WO2010142934A1 - Dérivés d'indole en tant que ligands des récepteurs crth2 - Google Patents

Dérivés d'indole en tant que ligands des récepteurs crth2 Download PDF

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WO2010142934A1
WO2010142934A1 PCT/GB2009/050671 GB2009050671W WO2010142934A1 WO 2010142934 A1 WO2010142934 A1 WO 2010142934A1 GB 2009050671 W GB2009050671 W GB 2009050671W WO 2010142934 A1 WO2010142934 A1 WO 2010142934A1
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fluoro
acetic acid
ylmethyl
methylindol
solution
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PCT/GB2009/050671
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English (en)
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George Hynd
John Gary Montana
Harry Finch
Rosa Arienzo
Shahadat Ahmed
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Pulmagen Therapeutics (Asthma) Limited
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Priority to PCT/GB2009/050671 priority Critical patent/WO2010142934A1/fr
Publication of WO2010142934A1 publication Critical patent/WO2010142934A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to a group of indole compounds, which are ligands of the CRTH2 receptor (Chemoattractant Receptor-homologous molecule expressed on T Helper cells type 2), and their use in the treatment of diseases responsive to modulation of CRTH2 receptor activity, principally diseases having a significant inflammatory component.
  • the invention also relates to novel members of that class of ligands and pharmaceutical compositions containing them.
  • Mast cells are known to play an important role in allergic and immune responses through the release of a number of mediators, such as histamine, leukotrienes, cytokines, prostaglandin D 2 , etc (Boyce; Allergy Asthma Proc, 2004, 25, 27-30).
  • Prostaglandin D 2 is the major metabolite produced by the action of cyclooxygenase on arachadonic acid by mast cells in response to allergen challenge (Lewis et al; J. Immunol., 1982, 129, 1627-1631 ). It has been shown that PGD 2 production is increased in patients with systemic mastocytosis (Roberts; N. Engl. J. Med., 1980, 303, 1400-1404), allergic rhinitis (Naclerio et al; Am. Rev. Respir. Dis., 1983, 128, 597-602; Brown et al; Arch. Otolarynol.
  • PGD 2 mediates it effects through two receptors, the PGD 2 (or DP) receptor (Boie et al; J. Biol. Chem., 1995, 270, 18910-18916) and the chemoattractant receptor-homologous molecule expressed on Th2 (or CRTH2) (Nagata et al; J. Immunol., 1999, 162, 1278-1289; Powell; Prostaglandins Luekot. Essent. Fatty Acids, 2003, 69, 179-185). Therefore, it has been postulated that agents that antagonise the effects of PGD 2 at its receptors may have beneficial effects in a number of disease states.
  • the CRTH2 receptor has been shown to be expressed on cell types associated with allergic inflammation, such as basophils, eosinophils, and Th2-type immune helper cells (Hirai et al; J. Exp. Med., 2001 , 193, 255-261).
  • the CRTH2 receptor has been shown to mediate PGD 2 -mediated cell migration in these cell types (Hirai et al; J. Exp. Med., 2001 , 193, 255-261), and also to play a major role in neutrophil and eosinophil cell recruitment in a model of contact dermatitis (Takeshita et al; Int. Immunol., 2004, 16, 947-959).
  • Transgenic mice over expressing PGD 2 synthase exhibit an enhanced pulmonary eosinophilia and increased levels of Th2 cytokines in response to allergen challenge (Fujitani et al, J. Immunol., 2002, 168, 443-449).
  • exogenously administered CRTH2 agonists enhance the allergic response in sensitised mice (Spik et al; J. Immunol., 2005, 174, 3703-3708).
  • rats exogenously applied CRTH2 agonists cause a pulmonary eosinophilia but a DP agonist (BW 245C) or a TP agonist (I-BOP) showed no effect (Shirashi et al; J. Pharmacol.
  • CRTH2 antagonists may have valuable properties for the treatment of diseases mediated by PGD 2 .
  • Ramatroban a number of other CRTH2 antagonists have been described. Examples include: indole acetic acids (WO2008/012511 ; WO2007/065684; WO2007/045867; WO2006/034419; WO2005/094816; WO2005/044260; WO2005/040114; WO2005/040112; GB2407318;
  • X is -SO 2 - or * -SO 2 NR 3 - wherein the bond marked with an asterisk is attached to Ar 1 ;
  • R 1 is hydrogen, fluoro, chloro, CN or CF 3 ;
  • R 2 is hydrogen, fluoro or chloro;
  • R 3 is hydrogen, d-Csalkyl or C 3 -C 7 cycloalkyl;
  • Ar 1 is phenyl or a 5- or 6-membered heteroaryl group selected from furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, wherein the phenyl or heteroaryl groups are optionally substituted by one or more substituents independently selected from fluoro, chloro, CN, C 3 -C 7 cycloalkyl, -O(C r C 4 alkyl) or d-Cealkyl, the latter two groups being optionally substituted by one or more fluoro atoms;
  • Ar 2 is phenyl or 5- or 6-membered heteroaryl group selected from pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazo
  • the present invention provides a group of specific compounds falling within the scope of, but not specifically disclosed in our copending application PCT/GB2008/004107 referred to above.
  • the invention provides a compound selected from the group consisting of
  • Compounds with which the invention is concerned are CRTH2 receptor antagonists, but they may also have beneficial effects at other prostanoid receptors, such as the PGD 2 receptor or the thromboxane A 2 receptor.
  • the compounds of the invention may be prepared or recovered in the form of salts, and in some cases as ⁇ /-oxides, hydrates, and solvates thereof.
  • the invention also includes (i) use of a compound with which the invention is concerned for the treatment of, or in the manufacture of a medicament for use in, the treatment of conditions responsive to modulation of CRTH2 receptor activity, and (ii) a method of treatment of conditions responsive to modulation of CRTH2 receptor activity, comprising administering to a patient suffering such disease an effective amount of a compound with which the invention is concerned.
  • Examples of conditions responsive to modulation of CRTH2 receptor activity include asthma, rhinitis, allergic airway syndrome, allergic rhinobronchitis, bronchitis, chronic obstructive pulmonary disease (COPD), nasal polyposis, sarcoidosis, farmer's lung, fibroid lung, cystic fibrosis, chronic cough, conjunctivitis, atopic dermatitis, Alzheimer's disease, amyotrophic lateral sclerosis, AIDS dementia complex, Huntington's disease, frontotemporal dementia, Lewy body dementia, vascular dementia, Guillain-Barre syndrome, chronic demyelinating polyradiculoneurophathy, multifocal motor neuropathy, plexopathy, multiple sclerosis, encephalomyelitis, panencephalitis, cerebellar degeneration and encephalomyelitis, CNS trauma, migraine, stroke, rheumatoid arthritis, ankylosing spondylitis, Behget's Disease, bursitis,
  • the compounds with which the invention is concerned are primarily of value for the treatment of asthma, chronic obstructive pulmonary disease, rhinitis, allergic airway syndrome, or allergic rhinobronchitis.
  • Psoriasis, atopic and non- atopic dermatitis Crohn's disease, ulcerative colitis, and irritable bowel disease are other specific conditions where the present compounds may have particular utility.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound with which the invention is concerned in admixture with a pharmaceutically acceptable carrier or excipient.
  • salt includes base addition, acid addition and quaternary salts.
  • Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, for example sodium and potassium hydroxides; alkaline earth metal hydroxides, for example calcium, barium and magnesium hydroxides; with organic bases, for example ⁇ /-methyl-D-glucamine, choline tris(hydroxymethyl) aminomethane, L-arginine, L-lysine, ⁇ /-ethyl piperidine, dibenzylamine and the like.
  • bases such as alkali metal hydroxides, for example sodium and potassium hydroxides; alkaline earth metal hydroxides, for example calcium, barium and magnesium hydroxides; with organic bases, for example ⁇ /-methyl-D-glucamine, choline tris(hydroxymethyl) aminomethane, L-arginine, L-lysine, ⁇ /-ethyl piperidine, dibenzylamine and the like.
  • Specific salts with bases include the piperazine, ethanolamine, benzathine, calcium, diolamine, meglumine, olamine, potassium, procaine, sodium, tromethamine and zinc salts.
  • Those compounds of the invention which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, for example with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids, for example acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p- toluenesuiphonic, benzoic, benzenesulfonic, glutamic, lactic and mandelic acids and the like.
  • hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
  • organic acids for example ace
  • a compound contains a quaternary ammonium group acceptable counter-ions may be, for example chlorides, bromides, sulfates, methanesulfonates, benzenesulfonates, toluenesulfonates (tosylates), napadisylates (naphthalene-1 ,5- disulfonates or naphthalene-1 -(sulfonic acid)-5-sulfonates), edisylates (ethane-1 ,2- disulfonates or ethane-1 -(sulfonic acid)-2-sulfonates), isethionates (2-hydroxyethylsulfonates), phosphates, acetates, citrates, lactates, tartrates, mesylates, maleates, malates, fumarates, succinates, xinafoates, p-acetamidobenzoates and the like; wherein the number of
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • Compounds with which the invention is concerned may exist in one or more stereoisomeric form, because of the presence of asymmetric atoms or rotational restrictions, and in such cases can exist as a number of stereoisomers with R or S stereochemistry at each chiral centre or as atropisomers with R or S stereochemistry at each chiral axis.
  • the invention includes all such enantiomers and diastereoisomers and mixtures thereof.
  • prodrug means a compound that is convertible in vivo by metabolic means (for example, by hydrolysis, reduction or oxidation) to a compound of the invention.
  • an ester prodrug of a compound of the invention may be convertible by hydrolysis in vivo to the parent molecule.
  • esters examples include acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-toluoyl-tartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluene-sulphonates, cyclohexylsulphamates and quinates.
  • ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, 379. Compositions
  • the compounds with which the invention is concerned are CRTH2 receptor antagonists, and are useful in the treatment of diseases, which benefit from such modulation.
  • diseases include asthma, rhinitis, allergic airway syndrome, bronchitis and chronic obstructive pulmonary disease.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trial, as is required in the pharmaceutical art. In general, the daily dose range will lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, often 0.01 mg to about 50 mg per kg, for example 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulfate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • almond oil fractionated coconut oil
  • oily esters such as glycerine, propylene
  • the drug may be made up into a cream, lotion or ointment.
  • Cream or ointment formulations which may be used for the drug, are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
  • the drug may also be formulated for inhalation, for example as a nasal spray, or dry powder or aerosol inhalers.
  • the active compound is preferably in the form of microparticles. They may be prepared by a variety of techniques, including spray-drying, freeze-drying and micronisation. Aerosol generation can be carried out using, for example, pressure-driven jet atomizers or ultrasonic atomizers, preferably using propellant-driven metered aerosols or propellant-free administration of micronized active compounds from, for example, inhalation capsules or other "dry powder" delivery systems.
  • the active ingredient may also be administered parenterally in a sterile medium.
  • the drug can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • Other compounds may be combined with compounds with which the invention is concerned for the prevention and treatment of prostaglandin-mediated diseases.
  • the present invention is also concerned with pharmaceutical compositions for preventing and treating PGD 2 -mediated diseases comprising a therapeutically effective amount of a compound of the invention and one or more other therapeutic agents.
  • Suitable therapeutic agents for a combination therapy with compounds of the invention include, but are not limited to: (1) corticosteroids, such as fluticasone, ciclesonide or budesonide; (2) ⁇ 2-adrenoreceptor agonists, such as salmeterol, indacaterol or formoterol; (3) leukotriene modulators, for example leukotriene antagonists such as montelukast, zafirulast or pranlukast or leukotriene biosynthesis inhibitors such as Zileuton or BAY-1005; (4) anticholinergic agents, for example muscarinic-3 (M3) receptor antagonists such as tiotropium bromide; (5) phosphodiesterase-IV (PDE-IV) inhibitors, such as roflumilast or cilomilast; (6) antihistamines, for example selective histamine-1 (H 1) receptor antagonists, such as fexofenadine, citirizine, loratidine or astem
  • the weight ratio of the compound of the invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the following examples describe the preparation of the compounds of the invention: Examples
  • Mass Spectrometry (LCMS) experiments to determine retention times and associated mass ions were performed using the following methods: Method A: experiments were performed on a Micromass Platform LCT spectrometer with positive ion electrospray and single wavelength UV 254 nm detection using a Higgins Clipeus C18 5 ⁇ m 100 x 3.0 mm column and a 2 mL / minute flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes. The final solvent system was held constant for a further 2 minutes.
  • Method B experiments were performed on a Micromass Platform LC spectrometer with positive and negative ion electrospray and ELS / Diode array detection using a Phenomenex Luna C18 (2) 30 x 4.6 mm column and a 2 mL / minute flow rate.
  • the solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.50 minutes followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 0.50 minutes.
  • Method C experiments were performed on a Waters Micromass ZQ2000 quadrapole mass spectrometer with positive ion and negative ion mode electrospray and single wavelength UV 254 nm detection using a Higgins Clipeus C18 5 ⁇ m 100 x 3.0 mm column and a 1 mL / minute flow rate.
  • the initial solvent system was 85% water containing 0.1% formic acid (solvent A) and 15% methanol containing 0.1 % formic acid (solvent B) for the first minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 12 minutes.
  • the final solvent system was held constant for a further 7 minutes.
  • Method D experiments were performed on a Micromass Platform LC spectrometer with positive and negative ion electrospray and ELS / Diode array detection using a Phenomenex Luna C18 (2) 30 x 4.6 mm column and a 2 mL / minute flow rate.
  • the solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% methanol containing 0.1% formic acid (solvent B) for the first 0.50 minutes followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 0.50 minutes.
  • Method E experiments were performed on a Waters ZMD quadrapole mass spectrometer with an electrospray source operating in positive and negative ion mode and ELS / Diode array detection using a Phenomenex Luna C18(2) 30 x 4.6 mm column and a 2 mL / minute flow rate or equivalent.
  • the solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% methanol containing 0.1 % formic acid (solvent B) for the first 0.50 minutes followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 1 minute.
  • Method F experiments were performed on a Waters Micro triple quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC system with a DAD UV detector.
  • the spectrometer has an electrospray source operating in positive and negative ion mode and DAD/ ELS Additional array detection using a Higgins Clipeus C18 100 x 3.0 mm column and a 1 ml_ / minute flow rate.
  • the solvent system was 85% water containing 0.1 % formic acid (solvent A) and 15% methanol containing 0.1 % formic acid (solvent B) for the first 1.0 minutes followed by a gradient up to 5% solvent A and 95% solvent B over the next 12 minutes. The final solvent system was held constant for a further 7 minutes.
  • Microwave experiments were carried out using a Personal Chemistry Smith SynthesizerTM, which uses a single-mode resonator and dynamic field tuning, both of which give reproducibility and control. Temperatures from 40-250 0 C can be achieved, and pressures of up to 20 bars can be reached. Two types of vial are available for this processor, 0.5-2.0 mL and 2.0-5.0 mL.
  • Reverse-phase preparative HPLC purifications were carried out using Genesis 7 micron C-18 bonded silica stationary phase in columns 10 cm in length and 2 cm internal diameter.
  • the mobile phase used was mixtures of acetonitrile or methanol and water (both buffered with 0.1% v/v trifluoroacetic acid or formic acid) with a flow rate of 10-20 mL per minute and typical gradients of 10 to 90% organic modifier ramped up over 30 to 40 minutes.
  • Fractions containing the required product identified by LCMS analysis
  • Example 1 ⁇ 3-[3-chloro-4- ⁇ pyridine-2-sulfonyl)isothiazol-5-ylmethyl]-5-fluoro- 2-methylindol-1-yl ⁇ acetic acid
  • the reaction mixture was stirred at room temperature for 1.5 hours then concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether, then the aqueous phase was acidified with 1.0 M aqueous hydrochloric acid solution and agitated under reduced pressure for 15 minutes. The resulting precipitate was collected then dissolved in a small amount of acetonitrile and water and freeze-dried to afford the title compound (0.055 g).
  • the aqueous phase was acidified to pH 2 with 1.0 M aqueous hydrochloric acid solution and re-extracted with ethyl acetate and the combined organic extract was dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound.
  • the reaction mixture was stirred at room temperature for 1 hour then the solution was diluted with water and concentrated to low bulk under reduced pressure.
  • the residue was acidified by addition of 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by preparative reverse-phase HPLC and the pure fractions were freeze-dried to afford the title compound (0.021 g) as a white solid.
  • Preparation 12a 4-chloro-5-f1 ,31dioxolan-2-yl-2-methylthiazole
  • 2,4-dichloro-5-[1 ,3]dioxolan-2-ylthiazole (0.50 g) in tetrahydrofuran (20 ml_) at -78 0 C under nitrogen was added dropwise 1.6 M methyl lithium solution in diethyl ether (1.7 ml_).
  • the reaction mixture was stirred for 1 hour then iodomethane (0.41 ml.) was added and stirring continued at -78°C for 1 hour.
  • the reaction was quenched with water then allowed to warm up to room temperature and poured into brine.
  • the crude material was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (0:1 to 1 :0 by volume) to afford the title compound (0.14 g) as a yellow oil.
  • the reaction mixture was stirred for 1 hour then concentrated under reduced pressure.
  • the resultant solution was acidified with 1.0 M aqueous hydrochloric acid solution and was extracted with ethyl acetate. The organic layer was washed with brine then dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as a white solid (0.020 g).
  • reaction mixture was heated at 11O 0 C for 2 hours then a further aliquot of tefra/ ⁇ s(triphenylphosphine)palladium (0.20 g) and 2.0 M solution of trimethylaluminium in toluene (0.5 mL) was added and the reaction mixture stirred at 11O 0 C for 1 hour.
  • the reaction mixture was cooled to 0 0 C then quenched by addition of saturated aqueous sodium sulfate solution. The mixture was filtered and the filtrate was concentrated under reduced pressure.
  • the receptor binding assay is performed in a final volume of 200 ⁇ l_ binding buffer [10 mM BES (pH 7.4), 1 mM EDTA, 10 mM manganese chloride, 0.01% BSA] and 1 nM [ 3 H]-PGD 2 (Amersham Biosciences UK Ltd). Ligands are added in assay buffer containing a constant amount of DMSO (1 % by volume). Total binding is determined using 1% by volume of DMSO in assay buffer and non-specific binding is determined using 10 ⁇ M of unlabeled PGD 2 (Sigma).
  • HEK Human embryonic kidney
  • HEK cell membranes 3.5 ⁇ g expressing the CRTH2 receptor are incubated with 1.5 mg wheatgerm agglutinin SPA beads and 1 nM [ 3 H]-PGD 2 (Amersham Biosciences UK Ltd) and the mixture incubated for 3 hours at room temperature.
  • Bound [ 3 H]-PGD 2 is detected using a Microbeta TRILUX liguid scintillation counter (Perkin Elmer).
  • Compound IC 50 value is determined using a 6-point dose response curve in duplicate with a semi-log compound dilution series. IC 50 calculations are performed using Excel and XLfit (Microsoft), and this value is used to determine a K 1 value for the test compound using the Cheng-Prusoff eguation.
  • the GTP ⁇ S Assay is performed in a final volume of 200 mL assay buffer (20 mM HEPES pH 7.4, 10 mM MgCI 2 , 100 mM NaCI, 10 ⁇ g/mL saponin). DMSO concentrations are kept constant at 1% by volume.
  • Human embryonic kidney (HEK) cell membranes (3.5 ⁇ g) expressing the CRTH2 receptor are incubated with the compounds for 15 min at 3O 0 C prior to addition of PGD 2 (30 nM final concentration) and GTP (10 ⁇ M final concentration). The assay solutions are then incubated for 30 minutes at 3O 0 C, followed by addition of [ 35 S]-GTPyS (0.1nM final concentration).
  • the assay plate is than shaken and incubated for 5 minutes at 3O 0 C. Finally, SPA beads (Amersham Biosciences, UK) are added to a final concentration of 1.5 mg/well and the plate shaken and incubated for 30 minute at 3O 0 C. The sealed plate is centrifuged at 1000 g for 10 mins at 30 0 C and the bound [ 35 S]-GTPyS is detected on Microbeta scintillation counter (Perkin Elmer). Compound IC 50 value is determined using a 6-point dose response curve in duplicate with a semi-log compound dilution series.
  • IC 50 calculations are performed using Excel and XLfit (Microsoft), and this value is used to determine a Ki value for the test compound using the Cheng-Prusoff equation.
  • Biological Results All compounds of the Examples above were tested in the CRTH2 radioligand binding assay described above; the compounds had a K 1 value of less than 500 nM in the binding assay. For example, Examples 1 , 4, 6 and 8 had K, values of 2.1 , 0.8, 0.9 and 16 nM respectively. In the GTP ⁇ S functional assay, Examples 4 and 6, had K, values of less than 1.0 nM.

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Abstract

La présente invention a pour objet les composés suivants qui sont des antagonistes du CRTH2, utiles dans le traitement des maladies respiratoires : l'acide {3-[3-chloro-4-(pyridine-2-sulfonyle) isothiazol-5-ylméthyle]-5-fluoro-2-méthylindol-1-yle} acétique, l'acide [3-(5-benzène sulfonyl-3-méthyl-3H-imidazol-4-ylméthyle)-5-fluoro-2- méthylindol-1-yle] acétique, l'acide [3-(5-benzène sulfonyloxazol-4-ylméthyle)-5-fluoro-2-méthylindol-1-yle] acétique, l'acide [3-(3-benzène sulfonyl-4-méthylthiophèn-2-ylméthyle)-5-fluoro-2-méthylindol-1- yle] acétique, l'acide {5-fluoro-2-méthyl-3-[2-(pyridine-2-ylsulfamoyle) benzyle] indol-1-yle} acétique, l'acide {5-fluoro-2-méthyl-3-[4-méthyl-3-(pyridine-2-sulfonyle) thiophène-2- ylméthyle] indol-1-yle} acétique, l'acide {5-fluoro-2-méthyl-3-[3-méthyl-5-(pyridine-2-sulfonyle)-3H-imidazol-4-ylméthyle] indol-1-yle} acétique, l'acide {5-fluoro-3-[2-(3-fluorophénylsulfamoyle) pyridine-3-ylméthyle]-2-méthylindol-1-yle} acétique, l'acide [3-(4-benzène sulfonyloxazol-5-ylméthyle)-5-fluoro-2-méthylindol-1-yle] acétique, l'acide {3-[2-(3-cyanophénylsulfamoyle) benzyle]-5-fluoro-2-méthylindol-1-yle} acétique, l'acide [3-(4-benzène sulfonylthiazol-5-ylméthyle)-5-chloro-2-méthyl-indol-1-yle] acétique, l'acide [3-(4-benzène sulfonyl-2-méthylthiazol-5-ylméthyle)-5-fluoro-2-méthylindol-1- yle] acétique, et l'acide [3-(4-benzène sulfonyl-3-méthylisothiazol-5-ylméthyle)-5-fluoro-2- méthylindol-1-yle] acétique.
PCT/GB2009/050671 2009-06-12 2009-06-12 Dérivés d'indole en tant que ligands des récepteurs crth2 WO2010142934A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9096595B2 (en) 2011-04-14 2015-08-04 Actelion Pharmaceuticals Ltd 7-(heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid derivatives and their use as prostaglandin D2 receptor modulators
JP2017501222A (ja) * 2013-12-17 2017-01-12 アトピックス テラピューティクス リミテッド ３−置換（インドール−１−イル）酢酸エステルの製造方法
WO2017120429A1 (fr) 2016-01-07 2017-07-13 CS Pharmasciences, Inc. Inhibiteurs sélectifs de mutants cliniquement importants de la tyrosine kinase de l'egfr
WO2017119732A1 (fr) 2016-01-08 2017-07-13 Samsung Electronics Co., Ltd. Dispositif électronique, et son procédé de fonctionnement
WO2017156341A1 (fr) 2016-03-09 2017-09-14 Beijing Percans Oncology Co. Ltd. Cultures en suspension de cellules tumorales et procédés associés
US9850241B2 (en) 2014-03-18 2017-12-26 Idorsia Pharmaceuticals Ltd Azaindole acetic acid derivatives and their use as prostaglandin D2 receptor modulators
US9879006B2 (en) 2014-03-17 2018-01-30 Idorsia Pharmaceuticals Ltd Azaindole acetic acid derivatives and their use as prostaglandin D2 receptor modulators
US9951010B2 (en) 2014-09-13 2018-04-24 Sunshine Lake Pharma Co., Ltd. Compounds as CRTH2 antagonist and uses thereof
US10351560B2 (en) 2015-09-15 2019-07-16 Idorsia Pharmaceuticals Ltd Crystalline forms

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008012511A1 (fr) * 2006-07-22 2008-01-31 Oxagen Limited Composés présentant une activité d'antagonistes crth2
WO2009063215A2 (fr) * 2007-11-13 2009-05-22 Oxagen Limited Utilisation de composés antagonistes de crth2

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008012511A1 (fr) * 2006-07-22 2008-01-31 Oxagen Limited Composés présentant une activité d'antagonistes crth2
WO2009063215A2 (fr) * 2007-11-13 2009-05-22 Oxagen Limited Utilisation de composés antagonistes de crth2

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9096595B2 (en) 2011-04-14 2015-08-04 Actelion Pharmaceuticals Ltd 7-(heteroaryl-amino)-6,7,8,9-tetrahydropyrido[1,2-a]indol acetic acid derivatives and their use as prostaglandin D2 receptor modulators
JP2017501222A (ja) * 2013-12-17 2017-01-12 アトピックス テラピューティクス リミテッド ３−置換（インドール−１−イル）酢酸エステルの製造方法
US9879006B2 (en) 2014-03-17 2018-01-30 Idorsia Pharmaceuticals Ltd Azaindole acetic acid derivatives and their use as prostaglandin D2 receptor modulators
US10301309B2 (en) 2014-03-17 2019-05-28 Idorsia Pharmaceuticals Ltd Azaindole acetic acid derivatives and their use as prostaglandin D2 receptor modulators
US9850241B2 (en) 2014-03-18 2017-12-26 Idorsia Pharmaceuticals Ltd Azaindole acetic acid derivatives and their use as prostaglandin D2 receptor modulators
US9951010B2 (en) 2014-09-13 2018-04-24 Sunshine Lake Pharma Co., Ltd. Compounds as CRTH2 antagonist and uses thereof
US10351560B2 (en) 2015-09-15 2019-07-16 Idorsia Pharmaceuticals Ltd Crystalline forms
WO2017120429A1 (fr) 2016-01-07 2017-07-13 CS Pharmasciences, Inc. Inhibiteurs sélectifs de mutants cliniquement importants de la tyrosine kinase de l'egfr
WO2017119732A1 (fr) 2016-01-08 2017-07-13 Samsung Electronics Co., Ltd. Dispositif électronique, et son procédé de fonctionnement
WO2017156341A1 (fr) 2016-03-09 2017-09-14 Beijing Percans Oncology Co. Ltd. Cultures en suspension de cellules tumorales et procédés associés

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