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WO2007045867A1 - Composes 3-aminoindole utilises en tant que ligands du recepteur crth2 - Google Patents

Composes 3-aminoindole utilises en tant que ligands du recepteur crth2 Download PDF

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Publication number
WO2007045867A1
WO2007045867A1 PCT/GB2006/003872 GB2006003872W WO2007045867A1 WO 2007045867 A1 WO2007045867 A1 WO 2007045867A1 GB 2006003872 W GB2006003872 W GB 2006003872W WO 2007045867 A1 WO2007045867 A1 WO 2007045867A1
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Prior art keywords
compound
hydrogen
chloro
cycloalkyl
alkyl
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PCT/GB2006/003872
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English (en)
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Nicholas Charles Ray
George Hynd
Rosa Arienzo
Harry Finch
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Argenta Discovery Limited
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Publication of WO2007045867A1 publication Critical patent/WO2007045867A1/fr

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    • 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to a class of 3-aminoindole 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 cyclooxygenase metabolite of arachadonic acid produced 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).
  • 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.
  • CRTH2 antagonists can also be used in the treatment of eosinophilic disorders such as Churg-Strauss syndrome and sinusitis; basophil associated diseases such as chronic urticaria; inflammatory diseases associated with T lymphocytes including
  • CRTH2 antagonists include: indole-acetic acids (WO2003/022813; WO2003/066046; WO2003/066047; WO2003/097042; WO2003/097598;
  • WO2005/040114; WO2005/044260 tetrahydroquinolines
  • EP1413306; EP1435356; WO2004/032848; WO2004/035543; WO2005/007094 tetrahydroquinolines
  • phenylacetic acids WO2004/058164; WO2004/089884; WO2004/089885; WO2005/018529.
  • One aspect of the invention provides a compound of general formula [I] or a pharmaceutically acceptable salt, N-oxide, hydrate, or solvate thereof:
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen, (CrC 6 ) alkyl, (C 1 -C 6 ) haloalkyl, halo, -S(O) n R 10 , -NR 11 SO 2 R 10 , -SO 2 N(R 11 ) 2 , -N(R 11 ) 2 , -NR 11 C(O)R 10 , -C(O)N(R 11 ) 2 , - CO 2 R 11 , -C(O)R 10 , CN or a group OR 12 ; wherein each R 10 is independently (CrC 6 )alkyl, (C 1 -C 6 ) haloalkyl, cycloalkyl, aryl, or heteroaryl;
  • R 11 is independently hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, cycloalkyl, aryl, or heteroaryl;
  • R 12 is hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, cycloalkyl, or a group - SO 2 R 10 , wherein n is O 1 or 2;
  • R 5 and R 6 are independently hydrogen, (CrC 6 ) alkyl or (CrC 6 ) haloalkyl, or R 5 and R 6 together with the atom to which they are attached form a cycloalkyl group;
  • R 7 is hydrogen, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) haloalkyl;
  • R 8 is aryl, heteroaryl, aryl-fused-heterocycloalkyl, heteroaryl-fused-cycloalkyl, heteroaryl-fused-heterocycloalkyl or aryl-fused-cycloalkyl;
  • R 9 is hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, or cycloalkyl.
  • Compounds with which the invention is concerned are CRTH2 receptor antagonists, and are selective over the DP receptor.
  • a second aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound (I) as defined above together with one or more pharmaceutically acceptable carriers.
  • a third aspect of the invention is the use of a compound (I) as defined above, or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof, in the manufacture of a composition for treatment of conditions responsive to modulation of CRTH2 receptor activity.
  • a fourth aspect of the invention is 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 (I) as defined above, or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof.
  • a compound (I) as defined above or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof.
  • Important conditions responsive to modulation of CRTH2 receptor activity include asthma, chronic obstructive pulmonary disease, allergic airway syndrome, bronchitis, cystic fibrosis, emphysema and rhinitis,
  • CRTH2 receptor activity Other conditions responsive to modulation of CRTH2 receptor activity include psoriasis, dermatitis (atopic and non-atopic), Crohn's disease, ulcerative colitis, and irritable bowel disease.
  • (C a -C b ) alkyl wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms.
  • a 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
  • (C a -C b ) fluoroalkyl wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms in which the hydrogen atoms all replaced by fluorine (fully fluorinated) or in which some of the hydrogen atoms are replaced by fluorine (partially fluorinated).
  • the term includes, for example -CF 3 , -CHF 2 , -CFH 2 , and CF 3 CH 2 -.
  • Carbocyclic refers to an optionally substituted mono-, bi- or tricyclic, radical having up to 16 ring atoms, all of which are carbon, and includes aryl and cycloalkyl.
  • cycloalkyl refers to an optionally substituted monocyclic saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • aryl refers to an optionally substituted mono-, bi- or tri-cyclic carbocyclic aromatic radical, and includes radicals having two monocyclic carbocyclic aromatic rings which are directly linked by a covalent bond.
  • Aryl radicals may have, for example, from 6 to 14 ring carbon atoms, preferably from
  • aryl radicals 6 to 10 carbon atoms.
  • aryl radicals are phenyl, biphenyl and napthyl.
  • aryl-fused-cycloalkyl refers to a carbocyclic radical consisting of a monocyclic aryl ring, such as phenyl, fused to a cycloalkyl group, in which the aryl and cycloalkyl parts are as defined herein.
  • exemplary aryl-fused- cycloalkyl groups include tetrahydronaphthyl and indanyl.
  • the aryl-fused-cycloalkyl radical may be attached to the remainder of the molecule by any available carbon atom.
  • heteroaryl refers to an optionally substituted mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O, and includes radicals having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, which are directly linked by a covalent bond.
  • Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl and indazolyl.
  • heterocycloalkyl or “heterocyclyl” or “heterocyclic” includes “heteroaryl” as defined above, and in addition means an optionally substituted mono-, bi- or tri-cyclic non-aromatic radical containing one or more heteroatoms selected from S, N and O, and to groups consisting of a monocyclic non-aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical.
  • radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, quinolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.
  • heteroaryl-fused-cycloalkyl means a heterocyclic radical consisting of monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a cycloalkyl group, in which the heteroaryl and cycloalkyl parts are as defined herein.
  • exemplary heteroaryl-fused-cycloalkyl groups include tetrahydroquinolinyl and tetrahydrobenzofuranyl.
  • the heteroaryl-fused-cycloalkyl group may be attached to the remainder of the molecule by any available carbon or nitrogen atom.
  • aryl-fused-heterocycloalkyl refers to a heterocyclic radical consisting of a monocyclic aryl ring, such as phenyl, fused to a heterocycloalkyl group, in which the aryl and heterocycloalkyl parts are as defined above.
  • exemplary aryl-fused-heterocycloalkyl groups include tetrahydroquinolinyl, indolinyl, benzodioxinyl, benxodioxolyl, dihydrobenzofuranyl and isoindolonyl.
  • the aryl-fused-heterocycloalkyl radical may be attached to the remainder of molecule by any available carbon or nitrogen atom.
  • heteroaryl-fused-heterocycloalkyl refers to a heterocyclic radical consisting of a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a heterocycloalkyl group, in which the heteroaryl and heterocycloalkyl parts are as defined herein.
  • exemplary heteroaryl-fused- heterocycloalkyl groups include dihydrodioxinopyridinyl, dihydropyrrolopyridinyl, dihydrofuranopyridinyl and dioxolopyridinyl.
  • the heteroaryl-fused-heterocycloalkyl group may be attached to the remainder of the molecule by any available carbon or nitrogen atom.
  • substituted as applied to any moiety herein means substituted with up to four compatible substituents, each of which independently may be, for example, (Ci-C 6 ) alkyl, cycloalkyl, (C 1 -C 6 ) alkoxy, hydroxy, hydroxy(C r C 6 ) alkyl, mercapto, mercapto(Ci-C 6 ) alkyl, (C 1 -C 6 ) alkylthio, phenyl, monocyclic heteroaryl having 5 or 6 ring atoms, halo (including fluoro, bromo and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), oxo, -COOH, -COOR A , -COR A , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -CONHR A , -SO
  • 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, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl- D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.
  • bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl- D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl pipe
  • Specific salts with bases include the benzathine, calcium, diolamine, meglumine, olamine, potassium, procaine, sodium, tromethamine and zinc salts.
  • Those compounds (I) which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g.
  • Compounds with which the invention is concerned which may exist in one or more stereoisomer ⁇ 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 atropisomeres with R or S stereochemistry at each chiral axis.
  • the invention includes all such enantiomers and diastereoisomers and mixtures thereof.
  • prodrugs such as esters
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of formula (I).
  • metabolic means e.g. by hydrolysis, reduction or oxidation
  • an ester prodrug of a compound of formula (I) may be convertible by hydrolysis in vivo to the parent molecule.
  • esters of compounds of formula (I) are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, jOtoluene- sulphonates, cyclohexylsulphamates and quinates.
  • ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, 379. As used in herein, references to the compounds of formula (I) are meant to also include the prodrug forms.
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen, (C 1 -C 6 ) alkyl, for example methyl, ethyl, or n- or iso-propyl; (C 1 -C 6 ) fluoroalkyl, for example trifluoromethyl or difluoromethyl; cycloalkyl, for example cyclopropyl or cyclobutyl; halo, for example fluoro, chloro or bromo; -S(O) n R 10 , -SO 2 N(R 11 ) 2 , -N(R 11 ) 2 , -NR 11 C(O)R 10 , -CO 2 R 11 , - C(O)R 10 , CN or a group OR 12 ; wherein each R 10 is independently d-C- 6 alkyl, for example methyl, ethyl, or n- or iso-propyl; fully or partially fluorinated C 1 -C 6 alky
  • R 1 -R 4 are:
  • R 1 is hydrogen; 5 R 2 is chloro;
  • R 3 is hydrogen
  • R 4 is hydrogen
  • R 5 and R 6 are independently hydrogen, (C 1 -C 6 ) alkyl, for example methyl, ethyl, or n- or iso-propyl; (CrC 6 ) fluoroalkyl, for example trifluoromethyl or
  • cycloalkyl for example cyclopropyl or cyclobutyl, or R 5 and R 6 together with the atom to which they are attached form a cycloalkyl ring such as a cyclopropyl ring.
  • R 5 and R 6 are hydrogen.
  • R 7 is hydrogen, (C 1 -C 6 ) alkyl, for example methyl, ethyl, or n- or iso-propyl; (CrC 6 ) fluoroalkyl, for example trifluoromethyl or difluoromethyl. Presently it is 15 preferred that R 7 be methyl.
  • R 8 is optionally substituted aryl such as phenyl or naphthy); heteroaryl for example quinolinyl, pyridyl, thienyl, furanyl, azolyl, thiazolyl, diazolyl, or imidazolyl, aryl-fused-heterocycloalkyl, for example tetrahydroquinolinyl, indolinyl, benzodioxinyl, benxodioxolyl, dihydrobenzofuranyl and isoindolonyl; heteroaryl-fused-cycloalkyl, for 20 example tetrahydroquinolyl; heteroaryl-fused-heterocycloalkyl, for example indolinyl, benzodioxinyl, benzodioxolyl, dihydrobenzofuranyl or isoindolonyl; or aryl-fused- cycloalkyl group such as
  • R 8 is optionally substituted phenyl.
  • Optional substituents in R 8 include: fluoro, chloro, phenyl, methanesulfonyl, 4-ethanesulfonylphenyl, 25 trifluoromethyl, morpholine-4-sulfonyl, pyrrolidine- 1-carbonyl, and cyclobutylcarbamoyl.
  • R 8 radicals include 4-chlorophenyl, 2- chlorophenyl, 4-(trifluoromethyl)phenyl, 4-(methylsulfonyl)phenyl, 4-fluorophenyl, 2- naphthyl, 1-naphthyl, 2,3-dichlorophenyl, 8-quinolinyl, 3,5-dichlorophenyl, 3,4- dichlorophenyl.
  • R 9 is hydrogen, (C 1 -C 6 ) alkyl, for example methyl, ethyl, or n- or iso-propyl;
  • (C 1 -C 6 ) fluoroalkyl for example trifluoromethyl or difluoromethyl
  • cycloalkyl for example cyclopropyl or cyclobutyl.
  • R 9 be hydrogen.
  • compositions include those of the Examples herein, and pharmaceutically acceptable salts, N-oxides, hydrates or 35. solvates thereof.
  • 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 which benefit from such modulation. Examples of such diseases are referred to above, and include asthma, rhinitis, allergic airway syndrome, and bronchitis.
  • 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 polyvinyl-pyrrolidone; 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; nonaqueous 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
  • nonaqueous vehicles which may include edible oils
  • almond oil fractionated coconut oil
  • oily esters such as glycerine, propylene glycol
  • 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 a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • compositions for preventing and treating PGD 2 -mediated diseases comprising a therapeutically effective amount of a compound of the invention of formula [I] and one or more other therapeutic agents.
  • Suitable therapeutic agents for a combination therapy with compounds of formula [I] 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 (H1) receptor antagonists, such as fexofenadine, citirizine, loratidine or
  • 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 present invention is also concerned with processes for preparing the compounds of this invention.
  • the compounds can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein.
  • the compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention.
  • the examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
  • Suitable ester protecting groups include, for example, methyl or ethyl, which may be removed by acid- or base-catalysed aqueous hydrolysis or by treatment with potassium trimethylsilanoate in a solvent such as THF; benzyl, which may be removed by catalytic hydrogenation, or te/f-butyl, which may be removed by treatment with a strong acid such as trifluoroacetic acid/dichloromethane mixtures, or a solution of hydrogen chloride in dioxane.
  • the reaction solvent may be a polar organic solvent such as pyridine or tetrahydrofuran.
  • polar organic solvent such as pyridine or tetrahydrofuran.
  • Compounds of formula [lll-a] may be prepared by the reaction between a compound of formula [IV-a], wherein R 1 , R 2 , R 3 , R 4 R 5 , R 6 , R 7 and X are as defined above, and an appropriate compound of formula [IX], wherein R 9 is as defined above, and LG represents a suitable leaving group (for example, chloro, bromo, or methanesulfonyloxy).
  • R 6 , R 7 and X are as defined above, into those of formula [IV-a] may conveniently be achieved by reduction with zinc/acetic acid or with hydrogen in the presence of a suitable catalyst, such as palladium supported on carbon.
  • Compounds of formula [V-a] may be prepared from compounds of formula [Vl-a], wherein R 1 , R 2 , R 3 , R 4 R 5 , R 6 R 7 and X are as defined above, by nitration with nitric acid and acetic anhydride, at a temperature between -8O 0 C and room temperature.
  • Compounds of formula [Vl-a] may be prepared from compounds of formula [Vll-a], wherein R 1 , R 2 , R 3 , R 4 and R 7 are as defined above, by reaction with a compound of general formula [X], wherein R 5 and R 6 are as defined in formula [I], X is as defined above and LG is a leaving group, such as a halogen, particularly chlorine, bromine or an iodine atom.
  • the alkylation reaction is carried out in the presence of a base (for example, potassium carbonate) in an inert solvent (for example, ⁇ /, ⁇ /-dimethylformamide).
  • 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% acetonithle 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% solvent A and 5% 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
  • 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 bar 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 le ⁇ gth and 2 cm internal diameter.
  • the mobile phase used was mixtures of acetonitrile and water (both buffered with 01% v/v trifluoroacetic acid) with a flow rate of 10 mL per minute and typical gradients of 40 to 90% organic modifier ramped up over 30 to 40 minutes.
  • Fractions containing the required product (identified by LC-MS analysis) were pooled, the organic fraction removed by evaporation, and the remaining aqueous fraction lyophilised, to give the final product.
  • Nitric acid (90%, 0.74 mL) was added to stirred acetic anhydride (11 mL) at O 0 C and the resulting solution was left to stand at room temperature for ten minutes.
  • This solution was added slowly to a solution of (5-chloro-2-methyl-indol-1-yl)acetic acid methyl ester (1.3 g) in acetic anhydride (27 mL) at -7O 0 C and the resulting mixture was allowed to warm to room temperature over three hours.
  • the reaction mixture was poured onto a mixture of ice and water and stirred for one hour.
  • the resulting precipitate was collected by filtration and dried to afford (5-chloro-2-methyl- 3-nitroindol-1-yl)acetic acid methyl ester (1.4 g).
  • Biphenyl-4-sulfonyl chloride (0.12 g) was added to a stirred solution of (3- amino-5-chloro ⁇ 2-methylindol-1-yl)acetic acid methyl ester hydrochloride (compound of Preparation 1c, 0.10 g) in pyridine (5.0 ml_) at room temperature. After thirty minutes the pyridine was removed under reduced pressure and the residue washed with 1.0 M aqueous hydrochloric acid to afford [3-(biphenyl-4-sulfonylamino)-5- chloro-2-methylindol-1-yl]acetic acid methyl ester, 0.17 g.
  • 2,3-Dichlorobenzenesulfonyl chloride (0.12 g) was added to a stirred solution of (3-amino-5-chloro-2-methylindol-1-yl)acetic acid methyl ester hydrochloride (compound of Preparation 1c, 0.10 g) in pyridine (5.0 mL) at room temperature. After thirty minutes the pyridine was removed under reduced pressure and the residue washed with 1.0 M aqueous hydrochloric acid to afford [5-chloro-3-(2,3-dichloro- benzenesulfonylamino)-2-methylindol-1-yl]acetic acid methyl ester, 0.18 g.
  • 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 liquid 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.
  • Compounds of the invention that have been tested in the binding assay are illustrated below in the following Table.
  • the GTP ⁇ S Assay is performed in a final volume of 200 ml_ assay buffer (2OmM HEPES pH 7.4, 1OmM MgCI 2 , 10OmM 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 (3OnM 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 (0.1 nM 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 1.5mg/well and the plate shaken and incubated for 30 minute at 3O 0 C. The sealed plate is centrifuged at 1000g 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 5O 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.
  • Examples 1 and 9 had a Ki of ⁇ 1 ⁇ M in this assay, and Example 8 was shown to have a Ki ⁇ 10OnM in this assay.

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Abstract

La présente invention a trait à des composés de formule (I), qui sont des antagonistes du récepteur CRTH2 et sont utiles pour traiter les troubles à composante inflammatoire. Dans ladite formule, R1, R2, R3 et R4 sont indépendamment l’hydrogène, un alkyle en C1 à C6, un halogénoalkyle en C1 à C6, un groupe halogéno, -S(O)nR10, -NR11SO2R10, -SO2N(R11)2, -N(R11)2, -NR11C(O)R10, -C(O)N(R11)2, -CO2R11, -C(O)R10, CN ou un groupe OR12 ;chaque R10 est indépendamment un alkyle en C1 à C6, un halogénoalkyle en C1 à C6, un cycloalkyle, un aryle, ou un hétéroaryle ; R11 est indépendamment l’hydrogène, un alkyle en C1 à C6, un halogénoalkyle en C1 à C6, un cycloalkyle, un aryle, ou un hétéroaryle ; R12 est l’hydrogène, un alkyle en C1 à C6, un halogénoalkyle en C1 à C6, un cycloalkyle ou un groupe -SO2R10, n valant O, 1 ou 2 ; R5 et R6 sont indépendamment l’hydrogène, un alkyle en C1 à C6 ou un halogénoalkyle en C1 à C6, ou bien R5 et R6 forment conjointement, avec l’atome auquel il sont liés, un groupe cycloalkyle ; R7 l’hydrogène, un alkyle en C1 à C6 ou un halogénoalkyle en C1 à C6 ; R8 est un aryle, un hétéroaryle, un hétérocycloalkyle fusionné avec un aryle, un cycloalkyle fusionné avec un hétéroaryle, un hétérocycloalkyle fusionné avec un hétéroaryle ou encore un cycloalkyle fusionné avec un aryle ; enfin R9 est l’hydrogène, un alkyle en C1 à C6, un halogénoalkyle en C1 à C6, ou un cycloalkyle.
PCT/GB2006/003872 2005-10-19 2006-10-18 Composes 3-aminoindole utilises en tant que ligands du recepteur crth2 WO2007045867A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
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EP2327693A1 (fr) 2007-12-14 2011-06-01 Pulmagen Therapeutics (Asthma) Limited Indoles et leurs utilisation thérapeutiques
JP2012500189A (ja) * 2008-08-15 2012-01-05 エフ．ホフマン−ラ ロシュ アーゲー ビアリールアミノテトラリン
JP2012500188A (ja) * 2008-08-15 2012-01-05 エフ．ホフマン−ラ ロシュ アーゲー モノアリールアミノテトラリン
US8143304B2 (en) 2006-08-07 2012-03-27 Actelion Pharmaceutical Ltd. (3-amino-1,2,3,4-tetrahydro-9 H-carbazol-9-yl)-acetic acid derivatives
EP2457900A1 (fr) 2010-11-25 2012-05-30 Almirall, S.A. Nouveaux dérivés de pyrazole présentant un comportement antagoniste CRTH2
WO2013088109A1 (fr) 2011-12-16 2013-06-20 Oxagen Limited Combinaison d'un antagoniste de crth2 et d'un inhibiteur de pompe à protons pour le traitement de l'œsophagite à éosinophiles
US8697869B2 (en) 2010-03-22 2014-04-15 Actelion Pharmaceuticals Ltd. 3-(heteroaryl-amino)-1,2,3,4-tetrahydro-9H-carbazole derivatives and their use as prostaglandin D2 receptor modulators
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
CN105461693A (zh) * 2014-09-26 2016-04-06 广东东阳光药业有限公司 Crth2拮抗剂化合物及其用途
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
US10351560B2 (en) 2015-09-15 2019-07-16 Idorsia Pharmaceuticals Ltd Crystalline forms
WO2021263278A1 (fr) * 2020-06-23 2021-12-30 The Scripps Research Institute Agonistes rev-erb pour le traitement de troubles inflammatoires à médiation par th17
WO2023122093A1 (fr) * 2021-12-20 2023-06-29 University Of Florida Research Foundation, Incorporated Agonistes rev-erb pour des troubles inflammatoires à médiation par th17

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EP1505061A1 (fr) * 2002-05-16 2005-02-09 SHIONOGI & CO., LTD. Compose comprenant un antagonisme du recepteur de pdg2
WO2005019171A1 (fr) * 2003-08-18 2005-03-03 Astrazeneca Ab Derives d'indoles substitues pour compositions pharmaceutiques permettant de traiter les troubles respiratoires

Patent Citations (3)

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EP1505061A1 (fr) * 2002-05-16 2005-02-09 SHIONOGI & CO., LTD. Compose comprenant un antagonisme du recepteur de pdg2
WO2003101961A1 (fr) * 2002-05-30 2003-12-11 Astrazeneca Ab Nouveaux indoles substitues
WO2005019171A1 (fr) * 2003-08-18 2005-03-03 Astrazeneca Ab Derives d'indoles substitues pour compositions pharmaceutiques permettant de traiter les troubles respiratoires

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8143304B2 (en) 2006-08-07 2012-03-27 Actelion Pharmaceutical Ltd. (3-amino-1,2,3,4-tetrahydro-9 H-carbazol-9-yl)-acetic acid derivatives
EP2327693A1 (fr) 2007-12-14 2011-06-01 Pulmagen Therapeutics (Asthma) Limited Indoles et leurs utilisation thérapeutiques
JP2012500189A (ja) * 2008-08-15 2012-01-05 エフ．ホフマン−ラ ロシュ アーゲー ビアリールアミノテトラリン
JP2012500188A (ja) * 2008-08-15 2012-01-05 エフ．ホフマン−ラ ロシュ アーゲー モノアリールアミノテトラリン
US8697869B2 (en) 2010-03-22 2014-04-15 Actelion Pharmaceuticals Ltd. 3-(heteroaryl-amino)-1,2,3,4-tetrahydro-9H-carbazole derivatives and their use as prostaglandin D2 receptor modulators
EP2457900A1 (fr) 2010-11-25 2012-05-30 Almirall, S.A. Nouveaux dérivés de pyrazole présentant un comportement antagoniste CRTH2
WO2012069175A1 (fr) 2010-11-25 2012-05-31 Almirall, S.A. Nouveaux dérivés de pyrazole possédant un comportement antagoniste de crth2
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
WO2013088109A1 (fr) 2011-12-16 2013-06-20 Oxagen Limited Combinaison d'un antagoniste de crth2 et d'un inhibiteur de pompe à protons pour le traitement de l'œsophagite à éosinophiles
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
CN105461693A (zh) * 2014-09-26 2016-04-06 广东东阳光药业有限公司 Crth2拮抗剂化合物及其用途
CN105461693B (zh) * 2014-09-26 2019-10-25 广东东阳光药业有限公司 Crth2拮抗剂化合物及其用途
US10351560B2 (en) 2015-09-15 2019-07-16 Idorsia Pharmaceuticals Ltd Crystalline forms
WO2021263278A1 (fr) * 2020-06-23 2021-12-30 The Scripps Research Institute Agonistes rev-erb pour le traitement de troubles inflammatoires à médiation par th17
WO2023122093A1 (fr) * 2021-12-20 2023-06-29 University Of Florida Research Foundation, Incorporated Agonistes rev-erb pour des troubles inflammatoires à médiation par th17

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