CN101260108B - Mercaptopyrrolidone carbon penems derivatives - Google Patents
Mercaptopyrrolidone carbon penems derivatives Download PDFInfo
- Publication number
- CN101260108B CN101260108B CN2008100867340A CN200810086734A CN101260108B CN 101260108 B CN101260108 B CN 101260108B CN 2008100867340 A CN2008100867340 A CN 2008100867340A CN 200810086734 A CN200810086734 A CN 200810086734A CN 101260108 B CN101260108 B CN 101260108B
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- China
- Prior art keywords
- methyl
- tetramethyleneimine
- compound
- oxygen
- acceptable salt
- Prior art date
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- -1 Mercaptopyrrolidone carbon penems Chemical class 0.000 title claims abstract description 137
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 20
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 208000035473 Communicable disease Diseases 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 159000000003 magnesium salts Chemical class 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 150000003751 zinc Chemical class 0.000 claims description 2
- OTTZHAVKAVGASB-UHFFFAOYSA-N hept-2-ene Chemical compound CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 claims 12
- 238000002360 preparation method Methods 0.000 abstract description 41
- 150000002148 esters Chemical class 0.000 abstract description 23
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 150000004677 hydrates Chemical class 0.000 abstract 2
- 150000003573 thiols Chemical class 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 239000002585 base Substances 0.000 description 22
- 238000002347 injection Methods 0.000 description 21
- 239000007924 injection Substances 0.000 description 21
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- 238000006243 chemical reaction Methods 0.000 description 16
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 230000007062 hydrolysis Effects 0.000 description 15
- 238000006460 hydrolysis reaction Methods 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 230000000845 anti-microbial effect Effects 0.000 description 14
- 229910052760 oxygen Inorganic materials 0.000 description 14
- 239000001301 oxygen Substances 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 10
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 8
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 125000006502 nitrobenzyl group Chemical group 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
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- 229910001629 magnesium chloride Inorganic materials 0.000 description 5
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 5
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
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- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs the medical and pharmaceutical technical field, in particular to novel derivatives of thiol pyrrolidone carbapenem shown in formula (I), as well as pharmaceutically acceptable salts, easily hydrolyzed esters and isomers thereof, and hydrates of the derivatives, and hydrates of the esters or the salts of the derivatives, wherein R<1>, R<2>, R<3> and n are defined in the instruction. The invention also relates to a preparation method for the compounds, combinations containing the compounds, and an application of the compounds to medicines used to treat and/or prevent the contagious diseases.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to the hydrate of ester, its isomer, its hydrate and the ester or the salt of Mercaptopyrrolidone carbon penems derivatives, its pharmacy acceptable salt, its facile hydrolysis, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds are used for preparing the application of the medicine that treats and/or prevents infectious diseases.
2, background technology
Carbapenems is the New-type wide-spectrum that grows up the seventies in 20th century, anti-enzyme, efficient β-Nei Xiananleikangshengsu.1976, find first carbapenem antibiotic---sulfomycin, but because poor chemical stability fails to be used for clinical.Afterwards sulfomycin is carried out the chemical structure transformation and produced a series of Carbpenem derivants.This similar drug that has gone on the market at present has imipenum, panipenem, meropenem, S-4661, biapenem, ertapenem etc.
Its constructional feature is, the sulphur that the penam parent nucleus is 1 is replaced by carbon, and 2 have two keys, the effect of the five-ring of compound penicillin and the conjugated double bond activation beta-lactam nucleus of cynnematin; 6 hydroxyethyl side chains are transoid conformation.
For example, in CN97196245.6, disclose Carbpenem derivants, wherein mercapto pyrrolidine ketone has been connected on the 3-position of carbapenem ring.Structural formula is as follows:
The derivative of its described compound, salt or ester mainly are to be used in the medicine of preparation anti-helicobacter pylori, be mainly used in treatment and prevention by the caused infectious diseases of helicobacter pylori, though good antibacterial activity is arranged, because the chemical sproof continuous increase of clinical bacteria at present, effect to resistant organism is still undesirable, the antimicrobial spectrum relative narrower, and effect is not satisfied, owing to the limitation of drug administration by injection, can not meet clinical needs simultaneously.Therefore, the carbapenem compound with high PBPs avidity and DHP-I resistance becomes the emphasis of such drug development.
3, summary of the invention
Technical scheme of the present invention is as follows:
The invention provides the hydrate of ester, its isomer, its hydrate and the ester or the salt of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis:
Wherein:
R
1Expression hydrogen atom or C
1-6Alkyl;
R
2Representation carboxy, a COOR
4Or the ester of facile hydrolysis, described R
4The representation carboxy protecting group;
R
3The expression hydrogen atom, amino protecting group,
N represents the integer of 0-3.
Preferred compound is:
Wherein, R
1Represent hydrogen atom or C
1-4Alkyl;
R
2Representation carboxy ,-COOR
4Or the ester of facile hydrolysis,
Described R
4The representation carboxy protecting group is selected from methyl, methoxymethyl, first thiomethyl, benzyloxymethyl, phenacyl, ethyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl,
The ester of described facile hydrolysis is selected from alkyloyloxyethyl alkyl ester, alkoxyl group acyloxyalkyl group ester, cycloalkanes acyloxyalkyl group ester, cycloalkyloxy acyloxyalkyl group ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
R
3The expression hydrogen atom, amino protecting group,
Described amino protecting group is selected from methyl, ethyl, the tertiary butyl, benzyl, formyl radical, ethanoyl, allyloxy carbonyl, phenacyl, tert-butoxycarbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, 3-acetoxyl group propyl group or diazo;
N represents 0,1 or 2.
Further preferred compound is:
Wherein, R
1Represent hydrogen atom or methyl;
R
2Representation carboxy ,-COOR
4Or the ester of facile hydrolysis,
Described R
4The representation carboxy protecting group is selected from methyl, the tertiary butyl, allyl group, benzyl, to nitrobenzyl, to methoxy-benzyl or diphenyl methyl,
The ester of described facile hydrolysis, be selected from propionyl oxygen methyl esters, butyryl oxygen methyl esters, tertiary butyl methanoyl methyl esters, the different third oxygen methanoyl methyl esters, different third oxygen methanoyl-1-ethyl ester, hexamethylene alcoxyl methanoyl-1-ethyl ester or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
R
3The expression hydrogen atom, amino protecting group,
Described amino protecting group is selected from methyl, the tertiary butyl, formyl radical, tert-butoxycarbonyl, allyloxy carbonyl, to the nitro benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl or diazo;
N represents 0,1 or 2.
Further preferred compound is:
Wherein, R
1Represent methylidene;
R
2Representation carboxy ,-COOR
4Or the ester of facile hydrolysis,
Described R
4The representation carboxy protecting group is selected from methyl, the tertiary butyl, to nitrobenzyl, allyl group or benzyl,
The ester of described facile hydrolysis is selected from propionyl oxygen methyl esters, butyryl oxygen methyl esters, tertiary butyl methanoyl methyl esters, the different third oxygen methanoyl methyl esters or (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl esters;
R
3The expression hydrogen atom, amino protecting group,
Described amino protecting group is selected from methyl, the tertiary butyl, formyl radical, tert-butoxycarbonyl, allyloxy carbonyl or diazo;
N represents 0,1 or 2.
" C of the present invention
1-6Alkyl " comprise methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, n-pentyl, neo-pentyl, isopentyl, hexyl etc.
" carboxyl-protecting group " of the present invention refers to that routine is used for the blocking group of substituted carboxylic acid acid proton.This examples of groups comprises: methyl, methoxymethyl, the first thiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, the methoxyethyl methyl, allyl group, benzyloxymethyl, phenacyl, to bromobenzene formyl methyl, the Alpha-Methyl phenacyl, to the methoxybenzoyl methyl, the diacyl methyl, the N-phthalimidomethyl, ethyl, 2,2,2-three chloroethyls, the 2-halogenated ethyl, ω-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 2-(p-nitrophenyl sulfenyl) ethyl, 2-(to the toluene sulfenyl) ethyl, 1-methyl isophthalic acid-styroyl, the tertiary butyl, cyclopentyl, cyclohexyl, two (ortho-nitrophenyl base) methyl, 9-fluorenyl methyl, 2-(9, the 10-dioxo) fluorenyl methyl, 5-hexichol sulfenyl, benzyl, 2,4, the 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, piperonyl, the 4-picolyl, trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, the sec.-propyl dimetylsilyl, diphenyl methyl, the phenyl dimetylsilyl, the S-tertiary butyl, the S-phenyl, the S-2-pyridyl, N-hydroxy piperidine base, N-hydroxyl succinimido, N-hydroxyl phthaloyl imino, N-hydroxybenzotriazole base, O-acyl group oxime, 2,4-dinitrobenzene sulfenyl, 2-alkyl-1, the 3-oxazoline, 4-alkyl-5-oxo-1, the 3-oxazolidine, 5-alkyl-4-oxo-1, the 3-diox, the triethyl stannane, tri-n-butyl stannane; N, N '-di-isopropyl hydrazides etc.
" amino protecting group " of the present invention refers to that routine is used for the blocking group of substituted-amino acid proton, this type of examples of groups comprises: diazo, methyl, encircle third methyl, 1-methyl isophthalic acid-ring third methyl, the diisopropyl methyl, the 9-fluorene methyl, 9-(2-sulfo-) fluorene methyl, furfuryl, 2,2, the 2-trichloromethyl, the 2-halogenated methyl, ethyl, 2-iodine ethyl, 2-trimethyl silyl ethyl, 2-methylmercaptoethyl, 2-methylsulfonyl ethyl, 2-(p-toluenesulfonyl) ethyl, 2-phosphorus base ethyl, 1,1-dimethyl-3-(N, N-dimethylformamide base) propyl group, 1,1-phenylbenzene-3-(N, the N-diethylin) propyl group, 1-methyl isophthalic acid-(adamantyl) ethyl, 1-methyl isophthalic acid-styroyl, 1-methyl isophthalic acid-(3, the 5-dimethoxy phenyl) ethyl, 1-methyl isophthalic acid-(4-xenyl) ethyl, 1-methyl isophthalic acid-(to the phenylazo-phenyl) ethyl, 1,1-dimethyl-2,2,2-three chloroethyls, 1,1-dimethyl-2-cyanoethyl, isobutyl-, the tertiary butyl, tert-pentyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl, the 1-methylcyclohexyl, the 1-adamantyl, isobornyl, vinyl, allyl group, cinnamyl, phenyl, 2,4,6-tri-tert phenyl, the m-nitro base, the S-phenyl, the 8-quinolyl, N-hydroxy piperidine base, 4-(1,4-lupetidine base), 4,5-phenylbenzene-3-oxazoline-2-ketone, benzyl, 2,4, the 6-trimethyl benzyl, to methoxy-benzyl, 3, the 5-dimethoxy-benzyl, to oxy-benzyl in the last of the ten Heavenly stems, to nitrobenzyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, to bromobenzyl, the benzyl chloride base, 2, the 4-dichloro benzyl, to the cyano group benzyl, adjacent (N, N-dimethylformamide base) benzyl, between-chloro-is right-the acyloxy benzyl, to (dihydroxyl boryl) benzyl, to (phenylazo-) benzyl, to (to the anisole azo-group) benzyl, 5-benzoisoxazole ylmethyl, 9-anthryl methyl, diphenyl-methyl, phenyl (ortho-nitrophenyl base) methyl, two (2-pyridyl) methyl, 1-methyl isophthalic acid-(4-pyridyl) ethyl, the isonicotine base, the S-benzyl, the fixed basic carbonyl of N '-piperazine, the carbamate of N '-p-toluenesulfonyl aminocarboxyl and N '-phenylamino thiocarbonyl; Formyl radical, ethanoyl, ethanoyl-pyridine, (N '-the dithio benzyloxycarbonyl amino) ethanoyl, 3-phenyl propionyl, 3-(to hydroxyphenyl) propionyl, 3-(ortho-nitrophenyl base) propionyl, 2-methyl-2-(ortho-nitrophenyl oxygen base) propionyl, 2-methyl-2-(adjacent phenylazo-phenoxy group) propionyl, 4-chloro butyryl radicals, isobutyryl, adjacent nitro cinnamoyl, the pyridine formyl radical, N '-acetyl methionyl, N '-benzoyl-phenylalkyl, benzoyl, to the phenyl benzoyl, to anisoyl, o-nitrobenzoyl, the acid amides of adjacent (benzoyloxy methyl) benzoyl and right-P-benzoyl; Phthaloyl, 2, the inferior acid amides of the ring of 3-phenylbenzene maleoyl and dithio succinyl; Allyl group; allyloxy carbonyl; tert-butoxycarbonyl; to the nitro benzyloxycarbonyl; to methoxyl group benzyloxy base carbonyl; phenacyl; 3-acetoxyl group propyl group; 4-nitro-1-cyclohexyl-2-oxo-3-tetramethyleneimine-3-base; quaternary ammonium salt; methoxymethyl; 2-chloroethoxy methyl; benzyloxymethyl; the valeryl methyl; [1-(alkoxycarbonyl amido)]-2; 2; 2; trifluoroethyl; [1-Trifluoromethyl-1-(to the chlorophenoxy methoxyl group) 2; 2; 2;-trifluoro] ethyl; the 2-THP trtrahydropyranyl; 2; the 4-dinitrophenyl; benzyl; 3; the 4-dimethoxy-benzyl; adjacent nitrobenzyl; two (p-methoxyphenyl) methyl; trityl; (p-methoxyphenyl) diphenyl methyl; phenylbenzene-4-pyridylmethyl; 2-picolyl N '-oxide compound; 5-two phenylpropyl alcohol suberane bases; (N '; N '-dimethylaminomethylene); N; N '-isopropylidene; 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; nitro; nitroso-group; oxide compound; diphenylphosphino; diformazan sulfenyl phosphinyl; hexichol sulfenyl phosphinyl; the diethyl phosphoryl; the dibenzyl phosphoryl; the diphenylphosphine acyl group; phosphoryl; trimethyl silyl; thiophenyl; the ortho-nitrophenyl sulfenyl; 2; 4-dinitrobenzene sulfenyl; 2-nitro-4-anisole sulfenyl; three benzylthios; benzenesulfonyl; to the anisole alkylsulfonyl; 2; 4,6-Three methyl Benzene alkylsulfonyl; methyl sulphonyl; the benzene methylsulfonyl; to the toluene methylsulfonyl; trifluoromethyl sulfonyl; phenacyl alkylsulfonyl etc.
Further preferred individual compound is selected from:
Chemical name: (4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-1H-tetramethyleneimine-3-yl) tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, hereinafter to be referred as compound 1:
Structural formula:
Chemical name: (4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-1H-azetidine-3-yl) tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid, hereinafter to be referred as compound 2:
Structural formula:
Chemical name: (4R; 5S, 6S)-3-[(3S)-the amino tertiary butyl of 2-oxo-1-[[N-[(2-) ethanoyl]-tetramethyleneimine-3-yl] tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2; 0]-2-alkene-2-carboxylic acid, hereinafter to be referred as compound 3:
Structural formula:
Chemical name: (4R; 5S; 6S)-3-[(3S)-and the amino tertiary butyl of 2-oxo-1-[[N-[(2-) ethanoyl]-azetidine-3-yl] tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3; 2; 0]-2-alkene-2-carboxylic acid, hereinafter to be referred as compound 4:
Structural formula:
Chemical name: (4R; 5S; 6S)-3-[(3S)-and the amino tertiary butyl of 2-oxo-1-[[N-[(2-) kharophen] formyl radical-tetramethyleneimine-3-yl] tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3; 2; 0]-2-alkene-2-carboxylic acid, hereinafter to be referred as compound 5:
Structural formula:
Chemical name: (4R; 5S; 6S)-3-[(3S)-and the amino tertiary butyl of 2-oxo-1-[[N-[(2-) kharophen] formyl radical-azetidine-3-yl] tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3; 2; 0]-2-alkene-2-carboxylic acid, hereinafter to be referred as compound 6:
Structural formula:
The present invention also provides the preparation method of above-claimed cpd, but is not limited only to following method, and reaction equation is as follows:
Reactions steps:
Step 1: the preparation of intermediate 1
In the exsiccant reaction flask, add raw material 1 and tetrahydrofuran (THF), after the stirring and dissolving, add potassium carbonate powder, be warming up to backflow.Drip the tetrahydrofuran solution of raw material 2.After dropwising, the insulated and stirred reaction.With reacting liquid filtering, be evaporated to driedly, add hydrochloric acid, stir, regulate pH value with dilute alkaline soln, separate out solid, solid is with methanol/acetone mixing solutions recrystallization, and is must the side chain sulfhydryl compound standby.
In the dry reaction bottle, add the acetonitrile solution of raw material 3, cooling, the acetonitrile solution of adding diisopropylethylamine and prepared side chain sulfhydryl compound stirs.After reaction finishes, add the ethyl acetate dilution, water, saturated salt washing successively, organic layer drying, concentrated gets intermediate 1.
The preparation of step 2 intermediate 2
Intermediate 1 is added in the methylene dichloride, adding methyl-phenoxide and Nitromethane 99Min., the Nitromethane 99Min. solution of dropping aluminum chloride stirs under low temperature, adds entry, separates out solid, filters, and gets filter cake, and promptly intermediate 2.
The preparation of step 3 The compounds of this invention
Intermediate 2 is dissolved in the mixed solution of THF and water, adds palladium-charcoal and magnesium chloride, stirring reaction under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal adds THF in the filtrate, and water layer is collected in layering.In THF, add magnesium chloride again, leave standstill, divide water-yielding stratum, repetitive operation 1 time.Water merges, and slowly splashes into methyl alcohol, stirs, and filters, and filter cake water-Virahol recrystallization promptly gets The compounds of this invention.
R in the above reaction equation
1, R
3, n representative meaning as mentioned before, the carboxyl on the The compounds of this invention carbapenem parent nucleus also can be protected by carboxyl-protecting group, perhaps can adult in the ester of facile hydrolysis, the i.e. described The compounds of this invention of general formula (I).
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention comprises acetate, mesylate, maleate, succinate, tartrate, Citrate trianion, fumarate, hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt.
The ester of the compound facile hydrolysis that the present invention is claimed, comprise the alkyloyloxyethyl alkyl ester, for example acetyl oxygen methyl esters, propionyl oxygen methyl esters, butyryl oxygen methyl esters, sec.-propyl methanoyl methyl esters, tertiary butyl methanoyl methyl esters, neo-pentyl methanoyl methyl esters, isobutyl-methanoyl methyl esters, new penta acetyl oxygen methyl esters, decoyl oxygen methyl esters, caprinoyl oxygen methyl esters etc.; The alkyl oxy carbonyl oxygen alkyl ester, for example methoxy methyl acyl-oxygen methyl esters, (ethoxymethyl) acyl-oxygen methyl esters, isopropoxy methanoyl-1-ethyl ester, hexyloxy methanoyl-1-ethyl ester, octyloxy methanoyl-1-ethyl ester, the last of the ten Heavenly stems oxygen base methanoyl-1-ethyl ester, dodecyloxy methanoyl-1-ethyl ester etc.; Alkoxyl group methyl esters, for example methoxy methyl esters, the different third oxygen methyl esters of 1-etc.; Alkyl amido methyl esters, for example formamido group methyl esters, kharophen methyl esters etc.; Cycloalkanes acyloxyalkyl group ester, for example cyclohexyl methanoyl methyl esters, cyclohexyl methanoyl-1-ethyl ester, 1-methyl-cyclohexyl alkyl methanoyl-1-ethyl ester, 4-methyl-cyclohexyl alkyl methanoyl methyl esters etc.; Cycloalkyloxy acyloxyalkyl group ester, for example pentamethylene oxygen base methanoyl-1-ethyl ester, hexamethylene alkoxyl group methanoyl-1-ethyl ester etc.; (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester, 2-[(2-methyl propoxy-) carbonyl]-2-amylene ester etc.Be preferably propionyl oxygen methyl ester, butyroxymethyl ester, tertiary butyl methanoyl methyl ester, the different third oxygen methanoyl methyl ester, different third oxygen methanoyl-1-ethyl ester, hexamethylene alcoxyl methanoyl-1-ethyl ester, (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester etc.
Isomer of the present invention is meant that its all differences are to stereoisomerism, along anti-geometrical isomer, 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, that is: on the 4-position; On the 5-position; On the 6-position; On the 8-position.
The ester of the compound shown in the general formula (I), its pharmacy acceptable salt, its facile hydrolysis, its isomer can be hydrate forms.Hydration can be finished in preparation process or can be utilized the water absorbability of original anhydrous product to carry out gradually.
The present invention is further claimed to comprise the hydrate of ester, its isomer, its hydrate or its ester or salt of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of other active pharmaceutical ingredients, as cilastatin and sodium salt, Betamipron etc.
The present invention is further claimed to comprise the hydrate of ester, its isomer, its hydrate or its ester or salt of arbitrary compound recited above, its pharmacy acceptable salt, its facile hydrolysis and the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner; for clinically or pharmaceutically acceptable arbitrary formulation, be preferably oral preparations or injection.Wherein contain the compound 0.05g～5g shown in the general formula (I) of physiology significant quantity, can be 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g etc.
The hydrate of the ester of the arbitrary compound of the present invention, its pharmacy acceptable salt, its facile hydrolysis, its isomer, its hydrate or its ester or salt, 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 present invention also provides Mercaptopyrrolidone carbon penems derivatives to treat and/or prevent application in the medicine of infectious diseases in preparation.Mercaptopyrrolidone carbon penems derivatives of the present invention all has better antibacterial activity to gram-positive and negative, aerobic and anerobe and hospital clinical pathogenic bacteria such as MSSA (MSSA), methicillin-resistant staphylococcus aureus (MRSA), Pseudomonas aeruginosa and acinetobacter bacterium, can be used for treating and/or preventing the various diseases that causes by pathogenic micro-organism, as respiratory tract infection and urinary tract infection.
Usually, have been found that carbapenems is nontoxic to warm-blooded animal, and this general rule also is applicable to The compounds of this invention.Preferred compound of the present invention can prevent the needed excessive dosage of infectation of bacteria to the mouse administration, is not observed by caused tangible poisoning aura of The compounds of this invention or side effect.
Mercaptopyrrolidone carbon penems derivatives of the present invention is compared with immediate prior art, has the following advantages:
(1) The compounds of this invention has good anti-microbial activity and shows hypotoxicity, can being used for the treatment of and/or preventing various Mammalss (comprising the mankind) by the caused various diseases of sensitive organism by safety;
(2) the present invention has carried out in the body and external antibacterial tests, show that The compounds of this invention is strong to PBPs avidity, has a broad antifungal spectrum, the anti-microbial activity height, gram-positive and negative, aerobic and anerobe and hospital clinical pathogenic bacteria all there are better antibacterial activity, especially gram-positive and negative resistant organism are demonstrated outstanding anti-microbial activity;
(3) The compounds of this invention is stable to β-Nei Xiananmei and DHP-1, can single medicine administration;
(4) it is lasting that The compounds of this invention has anti-microbial effect, and medication is convenient;
(5) The compounds of this invention preparation technology is simple, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
Below further set forth the beneficial effect of Mercaptopyrrolidone carbon penems derivatives of the present invention by in-vitro antibacterial experiment, but this should be interpreted as that Mercaptopyrrolidone carbon penems derivatives of the present invention only has following beneficial effect.
The antimicrobial spectrum of experimental example The compounds of this invention and antibacterial activity in vitro
For trying bacterial classification:
The clinical isolates strain
Gram positive organism: MSSA (MSSA) 25 strains, methicillin-resistant staphylococcus aureus (MRSA) 22 strains, responsive streptococcus pneumoniae (PSSP) 15 strains of penicillin, penicillin resistant streptococcus pneumoniae (PRSP) 16 strains, enterococcus faecalis 20 strains, faecium 15 strains;
Gram-negative bacteria: 13 strains of ampicillin sensitive hemophilus influenzae, hemophilus influenzae 15 strains of anti-Ampicillin Trihydrate, escherichia coli 12 strains, Klebsiella Pneumoniae 23 strains, Proteus mirabilis 21 strains, serratia marcescens 17 strains, enterobacter cloacae 16 strains, Pseudomonas aeruginosa 20 strains, 15 strains of Moraxella catarrhalis bacterium; Hp 15 strains.
Anerobe: bacteroides fragilis 5 strains.
Trial-product:
Compound 1-6: title is made by oneself as mentioned before;
Imipenum: commercial;
Meropenem: commercial;
The CN97196245.6 compound of coming into the open: the preparation method is referring to patent CN97196245.6, the structure scape technology of passing away.
Experimental technique:
Agar dilution.
Experimental result and conclusion:
Table 1 The compounds of this invention is to the anti-microbial activity of clinical separation gram positive organism
Table 2 The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
Table 2 (continuing) The compounds of this invention is to the anti-microbial activity of clinical separation gram-negative bacteria
Table 3 The compounds of this invention is to the anti-microbial activity of clinical separation anerobe
By table 1 experimental result as can be known, Mercaptopyrrolidone carbon penems derivatives of the present invention has good antibacterial activity to clinical isolating all kinds of gram positive organisms, and its anti-microbial activity is better than imipenum, meropenem and the CN97196245.6 compound of coming into the open.
By table 2 experimental result as can be known, compare with the compound of coming into the open than imipenum, meropenem and CN97196245.6, Mercaptopyrrolidone carbon penems derivatives of the present invention has stronger anti-microbial activity to clinical isolating all kinds of gram-negative bacterias.
By table 3 experimental result as seen, Mercaptopyrrolidone carbon penems derivatives of the present invention has the excellent antibiotic activity to clinical isolating anerobe, and is stronger than the come into the open anti-microbial activity of compound of imipenum, meropenem and CN97196245.6.
Above-mentioned experimental result shows that The compounds of this invention is compared with immediate prior art, and effect is more excellent, has has a broad antifungal spectrum, advantage that anti-microbial activity is high, for having the carbapenem antibiotics of 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 (3S)-
The preparation of 2-oxo-3-sulfydryl-1-(N-tertbutyloxycarbonyl tetramethyleneimine-3-yl) tetramethyleneimine
In the exsiccant reaction flask, add (3S)-3-formyl sulfydryl-2-oxo-pyrrolidine 14.5g (0.1mol) and 200ml tetrahydrofuran (THF), after the stirring and dissolving, add potassium carbonate powder 14g, be warming up to backflow.Drip the tetrahydrofuran solution of N-1-tert.-butoxy-3-bromo-tetramethyleneimine 25g (0.1mol)/100ml.After dropwising, insulated and stirred reaction 2h.With reacting liquid filtering, be evaporated to driedly, add the hydrochloric acid 100ml of 3mol/L, stir 2h, regulate more than the pH8 with dilute alkaline soln, separate out yellow solid, solid is with methanol/acetone mixing solutions recrystallization, faint yellow solid 21g, yield: 73.4%.
Embodiment 2
(3S)-preparation of 2-oxo-3-sulfydryl-1-(N-tertbutyloxycarbonyl azetidine-3-yl) tetramethyleneimine
In the exsiccant reaction flask, add (3S)-3-formyl sulfydryl-2-oxo-pyrrolidine 14.5g (0.1mol) and 300ml tetrahydrofuran (THF), after the stirring and dissolving, add potassium carbonate powder 14g, be warming up to backflow.Add 3-bromo-N-tertbutyloxycarbonyl azetidine 26g (0.11mol) in batches, finish back insulated and stirred reaction 4h, with reacting liquid filtering, be evaporated to driedly, add the hydrochloric acid 100ml of 3mol/L, stir 2h, be adjusted to alkalescence with dilute alkaline soln, separate out yellow solid, solid is with methanol/acetone mixing solutions recrystallization, get faint yellow solid 18.7g, yield: 65.3%.
Embodiment 3 (4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-tertbutyloxycarbonyl tetramethyleneimine-3-yl) tetramethyleneimine 3-yl] sulfenyl
-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
In the dry reaction bottle, add (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-and acetonitrile (180ml) solution of 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 17.8g (30mmol) is chilled to below-10 ℃, adds the acetonitrile 100ml solution of diisopropylethylamine 7ml and (3S)-2-oxo-3-sulfydryl-1-(N-tertbutyloxycarbonyl tetramethyleneimine-3-yl) tetramethyleneimine 10g (35mmol), and 0 ℃ is stirred 15h.After reaction finishes, add ethyl acetate 500ml dilution, water, saturated salt washing successively, organic layer drying, concentrated gets light yellow solid 15.8g, yield: 82.7%.
Embodiment 4 (4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-tertbutyloxycarbonyl azetidine-3-yl) tetramethyleneimine-3-yl] sulfenyl
-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 3.Throw (4R, 5S, 6S)-3-hexichol oxygen phosphorus acyloxy-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 17.8g (30mmol), (3S)-2-oxo-3-sulfydryl-1-(N-tertbutyloxycarbonyl azetidine-3-yl) tetramethyleneimine 9g (33mmol).Get target compound 14.3g, yield: 77.1%.
Embodiment 5 (4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-1H-tetramethyleneimine-3-yl) tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyl
Ethyl]-4-methyl-7-oxygen-1-oxabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
With (4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-tertbutyloxycarbonyl tetramethyleneimine-3-yl) tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-the 100ml methylene dichloride of 2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 15.8g (25mmol) in, add methyl-phenoxide 20ml and Nitromethane 99Min. 40ml, in-50 ℃ of Nitromethane 99Min. solution 200ml that drip the 1mol/L aluminum chloride down,-40 ℃ are stirred 2h, add entry 400ml, separate out solid, filter, filter cake need not drying can drop into down the step use.
Embodiment 6 (4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-1H-azetidine-3-yl) tetramethyleneimine 3-yl] sulfenyl
-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy's preparation
Concrete preparation method's reference example 5.Throw (4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-tertbutyloxycarbonyl azetidine-3-yl) tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy 15.4g (25mmol).Get target compound, directly drop into step use down.
Embodiment 7 (4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-1H-tetramethyleneimine-3-yl) tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyl
Ethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid (compound 1)
With (4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-1H-tetramethyleneimine-3-yl) tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy is dissolved in the mixed solution of 90mlTHF and water 55ml, add 10% palladium-charcoal (3g) and magnesium chloride (1.5g), stirring reaction 2h under the room temperature 5MPa hydrogen pressure, filtering palladium charcoal adds THF400ml in the filtrate, water layer is collected in layering.In THF, add magnesium chloride 0.8g again, leave standstill, divide water-yielding stratum, repetitive operation 1 time.Water merges, and 0 ℃ slowly splashes into methyl alcohol 58ml, and-10 ℃ are stirred 1h, filters, and filter cake water-Virahol recrystallization gets white crystal 5.1g, yield: 51.6%.
Molecular formula: C
18H
25N
3O
5S
Molecular weight: 395.47
Ultimate analysis: C, 54.64%; H, 6.52%; N, 10.47%; S, 8.00%
(calculate: C, 54.67%; H, 6.37%; N, 10.63%; S, 8.11%)
Embodiment 8 (4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-1H-azetidine-3-yl) tetramethyleneimine-3-yl] sulfenyl
-6-[(1R)-the 1-hydroxyethyl]-preparation of 4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxylic acid (compound 2)
Concrete preparation method's reference example 7.Throw (4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-1H-azetidine-3-yl) tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0]-2-alkene-2-carboxy acid mutual-nitro carbobenzoxy.Get target compound 5.5g, yield: 57.1%.
Molecular formula: C
17H
23N
3O
5S
Molecular weight: 381.45
Ultimate analysis: C, 53.59%; H, 6.23%; N, 10.85%; S, 8.34%
(calculate: C, 53.53%; H, 6.08%; N, 11.02%; S, 8.41%)
Can also prepare following compound according to above embodiment preparation method
Chemical name: (4R; 5S, 6S)-3-[(3S)-the amino tertiary butyl of 2-oxo-1-[[N-[(2-) ethanoyl]-tetramethyleneimine-3-yl] tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2; 0]-and 2-alkene-2-carboxylic acid, structural formula:
Chemical name: (4R; 5S, 6S)-3-[(3S)-the amino tertiary butyl of 2-oxo-1-[[N-[(2-) ethanoyl]-azetidine-3-yl] tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2; 0]-and 2-alkene-2-carboxylic acid, structural formula:
Chemical name: (4R; 5S, 6S)-3-[(3S)-the amino tertiary butyl of 2-oxo-1-[[N-[(2-) kharophen] formyl radical-tetramethyleneimine-3-yl] tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2; 0]-and 2-alkene-2-carboxylic acid, structural formula:
Chemical name: (4R; 5S, 6S)-3-[(3S)-the amino tertiary butyl of 2-oxo-1-[[N-[(2-) kharophen] formyl radical-azetidine-3-yl] tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2; 0]-and 2-alkene-2-carboxylic acid, structural formula:
The preparation of embodiment 9 The compounds of this invention aseptic powder injections
1, prescription:
Prescription 1:
Any one 250g (in compound) in the compound 1-6 or derivatives thereof
Prepare 1000 altogether
Prescription 2:
Any one 500g (in compound) in the compound 1-6 or derivatives thereof
Prepare 1000 altogether
Prescription 3:
Any one 1000g (in compound) in the compound 1-6 or derivatives thereof
Prepare 1000 altogether
Prescription 4:
Any one 2000g (in compound) in the compound 1-6 or derivatives thereof
Prepare 1000 altogether
2, preparation technology: will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process; Take by weighing raw material (feeding intake after the conversion) by prescription, sterilized powder is placed the portioning machine packing, detect loading amount at any time; Jump a queue, gland, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 10 The compounds of this invention tablets
1, prescription:
Prescription 1:
Any one 250g (in compound) in the compound 1-6 or derivatives thereof
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 40g
Microcrystalline Cellulose 40g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
Prescription 2:
Any one 125g (in compound) in the compound 1-6 or derivatives thereof
Pregelatinized Starch 50g
Low-substituted hydroxypropyl cellulose 40g
Microcrystalline Cellulose 40g
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel 4.0g
Magnesium Stearate 4.0g
Carboxymethylstach sodium 2.0g
Prepare 1000 altogether
2, preparation technology: raw material pulverizing is crossed 100 mesh sieves, and all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby; Take by weighing raw material and auxiliary material according to recipe quantity; Hypromellose 2% the aqueous solution made soluble in water is standby; With in the compound 1-6 or derivatives thereof any one, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose mix, it is an amount of to add the 2%HPMC aqueous solution, stirs, and makes suitable softwood; Cross 20 mesh sieve system particles; Particle is dried under 60 ℃ condition; Dry good particle adds Magnesium Stearate, micropowder silica gel and carboxymethylstach sodium, crosses the whole grain of 18 mesh sieves, 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.
Claims (9)
1. the compound shown in the general formula (I) or its pharmacy acceptable salt:
Wherein:
R
1Expression hydrogen atom or C
1-6Alkyl;
R
2Representation carboxy;
R
3The expression hydrogen atom,
N represents the integer of 0-3.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein, R
1Represent hydrogen atom or C
1-4Alkyl;
R
2Representation carboxy;
R
3The expression hydrogen atom,
N represents 0,1 or 2.
3. compound as claimed in claim 2 or its pharmacy acceptable salt:
Wherein, R
1Represent hydrogen atom or methyl;
R
2Representation carboxy;
R
3The expression hydrogen atom,
N represents 0,1 or 2.
4. compound as claimed in claim 3 or its pharmacy acceptable salt:
Wherein, R
1Represent methylidene;
R
2Representation carboxy;
R
3The expression hydrogen atom,
N represents 0,1 or 2.
5. compound as claimed in claim 4 or its pharmacy acceptable salt:
(4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-1H-tetramethyleneimine-3-yl) tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(3S)-and 2-oxo-1-(N-1H-azetidine-3-yl) tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(3S)-and the amino tertiary butyl of 2-oxo-1-[N-[(2-) ethanoyl]-tetramethyleneimine-3-yl] tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(3S)-and the amino tertiary butyl of 2-oxo-1-[N-[(2-) ethanoyl]-azetidine-3-yl] tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid,
(4R, 5S, 6S)-3-[(3S)-and the amino tertiary butyl of 2-oxo-1-[N-[(2-) kharophen] formyl radical-tetramethyleneimine-3-yl] tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3,2,0] hept-2-ene"-2-carboxylic acid, or
(4R; 5S; 6S)-3-[(3S)-and the amino tertiary butyl of 2-oxo-1-[N-[(2-) kharophen] formyl radical-azetidine-3-yl] tetramethyleneimine-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo-[3; 2; 0] hept-2-ene"-2-carboxylic acid, and pharmacy acceptable salt.
6. as the described compound of the arbitrary claim of claim 1～5 or its pharmacy acceptable salt, its pharmacy acceptable salt is acetate, mesylate, maleate, succinate, tartrate, Citrate trianion, fumarate, hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt.
7. the pharmaceutical composition that comprises the described compound of the arbitrary claim of claim 1～5 or its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner is pharmaceutically acceptable arbitrary formulation.
8. pharmaceutical composition as claimed in claim 7 contains the described compound of the arbitrary claim of claim 1～5 or its pharmacy acceptable salt 0.05g～5g as essential activeconstituents.
As the described compound of the arbitrary claim of claim 1～5 or its pharmacy acceptable salt in the application that is used for preparing the medicine that treats and/or prevents infectious diseases.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5373002A (en) * | 1990-03-27 | 1994-12-13 | Banyu Pharmaceutical Co., Ltd. | 2-(substituted pyrrolidinylthio) carbapenem derivatives |
| GB2279073A (en) * | 1993-06-15 | 1994-12-21 | Dong Kook Pharm Co Ltd | 1-beta-methyl-2-thiolic carbapenem derivatives |
| CN1225011A (en) * | 1996-05-09 | 1999-08-04 | 三共株式会社 | Anti-helicobacter pylori compositions containing 1-methylcarbapenem derivatives as the active ingredient |
-
2008
- 2008-03-10 CN CN2008100867340A patent/CN101260108B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5373002A (en) * | 1990-03-27 | 1994-12-13 | Banyu Pharmaceutical Co., Ltd. | 2-(substituted pyrrolidinylthio) carbapenem derivatives |
| GB2279073A (en) * | 1993-06-15 | 1994-12-21 | Dong Kook Pharm Co Ltd | 1-beta-methyl-2-thiolic carbapenem derivatives |
| CN1225011A (en) * | 1996-05-09 | 1999-08-04 | 三共株式会社 | Anti-helicobacter pylori compositions containing 1-methylcarbapenem derivatives as the active ingredient |
Non-Patent Citations (1)
| Title |
|---|
| JP特开2003-183281A 2003.07.03 |
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