CN105636966A - 抗细菌铁载体-氨基青霉素缀合物 - Google Patents
抗细菌铁载体-氨基青霉素缀合物 Download PDFInfo
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- CN105636966A CN105636966A CN201380077567.2A CN201380077567A CN105636966A CN 105636966 A CN105636966 A CN 105636966A CN 201380077567 A CN201380077567 A CN 201380077567A CN 105636966 A CN105636966 A CN 105636966A
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- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 39
- 230000003115 biocidal effect Effects 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 35
- 229960003022 amoxicillin Drugs 0.000 claims abstract description 19
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims abstract description 19
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229960000723 ampicillin Drugs 0.000 claims abstract description 18
- 241000894006 Bacteria Species 0.000 claims abstract description 17
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims description 105
- 239000000203 mixture Substances 0.000 claims description 37
- -1 nitro, amino Chemical group 0.000 claims description 29
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 17
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical group O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
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- 239000012453 solvate Substances 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- QJBZDBLBQWFTPZ-UHFFFAOYSA-N pyrrolnitrin Chemical group [O-][N+](=O)C1=C(Cl)C=CC=C1C1=CNC=C1Cl QJBZDBLBQWFTPZ-UHFFFAOYSA-N 0.000 claims description 8
- 229960003276 erythromycin Drugs 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
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- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical group CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 claims description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical group 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 claims description 6
- 230000001629 suppression Effects 0.000 claims description 6
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Chemical group CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 claims description 5
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- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical group CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 claims description 5
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- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical group C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 claims description 4
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical group C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
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- 229930027917 kanamycin Chemical group 0.000 claims description 4
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 claims description 4
- 229930182823 kanamycin A Chemical group 0.000 claims description 4
- 229960002132 pyrrolnitrin Drugs 0.000 claims description 4
- 229960002135 sulfadimidine Drugs 0.000 claims description 4
- ASWVTGNCAZCNNR-UHFFFAOYSA-N sulfamethazine Chemical group CC1=CC(C)=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ASWVTGNCAZCNNR-UHFFFAOYSA-N 0.000 claims description 4
- XIYOPDCBBDCGOE-IWVLMIASSA-N (4s,4ar,5s,5ar,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methylidene-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical group C=C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1[C@H](O)[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O XIYOPDCBBDCGOE-IWVLMIASSA-N 0.000 claims description 3
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical group C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 claims description 3
- DHPRQBPJLMKORJ-XRNKAMNCSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical group C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O DHPRQBPJLMKORJ-XRNKAMNCSA-N 0.000 claims description 3
- MINDHVHHQZYEEK-UHFFFAOYSA-N (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid ester with 9-hydroxynonanoic acid Chemical group CC(O)C(C)C1OC1CC1C(O)C(O)C(CC(C)=CC(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-UHFFFAOYSA-N 0.000 claims description 3
- VLKSXJAPRDAENT-OWGHDAAGSA-N 3-[(3r,6r,9s,16s,19r,22s,25s)-3,9-bis(2-amino-2-oxoethyl)-16-[(1r)-1-hydroxyethyl]-19-(hydroxymethyl)-6-[(4-hydroxyphenyl)methyl]-13-octyl-2,5,8,11,15,18,21,24-octaoxo-1,4,7,10,14,17,20,23-octazabicyclo[23.3.0]octacosan-22-yl]propanoic acid Chemical group C([C@H]1NC(=O)[C@H](CC(N)=O)NC(=O)CC(NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@@H](CC(N)=O)NC1=O)CCCCCCCC)C1=CC=C(O)C=C1 VLKSXJAPRDAENT-OWGHDAAGSA-N 0.000 claims description 3
- 241000588626 Acinetobacter baumannii Species 0.000 claims description 3
- 229930183010 Amphotericin Chemical group 0.000 claims description 3
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Chemical group OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 claims description 3
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Chemical group C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 claims description 3
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical group O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims description 3
- 229930182566 Gentamicin Chemical group 0.000 claims description 3
- 229930193140 Neomycin Chemical group 0.000 claims description 3
- 239000004100 Oxytetracycline Chemical group 0.000 claims description 3
- 241000589516 Pseudomonas Species 0.000 claims description 3
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical group CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 claims description 3
- PJSFRIWCGOHTNF-UHFFFAOYSA-N Sulphormetoxin Chemical group COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC PJSFRIWCGOHTNF-UHFFFAOYSA-N 0.000 claims description 3
- UFUVLHLTWXBHGZ-MGZQPHGTSA-N [(2r,3r,4s,5r,6r)-6-[(1s,2s)-2-chloro-1-[[(2s,4r)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-4,5-dihydroxy-2-methylsulfanyloxan-3-yl] dihydrogen phosphate Chemical group CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@@H](SC)O1 UFUVLHLTWXBHGZ-MGZQPHGTSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 229960004821 amikacin Drugs 0.000 claims description 3
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical group O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 claims description 3
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- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical group O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 claims description 3
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical group O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 claims description 3
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- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical group C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 claims description 3
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- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical group ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 claims description 3
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- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical group CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 claims description 3
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- DDHVILIIHBIMQU-YJGQQKNPSA-L mupirocin calcium hydrate Chemical group O.O.[Ca+2].C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1.C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1 DDHVILIIHBIMQU-YJGQQKNPSA-L 0.000 claims description 3
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- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical group C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 claims description 3
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- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical group O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 claims description 2
- TYMABNNERDVXID-DLYFRVTGSA-N Panipenem Chemical group C([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1S[C@H]1CCN(C(C)=N)C1 TYMABNNERDVXID-DLYFRVTGSA-N 0.000 claims description 2
- KLFSEZJCLYBFKQ-WXYNYTDUSA-N [(3s)-3-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1,5-dihydroxy-4-oxopyridin-2-yl)methoxyimino]acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] hydrogen sulfate Chemical group O=C1N(OS(O)(=O)=O)C(C)(C)[C@@H]1NC(=O)C(\C=1N=C(N)SC=1)=N/OCC1=CC(=O)C(O)=CN1O KLFSEZJCLYBFKQ-WXYNYTDUSA-N 0.000 claims description 2
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- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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Abstract
合成了具有三脚架式主链的人造三儿茶酚盐铁载体及其与氨苄西林和阿莫西林的缀合物。与母体药物相比,两种缀合物均表现出显著增强的针对革兰氏阴性物种尤其是针对铜绿假单胞菌的体外抗细菌活性。所述缀合物似乎通过诱导的细菌铁转运过程被同化,因为其活性与铁浓度反向相关。所述容易合成的三儿茶酚盐铁载体可与作为缀合物的多种药物一起使用以靶向抗生素抗性革兰氏阴性细菌。
Description
相关申请
本申请要求2013年4月18日提交的美国申请序列号13/865,801的优先权,所述申请的全部内容据此通过引用并入。
政府支持
本发明是根据美国国家卫生研究院颁发的合同号AI054193和T32GM075762在政府支持下进行的。美国政府享有本发明的某些权利。
发明背景
抗微生物剂抗性在革兰氏阴性病原体中的发展对全球公共卫生造成严重威胁。在革兰氏阴性细菌的几种抗生素抗性机理中,主要问题是其外膜(充当屏障以阻止抗生素通过被动扩散吸收)的低渗透性。因此,开发克服这种渗透性介导的抗性的方法是重要的治疗目标。
在感染过程中,大多数微生物通过合成和利用高亲和力铁离子螯合剂(称为铁载体)同化生理上必需的铁。Fe(III)-铁载体复合物是公认的并通过特定受体引发穿过细菌细胞膜的主动转运。抗生素与铁载体的连接产生可能的"特洛伊木马(TrojanHorse)"缀合物,其可通过病原菌的铁吸收系统进入病原菌中,从而规避所述渗透性介导的药物抗性问题。虽然天然和人造铁载体-药物缀合物(含铁抗菌素(sideromycin))的研究已证实其对于开发抗微生物剂的潜力,但还需要进行其它研究以开发足够选择性的活性剂。因此本领域需要新的具有选择性抗菌活性的铁载体模拟物。
铜绿假单胞菌(Pseudomonasaeruginosa)是一种危害免疫受损患者(包括患有囊性纤维化(CF)、癌症或AIDS的那些患者)的机会性革兰氏阴性细菌。所述感染一旦形成将很难根除,因为铜绿假单胞菌本质上对很多现有抗生素(包括β-内酰胺)有抗性。穿过细胞包膜的穿透不足是铜绿假单胞菌对β-内酰胺抗生素诸如氨苄西林和阿莫西林的抗性的重要因素。
像许多其它类型的细菌一样,铜绿假单胞菌菌株已形成从其它物种(异种铁载体)识别并转运Fe(III)-铁载体复合物的受体以获得有竞争性的生长优势。肠菌素(Enterobactin)是主要在革兰氏阴性细菌(诸如大肠杆菌(Escherichiacoli)和鼠伤寒沙门氏菌(Salmonellatyphimurium))中发现的三儿茶酚盐(tris-catecholate)铁载体。肠菌素还可促进铜绿假单胞菌的铁吸收且所述吸收可由肠菌素在铁限制性条件下特异性诱导。利用肠菌素作为梭子(shuttle)以将抗生素递送到铜绿假单胞菌和其它产生细菌中是受到追捧的诱人策略。然而,这种方法将受到综合挑战因为肠菌素没有适于药物缀合的功能性或位点。因此,需要新的铁载体缀合物以推进抗生素选择性的研究并提供有效针对耐药性细菌的抗生素。
概述
本发明提供相对简单的铁载体模拟物和各种抗生素的合成缀合物。所述缀合物可展示选择性的强效抗细菌活性,包括抗假单胞菌活性,而所述母体抗生素其自身是无活性的。本发明提供包含本文描述的化合物的铁转运介导的药物递送系统。所述化合物可包括具有三脚架式主链并作为与抗生素(诸如氨苄西林或阿莫西林)的缀合物的三儿茶酚盐铁载体。
与所述母体药物相比,如本文所述评估的缀合物表现出显著增强的针对革兰氏阴性物种尤其针对铜绿假单胞菌的抗细菌活性。所述缀合物可通过诱导的细菌铁转运过程被同化并且其活性典型地与铁浓度反向相关。所述容易合成的三儿茶酚盐铁载体可用于制备各种药物缀合物以靶向抗生素抗性革兰氏阴性细菌。
因此,本发明提供一种式(I)的化合物:
其中
X为通过酯键或酰胺键共价连接到式(I)所示结构上的抗生素;
m为0或1-11;
每个R1独立地为H、-C(=O)烷基、-C(=O)芳基或-C(=O)O-烷基;
每个R2独立地为H、烷基、烷氧基、羟基、羧基、卤基、硝基、氨基或氰基;且
每个n独立地为1、2或3;
或其药学上可接受的盐或溶剂合物。
在一个实施方案中,每个R1为(C1-C6)烷酰基团。在一个实施方案中,每个R1为乙酰基、丙酰基或苯甲酰基。在一个具体实施方案中,每个R1为乙酰基。在另一个具体实施方案中,每个R1为H。
在一个实施方案中,每个R2为H、烷基、烷氧基或羟基。在一个具体实施方案中,每个R2为H。R2还可为以下对于取代基的定义所描述的取代基。
在一些实施方案中,每个R1是相同的,而在其它实施方案中,R1基团可以不同。同样,在各种实施方案中,每个R2可相同,而在其它实施方案中,例如,根据所选择的用于制备所述化合物的起始原料,R2基团可以彼此不同。
在一个实施方案中,每个n为1。在其它实施方案中,n可独立地为1、2或3;或1或2;或2或3。在一些实施方案中,m可为0、1、2、3、4、5、6、7、8、9、10、11,或从上述整数的任意一个到上述整数的任意另一个的范围。在各种实施方案中,m为0、1、2或3。在一些实施方案中,由字母m标记的括号的碳及其相邻的亚甲基可由如下所定义的接头置换。
变量X可为,例如,阿米卡星、阿莫西林、氨苄西林、两性霉素、芽孢菌霉素、头孢噻吩、氯霉素、氯四环素、环丙沙星、克林霉素、磷酸克林霉素、环丝氨酸(cycloserince)、达托霉素、地美环素、多柔比星、多西环素、红霉素、乙胺丁醇、红霉素、庆大霉素、异烟肼、卡那霉素、林可霉素、氯拉卡比、美他环素、莫匹罗星、新霉素、制霉菌素、氧四环素、吡咯尼群(pyrrolnitrin)、利福平、罗利环素、链霉素、磺胺醋酰、磺胺苯酰、磺胺嘧啶、磺胺多辛、磺胺甲基嘧啶、磺胺二甲基嘧啶(sulfamethazine)、磺胺甲噻二唑(sulfamethizole)、磺胺甲噁唑、磺胺异噁唑或四环素。在某些具体实施方案中,X为氨苄西林或阿莫西林。
在某些具体实施方案中,所述式(I)化合物为
本发明还提供所述式(I)化合物的组合物,例如,式(I)化合物与药学上可接受的稀释剂、赋形剂或载体的组合。
本发明进一步提供治疗革兰氏阴性细菌感染的方法。所述方法可包括向有需要的受试者施用有效治疗量的本文描述的化合物,从而治疗所述细菌感染。本发明还进一步提供杀伤或抑制革兰氏阴性细菌生长的方法,其中所述方法包括使所述细菌与有效致死量或抑制量的本文描述的化合物接触。所述细菌感染可由抗生素抗性细菌引起。在一些实施方案中,所述细菌感染由假单胞菌细菌引起。在一些具体实施方案中,所述细菌感染可由铜绿假单胞菌、大肠杆菌、鲍氏不动杆菌(Acinetobacterbaumannii)或鼠伤寒沙门氏菌引起。
本发明还提供增强革兰氏阴性细菌细胞膜对抗生素的渗透性的方法,其包括使抗生素与式(A)化合物缀合以提供式(I)的化合物,并将所述化合物施用到细菌细胞膜,从而由于所述抗生素与所述铁载体的缀合而增强革兰氏阴性细菌细胞膜对所述抗生素的渗透性。
本发明另外提供本文所述式的新型化合物,用于合成所述化合物的中间体,以及制备所述化合物的方法。本发明还提供本文所述式的化合物,其可用作用于合成其它适用的化合物的中间体。
附图简述
以下附图构成说明书的一部分并且被包括以进一步证明本发明的某些实施方案或各种方面。在一些情况下,可以通过参考附图结合本文提出的详细描述最好理解本发明的实施方案。本说明书和附图可能突出强调了本发明的某一特定实施例或某一方面。然而,本领域技术人员将理解所述实施例或方面的部分可结合本发明的其它实施例或方面使用。
图1.肠菌素1和三儿茶酚盐铁载体2的结构。
图2.根据各种实施方案的本发明的中间体和化合物的实例。
发明详述
本发明提供铁转运介导的药物递送化合物和方法。已评估所述化合物的合成与功效并且已发现选择性抗假单胞菌化合物。本发明提供相对简单的铁载体模拟物和抗生素的各种合成缀合物,所述缀合物具有选择性的强效抗细菌活性,而所述母体抗生素其自身活性较低或基本上完全无活性。
受体结合和Fe(III)-肠菌素转运的研究显示未取代的三儿茶酚铁中心和所述配位的儿茶酚酰胺基团对于识别为铁载体是必不可少的。为了开发微生物选择性含铁抗菌素的实际合成,开发出如同2(图1)的具有远离铁结合位点的接头的简化对称铁载体类似物作为适合的支架用于与抗生素的缀合。
三儿茶酚盐铁载体9及其氨基青霉素缀合物(10和11)的合成概述于方案1中。作为所述人造铁载体的主链,三氨基甲酸酯4由三腈3根据公布的工序(Unciti-Broceta等人,J.Med.Chem.2008,51,4076)配以少许改进合成。
方案1.所述三儿茶酚盐铁载体和缀合物10和11的合成。
试剂和条件:(a)1.BH3-THF、THF,回流;2.Boc2O、Et3N、MeOH,回流,83%用于2个步骤;(b)NiCl2、NaBH4、MeOH,超声处理,室温,92%;(c)甲基琥珀酰氯、Et3N、CH2Cl2,0℃至室温,75%;(d)6NHCl,回流,100%;(e)2,3-二酰氧苯甲酰氯8,NaHCO3/THF水溶液,0℃至室温,57%;(f)1.氯甲酸异丁酯、N-甲基吗啉、THF,0℃;2.氨苄西林或阿莫西林、Et3N、THF/H2O,0℃至室温,55%(用于10),50%(用于11)。
简单地说,将三腈3用THF中的硼烷还原并用Boc2O保护所得的三胺以得到三氨基甲酸酯4。在催化剂量的NiCl2的存在下利用NaBH4完成4中硝基的还原以得到胺5(92%收率)。利用甲基琥珀酰氯对胺5的处理提供琥珀酸盐衍生物6,其中所述羧基末端随后充当与氨基青霉素的耦合位点。
利用6NHCl对6的处理实现同时去除Boc保护基水解甲基酯以得到作为其trisHCl盐的三氨基酸7(收率定量)。使用酰化儿茶酚盐作为铁载体组分具有不仅促进合成并且防止儿茶酚基团的药理学副作用的益处。所述酰化儿茶酚盐可作为所需铁结合儿茶酚的前药同时避免由儿茶酚O-甲基转移酶(COMT)(其可导致铁载体活性所必需的有效铁结合能力的永久损耗)引起的可能的甲基化。因此,利用2,3-二酰氧苯甲酰氯8将三氨基酸7在碳酸氢钠水溶液中酰化以得到三脚架式的铁载体9,其可作为共同中间体用于通过酰胺键联或酯键联连接含各种氨基或羟基的药物。可制备化合物9的各种类似物,诸如式(A)化合物,以作为相似中间体用于与抗生素缀合。
作为原理验证研究,选择两种氨基青霉素、氨苄西林和阿莫西林(其本身对铜绿假单胞菌的野生型菌株不具活性)用于缀合物的合成。因此,通过铁载体9与氨苄西林和阿莫西林的混合酸酐将铁载体9耦合以分别提供缀合物10和11。首先通过琼脂孔扩散实验评估缀合物10和11对铜绿假单胞菌菌株的集合的抗细菌能力。同样通过在富铁和缺铁培养基中进行测定探测了铁浓度对抗细菌活性的影响。
如表1所示,所述母体药物,氨苄西林和阿莫西林,由于低的膜渗透性,对铜绿假单胞菌的野生型菌株(KW799/wt,PAO1,Pa4,和Pa6)无活性或仅有微弱活性。这在测定中通过所述铜绿假单胞菌可渗透突变体K799/61的抑制研究来证实,其中通过其诱导的大区域抑制显示,两种药物都具有高活性。因此,铜绿假单胞菌菌株具有这些经典抗生素的靶标,但通常不能通过被动扩散接近它们。
表1.琼脂扩散抗细菌敏感性测定中生长抑制区域的直径(mm)。
p,在抑制区域内部分清晰的抑制区域/菌落;P,在抑制区域内不清晰的抑制区域/多个菌落;h:表明仅少许生长抑制可检测到;将溶于1:9DMSO/MeOH的各个化合物的精确50μL0.2mM溶液加入琼脂培养基(StandardINutrientAgar,Serva或MuellerHintonIIAgar,Becton,DickinsonandCompany)内的9mm孔中;37℃下孵育24小时后读取抑制区域。
a化合物10在0.1mM下测试。
将铁载体部分加入到氨苄西林或阿莫西林中显著增加其对野生型铜绿假单胞菌菌株(Pa6除外)的抗菌活性,尤其在缺铁培养基中(其反映在感染宿主体内的情况)。作为两个对照样本,铁载体9及其与苯基甘氨酰胺的缀合物(无β-内酰胺片段的10的类似物,见以下实施例)在所述琼脂孔扩散实验中没有显示任何抑制效果,清楚表明所观察到的缀合物10和11的活性完全归因于β-内酰胺弹头(warhead)。
编码铁载体转运系统的基因的表达在细菌中由低的铁利用率诱导,但在铁充足时受到抑制。因此,缀合物10和11的活性增加代表在铁限制性条件下在病原体细胞表面的适当的铁载体受体的表达增加。这在利用铜绿假单胞菌K648(具有其天然铁载体绿脓假单胞菌荧光素(pyoverdin)和铜绿假单胞菌螯铁蛋白(pyochelin)生物合成缺陷的菌株)的测定中被证实。而缀合物10和11在富铁培养基中均对K648菌株无活性,所述活性在缺铁培养基中测试时大幅增加,表明所述缀合物的吸收在铁限制性条件下受到诱导。有趣的是,缀合物10和11即使在缺铁条件下均显示对临床分离铜绿假单胞菌Pa6无活性,可能是因为Pa6以及PAO1和Pa4在它们产生和利用的绿脓假单胞菌荧光素类型上各不相同。
利用野生型大肠杆菌H1443和突变体H1876(在其肠菌素介导的铁转运系统中具有缺陷)进行抗细菌活性对铁载体受体的依赖性的进一步研究(表1)。与所述野生型菌株H1443相比,所述两种缀合物对所述三重突变体H1876(fepA-、cir-、fiu-,编码Fe(III)-肠菌素的受体及其在大肠杆菌内的水解产物的基因)的活性均大幅降低,清楚地表明所述缀合物利用肠菌素介导的铁转运系统穿透所述细菌外膜屏障。
对缀合物10和11进行进一步测定以确定其在富铁和缺铁培养基中的最小抑制浓度(MIC,以μM表示)(表2)。两种缀合物在缺铁培养基中均表现出对铜绿假单胞菌的各种野生型菌株的优良的抗细菌活性,MIC在0.05至0.39μM范围内,而氨苄西林和阿莫西林通常是无活性的(>100μM)。唯一的例外是Pa6,两种缀合物对其均无活性,与来自所述琼脂扩散测定的观察一致。在富铁培养基中,所述缀合物的抑制活性大幅受损,进一步证实所述培养基的铁浓度调节铁载体外膜受体的表达并且因此与所述铁载体-药物缀合物的活性反向相关。
表2.铁载体-β-内酰胺缀合物10和11的体外抗细菌活性(MIC)。
a根据CLSI指南(methodsforDilutionAntimicrobialSusceptibilityTestsforBacteriathatGrowAerobically,第八版(Villanova,PA,USA),临床和实验室标准研究所(ClinicalandLaboratoryStandardsInstitute)(CLSI),2009,批准标准文件M07-A7)在Mueller-Hinton肉汤No.2(MHII)中使用肉汤微稀释法通过目视终点分析测定MIC90值(μM)。
b对各个化合物进行一式三份测试。
还针对选定的大肠杆菌和肺炎克雷伯氏菌(Klebsiellapneumoniae)菌株对缀合物10和11进行测试,其两者在铁限制性条件下均能够合成肠菌素及其降解产物并将其用于铁吸收。当针对大肠杆菌测试时,相对于氨苄西林,缀合物10显示出8倍增加而缀合物11几乎与阿莫西林等效。与在铜绿假单胞菌菌株中观察到的活性增强形成鲜明对比,发现两种缀合物对肺炎克雷伯氏菌均无活性(>100μM)。似乎铜绿假单胞菌、大肠杆菌和肺炎克雷伯氏菌,被诱导或内在地具有利用三儿茶酚盐2作为铁载体用于铁吸收的不同能力。来自肺炎克雷伯氏菌的高MIC的另一种可能性是抗性突变体在测定的时间过程中可以生长并增殖。在暴露于基于儿茶酚的铁载体-氯拉卡比缀合物的大肠杆菌(Ghosh等人,Chem.Biol.1996,3,1011)和暴露于绿脓假单胞菌荧光素-氨苄西林缀合物的铜绿假单胞菌(Kinzel等人,J.Antibiot.1998,51,499)的研究中观察到类似现象。突变体的分离和在所述缀合物的存在下的细菌生长动力学的研究目前正在研究中。
概括地说,合成并研究了具有三脚架式主链的人造三儿茶酚盐铁载体及其与氨苄西林和阿莫西林的缀合物。相对于所述母体药物,两种缀合物均表现出针对革兰氏阴性物种尤其是针对铜绿假单胞菌的显著增强的抗细菌活性。所述缀合物利用与能量依赖性活性细菌铁吸收系统来绕过所述革兰氏阴性外膜渗透性屏障,这解释了其活性增强的原因。所述容易合成的三儿茶酚盐铁载体可用作具有针对革兰氏阴性细菌的不同的细胞靶标和作用方式的新型药物缀合物。
定义
如本文所用,所述术语具有以下含义。本说明书中使用的所有其它术语和短语具有其如本领域技术人员将理解的普通含义。可通过参考技术词典,诸如由R.J.Lewis,JohnWiley&Sons完成的Hawley’sCondensedChemicalDictionary第14版,NewYork,N.Y.,2001,得到此类普通含义。
在本说明书中提到的"一个/一种(one)实施方案","一个/一种(an)实施方案",等等,表明所述实施方案可能包括某一特定方面、特征、结构、部分或特性,但并非每个实施方案都必然包括那个方面、特征、结构、部分或特性。此外,此类短语可能但未必,是指在本说明书的其它部分中提及的相同实施方案。进一步,当结合一个实施方案来描述某一特定方面、特征、结构、部分或特性时,无论是否明确描述,使得此类方面、特征、结构、部分或特性影响或与其它实施方案有联系是在本领域的技术人员知识范围内的。
除非上下文中另外明确指明,否则单数形式“一种/一个(a)”、“一种/一个(an)”和“该(the)”包括复数指代物。因此,例如,提到"一种化合物"包括多种此类化合物,所以一种化合物X包括多种化合物X。进一步指出,撰写权利要求可排除任何可选元素。因此,该陈述意图用作与权利要求要素的描述联合使用排他性术语,诸如“单独”“仅仅”等或使用“否定”限制的在先基础。
术语"和/或"意指本术语与之有关联的术语的任意一个、任意组合或全部。所述短语"一个或多个/一种或多种"是本领域技术人员容易理解的,尤其当在其使用的上下文中阅读时。例如,在苯环上的一个或多个取代基是指一至五个,或一至四个,例如如果该苯环被双取代。
术语"约"可指所述指定值的±5%、±10%、±20%或±25%的变化。例如,"约50"百分比在一些实施方案中可支持从45至55百分比的变化。对于整数范围,术语"约"可包括在所述范围的每一端大于和/或小于所述整数的一个或两个整数。除非本文另外说明,术语"约"意图包括临近在单独成分、组合物或实施方案的功能性方面等效的所述范围的数值,例如,重量百分比。
如熟练技术人员将理解的,所有数字,包括表示成分的量、性质诸如分子量、反应条件等等的那些,为近似值并且被理解为在一切情况下可任选地被术语"约"修饰。这些数值可根据本领域技术人员试图得到的期望性质利用本文描述的教导变化。还应理解此类数值固有地包含必然由在其各自的测试测量中发现的标准偏差引起的可变性。
如本领域技术人员将理解的,对于任何和所有目的,特别在提供书面描述方面,本文所述的所有范围还包含任何和所有可能的子范围及其子范围的组合,以及构成所述范围的单独数值,特别是整数值。所述范围(例如,重量百分比或碳基团)包括在此范围内的每个特定值、整数、小数或恒等式。任何所列范围均可以容易地被认为充分说明并且使同一范围可分解为至少两等份、三等份、四等份、五等份或十等份。作为非限制性实施例,本文讨论的每个范围可以容易地分解为下三分之一、中三分之一和上三分之一,等等。同样如本领域技术人员将理解的,所有语言诸如"多至"、"至少"、"大于"、"小于"、"多于"、"或以上",等等,包括所述数字并且此类术语是指随后可分解为如上所述的子范围的范围。以同样的方式,本文所述所有比率还包括落在所述较宽比率中的所有子比率。因此,对于自由基、取代基和范围所述的特定值仅用于说明;这些值不排除其它定义值或在自由基和取代基的定义范围内的其它值。
本领域技术人员还将容易地认识到,当成员被以共同的方式分组在一起,诸如马库什组(Markushgroup)时,本发明不仅包括总体上列出的整个组,还单独地包括组的每个成员以及主要组的所有可能的亚组。另外,对于所有的目的,本发明不仅包括了主要组,还包括了缺失一个或多个组成员的主要组。因此,本发明设想,明确排除列举的组的成员中的任何一个或多个。因此,附带条件可通过任何一个或多个所述元素、种类或实施方案适用于任一个所公开的类别或实施方案,可从此类类别或实施方案中排除,例如,用在明确的否定限制中。
术语"接触(contacting)"是指例如,在溶液中、在反应混合物中、体外或体内接触(touching)、使接触或带到中度或紧密接近(包括在细胞或分子水平)的行为,例如,以引起生理反应、化学反应或物理变化。
"有效量"是指有效治疗疾病、病症和/或疾患,或带来所述效果的量。例如,有效量可为有效降低正在治疗的所述疾患或症状的进展或严重程度的量。治疗有效量的测定完全在本领域技术人员的能力范围内。术语"有效量"意图包括本文描述的化合物的量,或本文描述的化合物的组合的量,例如,有效治疗或预防在宿主内的疾病或病症,或治疗所述疾病或病症的症状的量。因此,"有效量"通常指提供所述预期效果的量。
术语"治疗(treating)"、"治疗(treat)"和"治疗(treatment)"包括(i)预防疾病、病理学或医学疾患的发生(例如,预防);(ii)抑制所述疾病、病理学或医学疾患或阻止其形成;(iii)缓解所述疾病、病理学或医学疾患;和/或(iv)减少与所述疾病、病理学或医学疾患相关的症状。因此,术语"治疗(treat)"、"治疗(treatment)"和"治疗(treating)"可延伸至预防并且可包括预防(prevent)、预防(prevention)、预防(preventing)、降低、阻止或逆转正在治疗的所述疾患或症状的进展或严重程度。因此,术语"治疗(treatment)"可酌情包括医疗施用、治疗性施用和/或预防性施用。
术语"抑制(inhibit)"、"抑制(inhibiting)"、和"抑制(inhibition)"是指减缓、停止或逆转疾病、感染、疾患或细胞群的生长或进展。例如,与在所述治疗或接触不存在的情况下发生的生长或进展相比,所述抑制可大于约20%、40%、60%、80%、90%、95%或99%。
下列对于自由基、取代基和范围的特定值仅用于说明;这些值不排除其它定义值或在自由基和取代基的定义范围内的其它值。总称包括其种类的每一个。例如,术语卤基包括且明确可为氟、氯、溴或碘。
术语"烷基"是指具有,例如,1-20个碳原子,和通常1-12、1-10、1-8、1-6或1-4个碳原子的支链、非支链或环烃。实例包括,但不限于,甲基、乙基、1-丙基、2-丙基(异丙基)、1-丁基、2-甲基-1-丙基(异丁基)、2-丁基(仲丁基)、2-甲基-2-丙基(叔丁基)、1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、己基、辛基、癸基、十二烷基等。所述烷基可为未取代的或任选地取代的,例如,具有以下所述的取代基。所述烷基也可任选地部分或全部未取代的。因此,在某些实施方案中,烷基的描述可任选地包括烯基或炔基。如上所述和所例证,所述烷基根据其使用的上下文可为单价烃基或可为二价烃基(即,亚烷基)。
术语"烷氧基"是指基团烷基-O-,其中烷基如本文所定义。烷氧基的实例包括,但不限于,甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基、1,2-二甲基丁氧基等。所述烷氧基可为未取代或取代的。
术语"芳基"是指从母体芳族环体系的单个碳原子上除去至少一个氢原子得到的芳族烃基。所述基团连接位置可在母体环体系的饱和或不饱和碳原子上。所述芳基基团在环骨架上可具有6至20个碳原子,例如,约6-10个碳原子。所述芳基基团可具有单环(例如,苯基)或多个稠环,其中至少一个环为芳香族的(例如,萘基、二氢菲基、芴基或蒽基)。典型的芳基基团包括,但不限于,衍生自苯、萘、蒽、联苯等的基团。所述芳基可为未取代的或任选地取代的,如对烷基基团所描述的。
"接头"或"连接基团"是指连接至分子的其它基团的有机或无机链或部分。接头可为,例如,基团L,其中L为亚烷基、亚烯基、芳基双自由基、式-W-Z-W-的直接键或二价基团;其中每个W独立地为-N(R')C(=O)-、-C(=O)N(R')-、-OC(=O)-、-C(=O)O-、-O-、-S-、-S(O)-、-S(O)2-、-N(R')-、-C(=O)-、-(CH2)n-(其中n为1-3)、-(CX*2)-、-(CH2)n-(CX*2)-(其中n为1-3)或直接键;且Z为选自二价部分,其选自(C1-C12)烷基、(C2-C12)烯基、(C2-C12)炔基、(C3-C8)环烷基、(C6-C10)芳基、-N(R')C(=O)-、-C(=O)N(R')-、-OC(=O)-、-C(=O)O-、-N(R')-、-C(=O)-、-(CX*2)-、-(CH2)n-(CX*2)-(其中n为1-3)、-(OCH2-CH2)n-(其中n为1至约10)、-C(O)NH(CH2)n-(其中n为1至约6)、-OP(O)(OH)O-、-OP(O)(OH)O(CH2)n-(其中n为1至约6),-OP(O)(OH)OCH2CH(OH)CH2-、-N+(Me)2(CH2)n-(其中n为1至约6);或(C1-C12)烷基、(C2-C12)烯基、(C2-C12)炔基,或任选地在两个碳之间或在碳和氧之间被(C3-C8)环烷基、杂芳基、杂环或(C6-C10)芳基中断的-(OCH2-CH2)n-(其中n为1至约6);或Z为直接键。
术语"取代的"意指在使用"取代的"表述指示的基团上的一个或多个(例如,1个、2个、3个、4个或5个;在一些实施方案中1个、2个或3个;以及在其它实施方案中1个或2个)氢原子"被"取代基"置换。所述取代基可为所示基团的选择之一,或其可为本领域技术人员熟知的适合基团,条件是不超过所取代的原子的正常化合价,并且所述取代获得稳定化合物。适合的取代基包括,例如,烷基、烯基、炔基、烷氧基、卤基、卤代烷基、羟基、羟基烷基、芳基、芳酰基、杂芳基、杂环、环烷基、烷酰基、烷氧基羰基、氨基、烷基氨基、二烷基氨基、三氟甲硫基、二氟甲基、酰氨基、硝基、三氟甲基、三氟甲氧基、羧基、羧基烷基、酮基、硫代、烷硫基、烷基亚磺酰基、烷基磺酰基、芳基亚磺酰基、芳基磺酰基、杂芳基亚磺酰基、杂芳基磺酰基、杂环亚磺酰基、杂环磺酰基、磷酸盐、硫酸盐、羟基胺、羟基(烷基)胺和氰基,以及在本公开的方案和附图中显示的部分,及其组合。另外,适合的取代基可为,例如,-X、-R、-O-、-OR、-SR、-S-、-NR2、-NR3、=NR、-CX3、-CN、-OCN、-SCN、-N=C=O、-NCS、-NO、-NO2、=N2、-N3、NC(=O)R、-C(=O)R、-C(=O)NRR、-S(=O)2O-、-S(=O)2OH、-S(=O)2R、-OS(=O)2OR、-S(=O)2NHR、-S(=O)R、-OP(=O)(OR)2、-P(=O)(OR)2、-OP(=O)(OH)(OR)、-P(=O)(OH)(OR)、-P(=O)(O-)2、-P(=O)(OH)2、-C(=O)R、-C(=O)X、-C(S)R、-C(O)OR、-C(O)O-、-C(S)OR、-C(O)SR、-C(S)SR、-C(O)NRR、-C(=S)NRR、-C(=NR)NRR,其中每个X独立地为卤素("卤基"):F、Cl、Br或I;且每个R独立地为H、烷基、芳基、(芳基)烷基(例如,苄基)、杂芳基、(杂芳基)烷基、杂环、杂环(烷基)或保护基。如本领域技术人员将容易理解的,当取代基为酮基(=O)或硫代(=S)等时,被取代原子上的两个氢原子则被置换。在一些实施方案中,一个或多个上述取代基被从被取代基团上的取代基的潜在值的组中排除。
术语"溶剂合物"是指具有一个或多个与其固体结构相关的溶剂分子的固体化合物。当固体化合物从溶剂中结晶时可形成溶剂合物,其中一个或多个溶剂分子成为固体结晶基体的组成部分。本文描述的式的化合物可为溶剂合物,例如,乙醇溶剂合物。溶剂合物另一种类型是水合物。"水合物"同样是指具有一个或多个在分子水平与其固体或晶体结构密切相关的水分子的固体化合物。水合物是溶剂合物的特定类型。当化合物在水中固化或结晶时可形成水合物,其中一个或多个水分子成为固体结晶基体的组成部分。本文描述的式的化合物可为水合物。
抗生素是抑制细菌或真菌生长或杀伤细菌或真菌的药剂。抗生素可通过酰胺或其它连接基团与式(I)的结构连接。因此,任何具有可用羟基或氨基的抗生素可,或通过胺和式(A)的羧基基团的直接缩合(诸如在化合物9中),或通过首先进行所述抗生素的羟基到胺的官能团转化,然后与式(A)形成酰胺,来与式(A)的结构连接。可与式(A)连接以提供式(I)的化合物的抗生素包括,但不限于,林可霉素家族(最初从林可链霉菌重新获得的一类抗生素药剂)的抗生素;四环素家族(最初从金色链霉菌重新获得的一类抗生素剂)的抗生素;和硫基抗生素诸如磺胺类。多种抗生素可与式(A)缀合,诸如在http://en.wikipedia.org/wiki/Antibacterial中描述的抗细菌剂。一些特定适用的实例包括以下。
可被缀合的β-内酰胺包括青霉烯类、碳青霉烯类(亚胺培南、美罗培南、厄他培南(ertapeneme)、多利培南、帕尼培南、比阿培南等),单环β-内酰胺类(氨曲南、替吉莫南(tigimonam)、卡卢莫南、BAL30072等),以及各种其它β-内酰胺细胞包膜抗生素(见:http://en.wikipedia.org/wiki/Monobactam)。
林可霉素家族的一些适合的抗生素的特定实例包括林可霉素、克林霉素和磷酸克林霉素。
大环内酯抗生素的特定实例包括红霉素、阿奇霉素、克拉霉素、地红霉素、罗红霉素、泰利霉素、碳霉素A、交沙霉素、吉他霉素、麦迪霉素/醋酸麦迪霉素、竹桃霉素、索里霉素、螺旋霉素、醋竹桃霉素和泰乐菌素(tylosin/tylocine)。
酮内酯抗生素的特定实例包括泰利霉素、喹红霉素、索里霉素、螺旋霉素、安沙霉素、竹桃霉素、碳霉素和泰乐菌素。
四环素家族的抗生素的特定实例包括四环素自身、氯四环素、氧四环素、地美环素、罗利环素、美他环素和多西环素。
硫基抗生素的特定实例包括磺胺类磺胺醋酰、磺胺苯酰、磺胺嘧啶、磺胺多辛、磺胺甲基嘧啶、磺胺二甲基嘧啶、磺胺甲噻二唑、磺胺异噁唑和磺胺甲噁唑。
可连接的抗生素的进一步实例包括噁唑烷酮类诸如zyvox(利奈唑胺)、肽抗生素诸如多粘菌素、喹诺酮类、氟喹诺酮类(http://en.wikipedia.org/wiki/Quinolone)、氨基糖苷类(http://en.wikipedia.org/wiki/Aminoglycoside)和利福霉素(http://en.wikipedia.org/wiki/Rifamycin)。
可连接的抗生素还可包括各种抗细菌剂、抗真菌剂、抗霉菌剂和抗病毒剂;青霉素类诸如氨苄西林或阿莫西林;头孢菌素类诸如头孢噻吩和ceclor(头孢克洛);氨基糖苷类诸如卡那霉素;大环内酯类诸如红霉素、制霉菌素和两性霉素;和所述抗生素阿米卡星、芽孢菌霉素、氯霉素、多柔比星、多西环素、乙胺丁醇、红霉素、庆大霉素、异烟肼、卡那霉素、碳头孢菌素类诸如lorabid(氯拉卡比)、莫匹罗星、新霉素、吡咯尼群、利福平、链霉素和万古霉素。
一般合成方法
本文描述的化合物的制备可根据以下实施例中的方法制备,或可根据有机合成领域内的已知技术制备。用于将抗生素缀合到式(I)的许多连接基团可商购获得,和/或如本领域内所述制备。关于用于制备本文描述的化合物(特别是关于利用连接基团)的一般合成方法的信息,可见于GregT.Hermanson,BioconjugateTechniques,AcademicPress,SanDiego,CA(1996)。可用于将抗生素和式(A)连接的有用接头和缀合技术由Roosenberg等人,Curr.Med.Chem.2000,7,159;Wittmann等人,Bioorg.Med.Chem.2002,10,1659;和Heinisch等人,J.Med.Chem.2002,45,3032进一步描述。本领域技术人员熟知的其它有用反应在以下文献中引用:March'sAdvancedOrganicChemistryReactions,Mechanisms,andStructure,第5版,由MichaelB.Smith和JerryMarch,JohnWiley&Sons出版;和Wuts等人(1999),ProtectiveGroupsinOrganicSynthesis,第3版,JohnWiley&Sons,出版。
制备本发明的化合物的方法在某些情况下可产生异构体。尽管本发明的方法并不总是需要分离这些异构体,但必要时可通过本领域已知的方法完成此类分离。例如,可使用制备型高效液相色谱法进行异构体纯化,例如,通过使用具有手性填料的色谱柱。
可通过使具有可用的羟基或胺基团或还原成醇后的羧基的抗生素与式(A)化合物缩合容易地制备式(I)化合物:
其中Y为离去基团诸如卤素(例如,与胺或醇耦合),例如,氯化物。所述式(A)的-C(=O)Y部分还可为激活的羰基或活性酯,并且其余变量如对于式(I)所述。此类缩合可在适合的溶剂或碱(例如,三乙基胺等)的存在下进行,通常在室温或室温以下有利。如果所述抗生素不具有可用的胺部分但具有可用于与式(A)形成键联的羟基,所述抗生素的羟基基团可被直接耦合以形成酯或首先用诸如具有末端(任选受保护的)氨基的链烷酸(例如,2-氨基乙酸或3-氨基丙酸)的基团酯化,随后通过上述缩合反应来提供本发明的化合物。
药物制剂
本文描述的化合物可用于制备治疗性药物组合物,例如,通过使所述化合物与药学上可接受的稀释剂、赋形剂或载体组合。所述化合物可添加到盐或溶剂合物形式的载体中。例如,在化合物为足够碱性或酸性以形成稳定的无毒酸盐或碱盐的情况下,化合物作为盐进行施用可能是适当的。药学上可接受的盐的实施例为用形成生理上可接受的阴离子的盐类形成的有机酸加成盐,例如,甲苯磺酸盐、甲烷磺酸盐、乙酸盐、柠檬酸盐、丙二酸盐、酒石酸盐、琥珀酸盐、苯甲酸盐、抗坏血酸盐、α-酮戊二酸盐和β-甘油磷酸盐。也可形成适合的无机盐,包括盐酸盐、卤化物、硫酸盐、硝酸盐、碳酸氢盐和碳酸盐。
药学上可接受的盐可使用本领域熟知的标准程序获得,例如通过使足够碱性的化合物(诸如胺)与适合的酸反应以提供生理上可接受的离子化合物。也可通过类似方法制备碱金属(例如,钠、钾或锂)或碱土金属(例如,钙)的羧酸盐。
本文描述的式的化合物可被配制成药物组合物并以各种形式施用到哺乳动物宿主,诸如人患者。所述形式可明确适应于选定的施用途径,例如,经口或非肠道施用,通过静脉内、肌肉内、局部或皮下途径。
本文描述的化合物可与药学上可接受的媒介物(诸如惰性稀释剂或可同化的食用载体)组合进行全身施用。对于经口施用,可将化合物封装于硬壳或软壳明胶胶囊中,压缩成片剂,或直接并入患者饮食的食物中。化合物还可与一种或多种赋形剂组合并以可摄取片剂、口含片、锭剂、胶囊、酏剂、混悬液、糖浆、粉片等形式使用。此类组合物和制剂典型地含有至少0.1%的活性化合物。所述组合物和制剂的百分比可变化并可便利地为给定单位剂型的重量的约0.5%至约60%、约1%至约25%或约2%至约10%。活性化合物在此类治疗适用的组合物中的量可为使有效剂量水平可获得的量。
所述片剂、锭剂、丸剂、胶囊等还可含有以下中一种或多种:粘合剂诸如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂诸如磷酸氢二钙;崩解剂诸如玉米淀粉、马铃薯淀粉、藻酸等;和润滑剂诸如硬脂酸镁。可加入甜味剂诸如蔗糖、果糖、乳糖或阿斯巴甜;或调味剂诸如胡椒薄荷、冬青油或樱桃调味剂。当所述单位剂型为胶囊时,其可含有,除上述类型的材料外,液体载体,诸如植物油或聚乙二醇。各种其它材料可作为包衣存在或用于另外修饰固体单位剂型的物理形态。例如,片剂、丸剂或胶囊可用明胶、蜡、虫胶或糖等包衣。糖浆或酏剂可含有所述活性化合物、蔗糖或果糖作为甜味剂,对羟基苯甲酸甲酯和丙酯作为防腐剂、染料以及诸如樱桃和橙子味道的调味剂。用于制备任何单位剂型的任何材料应为药学上可接受的并且在采用的量内基本无毒。另外,可将所述活性化合物并入缓释制剂和设备中。
可通过灌注或注射静脉内或腹腔内施用所述活性化合物。所述活性化合物的溶液或其盐或可在水中制备,任选地与无毒表面活性剂混合。分散液可在甘油、液体聚乙二醇、甘油三乙酸酯或其混合物中制备,或在药学上可接受的油中制备。在储存和使用的普通条件下,制剂可含有防腐剂以防止微生物生长。
适于注射或灌注的药物剂型可包括包含适于临时制备无菌可注射或可灌注溶液或分散液的所述活性成分(任选地封装于脂质体中)的无菌水溶液、分散液或无菌粉末。在制备和储存的条件下所述最终剂型应为无菌、流动且稳定的。所述液体载体或媒介物可为溶剂或液体分散介质,包括,例如,水、乙醇、多元醇(例如,甘油、丙二醇,液体聚乙二醇等)、植物油、无毒甘油酯及其适合的混合物。可通过例如形成脂质体,维持在分散液情况下所需的粒径,或使用表面活性剂,维持适当的流动性。防止微生物作用可通过各种抗细菌和/或抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞(thimerosal)等)来达成。在许多情况下,可优选地包括等渗剂,例如,糖、缓冲剂或氯化钠。可通过延迟吸收的试剂(例如单硬脂酸铝和/或明胶)引起可注射组合物的延长吸收。
可通过将所需量的活性化合物与以上列举的各种其它成分在适当溶剂中结合,根据需要,任选地随后进行过滤灭菌来制备无菌可注射溶液。在用于制备无菌可注射溶液的无菌粉末的情况下,制备方法可包括真空干燥和冷冻干燥技术,其产生所述活性成分外加存在于所述溶液中的任何其它所需成分的粉末。
对于局部施用,化合物可以纯的形式施加,例如,当其为液体时。然而,将通常合乎需要的是将所述活性剂,例如,与皮肤病学上可接受的可为固体、液体或凝胶等的载体组合,作为组合物或制剂施用至皮肤。
适用的固体载体包括磨碎的固体,如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等。适用的液体载体包括水、二甲基亚砜(DMSO)、醇、二醇或水-醇/二醇掺合物,其中可将化合物在有效水平,任选地借助于无毒表面活性剂溶解或分散。可添加诸如芳香剂及其它抗微生物剂的佐剂来使用于给定用途的性质最优化。所得液体组合物可自吸收垫施用,用于浸渍绷带和其它敷料,或使用泵型喷雾器或气雾剂喷雾器喷涂于受影响区域上。
诸如合成聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性矿物质的增稠剂也可与液体载体一起用于形成用于直接向使用者的皮肤施用的可涂敷糊剂、凝胶、软膏、皂剂等。
用于将活性剂递送至皮肤的皮肤病学组合物的实例为本领域所知;例如,见美国专利号4,992,478(Geria),4,820,508(Wortzman),4,608,392(Jacquet等人)和4,559,157(Smith等人)。此类皮肤病学组合物可与本文描述的化合物组合使用,其中此类组合物的成分可任选地由本文描述的化合物或本文描述的可加入所述组合物的化合物代替
本文描述的化合物的适用剂量可通过比较其在动物模型中的体外活性和体内活性确定。用于将小鼠和其它动物中的有效剂量外推至人的方法为本领域所知;例如见美国专利号4,938,949(Borch等人)。在治疗中使用所需的化合物或其活性盐或衍生物的量将不仅随所选特定化合物或盐而变化,而且也随施药途径、所治疗疾患的性质以及患者的年龄和状况而变化,且将最终由主治医师或临床医师裁量。
所述化合物可便利地以单位剂型施用,例如,每单位剂型含活性成分5至1000mg/m2,便利地含活性成分10至750mg/m2,更便利地含活性成分50至500mg/m2。所需剂量可便利地以单次剂量提供或以在适当间隔下施用的分次剂量提供,例如以每天两次、三次、四次或四次以上亚剂量提供。所述亚剂量自身可进一步分成例如许多次个别宽松间隔施用。
本发明提供治疗哺乳动物感染的治疗方法,其涉及向患有感染的哺乳动物施用有效量的本文描述的化合物或组合物。哺乳动物包括灵长类动物、人、啮齿类动物、犬科动物、猫科动物、牛科动物、绵羊、马、猪、山羊、牛科动物等。所述感染可为细菌感染,例如,由本文描述的细菌引起的感染。
本发明的化合物治疗细菌感染的能力可通过使用本领域熟知的测定来确定。例如,治疗方案的设计、毒性评估、数据分析、细胞杀伤定量和使用抗细菌筛选的生物学意义为已知。另外,化合物治疗细菌感染或杀伤或抑制细菌的能力可使用如以下实施例描述的测定来确定。
下列实施例意图说明以上发明且不应被解释为限定其范围。本领域技术人员将容易认识到所述实施例提出许多其它可实践本发明的方式。应理解可在保持处于本发明的范围内的同时作出许多变化和修改。
实施例
实施例1.化合物制备
一般信息。所有反应在氩气下通过使用标准技术进行。所有溶剂和试剂获自商业来源并且除非另外说明否则不经进一步纯化直接使用。从钠和二苯甲酮中蒸馏四氢呋喃(THF)。在紫外光、碘或KMnO4染色下可视的0.25mm硅胶板上通过薄层色谱法(TLC)对反应进行监测。使用SorbentTechnologies硅胶60(32-63μm)进行硅胶柱层析。反相C18硅胶(ReversePhaseC18SilicaGel)由EliLilly慷慨赠予并且在环境温度下在Varian600MHz光谱仪上记录Co.NMR光谱。使用YMCProC18反相柱(3.0×50mm)进行HPLC分析。使用的流动相为10mM乙酸铵HPLC级水溶液(A)和HPLC级乙腈(B)。由以下形成梯度:在10min内为5%–80%的B,之后2min内为80%–95%的B,然后3min内为95%–5%的B,流速为0.7mL/min(总运行时间为15min)。在Waters制备型二元泵系统上使用紫外探测器(254nm)和YMC-PackProC18柱(150×20mm,粒径5μm)以15mL/min的流速进行制备型HPLC纯化。溶剂梯度由流速为15mL/min的10mM乙酸铵水溶液和乙腈形成。
根据公开的程序制备下列化合物:三腈3(Newkome等人,J.Org.Chem.,1988,53,5552-5554),甲基琥珀酰氯(Cason,J.Org.Synth.,1945,25,19)和2,3-二乙酰氧基苯甲酸(Bergeron等人,J.Org.Chem.,1980,45,1589-1592)。化合物4-10的结构在图2中示出。
硝基三氨基甲酸酯4.该化合物由改进的两步文献程序(Unciti-Broceta等人,J.Med.Chem.,2008,51,4076-4084)制备。向三腈3(3.30g,15.0mmol)在10mL的无水THF中的悬浮液中加入BH3-THF复合物(1.0MinTHF,75mL,75.0mmol)。将所述溶液加热回流16h。冷却至室温(约22℃)后,加入浓HCl以破坏过量的硼烷并将混合物用蒸气浴加热30min。在真空下除去所有溶剂并用40%NaOH溶液(20mL)使残余物碱化并用CH2Cl2(100mL×3)萃取。将合并的有机层经Na2SO4干燥并过滤。蒸发溶剂得到溶于40mLMeOH中的粗胺。向该溶液中加入Et3N(8.4mL,60.0mmol)和Boc2O(10.8g,49.5mmol)并将混合物加热回流6h。在真空下除去溶剂后,将残余物溶于200mLEtOAc中且有机层用0.5NHCl和盐水依次洗涤,经Na2SO4干燥并过滤。在真空下除去溶剂并将残余物在硅胶柱(己烷:EtOAc=3:1至1:1)上通过层析法纯化以得到呈无色油的化合物4(6.63g,2步83%):1HNMR(600MHz,CDCl3)δ4.86(br.s.,3H),3.00-3.05(m,6H),1.75-1.89(m,6H),1.23-1.42(m,33H);13CNMR(150MHz,CDCl3)δ156.1,93.9,79.2,40.2,32.7,28.4,24.3。
氨基三氨基甲酸酯5.在超声波浴中,将NiCl2-6H2O(67mg,0.25mmol)溶于3mLMeOH。一次性加入NaBH4(29mg,0.75mmol)并将所得黑色悬浮液超声处理30min。向上述悬浮液中依次加入溶于3mLMeOH的化合物4(250mg,0.5mmol)和NaBH4(57mg,1.5mmol)。在加入额外的NaBH4(57mg,1.5mmol)之前将混合物超声处理30min。30min后,使混合物通过Celite的短垫来过滤并蒸发溶剂。将残余物在10mL水和20mLCH2Cl2之间分配。用CH2Cl2(10mL×3)萃取水层并用盐水洗涤合并的有机层,经Na2SO4干燥并过滤。在真空下蒸发溶剂以得到呈白色泡沫的胺5(217mg,92%):1HNMR(600MHz,CDCl3)δ4.66(br.s.,3H),3.07-3.12(m,6H),1.35-1.52(m,33H),1.25-1.35(m,6H);13CNMR(150MHz,CDCl3)δ156.2,79.3,53.0,41.2,37.3,28.6,24.4;HRMS(ESI)计算值C25H51N4O6(M+H)+:503.3803,实测值503.3815。
琥珀酸甲酯6.向化合物5(1.12g,2.23mmol)的溶液和Et3N(0.62mL,4.46mmol)的10mLCH2Cl2溶液(冷却至0℃)中加入甲基琥珀酰氯(0.52mL,4.23mmol)。将混合物在0℃下搅拌1h且在室温下搅拌1h。在真空下除去溶剂并将残余物在50mLEtOAc和50mL水之间分配。用EtOAc(50mL×3)萃取水层并依次用饱和NaHCO3和盐水洗涤合并的有机层,经Na2SO4干燥并过滤。在真空下除去溶剂后,将所述残余物在硅胶柱(含50-100%EtOAc的己烷)上通过层析法纯化以得到呈白色蜡状固体的化合物6(1.03g,75%):mp=140-142℃;1HNMR(600MHz,CDCl3)δ5.48(br.s.,1H),4.76(br.s.,3H),3.67(s,3H),3.04-3.10(m,6H),2.62(t,J=6.75Hz,2H),2.40(t,J=6.75Hz,2H),1.59-1.69(m,6H),1.42(s,27H),1.39(br.s.,6H);13CNMR(150MHz,CDCl3)δ173.9,170.9,156.3,79.3,58.6,52.1,40.8,32.3,31.8,29.4,28.6,23.8;HRMS(ESI)计算值C30H57N4O9(M+H)+:617.4120,实测值617.4133。
三氨基酸HCl盐7.将化合物6(880mg,1.43mmol)在20mL6MHCl中的悬浮液加热回流30min。冷却至室温后,在真空下除去所有溶剂。将油状残余物溶于10mL水中并冻干以以定量收率得到呈透明固体的三氨基酸7的HCl盐:1HNMR(600MHz,D2O)δ2.92(t,J=7.48Hz,6H),2.56(t,J=6.75Hz,2H),2.47(t,J=6.75Hz,2H),1.64-1.70(m,6H),1.49-1.58(m,6H);13CNMR(150MHz,D2O)δ177.0,174.1,58.0,39.5,30.8,30.5,28.9,20.7;HRMS(ESI)计算值C14H31N4O3(M+H)+:303.2391,实测值303.2398。
2,3-二酰氧苯甲酰氯8.向2,3-二乙酰氧基苯甲酸(2.38g,10mmol)在30mLCH2Cl2的悬浮液中加入乙酰氯(1.72mL,20mmol)和无水DMF(0.1mL)。将溶液在室温下搅拌1h且在真空下除去所有溶剂以得到立即用于下一步骤的呈黄色半固体的粗酰氯8。
三儿茶酚盐铁载体9.使用注射泵以1mL/min的速率向盐7(575mg,1.4mmol)的20mL0.5MNaHCO3溶液(冷却至0℃)中加入酰氯8(1.2g,4.69mmol,假设来自上一步的定量收率)的20mLTHF溶液。加入后,将混合物在0℃下搅拌1h并在室温下搅拌1h。在真空下除去THF后,用3MHCl将水溶液酸化至pH=2并用EtOAc(20mL×3)萃取。用盐水洗涤合并的有机层,经Na2SO4干燥,过滤并在真空下浓缩。将残余物在反相硅胶柱(C18,CH3CN:H2O=1:2至2:3)上通过层析法纯化。将包含产物的部分合并并冻干以得到呈白色固体的化合物9(0.77g,57%):1HNMR(600MHz,CDCl3)δ7.51(dd,J=7.5,1.9Hz,3H),7.21-7.30(m,6H),6.62(t,J=5.6Hz,3H),5.67(s,1H),3.31-3.35(m,6H),2.49-2.52(m,2H),2.26-2.32(m,20H),1.70-1.75(m,6H),1.48-1.52(m,6H);13CNMR(150MHz,CDCl3)δ174.9,171.9,168.8,168.6,165.8,143.1,140.3,130.7,126.8,126.5,125.8,58.8,40.1,32.1,31.6,29.2,23.3,20.8,20.8;HRMS(ESI)计算值C47H55N4O18(M+H)+:963.3506,实测值963.3533;HPLC保留时间5.03min。
氨苄西林缀合物10.向酸9(22mg,0.023mmol)的溶液和N-甲基吗啉(2.5μL,0.023mmol)的1mL无水THF溶液(冷却至0℃)中加入氯甲酸异丁酯(3.0μL,0.023mmol)且将混合物在此温度下搅拌1小时。加入氨苄西林三水合物(10.6mg,0.026mmol)溶液和Et3N(10μL)的1mLTHF/H2O(4:1)溶液且将混合物在0℃下搅拌1h并在室温下搅拌1h。在真空下除去THF后,将残余物溶于5mL水中并用1NHCl将溶液酸化至pH=2。所得悬浮液用EtOAc(5mL×3)萃取并用盐水洗涤合并的有机层,经Na2SO4干燥并过滤。在真空下除去溶剂并将残余物通过制备型HPLC纯化。将包含产物的部分合并并冻干以得到呈白色固体的缀合物10(16.4mg,55%):1HNMR(600MHz,DMSO-d6)δ9.06(d,J=7.6Hz,1H),8.54(d,J=8.5Hz,1H),8.31(t,J=5.6Hz,3H),7.40-7.44(m,5H),7.24-7.36(m,9H),7.12(s,1H),5.71(d,J=8.2Hz,1H),5.46(dd,J=7.9,4.1Hz,1H),5.35(d,J=4.1Hz,1H),4.11(s,1H),3.12-3.16(m,6H),2.43-2.45(m,2H),2.30-2.34(m,2H),2.27(s,9H),2.20(s,9H),1.59-1.65(m,6H),1.53(s,3H),1.37-1.43(m,9H);HRMS(ESI)计算值C63H72N7O21S(M+H)+:1294.4496,实测值1294.4522;HPLC保留时间5.57min。
阿莫西林缀合物11.以类似于从阿莫西林(15.2mg,50%)制备缀合物10的方式制备阿莫西林缀合物11并纯化:1HNMR(600MHz,DMSO-d6)δ8.86(d,J=7.9Hz,1H),8.38(d,J=8.2Hz,1H),8.31(t,J=5.6Hz,3H),7.42-7.44(m,3H),7.31-7.36(m,6H),7.18(d,J=8.5Hz,2H),7.12(s,1H),6.68(d,J=8.5Hz,2H),5.55(d,J=8.2Hz,1H),5.44(dd,J=8.1,4.0Hz,1H),5.33(d,J=3.8Hz,1H),4.07(s,1H),3.10-3.16(m,6H),2.38-2.42(m,2H),2.29-2.33(m,2H),2.27(s,9H),2.20(s,9H),1.60-1.64(m,6H),1.53(s,3H),1.37-1.43(m,9H);HRMS(ESI)计算值C63H71N7NaO22S(M+Na)+:1332.4265,实测值1332.4279;HPLC保留时间5.30min。
苯基甘氨酰胺缀合物S1。
向酸9(38mg,0.039mmol)的溶液和N-甲基吗啉(4.5μL,0.041mmol)的1.5mL无水THF溶液(冷却至0℃)中加入氯甲酸异丁酯(5.2μL,0.040mmol)且将混合物在此温度下搅拌1小时。加入D-苯基甘氨酰胺(8.6mg,0.057mmol)溶液和Et3N(10μL)的1mLTHF/H2O(4:1)溶液且将混合物在0℃下搅拌1h并在室温下搅拌1h。在真空下除去THF后,将残余物悬浮于H2O(5mL)中并用EtOAc(5mL×3)萃取。将合并的有机层经Na2SO4干燥并过滤。在真空下除去溶剂并将残余物在硅胶柱(含5-8%MeOH的CH2Cl2)上通过层析法纯化以得到呈白色固体的缀合物S1(28mg,66%):1HNMR(600MHz,DMSO-d6)δ8.41(d,J=7.9Hz,1H),8.31(t,J=5.3Hz,3H),7.65(br.s.,1H),7.25-7.45(m,14H),7.13和7.12(2×s,2H),5.36(d,J=8.2Hz,1H),3.11-3.17(m,6H),2.35-2.48(m,2H),2.30-2.34(m,2H),2.28(s,9H),2.21(s,9H),1.58-1.67(m,6H),1.37-1.44(m,6H);HRMS(ESI)计算值C55H63N6O18(M+H)+:1095.4193,实测值1095.4203。
实施例2.抗生素测定
一般材料和方法。所有液体和培养基在使用前通过高压灭菌法(121℃,15min)进行灭菌。所有水溶液和培养基使用蒸馏、去离子和过滤水(MilliporeMilli-QAdvantageA10WaterPurificationSystem)制备。Luria肉汤(LB)购自VWR。Mueller-HintonNo.2肉汤(MHII肉汤;经阳离子调节)购自Sigma-Aldrich(St.Louis,MO)。通过将0.8mL1mg/mL的2,2'-联吡啶无菌水溶液加入到49.2mLMHII肉汤中制备缺铁(-Fe)MHII肉汤。通过将0.8mL1mg/mL的FeCl3无菌水溶液加入到49.2mLMHII肉汤中制备富铁(+Fe)MHII肉汤。Mueller-HintonNo.2琼脂(MHII琼脂;HiMediaLaboratories)购自VWR。通过在缓慢搅拌下将0.5mL1mg/mL的2,2’-联吡啶无菌水溶液加入到34mL熔化的MHII琼脂中制备缺铁(-Fe)MHII琼脂。通过在缓慢搅拌下将0.5mL1mg/mL的FeCl3无菌水溶液加入到34mL熔化的MHII琼脂中制备富铁(+Fe)MHII琼脂。相关技术另见Wencewicz,T.A.Dissertation,UniversityofNotreDame,NotreDame,IN,2011。
通过琼脂扩散测定进行抗细菌敏感性测试。所述化合物的抗细菌活性通过改进的Kirby-Bauer琼脂扩散测定来确定。过夜培养的测试微生物在LB肉汤中生长18-24h并根据0.5BaSO4McFarland标准在盐水溶液(0.9%NaCl)中制备1.5×106CFU/mL标准混悬液。将该标准化混悬液(0.1mL)加入到34mL无菌、熔化的琼脂(-Fe或+Fe)(调节至47-50℃)中。在缓慢搅拌后,将接种的琼脂培养基倒入无菌塑料皮氏培养皿(petridish)(145mm×20mm)中并在火焰旁将盖子半开使其凝固约30min。从所述皮氏培养皿琼脂中剪下直径为9.0mm的孔并精确填充50μL样本溶液。将皮氏培养皿在37℃下孵育18-24h并在24h后用电子卡尺测量抑制区域直径(mm)。
通过肉汤微稀释法测定确定MIC90值。所述化合物的抗细菌活性根据临床和实验室标准研究所(CLSI,前身为NCCLS)指南通过使用肉汤微稀释法测量其最小抑制浓度(MIC90's)来确定。在96-孔微量滴定板的每个孔中填充50μL无菌肉汤培养基(-Fe或+Fe)。将每个测试化合物溶于DMSO制成20mM溶液,然后用无菌肉汤介质(-Fe或+Fe)稀释至400或800μM。将精确50μL所述化合物溶液加入微量滴定板的第一个孔中并沿板的每一排进行2倍连续稀释。然后将精确50μL细菌接种物(5×105CFU/mL的肉汤培养基)加入到每个孔中得到100μL/孔的总体积。将板在37℃下孵育20h然后检查每个孔的细菌生长。通过培养基相对于填充DMSO标准物的一排孔的浊度所判断记录作为抑制90%细菌生长所需的最低化合物浓度(μM)的MIC90。
实施例3.药物剂型
下列制剂举例说明可用于本文描述的式的化合物、本文明确公开的化合物或其药学上可接受的盐或溶剂合物(以下称为'化合物X')的治疗性或预防性施用的代表性药物剂型:
这些制剂可通过药学领域熟知的常规程序制备。应当理解上述药物组合物可以根据熟知的制药技术进行改变以便适应不同的量和类型的活性成分“组合物X”。气溶胶制剂(vi)可以与一种标准的、计量的气溶胶分配器结合使用。另外,这些具体的成分和比例是用于说明目的。根据感兴趣的剂型的希望特性,成分可以换成适合的等效物并且可以改变比例。
虽然以上关于所披露的实施方案和实例描述了具体的实施方案,但这些实施方案和实例仅是说明性的并且不限制本发明的范围。可以根据本领域的普通技术来进行改变和变更,而不背离本发明如在以下权利要求书中限定的较宽方面。
所有出版物、专利和专利文件均通过引用并入本文,如同通过引用单独地并入一般。由此将理解没有与本公开不一致的限制。已经关于各种具体和优选的实施方案以及技术对本发明进行了描述。然而,应理解可在保持处于本发明的精神和范围内的同时作出许多变化和修改。
Claims (19)
1.一种式(I)的化合物:
其中
X为通过酯键或酰胺键共价连接到式(I)所示结构上的抗生素;
m为0或1-11;
每个R1独立地为H、-C(=O)烷基、-C(=O)芳基或-C(=O)O-烷基;
每个R2独立地为H、烷基、烷氧基、羟基、羧基、卤基、硝基、氨基或氰基;且
每个n独立地为1、2或3;
或其药学上可接受的盐或溶剂合物。
2.根据权利要求1所述的化合物,其中每个R1为乙酰基、丙酰基或苯甲酰基。
3.根据权利要求1所述的化合物,其中每个R2为H、烷基、烷氧基或羟基。
4.根据权利要求1所述的化合物,其中每个R2为H。
5.根据权利要求1所述的化合物,其中每个n为1。
6.根据权利要求1所述的化合物其中m为0、1、2或3。
7.根据权利要求1所述的化合物,其中X为阿米卡星、阿莫西林、氨苄西林、两性霉素、氨曲南、芽孢菌霉素、BAL30072、比阿培南、卡卢莫南、头孢克洛、头孢噻吩、氯霉素、氯四环素、环丙沙星、克林霉素、磷酸克林霉素、环丝氨酸、达托霉素、地美环素、多利培南、多柔比星、多西环素、厄他培南、红霉素、乙胺丁醇、红霉素、庆大霉素、亚胺培南、异烟肼、卡那霉素、林可霉素、氯拉卡比、美罗培南、美他环素、莫匹罗星、新霉素、制霉菌素、氧四环素、帕尼培南、吡咯尼群、利福平、罗利环素、链霉素、磺胺醋酰、磺胺苯酰、磺胺嘧啶、磺胺多辛、磺胺甲基嘧啶、磺胺二甲基嘧啶、磺胺甲噻二唑、磺胺甲噁唑、磺胺异噁唑、四环素或替吉莫南。
8.根据权利要求1所述的化合物,其中X为氨苄西林或阿莫西林。
9.根据权利要求1所述的化合物,其中所述化合物为
10.一种组合物,其包含根据权利要求1所述的化合物和药学上可接受的稀释剂或载体。
11.一种治疗革兰氏阴性细菌感染的方法,其包括向有需要的受试者施用有效治疗量的根据权利要求1所述的化合物,从而治疗所述细菌感染。
12.根据权利要求11所述的方法,其中所述细菌感染由抗生素抗性细菌引起。
13.根据权利要求11所述的方法,其中所述细菌感染由假单胞菌细菌引起。
14.一种治疗革兰氏阴性细菌感染的方法,其包括向有需要的受试者施用有效治疗量的根据权利要求10所述的组合物,从而治疗所述细菌感染。
15.一种杀伤或抑制革兰氏阴性细菌生长的方法,其包括使所述细菌与有效致死量或抑制量的根据权利要求1所述的化合物接触。
16.根据权利要求15所述的方法,其中所述细菌感染由抗生素抗性细菌引起。
17.根据权利要求15所述的方法,其中所述细菌感染由假单胞菌细菌引起。
18.根据权利要求15所述的方法,其中所述细菌感染由铜绿假单胞菌、大肠杆菌、鲍氏不动杆菌或鼠伤寒沙门氏菌引起。
19.一种杀伤或抑制革兰氏阴性细菌生长的方法,其包括使所述细菌与有效致死量或抑制量的根据权利要求10所述的组合物接触。
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