CN101323615B - Pennem derivates containing formamide heterocycle sulfonic acid amide sulfhydryl pyrrolidine - Google Patents
Pennem derivates containing formamide heterocycle sulfonic acid amide sulfhydryl pyrrolidine Download PDFInfo
- Publication number
- CN101323615B CN101323615B CN2008101097028A CN200810109702A CN101323615B CN 101323615 B CN101323615 B CN 101323615B CN 2008101097028 A CN2008101097028 A CN 2008101097028A CN 200810109702 A CN200810109702 A CN 200810109702A CN 101323615 B CN101323615 B CN 101323615B
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- CN
- China
- Prior art keywords
- methyl
- acid
- amino
- tetramethyleneimine
- formyl
- 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.)
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- -1 sulfhydryl pyrrolidine Chemical compound 0.000 title claims description 98
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title abstract description 34
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 title abstract description 10
- 125000000623 heterocyclic group Chemical group 0.000 title abstract description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 239000003814 drug Substances 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 3
- OTTZHAVKAVGASB-UHFFFAOYSA-N hept-2-ene Chemical compound CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 claims description 68
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 50
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 29
- 239000002253 acid Substances 0.000 claims description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229910052788 barium Inorganic materials 0.000 claims description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229960002442 glucosamine Drugs 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 229960003194 meglumine Drugs 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 54
- 150000002148 esters Chemical class 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract 2
- 150000002961 penems Chemical class 0.000 abstract 1
- 229940124530 sulfonamide Drugs 0.000 abstract 1
- 150000003456 sulfonamides Chemical class 0.000 abstract 1
- 125000003396 thiol group Chemical group [H]S* 0.000 abstract 1
- 239000002585 base Substances 0.000 description 23
- 238000002347 injection Methods 0.000 description 22
- 239000007924 injection Substances 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 241000894006 Bacteria Species 0.000 description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 11
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical compound OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 description 8
- 230000000845 anti-microbial effect Effects 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 230000003115 biocidal effect Effects 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 125000006502 nitrobenzyl group Chemical group 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- 239000005864 Sulphur Substances 0.000 description 6
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 description 6
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- 238000001228 spectrum Methods 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- 206010011224 Cough Diseases 0.000 description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- 229920000881 Modified starch Polymers 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
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- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 230000000843 anti-fungal effect Effects 0.000 description 4
- 229940121375 antifungal agent Drugs 0.000 description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
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- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000011122 softwood Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- JLZWQNRGNMXIJY-UHFFFAOYSA-N triethylstannane Chemical compound CC[SnH](CC)CC JLZWQNRGNMXIJY-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 235000020985 whole grains Nutrition 0.000 description 1
Abstract
The invention pertains to the technical field of medicines and particularly relates to a penem derivative containing formamide heterocyclic sulfonamide sulfhydryl pyrrolidine as showed in a general formula (1), a pharmaceutically acceptable salt thereof, easily hydrolyzable ester thereof and isomers thereof, wherein, R <1>, R<2>, R<3> and X are defined as in a specification. The invention also relates to a preparation method of the compounds, medical compositions containing the compounds and the application of the compounds in preparing medicines for curing and/or preventing infectious diseases.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to contain Pennem derivates, its pharmacy acceptable salt of formamide heterocycle sulfonic acid amide sulfhydryl pyrrolidine, the ester of its facile hydrolysis, its isomer, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds are in the purposes that is used for preparing the medicine that treats and/or prevents infectious diseases.
2, background technology
Carbapenem antibiotic is the class β-Nei Xiananleikangshengsu that the seventies grows up.Because of its has a broad antifungal spectrum, anti-microbial activity is strong, and stable to β-Nei Xiananmei, and receives much concern.Its constructional feature is, the sulphur that the penam parent nucleus is 1 is replaced by carbon, and 2 have two keys, the effect of the five-ring of compound penicillin and the conjugated double bond activation beta-lactam nucleus of cynnematin; 6 hydroxyethyl side chains are transoid conformation.
Representative is imipenum and panipenem.Imipenum all has very strong activity to gram-positive microorganism, negative bacterium, aerophil, anerobe, stable to various β-Nei Xiananmeis, there is not cross resistance with other microbiotic, but easily by dehydropeptidase of kidney-I (DHP-I) degraded rapidly, must share with kidney peptidase inhibitors-cilastatin clinically in vivo.Panipenem is stable to various beta-lactams, and stable to DHP-I, the resisting pseudomonas aeruginosa activity is better than imipenum, but because of it has slight renal toxicity, so need share with kidney protective material Betamipron.
The imipenum panipenem
Discover that further methyl is introduced in 1 β position, can strengthen the chemical stability, anti-microbial activity of carbapenem and the stability of DHP-I.As ertapenem, belong to the long-acting injection carbapenem, in the listing of a plurality of countries.(PBP-2 and PBP-3) has high avidity to penicillin-binding protein, the activity of anti-gram positive organism is a little less than imipenum, the activity of anti-gram-negative bacteria is better than imipenum, anti-wide spectrum and extended spectrum produce bacterium such as intestinal bacteria and Klebsiella Pneumoniae effect surpass the third generation and the 4th generation the carbapenem rhzomorph.Has a broad antifungal spectrum is eliminated long half time, and tissue permeability is good, and intramuscularly bioavailability height is used for the treatment of abdominal cavity infection, skin and skin soft-tissue infection, urinary tract infections, gynecological infection and pneumonia etc., but poor to hospital infection pathogenic bacteria antibacterial effect.
Ertapenem sodium
Therefore, need research and development the hospital clinical infection pathogen to be had the stable carbapenem antibiotic of better anti-microbial activity.
3, summary of the invention
Technical scheme of the present invention is as follows:
The invention provides the ester and the isomer thereof of the compound shown in the general formula (1), its pharmacy acceptable salt, facile hydrolysis:
Wherein, R
1Represent hydrogen atom or carboxyl-protecting group;
R
2The following groups that representative is replaced by one or more sulfuryl aminos:
R
3Represent hydrogen atom or low alkyl group;
X is hydrogen atom or amino protecting group.
Preferred compound is:
Wherein, R
1Represent hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, ethyl, the tertiary butyl, methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2The following groups that representative is replaced by one or more sulfuryl aminos:
R
3Represent hydrogen atom, methyl or ethyl;
X is hydrogen atom or amino protecting group,
Described amino protecting group is selected from methyl, ethyl, the tertiary butyl, benzyl, formyl radical, ethanoyl, allyloxy carbonyl, phenacyl, tert-butoxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, 3-acetoxyl group propyl group or diazo.
Further preferred compound is:
Wherein, R
1Represent hydrogen atom or carboxyl-protecting group,
Described carboxyl-protecting group is selected from methyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl;
R
2The following groups that representative is replaced by a sulfuryl amino:
R
3Represent hydrogen atom or methyl;
X is hydrogen atom or amino protecting group,
Described amino protecting group is selected from methyl, the tertiary butyl, formyl radical, allyloxy carbonyl, tert-butoxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl or diazo.
" low alkyl group " of the present invention is C
1-6The alkyl of straight or branched is as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl etc.
" carboxyl-protecting group " of the present invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: methoxymethyl, the first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, the methoxyethyl methyl, benzyloxymethyl, phenacyl, allyl group, to bromobenzene formyl methyl, the Alpha-Methyl phenacyl, to the methoxybenzoyl methyl, the diacyl methyl, the N-phthalimidomethyl, methyl, ethyl, diphenyl methyl, 2,2,2-three chloroethyls, the 2-halogenated ethyl, 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, the 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, the sec.-propyl dimetylsilyl, the phenyl dimetylsilyl, the S-tertiary butyl, the S-phenyl, the S-2-pyridyl, N-hydroxy piperidine base, N-hydroxyl succinimido, N-hydroxyl phthaloyl imino, N-hydroxybenzotriazole base, O-acyl group oxime, 2,4-dinitrobenzene sulfenyl, 2-alkyl-1, the 3-oxazoline, 4-alkyl-5-oxo-1, the 3-oxazolidine, 5-alkyl-4-oxo-1, the 3-diox, the triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides etc.
" amino protecting group " of the present invention refers to that routine is used for the blocking group of substituted-amino acid proton, this type of examples of groups comprises: methyl, ethyl, encircle third methyl, 1-methyl isophthalic acid-ring third methyl, the diisopropyl methyl, the 9-fluorene methyl, 9-(2-sulfo-) fluorene methyl, furfuryl, 2,2, the 2-trichloromethyl, the 2-halogenated methyl, 2-iodine ethyl, 2-trimethyl silyl ethyl, 2-methylmercaptoethyl, 2-methylsulfonyl ethyl, 2-(p-toluenesulfonyl) ethyl, 2-phosphorus base ethyl, 1,1-dimethyl-3-(N, N-dimethylformamide base) propyl group, 1,1-phenylbenzene-3-(N, the N-diethylin) propyl group, 1-methyl isophthalic acid-(adamantyl) ethyl, 1-methyl isophthalic acid-styroyl, 1-methyl isophthalic acid-(3, the 5-dimethoxy phenyl) ethyl, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-methyl isophthalic acid-(to the phenylazo-phenyl) ethyl, 1,1-dimethyl-2,2,2-three chloroethyls, 1,1-dimethyl-2-cyanoethyl, isobutyl-, the tertiary butyl, tert-pentyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl, the 1-methylcyclohexyl, the 1-adamantyl, isobornyl, vinyl, allyl group, cinnamyl, phenyl, 2,4,6-tri-tert phenyl, the m-nitro base, the S-phenyl, the 8-quinolyl, N '-hydroxy piperidine base, 4-(1,4-lupetidine base), 4,5-phenylbenzene-3-oxazoline-2-ketone, benzyl, 2,4, the 6-trimethyl benzyl, to methoxy-benzyl, to methoxyl group benzyloxy base carbonyl, 3, the 5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, to the nitro benzyloxycarbonyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, to bromobenzyl, the benzyl chloride base, 2, the 4-dichloro benzyl, to the cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, between-chloro-is right-the acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to the anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (ortho-nitrophenyl base) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, the isonicotine base, the S-benzyl, the fixed basic carbonyl of N '-piperazine, the carbamate of N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl; Formyl radical, ethanoyl, ethanoyl-pyridine, (N '-the dithio benzyloxycarbonyl amino) ethanoyl, 3-phenyl propionyl, 3-(to hydroxyphenyl) propionyl, 3-(ortho-nitrophenyl base) propionyl, 2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl, 2-methyl-2-(adjacent phenylazo-phenoxy group) propionyl, 4-chloro butyryl radicals, isobutyryl, adjacent nitro cinnamoyl, the pyridine formyl radical, N '-acetyl methionyl, N '-benzoyl-phenylalkyl, benzoyl, to the phenyl benzoyl, to anisoyl, o-nitrobenzoyl, the acid amides of adjacent (benzoyloxy methyl) benzoyl and right-P-benzoyl; Phthaloyl, 2, the inferior acid amides of the ring of 3-phenylbenzene maleoyl and dithio succinyl; Tert-butoxycarbonyl; allyl group; allyloxy carbonyl; phenacyl; 3-acetoxyl group propyl group; 4-nitro-1-cyclohexyl-2-oxo-3-tetramethyleneimine-3-base; quaternary ammonium salt; methoxymethyl; 2-chloroethoxy methyl; benzyloxymethyl; the valeryl methyl; [1-(alkoxycarbonyl amido)]-2; 2; 2; trifluoroethyl; [1-Trifluoromethyl-1-(to the chlorophenoxy methoxyl group) 2; 2; 2;-trifluoro] ethyl; the 2-THP trtrahydropyranyl; 2; the 4-dinitrophenyl; benzyl; 3; the 4-dimethoxy-benzyl; adjacent nitrobenzyl; two (p-methoxyphenyl) methyl; trityl; (p-methoxyphenyl) diphenyl methyl; phenylbenzene-4-pyridylmethyl; 2-picolyl-N '-oxide compound; 5-two phenylpropyl alcohol suberane bases; N '; N '-dimethylaminomethylene; N '-isopropylidene; benzylidene; to the methoxyl group benzylidene; to the nitro benzylidene; salicylidene; 5-chlorine salicylidene; diphenylmethylene; (5-chloro-2-hydroxyphenyl) phenylmethylene; (acyl group vinyl); 5; 6-dimethyl-3-oxo-1-cyclohexenyl; borine; [phenyl (pentacarbonyl chromium or tungsten)] carbonyl; copper or chelates of zinc; nitro; nitroso-group; oxide compound; diphenylphosphino; diformazan sulfenyl phosphinyl; hexichol sulfenyl phosphinyl; the diethyl phosphoryl; the dibenzyl phosphoryl; the diphenylphosphine acyl group; phosphoryl; trimethyl silyl; thiophenyl; the ortho-nitrophenyl sulfenyl; 2; 4-dinitrobenzene sulfenyl; 2-nitro-4-anisole sulfenyl; three benzylthios; benzenesulfonyl; to the anisole alkylsulfonyl; 2; 4,6-Three methyl Benzene alkylsulfonyl; methyl sulphonyl; the benzene methylsulfonyl; to the toluene methylsulfonyl; trifluoromethyl sulfonyl; the phenacyl alkylsulfonyl; diazo etc.
Part of compounds of the present invention
Further preferred compound comprises:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(2-sulfonamido-pyridine-6-yl) amino]-1-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, hereinafter to be referred as compound 1, its structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-thiazol-2-yl) amino]-1-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, hereinafter to be referred as compound 2, its structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-oxazoles-2-yl) amino]-1-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, hereinafter to be referred as compound 3, its structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-furans-2-yl) amino]-1-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, hereinafter to be referred as compound 4, its structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-thiophene-2-yl) amino]-1-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, hereinafter to be referred as compound 5, its structural formula is as follows:
Chemical name: (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-1-pyrroles-2-yl) amino]-1-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, hereinafter to be referred as compound 6, its structural formula is as follows:
The present invention also provides the preparation method of above-claimed cpd:
Reaction equation:
Reactions steps:
The preparation of step 1 intermediate (I)
In the exsiccant reaction flask, add (2S; 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine; anhydrous tetrahydro furan under nitrogen protection, adds 1 in room temperature; 1-carbonyl dimidazoles (CDI) reaction; tetrahydrofuran solution adding raw material 1 below 0 ℃ continues reaction, drips 1mol/L hydrochloric acid then; with ethyl acetate extraction; organic phase is water successively; the saturated nacl aqueous solution washing, concentrating under reduced pressure, resistates adds the hydrochloric acid of 3mol/L; stir; be adjusted to alkalescence with dilute alkaline soln, separate out solid, solid is with ethyl acetate-hexanaphthene (5: 1) mixing solutions recrystallization; get solid, i.e. intermediate (I).
The preparation of step 2 intermediate (II)
In the dry reaction bottle, the acetonitrile solution that adds raw material 2 is chilled to below-10 ℃, the acetonitrile solution that adds diisopropylethylamine and intermediate (I), 0 ℃ of stirring after reaction finishes, adds the ethyl acetate dilution, water, saturated salt washing successively, organic layer drying, concentrated gets yellow solid, i.e. intermediate (II).
The preparation of step 3 invention compound (III)
In the methylene dichloride with intermediate (II), add methyl-phenoxide and Nitromethane 99Min., in-50 ℃ of Nitromethane 99Min. solution that drip the 1mol/L aluminum chloride down,-40 ℃ of stirrings add entry, separate out solid, filter, filter cake is dissolved in the mixed solution of THF and water, add 10% palladium-charcoal, stirring reaction under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal adds THF in the filtrate, water layer is collected in layering, adds 5% magnesium chloride brine again in THF, leave standstill, divide water-yielding stratum, repetitive operation, water merges, 0 ℃ slowly splashes into methyl alcohol, filter cake water-Virahol recrystallization is filtered in-10 ℃ of stirrings, get white crystal, i.e. invention compound (III).
R in the above reaction equation
2, R
3The group of representative as mentioned before.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention is organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, and wherein organic acid comprises acetate, trifluoroacetic acid, methylsulfonic acid, toluenesulphonic acids, toxilic acid, succsinic acid, tartrate, citric acid, fumaric acid; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid; Organic bases comprises meglumine, glucosamine; Mineral alkali comprises the basic cpd of sodium, potassium, barium, calcium, magnesium, zinc, lithium.
The ester that the claimed compound of the present invention is easy to hydrolysis is the compound that its carboxyl exists with the ester group form that is easy to hydrolysis.These esters can be conventional, lower alkane acyloxyalkyl group ester for example, acetoxyl methyl ester, pivalyl oxygen methyl ester, 1-acetoxyl ethyl ester, 1-pivalyl oxygen ethyl ester; Lower alkoxycarbonyl oxyalkyl ester, methoxycarbonyl oxygen methyl ester, 1-ethoxycarbonyl-oxygen ethyl ester, 1-sec.-propyl ketonic oxygen ethyl ester; The lactone group ester, cumarone ketone group ester, sulfo-benzo furanonyl ester; The lower alkoxy methyl ester, methoxymethyl ester; Lower alkane acyl amino methyl ester, the acetylamino methyl ester.The ester that also can use other is for example: benzyl ester and cyano methyl ester.Other examples of these esters are as follows: (2,2-dimethyl-1-oxygen propoxy-) methyl ester; (1RS)-1-acetoxyl group ethyl ester; 2-[(2-methyl propoxy-) carbonyl]-the pentenyl ester; The 1-[[(1-methyl ethoxy) carbonyl] oxygen] ethyl ester; 1-(acetoxyl) ethyl ester; (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester; The 1-[[(cyclohexyloxy) carbonyl] oxygen] ethyl ester; 3,3-dimethyl-2-oxo butyl ester.It is evident that for the professional of this area the ester that is easy to hydrolysis of The compounds of this invention can form at the free carboxy place of this compound, for example at 4 carboxyl place.
Isomer of the present invention is meant its all differences to stereoisomerism, diastereo-isomerism and tautomeric form.When a key was represented with a wedge, this showed that this key will come out from paper on three-dimensional, and when a key was shade, this showed that this key will return in the paper on three-dimensional.Formula (1) compound has many three-dimensional centers, that is: on the 4-position; On the 5-position; On the 6-position.
The present invention includes the ester of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of isomer and other active pharmaceutical ingredients thereof, as cilastatin and sodium salt thereof, Betamipron.
The present invention is the claimed ester of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of isomer and one or more pharmaceutical carriers and/or thinner thereof of comprising further; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations or injection.Wherein contain the compound 0.05g～5g shown in the general formula (1) of physiology significant quantity, can be 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 etc.
The ester of The compounds of this invention, its pharmacy acceptable salt, its facile hydrolysis and isomer thereof can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
Usually, have been found that carbapenems is nontoxic to warm-blooded animal, and this general rule also is applicable to The compounds of this invention.With preferred compound of the present invention can prevent the needed excessive dosage of infectation of bacteria, not to be noted by caused tangible poisoning aura of The compounds of this invention or side effect to the mouse administration.
The present invention also provide new carbapenem antibiotic preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes.The new carbapenem antibiotic of the present invention all has better antibacterial activity to gram-positive microorganism, Gram-negative bacteria, aerophil, anerobe and hospital clinical pathogenic bacteria such as Pseudomonas aeruginosa and acinetobacter bacterium, can be used for treating and/or preventing the various diseases that causes by pathogenic micro-organism, as respiratory tract infection and urinary tract infection.
Carbapenem antibiotic of the present invention compared with prior art has the following advantages:
(1) The compounds of this invention (1) has good anti-microbial activity and shows hypotoxicity, can by safety be used for the treatment of and/or to prevent various Mammalss (as mouse, rat, rabbit, dog, cat, ox, pig etc.) to comprise human by the caused various diseases of germ, as pulmonary infection and urinary tract infections etc.;
(2) The compounds of this invention (1) has a broad antifungal spectrum all has better antibacterial activity to gram-positive microorganism, Gram-negative bacteria, aerophil, anerobe and hospital clinical pathogenic bacteria;
(3) The compounds of this invention (1) has good activity in digestive tube, can be through the gi system administration;
(4) The compounds of this invention (1) can drug administration by injection, bioavailability height, long half time;
(5) The compounds of this invention (1) preparation technology is simple, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
Below further set forth the beneficial effect that contains the Pennem derivates of formamide heterocycle sulfonic acid amide sulfhydryl pyrrolidine of the present invention by in-vitro antibacterial experiment, but this should be interpreted as that the southern antibiotics of training of the present invention only has following beneficial effect.
The antibacterial activity in vitro of experimental example The compounds of this invention
For trying bacterial classification: following clinical isolates strain
Gram positive organism: MSSA (MSSA) 21 strains, methicillin-resistant staphylococcus aureus (MRSA) 13 strains, methicillin-sensitivity staphylococcus epidermidis (MSSE) 18 strains, methicillin-resistant staphylococcus epidermidis (MRSE) 11 strains, responsive streptococcus pneumoniae (PSSP) 25 strains of penicillin, penicillin resistance streptococcus pneumoniae (PRSP) 15 strains, streptococcus pyogenes 20 strains, enterococcus faecalis 16 strains;
Gram-negative bacteria: hemophilus influenzae 15 strains, escherichia coli 18 strains, klepsiella pneumoniae 22 strains, Proteus mirabilis 17 strains, enterobacter cloacae 13 strains, Pseudomonas aeruginosa 21 strains; Grain-negative anerobe: bacteroides fragilis 8 strains.
Trial-product:
The compounds of this invention 1-6, self-control, its chemical name and structural formula are as mentioned before;
Imipenum, meropenem: commercial.
Experimental technique: agar dilution.
Experimental result and conclusion:
Table 1 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
By table 1 experimental result as seen, compare with meropenem with imipenum, The compounds of this invention 1-6 all has the excellent antibiotic activity to the clinical isolating examination gram positive organism that supplies.
Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
By table 2 experimental result as seen, compare with meropenem with imipenum, The compounds of this invention 1-6 comprises that to clinical isolating for the examination gram-negative bacteria Grain-negative anerobe has the excellent antibiotic activity.
Above-mentioned experimental result shows, The compounds of this invention all has potent anti-microbial effect to gram positive organism, negative bacterium and resistant organism thereof and anerobe, compares with immediate prior art, and anti-microbial activity quite or better, and has a broad antifungal spectrum has the good clinical application potential.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
Embodiment 1 (2S, 4S)-4-sulfydryl-2-formyl [(2-sulfonamido-pyridine-6-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine
Preparation
In the exsiccant reaction flask, add (2S; 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine 7.8g (27mmol); anhydrous tetrahydro furan 100ml; under nitrogen protection; add 1 in room temperature; 1-carbonyl dimidazoles (CDI) 6.5g (40mmol), reaction 0.5h is at the tetrahydrofuran solution (50mmol/100ml) that adds 8.7g 6-aminopyridine-2-sulphonamide below 0 ℃; continue reaction 0.5h; drip 1mol/L hydrochloric acid 40ml then, extract with ethyl acetate (50ml * 2), organic phase is water successively; the saturated nacl aqueous solution washing; concentrating under reduced pressure; resistates adds the hydrochloric acid 100ml of 3mol/L, stirs 2h, is adjusted to alkalescence with dilute alkaline soln; separate out solid; solid gets solid 9.3g, yield: 85.2% with ethyl acetate-hexanaphthene (5: 1) mixing solutions recrystallization.
Embodiment 2 (2S, 4S)-4-sulfydryl-2-formyl [(4-sulfonamido-thiazol-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine
Preparation
Concrete operations reference example 1, throw (2S, 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine 7.8g (27mmol), thiazolamine-4-sulphonyl ammonia 9g (50mmol), get (2S, 4S)-and 4-sulfydryl-2-formyl [(4-sulfonamido-thiazol-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 8.9g, yield: 81.2%.
Embodiment 3 (2S, 4S)-4-sulfydryl-2-formyl [(4-sulfonamido-oxazoles-2-yl) amino]-1-(uncle
Butoxy carbonyl) tetramethyleneimine
Preparation
Concrete operations reference example 1, throw (2S, 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine 7.8g (27mmol), 2-An Ji oxazole-4-sulphonyl ammonia 8.2g (50mmol), get (2S, 4S)-and 4-sulfydryl-2-formyl [(4-sulfonamido-oxazoles-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 8.4g, yield: 78.9%.
Embodiment 4 (2S, 4S)-4-sulfydryl-2-formyl [(4-sulfonamido-furans-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine
Preparation
Concrete operations reference example 1, throw (2S, 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine 7.8g (27mmol), the amino furans of 2--4-sulphonyl ammonia 8.1g (50mmol), get (2S, 4S)-and 4-sulfydryl-2-formyl [(4-sulfonamido-furans-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 8.8g, yield: 83.5%.
Embodiment 5 (2S, 4S)-4-sulfydryl-2-formyl [(4-sulfonamido-thiophene-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine
Preparation
Concrete operations reference example 1, throw (2S, 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine 7.8g (27mmol), 2-aminothiophene-4-sulphonyl ammonia 8.9g (50mmol), get (2S, 4S)-and 4-sulfydryl-2-formyl [(4-sulfonamido-thiophene-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 8.5g, yield: 77.6%.
Embodiment 6 (2S, 4S)-4-sulfydryl-2-formyl [(4-sulfonamido-1-tertbutyloxycarbonyl pyrroles-2-yl) amino]-1-(tertiary butyloxycarbonyl
Base) preparation of tetramethyleneimine
Concrete operations reference example 1, throw (2S, 4S)-4-acetylthio-2-carboxyl-1-(tertbutyloxycarbonyl) tetramethyleneimine 7.8g (27mmol), 2-amino (1-tertbutyloxycarbonyl) pyrroles-4-sulphonyl ammonia 9g (50mmol), get (2S, 4S)-and 4-sulfydryl-2-formyl [(4-sulfonamido-1-tertbutyloxycarbonyl pyrroles-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 9.9g, yield: 74.8%.
Embodiment 7 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [(2-sulfonamido-pyridine-6-yl) amino]-1-(tertbutyloxycarbonyl) pyrrole
Cough up alkane-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] 2-in heptan alkene-2-carboxy acid mutual-nitro carbobenzoxy
Preparation
In the dry reaction bottle, add (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] the acetonitrile 120ml solution of hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol) is chilled to below-10 ℃, add diisopropylethylamine 5ml and (2S, 4S)-the acetonitrile 80ml solution of 4-sulfydryl-2-formyl [(2-sulfonamido-pyridine-6-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 8.9g (22mmol), 0 ℃ is stirred 15h, after reaction finishes, add ethyl acetate 300ml dilution, successively water, the saturated salt washing, the organic layer drying, concentrate, get yellow solid 9.8g, yield: 65.4%.
Embodiment 8 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [(4-sulfonamido-thiazol-2-yl) amino]-1-(tertbutyloxycarbonyl) pyrrole
Cough up alkane-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy
Preparation
Concrete preparation method's reference example 7; throw (4R; 5S; 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3; 2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), (4S)-4-sulfydryl-1-(N-1-hydroxyethyl-5-t-butoxycarbonyl amino-tetramethyleneimine-2-yl) formyl radical-N-tertbutyloxycarbonyl-tetramethyleneimine 9.0g (22mmol); get product 9.4g, yield: 62.3%.
Embodiment 9 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [(4-sulfonamido-oxazoles-2-yl) amino]-1-(tertbutyloxycarbonyl) pyrrole
Cough up alkane-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy
Preparation
Concrete preparation method's reference example 7, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), (2S, 4S)-and 4-sulfydryl-2-formyl [(4-sulfonamido-oxazoles-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 8.6g (22mmol), get product 9.9g, yield: 67.1%.
Embodiment 10 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [(4-sulfonamido-furans-2-yl) amino]-1-(tertbutyloxycarbonyl) pyrrole
Cough up alkane-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy
Preparation
Concrete preparation method's reference example 7, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), (2S, 4S)-and 4-sulfydryl-2-formyl [(4-sulfonamido-furans-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 8.6g (22mmol), get product 9.9g, yield: 67.1%.
Embodiment 11 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [(4-sulfonamido-thiophene-2-yl) amino]-1-(tertbutyloxycarbonyl) pyrrole
Cough up alkane-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy
Preparation
Concrete preparation method's reference example 7, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), (2S, 4S)-and 2-formyl [(4-sulfonamido-thiophene-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 9.0g (22mmol), get product 9.7g, yield: 64.8%.
Embodiment 12 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [(4-sulfonamido-1-tertbutyloxycarbonyl pyrroles-2-yl) ammonia
Base]-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] heptan-2-
Alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 7, throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 11.9g (20mmol), (2S, 4S)-and 4-sulfydryl-2-formyl [(4-sulfonamido-1-tertbutyloxycarbonyl pyrroles-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine 9.9g (22mmol), get product 10.3g, yield: 61.4%.
Embodiment 13 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(2-sulfonamido-pyridine-6-yl) amino]-1-tetramethyleneimine-4-yl] sulphur
Base-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Will (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [(2-sulfonamido-pyridine-6-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-the 50ml methylene dichloride of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 7.5g (10mmol) in, add methyl-phenoxide 10ml and Nitromethane 99Min. 20ml, in-50 ℃ of Nitromethane 99Min. solution 100ml that drip the 1mol/L aluminum chloride down ,-40 ℃ are stirred 2h, add entry 200ml, separate out solid, filter, filter cake is dissolved in the mixed solution of 400mlTHF and water 30ml, add 10% palladium-charcoal 2g, stirring reaction 2h under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal adds THF 150ml, layering in the filtrate, collect water layer, in THF, add 5% magnesium chloride brine 20ml again, leave standstill, divide water-yielding stratum, repetitive operation 1 time, water merges, and 0 ℃ slowly splashes into methyl alcohol 30ml, and-10 ℃ are stirred 1h, filter, filter cake water-Virahol recrystallization gets white crystal 2.3g, yield: 45.6%.
Molecular formula: C
20H
25N
5O
7S
2
Molecular weight: 511.57
Ultimate analysis:
Measured value: C, 46.82%; H, 5.06%; N, 13.54%; S, 12.36%
Theoretical value: C, 46.96%; H, 4.93%; N, 13.69%; S, 12.54%
Embodiment 14 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-thiazol-2-yl) amino]-1-tetramethyleneimine-4-yl] sulphur
Base-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Concrete preparation method's reference example 13, throw (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-thiazol-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 7.5g (10mmol), get target product 2.2g, yield: 42.7%.
Molecular formula: C
18H
23N
5O
7S
3
Molecular weight: 517.6
Ultimate analysis:
Measured value: C, 41.43%; H, 4.65%; N, 13.40%; S, 18.33%
Theoretical value: C, 41.77%; H, 4.48%; N, 13.53%; S, 18.58%
Embodiment 15 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-oxazoles-2-yl) amino]-1-tetramethyleneimine-4-yl] sulphur
Base-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Concrete preparation method's reference example 13, throw (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-oxazoles-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 7.4g (10mmol), get target product 2.3g, yield: 46.1%.
Molecular formula: C
18H
23N
5O
8S
2
Molecular weight: 501.53
Ultimate analysis:
Measured value: C, 43.02%; H, 4.83%; N, 13.80%; S, 12.63%
Theoretical value: C, 43.11%; H, 4.62%; N, 13.96%; S, 12.79%
Embodiment 16 (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-furans-2-yl) amino]-1-tetramethyleneimine-4-yl] sulphur
Base-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Concrete preparation method's reference example 13, throw (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-furans-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 7.4g (10mmol), get target product 2.4g, yield: 48.9%.
Molecular formula: C
19H
24N
4O
8S
2
Molecular weight: 500.55
Ultimate analysis:
Measured value: C, 45.51%; H, 4.98%; N, 11.02%; S, 12.63%
Theoretical value: C, 45.59%; H, 4.83%; N, 11.19%; S, 12.81%
Embodiment 17 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [(4-iodoxy amino-thiophene-2-yl) ammonia
Base]-1-tetramethyleneimine-4-yl] sulphur
Base-6-[(1R)-1-hydroxyethyl]-preparation of the assorted dicyclo of 4-methyl-7-oxygen-1-fluorine-[3,2,0] hept-2-ene"-2-carboxylic acid
Concrete preparation method's reference example 13, throw (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [(4-sulfonamido-thiophene-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 7,5g (10mmol) gets target product 2.4g, yield: 46.9%.
Molecular formula: C
19H
24N
4O
7S
3
Molecular weight: 516.61
Ultimate analysis:
Measured value: C, 44.06%; H, 4.83%; N, 10.72%; S, 18.45%
Theoretical value: C, 44.17%; H, 4.68%; N, 10.85%; S, 18.62%
Embodiment 18 (4R, 5S, 6S)-3-[(2S, 4S)-2-formyl [(4-sulfonamido-1-pyrroles-2-yl) amino]-1-tetramethyleneimine-4-yl]
Sulfenyl-6-[(1R)-1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid
Concrete preparation method's reference example 13, throw (4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-1-tertbutyloxycarbonyl pyrroles-2-yl) amino]-1-(tertbutyloxycarbonyl) tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy 8.3g (10mmol), get target product 2.1g, yield: 42.7%.
Molecular formula: C
19H
25N
5O
7S
2
Molecular weight: 499.56
Ultimate analysis:
Measured value: C, 45.45%; H, 5.21%; N, 14.10%; S, 12.68%
Theoretical value: C, 45.68%; H, 5.04%; N, 14.02%; S, 12.84%
The preparation of embodiment 19 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Any one 250g (in compound) in the The compounds of this invention 1-6 or derivatives thereof
Prepare 1000 altogether
Prescription 2:
Any one 500g (in compound) in the The compounds of this invention 1-6 or derivatives thereof
Prepare 1000 altogether
Prescription 3:
Any one 1000g (in compound) in the The compounds of this invention 1-6 or derivatives thereof
Prepare 1000 altogether
Prescription 4:
Any one 2000g (in compound) in the The compounds of this invention 1-6 or derivatives thereof
Prepare 1000 altogether
2, preparation technology:
(1) will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process;
(2) take by weighing raw material (feeding intake after the conversion) by prescription, sterilized powder is placed the portioning machine packing, detect loading amount at any time;
(3) jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 20 The compounds of this invention tablets
1, prescription:
Prescription 1:
Any one 250g (in compound) in the The compounds of this invention 1-6 or derivatives thereof
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 40g
Microcrystalline Cellulose 40g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
Prescription 2:
Any one 125g (in compound) in the The compounds of this invention 1-6 or derivatives thereof
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 40g
Microcrystalline Cellulose 40g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
2, preparation technology:
(1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
(2) take by weighing raw material and auxiliary material according to recipe quantity.
(3) hypromellose 2% the aqueous solution made soluble in water is standby.
(4) with in the The compounds of this invention 1-6 or derivatives thereof any one, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose mix, it is an amount of to add the 2%HPMC aqueous solution, stirs, and makes suitable softwood.
(5) cross 20 mesh sieve system particles.
(6) particle is dried under 60 ℃ condition.
(7) dry good particle adds Magnesium Stearate, micropowder silica gel and carboxymethylstach sodium, crosses the whole grain of 18 mesh sieves, mixes.
(8) sampling, the work in-process chemical examination.
(9) the sheet weight sheet of determining according to chemical examination.
(10) finished product is examined entirely, the packing warehouse-in.
Claims (9)
1. the compound shown in the general formula (1) or its pharmacy acceptable salt:
Wherein, R
1Represent hydrogen atom;
R
2The following groups that representative is replaced by one or more sulfuryl aminos:
R
3Represent hydrogen atom or C
1-6Alkyl;
X is a hydrogen atom.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein, R
1Represent hydrogen atom;
R
2The following groups that representative is replaced by one or more sulfuryl aminos:
R
3Represent hydrogen atom, methyl or ethyl;
X is a hydrogen atom.
3. compound as claimed in claim 2 or its pharmacy acceptable salt:
Wherein, R
1Represent hydrogen atom;
R
2The following groups that representative is replaced by a sulfuryl amino:
R
3Represent hydrogen atom or methyl;
X is a hydrogen atom.
4. compound as claimed in claim 3 is selected from:
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(2-sulfonamido-pyridine-6-yl) amino]-1-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-thiazol-2-yl) amino]-1-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-oxazoles-2-yl) amino]-1-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-furans-2-yl) amino]-1-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-thiophene-2-yl) amino]-1-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, or
(4R, 5S, 6S)-3-[(2S, 4S)-and 2-formyl [(4-sulfonamido-1-pyrroles-2-yl) amino]-1-tetramethyleneimine-4-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, or its pharmacy acceptable salt.
5. each described compound of claim 1～4, its pharmacy acceptable salt is organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts, and wherein organic acid comprises acetate, trifluoroacetic acid, methylsulfonic acid, toluenesulphonic acids, toxilic acid, succsinic acid, tartrate, citric acid, fumaric acid; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid; Organic bases comprises meglumine, glucosamine; Mineral alkali comprises the basic cpd of sodium, potassium, barium, calcium, magnesium, zinc, lithium.
6. the pharmaceutical composition that comprises each described compound of claim 1～4 or its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner.
7. pharmaceutical composition as claimed in claim 6 is pharmaceutically acceptable arbitrary formulation.
8. pharmaceutical composition as claimed in claim 6 contains each described compound of claim 1～4 or its pharmacy acceptable salt 0.05g～5g as essential active ingredient.
9. each described compound of claim 1～4 or its pharmacy acceptable salt are in the application that is used for preparing the medicine that treats and/or prevents infectious diseases.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0126587A1 (en) * | 1983-05-09 | 1984-11-28 | Sumitomo Pharmaceuticals Company, Limited | Carboxylic thio-pyrrolidinyl beta-lactam compounds and production thereof |
| EP0581502A1 (en) * | 1992-07-21 | 1994-02-02 | Zeneca Limited | Antibiotic carbapenem compounds |
| EP0581501A1 (en) * | 1992-07-21 | 1994-02-02 | Zeneca Limited | Antibiotic carbapenem compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0126587A1 (en) * | 1983-05-09 | 1984-11-28 | Sumitomo Pharmaceuticals Company, Limited | Carboxylic thio-pyrrolidinyl beta-lactam compounds and production thereof |
| EP0581502A1 (en) * | 1992-07-21 | 1994-02-02 | Zeneca Limited | Antibiotic carbapenem compounds |
| EP0581501A1 (en) * | 1992-07-21 | 1994-02-02 | Zeneca Limited | Antibiotic carbapenem compounds |
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| JP昭60-233076A 1985.11.19 |
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