CN102898425B - 4,5-glyoxalidine [1,2-a] quinoline derivative and application of 4,5- glyoxalidine [1,2-a] quinoline derivative - Google Patents
4,5-glyoxalidine [1,2-a] quinoline derivative and application of 4,5- glyoxalidine [1,2-a] quinoline derivative Download PDFInfo
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Abstract
The invention relates to a 4,5-glyoxalidine [1,2-a] quinoline derivative shown as the following formula (1) and application of the 4,5- glyoxalidine [1,2-a] quinoline derivative, wherein R represents C1-C12 alkyls, benzyl and substituted benzyl, Y represents H, O and N, and R1 represents C1-C12 alkyls, phenyl, substituted phenyl, benzyl and substituted benzyl. The invention also provides a medicine composition containing the derivative and salts of the derivative, and application of the derivative and the salts of the derivative to antibacterial medicine preparation. The derivative and the salts of the derivative respectively have the inhibition effects on staphylococcus aureus, escherichia coli, other gram-negative bacteria (such as pseudomonas aeruginosa, Klebsiella pneumoniae, proteusbacillus vulgaris, salmonella and pasteurella) and gram-positive bacteria, and in other aspects, the antibacterial effect is better than that of ciprofloxacin and amoxicillin.
Description
Technical field
The invention belongs to new compound medicine field, relate to a kind of 4,5-glyoxalidine [1,2-a] quinoline and the application in preparation antibacterials thereof.
Background technology
20th century antibacterials development achievement splendidness.The mid-1930s, sulfa drugs entered clinical, the beginning of the forties discovery of penicillin, immediately find large quantities of important microbiotic such as paraxin, tsiklomitsin, macrolide, then there are again the appearances such as semisynthetic penicillin, cynnematin, Comprecin, make effectively to treat various bacteriums infection and become possibility, for ensureing human health, prolongs life has been made outstanding contribution.Along with microbiotic widespread use, there are clinically two problems: the one, bacterial drug resistance increases year by year, causes some microbiotic curative effects to reduce, even invalid; The 2nd, some non-pathogenic bacterias become conditioned pathogen.In order to improve result for the treatment of, the novel cpd of the mechanism of constitutional features that need to be new and new effect occurs.
Current antibacterials from structure classification mainly contain beta-lactam, glycopeptide class, aminoglycoside, tetracyclines, quinolones, polypeptide class, polyenoid class, sulfamido, ketolide, oxazolone class, paraxin, Macrolide etc., taking nitrogen heterocyclic ring compounds as main.In nitrogen-containing heterocycle compound, except above-mentioned a few class medicines, the antibacterial or fungicidal activity that indolizidine alkaloid class material is done well, just has many indolizidine alkaloid class materials in disinfectant use in agriculture, show good biological activity.In the pyrrolizidine alkaloid drug development of the microorganism pathogenic to people, the 2-benzimidazolyl derivatives that Yadav etc. are synthetic, the pyridine-imidazole compound that Al-Tel etc. are synthetic etc., bacterium and fungi that many people of causing are infected show good bacteriostatic activity.From above example, the antibacterials that can suppress or kill human disease bacterium and fungi from indolizidine alkaloid exploitation are more feasible.
6-hydroxyl-3,4-dihydro-1H-quinoline-2-one-, Chinese another name: 3,4-dihydro-6-hydroxyl-2 (1H)-quinolinone, 3,4-dihydro-6-hydroxyl-2 (1H)-quinolinone, 6-hydroxyl-3,4-dihydro-quinolinone, English name: 6-Hydroxy-3,4-dihydro-1H-quinoline-2-one, CAS No.54197-66-9, molecular formula C
9h
9nO
2, molecular weight 163.1733, chemical structural formula is as figure below:
Find through research, 6-hydroxyl-3,4-dihydro-1H-quinoline-2-one-has multiple pharmacologic action, such as antibacterium, anti-inflammatory, antithrombotic formation and antiviral activity etc., but the anti-microbial property of this compound is not fine, therefore, need to do further improvement to the anti-microbial effect of this compound.
Summary of the invention
The first object of the present invention is to provide a kind of 4,5-glyoxalidine [1,2-a] quinoline, solves current antibiotic application and is restricted, and easily causes bacterium to produce resistance, causes the problem that need to synthesize new antibacterials.
The second object of the present invention is to provide the pharmaceutical composition that contains 4,5-glyoxalidine [1,2-a] quinoline.
The 3rd object of the present invention is to provide the application of 4,5-glyoxalidine [1,2-a] quinoline in preparation antibacterials.
The present invention is achieved through the following technical solutions: the invention provides by 4 of following general formula (I) expression 5-glyoxalidine [1,2-a] quinoline and salt thereof:
Wherein: R represents C
1-C
12alkyl, phenmethyl and substituted benzene methyl;
Y represents H, O, N;
R
1represent C
1-C
12alkyl, phenyl, substituted-phenyl, phenmethyl and substituted benzene methyl.
Wherein, C
1-C
12alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl of straight chain or side chain etc.; Substituted-phenyl refers in the ortho position of phenyl ring, a position, contraposition and has halogen and the C such as single or multiple fluorine, chlorine, bromine, iodine
1-C
5alkyl, C
1-C
5the phenyl that alkoxyl group, trifluoromethyl, methylsulfonyl, sulfamyl etc. replace; Substituted benzene methyl refers in the ortho position of phenyl ring, a position, contraposition and has halogen and the C such as single or multiple fluorine, chlorine, bromine, iodine
1-C
5alkyl, C
1-C
5the phenmethyl that alkoxyl group, trifluoromethyl, methylsulfonyl, sulfamyl etc. replace.
Of the present invention 4,5-glyoxalidine [1,2-a] salt of quinoline refers to pharmacy acceptable salt, for example, react the salt generating with hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, methylsulfonic acid, dextrocamphoric acid, oxalic acid.
Further preferred, wherein substituted-phenyl is halogenophenyl.
Preferably, wherein substituted benzene methyl is halogeno-benzene methyl.
Preferably, wherein R represents heptyl.
Preferably, wherein Y represents H.
Further preferred, wherein R represents heptyl, and Y represents H.
Compound of the present invention comprises:
7-propoxy--4,5-glyoxalidine [1,2-a] quinoline (1)
7-hexyloxy-4,5-glyoxalidine [1,2-a] quinoline (2)
7-oxygen in heptan base-4,5-glyoxalidine [1,2-a] quinoline (3)
7-butoxy-4,5-glyoxalidine [1,2-a] quinoline (4)
7-(4-methylbenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline (5)
7-(4-bromobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline (6)
1-isoamylamino-7-hexyloxy-4,5-glyoxalidine [1,2-a] quinoline (7)
1-(3-chlorobenzene amino)-7-hexyloxy-4,5-glyoxalidine [1,2-a] quinoline (8)
1-aminotoluene base-7-butoxy-4,5-glyoxalidine [1,2-a] quinoline (9)
1-(4-methylbenzene methylamino-)-7-propoxy--4,5-glyoxalidine [1,2-a] quinoline (10)
1-penta amino-7-benzyloxy-4,5-glyoxalidine [1,2-a] quinoline (11)
1-aminotoluene base-7-oxygen in heptan base-4,5-glyoxalidine [1,2-a] quinoline (12)
1-(3,4-dichlorobenzene amino)-7-(4-fluorobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline (13)
1-(2,6-difluorobenzene methylamino-)-7-(4-fluorobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline (14)
1-phenoxy group-7-propoxy--4,5-glyoxalidine [1,2-a] quinoline (15)
1-(4-methoxyphenoxy)-7-propoxy--4,5-glyoxalidine [1,2-a] quinoline (16)
1-benzyloxy-7-butoxy-4,5-glyoxalidine [1,2-a] quinoline (17)
1-(4-fluorobenzene methoxyl group)-7-propoxy--4,5-glyoxalidine [1,2-a] quinoline (18)
1-isopropoxy-7-benzyloxy-4,5-glyoxalidine [1,2-a] quinoline (19)
1-(4-chlorobenzene methoxyl group)-7-oxygen in heptan base-4,5-glyoxalidine [1,2-a] quinoline (20)
1-(4-4-trifluoromethylphenopendant)-7-(4-bromobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline (21)
1-(2-fluorobenzene methoxyl group)-7-(4-fluorobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline (22)
Compound of the present invention is prepared by following steps:
1, taking general formula I I as starting raw material,
In ethanol solution, with the mol ratio phenmethyl chlorine back flow reaction that is 1:1.125 20 hours, obtain compound III:
2, compound III is under acetonitrile and triethylamine exist, and with equimolar thiophosphoric anhydride heating reflux reaction 12 hours, obtains compound IV:
3, then in dehydrated alcohol, compound IV and equimolar aminoacetaldehyde dimethanol, back flow reaction 24h; Steam except dehydrated alcohol afterwards, add 100 ° of C of acetic acid to continue reaction 4h, reaction finishes rear steaming and desolventizes, and obtains compound V by column chromatography:
4, at H
2(60psi), under environment, compound V is through palladium carbon (20%H
2o) catalysis, 60 ° of C reaction 4h, filtration catalizer, solvent evaporated obtain compound VI:
5, compound VI respectively with halo straight or branched C
1-C
12alkane, phenmethyl chlorine and substituted benzene methyl chlorine react 4 hours, the compound that must be represented by general formula I (Y=H):
6,, at-10 ° of C, Compound I (Y=H) is reacted with N-bromo-succinimide and is obtained the compound that represented by general formula VII in tetracol phenixin.
7, the compound being represented by general formula VII respectively with straight or branched C
1-C
12fatty alcohol, phenol and fortified phenol, aniline and substituted aniline, phenylcarbinol and substituted benzyl alcohol, aminotoluene and substituted benzoyl ammonia react approximately 4 ~ 5 hours, the compound that obtains being represented by general formula I.
Reaction scheme is as follows:
Of the present invention 4,5-glyoxalidine [1,2-a] quinoline and salt thereof is as effective constituent, can be made into conventional formulation with conventional pharmaceutical carrier, be prepared into be applicable to the interior administration of oral, non-enteron aisle (vein or subcutaneous) and nose tablet or sugar coated tablet, sublingual tablet, capsule, gelatine capsule, suppository, creme, ointment, for skin, gelifying agent, injectable formulation maybe can use the formulations such as suspension agent.The dosage of compound of the present invention, concerning adult, every day, 500-1000mg was proper.
Of the present invention 4,5-glyoxalidine [1,2-a] quinoline and salt thereof can be used for preparing antibacterials, and bacterium infects in treatment.
Adopt the positively effect of technique scheme: of the present invention 4,5-glyoxalidine [1,2-a] quinoline and acceptable salts thereof be to streptococcus aureus and intestinal bacteria, and all inhibited to other Gram-negative bacterias (as Pseudomonas aeruginosa, Klebsiella pneumonia, Bacillus proteus, Salmonellas, pasteurellosis bacillus etc.) and gram positive organism (as suis), antibacterial effect is better than Ciprofloxacin and amoxycilline Trihydrate bp in some respects, therefore, this compound can be used for preparing antibacterials, for the research and development of antibacterials provide new thinking.
Embodiment
The chemical reagent source explanation using in the present invention:
Starting raw material 6-hydroxyl-3,4-dihydro-1H-quinoline-2-one-is purchased from Sigma Chinese companies, and aminoacetaldehyde dimethanol is purchased from Beijing coupling Science and Technology Ltd., and other reagent, purchased from traditional Chinese medicines group Shenyang chemical reagent factory, are analytical pure.
The bacterial classification source explanation using in the present invention:
Streptococcus aureus (S.aureus) ATCC 6538, intestinal bacteria (E.coli) ATCC 8739, Pseudomonas aeruginosa (P.aeruginosa) ATCC27853, Klebsiella pneumonia (K.peneumoniae) ATCC 700603, Bacillus proteus (Proteusbacillus vulgaris) ATCC35659, Salmonellas (Salmonella) ATCC14028, pasteurellosis bacillus (Pasteurella) ATCC12948, suis (Streptococcus) ATCC 29212 is all purchased from Shanghai Kun Ken biochemical industry company limited.
Below by embodiment, test example and example of formulations, technical scheme of the present invention is described further, but should not be construed as limitation of the present invention, wherein, embodiment is for illustrating the preparation of compound and the preparation of antibacterials, test example is for the pharmacological action of compound of the present invention and the superiority with respect to other antibacterials are described, example of formulations is for illustrating the pharmaceutical preparation comprising by compound provided by the invention.
[embodiment 1] 6-benzyloxy-3, the preparation of 4-dihydro-1H-quinoline-2-one-
By benzene first chlorine (113g, 0.90mol) put into round-bottomed flask, add sodium hydroxide (36g, 0.90mol) and 6-hydroxyl-3,4-dihydro-1H-quinoline-2-one-(13.0g, 0.80mol), then add anhydrous dehydrated alcohol (500mL), reaction solution heating reflux reaction 20h is complete through TLC confirmatory reaction.Solvent evaporated, residue is poured in frozen water, filters, dry, obtains white powder.
[embodiment 2] 6-benzyloxy-3, the preparation of 4-dihydro-1H-quinoline-2-thioketones
Acetonitrile (900mL) and triethylamine (300mL) are poured in round-bottomed flask.Under ice-water bath, add in batches thiophosphoric anhydride (166g, 0.75mol) and constantly stir, after thiophosphoric anhydride all dissolves, add compound 6-benzyloxy-3,4-dihydro-1H-quinoline-2-one-(180g, 0.75mol).Stirring and refluxing reaction 12h.Remove solvent under reduced pressure, residue obtains yellow powder through anhydrous dehydrated alcohol recrystallization.
[embodiment 3] 7-benzyloxy-4, the preparation of 5-glyoxalidine [1,2-a] quinoline
By 6-benzyloxy-3,4-dihydro-1H-quinoline-2-thioketones (110g, 0.43mol), aminoacetaldehyde dimethylacetal (45g, 0.43mol) and triethylamine (101g, 1mol) add in round-bottomed flask, then add anhydrous dehydrated alcohol (300mL), reaction solution reflux 24h.Complete through TLC chromatogram confirmatory reaction.Steaming desolventizes, and in residue, adds acetic acid (150mL), in 100 ° of C reaction 4h, complete through TLC confirmatory reaction.Steaming desolventizes, and obtains sterling with column chromatography for separation, obtains 40.56g, yield 36%.
1H-NMR(400MHz,CD
2Cl
2)δ:2.88-3.09(m,4H,H-4,H-5),5.08(s,2H,-OCH
2-),6.91-7.05(m,2H,H-6,H-8),7.19-7.22(d,1H,H-9),7.31-7.42(m,5H,Ar-H),7.48-7.50(m,2H,H-1,H-2).MS m/z 277(M+1).
[embodiment 4] 7-hydroxyl-4, the preparation of 5-glyoxalidine [1,2-a] quinoline
By 7-benzyloxy-4,5-glyoxalidine also [1,2-a] quinoline (20g, 0.076mol) is put into reaction also, adds palladium carbon (5g, 20%), then adds without anhydrous water dehydrated alcohol (100mL).At H
2(60 ° of C, 45psi) reaction 24h under environment.Complete through TLC confirmatory reaction.Filtering palladium carbon, steams and desolventizes to obtain crude product, is directly used in next step reaction.
[embodiment 5] 7-propoxy--4, the preparation of 5-glyoxalidine [1,2-a] quinoline (1)
By 7-hydroxyl-4,5-dihydro miaow [1,2-a] quinoline (1g, 5.4mmol) is put into flask with NaOH (0.24g, 6.0mmol), adds DMF (50mL).In solution upward, add N-PROPYLE BROMIDE (12.0mmol), 60 ° of C reaction 4h of reaction solution heating, TLC shows that reaction finishes.Steaming desolventizes, and anhydrous dehydrated alcohol recrystallization for residue, obtains 1.11g, yield 81%.
1H-NMR(CDCl
3,300MHz)δ:0.93(t,3H,J=7.1Hz,-CH
3),1.80-1.84(m,2H,-CH
2-),2.97-3.20(m,4H,H-4,H-5),4.05(t,2H,J=6.5Hz,-OCH
2-),6.81-6.89(m,2H,H-6,H-8),7.12-7.20(d,1H,H-9),7.41-7.47(m,2H,H-1,H-2).MS m/z 257(M+1).
[embodiment 6] 7-hexyloxy-4, the preparation of 5-glyoxalidine [1,2-a] quinoline (2)
Mode described in similar preparation example 5, by 7-hydroxyl-4,5-dihydro miaow [1,2-a] quinoline (1g, 5.4mmol) is put into flask with NaOH (0.24g, 6.0mmol), adds dimethyl formamide, i.e. DMF (50mL).In solution upward, add bromohexane (6.0mmol), 60 ° of C reaction 4h of reaction solution heating, TLC shows that reaction finishes.Steaming desolventizes, and anhydrous dehydrated alcohol recrystallization for residue, obtains 1.13g, yield 78%.
1H-NMR(CDCl
3,300MHz)δ:0.92(t,3H,J=7.0Hz,-CH
3),1.35-1.83(m,8H,-(CH
2)
4-),3.01-3.24(m,2H,H-4,H-5),3.98(t,2H,J=6.5Hz,-OCH
2-),6.83-6.91(m,2H,H-6,H-8),7.11-7.19(d,1H,H-9),7.49-7.56(m,2H,H-1,H-2).MS m/z 271(M+1).
[embodiment 7] 7-oxygen in heptan base-4, the preparation of 5-glyoxalidine [1,2-a] quinoline (3)
Mode described in similar preparation example 5, by 7-hydroxyl-4,5-dihydro miaow [1,2-a] quinoline (1g, 5.4mmol) is put into flask with NaOH (1g, 5.4mmol), adds DMF (50mL).In solution upward, add heptyl bromide (6.0mmol), 60 ° of C reaction 4h of reaction solution heating, TLC shows that reaction finishes.Steaming desolventizes, and residue dehydrated alcohol recrystallization, obtains 1.23g, yield 80%.
1H-NMR(CDCl
3,300MHz)δ:0.88-1.88(m,13H,-(CH
2)
5CH
3),3.00-3.23(m,2H,H-4,H-5),3.98(t,2H,J=6.5Hz,-OCH
2-),6.89-6.95(m,2H,H-6,H-8),7.09-7.18(d,1H,H-9),7.44-7.50(m,2H,H-1,H-2).MS m/z 285(M+1).
Adopt above-mentioned same method, replace respectively heptyl bromide to react with n-butyl bromide, 4-fluorobenzene methyl chloride, 4-methylbenzene methyl chloride, 4-Brombenzyl chlorine, prepare following compound:
7-butoxy-4,5-glyoxalidine [1,2-a] quinoline (4),
7-(4-fluorobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline,
7-(4-methylbenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline (5),
7-(4-bromobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline (6).
[embodiment 8] 1-bromo-7-oxygen in heptan base-4, the preparation of 5-glyoxalidine [1,2-a] quinoline
At-10 ° of C, to compound (3) 7-oxygen in heptan base-4, the CCl of 5-glyoxalidine [1,2-a] quinoline (1g, 3.5mmol)
4(50mL) in solution, slowly add N-bromo-succinimide (NBS) (0.62g, 3.5mmol), continue reaction 15min.Filtering insolubles, in filtrate, add water (50mL), extraction, collected organic layer, anhydrous sodium sulfate drying, solvent evaporated obtains crude product, is directly used in next step reaction.
1H-NMR(CDCl
3,300MHz)δ:0.87-1.86(m,13H,-(CH
2)
5CH
3),2.98-3.21(m,2H,H-4,H-5),3.95(t,2H,J=6.5Hz,-OCH
2-),6.91-6.95(m,2H,H-6,H-8),7.12-7.19(d,1H,H-9),7.43(s,1H,H-2).MS m/z 363(M+1),365(M+3).
Adopt and use the same method, with 7-propoxy--4,5-glyoxalidine [1,2-a] quinoline (1), 7-hexyloxy-4,5-glyoxalidine [1,2-a] quinoline (2), 7-butoxy-4,5-glyoxalidine [1,2-a] quinoline (4), 7-benzyloxy-4,5-glyoxalidine [1,2-a] quinoline, 7-(4-fluorobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline, 7-(4-bromobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline (6) is substrate, reacts with NBS, prepare following compound, for next step reaction:
The bromo-7-of 1-propoxy--4,5-glyoxalidine [1,2-a] quinoline,
The bromo-7-of 1-hexyloxy-4,5-glyoxalidine [1,2-a] quinoline,
The bromo-7-of 1-butoxy-4,5-glyoxalidine [1,2-a] quinoline,
The bromo-7-of 1-benzyloxy-4,5-glyoxalidine [1,2-a] quinoline,
The bromo-7-of 1-(4-fluorobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline,
The bromo-7-of 1-(4-bromobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline.
[embodiment 9] 1-aminotoluene base-7-oxygen in heptan base-4, the preparation of 5-glyoxalidine [1,2-a] quinoline (12)
By the bromo-7-of 1-oxygen in heptan base-4,5-dihydro miaow [1,2-a] quinoline (0.1g, 0.28mmol) is put into flask with TEA (0.031g, 0.31mmol), adds DMF (10mL).In solution upward, add benzene methanamine (0.033g, 0.31mmol), 80 ° of C reaction 4h of reaction solution, TLC shows that reaction finishes.Steaming desolventizes, and residue dehydrated alcohol recrystallization, obtains 0.08g, yield 73%.
1H-NMR(CDCl
3,300MHz)δ:0.92(t,3H,J=7.1Hz,-CH
3),1.33-1.81(m,6H,-(CH
2)
3-),2.93-3.17(m,4H,H-4,H-5),3.75,(s,1H,-NH-),4.05(t,2H,J=6.5Hz,-OCH
2-),4.43(s,2H,-CH
2-),6.81-6.89(m,2H,H-6,H-8),7.12-7.20(d,1H,H-9),7.31-7.35(m,5H,Ar-H),7.45(s,1H,H-2).MS m/z 390(M+1).
[embodiment 10] 1-(4-chlorobenzene methoxyl group)-7-oxygen in heptan base-4, the preparation of 5-glyoxalidine [1,2-a] quinoline (20)
Mode described in similar embodiment 9, by the bromo-7-of 1-oxygen in heptan base-4,5-dihydro miaow [1,2-a] quinoline (0.1g, 0.28mmol) is put into flask with TEA (0.031g, 0.31mmol), adds DMF (10mL).In solution upward, add 4-chlorobenzene methanol (0.044g, 0.31mmol), 80 ° of C reaction 5h of reaction solution, TLC shows that reaction finishes.Steaming desolventizes, and residue dehydrated alcohol recrystallization, obtains 0.09g, yield 78%.
1H-NMR(CDCl
3,300MHz)δ:0.89(t,3H,J=7.1Hz,-CH
3),1.30-1.78(m,6H,-(CH
2)
3-),2.95-3.09(m,4H,H-4,H-5),4.43(s,2H,-CH
2-),5.05(s,2H,-OCH
2-),6.80-6.86(m,2H,H-6,H-8),7.18-7.22(d,1H,H-9),7.33-7.38(m,4H,Ar-H),7.50(s,1H,H-2).MSm/z 425(M+1),427(M+3).
Equally, adopt the mode described in similar embodiment 9 and embodiment 10, prepare following compound:
The bromo-7-of 1-hexyloxy-4 of 1, preparing with embodiment 8,5-glyoxalidine [1,2-a] quinoline reacts with isobutylcarbylamine, m-chloro aniline respectively, prepares following compound:
1-isoamylamino-7-hexyloxy-4,5-glyoxalidine [1,2-a] quinoline (7),
1-(3-chlorobenzene amino)-7-hexyloxy-4,5-glyoxalidine [1,2-a] quinoline (8);
The bromo-7-of 1-butoxy-4 of 2, preparing with embodiment 8,5-glyoxalidine [1,2-a] quinoline reacts with benzene methanamine, phenylcarbinol respectively, prepares following compound:
1-aminotoluene base-7-butoxy-4,5-glyoxalidine [1,2-a] quinoline (9),
1-benzyloxy-7-butoxy-4,5-glyoxalidine [1,2-a] quinoline (17);
The bromo-7-of 1-propoxy--4 of 3, preparing with embodiment 8,5-glyoxalidine [1,2-a] quinoline respectively with to methyl benzene methanamine, phenol, p methoxy phenol, fluorophenyl methanol is reacted, prepares following compound:
1-(4-methylbenzene methylamino-)-7-propoxy--4,5-glyoxalidine [1,2-a] quinoline (10),
1-phenoxy group-7-propoxy--4,5-glyoxalidine [1,2-a] quinoline (15),
1-(4-methoxyphenoxy)-7-propoxy--4,5-glyoxalidine [1,2-a] quinoline (16),
1-(4-fluorobenzene methoxyl group)-7-propoxy--4,5-glyoxalidine [1,2-a] quinoline (18);
The bromo-7-of 1-benzyloxy-4 of 4, preparing with embodiment 8,5-glyoxalidine [1,2-a] quinoline reacts with amylamine, Virahol respectively, prepares following compound:
1-penta amino-7-benzyloxy-4,5-glyoxalidine [1,2-a] quinoline (11),
1-isopropoxy-7-benzyloxy-4,5-glyoxalidine [1,2-a] quinoline (19);
5, the bromo-7-of 1-(4-fluorobenzene methoxyl group)-4 preparing with embodiment 8,5-glyoxalidine [1,2-a] quinoline respectively with 3,4-DCA, 2,6-difluoroaniline, face fluorophenyl methanol and react, prepare following compound:
1-(3,4-dichlorobenzene amino)-7-(4-fluorobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline (13),
1-(2,6-difluorobenzene methylamino-)-7-(4-fluorobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline (14),
1-(2-fluorobenzene methoxyl group)-7-(4-fluorobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline (22);
6, the bromo-7-of 1-(4-bromobenzene methoxyl group)-4 preparing with embodiment 8,5-glyoxalidine [1,2-a] quinoline and 4-trifloro methyl phenol react, and prepare following compound:
1-(4-4-trifluoromethylphenopendant)-7-(4-bromobenzene methoxyl group)-4,5-glyoxalidine [1,2-a] quinoline (21).[test example 1] antibacterial pharmacological evaluation
By the compound of general formula I representative, positive control amoxycilline Trihydrate bp and Ciprofloxacin use respectively sesquialter By Dilution its to streptococcus aureus (S.aureus) ATCC 6538 and intestinal bacteria (E.coli) ATCC 8739 minimal inhibitory concentrations (MIC).Substratum is selected MH substratum, and solid plate is selected MH solid medium (Shanghai epoch Bioisystech Co., Ltd).
By the compound of the general formula I representative of different concns after doubling dilution, positive control amoxycilline Trihydrate bp and Ciprofloxacin (DMSO solution), be added to respectively in 96 hole polystyrene plates of sterilizing, the the 1st to the 11st hole adds liquid, every hole 10 μ l, the 1st hole to the 11 hole drug levels are respectively 128,64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/ml, and the 12nd not dosing of hole is as growth control.After frost drying, seal ,-20 DEG C save backup below.
Be 1 × 10 by the bacterial count of preparing with growth method
6-1 × 10
7bacterium liquid, in every hole, add 100 μ l, in the rearmounted 35 ° of C normal air incubators of sealing, hatch 16-20h.When test hemophilus, when streptococcus, incubation time is 20-24h, incubation time 24h when test staphylococcus and faecalis test.
Get the bacterium liquid 100 μ l in 96 hole polystyrene plate holes, evenly coat solid plate, put in 35 ° of C normal air incubators, hatch 16-20h judged result.Colony number <5 on solid plate, being considered as medicine has bacteriostatic activity to this bacterial strain.
Compound (1-22), amoxycilline Trihydrate bp and Ciprofloxacin are as shown in table 1 to the bacteriostatic test result of S.aureus and E.coli.
The MIC (μ g/mL) of table 1 compound (1-22) to S.aureus and E.coli
As can be seen from the table, the compound 1-22 of synthesized, majority of compounds is better than contrast medicine amoxycilline Trihydrate bp and Ciprofloxacin to the inhibition activity of S.aureus and E.coli.Wherein the bacteriostatic activity of compound 3 is better than other compounds.
The antibacterial pharmacological evaluation of [test example 2] compound 3
Compound 3 is to several Gram-negative bacterias (Pseudomonas aeruginosa (P.aeruginosa) ATCC27853, Klebsiella pneumonia (K.peneumoniae) ATCC 700603, Bacillus proteus (Proteusbacillus vulgaris) ATCC35659, Salmonellas (Salmonella) ATCC14028, pasteurellosis bacillus (Pasteurella) ATCC12948), the inhibition activity experiment of gram positive organism (suis (Streptococcus) ATCC 29212) adopts the method for test example 1.
The MIC (μ g/mL) of table 2 compound 3 to six kinds of bacterium
Result is as shown in table 2, and as seen from Table 2, compound 3 shows certain inhibition activity to Pseudomonas aeruginosa, suitable with Ciprofloxacin, is better than amoxycilline Trihydrate bp.Active in Ciprofloxacin to the inhibition of Klebsiella pneumonia.Be 16 μ g/mL to the MIC of Bacillus proteus, be better than contrast medicine amoxycilline Trihydrate bp and Ciprofloxacin.Be 64 μ g/mL to the MIC of Salmonellas, be better than contrast medicine amoxycilline Trihydrate bp and Ciprofloxacin.Be 2 μ g/mL to the MIC of pasteurellosis bacillus, be better than equally amoxycilline Trihydrate bp and Ciprofloxacin.
Therefore, compound of the present invention has wide market outlook in the preparation of antibacterials.
[example of formulations 1]
Prepare tablet according to methods known in the art, every contains following compositions:
[example of formulations 2]
Prepare capsule according to methods known in the art, in each capsule, contain following compositions:
Claims (2)
1. by 4 of following general formula (I) expression, 5-glyoxalidine [1,2-
a] quinoline and salt thereof:
（I）
Wherein: R represents heptyl, Y represents H.
2. claimed in claim 14,5-glyoxalidine [1,2-
a] quinoline and the application of salt in preparation antibacterials thereof.
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| WO1999040094A1 (en) * | 1998-02-09 | 1999-08-12 | Bayer Aktiengesellschaft | Agent for sealing metallic ground coats, especially ground coats consisting of zinc or zinc alloys |
| WO2001029038A1 (en) * | 1999-10-18 | 2001-04-26 | Kabushiki Kaisha Yakult Honsha | Tricyclic fused-imidazole derivatives |
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| WO1999040094A1 (en) * | 1998-02-09 | 1999-08-12 | Bayer Aktiengesellschaft | Agent for sealing metallic ground coats, especially ground coats consisting of zinc or zinc alloys |
| WO2001029038A1 (en) * | 1999-10-18 | 2001-04-26 | Kabushiki Kaisha Yakult Honsha | Tricyclic fused-imidazole derivatives |
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