CN1025331C - 联苯甲烷衍生物及其药用盐的制备方法 - Google Patents
联苯甲烷衍生物及其药用盐的制备方法 Download PDFInfo
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- CN1025331C CN1025331C CN90108025A CN90108025A CN1025331C CN 1025331 C CN1025331 C CN 1025331C CN 90108025 A CN90108025 A CN 90108025A CN 90108025 A CN90108025 A CN 90108025A CN 1025331 C CN1025331 C CN 1025331C
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- Prior art keywords
- methyl
- nmr
- pyridine
- imidazo
- biphenyl
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- ZWZGXLKXKAPXMZ-UHFFFAOYSA-N 2,2'-dihydroxy-3,3'-dimethoxy-5,5'-dipropyldiphenylmethane Chemical class COC1=CC(CCC)=CC(CC=2C(=C(OC)C=C(CCC)C=2)O)=C1O ZWZGXLKXKAPXMZ-UHFFFAOYSA-N 0.000 title abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 84
- -1 amine salt Chemical class 0.000 claims description 58
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 53
- 238000002360 preparation method Methods 0.000 claims description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 238000009833 condensation Methods 0.000 claims description 9
- 230000005494 condensation Effects 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 239000012312 sodium hydride Substances 0.000 claims description 9
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical class C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims description 5
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 5
- 125000005905 mesyloxy group Chemical group 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 239000002798 polar solvent Substances 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- CFQPVBJOKYSPKG-UHFFFAOYSA-N 1,3-dimethylimidazol-2-one Chemical compound CN1C=CN(C)C1=O CFQPVBJOKYSPKG-UHFFFAOYSA-N 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- VWWMGPCUZVOLLK-UHFFFAOYSA-N 2-[4-[(2-cyclopropyl-7-methylimidazo[4,5-b]pyridin-3-yl)methyl]phenyl]benzoic acid Chemical compound C1CC1C1=NC=2C(C)=CC=NC=2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O VWWMGPCUZVOLLK-UHFFFAOYSA-N 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000007859 condensation product Substances 0.000 claims 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 2
- BIFKOXVCOFSXCC-UHFFFAOYSA-N 1,1'-biphenyl;methane Chemical class C.C1=CC=CC=C1C1=CC=CC=C1 BIFKOXVCOFSXCC-UHFFFAOYSA-N 0.000 claims 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- UWNADWZGEHDQAB-UHFFFAOYSA-N i-Pr2C2H4i-Pr2 Natural products CC(C)CCC(C)C UWNADWZGEHDQAB-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims 1
- 206010020772 Hypertension Diseases 0.000 abstract description 10
- 206010019280 Heart failures Diseases 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- 239000000243 solution Substances 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- 238000001035 drying Methods 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 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 21
- 238000003756 stirring Methods 0.000 description 20
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 16
- 206010047139 Vasoconstriction Diseases 0.000 description 15
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- 238000006243 chemical reaction Methods 0.000 description 14
- 239000012141 concentrate Substances 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- 238000001953 recrystallisation Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 12
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 12
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- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 12
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- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
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- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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Abstract
通式(I)的联苯甲烷衍生物及其药用盐的制备方法,是将咪唑衍生物与联苯甲烷衍生物进行缩合,再将缩合产物与适合的试剂反应,得到通式(I)的化合物(各取代基见说明书)。通式(I)的联苯甲烷衍生物可有效地用于治疗和防治高血压和心脏病。
Description
本发明涉及一种缩合的咪唑化合物及其药用盐,它们显示出优良的药物活性。更具体地说,本发明涉及新的联苯甲烷衍生物及其药用盐,它们可有效地用作高血压的治疗剂和/或心脏病的治疗剂。
在日本,约有20%(即约2000万)的人患有高血压,这种病是各种脑病、心脏病等的严重诱发因素。在实际中,现已在临床上使用了噻嗪类高血压利尿剂、β-阻断剂、钙拮抗药、ACE抑制剂等等来治疗高血压。
但是,高血压的起源和病理很不相同,仅使用一种药物很难显著控制所有类型的高血压。此外,从安全考虑,β-阻断剂因付作用造成心律衰竭和支气管扩张;利尿剂产生付作用,如高尿酸血症,***糖新陈代谢和***脂肪新陈代谢;而ACE抑制剂造成咳嗽等付作用。
在上述条件下,人们仍需要各种类型的、更好的、能通过不同机理显示出它们的作用的降压药。
本发明人对具有非肽血管紧张肽Ⅱ拮抗活性的化合物作了多年广泛和深入的研究,发现下述联苯甲烷衍生物具有优良的活性。
在本技术领域中提出的具有血管肽张肽Ⅱ拮抗活性的咪唑化
合物的例子有下述日本专利公开透露的化合物:公开未决号148788/1979,71073/1981,71074/1981,98270/1982,157768/1983和23868/1988。此外,日本专利公开未决号240683/1987提出4,5,6,7-四氢-1H-咪唑并〔4,5,-c〕吡啶-6-羧酸衍生物。任何上述化合物都与发明的化合物不同,以下将以结构式的形式进行说明。
本发明涉提供了一种下式(Ⅰ)的联苯甲烷衍生物或其药用盐
其中R1是氢,烷基,环烷基,卤代烷基,-S-R7,-SO2R7,-C=C-R7或-(CH2)P-OR7(R7是氢,烷基,环烷基或卤代烷基,P是0或1),-A1=A2-A3=A4-是-CH=CH-CH=CH-,-N=CHCH=CH-,-CH=N-CH=CH-,-CH=CH-N=CH-,-CH=CH-CH=N-或-CH=N-CH=N-,R2和R3各为氢,卤素,低级烷基,低级烷氧基,氨基甲酰基或氰基,R4是氢或低级烷基,R5是1H-四唑-5-基,羧基(-COOH)或羧酸酯和R是氢,卤素,羟基或低级烷氧基。
最好,R5是羧基或1H-四唑-5-基。R5可以是具有1-6个碳原子的烷基的羧酸酯。
最好,R1是选自甲基,乙基,丙基,甲氧基,乙氧基和环丙基的烷基;且-A1=A2-A3=A4-是-CH=CH-CH=N-。
最好,R2是A1上的氢且R3是A3上的甲基;R2是A1上的甲基且R3是A3上的甲基;或R2是A1上的甲基且R3是A3上的氢。
最好,R4是氢且R6是氢。
以下两种化合物是最优选的:
7-甲基-2-正丙基-3-〔(2′-(1H-四唑-5-基)-联苯-4-基)甲基]-3H-咪唑并〔4,5,-b〕吡啶
3-〔(2′-羧基联苯-4-基)甲基〕-2-环丙基-7-甲基-3H-咪唑并〔4,5-b〕吡啶
以下化合物是优选的:
2-乙基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
3-{(2′-羧基联苯-4-基)甲基}-7-甲基-2-正丙基-3H-咪唑并〔4,5-b〕吡啶
2-环丙基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
3-{(5′-氯-2′-(1H-四唑-5-基)联苯-4-
基}甲基〕-7-甲基-2-正丙基-3H-咪唑并〔4,5-b〕吡啶
3-{(2′-羧基联苯-4-基)甲基}-2-乙硫基-7-甲基-3H-咪唑并〔4,5-b〕吡啶
3-{(2′-羧基-5′-氯联苯-4-基)甲基}-2-环丙基-7-甲基-3H-咪唑并〔4,5-b〕吡啶
2-正丙基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
2-甲氧基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
2-环丙基-5,7-二甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
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
5,7-二甲基-2-正丙基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
3-{(2′-羧基联苯-4-基)甲基}-2-正丙基-5,7-二甲基-3H-咪唑并〔4,5-b〕吡啶
2-乙氧基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
7-甲基-2-丙炔基-3-〔{2′-(1H-四唑-5-
基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
7-甲基-2-(1-丙氧基)-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
2-乙硫基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯基-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
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
2-乙氧基-5,7-二甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
5,7-二甲基-2-甲氧基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
5,7-二甲基-2-正丙氧基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
3-{(2′-羧基联苯-4-基)甲基}-2-乙氧基-7-甲基-3H-咪唑并〔4,5-b〕吡啶
3-{(2′-羧基联苯-4-基)甲基}-2-甲氧基-7-甲基-3H-咪唑并〔4,5-b〕吡啶
3-{(2′-羧基联苯-4-基)甲基}-7-甲基-2-正丙氧基-3H-咪唑并〔4,5-b〕吡啶
3-{(2′-羧基联苯-4-基)甲基}-5,7-二甲基-2-甲氧基-3H-咪唑并〔4,5-b〕吡啶
3-{(2′-羧基联苯-4-基)甲基}-5,7-二甲基-2-丙氧基-3H-咪唑并〔4,5-b〕吡啶
本发明还提供了一种含有药用有效量的上述联苯甲烷衍生物或其药用盐和药用载体的药物组合物。
本发明还提供了一种防治高血压或心脏病的方法,即给患者服用一种药用有效量的上述联苯甲烷衍生物或其药用盐。
本发明的化合物包括以下通式(Ⅰ)表示的联苯甲烷衍生物及其药用盐:
其中R1是氢原子,烷基,环烷基,卤代烷基或式-S-R7表示的基团(其中R7是氢原子,烷基,环烷基或卤代烷基),-A1=A2-A3=A4-是式-CH=CH-CH=CH-表示的基团,式-N=CH-CH=CH-表示的基团,式-CH=N-CH=CH-表示的基团,式-CH=CH-N=CH-表示的基团或式-CH=CH-CH=N-表示的基团,R2和R3可相同或不同,各为氢原子,卤原子,低级烷基,低级烷氧基,氨基甲酰基或氰基;
R4是氢原子或低级烷基;
R5是下式表示的基团
或羧基;以及
R6是氢原子,卤原子,羟基或低级烷氧基。
在本发明的化合物中,上述定义R2,R3和R4所用术语“低级烷基”指的是C1-C6直链或支链烷基,其例子包括甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基,正戊基(戊基),异戊基,新戊基,叔戊基,1-甲基丁基,2-甲基丁基,1,2-二甲基丙基,正己基,异己基,1-甲基戊基,2-甲基戊基,3-甲基戊基,1,1-二甲基丁基,1,2-二甲基丁基,2,2-二甲基丁基,1,3-二甲基丁基,2,3-二甲基丁基,3,3-二甲基丁基,1-乙基丁基,2-乙基丁基,1,1,2-三甲基丙基,1,2,2-四甲基丙基,1-乙基-1-甲基丙基和1-乙基-2-甲基丙基,其中,最好是甲基和乙基,最佳是乙基。在定义R4时所用的术语低级烷基,尤以甲基为最佳。
定义R2,R3和R4时所用的术语,低级烷氧基”指的是由上述低级烷基衍生的低级烷氧基,如甲氧基,乙氧基和丙氧基,其中尤以甲氧基最理想。
定义R2,R3和R6所用术语“卤素”指的是氯原子,溴原子,氟原子等。
定义R1所用术语“烷基”最好指的是C1-C10直链或支链烷基。除了上述C1-C6烷基外,这种烷基还包括正庚基,正辛基,正壬基和正癸基和支链烷基。其中,最好是C1-C8直链或支链基,其最优选的例子有甲基,乙基,正丙基,异丙基,正丁基和异戊基。
上述R1的优选方案也可应用到R7。
术语“卤代烷基”指的是这样的基团,即上述烷基的任意一个或多个氢原子被卤原子、特别是氟原子取代。
术语“环烷基”指的是例如C3-C6环烷基,最理想的是环丙基和环丁基。
式-A1=A2-A3=A4-表示的基团指的是:
①式-CH=CH-CH=CH-表示的基团;
②式-N=CH-CH=CH-表示的基团;
③式-CH=N-CH=CH-表示的基团;
④式-CH=CH-N=CH-表示的基团;或
⑤式-CH=CH-CH=N-表示的基团。
在本发明的化合物中,与咪唑环缩合的部分的具体例子包括以下基团:
在本发明中,由式-A1=A2-A3=A4-表示的基团最理想的是由式(5)-CH=CH-CH=N-表示的基团,式(2)-N=CH-CH=CH-表示的基团次之。
上述苯并咪唑或咪唑并吡啶环可由上述R2和R3取代。取代基的优选例子有低级烷基,最理想的苯并咪唑或咪唑并吡啶环是由甲基单取代的环。
术语“药用盐”可以是任何盐,只要它可用于本发明即可,其例子有铵盐、钠盐、钾盐、盐酸盐、氢溴酸盐、甲磺酸盐和硫酸盐。
此外,一些上述化合物可以水合物或旋光活性异构体的形式存在。当然,这些化合物是在本发明的范围内。
以下说明制备本发明的化合物的代表性方法:
制备方法1
可按以下方法制备通式(1)化合物(其中R是由下式
表示的四唑基):
在上述式子中,R1,R2,R3,R4,R6和式-A1=A2-A3=A4-表示的基团分别定义如上,且X是卤原子,甲磺酰氧基或对甲苯磺酰氧基
(第一步)
用传统方法将通式(Ⅱ)表示的缩合咪唑衍生物与通式(Ⅲ)表示的腈化合物缩合,制备通式(Ⅳ)表示的化合物。
上述反应通常在碱存在下进行的。碱的例子有氢化钠,氢化锂,碳酸钾,碳酸钠,醇化钠,叔丁氧钾,氢氧化钠,氢氧化钾,三乙胺和二异丙基乙胺。
二甲基甲酰胺,二甲基亚砜,N-甲基吡咯烷酮,1,3-二甲基-2-咪唑啉酮,二恶烷,乙醇,丙酮等最好用作反应溶剂。
在式中,X是卤原子,甲磺酰氧基或对甲苯磺酰氧基,卤原子可以是氯,溴,碘等。
在本工序中,其最优选的实例包括以下两种,一是用氢化锂或氢化钠作为碱在一质子极性溶剂中(如二甲基甲酰胺)形成金属盐(1),然后,在0℃-室温下,用联苄基甲基卤(X=Cl,Br)进行烷基化;二是用醇化钠作为碱在醇中形成钠盐(1),然后用联苯基甲基卤化物(X=cl,Rr)在室温下进行烷基化。
在本工序中可用作原料的通式(Ⅲ)表示的化合物可按下述文献介绍的方法制备(例如参见A.I.Meyers等人,J.有机化学,43,1372(1978)或日本专利未决公开号
23868/1988)。
(第二步)
通过在一质子极性溶剂中加热,使通式(Ⅳ)表示的化合物与通式(Ⅴ)表示的叠氮化物反应,制备通式(Ⅵ)表示的化合物。
最好在胺盐如氯化铵(见J.P.Hurwitz等人,J.有机化学,26,3392(1961))、三乙胺盐酸盐(见P.P.Bernstein等人,合成,1133(1987))或吡啶盐酸盐(见H.Nakai等人,J.医药化学,31,84(1988))存在下加热叠氮化钠,同时在120-150℃下搅拌溶剂如二甲基甲酰胺,N-甲基吡咯烷酮或1,3-二甲基-2-咪唑啉酮来合成通式(Ⅵ)表示的化合物。
当R′是-(CH2)-OR7(P是0或R7是烷基)时,起始化合物(Ⅱ)(其中R′是烷氧基)可用于以上所示的方法。另一种方法包括用起始化合物(Ⅱ)(其中R1是-S-烷基)进行步骤(Ⅰ)和(Ⅱ),然后氧化所得化合物(Ⅵ′)(其中R1是-SO2-烷基)并使磺酰化合物(Ⅵ′)与一种带有-R7OM(R7是烷基,M是金属如钠和钾)的化合物反应,得到其中R1是烷氧基的最终化合物。
制备方法2
举例来说,用以下方法可以制备通式(Ⅰ)表示的化合物(其中R5是羧基):
在上述式子中,R1,R2,R3,R6和由式-A1=A2-A3=A4-表示的基团分别定义如上。
(第一步)
在一步骤中,用传统方法使通式(Ⅱ)表示的缩合咪唑衍生物与通式(Ⅶ)表示的酯进行缩合,制备通式(Ⅷ)表示的化合物。
R8可以是任意基团,只要它能与羧酸结合成酯便可,其代表性例子有甲基和乙基。
本发明一般是在碱存在下进行的。碱的优选例子有氢化钠,氢化锂,碳酸钾,碳酸钠,醇化钠,叔丁氧钾,氢氧化钠,氢氧化钾,三乙胺和二异丙基乙胺。
反应用的溶剂的优选例子有二甲基甲酰胺,二甲基亚砜,N-甲基吡咯烷酮,1,3-二甲基-2-咪唑烷酮,二恶烷,乙醇和丙酮。
在该式中,X是卤原子,甲磺酰氧基或对甲苯磺酰氧基,而卤原子是氯,溴或碘。
在本方法中,其特别优选的例子有两种,一种是在质子极性溶剂(如二甲基甲酰胺)中,用氢化锂或氢化钾作为碱来形成金属盐(1),然后在0℃-室温下用联苯甲基卤化物(X=Cl,Br)进行烷基化;另一种是在醇中用醇化钠作为碱形成钠盐(1),然后在室温下用联苯甲基卤化物(X=cl,Br)进行烷基化。
(第二步)
在此步骤中,将通式(Ⅷ)表示的酯水解,制备本发明目的物质之一,即通式(Ⅸ)表示的化合物。
用传统工序水解酯,若R8为低级烷基如甲基或乙基,则通过例如在含乙醇和氢氧化钠水溶液的混合溶剂中回流加热该酯,很容易将酯转化成羧酸。虽然优选碱解,但任何方法均可使用,只要它能消除羧酸的保护基便可。
如上所示,本发明的化合物可通过方法(Ⅰ)制备,其中R5是四唑基,缩合的咪唑(Ⅱ)和联苯基甲烷化合物(Ⅲ)通过缩合相互反应且R5的氰基与叠氮化物(Ⅴ)转化成四唑基。
按照方法(Ⅱ),当R5是羧基或羧基酯时,缩合的咪唑基(Ⅱ)和联苯基甲烷化合物(Ⅶ)缩合成化合物(Ⅷ),该化合物(Ⅷ)带有R5的羧酸酯基-COOR8。通过水解化合物(Ⅷ),可得到其中R5是-COOH的化合物。
通过以下药物实验例子更详细地说明本发明的化合物的效果。
药物实验例
1.实验方法
(1)用免主动脉条模型,血管紧缩肽Ⅱ对挛缩的拮抗作用
用戊巴比妥钠麻醉2-3kg重的雄新西兰白免,取出胸主动脉。从该胸主动脉制备宽1.5-2mm、长15-20mm主动脉的螺旋制件,并将其悬浮在一个10ml的含Krebs碳酸氢
盐溶液的Magnus容器中(Krebs碳酸氢盐(mM):Nacl118.4,Kcl4.7,Cacl22.0,MgSO4.7H2O1.2,NaHCO325.0,KH2PO41.2,葡萄糖11.1)。加入10-5M消炎痛以消除***素的影响。将Krebs液保持在37℃,并鼓入95%O2-5%CO2。将1克初始张力加到该条上,并使其静置约1小时。然后,加入50mMKcl以减少挛缩。稳定挛缩之后,清洗该条。上述工序重复两次,且第二次挛缩当作100%挛缩率。
之后,累积加入10-10-3×10-6血管紧缩肽Ⅱ以制备药剂反应曲线。研究血管紧缩肽Ⅱ拮抗药的拮抗活性时,在加入10-10M血管紧缩肽前40分钟,加入浓度为10-6-10-9M的试验化合物以观察剂量反应取线向右边(right)移动情况。使用等长压电变换器(TB611T,Nihon Koden公司产)通过载体放大器(AP620G或AP621G,NihonkODEN公司产),在多笔记录仪(R-10,Rika Denki Kogyo有限公司产)上记录收缩情况。利用Schild方程式,通过计算PA2值的浓度负对数(-log)(即构成活性剂2药剂比的竞争性拮抗药的浓度)来测定血管紧缩肽Ⅱ的拮抗作用效力。结果示于表1。
(2)血管紧缩肽Ⅱ对具有封闭神经元的麻醉的鼠
(Wister Kyote)抑制增压反应。
用50mg/kg戊巴比妥钠腹膜内给药的方法,麻醉9-
25周龄Wister Koto雄鼠,并给颈动脉和颈静脉插套管。将颈动脉套管连到压电变换器(TP-200T)上采用复写器(RM-6000,Nikoo Koden公司产),通过载体放大器(AP-601G,Nihon Koden公司产)和使用集成脉波的平均血压测定板(Nihon Koden公司)进行记录。将10mg/kg安血定通过颈静脉管静脉内给药,以进行神经元封锁。血压稳定之后,将0.003-0.1或0.3μg/kg血管紧缩素Ⅱ以静脉内累积给药(时间间隔为各药剂中的增压反应应能基本上复原)从而制备药剂反应曲线。然后,将0.1-10mg/kg试验化合物静脉内给药,在该试验化合物给药3分钟后,再次静脉内注射0.03-1μg/kg血管紧缩肽Ⅱ,以测定药剂增压反应曲线向左边移动率。从拮抗药(A,mg/kg,i.v)和上述移动率(B)测定产生药剂-增压反应曲线向右边双倍移动所需的药剂(C=ED50,mg/kg,i.v.)。
C= (A)/(B/2) (mg/kg,i.v.)
-结果示于表1。
2.实验结果:
本发明的化合物的药物实验(1)和(2)的结果示于表1。
从以上药物实验例可以看出,本发明的化合物具有显著优良的血管紧缩肽Ⅱ拮抗作用。
此外,将上述表1中所列的化合物1,2,5和6悬浮在0.5%MC(甲基纤维素),并将悬浮液口服到8周龄雄SD(Sprague Dawley)鼠(每组四只鼠),剂量为100mg/kg/天,共服7天。观察鼠的情况,直至最终服药后24小时。结果在所有服用上述化合物(化合物,1,2,5和6)的组中,未观察到死亡。
所以,根据血管紧缩肽Ⅱ的拮抗作用,本发明的化合物可用于预防和治疗高血压、心脏病和血管紧缩素拮抗作用有效的其它疾病。具体地说,它们可用作高血压的治疗和防治剂(如原发、继发、肾血管性或恶性高血压),以及心脏病的治疗和预防药。此外,如上所述,本发明的化合物安全性高,因此赋予本发明很高价值。
当本发明的化合物用作药物时,它们可口服或肠胃外给药。本发明化合物的剂量取决于患者的症状、年龄、姓别和敏感程度;给药方法;给药的时间及间隔,以及药物制剂的性质、配方和种类等等,所以对剂量没有特别限制。
就口服来说,本发明的化合物一般以成人每天约1-1000mg、最好约5-500mg分1-3分服用。就注射来说,剂量一般约1-3000μg/kg、最好约3-1000μg/kg。
若制备口服固体制剂,将活性成份与载体和(需要的话)粘合剂、崩解剂、润滑剂、着色剂、矫味剂等混合,然后用传统方法制
备片剂、涂复的片剂、颗粒、粉末和胶囊。
载体的例子有乳糖、玉米淀粉、蔗糖、葡糖、山梨醇、晶体纤维素和二氧化硅。粘合剂的例子有聚乙烯醇、聚乙烯醚、乙基纤维素、甲基纤维素、***胶、黄蓍胶、明胶、虫胶、羟丙基纤维素、羟丙基甲基维素、柠蒙酸钙、糊精和果胶。润滑剂的例子有硬质酸镁、滑石、聚乙二醇、二氧化硅和氢化植物油。任何允许加到药物中的着色剂均可使用。矫味剂的例子包括可可豆粉、薄荷醇、芳香粉、薄荷粉、冰片和柠蒙树皮粉。当然,可将糖涂料、明胶涂料以及(需要的话)合适的其它涂料涂覆到这些片剂和粒剂上。
若制备注射剂,将PH改性剂、缓冲剂、悬浮剂、加溶剂、稳定剂、强壮剂、防腐剂等加到活性成份中,然后按照传统工序制备静脉内、皮下和肌肉注射剂。在此情况下,这些制剂可通过传统工序冰干。
悬浮剂的例子有甲基纤维素、多乙氧基醚80、羟乙基纤维素、***树胶、羟甲基纤维素纳和聚氧乙烯山梨醇一月桂酸酯。
加溶剂的例子有聚氧乙烯氢化蓖麻油、多乙氧基醚、烟酰胺、聚氧乙烯山梨醇-月桂酸酯、Macrogol和蓖麻油脂肪酸的乙基酯。
稳定剂的例子有亚硫酸钠、焦亚硫酸钢和醚,防腐剂的例子有对羟甲基苯甲酸甲酯、对羟甲基苯甲酸乙酯、山梨酸、苯酚、甲苯酚和氯甲苯酚。
以下用实施例的方式说明本发明的代表性化合物。可以理解,本发明并不仅限于这些实施例。
除了实施例之外,还给出了制备例,这些制备例中介绍了制备本发明目的化合物用的原料的制备方法。
在化学结构式中,Me是甲基,Et是乙基,n-Pr是正丙基且n-Bu是正丁基。
制备例1
4-氯-2-甲氧基苯甲酰氯
在室温下,将120ml亚硫酰氯滴加到75克4-氯-2-茴香酸中,混合物于室温搅拌12小时。将反应混合物浓缩结晶。晶体不经纯化用于后续反应。
制备例2
2-(4-氯-2-甲氧基苯基)-4,4-二甲基恶唑啉
将80克2-氨基-2-甲基-1-丙基醇溶于350ml二氯甲烷,溶液冷却到-5℃。4-氯-2-甲氧基苯甲酰氯溶于180ml二氯甲烷,然后缓慢滴加到冷却的溶液中。滴加完毕后,混合物于室温搅拌2小时。过滤反应混合物,用二氯甲烷洗涤晶体,稀盐酸加到滤液中,然后进行相分离,得到有机相。用无水硫酸镁干燥有机相,然后浓缩。室温下,将120ml亚硫酰氯缓慢添加到106克所得油质物质中。反应混合物再搅拌1小时,然后浓缩。将水加到浓缩液中以使PH值调节到11。加入氯仿,混合物萃取,无水硫酸镁干燥,然后浓缩。残余物用色谱柱(氯仿)纯化。产率为62.3克。
·NMR(90MHz,CDCl3,δ,):
7.65(d,1H,J=8Hz),7.00~6.81(m,2H),4.05(s,2H),3.87(s,3H),1.39(s,6H)
制备例3
2-(4-氯-4′-甲基联苯-2-基)-4,4-二甲基恶唑啉
在氮气流下,将46.0克4-溴甲苯的THF溶液(450ml)加到6.38克镁中。回流加热40分钟后,于室温下将反应混合物滴加到30克2-(4-氯-2-甲氧基苯基)-4,4-二甲基恶唑啉的THF溶液(260ml)。混合物于室温下搅拌2小时,然后冷却,往其中加入含水氯化铵。混合物用乙酸乙酯萃取,萃取物用氢氧化钠稀溶液和盐水溶液洗涤,用无水硫酸镁干燥,然后浓缩,得到38克粗标题化合物。
·NMR(90MHz,CDCl3,δ):
7.64(d,1H,J=8Hz),7.40~7.00(m,6H),3.79(s,2H),2.38(s,3H),1.29(s,6H)
制备例4
4-氯-2-(4-甲基苯基)苯甲酸
将500ml4.6N盐酸加到38克2-(4-氯-4′-甲基联苯-2-基)-4,4-二甲基恶唑啉中,混合物回流加热36小时。冷却后,回流液用一种含***和乙酸乙酯的混合溶剂萃取,水洗,无水硫酸镁干燥,然后浓缩。残余物用THF-异丙醚-己烷重结晶,得到17.5克标题化合物。
·m.p.(℃):143.5~146
·NMR(90MHz,CDCl3,δ):
9.30(bs,1H),7.87(1H,d,J=8Hz),7.46~7.20(m,2H),7.18(s,4H),2.38(s,3H)
按照制备例1-4中介绍的方法制备合成本发明化合物用的以下原料。
(1)3-甲氧基-2-(4-甲基苯基)苯甲酸
·m.p.(℃):180.5~181
·NMR(90MHz,CDCl3,δ):
9.40(bs,1H),7.55~6.98(m,3H),7.06(s,4H),3.73(s,3H),2.38(s,3H)
(2)4-甲氧基-2-(4-甲基苯基)苯甲酸
·m.p.(℃):176~179
·NMR(90MHz,CDCl3,δ):
9.40(bs,1H),7.96(d,1H,J=8Hz),7.18(s,4H),6.97~6.66(m,2H),3.84(s,3H),2.39(s,3H)
(3)5-氯-2-(4-甲基苯基)苯甲酸
·m.p.(℃):143~145
·NMR(90MHz,CDCl3,δ):
10.05(bs,1H),7.88(d,1H,J=2Hz),7.49(dd,1H,J=2Hz,8Hz),7.26(d,1H,J=8Hz),7.16(s,4H),2.37(s,4H)
(4)5-甲氧基-2-(4-甲基苯基)苯甲酸
·NMR(90MHz,CDCl3,δ):
9.40(bs,1H),7.37~6.82(m,7H),3.81(s,3H),2.32(s,3H)
制备例5
4-氯-2-(4-甲基苯基)苯酰胺
将40ml亚硫酰氯滴加到12.4克4-氯-2-(4-甲基苯基)苯甲酸中,混合物回流加热2小时。浓缩反应混合物。在此工序中,加入甲苯以尽可能多地蒸掉亚硫酰氯。将残余物溶于120ml四氢呋喃,并在-12~-5℃内温下,将氨气吹入溶液。水和氯仿加到反应混合物中,对混合物进行相分离。水洗有机相,然后用无水硫酸镁干燥。浓缩干燥的有机相,然后用四氢呋喃-异丙醚重结晶,得到9.1克标题化合物。
·m.p.(℃):162~163.5
·NMR(90MHz,CDCl3,δ):
7.72(d,1H,J=8Hz),7.42~7.08(m,2H),7.16(s,4H),2.39(s,3H)
制备例6
4-氯-2-(4-甲基苯基)苯基氰
将26ml亚硫酰氯滴加到8.9克4-氯-2-(4-甲基苯基)苯酰胺中,混合物回流加热2.5小时。用甲苯尽可能多地蒸掉过量的亚硫酰氯。残余物用四氢呋喃-异丙醚-正己烷的混合溶剂重结晶,得到7.2克产品。
·m.p.(℃):48~50℃
·NMR(90MHz,CDCl3,δ):
7.66(d,1H,J=8Hz),7.60~7.15(m,6H),2.38(s,3H)
按照制备例5-6中介绍的方法制备合成本发明化合物用的下述原料。
(1)3-甲氧基-2-(4-甲基苯基)苯基氰
·m.p.(℃):94.5~96
·NMR(90MHz,CDCl3,δ):
7.45~7.10(m,7H),3.78(s,3H),2.41(s,3H)
(2)4-甲氧基-2-(4-甲基苯基)苯基氰
·m.p.(℃):121~123
·NMR(90MHz,CDCl3,δ):
7.66(d,1H,J=8Hz),7.50~7.15(m,4H),7.00~6.78(m,2H),3.88(s,3H),2.42(s,3H)
(3)5-氯-2-(4-甲基苯基)苯基氰
·m.p.(℃):111~113.5
·NMR(90MHz,CDCl3,δ):
7.75~7.15(s,7H),2.42(s,3H)
(4)5-甲氧基-2-(4-甲基苯基)苯基氰
·m.p.(℃):152~155
·NMR(90MHz,CDCl3,δ):
7.45~6.93(m,7H),3.91(s,3H),2.44(s,3H)
制备例7
2-(4-溴甲基苯基)-4-氯苯基氰
在220ml四氯化碳中,将6.83克4-氯-2-(4-甲基苯基)苯基氰、5.34克N-溴琥珀酰亚胺和0.1克α,α′-偶氮双(异丁腈)回流加热2小时。滤除琥珀酰亚胺,并浓缩滤液。残余物用四氢呋喃-异丙醚的混合溶剂结晶。产量为5.6克。
·m.p.(℃):122~125
·NMR(90MHz,CDCl3,δ):
7.69(d,2H,J=8Hz),7.52(s,4H),7.48(d,1H,J=2Hz),7.40(dd,1H,J=2Hz,8Hz),4.53(s,2H)
制备例8
2-(4-甲基苯基)苯甲酸甲酯
将溶于12ml甲醇中的6克硫酸加到3.2克2-(4-甲基苯基)苯甲酸中(见A.I.Meyers等人,J.有机化学,43,1372(1978)),混合物回流加热8小时。冷却回流液,例入冰水中,用氨水弱碱化并用***萃取。萃取物用无
水硫酸镁干燥,浓缩干燥的萃取物,残余物用正己烷重结晶,得到2.4克标题化合物。
m.p.(℃):54-57
制备例9
2-(4-溴甲基苯基)苯甲酸甲酯
在110ml四氯化碳中,将2.0克2-(4-甲基苯基)苯甲酸甲酯,1.6克N-溴琥珀酰亚胺和0.05克α,α′-偶氮双(异丁腈)回流加热2小时。滤除琥珀酰亚胺。浓缩滤液,残余物用正己烷-异丙醚的混合溶剂重结晶,制得1.6克标题化合物。
m.p.(℃):50-51
制备例10
(1)2-氨基-4-正丙基吡啶
将75克(0.62M)4-正丙基吡啶和28克(0.73M)叠氮化钠加到250ml二甲苯中,混合物回流加热10小
时。在冰冷却下,将少量水加到反应混合物中以分解过量的叠氮化钠。反应混合物用乙酸乙酯萃取,无水硫酸镁干燥,然后用色谱柱(二氯甲烷-甲醇50∶1→20∶1)纯化。产量是33克(黑紫色固体)。
·NMR(90MHz,CDCl3,δ):
7.90(d,1H,J=5Hz),6.46(dd,1H,J=5Hz,1Hz),6.28(d,1H,J=1Hz),4.50(bs,2H),2.44(t,2H,J=7Hz),1.82~1.30(m,2H),0.94(t,3H,J=7Hz)
(2)2,3-二氨基-4-正丙基吡啶
在25℃或以下内温及冰冷却下,将33克(0.24M)2-氨基-4-正丙基吡啶小批量加到120ml浓硫酸中。在20℃或以下内温及冰冷却下,往其中滴加17ml(0.38M)浓硝酸。滴加完毕后,除去冷却浴,混合物于室温下静置1小时。温度逐渐升高,将混合物于95℃搅拌1小时。把混合物倒入冰中,往其中加入浓氨水以碱化,然后用乙酸乙酯萃取。用无水硫酸镁干燥萃取物,真空蒸掉溶剂,得到2-氨基-3-硝基-4-正丙基吡啶与2-氨基-5-硝基-4-正丙基吡啶的固体混合物。
将混合物悬浮在甲醇中,在钯碳存在下催化氢化。滤除钯碳,
真空蒸掉溶剂。用硅胶层析纯化残余物。产量显2.6克(棕色晶体)。
·NMR(90MHz,CDCl3,δ):
7.55(d,1H,J=5Hz),6.50(d,1H,J=5Hz),3.80(bs,4H),2.47(t,2H,J=7Hz),1.88~1.40(m,2H),1.00(t,3H,J=7Hz)
(3)2-乙基-7-正丙基-咪唑并〔4,5-b〕吡啶
将2.6克(0.017M)2,3-二氨基-4-正丙基吡啶和1.4ml(0.019M)丙酸加到15ml磷酸中,混合物于140-150℃干燥20小时。将其冷却到室温,例入冷的NaOH水溶液中,然后用乙酸乙酯萃取。萃取物用硫酸镁干燥,真空蒸掉溶剂,制得基本上纯的标色油质目的产物。产量为2.9克(该化合物用作制备以下原料(29)的原料)。
·NMR(90MHz,CDCl3,δ):
8.10(d,1H,J=5Hz),7.02(d,1H,J=5Hz),3.10(q,4H,J=7Hz),2.08~1.68(m,2H),1.56(t,3H,J=7Hz),1.04(t,3H,J=7Hz)
制备例11
2-环丙基-7-甲基-3H-咪唑并〔4,5-b〕吡啶
将30ml环丙烷羧酸和70ml磷酸(85%)加到15克2,3-二氨基-4-甲基吡啶中,并在130℃内温下将混合物搅拌12小时。冷却反应混合物,倒入140克氢氧化钾于420ml水的溶液中,然后用氯仿萃取。萃取物用无水硫酸镁干燥,然后浓缩。残余物用色谱柱(氯仿∶乙醇=97∶3)纯化。产量为14.1克,并将产物用乙酸乙酯-异丙醚重结晶,得到纯态标题化合物,其熔点为203-204℃。
·NMR(90MHz,CDCl3,δ):
8.16(d,1H,J=5Hz),7.00(d,1H,J=5Hz),2.68(s,3H),2.50~2.10(m,1H),1.40~1.12(m,4H)
制备例12
按照上述制备例10(3)和制备例11中介绍的方法制备以下化合物。这些化合物在制备本发明的化合物中用作原料。
·NMR(90MHz,CDCl3,δ):
8.15(d,1H,J=5Hz),7.02(d,1H,J=5Hz),3.06(t,2H,J=7Hz),2.68(s,3H),2.14~1.70(m,2H),1.70~1.10(m,2H),0.97(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
13.01(bs,1H),8.22(s,1H),3.01(t,2H,J=7Hz),2.72(s,3H),2.20~1.70(m,2H),1.08(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.12(d,1H,J=1Hz),7.81(d,1H,J=1Hz),3.02(t,2H,J=7Hz),2.49(s,3H),2.20~1.72(m,2H),1.08(s,3H)
·NMR(90MHz,CDCl3,δ):
12.80(bs,1H),8.31(d,1H,J=2Hz),8.12(d,1H,J=2Hz),2.36(q,2H,J=7Hz),1.33(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.24(d,1H,J=5Hz),7.06(d,1H,J=5Hz),4.00(quint,1H,J=8Hz),2.75(s,3H),2.86~1.96(m,6H)
·NMR(400MHz,CDCl3,δ):
8.15(d,1H,J=5Hz),7.01(d,1H,J=5Hz),3.40(q,2H,J=8Hz),2.66(s,3H),1.48(t,3H,J=8Hz)
·NMR(90MHz,CDCl3,δ):
8.14(d,1H,J=5Hz),6.67(d,1H,J=5Hz),4.10(s,3H),3.00(t,2H,J=8Hz),2.20~1.70(m,2H),1.08(t,3H,J=8Hz)
·NMR(90MHz,CDCl3,δ):
8.23(d,1H,J=5Hz),7.02(d,1H,J=5Hz),4.88(s,2H),3.57(s,3H),2.70(s,3H)
·NMR(90MHz,CDCl3,δ):
8.10(d,1H,J=5Hz),7.10~6.60(m,2H),6.46(dd,1H,J=15Hz,1Hz),2.55(s,3H),1.99(dd,3H,J=6Hz,1Hz)
·NMR(400MHz,CDCl3,δ):
8.34~8.02(m,3H),7.64~7.36(m,3H),7.03(d,1H,J=5Hz),2.64(s,3H)
·NMR(400MHz,CDCl3,δ):
8.04(d,1H,J=5Hz),6.92(d,1H,J=5Hz),3.50~3.00(m,1H),2.52(m,3H),2.24~1.46(m,8H)
·NMR(400MHz,DMSO-d6,δ):
8.97(1H,s),8.84(1H,s),2.87(2H,t,J=8Hz),1.88~1.78(2H,m),0.96(3H,t,J=8Hz)
·NMR(400MHz,CDCl3,δ):
6.90(1H,s),2.98(2H,t,J=8Hz),2.66(3H,s),2.65(3H,s),1.94~1.85(2H,m),1.037(3H,t,J=8Hz)
·NMR(400MHz,CDCl3,δ):
6.84(1H,s),2.66(3H,s),2.58(3H,s),2.21~2.15(1H,m),1.26~1.22(2H,m),1.12~1.07(2H,m)
制备例13
2-正丁基-1-{(5′-氯-2′-氰基联苯-4-基)甲基}苯并咪唑
将522克2-正丁基苯并咪唑溶于10ml二甲基甲酰胺并滴加到130克氢化钠中。将混合物于室温下搅拌30分钟,往里滴加920mg溶于10ml二甲基甲酰胺的2-(4-溴甲基苯基)-4-氯苯基氰。混合物于室温搅拌10分钟,然后过滤。浓缩滤液,并将水和乙酸乙酯加到残余物中。分离有机相,用无水硫酸镁干燥,然后浓缩。残余物用色谱柱(氯仿∶乙醇=98∶2)纯化(产量:1.12克)。
·NMR(90MHz,CDCl3,δ):
7.82~6.95(m,11H),5.38(s,2H),2.83(t,2H,J=7Hz),2.00~1.15(m,2H),0.92(t,3H,J=7Hz)
制备例14
3-{(2′-氰基联苯-4-基)甲基}-2-乙基-3H-咪唑并〔4,5-b〕吡啶
将735mg2-乙基咪唑并〔4,5-b〕吡啶溶于15ml二甲基甲酰胺并滴加到220mg氢化钠中。混合物于室温搅拌30分钟,往里滴加溶于15ml二甲基甲酰胺中的1.4克2-(4-溴甲基苯基)苯基氰。混合物于室温搅拌10分钟,然后过滤。浓缩滤液,并将水和乙酸乙酯加到残余物中。分离有机相,用无水硫酸镁干燥,然后浓缩。用硅胶柱色层分离法纯化残余物,并把洗脱液从2%乙醇-98%氯仿逐渐变化到5%乙醇-95%氯仿进行洗脱,以分离区域异聚体。第一种洗脱馏分为目的标题化合物(产量:800mg)。
·NMR(90MHz,CDCl3,δ):
8.34(dd,1H,J=1Hz,5Hz),8.02(dd,1H,J=1Hz,8Hz),7.78~6.95(m,9H),5.55(s,2H),2.87(q,2H,J=7Hz),1.42(t,3H,J=7Hz)
第二种洗脱馏分是1-{(2′-氰基联苯-4-基)甲基}-2-乙基-1H-咪唑并〔4,5-b〕吡啶(产量:200mg)。
·NMR(90MHz,CDCl3,δ):
8.53(dd,1H,J=1Hz,5Hz),7.82~6.90(m,10H),5.41(s,2H),2.93(q,2H,J=7Hz),1.47(t,3H,J=7Hz)
第三种洗脱馏分是4-{(2′-氰基-联苯-4-基)甲基}-2-乙基-4H-咪唑并〔4,5-b〕吡啶(产量:570克)。
·NMR(90MHz,CDCl3,δ):
8.07(d,1H,J=7Hz),7.82~7.26(m,9H),7.02(dd,1H,J=7Hz,7Hz),5.88(s,2H),3.09(q,2H,J=7Hz),1.49(t,3H,J=7Hz)
通过测量NOE(核极化效应)测定区域异构体的结构。
制备例15
(a)2-正丁基-1-〔(2′-氰基联苯-4-基)甲基〕-1H-咪唑并〔4,5-c〕吡啶和(b)2-正丁基-3-〔(2′-氰基联苯-4-基)甲基〕-3H-咪唑并〔4,5-c〕-吡啶
将6.0克(0.37M)2-正丁基咪唑并〔4,5-c〕吡啶和10克(0.037M)2-(4-溴甲基苯基)-苯基氰悬浮在50ml二甲基甲酰胺中,在室温及搅拌下,立刻往里加入1.6克(0.040M)氢化钠。加入30分钟后,往里加入水,并用乙酸乙酯萃取混合物。萃取物用硫酸镁干燥。真空蒸掉溶剂,残余物用硅胶色层法纯化。第一种洗脱馏分是2-亚丁基-3-〔2′-氰基联基-4-基)甲基〕-3H-咪唑并〔4,5-c〕吡啶(产量160mg,棕色油质物质),第二种洗脱馏分是2-正丁基-1-〔(2′-氰基联苯-4-基)甲基〕-1H-咪唑并〔4,5-c〕吡啶(产量200mg,棕色油质物质)。
(a)·NMR(90MHz,CDCl3,δ):
8.60(s,1H),8.38(d,1H,J=5Hz),7.82~7.00(m,9H),5.46(s,2H),2.92(t,2H,J=7Hz),2.08~1.30(m,4H),0.96(t,3H,J=7Hz)
(b)·NMR(90MHz,CDCl3,δ):
9.04(s,1H),8.32(d,1H,J=5Hz),7.80~7.00(m,9H),5.40(s,2H),2.90(t,2H,J=7Hz),2.07~1.20(m,4H),0.96(t,3H,J=7Hz)
制备例16
按照制备例13-15介绍的方法制备以下合成本发明化合物用的原料化合物。
以下给出制得化合物的化学结构式。
·NMR(90MHz,CDCl3,δ):
7.85~7.62(m,1H),7.45~6.85(m,10H),5.40(s,2H),3.75(s,3H),2.86(t,2H,J=7Hz),2.02~1.10(m,4H),0.92(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.34(dd,1H,J=1Hz,5Hz),8.01(dd,1H,J=1Hz,8Hz),7.78~7.06(m,9H),5.56(s,2H),2.83(t,2H,J=7Hz),2.00~1.56(m,2H),1.54~1.05(m,4H),0.87(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
7.86~7.00(m,11H),5.40(s,2H),2.86(t,2H,J=7Hz),2.03~1.15(m,4H),0.93(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.33(dd,1H,J=1Hz,5Hz),8.01(dd,1H,J=1Hz,8Hz),7.74~7.05(m,8H),5.56(s,2H),2.83(t,2H,J=7Hz),2.00~1.15(m,4H),0.92(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.34(dd,1H,J=1Hz,5Hz),8.02(dd,1H,J=1Hz,8Hz),7.72~7.05(m,8H),5.56(s,2H),2.84(t,2H,J=7Hz),2.00~1.17(m,4H),0.92(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.34(dd,1H,J=1Hz,5Hz),8.01(dd,1H,J=1Hz,8Hz),7.75~7.05(m,6H),7.00~6.82(m,2H),5.56(s,2H),3.87(s,3H),2.85(t,2H,J=7Hz),2.02~1.15(m,4H),0.93(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
7.83~7.35(m,4H),7.33~6.98(m,5H),6.98~6.77(m,2H),5.40(s,2H),3.87(s,3H),2.87(t,2H,J=8Hz),2.06~1.22(m,4H),0.94(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.34(dd,1H,J=1Hz,5Hz),8.02(dd,1H,J=1Hz,8Hz),7.75~7.12(m,8H),5.57(s,2H),2.82(t,2H,J=7Hz),2.10~1.62(m,2H),1.02(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.34(dd,1H,J=1Hz,5Hz),8.01(dd,1H,J=1Hz,8Hz),7.80~7.00(m,8H),5.56(s,2H),2.82(t,2H,J=7Hz),2.12~1.58(m,2H),1.02(t,3H,J=7Hz)
·NMR(90MHz,DMSO-d6,δ):
7.85~7.00(m,12H),5.39(s,2H),2.84(t,2H,J=7Hz),2.04~1.20(m,4H),0.92(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
7.80~6.70(m,11H),5.36(s,2H),2.85(t,2H,J=7Hz),2.04~1.20(m,4H),0.95(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
7.80~6.70(m,11H),5.32(s,2H),2.86(t,2H,J=7Hz),2.04~1.24(m,4H),0.96(t,3H,J=7Hz)
8.30(dd,1H,J=5Hz,1Hz),7.98(dd,1H,J=8Hz,1Hz),7.78~7.04(m,9H),5.54(s,2H),2.86(t,2H,J=7Hz),2.02~1.22(m,4H),0.94(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.28(dd,1H,J=5Hz,1Hz),7.96(dd,1H,J=8Hz,1Hz),7.50~6.96(m,8H),5.52(s,2H),3.76(s,3H),2.84(t,2H,J=7Hz),2.04~1.16(m,4H),0.92(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.30(dd,1H,J=5Hz,1Hz),7.96(dd,1H,J=8Hz,1Hz),7.80~7.08(m,9H),5.54(s,2H),2.84(t,2H,J=7Hz),2.10~1.66(m,2H),1.04(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
7.84~7.60(m,1H),7.52~6.98(m,10H),5.36(s,2H),3.84(s,3H),2.88(t,2H,J=7Hz),2.04~1.20(m,4H),0.95(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.49(dd,1H,J=5Hz,1Hz),8.07~7.01(m,10H),5.48(s,2H),2.90(t,2H,J=7Hz),2.04~1.10(m,4H),0.93(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.16(d,1H,J=5Hz),7.80~7.06(m,8H),7.00(d,1H,J=5Hz),5.54(s,2H),2.85(t,2H,J=7Hz),2.70(s,3H),2.04~1.60(m,2H),1.02(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.16(d,1H,J=5Hz),7.76~7.08(m,8H),7.00(d,1H,J=5Hz),5.54(s,2H),2.88(q,2H,J=7Hz),2.72(s,3H),1.40(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.17(d,1H,J=5Hz),7.80~7.10(m,8H),7.02(d,1H,J=5Hz),5.52(s,2H),2.72(s,3H),2.63(s,3H)
·NMR(90MHz,CDCl3,δ):
8.16(d,1H,J=5Hz),7.80~7.08(m,8H),7.00(d,1H,J=5Hz),5.52(s,2H),2.86(t,2H,J=6Hz),1.96~1.16(m,4H),0.92(t,3H,J=6Hz)
·NMR(90MHz,CDCl3,δ):
8.23(d,1H,J=5Hz),7.80~6.99(m,14H),5.60(s,2H),2.76(s,3H)
·NMR(90MHz,CDCl3,δ):
8.12(d,1H,J=5Hz),7.80~7.10(m,8H),6.94(d,1H,J=5Hz),5.62(s,2H),2.64(s,3H)2.36~2.14(m,1H),1.40~0.90(m,4H)
·NMR(90MHz,CDCl3,δ):
8.16(d,1H,J=5Hz),7.80~7.06(m,8H),6.98(d,1H,J=5Hz),5.56(s,2H),3.44~2.90(m,1H),2.70(s,3H),2.40~1.40(m,8H)
·NMR(90MHz,CDCl3,δvalue):
8.22(d,1H,J=5Hz),7.80~7.12(m,8H),7.03(d,1H,J=5Hz),5.54(s,2H),3.08(t,2H,J=6Hz),2.89(q,2H,J=6Hz),2.10~1.70(m,2H),1.38(t,3H,J=6Hz),1.06(t,3H,J=6Hz)
·NMR(90MHz,CDCl3,δ):
8.18(d,1H,J=5Hz),7.80~6.94(m,9H),5.48(s,2H),3.80~3.40(m,1H),2.74(s,3H),2.66~1.88(m,6H)
·NMR(90MHz,CDCl3,δ):
8.18(d,1H,J=5Hz),7.80~7.10(m,8H),7.01(d,1H,J=5Hz),5.57(s,2H),3.10~2.80(m,1H),2.72(s,3H),2.04~1.60(m,2H),1.34(d,3H,J=6Hz),0.84(t,3H,J=6Hz)
8.18(d,1H,J=5Hz),7.80~7.10(m,8H),7.02(d,1H,J=5Hz),5.56(s,2H),2.76(d,2H,J=6Hz),2.40~1.08(m,1H),1.00(d,6H)
·NMR(90MHz,CDCl3,δ):
8.20(d,1H,J=5Hz),7.84~6.90(m,9H),5.57(s,2H),3.40~3.00(m,1H),2.70(s,3H),1.37(s,6H,J=7Hz)
8.38(d,1H,J=2Hz),8.13(d,1H,J=2Hz),7.82~7.10(m,8H),5.51(s,2H),2.87(q,2H,J=7Hz),1.41(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.18(d,1H,J=6Hz),7.80~7.08(m,8H),6.68(d,1H,J=6Hz),5.52(s,2H),4.10(s,3H),2.80(t,2H,J=6Hz),2.10~1.64(m,2H),1.01(t,3H,J=6Hz)
·NMR(90MHz,CDCl3,δ):
8.28(d,1H,J=6Hz),7.80~7.20(m,8H),7.06(d,1H,J=6Hz),5.68(s,2H),4.69(s,2H),3.40(s,3H),2.72(s,3H)
·NMR(90MHz,CDCl3,δ):
8.17(d,1H,J=5Hz),7.84~7.28(m,8H),7.00(d,1H,J=5Hz),6.16(q,1H,J=8Hz),2.80(t,2H,J=6Hz),2.69(s,3H),2.17(d,3H,J=8Hz),2.00~1.60(m,2H),0.98(t,3H,J=6Hz)
·NMR(90MHz,CDCl3,δ):
8.15(d,1H,J=5Hz),7.74(dd,1H,J=8Hz,1Hz),7.61(td,1H,J=8Hz,1Hz),7.51~7.39(m,6H),6.99(d,1H,J=5Hz),5.46(s,2H),3.40(q,2H,J=7Hz),2.65(s,3H),1.45(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.15(d,1H,J=5Hz),7.74(d,1H,J=8Hz),7.61(td,1H,J=8Hz,1Hz),7.51~7.39(m,6H),7.00(d,1H,J=5Hz),5.46(s,2H),2.80(s,3H),2.65(s,3H)
·NMR(90MHz,CDCl3,δ):
7.96(d,1H,J=8Hz),7.80~7.07(m,9H),5.51(s,2H),2.83(q,2H,J=8Hz),1.40(t,3H,J=8Hz)
·NMR(90MHz,CDCl3,δ):
8.20(d,1H,J=5Hz),7.72~7.05(m,7H),7.03
(d,1H,J=5Hz),5.55(s,2H),2.83(t,2H,J=7Hz),2.69(s,3H),2.02~1.60(m,2H),1.00(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.17(d,1H,J=1Hz),7.85~7.05(m,9H),5.53(s,2H),2.81(t,2H,J=7Hz),2.47(s,3H),2.08~1.61(m,2H),1.01(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.26(s,1H),7.78~7.05(m,9H),5.51(s,2H),2.83(t,2H,J=7Hz),2.71(s,3H),2.03~1.57(m,2H),1.00(t,3H,J=7Hz)
·NMR(400MHz,CDCl3,δ):
7.75(1H,dd,J=8Hz,1Hz),7.63(1H,td,J=8Hz,1Hz),7.49(2H,d,J=8Hz),7.46(1H,dd,J=8Hz,1Hz),7.43(1H,td,J=8Hz,1Hz),7.30(2H,d,J=8Hz),6.88(1H,s),5.64(2H,s),2.59(6H,s),1.93~1.86(1H,m),1.19~1.15(2H,m),1.03~0.98(2H,m)
9.20(1H,s),9.06(1H,s),8.17(1H,s),7.76(1H,dd,J=8Hz,1Hz),7.64(1H,td,J=8Hz,1Hz),7.56(2H,d,J=8Hz),7.48~7.43(4H,m),5.54(2H,s)
·NMR(400MHz,CDCl3,δ):
9.09(1H,s),8.97(1H,s),7.75(1H,d,J=8Hz),7.63(1H,td,J=8Hz,1Hz),7.52(2H,d,J=8Hz),7.45(1H,d,J=8Hz),7.44(1H,td,J=8Hz,1Hz),7.28(2H,d,J=8Hz),5.52(2H,s),2.85(2H,t,J=8Hz),1.94~1.85(2H,m),1.03(3H,t,J=8Hz)
·NMR(400MHz,CDCl3,δ):
7.75(1H,dd,J=8Hz,1Hz),7.62(1H,td,J=8Hz,1Hz),7.49~7.41(4H,m),7.23(2H,d,J=8Hz),6.91(1H,s),5.54(2H,s),2.78(2H,t,J=8Hz),2.64(3H,s),2.60(3H,s),1.82~1.73(2H,m),0.98(3H,t,J=8Hz)
制备例17
(1)4-氯-2,3-二氨基吡啶
将3.6克2-氨基-4-氯-3-硝基吡啶加到21ml甲醇和24ml浓盐酸中,强搅拌混合物。将铁粉以若干小份加到混合物中,加入完毕后10分钟,把混合物倒入冰冷的浓氨水中,并用乙酸乙酯萃取。萃取物用硫酸镁干燥,并真空蒸掉溶剂,残余物用硅胶色层法纯化(CHcl∶MeOH=20∶1→10∶1),以制备2.6克紫白色晶体4-氯-2,3-二氨基吡啶。
·NMR(90MHz,CDCl3,δ):
7.20(d,1H,J=5Hz),6.48(d,1H,J=5Hz),5.74(bs,2H),4.87(bs,2H)
(2)7-氯-2-正丙基-3H-咪唑并〔4,5-b〕吡啶
500mg4-氯-2,3-二氨基吡啶溶于THF,往里依次加入860mg二环己基碳化二亚胺,570mgN-羟基苯并
***和0.4ml正丁酸。在室温下,混合物搅拌过夜,并滤出固体。固体彻底用乙酸乙酯洗涤。收集母液和洗液,并真空蒸掉溶剂。残余物用硅胶色谱法(CH2cl2∶MeOH=40∶1)纯化。将真空蒸掉溶剂后得到的固体加热到140℃。30分钟后,再将固体温度变为室温,固体用色谱柱(CH2cl2∶MeOH=20∶1)纯化,得到200mg含某些杂质的7-氯-2-正丙基-3H-咪唑并〔4,5-b〕吡啶。
(3)7-氯-2-正丙基-3-〔(2′-甲氧基羰基联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
将200mg上述制备的7-氯-2-正丙基-3H-咪唑并〔4,5-b〕吡啶和380mg2-(4-溴甲基苯基)苯甲酸甲酯溶于二甲基甲酰胺,并将50mg氢化钠加到溶液中。混合物于室温下搅拌30分钟,往里加入水,然后用乙酸乙酯萃取。萃取物用硫酸镁干燥,并真空蒸掉溶剂。残余物用硅胶柱色层法纯化(苯∶乙酸乙酯=40∶1→20∶1),得到呈无色油质物质的目的产物。产量为140mg。
·NMR(90MHz,CDCl3,δ):
8.23(d,1H,J=5Hz),7.82(dd,1H,J=8Hz,1Hz),7.51(td,1H,J=8Hz,1Hz),7.40(td,1H,J=8Hz,1Hz),7.30(dd,1H,J=8Hz,1Hz),7.27~7.23(m,3H),7.16(d,2H,J=8Hz),5.53(s,2H),3.61(s,3H),2.85(t,2H,J=8Hz),1.88~1.78(m,2H),1.00(t,3H,J=8Hz)
制备例18
(1)2-巯基-7-甲基-3H-咪唑并〔4,5-b〕吡啶
在20℃或以下,将溶于30ml乙醇中的5克氢氧化钾滴加到15克2,3-二氨基-4-甲基吡啶于15ml二硫化碳和60ml甲醇中的溶液中,混合物回流2小时。往里加入水和7ml浓盐酸,然后加入乙酸以弱酸化混合物。用过滤的方法回收沉淀出的固体。固体用少量甲醇洗两遍,然后干燥,得到12.3克2-巯基-7-甲基-3H-咪唑并〔4,5-b〕吡啶粘土质固体。
·NMR(400MHz,DMSO-d6):
13.01(bs,1H9,12.83(bs,1H),7.95(d,1H,J=5Hz),6.94(d,1H,J=5Hz),2.36(s,3H)
(2)7-甲基-2-甲硫基-3H-咪唑并〔4,5-b〕吡啶
在室温下,将130mg氢化钠滴加到500mg2-巯基-7-甲基-3H-咪唑并〔4,5-b〕吡啶于二甲基甲酰胺中的溶液中。混合物搅拌10分钟,往里加入0.21ml碘甲烷,然后反应30分钟。水加到反应混合物中,并用乙酸乙酯萃取混合物。萃取物用硫酸镁干燥,并真空蒸掉溶剂。所得固体用少量乙酸乙酯洗涤,得到210mg7-甲基-2-甲硫基-3H-咪唑并〔4,5-b〕吡啶泥黄色固体。
(3)7-甲基-2-甲硫基-3-〔(2′-甲氧基羰基联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
200mg7-甲基-2-甲硫基-3H-咪唑并〔4,5-b〕吡啶和370mg2-(4-溴甲基苯基)苯甲酸甲酯溶于二甲基甲酰胺中,并于室温及搅拌下,将48mg氢化钠加到溶液
中。反应进行30分钟。反应混合物中加入水,并用乙酸乙酯萃取混合物,萃取物用硫酸镁干燥,并真空蒸掉溶剂。残余物用硅胶色层法纯化(苯∶乙酸乙酯=10∶1→3∶2),得到呈无色油质物质的目的产物。产量为60mg。
·NMR(90MHz,CDCl3,δ):
8.23(d,1H,J=5Hz),7.82(dd,1H,J=8Hz,1Hz),7.51(td,1H,J=8Hz,1Hz),7.40(td,1H,J=8Hz,1Hz),7.30(dd,1H,J=8Hz,1Hz),7.27~7.23(m,3H),7.16(d,2H,J=8Hz),5.53(s,2H),3.61(s,3H),2.85(t,2H,J=8Hz),1.88~1.78(m,2H),1.00(t,3H,J=8Hz)
制备例19
2-环丙基-3-{(2′-甲氧基羰基联苯-4-基)甲基}-7-甲基-3H-咪唑并〔4,5-b〕吡啶
将1.64克溶于30ml二甲基甲酰胺中的2-环丙基-7-甲基-3H-咪唑并〔4,5-b〕吡啶滴加到400mg氢化钠中。混合物于室温搅拌30分钟,往里滴加3.1克溶于20ml二甲基甲酰胺中的2-(4-溴甲基苯基)苯甲酸甲酯。混合物
搅拌10分钟,然后冷却,并往里加入氯化铵水溶液。混合物用乙酸乙酯萃取。萃取物水洗两遍,用无水硫酸镁干燥,然后浓缩。残余物经色谱柱纯化(氯仿∶乙醇=99∶1)。第一种洗脱异构体为标题化合物(产量:1.32克)。
·NMR(90MHz,CDCl3,δ):
8.16(d,1H,J=5Hz),7.85~7.63(m,1H),7.56~7.10(m,1H),7.22(s,4H),6.98(d,1H,J=5Hz),5.62(s,2H),3.60(s,3H),2.64(s,3H),2.10~1.80(m,1H),1.30~0.82(m,4H)
2-羟甲基-3-〔(2′-甲氧基羰基-联苯-4-基)甲基〕-7-甲基-3H-咪唑并〔4,5-b〕吡啶
将50ml(50毫摩尔)1M三溴化硼的二氯甲烷溶液以一滴一滴加到100ml3.3克(8.2毫摩尔)3-〔(2′-甲氧基羰基-联苯-4-基)甲基〕-2-甲氧基甲基-7-甲基-3H-咪唑并〔4,5-b〕吡啶的二氯甲烷溶液,同时进行搅拌和用冰冷却。混合物再于室温下搅拌12小时。将甲醇滴加到产物混合物中,同时进行搅拌和用冰冷却,然后减压蒸掉溶剂。残余物与水混合,并用碳酸氢钠中和。将其用乙酸弱酸化并轻轻倒出上清液以除去水。将甲醇加到残余物中并减压将其蒸掉。用乙醇-异丙醚重结晶,得到2.4克目的化合物。
制备例20
按照制备例17介绍的方法制备以下化合物。
·NMR(90MHz,CDCl3,δ):
7.80~6.85(m,12H),5.42(s,2H),3.58(s,3H),2.79(t,2H,J=7Hz),1.85~1.00(m,4H),0.86(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.21(d,1H,J=5Hz),7.90~7.72(m,1H),7.58~6.94(s,8H),5.52(s,2H),3.59(s,3H),2.87(q,2H,J=8Hz),2.69(s,3H),1.35(t,3H,J=8Hz)
·NMR(90MHz,CDCl3,δ):
8.20(d,1H,J=5Hz),7.93~7.74(m,1H),7.55~6.90(m,8H),5.53(s,2H),3.59(s,3H),2.83(t,2H,J=7Hz),2.69(s,3H),1.95~1.56(m,2H),1.00(t,3H,J=7Hz)
·NMR(90MHz,CDCl3,δ):
8.20(d,1H,J=5Hz),7.86~7.68(m,1H),7.57~6.92(m,8H),5.52(s,2H),3.60(s,3H),2.85(t,2H,J=7Hz),2.69(s,3H),1.96~1.14(m,4H),0.91(t,3H,J=7Hz)
·NMR(400MHz,CDCl3,δ):
8.21(d,1H,J=5Hz),7.80(d,1H,J=8Hz),7.50(t,1H,J=8Hz),7.39(t,1H,J=8Hz),7.29(d,1H,J=8Hz),7.23(d,2H,J=8Hz),7.14(d,2H,J=8Hz),7.03(d,1H,J=5Hz),5.56(s,2H),3.58(s,3H),3.24~3.13(m,1H),2.71(s,3H),1.36(d,6H,J=7Hz)
·NMR(400MHz,CDCl3,δ):
8.22(d,1H,J=5Hz),7.81(d,1H,J=8Hz),7.50(t,1H,J=8Hz),7.40(t,1H,J=8Hz),7.30(d,1H,J=8Hz),7.24(d,2H,J=8Hz),7.18(d,2H,J=8Hz),7.04(d,1H,J=5Hz),5.51(s,2H),3.61(s,3H),2.68(s,3H),2.58(s,3H)
·NMR(400MHz,CDCl3,δ):
8.15(d,1H,J=5Hz),7.79(d,1H,J=8Hz),7.49(td,1H,J=8Hz,1Hz),7.38(td,1H,J=8Hz,1Hz),7.35~7.29(m,3H),7.23(d,1H,J=8Hz),6.99(dd,2H,J=5Hz,1Hz),5.44(s,2H),3.59(s,3H),3.39(q,2H,J=8Hz),2.64(s,3H),1.44(t,3H,J=8Hz)
·NMR(400MHz,CDCl3,δ):
8.28(d,1H,J=5Hz),8.00(d,1H,J=8Hz),7.75(td,1H,J=8Hz,1Hz),7.46(td,1H,J=8Hz,1Hz),7.38(d,1H,J=8Hz),7.31~7.11(m,4H),7.05(d,1H,J=5Hz),5.65(s,2H),4.65(s,2H),3.60(s,3H),3.38(s,3H),2.71(s,3H)
·NMR(400MHz,DMSO-d6,δ):
8.23(1H,d,J=5Hz),7.73(1H,dd,J=8Hz,1Hz),,7.61(1H,td,J=8Hz,1Hz),7.48(1H,td,J=8Hz,1Hz),7.40(1H,dd,J=8Hz,1Hz),7.28(2H,d,J=8Hz),7.24(2H,d,J=8Hz),7.14(1H,d,J=5Hz),5.64(2H,s),4.73(2H,s),3.56(3H,s),2.59(3H,s)
·NMR(400MHz,CDCl3,δ):
9.08(1H,s),8.97(1H,s),7.84(1H,dd,J=8Hz,1Hz),7.53(1H,td,J=8Hz,1Hz),7.42(1H,td,J=8Hz,1Hz),7.31(1H,dd,J=8Hz,1Hz),7.28(2H,d,J=8Hz),7.20(2H,d,J=8Hz),5.50(2H,s),3.61(3H,s),2.86(2H,t,J=8Hz),1.95~1.85(2H,m),1.04(3H,t,J=8Hz)
·NMR(400MHz,CDCl3,δ):
7.80(1H,dd,J=8Hz,1Hz),7.51(1H,td,J=8Hz,1Hz),7.39(1H,td,J=8Hz,1Hz),7.31(1H,dd,J=8Hz,1Hz),7.23(2H,d,J=8Hz),7.15(2H,d,J=8Hz),6.90(1H,s),5.51(2H,s),3.59(3H,s),2.77(2H,t,J=8Hz),2.64(3H,s),2.60(3H,s),1.81~1.72(2H,m),0.98(3H,t,J=8Hz)
·NMR(400MHz,CDCl3,δ):
7.80(1H,dd,J=8Hz,1Hz),7.50(1H,td,J=8Hz,1Hz),7.39(1H,td,J=8Hz,1Hz),7.31(1H,dd,J=8Hz,1Hz),7.24(2H,d,J=8Hz),7.21(2H,d,J=8Hz),6.87(1H,s),5.60(2H,s),3.60(3H,s),2.58(6H,s),1.94~1.87(1H,m),1.19~1.15(2H,m),1.02~0.97(2H,m)
实施例1
2-正丁基-1-〔{5′-氯-2′-(1H-四唑-5-基)-联苯-4-基}甲基〕苯并咪唑
将1.2克制备例8制得的2-正丁基-1-{(5′-氯-2′-氰基联苯-4-基)甲基}苯并咪唑、910mg叠氮化钠和750mg氯化铵加热,同时在50ml二甲基甲酰胺反应溶剂中,在125℃内温下搅拌50小时。冷却之后,往里加入氢氧化钠稀溶液和乙酸乙酯以进行相分离,从而得到水相。水相用乙酸弱酸化,用氯仿萃取并用水洗。萃取物用无水硫酸镁干燥,残余物用硅胶色层法纯化(氯仿∶乙醇∶乙醇=98∶2∶0.2)。浓缩目的标题化合物组分,然后用乙酸乙酯-异丙醚甲醇重结晶。产量为450mg。
·m.p.(℃):152~155
·NMR(90MHz,CDCl3,δ):
7.70~7.00(m,7H),7.06(s,4H),5.50(s,2H),2.82(t,2H,J=7Hz),1.90~1.00(m,4H),0.87(t,3H,J=7Hz)
实施例2
2-乙基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
将10克(0.027M)3-(2′-氰基联苯-4-基)甲基〕-2-乙基-7-甲基-3H-咪唑并〔4,5-b〕吡啶、5.3克(0.081M)叠氮化钠和5.6克(0.041M)三乙胺氢氯化物悬浮在70mlN-甲基吡咯烷酮。将油浴的温度在20分钟内提高到150-160℃,同时用搅拌器搅拌,6小时后,将温度恢复到室温,并加入水。用乙酸乙酯(50ml×3)洗涤混合物。水相用乙酸乙酯酸化,用乙酸乙酯(100ml×5)萃取。萃取物用硫酸镁干燥,并真空蒸掉溶剂。用中等压力色谱柱(SiO2,ACOEt∶EtOH=4.0∶1→20∶1→10∶1)纯化呈黑棕色油质物质的残余物。产量为11克(棕色油质物质)。
将油质物质溶于乙酸乙酯中,加入活性炭。混合物于50℃搅拌15分钟,然后经过自然过滤(无显著脱色)。真空蒸掉溶剂,产物用己烷-氯甲烷结晶。产量为4.9克。产物为白色晶体。
·NMR(90MHz,DMSO-d6,δ):
8.19(d,1H,J=5Hz),7.89~7.41(m,4H),7.23~6.91(m,5H),5.53(m,2H),2.86(q,2H,J=6Hz),2.59(m,3H),1.18(t,3H,J=6Hz)
实施例3
7-甲基-2-正丙基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
在138℃内温下,将5.3克3-〔(2′-氰基联苯-4-基)甲基〕-7-甲基-2-正丙基-3H-咪唑并〔4,5-b〕吡啶、5.85克叠氮化钠和6.19克三乙胺盐酸化物在2120mlN-甲基吡咯烷酮反应溶剂中加热8小时,同时进行搅拌。冷却之后,加入稀释氢氧化钠水溶液和乙酸乙酯,以产生相分离,得到水相。水相用乙酸弱酸化并用乙酸乙酯萃取三遍,萃取物水洗三遍。将甲醇加到经水洗的萃取物中以溶解有机相中的沉淀的晶体,且将有机相用无水硫酸镁干燥。浓缩干燥的有机相,残余物经硅胶色层法纯化(氯仿∶乙醇∶乙酸=97∶3∶0.2)。浓缩目的标题组分并用乙醇重结晶。产量为4.6克。熔点为200-202℃
·NMR(90MHz,DMSO-d6,δ):
8.14(d,1H,J=5Hz),7.87~7.32(m,4H),7.18~6.92(m,5H),5.49(s,1H),2.78(t,2H,J=7Hz),2.55(s,3H),1.94~1.43(m,2H),0.92(t,3H,J=7Hz)
实施例4
按照实施例1-3中介绍的方法合成以下化合物。以下给出合成化合物的名称,化学结构式和物理常数。
(1)2-正丁基-1-〔{2′-甲氧基-6′-(1H-四唑-5-基)联苯-4-基}甲基〕苯并咪唑
·m.p.(℃):230.5~233
·NMR(90MHz,DMSO-d6,δ):
7.65~7.00(m,7H),6.98(s,4H),5.45(s,2H),3.71(s,3H),2.78(t,2H,J=7Hz),1.85~1.05(m,4H),0.87(t,3H,J=7Hz)
(2)2-正戊基-3-〔{2′-(1H-四唑-5-基)联苄-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):158~161
·NMR(90MHz,DMSO-d6,δ):
8.29(dd,1H,J=5Hz),7.99(dd,1H,J=1Hz,8Hz),7.80~7.35(m,4H),7.24(dd,1H,J=5Hz,8Hz),7.06(s,4H),5.51(s,2H),2.81(t,2H,J=8Hz),1.90~1.00(m,6H),0.83(t,3H,J=7Hz)
(3)2-正丁基-1-〔{4′-氯-2′-(1H-四唑-5-基)联苯-4-基}甲基〕苯并咪唑
·m.p.(℃):202~204
·NMR(90MHz,DMSO-d6,δ):
7.78~6.95(m,7H),7.03(s,4H),5.49(s,2H),2.82(t,2H,J=7Hz),1.90~1.00(m,4H),0.86(t,3H,J=7Hz)
(4)2-正丁基-5-甲氧基-1-〔{2′-1H-四唑-5-基)联苯-4-基}甲基〕苯并咪唑
·NMR(90MHz,DMSO-d6,δ):
7.79~7.43(m,4H),7.37(d,1H,J=9Hz),7.14(d,1H,J=3Hz),7.07(s,4H),6.81(dd,1H,J=9Hz,3Hz),5.45(s,2H),3.77(s,3H),2.78(t,2H,J=6Hz),1.85~1.10(m,4H),0.86(t,3H,J=6Hz)
(5)2-正丁基-4-氨基甲酰基-1-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕苯并咪唑
·NMR(90MHz,DMSO-d6,δ):
7.95~6.84(m,11H),5.53(s,2H),2.90(t,2H,J=6Hz),1.93~1.13(m,4H),0.87(t,3H,J=6Hz)
(6)2-正丁基-5-羟基-1-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕苯基咪唑
·NMR(90MHz,DMSO-d6,δ):
7.79~6.76(m,10H),6.67(dd,1H,J=9Hz,3Hz),5.39(s,2H),2.77(t,2H,J=6Hz),1.87~1.11(m,4H),0.86(t,3H,J=6Hz)
(7)2-正丁基-3-〔{2′-(1H-四唑-5-基)-联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·NMR(90MHz,DMSO-d6,δ):
8.34(dd,1H,J=5Hz,1Hz),8.02(dd,1H,J=8Hz,1Hz),7.81~7.41(m,4H),7.27(dd,1H,J=5Hz,8Hz),7.07(s,4H),5.55(s,2H),2.82(t,2H,J=6Hz),1.90~1.13(m,4H),0.87(t,3H,J=6Hz)
(8)2-正丁基-1-〔{5′-甲氧基-2′-(1H-四唑-5-基)联苯-4-基}甲基〕苯基咪唑
·m.p.(℃):140~143
·NMR(90MHz,DMSO-d6,δ):
7.66~7.30(m,3H),7.25~6.80(m,8H),5.47(s,2H),3.84(s,3H),2.82(t,2H,J=7Hz),1.90~1.05(m,4H),0.87(t,3H,J=7Hz)
(9)3-〔{5′-氯-2′-(1H-四唑-5-基)联苯-4-基}甲基〕-2-正丙基-3H-咪唑并〔4,5-b〕吡啶
·NMR(90MHz,DMSO-d6,δ):
8.29(dd,1H,J=1Hz,5Hz),8.00(dd,1H,J=1Hz,8Hz),7.75~7.30(m,3H),7.25(dd,1H,J=5Hz,8Hz),7.09(s,4H),5.52(s,2H),2.79(t,2H,J=7Hz),1.95~1.45(m,2H),0.93(t,3H,J=7Hz)
(10)3-〔{4′-氯-2′-(1H-四唑-5-基)联苯-4-基}甲基〕-2-正丙基-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):180~183
·NMR(90MHz,DMSO-d6,δ):
8.29(dd,1H,J=1Hz,5Hz),7.99(dd,1H,J=1Hz,8Hz),7.80~7.37(m,3H),7.25(dd,1H,J=5Hz,8Hz),7.06(s,4H),5.51(s,2H),2.79(t,2H,J=7Hz),1.95~1.42(m,2H),0.92(t,3H,J=7Hz)
(11)2-正丁基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-c〕吡啶铵盐
·NMR(90MHz,DMSO-d6,δ):
8.85(s,1H),8.27(d,1H,J=5Hz),7.75~7.25(m,5H),7.19~6.84(m,4H),5.50(s,2H),2.86(t,2H,J=6Hz),1.92~1.08(m,4H),0.85(t,3H,J=6Hz)
(12)2-正丙基-1-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-1H-咪唑并〔4,5-b〕吡啶
·NMR(90MHz,DMSO-d6,δ):
8.31(dd,1H,J=1Hz,5Hz),7.88(dd,1H,J=1Hz,8Hz),7.76~7.32(m,2H),7.16(dd,1H,J=5Hz,8Hz),7.06(s,4H),5.53(s,2H),2.88(t,2H,J=6Hz),1.90~1.16(m,2H),0.92(t,3H,J=6Hz)
(13)2,7-二甲基-3〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-c〕吡啶铵盐
·NMR(90MHz,DMSO-d6,δ):
8.12(d,1H,J=5Hz),7.64~7.24(m,4H),7.10~6.96(m,5H),5.44(s,2H),2.55(s,3H),2.53(s,3H)
(14)2-正丁基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶铵盐
·NMR(90MHz,DMSO-d6,δ):
8.14(d,1H,J=5Hz),7.60~7.20(m,4H),7.16~6.80(m,5H),5.46(s,2H),2.84(t,2H,J=7Hz),2.60(s,2H,J=7Hz),1.84~1.10(m,4H),0.96(t,3H,J=6Hz)
(15)7-甲基-2-苯基-3〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶铵盐
·NMR(90MHz,CDCl3,δ):
8.22(d,1H,J=5Hz),7.80~7.30(m,9H),7.16(d,1H,J=5Hz),7.04~6.80(m,4H),5.56(s,2H),2.65(s,3H)
(16)2-环丙基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶铵盐
·NMR(90MHz,DMSO-d6,δ):
8.06(d,1H,J=5Hz),7.60~7.16(m,4H),7.12~6.88(m,5H),5.54(s,2H),2.50(s,3H),2.40~2.04(m,1H),1.08(d,4H,J=6Hz)
(17)2-环戊基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶铵盐
·NMR(90MHz,DMSO-d6,δ):
8.08(d,1H,J=5Hz),7.70~7.20(m,4H),7.10~6.80(m,5H),5.50(s,2H),3.50~3.04(m,1H),2.56(s,3H),2.10~1.40(m,8H)
(18)2-乙基-7-正丙基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶铵盐
·NMR(90MHz,DMSO-d6,δ):
8.16(d,1H,J=5Hz),7.68~7.18(m,4H),7.10~6.90(m,5H),5.44(s,2H),3.10~2.60(m,4H),2.0~1.60(m,2H),1.18(t,3H,J=6Hz),0.96(t,3H,J=6Hz)
(19)2-环丁基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶铵盐
·NMR(90MHz,DMSO-d6,δ):
8.14(d,1H,J=5Hz),7.64~7.20(m,4H),7.16~6.84(s,5H),5.38(s,2H),3.90~3.60(m,1H),2.60(s,3H),2.55~1.80(m,6H)
(20)(±)7-甲基-2-(1-甲基丙基)-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶铵盐
·NMR(90MHz,DMSO-d6,δ):
8.14(d,1H,J=5Hz),7.64~7.24(m,4H),7.12~6.86(m,5H),5.50(s,2H),3.22~2.84(m,1H),2.58(s,3H),1.96~1.42(m,2H),1.21(d,3H,J=6Hz),0.76(t,3H,J=6Hz)
(21)(7-甲基-2-(2-甲基丙基)-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶铵盐
·NMR(90MHz,DMSO-d6,δ):
8.15(d,1H,J=5Hz),7.64~7.26(m,4H),7.16~6.86(m,5H),5.48(s,2H),2.74(d,2H,J=6Hz),2.60(s,3H),2.38~2.00(m,1H),3.96(d,6H)
(22)2,7-二乙基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶铵盐
·NMR(90MHz,DMSO-d6,δ):
8.18(d,1H,J=5Hz),7.62~7.20(m,4H),7.14~6.96(m,5H),5.46(s,2H),3.00(q,2H,J=6Hz),2.86(q,2H,J=6Hz),1.36(t,3H,J=6Hz),1.32(t,3H,J=6Hz)
(23)2-正丁基-1-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕苯并咪唑
·m.p.(℃):232~235
·NMR(90MHz,DMSO-d6,δ):
7.80~7.34(m,6H),7.33~6.95(m,2H),7.05(s,4H),5.48(s,2H),2.82(t,2H,J=7Hz),1.93~1.08(m,4H),0.88(t,3H,J=7Hz)
(24)2-正丁基-4-甲基-1-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕苯并咪唑铵盐
·NMR(90MHz,DMSO-d6,δ):
7.79~7.41(m,4H),7.39~6.87(m,7H),5.50(s,2H),2.82(t,2H,J=7Hz),2.54(s,3H),1.86~1.20(m,4H),0.88(t,3H,J=7Hz)
(25)2-正丁基-5-氟-1-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕苯并咪唑
·NMR(90MHz,DMSO-d6,δ):
7.75~7.27(m,6H),7.19~6.87(m,5H),5.49(s,2H),2.81(t,2H,J=7Hz),1.85~1.13(m,4H),0.86(t,3H,J=7Hz)
(26)2-正丁基-5-氟-1-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕苯基咪唑
·NMR(90MHz,DMSO-d6,δ):
7.57~7.30(m,6H),7.25~6.87(m,5H),5.49(s,2H),2.78(t,2H,J=7Hz),1.87~1.11(m,4H),0.84(t,3H,J=7Hz)
(27)2-正丁基-3-〔{4′-氯-2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):161~163
·NMR(90MHz,DMSO-d6,δ):
8.28(dd,1H,J=1Hz,5Hz),7.99(dd,1H,J=1Hz,8Hz),7.82~7.35(m,3H),7.24(dd,1H,J=5Hz,8Hz),7.07(s,4H),5.51(s,2H),2.81(t,2H,J=8Hz),1.90~1.00(m,4H),0.85(t,3H,J=7Hz)
(28)2-乙基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):142~145
·NMR(90MHz,DMSO-d6,δ):
8.34(dd,1H,J=1Hz,5Hz),8.02(dd,1H,J=1Hz,8Hz),7.75~7.37(m,4H),7.24(dd,1H,J=5Hz,8Hz),7.06(s,4H),5.50(s,2H),2.83(q,2H,J=7Hz),1.25(t,3H,J=7Hz)
(29)2-正丁基-3-〔{5′-氯-2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·NMR(90MHz,DMSO-d6,δ):
8.29(dd,1H,J=1Hz,5Hz),8.00(dd,1H,J=1Hz,8Hz),7.75~6.90(m,4H),7.09(s,4H),5.52(s,2H),2.81(t,2H,J=7Hz),1.90~1.05(m,4H),0.86(t,3H,J=7Hz)
(30)2-正丁基-3-〔{5′-甲氧基-2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·NMR(90MHz,DMSO-d6,δ):
8.29(dd,1H,J=1Hz,5Hz),7.99(dd,1H,J=1Hz,8Hz),7.57(d,1H,J=9Hz),7.33~6.80(m,7H),5.51(s,2H),3.85(s,3H),2.82(t,2H,J=7Hz),1.90~1.05(m,4H),0.86(t,3H,J=7Hz)
(31)2-正丁基-3-〔{4′-甲氧基-2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·NMR(90MHz,DMSO-d6,δ):
8.33(dd,1H,J=5Hz,1Hz),8.03(dd,1H,J=8Hz,1Hz),7.59~6.80(m,8H),5.53(s,2H),3.86(s,3H),2.85(t,2H,J=6Hz),1.93~1.10(m,4H),0.88(t,3H,J=6Hz)
(32)2-正丙基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):226~229.5
·NMR(90MHz,DMSO-d6,δ):
8.30(dd,1H,J=5Hz),8.01(dd,1H,J=8Hz,1Hz),7.82~7.37(m,4H),7.26(dd,1H,J=8Hz,1Hz),7.09(s,3H),5.54(s,2H),2.79(t,2H,J=6Hz),1.95~1.39(m,2H),0.92(t,3H,J=6Hz)
(33)2-正丙基-3-〔{4′-甲氧基-2′-(1H-四唑-5-基)联苯-4-基}甲基〕苯并咪唑
·NMR(90MHz,DMSO-d6,δ):
7.73~7.03(m,7H),7.00(s,4H),5.46(s,2H),3.83(s,3H),2.82(t,2H,J=6Hz),1.88~1.12(m,4H),0.86(t,3H,J=6Hz)
(34)2-正丁基-1-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕苯并咪唑并〔4,5-c〕吡啶铵盐
·NMR(90MHz,DMSO-d6,δ):
8.84(s,1H),8.21(d,1H,J=5Hz),7.79~7.34(m,5H),7.07(s,4H),5.57(s,2H),2.88(t,2H,J=6Hz),1.92~1.08(m,4H),0.84(t,3H,J=6Hz)
(35)2-异丙基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶铵盐
·NMR(90MHz,DMSO-d6,δ):
8.14(d,1H,J=5Hz),7.60~6.80(m,9H),5.48(s,2H),4.90(bs,4H),3.42~3.00(m,1H),2.56(s,3H),1.23(d,6H,J=7Hz)
(36)2-溴-2-乙基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·NMR(90MHz,DMSO-d6,δ):
8.38(d,1H,J=2Hz),8.27(d,1H,J=2Hz),7.70~6.85(m,8H),5.48(s,2H),2.83(q,2H,J=7Hz),1.24(t,3H,J=7Hz)
(37)5-氯-2-乙基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):258(dec)
·NMR(90MHz,DMSO-d6,δ):
8.07(d,1H,J=8Hz),7.70~7.35(m,4H),7.31(d,1H,J=8Hz),7.07(s,4H),5.46(s,2H),2.81(q,2H,J=7Hz),1.24(t,3H,J=7Hz)
(38)3-〔{5′-氯-2′-(1H-四唑-5-基)联苯-4-基}甲基〕-7-甲基-2-正丙基-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):157~159
·NMR(90MHz,DMSO-d6,δ):
8.14(d,1H,J=8Hz),7.75~7.48(m,3H),7.08~6.97(m,5H),5.49(s,2H),2.78(t,2H,J=7Hz),2.55(s,3H),1.92~1.45(m,2H),0.92(t,3H,J=7Hz)
(39)6-甲基-2-正丙基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):144~147
·NMR(90MHz,DMSO-d6,δ):
8.12(d,1H,J=1Hz),7.88~7.26(m,5H),7.05(s,4H),5.47(s,2H),2.77(t,2H,J=7Hz),0.91(t,3H,J=7Hz)
(40)6-氯-7-甲基-2-正丙基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):233~235
·NMR(90MHz,DMSO-d6,δ):
8.27(s,1H),7.75~7.30(m,4H),7.05(s,4H),5.48(s,2H),2.79(t,2H,J=7Hz),2.58(s,3H),1.93~1.45(m,2H),0.92(t,3H,J=7Hz)
(41)7-甲氧基-2-正丙基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):130~135
·NMR(90MHz,DMSO-d6,δ):
8.11(d,1H,J=5Hz),7.60~6.88(m,8H),6.80(d,1H,J=5Hz),5.42(s,4H),4.04(s,3H),2.76(t,2H,J=7Hz),1.96~1.50(m,2H),0.92(t,3H,J=7Hz)
(42)2-甲氧基甲基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):127~135
·NMR(90MHz,DMSO-d6,δvalue):
8.18(d,1H,J=5Hz),7.60~6.94(m,9H),5.48(s,2H),4.64(s,2H),3.29(s,3H),2.60(s,3H)
(43)7-甲氧基-2-正丙基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶铵盐
·m.p.(℃):118~130
·NMR(90MHz,DMSO-d6,δ):
8.10(d,1H,J=5Hz),7.68~7.36(m,4H),7.32~6.92(m,5H),6.02(q,1H,J=8Hz),2.80(t,2H,J=6Hz),2.56(s,3H),2.06(d,3H,J=8Hz),1.96~1.50(m,2H),0.96(t,3H,J=6Hz)
(44)2-乙硫基-7-甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶铵盐
·m.p.(℃):149~159
·NMR(400MHz,CDCl3+DMSO-d6,δ):
8.08(d,1H,J=5Hz),7.68(dd,1H,J=7Hz,1Hz),7.48(td,1H,J=8Hz,1Hz),7.44~7.37(m,2H),7.19(d,2H,J=8Hz),7.09(d,2H,J=8Hz),6.99(d,1H,J=5Hz),4.97(s,2H),3.38(q,2H,J=7Hz),2.61(s,3H),1.45(t,3H,J=7Hz)
(45)7-甲基-2-甲硫基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶铵盐
·m.p.(℃):150~175
·NMR(400MHz,CDCl3+DMSO-d6,δ):
8.10(d,1H,J=5Hz),7.66(dd,1H,J=8Hz,1Hz),7.50~7.36(m,3H),7.19(d,2H,J=8Hz),7.14(d,2H,J=8Hz),7.00(d,1H,J=5Hz),5.36(s,2H),2.79(s,3H),2.62(s,3H)
(46)2-乙氧基-5,7-二甲基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
(47)5,7-二甲基-2-甲氧基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并
〔4,5-b〕吡啶
(48)5,7-二甲基-2-正丙氧基-3-〔{2′-(1H-四唑-5-基)联苯-4-基}甲基〕-3H-咪唑并〔4,5-b〕吡啶
实施例5
3-{2′-羧基联苯-4-基)甲基}-2-环丙基-7-甲基-3H-咪唑并〔4,5-b〕吡啶
将40ml乙醇和20ml10%NaOH水溶液加到1.32克2-环丙基-3-{2′-羧基联苯-4-基)甲基}-7-甲基-3H-咪唑并〔4,5-b〕吡啶中,并将混合物回
流2小时,将反应混合物浓缩成30ml,冷却和用2N盐酸和乙酸中和,过滤收集沉淀出的晶体并用水重结晶。产量为1.03克。·m.p.(℃):221~224
·NMR(90MHz,DMSO-d6,δ):
8.12(d,1H,J=5Hz),8.75~8.20(m,4H),7.26(s,4H),7.04(d,1H,J=5Hz),5.63(s,2H),2.50~2.05(m,1H),1.24~0.90(m,4H)
按照实施例5介绍的方法合成以下化合物。以下将给出合成出的化合物的名称、化学结构式和物理常数。
(1)2-丁基-1-{(2′-羧基联苯-4-基)甲基}苯并咪唑
·m.p.(℃):233~235
·NMR(90MHz,DMSO-d6,δ):
7.75~6.90(m,12H),5.48(s,2H),2.82(t,2H,J=7Hz),1.95~1.05(m,4H),0.84(t,3H,J=7Hz)
(2)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
·m.p.(℃):222~224
·NMR(90MHz,DMSO-d6,δ):
8.16(d,1H,J=5Hz),7.75~6.96(m,9H),5.52(s,2H),2.86(q,2H,J=7Hz),2.57(s,3H),1.27(t,3H,J=7Hz)
(3)3-{(2′-羧基联苯-4-基)甲基}-7-甲基-2-正丙基-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):260~263
·NMR(90MHz,DMSO-d6,δ):
8.15(d,1H,J=5Hz),7.75~6.95(m,9H),5.53(s,2H),2.82(t,2H,J=7Hz),2.56(s,3H),2.00~1.48(m,2H),0.94(t,3H,J=7Hz)
(4)2-正丁基-3-{(2′-羧基联苯-4-基)甲基}-7-甲基-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):230~232
·NMR(400MHz,DMSO-d6,δ):
8.15(d,1H,J=5Hz),7.68(d,1H,J=8Hz),7.52(t,1H,J=8Hz),7.41(t,1H,J=8Hz),7.30(d,1H,J=8Hz),7.60(d,2H,J=8Hz),7.15(d,2H,J=8Hz),7.07(d,1H,J=5Hz),5.52(s,2H),2.83(t,2H,J=8Hz),2.54(s,3H),1.72~1.60(m,2H),1.40~1.28(m,2H),0.84(t,3H,J=8Hz)
(5)3-{(2′-羧基联苯-4-基)甲基}-2-异丙基-7-甲基-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):241~244
·NMR(400MHz,DMSO-d6,δ):
8.17(d,1H,J=5Hz),7.70(d,1H,J=8Hz),7.54(t,1H,J=8Hz),7.43(t,1H,J=8Hz),7.33(d,1H,J=8Hz),7.27(d,2H,J=8Hz),7.16(d,2H,J=8Hz),7.10(d,1H,J=5Hz),5.56(s,2H),3.45~3.20(m,1H),2.58(s,4H),1.25(d,6H,J=7Hz)
(6)3-{(2′-羧基联苯-4-基)甲基}-2,7-二甲基-3H-咪唑并〔4,5-b〕吡啶
·m.p.(℃):257~259
·NMR(400MHz,DMSO-d6,δ):
8.16(d,1H,J=5Hz),7.70(d,1H,J=8Hz),7.54(t,1H,J=8Hz),7.43(t,1H,J=8Hz),7.33(d,1H,J=8Hz),7.28(d,2H,J=8Hz),7.20(d,2H,J=8Hz),7.08(d,1H,J=5Hz),5.52(s,2H),2.55(s,3H),2.54(s,3H)
(7)7-甲基-2-(1-丙烯基)-3-{(2′-羧基联苯-4-基)甲基}-3H-咪唑并〔4,5-b〕吡啶
·NMR(400MHz,DMSO-d6,δ):
8.14(d,1H,J=5Hz),7.67(d,1H,J=8Hz),7.51(td,1H,J=8Hz,1Hz),7.40(td,1H,J=8Hz,1Hz),7.29(d,1H,J=8Hz),7.27~7.10(m,5H),7.08(d,1H,J=5Hz),6.78(d,1H,J=15Hz),5.59(s,2H),2.56(s,3H),1.96(d,3H,J=8Hz)
(8)7-氯-2-正丙基-3-{(2′-羧基联苯-4-基)甲基}-3H-咪唑并〔4,5-b〕吡啶
·NMR(400MHz,CDCl3+DMSO-d6,δ):
8.19(d,1H,J=5Hz),7.82(d,1H,J=7Hz),7.44(t,1H,J=7Hz),7.34(t,1H,J=7Hz),7.29~7.20(m,4H),7.11(d,2H,J=8Hz),5.49(s,2H),2.81(t,2H,J=8Hz),1.84~1.73(m,2H),0.96(t,3H,J=8Hz)
(9)7-甲基-2-甲硫基-3-〔(2′-羧基联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
·NMR(400MHz,CDCl3+DMSO-d6,δ):
8.13(d,1H,J=5Hz),7.80(dd,1H,J=7Hz,1Hz),7.47(td,1H,J=7Hz,1Hz),,7.39~7.28(m,6H),7.00(d,1H,J=5Hz),5.41(s,2H),2.79(s,3H),2.64(s,3H)
(10)7-甲氧基甲基-7-甲基-3-〔(2′-羧基联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
·NMR(400MHz,DMSO-d6,δ):
8.23(d,1H,J=5Hz),7.67(d,1H,J=8Hz),7.51(td,1H,J=8Hz,1Hz),7.40(td,1H,J=8Hz,1Hz),7.30(d,1H,J=8Hz),7.26~7.13(m,4H),7.13(d,1H,J=5Hz),5.55(s,2H),4.66(s,2H),2.26(s,3H),2.56(s,3H)
(11)2-环丁基-7-甲基-3-〔(2′-羧基联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
·NMR(400MHz,DMSO-d6,δ):
8.15(d,1H,J=5Hz),7.69(d,1H,J=8Hz),7.52(td,1H,J=8Hz,1Hz),7.42(td,1H,J=8Hz,1Hz),7.31(d,1H,J=8Hz),7.25(d,2H,J=8Hz),7.13(d,2H,J=8Hz),7.08(d,1H,J=5Hz),5.43(s,2H),3.81(quint,1H,J=8Hz),2.58(s,3H),2.45~2.33(m,2H),2.25~2.16(m,2H),2.06~1.93(m,1H),1.90~1.80(m,1H)
(12)2-乙硫基-7-甲基-3-〔(2′-羧基联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
·NMR(400MHz,CDCl3+DMSO-d6,δ):
8.11(d,1H,J=5Hz),7.02(d,1H,J=8Hz),7.51(td,1H,J=8Hz,1Hz),7.41(td,1H,J=8Hz,1Hz),7.34~7.22(m,5H),7.04(d,1H,J=5Hz),5.41(s,2H),3.39(q,2H,J=8Hz),2.58(s,3H),1.44(t,1H,J=8Hz)
(13)3-{(2′-羧基联苯-4-基)甲基}-2-乙氧基-7-甲基-3H-咪唑并〔4,5-b〕吡啶
(14)3-{(2′-羧基联苯-4-基)甲基}-2-甲氧基-7-甲基-3H-咪唑并〔4,5-b〕吡啶
(15)3-{(2′-羧基联苯-4-基)甲基}-7-甲基-2-正丙氧基-3H-咪唑并〔4,5-b〕吡啶
(16)3-{(2′-羧基联苯-4-基)甲基}-5,7-二甲基-2-乙氧基-3H-咪唑并〔4,5-b〕吡啶
(17)3-{(2′-羧基联苯-4-基)甲基}-5,7-二甲基-2-甲氧基-3H-咪唑并〔4,5-b〕吡啶
(18)3-{(2′-羧基联苯-4-基)甲基}-5,7
-二甲基-2-正丙氧基-3H-咪唑并〔4,5-b〕吡啶
实施例6
2-乙基磺酰基-7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
将6.4克(15毫摩尔)2-乙硫基-7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶溶于150ml二氯甲烷,将3.94克(23毫摩尔间氯过苯甲酸的二氯甲烷溶液(150ml)滴加一到该溶液中,历时40分钟,同时搅拌和用水和冰冷却。混合物于室温搅拌20分钟。反应产物混合物单独用10%碳酸氢钠水溶液、碳酸氢钠的饱和水溶液和饱和盐水洗涤。分离和取出二氯甲烷相,然后用无水硫酸镁干燥。减压蒸掉溶剂,残余物用硅胶色层法处理,从乙酸乙酯和甲醇洗脱液(9∶1V/V)得到5.93克以上标题化合物。
实施例7
2-甲氧基-7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
将420mg(2.2毫摩尔)甲醇钠的28%甲醇溶液加到10ml甲醇溶液中(此甲醇溶液由0.44克(0.96毫摩尔)2-乙基磺酰基-7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶分散在150ml二甲氯甲烷构成〕。混合物回流40分钟。减压蒸掉溶剂。残余物与水混合并用2NHcl中和。具有二氯甲烷的萃取物用饱和盐水洗涤,并用无水硫酸镁干燥。减压蒸掉溶剂。残余物用乙醇和***重结晶处理,得到300mg上述标题化合物。
实施例7-1
2-乙氧基-7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶按实施例7所示同样方式得到。
实施例8
2-正丁氧基-7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
将100mg(1.3毫摩尔)正丁醇、400mg(3.6毫摩尔)叔丁氧钾和DMF的混合物于80℃加热5分钟。将200mg(0.65毫摩尔)2-乙基磺酰基-7-甲基-3-〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶加到混合物中。所得物质加热2小
时。反应产物混合物与水混合,用2NHcl中和,然后用二氯甲烷萃取。二氯甲烷相用饱和盐水洗涤,用无水硫酸镁干燥。减压蒸掉溶剂,残余物用***-己烷-二氯甲烷处理或重结晶,得到140mg目的化合物。
按上述同样工序制备以下化合物:
7-甲基-2-正丙氧基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
2-异丙氧基-7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
2-环丙基甲氧基-7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
实施例9
7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-1,3-二氢-2-氧代-咪唑并〔4,5-b〕吡啶
将90mg(0.23毫摩尔)2-甲氧基-7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶和1ml48% HBr的混合物于室温下搅拌1.5小时。产物混合物与水混合得到晶体,取出晶体并用水洗,得到70mg目的化合物。
实施例10
2-羟甲基-7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
将410mg(1毫摩尔)2-甲氧基甲基-7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶的二氯甲烷溶液(30ml)搅拌,用冰冷却。在此过程中,逐滴滴加1M三溴化硼的二氯甲烷溶液(10ml,10毫摩尔)。在室温下,进一步搅拌混合物。边搅拌,边冷却反应产物混合物。在此过程中,逐滴加入甲醇。减压蒸掉溶剂。残余物与水混合,用碳酸氢钠中和,用乙酸调成弱酸性并滗除水。歼余物与醇混合。减压蒸掉溶剂。残余物用异丙醚重结晶处理,得到330mg目的化合物。
实施例11
2-氯甲基-7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶
将20ml二氯甲烷和2.3克(5.5毫摩尔)2-羟甲基-7-甲基-3〔(2′-(1H-四唑-5-基)联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶的混合物搅拌,用冰冷却。在此步骤中,往里加入1.6ml亚硫酰氯。在室温下,再搅拌混合物1小时。减压蒸掉溶剂。残余物与水混合,用碳酸氢钠中和,用乙酸调成弱酸性并用二氯甲烷萃取。二氯甲烷相用饱和盐水洗涤,用无水硫酸镁干燥。减压蒸掉溶剂。残余物用二氯甲烷
重结晶处理,得到1.37mg目的化合物。
实施例12
3-〔(2′-羧基联苯-4-基)甲基〕-2-羟甲基-7-甲基-3H-咪唑并〔4,5-b〕吡啶
将8ml 10%氢氧化钠水溶液(含500mg(1.3毫摩尔)2-羟甲基-3-〔(2′-甲氧基羰基联苯-4-基)甲基〕-7-甲基-3H-咪唑并〔4,5-b〕吡啶)和20ml乙醇的混合物回流加热2小时。除去不溶物,浓缩滤液。残余物与水混合并用乙酸乙酯洗涤。水相用2N盐酸和乙酸弱酸化。取出晶体沉淀,并用水洗,干燥,得到400mg标题化合物。
实施例13
按照前述实施例和制备例之一的方法,得到以下化合物。
·NMR(400MHz,DMSO-d6,δ):
8.50(1H,d,J=5Hz),7.64~7.51(4H,m),7.48(1H,dd,J=1Hz,5Hz),7.17(2H,d,J=8Hz),7.04(2H,d,J=8Hz),5.82(2H,s),3.52(2H,q,J=7Hz),2.66(3H,s),1.22(3H,t,J=7Hz)
·NMR(400MHz,DMSO-d6,δ):
8.0(1H,d,J=5Hz),7.64(2H,d,J=8Hz),7.56(1H,td,J=8Hz,1Hz),7.51(1H,d,J=8Hz),7.16(2H,d,J=8Hz),7.04(2H,d,J=8Hz),7.01(1H,d,J=5Hz),5.23(2H,s),4.14(3H,s),2.48(3H,s)
·NMR(400MHz,DMSO-d6,δ):
7.99(1H,d,J=5Hz),7.65(2H,d,J=8Hz),7.56(1H,t,J=8Hz),7.51(1H,d,J=8Hz),7.18(2H,d,J=8Hz),7.04(2H,d,J=8Hz),7.00(1H,d,J=5Hz),5.21(2H,s),4.57(2H,q,J=7Hz),2.46(3H,s),1.37(3H,t,J=7Hz)
·NMR(400MHz,DMSO-d6,δ):
8.00(1H,d,J=5Hz),7.65(2H,dd,J=8Hz,1Hz),7.57(1H,td,J=8Hz,1Hz),7.51(1H,d,J=8Hz),7.20(2H,d,J=8Hz),7.05(2H,d,J=8Hz),7.00(1H,d,J=5Hz),5.24(2H,s),4.48(2H,t,J=7Hz),2.47(3H,s),1.81~1.73(2H,m),0.93(3H,t,J=7Hz)
·NMR(400MHz,DMSO-d6,δ):
8.00(1H,d,J=5Hz),7.65(2H,dd,J=8Hz,1Hz),7.56(1H,td,J=8Hz,1Hz),7.18(2H,d,J=8Hz),7.04(2H,d,J=8Hz),7.00(1H,d,J=5Hz),5.21(2H,s),4.52(2H,t,J=7Hz),2.47(3H,s),1.77~1.70(2H,m),1.41~1.32(2H,m),0.90(3H,t,J=7Hz)
·NMR(400MHz,DMSO-d6,δ):
7.98(1H,d,J=5Hz),7.64(2H,d,J=8Hz),7.56(1H,t,J=8Hz),7.51(1H,d,J=8Hz),7.18(2H,d,J=8Hz),7.04(2H,d,J=8Hz),6.99(1H,d,J=5Hz),5.35~5.30(1H,m),5.18(2H,s),2.47(3H,s),1.36(6H,d,J=6Hz)
·NMR(400MHz,DMSO-d6,δ):
7.99(1H,d,J=5Hz),7.64(2H,d,J=8Hz),7.55(1H,t,J=8Hz),7.50(1H,d,J=8Hz),7.21(2H,d,J=7Hz),7.05(2H,d,J=7Hz),6.99(1H,d,J=5Hz),5.23(2H,s),4.38(2H,d,J=8Hz),2.46(3H,s),1.36~1.25(1H,m),0.63~0.50(2H,m),0.41~0.35(2H,m)
·NMR(400MHz,DMSO-d6,δ):
11.36(1H,s),7.83(1H,d,J=5Hz),7.66(1H,dd,J=8Hz,1Hz),7.65(1H,d,J=8Hz),7.56(1H,td,J=8Hz,1Hz),7.52(1H,d,J=8Hz),7.23(2H,d,J=8Hz),7.04(2H,d,J=8Hz),6.89(1H,d,J=5Hz),5.00(2H,s),2.31(3H,s)
·NMR(400MHz,DMSO-d6,δ):
8.19(1H,d,J=5Hz),7.61(2H,t,J=8Hz),7.52(1H,t,J=8Hz),7.47(1H,d,J=8Hz),7.14(2H,d,J=8Hz),7.11(1H,d,J=5Hz),7.03(2H,d,J=8Hz),5.56(2H,s),4.67(2H,s),2.55(3H,s)
·NMR(400MHz,DMSO-d6,δ):
9.15(1H,s),8.92(1H,s),8.72(1H,s),7.61(2H,d,J=7Hz),7.53(1H,d,J=7Hz),7.46(1H,d,J=7Hz),7.24(2H,d,J=7Hz),7.03(2H,d,J=7Hz),5.48(2H,s)
·NMR(400MHz,DMSO-d6,δ):
9.07(1H,s),8.90(1H,s),7.66(2H,d,J=8Hz),7.57(1H,t,J=8Hz),7.52(1H,d,J=8Hz),7.14(2H,d,J=8Hz),7.07(2H,d,J=8Hz),5.52(2H,s),2.84(2H,t,J=8Hz),1.78~1.69(2H,m),0.93(3H,t,J=8Hz)
·NMR(400MHz,DMSO-d6,δ):
8.18(1H,d,J=5Hz),7.66(1H,dd,J=8Hz,1Hz),7.51(1H,td,J=8Hz,1Hz),7.40(1H,td,J=8Hz,1Hz),7.30(1H,dd,J=8Hz,1Hz),7.23(4H,s),7.09(1H,d,J=5Hz),5.57(2H,s),4.70(2H,s),2.54(3H,s)
·NMR(400MHz,DMSO-d6,δ):
8.27(1H,d,J=5Hz),7.68~7.64(2H,m),7.56(1H,t,J=8Hz),7.51(1H,d,J=8Hz),7.18(1H,d,J=5Hz),7.18(2H,d,J=8Hz),7.04(2H,d,J=8Hz),5.60(2H,s),5.05(2H,s),2.60(3H,s)
·NMR(400MHz,DMSO-d6,δ):
7.63(1H,td,J=8Hz,1Hz),7.61(1H,dd,J=8Hz,1Hz),7.54(1H,td,J=8Hz,1Hz),7.48(1H,dd,J=8Hz,1Hz),7.01(4H,s),6.91(1H,s),5.43(2H,s),2.68(2H,t,J=8Hz),2.47(6H,s),1.68~1.59(2H,m),0.87(3H,t,J=8Hz)
·NMR(400MHz,DMSO-d6,δ):
7.60(1H,d,J=8Hz),7.45(1H,t,J=8Hz),7.37(1H,t,J=8Hz),7.27(1H,d,J=8Hz),7.26(2H,d,J=8Hz),7.08(2H,d,J=8Hz),6.92(1H,),5.46(2H,s),2.73(2H,t,J=8Hz),2.49(6H,s),1.74~1.65(2H,m),0.89(3H,t,J=8Hz)
·NMR(400MHz,DMSO-d6,δ):
9.08(1H,s),8.91(1H,s),7.71(1H,d,J=8Hz),7.55(1H,t,J=8Hz),7.44(1H,t,J=8Hz),7.34(1H,d,J=8Hz),7.30(2H,d,J=8Hz),7.23(2H,d,J=8Hz),5.54(2H,s),2.89(2H,t,J=8Hz),1.81~1.75(2H,m),0.95(3H,t,J=8Hz)
·NMR(400MHz,DMSO-d6,δ):
7.67(1H,td,J=8Hz,1Hz),7.65(1H,d,J=8Hz),7.57(1H,td,J=8Hz,1Hz),7.52(1H,d,J=8Hz),7.12(2H,d,J=8Hz),7.05(2H,d,J=8Hz),6.92(1H,s),5.54(2H,s),2.49(3H,s),2.44(3H,s),2.17~2.11(1H,m),0.99~0.95(4H,m)
·NMR(400MHz,DMSO-d6,δ):
7.71(1H,dd,J=8Hz,1Hz),7.55(1H,td,J=8Hz,1Hz),7.44(1H,td,J=8Hz,1Hz),7.34(1H,dd,J=8Hz,1Hz),7.29(2H,d,J=8Hz),7.23(2H,d,J=8Hz),6.95(1H,s),5.60(2H,s),2.49(3H,s),2.45(3H,s),2.25~2.18(1H,m),1.05~1.00(4H,m)
·NMR(400MHz,DMSO-d6,δ value):
8.12(d,1H,J=5Hz),7.66~7.60(m,2H),7.54(td,1H,J=8Hz,1Hz),7.49(dd,1H,J=8Hz,1Hz),7.08(d,2H,J=8Hz),7.05(d,1H,J=5Hz),7.02(d,2H,J=8Hz),5.45(s,2H),2.52(s,3H),2.48(s,3H)
·NMR(400MHz,DMSO-d6,δ value):
8.54(s,1H),8.23(d,1H,J=5Hz),7.68~7.62(m,2H),7.56(td,1H,J=8Hz,1Hz),7.49(d,1H,J=8Hz),7.24(d,2H,J=8Hz),7.12(d,1H,J=5Hz),7.05(d,2H,J=8Hz),5.49(s,2H),2.58(s,3H)
·NMR(400MHz,CDCl3,δ):
8.22(d,1H,J=5Hz),7.74(d,1H,J=8Hz),7.62(td,1H,J=8Hz,1Hz),7.51~7.40(m,4H),7.27(d,2H,J=8Hz),7.05(d,1H,J=5Hz),5.54(s,2H),2.69(s,3H),2.60(s,3H)
·NMR(400MHz,CDCl3,δ):
8.32(d,1H,J=5Hz),8.24~8.17(bs,1H),7.40(d,1H,J=8Hz),7.63(td,1H,J=8Hz,1Hz),7.52(d,2H,J=8Hz),7.48~7.39(m,4H),7.11(d,1H,J=5Hz),5.59(s,2H),2.72(s,3H)
·NMR(400MHz,CDCl3,δ):
8.16(d,1H,J=5Hz),7.02(d,1H,J=5Hz),2.73(s,3H),2.68(s,3H)
·NMR(400MHz,CDCl3,δ):
8.30(d,1H,J=5Hz),8.28(s,1H),7.09(d,1H,J=5Hz),2.70(s,3H)
·NMR(400MHz,CDCl3,δ):
8.36(dd,1H,J=1Hz,5Hz),8.03(dd,1H,J=1Hz,8Hz),7.81(dd,1H,J=1Hz,8Hz),7.51(td,1H,J=8Hz,1Hz),7.40(td,1H,J=8Hz,1Hz),7.31(dd,1H,J=1Hz,8Hz),7.24(d,2H,J=8Hz),7.23(dd,1H,J=5Hz,8Hz),7.18(d,2H,J=8Hz),5.54(s,2H),3.61(s,3H),2.87(q,J=8Hz),1.41(t,3H,J=8Hz)
·NMR(400MHz,CDCl3,δ):
8.33(dd,1H,J=1Hz,5Hz),7.95(dd,1H,J=1Hz,8Hz),7.82(dd,1H,J=1Hz,8Hz),7.52(td,1H,J=8Hz,1Hz),7.41(td,1H,J=8Hz,1Hz),7.33(dd,1H,J=1Hz,8Hz),7.27(s,4H),7.21(dd,1H,J=5Hz,8Hz),5.67(s,2H),3.63(s,3H),2.06~1.96(m,1H),1.28~1.21(m,2H),1.11~1.04(m,2H)
·NMR(400MHz,CDCl3,δ):
8.46(dd,1H,J=1Hz,5Hz),7.84(dd,1H,J=1Hz,8Hz),7.55~7.49(m,2H),7.41(td,1H,J=8Hz,1Hz),7.31(dd,1H,J=1Hz,8Hz),7.28(d,2H,J=8Hz),7.15(d,2H,J=8Hz),7.09(dd,1H,J=5Hz,8Hz),5.51(s,2H),3.64(s,3H),2.07~1.95(m,2H),1.43~1.35(m,2H),1.16~1.08(m,2H)
·NMR(400MHz,CDCl3,δvalue):
8.19(d,1H,J=5Hz),7.70(d,1H,J=8Hz),7.37(dd,1H,J=2Hz,8Hz),7.31(d,1H,J=2Hz),7.25~7.20(m,4H),7.01(d,1H,J=5Hz),5.63(s,2H),3.61(s,3H),2.65(s,3H),2.00~1.92(m,1H),1.24~1.17(m,2H),1.08~1.00(m,2H)
·NMR(400MHz,CDCl3,δ):
7.95(d,1H,J=8Hz),7.82(dd,1H,J=1Hz,8Hz),7.51(td,1H,J=8Hz,1Hz),7.40(td,1H,J=8Hz,1Hz),7.31(dd,1H,J=1Hz,8Hz),7.25(d,2H,J=8Hz),7.23(d,1H,J=8Hz),7.17(d,2H,J=8Hz),5.49(s,2H),3.62(s,3H),2.83(q,2H,J=8Hz),1.39(t,3H,J=8Hz)
·NMR(400MHz,CDCl3,δ):
7.86(d,1H,J=8Hz),7.53(td,1H,J=8Hz,1Hz),7.46(d,1H,J=8Hz),7.42(td,1H,J=8Hz,1Hz),7.32(d,1H,J=8Hz),7.27(d,2H,J=8Hz),7.14(d,1H,J=8Hz),7.06(d,2H,J=8Hz),5.38(s,2H),3.65(s,3H),2.93(q,2H,J=8Hz),1.46(t,3H,J=8Hz)
·NMR(400MHz,CDCl3,δ):
8.40(d,1H,J=2Hz),8.14(d,1H,J=2Hz),7.83(dd,1H,J=1Hz,8Hz),7.51(td,1H,J=8Hz,1Hz),7.40(td,1H,J=8Hz,1Hz),7.30(dd,1H,J=1Hz,8Hz),7.25(d,2H,J=8Hz),7.17(d,2H,J=8Hz),5.50(s,2H),3.62(s,3H),2.87(q,2H,J=8Hz),1.40(t,3H,J=8Hz)
·NMR(400MHz,CDCl3,δ):
8.18(d,1H,J=2Hz),7.82~7.19(m,2H),7.51(td,1H,J=8Hz,1Hz),7.40(td,1H,J=8Hz,1Hz),7.30(dd,1H,J=1Hz,8Hz),7.23(d,2H,J=8Hz),7.15(d,2H,J=8Hz),5.51(s,2H),3.61(s,3H),2.80(t,2H,J=8Hz),2.48(s,3H),1.90~1.78(m,2H),1.00(t,3H,J=8Hz)
·NMR(400MHz,CDCl3,δ):
8.28(s,1H),7.82(dd,1H,J=1Hz,8Hz),7.51(td,1H,J=8Hz,1Hz),7.41(td,1H,J=8Hz,1Hz),7.31(dd,1H,J=1Hz,8Hz),7.25(d,2H,J=8Hz),7.15(d,2H,J=8Hz),5.50(s,2H),3.62(s,3H),2.83(t,2H,J=8Hz),2.72(s,3H),1.87~1.75(m,2H),1.01(t,3H,J=8Hz)
·NMR(400MHz,CDCl3,δ):
8.30(d,1H,J=5Hz),7.83(dd,1H,J=1Hz,8Hz),7.52(td,1H,J=8Hz,1Hz),7.41(td,1H,J=8Hz,1Hz),7.32(dd,1H,J=1Hz,8Hz),7.27(d,2H,J=8Hz),7.02(d,2H,J=8Hz),6.83(d,1H,J=5Hz),5.71(s,2H),3.63(s,3H),2.48(s,3H),1.98~1.89(m,1H),1.39~1.32(m,2H),1.11~1.03(m,2H)
·m.p.:235~238℃
·NMR(400MHz,DMSO-d6,δ):
8.32(dd,1H,J=1Hz,5Hz),8.20(dd,1H,J=1Hz,8Hz),7.70(dd,1H,J=1Hz,8Hz),7.54(td,1H,J=8Hz,1Hz),7.44(td,1H,J=8Hz,1Hz),7.34(dd,1H,J=1Hz,8Hz),7.30~7.24(m,3H),7.20(d,2H),5.56(s,2H),2.89(q,2H,J=8Hz),1.29(t,3H,J=8Hz)
·m.p.:246.5~248.5℃
·NMR(400MHz,DMSO-d6,δ):
8.27(dd,1H,J=1Hz,5Hz),7.92(dd,1H,J=1Hz,8Hz),7.71(dd,1H,J=1Hz,8Hz),7.54(td,1H,J=8Hz,1Hz),7.43(td,1H,J=8Hz,1Hz),7.34(dd,1H,J=1Hz,8Hz),7.29(s,4H),7.23(dd,1H,J=5Hz,8Hz),5.67(s,2H),2.37~2.19(m,1H),1.13~1.02(m,4H)
·m.p.:227~229℃
·NMR(400MHz,DMSO-d6,δ):
8.31(dd,1H,J=1Hz,5Hz),7.94(dd,1H,J=1Hz,8Hz),7.71(dd,1H,J=1Hz,8Hz),7.54(td,1H,J=8Hz,1Hz),7.43(td,1H,J=8Hz,1Hz),7.34(dd,1H,J=1Hz,8Hz),7.31(d,2H,J=8Hz),7.24(d,2H,J=8Hz),7.17(dd,1H,J=5Hz,8Hz),5.69(s,2H),2.41~2.33(m,1H),1.19~1.06(m,4H)
·m.p.:256~259℃
8.13(d,1H,J=5Hz),7.74(d,1H,J=8Hz),7.51(dd,1H,J=2Hz,8Hz),7.40(d,1H,J=2Hz),7.31(d,2H,J=8Hz),7.27(d,2H,J=8Hz),7.05(d,1H,J=5Hz),5.65(s,2H),2.51(s,3H),2.32~2.24(m,1H),1.08~1.00(m,4H)
·m.p.:248~251℃
·NMR(400MHz,DMSO-d6,δ):
12.75(bs,1H),8.10(d,1H,J=8Hz),7.72(d,1H,J=8Hz),7.55(t,1H,J=8Hz),7.44(t,1H,J=8Hz),7.37~7.32(m,2H),7.31(d,2H,J=8Hz),7.18(d,2H,J=8Hz),5.53(s,2H),2.87(q,2H,J=8Hz),1.28(t,3H,J=8Hz)
·m.p.:280~282℃
·NMR(400MHz,DMSO-d6,δ):
12.74(bs,1H),8.06(d,1H,J=8Hz),7.71(dd,1H,J=1Hz,8Hz),7.55(td,1H,J=8Hz,1Hz),7.44(td,1H,J=8Hz,1Hz),7.33(dd,1H,J=1Hz,8Hz),7.32~7.28(m,3H),7.16(d,2H,J=8Hz),5.60(s,2H),2.93(q,2H,J=8Hz),1.30(t,3H,J=8Hz)
·m.p.:235~237℃
·NMR(400MHz,DMSO-d6,δ):
8.42(d,1H,J=2Hz),8.32(d,1H,J=2Hz),7.71(dd,1H,J=1Hz,8Hz),7.55(td,1H,J=8Hz,1Hz),7.44(td,1H,J=8Hz,1Hz),7.33(dd,1H,J=1Hz,8Hz),7.28(d,2H,J=8Hz),7.20(d,2H,J=8Hz),5.55(s,2H),2.91(q,2H,J=8Hz),1.28(t,3H,J=8Hz)
·m.p.:208~210℃
·NMR(400MHz,DMSO-d6,δ):
8.16(d,1H,J=2Hz),7.83(d,1H,J=2Hz),7.70(dd,1H,J=1Hz,8Hz),7.54(td,1H,J=8Hz,1Hz),7.43(td,1H,J=8Hz,1Hz),7.33(dd,1H,J=1Hz,8Hz),7.27(d,2H,J=8Hz),7.17(d,2H,J=8Hz),5.53(s,2H),2.82(t,2H,J=8Hz),2.42(s,3H),1.80~1.70(m,2H),0.94(t,3H,J=8Hz)
·m.p.:189~191℃
·NMR(400MHz,DMSO-d6,δ):
12.73(bs,1H),8.31(s,1H),7.71(dd,1H,J=1Hz,8Hz),7.55(td,1H,J=8Hz,1Hz),7.44(td,1H,J=8Hz,1Hz),7.33(dd,1H,J=1Hz,8Hz),7.28(d,2H,J=8Hz),7.18(d,2H,J=8Hz),5.55(s,2H),2.85(t,2H,J=8Hz),2.61(s,3H),1.80~1.69(m,2H),0.95(t,3H,J=8Hz)
·NMR(400MHz,DMSO-d6,δ):
8.16(d,1H,J=5Hz),7.70(d,1H,J=8Hz),7.54(t,1H,J=8Hz),7.43(t,1H,J=8Hz),7.35(d,1H,J=8Hz),7.32(d,2H,J=8Hz),7.02(d,2H,J=8Hz),6.90(d,1H,J=5Hz),5.83(s,2H),2.44(s,3H),2.31~2.23(m,1H),1.15~1.02(m,4H)
表1
化合 产生血管紧缩酞增压
物编 试验化合物和结构式 pA2反应向右边双倍移动
号 所需的剂量
(mg/kg,i.v.)
4
8.00 1.57
5
10.33 0.029
表1(续)
化合 产生血管紧缩酞增压
物编 试验化合物和结构式 pA2反应向右边双倍移动
号 所需的剂量
(mg/kg,i.v.)
8
8.37 0.71
表1(续)
化合 产生血管紧缩酞增压
物编 试验化合物和结构式 pA2反应向右边双倍移动
号 所需的剂量
(mg/kg,i.v.)
17
8.45 0.17
表1(续)
化合 产生血管紧缩酞增压
物编 试验化合物和结构式 pA2反应向右边双倍移动
号 所需的剂量
(mg/kg,i.v.)
18
8.67 0.075
19
8.31 0.25
20
8.28 0.41
21
10.94 0.071
表1(续)
化合 产生血管紧缩酞增压
物编 试验化合物和结构式 pA2反应向右边双倍移动
号 所需的剂量
(mg/kg,i.v.)
24
10.86 0.015
表1(续)
化合 产生血管紧缩酞增压
物编 试验化合物和结构式 pA2反应向右边双倍移动
号 所需的剂量
(mg/kg,i.v.)
29
8.47 0.060
30
9.88 0.016
Claims (13)
1、制备具有通式(Ⅰ)的联苯甲烷衍生物或其药用盐方法,
(式中R1为C1-6烷基、C3-6环烷基、C1-6卤代烷基、-S-R7、-SO2-R7、-C≡C-R7或-(CH2)p-OR7,其中R7为C1-6烷基、C3-6环烷基、C1-6卤代烷基,p为0或1;-A1=A2-A3=A4-是-CH=CH-CH=CH-、-N=CH-CH=CH-、-CH=N-CH=CH-、-CH=CH-N=CH-、-CH=CH-CH=N-或-CH=N-CH=N-;R2和R3各为氢、卤素、低级烷基、低级烷氧基、氨甲酰基;R4为氢或低级烷基;R5为1H-四唑-5-基、羧基或羧酸C1-6烷基酯;R6为氢、卤素或低级烷氧基)
该方法是将由通式(Ⅱ)代表的咪唑衍生物
与联苯甲烷化合物(Ⅲ)或(Ⅶ)
(式中R1、R2、R3、R4、R6以及以式-A1=A2-A3=A4-代表的基团分别如上所定义;X为卤原子、甲磺酰氧基或对甲苯磺酰氧基;
R8为C1-8烷基)在碱存在下于0℃-室温的温度范围在一质子极性溶剂中进行缩合,得到通式(Ⅳ)的缩合产物
再将式(Ⅳ)的缩合产物与适合的试剂在胺盐存在下在质子极性溶剂中加热至120-150℃进行反应,得到通式(Ⅰ)的化合物;需要时将得到的化合物以药物学上常用的方法用酸或碱把它们转变成药用盐。
2、权利要求1所述的方法,其特征是R5为1H-四唑-5-基,其缩合产物与一叠氮化合物在非质子传递极性溶剂中加热进行反应。
3、权利要求2所述方法,其特征是叠氮化合物以X-N3为代表,其中的X为卤原子、甲磺酰氧基或对甲苯磺酰氧基。
4、权利要求1所述方法,其特征是R5为一羧基,并将其缩合产物进行水解。
5、权利要求4所述方法,其特征是水解是在包括乙醇和氢氧化钠水溶液的混合溶剂中将得到的产物进行回流加热。
6、权利要求4所述方法,其特征是水解是在碱存在下进行的。
7、权利要求1-6所述方法,其特征在于所说的碱选自氢化钠、氢化锂、碳酸钾、碳酸钠、乙醇钠、叔丁醇钠、氢氧化钠、氢氧化钾、三乙胺和二异丁基乙胺。
8、权利要求7所述方法,其特征是所说溶剂选自二甲基甲酰胺、二甲亚砜、N-甲基吡咯烷酮。1,3-二甲基-2-咪唑啉酮、二噁烷、乙醇和丙酮。
9、权利要求1所述方法,其特征是R1选自甲基、乙基、丙基、甲氧基、乙氧基和环丙基。
10、权利要求1所述方法,其特征是-A1=A2-A3=A4-是-CH=CH-CH=N-。
11、权利要求1所述方法,其特征是R2为A1上的甲基,R3为A3上的甲基;或者R2为A1上的甲基,R3为A3上的氢。
12、权利要求1所述方法,其特征是R4为氢,R6为氢。
13、权利要求1所述方法,其特征是联苯甲烷衍生物为7-甲基-2-正丙基-3-〔2′(1H-四唑-5-基)-联苯-4-基)甲基〕-3H-咪唑并〔4,5-b〕吡啶或3-〔(2′-羧基联苯-4-基)甲基〕-2-环丙基-7-甲基-3H-咪唑并〔4,5-b〕吡啶。
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JP251761/89 | 1989-09-29 | ||
JP25176189 | 1989-09-29 | ||
JP33664089 | 1989-12-27 | ||
JP336640/89 | 1989-12-27 |
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EP (3) | EP0598702B1 (zh) |
JP (2) | JP2608341B2 (zh) |
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- 1990-09-28 CA CA002026533A patent/CA2026533A1/en not_active Abandoned
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