CN103113295A - Alkyl-substituted quinolinone compound with side chains as well as preparation method, pharmaceutical composition and application thereof - Google Patents
Alkyl-substituted quinolinone compound with side chains as well as preparation method, pharmaceutical composition and application thereof Download PDFInfo
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Abstract
The invention provides an alkyl-substituted quinolinone compound with side chains. The alkyl-substituted quinolinone compound has a chemical structure represented by formula I, the name of the alkyl-substituted quinolinone compound is 2-(4'-methyl-)heptane-3-methyl-4(1H)-quinolinone, the chemical formula of the alkyl-substituted quinolinone compound is C18H22NO, and the alkyl-substituted quinolinone compound is named as heptanone. The invention further provides an application of pharmaceutical composition of the compound provided by the invention in preparation of drugs for prevention and/or treatment of gastritis caused by Helicobacter pylori. According to the alkyl-substituted quinolinone compound, a first-site N of the quinolinone is not hydroxylated, and a second-site of the quinolinone is substituted by 4-methyl-heptane; the quinolinone is prepared by utilizing total synthesis; and the compound, represented by the formula I and provided by the invention, has a relatively high selective inhibition effect on the Helicobacter pylori and is an efficient proton pump inhibitor, so that a possibility for developing a novel drug for treating the gastritis caused by the Helicobacter pylori is provided.
Description
Technical field
The invention provides a kind of alkyl substd quinolines ketone compound, preparation method and pharmaceutical composition and purposes with side chain, belong to medical technical field.
Background technology
Helicobacter pylori (Helicobacter pylori) is a kind of gram-negative Helicobacter pylori that is colonizated in gastric mucosa, be the important paathogenic factor that causes chronic gastritis and peptic gastric ulcer, the World Health Organization has classified it as the I class carcinogen of stomach malignancy such as gastric mucosa dependency lymphoid tissue lymphoma and adenocarcinoma of stomach.The H.pylori chronic infection rate is up to more than 50% in whole world crowd, and the ratio of developing country's infection population has even reached 70 ~ 90%.The epidemiology survey in 2001 ~ 2004 years of the sick branch of digestion of Chinese Medical Association shows that China's Helicobacter Pylori Infection Rate is 40% ~ 90%, average out to 59%; The childhood infection rate is 25% ~ 59%, and is average 40%, and every year on average with 0.5%～1% speed increase.The helicobacter pylori infection disease has become one of the most serious and urgent public health problem in the world today.
Treatment by the microbial digestive system of helicobacter pylorus more and more receives publicity clinically and payes attention to, the triple therapy of exemplary application proton pump inhibitor (PPI)+amoxycilline Trihydrate bp+clarithromycin clinically at present, long because of the course for the treatment of, the antimicrobial drug consumption is large, patient digestive tract reaction occurs and feels sick, vomits, suffers from abdominal pain, suffers from diarrhoea, even occurs pseudomembranous enteritis etc., cause patient's compliance to reduce, Chang Buneng completes the whole course for the treatment of, and in time put off the generation resistance, the eradication rate that causes using this scheme reduces gradually, becomes the problem that needs to be resolved hurrily clinically.Vaccine development is successfully that the microbial peptide ulceration of prevention helicobacter pylorus is brought hope, but because the Heliobacter pylori antigen immunogenicity is very low, the immunne response that causes is limited, need to use simultaneously adjuvant (coli heat-sensitive toxin LT), the toxicity of adjuvant has limited again clinical application, and pasting is not that some Hp albumen and people's albumen have high homology, orally causes that immunoreactive amount of vaccine can cause increasing the weight of of gastritis again, namely gastritis after the immunity, cause its compliance to reduce.Treatment by Chinese herbs has certain effect, and side effect is smaller, but medicine time is longer, be only applicable to the low weight patient of symptom, and curative ratio is low.Therefore, the exploitation Anti-helicobacter pylori drugs receives publicity, and becomes one of the emphasis of present drug research and focus.
Since 1962 find first Comprecin Nalidixic Acid that contains 4-quinolinone parent nucleus, many scholars are devoted to research and develop this class medicine, particularly obtained in the recent decade the leap progress, developed fourth generation quinolone, be used for the treatment of Gram-negative bacteria and part gram-positive microorganism, but this class medicine is undesirable to the microbial digestive system effect for the treatment of helicobacter pylorus.In prior art, many parts of documents disclose quinolinone and uses thereof.for example, CN1391896 discloses a kind of antianaphylactic novel quinoline ketone compound, CN1150420 discloses the 4-qualone derivative and salt is used for the recycle system and respiratory system disease, CN1056305 discloses a kind of new 4(1H) quinoline ketone derivative is used for the treatment of the cardiovascular system respiratory system disease of unifying, related to the present invention only have a kind of 1-hydroxyl-2-(2-of relating in the disclosed medical compsns. against helicobacter pylori of CN1255853 anti--the nonene base)-3-methyl-4(1H)-quinolinone, but the structure of quinolinone described in CN1255853, preparation method and function and the present invention are different.1 N is by hydroxylation for the described quinolinone structure of CN1255853,2 by 2-anti--the nonene base replaces.But, can not be used for solve the problem of the digestive system that the treatment Hp causes.
Summary of the invention
For the prior art above shortcomings, technical problem to be solved by this invention provides a kind of novel quinoline ketone compound for the treatment of the digestive system that Hp causes and preparation method thereof.
Another object of the present invention is to provide the drug regimen that obtains with this quinolinone compounds, and is applied to treat the digestive system that Hp causes.
Solve the problems of the technologies described above, the present invention adopts following technical scheme:
A kind of alkyl substd quinolines ketone compound with side chain; It is characterized in that, its chemical structure is suc as formula I, its name be called the 2-(4`-methyl-) heptane base-3-methyl-4(1H)-quinolinone, its chemical formula is C
18H
22NO, called after quinoline in heptan ketone.
Further, formula I compound is amorphous substance or crystal type.
The preparation method of described formula I quinolinone compounds comprises the steps:
(1) get adjacent PAPP 13mmol, 4-methyl capryl(yl)chloride 20mmol puts in the two neck round-bottomed flasks of 250ml, add pyridine 18mmol, methylene dichloride 60-80ml, at room temperature stirring reaction 4-20 hour, add saturated ammonium chloride solution 60-100ml, get organic phase, concentrating under reduced pressure, residual thing silica gel column chromatography, collect object, concentrating under reduced pressure, drying obtains 4-methyl-decoyl PAPP;
(2) with step (1) 4-methyl decoyl PAPP 11mmol, put in the two neck round-bottomed flasks of 250ml, add tertiary butyl sodium alkoxide 30-40mmol, anhydrous organic solvent 180-240ml, back flow reaction 4-36 hour, concentrating under reduced pressure reclaimed ethanol, adds water 100-200ml wash-out once, residual thing silica gel column chromatography, collect object, concentrating under reduced pressure, drying, obtain the 2-(4`-methyl-) heptane base-3-methyl-4(1H)-quinolinone, be formula I compound.
A kind of pharmaceutical composition, it is characterized in that, comprise the formula I, it is unit dosage form, and wherein said unit dosage form is selected from: tablet, capsule, granule, injection liquid, injectable powder, transdermal patch, ointment, gelifying agent, suppository, oral liquid, oral administration mixed suspension, injectable emulsion, Orally taken emulsion etc., slow releasing tablet or controlled release tablet.
A kind of pharmaceutical composition is characterized in that, comprises formula formula I compound, for the preparation of the medicine for the treatment of duodenal ulcer, stomach ulcer, reflux esophagitis medicine or hyperchlorhydria; It is the amount in unit dosage form, with formula I compound, C
18H
22The NO meter is respectively 80-150mg.
A kind of pharmaceutical composition is characterized in that, comprises formula I compound, for the preparation of the purposes in the medicine that prevents and/or treats the digestive system that Hp causes.
In the present invention, term " treatment " has its general implication, and refer to especially adopt formula I compound of the present invention or pharmaceutical composition to process to the digestive system patient that Hp causes at this paper, produce treatment, the effect such as cure, alleviate, alleviate to the digestive system patient that described Hp is caused.Similarly, as used herein, term " prevention " has its general implication, and refer to especially adopt formula I compound of the present invention or pharmaceutical composition to process to suffering from the digestive system that Hp of the present invention causes or the digestive system that Hp of the present invention causes being had the risk person of suffering from this paper, to the digestive system that described Hp is caused produce prevent, prevent, stop, the effect such as partition.
As used herein, term " pharmacy is acceptable " typically refers to pharmacy field and can use, and to product or harmless to Mammals, or has rational or acceptable interests/risk ratio.
As used herein, term " carrier " and " vehicle " can be carrier and the vehicle of any routine in pharmacy field.Concrete carrier and the selection of vehicle will be depended on administering mode or disease type and the state that is used for the treatment of particular patient.Be used for the preparation method of suitable drug composition of specific administration pattern fully in pharmaceutical field technician's ken.For example, can be used as carrier, vehicle, thinner, weighting agent, solvent, balustrade, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier and the lubricant etc. that pharmaceutically acceptable carrier or vehicle comprise the pharmaceutical field routine.In case of necessity, can also comprise flavouring agent, preservative and sweetener etc.
As used herein, term " digestive system that Hp causes " has the general sense of its medical field.
As used herein, term " significant quantity " refers to the amount of active ingredient of the present invention, and this amount can effectively prevent and/or treat the digestive system that Hp of the present invention causes.
As used herein, term " pharmaceutical composition " or " medicine box product " have its general implication, and can refer to narrow sense pharmaceutical preparation or pharmaceutical dosage form in this article, and it can comprise or not comprise pharmaceutical excipient.Can adopt the particularly routine techniques in formulation art of pharmacy field, prepare the combination of pharmaceutical composition of the present invention or compound medicine.According to pharmaceutical composition of the present invention, it is the pharmaceutical dosage form that goes for oral administration, parenteral admin or topical, topical administration.According to pharmaceutical composition of the present invention, described pharmaceutical dosage form includes but not limited to: tablet, capsule, granule, pulvis, injection liquid, injectable powder, transdermal patch, ointment, gelifying agent, suppository, oral liquid, oral administration mixed suspension, injectable emulsion, Orally taken emulsion etc., slow releasing tablet, controlled release tablet etc.The medicine of above-mentioned various formulations all can be according to the ordinary method preparation of pharmaceutical field.
As medicament administration during in the animal subject patient, they can give with itself, namely do not add any above-mentioned pharmaceutically acceptable carrier, and pharmaceutical composition of the present invention directly is applied to the patient with original shape when pharmaceutical composition of the present invention or medicine box product; Can be perhaps to contain more preferably 10-90% for example of 1-99%(for example) formula I compound be combined into pharmaceutical composition with pharmaceutically acceptable carrier after give the human or animal.
Activeconstituents in formula I compound of the present invention or pharmaceutical composition or medicine box product, its actual dosage level and the time-histories of using can change, in order to obtain a kind of amount of activeconstituents, this amount is for specific tested individuality, composition and application process, the treatment that can effectively obtain to expect is replied, and to tested individual nontoxicity.Certainly the active compound amount of gained, can change the actual dose level of the formula I compound in the present invention or medicine box product, so that can effectively obtain required therapeutic response for concrete patient, composition and administering mode.Will be appreciated that, total daily dosage portion of the formula I compound in formula I compound of the present invention or pharmaceutical composition or medicine box product must be examined the doctor by the master and maked decision in the medical judgment scope reliably.For any concrete patient, the concrete horizontal fibrous root for the treatment of effective dose is decided according to many factors, and described factor comprises the severity of the obstacle for the treatment of and this obstacle; The activity of the particular compound that adopts; The concrete composition that adopts; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound that adopts, route of administration and excretion rate; The treatment time length; The medicine that is used in combination with the particular compound that adopts or uses simultaneously; And the known similar factor of medical field.
Formula I compound in formula I compound of the present invention or pharmaceutical composition or medicine box product, as indicated above, their concrete dosage can be determined according to existing knowledge by those skilled in the art.If necessary, effectively per daily dose can be divided into multiple doses for the administration purpose.Therefore, unit-dose composition or pharmaceutical preparation unit can contain this quantity or its divided dose, to consist of per daily dose.For medicine box product of the present invention, formula I compound wherein is applied to tested individuality according to the regular hour order, such as both using simultaneously, use with the interval of optional order etc.
Formula I compound in pharmaceutical composition of the present invention can be mixed with solid or liquid form for oral administration especially specially.
In yet another aspect, formula I compound in pharmaceutical composition of the present invention or medicine box product can tolerate with one or more nontoxic physiology or acceptable thinner, carrier, auxiliary material or vehicle (this paper can be referred to as carrier with them〉together be mixed with composition, with solid or liquid form oral administration or topical etc.
Formula I compound in pharmaceutical composition of the present invention or medicine box product also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agents and anti-mycotic agent, such as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc. can guarantee to prevent the effect of microorganism.Also expectation comprises isotonic agent, such as carbohydrate, sodium-chlor etc.By using the material that can postpone absorption, for example aluminum monostearate and gelatin.
Also can contain suspension agent except the active ingredient beyond the region of objective existence in suspensoid, such as ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, the mixture etc. of aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials partially.
Formula I compound in pharmaceutical composition of the present invention or medicine box product can be solid dosage for oral administration, and described solid dosage for oral administration comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound can be accepted vehicle or carrier such as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade and/or following material with the medicine of at least a inertia and mix: a) weighting agent or extender such as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks such as glycerine; D) disintegrating agent such as agar, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate and sodium carbonate; E) solution retarding agent such as paraffin; F) absorb accelerator such as quaternary ammonium compound; G) wetting agent such as hexadecanol and Zerol; H) sorbent material such as kaolin and wilkinite, and lubricant such as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.In the situation that capsule, tablet and pill also can comprise buffer reagent in described formulation.
Formula I compound in pharmaceutical composition of the present invention or medicine box product can be liquid dosage form for oral administration, and described liquid dosage form for oral administration comprises the acceptable emulsion of medicine, solution, suspensoid, syrup and elixir.Liquid dosage form also can contain this area inert diluent commonly used except containing the active ingredient beyond the region of objective existence, for example water or other solvents, solubilizing agent and emulsifying agent be ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1 for example, and the lipid acid of 3-dihydroxyl-butyleneglycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, four oxygen furfuryl alcohols, polyoxyethylene glycol and sorbitan extremely reaches their mixture.
Formula I compound of the present invention, through physical and chemical property determining, ultraviolet, infrared, mass spectrum and Analysis of Nuclear Magnetic Resonance are finally proved conclusively its structure.
Compared to existing technology, the present invention has following beneficial effect:
1 N of quinolinone of the present invention is not by hydroxylation, and 2 are replaced by 4 methyl-heptane base; Quinolinone of the present invention is complete synthesis; Particularly the present invention not only has than outside the stronger anti-helicobacter pylori activity of the described quinolinone of CN1255853, also has the equal restraining effect of the proton pump that is better than omeprazole that the described quinolinone of CN1255853 is not had, and to the normal beneficial body bacterium unrestraint effect of human intestinal, thereby overcome its technological deficiency, caused that for the present invention is used for the treatment of Hp digestive system infection and treatment digestive system and ulcer provide possibility.
the important breakthrough of the applicant in bearing national great new drug initiative subject study be, 2 quilt different carbonatoms purpose saturated alkyls of 4-quinolinone parent nucleus or replace with the saturated alkyl of side chain, and this 4-quinolinone also has anti-Hp effect, further, the alkyl of 2 the different carbonatoms purpose of use band side chains of 4-quinolinone parent nucleus replaces, and 3 when be methyl substituted, generation has stronger anti-Hp effect, further, increase with carbon atom number in 2 substituted alkyls, when particularly being had the side chain alkyl to replace, not only have anti Helicobacter pylori activity surpass the disclosed 1-hydroxyl-2-(2-of CN1255853 anti--the nonene base)-3-methyl-4(1H)-quinolinone, but also the proton pump restraining effect is also significantly strengthened, be better than omeprazole, and to the normal beneficial body bacterium of human intestinal such as lactobacterium acidophilus, Lactococcus lactis and thermophilus streptococcus etc. are without any effect, thereby overcome to have showed technological deficiency is arranged, for both having can be used for treating Hp, the present invention caused the digestive system infection disease, can be used for again digestive system and ulcer possibility is provided.
The pharmaceutical composition of formula I compound provided by the invention and medicine box product are through researchs such as pharmacodynamics, toxicology, preparation technology, quality examination and study on the stability.The applicant finds compound shown in formula I of the present invention and drug regimen thereof and clinical existing main flow medicine relatively through experiment repeatedly, also has following advantage:
1. the anti-Hp effect of formula I same dose of the present invention is better than existing chemicals amoxycilline Trihydrate bp and clindamycin.
2. formula I same dose of the present invention to the proton pump restraining effect, is better than the chemicals omeprazole.
3. the normal beneficial body bacterium of formula I human intestinal of the present invention is without effect, and selectivity is better than existing chemicals amoxycilline Trihydrate bp and clindamycin.
For above-mentioned advantage, the applicant will in aftermentioned embodiment the inside, also will enumerate specific embodiment and experimental data and make an explanation, illustrate and verify.
Embodiment
For showing effect of the present invention, further illustrate the present invention below by specific embodiment or test example.But, should be understood to, these embodiment or test example are only used for the use that specifically describes more in detail, and should not be construed as for limiting in any form the present invention.
The present invention carries out general and or concrete description to the material and the test method that use in test.Although for to realize that many materials and working method that the object of the invention is used are well known in the art, the present invention still does to describe in detail as far as possible at this.Those skilled in the art know that hereinafter, if do not specify, material therefor of the present invention and working method are well known in the art.
Embodiment 1, preparation quinoline ketone compound in synthetic heptan:
1. get adjacent PAPP 13mmol, 4-methyl-capryl(yl)chloride 20mmol puts in the two neck round-bottomed flasks of 250ml, add pyridine 18mmol, methylene dichloride 60-80ml, at room temperature stirring reaction 4-20 hour, add saturated ammonium chloride solution 60-100ml, get organic phase, concentrating under reduced pressure, residual thing silica gel column chromatography, collect object, concentrating under reduced pressure, drying obtains 4-methyl-Xin PAPP;
2. with step (1) 4-methyl-decoyl PAPP 11mmol, put in the two neck round-bottomed flasks of 250ml, add tertiary butyl sodium alkoxide 30-40mmol, anhydrous organic solvent 180-240ml, back flow reaction 4-36 hour, concentrating under reduced pressure reclaims ethanol, adds water 100-200ml wash-out once, residual thing silica gel column chromatography, collect object, concentrating under reduced pressure, drying, obtain the 2-(4`-methyl-) heptane base-3-methyl-4(1H)-quinolinone.
Detected result: unformed powder, in methyl alcohol, crystallization obtains tabular crystal, fusing point: 188-190 ℃,
3500(NH), 1740 (C=O); ESI-MS m/z[M+H]
+=: 272;
1H NMR (DMSO-d6,500MHz): δ=11.35 (s, 1H), 8.04 (d, J=8.0Hz, 1H), 7.57-7.47 (m, 2H), (7.24 t, J=8.0Hz, 1H), 2.69-2.60 (m, 2H), 1.97 (s, 3H), 1.60-1.14 (m, 9H), 0.94 (t, J=6.5Hz, 3H), (0.86 t, J=6.5Hz, 3H);
13C NMR (DMSO-d6,500MHz): δ=176.2,149.9,139.2,130.8,124.9,122.9,122.1,117.4,113.4,40.0,39.9,39.7,39.5,39.4,39.2,39.0,35.7,35.34,32.4,29.5,28.6,22.3,19.3,13.9,10.1.
The final conclusive evidence of above-mentioned synthetic the compounds of this invention for the 2-(4`-methyl-) heptane base-3-methyl-4(1H)-quinolinone, chemical formula is C
18H
22NO.Called after quinoline in heptan ketone generically.Chemical structure is as follows:
Embodiment 2, prepare the method for quinoline ketone tablet in heptan:
Take embodiment 1 preparation heptan the quinoline ketone compound as raw material, preparation quinoline ketone tablet in heptan, the formula of 1000 tablets is as follows:
| Heptan, quinoline ketone was (with C 18H 22The NO meter) | The auxiliary materials such as starch |
| 100 | 150 |
Former, auxiliary material are mixed, be ground into fine powder, cross 100 mesh sieves, by the formula taken amount, compression molding, packing gets final product.
Embodiment 3, prepare the method for quinoline ketone capsule in heptan:
Take embodiment 1 preparation heptan the quinoline ketone compound as raw material, preparation quinoline ketone capsule in heptan, the formula of 1000 capsules is as follows:
| Heptan, quinoline ketone was (with C 18H 22The NO meter) | The auxiliary materials such as starch |
| 100 | 150 |
Former, auxiliary material are mixed, be ground into fine powder, cross 100 mesh sieves, by the formula taken amount, granulation, packing get final product.
Biological test 1: heptan quinoline ketone anti-microbial effect:
according to document (Ibrahim M, Khan AA, Tiwari SK, et a1.Antimierobial activity of Sapindus mukorossi and Rheum emodi extracts against H.priori:in vitro and in vivo studies.World J Gastroenterol, 2006.14:7136-7142.) method carried out testing (table 1) to Hp SW-2 and the reference culture effect of the anti-clinical separation of quinoline ketone in heptan, test-results prompting quinoline ketone in heptan is better than amoxycilline Trihydrate bp and clindamycin to clinical separation and standard Hp strain restraining effect.
The MIC(unit of table 1 quinoline in heptan ketone to the Hp growth: μ g/ml)
Biological test 2: heptan, quinoline ketone was on the impact of human intestinal probiotic bacterium:
Be the milk-acid bacteria substratum with MRS, with lactobacillus plantarum AS1.577, the Lactobacillus acidophilus 6082, thermophilus streptococcus 6035, Lactococcus lactis 6029, lactobacillus johnsonii 21001, bifidobacterium 6173 and lactobacillus paraceasi 6112 are the target body bacterium, according to document Li Yi Kui (the pharmacology of Chinese materia medica experimental methodology. Shanghai: Shanghai science tech publishing house, 1991:286) method carry out U.S. quinoline ketone and heptan quinoline ketone on the impact for the examination bacteria growing, and with amoxycilline Trihydrate bp and the positive contrast of clindamycin.Test-results shows that amoxycilline Trihydrate bp and clindamycin reach the 30mm left and right to above-mentioned for examination probiotic bacterium bacteriostatic diameter when 0.001mg/ml, and heptan, quinoline ketone tried milk-acid bacteria in 0.001-10mg/ml unrestraint effect to supplying, and the prompting the compounds of this invention has better selectivity.
Impact (the antibacterial circle diameter: mm) of table 3 quinoline in heptan ketone on the human intestinal probiotic bacterium
Biological test 3: heptan, quinoline ketone was to the effect of proton pump:
Method bright according to document Xu Rui and Zhang Jianjun (Chinese pharmacology communication the 29 volume third phase in 2012) carried out U.S. quinoline ketone and heptan quinoline ketone to proton pump (H
++ K
++ ATP enzyme) restraining effect test (table 3).Result shows that heptan, quinoline ketone inhibiting rate was better than omeprazole.
Table 3 quinoline in heptan ketone is to proton pump (H
++ K
++ ATP enzyme) effect
Comprehensive evaluation mark: calculate the analog synthesis score value by computer medicine aided design.
Biological test 4: heptan, quinoline ketone was to the therapeutic action of experimental animal ulcer:
According to document Maria doCarmo Souzaa, Angela M á rcia Selhorst Beserraa, with (Journal of Ethnopharmacology 123 (2009) the 452 – 458) method such as Dely Cristina Martinsa, male Wistar rat (170-200g) inoculation Hp AATTCC43504 bacterial strain bacterium liquid (9 * 10
8Cfu/ml), after infecting for 1 week, begin treatment, by 2.5,5.0 and the 10mg/kg gastric infusion, and with the positive medicine contrast of triple therapy, administration every day 1 time, continuous 10 days, after drug withdrawal, second day was dissected inspection (table 4).Experimental result shows that heptan, quinoline ketone had better therapeutic action to Helicobacter pylori infection and animal stomach ulcer.
The therapeutic action of table 4 quinoline in heptan ketone to experimental animal ulcer
The present invention is that research is found in the Ministry of Science and Technology that the applicant bears great new drug initiative scientific research project, has the anti-Hp of efficient selective and suppresses the proton pump effect through repeatedly testing conclusive evidence formula I.Bring glad tidings for the Digestive tract patient to the exploitation of formula I compound, prospects for commercial application of the present invention is very good.
Compound of the present invention has the anti-Hp of selectivity and suppresses the effect such as proton pump, thus for a kind of new treatment Hp of exploitation cause that refining system infects and the drug provision of ulcer possibility.
Need to prove at last, above embodiment is only in order to illustrate technical scheme of the present invention but not the restriction technologies scheme, those of ordinary skill in the art is to be understood that, those are modified or are equal to replacement technical scheme of the present invention, and do not break away from aim and the scope of the technical program, all should be encompassed in the middle of claim scope of the present invention.
Claims (8)
1. alkyl substd quinolines ketone compound with side chain; It is characterized in that, its chemical structure is suc as formula I, its name be called the 2-(4`-methyl-) heptane base-3-methyl-4(1H)-quinolinone, its chemical formula is C
18H
22NO, called after quinoline in heptan ketone;
2. according to claim 1 with the alkyl substd quinolines ketone compound of side chain, it is characterized in that, the formula I is amorphous substance or crystal type.
3. according to claim 1 with the alkyl substd quinolines ketone compound of side chain, it is characterized in that, adopt the method that is prepared as follows:
(1) get adjacent PAPP 13mmol, 4-methyl capryl(yl)chloride 20mmol puts in the two neck round-bottomed flasks of 250ml, add pyridine 18mmol, methylene dichloride 60-80ml, at room temperature stirring reaction 4-20 hour, add saturated ammonium chloride solution 60-100ml, get organic phase, concentrating under reduced pressure, residual thing silica gel column chromatography, collect object, concentrating under reduced pressure, drying obtains 4-methyl-decoyl PAPP;
(2) with step (1) 4-methyl decoyl PAPP 11mmol, put in the two neck round-bottomed flasks of 250ml, add tertiary butyl sodium alkoxide 30-40mmol, anhydrous organic solvent 180-240ml, back flow reaction 4-36 hour, concentrating under reduced pressure reclaimed ethanol, adds water 100-200ml wash-out once, residual thing silica gel column chromatography, collect object, concentrating under reduced pressure, drying, obtain the 2-(4`-methyl-) heptane base-3-methyl-4(1H)-quinolinone, be formula I compound.
4. according to claim 3 with the alkyl substd quinolines ketone compound of side chain, it is characterized in that, described synthesis step 1 reacts under 10-30 ℃; Described synthesis step 2 refluxes at the temperature of 60-80 ℃, preferred 5 to 8 hours of described backflow.
5. according to claim 3 with the alkyl substd quinolines ketone compound of side chain, it is characterized in that, comprise formula I compound, it is unit dosage form, and wherein said unit dosage form is selected from: tablet, capsule, granule, injection liquid, injectable powder, transdermal patch, ointment, gelifying agent, suppository, oral liquid, oral administration mixed suspension, injectable emulsion, Orally taken emulsion etc., slow releasing tablet or controlled release tablet.
6. a pharmaceutical composition, is characterized in that, comprises formula I compound, for the preparation of the medicine for the treatment of duodenal ulcer, stomach ulcer, reflux esophagitis medicine or hyperchlorhydria.
7. pharmaceutical composition according to claim 6, is characterized in that, comprise formula I compound, it is the amount in unit dosage form, with formula I compound, C
18H
22The NO meter is respectively 80-150mg.
8. a pharmaceutical composition, is characterized in that, comprises formula I compound, for the preparation of the purposes in the medicine that prevents and/or treats the digestive system that Hp causes.
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| CN103664777A (en) * | 2013-10-09 | 2014-03-26 | 重庆理工大学 | 2-undecyl-3-methyl-hydroxyl-quinoline compound as well as preparation method, pharmaceutical composition and use thereof |
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| US6080757A (en) * | 1996-06-06 | 2000-06-27 | Pfizer Inc | Antibiotic quinolones and derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6080757A (en) * | 1996-06-06 | 2000-06-27 | Pfizer Inc | Antibiotic quinolones and derivatives |
Non-Patent Citations (1)
| Title |
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| CHRISTIAN EDIDAMSHAUS ETAL: "Synthesis of 4-Quinolones via Cyclocondensation of Substituted ortho-Amidoacetophenones:A Refit to the Camps Cyclization by Applying Trimethylsilyl Trifluoromethanesulfonate/Triethylamine", 《SYNTHESIS》, vol. 20, 31 October 2011 (2011-10-31), pages 3261 - 3266 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664777A (en) * | 2013-10-09 | 2014-03-26 | 重庆理工大学 | 2-undecyl-3-methyl-hydroxyl-quinoline compound as well as preparation method, pharmaceutical composition and use thereof |
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Inventor after: Xu Xiuying Inventor after: Zheng Yimin Inventor after: Wang Rui Inventor after: Zhang Yunling Inventor after: Chen Haiqin Inventor before: Zheng Yimin Inventor before: Xu Xiuying Inventor before: Wang Rui Inventor before: Liu Hong Inventor before: Zhang Xinrui |
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Free format text: CORRECT: INVENTOR; FROM: ZHENG YIMIN XU XIUYING WANG RUI LIU HONG ZHANG XINRUI TO: XU XIUYING ZHENGYIMIN WANG RUI ZHANG YUNLING CHEN HAIQIN |
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Application publication date: 20130522 |