CN102584827A - Carbapenem compound containing sulfuryl amine heterocyclic methylamino formoxyl pyrrolidine - Google Patents
Carbapenem compound containing sulfuryl amine heterocyclic methylamino formoxyl pyrrolidine Download PDFInfo
- Publication number
- CN102584827A CN102584827A CN2011104626646A CN201110462664A CN102584827A CN 102584827 A CN102584827 A CN 102584827A CN 2011104626646 A CN2011104626646 A CN 2011104626646A CN 201110462664 A CN201110462664 A CN 201110462664A CN 102584827 A CN102584827 A CN 102584827A
- Authority
- CN
- China
- Prior art keywords
- methyl
- hydroxyethyl
- oxo
- azabicyclo
- hept
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 Carbapenem compound Chemical class 0.000 title claims abstract description 97
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title abstract 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- 238000002360 preparation method Methods 0.000 claims abstract description 59
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 150000002148 esters Chemical class 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 63
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 54
- 125000003368 amide group Chemical group 0.000 claims description 51
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 51
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 46
- 230000007062 hydrolysis Effects 0.000 claims description 19
- 238000006460 hydrolysis reaction Methods 0.000 claims description 19
- 125000005605 benzo group Chemical group 0.000 claims description 16
- 125000001544 thienyl group Chemical group 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000002541 furyl group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 208000015181 infectious disease Diseases 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- OTTZHAVKAVGASB-UHFFFAOYSA-N 2-heptene Natural products CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 8
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 8
- 125000005493 quinolyl group Chemical group 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 claims description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 6
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 6
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 6
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 5
- 125000005873 benzo[d]thiazolyl group Chemical group 0.000 claims description 5
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 claims description 2
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- NXHBZIXZNOPQSG-UHFFFAOYSA-N isoquinoline-3-sulfonamide Chemical compound NS(=O)(=O)c1cc2ccccc2cn1 NXHBZIXZNOPQSG-UHFFFAOYSA-N 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 4
- 208000035473 Communicable disease Diseases 0.000 abstract description 2
- 239000002585 base Substances 0.000 description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 34
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 32
- 239000002253 acid Substances 0.000 description 26
- 239000000047 product Substances 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000011259 mixed solution Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound 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 description 10
- 229960002770 ertapenem Drugs 0.000 description 10
- 239000008367 deionised water Substances 0.000 description 9
- 229910021641 deionized water Inorganic materials 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
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- 238000005406 washing Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- 238000003810 ethyl acetate extraction Methods 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 159000000000 sodium salts Chemical class 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 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 description 6
- 229960002260 meropenem Drugs 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical class OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 5
- 0 C[C@]([C@]([C@@](*12)C(C)C(S[C@](C*3)C[C@]3C(N(C)c3cc(*)ccc3)=O)=C1C(O)=O)C2=O)O Chemical compound C[C@]([C@]([C@@](*12)C(C)C(S[C@](C*3)C[C@]3C(N(C)c3cc(*)ccc3)=O)=C1C(O)=O)C2=O)O 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 230000003115 biocidal effect Effects 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- LQXNIPLTFRANDL-UHFFFAOYSA-N 1-azabicyclo[3.2.0]hept-2-ene Chemical compound C1=CCC2CCN21 LQXNIPLTFRANDL-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
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- 230000009286 beneficial effect Effects 0.000 description 3
- 239000012964 benzotriazole Substances 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 2
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 2
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- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- DMDUQBFGFRRDKJ-UHFFFAOYSA-N 6-(aminomethyl)-1H-indole-2-sulfonamide Chemical compound C1=CC2=C(C=C1CN)NC(=C2)S(=O)(=O)N DMDUQBFGFRRDKJ-UHFFFAOYSA-N 0.000 description 1
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- CWXYHOHYCJXYFQ-UHFFFAOYSA-N Betamipron Chemical compound OC(=O)CCNC(=O)C1=CC=CC=C1 CWXYHOHYCJXYFQ-UHFFFAOYSA-N 0.000 description 1
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- 244000052616 bacterial pathogen Species 0.000 description 1
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- MRMBZHPJVKCOMA-YJFSRANCSA-N biapenem Chemical compound C1N2C=NC=[N+]2CC1SC([C@@H]1C)=C(C([O-])=O)N2[C@H]1[C@@H]([C@H](O)C)C2=O MRMBZHPJVKCOMA-YJFSRANCSA-N 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
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- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
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- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical class C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
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- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002815 nickel Chemical class 0.000 description 1
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- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- CQDAMYNQINDRQC-UHFFFAOYSA-N oxatriazole Chemical compound C1=NN=NO1 CQDAMYNQINDRQC-UHFFFAOYSA-N 0.000 description 1
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- MQKPEUAOJLJUMD-UHFFFAOYSA-N phenol;piperazine Chemical compound C1C[NH2+]CCN1.[O-]C1=CC=CC=C1 MQKPEUAOJLJUMD-UHFFFAOYSA-N 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N phenyl bromide Natural products BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
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- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
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- 239000013558 reference substance Substances 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960000658 sumatriptan succinate Drugs 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
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- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 235000019587 texture Nutrition 0.000 description 1
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- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicine, in particular to a carbapenem compound containing sulfuryl amine heterocyclic methylamino formoxyl pyrrolidine shown as a general formula (I), a pharmaceutically-acceptable salt thereof, an easily-degradable ester thereof, a stereoisomeride thereof, a solvent compound thereof and an intermediate shown as a formula (II), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and A are defined as the specifications. The invention further relates to preparation methods of these compounds, a medicinal preparation containing the compounds, and applications of these compounds to preparation of a medicament for treating and/or preventing infectious diseases.
Description
1, technical field
The invention belongs to medical technical field; The ester, its steric isomer, its solvated compounds and its midbody that relate to the carbapenem compounds that contains amino-sulfonyl heterocycle methylamino carbonyl pyrrolidine, its pharmacy acceptable salt, its facile hydrolysis; The preparation method of these compounds; The pharmaceutical prepn that contains these compounds, and these compounds are in the purposes that is used for preparing the medicine that treats and/or prevents infection.
2, background technology
Carbapenem antibiotic is one type of β-Nei Xiananleikangshengsu that last century, the seventies grew up.Because of its has a broad antifungal spectrum, anti-microbial activity is strong, and stable to β-Nei Xiananmei, and receives much concern.
This similar drug that has gone on the market at present has imipenum, meropenem, S-4661, biapenem, ertapenem.Listing be imipenum at first, and gram-positive microorganism is had better antibacterial activity, yet separately during medication, is prone to by dehydropeptidase of kidney (DHP-I) degraded in vivo and loses anti-microbial activity, need and the cilastatin coupling; Meropenem is 1 Beta-methyl carbapenem antibiotic, and Gram-negative bacteria is had better antibacterial activity, and DHP-I is had stronger stability, medication separately; The ertapenem long half time has better antibacterial activity to Gram-negative bacteria.
In recent years,, cause the continuous increase of bacterial drug resistance, therefore, be badly in need of research and development and have better antibacterial activity because the microbiotic clinical application is too much, good chemicalstability, to DHP-I stable and have than the long half-lift carbapenem antibiotic.
3, summary of the invention
The present invention provides one type of anti-microbial activity good, and chemicalstability is strong, to DHP-I stable and have than the long half-lift carbapenem antibiotic, technical scheme of the present invention is following:
Compound shown in the logical formula I, its pharmacy acceptable salt, and steric isomer:
Wherein: R
1Represent the 1-hydroxyethyl, 1-fluoro ethyl or methylol;
R
2Represent Wasserstoffatoms or C
1-6Alkyl;
R
3Represent Wasserstoffatoms or carboxyl-protecting group;
R
4, R
5, R
6, R
7Independently represent Wasserstoffatoms or C respectively
1-6Alkyl;
R
8, R
9Independently represent Wasserstoffatoms, C respectively
1-6Alkyl or halo C
1-6Alkyl, perhaps R
8, R
9Form 3-8 unit naphthenic base with the carbon atom that is connected;
A represents the thick heteroaryl of 5-8 single heteroaryl of unit or 9-14 unit.
Compound shown in the logical formula I, its pharmacy acceptable salt, and the optimal technical scheme of steric isomer is:
Wherein: R
1Represent the 1-hydroxyethyl, 1-fluoro ethyl or methylol;
R
2Represent Wasserstoffatoms or C
1-6Alkyl;
R
3Represent Wasserstoffatoms or carboxyl-protecting group;
R
4, R
5, R
6, R
7Independently represent Wasserstoffatoms or C respectively
1-6Alkyl;
R
8, R
9Independently represent Wasserstoffatoms, C respectively
1-6Alkyl or halo C
1-6Alkyl, perhaps R
8, R
9Form 3-8 unit naphthenic base with the carbon atom that is connected;
A represents 5-6 single heteroaryl of unit or 9-10 unit benzo heteroaryl.
Compound shown in the logical formula I, its pharmacy acceptable salt, and the optimal technical scheme of steric isomer is:
Wherein: R
1Represent the 1-hydroxyethyl;
R
2Represent methylidene;
R
3Represent Wasserstoffatoms or to nitrobenzyl;
R
4, R
5Independently represent Wasserstoffatoms respectively;
R
6, R
7Independently represent Wasserstoffatoms respectively, methyl, ethyl or propyl group;
R
8, R
9Independently represent Wasserstoffatoms respectively, methyl, methyl fluoride, trifluoromethyl or 2,2,2-trifluoroethyl, perhaps R
8, R
9Form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl with the carbon atom that is connected;
A represents pyridyl, pyrimidyl, thienyl, thiazolyl, thiadiazolyl group, 4,5-dihydro-thiazolyl 、 oxazolyl 、 isoxazolyl 、 oxadiazole base, pyrryl, imidazolyl, pyrazolyl, triazol radical, benzofuryl, benzoxazolyl, benzothienyl, benzothiazolyl, indyl, pseudoindoyl, benzimidazolyl-, indazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl or cinnolines base.
Compound shown in the logical formula I, its pharmacy acceptable salt, and the optimal technical scheme of steric isomer is:
Wherein: R
1Represent the 1-hydroxyethyl;
R
2Represent methylidene;
R
3Represent Wasserstoffatoms or to nitrobenzyl;
R
4, R
5Independently represent Wasserstoffatoms respectively;
R
6, R
7Independently represent Wasserstoffatoms respectively, methyl or ethyl;
R
8, R
9Independently represent Wasserstoffatoms respectively;
A represents pyridyl, pyrimidyl, thienyl, thiazolyl, 1,3,4-thiadiazolyl group, 1; 2,4-thiadiazolyl group, 4,5-dihydro-thiazolyl 、 oxazolyl 、 isoxazolyl, 1; 3; 4-oxadiazole base, 1,2,4-oxadiazole base, pyrryl, imidazolyl, pyrazolyl, 1; 2,4-triazol radical, benzo [b] furyl, benzo [c] furyl, benzo [d] oxazolyl, benzo [b] thienyl, benzo [c] thienyl, benzo [d] thiazolyl, indyl, pseudoindoyl, benzo [d] imidazolyl, indazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl or cinnolines base.
Compound shown in the logical formula I, its pharmacy acceptable salt, and the optimal technical scheme of steric isomer is:
Wherein: R
1Represent the 1-hydroxyethyl;
R
2Represent methylidene;
R
3, R
4, R
5Independently represent Wasserstoffatoms respectively;
R
6, R
7Independently represent Wasserstoffatoms respectively, methyl or ethyl;
R
8, R
9Independently represent Wasserstoffatoms respectively;
A represents pyridyl, pyrimidyl, thienyl, thiazolyl, 1,3,4-thiadiazolyl group, 1; 2; 4-thiadiazolyl group 、 oxazolyl, 1,3,4-oxadiazole base, 1; 2,4-oxadiazole base, pyrryl, imidazolyl, benzo [b] furyl, benzo [b] thienyl, benzo [d] thiazolyl, indyl, benzo [d] imidazolyl, indazolyl, quinolyl or isoquinolyl.
Part of compounds of the present invention is:
" C of the present invention
1-6Alkyl " alkyl that contains 1-6 carbon atom of expression straight chain, side chain; specific examples includes but not limited to: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec.-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methylbutyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1; 3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl-butyl, 1-methyl-2-methyl-propyl etc.
" 3-8 unit naphthenic base " according to the invention expression contains the cyclic alkyl of 3-8 atom, and specific examples includes but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, methyl cyclopropyl, dimethyl-cyclopropyl, methyl cyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, Dimethylcyclohexyl etc.
" halo C of the present invention
1-6Alkyl " in " halo " be meant C
1-6One or more Wasserstoffatoms on the carbon atom in the alkyl is replaced by halogen atom." halogen atom " comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" the single heteroaryl of 5-8 unit " of the present invention expression contains a undersaturated cyclic group with aromaticity that is selected from O, S, the heteroatomic 5-8 of a N annular atoms at least; Specific examples includes but not limited to: furyl, thienyl, dihydro-thiophene base, phosphurane base, dithia cyclopentenyl, thiazolyl, isothiazolyl, 1,3,4-thiadiazolyl group, 1; 2; 4-thiadiazolyl group, 4,5-dihydro-thiazolyl 、 oxazolyl, dihydro-oxazole base 、 isoxazolyl, dihydro-isoxazole base, 1,3; 4-oxadiazole base, 1; 2,4-oxadiazole Ji 、 oxatriazole base, pyrryl, imidazolyl, pyrazolyl, pyrazoline base, 1,2; 4-triazol radical, tetrazyl, pyridyl, pyrimidyl, pyranyl, 2H-pyranyl 、 oxazinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazine base, oxepin base, thia cycloheptatriene base, nitrogen heterocyclic heptantriene base, 1,3-diazacyclo heptantriene base, nitrogen heterocyclic octatetraene base etc." the single heteroaryl of 5-6 unit " of the present invention refers to the specific examples that contains 5-6 annular atoms in the above-mentioned instance.
" 9-14 unit thick heteroaryl " of the present invention expression contain at least one be selected from O, S, the heteroatomic 9-14 of a N annular atoms couple together the undersaturated condensed ring structure that forms by shared each other two the adjacent atoms of two or more ring texturees with aromaticity, specific examples includes but not limited to: benzofuryl, benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl-, indazolyl, benzotriazole base, quinolyl, isoquinolyl, acridyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridinyl etc.
" 9-10 unit benzo heteroaryl " of the present invention represented phenyl ring and contained a condensed ring group that is selected from O, S, the single heteroaryl formation of the heteroatomic 5-6 of N unit at least; Specific examples includes but not limited to: benzo [b] furyl, benzo [c] furyl, benzo [d] oxazolyl, benzo [b] thienyl, benzo [c] thienyl, benzo [d] thiazolyl, indyl, pseudoindoyl, benzo [d] imidazolyl, indazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl, cinnolines base, benzotriazole base, 2H-chromogen thiazolinyl, 4H-chromogen thiazolinyl, 4H-1,3-benzoxazinyl etc.
" carboxyl-protecting group " according to the invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups includes but not limited to: methyl, methoxymethyl, first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, methoxyethyl methyl, allyl group, benzyloxymethyl, phenacyl-, to bromobenzene formyl methyl, Alpha-Methyl phenacyl-, to methoxybenzoyl methyl, diacyl methyl, N phlhalimide ylmethyl, ethyl, 2; 2; 2-three chloroethyls, ω-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 2-(p-nitrophenyl sulfenyl) ethyl, 2-(to the toluene sulfenyl) ethyl, 1-methyl isophthalic acid-styroyl, the tertiary butyl, cyclopentyl, cyclohexyl, two (ortho-nitrophenyl base) methyl, 9-fluorenyl methyl, 2-(9; The 10-dioxo) fluorenyl methyl, 5-hexichol sulfenyl, benzyl, 2; 4; The 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, sec.-propyl dimetylsilyl, diphenyl methyl, phenyl dimetylsilyl, the S-tertiary butyl, S-phenyl, S-2-pyridyl, N-hydroxy piperidine base, N-succinimido, N phlhalimide base, N-benzotriazole base, O-acyl group oxime, 2; 4-dinitrobenzene sulfenyl, 2-alkyl-1; 3-oxazoline, 4-alkyl-5-oxo-1; 3-oxazolidine, 5-alkyl-4-oxo-1,3-diox, triethyltin alkyl, tri-n-butyl tin alkyl; N, N '-di-isopropyl hydrazides etc.
The present invention also protects the preparation method of the said compound of formula I
The preparation method of The compounds of this invention comprises ester, its steric isomer or its solvated compounds that makes compound, its pharmacy acceptable salt, its facile hydrolysis shown in the logical formula III; Ester, its steric isomer or its solvated compounds generation nucleophilic substitution reaction with compound shown in the formula II, its pharmacy acceptable salt, its facile hydrolysis
Wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9With A such as preamble definition; L represents leavings group.
Above-mentioned " leavings group " can be the group that nucleophilic residues is left away, and for example can be halogens such as chlorine, bromine, iodine; Halogenated methoxies such as trichlorine methoxyl group; Lower alkane such as mesyloxy, ethanesulfonyloxy group sulfonyloxy; Halo lower alkane sulfonyloxies such as trifluoro-methanesulfonyl oxy, five fluorine ethanesulfonyloxy groups; Arylsulfonyloxies such as phenylsulfonyloxy, tolysulfonyl oxygen base, p-nitrophenyl sulfonyloxy; Perhaps aryl phosphorus acyloxy such as diphenylphosphine acyloxy, preferred aryl groups phosphorus acyloxy, more preferably diphenylphosphine acyloxy (O-P (=O) (OPh)
2).
Above-claimed cpd of the present invention can adopt method and/or known other technology of those of ordinary skills of describing in the following flow process to synthesize, but is not limited only to following method.
Reaction equation is following:
Reactions step:
The preparation of step 1 formula 1 compound
Under nitrogen protection, in reaction flask, add raw material 1, raw material 2 and acetonitrile stir, and question response finishes, water and ethyl acetate extraction, organic layer is used Na
2SO
4Drying, vacuum concentration, column chromatography purification gets formula 1 compound.
The preparation of step 2 formula 2 compounds
Under nitrogen protection, in reaction flask, add raw material 3, formula 1 compound, acetonitrile, slowly drip triethylamine (TEA), stir, concentrating under reduced pressure, preparation HPLC purifying gets formula 2 compounds.
The preparation of step 3 formula 3 compounds
Adding formula 2 compounds in the hydrogenation still, Pd/C, the mixed solution of THF and water, feeding hydrogen stirs, and question response finishes, and removes by filter Pd/C, and filtrating is used ethyl acetate extraction, and water layer is with preparation HPLC purifying, and lyophilize gets formula 3 compounds.
R among the above-mentioned preparation method
1, R
2, R
4, R
5, R
6, R
7, R
8, R
9, A and L such as preamble be said; R
10Representation carboxy protection base.
The present invention further requires to protect the midbody of compound shown in the formula I in the preparation process, i.e. compound shown in the formula II, wherein, R
4, R
5, R
6, R
7, R
8, R
9With A such as preamble definition.
" pharmacy acceptable salt " of the above-mentioned arbitrary compound of the present invention comprises an alkali metal salt, like sodium salt, sylvite, lithium salts etc.; Alkaline earth salt is like calcium salt, magnesium salts etc.; Other metal-salts are like aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts is like ammonium salt; Organic alkali salt; Like uncle's octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycocoll alkyl ester salt, ethylenediamine salt, N-NMG salt, guanidinesalt, diethyl amine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-styroyl amine salt, piperazine salt, tetramethyl-amine salt, three (methylol) amido methane salt; Halogen acid salt is like hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt is like nitrate salt, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulphonate is like mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate is like benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt is like acetate, malate, fumarate, SUMATRIPTAN SUCCINATE, Citrate trianion, tartrate, oxalate, PHENRAMINE MALEATE etc.; Amino acid salts is like glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.
" ester of facile hydrolysis " of the above-mentioned arbitrary compound of the present invention be meant those can be in human body hydrolysis generate the pharmaceutically acceptable ester of parent compound.It is obvious that for the professional of this area, and the ester that is easy to hydrolysis of The compounds of this invention can form at the free carboxy or the hydroxyl place of this compound, can make through ordinary method.
" steric isomer " of the above-mentioned arbitrary compound of the present invention comprises that all differences are to stereoisomerism, diastereo-isomerism and tautomeric form.When a key was represented with a wedge, this was illustrated in three-dimensional this key of going up and will comes out from paper, and when a key was shade, this was illustrated in three-dimensional this key of going up and will returns in the paper.The formula I compound has many three-dimensional centers, be included on the 4-position, on the 5-position, first-class in the 6-position.
" solvolyte " of the above-mentioned arbitrary compound of the present invention is meant medicine in crystallisation process, makes the crystallization that obtains that changes of crystalline lattice be called solvolyte because of solvent molecule adds.Like solvent is water, then is called hydrate, is organic solvent like solvent, then is called the organic solvent thing.
The present invention further requires to protect the pharmaceutical composition of the ester, its steric isomer or its solvated compounds and other active pharmaceutical ingredients that comprise arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis, like cilastatin and sodium salt, CS-443 etc.
The present invention also comprises ester, its steric isomer or its solvated compounds of above-mentioned arbitrary compound, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical prepn of one or more pharmaceutical carriers and/or thinner; Can be mixed with clinically or pharmaceutically acceptable arbitrary formulation with mode known in the art, be applied to the patient who needs this treatment with oral, parenteral, rectum or through modes such as lung administrations.When being used for oral administration, can be made into conventional solid preparation, like tablet, capsule, pill, granule etc.; Also can be made into oral liquid, like oral solution, oral suspensions, syrup etc.When processing oral prepns, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.When being used for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When processing injection, can adopt the ordinary method production in the existing pharmacy field, during the preparation injection, can not add additives, also can add suitable additives according to the character of medicine.When being used for rectal administration, can be made into suppository etc.Be used for when the lung administration, can be made into inhalation or sprays etc.Contain the compound 0.01g～10g shown in the formula I of physiology significant quantity in the per unit preparation, can be 0.01g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 10g etc.
The present invention also provides The compounds of this invention to treat and/or prevent the purposes of infectious disease medicament in preparation.The compounds of this invention all has better antibacterial activity to gram-positive, negative bacterium and hospital clinical pathogenic bacteria such as streptococcus pneumoniae; And The compounds of this invention is stable to β-Nei Xiananmei and people's kidney DHP-I; Can be used to treat the following infection due to the sensitive organism: (1) respiratory system infection, like chronic bronchitis, pneumonia, lung abscess and pyothorax etc.; (2) infect in the abdomen, like cholecystitis, cholangitis, liver abscess and peritonitis etc.; (3) uropoiesis, genital system infection are like pyelonephritis, complicacy urocystitis, adnexitis, prenatal infection, pelvic inflammatory disease and uterus inflammation of connective tissue etc.; (4) bone, joint and skin and soft tissue infection are like cellulitis around cellulitis, perianal abscess, osteomyelitis, sacroiliitis, trauma wound infection, burn wound infection, operative incision infection, jawbone and the jawbone etc.; (5) eye and otorhinolaryngology infect; (6) other severe infections is like meningitis and septicemia etc.
Below further set forth the beneficial effect of The compounds of this invention, other compound of the present invention with test in cited part The compounds of this invention have identical beneficial effect, but should this be interpreted as that The compounds of this invention only has following beneficial effect.
The antibacterial activity in vitro of experimental example 1 The compounds of this invention
Supply the examination bacterial classification:
Gram-positive microorganism: staphylococcus epidermidis, streptococcus aureus;
Severe oxygen bacterium: streptococcus pneumoniae, Streptococcus viridans;
Gram-negative bacteria: the Klebsiella Pneumoniae of Klebsiella Pneumoniae, product ESBLs.
Above strains tested is all available from the outer cardiovascular diseases hospital of Beijing mound, Shanghai benevolence Ji hospital, Xijing hospital of affiliated hospital of The Fourth Military Medical University.
Trial-product:
The compounds of this invention, self-control, its chemical name and structural formula are seen the preparation embodiment of each compound; Meropenem, ertapenem is commercial.
Experimental technique: agar dilution, with reference to Clinical And Laboratory Standards Institute.Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Seventh Edition.CLSI Document M7-A7.Vol 26, No.2, Wayne, PA:Clinical And Laboratory Standards Institute, 2006.
Experimental result and conclusion:
The antibacterial activity in vitro of table 1 The compounds of this invention
Visible by table 1, The compounds of this invention to the bacteriostatic activity of above-mentioned strains tested and ertapenem quite or better, with meropenem quite or poor slightly.
The antibacterial activity in vitro of table 2 The compounds of this invention
---representative does not have the activity of test to this bacterial strain
Visible by table 2, The compounds of this invention is compared with ertapenem with meropenem the bacteriostatic activity of above-mentioned strains tested, and is quite perhaps better.
Pharmacokinetics experiment in the rat body of experimental example 2 The compounds of this invention
The animal subject male SD rat, 3/compound, body weight 220-250g.
Trial-product part of compounds of the present invention, self-control; Use physiological saline solution.
Reference substance ertapenem (injection ertapenem sodium), commercial; Use physiological saline solution.
Experimental technique
Administration ertapenem, compound 1,6,11 intravenous injection administrations (IV), dosage is 5mg/kg, administration volume 2mL/kg; Compound 47,48 intravenous injection administrations (IV), dosage is 2mg/kg, administration volume 2mL/kg.
Took a blood sample 0 hour, 0.083 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, each time point was taked 100 μ L left and right sides whole bloods, centrifugal 5 minutes separated plasmas in the supercentrifuge of 2000g, and blood plasma is frozen in-80 ℃ of refrigerators.
Plasma sample is analyzed
Ertapenem, The compounds of this invention: get 30 μ L blood plasma, add mark in the 100 μ L (meropenem: 500ng/mL MeOH solution), 1500 rev/mins of vortexs 2 minutes, then 12000 rev/mins centrifugal 5 minutes, get supernatant, use LC-MS/MS to analyze.
Experimental result is seen table 3.
The P of Rats K evaluation result (IV) of table 3 The compounds of this invention
Conclusion: we can find out through above data, and in the rat body, the long half time of The compounds of this invention 47,48 is in ertapenem; The transformation period and the ertapenem of compound 1,6,11 are suitable.
4, embodiment
Below, foregoing of the present invention is done further to specify through the embodiment of embodiment form.But should this scope that is interpreted as the above-mentioned theme of the present invention only not limited to following examples.
Embodiment 1 (4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-aminosulfonyl yl pyridines-2-
Base) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-preparation of 1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (compound 1)
Step 1 (2S, 4S)-4-sulfydryl-2-[(5-aminosulfonyl yl pyridines-2-yl) methyl amido formyl radical] tetramethyleneimine-1-carboxy acid mutual-nitro carbobenzoxy's preparation
In the exsiccant reaction flask; Will (1S, 4S)-(3.3g is 0.0107mol) with 2-amino methyl-5-aminosulfonyl yl pyridines (2.7g for 3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxy acid mutual-nitro carbobenzoxy; 0.0144mol) be dissolved among the acetonitrile 200mL; Reaction solution is stirred overnight under room temperature, filters out solid, directly is used for step reaction down.
Step 2 (4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-3-[(3S, 5S)-1-(to the nitro carbobenzoxy-(Cbz))-5-[(5-aminosulfonyl yl pyridines-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
In the exsiccant reaction flask; Step 1 gained solid is dissolved in acetonitrile; Add (4R, 5S, 6S)-3-(hexichol oxygen phosphorus acyloxy)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) (6.4g; 0.0107mol) and diisopropylethylamine (DIEA) (5.5g, 0.0428mol).Reaction mixture is stirred overnight at room temperature, and with ETHYLE ACETATE and water extraction, organic layer is used Na then
2SO
4Drying, concentrating under reduced pressure gets yellow solid product (4.50g, 50.1%).
The preparation of step 3 compound 1
(1.26g 0.0015mol) is dissolved in the mixed solution (10mL: 10mL), add 10%Pd/C (1g) of THF and water with step 2 products therefrom; Join in the hydrogenation still, feed hydrogen, stirring at room 2 hours; Remove by filter Pd/C, and with THF and deionized water wash.Merging filtrate is used ethyl acetate extraction.Water layer is with preparation HPLC purifying, and lyophilize gets solid product (300mg, 38.1%).
Molecular formula: C
21H
27N
5O
7S
2Molecular weight: 525.60 MS (M+1): 526
1H-NMR(400MHz，DMSO-d
6)：δ1.14(3H，d)，1.15(3H，d)，1.62(1H，m)，2.56(1H，m)，2.67(1H，m)，3.19(2H，dd)，3.43(1H，m)，3.57(1H，t)，3.82(1H，t)，3.96(1H，t)，4.16(1H，d)，4.43(2H，m)，5.06(1H，s)，7.48(1H，d)，7.57(2H，s)，8.14(1H，dd)，8.78(1H，t)，8.88(1H，d).
The preparation of step 4 compound 1 sodium salt
(0.53g 1mmol) is dissolved in the 4mL deionized water compound 1 that step 3 is prepared, and is cooled to about 0 ℃ under stirring, and slowly adds powdery sodium hydrogencarbonate 0.1g, and insulated and stirred 2 hours is used preparation HPLC purifying, and freeze-drying gets the 0.38g sodium salt, yield 69.4%.
Embodiment 2 (4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl thiophene-2-
Base) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-preparation of 1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (compound 6)
Step 1 (2S, 4S)-4-sulfydryl-2-[(5-amino-sulfonyl thiophene-2-yl) methyl amido formyl radical] tetramethyleneimine-1-carboxy acid mutual-nitro carbobenzoxy's preparation
In the exsiccant reaction flask, add (1S; 4S)-and 3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxy acid mutual-nitro carbobenzoxy (2.7g, 8.8mmol), 2-amino-sulfonyl-5-amino methyl thiophene (1.1g; 5.8mmol) and acetonitrile, under ice bath and nitrogen protection, stirred 4 hours.Reaction mixture is poured in the water, used ethyl acetate extraction.Organic layer is used Na
2SO
4Drying, vacuum concentration, column chromatography purification gets product (1.5g, 51.7%).
Step 2 (4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-3-[(3S, 5S)-1-is to nitro carbobenzoxy-(Cbz)-5-[(5-amino-sulfonyl thiophene-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With step 1 products therefrom (1.5g; 3.0mmol) and triethylamine (TEA) (0.61g 6.0mmol) is dissolved in the acetonitrile, under ice bath and nitrogen protection, adds (4R; 5S; 6S)-3-(hexichol oxygen phosphorus acyloxy)-6-[(R)-the 1-hydroxyethyl]-(1.78g, 3.0mmol), mixture stirred 2 hours down at 0 ℃ 4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP).Reaction mixture is poured in the water, filtered, get product (2.2g, 86.8%).
The preparation of step 3 compound 6
(2.2g, 2.6mmol), Pd/C (1.1g) joins mixed solution (100mL, the V of THF and water with step 2 products therefrom
THF: V
Water=7: 3), then mixed solution being poured in the hydrogenation still, is 4MPa at hydrogen pressure, and temperature of reaction is 27 ℃-30 ℃ reacted 2 hours down, removed by filter Pd/C, with the mixed solution (V of THF and deionized water
THF: V
Water=2: 3) washing.Merging filtrate and washings, with ETHYLE ACETATE (30ml * 3) extraction, water layer is with preparation liquid phase purifying, and lyophilize gets white solid (0.027g, 2.0%).
Molecular formula: C
20H
26N
4O
7S
3Molecular weight: 530.64 MS (M+1): 531
1H-NMR(400MHz，DMSO-d
6)：δ1.13(3H，d)，1.15(3H，d)，1.50(1H，m)，2.56(2H，m)，3.19(1H，dd)，3.49(1H，dd)，3.69(1H，t)，3.91(1H，m)，4.13(1H，q)，4.40(2H，t)，5.04(1H，d)，6.94(1H，d)，7.36(1H，d)，7.60(2H，s)，8.72(1H，t).
The preparation of step 4 compound 6 sodium salts
The compound 60.53g (1mmol) of step 3 preparation is dissolved in the 4mL deionized water, is cooled to about 0 ℃ under stirring, slowly add powdery sodium hydrogencarbonate 0.1g, insulated and stirred 2 hours gets the 0.40g sodium salt, yield 72.4% with preparation HPLC purifying.
Embodiment 3 (4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl thiazole-2-
Base) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-preparation of 1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (compound 11)
Step 1 (4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-3-[(3S, 5S)-1-is to nitro carbobenzoxy-(Cbz)-5-[(5-amino-sulfonyl thiazol-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With 2-amino methyl-5-amino-sulfonyl thiazole (2.0g, 10mmol), (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxy acid mutual-nitro carbobenzoxy (3.1g; 10mmol), and tri-n-butyl phosphine (2g, 10mmol) and diisopropylethylamine (DIPEA) (2.6g; 20mmol) be dissolved in the acetonitrile (20mL) stirred overnight under room temperature and nitrogen protection.Under 0 ℃; Reaction mixture is joined (4R; 5S; 6S)-3-(hexichol oxygen phosphorus acyloxy)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) (6g, 10mmol) and triethylamine (2.0g is in acetonitrile 20mmol) (40mL) solution.Mixed solution is risen to room temperature, stirred overnight under nitrogen protection.Then reaction mixture under reduced pressure concentrates, and obtains the oily residue, through silica gel column chromatography, preparation HPLC purifying, gets product (0.81g, 9.56%).
The preparation of step 2 compound 11
Adding step 1 products therefrom in the hydrogenation still (5.08g, 0.006mol), the mixed solution (10mL: 10mL) of THF and water; 10%Pd/C (1g); At hydrogen pressure is stirring at room 2 hours under the 30PSI, removes by filter Pd/C, and with THF and deionized water wash.Merging filtrate is used ethyl acetate extraction.Water layer is with preparation HPLC purifying, and lyophilize gets product (300mg, 9.4%).
Molecular formula: C
19H
25N
5O
7S
3Molecular weight: 531.63 MS (M+1): 532.0
1H-NMR(400MHz，DMSO-d
6)：δ1.03(3H，d)，1.11(3H，d)，1.58(1H，m)，2.59(1H，m)，3.00(1H，d)，3.13(3H，m)，3.70(1H，m)，3.86(1H，m)，3.93(1H，d)，4.39(1H，dd)，4.63(1H，dd)，4.93(1H，d)，7.92(1H，s)，8.34(2H，b?r.s)，δ8.93(1H，t).
The preparation of step 3 compound 11 sodium salts
(0.80g 1mmol) is dissolved in the THF (10mL), adds NaHCO with step 1 products therefrom
3Solution (0.08g, 1mmol; Water: 5mL) and 10%Pd/C (1g contains 50% water).Mixture stirred under room temperature and atmosphere of hydrogen 5 hours tempestuously.Remove by filter Pd/C, use the diethyl ether washed twice, water layer through preparation HPLC purifying, freeze-drying, gets product (280mg, 50.7%) under neutrallty condition.
Embodiment 4 (4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(2-amino-sulfonyl benzo [b]
Furans-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (compound 39)
Preparation
Step 1 (2S, 4S)-4-sulfydryl-2-[(2-amino-sulfonyl benzo [b] furans-6-yl) methyl amido formyl radical] tetramethyleneimine-1-carboxy acid mutual-nitro carbobenzoxy's preparation
With 2-amino-sulfonyl-6-amino methyl benzo [b] furans (1.357g, 6.0mmol) with (1S, 4S)-(1.850g 6.0mmol) is dissolved among the DMF 3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxy acid mutual-nitro carbobenzoxy, stirring at room 2 hours.Mixed solution is poured in the water, used ethyl acetate extraction.Organic layer is used Na
2SO
4Drying, vacuum concentration, bullion is used purification by silica gel column chromatography.Get product (2.541g, 79.2%).
Step 2 (4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-3-[(3S, 5S)-1-(to the nitro carbobenzoxy-(Cbz))-5-[(2-amino-sulfonyl benzo [b] furans-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With step 1 products therefrom (2.566g; 4.8mmol) and (4R, 5S, 6S)-3-(hexichol oxygen phosphorus acyloxy)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) (2.854g; 4.8mmol) be dissolved among the DMF; (0.971g, 9.6mmol), stirring at room is 2 hours under nitrogen protection to add triethylamine (TEA).Reaction mixture is poured in the water, filtered.Get product (3.547g, 84.0%).
The preparation of step 3 compound 39
(3.516g, 4.0mmol), Pd/C (2.3g) joins mixed solution (120mL, the V of THF and water with step 2 products therefrom
THF: V
Water=7: 3).Then mixed solution being poured in the hydrogenation still, is 4MPa at hydrogen pressure, and temperature of reaction is 27 ℃-30 ℃ reacted 2 hours down, removed by filter Pd/C, with the mixed solution (V of THF and deionized water
THF: V
Water=2: 3) washing.Merging filtrate and washings, with ETHYLE ACETATE (30ml * 3) extraction, water layer is with preparation liquid phase purifying, and lyophilize gets white solid (0.119g, 5.3%).
Molecular formula: C
24H
28N
4O
8S
2Molecular weight: 564.63 MS (M+1): 565
1H-NMR(400MHz，DMSO-d
6)：δ1.13(3H，d)，1.15(3H，d)，1.54(1H，m)，2.53(1H，m)，2.58(1H，m)，3.18(1H，dd)，3.39(2H，m)，3.53(1H，t)，3.73(1H，t)，3.94(1H，s)，4.13(1H，dd)，4.42(2H，m)，5.04(1H，s)，7.29(1H，d)，7.40(1H，s)，7.54(1H，s)，7.72(1H，d)，8.00(2H，s)，8.60(1H，t).
Embodiment 5 (4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(3-amino-sulfonyl-1H-Yin
Diindyl-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (compound 47)
Preparation
Step 1 (2S, 4S)-4-sulfydryl-2-[(3-amino-sulfonyl-1H-indoles-6-yl) methyl amido formyl radical] tetramethyleneimine-1-carboxy acid mutual-nitro carbobenzoxy's preparation
With 3-amino-sulfonyl-6-aminomethylindole (1.126g, 5.0mmol) with (1S, 4S)-(1.542g 5.0mmol) is dissolved among the DMF 3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxy acid mutual-nitro carbobenzoxy, stirring at room 2 hours.Mixed solution is poured in the water, used ethyl acetate extraction.Organic layer is used Na
2SO
4Drying, vacuum concentration, bullion is used purification by silica gel column chromatography.Get product (2.159g, 81%).
Step 2 (4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-3-[(3S, 5S)-1-(to the nitro carbobenzoxy-(Cbz))-5-[(3-amino-sulfonyl-1H-indoles-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With step 1 products therefrom (2.188g; 4.1mmol) and (4R, 5S, 6S)-3-(hexichol oxygen phosphorus acyloxy)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) (2.437g; 4.1mmol) be dissolved among the DMF; (0.888g, 8.8mmol), stirring at room is 2 hours under nitrogen protection to add triethylamine (TEA).Reaction mixture is poured in the water, filtered.Get product (3.020g, 84%).
The preparation of step 3 compound 47
(2.985g, 3.4mmol), Pd/C (2.0g) joins mixed solution (120mL, the V of THF and water with step 2 products therefrom
THF: V
Water=7: 3).Reaction suspends, and reaction solution is poured in the H-H reaction still, in hydrogen (4MPa) protection and 27 ℃-30 ℃ stirrings 2 hours down, removes by filter Pd/C, with the mixed solution (V of THF and deionized water
THF: V
Water=2: 3) washing.Merging filtrate and washings, with ETHYLE ACETATE (30ml * 3) extraction, water layer is with preparation HPLC purifying, and lyophilize gets white solid (0.187g, 9.7%).
Molecular formula: C
24H
29N
5O
7S
2Molecular weight: 563.65 MS (M+1): 564
1H-NMR(400MHz，DMSO-d
6)：δ1.06(3H，d)，1.11(3H，d)，1.60(1H，m)，2.53(1H，m)，2.66(1H，dd)，3.15(1H，dd)，3.52(1H，m)，3.71(1H，dd)，3.93(1H，t)，4.09(1H，dd)，4.33(1H，dd)，4.45(1H，dd)，5.03(1H，s)，7.06(1H，d)，7.10(2H，s)，7.42(1H，s)，7.73(1H，d)，7.76(1H，d)，8.47(1H，t)，12.4(1H，br.S).
The preparation of step 4 compound 47 sodium salts
The compound 470.56g (1mmol) of step 3 preparation is dissolved in the 4mL deionized water, is cooled to about 0 ℃ under stirring, slowly add powdery sodium hydrogencarbonate 0.1g, insulated and stirred 2 hours gets the 0.41g sodium salt, yield 70.0% with preparation HPLC purifying.
Embodiment 6 (4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(2-amino-sulfonyl-1H-Yin
Diindyl-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (compound 48)
Preparation
Step 1 (2S, 4S)-4-sulfydryl-2-[(2-amino-sulfonyl-1H-indoles-6-yl) methyl amido formyl radical] tetramethyleneimine-1-carboxy acid mutual-nitro carbobenzoxy's preparation
With 2-amino-sulfonyl-6-aminomethylindole (1.352g, 6.0mmol) with (1S, 4S)-(1.848g 6.0mmol) is dissolved among the DMF 3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxy acid mutual-nitro carbobenzoxy, stirring at room 2 hours.Mixed solution is poured in the water, handled with ETHYLE ACETATE.Organic layer is used Na
2SO
4Drying, vacuum concentration, bullion is used purification by silica gel column chromatography.Get product (2.366g, 73.9%).
Step 2 (4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-3-[(3S, 5S)-1-(to the nitro carbobenzoxy-(Cbz))-5-[(2-amino-sulfonyl-1H-indoles-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With step 1 products therefrom (2.348g; 4.4mmol) and (4R, 5S, 6S)-3-(hexichol oxygen phosphorus acyloxy)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) (2.632g; 4.4mmol) be dissolved among the DMF; (0.888g, 8.8mmol), stirring at room is 2 hours under nitrogen protection to add triethylamine (TEA).Reaction mixture is poured in the water, filtered.Get product (3.164g, 82%).
The preparation of step 3 compound 48
(3.160g, 3.6mmol), Pd/C (2.1g) joins mixed solution (120mL, the V of THF and water with step 2 products therefrom
THF: V
Water=7: 3).Reaction suspends, and reaction solution is poured in the H-H reaction still, in hydrogen (4MPa) protection and 27 ℃-30 ℃ stirrings 2 hours down, removes by filter Pd/C, with the mixed solution (V of THF and deionized water
THF: V
Water=2: 3) washing.Merging filtrate and washings, with ETHYLE ACETATE (30ml * 3) extraction, water layer is with preparation HPLC purifying, and lyophilize gets white solid (0.140g, 6.9%).
Molecular formula: C
24H
29N
5O
7S
2Molecular weight: 563.65 MS (M+1): 564
1H-NMR(400MHz，DMSO-d
6)：δ1.13(3H，d)，1.15(3H，d)，1.83(1H，m)，2.62(1H，m)，2.83(1H，m)，3.14(1H，m)，3.46(1H，m)，3.63(1H，t)，3.92(2H，m)，4.08(1H，d)，4.33(1H，d)，4.49(1H，s)，5.02(1H，d)，6.77(1H，s)，6.96(1H，d)，7.40(1H，s)，7.55(1H，d)，7.86(2H，s)，8.58(1H，s).
Claims (10)
1. ester, its steric isomer or its solvated compounds of the compound shown in the logical formula I, its pharmacy acceptable salt, its facile hydrolysis:
Wherein: R
1Represent the 1-hydroxyethyl, 1-fluoro ethyl or methylol;
R
2Represent Wasserstoffatoms or C
1-6Alkyl;
R
3Represent Wasserstoffatoms or carboxyl-protecting group;
R
4, R
5, R
6, R
7Independently represent Wasserstoffatoms or C respectively
1-6Alkyl;
R
8, R
9Independently represent Wasserstoffatoms, C respectively
1-6Alkyl or halo C
1-6Alkyl, perhaps R
8, R
9Form 3-8 unit naphthenic base with the carbon atom that is connected;
A represents the thick heteroaryl of 5-8 single heteroaryl of unit or 9-14 unit.
2. the ester of compound as claimed in claim 1, its pharmacy acceptable salt, its facile hydrolysis, its steric isomer or its solvated compounds:
Wherein: R
1Represent the 1-hydroxyethyl, 1-fluoro ethyl or methylol;
R
2Represent Wasserstoffatoms or C
1-6Alkyl;
R
3Represent Wasserstoffatoms or carboxyl-protecting group;
R
4, R
5, R
6, R
7Independently represent Wasserstoffatoms or C respectively
1-6Alkyl;
R
8, R
9Independently represent Wasserstoffatoms, C respectively
1-6Alkyl or halo C
1-6Alkyl, perhaps R
8, R
9Form 3-8 unit naphthenic base with the carbon atom that is connected;
A represents 5-6 single heteroaryl of unit or 9-10 unit benzo heteroaryl.
3. the ester of compound as claimed in claim 2, its pharmacy acceptable salt, its facile hydrolysis, its steric isomer or its solvated compounds:
Wherein: R
1Represent the 1-hydroxyethyl;
R
2Represent methylidene;
R
3Represent Wasserstoffatoms or to nitrobenzyl;
R
4, R
5Independently represent Wasserstoffatoms respectively;
R
6, R
7Independently represent Wasserstoffatoms respectively, methyl, ethyl or propyl group;
R
8, R
9Independently represent Wasserstoffatoms respectively, methyl, methyl fluoride, trifluoromethyl or 2,2,2-trifluoroethyl, perhaps R
8, R
9Form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl with the carbon atom that is connected;
A represents pyridyl, pyrimidyl, thienyl, thiazolyl, thiadiazolyl group, 4,5-dihydro-thiazolyl 、 oxazolyl 、 isoxazolyl 、 oxadiazole base, pyrryl, imidazolyl, pyrazolyl, triazol radical, benzofuryl, benzoxazolyl, benzothienyl, benzothiazolyl, indyl, pseudoindoyl, benzimidazolyl-, indazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl or cinnolines base.
4. the ester of compound as claimed in claim 3, its pharmacy acceptable salt, its facile hydrolysis, its steric isomer or its solvated compounds:
Wherein: R
1Represent the 1-hydroxyethyl;
R
2Represent methylidene;
R
3Represent Wasserstoffatoms or to nitrobenzyl;
R
4, R
5Independently represent Wasserstoffatoms respectively;
R
6, R
7Independently represent Wasserstoffatoms respectively, methyl or ethyl;
R
8, R
9Independently represent Wasserstoffatoms respectively;
A represents pyridyl, pyrimidyl, thienyl, thiazolyl, 1,3,4-thiadiazolyl group, 1; 2,4-thiadiazolyl group, 4,5-dihydro-thiazolyl 、 oxazolyl 、 isoxazolyl, 1; 3; 4-oxadiazole base, 1,2,4-oxadiazole base, pyrryl, imidazolyl, pyrazolyl, 1; 2,4-triazol radical, benzo [b] furyl, benzo [c] furyl, benzo [d] oxazolyl, benzo [b] thienyl, benzo [c] thienyl, benzo [d] thiazolyl, indyl, pseudoindoyl, benzo [d] imidazolyl, indazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl or cinnolines base.
5. the ester of compound as claimed in claim 4, its pharmacy acceptable salt, its facile hydrolysis, its steric isomer or its solvated compounds:
Wherein: R
1Represent the 1-hydroxyethyl;
R
2Represent methylidene;
R
3, R
4, R
5Independently represent Wasserstoffatoms respectively;
R
6, R
7Independently represent Wasserstoffatoms respectively, methyl or ethyl;
R
8, R
9Independently represent Wasserstoffatoms respectively;
A represents pyridyl, pyrimidyl, thienyl, thiazolyl, 1,3,4-thiadiazolyl group, 1; 2; 4-thiadiazolyl group 、 oxazolyl, 1,3,4-oxadiazole base, 1; 2,4-oxadiazole base, pyrryl, imidazolyl, benzo [b] furyl, benzo [b] thienyl, benzo [d] thiazolyl, indyl, benzo [d] imidazolyl, indazolyl, quinolyl or isoquinolyl.
6. the ester of compound as claimed in claim 5, its pharmacy acceptable salt, its facile hydrolysis, its steric isomer or its solvated compounds are selected from:
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-aminosulfonyl yl pyridines-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-3-[(3S, 5S)-5-[[5-(N-methyl amido alkylsulfonyl) pyridine-2-yl] methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl pyridin-3-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl pyrimidine-2-base) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl thiophene-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(3S, 5S)-5-[[5-(N-ethyl amido alkylsulfonyl) thiophene-2-yl] methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(4-amino-sulfonyl thiophene-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl thiazol-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(4-amino-sulfonyl thiazol-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl-1,3,4-thiadiazoles-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(3-amino-sulfonyl-1,2,4-thiadiazoles-5-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl-1,2,4-thiadiazoles-3-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-aminosulfonyl base oxazole-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(4-aminosulfonyl base oxazole-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl-1,3,4-oxadiazole-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(3-amino-sulfonyl-1,2,4-oxadiazole-5-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl-1,2,4-oxadiazole-3-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl-1H-pyrroles-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(4-amino-sulfonyl-1H-pyrroles-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl-1H-imidazoles-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(4-amino-sulfonyl-1H-imidazoles-2-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(2-amino-sulfonyl benzo [b] furans-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(3-amino-sulfonyl benzo [b] furans-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(2-amino-sulfonyl benzo [b] thiophene-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(3-amino-sulfonyl benzo [b] thiophene-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(2-amino-sulfonyl benzo [d] thiazole-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(3-amino-sulfonyl-1H-indoles-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(2-amino-sulfonyl-1H-indoles-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(2-amino-sulfonyl-1H-benzo [d] imidazoles-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(3-amino-sulfonyl-1H-indazole-6-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(2-amino-sulfonyl quinoline-7-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(3-amino-sulfonyl quinoline-7-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(4-amino-sulfonyl quinoline-7-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid and
(4R, 5S, 6S)-6-[(R)-the 1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(3-amino-sulfonyl isoquinoline 99.9-7-yl) methyl amido formyl radical] tetramethyleneimine-3-base sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
7. contain the pharmaceutical prepn of ester, its steric isomer or its solvated compounds of each described compound of claim 1～6, its pharmacy acceptable salt, its facile hydrolysis, it is characterized in that comprising one or more pharmaceutical carriers.
8. be used to prepare the purposes of the medicine that treats and/or prevents infection like ester, its steric isomer or its solvated compounds of each described compound of claim 1～6, its pharmacy acceptable salt, its facile hydrolysis.
9. the method for the said compound of formula I is led in preparation; This method comprises ester, its steric isomer or its solvated compounds that makes compound, its pharmacy acceptable salt, its facile hydrolysis shown in the logical formula III; Ester, its steric isomer or its solvated compounds generation nucleophilic substitution reaction with compound shown in the logical formula II, its pharmacy acceptable salt, its facile hydrolysis
Wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9With A in the claim 1 definition; L represents leavings group.
10. ester, its steric isomer or its solvated compounds of the logical described compound of formula II, its pharmacy acceptable salt, its facile hydrolysis:
Wherein, R
4, R
5, R
6, R
7, R
8, R
9With A in the claim 1 definition.
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| CN101367815A (en) * | 2007-06-28 | 2009-02-18 | 山东轩竹医药科技有限公司 | Six-membered ring methanamide substituted sulfhydryl pyrrolidine carbpenem compound |
| CN101367810A (en) * | 2007-06-28 | 2009-02-18 | 山东轩竹医药科技有限公司 | Novel carbpenem antibiotic |
| CN101372489A (en) * | 2007-06-28 | 2009-02-25 | 山东轩竹医药科技有限公司 | Carbapenem derivative containing sulfhydryl pyrrolidine formamide benzyl |
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| CN101323615A (en) * | 2007-06-11 | 2008-12-17 | 山东轩竹医药科技有限公司 | Pennem derivates containing formamide heterocycle sulfonic acid amide sulfhydryl pyrrolidine |
| CN101367815A (en) * | 2007-06-28 | 2009-02-18 | 山东轩竹医药科技有限公司 | Six-membered ring methanamide substituted sulfhydryl pyrrolidine carbpenem compound |
| CN101367810A (en) * | 2007-06-28 | 2009-02-18 | 山东轩竹医药科技有限公司 | Novel carbpenem antibiotic |
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