CN1958568B - A kind of compound for preventing or curing infection of helicobacter pylori, preparation method, and application - Google Patents
A kind of compound for preventing or curing infection of helicobacter pylori, preparation method, and application Download PDFInfo
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- CN1958568B CN1958568B CN2005101100154A CN200510110015A CN1958568B CN 1958568 B CN1958568 B CN 1958568B CN 2005101100154 A CN2005101100154 A CN 2005101100154A CN 200510110015 A CN200510110015 A CN 200510110015A CN 1958568 B CN1958568 B CN 1958568B
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- ZKEUFANNIHTNMR-UHFFFAOYSA-N N/C(/CSc1cc(cccc2)c2cc1)=N\O Chemical compound N/C(/CSc1cc(cccc2)c2cc1)=N\O ZKEUFANNIHTNMR-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/14—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to hydrogen atoms or to acyclic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
Abstract
This invention relates to a compound for treating or preventing bacteria infection, especially Helicobacter pylori infection, and accompanied diseases, and its preparation method and medical applications.
Description
Technical field
The present invention relates to prevention or treatment and infect the disease cause or to follow or compound, its preparation method and the medical usage of symptom by some bacterium (especially helicobacter pylori).
Background technology
(Helicobacterpylori is a kind of grow in stomach mucous membrane layer, microanaerobic gram negative bacterium H.pylori) to helicobacter pylori, it is reported that the whole world has half population can infect this pathogenic bacteria in life approximately.Nineteen eighty-three Marshall separates from gastritis sufferer's stomach mucous membrane sample first with Warren and obtains helicobacter pylori, this important discovery changed people to peptic ulcer disease because of understanding, therefore greatly promoted the development of gastroenterology research, two people also obtain Nobel's physiology in 2005 or medical science prize.Now clear and definite, helicobacter pylori is not only the arch-criminal who produces peptide ulceration, but also be gastritis and cancer of the stomach main diseases because of.Therefore, the World Health Organization is classified as I class carcinogens with it.
Helicobacter pylori spread path and bad life habits and diet residential areas are closely related, propagate very easily mutually in the daily life and infect.Though the infection rate developed country helicobacter pyloris such as the U.S. and West Europe has begun to descend, to developing countries' (comprising China), this numeral still gains momentum.Helicobacter pylori infection not only can cause a series of disease of upper digestive tract such as comprising chronic gastritis, peptide ulceration, non-ucler dyspepsia, adenocarcinoma of stomach, stomach non_hodgkin lymphoma and mucosa associated lymphoid tissue lymphoma, but also be associated with cardiovascular and cerebrovascular diseases, autoimmune disorder and some dermopathic morbidity or progress, thereby human beings'health and life in serious harm.
The poor effect of single antibiotic therapy helicobacter pylori infection, and make bacterium produce resistance easily.The treatment plan that medical circle is recommended is to unite to use proton pump inhibitor or ranitidine bismuth citrate to add two or three microbiotic i.e. so-called " triple therapy " or " quadruple chemotherapy ".Anti helicobacter pylori medicine thing commonly used at present comprises metronidazole, clarithromycin, amoxycilline Trihydrate bp, tsiklomitsin and Nifurazolidone etc.Because antibiotic long-term unreasonable use, helicobacter pylori is on the increase the resistance phenomenon of said medicine (special metronidazole and clarithromycin), has a strong impact on clinical result of treatment.
The difficulty that is faced on infection population that the whole world is huge and the clinical treatment calls anti-helicobacter pylori to infect the generation of new drug.This class drug candidate with good DEVELOPMENT PROSPECT should embody following characteristics: (1) structure is brand-new, and mechanism of action is different from existing medicine: (2) anti-microbial activity is strong, meets acid and stablizes; (3) narrow antimicrobial spectrum, the selectivity height, still effective to drug-fast helicobacter pylori; (4) use the difficult resistance phenomenon that takes place repeatedly.
Aminopeptidase is that a class can the catalytic pyrolysis polypeptide and the proteolytic enzyme of protein N terminal amino-acid residue, extensively be present in protokaryon and the eukaryotic cell, in the protein course of processing, be responsible for the initial amino acid of excision new polypeptide chain N end, protein maturation, transhipment in cell and location and function are regulated very important, by the cell physiological function of bringing into normal play essential.Therefore, aminopeptidase is a drug target that has much potentiality.The currently reported inhibitor of some aminopeptidases that shows has the activity that suppresses bacterium or parasite growth.(Leucyl aminopeptidase is a modulability biological enzyme rare in the aminopeptidase family LAP) to the leucine aminopeptidase(LAP) that the clone obtains from helicobacter pylori, infers that it is most important to the normal activities of keeping helicobacter pylori.
The present invention is a starting point with recombinant expressed helicobacter pylori leucine aminopeptidase(LAP), sets up based on the dynamic (dynamical) high flux screening model of relevant enzyme, has found that by extensive random screening a class specific effect is in the inhibitor of this enzyme.Experiment shows that this compounds has certain anti-microbial activity to helicobacter pylori.The invention provides the correlation technique and the application thereof of a synthetic class novel anti helicobacter pylori medicine.
Summary of the invention
The purpose of this invention is to provide pharmaceutically acceptable salt of a kind of formula I compound that can suppress infectation of bacteria (especially helicobacter pylori) or its;
Another object of the present invention has provided a kind of method of preparation I compound;
Another object of the present invention has provided a kind of pharmaceutical composition that contains formula I compound;
Another object of the present invention has provided the purposes that formula I compound is used to prepare disease medicaments such as prevention or treatment peptide ulceration.
The invention provides by suppressing the active series compound that stops some bacterium (especially helicobacter pylori) growth of leucine aminopeptidase(LAP), increased antibiotic member.The present invention relates to have the compound of following molecular formula I, or acceptable salt on its pharmacology:
Wherein Ar is following any one substituting group:
R
1, R
2For following arbitrarily any one, two or three substituting groups: comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, C
1-C
4Alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group; Aryl; 2-, 3-or 4-position pyridyl; Furyl; Pyranyl; Thienyl; Pyrryl; Contain and comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at 2-, 3-or the 4-position pyridyl of interior any one, two or three replacements; Contain and comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements.X is O, NH, NCH
3Or S; N is 0-8 integer;
Y is H, O, S, NH, NCH
3, or NOH;
Z is amino, C
1-C
4Monoalkyl or two alkyl-substituted amino, or comprise aryl, 2-, 3-or 4-position pyridyl, furyl, pyranyl, thienyl, pyrryl is at interior any one or the amino of two replacements.
Preferably, this series compound has, but is not limited to following molecular formula II:
The compound of being contained in the chemical structure of general formula of the present invention can with following logical method preparation (concrete grammar is referring to Journal ofmedicinal chemistry, 1993,36 (17): 2485-2493):
1eq ArXH, 1-2eq salt of wormwood are joined in an amount of acetone, methylene dichloride, chloroform or the ethyl acetate and refluxes, slowly drip acetone, methylene dichloride, chloroform or the ethyl acetate solution of 1-1.5eq Cl (CH2) nCN.After dropwising, continue stirring and refluxing 2-20 hour, obtain intermediate 2.
Get 1eq intermediate 2 and be dissolved in an amount of dehydrated alcohol, boil and reflux.The sodium Metal 99.5 of 10-20eq is slowly added.In the mixture impouring dilute hydrochloric acid, add an amount of dehydrated alcohol again.Leach inorganic filter thing, add 85% dehydrated alcohol cooling, separate out the hydrochloride of amine, filter.
Get intermediate 2 and mix, more than 70-100 ℃ of stirring reaction 2h, filter with an amount of 60-90% sulfuric acid.Filter cake is transferred in the reaction flask, adds the ammoniacal liquor neutralization under stirring, the control neutral temperature is no more than 50 ℃, and keeps the neutral pH value about 5-7, filters, and leaches solid ammonium sulfate.Solid is separated out in cooling, obtains acid amides.
Get 1eq intermediate 2, the 2eq oxammonium hydrochloride is dissolved in an amount of dimethyl sulfoxide (DMSO) or DMF, stirs the methanol solution that adds the 2-4eq sodium methylate down, is warming up to 60-90 ℃ of reaction more than 1 hour.Reducing pressure steams excessive methyl alcohol, and residuum adds entry and stirs, and adds the ethyl acetate layering, and water layer washs with ethyl acetate, merges organic phase, and dry, concentrated, column chromatography gets the product oxime.
In addition preferably, this series compound or its acceptable salt on pharmacology is the form with pharmaceutical composition, or separately, or acceptable carrier or vehicle are united and provided on pharmacology.The present invention also provides the medicine box that comprises above-claimed cpd, is used for prevention or treatment by infectation of bacteria, helicobacter pylori for example, disease that causes or follow or symptom.
On the other hand, the present invention relates to combined preparation, this combined preparation comprises a kind of optionally bacteria growing inhibiting that has, and especially suppresses the active compound of helicobacter pylori leucine aminopeptidase(LAP), or on its pharmacology acceptable salt and a kind of on pharmacology acceptable carrier or vehicle.Preferably, this combined preparation comprise on a kind of compound or its pharmacology acceptable salt and a kind of on pharmacology acceptable carrier or vehicle.
The present invention also provides the medicine box that comprises above-mentioned combined preparation.The present invention also further provides above-mentioned combined preparation treatment of application or prevention by infectation of bacteria, for example helicobacter pylori infection, the disease that causes or follow or the method for symptom and medicine box.
Embodiment
In order to illustrate summary of the invention and not limited to by it, invention is divided into following trifle is described in detail.
The A definition
Unless otherwise defined, technology that the present invention is used and scientific term have same meaning with the general understanding of the current techique in field under the present invention.The application of all patents that derive from gene pool and other databases that this place mentions, application, announcement and other publications and sequence are taken in comprehensively to be quoted as a reference.If the definition that the application of all patents that derive from gene pool and other databases of the definition that this section is illustrated and this patent ginseng usefulness, application, announcement and other publications and sequence are taken in and quoted is set forth opposite, or when inconsistent, the definition of illustrating with this section is as the criterion.
The present invention is used, and " one " or " one " refers to " at least one " or " one or more ".
The present invention is used, and " helicobacter pylori " refers to that a class grows in stomach mucous membrane layer, microanaerobic gram negative bacillus bacterial strain.
The present invention is used, and " by disease or the symptom that helicobacter pylori infection caused or followed " refers to the disease and the symptom that are caused separately by helicobacter pylori infection, or is caused jointly by heredity and/or acquired other factors and condition.
" significant quantity " of the compound that is used for the treatment of a certain specified disease that the present invention is used refers to enough improve or alleviate to a certain extent the amount of the sick symptom that accompanies therewith.This dosage can the single dose administration, also can be according to the treatment plan administration.But this dosage cure diseases, but be typically administration in order to improve this symptom.May need for improving the symptom repeat administration.
The present invention is used, and " acceptable salt, ester or other derivatives on the pharmacology " comprises any salt, ester or derivative that the field of medicine and chemical technology technician is easy to prepare with currently known methods.The compound of deriving like this and generating can not have toxic action to animal and human's administration.This compound or have pharmaceutical activity, or prodrug.
The present invention is used, and " treatment " refers to that disease and symptom are improved in any way, or other useful changes.Treatment also comprises the application of The compounds of this invention on medicine.
The present invention is used, and the symptom that gives a certain specified disease of a certain certain drug composition " improvement " is meant any alleviating, and is no matter permanent, interim, of short duration over a long time, can both owing to or relevant with using of this pharmaceutical composition.
The present invention is used, " pure basically " is meant enough even, can not survey impurity by the field of medicine and chemical technology technician for the standard method of analysis of estimating purity and using, described standard method of analysis is just like thin layer chromatography (TLC), gel electrophoresis and high performance liquid chromatography (HPLC).Even perhaps enough pure also refer to be further purified can not change the observable physicochemical property of this material, for example enzymic activity and biological activity.Being used for purifying compounds and making chemical pure basically method, is that the field of medicine and chemical technology technician is known.Yet chemical pure basically compound can be the mixture of steric isomer or isomers.In this case, be further purified the specific activity that perhaps can increase compound.
The present invention is used, and " prodrug " is meant a kind of compound of vivo medicine-feeding, and this compound can be by metabolism, or be converted into biologically, on the pharmacology or the activity form on the therapeutics.In order to make prodrug, pharmaceutical active compounds will be modified, and this active compound is produced by metabolic process again.Prodrug can be designed to change its metabolic stability, or the precursor of transportation characterization, to cover its side effect or toxicity, improves the sense of taste of medicine, or changes other characteristics.Rely on the knowledge of pharmacokinetics and medicine internal metabolism, in case active compound is known on the pharmacology, field of medicine and chemical technology technician just can design the prodrug of this compound.[referring to Nogrady, Medicinal Chemistry A Biochemical Approach, OxfordUniversity Press, New York, pages388-392 (1985)].
Term " basically " is identical even or similar, can in context, change to some extent the understanding of correlation technique according to the field of medicine and chemical technology technician, and be generally at least 70%, be preferably at least 80%, more excellently be at least 90%, optimum at least 95% identical.
Here used " composition " refers to any mixture.Can be solution, suspension, liquid, powder, ointment, water-based, nonaqueous or their any combination.
Here used " associating " refers to any associating between two or more.
Term used herein " object " comprises humans and animals, for example, and dog, cat, ox, pig, rodent etc.Experienced implementer should understand object for being suitable for and being ready to by infectation of bacteria, helicobacter pylori infection for example, and disease that causes or follow or symptom are treated and are prevented.
Any protectiveness group used herein, the abbreviation of amino acid and other compounds, consistent with their abbreviations general, that generally acknowledge or the biochemical name of IUPAC-IUB council promulgation, unless stated otherwise.[seeing Biochem.11:1726 (1972)].
The B antiseptic-germicide
The present invention is added in the microbiotic series by providing the active inhibited medicine of some bacterium leucine aminopeptidase(LAP).One aspect of the present invention relates to a kind of compound with following molecular formula I, or acceptable salt on its pharmacology:
Wherein Ar is following any one substituting group:
R
1, R
2For following arbitrarily any one, two or three substituting groups: comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, C
1-C
4Alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group; Aryl; 2-, 3-or 4-position pyridyl; Furyl; Pyranyl; Thienyl; Pyrryl; Contain and comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the aryl of two or three replacements; Contain and comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at 2-, 3-or the 4-position pyridyl of interior any one, two or three replacements; Contain and comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the furyl of two or three replacements; Contain and comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyranyl of two or three replacements; Contain and comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the thienyl of two or three replacements; Contain and comprise C
1-C
4Alkyl, nitro, cyano group, carboxyl, ester group, aldehyde radical, halogen, hydroxyl, alkoxyl group, amido, amide group, carbonamido, sulfydryl, methylthio group, ethylmercapto group at interior any one, the pyrryl of two or three replacements.X is O, NH, NCH3 or S; N is 0-8 integer;
Y is H, O, S, NH, NCH
3, or NOH;
Z is amino, C
1-C
4Monoalkyl or two alkyl-substituted amino, or comprise aryl, 2-, 3-or 4-position pyridyl, furyl, pyranyl, thienyl, pyrryl is at interior any one or the amino of two replacements.
Preferably, this series compound has, but is not limited to following molecular formula II:
Compound of the present invention can be a specific steric isomer, for example cis or transconfiguration, or their mixture.Here the compound of Kao Lving comprises that all have the classes of compounds of pharmaceutical activity, or its solution or mixture.Also comprise its hydration type, the aqueous solution of these compounds for example, hydrolysate or ionization product; And these compounds can contain the bound water molecule of different quantities.
Compound of the present invention can prepare or synthesize according to any suitable method.Preferably, prepare this compound in order to the synthesis method of quoting as proof in the following E joint.
Also have, preferably, acceptable salt provides with the form of pharmaceutical composition on this compound or its pharmacology, and is perhaps independent, perhaps combines with acceptable carrier or vehicle on a kind of pharmacology.
Compound of the present invention can prepare with the form of any suitable acid with acceptable salt on its pharmacology.For example; Mineral acid example hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, or the like all can use.In other examples, organic acid such as formic acid, acetate, propionic acid, phenylformic acid, toxilic acid, fumaric acid, succsinic acid, tartrate, citric acid or the like all can use.Another example, alkylsulphonic acid such as methylsulphonic acid, ethylsulfonic acid etc. can use.Also have an example, aryl sulfonic acid, Phenylsulfonic acid for example, tosic acid etc. all can use.
Can treat any object with present method, preferred mammal, more preferably people.
Present method can be used to prevent and treat any disease and symptom that is caused by helicobacter pylori infection.Preferred disease is chronic gastritis, peptide ulceration, non-ucler dyspepsia, adenocarcinoma of stomach, stomach non_hodgkin lymphoma and mucosa associated lymphoid tissue lymphoma etc.
When disease that causes by above-mentioned infectation of bacteria in prevention or treatment and symptom, can use separately or unite and use compound of the present invention with other gone on the market proton pump inhibitor, bismuth agent and the microbiotic that maybe will go on the market.Any suitable proton pump inhibitor, bismuth agent and microbiotic all can be united use with compound of the present invention.Typical antibiosis have metronidazole, clarithromycin, amoxycilline Trihydrate bp, tsiklomitsin and Nifurazolidone; Other microbiotic comprise penicillin and derivative, cynnematin and derivative thereof, macrolide antibiotics, aminoglycoside antibiotics, tetracycline antibiotics, new glycopeptide antibiotics, polypeptide antibiotics, Novel Quinolone class microbiotic, oxazolidine ketone microbiotic, dihydrofolate reductase inhibitor and various microbiotic tougheners etc.
Do not give above-mentioned microbiotic when in a preferred embodiment of the invention, using The compounds of this invention.More preferably, induce the caused disease of drug-fast strain and the symptom of generation by above-mentioned microbiotic with compounds for treating of the present invention or prevention.
Can be by any suitable method separately with compound administration of the present invention, or unite use with other suitable microbiotic.For example, can pass through intracavitary administration, subcutaneous injection, intravenous injection, intramuscularly, the intradermal injection, oral or local with compound administration of the present invention, or with acceptable salt administration on its pharmacology.
In specific embodiments, present method further comprises to be diagnosed and prognosis evaluation the bacterial infection of administration object.Can use any suitable method to be used to diagnose and assess the prognosis of infectation of bacteria.Diagnosis and prognosis can be based on the bacterioprotein that detects and/or identify any or all, for example its enzyme, antigen, antibody, nucleic acid or other pathologic and clinical marker thing and symptoms.For example, the diagnosis or the method for prognosis that can use international monopoly WO01/44815 and United States Patent (USP) 5,571,674 to disclose.
The C combined preparation, the method for medicine box and drug combination
On the other hand, the present invention also relates to combined preparation, this unite comprise a kind of to bacterium, helicobacter pylori particularly, selectivity suppresses the active compound of its leucine aminopeptidase(LAP), or acceptable salt and one or more microbiotic on its pharmacology.
Preferably, this drug combination comprises acceptable salt and one or more microbiotic on a kind of compound or its pharmacology, and this compound has the substituting group of above-mentioned described molecular formula I, II and definition.
In combined preparation of the present invention, can use any suitable microbiotic.In a particular, be used for combined preparation of the present invention and can comprise in the above-mentioned microbiotic one or more.
In another particular, provide a kind of treatment or prevention by infectation of bacteria, helicobacter pylori infection for example, the disease that causes or follow or the method for symptom, this method comprises needs and is ready to treat or the object that prevents gives the above-mentioned combined preparation of significant quantity, or acceptable salt on its pharmacology, thereby treat or prevent above-mentioned disease or symptom.
In another particular, a medicine box is provided, it comprises on compound of the present invention or its pharmacology acceptable salt and uses on above-claimed cpd or its pharmacology acceptable salt to prevent and treat infectation of bacteria, for example helicobacter pylori infection, the disease that causes or the operation instruction of symptom.
In another embodiment, provide a medicine box, comprised above-mentioned combined preparation and use described combined preparation treatment or prevention, for example helicobacter pylori infection, the disease that causes or the operation instruction of symptom by infectation of bacteria.
D prescription and dosage
According to the present invention, compound of the present invention, separately or with other medicament, carrier or vehicle associating, for any suitable route of administration is formulated preparation, for example intracavitary administration, subcutaneous injection, intravenous injection, intramuscularly, intradermal are injected, oral or local application.Present method can be used injecting and administering preparations, with the form of single dose at ampoule, or in the multi-dose container with the buffer reagent drug administration by injection that adds.Preparation can be taked following form such as suspension, solution or the emulsion in oiliness or aqueous media.Preparation can contain prescription reagent such as suspensoid, stablizer and/or dispersion agent.In addition, before the use, activeconstituents can powder type and suitable carriers, aseptic no heat source water or other solvents formation formulation.Local application of the present invention can adopt foam, gel, and ointment, ointment changes leather diaphragm, or paste.
The dosage size of treatment or prevention is the seriousness of feelings and route of administration and change to some extent due to illness.Dosage can react different because of age, body weight, healthy state and individual patient with the medication frequency.
It is to be noted (the diagnosis and treatment doctor also should know), according to toxicity and side reaction, the termination of must taking the necessary measures, interruption or reduction therapeutic dose.On the contrary, if clinical response not obvious (getting rid of toxicity and side reaction), the doctor should suitably adjust treatment plan, improves dosage.
Any suitable route of administration all may be utilized.Formulation comprises tablet, lozenge, beans shape capsule, dispersion agent, suspension agent, solution, capsule, diaphragm and analogue etc.
In actual applications, compound of the present invention is united separately or with other preparations, can be according to general pharmacology hybrid technology and pharmaceutical carrier or vehicle, and for example β-cyclodextrin and 2-hydroxyl-propyl group-β-cyclodextrin is closely mixed.According to the needs of dispensing, can adopt the special carrier of universal support, part or parenteral route.Prepare non-parenteral dosage forms, for example intravenous injection or the composition inculcated can adopt similar medicine medium, water known in those skilled in the art, ethylene glycol, oil, buffer reagent, sugar, sanitas, liposome etc.The example of this non-enteron aisle composition comprises, but is not restricted to dextrose, physiological saline or other solution of 5%W/V.The total dose of compound of the present invention, separately or and other preparation Combined Preparation, the administration of available bottle intravenous fluid, volume is approximately from 1 milliliter to 2000 milliliters.According to the total dose of administration, the dilution liquid measure also can be different.
The present invention also provides the medicine box of realizing treatment plan.This medicine box is united the compound of the present invention of effective dose separately or with other reagent with acceptable form on the pharmacology, is included in one or more containers.Preferably medicament forms is and Sterile Saline, dextrose solution, and buffered soln, or other drug is learned upward, and acceptable sterile liquid share.Perhaps, composition can be by freeze-drying or drying; In this case, medicine box is randomly further with acceptable solution on a kind of pharmacology, and preferred aseptic solution is included in the container, is formed for injecting the solution of purpose to reformulate mixture.Acceptable solution is salt brine solution and dextrose solution on the typical pharmacology.
In another embodiment, medicine box of the present invention further comprises and is used for the preferred with the pin of sterile form packing or the alcohol pads of syringe and/or packing of injectable composition.Can randomly comprise specification sheets for doctor or patient's use.
E embodiment
Laboratory apparatus and reagent
The HP1100HPLC system possesses binary gradient pump, online vacuum degassing machine, automatic sampler, column oven and photodiode array detector.Chromatographic column is ZORBAX ODS (4.6x250mm), and moving phase is methanol (80:20), and flow velocity is 1ml/min, and the detection wavelength is 254nm.
All solvents are the HPLC level.The MS collection of illustrative plates is recorded by PE API2000LC/MS/MS mass spectrometer.The 1H-NMR data are recorded by Institute of Analysis of Shanghai Pharmaceutical Inst., Chinese Academy of Sciences.All synthetic starting raw materials are the commercially available prod
Embodiment 1
0.020mol compound 1,0.025mol salt of wormwood are joined in the 50ml acetone and refluxes, slowly drip 0.026molCl (CH
2) the acetone soln 10ml of nCN.After dropwising in 30 minutes, continued stirring and refluxing 18 hours, cooling concentrates.Add 50ml ethyl acetate and 50ml water stratification.Water layer merges organic phase with ethyl acetate (20ml) washing 3 times, anhydrous sodium sulfate drying, concentrated, and column chromatography gets light yellow solid.Synthesize following compound with this method:
1HNMR(CDCl
3)：3.66(s，2H)，7.54(m，3H)，7.81(m，3H)，8.05(s，1H).
1HNMR(CDCl
3)：4.68(s，2H)，7.08(m，2H)，7.35(m，2H)，7.68(m，3H)
2.64mmol compound 2,5.29mmol oxammonium hydrochloride are dissolved in an amount of dimethyl sulfoxide (DMSO), stir the methanol solution (the 1.0g sodium Metal 99.5 is dissolved in the 20ml methyl alcohol) that adds the 4.1ml sodium methylate down, be warming up to 80 ℃ of reactions 1.5 hours.Decompression steams methyl alcohol, and residuum adds 50ml water stirring 1 hour, adds the layering of 50ml ethyl acetate, and water layer merges organic phase with ethyl acetate (20ml) washing 3 times, anhydrous sodium sulfate drying, concentrated, and column chromatography gets pale solid.Synthesize following compound with this method:
1HNMR(CDCl
3)：3.68(s，2H)，4.90(s，2H)，7.45(s，3H)，7.76(s，3H)，7.85(s，1H).
1HNMR(DMSO-D
6)：4.47(s，2H)，5.62(s，2H)，7.17(m，1H)，7.38(m，3H)，7.77(m，3H)
The activity of embodiment 2 novel antibacterial series compounds
The leucine aminopeptidase(LAP) of helicobacter pylori is an allosteric enzyme, and hydrolysis specifically has the peptide bond of amino-acid residues such as Leu-, and its activity is regulated and control by divalent cation.Under the reaction conditions of 37oC, 50mM Tris-HCl (pH8.0) damping fluid and 0.5mM MnCl2, but leucine aminopeptidase(LAP) catalytic hydrolysis substrate L-leu-p-nitroanilide, and the product pNA (p-Nitroaniline) of generation has characteristic light to absorb at the 405nm place.By Spectra MAX340Microplate Reader absorbancy is detected, and converse relative inhibition [the Lei Dong of testing sample to leucine aminopeptidase(LAP), Ni Cheng, Ming-Wei Wang, Junfeng Zhang, Chang Shu and De-Xu Zhu.The leucyl aminopeptidase from Helicobacter pylori isan allosteric enzyme.Microbiology, 2005,151:2017-2023].In view of the above, by 32000 samples being carried out bioactivity screening and multiple sieve checking, finds a series of leucine aminopeptidase(LAP) to be had the active compound of inhibition, its half-inhibition concentration (IC50) is between 2-9 μ M.
In order to study the influence of above-claimed cpd, adopt agar dilution to measure their minimal inhibitory concentrations (MIC) to helicobacter pylori reference culture ATCC43504 to the helicobacter pylori life cycle.The result shows that compound N C00072450 has certain anti-helicobactor pylori activity, and its MIC value is 32 μ g/ml (seeing the following form).
Table 1. related compound of the present invention gathers (the positive contrast of Bestatin) to the restraining effect of leucine aminopeptidase(LAP) and helicobacter pylori reference culture ATCC43504
Above-mentioned example is as an illustration purpose only, and scope of the present invention is not so limited.It is conspicuous making amendment concerning the technician of field of medicine and chemical technology, and the present invention only is subjected to the restriction of claims scope.
Claims (4)
1. acceptable salt suppresses application in the medicine of helicobacter pylori infection in preparation on the following compound of a structural formula or its pharmacology,
Wherein Ar is:
X is O or S;
N is 1;
Y is NOH;
Z is amino.
2. the application of acceptable salt in the medicine of preparation inhibition helicobacter pylori infection on the compound of a following structural formula or its pharmacology,
3. one kind contains the effective dose of compound described in claim 1 or 2 and pharmacy acceptable salt thereof and the application of composition in preparing the medicine that suppresses helicobacter pylori infection that assistant agent is formed.
4. the application of composition according to claim 3 in the medicine of preparation inhibition helicobacter pylori infection, it is characterized in that, described composition comprises proton pump inhibitor, bismuth agent and microbiotic, and described microbiotic refers to metronidazole, penicillin and derivative thereof, cynnematin and derivative thereof, macrolide antibiotics, aminoglycoside antibiotics, tetracycline antibiotics, new glycopeptide antibiotics, polypeptide antibiotics, Novel Quinolone class microbiotic, oxazolidine ketone microbiotic, dihydrofolate reductase inhibitor.
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| CN2005101100154A CN1958568B (en) | 2005-11-03 | 2005-11-03 | A kind of compound for preventing or curing infection of helicobacter pylori, preparation method, and application |
| PCT/CN2006/002911 WO2007051408A1 (en) | 2005-11-03 | 2006-10-30 | Compounds for preventing or treating the h.pylori infection, preparation methods and use therrof |
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| EP2552893B1 (en) | 2010-03-31 | 2014-10-29 | Actelion Pharmaceuticals Ltd. | Antibacterial isoquinolin-3-ylurea derivatives |
| AR088729A1 (en) | 2011-03-29 | 2014-07-02 | Actelion Pharmaceuticals Ltd | DERIVATIVES OF 3-UREIDOISOQUINOLIN-8-ILO AND A PHARMACEUTICAL COMPOSITION |
| CN109096156B (en) * | 2018-09-28 | 2021-01-15 | 吉首大学 | Disulfonyl meta-aryl diamine urease inhibitor and preparation method and application thereof |
| CN113754564B (en) * | 2021-08-02 | 2022-08-26 | 湖南大学 | Antibacterial amidine oligomer with drug resistance and preparation method and application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CS213038B1 (en) * | 1980-09-09 | 1982-03-26 | Miroslav Protiva | Arylthioacetamidoximes |
| US4895861A (en) * | 1989-04-21 | 1990-01-23 | American Home Products Corporation | Novel naphthalenyl-3H-1,2,3,5-oxathiadiazole 2-oxides useful as antihyperglycemic agents |
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| US3775478A (en) * | 1972-05-30 | 1973-11-27 | Dow Chemical Co | Substituted phenylthioamidines |
| US3790679A (en) * | 1972-05-30 | 1974-02-05 | Dow Chemical Co | Urinary antiseptic method with thioacetamidines |
| US3847986A (en) * | 1973-05-30 | 1974-11-12 | Dow Chemical Co | Substituted phenylthioamidines |
| US3933912A (en) * | 1973-09-27 | 1976-01-20 | The Dow Chemical Company | Substituted phenylthioamidines |
| US3994976A (en) * | 1974-07-08 | 1976-11-30 | The Dow Chemical Company | Substituted phenylthioamidines |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CS213038B1 (en) * | 1980-09-09 | 1982-03-26 | Miroslav Protiva | Arylthioacetamidoximes |
| US4895861A (en) * | 1989-04-21 | 1990-01-23 | American Home Products Corporation | Novel naphthalenyl-3H-1,2,3,5-oxathiadiazole 2-oxides useful as antihyperglycemic agents |
Non-Patent Citations (1)
| Title |
|---|
| IRENA CERVENA ET AL,.synthesis of arylthioacetamidoximes as potentialantidepressants.Collection Czechoslovak Chem. Commun.46.1981,461188-1198. * |
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