WO2013080167A1 - Composés pour le traitement de la tuberculose - Google Patents

Composés pour le traitement de la tuberculose Download PDF

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Publication number
WO2013080167A1
WO2013080167A1 PCT/IB2012/056853 IB2012056853W WO2013080167A1 WO 2013080167 A1 WO2013080167 A1 WO 2013080167A1 IB 2012056853 W IB2012056853 W IB 2012056853W WO 2013080167 A1 WO2013080167 A1 WO 2013080167A1
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Prior art keywords
compound
formula
tuberculosis
mycobacterium tuberculosis
organism
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PCT/IB2012/056853
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English (en)
Inventor
Girish Badrinath Mahajan
Prabhu Dutt Mishra
Ashwini VARTAK
Prashant SHANBHAG
Amarjit SAWANT
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Piramal Enterprises Limited
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Publication of WO2013080167A1 publication Critical patent/WO2013080167A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/15—Depsipeptides; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • the present invention relates to a method for the treatment of tuberculosis in a subject by administering to the subject a therapeutically effective amount of the compound of Formula 1 (as described herein), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof.
  • the present invention also relates to a pharmaceutical composition comprising the compound of Formula 1 as an active ingredient for use in the treatment of tuberculosis.
  • Tuberculosis is a common lethal infectious disease caused by various strains of mycobacteria, particularly Mycobacterium tuberculosis (MTB).
  • MTB Mycobacterium tuberculosis
  • the distribution of tuberculosis is not uniform across the globe. Approximately fifty million people are infected with TB worldwide. Of those infected, about ten million people may develop active disease and there will be close to three million deaths annually due to tuberculosis.
  • Tuberculosis can affect any organ of the body and is manifested in several different forms, but the primary site of infection is the lung. Tuberculosis of the lungs usually spreads through the air when people who have an active MTB infection cough, or sneeze. The classic symptoms are a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss. Diagnosis relies on radiology (commonly chest X-rays), a tuberculin skin test, blood tests, as well as microscopic examination and microbiological culture of body fluids.
  • Effective tuberculosis treatment involves use of antibiotics. Unusual structure and chemical composition of the mycobacterial cell wall makes many antibiotics ineffective and hinders the entry of the anti-tubercular drugs. Instead of the short course of antibiotics typically used to cure other bacterial infections, TB requires much longer period of treatment (around six to twenty four months) to entirely eliminate mycobacteria from the body.
  • the two antibiotics most commonly used for the treatment of tuberculosis are isoniazid and rifampicin.
  • Multidrug resistant tuberculosis is a form of tuberculosis that is resistant to at least two of the front-line antitubercular drugs, isoniazid and rifampicin. MDR-TB is treated with second line antitubercular drugs like fluoroquinolones, para- aminosalicyclic acid, thioacetazone and aminoglycosides such as amikacin, kanamycin or capreomycin.
  • MDR-TB The treatment of MDR-TB is associated with prolonged illness and disability. The average recommended duration of treatment is two years. Second line antitubercular drugs are generally considered to be less effective, show adverse reactions, and poor bioavailability in the lungs, which is detrimental for disease eradication (Eur. Respir. J., 2002, Supplement 36, 66S-77S).
  • Fusaricidins are known antibiotics that have a ring structure composed of six amino acid residues in addition to 15-guanidino-3-hydroxypentadecanoic acid (GHPD).
  • GHPD 15-guanidino-3-hydroxypentadecanoic acid
  • Various analogs of Fusaricidins (LI-F03, LI-F04, LI-F05, LI-F06, LI-F07 and LI-F08) were isolated from culture broth of Paenibacillus polymyxa and have been characterised (The Journal of Antibiotics, 1987, 40, 1506-1514; Biochemical and Biophysical Research Communications, 2008, 365, 89-95).
  • Fusaricidin A, B, C and D were isolated from culture broth of Bacillus polymyxa KT-8, and were reported to be active against fungi and gram- positive bacteria (The Journal of Antibiotics, 1996, 49, (2), 129-135; The Journal of Antibiotics, 1997, 50, (3), 220-228).
  • the inventors of the present invention have found that the compound of Formula 1 (Fusaricidin B) is active against both, Mycobacterium tuberculosis and multidrug resistant Mycobacterium tuberculosis, and hence, is useful in the treatment of TB and MDR-TB.
  • the present invention relates to a method for the treatment of tuberculosis in a subject comprising administering to the subject, a therapeutically effective amount of the compound of Formula 1 (as described herein), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a derivative thereof.
  • the present invention also relates to the compound of Formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a derivative thereof, for use in the treatment of tuberculosis.
  • the present invention also relates to a method of inhibiting growth of Mycobacterium tuberculosis organism, comprising contacting the Mycobacterium tuberculosis organism in vitro or ex vivo with the compound of Formula 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a derivative thereof, in an amount sufficient to inhibit the growth of Mycobacterium tuberculosis organism.
  • the present invention also relates to a pharmaceutical composition, comprising the compound of Formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a derivative thereof, and at least one pharmaceutically acceptable carrier, for use in the treatment of tuberculosis.
  • the present invention also relates to a use of the compound of Formula 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a derivative thereof, for the manufacture of a medicament for the treatment of tuberculosis.
  • Fusaricidins are antibiotics which have a ring structure composed of six amino acid residues in addition to 15-guanidino-3-hydroxypentadecanoic acid (GHPD) isolated from fermentation of Paenibacillus sp., and have excellent antifungal activity.
  • GHPD 15-guanidino-3-hydroxypentadecanoic acid
  • the present invention provides Fusaricidins having the following general formula, for use in the treatment of tuberculosis. wherein,
  • Xi, X 2 and X 3 are amino acids as described in Table 1 Table 1
  • the present invention provides Fusaricidin B represented by Formula 1 (referred to herein as the compound of Formula 1),
  • the present invention relates to a method for the treatment of tuberculosis in a subject comprising administering to the subject, a therapeutically effective amount of the compound of Formula 1 (as described herein), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a derivative thereof.
  • the compound of Formula 1 has the molecular formula C42H76N10O11 (molecular weight 896).
  • the compound of Formula 1 was characterised by the physico-chemical and spectral properties, such as mass spectrum (MS) and nuclear magnetic resonance (NMR) spectroscopic data as discussed herein below.
  • MS mass spectrum
  • NMR nuclear magnetic resonance
  • the compound has been identified as Fusaricidin B by comparing the spectral data with the data reported in the literature (Journal of Antibiotics, 1997, 50 (3), 220 - 228).
  • the compound of Formula 1 is found to be active against Mycobacterium tuberculosis. Accordingly, the compound of Formula 1 is useful in the treatment of tuberculosis.
  • the present invention encompasses within its scope, use of the compound of Formula 1 i.e. Fusaricidin B that is obtained by a synthetic method and/or from natural sources including microorganisms; for the treatment of tuberculosis.
  • One microorganism from which the compound of Formula 1 is isolated belongs to eubacteria (PM0834793/MTCC5620) (herein after referred to as culture no. PM0834793), which is isolated from the soil sample collected from the land near the hot-springs located in Tamilkashi district of Uttranchal State, India.
  • a process for the production of the compound of Formula 1 from the culture no. PM0834793 comprises the steps of:
  • step (c) involving purification of the compound of Formula 1 is carried out by using purification procedures generally used in the related art.
  • compound of Formula 1 refers to Fusaricidin B.
  • Fusaricidin B refers to a synthetically prepared Fusaricidin B and/or that obtained from other natural sources including microorganisms.
  • pharmaceutically acceptable refers to a compound or a carrier or an additive or a salt that is not biologically or otherwise undesirable.
  • a pharmaceutically acceptable compound or a salt must not cause any undesirable biological effects or interact in an undesirable manner with any of the other ingredients of the pharmaceutical composition in which it is contained.
  • pharmaceutically acceptable carrier means a diluent, excipient, encapsulating material or formulation auxiliary, which is non-toxic, and inert, which does not have undesirable affect on a subject, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to the target site without affecting the activity of the agent.
  • therapeutically effective amount means an amount of the compound of Formula 1 or a composition comprising said compound, sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid side effects, if any (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
  • therapeutically effective amount of the compound of Formula 1 or the composition containing said compound, for the treatment will vary with the severity of tuberculosis being treated, the age and physical condition of the subject (patient), the duration of the treatment, the nature of concurrent therapy, the particular pharmaceutically acceptable carrier utilized, and like factors.
  • an amount sufficient as used herein in relation to inhibiting the growth of Mycobacterium tuberculosis organism, means an amount of the compound of Formula 1 or a composition comprising said compound, sufficient to significantly induce inhibition of the growth of Mycobacterium tuberculosis organism.
  • treating have their ordinary or customary meanings, and include alleviating the infection or disease, slowing the progression of, attenuation or cure of the existing disease, in this case tuberculosis.
  • subject refers to an animal, preferably a mammal, and most preferably a human.
  • mammal refers to warm-blooded vertebrate animals of the class mammalia, including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • mammal includes without limitations animals such as cat, dog, horse, rabbit, bear, fox, wolf, monkey, deer, mouse, pig as well as human.
  • pharmaceutically acceptable salt(s) is meant to include salt(s) of the compound of Formula 1, which are prepared with acids or bases.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, magnesium, ammonium or an organic base salt.
  • pharmaceutically acceptable organic base addition salts include those derived from organic bases such as lysine, arginine or guanidine.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid or sulfuric acid, as well as the salts derived from organic acids such as acetic acid, propionic acid, oxalic acid, maleic acid, benzoic acid, succinic acid, fumaric acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid or methanesulfonic acid.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid or sulfuric acid
  • organic acids such as acetic acid, propionic acid, oxalic acid, maleic acid, benzoic acid, succinic acid, fumaric acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid or methanesulfonic acid.
  • mutant refers to an organism or cell carrying a mutation, which is an alternative phenotype to the wild-type.
  • variable refers to an individual organism that is recognizably different from an arbitrary standard type in that species.
  • the term "nutrient” refers to a substance that provides nourishment for growth or metabolism.
  • Preliminary identification of culture no. PM0834793, from which the compound of Formula 1 (Fusaricidin B) is produced is performed by examination of its colony characteristics. The colonies are picked up with sterile needle by viewing the colony morphology through stereo microscope (SM). Culture no. PM0834793 has been identified as a microorganism belonging to eubacteria.
  • the screening for suitable mutants and variants which can produce the compound according to the invention can be confirmed by HPLC, NMR, MS and/or determination of biological activity of the active compounds accumulated in the culture broth, for example by testing the compounds for anti-tuberculosis activity or by a combination thereof.
  • the medium and/or nutrient medium used for isolation and cultivation of culture no. PM0834793, from which the compound of Formula 1 is produced preferably contains sources of carbon, nitrogen and nutrient inorganic salts.
  • the carbon sources are, for example, one or more of starch, glucose, sucrose, dextrin, fructose, molasses, glycerol, lactose, or galactose.
  • a preferred carbon source is soluble starch and glucose.
  • the sources of nitrogen are, for example, one or more of soyabean meal, casein, peanut meal, yeast extract, beef extract, peptone, malt extract, corn steep liquor, gelatin, tryptone or casamino acids.
  • Preferred nitrogen source is casein, peptone, beef extract and yeast extract.
  • the nutrient inorganic salts are, for example, one or more of sodium chloride, potassium chloride, calcium chloride, manganese chloride, magnesium chloride, strontium chloride, cobalt chloride, potassium bromide, sodium fluoride, sodium hydrogen phosphate, potassium hydrogen phosphate, dipotassium hydrogen phosphate, disodium phosphate, calcium carbonate, sodium bicarbonate, sodium silicate, sodium nitrate, ammonium nitrate, potassium nitrate, sodium sulphate, ammonium sulphate, ammonium heptamolybdate, ferric citrate, copper sulphate, magnesium sulphate, ferrous sulphate, zinc sulphate or boric acid.
  • Calcium carbonate, sodium chloride and potassium nitrate are the preferred inorganic salts.
  • culture no. PM0834793 was purified and maintained on slants of agarified soyabean casein digest medium (SCDM); [Hi Media, Mumbai, Maharashtra, India Catalogue no. MO11-500G].
  • SCDM soyabean casein digest medium
  • the culture is preserved in glycerol vials with preservation media composed of 20 % glycerol, 0.3 % tryptone and yeast extract and is stored at -80 °C.
  • Seed culture cultivation of culture no. PM0834793 may be carried out at a temperature ranging from 27 °C to 33 °C and a pH of about 6.0 to 8.5, for 40-55 h at 240- 260 rpm (revolutions per minute).
  • culture no. PM0834793 seed is cultivated at 29 °C -31 °C and a pH of about 7.0-7.8, for 45- 50 h at 245-255 rpm.
  • the production of the compound of Formula 1 may be carried out by cultivating culture no PM0834793 by fermentation at a temperature ranging from 27 °C to 33 °C and a pH of about 6.0 to 8.5, for 40-55 h at 240- 260 rpm.
  • culture no. PM0834793 is cultivated at 29 °C-31 °C and pH 7.0-7.8 for 45-50 h at 240- 250 rpm.
  • the production of the compound of Formula 1 may be carried out by cultivating culture no. PM0834793 in a suitable nutrient broth under conditions described herein.
  • the progress of fermentation and production of the compound of Formula 1 may be detected by high performance liquid chromatography (HPLC) and by measuring the bioactivity in anti- infective screening test models using organisms such as Staph, aureus 209P, Escherichia faecium VRE 323, Candida albicans, Escherichia coli 20732, and Aspergillus fumigatus.
  • HPLC high performance liquid chromatography
  • Fermentation is a process of growing microorganisms for the production of various chemical or pharmaceutical compounds. Microbes are normally incubated under specific conditions in the presence of nutrients. Whole broth is obtained after completing the process of fermentation. The whole broth is subjected to centrifugation which results in formation of cell mass and culture filtrate, which can be processed further by processes described herein.
  • the compound of Formula 1 present in the culture broth may be isolated using different extraction methods and chromatographic techniques.
  • the compound of Formula 1 may be recovered from the culture filtrate by extraction with a water immiscible solvent such as petroleum ether, dichloromethane, chloroform, ethyl acetate, 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 and Haas Industries, USA) or adsorption on activated charcoal. These techniques may be used repeatedly, alone or in combination.
  • a water immiscible solvent such as petroleum ether, dichloromethane, chloroform, ethyl acetate, diethyl ether or butanol
  • polymeric resins such as "Diaion HP-20 ® " (Mitsubishi Chemical Industries Limited, Japan), “Amberlite XAD ® “ (Rohm and Haas Industries, USA) or adsorption on activated charcoal.
  • the active material may be recovered from the cell mass by treatment with a water miscible solvent such as methanol, acetone, acetonitrile, n-propanol, or iso-propanol or by extraction with a water immiscible solvent such as petroleum ether, dichloromethane, chloroform, ethyl acetate or butanol.
  • a water miscible solvent such as methanol, acetone, acetonitrile, n-propanol, or iso-propanol
  • a water immiscible solvent such as petroleum ether, dichloromethane, chloroform, ethyl acetate or butanol.
  • One other option to recover the active material involves extracting the whole broth with a solvent selected from petroleum ether, dichloromethane, chloroform, ethyl acetate, methanol, acetone, acetonitrile, n-propanol, iso-propanol, or butanol.
  • a solvent selected from petroleum ether, dichloromethane, chloroform, ethyl acetate, methanol, acetone, acetonitrile, n-propanol, iso-propanol, or butanol.
  • the active material is obtained from the whole broth using methanol for extraction, followed by concentration and chromatography using Diaion HP-20. Concentration and lyophilization of the eluates of Diaion HP-20 column, give the active crude material.
  • the compound of Formula 1 may be recovered from the crude material by fractionation using any of the following techniques: dilution with water and extraction with a water immiscible solvent such as petroleum ether, dichlorome thane, chloroform, ethyl acetate, diethyl ether or butanol; normal phase chromatography (using alumina or silica gel as stationary phase; eluents such as petroleum ether, ethyl acetate, dichloromethane, acetone, chloroform, methanol, or combinations thereof; and additions of amines such as NEt 3 ); reverse phase chromatography (using reverse phase silica gel such as dimethyloctadecylsilylsilica gel, (RP-18) or dimethyloctylsilyl silica gel (RP-8) as stationary phase; and eluents such as water, buffers (for example, phosphate, acetate, citrate (pH 2-8)), and organic solvent
  • stereoisomer is a general term used for all isomers of the compound of Formula 1, that differ only in the orientation of their atoms in space.
  • the term isomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates or racemic mixtures) and isomers of compounds with more than one chiral center that are not mirror images of one another (diaisomers).
  • the compound of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, individual diaisomers, or enantiomers, or may exist as geometric isomers, with all isomeric forms of said compound being included in the present invention.
  • tautomer refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.
  • the compound of Formula 1, or a stereoisomer, or a tautomer thereof may be converted into their pharmaceutically acceptable salts, which are all contemplated by the present invention.
  • salts may be prepared by standard procedures known to one skilled in the art, for example, salts like sodium and potassium salts, may be prepared by treating the compound of Formula 1 , or a stereoisomer, or a tautomer thereof, with a suitable sodium or potassium base, for example sodium hydroxide or potassium hydroxide.
  • salts like hydrochloride and sulphate salts may be prepared by treating the compound of Formula 1, or a stereoisomer, or a tautomer, thereof, with a suitable acid, for example hydrochloric acid, or sulphuric acid.
  • the derivative of the compound of Formula 1 may be an ester or ether of the compound of Formula 1.
  • the ester and ether of the compound of Formula 1 can be prepared by following the methods described in the literature (Advanced Organic Chemistry, 1992, 4 th Edition, J. March, John Wiley & Sons).
  • the compound of Formula 1 has activity against Mycobacterium tuberculosis organism, which is sensitive or multi drug resistant such as M. tuberculosis H37Rv; M. tuberculosis Clinical isolate - S (Streptomycin), H (Isoniazid or Isonicotinyl hydrazine), R (Rifampicin) and E (Ethambutol) - resistant.
  • M. tuberculosis H37Rv M. tuberculosis Clinical isolate - S (Streptomycin), H (Isoniazid or Isonicotinyl hydrazine), R (Rifampicin) and E (Ethambutol) - resistant.
  • Mycobacterium or “Mycobacterium species” refers to Gram-positive, non-motile, pleomorphic rods related to the actinomyces.
  • MDR-TB multi-drug resistant tuberculosis describes strains of tuberculosis that are resistant to at least the two first-line TB drugs, isoniazid and rifampicin.
  • the present invention relates to a method of treating tuberculosis in a subject, comprising administering to the subject a therapeutically effective amount of the compound of Formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof.
  • the present invention relates to a method of treating tuberculosis in a subject, comprising administering to the subject in need thereof a therapeutically effective compound of Formula 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof.
  • the present invention relates to a method of inhibiting growth of the Mycobacterium tuberculosis organism, comprising contacting the Mycobacterium tuberculosis organism with the compound of Formula 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof in an amount sufficient to inhibit growth of the organism.
  • the method of inhibiting growth of the Mycobacterium tuberculosis organism may be in vitro or ex vivo, comprising contacting the organism in vitro or ex vivo with the compound of Formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof, in an amount sufficient to inhibit the growth of the organism.
  • the present invention relates to a method of inhibiting growth of Mycobacterium tuberculosis organism, comprising contacting the Mycobacterium tuberculosis organism in vitro with the compound of Formula 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof, in an amount sufficient to inhibit the growth of the organism.
  • the present invention relates to a method of inhibiting growth of Mycobacterium tuberculosis organism comprising contacting the Mycobacterium tuberculosis organism ex vivo with the compound of Formula 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof, in an amount sufficient to inhibit the growth of the organism.
  • the compound of Formula 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof may be administered to animals, such as mammals, including humans, to a subject who is diagnosed with tuberculosis, and in the form of a pharmaceutical composition.
  • the present invention also relates to the compound of Formula 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof, for use in the production of medicaments for the treatment of tuberculosis.
  • the present invention also relates to use of the compound of Formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof, for the treatment of tuberculosis.
  • Tuberculosis for the treatment of which the compound of Formula 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof is provided is caused by Mycobacterium tuberculosis organism.
  • the Mycobacterium tuberculosis organism is a sensitive Mycobacterium tuberculosis organism or a multi drug resistant Mycobacterium tuberculosis organism or a combination thereof.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof, together with a pharmaceutically acceptable carrier.
  • the effective amount of the compound of Formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative as the active ingredient in the pharmaceutical compositions ranges from about 10 mg to 1000 mg.
  • the present invention further relates to a pharmaceutical composition which contains a therapeutically effective amount of the compound of Formula 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof, together with a pharmaceutically acceptable carrier, wherein the said pharmaceutical composition is adapted for use in the treatment of tuberculosis.
  • the present invention also relates to a method for the manufacture of a medicament containing the compound of Formula 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof, for use in the treatment of tuberculosis.
  • the compound of Formula 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a derivative thereof may be administered orally, nasally, topically, subcutaneously, intramuscularly, intravenously, or by other modes of administration.
  • compositions which contain the compound of Formula 1, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, with other pharmaceutically active substances may be prepared by mixing the compound of Formula 1 with one or more pharmacologically acceptable auxiliaries and/or excipients such as, wetting agents, solubilisers such as surfactants, vehicles, tonicity agents, fillers, colorants, masking flavors, lubricants, disintegrants, diluents, binders, plasticizers, emulsifiers, ointment bases, emollients, thickening agents, polymers, lipids, oils, cosolvents, complexation agents, or buffer substances, and converting 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.
  • auxiliaries and/or excipients
  • Formulations for parenteral administration can be in the form of aqueous or nonaqueous isotonic sterile injection solutions, suspensions or fat emulsions.
  • the parenteral form used for injection must be fluid to the extent that easy syringability exists.
  • These solutions or suspensions can be prepared from sterile concentrated liquids, powders or granules.
  • Excipients used in parenteral preparations also include, without limitation, stabilizing agents (e.g. carbohydrates, amino acids and polysorbates, such as 5 % dextrose), solubilizing agents (e.g. cetrimide, sodium docusate, glyceryl monooleate, polyvinylpyrolidone (PVP) and polyethylene glycol (PEG)), surfactants (e.g. polysorbates, tocopherol PEG succinate, poloxamer and CremophorTM), buffers (e.g. acetates, citrates, phosphates, tartrates, lactates, succinates, amino acids and the like), antioxidants and preservatives (e.g.
  • stabilizing agents e.g. carbohydrates, amino acids and polysorbates, such as 5 % dextrose
  • solubilizing agents e.g. cetrimide, sodium docusate, glyceryl monooleate, polyvinylpyrolidone (PVP) and polyethylene
  • BHA, BHT, gentisic acids vitamin E, ascorbic acid, sodium ascorbate and sulfur containing agents such as sulfites, bisulfites, metabisulfites, thioglycerols, thioglycolates and the like), tonicity agents (for adjusting physiological compatibility), suspending or viscosity agents, antibacterials (e.g. thimersol, benzethonium chloride, benzalkonium chloride, phenol, cresol and chlorobutanol), chelating agents, and administration aids (e.g. local anesthetics, anti-inflammatory agents, anti-clotting agents, vaso-constrictors for prolongation and agents that increase tissue permeability), and combinations thereof.
  • agents such as sulfites, bisulfites, metabisulfites, thioglycerols, thioglycolates and the like
  • tonicity agents for adjusting physiological compatibility
  • suspending or viscosity agents e.g
  • Parenteral formulations using hydrophobic carriers include, for example, fat emulsions and formulations containing lipids, lipospheres, vesicles, particles and liposomes.
  • Fat emulsions include in addition to the above-mentioned excipients, a lipid and an aqueous phase, and additives such as emulsifiers (e.g. phospholipids, poloxamers, polysorbates, and polyoxyethylene castor oil), and osmotic agents (e.g. sodium chloride, glycerol, sorbitol, xylitol and glucose).
  • emulsifiers e.g. phospholipids, poloxamers, polysorbates, and polyoxyethylene castor oil
  • osmotic agents e.g. sodium chloride, glycerol, sorbitol, xylitol and glucose.
  • Liposomes include natural or derived phospholipids and optionally stabilizing agents such as
  • the parenteral unit dosage form of the compound of Formula 1 can be a ready-to-use solution of the compound of Formula 1 in a suitable carrier in sterile, hermetically sealed ampoules or in sterile pre-loaded syringes.
  • the suitable carrier optionally comprises any of the above-mentioned excipients.
  • the unit dosage of the compound of Formula 1 of the present invention can be in a concentrated liquid, powder or granular form for ex tempore reconstitution in the appropriate pharmaceutically acceptable carrier, such as sterile water, at the time of delivery.
  • the appropriate pharmaceutically acceptable carrier such as sterile water
  • powder forms optionally include bulking agents (e.g. mannitol, glycine, lactose, sucrose, trehalose, dextran, hydroxyethyl starch, ficoll and gelatin), and cryo or lyoprotectants.
  • IV intravenous
  • a sterile formulation of the pharmaceutical compositions of the present invention and optionally one or more additives, including solubilizers or surfactants can be dissolved or suspended in any of the commonly used intravenous fluids and administered by infusion.
  • Intravenous fluids include, without limitation, physiological saline, phosphate buffered saline, 5 % dextrose in water or Ringer's TM solution.
  • a sterile formulation of the pharmaceutical compositions of the present invention can be dissolved and administered in a pharmaceutical diluent such as Water-for-Injection (WFI), physiological saline or 5 % dextrose in water.
  • a pharmaceutical diluent such as Water-for-Injection (WFI), physiological saline or 5 % dextrose in water.
  • WFI Water-for-Injection
  • a suitable insoluble form of the pharmaceutical compositions may be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, e.g. an ester of a long chain fatty acid such as ethyl oleate.
  • the method of administration which is suitable in a specific case depends on the type of Mycobacterium tuberculosis organism to be treated and on the stage of the respective infection or disease caused by the Mycobacterium tuberculosis organism. Further, the method of administration can be optimized by a medical practitioner using methods known in the art.
  • the dose of the compound of Formula 1 may vary depending upon the physical characteristics of the subject, the severity of the subject's symptoms, the formulation and the means used to administer the active ingredient i.e. the compound, and the method being practiced.
  • the specific dose for a given subject is usually set by the judgment of the attending physician or medical practitioner.
  • the dose of the compound of Formula 1 typically ranges from about 0.5 mg/kg body weight to about 200 mg/kg body weight or the dose of the compound of Formula 1 may range from about 1 to about 100 mg/kg or the dose of the compound of Formula 1 may range from about 5 to about 50 mg/kg, regardless of the formulation.
  • a dose of the compound of Formula 1 greater than 200 mg/kg body weight may be required for the treatment of tuberculosis.
  • Suitable frequencies of administration may vary based on whether administration is for the purposes of treatment or prophylaxis of tuberculosis (the Mycobacterium tuberculosis infection).
  • Administration frequencies of doses for the treatment of a subject having a Mycobacterium tuberculosis infection, prophylaxis or prevention of Mycobacterium tuberculosis infection include 4, 3, 2 or once daily, every other day, every third day, every fourth day, every fifth day, every sixth day, once weekly, every eight days, every nine days, every ten days, bi-weekly, monthly or bi-monthly.
  • the course of treatment may require the administration of many doses over many days, such as administration of 4, 3, or 2 doses or a single dose daily over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more days.
  • the dosage may be administered as an oral formulation for example, as a capsule, or slowly over a period of time, such as with an intravenous administration.
  • the administering period can be a matter of minutes, such as about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 or more minutes, or a period of hours, such as about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 or more hours.
  • a pharmaceutical composition, containing the compound of Formula 1 can also be administered to a subject, in particular a human, with another therapeutically active agent or a pharmaceutical composition containing the therapeutically active agent.
  • the therapeutically active agent that may be used in conjunction with the compound of Formula 1 may be an anti tuberculosis agent such as isoniazid and rifampicin, known to be useful in treating infections caused by Mycobacterium tuberculosis.
  • the soil sample was collected from a land near hot-springs in Tamilashi District of Tamilanchal State, India, in a sterile container and was stored at 2 °C - 4 °C throughout the journey back to Piramal Life Sciences Limited, Goregaon, Mumbai, India.
  • the suspension of soil (1 g) in saline (9 mL) was diluted to 10 "3 . 100 ⁇ L ⁇ of this dilution was spread on the isolation media.
  • the isolation plates were incubated at 30 °C for 30 days and were observed periodically macro and microscopically. Colonies were picked up with sterile needle by viewing the colony morphology.
  • PM0834793 was one such eubacteria colony isolated by this procedure.
  • culture PM0834793 belongs to eubacteria class
  • SCDM was used as seed medium.
  • the above medium was distributed in 40 mL amounts in 500 mL capacity Erlenmeyer flasks. Each flask was inoculated with a loopful of the well-grown slant culture (culture no. PM0834793). The flasks were incubated at 30 °C for 48 h on shaker at 250 rpm to obtain the seed culture.
  • SM12 [contains % (w/v): Glucose 5 g, yeast extract 1.1 g, sodium chloride 0.25 g, calcium carbonate 0.5 g, peptone 0.4 g, beef extract 0.4 g; volume made using water and pH adjusted to 7.2 using 1.0 M NaOH].
  • the flasks were incubated on shaker at 30 °C and 250 rpm for 48 h.
  • the bioactivity was tested for anti-infective activity in agar diffusion assay in the test models S. aureus 209P, E. faecium VRE 323, C. albicans, and E. coli 20732.
  • the culture broth (60 L) was stirred with methanol (1 : 1) for 1 h and was filtered. The filtrate was concentrated to remove methanol. The aqueous portion was subjected to Diaion HP-20 resin (Mitsubishi Chemical Industries Limited, Japan) chromatography. The column was sequentially eluted with water (12 L) and mixture of water and methanol (2:8, 12 L). The water-methanol elutate was concentrated and lyophilized to obtain crude extract. Yield: 51 g.
  • step 1 The crude extract (as obtained in step 1) was further suspended in water (240 mL) and extracted with n-butyl alcohol (240 mL). Organic layer was separated and solvent was evaporated to obtain n-butyl alcohol fraction (38 g) which was processed by column chromatography (silica gel, 400 g, 100-200 mesh, solvent: methanol in chloroform). The fraction containing compound of Formula 1 was eluted with 20 % methanol in chloroform, which was concentrated to obtain the semi pure compound. Yield: 11 g. Step 3
  • the semi pure compound (as obtained in step 2) was further purified by using Sephadex LH-20 resin chromatography using methanol as eluating solvent Active eluates were pooled and concentrated to obtain the semi pure compound. Yield: 1.7 g.
  • the semi pure compound (as obtained in step 3) was further purified using reverse phase silica gel (RP-18) cartridge (1 g, Phenomenex, 8B - S100 - JDG Starta-X - 33 ⁇ polymeric sorbent), eluted with acetonitrile and water gradient (1 to 100 % acetonitrile in water) and the fractions were monitored by bioactivity. The active fractions were pooled, solvent was evaporated to obtain semi pure compound of Formula 1. Yield: 390 mg.
  • RP-18 reverse phase silica gel
  • UV Detection 220 nm
  • HPLC Cold-Lichrosphere RP-18, 125 x 4 mm, 5 micron;
  • Solvent system Acetonitrile : 0.1 % aqueous trifluoroacetic acid
  • the compound of Formula 1 was characterised to be Fusaricidin B by comparing physical and spectral data with that reported in the literature (Journal of Antibiotics, 1997, 50(3), 220 - 228).
  • the activity against Mycobacterium tuberculosis organism can be determined by using BACTEC MGIT 960 System from Becton Dickinson (BD), USA.
  • the BACTEC 960 instrument is an automated system that exploits the fluorescence of an oxygen sensor to detect growth of mycobacteria in culture as described in a reference, Journal of Clinical Microbiology, 2006, 44 (3), 811-818. It is specially designed to accommodate Mycobacteria Growth Indicator Tube (MGIT) that contains a fluorescent compound embedded in silicone on the bottom of a tube.
  • MGIT Mycobacteria Growth Indicator Tube
  • the fluorescent compound is sensitive to the presence of oxygen dissolved in the broth. The initial concentration of the dissolved oxygen quenches the emission of fluorescence from the compound, and little fluorescence can be detected. Later, actively growing and respiring microorganisms consume oxygen, which allows compound to fluoresce.
  • Non-MDR strain Mycobacterium tuberculosis complex
  • MDR strain Mycobacterium tuberculosis complex
  • test compound added to the medium is bacteriostatic or bactericidal to the test mycobacteria, it would inhibit growth of the mycobacteria and therefore, there would be little or no oxygen consumption, and ultimately there would be little or no fluorescence of the sensor. Whereas the growth control will grow uninhibited and will have increasing fluorescence. Growth is monitored by the BACTEC 960 instrument which automatically interprets results as resistant (R) or susceptible (S). To determine the 1 % proportion of resistance, the bacterial inoculum used in the control vial is 100 fold less than that used for the drug-containing vial.
  • Two MGIT tubes were inoculated with the test culture. A known concentration of a test compound was added to one of the MGIT tubes, and growth was compared with the MGIT tube without the test compound (growth control).
  • the minimum concentration of the compound of Formula 1 required to exhibit its effect against Non-MDR-TB strain was between 0.05 and 0.1 ⁇ g/mL and against MDR-TB strain was between 1 and 2 ⁇ g/mL ⁇ .
  • MICs against drug-susceptible and MDR-TB isolates were, respectively, 0.05-0.1 ⁇ g/mL and 1.0-2.0 ⁇ g/mL for compound of Formula 1.

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Abstract

L'invention concerne un procédé pour le traitement de la tuberculose, comprenant l'administration à un sujet en ayant besoin, d'une quantité thérapeutiquement efficace d'un composé de Formule 1, (comme indiqué dans la description), ou d'un stéréoisomère, d'un tautomère, de sels pharmaceutiquement acceptables, ou de dérivés de celui-ci, tels que les esters et les éthers. L'invention concerne en outre une composition pharmaceutique comprenant le composé de Formule 1 et au moins un support pharmaceutiquement acceptable, pour une utilisation dans le traitement de la tuberculose.
PCT/IB2012/056853 2011-12-02 2012-11-30 Composés pour le traitement de la tuberculose WO2013080167A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015107482A1 (fr) * 2014-01-17 2015-07-23 Piramal Enterprises Limited Association pharmaceutique pour traiter la tuberculose

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KAJIMURA, Y. ET AL.: "Fusaricidins B, C and D, New Depesipeptide Antibiotics Produced by Bacillus polymyxa KT-8: Isolation, Structure Elucidation and Biological Activity", THE JOURNAL OF ANTIBIOTICS, vol. 50, no. 3, 1997, pages 220 - 228, XP002993805 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015107482A1 (fr) * 2014-01-17 2015-07-23 Piramal Enterprises Limited Association pharmaceutique pour traiter la tuberculose

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