WO2015107482A1 - Association pharmaceutique pour traiter la tuberculose - Google Patents

Association pharmaceutique pour traiter la tuberculose Download PDF

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Publication number
WO2015107482A1
WO2015107482A1 PCT/IB2015/050327 IB2015050327W WO2015107482A1 WO 2015107482 A1 WO2015107482 A1 WO 2015107482A1 IB 2015050327 W IB2015050327 W IB 2015050327W WO 2015107482 A1 WO2015107482 A1 WO 2015107482A1
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Prior art keywords
compound
tuberculosis
tubercular
treatment
drug
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PCT/IB2015/050327
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English (en)
Inventor
Geetanjali CHIMOTE
Tanvi PATIL
Urvashi PANGHAL
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Piramal Enterprises Limited
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Publication of WO2015107482A1 publication Critical patent/WO2015107482A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 pharmaceutical combination comprising compound I (as described herein) and at least one anti-tubercular agent for use in the treatment of tuberculosis.
  • the present invention also relates to a method for the treatment of tuberculosis comprising administering to a subject in need thereof the compound I in combination with at least one anti-tubercular agent.
  • Tuberculosis is a common lethal infectious disease caused by various species of mycobacteria, particularly Mycobacterium tuberculosis (MTB).
  • MTB Mycobacterium tuberculosis
  • HAV Human immunodeficiency virus
  • Tuberculosis primarily affects the lungs, but it may also affect various organs of the body. Tuberculosis of the lungs usually spreads through the air when a person having lung TB coughs, or sneezes or transmits respiratory fluids, the TB germs get propelled in the air. Other persons can get infected if a few of these TB germs are inhaled by them and the infected person has a lifetime risk of falling ill with TB. The common symptoms of TB are chronic cough with blood-tinged sputum, chest pain, 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 such as sputum.
  • radiology commonly chest X-rays
  • a tuberculin skin test a tuberculin skin test
  • blood tests as well as microscopic examination and microbiological culture of body fluids such as sputum.
  • MDR-TB Multi-Drug Resistant TB
  • HIV-associated TB can be more complex.
  • Effective tuberculosis treatment involves use of antibiotics, primarily referred to as anti- tubercular drugs.
  • antibiotics primarily referred to as anti- tubercular drugs.
  • unusual structure and chemical composition of the mycobacterial cell wall hinders the entry of the anti-tubercular drugs and makes many antibiotics ineffective.
  • TB requires much longer period of treatment (around six to twenty four months) to entirely eliminate mycobacteria from the body.
  • the first-line treatment of TB involves use of the anti-tubercular drugs namely rifampicin, isoniazid, pyrazinamide and ethambutol; in combination.
  • MDR-TB Multi-drug resistant tuberculosis
  • MDR-TB is a form of tuberculosis that is resistant to two or more of the primary anti-tubercular drugs used in the treatment of tuberculosis. It has been found that MDR-TB is caused by organisms that are resistant to isoniazid and rifampicin as well as to any fluoroquinolone and any of the second-line anti-tubercular injectable drugs such as amikacin, kanamycin or capreomycin.
  • the current standard treatment for first-time TB patients includes isoniazid, rifampicin, pyrazinamide and ethambutol for 2 months, followed by isoniazid and rifampicin for 4 months.
  • the treatment mainly involves oral administration of the drugs (WHO Patients Guidelines, 2010). These treatment regimens involving oral administration are associated with poor plasma half-life and dose related adverse effects such as hepatotoxicity, nephrotoxicity and peripheral toxicity, which result in patient non-compliance and treatment failure. Moreover, of the orally administered drugs, only a small fraction of the administered drug reaches the site of action. Thus, the existing tuberculosis treatment is associated with dose related side effects, poor reach of the drug to the target organ and short stay of the drugs in the lungs, which is detrimental for the eradication of TB and favourable for generation of drug resistant strains.
  • the present invention relates to a pharmaceutical combination comprising the compound I (as described herein) and at least one anti-tubercular agent for use in the treatment of tuberculosis.
  • the present invention relates to a method of treating tuberculosis comprising administering to a subject in need thereof, a therapeutically effective amount of the compound I; in combination with a therapeutically effective amount of at least one anti- tubercular agent.
  • the present invention relates to use of the compound I in combination with at least one anti-tubercular agent for the treatment of tuberculosis.
  • the present invention relates to use of the compound I in combination with at least one anti-tubercular agent; for the manufacture of a medicament for the treatment of tuberculosis.
  • the present invention relates to a pharmaceutical kit comprising a container containing: (i) a compound I, (ii) one or two or three or four anti-tubercular agents, and (iii) optionally, a package insert comprising instructions for using compound I in combination with the anti-tubercular agent(s) for the treatment of tuberculosis.
  • a method for the treatment of latent tuberculosis comprising administering to a subject in need thereof a therapeutically effective amount of the compound I.
  • the compound I is provided for use in the treatment of latent tuberculosis.
  • Figure 1 depicts the MIC (Minimum Inhibitory Concentration) of each of the compound I and rifampicin alone; and of the combination of the compound I and rifampicin; and the effect of said combination on Mycobacterium tuberculosis (H 37 RV) strain in terms of FICI (Fractional Inhibitory Concentration Index).
  • Figure 2 depicts the MIC of each of the compound I and ethambutol alone; and of the combination of the compound I and ethambutol; and the effect of said combination on Mycobacterium tuberculosis (H 37 Rv) strain in terms of FICI.
  • Figure 3 depicts the MIC of each of the compound I and amoxicillin alone; and of the combination of the compound I and amoxicillin; and the effect of said combination on rifampicin resistant Mycobacterium tuberculosis (H 37 Rv-R) strain in terms of FICI.
  • Figure 4 depicts the MIC of each of the compound I and ethionamide alone; and of the combination of the compound I and ethionamide; and the effect of said combination on rifampicin resistant Mycobacterium tuberculosis (H 37 Rv-R) strain in terms of FICI.
  • the term “and/or” refers to at least one or both of the cases which it connects.
  • the term “compound I and/or anti-tubercular agent” refers to "at least one of compound I and anti-tubercular agent", which includes the compound I, anti-tubercular agent and combination of the compound I and anti-tubercular agent.
  • anti-tubercular agents or "anti-tubercular drugs” refers to any therapeutic agent, a known drug, an investigational drug or a group of drugs which is suitable for inhibition of the growth or the destruction of Mycobacterium species, particularly Mycobacterium tuberculosis and is therefore, useful or potentially useful for the treatment of tuberculosis.
  • anti-tubercular agents and “anti-tubercular drugs” are used exchangeably.
  • pharmaceutical combination means the combined administration of the compound I (as described herein) and at least one anti- tubercular agent; such that the said compound I and the anti-tubercular agent(s) can be administered at the same time or separately within time intervals.
  • synergistic refers to the therapeutic effect achieved with the combination of the present invention and/or through the method of treating tuberculosis of this invention; is greater than the sum of the effects that result from using the compound I and the anti-tubercular agents separately.
  • synergy would provide greater efficacy at the same doses, and/or would prevent or delay the development of drug resistance (e.g. mono-drug or multi-drug resistance) to tuberculosis.
  • therapeutically effective amount means an amount of the compound I and/or at least one anti-tubercular agent effective in producing the desired therapeutic response in a particular patient (subject) suffering from tuberculosis.
  • therapeutically effective amount includes the amount of the compound, when administered that induces a positive modification in the disease or condition (e.g. tuberculosis) or is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of tuberculosis in a subject.
  • therapeutic amount of the compounds i.e.
  • the amount of each of the compound used for the treatment of a subject is low enough to avoid undesired or severe side effects, within the scope of sound medical judgment.
  • the therapeutically effective amount of each of the compound I and the anti-tubercular agent(s) when used in combination will vary with the age and physical condition of the end user, the severity of tuberculosis, the duration of the treatment, the nature of any other concurrent therapy, the specific type of anti-tubercular agent employed for the treatment, the particular pharmaceutically acceptable carrier utilized in the pharmaceutical compositions containing the compounds (the compound I and the anti- tubercular agent(s)) and other relevant factors.
  • subject refers to an animal, particularly a mammal, and particularly, a human.
  • mammal refers to warm-blooded vertebrate animals of the class "Mammalia”, including humans, characterized by covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and the human.
  • beneficial or desired therapeutic effects include, but are not limited to, alleviation of symptoms, diminishment of extent of the disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • those (the subjects) in need of treatment include those already having the condition or disease as well as those prone to have the condition or disease.
  • the term disease or condition refers to tuberculosis.
  • pharmaceutically acceptable means the carrier, diluent, excipient, and/or salt used in the composition should be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • “Pharmaceutically acceptable” also means that the compositions or dosage forms are within the scope of sound medical judgment, suitable for use for a subject such as an animal or human without excessive toxicity, irritation, allergic response, or other problems or complication, commensurate with a reasonable benefit/risk ratio.
  • tuberculosis refers to a diseases or a condition caused by Mycobacterium tuberculosis and encompasses within its scope all the forms of tuberculosis including active tuberculosis and latent tuberculosis.
  • latent tuberculosis is defined below.
  • active tuberculosis refers to drug- sensitive tuberculosis, drug resistant tuberculosis including mono-drug resistant tuberculosis, multi-drug resistant (MDR) tuberculosis, and extensively drug-resistant (XDR) tuberculosis.
  • drug- sensitive tuberculosis refers to tuberculosis caused by Mycobacterium tuberculosis organisms that are known or presumed to be sensitive or susceptible to the first-line anti-tubercular agents such as isoniazid, rifampicin (rifampin), pyrazinamide, ethambutol, streptomycin, rifapentine, rifabutin and any other anti-tubercular agent to which the Mycobacterium tuberculosis organism is found to be susceptible.
  • first-line anti-tubercular agents such as isoniazid, rifampicin (rifampin), pyrazinamide, ethambutol, streptomycin, rifapentine, rifabutin and any other anti-tubercular agent to which the Mycobacterium tuberculosis organism is found to be susceptible.
  • multi-drug resistant tuberculosis signify that the disease is resistant to some of the most frequently used anti-tubercular drugs such as rifampicin and isoniazid.
  • exensively drug-resistant tuberculosis refers to a subset multi-drug resistant tuberculosis with additional resistance to any one of the second-line anti-tuberculosis drugs e.g. kanamycin, amikacin and capreomycin.
  • latent tuberculosis conceptually denotes a state in which Mycobacterium tuberculosis persists within its host without causing symptoms or signs while maintaining viability with the potential to replicate and cause symptomatic disease (Drug Discovery Today, 2012, 17, 514-521). This term may be alternatively referred to as “latent tuberculosis infection (LTBI)".
  • LTBI latent tuberculosis infection
  • the persons at a risk of developing latent tuberculosis infection (LTBI) who are considered for prophylaxis and/or treatment of Mycobacterium tuberculosis infection includes health care workers employed at facilities where persons receive treatment for TB, persons with recent close contact with a person known to have active TB, persons infected with HIV, intravenous drug abusers and persons migrated from countries with high prevalence of TB, persons earlier infected with active TB as well as those with underlying medical conditions such as diabetes mellitus, silicosis, end stage renal disease, immunosuppressive therapy, hematological malignancy, malnourished or who lost more than 10 % of their ideal body weight, gastrectomy or jejunoileal bypass (Respirology, 2013, 18, 205-216).
  • LTBI latent tuberculosis infection
  • latent tuberculosis refers to drug-sensitive latent tuberculosis and/or drug resistant latent tuberculosis.
  • compound I is used alone, wherever appropriate, it is deemed to include a stereoisomer, or a tautomer or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical combination comprising compound I and at least one anti-tubercular agent.
  • the compound I contained in the pharmaceutical combination of the present invention can be used in the form of its stereoisomer (isomer) or a pharmaceutically acceptable salt thereof.
  • the compound I can also be used in its crystalline or amorphous forms. In general, all physical forms are suitable for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • the compound I that is contained in the pharmaceutical combination and used in the method of treatment of tuberculosis of the present invention is described in the PCT Application Publication No. WO2011027290 (the WO'290 Appln.) wherein the said compound I is referred to as the compound of Formula 1(a).
  • the WO'290 Appln. also describes the production of the compound I and the manufacture of pharmaceutical composition containing the said compound I.
  • the WO'290 Appln. describes that the compound I can be used for the treatment or prevention of a disease or disorder caused by bacterial infection. It is also reported in WO'290 Appln. that the said compound can also be used in the treatment of tuberculosis.
  • the said compound can be produced from a microorganism namely strain of Streptomyces species (PM0626271/ MTCC 5447), deposited with Microbial Type Culture Collection (MTCC), Institute of Microbial Technology, Sector 39- A, Chandigarh -160 036, India.
  • a microorganism namely strain of Streptomyces species (PM0626271/ MTCC 5447), deposited with Microbial Type Culture Collection (MTCC), Institute of Microbial Technology, Sector 39- A, Chandigarh -160 036, India.
  • the compound I can be produced from culture no. PM0626271, its mutants and variants, comprising the steps of: growing the culture no. PM0626271 under submerged aerobic conditions in a nutrient medium containing one or more sources of carbon and one or more sources of nitrogen and optionally nutrient inorganic salts and/or trace elements; isolating the compound I, from the culture broth; and purifying the said compound I, using purification procedures generally used in the art.
  • the details as to the aerobic conditions and the nutrient medium used in the production of the compound I are as described in the WO'290 Appln.
  • the compound I and/or isomers thereof can be converted into their pharmaceutically acceptable salts, which can be used in the pharmaceutical combination and/or method for the treatment of tuberculosis according to the present invention.
  • the present invention relates to a pharmaceutical combination comprising the compound I and at least one anti-tubercular agent for use in the treatment of tuberculosis.
  • the present invention relates to a method of treating tuberculosis comprising administering to a subject in need thereof, a therapeutically effective amount of the compound I; in combination with a therapeutically effective amount of at least one anti- tubercular agent.
  • the present invention relates to use of the compound I in combination with at least one anti-tubercular agent for the treatment of tuberculosis. In a further aspect, the present invention relates to use of a compound I in combination with at least one anti-tubercular agent; for the manufacture of a medicament for the treatment of tuberculosis.
  • the present invention relates to a pharmaceutical kit comprising a container containing: (i) a compound I, (ii) one or two or three or four anti-tubercular agents; and (iii) optionally, a package insert comprising instructions for using the compound I in combination with the anti-tubercular agent(s) for the treatment of tuberculosis.
  • the tuberculosis is a drug-sensitive tuberculosis. In another embodiment of the present invention, the tuberculosis is a drug resistant tuberculosis; wherein the drug resistant tuberculosis can be a mono-drug resistant tuberculosis, multi-drug resistant (MDR) tuberculosis or extensively drug-resistant (XDR) tuberculosis.
  • MDR multi-drug resistant
  • XDR extensively drug-resistant
  • the present invention relates to a pharmaceutical combination comprising the compound I and at least one anti-tubercular agent for use in the treatment of drug-sensitive tuberculosis.
  • the present invention relates to a pharmaceutical combination comprising the compound I and at least one anti-tubercular agent for use in the treatment of drug-resistant tuberculosis.
  • the present invention relates to a pharmaceutical combination comprising the compound I and at least one anti-tubercular agent for use in the treatment of mono-drug resistant tuberculosis.
  • the present invention relates to a pharmaceutical combination comprising the compound I and at least one anti-tubercular agent for use in the treatment of multi-drug resistant (MDR) tuberculosis.
  • MDR multi-drug resistant
  • the present invention relates to a pharmaceutical combination comprising the compound I and at least one anti-tubercular agent for use in the treatment of latent tuberculosis (LTB).
  • LTB latent tuberculosis
  • the present invention relates to a method of treating drug-sensitive tuberculosis comprising administering to a subject in need thereof, a therapeutically effective amount of the compound I; in combination with a therapeutically effective amount of at least one anti-tubercular agent.
  • the present invention relates to a method of treating drug- resistant tuberculosis comprising administering to a subject in need thereof, a therapeutically effective amount of the compound I; in combination with a therapeutically effective amount of at least one anti-tubercular agent.
  • the present invention relates to a method of treating mono-drug resistant tuberculosis comprising administering to a subject in need thereof, a therapeutically effective amount of the compound I; in combination with a therapeutically effective amount of at least one anti-tubercular agent.
  • the present invention relates to a method of treating multi-drug resistant (MDR) tuberculosis comprising administering to a subject in need thereof, a therapeutically effective amount of the compound I; in combination with a therapeutically effective amount of at least one anti-tubercular agent.
  • MDR multi-drug resistant
  • the present invention relates to a method of treating latent tuberculosis comprising administering to a subject in need thereof, a therapeutically effective amount of the compound I; in combination with a therapeutically effective amount of at least one anti-tubercular agent.
  • the present invention relates to use of the compound I in combination with at least one anti-tubercular agent for the treatment of drug-sensitive tuberculosis.
  • the present invention relates to use of the compound I in combination with at least one anti-tubercular agent for the treatment of drug resistant tuberculosis. In another embodiment, the present invention relates to use of the compound I in combination with at least one anti-tubercular agent for the treatment of mono-drug resistant tuberculosis.
  • the present invention relates to use of the compound I in combination with at least one anti-tubercular agent for the treatment of multi-drug resistant tuberculosis. In another embodiment, the present invention relates to use of the compound I in combination with at least one anti-tubercular agent for the treatment of latent tuberculosis.
  • anti-tubercular agents at least one used in reference to anti-tubercular agents will be understood to mean “one or more anti-tubercular agents", i.e. one, two, three, four or more anti-tubercular agents that can be used in combination with the compound I in the treatment of tuberculosis.
  • the anti-tubercular agent is selected from: isoniazid, rifampicin (rifampin), rifapentine, rifabutin, pyrazinamide, ethambutol, streptomycin, 4-aminosalicylic acid, amoxicillin, amikacin, capreomycin, kanamycin, viomycin, cycloserine, ethionamide, moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, clofazimine, metronidazole, imipenem, meropenem, thioacetazone, terizidone, PA-824 (Novartis), SB-240683 (pascolizumab) (GlaxoSmithKline), AZD-5847 (AstraZeneca), SQ-109 (Sequella and National Institutes of Health), LL-3858 (Lupin), bed
  • the anti-tubercular agent is selected from: isoniazid, rifampicin (rifampin), rifapentine, rifabutin, pyrazinamide, ethambutol, streptomycin, amikacin, capreomycin, kanamycin, cycloserine, ethionamide, moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, clofazimine, linezolid, bedaquiline or metronidazole.
  • rifampicin rifampin
  • rifapentine rifapentine
  • rifabutin pyrazinamide
  • ethambutol pyrazinamide
  • streptomycin amikacin
  • capreomycin kanamycin
  • cycloserine ethionamide
  • moxifloxacin ciprofloxacin
  • ofloxacin
  • the anti-tubercular agent is selected from isoniazid, rifampicin (rifampin), pyrazinamide, ethambutol, streptomycin, rifapentine or rifabutin.
  • the anti-tubercular agents namely isoniazid, rifampicin (rifampin), pyrazinamide, ethambutol, streptomycin and rifabutin are conventionally referred to as first-line anti-tubercular drugs.
  • the anti-tubercular agents namely moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin, and levofloxacin belong to the class of fluoroquinolones.
  • reference to fluoroquinolone indicates reference to any one of moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin and levofloxacin.
  • the compound I is used in combination with one anti-tubercular agent selected from isoniazid, rifampicin (rifampin), rifapentine, rifabutin, pyrazinamide, ethambutol, streptomycin, 4- amino salicylic acid, amoxicillin, amikacin, capreomycin, kanamycin, viomycin, cycloserine, ethionamide, moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, clofazimine, metronidazole, imipenem, meropenem, thioacetazone, terizidone, PA-824, SB-240683 (pascolizumab), AZD-5847, SQ-109, LL-
  • the anti-tubercular agent is rifampicin.
  • the anti-tubercular agent is isoniazid.
  • the anti-tubercular agent is ethambutol.
  • the anti-tubercular agent is pyrazinamide.
  • the anti-tubercular agent is streptomycin.
  • the anti-tubercular agent is bedaquiline
  • the anti-tubercular agent is a fluoroquinolone selected from moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin or levofloxacin.
  • the anti-tubercular agent is amoxicillin.
  • the anti-tubercular agent is ethionamide.
  • the anti-tubercular agent is kanamycin.
  • the anti-tubercular agent is cycloserine.
  • the anti-tubercular agent is amikacin.
  • the anti-tubercular agent contained in the combination is capreomycin.
  • the compound I is used in combination with two anti-tubercular agents independently selected from: isoniazid, rifampicin (rifampin), rifapentine, rifabutin, pyrazinamide, ethambutol, streptomycin, 4-aminosalicylic acid, amoxicillin, amikacin, capreomycin, kanamycin, viomycin, cycloserine, ethionamide, moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, clofazimine, metronidazole, imipenem, meropenem, thioacetazone, terizidone, PA-824, SB- 240683 (pascolizumab), AZD-5847, SQ-109
  • the two anti-tubercular agents are rifampicin and isoniazid.
  • the two anti-tubercular agents are rifampicin and ethambutol.
  • the two anti-tubercular agents are rifampicin and pyrazinamide.
  • the two anti-tubercular agents are isoniazid and ethambutol.
  • the two anti-tubercular agents are isoniazid and pyrazinamide.
  • the two anti-tubercular agents are ethambutol and pyrazinamide.
  • the two anti-tubercular agents are rifampicin and streptomycin.
  • the two anti-tubercular agents are isoniazid and streptomycin.
  • the two anti-tubercular agents are ethambutol and streptomycin.
  • the two anti-tubercular agents are pyrazinamide and streptomycin.
  • the two anti-tubercular agents are rifampicin and bedaquiline.
  • the two anti-tubercular agents are rifabutin and isoniazid.
  • the two anti-tubercular agents are amoxicillin and a fluoroquinolone selected from moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin or levofloxacin.
  • the two anti-tubercular agents are ethionamide and a fluoroquinolone selected from moxifloxacin, ciprofloxacin, ofloxacin or levofloxacin. In yet another embodiment, the two anti-tubercular agents are amikacin and a fluoroquinolone selected from moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin or levofloxacin.
  • the two anti-tubercular agents are cycloserine and a fluoroquinolone selected from moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin or levofloxacin.
  • the two anti-tubercular agents are terizidone and a fluoroquinolone selected from moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin or levofloxacin. In yet another embodiment, the two anti-tubercular agents are amoxicillin and terizidone.
  • the two anti-tubercular agents are ethionamide and 4- amino salicylic acid.
  • the two anti-tubercular agents are ethionamide and amoxicillin.
  • the two anti-tubercular agents are rifampicin and amoxicillin.
  • the two anti-tubercular agents are pyrazinamide and 4- amino salicylic acid. In yet another embodiment, the two anti-tubercular agents are pyrazinamide and bedaquiline.
  • the two anti-tubercular agents are metronidazole and a fluoroquinolone selected from moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin or levofloxacin. In yet another embodiment, the two anti-tubercular agents are rifapentine and isoniazid.
  • the compound I is used in combination with three anti-tubercular agents independently selected from isoniazid, rifampicin (rifampin), rifapentine, rifabutin, pyrazinamide, ethambutol, streptomycin, 4-aminosalicylic acid, amoxicillin, amikacin, capreomycin, kanamycin, viomycin, cycloserine, ethionamide, moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, clofazimine, metronidazole, imipenem, meropenem, thioacetazone, terizidone, PA-824, SB -240683 (pascolizumab), AZD- 5847, SQ-109, LL-3858, bedaquiline (TMC-207),
  • the three anti-tubercular agents are rifampicin, isoniazid and ethambutol.
  • the three anti-tubercular agents are rifampicin, isoniazid and pyrazinamide. In yet another embodiment, the three anti-tubercular agents are rifampicin, isoniazid and streptomycin.
  • the three anti-tubercular agents are rifampicin, ethambutol and pyrazinamide.
  • the three anti-tubercular agents are rifampicin, ethambutol and streptomycin.
  • the three anti-tubercular agents are isoniazid, ethambutol and pyrazinamide.
  • the three anti-tubercular agents are isoniazid, ethambutol and streptomycin. In yet another embodiment, the three anti-tubercular agents are ethambutol, pyrazinamide and streptomycin.
  • the three anti-tubercular agents are amoxicillin, ethionamide and a fluoroquinolone selected from moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin or levofloxacin.
  • the three anti-tubercular agents are amikacin, ethionamide and a fluoroquinolone selected from moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin or levofloxacin.
  • the three anti-tubercular agents are cycloserine, 4- amino salicylic acid and a fluoroquinolone selected from moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin or levofloxacin.
  • the three anti-tubercular agents are rifampicin, pyrazinamide and ethionamide.
  • the three anti-tubercular agents are pyrazinamide, ethambutol and ethionamide.
  • the three anti-tubercular agents are pyrazinamide, bedaquiline and a fluoroquinolone selected from moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin or levofloxacin.
  • the three anti-tubercular agents are isoniazid, pyrazinamide and ethionamide.
  • the compound I and at least one anti-tubercular agent are administered simultaneously.
  • the compound I and at least one anti-tubercular agent are administered sequentially.
  • the compound I is administered prior to the administration of the anti-tubercular agent(s).
  • the anti-tubercular agent(s) is/are administered prior to the administration of the compound I.
  • the compound I in another embodiment, in the pharmaceutical combination and/or the method of treatment of tuberculosis and/or the use for the treatment of tuberculosis according to the present invention; is administered at about the same time as administration of the anti- tubercular agent(s). In an embodiment, in the pharmaceutical combination and/or the method of treatment of tuberculosis and/or the use for the treatment of tuberculosis according to the present invention; the compound I and anti-tubercular agent(s) are administered once a day.
  • the compound I is administered once a day, while the anti-tubercular agent(s) is/are administered twice a day.
  • the compound I is administered twice a day, while the anti-tubercular agent(s) is/are administered once a day.
  • the compound I and the anti-tubercular agent(s) are administered twice a day.
  • the compound I and anti-tubercular agent(s) are administered one time weekly, two times weekly, three times weekly, four times weekly, five times weekly or every other day.
  • the pharmaceutical combination and/or the method of treatment and/or the use according to the present invention can prevent relapse of tuberculosis after completion of the treatment.
  • the compound I and/or one or more of the anti-tubercular agent(s) can be administered in the form of a pharmaceutical composition containing the said compound I and/or one or more of the anti-tubercular agent(s) and at least one pharmaceutically acceptable excipient or carrier.
  • the pharmaceutically acceptable excipients or carriers used in the pharmaceutical composition can any conventionally known pharmaceutically acceptable excipients or carriers, which can be selected depending on the dosage form and the route of administration of the compound I and the anti-tubercular agents.
  • the compound I and/or one or more of the anti-tubercular agent(s) can be administered by any conventional routes of administration including, but not limited to, orally, parenterally, nasally, rectally or by inhalation.
  • the compound I and/or one or more of the anti-tubercular agent(s) can be administered parenterally such as, by intramuscular, intrathecal, subcutaneous, intraperitoneal, intravenous bolus injection or intravenous infusion.
  • Parenteral administration can be accomplished by incorporating the compound I and/or anti-tubercular agent into a solution or suspension.
  • the compound I and/or one or more of the anti-tubercular agent(s) can be administered in a form suitable for oral administration such as tablets, lozenges, aqueous or oily suspensions, granules, powders, cachets, emulsions, capsules, syrups, elixirs and the like.
  • the compound I and/or one or more of the anti-tubercular agent(s) can be administered rectally.
  • the rectal administration includes administering the compounds into the rectum or large intestine. This can be accomplished using suppositories or enemas. Suppository formulations can be made by methods known in the art.
  • the compound I and/or one or more of the anti-tubercular agent(s) can be administered nasally, which includes nasally administering to the subject therapeutically effective amounts of the compounds.
  • the nasal administration includes administering the compounds to the mucous membranes of the nasal passage or nasal cavity of the patient.
  • the modes of nasal administration of the combination include for example, a nasal spray, nasal drop, suspension, gel, ointment, cream or powder. Administration of the compounds may also take place using a nasal tampon or nasal sponge.
  • the compound I and/or one or more of the anti-tubercular agent(s) can be administered by inhalation.
  • the well-known methods of delivering inhaled medications include nebulizers, pressurized multi dose inhalers, vaporizer, metered-dose inhaler (MDI) and dry powder inhalers (DPI).
  • the drug e.g. the compound I and/or one or more of the anti-tubercular agent(s)
  • the drug to be delivered can be in a solid or liquid formulation (including any semi-solid, colloidal, or semi-liquid forms, etc.).
  • the medical port is adapted to convert the drug from a solid or liquid form into an aerosol form for delivery into the purified air stream to the subject (e.g.
  • the anti-tubercular effect of the compounds (compound I and/or anti-tubercular agents) contained in the pharmaceutical composition can be delayed or prolonged through a proper formulation.
  • a slowly soluble pellet of the compound can be prepared and incorporated in a tablet or capsule.
  • the technique can be improved by making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film which resists dissolution for a predictable period of time.
  • Even the parenteral preparations can be made long acting, by dissolving or suspending the compound in oily or emulsified vehicles which allow it to disperse only slowly in the serum.
  • the effective doses of the compound I and/or anti-tubercular agents used for administration vary depending on the severity of the disease (tuberculosis), the severity of symptoms, the age, sex, body weight and sensitivity difference of the subject (the patient), the mode, time, interval and duration of administration, the nature and type of formulation, etc.
  • the compound I and/or one or more anti-tubercular agents are administered in a time frame where both the agents are still active.
  • One skilled in the art would be able to determine such a time frame by determining the half life of the administered compounds.
  • the compound I and one or more anti-tubercular agents can be administered simultaneously or sequentially and when administered sequentially in any order.
  • the compound I and anti- tubercular agents are administered in the manner that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.
  • the dosage of the therapeutic agents (compound I and/or anti-tubercular agent(s)) to be administered should be selected to produce the desired effect.
  • a suitable dosage of the compound I can be from about 0.01 mg/kg body weight per day to about 100 mg/kg body weight per day; particularly, from about 0.1 mg/kg body weight per day to about 50 mg/kg body weight per day.
  • a suitable dosage of the anti-tubercular agents can be from about 0.01 mg/kg body weight per day to about 100 mg/kg body weight per day; particularly, from about 0.1 mg/kg body weight per day to about 50 mg/kg body weight per day.
  • the compound I can be administered from about 10 mg/day to about 500 mg/day.
  • the anti-tubercular agents can be administered from about 10 mg/day to about 1500 mg/day. According to the present invention, it is also observed that when the compound I is administered in combination with one or more anti-tubercular agents; a synergistic effect is exhibited by the combination or such a combined use of the said compounds.
  • the present invention relates to a pharmaceutical kit comprising a container containing (i) compound I, (ii) one or two or three or four anti-tubercular agents, and (iii) optionally, a package insert comprising instructions for using the compound I in combination with the anti-tubercular agent(s) for the treatment of tuberculosis.
  • the kit may contain two or more separate containers for the compound I and the anti- tubercular agent(s).
  • the package insert includes information about the indication, usage, doses, direction for administration, contraindications, precautions and warnings.
  • the suitable container that can be used includes a bottle, a vial, an ampoule, a syringe or a blister pack.
  • the pharmaceutical kit consists of unit dosage forms, for use from about one month to about nine months.
  • the TB patient kit contains the full course of treatment for single patient and thus assures the TB patient that drugs for the full course of treatment are reserved for the patient at the outset of treatment.
  • the kit provides health workers with a container that has all required medicines in the necessary strengths and quantities. This helps to limit confusion and makes it easier to monitor the regularity of the treatment, thereby avoiding nonadherence to the TB drugs.
  • the present inventors have also found that the compound I (as described herein) alone has potential in the treatment of latent tuberculosis. Accordingly, the present invention relates to the compound I (as described herein) for use in the treatment of latent tuberculosis (LTB).
  • LTB latent tuberculosis
  • a method of treating latent tuberculosis comprising administering to a subject in need thereof a therapeutically effective amount of the compound I.
  • the compound I for the treatment of latent tuberculosis can be administered in the form of pharmaceutical composition containing the said compound and at least one pharmaceutically acceptable excipient or carrier.
  • the compound of formula I can be administered by any conventional routes of administration including, but not limited to, orally, parenterally, nasally, rectally or by inhalation.
  • the dosage of the compound I to be administered for the treatment of latent tuberculosis should be selected to produce the desired effect.
  • a suitable dosage of the compound I can be from about 0.01 mg/kg body weight per day to about 500 mg/kg body weight per day; particularly, from about 0.1 mg/kg body weight per day to about 250 mg/kg body weight per day.
  • the present invention particularly use of the compound I in combination with one or more anti-tubercular agents has been evaluated using certain assay methods/systems, and in several different administrative schedules in vitro and in vivo.
  • the experimental details are as provided herein below.
  • MTB Mycobacterium tuberculosis
  • PBS Phosphate buffer saline
  • VRE Vancomycin Resistant Enteriococci
  • the process for the production of compound I involves growing the culture no. PM0626271 (a microorganism namely strain of Streptomyces species) under submerged aerobic conditions in a nutrient medium containing one or more sources of carbon and one or more sources of nitrogen and optionally, nutrient inorganic salts and/or trace elements.
  • PM0626271 a microorganism namely strain of Streptomyces species
  • the medium and/or nutrient medium used for isolation and cultivation of culture no. PM0626271, which produces the compound I 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.
  • Preferred carbon sources are soluble starch and glucose.
  • the sources of nitrogen are, for example, one or more of soybean meal, peanut meal, yeast extract, beef extract, peptone, malt extract, corn steep liquor, gelatin, or casamino acids. Preferred nitrogen sources are peptone and yeast extract.
  • the nutrient inorganic salts are, for example, one or more of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, ferric chloride, strontium chloride, cobalt chloride, potassium bromide, sodium fluoride, sodium hydrogen phosphate, potassium hydrogen phosphate, dipotassium hydrogen phosphate, magnesium phosphate, calcium carbonate, sodium bicarbonate, sodium silicate, ammonium nitrate, potassium nitrate, ferrous sulphate, sodium sulphate, ammonium sulphate, magnesium sulphate, ferric citrate, boric acid or trace salt solution such as copper sulphate, manganese chloride or zinc sulphate.
  • Calcium carbonate, sodium chloride, and magnesium chloride are the preferred nutrient inorganic salts.
  • culture no. PM0626271 can be carried out at a temperature ranging from 22 °C to 36 °C and a pH of about 7.5 to 8.0. Typically, culture no. PM0626271 is maintained at 25 °C to 27 °C and a pH of about 7.4 to 7.8. The well- grown cultures can be preserved in the refrigerator at 4 °C to 8 °C.
  • Seed culture cultivation of culture no. PM0626271 can be carried out at a temperature ranging from 25 °C to 36 °C and a pH of about 7.5 to 8.0 for 66 h to 75 h at 200 rpm to 280 rpm.
  • culture no. PM0626271 seed is cultivated at 29 °C to 31 °C and a pH of about 7.4 to 7.8, for 72 h at 230 rpm to 250 rpm.
  • the production of the compound I can be carried out by cultivating culture no PM0626271 by fermentation at a temperature ranging from 26 °C to 36 °C and a pH of about 6.5 to 8.5, for 24 h to 96 h at 60 rpm to 140 rpm and 100 1pm to 200 1pm aeration.
  • culture no. PM0626271 is cultivated at 30 °C to 32 °C and pH 7.4 to 7.8 for 40 h to 96 h at 90 rpm and 110 1pm aeration.
  • the progress of fermentation and production of the compound can be detected by high performance liquid chromatography (HPLC) and by measuring the bioactivity of the culture broth against Staphylococci and/or Enterococci species by the known microbial agar plate diffusion assay method.
  • HPLC high performance liquid chromatography
  • the preferred culture is Staphylococcus aureus E710, which is a strain resistant to methicillin, a ⁇ -lactam antibiotic reported in the literature, and Enterococcus faecium R2 (VRE) which is resistant to vancomycin.
  • the compound may be present in the culture filtrate as well as in cell mass and can be isolated using known separation techniques such as solvent extraction and column chromatography.
  • the compound I 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, 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 U.S.A.), activated charcoal, or by ion exchange chromatography at pH 5 to 9.
  • 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 U.S.A.), activated charcoal, or by
  • the active material can be recovered from the cell mass by extraction with a water miscible solvent such as methanol, acetone, acetonitrile, n-propanol, or iso-propanol or 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.
  • the active material is extracted with eth
  • the compound I can be recovered from the crude material by fractionation using any of the following techniques: normal phase chromatography (using alumina or silica gel as stationary phase; and eluents such as petroleum ether, ethyl acetate, dichloromethane, acetone, chloroform, methanol, or combinations thereof); reverse phase chromatography (using reverse phase silica gel such as dimethyloctadecylsilyl silica 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 to 8)], and organic solvents (for example, methanol, acetonitrile, acetone, tetrahydrofuran, or combinations of these solvents); gel permeation chromatography (using resins such as Sephadex LH-20® (Pharmacia Chemical Industries, Sweden), TSKgel® Toyope
  • Method A Solvent Evaporation method
  • 30 mL of methanol is added and the mixture is transferred to a 250 mL RB flask.
  • 30 mL of SLF is poured into the mixture slowly.
  • the solvents are evaporated by using a rotary evaporator (Buchi GMBH, Switzerland).
  • the water bath is set at 45 °C and rotation is set at 100 rpm.
  • the vacuum controller is set to a pressure of 400 mBar. Evaporated solvents are collected in a glass solvent collector.
  • Method B Solvent free lipid self assembly method 20 mg of compound I and 20 mg of DPPC (1 : 20 w/w) are added to a RB flask containing 20 to 30 glass beads and 30 mL of SLF. The mixture is subjected to rotation of 100 rpm at a temperature of 45QC for one hour. The formulation obtained is subjected to centrifugation and filtration as described in Method A. Examples:
  • Activity of the compound I and/or pharmaceutical combinations of compound I can be determined according to any effective in vitro or in vivo assay method.
  • the objective of this study was to evaluate the efficacy of the combination of the compound I and anti-tubercular agents selected from rifampicin and/or ethambutol against infection caused by drug sensitive Mycobacterium tuberculosis (H 37 RV).
  • Test compounds Compound I (prepared in-house as indicated in the above reference example
  • Dose preparation a) Compound I was weighed and dissolved in DMSO to obtain a stock solution. b) Rifampicin was weighed and dissolved in sterile PBS to obtain a stock solution. c) Ethambutol was weighted and dissolved in sterile distilled water to obtain a stock solution.
  • Test system Mycobacterium tuberculosis f1 ⁇ 2Rv, which was obtained from ATCC
  • the mycobacterial (anti-tubercular) activity of the compound I in combination with rifampicin and ethambutol was individually evaluated against Mycobacterium tuberculosis (MTB) (H37RV) by the checker board titration assay in sterile 96-well microtiter plates. Two-fold serial dilutions of all the test compounds were prepared in 96-well microtiter plates, and 0.01 mL MTB (H 37 Rv) suspension (3X10 6 CFU/mL) was added to each well. Each test compound was tested at concentrations of 4, 2, 1, 0.5, 0.25, 0.125 times their respective MIC. Following 7 days of incubation at 37 °C, MICs of the combinations of the test compounds were read as colorimetric change. Fractional inhibitory concentration (FIC) indices for MTB (H37RV) were calculated.
  • FIC Fractional inhibitory concentration
  • FIC index Fractional inhibitory concentrations
  • FIC index FIC A + FIC B
  • FIC B (MIC B of drug B in presence of drug A/MIC of drug B alone)
  • the combination index of ⁇ 0.5 is considered synergistic, an index of > 0.5 and ⁇ 4 is considered additive and an index of > 4 indicates antagonistic activity of the compounds (drugs) that are used in combination.
  • Example 2 In-Vitro study of the combination of the compound I with anti-tubercular agent for the treatment of drug resistant tuberculosis
  • the objective of this study was to evaluate the efficacy of the combination of the compound I and anti-tubercular agents selected from amoxicillin and/or ethionamide against infection caused by rifampicin resistant Mycobacterium tuberculosis (H 37 RV-R). Materials:
  • Test compounds Compound I (prepared in-house as indicated in the above reference example
  • Dose preparation a) Compound I was weighed and dissolved in DMSO to obtain a stock solution. b) Amoxicillin and ethionamide were weighted and dissolved in sterile distilled water to obtain their respective stock solutions.
  • Test system Mycobacterium tuberculosis (H 37 Rv-R), which was obtained from ATCC
  • the mycobacterial (anti-tubercular) activity of the compound I in combination with amoxicillin and ethionamide was individually evaluated against rifampicin resistant Mycobacterium tuberculosis (MTB) (H37RV-R) by the checker board titration assay in sterile 96- well microtiter plates. Two-fold serial dilutions of all the test compounds were prepared in 96- well microtiter plates, and 0.1 mL of MTB (H37RV-R) suspension (3X10 6 CFU/mL) was added to each well. Each test compound was tested at concentrations 4, 2, 1, 0.5, 0.25, 0.125 times their respective MIC. Following 7 days of incubation at 37 °C, MICs of drug combinations were read as colorimetric change. Fractional inhibitory concentration (FIC) indices for MTB (H37RV-R) were calculated.
  • MTB Mycobacterium tuberculosis
  • FIC index FIC A + FIC B
  • FIC B (MIC B of drug B in presence of drug A/MIC of drug B alone)
  • the combination index of ⁇ 0.5 is considered synergistic, an index of > 0.5 and ⁇ 4 considered additive and an index of > 4 indicates antagonistic activity.
  • checkerboard microtiter plate assay is used to test the in-vitro bactericidal activities of antimicrobial drug combinations against microbial agents by determining the FICs of all combinations tested.
  • checkerboard microdilution assay a 96-well microtiter plate is loaded horizontally with increasing concentration of any drug A, and vertically with increasing concentration of any drug B. This setup enables to scan the microplate from direction of increasing concentration that spans the therapeutic range from susceptible to resistant.
  • Each drug is also present in single column as a single agent to determine the MIC in absence of other drug.
  • Checker board assay for evaluating the bactericidal activity of antimicrobial drug combinations is a modified microtiter plate Alamar Blue assay.
  • Alamar Blue is a proven cell viability indicator that uses the natural reducing power of living cells to convert resazurin, a non- fluorescent indicator dye to the bright red fluorescent molecule, resorufin.
  • the active ingredient of Alamar Blue (resazurin) upon entering the cells is reduced to resorufin, which produces very bright red fluorescence.
  • the viable cells continuously convert resazurin to resorufin, thereby generating a semi-quantitative measure of viability and cytotoxicity.
  • the amount of fluorescence produced is proportional to the number of living cells.
  • the assay is performed under aseptic conditions using sterile clear bottom 96 well plates.
  • the plate is sealed and incubated in the C0 2 incubator at 37 °C for 5 days.
  • fractional inhibitory concentrations will be calculated on the basis of MIC values of each drug alone and in combination by using following formula:
  • FIC index FIC A + FIC B
  • FIC B (MIC B of drug B in presence of drug A/MIC of drug B alone)
  • the FIC index of ⁇ 0.5 is considered synergistic, an index of > 0.5 and ⁇ 4 considered additive and an index of > 4 indicates antagonistic activity of the compounds (drugs) that are used in combination.
  • Test compounds Compound I (prepared in-house as indicated in the above reference example
  • DMSO Sigma-Aldrich-Chemie Gmbh, Germany
  • Dose preparation a) Compound I was weighed and dissolved in DMSO to obtain a stock solution. b) Rifampicin was weighed and dissolved in sterile PBS to obtain a stock solution. c) Kanamycin was weighted and dissolved in sterile distilled water to obtain a stock solution.
  • Test system Mycobacterium tuberculosis f1 ⁇ 2Rv, which was obtained from ATCC
  • the mycobacterial (anti-tubercular) activity of the compound I for latent tuberculosis was evaluated against the latent Mycobacterium tuberculosis (L-MTB) (H 37 Rv) by the modified Wayne assay (Infection and Immunity, 1996, 64(6), 2062-9).
  • L-MTB latent Mycobacterium tuberculosis
  • H 37 Rv Mid-log-phase aerobic Mycobacterium tuberculosis (H 37 Rv) cultures were diluted 100-fold in Middlebrook' s 7H9/ADC (Difco, BD India) medium and transferred to 150 mL flask and sealed.
  • Middlebrook' s 7H9/ADC Daifco, BD India
  • a 96-well microtiter plates 0.1 mL of the above L-MTB suspension was added to each well followed by the addition of all the drugs in the concentration of 10, 5, 2.5, 1, 0.5 and 0.25 ⁇ g/mL.
  • 96-well microtiter plates were incubated at 37 °C for 4 and 8 days post treatment. Post 4 days treatment 0.1 mL of culture was drawn from the middle of the culture well and plated onto 7H l l/O ADC agar plates (Difco, BD India). The plates were incubated at 37 °C and the CFU were enumerated 4 weeks later. Analysis:
  • L-MTB latent Mycobacterium tuberculosis
  • H37RV latent Mycobacterium tuberculosis
  • Test compounds Compound I (prepared in-house as indicated in the above reference example
  • DMSO Sigma-Aldrich-Chemie Gmbh, Germany
  • Dose preparation a) Compound I was weighed and dissolved in DMSO to obtain a stock solution. b) Rifampicin was weighed and dissolved in sterile PBS to obtain a stock solution. c) Kanamycin was weighted and dissolved in sterile distilled water to obtain a stock solution.
  • Test system Mycobacterium tuberculosis H 37 RV-R, which was obtained from ATCC
  • the mycobacterial (anti-tubercular) activity of the compound I was evaluated against the rifampicin resistant latent Mycobacterium tuberculosis (L-MTB) (H 37 Rv-R) by the modified Wayne assay.
  • L-MTB latent Mycobacterium tuberculosis
  • Mid-log-phase aerobic rifampicin resistant Mycobacterium tuberculosis (H 37 Rv-R) cultures were diluted 100-fold in Middlebrook' s 7H9/ADC (Difco, BD India) medium and transferred to 150 mL flask and sealed.
  • Middlebrook' s 7H9/ADC Daifco, BD India
  • a 96-well microtiter plates 0.1 mL of the above L-MTB suspension was added to each well followed by the addition of all the drugs in the concentration of 10, 5, 2.5, 1, 0.5 and 0.25 ⁇ g/mL.
  • 96-well microtiter plates were incubated at 37 °C for 4 and 8 days post treatment. Post 4 days treatment 0.1 mL of culture was drawn from the middle of the culture well and plated onto 7H1 I/O ADC agar plates (Difco, BD India). The plates were incubated at 37 °C and the CFU were enumerated 4 weeks later. Analysis:
  • L-MTB latent Mycobacterium tuberculosis
  • L-MTB latent Mycobacterium tuberculosis
  • the culture flask contains methylene blue dye (l ⁇ g/ml) as an indicator of oxygen depletion.
  • the objective of this study was to evaluate the efficacy of the combination of compound I and one or more anti-tubercular agents selected from isoniazid and rifampicin in a murine model against infection caused by Mycobacterium tuberculosis (H 37 RV).
  • Test items Compound I (prepared in-house as indicated in the above reference example i);
  • Test system a) Mus musculus (Murine), BalbC strain, 2-3 Months, 19-20 g (Piramal
  • mice per group were treated for 3 months.
  • RIF rifampicin
  • INH isoniazid
  • oesophageal cannula gavage 5 times weekly in a volume of 0.1 mL.
  • the said compound was given 5 times weekly in a volume of 0.03 mL.
  • Pulmonary TB is the most frequently occurring form of tuberculosis. This infection affects the lungs resulting in cavitations. Since lungs are the most affected organs, the pulmonary route was chosen for achieving direct compound delivery to site of infection, maximizing local concentration and limiting systemic exposure. Since pulmonary administration once a day retains pulmonary concentration for 24 h, once a day dosing was done.
  • Bacterial Strain Mycobacterium tuberculosis (H 37 RV) frozen aliquots were subcultured in Middlebrook 7H9 broth (Difco, BD India) supplemented with 10 % oleic acid albumin dextrose catalyse (OADC) (Difco, BD India) and 0.05 % Tween 80 (Sigma). The culture was adjusted to the count of 3X10 CFU/mL and used for aerosol infection.
  • Middlebrook 7H9 broth Difco, BD India
  • OADC oleic acid albumin dextrose catalyse
  • Necropsy After 1 month, 2 months and 3 months of treatment, animals were sacrificed and necropsy was performed. The chest and peritoneal cavities were opened and the lungs and spleen were inspected to determine the number of superficial lesions, and their weights were recorded. The caudal left lung lobe was placed in 10 % neutral buffered formalin for histopathological evaluation. For bacteriology, the caudal right lung lobe and spleen tissue were homogenized separately in 2 mL of Middlebrook's 7H9/ADC (Difco, BD India) medium with a tissue homogenizer.
  • Middlebrook's 7H9/ADC Daifco, BD India
  • the homogenates were diluted with sterile PBS, and aliquots for each tissue dilution were inoculated onto duplicate 7H11/OADC agar plates (Difco, BD India). The plates were incubated at 37 °C for 6 to 8 weeks. Visible CFU were counted, and data are expressed as Log ! oCFU.
  • the lung CFU count in the murine model after 1 month, 2 months and 3 months treatment with a combination of rifampicin and isoniazid; and a combination of compound I, rifampicin and isoniazid against Mycobacterium tuberculosis (H 37 RV) is presented in Table 7.
  • the spleen CFU count in the murine model after 1 month, 2 months and 3 months treatment with a combination of rifampicin and isoniazid; and a combination of compound I, rifampicin and isoniazid against Mycobacterium tuberculosis (H 37 Rv) is presented in Table 8.
  • Table 7 Effect of the combination of compound I, rifampicin and isoniazid against Mycobacterium tuberculosis in murine model in terms of lungs CFU count
  • Table 8 Effect of the combination of compound I, rifampicin and isoniazid against Mycobacterium tuberculosis in murine model in terms of spleen CFU count

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Abstract

La présente invention porte sur une combinaison pharmaceutique comprenant un composé (I) (tel que décrit dans la description) et au moins un agent antituberculeux destiné à être utilisé pour traiter la tuberculose. La présente invention porte en outre sur une méthode de traitement de la tuberculose, comprenant l'administration, à un sujet en ayant besoin, d'une quantité thérapeutiquement efficace d'un composé (I) et d'une quantité thérapeutiquement efficace d'au moins un agent antituberculeux. L'association pharmaceutique de la présente invention présente un effet synergique lorsqu'elle est utilisée pour traiter la tuberculose.
PCT/IB2015/050327 2014-01-17 2015-01-16 Association pharmaceutique pour traiter la tuberculose WO2015107482A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017120529A1 (fr) 2016-01-08 2017-07-13 Institute For Systems Biology Procédés pour identifier des composés antituberculeux
CN107335058A (zh) * 2017-07-31 2017-11-10 暨南大学 一种2,6‑二取代吡啶‑4‑硫代甲酰胺的新用途
WO2018158280A1 (fr) 2017-03-01 2018-09-07 Janssen Sciences Ireland Uc Polythérapie
WO2018191628A1 (fr) * 2017-04-14 2018-10-18 The Regents Of The University Of California Multithérapies médicamenteuses pour le traitement de la tuberculose
CN112022992A (zh) * 2020-03-25 2020-12-04 博奥生物集团有限公司 一种快速优化中药组方的方法及抗耐药结核应用
CN114732818A (zh) * 2022-04-29 2022-07-12 首都医科大学附属北京胸科医院 一种抗特发性肺纤维化药物尼达尼布在结核病治疗中的应用
EP3906251A4 (fr) * 2019-01-05 2022-10-05 Foundation For Neglected Disease Research Peptides thiazolyle pour le traitement d'infections mycobactériennes non tuberculeuses

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011027290A1 (fr) * 2009-09-02 2011-03-10 Piramal Life Sciences Limited Composés antibiotiques
WO2012017405A1 (fr) * 2010-08-05 2012-02-09 Piramal Life Sciences Limited Formulation de microparticules pour administrer un médicament pulmonaire à base de molécule anti-infectieuse afin de traiter les maladies infectieuses
WO2013080167A1 (fr) * 2011-12-02 2013-06-06 Piramal Enterprises Limited Composés pour le traitement de la tuberculose

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011027290A1 (fr) * 2009-09-02 2011-03-10 Piramal Life Sciences Limited Composés antibiotiques
WO2012017405A1 (fr) * 2010-08-05 2012-02-09 Piramal Life Sciences Limited Formulation de microparticules pour administrer un médicament pulmonaire à base de molécule anti-infectieuse afin de traiter les maladies infectieuses
WO2013080167A1 (fr) * 2011-12-02 2013-06-06 Piramal Enterprises Limited Composés pour le traitement de la tuberculose

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017120529A1 (fr) 2016-01-08 2017-07-13 Institute For Systems Biology Procédés pour identifier des composés antituberculeux
US10472687B2 (en) 2016-01-08 2019-11-12 Institute For Systems Biology Methods to identify antituberculosis compounds
WO2018158280A1 (fr) 2017-03-01 2018-09-07 Janssen Sciences Ireland Uc Polythérapie
WO2018191628A1 (fr) * 2017-04-14 2018-10-18 The Regents Of The University Of California Multithérapies médicamenteuses pour le traitement de la tuberculose
CN107335058A (zh) * 2017-07-31 2017-11-10 暨南大学 一种2,6‑二取代吡啶‑4‑硫代甲酰胺的新用途
EP3906251A4 (fr) * 2019-01-05 2022-10-05 Foundation For Neglected Disease Research Peptides thiazolyle pour le traitement d'infections mycobactériennes non tuberculeuses
CN112022992A (zh) * 2020-03-25 2020-12-04 博奥生物集团有限公司 一种快速优化中药组方的方法及抗耐药结核应用
CN112022992B (zh) * 2020-03-25 2022-04-05 博奥生物集团有限公司 一种快速优化中药组方的方法及抗耐药结核应用
CN114732818A (zh) * 2022-04-29 2022-07-12 首都医科大学附属北京胸科医院 一种抗特发性肺纤维化药物尼达尼布在结核病治疗中的应用

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