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WO2013142326A1 - Benz imidazoles substitués 5-carbonylamino-/ (sulfonamido-) et utilisation de celui-ci et le traitement de la tuberculose - Google Patents

Benz imidazoles substitués 5-carbonylamino-/ (sulfonamido-) et utilisation de celui-ci et le traitement de la tuberculose Download PDF

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Publication number
WO2013142326A1
WO2013142326A1 PCT/US2013/032083 US2013032083W WO2013142326A1 WO 2013142326 A1 WO2013142326 A1 WO 2013142326A1 US 2013032083 W US2013032083 W US 2013032083W WO 2013142326 A1 WO2013142326 A1 WO 2013142326A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
patient
pharmaceutically acceptable
acceptable salt
Prior art date
Application number
PCT/US2013/032083
Other languages
English (en)
Inventor
Iwao Ojima
Original Assignee
The Research Foundation Of State University Of New York
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Research Foundation Of State University Of New York filed Critical The Research Foundation Of State University Of New York
Publication of WO2013142326A1 publication Critical patent/WO2013142326A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • infectious diseases especially those associated with, for example, Mycobacterium tuberculosis or Francisella tularensis.
  • Tuberculosis was one of the first infectious diseases to be identified as associated with the aforesaid bacteria. More than fifty years of research has been directed to controlling and eliminating this disease. However, the eradication of TB is still one of the most prominent challenges for basic and clinical research scientists.
  • MDR-TB multidrug-resistance
  • MDR-TB is much more difficult to treat than sensitive TB, requiring administration of more expensive, second-line antibiotics for up to two years.
  • the frequency of resistance to at least one of the first-line TB drugs ranged from 1.7% in Brazil to 36.9% in Estonia.
  • the frequency of resistance is indicative of the global problem involving not only the spread of Mtb, but also the treatment.
  • Tularemia is primarily enzootic; however, in humans, it causes lesions and flu-like symptoms. Finding new methods of treating F. tularensis is of great importance because it is one of the most pathogenic microorganisms presently known. As such, it is currently listed as a category A select agent by the Centers for Disease Control and
  • FtsZ Filamenting temperature sensitive mutant Z
  • the invention relates to a compound having the formula:
  • the invention realtes to a compound of formula I:
  • R represents
  • R represents
  • the invention realtes to a compound of formula II:
  • R 4 represents
  • the invention relates to a benzimidazole intermediate having the formula:
  • the invention also relates to methods of treating a patient infected by Mycobacterium tuberculosis or Francisella tularensis by administering to the patient a benzimidazole of the invention or a pharmaceutically acceptable salt thereof.
  • the invention relates to the novel benzimidazole derivatives shown in Table I and their intermediates shown in Table II, and the benzimidazole derivatives of formula I and II.
  • These benzimidazole derivatives or pharmaceutically acceptable salts thereof can be used to treat a pateint infected by Mycobacterium tuberculosis or Francis ella tularensis.
  • the benzimidazole derivates in Table I have unexpectedly high activities against Mycobacterium tuberculosis and/or Francisella tularensis.
  • R 2 represents
  • R 3 represents
  • R 5 represents
  • R represents In this specification, groups of various parameters containing multiple members are described. Within a group of parameters, each member may be combined with any one or more of the other members to make additional sub-groups. For example, if the members of a group are a, b, c, d, and e, additional sub-groups specifically contemplated include any two, three, or four of the members, e.g., a and c; a, d, and e; b, c, d, and e; etc.
  • the members of a first group of parameters may be combined with the members of a second group of parameters, e.g., A, B, C, D, and E.
  • a first group of parameters e.g., a, b, c, d, and e
  • a second group of parameters e.g., A, B, C, D, and E.
  • Any member of the first group or of a sub-group thereof may be combined with any member of the second group or of a sub-group thereof to form additional groups, i.e., b with C; a and c with B, D, and E, etc.
  • the instant invention further contemplates embodiments in which each element listed under one group may be combined with each and every element listed under any other group.
  • a stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • the benzimidazoles of the present invention can be synthesized by methods known in the art.
  • the following scheme represents one approach to the synthesis of the compounds of the invention.
  • Scheme 1 shows an example of a synthesis that yields 2,5,6-trisubstituted benzimidazoles of the invention.
  • the compounds of the invention may be made using polymer- assisted solution-phase (PASP) synthesis.
  • PASP is a parallel synthesis method for creation of a trisubstituted benzimidazoles (BAZ-1) library using 2,4-dinitro-5-fluoroaniline (1) as the starting material.
  • the first step involves the nucleophilic substitution of compound 1 with a secondary amine in the presence of ⁇ , ⁇ -diisopropylethylamine.
  • the reaction produces compound 2 in high yields and purity at room temperature.
  • the free aromatic amino group of compound 5 is modified in different ways.
  • anhydride, acyl chloride, sulfonyl chloride, and isocyanate are used as modifying agents.
  • the modification of the aromatic amine moiety takes place smoothly in dry dichloromethane and all excess acylating reagents are scavenged by commercially available aminomethylated polystyrene resin (from nova-biochem) to give the desired product 6 in 80-95% yield.
  • Scheme 3 shows the synthesis of 2,5,7-trisubstituted benzimidazoles of the invention.
  • the present invention also relates to pharmaceutically acceptable salts of the
  • the pharmaceutically acceptable salts include the conventional non- toxic salts of the benzimidazole derivatives as formed, e.g., from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • the pharmaceutically acceptable salts of the benzimidazole derivatives of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • the invention also relates to a method of treating a patient infected with Mycobacterium tuberculosis or Mycobacterium avium complex, which includes Mycobacterium avium and Mycobacterium intracellular e.
  • the method comprises administering to the patient the compound of Table I or a pharmaceutically acceptable salt thereof.
  • the method and compounds of the invention may be employed alone, or in combination with other anti-bacterial agents.
  • Other anti-bacterial agents include isoniazid, rifampin, pyrazinamide, rifabutin, streptomycin and ciprofloxacin.
  • the combination of these anti-bacterial agents and the compounds of the invention will provide new agents for the treatment of tuberculosis, including MDR-TB and XDR-TB, and pulmonary MAC disease.
  • An effective amount of a compound of Table I or a pharmaceutically acceptable salt thereof as used herein is any amount effective to treat a patient infected by Mtb, Mycobacterium avium complex, or Francisella tularensis. Modes of administration and doses can be determined by those having skill in the art. An effective amount of the compound will vary with the group of patients (age, sex, weight, etc.), the nature and severity of the condition to be treated, the particular compound administered, and its route of administration. Amounts suitable for administration to humans are routinely determined by physicians and clinicians during clinical trials. The minimum dose of the compound is the lowest dose at which efficacy is observed.
  • the minimum dose of the compound may be about O.lmg/kg/day, about 1 mg/kg/day, or about 3 mg/kg/day.
  • the maximum dose of the compound is the highest dose at which efficacy is observed in a patient, and side effects are tolerable.
  • the maximum dose of the compound may be about 10 mg/kg/day, about 9 mg/kg/day, or about 8 mg/kg/day. In another embodiment, the maximum dose of the compound may be up to about 50 mg/kg/day.
  • a benzimidazole derivative useful in the methods of the present invention may be administered by any method known in the art.
  • administration include oral and systemic administration.
  • Systemic administration can be enteral or parenteral.
  • Liquid or solid (e.g., tablets, gelatin capsules) formulations can be employed.
  • Parenteral administration of the benzimidazole derivative include, for example intravenous, intramuscular, and subcutaneous injections.
  • a chemical compound may be administered to a patient by sustained release, as is known in the art.
  • Sustained release administration is a method of drug delivery to achieve a certain level of the drug over a particular period of time.
  • routes of administration include oral, topical, intrabronchial, or intranasal administration.
  • liquid or solid formulations may be used.
  • formulations suitable for oral administration include tablets, gelatin capsules, pills, troches, elixirs, suspensions, syrups, and wafers.
  • Intrabronchial administration can include an inhaler spray.
  • administration of a chemical compound can be accomplished by a nebulizer or liquid mist.
  • the chemical compound can be formulated in a suitable pharmaceutical carrier.
  • a pharmaceutical carrier is considered to be synonymous with a vehicle or an excipient as is understood by practitioners in the art. Examples of carriers include starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums and glycols.
  • the chemical compound can be formulated into a composition containing one or more of the following: a stabilizer, a surfactant, preferably a nonionic surfactant, and optionally a salt and/or a buffering agent.
  • the stabilizer may, for example, be an amino acid, such as for instance, glycine; or an oligosaccharide, such as for example, sucrose, tetralose, lactose or a dextran.
  • the stabilizer may be a sugar alcohol, such as for instance, mannitol; or a combination thereof.
  • the stabilizer or combination of stabilizers constitutes from about 0.1% to about 10% weight for weight of the chemical compound.
  • the surfactant is preferably a nonionic surfactant, such as a polysorbate.
  • suitable surfactants include Tween 20, Tween 80; a polyethylene glycol or a polyoxyethylene polyoxypropylene glycol, such as Pluronic F-68 at from about 0.001% (w/v) to about 10% (w/v).
  • Other preferred surfactants include Solutol H-15 and Cremophore EL.
  • the salt or buffering agent may be any salt or buffering agent, such as for example sodium chloride, or sodium/potassium phosphate, respectively.
  • the buffering agent maintains the pH of the chemical compound formulation in the range of about 5.5 to about 7.5.
  • the salt and/or buffering agent is also useful to maintain the osmolality at a level suitable for administration to a patient.
  • the salt or buffering agent is present at a roughly isotonic concentration of about 150 mM to about 300 mM.
  • the chemical compound can be formulated into a composition which may additionally contain one or more conventional additives.
  • additives include a solubilizer such as, for example, glycerol; an antioxidant such as for example, benzalkonium chloride (a mixture of quaternary ammonium compounds, known as "quart"), benzyl alcohol, chloretone or chlorobutanol; anaesthetic agent such as, for example a morphine derivative; or an isotonic agent etc.
  • a solubilizer such as, for example, glycerol
  • an antioxidant such as for example, benzalkonium chloride (a mixture of quaternary ammonium compounds, known as "quart"), benzyl alcohol, chloretone or chlorobutanol
  • anaesthetic agent such as, for example a morphine derivative
  • the composition may be stored under nitrogen gas in vials sealed with impermeable stoppers.
  • SB-P17G-C4 SB-P17G-C8
  • SB-P17G-C8 SB-P1G- C12
  • SB-P3G2-OL1 SB-P6B-C12
  • SB-OL1-C8 SB-OL1-C8
  • the organic layer was dried over magnesium sulfate.
  • the crude product was purified by flash chromatography on silica gel (gradient: 30-70% ethyl acetate /hexanes) to obtain the product which was then treated with activated charcoal to yield the product as a white solid (130 mg, 86%).
  • reaction mixture was diluted with dichloromethane followed by the addition of triethylamine.
  • the reaction mixture was transferred to a separatory funnel and the organic layer was washed with water, sodium bicarbonate and finally brine.
  • the organic layer was dried over magnesium sulfate and concentrated using rotary evaporator.
  • the crude product was purified by flash chromatography (column was packed with hexane, 30% ethyl acetate was used with gradual increase to 50% ethyl acetate) to obtain the product as a white solid (83 mg, 85% yield). 1H
  • MIC values were determined using the microplate dilution method reported by R. A. Slayden et al, "The role ofKasA and KasB in the biosynthesis of meromy colic acids and isoniazid resistance in Mycobacterium tuberculosis", Tuberculosis (Edinburgh, 2002) Vol. 82, pagesl49-60.
  • Bacteria were cultivated in liquid medium to an optical density of -0.4 at 600 nm. The bacterial cultures were then prepared for testing by diluting 1: 100 in liquid medium. A total of 50 ⁇ L ⁇ of each culture was added to each well of a 96-well optical plate. Analogs were prepared at 60 ⁇ in 100% DMSO. Compound stock solutions were diluted 1:2 in liquid medium and then distributed in the plate as 2-fold serial dilutions to achieve a concentration range of 200-0.2 mg/mL in a total final volume of 100 ⁇ L ⁇ The plates were incubated at 37 °C and evaluated for the presence of bacterial growth or non-growth by optical density using an inverted plate reading method. The MIC99 was determined to be the lowest concentration of compound that inhibited bacterial growth. MIC values shown below in Table III represent measurements performed independently in triplicate.
  • Broth cultures were then incubated for 18hrs at 37°C passed 1:20 and incubated for an additional 8 h at 37°C.
  • Bacteria were then diluted to a concentration of lxlO 7 colony forming units (CFU)/mL in modified Mueller-Hinton (MMH) broth and 50 ⁇ ⁇ added to each well for each test plate.
  • CFU colony forming units
  • MMH modified Mueller-Hinton
  • Trisubstituted benzimidazole compound library was screened in a percent inhibition high-throughput fashion against F. tularensis LVS in a 96-well plate format. All compounds were diluted in MMH broth to concentrations of 10, 2 and 0.4 ⁇ g/mL in a 50 ⁇ volume/well.
  • MIC determination compounds were added to the 96-well plate starting at 512 ⁇ g/mL in the first column and serially diluted 1:2 to column 12 for a final concentration of 0.25 in MMH broth.
  • MIC plates were incubated at 37°C for 18 h at which time 10 of Alamar Blue (Invitrogen, Carlsbad, California) was added to each well and plates were incubated for an additional 4 h.
  • Reduction of Alamar Blue was determined by absorbance readings at wavelengths of 570 and 600 nm using a microplate reader (Biotek, Winooski, VT). Percent growth reduction was calculated and MIC 90 values were determined by plotting the percentage inhibition calculated from spectrophotometric readings over the drug concentration series.
  • the cytotoxicity of the compounds was tested against Vero cells.
  • Epithelial cells from the kidneys of the African Green Monkey were used to start the Vero cell line.
  • Vero cells were grown in L15 media without C0 2 .
  • Serial 2-fold dilutions of the drugs were prepared (200 ⁇ g/mL to 50 ⁇ g/mL) in triplicate using 96-well microtiter plates. The cells were added to the plates to a final concentration of 1.25 x 10 5 /well in media containing Resazurin for a final concentration 25 ⁇ g/mL. The plates were incubated for 3 days at 37 °C.
  • the LD was the lowest drug concentration that inhibited cell growth and the resazurin was not reduced.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux benzimidazoles substitués 5-/ 6-ou 5-/ 7- et des sels pharmaceutiquement acceptables de ceux-ci. Un Autre aspect de la présente invention se rapporte à leur utilisation dans le traitement d'un patient infecté par la Mycobacterium tuberculosis ou Francisella tularensis.
PCT/US2013/032083 2012-03-23 2013-03-15 Benz imidazoles substitués 5-carbonylamino-/ (sulfonamido-) et utilisation de celui-ci et le traitement de la tuberculose WO2013142326A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US201261614908P 2012-03-23 2012-03-23
US201261614898P 2012-03-23 2012-03-23
US61/614,898 2012-03-23
US61/614,908 2012-03-23
US201261691009P 2012-08-20 2012-08-20
US61/691,009 2012-08-20
US201361767891P 2013-02-22 2013-02-22
US61/767,891 2013-02-22

Publications (1)

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WO2013142326A1 true WO2013142326A1 (fr) 2013-09-26

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015077276A1 (fr) * 2013-11-22 2015-05-28 The Research Foundation For The State University Of New York Benzimidazoles et leur utilisation dans le traitement de la tuberculose
CN104945329A (zh) * 2014-03-24 2015-09-30 中国医学科学院医药生物技术研究所 抗结核药物及抗结核药物筛选方法
US10287617B2 (en) 2014-03-11 2019-05-14 Colorado State University Research Foundation Methods for in vitro—in vivo efficacy determination

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008130669A1 (fr) * 2007-04-20 2008-10-30 The Research Foundation Of State University Of New York Benzimidazoles et compositions pharmaceutiques de ceux-ci

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008130669A1 (fr) * 2007-04-20 2008-10-30 The Research Foundation Of State University Of New York Benzimidazoles et compositions pharmaceutiques de ceux-ci

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A. KRUNNER ET AL.: "Drug resistant tuberculosis in Estonia", INT. J. TUBERC. LUNG DIS., vol. 2, 1998, pages 130 - 133
KUMAR, KUNAL; AWASTHI, DIVYA ET AL: "Novel Trisubstituted Benzimidazoles, Targeting Mtb FtsZ, as a New Class of Antitubercular Agents", J.MED.CHEM., vol. 54, no. 1, 12 February 2010 (2010-02-12), pages 374 - 371, XP002697232 *
R. A. SLAYDEN ET AL.: "The role of KasA and KasB in the biosynthesis of meromycolic acids and isoniazid resistance in Mycobacterium tuberculosis", TUBERCULOSIS, vol. 82, 2002, pages L49 - 60

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015077276A1 (fr) * 2013-11-22 2015-05-28 The Research Foundation For The State University Of New York Benzimidazoles et leur utilisation dans le traitement de la tuberculose
CN106061951A (zh) * 2013-11-22 2016-10-26 纽约州立大学研究基金会 苯并咪唑及其在结核病治疗中的用途
US9845296B2 (en) 2013-11-22 2017-12-19 The Research Foundation For The State University Of New York Benzimidazoles and their use in the treatment of tuberculosis
US10287617B2 (en) 2014-03-11 2019-05-14 Colorado State University Research Foundation Methods for in vitro—in vivo efficacy determination
CN104945329A (zh) * 2014-03-24 2015-09-30 中国医学科学院医药生物技术研究所 抗结核药物及抗结核药物筛选方法
CN104945329B (zh) * 2014-03-24 2017-09-01 中国医学科学院医药生物技术研究所 抗结核药物

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