CN1313466C - 1,3,4 furodiazole carbon-penillien compound, preparation method and application - Google Patents
1,3,4 furodiazole carbon-penillien compound, preparation method and application Download PDFInfo
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Abstract
The present invention provides a 1, 3, 4-azoxime carbapenem compound with a structure shown as formula I, a preparing method thereof and antibacterial applications thereof. In the formula I, R1 is at least one selected from hydrogen, alkyl of C1 to C6, amidogen, low-grade alkylamidogen, acylamide radicals, alkyl carbonyl of C1 to C6, arylcarbonyl, sulfhydryl, alkylthio of C1 to C6, arylthio, hydroxy, alkoxyl of C1 to C6, aryloxy or halogen; R2 represents hydrogen, alkali metal, ammonium salts or ester residues which can hydrolyze in organisms; R2 represents hydrogen, alkali metal, ammonium salts or ester residues which can hydrolyze in organisms.
Description
Technical field
The present invention the present invention relates to a kind of carbapenem compounds, specifically, is a class 1,3,4-oxadiazole carbapenem compounds, and preparation method thereof and this compounds as the purposes of antibacterials.
Background technology
Carbapenem (Carbapenem is shown in structural formula V) compound is the beta-lactam compound of the class brand new that grows up of the seventies, and the characteristics of its structure are: the sulphur that the penem parent nucleus is 1 is replaced by carbon, and has two keys at 2.The effect of the five-ring of this structure is compound penicillin and the conjugated double bond activation beta-lactam nucleus of cynnematin has best substituting group and stereochemistry feature concurrently on chemical structure, promptly there is the hydroxyethyl of (8R) configuration 6-position, 5, the beta-lactam that 6-is trans, three chiral carbon be configured as (5R, 6S, 8R), significantly different with common carbapenem cisoid conformation, and has a broad antifungal spectrum, anti-microbial activity is strong, stable to β-Nei Xiananmei, so very noticeable in antibiotic field.
The most representative in being developed as antibiotic carbapenem derivative is imipenum (Imipenem, shown in the structural formula VI) and panipenem (Panipenem, shown in the structural formula VII), the both is the active drug that current treatment severe bacterial infections comprises that multi-drug resistant bacteria infects.
Imipenum (Imipenem) all has very strong activity to gram-positive microorganism, negative bacterium, aerophil, anerobe, stable to various β-Nei Xiananmeis, and there is not cross resistance with other microbiotic, but imipenum is easily degraded rapidly by dehydropeptidase of kidney-I (DHP-I) in vivo and is opened beta-lactam nucleus (Kropp K, Sudelof J G, Hajdu R et al.Antimicrob Chemother 1983,12 (Suppl.D): 1-35), thereby must share with kidney peptidase inhibitors-cilastatin (Cilastatin) clinically.
Panipenem (Panipenem) is highly stable to various β-Nei Xiananmei; stable to DHP-I; the resisting pseudomonas aeruginosa activity is better than imipenum; not highly effective streptococcus aureus of third generation cephalosporin and enterococcus faecalis also there is excellent activity; but because of it has slight renal toxicity, so need share with kidney protective material Betamipron (Betaminpron).
To further discovering of carbapenem derivative, methyl is introduced in 1-β position, can strengthen the chemical stability, anti-microbial activity of carbapenem and to the stability of DHP-I, caused further investigation thus, particularly introduced the research that side chain is introduced in methyl and C-2 position in 1-β position to the structure activity relationship and the mechanism of action of carbapenem antibiotic.Meropenem (the Meropenem that has wherein developed, shown in the formula VIII), (Sunagawa M, Matsumura H, Inoue T et al.J Antibiot 1990,43:519-32), be the carbapenem antibiotic of super wide spectrum, compare with imipenum, in the C-1 position monomethyl is arranged, it can increase the stability to DHP-I, thereby does not have renal toxicity, can single agent administration.Though clinical evaluation is thought efficient, safe microbiotic, (Methicillin-Resistant Straphylococcus Aureus MRSA) lacks more effective anti-microbial activity to this medicine to modal pathogenic bacteria of nosocomial infection streptococcus aureus.
Biapenem (biapenem, L-627, Japanese Lederle) is the injection beta-methyl carbapenem that need not share DHP-I and kidney toxinicide, has a broad antifungal spectrum; Anti-gram positive organism is active similar to imipenum, and golden grape and streptococcus faecium are lower than imipenum slightly; The activity of anti-gram-negative bacteria is identical with imipenum or stronger; The activity of anaerobe resistant is also identical with imipenum; All highly stable to part hydroxyl imines cephalosporinase (oxyiminocephalosporase) β-Nei acyl enzyme in addition that xanthomonas maltophilia produces, and very strong restraining effect is arranged.Treat 1255 routine various infection, clinical effective rate is 87.7%, bacteria clearance is 85.6%, and wherein gram positive organism is 88.8%, negative bacterium 86.2%, anerobe 90.0%, polyinfection is 81.8%, and in 1344 examples of statistics, untoward reaction has 29 examples (2.2%), be mainly symptom of digestive tract (1.3%) and allergic symptom (1%), nervus centralis symptom do not occur; Adopt double-blind method relatively to treat the complicacy urinary tract infections, this medicine (300mg * 2/d) and imipenum (curative effect and the equal no significant difference of side effect of 500mg * 2/d).
Summary of the invention
The present invention is through research and screening to structure activity relationship, the new carbapenem compounds of one class is proposed, promptly 1,3,4-oxadiazole carbapenem compounds (is to have 1,3 on the C2 position, the carbapenem compounds of 4-oxadiazole side chain), and the synthetic method of this compounds, simultaneously, the present invention also provides this compounds as the purposes in the antibacterials.
The object of the present invention is to provide a kind of 1,3,4-oxadiazole carbapenem compounds, this compounds can broad-spectrum antimicrobial.
The present invention also aims to provide 1,3, the synthetic route of 4-oxadiazole carbapenem compounds.
The present invention also aims to provide this 1,3, the antibacterial application of 4-oxadiazole carbapenem compounds, that is, this carbapenem antibiotic is in the application of preparation in the antibiotic medicine.
The present invention also aims to provide a kind of pharmaceutical composition, wherein contain above-mentioned 1,3,4-oxadiazole carbapenem compounds.
For achieving the above object, the invention provides a kind of 1,3,4-oxadiazole carbapenem compounds, its C-2 position at 1-β beta-methyl carbapenem bicyclic mother nucleus is connected with 2-position (phenyl of replacement)-5-methyl mercapto-1,3,4-oxadiazole side chain, this compound has the structure suc as formula I:
Wherein, R
1Be selected from hydrogen, C
1-6Alkyl, amino, low-grade alkane amino, amide group, C
1-6Alkyl-carbonyl, aryl carbonyl, sulfydryl, C
1-6Alkylthio, artyl sulfo, hydroxyl, C
1-6Alkoxyl group, aryloxy and halogen at least one; R
2Be hydrogen, basic metal, ammonium salt or the ester residue of hydrolysis in vivo; R
2Be hydrogen, basic metal, ammonium salt or the ester residue of hydrolysis in vivo.
Above-claimed cpd has the pharmacologically active of broad-spectrum antimicrobial, can be used for preparing the medicine of antibiotic class.
In the present invention, described C
1-6Alkyl can be methyl, ethyl, n-propyl, sec.-propyl, allyl group, cyclopropyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl etc., wherein, preferable methyl, ethyl, n-propyl, sec.-propyl, more preferably methyl, ethyl, most preferable.
Described C
1-6Alkylamino radical can be methylamino, ethylamino-, Tri N-Propyl Amine base, sec.-propyl amido, cyclopropyl amido, normal-butyl amido, isobutyl-amido, sec-butyl amido, tertiary butyl amido, n-pentyl amido, isopentyl amido, n-hexyl amido, isohexyl amido etc.;
Described amide group nail base amide group, buserelin base, n-propyl amide group, sec.-propyl amide group, allyl group amide group, cyclopropyl amide base, normal-butyl amide group, isobutyl-amide group, n-pentyl amide group, n-hexyl amide group, phenyl amide base, tolyl amide group etc.
Described C
1-6Alkyl-carbonyl can be carbonyls such as methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, sec.-propyl carbonyl, allyl group carbonyl, cyclopropyl carbonyl, normal-butyl carbonyl, isobutyl-carbonyl, sec-butyl carbonyl, tertiary butyl carbonyl, n-pentyl carbonyl, isopentyl carbonyl, n-hexyl carbonyl, isohexyl etc.
Described aryl carbonyl refers to phenylcarbonyl group, tolyl carbonyl, xylyl carbonyl or pyridyl carbonyl etc.
Described C
1-6Alkylthio can be methylthio group, ethylmercapto group, positive rosickyite base, iprotiazem base, cyclopropyl sulfenyl, positive butylthio, isobutyl sulfenyl, secondary butylthio, uncle's butylthio, positive penta sulfenyl, isoamyl sulfenyl, just own sulfenyl, dissident's sulfenyl etc.;
Described artyl sulfo refers to phenyl sulfenyl, tolyl sulfenyl, xylyl sulfenyl etc.
Described C
1-6Alkoxyl group can be methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, positive hexyloxy, different hexyloxy etc., preferred methoxyl group;
Described aryloxy refers to phenyl oxygen base, tolyl oxygen base, xylyl oxygen base etc.
Described halogen refers to fluorine, chlorine, bromine, iodine etc., preferred chlorine.
The object lesson of R1 can comprise: methyl, chlorine, hydroxyl, methoxyl group (comprises that the position is the ortho position, the above-mentioned group of a contraposition or a position, for example, ortho position methyl, between the position methyl, the contraposition methyl, the contraposition chloro, the ortho position chloro, between the position chloro, vicinal hydroxyl groups, meta-hydroxyl, the contraposition hydroxyl, the ortho position methoxyl group, between the position methoxyl group, the contraposition methoxyl group), ethyl, hydrogen, n-propyl, allyl group, cyclopropyl, cyclopentyl, cyclohexyl, methylamino, ethylamino-, the Tri N-Propyl Amine base, the allyl group amido, isopropylamine base, cyclopropyl amino, cyclohexylamino, formamido-, acetamido, the methyl carbonyl, the ethyl carbonyl, the n-propyl carbonyl, the sec.-propyl carbonyl, the allyl group carbonyl, cyclopropyl carbonyl, phenylcarbonyl group, the tolyl carbonyl, methoxyl group, oxyethyl group, methylthio group, ethylmercapto group, positive rosickyite base, the iprotiazem base, ring rosickyite base, the phenyl sulfenyl, tolyl sulfenyl etc.
In a preferred embodiment of the invention, R1 is preferably hydrogen, methyl, methoxyl group, chlorine or hydroxyl.
R among the present invention
2Can be hydrogen, perhaps basic metal, as sodium salt, sylvite etc., perhaps ammonium salt (inorganic salt and the organic salt that comprise ammonium, for example triethylamine salt etc.), perhaps ester residue of hydrolysis etc. in vivo, wherein, R
2Particular certain cancers or sylvite, most preferably sodium salt.
Described hydrolyzable in vivo ester residue can be the ester residue that hydrolyzable in vivo becomes corresponding carboxylic acid, refers in particular to C
1-C
4Alkyl ester (as methyl esters, ethyl ester etc.); C
1-C
4Alkyl oxy carbonyl oxygen-(C
1-C
4Alkyl) ester (as 1-(methoxy carbonyl oxygen base) ethyl ester, 1-(ethoxy carbonyl oxygen base) ethyl ester, 1-(the different third oxygen carbonyl oxygen base) ethyl ester, tertiary butyloxycarbonyl oxygen base methyl esters etc.); C
5-C
6Ring alkyl oxy carbonyl oxygen-(C
1-C
4Alkyl) ester (as encircling penta oxygen carbonyl oxygen base methyl esters, 1-(encircling penta oxygen carbonyl oxygen base) ethyl ester, 1-(hexamethylene oxygen carbonyl oxygen base) ethyl ester etc.); C
2-C
5Alkanoyloxy-(C
1-C
4Alkyl) ester (as acetoxyl group methyl esters, 1-(acetoxyl group) ethyl ester, isobutyl acyloxy methyl esters, 1-(isobutyl acyloxy) ethyl ester, pivalyl oxygen base methyl esters etc.).
The invention allows for 1,3 of formula I structure, the application of 4-thiadiazoles carbapenem compounds in preparation antibacterials (for example microbiotic).
It is the antimicrobial compound (pharmaceutical preparation) of effective constituent that the present invention also provides with the compound of above-mentioned formula I structure, can for example vehicle, thinner etc. are mixed and made into formulation gastrointestinal administrations such as tablet, capsule, granule, powder or syrup or make formulations such as injection with administered in parenteral form with this compound and pharmaceutically useful auxiliary material.
The said medicine preparation can prepare by ordinary method.Described auxiliary material can comprise vehicle (for example carbohydrate derivative such as lactose, sucrose, glucose, mannitol and Sorbitol Powder; Starch derivative such as W-Gum, potato starch, dextrin and carboxymethyl starch; Derivatived cellulose such as crystalline cellulose, hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, Xylo-Mucine; Gum arabic; Dextran; Silicate derivative such as metasilicic acid magnalium; Phosphate derivative such as calcium phosphate; Carbonate derivative such as lime carbonate; Sulfate-derivatives such as calcium sulfate etc.), tackiness agent (gelatin for example, polyvinylpyrrolidone and polyoxyethylene glycol), disintegrating agent (for example derivatived cellulose such as Xylo-Mucine, polyvinylpyrrolidone), lubricant (talcum for example, calcium stearate, Magnesium Stearate, spermaceti, boric acid, Sodium Benzoate, leucine), stablizer (methyl p-hydroxybenzoate, propylparaben etc.), correctives (Chang Yong sweeting agent for example, acidic flavoring agent and spices etc.), thinner and injection liquid are with solvent (water for example, ethanol and glycerine etc.).
Compound of the present invention and the clinical administration dosage that contains described compound compositions are different and different with patient's age, sex, race, the state of an illness etc., general adult's about 0.01-5000mg/ day of dosage, preferred 1-1000mg/ day, more preferably 5-500mg/ day.
Carbapenem compounds shown in the formula I provided by the invention can be by making the 2-position have leavings group and have (I represents with the general formula I) carbapenem compounds and methyl mercapto-2-position (phenyl of replacement)-1 of the 1-β beta-methyl carbapenem bicyclic mother nucleus of protecting group on carboxyl; 3,4-oxadiazole derivative (representing with general formula III) reaction prepares.
In the formula, R
1As above definition, R
3Be leavings group, R
4Be carboxyl-protecting group.
Can adopt any feasible method to connect parent nucleus and side chain, obtain the carbapenem compound of formula I of the present invention.
Used carboxyl-protecting group R
4Can be allyl group, the tertiary butyl, benzyl, diphenyl-methyl, to nitrobenzyl, to methoxy-benzyl, be preferably allyl group or to nitrobenzyl; R
3Be leavings group, the promptly known reactive group of leaving away is so that parent nucleus is activated preferred diphenylphosphine acyloxy or trifluoro-methanesulfonyl oxy.
Above-mentioned 2-position has leavings group and have (I represents with the general formula I) carbapenem compounds and methyl mercapto-2-position (phenyl of replacement)-1 of the 1-β beta-methyl carbapenem bicyclic mother nucleus of protecting group on carboxyl, 3,4-oxadiazole derivative (representing with general formula III) all can be buied by commercially available, also can synthesize voluntarily and obtain, for example, the synthetic of 1-β beta-methyl carbapenem bicyclic mother nucleus with structural formula II can (for example Kondo K.Seki M.Kuroda T et al.J Org Chem 1995 with reference to the document of open record, 60,1096-97); The synthetic of compound III can be with reference to the document of open record (for example Chang H L, Lee IC and Kee J L.Bull.Korean Chem.Soc.2001, Vol.22 (10) 1153-1155).
According to the preferred embodiment of the invention, the synthetic route of compound III can for:
The condition of reaction conditions: step a is at methylsulfonic acid (MeSO
3H) and chloroacetyl chloride (ClCH
2COCl) reflux in the solvent; The condition of step b is at ethyl acetate and thioacetic acid potassium (CH
3COSK) in, react under the room temperature; The condition of step c is reacted then in MeOH, and in HCOOH for reacting in KOH earlier, and temperature is 0～-10 ℃.
According to the preferred embodiment of the invention, to use the diphenyl phosphoester or the triflate of activatory 1-β beta-methyl carbapenem bicyclic mother nucleus, and side chain is introduced its C-2 position, this synthetic route is as follows:
According to such scheme; the synthetic of carbapenem compounds of the present invention preferably includes: with side chain 2-position (phenyl of replacement)-5-methyl mercapto-1; 3; 4-oxadiazole and described 2-position have leavings group and are having the 1-β beta-methyl carbapenem bicyclic mother nucleus (acetonitrile or dimethyl formamide etc.) in solvent of protecting group on the carboxyl; diisopropyl ethyl amine in alkalescence; triethylamine or sodium hydride effect be reaction down; 2-phenyl-5-methyl mercapto-1 is introduced in 2-position at described 1-β beta-methyl carbapenem bicyclic mother nucleus; 3; 4-oxadiazole side chain, and then obtain pharmaceutically useful acid; salt or in vivo hydrolyzable become the ester of corresponding carboxylic acid.
Compound vitro antibacterial activity experiment of the present invention
Experiment purpose: 7 compounds of new synthetic carbapenems of the present invention are carried out in-vitro antibacterial with the safe energy of contrast medicine, Meropenem, biapenem measure, therefrom filter out kind with anti-microbial activity.
Experimental technique: the standard agar plate doubling dilution that adopts NCCL to propose carries out minimal inhibitory concentration (MIC) to the survey compound and measures.Judge the power of the anti-microbial activity and the anti-microbial effect of compound with the MIC value.
The test medicine:
1. contrast medicine: safe can the Meropenem biapenem
2. investigational agent: S-1 (R
1-ortho position methyl) S-2 (R
1-position methoxyl group) S-3 (R
1-contraposition methoxyl group) S-4 (R
1-contraposition methyl) S-5 (R
1-vicinal hydroxyl groups) S-6 (R
1-ortho position chlorine) S-7 (R
1-H)
Measure compound concentrations scope: 256mg/L-0.008mg/L
Measure bacterium 30 strains: MRSA (methicillin-resistant staphylococcus aureus) 10 strains;
MSSA (MSSA) 5 strains;
MRSE (methicillin resistance staphylococcus epidermidis) 10 strains;
MSSE (methicillin-sensitivity staphylococcus epidermidis) 5 strains.
Quality Control bacterium: streptococcus aureus ATC29213
Experimental result: the carbapenems new compound compares (seeing Table 1) to the outer anti-microbial effect of survey thalline
Conclusion: 7 kinds of new compounds of institute's carbon determination penems are better with S-2, S-3, S-5, S-6 to the MRSA anti-microbial activity, and the MIC90 value all is lower than 1/2 times of Meropenem, safe energy, is lower than 1/4 times of biapenem; In MRSE, MSSA, MSSE anti-microbial activity, S-5 is faint in the safe energy of contrast medicine, Meropenem (1/2-1/4 doubly); S-1, S-2 are weaker than 1/4 times of the safe energy of contrast medicine, Meropenem.
According to MIC experimental result to MRSA, MRSE, MSSA, four kinds of bacterium of MSSE, we think S-5 in 7 new compounds being measured have the most approaching contrast medicine safe can, the anti-microbial effect of Meropenem and biapenem.Because the contrast medicine is present this area drug effect the strongest best, active super Broad spectrum antibiotics, though therefore above-mentioned 7 kinds of compounds approach the drug effect of above-mentioned contrast medicine in the external activity experiment, still be worth carrying out the further expansion bacterium spectrum of the inside and outside anti-microbial activity of body, activity in vivo, pharmacokinetics, toxicity assessment, the research of sample.So that accurately estimate the value of its anti-microbial activity and development and use.
Table 1. carbapenems new compound MIC50, MIC90 value (mk/L)
| The medicine name | MRSA (10 strain) | MRSE (10 strain) | MSSA (5 strain) | MSSE (5 strain) | ||||
| MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | MIC50 | MIC90 | |
| S-1 S-2 S-3 S-4 S-5 S-6 S-7 IMPN MEPN BAPN | ＞256 128 256 ＞256 128 256 ＞256 64 64 32 | ＞256 256 256 ＞256 256 256 ＞256 128 128 64 | 4 4 8 ＞256 4 128 32 0.5 0.5 0.125 | 64 32 32 ＞256 16 256 256 4 8 2 | 2 2 4 ＞256 1 32 32 0.5 0.5 0.062 | 2 2 4 ＞256 1 32 32 0.5 0.05 0.125 | 1 1 2 ＞256 1 32 16 0.25 0.25 0.062 | 1 1 2 ＞256 1 32 32 0.5 0.5 0.062 |
Experiment showed, method for preparing formula I structure of the present invention 1,3,4-thiadiazoles carbapenem compounds has anti-microbial effect, can be used for preparing antibacterials (for example microbiotic).
Embodiment
Describe technical scheme of the present invention in conjunction with the embodiments in detail, but do not limit protection scope of the present invention.
Embodiment 1:2-phenyl-5-chloromethyl-1,3,4-oxadiazole (2) synthetic
In being housed, the three-necked bottle of drying tube adds compound (1) (5.4g, 40mmol) and toluene (100ml), slowly add methylsulfonic acid (2.6ml, 40mmol), stirred 10 minutes, add chloroacetyl chloride (3.9ml, 40mmol), refluxed 6 hours, and reduced to room temperature, add saturated sodium bicarbonate solution (260ml) and transfer pH=8.5, tell organic layer, water merges the saturated common salt water washing with dichloromethane extraction twice, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtains white crystal product (2) (7g, 89.7%).
1H-NMR(CDCl
3)δ：4.81(s，2H，CH
2)，7.03-7.81(m，5H，Ar)。
Embodiment 2:2-phenyl-5-ethanethioyl methyl isophthalic acid, 3,4-oxadiazole (3) synthetic
In reaction flask, add compound (2) (7g, 36mmol), ethyl acetate (35ml) and thioacetic acid potassium (6.2g, 54mmol), room temperature reaction 5 hours, add entry (40ml), tell organic layer and wash anhydrous magnesium sulfate drying, concentrating under reduced pressure with saturated common salt, obtain yellow solid product (3) (6.74g, 80%).
1H-NMR(CDCl
3)δ：2.4(s，3H，CH
3)，4.81(s，2H，CH
2)，7.03-7.81(m，5H，Ar)。
Embodiment 3:2-phenyl-5-methyl mercapto-1,3,4-oxadiazole (4) synthetic
(1.77g 7.5mmol) and methyl alcohol (15ml), is cooled to 0 ℃ to add compound (3) in reaction flask, add potassium hydroxide (0.42g, methanol solution 7.5mmol), room temperature reaction 0.5 hour, adding formic acid (0.3ml, 7.9mmol), reaction solution adds in the saturated aqueous common salt, tell organic layer, organic layer is washed with the saturated potassium hydrogen carbonate aqueous solution, tells organic layer, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtains yellow solid product (4) (13.7g, 95%).
Embodiment 4:2-(4-aminomethyl phenyl)-5-chloromethyl-1,3,4-oxadiazole (6) synthetic
With compound (5) is raw material, and the method operation according to identical with embodiment 1 obtains product (6).
1H-NMR(CDCl
3)δ：2.38(s，3H，CH
3)，4.81(s，2H，CH
2)，7.03-7.81(m，4H，Ar)。
Embodiment 5:2-(4-aminomethyl phenyl)-5-ethanethioyl methyl isophthalic acid, 3,4-oxadiazole (7) synthetic
With compound (6) is raw material, and the method operation according to identical with embodiment 2 obtains product (7).
1H-NMR(CDCl
3)δ：1.21(s，3H，CH
3)，2.38(s，3H，CH
3)，4.81(s，2H，CH
2)，7.03-7.81(m，4H，Ar)。
Embodiment 6:2-(4-aminomethyl phenyl)-5-methyl mercapto-1,3,4-oxadiazole (8) synthetic
With compound (7) is raw material, and the method operation according to identical with embodiment 3 obtains product (8).
Embodiment 7:2-(4-p-methoxy-phenyl)-5-chloromethyl-1,3,4-oxadiazole (6) synthetic
With compound (9) is raw material, and the method operation according to identical with embodiment 1 obtains product (10).
Embodiment 8:2-(4-p-methoxy-phenyl)-5-ethanethioyl methyl isophthalic acid, 3,4-oxadiazole (11) synthetic
With compound (10) is raw material, and the method operation according to identical with embodiment 2 obtains product (11).
1H-NMR(CDCl
3)δ：2.41(s，3H，CH
3)，3.89(s，3H，CH
3)，4.39(s，2H，CH
2)，7.23(dd，2H，Ar)，8.10(dd，2H，Ar)。
Embodiment 9:2-(4-p-methoxy-phenyl)-5-methyl mercapto-1,3,4-oxadiazole (12) synthetic
With compound (11) is raw material, and the method operation according to identical with embodiment 2 obtains product (12).EI-MS：m/z 543[M
+-CH
3]。
Embodiment 10:2-(2-p-methoxy-phenyl)-5-methyl mercapto-1,3,4-oxadiazole (13) synthetic
With the O-methoxy benzoyl hydrazine is raw material, and the method operation according to identical with embodiment 1,2,3 obtains product (13).
Embodiment 11:2-(3-p-methoxy-phenyl)-5-methyl mercapto-1,3,4-oxadiazole (14) synthetic
With the meta-methoxy benzoyl hydrazine is raw material, and the method operation according to identical with embodiment 1,2,3 obtains product (14).
Embodiment 12:2-(2-hydroxy phenyl)-5-methyl mercapto-1,3,4-oxadiazole (15) synthetic
With the o-hydroxy formyl hydrazine is raw material, and the method operation according to identical with embodiment 1,2,3 obtains product (15).
Embodiment 13:2-(2-chloro-phenyl-)-5-methyl mercapto-1,3,4-oxadiazole (16) synthetic
With adjacent chlorobenzoyl hydrazine is raw material, and the method operation according to identical with embodiment 1,2,3 obtains product (16).
Embodiment 14:(1R, 5R, 6S)-2-(2-phenyl-1,3,4-oxadiazole-5-methyl sulphur-)-6-[(1R)-the 1-hydroxyl]-1-methyl carbon mould-2-alkene-3-carboxy acid mutual-nitro carbobenzoxy (18) synthetic
In reaction flask, add compound (17, be purchased, also can literature method make Heterocycles 1993.36.1729) (1.74g, 2.93mmol), acetonitrile (15ml), be cooled to 0 ℃, and the adding diisopropyl ethyl amine (0.78ml, 4.7mmol), add compound (the 4) (0.9g that obtains among the embodiment 3 again, 4.7mmol), reacting 3 hours, reaction solution adds in the saturated aqueous common salt, tell organic layer, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtains oily matter, VLC separates, hexanaphthene: ethyl acetate=2: 1 wash-outs obtains yellow solid product (18) (1.1g, 70%).Wherein, PNB is to the nitrobenzyl ester.ESI-MS：m/z 537[M
++H]。
1H-NMR(DMSO)δ：1.14(3H，d)，1.16(3H，d)，3.78(1H，m)，3.98(1H，m)，4.21(1H，m)，4.55(2H，dd)，5.10(1H，d)，5.27-5.42(2H，m)，7.58-7.68(5H，m)，7.95-7.97(2H，m)，8.16-8.90(2H，m)。
Embodiment 15:(1R, 5R, 6S)-2-(2-phenyl-1,3,4-oxadiazole-5-methyl sulphur-)-6-[(1R)-the 1-hydroxyl]-1-methyl carbon mould-2-alkene-3-carboxylic acid potassium (19) synthetic
(0.2g 0.37mmol), 4ml tetrahydrofuran (THF) and 6ml phosphoric acid buffer, starts stirring, adds 0.08g palladium carbon again, feeds hydrogen, reaction 6h to add compound (18) in reaction flask.Filter, wash with ethyl acetate, the aqueous solution separates with macroporous resin, gets faint yellow crystallization (19) (100mg, 66.7%).
ESI-MS：m/z 440[M
++H]
1H-NMR(DMSO)。
Embodiment 16:(1R, 5R, 6S)-2-(2-(4-aminomethyl phenyl)-1,3,4-oxadiazole-5-methyl sulphur-)-6-[(1R)-the 1-hydroxyl]-1-methyl carbon mould-2-alkene-3-carboxy acid mutual-nitro carbobenzoxy (20) synthetic
With the compound (8) that obtains among compound (17) and the embodiment 6 is raw material, and the method operation according to identical with embodiment 14 obtains product (20).
ESI-MS：m/z 550[M
++H]。
1H-NMR(DMSO)δ：1.14(3H，d)，1.16(3H，d)，3.78(1H，m)，3.98(1H，m)，4.21(1H，m)，4.55(2H，dd)，5.10(1H，d)，5.27-5.42(2H，m)，7.58-7.68(5H，m)，7.95-7.97(2H，m)，8.16-8.90(2H，m)。
Embodiment 17:(1R, 5R, 6S)-2-(2-(4-p-methoxy-phenyl)-1,3,4-oxadiazole-5-methyl sulphur-)-6-[(1R)-the 1-hydroxyl]-1-methyl carbon mould-2-alkene-3-carboxy acid mutual-nitro carbobenzoxy (21) synthetic
With the compound (12) that obtains among compound (17) and the embodiment 9 is raw material, and the method operation according to identical with embodiment 14 obtains product (21).
ESI-MS：m/z 566[M
++H]。
1H-NMR(DMSO)δ：1.14-1.68(6H，m)，3.42-3.44(1H，m)，3.76-3.84(4H，m)，3.97-4.02(1H，m)，4.21-4.26(1H，m)，4.47-4.57(2H，dd)，5.07-5.10(1H，m)，5.25-5.45(2H，m)，7.12-8.19(8H，m)。
Embodiment 18:(1R, 5R, 6S)-2-(2-(4-p-methoxy-phenyl)-1,3,4-oxadiazole-5-methyl sulphur-)-6-[(1R)-the 1-hydroxyl]-1-methyl carbon mould-2-alkene-3-carboxylic acid potassium (22) synthetic
With compound (21) is raw material, and the method operation according to identical with embodiment 15 obtains product (22).
ESI-MS：m/z 470[M
++H]。
Embodiment 19:(1R, 5R, 6S)-2-(2-(2-p-methoxy-phenyl)-1,3,4-oxadiazole-5-methyl sulphur-)-6-[(1R)-the 1-hydroxyl]-1-methyl carbon mould-2-alkene-3-carboxy acid mutual-nitro carbobenzoxy (23) synthetic
With the compound (13) that obtains among compound (17) and the embodiment 10 is raw material, and the method operation according to identical with embodiment 14 obtains product (23).
ESI-MS：m/z 566[M
++H]。
1H-NMR(DMSO)δ：1.14-1.68(6H，m)，3.57-3.84(4H，m)，3.99-4.05(1H，m)，4.18-4.21(1H，m)，4.45-4.58(2H，dd)，5.08-5.11(1H，m)，5.26-5.45(2H，m)，7.10-8.19(8H，m)。
Embodiment 20:(1R, 5R, 6S)-2-(2-(2-p-methoxy-phenyl)-1,3,4-oxadiazole-5-methyl sulphur-)-6-[(1R)-the 1-hydroxyl]-1-methyl carbon mould-2-alkene-3-carboxylic acid potassium (24) synthetic
With compound (23) is raw material, and the method operation according to identical with embodiment 15 obtains product (24).
ESI-MS：m/z 470[M
++H]。
Embodiment 21:(1R, 5R, 6S)-2-(2-(3-p-methoxy-phenyl)-1,3,4-oxadiazole-5-methyl sulphur-)-6-[(1R)-the 1-hydroxyl]-1-methyl carbon mould-2-alkene-3-carboxy acid mutual-nitro carbobenzoxy (25) synthetic
With the compound (14) that obtains among compound (17) and the embodiment 11 is raw material, and the method operation according to identical with embodiment 14 obtains product (25).
ESI-MS：m/z 566[M
++H]。
1H-NMR(DMSO)δ：1.14-1.68(6H，m)3.3-3.83(4H，m)，3.96-4.00(1H，m)，4.20-4.23(1H，m)，4.48-4.60(2H，dd)，5.09-5.11(1H，m)，5.26-5.44(2H，m)，7.19-8.18(8H，m)。
Embodiment 22:(1R, 5R, 6S)-2-(2-(3-p-methoxy-phenyl)-1,3,4-oxadiazole-5-methyl sulphur-)-6-[(1R)-the 1-hydroxyl]-1-methyl carbon mould-2-alkene-3-carboxylic acid potassium (26) synthetic
With compound (25) is raw material, and the method operation according to identical with embodiment 15 obtains product (26).
ESI-MS：m/z 470[M
++H]。
Embodiment 23:(1R, 5R, 6S)-2-(2-(2-hydroxy phenyl)-1,3,4-oxadiazole-5-methyl sulphur-)-6-[(1R)-the 1-hydroxyl]-1-methyl carbon mould-2-alkene-3-carboxy acid mutual-nitro carbobenzoxy (27) synthetic
With the compound (15) that obtains among compound (17) and the embodiment 12 is raw material, and the method operation according to identical with embodiment 14 obtains product (27).
ESI-MS：m/z 552[M
++H]。
1H-NMR(DMSO)δ：1.14-1.68(6H，m)，3.42-3.44(1H，m)，3.76-3.84(2H，m)，3.97-4.02(1H，m)，4.21-4.26(1H，m)，4.47-4.57(1H，dd)，5.07-5.10(1H，m)，5.25-5.45(2H，m)，7.12-8.19(8H，m)。
Embodiment 24:(1R, 5R, 6S)-2-(2-(2-chloro-phenyl-)-1,3,4-oxadiazole-5-methyl sulphur-)-6-[(1R)-the 1-hydroxyl]-1-methyl carbon mould-2-alkene-3-carboxy acid mutual-nitro carbobenzoxy (28) synthetic
With the compound (16) that obtains among compound (17) and the embodiment 13 is raw material, and the method operation according to identical with embodiment 14 obtains product (28).
ESI-MS：m/z 566[M
++H]。
1H-NMR(DMSO)δ：1.06-1.98(6H，m)，3.74-3.81(1H，m)，3.91-4.03(1H，m)，4.18-4.26(1H，m)，4.55-4.62(2H，dd)，5.08-5.19(1H，m)，5.22-5.45(2H，m)，7.13-8.30(8H，m)。
Claims (8)
1, a kind of 1,3,4-oxadiazole carbapenem compounds, this compound has the structure suc as formula I:
Wherein, R
1Be selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, allyl group, cyclopropyl, hydroxyl, methoxyl group, oxyethyl group, positive propoxy, isopropoxy and the halogen at least one; R
2For basic metal or to the nitrobenzyl ester.
2, claim 1 is described 1,3,4-oxadiazole carbapenem compounds, wherein, R
1Be hydrogen, methyl, ethyl, methoxyl group, chlorine or hydroxyl.
3, claim 1 is described 1,3,4-oxadiazole carbapenem compounds, wherein R
2For sodium or potassium or to the nitrobenzyl ester.
4, claim 1-3 arbitrary described 1,3, the preparation method of 4-oxadiazole carbapenem compounds, comprise 5-methyl mercapto-2-position (phenyl of replacement)-1 that carbapenem compounds with 1-β beta-methyl carbapenem bicyclic mother nucleus that general formula I I represents and general formula III are represented, 3,4-oxadiazole derivatives reaction
Wherein, the carbapenem compounds of described 1-β beta-methyl carbapenem bicyclic mother nucleus has leavings group R for the 2-position
3And on carboxyl, have a protecting group R
4Compound, reaction solvent is acetonitrile or dimethyl formamide, R in the compound III
1Be selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, allyl group, cyclopropyl, hydroxyl, methoxyl group, oxyethyl group, positive propoxy, isopropoxy and the halogen at least one.
5, claim 4 is described 1,3, the preparation method of 4-oxadiazole carbapenem compounds, wherein leavings group R
3Be diphenylphosphine acyloxy or trifluoro-methanesulfonyl oxy; Carboxyl-protecting group R
4For allyl group, the tertiary butyl, benzyl, diphenyl-methyl, to nitrobenzyl or to methoxy-benzyl.
6, claim 4 is described 1,3, and the preparation method of 4-oxadiazole carbapenem compounds wherein, also adds diisopropyl ethyl amine or triethylamine or sodium hydride in the reaction of the compound of described general formula I I and the compound of general formula III.
7, claim 1 is described 1,3, the purposes of 4-oxadiazole carbapenem compounds in the preparation antibacterials.
8, a kind of pharmaceutical composition, each is described 1,3 wherein to contain claim 1～3,4-oxadiazole carbapenem compounds.
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| CN1958587B (en) * | 2005-11-04 | 2010-12-08 | 四川贝力克生物技术有限责任公司 | Method for preparing (1R,5R,6S) 2[5-(2- pyridyl)-1,3,4 - thiadiazoles -2- sulfur]-6 [(1R)-1 ethoxyl] 1- beta methyl Carbapenems 3- carboxylic acid or its salt |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994014811A1 (en) * | 1992-12-21 | 1994-07-07 | Chong Kun Dang Corp. | 2-(2-substituted pyrrolidin-4-yl)thio-carbapenem derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994014811A1 (en) * | 1992-12-21 | 1994-07-07 | Chong Kun Dang Corp. | 2-(2-substituted pyrrolidin-4-yl)thio-carbapenem derivatives |
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