BRPI0709833A2 - new antibacterial compounds - Google Patents

Abstract

New Antibacterial Compounds "New Antibacterial Compounds" where this invention relates to a new purified compound PM181104, of formula: molecular weight 1514 and molecular formula C ~ 69 ~ H ~ 66 ~ N ~ 18 ~ 0 ~ 13 ~ S ~ 5 ~; which is obtained by fermentation of the microorganism belonging to the Kocuria species (ZMA B-1 / MTCC 5269). The invention includes all stereoisomeric forms and all tautomeric forms of compound PM1 81104 and pharmaceutically acceptable salts and derivatives such as esters and ethers. The present invention also relates to processes for the production of new antibacterial compounds, to the production of the microorganism belonging to the Kocuria species (ZMA B-1 / MTCC 5269), and to pharmaceutical compositions containing the new compounds as an active component and their use in medicines for the treatment and prevention of diseases caused by bacterial infections.

Description

Patent Descriptive Report for "New Antibacterial Compounds"

Field of the Invention

This invention relates to a novel compound PM181104, antibacterial activity, which is obtained by fermentation of the Kocuria species (ZMA B-I / MTCC5269). The invention also includes all stereoisomeric forms and all tautomeric forms of compound PMl 81104 and pharmaceutically acceptable salts and derivatives thereof. The present invention further relates to processes for the production of novel antibacterial compounds, the production of a Kocuria species organism (ZMA BI / MTCC5269), and pharmaceutical compositions containing the novel compounds as active ingredients and their use in medicaments for treatment and prevention. from diseases caused by bacterial infections.

Background of the Invention

The emergence of bacterial resistance to numerous antimicrobial agents such as beta-lactam antibiotics, macrolides, quinolones, and vancomycin is becoming a major health problem worldwide (Trends In Microbiology, 1994, 2, 422-425). The most significant problem in clinical practice is the increased incidence of methicillin-resistant Staphylococcusaureus (MRSA) infections. Currently, the only effective treatment for several resistant MRSA infections is avancomycin. However, there are numerous reports of vancomycin resistance withdrawal in some MRSA isolates (Antimicrobial Agents and Chemotherapy, 1998, 42, 2188-2192). Another group of recently clinically important multidrug-resistant bacteria is Enterococci, some of which are also resistant to vancomycin. The appearance of vancomycin-resistant Enterococci (VRE) infections has led doctors to a dilemma. Combinations of Linezolid, an oxazolidinone compound, and streptogramin are the new preferred drugs for treating MRSA infections. However, resistance to these deoxazolidinone drugs (Clinical Infectious Diseases, 2003, 36, supplement1, S11-S23; Annals of Pharmacotherapy, 2003, 37, 769-74) streptogramin (Current Drug Targets Infectious Disorders, 2001,1, 215- 25) and various glycopeptides (Clinical Infectious Diseases, 2003, 36, supplement 1, S11-S23) require further development of agents with alternative targets or modes of action. The increasing resistance of the important pathogen acquired by Streptococcus pneumoniae to penicillin and other antibacterials is also becoming a worldwide health problem. Multiple drug resistant Myobaeterium tubereulosis strains are emerging in several countries. The emergence and spread of resistant nosocomial and societally acquired pathogens is becoming a major threat to global public health.

There is an urgent need to discover new compounds that can be used as drugs to treat bacterially infected patients, particularly multi-drug resistant bacteria such as MRSA and VRE.

Summary of the Invention

The present invention relates to a novel compost purified (hereinafter referred to as PM181104), isolated from the fermented broth of the microorganism belonging to the Kocuria species (ZMA B-1 / MTCC 5269), with antibacterial activity.

The invention also relates to all stereoisomeric forms and all tautomeric forms of PM181104 and ester and ether pharmaceutically acceptable salts thereof represented by I (as described in this report).

The compound PM1881104, and isomers, and pharmaceutically acceptable salts and ether ester type derivatives thereof, are useful for the treatment and prevention of diseases caused by bacteria, particularly multidrug resistant bacteria such as MRSA and VRE.

The invention further relates to pharmaceutical compositions comprising the novel compound PM181104, an isomer, a pharmaceutically acceptable salt, an ester or ether derivative thereof, as an active component for the treatment of medical conditions caused by bacteria, particularly multi-drug resistant bacteria such as MRSA and VRE

The present invention further relates to processes for the production of compound PM181104 and / or isomers thereof from a Kocuria (ZMA B-I / MTCC5269) species organism.

The present invention also relates to processes for producing microorganism belonging to the species Kocuria (ZMA BI / MTCC 5269) which by culture produces the compound PM181104 and its isomers. The present invention also relates to processes for the production of ester type derivatives. and ester of compound PMl 81104.

Description of Drawings

FIG. 1 shows the ultraviolet (UV) absorption spectrum of PM181104.

FIG. 2 shows the infrared (IR) absorption spectrum of PM181104.

FIG. 3 shows the 1H-NMR spectrum (500 MHz) of PM181104 in DMSO-d6.

FIG. 4 shows the 13 C-NMR (125 MHz) spectrum of PM181104 in DMSO-d6.

Detailed Description of the Invention

The present invention provides a novel antibacterial compound PM81104 and also includes all stereoisomeric forms and all tautomeric forms of PM81104 and and pharmaceutically acceptable salts thereof, such as esters and ethers thereof. Accordingly, the present invention relates to novel antibacterial compounds of formula I. where: R = H (PM181104), alkyl, alkylcarbonyl, (HO) 2PO-, alkyl-OPO (OH) -, (alkyl-O) 2P0-, cycloalkyl, cycloalkylcarbonyl, aryl, arylcarbonyl, heterocyclyl and heterocyclyl carbonyl. As used herein, the term "alkyl" whether used alone or as part of a substituent group, refers to the oradical of saturated aliphatic groups, including straight or branched alkyl groups. In addition, unless otherwise indicated, the term "alkyl" includes unsubstituted alkyl groups as well as alkyl groups, which are substituted with one or more different substituents. In preferred embodiments, a straight chain or branched chain alkyl has 20 or less carbon atoms in its backbone (e.g., CrC20 for straight chain, Cs-C20 for branched chain). Examples of alkyl residues containing from 1 to 20 carbon atoms are: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, heptadecyl and eicosyl, the n-isomers of all of these. residues: isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 2,3,4-trimethylhexyl, isodecyl, sec-butyl, or tert-butyl. A substituted alkyl refers to an alkyl residue in which one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms are substituted by substituents, for example halogen, hydroxyl, sulfonyl, alkoxy, cycloalkyl, cyano , azido, amino, acyloxy, heterocycle, aralkyl, aryl or fluorescent groups such as the NBD [N- (7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino] or BODIPI [4,4-difluoro] group -5,7-dimethyl-4-bora-3a, 4a-diaza-s-indacene. As used herein, the term "cycloalkyl" refers to a saturated monocyclic or bicyclic ring system containing 3 -10 carbon atoms, and most preferably having 3, 4, 5, 6 or 7 carbon atoms in the ring structure. Examples of cycloalkyl residues containing 3, 4, 5, 6 or 7 ring carbon atoms are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptiyl. In addition, unless otherwise indicated, the term 'cycloalkyl' includes unsubstituted cycloalkyl and cycloalkyl which is substituted with one or more equal or different groups selected from halogen, hydroxyl, alkoxy, alkyl, cycloalkyl, cyano, amino, aminoalkyl, acyloxy heterocycle, aralkyl, and / or an aryl group.

As used herein, the term "aryl" refers to a monocyclic or polycyclic hydrocarbon group having up to 10 carbon atoms in the ring, in which at least one carboxylic ring having a conjugated π electron system is present. C10 -aryl include phenyl, naphthyl or biphenyl, especially phenyl and naphthyl. Aryl residues, for example phenyl or naphthyl, in general may optionally be substituted with one or more substituents, up to five identical or different substituents selected from the group consisting of halogen, alkyl, hydroxyl, acyloxy, amino, amino substituted, cyano.

The term "heterocyclyl" refers to a partially unsaturated or aromatic saturated heterocyclyl monocyclic or polycyclic ring system containing 5, 6, 7, 8, 9 or 10 ring atoms, of which 1,2 or 3 are the same or different selected heteroatoms. of: nitrogen, oxygen and sulfur. Suitable examples of such heterocyclyl groups are pyridinyl, piperazinyl, piperidinyl, imidazolyl, pyrrolidinyl and morpholinyl. In the heterocyclic polycyclic ring system the heterocyclyl may comprise fused rings in which two or more carbons are common to two adjacent rings, or bridged rings in which the rings are joined through nonadjacent atoms. In the heterocyclic polycyclic ring system the heterocyclyl preferably comprises two fused (bicyclic) rings, of which at least one is a 5- or 6-membered heterocyclic ring. Exemplary bicyclic heterocyclic groups include benzoxazolyl, quinolyl, isoquinolyl, carbazolyl, indolyl, isoindolyl, phenoxazinyl, benzothiazolyl, benzimidazolyl, benzoxadiazolyl and benzofurazanyl. Heterocyclyl residues in general may optionally be substituted by one or more same or different substituents selected from the group consisting of halogen, alkyl, hydroxy, acyloxy, amino, substituted amino, cyano. According to a preferred embodiment of the present invention, group R in formula I may represent H, CH 3 CH 2 CH 2 CO, CH 3 (CH 2) 15 CH 2 CO or According to a more preferred embodiment, the novel compound PMl 81104 represented by the formula I above (where R = H) is isolated from the fermented broth of the Kocuria microorganism (ZMA BI / MTCC 5269) and The new compound PMl 81104 has the molecular formula C69H66N18Oi3S5 (molecular weight 1514) and may be characterized by any or more of its physicochemical and spectral properties, such as high performance liquid chromatography (HPLC), mass spectrum (MS ), noultraviolet (UV), infrared (IR) and nuclear magnetic resonance (NMR) spectroscopic data discussed further The structure of the new compound PM81104 was elucidated and its complete characterization was done by HPLC, MS, UV, IR and NMR spectroscopic data. The structure was confirmed by the 3-dimensional (3D) NMR study of 15N and 13Cbioactive-labeled PMl81104.The compound PMl81104 and its ether-ester derivatives are new active antibiotics against bacteria, particularly multi-drug resistant bacteria such as MRSA and VRE. which may be used for the production of PMl 81104, is a strain of the species Kocuria (ZMA B-1 / MTCC 5269), hereinafter referred to as culture No. ZMA B-1, isolated from a marine sample collected at Palk Bay off the coast of Tamil.

Nadu, India.

The present invention further provides a process for the production of compound PM181104 from culture No. ZMA B-1, its mutants and variants, comprising the steps of: cultivating culture No. ZMA BI under submerged aerobic conditions in a nutrient medium containing one or more sources. carbon and one or more nitrogen sources and optionally inorganic nutrient salts and / or trace elements; isolating compound PM1 81104 from the culture broth; and purifying compound PMl 81104 using purification procedures generally used in the related art.

As used herein, the term "mutant" refers to a mutation-containing organism or cell, which is an alternative phenotype for the wild type.

As used in this report, the term "variant" refers to an individual organism that is admittedly different from an arbitrary standard type in that species.

Preliminary identification of culture No. ZMA B-1, which is the producer of PMl 91104, was performed by examination of its colony morphology, wet mount observations and reaction to Gram stain. Microscopic studies of the isolated culture No. ZMA B-I strain were performed in Zobell Broth 2216 (Broth 2216), containing 1.5% of agar and observations were made at 1, 2 and 3 days of incubation at 25 ° C.

The culture in Zobell 2216 Marine Broth (2216 Marine Broth) containing 1.5% agar develops as colonies of 2 mm diameter with smooth surface, orange-yellow pigmentation, regular margin, and soft consistency. Diffusible pigments are not observed in this medium. Under phase-contrast optical microscope, coconuts are observed at 400x magnification. the cocossos are well separated and isolated. They are Gram-positive and immovable. The observed morphology classifies this organism as a member of the Micrococcaceae family. Identification of isolates was performed by comparing their 16S rRNA polymerase chain reaction (PCR) with existing sequences available on the National Center for Biotechnology Information (NCBI) website (URL: http: //www.ncbi.nlm.nih. gov /). Culture No. ZMA BI has been deposited with the Microbial Type Culture Collection (MTCC), Institute of Microbial Technology, Sector 39-A, Chandigarh-160 036, India, an International Depository Authority (IDA) recognized by the World Health Organization. Intellectual Property (WIPO) and has been assigned MTCC Accession Number 5269. In addition to the specific microorganism described in this report, it should be understood that mutants, such as those produced by chemical or physical mutagens including X-rays, UV rays, etc. and organisms whose genetic makeup has been modified by molecular biology techniques can also be grown to produce compound PM1 81104.

Screening for suitable mutants and variants which may produce the compound according to the invention may be confirmed by HPLC and / or by determining the biological activity of the accumulated active compounds in the culture, for example by testing the compounds for antibacterial activity.

The medium and / or nutrient medium used for isolation and cultivation of culture No. ZMA B-1, which produces compound PMl 81104, preferably contain sources of nutrient carbon, nitrogen and inorganic salts. Carbon sources are, for example, one or more of starch, glucose, sucrose, dextrin, fructose, molasses, glycerol, lactose, or galactose. A preferred carbon source is glucose. Nitrogen sources are, for example, one or more soy flour, peanut flour, yeast extract, meat extract, peptone, malt extract, macerated corn liquor, gelatin, or "casamion" acids. Preferred nitrogen sources are peptone and yeast extract. Nutrient inorganic salts are, for example, one or more of sodium chloride, depotassium chloride, calcium chloride, magnesium chloride, de-strontium chloride, potassium bromide, sodium fluoride, sodium acid phosphate, potassium acid phosphate, disodium phosphate, decalcium carbonate, sodium bicarbonate, sodium silicate, ammonium nitrate, potassium nitrate, sodium sulfate, ammonium sulfate, magnesium sulfate, ferric citrate or boric acid. Calcium carbonate, sodium chloride and magnesium chloride are preferred. Maintenance of culture No. ZMA B-I may be performed at a temperature ranging from 21 ° C to 35 ° C and a pH of about 6.5 to 8.5. Typically, culture No. ZMA B-I is maintained at 27-29 ° C and a pH of about 7.4 - 7.8. Well-grown crops can be refrigerated at 4 ° C-8 ° C.

Cultivation of culture by sowing of culture No. ZMA BI may be carried out at a temperature ranging from 250 ° C to 350 ° C and a pH of about 6.5 to 8.5 for 20 - 55 hours at 200-280 rpm. The seed of culture No. ZMA B1 is grown at 29-31 ° C and a pH of about 7.4 - 7.8 for 24-48 hours at 230-250rpm.

The production of compound PM1 81104 can be carried out by cultivating culture No. ZMA B1 by fermentation at a temperature ranging from 26 ° C to 36 ° C and a pH of about 6.5 to 8.5 for 24-96 hours at 60 ° C. -140 rpm and 100-200 lpm aeration. Typically, ZMA B-I culture is grown at 30-32Â ° C and pH 7.4-7.8 for 40-72 hours at 90-110 rpm and aeration at 140-160 lpm.

Compound PM1 81104 can be produced by cultivating culture No. ZMA B-I in a suitable nutrient broth under the conditions described in this report, preferably under submerged aerobic conditions, for example in shake flasks, as well as in laboratory fermenters. The progress of fermentation and production of compound PMl 81104 can be detected by high performance liquid chromatography (HPLC) by measuring the broth bioactivity against Staphylococci and / or Enterococci species by the well known microbial agar plate diffusion assay method. The preferred culture is Staphylococcus aureus 3066, which is a methicillin resistant strain, a β-lactam antiobotic reported in the literature, and Enterococcus faeeium R2 (VRE) which is resistant to vancomycin. In the resulting culture broth, PMl 81104 is present in culture filtrate as well as cell mass and can be isolated using known separation techniques such as solvent extraction and column chromatography. Thus, PMl81104 can be recovered from the culture filtrate by extraction at a pH of about 5 to 9 with a water-immiscible solvent such as petroleum ether, dichloromethane, chloroform, ethylacetate, diethyl ether or butanol, or by hydrophobic interaction chromatography using polymeric resins such as "Diaion HP-20®" (Mitsubishi Chemical Industries Limited, Japan), "Amberlite XAD®" (Rohm & Haas Industries USA), coal, or by ion exchange chromatography at pH 5-9. Active material It may be recovered from the cell mass by extraction with a water miscible solvent such as methanol, acetone, acetonitrile, n-propanol, or isopropanol or with a water immiscible solvent such as petroleum ether, dichloromethane, chloroform, ethyl acetate or butanol. Another option is to extract the total alkali with a solvent selected from petroleum ether, dichloromethane, chloroform, ethyl acetate, methanol, acetone, acetonitrile, n-propanol, isopropanol, or butanol. Typically, the active material is extracted with ethyl acetate from the total broth. Concentration and lyophilization of the extracts give the active crude material. The compound PM181104 of the present invention can be recovered from the crude material by fractionation using any of the following techniques: normal phase chromatography. (using alumina or silica gel as the stationary phase; eluents such as petroleum ether, ethyl acetate, dichloromethane, acetone, chloroform, methanol, or combinations thereof; and amine additions such as NEt3); reverse phase chromatography (using reverse phase silica gel such as dimethyloctadecylsilyl silica gel, (RP-18) or dimethyloctylsilyl silica gel (RP-8) as the stationary phase; eluents such as water, buffers (eg phosphate, acetate, citrate ( pH 2-8)), and organic solvents (e.g., methanol, acetonitrile, acetone, tetrahydrofuran, or non-solvent combinations)); gel permeation chromatography (using resins such as Sephadex LH-20® (Pharmacia Chemical Industries, Sweden), TSKgel® Toyopearl HW (TosoHaas, Tosoh Corporation, Japan) in solvents such as methanol, chloroform, acetone, ethylacetate, or combinations thereof, or Sephadex® G-10 and G-25 in water); or by counter-current chromatography (using a biphasic eluent system consisting of two or more solvents such as water, methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran, acetone, acetonitrile, methylene chloride, chloroform, ethyl acetate, petroleum ether, benzene, and toluene). These techniques may be used repeatedly, alone or in combination. A typical method is reverse phase silica gel chromatography (RP-18). Compound PM1 81104 and isomers thereof can be converted to their pharmaceutically acceptable salts which are all contemplated by the present invention. The salts may be prepared by traditional procedures known to the skilled artisan, for example salts such as sodium and potassium salts, may be prepared by treating the compound PMl 81104 and its isomers with a suitable sodium or potassium base, for example sodium hydroxide, hydroxide. The esters and ethers of compound PM1881104 represented by formula I may be prepared by the methods given in the literature (Advanced Organic Chemistry, 1992.4th Edition, J. March, John Wiley & Sons). Esters may also be prepared by the method described in the literature (J. Med. Chemistry, 1992, 35, 145-151). In a preferred embodiment of the invention, compounds of formula I wherein R is alkyl, cycloalkyl, aryl or heterocyclyl are prepared by reacting PM181104 with an appropriate acid having the formula RCOOH; where R is alkyl, cycloalkyl, aryl or heterocyclyl, in the presence of a coupling agent such as dicyclohexyl carbodimide (DCC) and catalytic amounts of a base such as dimethylamino pyridine (DMAP).

Phosphate esters may be prepared by a method described in the literature (Bioorganic & Medicinal Chemistry Letters, 1994, vol. 4, No. 21, 2567-2572). Esters may be prepared by the method described in US Patent No. 7,022,667, which is herein disclosed. incorporated reference title.

Compound PM1 81104 has antibacterial activity against a wide range of bacterial strains. MP1 81104, stereoisomers, pharmaceutically acceptable salts and derivatives such as esters and ethers thereof, alone or together, may be administered to animals, such as mammals, including humans, as pharmaceuticals and in the form of pharmaceutical compositions. Accordingly, the present invention also relates to compound PM181104, its stereoisomers, its pharmaceutically acceptable salts and its ester and ether derivatives for use as pharmaceuticals and the use of the compound PM181104, stereoisomers, pharmaceutically acceptable salts and their ester and ether derivatives for drug production. The present invention further relates to pharmaceutical compositions containing an effective amount of the compound PM1881104 and / or stereoisomers and / or one or more pharmaceutically acceptable salts and / or particularly derived esters and ethers thereof together with a pharmaceutically acceptable carrier. The effective amount of compound PM1 81104, or stereoisomers thereof, or pharmaceutically acceptable salts thereof or derivatives thereof as the active component in pharmaceutical preparations usually ranges from about 0.01 to 100mg.

The present invention also relates to a method for preparing a medicament containing the compound PM1881104 and / or stereoisomers and / or one or more pharmaceutically acceptable salts and / or ester ester derivatives thereof, for the treatment and prevention of infections caused by infections. bacterial.

The compounds of the present invention are particularly useful as antibacterial agents. The present invention therefore relates to the use of the compound PM181104 and / or stereoisomers and / or one or more pharmaceutically acceptable salts and / or derivatives thereof for the manufacture of a medicament for the prevention or treatment of diseases caused by bacterial infections. Bacterial infections for whose treatment the compounds of the present invention are used may be caused by bacteria belonging to the Staphylococci, Streptococci, Enterococci and Bacilli species.

The term "Staphylococcus species" refers to a Gram-positive bacterium that appears as grape clusters when viewed under a microscope and as large round golden yellow colonies, usually with β-hemolysis, when grown on blood agar plates. Staphylococcus aureus belonging to the species Staphylococci causes a variety of suppurative infections (which form pus) such as superficial skin lesions such as boils, styes and furunculosis; more serious infections such as pneumonia, mastitis, phlebitis, and urinary tract infections; rooted infections, such as osteomyelitis and endocarditis. Stephylococcus aureus is a major cause of nosocomial (hospital) infection of surgical wounds and infections associated with medical retention devices. Staphylocoeeusaureus causes food poisoning by releasing enterotoxins in foods, and toxic shock syndrome by releasing superantigens into the bloodstream.

The term "Streptococcus species" refers to a genus of spherical Gram-positive bacteria, and to a member of phylogenetic. Streptococci are lactic acid bacteria. Streptococci are responsible for infectious diseases such as meningitis, bacterial pneumonia, endocarditis, erysipelas and necrotizing ascites ('carnivorous' bacterial infections). The term 'Enterococci' refers to a genus of lactic acid bacteria. from the phylum Firmicutas. They are Gram-positive cococci that usually occur in pairs (diplococci), enterococci are anaerobicfactivative organisms. Enterococci are among the most frequent causes of nosocomial infections. Enterococci develop resistance to antibiotics such as gentamycin and vancomycin. The term "Bacillus species" refers to a large number of diverse gram-positive, gram-positive bacteria that are movable by peritrophic flagella and are aerobic. She is also a member of the Pharmacists division. Members of this genus are capable of producing endospores that are highly resistant to unfavorable environmental conditions. Bacillus cereusque belongs to the species Bacillus causes two types of food poisoning. One type is characterized by symptoms of nausea, vomiting and abdominal cramps. The second type is manifested by abdominal cramps and diarrhea. Infections attributed to Bacillus subtilis that belong to the Bacillus species include bacteremia, endocarditis, pneumonia, and septicemia in compromised immunological patients. The compounds of the present invention may be administered orally, nasal, topically, subcutaneously, intramuscularly, intravenously, or otherwise. Pharmaceutical compositions containing PM81104 or a stereoisomer or a pharmaceutically acceptable salt or ester or ether derivative thereof, with other pharmaceutically active substances may be prepared by mixing the active compounds with one or more pharmaceutically tolerated auxiliaries and / or excipients such as wetting agents, solubilising agents such as surfactants, vehicles, tonicity agents, fillers, dyes, masking flavors, lubricants, disintegrants, diluents, binders, plasticizers, emulsifiers, ointment bases, emollients, thickeners, polymers, lipids, oils, co-s solvents, complexing agents, or buffering substances, and conversion of the mixture into a suitable pharmaceutical form such as, for example, tablets, coated tablets, capsules, granules, powders, creams, ointments, gels, syrup, emulsions, suspensions, or solutions suitable for parenteral administration. .

Examples of auxiliaries and / or excipients which may be mentioned are chromophore, poloxamer, debenzalconium chloride, sodium lauryl sulfate, dextrose, glycerine, magnesium stearate, polyethylene glycol, starch, dextrin, lactose, cellulose, carboxymethyl sodium cellulose, talc, agar. agar, mineral oil, animal oil, vegetable oil, waxes and minerals, paraffin, gels, propylene glycol, benzyl alcohol, dimethylacetamide, ethanol, polyglycols, tween 80, solutol HS 15, and water.

Comotal active substances can also be administered without vehicles or diluents in a suitable form, for example in capsules.

As is common, the galenic formulation and method of administration as well as the dosage range that are suitable in a particular case depend on the species being treated and the condition or condition thereof, and can be optimized using known methods. On average, the daily dose of active compound in a patient ranges from 0.0005 mg to 15 mg per kg, typically 0.001 mg to 7.5 mg per kg.

The following are illustrative examples of this invention and these do not limit its scope.

Isolation of Culture No. ZMA B-1 from a Marine Source

a) Insulation medium composition:

Zobell 2216 marine broth (agarified with 1.5% agar agar) Peptic digested animal tissue materials 5.0 g, yeast extract 1.0 g, ferric citrate 0.1 g, sodium chloride 19.45 g, sodium chloride magnesium 8.8 g, sodium phosphate 3.24 g, calcium chloride 1.8 g, potassium chloride 0.55 g, sodium bicarbonate 0.16 g, potassium bromide 80.0 mg, strontium chloride34.0 mg, boric acid 22.0 mg, sodium silicate 4.0 mg, sodium fluorate 2.4 mg, ammonium nitrate 1.6 mg, disodium phosphate 8.0 mg, agar powder 15.0 g, double distilled water 1 1.0 L final pH (at 25 ° C) 7.4-7.8.

b) Procedure

The sponge sample, Spirastrella inconstans var. digitata (Dendy) was collected from Palk Bay off the coast of Tamil Nadu, India, by SCUBA diving, from a depth of three meters. The sponge sample was rinsed in sterile seawater and immediately transferred to sterile polyethylene containers. The containers were stored at -20 ° C and transported with temperature being kept below 0 ° C for later study in the laboratory. Upon arrival at the laboratory, the corresponding samples were stored below 0 ° C and later thawed to room temperature (250 ° C ± 2 ° C) immediately prior to culture isolation. The corresponding sample was cut aseptically into 2 x 2 cm pieces and suspended in 5 ml sterile seawater in a 25 ml sterile test tube. The test tube was centrifuged for 30 seconds; seawater was removed by drainage and fresh tidal water was added. The same process was repeated three times. Finally, seawater was removed by drainage and the sponge opaque was placed in petri dishes containing the above-mentioned isolation medium [Zobell2216 broth (agarified with 1.5% agar agar); HiMedia]. The depetri plate was incubated at room temperature (25 ± 2 ° C) until growth was observed in the plates. The colonies that grew in the plates were isolated based on the characteristics of the colony streaked in petri dishes containing the aforementioned isolation medium [Zobell 2216 Broth (1.5% agar agar); HiMedia]. The isolates were repeatedly subcultured until culture No. ZMA B-Ipura was obtained. Culture No. ZMA B-I was thus isolated from among the developing microorganisms as a single isolate.

Example 2

Culture Purification No. ZMA B-I

a) Insulation medium composition:

Zobell 2216 Broth (1.5% agar agar) Peptona 5.0 g, yeast extract 1.0 g, ferric citrate 0.1 g, 15 sodium chloride 19.45 g, magnesium chloride 8, 8 g, sodium sulfate 3.24 g, calcium chloride 1.8 g, potassium chloride 0.55 g, sodium bicarbonate 0.16 g, potassium bromide 0.08 g, strontium chloride 34.0 mg, acid boric 22.0 mg, sodium silicate 4.0 mg, sodium fluorate 2.4 mg, ammonium nitrate 1.6 mg, disodium phosphate 8.0 mg, agar 15.0 g, demineralised water 1.0 L, pH 7.4-7.8.

b) Procedure

The culture was available in Zobell 2216 broth (1.5% agar agar agarified) in 15 mm diameter petri dishes. Growth in the petri dish was streaked onto a sloping surface with Zobell 2216 broth (1.5% agar agar). The sloped surface was incubated for 2 days at 25 ° C. One of the simple colonies of the upper port of the sloping bed was transferred to fresh inclined surfaces. Tilted surfaces were incubated for 2 days at 25 ° C. These were then used for packet shaker fermentation for the purpose of primary anti-infectious screening.Example 3

Maintenance of the producing strain - culture No. ZMA B-1a) Media composition (Zobell 2216 marine broth): Pepton 5.0 g, yeast extract 1.0 g, ferric citrate 0.1 g, sodium chloride 19.45 g, magnesium chloride 8.8 g, sodium sulfate 3.24 g, calcium chloride 1.8 g, potassium chloride 0.55 g, sodium bicarbonate 0.16 g, potassium bromide 0.08 g, chloride strontium 34.0 mg, boric acid 22.0 mg, sodium silicate 4.0 mg, sodium fluorate 2.4 mg, ammonium nitrate 1.6 mg, phosphate diisodium 8.0 mg, agar 15.0 g, demineralised water 1.0 L, pH 7.4-7.8.

b) After completely dissolving the components by heating, the resulting solution was distributed into test tubes and sterilized at 1210 ° C for 30 minutes. The assay tubes were cooled and allowed to solidify in a slanted position. The slanted agar surfaces were streaked with the growth of culture No. ZMA B-I by a wire loop and incubated at 27-29 ° C until good growth was observed. Well-developed cultures were stored in the refrigerator at 4-8 ° C.

Example 4

Fermentation of culture No. ZMA B-I in shake flasks

(a) Composition of the sowing medium (Zobell2216 marine broth):

Peptone 5.0 g, yeast extract 1.0 g, ferric citrate 0.1 g, sodium chloride 19.45 g, magnesium chloride 8.8 g, sodium sulfate 3.24 g, calcium chloride 1.8 g, potassium chloride 0.55 g, sodium bicarbonate 0.16 g, potassium bromide 0.08 g, strontium chloride 34.0 mg, boric acid 2.0 mg, sodium silicate 4.0 mg, sodium fluorate2, 4 mg, ammonium nitrate 1.6 mg, disodium phosphate 8.0 mg, demineralized water 1.0 L, pH 7.4-7.8.

b) The above medium was distributed in 40 ml amounts of 500 ml Erlenmeyer packs and autoclaved at 121 ° C for 30 minutes. The flasks were cooled to room temperature and each flask was inoculated with a loop of the well-developed producing strain (culture No. ZMAB-1) on the sloped surface and shaken in a gyratory shaker for 24-48 hours at 230-30 ° C. 250 rpm at 30 ° C (± 1 ° C) to give a sowing crop.

c) Composition of the production medium:

Peptone 5.0 g, yeast extract 1.0 g, ferric citrate 0.1 g, sodium chloride 19.45 g, magnesium chloride 8.8 g, disodium sulfate 3.24 g, calcium chloride 1.8 g, potassium chloride 0.55 g, sodium bicarbonate 0.16 g, potassium bromide 0.08 g, strontium chloride 34.0 mg, boric acid 22.0 mg, sodium silicate 4.0 mg, sodium fluorate 2.4 mg, ammonium nitrate 1.6 mg, phosphate disodium 8.0 mg, demineralized water 1.0 L, pH 7.4-7.8

d) 40 ml of the production medium in 500 ml capacity Erlenmeyer flasks were autoclaved at 121 ° C for 30 minutes, cooled to 29 - 30 ° C and seeded with 2 ml of the seeding culture mentioned in example 4b.

e) Fermentation parameters

Temperature 29-30 ° C; stirring 230-250 rpm; Harvest time 48-72 hours.

The production of compound PM181104 in the fermentation broth was determined by bioactivity testing against Enterococcus faeeiumR2 (VRE) and / or S.aureus 3066 strain MRSA using the agar well diffusion method. The pH of the culture broth was 7.0 - 8.0. The culture broth was harvested and the total broth was used to test the bioactivity, which is indicative of the presence of PM181104 compound in the fermented broth.

Example 5

Preparation of seeding culture in parafermentation shake flasks

a) Medium composition:

Peptone 5.0 g, yeast extract 1.0 g, ferric citrate 0.1 g, sodium chloride 19.45 g, magnesium chloride 8.8 g, disodium sulfate 3.24 g, calcium chloride 1.8 g, potassium chloride 0.55 g, sodium bicarbonate 0.16 g, potassium bromide 0.08 g, strontium chloride 34.0 mg, boric acid 22.0 mg, sodium silicate 4.0 mg, sodium fluorate 2.4 mg, ammonium nitrate 1.6 mg, phosphate disodium 8.0 mg, demineralized water 1.0 L, pH 7.4-7.8.b) The above medium was distributed in amounts of 200 ml Erlenmeyer packs. of 11 and treated in an autoclave at 121 ° C for 30 minutes. The flasks were cooled to room temperature and each flask was inoculated with a well-developed strain (culture no. ZMA B-1) loop over sloping surface and shaken on a rotary shaker for 24-48 hours at 230-250 rpm at 29-31 ° C to give a ripple culture.

Example 6

Cultivation of culture n ° ZMA B-I in yeast

a) Production medium composition: Glucose 50.0 g, yeast extract 11.0 g, peptone 4.0 g, meat extract 4.0 g, calcium carbonate 5 g, sodium chloride 2.5 g, water demineralized 1 L, pH 7.6 (before sterilization).

(b) 250 l of the production medium in 300 l of yeast together with 80 ml of desmophen as a defoaming agent was sterilized in situ for 30 minutes at 121 ° C, cooled to 29 - 31 ° C and seeded with 6 l of the sowing culture mentioned in example 5b. .

c) Fermentation parameters: Temperature 30-32 ° C; stirring 100 rpm; aeration 150lpm; harvest time 44-66 hours. Production of PMl 81104 in the fermentation broth was determined by testing bioactivity against S. aureus 3066 (cepaMRSA) and / or Enterococcus faeeium R2 (VRE) using the agar well diffusion method. The harvest pH of the culture broth was 7.0 - 8.0. The culture broth was harvested and the total broth was used for isolation and purification of compound PM81104.

Example 7

Isolation and Purification of Compound PM1 81104 The total broth (240 L) of Example 6 was collected and extracted using ethyl acetate (240 L) with stirring in a glass vessel. The organic layer was separated using a disc stack separator (Alfa-laval, model No. LAPX404) and concentrated to give crude extract (296 g). The crude material obtained was stirred and sonicated for 30 minutes using petroleum ether (3 X 1 L) and filtered to an insoluble residue (38 g), which was chromatographed by vacuum liquid chromatography using the following method.

The insoluble residue (35.5 g) was dissolved in a mixture of methanol and acetonitrile (3: 1, 400 ml) and pre-adsorbed on LiChroprep RP-18 [25-40 μ, 40 g] and applied to a funnel filter ( grade G-4; 10 cm χ 10.5 cm) coated with LiChroprep RP-18 adsorbent (25-40 μ, 110 g). Elution using home vacuum (100-120 mm) was initially done with water (4 L), followed by water: methanol (1: 1, 5 L), methanol (3 L), methanol: acetonitrile (2.5 L) and acetonitrile. Purification monitoring was done by bioassay against Ent. faecium R2 and / or S. aureus 3066 and / or HPLCanalytic. Compound PM1 81104 was detected in methanol and ethanol: acetonitrile & acetonitrile fractions. Similar fractions were pooled and concentrated to obtain semi-pure material (1.826 g).

Final purification was by repeated preparative HPLC using the following conditions: Column: Eurospher RP-18 (10μ, 32x250 mm) Eluent: Acetonitrile: Water (56:44) Flow rate: 50 ml / minDetection (UV): 220 nm retention: 12-14 minPurity of fractions was verified by contraEnt bioassay. faecium R2 and / or S. aureus 3066 and / or HPLCanalytic. Eluted materials containing compound PM81104 were combined and concentrated under reduced pressure to remove solvent to obtain pure decomposed 600 mg.

The physicochemical and spectral properties of compoundPMl 81104

Appearance: White amorphous solid Melting Point:> 300 ° C (decomposition) Solubility: Methanol, DMSOHPLC: Rt 5.61 minutes

Column: Kromasil Cl8 (5 μ; 150χ4.6 mm I.D.) (Column temperature 40 ° C) Mobile phase: acetonitrile: water (1: 1) Vol. injection time: 10 μΐ (0.1 mg / ml concentration in fasemobile)

Flow rate: 1 ml / minDetection: 220 nm

HR-ESI (+) MS m / z: 1515.3733 (M + H) Molecular Formula: C69H66Ni8O1S5 Molecular Weight: 1514UV (MeOH): 205.2, 220.6 and 306.2 nm (refer to Figure 1)

IR (KBr): 3368, 2981.1654, 1516, 1429, 1314, 1199.1269, 1074, 1034, 805, 580 cm -1 (refer to Figure 2) 1 H NMR: refer to Table 1 and Figure 313C NMR: Refer to Table 2 and Figure 4Table 1: 1H NMR of compound PM181104 in DMSO-d6

<table> table see original document page 23 </column> </row> <table> <table> table see orginal document page 24 </column> </row> <table>

Table 2: 13C NMR of compound PM181104 in DMSO-d6

<table> table see original document page 24 </column> </row> <table>

* two carbons

BIOLOGICAL EVALUATION OF COMPOUND PMI 81104

In vitro Assay

Example 8

In vitro potency was established by minimum inhibitory concentration (MIC) determinations of compound PMl 81104 against bacterial strains using the Macro-broth dilution method according to the guidelines of the National Committee for Clinical Laboratory Standards (2000) [Journal of Anti-microbialChemotherapy, 2002 , 50, 125-128 (Cross Reference 8: Antimicrobial Methodsfor Dilution Susceptibility Tests for thatGrow Aerobically-Fifth Edition Bacteria: Approved Standard M7-A5.NCCLS, Wayne, PA, USA)]. Unless otherwise indicated, Mueller-Hinton broth was used as a half-nutrient for the assay. Linezolid (manufactured by GlenmarkPharma Ltd; Lot No: K2005028) was used as the known standard in all in vitro experiments. For preparation of the stock solution compound PM81104 was dissolved in chloroform (5% of the total required volume) and diluted using methanol (95% of the total required volume).

Result:

The results obtained are shown in Table 3 below and show that compound PMl 81104 is useful in the treatment of bacterial infections.

Table 3: MICs of compound PM181104 against bacterial strains

<table> table see original document page 25 </column> </row> <table> <table> table see original document page 26 </column> </row> <table>

The abbreviations used in table 3 are -

S: Staphylococcus

E: Enterococei

B: Bacillus

In vivo essay

In vivo potency was established by determination of the protective dose (PD) of compound PMl81104 for its antibiotic activity in three animal models using Balb / Cmachos or female mice.

The models used were generic end-use efficacy testing models and organ / tissue-specific efficacy testing models. The generic purpose efficacy testing models used were the systemic infection model (septicemia) and the localized infection model (neutropenic thigh model). The organ / tissue specific infection models used to test efficacy were models of renal infection, lung infection, and skin abscess.

Example 9

Systemic infection model Animals were intraperitoneally infected with -IO8 a109 cfu from a culture of overnight methicillin-resistant Staphylococcus aureus E710 (MRSA) culture suspended in normal saline (0.85% sodium chloride). The PM81104 solution was prepared in the chromophore-ethanol formulation described in Example 14. The solution was administered intravenously at doses of 5 mg, 2.5 mg and 1.25 mg / kg immediately after infection. Each experimental group consisted of ten animals. PM10 PD10O 81104 for the desepticemia model was determined to be 5 mg / kg compared to the Linezolid reference antibiotic (manufactured by GlenmarkPharma Ltd; Lot No: K2005028) which showed PD10O at 25mg / kg. Example 10

Neutropenic Thigh ModelMice were neutropenic with cyclophosphamide (150mg and 100mg / kg) 96 hours and 24 hours, respectively, prior to S.aureus E-710 infection. The animals were infected intramuscularly with S.aureus E-710 grown overnight, suspended in normal saline solution (0.85% sodium chloride). Each experimental group consisted of six animals. PM1 81104 was prepared in a chromophore-ethanol formulation as described in example 14. The solution was administered intravenously at a dose of 5 mg / kg two hours after infection. The animals were sacrificed at various times and the thigh tissue was harvested to determine viable counts. A reduction of approximately 1 Iog was observed with PMl 81104 at a dose of 5 mg / kg within 6 hours, which was comparable to the reference antibiotic used, namely Linezolid (manufactured by GlenmarkPharma Ltd; Lot No: K2005028) at one dose. 25 mg / kg.Example 11Modeling of kidney infection

0.2 ml of 2% carrageenan λ was administered intravenously to Balb / C mice 7 days before infection. A culture of Enteroeoceus faeeium ATCC 47077 in the developing stage at night adjusted to approximately 109 cfu / ml was injected intravenously into the mice at a volume of 0.2 ml. A solution of PM181104, prepared in decremophore-ethanol formulation in the manner described in Example 14, was administered intravenously to the mice 4 hours, 24 hours and 48 hours after infection. 72 hours after infection, the animals were sacrificed and the kidneys were collected to determine the bacterial load. A reduction in bacterial count of approximately 1 log was observed with PM181104 at a dose of 5 mg / kg, which was comparable to the reference antibiotics used, namely Linezolid (manufactured by Genemark Pharma Ltd; Lot No: K2005028) at 25 mg / kg hydrochloride. of vancomycin (manufactured by HiMedia; Catalog #: RM217-500mg; Lot #: 06-0350) at a dose of 150 mg / kg.

Example 12

Pulmonary infection model

Balb / C mice were neutropenic by intraperitoneal administration of cyclophosphamide 200 mg / kg four days and two days before infection. On the day of infection, mice had been anesthetized and infected with a culture suspension in the S. aureus E-710 faselog having a bacterial density of approximately 10 6 to 10 7 cfu / ml. 24 and 36 hours after infection, the respective first and second doses of the drug were administered intravenously. 48 hours after infection, the animals underwent human euthanasia and their lungs were aseptically collected to determine the viable count of the bacteria. In this model, PM181104 was tested at a dose of 5mg / kg prepared in the chromophore-ethanol formulation as described in example 14. Two reference antibiotics, namely Linezolid (single dose 80 mg / kg 24 hours after infection) Evancomycin (110 mg / kg, two doses 24 and 48 hours after infection) were used as positive controls. PM181104 exhibited bacteriostatic activity, which was comparable to Linezolid reference (manufactured by Glenmark Pharma Ltd; Loten: K2005028). The reference vancomycin hydrochloride (manufactured by HiMedia; Catalog #: RM2-17-500mg; Lot #: 06-0350) showed a bactericidal profile. There is a difference of approximately 2 Iog in bacterial count in the lungs of the PM1 81104-treated animals compared to that of the untreated control animals.

Example 13

Skin abscess model

Balb / C mice were subcutaneously infected with approximately 108 of a overnight cultured methicillin-resistant S.aureus E710 (MRSA) culture. Bacteria were suspended in a 1: 1 mixture of 2% cytodex globules in normal saline (0.85% sodium chloride). PM1 81104 was prepared in a chromophore-ethanol formulation as described in example 14. The solution was administered intravenously at doses of 2.5 mg, 5 mg and 10 mg / kg, two hours after infection. Each experimental group consisted of six animals. Following abscess formation the animals were sacrificed and the abscess collected to determine viable counts. A reduction in bacterial counts of approximately 1 Iog was observed with PMl 81104 at a dose of 5 mg / kg, which was comparable to the reference antibiotic used, namely Linezolid (manufactured by GlenmarkPharma Ltd; Lot No: K2005028) at one dose. 50 mg / kg. COMPOUND FORMULATION PM181104

Example 14

Injectable formulations were prepared by the following general method:

Ethanol and EL creamer were mixed at a ratio of 1: 1 (by weight). To this end, PM1 81104 was added and centrifuged. This mixture was sonicated at 25 ° C. This mixture (considering it as a 10% constituent) was diluted by the addition of water (90%) and centrifuged to obtain the injectable formulation.

COMPOUND BY-PRODUCTS PMl81104

Example 15

PMl81104A butyric acid ester derivative a solution of PM181104 (0.13 g, 0.085 mmol) in dichloromethane (2 ml), butyric acid (0.008 μΐ, 0.085 mmol), DCC (0.018 g, 0.085 mmol) and a catalytic amount of DMAP (0.002 g, 0.016 mmol) was added and the reaction mixture was stirred for 18 hours in a nitrogen atmosphere. To the reaction mixture, cold water was added and the organic layer was separated; The aqueous layer was extracted with dichloromethane (3 x 50ml), the organic extracts were combined and washed with water (2x30ml). The organic layer was dried over concentrated anhydrous sodium phosphate. The crude product was purified using column chromatography [silica gel (60-120 mesh], 4% methanol in chloroform] to obtain the title compound as a white solid. Yield: 0.11 g (81%); MS m / z (ESI ): 1585 (M + H)

The butyric acid ester derivative of PMl81104 had a MIC value of 2.5 μg / ml against E. faecium R-2 cepabacterial (VRE).

Example 16

PM181104 Stearic Acid Type Ester Derivative

To a solution of PM181104 (0.12 g, 0.079 mmol) in dichloromethane (2 mL), stearic acid (0.022 μΐ, 0.079 mmol), DCC (0.016 g, 0.079 mmol) and a catalytic amount of DMAP (0.002 g, 0.016 mmol) ) were added and the reaction mixture was stirred for 6 hours in a nitrogen atmosphere. To the reaction mixture, cold water was added and the organic layer was separated; The aqueous layer was extracted with dichloromethane (3x50 ml), the organic extracts were combined and washed with water (2 x 30 ml). The organic layer was dried over concentrated anhydrous sodium phosphate. The crude product was purified using column chromatography [silica gel (60-120 mesh], 4% methanol in chloroform] to obtain the title compound as a white solid. Yield: 0.1 g (71%); MS m / z ( ESI): 1781 (M + H).

The stearic acid ester derivative of PMl81104 had an MIC value of 1.25 μg / ml against the E. faecium R-2 cepabacterial (VRE). Example 17

Nicotinic acid ester type derivative of PMl 81104A a solution of PM181104 (0.02 g, 0.013 mmol) in N, N-dimethylformamide (1 ml), nicotinic acid (0.008 g, 0.065 mmol), DCC (0.014 g, 0.065 mmol) and a catalytic amount of DMAP (0.0008 g, 0.0065 mmol) were added and the reaction mixture was stirred for 18 hours in a nitrogen atmosphere. Solvent was removed and to the residue was added 10 ml of dichloromethane. Undissolved urea was filtered and the filtrate was flushed with water (2 x 10 ml). The organic layer was dried over anhydrous sodium phosphate and concentrated to dryness. The product was purified by column chromatography [C-18 transverse column (Eurosphere, 20 nm), 55% acetonitrile in water] to obtain the title compound as a white solid. Yield: 0.011 g (56%); MS m / z (ESI): 1621 (M + H) .The nicotinic acid ester derivative of PM1 81104 has been tested against bacterial strains. The results obtained are shown in table 4 below, and demonstrate that the nicotinic acid ester derivative of PMl 81104 is useful in the treatment of bacterial infections.

Table 4: MICs of the acid ester derivative

<table> table see original document page 31 </column> </row> <table>

Claims (22)

1. "New Antibacterial Compounds" characterized by new compounds of formula I below: <formula> formula see original document page 32 </formula> where R = H, alkyl, alkylcarbonyl, (HO) 2PO-, alkyl-OPO (OH ) -, (alkyl-O) 2 O-, cycloalkyl, cycloalkylcarbonyl, aryl, arylcarbonyl, heterocyclyl and heterocyclyl carbonyl; or stereoisomers outautomers or pharmaceutically acceptable salts thereof. 2. "New Antibacterial Compounds" characterized in that it is a New compound, PM181104 according to claim 1, wherein in the compounds of formula I, R is H, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof. 3. "New antibacterial compounds", characterized in that it is a new compound, PM181104 according to claim 2, or a stereoisomer or a tautomer thereof, with antibacterial activity, which is isolated from the fermented broth of the microorganism belonging to the Kocuria species (ZMA B-1). (MTCC 5269) is characterized by: (a) molecular weight 1514, (b) molecular formula C69H66N18O13S5, (c) UV spectrum as shown in Figure 1, (d) IR spectrum as shown in Figure 2, (e) 1 H NMR spectrum as shown in Figure 3, (f) 13 C NMR spectrum as shown in Figure 4. "Novel Antibacterial Compounds" characterized in that it is a process for the production of compound PM181104 according to claim 2 or 3, comprising the steps of: (a) cultivating the microorganism of the Kocuria species (ZMAB-1 / MTCC 5269) or one of variants or mutants under aerobic conditions submerged in a nutrient medium containing carbon and nitrogen sources to produce compound PM181104, (b) isolate compound PMl81104 from fermented broth, and (c) purify compound PMl 81104. 5. "Novel Antibacterial Compounds" according to claim 4, further comprising the step of converting compound PM181104 into its pharmaceutically acceptable salt. 6. "Novel antibacterial compounds" according to claim 4, further comprising the step of reacting compound PM81104 with an acid having the formula RCOOH; wherein R is alkyl, cycloalkyl, aryl or heterocyclyl, to obtain new compounds of formula I according to claim 1, wherein R = alkyl, cycloalkyl, aryl and heterocyclyl. 7. "New antibacterial compounds" according to claim 1, characterized in that R = CH3CH2CH2CO, CH3 (CH2) 15CH2CO or 8. "Novel Antibacterial Compounds" comprising a pharmaceutical composition comprising an effective amount of the compounds according to claim 1 with at least one excipient or additive or a pharmaceutically acceptable auxiliary. 9. "New Antibacterial Compounds" according to Claim 8, characterized in that the pharmaceutical composition is in the form of a tablet, coated tablet, capsule, granule, powder, cream, ointment, gel, emulsion, suspension, or solution for injection. "Novel Antibacterial Compounds" according to claim 8, wherein said composition is adapted for the treatment of bacterial infections. 11. "New Antibacterial Compounds" according to claim 10, wherein said bacterial infection is caused by bacteria belonging to the Staphylococci, Streptococci, Enterococci or Bacilli species. 12. "New Antibacterial Compounds" according to claim 11, characterized. where said bacteria belong to the species Staphylococci or Enterococci. 13. "New Antibacterial Compounds" according to claim 12, characterized. wherein said bacterium belonging to the Staphylococcus species is resistant to methicillin. 14. "New Antibacterial Compounds" according to claim 12, characterized. wherein said bacterium belonging to the Staphylococcus species is resistant to vancomycin. 15. "Novel Antibacterial Compounds" according to claim 12, characterized in that said bacterium belonging to Enterococci is resistant to vancomycin. "Novel Antibacterial Compounds" characterized in that it is a method of treating a bacterial infection comprising administering to a mammal in need thereof an effective amount of a compound according to claim 1. 17. "New Antibacterial Compounds" according to claim 16, wherein the bacterial infection is caused by bacteria belonging to the Staphylococci, Streptococci, Enterococci and Bacilli species. 18. "New Antibacterial Compounds" according to claim 17, characterized in that the bacterial infection is caused by bacteria belonging to the Staphylococci or Enterococci species. 19. "Novel Antibacterial Compounds" according to Claim 18, characterized in that said bacterium belongs to the Staphylococcus species and is resistant to methicillin-resistant methicillin. 20. "Novel Antibacterial Compounds" according to Claim 18, characterized in that said bacterium belonging to the Staphylococcus species is resistant to vancomycin-resistant methicillin. 21. "New Antibacterial Compounds" according to claim 18, characterized in that the bacterium belonging to the Enterococci species is resistant to vancomycin. 22. "New Antibacterial Compounds" according to claim 1, characterized for the production of a medicament for treating a bacterial infection.