CN102827247B - New sansanmycins, and their uses as anti-tuberculous medicines - Google Patents
New sansanmycins, and their uses as anti-tuberculous medicines Download PDFInfo
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- 0 CC(C(C(NC=C(CC1O*)OC1N(C=CC(N1)=O)C1=O)=O)NC(C(CCSC)NC(NC(Cc1c[n]c2ccccc12)C(N=O)=O)=O)=O)N(C)C(C(Cc1cc(O*)ccc1)N(*)*)=O Chemical compound CC(C(C(NC=C(CC1O*)OC1N(C=CC(N1)=O)C1=O)=O)NC(C(CCSC)NC(NC(Cc1c[n]c2ccccc12)C(N=O)=O)=O)=O)N(C)C(C(Cc1cc(O*)ccc1)N(*)*)=O 0.000 description 1
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Abstract
The invention relates to new sansanmycins, and their uses as anti-tuberculous medicines. The sansanmycins are compounds having a general formula represented by formula I, or their pharmaceutically acceptable salts or solvates, and all symbols in the formula I are shown in the specification. The invention also discloses a preparation method of the compounds of the formula I, medicinal compositions containing the compounds, and uses of the compounds as anti-infective medicines. The compounds have an effective antibacterial effect, and especially have a Mycobacterium tuberculosis infection resisting effect.
Description
Technical field
The invention belongs to medicinal chemistry arts, be specifically related to the compound that can be used as bacterial inhibitor that a class is new, in particular to class uridine peptide antibiotics with anti-microbial activity and preparation method thereof, and this compounds as medicine particularly as the application in antibacterials such as anti-tuberculosis drugs.
Background technology
Tuberculosis (TB) is the communicable disease caused by mycobacterium tuberculosis, and it popularly increases the weight of again in recent years.China is one of 22 TB high burden countries in the whole world, and morbidity is high, and resistant rate is also high.According to the World Health Organization (WHO) statistics, China about 5.5 hundred million people has infected tubercule bacillus, and wherein resistance patient is more than 400,000, be increase newly in the world tuberculosis case at most, one of country that multidrug resistance tuberculosis incidence is the highest.Therefore, TB becomes the whole world, the particularly public health extremely paid close attention to of China and social concern again.At present, the medicine that clinical widely used anti-TB medicine is researched and developed before remaining the seventies in last century, as vazadrine (INH), Rifampin (RFP), pyrazinoic acid amide and Tibutol etc., because its effective anti-TB effect is the line medication that clinical TB treats always.But, due to causes such as the life-time service of this type of medicine and the drug treatment length of TB patient, inevitably create the resistance problems be on the rise; Also there is the toxic side effect such as hepatic and renal function damage, gastrointestinal reaction in these medicines simultaneously, and part limits the Clinical practice of this type of medicine.Especially China is a TB country occurred frequently, and problems faced is severeer.From eighties of last century middle nineteen seventies, RNA polymerase inhibitor---Rifampin be used successfully to clinical since, do not have over nearly 40 years a kind of be specifically designed to TB treatment drug development success; Also the tuberculosis material standed for having no new texture skeleton occurs.Therefore, the anti-TB new drug of research novel targets, novel mechanism or new chemical entities, to overcome " resistance of TB medicine " this global problem, has become one of the emphasis and focus of global scientist research in recent years.
People have obtained and have characterized a kind of uridine peptide antibiotics Sansanmycin with Ad tuberculosis activity, can be abbreviated as SSA in this article.Such as document (Yunying Xie, et al.A New Nucleosidyl-peptide Antibiotic, Sansanmycin, The Journal of Antibiotics.2007,60 (2): 158-161) disclose in detail the preparation of this uridine peptide antibiotics of SSA, structural analysis, sign and the anti-microbial activity to some bacterium (such as Mycobacterium tuberculosis, Pseudomonas aeruginosa, streptococcus aureus and intestinal bacteria) in.The chemical structural formula of Sansanmycin is as follows:
People still expect to have novelty and effective antimicrobial drug such as antituberculotic medicine for clinical.
Summary of the invention
The object of the invention is searching and there is effective antibacterial new compound.The wonderful discovery of the present inventor, the replacement uridine peptide antibiotics with formula I structure has the effect of desirable.The present invention is based on this find and be accomplished.
For this reason, first aspect present invention provides with compounds of Formula I:
Or its pharmacologically acceptable salts or solvate, wherein
R
1be selected from C
1-6alkyl-C (O)-, C
1-6alkyl-O-C (O)-, C
1-6alkyl-S (O)
2-, aryl-S (O)
2-, aryl-C (O)-, C
1-6alkyl-, aryl-C
1-6alkyl-, wherein said alkyl and aryl optionally such as, are selected from following substituting group by 1-3 (such as 1-2,1 or 2) independently of one another and replace: halogen, C
1-6alkyl-, C
1-6alkyl-O-;
R
2be selected from: hydrogen, C
1-6alkyl-C (O)-;
R
3be selected from: hydrogen, C
1-6alkyl-C (O)-;
R
4be selected from: hydrogen, C
1-6alkyl.
Compound according to a first aspect of the present invention, wherein said aryl is phenyl.
Compound according to a first aspect of the present invention, wherein said alkyl is the alkyl of straight or branched.
Compound according to a first aspect of the present invention, wherein said C
1-6alkyl is selected from following alkyl: C
1-6alkyl, C
1-5alkyl, C
1-4alkyl, C
1-3alkyl, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, hexyl.
Compound according to a first aspect of the present invention, wherein said halogen is selected from: fluorine, chlorine, bromine, iodine.In one embodiment, described halogen is selected from: fluorine, chlorine, bromine.
Compound according to a first aspect of the present invention, wherein R
1be selected from C
1-4alkyl-C (O)-, C
1-4alkyl-O-C (O)-, C
1-4alkyl-S (O)
2-, phenyl-S (O)
2-, phenyl-C (O)-, C
1-6alkyl-, phenyl-C
1-4alkyl-, wherein said alkyl and phenyl are optionally selected from following substituting group by 1-2 independently of one another and replace: halogen, C
1-4alkyl-, C
1-4alkyl-O-.
Compound according to a first aspect of the present invention, wherein R
2be selected from: hydrogen, C
1-4alkyl-C (O)-.
Compound according to a first aspect of the present invention, wherein R
3be selected from: hydrogen, C
1-4alkyl-C (O)-.
Compound according to a first aspect of the present invention, wherein R
4be selected from: hydrogen, C
1-4alkyl.
Compound according to a first aspect of the present invention, it is selected from:
Or its pharmacologically acceptable salts or solvate.
Compound according to a first aspect of the present invention, it is compound prepared by the embodiment of the present invention or its pharmacologically acceptable salts or solvate.
Second aspect present invention provides the method preparing formula I described in any one of first aspect present invention, and it comprises the following steps:
A) in solvent (such as water), under alkali (such as sodium hydroxide) exists, SSA and acid anhydrides (such as diacetyl oxide) are reacted, obtains formula I; Or
B) in solvent (such as DMSO), under alkali (such as triethylamine, salt of wormwood) exists, make SSA and be selected from following compound to react: C
1-6alkyl-C (O)-halogen, C
1-6alkyl-O-C (O)-halogen, C
1-6alkyl-S (O)
2-halogen, aryl-S (O)
2-halogen, aryl-C (O)-halogen, C
1-6alkyl-Halogen, aryl-C
1-6alkyl-Halogen, obtains formula I.
Method according to a second aspect of the present invention, wherein said alkyl and aryl optionally such as, are selected from following substituting group by 1-3 (such as 1-2,1 or 2) independently of one another and replace: halogen, C
1-6alkyl-, C
1-6alkyl-O-.
Method according to a second aspect of the present invention, wherein said aryl is phenyl.
Method according to a second aspect of the present invention, wherein said alkyl is the alkyl of straight or branched.
Method according to a second aspect of the present invention, wherein said C
1-6alkyl is selected from following alkyl: C
1-6alkyl, C
1-5alkyl, C
1-4alkyl, C
1-3alkyl, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, hexyl.
Method according to a second aspect of the present invention, wherein said halogen is selected from: fluorine, chlorine, bromine, iodine.In one embodiment, described halogen is selected from: fluorine, chlorine, bromine.
Method according to a second aspect of the present invention, it also comprises the step making gained formula I carry out purifying.In one embodiment, described is use preparative liquid chromatography method purifying.Such as can reference (such as Yunying Xie, et al.A New Nucleosidyl-peptide Antibiotic, Sansanmycin, The Journal of Antibiotics.2007, in detail disclosed in 60 (2): 158-161) method carries out purifying.
Method according to a second aspect of the present invention, method (the such as Yunying Xie that wherein said raw material SSA can be recorded by document, et al.The Journal of Antibiotics.2007, the method recorded in 60 (2): 158-161) obtain, the SSA recorded in the document is obtained with the bacterial strain Streptomyces sp SS of preserving number CGMCC No.1764 preservation by the present inventor/applicant.
In the preparation method of second aspect present invention, where necessary, in formula I preparation process; undesirable reaction is there is for preventing some group (as amino, hydroxyl etc.); need to be protected these groups, meanwhile, removed protecting group in due course.These embodiments are too numerous to enumerate, and the use of the protecting group specifically do not mentioned and the method for deprotection also belong within scope of the present invention.
Third aspect present invention relates to a kind of pharmaceutical composition, and it comprises the formula I described in any one of first aspect present invention, and one or more optional pharmaceutically acceptable carriers or vehicle.
Fourth aspect present invention relates to formula I described in any one of first aspect present invention for the preparation for the treatment of and/or preventing Mammals (the comprising people) infectious diseases (disease such as caused by bacteriological infection, the disease such as caused by mycobacterium tuberculosis infection, such as tuberculosis) medicine in purposes.
Fifth aspect present invention relates to one in Mammals in need, treats and/or prevents Mammals (the comprising people) infectious diseases (disease such as caused by bacteriological infection, the disease such as caused by mycobacterium tuberculosis infection, such as tuberculosis) method, the method comprises to the formula I described in any one of first aspect present invention of administration in need treatment significant quantity.
Sixth aspect present invention relates to and is used for the treatment of and/or prevents Mammals (the comprising people) infectious diseases (disease such as caused by bacteriological infection, the disease such as caused by mycobacterium tuberculosis infection, such as tuberculosis) pharmaceutical composition, this pharmaceutical composition comprises the formula I described in any one of first aspect present invention, and one or more optional pharmaceutically acceptable carriers or vehicle.
Seventh aspect present invention also relates to and is used for the treatment of and/or prevents Mammals (the comprising people) infectious diseases (disease such as caused by bacteriological infection, the disease such as caused by mycobacterium tuberculosis infection, such as tuberculosis) the formula I described in any one of first aspect present invention.
Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.
The invention will be further described below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
According to the present invention, in formula I, the position mark of each atomic group can reference Yunying Xie, et al.The Journal of Antibiotics.2007, and mode described in 60 (2): 158-161 is carried out.Such as, as the formula I of SSA derivative, for SSA, be substituted in its structural formula and the position that becomes each carbon atom of the compounds of this invention is respectively m-Tyr-2, m-Tyr-3 ', Sugar-2, concrete mark is as follows:
In the present invention, term " halogen " or " halo " refer to fluorine, chlorine, bromine and iodine.
In the method for synthetic compound of formula i of the present invention, the various starting material reacting used are that those skilled in the art can prepare according to existing knowledge, or can be obtained by the known method of document, or can be buied by business.Intermediate used in above reaction scheme, starting material, reagent, reaction conditions etc. all can have knowledge according to those skilled in the art can make appropriate change.Or those skilled in the art also method can synthesize other not specifically enumerated formula I of the present invention according to a second aspect of the present invention.
Formula I of the present invention can use with other active ingredient combinations, as long as it does not produce other detrimental actions, and such as anaphylaxis.
Active compound shown in formula I can be used as unique Antibiogics usage, or can with one or more other antibacterials conbined usage.Combination therapy by by each treatment component simultaneously, order or separate administration to realize.
Term used herein " composition " means to comprise the product of each appointment composition comprising specified amount, and any product directly or indirectly produced from the combination of each appointment composition of specified amount.In the present invention, term " composition " can exchange with " pharmaceutical composition " and use.
Compound of the present invention can use with the form derived from mineral acid or organic acid pharmacologically acceptable salts.Word " pharmacologically acceptable salts " refers within the scope of reliable medical judgment, is suitable for not occurring excessive toxicity, stimulation, anaphylaxis etc. with the mankind and zootic contact tissue, and the salt matched with rational effect/Hazard ratio.Pharmacologically acceptable salts is well known in the art.Such as, S.M.Berge, et al., J.Pharmaceutical Sciences, has been described in detail pharmacologically acceptable salts in 1977,66:1.Described salt, by making the free alkali functionality of the compounds of this invention and suitable organic acid reaction, is prepared at the final abstraction and purification process situ of the compounds of this invention or prepares separately.Representational acid salt includes but not limited to acetate, adipate, alginates, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (different thiosulphate, isothionate), lactic acid salt, maleate, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.Equally, Basic nitrogen-containing groups can be quaternized with following material: elementary alkyl halide is as the muriate of methyl, ethyl, propyl group and butyl, bromide and iodide; Dialkyl sulfate is as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long chain halide is as the muriate of decyl, dodecyl, tetradecyl and octadecyl, bromide and iodide; Arylalkyl halide as bromotoluene and phenethyl bromide and other.Therefore dissolved in or be scattered in the product of water or oil.The sour example that can be used to be formed the acceptable acid salt of pharmacy comprises mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid, and organic acid is as oxalic acid, toxilic acid, succsinic acid and citric acid.
Base addition salt by make the compounds of this invention containing carboxylic moiety and suitable alkali reaction, in the final abstraction and purification process situ preparation of the compounds of this invention, the oxyhydroxide of the acceptable metallic cation of described alkali such as pharmacy, carbonate and supercarbonate, or ammonia or organic primary amine, secondary amine or tertiary amine.
Pharmacologically acceptable salts includes but not limited to that positively charged ion based on basic metal or alkaline-earth metal is as lithium, sodium, potassium, calcium, magnesium and aluminium salt etc., and nontoxic quaternary ammonium and amine positively charged ion, comprise ammonium, tetramethyl-ammonium, tetraethyl ammonium, ammonium methyl, Dimethyl Ammonium, trimethyl ammonium, triethyl ammonium, diethyl ammonium and ethyl ammonium etc.Other the representative organic amines that can be used for being formed base addition salt comprise quadrol, thanomin, diethanolamine, piperidines, piperazine etc.
Formula I also comprises its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester, formula I and its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester can also form solvate, such as hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that can discharge described activeconstituents in vivo after metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.In general, for object of the present invention, as suitable with non solvate form in the solvate form thereof of water, ethanol etc. with the acceptable solvent of pharmacy.
Below the structure of the exemplary compounds more of the present invention represented with formula I and the activity (MIC) of Ad tuberculosis H37Rv thereof are listed in, Determination of Antibacterial Activity method is wherein shown in embodiment part.
Below the activity (MIC, μ g/mL) of some example compound of the present invention to Mycobacterium tuberculosis is listed in:
| Compound numbers | H37Rv | Bacterial strain 2199* |
| SSA | 16 | 32 |
| SSA-23A | 8 | 8 |
| INH | 40 | |
| RFP | 20 |
Note *: the Mycobacterium tuberculosis bacterial strain 2199 deriving from Chinese tuberculosis patient is Rifampin and Isoniazid-resistant strain.
The active compound amount of gained the actual dose level of each activeconstituents in pharmaceutical composition of the present invention can be changed, so that effectively can obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level must according to the activity of particular compound, route of administration, treat the severity of the patient's condition and the patient's condition of patient to be treated and medical history and select.But the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.
When for above-mentioned treat and/or prevent or other treatment and/or prevention time, a kind of the compounds of this invention treating and/or preventing significant quantity can be applied in a pure form, or with the acceptable ester of pharmacy or prodrug forms (when there are these forms) application.Or described compound can accept the pharmaceutical composition administration of vehicle containing this object compound and one or more medicines.The compounds of this invention that word " treats and/or prevents significant quantity " refers to the compound of the q.s of the reasonable effect/Hazard ratio treatment obstacle being applicable to any therapeutic treatment and/or prevention.But it should be understood that total daily dosage portion of the compounds of this invention and composition must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the severity of this obstacle; The activity of the particular compound adopted; The concrete composition adopted; Age of patient, body weight, general health situation, sex and diet; The administration time of the particular compound adopted, route of administration and excretion rate; The treatment time length; The medicine combinationally using with adopted particular compound or use simultaneously; And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.In general, formula I is used for the dosage of Mammals particularly people can between 0.001 ~ 1000mg/kg body weight/day, such as, between 0.01 ~ 100mg/kg body weight/day, such as, between 0.01 ~ 10mg/kg body weight/day.
The pharmaceutical carrier using those skilled in the art to be familiar with can be prepared into the pharmaceutical composition of the compounds of this invention containing effective dose.Therefore the present invention goes back the pharmaceutical composition of providing package containing the compounds of this invention formulated together with one or more nontoxic drug acceptable carriers.Described pharmaceutical composition can to become with solid or liquid form is for oral administration, for parental injection or for rectal administration by particular formulation especially.
Described pharmaceutical composition can be mixed with many formulations, is convenient to administration, such as, and oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, adding injection water before the injection can use immediately).In described pharmaceutical composition, carrier comprises: the tackiness agent that oral preparations uses is (as starch, normally corn, wheat or rice starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone), thinner is (as lactose, dextrose, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose, and/or glycerine), lubricant is (as silicon-dioxide, talcum, stearic acid or its salt, normally Magnesium Stearate or calcium stearate, and/or polyoxyethylene glycol), if and need, also containing disintegrating agent, as starch, agar, Lalgine or its salt, normally sodiun alginate, and/or effervescent mixture, solubility promoter, stablizer, suspension agent, non-pigment, correctives etc., the sanitas that injectable preparation uses, solubilizing agent, stablizer etc., the matrix, thinner, lubricant, sanitas etc. of topical formulations.Pharmaceutical preparation can oral administration or parenteral (such as intravenously, subcutaneous, intraperitoneal or local) administration, if some drugs is unstable under stomach condition, can be mixed with enteric coated tablets.
More particularly, pharmaceutical composition of the present invention by oral, rectum, parenteral, pond, intravaginal, intraperitoneal, locally (as by powder, ointment or drops), mouth cheek give the mankind and other Mammalss, or give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise the administering mode of intravenously, intramuscular, intraperitoneal, breastbone interior, subcutaneous and intra-articular injection and transfusion.
The composition being suitable for parental injection can comprise physiologically acceptable sterile, aqueous or non-aqueous liquor, dispersion agent, suspensoid or emulsion, and for reconstructing the sterile powders of sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial example comprise water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (as sweet oil), injectable organic ester as ethyl oleate and their suitable mixture.
These compositions also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agent and anti-mycotic agent, such as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc., can guarantee the effect preventing microorganism.Also expect to comprise isotonic agent, such as carbohydrate, sodium-chlor etc.Such as, by using the material that can postpone to absorb, aluminum monostearate and gelatin, the prolongation that can reach injectable drug form absorbs.
Also suspension agent can be contained in addition to the active compound, the mixture etc. of such as ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, partially aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials in suspensoid.
In some cases, be the effect of prolong drug, expect absorption that is subcutaneous or intramuscular injection of drugs of slowing down.This realizes by using the crystal of poorly water-soluble or the liquid suspension of amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Or, the delay of the medicament forms of parenteral admin absorb by by this medicine dissolution in or be suspended in oily vehicle and realize.
Injectable depot formulations form is by preparing at the microcapsule matrix of biodegradable polymer as formed medicine in polylactide-polyglycolide (polylactide-polyglycolide).According to the character of the ratio of medicine and polymkeric substance and the concrete polymkeric substance adopted, drug releasing rate can be controlled.The example of other biological degradable polymer comprises poe class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can be prepared in the liposome compatible with bodily tissue or micro emulsion by pharmaceutical pack being embedded in.
Injectable formulation can such as by filtering with bacterial filter or carrying out sterilizing by the disinfectant mixing aseptic solid composite form, and described solids composition can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
The compounds of this invention or its composition can by oral method or parenteral administration modes.Oral administration can be tablet, capsule, Drug coating, and parenteral preparation has injection and suppository etc.These preparations are prepared according to method appreciated by those skilled in the art.In order to the auxiliary material manufacturing tablet, capsule, Drug coating used is conventional auxiliary material, such as starch, gelatin, gum arabic, silica, polyoxyethylene glycol, liquid dosage form solvent used is as water, ethanol, propylene glycol, vegetables oil (as Semen Maydis oil, peanut oil, olive wet goods).Other auxiliary material, such as tensio-active agent is also had, lubricant, disintegrating agent, sanitas, correctives and pigment etc. containing in the preparation of the compounds of this invention.In tablet, capsule, Drug coating, injection and suppository containing the dosage of formula I be with unit dosage form in the compound gauge that exists calculate.In unit dosage form, the general content of formula I is 0.01-5000mg, and preferred unit dosage form contains 0.1-500mg, and preferred unit dosage form contains 1-300mg.Specifically, the solid dosage for oral administration that the present invention can provide comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound can accept vehicle or carrier such as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade and/or following material with the medicine of at least one inertia and mix: a) weighting agent or extender are as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent is as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks is as glycerine; D) disintegrating agent is as agar, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate and sodium carbonate; E) solution retarding agents is as paraffin; F) accelerator is absorbed as quaternary ammonium compound; G) wetting agent is as hexadecanol and Zerol; H) sorbent material as kaolin and wilkinite and i) lubricant as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.When capsule, tablet and pill, in described formulation, also buffer reagent can be comprised.
The solids composition of similar type uses excipients as lactose and high molecular weight polyethylene glycol etc., also can be used as the weighting material in soft capsule and hard capsule.
Tablet, dragee (dragees), capsule, pill can be prepared with the solid dosage of granule together with dressing and shell material other clothing materials as known in enteric coating material and field of medicine preparations.These solid dosages optionally can contain opalizer, and its composition also can make its just or preferentially at certain position of enteron aisle optionally with delayed mode release of active ingredients.The example of operable embedding composition comprises polymer substance and wax class.If be applicable to, active compound also can be made into microencapsulated form with one or more above-mentioned vehicle.
Liquid dosage form for oral administration comprises the acceptable emulsion of pharmacy, solution, suspensoid, syrup and elixir.Liquid dosage form is except the inert diluent also can commonly used containing this area containing active ingredient beyond the region of objective existence, such as water or other solvents, the fatty acid ester of solubilizing agent and emulsifying agent such as ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), polyoxyethylene glycol and sorbitan and their mixture.Oral compositions also can comprise auxiliary material except comprising inert diluent, such as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and flavouring agent.
Composition for rectum or vagina administration is preferably suppository.Suppository is prepared by being mixed with suitable non-irritating excipient or carrier such as theobroma oil, polyoxyethylene glycol or suppository wax by the compounds of this invention, they are at room temperature solid, but be then liquid under body temperature, therefore can melt in rectal cavity or vaginal canal and discharge active compound.
Compound of the present invention and composition thereof are also considered for topical.The dosage form giving the compounds of this invention for local comprises powder, sprays, ointment and inhalation.Aseptically by active compound and pharmaceutically acceptable carrier and any required sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, eye ointment, powder and solution are also considered within the scope of the present invention.
The compounds of this invention also can liposomal form administration.As known in the art, liposome obtains with phosphatide or other lipid materials usually.Liposome formed by the single or multiple lift aquation liquid crystal be scattered in water-bearing media.Any nontoxic, physiology that can form liposome can to accept and metabolizable lipid all can use.The present composition of liposomal form, except containing except the compounds of this invention, also can contain stablizer, sanitas, vehicle etc.Preferred lipid is phosphatide that is natural and that synthesize and phosphatidylcholine (Yelkin TTS), and they can use separately or together.The method forming liposome is well known in the art.See such as Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p.33.
The present inventor is surprised to find, and the 13-shown in structural formula I replaces uridine peptide antibiotics has restraining effect to Mycobacterium tuberculosis (such as H37Rv).Therefore, compound of the present invention can be used for treating and/or preventing Mammals (comprising people) infectious diseases (disease such as caused by bacteriological infection, the disease such as caused by mycobacterium tuberculosis infection, such as tuberculosis).
Embodiment
Further illustrate the present invention below by concrete preparation embodiment and biological test example, but should be understood to, these embodiments and test example are only used for the use specifically described more in detail, and should not be construed as limiting the present invention in any form.
The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and working method are well known in the art.
A, embodiment part
The synthesis of embodiment 1:SSA-1A
Get 50%SSA 90mg(0.104mmol) be dissolved in 2ml distilled water, add 20 μ l diacetyl oxides (0.208mmol), add 1mol/L NaOH solution and adjust PH to about 6, stirring at room temperature 3 hours.Preparative liquid chromatography purifying, obtains white powder 11.2mg, and yield 23.73%, ESI (-) is 946.4,
1h NMR (600M HZ, DMSO-d
6): δ 1.72 (3H, S, H
n-CO-CH3), 2.24 (3H, S, H
ar-O-CO-CH3), 4.73 (1H, m, H
m-Tyr-2), 6.92(1H, S, H
m-Tyr-2 '), 6.94(1H, d, J=7.2HZ, H
m-Tyr-4 '), 6.95(1H, d, J=7.2HZ, H
m-Tyr-6 '), 7.01(1H, t, J=7.2HZ, H
m-Tyr-5 ').The numerical value of the Sansanmycin that all the other signals and document (Yunying Xie, et al.The Journal of Antibiotics.2007,60 (2): 158-161) are reported is identical.H
m-Tyr-2chemical shift by δ 3.90 to low field displacement to δ 4.73, illustrate that free amine group is acylated; H-2 ' on m-Tyr, 4 ', 6 ' all to low field displacement, and 5 ' to high field displacement, illustrates that upper 3 ' the position phenolic hydroxyl group of m-Tyr is acylated.
The synthesis of embodiment 2:SSA-1B
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml distilled water, add 40 μ l diacetyl oxides (0.417mmol), add 1mol/L NaOH solution and adjust PH to about 6, stirring at room temperature 5 hours.Preparative liquid chromatography purifying, obtains white powder 3.5mg, and yield 7.09%, ESI (-) is 988.4,
1h NMR (600M HZ, DMSO-d
6): δ 1.72 (3H, S, H
n-CO-CH3), 1.98(3H, S, H
r-O-CO-CH3), 2.24 (3H, S, H
ar-O-CO-CH3), 4.73 (1H, m, H
m-Tyr-2), 5.37(1H, m, H
sugar-2), 6.95(1H, S, H
m-Tyr-2 '), 6.96(1H, d, J=7.2HZ, H
m-Tyr-4 '), 6.97(1H, d, J=7.2HZ, H
m-Tyr-6 '), 7.03(1H, t, J=7.2HZ, H
m-Tyr-5 ').All the other signals are identical with Sansanmycin.The same with SSA-1A, can judge that free amine group and upper 3 ' the position phenolic hydroxyl group of m-Tyr are acylated by the change of m-Tyr signal; H
sugar-2to low field displacement, illustrate that the hydroxyl on sugar-2 is acylated.
The synthesis of embodiment 3:SSA-2
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 45ul triethylamine (0.312mmol), add 18ul bromoacetyl bromide (0.208mmol), stirring at room temperature 2 hours.Preparative liquid chromatography purifying, obtains white powder 5.7mg, and yield 11.11%, ESI (-) is 982.3,984.3,1H NMR (500M HZ, DMSO-d6): δ 4.32 (2H, S, H-Br-CH2), 4.70 (1H, m, Hm-Tyr-2).All the other signals are identical with Sansanmycin.The chemical shift of Hm-Tyr-2, to low field displacement to δ 4.70, illustrates that free amine group is acylated.
The synthesis of embodiment 4:SSA-3
Get 50%SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 60 μ l triethylamines (0.417mmol), add 31 μ l chloroacetyl chlorides (0.417mmol), stirring at room temperature 5 hours.Preparative liquid chromatography purifying, obtains white powder 6.5mg, and yield 13.27%, ESI (-) is 938.6,
1h NMR (500M HZ, DMSO-d
6): δ 4.18 (2H, S, H
-Cl-CH2), 4.72 (1H, m, H
m-Tyr-2).All the other signals are identical with Sansanmycin.H
m-Tyr-2chemical shift to low field displacement to δ 4.72, illustrate that free amine group is acylated.
The synthesis of embodiment 5:SSA-6
Get 50%SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 30 μ l triethylamines (0.208mmol), add 8 μ l methyl-chloroformates (0.104mmol), stirring at room temperature 1 hour.Preparative liquid chromatography purifying, obtains white powder 4.5mg, and yield 9.37%, ESI (-) is 920.6,
1h NMR (500M HZ, DMSO-d6): δ 3.00 (3H, S, O-CH3), 4.41 (1H, m, H
m-Tyr-2).All the other signals are identical with Sansanmycin.H
m-Tyr-2chemical shift to low field displacement to δ 4.41, illustrate that free amine group is acylated.
The synthesis of embodiment 6:SSA-7A
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 30 μ l triethylamines (0.208mmol), add 20 μ l Vinyl chloroformates (0.208mmol), stirring at room temperature 4 hours.Preparative liquid chromatography purifying, obtains white powder 10.1mg, and yield 20.72%, ESI (-) is 934.6,
1h NMR (500M HZ, DMSO-d
6): δ 0.93 (3H, t, J=8.4HZ, H
cH3), 3.87(2H, q, J=8.4HZ, H
cH2), 4.40 (1H, m, H
m-Tyr-2).All the other signals are identical with Sansanmycin.H
m-Tyr-2chemical shift to low field displacement to δ 4.40, illustrate that free amine group is acylated.
The synthesis of embodiment 7:SSA-8
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 30 μ l triethylamines (0.208mmol), add 15 μ l chloroformic acid benzyl esters (0.104mmol), stirring at room temperature 4 hours.Preparative liquid chromatography purifying, obtains white powder 4.2mg, and yield 8.09%, ESI (-) is 996.7,
1h NMR (500M HZ, DMSO-d
6): 4.92 (2H, S, H
ar-CH2-O-CO-), 4.76 (1H, m, H
m-Tyr-2), 7.30(2H, m, H-Ar), 7.28(2H, m, H-Ar), 7.27(1H, m, H-Ar).All the other signals are identical with Sansanmycin.H
m-Tyr-2chemical shift to low field displacement to δ 4.76, illustrate that free amine group is acylated.
The synthesis of embodiment 8:SSA-9
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 45ul triethylamine (0.312mmol), add 16ul Methanesulfonyl chloride (0.208mmol), 40 DEG C are stirred 6 hours.Preparative liquid chromatography purifying, obtains white powder 3.5mg, and yield 7.13%, ESI (-) is 940.4,
1h NMR (600M HZ, DMSO-d
6): 2.70 (3H, S, H
cH3-SO2-), 4.14 (1H, m, H
m-Tyr-2).All the other signals are identical with Sansanmycin.H
m-Tyr-2chemical shift to low field displacement to δ 4.14, illustrate that free amine group is acylated.
The synthesis of embodiment 9:SSA-10
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 45 μ l triethylamines (0.312mmol), add 13 μ l benzene sulfonyl chlorides (0.104mmol), 40 DEG C are stirred 4 hours.Preparative liquid chromatography purifying, obtains white powder 1.5mg, and yield 2.87%, ESI (-) is 1002.2,
1h NMR (500M HZ, DMSO-d
6): 4.21 (1H, m, H
m-Tyr-2), 7.38(2H, d, J=7.5HZ, H-Ar), 7.49(3H, t, J=7.5HZ, H-Ar).All the other signals are identical with Sansanmycin.H
m-Tyr-2chemical shift to low field displacement to δ 4.21, illustrate that free amine group is acylated.
The synthesis of embodiment 10:SSA-11
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 45 μ l triethylamines (0.312mmol), add 22mg to Methoxybenzenesulfonyl chloride (0.104mmol), 40 DEG C are stirred 3 hours.Preparative liquid chromatography purifying, obtains white powder 4.2mg, and yield 7.80%, ESI (-) is 1032.3,
1h NMR (500M HZ, DMSO-d
6): 3.73 (3H, S, H
ar-O-CH3), 4.21 (1H, m, H
m-Tyr-2), 7.01(2H, br, H-Ar), 7.48(2H, br, H-Ar).All the other signals are identical with Sansanmycin.H
m-Tyr-2chemical shift to low field displacement to δ 4.21, illustrate that free amine group is acylated.
The synthesis of embodiment 11:SSA-12
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 45 μ l triethylamines (0.312mmol), add 20mg p-methyl benzene sulfonic chloride (0.104mmol), 40 DEG C are stirred 4 hours.Preparative liquid chromatography purifying, obtains white powder 5.2mg, and yield 9.81%, ESI (-) is 1016.2,
1h NMR (500M HZ, DMSO-d
6): 2.27 (3H, S, H
ar-CH3), 4.11 (1H, m, H
m-Tyr-2), 7.17(2H, d, H-Ar), 7.49(2H, d, H-Ar).All the other signals are identical with Sansanmycin.H
m-Tyr-2chemical shift to low field displacement to δ 4.11, illustrate that free amine group is acylated.
The synthesis of embodiment 12:SSA-13
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 150ul triethylamine (1.04mmol), add 24ul Benzoyl chloride (0.208mmol), 40 DEG C are stirred 8 hours.Preparative liquid chromatography purifying, obtains white powder 6.4mg, and yield 12.69%, ESI (-) is 966.5,
1h NMR (600M HZ, DMSO-d
6): 7.82 (2H, d, H-Ar), 7.43 (2H, t, H
m-Tyr-2), 7.49(1H, t, H-Ar), 4.18 (1H, m, H
m-Tyr-2).All the other signals are identical with Sansanmycin.H
m-Tyr-2chemical shift to low field displacement to δ 4.18, illustrate that free amine group is acylated.
The synthesis of embodiment 13:SSA-20
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 45ul triethylamine (0.312mmol), add 32ul methyl iodide (0.520mmol), 40 DEG C are stirred 6 hours.Preparative liquid chromatography purifying, obtains white powder 5.2mg, and ESI (-) is 890.8,
1h NMR (600M HZ, DMSO-d
6): δ 2.21 (2.19) (6H, S, H
n-CH3), all the other signals are identical with Sansanmycin, illustrate that end N is by di-methylation.
The synthesis of embodiment 14:SSA-21A
Get 50% SSA90mg(0.104mmol) be dissolved in 2ml DMSO, add 29mg salt of wormwood (0.208mmol), add 31ul monobromethane (0.416mmol), 40 DEG C are stirred 6 hours.Preparative liquid chromatography purifying, obtains white powder 4.1mg, and yield 8.83%, ESI (-) is 890.9.
The synthesis of embodiment 15:SSA-24
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 45ul triethylamine (0.312mmol), add 61ul propyl iodide (0.624mmol), 40 DEG C are stirred 4 hours.Preparative liquid chromatography purifying, obtains white powder 4.2mg, and yield 8.89%, ESI (+) is 905.9,1H NMR (600M HZ, DMSO-d
6): δ 1.57 (2H, m, H
-CH2-), 0.88 (3H, t, H
-CH3), 2.52 (2H, br, H
n-CH2), all the other signals are identical with Sansanmycin, illustrate that propyl group is connected in N-terminal.
The synthesis of embodiment 16:SSA-23A
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 45ul triethylamine (0.312mmol), add 62ul Iso-Propyl iodide (0.624mmol), 40 DEG C are stirred 4 hours.Preparative liquid chromatography purifying, obtain white powder 3.4mg, yield 7.21%, ESI (-) is 904.4, 1H NMR (600M HZ, DMSO-d6): δ 0.75-1.08 (9H, m, H-CH3), 1.97 (3H, s, HMet-S-CH3), 2.35 (2H, m, HMet-4), 2.41-2.64 (3H, m, Hsugar-3 Hm-Tyr-3), 2.69 (2.87) (3H, S, HAMBA-N-CH3), 2.74-2.84 (2H, m, Hm-Tyr-3), 3.01 (1H, t, HTrp-3), 2.95 (1H, t, HTrp-3), 3.87-4.77 (6H, Hm-Tyr-2, HMet-2, HAMBA-2, HSugar-2, HTrp-2, HAMBA-3), 5.64 (5.46) (1H, d, J=7.8HZ, HUracil-5), 5.96 (5.92) (1H, s br, HSugar-1), 5.77 (5.76) (1H, s br, HSugar-5), 6.41-6.69 (3H, m, H-Ar), 6.91-7.15 (4H, m, H-Ar), 7.27 (1H, b, H-Ar), 7.40-7.71 (2H, m, H-Ar)..
The synthesis of embodiment 17:SSA-27
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 60ul triethylamine (0.416mmol), add 24ul iodo-n-butane (0.208mmol), 40 DEG C are stirred 5 hours.Preparative liquid chromatography purifying, obtains white powder 4.3mg, and yield 8.96%, ESI (-) is 918.2,1H NMR (600M HZ, DMSO-d6): δ 1.55 (2H, m, H-CH2), 1.33 (2H, m, H-CH2), 0.93 (3H, t, H-CH3), 2.54 (2H, br, HN-CH2), all the other signals are identical with Sansanmycin, illustrate that butyl is connected in N-terminal.
The synthesis of embodiment 18:SSA-28
Get 50%SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 60ul triethylamine (0.416mmol), add 68ul iodo Skellysolve A (0.520mmol), 40 DEG C are stirred 4 hours.Preparative liquid chromatography purifying, obtains white powder 3.5mg, and yield 7.18%, ESI (+) is 934.6,1H NMR (600M HZ, DMSO-d6): δ 1.37 (2H, m, H-CH2), 1.20 (4H, m, H-CH2), 0.84 (3H, t, H-CH3), 2.54 (2H, br, HN-CH2), all the other signals are identical with Sansanmycin, illustrate that amyl group is connected in N-terminal.
The synthesis of embodiment 19:SSA-29
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 60ul triethylamine (0.416mmol), add 96ul iodo isobutane (0.832mmol), 40 DEG C are stirred 4 hours.Preparative liquid chromatography purifying, obtains white powder 8.0mg, and yield 16.67%, ESI (-) is 918.2.
The synthesis of embodiment 20:SSA-30
Get 50% SSA 90mg(0.104mmol) be dissolved in 2ml DMSO, add 45ul triethylamine (0.312mmol), add 27ul 2,4-difluoro cylite (0.208mmol), 40 DEG C are stirred 2 hours.Preparative liquid chromatography purifying, obtains white powder 8.5mg, and yield 16.50%, ESI (-) is 988.2.
B, test example part
Test example 1: the compounds of this invention Determination of Antibacterial Activity (MIC)
Tubercule bacillus H
37mIC (μ g/ml) measuring method of Rv: mycobacterium trace quick medicine-sensitive test method(s) directly perceived
Materials and methods
1, test medicine: some exemplary compounds of the present invention, contrast medicine SSA is the self-control of this laboratory, and contrast drug isoniazid (INH) and Rifampin (RFP) are SIGMA Products.
2, experimental strain: mycobacterium tuberculosis type strain H
37rv.
3, substratum: 7H9 liquid nutrient medium is Difco product.
4, method, reference literature Cllins et al.Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium.Antimicrobial Agents Chemother, 1997, 1004-1009 carries out, specific as follows: aseptic 96 orifice plates, 200 μ l aqua sterilisas add in each hole of surrounding of 96 orifice plates, evaporate to prevent the composition of each experimental port in culturing process, precision takes each compound 1mg respectively, add sterile purified water 1ml, make the storing solution of 1000 μ g/ml, INH aseptic distillation water dissolution, RFP dimethyl formamide dissolves, 0.22 μm of filtering with microporous membrane.7H9 substratum (not tween 80) is used to dilute for required each two times of concentration respectively, add 96 orifice plate 100 μ l, the final concentration of investigational agent (the compounds of this invention) and SSA is: 128.0,64.0,32.0,16.0,8.0,4.0,2.0,1.0,0.5,0.25,0.125,0.0625 μ g/ml.Contrast medicine INH and RFP final concentration are: 32.0,16.0,8.0,4.0,2.0,1.0,0.5,0.25,0.125,0.0625,0.032 μ g/ml.Select eugonic each strain culture on modified Russell medium, make bacterial suspension inoculation in 7H9 liquid nutrient medium, hatch 10-14 for 37 DEG C, to grow to turbidity be that McFarland1(is equivalent to 10
7cUF/ml), after dilution, 100 μ l are inoculated, bacterium liquid final concentration 1 × 10 in every hole
6cFU/ml.If 2 containing the growth control hole of antimicrobial drug, be placed in 37 DEG C and hatch.Growth control hole 20 μ l 10 × Alamar Blue(Setotec Products is added after 5th day) and the mixed solution of 5% tween 80 50 μ l, hatch 24h for 37 DEG C, if color becomes pink colour from blueness, in the hole of each Experimental agents, then add Alamar Blue and the tween 80 mixed solution of above-mentioned amount, hatch 24h for 37 DEG C, record the color in each hole, MIC is defined as the lowest concentration of drug stoping colour-change (becoming pink colour from blueness).Result shows that the compounds of this invention has positive effect in Ad tuberculosis, such as the compound of embodiment 1-12, embodiment 14-20, and their MIC value (μ g/mL) is all less than or equal to 8.
Test example 2: the drug of the compounds of this invention
1, test medicine: exemplifying compound, contrast medicine SSA is the self-control of this laboratory, and contrast drug isoniazid (INH) and Rifampin (RFP) are SIGMA Products.
2, experimental strain: mycobacterium tuberculosis type strain H
37rv, resistance tubercule bacillus 2199.
3, substratum and method are with test example 1.
Result shows that the compounds of this invention has positive effect in Ad tuberculosis.
Claims (3)
1. be selected from following compound:
Or its pharmacologically acceptable salts.
2. a pharmaceutical composition, it comprises compound described in claim 1, and one or more optional pharmaceutically acceptable carriers or vehicle.
3. compound described in claim 1 is for the preparation of the purposes treated and/or prevented in the medicine of mammalian infections disease.
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| CN105755076B (en) * | 2016-04-11 | 2020-02-11 | 中国医学科学院医药生物技术研究所 | Method for obtaining SANSANMYCIN structural analogue by mutation synthesis |
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| US6228842B1 (en) * | 1998-11-06 | 2001-05-08 | Microcide Pharmaceuticals, Inc. | Pacidamycins produced by Streptomyces coeruleorubidus |
| CN101153052A (en) * | 2006-09-29 | 2008-04-02 | 中国医学科学院医药生物技术研究所 | Uridine peptide antibiotic, pharmaceutically acceptable salt, producing method and uses thereof |
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| US5039663A (en) * | 1986-05-20 | 1991-08-13 | Sankyo Company Limited | Antibiotics called "mureidomycins A, B, C, and D" and their therapeutic use |
| US6228842B1 (en) * | 1998-11-06 | 2001-05-08 | Microcide Pharmaceuticals, Inc. | Pacidamycins produced by Streptomyces coeruleorubidus |
| CN101153052A (en) * | 2006-09-29 | 2008-04-02 | 中国医学科学院医药生物技术研究所 | Uridine peptide antibiotic, pharmaceutically acceptable salt, producing method and uses thereof |
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