CN114230522A - 一种咪唑-2-羧酸类金属β-内酰胺酶抑制剂及其制备方法和用途 - Google Patents
一种咪唑-2-羧酸类金属β-内酰胺酶抑制剂及其制备方法和用途 Download PDFInfo
- Publication number
- CN114230522A CN114230522A CN202111236198.XA CN202111236198A CN114230522A CN 114230522 A CN114230522 A CN 114230522A CN 202111236198 A CN202111236198 A CN 202111236198A CN 114230522 A CN114230522 A CN 114230522A
- Authority
- CN
- China
- Prior art keywords
- compound
- imidazole
- carboxylic acid
- ring
- beta
- 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.)
- Pending
Links
- 239000003781 beta lactamase inhibitor Substances 0.000 title claims abstract description 22
- 229940126813 beta-lactamase inhibitor Drugs 0.000 title claims abstract description 22
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 229910052751 metal Inorganic materials 0.000 title claims abstract description 10
- 239000002184 metal Substances 0.000 title claims abstract description 10
- KYWMCFOWDYFYLV-UHFFFAOYSA-N 1h-imidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CN1 KYWMCFOWDYFYLV-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 120
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 claims abstract description 27
- 229960002260 meropenem Drugs 0.000 claims abstract description 27
- 108060004734 metallo-beta-lactamase Proteins 0.000 claims abstract description 16
- 102000020235 metallo-beta-lactamase Human genes 0.000 claims abstract description 16
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 15
- -1 amino, hydroxy Chemical group 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 239000003782 beta lactam antibiotic agent Substances 0.000 claims description 10
- 239000002132 β-lactam antibiotic Substances 0.000 claims description 10
- 229940124586 β-lactam antibiotics Drugs 0.000 claims description 10
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical class [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 229940124350 antibacterial drug Drugs 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000003242 anti bacterial agent Substances 0.000 claims description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 101710150697 Inositol monophosphatase 1 Proteins 0.000 claims description 3
- 101710126181 Insulin-like growth factor 2 mRNA-binding protein 1 Proteins 0.000 claims description 3
- 101000740455 Klebsiella pneumoniae Metallo-beta-lactamase type 2 Proteins 0.000 claims description 3
- 102100029083 Minor histocompatibility antigen H13 Human genes 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 23
- 102000004190 Enzymes Human genes 0.000 abstract description 20
- 108090000790 Enzymes Proteins 0.000 abstract description 20
- 230000002401 inhibitory effect Effects 0.000 abstract description 20
- 229940079593 drug Drugs 0.000 abstract description 19
- 241000894006 Bacteria Species 0.000 abstract description 12
- 206010059866 Drug resistance Diseases 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 9
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 abstract description 9
- 230000002441 reversible effect Effects 0.000 abstract description 6
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 110
- 238000006243 chemical reaction Methods 0.000 description 53
- 230000015572 biosynthetic process Effects 0.000 description 46
- 238000003786 synthesis reaction Methods 0.000 description 46
- 238000005160 1H NMR spectroscopy Methods 0.000 description 39
- 239000007787 solid Substances 0.000 description 37
- 238000004809 thin layer chromatography Methods 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 19
- 238000004440 column chromatography Methods 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 229940125904 compound 1 Drugs 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000007788 liquid Substances 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 16
- 239000012043 crude product Substances 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 12
- 241000588724 Escherichia coli Species 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- JMHMSRUKQIGVQC-UHFFFAOYSA-N 1-(1-phenylethyl)imidazole-2-carboxylic acid Chemical compound CC(C1=CC=CC=C1)N2C=CN=C2C(=O)O JMHMSRUKQIGVQC-UHFFFAOYSA-N 0.000 description 9
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- 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 description 8
- 229940126657 Compound 17 Drugs 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- HUGZJTRIKWMRAL-UHFFFAOYSA-N 1-benzyl-5-methylimidazole-4-carboxylic acid Chemical compound CC1=C(C(O)=O)N=CN1CC1=CC=CC=C1 HUGZJTRIKWMRAL-UHFFFAOYSA-N 0.000 description 7
- DILSIJUSCNBOKF-UHFFFAOYSA-N OC(C1=NC=CN1CCCC1=CC=CC=C1)=O Chemical compound OC(C1=NC=CN1CCCC1=CC=CC=C1)=O DILSIJUSCNBOKF-UHFFFAOYSA-N 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- VNCFILBKRNHAAT-UHFFFAOYSA-N OC(=O)C1=NC=CN1CC1=CC=C(C#N)C=C1 Chemical compound OC(=O)C1=NC=CN1CC1=CC=C(C#N)C=C1 VNCFILBKRNHAAT-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 238000010931 ester hydrolysis Methods 0.000 description 6
- UHYNYIGCGVDBTC-UHFFFAOYSA-N ethyl 1h-imidazole-2-carboxylate Chemical compound CCOC(=O)C1=NC=CN1 UHYNYIGCGVDBTC-UHFFFAOYSA-N 0.000 description 6
- XQLMTQUHXZUQBR-UHFFFAOYSA-N 1-(furan-3-ylmethyl)imidazole-2-carboxylic acid Chemical compound OC(=O)c1nccn1Cc1ccoc1 XQLMTQUHXZUQBR-UHFFFAOYSA-N 0.000 description 5
- RAVXGLOWJOKQHB-UHFFFAOYSA-N 1-(pyridin-2-ylmethyl)imidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CN1CC1=CC=CC=N1 RAVXGLOWJOKQHB-UHFFFAOYSA-N 0.000 description 5
- NKVHFZAVHWAVCA-UHFFFAOYSA-N 1-(thiophen-3-ylmethyl)imidazole-2-carboxylic acid Chemical compound OC(=O)c1nccn1Cc1ccsc1 NKVHFZAVHWAVCA-UHFFFAOYSA-N 0.000 description 5
- VYSVSKWMPVUZGC-UHFFFAOYSA-N 1-[(1-methylpyrazol-4-yl)methyl]imidazole-2-carboxylic acid Chemical compound Cn1cc(Cn2ccnc2C(O)=O)cn1 VYSVSKWMPVUZGC-UHFFFAOYSA-N 0.000 description 5
- KQXXEVHWYQOTIG-UHFFFAOYSA-N 1-[(3,4-difluorophenyl)methyl]imidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CN1CC1=CC=C(F)C(F)=C1 KQXXEVHWYQOTIG-UHFFFAOYSA-N 0.000 description 5
- IGFKMGCIUSIHQI-UHFFFAOYSA-N 1-[(4-bromothiophen-2-yl)methyl]imidazole-2-carboxylic acid Chemical compound OC(=O)c1nccn1Cc1cc(Br)cs1 IGFKMGCIUSIHQI-UHFFFAOYSA-N 0.000 description 5
- OPDVMFVDEPEQBS-UHFFFAOYSA-N 1-[(5-chlorothiophen-2-yl)methyl]imidazole-2-carboxylic acid Chemical compound OC(=O)c1nccn1Cc1ccc(Cl)s1 OPDVMFVDEPEQBS-UHFFFAOYSA-N 0.000 description 5
- RTWJBKXBFOXBIC-UHFFFAOYSA-N 1-benzyl-4-phenylimidazole-2-carboxylic acid Chemical compound OC(C1=NC(C2=CC=CC=C2)=CN1CC1=CC=CC=C1)=O RTWJBKXBFOXBIC-UHFFFAOYSA-N 0.000 description 5
- QEEBXPXPYKOARL-UHFFFAOYSA-N 1-benzylimidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CN1CC1=CC=CC=C1 QEEBXPXPYKOARL-UHFFFAOYSA-N 0.000 description 5
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 5
- OQFUWEBOOFSVCO-UHFFFAOYSA-N CCC(C1=CC=CC=C1)N1C(C(O)=O)=NC=C1 Chemical compound CCC(C1=CC=CC=C1)N1C(C(O)=O)=NC=C1 OQFUWEBOOFSVCO-UHFFFAOYSA-N 0.000 description 5
- RQELVWJEDXEHAG-UHFFFAOYSA-N OC(C(C1=CC=CC=C1)N1C(C(O)=O)=NC=C1)=O Chemical compound OC(C(C1=CC=CC=C1)N1C(C(O)=O)=NC=C1)=O RQELVWJEDXEHAG-UHFFFAOYSA-N 0.000 description 5
- SUSKFKNHZHASHN-UHFFFAOYSA-N OC(C1=NC(C2CC2)=CN1CC1=CC=CC=C1)=O Chemical compound OC(C1=NC(C2CC2)=CN1CC1=CC=CC=C1)=O SUSKFKNHZHASHN-UHFFFAOYSA-N 0.000 description 5
- QEJBNXASNOIUIX-UHFFFAOYSA-N OC(C1=NC=CN1CC(C=C1)=CC(Cl)=C1Cl)=O Chemical compound OC(C1=NC=CN1CC(C=C1)=CC(Cl)=C1Cl)=O QEJBNXASNOIUIX-UHFFFAOYSA-N 0.000 description 5
- LQWOJDRXMAFUSC-UHFFFAOYSA-N OC(C1=NC=CN1CC1=CC(Br)=CC(Br)=C1)=O Chemical compound OC(C1=NC=CN1CC1=CC(Br)=CC(Br)=C1)=O LQWOJDRXMAFUSC-UHFFFAOYSA-N 0.000 description 5
- 229940125846 compound 25 Drugs 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- 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 description 4
- BKOGLHZRIDSKKO-UHFFFAOYSA-N 1-(2-phenoxyethyl)imidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CN1CCOC1=CC=CC=C1 BKOGLHZRIDSKKO-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- YFRNSZULRBZDAD-UHFFFAOYSA-N CC1=CN(CC2=CC=CC=C2)C(C(O)=O)=N1 Chemical compound CC1=CN(CC2=CC=CC=C2)C(C(O)=O)=N1 YFRNSZULRBZDAD-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- GHOTUGPXTBJWOS-UHFFFAOYSA-N OC(C1=NC=C(C2=CC=CC=C2)N1CC1=CC=CC=C1)=O Chemical compound OC(C1=NC=C(C2=CC=CC=C2)N1CC1=CC=CC=C1)=O GHOTUGPXTBJWOS-UHFFFAOYSA-N 0.000 description 4
- BUFSTLRXNJYVJX-UHFFFAOYSA-N OC(C1=NC=C(C2CC2)N1CC1=CC=CC=C1)=O Chemical compound OC(C1=NC=C(C2CC2)N1CC1=CC=CC=C1)=O BUFSTLRXNJYVJX-UHFFFAOYSA-N 0.000 description 4
- JIVPUZALEKAWPV-UHFFFAOYSA-N OC(C1=NC=CN1CC(C1=CC=CC=C1)=O)=O Chemical compound OC(C1=NC=CN1CC(C1=CC=CC=C1)=O)=O JIVPUZALEKAWPV-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 125000005605 benzo group Chemical group 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- CLOMRRFEJDGMBE-UHFFFAOYSA-N 1-benzyl-5-cyclopropylimidazole Chemical compound C1=NC=C(C2CC2)N1CC1=CC=CC=C1 CLOMRRFEJDGMBE-UHFFFAOYSA-N 0.000 description 3
- XEZPQNRXMLVHHC-UHFFFAOYSA-N 1-benzyl-5-methylimidazole-2-carboxylic acid Chemical compound CC1=CN=C(C(O)=O)N1CC1=CC=CC=C1 XEZPQNRXMLVHHC-UHFFFAOYSA-N 0.000 description 3
- KNXKLFHJIFGYMG-UHFFFAOYSA-N 5-benzyl-1,3-oxazole-4-carboxylic acid Chemical compound N1=COC(CC=2C=CC=CC=2)=C1C(=O)O KNXKLFHJIFGYMG-UHFFFAOYSA-N 0.000 description 3
- HVKBEODEJZOBGK-UHFFFAOYSA-N 5-benzyl-1,3-thiazole-4-carboxylic acid Chemical compound N1=CSC(CC=2C=CC=CC=2)=C1C(=O)O HVKBEODEJZOBGK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HKSGRTUCPFVDKP-UHFFFAOYSA-N CC(CN1C(C(O)=O)=NC=C1)C1=CC=CC=C1 Chemical compound CC(CN1C(C(O)=O)=NC=C1)C1=CC=CC=C1 HKSGRTUCPFVDKP-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
- 102000006635 beta-lactamase Human genes 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 3
- UDWGOYHXWHWLAW-UHFFFAOYSA-N 1-benzyl-4-phenylimidazole Chemical compound C1=NC(C=2C=CC=CC=2)=CN1CC1=CC=CC=C1 UDWGOYHXWHWLAW-UHFFFAOYSA-N 0.000 description 2
- BUKITYALZCIHTM-UHFFFAOYSA-N 1-benzyl-5-methylimidazole Chemical compound CC1=CN=CN1CC1=CC=CC=C1 BUKITYALZCIHTM-UHFFFAOYSA-N 0.000 description 2
- SXVRSCIZJBGJGB-UHFFFAOYSA-N 1-chloropropan-2-ylbenzene Chemical compound ClCC(C)C1=CC=CC=C1 SXVRSCIZJBGJGB-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 2
- NJWIMFZLESWFIM-UHFFFAOYSA-N 2-(chloromethyl)pyridine Chemical compound ClCC1=CC=CC=N1 NJWIMFZLESWFIM-UHFFFAOYSA-N 0.000 description 2
- GBMGBPADBDLEKL-UHFFFAOYSA-N 2-[(6-chloro-1h-benzimidazol-2-yl)sulfanyl]acetic acid Chemical compound C1=C(Cl)C=C2NC(SCC(=O)O)=NC2=C1 GBMGBPADBDLEKL-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 2
- 108020004256 Beta-lactamase Proteins 0.000 description 2
- CXQXLYKHHWPHHF-UHFFFAOYSA-N CCOC(=O)C1=NC=CN1C(C)C2=CC=CC=C2 Chemical compound CCOC(=O)C1=NC=CN1C(C)C2=CC=CC=C2 CXQXLYKHHWPHHF-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 125000005997 bromomethyl group Chemical group 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- SYBQNCMETFYWLO-UHFFFAOYSA-N methyl 2-amino-5-benzyl-1,3-thiazole-4-carboxylate Chemical compound N1=C(N)SC(CC=2C=CC=CC=2)=C1C(=O)OC SYBQNCMETFYWLO-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052717 sulfur Chemical group 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 239000001815 (2R)-2-phenylpropan-1-ol Substances 0.000 description 1
- 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 description 1
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- IXRPSXPLZBCCLC-UHFFFAOYSA-N 1-benzyl-4-methylimidazole Chemical compound C1=NC(C)=CN1CC1=CC=CC=C1 IXRPSXPLZBCCLC-UHFFFAOYSA-N 0.000 description 1
- KKKDZZRICRFGSD-UHFFFAOYSA-N 1-benzylimidazole Chemical compound C1=CN=CN1CC1=CC=CC=C1 KKKDZZRICRFGSD-UHFFFAOYSA-N 0.000 description 1
- CRRUGYDDEMGVDY-UHFFFAOYSA-N 1-bromoethylbenzene Chemical compound CC(Br)C1=CC=CC=C1 CRRUGYDDEMGVDY-UHFFFAOYSA-N 0.000 description 1
- RNDNSYIPLPAXAZ-UHFFFAOYSA-N 2-Phenyl-1-propanol Chemical compound OCC(C)C1=CC=CC=C1 RNDNSYIPLPAXAZ-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- BNFGUBCFRVUHJH-UHFFFAOYSA-N 5-cyclopropyl-1h-imidazole Chemical compound C1CC1C1=CNC=N1 BNFGUBCFRVUHJH-UHFFFAOYSA-N 0.000 description 1
- JYKNMRPMJXDBJS-UHFFFAOYSA-N 5-methyl-imidazole-2-carboxylic acid Chemical compound CC1=CN=C(C(O)=O)N1 JYKNMRPMJXDBJS-UHFFFAOYSA-N 0.000 description 1
- XHLKOHSAWQPOFO-UHFFFAOYSA-N 5-phenyl-1h-imidazole Chemical compound N1C=NC=C1C1=CC=CC=C1 XHLKOHSAWQPOFO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- HWPJEXOZOQKYME-UHFFFAOYSA-N C[N+]#[C-].CC(O)=O Chemical compound C[N+]#[C-].CC(O)=O HWPJEXOZOQKYME-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- LHPXYPROPRFEQE-UHFFFAOYSA-N Methylhalfordinol Chemical compound C1=CC(OC)=CC=C1C1=CN=C(C=2C=NC=CC=2)O1 LHPXYPROPRFEQE-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- MBGFFORFAAAGMB-UHFFFAOYSA-N N1=CSC(CC=2C=CC=CC=2)=C1C(=O)OC Chemical compound N1=CSC(CC=2C=CC=CC=2)=C1C(=O)OC MBGFFORFAAAGMB-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- SMOBCLHAZXOKDQ-ZJUUUORDSA-N [(2s,5r)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl] hydrogen sulfate Chemical compound O=C([C@H]1N2C[C@@](CC1)(N(C2=O)OS(O)(=O)=O)[H])NC1CCNCC1 SMOBCLHAZXOKDQ-ZJUUUORDSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical group 0.000 description 1
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960002379 avibactam Drugs 0.000 description 1
- NDCUAPJVLWFHHB-UHNVWZDZSA-N avibactam Chemical compound C1N2[C@H](C(N)=O)CC[C@@]1([H])N(OS(O)(=O)=O)C2=O NDCUAPJVLWFHHB-UHNVWZDZSA-N 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 229960003324 clavulanic acid Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- IKHCKQVOPBTOEG-UHFFFAOYSA-N ethyl 1-benzylimidazole-2-carboxylate Chemical compound CCOC(=O)C1=NC=CN1CC1=CC=CC=C1 IKHCKQVOPBTOEG-UHFFFAOYSA-N 0.000 description 1
- HKTCARWISGVHPQ-UHFFFAOYSA-N ethyl 5-benzyl-1,3-oxazole-4-carboxylate Chemical compound N1=COC(CC=2C=CC=CC=2)=C1C(=O)OCC HKTCARWISGVHPQ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229940042040 innovative drug Drugs 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- HKMLRUAPIDAGIE-UHFFFAOYSA-N methyl 2,2-dichloroacetate Chemical compound COC(=O)C(Cl)Cl HKMLRUAPIDAGIE-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940041009 monobactams Drugs 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- XBRSNMYZHZKDSW-UHFFFAOYSA-N n-(4-hydroxyphenyl)thiophene-2-carboxamide Chemical compound C1=CC(O)=CC=C1NC(=O)C1=CC=CS1 XBRSNMYZHZKDSW-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 229940100595 phenylacetaldehyde Drugs 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229950011310 relebactam Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
- 229960005256 sulbactam Drugs 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 description 1
- 229960003865 tazobactam Drugs 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明属于药物化学领域,具体涉及一种咪唑-2-羧酸类金属β-内酰胺酶抑制剂及其制备方法和用途。
背景技术
β-内酰胺类抗生素具有杀菌活性强、毒性低、适应症广及临床疗效好等优点,在抗菌药物中一直占据非常重要的位置。临床最常用的β-内酰胺类抗生素主要有青霉素、头孢菌素类、碳青霉烯类、单环β-内酰胺类等。然而,近年来细菌对该类药物的耐药性不断增加,严重影响了此类药物的疗效。β-内酰胺酶按Ambler分类法分为A、B、C、D四类,其中A、C、D类活性中心因包含重要的丝氨酸,而被称为丝氨酸β-内酰胺酶(SBLs);B类活性中心均具有一个或两个锌离子,因此被称为金属β-内酰胺酶(MBLs)。致病菌产生的丝氨酸β-内酰胺酶和金属β-内酰胺酶可水解抗生素化学结构中四元β-内酰胺环,破坏抗生素关键药效团结构,从而使抗生素失效,是目前最主要的耐药机制。β-内酰胺酶抑制剂与β-内酰胺类抗生素联用是克服细菌耐药的主要方法之一,其原理是β-内酰胺酶抑制剂阻止酶对β-内酰胺类抗生素的水解,从而使抗生素发挥其原有的抗菌作用。目前已有6种SBL抑制剂,包括克拉维酸、舒巴坦、他唑巴坦、阿维巴坦、Vaborbactam和Relebactam,陆续被批准分别与多种β-内酰胺类抗生素联用,来增加β-内酰胺类抗生素对耐药菌的抗菌活性,克服β-内酰胺类抗生素耐药性问题。然而,这些靶向SBL的药物分子对表达MBL的耐药菌几乎无效。
近些年产MBL耐药菌不断地出现和蔓延,且几乎对所有β-内酰胺类抗生素耐药,已威胁到全球人类的生命健康。尽管目前已经报道了大量的MBL抑制剂,且部分抑制剂也表现较好的体外和体内活性,但截至目前仍无MBL抑制剂被批准用于临床,且鲜有进入临床研究的药物。因此,目前亟待研发更多高活性且具有成药性的MBL抑制剂,为靶向MBL克服抗生素耐药的创新药物研究提供候选化合物。
本发明的申请人前期公开了一种1-取代-1H-咪唑-2-羧酸类化合物及其作为金属β-内酰胺酶抑制剂的用途(参见申请号为202010121054.9的中国专利申请)。该申请公开了化合物1-苄基-1H-咪唑-2-羧酸,该化合物对MBLs具有较好的抑制活性,特别是对于VIM-2,其IC50值达到0.48μM。但是,该化合物对MBLs的抑制活性还无法满足实际需求,需要开发出对MBLs具有更高的抑制活性的药物。
发明内容
本发明的目的在于提供一种咪唑-2-羧酸类金属β-内酰胺酶抑制剂及其制备方法和用途。
本发明提供了种式I所示化合物、或其盐、或其立体异构体、或其晶型、或其溶剂合物、或其氘代物:
其中,X为无或C1~3亚烷基;
B环为苯环或噻吩环;
Ra为氢或YRd,Y为无或C1~3亚烷基,Rd选自5~6元芳环、5~6元杂芳环;
Rb为氢或WRe,W为无或C1~3亚烷基,Re选自5~6元芳环、5~6元杂芳环;
m为0~5的整数,Rc独立的选自氢、卤素、硝基、5~6元芳环、5~6元杂芳环;或者,m为2,且2个Rc连接成环;
进一步地,所述化合物的结构如式II所示:
其中,X为无或C1~3亚烷基;
Ra为氢或YRd,Y为无或C1~3亚烷基,Rd选自5~6元芳环、5~6元杂芳环;
Rb为氢或WRe,W为无或C1~3亚烷基,Re选自5~6元芳环、5~6元杂芳环;
m为0~5的整数,Rc独立的选自氢、卤素、硝基、5~6元芳环、5~6元杂芳环;或者,m为2,且2个Rc连接成环。
进一步地,所述化合物的结构如式III所示:
其中,Ra、Rb上所述;
A环为5~6元芳基、5~6元杂芳基;
n为0~3的整数;
Rf独立的选自氢、氨基、羟基、C1~5烷基、C1~5烷氧基。
进一步地,所述化合物的结构如式IV所示:
其中,Rf选自氢、氨基、羟基、C1~3烷基、C1~3烷氧基。
进一步地,所述化合物的结构如式IV所示:
其中,X为无或亚甲基;
进一步地,所述化合物的结构如式V所示:
其中,m为0~5的整数,Rc独立的选自氢、卤素。进一步地,所述化合物的结构选自:
本发明还提供了一种金属β-内酰胺酶抑制剂,所述金属β-内酰胺酶抑制剂是以上述化合物、或其盐、或其立体异构体、或其晶型、或其溶剂合物、或其氘代物为活性成分,加上药学上可接受的辅料制成的制剂。
本发明还提供了上述化合物、或其盐、或其立体异构体、或其晶型、或其溶剂合物、或其氘代物在制备金属β-内酰胺酶抑制剂中的用途;优选地,所述金属β-内酰胺酶为VIM-2、NDM-1、IMP-1、VIM-1或VIM-5。
本发明还提供了一种抗菌的联合用药物,它含有相同或者不同规格的同时或者分别给药的上述化合物、或其盐、或其立体异构体、或其晶型、或其溶剂合物、或其氘代物和抗菌药物,以及药学上可接受的载体;
优选地,所述抗菌药物为β-内酰胺类抗生素,所述β-内酰胺类抗生素优选为美罗培南。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~b烷基表示任何含“a”至“b”个碳原子的烷基。例如,C1~5烷基是指包含1~5个碳原子的直链或支链的烷基。例如,C1~3亚烷基是指包含1~3个碳原子的直链或支链的亚烷基,包括亚甲基、亚乙基、亚丙基。
“芳环”指具有共轭的π电子体系的全碳单环或稠合多环,例如苯和萘。所述芳环可以稠合于其它环状结构(包括饱和、不饱和环),但不能含有杂原子如氮、氧或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。
“杂芳环”指包含一个到多个杂原子的具有共轭的π电子体系的单环或稠合多环。含有至少一个选自N、O或S的环杂原子,其余环原子是C,另外具有完全共轭的π电子系统。例如呋喃、吡咯、喹啉、噻吩、吡啶、吡唑、N-烷基吡咯、嘧啶、吡嗪、咪唑、四唑、噻吩并吡啶基等。所述杂芳环可以稠合于芳环、杂环或烷烃环上。
卤素氟、氯、溴或碘。
氘代物指化合物中的一个或两个以上的氢原子被氘替换后得到的化合物。
本发明式I所示结构中,当m为2,且2个Rc连接成环时,所述的环包括未取代或取代的环。
实验结果表明,本发明提供的化合物对金属β-内酰胺酶具有良好的抑制效果。特别地,与化合物1相比,化合物3、5、13、18、17-a~19-a、22-a、24-a~26-a、29-a、30-a、34-a、36-a、37-a对MBL酶VIM-2的抑制效果显著提高。本发明的化合物能够用于制备金属β-内酰胺酶抑制剂,应用前景广阔。
此外,本发明的化合物能够逆转耐药工程菌对美罗培南的耐药性,能够逆转耐药临床分离菌株对美罗培南的耐药性,显著提高美罗培南的抗菌效果。本发明化合物与抗菌药物美罗培南联用能够显著提高美罗培南对耐药菌的抗菌效果,在制备联合用抗菌药物中具有良好的应用前景。
本发明化合物的制备方法简单,适合工业化生产。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为化合物3的1H-NMR(400MHz,DMSO-d6)谱图。
图2为化合物3的13C-NMR(101MHz,DMSO-d6)谱图。
图3为化合物5的1H-NMR(400MHz,DMSO-d6)谱图。
图4为化合物5的13C-NMR(101MHz,DMSO-d6)谱图。
图5为化合物13的1H-NMR(400MHz,DMSO-d6)谱图。
图6为化合物18的HRMS谱图。
图7为化合物28的1H-NMR(400MHz,DMSO-d6)谱图。
图8为化合物28的13C-NMR(101MHz,DMSO-d6)谱图。
图9为化合物28的HRMS谱图。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
实施例1:1-苄基-1H-咪唑-2-羧酸(1)的合成
将1H-咪唑-2-羧酸乙酯(300mg,2.14mmol)溶于15mL N,N-二甲基甲酰胺中,加入碳酸铯(1392mg,4.29mmol)和溴化苄(500mg,3.21mmol),在常温下反应5h,TLC检测反应完全,停止反应,加水溶解,EA萃取(3×40mL),合并有机层,经饱和食盐水洗涤、无水硫酸钠干燥后,过滤浓缩得粗品。经柱层析纯化(PE:EA=4:1)得无色液体化合物1-苄基-1H-咪唑-2-羧酸乙酯400mg,yield 77%。
将化合物1-苄基-1H-咪唑-2-羧酸乙酯(400mg,1.64mmol)溶于20mL EtOH:H2O=2:1的混合溶剂中,搅拌下加入氢氧化钠(131mg,3.28mmol),加毕,常温反应1h,TLC检测反应完全,停止反应,3N HCl调pH至7-8左右,减压浓缩后经柱层析纯化(DCM:MeOH=10:1)得白色固体(1)320mg,yield 90%,purity 98%。1H NMR(400MHz,DMSO-d6)δ7.34-7.28(m,6H),6.69(s,1H),5.75(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ138.29,137.87,129.13,129.10,128.17,127.91,120.05,49.93ppm.HRMS:m/z calcd for C11H10N2O2[M+H]+203.0815,found 203.0818.
实施例2:1-(4-氰基苄基)-1H-咪唑-2-羧酸(2)的合成
该化合物的第一步参照化合物1的合成,第二步将1-(4-氰基苄基)-1H-咪唑-2-羧酸乙酯(60mg,0.24mmol)溶于20mL EtOH:H2O=2:1的混合溶剂中,搅拌下加入氢氧化锂(20mg,0.47mmol),加毕,常温反应1h,TLC检测反应完全,停止反应,3N HCl调pH至7-8左右,减压浓缩后经柱层析纯化(DCM:MeOH=10:1)得1-(4-氰基苄基)-1H-咪唑-2-羧酸(2)白色固体40mg,yield 75%,purity 96%。1H NMR(400MHz,DMSO-d6)δ7.77(d,J=8.0Hz,2H),7.39(d,J=6.4Hz,3H),6.70(s,1H),5.83(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ144.35,133.91,133.27,133.02,128.70,119.14,110.74,50.01ppm.HRMS:m/z calcd for C12H9N3O2[M+H]+228.0768,found 228.0761.
该化合物参照化合物1的合成,得1-(3,4-二氯苄基)-1H-咪唑-2-羧酸(3)白色固体270mg,yield 80%,purity 96%。1H NMR(400MHz,DMSO-d6)δ7.54-7.52(m,2H),7.25(dd,J=8.4Hz,J=2.0Hz,1H),7.22(s,1H),6.83(s,1H),5.77(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ162.51,145.30,140.78,139.48,137.98,131.35,130.97,130.25,130.01,129.40,128.38,126.91,122.52,120.01,49.08,48.58ppm.HRMS:m/z calcd for C12H8Cl2N2O2[M+H]+271.0036,found 271.0013.
实施例4:1-(3,4-二氟苄基)-1H-咪唑-2-羧酸(4)的合成
该化合物参照化合物1的合成,得1-(3,4-二氟苄基)-1H-咪唑-2-羧酸(4)白色固体200mg,yield 85%,purity 97%。1H NMR(400MHz,DMSO-d6)δ7.82(s,1H),7.50-7.37(m,2H),7.23(s,1H),7.15-7.12(m,1H),6.94(s,1H),5.20(s,2H)ppm.HRMS:m/z calcd forC11H8F2N2O2[M+H]+239.0627,found 239.0631.
该化合物参照化合物1的合成,得1-(3,5-二溴苄基)-1H-咪唑-2-羧酸(5)白色固体340mg,yield 90%,purity 95%。1H NMR(400MHz,DMSO-d6)δ7.72(t,J=1.6Hz,1H),7.51-7.49(m,2H),7.28(s,1H),6.85(s,1H),5.77(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ162.09,145.20,144.33,143.04,138.04,133.14,132.61,130.03,129.97,129.47,126.79,123.13,122.84,122.66,120.06,49.07,48.49ppm.
实施例6:1-(吡啶-2-基甲基)-1H-咪唑-2-羧酸(6)的合成
将吡啶-2-基甲醇(200mg,1.83mmol)溶于10mL干燥的二氯甲烷中,在常温搅拌下加入二氯亚砜(650mg,5.50mmol),加毕升温至60℃反应5h,TLC检测反应完全,停止反应,减压蒸干溶剂得2-(氯甲基)吡啶粗品。用N,N-二甲基甲酰胺8mL溶解2-(氯甲基)吡啶粗品,加入1H-咪唑-2-羧酸乙酯(205mg,1.46mmol)和碳酸铯(650mg,3.66mmol)升温至80℃反应2h,TLC检测反应完全,停止反应,加水溶解,EA萃取(3×40mL),合并有机层,经饱和食盐水洗涤、无水硫酸钠干燥后,过滤浓缩得粗品。经柱层析纯化(PE:EA=1:2)得无色透明油状液体化合物(6a)280mg,yield 60%。
将6a水解,参照化合物1的水解,得1-(吡啶-2-基甲基)-1H-咪唑-2-羧酸(6)白色固体120mg,yield 85%,purity 95%。1H NMR(400MHz,DMSO-d6)δ8.54(d,J=4.8Hz,1H),7.77(s,1H),7.34-7.32(m,1H),7.21(s,1H),7.15(d,J=7.6Hz,1H),6.93(s,1H),5.30(s,2H)ppm.HRMS:m/z calcd for C10H9N3O2[M-H]-202.0622,found 202.0610.
实施例7:1-((2-甲基吡啶-3-基)甲基)-1H-咪唑-2-羧酸(7)的合成
该化合物参照化合物6的合成,得1-((2-甲基吡啶-3-基)甲基)-1H-咪唑-2-羧酸(7)白色固体180mg,yield 80%,purity 95%。1H NMR(400MHz,DMSO-d6)δ8.38(dd,J=4.8Hz,J=1.6Hz,1H),7.78(s,1H),7.44(d,J=4.4Hz,1H),7.41-7.39(m,1H),7.22(s,1H),6.96(s,1H),5.33(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ162.09,145.20,144.33,143.04,138.04,133.14,132.61,130.03,129.97,129.47,126.79,123.13,122.84,122.66,120.06,49.07,48.49ppm.HRMS:m/z calcd for C10H8ClN3O2[M+H]+238.0378,found 238.0374.
实施例8:1-(噻吩-3-基甲基)-1H-咪唑-2-羧酸(8)的合成
该化合物参照化合物6的合成,得1-(噻吩-3-基甲基)-1H-咪唑-2-羧酸(8)白色固体160mg,yield 82%,purity 95%。1H NMR(400MHz,DMSO-d6)δ7.73(s,1H),7.53-7.50(m,1H),7.40(s,1H),7.19(s,1H),7.05(d,J=4.8Hz,1H),6.89(s,1H),5.18(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ138.47,137.62,127.81,127.31,123.91,123.20,120.01,45.20ppm.HRMS:m/z calcd for C9H8N2O2S[M-H]-207.0234,found 207.0215.
实施例9:1-(呋喃-3-基甲基)-1H-咪唑-2-羧酸(9)的合成
该化合物参照化合物6的合成,得1-(呋喃-3-基甲基)-1H-咪唑-2-羧酸(9)无色透明液体100mg,yield 75%,purity 97%。1H NMR(400MHz,DMSO-d6)δ7.69-7.86(m,2H),7.17(s,1H),6.89(s,1H),6.47(s,1H),5.03(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ144.41,141.24,137.54,128.99,122.34,119.75,110.83,41.01ppm.
实施例10:1-((4-溴噻吩-2-基)甲基)-1H-咪唑-2-羧酸(10)的合成
该化合物参照化合物6的合成,得1-((4-溴噻吩-2-基)甲基)-1H-咪唑-2-羧酸(10)白色固体120mg,yield 81%,purity 95%。1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.61(d,J=1.2Hz,1H),7.54(d,J=1.6Hz,1H),7.32(s,1H),7.22(s,1H),7.14(d,J=4.4Hz,2H),6.90(s,1H),6.89(s,1H),5.90(s,2H),5.40(s,2H)ppm.HRMS:m/z calcd forC9H7BrN2O2S[M–H]-284.9339,found 284.9305and 286.9284.
实施例11:1-((5-氯噻吩-2-基)甲基)-1H-咪唑-2-羧酸(11)的合成
该化合物参照化合物6的合成,得1-((5-氯噻吩-2-基)甲基)-1H-咪唑-2-羧酸(11)白色固体115mg,yield 82%,purity 95%。1H NMR(400MHz,DMSO-d6)δ7.74(s,1H),7.43(s,1H),7.21(s,1H),7.07(s br,1H),7.02(m,2H),6.96(d,J=3.6Hz,1H),6.90(s,1H),5.83(s,2H),5.35(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ158.17,139.89,139.05,137.56,129.46,129.19,128.63,128.27,127.30,126.75,124.04,123.78,119.73,45.94,44.62ppm.HRMS:m/z calcd for C9H7ClN2O2S[M+H]+242.9990,found 242.9989.
实施例12:1-((1-甲基-1H-吡唑-4-基)甲基)-1H-咪唑-2-羧酸(12)的合成
该化合物参照化合物6的合成,得1-((1-甲基-1H-吡唑-4-基)甲基)-1H-咪唑-2-羧酸(12)白色固体80mg,yield 95%,purity 95%。1H NMR(400MHz,DMSO-d6)δ7.69(s,2H),7.42(s,1H),7.15(s,1H),6.87(s,1H),5.02(s,2H),3.79(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ138.57,137.23,130.44,128.56,119.69,117.69,40.70,38.95ppm.HRMS:m/z calcdfor C9H7ClN2O2S[M+H]+242.9990,found 242.9990.
实施例13:1-((2-氨基苯并[d]噻唑-6-基)甲基)-1H-咪唑-2-羧酸(13)的合成
将6-甲基苯并[d]噻唑-2-胺(500mg,3.05mmol)和4-二甲氨基吡啶(74mg,0.61mmol)溶于15mL二氯甲烷中,在常温下加入二碳酸二叔丁酯(1995mg,9.15mmol),加毕,常温反应1h,TLC检测反应完全,停止反应,减压蒸干二氯甲烷,过柱层析纯化(PE:EA=80:1)得700mg(6-甲基苯并[d]噻唑-2-基)氨基甲酸叔丁酯白色固体;第二步将700mg(6-甲基苯并[d]噻唑-2-基)氨基甲酸叔丁酯,N-溴代琥珀酰亚胺(707mg,3.99mmol)和偶氮二异丁腈(84mg,0.53mmol)溶于20mL四氯化碳中,升温至80℃搅拌6h,TLC检测反应完全,停止反应,减压蒸干四氯化碳,过柱层析纯化(PE:EA=80:1)得(6-(溴甲基)苯并[d]噻唑-2-基)氨基甲酸叔丁酯白色固体350mg;第三步将(6-(溴甲基)苯并[d]噻唑-2-基)氨基甲酸叔丁酯(200mg,0.58mmol)和1H-咪唑-2-羧酸乙酯(65mg,0.46mmol)溶于15mL N,N-二甲基甲酰胺中,加入碳酸铯(337mg,1.16mmol),在常温下反应5h,TLC检测反应完全,停止反应,加水溶解,EA萃取(3×40mL),合并有机层,经饱和食盐水洗涤、无水硫酸钠干燥后,过滤浓缩得粗品。经柱层析纯化(PE:EA=4:1)得白色固体化合物1-((2-((叔丁氧基羰基)氨基)苯并[d]噻唑-6-基)甲基)-1H-咪唑-2-羧酸乙酯200mg,yield 86%;第四步将1-((2-((叔丁氧基羰基)氨基)苯并[d]噻唑-6-基)甲基)-1H-咪唑-2-羧酸乙酯200mg溶于10mL二氯甲烷中,在常温下加入二氯甲烷体积40%的三氟乙酸,常温搅拌3h,TLC检测反应完全,停止反应,减压蒸干溶剂,过柱层析纯化(PE:EA=5:1)得1-((2-氨基苯并[d]噻唑-6-基)甲基)-1H-咪唑-2-羧酸乙酯(13a)白色固体120mg,yield 80%。
将13a水解,参照化合物1的水解步骤,得1-((2-氨基苯并[d]噻唑-6-基)甲基)-1H-咪唑-2-羧酸(13)白色固体100mg,yield 90%,purity 95%。1H NMR(400MHz,DMSO-d6)δ7.61(d,J=1.2Hz,1H),7.48(m,2H),7.25-7.21(m,2H),7.15(s,1H),6.77(s,1H),5.97(sbr,1H),5.77(s,2H)ppm.
实施例14:1-((2-氨基苯并[d]噻唑-4-基)甲基)-1H-咪唑-2-羧酸(14)的合成
该化合物参照化合物13的合成,得1-((2-氨基苯并[d]噻唑-4-基)甲基)-1H-咪唑-2-羧酸(14)白色固体80mg,yield 87%,purity 95%。1H NMR(400MHz,DMSO-d6)δ7.75(s,2H),7.62-7.57(m,1H),7.22(s,1H),6.97-6.96(m,1H),6.88(s,1H),5.97(s br,1H),5.37(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ167.42,151.29,137.97,131.49,128.72,126.78,125.07,121.23,121.07,120.24,47.28ppm.HRMS:m/z calcd for C12H10N4O2S[M-H]-275.0597,found 275.0597.
实施例15:1-((3-甲基-4-(2,2,2-三氟乙氧基)吡啶-2-基)甲基)-1H-咪唑-2-羧酸(15)的合成
该化合物参照化合物6的合成,得1-((3-甲基-4-(2,2,2-三氟乙氧基)吡啶-2-基)甲基)-1H-咪唑-2-羧酸(15)淡黄色固体300mg,yield 84%,purity 97%。1H NMR(400MHz,DMSO-d6)δ8.31(d,J=5.6Hz,1H),8.18(d,J=5.6Hz,1H),7.49(d,J=1.6Hz,1H),7.34(d,J=1.6Hz,1H),5.93(s,2H),5.32(s,2H),4.91(qd,J=8.8,3.8Hz,4H),2.19(s,3H).HRMS:m/z calcd for C13H12F3N3O3[M-H]-314.0753,found 314.0758.
实施例16:1-((4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基)甲基)-1H-咪唑-2-羧酸(16)的合成
该化合物参照化合物6的合成,得1-((4-(3-甲氧基丙氧基)-3-甲基吡啶-2-基)甲基)-1H-咪唑-2-羧酸(16)淡黄色油状液体300mg,yield 81%,purity 95%。1H NMR(400MHz,DMSO-d6)δ8.48(d,J=5.2Hz,1H),7.74(d,J=5.6Hz,1H),7.35(d,J=1.4Hz,1H),7.14(d,J=1.4Hz,1H),5.32(s,2H),5.32(s,2H),4.29(m,2H),3.35(m,2H),3.23(s,3H),2.39(s,3H),2.00(m,2H).HRMS:m/z calcd for C15H19N3O4[M-H]-305.1374,found305.1366.
实施例17:1-苄基-4-苯基-1H-咪唑-2-羧酸(17)的合成
第一步将4-苯基-1H-咪唑(200mg,1.85mmol)溶于10mL乙腈中,加入碳酸铯(1203mg,3.70mmol)和溴化苄(380mg,2.22mmol),在常温下反应15min,TLC检测反应完全,停止反应,减压蒸干有机溶剂,加水用EA萃取(3×40mL),合并有机层,经饱和食盐水洗涤、无水硫酸钠干燥后,过滤浓缩得粗品。经柱层析纯化(PE:EA=1:1)得无色透明油状液体化合物1-苄基-4-苯基-1H-咪唑(8a)100mg,yield 27%;第二步将1-苄基-4-苯基-1H-咪唑(600mg,3.03mmol)溶于10mL氯甲酸乙酯中,并在冰浴下缓慢滴加三乙胺直至氯甲酸乙酯全部反应完全变为固体,TLC监测反应,若原料未反应完全则再加氯甲酸乙酯溶解,在冰浴下滴加三乙胺,此步骤反复TLC监测原料基本反应完全,加水稀释用EA萃取(3×40mL),合并有机层,经柱层析纯化(PE:EA=6:1)得无色透明油状液体化合物1-苄基-4-环丙基-1H-咪唑-2-羧酸乙酯(17a)200mg,yield 25%。
将17a水解,参照化合物1的水解,得1-苄基-4-苯基-1H-咪唑-2-羧酸(17)白色固体150mg,yield 83%,purity 95%。1H NMR(400MHz,DMSO-d6)δ7.82-7.68(m,3H),7.38-7.17(m,9H),5.75(s,2H)ppm.HRMS:m/z calcd for C17H14N2O2[M+H]+279.1134,279.1128.
实施例18:1-苄基-5-苯基-1H-咪唑-2-羧酸(18)的合成
将1-苄基-1H-咪唑(50mg,0.32mmol)、溴苯(99mg,0.63mmol)、三(2-呋喃)磷化氢(8mg,0.032mmol)、碳酸钾(44mg,0.32mmol)、醋酸钯(4mg,0.016mmol)置于三颈瓶中,充入氩气保护,加入N,N-二甲基乙酰胺5mL溶解,升温至150℃反应5h,TLC检测反应,原料基本反应完全,停止反应,加水溶解,EA萃取(3×40mL),合并有机层,经饱和食盐水洗涤、无水硫酸钠干燥后,过滤浓缩得粗品。经柱层析纯化(PE:EA=1:1)得棕色油状液体化合物30mg,yield 40%.
最后两步与化合物17合成路线相同,参考化合物17的合成,得到1-苄基-5-苯基-1H-咪唑-2-羧酸(18)15mg,yield 80%,purity 96%。HRMS:m/z calcd for C17H14N2O2[M+H]+279.1134,found 279.1128.
该化合物参照化合物17的合成,得1-苄基-4-环丙基-1H-咪唑-2-羧酸(19)白色固体10mg,yield 80%,purity 95%。1H NMR(400MHz,DMSO-d6)δ7.55(d,J=0.8Hz,1H),7.38-7.34(m,2H),7.32-7.28(m,2H),7.26-7.23(m,2H),6.87(d,J=1.2Hz,1H),1.76-1.71(m,1H),0.73-0.69(m,2H),0.60-0.56(m,2H)ppm.HRMS:m/z calcd for C14H14N2O2[M+H]+243.1128,found 243.1153.
实施例20:1-苄基-5-环丙基-1H-咪唑-2-羧酸(20)的合成
将5-环丙基-1H-咪唑(500mg,4.60mmol)溶于15mL四氢呋喃中,依次加入N-甲基二环己基胺(1083mg,5.56mmol)和2-(三甲基硅烷基)乙氧甲基氯(SEM-Cl)(928mg,5.56mmol),常温搅拌2h,TLC检测反应完全,停止反应,减压蒸干有机溶剂,出现分层现象,收集下层得到5-环丙基-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑粗品;接着将5-环丙基-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑粗品溶于10mL乙腈中,升温至80℃反应3h,TLC检测反应完全,停止反应,减压蒸干有机溶剂,过柱层析纯化(PE:EA=1:1)得无色透明油状液体化合物1-苄基-5-环丙基-1H-咪唑;然后将1-苄基-5-环丙基-1H-咪唑置于三颈瓶中,充入氩气保护,加入四丁基氟化铵的四氢呋喃溶液(1.0M/L)10mL,升温至80℃回流反应2h,脱去保护基SEM,暴露出3-位氮原子,得到化合物1-苄基-5-环丙基-1H-咪唑。
最后两步与化合物17合成路线相同,参考化合物17的合成,得到1-苄基-5-环丙基-1H-咪唑-2-羧酸(20)10mg,yield 80%,purity 96%。1H NMR(400MHz,DMSO-d6)δ7.66(s,1H),7.38-7.25(m,3H),7.17-7.09(m,2H),6.66-6.58(m,1H),5.95-5.90(m,1H),5.25(m,1H),1.55-1.50(m,1H),0.77-0.73(m,2H),0.45-0.42(m,2H)ppm.HRMS:m/z calcd forC14H14N2O2[M+H]+243.1128,found 243.1113.
实施例21:1-苄基-4-甲基-1H-咪唑-2-羧酸(21)的合成
将4-甲基-1H-咪唑(200mg,2.44mmol)溶于10mL乙腈中,加入碳酸铯(1586mg,4.88mmol)活化2h后加入溴化苄(501mg,2.93mmol),在常温下反应30h,TLC检测反应原料基本反应完全,停止反应,减压蒸干有机溶剂,加水用EA萃取(3×40mL),合并有机层,经饱和食盐水洗涤、无水硫酸钠干燥后,过滤浓缩得粗品。经柱层析纯化(PE:EA=4:1)得白色固体化合物1-苄基-4-甲基-1H-咪唑300mg,yield 71%;(PE:EA=2:1)得白色固体化合物1-苄基-5-甲基-1H-咪唑30mg,yield 7%。
最后两步与化合物17合成路线相同,参考化合物17的合成,得到1-苄基-4-甲基-1H-咪唑-2-羧酸(20)25mg,yield 83%,purity 97%。1H NMR(400MHz,DMSO-d6)δ7.28-7.22(m,5H),6.85(s,1H),5.75(s,2H),2.06(s,3H)ppm.13C NMR(101MHz,DMSO-d6)δ162.63,143.98,139.58,134.70,128.76,128.01,127.60,119.07,50.02,13.68ppm.HRMS:m/zcalcd for C12H12N2O2[M+H]+217.0977,found 217.0972.
实施例22:1-苄基-5-甲基-1H-咪唑-2-羧酸(22)的合成
将21合成中得到的1-苄基-5-甲基-1H-咪唑参照化合物17最后两步的做法可得到5-甲基-1H-咪唑-2-羧酸(20)10mg,yield 80%,purity 95%。1H NMR(400MHz,DMSO-d6)δ7.28-7.23(m,3H),7.04(s,2H),6.47-6.32(m,1H),5.82(s,2H),2.01(s,3H)ppm.
实施例23:1-丁烯-4-甲基-1H-咪唑-2-羧酸(23)的合成
该化合物参照化合物21的合成,得1-丁烯-4-甲基-1H-咪唑-2-羧酸(23)白色固体50mg,yield 87%,purity 96%。1H NMR(400MHz,DMSO-d6)δ6.87(s,1H),5.78-5.70(m,1H),5.02-4.95(m,2H),4.47(t,J=6.8Hz,2H),2.45-2.40(m,2H),2.06(d,J=6.8Hz,3H)ppm.HRMS:m/z calcd for C9H12N2O2[M+H]+181.0977,found 181.0972.
实施例24:1-丁烯-5-甲基-1H-咪唑-2-羧酸(24)的合成
该化合物参照化合物22的合成,得1-丁烯-5-甲基-1H-咪唑-2-羧酸(24)白色固体13mg,yield 80%,purity 96%。1H NMR(400MHz,DMSO-d6)δ7.67(s,1H),6.68(s,1H),5.82-5.73(m,1H),5.05-4.98(m,2H),4.49(s,1H),3.96(t,J=6.8Hz,1H),2.44-2.40(m,2H),2.20-2.17(m,3H)ppm.
实施例25:1-(1-苯乙基)-1H-咪唑-2-羧酸(25)的合成
将1H-咪唑-2-羧酸乙酯(300mg,2.14mmol)溶于15mL N,N-二甲基甲酰胺中,加入碳酸铯(1392mg,4.29mmol)和(1-溴乙基)苯(595mg,3.21mmol),在常温下反应5h,TLC检测反应完全,停止反应,加水溶解,EA萃取(3×40mL),合并有机层,经饱和食盐水洗涤、无水硫酸钠干燥后,过滤浓缩得粗品。经柱层析纯化(PE:EA=6:1)得无色液体化合物1-(1-苯乙基)-1H-咪唑-2-羧酸乙酯(25a)400mg,yield 77%。
最后一步酯水解参照化合物1的水解过程,得白色固体1-(1-苯乙基)-1H-咪唑-2-羧酸(25)320mg,yield 90%,purity 97%。1H NMR(400MHz,DMSO-d6)δ7.38–7.32(m,2H),7.29–7.25(m,5H),5.54(q,J=7.2Hz,1H),1.79(d,J=7.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ143.04,136.63,129.02,128.09,126.53,118.49,55.89,21.83.HRMS:m/z calcd forC12H12N2O2[M+H]+217.0977,found 217.0972.
实施例26:1-(1-苯丙基)-1H-咪唑-2-羧酸(26)的合成
该化合物参照化合物25的合成,得1-(1-苯丙基)-1H-咪唑-2-羧酸(26)白色固体130mg,yield 87%,purity 95%。1H NMR(400MHz,DMSO-d6)δ7.82(s,1H),7.39–7.25(m,6H),5.22(dd,J=9.0,6.8Hz,1H),2.20(dtt,J=33.4,13.8,7.0Hz,2H),0.80(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ141.83,136.95,129.05,128.17,127.13,118.26,62.42,49.07,28.06,11.43.HRMS:m/z calcd for C13H14N2O2[M+H]+231.1143,found 231.1128.
实施例27:1-(羧基(苯基)甲基)-1H-咪唑-2-羧酸(27)的合成
该化合物参照化合物25的合成,只是在酯水解时需要同时水解两个酯键,应适当增加氢氧化钠的当量,得1-(羧基(苯基)甲基)-1H-咪唑-2-羧酸(27)白色固体310mg,yield91%,purity 97%。1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.42(t,J=5.5Hz,4H),7.32(s,1H),7.03(s,1H),6.26(s,1H).
实施例28:1-苯乙基-1H-咪唑-2-羧酸(28)的合成
该化合物参照化合物25的合成,得1-苯乙基-1H-咪唑-2-羧酸(28)白色固体290mg,yield 90%,purity 96%。1H NMR(400MHz,DMSO-d6)δ7.24(tt,J=14.6,7.2Hz,5H),6.99(s,1H),6.72(s,1H),4.70–4.64(m,2H),3.04–2.98(m,2H).HRMS:m/z calcd forC12H12N2O2[M+H]+217.0977,found 217.0972.
实施例29:1-(2-苯丙基)-1H-咪唑-2-羧酸(29)的合成
将2-苯基丙-1-醇(200mg,1.47mmol)溶于10mL干燥的二氯甲烷中,在常温搅拌下加入二氯亚砜(875mg,7.35mmol),加毕升温至60℃反应5h,TLC检测反应完全,停止反应,减压蒸干溶剂得(1-氯丙烷-2-基)苯粗品。用8mL N,N-二甲基甲酰胺溶解(1-氯丙烷-2-基)苯粗品,加入1H-咪唑-2-羧酸乙酯(72mg,0.80mmol)和碳酸铯(211mg,0.64mmol)升温至80℃反应2h,TLC检测反应完全,停止反应,加水溶解,EA萃取(3×40mL),合并有机层,经饱和食盐水洗涤、无水硫酸钠干燥后,过滤浓缩得粗品。经柱层析纯化(PE:EA=1:2)得无色透明油状液体化合物1-(2-苯丙基)-1H-咪唑-2-羧酸乙酯(29a)25mg,yield 15%.
最后一步酯水解参照化合物1的水解过程,得无色油状液体20mg,yield85%,purity 96%.1H NMR(400MHz,DMSO-d6)δ7.44(s,1H),7.27–7.18(m,5H),7.05(s,1H),4.13(d,J=7.6Hz,2H),3.19(dd,J=14.4,7.2Hz,1H),1.16(d,J=7.0Hz,3H).HRMS:m/z calcdfor C13H14N2O2[M+H]+231.1134,found 231.1128.
实施例30:1-(2-氧代-2-苯乙基)-1H-咪唑-2-羧酸(30)的合成
将1H-咪唑-2-羧酸乙酯(200mg,1.43mmol)溶于10mL N,N-二甲基甲酰胺中,加入三乙胺(289mg,2.86mmol)和2-溴-1-苯基乙-1-酮(426mg,2.14mmol),在常温下反应5h,TLC检测反应完全,停止反应,加水溶解,EA萃取(3×40mL),合并有机层,经饱和食盐水洗涤、无水硫酸钠干燥后,过滤浓缩得粗品。经柱层析纯化(PE:EA=1:2)得无色透明油状液体化合物1-(2-氧代-2-苯基乙基)-1H-咪唑-2-羧酸乙酯(30a)210mg,yield 56%.最后一步酯水解参照化合物1的水解过程,得无色油状液体1-(2-氧代-2-苯乙基)-1H-咪唑-2-羧酸(30)195mg,yield 95%,purity 97%。1H NMR(400MHz,DMSO-d6)δ8.04(m,3H),7.62–7.56(m,3H),7.19(d,J=1.0Hz,1H),6.14(s,2H).13C NMR(101MHz,DMSO)δ194.01(s),161.59(s),144.82(s),138.83(s),135.39(s),134.07(s),129.31(s),128.36(s),125.23(s),124.29(s),121.40(s),54.82(s).HRMS:m/z calcd for C12H10N2O3[M+H]+231.0770,found231.764.
实施例31:1-(3-苯丙基)-1H-咪唑-2-羧酸(31)的合成
该化合物参照化合物25的合成,得1-(3-苯丙基)-1H-咪唑-2-羧酸(31)白色固体120mg,yield 90%,purity 97%。1H NMR(400MHz,DMSO-d6)δ7.64(s,1H),7.20(m,5H),6.91(s,1H),3.98(t,J=8.0Hz,2H),2.54(d,J=8.0Hz,2H),2.07–2.00(m,2H).HRMS:m/z calcdfor C13H14N2O2[M+H]+231.1128,found 231.1111.
实施例32:1-(2-苯氧基乙基)-1H-咪唑-2-羧酸(32)的合成
该化合物参照化合物25的合成,得1-(2-苯氧基乙基)-1H-咪唑-2-羧酸白色固体150mg,yield 90%,purity 96%。1H NMR(400MHz,DMSO-d6)δ7.44(s,1H),7.29(m,2H),7.24(m,3H),7.05(s,1H),4.13(d,J=8.0Hz,2H),3.25–3.12(m,1H),1.16(d,J=8.0Hz,3H).HRMS:m/z calcd for C12H12N2O3[M+H]+233.0921,found 231.1111.
实施例33:5-苄基恶唑-4-羧酸(33)的合成
在冰浴下向8mL叔丁醇钾的四氢呋喃溶液中(1.0M/L)缓慢滴加异腈基乙酸甲酯(175mg,1.56mmol),在冰浴中反应10min后,将2-苯基乙酰氯(200mg,1.30mmol)缓慢滴加进反应液中,加毕升至常温反应2h,TLC检测反应完全,停止反应,将反应液加入饱和氯化铵水溶液中,EA萃取(3×40mL),合并有机层,经柱层析纯化(PE:EA=2:1)得黄色透明油状液体化合物5-苄基恶唑-4-羧酸乙酯(2a)18mg,yield 6%.
最后一步酯水解参照化合物1的水解过程,得无色油状液体5-苄基恶唑-4-羧酸(31)20mg,yield 84%,purity 95%。1H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.27(d,J=4.4Hz,4H),7.23(d,J=1.6Hz,1H),4.43(s,2H).
实施例34:5-苄基噻唑-4-羧酸(34)的合成
将2,2-二氯乙酸甲酯(2000mg,14mmol)和苯乙醛(1340mg,11mmol)溶于20mL乙醚中,在0℃下缓慢加入30%甲醇钠溶液(832mg,15mmol)溶液,加毕,在0℃下反应1h后移至常温过夜反应,用饱和氯化钠水溶和乙醚萃取,收集有机相减压浓缩得中间体粗品,随后将中间体溶于甲醇并加入硫脲(836mg,11mmol),升温至65℃回流反应1h,TLC检测再无产品生成,停止反应,减压蒸干甲醇,经柱层析纯化(PE:EA=1:1)得黄色固体化合物2-氨基-5-苄基噻唑-4-羧酸甲酯400mg,yield 15%;将2-氨基-5-苄基噻唑-4-羧酸甲酯(400mg,1.6mmol)溶于5mL 30%的次磷酸溶液中,在冰浴下缓慢滴加亚硝酸钠(222mg,3.2mmol)水溶液,加毕,在0℃下反应1h后移至常温反应,TLC检测反应完全,停止反应,加水稀释反应液,用饱和碳酸氢钠水溶液调pH至弱碱性,EA萃取(3×40mL),合并有机层减压浓缩,经柱层析纯化(PE:EA=2:1)得黄色固体化合物5-苄基噻唑-4-羧酸甲酯(32a)200mg,yield 54%。
最后一步酯水解参照化合物1的水解过程,得无色油状液体5-苄基恶唑-4-羧酸(31)150mg,yield 84%,purity 99%。1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),7.34-7.24(m,5H),4.57(s,2H)ppm.13C NMR(101MHz,DMSO-d6)δ163.91,152.10,149.05,142.51,140.28,129.15,128.99,127.25,32.78ppm.HRMS:m/z calcd for C11H9NO2S[M+H]+220.0427,found 220.0429;[M-H2O+H]+202.0327,found 202.0317.。
实施例35:1-苄基-5-甲基-1H-咪唑-4-羧酸(35)的合成
该化合物参照化合物1的合成,得1-苄基-5-甲基-1H-咪唑-4-羧酸(33)白色固体182mg,yield 90%,purity 96%。1H NMR(400MHz,DMSO-d6)δ12.69(s,1H),7.94(s,1H),7.29(dd,J=19.6,7.4Hz,3H),7.11(d,J=7.2Hz,2H),5.49(s,2H),2.35(s,3H).
实施例36:1-苄基-1H-苯并[d]咪唑-2-羧酸(36)的合成
该化合物参照化合物1的合成,得1-苄基-1H-苯并[d]咪唑-2-羧酸(34)白色固体125mg,yield 82%,purity 96%。1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.88–7.84(m,1H),7.37–7.26(m,6H),7.21(d,J=2.0Hz,1H),5.36(s,2H).13C NMR(101MHz,CDCl3)δ144.05(s),143.22(s),135.52(s),133.98(s),129.05(s),128.27(s),127.11(s),123.09(s),122.27(s),120.47(s),110.02(s),48.84(s).HRMS:m/z calcd for C15H12N2O2[M+H]+253.0899,found 253.0896.
实施例37:化合物17-a~38-a的合成
参照上述制备方法,采用本领域的常规合成方法,分别得到化合物17-a~38-a,化合物17-a~38-a的合成原料和结构表征数据分别如表1所示:
表1化合物17-a~38-a的合成原料和结构表征
以下通过实验例证明本发明的有益效果。
实验例1:化合物对MBL酶的体外抑制活性
1、实验方法
分别利用5种典型MBL酶(VIM-2、NDM-1、IMP-1、VIM-1、VIM-5)作用靶点进行测试受试化合物的单浓度抑制率和IC50值的测定。
将0.6μL工作液(终浓度为100μM/10μM)、39.4μL Buffer C和10μLMBL酶溶液(酶终浓度为0.2nM)依次加入测试孔中,保持60μL总体积不变,先在对照组中加入40μL Buffer C和10μL MBL酶溶液(酶终浓度为0.2nM),室温反应10min后加入10μL FC-5底物溶液(底物终浓度为5μM)。在Thermo VARIOSKAN LUX酶标仪的380nm的激发波长和460nm的发射波长下测试酶动力学反应过程的荧光强度,参照上述单浓度活性实验方法,分别测试受试化合物在10个浓度梯度下酶动力学反应过程的荧光强度。根据测得的荧光强度变化与化合物浓度,使用GrapHPad Prism软件计算得到IC50值。
2、实验结果
表2化合物1~16对MBL酶的IC50
从表2可以看出,本发明化合物对MBL酶具有良好的抑制效果。特别地,化合物1对VIM-2的IC50为0.48μM,化合物3、5、13对VIM-2的IC50分别低至0.014μM、0.014μM、0.019μM。说明本发明化合物3、5、13对VIM-2的抑制效果比化合物1显著提高。
表3化合物1、17-24对MBL酶的抑制活性
从表3可以看出,本发明化合物对MBL酶具有良好的抑制效果。特别地,化合物1对VIM-2的IC50为0.48μM,化合物18对VIM-2的IC50低至0.015μM。说明本发明化合物18对VIM-2的抑制效果比化合物1显著提高。
表4化合物1、25-32对MBL酶的IC50
从表4可以看出,本发明化合物对MBL酶具有良好的抑制效果。特别地,化合物1对VIM-2的IC50为0.48μM,化合物28对VIM-2的IC50低至0.11μM。说明本发明化合物18对VIM-2的抑制效果比化合物1提高。
表5化合物1、33-36对MBL酶的IC50
从表5可以看出,与化合物1相比,化合物33-36对VIM-2的抑制效果降低了。
表6化合物17-a~38-a对MBL酶的IC50
从表6可以看出,本发明化合物对MBL酶具有良好的抑制效果。特别地,化合物1对VIM-2的IC50为0.48μM,化合物17-a~19-a、22-a、24-a~26-a、29-a、30-a、34-a、36-a、37-a对VIM-2的IC50低至0.15μM以下,对VIM-2的抑制效果比化合物1提高。
上述实验结果表明,本发明提供的化合物对MBL酶具有良好的抑制效果。特别地,与化合物1相比,化合物3、5、13、18、17-a~19-a、22-a、24-a~26-a、29-a、30-a、34-a、36-a、37-a对MBL酶VIM-2的抑制效果显著提高。
实验例2:抗菌活性测试
1、实验方法
在-80℃于MHA平板上复苏所需耐药菌株,35℃培养18-20h。将待测β-内酰胺酶抑制剂以及美罗培南配制成储备液。然后在96孔板将美罗培南储备液稀释成一系列一定浓度药液,并加入相应的β-内酰胺酶抑制剂储备液。将细菌用生理盐水调至OD630为0.08-0.13后加入对应孔中,于35℃孵箱中,静置培养16-20h。实验结果以可以完全或明显抑制细菌生长的最低浓度为联合用药时美罗培南的最小抑菌浓度(MIC)。
以不加β-内酰胺酶抑制剂,只加美罗培南最为对照。
所需耐药菌株:表达VIM-2的大肠杆菌工程菌E.coli C1541、E.coli C1542、E.coli C1580,来源于重庆第一人民医院;临床分离菌株PA W35(能产生VIM-2酶),来源于四川省人民医院。
2、实验结果
表7化合物13在100μg/mL下与美罗培南联用对工程菌的MIC
表7中,MIC的单位为μg/mL。
从表7可以看出,不加β-内酰胺酶抑制剂时,美罗培南对表达VIM-2的大肠杆菌工程菌E.coli C1541、E.coli C1542、E.coli C1580的MIC分别为16μg/mL、16μg/mL、32μg/mL。与100μg/mL化合物13联用后,美罗培南对表达VIM-2的大肠杆菌工程菌E.coli C1541、E.coli C1542、E.coli C1580的MIC均降低至<0.25μg/mL,抑菌效果提高了64倍以上。说明本发明的化合物13能够逆转耐药工程菌对美罗培南的耐药性,显著提高美罗培南的抗菌效果。
表8化合物13(100μg/mL)与美罗培南联用对临床分离菌株的MIC
表8中,MIC的单位为μg/mL。
从表8可以看出,不加β-内酰胺酶抑制剂时,美罗培南对临床分离菌株PA W35的MIC为64μg/mL。与100μg/mL化合物13联用后,美罗培南对临床分离菌株PA W35的MIC均降低至16μg/mL,抑菌效果提高了4倍。说明本发明的化合物13能够逆转耐药临床分离菌株对美罗培南的耐药性,显著提高美罗培南的抗菌效果。
上述实验结果表明,本发明化合物13与抗菌药物美罗培南联用能够显著提高美罗培南对耐药菌的抗菌效果。
综上,本发明提供了式I所示的化合物。该化合物对金属β-内酰胺酶具有良好的抑制效果。特别地,与化合物1相比,化合物3、5、13、18、17-a~19-a、22-a、24-a~26-a、29-a、30-a、34-a、36-a、37-a对MBL酶VIM-2的抑制效果显著提高。此外,本发明的化合物能够逆转耐药细菌对美罗培南的耐药性,显著提高美罗培南的抗菌效果。本发明提供的化合物能够用于制备金属β-内酰胺酶抑制剂以及抗菌的联合用药物,应用前景广阔。
Claims (10)
8.一种金属β-内酰胺酶抑制剂,其特征在于:所述金属β-内酰胺酶抑制剂是以权利要求1~7任一项所述化合物、或其盐、或其立体异构体、或其晶型、或其溶剂合物、或其氘代物为活性成分,加上药学上可接受的辅料制成的制剂。
9.权利要求1~7任一项所述化合物、或其盐、或其立体异构体、或其晶型、或其溶剂合物、或其氘代物在制备金属β-内酰胺酶抑制剂中的用途;优选地,所述金属β-内酰胺酶为VIM-2、NDM-1、IMP-1、VIM-1或VIM-5。
10.一种抗菌的联合用药物,其特征在于:它含有相同或者不同规格的同时或者分别给药的权利要求1~7任一项所述化合物、或其盐、或其立体异构体、或其晶型、或其溶剂合物、或其氘代物和抗菌药物,以及药学上可接受的载体;
优选地,所述抗菌药物为β-内酰胺类抗生素,所述β-内酰胺类抗生素优选为美罗培南。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111236198.XA CN114230522A (zh) | 2021-10-22 | 2021-10-22 | 一种咪唑-2-羧酸类金属β-内酰胺酶抑制剂及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111236198.XA CN114230522A (zh) | 2021-10-22 | 2021-10-22 | 一种咪唑-2-羧酸类金属β-内酰胺酶抑制剂及其制备方法和用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114230522A true CN114230522A (zh) | 2022-03-25 |
Family
ID=80743217
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111236198.XA Pending CN114230522A (zh) | 2021-10-22 | 2021-10-22 | 一种咪唑-2-羧酸类金属β-内酰胺酶抑制剂及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114230522A (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023160582A1 (zh) * | 2022-02-28 | 2023-08-31 | 四川大学 | 一种噻唑胺类mbl抑制剂及其制备方法和用途 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111187218A (zh) * | 2020-02-26 | 2020-05-22 | 四川大学 | 1-取代-1H-咪唑-2-羧酸类化合物在制备金属β-内酰胺酶抑制剂中的用途 |
CN111253317A (zh) * | 2020-02-26 | 2020-06-09 | 四川大学 | 一种1-取代-1h-咪唑-2-羧酸类化合物 |
WO2021115444A1 (zh) * | 2019-12-13 | 2021-06-17 | 苏州信诺维医药科技股份有限公司 | 单环β-内酰胺化合物及其用途 |
CN113209090A (zh) * | 2021-04-07 | 2021-08-06 | 中国人民解放军南部战区总医院 | 甲巯咪唑在作为和/或制备金属β-内酰胺酶抑制剂中的应用 |
-
2021
- 2021-10-22 CN CN202111236198.XA patent/CN114230522A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021115444A1 (zh) * | 2019-12-13 | 2021-06-17 | 苏州信诺维医药科技股份有限公司 | 单环β-内酰胺化合物及其用途 |
CN111187218A (zh) * | 2020-02-26 | 2020-05-22 | 四川大学 | 1-取代-1H-咪唑-2-羧酸类化合物在制备金属β-内酰胺酶抑制剂中的用途 |
CN111253317A (zh) * | 2020-02-26 | 2020-06-09 | 四川大学 | 一种1-取代-1h-咪唑-2-羧酸类化合物 |
CN113209090A (zh) * | 2021-04-07 | 2021-08-06 | 中国人民解放军南部战区总医院 | 甲巯咪唑在作为和/或制备金属β-内酰胺酶抑制剂中的应用 |
Non-Patent Citations (2)
Title |
---|
REGISTRY: "Registry" * |
RONG LI,等: ""Design, Synthesis, and Biological Evaluation of New 1H-Imidazole-2-Carboxylic Acid Derivatives as Metallo-β-Lactamase Inhibitors"" * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023160582A1 (zh) * | 2022-02-28 | 2023-08-31 | 四川大学 | 一种噻唑胺类mbl抑制剂及其制备方法和用途 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101098870B (zh) | 新型稠环咪唑衍生物 | |
AU2016363937B2 (en) | Inhibitors of metallo-beta-lactamases | |
JP6896628B2 (ja) | 細菌感染症の治療のための抗微生物性ポリミキシン | |
CN105143216B (zh) | 抗菌双芳香族衍生物 | |
CA2903463A1 (en) | Bet bromodomain inhibitors and therapeutic methods using the same | |
KR920008709B1 (ko) | 2β-치환-메틸페니실란산 유도체 및 그의 염 및 에스테르 | |
WO1997021676A1 (en) | Azetidinone compounds for the treatment of atherosclerosis | |
EP3137461B1 (en) | Method of preparing an optically active pde10 inhibitor | |
WO2015049629A1 (en) | Imidazoquinoline compounds as bromodomain inhibitors | |
WO2018215799A1 (en) | Inhibitors of metallo-beta-lactamases | |
CN114230522A (zh) | 一种咪唑-2-羧酸类金属β-内酰胺酶抑制剂及其制备方法和用途 | |
BE898123A (fr) | Nouveaux dérivés d'acides 4-oxo-1, 4-dihydronicotinique, leurs sels, un procédé pour leur production et agents antibactériens les contenant. | |
CN111187218B (zh) | 1-取代-1H-咪唑-2-羧酸类化合物在制备金属β-内酰胺酶抑制剂中的用途 | |
Liu et al. | Design, synthesis and biological evaluation of novel 3-hydroxypyridin-4 (1H)-ones based hybrids as Pseudomonas aeruginosa biofilm inhibitors | |
JP7299350B2 (ja) | Rip-1キナーゼ阻害剤としての二環式化合物およびその使用 | |
WO2024007883A1 (zh) | 一类噻唑胺-二氮杂双环辛酮缀合衍生物及其用途 | |
CN113214302B (zh) | 一种抑制金属β-内酰胺酶和/或丝氨酸β-内酰胺酶的3-取代五元环状硼酸酯衍生物 | |
CN111253317B (zh) | 一种1-取代-1h-咪唑-2-羧酸类化合物 | |
AU2014359456A1 (en) | Sulfoximine substituted quinazolines for pharmaceutical compositions | |
CN101337948B (zh) | 1,5-苯并硫氮杂卓类化合物及其制备方法和应用 | |
JPH02288A (ja) | 置換ペネム誘導体 | |
CA3168824A1 (en) | Sulfonamide or sulfinamide compound having effect of inducing brd4 protein degradation and pharmaceutical use thereof | |
CN113150022B (zh) | 3-取代五元环状硼酸酯衍生物及其药物组合物和制药用途 | |
AU2014221468B2 (en) | Substituted (R)-3-(4-methylcarbamoyl-3-fluorophenylamino)tetrahydrofuran-3-enecarboxylic acid (variants) and ester thereof, method for producing and using same | |
CN111662239B (zh) | 1,2,4-三唑类化合物及其制法和药物用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220325 |