CN101759710B - Cephalosporin derivatives containing substitutional nitrogen heterocycle - Google Patents

Cephalosporin derivatives containing substitutional nitrogen heterocycle Download PDF

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CN101759710B
CN101759710B CN2009100028720A CN200910002872A CN101759710B CN 101759710 B CN101759710 B CN 101759710B CN 2009100028720 A CN2009100028720 A CN 2009100028720A CN 200910002872 A CN200910002872 A CN 200910002872A CN 101759710 B CN101759710 B CN 101759710B
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thia
azabicyclic
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CN101759710A (en
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黄振华
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Hainan Sihuan Pharmaceutical Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

The invention belongs to the technical field of medicine, in particular relating to cephalosporin derivatives containing substitutional nitrogen heterocycle shown in general formula (I), pharmaceutically acceptable salt, easily hydrolyzed ester or isomer thereof, wherein, R1, R2, R3, R4, R5, R6, X and n are defined as specification; and the invention further relates to a preparation method of compounds, a pharmaceutical composition containing the compounds, and an application of the compounds in preparing a medicine for treating and/or preventing infectious diseases.

Description

The cephalosporins derivatives that contains the nitrogen heterocyclic of replacement
1, technical field
The invention belongs to medical technical field, be specifically related to contain cephalosporins derivatives, its pharmacy acceptable salt of the nitrogen heterocyclic of replacement, ester or its isomer of its facile hydrolysis, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds treat and/or prevent purposes in the medicine of infectious diseases in preparation.
2, background technology
Cephalosporins (Cephalosporins) is by isolating cephalosporin in the crown head spore bacteria culture fluid, a series of semisynthetic antibiotics that obtain through transforming side chain.Its advantage is: has a broad antifungal spectrum, and to acid and more stable to various bacteriogenic β-Nei Xiananmeis.
Twentieth century is since the seventies, and the new variety of multiple cynnematin enter clinical one after another, is the treatment infectation of bacteria, and infection due to the drug-fast bacterial strain of antimicrobial drugs such as penicillins, ward infection and penicillin anaphylaxis person are infected provides good antibiotic kind especially.Why cynnematin becomes clinical microbiotic commonly used, and major cause is that it not only has the good pharmacology characteristics of similar penicillin, and the advantage that is more suitable for clinical needs is arranged.For example, its target site is at the cell walls of bacterium, so toxicity is humble, can be used for children's, old man, gravid woman and nursing women safely; The tissue distribution of medicine is good, and the kind that can see through hemato encephalic barrier smoothly is more, is applicable to the infectation of bacteria at various positions; Cause allergic reaction particularly that the incidence of anaphylactic shock is starkly lower than penicillins, can carefully be used for penicillin anaphylaxis person.These advantages all make cephalosporins have high clinic actual value, are current exploitation class microbiotic faster.
Cephalosporin antibiotic is to be widely used in clinical antibacterials, developed into for the 4th generation, the antimicrobial spectrum in each generation is different, the first-generation is based on anti-gram positive organism, relatively poor to the gram-negative bacteria activity, the anti-gram-negative bacteria of second generation cephalosporin is active to be improved, the anti-gram-negative bacteria of third generation cephalosporin and anti-gram positive organism activity are than balance, the 4th generation cynnematin anti-gram positive organism and gram-negative bacteria activity all improve greatly, especially to the activity of pseudomonas aeruginosa, the gold standard medicine ceftazime of more anti-pseudomonas aeruginosa is better.This similar drug that has gone on the market at present has cefpirome, cefepime, Wincef and Cefozopran etc.Cefpirome Sulfate be the 4th generation cynnematin, has a broad antifungal spectrum, anti-microbial effect are strong, and Gram-negative bacteria is had good antibacterial activity, structural formula is as follows:
Figure G2009100028720D00011
Cefpirome Sulfate
Yet because prolonged application clinically causes bacterium that cephalosporin analog antibiotic is produced resistance, greatly influenced the antibiotic curative effect of cephalosporin analog antibiotic, influenced its application clinically.In recent years, the infection that Pseudomonas aeruginosa causes is increasing, resistance strengthens day by day, has become the representative bacterium of conditioned pathogen, and the transmissible disease that causes has become serious clinical problem, presses for by structure of modification and seeks new antibiotic.
3, summary of the invention
The purpose of this invention is to provide novel high-activity and resistant organism is had the cephalosporins derivatives of the nitrogen heterocyclic that contains replacement of excellent activity.
Another object of the present invention provides cephalosporins derivatives pharmaceutical composition and the preparation that comprises novel high-activity of the present invention and resistant organism is had the nitrogen heterocyclic that contains replacement of excellent activity.
An also purpose of the present invention provides novel high-activity and resistant organism is had the cephalosporins derivatives of the nitrogen heterocyclic that contains replacement of excellent activity treat and/or prevent purposes in the medicine of infectious diseases in preparation.
Technical scheme of the present invention is as follows:
The invention provides ester or its isomer of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis:
Figure G2009100028720D00021
Wherein: R 1And R 2Independently be hydrogen atom or amino protecting group respectively;
X is CR 7Or N, wherein R 7Be hydrogen atom or halogen atom;
R 3Be hydrogen atom, C 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl,
Described C 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl is not substituted or is selected from halogen atom, hydroxyl, carboxyl or amino substituting group by 1～5 and replaces;
R 4Be hydrogen atom, C 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl,
Described C 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl is not substituted or is replaced by 1～5 substituting group that is selected from carboxyl, carbamyl, amino-sulfonyl, amino, nitro, cyano group, sulfonic group, hydroxyl or halogen atom;
R 5And R 6Independently be hydrogen atom respectively, carboxyl, amino, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, sulfonic acid amido, halogen atom, C 1-6Alkyl, C 1-6Alkoxyl group, C 2-6Thiazolinyl, C 2-6Alkynyl, aryl C 1-6Alkyl, heterocyclic radical C 1-6Alkyl ,-NHCOR 8,-NHSO 2R 8Or-NHSOR 8, R wherein 8Be C 1-6Alkyl, aryl, aryl C 1-6Alkyl, heterocyclic radical or heterocyclic radical C 1-6Alkyl, perhaps R 5With R 6Connect into contain the heteroatomic 3-8 of 0-3 unit cyclic group and pyrrole ring carry out thick with, described heteroatoms is selected from N, O or S,
Described C 1-6Alkyl, C 1-6Alkoxyl group, C 2-6Thiazolinyl, C 2-6Alkynyl is not substituted or is replaced by 1～5 substituting group that is selected from carboxyl, amino, nitro, cyano group, hydroxyl, sulfonic group, carbamyl, amino-sulfonyl or halogen atom,
Described aryl, aryl C 1-6Alkyl or heterocyclic radical, heterocyclic radical C 1-6Alkyl or 3-8 unit cyclic group is not substituted or is replaced by 1～5 Q,
Described Q is carboxyl, amino, hydroxyl, nitro, cyano group, halogen atom, formamido-, formamyl, amino-sulfonyl, sulfonic group, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, halo C 1-6Alkyl, halo C 1-6Alkoxyl group, carbamyl C 1-6Alkyl, amino-sulfonyl C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 1-6Alkyl-carbonyl, C 1-6Alkyl amine group formyl radical, C 1-6Alkyl sulphonyl, C 1-6Alkyl amine group alkylsulfonyl, C 1-6Alkyl sulphinyl, C 1-6Alkyl amine group sulfinyl, two (C 1-6Alkyl) amido formyl radical, two (C 1-6Alkyl) amido alkylsulfonyl, two (C 1-6Alkyl) amido sulfinyl, C 1-6Alkyl oxygen carbonyl or C 1-6Alkyl carbonyl oxy;
N is 1～3 integer.
Preferred compound is:
Wherein: R 1And R 2Independently be hydrogen atom or amino protecting group respectively;
X is CR 7Or N, wherein R 7Be hydrogen atom or halogen atom;
R 3Be hydrogen atom, C 1-4Alkyl, C 2-4Thiazolinyl or C 2-4Alkynyl,
Described C 1-4Alkyl, C 2-4Thiazolinyl or C 2-4Alkynyl is not substituted or is selected from halogen atom, hydroxyl, carboxyl or amino substituting group by 1～3 and replaces;
R 4Be hydrogen atom, C 1-4Alkyl, C 2-4Thiazolinyl or C 2-4Alkynyl,
Described C 1-4Alkyl, C 2-4Thiazolinyl or C 2-4Alkynyl is not substituted or is replaced by 1～3 substituting group that is selected from carboxyl, carbamyl, amino-sulfonyl, amino, hydroxyl or halogen atom;
R 5And R 6Independently be hydrogen atom respectively, carboxyl, amino, nitro, cyano group, hydroxyl, formamyl, amino-sulfonyl, formamido-, sulfonic acid amido, halogen atom, C 1-4Alkyl, C 1-4Alkoxyl group ,-NHCOR 8,-NHSO 2R 8Or-NHSOR 8, R wherein 8Be C 1-4Alkyl, aryl or aryl C 1-4Alkyl, perhaps R 5With R 6Connect into contain the heteroatomic 4-7 of 0-2 unit cyclic group and pyrrole ring carry out thick with, described heteroatoms is selected from N, O or S,
Described C 1-4Alkyl or C 1-4Alkoxyl group is not substituted or is replaced by 1～3 substituting group that is selected from carboxyl, amino, nitro, cyano group, hydroxyl, sulfonic group, carbamyl, amino-sulfonyl or halogen atom, and described aryl or 4-7 unit cyclic group are not substituted or are replaced by 1～3 Q,
Described Q is carboxyl, amino, hydroxyl, nitro, cyano group, halogen atom, formamido-, formamyl, amino-sulfonyl, sulfonic group, C 1-4Alkyl, C 1-4Alkoxyl group, C 1-4Alkylthio, halo C 1-4Alkyl, halo C 1-4Alkoxyl group, carbamyl C 1-4Alkyl, amino-sulfonyl C 1-4Alkyl, C 2-4Thiazolinyl, C 2-4Alkynyl, C 1-4Alkyl-carbonyl, C 1-4Alkyl amine group formyl radical, C 1-4Alkyl sulphonyl, C 1-4Alkyl amine group alkylsulfonyl, C 1-4Alkyl sulphinyl, C 1-4Alkyl amine group sulfinyl, two (C 1-4Alkyl) amido formyl radical, two (C 1-4Alkyl) amido alkylsulfonyl, two (C 1-4Alkyl) amido sulfinyl, C 1-4Alkyl oxygen carbonyl or C 1-4Alkyl carbonyl oxy;
N is 1 or 2.
Preferred again compound is:
Wherein: R 1And R 2Independently be hydrogen atom or amino protecting group respectively;
X is CR 7Or N, wherein R 7Be hydrogen atom, fluorine atom or chlorine atom;
R 3Be hydrogen atom or C 1-4Alkyl, described C 1-4Alkyl is not substituted or is replaced by 1～3 substituting group that is selected from halogen atom, hydroxyl or carboxyl;
R 4Be hydrogen atom or C 1-4Alkyl, described C 1-4Alkyl is not substituted or is replaced by 1～3 substituting group that is selected from carboxyl, amino, hydroxyl or halogen atom;
R 5, R 6Independently be hydrogen atom respectively, carboxyl, amino, hydroxyl, formamyl, amino-sulfonyl, halogen atom, C 1-4Alkyl or C 1-4Alkoxyl group, perhaps R 5With R 6Connect into contain the heteroatomic 5-6 of 0-1 unit cyclic group and pyrrole ring carry out thick with, described heteroatoms is selected from N, O or S,
Described C 1-4Alkyl or C 1-4Alkoxyl group is not substituted or is replaced by 1～3 substituting group that is selected from carboxyl, amino, hydroxyl, carbamyl, amino-sulfonyl or halogen atom, and the first cyclic group of described 5-6 is not substituted or is replaced by 1～3 Q,
Described Q is carboxyl, amino, hydroxyl, nitro, cyano group, halogen atom, formamido-, formamyl, amino-sulfonyl, sulfonic group, C 1-4Alkyl, C 1-4Alkoxyl group, halo C 1-4Alkyl, halo C 1-4Alkoxyl group, carbamyl C 1-4Alkyl, amino-sulfonyl C 1-4Alkyl, C 2-4Thiazolinyl, C 2-4Alkynyl, C 1-4Alkyl-carbonyl, C 1-4Alkyl amine group formyl radical, C 1-4Alkyl sulphonyl, C 1-4Alkyl amine group alkylsulfonyl, C 1-4Alkyl sulphinyl, C 1-4Alkyl amine group sulfinyl, two (C 1-4Alkyl) amido formyl radical, two (C 1-4Alkyl) amido alkylsulfonyl, two (C 1-4Alkyl) amido sulfinyl, C 1-4Alkyl oxygen carbonyl or C 1-4Alkyl carbonyl oxy;
N is 1 or 2.
Further preferred compound is:
Wherein: R 1And R 2Independently be hydrogen atom respectively;
X is CH or N;
R 3Be hydrogen atom, be not substituted or by the C of carboxyl substituted 1-4Alkyl;
R 4Be hydrogen atom, methyl, ethyl, propyl group or sec.-propyl;
R 5And R 6Independently be hydrogen atom respectively, methyl, perhaps R 5With R 6Connect into contain the heteroatomic 5-6 of 0-1 unit cyclic group and pyrrole ring carry out thick with, described heteroatoms is selected from N, O or S,
The first cyclic group of described 5-6 is not substituted or is replaced by 1～2 Q, and described Q is amino, methyl;
N is 1 or 2.
Further preferred compound is:
Wherein: R 1And R 2Independently be hydrogen atom respectively;
X is CH or N;
R 3Be hydrogen atom, methyl or isobutyl acidic group;
R 4Be methyl;
R 5And R 6Independently be hydrogen atom respectively, methyl, perhaps R 5With R 6Connect into contain the heteroatomic 5-6 of 0-1 unit cyclic group and pyrrole ring carry out thick with, described heteroatoms is the O atom,
The first cyclic group of described 5-6 is not substituted or is replaced by 1 Q, and described Q is amino, methyl;
N is 1.
" halogen atom " of the present invention is meant fluorine atom, chlorine atom, bromine atoms, iodine atom etc.
" C of the present invention 1-6Alkyl " be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, neo-pentyl, 3-amyl group, n-hexyl, 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, 1,2-dimethyl propyl, cyclopropyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl etc.
" C of the present invention 2-6Thiazolinyl " be meant that the carbonatoms that contains two keys is straight or branched or the cyclic thiazolinyl of 2-6, for example can be vinyl; the 1-propenyl; 1-propyl group-2-alkene; 2-propenyl; 1-butylene base; 1-butyl-2-alkene, 1-butyl-3-alkene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1-methyl isophthalic acid-propyl group-2-alkene, 2-methyl isophthalic acid-propyl group-2-alkene, the 1-pentenyl, 1-amyl group-2-alkene, 1-amyl group-3-alkene, 1-amyl group-4-alkene, 1-methyl isophthalic acid-butenyl, the 2-methyl-1-butene thiazolinyl, the 3-methyl-1-butene base, 1-methyl isophthalic acid-butyl-2-alkene, 2-methyl-1-butene base-2-alkene, 3-methyl isophthalic acid-butyl-2-alkene, 1-methyl isophthalic acid-butyl-3-alkene, 2-methyl-1-butene base-3-alkene, 3-methyl isophthalic acid-butyl-3-alkene, the 1-hexenyl, 1-hexyl-2-alkene, 1-hexyl-3-alkene, 1-hexyl-4-alkene, 1-hexyl-5-alkene, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, the 4-methyl-1-pentene base, 1-methyl-1-pentene base-2-alkene, 2-methyl-1-pentene base-2-alkene, 3-methyl-1-pentene base-2-alkene, 4-methyl-1-pentene base-2-alkene, 1-methyl-1-pentene base-3-alkene, 2-methyl-1-pentene base-3-alkene, 3-methyl-1-pentene base-3-alkene, 4-methyl-1-pentene base-3-alkene, 1-methyl-1-pentene base-4-alkene, 2-methyl-1-pentene base-4-alkene, 3-methyl-1-pentene base-4-alkene, 4-methyl-1-pentene base-4-alkene, the cyclobutene base, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl etc.
" C of the present invention 2-6Alkynyl " be meant and contain the alkynyl that the triple-linked carbonatoms is the straight or branched of 2-6, for example can be ethynyl; the 1-proyl; 1-propyl group-2-alkynes; ethyl acetylene base; 1-butyl-2-alkynes; 1-butyl-3-alkynes, the 1-pentynyl, 1-amyl group-2-alkynes, 1-amyl group-3-alkynes, 1-amyl group-4-alkynes, 3-methyl isophthalic acid-butynyl, 1-methyl isophthalic acid-butyl-2-alkynes, 1-methyl isophthalic acid-butyl-3-alkynes, 2-methyl-1-butene base-3-alkynes, 1-hexin base, 1-hexyl-2-alkynes, 1-hexyl-3-alkynes, 1-hexyl-4-alkynes, 1-hexyl-5-alkynes, 3-methyl-1-pentene alkynyl, 4-methyl-1-pentene alkynyl, 1-methyl-1-pentene base-2-alkynes, 4-methyl-1-pentene base-2-alkynes, 1-methyl-1-pentene base-3-alkynes, 2-methyl-1-pentene base-3-alkynes etc.
" aryl " of the present invention be meant aromatic ring for example the phenyl of phenyl, replacement (for example benzyl, styroyl) and thick and aromatic nucleus naphthyl etc. for example.
" containing 0-3 the first cyclic group of heteroatomic 3-8 " of the present invention comprises (1) and do not contain the first cyclic group of heteroatomic 3-8, is selected from cyclopropane, tetramethylene, hexanaphthene, suberane, cyclooctane, cyclobutene, cyclopentenes, tetrahydrobenzene, cyclopentadiene, cyclohexadiene or phenyl etc.; (2) contain 1-3 the first cyclic group of heteroatomic 3-8, be selected from ethylenimine, the 2H-ethylenimine, diazacyclo propane, 3H-diazacyclo propylene, azetidine, 1, the 2-diazetidine, azete, 1, the 2-diazetine, the pyrroles, pyrrolin, tetramethyleneimine, imidazoles, 4, the 5-glyoxalidine, imidazolidine, pyrazoles, 4, the 5-pyrazoline, pyrazolidine, 1,2, the 3-triazole, 1,2, the 4-triazole, tetrazolium, pyridine, the 2-pyridone, the 4-pyridone, piperidines, pyridazine, pyrimidine, pyrazine, piperazine, 1,2, the 3-triazine, 1,2, the 4-triazine, 1,3, the 5-triazine, 1,2,4, the 5-tetrazine, the nitrogen heterocyclic heptantriene, 1,2-diazacyclo heptantriene, 1,3-diazacyclo heptantriene, 1,4-diazacyclo heptantriene, the nitrogen heterocyclic octatetraene, 1,4-dihydro-1,4-diazacyclo sarohornene etc., preferred pyrroles, pyridine, oxyethane, dioxirane, thiirane, trimethylene oxide, 1, the 2-dioxetane, Thietane, 1,2-dithia cyclobutene, furans, dihydrofuran, tetrahydrofuran (THF), thiophene, 2, the 5-dihydro-thiophene, tetramethylene sulfide, 1, the 3-dioxolane, 1,2-dithia cyclopentenes, 1, the 3-dithiolane, the 2H-pyrans, the 2H-pyran-2-one, 3,4-dihydro 2H-pyrans, 5,6-dihydro 2H-pyrans, the 4H-pyrans, tetrahydropyrans, 4H-pyrans-4-ketone, 1, the 4-Dioxin, 1,4-dithia cyclohexadiene, 1, the 4-oxathiin, 1, the 4-dioxane, 1, the 3-dioxane, 1, the 3-oxathiane, oxepin, thia cycloheptatriene or 1,4-dioxane sarohornene etc.
" heterocyclic radical " of the present invention for containing 1-3 the first cyclic group of heteroatomic 3-8, wherein 3-8 unit cyclic group as hereinbefore defined.
" 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: the diisopropyl methyl; the 9-fluorene methyl; 9-(2-sulfo-) fluorene methyl; furfuryl; trichloromethyl; 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-methylformamide base) propyl group; 1; 1-phenylbenzene-3-(N; the N dimethylamine base) 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; the 1-methylcyclohexyl; the 1-adamantyl; isobornyl; cinnamyl; 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); 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; 2; the 4-dichloro benzyl; to the cyano group benzyl; adjacent (N-methylformamide 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; N '-piperidino carbonyl; N '-p-toluenesulfonyl aminocarboxyl; the carbamate of N '-anilino thiocarbonyl; formyl radical; ethanoyl; acetylpyridine; (N '-dithio carbobenzoxy-(Cbz) amido) 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; adjacent (benzoyloxy methyl) benzoyl; acid amides to benzoyl; phthaloyl; 2; 3-phenylbenzene maleoyl; the inferior acid amides of the ring of dithio succinyl; tert-butoxycarbonyl; allyl group; allyloxy carbonyl; phenacyl; 3-acetoxyl group propyl group; 4-nitro-1-cyclohexyl-2-oxo-3-pyrrolidyl; quaternary ammonium salt; methoxymethyl; 2-chloroethoxy methyl; benzyloxymethyl; the valeryl methyl; [1-(carbalkoxy amido)]-2; 2; the 2-trifluoroethyl; [1-Trifluoromethyl-1-(to the chlorophenoxy methoxyl group)-2; 2; the 2-trifluoro] ethyl; the 2-THP trtrahydropyranyl; 2; the 4-dinitrophenyl; 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 '-dimethylin methylene radical; benzylidene; to the methoxyl group benzylidene; to the nitro benzylidene; salicylidene; 5-chlorine salicylidene; diphenylmethylene; (5-chloro-2-hydroxyphenyl) phenylmethylene; the acyl group vinyl; 5; 6-dimethyl-3-oxo-1-cyclohexenyl; borine; [phenyl (pentacarbonyl chromium or tungsten)] carbonyl; copper or chelates of zinc; 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.
Particularly preferred compound comprises:
Chemical name: (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 1, its structural formula is as follows:
Figure G2009100028720D00071
Chemical name: (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the Z-2-methoxy imino] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 2, its structural formula is as follows:
Chemical name: (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 3, its structural formula is as follows:
Figure G2009100028720D00073
Chemical name: (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 4, its structural formula is as follows:
Chemical name: (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 5, its structural formula is as follows:
Figure G2009100028720D00081
Chemical name: (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 6, its structural formula is as follows:
Figure G2009100028720D00082
Chemical name: (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles-2-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 7, its structural formula is as follows:
Figure G2009100028720D00083
Chemical name: (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the Z-2-methoxy imino] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 8, its structural formula is as follows:
Figure G2009100028720D00084
Chemical name: (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 9, its structural formula is as follows:
Figure G2009100028720D00091
Chemical name: (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 10, its structural formula is as follows:
Figure G2009100028720D00092
Chemical name: (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 11, its structural formula is as follows:
Figure G2009100028720D00093
Chemical name: (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 12, its structural formula is as follows:
Figure G2009100028720D00094
Chemical name: (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 13, its structural formula is as follows:
Figure G2009100028720D00095
Chemical name: (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the Z-2-methoxy imino] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 14, its structural formula is as follows:
Figure G2009100028720D00101
Chemical name: (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 15, its structural formula is as follows:
Figure G2009100028720D00102
Chemical name: (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 16, its structural formula is as follows:
Figure G2009100028720D00103
Chemical name: (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 17, its structural formula is as follows:
Figure G2009100028720D00104
Chemical name: (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, hereinafter to be referred as compound 18, its structural formula is as follows:
Figure G2009100028720D00111
Chemical name: (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formate hydrochlorate, hereinafter to be referred as compound 19, its structural formula is as follows:
Figure G2009100028720D00112
Chemical name: (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles-2-yl also) Hemisulphate of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid, hereinafter to be referred as compound 20, its structural formula is as follows:
Chemical name: (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) three/monophosphate of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid, hereinafter to be referred as compound 21, its structural formula is as follows:
Figure G2009100028720D00114
The present invention also provides the preparation method of above-claimed cpd:
Reaction equation:
Reactions steps:
The preparation of compound shown in the step 1 formula A
In the exsiccant reaction flask, add Freon 113, under nitrogen protection, add raw material 1, hexamethyl two silicon n-formyl sarcolysine alkane (HMDS), reflux 2～15h is cooled to 2～15 ℃ under the nitrogen protection.Under the nitrogen protection, splash into tetramethylsilane (TMSI), vigorous stirring reaction under the room temperature, decompress filter is stirred in the ice-water bath cooling.Filter cake washs with Freon 113, and filtrate collection is in the flask of precooling.Under nitrogen protection, in this solution, drip the Freon 113 solution that contains raw material 2 under 0～-5 ℃, dropwise,, slowly drip methyl alcohol then, stir in reaction 1～5h.The reaction solution decolouring, suction filtration, filtrate decompression is concentrated into dried, recrystallizing methanol, suction filtration, drying gets compound shown in the formula A.
The preparation of compound shown in the step 2 formula B
In reaction flask, compound shown in the step gained formula A adds chloroform in the adding, drips triethylamine in-30～0 ℃ of scope to pH7.3～7.8, is stirred to whole dissolvings.Add raw material 3 then, stirring reaction 5～20h, reaction process constantly drips triethylamine makes reaction solution pH maintain 7.0～7.5.The reaction after-filtration that finishes adds entry, divides water-yielding stratum, and organic layer is with activated carbon decolorizing 10min～1h, suction filtration, filtrate decompression concentrate faint yellow solid, i.e. compound crude product shown in the formula B.In small amount of deionized water, the sodium hydrogen carbonate solution with 5% is slowly regulated pH6.5～7.0 under ice bath with dissolving crude product, adds the acetone of 5～50 times of amounts then, and stirring and crystallizing is filtered, and filter cake gets compound shown in the formula B with methyl alcohol and acetonitrile mixed solution recrystallization.
R in the above reaction equation 1, R 2, R 3, R 5, R 6, X and n such as preamble define, i.e. compound shown in the general formula (I).
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention comprises the salt that forms with mineral acid, example hydrochloric acid, Hydrogen bromide, phosphoric acid, the salt of sulfuric acid etc.; With the salt of organic acid formation, as acetate, trifluoroacetic acid, citric acid, formic acid, toxilic acid, oxalic acid, Succinic Acid, phenylformic acid, tartrate, fumaric acid, amygdalic acid, xitix, oxysuccinic acid, the salt of methylsulfonic acid or toluenesulphonic acids etc.; These acid salt can be according to any universal method preparation.In addition, compound (I) also can form non-toxic salt with alkali, comprises by metal deutero-salt, ammonium salt, by organic bases deutero-quaternary ammonium salt and amino acid salts.The example of preferred metal-salt has by basic metal deutero-salt, for example lithium (Li +), sodium (Na +), potassium (K +); By alkaline-earth metal deutero-salt, for example calcium (Ca 2+), magnesium (Mg 2+); Other metallic cation salt such as iron (Fe 2+Or Fe 3+), aluminium (Al 3+) and zinc (Zn 2+) ion is also included within the scope of the present invention; Example by organic bases deutero-quaternary ammonium salt comprises meglumine salt, glucosamine salt, trismethylamine salt, triethyl amine salt, tetramethyl-amine salt, tetraethyl-amine salt, phenmethyl trismethylamine salt, phenyl triethyl amine salt etc.; Comprise and pyridine, morpholine, picoline, N-methyl piperidine, N-ethylpiperidine, dicyclohexylamine, PROCAINE HCL, PHARMA GRADE, dibenzyl amine, N the salt that N '-dibenzyl-ethylene diamines, alkylamine or dialkylamine form by amine deutero-salt; Amino acid salts is as arginic acid salt, aspartate, glutaminate, lysine salt etc.
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, methyl acetate, ethyl acetate, pivalyl oxygen methyl ester, 1-pivalyl oxygen ethyl ester; Lower alkanols alcoxyl ketonic oxygen alkyl ester, methoxycarbonyl oxygen methyl ester, 1-ethoxycarbonyl-oxygen ethyl ester, 1-sec.-propyl oxygen ketonic oxygen ethyl ester; The lactone group ester, cumarone ketone group ester, sulfo-benzo furanonyl ester; Lower alkanols alcoxyl ylmethyl ester, methoxymethyl ester, ethoxyl methyl ester, pentyloxy methyl ester; Lower alkane acyl amine ylmethyl ester, the acetamidomethyl 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-oxopropoxy) methyl ester; 1-acetoxyl group ethyl ester; 2-[(2-methyl propoxy-) carbonyl]-the pentenyl ester; The 1-[[(1-methyl ethoxy) carbonyl] oxygen] 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 2 carboxyl place.
Isomer of the present invention is meant that its all differences are 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 (I) compound has many three-dimensional centers, for example on the 6-position, the 7-position is first-class.
The present invention includes the ester of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis or the pharmaceutical composition of its isomer and other active pharmaceutical ingredients, described other active pharmaceutical ingredients be selected from Sulbactam and sodium salt, Unasyn Oral, Tazobactam Sodium and sodium salt thereof, the clavulanic acid sylvite etc. any one or multiple.
The present invention is the claimed ester of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis or the pharmaceutical composition of its isomer and one or more pharmaceutical carriers and/or thinner of comprising further.Described composition can be made clinically or pharmaceutically acceptable arbitrary formulation, is preferably oral preparations, injection.Wherein contain the compound 0.01g～10g shown in the general formula (I) of physiology significant quantity, preferred 0.1～5g can be 0.1g, 0.125g, 0.25g, 0.5g, 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 or its isomer 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.
The cephalosporins derivatives that the present invention also provides the nitrogen heterocyclic that contains replacement treats and/or prevents purposes in the medicine of infectious diseases in preparation.The cephalosporins derivatives that contains the nitrogen heterocyclic of replacement of the present invention has has a broad antifungal spectrum and the strong characteristics of anti-microbial activity, gram-positive microorganism and Gram-negative bacteria all there is good antibacterial activity, can be used for treating and/or preventing the various diseases that causes by pathogenic micro-organism, for example be used for prevention and treatment humans and animals by pathogenic microbial respiratory system, urinary system, Otorhinolaryngologic Department, gynaecology and skin soft-tissue infection etc.
The cephalosporins derivatives that contains the nitrogen heterocyclic of replacement of the present invention is compared with immediate prior art, has the following advantages:
The The compounds of this invention antimicrobial spectrum is wider, and gram-positive microorganism and Gram-negative bacteria are had good antibacterial activity, especially has good especially activity for Pseudomonas aeruginosa, and β-Nei Xiananmei is had better stability.
Below further set forth the beneficial effect of the cephalosporins derivatives of the nitrogen heterocyclic that contains replacement of the present invention by antibacterial activity test, but this should be interpreted as that the cephalosporins derivatives that contains the nitrogen heterocyclic of replacement 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 is all bought in public institution.
Gram-positive microorganism: MSSA (MSSA), methicillin-sensitivity staphylococcus epidermidis (MSSE), penicillin resistant streptococcus pneumoniae (PRSP);
Gram-negative bacteria: intestinal bacteria, Klebsiella Pneumoniae (producing ESBLs, i.e. extended spectrum), Pseudomonas aeruginosa.
Trial-product: compound 1～18, its chemical name and preparation method see the preparation embodiment of each compound;
Cefpirome: the injection Cefpirome Sulfate, commercial; Ceftazime: ceftazidime for inj, commercial.
Experimental technique: agar dilution, with reference to " pharmacological testing methodology " P1659-1660, People's Health Publisher, chief editor: Xu Shuyun etc., release: the 1st edition the 3rd edition the 5th printing January in 2002 in August nineteen eighty-two.
Table 1 The compounds of this invention is to clinical separation gram-positive microorganism anti-microbial activity
By table 1 experimental result as seen, The compounds of this invention all has better antibacterial activity to clinical above Gram-positive representative strain: all in all compare with ceftazime, the The compounds of this invention anti-microbial activity is stronger; Compare with cefpirome, compound 1,2,5,7,8,11,12,13,14,17,18 anti-microbial activities are stronger, and compound 3,6,15 anti-microbial activities are suitable, and compound 4,10,16 anti-microbial activities are poor slightly.
Table 2 The compounds of this invention is to clinical separation Gram-negative bacteria anti-microbial activity
Figure G2009100028720D00161
By table 2 experimental result as seen, The compounds of this invention all has the excellent antibiotic activity to clinical above Gram-negative representative strain, especially the Pseudomonas aeruginosa anti-microbial activity is had unusual effect.All in all compare with ceftazime, the The compounds of this invention anti-microbial activity is stronger; Compare with cefpirome, compound 1,2,5,6,7,8,11,12,13,14,15,17,18 anti-microbial activities are stronger, and compound 3,9,16 anti-microbial activities are suitable, and compound 4,10 anti-microbial activities are poor slightly.
Experiment conclusion: above-mentioned experimental result shows that The compounds of this invention is compared with immediate prior art, has has a broad antifungal spectrum, anti-microbial activity height, to the more stable advantage of β-Nei Xiananmei.Wherein compound 1,2,5,7,8,11,12,13,14,17 and 18 anti-gram positive organism activity are especially outstanding, 1,2,5,6,7,8,11,12,13,14,15,17 and 18 pairs of Pseudomonas aeruginosas of compound have significant anti-microbial activity, and they all are the new compounds with 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 (6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 1)
Step 1 (6R, 7R)-preparation of 7-amino-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
In the exsiccant reaction flask; add Freon 113 100mL; under nitrogen protection; add (6R; 7R)-7-amino-3-acetyl-o-methyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid (7-ACA) 13.6g (50mmol); hexamethyl two silicon n-formyl sarcolysine alkane (HMDS) 11.5mL (55mmol), reflux 8h is cooled to 10 ℃ under the nitrogen protection.Under the nitrogen protection, splash into TMSI 8mL (56mmol), vigorous stirring reaction 6h under the room temperature, ice-water bath is cooled to 0 ℃, stirs 30min, decompress filter.Filter cake washs with Freon 113, and filtrate collection is in the flask of precooling.Under nitrogen protection, dropping contains 6.2g (50mmol) 5-methyl-3,5-dihydro-1H-furo [3 in this solution under 0 ℃; 4-c] pyrroles's 50mL Freon 113 solution, dropwise, in 0～5 ℃ of reaction 2h; slowly drip methyl alcohol 25mL then, 0～5 ℃ is stirred 30min.The reaction solution decolouring, suction filtration, filtrate decompression is concentrated into dried, recrystallizing methanol, suction filtration, dry, (6R, 7R)-7-amino-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 9.9g, yield is 58.9%.
The preparation of step 2 compound 1
In reaction flask, add (6R, 7R)-7-amino-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.4g (25mmol), add chloroform 150mL, drip triethylamine below-20 ℃, be stirred to whole dissolvings to pH7.3～7.8.Add (Z)-2-(2-amino-1,3-thiazoles-4-yl)-2-methoxy imino-thioacetic acid (S-2-benzothiazole) ester 10.5g (30mmol) then, stirring reaction 12h, reaction process constantly drips triethylamine maintains about 7.2 reaction solution pH.React the after-filtration that finishes, add 50mL water, divide water-yielding stratum, organic layer activated carbon decolorizing 30min, suction filtration, filtrate decompression concentrate faint yellow solid, i.e. (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt crude product.With dissolving crude product in small amount of deionized water, sodium hydrogen carbonate solution with 5% is slowly regulated pH6.5～7.0 down in ice bath, the acetone that adds 10 times of amounts then, stirring and crystallizing, filter, filter cake methyl alcohol and acetonitrile mixed solution recrystallization, get (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.3g, yield is 63.9%.
Molecular formula: C 21H 22N 6O 6S 2Molecular weight: 518.57
Ultimate analysis: C:48.51%, H:4.39%, N:16.07%, S:12.45%
Theoretical value: C:48.64%, H:4.28%, N:16.21%, S:12.37%
Mass spectrum (m/e): 519 (M+1)
Embodiment 2 (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy imino] acetamido]-3-(5-methyl-3,5-dihydro -1H-furo [3,4-c] pyrroles-5-yl) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 2)
Preparation method's reference example 1 step 2, throw (6R, 7R)-7-amino-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.4g (25mmol), (Z)-2-(5-amino-1,2,4-thiadiazoles-5-yl)-2-methoxy imino-thioacetic acid (S-2-benzothiazole) ester 10.5g (30mmol).Get (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-5-yl)-and the Z-2-methoxy imino] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.0g, yield is 61.3%.
Molecular formula: C 20H 21N 7O 6S 2Molecular weight: 519.55
Ultimate analysis: C:45.07%, H:4.21%, N:18.75%, S:12.46%
Theoretical value: C:45.23%, H:4.07%, N:18.87%, S:12.34%
Mass spectrum (m/e): 520 (M+1)
Embodiment 3 (6R, 7R)-7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrrole Cough up-the 5-yl) preparation of the hot 2-alkene of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0]-2-formic acid inner salt (compound 3)
Preparation method's reference example 1 step 2, throw (6R, 7R)-7-amino-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.4g (25mmol), (Z)-2-(thiazolamine-4-yl)-2-oximido-thioacetic acid (S-2-benzothiazole) ester 10.1g (30mmol).Get (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 6.8g, yield is 54.2%.
Molecular formula: C 20H 20N 6O 6S 2Molecular weight: 504.54
Ultimate analysis: C:47.53%, H:4.16%, N:16.49%, S:12.80%
Theoretical value: C:47.61%, H:4.00%, N:16.66%, S:12.71%
Mass spectrum (m/e): 505 (M+1)
Embodiment 4 (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-oximido] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 4)
Preparation method's reference example 1 step 2, throw (6R, 7R)-7-amino-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.4g (25mmol), (Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-oximido-thioacetic acid (S-2-benzothiazole) ester 10.1g (30mmol).Get (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 6.7g, yield is 52.8%.
Molecular formula: C 19H 19N 7O 6S 2Molecular weight: 505.53
Ultimate analysis: C:45.02%, H:3.90%, N:19.18%, S:12.76%
Theoretical value: C:45.14%, H:3.79%, N:19.39%, S:12.69%
Mass spectrum (m/e): 506 (M+1)
Embodiment 5 (6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(5-methyl-3,5-dihydro -1H-furo [3,4-c] pyrroles-5-yl) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 5)
Preparation method's reference example 1 step 2, throw (6R, 7R)-7-amino-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.4g (25mmol), (Z)-2-(thiazolamine-4-yl)-2-(the special butyl ester of isopropyl oxygen imino-2-carboxylic acid)-thioacetic acid (S-2-benzothiazole) ester 10.1g (30mmol).Get (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-(the special butyl ester of isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) crude product of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt.
Crude product is dropped in the 100mL exsiccant reaction flask, add the acetonitrile of 50mL, be cooled to 0 ℃, add the anhydrous formic acid of 9mL again,, drip 98% the vitriol oil of 3mL then, react 3 hours 0 ℃ of stirring reaction 2 hours, filtration, filter cake washs with acetonitrile.Filter cake is dissolved in the small amount of deionized water, sodium hydrogen carbonate solution with 5% is slowly regulated about pH7.0 down in ice bath, the acetone that adds 10 times of amounts then, stirring and crystallizing, filter, filter cake methyl alcohol and acetonitrile mixed solution recrystallization, get (6R, 7R)-7-[2-[(2-aminothiazole-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 7.4g, yield is 50.3%.
Molecular formula: C 23H 25N 7O 7S 2Molecular weight: 590.63
Ultimate analysis: C:48.72%, H:4.58%, N:14.11%, S:11.02%
Theoretical value: C:48.81%, H:4.44%, N:14.23%, S:10.86%
Mass spectrum (m/e): 591 (M+1)
Embodiment 6 (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(5-methyl -3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 6) Preparation
Preparation method's reference example 5, throw (6R, 7R)-7-amino-3-(6,7-dihydro-5H-pyrrolo-[1,2-e] imidazoles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.4g (25mmol), (Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(the special butyl ester of isopropyl oxygen imino-2-carboxylic acid)-thioacetic acid (S-2-benzothiazole) ester 10.1g (30mmol).Get (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 7.1g, yield is 48.2%.
Molecular formula: C 23H 25N 7O 8S 2Molecular weight: 591.62
Ultimate analysis: C:46.56%, H:4.38%, N:16.43%, S:10.95%
Theoretical value: C:46.69%, H:4.26%, N:16.57%, S:10.84%
Mass spectrum (m/e): 592 (M+1)
Embodiment 7 (6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene And [c] pyrroles-2-yl) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 7)
Step 1 (6R, 7R)-preparation of 7-amino-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles-2-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
Preparation method's reference example 1 step 1, throw (6R, 7R)-7-amino-3-acetyl-o-methyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid (7-ACA) 13.6g (50mmol), 2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles 6.1g (50mmol) also.(6R, 7R)-7-amino-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles-2-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 10.4g, yield is 62.4%.
Preparation method's reference example 1 step 2, throw (6R, 7R)-7-amino-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.3g (25mmol), (Z)-2-(2-amino-1,3-thiazoles-4-yl)-2-methoxy imino-thioacetic acid (S-2-benzothiazole) ester 10.5g (30mmol).Get (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) the highly finished product 7.4g of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt, yield is 57.2%.
Molecular formula: C 22H 24N 6O 5S 2Molecular weight: 516.59
Ultimate analysis: C:51.02%, H:4.82%, N:16.18%, S:12.53%
Theoretical value: C:51.15%, H:4.68%, N:16.27%, S:12.41%
Mass spectrum (m/e): 517 (M+1)
Embodiment 8 (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy imino] acetamido]-(2-methyl-2,4,5,6-four for 3- Hydrogen cyclopenta [c] pyrroles) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 8)
Preparation method's reference example 1 step 2, throw (6R, 7R)-7-amino-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.3g (25mmol), (Z)-2-(5-amino-1,2,4-thiadiazoles-5-yl)-2-methoxy imino-thioacetic acid (S-2-benzothiazole) ester 10.5g (30mmol).Get (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-5-yl)-and the Z-2-methoxy imino] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 7.3g, yield is 56.1%.
Molecular formula: C 21H 23N 7O 5S 2Molecular weight: 517.58
Ultimate analysis: C:48.57%, H:4.60%, N:18.79%, S:12.46%
Theoretical value: C:48.73%, H:4.48%, N:18.94%, S:12.39%
Mass spectrum (m/e): 518 (M+1)
Embodiment 9 (6R, 7R)-7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(2-first Base-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) The preparation of methylene radical-8-oxo-5-thia-1-azepine two embryos [4.2.0] oct-2-ene-2-formic acid inner salt (compound 9)
Preparation method's reference example 1 step 2, throw (6R, 7R)-7-amino-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.3g (25mmol), (Z)-2-(thiazolamine-4-yl)-2-oximido-thioacetic acid (S-2-benzothiazole) ester 10.1g (30mmol).Get (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 7.1g, yield is 56.8%.
Molecular formula: C 21H 22N 6O 5S 2Molecular weight: 502.57
Ultimate analysis: C:50.06%, H:4.59%, N:16.62%, S:12.84%
Theoretical value: C:50.19%, H:4.41%, N:16.72%, S:12.76%
Mass spectrum (m/e): 503 (M+1)
Embodiment 10 (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-oximido] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene And [c] pyrroles) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 10)
Preparation method's reference example 1 step 2, throw (6R, 7R)-7-amino-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.3g (25mmol), (Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-oximido-thioacetic acid (S-2-benzothiazole) ester 10.1g (30mmol).(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 6.9g, yield is 54.5%.
Molecular formula: C 20H 21N 7O 5S 2Molecular weight: 503.55
Ultimate analysis: C:47.58%, H:4.42%, N:19.29%, S:12.91%
Theoretical value: C:47.70%, H:4.20%, N:19.47%, S:12.74%
Mass spectrum (m/e): 504 (M+1)
Embodiment 11 (6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino 2-carboxylic acid)] acetamido]-3-(2-methyl-2,4,5,6- Tetrahydro cyclopentyl alkene is [c] pyrroles also) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 11)
Preparation method's reference example 5, throw (6R, 7R)-7-amino-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.3g (25mmol), (Z)-2-(thiazolamine-4-yl)-2-(the special butyl ester of isopropyl oxygen imino-2-carboxylic acid)-thioacetic acid (S-2-benzothiazole) ester 13.8g (30mmol).Get (6R, 7R)-7-[2-[(2-aminothiazole-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 7.2g, yield is 48.9%.
Molecular formula: C 25H 28N 6O 7S 2Molecular weight: 588.66
Ultimate analysis: C:50.96%, H:4.88%, N:14.15%, S:10.93%
Theoretical value: C:51.01%, H:4.79%, N:14.28%, S:10.89%
Mass spectrum (m/e): 589 (M+1)
Embodiment 12 (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-(different third oxygen imido Base-2-carboxylic acid)] acetamido]-3-(2-methyl -2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) system of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 12) Be equipped with
Preparation method's reference example 5, throw (6R, 7R)-7-amino-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.3g (25mmol), (Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(the special butyl ester of isopropyl oxygen imino-2-carboxylic acid)-thioacetic acid (S-2-benzothiazole) ester 13.9g (30mmol).Get (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 6.8g, yield is 46.4%.
Molecular formula: C 24H 27N 7O 7S 2Molecular weight: 589.64
Ultimate analysis: C:48.72%, H:4.78%, N:16.55%, S:10.97%
Theoretical value: C:48.89%, H:4.62%, N:16.63%, S:10.88%
Mass spectrum (m/e): 590 (M+1)
Embodiment 13 (6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-(2-methyl-4,5,6,7-tetrahydrochysene-2H-is different for 3- Indoles-2-yl) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 13)
Step 1 (6R, 7R)-preparation of 7-amino-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt
Preparation method's reference example 1 step 1, throw (6R, 7R)-7-amino-3-acetyl-o-methyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid (7-ACA) 13.6g (50mmol), 2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole 6.8g (50mmol).(6R, 7R)-7-amino-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 10.8g, yield is 62.4%.
Preparation method's reference example 1 step 2, throw (6R, 7R)-7-amino-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.7g (25mmol), (Z)-2-(2-amino-1,3-thiazoles-4-yl)-2-methoxy imino-thioacetic acid (S-2-benzothiazole) ester 10.5g (30mmol).Get (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles also) the highly finished product 8.0g of the hot 2-alkene of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0]-2-formic acid inner salt, yield is 60.2%.
Molecular formula: C 23H 26N 6O 5S 2Molecular weight: 530.62
Ultimate analysis: C:52.02%, H:4.82%, N:16.18%, S:12.03%
Theoretical value: C:52.06%, H:4.94%, N:15.84%, S:12.09%
Mass spectrum (m/e): 531 (M+1)
Embodiment 14 (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy imino] acetamido]-(2-methyl-4,5,6,7-four for 3- Hydrogen-2H-isoindole-2-yl) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 14)
Preparation method's reference example 1 step 2, throw (6R, 7R)-7-amino-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.7g (25mmol), (Z)-2-(5-amino-1,2,4-thiadiazoles-5-yl)-2-methoxy imino-thioacetic acid (S-2-benzothiazole) ester 10.5g (30mmol).Get (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the Z-2-methoxy imino] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 7.5g, yield is 56.1%.
Molecular formula: C 22H 25N 7O 5S 2Molecular weight: 531.61
Ultimate analysis: C:49.57%, H:4.60%, N:18.69%, S:12.16%
Theoretical value: C:49.70%, H:4.74%, N:18.44%, S:12.06%
Mass spectrum (m/e): 532 (M+1)
Embodiment 15 (6R, 7R)-7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2- Base) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 15)
Preparation method's reference example 1 step 2, throw (6R, 7R)-7-amino-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.7g (25mmol), (Z)-2-(thiazolamine-4-yl)-2-oximido-thioacetic acid (S-2-benzothiazole) ester 10.1g (30mmol).Get (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 7.3g, yield is 56.8%.
Molecular formula: C 22H 24N 6O 5S 2Molecular weight: 516.59
Ultimate analysis: C:51.06%, H:4.69%, N:16.26%, S:12.44%
Theoretical value: C:51.15%, H:4.68%, N:16.27%, S:12.41%
Mass spectrum (m/e): 517 (M+1)
Embodiment 16 (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-oximido] acetamido]-(2-methyl-4,5,6,7-tetrahydrochysene-2H-is different for 3- Indoles-2-yl) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 16)
Preparation method's reference example 1 step 2, throw (6R, 7R)-7-amino-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.7g (25mmol), (Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-oximido-thioacetic acid (S-2-benzothiazole) ester 10.1g (30mmol).(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 5.8g, yield is 44.5%.
Molecular formula: C 21H 23N 7O 5S 2Molecular weight: 517.58
Ultimate analysis: C:48.85%, H:4.42%, N:18.92%, S:12.35%
Theoretical value: C:48.73%, H:4.48%, N:18.94%, S:12.39%
Mass spectrum (m/e): 518 (M+1)
Embodiment 17 (6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(2-methyl-4,5,6,7- Tetrahydrochysene-2H-isoindole-2-yl) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 17)
Preparation method's reference example 5, throw (6R, 7R)-7-amino-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.7g (25mmol), (Z)-2-(thiazolamine-4-yl)-2-(the special butyl ester of isopropyl oxygen imino-2-carboxylic acid)-thioacetic acid (S-2-benzothiazole) ester 13.8g (30mmol).Get (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.7g, yield is 57.5%.
Molecular formula: C 26H 30N 6O 7S 2Molecular weight: 602.68
Ultimate analysis: C:50.96%, H:4.88%, N:14.15%, S:10.93%
Theoretical value: C:51.81%, H:5.02%, N:13.94%, S:10.64%
Mass spectrum (m/e): 603 (M+1)
Embodiment 18 (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(2-methyl -4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) system of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt (compound 18) Be equipped with
Preparation method's reference example 5, throw (6R, 7R)-7-amino-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.7g (25mmol), (Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-(the special butyl ester of isopropyl oxygen imino-2-carboxylic acid)-thioacetic acid (S-2-benzothiazole) ester 13.9g (30mmol).Get (6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and Z-2-(isopropyl oxygen imino-2-carboxylic acid)] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 8.4g, yield is 55.0%.
Molecular formula: C 25H 29N 7O 7S 2Molecular weight: 603.67
Ultimate analysis: C:49.72%, H:4.78%, N:16.25%, S:10.67%
Theoretical value: C:49.74%, H:4.84%, N:16.24%, S:10.62%
Mass spectrum (m/e): 604 (M+1)
Embodiment 19 (6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(5-methyl-3,5-dihydro-1H-furans And [3,4-c] pyrroles-5-yl) preparation of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formate hydrochlorate (compound 19)
In reaction flask, add (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(5-methyl-3,5-dihydro-1H-furo [3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 519mg (1mmol), it is dissolved in the 2mL water, ice bath is transferred pH9～10 with 10% sodium hydroxide solution down, transfer pH2.2 to 2.6, stirring reaction 0.5h with 37% hydrochloric acid then.Drip 20mL and continue stirring and crystallizing behind the acetone, suction filtration, washing, the filter cake recrystallizing methanol, vacuum-drying obtains its hydrochloride 401mg, yield 72.3%.
Embodiment 20 (6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene And [c] pyrroles-2-yl) preparation of the Hemisulphate (compound 20) of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid
In reaction flask, add (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2-methyl-2,4,5,6-tetrahydro cyclopentyl alkene is [c] pyrroles-2-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 517mg (1mmol), it is dissolved in the 2mL water, ice bath is transferred pH9～10 with 10% sodium hydroxide solution down, transfers pH2.0 to 2.3, stirring reaction 0.5h with 1M sulfuric acid then.Drip 20mL and continue stirring and crystallizing behind the acetone, suction filtration, washing, filter cake ethanol/isopropylcarbinol (1: 2) mixed solution recrystallization, vacuum-drying obtains its Hemisulphate 372mg, yield 65.7%.
Embodiment 21 (6R, 7R))-7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-(2-methyl-4,5,6,7-tetrahydrochysene-2H-is different for 3- Indoles-2-yl) preparation of the three/monophosphate (compound 21) of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid
In reaction flask, add (6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2-methyl-4,5,6,7-tetrahydrochysene-2H-isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt 531mg (1mmol), it is dissolved in the 2mL water, ice bath is transferred pH9～10 with 10% sodium hydroxide solution down, transfers pH2.0 to 2.2, stirring reaction 0.5h with 35% phosphoric acid then.Drip 20mL and continue stirring and crystallizing behind the acetone, suction filtration, washing, the filter cake recrystallizing methanol, vacuum-drying obtains its hydrochloride 322mg, yield 57.2%.
With reference to above-mentioned preparation method, also prepared following compound:
Chemical name Molecular formula Molecular weight Mass spectrum (m/e)
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(1,3,4-trimethylammonium-1H-pyrroles-1-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 21H 24N 6O 5S 2 504.58 505
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(1,3,4-trimethylammonium-1H-pyrroles-1-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 20H 22N 6O 5S 2 490.56 491
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(1,3,4-trimethylammonium-1H-pyrroles-1-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 24H 28N 6O 7S 2 576.65 577
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy imino] acetamido]-3-(1,3,4-trimethylammonium-1H-pyrroles-1-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 20H 23N 7O 5S 2 505.57 506
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-oximido] acetamido]-3-(1,3,4-trimethylammonium-1H-pyrroles-1-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 19H 21N 7O 5S 2 491.54 492
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(1,3,4-trimethylammonium-1H-pyrroles-1-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 23H 27N 7O 7S 2 577.63 578
(6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(1,5-dimethyl-1,5-pyrrolin be [3,4-b] pyrroles-5-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 22H 23N 7O 5S 2 529.59 530
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(1,5-dimethyl-1,5-pyrrolin be [3,4-b] pyrroles-5-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 21H 21N 7O 5S 2 515.57 516
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(1,5-dimethyl-1,5-pyrrolin be [3,4-b] pyrroles-5-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 25H 27N 7O 7S 2 601.65 602
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the Z-2-methoxy imino] acetamido]-3-(1,5-dimethyl-1,5-pyrrolin be [3,4-b] pyrroles-5-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 21H 22N 8O 5S 2 530.58 531
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-(1,5-dimethyl-1,5-pyrrolin be [3,4-b] pyrroles-5-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 20H 20N 8O 5S 2 516.55 517
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(1,5-dimethyl-1,5-pyrrolin be [3,4-b] pyrroles-5-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 24H 26N 8O 7S 2 602.64 603
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2-methyl-2,4-dihydro cyclopenta [c] pyrroles-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 22H 22N 6O 5S 2 514.58 515
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(2-methyl-2,4-dihydro cyclopenta [c] pyrroles-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 21H 20N 6O 5S 2 500.55 501
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(2-methyl-2,4-dihydro cyclopenta [c] pyrroles-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 25H 26N 6O 7S 2 586.64 587
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-the Z-2-methoxy imino] acetamido]-3-2-methyl-2,4-dihydro cyclopenta [c] pyrroles-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 21H 21N 7O 5S 2 515.57 516
Chemical name Molecular formula Molecular weight Mass spectrum (m/e)
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-oximido] acetamido]-3-(2-methyl-2,4-dihydro cyclopenta [c] pyrroles-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] suffering-2-alkene-2-formic acid inner salt C 20H 19N 7O 5S 2 501.54 502
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(2-methyl-2,4-dihydro cyclopenta [c] pyrroles-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 24H 25N 7O 7S 2 587.63 588
(6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2-methyl-2,4,6,7-tetrahydropyrans [4,3-c] pyrroles-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 22H 24N 6O 6S 2 532.59 533
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(2-methyl-2,4,6,7-tetrahydropyrans [4,3-c] pyrroles-2-yl) the hot 2-alkene of methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0]-2-formic acid inner salt C 21H 22N 6O 6S 2 518.57 519
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(2-methyl-2,4,6,7-tetrahydropyrans [4,3-c] pyrroles-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 25H 28N 6O 8S 2 604.66 605
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the Z-2-methoxy imino] acetamido]-3-(2-methyl-2,4,6,7-tetrahydropyrans [4,3-c] pyrroles-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 21H 23N 7O 6S 2 533.58 534
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-(2-methyl-2,4,6,7-tetrahydropyrans [4,3-c] pyrroles-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 20H 21N 7O 6S 2 519.55 520
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(2-methyl-2,4,6,7-tetrahydropyrans [4,3-c] pyrroles-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 24H 27N 7O 8S 2 605.64 606
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2,5-dimethyl-1,2,3, the 5-Pyrrolidine is [4,3-c] pyrroles-2-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 22H 25N 7O 5S 2 531.61 532
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(2,5-dimethyl-1,2,3, the 5-Pyrrolidine is [4,3-c] pyrroles-2-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 21H 23N 7O 5S 2 517.58 518
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(2,5-dimethyl-1,2,3, the 5-Pyrrolidine is [4,3-c] pyrroles-2-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 25H 29M 7O 7S 2 603.67 604
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the Z-2-methoxy imino] acetamido]-3-(2,5-dimethyl-1,2,3, the 5-Pyrrolidine is [4,3-c] pyrroles-2-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 21H 24N 8O 5S 2 532.6 533
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-and the 2-oximido] acetamido]-3-(2,5-dimethyl-1,2,3, the 5-Pyrrolidine is [4,3-c] pyrroles-2-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 20H 22N 8O 5S 2 518.57 519
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(2,5-dimethyl-1,2,3, the 5-Pyrrolidine is [4,3-c] pyrroles-2-yl also) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 24H 28N 8O 7S 2 604.66 605
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2,5-dimethyl isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 24H 24N 6O 5S 2 540.61 541
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(2,5-dimethyl isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 23H 22N 6O 5S 2 526.59 527
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(2,5-dimethyl isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 27H 28N 6O 7S 2 612.68 613
Chemical name Molecular formula Molecular weight Mass spectrum (m/e)
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy imino] acetamido]-3-(2,5-dimethyl isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 23H 23N 7O 5S 2 541.6 542
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-oximido] acetamido]-3-(2,5-dimethyl isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 22H 21N 7O 5S 2 527.58 528
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(2,5-dimethyl isoindole-2-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 26H 27N 7O 7S 2 613.67 614
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(2-methyl-2H-pyrrolo-[3,4-c] pyridine-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 22H 21N 7O 5S 2 527.58 528
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(2-methyl-2H-pyrrolo-[3,4-c] pyridine-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 21H 19N 7O 5S 2 513.55 514
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(2-methyl-2H-pyrrolo-[3,4-c] pyridine-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 25H 25N 7O 7S 2 599.64 600
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-the Z-2-methoxy imino] acetamido]-3-(2-methyl-2H-pyrrolo-[3,4-c] pyridine-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 21H 20N 8O 5S 2 528.56 529
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-oximido] acetamido]-3-(2-methyl-2H-pyrrolo-[3,4-c] pyridine-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 20H 18N 8O 5S 2 514.54 515
(6R, 7R)-7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(2-methyl-2H-pyrrolo-[3,4-c] pyridine-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 24H 24N 8O 7S 2 600.63 601
(6R, 7R)-and 7-[[2-(thiazolamine-4-yl)-Z-2-methoxy imino] acetamido]-3-(5-methyl-3,5-dihydro-1H-thieno-[3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 21H 22N 6O 5S 3 534.63 535
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-2-oximido] acetamido]-3-(5-methyl-3,5-dihydro-1H-thieno-[3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 20H 20N 6O 5S 3 520.61 521
(6R, 7R)-7-[[2-(thiazolamine-4-yl)-Z-2-(isopropyl oxygen imino-2-carboxylic acid)]-3-(5-methyl-3,5-dihydro-1H-thieno-[3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 24H 26N 6O 7S 3 609.69 610
(6R, 7R)-and 7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-Z-2-methoxy imino] acetamido]-3-(5-methyl-3,5-dihydro-1H-thieno-[3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 20H 21N 7O 5S 3 535.62 536
(6R, 7R)-and 7-[[2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-oximido] acetamido]-3-(5-methyl-3,5-dihydro-1H-thieno-[3,4-c] pyrroles-5-yl) methylene radical-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid inner salt C 19H 19N 7O 5S 3 521.59 522
The preparation of example of formulations 1 The compounds of this invention sterile packaged preparation
1, prescription
Prescription 1 prescription 2
Compound 5 1000g compounds 11 750g
Methionin 1000g arginine 1250g
Prepare 1000 altogether and prepare 1000 altogether
2, preparation technology: will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process; Take by weighing raw material and auxiliary material (aseptic raw material can be used sterilization crystallization process, spray drying method for preparation) by prescription, pulverize mixing, place the portioning machine packing, detect loading amount at any time; Jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of example of formulations 2 The compounds of this invention freeze-dried powders
1, prescription
Prescription 1 prescription 2
Compound 12 250g compounds 17 100g
N.F,USP MANNITOL 750g Dextran 40 0g
An amount of water for injection of water for injection is an amount of
Prepare 1000 2, preparation technology altogether: prepare 1000 altogether and draw the place
The compound of side's amount, adding water for injection is an amount of, and heating is stirred, and makes its dissolving, and liquid volume added 0.1% needle-use activated carbon stirred 15 minutes, filtered, and is standby.Get the N.F,USP MANNITOL (or dextran) of recipe quantity, adding water for injection is an amount of, and heating is stirred, and makes dissolving, adds solution amount 0.1% needle-use activated carbon, stirs 15 minutes, filters, and is standby.With above-mentioned two kinds of liquid mixing, transfer appropriate pH, benefit adds to the full amount of water for injection, and under aseptic condition, with 0.2 μ m millipore filtration Entkeimung, behind the mensuration content, is sub-packed in 1000 control vials.Glass tube vial after the can is inserted in advance in the lyophilizer, is refrigerated to-37 ℃ of insulations 3.5 hours, vacuumizes, about 1.5 ℃ of/hour intensifications, after temperature reaches 0 ℃, be warming up to 36 ℃ by 1.5 ℃/hour, dry two hours (vacuum degree control is below the 0.1mm mercury column) of high-temperature vacuum.Jump a queue, gland, after quality inspection is qualified, packing, promptly.
The preparation of example of formulations 3 The compounds of this invention tablets
1, prescription:
Compound 18 125g
Starch 200g
Hydroxypropylcellulose 40g
Microcrystalline Cellulose 45g
The 50% aqueous ethanolic solution 85g of 1%HPMC
Micropowder silica gel 3g
Magnesium Stearate 2g
Prepare 1000 altogether
2, preparation technology: take by weighing raw material and auxiliary material according to prescription, raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively; Raw material, starch, hydroxypropylcellulose and Microcrystalline Cellulose are mixed, add mixer-granulator, add 50% aqueous ethanolic solution of 1%HPMC, stirred 15 minutes, make particle; Particle is dried being lower than under 60 ℃ the condition; Dry good particle adds micropowder silica gel and Magnesium Stearate, and whole grain mixes; Sampling, the work in-process chemical examination; According to the definite sheet weight sheet of chemical examination; Finished product is examined entirely, the packing warehouse-in.
The preparation of example of formulations 4 The compounds of this invention gelifying agents
1, prescription
Compound 1 10g
Carbopol 940 8g
Ethanol 50g
Glycerine 50g
Tween 80 2g
Ethyl p-hydroxybenzoate 0.5g
Distilled water is to 1000g
Prepare 100 altogether
2, preparation technology: under agitation, Xiang Shuizhong stirs and adds carbopol 940, adds compound 1 in glycerine and tween 80, and stirring and dissolving adds in the above-mentioned dispersion system; With the ethyl p-hydroxybenzoate dissolve with ethanol, add in the above-mentioned solution, stir evenly, the gelifying agent of water-soluble base.

Claims (9)

1. the compound shown in the general formula (I) or its pharmacy acceptable salt:
Figure FSB00000558927400011
Wherein: R 1And R 2Independently be hydrogen atom respectively;
X is CR 7Or N, wherein R 7Be hydrogen atom;
R 3Be hydrogen atom or C 1-6Alkyl, described C 1-6Alkyl is not substituted or is replaced by 1～5 substituting group that is selected from halogen atom or carboxyl;
R 4Be hydrogen atom or C 1-6Alkyl;
R 5With R 6Connect into and contain the heteroatomic 3-8 unit's cyclic group of 0-3 and pyrrole ring condenses, described heteroatoms is selected from N, O or S; N is 1～3 integer.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein: R 1And R 2Independently be hydrogen atom respectively;
X is CR 7Or N, wherein R 7Be hydrogen atom;
R 3Be hydrogen atom or C 1-4Alkyl, described C 1-4Alkyl is not substituted or is replaced by 1～3 substituting group that is selected from halogen atom or carboxyl;
R 4Be hydrogen atom or C 1-4Alkyl;
R 5With R 6Connect into and contain the heteroatomic 4-7 unit's cyclic group of 0-2 and pyrrole ring condenses, described heteroatoms is selected from N, O or S; N is 1 or 2.
3. compound as claimed in claim 2 or its pharmacy acceptable salt:
Wherein: R 1And R 2Independently be hydrogen atom respectively;
X is CR 7Or N, wherein R 7Be hydrogen atom;
R 3Be hydrogen atom or C 1-4Alkyl, described C 1-4Alkyl is not substituted or is replaced by 1～3 substituting group that is selected from halogen atom or carboxyl;
R 4Be hydrogen atom or C 1-4Alkyl;
R 5With R 6Connect into and contain the heteroatomic 5-6 unit's cyclic group of 0-1 and pyrrole ring condenses, described heteroatoms is selected from N, O or S; N is 1 or 2.
4. compound as claimed in claim 3 or its pharmacy acceptable salt:
Wherein: R 1And R 2Independently be hydrogen atom respectively;
X is CH or N;
R 3Be hydrogen atom, be not substituted or by the C of carboxyl substituted 1-4Alkyl;
R 4Be hydrogen atom, methyl, ethyl, propyl group or sec.-propyl;
R 5With R 6Connect into and contain the heteroatomic 5-6 unit's cyclic group of 0-1 and pyrrole ring condenses, described heteroatoms is selected from N, O or S; N is 1 or 2.
5. compound as claimed in claim 4 or its pharmacy acceptable salt:
Wherein: R 1And R 2Independently be hydrogen atom respectively;
X is CH or N;
R 3Be hydrogen atom or methyl;
R 4Be methyl;
R 5With R 6Connect into and contain the heteroatomic 5-6 unit's cyclic group of 0-1 and pyrrole ring condenses, described heteroatoms is the O atom; N is 1.
6. compound or its pharmacy acceptable salt are selected from:
Figure FSB00000558927400021
Figure FSB00000558927400031
Figure FSB00000558927400041
Figure FSB00000558927400051
7. comprise the pharmaceutical composition of each described compound of claim 1～6 or its pharmacy acceptable salt, it is characterized in that comprising one or more pharmaceutical carriers and/or thinner.
8. pharmaceutical composition as claimed in claim 7 is characterized in that containing each described compound of claim 1～6 or its pharmacy acceptable salt 0.01g～10g as essential activeconstituents.
9. each described compound of claim 1～6 or its pharmacy acceptable salt treat and/or prevent application in the medicine of infectious diseases in preparation.
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