[go: up one dir, main page]

WO2016055607A1 - Benzothiazole derivative useful in the treatment of chagas disease - Google Patents

Benzothiazole derivative useful in the treatment of chagas disease Download PDF

Info

Publication number
WO2016055607A1
WO2016055607A1 PCT/EP2015/073365 EP2015073365W WO2016055607A1 WO 2016055607 A1 WO2016055607 A1 WO 2016055607A1 EP 2015073365 W EP2015073365 W EP 2015073365W WO 2016055607 A1 WO2016055607 A1 WO 2016055607A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
formula
acid
mmol
Prior art date
Application number
PCT/EP2015/073365
Other languages
English (en)
French (fr)
Inventor
Julio ALONSO PADILLA
Adam Kenneth Charnley
Ignacio COTILLO TORREJON
Mark ELBAN
Terry Vincent Hughes
Albane Marie KESSLER
Beth Anne KNAPP-REED
Yiqian LIAN
Jose Julio Martin
Imanol PENA URQUIZA
Ana RODRIGUEZ FERNANDEZ
Original Assignee
Glaxosmithkline Intellectual Property Development Limited
New York University School Of Medicine
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 Glaxosmithkline Intellectual Property Development Limited, New York University School Of Medicine filed Critical Glaxosmithkline Intellectual Property Development Limited
Publication of WO2016055607A1 publication Critical patent/WO2016055607A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis

Definitions

  • the present invention relates to a novel compound, 3-(benzo[d]thiazol-5-yl)-5- (methylamino)-l-(2,2,2-trifluoroethyl)-lH-pyrazole-4-carboxamide, salts thereof, processes for its preparation, compositions comprising it, and to its use in therapy, in particular in the treatment or prevention of Chagas disease.
  • Chagas disease is an anthropozoonosis due to the flagellated protozoan parasite Trypanosoma cruzi. It is transmitted to humans and other mammals by infected faeces of a blood-sucking triatominae bug through the insect sting, another skin break or 15 through mucous membranes, including conjunctiva or oral/digestive mucosa, occasionally
  • the triatomine bug thrives under poor housing conditions (for example, mud walls, thatched roofs), so in endemic countries, people living in rural areas are at greatest risk for acquiring infection.
  • the recent migration of populations from countries endemic for the disease has increased the
  • Chagas disease presents itself in 2 phases.
  • the initial, acute phase lasts for about 2 months after infection.
  • a high number of parasites circulate in 35 the blood.
  • symptoms are absent or mild, but can include fever, headache,
  • Benznidazole and nifurtimox are the only trypanocidal drugs available with proven efficacy against Chagas disease. Both medicines are almost 100% effective in curing the disease if given soon after infection at the onset of the acute phase. However, the efficacy of both diminishes the longer a person has been infected. Furthermore, benznidazole and nifurtimox are not consistently used in part because of their substantial side effects (peripheral neurotoxicity, digestive system irritation and serious dermatological conditions).
  • WO2011/045415 discloses certain beta-amyloid binding compounds for use in detecting amyloid deposits in body organs and in Alzheimer's disease.
  • the present invention relates to the pyrazole derivative 3-(benzo[d]thiazol-5-yl)-5- (methylamino)-l-(2,2,2-trifluoroethyl)-lH-pyrazole-4-carboxamide, a compound having the Formula (I):
  • the present invention also relates to pharmaceutical compositions comprising a) the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable carriers.
  • the present invention also relates to methods of treating Chagas disease comprising administration of a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the invention relates to the compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • the invention relates to the compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of Chagas disease.
  • the invention relates to the use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of Chagas disease.
  • the present invention is directed to 3-(benzo[d]thiazol-5-yl)-5- (methylamino)-l-(2,2,2-trifluoroethyl)-lH-pyrazole-4-carboxamide, the compound of formula (I):
  • references herein to compounds of the invention mean the compound of formula (I) as the free base, or as a salt, for example a pharmaceutically acceptable salt.
  • the compound of formula (I) is in the form of a free base. In a further aspect of the invention, the compound of formula (I) is in the form of a pharmaceutically acceptable salt.
  • Salts of the compound of formula (I) include pharmaceutically acceptable salts and salts which may not be pharmaceutically acceptable but may be useful in the preparation of the compound of formula (I) and pharmaceutically acceptable salts thereof.
  • the compound of formula (I) is in the form of a pharmaceutically acceptable salt. Salts may be derived from certain inorganic or organic acids.
  • salts are pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts include acid addition salts.
  • suitable salts see Berge eta/., J. Pharm. Sci., 66:1-19 (1977).
  • Examples of pharmaceutically acceptable acid addition salts of the compound of formula (I) include inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, orthophosphoric acid, nitric acid, phosphoric acid, or sulphuric acid, or with organic acids such as, for example, methanesu I phonic acid, ethanesulphonic acid, p-toluenesu I phonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid, tartaric, benzoic, glutamic, aspartic, benzenesulphonic, naphthalenesulphonic such as 2-naphthalenesuphonic, hexanoic acid or acetylsalicylic acid.
  • inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, orthophosphoric acid, n
  • the compound of Formula (I) is in the form of a hydrochloride or trifluoroacetate salt.
  • 3-(benzo[d]thiazol- 5-yl)-5-(methylamino)-l-(2,2,2-trifluoroethyl)-lH-pyrazole-4-carboxamide trifluoroacetate is provided.
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compound of formula (I). Salts may be formed using techniques well-known in the art, for example by precipitation from solution followed by filtration, or by evaporation of the solvent.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable acid (such as hydrobromic, hydrochloric, sulphuric, maleic, />toluenesulphonic, methanesu I phonic, naphthalenesulphonic or succinic acids), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • a suitable acid such as hydrobromic, hydrochloric, sulphuric, maleic, />toluenesulphonic, methanesu I phonic, naphthalenesulphonic or succinic acids
  • solvates complexes with solvents in which they are reacted or from which they are precipitated or crystallised. These complexes are known as "solvates".
  • a complex with water is known as a "hydrate”.
  • Solvents with high boiling points and/or solvents with a high propensity to form hydrogen bonds such as water, ethanol, /so-propyl alcohol, and /V-methyl pyrrolidinone may be used to form solvates.
  • Methods for the identification of solvates include, but are not limited to, NMR and microanalysis.
  • Solvates of the compound of formula (I) are within the scope of the invention.
  • the term solvate encompasses solvates of both a free base compound as well as any salt thereof.
  • Certain of the compounds of the invention may contain chiral atoms and hence may exist in one or more stereoisomeric forms.
  • the present invention encompasses all of the stereoisomers of the compounds of the invention, including optical isomers, whether as individual stereoisomers or as mixtures thereof including racemic modifications.
  • Any stereoisomer may contain less than 10% by weight, for example less than 5% by weight, or less than 0.5% by weight, of any other stereoisomer.
  • any optical isomer may contain less than 10% by weight, for example less than 5% by weight, or less than 0.5% by weight, of its antipode.
  • Certain of the compounds of the invention may exist in tautomeric forms. It will be understood that the present invention encompasses all of the tautomers of the compounds of the invention whether as individual tautomers or as mixtures thereof.
  • the compounds of the invention may be in crystalline or amorphous form. Furthermore, some of the crystalline forms of the compounds of the invention may exist as polymorphs, all of which are included within the scope of the present invention. The most thermodynamically stable polymorphic form or forms of the compounds of the invention are of particular interest.
  • Polymorphic forms of compounds of the invention may be characterised and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid-state nuclear magnetic resonance (ssNMR).
  • XRPD X-ray powder diffraction
  • IR infrared spectroscopy
  • Raman spectroscopy Raman spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • ssNMR solid-state nuclear magnetic resonance
  • the present invention also includes all suitable isotopic variations of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • An isotopic variation of a compound of formula (I), or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 18 F and 36 CI, respectively.
  • isotopic variations of a compound of formula (I) or a salt or solvate thereof are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of a compound of formula (I), or a pharmaceutically salt thereof can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
  • the compound of formula (I) and salts thereof may be prepared by the methodology described hereinafter, constituting further aspects of this invention. Accordingly, there is provided a process for the preparation of the compound of formula (I), or a salt thereof.
  • the compound of Formula (I) may be prepared by reaction of a compound of Formula
  • an acid for example sulphuric acid or hydrochloric acid
  • a suitable solvent for example a mixture of toluene and dioxane.
  • the compound of Formula (II) may be prepared by reaction of a compound of Formula (III)
  • a suitable amine methylating agent for example triethylorthoformate followed by reducing agent for example sodium borohydride, or iodomethane in the presence of a suitable base, for example sodium hydride, in a suitable solvent, for example ethanol or dimethylformamide, at a convenient temperature, for example room temperature or 0°C.
  • a suitable amine methylating agent for example triethylorthoformate followed by reducing agent for example sodium borohydride, or iodomethane in the presence of a suitable base, for example sodium hydride, in a suitable solvent, for example ethanol or dimethylformamide, at a convenient temperature, for example room temperature or 0°C.
  • the compound of Formula (III) may be prepared by reaction of a compound of Formula (IV)
  • a suitable ring-closing agent for example (2,2,2-trifluoroethyl)hydrazine
  • a suitable base for example triethylamine or DIPEA
  • a suitable solvent for example ethanol or MeOH
  • the compound of Formula (IV) may be prepared by reaction of a compound of Formula (V)
  • a suitable methylating agent for example trimethylsilyldiazomethane or iodomethane
  • a suitable solvent for example a mixture of acetonitrile and methanol or DMF
  • a suitable base for example DIPEA or lithium carbonate
  • the compound of Formula (V) may be prepared by reaction of a compound of Formula (VI)
  • a suitable solvent for example a mixture of tetrahydrofuran and toluene, at a convenient temperature, for example room temperature.
  • the compound of Formula (VI) may be prepared by reaction of a compound of Formula (VII)
  • a suitable halogenating agent for example thionyl chloride or oxalyl chloride
  • a suitable solvent for example toluene or DMF
  • conventional methods of heating and cooling may be employed, for example temperature-regulated oil-baths or temperature-regulated hot-blocks, and ice/salt baths or dry ice/acetone baths respectively.
  • Conventional methods of isolation for example extraction from or into aqueous or non-aqueous solvents may be used.
  • Conventional methods of drying organic solvents, solutions, or extracts such as shaking with anhydrous magnesium sulphate, or anhydrous sodium sulphate, or passing through a hydrophobic frit, may be employed.
  • Conventional methods of purification for example crystallisation and chromatography, for example silica chromatography or reverse-phase chromatography, may be used as required.
  • Crystallisation may be performed using conventional solvents such as ethyl acetate, methanol, ethanol, or butanol, or aqueous mixtures thereof. It will be appreciated that specific reaction times and temperatures may typically be determined by reaction-monitoring techniques, for example thin-layer chromatography and LC-MS.
  • the absolute stereochemistry of compounds may be determined using conventional methods, such as X-ray crystallography.
  • references herein to treatment refer to the treatment of established conditions.
  • the compound of formula (I) and pharmaceutically acceptable salts thereof may, depending on the condition, also be useful in the prevention of certain diseases.
  • there is provided the treatment or prevention of a disease there is provided the treatment of a disease.
  • a method of treatment or prevention of Chagas disease comprises administering to a human subject in need thereof, a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered as the bulk substance, it is preferable to present the active ingredient in a pharmaceutical formulation, for example, wherein the agent is in admixture with at least one pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a) the compound of Formula (I) or a pharmaceutically acceptable salt thereof and b) one or more pharmaceutically acceptable carriers.
  • carrier refers to a diluent, excipient, and/or vehicle with which an active compound is administered.
  • the pharmaceutical compositions of the invention may contain combinations of more than one carrier.
  • Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions.
  • Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin, 18th Edition. The choice of pharmaceutical carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the pharmaceutical compositions may comprise, in addition to the carrier, any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilizing agent(s).
  • pharmaceutically acceptable refers to salts, molecular entities and other ingredients of compositions that are generally physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human).
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in mammals, and more particularly in humans.
  • a “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used in the present application includes both one and more than one such excipient.
  • the present invention is further related to a pharmaceutical composition for the treatment or prevention of Chagas disease comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
  • the present invention is even further related to a pharmaceutical composition comprising a) 10 to 2000 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and b) 0.1 to 2 g of one or more pharmaceutically acceptable excipients.
  • the present invention relates to a pharmaceutical composition comprising a) 1 to 2000 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and b) 0.1 to 2 g of one or more pharmaceutically acceptable excipients.
  • compositions for use in accordance with the present invention may be in the form of oral, parenteral, transdermal, inhalation, sublingual, topical, implant, nasal, or enterally administered (or other mucosally administered) suspensions, capsules or tablets, which may be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition is formulated for oral administration.
  • the compounds of the invention can be administered for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • oral compositions are slow, delayed or positioned release (e.g., enteric especially colonic release) tablets or capsules.
  • This release profile can be achieved, for example, by use of a coating resistant to conditions within the stomach but releasing the contents in the colon or other portion of the GI tract wherein a lesion or inflammation site has been identified.
  • a delayed release can be achieved by a coating that is simply slow to disintegrate.
  • the two (delayed and positioned release) profiles can be combined in a single formulation by choice of one or more appropriate coatings and other excipients. Such formulations constitute a further feature of the present invention.
  • Suitable compositions for delayed or positioned release and/or enteric coated oral formulations include tablet formulations film coated with materials that are water resistant, pH sensitive, digested or emulsified by intestinal juices or sloughed off at a slow but regular rate when moistened.
  • Suitable coating materials include, but are not limited to, hydroxypropyl methylcellulose, ethyl cellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, polymers of metacrylic acid and its esters, and combinations thereof.
  • Plasticizers such as, but not limited to polyethylene glycol, dibutylphthalate, triacetin and castor oil may be used.
  • a pigment may also be used to color the film.
  • Suppositories are be prepared by using carriers like cocoa butter, suppository bases such as Suppocire C, and Suppocire NA50 (supplied by Gattefosse GmbH, D-Weil am Rhein, Germany) and other Suppocire type excipients obtained by interesterification of hydrogenated palm oil and palm kernel oil (C 8 -Ci 8 triglycerides), esterification of glycerol and specific fatty acids, or polyglycosylated glycerides, and whitepsol (hydrogenated plant oils derivatives with additives).
  • Enemas are formulated by using the appropriate active compound according to the present invention and solvents or excipients for suspensions.
  • Suspensions are produced by using micronized compounds, and appropriate vehicle containing suspension stabilizing agents, thickeners and emulsifiers like carboxymethylcellulose and salts thereof, polyacrylic acid and salts thereof, carboxyvinyl polymers and salts thereof, alginic acid and salts thereof, propylene glycol alginate, chitosan, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, N-vinylacetamide polymer, polyvinyl methacrylate, polyethylene glycol, pluronic, gelatin, methyl vinyl ether-maleic anhydride copolymer, soluble starch, pullulan and a copolymer of methyl acrylate and 2-ethylhexyl acrylate lecithin, lecithin derivatives, propylene glycol fatty acid esters, glycerin fatty acid esters
  • materials may be incorporated into the matrix of the tablet e.g. hydroxypropyl methylcellulose, ethyl cellulose or polymers of acrylic and metacrylic acid esters. These latter materials may also be applied to tablets by compression coating.
  • compositions can be prepared by mixing a therapeutically effective amount of the active substance with a pharmaceutically acceptable carrier that can have different forms, depending on the way of administration.
  • Pharmaceutical compositions can be prepared by using conventional pharmaceutical excipients and methods of preparation.
  • the forms for oral administration can be capsules, powders or tablets where usual solid vehicles including lactose, starch, glucose, methylcellulose, magnesium stearate, di-calcium phosphate, mannitol may be added, as well as usual liquid oral excipients including, but not limited to, ethanol, glycerol, and water. All excipients may be mixed with disintegrating agents, solvents, granulating agents, moisturizers and binders.
  • compositions e.g., starch, sugar, kaolin, binders disintegrating agents
  • preparation can be in the form of powder, capsules containing granules or coated particles, tablets, hard gelatin capsules, or granules without limitation, and the amount of the solid carrier can vary (between 1 mg to lg). Tablets and capsules are the preferred oral composition forms.
  • compositions containing the compounds of the present invention may be in any form suitable for the intended method of administration, including, for example, a solution, a suspension, or an emulsion.
  • Liquid carriers are typically used in preparing solutions, suspensions, and emulsions.
  • Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof.
  • the liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like.
  • Suitable organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols.
  • Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like.
  • the carrier can also be an oily ester such as ethyl oleate, isopropyl myristate, and the like.
  • Compositions of the present invention may also be in the form of microparticles, microcapsules, liposomal encapsulates, and the like, as well as combinations of any two or more thereof.
  • Examples of pharmaceutically acceptable disintegrants for oral compositions useful in the present invention include, but are not limited to, starch, pre-gelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, alginates, resins, surfactants, effervescent compositions, aqueous aluminum silicates and crosslinked polyvinylpyrrolidone.
  • binders for oral compositions useful herein include, but are not limited to, acacia; cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose or hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane resin, alginates, magnesium-aluminum silicate, polyethylene glycol or bentonite.
  • acacia cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose or hydroxyethylcellulose
  • gelatin glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xant
  • Examples of pharmaceutically acceptable fillers for oral compositions include, but are not limited to, lactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (particularly microcrystalline cellulose), dihydro- or anhydro- calcium phosphate, calcium carbonate and calcium sulfate.
  • Examples of pharmaceutically acceptable lubricants useful in the compositions of the invention include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, and colloidal silicon dioxide.
  • suitable pharmaceutically acceptable flavourings for the oral compositions include, but are not limited to, synthetic aromas and natural aromatic oils such as extracts of oils, flowers, fruits (e.g., banana, apple, sour cherry, peach) and combinations thereof, and similar aromas. Their use depends on many factors, the most important being the organoleptic acceptability for the population that will be taking the pharmaceutical compositions.
  • suitable pharmaceutically acceptable dyes for the oral compositions include, but are not limited to, synthetic and natural dyes such as titanium dioxide, beta-carotene and extracts of grapefruit peel.
  • Suitable examples of pharmaceutically acceptable sweeteners for the oral compositions include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose and sucrose.
  • Suitable examples of pharmaceutically acceptable buffers include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate and magnesium hydroxide.
  • Suitable examples of pharmaceutically acceptable surfactants include, but are not limited to, sodium lauryl sulfate and polysorbates.
  • Suitable examples of pharmaceutically acceptable preservatives include, but are not limited to, various antibacterial and antifungal agents such as solvents, for example ethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternary ammonium salts, and parabens (such as methyl paraben, ethyl paraben, propyl paraben, etc.).
  • solvents for example ethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternary ammonium salts, and parabens (such as methyl paraben, ethyl paraben, propyl paraben, etc.).
  • Suitable examples of pharmaceutically acceptable stabilizers and antioxidants include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), thiourea, tocopherol and butyl hydroxyanisole.
  • EDTA ethylenediaminetetraacetic acid
  • thiourea thiourea
  • tocopherol thiourea
  • butyl hydroxyanisole ethylenediaminetetraacetic acid
  • the compounds of the invention may also, for example, be formulated as suppositories e.g., containing conventional suppository bases for use in human or veterinary medicine or as pessaries e.g., containing conventional pessary bases.
  • the compounds according to the invention may be formulated for topical administration, for use in human and veterinary medicine, in the form of ointments, creams, gels, hydrogels, lotions, solutions, shampoos, powders (including spray or dusting powders), pessaries, tampons, sprays, dips, aerosols, drops ⁇ e.g., eye ear or nose drops) or pour- ons.
  • the compounds of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • mineral oil liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • compositions may also contain other pharmaceutically acceptable excipients, such as polymers, oils, liquid carriers, surfactants, buffers, preservatives, stabilizers, antioxidants, moisturizers, emollients, colorants, and flavourings.
  • pharmaceutically acceptable polymers suitable for such topical compositions include, but are not limited to, acrylic polymers; cellulose derivatives, such as carboxymethylcellulose sodium, methylcellulose or hydroxypropylcellulose; natural polymers, such as alginates, tragacanth, pectin, xanthan and cytosan.
  • the compounds of the present invention can be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g., a hydrofluoroalkane such as 1,1,1,2- tetrafluoroethane (HFA 134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), or a mixture thereof.
  • a suitable propellant e.g., a hydrofluoroalkane such as 1,1,1,2- tetrafluoroethane (HFA 134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), or a mixture thereof.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g., using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g., sorbitan trioleate.
  • a lubricant e.g., sorbitan trioleate.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds according to the invention may be delivered for use in human or veterinary medicine via a nebulizer.
  • compositions of the invention may contain from 0.01 to 99% weight per volume of the active material.
  • the composition will generally contain from 0.01-10%, more preferably 0.01-1% of the active compound.
  • a therapeutically effective amount of the compounds of the present invention can be determined by methods known in the art.
  • the therapeutically effective quantities will depend on the age and on the general physiological condition of the subject, the route of administration and the pharmaceutical formulation used.
  • the therapeutic doses will generally be between about 1 and 2000 mg/day, 5 and 2000 mg/day, 10 and 2000 mg/day and suitably between about 30 and 1500 mg/day. Other ranges may be used, including, for example, 50-500 mg/day, 50-300 mg/day, 50-100 mg/day, 100-200 mg/day, 5-100 mg/day, 5-50 mg/day.
  • the daily dose as employed for acute or chronic human treatment will range from 0.01 to 250 mg/kg body weight, suitably 0.1-5 mg/kg body weight, suitably 0.1-10 mg/kg body weight, suitably 2-100 mg/kg body weight, or suitably 5-60 mg/kg body weight, which may be administered in one to four daily doses, for example, depending on the route of administration and the condition of the subject.
  • each unit will contain 1 mg to 2 g of active ingredient, suitably 10 mg to 2 g of active ingredient, suitably 200 mg to 1 g of active ingredient, suitably 5 to 300 mg of active ingredient.
  • Administration may be once a day, twice a day, or more often, and may be decreased during a maintenance phase of the disease or disorder, e.g. once every second or third day instead of every day or twice a day.
  • the dose and the administration frequency will depend on the clinical signs with the reduction or absence of at least one or more, preferably more than one, clinical signs of the acute phase known to the person skilled in the art.
  • administration is once daily oral dosing.
  • the present invention provides a combination comprising a) the compound of Formula (I) or a pharmaceutically acceptable salt thereof and b) one or more further therapeutically active agents.
  • compositions comprising a combination as defined above together with one or more pharmaceutically acceptable carriers thereof represent a further aspect of the invention.
  • ⁇ NMR spectra were recorded in either CDCI 3 or DMSO-d6 on a Bruker DPX 400 MHz.
  • the internal standard used was the residual protonated solvent at 7.26 ppm for CDCI3 or 2.49 ppm for DMSO-d6.
  • UV detection range 210 to 350nm
  • Mass spectrum Recorded on a mass spectrometer using alternative-scan positive and negative mode electrospray ionization
  • Solvents A: 0.1% v/v formic acid in water
  • UV detection range 210 to 350nm
  • Mass spectrum Recorded on a mass spectrometer using alternative-scan positive and negative mode electrospray ionization
  • Solvents A: 0.02% v/v trifluoroacetic acid in water
  • the reaction mixture was evaporated to dryness.
  • the crude (6.5 g) was purified by flash- chromatography (150 g Si02, eluting with a gradient Cy:EtOAc 60:40 to 40:60), to obtain 1.2 g of the desired product [l,3-benzothiazol-5-yl(methoxy)methylidene]propanedinitrile with a purity of 80% and other 541 mg of contaminated product (50% purity).
  • NIH-3T3 cells mouse endothelial fibroblasts used as host-cells in the T. cruzi intracellular assay were made available by GSK-Biological Reagents and Assay Development Department (BRAD, Stevenage, UK). Cell line was grown at 37 °C, 5% C02 and >95% humidity, in DMEM (Life-Technologies) supplemented with 10% FBS (Biowest, USA), 100 U/mL penicillin (Sigma-Aldrich), 100 ⁇ g/mL streptomycine (Sigma-Aldrich), and 4 mM L-Glutamine (Sigma-Aldrich).
  • NIH-3T3 cells required for the whole HTS campaign were produced in advance and stored frozen at - 150°C until needed. Freezing medium contained 90% FBS and 10% DMSO and cells were frozen in 5 mL cryo-vials. On average, vials cell density was 1.7x107 cells per mL and the quality control assessment indicated that the percentage of viability was in all cases over 95.5%.
  • H9c2 rat cardiomyocytes
  • ECACC European Cell Cultures Collection
  • Salisbury UK
  • H9c2 rat cardiomyocytes
  • DMEM fetal bovine serum
  • T. cruzi parasites from the Tulahuen strain expressing ⁇ -galactosidase were kindly provided by Dr. Buckner (University of Washington, Seattle, USA; Buckner et al., 1996). Parasites were maintained in culture by weekly infection of LLC-MK2 cells (green monkey kidney epithelial cells, purchased from the European Cell Cultures Collection (ECACC reference 85062804)) in the same DMEM formulation used for cell growth, but supplemented with 2% FBS instead. Trypomastigote forms were obtained from the supernatants of LLC-MK2 infected cultures harvested between days 5 and 9 of infection as described in Bettiol et al (2009) PLoS Negl Trop Dis 3:e384.
  • LLC-MK2 cells green monkey kidney epithelial cells, purchased from the European Cell Cultures Collection (ECACC reference 85062804)
  • Trypomastigote forms were obtained from the supernatants of LLC-MK2 infected cultures harvested between days 5 and 9 of infection as described in Bett
  • trypomastigotes were made in T225 cm 2 flasks (Corning Inc., NY, USA) to ensure an appropriate quantity of parasites for the whole HTS campaign.
  • the number of trypomastigotes per ml. was determined in a Neubauer cell chamber and their density brought to 1x108 trypomastigotes per ml. for freezing purposes, which was accomplished in a 90% FBS, 10% DMSO freezing medium, following standard procedures.
  • the assay developed was adapted from the one previously described by Bettiol et al. (2009) PLoS Negl Trop Dis 3:e384, which had been used in the anti-T. cruzi HTS performed at the Broad Institute (Harvard, USA). Active compounds in this assay format will target intracellular T. cruzi amastigotes growing in NIH-3T3 murine fibroblasts, though to a shorter extent they may also target free swimming trypomastigotes and/or the host-parasite interactions required for the parasite invasion.
  • the assay was set up in 1536-wells tissue culture surface treated plates (Greiner Cat. # 782092).
  • the biological reagents consisted of NIH-3T3 host cells and trypomastigotes parasitic cells, thawed and straight forwardly mixed at a 1: 1 (v:v) ratio.
  • both cell types were set to a 3.3x105 cells/mL dilution in assay DMEM by means of a CASY cell counter device (Roche-Applied Science) using a 60 ⁇ capillary.
  • 6 ⁇ _ of the mixture were dispensed per well (about 1x103 host-cells and 1x103 parasites) with a Multidrop Combi liquid handling apparatus (Thermo Scientific). Beforehand, a 1.67x105 trypomastigotes per ml.
  • H9c2 cells (rat cardiomyocytes) were seeded in T-225 flasks (225 cm2 culture surface; Corning Inc., NY, USA) in DMEM-10% FBS for 4 hours to allow attachment. Cells were then washed once with PBS before infection. T. cruzi trypomastigotes, collected at days 5 to 8 after infection, from LLC-MK2 parasite infected cultures, were allowed to swim out for 4 hours at 37°C from a centrifuged pellet (2,500 rpm/10 min/room temperature). Trypomastigotes were then collected and counted in a CASY Cell Counter (Roche- Applied-Science).
  • Trypomastigotes in supplemented DMEM, were added to H9c2 cultures in a multiplicity of infection (MOI) of 1 and incubated for 18 hours. Cells were washed once with PBS before incubation of the infected H9c2 monolayer with trypsin (Life- Technologies) to detach cells from the flask. Cells were counted in a CASY Cell Counter (Roche-Applied-Science) using a 150 ⁇ capillary and their density set at 5x104 cells per ml. in supplemented assay DMEM. Infected H9c2 cells were dispensed into the 384 wells ⁇ Oear bottom, Poly-Lysine coated plate (Greiner, Cat.
  • Example 1 The compounds of Example 1 and 2 had the following activity:

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/EP2015/073365 2014-10-10 2015-10-09 Benzothiazole derivative useful in the treatment of chagas disease WO2016055607A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP14382386 2014-10-10
EP14382386.2 2014-10-10

Publications (1)

Publication Number Publication Date
WO2016055607A1 true WO2016055607A1 (en) 2016-04-14

Family

ID=51790658

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2015/073365 WO2016055607A1 (en) 2014-10-10 2015-10-09 Benzothiazole derivative useful in the treatment of chagas disease

Country Status (3)

Country Link
AR (1) AR102215A1 (es)
UY (1) UY36350A (es)
WO (1) WO2016055607A1 (es)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009074812A1 (en) * 2007-12-13 2009-06-18 Prolysis Ltd Antibacterial condensed thiazoles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009074812A1 (en) * 2007-12-13 2009-06-18 Prolysis Ltd Antibacterial condensed thiazoles

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MERCEDES GONZÁLEZ ET AL: "Novel compounds to combat trypanosomatid infections: a medicinal chemical perspective", EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 21, no. 5, 1 May 2011 (2011-05-01), pages 699 - 715, XP055211988, ISSN: 1354-3776, DOI: 10.1517/13543776.2011.565334 *
PADRÓ J M ET AL: "Development of an ionic liquid-based dispersive liquid-liquid microextraction method for the determination of nifurtimox and benznidazole in human pl", TALANTA, ELSEVIER, AMSTERDAM, NL, vol. 107, 5 January 2013 (2013-01-05), pages 95 - 102, XP028578417, ISSN: 0039-9140, DOI: 10.1016/J.TALANTA.2012.12.050 *

Also Published As

Publication number Publication date
UY36350A (es) 2016-06-01
AR102215A1 (es) 2017-02-15

Similar Documents

Publication Publication Date Title
ES2218617T3 (es) Cromanos sustituidos con sulfonamida, procedimiento para su preparacion, su uso como medicamento o agente de diagnostico, asi como medicamentos que los contienen.
JP6697808B2 (ja) 感覚有毛細胞の死を防ぐまたは処置するための化合物と方法
JP2022078094A (ja) Ｏｌｉｇ２活性の阻害
US8822519B2 (en) Compound with agitation effect on peroxisome proliferator-activated receptor process for its preparation and use thereof
US20240300943A1 (en) Novel salts of heterocyclic compound as protein kinase inhibitor and uses thereof
TWI859480B (zh) Sarm1酶活性抑制劑及其在神經退行性疾病中的應用
TW201718590A (zh) 化合物
JP2008526949A (ja) 新規の抗マラリア薬９ａ−カルバモイル−アミノアルキルおよび９ａ−チオカルバモイル−アミノアルキルアザライド
CN104926804B (zh) 一类具有抗肿瘤作用的化合物、其制备方法和用途
EP3520795B1 (en) Composition comprising combination of trh analog with arundic acid, and pharmaceutically acceptable salt of arundic acid
WO2016055607A1 (en) Benzothiazole derivative useful in the treatment of chagas disease
US8809555B2 (en) Anti-leishmanial compound and anti-leishmanial drug
CN113527153A (zh) 一类抑制肠道炎症反应的活性化合物
TW201625543A (zh) 羥吡啶酮衍生物，其醫藥組合物，及其用於發炎性、神經退化性或免疫媒介疾病之治療用途
CN112778156A (zh) 双酰肼结构类化合物、其制备方法及其应用
US11345682B2 (en) Polymorph of HDAC6-selective inhibitor and application thereof
CN109721557A (zh) 来曲唑晶ii型固体物质及制备方法和其药物组合物与用途
CN113072562B (zh) 一种GSK-3β抑制剂及其制备方法与应用
US20240368105A1 (en) 2-diarylmethyl-4-aminotetrahydropyran derivatives and related compounds as anticancer, antiinflammatory, antifibrotic and neuroprotective agents
CN112390846B (zh) 一种抗肿瘤药物的晶型及其制备方法
CN110452168B (zh) N-苯基-n-喹啉羧酸类化合物及其制法和药物用途
DK153760B (da) Analogifremgangsmaade til fremstilling af estre af 2-thenoylmercaptopropionylglycin
CN106397411B (zh) 5-羟色胺受体激动剂及其制备方法和用途
CN117320701A (zh) 一种降低肝脏中甘油三酯合成的方法
CN112480104A (zh) 硝唑尼特衍生物及其医药用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15778309

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15778309

Country of ref document: EP

Kind code of ref document: A1