CN111265518A - 含有联苯衍生物混合物的组合物及其用途 - Google Patents
含有联苯衍生物混合物的组合物及其用途 Download PDFInfo
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- CN111265518A CN111265518A CN202010082960.2A CN202010082960A CN111265518A CN 111265518 A CN111265518 A CN 111265518A CN 202010082960 A CN202010082960 A CN 202010082960A CN 111265518 A CN111265518 A CN 111265518A
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- biphenyl
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- methyl
- tetrazol
- amino
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- 239000000203 mixture Substances 0.000 title claims abstract description 41
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 241000196324 Embryophyta Species 0.000 claims abstract description 16
- 241000894006 Bacteria Species 0.000 claims abstract description 6
- 241000191940 Staphylococcus Species 0.000 claims abstract description 6
- 239000000284 extract Substances 0.000 claims abstract description 5
- -1 benzyl N-pentanoyl-N- ((2'- (2-trityl-2H-tetrazol-5-yl) - [1,1' -biphenyl ] -4-yl) methyl) -L-valine ester Chemical class 0.000 claims description 49
- 229960004295 valine Drugs 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 18
- 239000000419 plant extract Substances 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- JXTNUXJSXXIIFE-VISDOYDDSA-N (e,4r)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(4-phenylphenyl)pent-2-enoic acid Chemical compound C1=CC(C[C@H](\C=C(/C)C(O)=O)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 JXTNUXJSXXIIFE-VISDOYDDSA-N 0.000 claims description 6
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- DOBNVUFHFMVMDB-BEFAXECRSA-N (2r,4s)-4-(3-carboxypropanoylamino)-2-methyl-5-(4-phenylphenyl)pentanoic acid Chemical compound C1=CC(C[C@H](C[C@@H](C)C(O)=O)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 DOBNVUFHFMVMDB-BEFAXECRSA-N 0.000 claims description 4
- 241000218229 Humulus japonicus Species 0.000 claims description 4
- 240000000249 Morus alba Species 0.000 claims description 4
- 235000008708 Morus alba Nutrition 0.000 claims description 4
- 235000006484 Paeonia officinalis Nutrition 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 229950001902 dimevamide Drugs 0.000 claims description 4
- QOCQMJHAWNNWAV-BKELBIJQSA-N ethyl (e,4r)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(4-phenylphenyl)pent-2-enoate Chemical compound C1=CC(C[C@H](/C=C(\C)C(=O)OCC)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 QOCQMJHAWNNWAV-BKELBIJQSA-N 0.000 claims description 4
- 241001673062 Achromobacter xylosoxidans Species 0.000 claims description 3
- 241000607528 Aeromonas hydrophila Species 0.000 claims description 3
- 241000588923 Citrobacter Species 0.000 claims description 3
- 241000186216 Corynebacterium Species 0.000 claims description 3
- 241000186427 Cutibacterium acnes Species 0.000 claims description 3
- 241001467579 Microbacterium arborescens Species 0.000 claims description 3
- 241000588655 Moraxella catarrhalis Species 0.000 claims description 3
- 241000187479 Mycobacterium tuberculosis Species 0.000 claims description 3
- 241000588770 Proteus mirabilis Species 0.000 claims description 3
- 241000588767 Proteus vulgaris Species 0.000 claims description 3
- 241001147691 Staphylococcus saprophyticus Species 0.000 claims description 3
- 241000122973 Stenotrophomonas maltophilia Species 0.000 claims description 3
- 241000194017 Streptococcus Species 0.000 claims description 3
- 241001134658 Streptococcus mitis Species 0.000 claims description 3
- 241000194023 Streptococcus sanguinis Species 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 229940055019 propionibacterium acne Drugs 0.000 claims description 3
- 229940007042 proteus vulgaris Drugs 0.000 claims description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 claims description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 claims description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 2
- RRTDLQNPIWMFBR-RRHRGVEJSA-N (2R)-3-methyl-2-[pentanoyl-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]amino]butanoic acid Chemical compound C(CCCC)(=O)N([C@H](C(C)C)C(=O)O)CC1=CC=C(C=C1)C1=C(C=CC=C1)C1=NN=NN1C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 RRTDLQNPIWMFBR-RRHRGVEJSA-N 0.000 claims description 2
- HQCWKLWGCQAUOU-RRHRGVEJSA-N (2R)-3-methyl-2-[pentanoyl-[[4-[2-(2-trityltetrazol-5-yl)phenyl]phenyl]methyl]amino]butanoic acid Chemical compound C(CCCC)(=O)N([C@H](C(C)C)C(=O)O)CC1=CC=C(C=C1)C1=C(C=CC=C1)C=1N=NN(N1)C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 HQCWKLWGCQAUOU-RRHRGVEJSA-N 0.000 claims description 2
- SUSGLSGJNZTCOT-GCJKJVERSA-N (2R,4S)-2-methyl-4-[(4-oxo-4-propan-2-yloxybutanoyl)amino]-5-(4-phenylphenyl)pentanoic acid Chemical compound C1(=CC=C(C=C1)C[C@H](C[C@H](C(=O)O)C)NC(CCC(=O)OC(C)C)=O)C1=CC=CC=C1 SUSGLSGJNZTCOT-GCJKJVERSA-N 0.000 claims description 2
- MZDRJPZNLPSUPV-BEFAXECRSA-N (2R,4S)-4-(2,5-dioxopyrrolidin-1-yl)-2-methyl-5-(4-phenylphenyl)pentanoic acid Chemical compound C1(=CC=C(C=C1)C[C@H](C[C@H](C(=O)O)C)N1C(CCC1=O)=O)C1=CC=CC=C1 MZDRJPZNLPSUPV-BEFAXECRSA-N 0.000 claims description 2
- AUNLGZJEDPUZSE-UTKZUKDTSA-N (2R,4S)-4-[(4-ethoxy-4-oxobutanoyl)amino]-2-methyl-5-(4-phenylphenyl)pentanoic acid Chemical compound C1=CC(C[C@H](C[C@@H](C)C(O)=O)NC(=O)CCC(=O)OCC)=CC=C1C1=CC=CC=C1 AUNLGZJEDPUZSE-UTKZUKDTSA-N 0.000 claims description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 2
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 claims description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 2
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 claims description 2
- YNELJETWNMPEEH-OXQOHEQNSA-N (2r,4r)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(4-phenylphenyl)pentanoic acid Chemical compound C1=CC(C[C@@H](C[C@@H](C)C(O)=O)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 YNELJETWNMPEEH-OXQOHEQNSA-N 0.000 claims description 2
- YNELJETWNMPEEH-UZLBHIALSA-N (2r,4s)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(4-phenylphenyl)pentanoic acid Chemical compound C1=CC(C[C@H](C[C@@H](C)C(O)=O)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 YNELJETWNMPEEH-UZLBHIALSA-N 0.000 claims description 2
- WQQLDAFJPWYZCC-DYVFJYSZSA-N (2r,4s)-4-amino-2-methyl-5-(4-phenylphenyl)pentanoic acid Chemical compound C1=CC(C[C@@H](N)C[C@@H](C)C(O)=O)=CC=C1C1=CC=CC=C1 WQQLDAFJPWYZCC-DYVFJYSZSA-N 0.000 claims description 2
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 claims description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 2
- NSXSCTCKWRSTHJ-KRWDZBQOSA-N (2s)-3-methyl-2-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methylamino]butanoic acid Chemical compound C1=CC(CN[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 NSXSCTCKWRSTHJ-KRWDZBQOSA-N 0.000 claims description 2
- HQCWKLWGCQAUOU-FAIXQHPJSA-N (2s)-3-methyl-2-[pentanoyl-[[4-[2-(2-trityltetrazol-5-yl)phenyl]phenyl]methyl]amino]butanoic acid Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN(C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)N=N1 HQCWKLWGCQAUOU-FAIXQHPJSA-N 0.000 claims description 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 claims description 2
- PTLZEWHOZCZLAQ-SBUREZEXSA-N (2s,3s)-3-methyl-2-[pentanoyl-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]amino]pentanoic acid Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H]([C@@H](C)CC)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 PTLZEWHOZCZLAQ-SBUREZEXSA-N 0.000 claims description 2
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- YNELJETWNMPEEH-JXFKEZNVSA-N (2s,4s)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(4-phenylphenyl)pentanoic acid Chemical compound C1=CC(C[C@H](C[C@H](C)C(O)=O)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 YNELJETWNMPEEH-JXFKEZNVSA-N 0.000 claims description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 2
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 claims description 2
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Landscapes
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明提供了一种含有互不相同的第一联苯衍生物与第二联苯衍生物混合物的组合物,所述联苯衍生物的具体定义见说明书。本发明所述的混合物能协同地增强短毛独活全株等植物的提取物对阿尔莱特葡萄球菌等细菌的抑制作用。
Description
技术领域
本发明属于医药技术领域,具体涉及一种含有联苯衍生物的混合物的组合物及其用途。
背景技术
医院感染是影响医院医疗质量的重要问题。随着现代医学技术的不断发展进步,抗菌药物大量使用,临床病原菌的耐药菌株不断增加。因此,提高已有药物的抗菌活性,将会有助于改善细菌性感染患者的治疗效果。
Castellano S等人披露了一系列具有抗菌活性的联苯衍生物(Farmaco.2003Aug;58(8):563-8.)。
植物提取物中富含有多种具有抗菌活性的成分,比如,姚翰文等人在《丁香等29种植物提取物抑菌活性的筛选》一文种披露称丁香等29种植物提取物均具有一定的抑菌活性。
众所周知的是,中药的疗效是通过一系列相似结构的化合物群(有效成分)的协同作用而体现的。因此,寻找能与植物提取物发生协同作用的化合物群,为中西医结合治疗疑难病症提供了新的途径。
发明内容
本发明的目的在于提供一种含有互不相同的第一联苯衍生物与第二联苯衍生物的混合物的组合物,所述的混合物能与北短毛独活全株、升麻根茎、桑根皮、葎草全株、牡丹根皮、延胡索块茎等植物的提取物产生协同的抗菌作用。
为了实现上述目的,本发明一方面提供了含有互不相同且选自如下所示化合物1~72的第一联苯衍生物与第二联苯衍生物的混合物的组合物:
苄基N-戊酰基-N-((2'-(2-三苯甲基-2H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸酯(化合物1),
((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸(化合物2),
甲基((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸酯(化合物3),
乙基N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸酯(化合物4),
N-戊酰基-N-((2'-(1-三苯甲基-1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸(化合物5),
N-戊酰基-N-((2'-(2-三苯甲基-2H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸(化合物6),
N-戊酰基-N-((2'-(1-三苯甲基-1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-D-缬氨酸(化合物7),
N-戊酰基-N-((2'-(2-三苯甲基-2H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-D-缬氨酸(化合物8),
4'-溴-[1,1'-联苯]-2-甲腈(化合物9),
5-(4'-溴-[1,1'-联苯]-2-基)-2H-四氮唑(化合物10),
2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-甲醛(化合物11),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-2-甲基丙烷-1-胺(化合物12),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)戊酰胺(化合物13),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-异亮氨酸(化合物14),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-甲酰基戊酰胺(化合物15),
4'-(溴甲基)-[1,1'-联苯]-2-甲腈(化合物16),
甲基((2'-氰基-[1,1'-联苯]-4-基)甲基)-L-缬氨酸酯(化合物17),
甲基N-((2'-氰基-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸酯(化合物18),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-(4-羟基戊酰基)缬氨酸(化合物19),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-异丁基戊酰胺(化合物20),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-甲酰基-L-缬氨酸(化合物21),
甲基N-戊酰基-N-((2'-(1-三苯甲基-1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸酯(化合物22),
(S)-5-(4'-((N-(1-羧基-2-甲基丙基)戊酰氨基)甲基)-[1,1'-联苯]-2-基)-1H-四氮唑4-氧化物(化合物23),
(E)-N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-2-甲基丙烷-1-亚胺(化合物24),
N-((2'-甲脒基-[1,1'-联苯]-4-基)甲基)-N-(羟基甲基)戊酰胺(化合物25),
(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸(化合物27),
乙基(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸酯(化合物28),
甲基N-(2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)-N-甲基-L-缬氨酸酯(化合物29),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-丙酰基-L-缬氨酸(化合物31),
2-(N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)戊酰氨基)-3-甲基丁-2-烯酸(化合物32),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-丙氨酸(化合物33),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-D-缬氨酸(化合物34),
苄基N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸酯(化合物35),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-丁酰基-L-缬氨酸(化合物36),
甲基N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸酯(化合物37),
苄基N-戊酰基-N-((2'-(1-三苯甲基-1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸酯(化合物38),
4-(((2S,4S)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸(化合物39),
4-(((2R,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸(化合物40),
4-(((2R,4S)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸(化合物41),
(3R,5S)-5-([1,1'-联苯]-4-基甲基)-3-甲基吡咯烷-2-酮(化合物42),
乙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-(2,5-二氧代吡咯烷-1-基)-2-甲基戊酸酯(化合物43),
(3S,5S)-5-([1,1'-联苯]-4-基甲基)-3-甲基吡咯烷-2-酮(化合物44),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰氨基)-2-甲基戊酸(化合物45),
(2R,4R)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸(化合物46),
(2S,4R)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸(化合物47),
(2S,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸(化合物48),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸(化合物49),
乙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸酯(化合物50),
乙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸酯(化合物51),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸(化合物52),
(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸(化合物53),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-异丙氧基-4-氧代丁酰氨基)-2-甲基戊酸(化合物54),
异丙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-异丙氧基-4-氧代丁酰氨基)-2-甲基戊酸酯(化合物55),
乙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-异丙氧基-4-氧代丁酰氨基)-2-甲基戊酸酯(化合物56),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-乙氧基-4-氧代丁酰氨基)-2-甲基戊酸(化合物57),
乙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-乙氧基-4-氧代丁酰氨基)-2-甲基戊酸酯(化合物58),
4-((3R,5S)-5-([1,1'-联苯]-4-基甲基)-3-甲基-2-氧代吡咯烷-1-基)-4-氧代丁酸(化合物59),
异丙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-(2,5-二氧代吡咯烷-1-基)-2-甲基戊酸酯(化合物60),
乙基(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸酯(化合物61),
(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸(化合物62),
(R,E)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊-2-烯酸(化合物63),
乙基(R,E)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊-2-烯酸酯(化合物64),
叔丁基(R)-(1-([1,1'-联苯]-4-基)-3-羟基丙烷-2-基)氨基甲酸酯(化合物65),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰氨基)-2-甲基戊酸(化合物66),
异丙基4-((3R,5S)-5-([1,1'-联苯]-4-基甲基)-3-甲基-2-氧代吡咯烷-1-基)-4-氧代丁酸酯(化合物67),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-(2,5-二氧代吡咯烷-1-基)-2-甲基戊酸(化合物68),
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-异丙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸(化合物69),
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-甲氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸(化合物70),
(Z)-4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁-2-烯酸(化合物71),
(R,Z)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸(化合物72)。
一方面优选的,本发明所述组合物中所述的第一联苯衍生物与第二联苯衍生物的质量比在0.01:1~100:1之间。
另一方面优选的,本发明所述的组合物中进一步含有植物提取物。
进一步优选的,本发明所述的植物提取物是选自北短毛独活全株、升麻根茎、桑根皮、葎草全株、牡丹根皮、延胡索块茎中的一种植物的提取物。
另一方面优选的,本发明所述的组合物可制成口服固体制剂。
更优选的,本发明所述的口服固体制剂是选自片剂、胶囊剂与胶囊剂中的一种。
本发明另一方面提供了如前所述的组合物在制备用于治疗细菌感染性疾病中的用途。
优选的,本发明所述细菌感染性疾病是由选自非脱羧勒克菌、缓症链球菌、奇异变形杆菌、卡他莫拉菌、阿尔莱特葡萄球菌、树枝状微杆菌、嗜麦芽窄食单胞菌、柯氏柠檬酸杆菌、松鼠葡萄球菌、银色棒状杆菌、木糖氧化无色杆菌、腐生葡萄球菌、米勒链球菌、痤疮丙酸杆菌、嗜根考克氏菌、奥斯陆莫拉菌、结核分枝杆菌、普通变形杆菌、嗜水气单胞菌、血链球菌中的一种细菌感染所致的疾病。
体外试验结果显示,本发明所述的联苯衍生物的混合物能与北短毛独活全株、升麻根茎、桑根皮、葎草全株、牡丹根皮、延胡索块茎等多种植物的提取物产生协同的抗菌作用
具体实施方式
以下实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。对所公开的实施例的下述说明,使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的,本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下,在其它实施例中实现。因此,本发明将不会被限制于本文所示的这些实施例中,而是可以应用于符合与本文所公开的原理和新颖特点相一致的更宽的范围。虽然在本发明的实施或测试中可以使用与本发明中所述相似或等价的任何方法和材料,本文在此处列举优选的方法和材料。
制备例1植物提取物的制备
采用超声波提取法,将阴干的植物材料在40℃下烘干,粉碎后过40目筛,放入自封袋中。试验前称取50g的植物干粉,加入不同的有机溶剂进行超声波提取(如表1所示),每次60min,重复提取3次。过滤后浓缩至干,保存于4℃冰箱内待用。
表1不同植物提取物超声波提取的有机溶剂
试验例1联苯衍生物的混合物对植物提取物抗菌活性的影响
本发明采用李萍等人(食品与发酵工业,2017,43(02):232-238.)所披露的方法测定如下所示受试物①~③对不同细菌的抑制作用。
(1)受试药物:①:取联苯衍生物化合物X与Y(X、Y选自1~72,且X≠Y),以特定的质量比(R1)混合,记为MIX(X-Y);②:制备例1得到的植物提取物(PEZ,Z选自1~6);③:①与②的受试物以质量比(R2)形成的混合物,记为MIX(X-Y-PEZ)。
(2)试验方法
①供试样品溶液配制:取一定量的受试物,用DMF作溶剂,采用特定倍数连续稀释法配制6个浓度的供试样品溶液。
②菌悬液制备:活化后的菌种接入液体培养基(不加琼脂),摇床培养。细菌用平板稀释法计算菌落数,用无菌生理盐水调节细菌悬液浓度均为107CFU/mL。
③琼脂-孔洞扩散法测定抑菌活性操作步骤:灭菌培养基冷至50℃,加入6mL菌悬液,混匀,倒入直径9cm培养皿中,每皿15mL,静置45min。在固化后的培养基上用无菌打孔器均匀打孔(直径7mm),记号。每孔加入40μL供试样品溶液,DMF作空白对照。细菌37℃培养18h,测量并记录抑菌圈直径(mm),每个浓度重复3次,取平均值作为测定结果,按下式计算对供试菌种抑制率(IR)。
对于MIX(X-Y)与PEZ而言,采用IR对MIX(X-Y)的总浓度与PEZ的受试浓度(ng/mL)的对数(log(c))作图,根据线性回归方程计算出产生特定fa的抑制率时各受试物的浓度,分别记为ICfa(A)与ICfa(PEZ)。对于MIX(X-Y-PEZ)而言,采用IR对其中采用IR对MIX(X-Y)浓度(ng/mL)的对数作图,根据线性回归方程计算出产生特定fa的抑制率时MIX(X-Y-PEZ)中MIX(X-Y)的浓度,记为ICfa(mixA)。
根据下式计算产生特定fa抑制率时的联合用药指数(CI)。
CI<1时,即表示存在协同作用,CI越小,协同作用越强。
表2.1受试物对非脱羧勒克菌的抑制作用
表2.2受试物对缓症链球菌的抑制作用
表2.3受试物对奇异变形杆菌的抑制作用
表2.4受试物对卡他莫拉菌的抑制作用
表2.5受试物对阿尔莱特葡萄球菌的抑制作用
表2.6受试物对树枝状微杆菌的抑制作用
表2.7受试物对嗜麦芽窄食单胞菌的抑制作用
表2.8受试物对柯氏柠檬酸杆菌的抑制作用
表2.9受试物对松鼠葡萄球菌的抑制作用
表2.10受试物对银色棒状杆菌的抑制作用
表2.11受试物对木糖氧化无色杆菌的抑制作用
表2.12受试物对腐生葡萄球菌的抑制作用
表2.13受试物对米勒链球菌的抑制作用
表2.14受试物对痤疮丙酸杆菌的抑制作用
表2.15受试物对嗜根考克氏菌的抑制作用
表2.16受试物对奥斯陆莫拉菌的抑制作用
表2.17受试物对结核分枝杆菌的抑制作用
表2.18受试物对普通变形杆菌的抑制作用
表2.19受试物对嗜水气单胞菌的抑制作用
表2.20受试物对血链球菌的抑制作用
实施例1含有联苯衍生物混合物的组合物的固体制剂的制备
处方
制备方法
取处方量的活性成分与辅料,均过100目筛。取活性成分、乳糖、微晶纤维素、交联聚维酮与淀粉充分混匀;取处方量的羟丙甲纤维素,配制成依羟丙甲纤维素计浓度为10%的溶液,用乳酸调节pH至3.0~4.0,加入至上述混合物料中制软材,以16目筛制粒,80℃干燥3~4h。用16目筛整粒,加入处方量的微粉硅胶与硬脂酸镁混合混匀,灌装成每粒重约500mg的胶囊;
取处方量的活性成分与辅料,均过100目筛。取活性成分、乳糖、微晶纤维素、交联聚维酮与淀粉充分混匀;取处方量的羟丙甲纤维素,配制成依羟丙甲纤维素计浓度为10%的溶液,用乳酸调节pH至3.0~4.0,加入至上述混合物料中制软材,以16目筛制粒,80℃干燥3~4h。用16目筛整粒,加入处方量的微粉硅胶与硬脂酸镁混合混匀,分装成每袋重约5g的颗粒剂;
取处方量的活性成分与辅料,均过100目筛。取活性成分、乳糖、微晶纤维素、交联聚维酮与淀粉充分混匀;取处方量的羟丙甲纤维素,配制成依羟丙甲纤维素计浓度为10%的溶液,用乳酸调节pH至3.0~4.0,加入至上述混合物料中制软材,以16目筛制粒,80℃干燥3~4h。用16目筛整粒,加入处方量的微粉硅胶与硬脂酸镁混合混匀,压制成每片重约500mg的片剂。
Claims (8)
1.含有互不相同且选自如下所示化合物1~72的第一联苯衍生物与第二联苯衍生物的混合物的组合物:
苄基N-戊酰基-N-((2'-(2-三苯甲基-2H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸酯(化合物1),
((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸(化合物2),
甲基((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸酯(化合物3),
乙基N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸酯(化合物4),
N-戊酰基-N-((2'-(1-三苯甲基-1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸(化合物5),
N-戊酰基-N-((2'-(2-三苯甲基-2H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸(化合物6),
N-戊酰基-N-((2'-(1-三苯甲基-1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-D-缬氨酸(化合物7),
N-戊酰基-N-((2'-(2-三苯甲基-2H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-D-缬氨酸(化合物8),
4'-溴-[1,1'-联苯]-2-甲腈(化合物9),
5-(4'-溴-[1,1'-联苯]-2-基)-2H-四氮唑(化合物10),
2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-甲醛(化合物11),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-2-甲基丙烷-1-胺(化合物12),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)戊酰胺(化合物13),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-异亮氨酸(化合物14),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-甲酰基戊酰胺(化合物15),
4'-(溴甲基)-[1,1'-联苯]-2-甲腈(化合物16),
甲基((2'-氰基-[1,1'-联苯]-4-基)甲基)-L-缬氨酸酯(化合物17),
甲基N-((2'-氰基-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸酯(化合物18),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-(4-羟基戊酰基)缬氨酸(化合物19),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-异丁基戊酰胺(化合物20),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-甲酰基-L-缬氨酸(化合物21),
甲基N-戊酰基-N-((2'-(1-三苯甲基-1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸酯(化合物22),
(S)-5-(4'-((N-(1-羧基-2-甲基丙基)戊酰氨基)甲基)-[1,1'-联苯]-2-基)-1H-四氮唑4-氧化物(化合物23),
(E)-N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-2-甲基丙烷-1-亚胺(化合物24),
N-((2'-甲脒基-[1,1'-联苯]-4-基)甲基)-N-(羟基甲基)戊酰胺(化合物25),
(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸(化合物27),
乙基(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸酯(化合物28),
甲基N-(2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)-N-甲基-L-缬氨酸酯(化合物29),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-丙酰基-L-缬氨酸(化合物31),
2-(N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)戊酰氨基)-3-甲基丁-2-烯酸(化合物32),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-丙氨酸(化合物33),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-D-缬氨酸(化合物34),
苄基N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸酯(化合物35),
N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-丁酰基-L-缬氨酸(化合物36),
甲基N-((2'-(1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-N-戊酰基-L-缬氨酸酯(化合物37),
苄基N-戊酰基-N-((2'-(1-三苯甲基-1H-四氮唑-5-基)-[1,1'-联苯]-4-基)甲基)-L-缬氨酸酯(化合物38),
4-(((2S,4S)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸(化合物39),
4-(((2R,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸(化合物40),
4-(((2R,4S)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸(化合物41),
(3R,5S)-5-([1,1'-联苯]-4-基甲基)-3-甲基吡咯烷-2-酮(化合物42),
乙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-(2,5-二氧代吡咯烷-1-基)-2-甲基戊酸酯(化合物43),
(3S,5S)-5-([1,1'-联苯]-4-基甲基)-3-甲基吡咯烷-2-酮(化合物44),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰氨基)-2-甲基戊酸(化合物45),
(2R,4R)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸(化合物46),
(2S,4R)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸(化合物47),
(2S,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸(化合物48),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸(化合物49),
乙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸酯(化合物50),
乙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸酯(化合物51),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸(化合物52),
(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸(化合物53),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-异丙氧基-4-氧代丁酰氨基)-2-甲基戊酸(化合物54),
异丙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-异丙氧基-4-氧代丁酰氨基)-2-甲基戊酸酯(化合物55),
乙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-异丙氧基-4-氧代丁酰氨基)-2-甲基戊酸酯(化合物56),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-乙氧基-4-氧代丁酰氨基)-2-甲基戊酸(化合物57),
乙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-乙氧基-4-氧代丁酰氨基)-2-甲基戊酸酯(化合物58),
4-((3R,5S)-5-([1,1'-联苯]-4-基甲基)-3-甲基-2-氧代吡咯烷-1-基)-4-氧代丁酸(化合物59),
异丙基(2R,4S)-5-([1,1'-联苯]-4-基)-4-(2,5-二氧代吡咯烷-1-基)-2-甲基戊酸酯(化合物60),
乙基(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸酯(化合物61),
(R,E)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸(化合物62),
(R,E)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊-2-烯酸(化合物63),
乙基(R,E)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊-2-烯酸酯(化合物64),
叔丁基(R)-(1-([1,1'-联苯]-4-基)-3-羟基丙烷-2-基)氨基甲酸酯(化合物65),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰氨基)-2-甲基戊酸(化合物66),
异丙基4-((3R,5S)-5-([1,1'-联苯]-4-基甲基)-3-甲基-2-氧代吡咯烷-1-基)-4-氧代丁酸酯(化合物67),
(2R,4S)-5-([1,1'-联苯]-4-基)-4-(2,5-二氧代吡咯烷-1-基)-2-甲基戊酸(化合物68),
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-异丙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸(化合物69),
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-甲氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸(化合物70),
(Z)-4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁-2-烯酸(化合物71),
(R,Z)-5-([1,1'-联苯]-4-基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸(化合物72)。
2.根据权利要求1的组合物,其特征在于,所述的第一联苯衍生物与第二联苯衍生物的质量比在0.01:1~100:1之间。
3.根据权利要求1或2的给我,其特征在于,所述的组合物中进一步含有植物提取物。
4.根据权利要求3的组合物,其特征在于,所述的植物提取物是选自短毛独活全株、升麻根茎、桑根皮、葎草全株、牡丹根皮、延胡索块茎中的一种植物的提取物。
5.根据权利要求1或2的组合物,其特征在于,所述的组合物可制成口服固体制剂。
6.根据权利要求5的组合物,其特征在于,所述的口服固体制剂是选自片剂、胶囊剂与胶囊剂中的一种。
7.根据权利要求1或2的组合物在制备用于治疗细菌感染性疾病中的用途。
8.根据权利要求7的用途,其特征在于,所述细菌感染性疾病是由选自非脱羧勒克菌、缓症链球菌、奇异变形杆菌、卡他莫拉菌、阿尔莱特葡萄球菌、树枝状微杆菌、嗜麦芽窄食单胞菌、柯氏柠檬酸杆菌、松鼠葡萄球菌、银色棒状杆菌、木糖氧化无色杆菌、腐生葡萄球菌、米勒链球菌、痤疮丙酸杆菌、嗜根考克氏菌、奥斯陆莫拉菌、结核分枝杆菌、普通变形杆菌、嗜水气单胞菌、血链球菌中的一种细菌感染所致的疾病。
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