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WO2022107167A1 - Composés hétérocycliques bicycliques pour le traitement de la tuberculose - Google Patents

Composés hétérocycliques bicycliques pour le traitement de la tuberculose Download PDF

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Publication number
WO2022107167A1
WO2022107167A1 PCT/IN2021/051081 IN2021051081W WO2022107167A1 WO 2022107167 A1 WO2022107167 A1 WO 2022107167A1 IN 2021051081 W IN2021051081 W IN 2021051081W WO 2022107167 A1 WO2022107167 A1 WO 2022107167A1
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Prior art keywords
compound
pharmaceutically acceptable
stereoisomer
arh
acceptable salt
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PCT/IN2021/051081
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English (en)
Inventor
Gangireddy Sujeevan REDDY
Rebecca Kristina EDWIN
Parimal Misra
Manojit Pal
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Dr Reddy's Institute Of Life Sciences
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Publication of WO2022107167A1 publication Critical patent/WO2022107167A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • C07D405/06—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 linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to bicyclic heterocyclic compounds and their uses, particularly as inhibitors of chorismate mutase (CM).
  • CM chorismate mutase
  • Tuberculosis or TB is a common and infectious lung disease generally caused by the bacteria called Mycobacterium tuberculosis (MTB). Roughly, 25% of the world population is assumed to be infected by TB. Indeed, TB remained one of the leading causes of death worldwide due to (i) the extended duration (6-9 months) of treatment, (ii) higher prevalence of (multi or extensive) drug resistance, (iii) comorbidity with HIV- AIDS and (iv) decreased interest/effort in anti -infective drug research.
  • MTB Mycobacterium tuberculosis
  • CM chorismate mutase or CM (EC 5.4.99.5) that catalyzes the Claisen rearrangement of chorismate to prephenate is considered as an attractive target for the identification of effective antibacterial agents due to its absence in animals but not in bacteria.
  • researchers have been focused to develop potential inhibitors of CM for the treatment of TB.
  • the present invention provides bicyclic heterocyclic compounds as inhibitors of CM.
  • the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,
  • R 1 at each occurrence, is independently selected from hydrogen, alkyl, acyl, hydroxy, halo, haloalkyl, and nitro;
  • R 2 at each occurrence, is independently selected from hydrogen, alkyl, hydroxy, halo, haloalkyl, and -CO2R 5 ;
  • R 3 and R 4 each independently is alkyl
  • R 5 is hydrogen or alkyl; m is 1 to 4; n is 1 to 6; and p is 1 to 4.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present invention provides a method of treating a disease or condition in a subject wherein inhibition of CM provides a benefit.
  • the method comprises administering a therapeutically effective amount of a compound of formula (I) to the subject in need thereof.
  • the present invention also provides a method of treating a subject infected with tuberculosis comprising administering to the subject a therapeutically effective amount of the compound of Formula (I).
  • an element means one element or more than one element.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon that may be substituted or unsubstituted. In certain embodiments, the alkyl is C 1 -C 6 alkyl. Examples of “alkyl” include, but are not limited, to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, isobutyl and the likes thereof.
  • acyl refers to the group defined as -C(O)R, wherein R is a substituted or unsubstituted alkyl, or aryl.
  • R is a substituted or unsubstituted alkyl, or aryl.
  • alkyl and aryl as described herein.
  • Examples of acyl groups include, but are not limited to, acetyl, propanoyl, butanoyl and benzoyl.
  • aryl refers to optionally substituted unsaturated or partially saturated aromatic ring system having five to ten carbon atoms which are monocyclic, bicyclic, or polycyclic and may optionally be replaced by one or more hetero atoms selected from N, O and S.
  • exemplary aryl groups include phenyl, naphthyl, indanyl, biphenyl and the likes thereof.
  • haloalkyl refers to an alkyl group substituted by one or more halo groups, wherein the alkyl and halo are same as defined herein.
  • hydroxyalkyl include, but are not limited to fluoromethyl, difluoromethyl trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • the term 'compound(s)' comprises the compounds disclosed in the present invention.
  • compounds of the present invention or “compound(s) of the disclosure” refers to compounds of formula (I), (IA) and/or (IB) as herein defined, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their enantiomers, their appropriate N-oxides, their pharmaceutically acceptable salts, their pharmaceutically acceptable hydrates, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • halo or halogen refers to fluorine, chlorine, bromine, or iodine.
  • hydroxy or "hydroxyl” refers to -OH group.
  • nitro refers to -NO2 group.
  • the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
  • “optionally substituted alkyl” refers to the alkyl may be substituted as well as the event or circumstance where the alkyl is not substituted.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” refers to the salts of the compounds, that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Such salts include: salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, 2- dimethylaminoethanol, isopropylamine, morpholine, piperazine, piperidine, procaine, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, spermidine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine
  • Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, and the likes thereof.
  • “Pharmaceutically acceptable solvates” may be hydrates or comprising other solvents of crystallization such as alcohols.
  • prevents refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
  • prevent also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
  • the term “tuberculosis” refers to the disease or condition caused by an infection in a subject of one or more species of the Mycobacterium tuberculosis complex.
  • the term “tuberculosis” includes latent tuberculosis (LTBI), non-drug resistant tuberculosis, multiple drug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XRD-TB).
  • latent tuberculosis includes an infection of a subject caused by one or more species of Mycobacterium tuberculosis complex but where the subject does not necessarily exhibit symptoms a tuberculosis disease.
  • non-drug resistant tuberculosis includes tuberculosis caused by an infection by one or more species of the Mycobacterium tuberculosis complex that exhibits no antibacterial resistance to standard tuberculosis therapy.
  • multiple drug resistant tuberculosis (MDR TB) includes tuberculosis caused by an infection by of one or more species of the Mycobacterium tuberculosis complex that is resistant to two or more anti- TB drugs such as rifampicin and isoniazid.
  • XDR-TB expressly drug resistant tuberculosis
  • tuberculosis caused by an infection by one or more species of the Mycobacterium tuberculosis complex that is resistant to rifampicin and isoniazid, plus any member of the quinolone family, and is also resistant to at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin).
  • the tuberculosis infection is acute.
  • the tuberculosis infection is chronic.
  • R 7 and R 8 together with the nitrogen they are attached with, form a 4 to 8 membered ring which can be substituted or unsubstituted.
  • the substituents in the aforementioned "substituted” groups cannot be further substituted.
  • the substituent on “substituted alkyl” is "substituted aryl”
  • the substituent on “substituted aryl” cannot be "substituted alkenyl".
  • stereoisomer or “stereoisomers” refers to any enantiomers, diastereomers or geometrical isomers of the compounds of formula (I), (IA), or (IB), wherever they are chiral or when they bear one or more double bond.
  • compounds of the formula (I) and related formulae are chiral, they can exist in racemic or in optically active form. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as -isomers and /-isomers and mixtures thereof.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds of the present invention may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • E Electronic Data
  • Z data isomers
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.
  • Different polymorphs of a compound of formula (I), (IA) and/or (IB) of present invention may be prepared by crystallization of the corresponding compound of formula (I), (IA) and/or (IB) under different conditions. For example, making use of commonly used solvents or their mixtures for recrystallization, crystallization at different temperature ranges, different cooling techniques like very fast to very slow cooling during crystallization procedure, by exposing to room temp, by heating or melting the compound followed by gradual cooling and the like.
  • the presence of polymorphs may be determined by one or more methods like solid probe NMR spectroscopy, DSC, TGA, Powder X-Ray diffraction and IR.
  • terapéuticaally effective amount refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
  • treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein, R 1 , at each occurrence, is independently selected from hydrogen, alkyl, acyl, hydroxy, halo, haloalkyl, and nitro;
  • R 2 at each occurrence, is independently selected from hydrogen, alkyl, hydroxy, halo, haloalkyl, and -CO2R 5 ;
  • R 3 and R 4 each independently is alkyl; R 5 is hydrogen or alkyl; m is 1 to 4; n is 1 to 6; and p is 1 to 4.
  • the compound of formula (I) is a compound of formula (IA): or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein R 1 , R 2 , m, n and p are same as defined in formula (I). In certain embodiments, the compound of formula (I) is a compound of formula
  • R 1 at each occurrence, in the compound of formula (I), (IA) and/or (IB), or a pharmaceutically acceptable salt or a stereoisomer thereof, is selected from hydrogen, alkyl, acyl, halo and nitro.
  • R 1 at each occurrence, is independently selected from hydrogen and alkyl.
  • alkyl is C 1 -C 6 alkyl.
  • R 1 is methyl.
  • R 1 at each occurrence, is independently selected from hydrogen and acyl.
  • acyl is acetyl.
  • R 1 at each occurrence, is independently selected from hydrogen and nitro. In further embodiments, R 1 is hydrogen.
  • R 1 at each occurrence, is independently selected from hydrogen and halo.
  • halo at each occurrence, is bromo or chloro.
  • n in the compound of formula (I), (IA) and/or (IB), or a pharmaceutically acceptable salt or a stereoisomer thereof, is 1 to 4. In further embodiments, m is 1. In some instances, m is 2.
  • n, in the compound of formula (I), (IA) and/or (IB), or a pharmaceutically acceptable salt or a stereoisomer thereof is 1 to 6. In further embodiments, n is 1. In some instances, n is 2.
  • m is 1 or 2 and n is 1 or 2.
  • R 2 at each occurrence, in the compound of formula (I) and/or (IA) or a pharmaceutically acceptable salt or a stereoisomer thereof, is hydrogen. In some embodiments, R 2 is halo.
  • R 3 in the compound of formula (I) and/or (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof, is alkyl. In further embodiments, R 3 is C 1 -C 6 alkyl. In some instances, R 3 is propyl.
  • R 4 in the compound of formula (I) and/or (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof, is alkyl. In further embodiments, R 4 is C 1 -C 6 alkyl. In some instances, R 4 is methyl.
  • the compounds of formula (I), (IA) and/or (IB) are inhibitors of CM.
  • the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention and their uses.
  • Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H ("D"), 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 35 S, 18 F, 36 C1, 123 I and 125 I.
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.
  • the present invention provides a compound selected from:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula (I), (IA) and/or (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more pharmaceutically acceptable excipients or carriers or diluents.
  • the pharmaceutical composition comprises at least one compound of formula (I), (IA) and/or (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof, an anti-tuberculosis drug and a pharmaceutically acceptable carrier.
  • the anti-tuberculosis drug is selected from a group comprising amikacin, bedaquiline, capreomycin, contezolid, cycloserine, delamanid, delpazolid, ethambutol, ethionamide, isoniazid, kanamycin, levofloxacin, macozinone, moxifloxacin, ofloxacin, para-aminosalicylic acid, pretomanid, prothionamide, pyrazinamide, rifabutin, rifampicin or streptomycin, tilezolid terizidone, and thionamide.
  • the present invention provides a pharmaceutical composition comprising the compound of formula (I), for use in treating a subject suffering from a disease or condition associated with aberrant activity of CM.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compounds described in the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier or enclosed within a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • the compounds of the present invention may be used as single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials.
  • the compounds of the invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention.
  • the pharmaceutical composition of the present invention comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents, and the like.
  • a pharmaceutically acceptable carrier can contain pharmaceutically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
  • pharmaceutically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • carbohydrates such as glucose, sucrose or dextrans
  • antioxidants such as ascorbic acid or glutathione
  • chelating agents such ascorbic acid or glutathione
  • low molecular weight proteins or other stabilizers or excipients include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable carrier, including a pharmaceutically acceptable agent depends, for example, on the route of administration of the composition.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, pharmaceutically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • the pharmaceutical composition can be administered by oral, parenteral or inhalation routes.
  • parenteral administration include administration by injection, percutaneous, transmucosal, intranasal and transpulmonary administrations.
  • suitable carriers include, but are not limited to, sterile water, salt solutions, sugar, alcohols, polyethylene glycols, olive oil, peanut oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid esters, fatty acid amines, fatty acid monoglycerides and diglycerides, and polyoxyethylene.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, preserving agents, sweetening agents, wetting agents, suspending agents, buffers, flavouring agents, colorants, or any combination of the foregoing.
  • compositions may be in conventional forms, for example, tablets, capsules, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
  • Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition can be carried out using any of the accepted routes of administration of pharmaceutical compositions.
  • the route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular or topical.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as a compound of the invention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • Compositions or compounds may also be administered as a bolus, electuary or paste.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
  • Solid oral formulations may contain, along with the active compound, lubricants, diluents, binding agents, disintegrating agents, wetting agents, preservatives, and in general, non-toxic, pharmacologically inactive substances used in pharmaceutical compositions.
  • the formulations may contain, lubricants, for example, calcium stearate, magnesium stearate, stearic acid, talc, silica or polyethylene glycols; diluents, for example, cellulose, sucrose, powdered sugar, com starch, lactose, dextrose saccharose, dry starch, potato starch, mannitol, sorbitol, inositol, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate and mixtures thereof; binding agents, for example, Arabic gum, carboxymethylcellulose, gelatin methylcellulose, polyvinyl pyrrolidone or starches; disintegrating agents, for example, alginic acid, alginates, starch or starch glycolate; wetting agents, for example, lecithin, laurylsulphates or polysorbates; preservatives, for example, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozo
  • Excipients such as cocoa butter, suppository waxes, colouring agents, coating agents, sweeteners, flavouring agents and perfuming agents may also be present in the composition.
  • Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.
  • Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
  • compositions of the present invention may be prepared by conventional techniques known in literature.
  • Suitable doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present invention.
  • the preset invention provides a method of treating a subject infected with tuberculosis or Mycobacterium infection comprising administering to the subject a therapeutically effective amount of the compound of the present invention.
  • the tuberculosis infection is latent, active, drugresistant, extensively drug-resistant, or multi-drug resistant.
  • the infected subject is afflicted with pulmonary tuberculosis or extrapulmonary tuberculosis.
  • the method further comprises administering an amount of an anti-tuberculosis drug to the subject.
  • the anti-tuberculosis drug is as described above.
  • the method wherein the amount of the compound and the amount of the anti-tuberculosis drug when taken together may be more effective to treat the tuberculosis or Mycobacterium infection than the anti-tuberculosis drug alone.
  • the subject is a mammal such as a human or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • the aqueous solution is pyrogen-free or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues, or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, and lyophile for reconstitution, powder, solution, syrup, suppository, injection, or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15
  • the present invention relates to a compound or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.
  • the present invention further provides use of compound(s) of the present invention for the manufacture of a medicament.
  • the disclosure provides use of a compound of the present invention, or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for use in treating a subject of a condition, disease or disorder responsive to inhibition of the CM.
  • the condition, disease, or disorder is tuberculosis.
  • the present invention provides a method of treating a condition, disease, or disorder in a subject, wherein inhibition of CM provides a benefit, comprising administering a therapeutically effective amount of a compound of formula (I), (IA) and/or (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof, to the subject in need thereof.
  • the disease or disorder is tuberculosis.
  • the present invention provides a method of treating or preventing TB in a subject, comprising administering a therapeutically effective amount of a compound of formula (I), (IA) and/or (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof to the subject in need thereof.
  • the present invention also provides a process for the preparation of the compounds of formula (I) are set forth in the below Examples and/or generalized Scheme.
  • Scheme can be adapted to produce the compounds of general formula (I) and pharmaceutically acceptable salts or stereo isomers of compounds of general formula (I) according to the present invention.
  • a compound of formula P is coupled with a compound of formula Q in presence of a suitable palladium catalyst such as (PPh 3 )PdCl 2 and optionally in the presence of a copper (I) cocatalyst (such as Cui) in a base such as Et 3 N, and optionally in a suitable solvent to yield a compound of formula (I).
  • a suitable palladium catalyst such as (PPh 3 )PdCl 2
  • a copper (I) cocatalyst such as Cui
  • a base such as Et 3 N
  • the triazinone derivative (O) was prepared by treating the corresponding 4- amino- 1 -methyl-3-propyl- 17/-pyrazole-5-carboxamide or 2-aminobenzamide derivative with NaNCL and HC1 according to the known procedure (F. Chang et al., Synthesis and nematicidal activities of l,2,3-benzotriazin-4-one derivatives containing thiourea and acylthiourea against meloidogyne incognita, Bioorganic & Medicinal Chemistry Letters 27 (2017) 2641-2644).
  • MtbCM Mycobacterium tuberculosis chorismate mutase gene was PCR amplified and cloned into expression vector pET22b. MtbCM was purified from over expressed culture of BL21 (DE3) harboring pET22b/ MtbCM by Ni-NTA affinity chromatography. The substrate chorismic acid was obtained from Sigma (SIGMA cat # 1701).
  • CM chorismate mutase
  • the reaction volume of the assay was maintained at 100 pl.
  • the substrate chorismic acid (2 mM) was pre incubated at 37 °C for 5 min in the buffer containing 50 mM Tris-HCl (pH 7.5), 0.5 mM EDTA, 0.1 mg/ml bovine serum albumin, and 10 mM ⁇ -mercaptoethanol.
  • the reaction was started by adding 180 pmol of CM enzyme to the pre-warmed chorismic acid solution.
  • CM [A274 ⁇ S + (E’ + C) ⁇ - A274 (S + C)] / [A274 (S + E) - A274 (S)]

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de formule (I), ou un sel pharmaceutiquement acceptable ou un stéréoisomère de celui-ci, le cycle A, R1, m et n étant tels que définis dans la description. La présente invention concerne également des compositions comprenant de tels composés, l'utilisation de tels composés et des procédés de traitement d'un état, d'une maladie ou d'un trouble à l'aide de tels composés et/ou compositions.
PCT/IN2021/051081 2020-11-18 2021-11-18 Composés hétérocycliques bicycliques pour le traitement de la tuberculose WO2022107167A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4296674A1 (fr) 2022-06-20 2023-12-27 Université Toulouse III - Paul Sabatier Molécules innovantes réduisant la virulence des mycobactéries pour le traitement de la tuberculose

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
K. SHIVA KUMAR ET AL.: "Cu-mediated N-arylation of 1,2,3-triazin-4-ones: Synthesis of fused triazinone derivatives as potential inhibitors of chorismate mutase", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, 2012, pages 1146 - 1150, XP029121679, DOI: 10.1016/j.bmcl. 2011.11.09 6 *
KUNAL ROY ; SOMNATH PAUL: "Docking and 3D QSAR studies of protoporphyrinogen oxidase inhibitor 3H-pyrazolo[3,4-d][1,2,3]triazin-4-one derivatives", JOURNAL OF MOLECULAR MODELING, SPRINGER, DE, vol. 16, no. 1, 19 June 2009 (2009-06-19), DE , pages 137 - 153, XP019805718, ISSN: 0948-5023 *
REYNOLDS, R. C. ET AL.: "High throughput screening of a library based on kinase inhibitor scaffolds against Mycobacterium tuberculosis H37Rv", TUBERCULOSIS, vol. 92, no. 1, 2012, pages 72 - 83, XP002729986, DOI: 10.1016/j.tube. 2011.05.00 5 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4296674A1 (fr) 2022-06-20 2023-12-27 Université Toulouse III - Paul Sabatier Molécules innovantes réduisant la virulence des mycobactéries pour le traitement de la tuberculose

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