CN102584827B - Containing the carbapenem compounds of sulfuryl amine heterocyclic methylamino formoxyl pyrrolidine - Google Patents
Containing the carbapenem compounds of sulfuryl amine heterocyclic methylamino formoxyl pyrrolidine Download PDFInfo
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- CN102584827B CN102584827B CN201110462664.6A CN201110462664A CN102584827B CN 102584827 B CN102584827 B CN 102584827B CN 201110462664 A CN201110462664 A CN 201110462664A CN 102584827 B CN102584827 B CN 102584827B
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- methyl
- hydroxyethyl
- oxo
- azabicyclo
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
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- 125000001544 thienyl group Chemical group 0.000 claims description 15
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 11
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 10
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- 206010071699 Infectious pleural effusion Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010056254 Intrauterine infection Diseases 0.000 description 1
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- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 206010024652 Liver abscess Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
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- 206010035664 Pneumonia Diseases 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
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- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 206010039361 Sacroiliitis Diseases 0.000 description 1
- 206010049677 Salpingo-oophoritis Diseases 0.000 description 1
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- 241000191967 Staphylococcus aureus Species 0.000 description 1
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- 206010048038 Wound infection Diseases 0.000 description 1
- 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 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- 238000009635 antibiotic susceptibility testing Methods 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229950007599 betamipron Drugs 0.000 description 1
- MRMBZHPJVKCOMA-YJFSRANCSA-N biapenem Chemical compound C1N2C=NC=[N+]2CC1SC([C@@H]1C)=C(C([O-])=O)N2[C@H]1[C@@H]([C@H](O)C)C2=O MRMBZHPJVKCOMA-YJFSRANCSA-N 0.000 description 1
- 229960003169 biapenem Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
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- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
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- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- CHVJITGCYZJHLR-UHFFFAOYSA-N cyclohepta-1,3,5-triene Chemical compound C1C=CC=CC=C1 CHVJITGCYZJHLR-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- 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 1
- 230000000694 effects Effects 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000002302 glucosamines Chemical class 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical class C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- USKZHEQYENVSMH-UHFFFAOYSA-N hepta-1,3,5-triene Chemical compound CC=CC=CC=C USKZHEQYENVSMH-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical class [H]O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
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- 208000014674 injury Diseases 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
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- 239000000314 lubricant Substances 0.000 description 1
- 201000003453 lung abscess Diseases 0.000 description 1
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- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002815 nickel Chemical class 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- CQDAMYNQINDRQC-UHFFFAOYSA-N oxatriazole Chemical compound C1=NN=NO1 CQDAMYNQINDRQC-UHFFFAOYSA-N 0.000 description 1
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- MQKPEUAOJLJUMD-UHFFFAOYSA-N phenol;piperazine Chemical compound C1C[NH2+]CCN1.[O-]C1=CC=CC=C1 MQKPEUAOJLJUMD-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 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
- 235000019587 texture Nutrition 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to medical art; be specifically related to the ester containing the carbapenem compounds of sulfuryl amine heterocyclic methylamino formoxyl pyrrolidine, its pharmacy acceptable salt, its facile hydrolysis shown in logical formula I, its steric isomer, its solvated compounds and the intermediate shown in formula II, wherein R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9with A as in specification sheets define, the invention still further relates to the preparation method of these compounds, the pharmaceutical preparation containing these compounds, and these compounds are for the preparation of the purposes treated and/or prevented in the medicine of infectious diseases.
Description
1, technical field
The invention belongs to medical art; relate to containing the ester of the carbapenem compounds of sulfuryl amine heterocyclic methylamino formoxyl pyrrolidine, its pharmacy acceptable salt, its facile hydrolysis, its steric isomer, its solvated compounds and its intermediate; the preparation method of these compounds; pharmaceutical preparation containing these compounds, and these compounds are for the preparation of the purposes treated and/or prevented in the medicine of infectious diseases.
2, background technology
Carbapenem antibiotic is the class β-lactam antibitics that last century, the seventies grew up.Because of its has a broad antifungal spectrum, anti-microbial activity is strong, and stablizes β-lactamase, and receives much concern.
This similar drug gone on the market at present has imipenum, meropenem, S-4661, biapenem, ertapenem.What go on the market at first is imipenum, has good anti-microbial activity to gram-positive microorganism, but during independent medication, is easily lost anti-microbial activity by dehydropeptidase of kidney (DHP-I) degraded in vivo, need and cilastatin coupling; Meropenem is 1 Beta-methyl carbapenem antibiotic, has good anti-microbial activity to Gram-negative bacteria, has stronger stability to DHP-I, can medication separately; Ertapenem long half time, has good anti-microbial activity to Gram-negative bacteria.
ertapenem
In recent years, because microbiotic clinical application is too much, cause the continuous increase of bacterial drug resistance, therefore, be badly in need of research and development and there is good anti-microbial activity, good chemical stability, DHP-I is stablized and have compared with long half-lift carbapenem antibiotic.
3, summary of the invention
The invention provides a class anti-microbial activity good, chemical stability is strong, DHP-I is stablized and have compared with long half-lift carbapenem antibiotic, technical solution of the present invention is as follows:
Logical compound shown in formula I, its pharmacy acceptable salt, and steric isomer:
Wherein: R
1represent 1-hydroxyethyl, 1-fluoro ethyl or methylol;
R
2represent hydrogen atom or C
1-6alkyl;
R
3represent hydrogen atom or carboxyl-protecting group;
R
4, R
5, R
6, R
7representative hydrogen atom independently or C
1-6alkyl;
R
8, R
9representative hydrogen atom independently, C
1-6alkyl or halo C
1-6alkyl, or R
8, R
93-8 unit cycloalkyl is formed together with the carbon atom be connected;
A represents the thick heteroaryl of the 5-8 single heteroaryl of unit or 9-14 unit.
Logical compound shown in formula I, its pharmacy acceptable salt, and the optimal technical scheme of steric isomer is:
Wherein: R
1represent 1-hydroxyethyl, 1-fluoro ethyl or methylol;
R
2represent hydrogen atom or C
1-6alkyl;
R
3represent hydrogen atom or carboxyl-protecting group;
R
4, R
5, R
6, R
7representative hydrogen atom independently or C
1-6alkyl;
R
8, R
9representative hydrogen atom independently, C
1-6alkyl or halo C
1-6alkyl, or R
8, R
93-8 unit cycloalkyl is formed together with the carbon atom be connected;
A represents the 5-6 single heteroaryl of unit or 9-10 unit benzo heteroaryl.
Logical compound shown in formula I, its pharmacy acceptable salt, and the optimal technical scheme of steric isomer is:
Wherein: R
1represent 1-hydroxyethyl;
R
2represent methyl;
R
3represent hydrogen atom or to nitrobenzyl;
R
4, R
5representative hydrogen atom independently;
R
6, R
7representative hydrogen atom independently, methyl, ethyl or propyl group;
R
8, R
9representative hydrogen atom independently, methyl, methyl fluoride, trifluoromethyl or 2,2,2-trifluoroethyl, or R
8, R
9cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is formed together with the carbon atom be connected;
A represents pyridyl, pyrimidyl, thienyl, thiazolyl, thiadiazolyl group, 4,5-dihydro-thiazolyl, oxazolyl, isoxazolyl, oxadiazolyls, pyrryl, imidazolyl, pyrazolyl, triazol radical, benzofuryl, benzoxazolyl, benzothienyl, benzothiazolyl, indyl, pseudoindoyl, benzimidazolyl-, indazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl or cinnolines base.
Logical compound shown in formula I, its pharmacy acceptable salt, and the optimal technical scheme of steric isomer is:
Wherein: R
1represent 1-hydroxyethyl;
R
2represent methyl;
R
3represent hydrogen atom or to nitrobenzyl;
R
4, R
5representative hydrogen atom independently;
R
6, R
7representative hydrogen atom independently, methyl or ethyl;
R
8, R
9representative hydrogen atom independently;
A represents pyridyl, pyrimidyl, thienyl, thiazolyl, 1, 3, 4-thiadiazolyl group, 1, 2, 4-thiadiazolyl group, 4, 5-dihydro-thiazolyl, oxazolyl, isoxazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 4-oxadiazolyl, pyrryl, imidazolyl, pyrazolyl, 1, 2, 4-triazol radical, benzo [b] furyl, benzo [c] furyl, benzo [d] oxazolyl, benzo [b] thienyl, benzo [c] thienyl, benzo [d] thiazolyl, indyl, pseudoindoyl, benzo [d] imidazolyl, indazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl or cinnolines base.
Logical compound shown in formula I, its pharmacy acceptable salt, and the optimal technical scheme of steric isomer is:
Wherein: R
1represent 1-hydroxyethyl;
R
2represent methyl;
R
3, R
4, R
5representative hydrogen atom independently;
R
6, R
7representative hydrogen atom independently, methyl or ethyl;
R
8, R
9representative hydrogen atom independently;
A represents pyridyl, pyrimidyl, thienyl, thiazolyl, 1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, pyrryl, imidazolyl, benzo [b] furyl, benzo [b] thienyl, benzo [d] thiazolyl, indyl, benzo [d] imidazolyl, indazolyl, quinolyl or isoquinolyl.
Part of compounds of the present invention is:
" C of the present invention
1-6alkyl " represent straight chain, the alkyl containing 1-6 carbon atom of side chain, specific examples includes but not limited to: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3, 3-dimethylbutyl, 2, 2-dimethylbutyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 2-ethyl-butyl, 1-methyl-2-methyl-propyl etc.
" 3-8 unit cycloalkyl " of the present invention represents the cyclic alkyl containing 3-8 atom, and specific examples includes but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, methylcyclopropyl groups, Dimethvlcvclopropvl, methyl-cyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, Dimethylcyclohexyl etc.
" halo C of the present invention
1-6alkyl " in " halo " refer to C
1-6one or more hydrogen atom on carbon atom in alkyl is replaced by halogen atom." halogen atom " comprises fluorine atom, chlorine atom, bromine atoms, atomic iodine.
" the single heteroaryl of 5-8 unit " of the present invention represents that at least containing one is selected from O, S, the undersaturated cyclic group with aromaticity of the heteroatomic 5-8 of a N annular atoms, specific examples includes but not limited to: furyl, thienyl, dihydro-thiophene base, phosphurane base, dithiole base, thiazolyl, isothiazolyl, 1, 3, 4-thiadiazolyl group, 1, 2, 4-thiadiazolyl group, 4, 5-dihydro-thiazolyl, oxazolyl, dihydro-oxazole base, isoxazolyl, dihydro-isoxazole base, 1, 3, 4-oxadiazolyl, 1, 2, 4-oxadiazolyl, oxatriazole base, pyrryl, imidazolyl, pyrazolyl, pyrazoline base, 1, 2, 4-triazol radical, tetrazyl, pyridyl, pyrimidyl, pyranyl, 2H-pyranyl, oxazinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazine base, oxepin base, thia cycloheptatriene base, nitrogen heterocyclic heptantriene base, 1, 3-diazacyclo heptantriene base, azepine cyclooctatetraenyl etc." the single heteroaryl of 5-6 unit " of the present invention refers to the specific examples containing 5-6 annular atoms in above-mentioned example.
" the thick heteroaryl of 9-14 unit " of the present invention represents that at least containing one is selected from O, S, the sharing two adjacent atoms each other by two or more ring texturees and couple together the undersaturated condensed cyclic structure with aromaticity formed of the heteroatomic 9-14 of a N annular atoms, specific examples includes but not limited to: benzofuryl, benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl-, indazolyl, benzotriazole base, quinolyl, isoquinolyl, acridyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridinyl etc.
" 9-10 unit benzo heteroaryl " of the present invention represents phenyl ring and is at least selected from O containing one, S, the condensed ring group that the single heteroaryl of N heteroatomic 5-6 unit is formed, specific examples includes but not limited to: benzo [b] furyl, benzo [c] furyl, benzo [d] oxazolyl, benzo [b] thienyl, benzo [c] thienyl, benzo [d] thiazolyl, indyl, pseudoindoyl, benzo [d] imidazolyl, indazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl, cinnolines base, benzotriazole base, 2H-chromogen thiazolinyl, 4H-chromogen thiazolinyl, 4H-1, 3-benzoxazinyl etc.
" carboxyl-protecting group " of the present invention refers to the conventional blocking group for substituted carboxylic acid acid proton.The example of this group includes but not limited to: methyl, methoxymethyl, first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, methoxyethyl methyl, allyl group, benzyloxymethyl, phenacyl, to Bromophenac rLl, Alpha-Methyl phenacyl, to methoxyphenacyl, diacyl methyl, N phlhalimide ylmethyl, ethyl, 2,2,2-trichloroethyl, ω-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 2-(p-nitrophenyl sulfenyl) ethyl, 2-(to Tolylsulfanvl) ethyl, 1-methyl isophthalic acid-styroyl, the tertiary butyl, cyclopentyl, cyclohexyl, two (O-Nitrophenylfluorone) methyl, 9-fluorenyl methyl, 2-(9,10-dioxo) fluorenyl methyl, 5-hexichol sulfenyl, benzyl, 2,4,6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, i-propyldimethylsilyl, diphenyl methyl, phenyldimethylsilyl, the S-tertiary butyl, S-phenyl, S-2-pyridyl, N-hydroxy piperidine base, N-succinimido, N phlhalimide base, N-benzotriazole base, O-acyl group oxime, 2,4-dinitrobenzene sulfenyl, 2-alkyl-1,3-oxazoline, 4-alkyl-5-oxo-1,3-oxazolidine, 5-alkyl-4-oxo-1,3-diox, triethyltin alkyl, tri-n-butyl tin alkyl, N, N '-di-isopropyl hydrazides etc.
The present invention also protects the preparation method of compound described in formula I
The preparation method of the compounds of this invention comprises the ester, its steric isomer or its solvated compounds that make compound shown in logical formula III, its pharmacy acceptable salt, its facile hydrolysis, with the ester of compound shown in formula II, its pharmacy acceptable salt, its facile hydrolysis, its steric isomer or its solvated compounds generation nucleophilic substitution reaction
Wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9with A as defined hereinabove; L represents leavings group.
Above-mentioned " leavings group " can be the group that nucleophilic residues is left away, such as, can be the halogens such as chlorine, bromine, iodine; The halogenated methoxies such as trichloromethoxy; The lower alkanesulfonyl such as mesyloxy, ethanesulfonyloxy group oxygen base; The halogen-lower alkane sulfonyl oxies such as trifluoro-methanesulfonyl oxy, five fluorine ethanesulfonyloxy groups; The arylsulfonyloxies such as phenylsulfonyloxy, tolysulfonyl oxygen base, p-nitrophenyl sulfonyloxy; Or the aryl phosphorus acyloxy such as diphenylphosphine acyloxy, preferred aryl groups phosphorus acyloxy, more preferably diphenylphosphine acyloxy (-O-P (=O) (OPh)
2).
Above-claimed cpd of the present invention can adopt the method that describes in following flow process and/or other technology known to persons of ordinary skill in the art to synthesize, but is not limited only to following methods.
Reaction equation is as follows:
Reactions steps:
The preparation of step 1 formula 1 compound
Under nitrogen protection, add raw material 1 in reaction flask, raw material 2 and acetonitrile, stir, question response is complete, with water and extraction into ethyl acetate, and organic layer Na
2sO
4drying, vacuum concentration, column chromatography purification, obtains formula 1 compound.
The preparation of step 2 formula 2 compound
Under nitrogen protection, add raw material 3, formula 1 compound, acetonitrile, slowly drip triethylamine (TEA) in reaction flask, stir, concentrating under reduced pressure, preparative HPLC purifying, obtains formula 2 compound.
The preparation of step 3 formula 3 compound
In hydriding reactor, add formula 2 compound, Pd/C, the mixed solution of tetrahydrofuran (THF) and water, passes into hydrogen, and stir, question response is complete, and cross and filter Pd/C, filtrate is extracted with ethyl acetate, and water layer preparative HPLC is purified, lyophilize, obtains formula 3 compound.
R in above-mentioned preparation method
1, R
2, R
4, R
5, R
6, R
7, R
8, R
9, A and L as mentioned before; R
10representation carboxy protecting group.
The intermediate of compound in preparation process shown in the further claimed formula I of the present invention, the compound namely shown in formula II, wherein, R
4, R
5, R
6, R
7, R
8, R
9with A as defined hereinabove.
" pharmacy acceptable salt " of the above-mentioned arbitrary compound of the present invention comprises an alkali metal salt, as sodium salt, sylvite, lithium salts etc.; Alkaline earth salt, as calcium salt, magnesium salts etc.; Other metal-salts, as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts, as ammonium salt; Organic alkali salt, as tertiary octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidinesalt, diethylamine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-styroyl amine salt, piperazine salt, tetramethyl-amine salt, three (methylol) aminomethane salt; Halogen acid salt, as hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt, as nitrate, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulfonate, as mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate, as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt, as acetate, malate, fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate etc.; Amino acid salts, as glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.
" ester of facile hydrolysis " of the above-mentioned arbitrary compound of the present invention refers to that those can be hydrolyzed the pharmaceutically acceptable ester generating parent compound in human body.It is evident that for those skilled in the art, the ester being easy to be hydrolyzed of the compounds of this invention can be formed at the free carboxy of this compound or hydroxyl place, can be obtained by ordinary method.
" steric isomer " of the above-mentioned arbitrary compound of the present invention comprises all differences to stereoisomerism, diastereo-isomerism and tautomeric form.When a key represents with a wedge, this to show that in three-dimensional this key will from paper out, and when a key is shade, this shows that this key will return in paper in three-dimensional.Formula I compound has many Stereocenters, to be included on 4-position, on 5-position, first-class in 6-position.
" solvate " of the above-mentioned arbitrary compound of the present invention refers to that medicine is in crystallisation process, makes the crystallization obtained that changes of the lattice of crystallization be called solvate because solvent molecule adds.If solvent is water, be then called hydrate, if solvent is organic solvent, be then called organic solvate.
The present invention is the claimed pharmaceutical composition comprising arbitrary compound recited above, its pharmacy acceptable salt, the ester of its facile hydrolysis, its steric isomer or its solvated compounds and other active pharmaceutical ingredients further, as cilastatin and sodium salt, Betamipron etc.
The present invention also comprises the pharmaceutical preparation of above-mentioned arbitrary compound, its pharmacy acceptable salt, the ester of its facile hydrolysis, its steric isomer or its solvated compounds and one or more pharmaceutical carriers and/or thinner, can be mixed with clinically by manner known in the art or pharmaceutically acceptable arbitrary formulation, with oral, parenteral, rectum or be applied to through modes such as lung administrations the patient needing this treatment.During for oral administration, 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.When making oral preparations, suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc. can be added.During for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When making injection, the ordinary method in existing pharmacy field can be adopted to produce, during preparation injection, can not additives be added, also can add suitable additives according to the character of medicine.During for rectal administration, can be made into suppository etc.For through lung administration time, can be made into inhalation or sprays etc.Compound 0.01g ~ the 10g shown in formula I containing physiology significant quantity in per unit preparation can be 0.01g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 10g etc.
Present invention also offers the compounds of this invention treats and/or prevents infectious disease medicament purposes in preparation.The compounds of this invention all has good anti-microbial activity to gram-positive, negative bacterium and hospital clinical pathogenic bacteria such as streptococcus pneumoniae, and the compounds of this invention is stablized β-lactamase and people's kidney DHP-I, may be used for treating the following infection caused by sensitive organism: (1) respiratory system infection, as chronic bronchitis, pneumonia, lung abscess and pyothorax etc.; (2) infect in abdomen, as cholecystitis, cholangitis, liver abscess and peritonitis etc.; (3) uropoiesis, genital system infection, as pyelonephritis, complicacy urocystitis, adnexitis, intra-uterine infection, pelvic inflammatory disease and uterus inflammation of connective tissue etc.; (4) bone, joint and Skin and soft tissue infection, as cellulitis, perianal abscess, osteomyelitis, sacroiliitis, trauma wound infection, Burn Infection, surgery cut infection, jawbone and jawbone surrounding cells cellulites etc.; (5) eye and otorhinolaryngology infect; (6) other severe infections, as meningitis and septicemia etc.
Below set forth the beneficial effect of the compounds of this invention further, other compound of the present invention has identical beneficial effect with part the compounds of this invention cited in test, but this should be interpreted as the compounds of this invention only has following beneficial effect.
the antibacterial activity in vitro of experimental example 1 the compounds of this invention
For examination bacterial classification:
Gram-positive microorganism: staphylococcus epidermidis, streptococcus aureus;
Severe oxygen bacterium: streptococcus pneumoniae, Streptococcus viridans;
Gram-negative bacteria: the Klebsiella Pneumoniae of Klebsiella Pneumoniae, product ESBLs.
Above strains tested is all purchased from Beijing Fu Wai cardiovascular diseases hospital, Shanghai Ren Ji hospital, Xijing hospital of affiliated hospital of The Fourth Military Medical University.
Trial-product:
The compounds of this invention, self-control, its chemical name and structural formula are shown in the preparation embodiment of each compound; Meropenem, ertapenem is commercial.
Experimental technique: agar dilution, with reference to Clinical And Laboratory Standards Institute.Methods forDilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; ApprovedStandard-Seventh Edition.CLSI Document M7-A7.Vol 26, No.2, Wayne, PA:Clinical AndLaboratory Standards Institute, 2006.
Experimental result and conclusion:
The antibacterial activity in vitro of table 1 the compounds of this invention
From table 1, the compounds of this invention to the bacteriostatic activity of above-mentioned strains tested and ertapenem quite or better, with meropenem quite or slightly poor.
The antibacterial activity in vitro of table 2 the compounds of this invention
---representative does not have to test the activity to this bacterial strain
From table 2, the bacteriostatic activity of the compounds of this invention to above-mentioned strains tested is compared with ertapenem with meropenem, quite or better.
the Pharmacokinetics in Rat experiment of experimental example 2 the compounds of this invention
Animal subject male SD rat, 3/compound, body weight 220-250g.
Trial-product part of compounds of the present invention, self-control; Use physiological saline solution.
Reference substance ertapenem (injection ertapenem), commercial; Use physiological saline solution.
Experimental technique
Administration ertapenem, compound 1,6,11 intravenous injection administration (IV), dosage is 5mg/kg, administration volume 2mL/kg; Compound 47,48 intravenous injection administration (IV), dosage is 2mg/kg, administration volume 2mL/kg.
Take a blood sample 0 hour, 0.083 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, each time point taked 100 μ about L whole bloods, and centrifugal 5 minutes separated plasmas in the supercentrifuge of 2000g, blood plasma is frozen in-80 DEG C of refrigerators.
Plasma sample analysis
Ertapenem, the compounds of this invention: get 30 μ L blood plasma, add mark (meropenem: 500ng/mL MeOH solution) in 100 μ L, 1500 revs/min of vortexs 2 minutes, then 12000 revs/min centrifugal 5 minutes, get supernatant liquor, use LC-MS/MS to analyze.
Experimental result is in table 3.
The P of Rats K evaluation result (IV) of table 3 the compounds of this invention
Conclusion: we can find out by above data, in rat body, the long half time of the compounds of this invention 47,48 is in ertapenem; The transformation period of compound 1,6,11 is suitable with ertapenem.
4, embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples.
embodiment 1 (4R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-aminosulfonyl yl pyridines-2-
base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl] preparation of-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (compound 1)
The preparation of step 1 (2S, 4S)-4-sulfydryl-2-[(5-aminosulfonyl yl pyridines-2-base) methyl amido formacyl] tetramethyleneimine-1-carboxy acid mutual-nitro carbobenzoxy
In the reaction flask of drying; by (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxy acid mutual-nitro carbobenzoxy (3.3g; 0.0107mol) with 2-amino methyl-5-aminosulfonyl yl pyridines (2.7g; 0.0144mol) be dissolved in acetonitrile 200mL; reaction solution, in room temperature for overnight, filters out solid, is directly used in the next step.
Step 2 (4R; 5S; 6S) the preparation of-6-[(R)-1-hydroxyethyl]-4-methyl-3-[(3S, 5S)-1-(to nitrobenzyloxycarbonyl)-5-[(5-aminosulfonyl yl pyridines-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy
In the reaction flask of drying, step 1 gained solid is dissolved in acetonitrile, add (4R, 5S, 6S)-3-(hexichol oxygen phosphorus acyloxy)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) (6.4g, 0.0107mol) with diisopropylethylamine (DIEA) (5.5g, 0.0428mol).Reaction mixture at room temperature stirs and spends the night, then with ethyl acetate and water extraction, and organic layer Na
2sO
4drying, concentrating under reduced pressure, obtains yellow solid product (4.50g, 50.1%).
The preparation of step 3 compound 1
By step 2 products therefrom (1.26g, 0.0015mol) be dissolved in the mixed solution (10mL: 10mL) of tetrahydrofuran (THF) and water, add 10%Pd/C (1g), join in hydriding reactor, pass into hydrogen, stirring at room temperature 2 hours, crosses and filters Pd/C, and with tetrahydrofuran (THF) and deionized water wash.Merging filtrate, is extracted with ethyl acetate.Water layer preparative HPLC is purified, lyophilize, obtains solid product (300mg, 38.1%).
Molecular formula: C
21h
27n
5o
7s
2molecular weight: 525.60 MS (M+1): 526
1H-NMR(400MHz，DMSO-d
6)：δ1.14(3H，d)，1.15(3H，d)，1.62(1H，m)，2.56(1H，m)，2.67(1H，m)，3.19(2H，dd)，3.43(1H，m)，3.57(1H，t)，3.82(1H，t)，3.96(1H，t)，4.16(1H，d)，4.43(2H，m)，5.06(1H，s)，7.48(1H，d)，7.57(2H，s)，8.14(1H，dd)，8.78(1H，t)，8.88(1H，d).
The preparation of step 4 compound 1 sodium salt
The compound 1 (0.53g, 1mmol) step 3 prepared is dissolved in 4mL deionized water, about stirring borehole cooling to 0 DEG C, slowly add powdery sodium bicarbonate 0.1g, insulated and stirred 2 hours, purifies with preparative HPLC, freeze-drying obtains 0.38g sodium salt, yield 69.4%.
embodiment 2 (4R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl thiophene-2-
base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl] preparation of-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (compound 6)
The preparation of step 1 (2S, 4S)-4-sulfydryl-2-[(5-amino-sulfonyl thiophene-2-base) methyl amido formacyl] tetramethyleneimine-1-carboxy acid mutual-nitro carbobenzoxy
(1S is added in the reaction flask of drying; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxy acid mutual-nitro carbobenzoxy (2.7g; 8.8mmol); 2-amino-sulfonyl-5-amino methyl thiophene (1.1g; 5.8mmol) and acetonitrile, at ice bath and stirred under nitrogen atmosphere 4 hours.Reaction mixture is poured into water, is extracted with ethyl acetate.Organic layer Na
2sO
4drying, vacuum concentration, column chromatography purification, obtains product (1.5g, 51.7%).
Step 2 (4R; 5S; 6S) the preparation of-6-[(R)-1-hydroxyethyl]-4-methyl-3-[(3S, 5S)-1-is to nitrobenzyloxycarbonyl-5-[(5-amino-sulfonyl thiophene-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy
By step 1 products therefrom (1.5g; 3.0mmol) with triethylamine (TEA) (0.61g; 6.0mmol) be dissolved in acetonitrile; (4R is added under ice bath and nitrogen protection; 5S; 6S)-3-(hexichol oxygen phosphorus acyloxy)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) (1.78g; 3.0mmol), mixture stirs 2 hours at 0 DEG C.Reaction mixture is poured into water, filters, obtain product (2.2g, 86.8%).
The preparation of step 3 compound 6
By step 2 products therefrom (2.2g, 2.6mmol), Pd/C (1.1g) joins mixed solution (100mL, the V of tetrahydrofuran (THF) and water
tHF: V
water=7: 3), then pouring in hydriding reactor by mixed solution, is 4MPa at hydrogen pressure, and temperature of reaction is react 2 hours at 27 DEG C-30 DEG C, crosses and filters Pd/C, with the mixed solution (V of tetrahydrofuran (THF) and deionized water
tHF: V
water=2: 3) wash.Merging filtrate and washings, with ethyl acetate (30ml × 3) extraction, water layer preparation liquid phase is purified, and lyophilize, obtains white solid (0.027g, 2.0%).
Molecular formula: C
20h
26n
4o
7s
3molecular weight: 530.64 MS (M+1): 531
1H-NMR(400MHz，DMSO-d
6)：δ1.13(3H，d)，1.15(3H，d)，1.50(1H，m)，2.56(2H，m)，3.19(1H，dd)，3.49(1H，dd)，3.69(1H，t)，3.91(1H，m)，4.13(1H，q)，4.40(2H，t)，5.04(1H，d)，6.94(1H，d)，7.36(1H，d)，7.60(2H，s)，8.72(1H，t).
The preparation of step 4 compound 6 sodium salt
The compound 60.53g (1mmol) step 3 prepared is dissolved in 4mL deionized water, about stirring borehole cooling to 0 DEG C, slowly adds powdery sodium bicarbonate 0.1g, insulated and stirred 2 hours, purifies and obtain 0.40g sodium salt, yield 72.4% with preparative HPLC.
embodiment 3 (4R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(5-amino-sulfonyl thiazole-2-
base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl] preparation of-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (compound 11)
Step 1 (4R; 5S; 6S) the preparation of-6-[(R)-1-hydroxyethyl]-4-methyl-3-[(3S, 5S)-1-is to nitrobenzyloxycarbonyl-5-[(5-amino-sulfonyl thiazol-2-yl) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy
By 2-amino methyl-5-amino-sulfonyl thiazole (2.0g; 10mmol); (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxy acid mutual-nitro carbobenzoxy (3.1g; 10mmol), tri-n-butyl phosphine (2g, 10mmol) and diisopropylethylamine (DIPEA) (2.6g; 20mmol) be dissolved in acetonitrile (20mL), spend the night in room temperature and stirred under nitrogen atmosphere.At 0 DEG C, reaction mixture is joined (4R, 5S, 6S)-3-(hexichol oxygen phosphorus acyloxy)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) (6g, 10mmol) with in acetonitrile (40mL) solution of triethylamine (2.0g, 20mmol).Mixed solution is risen to room temperature, stirs under nitrogen protection and spend the night.Then reaction mixture under reduced pressure concentrates, and obtains oily residue, through silica gel column chromatography, preparative HPLC purifying, obtains product (0.81g, 9.56%).
The preparation of step 2 compound 11
Step 1 products therefrom (5.08g is added in hydriding reactor, 0.006mol), the mixed solution (10mL: 10mL) of tetrahydrofuran (THF) and water, 10%Pd/C (1g), stirring at room temperature 2 hours under hydrogen pressure is 30PSI, cross and filter Pd/C, and with tetrahydrofuran (THF) and deionized water wash.Merging filtrate, is extracted with ethyl acetate.Water layer preparative HPLC is purified, lyophilize, obtains product (300mg, 9.4%).
Molecular formula: C
19h
25n
5o
7s
3molecular weight: 531.63 MS (M+1): 532.0
1H-NMR(400MHz，DMSO-d
6)：δ1.03(3H，d)，1.11(3H，d)，1.58(1H，m)，2.59(1H，m)，3.00(1H，d)，3.13(3H，m)，3.70(1H，m)，3.86(1H，m)，3.93(1H，d)，4.39(1H，dd)，4.63(1H，dd)，4.93(1H，d)，7.92(1H，s)，8.34(2H，b r.s)，δ8.93(1H，t).
The preparation of step 3 compound 11 sodium salt
Step 1 products therefrom (0.80g, 1mmol) is dissolved in tetrahydrofuran (THF) (10mL), adds NaHCO
3solution (0.08g, 1mmol; Water: 5mL) and 10%Pd/C (1g, the water containing 50%).Mixture stirs 5 hours tempestuously under room temperature and atmosphere of hydrogen.Cross and filter Pd/C, with diethyl ether twice, water layer, in neutral conditions through preparative HPLC purifying, freeze-drying, obtains product (280mg, 50.7%).
embodiment 4 (4R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(2-amino-sulfonyl benzo [b]
furans-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (compound 39)
preparation
The preparation of step 1 (2S, 4S)-4-sulfydryl-2-[(2-amino-sulfonyl benzo [b] furans-6-base) methyl amido formacyl] tetramethyleneimine-1-carboxy acid mutual-nitro carbobenzoxy
By 2-amino-sulfonyl-6-amino methyl benzo [b] furans (1.357g; 6.0mmol) with (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxy acid mutual-nitro carbobenzoxy (1.850g; 6.0mmol) be dissolved in DMF, stirring at room temperature 2 hours.Mixed solution is poured into water, is extracted with ethyl acetate.Organic layer Na
2sO
4drying, vacuum concentration, crude product purification by silica gel column chromatography.Obtain product (2.541g, 79.2%).
Step 2 (4R; 5S; 6S) the preparation of-6-[(R)-1-hydroxyethyl]-4-methyl-3-[(3S, 5S)-1-(to nitrobenzyloxycarbonyl)-5-[(2-amino-sulfonyl benzo [b] furans-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy
By step 1 products therefrom (2.566g; 4.8mmol) with (4R; 5S; 6S)-3-(hexichol oxygen phosphorus acyloxy)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) (2.854g; 4.8mmol) be dissolved in DMF; add triethylamine (TEA) (0.971g; 9.6mmol), stirring at room temperature 2 hours under nitrogen protection.Reaction mixture is poured into water, filters.Obtain product (3.547g, 84.0%).
The preparation of step 3 compound 39
By step 2 products therefrom (3.516g, 4.0mmol), Pd/C (2.3g) joins mixed solution (120mL, the V of tetrahydrofuran (THF) and water
tHF: V
water=7: 3).Then pouring in hydriding reactor by mixed solution, is 4MPa at hydrogen pressure, and temperature of reaction is react 2 hours at 27 DEG C-30 DEG C, crosses and filters Pd/C, with the mixed solution (V of tetrahydrofuran (THF) and deionized water
tHF: V
water=2: 3) wash.Merging filtrate and washings, with ethyl acetate (30ml × 3) extraction, water layer preparation liquid phase is purified, and lyophilize, obtains white solid (0.119g, 5.3%).
Molecular formula: C
24h
28n
4o
8s
2molecular weight: 564.63 MS (M+1): 565
1H-NMR(400MHz，DMSO-d
6)：δ1.13(3H，d)，1.15(3H，d)，1.54(1H，m)，2.53(1H，m)，2.58(1H，m)，3.18(1H，dd)，3.39(2H，m)，3.53(1H，t)，3.73(1H，t)，3.94(1H，s)，4.13(1H，dd)，4.42(2H，m)，5.04(1H，s)，7.29(1H，d)，7.40(1H，s)，7.54(1H，s)，7.72(1H，d)，8.00(2H，s)，8.60(1H，t).
embodiment 5 (4R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(3-amino-sulfonyl-1H-Yin
diindyl-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (compound 47)
preparation
The preparation of step 1 (2S, 4S)-4-sulfydryl-2-[(3-amino-sulfonyl-1H-indoles-6-base) methyl amido formacyl] tetramethyleneimine-1-carboxy acid mutual-nitro carbobenzoxy
By 3-amino-sulfonyl-6-aminomethylindole (1.126g; 5.0mmol) with (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxy acid mutual-nitro carbobenzoxy (1.542g, 5.0mmol) is dissolved in DMF, stirring at room temperature 2 hours.Mixed solution is poured into water, is extracted with ethyl acetate.Organic layer Na
2sO
4drying, vacuum concentration, crude product purification by silica gel column chromatography.Obtain product (2.159g, 81%).
Step 2 (4R; 5S; 6S) the preparation of-6-[(R)-1-hydroxyethyl]-4-methyl-3-[(3S, 5S)-1-(to nitrobenzyloxycarbonyl)-5-[(3-amino-sulfonyl-1H-indoles-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy
By step 1 products therefrom (2.188g; 4.1mmol) with (4R; 5S; 6S)-3-(hexichol oxygen phosphorus acyloxy)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) (2.437g; 4.1mmol) be dissolved in DMF; add triethylamine (TEA) (0.888g; 8.8mmol), stirring at room temperature 2 hours under nitrogen protection.Reaction mixture is poured into water, filters.Obtain product (3.020g, 84%).
The preparation of step 3 compound 47
By step 2 products therefrom (2.985g, 3.4mmol), Pd/C (2.0g) joins mixed solution (120mL, the V of tetrahydrofuran (THF) and water
tHF: V
water=7: 3) in.Reaction suspends, and reaction solution is poured in H-H reaction still, stirs 2 hours at hydrogen (4MPa) protection and 27 DEG C-30 DEG C, filter Pd/C, with the mixed solution (V of tetrahydrofuran (THF) and deionized water
tHF: V
water=2: 3) wash.Merging filtrate and washings, with ethyl acetate (30ml × 3) extraction, water layer preparative HPLC is purified, lyophilize, obtains white solid (0.187g, 9.7%).
Molecular formula: C
24h
29n
5o
7s
2molecular weight: 563.65 MS (M+1): 564
1H-NMR(400MHz，DMSO-d
6)：δ1.06(3H，d)，1.11(3H，d)，1.60(1H，m)，2.53(1H，m)，2.66(1H，dd)，3.15(1H，dd)，3.52(1H，m)，3.71(1H，dd)，3.93(1H，t)，4.09(1H，dd)，4.33(1H，dd)，4.45(1H，dd)，5.03(1H，s)，7.06(1H，d)，7.10(2H，s)，7.42(1H，s)，7.73(1H，d)，7.76(1H，d)，8.47(1H，t)，12.4(1H，br.S).
The preparation of step 4 compound 47 sodium salt
The compound 470.56g (1mmol) step 3 prepared is dissolved in 4mL deionized water, about stirring borehole cooling to 0 DEG C, slowly adds powdery sodium bicarbonate 0.1g, insulated and stirred 2 hours, purifies and obtain 0.41g sodium salt, yield 70.0% with preparative HPLC.
embodiment 6 (4R, 5S, 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(2-amino-sulfonyl-1H-Yin
diindyl-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid (compound 48)
preparation
The preparation of step 1 (2S, 4S)-4-sulfydryl-2-[(2-amino-sulfonyl-1H-indoles-6-base) methyl amido formacyl] tetramethyleneimine-1-carboxy acid mutual-nitro carbobenzoxy
By 2-amino-sulfonyl-6-aminomethylindole (1.352g; 6.0mmol) with (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxy acid mutual-nitro carbobenzoxy (1.848g, 6.0mmol) is dissolved in DMF, stirring at room temperature 2 hours.Mixed solution is poured into water, uses ethyl acetate process.Organic layer Na
2sO
4drying, vacuum concentration, crude product purification by silica gel column chromatography.Obtain product (2.366g, 73.9%).
Step 2 (4R; 5S; 6S) the preparation of-6-[(R)-1-hydroxyethyl]-4-methyl-3-[(3S, 5S)-1-(to nitrobenzyloxycarbonyl)-5-[(2-amino-sulfonyl-1H-indoles-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy
By step 1 products therefrom (2.348g; 4.4mmol) with (4R; 5S; 6S)-3-(hexichol oxygen phosphorus acyloxy)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) (2.632g; 4.4mmol) be dissolved in DMF; add triethylamine (TEA) (0.888g; 8.8mmol), stirring at room temperature 2 hours under nitrogen protection.Reaction mixture is poured into water, filters.Obtain product (3.164g, 82%).
The preparation of step 3 compound 48
By step 2 products therefrom (3.160g, 3.6mmol), Pd/C (2.1g) joins mixed solution (120mL, the V of tetrahydrofuran (THF) and water
tHF: V
water=7: 3) in.Reaction suspends, and reaction solution is poured in H-H reaction still, stirs 2 hours at hydrogen (4MPa) protection and 27 DEG C-30 DEG C, filter Pd/C, with the mixed solution (V of tetrahydrofuran (THF) and deionized water
tHF: V
water=2: 3) wash.Merging filtrate and washings, with ethyl acetate (30ml × 3) extraction, water layer preparative HPLC is purified, lyophilize, obtains white solid (0.140g, 6.9%).
Molecular formula: C
24h
29n
5o
7s
2molecular weight: 563.65 MS (M+1): 564
1H-NMR(400MHz，DMSO-d
6)：δ1.13(3H，d)，1.15(3H，d)，1.83(1H，m)，2.62(1H，m)，2.83(1H，m)，3.14(1H，m)，3.46(1H，m)，3.63(1H，t)，3.92(2H，m)，4.08(1H，d)，4.33(1H，d)，4.49(1H，s)，5.02(1H，d)，6.77(1H，s)，6.96(1H，d)，7.40(1H，s)，7.55(1H，d)，7.86(2H，s)，8.58(1H，s).
Claims (10)
1. the compound shown in general formula (I) or its pharmacy acceptable salt:
Wherein: R
1represent 1-hydroxyethyl, 1-fluoro ethyl or methylol;
R
2represent hydrogen atom or C
1-6alkyl;
R
3represent hydrogen atom or carboxyl-protecting group;
R
4, R
5, R
6, R
7representative hydrogen atom independently or C
1-6alkyl;
R
8, R
9representative hydrogen atom independently, C
1-6alkyl or halo C
1-6alkyl;
A represents the thick heteroaryl of the 5-8 single heteroaryl of unit or 9-14 unit.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein: R
1represent 1-hydroxyethyl, 1-fluoro ethyl or methylol;
R
2represent hydrogen atom or C
1-6alkyl;
R
3represent hydrogen atom or carboxyl-protecting group;
R
4, R
5, R
6, R
7representative hydrogen atom independently or C
1-6alkyl;
R
8, R
9representative hydrogen atom independently, C
1-6alkyl or halo C
1-6alkyl;
A represents the 5-6 single heteroaryl of unit or 9-10 unit benzo heteroaryl.
3. compound as claimed in claim 2 or its pharmacy acceptable salt:
Wherein: R
1represent 1-hydroxyethyl;
R
2represent methyl;
R
3represent hydrogen atom or to nitrobenzyl;
R
4, R
5representative hydrogen atom independently;
R
6, R
7representative hydrogen atom independently, methyl, ethyl or propyl group;
R
8, R
9representative hydrogen atom independently, methyl, methyl fluoride, trifluoromethyl or 2,2,2-trifluoroethyl;
A represents pyridyl, pyrimidyl, thienyl, thiazolyl, thiadiazolyl group, 4,5-dihydro-thiazolyl, oxazolyl, isoxazolyl, oxadiazolyls, pyrryl, imidazolyl, pyrazolyl, triazol radical, benzofuryl, benzoxazolyl, benzothienyl, benzothiazolyl, indyl, pseudoindoyl, benzimidazolyl-, indazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl or cinnolines base.
4. compound as claimed in claim 3 or its pharmacy acceptable salt:
Wherein: R
1represent 1-hydroxyethyl;
R
2represent methyl;
R
3represent hydrogen atom or to nitrobenzyl;
R
4, R
5representative hydrogen atom independently;
R
6, R
7representative hydrogen atom independently, methyl or ethyl;
R
8, R
9representative hydrogen atom independently;
A represents pyridyl, pyrimidyl, thienyl, thiazolyl, 1, 3, 4-thiadiazolyl group, 1, 2, 4-thiadiazolyl group, 4, 5-dihydro-thiazolyl, oxazolyl, isoxazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 4-oxadiazolyl, pyrryl, imidazolyl, pyrazolyl, 1, 2, 4-triazol radical, benzo [b] furyl, benzo [c] furyl, benzo [d] oxazolyl, benzo [b] thienyl, benzo [c] thienyl, benzo [d] thiazolyl, indyl, pseudoindoyl, benzo [d] imidazolyl, indazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, phthalazinyl or cinnolines base.
5. compound as claimed in claim 4 or its pharmacy acceptable salt:
Wherein: R
1represent 1-hydroxyethyl;
R
2represent methyl;
R
3, R
4, R
5representative hydrogen atom independently;
R
6, R
7representative hydrogen atom independently, methyl or ethyl;
R
8, R
9representative hydrogen atom independently;
A represents pyridyl, pyrimidyl, thienyl, thiazolyl, 1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, pyrryl, imidazolyl, benzo [b] furyl, benzo [b] thienyl, benzo [d] thiazolyl, indyl, benzo [d] imidazolyl, indazolyl, quinolyl or isoquinolyl.
6. compound as claimed in claim 5 or its pharmacy acceptable salt:
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(5-aminosulfonyl yl pyridines-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-3-[(3S; 5S)-5-[[5-(N-methyl amido alkylsulfonyl) pyridine-2-base] methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(5-amino-sulfonyl pyridin-3-yl) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(5-amino-sulfonyl pyrimidine-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(5-amino-sulfonyl thiophene-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-3-[(3S; 5S)-5-[[5-(N-ethyl amido alkylsulfonyl) thiophene-2-base] methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(4-amino-sulfonyl thiophene-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(5-amino-sulfonyl thiazol-2-yl) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(4-amino-sulfonyl thiazol-2-yl) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(5-amino-sulfonyl-1; 3; 4-thiadiazoles-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(3-amino-sulfonyl-1; 2; 4-thiadiazoles-5-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(5-amino-sulfonyl-1; 2; 4-thiadiazoles-3-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(5-aminosulfonyl base oxazole-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(4-aminosulfonyl base oxazole-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(5-amino-sulfonyl-1; 3; 4-oxadiazole-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(3-amino-sulfonyl-1; 2; 4-oxadiazole-5-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(5-amino-sulfonyl-1; 2; 4-oxadiazole-3-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(5-amino-sulfonyl-1H-pyrroles-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(4-amino-sulfonyl-1H-pyrroles-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(5-amino-sulfonyl-1H-imidazoles-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(4-amino-sulfonyl-1H-imidazoles-2-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(2-amino-sulfonyl benzo [b] furans-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(3-amino-sulfonyl benzo [b] furans-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(2-amino-sulfonyl benzo [b] thiophene-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(3-amino-sulfonyl benzo [b] thiophene-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(2-amino-sulfonyl benzo [d] thiazole-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(3-amino-sulfonyl-1H-indoles-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(2-amino-sulfonyl-1H-indoles-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(2-amino-sulfonyl-1H-benzo [d] imidazoles-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(3-amino-sulfonyl-1H-indazole-6-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(2-amino-sulfonyl quinoline-7-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(3-amino-sulfonyl quinoline-7-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S; 5S)-5-[(4-amino-sulfonyl quinoline-7-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid, and
(4R; 5S; 6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S, 5S)-5-[(3-amino-sulfonyl isoquinoline 99.9-7-base) methyl amido formacyl] pyrrolidin-3-yl sulfenyl]-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxylic acid.
7. the pharmaceutical preparation containing compound described in any one of claim 1 ~ 6 or its pharmacy acceptable salt, is characterized in that comprising one or more pharmaceutical carriers.
8. the compound as described in any one of claim 1 ~ 6 or its pharmacy acceptable salt are for the preparation of the purposes of medicine treating and/or preventing infectious diseases.
9. prepare the method for general formula (I) described compound, the method comprises makes compound or its pharmacy acceptable salt shown in general formula (III), with compound general formula (II) Suo Shi or its pharmacy acceptable salt generation nucleophilic substitution reaction
Wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9with A as defined in claim 1; L represents leavings group.
10. the compound described in general formula (II) or its pharmacy acceptable salt:
Wherein, R
4, R
5, R
6, R
7, R
8, R
9with A as defined in claim 1.
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|---|---|---|---|---|
| CN101323615A (en) * | 2007-06-11 | 2008-12-17 | 山东轩竹医药科技有限公司 | Pennem derivates containing formamide heterocycle sulfonic acid amide sulfhydryl pyrrolidine |
| CN101367810A (en) * | 2007-06-28 | 2009-02-18 | 山东轩竹医药科技有限公司 | Novel carbpenem antibiotic |
| CN101367815A (en) * | 2007-06-28 | 2009-02-18 | 山东轩竹医药科技有限公司 | Six-membered ring methanamide substituted sulfhydryl pyrrolidine carbpenem compound |
| CN101372489A (en) * | 2007-06-28 | 2009-02-25 | 山东轩竹医药科技有限公司 | Carbapenem derivative containing sulfhydryl pyrrolidine formamide benzyl |
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2011
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101323615A (en) * | 2007-06-11 | 2008-12-17 | 山东轩竹医药科技有限公司 | Pennem derivates containing formamide heterocycle sulfonic acid amide sulfhydryl pyrrolidine |
| CN101367810A (en) * | 2007-06-28 | 2009-02-18 | 山东轩竹医药科技有限公司 | Novel carbpenem antibiotic |
| CN101367815A (en) * | 2007-06-28 | 2009-02-18 | 山东轩竹医药科技有限公司 | Six-membered ring methanamide substituted sulfhydryl pyrrolidine carbpenem compound |
| CN101372489A (en) * | 2007-06-28 | 2009-02-25 | 山东轩竹医药科技有限公司 | Carbapenem derivative containing sulfhydryl pyrrolidine formamide benzyl |
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