WO2009044134A1 - Indolizine derivatives with crth2 receptor affinity for the treatment of inflammatory diseases - Google Patents

Abstract

Compounds of formula (I) are ligands of the CRTH2 receptor useful in the treatment of, for example, inflammatory respiratory diseases: R1 is fluoro, chloro, CN or CF3; R2 is hydrogen, fluoro or chloro; X is -CH2-, or - S(O)n-; Ar1 is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or heteroaryl rings are optionally substituted with one substituent selected from fluoro, chloro, CN, -O(C1C3alkyl) or C1-C3alkyl, the latter two groups being optionally substituted by one or more fluoro atoms; Y is -CR3R4-, -C(O)-, -O-, -S(O)n- or -NR3-; R3 and R4 independently represent hydrogen or C1C3alkyl; Ar2 is phenyl or 5- or 6- membered heteroaryl, wherein the phenyl or heteroaryl rings are optionally substituted by one or more substituents independently selected from halogen, - CN, -S(O)nR5, -S(O)2NR6R7, -NR6S(O)2R5 -NR6R7, -NR6COR5, -CONR6R7, - COR5, -OR6, C1C6alkyl or C3-C7cycloalkyl, the latter two groups being optionally substituted by one or more fluoro atoms; R5 is C1C6alkyl or C3-C7cycloalkyl, optionally substituted by one or more fluoro atoms; R6 and R7 independently represent hydrogen, C1C6alkyl or C3-C7cycloalkyl, the latter two groups being optionally substituted by one or more fluoro atoms; and n is O, 1 or 2.

Description

INDOLIZINE DERIVATIVES WITH CRTH2 RECEPTOR AFFINITY FOR THE TREATMENT OF INFLAMMATORY DISEASES

This invention relates to a class of indolizine 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.

Background to the invention

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 D₂, etc (Boyce; Allergy Asthma Proc, 2004, 25, 27-30). Prostaglandin D₂ (PGD₂) is the major metabolite produced by the action of cyclooxygenase on arachadonic acid by mast cells in response to allergen challenge (Lewis et al; J. Immunol., 1982, 129, 1627-1631). It has been shown that PGD₂ 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. Head Neck Surg., 1987, 113, 179-183; Lebel et al; J. Allergy CHn. Immunol., 1988, 82, 869-877), bronchial asthma (Murray et al; N. Engl. J. Med., 1986, 315, 800-804; Liu et at, Am. Rev. Respir. Dis., 1990, 142, 126-132; Wenzel et al; J. Allergy Clin. Immunol., 1991 , 87, 540-548), and urticaria (Heavey et al; J. Allergy Clin. Immunol., 1986, 78, 458-461). PGD₂ mediates it effects through two receptors, the PGD₂ (or DP) receptor (Boie et al; J. Biol. Chem., 1995, 270, 18910-18916) and the chemoattractant receptor-homologous molecule expressed on Th2 (or CRTH2) (Nagata et al; J. Immunol., 1999, 162, 1278- 1289; Powell; Prostaglandins Luekot. Essent. Fatty Acids, 2003, 69, 179-185). Therefore, it has been postulated that agents that antagonise the effects of PGD₂ at its receptors may have beneficial effects in number of disease states.

The CRTH2 receptor has been shown to be expressed on cell types associated with allergic inflammation, such as basophils, eosinophils, and Th2-type immune helper cells (Hirai et al; J. Exp. Med., 2001 , 193, 255-261). The CRTH2 receptor has been shown to mediate PGD₂-mediated cell migration in these cell types (Hirai et al; J. Exp. Med., 2001, 193, 255-261), and also to play a major role in neutrophil and eosinophil cell recruitment in a model of contact dermatitis (Takeshita et al; Int. Immunol., 2004, 16, 947-959). Ramatroban {(3R)-3-[(4- fluorophenyl)sulphonylamino]-1 ,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid}, a dual CRTH2 and thromboxane A₂ receptor antagonist, has been shown to attenuate these responses (Sugimoto et at, J. Pharmacol. Exp. Ther., 2003, 305, 347-352; Takeshita et al; op. cit). The potential of PGD₂ both to enhance allergic inflammation and induce an inflammatory response has been demonstrated in mice and rats. Transgenic mice over expressing PGD₂ 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). In addition, exogenously administered CRTH2 agonists enhance the allergic response in sensitised mice (Spik et al; J. Immunol., 2005, 174, 3703-3708). In rats exogenously applied CRTH2 agonists cause a pulmonary eosinophilia but a DP agonist (BW 245C) or a TP agonist (I-BOP) showed no effect (Shirashi et at, J. Pharmacol. Exp Ther., 2005, 312, 954-960). These observations suggest that CRTH2 antagonists may have valuable properties for the treatment of diseases mediated by PGD₂.

In addition to Ramatroban a number of other CRTH2 antagonists have been described. Examples include: indoleacetic acids (WO2007/065684; WO2007/045867; WO2006/034419; W 02005/094816; 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), quinolines (WO2007/036743), tetrahydroquinolines (WO2006/091674; US2005/256158; WO2005/100321 ; WO2005/007094; WO2004/035543; WO2004/032848; EP1435356; EP1413306), phenoxyacetic acids (WO2007/062678; WO2007/062773; WO2006/125596; WO2006/125593; WO2006/056752; WO2005/115382; WO2005/105727; WO2005/018529; WO2004/089885; WO2004/089884) and phenylacetic acids (WO2004/058164). Our copending international applications WO2006/136859, WO2007/031747 and WO2008/113965 are concerned with indolizine acetic acid derivatives having CRTH2 antagonistic activity.

Detailed Description of the Invention

One aspect of the invention provides indolizine derivatives of formula (I):

(D

R¹ is fluoro, chloro, CN or CF₃;

R ₃2 is hydrogen, fluoro or chloro;

X is -CH₂-, or -S(O)_n-;

Ar¹ is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or heteroaryl rings are optionally substituted with one substituent selected from fluoro, chloro, CN,

-O(CrC₃alkyl) or C_rC₃alkyl, the latter two groups being optionally substituted by one or more fluoro atoms;

Y is -CR l3¹Wn4-, -C(O)-, -O-, -S(O)_n- or -NR 3^J- .;

R³ and R⁴ independently represent hydrogen or C_rC₃alkyl;

Ar² is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or heteroaryl rings are optionally substituted by one or more substituents independently selected from halogen, -CN, -S(O)_nR⁵, -S(O)₂NR⁶R⁷, -NR⁶S(O)₂R⁵ -NR⁶R⁷, - NR⁶COR⁵, -CONR⁶R⁷, -COR⁵, -OR⁶, d-C₆alkyl or C₃-C₇cycloalkyl, the latter two groups being optionally substituted by one or more fluoro atoms;

R⁵ is CrC₆alkyl or C₃-C₇cycloalkyl, optionally substituted by one or more fluoro atoms;

R⁶ and R⁷ independently represent hydrogen, CrC₆alkyl or C₃-C₇cycloalkyl, the latter two groups being optionally substituted by one or more fluoro atoms; and

n is 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 PGD₂ receptor or the thromboxane A₂ receptor.

Compounds of formula (I) above may be prepared or recovered in the form of salts, and in some cases as Λ/-oxides, hydrates, and solvates thereof. Any reference herein, including the claims herein, to "compounds of the invention", "compounds with which the invention is concerned" or "compounds of formula (I)" and the like, includes reference to salts, particularly pharmaceutically acceptable salts, Λ/-oxides, hydrates, and solvates of such compounds.

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 polyradiculoneuropathy, multifocal motor neuropathy, plexopathy, multiple sclerosis, encephalomyelitis, panencephalitis, cerebellar degeneration and encephalomyelitis, CNS trauma, migraine, stroke, rheumatoid arthritis, ankylosing spondylitis, Behget's Disease, bursitis, carpal tunnel syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, dermatomyositis, Ehlers-Danlos Syndrome (EDS), fibromyalgia, myofascial pain, osteoarthritis (OA), osteonecrosis, psoriatic arthritis, Reiter's syndrome (reactive arthritis), sarcoidosis, scleroderma, Sjogren's Syndrome, soft tissue disease, Still's Disease, tendinitis, polyarteritis Nodossa, Wegener's Granulomatosis, myositis (polymyositis dermatomyositis), gout, atherosclerosis, lupus erythematosus, systemic lupus erythematosus (SLE), type I diabetes, nephritic syndrome, glomerulonephritis, acute and chronic renal failure, eosinophilia fascitis, hyper IgE syndrome, sepsis, septic shock, ischemic reperfusion injury in the heart, allograft rejection after transplantations, and graft versus host disease.

However, 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 comprising a compound with which the invention is concerned in admixture with a pharmaceutically acceptable carrier or excipient.

Terminology

As used herein, the term "(C_a-Cb)alkyl" wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms. Thus when a is 1 and b is 6, for example, the term includes methyl, ethyl, π-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, f-butyl, n-pentyl and n-hexyl. As used herein the term "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.

As used herein the unqualified term "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.

As used herein the unqualified term "heteroaryl" refers to a mono-, bi- or tricyclic 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.

As used herein the term "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 Λ/-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, Λ/-ethyl piperidine, dibenzylamine and the like. 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. Where a compound contains a quaternary ammonium group acceptable counter-ions may be, for example chlorides, bromides, sulfates, methanesulfonates, benzenesulfonates, toluenesulfonates (tosylates), napadisylates (naphthalene-1 ,5-disulfonates or naphthalene-1- (sulfonic acid)-5-sulfonates), edisylates (ethane-1 ,2-disulfonates or ethane-1- (sulfonic acid)-2-sulfonates), isethionates (2-hydroxyethylsulfonates), phosphates, acetates, citrates, lactates, tartrates, mesylates, maleates, malates, fumarates, succinates, xinafoates, p-acetamidobenzoates and the like; wherein the number of quaternary ammonium species balances the pharmaceutically acceptable salt such that the compound has no net charge.

Salts are discussed in the "Handbook of Pharmaceutical Salts. Properties, selection and use", P. Heinrich Stahl & Camille G. Wermuth, Wiley-VCH, 2002.

The term '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. The term '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.

Use of prodrugs, such as esters, of compounds with which the invention is concerned is also part of the invention. "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). For example an ester prodrug of a compound of formula (I) may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of formula (I) are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. Examples of 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.

Structural aspects of compounds with which the invention is concerned R¹ is fluoro, chloro, CN or CF₃ and R² is hydrogen, fluoro or chloro. In one particular subset of compounds of the invention R² is hydrogen and R¹ is CN, but all combinations of the permitted substituents R¹ and R² are allowed.

X is -CH₂-, or -S(O)_n-. Currently preferred are compounds wherein X is -CH₂ -.

Ar¹ is phenyl or 5- or 6-membered heteroaryl. Examples of such rings include phenyl, pyrrole, imidazole, furan, thiophene, oxazole, thiazole, pyrazole, isoxazole, isothiazole, pyridine, pyridazine, pyrimidine and pyrazine.

Ring Ar¹ may optionally be substituted with one substituent selected from fluoro, chloro, CN, -0(C₁-C_SaIkVl) such as methoxy or Ci-C₃alkyl such as methyl, the latter two groups being optionally substituted by one or more fluoro atoms, as in the case of trifluormethoxy or trifluorom ethyl.

Y is -CR³R⁴-, -C(O)-, -O-, -S(O)_n-, or -NR³-, wherein R³ and R⁴ independently represent hydrogen or d-C₃alkyl such as methyl or ethyl. When Y is O or -NR³-, the nitrogen or oxygen thereof is preferably linked to ring carbon atoms in rings Ar¹ and Ar², to avoid possible instability arising from a nitrogen-nitrogen or nitrogen-oxygen link. Currently preferred are compounds wherein Y is -SO₂-.

Ar² is phenyl or 5 or 6 membered heteroaryl. Examples of such rings include phenyl, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, pyridine, pyridazine, pyrimidine and pyrazine. Ring Ar² may optionally be substituted by one or more substituents independently selected from halogen, -CN, -S(O)_nR⁵, -S(O)₂NR⁶R⁷, -NR⁶S(O)₂R⁵

-NR⁶R⁷,

-NR⁶COR⁵, -CONR⁶R⁷, -COR⁵, -OR⁶, C_rC₆alkyl or C₃-C₇cycloalkyl, wherein R⁵ is Ci-C₆alkyl such as methyl, ethyl or n- or iso-propyl, or C₃-C₇cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl, and R⁶ and R⁷ independently represent hydrogen, CrC₆alkyl such as methyl, ethyl or n- or iso-propyl, or C₃-C₇cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; the latter two groups being optionally substituted by one or more fluoro atoms. When R⁵, R⁶ and R⁷ are C₁- C₆alkyl or Cβ-C_/cycloalkyl, such groups may be substituted by one or more fluoro atoms;

Specific examples of optional substituents in Ar¹ and Ar² include chloro, fluoro, - CN, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, isopropoxy, cyclopropoxy, trifluoromethoxy and methanesulfonyl.

Specific compounds of the invention include those of the Examples herein.

Compositions As mentioned above, 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. Examples of such diseases are referred to above, and include asthma, COPD, 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. 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. The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties. Orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

For topical application to the skin, 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. For delivery by inhalation, 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. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.

Other compounds may be combined with compounds with which the invention is concerned for the prevention and treatment of prostaglandin-mediated diseases. Thus the present invention is also concerned with pharmaceutical compositions for preventing and treating PGD₂-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) β2- 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 astemizole; (7) antitussive agents, such as codeine or dextramorphan; (8) non-selective COX-1 / COX-2 inhibitors, such as ibuprofen or ketoprofen; (9) COX-2 inhibitors, such as celecoxib and rofecoxib; (10) VLA-4 antagonists, such as those described in WO97/03094 and WO97/02289; (11) TACE inhibitors and TNF-α inhibitors, for example anti-TNF monoclonal antibodies, such as Remicade and CDP-870 and TNF receptor immunoglobulin molecules, such as Enbrel; (12) inhibitors of matrix metalloprotease, for example MMP12; (13) human neutrophil elastase inhibitors, such as those described in WO2005/026124, WO2003/053930 and WO06/082412; (14) A2a agonists such as those described in EP1052264 and EP1241176 (15) A2b antagonists such as those described in WO2002/42298; (16) modulators of chemokine receptor function, for example antagonists of CCR3 and CCR8; (17) compounds which modulate the action of other prostanoid receptors, for example a thromboxane A₂ antagonist; and (18) agents that modulate Th2 function, such as PPAR agonists.

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.

Synthesis

There are multiple synthetic strategies for the synthesis of the compounds with which the present invention is concerned, but all rely on known chemistry, known to the synthetic organic chemist. Thus, compounds of the invention can be synthesised according to procedures described in the standard literature and are well-known to the one skilled in the art. Typical literature sources are "Advanced organic chemistry, 4^th Edition (Wiley), J. March, "Comprehensive Organic Transformation/', 2^nd Edition (Wiley), R. C. Larock, "Handbook of Heterocyclic Chemistry", 2^nd Edition (Pergamon), A. R. Katritzky, review articles such as found in "Synthesis", "Ace. Chem. Res.", "Chem. Rev", or primary literature sources identified by standard literature searches online or from secondary sources such as "Chemical Abstracts" or "Beilsteirf. The extensive literature relating to the synthesis of indolizine compounds is especially relevant, of course.

It may be necessary to protect reactive functional groups (for example, hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of formula (I) to avoid their unwanted participation in a reaction leading to the formation of compounds of formula (I). Conventional protecting groups, for example those described by T. W. Greene and P. G. M. Wuts in "Protective groups in organic chemistry" John Wiley and Sons, 1999, may 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 formula (I) wherein X is a -CH₂- group are represented by compounds of formula (Ia) (Scheme 1). Compounds of the invention of formula (Ia) may conveniently be prepared by the reaction between an aldehyde of formula (II) and a compound of formula (III), wherein E represents hydrogen or alkyl group. The reaction is carried out under acidic reductive conditions, for example a mixture of trifluoroacetic acid and triethylsilane. It is to be understood that if the reaction is carried out on a protected form of (III) an appropriate deprotection step will be required to obtain the desired compound of the invention (Ia).

(III) (H) (Ia)

Scheme 1

Compounds of formula (II) are commercially available or can be prepared by known methods. Compounds of formula (III) may be prepared from compounds of formula of (IV) by reaction with a compound of formula (V), in the presence of a suitable catalyst, such as copper bronze or copper powder (Scheme 2). Compounds of formula (V) are commercially available or can be prepared by known methods.

(V) (IV) (III)

Scheme 2

Compounds of formula (IV) may be prepared by the reaction between a compound of formula (Vl) and a suitable alkylating agent of formula (VII), wherein LG represents a suitable leaving group such as chloro, bromo, or methanesulfonyloxy (Scheme 3). Typically, the alkylation reaction is carried out in the presence of a base such as sodium hydrogen carbonate or pyridine in an inert solvent such as acetonitrile. Compounds of formula (Vl) and (VII) are commercially available or can be prepared by known methods.

(VII) (Vl) (IV)

Scheme 3

Compounds of formula (I) wherein X is a -S- group are represented by compounds of formula (Ib) (Scheme 4). Compounds of formula (Ib) may be prepared by the reaction between a compound of formula (III) and a disulfide of formula (VIII) in the presence of sulfuryl chloride.

Scheme 4 Alternatively a thiol of formula (IX) may be used in place of a disulfide of formula (VIII) (Scheme 5). Compounds of formula (VIII) and (IX) are commercially available or can be prepared by known methods.

HS,

-Ar² (IX)

Scheme 5

Compounds of formula (I) wherein X is a -S(O)₂- group are represented by compounds of formula (Ic) (Scheme 6). Compounds of formula (Ic) 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.

(Ib) (Ic)

Scheme 6

Examples

¹H NMR spectra were recorded at ambient temperature using a Varian Unity Inova (400MHz) spectrometer with a triple resonance 5 mm probe spectrometer. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations have been used: br s = broad singlet, s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, m = multiplet.

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 μm 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

Example 1 : [1-(1-benzenesulfonyl-1 H-pyrrol-2-ylmethyl)-7-cyano-2- methylindolizin-3-yl]acetic acid

Preparation 1a: 2-methylisonicotinonitrile

A mixture of 2-chloroisonicotinonitrile (28 g), tetrakis(triphenylphosphine)palladium(0) (5.0 g), trimethylaluminium (2.0 M in hexanes, 110 mL) and 1 ,4-dioxane (400 mL) was heated at reflux for 2 hours. The mixture was cooled to room temperature, diluted with 1.0 M aqueous hydrochloric acid solution and the organic phase extracted with 1.0 M aqueous hydrochloric acid solution. The combined aqueous phases were washed with diethyl ether, basif ied by the addition of concentrated aqueous sodium hydroxide solution and then extracted with diethyl ether. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to afford title compound, 24g.

¹H NMR (CDCI₃): δ 2.65 (s, 3H), 7.35 (m, 1H), 7.40 (br s, 1H), 8.70 (d, J = 5.0 Hz, 1 H).

Preparation 1 b: 2-methylindolizine-7-carbonitrile

A mixture of 2-methylisonicotinonitrile (4.0 g), 1 -bromopropan-2-one (9.3 g), sodium hydrogen carbonate (6.8 g) and acetonitrile (40 mL) was heated at reflux for 14 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate gave title compound as a yellow solid, 1.5 g.

¹H NMR (CDCI₃): δ 2.35 (s, 3H), 6.50 (dd, J = 1.6, 7.2 Hz, 1 H), 6.55 (br s, 1H), 7.25 (br s, 1 H), 7.70 (br s, 1 H), 7.80 (m, 1 H).

Preparation 1c: (7-cyano-2-methylindolizin-3-yl)acetic acid ethyl ester

A solution of ethyl diazoacetate (5.4 mL) in toluene (40 mL) was added portionwise to a mixture of 2-methylindolizine-7-carbonitrile (8.1 g), copper bronze (3.3 g) and toluene (200 mL) at reflux. The resulting mixture was heated at reflux for 2 hours, cooled to room temperature and then filtered. The filtrate was concentrate under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (9:1 to 0:1 by volume) to afford title compound, 5.7 g. ¹H NMR (CDCI₃): δ 1.25 (t, J = 7.1 Hz, 3H), 2.35 (s, 3H), 3.90 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 6.55 (m, 1H), 6.60 (d, J = 1.7 Hz, 1H), 7.70 (br s, 1H), 7.85 (d, J = 7.1 Hz, 1 H).

Preparation 1d: [1-(1 -benzenesulfonyl-1 H-pyrrol-2-ylmethyl)-7-cyano-2- methylindolizin-3-yl]acetic acid ethyl ester

A mixture of (7-cyano-2-methylindolizin-3-yl)acetic acid ethyl ester (0.10 g), 1- benzenesulfonyl-1H-pyrrole-2-carbaldehyde (0.11 g) and dichloromethane (15 ml_) at O⁰C was treated dropwise with triethylsilane (0.31 ml_) followed by trifluoroacetic acid (0.091 mL) and the resulting mixture was stirred at O⁰C for 1 hour and then at room temperature for 5 days. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethylacetate (100:0 to 95:5 by volume) to afford title compound as a yellow solid, 0.11 g.

MS: ESI (+ve) (Method B): 462 (M+H)⁺, Retention time 4.3 min.

Preparation 1 e: [1 -(1 -benzenesulfonyl-1 H-pyrrol-2-ylmethyl)-7-cyano-2- methylindolizin-3-yl]acetic acid

A mixture of [1-(1 -benzenesulfonyl-1 H-pyrrol-2-ylmethyl)-7-cyano-2- methylindolizin-3-yOacetic acid ethyl ester (0.080 g), tetrahydrofuran (4.5 mL) and water (1.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.86 mL) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid solution, extracted with ethyl acetate and the combined extracts dried over magnesium sulfate. The mixture was concentrated under reduced pressure and the residue purified by preparative reverse-phase HPLC using a gradient of acetonitriie in water to afford title compound, 0.009 g. ¹H NMR (CD₃OD): δ 2.04 (s, 3H), 3.83 (s, 2H), 4.15 (s, 2H)₁ 5.75 (dd, J = 1.7, 2.9 Hz, 1 H), 6.22 (t, J = 3.4 Hz, 1 H), 6.43 (dd, J = 1.7, 7.4 Hz, 1 H), 6.92 (s, 1 H), 7.35-7.41 (m, 3H), 7.49-7.54 (m, 3H), 7.85 (d, J = 7.0 Hz, 1 H). MS: ESI (+ve) (Method A): 434 (M+H)⁺, Retention time 11.1 min.

Examaple 2: {7-cyano-2-methyl-1-[1-(4-trifluoromethylbenzenesulfonyl)-1 H- pyrrol-2-ylmethyl]indolizin-3-yl}acetic acid

Preparation 2a: 1 -(4-trif luoromethylbenzenesulfonyl)-1 H-pyrrole-2-carbaldehyde

To a stirred suspension of sodium hydride (60 % in oil, 0.31 g) in N₁N- dimethylformamide (10 ml.) at O⁰C was added 1 H-pyrrole-2-carbaldehyde (0.5 g). The mixture was stirred at O⁰C for 1 hour and then 4- trifluoromethylbenzenesulfonyl chloride (1.6 g) was added and the resulting mixure was stirred at room temperature for 3 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution. The mixture was dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane gave title compound as a yellow oil.

¹H NMR (CDCI₃): δ 6.48 (t, J = 3.4 Hz, 1H), 7.19 (dd, J = 1.7, 3.8 Hz, 1H), 7.71 (m, 1 H), 7.81 (m, 2H), 8.10 (m, 2H), 9.79 (s, 1 H). Preparation 2b: {7-cyano-2-methyl-1 -[1 -(4-trifluoromethylbenzenesulfonyl)-1 H- pyrrol-2-ylmethyl]indolizin-3-yl}acetic acid ethyl ester

The title compound was prepared by the method of Preparation 1d using (7- cyano-2-methylindolizin-3-yl)acetic acid ethyl ester and 1-(4- trifluoromethylbenzenesulfonyl)-1 H-pyrrole-2-carbaldehyde.

MS: ESI (+ve) (Method B): 530 (M+H)⁺, Retention time 4.4 min.

Preparation 2c: {7-cyano-2-methyl-1-[1-(4-trifluoromethylbenzenesulfonyl)-1H- pyrrol-2-ylmethyl]indolizin-3-yl}acetic acid

A mixture of {7-cyano-2-methyl-1-[1-(4-trifluoromethylbenzenesulfonyl)-1H- pyrrol-2-ylmethyl]indolizin-3-yl}acetic acid ethyl ester (0.16 g) and tetrahydrofuran (5.0 ml_) was treated with 1.0 M aqueous lithium hydroxide solution (0.60 ml_) and the resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue acidified by the addition of 1.0 M aqueous hydrochloric acid solution and then extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purifed by column chromatography on silica gel, eluting with a mixture of dichloromethane, ethyl acetate and formic acid to afford title compound as a yellow solid, 0.080 g.

1H NMR (DMSO-d6): δ 1.94 (s, 3H), 3.90 (s, 2H), 4.16 (s, 2H), 5.91 (dd, J = 1.7, 3.1 Hz, 1H), 6.30 (t, J = 3.3 Hz, 1H), 6.47 (dd, J = 1.7, 7.4 Hz, 1H), 7.09 (m, 1H), 7.49 (dd, J = 1.7, 3.3 Hz, 1 H), 7.60 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.91 (dd, J = 0.6, 7.4 Hz, 1 H), 12.60 (br s, 1 H). MS: ESI (+ve) (Method A): 502 (M+H)⁺, Retention time 11.9 min.

Biological Methods

Compounds of the invention were tested using the following biological test methods to determine their ability to displace PGD₂ from the CRTH2 receptor. CRTH2 Radioligand Binding Assay

The receptor binding assay is performed in a final volume of 200 μl_ binding buffer [10 mM BES (pH 7.4), 1 mM EDTA, 10 mM manganese chloride, 0.01 % BSA] and 1 nM [³H]-PGD₂ (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 nonspecific binding is determined using 10 μM of unlabeled PGD₂ (Sigma). Human embryonic kidney (HEK) cell membranes (3.5 μg) expressing the CRTH2 receptor are incubated with 1.5 mg wheatgerm agglutinin SPA beads and 1 nM [³H]-PGD₂ (Amersham Biosciences UK Ltd) and the mixture incubated for 3 hours at room temperature. Bound [³H]-PGD₂ is detected using a Microbeta TRILUX liquid scintillation counter (Perkin Elmer). Compound IC₅₀ value is determined using a 6-point dose response curve in duplicate with a semi-log compound dilution series. IC₅₀ 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

All compounds of the Examples above were tested in the CRTH2 radioligand binding assay described above; the compounds had a Ki value of less than 1 μM in the binding assay. For example, Example 1 had a Ki value of 15 nM.

Claims

Claims:

1. A compound which is an indolizine derivative of formula (I):

wherein

R¹ is fluoro, chloro, CN or CF₃;

R² is hydrogen, fluoro or chloro;

X is -CH₂- or -S(O)_n-;

Ar¹ is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or heteroaryl ring is optionally substituted with one substituent selected from fluoro, chloro, CN,

-O(Ci-C₃alkyl) and Ci-C₃alkyl, the latter two groups being optionally substituted by one or more fluoro atoms;

Y is -CR³R⁴-, -C(O)-, -O-, -S(O)_n- or -NR³-;

R³ and R⁴ independently represent hydrogen or C<i-C₃alkyl;

Ar² is phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or heteroaryl ring is optionally substituted by one or more substituents independently selected from halogen, -CN, -S(O)_nR⁵, -S(O)₂NR⁶R⁷, -NR⁶S(O)₂R⁵ -NR⁶R⁷, -NR⁶COR⁵, -CONR⁶R⁷, -COR⁵, -OR⁶, Ci-C₆alkyl and C₃-C₇cycloalkyl, the latter two groups being optionally substituted by one or more fluoro atoms; R⁵ is CrC₆alkyl or C₃-C₇cycloalkyl, optionally substituted by one or more fluoro atoms;

R⁶ and R⁷ independently represent hydrogen, C_rC₆alkyl or C₃-C₇cycloalkyl, the latter two groups being optionally substituted by one or more fluoro atoms; and

n is 0, 1 or 2.

2. A compound as claimed in claim 1 wherein R² is hydrogen.

3. A compound as claimed in claim 1 or claim 2 wherein R¹ is CN.

4. A compound as claimed in any of the preceding claims wherein X is - CH₂-.

5. A compound as claimed in any of the preceding claims wherein ring Ar¹ is selected from phenyl, pyrrole, imidazole, furan, thiophene, oxazole, thiazole, pyrazole, isoxazole, isothiazole, pyridine, pyridazine, pyrimidine and pyrazine.

6. A compound as claimed in any of the preceding claims wherein X and Y are linked to adjacent ring atoms of ring Ar¹.

7. A compound as claimed in any of the preceding claims wherein Y is - SO₂-.

8. A compound as claimed in any of the preceding claims wherein ring Ar² is selected from phenyl, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, pyridine, pyridazine, pyrimidine and pyrazine.

9. A compound as claimed in any of the preceding claims wherein any optional substituents in Ar¹ and Ar² are selected from chloro, fluoro, -CN, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, isopropoxy, cyclopropoxy, trifluoromethoxy and methanesulfonyl.

10. A compound as claimed in claim 1 having the structure of any of the compounds prepared in the Examples herein.

11. A pharmaceutical composition comprising a compound as claimed in any of the preceding claims and a pharmaceutically acceptable carrier.

12. Use of a compound as claimed in any of claims 1 to 10 for the manufacture of a composition for the treatment of asthma, chronic obstructive pulmonary disease, rhinitis, allergic airway syndrome, or allergic rhinobronchitis.

13. Use of a compound as claimed in any of claims 1 to 10 for the manufacture of a composition for the treatment of psoriasis, atopic and non- atopic dermatitis, Crohn's disease, ulcerative colitis, or irritable bowel disease.

14. A method of treatment of asthma, chronic obstructive pulmonary disease, rhinitis, allergic airway syndrome, or allergic rhinobronchitis, comprising administering to a patient suffering such disease an effective amount of a compound as claimed in any of claims 1 to 10.

15. A method of treatment of psoriasis, atopic and non-atopic dermatitis, Crohn's disease, ulcerative colitis, or irritable bowel disease, comprising administering to a patient suffering such disease an effective amount of a compound as claimed in any of claims 1 to 10.