CN104788503A - Ferrocene-quinolone amide compound as well as preparation method and application thereof - Google Patents
Ferrocene-quinolone amide compound as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a series of ferrocene-quinolone amide compounds as well as a preparation method and application thereof. The preparation method comprises the following steps: 1) selecting quinolone bulk drug according to a target compound to be prepared, placing the selected quinolone bulk drug and methyl alcohol in a reactor to be subjected to reflux reaction, adjusting the pH of the reaction liquid to be 8-10, then, extracting by using an extraction agent, collecting an organic phase, and removing the solvent through evaporation, so as to obtain corresponding floxacin methyl ester; 2) taking the floxacin methyl ester and triethylamine, placing the floxacin methyl ester and triethylamine in a first organic solvent, and adding chlorocarbonyl ferrocene for reaction under the protection of inert gas, and performing suction filtration, so as to obtain an intermediate body; 3) taking the intermediate body and an alkaline substance, dissolving the intermediate body and the alkaline substance with a second organic solvent, performing reflux reaction, adjusting the pH of the reaction liquid to be 1-4, filtering, and collecting sediments, so as to obtain the target compound. The compound provided by the invention has obvious inhibiting effect on certain bacteria, and is expected to be used for preparing antibacterial drug.
Description
Technical field
The present invention relates to ferrocene-quinolone heterocomplex, be specifically related to class ferrocene-quinolone amides and its preparation method and application.
Background technology
Quinolones has become a class synthetic antibacterial drug of clinical widely used wide spectrum, efficient, low toxicity, is mainly used in treating the systemic diseases such as gi tract, urinary tract and the respiratory tract caused by bacteriological infection.
[1-2]but along with the further expansion that quinolones uses, the resistance phenomenon of bacterium to medicine is day by day serious
[3], the toxicity of cardiovascular systems, cental system, hepatic and renal tissue etc. that simultaneously some fluoroquinolones produce medication person is also subject to extensive concern
[4-5], the novel promise ketone antibacterials constantly developed that antimicrobial spectrum is wider, curative effect is higher, selectivity is stronger, side effect is lower and have a better anti-drug resistance are the priority research areass of new drug development always
[6].In addition, document in recent years repeatedly reports the non-classical biological activity of its derivative, as antitumor, antiviral, ischemia resisting is active and as HIV-1 integrase inhibitor etc., wherein anti-tumor activity the most significantly, material standed for SNS-595 as antitumor in quinolone, entered II phase clinical investigation phase at present, its structural formula is shown below:
Ferrocene (Ferrocene writes a Chinese character in simplified form FcH) is a kind of organometallics with special stability, and its derivative has the features such as toxicity is low, hydrophobicity is good, makes the fusion that itself and biomacromolecule can be good.
Carbostyril compound and other are had different bioactive drug molecule and can form heterozygote (hybrids) by covalent linkage is connected, these heterozygotes likely overcome drug resistance problems thorny clinically at present by acting on respective target spot, reduce the risk occurring new Resistant strain.But have not yet to see and quinolone structure and ferrocene pharmacophore have been carried out heterozygosis gained ferrocene-quinolone amides and bioactive relevant report thereof.
Summary of the invention
The technical problem to be solved in the present invention is to provide a series of new ferrocene-quinolone amides, and their preparation method and application.
Ferrocene of the present invention-quinolone amides husky for the quinolone of listing star medicine and Ferrocene and its derivative is carried out the compound that heterozygosis obtains; Specifically, be in the nitrogen heterocyclic ring of the C-7 position of the husky star medicine of the quinolone of listing, introduce the compound that ferrocene and derivatize group thereof obtain; More specifically, be ferrocene-quinolone amides or its pharmacy acceptable salt with structure as shown in following formula I, (II), (III) or (IV):
The preparation method of ferrocene of the present invention-quinolone amides, comprises following step and gathers:
1) quinolone bulk drug is chosen according to target compound to be prepared, the quinolone bulk drug chosen and methyl alcohol are placed in reactor back flow reaction, gained reaction solution regulates its pH=8 ~ 10, then extract with extraction agent, collect organic phase, steaming desolventizes, and obtains corresponding husky star methyl esters; Described quinolone bulk drug is Ciprofloxacin, norfloxicin, enoxacin or Clinafloxacin;
2) step 1 is got) the husky star methyl esters of gained and triethylamine, be placed in the first organic solvent, under protection of inert gas, then add ferrocene formyl chloride and react, suction filtration, obtains intermediate;
3) step 2 is got) gained intermediate and alkaline matter the second organic solvent dissolution, back flow reaction, gained reaction solution regulates its pH=1 ~ 4, and filter, collecting precipitation, obtains target compound.
The step 1 of above-mentioned preparation method) in, methyl alcohol is both as the raw material participating in reaction, also use as solvent, the amount of methyl alcohol of adding preferably be greater than methyl alcohol and quinolone bulk drug react needed for amount, under normal circumstances, when methyl alcohol and quinolone bulk drug react, the ratio of the amount of substance both them is 15:1 ~ 40:1.Described extraction agent is identical with prior art, is generally methylene dichloride, chloroform or ethyl acetate.The organic phase of collecting preferably is washed to pH=7 ~ 8, and then with anhydrous sodium sulfate drying, then steaming desolventizes.In this step, back flow reaction is normally carried out under the boiling point lower than the first organic solvent, preferably carries out under 50 ~ 80 DEG C of conditions.Thin-layer chromatography (TLC) tracing detection can be adopted during reaction to react whether completely.In order to add the carrying out of fast response, the catalyzer vitriol oil can also be added before the reaction.The add-on of the described vitriol oil can be 2 ~ 10 times of quinolone bulk drug amount of substance usually.The pH value of the rear gained reaction solution of reaction is normally regulated with basic solution, as saturated sodium carbonate solution, saturated sodium bicarbonate solution, the sodium hydroxide of lower concentration (5 ~ 20w/w%) or potassium hydroxide solution etc.Preferably regulate pH value to 8.5 ~ 9.5 of the rear gained reaction solution of reaction, be so more conducive to extraction.
The step 2 of above-mentioned preparation method) in, the first described organic solvent is normally selected from one or more the combination in tetrahydrofuran (THF), ethylene dichloride, chloroform and ethyl acetate.In order to improve the productive rate of product, above-mentioned first organic solution preferably not water content.When the first organic solvent be chosen as above-mentioned two or more combination time, the proportioning between them can be any proportioning.The usage quantity of the first organic solvent is advisable can dissolve the raw material participating in reaction usually.In this step, reaction is normally carried out under 10 ~ 45 DEG C of conditions, and reaction is preferably carried out under agitation; Because the reaction after adding ferrocene formyl chloride is thermopositive reaction, therefore, preferably under condition of ice bath, add ferrocene formyl chloride, react under moving to relevant temperature afterwards again; Be more preferably ferrocene formyl chloride with in the solution slowly joined again after a small amount of first organic solvent dissolution containing husky star methyl esters and triethylamine.The ratio of the amount of substance of described husky star methyl esters, triethylamine and ferrocene formyl chloride can be 1:1 ~ 3:1 ~ 3.
The step 3 of above-mentioned preparation method) in, described alkaline matter can be alkali conventional in prior art, as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, salt of wormwood etc.; Preferably alkaline matter is first mixed with intermediate with after the second organic solvent wiring solution-forming again.In order to higher productive rate can be obtained, preferably adopt sodium hydroxide or potassium hydroxide.Usual dilute hydrochloric acid, dilute sulphuric acid or dust technology etc. regulate the pH value of reaction solution, preferably regulate gained reaction solution to regulate its pH=2 ~ 3.Consider from cost-saving angle, after reacting completely, gained reaction solution first can steam the pH value except regulating reactant after partial solvent again.The precipitation of collecting can first be washed by water and/or ethyl acetate, to remove unreacted raw material or other impurity completely.In this step, back flow reaction is normally carried out under the boiling point lower than the second organic solvent, preferably carries out under 50 ~ 90 DEG C of conditions.Thin-layer chromatography (TLC) tracing detection can be adopted during reaction to react whether completely.In this step, the second described organic solvent is alcohols material, and preferably containing the alcohol of 1 ~ 3 carbon atom, as methyl alcohol, ethanol, propyl alcohol, also can be selected from combinations two or more arbitrarily in methyl alcohol, ethanol and propyl alcohol, the ratio of combination can be any proportioning.The usage quantity of the second organic solvent is advisable can dissolve the raw material participating in reaction usually.
Ferrocene formyl chloride involved in preparation method of the present invention can with reference to existing document (Li Baoguo, Bian Zhanxi, Hu Ruijue, Zhao Haiying, the synthesis of ferrocene deriv, press of University of the Inner Mongol, Huhehaote, 2003) be prepared, specifically can be prepared as follows:
Get ferrocenecarboxylic acid and benzene, under protection of inert gas, slowly add excessive phosphorus pentachloride several times, stirring at room temperature 3 ~ 4h; remove benzene under reduced pressure, petroleum ether extraction obtains dark red solution, underpressure distillation; cooling, separates out scarlet needle-like crystal, is ferrocene formyl chloride.
In the method for the invention, when the quinolone bulk drug selected be Ciprofloxacin, norfloxicin, enoxacin or Clinafloxacin (their structure is respectively as shown in following 1a, 1b, 1c and 1e) time, target product obtained is according to the method described above respectively the ferrocene-quinolone amides of formula I, (II), (III) and (IV) shown structure.
Below to be chosen as Ciprofloxacin when quinolone bulk drug, provide synthesis and obtain the synthetic route of compound shown in formula I:
Wherein, 1a is Ciprofloxacin, 2a is Ciprofloxacin methyl esters, 3 is ferrocene formyl chloride, 4a is 7-(4-ferrocene acyl piperazine base)-1-cyclopropyl-6-fluorin-4-oxygen-1, 4-dihydro-quinolone-3-carboxylate methyl ester i.e. (7-(4-ferrocenecarbonyl-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid methyl ester), 5a is the 7-of compound shown in formula I (4-ferrocene acyl piperazine base)-1-cyclopropyl-6-fluorin-4-oxygen-1, 4-dihydro-quinolone-3-carboxylic acid i.e. (7-(4-ferrocenecarbonyl-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid).
In order to obtain more highly purified target product, method of the present invention preferably also comprises at least one in following three kinds of process: a, by step 1) the husky star methyl esters of gained enters next step operation again after carrying out purifying; B, to step 2) intermediate of gained enters next step operation again after carrying out purifying; C, to step 3) target product of gained carries out purifying.
Particularly, the operation husky star methyl esters being carried out to purifying can be that the husky star methyl esters of gained is carried out silica gel column chromatography, and with the eluent be made up of methyl alcohol and methylene dichloride, elutriant removes solvent under reduced pressure, obtains the husky star methyl esters after purifying; The volume ratio of described methyl alcohol and methylene dichloride is preferably 1:5 ~ 15.
Operation intermediate being carried out to purifying can be that the intermediate of gained is carried out silica gel column chromatography, and with the eluent be made up of methyl alcohol and methylene dichloride, elutriant removes solvent under reduced pressure, obtains the intermediate after purifying; The volume ratio of described methyl alcohol and methylene dichloride is preferably 1:10 ~ 25.
Operation gained target product being carried out to purifying is that the target product of gained is carried out recrystallization, and recrystallization solvent used is generally acetone, ethylene dichloride, chloroform and ethyl acetate etc.
The present invention also comprises above-mentioned ferrocene-quinolone amides or the application of its pharmacy acceptable salt in preparation antibacterials.Specifically, be above-mentioned ferrocene-quinolone amides or the application of its pharmacy acceptable salt in the anti-gram-bacteria medicine of preparation; Furthermore, be that above-mentioned ferrocene-quinolone amides or its pharmacy acceptable salt are preparing the application in resisting gram-positive bacteria and/or against gram-negative bacteria medicine; Further, the application being above-mentioned ferrocene-quinolone amides or its pharmacy acceptable salt in the anti-Bacillus subtillis of preparation and/or anti-staphylococcus aureus and/or Pseudomonas aeruginosa and/or intestinal bacteria medicine.
The present invention also comprises the antibacterials prepared for active substance with above-mentioned ferrocene-quinolone amides or its pharmacy acceptable salt further.
Compared with prior art, the present invention carries out with the husky star medicine of quinolone and ferrocene pharmacophore new ferrocene-quinolone amides that heterozygosis obtains a series of novel structure, synthetic method is simple to operation, synthesize the compound obtained, to bacteriums such as Bacillus subtillis, staphylococcus aureus, Pseudomonas aeruginosa, intestinal bacteria, there is obvious restraining effect, be expected to for the preparation of antibacterials.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, and to understand content of the present invention better, but the present invention is not limited to following examples.
Compound shown in formula I is prepared with reference to the aforementioned synthetic route provided.
Embodiment 1: the preparation of Ciprofloxacin methyl esters (compound 2a)
In flask, add Ciprofloxacin 1.35g (4mmol), 50mL methyl alcohol, slowly drip the 2mL vitriol oil, backflow 24h, steam except most of solvent, adjust pH to 9 with saturated sodium bicarbonate solution, then use CH
2cl
2(3 × 20mL) extracts, and merge organic layer, being washed to pH is 8, organic over anhydrous Na
2sO
4dry a few hours, filter, after removing solvent under reduced pressure, with silica gel column chromatography, (eluent is V
(methyl alcohol): V
(methylene dichloride)=1:10) purifying obtains 0.704g Ciprofloxacin methyl esters (white solid), productive rate 51%, fusing point 253-254 DEG C.
With reference to the method for above-described embodiment 1, prepare other husky star methyl esters (norfloxicin methyl esters, enoxacin methyl esters, Clinafloxacin methyl esters), specific as follows:
Repeat embodiment 1, unlike: 1. replace Ciprofloxacin with norfloxicin, 2. adjust pH to 8 with saturated sodium bicarbonate solution, being 3. washed to pH is 7.Purified 0.826g norfloxicin methyl esters (white solid), productive rate 62%, fusing point 245-247 DEG C.
Repeat embodiment 1, unlike: 1. replace Ciprofloxacin with enoxacin, 2. before back flow reaction, do not drip the vitriol oil, being 3. washed to pH is 9.Purified 0.704g enoxacin methyl esters (light yellow solid), productive rate 55%, fusing point 267-269 DEG C.
Repeat embodiment 1, unlike: 1. replace Ciprofloxacin with Clinafloxacin, 2. before back flow reaction, do not drip the vitriol oil, 3. adjust pH to 10 with saturated sodium carbonate solution.Purified 0.699g Clinafloxacin methyl esters (white solid), productive rate 48%, fusing point 281-283 DEG C.
Embodiment 2: the preparation of ferrocene formyl chloride (compound 3)
The dry ferrocenecarboxylic acid of 4.6g (0.02mmol) and 80mL dry-out benzene is added in three-necked flask; under nitrogen protection; slowly add 6.24g (0.03mmol) phosphorus pentachloride several times, stirring at room temperature 3h, decompression steams benzene; sherwood oil (60 ~ 90 DEG C) extracts to obtain dark red solution; underpressure distillation, cooling, separates out scarlet needle-like crystal; productive rate 80%, mp:48 ~ 49 DEG C.
Embodiment 3:(7-(4-ferrocenecarbonyl-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1; the preparation of 4-dihydro-quinoline-3-carboxylic acid methyl ester (chemical name is: 7-(4-ferrocene acyl piperazine base)-1-cyclopropyl-6-fluorin-4-oxygen-Isosorbide-5-Nitrae-dihydro-quinolone-3-carboxylate methyl ester) (compound 4a)
Ciprofloxacin methyl esters 0.345g (1mmol) is added in dry double-neck flask; the anhydrous THF of 15mL; 0.4mL triethylamine; nitrogen protection; stir under ice-water bath; slowly inject with syringe the anhydrous THF solution that 5mL is dissolved with ferrocene formyl chloride (1.2mmol), be transferred to stirring at room temperature 24h after 10 minutes, suction filtration can obtain compound 4a, and (impure, (eluent is V to use silica gel column chromatography
(methyl alcohol): V
(methylene dichloride)=1:20) purifying).Yellow solid, mp:186 ~ 189 DEG C, productive rate 72%.IR (KBr) v/cm
-1: 3450.20,1725.72,1619.44,1480.06,1443.05,1384.21,1332.78,1258.77,1169.55,1105.32,1011.04,932.58,803.54.
1h NMR (500MHz, CDCl
3) δ 8.53 (s, 1H, ArH), 8.02 (d, J=13.1Hz, 1H ,-CH=), 7.26 (d, J=7.0Hz, 1H, ArH), 4.63 – 4.58 (m, 2H, FcH), 4.37 – 4.34 (m, 2H, FcH), 4.27 (s, 5H, FcH), 3.96 (s, 4H ,-CH
2nHCH
2-), 3.91 (s, 3H, COOCH
3), 3.46 – 3.41 (m, 1H ,-CH
2cHCH
2-), 3.26 (d, J=4.5Hz, 4H ,-N (CH
2)
2), 1.33 (q, J=6.6Hz, 2H ,-CH
2cHCH
2-), 1.15 (q, J=6.6Hz, 2H ,-CH
2cHCH
2-);
13c NMR (125MHz, CDCl
3) δ 172.98,170.05,166.27,154.32,152.35,148.40,144.19,144.10,137.99,123.45,123.39,113.53,113.35,110.18,105.07,78.15,70.34,69.96,69.37,58.38,52.02,50.23,34.53,18.41.HRMS (ESI): m/z [M+Na]
+calcd for C
29h
28fFeN
3o
4: 557.39; Found:558.05.
Embodiment 4:7-(4-ferrocenecarbonyl-piperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1; the preparation of 4-dihydro-quinoline-3-carboxylic acid methyl ester (chemical name is: 7-(4-ferrocene acyl piperazine base)-1-ethyl-6-fluorin-4-oxygen-Isosorbide-5-Nitrae-dihydro-quinolone-3-carboxylate methyl ester) (compound 4b)
Preparation method with embodiment 3, unlike: 1. replace Ciprofloxacin methyl esters with norfloxicin methyl esters, 2. replace anhydrous THF with methylene dichloride.Obtain compound 4b, in yellow solid, mp:218 ~ 220 DEG C, productive rate 47.2%.IR (KBr) v/cm
-1: 3450.17,1685.24,1625.93,1475.89,1443.05,1381.96,1313.20,1256.58,1171.27,1110.30,1008.83,934.85,805.39.
1h NMR (500MHz, CDCl
3) δ 8.65 – 7.08 (s, 3H, ArH), 4.60-4.28 (m, 9H, FcH), 3.88-3.39 (m, 13H ,-N (CH
2)
2,-OCH
3), 1.38-17 (m, 3H ,-CH
2cH
3);
13c NMR (125MHz, CDCl
3) δ 168.96,153.88,151.92,149.29,144.49,144.41,112.55,112.49,112.27,106.64,78.21,70.69,69.95,69.81,51.67,50.40,48.58,40.41,39.58,14.79.HRMS (ESI): m/z [M+Na]
+calcd for C
28h
29fFeN
3o
4: 546.15; Found:546.15.
Embodiment 5:7-(4-ferrocenecarbonyl-piperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1; 4-dihydro-[1; 8] (chemical name is naphthyridine-3-carboxylic acid methyl ester: 7-(4-ferrocene acyl piperazine base)-1-ethyl-6-fluorin-4-oxygen-1; 4-dihydro-[1,8] naphthyridines-3-carboxylate methyl ester) preparation of (compound 4c)
Preparation method with embodiment 3, unlike: 1. replace Ciprofloxacin methyl esters with enoxacin methyl esters, 2. replace anhydrous THF with chloroform.Obtaining 4c is yellow solid, mp:180 ~ 182 DEG C, productive rate 71.5%.IR (KBr) v/cm
-1: 3440.37,1617.96,1493.98,1384.34,1322.00,1256.33,1104.13,829.15.
1h NMR (500MHz, CDCl
3) δ 8.69 – 7.96 (m, 2H, ArH), 4.61-3.83 (m, 9H, FcH), 3.74 (m, 3H ,-OCH
3), 3.35 (m, 10H ,-N (CH
2)
2,-CH
2cH
3), 1.38-1.23 (m, 3H ,-CH
2cH
3);
13c NMR (125MHz, CDCl
3) δ 169.15,148.45,123.49,78.02,70.74,69.90,51.74,47.16,46.71,40.58,39.72,15.24.HRMS (ESI): m/z [M+Na]
+calcd for C
27h
27fFeN
4o
4: 546.37; Found:547.14.
Embodiment 6:6-(3-ferrocenecarbonyl-pyrrolidin-1-yl)-5-chloro-4-cyclopropyl-7-fluoro-1-oxo-1; the preparation of 4-dihydro-naphthalene-2-carboxylic acid methyl ester (chemical name is: the fluoro-1-oxygen-Isosorbide-5-Nitrae-dihydronaphthalene-2-carboxylate methyl ester of 6-(3-ferrocene acyl pyrroline alkyl)-5-chloro-4-cyclopropyl-7-) (compound 4e)
Preparation method with embodiment 3, unlike, 1. replace Ciprofloxacin methyl esters with Clinafloxacin methyl esters, 2. replace anhydrous THF with ethyl acetate.Obtaining 4e is yellow solid, mp:236 ~ 237 DEG C, productive rate 52.1%.IR (KBr) v/cm
-1: 3453,1734,1697,1609,1445,1385,1321,1256,1164,1105,1008,801.
1h NMR (500MHz, CDCl
3) δ 8.68 – 8.03 (m, 2H, ArH), 4.60-4.22 (m, 9H, FcH), 4.22 (1H ,-CONH), 3.92 (m, 6H ,-N (CH
2)
2)), 3.33 (m, 4H ,-OCH
3, CHNH), 1.92 (m, 1H ,-CH (CH
2)
2), 1.25-0.93 (m, 4H ,-CH (CH
2)
2);
13c NMR (125MHz, CDCl
3) δ 172.31,170.06,165.68,152.69,152.67,142.36,142.34,137.03,127.37,112.85,112.66,110.67,77.31,69.96,52.19,51.26,40.22,11.39,11.03.HRMS (ESI): m/z [M+Na]
+calcd for C
29h
27clFFeN
3o
4: 591.84; Found:592.107.
Embodiment 7:7-(4-ferrocenecarbonyl-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1; the preparation of 4-dihydro-quinoline-3-carboxylic acid (chemical name for: 7-(4-ferrocene acyl piperazine base)-1-cyclopropyl-6-fluorin-4-oxygen-Isosorbide-5-Nitrae-dihydro-quinolone-3-carboxylic acid) (compound 5a and formula I shown in compound)
In flask, add 4a 0.278g (0.5mmol), 15mL contains the methanol solution of 1M KOH, 70 DEG C of stirring and refluxing 2h (TLC tracking).After question response is complete, the most of methyl alcohol of decompression removing, is then neutralized to pH=2 with 3M hydrochloric acid, separates out yellow mercury oxide, filter, and uses the washing of water, ethyl acetate successively, obtains yellow solid 5a.Mp:256 ~ 257 DEG C, productive rate 82%.IR (KBr) v/cm
-1: 3427,2338,1739,1621,1468,1384,1333,1256,1174,1010,830.
1h NMR (500MHz, CD
3oD) δ 8.43 (s, 1H, ArH), 8.08 (d, J=13.1Hz, 1H ,-CH=), 7.16 (d, J=7.0Hz, 1H, ArH), 4.65 – 4.48 (m, 2H, FcH), 4.35 – 4.31 (m, 2H, FcH), 4.24 (s, 5H, FcH), 3.91 (s, 4H ,-CH
2nHCH
2-), 3.85 (s, 3H, COOCH
3), 3.44 – 3.40 (m, 1H ,-CH
2cHCH
2-), 3.23 (d, J=4.5Hz, 4H ,-N (CH
2)
2), 1.30 (q, J=6.6Hz, 2H ,-CH
2cHCH
2-), 1.11 (q, J=6.6Hz, 2H ,-CH
2cHCH
2-);
13c NMR (125MHz, CD
3oD) δ 172.90,170.01,166.07,154.20,152.30,148.32,144.11,137.78,123.37,123.31,113.43,113.25,110.06,105.01,78.10,70.04,69.76,69.25,58.31,52.02,34.43,18.38.HRMS (ESI): m/z [M+Na]
+calcd for C
28h
26fFeN
3o
4: 543.38; Found:544.04.
Embodiment 8:7-(4-ferrocenecarbonyl-piperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1; the preparation of 4-dihydro-quinoline-3-carboxylic acid (chemical name for: 7-(4-ferrocene acyl piperazine base)-1-ethyl-6-fluorin-4-oxygen-Isosorbide-5-Nitrae-dihydro-quinolone-3-carboxylic acid) (compound 5b and formula II shown in compound)
Preparation method with embodiment 7, unlike: 1. with 4b replace 4a, 2. with NaOH replace KOH, be 3. neutralized to pH=3 with 3M hydrochloric acid.Obtain compound 5b, in yellow solid, mp:277 ~ 278 DEG C, productive rate 87%.IR (KBr) v/cm
-1: 3430,1733,1622,1477,1380,1256,1178,1033,816.
1hNMR (500MHz, CD
3oD) δ 8.54 – 7.01 (s, 3H, ArH), 4.56-4.21 (m, 9H, FcH), 3.81-3.30 (m, 13H ,-N (CH
2)
2,-OCH
3), 1.34-1.11 (m, 3H ,-CH
2cH
3);
13c NMR (125MHz, CD
3oD) δ 168.85,153.74,151.82,149.20,144.41,144.37,112.50,112.41,112.15,106.59,78.16,70.61,69.87,69.80,51.60,50.34,48.52,40.37,39.53,14.71.HRMS (ESI): m/z [M+Na]
+calcd for C
27h
27fFeN
3o
4: 532.37; Found:531.75.
Embodiment 9:7-(4-ferrocenecarbonyl-piperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1; 4-dihydro-[1; 8] (chemical name is naphthyridine-3-carboxylic acid: 7-(4-ferrocene acyl piperazine base)-1-ethyl-6-fluorin-4-oxygen-1; 4-dihydro-[1,8] naphthyridines-3-carboxylic acid) preparation of (compound 5c and formula III shown in compound)
Preparation method with embodiment 7, unlike: 1. replace 4a with 4c, 2. replace the methanol solution of KOH with the ethanolic soln of NaOH, 3. back flow reaction is carried out under 80 DEG C of conditions, is 4. neutralized to pH=4 with 2M sulfuric acid.Obtain compound 5c, in yellow solid, mp:281 ~ 282 DEG C, productive rate 83%.IR (KBr) v/cm
-1: 3426,1728,1631,1474,1444,1379,1259,1007,810.
1h NMR (500MHz, CD
3oD) δ 8.60 – 7.85 (m, 2H, ArH), 4.59-3.76 (m, 9H, FcH), 3.70 (m, 3H ,-OCH
3), 3.30 (m, 10H ,-N (CH
2)
2,-CH
2cH
3), 1.31-1.19 (m, 3H ,-CH
2cH
3);
13cNMR (125MHz, CD
3oD) δ 169.08,148.37,123.44,78.01,70.67,69.83,51.70,47.11,46.64,40.55,39.65,15.11.HRMS (ESI): m/z [M+Na]
+calcd forC
26h
25fFeN
4o
4: 532.35; Found:533.12.
Embodiment 10:6-(3-ferrocenecarbonyl-pyrrolidin-1-yl)-5-chloro-4-cyclopropyl-7-fluoro-1-oxo-1; the preparation of 4-dihydro-naphthalene-2-carboxylic acid (chemical name for: the fluoro-1-oxygen-Isosorbide-5-Nitrae-dihydronaphthalene-2-carboxylic acid of 6-(3-ferrocene acyl pyrroline alkyl)-5-chloro-4-cyclopropyl-7-) (compound 5e and formula IV shown in compound)
Preparation method with embodiment 7, unlike: 1. replace 4a with 4e, 2. replace the methanol solution of KOH with the propanol solution of KOH, 3. back flow reaction is carried out under 50 ~ 60 DEG C of conditions, is 4. neutralized to pH=1 with 2M hydrochloric acid.Obtain compound 5e, in yellow solid, mp:265 ~ 266 DEG C, productive rate 85%.IR (KBr) v/cm
-1: 3431,1730,1614,1441,1384,1259,1171,1112,1008,809.
1hNMR (500MHz, CD
3oD) δ 8.59 – 7.92 (m, 2H, ArH), 4.55-4.20 (m, 9H, FcH), 4.21 (1H ,-CONH), 3.86 (m, 6H ,-N (CH
2)
2)), 3.30 (m, 4H ,-OCH
3, CHNH), 1.89 (m, 1H ,-CH (CH
2)
2), 1.21-0.89 (m, 4H ,-CH (CH
2)
2);
13c NMR (125MHz, CD
3oD) δ 172.28,170.01,165.60,152.61,152.59,142.26,137.01,127.32,112.80,112.61,110.62,77.27,69.92,52.13,51.20,40.20,11.31,11.01.HRMS (ESI): m/z [M+Na]
+calcd for C
28h
25clFFeN
3o
4: 577.82; Found:578.31.
Embodiment 10: ferrocene-quinolone amides antibacterial activity in vitro research
(1) preparation of nutrient solution
RPMI1640 nutrient solution: RPMI1640 10g, NaHCO
32.0g, MOPS 34.5g (0.165M), adds tri-distilled water 900mL and dissolves, and 1N NaOH adjusts pH to 7.0 (25 DEG C), is settled to 1000mL, filters sterilization, 4 DEG C of preservations.
Husky fort glucose agar medium (SDA): peptone 10g, glucose 40g, agar 18g, add tri-distilled water 900mL and dissolve, add 2mg/mL chloramphenicol solution 50mL, adjustment pH to 7.0, is settled to 1000mL, 4 DEG C of preservations after autoclaving.
YEPD nutrient solution: yeast extract 10g, peptone 20g, glucose 20g, add tri-distilled water 900mL and dissolve, add 2mg/mL chloramphenicol solution 50mL, be settled to 1000mL, 4 DEG C of preservations after autoclaving.
(2) bacterium solution preparation
Before experiment, on a small quantity, be seeded to 1mL YEPD nutrient solution with inoculation circle from picking streptococcus aureus, Bacillus subtilus, intestinal bacteria, Pseudomonas aeruginosa 4 DEG C of SDA substratum preserved, in 35 DEG C, 250rpm shaking culture, activation 16h, makes bacterium be in later stage exponential phase of growth.Get this bacterium liquid in 1mLYEPD nutrient solution, again activate with aforesaid method, after 16h, with blood cell counting plate counting, with RPMI1640 nutrient solution adjustment bacterial concentration to 1 × 10
3~ 5 × 10
3cfu/mL.
(3) drug solution preparing
Test medicine is made into 1mg/mL solution with DMSO respectively ,-20 DEG C of preservations, before experiment, 35 DEG C of incubators is put in liquid taking-up and melts for subsequent use.Concentration gradient is made into by four times of dilution methods during test.Being made into final test concentration is 50,12.5,3.125,0.781,0.195,0.049 μ g/mL.
(4) preparation of drug sensitive plate
Bacterial suspension is in RPMI1640 substratum, and dispersion concentration is approximately 1 × 10
3~ 5 × 10
3cfu/mL, joins the first row of 96 orifice plates by substratum, every hole 100 μ L, as blank (negative control).Second row adds bacterium liquid, and every hole 100 μ L, does not add tested sample, as reagent blank.The gradient solution prepared by sample, joins 3rd ~ 12 rows of 96 orifice plates, makes ultimate density be 50,12.5,3.125,0.781,0.195,0.049 μ g/mL with the amount of every hole 11 μ L.Each concentration gradient does three parallel laboratory tests.The incubator 96 orifice plates being put into 37 DEG C is cultivated 24 hours, then every hole 25 μ L is added containing in the D-hanks solution of 4mg MTT/mL, cultivate 4 hours under similarity condition again, add every hole 100 μ L SDS lysate (90mL tri-distilled water+10g SDS+5mL Virahol+2mL concentrated hydrochloric acid) and cultivate 12h afterwards.
(5) MIC value judges
Under 570nm, measure OD value by microplate reader, be calculated as follows inhibiting rate:
Inhibiting rate=[1-(test sample OD value-blank OD value)/(negative control OD value-blank OD value)] × 100
The minimum concentration being not less than 50% using inhibiting rate is as the MIC50 (minimum inhibitory concentration) of sample.When the MIC value of medicine exceedes mensuration concentration range, add up by the following method: when MIC value is higher than maximum concentration 50 μ g/mL, count " >50 μ g/mL "; MIC value be minimum concentration or below minimum concentration time, do not distinguish, all count "≤0.0049 μ g/mL ".
The MIC value recorded is shown in Table 1.
Ferrocene listed by table 1 the present invention-quinolone heterocomplex is to the MIC value (μM) of bacterium
From table 1, the anti-microbial activity of part ferrocene-quinolone amides increases relative to bulk drug, wherein compound 5e (ferrocene-Clinafloxacin heterocomplex) is 0.006 μM to the MIC value of streptococcus aureus, is 20 times of female medicine Clinafloxacin.Therefore, being effectively feasible by ferrocene pharmacophore and this layout strategy of quinolone medicine heterozygosis for improving anti-microbial activity, being worth further investigation to be further developed to novel antibacterial medicine.
Claims (10)
1. there is ferrocene-quinolone amides or its pharmacy acceptable salt of structure as shown in following formula I, (II), (III) or (IV):
2. the preparation method of ferrocene described in claim 1-quinolone amides, comprises following step and gathers:
1) quinolone bulk drug is chosen according to target compound to be prepared, the quinolone bulk drug chosen and methyl alcohol are placed in reactor back flow reaction, gained reaction solution regulates its pH=8 ~ 10, then extract with extraction agent, collect organic phase, steaming desolventizes, and obtains corresponding husky star methyl esters; Described quinolone bulk drug is Ciprofloxacin, norfloxicin, enoxacin or Clinafloxacin;
2) step 1 is got) the husky star methyl esters of gained and triethylamine, be placed in the first organic solvent, under protection of inert gas, then add ferrocene formyl chloride and react, suction filtration, obtains intermediate;
3) step 2 is got) gained intermediate and alkaline matter the second organic solvent dissolution, back flow reaction, gained reaction solution regulates its pH=1 ~ 4, and filter, collecting precipitation, obtains target compound.
3. preparation method according to claim 2, is characterized in that: step 2) in, the first described organic solvent is one or more the combination be selected from tetrahydrofuran (THF), ethylene dichloride, chloroform and ethyl acetate.
4. preparation method according to claim 2, is characterized in that: the second described organic solvent is alcohols material.
5. preparation method according to claim 2, is characterized in that: the second described organic solvent is the alcohol containing 1 ~ 3 carbon atom.
6. preparation method according to claim 2, is characterized in that: step 3) in, described alkaline matter is sodium hydroxide or potassium hydroxide.
7. the preparation method according to any one of claim 2 ~ 6, is characterized in that: step 1) in, before carrying out back flow reaction, add the catalyzer vitriol oil.
8. the preparation method according to any one of claim 2 ~ 6, is characterized in that: step 1) in, enter next step operation after the husky star methyl esters of gained is carried out purifying again.
9. the preparation method according to any one of claim 2 ~ 6, is characterized in that: step 2) in, enter next step operation after the intermediate of gained is carried out purifying again.
10. ferrocene according to claim 1-quinolone amides or the application of its pharmacy acceptable salt in preparation antibacterials.
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| EP2497775A1 (en) * | 2011-03-11 | 2012-09-12 | Ruprecht-Karls-Universität Heidelberg | Ferrocene-based compounds and their use as ROS regulating prodrugs |
| CN102918051A (en) * | 2010-03-16 | 2013-02-06 | 诺马德卡谟·加林多塞维利亚 | N6-(methylferrocene) quinazoline-2, 4, 6-triamine (H2) and derivatives thereof, and prodrugs for use as antibacterial, antiparasitic, antiprotozoal and antileishmanial agents |
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| CN111620901B (en) * | 2020-06-08 | 2023-03-21 | 蚌埠医学院第二附属医院 | Fluoroquinolone compound containing siloxane group, preparation method and application thereof |
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