CN1012614B - Ceph-3-ene-4-carboxylic acid derivatives and the prepn. - Google Patents

Ceph-3-ene-4-carboxylic acid derivatives and the prepn.

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Publication number
CN1012614B
CN1012614B CN86104805A CN86104805A CN1012614B CN 1012614 B CN1012614 B CN 1012614B CN 86104805 A CN86104805 A CN 86104805A CN 86104805 A CN86104805 A CN 86104805A CN 1012614 B CN1012614 B CN 1012614B
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acid
isoxazole
chlorine
carboxylic acid
tetrazolium
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CN86104805A (en
Inventor
桑多尔·埃利克
卡塔林·马罗希
米克洛斯·米霍克
伊尔迪科·米霍克·尼·伯贝利
桑多尔·詹克索
伊斯特万·科瓦斯
玛丽亚·康亚·尼·詹科维奇
伊洛纳·基斯·尼·洛斯
卡罗利·莱姆普特
加伯尔·多莱沙尔
约瑟夫·费特
吉尤拉·霍恩亚克
约瑟夫·尼特拉
吉尤拉·希米格
卡洛利·萨尤尔
苏萨纳·格姆伯斯
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Teva Pharmaceutical Works PLC
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Biogal Gyogyszergyar Rt
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

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  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a process for preparing the novel 7-(3-chloroisoxazol-5-yl)-acetamido-3-(1-methyl-1H-1,2,3,4-tetrazol-5-yl)-thiomethylceph-3-em-4-carboxylic acid of the formula I and its pharmacologically suitable salts. The compound of the formula I shows high activity on a wide range of microorganisms and is suitable as active ingredient for pharmaceutical products which can be administered orally.

Description

Ceph-3-ene-4-carboxylic acid derivatives and the prepn.
The present invention relates to the preparation method of new cephalo-3-alkene-4-carboxylic acid (ceph-3-em-4-Carboxylicacid) derivative.
The invention provides preparation 7-(3-chlorine-isoxazole-5-bases)-acetylaminohydroxyphenylarsonic acid 3-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-thiomethyl-cephalo-3-alkene-4-carboxylic acid and pharmacology thereof on the method for acceptable salt, this method comprises:
(a) will have the structure formula II
Figure 86104805_IMG6
（Ⅱ）
3-chlorine-isoxazole-acetate or its reactive derivative with have a structure formula III
Figure 86104805_IMG7
（Ⅲ）
7-amino-3-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-thiomethyl-cephalo-3-alkene-4-carboxylic acid reaction, from reaction mixture, separate obtaining structural formula and be (I) again with known method
（Ⅰ）
7-(3-chlorine-isoxazole-5-bases)-acetylaminohydroxyphenylarsonic acid 3-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-thiomethyl-cephalo-3-alkene-4-carboxylic acid, if necessary, can adopt known method to be translated into acceptable salt on its pharmacology, isolate this salt by known method again, perhaps;
(b) will have the structure formula IV
Figure 86104805_IMG9
（Ⅳ）
1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-base-mercaptan and 7-(3-chlorine-isoxazole-5-bases)-acetylaminohydroxyphenylarsonic acid cephalosporinic acid (7-(3-chloro-isoxazole-5-yl)-acetamido-cephalosporanic acid) reaction, separate with known method then and obtain 7-(3-chlorine-isoxazole-5-bases of structural formula for (I))-acetylaminohydroxyphenylarsonic acid 3-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-thiomethyl-cephalo-3-alkene-4-carboxylic acid, also can adopt known method to convert it into acceptable salt on its pharmacology as required, from reaction mixture, isolate this salt by known method again.
According to preparation method of the present invention (a), 3-chlorine-isoxazole acetate or its reactive derivative and 7-amino-3-(1-methyl isophthalic acid H-1 that will have the structure formula II with structure formula III, 2,3,4-tetrazolium-5-yl)-thiomethyl-cephalo-3-alkene-4-carboxylic acid reaction.This reaction can be at solvent, preferably the aqueous acetone medium or with the not miscible organic solvent of water in carry out.This reaction is under agitation carried out, and the reaction times was generally 30 minutes to 3 hours.
To have the 1-methyl isophthalic acid H-1 of structure formula IV according to preparation method of the present invention (b), 2,3,4-tetrazolium-5-base-mercaptan and 7-(3-chlorine-isoxazole-5-base)-reaction of acetylaminohydroxyphenylarsonic acid cephalosporinic acid.
This reaction can be carried out in solvent, and this solvent is the mixture of water and acetone preferably, and its temperature of reaction is 30～90 ℃, and preferably between 60 ℃ and 65 ℃, pH value scope is 4.5～6.0.Reaction times was generally 2 to 10 hours.
In the technical field of semi-synthetic beta-lactam derivatives,, carried out a large amount of experiments in order to prepare compound with wide or special antimicrobial spectrum.The noticeable this compound of one class comprises isoxazolyl replacement or unsubstituted, and they are attached on the 6th carbon atom on 6-amino-penicillinic acid by kharophen respectively and on the 7th carbon atom of 7-amino-cephalosporinic acid (7-amino-cephalosporanicacid).The significant anti-microbial effect of several demonstrations in this composition.
Known that some become the compound of active drug, they contain a substituted isoxazole-4-base-kharophen group on the 6th of penicillin group.Such compound is disclosed in United States Patent (USP) NO.2,996,501 and NO.3,239,507 and French Patent NO.BSMNO.6432 on.
At United States Patent (USP) NO.4, the derivative of penicillin and cynnematin is disclosed on 394,504, these derivatives also have an alkoxyl group-imino group on the alpha-position of Zai isoxazole ring except that containing amino-isoxazole-5-bases of 3--kharophen group.Disclosed these compounds have the activity that very important staphylococcus belongs to bacterium in above-mentioned United States Patent (USP).
At DOSNO.2, in 155,081, put down in writing and contained (3-substituted-phenyl)-isoxazole-5-bases-penicillin of kharophen group and derivative of cynnematin.But has important antibacterial effect for used experiment microorganism without any the openly also proof this phenyl-isoxazole oxazole derivatives of reality.
At DOSNO.2, other isoxazole-5-bases-kharophen derivative is disclosed in 409,949.But these derivatives De isoxazole ring has linked other substituting group on the position of phenyl substituent.
The therapeutic action and the pharmacological action that are recorded in a part of compound on the above-mentioned DOS are measured.But these test molecules do not demonstrate any outstanding anti-microbial activity to used test microorganism.
Give the MIC(minimal inhibitory concentration of some compound) value, but these values also do not reach as active ingredient in the medicine the activity value that must reach.
The objective of the invention is to prepare new cephalo-3-alkene-4-carboxylic acid derivative with outstanding pharmacological properties.
Be surprisingly found out that, new 7-(3-chlorine-isoxazole-5-base) with structure formula I-acetylaminohydroxyphenylarsonic acid 3-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-thiomethyl-cephalo-3-alkene-4-carboxylic acid and pharmacology thereof on acceptable salt demonstrate very high, very useful anti-microbial effect.This is confirmed by chemotherapeutical evaluation and pharmacological testing.Although 7-(3-chlorine-isoxazole-5-bases that this is new)-acetylaminohydroxyphenylarsonic acid 3-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-thiomethyl-cephalo-3-alkene-4-carboxylic acid cpd drops on DOSNO.2,409, in the general structure in 949, but in above-mentioned DOS, both do not describe its preparation method, do not announced its physical-chemical data and characteristic constant and MIC value yet.
7-(3-chlorine-isoxazole-5-base)-and acetylaminohydroxyphenylarsonic acid 3-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-anti-microbial activity of thiomethyl-cephalo-3-alkene-4-carboxylic acid illustrates by its MIC value.Test this compound with some experiment microorganisms, and, will the results are summarized in the table I with the medicine that can obtain from the market thing for referencial use.(seeing Table I)
Absorption test discloses surprisingly: the compound with structure formula I is (according to its MIC value, it can be regarded as the cephalosporins derivatives of the s-generation) different with other antibiotic of this class, demonstrate an absorptive index, this index makes this compound can be used for being suitable in the preparation of pharmaceutical composition for oral administration.These structures are listed in the table II.(seeing Table II)
Absorptive index=(oral median effective dose (milligram/kilogram))/((mouse is oral) subcutaneous injection median effective dose (milligram/kilogram))
Acute toxinology experiment shows that in the peculiar acute dose of beta-lactam, this compound with structure formula I is nontoxic.The peritoneal injection of 2500 milligrams/kilogram (body weight) or oral administration dosage all can not kill any mouse.
LD 50(medium lethal dose)=2500 milligram/kg body weight.
In order to determine that structural formula is the absorptivity of the compound of (I), also carried out pharmacokinetics test.This test is that the mouse in the CFLP kind carries out in the mode of peritoneal injection and oral administration on one's body.The aqueous solution with the structure formula I compound of proper concn is handled 20 mouse simultaneously.Dosage: when peritoneal injection dosage standard is 20 milligrams/kilogram (body weight), get concentration and be 0.1 milliliter of the solution of 4 mg/ml; When oral administration dosage standard is 80 milligrams/kilogram (body weight), get concentration and be 0.4 milliliter of the solution of 4 mg/ml.The mean body weight of mouse is 20 grams.Method bloodletting (utilization adds heparin and prevents Trostin M) at preset time utilization broken end.
(microorganism is used in test: Bacillus subtilus ATCC 6633) to have measured the content of active ingredient in the blood with method of microorganism.It the results are summarized in the table III.
The table III
A) peritoneal injection administration (20 milligrams/kg body weight)
Time (hour) the interior active component content (mg/litre) of blood
0.15 1.23
0.30 2.6
0.45 1.23
1 0
B) oral administration (80 milligrams/kg body weight)
Time (hour) the interior active component content (mg/litre) of blood
0.15 0.35
0.30 0.70
0.45 0.58
1 0.46
1.5 0.22
2 0
Beagle has also been carried out the absorption test of structure formula I compound.Test compound is that (consumption is 20 a milligrams/kg body weight during administered intramuscular by oral and administered intramuscular; Consumption is 80 a milligrams/kg body weight during oral administration).Test is Bacillus subtilus ATCC 6633 with microorganism.Adopt vein to extract and obtain blood.The results are shown in the table IV.
The table IV
A) administered intramuscular (20 milligrams/kg body weight)
Time (hour) the interior active component content (mg/litre) of blood
0.5 54.6-55.6
1 29.7-31.1
1.5 10.6
2 5.0-5.1
3 1.82-1.88
5 0.34
B) oral administration (80 milligrams/kg body weight)
Time (hour) the interior active component content (mg/litre) of blood
0.5 0.63-0.645
1 0.645-0.67
1.5 3.1
2 5.7-5.8
3 7.5
5 2.78
Concentration curve under oral administration in the blood shows that the compound of structure formula I is suitable for making medicinal preparation for oral administration.
Measured the combine situation of structure formula I compound with serum protein.Two kinds of methods have been adopted, one is based on equilibrium dialysis (Scholten:Antibiot.Chemother.No.12.103 page or leaf/1964), another " big plate " method (F.Kawanagh:Analytical Microbiol.Acad Press N.Y/1963) that is so-called.The combination rate of structure formula I compound and serum protein is 50～70%.This numerical value shows that also this compound is suitable for orally using.
On CFLP kind mouse, finish the activity in vivo test of structure formula I compound.In order to determine ED 50(median effective dose) value makes mouse infection with 6～8 hours microorganisms cultures in hypodermic mode; Used 10 * the LD that reaches in right amount 100After infecting 1 hour, treat these animals with the aqueous solution of test compound.With the compound as a comparison of available medicine on the market.Estimate these results with the Litchfield-wilcoxon method.According to the data characteristics of beta-lactam in the prior art, the animal of finding to have infected staphylococcus or Bacillus proteus with structure formula I compounds for treating is after 48 hours, and in fact the number of the animal that lives does not change.
For description architecture formula I compound than DOSNo.2,409,949 compound has bigger activity, carries out following experiment according to the method for describing in this document.
The table V
Compare ED 50Value, its unit is a milligram/kilogram.
Experimental animal: other CFLP kind mouse of Combination, mean body weight are 20 grams.
The bacterium that is used to infect: see Table
Route of infection: peritoneal injection, in 2.5% Saliva Orthana
Activeconstituents therapeutic modality staphylococcus aureus SMITH
ED 50(milligram/kilogram)
The subcutaneous injection 0.23 of structure formula I
（0.06-0.8）
Compound oral 4.3
（0.6-28.0）
Compound H * subcutaneous injection 24.6
（15.9-38.2）
Compound F 17-hydroxy-corticosterone * * oral 75.7
（40.2-142.7）
* 7-((3-Lv isoxazole-5-base)-kharophen)-cephalosporinic acid sodium
* 7-((3-Lv isoxazole-5-base)-kharophen)-3-((5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl) thiomethyl)-cephalo-3-alkene-4-carboxylic acid sodium
Another aspect of the present invention provides some pharmaceutical compositions, these pharmaceutical compositions contain compound 7-(3-chlorine-isoxazole-5-bases as active ingredient)-acetylaminohydroxyphenylarsonic acid 5-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-thiomethyl-cephalo-3-alkene-4-carboxylic acid or its pharmacology on acceptable salt, and suitable inert solid or liquid medicine carrier.
Can utilize that known method prepares aforementioned pharmaceutical compositions in the pharmaceutical industry.
Following examples will the present invention will be described in more detail, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
7-(3-chlorine-isoxazole-5-bases)-and acetylaminohydroxyphenylarsonic acid 3-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-preparation of thiomethyl-cephalo-3-alkene-4-carboxylic acid and sodium salt thereof
The 3-chlorine-isoxazole-5-bases-acetate of 4.99 grams (30.9 mmole) and the phosphorus pentachloride of 7.07 grams (33.99 mmole) are dissolved under the stirring that does not stop in 120 milliliters of dry-out benzene.Allow reaction mixture standing over night at room temperature, again 60 ℃ of reactions 1 hour down.Distill out benzene, residue is handled several times with dry oil ether, sherwood oil is removed in decantation and evaporation.Again residuum is dissolved in 40 milliliters the anhydrous propanone, 0～5 ℃, constantly within 50 minutes, this solution is added to by 6.75 gram (20.6 mmole) 7-amino-3-(1-methyl isophthalic acid H-1 under stirring, 2,3,4-tetrazolium-5-yl)-solution that thiomethyl-cephalo-3-alkene-4-carboxylic acid, 5.2 gram (61.8 mmole) sodium bicarbonates, 144 ml waters and 103 milliliters of acetone mix in.After adding, reaction mixture was stirred 1 hour down at 0-5 ℃, at room temperature stirred again 2 hours, with saturated sodium bicarbonate solution the pH value is transferred to 7-8 simultaneously.Adding dilute sulphuric acid, this mixed solution is acidified to pH value is 1.5～2, and with ethyl acetate extraction three times, consumption is 100 milliliters at every turn.Use the dried over mgso acetic acid ethyl acetate extract, remove and desolvate.
Residue with after the ether processing evaporation filters, washs and drying.So just obtain 3.5 gram 7-(3-chlorine ,-isoxazole-5-bases)-acetylaminohydroxyphenylarsonic acid 3-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-thiomethyl-cephalo-3-alkene-4-carboxylic acid.
Above-claimed cpd is dissolved in anhydrous propanone, adds 1 normal anhydrous sodium acetate in 10% methanol solution again.This solution was stirred 1 hour down at 20 ℃,, promptly is settled out 7-(3-chlorine-isoxazole-5-bases with the dilution of equal-volume ether)-acetylaminohydroxyphenylarsonic acid 3-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-sodium salt of thiomethyl-cephalo-3-alkene-4-carboxylic acid.
Characteristic is as follows:
' H nucleus magnetic resonance: (DMSO-d 6)
3.52（ABq，2H，H-2），3.90（S，3H，N-CH 3）
3.97（S，2H，CH 2CO），4.35（ABq，2H，H-10）
4.97（d，1H，H-6），5.52（q，1H，H-7）
6.67（S，1H，H-Ar），9.25（d，1H，C 7-NH）
Fusing point: 150～155 ℃ (decomposition)
Embodiment 2
7-(3-chlorine-isoxazole-5-bases)-and acetylaminohydroxyphenylarsonic acid 3-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-preparation of thiomethyl-cephalo-3-alkene-4-carboxylic acid and sodium salt thereof
The pentachlorophenol of 10.68 grams (0.04 mole) and the dicyclohexylcarbodiimide of 8.32 grams (0.04 mole) are dissolved in 230 milliliters of anhydrous methylene chlorides, add the 3-chlorine-isoxazole-5-bases-acetate of 6.4 grams (0.04 mole) immediately.This reaction mixture was at room temperature stirred one day, remove by filter sedimentary dicyclohexylcarbodiimide.Reach under the constantly stirring at 0 ℃, the dichloromethane solution of the five chlorophenyl ester that obtains like this is added to 7-amino-3-(1-methyl isophthalic acid H by 13.2 grams (0.04 mole), 1,2,3,4-tetrazolium-5-yl)-solution that the triethylamine of thiomethyl-cephalo-3-alkene-4-carboxylic acid, 16.8 milliliters (0.12 moles) and 120 milliliters of methylene dichloride are formed in.After adding, this reaction mixture is heated to room temperature, and under this temperature, stirred 1 hour.After reaction was finished, methylene dichloride was removed in vacuum distilling, and residue is dissolved in the aquifer ethyl, is that sulfuric acid acidation to the pH value of 2N is 2 with equivalent concentration, with different being separated, using the dried over mgso organic layer, and distills.Residue is ground with ether, filter, washing and at room temperature in vacuum with five phosphorus oxide dryings.Products therefrom is converted into sodium salt according to embodiment 1 described method, promptly gets 12 gram sodium salts, productive rate is that the productive rate of 61%(free acid is 63.8%).
Embodiment 3
7-(3-chlorine-isoxazole-5-bases)-and acetylaminohydroxyphenylarsonic acid 3-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-preparation of thiomethyl-cephalo-3-alkene-4-carboxylic acid and sodium salt thereof
With the sodium bicarbonate of 0.084 gram (1 mmole) and 7-(3-chlorine-isoxazole-5-bases of 0.415 gram (1 mmole))-the kharophen cephalosporinic acid is dissolved in the mixed solution of 17 ml waters and 8 milliliters of acetone, and add 0.14 the gram (1.2 mmole) 1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-base-mercaptan, this reaction mixture left standstill under 60-65 ℃ 8 hours, adds saturated sodium bicarbonate solution its pH value is transferred to 5.0-5.5.
After reaction is finished, be that the hydrochloric acid of 3N transfers to 2 with the pH value with equivalent concentration.With this mixed solution of ethyl acetate extraction,, residue is ground with ether the organic phase evaporation.So just obtain the free acid that 0.35 gram will prepare, its productive rate is 74.5%.
The gained free acid is converted into sodium salt by the method for implementing 1.
The table I
Test microorganism structure formula I Cephalexin Monohydrate Micro/Compacted cefuroxime cefoxitin
Compound (cefalexin) (cefuroxim) (cefoxitin)
Bacterium bronchisepticus 12.5 500 500 100
Dust Xi Shi intestinal bacteria
K12 0.5 6.2 2 1.6
Dust Xi Shi intestinal bacteria
6R 25 15.6 4 1.6
Intestinal bacteria
Poliresistens 100 500 250 100
Staphylococcus aureus
SMITH 0.06 0.8 0.8 1.2
Staphylococcus epidermidis
ATCC
I-12228 0.03 0.8 0.8 0.6
Intestinal bacteria R-222 0.5 6.2 4 3.1
Intestinal bacteria R-15 1.6 6.2 4 3.1
Klebsiella
ATCC10.031 0.16 6.2 0.08 12.5
Proteus vulgaris XL 100 500 62.5 3.1
Pseudomonas aeruginosa
NTCT10.490 100 500 500 100
Salmonella
Typhoid fever bacterium 0.5 6.2 4 3.1
Bacillus subtilus
ATCC6633 0.015 0.3 0.1 0.1
Staphylococcus aureus 1,110 1.25 62.5 125 25
Staphylococcus aureus 53 0.25 2.5 1.6 12.5
Ight soil staphylococcus 50 250 500 100
Staphylococcus
haemoliticus
pneumo 0.03 0.31 0.008 0.6
Staphylococcus
haemoliticus
A118 0.06 0.31 - 0.3
Staphylococcus
haemoliticus
Robb 0.03 1.25 0.003 1.2
The table II
The activeconstituents absorptive index
Staphylococcus aureus SM ITH salmonella typhosa Bacillus proteus XL
The compound 20 1-2 1-2 of structure formula I
Cefuroxime 30 0.001 4
Cefoxitin 7-8 0.001/
Cefadole (cefamandol) 5 20/
Cephalexin Monohydrate Micro/Compacted 1 1/
Cefotaxime (cefotaxim) 0.001 0.001 0.001

Claims (2)

1, the preparation method who has acceptable salt on 7-(3-chlorine-isoxazole-5-base)-acetylaminohydroxyphenylarsonic acid 3-(1-methyl isophthalic acid H-1,2,3, the 4-tetrazolium-5-yl)-thiomethyl-cephalo-3-alkene-4-carboxylic acid of structure formula I and the pharmacology thereof,
Figure 86104805_IMG2
(Ⅰ)
This method comprises:
(a) will have the structure formula II
Figure 86104805_IMG3
(Ⅱ)
3-chlorine-isoxazole-acetate or its reactive derivative with have a structure formula III
Figure 86104805_IMG4
(Ⅲ)
7-amino-3-(1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-yl)-thiomethyl-cephalo-3-alkene-4-carboxylic acid reaction, from reaction mixture, isolate 7-(3-chlorine-isoxazole-5-base)-acetylaminohydroxyphenylarsonic acid 3-(1-methyl isophthalic acid H-1 with known method again with structure formula I, 2,3,4-tetrazolium-5-yl)-thiomethyl-cephalo-3-alkene-4-carboxylic acid, if desired, can adopt known method to be translated into acceptable salt on its pharmacology, from reaction mixture, isolate this salt by known method again, perhaps
(b) will have the structure formula IV
(Ⅳ)
1-methyl isophthalic acid H-1,2,3,4-tetrazolium-5-base-mercaptan and 7-(3-chlorine-isoxazole-5-bases)-acetylaminohydroxyphenylarsonic acid cephalosporinic acid reaction is isolated 7-(3-chlorine-isoxazole-5-bases)-acetylaminohydroxyphenylarsonic acid 3-(the 1-methyl isophthalic acid H-1 of structural formula for (I) with known method again, 2,3,4-tetrazolium-5-yl)-thiomethyl-cephalo-3-alkene-4-carboxylic acid, if desired, can adopt known method to be translated into acceptable salt on its pharmacology, isolate this salt by known method again.
2, according to the preparation method of claim 1 method (a), wherein structural formula is its muriate or five chlorophenyl ester for the reactive derivative of the 3-chlorine-isoxazoles-acetate of (II).
CN86104805A 1985-07-16 1986-07-16 Ceph-3-ene-4-carboxylic acid derivatives and the prepn. Expired CN1012614B (en)

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HU852725A HU203243B (en) 1985-07-16 1985-07-16 Process for producing cefalosporin derivative

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FI83877C (en) 1991-09-10
IT1196494B (en) 1988-11-16
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FI862965A (en) 1987-01-17
NL8601842A (en) 1987-02-16
GB2177696B (en) 1989-01-05
CN86104805A (en) 1987-02-18
HU203243B (en) 1991-06-28
KR930007263B1 (en) 1993-08-04
GR861855B (en) 1986-11-18
FI83877B (en) 1991-05-31
FI862965A0 (en) 1986-07-16
ATA192686A (en) 1989-07-15
IL79410A0 (en) 1986-10-31
IT8621135A0 (en) 1986-07-15
HUT48890A (en) 1989-07-28
FR2591598B1 (en) 1990-01-26
DE3623900A1 (en) 1987-01-29
JPS6222787A (en) 1987-01-30
FR2591598A1 (en) 1987-06-19
GB2177696A (en) 1987-01-28
GB8617181D0 (en) 1986-08-20
KR870001219A (en) 1987-03-12

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