CN1073437A - 药用化合物 - Google Patents
药用化合物 Download PDFInfo
- Publication number
- CN1073437A CN1073437A CN92111625A CN92111625A CN1073437A CN 1073437 A CN1073437 A CN 1073437A CN 92111625 A CN92111625 A CN 92111625A CN 92111625 A CN92111625 A CN 92111625A CN 1073437 A CN1073437 A CN 1073437A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- group
- compound
- phenyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 59
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- -1 trifluoromethoxy, carboxyl Chemical group 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000004185 ester group Chemical group 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 54
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- WAVNYPVYNSIHNC-UHFFFAOYSA-N 2-benzylidenepropanedinitrile Chemical compound N#CC(C#N)=CC1=CC=CC=C1 WAVNYPVYNSIHNC-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 206010020718 hyperplasia Diseases 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 5
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- 238000001816 cooling Methods 0.000 description 5
- 238000011161 development Methods 0.000 description 5
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- 238000001704 evaporation Methods 0.000 description 5
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- 235000019359 magnesium stearate Nutrition 0.000 description 5
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- 239000008107 starch Substances 0.000 description 5
- 229940032147 starch Drugs 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- JJNZXLAFIPKXIG-UHFFFAOYSA-N 2-Chlorobenzylidenemalononitrile Chemical compound ClC1=CC=CC=C1C=C(C#N)C#N JJNZXLAFIPKXIG-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 4
- 150000003053 piperidines Chemical class 0.000 description 4
- 125000004309 pyranyl group Chemical class O1C(C=CC=C1)* 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
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- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000021523 carboxylation Effects 0.000 description 3
- 238000006473 carboxylation reaction Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229960002989 glutamic acid Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Natural products CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 3
- JRODTAYHOOTVGS-UHFFFAOYSA-N 2-[(4-chloro-3-nitrophenyl)methylidene]propanedinitrile Chemical compound [O-][N+](=O)C1=CC(C=C(C#N)C#N)=CC=C1Cl JRODTAYHOOTVGS-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 2
- 102000013275 Somatomedins Human genes 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- IRXBNHGNHKNOJI-UHFFFAOYSA-N butanedioyl dichloride Chemical compound ClC(=O)CCC(Cl)=O IRXBNHGNHKNOJI-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
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- 239000007924 injection Substances 0.000 description 2
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- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 2
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Abstract
式(I)药用化合物及其盐,其中取代基定义如说
明书。
Description
本发明涉及药用化合物、其制备方法和用途。
某些苯基取代的萘并[1,2-b]吡喃描述于
Elagamey A.et al,Indian Journal of Chemistry,29B,885-886,(1990),和Collection Czechoslovak Chem.Commun.,53(7),1534-1538,(1988)。
所公开的化合物不具有生物活性。
本发明化合物是下式合化物及其盐:
式中n是0,1或2,R′联结在5、6、7、8、9或10位中的任一位置上,每一个R′是囟素、三氟甲基、C1-4烷氧基、羟基、硝基、C1-4烷基、C1-4烷硫基、羟基-C1-4烷基、羟基-C1-4烷氧基、三氟甲氧基、羧基、-COOR5、-CONR6R7或-NR6R7,其中R5是酯基,R6和R7各自是氢或C1-4烷基;
R2是苯基、萘基或选自噻吩基、吡啶基、苯并噻吩基、喹啉基、苯并呋喃基或苯并咪唑基的杂芳基,所述苯基、萘基和杂芳基也可以是取代的;或者R2是呋喃基或被C1-4烷基取代的呋喃基;
R3是氰基、羧基、-COOR8、-CONR9R10或R11SO2-,其中R8是酯基,R9和R10各自为氢或C1-4烷基,R11是C1-4烷基或可被取代的苯基;R4是-NR12R13、NHCOR12、-N(COR12)2或-N=CHOCH2R12,其中R12和R13各自是氢或可被羧基取代的C1-4烷基,
其中X是C2-4亚烷基,或-NHSO2R14,其中R14是C1-4烷基或可被取代的苯基;
但前提是:当n是O、R3是氰基和R4是-NH2时,R2不是苯或对位有氯、羧基或甲氧基取代基的苯。
本发明化合物在试验中发现具有活性,表明它们能有效治疗免疫疾病和细胞过量增生或酶释放起重要作用的疾病。
上述式(Ⅰ)中,囟素是例如氟、氯或溴,尤其是氯。C1-4烷基包括例如甲基、乙基、丙基和丁基,最好是甲基或乙基。C1-4烷氧基是一个通过氧与芳基核相连的烷基。羟烷基是一个被羟基取代的烷基,最好是HO(CH2)x,其中X是1至4。羟基烷氧基是被羟基取代的烷氧基,最好是HO(CH2)xO,其中X是1至4。C1-4烷硫基是通过硫原子连接的C1-4烷基。
取代的苯基是被一个或多个,最好是1个或2个取代基取代的苯基,所述取代基各自选自囟素、三氟甲基、C1-4烷氧基、羟基、硝基、C1-4烷基、C1-4烷硫基、羟基-C1-4烷基、羟基-C1-4烷氧基、三氟甲氧基、羧基、-COOR15、-CONR16R17或-NR16R17,其中R15是酯基、R16和R17各自是氢或C1-4烷基。取代的萘基或杂芳基可以被类似地取代。此外,取代的苯基包括相邻原子被-O(CH2)mO-(其中m是1,2或3)取代的苯基。
当n是1或2,且在萘核上有1或两个取代基时,它们可以在5到10位的任何位置。当有两个取代基时,它们可相同或不同。最好萘核是未取代的或在5,6或9位上有一个取代基。
当R2是杂芳基时,它最好是2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-苯并噻吩基、3-苯并噻吩基、2-喹啉基、3-喹啉基、2-苯并呋喃基、3-苯并呋喃基或2-苯并咪唑基、2-呋喃基或3-呋喃基。萘基在1位或2位连接。上述基团可在任一有空的位置上取代,但最好是未取代的。基团R的优选值是可取代的苯基,最好是单取代的,尤其是被硝基或三氟甲基取代。
基团R3最好是氰基。当R3是-COOR8时,R8可以是任何酯基,最好是C1-4烷基,尤其是甲基或乙基。
基团R4最好是-NR12R13,尤其是-NH2
式(Ⅰ)化合物中一组特别的化合物是如下定义的式(Ⅰ)化合物:n是0,1或2;R′连接于5,6,7,8,9或10位中的任一位置且R′是囟素、三氟甲基或C1-4烷氧基;R2是可以被一个或两个选自硝基、三氟甲基、囟素、C1-4烷基和C1-4烷氧基的取代基取代的苯基、萘基或杂芳基,或者R2是可以被C1-4烷基取代的呋喃基;R3是硝基、羧基、-COOR8或CONR9R10,其中R8是酯基,R9和R10各自是氢或C1-4烷基;R4是-NR12R13、-NHCOR12或-N(COR12)2或-NHSO2R14,其中R12和R13各自是氢或C1-4烷基,R14是烷基或是可被1至3个各自选自C1-4烷基、C1-4烷氧基、硝基和囟素的取代基取代的苯基;其前提是当n是O,R3是氰基且R4是-NH2时,R2不是苯基或对位被一个氯、羟基或甲氧基取代基取代的苯基。
一组特别优选的化合物是
式中R′是氢、C1-4烷氧基或囟素,且R18是硝基或三氟甲基。R′基团最好连接在5,6或9位上。
应当理解,例如当R′和R3是-COOH时,存在成盐的可能性。它们可从熟知的任何碱衍生而得。碱盐的例子是由氢氧化铵和碱金属和碱土金属的氢氧化物、碳酸盐和碳酸氢盐衍生而得的盐以及由脂肪和芳香胺、脂肪二胺和羟基烷基胺衍生而得的盐。在所述盐的制备中特别有用的碱包括:氢氧化铵、碳酸钾、碳酸氢钠、氢氧化锂、氢氧化钙、甲胺、二乙胺、乙二胺、环己胺和乙醇胺。特别优选的是钾盐、钠盐和锂盐的形式。
除药学上可接受的盐之外,本发明还包括其它盐。它们可以在化合物的纯化中或在其它例如药学上可接受的酸加成盐的制备中用作中间体,或者用于鉴定、表征或纯化。
当R1和R3分别为-COOR5和-COOR8时,化合物是酯。酯基可以是任何常规基团,例如由醇、特别是C1-4醇衍生而来的酯。从而,R5和R8优选C1-4烷基。
应当理解,本发明化合物含有产生对映体的不对称碳原子。制得的化合物通常是外消旋体,可方便地直接使用,但如果需要,可用常规技术分离出单独的对映体。所述外消旋体和单独的对映体构成了本发明的一部分。
本发明还包括生产上述式(Ⅰ)化合物的方法,它包括:
(1)将式(Ⅱ)化合物与式(Ⅲ)化合物反应,生成R4是-NH2的式(Ⅰ)化合物,式(Ⅱ)和式(Ⅲ)如下:
或者
(2)将式(Ⅳ)化合物转化为R4是-NR12R13、-NHCOR12、-N(COR12)2、-N=CHOCH2R12、-NHSO2R14或
的式(Ⅰ)化合物,式(Ⅳ)如下:
就方法(1)而言,反应最好在有机溶剂(例如乙醇)的存在下,在0℃~100℃进行。式(Ⅱ)化合物是已知的或者可以用已知方法合成。
最好在有机碱催化剂(如吡啶)和有机溶剂(例如乙醇)的存在下,于20~100℃下将适当的式R3CH2CN的腈与式R2CHO的醛反应制得式(Ⅲ)反应物。腈和醛是公知的化合物或者可用本领域公知的方法制得。
就方法(2)而言,游离烯胺可通过反应(Ⅰ)制得,并随后转化为R4取其它值的化合物。例如,游离的胺基可用式R12X或R13X(X是囟素)或(R12)2SO4或(R13)2SO4试剂烷基化得一或二烷基化产物。类似地,胺基可用乙酰氯或酸酐例如R12COX和(R12CO)2O酰化得到R4是-NHCOR12或-N(COR12)2的化合物。与适当的原甲酸三烷基酯反应可制得R4是-N=CHOCH2R12的化合物;与磺酰囟R14SO2X反应可制得R4是NHSO2R14的化合物。
如上所述,该化合物具有药学活性。它们对于细胞分裂有抗增生效应,从而表明可用来治疗细胞过度增生或酶释放在病理学中起重要作用的疾病。
例如,本发明化合物在10μM以下的IC50浓度下抑制3T3纤维细胞的自然增生。
此外,在Lacombe P.等人,FEBS,3048,191,227-230描述的试验中,该化合物显示出通过抑制刀豆球蛋白A引起的T细胞增生改善了免疫应答。通常,本发明化合物在试验中的IC50值低于10μM。
该化合物还抑制NS-1鼠B-淋巴瘤系的细胞增生和牛视网膜毛细血管内皮细胞中佛波醇酯激发的纤维蛋白溶酶原活化剂的合成。
K.Deshmukh Phadke,M.Lawrence和S.Nanda Biochem.Biophys.Res.Commun.1978,85,490-496描述的试验中还观察到它能抑制软骨细胞中巨噬细胞调节的介质所引发的中性蛋白酶释放。
上述性质表明它们能够治疗广泛的疾病,例如:风湿性关节类、动脉粥样硬化、肝硬变、纤维变性和癌症,还可用来治疗自身免疫疾病,例如:全身狼疮,以及防止移植物排斥。它们还适用于骨关节炎和糖尿病并发症的治疗。
此外,本发明化合物表现出对血管平滑细胞增生的抑制。用培养的取自兔子主动脉的平滑细胞,并测定DNA合成,确定增生情况可以证实这一点。细胞是按Ross.J.of Cell Bio.50:172(1971)所述的移出方法得到的。将细胞置于有96井的微量滴定板5天。培养物融合,生长受阻。然后将细胞移至Dulbeco改良的Eagle氏培养基(DMEM)中,该培养基含0.52%贫血小板血浆,2mM L-谷氨酸,100U/ml青霉素,100μg/ml链霉素,1μc/ml3H-胸苷,20ng/ml取自血小板的生长因子和不同浓度的本发明化合物。在二甲基亚砜中制备化合物的贮备溶液,然后在上述测定培养基中稀释至适当浓度(0.01~10μg/ml)细胞在5%CO2/95%空气中于37℃下孵化24小时。满24小时后,用甲醇固定细胞。然后按Bonin等人,Exp.Cell Res.181∶475-482(1989)所述的闪烁计数方法测定掺入DNA中的3H-胸苷。
通过对呈指数生长的细胞效应的测定,进一步证实了本发明化合物对平滑肌细胞增生的抑制。将取自兔子动脉的平滑肌细胞接种在12井组织培养板上的DMEM中,DMEM中含10%牛胎儿血清,2mM L-谷氨酸,100U/ml青霉素和100μg/ml链霉素。24小时后,缚住细胞,用含2%贫血小板血浆、2mM L-谷氨酸、100U/ml青霉素、100μg/ml链霉素、40ng/ml取自血小板的生长因子及所示浓度的该化合物的DMEM替换原培养基。令细胞生长4天,用胰蛋白酶处理细胞,用ZM-Coulter计数器将各培养液中的细胞计数。
上述实试的活性表明,本发明化合物能够治疗再狭窄,所述再狭窄的特征是:对于损伤的反应平滑肌细胞的迁移和增生。
本发明还包括含有药学上可接受的稀释剂或载体以及本发明化合物或其药学上可接受盐的药用组合物。
本发明化合物可以多种途径给药,例如,口服或直肠途径、局部或非肠道给药(例如注射),本发明化合物通常是以药用组合物的形式应用。所述组合物构成了本发明的一个方面,它按制药领域内熟知的方法制得,包含至少一种活性化合物以及药学上可接受的稀释剂或载体。在本发明组合物的制造过程中,通常将活性成分与载体混合,用载体稀释,和/或用载体包裹,例如,载体可以是胶囊、小药囊、纸或其它包容物。当载体用作稀释剂时,它可以是固体、半固体、或液体材料,它起着活性成分的载体、赋形剂或介质的作用。从而,本发明组合物可以是片剂、锭剂、小囊、扁囊剂、酏剂、混悬剂的形式,作为固体或液体介质。含有例如不超过10%(重量)活性化合物的软膏剂、软和硬明胶囊、栓剂、注射液和混悬剂和灭菌包装粉剂。
例如,适当的载体有:乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯树胶、磷酸钙、藻朊酸盐、黄蓍胶、明胶、糖浆、甲基纤维素、羟基苯甲酸甲酯和丙酯、滑石、硬脂酸镁和矿物油。已如本领域熟知的那样,可制成注射组合物,以便给药后向患者提供活性成分的迅速、持续或延缓释放。
当该组合物制成单位剂型时,每一单位剂型最好包含5mg~500mg,例如25mg~200mg活性成分。“单位剂型”是指对于人和动物适宜作为单位剂量的物理上分散的单位,与单位含有预定量的活性物质和需要的药用载体,该活性物质的量是为了产生期望的治疗效果计算而得的。
该活性化合物在很宽的剂量范围内有效。例如,日剂量通常为0.5-300mg/kg,5-100mg/kg更常用。但是,应当明白,给药量将由医师根据相关情况,包括待治疗的病情、给予的化合物的选择和选定的给药路线来确定。因此,上述范围无意对本发明范围进行任何限制。
下述实施例用来说明本发明。
实施例1
将3-(三氟甲基)苯甲醛(9.2g)和氰基乙酸乙酯(5.3ml)溶于乙醇(20ml),将该溶液加热至回流温度。中断加热,加2滴哌啶,一旦剧烈的反应开始平息便再次加热,于回流温度保持1小时。用冰水溶将溶液冷却,加水(30ml),滤出2-氰基-3-[3-(三氟甲基)苯基)]丙烯酸乙酯白色晶体,水洗并干燥,m.p.79℃。
按类似方法制备了下列化合物
2-氰基-3-[4-(三氟甲基)苯基]丙烯酸乙酯,m.p.114℃
2-氰基-3-[2-(三氟甲基)苯基]丙烯酸乙酯,m.p.74℃
2-硝基亚苄基丙二腈,m.p.141℃
3-硝基亚苯基丙二腈,m.p.108℃
4-硝基亚苄基丙二腈,m.p.162℃
3-氯亚苄基丙二腈,m.p.118℃
3-氟亚苄基丙二腈,m.p.91℃
3-溴亚苄基丙二腈,m.p.105℃
2-(三氟甲基)-亚苄基丙二腈,m.p.46℃
3-(三氟甲基)-亚苄基丙二腈,m.p.81℃
4-(三氟甲基)-亚苄基丙二腈,m.p.109℃
4-(2,2-二甲基乙基)-亚苄基丙二腈,m.p.92℃
3-吡啶羧化丙二腈,m.p.89℃。
2-硫代苯羧化丙二腈,m.p.98℃。
3-甲氧基亚苄基丙二腈,m.p.102℃
3-三氟甲氧基亚苄基丙二腈,m.p.73℃
3-氯-4-氟基亚苄基丙二腈,m.p.111℃
3-溴-4-氟基亚苄基丙二腈,m.p.122.5℃
3-甲酯基亚苄基丙二腈,m.p.125℃
3-羟基亚苄基丙二腈,m.p.152℃
2-氰基-(3-硝基苯基)丙烯酰胺,m.p.140℃
3,4-二氯亚苄基丙二腈,m.p.154℃
3,4-二甲氧基亚苄基丙二腈,m.p.137℃
3,4-(亚甲基二氧代)亚苄基丙二腈,m.p.201-202℃
4-氯-3-硝基亚苄基丙二腈m.p.142℃
2-硝基-4-硫代苯羧化丙二腈,m.p.103-104℃
α-甲磺酰基-3-硝基肉桂氰,m.p.157℃
4-氯-3-硝基亚苄基丙二腈,m.p.117℃
4-(1-哌啶子基)-3-硝基亚苄基丙二腈,m.p.154℃
实施例2
室温下将1-萘醇(1.44g)与乙醇(20ml)共同搅拌,向所得混悬液中加3-(三氟甲基)亚苄基丙二腈(2.23g)和哌啶(1ml)。所有固体均溶解并放热。几分钟后,2-氨基-4-[3-(三氟甲基)苯基]-4H-萘并[1,2-b]吡喃-3-甲腈晶体从溶液中析出,继续搅拌1小时后,滤集晶体,乙醇洗,干燥。用乙醇重结晶得白色晶体,m.p.215.5-216.5℃。
按类似方法制得了下列化合物
2-氨基-4-[3-(三氟甲基)苯基]-4-萘并[1,2-b]吡喃
3-甲酸乙酯,m.p.156.5-157℃
2-氨基-4-[4-(三氟甲基)苯基]-4-萘并[1,2-b]吡喃
3-甲酸乙酯,m.p.124-126℃
2-氨基-4-[2-(三氟甲基)苯基]-4-萘并[1,2-b]吡喃
3-甲酸乙酯,m.p.144-146℃
2-氨基-4-(2-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.142-143.5℃
2-氨基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.214.5-216℃
2-氨基-4-(4-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.229-231℃
2-氨基-4-[2-(三氟甲基)苯基]-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.239-240℃
2-氨基-4-[3-(三氟甲基)苯基]-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.215.5-216.5℃
2-氨基-4-[4-(三氟甲基)苯基]-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.234-239.5℃
2-氨基-6-氯-4-[3-(三氟甲基)苯基]-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.179-181℃
2-氨基-6-甲氧基-4-[3-(三氟甲基)苯基]-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.216-218℃
2-氨基-4-(3-氟苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.240-242℃
2-氨基-4-(3-溴苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.234-235.5℃
2-氨基-4-(3-氯苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.226-228℃
2-氨基-4-[4-(2,2-二甲基乙基)苯基]-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.240-243℃
2-氨基-4-(3-吡啶基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.205-207℃
2-氨基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲酸乙酯,m.p.152.5-153.5℃
2-氨基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲酰胺,m.p.205-206.5℃
2-氨基-7-甲氧基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.242-246℃
2-氨基-8-甲氧基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.234-236℃
2-氨基-9-甲氧基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.244-245℃
2-氨基-3-氰基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.244-248℃
2-氨基-3-氰基-4-(3-甲氧基苯基)-4H-萘并[1,2-b]吡喃-6-甲酸,m.p.280℃(分解)
2-氨基-3-氰基-4-(3-羟基苯基)-4H-萘并[1,2-b]吡喃-6-甲酸,m.p.252-256℃
2-氨基-3-氰基-4-[3-(三氟甲氧基苯基)]-4H-萘并[1,2-b]吡喃-6-甲酸,m.p.253-254.5℃
2-氨基-3-氰基-4-(3-羧基苯基)-4H-萘并[1,2-b]吡喃-6-甲酸,m.p.>300℃(分解)
2-氨基-4-(3-甲氧基苯基)-4H-萘并[1,2-b]吡喃-3-二甲腈,m.p.139-142.5℃
2-氨基-4-(3-羧甲氧基苯基)-4H-萘并[1,2-b]吡喃-3-二甲腈,m.p.235-236℃
2-氨基-4-[3-(三氟甲氧基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.194.5-196.5℃
2-氨基-4-(3-氯-4氟苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.211-211.5℃
2-氨基-4-(3-溴-4-氟苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.209.5-210.5℃
2-氨基-7-羟基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.237-239℃
2-氨基-4-(4-氯-3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.249-251℃
[2-氨基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-基]甲基砜,m.p.173℃
2-氨基-4-(2-硝基-4-噻吩基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.187-188℃
2-氨基-4-(4-氯-3硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.218-220℃
2-氨基-4-(3,4-亚甲基二氧基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.249-252℃
2-氨基-4-(3,4-二甲氧基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.207-209.5℃
2-氨基-4-(3,4-二氯苯基)-4H-萘并[1,2-b]吡喃-3-二甲腈,m.p.247-249℃
实施例3
搅拌下,将3-硝基苯甲醛(84.5g)和丙二腈(37g)的乙醇(560ml)溶液加热至回流温度。暂停加热,加入10滴哌啶,将溶液再搅拌15分钟。用冰水溶将该溶液冷却至5℃,向所得的搅拌的中间体混悬液中先后加入1-萘醇(80.7g)和哌啶(15ml)。将混悬液加热回流10分钟,搅拌至室温。滤出2-氨基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈奶油色晶体,用乙醇洗至完全脱色,干燥,m.p.214.5-216℃
实施例4
将2-氨基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈(10.3g)溶于无水二甲基甲酰胺(60ml)中,在冰水浴中搅拌冷却。先后加入乙酰氯(12.4ml)和吡啶(14.3ml),室温下搅拌3天后,最初沉淀的固体再次溶解,得棕色粘性溶液。将其分配于盐水和氯仿中,用更多的盐水洗涤氯仿提取液,硫酸镁干燥,过滤并蒸发至干。
残留物溶于最少量的氯仿中,通过“闪”二氧化硅柱,用眼估计氯仿和含产物馏分,蒸发,用乙醚和少量甲醇研制。滤出黄色2-二乙酰基氨基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,用乙醚洗涤,m.p.153-154℃。
按类似方法制得了下述化合物:
2-二乙酰基氨基-4-[3-(三氟甲基)苯基]-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.138.5-139.5℃
实施例5
将2-二乙酰基氨基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈(3.62g)溶于氯仿(200ml),在Ⅲ级氧化铝(36g)存在下,室温下机械搅拌24小时。将混悬液过滤。用含5%甲醇的氯仿溶液将氧化铝垫洗透,合并滤液,蒸发,用少许氯仿研制残留物。将白色固体溶于二氧六环(50ml),静置24小时,杂质沉淀析出,滤出。将水(200ml)加入滤液中,滤出产生的固体,水洗并干燥。将该固体通过氯仿“闪”二氧化硅柱。合并含产物的馏分,蒸发至干,用甲醇研制得2-乙酰氨基-4-(3-硝基苯基)-萘并[1,2-b]吡喃-3-甲腈,黄色晶体,m.p.234.5-236℃。
实施例6
将2-氨基-4-(3-氯-4-氟苯基)-4H-萘并[1,2-b]吡喃-3-甲腈(3.12g)在原甲酸三乙酯(40ml)中加热回流24小时。馏去80-140℃馏分,再加入原甲酸三乙酯(40ml),继续回流24小时。溶液蒸发至干。将胶状残留物溶于氯仿,经过“闪”二氧化硅柱,用含30%。己烷的氯仿溶液洗脱。合并含产物馏分,蒸发并用乙酸乙酯研制,得4-(3-氯-4-氟苯基)-2-乙氧基亚甲基氨基-4H-萘并[1,2-b]哟吡喃-3-甲腈,白色晶体,m.p.146-148℃
类似地制得了:
2-乙氧基亚甲基氨基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.181.5℃-183℃;
4-(4-氯-3-硝基苯基)-2-乙氧基亚甲基氨基-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.184.5-186℃
实施例7
室温下,将2-氨基-4-(4-氯-3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈(3.8g)溶于四氢呋喃(30ml)中,先后加入吡啶(2.02ml)和琥珀酰氯(1.34ml),将溶液搅拌24小时。再加入吡啶(2.02ml)和琥珀酰氯(1.34ml)。将溶液加热回流6小时,冷却,倾入水中。用氯仿提取中。用盐水洗氯仿提取液,硫酸镁干燥,经过一硅柱,以30%乙烷的氯仿溶液洗脱,蒸发至干,用乙酸乙酯研制,得1.07g 4-(4-氯-3-硝基苯基)-2-(N-琥珀酰亚氨基)-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.215.5-217℃。
实施例8
将4-(4-氯-3-硝基苯基)-2-乙氧基亚甲基氨基-4H-萘并[1,2-b]吡喃-3-甲氰(4.3g)溶于四氢呋喃(70ml)中,搅拌下分批加入硼氢化钠(2.7g)、1小时后,用冰水冷却该混悬液,滴加1M盐酸(20ml),接着加水(200ml)。滤出黄色产物,水洗、干燥。将其溶于热氯仿中,经过氯仿“闪”二氧化硅柱。合并含产物馏分,蒸发至干,用乙醚研制,得4-(4-氯-3-硝基苯基)-2-甲氨基-4H-萘并[1,2-b]吡喃-3-甲腈,m.p.278.5-279℃。
实施例9
将2-氨基-4-(4-氯-3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈(3.8g)溶于2-丁醇(100ml)中,搅拌下加入硫酸二甲酯(2.4ml)和碳酸钾(3.5g)。将该混悬液加热回流2小时。再加硫酸二甲酯(2.4ml)和碳酸钾(3.5g)。将溶液再加热22小时,冷却,过滤、蒸发至干,残留物溶于热氯仿,经过“闪”色谱柱,先后用20%己烷-氯仿(1升)和10%己烷-氯仿(1升)洗脱。再用氯仿完成洗脱。合并含产物馏分,蒸发至干,残留物用乙醚研制。用甲苯重结晶得4-(4-氯-3-硝基苯基)-2-二甲氨基-4H-萘并[1,2-b]吡喃-3-甲腈,黄色晶体,m.p.217.5-218.5℃,
实施例10
将4-(4-氯-3-硝基苯基)-2-(N-琥珀酰亚氨基)-4H-萘并[1,2-b]吡喃-3-甲腈(0.41g)溶于四氢呋喃(20ml)中。加入2M氢氧化钠(0.94ml),室温搅拌2天。将溶液蒸发至干,将残留物溶于水(50ml)中并过滤之。向滤液中加乙酸(1.14ml),滤出米色沉淀物N-[4-(4-氯-3-硝基苯基)-3-氰基-4H-萘并[1,2-b]吡喃-2-基]-琥珀酸,水洗,干燥,m.p>300℃
实施例11
软明胶胶囊
每一软明胶胶囊包含:
活性成分 150mg
花生油 150mg
混合后,用适当的设备将混合物装入软明胶胶囊中。
实施例12
硬明胶胶囊
每一胶囊含
活性成分 50mg
PEG4000 250mg
将PEG4000熔化,与活性成分混合。在熔融态时将混合物装入胶囊壳中,静置冷却。
实施例13
每片含10mg活性成分的片剂按下法制成:
活性成分 10mg
淀粉 160mg
微晶纤维素 100mg
聚乙烯基吡咯烷酮
(10%水溶液) 13mg
羧甲基淀粉钠 14mg
硬脂酸镁 3mg
总计 300mg
将活性成分、淀粉和纤维素充分混合。将聚乙烯基吡咯烷酮溶液与所得粉末混合,过筛。如此制造的颗粒干燥后再过筛。然后将羧甲基淀粉钠和硬脂酸镁加到颗粒中,混合后在制压机中压片,每片重300mg。
实施例14
每粒含20mg活性成分的胶囊制备如下:
活性成分 20gm
干淀粉 178mg
硬脂酸镁 2mg
总计 200mg
将活性成分、淀粉和硬脂酸镁过筛,装入硬明胶囊中,每粒200mg。
实施例15
用刀豆球蛋白A对大鼠脾细胞的应答作为测定本发明化合物活性的主要体外测定方法。文献中已描述了许多测定刀豆球蛋白A应答的方法。所用方法类似于Lacombe.P.等人,FEBS 3048 191 227-230所述的方法。我们采用每个培养井2×105个细胞,刀豆球蛋白A用量为1μg/ml。巯基乙醇(2×10M-5)是必须的,在细胞收集前6小时加0.25μCi氚标记的胸苷。
下列化合物的IC50值在0.006~2.0μM范围内。
2-氨基-4-(3-硝基苯-基)-4H-萘并[1,2-b]吡喃-3-甲酸乙酯。
2-氨基-4-(3-硝基苯-基)-4H-萘并[1,2-b]吡喃-3-甲腈。
2-氨基-9-甲氧基-4-(3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈。
2-氨基-4-[3-(三氟甲基)苯基]-4H-萘并[1,2-b]吡喃-3-甲腈。
2-二乙酰胺基-4-[3-(三氟甲基)苯基]-4H-萘并[1,2-b]吡喃-3-甲腈。
2-氨基-4-(3-氯苯基)-4H-萘并[1,2-b]吡喃-3-甲腈。
2-氨基-4-(3-氟苯基)-4H-萘并[1,2-b]吡喃-3-甲腈。
2-氨基-4-(3-吡啶基)-4H-萘并[1,2-b]吡喃-3-甲腈。
2-氨基-4-(3-甲酯基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈。
2-氨基-4-(3-氯-4-氟苯基)-4H-萘并[1,2-b]吡喃-3-甲腈。
2-氨基-4-(4-氯-3-硝基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈。
2-氨基-4-(3-三氟甲氧基苯基)-4H-萘并[1,2-b]吡喃-3-甲腈。
Claims (6)
1、下式化合物及其盐的制备方法,
式中n是0,1或2,R′联结在5、6、7、8、9或10位中的任一位置上,每一个R′是囟素、三氟甲基、C1-4烷氧基、羟基、硝基、C1-4烷基、C1-4烷硫基、羟基-C1-4烷氧基、三氟甲氧基、羧基、-COOR5、-CONR6R7或-NR6R7,其中R5是酯基,R6和R7各自是氢或C1-4烷基;
R2是苯基、萘基或选自噻吩基、吡啶基、苯并噻吩基、喹啉基、苯并呋喃基或苯并咪唑基的杂芳基,所述苯基、萘基和杂芳基也可以是取代的;或者
R2是呋喃基或被C1-4烷基取代的呋喃基;
R3是氰基、羧基、-COOR8、-CONR9R10或R11SO2-,其中R8是酯基,
R9和R10各自为氢或C1-4烷基,R11是C1-4烷基或可被取代的苯基;
R4是-NR12R13、NHCOR12、-N(COR12)2或-N=CHOCH2R12,其中R12和
R13各自是氢或可被羧基取代的C1-4烷基,
其中X是C2-4亚烷基,或-NHSO2R14,其中R14是C1-4烷基或可被取代的苯基;
前提是:当n是O、R3是氰基和R4是-NH2时,R2不是苯或对位有氯、羧基或甲氧基取代基的苯;
它包括:
(1)将式(Ⅱ)化合物与式(Ⅲ)化合物反应,生成R4是-NH2的式(Ⅰ)化合物,式(Ⅱ)和式(Ⅲ)如下:
(2)将式(Ⅳ)化合物转化为R4是-NR12R13、-NHCOR12、-N(COR12)2、-N=CHOCH2R12、-NHSO2R14或
的式(Ⅰ)化合物,式(Ⅳ)如下:
2、权利要求1化合物的制备方法,其中,n是0,1或2;R′连接于5,6,7,8,9或10位中的任一位置且R′是囟素、三氟甲基或C1-4烷氧基;R2是可以被一个或两个选自硝基、三氟甲基、囟素、C1-4烷基和C1-4烷氧基的取代基取代的苯基、萘基或杂芳基,或者R2是可以被C1-4烷基取代的呋喃基;R3是硝基、羧基、-COOR8或CONR9R10,其中R8是酯基,R9和R10各自是氢或C1-4烷基;R4是-NR12R13、-NHCOR12或-N(COR12)2或-NHSO2R14,其中R12和R13各自是氢或C1-4烷基,R14是烷基或是可被1至3个各自选自C1-4烷基、C1-4烷氧基、硝基和囟素的取代基取代的苯基;其前提是当n是0,R3是氰基且R4是-NH2时,R2不是苯基或对位被一个氯、羟基或甲氧基取代基取代的苯基。
3、权利要求1或2化合物的制备方法,其中n是0或1,R′是C1-4烷氧基或囟素。
4、权利要求1至3化合物的制备方法,其中R2是可被1个或2个取代基取代的苯基,所述取代基各自选自囟素、三氟甲基、C1-4烷氧基、羟基、硝基、C1-4烷基、C1-4烷硫基、羟基-C1-4烷基、羟基-C1-4烷氧基、三氟甲氧基、羧基、-COOR15、-CONR16R17或-NR16R17,其中R15是酯基、R16和R17各自是氢或C1-4烷基。
5、权利要求1至4任一权项所述化合物的制备方法,其中R3是氰基。
6、权利要求1至5任一权项所述化合物的制备方法,其中R4是-NH2。
7、一种药用组合物的制备方法,它包括将权利要求1化合物或其药学上可接受的盐与药学上可接受的稀释剂或载体混合。
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GB919121358A GB9121358D0 (en) | 1991-10-09 | 1991-10-09 | Pharmaceutical compounds |
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GB9213058.2 | 1992-06-19 | ||
GB929213058A GB9213058D0 (en) | 1992-06-19 | 1992-06-19 | Pharmaceutical compounds |
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US (1) | US5284868A (zh) |
EP (1) | EP0537949B1 (zh) |
JP (1) | JPH05194477A (zh) |
KR (1) | KR100228841B1 (zh) |
CN (1) | CN1034938C (zh) |
AT (1) | ATE167859T1 (zh) |
AU (1) | AU658003B2 (zh) |
CA (1) | CA2079428A1 (zh) |
CZ (1) | CZ281688B6 (zh) |
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MX (1) | MX9205714A (zh) |
MY (1) | MY111368A (zh) |
NO (1) | NO301587B1 (zh) |
NZ (1) | NZ244627A (zh) |
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US5407955A (en) * | 1994-02-18 | 1995-04-18 | Eli Lilly And Company | Methods for lowering serum cholesterol and inhibiting smooth muscle cell proliferation, restenosis, endometriosis, and uterine fibroid disease |
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US7015328B2 (en) | 2001-05-16 | 2006-03-21 | Cytovia, Inc. | Substituted coumarins and quinolines and analogs as activators of caspases and inducers of apoptosis and the use thereof |
US7528164B2 (en) * | 2002-05-16 | 2009-05-05 | Cytovia, Inc. | Substituted 4-aryl-4h-pyrrolo[2,3-h]chromenes and analogs as activators of caspases and inducers of apoptosis and the use thereof |
EP1513515A2 (en) * | 2002-05-16 | 2005-03-16 | Cytovia, Inc. | Substituted 4h-chromenes, 2h-chromenes, chromans and analogs as activators of caspases and inducers of apoptosis and the use thereof |
US20040127519A1 (en) * | 2002-12-12 | 2004-07-01 | Pharmacia Corporation | Method of using aminocyanopyridine compounds as mitogen activated protein kinase-activated protein kinase-2 inhibitors |
US20040127511A1 (en) * | 2002-12-12 | 2004-07-01 | Pharmacia Corporation | Tricyclic aminocyanopyridine inhibitors of mitogen activated protein kinase-activated protein kinase-2 |
US20080194636A1 (en) * | 2004-09-09 | 2008-08-14 | Howard Florey Institute Of Experimental Physiology And Medicine | Enzyme Inhibitors and Uses Thereof |
EP2532390B1 (en) * | 2005-02-16 | 2016-08-17 | Md Bioalpha Co., Ltd. | Pharmaceutical composition for liver diseases. |
US20080183282A1 (en) * | 2006-03-09 | 2008-07-31 | Saul Yedgar | Use of lipid conjugates for the coating of stents and catheters |
WO2009065169A1 (en) | 2007-11-19 | 2009-05-28 | Howard Florey Institute | Insulin-regulated aminopeptidase (irap) inhibitors and uses thereof |
EA015364B1 (ru) * | 2009-03-18 | 2011-06-30 | Учреждение Российской Академии Наук Институт Элементоорганических Соединений Им. А.Н. Несмеянова Ран (Инэос Ран) | 6,6'-диизопропил-8,8'-диметил-2,2'-динитро-3,3'-бис(трифторметил)- 3н,3'н-[9,9']ди[бензо(f)хроменил]-5,10,5',10'-тетраол, обладающий противоопухолевой и противогрибковой активностью, и способ его получения |
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CN104185631A (zh) * | 2011-11-10 | 2014-12-03 | 纪念斯隆-凯特琳癌症中心 | 用2-氨基-4H-萘并[1,2-b]吡喃-3-甲腈治疗卵巢癌 |
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NO923910L (no) | 1993-04-13 |
FI924551A (fi) | 1993-04-10 |
FI924551A0 (fi) | 1992-10-08 |
CZ281688B6 (cs) | 1996-12-11 |
NO923910D0 (no) | 1992-10-08 |
CA2079428A1 (en) | 1993-04-10 |
IL103356A (en) | 1998-02-22 |
KR100228841B1 (ko) | 1999-11-01 |
MX9205714A (es) | 1993-04-01 |
EP0537949B1 (en) | 1998-07-01 |
DK0537949T3 (da) | 1999-02-15 |
AU658003B2 (en) | 1995-03-30 |
NO301587B1 (no) | 1997-11-17 |
TW221292B (zh) | 1994-02-21 |
US5284868A (en) | 1994-02-08 |
DE69226060T2 (de) | 1998-11-19 |
EP0537949A1 (en) | 1993-04-21 |
RU2071472C1 (ru) | 1997-01-10 |
CZ303592A3 (en) | 1993-12-15 |
ES2117035T3 (es) | 1998-08-01 |
PH30659A (en) | 1997-09-16 |
JPH05194477A (ja) | 1993-08-03 |
AU2621692A (en) | 1993-04-22 |
DE69226060D1 (de) | 1998-08-06 |
ATE167859T1 (de) | 1998-07-15 |
MY111368A (en) | 1999-12-31 |
HU9203183D0 (en) | 1992-12-28 |
HUT62281A (en) | 1993-04-28 |
NZ244627A (en) | 1994-12-22 |
IL103356A0 (en) | 1993-03-15 |
HU218916B (hu) | 2000-12-28 |
KR930007931A (ko) | 1993-05-20 |
CN1034938C (zh) | 1997-05-21 |
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