CN116284051A - Cefodinic acid derivative and preparation method and application thereof - Google Patents
Cefodinic acid derivative and preparation method and application thereof Download PDFInfo
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- CN116284051A CN116284051A CN202310253944.9A CN202310253944A CN116284051A CN 116284051 A CN116284051 A CN 116284051A CN 202310253944 A CN202310253944 A CN 202310253944A CN 116284051 A CN116284051 A CN 116284051A
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- cefdinir
- acid derivative
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- 239000002253 acid Substances 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 claims abstract description 104
- 229960003719 cefdinir Drugs 0.000 claims abstract description 103
- 239000003814 drug Substances 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- 241000193996 Streptococcus pyogenes Species 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 7
- 241000191967 Staphylococcus aureus Species 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 241000588724 Escherichia coli Species 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 241000894006 Bacteria Species 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 10
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
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- 239000003960 organic solvent Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
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- 238000002474 experimental method Methods 0.000 description 6
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- 239000000126 substance Substances 0.000 description 3
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- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
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- 229930186147 Cephalosporin Natural products 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
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- 239000012895 dilution Substances 0.000 description 2
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- 125000005313 fatty acid group Chemical group 0.000 description 2
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- 229960001008 heparin sodium Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229940124588 oral cephalosporin Drugs 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
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- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- NGGGZUAEOKRHMA-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxy]-3-oxopropanoic acid Chemical compound CC(C)(C)OC(=O)CC(O)=O NGGGZUAEOKRHMA-UHFFFAOYSA-N 0.000 description 1
- XUSNPFGLKGCWGN-UHFFFAOYSA-N 3-[4-(3-aminopropyl)piperazin-1-yl]propan-1-amine Chemical compound NCCCN1CCN(CCCN)CC1 XUSNPFGLKGCWGN-UHFFFAOYSA-N 0.000 description 1
- 206010001076 Acute sinusitis Diseases 0.000 description 1
- 241001619326 Cephalosporium Species 0.000 description 1
- 208000037041 Community-Acquired Infections Diseases 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 241000588655 Moraxella catarrhalis Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 201000008837 acute maxillary sinusitis Diseases 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
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- 238000012258 culturing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
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- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
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- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 235000020030 perry Nutrition 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
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- 230000002035 prolonged effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 241000894007 species Species 0.000 description 1
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- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
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- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Images
Classifications
-
- 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
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
-
- 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
- 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
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to a cefdinir acid derivative and a preparation method and application thereof. The derivative has better antibacterial activity, obviously prolongs the half life of the medicine, realizes the super-long-acting of the medicine, improves the bioavailability of the medicine, and can reduce the administration frequency of the medicine. In addition, the preparation method of the compound disclosed by the invention is low in cost, simple in steps, mild in reaction condition, green and environment-friendly, does not involve heating or ultralow-temperature reaction, has higher yield and purity of the obtained product, and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of biological medicine. More particularly, relates to a cefdinir acid derivative and a preparation method and application thereof.
Background
Cefdinir was classified as an advanced broad-spectrum or third generation oral cephalosporin antibacterial drug (Guay D.R. Cefedinir: an advanced-generation, broad-spectrum oral cephalosporin [ J ]. Clinical Therapeutics 2002,24 (4): 473-489.), first synthesized in 1988, and later approved by the U.S. Food and Drug Administration (FDA) in 1997 for the treatment of community-acquired infections (Perry C.M. and Scott L.J. Cefdinir: a review of its use in the management of mild-to-moderate bacterial infections [ J ]. Drugs 2004, 64:1433-1464.). Cefdinir is an oral broad spectrum cephalosporin with broad spectrum activity against many gram negative and positive aerobic bacteria including streptococcus pneumoniae, staphylococcus aureus, streptococcus pyogenes, haemophilus influenzae and moraxella catarrhalis. It is approved for the treatment of acute bacterial exacerbations of community-acquired pneumonia, chronic bronchitis, acute chronic bronchitis, sinusitis, acute maxillary sinusitis, pharyngitis/tonsillitis, acute bacterial otitis media and skin structure infections in uncomplicated skin and adult patients (Marchese a., savrino d., debbaia e.a., pesce a. And Schito g.c. anti-bacterial activity of cefdinir, a new oral thin-generation cephalosporin, alone and in combination with other antibiotics, at supra-and sub-MIC levels [ J ]. The Journal of Antimicrobial chemotherapy.1995,35 (1): 53-66; perry c.m. and Scott l.j. Cefdinir: a review of its use in the management of mild-to-moderate bacterial infections [ J ]. Drugs.2004,64:1433-1464 ].
However, in practical applications, it was found that the absolute oral bioavailability of cefdinir is only 21-25% (Perry C.M. and Scott L.J. Cefdinir: a review of its use in the management of mild-to-moderate bacterial infections [ J ]. Drug.2004, 64:1433-1464.), probably because cefdinir is rapidly absorbed from the gastrointestinal tract and is eliminated mainly by renal clearance of the original drug, the final treatment half-life is only 1.5 hours, greatly affecting the bioavailability of cefdinir in the organism. Thus, achieving longer half-life, reduced frequency of administration, improved bioavailability remains a technical problem that those skilled in the art are pressing to address.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings of short half-life and low bioavailability of the existing cefdinir, and provides the cefdinir acid derivative which has longer half-life, reduces the administration frequency and improves the bioavailability.
The invention aims to provide a preparation method of the cefdinir acid derivative.
The invention also aims to provide application of the cefdinir acid derivative in preparation of antibacterial drugs.
The above object of the present invention is achieved by the following technical scheme:
a cefdinir acid derivative having the structure of formula (I):
wherein n is an integer of 0 to 17.
Preferably, n is an integer of 1 to 15. More preferably, n is an integer of 1 to 5.
During research and application of drugs, factors that affect the action of the drug or affect the application of the drug often appear. Such as poor bioavailability due to poor pharmacokinetic properties, or excessive or slow metabolism due to chemical structure. In order to solve the problems, the invention changes the structure of some functional groups in cefdinir on the basis of retaining the original basic chemical structure of the medicine, develops a site-specific side chain modification technology, breaks through an ultra-long-acting medicine molecule modification technology, greatly prolongs the half life of the synthesized compound, and realizes the ultra-long-acting of the medicine on the premise of ensuring the medicine effect. The medicine has the advantages of prolonging the acting time of the medicine, mainly slowing down the metabolism speed and excretion speed of the medicine, prolonging the half life of the medicine, increasing the residence time of the medicine in tissues, and bringing great convenience to the medicine treatment of patients needing to take medicine for a long time or patients with difficult medicine taking and chronic patients.
In addition, the invention also provides a preparation method of the cefdinir acid derivative, and the synthetic route is as follows:
the method specifically comprises the following steps:
s1, carrying out acyl chlorination reaction on a compound a, and then carrying out substitution reaction on the compound a and a compound b to obtain a compound c;
s2, removing tert-butyl ester from the compound c obtained in the step S1, and purifying to obtain a compound of the formula (I);
wherein n is defined as defined above.
Further, in step S1, the acyl chloride reagent of the acyl chloride reaction is selected from one of oxalyl chloride, thionyl chloride, phosphorus pentachloride, oxalyl chloride, thionyl chloride, phosphorus trichloride, and sulfonyl chloride.
Preferably, the molar ratio of compound a to the acid chloride reagent is 1: (1.01-1.5).
Further, in step S1, the acid chloride reaction is performed under an inert gas atmosphere.
Specifically, in step S1, the step of the acyl chlorination reaction is as follows: adding a compound a and an organic solvent into a reaction container, cooling to 0-5 ℃ under stirring, dropwise adding excessive acyl chloride reagent, simultaneously adding DMF under nitrogen protection, controlling the system to react at 25-35 ℃ after the addition, removing the first organic solvent and the excessive acyl chloride reagent under vacuum after the reaction, and dissolving with the first organic solvent for subsequent reaction.
Preferably, the organic solvent is selected from one or more of dichloromethane, chloroform or tetrahydrofuran.
Further, in step S1, the substitution reaction is performed in the presence of a catalyst and an organic base. Preferably, the organic base is selected from one or more of triethylamine, tributylamine, diethylamine, diisopropylethylamine and pyridine. Preferably, the catalyst is DMAP or DBU.
Further, in the step S1, the temperature of the substitution reaction is 25 to 35 ℃.
Preferably, in step S1, the substitution reaction is performed in the presence of an organic solvent selected from one or more of dichloromethane, chloroform, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, 2-methyltetrahydrofuran.
Preferably, in step S1, the molar ratio of the organic base to the compound b is (1 to 3): 1.
in step S1, after the substitution reaction is completed, the solution is diluted with ethyl acetate, washed with saturated saline and water, dried and subjected to silica gel column chromatography, and the volume ratio of methyl chloride to methanol is 10-3: 1 gradient elution.
Further, in step S2, the t-butyl-removing reaction is performed in the presence of an inorganic base. Preferably, the inorganic base is selected from one or more of sodium hydroxide, calcium hydroxide, aluminum hydroxide, sodium carbonate and sodium bicarbonate.
Preferably, the tert-butyl ester removal reaction is carried out in the presence of an organic solvent, wherein the organic solvent is composed of water, methanol and THF according to the volume ratio of 1 (1-1.2).
Preferably, in step S2, the molar ratio of the inorganic base to the compound b in step S1 is (2 to 3): 1.
in addition, the invention also claims the application of the cefdinir acid derivative in preparing antibacterial drugs.
Further, the bacteria include staphylococcus aureus, escherichia coli, streptococcus pyogenes and klebsiella pneumoniae.
Further, the medicament is in the form of oral administration, injection or spray.
The invention has the following beneficial effects:
the cefdinir acid derivative provided by the invention has good antibacterial activity, meanwhile, the half life of the medicine is obviously prolonged, the super-long-acting of the medicine is realized, the bioavailability of the medicine is improved, and the administration frequency of the medicine can be reduced. In addition, the preparation method of the compound disclosed by the invention is low in cost, simple in steps, mild in reaction condition, green and environment-friendly, does not involve heating or ultralow-temperature reaction, has higher yield and purity of the obtained product, and is suitable for large-scale production.
Drawings
FIG. 1 is an HPLC chromatogram of cefdinir acid derivative 1 in example 1 of the present invention.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
EXAMPLE 1 preparation of cefdinir acid derivative 1
The preparation of the cefdinir acid derivative 1 specifically comprises the following steps:
s1, preparing acyl chloride: 0.192g of compound a (mono-tert-butyl malonate) (1.2 mmol) and 5mL of dichloromethane were added to a 15mL reaction tube at 0℃under the protection of nitrogen, oxalyl chloride (1.2 mmol) was added thereto, a drop of DMF was added dropwise thereto, the mixture was stirred at room temperature for reaction for 4 hours, and then the mixture was dried by spinning, after removing the solvent and unreacted oxalyl chloride, 2mL of DCM was added again for dissolution to obtain a reaction solution A;
s2, preparation of a tert-butyl ester protected cefdinir acid derivative: cefdinir (0.3995 g,1 mmol) is dissolved in 5mL of DCM, 3.0mmol of triethylamine and 0.1mmol of DMAP are added to the solution to obtain a reaction solution B, the solution B is vigorously stirred and cooled to 0 ℃, the reaction solution A obtained in the step S1 is slowly dripped into the reaction solution B (about 10 minutes of the dripping process), reflux reaction is carried out for 4 to 6 hours, after TLC detection reaction is completed, the solution is cooled to room temperature, and 1mL of water is added for quenching reaction; 10mL of ethyl acetate is added for dilution, 10mL of saturated saline and 10mL of water are respectively used for washing, the organic phase is dried and then is subjected to silica gel column chromatography, and the volume ratio of dichloromethane to methanol is 10-3: 1, performing gradient elution to obtain a tert-butyl protected cefdinir acid derivative;
s3, adding the tert-butyl ester protected cefdinir acid derivative (1 mmol) obtained in the step S2 into a solution (15 ml) of NaOH (2 mmol) in water/methanol/THF (V: V: 1), stirring at room temperature for reaction overnight, removing methanol and THF by rotary evaporation, adding dilute hydrochloric acid (5%) to adjust the pH of the solution to 3-4 (in the actual operation process, slowly dropwise adding excessive hydrochloric acid and hydroxylamine while stirring to prevent hydrochloride from being formed, adding triethylamine to adjust if the hydrochloric acid is excessively added), separating out solids, adding ethyl acetate for extraction, drying an organic phase, removing a solvent to obtain white solid d (yield 75%, purity is 99.8%), and directly filtering to obtain a solid substance after solid separation.
Product structure confirmation:
the white solid obtained in step S3 was identified by LC-MS using 5% MeOH/H 2 O was used as an initial, gradient (5%/min rate of MeOH increase) at a flow rate of 0.6mL/min, elution analysis for 15 min, results see FIG. 1; is identified as cefdinir acid derivative 1, [ M+H ]] + Calculated as 481.45, [ M+H ]] + The actual measurement value was 481.52.
EXAMPLE 2 preparation of cefdinir acid derivatives 2-6
Referring to the preparation method of example 1, the cefdinir acid derivatives 2 to 6 were prepared by substituting the structure of compound a therein, see specifically table 1.
TABLE 1 Cefodinitrile acid derivatives
EXAMPLE 3 determination of in vitro antimicrobial Activity of cefdinir acid derivatives
1. The experimental method comprises the following steps:
(1) Determination of MIC by agar plate dilution method: preparing cefdinir and cefdinir acid derivative with sterilized water for injection, diluting to 12 concentrations, and refining1mL of cefdinir and the cefdinir acid derivative with different concentrations are measured and uniformly mixed with 14mL of Mueller-Hinton agar culture medium in a 9cm culture dish, so that the final dilution concentrations of the cefdinir and the cefdinir acid derivative are 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625 and 0.0313mg/L respectively; inoculating test bacteria (staphylococcus aureus and escherichia coli) on a medicine-containing culture dish by using a multipoint inoculating instrument, simultaneously setting a medicine-free culture dish as a control, culturing for 24 hours at 37 ℃ to obtain the MIC of the lowest concentration of the medicine inhibiting the bacterial growth, and simultaneously calculating the MIC of cefdinir and the cefdinir acid derivatives 1-6 of the invention R 、MIC 90 。
(2) Test tube dilution method for determining antibacterial effect of cefdinir and cefdinir alkanoic acid derivative on streptococcus pyogenes and klebsiella pneumoniae: the antibacterial effect of cefdinir and the cefdinir acid derivative 4 on streptococcus pyogenes and klebsiella pneumoniae is measured by the agar plate dilution method according to the reference (1), wherein the growth environment and the observation mode of the bacterial liquid are changed according to the growth conditions of different bacterial species, and the culture time is 24-48 hours.
2. Experimental results:
TABLE 2 antibacterial Activity against Staphylococcus aureus, escherichia coli
As can be seen from the Table, in MIC experiments of Staphylococcus aureus and Escherichia coli, MIC of cefdinir acid derivatives 1, 2, 3, 4 90 Are all equivalent to cefdinir, and MIC of the cefdinir acid derivatives 5 and 6 90 Are slightly larger than cefdinir. This phenomenon may occur because the cefdinir acid derivative 1, 2, 3, 4 (when n.ltoreq.5 in the structural formula of the cefdinir acid derivative) has an increased fatty chain relative to cefdinir, but it does not affect the drugThe effective mass plays a role; whereas the longer fatty chains of the cefdinir acid derivatives 5, 6 (where n.gtoreq.6 in the formula) alter the dipole moment of the drug molecule, weakening the interaction between the compound and the bioreceptor molecule and thus leading to MIC 90 And becomes larger.
TABLE 3 antibacterial Activity against Streptococcus pyogenes and Klebsiella pneumoniae
As can be seen from the table, in MIC experiments of Streptococcus pyogenes and Klebsiella pneumoniae, MIC of cefdinir acid derivative 4 90 Are all comparable to cefdinir.
The above results demonstrate that the cefdinir acid derivative has increased fatty chain relative to cefdinir in vitro against staphylococcus aureus, escherichia coli, streptococcus pyogenes and klebsiella pneumoniae, but still maintains good antibacterial activity.
EXAMPLE 4 half-life study of cefdinir acid derivative in single dose
The half-lives of cefdinir and the cefdinir acid derivative of the invention in a single administration were determined by oral and subcutaneous injection administration, respectively.
1. The experimental method comprises the following steps:
(1) 42 SPF-class SD rats, female, quality 220-240 g; rats were equally divided into 7 groups according to body weight: group A (cefdinir), group B (cefdinir acid derivative 1), group C (cefdinir acid derivative 2), group D (cefdinir acid derivative 3), group E (cefdinir acid derivative 4), group F (cefdinir acid derivative 5) and group G (cefdinir acid derivative 6), after 12 hours of fast, the cefdinir and the cefdinir acid derivatives 1-6 (cefdinir or cefdinir acid derivative are dissolved in normal saline) are injected subcutaneously respectively, 20mg/kg, and the administration dose is determined according to a predetermined experiment. And respectively taking 0.2mL of blood from tail vein before administration and 0.25, 0.5, 1, 1.5, 2, 3, 4,6, 12 and 24 hours after administration into a sterile heparin sodium anticoagulation tube, standing for 1 hour, centrifuging at 3000rpm for 10 minutes, and taking supernatant.
(2) 42 SPF-class SD rats, female, quality 220-240 g; rats were equally divided into 7 groups according to body weight: group A (cefdinir), group B (cefdinir acid derivative 1), group C (cefdinir acid derivative 2), group D (cefdinir acid derivative 3), group E (cefdinir acid derivative 4), group F (cefdinir acid derivative 5) and group G (cefdinir acid derivative 6), after 12 hours of fast, oral administration (stomach-filling) of cefdinir and cefdinir acid derivatives 1-6 (cefdinir or cefdinir acid derivative dissolved in physiological saline) respectively, 40mg/kg, the administration dose according to the equivalent dose of human body is determined according to the pre-experiment. And respectively taking 0.2mL of blood from tail vein before administration and 0.25, 0.5, 1, 1.5, 2, 3, 4,6, 12 and 24 hours after administration into a sterile heparin sodium anticoagulation tube, standing for 1 hour, centrifuging at 3000rpm for 10 minutes, and taking supernatant.
The content of cefdinir acid or a derivative of cefdinir acid in the obtained supernatant was determined, non-compartmental model fitting was performed using BAPP 2.0 software, and relevant pharmacokinetic parameters were automatically calculated from the obtained data, with the results being shown in table 4.
2. Experimental results:
TABLE 4 half-lives (t 1/2 (h); x+ -s, n=6) for different modes of administration for one dose
| Medicament | Oral administration (stomach-lavage) | Subcutaneous injection |
| Cefdinir | 0.54±0.04 | 0.34±0.09 |
| Cephalosporium (L.) kuntzeDi- |
0.64±0.08 | 0.53±0.10 |
| |
1.54±0.15 | 1.37±0.12 |
| |
2.84±0.15 | 2.18±0.22 |
| |
3.84±0.24 | 3.13±0.26 |
| |
3.41±0.57 | 3.07±0.32 |
| |
3.52±0.32 | 3.49±0.19 |
It can be seen from the table that the half-life of the cefdinir acid derivative, whether administered orally or subcutaneously, is increased to a different extent relative to cefdinir; in the orally administered group, the half-lives of cefdinir acid derivatives 4 (3.84 hours), 5 (3.41 hours), 6 (3.52 hours) could be up to 6.39, 6.31, 6.52 times that of cefdinir (0.54 hours), respectively; in the subcutaneous injection group, the half-lives of cefdinir acid derivatives 4 (3.13 hours), 5 (3.07 hours), 6 (3.49 hours) were able to reach 9.21, 9.03, 10.26 times that of cefdinir (0.34 hours), respectively. The half-life values show a rule that the half-life values are not significantly different among the cefdinir acid derivatives 4/5/6> 3> 2> 1, and 4, 5, 6.
The experimental results were analyzed, probably because the half-life of the cefdinir acid derivative of the invention can be significantly improved by increasing the fatty acid side chain when the fatty acid side chain is shorter; when the length of the side chain of the fat is increased to a certain length, the length of the side chain of the fat (when n is more than 5 in the structural formula of the cefdinir acid derivative) is continuously increased, and the half life of the cefdinir acid derivative is not obviously influenced.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (10)
1. A cefdinir acid derivative characterized by having the structure of formula (I):
wherein n is an integer of 0 to 17.
2. The cefdinir acid derivative according to claim 1 wherein n is an integer from 1 to 15.
3. The cefdinir acid derivative according to claim 2 wherein n is an integer from 1 to 5.
4. A process for the preparation of a cefdinir acid derivative according to any one of claims 1 to 3, characterized by the following synthetic route:
the method specifically comprises the following steps:
s1, carrying out acyl chlorination reaction on a compound a, and then carrying out substitution reaction on the compound a and a compound b to obtain a compound c;
s2, removing tert-butyl ester from the compound c obtained in the step S1, and purifying to obtain a compound of the formula (I);
wherein n is as defined in any one of claims 1 to 3.
5. The method according to claim 4, wherein in step S1, the acid chloride reagent for the acid chloride reaction is selected from one of oxalyl chloride, thionyl chloride, phosphorus pentachloride, oxalyl chloride, thionyl chloride, phosphorus trichloride, and sulfuryl chloride.
6. The process according to claim 4, wherein in step S1, the substitution reaction is carried out in the presence of a catalyst and an organic base.
7. The process according to claim 4, wherein in step S2, the t-butyl-removing reaction is carried out in the presence of an inorganic base.
8. Use of a cefdinir acid derivative according to any one of claims 1-3 in the preparation of an antibacterial medicament.
9. The use according to claim 8, wherein the bacteria comprise staphylococcus aureus, escherichia coli, streptococcus pyogenes and klebsiella pneumoniae.
10. The use according to claim 8, wherein the medicament is in the form of an oral, injectable or spray formulation.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60105683A (en) * | 1983-11-14 | 1985-06-11 | Meiji Seika Kaisha Ltd | Novel cephem compound and production thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60105683A (en) * | 1983-11-14 | 1985-06-11 | Meiji Seika Kaisha Ltd | Novel cephem compound and production thereof |
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