶液。催化剂在室温下再搅拌10分钟。然后加入23.23g(0.115mol)的1-溴-2-硝基苯的100ml无水的四氢呋喃。然后将甲苯基锌化氯通过大直径套管转移到第二个烧瓶中。将反应混合物在室温下再搅拌45分钟。然后在放置蒸发器上蒸去大部分四氢呋喃。得到的油状物分配在乙酸乙酯和1.0N盐酸中。有机层连续用水和盐水洗涤干燥(MgSO4),过滤,蒸发。得到的剩余油状物用硅胶快速层析纯化,淋洗剂为含10%乙酸乙酯-己烷蒸发并在真空干燥后,得到粘性黄色油状体产物15.43g(63%)。
NMR(CDCl3):δ2.36(s,3H),7.16-7.24(m,4H),7.38-7.46(m,2H),7.55-7.62(m,1H),7.80(d,J=10Hz,1H);MS(FAB)m/e 214(MH+).
步骤2:4-溴代甲基-2′-硝基联苯
在装有机械搅动器,回流冷凝管和塞子的2升(24/40)三口圆底烧瓶中,加入15.427g(72mmol)4-甲基-2′-硝基[1,1′-联苯],1.2升四氯化碳,14.164g(80mmol)N-溴代丁二酰亚胺,0.50g 2,2′-偶氮二-(2-甲基丙腈)。通氮气,搅拌回流反应混合物4小时,然后冷至室温并过滤。滤液真空蒸发,得到的剩余油状物用硅胶快速层析纯化,淋洗剂为含10%乙酸乙酯-己烷。蒸发纯净部分得到黄色晶形固体产物(7.83g,37%)。
mp 109-110℃;NMR(CDCl3):δ4.52(s,2H),7.24-7.30(m,2H),7.40-7.52(m,4H),7.58-7.65(m,1H),7.86(d,J=10Hz,1H);MS(FAB)m/e 294(MH+).
步骤3:7-甲基-3-[(2′-硝基联苯-4-基)甲基]-2-丙基-3H-咪唑并〔4,5-b〕吡啶
向含有0.913g(5.2mmol)7-甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶的10ml无水二甲基甲酰胺溶液中加入0.210g(5.7mmol)60%氢化钠的矿物油分散体。通氮气,并将反应混合物磁力搅拌2小时,加入1.675g(5.7mmol)固体4-溴代甲基-2′-硝基联苯。反应混合物在室温下继续搅拌1小时,然后分配于乙酸乙酯和水中。萃取有机层,并用盐水洗,硫酸镁干燥,过滤并蒸发。得到的剩余油状体用硅胶快速层析纯化,淋洗剂为含75%乙酸乙酯-己烷,蒸发纯组分后,真空干燥,得到褐色固体产物1.009g(50%)。
NMR(CDCl3)δ0.97(t,J=8Hz,3H),1.70-1.83(m,2H),2.66(s,3H),2.81(t,J=10Hz,2H),5.52(s,2H),7.02(d,J=6Hz,1H),7.14-7.25(m,4H),7.36(d,J=10Hz,1H),7.42-7.48(m,1H),7.56-7.61(m,1H),7.82(d,J=10Hz,1H),8.20(d,J=6Hz,1H);MS(FAB)m/e 387(MH+).
步骤4:3-(2′-氨基联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶
向0.475g(1.23mmol)7-甲基-3-[(2′-硝基联苯-4-基)甲基]-2-丙基-3H-咪唑并〔4,5-b〕吡啶的15ml无水乙醇溶液中,加入50mg载于碳上含10%钯催化剂,将反应混合物在帕尔装置(parr apparatus)中用40磅/平方英寸氢气氢化。1小时后还原完全,将反应混合物过滤,真空蒸发,得到褐色固体(0.416g,95%),产物不需进一步纯化,可直接用在以后反应中。
NMR(CDCl3)δ0.98(t,J=8Hz,3H),1.70-1.86(m,3H),2.66(s,3H),2.83(t,J=10Hz,2H),3.64-3.72(br s,2H),5.52(s,2H),6.70-6.82(m,2H),7.00-7.19(m,5H),7.36(d,J=10Hz,2H),8.20(d,J=6Hz,1H);MS(FAB)m/e 357(MH+).
步骤5:7-甲基-2-丙基-3-(2′-三氟甲基亚磺酰氨基联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
室温下,通氮气并磁力搅拌含有0.115g(0.32mmol)步骤4的产物和0.092g(0.45mmol)2,6-二-叔丁基-4-甲基吡啶的1.5ml无水二氯甲烷溶液,并加入65ml(0.39mmol)三氟甲磺酸酐,在氮气氛中再续搅拌45分钟后,将反应混合物分散于乙酸乙酯和水中。萃取有机层,并用0.5N盐酸,水,盐水洗涤,硫酸镁干燥,过滤,蒸发。得到的剩余油状物用硅胶快速层析纯化,淋洗剂为75%乙酸乙酯-己烷,将洗脱液蒸干后,真空干燥,得到非晶形固体产物0.099g(63%)。
:NMR(CDCl3)δ0.98(t,J=9Hz,3H),1.74-1.86(m,2H),2.68(s,3H),2.82(t,J=10Hz,2H),5.54(s,2H),7.04(d,J=6Hz,1H),7.18-7.31(m,6H),7.33-7.41(m,1H),7.59(d,J=10Hz,1H),8.20(d,J=6Hz,1H);MS(FAB)m/e 489(MH+).
实例42
步骤1:5.7-二甲基-2-乙基-3-[2′-硝基联苯-4-基)甲基]-3H-咪唑并〔4,5-b〕吡啶
向含有0.199g(1.13mmol)5,7-二甲基-2-乙基-3H-咪唑并〔4,5-b〕吡啶的5ml无水二甲基甲酰胺中,加入0.050g(1.25mmol)60%氢化钠矿物油分散体。通氮气,磁力搅拌反应混合液30分钟,再加入0.365g(1.25mmol)4-溴甲基-2′-硝基联苯固体。将反应混合物在室温下再搅拌1.5小时,然后分散于乙酸乙酯和水中。萃取有机层,并用盐水洗,硫酸镁干燥,过滤,蒸发。得到的剩余物油状物用硅胶快速层析纯化,淋洗剂为50%乙酸乙酯-己烷,将纯净部分洗脱液蒸发后真空干燥,得到褐色固体产物0.340g(77%)
:NMR(CDCl3)δ1.31(t,J=10Hz,3H),2.58(s,3H),2.62(s,3H),2.78(q,J=10Hz,2H),5.48(s,2H),6.88(s,1H),7.14-7.24(m,4H),7.34-7.38(m,1H),7.42-7.48(m,1H),7.54-7.60(m,1H),7.83,(d,J=10Hz,1H);MS(FAB)m/e 387(MH+).
步骤2:3-(2′-氨基联苯-4-基)甲基-5,7-二甲基-2-乙-3H-咪唑并〔4,5-b〕吡啶
向含有0.340g(0.88mol)的步骤1产物的15ml无水乙醇溶液中,加入35mg10%载于碳上的钯催化剂,在帕尔装置中,用压力为40磅/平方英寸的氢气氢化。1.5小时后还原完全,将反应混合物过滤,真空蒸发,得到褐色固体(0.300g,95%),产物不需进一步纯化,可直接用在以后步骤中。
NMR(CDCl3)δ1.33(t,J=10Hz,3H),2.59(s,3H),2.64(s,3H),2.84(q,J=10Hz,2H),3.70(br s,2H),5.48(s,2H),6.70-6.82(m,2H),6.90(s,1H),7.03-7.22(m,4H),7.36(d,J=10Hz,2H);MS(FAB)m.e 357(MH+).
步骤3:5,7-二甲基-2-乙基-3-(2′-三氟甲基亚磺酰氨基-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
在0℃,通氮气,磁力搅拌条件下,向含有0.300g(0.84mmol)步骤2的产物和0.190g(0.93mmol)2,6-二-叔丁基-4-甲基吡啶的5.0ml二氯甲烷溶液中,加入156ml(0.93mmol)三氟代甲磺酸酐。反应混合物在氮气氛中继续搅拌1小时,并缓慢加热到室温,然后将反应混合物分散于乙酸乙酯和水中。萃取有机层,并依次用0.5N盐酸,水,盐水洗涤,硫酸镁干燥,过滤并蒸发。剩余油状物用硅胶快速层析纯化,淋洗剂为乙酸乙酯,得到半纯净产物。浓缩部分用硅胶柱重新层析,淋洗剂为含5%甲醇的三氯甲烷,蒸发后真空干燥,得到非晶形固体产物0.090g(22%)。
NMR(CDCl3)δ1.33(t,J=10Hz,3H),2.58(s,3H),2.63(s,3H),2.79(q,J=10Hz,2H),5.51(s,2H),6.89(s,1H),7.21-7.31(m,6H),7.34-7.40(m,1H),7.58(d,J=11Hz,1H);MS(FAB)m/e 489(MH+).
实例43
步骤1:2′-甲基联苯-4-羧酸甲酯
将装有机械搅拌器,顶部有氮气导管的500ml恒压滴液漏斗、隔膜的2升三口(24/40)圆底烧瓶烘干,冷却,然后通氮气,加入含70.00g(0.409mol)的邻-溴甲苯的350ml无水四氢呋喃溶液。搅拌溶液,并冷至-78℃,在45分钟,通过滴液漏斗加入481ml(0.818mol)1.7M叔-丁基锂的戊烷溶液。滴加完毕,移去冷浴,将反应混合物搅拌45分钟,并加热至室温。在滴液漏斗中再装入409ml(0.409mmol)1.0M氯化锌的乙醚溶液在20分内,滴入到反应混合物中。将另一个装有机械搅拌器、氮气导管,隔膜的2升三口(24/40)圆底烧瓶烘干,冷却。然后在通氮气情况下,加入8.93g(13.7mmol)二-(三苯基膦)镍化氯(Ⅱ),58.71g(0.273mol)2-溴代苯甲酸甲酯和450ml无水四氢呋喃。通过大口径导管将甲苯基氯化锌的悬浮液转移到第二个烧瓶中,室温下将反应混合物再搅拌45分钟,然后在旋转蒸发器上移动大部分四氢呋喃。得到的油状体分散于乙酸乙酯(500ml)和水(300ml)中。有机层连续被水,5%盐酸,水,盐水,洗涤,然后干燥(MgSO4),过滤,蒸发。得到的剩余物油状体用Waters Prep 500高效液相色谱柱(HPLC)(2硅包),淋洗剂为含1.5%乙酸乙酯的己烷,以十一次分离淋洗(混合组分再循环,每次注射10g)。纯净部分蒸发,并在真空中除去剩余溶剂得到53.42g(74%)无色油状体。
NMR(CDCl3)δ2.25(s,3H),3.93(s,3H),7.19-7.28(m,4H),7.39(d,J=12Hz,2H),8.08(d,J=12Hz,2H);MS(FAB)m/e(MH+).
步骤2:2′-溴甲基联苯-4-羧酸甲酯
在装有机械搅拌器,回流冷凝管且在其上部有氮气导管,温度计的5升三口(24/40)圆底烧瓶中,加入53.42g(0.204mol)2′-甲基联苯-4-羧酸甲酯,3.4升四氯化碳,38.09g(0.214mol)N-溴丁二酰亚胺和2.0g 2,2′-偶氮二(2-甲基丙腈)。用氮气冲洗烧瓶,排出空气,然后开始搅拌,回流反应物5小时。待反应混合物冷至室温后,过滤并蒸发。得到的剩余油状体用二氯甲烷-己烷重结晶纯化,得到48.48g(78%)产物
mp:80-81℃;NMR(CDCl3)δ3.94(s,3H),4.40(s,2H),7.20-7.26(m,1H),7.32-7.41(m,2H),7.48-7.54(m,3H),8.12(d,J=12Hz,2H);MS(EI)m/e 304,306(M+).
分析:(C15H13BrO2)C,H
步骤3:2′-[(氨基亚氨基甲基)硫代]甲基联苯-4-羧酸甲酯氢溴化物
向含4.120g(54.1mmol)硫脲的80ml无水乙醇中加入有15.01g(49.2mmol)2′-溴甲基联苯-4-羧酸甲酯的25ml无水乙醇溶液,磁力搅拌混合液,并回流4小时。冷至室温后,将在反应结晶出来的部分产物过滤分离。其余的产物通过向滤液中加乙醚结晶出来,过滤,并合并所有产物,真空干燥,得到异硫脲鎓盐(isothiouronium)17.108g(91%)。
mp.233-234℃;MS(FAB)m/e 301(MH+-Br)
步骤4:2′-(N-叔-丁基亚磺酰氨基)甲基联苯-4-羧酸甲酯
在500ml(24/40)圆底烧瓶中,加入含7.58g(19.9mmol)步骤3产物的175ml冰醋酸和25ml水的悬浮液,于0℃下磁力搅拌,并通过毛细移液管通入氯气反应。20分钟后,停止氯化作用,得到均相的黄绿色溶液,500ml水稀释。分离的油层用乙醚萃取。有机层用水,5%的硫代硫酸钠水溶液,盐水洗涤,然后干燥(MgSO4),过滤和蒸发。得到的剩余油状物用乙醚-己烷结晶,并在真空中短暂干燥,得到磺酰氯:MS(EI)m/e 324(M+)。该磺酰氯然后溶于20ml二氯甲烷中,并将该溶液慢慢滴加到搅拌着的含有10ml(95.0mmol)叔丁胺的20ml二氯甲烷溶液中,室温搅拌20分后,将反应混合物分散于二氯甲烷和水中。有机层用1N盐酸,水洗涤,并干燥(MgSO4),过滤和蒸发。得到的产物用硅胶快速层析纯化,淋洗剂为含25%乙酸乙酯的己烷,得到5.050g(70%)粘性油状体氨磺酰化合物。
:NMR(CDCl3)δ1.16(s,9H),3.94(s,3H),4.28(s,2H),7.24-7.29(m,1H),7.36-7.43(m,2H),7.45(d,J=12Hz,1H),7.64-7.70(m,1H),8.08(d,J=12Hz,1H);MS(EI)m/e 361(M+)。
步骤5:2-N-叔-丁基亚磺酰氨基甲基-4-羟甲基联苯
向磁力搅拌的含5.050g(14.0mmol)的氨磺酰-酯化合物(步骤4)的25ml无水四氢呋喃溶液中,于室温下通氮氯用注射器慢慢加入18ml(18.0mmol)1.0M的氢化锂铝的四氢呋喃溶液,室温下将反应混合物搅拌5小时。然后滴加水分解过量的还原剂。所得的悬浮液用乙酸乙酯稀释,水层用浓盐酸酸化至沉淀出的盐重新溶解为止。萃取并分离有机层,并用水,盐水洗涤,干燥(MgSO4),过滤并蒸发。得到的剩余油状体用硅胶快速层析纯化,淋洗剂为含75%乙酸乙酯的己烷,将纯净部分蒸发并真空干燥后,得到2.282g(49%)粘性油状产物。
NMR(CDCl3)δ1.15(s,9H),1.56(s,1H),3.87(s,1H),4.32(2,2H),4.74(br s,2H),7.24-7.28(m,1H),7.34-7.45(m,6H),7.64-7.69(m,1H);MS(EI)m/e 333(M+).
步骤6:2-N-叔丁基亚磺酰氨基-4′-碘甲基-联苯
在一装有磁力搅拌棒和隔膜的干燥的15ml(14/20)圆底烧瓶中,依次加入1.162g(3.49mmol)步骤5的产物,7.0ml二氯甲烷,0.73ml(5.23mmol)三乙胺,通氮气,在0℃搅拌。用注射器慢慢加入甲磺酰氯(0.33ml,4.18mmol),然后搅拌反应混合物30分钟。然后将反应混合物分散于二氯甲烷和水中;分离有机层,并干燥(MgSO4),过滤和蒸发。得到的剩余油状物重新溶于3.0ml丙酮中,室温磁力搅拌,并用含1.045g(7.0mmol)碘化钠的10ml丙酮处理。搅拌15分之后,真空浓缩反应混合物,得到的剩余物分散于乙酸乙酯和水中。然后分离有机层,并用5%硫代硫酸钠溶液,盐水洗涤,干燥(MgSO4),过滤,蒸发并真空干燥,得到1.486g(96%)粘性油状碘化物。NMR(CDCl3)δ1.14(s,9H),3.87(宽的单峰,1H),4.30(s,2H),4.48(s,2H),7.24-7.32(m,3H),7.34-7.46(m,4H),7.64-7.68(m,1H);MS(EI)m/e 443(M+)。
步骤7:3-(2′-N-叔-丁基亚磺酰氨基甲基联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶
向含0.587g(3.35mmol)7-甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶的8.0ml无水二甲基甲酰胺溶液中加入0.161g(4.02mmol)60%氢化钠的矿物油分散体,并且将该反应混合物在氮气保护下室温搅拌30分钟。此时,用套管将含1.486g(3.35mmol)步骤6的产物的2.0ml无水二甲基甲酰胺溶液转到反应混合物中。将反应混合物在室温下再搅拌45分钟,然后分散于乙酸乙酯和水中。有机层分离,并用水,盐水洗涤,干燥(MgSO4),过滤和蒸发。得到的剩余油状物用硅胶快速层析纯化,淋洗剂为乙酸乙酯。蒸发适宜部分,真空干燥,得到粘性油状产物0.982g(60%)。
NMR(CDCl3)δ0.98(t,J=10Hz,3H),1.11(s,9H),1.82(m,2H),2.67(s,3H),2.84(t,J=10Hz,2H),3.88(s,1H),4.24(s,2H),5.51(s,2H),7.02(d,J=8Hz,1H),7.14-7.24(m,3H),7.26-7.37(m,4H),7.60-7.65(m,1H),8.18(d,J=8Hz,1H);MS(EI)m/e 490(M+).
步骤8:7-甲基-2-丙基-3-(2′-亚磺酰氨基甲基-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
在0.982g(2.00mmol)步骤7产物的2.0ml二氯甲烷溶液中加入2.0ml三氟乙酸,反应混合物在室温下,氮气保护搅拌16小时。然后真空浓缩反应混合物。得到的剩余物用硅胶快速层析纯化,淋洗剂为含80%乙酸乙酯的己烷。在浓缩纯净部分之后,真空干燥得到非晶形固体伯氨磺酰(Primary sulfonamide)产物0.835g(96%)。
NMR(CDCl3)δ1.02(t,J=10Hz,3H),1.76-1.88(m,2H),2.74(s,3H),3.08(t,J=10Hz,2H),4.29(s,2H),4.63(br s,2H),5.63(s,2H),7.17-7.40(m,8H),7.58-7.64(m,1H),8.33(d,J=8Hz,1H);MS(EI)m/e 434(M+).
步骤9:3-(2′-(N-乙酰基)亚磺酰氨基甲基联苯-4-基)甲基-7-甲基-2-丙基-3H-咪唑并〔4,5-b〕吡啶
向乙酸酐(0.5ml)和吡啶(0.5ml)溶液中加入0.034g(0.078mmol)步骤8的产物,所得到反应混合物在室温下,氮气保护磁力搅拌16小时。真空蒸发反应混合物,得到的剩余物用硅胶快速层析纯化,淋洗剂为乙酸乙酯。蒸发纯净部分接收液并真空干燥得到0.018g(49%)白色泡沫状产物。
NMR(CDCl3)δ1.03(t,J=10Hz,3H),1.94(m,2H),2.05(s,3H),2.86(s,3H),3.21(t,J=10Hz,2H),4.55(s,2H),5.66(s,2H),7.16-7.38(m,8H),7.46-7.49(m,1H),8.47(d,J=8Hz,1H),8.92(br s,1H);MS(EI)m/e 476(M+).
实例44
5-溴-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
步骤1:5-氯-2-乙基-7-甲基咪唑并〔4,5-b〕吡啶
将2-乙基-7-甲基咪唑并〔4,5-b〕吡啶(28g,174mmol)和间-氯过苯甲酸(80-90%,44.6g)的三氯甲烷(300ml)溶液加热回流0.5小时。将混合物浓缩并纯化(SiO2,100% CH2Cl2梯度改变到30%CH2Cl2/MeOH),得到29.8g 2-乙基-7-甲基-咪唑并〔4,5-b〕吡啶-4-氧化物固体。
1H NMR(300MHz,CD3OD)δ8.13(d,1H,J=6Hz),7.13(d,1H,J=6Hz),3.01(q,2H,J=7.5Hz),2.60(s,3H),1.46(t,3H,J=7.5Hz).
将N-氧化物(29.75g,0.168mol),CHCl3(25ml)和POCl3(160ml)混合物在80℃加热1小时。然后倒进冰中后,小心滴加NH4OH中和混合物,然后用EtOAc萃取。浓缩得到23.8g固体5-氯-2-乙基-7-甲基咪唑并〔4,5-b〕吡啶。
1H NMR(250MHz,CDCl3)δ7.07(s,1H),3.10(q,2H,J=7.5Hz),2.67(s,3H),1.48(t,3H,J=7.5Hz)。
步骤2:5-溴-2-乙基-7-甲基咪唑并〔4,5-b〕吡啶
将上述氯化物(22.2g,0.113mol)的30% HBr-HOAc混合物在100℃加热19小时。然后将混合物倒进冰中,用NH4OH中和,萃取(5×EtOAc),浓缩有机层,并用EtOAc结晶得到15g(主要产物)固体溴化物。
1H NMR(300MHz,CDCl3)δ7.22(s,1H),3.13(q,2H,J=7.5Hz),2.66(s,3H),1.47(t,3H,J=7.5Hz)。
步骤3:5-溴-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物由5-溴-2-乙基-7-甲基咪唑并〔4,5-b〕吡啶按实例7中所述方法制得。
1H NMR(300MHz,CD3OD)δ7.68-7.62(m,2H),7.57-7.50(m,2H),7.31(s,1H),7.13-7.05(m,4H),5.51(s,2H),2.87(q,2H,J=7.5Hz),2.62(s,3H),1.26(t,3H,J=7.5Hz)。
实例45
5-氯-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物由5-氯-2-乙基-7-甲基咪唑并〔4,5-b〕吡啶按实例7中所述方法制得。
1H NMR(300MHz,CD3OD)δ7.65-7.59(m,2H),7.57-7.49(m,2H),7.17(s,1H),7.10(表观单峰,4H),5.05(s,2H),2.86(q,2H,J=7.5Hz),2.63(s,3H),1.26(t,3H,J=7.5Hz)。
实例46
5-氰基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
将5-溴-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(41mg),CuCN(80mg)和吡啶(0.2ml)混合物在160℃加热搅拌4小时。在加热过程中吡啶被蒸馏掉。加热到50℃,使冷的黑色块状物在15分内溶于2ml20%KCN水溶液中。滴加乙酸(2ml)(注意:放出HCN),萃取混合物(2×EtOAc)。干燥有机层(Na2SO4),浓缩,纯化(SiO2,80/20/1 CH2Cl2/-MeOH-NH4OH)得到26mg固体标题化合物。
1H NMR(250MHz,CD3OD)δ7.66-7.45(m,7.57有一单峰),5H),7.15-7.04(m,4H),5.53(s,2H),2.91(q,2H,J=7.5Hz),2.66(s,3H),1.27(t,3H,J=7.5Hz)。
实例47
5-羧基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
室温下向纯的5-氰基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(20mg)加入H2SO4(0.5ml)和水(0.25ml)。将反应混合物在100℃加热3小时,然后冷至0℃,滴加NH4OH使混合物呈碱性。再滴加甲醇(5ml)然后将混合物过滤,浓缩并纯化(SiO2,60∶40∶1 CH2Cl2-CH3OH-NH4OH)得到17mg固体标题化合物。
FAB MS(M++1)=440;1H NMR(300MHz,CD3OD)δ7.90(s,1H),7.56-7.39(m,4H),7.05(表观单峰,4H),5.62(s,2H),2.86(q,2H,J=7.5Hz),2.67(s,3H),1.26(t,3H,J=7.5Hz)。
实例48
5-(乙氧基羰基)-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并-〔4,5-b〕吡啶
将干燥氯化氢作泡状通过5-羧基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(200mg)的EtOH(50ml)淤浆中,通入时间为30秒。混合物变成均相,然后在室温搅拌18小时。浓缩,中和(NH4OH),分散于稀的HOAC水溶液和EtOAc中,然后蒸发有机层得到220mg固体标题化合物。
1H NMR(300MHz,CD3OD)δ7.94(s,1H),7.63-7.56(m,2H),7.51(表观三重峰,2H,J=8Hz),7.12-7.03(AB 四重峰,4H),5.62(s,2H),4.44(q,2H,J=7.2Hz),2.86(q,2H,J=7.5Hz),2.70(s,3H),1.43(t,3H,J=7.2Hz),1.27(t,3H,J=7.5Hz)。
实施49
2-乙基-5-(甲氧基羰基)-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并-〔4,5-b〕吡啶
标题化合物与实例48类似的方法制得。
1H NMR(300MHz,CD3OD)δ7.98(s,1H),7.68-7.62(m,2H),7.54(表观三重峰,2H,J=8Hz),7.16-7.06(AB四重峰,4H),5.66(s,2H),3.99(s,3H),2.91(q,2H,J=7.5Hz,2.71(s,3H),1.28(t,3H,J=7.5Hz)。
实例50
5-(苄氧基羰基)-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用与实例48类似的方法制得。
FAB MS(M++1)=530;1H NMR(300MHz,CD3OD)δ7.96(s,1H),7.58-7.33(m,9H),7.12-7.03(AB四重峰,4H),5.60(s,2H),5.44(s,2H),2.90(q,2H,J=7.5Hz),2.68(s,3H),1.28(t,3H,J=7.5Hz)。
实例51
2-乙基-5-(异-丙氧基羰基)-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用与实例48类似的方法制得。
FAB MS(M++1)=482;1H NMR(300MHz,CD3OD)δ7.93(s,1H),7.57-7.38(m,4H),7.07(s,4H),5.61(s,2H),5.29(五重峰,1H,J=6.3Hz),2.89(q,2H,J=7.5Hz),2.69(s,3H),1.42(d,2H,J=6.3Hz),1.27(t,3H,J=7.5Hz)。
实例52
5-(正-丁氧基羰基)-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用与实例48类似的方法制得。
1H NMR(300MHz,CD3OD)δ7.92(s,1H),7.61(t,2H,J=7.6Hz),7.55-7.45(m,2H),7.18-7.03(AB四重峰,4H),5.62(s,2H),4.38(t,2H,J=6.6Hz),2.89(q,2H,J=7.5Hz),2.67(s,3H),1.84-1.73(m,2H),1.59-1.43(m,2H),1.26(t,3H,J=7.5Hz),0.99(t,3H,J=7.5Hz)
实例53
5-甲酰胺基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
室温下,向5-氰基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(22mg)中,加入0.63ml 0.5N氢氧化钠水溶液,甲醇(0.3ml)和H2O2(0.018ml)。搅拌16小时后,将溶液蒸发并纯化(SiO2,80/20/1 CH2Cl2/MeOH/NH4OH)得到20mg固体。
1H NMR(300MHz,CD3OD)δ7.91(s,1H),7.58-7.41(m,4H),7.12-7.03(AB四重峰,4H),5.58(s,2H),2.89(q,2H,J=7.5Hz),2.68(s,3H),1.27(t,3H,J=7.5Hz)
实例54
2-乙基-7-甲基-5-(吗啉-4-基)羰基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
室温下,向5-(乙氧基羰基)-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(30mg)在THF(1ml)中加入0.25ml吗啉和NaH(20mg,80% 分散体)。搅拌16小时后,加入1% HOAc水溶液(2ml)。萃取(EtOAc),纯化(SiO2,75/25/1 CH2Cl2/MeOH/NH4OH)得到10mg固体。
1H NMR(300MHz,CD3OD)δ7.62-7.52(m,2H),7.50-7.42(m,2H),7.40(s,1H),7.06(s,4H),5.52(s,2H),3.82-3.72(m,4H),3.58-3.46(m,4H),2.94(q,2H,J=7.5Hz),2.69(s,3H),1.30(t,3H,J=7.5Hz)。
实例55
2-乙基-7-甲基-5-(异丙基)-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
在-78℃向5-溴-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(75mg)的THF(2ml)中依次加入ZnCl2(1.58ml,1M/乙醚),异丙基镁化氯(0.79ml,2M/乙醚),四个三苯基膦基钯(15mg)。加完之后将反应加热至室温并搅拌16小时。萃取(用EtOAc从稀HOAc中),纯化(SiO2,80/20/1 CH2Cl2/MeOH/NH4OH)得到43mg固体。
1H NMR(300MHz,CD3OD)δ7.60-7.50(m,2H),7.45(t,2H,J=6.9Hz),7.12-7.00(m,5H),5.50(s,2H),3.10(五重峰,1H,J=6.9Hz),2.84(q,2H,J=7.5Hz),2.59(s,3H),1.31(d,6H,J=6.9Hz),1.24(t,3H,J=7.5Hz)。
实例56
5-乙基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用与实例55类似的方法制得。
1H NMR(300MHz,CD3OD)δ7.64-7.43(m,4H),7.12-7.00(m,5H),5.52(s,2H),2.90-2.78(m,4H),2.58(s,3H),1.35-1.19(m,6H)。
实例57
2-乙基-5-(正-己基)-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用与实例55类似的方法制得。
1H NMR(300MHz,CD3OD)δ7.60(t,2H,J=7.8Hz),7.54-7.44(m,2H),7.14-7.03(m,4H),7.06(s,1H),5.53(s,2H),2.90-2.78(m,4H),2.59(s,3H),1.78-1.64(m,2H),1.40-1.24(m,6H),1.24(t,3H),J=7.5Hz),0.86(t,3H,J=6Hz)。
实例58
2-乙基-7-甲基-5-苯基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用与实例55类似的方法制备。
1H NMR(300MHz,CD3OD)δ8.07(d,2H,J=7.2Hz),7.63(S,1H),7.58-7.34(m,7H),7.16-7.04(m,4H),5.56(s,2H),2.89(q,2H),J=7.5Hz),2.69(s,3H),1.29(t,3H,J=7.5Hz)。
实例59
2-乙基-7-甲基-5-(四唑-5-基)-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
将5-氰基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(54mg),三甲基甲锡烷基叠氮(79mg),甲苯(5ml),DMF(1ml)的混合物110℃加热24小时。浓缩并纯化(SiO2,70/30/1 CH2Cl2/MeOH/NH4OH),得到47mg固体。
1H NMR(300MHz,CD3OD)δ7.93(s,1H),7.56-7.38(m,4H),7.14-7.05(AB四重峰,4H),5.61(s,2H),2.86(q,2H,J=7.5Hz),2.71(s,3H),1.27(t,3H,J=7.5Hz)。
实例60
5-乙酰基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
在0℃,向5-氰基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(137mg)的THF(5ml)溶液中加入甲基镁化溴(0.70ml,3M/乙醚溶液)。搅拌6小时后,加入10%HOAc水溶液,并且将混合物在50℃加热10分钟,然后用EtOAc萃取。纯化(SiO2,93/3/4 CH2Cl2/MeOH/HOAc)得到40mg标题化合物。
1H NMR(300MHz,CD3OD)δ7.88(s,1H),7.67-7.60(m,2H),7.58-7.50(m,2H),7.28-7.05(AB四重峰,4H),5.63(s,2H),2.95(q,2H,J=7.5Hz),2.70(s,3H),2.68(s,3H),1.30(t,3H,J=7.5Hz)。
实例61
2-乙基-5-((RS)-1-羟基)乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
在0℃下,向5-乙酰基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(25mg)的MeOH(1ml)中加入NaBH4(50mg)。0.5小时之后,再加入1% HOAc水溶液(2ml)。萃取(EtOAc),纯化(SiO2,93/3/4 CH2Cl2/MeOH/HOAc)得到25mg标题化合物。
1H NMR(300MHz,CD3OD)δ7.58(t,2H,J=7.5Hz),7.48(t,2H,J=7.5Hz),7.27(s,1H),7.14-7.02(AB四重峰,4H),5.54(s,2H),4.94(q,1H,J=6.6Hz),2.85(q,2H,J=7.5Hz),2.63(s,3H),1.51(d,3H,J=6.6Hz),1.24(t,3H,J=7.5Hz)。
实例62
2-乙基-5-(羟甲基)-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
在-78℃,向5-(乙氧基羰基)-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(50mg)的THF(1ml)溶液中加入氢化二异丁基铝(0.534ml,1M/THF)。在-78℃反应1小时后,将混合物加热到室温,加入1%HOAc水溶液(2ml)萃取(EtOAc),纯化(SiO2,80/20/1 CH2Cl2/MeOH/NH4OH)得到28mg固体。
1H NMR(300MHz,CD3OD)δ7.57(t,2H,J=7.5Hz),7.48(t,2H,J=7.5Hz),7.26(s,1H),7.08-7.02(AB四重峰,4H),5.54(s,2H),4.74(s,2H),2.85(q,2H,J=7.5Hz),2.66(s,3H),1.26(t,3H,J=7.5Hz)。
实例63
2-乙基-5-(2-羟基丙-2-基)-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
在-78℃,向5-(乙氧基羰基)-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(43mg)的THF(1ml)溶液中加入溴化甲基镁(0.77ml,3M乙醚溶液)。萃取(EtOAc,从NH4Cl水溶液中萃取)纯化(SiO2,93/3/4 CH2Cl2/MeOH/HOAc),得到20mg标题化合物。
1H NMR(300MHz,CD3OD)δ7.56-7.40(m,4H),7.39(s,1H),7.24-7.04(AB四重峰,4H),5.50(s,2H),2.87(q,2H,J=7.5Hz),2.64(s,3H),1.59(s,6H),1.27(t,3H,J=7.5Hz).
实例64
2-乙基-5-(3-羟基戊-3-基)-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用与实例63类似的方法制备。
1H NMR(300MHz,CD3OD)δ7.65-7.59(m,2H),7.51(m,2H),7.30(s,1H),7.20-7.02(AB四重峰,4H),5.50(s,2H),2.90(q,2H,J=7.5Hz),2.65(s,3H),2.07-1.79(m,4H),1.27(t,3H,J=7.5Hz),0.68(t,6H,J=7.2Hz)。
实例65
5-氨基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
将5-溴-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(2.0g),水合肼(15ml)在120℃加热24小时。浓缩并纯化(SiO2,85/14/2 CH2Cl2/MeOH/NH4OH)得到1.80g 5-肼基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶。室温下,用氢气(1atm.)在W-2阮内镍(1ml,50%分散体/水)存在下将上述化合物在甲醇(50ml)中还原48小时,纯化(SiO2,85/14/2 CH2Cl2/MeOH/NH4OH)后,得到标题化合物(1.44g)。
1H NMR(300MHz,CD3OD)δ7.60-7.50(m,2H),7.49-7.42(m,2H),7.10-7.00(m,4H),6.38(s,1H),5.39(s,2H),2.79(q,2H,J=7.5Hz),2.49(s,3H),1.21(t,3H,J=7.5Hz)。
实例66
5-氨基-2-乙基-7-(三氟甲基)-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
0℃下,向2,6-二氨基-4-三氟甲基吡啶(173mg)的H2SO4(3ml)混合物中加入HNO3(0.048ml,d=1.40)。将搅拌着的混合物逐渐加热到室温,时间约1.5小时,然后倒在50g冰中,用NH4OH中和,EtOAc萃取,通过20g SiO2过滤(用EtOAc洗涤,至洗脱液为黄色为止),浓缩得到70mg 2,6-二氨基-3-硝基-4-三氟代甲基吡啶黄色固体。氢化该硝基化合物(65mg)的1∶1 THF/MeOH溶液(1atm H2,Ra-Ni,室温下16小时),过滤,浓缩,按实例21所概述的方法转化为标题化合物。
FAB MS(M++1)=465;1H NMR(300MHz,CD3OD)δ7.61(t,2H,J=7.8Hz),7.54-7.48(m,2H),7.13-7.04(AB四重峰,4H),6.74(s,1H),5.41(s,2H),2.79(q,2H,J=7.5Hz),1.16(t,3H,J=7.5Hz).
实例67
2-乙基-5-(甲基氨基)-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
将5-溴-2-乙基-7-甲基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(74mg),甲基胺(0.6g,EtOH(2ml)的混合物在弹中180℃加热反应16小时。浓缩并纯化(SiO2,90/9/1 CH2Cl2/MeOH/NH4OH)得到34.4mg标题化合物。
1H NMR(300MHz,CD3OD)δ7.60-7.51(m,2H),7.49-7.42(m,2H),7.17-7.05(m,4H),6.33(s,1H),5.44(s,2H),2.90(s,3H),2.79(q,2H,J=7.8Hz),2.47(s,3H),1.22(t,3H,J=7.8Hz)。
实例68
5-(二甲基氨基)-2-乙基-7-甲基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用与实例67的类似方法制得。
1H NMR(300MHz,CD3OD)δ7.60-7.52(m,2H),7.51-7.44(m,2H),7.18-7.05(AB四重峰,4H),6.52(s,1H),5.45(s,2H),3.12(s,6H),2.88(q,2H,J=7.8Hz),2.54(s,3H),1.24(t,3H,J=7.8Hz)。
实例69
5-(甲基氨基)-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用与实例20类似的方法制备。
1H NMR(300MHz,CD3OD)δ7.69-7.55(m,3H),7.55-7.45(m,2H),7.20-7.03(AB四重峰,4H),6.52(d,1H,J=8.7Hz),5.47(s,2H),2.92(s,3H),2.82(t,2H,J=7.3Hz),1.78-7.62(m,2H),0.96(t,3H,J=7.4Hz)。
实例70
5-(二甲基氨基)-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用与实施例20中类似的方法制备。
1H NMR(300MHz,CD3OD)δ7.67(d,1H,J=9Hz),7.60-7.40(m,4H),7.18-7.00(AB四重峰,4H),6.63(d,1H,J=9Hz),5.40(s,2H),3.10(s,6H),2.78(t,2H,J=7.5Hz),1.73-1.59(m,2H),0.93(t,3H,J=7.4Hz)。
实例71
2-乙基-5-(己基氨基)-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用与实例67类似的方法制备。
1H NMR(300MHz,CD3OD)δ7.57-7.48(m,2H),7.48-7.38(m,2H),7.15-7.02(AB四重峰,4H),6.28(s,1H),5.38(s,2H),3.33-3.28(m,2H),2.80(q,2H,J=7.5Hz),2.45(s,3H),1.68-1.55(m,2H),1.45-1,25(m,8H),1.21(t,3H,J=7.5Hz),0.87(t,3H,J=7.0Hz)。
实例72
5-(2-氨基乙基)氨基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用与实例67类似的方法制备。
1H NMR(300MHz,CD3OD)δ7.67(d,1H,J=6.6Hz),7.49-7.39(m,3H),7.07(d,2H,J=8Hz),6.89(d,2H,J=8Hz)6.33(s,1H),5.45(s,2H),3.55(t,2H,J=5Hz),3.12(t,2H,J=5Hz),2.89(q,2H,J=7.8Hz),2.50(s,3H),1.31(t,3H,J=7.8Hz)。
实例73
5-(羧基甲基)氨基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用与实例67类似的方法制备。
1H NMR(300MHz,CD3OD)δ7.53-7.35(m,4H),7.08-7.00(AB四重峰,4H),6.28(s,1H),5.35(s,2H),3.89(s,2H),2.74(q,2H,J=7.5Hz),2.49(s,3H),1.20(t,3H,J=7.5Hz)。
实例74
2-乙基-7-甲基-5-(4-吗啉代)-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例67所述的方法制备
1H NMR(300MHz,CD3OD)δ7.65-7.58(m,2H),7.51(t,2H,J=7.2Hz),7.17-7.05(AB四重峰,4H),6.67(s,1H),5.45(s,2H),3.81(t,2H,J=5Hz),3.53(t,2H,J=5Hz),2.87(q,2H,J=7.5Hz);2.56(s,3H),1.24(t,3H,J=7.5Hz)。
实例75
2-乙基-7-甲基-5-(甲基硫代)-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例67中所述的方法制备。
1H NMR(300MHz,CD3OD)δ7.68-7.61(m,2H),7.51(t,2H,J=7.8Hz),7.19-7.03(AB四重峰,4H),7.00(s,1H),5.52(s,2H),2.87(q,2H,J=7.8Hz),2.58(s,6H),1.26(t,3H,J=7.8Hz)。
实例76
2-乙基-5-羟基-7-甲基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例67所述的方法制备。
1H NMR(300MHz,CD3OD)δ7.61-7.52(m,2H),7.51-7.43(m,2H),7.06(表观单峰,4H),6.44(s,1H),5.41(s,2H),2.80(q,2H,J=7.5Hz),2.55(s,3H),1.22(t,3H,J=7.5Hz)。
实例77
5-乙氧基-2-乙基-7-甲基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例67所述的方法制备。
1H NMR(300MHz,CD3OD)δ7.64-7.57(m,2H),7.55-7.47(m,2H),7.17-7.04(AB四重峰,4H),6.52(s,1H),5.45(s,2H),4.35(q,2H,J=7.2Hz),2.86(q,2H,J=7.8Hz),2.56(s,3H),1.37(t,3H,J=7.2Hz),1.22(t,3H,J=7.8Hz)。
实例78
5-(乙酰氨基乙基)氨基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
0℃下,向5-(2-氨基乙基)氨基-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(20mg)的THF(1ml)中加入AcCl(3.4μl)和三乙胺(18μl)。反应1小时后,将溶剂蒸发,将得到的剩余物纯化(SiO2,80∶20∶1 CHCl3,MeOH,NH4OH),得到17mg标题化合物。
1H NMR(300MHz,CD3OD)δ7.63-7.45(m,4H),7.18-7.04(AB四重峰,4H),6.33(s,1H),5.43(s,2H),3.47(t,2H,J=5Hz),3.38(t,2H,J=5Hz),2.86(q,2H,J=7.8Hz),2.47(s,3H),1.90(s,3H),1.22(t,3H,J=7.8Hz)。
实例79
2-乙基-5-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例16所述的方法制备。
1H NMR(300MHz,CDCl3)δ7.85(d,1H,J=8Hz),7.59-7.47(m,2H),7.31(dd,1H,J=7.2,1.8Hz),7.16(d,1H,J=8Hz),6.92-6.74(AB四重峰,4H),5.32(s,2H),2.54(s,3H),2.52(q,2H),1.12(t,3H)。
实例80
5-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)-甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例16所述的方法制备。
1H NMR(300MHz,CD3OD)δ7.87(d,1H,J=8Hz),7.69-7.58(m,2H),7.59-7.49(m,2H),7.20(d,1H,J=8Hz),7.09(表观单峰,4H),5.57(s,2H),2.80(q,2H,J=7.5Hz),2.63(s,3H),0.96(t,3H,J=7.5Hz)。
实例81
6-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)-甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例16所述的方法制备。
1H NMR(300MHz,CD3OD)δ8.20(s,1H),7.82(s,1H),7.63-7.54(m,2H),7.52-7.44(m,2H),7.07(表观单峰,4H),5.53(s,2H),2.82(t,2H,J=7.5Hz),2.48(s,3H),1.80-1.75(m,2H),0.96(t,3H,J=7.5Hz)。
实例82
6-溴-7-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)-甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例10步骤1和实例7所述的方法制备。
1H NMR(300MHz,D6-丙酮)δ8.35(s,1H),7.78(d,1H),7.68-7.48(m,4H),7.18-7.08(AB四重峰,4H),5.55(s,2H),2.85(t,2H,J=7.5Hz),2.67(s,3H),1.80-1.75(m,2H),0.98(t,3H,J=7.5Hz)。
实例83
7-乙基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
将叔丁基锂(0.978ml,1.7M/戊烷)加到冷的(-78℃)7-甲基-2-丙基咪唑并〔4,5-b〕吡啶(97mg,0.554mmol)的THF(5ml)溶液中。2小时后,将反应加热到0℃约1分钟,然后又冷回到-78℃,加入MeI(0.172ml),在-78℃将混合物搅拌1小时,然后加热到0℃约反应1分钟,然后骤冷(NH4OH)。萃取并纯化(SiO2,2% MeOH/EtOAc),得到85mg7-乙基-2-丙基咪唑并〔4,5-b〕吡啶,将该化合物按实例7中B部分所用方法转化成标题化合物。
1H NMR(250MHz,CD3OD)δ8,28(d,1H,J=6Hz),7.72-7.65(m,2H),7.62-7.54(m,2H),7.22(d,1H,J=6Hz),7.17-7.08(AB四重峰,4H),5.61(s,2H),3.12(q,2H,J=9Hz),2.89(t,2H,J=9Hz),1.80-1.63(m,2H),1.41(t,3H,J=9Hz),0.99(t,3H,J=9Hz)。
实例84
7-异丙基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)-甲基-3H-咪唑并〔4,5-b〕吡啶
7-异丙基-2-丙基咪唑并〔4,5-b〕吡啶的制备是通过将7-乙基-2-丙基咪唑并〔4,5-b〕吡啶按实例83中第一部分所述的经过金属取代-烷基取代顺序的方法进行的。标题化合物用类似于实例7中B部分所述的方法制得。
1H NMR(300MHz,CDCl3)δ8.11(d,1H,J=5Hz),7.88(dd,1H,J=7.5,1.5Hz),7.58-7.46(m,2H),7.37-7.32(m,1H),7.04(d,1H,J=5Hz),7.03-6.85(AB四重峰,4H),5.37(s,2H),3.48-3.34(m,1H),2.56(t,2H,J=7.2Hz),1.76-1.62(m,2H),1.22(d,6H,J=6.6Hz),0.92(t,3H,J=7.2Hz)。
实例85
7-乙基-2-乙基-3-(2′-(四唑-5-基)联苯-4-基)-甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例83所述的方法制得。
1H NMR(250MHz,CD3OD).δ8.21(d,1H,J=5Hz),7.56-7.37(m,4H),7.15(d,1H,J=5Hz),7.09-6.97(AB四重峰,4H),5.53(s,2H),3.08(9.2H,J=8Hz),2.88(q,2H,J=7.5Hz),1.38(t,3H,J=7.5Hz),1.26(t,3H,J=7.5Hz)。
实例86
6-羟基甲基-7-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
在冷的(-78℃)搅拌着的2-丙基-6-溴-7-甲基咪唑并〔4,5-b〕吡啶(540mg,2.15mmol)的THF(20ml)溶液中,30秒内加入叔丁基锂(4.40ml,1.7M/戊烷)。45分钟之后,再加入二甲基甲酰胺(0.665ml),续搅拌10分钟,然后将反应加热至室温,并用20%的NH4Cl水溶液骤冷。用EtOAc萃取(4×10ml),纯化(SiO2,4% MeOH/EtOAc),得到2-丙基-7-甲基咪唑并-〔4,5-b〕吡啶-6-醛(2-propyl-7-methylimidazo[4,5-b]pyridine-6-carboxaldehyde)(350mg)。向搅拌着的冷的(0℃)上述醛(300mg)的甲醇化的(methanolic)(15ml)溶液中加入NaBH4(84mg),30分钟后,再加入HOAC(0.1ml),将混合物加热至室温,浓缩,纯化(SiO2,10%MeOH/CH2Cl2),得到190mg 6-羟甲基-7-甲基-2-丙基-咪唑并〔4,5-b〕吡啶油状物。标题化合物用类似于实例7中B部分所述的方法制得。
1H NMR(300MHz,CD3OD)δ8.25(s,1H),7.59-7.41(m,4H),7.18-7.09(AB四重峰,4H),5.52(s,2H),4.79(s,2H),2.83(t,2H,J=7.5Hz),2.70(s,3H),1.78-1.63(m,2H),0.96(t,3H,J=7.5Hz)。
实例87
2-丙基7-(对-甲苯基)-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例55所述的方法制得。
1H NMR(300MHz,CDCl3)δ7.95-7.84(m,3H),7.62-7.49(m,3H),7.43-7.33(m,2H),7.28-7.22(m,2H),6.98-6.93(AB四重峰,4H),5.45(s,2H),2.49(t,2H,J=7.5Hz),2.38(s,3H),1.68-1.54(m,2H),0.83(t,3H,J=7.5Hz)。
实例88
2-丙基-7-甲基-6-(对-甲苯基)-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例55中所述的方法制得。
1H NMR(300MHz,CDCl3)δ8.13(s,1H),7.64-7.54(m,2H),7.54-7.44(m,2H),7.32-7.24(m,2H),7.16-7.04(m,6H),5.57(s,2H),2.87(t,2H,J=7.5Hz),2.57(s,3H),2.42(s,3H),1.78-1.65(m,2H),0.99(t,3H,J=7.5Hz)。
实例89
5-氯-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)-甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用5-氯-2,3-吡啶二胺作原料按类似于实例9中所述的方法制得。
1H NMR(300MHz,1∶1 CD3OD/CDCl3)δ7.90(d,1H,J=8.4Hz),7.64-7.39(m,4H),7.24(d,1H,J=8.4Hz),7.10-7.00(AB四重峰,4H),5.44(s,2H),2.73(t,2H,J=7.5Hz),1.81-1.67(m,2H),0.94(t,3H,J=7.5Hz)。
实例90
6-氨基-5,7-二甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用3,5,6-三氨基-2,4-二甲基吡啶为原料按类似于实例20中所述的方法制得。
1H NMR(300MHz,CD3OD)δ7.62-7.52(m,2H),7.52-7.42(m,2H),7.06(s,4H),5.53(s,2H),2.85(t,2H,J=7.5Hz),2.53(s,3H),2.45(s,3H),1.72-1.55(m,2H),0.93(t,3H,J=7.5Hz)。
实例91
7-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)-甲基-3H-咪唑并〔4,5-b〕吡啶-4-氧化物
将7-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(9mg)和间-氯过氧苯甲酸(6mg)的三氯甲烷(2ml)溶液加热回流2小时。浓缩,纯化(SiO2,80∶20∶1 CH2Cl2/MeOH/NH4OH)得到4mg标题化合物固体。
1H NMR(300MHz,CD3OD)δ8.07(d,1H,J=6Hz),7.60-7.43(m,4H),7.19(d,1H,J=6Hz),7.09(s,4H),6.14(s,2H),2.82(t,2H,J=7.5Hz),2.63(s,3H),1.81-1.67(m,2H),0.98(t,3H,J=7.5Hz)。
实例92
5,7-二甲基-6-羟基-2-丙基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物的制备可通过将6-氨基-5,7-二甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶在浓盐酸中与1当量的NaNO2在室温下重氮化,然后加热至80℃,反应2小时,并依次进行中和(NH4OH)萃取、纯化完成的。
实例93
5,7-二甲基-2(3,3,3-三氟丙-2-基)-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物按类似于实例16的方法制备。
FAB MS(M++1)=478
实例94
2-(3-丁炔-1-基)-5,7-二甲基-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物按类似于实例16的方法制备。Rf=0.52(tlc.Merck kieselgel 60 F-254,40/10/1 CHCl3MeOH NH4OH)
实例95
5,7-二甲基-2-甲基-3-(2′-(四唑-5-基)联苯-4-基)-甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物按类似于实例16的方法制备。
FAB MS(M++1)=396.1H NMR(300MHz,CD3OD)δ7.62-7.53(m,2H),7.52-7.44(m,2H),7.08-7.00(AB四重峰,4H),7.02(s,1H),5.51(s,2H),2.58(s,3H),2.50(s,3H)
实例96
7-氯-2-乙基-5-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用5-甲基-2-乙基咪唑并〔4,5-b〕-吡啶作原料,按类似于实例44中步骤1和实例45所述的方法制得。
1H NMR(300MHz,CD3OD)δ7.68-7.56(m,2H),7.58-7.48(m,2H),7.26(s,1H),7.10(s,4H),5.55(s,2H),2.86(q,2H,J=7.5Hz),2.61(s,3H),1.25(t,3H,J=7.5Hz)。
实例97
2-乙基-5-甲基-7-(4-吗啉代)-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用7-氯-2-乙基-5-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶为原料,按类似于实例67所述的方法制备。
1H NMR(300MHz,CD3OD)δ7.60-7.50(m,2H),7.50-7.42(m,2H),7.12-6.90(AB四重峰,4H),6.51(s,1H),5.45(s,2H),3.95-3.78(m,8H),2.74(q,2H,J=7.5Hz),2.50(s,3H),1.22(t,3H,J=7.5Hz)。
实例98
2-乙基-5-甲基-7-(甲基氨基)-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例96所述的方法制备。
1H NMR(300MHz,CD3OD)δ7.58-7.49(m,2H),7.49-7.40(m,2H),7.11-6.90(AB四重峰,4H),6.37(s,1H),5.45(s,2H),3.04(s,3H),2.75(q,2H,J=7.5Hz),2.51(s,3H),1.26(t,3H,J=7.5Hz)。
实例99
7-(二甲基氨基)-2-乙基-5-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例96所述的方法制备。
1H NMR(300MHz,CD3OD)δ7.58-7.39(m,4H),7.13-6.87(AB四重峰,4H),6.36(s,1H),5.45(s,2H),3.46(s,6H),2.73(q,2H,J=7.5Hz),2.49(s,3H),1.25(t,3H,J=7.5Hz)。
实例100
2-乙基-5-甲基-7-(甲基硫代)-3-(2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用类似于实例75所述的方法制备。
1H NMR(300MHz,CD3OD)δ7.55-7.38(m,4H),7.18-6.95(AB四重峰,4H),7.00(s,1H),5.49(s,2H),2.81(q,2H,J=7.5Hz),2.62(s,3H),2.60(s,3H),1.22(t,3H,J=7.5Hz)。
实例101
5,7-二甲基-2-乙基-3-(4′-氯-2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
步骤1:2-氰基-4-硝基-4′-甲基联苯
在氮气保护下,向含有对-甲苯基三甲基锡(389mg,1.525mmol)的无水甲苯(5ml)溶液中,加入2-溴-5-硝基-苯腈(276mg,1.22mmol)和Pd(P Ph3)4(176mg,10mol %)。在氮气存在下,将反应搅拌回流24小时,然后冷至室温。混合物用EtOAc稀释,经过硅藻土填料过滤除去固体。将滤液真空浓缩,剩余物用硅胶柱进行快速色谱纯化,淋洗剂为己烷/乙酸乙酯(10∶1),得到214mg(74%)浅黄色固体标题产物。
1H NMR(300MHz,CDCl3)δ2.42(s,3H),7.32(d,2H),7.48(d,2H),7.69(d,1H),8.45(dd,1H),8.61(s,1H)。
步骤2:N-三苯基甲基-5-(4′-甲基-4-硝基联苯-2-基)四唑
标题化合物用2-氰基-4-硝基-4′-甲基联苯(步骤1产物)为原料,按欧洲专利申请EP0,291,969中已叙述的方法制备。
1H NMR(300MHz,CDCl3)δ2.28(s,3H),6.89(d,6H),6.98(AB四重峰,4H),7.22-7.37(化合物(comp.9H),7.56(d,1H)8.31(dd,1H),8.75(d,1H)。
步骤3:N-三苯基甲基-5-(4-氯-4′-甲基联苯-2-基)四唑
在室温下,用40磅/平方英寸的氢气在10%载于碳上的钯(50mg)存在下,氢化N-三苯基甲基-5-(4′-甲基-4-硝基联苯-2-基)四唑(0.115g,0.224mmol)的MeOH/DMF(2ml/12ml)溶液反应1小时。将反应用硅藻土过滤,滤液真空浓缩。在氢化作用中,三苯基甲基基团被去掉。粗的4-氨基化合物溶于冰醋酸(3ml)中,且将该溶液慢慢加到冷的(0℃)NaNO2(28.8mg,0.417mmol)的浓H2SO4(1ml)溶液中,将重氮化的溶液均匀搅拌2小时,然后慢慢加到凉的(0℃)CuCl(0.449mg,20当量)的浓HCl溶液中。将混合物搅拌30分钟,然后倒入水中,用Et2O/EtOAc萃取。合并有机萃取液,并且水,盐水洗涤,MgSO4干燥,真空浓缩。得到的产物用硅胶柱进行快速层析纯化,淋洗剂为己烷/乙酸乙酯/乙酸(80∶20∶1),得到27mg(两步产率,45%)5-(4-氯-4′-甲基-联苯-2-基)四唑。未取代的四唑溶于CH2Cl2(3.5ml)中,加入NEt3(0.035ml,2.5当量)和Ph3CCl(27mg,1.0当量)。反应30分之后,反应物用Et2O稀释,并用10%柠檬酸,1N NaOH和盐水洗涤。有机相用无水MgSO4干燥,并真空浓缩,得到51.2mg(100%)粗的N-三苯基甲基-5-(4-氯-4′-甲基-联苯-2-基)四唑产物。
1H NMR(300MHz,CDCl3,δ2.26(s,3H),6.91(d,6H),6.94(AB四重峰,4H),7.20-7.25(化合物(Comp),7H),7.43(dd,1H),7.99(dd,1H)。
步骤4:N-三苯基甲基-5-(4′-溴甲基-4-氯-联苯-2-基)四唑
标题化合物用N-三苯基甲基-5-(4-氯-4′-甲基-联苯-2-基)四唑(步骤1到3)为原料,按欧洲专利申请EP0,291,969中已述方法制备。
步骤5:5,7-二甲基-2-乙基-3-(4′-氯-2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
标题化合物用5,7-二甲基-2-乙基咪唑并〔4,5-b〕-吡啶和N-三苯基甲基-5-(4′-溴甲基-4-氯代联苯-2-基)四唑为原料,按类似实例7的方法制备。标题化合物以其盐酸盐形式分离得到。
1H NMR(300MHz,CD3OD)δ1.38(t,3H),2.72(s,6H),3.28(q,2H),5.82(s,2H),7.18(d,2H),7.36(d,2H),7.44(s,1H),7.58(d,1H),7.72(dd,1H),7.76(d,1H);FAB质谱,m/e 444(M+H),C24H22N7Cl计算值,444)。
实例102
5,7-二甲基-2-乙基-3-(4′-氟-2′-(四唑-5-基)-联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
按与实例102类似的方法,用表1所列的中间体来制备这种和其它血管紧张肽Ⅱ拮抗物。
实例103
5-(乙酰氧基甲基)-2-乙基-7-甲基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶
将2-乙基-5-(羟甲基)-7-甲基-3-((2′-四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(34mg),乙酸酐(0.25ml),和三乙胺(0.5ml)的CH2Cl2(2ml)混合物室温搅拌3小时。从HOAc稀的水溶液中萃取(EtOAc),并纯化(SiO2,80/20/1 CH2Cl2/MeOH/NH4OH),得到30mg标题化合物。
FAB MS:M+1=468;1H NMR(300MHz,CD3OD)δ7.66-7.57(m,2H),7.55-7.46(m,2H),7.19(s,1H),7.13-7.02(AB四重峰,4H),5.53(s,2H),5.23(s,2H),2.86(q,2H,J=7.5Hz),2.63(s,3H),2.11(s,3H),1.25(t,3H,J=7.5Hz)。
实例104
含有本发明化合物的典型药物组合物
A:每粒胶囊中含50mg活性组分的干燥充填胶囊。
组分 每粒胶囊中含量(mg)
7-甲基-2-丙基-3- 50
(2′-(四唑-5-基)联苯
-4-基)甲基-3H-咪唑并
〔4,5-b〕吡啶
乳糖 149
硬脂酸镁 1
胶囊(大小No.1) 200
将7-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶破碎成60号粉末,将乳糖和硬脂酸镁通过在上述粉末上的60号吸湿布。然后将合并的组分混合10分钟,填入1号干燥明胶胶囊中。
B:片剂
典型片剂含有7-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(25mg),美国药典(USP)的预胶凝化淀粉(82mg),微晶纤维素(82mg)和硬脂酸镁(1mg)。
C.复合片剂(Combination Tablet)
典型复合片剂中含有如一种象氢氯化硫代叠氮(hydrochlorothiazide)的利尿剂(7.5mg),氢氯化硫代叠氮(hydrochlorothiazide)(50mg),美国药典(USP)的预胶化淀粉(82mg),微晶纤维素(82mg)和硬脂酸镁(1mg)。
D.栓剂
适合直肠施药的典型栓剂制剂中含有7-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(1-25mg),丁基化的羟基苯甲醚(0.08-1.0mg),乙二胺四乙酸二钠钙盐(0.25-0.5mg)和聚乙二醇(775-1600mg)。
其它栓剂制剂可以通过上述栓剂中某些成分制备。如用丁基化的羟基甲苯(0.04-0.08mg)取代乙二胺四乙酸二钠钙盐,氢化的植物油(675-1400mg)如suppocire L,We cobee FS,We cobee M,Witepsols和其它类似的植物油取代聚乙二醇。并且,这些栓剂制剂也可以包含另外一种活性成份的药物有效量,如上面C中所述,这种活性成份如另外一种抗高血压剂和/或一种利尿剂和/或一种血管紧张肽转换酶和/或钙通道阻滞剂(Calcium channel blocker)。
E:注射剂
典型的注射制剂含有7-甲基-2-丙基-3-(2′-(四唑-5-基)联苯-4-基)甲基-3H-咪唑并〔4,5-b〕吡啶(5.42mg),二价无水磷酸钠(11.4mg),苄醇(0.01ml)和注射剂用水(1.0ml)。这种注射制剂也可以含有另外一种活性成份的药物有效量,这种活性成份如另一种抗高血压剂和/或一种利尿剂和/或一种血管紧张肽转换酶和/或钙通道阻滞剂。
Claims (59)
1、制备下式化合物及其药物上可接受的盐的方法:
其中
R1是
(a)-CO2R4,
(b)-SO3R5,
(c)-NHSO2CF3,
(d)-PO(OR5)2,
(e)-SO2-NH-R9,
(f)-CONHOR5,
(h)-SO2NH-杂芳基,
(i)-CH2SO2NH-杂芳基,
(j)-SO2NHCO-R23,
(k)-CH2SO2NHCO-R23,
(l)-CONH-SO2R23,
(m)-CH2CONH-SO2R23,
(n)-NHSO2NHCO-R23,
(o)-NHCONHSO2-R23,
(p)-SO2NHCONR23,
其中杂芳基是未被取代的,单取代的或双取代的5或6元芳香环,该芳香环可以任意含有1-3个杂原子,杂原子选自O、N或S,其中取代基选自以下基团:-OH,-SH,-C1-C4烷基,-C1-C4烷氧基,卤原子(Cl,Br,F,I),-NO2,-CO2H,-CO2-C1-C4-烷基,-NH2,-NH(C1-C4烷基)和-N(C1-C4烷基)2;
R2a和R2b分别是H,卤原子(Cl,Br,I,F),-NO2,-NH2,C1-C4-烷基氨基,二(C1-C4烷基)氨基,-SO2NHR9,CF3,C1-C4-烷基,或C1-C4-烷氧基;
R3a是(a)H,
(b)卤原子(Cl,Br,I,F)
(c)C1-C6-烷基,
(d)C1-C6-烷氧基,
(e)C1-C6-烷氧基烷基,
R3b是(a)H,
(b)卤原子(Cl,Br,I,F),
(c)NO2,
(d)C1-C6-烷基,
(e)C1-C6-酸基,
(f)C1-C6-环烷基,
(g)C1-C6-烷氧基,
(h)-NHSO2R4,
(i)羟基C1-C4-烷基,
(j)芳基C1-C4-烷基,
(k)C1-C4烷硫基
(l)C1-C4烷基亚磺酰基,
(m)C1-C4-烷基磺酰基,
(n)NH2
(o)C1-C4烷基氨基
(p)C1-C4-二烷基氨基
(q)氟化C1-C4烷基
(r)-SO2-NHR9
(s)芳基或
(t)呋喃基;
其中芳基是任意被一个或两个取代基取代的苯基或萘基,这些取代基选自以下基团:卤原子(Cl,Br,I,F),C1-C4-烷基,C1-C4-烷氧基,NO2,CF3,C1-C4-烷硫基,OH,NH2,NH(C1-C4-烷基),N(C1-C4-烷基)2,CO2H,和CO2-C1-C4-烷基;
R4是H,直链或支链C1-C6-烷基,芳基或-CH2-芳基,该芳基如上述定义;
E是一个单键,-NR13(CH2)s-,
-s(O)x-(CH2)s-,在此x为0-2,s为0-5,-CH(OH)-,-O-,-CO-;
R6是(a)芳基,如上述定义,是任意被1或2个取代基取代的,这些取代基选自卤原子(Cl,Br,I,F)-O-C1-C4-烷基,C1-C4-烷基,-NO2,-CF3,-SO2NR9R10,-S-C1-C4-烷基,-OH,-NH2,C3-C7-环烷基,C3-C10-链烯基;
(b)直链或支链C1-C9-烷基,C2-C6-链烯基或C2-C6炔基,均可分别被取代基任意取代,这些取代基选自以下基团:如上述定义的芳基,C3-C7-环烷基,卤原子(Cl,Br,I,F)-OH,-NH2,-NH(C1-C4-烷基)2,-NH-SO2R4,-COOR4,-CF3,-CF2CH3,-SO2NHR9,或
(c)未被取代、单取代或双取代芳香5或6元环,该环可含有一或两个选自N,O或S的原子,并且其中取代基选自以下基团:-OH,-SH,C1-C4-烷基,C1-C4烷氧基-CF3,卤原子(Cl,Br,I,F),或NO2;
(d)全氟代-C1-C4-烷基,
(e)任意被C1-C4烷基或-CF3单或双取代的C3-C7-环烷基;
R9是H,C1-C5-烷基,芳基或-CH2-芳基,在此芳基如上述定义;
R10是H,C1-C4-烷基;
R12是-CN,-NO2或-CO2R4;
R13是H,-CO(C1-C4-烷基),C1-C6-烷基,烯丙基,C3-C6环烷基,苯基或苄基;
R14是H,C1-C8-烷基,C1-C8-全氟烷基,C3-C6环烷基,苯基或苄基;
R15是H,C1-C6-烷基;
R16是H,C1-C6-烷基,C3-C6环烷基,苯基或苄基;
R17是-NR9R10,-OR10,-NHCONH2,-NHCSNH2,
R18和R19分别是C1-C4烷基或共同形成-(CH2)q-,在此q为2或3;
R20是H,-NO2,-NH2,-OH,或-OCH3;
R23是(a)如上述定义的芳基,
(b)如上述定义的杂芳基,
(c)C3-C4-环烷基,
(d)任意被取代基取代的C1-C4烷基,这些取代基选自以下基团;如上述定义的芳基,如上述定义的杂芳基,-OH,-SH,-C1-C4-烷基,-O(C1-C4-烷基),-S(C1-C4-烷基),-CF3,卤原子(Cl,Br,F,I),-NO2,-CO2H,-CO2-C1-C4-烷基,-NH2,NH(C1-C4-烷基),-NHCOR4a,-N(C1-C4烷基)2,-PO3H,-PU(OH)(C1-C4-烷基),-PO(OH)(芳基)或-PO(OH)(O-C1-C4-烷基),
(e)全氟-C1-C4-烷基;
x不存在或者是
(a)一个碳-碳单键,
(b)-CO-,
(c)-O-,
(d)-S-,
(h)-OCH2-,
(i)-CH2O-
(j)-SCH2-,
(k)-CH2S-,
(l)-NHC(R9)(R10),
(m)-NR9SO2-,
(n)-SO2NR9-,
(o)-C(R9)(R10)NH-,
(p)-CH=CH-,
(q)-CF=CF-,
(r)-CH=CF-,
(s)-CF=CH-,
(t)-CH2CH2-,
(u)-CF2CF2-,
Z是、O,NR13或S;
-A-B-C-D-代表连接在咪唑上饱和的或不饱和的6元杂环的组成原子,该杂环含有1-3个氮原子,并且包括下列结构:
其中:
R7基团可以相同或不同,并且代表:
(a)氢,
(b)C1-C6直链或支链烷基,或C2-C6链烯基,或炔基,均可分别被取代或未被取代,取代基选自:
i)-OH,
ii)C1-C4-烷氧基,
iii)-CO2R4,
iv)-OCOR4,
viii)-N(R4)2,
ix)如上述定义的芳基,
x)如下述(p)中定义的杂环,
xi)-S(O)xR23,
xii)四唑-5-基,
xiii)-CONHSO2R23,
xiv)-SO2NH-杂芳基,
xv)-SO2NHCOR23,
xix)-OP(OR4)2,
xx)-PO(OR4)R9,
C)卤原子,如氯、溴、碘,
d)全氟-C1-C4-烷基,
e)-OH,
f)-NH2,
i)-OR23,
j)-CO2R4,
k)-CON(R4)2,
l)-NH-C3-C7-环烷基,
m)C3-C7环烷基,
n)如上述定义的芳基,或
o)5或6元饱和的或不饱和的杂环,该环最多含有三个杂原子,杂原子选自O,N或S,其中S可以以亚矾或矾的形式存在,并且该杂环任意被1个或两个取代基所取代,这些取代基选自以下基团:卤原子(Cl,Br,F,I),C1-C4-烷基,C1-C4-烷氧基,C1-C4-S(O)x-,在此x如上述定义,CF3,NO2,OH,CO2H,CO2-C1-C4-烷基,NH2,NH(C1-C4-烷基)或N(R4)2,
p)-CN,
q)
r)-SO2N(R4)2,
s)四唑-5-基,
t)-CONHSO2R23,
u)-PO(OR4)2,
v)-NHSO2CF3,
w)-SO2NH-杂芳基,
x)-SO2NHCOR23
y)-S(O)x-R23
z)
aa)-PO(OR4)R9,
bb)-NHSO2R23,
cc)-NHSO2NHR23,
dd)-NHSO2NHCOR23,
ee)NHCONHSO2R23,
ff)-N(R4)CO2R23,
jj)-CO-C1-C4-芳基,
kk)-SO2NH-CN,
R8基团可以相同或不同并且代表:
a)氢,
b)未被取代或被羟基,C1-C4-烷氧基,-N(R4)2,-CO2R4或C3-C5-环烷基取代的C1-C6-烷基或链烯基,
c)C3-C5环烷基,
R8a是R8或C1-C4酰基,
R9a基团可以相同或不同并且代表:
a)氢,
b)未被取代或被下述基团取代的C1-C6烷基:
i)羟基,
ii)-CO2R4,
iii)-CONHR4,或
iv)-CON(R4)2,
该方法包括式1化合物与式2化合物反应,去除保护基团后,如果需要可以进行纯化,得到所述式(Ⅰ)化合物,并可任意通过常规方法制备该化合物的盐,式1和式2如下:
式中R6、A、B、C、D、E、R1、R2a、R2b、R3a、R3b和X的定义如上,Q为离去基团。
2、根据权利要求1的方法,其中所述化合物1在与化合物2反应前,先在适宜的极性溶剂中用碱处理。
3、根据权利要求2的方法,其中所述碱选自碱金属氢化物,烷基锂,金属醇盐或叔胺。
4、根据权利要求2的方法,其中所述极性溶剂选自四氢呋喃、二噁烷,二甲基甲酰胺、二甲亚砜或醇类。
5、根据权利要求1的方法,其中所述离去基团是囟化物或拟囟化物。
6、根据权利要求1的方法,其中所述化合物(Ⅰ)是通过提取、结晶或层析方法制备和纯化的。
8、根据权利要求7的方法,其中所述化合物3在非质子传递溶剂中,与适宜的羧酸活化剂反应,得到活化羧酸中间体,在适宜的叔胺碱存在下,用所述式4化合物或预制的式4化合物的碱金属盐处理该活化羧酸中间体。
9、根据权利要求8的方法,其中所述羧酸活化剂选自碳酰二咪唑,碳化二亚胺,草酰氯、亚硫酰氯、五氯化磷、氯甲酸酯,或N(N,N-二苯基氨基甲酰基)氯化吡啶鎓。
10、根据权利要求8的方法,其中所述非质子传递溶剂选自苯、甲苯、二甲苯、四氢呋喃、二噁烷、二甘醇二甲醚、二甲基甲酰胺、二甲亚砜、四烷基脲或乙腈。
11、根据权利要求8的方法,其中所述预制式4化合物的碱金属盐是在溶剂中通过式4化合物与碱金属氢化物或烷基锂反应制取的,所述溶剂选自苯、甲苯、二甲苯、四氢呋喃、二噁烷、二甘醇二甲醚、二甲基甲酰胺、二甲亚砜或四烷基脲。
13、根据权利要求12的方法,其中所述化合物6的反应衍生物是在适宜的非质子传递溶剂中和在适宜的叔胺碱存在下,通过式5化合物或预制的式5化合物的碱金盐反应制备的。
14、根据权利要求12的方法,其中式6化合物的反应衍生物是在适宜的溶剂中,通过式6化合物与适宜的羧酸活化剂反应得到的。
15、根据权利要求13或14的方法,其中所述溶剂选自苯、甲苯、二甲苯、四氢呋喃、二噁烷、二甘醇二甲醚、二氯甲烷、氯仿、二甲基甲酰胺、二甲亚砜、四烷基脲或乙腈。
16、根据权利要求15的方法,其中所述羧酸活化剂选自碳酰二咪唑,碳化二亚胺,草酰氯、亚硫酰氯、五氯化磷、氯甲酸酯,或N(N,N-二苯基氨基甲酰基)氯化吡啶鎓。
18、根据权利要求17的方法,其中所述式5化合物与式7化合物或式7a化合物在适宜的非质子传递溶剂中和在适宜的叔胺碱存在下进行反应。
19、根据权利要求18的方法,其中所述非质子传递溶剂选自苯、甲苯、二甲苯、四氢呋喃、二噁烷、二氯甲烷、氯仿、二甘醇二甲醚、二甲基甲酰胺、二甲亚砜、四烷基脲或乙腈。
21、根据权利要求20的方法,其中所述式8和式9化合物是在适宜的非质子传递溶剂中和在有机过渡金属催化剂存在下进行反应。
22、根据权利要求21的方法,其中所述非质子传递溶剂选自苯、甲苯、二甲苯、四氢呋喃、二噁烷、二甘醇二甲醚、二甲基甲酰胺、二甲亚砜、四烷基脲或乙腈。
23、根据权利要求21的方法,其中所述催化剂选自有机钯、有机镍-钯、有机铁-镍或有机铁-钯基化合物。
24、根据权利要求20的方法,其中所述离去基团是囟化物(Cl,Br,F,I)或拟囟化物。
25、根据权利要求24的方法,其中所述拟囟化物选自甲磺酰,三氟甲磺酰,苄甲磺酰或p-甲苯磺酰。
27、根据权利要求26的方法,其中所述式9和式10化合物是在适宜的非质子传递溶剂中和在有机过渡金属催化剂存在下进行反应的。
28、根据权利要求27的方法,其中所述非质子传递溶剂选自苯、甲苯、二甲苯、四氢呋喃、二烷、二甘醇二甲醚、二甲基甲酰胺、二甲亚砜、四烷基脲或乙腈。
29、根据权利要求27的方法,其中所述催化剂选自有机钯、有机镍-钯、有机铁-镍或有机铁-钯基化合物。
30、根据权利要求26的方法,其中所述离去基团是囟化物(Cl,Br,F,I)或拟囟化物。
31、根据权利要求30的方法,其中所述拟囟化物选自甲磺酰,三氟甲磺酰,苄甲磺酰或p-甲苯磺酰。
32、制备式(Ⅰ)化合物及其药物上可接受的盐的方法,该方法包括式11化合物与式12,13或14化合物反应,去除保护基团后,如果需要可进行纯化,得到该式(Ⅰ)化合物,并可任意通过常规方法制备该化合物的盐,式(Ⅰ)如下:
式中R1、R2a、R2b、R3a、R3b、R6、A、B、C、D和E的定义如权利要求1;
式11如下:
式中R1、R2a、R2b、R3a、R3b、A、B、C、D和E的定义如上。
式12,13和14如下:
式中R6和E的定义如上,去除保护基团后使式11化合物闭环,则式12化合物中L是O,NH,〔O-(C1-C6烷基)〕2或囟化物〔(Cl,Br,F,I)〕2,式14化合物中L是O-(C1-C6-烷基)或S-(C1-C6-烷基)。
33、根据权利要求32的方法,其中所述离去基团选自囟化物(Cl,Br,F,I),氢氧化物,醇盐或硫代烷基。
34、根据权利要求32的方法,其中式11和12或11和13或11和14化合物的混合物在约0℃-200℃温度下和纯或适宜的溶剂中进行加热。
35、根据权利要求34的方法,该方法包括酸催化剂的存在。
36、根据权利要求35的方法,其中所述酸催化剂选自酰基囟、有机羧酸、酸式磺酸盐、酸式硫酸盐和酸式磷酸盐。
37、根据权利要求34的方法,其中所述溶剂选自囟代烃、苯、甲苯、二甲苯、醇类、二甲基甲酰胺、二甲亚砜或四烷基脲。
38、根据权利要求33的方法,其中所述离去基团为囟化物(Cl,Br,F,I)时,该反应是在碱或酸清除剂存在下于非质子传递溶剂中进行的。
39、制备式(Ⅰ)化合物及其药物上可接受的盐的方法,该方法包括在纯的或适宜的溶剂中加热式15化合物反应,去除保护基团后使式15化合物闭环,如果需要可进行纯化,得到该式(Ⅰ)化合物,并可任意通过常规方法制备该化合物的盐,式(Ⅰ)如下:
式中R1、R2a、R2b、R3a、R3bR6、A、B、C、D和E的定义如权利要求1;
式15如下:
式中R1、R2a、R2b、R3a、R3b、R6、A、B、C、D、E和R的定义如上,L是O或NH。
40、根据权利要求39的方法,其中所述溶剂选自囟化烃、苯、甲苯、二甲苯、醇类、二甲基甲酰胺、二甲亚砜、四烷基脲或乙腈。
41、根据权利要求39的方法,其中所述加热是在酸催化剂存在下进行的。
42、根据权利要求41的方法,其中所述酸催化剂选自酰基囟,有机羧酸、酸式磺酸盐、酸式硫酸盐和酸式磷酸盐。
43、制备式(Ⅰ)化合物及其药物上可接受的盐的方法,该方法包括在纯的或适宜的溶剂中加热式16化合物,去除保护基团后,使式16化合物闭环,如果需要可进行纯化,得到该式(Ⅰ)化合物,并可任意通过常规方法制备该化合物的盐,式(Ⅰ)如下:
式中R1、R2a、R2b、R3a、R3b、R6、A、B、C、D和E的定义如权利要求1;
式16如下:
式中R1、R2a、R2b、R3a、R3b、R6、A、B、C、D和E的定义如上,L是O或NH。
44、根据权利要求43的方法,其中所述溶剂选自囟化烃、苯、甲苯、二甲苯、醇类、二甲基甲酰胺、二甲亚砜、四烷基脲或乙腈。
45、根据权利要求43的方法,其中所述加热是在酸催化剂存在下进行的。
46、根据权利要求45的方法,其中所述酸催化剂选自酰基囟,有机羧酸、酸式磺酸盐、酸式硫酸盐和酸式磷酸盐。
48、根据权利要求47的方法,其中所述稳定基团或保护基团选自-CO-(C1-C6-烷基),-CO-芳基,-SO2-(C1-C6-烷基),-SO2-芳基,CO2-(C1-C6-烷基)或CO2-芳基。
49、根据权利要求47的方法,其中L是O,并从反应混合物中释放和除去水份。
50、根据权利要求47的方法,其中所述溶剂选自多磷酸,(C1-C6-烷基)-磺酸,囟代烃、苯、甲苯、二甲苯和二甲亚砜。
51、根据权利要求47的方法,其中所述加热是在酸催化剂存在下进行的。
52、根据权利要求51的方法,其中所述酸催化剂选自酰基囟,有机羧酸,酸式磺酸盐、酸式硫酸盐,酸式磷酸盐或路易斯酸。
53、根据权利要求52的方法,其中所述路易斯酸选自三囟化铝、三囟化铁、四氯化钛、钛族第Ⅳ组一类化合物,氯化锡和四囟化硼。
54、制备式(Ⅰ)化合物及其药物上可接受的盐的方法,该方法包括在纯的或适宜的溶剂中加热式18化合物,去除保护基团后使式18化合物闭环,如果需要可以进行纯化,得到所述式(Ⅰ)化合物,并可任意通过常规方法制取该化合物的盐,式(Ⅰ)如下:
式中R1、R2a、R2b、R3a、R3b、R6、A、B、C、D和E的定义如上,
式18如下:
式中R1、R2a、R2b、R3a、R3b、R6、R7和E的定义如上,L是O或NH。
55、根据权利要求54的方法,其中L是O,并从反应混合物中释放和除去水份。
56、根据权利要求54的方法,其中所述溶剂选自多磷酸,(C1-C6-烷基)-磺酸,囟代烃、苯、甲苯、二甲苯和二甲亚砜。
57、根据权利要求54的方法,其中所述加热是在酸催化剂存在下进行的。
58、根据权利要求57的方法,其中所述酸催化剂选自酰基囟,有机羧酸,酸式磺酸盐、酸式硫酸盐,酸式磷酸盐或路易斯酸。
59、根据权利要求58的方法,其中所述路易斯酸选自三囟化铝、三囟化铁、四氯化钛、钛族第Ⅳ组一类化合物,氯化锡和四囟化硼。
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US35897189A | 1989-05-30 | 1989-05-30 | |
US07/516,286 US5332744A (en) | 1989-05-30 | 1990-05-04 | Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists |
US516,286 | 1990-05-04 | ||
US358,971 | 1990-05-04 |
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CA (1) | CA2017773A1 (zh) |
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IL (1) | IL94390A (zh) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1038511C (zh) * | 1992-06-17 | 1998-05-27 | 默克专利股份有限公司 | 咪唑并吡啶及其制备方法和制药的应用 |
CN107674073A (zh) * | 2010-05-17 | 2018-02-09 | 印蔻真治疗公司 | 作为蛋白激酶调节剂的3,5‑二取代‑3h‑咪唑(或[1,2,3]三唑)并[4,5‑b]吡啶化合物 |
Families Citing this family (170)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE64514B1 (en) * | 1989-05-23 | 1995-08-09 | Zeneca Ltd | Azaindenes |
US5223499A (en) * | 1989-05-30 | 1993-06-29 | Merck & Co., Inc. | 6-amino substituted imidazo[4,5-bipyridines as angiotensin II antagonists |
EP0415886A3 (en) * | 1989-08-30 | 1991-10-23 | Ciba-Geigy Ag | Aza compounds |
IE70593B1 (en) * | 1989-09-29 | 1996-12-11 | Eisai Co Ltd | Biphenylmethane derivative the use of it and pharmacological compositions containing same |
US5250554A (en) * | 1989-10-24 | 1993-10-05 | Takeda Chemical Industries, Ltd. | Benzimidazole derivatives useful as angiotensin II inhibitors |
US5449682A (en) * | 1990-02-13 | 1995-09-12 | Merck & Co., Inc. | Angiotensin II antagonists incorporating a substituted benzyl element |
DK0443983T3 (da) * | 1990-02-19 | 1996-03-18 | Ciba Geigy Ag | Acrylforbindelser |
US5194379A (en) * | 1990-05-11 | 1993-03-16 | Merck & Co., Inc. | Microbial transformation process for the preparation of hydroxylanol imidazo (4,5-b) pyridines useful as angiotensin II receptor antagonists |
CA2041763A1 (en) | 1990-05-11 | 1991-11-12 | Sheih-Shung T. Chen | Microbial transformation process for antihypertensive products |
AU653524B2 (en) | 1990-06-08 | 1994-10-06 | Roussel-Uclaf | New imidazole derivatives, their preparation process, the new intermediates obtained, their use as medicaments and the pharmaceutical compositions containing them |
AU7983691A (en) * | 1990-06-15 | 1992-01-07 | G.D. Searle & Co. | 1h-substituted-imidazo{4,5-d}pyridazine compounds for treatment of cardiovascular disorders |
CA2044806A1 (en) * | 1990-07-18 | 1992-01-19 | Roland Jaunin | Purine derivatives |
CA2047029A1 (en) * | 1990-07-19 | 1992-01-20 | Shieh-Shung T. Chen | Microbial transformation process for antihypertensive products |
EP0470543A1 (de) * | 1990-08-10 | 1992-02-12 | Dr. Karl Thomae GmbH | Heterocyclische Imidazole, diese Verbindungen enthaltende Arzneimittel und Verfahren zur ihrer Herstellung |
IE70217B1 (en) * | 1990-08-15 | 1996-10-30 | British Bio Technology | Benzimidazole derivatives process for their preparation and application |
IE912874A1 (en) * | 1990-08-15 | 1992-02-26 | British Bio Technology | Compounds |
KR100232324B1 (ko) * | 1990-08-29 | 1999-12-01 | 로렌스 티. 마이젠헬더 | 허혈성 질환을 예방 및 치료하기 위한 트로폴론 유도체 및 그의 약학 조성물 |
US5703071A (en) * | 1990-08-29 | 1997-12-30 | Pharmacia & Upjohn Company | Tropolone derivatives and pharmaceutical composition thereof for preventing and treating ischemic diseases |
WO1992004343A1 (en) * | 1990-09-04 | 1992-03-19 | Yamanouchi Pharmaceutical Co., Ltd. | Novel tetrahydrobenzazole derivative |
US5091390A (en) * | 1990-09-20 | 1992-02-25 | E. I. Du Pont De Nemours And Company | Treatment of CNS disorders with 4,5,6,7-tetrahydro-1H-imidazo (4,5-)-pyridines and analogs |
US5210092A (en) * | 1990-09-25 | 1993-05-11 | Fujisawa Pharmaceutical Co., Ltd. | Angiotensin ii antagonizing heterocyclic derivatives |
US5470975A (en) * | 1990-10-16 | 1995-11-28 | E.R. Squibb & Sons, Inc. | Dihydropyrimidine derivatives |
WO1992007852A1 (en) * | 1990-10-25 | 1992-05-14 | G.D. Searle & Co. | Biphenylalkyl xanthine compounds for treatment of cardiovascular disorders |
US5124335A (en) * | 1991-01-30 | 1992-06-23 | Merck & Co., Inc. | Substituted pyrollo-fused 6 membered heterocycles as angiotensin ii antagonists |
SI9210098B (sl) * | 1991-02-06 | 2000-06-30 | Dr. Karl Thomae | Benzimidazoli, zdravila, ki te spojine vsebujejo, in postopek za njihovo pripravo |
US5472967A (en) * | 1991-02-20 | 1995-12-05 | Synthelabo | 4-pyrimidinone derivatives their preparation and their application in therapy |
US5616599A (en) * | 1991-02-21 | 1997-04-01 | Sankyo Company, Limited | Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use |
EP0502575A1 (en) * | 1991-03-06 | 1992-09-09 | Merck & Co. Inc. | Substituted 1-(2H)-isoquinolinones |
EP0503838A3 (en) * | 1991-03-08 | 1992-10-07 | Merck & Co. Inc. | Heterocyclic compounds bearing acidic functional groups as angiotensin ii antagonists |
CA2062558A1 (en) * | 1991-03-08 | 1992-09-09 | Prasun K. Chakravarty | Heterocyclic compounds bearing acidic functional groups as angiotensin ii antagonists |
US5236928A (en) * | 1991-03-19 | 1993-08-17 | Merck & Co., Inc. | Imidazole derivatives bearing acidic functional groups at the 5-position, their compositions and methods of use as angiotensin II antagonists |
US5187179A (en) * | 1991-03-22 | 1993-02-16 | Merck & Co., Inc. | Angiotensin II antagonists incorporating a substituted imidazo [1,2-b][1,2,4]triazole |
US5128327A (en) * | 1991-03-25 | 1992-07-07 | Merck & Co., Inc. | Angiotensin II antagonists incorporating a nitrogen containing six membered ring heterocycle |
US5177074A (en) * | 1991-03-26 | 1993-01-05 | Merck & Co., Inc. | Angiotensin ii antagonists incorporating a substituted thiophene or furan |
US5798364A (en) * | 1992-03-26 | 1998-08-25 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Imidazopyridines |
DE4110019C2 (de) * | 1991-03-27 | 2000-04-13 | Merck Patent Gmbh | Imidazopyridine, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zubereitungen |
US5164403A (en) * | 1991-04-05 | 1992-11-17 | G. D. Searle & Co. | N-arylheteroarylalkyl imidazol-2-one compounds for treatment of circulatory disorders |
US5151435A (en) * | 1991-04-08 | 1992-09-29 | Merck & Co., Inc. | Angiotensin ii antagonists incorporating an indole or dihydroindole |
TW274551B (zh) * | 1991-04-16 | 1996-04-21 | Takeda Pharm Industry Co Ltd | |
US5252574A (en) * | 1991-04-26 | 1993-10-12 | Merck & Co., Inc. | Angiotensin II antagonists incorporating a substituted thiophene or furan |
WO1992020662A1 (en) * | 1991-05-10 | 1992-11-26 | Merck & Co., Inc. | Acidic aralkyl triazole derivatives active as angiotensin ii antagonists |
US5198438A (en) * | 1991-05-07 | 1993-03-30 | Merck & Co., Inc. | Angiotensin ii antagonists incorporating a substituted thiophene or furan |
US5506361A (en) * | 1991-05-08 | 1996-04-09 | Theupjohn Company | Imidazobenzoquinones and composition for preventing or treating hypertension or congestive heart failure containing the same |
JPH05112533A (ja) * | 1991-05-08 | 1993-05-07 | Upjohn Co:The | イミダゾベンゾキノン類およびこれを有効成分とする高血圧・鬱血性心不全の予防・治療剤 |
US5162340A (en) * | 1991-05-10 | 1992-11-10 | Merck & Co., Inc. | Substituted 1-(2h)-isoquinolinones bearing acidic functional groups as angiotensin ii antagonists |
US5436259A (en) * | 1991-05-10 | 1995-07-25 | Merck & Co., Inc. | Substituted 1,2,4-triazolin-3-one compounds bearing acidic functional groups as balanced angiotensin II antagonists |
JPH06507608A (ja) * | 1991-05-16 | 1994-09-01 | グラクソ、グループ、リミテッド | ベンゾフラン誘導体 |
IL101860A0 (en) * | 1991-05-31 | 1992-12-30 | Ici Plc | Heterocyclic derivatives |
US5175164A (en) * | 1991-06-05 | 1992-12-29 | Merck & Co., Inc. | Angiotensin ii antagonists incorporating a substituted indole or dihydroindole |
GB9113626D0 (en) * | 1991-06-25 | 1991-08-14 | Ici Plc | Heterocyclic compounds |
GB9113628D0 (en) * | 1991-06-25 | 1991-08-14 | Ici Plc | Heterocyclic derivatives |
WO1993003033A1 (en) * | 1991-07-26 | 1993-02-18 | G. D. Searle & Co. | CARBONATE-SUBSTITUTED IMIDAZO[4,5-d] PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS |
US5332750A (en) * | 1991-09-04 | 1994-07-26 | Merck Patent Gesellschaft Mit Beschrankter Haftung | 1,2-dihydro-2-oxopyridines |
SG42942A1 (en) * | 1991-09-10 | 1997-10-17 | Tanabe Seiyaku Co | Imidazopyridine derivatives and process for preparation thereof |
US5354759A (en) * | 1991-09-12 | 1994-10-11 | Fujisawa Pharmaceutical Co., Ltd. | Angiotenin II antagonizing heterocyclic compounds |
GB9201789D0 (en) * | 1992-01-28 | 1992-03-11 | Fujisawa Pharmaceutical Co | Heterocyclic derivatives |
TW300219B (zh) * | 1991-09-14 | 1997-03-11 | Hoechst Ag | |
US5187159A (en) * | 1991-10-07 | 1993-02-16 | Merck & Co., Inc. | Angiotensin II antagonists incorporating a substituted 1,3-benzodioxole or 1,3-benzodithiole |
CA2079982A1 (en) * | 1991-10-07 | 1993-04-08 | Stephen E. De Laszlo | Substituted pyrazino (2,3-d)-pyrimidinones as angiotensin ii antagonists |
GB9121727D0 (en) * | 1991-10-14 | 1991-11-27 | Ici Plc | Heterocyclic compounds |
US5442062A (en) * | 1991-10-24 | 1995-08-15 | The Upjohn Company | Imidazole derivatives and pharmaceutical compositions containing the same |
FR2683819B1 (fr) * | 1991-10-28 | 1994-02-11 | Synthelabo | Derives de quinoleine, leur procede de preparation et leur application en therapeutique. |
DE4140519A1 (de) * | 1991-12-09 | 1993-06-17 | Merck Patent Gmbh | Benzofurane |
DE4141788A1 (de) * | 1991-12-18 | 1993-06-24 | Merck Patent Gmbh | Imidazopyridine |
US5378701A (en) * | 1991-12-27 | 1995-01-03 | Kyowa Hakko Kogyo | Tricyclic compounds |
ES2142817T3 (es) * | 1991-12-27 | 2000-05-01 | Kyowa Hakko Kogyo Kk | Compuestos triciclicos como antagonistas de la angiotensina ii. |
GB2263637A (en) * | 1992-01-28 | 1993-08-04 | Merck & Co Inc | Substituted imidazo-fused 6-membered carbocycle or heterocycle as neurotensin antagonists |
GB9201715D0 (en) * | 1992-01-28 | 1992-03-11 | Ici Plc | Chemical process |
US5312958A (en) * | 1992-01-31 | 1994-05-17 | Takeda Chemical Industries, Ltd. | Process for producing 4-bromomethylbiphenyl compounds |
FR2687677B1 (fr) * | 1992-02-24 | 1996-10-11 | Union Pharma Scient Appl | Nouveaux derives de polyazaindenes antagonistes des recepteurs a l'angiotensine ii ; leurs procedes de preparation, compositions pharmaceutiques les contenant. |
WO1993018030A1 (en) * | 1992-03-03 | 1993-09-16 | Fujisawa Pharmaceutical Co., Ltd. | Benzimidazole derivatives as angiotensin ii antagonists |
US5208235A (en) * | 1992-03-10 | 1993-05-04 | E. R. Squibb & Sons, Inc. | Indole- and benzimidazole-substituted imidazole derivatives |
US5208234A (en) * | 1992-03-10 | 1993-05-04 | E. R. Squibb & Sons, Inc. | Substituted imidazole phosphonic and phosphinic acid derivatives |
DE4208304A1 (de) * | 1992-03-16 | 1993-09-23 | Merck Patent Gmbh | 2-oxochinolinderivate |
EP0602246A4 (en) * | 1992-03-25 | 1995-07-05 | Green Cross Corp | ISOINDAZOLE COMPOUND. |
US5478832A (en) * | 1992-05-08 | 1995-12-26 | The Green Cross Corporation | Quinoline compounds |
EP0640080B1 (en) * | 1992-05-13 | 1997-10-22 | Syntex (U.S.A.) Inc. | Substituted indoles as angiotensin ii antagonists |
FR2693197B1 (fr) * | 1992-07-03 | 1994-09-23 | Synthelabo | Nouveaux dérivés de quinoléine, leur procédé de préparation et leur application thérapeutique. |
GB9218449D0 (en) | 1992-08-29 | 1992-10-14 | Boots Co Plc | Therapeutic agents |
EP0649424B1 (en) * | 1992-07-10 | 1998-10-07 | Knoll AG | Dioxcyclobutene derivatives as angiotensin ii antagonists |
EP0668864A1 (en) * | 1992-07-17 | 1995-08-30 | Merck & Co. Inc. | Substituted biphenylmethylimidazopyridines |
DE4225835A1 (de) * | 1992-08-05 | 1994-02-10 | Merck Patent Gmbh | Verfahren zur Herstellung von Imidazopyridinen |
US5359073A (en) * | 1992-11-24 | 1994-10-25 | G. D. Searle & Co. | Substituted-phenyl (N,N'-cycloalkyl/alkyl carboxamide)-1H/3H-imidazo[4,5-b]pyridine compounds as PAF antagonists |
US5376666A (en) * | 1992-11-30 | 1994-12-27 | The Du Pont Merck Pharmaceutical Company | Angiotension-II receptor blocking, azacycloalkyl or azacycloalkenyl |
CA2128014A1 (en) * | 1992-12-07 | 1994-06-23 | Toshikazu Shimizu | Process for the preparation of imidazopyridine derivatives and intermediates |
DE4242459A1 (de) * | 1992-12-16 | 1994-06-23 | Merck Patent Gmbh | Imidazopyridine |
CA2111662C (en) * | 1992-12-17 | 2004-11-23 | Hiroaki Yanagisawa | Biphenyl derivatives, their preparation and their use for the treatment of hypertension and cardiac disease |
IT1263804B (it) * | 1993-01-22 | 1996-09-03 | Luso Farmaco Inst | Derivati pirimidinonici fusi con eterocicli azotati ad attivita' a ii antagonista |
DE4302956A1 (de) * | 1993-02-03 | 1994-08-04 | Bayer Ag | Substituierte Imidazo(4,5-b)pyridine und Benzimidazole |
US5491172A (en) * | 1993-05-14 | 1996-02-13 | Warner-Lambert Company | N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents |
IL109431A (en) * | 1993-05-14 | 2001-01-11 | Warner Lambert Co | Pharmaceutical compositions containing n-acyl sulfamic acid esters (or thioesters), n-acyl sulfonamides, and n-sulfonyl carbamic acid esters (or thioesters), for regulating plasma cholesterol concentration, and certain such novel compounds |
DE4318813A1 (de) * | 1993-06-07 | 1994-12-08 | Merck Patent Gmbh | Imidazopyridine |
US5571813A (en) * | 1993-06-10 | 1996-11-05 | Beiersdorf-Lilly Gmbh | Fused pyrimidine compounds and their use as pharmaceuticals |
EP0628559B1 (en) * | 1993-06-10 | 2002-04-03 | Beiersdorf-Lilly GmbH | Pyrimidine compounds and their use as pharmaceuticals |
DE4320432A1 (de) * | 1993-06-21 | 1994-12-22 | Bayer Ag | Substituierte Mono- und Bipyridylmethylderivate |
US5338740A (en) * | 1993-07-13 | 1994-08-16 | Pfizer Inc. | Angiotensin II receptor antagonists |
DE4339868A1 (de) * | 1993-11-23 | 1995-05-24 | Merck Patent Gmbh | Imidazopyridazine |
DE4341453A1 (de) * | 1993-12-06 | 1995-06-08 | Merck Patent Gmbh | Imidazopyridine |
KR0151816B1 (ko) * | 1994-02-08 | 1998-10-15 | 강박광 | 신규의 치환된 피리딜 이미다졸 유도체 및 그의 제조방법 |
ES2079315B1 (es) * | 1994-02-24 | 1996-10-16 | Uriach & Cia Sa J | Nuevas imidazopiridinas. |
KR0151819B1 (ko) * | 1994-06-11 | 1998-10-15 | 강박광 | 신규의 피리딜 n-옥사이드로 치환된 피디딜이미다졸 유도체 및 그의 제조방법 |
DE4432860A1 (de) * | 1994-09-15 | 1996-03-21 | Merck Patent Gmbh | Imidazopyridine |
WO1999001454A1 (en) | 1997-07-03 | 1999-01-14 | Du Pont Pharmaceuticals Company | Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders |
US6365589B1 (en) | 1998-07-02 | 2002-04-02 | Bristol-Myers Squibb Pharma Company | Imidazo-pyridines, -pyridazines, and -triazines as corticotropin releasing factor antagonists |
US6124463A (en) * | 1998-07-02 | 2000-09-26 | Dupont Pharmaceuticals | Benzimidazoles as corticotropin release factor antagonists |
DE69940063D1 (de) * | 1998-07-06 | 2009-01-22 | Bristol Myers Squibb Co | Biphenylsulfonamide als zweifach aktive rezeptor antagonisten von angiotensin und endothelin |
US6638937B2 (en) | 1998-07-06 | 2003-10-28 | Bristol-Myers Squibb Co. | Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists |
TR200100047T2 (tr) | 1998-07-15 | 2001-10-22 | Teijin Limited | Tiyobenzimidazol türevleri |
TW526202B (en) * | 1998-11-27 | 2003-04-01 | Shionogi & Amp Co | Broad spectrum cephem having benzo[4,5-b]pyridium methyl group of antibiotic activity |
SE9903028D0 (sv) | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
AR037097A1 (es) | 2001-10-05 | 2004-10-20 | Novartis Ag | Compuestos acilsulfonamidas, composiciones farmaceuticas y el uso de dichos compuestos para la preparacion de un medicamento |
EP1521584A1 (en) | 2002-06-17 | 2005-04-13 | Glaxo Group Limited | Purine derivatives as liver x receptor agonists |
US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US7569574B2 (en) | 2002-08-22 | 2009-08-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Purine derivatives, the preparation thereof and their use as pharmaceutical compositions |
US7495005B2 (en) | 2002-08-22 | 2009-02-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, their preparation and their use in pharmaceutical compositions |
US7482337B2 (en) | 2002-11-08 | 2009-01-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
DE10254304A1 (de) | 2002-11-21 | 2004-06-03 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel |
US7566707B2 (en) | 2003-06-18 | 2009-07-28 | Boehringer Ingelheim International Gmbh | Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions |
DE10355304A1 (de) | 2003-11-27 | 2005-06-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 8-(Piperazin-1-yl)-und 8-([1,4]Diazepan-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
US7501426B2 (en) | 2004-02-18 | 2009-03-10 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
DE102004009039A1 (de) | 2004-02-23 | 2005-09-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und Verwendung als Arzneimittel |
US7393847B2 (en) | 2004-03-13 | 2008-07-01 | Boehringer Ingleheim International Gmbh | Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions |
US7439370B2 (en) | 2004-05-10 | 2008-10-21 | Boehringer Ingelheim International Gmbh | Imidazole derivatives, their preparation and their use as intermediates for the preparation of pharmaceutical compositions and pesticides |
JP2008503469A (ja) | 2004-06-17 | 2008-02-07 | ワイス | ゴナドトロピン放出ホルモン受容体アンタゴニスト |
RU2007101509A (ru) | 2004-06-17 | 2008-07-27 | Уайт (Us) | Способ получения антагонистов рецепторов гормона, высвобождающего гонадотропин |
DE102004030502A1 (de) | 2004-06-24 | 2006-01-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Imidazole und Triazole, deren Herstellung und Verwendung als Arzneimittel |
DE102004043944A1 (de) | 2004-09-11 | 2006-03-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 8-(3-Amino-piperidin-1-yl)-7-(but-2-inyl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
DE102004044221A1 (de) | 2004-09-14 | 2006-03-16 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 3-Methyl-7-butinyl-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
DE102004054054A1 (de) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
US7534796B2 (en) | 2005-02-18 | 2009-05-19 | Wyeth | Imidazo[4,5-b]pyridine antagonists of gonadotropin releasing hormone receptor |
US7538113B2 (en) | 2005-02-18 | 2009-05-26 | Wyeth | 4-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor |
US7582634B2 (en) | 2005-02-18 | 2009-09-01 | Wyeth | 7-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor |
US7531542B2 (en) | 2005-05-18 | 2009-05-12 | Wyeth | Benzooxazole and benzothiazole antagonists of gonadotropin releasing hormone receptor |
US7582636B2 (en) | 2005-05-26 | 2009-09-01 | Wyeth | Piperazinylimidazopyridine and piperazinyltriazolopyridine antagonists of Gonadotropin Releasing Hormone receptor |
DE102005035891A1 (de) | 2005-07-30 | 2007-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
NZ619413A (en) | 2006-05-04 | 2015-08-28 | Boehringer Ingelheim Int | Polymorphs of a dpp-iv enzyme inhibitor |
PE20110235A1 (es) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | Combinaciones farmaceuticas que comprenden linagliptina y metmorfina |
WO2008017670A1 (en) | 2006-08-08 | 2008-02-14 | Boehringer Ingelheim International Gmbh | Pyrrolo [3, 2 -d] pyrimidines as dpp-iv inhibitors for the treatment of diabetes mellitus |
US20100120694A1 (en) | 2008-06-04 | 2010-05-13 | Synergy Pharmaceuticals, Inc. | Agonists of Guanylate Cyclase Useful for the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders |
US7879802B2 (en) | 2007-06-04 | 2011-02-01 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
AR071175A1 (es) | 2008-04-03 | 2010-06-02 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un inhibidor de la dipeptidil-peptidasa-4 (dpp4) y un farmaco acompanante |
WO2009156889A1 (en) * | 2008-06-25 | 2009-12-30 | Pfizer Inc. | Diaryl compounds and uses thereof |
EP2321341B1 (en) | 2008-07-16 | 2017-02-22 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
UY32030A (es) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "tratamiento para diabetes en pacientes inapropiados para terapia con metformina" |
KR20190016601A (ko) | 2008-08-06 | 2019-02-18 | 베링거 인겔하임 인터내셔날 게엠베하 | 메트포르민 요법이 부적합한 환자에서의 당뇨병 치료 |
RU2011113823A (ru) | 2008-09-10 | 2012-10-20 | БЕРИНГЕР ИНГЕЛЬХАЙМ ИНТЕРНАЦИОНАЛЬ ГмбХ (DE) | Комбинированная терапия, предназначенная для лечения диабета и связанных с ним состояний |
US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
JP2012512848A (ja) | 2008-12-23 | 2012-06-07 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 有機化合物の塩の形態 |
AR074990A1 (es) | 2009-01-07 | 2011-03-02 | Boehringer Ingelheim Int | Tratamiento de diabetes en pacientes con un control glucemico inadecuado a pesar de la terapia con metformina |
US8372862B2 (en) | 2009-06-02 | 2013-02-12 | Korea Research Institute Of Chemical Technology | Pharmaceutical composition for preventing or treating osteoporosis or obesity comprising phenyltetrazole derivative |
KR101117128B1 (ko) * | 2009-06-02 | 2012-03-14 | 한국화학연구원 | 페닐테트라졸 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 골다공증 또는 비만의 예방 또는 치료용 약학적 조성물 |
JP2013512229A (ja) | 2009-11-27 | 2013-04-11 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 遺伝子型が同定された糖尿病患者のリナグリプチン等のddp−iv阻害薬による治療 |
BR112012028136A2 (pt) | 2010-05-05 | 2016-08-09 | Boehringer Ingelheim Int | terapia de combinaçao |
EP3725325B1 (en) | 2010-06-24 | 2023-05-31 | Boehringer Ingelheim International GmbH | Diabetes therapy |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
CN103781788B (zh) | 2011-07-15 | 2016-08-17 | 勃林格殷格翰国际有限公司 | 经取代的喹唑啉、其制备及其在药物组合物中的用途 |
US9567330B2 (en) * | 2011-07-15 | 2017-02-14 | Shionogi & Co., Ltd. | Azabenzimidazole derivative having AMPK-activating activity |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
EP3685839A1 (en) | 2012-05-14 | 2020-07-29 | Boehringer Ingelheim International GmbH | Linagliptin for use in the treatment of albuminuria and kidney related diseases |
WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
CA2905435A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
EP2970384A1 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
BR112015030326A2 (pt) | 2013-06-05 | 2017-08-29 | Synergy Pharmaceuticals Inc | Agonistas ultrapuros de guanilato ciclase c, método de fabricar e usar os mesmos |
GB201321741D0 (en) * | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
EP3110449B1 (en) | 2014-02-28 | 2023-06-28 | Boehringer Ingelheim International GmbH | Medical use of a dpp-4 inhibitor |
MX2018015089A (es) | 2016-06-10 | 2019-05-13 | Boehringer Ingelheim Int | Combinacion de linagliptina y metformina. |
TW201811759A (zh) | 2016-06-29 | 2018-04-01 | 加拿大蒙特利爾大學 | 二芳基甲基雜環 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3347290A1 (de) * | 1983-12-28 | 1985-07-11 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue 2-phenyl-imidazole, ihre herstellung und diese verbindungen enthaltende arzneimittel |
IL76546A (en) * | 1984-10-12 | 1988-12-30 | Warner Lambert Co | 9-(heteroarylalkyl)-6-purine(thi)one derivatives,their preparation and pharmaceutical compositions containing them |
DE3445299A1 (de) * | 1984-12-12 | 1986-06-19 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue imidazoderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
DE3522230A1 (de) * | 1985-06-21 | 1987-01-02 | Thomae Gmbh Dr K | Neue 2-arylimidazole, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
CA1334092C (en) * | 1986-07-11 | 1995-01-24 | David John Carini | Angiotensin ii receptor blocking imidazoles |
IE70593B1 (en) * | 1989-09-29 | 1996-12-11 | Eisai Co Ltd | Biphenylmethane derivative the use of it and pharmacological compositions containing same |
IL96019A0 (en) * | 1989-10-31 | 1991-07-18 | Fujisawa Pharmaceutical Co | Imidazole derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same |
-
1990
- 1990-05-14 IL IL9439090A patent/IL94390A/en not_active IP Right Cessation
- 1990-05-25 SK SK2568-90A patent/SK279218B6/sk unknown
- 1990-05-25 CZ CS902568A patent/CZ280696B6/cs unknown
- 1990-05-28 AU AU56024/90A patent/AU632127B2/en not_active Ceased
- 1990-05-28 PT PT94181A patent/PT94181B/pt not_active IP Right Cessation
- 1990-05-29 HU HU903243A patent/HUT55014A/hu unknown
- 1990-05-29 CA CA002017773A patent/CA2017773A1/en not_active Abandoned
- 1990-05-29 NO NO902384A patent/NO177387C/no unknown
- 1990-05-29 CN CN90103234A patent/CN1048546A/zh active Pending
- 1990-05-29 FI FI902661A patent/FI95908C/fi not_active IP Right Cessation
- 1990-05-30 EP EP19900305850 patent/EP0400974A3/en not_active Withdrawn
- 1990-05-30 JP JP2138653A patent/JPH0813816B2/ja not_active Expired - Lifetime
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1038511C (zh) * | 1992-06-17 | 1998-05-27 | 默克专利股份有限公司 | 咪唑并吡啶及其制备方法和制药的应用 |
CN107674073A (zh) * | 2010-05-17 | 2018-02-09 | 印蔻真治疗公司 | 作为蛋白激酶调节剂的3,5‑二取代‑3h‑咪唑(或[1,2,3]三唑)并[4,5‑b]吡啶化合物 |
US10590129B2 (en) | 2010-05-17 | 2020-03-17 | Rhizen Pharmaceuticals Sa | 3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of protein kinases |
Also Published As
Publication number | Publication date |
---|---|
EP0400974A3 (en) | 1991-10-23 |
CZ280696B6 (cs) | 1996-04-17 |
NO902384D0 (no) | 1990-05-29 |
CA2017773A1 (en) | 1990-11-30 |
NO177387B (no) | 1995-05-29 |
FI95908C (fi) | 1996-04-10 |
JPH0395181A (ja) | 1991-04-19 |
IL94390A (en) | 1996-03-31 |
FI902661A0 (fi) | 1990-05-29 |
NO902384L (no) | 1990-12-03 |
SK256890A3 (en) | 1998-08-05 |
CZ256890A3 (en) | 1995-02-15 |
AU632127B2 (en) | 1992-12-17 |
AU5602490A (en) | 1990-12-06 |
NO177387C (no) | 1995-09-06 |
HU903243D0 (en) | 1990-10-28 |
FI95908B (fi) | 1995-12-29 |
HUT55014A (en) | 1991-04-29 |
PT94181A (pt) | 1991-01-08 |
JPH0813816B2 (ja) | 1996-02-14 |
EP0400974A2 (en) | 1990-12-05 |
SK279218B6 (sk) | 1998-08-05 |
PT94181B (pt) | 1997-06-30 |
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