CN109734723A - Ofloxacin thiazole analog and its preparation method and application - Google Patents
Ofloxacin thiazole analog and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to Ofloxacin thiazole analogs and its preparation method and application, belong to chemosynthesis technical field, Ofloxacin thiazole analog and its officinal salt are as shown in general formula I, such compound has certain inhibitory activity to gram-positive bacteria, Gram-negative bacteria and fungi, it can be used for preparing antibacterium and/or antifungal drug, to provide more drug candidates efficiently, safe for clinical antimicrobial treatment, facilitate the clinical treatments such as the drug resistance for solving the problems, such as to be on the rise, obstinate invasive organism and emerging harmful microorganism.It prepares that raw material is simple, and cheap and easy to get and synthetic route is short.
Description
Technical field
The invention belongs to chemosynthesis technical fields, and in particular to Ofloxacin thiazole analog and preparation method thereof and answer
With.
Background technique
Quinolone drugs is one of most important line antibacterials, has high oral administration biaavailability, good medicine
For kinetic characteristics and excellent curative effect, effective force of morbidity and mortality caused by combating microorganisms pathogen has been used as it
Device.Since the 1960s, acidum nalidixicum was found, four generation quinolone drugs are successfully developed.To their work
Show that this kind of drug can target DNA gyrase and topoisomerase I V with Mechanism Study, to interfere the duplication of DNA, finally
Lead to bacterial cell death.However, due in clinical treatment excessively using even this kind of drug is abused, so that pathogenic bacteria is resistance to
Pharmacological property becomes increasingly severe, and gastroenteritis, and some side effects such as vomiting and cartilage damage also gradually appear, this is strong to the mankind
Health brings huge challenge, emphasizes to highlight exploitation more effectively with bigger potentiality, can effectively overcome side effect and resistance to
The pressing needs of the novel carbostyril derivatives of pharmacological property.Ofloxacin is as one of most common fluoroquinolones, at present
Being widely used in treatment includes pneumonia, urinary tract infections, including prostatitis and certain form of infectious diarrhea
A variety of diseases.Research is it has been shown that the carboxyl and carbonyl of Ofloxacin are the important originals for causing drug-resistant bacteria and multiple side effect
Cause, therefore will have very important significance to the modification of its carboxyl.
Azole is a kind of Five-membered Heterocyclic Compounds, is played an important role in field of medicinal chemistry, especially in azoles
In terms of class antibacterials.After azole is introduced quinolone, it was found that largely based on the azole derivative of quinolone, such compound
Not only with very strong bioactivity but also with high security.Thiazolamine is used as most representative azole compounds,
Since its unique structure contains nitrogen and sulphur atom, this makes its derivative have the function of good binding ability and its target spot phase
In conjunction with, thus such segment is widely used in the modification and research and development of drug by medical chemistry man.By weakly alkaline thiazolamine piece
Section and Ofloxacin heterozygosis, replace its weakly acidic carboxyl, will be expected to effectively overcome the side effect and drug resistance of Ofloxacin, from
And develop the broad spectrum antibiotic of the high activity of a series of new.
Summary of the invention
In view of this, one of the objects of the present invention is to provide Ofloxacin thiazole analog and its officinal salts；Purpose
Two be to provide the preparation method of Ofloxacin thiazole analog and its officinal salt；The third purpose is to provide Ofloxacin
The application of thiazole analog and its officinal salt in preparation antibacterium and/or antifungal drug；
In order to achieve the above objectives, the invention provides the following technical scheme:
1, Ofloxacin thiazole analog and its officinal salt, structure is as shown in general formula I:
In formula:
R1For amino, diazanyl, hydroxyl diazanyl, alcoxyl diazanyl, alkyl, benzal diazanyl, alkyl hydrazine base, benzene sulfonyl diazanyl or naphthalene
Acid imide；
R2, R3For hydrogen, trifluoromethyl, cyano, nitro, chlorine, fluorine, pyrrolidinyl, morpholinyl, piperazinyl or hexahydropyridine base,
The pyrrolidinyl, morpholinyl, piperazinyl or hexahydropyridine base contain one or more substituent groups.
Preferably,
R1For amino, alkyl, benzal diazanyl, alkyl hydrazine base, benzene sulfonyl diazanyl or naphthalimide；
R2, R3For hydrogen, trifluoromethyl, chlorine, fluorine, pyrrolidinyl, morpholinyl, piperazinyl or hexahydropyridine base.
Preferably, it is any one of following compounds:
Preferably, the officinal salt is hydrochloride, nitrate or acetate.
2, the preparation method of the Ofloxacin thiazole analog and its officinal salt, the method includes walking as follows
It is rapid:
A, it the preparation of intermediate II: using triethyl orthoformate as starting material, is obtained after nucleophilic displacement of fluorine, cyclisation corresponding
3- acetyl group quinolone intermediates, the 3- acetyl group quinolone intermediates again with bromoethanol through N- alkylated reaction closed loop,
Up to intermediate II -1 and II-2；
B, the preparation of intermediate III: being respectively starting material with intermediate II -1 and II-2, using glacial acetic acid as solvent, warp
Bromination is to get intermediate III -1, III-2 and III-3；
C, the preparation of Ofloxacin thiazole analog shown in general formula I: intermediate III being dissolved in solvent, is reacted with thiocarbamide,
Up to Ofloxacin thiazole analog shown in general formula I；
D, the preparation of the officinal salt of Ofloxacin thiazole analog shown in general formula I: by Ofloxacin thiazole shown in general formula I
Analog is dissolved in organic solvent, and pharmaceutically acceptable acid is added under agitation, reacts 8-12h to get Ofloxacin shown in general formula I
The officinal salt of thiazole analog.
Preferably,
In step a, alkali used in the N- alkylated reaction is potassium carbonate, and corresponding 3- acetyl is obtained after the cyclisation
The molar ratio of base quinolone intermediates and alkali is 1:1.2-1.5；
In step b, the temperature when bromination is 40-60 DEG C；
In step c, the solvent is dehydrated alcohol, and the temperature when thiocarbamide reacts is 70-80 DEG C；
In step d, the organic solvent is one of ethyl alcohol, ether, tetrahydrofuran or chloroform or a variety of mixed
Bonding solvent；The pharmaceutically acceptable acid is one of hydrochloric acid, nitric acid or acetic acid.
3, the Ofloxacin thiazole analog and its officinal salt are in preparation antibacterium and/or antifungal drug
Using.
Preferably, the bacterium is staphylococcus aureus, methicillin-resistant staphylococcus aureus, Krebs pneumonia
At least one of bacillus, Escherichia coli, enterococcus faecalis, Acinetobacter bauamnnii or pseudomonas aeruginosa；The fungi is the torrid zone
At least one of candidiasis, aspergillus fumigatus, Candida albicans or Candida parapsilosis bacterium.
The beneficial effects of the present invention are: the present invention designs principle of hybridization using drug, introduces in the position C-6 of Ofloxacin
Bioactive fragment aminothiazole, and a series of structure novels have been synthesized by the different modifying design to amino on thiazole ring
Ofloxacin thiazole analog, these compounds are through in vitro anti-microbial activity detection discovery to gram-positive bacteria (resistance to methoxy
XiLin staphylococcus aureus, enterococcus faecalis, staphylococcus aureus, staphylococcus aureus ATCC25923, golden yellow grape
Coccus ATCC29213), Gram-negative bacteria (K. pneumonia, Escherichia coli, pseudomonas aeruginosa, P. aeruginosa
Bacterium ATCC27853, Escherichia coli ATCC25922, Acinetobacter bauamnnii) and fungi (Candida albicans, Candida tropicalis,
Aspergillus fumigatus, Candida albicans ATCC90023, Candida parapsilosis bacterium ATCC20019) there is certain inhibitory activity, it can be with
It is used to prepare antibacterium and/or antifungal drug, to provide more candidate medicines efficiently, safe for clinical antimicrobial treatment
Object facilitates the clinics such as the drug resistance for solving to be on the rise, obstinate invasive organism and emerging harmful microorganism
Treatment problem.It prepares that raw material is simple, and cheap and easy to get and synthetic route is short.
Specific embodiment
Below by a preferred embodiment of the present invention will be described in detail.
Embodiment 1
The preparation of intermediate II
Bibliography " Cui, S.F.；Addla,D.；Zhou,C.H.Novel 3aminothiazolquinolones:
Design,synthesis,bioactive evaluation,SARs,and preliminary antibacterial
Mechanism.J.Med.Chem.2016,59,4488-4510. " and " Cheng, Y.；Avula,S.R.；Gao,W.W.；
Addla,D.；Tangadanchu,V.K.R.；Zhang,L.；Lin,J.M.；Zhou,C.H.Multi-targeting
exploration of new 2-aminothiazolyl quinolones:Synthesis,antimicrobial
evaluation,interaction with DNA,combination with topoisomerase IV and
Method system disclosed in penetrability into cells.Eur.J.Med.Chem.2016,124,935-945. "
It is standby.
Embodiment 2
The preparation of intermediate III -1
Compound II-1 (0.4g, 1.619mmol) and glacial acetic acid (10mL) are added in 50mL round-bottomed flask, at 0 DEG C
Br is added2(0.125g, 2.429mmol) then keeps reaction mixture 12 hours at 60 DEG C.Thin-layer chromatography tracks to instead
It should terminate.Concentrated again, extraction, column chromatography for separation, recrystallization, drying etc. post-process up to compound III-1 (150mg), produce
Rate 28.62%；Brown ceramic powder；Fusing point: 242-244 DEG C；1H NMR(600MHz,DMSO-d6)δ8.67(s,1H,quinolone-
5-H), 7.50 (dd, J=9.1,2.0Hz, 1H, quinolone-10-H), 7.33 (dd, J=9.4,2.2Hz, 1H,
quinolone-8-H),4.91(s,2H,CH2Br),4.58–4.55(m,2H,OCH2),4.52–4.46(m,2H,NCH2)ppm。
Embodiment 3
The preparation of intermediate III -2
Compound II-1 (0.4g, 1.619mmol) and glacial acetic acid (10mL) are added in 50mL round-bottomed flask, at 0 DEG C
Br is added2(0.125g, 2.429mmol) then keeps reaction mixture 12 hours at 60 DEG C.Thin-layer chromatography tracks to instead
It should terminate.Concentrated again, extraction, column chromatography for separation, recrystallization, drying etc. post-process up to compound III-2 (100mg), produce
Rate 30.72%；Brown ceramic powder；Fusing point: 168-170 DEG C；1H NMR(600MHz,DMSO-d6)δ8.81(s,1H,quinolone-
5-H),7.84(s,1H,CHBr2), 7.53 (dd, J=9.0,2.7Hz, 1H, quinolone-10-H), 7.37 (dd, J=9.4,
2.7Hz,1H,quinolone-8-H),4.63–4.50(m,4H,O-CH2-CH2-N)ppm。
Embodiment 4
The preparation of intermediate III -3
Compound II-2 (1.4g, 5.322mmol) and glacial acetic acid (25mL) are added in 150mL round-bottomed flask, at 0 DEG C
Br is added2(3g, 15.967mmol) then keeps reaction mixture 12 hours at 60 DEG C.Thin-layer chromatography tracks to reaction
Terminate.Concentrated again, extraction, column chromatography for separation, recrystallization, drying etc. post-process up to compound III-3 (1g), yield
55%；Brown ceramic powder；Fusing point: 230-232 DEG C；1H NMR(600MHz,DMSO-d6)δ8.84(s,1H,quinolone-5-H),
7.83(s,1H,-CHBr2), 7.82 (d, J=8.7Hz, 1H, quinolone-8-H), 7.58 (d, J=8.7Hz, 1H,
quinolone-9-H),4.69–4.61(m,2H,O-CH2),4.57–4.50(m,2H,N-CH2)ppm。
Embodiment 5
The preparation of compound I-1
In 100mL round-bottomed flask, by compound III-1 (0.1g, 0.3077mmol), thiocarbamide (0.026g,
0.338mmol) with ethyl alcohol (30mL), 70 DEG C of temperature control are stirred to react 4h, are cooled to room temperature, and thin-layer chromatography, which tracks to reaction, to be terminated,
Concentrated again, extraction, column chromatography for separation, recrystallization, drying etc. post-process up to compound I-1 (20mg), yield 21.50%；
Yellow powder；Fusing point > 250 DEG C；1H NMR(600MHz,DMSO-d6)δ8.55(s,1H,quinolone-5-H),7.68(s,1H,
), thiazole-4-H 7.49 (dd, J=9.3,2.4Hz, 1H, quinolone-10-H), 7.20 (dd, J=9.3,2.2Hz,
1H,quinolone-8-H),6.91(s,2H,Thazole-NH2),4.55(s,2H,C2-OCH2), 4.43 (d, J=4.1Hz,
2H,C2-NCH2)ppm。
Embodiment 6
The preparation of compound I-2
In 100mL round-bottomed flask, by compound III-3 (1g, 2.3874mmol), thiocarbamide (0.181g,
2.3874mmol) with ethyl alcohol (30mL), 70 DEG C of temperature control are stirred to react 4h, are cooled to room temperature, and thin-layer chromatography, which tracks to reaction, to be terminated,
Concentrated again, extraction, column chromatography for separation, recrystallization, drying etc. post-process up to compound I-2 (0.467g), yield
61.20%；White powder；Fusing point > 250 DEG C；1H NMR(600MHz,DMSO-d6)δ8.55(s,1H,quinolone-5-H),
7.82 (d, J=8.8Hz, 1H, quinolone-8-H), 7.68 (s, 1H, thiazole-4-H), 7.40 (d, J=8.8Hz, 1H,
quinolone-9-H),6.93(s,2H,thiazole-2-NH2),4.65–4.54(m,2H,C2-OCH2),4.47–4.37(m,
2H,C3-NCH2)ppm。
Embodiment 7
The preparation of compound I-3
In 100mL round-bottomed flask, by compound I-1 (0.3g, 0.990mmol), 1-Boc- piperazine (0.6g,
2.976mmol) with DMSO (5mL), 80 DEG C of temperature control are stirred to react 12h, are cooled to room temperature, and thin-layer chromatography, which tracks to reaction, to be terminated,
Concentrated again, extraction, column chromatography for separation, recrystallization, drying etc. post-process up to compound I-3 (0.06g), yield 12.93%；
Yellow powder；176-178 DEG C of fusing point；1H NMR(600MHz,DMSO-d6)δ8.31(s,1H,quinolone-5-H),8.10(s,
1H, thiazole-4H), 7.43 (d, J=8.3Hz, 1H, quinolone-10-H), 7.21 (d, J=8.5Hz, 1H,
quinolone-8-H),6.72(s,2H,thiazole-2-NH2),4.56–4.51(m,2H,C2-OCH2),4.36(s,2H,C3-
NCH2),3.39(s,2H,piperidine-CH2),3.26(s,2H,piperidine-CH2),2.28(s,4H,
piperidine-2CH2),1.37(s,9H,N-Boc-3CH3)ppm。
Embodiment 8
The preparation of compound I-4
In 100mL round-bottomed flask, by compound III-1 (0.25g, 0.769mmol), the thio first of 2- acetyl hydrazine -1-
Amide (0.102g, 0.769mmol) and ethyl alcohol (5mL), 80 DEG C of temperature control are stirred to react 3h, are cooled to room temperature, thin-layer chromatography tracking
Terminate to reaction, then concentrated, extraction, column chromatography for separation, recrystallization, drying etc. post-process up to compound I-4 (0.06g),
Yield 21.73%；Yellow powder；Fusing point > 250 DEG C；1H NMR(600MHz,DMSO-d6)δ10.16(s,1H,CO-NH),9.27
(s,1H,thiazole-2-NH),8.57(s,1H,quinolone-5-H),7.84(s,1H,thiazole-4-H),7.50
(dd, J=9.3,2.6Hz, 1H, quinolone-10-H), 7.22 (dd, J=9.4,2.7Hz, 1H, quinolone-8-H),
4.63–4.52(m,2H,C2OCH2),4.49–4.39(m,2H,C3-NCH2),1.92(s,3H,-CH3)ppm。
Embodiment 9
The preparation of compound I-5
In 100mL round-bottomed flask, by compound III-1 (0.15g, 0.461mmol), (E/Z) -2- benzal hydrazine -1-
Thioformamide (0.082g, 0.461mmol) and ethyl alcohol (10mL), 70 DEG C of temperature control are stirred to react 3h, are cooled to room temperature, thin layer color
Spectrum, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, recrystallization, drying etc. post-process up to compound I-5
(0.09g), yield 48.12%；Yellow powder；Fusing point > 250 DEG C；1H NMR(600MHz,DMSO-d6)δ12.06(s,1H,
thiazole-2-NH),8.59(s,1H,quionolone-5-H),8.08(s,1H,imine-CH),7.91(s,1H,
), thiazole-4-H 7.67 (d, J=7.7Hz, 2H, phenyl-2,6-H), 7.52 (dd, J=9.2,2.0Hz, 1H,
), quinolone-10-H 7.44 (t, J=7.4Hz, 2H, phenyl-3,5-H), 7.39 (t, J=7.1Hz, 1H,
), quinolone-8-H 7.26-7.20 (m, 1H, phenyl-4-H), 4.57 (d, J=4.4Hz, 2H, C2-OCH2),4.46(d,
J=4.3Hz, 2H, C3-NCH2)ppm。
Embodiment 10
The preparation of compound I-6
In 100mL round-bottomed flask, by compound III-1 (0.5g, 1.5389mmol), the thio first of 2- benzene sulfonyl hydrazide -1-
Amide (0.37g, 1.5389 4mmol) and ethyl alcohol (10mL), 70 DEG C of temperature control are stirred to react 3h, are cooled to room temperature, thin-layer chromatography with
Track to reaction terminates, then concentrated, extraction, column chromatography for separation, recrystallization, drying etc. post-process up to compound I-6
(0.35g), yield 49.17%；Yellow powder；Fusing point > 250 DEG C；1H NMR(600MHz,DMSO-d6)δ10.27(s,1H,SO2-
NH),9.73(s,1H,thiazole-NH),8.55(s,1H,quinolone-5-H),7.80(s,1H,thiazole-4-H),
7.76 (d, J=7.6Hz, 2H, phenyl 2-H, 6-H), 7.50 (d, J=9.0Hz, 1H, quinolone-10-H), 7.44 (d,
J=7.8Hz, 2H, phenyl 3-H, 5-H), 7.24 (d, J=9.2Hz, 1H, quinolone-8-H), 4.56 (s, 2H, C2-
OCH2),4.43(s,2H,C3-NCH2),2.40(s,3H,-CH3)。
Embodiment 11
The preparation of compound I-7
In 100mL round-bottomed flask, by compound III-1 (0.25g, 0.769mmol), 1- (bromo- 1, the 3- dioxo-of 6-
1H- benzisoquinoline -2 (3H)-yl) thiocarbamide (0.267g, 0.767mmol) and ethyl alcohol (10mL), 80 DEG C of temperature control are stirred to react 4h,
It is cooled to room temperature, thin-layer chromatography, which tracks to reaction, to be terminated, then the rear place such as concentrated, extraction, column chromatography for separation, recrystallization, drying
It manages up to compound I-7 (44mg), yield 10.0%；Yellow powder；Fusing point > 250 DEG C；1H NMR(600MHz,DMSO-d6)δ
10.35 (s, 1H, thiazole-NH), 8.71-8.65 (m, 2H, naphthalene-4,9-H), 8.46 (d, J=7.8Hz, 1H,
naphthalene-7-H),8.35(s,1H,quinolone-5-H),8.33–8.29(m,1H,naphthalene-8-H),
8.08 (dd, J=8.4,7.4Hz, 1H, naphthalene-5-H), 7.97 (s, 1H, thiazole-4-H), 7.48 (dd, J=
9.4,2.8Hz, 1H, quinolone-10-H), 7.19 (dd, J=9.4,2.8Hz, 1H, quinolone-8-H), 4.46-4.43
(m,2H,C2-OCH2),4.28–4.25(m,2H,C3-NCH2)ppm。
Embodiment 12
The in vitro anti-microbial activity of Ofloxacin thiazole analog
Using clinical trial standard (the Clinical and Laboratory for meeting United States National Committee's formulation
Standards Institute, CLSI) 96 hole micro-dilution methods, prepare in testing example 1 intermediate II -1 and II-2,
Ofloxacin thiazole analog made from III-1, III-2, the III-3 and embodiment 5-11 prepared in embodiment 2-4 is blue to leather
Family name's positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus, staphylococcus aureus
ATCC25923, staphylococcus aureus ATCC29213), Gram-negative bacteria (K. pneumonia, Escherichia coli, copper
Green pseudomonad, pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter bauamnnii) and fungi (white thought
Pearl bacterium, Candida tropicalis, aspergillus fumigatus, Candida albicans ATCC90023, Candida parapsilosis bacterium ATCC20019)
Minimum inhibitory concentration (MIC) dissolves a small amount of dimethyl sulfoxide of untested compound, and adding water dilution and concentration is made is 1.28mg/
The solution of mL, then be diluted to 128 μ g/mL with culture solution, 35 DEG C culture 24-72 hours, will sufficiently be shaken on culture plate to oscillator
After even, MIC is measured at wavelength 490nm, the results are shown in Table 1-3.
The external anti-gram positive bacteria activity of the intermediate and Ofloxacin thiazole analog that are prepared in 1 embodiment 1-11 of table
Data (MIC, μ g/mL)
The external anti-gram-negative bacteria activity of the intermediate and Ofloxacin thiazole analog that are prepared in 2 embodiment 1-11 of table
Data (MIC, μ g/mL)
From table 1,2 as can be seen that the intermediate and Ofloxacin thiazole analog that prepare in embodiment 1-11, to being tested
Bacterium show certain inhibiting effect, wherein Ofloxacin thiazole analog I-1 is aobvious to staphylococcus aureus and MRSA
Preferable bioactivity is shown, MIC value is respectively 32 and 64 μ g/mL.Surprisingly intermediate ofloxacin analogue
III-2 and III-3 also shows higher antibacterial activity, especially prominent to the antibacterial activity of MRSA and Klebsiella Pneumoniae.Its
He also shows different degrees of antibacterial activity at part of compounds.
The extracorporeal antifungal activity data of the intermediate and Ofloxacin thiazole analog that are prepared in 3 embodiment 1-11 of table
(MIC, μ g/mL)
From table 3 it can be seen that the intermediate and Ofloxacin thiazole analog that are prepared in embodiment 1-11, to what is tested
Fungi shows certain inhibiting effect, and wherein Ofloxacin thiazole analog I-1 is to Candida albicans ATCC90023 and closely flat
The antibacterial MIC value of sliding candidiasis ATCC20019 is 64 μ g/mL.In addition, Ofloxacin thiazole analog I-6 is to the torrid zone
The bioactivity that candidiasis has also showed that, MIC value are 32 μ g/mL.Ofloxacin analogue moiety intermediate
There is a good antifungal activity, bioactivity can compare favourably or even stronger with reference drug Fluconazole.
Embodiment 12
The pharmaceutical applications of Ofloxacin thiazole analog
According to above-mentioned antimicrobial acivity testing result, Ofloxacin thiazole analog of the invention has preferable anti-thin
Antibacterium, antifungal drug can be made for clinical use in bacterium, antifungal activity.These drugs are either single preparations of ephedrine, example
Such as it is made of a kind of Ofloxacin thiazole analog of structure with pharmaceutically acceptable auxiliary material；It is also possible to compound preparation, example
Such as by a kind of Ofloxacin thiazole analog of structure and existing antibacterium, Active antifungal compound (such as sulfamethoxazole, fluorine health
Azoles, phosphorus Fluconazole, Itraconazole etc.) and pharmaceutically acceptable auxiliary material be made, or it is husky by several oxygen fluorine of different structure
Star thiazole analog is made with pharmaceutically acceptable auxiliary material.The preparation type includes but is not limited to tablet, capsule, dissipates
Agent, granule, pill, injection, powder-injection, solution, suspension, emulsion, suppository, ointment, gelling agent, film, gas
The dosage forms such as mist agent, percutaneous absorption patch and various slow-release controlled-release preparations and nanometer formulation.
1, the preparation of compound I-1 tablet
Prescription: compound I-1 10g, lactose 187g, cornstarch 50g, magnesium stearate 3.0g, concentration expressed in percentage by volume are
70% ethanol solution is appropriate, and 1000 are made altogether.
Preparation method: by cornstarch with 105 DEG C dry 5 hours it is spare；Compound I-1 is mixed with lactose, cornstarch
Even, with 70% ethanol solution softwood, be sieved wet granular processed, adds magnesium stearate, tabletting to get；Every slice weight 250mg,
Active component content is 10mg.
2, the preparation of compound I-1 capsule
Prescription: compound I-1 25g, modified starch (120 mesh) 12.5g, microcrystalline cellulose (100 mesh) 7.5g, low substitution
Hydroxypropylcellulose (100 mesh) 2.5g, talcum powder (100 mesh) 2g, sweetener 1.25g, orange essence 0.25g, appropriate pigment, water are suitable
Amount, is made 1000.
Preparation method: after the compound I-1 of recipe quantity is ground into superfine powder, with the modified starch of recipe quantity, micro-
Crystalline cellulose, low-substituted hydroxypropyl cellulose, talcum powder, sweetener, orange essence and pigment mix, with water softwood, 12-14 mesh
Sieve granulation, 40-50 DEG C of dryings, be sieved whole grain, be packed into capsulae vacuus to get；Every slice weight 50mg, active component content 25mg.
3, the preparation of compound I-4 granule
Prescription: compound I-4 26g, dextrin 120g, sucrose 280g.
Preparation method: compound I-4, dextrin, sucrose being uniformly mixed, wet granulation, 60 DEG C of dryings, packing to get.
4, the preparation of compound I-4 injection
Prescription: 1000mL is made in compound I-4 10g, propylene glycol 500mL, water for injection 500mL altogether.
Preparation method: propylene glycol and injection water, stirring and dissolving Weigh Compound I-4, is added, adds 1g active carbon, sufficiently stirs
15 minutes are stood after mixing, with 5 μm of stud filtering decarbonizations, then the miillpore filter refined filtration for being successively 0.45 μm and 0.22 μm with aperture,
Last encapsulating in 10mL ampoule, 100 DEG C of circulation steam sterilizations 45 minutes to get.
5, the preparation of compound I-4 powder-injection
Preparation method: compound I-4 aseptic powdery aseptically dispense to get.
6, the preparation of compound I-6 eye drops
Prescription: compound I-6 3.78g, sodium chloride 0.9g, benzyl carbinol 3g, appropriate borate buffer solution, distilled water add to
1000mL。
Preparation method: Weigh Compound I-6, sodium chloride add in 500mL distilled water, with borate buffer solution tune after dissolution completely
PH to 6.5 is saved, adds distilled water to 1000mL, stirs evenly, filtering with microporous membrane is filling, sealing, 100 DEG C of circulation steam sterilizations 1
Hour to get.
7, the preparation of compound I-6 liniment
Prescription: compound I-6 4g, SOFT SOAP 7.5g, camphor 5g, distilled water add to 100mL.
Preparation method: the ethanol solution that camphor concentration expressed in percentage by volume is 95% is dissolved, spare；SOFT SOAP is heats liquefied,
Spare, potash fertilizer soap lye and camphor ethanol solution are added under constant stirring, then is gradually added into distilled water by Weigh Compound I-6, cream
Change completely after add distilled water to full dose to get.
8, the preparation of compound I-6 suppository
Prescription: compound I-6 4g, gelatin 14g, glycerol 70g, distilled water add to 100mL, and 100 pieces of metric system.
Preparation method: weighing gelatin and glycerol, adds distilled water to 100mL, and chemical combination is added when melting in the pasty state in 60 DEG C of heating of water-bath
Object I-6, stirs evenly, and when nearly solidification pours into vaginal plug mold, cooled and solidified to get.
9, the preparation of compound I-6 ointment
Prescription: 0.5-2g of compound I-6,6-8g of hexadecanol, 8-10g of albolene, 8-19g of atoleine, monoglyceride 2-
5g, 2-5g of polyoxyethylene (40) stearate, glycerol 5-10g, ethylparaben 0.1g, distilled water add to 100g.
Preparation method: hexadecanol, albolene, atoleine, monoglyceride and polyoxyethylene (40) stearate are heated complete
It is mixed after dissolving, keeps the temperature 80 DEG C, it is mutually spare as oil；It is molten by ethylparaben addition glycerol and distilled water, being heated to 85 DEG C
Solution, then oily phase is added under constant stirring, is added compound I-6 after emulsification, stirring it is cooling to get.
10, the preparation of intermediate III -2 and Fluconazole compound powder-injection
Prescription: intermediate III -2 50g, Fluconazole 50g, sodium benzoate 1g are made 100 bottles altogether.
Preparation method: taking intermediate III -2, Fluconazole and the sodium benzoate of recipe quantity, be uniformly mixed under aseptic conditions, packing
100 bottles to get.
11, the preparation of -3 aerosol of intermediate III
Prescription: intermediate III -3 2.5g, Span20 3g, talcum powder (100 mesh) 4g, F-11 add in right amount.
Preparation method: intermediate III -3, Span20 and talcum powder are set into dry a few hours in vacuum oven respectively, set drying
It is cooled to room temperature in device, is ground into micro mist with airslide disintegrating mill, then mix by recipe quantity, pours into closed container, trichlorine is added
One fluoromethane to specified amount to get.
Finally, it is stated that preferred embodiment above is only used to illustrate the technical scheme of the present invention and not to limit it, although logical
It crosses above preferred embodiment the present invention is described in detail, however, those skilled in the art should understand that, can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (8)
1. Ofloxacin thiazole analog and its officinal salt, which is characterized in that structure is as shown in general formula I:
In formula:
R1It is sub- for amino, diazanyl, hydroxyl diazanyl, alcoxyl diazanyl, alkyl, benzal diazanyl, alkyl hydrazine base, benzene sulfonyl diazanyl or naphthoyl
Amine；
R2, R3It is described for hydrogen, trifluoromethyl, cyano, nitro, chlorine, fluorine, pyrrolidinyl, morpholinyl, piperazinyl or hexahydropyridine base
Pyrrolidinyl, morpholinyl, piperazinyl or hexahydropyridine base contain one or more substituent groups.
2. Ofloxacin thiazole analog according to claim 1 and its officinal salt, which is characterized in that
R1For amino, alkyl, benzal diazanyl, alkyl hydrazine base, benzene sulfonyl diazanyl or naphthalimide；
R2, R3For hydrogen, trifluoromethyl, chlorine, fluorine, pyrrolidinyl, morpholinyl, piperazinyl or hexahydropyridine base.
3. Ofloxacin thiazole analog according to claim 2 and its officinal salt, which is characterized in that be following chemical combination
Any one of object:
4. Ofloxacin thiazole analog according to claim 1 and its officinal salt, which is characterized in that described pharmaceutically acceptable
Salt is hydrochloride, nitrate or acetate.
5. the preparation method of the described in any item Ofloxacin thiazole analogs of claim 1-4 and its officinal salt, feature
It is, described method includes following steps:
A, using triethyl orthoformate as starting material, corresponding 3- the preparation of intermediate II: is obtained after nucleophilic displacement of fluorine, cyclisation
Acetyl group quinolone intermediates, the 3- acetyl group quinolone intermediates again with bromoethanol through N- alkylated reaction closed loop to get
Intermediate II -1 and II-2；
B, the preparation of intermediate III: being respectively starting material with intermediate II -1 and II-2, using glacial acetic acid as solvent, through bromination,
Up to intermediate III -1, III-2 and III-3；
C, the preparation of Ofloxacin thiazole analog shown in general formula I: intermediate III is dissolved in solvent, reacted with thiocarbamide to get
Ofloxacin thiazole analog shown in general formula I；
D, the preparation of the officinal salt of Ofloxacin thiazole analog shown in general formula I: Ofloxacin thiazole shown in general formula I is similar
Object is dissolved in organic solvent, and pharmaceutically acceptable acid is added under agitation, reacts 8-12h to get Ofloxacin thiazole shown in general formula I
The officinal salt of analog.
6. according to the method described in claim 5, it is characterized in that,
In step a, alkali used in the N- alkylated reaction is potassium carbonate, and corresponding 3- acetyl group quinoline is obtained after the cyclisation
The molar ratio of promise ketone intermediate and alkali is 1:1.2-1.5；
In step b, the temperature when bromination is 40-60 DEG C；
In step c, the solvent is dehydrated alcohol, and the temperature when thiocarbamide reacts is 70-80 DEG C；
In step d, the organic solvent is that one of ethyl alcohol, ether, tetrahydrofuran or chloroform or a variety of mixing are molten
Agent；The pharmaceutically acceptable acid is one of hydrochloric acid, nitric acid or acetic acid.
7. the described in any item Ofloxacin thiazole analogs of claim 1-4 and its officinal salt in preparation antibacterium and/or
Application in antifungal drug.
8. application according to claim 7, which is characterized in that the bacterium is staphylococcus aureus, methicillin-resistant
Staphylococcus aureus, K. pneumonia, Escherichia coli, enterococcus faecalis, Acinetobacter bauamnnii or pseudomonas aeruginosa
At least one of；The fungi is in Candida tropicalis, aspergillus fumigatus, Candida albicans or Candida parapsilosis bacterium
At least one.
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| CN110305064A (en) * | 2019-07-31 | 2019-10-08 | 西南大学 | Sulphonyl azole compounds of ethoxy bridging and its preparation method and application |
| CN111087388A (en) * | 2019-12-27 | 2020-05-01 | 西南大学 | Hydrazone group bridged naphthalimide imidazole compound and preparation method and application thereof |
| CN115636785A (en) * | 2022-09-23 | 2023-01-24 | 西南大学 | Quinolone cyanoacetate compounds and pharmaceutically acceptable salts thereof, and preparation method and application thereof |
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| CN110305064A (en) * | 2019-07-31 | 2019-10-08 | 西南大学 | Sulphonyl azole compounds of ethoxy bridging and its preparation method and application |
| CN111087388A (en) * | 2019-12-27 | 2020-05-01 | 西南大学 | Hydrazone group bridged naphthalimide imidazole compound and preparation method and application thereof |
| CN115636785A (en) * | 2022-09-23 | 2023-01-24 | 西南大学 | Quinolone cyanoacetate compounds and pharmaceutically acceptable salts thereof, and preparation method and application thereof |
| CN115636785B (en) * | 2022-09-23 | 2024-05-28 | 西南大学 | Quinolone cyanoacetate compound and pharmaceutically acceptable salt thereof, and preparation method and application thereof |
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