WO2010040992A1 - Composés quinoline - Google Patents

Composés quinoline Download PDF

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WO2010040992A1
WO2010040992A1 PCT/GB2009/002372 GB2009002372W WO2010040992A1 WO 2010040992 A1 WO2010040992 A1 WO 2010040992A1 GB 2009002372 W GB2009002372 W GB 2009002372W WO 2010040992 A1 WO2010040992 A1 WO 2010040992A1
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alkyl
optionally substituted
cycloalkyl
formula
compounds
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PCT/GB2009/002372
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George Hynd
John Gary Montana
Harry Finch
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Argenta Oral Therapeutics Limited
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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
    • C07D215/36—Sulfur atoms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • This invention relates to a class of quinoline compounds which are ligands of the DP receptor and 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 DP and/or 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 Pro ⁇ , 2004, 25, 27-30).
  • Prostaglandin D 2 (PGD 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.
  • mice lacking the DP receptor have been shown to produce lower concentrations of Th2 cytokines and reduced accumulation of eosinophils and lymphocytes in the bronchial alveolar lavage fluid compared to wild-type mice after antigen challenge (Matsuoka et al; Science, 2000, 287, 2013-2017). Furthermore, the DP receptor-deficient mice exhibited much reduced airway sensitivity to acetylcholine after antigen challenge when compared to wild type mice. In addition, the DP receptor antagonist molecule S-5751 (Mitsumori et al; J. Med.
  • Chem., 2003, 46, 2436-2445 has been shown to inhibit both early (as assessed by sneezing, mucosal plasma exudation and nasal blockage) and late (as assessed by eosinophil infiltration) phase nasal responses in a guinea pig asthma model after oral dosing (Arimura et a ⁇ , J. Pharmacol. Exp. Ther., 2001 , 298, 411-419). Furthermore, S-5751 alleviated allergen-induced plasma exudation in the conjunctiva in an allergic conjunctivitis model and antigen- induced eosinophil infiltration into the lung in a guinea pig asthma model.
  • DP receptor gene Genetic variants with impaired expression of the DP receptor gene are linked to reduced asthma risk (Lilly et a ⁇ , Am. J. Respir. Cell MoI. Biol., 2005, 33, 224- 226).
  • 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 a ⁇ , 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 a/; J. Exp.
  • small molecules antagonists of DP and/or CRTH2 receptors may be useful in the treatment and/or prevention of diseases mediate by PGD2; for example, asthma and allergic diseases.
  • a number of DP antagonists have been described.
  • S-5751 described above, and related compounds based around bicycloheptanyl and oxabicycloheptanyl cores have been described as DP receptor antagonists, and, in some cases, as mixed PGD 2 receptor and thromboxane (TXA 2 or TP) receptor antagonists (WO2006/068162; US2004/0162323; WO2002/036583; WO2001/094309; WO2000/053573; WO1999/15502; WO1998/25915; WO1998/25919; WO1997/00853).
  • Other compounds that have been described as DP receptor antagonists include: prostaglandin-like compounds
  • WO2002/094830 WO2002/008186; WO2001/079169
  • phenylacetic acid analogues WO2005/028455; WO2003/078409
  • compounds based around a hydantoin core EP284202.
  • Ramatroban a number of other CRTH2 antagonists have been described. Examples include: indoleacetic acids (WO2007/065684;
  • WO2004/106302 WO2004/078719; WO2004/007451 ; WO2003/101981 ; WO2003/101961 ; WO2003/097598; WO2003/097042; WO2003/066047;
  • EP1413306 phenoxyacetic acids
  • WO2007/062678 WO2007/062773
  • WO2006/125596 WO2006/125593
  • WO2006/056752 WO2005/115382;
  • the quinoline template is a common one in compounds proposed for use as pharmaceuticals.
  • the compounds with which the present invention is concerned have a substitution pattern on the quinoline template which distinguishes them from specific known quinoline-type pharmaceuticals or known generally proposed classes of quinoline-type pharmaceuticals.
  • One aspect of the invention provides quinoline derivatives of formula (I) for medicinal use:
  • R 1 , R 2 , R 3 , R 4 and R 5 independently represent hydrogen, halogen, -S(O) n R 6 , -S(O) 2 NR 7 R 8 , -NR 7 S(O) 2 R 6 -NR 7 R 8 , -NR 7 COR 6 , -CONR 7 R 8 , -COR 6 , -NO 2 , -CN, -OR 7 , C r C 6 alkyl or C 3 -C 7 cycloalkyl, the latter two groups being optionally substituted by one or more fluoro atoms;
  • R 6 is CrC 6 alkyl or C 3 -C 7 cycloalkyl, optionally substituted by one or more fluoro atoms;
  • R 7 and R 8 independently represent hydrogen, C r C 6 alkyl or
  • A is -0-, -S(O) n , -CR 9 R 10 , -NR 11 or -C(O);
  • R 9 and R 10 independently represent a hydrogen, fluoro or C r C 6 alkyl
  • R 11 and R 12 independently represent hydrogen or CrC 6 alkyl
  • W is CrC 6 alkyl optionally substituted by one or more substituents independently selected from fluoro, aryl, heteroaryl or C 3 -C 7 cycloalkyl, the latter group being optionally substituted with one or more fluoro atoms;
  • X is a carboxylic acid group, a tetrazolyl group, or a group of formula -CONHS(O) 2 R 13 or -S(O) 2 NHCOR 13 ;
  • R 13 is aryl, heteroaryl, CrC 6 alkyl or C 3 -C 7 cycloalkyl, the latter two groups being optionally substituted by one or more fluoro atoms; n is O, 1 or 2.
  • Medicinal use of compounds of the invention includes use in therapy.
  • the series of compounds defined by formula (I) above is believed to be novel, except for the specific compounds referred to in Examples 1-10 herein, which are currently commercially available but for which no medicinal use has been proposed.
  • the invention therefore in includes compounds of formula (I) per se, with the exception of those of Examples 1-10 herein.
  • Compounds with which the invention is concerned are DP and/or CRTH2 receptor antagonists.
  • 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 DP and/or CRTH2 receptor activity, and (ii) a method of treatment of conditions responsive to modulation of DP and/or 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 DP and 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, Behcet's Disease,
  • 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, /7-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 tricyclic 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 ⁇ /-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, 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)amino-methane, L-arginine, L-lysine, ⁇ /-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, benzenesunfonic, 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, W ⁇ ley- 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 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.
  • 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-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, 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.
  • Radical A is -O-, -S(O) n -CR 12 R 13 Or -NR 9 wherein R 9 represents hydrogen,
  • Ci-C 6 alkyl such as methyl, ethyl, or n- or /so-propyl, or C 3 -C 7 cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl, and
  • R 12 and R 13 independently represent hydrogen, halogen such as fluoro or chloro,
  • Ci-C 6 alkyl such as methyl or ethyl, or
  • C 3 -C 7 cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl, the latter two C 1 -C 6 alkyl and C 3 -C 7 cycloalky groups being optionally substituted with one or more substituents independently selected from halogen such as fluoro, C 3 -C 7 cycloalkyl such as cyclopropyl,
  • R 9 is as defined and discussed above, and R 10 represents hydrogen, C 1 -C 6 alkyl such as methyl, ethyl, or n- or /so-propyl, or C 3 -C 7 cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; or R 12 and R 13 when attached to the same carbon atom may form a 3-8 membered ring optionally containing one or more atoms selected from O, S, -NR 14 and itself optionally substituted by one or more C 1 -C 3 alkyl or halogen atoms.
  • R 14 may be hydrogen, C 1 -C 6 alkyl such as methyl, C 3 -C 7 cycloalkyl such as cyclopropyl, -SO 2 R 11 or -C(O)C 1 -C 4 alkyl such as methyl-, ethyl- or n- or /so-propyl-carbonyl.
  • R 11 may be C 1 -C 6 alkyl such as methyl or ethyl, or C 3 -C 7 cycloalkyl such as cyclopropyl, and R 11 may be optionally substituted with one or more halogen atoms such as fluorine;
  • rings formed by R 12 and R 13 when attached to the same carbon atom include cyclopropyl, cyclopentyl, cyclohexyl, piperidinyl, and /V-(C 1 -C 6 alkyl) piperidinyl.
  • radical A be -S-.
  • R 12 and R 13 are as defined and discussed in relation to radical A above, and R 15 and R 16 independently represent hydrogen or C 1 -C 6 alkyl such as methyl or ethyl.
  • R 12 , R 13 , R 15 and R 16 are each hydrogen.
  • W is CrC 6 alkyl such as methyl, ethyl, n- or /so-propyl, n-, sec- or tert- butyl, or n-pentyl, optionally substituted by one or more substituents independently selected from halogen such as fluoro or chloro, aryl such as phenyl, heteroaryl such as pyridyl, pyrimidiyl, thienyl, thiazolyl, or imidazolyl, -
  • R 9 , R 10 , and R 11 are as defined and discussed above in connection with radical A, or C 3 -C 7 cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl, the latter group being optionally substituted with one or more halogen atoms; and
  • X is a carboxylic acid group, a tetrazolyl group, or a group of formula -CONHS(O) 2 R 6 or -S(O) 2 NHCOR 6 wherein R 6 is aryl such as phenyl, heteroaryl, such as pyridyl, CrC 6 alkyl such as metyl ethyl, n- or /so-propyl, or ⁇ -sec- or tert- butyl, or C 3 -C 7 cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl, the latter two Ci-C ⁇ alkyl and C 3 -C 7 cycloalkyl groups being optionally substituted by one or more halogen atoms.
  • R 6 is aryl such as phenyl, heteroaryl, such as pyridyl, CrC 6 alkyl such as metyl ethyl, n- or /so-
  • compositions As mentioned above, the compounds with which the invention is concerned are DP and/or CRTH2 receptor antagonists, and are useful in the treatment of diseases which benefit from such modulation. Examples of such diseases are referred to above, and include asthma, rhinitis, allergic airway syndrome and bronchitis. It will be understood that 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.
  • 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; 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 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 (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 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.
  • 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 the invention are accessible by the routes shown in
  • Intermediate compounds of formula (II) may conveniently be prepared by the reaction between an aniline of formula (IV) and a ⁇ -ketoester of formula (V), in which PG represents an appropriate ester function (for example, methyl or ethyl) (Scheme 2).
  • the reaction may be carried out neat or in the presence of a suitable dehydrating agent, such as polyphosphoric acid, p-toluenesulfonic acid or methanesulfonic acid.
  • PG represents an appropriate ester function (for example, methyl or ethyl)
  • Intermediate compounds of formula (Vl) may in turn be prepared from compounds of formula (II) by treatment with Lawesson's reagent [2,4-bis(4- methoxyphenyl)-2,4-dithioxo-1 ,3,2,4-dithiadiphosphetane] (Scheme 4).
  • the reaction is typically carried out at 80 to 12O 0 C, in a suitable solvent, such as benzene or toluene.
  • compounds of the invention of formula (Ib) may be prepared from intermediate compounds of formula (VII) by reaction with a thiol of formula (VIII) in the presence of a suitable base such as potassium carbonate (Scheme 5). It is to be understood that if the reaction is carried out on a protected form of thiol (VIII) an appropriate deprotection step will be required to obtain the desired compound of the invention (Ib).
  • compounds of the invention may be prepared by transformations of other compounds of the invention.
  • compounds of the invention of formula (Id) 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 8).
  • LCMS Mass Spectrometry experiments to determine retention times and associated mass ions 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.
  • Example 1 3-(6-methoxy-2-methyl-3-propylquinolin-4-ylsulfanyl)propionic acid (CAS No. 333424-02-5)
  • the receptor binding assay is performed in a final volume of 200 ⁇ l_ binding buffer (10 mM BES (pH7.4), 1 mM EDTA, 10 mM manganese chloride,
  • the reaction is terminated by rapid filtration through GF/C filters prewetted with brij 35 (1% by volume) using a Packard Cell harvester and the filter washed with 600 ⁇ L/well of wash buffer (10 mM BES pH7.4 and 120 mM NaCI).
  • the residual radioligand bound to the filter is determined using a Topcount liquid scintillation counter (Perkin Elmer).
  • Compound IC 50 value was determined using a 6-point dose response curve in duplicate with a semi-log compound dilution series. IC 50 calculations were performed using Excel and XL fit (Microsoft) and this value is used to determine a K 1 value for the test compound using the Cheng-Prusoff equation.
  • 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 Kj value for the test compound using the Cheng-Prusoff equation.
  • Biological Results are performed 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
  • Example 1 had Kj values of 320 and 390 nM in the DP and CRTH2 binding assays, respectively.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de formule (I) destiné à une utilisation médicinale : R1, R2, R3, R4 et R5 représentant indépendamment un hydrogène, un halogène, -S(O)nR6, -S(O)2NR7R8, -NR7S(O)2R6 -NR7R8, -NR7COR6, -CONR7R8, -COR6, -NO2, -CN, -OR7, un alkyle en C1 à C6 ou un cycloalkyle en C3 à C7, les deux derniers groupes étant éventuellement substitués par un ou plusieurs atomes de fluor ; R6 représentant un alkyle en C1 à C6 ou un cycloalkyle en C3 à C7, éventuellement substitué par un ou plusieurs atomes de fluor ; R7 et R8 représentant indépendamment un hydrogène, un alkyle en C1 à C6 ou un cycloalkyle en C3 à C7, les deux derniers groupes étant éventuellement substitués par un ou plusieurs atomes de fluor ; A représentant -O-, -S(O)n, -CR9R10, -NR11 ou -C(O) ; R9 et R10 représentant indépendamment un hydrogène, un fluoro ou un alkyle en C1 à C6 ; R11 et R12 représentant indépendamment un hydrogène ou un alkyle en C1 à C6 ; B représentant -C(R9R10)C(R9R10)- ou C(R11)=C(R12) ; et lorsque A représente -CR9R10, B peut de plus représenter -OCR9R10, -NR11CR9R10 ou -S(O)nCR9R10 ; W représentant un alkyle en C1 à C6 éventuellement substitué par un ou plusieurs substituants indépendamment choisis parmi un fluoro, un aryle, un hétéroaryle ou un cycloalkyle en C3 à C7, le dernier groupe étant éventuellement substitué par un ou plusieurs atomes de fluor ; et X représentant un groupe acide carboxylique, un groupe tétrazolyle, ou un groupe de formule -CONHS(O)2R13 ou -S(O)2NHCOR13 ; R13 représentant un aryle, un hétéroaryle, un alkyle en C1 à C6 ou un cycloalkyle en C3 à C7, les deux derniers groupes étant éventuellement substitués par un ou plusieurs atomes de fluor ; et n représentant 0, 1 ou 2.
PCT/GB2009/002372 2008-10-07 2009-10-05 Composés quinoline WO2010040992A1 (fr)

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US9199938B2 (en) 2011-11-04 2015-12-01 Hoffmann-La Roche Inc. Aryl-quinoline derivatives
WO2013103317A1 (fr) * 2012-01-05 2013-07-11 Clanotech Ab Composés quinoléine utilisés comme inhibiteurs de l'intégrine alpha5 bêta1 anti-angiogéniques pour traiter une fibrose ou des maladies liées à une fibrose
US9376393B2 (en) 2012-01-05 2016-06-28 Clanotech Ab Quinoline compounds which are anti-angiogenic integrin alpha5 beta1 inhibitors for use in the treatment of fibrosis or fibrosis-related diseases

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