CN1315845C - Methylene containing aminobeterocycle substitutional cephalosporin of amidinothioacetamide, preparation method and application - Google Patents
Methylene containing aminobeterocycle substitutional cephalosporin of amidinothioacetamide, preparation method and application Download PDFInfo
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- CN1315845C CN1315845C CNB200410050908XA CN200410050908A CN1315845C CN 1315845 C CN1315845 C CN 1315845C CN B200410050908X A CNB200410050908X A CN B200410050908XA CN 200410050908 A CN200410050908 A CN 200410050908A CN 1315845 C CN1315845 C CN 1315845C
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- China
- Prior art keywords
- preparation
- heterocyclic ring
- cynnematin
- methylene radical
- sulphur
- Prior art date
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Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 150000001780 cephalosporins Chemical class 0.000 title claims abstract description 16
- 229930186147 Cephalosporin Natural products 0.000 title claims abstract description 13
- 229940124587 cephalosporin Drugs 0.000 title claims abstract description 13
- LMDIZNLKYPDVER-UHFFFAOYSA-N 3-amino-3-iminopropanethioamide Chemical compound NC(=N)CC(N)=S LMDIZNLKYPDVER-UHFFFAOYSA-N 0.000 title abstract 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 239000005864 Sulphur Substances 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- -1 alkyl ketone Chemical class 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 6
- 239000011707 mineral Substances 0.000 claims description 6
- 235000010755 mineral Nutrition 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims 7
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 abstract description 10
- 241000192125 Firmicutes Species 0.000 abstract description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001291 vacuum drying Methods 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 8
- 230000000845 anti-microbial effect Effects 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 6
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 6
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 6
- ZTWBXCGKRKUYSY-UHFFFAOYSA-N piperazine-1-carboximidamide Chemical compound NC(=N)N1CCNCC1 ZTWBXCGKRKUYSY-UHFFFAOYSA-N 0.000 description 6
- 150000001782 cephems Chemical class 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 229940081561 rocephin Drugs 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- KTAVBOYXMBQFGR-MAODNAKNSA-J tetrasodium;(6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyimino-1-oxidoethylidene]amino]-3-[(2-methyl-5,6-dioxo-1h-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C KTAVBOYXMBQFGR-MAODNAKNSA-J 0.000 description 4
- KREOCUNMMFZOOS-UHFFFAOYSA-N 1,3-di(propan-2-yl)thiourea Chemical compound CC(C)NC(S)=NC(C)C KREOCUNMMFZOOS-UHFFFAOYSA-N 0.000 description 3
- 241000606768 Haemophilus influenzae Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 3
- 241000194017 Streptococcus Species 0.000 description 3
- 241000193998 Streptococcus pneumoniae Species 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 3
- 230000002949 hemolytic effect Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- JLLFFHVWBDFRIZ-UHFFFAOYSA-N 1,1-di(propan-2-yl)thiourea Chemical compound CC(C)N(C(C)C)C(N)=S JLLFFHVWBDFRIZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 102000016397 Methyltransferase Human genes 0.000 description 2
- 108060004795 Methyltransferase Proteins 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- 241000607768 Shigella Species 0.000 description 2
- 241000193996 Streptococcus pyogenes Species 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- DYAIAHUQIPBDIP-AXAPSJFSSA-N cefonicid Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](O)C=2C=CC=CC=2)CC=1CSC1=NN=NN1CS(O)(=O)=O DYAIAHUQIPBDIP-AXAPSJFSSA-N 0.000 description 2
- 229960004489 cefonicid Drugs 0.000 description 2
- 229960004261 cefotaxime Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- QSLPNSWXUQHVLP-UHFFFAOYSA-N $l^{1}-sulfanylmethane Chemical compound [S]C QSLPNSWXUQHVLP-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 1
- 102100025142 Beta-microseminoprotein Human genes 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 101100185029 Homo sapiens MSMB gene Proteins 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-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
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241001312524 Streptococcus viridans Species 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 241000684092 bacterium 1-4 Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 description 1
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 description 1
- 229960003585 cefmetazole Drugs 0.000 description 1
- XDZKBRJLTGRPSS-BGZQYGJUSA-N cefodizime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(C)=C(CC(O)=O)S1 XDZKBRJLTGRPSS-BGZQYGJUSA-N 0.000 description 1
- 229960001958 cefodizime Drugs 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- SLAYUXIURFNXPG-CRAIPNDOSA-N ceforanide Chemical compound NCC1=CC=CC=C1CC(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)CC(O)=O)CS[C@@H]21 SLAYUXIURFNXPG-CRAIPNDOSA-N 0.000 description 1
- 229960004292 ceforanide Drugs 0.000 description 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- 229960002588 cefradine Drugs 0.000 description 1
- CXHKZHZLDMQGFF-ZSDSSEDPSA-N cefuzonam Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=CN=NS1 CXHKZHZLDMQGFF-ZSDSSEDPSA-N 0.000 description 1
- 229950000807 cefuzonam Drugs 0.000 description 1
- 229940047526 cephalexin monohydrate Drugs 0.000 description 1
- 125000001271 cephalosporin group Chemical group 0.000 description 1
- QHTOIDKCEPKVCM-ZCFIWIBFSA-N cepham Chemical compound S1CCCN2C(=O)C[C@H]21 QHTOIDKCEPKVCM-ZCFIWIBFSA-N 0.000 description 1
- RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
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- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
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- 230000000968 intestinal effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- YGZIWEZFFBPCLN-UHFFFAOYSA-N n,3-bis(2-chloroethyl)-4-hydroperoxy-2-oxo-1,3,2$l^{5}-oxazaphosphinan-2-amine Chemical compound OOC1CCOP(=O)(NCCCl)N1CCCl YGZIWEZFFBPCLN-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000005331 phenylglycines Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical class O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The present invention relates to methylene containing aminobeterocycle substitutional cephalosporin of amidinothioacetamide, a preparation method and application, which discloses the chemical structure general formula of a methylene containing aminobeterocycle substitutional cephalosporin of amidinothioacetamide. The preparation method uses 7-amido-3-methylene containing aminobeterocycle substitution-cephalosporanic acid generates reaction with bromo-acetyl bromide and double-substitution thiourea to prepare the methylene containing aminobeterocycle substitutional cephalosporin of amidinothioacetamide. The obtained product has good antibacterial activity to Gram-positive bacteria.
Description
Technical field
The invention relates to new cynnematin, amidine sulphur acetamido cephalosporins derivatives that particularly a kind of new C3 methylene radical nitrogen heterocyclic ring that therapeutic activity is arranged replaces and synthetic and application thereof.
Technical background
Therefore the cephem microbiotic has good antimicrobial acivity and hypotoxicity to Mammals, and is the medicine of very useful treatment Mammals transmissible disease.
Cephalosporin analog antibiotic along with its resistance of wide clinical application also produces immediately, particularly become present serious clinical problem by the streptococcus aureus (MRSA) of Staphcillin resistance, the streptococcus pneumoniae (PRSP) of penicillin resistance and the transmissible disease that the resistance faecalis causes.Just because of this, strong request obtains new cephem microbiotic, to strengthen the microorganism active of these bacteriums of antagonism.
Transform on 7 side chains in the structure of modification of cynnematin and mainly contain cefotaxime acetic acid side chain series, as cefotaxime, rocephin;
Phenylglycine series is as Cephalexin Monohydrate Micro/Compacted, cefradine.And mainly concentrating on the C-3 position, the transformation of pharmacokinetics aspect introduces various functional groups.Current cynnematin structure of modification research field is comparatively active is modification to the C-3 position, the C3-of cephalosporin-group that the OAc group is contained S or N replaces, can improve and widen antibiotic effect, as sulfo-heterocyclic substituted on the 7-ACA3 position, can obviously strengthen cynnematin to the activity (Chinese microbiotic magazine, Vol.252 in 1988) of gram-positive microorganism and negative bacterium and improve stability to β-Nei Xiananmei.For example 3 be the tetrazole sulfydryl as cefoperazone, cefmetazole, 3 be the triazine sulfydryl as rocephin.3 be the thiadiazoles sulfydryl as Cephazolin, cefuzonam etc.C3 then can prolong metabolic half life for introducing acid functional group, reaches long-acting, and result of treatment efficiently is as rocephin, cefonicid.
Functional group is introduced in the C3 position of cephalosporin mother nucleus 7-ACA, obtain different intermediates, as these intermediates of 7-ACT, 7-TACS are commercial pharmaceutical intermediates in the prior art, the free amine group and the various thiocarbamide of these intermediates are carried out condensation, obtain the activity that a series of cephalosporins derivatives have anti-G+, G-, and to β-Nei Xiananmei stability and the wider drug metabolism phase.
C-3 substituting group used in the The compounds of this invention is known in the cephem field, but does not see in the past with C-7 substituting group among the present invention and combine.C-3 and the substituent combination of C-7 that the applicant finds in the The compounds of this invention to be provided have enlarged the cynnematin antimicrobial spectrum, have strengthened its activity to positive bacteria, thereby have had commercial viability.
Summary of the invention
The purpose of this invention is to provide the cepham streptozotocin derivative
Another object of the present invention provides the method for preparing cephalosporins derivatives
A further object of the present invention has provided pharmaceutical composition, the especially injection that this kind cephalosporins derivatives is made activeconstituents
A further object of the present invention has provided cephalosporins derivatives and has been used for the treatment of the gram positive bacteria infection purposes.
Technical solution of the present invention
Sulphur amidine acetamido cynnematin and/or its pharmacy acceptable salt that a kind of C3 methylene radical nitrogen heterocyclic ring replaces is characterized in that representing with following general formula
Wherein R1 is
Above-mentioned cynnematin is characterized in that a kind of unbound state, a kind of solvated compounds state.
Above-mentioned cynnematin, it is preferably the compound that following structural formula is represented:
Its chemistry 7a-((N, N-di-isopropyl) amidine sulphur acetamido) by name-3-((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-yl) methyl)-Cephalosporanic acid (cephalo piperazine amidine).
Above-described cephalo piperazine amidine can be its hydrobromate or amine salt.
The compound of general formula I also can be the compound of following structure:
The preparation method of the cynnematin of general formula I is characterized in that comprising:
1, the amino C-3 methyne of 7-nitrogen heterocyclic ring is replaced the dissolving of 4-carboxyl Cephalosporanic acid or be suspended in the appropriate solvent system; And, make solution molten fully clear with organic bases or mineral alkali regulator solution PH;
2, the settled solution with step 1 gained reacts with bromoacetyl bromide;
3, with the solution acidifying of step 2 gained;
4, with the same N of the product of step 3 gained, the two substituting thioureidos of N react;
5, the product that step 4 is obtained separates.
Described solvent is meant alkyl ketone, alkyl alcohol, the mixture of halogenated alkane or above-mentioned solvent.
Described alkyl ketone is meant acetone, methyl iso-butyl ketone (MIBK), and alkyl alcohol is meant methyl alcohol, ethanol, Virahol, and halogenated alkane is meant methylene dichloride.
The preparation method of described cynnematin, its organic bases is triethylamine, diethylamine, Tributylamine, tetramethyl guanidine, mineral alkali is sodium bicarbonate, yellow soda ash, NH
3Water etc.
The preparation method of described cynnematin, wherein hydrochloric acid, sulfuric acid, Glacial acetic acid, phosphoric acid are adopted in acidifying.
The preparation method of described cynnematin, wherein the amino C-3 methyne of 7-nitrogen heterocyclic ring replacement 4-carboxyl Cephalosporanic acid is selected from following compounds:
Described in the definition such as general formula I of R1.
N, the two substituting thioureidos of N are selected from following compounds:
The present invention also provides the preparation method of the cynnematin cephalo piperazine amidine with preferred construction formula II.It is characterized in that 7-amino-3-((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-yl) methyl sulphur))-reaction of Cephalosporanic acid and bromoacetyl bromide makes 7-acetobrom amino-3-((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as triazine-3-yl) methyl sulphur))-Cephalosporanic acid, with N, the reaction of N di-isopropyl thiourea makes a kind of cynnematin with anti-microbial activity again.Its reaction formula is as follows:
Detailed preparation method may further comprise the steps
1, with 7-amino-3-((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-yl) sulphur) methyl)-Cephalosporanic acid (7ACT) dissolves or is suspended in the appropriate solvent system.
Described solvent can be moisture or aqueous solvent system not, as ketone C1-C6 alkyl ketone particularly, as acetone, methyl iso-butyl ketone (MIBK).Diethyl ketone; The alcohols of C1-C6: methyl alcohol, ethanol, Virahol etc., nitrile: as acetonitrile; The mixed solvent of acid amides such as N,N-DIMETHYLACETAMIDE, dimethyl formamide etc. or above-mentioned solvent.
2, step 1 is obtained solution and make the solution clarification with organic amine or mineral alkali adjusting PH.
Described amine is triethylamine, diethylamine, Tributylamine, and mineral alkali is yellow soda ash, sodium bicarbonate, ammoniacal liquor etc.
3, step 2 being obtained solution reacts with bromoacetyl bromide.
Every mole of 7-ACT needs the bromoacetyl bromide of 0.5-3.0ml, preferred 1.2-2.4ml.
Its temperature of reaction is 0-50 ℃ of preferred 10-40 ℃,
Its reaction times is 10-60 minute, obtains settled solution
4, the reaction solution acidifying that step 3 is obtained also separates.Wherein hydrochloric acid, sulfuric acid, Glacial acetic acid, phosphoric acid are adopted in acidifying.
5, the product that step 4 is obtained dissolves or is suspended in the solvent, and with N, the N di-isopropyl thiourea reacts;
The mol ratio of acetobrom 7ACT and thiocarbamide is the 1.0-4.0 mole, and preferred 1-2.5 mole more preferably pulls out the 1.2-1.8 mole, temperature of reaction 0-42 ℃, and reaction times 30-300 minute.
Described solvent is the halo alkanes, ketone, alcohols or their mixed solvent.
6, the product separation that step 5 is obtained.Separation adopts certain methods commonly used to make it the precipitation byproduct of reaction as the adding solvent and impurity then is dissolved in the solvent, and the product purity Gao Keda of gained is more than 90%.
Described solvent is a ketone, alcohols, nitrile or their mixture.Ketone such as acetone, methyl iso-butyl ketone (MIBK), alcohols such as methyl alcohol, ethanol, nitrile such as acetonitrile or their mixture
The present invention also comprises provides a kind of cephalosporin intermediate, and available following general formula is represented:
The R1 definition is the same.
Above-mentioned intermediates preparation is characterized in that general formula VI and bromoacetyl bromide reaction are made.Specifically finish by 1 to 4 step among the detailed preparation method.
The present invention also comprises a kind of pharmaceutical composition, and the described compound that it comprises general formula I or II is activeconstituents and pharmaceutically acceptable carrier.
Aforementioned pharmaceutical compositions is as antiseptic-germicide.
Experimental technique commonly used is adopted in the external antimicrobial experiment of The compounds of this invention, and its minimum inhibitory concentration MIC (mg/l) is as shown in the table.
| Compound I I | Compound III | Compound IV | Compound V | |
| Gold Portugal bacterium | 1-4 | ?0.25-0.5 | 0.25-2 | |
| Form staph | 0.0312-2 | 0.5-2 | ||
| A organizes Hemolytic streptococcus | 2-8 | 0.125-1 | ||
| B organizes Hemolytic streptococcus | ?0.25-4 | 0.5-1 | ||
| Streptococcus viridans | 0.125-4 | |||
| Faecalis | 4-8 | ?4-8 | 2-8 | |
| Micrococcus scarlatinae | ?0.125-1 | 0.0312-0.5 | ||
| Streptococcus pneumoniae | 0.125-0.5 | 0.25-0.5 | ||
| Salmonella | 8-16 | 2-8 | ||
| Shigella | ?＞64 | 16-256 | ||
| Pseudomonas aeruginosa | ＞512 | ?＞256 | ＞512 | |
| Hemophilus influenzae | 8-16 | ?8-64 | ＞256 |
As seen from the above table, The compounds of this invention is to golden Portugal bacterium, form staph, micrococcus scarlatinae, streptococcus pneumoniae, Hemolytic streptococcus equal altitudes sensitivity, to the faecalis sensitivity, to Salmonella, Shigella, hemophilus influenzae medium sensitivity or resistance, Pseudomonas aeruginosa there is not antibiotic activity, show that above-claimed cpd has strong or stronger anti-microbial activity to G+, G-has activity to part.
Above-claimed cpd is obtained by third generation cephalosporin such as rocephin, Cefodizime, cefonicid, ceforanide transformation, at the C3 that keeps them is that functional group is constant down, N is introduced in the C7 position, the N di-isopropyl thiourea, described third generation cephalosporin has good susceptibility to G-, as intestinal bacteria, hemophilus influenzae etc., but, most of G+ is comprised the susceptibility of faecalis is poor to the Pseudomonas aeruginosa resistance.
The invention has the beneficial effects as follows by 7 of cephalo parent nucleus and introduce N, the synthetic a series of cephem microbiotic of the two substituting thioureidos of N, this class cephem is compared with third generation cephalosporin, has obviously increased the anti-microbial activity to gram-positive microorganism, particularly golden Portugal bacterium, resistance enterococcus spp have enlarged antimicrobial spectrum.
Specific embodiment
The preparation of 7a-((N, N-di-isopropyl) amidine sulphur acetamido)-3-((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-yl) methyl)-Cephalosporanic acid (cephalo piperazine amidine)
One, the preparation of intermediate
Example 1
With 50ml toluene, 50ml water adds in the there-necked flask, add 5 gram C-21 (0) 7-amino-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-yl] sulphur] methyl]-Cephalosporanic acid (having another name called 7-ACT), drip the 3.4ml triethylamine, stirring makes it dissolving, adds bromoacetyl bromide 3ml, the 30m15%NaHCO3 aqueous solution, reacted 2 hours, leave standstill phase-splitting, organic phase discards, water is transferred PH=3 with hydrochloric acid, 0-10 ℃ of growing the grain 2 hours, suction filtration, vacuum-drying gets 4 gram 7-acetobrom amino-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazine-3-yl] sulphur] methyl]-Cephalosporanic acid.
Example 2
Vinyl acetic monomer, each 60ml of water, 5 gram 7-ACT are added in the there-necked flasks, and 0-10 ℃ adds triethylamine 3.4ml to be stirred to solid molten entirely, adds bromoacetyl bromide 4.0ml, adds the 2ml triethylamine, reaction is finished, and adds hydrochloric acid and transfers PH=3, separates out solid, growing the grain body 2 hours, suction filtration, vacuum-drying gets 3.3 grams.
Example 3
Acetonitrile, each 60-60ml of water, 5 gram 7-ACT add in the there-necked flask, and 0-10 ℃ adds triethylamine 3.6ml, is stirred to the solid dissolving, adds the 4ml bromoacetyl bromide, mends 30ml5%NaHCO
3The aqueous solution, reaction is finished, and adds hydrochloric acid and transfers PH=3, separates out solid, growing the grain 2 hours, suction filtration, vacuum-drying gets 4.9 gram products.
Example 4
Methylene dichloride, each 250ml of water, 5 gram 7-ACT go in the there-necked flask, and the dropping triethylamine is molten clear to solid, adds bromoacetyl bromide 4ml, there are a large amount of solids to separate out, reacted 2 hours, standing demix is finished in reaction, and organic phase discards, water is transferred PH=3 with hydrochloric acid, growing the grain 2 hours, suction filtration, the product water is washed and starched, vacuum-drying gets 3.2 grams to moisture 2.0%.
Example 5
Acetone, each 50ml of water, 5 gram 7-ACT drip triethylamine and make it molten clear, add bromoacetyl bromide 4.0ml, add 5%NaHCO simultaneously
3Water 100ml reacted 1 hour, and reaction is finished, and transferred PH to 3 with hydrochloric acid, and a large amount of solids are separated out, growing the grain 2 hours, and suction filtration, product washes vacuum-drying with water, draws 4 grams.
Two, the preparation of product cephalo piperazine amidine
Example 1
There-necked flask adds methylene dichloride 200ml, C-21 (1) 2.0 restrains, drips a triethylamine 16ml and makes it to dissolve, add N, N-di-isopropyl thiourea 0.6 gram, back flow reaction is to reacting completely, and solid is separated out, cooling growing the grain 1 hour, suction filtration, vacuum-drying get 1.5 gram title compounds, PH=5.4, turbidity＜No. 1 (1 gram is dissolved in the 10ml water), product is very easily water-soluble.
HNMR (DMSO-d
6, 500Hz): 1.13 (m, 12H ,-CH-CH
3), 3.03 (q, 2H, J=22.0,7.0Hz ,-S-NH-CH-), 3.04,3.61 (d, 2H, the AB type, J=17.5Hz, C2-H), 3.58 (s, 3H ,-N-CH3), 3.88 (m, 4H ,-S-CH2-CO-,-CH-CH3), 4.15,4.35 (d, the 2H.AB type, J=12.5Hz ,-CH2-S-), 5.02 (d, 1H, J=5.0Hz, C6-H), 5.54 (d, 1H, J=4.5Hz, C7-H), 9.38 (s, 1H ,-NH-).
Example 2
Add 100ml methylene dichloride 100ml acetone 2 gram C-21 (1) in the there-necked flask, 0-10 ℃ drips diethylamine 1.4ml and makes it dissolving control PH5.0-7.5, adds thiocarbamide 0.8 gram, and back flow reaction is to reacting completely, growing the grain, suction filtration, vacuum-drying, 2.3 gram title compounds.HNMR result is with example 1.
N, N-diisopropylamidinateand sulphur acetamido-3-(5-carboxymethyl-4-methyl isophthalic acid, 3-thiazole-2-thiopurine methyltransferase) Cephalosporanic acid synthetic
One, the preparation of intermediate
5 gram TACS (7-amino-3-(5-carboxymethyl-4-methyl isophthalic acid, 3-thiazole-2-thiopurine methyltransferase) Cephalosporanic acid) (0.0124mole) add 50ml acetone and 80ml water, stir 0-5 ℃ of temperature control, drip 1.8ml triethylamine (0.013mole), finish.0.5 hour solid is molten clear, adds solid sodium bicarbonate 3.5 grams, drips 2.3ml bromoacetyl bromide (0.026mole) simultaneously, finishes reaction 1.5 hours in batches.Add 1 gram gac, stir decolouring 0.5 hour, suction filtration is washed carbon-coating with 10ml.Merge water, transfer PH=2-2.5 with 3N hydrochloric acid, separate out solid, 0-5 ℃ was stirred growing the grain 1 hour, and suction filtration, solid wash with water to PH=3,50 ℃ of vacuum-drying (＜0.08MPa ", acetobrom TACS5 gram, yield 77%.
Two, the preparation of product
In the 50ml methylene dichloride, add 5 gram acetobrom TACS (0.0096mole), stir temperature control and drip 1 for 0-5 ℃.The 6ml triethylamine, molten clear after 0.5 hour, add 1.9 gram N, N-di-isopropyl thiourea (0.0118mole), be warming up to 38-40 ℃ and be back to thiocarbamide and dissolve fully, refluxed about 0.5 hour and separate out yellow solid, insulation reaction 1.5 hours, lower the temperature then 0-5 ℃ and stirred growing the grain 1 hour, suction filtration, product washes twice with the 10ml methylene dichloride, and 75ml acetone is washed 2 times, 35 ℃ of vacuum-drying (＜0.08MPa〉target compound 4.2 grams, yield 75%.
Following compounds III, IV are, and to be starting raw material with commercial intermediate VI make according to the preparation method of cephalo piperazine amidine.
Wherein R1 is
Structural formula is as follows:
Nuclear magnetic resonance data is:
3.03,3.60 (d, 2H, the AB type, J=17.5Hz, C2-H)
5.00(d，1H，J＝5.9Hz，C6-H)
5.56(d，1H，J＝4.5Hz，C7-H)
9.36(s，1H，-NH-)
Nuclear magnetic resonance data is:
3.05,3.63 (d, 2H, the AB type, J=17.5Hz, C2-H)
5.04(d，1H，J＝5.9Hz，C6-H)
5.56(d，1H，J＝4.5Hz，C7-H)
9.40(s，1H，-NH-)。
Claims (10)
1, a kind of amidine sulphur acetamido cynnematin or its pharmacy acceptable salt of C3 methylene radical nitrogen heterocyclic ring replacement is characterized in that representing with following general formula:
Wherein R1 is
2, the amidine sulphur acetamido cynnematin of the described C3 methylene radical nitrogen heterocyclic ring replacement of claim 1 is characterized by following structural formula and represents:
Or
Or
Or
3, the preparation method of the amidine sulphur acetamido cynnematin of the described C3 methylene radical of claim 1 nitrogen heterocyclic ring replacement is characterized in that comprising:
(1), the amino C-3 methylene radical of 7-nitrogen heterocyclic ring is replaced the dissolving of 4-carboxyl Cephalosporanic acid or be suspended in the appropriate solvent system; And, make solution molten fully clear with organic bases or mineral alkali regulator solution PH;
(2), step 1 gained settled solution is reacted with bromoacetyl bromide;
(3), with the solution acidifying of step 2 gained;
(4), with the same N of product of step 3, the two substituting thioureidos of N react;
(5), the product that step 4 is obtained separates.
4, the preparation method of the amidine sulphur acetamido cynnematin of the described C3 methylene radical of claim 3 nitrogen heterocyclic ring replacement, its solvent is meant the mixture of alkyl ketone, alkyl alcohol, haloalkane or above-mentioned solvent.
5, the preparation method of the amidine sulphur acetamido cynnematin of the described C3 methylene radical of claim 3 nitrogen heterocyclic ring replacement, its organic bases is triethylamine, diethylamine, Tributylamine, tetramethyl guanidine, mineral alkali is yellow soda ash, sodium bicarbonate, ammoniacal liquor etc.
6, the preparation method of the amidine sulphur acetamido cynnematin of the described C3 methylene radical of claim 3 nitrogen heterocyclic ring replacement, wherein hydrochloric acid, sulfuric acid, Glacial acetic acid, phosphoric acid are adopted in acidifying.
7, the preparation method of the amidine sulphur acetamido cynnematin of the described C3 methylene radical of claim 3 nitrogen heterocyclic ring replacement, wherein the amino C-3 methylene radical of 7-nitrogen heterocyclic ring replacement 4-carboxyl Cephalosporanic acid is selected from following compounds:
The definition of R1 is described with claim 1;
N, the two substituting thioureidos of N are selected from following compounds:
8, a kind of cephalosporin intermediate, available following general formula is represented:
The definition of R1 is described with claim 1.
9, the preparation method of the described cephalosporin intermediate of claim 8 is characterized in that general formula VI and bromoacetyl bromide reaction are made.
10, a kind of antibacterial combination, the described compound that it comprises claim 1 or 2 is activeconstituents and pharmaceutically acceptable carrier.
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| CN111116610A (en) * | 2019-12-27 | 2020-05-08 | 广药白云山化学制药(珠海)有限公司 | Production method of cefoperazone sodium |
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| US7700581B2 (en) * | 2007-01-31 | 2010-04-20 | Guangzhou Baiyunshan Pharmaceutical Co., Ltd. | Cephalosporin compounds comprising a C3 thio-methyl moiety substituted with N-containing heterocyclic group, and a C7 thiourea acetamido group, their preparations and uses thereof |
| CN101555463B (en) * | 2008-04-08 | 2012-05-30 | 中国科学院上海生命科学研究院湖州工业生物技术中心 | Recombinant escherichia coli strain expressing cephalosporin deacetylase and construction method thereof |
| US20110118462A1 (en) * | 2009-11-18 | 2011-05-19 | Guangzhou Baiyunshan Pharmaceutical Co., Ltd. Guangzhou Baiyunshan Pharmaceutical Factory | N-heterocyclic substituent-containing antibiotic, preparation and use thereof |
| CN105461739B (en) * | 2014-09-09 | 2019-03-29 | 广州白云山医药集团股份有限公司白云山制药总厂 | Crystalline cephem piperazine amidine sodium and its preparation method and application |
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| CN101434611B (en) * | 2007-11-12 | 2013-01-09 | 广州市医药工业研究所 | Nitrogen heterocyclic ring substituted antibiotic, and preparation method and use thereof |
| CN111116610A (en) * | 2019-12-27 | 2020-05-08 | 广药白云山化学制药(珠海)有限公司 | Production method of cefoperazone sodium |
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