WO2016034971A1 - Dérivés sulfonamides utilisés en tant qu'inhibiteurs d'urat1 - Google Patents

Dérivés sulfonamides utilisés en tant qu'inhibiteurs d'urat1 Download PDF

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WO2016034971A1
WO2016034971A1 PCT/IB2015/056321 IB2015056321W WO2016034971A1 WO 2016034971 A1 WO2016034971 A1 WO 2016034971A1 IB 2015056321 W IB2015056321 W IB 2015056321W WO 2016034971 A1 WO2016034971 A1 WO 2016034971A1
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compound according
pharmaceutically acceptable
formula
compounds
compound
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PCT/IB2015/056321
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English (en)
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Robert Mckenzie Owen
Robert Ian Storer
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Pfizer Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached

Definitions

  • the invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes.
  • Uric acid is the final product of purine metabolism in humans. In humans, unlike many other animals, uric acid is not further broken down, but is predominantly (70%) excreted into the urine with the remaining 30% excreted in faeces. Hyperuricemia is defined as an excessive production or decreased excretion of uric acid and can occur as an overproduction or under excretion of serum uric acid (sUA), or a combination of the both. Renal under excretion of uric acid is the primary cause of hyperuricemia in about 90% of cases, while overproduction is the cause in less than 10%.
  • Increased sUA concentration above 6.8mg/dl_ results in crystallisation of uric acid in the form of salts, such as monosodium urate, and to precipitation of these crystals in joints, on tendons and in the surrounding tissues. These crystals (known as tophi) trigger a local immune- mediated inflammatory reaction, leading to gout.
  • the risk of gout increases with increased sUA levels.
  • Gout is a painful condition that can present in a number of ways, although the most usual is a recurrent attack of acute inflammatory arthritis (a red, tender, hot, swollen joint) often occurring in big toes, heels, knees, wrists and fingers.
  • Gout is treated by agents to both decrease the cause and effects of uric acid crystal inflammation and pain.
  • the pain associated with gout is commonly treated with pain and anti-inflammatory drugs such as nonsteroidal anti-inflammatory drugs (NSAI Ds), colchicine and steroids.
  • Agents that decrease sUA levels may be used to treat the cause of gout. These include agents that: inhibit the enzymes that result in uric acid production, such as xanthine oxidase inhibitors (e.g. allopurinol, febuxostat or tisopurine), or purine nucleoside phosphorylase (PNP) inhibitors (e.g. ulodesine); metabolise uric acid, such as urate oxidases - also known as uricases (e.g.
  • xanthine oxidase inhibitors e.g. allopurinol, febuxostat or tisopurine
  • PNP purine nucleoside phosphorylase
  • metabolise uric acid such as urate oxidases -
  • Uricosurics include agents that inhibit the transporters responsible for renal reabsorption of uric acid back into the blood, such as benziodarone, isobromindione, probenecid and sulphinpyrazone, and URAT1 inhibitors (e.g. benzbromarone).
  • URAT1 is also known as solute carrier family 22 (organic anion/cation transporter), member 12, and is encoded by the gene SLC22A12. Human genetic analysis has demonstrated that polymorphisms in the SLC22A12 gene are directly associated with changes in serum uric acid. Inhibitors of uric acid transport, such as URAT1 , are therefore effective in the treatment of gout.
  • URAT1 inhibitors for the treatment of gout are known.
  • WO201 1/159840 discloses phenylthioacetate URAT1 inhibitors.
  • WO2008/1 18758, WO2009/012242, WO2010/079443, WO2012/004706, WO2012/004714 and WO2012/004743 disclose sulphonamides.
  • WO2013/057722 discloses the use of a certain sulphonamide derivative for the treatment of gout. There is, however, an ongoing need to provide new URAT1 inhibitors that are good drug candidates.
  • preferred compounds should have one or more of the following properties: be well absorbed from the gastrointestinal tract; be metabolically stable; have a good metabolic profile, in particular with respect to the toxicity or allergenicity of any metabolites formed; or possess favourable pharmacokinetic properties whilst still retaining their activity profile as URAT1 inhibitors. They should be non-toxic and demonstrate few side-effects. Ideal drug candidates should exist in a physical form that is stable, non-hygroscopic and easily formulated.
  • each -CF 3 may be attached at any available carbon atom of the respective phenyl or pyridinyl ring.
  • E 1 Described below are a number of embodiments (E 1) of this first aspect of the invention, where for convenience E1 .1 is identical thereto.
  • E1 .3 The compound according to either E1.1 or E1 .2 that is 2-(trifluoromethyl)-N-(6- (trifluoromethyl)pyridin-3-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof.
  • E1 .4 The compound according to either E1.1 or E1 .2 that is 2-(trifluoromethyl)-N-(5- (trifluoromethyl)pyridin-3-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof. According to a second aspect of the invention there is provided a compound of formula (I)
  • each R 1 is independently: halogen; OH; CN; (C 1 -C 4 )alkyl optionally substituted by one, two or three F; or (C 1 -C 4 )alkyloxy optionally substituted by one, two or three F;
  • X 1 is phenyl or pyridinyl, wherein said phenyl or pyridinyl is substituted on a ring carbon atom by one, two or three R 2 ; each R 2 is independently: halogen; OH; CN; (C 1 -C 4 )alkyl optionally substituted by one, two or three F; (C 1 -C 4 )alkyl substituted by OH; (C 1 -C 4 )alkyloxy optionally substituted by one, two or three F; -O(CH 2 ) n (C 3 -C 4 )cycloalkyl; -CON R 3 R 4 ; or -SO 2 R 5 ; each R 3 and R 4 is independently H or (C 1 -C 4 )alkyl or, together with the nitrogen atom to which they are attached, form a saturated 4- to 6-membered nitrogen containing monocycle; each R 5 is independently (C 1 -C 4 )alkyl optionally substituted by one, two
  • E2 Described below are a number of embodiments (E2) of this second aspect of the invention, where for convenience E2.1 is identical thereto.
  • each R is independently: halogen; (C 1 -C 4 )alkyl optionally substituted by one, two or three F; (C 1 -C 4 )alkyloxy optionally substituted by one, two or three F; -OCH 2 (C 3 -C 4 )cycloalkyl or-O(CH 2 ) 2 (C 3 -C 4 )cycloalkyl.
  • each R is independently: halogen; (C 1 -C 4 )alkyl optionally substituted by one, two or three F; or (C 1 -C 4 )alkyloxy optionally substituted by one, two or three F.
  • E2.4 A compound according to E2.1 or a pharmaceutically acceptable salt thereof for use as a medicament wherein X 1 is phenyl substituted on a ring carbon atom by one, two or three R 2 .
  • E2.5 A compound according to E2.4 or a pharmaceutically acceptable salt thereof for use as a medicament wherein X 1 is phenyl substituted on a ring carbon atom by two or three R 2 .
  • E2.6 A compound according to either E2.1 or E2.4 of formula (Ic)
  • each R 2 is independently: halogen; CN; (C 1 -C 4 )alkyl optionally substituted by one, two or three F; (C 1 -C 4 )alkyloxy optionally substituted by one, two or three F; -CONR 3 R 4 ; or -SO 2 R 5 ; each R 3 and R 4 is independently H or (C 1 -C 4 )alkyl; and each R 5 is independently (C 1 -C 4 )alkyl optionally substituted by one, two or three F.
  • each R 2 is independently: F; CI; CN ; (C 1 -C 4 )alkyl optionally substituted by one, two or three F; (C 1 -C 4 )alkyloxy optionally substituted by one, two or three F; -CONH 2 ;-CONHCH 3 ; or -CON(CH 3 ) 2 .
  • E2.10 A compound according to any one of E2.1 to E2.9 or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder for which a URAT1 inhibitor is indicated.
  • AlkyI and alkoxy groups containing the requisite number of carbon atoms, can be unbranched or branched.
  • alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.
  • alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.
  • cycloalkyl examples include cyclopropyl and cyclobutyl.
  • Halo means fluoro, chloro, bromo or iodo.
  • references to compounds of the invention include compounds of formula (I) or pharmaceutically acceptable salts, solvates, or multi-component complexes thereof, or pharmaceutically acceptable solvates or multi-component complexes of pharmaceutically acceptable salts of compounds of formula (I), as discussed in more detail below.
  • Preferred compounds of the invention are compounds of formula (I) or pharmaceutically acceptable salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, ste
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • the skilled person will appreciate that the aforementioned salts include ones wherein the counterion is optically active, for example d-lactate or l-lysine, or racemic, for example dl-tartrate or dl-arginine.
  • compositions of formula (I) may be prepared by one or more of three methods:
  • 'hydrate' is employed when said solvent is water.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, de- acetone and d 6 -DMSO.
  • a currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995), incorporated herein by reference.
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • the compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid.
  • Such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition').
  • 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks.
  • Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').
  • multi-component complexes other than salts and solvates of compounds of formula (I) or pharmaceutically acceptable salts thereof wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts.
  • Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt.
  • Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference.
  • Chem Commun 17, 1889-1896
  • O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference.
  • the compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions.
  • the mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution).
  • Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'.
  • the compounds of the invention may be administered as prodrugs.
  • prodrugs certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design' , Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
  • Prodrugs can, for example, be produced by replacing appropriate functionalities present in a compound of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).
  • prodrugs examples include phosphate prodrugs, such as dihydrogen or dialkyl (e.g. di-tert- butyl) phosphate prodrugs. Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
  • metabolites of compounds of formula (I) that is, compounds formed in vivo upon administration of the drug.
  • Some examples of metabolites in accordance with the invention include, where the compound of formula (I) contains a phenyl (Ph) moiety, a phenol derivative thereof (-Ph > -PhOH);
  • Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Included within the scope of the invention are all stereoisomers of the compounds of the invention and mixtures of one or more thereof.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1 - phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1 - phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • chromatography typically HPLC
  • a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine.
  • the scope of the invention includes all crystal forms of the compounds of the invention, including racemates and racemic mixtures (conglomerates) thereof. Stereoisomeric conglomerates may also be separated by the conventional techniques described herein just above.
  • the scope of the invention includes all pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l , nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of the invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • Substitution with heavier 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.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • intermediate compounds as hereinafter defined, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined hereinbefore for compounds of formula (I).
  • the invention includes all polymorphs of the aforementioned species and crystal habits thereof.
  • the compounds of the invention may be prepared by any method known in the art for the preparation of compounds of analogous structure.
  • the compounds of the invention can be prepared by the procedures described by reference to the Schemes that follow, or by the specific methods described in the Examples, or by similar processes to either.
  • the skilled person will appreciate that it may be necessary or desirable at any stage in the synthesis of compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions.
  • it may be necessary or desirable to protect amino or carboxylic acid groups.
  • the protecting groups used in the preparation of the compounds of the invention may be used in conventional manner. See, for example, those described in 'Greene's Protective Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, fourth edition, (John Wiley and Sons, 2006), in particular chapter 7 ("Protection for the Amino Group"), incorporated herein by reference, which also describes methods for the removal of such groups.
  • compounds of formula (I) may be prepared from compounds of formula (II) and (III) as illustrated by Scheme 1 .
  • Compounds of formula (I) may be prepared by coupling compounds of formula (II) and (III) according to process step (i).
  • the sulphonamide formation reaction may be carried out under basic reaction conditions either with or without DMAP.
  • Preferred conditions comprise DMAP in anhydrous pyridine at from 30-60 °C; NMM or triethylamine in a combination of organic solvents such as DCM, THF, DME and DCE; stirring in a single solvent such as anhydrous pyridine or acetonitrile; or lithium hexamethyldisilazide in THF at from 4 °C to room temperature.
  • compounds of formula (I) wherein R 1 is para-F may be intercon verted into the corresponding compounds of formula (I) wherein R 1 is (C 1 -C 4 )alkyloxy or OH as illustrated by Scheme 2, wherein R 6 is (C 1 -C 4 )alkyl, H or a hydroxyl protecting group, such as 2-(methylsulfonyl)ethyl.
  • the interconversion may be effected according to process step (ii), an aromatic nucleophilic substitution reaction followed by, if necessary, process step (iii), a deprotection reaction.
  • Preferred process step (ii) conditions comprise potassium phosphate in DMSO at 80 °C.
  • preferred process step (ii) conditions comprise sodium hydride in NM P at room temperature, followed by deprotection according to process step (iii) by stirring in HCI in dioxane.
  • R 6 is a hydroxyl protecting group, such as 2-(methylsulfonyl)ethyl
  • this may be removed under the acid deprotection conditions of process step (iii) to afford R 1 as OH.
  • R 6 is a hydroxyl protecting group, such as 2-(methylsulfonyl)ethyl
  • this protecting group may also be effected under the conditions described in Scheme 2, process step (iii).
  • compounds of formula (I) wherein R 2 is nitrile may be interconverted to the corresponding compounds of formula (I) wherein R 2 is primary carboxamide by an oxidative hydrolysis reaction.
  • Preferred conditions comprise potassium carbonate and hydrogen peroxide in DMSO at room temperature.
  • excipients may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention together with one or more pharmaceutically acceptable excipients.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).
  • Suitable modes of administration include oral, parenteral, topical, inhaled/intranasal, rectal/intravaginal, and ocular/aural administration.
  • Formulations suitable for the aforementioned modes of administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays, liquid formulations and buccal/mucoadhesive patches.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt- granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets", Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6, 106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in "Pharmaceutical Technology On-line", 25(2), 1 -14, by Verma et al (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intra urethra I, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug- coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.
  • PGLA poly(dl-lactic-coglycolic)acid
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 , 1 , 1 ,2-tetrafluoroethane or 1 , 1 , 1 ,2,3,3,3- heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ to 1 00 ⁇ .
  • a typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 ⁇ g to 100mg of the compound of formula (I).
  • the overall daily dose will typically be in the range 1 ⁇ g to 200mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, microbicide, vaginal ring or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH- adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non- biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • Drug-cyclodextrin complexes for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser.
  • the total daily dose of the compounds of the invention is typically in the range 1 mg to 10g, such as 10mg to 1 g, for example 25mg to 500mg depending, of course, on the mode of administration and efficacy.
  • oral administration may require a total daily dose of from 50mg to 100mg.
  • the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • the compounds of the invention are useful because they exhibit pharmacological activity in animals, i.e. , URAT1 inhibition. More particularly, the compounds of the invention are of use in the treatment of disorders for which a URAT1 inhibitor is indicated.
  • the animal is a mammal, more preferably a human.
  • a compound of the invention for use as a medicament.
  • a compound of the invention for the treatment of a disorder for which a URAT1 inhibitor is indicated is indicated.
  • a method of treating a disorder in an animal comprising administering to said animal a therapeutically effective amount of a compound of the invention.
  • disorders for which a URAT1 inhibitor is indicated include diseases associated with high levels of uric acid in humans and other mammals including (but not limited to) hyperuricemia, asymptomatic hyperuricemia, gout (including juvenile forms), gouty arthritis, inflammatory arthritis, joint inflammation, deposition of urate crystals in the joint, tophaceous gout, chronic kidney disease, nephrolithiasis (kidney stones), Lesch- Nyhan syndrome and Kelley-Seegmiller syndrome.
  • Hyperuricemia may be defined by blood uric acid levels over 6.8 mg/dL. Guidelines for the management of hyperuricemia recommend that therapies aimed at lowering blood uric acid levels should be maintained until such blood uric acid levels are lowered to below 6.0 mg/dL, such as below 5.0 mg/dL.
  • asymptomatic hyperuricemia may nevertheless lead to the onset of diseases associated with high levels of uric acid.
  • the compounds of formula (I) may be used in the treatment of hyperuricemia where this is present together with one or more other diseases, such as kidney failure, type 2 diabetes, cardiovascular disease (e.g. hypertension, myocardial infarction, heart failure, coronary artery disease, cerebrovascular disease, atherosclerosis, angina, aneurism, hyperlipidemia and stroke), obesity, metabolic syndrome, myeloproliferative disorders, lymphoproliferative disorders and disorders associated with certain medications, such as a diuretic (e.g. a thiazide), an immunosuppressant (e.g. a cyclosporine therapy), a chemotherapeutic agent (e.g. cisplatin) or aspirin.
  • a diuretic e.g. a thiazide
  • an immunosuppressant e.g. a cyclosporine therapy
  • a URAT1 inhibitor may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of a disease associated with elevated blood uric acid levels.
  • Such combinations offer the possibility of significant advantages, including patient compliance, ease of dosing and synergistic activity.
  • the compound of the invention may be administered simultaneously, sequentially or separately in combination with the other therapeutic agent or agents.
  • the compounds of formula (I) may be administered in combination with one or more additional therapeutic agents.
  • Agents of interest include those that also lower blood uric acid levels.
  • Other agents of interest include those that reduce inflammation or pain.
  • the one or more additional therapeutic agents may be selected from any of the agents or types of agent that follow:
  • a xanthine oxidase inhibitor e.g. allopurinol, febuxostat or tisopurine
  • PNP purine nucleoside phosphorylase
  • a uricase e.g. pegloticase or rasburicase
  • a uricosuric such as an agent that inhibits one or more transporters responsible for reabsorption of uric acid back into the blood at renal or intestinal sites, for example another URAT1 inhibitor (e.g. benzbromarone, PN2107 or RDEA3170); a glucose transporter (GLUT) inhibitor, such as a GLUT9 inhibitor; an organic anion transporter (OAT) inhibitor, such as an OAT4 inhibitor or an OAT10 inhibitor; or an agent which inhibits one or more of the above transporters, such as benziodarone; isobromindione, probenecid, sulphinpyrazone, arhalofenate, tranilast, lesinurad or KUX-1 151 ; an agent that otherwise exerts blood uric acid lowering effects, such as amlodipine, atorvastatin, fenofibrate or indomethacin;
  • another URAT1 inhibitor e.g. benzbromarone, PN2107 or RDEA3170
  • an anti-inflammatory drug such as an NSAI D (e.g. celecoxib), colchicine, a steroid, an interleukin 1 inhibitor (e.g. rilonacept) or an agent that modulates inflammosome signaling cascades (e.g. an I RAK4 inhibitor); or
  • an NSAI D e.g. celecoxib
  • colchicine e.g. a steroid
  • interleukin 1 inhibitor e.g. rilonacept
  • an agent that modulates inflammosome signaling cascades e.g. an I RAK4 inhibitor
  • an agent that reduces pain such as an ion channel modulator (e.g. an inhibitor of Nav1.7, TRPV1 or TRPM2).
  • an ion channel modulator e.g. an inhibitor of Nav1.7, TRPV1 or TRPM2.
  • a compound of the invention together with one or more additional therapeutic agents which slow down the rate of metabolism of the compound of the invention, thereby leading to increased exposure in patients.
  • Increasing the exposure in such a manner is known as boosting.
  • This has the benefit of increasing the efficacy of the compound of the invention or reducing the dose required to achieve the same efficacy as an unboosted dose.
  • the metabolism of the compounds of the invention includes oxidative processes carried out by P450 (CYP450) enzymes, particularly CYP 3A4 and conjugation by U DP glucuronosyl transferase and sulphating enzymes.
  • agents that may be used to increase the exposure of a patient to a compound of the present invention are those that can act as inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzymes.
  • the isoforms of CYP450 that may be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4.
  • Suitable agents that may be used to inhibit CYP 3A4 include ritonavir, saquinavir, ketoconazole, N-(3,4-difluorobenzyl)-N-methyl-2- ⁇ [(4- methoxypyridin-3-yl)amino]sulfonyl ⁇ benzamide and N-(1 -(2-(5-(4-fluorobenzyl)-3- (pyridin-4-yl)-1 H-pyrazol-1-yl)acetyl)piperidin-4-yl)methanesulfonamide.
  • kits suitable for coadministration of the compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the invention provides a pharmaceutical product (such as in the form of a kit) comprising a compound of the invention together with one or more additional therapeutically active agents as a combined preparation for simultaneous, separate or sequential use in the treatment of a disorder for which a URAT1 inhibitor is indicated.
  • °C is degrees celcius
  • CDCI 3 is deutero-chloroform
  • DCE is dichloroethane
  • DCM is dichloromethane; methylene chloride;
  • DEA diethylamine
  • DMAP is dimethylaminopyridine
  • DME is dimethoxyethane
  • DMSO dimethyl sulphoxide
  • EtOAc is ethyl acetate
  • g is gram
  • HCI is hydrochloric acid
  • HPLC high pressure liquid chromatography
  • L is litre
  • m is multiplet
  • M is molar
  • MeCN is acetonitrile
  • MeOH is methanol
  • MHz is mega Hertz
  • MS m/z is mass spectrum peak
  • NaHCO 3 is sodium hydrogencarbonate
  • NaOH sodium hydroxide
  • NH 3 or NH 4 OH is ammonia or ammonium hydroxide
  • NMR nuclear magnetic resonance
  • pH is power of hydrogen
  • ppm is parts per million
  • py is pyridine
  • Rt is retention time
  • t is triplet
  • TBME is tert-butyl dimethyl ether
  • TEA is triethylamine
  • TFA is trifluoroacetic acid
  • THF is tetrahydrofuran
  • ⁇ L is microlitre
  • ⁇ m ⁇ is micromol
  • Preparative HPLC Method A Phenomenex Gemini C18 250 x 21 .2 mm, 8 ⁇ m; mobile phase A: MeCN, mobile phase B: 0.225% formic acid in water. Gradient time 10 mins; flow rate 30 mL/min.
  • Preparative HPLC Method B YMC-Actus Triart C18 150 x 30 mm, 5 ⁇ m; mobile phase A: MeCN, mobile phase B: 0.225% formic acid in water. Gradient time 10 mins; flow rate 30 mL/min.
  • LCMS Method A XBRI DGE 50 x 2.1 mm, 5 ⁇ m; mobile phase A: 0.0375% TFA in water; mobile phase B: 0.01875% TFA in MeCN; gradient from 1 % B to 5% B at 0.60 mins, further to 100% B at 4.00 mins and finally returning to 1 % B at 4.30-4.70 mins; flow rate 0.8 mL/min.
  • LCMS Method B XBRI DGE 50 x 2.1 mm, 5 ⁇ m; mobile phase A: 0.0375% TFA in water; mobile phase B: 0.01875% TFA in MeCN; gradient from 10% B to 100% B at 4.00 mins and finally returning to 1 % B at 4.30-4.70 mins; flow rate 0.8 mL/min.
  • LCMS Method C XBRI DGE 50 x 2.1 mm, 5 ⁇ m; mobile phase A: 0.05% NH 4 OH in water; mobile phase B: 100% MeCN; gradient from 5% B to 100% B at 3.40 mins, hold at 100% B to 4.20 mins and finally returning to 5% B at 4.21 -4.70 mins; flow rate 0.8 mL/min.
  • Examples 1 -66 were prepared according to the method described for Library Protocol 1 using either 2-(trifluoromethyl)benzenesulfonyl chloride, 2-chlorobenzenesulfonyl chloride or 2-cyanobenzenesulfonyl chloride and the appropriate amine. Where stated the title compounds were isolated as formate salts.
  • R 1 , X 1 and m are as described in formula (I) above.
  • Preparative HPLC Method A Phenomenex Gemini C18 250 x 21 .2 mm, 8 ⁇ m; mobile phase A: MeCN, mobile phase B: 0.225% formic acid in water. Gradient time 8 mins; flow rate 30 mL/min.
  • Preparative HPLC Method B Waters Sunfire C8 150 x 30 mm, 5 ⁇ m; mobile phase A: MeCN, mobile phase B: 0.225% formic acid in water. Gradient time 8 mins; flow rate 40 mL/min.
  • Preparative HPLC Method C DI KMA Diamonsil C18 200 x 25 mm, 5 ⁇ m; mobile phase A: MeCN, mobile phase B: 0.225% formic acid in water. Gradient time 10 mins; flow rate 25 mL/min.
  • Preparative HPLC Method D Agela DuraShell C18 150 x 21.2 mm, 5 ⁇ m; mobile phase A: MeCN, mobile phase B: 0.225% formic acid in water. Gradient time 12 mins; flow rate 25 mL/min. The retention times quoted in the table below were obtained using one of the following two LCMS methods:
  • LCMS Method A XBRI DGE 50 x 2.1 mm, 5 ⁇ m; mobile phase A: 0.05% NH 4 OH in water; mobile phase B: 100% MeCN; gradient from 5% B to 100% B at 3.40 mins, hold at 100% B to 4.20 mins and finally returning to 5% B at 4.21 -4.70 mins; flow rate 0.8 mL/min.
  • LCMS Method B XBRI DGE 50 x 2.1 mm, 5 ⁇ m; mobile phase A: 0.05% NH 4 OH in water; mobile phase B: 100% MeCN; gradient from 1 % B to 100% B at 3.40 mins, hold at 100% B to 4.20 mins and finally returning to 1 % B at 4.21 -4.70 mins; flow rate 0.8 mL/min.
  • Examples 67-129 were prepared according to the method described for Library Protocol 2 using one of the following five amines and the appropriate sulfonyl chloride as described in the table below.
  • Amines 2-aminobenzonitrile, 3-aminobenzonitrile, 2-amino-6-chlorobenzonitrile, 5-amino-2-chlorobenzonitrile and 4-amino-2-chlorobenzonitrile.
  • R 1 and X 1 are as described in formula (I) above.
  • a solution of the appropriate amine (X 1 NH 2 , 100 ⁇ m ⁇ ) in anhydrous pyridine (600 ⁇ L) was added a 1.2M solution of the appropriate sulfonyl chloride in anhydrous pyridine (100 ⁇ L, 120 ⁇ m ⁇ ) followed by DMAP (2 mg, 20 ⁇ m ⁇ ).
  • DMAP 2 mg, 20 ⁇ m ⁇
  • the reaction mixture was shaken at 30°C for 2 hours followed by 60°C for 16 hours before concentrating in vacuo and purifying by one of the four preparative HPLC methods described below.
  • the organic gradient used for each compound is described in the following table.
  • Preparative HPLC Method A Phenomenex Gemini C18 250 x 21 .2 mm, 8 ⁇ m; mobile phase A: MeCN, mobile phase B: 0.225% formic acid in water. Gradient time 8 mins; flow rate 30 mL/min.
  • Preparative HPLC Method B Waters Sunfire C8 150 x 30 mm, 5 ⁇ m; mobile phase A: MeCN, mobile phase B: 0.225% formic acid in water. Gradient time 8 mins; flow rate 40 mL/min.
  • Preparative HPLC Method C YMC-Actus Triart C18 150 x 30 mm, 5 ⁇ m; mobile phase A: MeCN, mobile phase B: 0.225% formic acid in water. Gradient time 9 mins; flow rate 30 mL/min.
  • Preparative HPLC Method D Agela DuraShell C18 150 x 21.2 mm, 5 ⁇ m; mobile phase A: MeCN, mobile phase B: 0.225% formic acid in water. Gradient time 10 mins; flow rate 30 mL/min.
  • LCMS Method A XBRIDGE 50 x 2.1 mm, 5 ⁇ m; mobile phase A: 0.0375%TFA in water; mobile phase B: 0.01875% TFA in MeCN; gradient from 1 % B to 5% B at 0.60 mins, further to 100% B at 4.00 mins and finally returning to 1 % B at 4.30-4.70 mins; flow rate 0.8 mL/min.
  • LCMS Method B XBRIDGE 50 x 2.1 mm, 5 ⁇ m; mobile phase A: 0.0375%TFA in water; mobile phase B: 0.01875% TFA in MeCN; gradient from 10% B to 100% B at 4.00 mins and finally returning to 1 % B at 4.30-4.70 mins; flow rate 0.8 mL/min.
  • LCMS Method C XBRI DGE 50 x 2.1 mm, 5 ⁇ m; mobile phase A: 0.05%NH 4 OH in water; mobile phase B: 100% MeCN; gradient from 5% B to 100% B at 3.40 mins, hold at 100% B to 4.20 mins and finally returning to 5% B at 4.21 -4.70 mins; flow rate 0.8 mL/min.
  • Examples 130-175 were prepared according to the method described for Library Protocol 3 using either 2-cyanobenzensulfonyl chloride or 2-(trifluoromethyl)benzenesulfonyl chloride and the appropriate amine as described below. Where stated the title compounds were isolated as formate salts.
  • Preparative HPLC Method A Boston Symmetrix ODS-H 150 x 30 mm, 5 ⁇ m; mobile phase A: Acetonitrile, mobile phase B: 0.1 % TFA in water. Gradient time 8 mins; flow rate 30 mL/min.
  • Preparative HPLC Method B Kromasil Eternity-5 C18 150 x 30 mm, 5 ⁇ m; mobile phase A: Acetonitrile, mobile phase B: 0.1 % TFA in water. Gradient time 10 mins; flow rate 30 mL/min.
  • LCMS Method A XBRI DGE 50 x 2.1 mm, 5 ⁇ m; mobile phase A: 0.0375% TFA in water; mobile phase B: 0.01875% TFA in MeCN; gradient from 1 % B to 5% B at 0.60 mins, further to 100% B at 4.00 mins and finally returning to 1 % B at 4.30-4.70 mins; flow rate 0.8 mL/min.
  • LCMS Method B XBRI DGE 50 x 2.1 mm, 5 ⁇ m; mobile phase A: 0.0375% TFA in water; mobile phase B: 0.01875% TFA in MeCN; gradient from 10% B to 100% B at 4.00 mins and finally returning to 1 % B at 4.30-4.70 mins; flow rate 0.8 mL/min.
  • Examples 176-184 were prepared according to the method described for Library Protocol 4 using 5-bromopyridin-3-amine and the appropriate sulfonyl chloride as described below. Where stated the title compounds were isolated as trifluoroacetate salts.
  • 6-(Trifluoromethyl)pyridin-3-amine (3.10 g, 19.1 mmol) was dissolved in acetonitrile (80 mL) and the resulting solution was heated to 80°C.
  • a solution of 3,5-dichloro-2- hydroxybenzenesulfonyl chloride (5.00 g, 19.1 mmol) in acetonitrile (20 mL) was added at 80°C and the reaction mixture was stirred at this temperature for 48 hours.
  • the reaction mixture was cooled, and concentrated in vacuo.
  • the residue was treated with 2M NaOH (aq) (100 mL), stirred at room temperature for 5 minutes and filtered.
  • the filtrate was washed with DCM (3 x 50 mL) before acidifying with cHCI.
  • the resulting precipitate was collected and dried under vacuum to afford the title compound as a white solid (3.78 g, 51 %).
  • Examples 207-217 were prepared according to the method indicated (i.e. one of the Methods 3-6 described above) using the appropriate sulfonyl chloride and amine and, where specified and unless otherwise indicated, purified using one of the following Preparative HPLC conditions:
  • Mobile Phase A 0.1 % formic acid in water
  • Mobile phase B 0.1 % formic acid in MeCN Gradient: from 5% B to 95% B at 7 minutes and return to 5% B at 9.1 minutes.
  • reaction mixture was heated at 80°C for 16 hours.
  • reaction mixture was cooled, concentrated in vacuo and purified using preparative HPLC as described below to yield the title compound.
  • Mobile phase A MeCN.
  • Mobile phase B 10 mM ammonium formate in water.
  • LCMS QC Phenomenex Gemini C18 4.6 X 50 mm 5 micron; (Mobile phase A: 0.01 % TFA in water, mobile phase B: 0.01 % TFA in MeCN).
  • Example 220 The title compound was prepared according to the method described for Example 220 using 2-trifluoromethylbenzenesulfonyl chloride and racemic-1 -(6-aminopyridin-2- yl)propan-1 -ol.
  • LCMS QC YMC ODS-AQ 2.0 x 50 mm, 5 micron; (Mobile phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA in MeCN).
  • the nucleotide sequence for the long isoform of URAT1 was C-terminally fused to that of enhanced green fluorescent protein (eGFP) (hereinafter referred to as URATI (L)GFP).
  • eGFP enhanced green fluorescent protein
  • the combined sequence was codon-optimised and custom synthesized.
  • the synthesized sequence was generated in pDON R221 Gateway entry vector (Invitrogen Life Technologies) prior to cloning in pLenti6.3/V5 Gateway destination vector (Invitrogen Life Technologies).
  • a schematic of the URAT1 (L)GFP construct follows.
  • the nucleotide and amino acid sequence of the URAT1 (L)GFP construct is set out below, which also shows alignment of the nucleotide sequence with NM_144585.
  • Alignment row 1 is the sequence from accession NM_144585.
  • Alignment row 2 is the sequence of the construct in the Gateway destination vector pLenti6.3V5/DEST (encoding URATI (L)GFP) with the nucleotide alignment indicated with NM_144585 above and the nucleotide numbering below.
  • Alignment row 3 is the amino acid translation with sequence annotation indicated in italics below.
  • Lentiviral particles were generated according to ViraPower HiPerform expression system procedure (Invitrogen Life Technologies) and used to transduce CHO cells. Blasticidin selection enabled the generation of a stable clonal pool of cells, confirmed by expression of GFP and V5 epitope.
  • the clonal pools were sorted using fluorescence- activated cell sorting (FACS) on the basis of GFP expression with the gating set at the top 50% of expression into single cells which were subsequently expanded to generate clonal lines.
  • FACS fluorescence- activated cell sorting
  • One clone was identified with the best assay performance as determined by maximal separation between complete inhibition of uric acid transport (with 10 ⁇ benzbromarone) and no inhibition (DMSO). This cell line was used for all screening activities and is referred to as CHO-URAT1 (L)GFP#8 or CHO#8.
  • the potency of the compounds of formula (I) as inhibitors of the URAT1 transporter was determined as follows.
  • CHO#8 cells were cultured in cell line maintenance flasks in medium consisting of Dulbecco's modified Eagle medium (DMEM) with high glucose and sodium pyruvate (4.5 g of glucose per litre, Invitrogen Life Technologies), supplemented with heat- inactivated foetal bovine serum (FBC, 10 % v/v), 1x NEAA (non-essential amino acids) and blasticidin (10 ⁇ g/ml). Cultures were grown in 175 cm 2 tissue culture flasks in a humidified incubator at approximately 37°C in approximately 95% air/5% CO 2 . Near confluent CHO#8 cell cultures were harvested by trypsinisation, re-suspended in culture medium and the process was repeated once or twice weekly to provide sufficient cells for use.
  • DMEM Dulbecco's modified Eagle medium
  • FBC heat- inactivated foetal bovine serum
  • FBC heat- inactivated foetal bovine serum
  • 1x NEAA non-essential amino
  • Assay ready flasks were generated by the same method, except the cells were not cultured in blasticidin. Assay ready frozen cells were generated by freezing 40,000,000 cells in 1 ml of FBS (without blasticidin) containing 10% DMSO per vial. One vial was sufficient for 5 assay plates. Each vial was thawed rapidly to 37°C, washed and re-suspended in pre- warmed culture medium for seeding onto assay plates. CHO#8 cells were seeded onto CytostarTM 96-well plates at a density of 5 x 10 5 cells per well. The cells were cultured for 1 day at approximately 37°C in a humidified incubator containing approximately 5% CO 2 in air. After approximately 24 hours culture, cells were used for uptake experiments.
  • chloride-containing buffer 136.7 mM NaCI, 5.36 mM KCI, 0.952 mM CaCI 2 , 0.441 mM KH 2 PO 4 , 0.812 mM MgSO 4 , 5.6 mM D-glucose, 0.383 mM Na 2 HPO 4 .2H 2 O, 10 mM HEPES, pH 7.4 with NaOH.
  • the cells were pre-incubated with another 50 ⁇ L of chloride-containing buffer for one hour at approximately 37°C in a humidified incubator containing approximately 5% CO 2 in air.
  • Assay compound plates were prepared by diluting the compounds of formula (I) with chloride-free buffer (125 mM Na-gluconate, 4.8 mM K-gluconate, 1 .3 mM Ca-gluconate, 1 .2 mM KH 2 PO 4 , 1 .2 mM MgSO 4 , 5.6 mM D-glucose, 25 mM HEPES, pH 7.4 with NaOH) in 100% DMSO to a final concentration of 1 % DMSO.
  • chloride-free buffer 125 mM Na-gluconate, 4.8 mM K-gluconate, 1 .3 mM Ca-gluconate, 1 .2 mM KH 2 PO 4 , 1 .2 mM MgSO 4 , 5.6 mM D-glucose, 25 mM HEPES, pH 7.4 with NaOH
  • [ 14 C]-Uric acid working stock was made by addition of radiolabeled compound to a final concentration of 120
  • the final assay concentration of solvent (DMSO) was 0.25%; the final assay concentration of [ 14 C]-uric acid was 30nM in chloride-free buffer and the final compound of formula (I) concentrations ranged from 0 to 10 ⁇ .
  • the vehicle comparator was DMSO (i.e. no inhibition of uric acid transport) and the pharmacological blockade (i.e. 100% inhibition of uric acid transport) was defined by ⁇ final assay concentration. After pre-incubation, cells were washed with 50 ⁇ L of chloride-free buffer and another 50 ⁇ L of chloride-free buffer was added.

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Abstract

L'invention concerne des dérivés sulfonamides, leur utilisation en médecine, des compositions les contenant, leurs procédés de préparation et des intermédiaires utilisés dans de tels procédés. Plus particulièrement, l'invention concerne un inhibiteur sulfonamide d'URAT1 de formule (I), ou un sel pharmaceutiquement acceptable de celui-ci, destiné à être utilisé en tant que médicament, dans laquelle R1, X1 et m sont tels que définis dans la description, et certains nouveaux inhibiteurs sulfonamides d'URAT1. Les inhibiteurs d'URAT1 sont potentiellement utiles pour le traitement d'un large éventail de troubles, notamment la goutte.
PCT/IB2015/056321 2014-09-04 2015-08-20 Dérivés sulfonamides utilisés en tant qu'inhibiteurs d'urat1 WO2016034971A1 (fr)

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CN109251184A (zh) * 2017-07-13 2019-01-22 浙江海正药业股份有限公司 一种2-三氟甲基苯磺酰胺类衍生物的医药用途
CN111943957A (zh) * 2019-05-17 2020-11-17 中国医学科学院药物研究所 喹啉甲酰胺类化合物及其制备方法和用途
CN115561367A (zh) * 2022-11-09 2023-01-03 山东海雅医药科技有限公司 痛风药物有关物质的高效液相色谱检测方法

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109251184A (zh) * 2017-07-13 2019-01-22 浙江海正药业股份有限公司 一种2-三氟甲基苯磺酰胺类衍生物的医药用途
CN109251184B (zh) * 2017-07-13 2021-06-15 浙江海正药业股份有限公司 一种2-三氟甲基苯磺酰胺类衍生物的医药用途
CN111943957A (zh) * 2019-05-17 2020-11-17 中国医学科学院药物研究所 喹啉甲酰胺类化合物及其制备方法和用途
CN115561367A (zh) * 2022-11-09 2023-01-03 山东海雅医药科技有限公司 痛风药物有关物质的高效液相色谱检测方法

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