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WO2009060209A1 - Composés aromatiques bicycliques fusionnés 6,6 et leur utilisation en thérapie - Google Patents

Composés aromatiques bicycliques fusionnés 6,6 et leur utilisation en thérapie Download PDF

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Publication number
WO2009060209A1
WO2009060209A1 PCT/GB2008/003758 GB2008003758W WO2009060209A1 WO 2009060209 A1 WO2009060209 A1 WO 2009060209A1 GB 2008003758 W GB2008003758 W GB 2008003758W WO 2009060209 A1 WO2009060209 A1 WO 2009060209A1
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Prior art keywords
mixture
alkyl
compound
optionally substituted
chlorobenzyl
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PCT/GB2008/003758
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English (en)
Inventor
George Hynd
John Gary Montana
Harry Finch
Shahadat Ahmed
Mathias Domostoj
Joelle Moise
Rosa Arienzo
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Argenta Discovery Limited
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Publication of WO2009060209A1 publication Critical patent/WO2009060209A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/49—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide
    • C07C45/50—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide by oxo-reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring 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
    • C07D401/10—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 aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to a class of 6,6-fused bicyclic aromatic compounds which are 5 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.
  • 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.
  • mice and rats Ther., 2003, 305, 347-352; Takeshita et al; op. cii).
  • the potential of PGD 2 both to enhance allergic inflammation and induce an inflammatory response has been demonstrated in mice and rats.
  • 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).
  • CRTH2 antagonists may have valuable properties for the treatment of diseases mediated by PGD 2 .
  • indole acetic acids WO2008/012511 ; WO2007/065684; WO2007/045867; WO2006/034419; WO2005/094816; WO2005/044260; WO2005/040114; WO2005/040112; GB2407318; WO2005/019171; WO2004/106302; WO2004/078719; WO2004/007451 ; WO2003/101981; WO2003/101961 ; WO2003/097598; WO2003/097042; WO2003/066047; WO2003/066046; WO2003/022813), indolizine acetic acids (WO2008/113965; WO2008/074966; WO2007/031747; WO2006/136859), pyrrole acetic acids (WO2007/144127; WO2006/063763), quinolines (WO2007/144127; WO2006/063763), quinolines (WO2007/144127;
  • One aspect of the invention provides compound of formula (I) or a pharmaceutically acceptable salt thereof: B2008/003758 (I) wherein:
  • A is selected from -CR 1 R 2 -, -CR 1 R 2 CR 1 R 2 - or -D(CR 1 R 2 )-, wherein D is O, NR 1 or S(O) n , and is attached to the Ar 1 ring;
  • R 1 and R 2 independently represent hydrogen or C r C 3 alkyl
  • B is -CH 2 -, -S(O) n -, or -O-;
  • Ar 1 is selected from one of the following formulae, wherein the bond marked 1 is attached to A while the bond marked 2 is attached to B;
  • R 3 , R 4 , R 5 , R 6 , R 7 and R 8 independently represent hydrogen, halogen, -CN, -OR 9 , -NR 10 R 11 , C r C 6 alkyl or C 3 -C 7 cycloalkyl, wherein the alkyl substituents are optionally substituted with one or more fluoro atoms;
  • R 9 is CrC 6 alkyl or C 3 -C 7 cycloalkyl, optionally substituted by one or more fluoro atoms;
  • R 10 and R 11 independently represent hydrogen, C r C 6 alkyl or C 3 -C 7 cycloalkyl, wherein the alkyl substituents are optionally substituted with one or more fluoro atoms;
  • Y is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or heteroaryl groups are optionally substituted by one or more substituents independently selected from halogen, -CN, -S(O) n R 9 , -S(O) 2 NR 12 R 13 , -NR 12 S(O) 2 R 9 -NR 12 R 13 , -NR 12 COR 9 , -CONR 12 R 13 , -COR 9 , -OR 9 , C r C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein the alkyl substituents are optionally substituted with one or more fluoro atoms and the phenyl
  • R 12 and R 13 independently represent hydrogen, CrC 6 alkyl or C 3 -C 7 cycloalkyl, wherein the alkyl substituent is optionally substituted with one or more fluoro atoms; or R 12 and R 13 when attached to the same atom may form a 3-8 membered ring optionally containing one or more ring components selected from -0-, -S(O) n - or -NR 14 -, and optionally substituted with one or more fluoro or C 1 -C 3 alkyl substituents;
  • R 14 is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, S(O) 2 R 15 or COR 15 ;
  • R 15 is CrC 6 alkyl or C 3 -C 7 cycloalkyl
  • n 0, 1 or 2.
  • Compounds (I) with which the invention is concerned are CRTH2 receptor antagonists, but they may also have beneficial effects at other prostanoid receptors, such as the DP receptor or the thromboxane A 2 receptor.
  • the invention also includes (i) use of a compound with which the invention is concerned 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, bursit
  • 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.
  • (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, f-butyl, n-pentyl and n-hexyl.
  • cycloalkyl refers to a monocyclic saturated carbocyclic radical having from 3-6 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • aryl refers to a 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 6 to 10 carbon atoms.
  • Illustrative of aryl radicals are phenyl, biphenyl and napthyl.
  • heteroaryl refers to a 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.
  • 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 /V-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L- arginine, L-lysine, A/-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 /V-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L- arginine, L-lysine, A/-ethyl piperidine, dibenzy
  • Specific salts with bases include the 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-toluenesulphonic, 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 acetic, tartaric, succinic,
  • 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
  • Salts are discussed in the "Handbook of Pharmaceutical Salts. Properties, selection and use", P. Heinrich Stahl & Camille G. Wermuth, Wiley-VCH, 2002.
  • '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 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 atropisomers 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 (for example, by hydrolysis, reduction or oxidation) to a compound of formula (I).
  • 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-jt>toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, jt>toluene- 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.
  • A may be -OCH 2 - or -OCH(CH 3 )- wherein the oxygen is attached to the Ar 1 ring system.
  • B may be -CH 2 -.
  • Y may be phenyl, optionally substituted as specified above; or Y may be a monocyclic 5- or 6-membered heteroaryl group, such as thiophene or pyridine, optionally substituted as specified above.
  • optional substituents in Y include chloro, fluoro, bromo, -CN, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, isopropoxy, cyclopropoxy, difluoromethoxy, trifluoromethoxy, methanesulfonyl, ethanesulfonyl or pyrazole.
  • substituents are chloro and pyrazolyl.
  • R 3 , R 4 and R 5 may independently be hydrogen, CrC 3 alkyl such as methyl, ethyl or isopropyl or a C 3 -C 6 cycloalkyl group such as cyclopropyl.
  • R 6 , R 7 and R 8 may independently be hydrogen, C r C 3 alkyl such as methyl, chloro, fluoro, bromo or trifluoromethyl.
  • A is -OCH 2 - or -OCH(CH 3 )- wherein the oxygen is attached to the ring carbon shown;
  • B is -CH 2 -, Y is as defined in relation to formula (I) above;
  • R 3 and R 4 are independently selected from hydrogen, methyl, ethyl, isopropyl and cyclopropyl;
  • R 6 , R 7 and R 8 are independently selected from hydrogen, methyl, chloro, fluoro, bromo and trifluoromethyl.
  • Y is phenyl, substituted by choro or pyrazolyl.
  • 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, chronic obstructive pulmonary disease, 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
  • 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 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 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 (H1) 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 compounds of the invention of formula (I) may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above.
  • the free acid form corresponding to isolated salts can be generated by acidification with a suitable acid such as acetic acid and hydrochloric acid and extraction of the liberated free acid into an organic solvent followed by evaporation.
  • a suitable acid such as acetic acid and hydrochloric acid
  • the free acid form isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic solvent followed by addition of the appropriate base and subsequent evaporation, precipitation, or crystallisation.
  • Compounds of formula (I), wherein B is a -CH 2 - group are represented by compounds of formula (Ia) (Scheme 1).
  • Compounds of the invention of formula (Ia) may be prepared from compounds of formula (II), wherein T is chloro, bromo, or iodo atom, or a trifluoromethanesulfonyloxy group and E is a hydrogen or alkyl group, by reaction with an organometallic reagent of formula (III), wherein M is an appropriately substituted boron, zinc or tin group.
  • the reaction may conveniently be carried out in the presence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium.
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium.
  • Compounds of formula (III) are commercially available or can be prepared by known methods.
  • Compounds of the invention of formula (Ib), wherein B represents a -S- group may be prepared by the reaction between a compound of formula (II) and a thiol of formula (IV) (Scheme 2).
  • the reaction may be carried out in the presence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium or tris(dibenzylideneacetone)dipalladium / 9,9-dimethyl-4,5-bis(diphenylphosphino xanthene.
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium or tris(dibenzylideneacetone)dipalladium / 9,9-dimethyl-4,5-bis(diphenylphosphino xanthene.
  • Compounds of formula (IV) are commercially available or can be prepared by known methods. It is to be understood that if the reaction is carried out on a protected form of (I
  • Compounds of the invention of formula (Ic), wherein B represents a -S(O)- or -S(O) 2 - group may be prepared by the oxidation of compounds of the invention of formula (Ib), with a suitable oxidising agent such as potassium peroxymonosulfate, meta- chloroperoxybenzoic acid or other well known oxidising agents (Scheme 3).
  • a suitable oxidising agent such as potassium peroxymonosulfate, meta- chloroperoxybenzoic acid or other well known oxidising agents (Scheme 3).
  • Intermediate compounds of formula (II), wherein A is a -0(CR 1 R 2 )- group may be prepared from compounds of formula of (V) by reaction with a suitable alkylating agent of formula (Vl), wherein LG group represents a suitable leaving group such as chloro, bromo or methanesulfonyloxy group (Scheme 4).
  • a suitable alkylating agent of formula (Vl) wherein LG group represents a suitable leaving group such as chloro, bromo or methanesulfonyloxy group (Scheme 4).
  • the alkylation reaction is carried out in the presence of a suitable base (for example, potassium carbonate) and solvent (for example, acetone or ⁇ /, ⁇ /-dimethylformamide).
  • a suitable base for example, potassium carbonate
  • solvent for example, acetone or ⁇ /, ⁇ /-dimethylformamide
  • Compounds of formula (I), wherein A is a -CR 1 R 2 - group are represented by compounds of formula (Id) (Scheme 5).
  • Compounds of the invention of formula (Id) may be prepared by the reaction between a compound of formula (VII) and (1-terf- butoxyvinyloxy)-te/t-butyldimethylsilane, followed by an appropriate ester deprotection step.
  • the reaction may carried out in the presence of a suitable catalyst (for example, tetrakis(triphenylphosphine)palladium) and base (for example, lithium acetate).
  • compounds of the invention of formula (Ie), wherein A represents a -CR 1 R 2 CR 1 R 2 - group may be prepared by the reaction between a compound of formula (VIl) and a compound of formula (VIII), followed by reduction with hydrogen in the presence of a suitable catalyst (for example, palladium supported on carbon) (Scheme 6).
  • a suitable catalyst for example, palladium supported on carbon
  • 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 % 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
  • Method C Agilent Scalar column C18, 5 ⁇ m (4.6 x 50 mm, flow rate 2.5 mL / min) eluting with a H 2 O-MeCN gradient containing 0.1% v/v formic acid over 7 minutes with UV detection at 215 and 254 nm.
  • Method D Agilent Scalar column C18, 5 ⁇ m (4.6 x 50 mm, flow rate 2.5 mL/min) eluting with a H 2 O-MeCN gradient containing 0.1% v/v NH 4 OH over 7 minutes with
  • 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 length and 2 cm internal diameter.
  • the mobile phase used was mixtures of acetonitrile and water (both buffered with 0.1 % v/v trifluoroacetic acid, acetic acid or formic acid) with a flow rate of 5-20 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
  • the pH of the filtrated was adjusted to 7 by the addition of 1.0 M aqueous hydrochloric acid solution, and the resulting precipitate was collected by filtration, washed with water and then dried to afford the title compound as a tan solid (0.30 g).
  • Lithium aluminium hydride (1.3 g) at 0 0 C was treated dropwise over a period of 15 minutes with a solution of aluminium trichloride (4.6 g) in diethyl ether (50 mL), and the resulting mixture was stirred at 0 0 C for 5 minutes. The mixture was treated dropwise with a solution of (4-amino-2,6-dimethylphenyl)-(4-chlorophenyl)methanone
  • the title compound was prepared by the method of Preparation 6g using [2-(4- chlorobenzyO- ⁇ -fluoroquinazolin- ⁇ -yloxylacetic acid methyl ester.
  • the title compound was prepared by the method of Preparation 6a using ⁇ /-(3,5- dimethylphenyl)acetamide and 4-fluorobenzoyl chloride.
  • a mixture of pyrazole (0.041 g), potassium carbonate (0.083 g) and N 1 N- dimethylformamide (5.0 ml_) was treated with ⁇ /-[4-(4-fluorobenzoyl)-3,5- dimethylphenyl]acetamide (0.14 g), and the resulting mixture was stirred at room temperature for 2 hours and then stirred at 120 0 C for 24 hours.
  • the mixture was treated with additional potassium carbonate (0.02 g) and stirred at 120 0 C for 2 hours.
  • the mixture was then treated with additional potassium carbonate (0.035 g) and pyrazole (0.017g) and then stirred at 120 0 C for 2 days.
  • the title compound was prepared by the method of Preparation 6c using (4-amino- 2,6-dimethylphenyl)-(4-pyrazol-1 -ylphenyl)methanone.
  • the title compound was prepared by the method of Preparation 6d using 3,5- dimethyl-4-(4-pyrazol-1-ylbenzyl)phenylamine.
  • the title compound was prepared by the method of Preparation 6f using 5,7- dimethyl-6-(4-pyrazol-1 -ylbenzyl)quinolin-4-ol.
  • Preparation 10i 4-chloro-7-(4-chlorobenzyl)-6,8-dimethyl-2H-isoquinolin-1 -one
  • a solution of 7-(4-chlorobenzyl)-6,8-dimethyl-2H-isoquinolin-1-one (0.30 g) in dimethyl acetamide (6.0 mt_) at 170 0 C was treated portionwise with a solution of N- chlorosuccinimide (0.16 g) in dimethylacetamide (4.0 ml_), and the resulting mixture was stirred at 170 0 C for 45 minutes.
  • the mixture was treated with additional cyclopropyl boronic acid (0.040 g) and tetrakis(triphenylphosphine) palladium(O) (0.05 g) and then stirred at 111 0 C for one hour.
  • the mixture was filtered through hyflo and the filtrate was concentrated under reduced pressure.
  • the residue was purified by flash chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:0 to 0:1 by volume) to afford the title compound (0.06 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 5O calculations are performed using Excel and XLfit (Microsoft), and this value is used to determine a Kj value for the test compound using the Cheng-Prusoff equation.

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Abstract

La présente invention concerne une classe de composés aromatiques bicycliques fusionnés 6,6 qui sont des ligands du récepteur CRTH2 (molécule homologue au récepteur chimiotactique exprimé sur les lymphocytes T amplificateurs de type 2) et leur utilisation dans le traitement des maladies qui réagissent à la modulation de l'activité du récepteur CRTH2, notamment les maladies ayant une composante inflammatoire significative. Cette invention porte également sur de nouveaux éléments de cette classe de ligands et sur des compositions pharmaceutiques contenant ces derniers.
PCT/GB2008/003758 2007-11-09 2008-11-07 Composés aromatiques bicycliques fusionnés 6,6 et leur utilisation en thérapie WO2009060209A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011162274A1 (fr) * 2010-06-23 2011-12-29 大正製薬株式会社 Dérivé d'isoquinoléine
EP2457900A1 (fr) 2010-11-25 2012-05-30 Almirall, S.A. Nouveaux dérivés de pyrazole présentant un comportement antagoniste CRTH2
US8575158B2 (en) 2010-07-05 2013-11-05 Actelion Pharmaceuticals Ltd. 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin D2 receptor modulators
US9169270B2 (en) 2012-07-05 2015-10-27 Actelion Pharmaceuticals Ltd. 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin D2 receptor modulators
US9255090B2 (en) 2011-12-21 2016-02-09 Actelion Pharmaceuticals Ltd. Heterocyclyl derivatives and their use as prostaglandin D2 receptor modulators
CN106966970A (zh) * 2013-02-26 2017-07-21 公益财团法人微生物化学研究会 具有抗癌作用及抗幽门螺杆菌活性的化合物及其制造方法、以及其用途
WO2020208138A1 (fr) * 2019-04-10 2020-10-15 Cellestia Biotech Ag Composés pour le traitement du cancer induit par un oncovirus et leurs procédés d'utilisation
US12030855B2 (en) 2018-06-21 2024-07-09 Cellestia Biotech Ag Process for making amino diaryl ethers and amino diaryl ethers hydrochloride salts
JP7624930B2 (ja) 2019-04-10 2025-01-31 セレスティア バイオテック アーゲー Ｎｏｔｃｈシグナル伝達経路の阻害剤及びがんの治療におけるその使用

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WO2007031747A1 (fr) * 2005-09-14 2007-03-22 Argenta Discovery Limited Dérivés de l’imdolizine en tant que ligands du récepteur crth2
WO2007036743A2 (fr) * 2005-09-30 2007-04-05 Argenta Discovery Limited Quinoleines et leur utilisation therapeutique
WO2007125405A2 (fr) * 2006-05-01 2007-11-08 Pfizer Products Inc. Composés hétérocycliques 2-amino-substitués à cycles fusionnés

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GB2253846A (en) * 1991-03-19 1992-09-23 Ici Plc Herbicidal substituted naphthalenes and azanaphthalenes
WO2004007451A1 (fr) * 2002-07-17 2004-01-22 Astrazeneca Ab Derives d'indole-3-soufre
WO2007031747A1 (fr) * 2005-09-14 2007-03-22 Argenta Discovery Limited Dérivés de l’imdolizine en tant que ligands du récepteur crth2
WO2007036743A2 (fr) * 2005-09-30 2007-04-05 Argenta Discovery Limited Quinoleines et leur utilisation therapeutique
WO2007125405A2 (fr) * 2006-05-01 2007-11-08 Pfizer Products Inc. Composés hétérocycliques 2-amino-substitués à cycles fusionnés

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2586772A4 (fr) * 2010-06-23 2013-11-13 Taisho Pharmaceutical Co Ltd Dérivé d'isoquinoléine
WO2011162274A1 (fr) * 2010-06-23 2011-12-29 大正製薬株式会社 Dérivé d'isoquinoléine
EP2586772A1 (fr) * 2010-06-23 2013-05-01 Taisho Pharmaceutical Co., Ltd. Dérivé d'isoquinoléine
CN103119024A (zh) * 2010-06-23 2013-05-22 大正制药株式会社 异喹啉衍生物
US8575158B2 (en) 2010-07-05 2013-11-05 Actelion Pharmaceuticals Ltd. 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin D2 receptor modulators
WO2012069175A1 (fr) 2010-11-25 2012-05-31 Almirall, S.A. Nouveaux dérivés de pyrazole possédant un comportement antagoniste de crth2
EP2457900A1 (fr) 2010-11-25 2012-05-30 Almirall, S.A. Nouveaux dérivés de pyrazole présentant un comportement antagoniste CRTH2
US9255090B2 (en) 2011-12-21 2016-02-09 Actelion Pharmaceuticals Ltd. Heterocyclyl derivatives and their use as prostaglandin D2 receptor modulators
US9169270B2 (en) 2012-07-05 2015-10-27 Actelion Pharmaceuticals Ltd. 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin D2 receptor modulators
CN106966970A (zh) * 2013-02-26 2017-07-21 公益财团法人微生物化学研究会 具有抗癌作用及抗幽门螺杆菌活性的化合物及其制造方法、以及其用途
US10202347B2 (en) 2013-02-26 2019-02-12 Microbial Chemistry Research Foundation Compound, production method therefor, and use of said compound
US12030855B2 (en) 2018-06-21 2024-07-09 Cellestia Biotech Ag Process for making amino diaryl ethers and amino diaryl ethers hydrochloride salts
WO2020208138A1 (fr) * 2019-04-10 2020-10-15 Cellestia Biotech Ag Composés pour le traitement du cancer induit par un oncovirus et leurs procédés d'utilisation
CN114007696A (zh) * 2019-04-10 2022-02-01 塞莱斯蒂亚生物技术股份公司 用于治疗肿瘤病毒诱导的癌症的化合物及其使用方法
JP7624930B2 (ja) 2019-04-10 2025-01-31 セレスティア バイオテック アーゲー Ｎｏｔｃｈシグナル伝達経路の阻害剤及びがんの治療におけるその使用

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