TW200812607A - Novel antibacterial compounds - Google Patents

Abstract

This invention relates to a novel purified compound PM181104, of formula: of molecular weight 1514 and molecular formula C69H66N18O13S5; which is obtained by fermentation of the microorganism belonging to Kocuria species (ZMA B-1/MTCC 5269). The present invention further relates to processes for the production of the compound PM181104, to the microorganism belonging to Kocuria species (ZMA B-1/MTCC 5269), pharmaceutical compositions containing the novel compound PM181104 as an active ingredient and their use in medicines for treatment and prevention of diseases caused by bacterial infections. The invention includes all stereoisomeric forms and all tautomeric forms of the compound PM181104 and pharmaceutically acceptable salts and derivatives such as esters and ethers thereof.

Description

200812607 IX. OBJECTS OF THE INVENTION: Field of the Invention The present invention relates to a novel compound PM1811G4 which has antibacterial activity and is obtained by microbial fermentation of a microorganism belonging to the library species (ZMA (tetra) mtcc 5269). The present invention relates to the procedure for producing the compound PM181104, and also to the microorganism belonging to the strain (zma B-1/MTCC 5269), and also acts as a pharmaceutical composition containing the novel compound PM1811G4. Factors, as well as use in medicines to treat and avoid diseases caused by bacterial infections. The present invention encompasses all domain variant forms of the compound PM1811G4 with all tautomeric forms' as well as pharmaceutically acceptable salts and derivatives such as the vinegars and _. BACKGROUND OF THE INVENTION The antibacterial properties exhibited by most antibacterial agents such as penicillin antibiotics, macrocyclic antibiotics, quinolones and vancomycin have gradually become an important global health issue (Trends out Microbiology, 1994, 2, 422-425). The most obvious question in clinical practice is the increase in the incidence of methicillin-resistant Staphylococcus aureus (Mrsa) infection. Currently, only vancomycin is available for the effective treatment of multi-resistant methicillin-resistant Staphylococcus aureus (MRSA) infection. However, there are many reports showing vancomycin resistance in certain methicillin-resistant Staphylococcus aureus (MRSA) isolates (Antimicrobial Agents and Chemotherapy, 1998, 42 2188-2192). Another clinically relevant multidrug-resistant bacterial population that has recently emerged 9 200812607 is Enterococcus, some of which also have vancomycin resistance. The emergence of vancomycin-resistant private ball (VRE) infection also creates a dilemma for the healer. A new drug selection for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection, a substance known as Linzolid antibiotics and streptozotocin. However, these inflamed ketones (Clinical Infectious Diseases, 2003, 36, supplement 1, SI 1-S23; Annals of Pharmacotherapy, 2003, 37, 769-74), current Drug Targets Infectious Disorders, 2001, 1, 215_25) with a variety of glycopeptides (Clinical Infecti〇us

The resistance of Diseases, 2003, 36, supplement 1, SI 1-S23) requires an alternative target or activity model for the expansion of the agent. In important communities, the resistance to the infection of penicillin and other antibiotics has gradually become a global health issue. The problem of a variety of drug resistance, Zhiyou, and Axillary strains has also emerged in many countries. The emergence and spread of anti-institutions and pathogens within the community has gradually become an important threat to global public issues. What is urgently needed is the discovery of a new compound that can be used as a drug for the treatment of patients with bacterial infections, especially methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Drug-resistant bacteria. Summary of the Invention The present invention relates to a novel refining compound (herein designated PM181104) which is isolated from a microbial fermentation medium belonging to the library tobacco species (zmab_1/MTCC5269) and has antibacterial activity. 200812607 • This field of PM18_ rides in a domain-independent form is associated with all tautomeric forms, and also with its pharmaceutically acceptable salts and its own vinegar and bribery organisms (as described herein) in a structural formula Said by z. The compound PM1811G is divided into 4 stages, the red-acceptable salt and its own vinegar and _derivatives are treated and prevented by bacteria, and the like is methicillin-resistant Staphylococcus aureus (MRSA) and Wanqi Diseases caused by multiple anti-neobacteria such as bacterium resistant enterococci (VRE) are useful. The present invention further relates to (4) synthetic finance, which comprises the compound PM1811G4, (5) different riding, red making, and its esters and scaly derivatives, as a treatment by bacteria, especially like methoxybenzene. A component of the healing conditions caused by penicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The present invention is further related to a procedure for producing the compound PM181104 and its isomers by a microorganism belonging to the bacterium 库 φ χ χ 5 5 269. The present invention also relates to the production of a strain belonging to the library name (ZM^ Bl/MTCC 5269) is related to microorganisms, which are used to culture the compound pM18i just as its isomer. [Detailed Description of the Invention] The present invention provides a novel antibacterial compound pm181104, which also contains all stereoisomeric forms of the compound PM181104. And all tautomeric forms, as well as pharmaceutically acceptable salts thereof and derivatives such as esters and ethers thereof. 200812607 Accordingly, the present invention and an antibacterial compound having the following structural formula i

Wherein R = hydrogen atom (PM1811G4), alkyl group, alkyl group, (Η〇) 2ρ〇·, alkyl_0P0(0H)_, (alkyl_0)2P0, cycloalkyl, cyclohexane carbonyl, An aromatic group, an aromatic group, a heterocyclic group, and a heterodyne group. • * In the series, the term, the silk, the * tube single sensitive or used, - replace the part of the group, meaning the root of the saturated aliphatic group, which covers, linear lining branch chain group. Moreover, unless otherwise stated, the operation, the alkyl group, and the fluorinated group replaced by one or more different substituents. In the New Zealand implementation, a linear or branched chain filament has 20 or fewer carbon atoms in its backbone (for example, for a straight bond and a Cl to C20, for a branched chain c3 to c20) ). Examples of the residue of a vinyl group containing from 1 to 20 carbon atoms are thiol, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, eleven, Ten-base, fourteen-base, seventeen-base and twenty-base, all of these residues are the same 12 200812607

Isomers: isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-didecylbutyl, pentyl, 3, decylpentyl, dissimilar Base, m-didecylhexyl, isodecyl, second butyl or tert-butyl. Substituted thiol is also meant to be a -silyl residue, wherein one or more gas atoms are replaced by a substituent, for example, 1, 2, 3, 4 or 5 hydrogen atoms are substituted, for example, 疋i, oxyhydrogen Root, acyl group, alkoxy group, cycloalkyl group, nitrogen group, stacking group, amino group, decyloxy group, heterocyclic group, base group, material group or like mouse _(7-based benzene·2_oxa .: ^ Dipyridyl) amino (10) d) or gas butterfly dipyrrole (Β (10) ΡΥ) ## 荣光群. As used herein, the term 'the term, ring-ringed, means that it is a pure form containing 3 to j, and * preferably has 3, 4, 5, 6 in the ring. Or 7 carbon atoms. Examples of the Wei group residual filaments containing 3, 4, 5, 6 L of carbon atoms are cyclopropyl, cyclobutyl, cyclodextyl or cycloheptyl. Further, unless otherwise stated, the term, cyclos oxide = ring: a heterocyclic group, an aromatic or an aromatic group. The soil-based group, the _ group, and at least one of the existing carbon slaves have a group of scorpion. In general, the residue of naphthene or biphenyl fragrant silk can be selectively substituted with up to five 13 200812607 oxime substitutes, which are selected from the following: dentin, alkyl, hydrogen and oxygen Root, decyloxy, amino, substituted amino, cyano. The term "heterocyclyl," which is meant to mean a saturated, partially saturated or aromatic monocyclic or polycyclic heterocyclic ring system containing 5, 6, 7, 8, 9 or 10 diatoms, of which 1, 2 Or 3 are the same or different heteroatoms selected from the following: nitrogen, oxygen and sulfur. A suitable example of such a heterocyclic group is pyridyl, piperazinyl, imidazolyl, pyrrolidine And morpholinyl. In a polycyclic cluster, a heterocyclic group may include a fusion ring or a bridged ring in which two adjacent rings share two or more carbon atoms, and in the bridged ring, the ring transmits a non-phase The adjacent atoms are bonded. In the polycyclic cluster, the preferred fluorene of the heterocyclic group includes two fusion rings (bicyclic), one of which is a 5- or 6-membered heterocyclic ring, and the other one is also a 5- or 6-membered heterocyclic ring. Examples of bicyclic heterocyclic clusters include benzoxanthene, sulfhydryl, sulfonyl, isoindolyl, oxime, π fluorenyl, oxime, phenoxazine, benzothiazole a benzoimidazolyl group, a benzofluorenyl group and a benzoxylfuranyl group. The heterocyclic group residue can generally be selectively utilized. Substituted by the same or different substituents, the substituents are selected from the group consisting of: i, pyrenyl, hydroxide, amino, decyloxy, substituted amino, cyano. According to a preferred embodiment of the invention, The R group in the formula I may be a jpYC0 hydrogen atom, CH3CH2CH2CO, CH3(CH2)15CH2CO or N〆. According to a more preferred embodiment, the novel compound represented by the above structural formula I (wherein R = a hydrogen atom) PM181104 can be isolated from microbial fermentation medium belonging to Cookella species 14 200812607 (ZMAB-1/MTCC5269), and

Then carry out refining. W The novel compound PM181104 has the molecular formula c69H66Ni8 (molecular enthalpy 1514) and can be given by any one or more of its physicochemical and spectral properties, such as the high performance liquid chromatography (HPLC) discussed below. ), mass spectrometry (MS), ultraviolet (UV), infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy data. • The structure of the novel compound PM181104 is illustrated, and its completeness is determined by high performance liquid chromatography (HPLC), mass spectrometry (MS), ultraviolet (uv), infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy. characteristic. The structure was read using a two-dimensional (3D) nuclear magnetic resonance study of 15 nitrogen and I3 carbons labeled PM181104. ★The compound ρμ18Π04 and its 赖 贞 derivative are resistant to bacteria - a new active antibiotic, especially for methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE ) and other multi-drug resistant bacteria. The microorganism which can be used to produce the compound ΡΜ18Π04 is a strain of the genus Coriolus 4 (ZMAB_1/MTCC lion), which will hereinafter be referred to as the culture number ZMA B-1, which is collected from the Palk Bay on the Tamii Nadu coast in India. Separation of marine samples. The present invention further provides a process for producing the compound PM18110, a mutant thereof and a variant thereof from the culture strain ZMAB-1, comprising the steps of: one containing a carbon and/or green nitrogen source and selectively nourishing the distress and/or trace elements In a neutral medium, the cultured strain 15 200812607 ZMAB-1 is cultured in the absence of oxygen; the compound pMl811〇4 is isolated from the medium; and the compound is refined by a refining step generally used in the related art. PM181104. As used herein, the term, mutant, means a mutant organism or cell which is a wild type alternative phenotype. As used herein, the term "deformed body" means a unique organism that can be distinguished from any standard form of the species. Colonies of the nickname ZMAB-1 itself can be utilized, Diverticulum observation and Gram staining reaction, preliminary identification of culture strain ΖΜΑ Β·1, cultured strain ΖΜΑΒ-1 was produced by PM181104. In Joan J 曰 medium containing 15% of the moon 22 2216 ( Zobell Marine Microscopic study of the isolated culture strain ZMAB-1 was carried out on Broth 2216), and the incubation period of 1, 2, and 3 days was observed at 25 ° C. On agar medium 2216 containing 1.5% agar (z〇beU Marine Broth2216) The culture is carried out, which will develop into a 2 mm diameter colony with a smooth surface, orange color, regular boundary and soft hardness. No diffusible pigment is observed in this medium. Under the phase contrast optical microscope, the cocci can be It was observed at a size of 40. The cocci were also well separated and isolated. It was Gram-positive and immobile. The observed form classified this organism as a member of the Micrococcaceae family. Compare the ribonucleotide ribonucleic acid (rRNA) with the existing sequence available on the National Center for Biotechnology Information (NCBI) (URL: http://www.ncbi.nlm.nih.gov/) The identification of the isolate. The culture strain ZMAB-1 has been deposited in the bacterial strain preservation center (MTCC), which is located in the World Intellectual Property Organization 16 200812607 (wipo). Biaj

Technology, Sector 39_A, Chandigarh-160 036, India, and has property natural gain number MTCC 5269. It should be understood that in addition to the specific microorganisms described herein, mutants produced using chemical or physical substances that induce X-rays, ultraviolet radiation, etc., induce mutations in organisms, and their genetic makeup have been adapted using molecular biotechnology. The organism can also be cultured to produce the compound PM181104. Screening for appropriate mutants or variants sufficient to produce a compound according to the invention may be confirmed by high performance liquid chromatography (HPLC) and/or biological activity determination of the compound of action in the medium, for example A method of testing the antibacterial activity of the compound is utilized. The medium and/or neutral medium used to isolate and culture the compound PM181104 cultured strain ZMAB-1 is preferably a source comprising carbon, nitrogen and a neutral inorganic salt. For example, the carbon source can be one or more of starch, glucose, sucrose, dextran, fructose; molasses, glycerol, lactose or galactose. A preferred source of carbon is glucose. For example, the nitrogen source may be one or more of soy flour, peanut meal, yeast extract, beef extract, protein, malt extract, corn syrup, animal glue or casadon acid. A preferred source of nitrogen is protein and yeast extract. For example, the source of the neutral heat engine salt may be sodium chloride, potassium chloride, chlorinated j-bow, magnesium chloride, gasification, desertification, sodium fluoride, sodium hydrogen hydride, hydrogen phosphate, Disodium acid disodium, calcium carbonate, sodium cesium carbonate, calcium citrate, ammonium nitrate, potassium nitrate, sodium sulfate, ammonium sulfate, magnesium sulfate, iron nitrate or iron borate. Calcium carbonate, sodium chloride 17 200812607 ^ It is preferred to use magnesium chloride. The culture number ZMA B-1 can be stored between the temperature range of 21 to 35 degrees Celsius and the pH value of about 6.5 to 8.5. In general, the culture strain ΖΜΑΒ-1 is stored between 27 degrees Celsius and 29 degrees Celsius and the acid value is approximately 7.4 to 7.8. The well grown culture can also be stored in a freezer between 4 and 8 degrees Celsius. Spring can be carried out between 25 ° C and 35 ° C and the acid test value is between 6.5 and 8.5, and the culture is carried out in the range of 2 〇 to % hr per minute. . In general, the culture strain ΖΜΑ Β·1 _ 疋 is carried out at a temperature range of 29 degrees Celsius to degrees and an acid test value of about 7.4 to 7.8, at 23 to 25 revolutions per minute. 24 to 48 hours of culture. It can be in the temperature range of 26 degrees Celsius to 36 degrees Celsius and the acid test value is about 6 5 S 8.5, at 6 〇 to 14 rpm and every minute (10) • 2 〇 0 升 升 '24 To the fermentation of 96 hours, the production of the compound ρΜ(8) ι 4 was carried out by culturing the culture number ZMA W. In general, the culture number is squeaked between 3 degrees Celsius and 32 degrees Celsius and the acid value is about Μ to ,, 9 to 110 rpm and 140 to 160 rpm. Under the liter, carry out 4 to 72 hours of cultivation. The production of the compound mi8 can be carried out in a suitable neutral medium by culturing the cultivar ZMA under the conditions described herein, preferably in the case of immersion without oxygen, for example An oscillating bottle method and a method of fermentation in a laboratory to produce the compound 200812607 811〇4 fermentation and production can be carried out by high-filament chromatography (HPLC) side and using known bacterial locus plate diffusion Test method, (4) The amount of biological activity of the culture solution of Staphylococcus and/or Enterococcus. Preferably, the cultured bacteria are the material of the resistant strain, and in the literature, it is a kind of β__amine, and the preferred culture can also be a kind of true R2 (VRE), which has anti-vancomycin resistance. miscellaneous. In the formed culture liquid towel, the compound ΡΜ18_^_ culture filtrate is also present in the cytoplasmic towel' and can be separated from the known mixed ribs such as f-column chromatography. Therefore, the compound pMi8i can be extracted from the cultured Jurassic and Laiyuan, and the _-Heshui non-mixed solvent is extracted under the surface of the acid value of 5 to 9, or borrowed from the resin to carry out the water-repellent reaction riding method. Mode, or _ in the range of 5 to 9 in the range of ion exchange riding method, the immiscible _ like petroleum bonds, dichlorohydrazine, trichloromethane, acetic acid, diethyl ether or Sterol, the polymer resin is like "Diaion he 2〇®,, (Mitsubishi Chem -

Industries Limited, Japan) >"Amberlite XAD®» (R〇hm and

Ha=IndustriesU.S.A), activated carbon. The active material can be extracted from the cytoplasm using a water-miscible solvent such as methanol, acetone, acetonitrile, n-propanol or isopropanol, or a trichlorocide such as petroleum ether or dichloromethane. Methane, acetic acid, diethyl ether or butyl _ and water are not miscible with solvents. An additional option is to extract the complete culture from a solvent selected from petroleum ether, dichlorosilane, chloroform, ethyl acetate, decyl alcohol, acetone, acetonitrile, n-propanol, isopropanol or butanol. liquid. Generally, the active material is extracted from the complete broth in the form of acetic acid. Extracts = 19 200812607 This natural action material is obtained by concentration and lyophilization. The compound PMl811G4 of the present invention can also be reconstituted from the natural material, which uses the following technique: lion residue: normal phase chromatography (using ^化铭 or _glyte as a stationary phase; using a stone like _, Ethyl acetate, methylene chloride, propylene ketone, trichloromethane, methanol or a combination thereof as an eluent; and using _ as an additive such as triethylamine (biliary 3); Analysis /ir (using a f-phase stone such as dimethyl octyl fluorenyl-based dream gel (RP-18) or dimethyl octyl methacrylate stone base gel (10) _8) Gel as a stationary phase; use like water, buffer (for example: phosphate, acetate, citrate (pH 2 to 8)) and organic solvents (for example: methanol, acetonitrile) , acetone, tetrahydrofuran or a combination of these solvents) as an eluent); gel penetrating layer hiding (used in the form of methanol, trichloromethane, _, acetic acid, or a combination thereof) Solvents like S-printed hadex LH-20® ( Ph_da Chemieal Industri%

Sweden ) ^ TSKgel® Toyopearl HW (TosoHaas, Tosoh Corporation, Japan) resin, or G-25 in water; or · Reverse flow chromatography (two-phase washing of two or more intestines) Liquid extraction system, these solvents are like water, methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran, acetone, acetonitrile, methylene chloride, trichloromethane, ethyl acetate, petroleum bonds, benzene With toluene). These techniques can be used repeatedly, individually or in combination. A typical method is chromatography using reverse phase Shiqi gum's spinel (RP-18). Both the compound ΡΜΙδΙΗΜ and its _ _ isomer can be converted into its «acceptable reliance, which is considered in the present invention. The salts can be prepared by standard procedures well known to those of ordinary skill in the art. For example, such as sodium and potassium salts, the PM1811〇4 can be treated with an appropriate sodium or potassium salt. Prepare the way things are like sodium hydroxide or potassium hydroxide. The compound pm1811〇4 represented by the structural formula I, the esters thereof and the Guankede towel and the mosquitoes are transferred (Advanced Organic Chemistry, 1992, 4th Edition, J. March, John Wiley & Sons·) . The esters thereof can be prepared by the method described in the literature (LMed Chemistry, 1992 35, l45_i5i). In a preferred embodiment of the present invention, for a compound wherein R is an alkyl group, a cycloalkyl group, an aromatic hydroxy group or a heterocyclic group and has the structural formula I, it may be in the presence of a combination medium and a salt-based catalyst. 'The compound PM181104 is obtained by reacting a suitable acid, such as dicyclohexyldiimide ammonium (Dcc), and the catalyst is like 4-diaminopyridine (DMAP), and the appropriate The acid has the formula RC00H; wherein R is a decyl group, a cycloalkyl group, an aromatic hydroxy group or a heterocyclic group. The phosphates can be prepared in the manner given in the literature (Bioorganic & Medicinal Chemistry Letters, 1994, vol 4, Μ〇 21, 2567-2572). Ethers can be prepared by the methods described in US Patent Να, which are hereby incorporated by reference. This compound ΡΜ181104 has an antibacterial activity against a wide range of bacterial strains. The compound ΡΜ181104, a stereoisomer, a pharmaceutically acceptable salt, such as its own ester and an ether derivative, can be applied to an animal, either alone or together, in the form of a pharmaceutical or pharmaceutical composition, 21 200812607 It is like applying to a human-mammal. Accordingly, the present invention also relates to the compound PM181104, its stereoisomers, its red-acceptable salts and its derivatives (IV) for pharmaceutical use, and the present invention also uses the compound PM1811G4, its domain isomers, and (iv) thereof. Cut accepting - related to its derivatives, the manufacture of agents with antibacterial activity.

The invention further relates to a compound of the above-mentioned (four) composition, which comprises an effective amount of the compound PM181104 and/or a stereoisomer and/or a pharmaceutically acceptable salt and/or its own 贞 and _ derivatives, Contains also - pharmaceutically acceptable vehicles. The effective amount of the compound PM1811G4 or stereoisomeric or (iv) acceptable bribe or its derivative as an active ingredient in pharmaceutical preparation, generally ranges from milligrams to (10) milligrams. The invention also relates to a method of preparing a medicament comprising the compound PM181104 and/or a stereoisomer and/or a pharmaceutically acceptable salt and/or a derivative thereof for treating and avoiding infection caused by (iv) infection The disease. This compound of the invention is particularly useful as an antibacterial vehicle. Accordingly, the present invention relates to the use of the compound U04 and/or stereoisomers and/or the acceptable cross-over/touch of the compound to produce a medicament for treating and avoiding diseases caused by infection. The present invention is a bacterial infection treatment of infections caused by fines such as staphylococci, chain_, enterococci or bacillus species. “Staphylococcus species” means a fine, gram-positive reaction that appears as a grape-like cluster when viewed through a microscope, and appears as a large, round golden yellow when grown on a fillet plate. Type 0 hemolysis. Gold feeds 'which belong to the staphylococcus species, will cause more than 22 200812607 kinds of suppuration (pus formation) infection, such as sores, stye and rickets, etc.; more serious infections like pneumonia, mastitis , phlebitis, meningitis and urinary tract infections; and deep infections like osteomyelitis and endocarditis. Jinxue Consulting is also a major factor in the infection of hospitals and hospitals. The extravagance of gold sputum will also cause food poisoning caused by the release of enterotoxin to food towels, sighing the complication of toxic shock caused by the release of superantigen to the current. The term "streptococcus species" means a gram-positive reaction of a member of the thick-walled phylum, a genus of the genus _. The globular g is a lactic acid bacterium. The chain-like species can be infected like "inflammatory, fine|§ pneumonia, ^ Xiaoyan, erysipelas and necrotizing fasciitis (,, carcinogenicity, bacterial infection) and other diseases. ... The term rib, enterococci, refers to the lactic acid bacteria of the thick-walled bacteria. , leather-positive cocci 'and usually appear in pairs (bipolar bacteria). Enterococcus is a functional anaerobic microorganism. Intestinal supplementation is the most f-causing bacteria causing nosocomial infections. Intestinal g also develops resistant antibiotics The ability of the elephant is capable of resisting the resistance of wholedamycin and vancomycin. The term 疋/, 8, Bacillus species, means a large amount of bacteria that disperse the bar-shaped leather positive reaction, which is caused by the flagella. The whip moves and has a good 1. It is also a member of the thick-walled lang. The member of this genus has the ability to make two snails. It is highly resistant to unfavorable environmental conditions. 8 kinds of food-like brakes on both sides of the food poisoning. One form is Private, feeding the symptoms of the abdomen (four). The second form of the main ^ Bay ^ has the characteristics of abdominal reduction and Lai. It belongs to the shaft of the species without the thorns of the sensation] including the patient in the compromised immune state (four), heart, heart 23 200812607 Membrane inflammation, pneumonia and septicemia. The compounds of the invention may be administered orally, nasally, topically, subcutaneously, intramuscularly (10), through the veins, or in any application mode.

(4) a composition containing PM1_4 or its _ difficult, or (4) acceptable dish or its touch, may also have other pharmaceutically active substances 'which may _mix the _ compound with - or a variety of pharmacology ^ allowable The preparation of the agent and/or the auxiliary drug, such as mixing and thirsty scraping, dissolving and weaving is a buffering substance, the dissolving coffee image is a surfactant, a f coloring agent, a sheet of _, a coffee, a coloring agent, a masking secret, and a lubricating Agent, disolvent, diluent, binder, plasticizer, emulsifier, ointment base, f-tantalum, paste, polymer, lipid, oily, complex solvent, missolving agent, and the mixture Conversion silk - a suitable pharmaceutical form, such as membrane =, occupation, peak, sputum, material, sputum, na, sugar, knee, suspension, suitable for the injection of the patient into the form of the solution. Examples of adjuvants and/or adjuvants that may be mentioned are hydrogenated castor oil, /Losham, chlorinated ammonium chloride, alkyl sulfate, glucose, glycerol, hard lauric acid, polyethylene Alcohol, glutinous rice powder, dextran, lactose, cellulose, _: cellulose-based sodium, talc, agar, mineral oil, animal oil, vegetable oil t organic and mineral wax, paraffin, gel, propylene glycol, benzyl alcohol, two Methylamine, ethanol, polyalcohol, emulsifier Tween 80, s〇1 Fu HS15 and ^. It is also possible to apply the active substance in a suitable form, e.g., in the form of a sputum, without a color developing sputum or a diluent. The method of applying the herb in a particular case is related to the dosage form and the dosage range, the species used for treatment, and the state of the individual condition or disease, and may be used in the field. The methods known in the art are optimized. On average, a patient's daily dose of the active compound is from 0.0005 mg to 15 mg per kg, typically from 1 mg to 7.5 mg per kg. The following is a description of the present invention, which is not intended to limit the scope of the present invention: Example 1 Isolation of cultured strain ZMAB4 from marine sources a) Ingredients of the isolated medium · Agar medium 2216 (Zobell Marine Broth 2216) (using 1 · 5 % agar for agarification) animal digestion tissue 5 · 0 g, yeast extract ι · 〇 gram, citric acid _ iron 0.1 gram, gasification sodium 19.45 gram, gasification town 8.8 kg, sodium sulphate 3.24 g ' 1.8 g of calcium chloride, 55 g of potassium chloride, 16 g of sodium bicarbonate, 80.0 mg of potassium bromide, 34.0 mg of barium chloride, 22.0 mg of boric acid, 4·0 mg of sodium citrate, sodium fluoride 2.4 mg, ammonium nitrate 1.6 mg, disodium hydrogen phosphate 8 · 0 mg, agar powder 15 · gram grams, double distilled water 1. 〇 liter, the final pH value (at 25 degrees Celsius) is 7.4 to 7.8. b) Procedure: Collect the spongy sample from the Indian coast of Palk Bay approximately three meters deep by scuba diving, taking /ra to var·d/g/ such as α (Dendy). The sponge 25 200812607 sample was washed with sterile seawater and immediately transferred to a sterile polyethylene container. The container is stored at minus 2G Celsius and is maintained at Celsius for transmission to the laboratory for further research. After arriving at the laboratory, the county, sputum sample $ is stored in at least thief 以 degree τ, and after the capture of the bacterium culture: unrolled to room temperature (25 degrees Celsius 2 degrees). The sponge sample was aseptically cut into 2 2 cm pieces and suspended in 5 liters of water-free towel in a 25 ml sterile test tube. Let the tube be weighed for 30 seconds; drain the water and add it to clean sea water. Repeat the same process three times. Finally, the seawater was drained and the sponge fragment was placed on a petri dish containing the above-mentioned separation medium "Zobell Marine Broth 2216 (agarized with 1.5% agar)]. The culture is cultured at a temperature of 25 ± 2 ° C until the growth can be observed in the culture phoenix. The colonies grown on the culture dish are separated according to the characteristics of the colony and contain the above-mentioned separation medium [ The petri dish 2216 (ζ〇Μ Manne Broth 2216) (agarized with 1.5% agar) was striped, and the separation was repeated until the pure culture number ZMAB- The culture number 2]^B-1 is thus separated into a single isolate from the grown microorganism. Example 2 Purification of the culture strain ZMAB-1 a) The composition of the separation medium: agar medium 2216 ( Zobell Marine Broth 2216 ) (agarized with 1 . 5 % agar) 26 200812607 - 5.0 g of digested protein, 1 g of yeast extract, 0. 1 g of ferric acid, 19.45 g of sodium gasification , magnesium chloride 8 · 8 grams, sodium sulfate 3.24 grams, calcium chloride 1.8 grams, potassium chloride 〇 · 55 grams, sodium bicarbonate 0 · 16 grams, potassium bromide 0.08 grams, gasification recorded 34.0 mg, rotten acid 22.0 mg , sodium citrate 4.0 mg, sodium fluoride 2.4 mg, ammonium nitrate 1.6 mg, disodium hydrogen phosphate 8.0 mg, agar 15.0 g, demineralized water L0 liter, pH (at 25 degrees Celsius) 7.4 to 7.8 ❿ b) Procedure: The medium was obtained on agar medium 2216 (Zobell MarineBroth 2216) (agarized with 1.5% agar) in a 15 mm diameter Petri dish. Growth on the Petri dish was on agar medium 2216 (Zobell) Marine Broth 2216) (agarized with 1.5% agar) is striped on the slope. The slope will be incubated at 25 ° C for two days. Convert one of the single colonies from the bed above the bevel to a new one. The bevel is also cultured for two days at 25 degrees C. These are then shaken for the purpose of basic anti-infective selection. Example 3 Maintaination of the producer strain-culture strain ΖΜΑΒ-1 a) The composition of the medium Agar medium 2216 (z〇beUMarine Broth 2216)): 5.0 g of digested protein, 1 g of yeast extract, 1 g of citrate, 19.45 g of sodium chloride, 8 · 8 g of magnesium chloride, 3 24 g of sodium sulfate, Barium chloride 1. 8 grams, potassium chloride 〇 · 55 grams, sodium carbonate 〇 ΐ 6 27 200812607 grams, desertification potassium 0.08 grams, cesium chloride 34.0 mg, acid 22 〇 mg, sodium citrate 4 · 0 mg , sodium fluoride 2.4 mg, ammonium nitrate 16 mg, disodium hydrogenate 8.0 mg, agar ΐ 5 · 〇 gram, demineralized water 1 liter, the pH value (at 25 degrees Celsius) is 7.4 to 7.8. b) After completely dissolving the element by heating, the formed solution was dispensed into a test tube and disinfected at 121 ° C for 3 minutes. The tube is cooled and then solidified in a beveled position. With the growth of the culture number ZMAB-1, the agar slant was formed into a stripe shape by a coil loop and cultured at 27 to 29 degrees Celsius until a good growth was observed. The well-grown culture bacteria are stored in a cold room at 4 to 8 degrees Celsius. Example 4 Fermentation of cultured strain ZMAB-1 by shake flask a) Composition of seed medium (Agar medium 2216 (Zobell Marine Broth 2216)): 5.0 g of digested protein, yeast extract ι·〇 grams, iron citrate 0.1 g 19.3 g of sodium gasification, 8.8 g of magnesium chloride, 3.24 g of sodium sulfate, 1.8 g of calcium chloride, 0.55 g of potassium carbonate, 0.16 g of sodium bicarbonate, 0.08 g of potassium bromide, 34.0 mg of gasification hydrazine, 22.0 mg of boric acid, Broken soda 4.0 housewife, 2.4 mg of sodium fluoride, 1.6 mg of succinic acid, 8. 0 mg of disodium hydrogen citrate, demineralized water ι·〇 liter, pH value (at 25 ° C) 7. 4 to 7.8. b) Dispense the above medium into a 500 ml cone 28 200812607 flask and apply pressure to the pressure cooker at 121 °C for 30 minutes. The flask was cooled to room temperature, and each flask was budded by a bacterial ring of a good growth producing strain (cultured strain ZMAB-1) on the inclined surface, and rotated at 30 (1) degrees Celsius. A shaking of 230 to 250 revolutions per minute was performed on the shaker and maintained for 24 to 48 hours to produce a seed culture. c) Composition of the production medium: 5.0 g of digested protein, L0 g of yeast extract, ferrocene citrate · 1 a g of gasification nano 19.45 g, magnesium gasification g, sodium sulphate 3 24 g, gasification calcium 1.8 g, chlorine Potassium sulphate 55 g, sodium bicarbonate 〇 16 g, > 0.08 g of potassium odor, 34.0 mg of lanthanum chloride, 22.0 mg of boric acid, 4·0 mg of sodium citrate, 2.4 mg of sodium fluoride, ammonium nitrate 16 mg, disodium hydrogen phosphate 8.0 mg, demineralized water 丨 〇 liter, pH value (at Celsius) is 7.4 to 7.8. d) Dispense 4 〇 ml of the production medium in a 500 ml capacity Erlenmeyer flask and apply pressure to a pressure cooker at 121 ° C for 30 minutes, cool to 29 to 30 ° C, and use the seeds mentioned in the sample 牝Media combination. e) Fermentation parameters: The temperature is 29 to 30 degrees Celsius; it is rotated at 23 to 25 revolutions per minute; the harvesting time is 48 to 72 hours. The agarite diffusion method was used to test resistance to vancomycin resistance (VRE) and/or methicillin resistance} material ball milling (MRSA) money, mosquitoes in the miscellaneous base (iv) the growth of the compound PM181104. The cultured acid value of this medium was 8 〇. 29 200812607 The medium was obtained and the intact medium was used as a biological activity test, which is an indicator of the presence of the compound pM1811〇4 in the fermentation medium. Example 5 Preparation of seed culture bacteria for fermentation by shake flask a) Composition of the medium: broad, digested protein 10 g, yeast extract 1.0 g, ferric citrate, α-gram, sodium chloride 19.45 g, magnesium chloride 8.8 g, sodium sulfate 3.24 g, gasification dance 1.8 g, chlorinated _ 〇 · 55 g, sodium bicarbonate 〇 16 g, potassium bromide 0.08 g, barium chloride 34.0 mg, boric acid 22.0 mg, sodium citrate 4 · 0 mg, sodium fluoride 2.4 mg, ammonium nitrate 16 mg, disodium hydrogen oxychloride 8.0 g, demineralized water 1 liter, pH 7.5 to 7.8 at 25 degrees Celsius. b) Dispense the medium described above to a volume of 2 liters into a 1 liter conical flask and perform a 30-minute pressure steel surface at 121 degrees Celsius. The flask was cooled to room temperature, and each flask was budded by a bacterial ring of a growth-producing strain (cultured strain ΖΜΑ B_l) on the inclined surface, and was incubated at a degree of Celsius (±1). Shake on a rotary shaker at 230 to 250 revolutions per minute for 24 to 48 hours to produce seed culture bacteria. Example 6 Culture of the culture strain ΖΜΑΒ-1 in a fermenter a) Composition of the production medium: 500 g of glucose, 11 gram of yeast extract, digested protein 30 200812607 Table 1: dimethyl sulfoxide-d6 (DMSO) -d6) 1 氲 NMR spectrum of the compound PM181104 peak δ peak δ peak δ 1 1.33-1.34 (d, 3 Η) 21 5.33 (m, 1H) 41 8.57-8.58 (d, 1H) 2 1.94 (m, 4H) 22 5.52 (s,m) 42 8.65 (s,1H) 3 2.05-2.06 (br m,1H) 23 5.63 (s, 1H) 43 8.81 (t,2H) 4 2.12 (br m,1H) 24 5.83 (s ,1H) 44 9.07 (s,1H) 5 2.25-2.28 (br d,1H) 25 5.92 (s,m) 45 9.16 (s,1H) 6 2.40-2.42 (brm,1H) 26 6.07 (s,m) 46 , 9.48 (s,1H) 7 2.68 (s,3H) 27 6.50 (s,1H) 47 10.03 (s,m) 8 2.76-2.82 (m,2H) 28 6.59-6.61 (d,2H) 9 2.97- 2.99 (d,1H) 29 6.86 (s,m) • 34 200812607

10 3.17-3.21 (m,1H) 30 7.04-7.06 (d,2H) 11 3.24-3.26 (m,2H) 31 7.17-7.18 (m,1H) 12 3.62 (t,2H) 32 7.26 (d, 4H) 13 3.69 (m,1H) 33 7.30 (s,1H) 14 3.77 (s,2H) 34 7.33-7.35 (d,1H) 15 4.49-4.50 (d,m) 35 7.53 (s,1H) 16 4.69-4.71 (t, 1H) 36 7.69 (s,1H) 17 4.80 (m,1H) 37 7.90 (s,1H) 18 4.89 (m,1H) 38 7.95 (s,1H) 19 4.93-4.97 (UH) 39 8.27- 8.29 (d,2H) 20 5.23 40 8.49-8.50 35 200812607 (UH) (d,1H) Table 2: 13-carbon nuclear magnetic resonance spectrum peak δ peak of compound PM181104 in dimercaptopurine-d6 (DMSO-d6) δ Peak δ 1 12.04 22 115.46* 43 151.04 2 16.88 23 116.92 44 152.08 3 25.16* 24 118.77 45 153.43 4 29.42 25 122.84 46 154.20 5 33.09 26 123.39 47 156.27 6 36.67 27 124.33 48 156.45 7 37.00 28 127.08 49 159.06 8 38.62 29 127.36 50 161.27 9 38.73 30 128.71* 51 161.54* 10 47.22 31 129.18 52 162.79 11 47.46 32 129.76* 53 163.35 12 47.88 33 130.11 54 165.58 13 48.88 34 130.99* 55 167.95 14 52.69 35 133.99 56 169.68 15 54 .43 36 135.17 57 170.39 16 59.92 37 136.87 58 171.03 17 60.56 38 137.67 59 171.77 18 77.80 39 140.92 60 171.96 19 103.89 40 147.97 61 173.51 36 200812607 20 104.94 41 149.73 62 174.14 21 107.52 42 150.83 63 174.90 Two carbon atoms Biological Evaluation of PM181104 In-vitro Test Example 8 In-vitro efficacy was established using the minimum inhibitory concentration (MIC) of the compound PM181104 anti-read strain, which is referred to by the National Clinical Testing Standards Board (2000) guidelines. Macroscopic medium dilution method [Journal of Anti-microbial Chemotherapy, 2002, 50, 125-128 (French Fork Reference 8: Method for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically-Fifth Edition: Approved Standard M7-A5· NCCLS, Wayne , PA, USA)]. Mueller-Hinton medium was used as a neutral medium for this test unless otherwise stated. In all in-vitro experiments, known standards of linezolid (manufactured by Glenmark Pharma Ltd; Batch no: K2005028) were employed. For the preparation of the stock solution, the compound ΡΜ181104 was dissolved in chloroform (5 % of the total volume required) and diluted with methanol (95% of the total volume required). Results: The results are shown in Table 3 below and demonstrate that the compound ΡΜ181104 has efficacy in treating bacterial infections. · Table 3: Minimum inhibitory concentration of this compound ΡΜ181104 antibacterial strain 37 200812607 (MIC) Test organism minimum inhibitory concentration Test organism minimum inhibitory concentration (μg/ml) (μg/ml) Staphylococcus aureus 0.03125 Epidermal grape ball 0.03125 KEM-MRSA1 Μ 32965 golden yellow grape ball 0.03125 dissolved J〇L sex grape 0.0625 bacteria mgm KEM-MRSA2 golden yellow grape ball 0.01563 Enterococcus 0.00781 bacteria KEM-VRE26 KEM-MRSA7 golden yellow grape ball 0.01563 Enterococcus 0.00391 bacteria KEM-VRE27 KEM -MRSA8 golden yellow grape ball 0.0625 Enterococcus 0.00781 bacteria KEM-VRE28 KEM-MRSA11 golden yellow grape ball 0.01563 Enterococcus 0.00391 bacteria KEM-VRE29 KEM-MRSA12 golden yellow grape ball 0.01563 Enterococcus faecalis 0.00781 bacteria (R-2) KEM-MRSA18 Golden yellow grape ball 0.00781 Enterococcus faecalis 0.00781 38 200812607 Bacteria KEM-MRSA19 (VR-1) Staphylococcus aureus KEM-MRSA20 0.01563 Enterococcus faecalis D-59 0.00781 Staphylococcus aureus KEM-MRSA21 0.01563 Enterococcus faecalis D18F 0.00781 Golden yellow Staphylococcus KEM-MRSA22 0. 0781 Enterococcus faecalis (02-D31P1) 0.00391 Staphylococcus aureus KEM-MRSA23 0.01563 Enterococcus faecalis 4045H 0.00781 Staphylococcus aureus KEM-MRSA24 0.0781 Enterococcus faecium (FH-1) 0.00391 Staphylococcus aureus KEM-MRSA25 0.01563 Cocci (uD.8b) 0.00391 Staphylococcus aureus Lilavati-MRSA 3 0.01563 Enterococcus faecalis 4073H 0.00781 39 200812607 Minimum inhibitory concentration of test organisms (μg/ml) Minimum inhibitory concentration of test organisms (μg/ml) Staphylococcus aureus Rehaja -MRSAl 0.03125 Enterococcus faecalis ATCC 51559 0.00781 Staphylococcus aureus Bom-MRSA2 0.0625 Enterococcus faecalis ATCC 51299 0.01563 Staphylococcus aureus subspecies Rainbow trout 33591 0.03125 Enterococcus faecalis ATCC 51575 0.03125 Golden yellow grape ball 789 (789) 0.00781 Enterococcus ATCC BAA 472 0.01563 Golden grape ball mill (20666) 0.01563 Cactus bacillus 0.00391 Golden grape ball Μ (3066) 0.03125 Bacillus subtilis ATCC 6633 0.00781 Golden grape ball M SG511 0.0625 Bacillus subtilis ____—^ ------ 0.01563 golden yellow grape ball M wien8 0.01563 giant pole ΥΆ1127 ------------- - 0.00781 Golden grape ball M wienl3 0.0625 Bacillus licheniformis — ——— 0.01563 -------- -----1 40 200812607 Golden yellow Grape ball M Cl 3184 0.0625 Streptococcus mutans 55 0.00391 Golden grape ball mill (E710) 0.03125 Streptococcus mutans 02 D5 Grl 0.01563 Staphylococcus aureus ATCC 29213 0.03125 Streptococcus mutans 4939(1) Η 0.00781 Staphylococcus epidermidis 5744IW 0.01563 Strong Streptococcus 0.00781 Staphylococcus epidermidis Pat 01IV 0.0625 Salmonella typhimurium Para A >1 Staphylococcus epidermidis 823 0.03125 Pseudomonas aeruginosa (M-35) >1 Staphylococcus epidermidis 6098 0.0625 Klebsiella pneumoniae >1 Staphylococcus epidermidis 649311 (2) W 0.0625 Heterotypic acid ## 2046E >1 Staphylococcus epidermidis 1022III W 0.00781 Escherichia coli % >1 The abbreviations used in Table 3 are: t Staphylococcus enterococcal name · Bacillus 200812607 ^ Living organisms The internal test for in vivo drug efficacy was established using the protective dose (PD) of the compound PM181104 antibacterial strain, representing three animals using male or female Balb/C mice. Type of antibacterial activity. The models used were a general purpose performance test model and an organ/tissue specific efficacy test model. The general purpose efficacy test models used were the systemic infection model (septicemia) and the local infection model (the neutrophil reduction thigh model). The organ/tissue specific infection models used for efficacy testing are kidney, lung infection, and skin acne models. Example 9 Systemic infection model was suspended in physiological saline (0.85% sodium sulphate), and the anti-drug gold sputum that grew overnight grew to break the E710 (MRSA) culture, using ~1〇8 to •10 colony formation. The amount of the unit is used to infect the animal intraperitoneally. The PM181104 solution in the hydrogenated castor oil-methanol form was prepared as described in Example 14. The intraperitoneal application of a 5 mg, 2.5 mg, and 125 gram dose solution per kg was performed immediately after infection. Each experimental group has ten animals. For the trichotomous disease model, the PD of ΡΜ1811〇4 was determined to be 5 mg per kg' to be compared with the standard antibacterial linacrine (manufactured by Ltd; Batch no·· K2005028). 25 mg for comparison. Example 10 42 200812607 The neutrophil-reducing thigh model utilizes dichloromethyl diacetic acid (5 〇 mg and 1 丨 per kg) at 96 hours and 24 hours, respectively, before infection with Jinsu, the luxury #广# E710. Mg) causes mice to have neutropenia. The animal is suspended in physiological saline (0.85% sodium carbonate), grown overnight, resistant to mineral susceptibility, and milled E710 (MRSA) culture, infected with ~1〇7 colony forming unit. . Each experimental group has six animals. The pm1811〇4 solution in the hydrogenated castor oil_methanol form was prepared as described in Example 14. Two hours after infection, the squamous; t 5 mg of New Zealand was applied in a membrane. The animal was sacrificed at different % points and its thigh tissue was removed to determine the total amount of energy development. A reduction in the logarithmic order was observed at a dose of 5 mg per kg of PM181104 at a 6 hour time point, which is equivalent to the standard antibacterial linings per gram of 25 I per gram of agent.

Between Pharma Ltd; Batch no: K2005028) is comparable. Example 11 Kidney Infection Model Balb/C mice were intraperitoneally administered with 2 ml of keratin in 7 days prior to infection. The logarithmic phase of the overnight growth, the ATCC47_ culture was adjusted to approximately 1 〇9 a per milliliter, and the mouse was intraperitoneally applied in a volume of 2 ml. The phantom oil was prepared as described in Example 14 and the phantom solution in the methanol form was applied intraperitoneally to the mice 4 hours, 24 hours and 48 hours after infection. At 72 hours post-infection, the animal was sacrificed and its kidneys were removed to determine the bacterial load 43 200812607. Approximately 1 step reduction in the total bacterial count was observed at a dose of 5 mg per kg of PM181104, which was performed with a standard antibacterial linalone (25% per kg) (manufactured by Glenmark Pharma Ltd; Batch ηο: Κ2005028) And a 150 mg dose of hydrogen peroxide vancomycin per kilogram (manufactured by HiMedia; Catalogue no: RM217-500mg; Lot no: 06-0350) is comparable. Example 12 Lung Infection Model Balb/C mice have neutropenia by administering 200 mg/kg of methyl-acetic acid per kg intraperitoneally two days and five days prior to infection. On the day of infection, the mice will be anesthetized and infected with a suspension of E710 log culture suspension having a bacterial density of about 106 to 107 colony forming units per ml. The first and second individual pharmaceutical agents are applied intraperitoneally 24 and 36 hours after infection. At 48 hours post infection, the animals were humanely euthanized and their lungs collected in a sterile manner to determine the total amount of bacterial development. In this model, a 5 mg dose of PM181104 solution per kg of the castor oil_sterol form was prepared as described in Example 14. Two standard antibacterial linezolids (80 mg per dose per kg I applied 24 hours after infection) and vancomycin hydrogen chloride (12 mg per kg applied 24 and 48 hours after infection) were used as positive control group. ? ] ^1811〇4 shows that the inhibition activity of Tian, Guo, and Lina _ (made by Gienmark pharma Ltd; Batchn〇: K2005028) is comparable. Hydrogen chloride 44 200812607 ‘Gumycin (made by HiMedia; Catalogue no: RM217-500mg;

Lot no: 06-0350) shows a sterilization curve. The total bacterial count in the lungs of the animals treated with ΡΜ18Π04 showed approximately a logarithmic difference of 2 orders compared to the untreated control animals. Example 13 Skin acne model Balb/C mice were subcutaneously infected with an over-grown drug-resistant golden axe boiled with extensive grinding E710 (MRSA) cultures using approximately 108 colony forming units. The bacteria were suspended in a 2% carrier cytodex bead 1:1 mixture in physiological saline (0.85% sodium chloride). The pM1811〇4 solution in the hydrogenated castor oil-sterol form was prepared as described in Example 14. The solution was administered intraperitoneally at a dose of 2.5 mg, 5 mg and 10 mg per kg two hours after infection. Each experimental group has six animals. After the formation of the sore, the animal is sacrificed and its skin is obtained to determine the total amount of development. At a dose of 5 mg per kg of ρΜ1811〇4, a total of approximately 1 log reduction in the total number of bacteria was observed, which was carried out in the 5 gram per kg dose of the “quasi-anti-sucking Linai sputum (by Gienmark pharma Ltd). Manufactured; BatChn〇: K2005028) is comparable. Example of formation of the compound PM181104 14 Injectable form is prepared in the following general manner: Mixing methanol with hydrogenated castor oil polyoxyethylene 45 in a weight ratio of 1:1 (by weight) 200812607 Aene. For this purpose, PM181104 was added and vortexed. The mixture was ultrasonically treated at 25 ° C. The mixture was diluted by adding water (90%) (considered 1%) Composition) and vortex it again to obtain the injectable form. Derivatives of the compound PM181104 Example 15 PM181104 of butyrate derivative to PM181104 solution in di-ethane (2 ml) (0.13 g, 〇· 〇85 mM) butyric acid (0.008 μl, 0.085 mmol), dicyclohexyldiimide ammonium (DCC, 0.018 g, 0.085 mmol), and 4-dimethylaminopyridine (DMAP, 0·) 002 grams, 0.016 millimeters The amount of catalyst in the ear, and the reaction temper was stirred for 18 hours under a nitrogen atmosphere. The reaction mixture was added with cold water, and the organic layer was separated; the aqueous layer was taken out with dichloroethane (3 x 50 ml), and the organic layer was extracted. The material was piled up and washed with water (2 x 30 ml). The organic layer was dried and concentrated by anhydrous sodium sulfate. The natural product was subjected to column chromatography [Shixi gel (60 to 120 mesh), Purification of 3% methanol in trichloromethane] to obtain a white solid compound. Yield: 0.11 g (81%); high resolution electrospray mass spectrometry: 1585 (M+H) PM181104 butyrate derivative The minimum inhibitory concentration (MIC) for the Enterococcus faecalis R-2 (VRE) bacterial strain is shown to be 2.5 micrograms per milliliter. 46 200812607 v Example 16 PM181104 stearate derivative to di-ethane (2 ml) In the PM181104 solution (0.12 g, 0.079 mmol), stearic acid (〇.〇22 μl, 0.079 mmol), dicyclohexyldiimide ammonium (DCC, 0.016 g, 0.079 mmol) Ear), with 4-dimethylaminopyridine (DMAP, 0.002 g) a catalyst amount of 0.016 mmol, and the reaction temper was stirred for 6 hours under a nitrogen atmosphere. The reaction mixture was added with cold water and the organic layer was separated; the water was taken out using di-hexane (3 x 50 ml). In the phase layer, the organic extract was deposited and washed with water (2 x 30 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated. The natural product was purified by column chromatography [Shixi gel (60 to 120 mesh), 3% decyl alcohol in tri-gas methane] to obtain a white solid compound. Output: 〇·1 gram (71%); high resolution EFI mass spectrometry: 1781 (Μ+Η) Lu Μ 181104 stearate derivative shows the minimum inhibitory concentration against Enterococcus faecalis R 2 (VRE) bacterial strain (MIC) is 125 micrograms per milliliter. Example 17 PM181104 nicotinic acid g-derived derivative of PM181104 solution (〇.〇2 g, 0.013 house Moule) in dimercaptocarboxamide (1 ml) was added to acid test (0 008 g, 〇·〇 65亳Moel), dicyclohexyldiimide ammonium (DCC, 0.014 g, 0.065 mmol), with 4-diaminopyridine (DMAP, 0.0008 g, 0.0065 mmol) 47 200812607 catalyst amount, and The reaction susceptor was stirred under nitrogen for 18 hours. The solvent was removed and 1 mL of dichloroethane was added to the residue. The undissolved urea was filtered and the filtrate was washed with water (2 x 10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. The natural product was purified by column chromatography [C-18 reverse phase column (Eurspher, 20 nm), 55% acetonitrile in water] to obtain a white solid compound. Output: 0.11 g (56%); high resolution EFI mass spectrometry: 1621 (M+H)

The nicotinic acid ester derivative of PM181104 will be tested on bacterial strains. The results are shown in Table 4 below, and demonstrate that the nicotinic acid ester derivative of the compound PM181104 has efficacy in treating bacterial infections. Table 4 Compound PM181104 The minimum inhibitory concentration (MIC) of the acid vinegar derivative for the bacteria in the test The minimum inhibitory concentration of the organism (μg/ml) Test the minimum inhibitory concentration of the organism (μg/ml) Enterococcus faecalis 0.312 feces Enterococcus 0.312 ATCC 51299 R-2 (VRE) Enterococcus faecalis 0.312 Golden Grapes >10 ATCC 51575 MM MRSA ATCC33591_ Enterococcus faecalis 0.312 Golden Grapes >10 ATCC BAA MM E7l〇472 Enterococcus faecalis 0.156 ATCC 51559 48 200812607 ^ [Simple description of the diagram] Figure 1 shows the ultraviolet absorption spectrum of the compound PM181104. Figure 2 shows the infrared absorption spectrum of the compound PM181104. Figure 3 shows the 1-hydrogen nuclear magnetic resonance spectrum of compound PM181104 in dimethyl sulfoxide-d6 (DMSO-d6). Figure 4 shows the 13 carbon nuclear magnetic resonance spectrum of compound PM181104 in dimercaptosulfoxide-d6 (DMSO-d6). [Main component symbol description] None 49

Claims (1)

200812607 X. Patent application scope: 1. A novel compound having the following knot Structure of construction I: Wherein R = hydrogen atom, alkyl group, alkyl group, (h〇) 2P〇_, alkyl group-ΟΡΟ(ΟΗ)-, (alkyl·〇)2ρ〇·, cycloalkyl, ring-burning, aromatic A thiol group, a aryl group, a heterocyclic, or a heterocyclic ring, or a stereoisomer, or a tautomer thereof, or a pharmaceutically acceptable salt. 2. The novel compound ρΜ18η〇4 as described in claim i, wherein in the formula I, R is a hydrogen atom, or a stereoisomer thereof, or a tautomer, or a Pharmaceutically acceptable salts. 3. The novel compound ΡΜ181104 as described in the second paragraph of the patent scope of the patent, or a stereoisomer or a tautomer thereof, which has an antibacterial activity 1 " raw, isolated compound belongs to the bacterium Microbial fermentation medium (zmaB_1/mtcc 5269) characterized by: < (a) Molecular weight is 1514, (b) Knife type is C69H66N18〇13S5, (c) Ultraviolet spectrum is shown in Fig. 1, 50 200812607 (I infrared spectrum is shown in Fig. 2, (e) i3H NMR The spectrum is shown in Fig. 3, and the (1) 3c NMR spectrum is shown in Fig. 4. 4. The process for manufacturing the compound as described in item 2 of the patent application, which includes the steps of the town: (8) In the nutrient medium containing carbon source and nitrogen source, the microbial bacterium (ZMAB_1/MTCC5269) or its variable frequency or mutant H is produced under the aerobic conditions to produce the compound PM181104, (8) self-fermentation The medium is isolated from the compound pM(8), and (c) the compound pM1811〇4 is purified. 5. The process of claim 4, further comprising the step of converting the compound PM181104 into its pharmaceutically acceptable form [ 6. The process of claim 4, further comprising the steps of: reacting the compound PM181104 with a compound of the formula Rc〇〇H^-acid, wherein R is an alkyl group, a cycloalkyl group Fang a hydroxy or heterocyclic group to obtain a novel compound of formula I as described in the scope of claim 2, wherein R = alkyl, cycloalkyl, aromatic _ or heterocyclic. The compound according to the first aspect of the invention, wherein r=ch3ch2ch2co, ch3(ch2)15^^^ 51 200812607 8. A pharmaceutical composition comprising - an effective amount of a compound of claim 1 having at least a pharmaceutically acceptable adjuvant, or an additive or an adjuvant. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is in the form of a tablet, a film-coated tablet, a capsule, a fine granule, a powder, a cream, an ointment, a mash, a latex, a suspension, or It is a liquid for injection. 。 The pharmaceutical composition of claim 8, wherein the composition is suitable for the treatment of a bacterial infection. The pharmaceutical composition according to the first aspect of the patent application, wherein the fineness = is caused by Staphylococcus, Streptococcus, Enterococcus or Bud. The pharmaceutical composition according to the item U, wherein the sputum belongs to the genus bacterium or enterococci. The pharmaceutical composition described in claim 12, wherein the bacterium belonging to the genus Corydalis is resistant. 14. Please refer to the finished product described in item 12, in which the bacteria belonging to the Staphylococcus species are resistant to vancomycin. The pharmaceutical composition described in Item 12 of Li Fanyuan, wherein the ball ___ has anti-vancomycin properties. A method of bacterial infection, which comprises efficacious to a compound in need of treatment, as claimed in the patent application 1 of the invention, such as Shen _ _ 16 er coffee, the towel infected with the bacteria 9· 10. 11. 12. 13. 52 200812607 疋 - caused by Staphylococcus, Streptococcus, Enterococcus or Bacillus species. 18. The method of claim 17, wherein the bacterial infection is caused by a species belonging to Staphylococcus or Streptococcus. 19. The method of claim 2, wherein the bacterium belonging to the genus Staphylococcus is resistant. The method of claim 18, wherein the bacterium belonging to the genus has anti-vancomycin resistance. Table 21. The bacterium of the method of claim 18 is resistant to vancomycin. The use of a drug/object for the treatment of a bacterial infection, as described in the scope of claim patent item i, 53